INFECTIONS OF THE

CENTRAL NERVOUS
SYSTEM
FOURTH EDITION

Editors
W. Michael Scheld, MD Christina M. Marra, MD
Bayer-Gerald L. Mandell Professor of Infectious Professor of Neurology
Diseases Adjunct Professor of Medicine (Infectious Diseases)
Professor, Myles H. Thaler Center for AIDS and University of Washington School of Medicine
Human Retrovirus Research Seattle, Washington
Professor of Medicine
Clinical Professor of Neurosurgery
Director, Pfizer Initiative in
International Health
University of Virginia Health System
Charlottesville, Virginia

Richard J. Whitley, MD
Distinguished University Professor
Loeb Scholar in Pediatrics
Professor of Pediatrics, Microbiology, Medicine,
and Neurosurgery
University of Alabama at Birmingham
Birmingham, Alabama

Scheld_FM.indd i 2/22/14 5:41 AM

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Library of Congress Cataloging-in-Publication Data

Infections of the central nervous system (Scheld)
Infections of the central nervous system / editors, W. Michael Scheld, Richard J. Whitley,
Christina M. Marra. Fourth edition.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4511-7372-7 (hardback : alk. paper)
ISBN-10: 1-4511-7372-5 (hardback : alk. paper)
I. Scheld, W. Michael, editor of compilation. II. Whitley, Richard J., editor of compilation.
III. Marra, Christina M., editor of compilation. IV. Title.
[DNLM: 1. Central Nervous System Infections. WL 301]
RC359.5
616.8dc23
2014004822

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 WITH GRATITUDE TO ALL OF OUR MENTORS
AND
TO OUR TRAINEES WHO UNIFORMLY GAVE MORE
THAN THEY RECEIVED

Scheld_FM.indd iii 2/22/14 5:41 AM

Scheld_FM.indd iv 2/22/14 5:41 AM
 CONTRIBUTORS

Philipp Agyeman, MD Itzhak Brook, MD, MSc

Research Fellow Professor
Neuroinfection Laboratory, Institute for Infectious Diseases Department of Pediatrics
University of Bern Georgetown University School of Medicine
Attending Physician Attending Physician in Infectious Diseases, Pediatrics
Department of Pediatrics Georgetown University Hospital
University of Bern Washington DC, Washington
Inselspital
Bern, Switzerland Mary T. Caserta, MD
Professor
Kelly J. Baldwin, MD Department of Pediatrics
Clerkship Director University of Rochester Medical Center School of Medicine
Department of Neurology and Dentistry
Temple University, School of Medicine Attending Physician
Philadelphia, Pennsylvania Department of Pediatrics
Associate Golisano Childrens Hospital
Department of Neurology Rochester, New York
Geisinger Medical Center
Danville, Pennsylvania Kevin A. Cassady, MD
Associate Professor
Kyra J. Becker, MD Department of Pediatric Infectious Diseases
Professor University of Alabama at Birmingham
Department of Neurology and Neurological Surgery Birmingham, Alabama
University of Washington School of Medicine
Seattle, Washington Matthias Cavassini
Private-Decent and Senior Lecturer
J. David Beckham, MD Chief of Service, Department Chair
Assistant Professor of Medicine and Neurology Service of Infectious Diseases, Department of Medicine
Departments of Medicine (Infectious Diseases) and University Hospital of Lausanne
Neurology Lausanne, Switzerland
University of Colorado School of Medicine
Aurora, Colorado Maxine Caws, PhD, MSc, BSc
Research Lecturer
Jeana L. Benwill, MD Department of Clinical Sciences
Assistant Professor of Medicine Liverpool School of Tropical Medicine
The University of Texas Health Science Center at Tyler Liverpool, United Kingdom
Tyler, Texas Head of TB Research Programme
Oxford University Clinical Research Unit
Sven Bergstrm, PhD Hospital for Tropical Diseases
Professor Ho Chi Minh City, Vietnam
Department of Molecular Biology
Ume University Won K. Chung, MD
Ume, Sweden Post-doctoral Fellow
Department of Internal Medicine, Division of Infectious
Ari Bitnun, MD, MSc, FRCPC Disease
Associate Professor University of Texas Medical Branch
Department of Pediatrics Galveston, Texas
University of Toronto
Staff Physician David J. Coffey, MD
Department of Pediatrics Associate Professor
The Hospital for Sick Children Department of Neurology
Toronto, Ontario, Canada Geisel School of Medicine at Dartmouth
Lebanon, New Hampshire

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 vi Contributors

Jeffrey I. Cohen, MD Carol Glaser, MD

Chief Chief
Laboratory of Infectious Diseases Encephalitis and Special Investigations Section
National Institute of Allergy and Infectious Diseases, Division of Communicable Disease Control
National Institutes of Health California Department of Public Health
Bethesda, Maryland Richmond, California
Associate Clinical Professor
Amanda C. Cohn, MD Department of Pediatrics, Division of Pediatric Infectious
Medical Epidemiologist Diseases
Division of Bacterial Diseases University of California, San Franciso
National Center for Immunizations and Respiratory Diseases, San Francisco, California
Centers for Disease Control and Prevention
Atlanta, Georgia John W. Gnann, Jr., MD
Professor
Moshe Ephros, MD Department of Medicine, Division of Infectious Diseases
Associate Clinical Professor Medical University of South Carolina
Department of Pediatrics Charleston, South Carolina
Faculty of Medicine
Technion-Israel Institute of Technology Denis Grandgirard, PhD
Director Senior Postdoc
Pediatric Infectious Disease Unit Neuroinfection Laboratory
Department of Pediatrics Institute for Infectious Diseases
Carmel Medical Center University of Bern
Haifa, Israel Bern, Switzerland

Jeremy Farrar, FRCP, FRCP(Ed), FMedSci, PhD, OBE Diane E. Griffin, MD, PhD
Director Professor and Alfred and Jill Sommer Chair
Oxford University Clinical Research Unit W. Harry Feinstone Department of Molecular Microbiology
Wellcome Trust Major Overseas Programme and Immunology
Ho Chi Minh City, Vietnam Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland
Kathleen R. Fink, MD
Assistant Professor Paul D. Griffiths, MD, DSc
Department of Radiology Professor of Virology
University of Washington Centre for Virology
Harborview Medical Center University College London Medical School
Seattle, Washington Royal Free London NHS Foundation Trust
London, United Kingdom
Sven Forner, BA
CJD Clinical Research Team John J. Halperin, MD
University of California, San Francisco Professor
UCSF Memory and Aging Center Departments of Neurology and Medicine
San Francisco, California Icahn School of Medicine at Mount Sinai
New York, New York
Michael D. Geschwind, MD, PhD Chair
Associate Professor Department of Neurosciences
Michael J. Homer Chair in Neurology Overlook Medical Center
University of California, San Francisco Summit, New Jersey
UCSF Memory and Aging Center
San Francisco, California Barry J. Hartman, MD
Clinical Professor of Medicine
Michael Giladi, MD, MSc Department of Medicine, Division of Infectious Diseases
Associate Professor of Medicine Weill Cornell Medical Center
Sackler Faculty of Medicine Attending Physician
Tel Aviv University Department of Medicine
The Infectious Disease Unit and the Bernard Pridan New York Presbyterian Hospital
Laboratory for Molecular Biology of Infectious Diseases New York, New York
Tel Aviv Medical Center
Tel Aviv, Israel Rodrigo Hasbun, MD, MPH
Associate Professor
Stefano Giulieri, MD Department of Medicine, Infectious Diseases
Chief Resident University of Texas Health Science Center
Service of Infectious Diseases, Department of Medicine Attending Physician
University Hospital of Lausanne Department of Medicine
Lausanne, Switzerland Memorial Hermann Hospital
Houston, Texas

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 Contributors vii

Dorothee Heemskerk, MSc, MD Matthias Klein, MD

Clinical Research Fellow Attending Physician
Oxford University Clinical Research Unit VN Department of Neurology
University of Oxford University of Munich
Ho Chi Minh City, Vietnam Klinikum Grosshadern
Munich, Germany
David C. Helfgott, MD
Assistant Professor of Medicine Serggio C. Lanata, MD
Internal Medicine Clinical Fellow
Weill Cornell Medical College Department of Neurology
Assistant Attending Physician University of California, San Francisco
Department of Medicine, Division of Infectious Diseases UCSF Memory and Aging Center
New York Presbyterian Hospital San Francisco, California
New York, New York
Stephen L. Leib, MD
Jerzy Hildebrand, MD, PhD Associate Professor
Professor of Neurology Neuroinfection Laboratory, Institute for Infectious Diseases
Department of Medicine University of Bern
Institut Jules Bordet Bern, Switzerland
Universit Libre de Bruxelles Head
Brussels, Belgium Biology Division, Spiez Laboratory
Swiss Federal Office for Civil Protection
Marc Hildebrand, MD, PhD Austrasse
Department of Medicine, Division of Infectious Diseases Spiez, Switzerland
Hpitaux Iris Sud
Brussels, Belgium Matthias Maiwald, MD, PhD
Adjunct Associate Professor
Susan E. Hoover, MD, PhD Department of Microbiology
Associate Professor National University of Singapore
Internal Medicine Consultant in Microbiology
University of South Dakota Sanford School of Medicine Department of Pathology and Laboratory Medicine
Sanford Health KK Womens and Childrens Hospital
Sioux Falls, South Dakota Singapore, Singapore

Jennifer L. Horan, MD, PharmD Carrie P. Marder, MD, PhD

Medical Instructor Acting Instructor
Department of Medicine Department of Radiology
Duke University Medical Center University of Washington
Durham, North Carolina Department of Radiology
University of Washington Medical Center
Alan C. Jackson, MD, FRCPC Seattle, Washington
Professor
Departments of Internal Medicine (Neurology) and Medical James D. Marks, MD, PhD
Microbiology Professor and Vice Chairman
University of Manitoba Department of Anesthesia and Perioperative Care
Head University of California, San Francisco
Section of Neurology, Internal Medicine Chief of Anesthesia
Health Sciences Centre Department of Anesthesia and Perioperative Care
Winnipeg, Canada San Francisco General Hospital
San Francisco, California
David W. Kimberlin, MD
Professor of Pediatrics Christina M. Marra, MD
Department of Pediatrics Professor of Neurology
University of Alabama at Birmingham Adjunct Professor of Medicine (Infectious Diseases)
Birmingham, Alabama University of Washington School of Medicine
Seattle, Washington
Louis V. Kirchhoff, MD, MPH
Professor Matthew McCarthy, MD
Departments of Internal Medicine (Infectious Diseases) and Fellow
Epidemiology Department of Medicine
University of Iowa Health Care Weill Cornell Medical Center
Staff Physician New York, New York
Medical Service
Department of Veterans Affairs Medical Center
Iowa City, Iowa

Deceased

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 viii Contributors

Tony M. McGrath, MD Adjanie Patabendige, PhD

Associate Professor NC3Rs David Sainsbury Fellow
Department of Pediatrics, Division of Child Neurology Department of Clinical Infection, Microbiology and
University of Alabama at Birmingham Immunology
Attending Physician Institute of Infection and Global Health
Division of Child Neurology University of Liverpool
Childrens of Alabama Liverpool, United Kingdom
Birmingham, Alabama
John R. Perfect, MD
Thomas O. McPharlin, RPh Professor
Clinical Associate Professor Department of Medicine
University of Washington School of Pharmacy Duke University Medical Center
Clinical Pharmacist Durham, North Carolina
Department of Neurology and Rehabilitation Medicine
Pharmacy William A. Petri, Jr., MD, PhD
Harborview Medical Center Professor and Chief
Seattle, Washington Division of Infectious Diseases
University of Virginia School of Medicine
Nancy E. Messonnier, MD Charlottesville, Virginia
Medical Epidemiologist
Division of Bacterial Diseases Hans-Walter Pfister, MD
National Center for Immunizations and Respiratory Diseases, Senior Consultant
Centers for Disease Control and Prevention Department of Neurology
Atlanta, Georgia University of Munich
Senior Consultant
Reto Antoine Meuli, MD, PhD Department of Neurology
Full Professor Klinikum Grosshadern
Department of Radiology Munich, Germany
University of Lausanne, Faculty of Biology and Medicine
Chief of Service, Department Chair Douglas G. Postels, MD
Department of Radiology Associate Professor
CHUV, University Hospital of Lausanne Department of Neurology
Lausanne, Switzerland Michigan State University
East Lansing, Michigan
Augusto Miravalle, MD
Assistant Professor of Neurology Didier Raoult, MD, PhD
Director, Neurology Residency Training Program Director
University of Colorado Denver School of Medicine URMITE UMR 7278, Facult de Mdecine
Aurora, Colorado Aix-Marseille Universit
Chief
John F. Modlin, MD Fdration de Microbiologie Clinique
Professor of Pediatrics and Medicine Hpital de la Timone
Department of Pediatrics and Medicine Marseille, France
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire David A. Relman, MD
Deputy Director for Research, Polio Thomas C. and Joan M. Merigan Professor
Global Development Departments of Medicine and Microbiology and Immunology
Bill & Melinda Gates Foundation Stanford University School of Medicine
Seattle, Washington Stanford, California
Chief
Jose G. Montoya, MD, FACP, FIDSA Infectious Diseases Section
Professor Veterans Affairs Palo Alto Health Care System
Department of Medicine Palo Alto, California
Stanford University
Attending Physician Susan Richardson, MD, CM
Department of Medicine Professor
Stanford Hospital and Clinics Department of Laboratory Medicine and Pathobiology
Stanford, California University of Toronto
Head
Shannon Moonah, MD, ScM Department of Paediatric Laboratory Medicine, Division of
Clinical and Research Fellow Microbiology
Division of Infectious Diseases The Hospital for Sick Children
University of Virginia School of Medicine Toronto, Ontario, Canada
Charlottesville, Virginia

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 Contributors ix

Jos R. Romero, MD Khoi Duc Than, MD

Professor Chief Resident
Department of Pediatrics Department of Neurosurgery
University of Arkansas for Medical Sciences University of Michigan
Director Ann Arbor, Michigan
Section of Infectious Diseases
Arkansas Childrens Hospital Allan R. Tunkel, MD, PhD
Little Rock, Arkansas Professor of Medicine
Associate Dean for Medical Education
Karen L. Roos, MD Warren Alpert Medical School of Brown University
John and Nancy Nelson Professor of Neurology Providence, Rhode Island
Professor of Neurological Surgery
Indiana University Health Neuroscience Center Kenneth L. Tyler, MD
Indianapolis, Indiana Reuler-Lewin Family Professor and Chair of Neurology
Professor of Medicine & Microbiology
Jeffrey P. Ross, MD Departments of Neurology, Medicine, and Microbiology
Assistant Clinical Professor University of Colorado Denver School of Medicine
Medicine Chair
University of New Mexico School of Medicine Department of Neurology
Albuquerque, New Mexico University of Colorado Hospital
Aurora, Colorado
Oren Sagher, MD
William F. Chandler Collegiate Professor Diederik van de Beek, MD, PhD
Department of Neurosurgery Professor
University of Michigan Department of Neurology
Neurosurgery Faculty Academic Medical Center
Department of Neurosurgery University of Amsterdam
University of Michigan Health System Amsterdam, The Netherlands
Ann Arbor, Michigan
Arun Venkatesan, MD, PhD
W. Michael Scheld, MD Assistant Professor
Bayer-Gerald L. Mandell Professor of Infectious Diseases Department of Neurology
Professor, Myles H. Thaler Center for AIDS and Human Johns Hopkins University School of Medicine
Retrovirus Research Director
Professor of Medicine Encephalitis Center
Clinical Professor of Neurosurgery Johns Hopkins Hospital
Director, Pfizer Initiative in International Health Baltimore, Maryland
University of Virginia Health System
Charlottesville, Virginia Richard J. Wallace, Jr.
Chairman
Jose A. Serpa, MD, MS Department of Microbiology
Assistant Professor Chief
Department of Medicine Infectious Disease Section
Baylor College of Medicine The University of Texas Health Science Center at Tyler
Attending Physician Tyler, Texas
Medicine
Ben Taub Hospital Thomas J. Walsh, MD, PhD (hon), FCCP, FAAM, FIDSA
Houston, Texas Director
Transplantation-Oncology Infectious Diseases Program
Tom Solomon, MD Chief
Director Infectious Diseases Translational Research Laboratory
Institute of Infection and Global Health Professor of Medicine, Pediatrics, and Microbiology &
University of Liverpool Immunology
Honorary Consultant Neurologist Henry Schueler Foundation Scholar
Department of Neurology Weill Cornell Medical Center and New York Presbyterian
Walton Centre NHS Foundation Trust Hospital
Liverpool, United Kingdom New York, New York

Terrie E. Taylor, DO Anthony C. Wang, MD

University Distinguished Professor Department of Neurosurgery
Osteopathic Medical Specialties University of Michigan
Michigan State University College of Osteopathic Medicine House Officer
East Lansing, Michigan Department of Neurosurgery
Scientific Director University of Michigan Health System
Blantyre Malaria Project Ann Arbor, Michigan
University of Malawi College of Medicine
Blantyre, Malawi

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 x Contributors

David F. Welch, PhD, D(ABMM) Joseph R. Zunt, MD, MPH

Medical Microbiologist Professor
Department of Pathology Departments of Neurology, Global Health, Medicine
Medical City (Infectious Diseases), Epidemiology
Dallas, Texas University of Washington
Attending Neurologist
A. Clinton White, Jr., MD Department of Neurology
Paul R. Stalnaker Distinguished Professor and Director Harborview Medical Center
Infectious Disease Division, Department of Internal Medicine Seattle, Washington
University of Texas Medical Branch
Galveston, Texas John Zurasky, MD
Neurocritical Care Medical Director
Richard J. Whitley, MD Department of Neurology
Distinguished University Professor Chair of Neurology
Loeb Scholar in Pediatrics Providence Health and Services Oregon
Professor of Pediatrics, Microbiology, Medicine, and Portland, Oregon
Neurosurgery
University of Alabama at Birmingham
Birmingham, Alabama

Gary P. Wormser, MD
Professor of Medicine
Departments of Microbiology and Immunology and
Pharmacology
New York Medical College
Chief
Division of Infectious Diseases
Westchester Medical Center
Valhalla, New York

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The first edition of Infections of the Central Nervous System
was published in 1991, a comprehensive treatise addressing
all aspects of central nervous system (CNS) infections for
advanced readers. In its preface, we clearly stated our goal: to
develop the gold standard reference text using the best infor-
mation from the best authors with the best format. Judging
from the reviews that followed publication, and from feed-
back that we received from colleagues, we believe that the first
edition succeeded in meeting our objectives.
The second edition of Infections of the Central Nervous
System was published in 1997 with identical goals and objec-
tives. The same format was followed, but the 37 chapters of
the first edition were expanded to 51 chapters. Reviews and
comments were again positive. The third edition, of 50 chap-
ters, was published in 2004, with a similar positive reception
from readers. A great deal of new information has accumu-
lated in the past decade, and we wanted to further improve
the book in other ways: hence the fourth edition. With this
explosion of new knowledge, the text has changed dramati-
cally, but we have retained the same editorial team. In ad-
dition, we have kept the same basic format: approximately
50 chapters divided into 10 sections.
As for previous editions, the first three chapters of the book
cover the approach to diagnosis of CNS infections, including
detailed discussion of diagnostic tests. The chapters that fol-
low provide an in-depth discussion of individual infectious
agents and the CNS diseases that they produce in humans,
including differential diagnosis, clinical symptoms and find-
ings, abnormalities on laboratory and imaging studies, treat-
ment, and prevention.
Although the number of chapters is approximately the
same as the third edition (51 versus 50), several other changes
are noteworthy. Every chapter has been extensively revised
and updated appropriately, with cited references through
early 2014. Some, reflecting a huge amount of new infor-
mation accumulated in the past decade, have been rewritten
Scheld_FM.indd xi
PREFACE
completely with essentially the same team of authors (e.g.,
Chapter 23 on the Pathogenesis and Pathophysiology of
Bacterial Infections). We have added one new chapter, on
acute encephalitis, by Glaser and Venkatesan. A discussion of
the diagnostic approach to the acute encephalitis syndrome
was lacking in the last edition as well as any mention of some
noninfectious entities (e.g., antiNMDA receptor encephalitis)
literally unknown at the time. Dr. Glaser headed the California
Encephalitis Project for much of the last decade, an effort
which has contributed substantially to our current knowledge
of encephalitis.
As with prior editions, we chose contributors with clinical
experience as well as basic and/or clinical investigative inter-
ests in their topic. Although many of the primary authors of
the chapters of the third edition have been retained, fully 21
of the 51 chapters of this edition employ a new author team
(11 chapters have completely new author teams). In choosing
these new authors, we attempted to maintain the excellence of
the prior editions while emphasizing cutting edge science and
a more international perspective. This is an outstanding group
overall drawn from the disciplines of medicine, pediatrics,
infectious diseases, neurology, neurosurgery, neurointensive
care, neuroradiology, virology, epidemiology, parasitology,
vaccines and prevention, and the basic neurosciences. Tables,
illustrations, and photographs have again been used liberally.
In many chapters, more than 50% of the references have been
published since 2012.
We plan to further develop and refine the book through
future editions. We will continue to provide a comprehensive
readable resource for all physicians who deal with infections
of the CNS. We welcome your comments.
W. Michael Scheld, MD
Richard J. Whitley, MD
Christina M. Marra, MD
xi
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Scheld_FM.indd xii 2/22/14 5:41 AM

We thank everyone who has helped us in the preparation of
this large book. Most importantly, we thank all of the authors
for their outstanding contributions, especially those who have
replaced prior author teams. As editors, we were privileged
to see their work first; as students of CNS infections, we
admire their special insights and expertise. Numerous other
colleagues provided helpful discussion, advice, and criticism.
Scheld_FM.indd xiii
ACKNOWLEDGMENTS
We are particularly grateful to our assistants, Lisa Cook and
Dunia Ritchey. The editorial staff at Lippincott Williams &
WilkinsJulie Goolsby, acquisitions editor, and Kristina
Oberle, development editordeserve our gratitude for ensur-
ing completion of the project. Finally, we thank our families
for their tolerance and support during interminable hours
required to bring this undertaking to closure.
xiii
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Scheld_FM.indd xiv 2/22/14 5:41 AM
 PREFACE TO THE FIRST EDITION
From the brain, and from the brain only, arise our pleasures, joys,
laughter and jests, as well as sorrows, pains, griefs and tears.... It is
the same thing which makes us mad or delirious, inspires us with
dread or fear, whether by night or by day, brings sleeplessness,
inopportune mistakes, aimless anxieties, absent-mindedness, and
acts that are contrary to habit. These things that we suffer all come
from the brain, when it is not healthy, but becomes abnormally
hot, cold, moist or dry.
Hippocrates, The Sacred Disease, Section XVII
Every physician, almost, hath his favourite disease, to which he
ascribes all the victories obtained over human nature. The gout,
the rheumatism, the stone, the gravel, and the consumption have
all their several patrons in the faculty; and none more than the
nervous fever, or the fever on the spirits.
Henry Fielding, Tom Jones, Book II, Chapter 9
I hasten to give you a sketch of the spotted fever in this place. It
made its first appearance about the beginning of January last: but
the instances were few and distant from each other, until last week.
Although it had proved fatal in most instances, seven only had died
belonging to this town, previous to the 25th of February. Since that
time the disorder has come upon us like a flood of mighty waters.
We have buried eight persons within the last eight days. About
twelve or fifteen new cases appeared on Thursday last; many of
them very sudden and violent. This was the most melancholy and
alarming day ever witnessed in this place. Seven or eight physicians
were continually engaged in the neighborhood north of the meet-
ing house, and I believe not one half hour passed in the forenoon
without presenting a new case. Pale fear and extreme anxiety were
visible in every countenance....
Reverend Festus Foster of Petersham, Massachusetts
in a letter to the editor of The Worchester Spy, 6 March 1810
These vignettes concerning central nervous system (CNS)
infections come down to us over a span of 25 centuries.
The Reverend Fosters graphic description of an outbreak of
meningococcemia and meningococcal meningitis in the late
winter of 1810 makes it easy to understand why these infec-
tions engendered fear among physicians and lay persons alike.
Today, even with the comforts of vastly better knowledge and
treatments, CNS infections continue to pose serious problems
in health care. Some CNS infections are common, occurring
either as sporadic cases or in epidemics. For example, major
outbreaks of meningococcal disease have occurred in Africa
and Asia during the past few years. Furthermore, despite
the introduction of new antimicrobial agents and diagnostic
techniques, the mortality associated with some infections of
the central nervous system remains high, particularly in tu-
berculosis, pneumococcal, and gram-negative aerobic bacil-
lary meningitis; rabies; tetanus; cryptococcal meningitis in
patients with acquired immunodeficiency syndrome (AIDS);
and Jakob-Creutzfeldt disease. The morbidity associated
with CNS infections may be even more important than the
death rate, especially in developing countries. Neurologic
Scheld_FM.indd xv
sequelae, elegantly described by Hippocrates above, may de-
prive survivors of hearing, intellect, or function, demeaning
the quality of human life and burdening health resources and
social services.
The distinctive nature and natural history of CNS infections
set them somewhat apart from the mainstream of infectious
diseases. The scope of todays knowledge of these infections
can no longer be presented adequately within the confines of
a subsection in a general textbook. Indeed, the understanding
and management of CNS infections is evolving toward a sub-
specialty in its own right. For these reasons, a new major text
seems justifiedhence this book, devoted to a comprehensive
coverage of human CNS infections.
The work is a comprehensive treatise for the advanced
reader on all aspects of CNS infections. The book occupies a
central niche between large general texts on pediatrics, medi-
cine, neurology, neurosurgery, and infectious diseases on the
one hand, and specialized single-subject treatises on the other.
We have assembled an outstanding group of contributors,
drawn from the ranks of internal medicine, pediatrics, neurol-
ogy, neurosurgery, infectious diseases, epidemiology, virology,
neuroradiology, and the basic neurosciences.
After a brief introduction that emphasizes the syndrome-
oriented clinical approach to the patient with a CNS syndrome
and fever, the book is divided into parts based on microorgan-
isms. The major CNS pathogens (viruses, bacteria, fungi, and
protozoa) receive the most attention, although rarer patho-
gens such as mycoplasmas, slow viruses, and helminths are
also covered in depth. In keeping with our philosophy that
advances in diagnosis, therapy, prognosis, and prevention
require better understanding of the pathogenesis and patho-
physiology of these disorders, an introductory chapter on
these subjects is included in each of the major sections of the
book. Within each section a syndromic approach has been
maintained whenever possible, but in many instances we felt
that specific diseases required separate coveragefor example,
tetanus, neurosyphilis, and Lyme disease. In some sections we
have separated processes that primarily present as meningitis
or meningoencephalitis from those that usually present as
focal CNS lesions. The book concludes with discussions on
two major diagnostic modalities: (i) evaluation of the cere-
brospinal fluid and (ii) neurodiagnostic imaging by computed
tomography and magnetic resonance imaging.
In choosing the contributors, we have sought individuals
with clinical experience as well as with active basic and/or
clinical investigative interests in their topic. We asked them to
take a comprehensive approach, ranging from recent advances
in molecular pathogenesis to the clinical manifestations,
therapy, and prevention of CNS infections. We also estab-
lished certain other ground rules. To gain a measure of unity
among the chapters, each contributor was asked to write
under common subheadings: history of the syndrome, epide-
miology, etiology, pathogenesis and pathology, clinical mani-
festations, approach to diagnosis, therapy, and prevention.
xv
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 xvi Preface to the First Edition
We asked authors to provide an extensive but not exhaus-
tive bibliography, emphasizing classical papers and recent
(19851991) references while limiting each chapter total to
350 citations or fewer. We strongly encouraged the liberal use
of tables, drawings, and photographs. Although a degree of
overlap between chapters is inevitable (and sometimes even
desirable) in a multiauthored volume, we have attempted to
minimize redundancies as much as possible.
From its inception 3 years ago, we intended that this should
be a gold standard reference text. We set out to bring
together the best information from the best authors in the best
Scheld_FM.indd xvi
format. Inevitably, the size and complexity of the field means
that we will fall short in some areas. Recognizing this, we hope
to develop and improve the book through future editions. Our
ambition will remain the same: to present the best available
comprehensive resource and reference text for all who deal
with infections of the central nervous system.
W. Michael Scheld
Richard J. Whitley
David T. Durack
2/22/14 5:41 AM
 CONTENTS

Contributors v
Preface xi
Acknowledgments xiii
Preface to the First Edition xv

PART I APPROACH TO THE PATIENT AND DIAGNOSTIC EVALUATION

Chapter 1 Introduction: Approach to the Patient with

Central Nervous System Infection 1
Christina M. Marra, Richard J. Whitley, and W. Michael Scheld

Chapter 2 Cerebrospinal Fluid in Central Nervous System Infections 4

Rodrigo Hasbun

Chapter 3 Imaging of Intracranial Infections 24

Carrie P. Marder and Kathleen R. Fink

PART II VIRAL INFECTIONS AND RELATED DISORDERS

Chapter 4 Pathogenesis and Pathophysiology of

Viral Infections of the Central Nervous System 49
Kevin A. Cassady and Richard J. Whitley

Chapter 5 Viral Meningitis and Aseptic Meningitis Syndrome 65

Jos R. Romero

Chapter 6 Encephalitis 84
Carol Glaser and Arun Venkatesan

Chapter 7 Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome 112

John F. Modlin and David J. Coffey

Chapter 8 Measles and Rubella 125

Diane E. Griffin

Chapter 9 Herpes Simplex Virus 137

Richard J. Whitley

Chapter 10 Neurologic Manifestations of Varicella and Herpes Zoster 157

John W. Gnann, Jr. and Richard J. Whitley

Chapter 11 Cytomegalovirus 168

Paul D. Griffiths

xvii

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 xviii Contents

Chapter 12 Epstein-Barr Virus 183

Susan E. Hoover, Jeffrey P. Ross, and Jeffrey I. Cohen

Chapter 13 Human Herpesvirus-6 191

Mary T. Caserta

Chapter 14 B Virus 204

Richard J. Whitley

Chapter 15 Arthropod-Borne Viral Encephalitides 210

Tom Solomon, Adjanie Patabendige, and Richard J. Whitley

Chapter 16 Meningitis and Encephalitis Caused by Mumps Virus 239

John W. Gnann, Jr.

Chapter 17 Rabies 251

Alan C. Jackson

Chapter 18 Human Prion Diseases 261

Serggio C. Lanata, Sven Forner, and Michael D. Geschwind

Chapter 19 Human Immunodeficiency Virus 286

Christina M. Marra

Chapter 20 Guillain-Barr Syndrome 299

Tony M. McGrath

Chapter 21 Acute Viral Myelitis 315

J. David Beckham and Kenneth L. Tyler

Chapter 22 Postinfectious Encephalomyelitis 331

Karen L. Roos and Augusto Miravalle

PART III BACTERIAL AND MYCOPLASMAL INFECTIONS

Chapter 23 Pathogenesis and Pathophysiology of Bacterial Infections 341

Philipp Agyeman, Denis Grandgirard, and Stephen L. Leib

Chapter 24 Acute Bacterial Meningitis 365

Karen L. Roos, Allan R. Tunkel, Diederik van de Beek, and W. Michael Scheld

Chapter 25 Mycoplasmal and Ureaplasmal Infections 420

Ari Bitnun and Susan Richardson

Chapter 26 Bartonella Infections, Including Cat-Scratch Disease 434

Michael Giladi, Moshe Ephros, and David F. Welch

Chapter 27 Rickettsioses, Anaplasmoses, and Q Fever 444

Didier Raoult

Chapter 28 Whipples Disease 461

Matthias Maiwald and David A. Relman

Chapter 29 Tuberculous Meningitis 474

Dorothee Heemskerk, Jeremy Farrar, and Maxine Caws

Chapter 30 Infections Due to Nontuberculous Mycobacteria 501

Jeana L. Benwill and Richard J. Wallace, Jr.

Chapter 31 Brain Abscess 522

Matthias Klein, Hans-Walter Pfister, Allan R. Tunkel, and W. Michael Scheld

Chapter 32 Epidural Abscess 550

Hans-Walter Pfister, Matthias Klein, Allan R. Tunkel, and W. Michael Scheld

Scheld_FM.indd xviii 2/22/14 5:41 AM

 Contents xix

Chapter 33 Subdural Empyema and Suppurative Intracranial Phlebitis 566

Barry J. Hartman and David C. Helfgott

Chapter 34 Complications of Infective Endocarditis 579

Stefano Giulieri, Reto Antoine Meuli, and Matthias Cavassini

Chapter 35 Iatrogenic Infections of the Central Nervous System 608

Kelly J. Baldwin and Joseph R. Zunt

PART IV CENTRAL NERVOUS SYSTEM SYNDROMES MEDIATED BY BACTERIAL TOXINS

Chapter 36 Botulism 621

James D. Marks

Chapter 37 Tetanus 634

Itzhak Brook

PART V SPIROCHETAL INFECTIONS

Chapter 38 Neurosyphilis 659

Christina M. Marra

Chapter 39 Neuroborreliosis: Nervous System Involvement with Borrelia Species 674

John J. Halperin, Sven Bergstrm, and Gary P. Wormser

PART VI FUNGAL INFECTIONS

Chapter 40 Fungal Meningitis 687

Jennifer L. Horan and John R. Perfect

Chapter 41 Space-Occupying Fungal Lesions 711

Matthew McCarthy and Thomas J. Walsh

PART VII PROTOZOAL AND HELMINTHIC INFECTIONS

Chapter 42 Cerebral Malaria 729

Douglas G. Postels and Terrie E. Taylor

Chapter 43 Toxoplasma gondii and Toxoplasmosis 745

Jose G. Montoya

Chapter 44 Trypanosomiasis 756

Louis V. Kirchhoff

Chapter 45 Free-Living and Parasitic Amebic Infections 770

Shannon Moonah and William A. Petri, Jr.

Chapter 46 Helminthic Infections 776

Jose A. Serpa, Won K. Chung, and A. Clinton White, Jr.

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 xx Contents

PART VIII CHRONIC MENINGITIS AND MENINGITIS OF NONINFECTIVE OR

UNCERTAIN ETIOLOGY

Chapter 47 Chronic Meningitis Syndrome and Meningitis of 805

Noninfective or Uncertain Etiology
Jerzy Hildebrand and Marc Hildebrand

PART IX NEUROSURGICAL MANAGEMENT

Chapter 48 Surgical Management of Central Nervous System Infections 819

Anthony C. Wang, Khoi Duc Than, and Oren Sagher

Chapter 49 Critical Care of Central Nervous System Infections 849

John Zurasky, Thomas O. McPharlin, and Kyra J. Becker

PART X PREVENTION

Chapter 50 Vaccines for Viral Diseases with Significant

Central Nervous System Manifestations 859
David W. Kimberlin

Chapter 51 Vaccines Against Bacterial Meningitis 876

Amanda C. Cohn and Nancy E. Messonnier

Index 891

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 PART I APPROACH TO THE PATIENT AND
DIAGNOSTIC EVALUATION
CHAPTER 1 INTRODUCTION: APPROACH TO
THE PATIENT WITH CENTRAL NERVOUS SYSTEM
INFECTION
CHRISTINA M. MARRA, RICHARD J. WHITLEY, AND W. MICHAEL SCHELD
Infections of the central nervous system (CNS) are notable
for their diversity. They range from common to rare, acute to
chronic, and benign to fatal. Although some are self-limited
or are easily cured with modern treatment, others are relent-
lessly progressive despite treatment or have no known treat-
ment. For the many CNS infections that are treatable, prompt
diagnosis and aggressive management afford the best chance
of recovery without sequelae.
The clinical hallmarks of CNS infection are fever, head-
ache, and alteration of mental status. Focal neurologic signs
may also be evident. Nonetheless, these four symptoms and
signs are nonspecific and can also be seen in noninfectious
CNS syndromes. To narrow the differential diagnosis, other
characteristics must be evaluated. Among these, risk factors
for CNS infections are particularly helpful. Physical exami-
nation may also yield information that provides clues to the
etiology of a given infection. An approach to the diagnosis of
CNS infections is shown in Figure 1.1.
RISK FACTORS FOR CENTRAL
NERVOUS SYSTEM INFECTIONS
Many infections of the CNS are geographically distributed or
occur seasonally. Therefore, a thorough travel history and con-
sideration of the date of onset of illness can provide clues to the
etiology. For example, Lyme disease is endemic in the northeast-
ern United States but uncommon in the southwestern states.
Similarly, transmission of arborviral encephalitides requires
the presence of an insect vector, and thus these illnesses most
commonly occur in summer and fall. Certain environments
facilitate acquisition and transmission of CNS infections, as ex-
emplified by outbreaks of meningococcal infection in military
recruits and college students. Concomitant illnesses such as
HIV infection or diabetes, alcoholism, receipt of immunosup-
pressant medications, or cancer chemotherapy all predispose to
specific CNS infections. Similarly, receipt of prophylactic thera-
pies protects against individual CNS infections. For example,
primary prophylaxis against Pneumocystis jiroveci pneumonia
with trimethoprim-sulfamethoxazole in HIV-infected individu-
als decreases the risk of CNS toxoplasmosis.
CLUES ON PHYSICAL
EXAMINATION
Physical examination in the setting of suspected CNS infec-
tion has three purposes: (a) to identify contraindications to
lumbar puncture, (b) to identify concomitant sites of infec-
tion or pathology that provide clues to the infectious etiology,
and (c) to define the site of CNS infection. Depressed level
of consciousness, focal neurologic abnormalities, or seizures
may indicate a structural CNS abnormality that poses a risk
Scheld_Ch01.indd 1
of brain or spinal cord herniation after lumbar puncture.
Such findings mandate neuroimaging before lumbar puncture.
Identification of concomitant pneumonia, diarrhea, and skin
or bone lesions may offer clues to the etiology of infection.
Most importantly, findings on neurologic examination allow
for identification of the most likely site or sites of infection
among cerebrospinal fluid (CSF) space, brain, or spinal cord
and allow for a syndrome recognition approach to diagno-
sis, as described below.
Acute Meningitis Syndrome
The dominant features of the acute meningitis syndrome are
acute onset over a few hours to a few days of fever, headache,
photophobia, stiff neck, and altered mental status. The latter
may range from simple irritability to confusion, obtundation,
or coma. Vomiting may occur, especially in young children. In
many cases, there is no warning, but an acute upper respira-
tory tract infection may precede the onset of meningitis by
a few days. The two leading causes of acute meningitis are
bacteria and viruses. The differential diagnosis includes nonin-
fectious conditions, such as systemic lupus erythematosus and
Behet syndrome, or rare chemical meningitis caused by non-
steroidal antiinflammatory drugs.
Subacute or Chronic Meningitis Syndrome
In contrast to acute meningitis, subacute and chronic men-
ingitis syndromes run their course over weeks, months, or
years. Because symptoms and signs may fluctuate, subacute or
chronic meningitides may be confused with the syndrome of
recurrent acute meningitis. Although in subacute and chronic
meningitis the clinical findings of fever, headache, stiff neck,
and altered mental status may resemble those of acute menin-
gitis, the time course is quite different. Onset is usually grad-
ual, often without any evident predisposing condition. Fever,
though often present, tends to be lower and less hectic than in
acute meningitis. The patient with chronic meningitis is likely
to be lethargic and generally debilitated, in addition to having
symptoms referable to the CNS. Focal neurologic findings are
more common than in acute meningitis, although less common
than in the space-occupying syndromes.
The differential diagnosis for subacute and chronic men-
ingitis is extensive. The most likely infectious causes are
tuberculosis; fungal infections including cryptococcosis, coc-
cidioidomycosis, and histoplasmosis; and spirochetal infections
including syphilis and Lyme disease. Important noninfectious
conditions include sarcoidosis, systemic lupus erythematosus,
systemic or primary CNS vasculitides, and neoplastic menin-
gitis. Establishing a specific diagnosis is challenging. Of the
important treatable conditions, cryptococcosis and syphilis
usually can be diagnosed or excluded quickly on the basis of
2/21/14 5:27 PM
 2 Part I: Approach to the Patient and Diagnostic Evaluation

Assess Risks for Infection

Exposures
Travel
Environment (daycare, military)
Season
Concomitant illnesses
CMI dysfunction (HIV, organ transplant)
Neutropenia (cancer chemotherapy)
Diabetes
Alcoholism
Prophylactic agents

Perform Physical Examination

Assess safety of lumbar puncture
Identity concomitant illness or pathology
Pneumonia
Diarrhea
Skin or bone lesions

Define Probable Site of Infection Neuroimaging

CSF
Acute meningitis
Subacute or chronic meningitis
Recurrent meningitis
Brain
Acute encephalitis
Chronic encephalitis
Space-occupying lesions
Toxin-mediated syndromes
Encephalopathy with systemic infections
Postinfectious syndromes
Spinal cord
Acute encephalomyelitis
Chronic encephalomyelitis
Space-occupying lesions
Toxin-mediated syndromes
Postinfectious syndromes

Laboratory Evaluation
Pathogen-specific CSF Evaluation
Pathogen nonspecific

FIGURE 1.1 Approach to the diagnosis of CNS infections. CMI, cell mediated immunity.

Scheld_Ch01.indd 2 2/21/14 5:27 PM

 Chapter 1: Introduction: Approach to the Patient with Central Nervous System Infection
serology or antigen detection. However, tuberculous meningi-
tis is more difficult to diagnose or exclude, and patients with
suspected tuberculous meningitis should be treated empirically
while evaluation continues. The decision whether and when to
obtain a meningeal biopsy is complex and depends on many
factors, including the unfortunate fact that in practice even
this invasive gold standard test often does not yield a defini-
tive diagnosis.
Acute Encephalitis Syndrome
The acute encephalitis syndrome is characterized by inflam-
mation of the cerebral cortex and is most commonly caused
by viruses. It shares many features with the acute meningitis
syndrome. Indeed, the two conditions often coexist as me-
ningoencephalitis. Acute encephalitis may be either diffuse
or focal. Focal encephalitis reflects tropism of some viruses
for specific locations in the CNS, such as temporal lobe infec-
tion by herpes simplex virus type 1 (HSV-1), or the anterior
horn cells in flavivirus infections, such as West Nile. Nonviral
organisms that may produce the acute encephalitis syndrome
include Rickettsia, Mycoplasma, and Bartonella species
that may cause encephalitis as one component of systemic
infection. Diverse conditions, including infective endocardi-
tis, Whipple disease, and recrudescent toxoplasmosis in the
immunocompromised host may cause diffuse or focal acute
encephalitis.
Chronic Encephalitis Syndrome
The chronic encephalitis syndrome shares many features
with the acute encephalitis syndrome. However, the onset is
more gradual and the course is less hectic. The clinical find-
ings may be less dramatic or less severe. The patient with
chronic encephalitis is likely to be generally debilitated rather
than acutely ill. Chronic encephalitis evolves over weeks to
months or years and relapses or recrudescences may occur.
Complications such as pressure sores, contractures, or demen-
tia may ensue in the course of disease.
Space-Occupying Lesion Syndrome
Patients with space-occupying brain lesions have focal neuro-
logic abnormalities referable to the location of the lesion or
lesions. These include cognitive abnormalities, weakness, sen-
sory changes, and visual loss. Clinical manifestations, such as
headache, nausea, or vomiting, often begin intermittently, but
they progress steadily to a crisis at about the time the patient is
admitted to the hospital. This crisis may consist of (a) a focal
or generalized seizure or (b) onset of obtundation progressing
to coma.
When a space-occupying lesion occurs in the extramedul-
lary space in the spinal canal, a distinctive set of manifestations
may develop in a typical sequence: first, localized back pain,
often severe; second, nerve root pain with associated altera-
tion in reflexes and sometimes paresthesias, often described
Scheld_Ch01.indd 3
3
as shooting sensations or electric shocks; third, motor
weakness followed by sensory changes with bowel or bladder
dysfunction; and fourth, paralysis, often accompanied by less-
ening in pain. The rate of progression from one stage to the
next is unpredictable. Because the incidence and severity of
neurologic sequelae depend on the stage of the disease and
the degree of neural damage sustained before intervention,
this syndrome presents an emergency that requires immediate
diagnosis and treatment.
Toxin-Mediated Syndromes
Microbial toxins mediate several distinctive neurologic syn-
dromes. The leading examples are tetanus and botulism.
Toxin-mediated conditions are the least likely to show the
usual manifestations of CNS infection, including fever, head-
ache, disturbance of consciousness, and focal neurologic signs.
For example, botulism is characterized by absence of fever and
normal consciousness in most patients.
Encephalopathy with Systemic Infection
Many systemic infections involve the CNS, for example, rick-
ettsial diseases, infective endocarditis, typhoid fever, malaria,
and Whipple disease. Usually, the systemic manifestations of
the disease dominate the clinical picture, but sometimes the
CNS findings are prominent. In a few cases, CNS symptoms
are the only features. Because this is such a large and varied
group of diseases, the syndromic approach to diagnosis is less
effective. In the setting of an undiagnosed CNS infectious syn-
drome, an important principle is to consider systemic infection
as a possible underlying cause.
Postinfectious Syndromes
Several important CNS syndromes can develop following mi-
crobial infections. The usual sequence begins with a common,
often rather trivial, viral infection that may go unnoticed.
A postinfectious neurologic syndrome develops. Rarely, these
syndromes follow routine vaccinations. Examples include
postinfectious encephalitis, postinfectious encephalomyelitis,
and transverse myelitis. These reactions are presumably medi-
ated by an immunologic response to the etiologic microbe or to
antigens revealed as a result of the initial infection. Although
rare, these syndromes can be severe or fatal.
CONCLUSION
A systematic approach to the patient with a suspected CNS
infection can be undertaken. This includes assessment of risks
and a careful physical examination to assess safety of lumbar
puncture, identify non-CNS sites of infection, and define the
site of CNS infection. A consideration of the different CNS
infection syndromes as outlined above can then be used to
promptly establish a diagnosis and implement therapy.
2/21/14 5:27 PM
 CHAPTER 2 CEREBROSPINAL FLUID IN
CENTRAL NERVOUS SYSTEM INFECTIONS
RODRIGO HASBUN
Infections within the central nervous system (CNS) frequently,
but not always, produce changes in cerebrospinal fluid (CSF).
The changes produced may provide invaluable information
about the nature of the infectious process and, in many cases,
may permit specific identification of the offending organism.
Despite the great diagnostic value of CSF analysis, however,
injudicious attempts to obtain CSF (as in the setting of in-
creased intracranial pressure) can sometimes cause brain her-
niation or death, and casual handling of the CSF obtained may
render the analysis useless.
This chapter is divided into three parts. The first part re-
views the anatomy of the CSF spaces, the physiology of CSF
production and reabsorption, and the effect of infection on
CSF physiology and composition. The second part discusses
methods of CSF analysis in CNS infections, and the third part
summarizes the CSF analysis in specific CNS infections.
ANATOMY AND PHYSIOLOGY
OF THE CEREBROSPINAL FLUID
COMPARTMENTS
The CSF is contained within two connecting compartments, the
cerebral ventricles and the subarachnoid space (1). Infectious
organisms may affect both compartments, and analysis of CSF
from both may reflect changes produced by infectious or para-
infectious processes within meninges, brain, or spinal cord.
The Ventricular System
The cerebral ventricular system represents, in greatly elabo-
rated form, the remnants of the embryologic neural tube. A
single layer of neuroglial-derived cells, the ventricular epen-
dyma, lines the ventricles; a dense network of astrocytic foot
processes backs these. The ventricular system consists of two
lateral ventricles, the third ventricle, and the fourth ventricle
(Fig. 2.1). The lateral ventricles are located within the cere-
brum and consist of frontal, temporal, and occipital horns;
these join at the ventricular trigone within the parietal lobe.
The third ventricle is an elongated, slitlike cavity that lies
within the midbrain and is bounded inferiorly by the hypo-
thalamus. The fourth ventricle overlies the brainstem from the
level of the midpons to the extreme rostral end of the spinal
cord. The roof of the fourth ventricle is the cerebellum poste-
riorly and the superior and inferior medullary veli anteriorly.
The fourth ventricle is roughly diamond shaped and is wid-
est at the lateral recesses, which lie between the superior and
middle cerebral peduncles.
The cerebral ventricles are connected to each other and with
the subarachnoid space through a series of small openings.
Each lateral ventricle drains into the third ventricle through
the foramen of Monro, located in the inferomedial wall of the
frontal horn. The third and fourth ventricles are connected by
the aqueduct of Sylvius, which extends through the midbrain.
Scheld_Ch02.indd 4
The fourth ventricle drains into the subarachnoid space
through three small openings, the foramina of Luschka and the
foramen of Magendie. The foramina of Luschka are located in
the lateral recesses of the fourth ventricle and are absent in up
to 20% of the population. The foramen of Magendie is located
in the midline and, in most persons, represents the major com-
munication between the fourth ventricle and the subarachnoid
space. As is discussed later, these narrow openings are impor-
tant in CNS infections because they represent the sites at which
obstruction of CSF flow may most easily occur.
The Meninges and Subarachnoid Space
The brain and spinal cord are surrounded by three layers of
meninges (2). The outermost layer of the meninges is a tough
fibrous membrane, the dura mater. Within the skull, the dura
forms the inner layer of the cranial periosteum and is tightly
adherent to bone. Below the foramen magnum, the dura and
periosteum diverge and are separated by a fat-filled epidural
space. The middle layer of meninges, the arachnoid, is joined
to the dura by a specialized layer of fibroblasts, the dural bor-
der cell layer. The cells of this inner dural border are devoid of
collagen and have few cellular junctions, providing a cleavage
plane in which infection may develop and rapidly spread. The
arachnoid covers the brain and spinal cord loosely and extends
outward along the course of cranial and spinal nerves.
The third layer of meninges, the pia mater, is continuous
with the surface of the brain and spinal cord. The pia mater
also follows vessels into brain and spinal cord parenchyma
and projects into the ventricles to form the choroid plexuses.
The pia mater and the ventricular ependyma merge at the
foramina of Luschka and Magendie. The CSF is contained
in the subarachnoid space, enclosed between the arachnoid
and the pia. The subarachnoid space surrounds the brain and
extends within the spinal canal to the level of the second sacral
vertebra. Within the skull, the subarachnoid space widens into
cisterns where pia and arachnoid are more widely separated by
irregularities in the contour of the brain. The largest of these,
the cisterna magna, surrounds the brainstem and the cerebel-
lum at the base of the skull and is occasionally used as a source
of CSF for analysis and culture. The subarachnoid space is
crossed by trabecular extensions of the arachnoid itself, by
cranial nerves, by a network of small arteries, the rete mirabile,
and by numerous bridging veins, which connect the meningeal
veins with the deeper intracranial venous system (2).
The subarachnoid space is normally a closed system.
Occasionally, however, congenital or posttraumatic communi-
cations may exist between the subarachnoid space and super-
ficial tissues and may provide a route for single or recurrent
episodes of meningitis. Congenital defects arise from incom-
plete closure of the neural tube. These defects may extend for
variable distances into subcutaneous tissues or to the cutaneous
surface and are most common in the upper cervical regions
and over the sacrum. Their presence may be suggested by a
cutaneous dimple or a patch of hair. Traumatic communications
2/21/14 5:27 PM
 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
into the subarachnoid space are most often associated with
basilar skull fractures. The most common sites of involvement
are (a) the thin layers of bone that separate the cranial cavity
from the paranasal sinuses and (b) the petrous bone, which
separates the auditory canals and mastoid from the cranial
cavity. In rare instances, traumatic defects may occur over the
cranial convexities or along the spinal column.
PHYSIOLOGY OF CEREBROSPINAL
FLUID PRODUCTION AND
REABSORPTION
CSF is produced by the choroid plexuses of the lateral,
third, and fourth ventricles and, to a lesser extent, by extra-
choroidal sites (1,3). In adults, the choroid plexus produces
approximately 500 mL of CSF per day, with 150 mL present
in the ventricular system at any time. The choroid plexuses are
specialized projections of vessels and pia mater into the ven-
tricular cavities. Each choroid plexus branches into frondlike
villi, each of which contains a capillary surrounded by loose
connective tissue and a layer of specialized ependymal cells
termed choroid epithelium. Choroidal epithelial cells, in con-
trast to ependymal cells elsewhere in the ventricular system,
are columnar in shape and are covered on their ventricular
surfaces by a brush border of microvilli. The villous structure
of the choroid plexus and the presence of microvilli greatly
increase the surface area available for secretion of CSF (1).
Scheld_Ch02.indd 5
5
FIGURE 2.1 The cerebral ventricles. Inset:
Shown are the structure of the fourth ventricle
and the locations of the foramina of Luschka
and Magendie. (From Greenlee JE. Anatomical
considerations in central nervous system infec-
tions. In: Mandell GL, Bennett JE, Dolin R, eds.
Principles and Practice of Infectious Diseases.
4th ed. New York: Churchill Livingstone; 1994:
821831, with permission.)
Formation of CSF involves both filtration and active
transport (1,3). Filtration of CSF varies inversely with
serum osmolality. In experimental animals, and possibly in
humans, CSF production changes 7% for each 1% change in
serum osmolality (4). Active secretion of CSF involves Na,
K-adenosine triphosphatase (ATPase)mediated transport of
sodium across choroidal epithelium into the ventricular lumen,
with water, chloride, and bicarbonate ions following through
facilitated transport. In experimental animals, the carbonic
anhydrase inhibitor acetazolamide reduces CSF secretion by
approximately 50%, whereas furosemide and ethacrynic acid
reduce CSF production by 25% to 35% (5). Simultaneous use
of both agents reduces CSF formation by 75%.
Reabsorption of CSF occurs through arachnoid villi. Most
of these are located along the superior sagittal sinus. Smaller
numbers of arachnoid villi are found along other intracranial
venous sinuses and around spinal nerve roots (1). During
health, the arachnoid villi along the superior sagittal sinus
provide the major site of CSF uptake. The arachnoid villi
along other sinuses and surrounding spinal nerve roots may
provide alternative sites of CSF absorption following superior
sagittal sinus thrombosis.
Each arachnoid villus represents an extension of the arach-
noid membrane through the dura mater into the lumen of the
venous sinus and functions as a one-way valve, permitting
unidirectional flow from CSF into blood. Early work by
Welch (6) demonstrated that the arachnoid villi have a critical
in vitro opening pressure of 2 to 5 cm H2O; this study also
demonstrated that particles up to the size of erythrocytes
2/21/14 5:27 PM
 6 Part I: Approach to the Patient and Diagnostic Evaluation
FIGURE 2.2 Uptake of CSF by an arachnoid villus. (From Fishman
RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed.
Philadelphia: WB Saunders; 1992, with permission.)
readily pass from CSF into blood, whereas particles larger
than 7.5 m are excluded. Although these early data suggested
that the arachnoid villi might provide a direct communication
between CSF and blood, studies using electron microscopy
have demonstrated that arachnoid villi and venous sinuses
are separated by a layer of endothelial cells connected by
tight junctions, and that movement of CSF and particulate
matter across the arachnoid villi occurs by transport within
giant vesicles (7,8) (Fig. 2.2). These giant vesicles, although
they provide efficient transfer of CSF into blood under normal
circumstances, can become obstructed by bacteria and inflam-
matory cells during meningitis or by red blood cells (RBCs)
during subarachnoid hemorrhage (9,10).
BRAIN AND CEREBROSPINAL
FLUID BARRIER SYSTEMS
The brain and CSF are contained within a series of barrier sys-
tems (1). These prevent entry of fluids, electrolytes, and other
substances from blood into CSF or brain by simple diffusion
and isolate the CNS from systemic immune responses. The
bloodbrain barrier (BBB) is formed by tight junctions between
endothelial cells of CNS capillaries and is further reinforced
by a surrounding layer of astrocytes, whose processes termi-
nate in overlapping fashion on the capillary walls. In contrast,
the bloodCSF barrier is formed by the endothelial cells of the
choroid plexus and the tight junctions that link them. The cells
of the pia mater, like those of choroid plexus and arachnoid
capillaries, are separated by gap junctions; entry of substances
from CSF into brain is modulated by a basement membrane
subjacent to the pia and by a continuous layer of astrocytes
beneath the basement membrane, forming a CSFbrain barrier.
The barrier systems that surround spinal cord and brain
exclude from the CNS most of the immunologic mechanisms
Scheld_Ch02.indd 6
that provide host defense elsewhere in the body. Normally,
T cells and B cells are present in very small numbers in CSF
and only rarely in brain; immunoglobulins and complement
are largely excluded from both CSF and brain; and opsonic
activity of CSF, even in the presence of meningitis, is far less
than that of serum (1114). Therefore, both the brain and the
CSF are poorly equipped to deal with infectious agents.
The barrier systems that isolate CSF, brain, and spinal
cord from blood are not static systems but, instead, are highly
dynamic in their ability to interact with and transport a
wide variety of substances (15). In addition, it is increasingly
recognized that the endothelial cells and astrocytes of the BBB
and the bloodCSF barrier are important sources of cytokines
(including tumor necrosis factor [TNF] and interleukins), and
that astrocytes, in addition to their abilities to regulate solute
entry into brain, have the ability to act as antigen-presenting
cells (16). The release of cytokines by endothelial cells and
astrocytes in response to bacterial endotoxins and other bacte-
rial products is fundamental in the production of inflammation
and injury during CNS infections and provides an extremely
important area for early therapy (9,1719).
MAINTENANCE OF
CEREBROSPINAL FLUID
HOMEOSTASIS
The BBB and the bloodCSF barrier maintain the cellular and
chemical elements of the CSF within narrow ranges (1,3,20).
Lipid-soluble substances within blood readily diffuse across
choroidal epithelium or vascular endothelium into CSF or brain
(3). Passage of fluid and ionically polar substances, however,
requires mechanisms for transport and facilitated diffusion.
Sodium enters CSF both by Na, K-ATPasemediated trans-
port during secretion of CSF and by passive diffusion (20).
Potassium is secreted into CSF by active transport mechanisms
and is actively removed from CSF into brain by transport
mechanisms that are believed to be located in astrocyte foot
processes. Movement of calcium, magnesium, and phospho-
rus into CSF and brain also occurs predominantly by active
transport, and the concentrations of these substances are rela-
tively independent of their concentrations in serum. Chloride
and bicarbonate, like potassium, are actively secreted into and
actively removed from CSF. Glucose, amino acids, amines,
and thyroid hormone enter the brain by carrier-mediated
transport mechanisms (1,15). Insulin and transferrin require
receptor-mediated transport (15). Although lipids complexed
to proteins were once thought to be excluded from the CNS,
it is now known that complexed lipids undergo dissociation
from their carrier proteins at the bloodbrain interface and
may enter the CNS without significant exodus of protein from
brain capillaries (15).
Chloride represents the major anion in CSF. Normal CSF
chloride concentration is 15 to 20 mEq/L higher than that in
serum. Early workers observed that CSF chloride concentrations
were lowered in tuberculous meningitis; for many years, levels
of CSF chloride were used to diagnose and follow the course
of this infection (1). It is now recognized, however, that the
lowered CSF chloride concentration observed in tuberculous
meningitis is nothing more than a reflection of lowered serum
chloride values and has no diagnostic or prognostic value.
The acidbase balance of the CSF, like its electrolyte con-
centration, tends to remain fairly constant despite fluctuations
in systemic acidbase balance. In CSF, as opposed to plasma,
however, movement of CO2 occurs readily by diffusion, whereas
movement of bicarbonate occurs more slowly by carrier-
mediated transport. The discrepancy in the rate of movement
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 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
of these two substances may produce delayed (and, at times,
paradoxical) responses in CSF pH as compared to systemic pH
during rapid changes in bicarbonate concentration (1). The CSF
acidbase balance is also maintained by the choroid plexuses,
which possess transport mechanisms capable of removing weak
organic acidsincluding antibiotics such as the penicillins,
cephalosporins, and aminoglycosidesfrom CSF (21,22).
Choroid plexus transport of antibiotics and other weak organic
acids can be blocked by probenecid.
ALTERATIONS OF
CEREBROSPINAL FLUID
DYNAMICS AND PRESSURE IN
CENTRAL NERVOUS SYSTEM
INFECTIONS: HYDROCEPHALUS,
INTRACRANIAL HYPERTENSION,
AND BRAIN HERNIATION
Acute or chronic CNS infections may produce profound alter-
ations in intracranial pressure (ICP) by obstructing CSF flow
or reabsorption, by behaving as space-occupying lesions, or by
producing hemorrhage or cerebral edema. These pathologic
consequences of infection, acting individually or together, may
cause brain herniation and death.
Alteration of Cerebrospinal Fluid Circulation
in Central Nervous System Infections
Impairment of normal CSF circulation may result in ventricu-
lar enlargement and hydrocephalus. Interruption of CSF reab-
sorption produces communicating hydrocephalus with normal
circulation of CSF through the ventricular system and into the
subarachnoid space. Communicating hydrocephalus is a com-
mon complication of bacterial meningitis and, in most cases,
results from obstruction of the arachnoid villi by bacteria and
white blood cells (WBCs) (9). Communicating hydrocephalus
may also result from functional occlusion of arachnoid villi
during severe meningitis or by RBCs in the course of subarach-
noid hemorrhage during bland or septic subarachnoid hemor-
rhage (10). Thrombosis of the superior sagittal sinus may also
block CSF reabsorption and thereby produce communicating
hydrocephalus. Occlusion of a large portion of the superior
sagittal sinus usually produces catastrophic, often hemor-
rhagic, cerebral infarction. Involvement of the anterior third
of the sinus, however, may be clinically silent except for the
development of hydrocephalus.
Obstructive hydrocephalus results from interruption of CSF
flow within the ventricular system or at its point of exit into
the subarachnoid space (2). This may be the consequence of
infection of the ventricular ependyma or basilar meninges or
may result from extrinsic compression of the ventricular sys-
tem by infection within brain parenchyma. Lesions producing
obstructive hydrocephalus most commonly involve the ventric-
ular system at its narrowest points: the foramina of Luschka and
Magendie, the fourth ventricle, the aqueduct of Sylvius, and the
foramina of Monro. Obstruction of the foramina of Luschka
and Magendie is characteristic of exudative basilar menin-
gitides such as those caused by Mycobacterium tuberculosis,
Coccidioides immitis, and Cryptococcus neoformans but may
also be seen in bacterial meningitis. Hydrocephalus as a result
of obliteration of the fourth ventricle is almost always extrinsic
and is the result of ventricular compression by large cerebel-
lar mass lesions such as cerebellar abscess or hemorrhage.
Scheld_Ch02.indd 7
7
Occlusion of the aqueduct of Sylvius by granulomatous epen-
dymitis may occur as a complication of tuberculosis, fungal
infections, or sarcoidosis. Mumps virus, which replicates in ven-
tricular ependymal cells, has been shown to produce congenital
aqueductal stenosis in experimental animals (23). Rare cases of
hydrocephalus have also been reported following mumps and
with Toscana meningoencephalitis in humans (24,25). Extrinsic
compression of the aqueduct of Sylvius may be produced by
abscesses or other localized infections within the pons or mid-
brain. Involvement of the foramen of Monro is almost always
unilateral and is the consequence of severe brain shifts caused
by abscess, focal encephalitis, or hemorrhage. Hydrocephalus
caused by the occlusion of one foramen of Monro is particularly
dangerous because the CSF trapped within the involved lateral
ventricle acts as a unilateral space-occupying lesion, greatly in-
creasing the risk of transtentorial brain herniation.
Computerized tomography (CT) and magnetic resonance
imaging (MRI) are invaluable in demonstrating the presence of
hydrocephalus and in determining its cause. Ventricular dilation
is common in the elderly and is characterized by symmetric ven-
tricular dilation accompanied by evidence of cerebral cortical
atrophy. In contrast, hydrocephalus is defined as a frontal horn
ratio (Evans index) of 0.3 or greater in the absence of cerebral
atrophy (26). Hydrocephalus that occurs from impaired CSF
circulation is accompanied by loss of cortical markings visible
on CT or MRI as the brain is forced outward against the skull
and by periventricular areas of increased lucency, represent-
ing transependymal leakage of CSF. Communicating hydro-
cephalus and hydrocephalus from obstruction of the foramina
of Luschka and Magendie are characterized by symmetric
enlargement of all four ventricles. Hydrocephalus from occlu-
sion of the fourth ventricle or aqueduct of Sylvius results in
loss of that structure on CT or MRI, with dilation of the third
and lateral ventricles. Hydrocephalus following compression
of the foramen of Monro is almost invariably associated with
an identifiable space-occupying lesion and a prominent midline
shift. Thrombosis of the superior sagittal sinus may be difficult
to detect as a cause of communicating hydrocephalus and can
be missed with the use of routine CT scanning. MRI and CT
venogram are more sensitive and are used to diagnose superior
sagittal sinus (SSS) thrombosis (27).
Intracranial Hypertension and
Brain Herniation
The normal mechanisms of CSF secretion and drainage main-
tain CSF pressure at a level less than 150 mm of CSF in most
patients. Infection, however, greatly alters these homeostatic
mechanisms; moreover, death during the acute stages of intra-
cranial CNS infections often results from extreme elevation in
ICP followed by brain herniation and respiratory arrest.
For a period of time, the intracranial contents are able to
compensate in response to space-occupying lesions before a rise
in ICP occurs. This compensatory ability is termed compliance
(dV/dP) and represents the ratio of changes in volume (dV) to
changes in pressure (dP). Compliance in response to space-
occupying intracranial lesions consists of several factors.
These include increased rate of reabsorption of CSF (this may
be prevented in meningitis by obstruction of the arachnoid
villi by cells and exudate); displacement of CSF; reduction
in the total volume of intracranial blood, predominantly by
compression of veins and venous sinuses; and plasticity of the
brain itself. Compliance is extremely limited when infection is
accompanied by a rapid increase in ICP, such as during acute
bacterial meningitis or subdural empyema. In contrast, the
ability of CNS compliance to compensate for increased ICP
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 8 Part I: Approach to the Patient and Diagnostic Evaluation
may be extensive where space-occupying lesions develop over
time (28). Once compliance is exceeded, however, the increase
in pressure in chronic lesions may occur rapidly.
The elevation in CSF pressure seen in infections and other
pathologic conditions is not constant but fluctuates consider-
ably. This fluctuation is usually not observed during the brief
period of measurement provided by LP but becomes an impor-
tant parameter to observe during monitoring of ICP. Minor
variation in pressure occurs during Cheyne-Stokes respiration
and during variations in blood pressure produced by Hering-
Breuer reflexes, the inflation and deflation reflexes that help
regulate the rhythmic ventilation of the lungs. More major
variations in ICP occur during plateau waves. These are
abrupt elevations in ICP (usually lasting 5 to 20 minutes) in
which ICP may reach 600 to 1,300 mm of CSF (50 to 100
mm Hg) (29,30). Plateau waves are believed to represent a
consequence of disturbed cerebrovascular autoregulation be-
cause of either abnormal sympathetic tone or cyclic changes
in perfusion in which mild hypotension is followed by cerebral
vasodilation and increased cerebral blood flow (30). Although
plateau waves may be without any detectable clinical effect,
they may also be associated with signs of brainstem compres-
sion and impending herniation.
Increased pressure that exceeds intracranial compliance
causes downward and backward shifting of the cerebrum
and brainstem (31). Minimal degrees of shift are well toler-
ated, but a more extensive shift may cause herniation of the
cingulate gyrus beneath the falx cerebri, herniation of the
uncus of the temporal lobe over the tentorium cerebelli, and
ultimately, herniation of the lower brainstem and cerebellar
tonsils into the foramen magnum. Herniation of the cingu-
late gyrus is usually asymptomatic. Uncal herniation, however,
initially produces compression of the third cranial nerve as it
passes beneath the tentorium; it subsequently causes compres-
sion of the midbrain, with resultant coma. The aqueduct of
Sylvius is often occluded during uncal herniation, and the re-
sultant hydrocephalus increases the mass effect already pres-
ent. Herniation of the cerebellar tonsils through the foramen
magnum, with compression of medullary respiratory centers
and respiratory arrest, is often the terminal event in CNS in-
fections. Occasionally, space-occupying lesions within the cer-
ebellum cause upward herniation of posterior fossa contents
through the tentorial notch (32). Extreme elevation of CSF
pressure may elevate ICP above systemic arterial perfusion
pressure, producing global cerebral and brainstem infarction.
Elevation in CSF pressure, as monitored by ICP monitor-
ing devices, may provide an indication of prognosis in bacterial
meningitis and possibly in other CNS infections. Rebaud et al.
(33) found that CSF pressures were significantly higher and
cerebral perfusion pressure were significantly lower (mean sys-
temic arterial pressure minus ICP) in patients who died due to
meningitis or encephalitis than in those who survived. Goitein
and Tamir (34) found that all pediatric patients with meningitis
or encephalitis who had a cerebral perfusion pressure more than
30 mm Hg survived, whereas those with lower pressures died.
CEREBROSPINAL FLUID ANALYSIS
IN CENTRAL NERVOUS SYSTEM
INFECTIONS
Indications for Lumbar Puncture
LP is essential in the diagnosis of bacterial, viral, or fungal
meningitis and may provide valuable information in encepha-
litis. LP is also used to diagnose subarachnoid hemorrhage in
Scheld_Ch02.indd 8
patients with a negative head CT scan. The procedure is of
little specific diagnostic value in the diagnosis of brain abscess
or parameningeal infections. Lumbar punctures (LPs) should
not be done in patients with impending herniation or with
intracranial mass lesions with severe mass effect. Furthermore,
inappropriate LP can cause patient death or serious neurologic
injury, and the procedure should never be initiated without
consideration of its potential danger to the patient.
Clinicians have relied on the meningeal signs (nuchal rigid-
ity, Kernig sign, Brudzinski sign) for over 100 years to evaluate
patients with suspected meningitis to help them decide who
should undergo a LP. A prospective study of 297 adults with
suspected meningitis documented a very low sensitivity of the
Kernig sign (sensitivity, 5%), Brudzinski sign (sensitivity, 5%),
and nuchal rigidity (sensitivity, 30%) (35). The absence of the
meningeal signs should not defer the performance of the LP.
The decision to perform a LP on those suspected of having
meningitis is largely based on a combination of clinical signs
and symptoms at presentations. The classic triad of fever, stiff
neck, and altered mental status was present in only 44% of
patients in a prospective study involving 696 patients with
confirmed bacterial meningitis (36). However, at least two
of the four symptoms of headache, fever, neck stiffness, and
altered mental status were found in 95% of patients.
Major Complications of Lumbar Puncture
Role of Head Computerized Tomography Scan Before
Lumbar Puncture and Risk of Brain Herniation
It has become a routine practice to obtain a CT scan of the
head prior to performing a LP in patients with suspected
meningitis. This is done to rule out the possibility of an
intracranial mass, hydrocephalus, edema, or any other signs of
increased ICP that could theoretically place the patient at risk
for cerebral herniation after CSF removal during the LP (37).
Herniation of the brain as the consequence of severe cerebral
edema or acute hydrocephalus can sometimes occur in acute
bacterial meningitis and other CNS infections. Clinically, this
is manifested by altered state of consciousness, abnormalities
in pupil reflexes, and decerebrate or decorticate posturing. The
incidence of herniation after LP even in patients with papill-
edema is approximately 1% (37).
In order to clarify the role of a screening CT scan, a pro-
spective study involving 301 adults with suspected meningitis
was done (38). Baseline characteristics that were associated
with an abnormal finding on head CT were age 60 years and
older, immunocompromised host (i.e., HIV/AIDS, immuno-
suppressive therapy, or transplantation), a history of CNS
disease, a history of seizure within 1 week before presenta-
tion, and any abnormality on neurologic examination. These
factors have now been included in the Infectious Diseases
Society of America guidelines to decide who should undergo
CT prior to the LP (39). The decision to obtain a brain CT
scan before LP should not result in delay in instituting anti-
biotic therapy because delay can increase mortality (40). It
should be also noted that herniation can occur in patients
with bacterial meningitis who have a normal brain CT scan.
The most reliable clinical signs of impending herniation
include deteriorating level of consciousness, brainstem signs,
and a very recent seizure (41).
Spinal Hematoma with Cord Compression
Case reports of LP in patients with severe disorders of blood
coagulation, thrombocytopenia, or in patients anticoagulated
with heparin or Coumadin have described complications
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 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
with either continued bleeding at the site of puncture or with
epidural or subdural hematomas that may compress the cauda
equina, thereby producing permanent neurologic injury (42).
These complications appear to be rare. In a study of 5,223 LPs
performed, no complications were seen in 941 children with
leukemia who had severe thrombocytopenia (platelet count
50) (43).
Introduction of Infection into the Subarachnoid Space
Inadvertent LP through an area of infection overlying the spi-
nal canal may result in seeding of the subarachnoid space and
meningitis. This is a particular risk in spinal epidural abscess
or subdural empyema but may occasionally occur in the set-
ting of superficial or deep paraspinal infections. The problem
can be avoided by entering the subarachnoid space at a level
well removed from the site of presumed infection. Thus, in
patients with known or suspected focal lumbar infection, spi-
nal fluid should be obtained under fluoroscopic guidance by
high cervical (C2) or cisternal puncture, whereas the lumbar
route should be used in patients with suspected cervical or
upper thoracic infections. Introduction of infection into the
subarachnoid space during LP in uninfected individuals has
been reported in 1 out of 50,000 LPs (44). The most com-
monly implicated organism is Streptococcus salivarius, and
this could be potentially prevented by using a mask during the
procedure (45).
PostLumbar Puncture Headache
The most frequent complication of LP is the postLP head-
ache, which can occur in 10% to 60% of patients, more com-
monly in young women with a lower body mass index (BMI)
and in pregnancy (46). The diagnosis is a clinical one, and it is
usually defined as a bilateral headache that worsens while sit-
ting up and improves lying down, develops within 7 days after
a LP, and disappears within 14 days (Fig. 2.3). It is thought
that the headache is caused by a CSF leak that decreases ICP.
This causes headache either by gravitational traction on sensi-
tive meningeal vascular coverings as a result of CSF volume
depletion or by activation of adenosine receptors as a result of
FIGURE 2.3 Gadolinium-enhanced MRI scan of a patient with intra-
cranial hypotension. There is diffuse, symmetric meningeal enhance-
ment (arrows).
Scheld_Ch02.indd 9
9
decreased CSF volume, which would cause cerebral vasodila-
tation and stretching of pain-sensitive cerebral structures (46).
The incidence of the postLP headache is not associated
with the volume of CSF removed, hydration, the position of
the patient (lying on their side or sitting up), or the opening
pressure (47). Factors that can be associated with a decrease
in the incidence of headache are the type and size of needle,
the direction of the bevel during needle placement, the replace-
ment of the stylet, and possibly the number of LP attempts
(47). Atraumatic needles with a blunt end are recommended by
the American Academy of Neurology to reduce the incidence
of postLP headaches (48). The blunt end produces a more
traumatic opening with tearing and disruption of the collagen
fibers that is closed faster by an immunologic reaction and
thus associated with a decrease incidence of headache (49).
Additionally, smaller needles have been shown to decrease
the incidence of the postLP headache (46). The direction
of the bevel should be parallel to the long axis of the spine
to decrease the incidence of headache. If the patient is lying
on his or her side, the bevel should face up. This way, the
needle will separate the dural collagen fibers, which also run
along the long axis of the spine, rather than cutting them (47).
Several techniques to treat the postLP headache exist
including the instillation of a blood patch, dextran, or saline
into the epidural space. A blood patch refers to the injection
of 20 to 30 mL of the patients fresh blood into the epidural
space. It is thought to work by closing the CSF leak by forming
a clot, and it works in about 70% to 98% of patients (47). If a
blood patch does not work, 20 mL of dextran or saline can be
injected into the epidural space to raise the epidural pressure
and reduce the CSF leak. Oral or intravenous caffeine can be
used because they act as a cerebral vasoconstrictor and blocks
adenosine receptors. Surgical closure of the dural gap is the
last resort (46).
Less Common Complications of Lumbar Puncture
Cortical Blindness. Downward displacement of the brainstem
in states of increased ICP may compress the posterior cerebral
arteries against the edge of the tentorium cerebelli, causing isch-
emic infarction of the occipital lobes and cortical blindness (31).
Although this complication of intracranial hypertension is often
accompanied by signs of uncal or tonsillar herniation, compres-
sion of the posterior cerebral arteries may also occur before other
signs of herniation appear. Prognosis for return of vision is poor.
Cervical Spinal Cord Infarction. Rarely, LP in the setting of
bacterial meningitis may be followed within a few hours by
respiratory arrest accompanied by flaccid tetraplegia (50).
A variety of mechanisms, including hypotension and vasculi-
tis, have been postulated as the cause of cervical cord ischemia
in these patients. In some patients, however, it is likely that
displacement of the cerebellar tonsils through the foramen
magnum as the result of greatly elevated ICP compresses the
anterior spinal artery or its penetrating branches, with resul-
tant ischemic infarction of the upper cord (50).
Technique of Lumbar Puncture
The LP was first performed by Quincke in 1891 on children
suffering from headaches in hopes to relieve their symptoms.
Soon after, using CSF as a diagnostic tool became the standard
way for evaluating patients with meningitis (47). The LP is
generally performed with the patient in the lateral recumbent
position in a fetal position with the knees flexed toward the
chest, and the neck slightly flexed. Only this position allows
the opening pressure to be measured. The other positions
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 10 Part I: Approach to the Patient and Diagnostic Evaluation
include sitting the patient upright on the edge of the bed and
bending forward over a bed stand or sitting with the feet sup-
ported and chest resting on the knees.
The spinal cord typically ends as the conus medullaris at
the L1 to L2 level in adults, and in children at the L3 to L4
level. The landmarks used are the anterior superior iliac crests,
which correlate with the L4 to L5 interspace. The needle may
be inserted between the L3 and L4, L4 and L5, or L5 and
S1 interspace (51). Insertion above the L3 level may puncture
the conus medullaris and should not be attempted. Also, the
needle should not be inserted over a skin infection or abscess
because this has the potential of inserting bacteria into the
CSF. The performer of the LP should follow a sterile technique
including hand washing, gloves, gown, and mask. After the
anterior superior iliac spine is identified, the spinous process
superior to the interspace is palpated. Prior to inserting the
spinal needle, local anesthetic should be utilized, usually 2 to 3
mL of lidocaine without epinephrine deposited subcutaneously
and then deeper, allowing 1 to 2 minutes for it to take effect.
The needle should be inserted 1 cm below this and directed in
a horizontal position toward the umbilicus to an approximate
depth of 2 cm (51). During the LP, if bone is encountered, the
needle should be withdrawn to the subcutaneous layer and
reinserted at a slightly different angle. The needle is inserted
until a pop is felt indicating penetration of the ligamentum
flavum and presence of the needle in the subarachnoid space.
The stylet is then removed and CSF obtained. A manometer
to measure the CSF pressure should be attached in all cases
if possible. If CSF is not obtained, rotate the needle as part of
the dura may be blocking the hole of the needle. If this does
not work, reinsert the stylet and advance the needle, stopping
frequently to withdraw the stylet (51).
Alternative Routes of Obtaining
Cerebrospinal Fluid
Cisternal, high cervical (C2), and ventricular approaches may
be used to obtain CSF if a lumbar approach is contraindicated
by infection or is technically impossible (1). Cisternal puncture
was initially described in 1923, but it can cause vascular injuries
(52,53). Spinal puncture at the level of the second cervical ver-
tebra under fluoroscopic guidance has been suggested as a less
hazardous approach than cisternal puncture, but its actual
value remains unproven. Ventricular CSF may be of great
diagnostic value if there is a predominantly intraventricular
infection with obstructive hydrocephalus or in the presence of
a ventriculoperitoneal shunt (54).
Routine Studies of Cerebrospinal Fluid
Studies routinely obtained at the time of LP include measure-
ment of CSF pressure, gross examination of the fluid for tur-
bidity or changes in color, measurement of CSF protein and
glucose concentrations, RBC and WBC counts, Gram and/or
acid-fast stains of CSF sediment, and Gram stain and bacte-
rial culture of the fluid. Differentiation of bacterial meningitis
from viral, mycobacterial, or fungal meningitis on the basis of
CSF abnormalities is presumptive unless an organism is cul-
tured or detected by antigen tests or PCR. Amounts of CSF
required by most laboratories for commonly obtained deter-
minations are listed in Table 2.1. Because clinical laborato-
ries differ in the amounts of CSF required for individual tests,
however, the clinician must determine the amounts of CSF re-
quired by the hospital laboratory for each intended test before
performing the LP.
Scheld_Ch02.indd 10
TA B L E 2 . 1
MINIMAL VOLUMES OF CEREBROSPINAL FLUID
REQUIRED FOR COMMON DIAGNOSTIC TESTSa
Test Volume of CSF Required
Cell count and differential 0.55.0 mLb
Glucose and protein 0.5 mLc
Bacterial culture 35 mLd
Mycobacterial culture; fungal 20 mLe
culture (includes acid-fast smear
and India ink preparation)
Viral culture and/or PCR 12 mL
Cryptococcal antigen 0.5 mL
VDRL 0.5 mL
Oligoclonal bands 2 mL serumf
VDRL, Venereal Disease Research Laboratory.
a
Volumes required represent minimal quantities of CSF required
by most hospital laboratories. The clinician should determine the
amounts of CSF required by his or her hospital laboratory by each
intended test before performing the LP.
b
Approximately 0.5 mL will be needed for cell count. Amount of
CSF required for differential will vary, depending on whether cyto-
centrifugation is used or material from centrifuged CSF sediment is
studied.
c
Blood drawn before initiating the LP should also be submitted with
spinal fluid for determination of simultaneous blood glucose level.
d
As little as 0.5 mL may be submitted for culture if there is great
difficulty obtaining fluid. However, the use of centrifuged sediment
from larger volumes of CSF will improve yield on culture in acute
bacterial meningitis. The use of large volumes of CSF is essential in
more chronic infections.
e
Yield on culture for acid-fast bacilli and fungi is, in general,
extremely poor unless large volumes of CSF (20 mL or more in
adults) are cultured.
f
Serum (25 mL) drawn before or after the LP should be submitted
for electrophoresis along with CSF.
Cerebrospinal Fluid Pressure
CSF pressure must be measured in the lateral decubitus
position with the head of the bed being flat. Opening CSF
pressure in healthy adults lies between 50 and 195 mm CSF
(1). Values higher than 200 mm are abnormal. Normal lumbar
CSF pressures in neonates and premature infants are signifi-
cantly lower, with mean values of 100 mm H2O and 95 mm
H2O, respectively (55). CSF pressure is not affected during
pregnancy (56). A CSF baseline pressure of greater than
250 mm H2O was associated with higher incidence of neuro-
logic complaints including papilledema, hearing loss, and with
mortality in AIDS patients with cryptococcal meningitis (57).
Extreme elevation of CSF pressure may also herald impending
brain herniation. Occasionally, CSF pressure may be normal
or even low in the setting of ongoing tonsillar herniation. The
falsely low readings obtained in this setting are believed to
reflect occlusion of the CSF space at the foramen magnum by
the herniated tonsils wedged against the lower brainstem. The
possibility of complete spinal block should be kept in mind if
CSF pressure falls to zero during the procedure.
Gross Appearance of the Spinal Fluid
Once CSF is obtained, it is centrifuged down to give a super-
natant. Normal CSF is colorless and clear. Under pathologic
conditions, CSF may become turbid, discolored, or both.
2/21/14 5:27 PM
 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections 11

The CSF may become turbid as a result of entry of cells, bacte-
ria, or fat; it can be made turbid by as few as 200 WBCs/mm3
or 400 RBCs/mm3 (1,58). CSF containing RBCs will be grossly
bloody if 6,000 or more RBCs are present per cubic millimeter,
and it will be cloudy and xanthochromic or pinkish if 400 to
6,000 cells are present (1).
The yellow discoloration of the supernatant is termed xan-
thochromia and is often used to distinguish between a so-called
bloody tap and subarachnoid hemorrhage. Xanthochromia can
be assessed visually or by spectrophotometric methodology by
scanning the CSF over a range of wavelengths. The discolor-
ation is from degradation products of hemoglobin from lysis of
RBCs. This usually forms 2 to 4 hours after RBCs have entered
the subarachnoid space (1), which is why some experts suggest
waiting at least 6 hours after the onset of headache when a
subarachnoid bleed is suspected because you may get a false-
negative result (58). A traumatic tap should clear as the CSF
is collected in serial vials but not in all cases of subarachnoid
hemorrhage. Xanthochromia resulting from lysis of RBCs is
initially a result of oxyhemoglobin. After 12 hours, the pig-
ment represents predominantly bilirubin (1). Visual assessment
of xanthochromia can be deceitful because it may also be seen
in the presence of increased amounts of protein, in metastatic
melanoma, or as a consequence of systemic hyperbilirubinemia
with a bilirubin level higher than 10 to 15 mg/dL. The most
appropriate and sensitive way to assess xanthochromia is by
spectrophotometry of the CSF to detect the hemoglobin break-
down products, oxyhemoglobin and bilirubin.
Cell Count and Differential
Enumeration and characterization of cells within spinal fluid
is of crucial value in the diagnosis of CNS infections and is
valuable in following the course of illness and response to
treatment (Table 2.2). Improperly handled or counted CSF,
however, can be a dangerous source of error. The cell count in
CSF tends to decrease over time and may be falsely low if mea-
sured after 30 to 60 minutes. This decrease in cell count occurs
partly because leukocytes and RBCs settle out over time if the
tube of CSF is allowed to stand. In addition, however, lysis of
RBCs, polymorphonuclear (PMN) leukocytes, and to a lesser
extent, lymphocytes begins in vitro within 1 to 2 hours of the
LP and may occasionally occur even more rapidly. WBCs also
adsorb to the glass or plastic walls of the tube and are not
easily dislodged by agitation. Because of these factors, the re-
duction in cell count that occurs over time is only partially
reversible if the tube is vigorously agitated before counting.
Any CSF destined for cell counts should, thus, be handled
carefully and expeditiously. Similarly, where serial tubes must
be counted to exclude a traumatic tap, the samples must be
handled in the same manner and counted at the same time by
the same person.
White Blood Cell Count
Quantification of numbers of cells in CSF can be carried
out manually, using a Neubauer counting chamber, but this
methodology is labor-intensive, time-consuming, technique-
dependent, and prone to variability. Although electronic cell
counters are available, they can have poor reproducibility
especially if the CSF samples have low WBC counts. Novel
instruments using flow cell digital imaging have excellent cor-
relation with manual hemacytometer method and should be
the method of choice (59). The accuracy of the cell count is
open to question unless the specimen is examined immediately
after the LP has been completed. Normally, CSF contains fewer

TA B L E 2 . 2
NORMAL CEREBROSPINAL FLUID VALUES OF IMPORTANCE IN INFECTIOUS
DISEASES OF THE NERVOUS SYSTEM: VALUES IN ADULTS, TERM INFANTS,
AND PREMATURE INFANTS

Parameter Adults Term Infants Premature Infants

Cell count (per cubic millimeter) 5 9a 9a

Percent polymorphonuclear leukocytes 0b 61b 57b
Protein (mg/dl) (lumbar)
Mean 30 90 115
Range 958 20170 65150
Glucose (mg/dl)
Meanc 62 52 50
Rangec 4580 34119 2463
CSF:blood glucose ratio
Mean 0.60 0.81 0.74
Range 0.50.8c 0.442.48 0.551.55

a
Cell counts in term and premature infants represent mean values. The range of cell counts found in nor-
mal neonates is 032 cells/mm3 and in premature infants is 029, with 2 standard deviations encompassing
a range of 022.4 cells/mm3 in term and 024.4 cells/mm3 in premature infants. By 1 month of age, normal
CSF contains 20 cells/mm3 (2).
b
Rare polymorphonuclear leukocytes may be seen in cytocentrifuged samples of CSF from normal adults.
This is not necessarily abnormal if the CSF leukocyte count is 4 cells/mm3 or less and if protein and glucose
levels are normal.
c
Assumes a blood glucose level of 70120 mg/dl. At high blood glucose levels (700 mg/dl), normal lower
limit of CSF: blood glucose ratios may approach 0.4 (see text).
Adapted from Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia:
WB Saunders; 1992, with permission.

Scheld_Ch02.indd 11 2/21/14 5:27 PM

 12 Part I: Approach to the Patient and Diagnostic Evaluation
than five cells per cubic millimeter (Table 2.2). Most of these
cells are small lymphocytes (nuclear diameter about 6 to 7 m)
with scant cytoplasm. Larger numbers of PMN leukocytes are
abnormal in uncentrifuged CSF. C. neoformans is similar in
size to a small CSF lymphocyte, and nonbudding forms may
be mistaken for these cells in the counting chamber, though not
in stained cytocentrifuged or otherwise concentrated samples.
Neonatal CSF usually contains 8 to 9 WBCs/mm3, and up to
32 WBCs/mm3 has been reported in the absence of disease (60)
(Table 2.2).
The WBC count is usually between 1,000 and 5,000/mm3
in untreated bacterial meningitis (60), and more than 90%
of patients with bacterial meningitis will have a WBC count
greater than 100 cells/mm3 (61). The most common three types
of viral meningitis in the United States (enterovirus, West Nile
virus, and herpes simplex virus) have a median WBC count
between approximately 100 and 250 cells/mm3 (25).
Differential White Blood Cell Count
A differential count of CSF leukocytes may be obtained fol-
lowing concentration of CSF through a Millipore filter, cen-
trifugation of a volume (usually 5 mL) of CSF, concentration
by sedimentation, or cytocentrifugation. The number of neu-
trophils is increased in various conditions. In adults with bac-
terial meningitis, neutrophils make up an average of 86.4%
of cells counted, with neutrophils making up an average of
34.2% of cells counted in aseptic meningitis (1,62). In the
early stages of meningitis, this distinction between bacterial
and viral etiologies may not be clear because a neutrophilic
pleocytosis (50% neutrophils) may accompany early viral
meningitis or encephalitis (63). Up to two thirds of enterovi-
ral meningitis cases initially have a neutrophilic predominance
(64). Within 12 to 24 hours, there is usually a shift from a
neutrophilic predominance to a lymphocytic predominance,
which is why some may suggest a repeat LP if the first LP
was nonspecific (47). A lymphocytic pleocytosis is typically
observed in patients with viral meningitis, M. tuberculosis,
Borrelia burgdorferi, Treponema pallidum, or C. neoformans,
as well as in neoplastic and drug-induced meningitis (63). In
AIDS-associated cryptococcal meningitis, CSF pleocytosis
may be absent, a finding that is associated with a worse
prognosis. Only up to 30% of patients with AIDS-associated
cryptococcal meningitis have a CSF WBC greater than 20 with
a lymphocytic predominance (57). In tuberculous meningitis,
the range of CSF pleocytosis is more commonly between 50
and 300 cells/mm3 with a lymphocytic predominance. Plasma
cells and eosinophils should not be present in normal CSF (60).
Increased numbers of B cells can be seen in neurosyphilis and
could represent another diagnostic option (65). Eosinophilic
meningitis can be caused by several parasitic infections, the
most common being angiostrongyliasis, gnathostomiasis,
toxocariasis, cysticercosis, schistosomiasis, baylisascariasis,
and paragonimiasis (66) (Table 2.3). In addition, however,
CSF eosinophilia has been reported in a wide variety of other
infectious and noninfectious conditions (Table 2.3), so detec-
tion of eosinophils within the CSF is not pathognomonic of
parasitic infestation (66).
Red Blood Cells
The presence of RBCs in CSF may result from a traumatic LP
or may indicate subarachnoid or parenchymal hemorrhage.
Grossly bloody fluid that clears visibly as CSF is collected sug-
gests a traumatic tap. Differentiation between a traumatic LP
and subarachnoid blood as the result of intracranial or intra-
spinal pathology becomes more difficult if only small numbers
Scheld_Ch02.indd 12
TA B L E 2 . 3
CONDITIONS ASSOCIATED WITH CEREBROSPINAL
FLUID EOSINOPHILIA
Parasitic infestations
Taenia solium (cysticercosis)
Angiostrongylus cantonensis
Gnathostoma spinigerum
Trichinella spiralis
Ascaris lumbricoides
Toxoplasma gondii
Toxocara cati
Toxocara canis
Other infectious agents or conditions
Mycobacterium tuberculosis
Treponema pallidum
Mycoplasma pneumoniae
Rocky Mountain spotted fever
Subacute sclerosing panencephalitis
Lymphocytic choriomeningitis virus
Fungal meningitides
Central nervous system disorders of noninfectious or
unknown origin
Idiopathic eosinophilic meningitis
Granulomatous meningitis
Malignant lymphoma
Hodgkin disease
Leukemia
Multiple sclerosis
Subarachnoid hemorrhage
Obstructive hydrocephalus with shunt
Reaction to intrathecal antibiotics
Data from references 1, 6165, with permission.
of RBCs are present. In such cases, one should compare num-
bers of RBCs present in CSF obtained at the beginning of
the LP with numbers present in CSF obtained at the end of
the procedure (e.g., one should count cells from tubes 1 or
2 and then from tube 4). The presence of xanthochromia in
samples centrifuged immediately after obtaining CSF argues
against a traumatic tap, although it must be kept in mind that
lysis of RBCs in vitro in CSF obtained during a traumatic tap
will produce xanthochromia if the specimen is allowed to sit.
Crenation of RBCs may occur in vitro and has no diagnos-
tic significance (67). Blood entering CSF during spontaneous
subarachnoid hemorrhage or as the result of a traumatic tap
contains WBCs and RBCs, and thus, the CSF leukocyte count
will increase. Numbers of WBCs relative to those of RBCs in
CSF after a traumatic tap should be consistent with the leuko-
cyte count of the peripheral blood, and the differential count
of CSF will be the same. In contrast, actual subarachnoid
hemorrhage often produces pleocytosis and alteration in the
differential count. A traumatic tap in the setting of CNS infec-
tion will increase the numbers of WBCs already present by an
amount that can be calculated by comparing the ratio of RBCs
to WBCs in CSF with that seen in peripheral blood.
2/21/14 5:27 PM
 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
Cerebrospinal Fluid Glucose
Most glucose present in CSF (Table 2.2) moves across the
choroid plexus and across ventricular and subarachnoid
capillaries by facilitated transport. A smaller amount of glu-
cose enters the CSF by simple diffusion. Glucose is removed
from CSF through utilization by cells lining the ventricles and
subarachnoid space and by transport across capillaries and
arachnoid villi. Entry of glucose occurs over time, and more
than 2 to 4 hours is required before serum and CSF glucose
levels reach equilibrium (1). In the absence of infection or
other pathologic conditions, CSF glucose levels are a predict-
able reflection of blood glucose, and the ratio of CSF to blood
glucose concentrations is approximately 0.6. The CSF glucose
level, equilibrated with a normal blood glucose level of 70 to
120 mg/dL, thus ranges between 45 and 80 mg/dL (Table 2.2).
Levels of glucose in ventricular fluid are 6 to 18 mg/dL higher
than those in lumbar fluid (1,68).
CNS infections may alter glucose transport across the
bloodCSF barrier, resulting in a low CSF glucose level,
termed hypoglycorrhachia (1). Further reduction in CSF glu-
cose levels may result from glucose consumption by WBCs
and organisms (1). Reduction of CSF glucose relative to blood
glucose is characteristic of meningitis caused by bacteria,
mycobacteria, or fungi (69,70). The CSF glucose level is usu-
ally normal during viral infections, but low CSF glucose levels
are occasionally observed in meningoencephalitis caused by
mumps, enteroviruses, lymphocytic choriomeningitis, herpes
simplex, and herpes zoster viruses (25,71). Low CSF glucose
values have also been described in CNS complications of
Mycoplasma pneumoniae infection, carcinomatous meningi-
tis, CNS sarcoidosis, and subarachnoid hemorrhage (7275).
During recovery from meningitis, CSF glucose levels tend
to return toward normal more rapidly than cell counts and
protein levels, making CSF glucose levels an important param-
eter to follow in assessing response to therapy (76,77).
Both reduction in CSF glucose values and altered ratios
of CSF to blood glucose levels are used as indicators of
infection. However, the literature contains a variety of recom-
mendations about the point at which CSF glucose should be
considered abnormally low (78); this is partly because of the
prolonged interval over which CSF glucose equilibrates with
serum glucose. In general, a CSF/blood glucose ratio less than
0.5 should be considered abnormal. In premature and full-
term infants, however, the normal CSF/blood glucose ratio is
0.74 to 0.96, and a ratio of 0.6 is usually considered abnor-
mal (79). In severe hyperglycemia, transport of glucose into
CSF may lag, and at a blood sugar level of 700 mg/dL, the
CSF/blood glucose ratio may approach 0.4. For this reason,
a ratio of 0.3 has been suggested as abnormal in diabetics
(80). Silver and Todd (78) addressed the problem of diag-
nostically significant hypoglycorrhachia in a study of 181
pediatric patients with CSF glucose levels less than 50 mg/dL
or a CSF/blood glucose ratio less than 50%. Patients ranged
in age from younger than 1 week to 14 years, with an average
age of 1 years. Their series included patients with bacterial
meningitis, aseptic meningitis, subarachnoid hemorrhage, and
CNS carcinomatosis but did not include patients with tuber-
culous or fungal meningitis. Blood for glucose analysis was
obtained 1 to 114 minutes before the LP (average interval,
30 minutes). Of 35 patients with bacterial meningitis in this
series, 27 (77%) had CSF glucose levels of 20 mg/dL or less,
whereas CSF glucose levels of 20 mg/dL or less were found in
only 10 (7%) of 146 patients with other conditions. A CSF
glucose level less than 20 mg/dL or a CSF/blood glucose ratio
less than 0.30 was highly correlated with bacterial meningi-
tis, whereas an absolute CSF glucose value between 20 and
50 mg/dL was nonspecific; also, a CSF/serum glucose ratio
Scheld_Ch02.indd 13
13
greater than 0.3 was felt to exclude most (but not all) cases
of bacterial meningitis. Additionally, Spanos, Harrell, and
Durack (81) performed a retrospective study of 422 patients
with acute bacterial or viral meningitis and found that CSF
glucose levels less than 18 mg/dL (1.9 mmol/L) and a CSF/
blood glucose ratio less than 0.23 were predictors of bacterial
meningitis. Furthermore, hypoglycorrhachia is associated with
an adverse clinical outcome in patients with meningitis and a
negative Gram stain (82).
Cerebrospinal Fluid Protein
Protein is largely excluded from CSF by the bloodCSF bar-
rier and, under normal conditions, reaches CSF by pinocytotic
transport across capillary endothelia (83). Total CSF protein
concentration in lumbar CSF of a healthy adult (Table 2.2) is
less than 45 mg, and the CSF/serum ratio of albumin is 1:200
(1,13). Mean values of lumbar CSF protein in healthy children
and adults have ranged from 23 to 38 mg/dL, and the extreme
upper and lower concentrations have been 58 and 9 mg,
respectively (1). The CSF protein level in premature and full-
term neonates may range between 20 and 170 mg/dL, with
a mean of 90 mg/dL (58) (Table 2.2). Protein concentrations
in cisternal and lumbar CSF are lower, ranging from 13 to
30 mg/dL (1). Elevation of protein concentration in the set-
ting of CNS infections results from disruption of tight junc-
tions between endothelial cells of venules and, to a lesser
extent, other small meningeal or parenchymal vessels (83).
Elevation of CSF protein level to more than 150 mg/dL may
cause the CSF to be xanthochromic. Extreme elevation of pro-
tein (to 1.5 g/dL) may cause formation of a weblike surface
pellicle or an actual clot, as may high levels of fibrinogen (1).
Levels of CSF protein may be falsely elevated by deteriorating
RBCs following subarachnoid hemorrhage or traumatic LP.
The amount of increase is roughly 1 mg/dL per 1,000 RBCs.
Accurate assessment of the contribution to total CSF protein
made by RBCs requires that the cell count and protein deter-
mination be carried out on the same tube of CSF.
Changes in the concentration of protein in CSF are the most
common and least specific of CSF alterations in disease and
are seen in a wide variety of infectious and noninfectious neu-
rologic conditions. Thus, an elevated CSF protein level, taken
alone, has little specific value in the diagnosis of CNS infections.
Elevation of CSF protein to levels more than 100 mg/dL, par-
ticularly if obtained on serial LPs, argues against viral infec-
tion, however, and Spanos, Harrell, and Durack (81) have
demonstrated that elevation of protein to a level of 220 mg/dL
(2.2 g/L) suggests bacterial meningitis. The CSF protein levels
return to normal more slowly than glucose levels and cell count
during recovery from meningitis and may remain abnormal for
months after parenchymal infections. Although elevation of
CSF protein is common in CNS infections, normal protein val-
ues are occasionally seen in all types of CNS infections, includ-
ing bacterial meningitis. In children with bacterial meningitis,
antibiotic administration more than 12 hours before the LP
is associated with lower CSF protein and higher CSF glucose
concentrations (84).
Cerebrospinal Fluid Immunoglobulins
Immunoglobulins are almost totally excluded from normal
CSF. The blood/CSF ratio of immunoglobulin G (IgG) in
normal CSF is usually in the range of 500:1. Immunoglobulin
M (IgM) is essentially absent from CSF. Studies with radio-
iodinated IgG have demonstrated that CSF IgG in healthy
individuals is derived entirely from serum, requiring 3 to
6 days to reach equilibrium (1). Immunoglobulins enter CSF
less readily than albumin; and in health, immunoglobulin/
albumin ratios in CSF are reduced relative to those in serum.
2/21/14 5:27 PM
 14 Part I: Approach to the Patient and Diagnostic Evaluation

Elevation in CSF immunoglobulins may follow disruption
of the BBB, allowing passage of immunoglobulins across
capillary endothelium, or may result from local antibody
synthesis within the brain. Increased levels of CSF IgG per se
have little diagnostic value in CNS infections. Detection of
oligoclonal IgG bands unique to CSF and not seen in serum
on gel electrophoresis provides strong evidence for an ongoing
immune response within the brain and is part of the diagnostic
criteria for multiple sclerosis (85).
Microscopic Methods for Detecting
Infectious Organisms
Gram Stain
Gram stain is of crucial value in providing rapid identification
of the offending organism in bacterial meningitis, and it is fast,
inexpensive, and fairly reliable (Fig. 2.4). It is usually the single
most important piece of information the clinician uses to guide
initial antibiotic therapy and should be an invariable part of
the CSF evaluation. Diagnostic accuracy of a properly prepared
Gram stain is a function of the number of organisms present,
the type of meningeal pathogen, and by the receipt of prior
antibiotic therapy (61). In one large study of bacterial men-
ingitis in children, prior antibiotic exposure did not alter the
sensitivity of the Gram stain but decreased the sensitivity of
the blood and CSF cultures by 18% and also altered the CSF
glucose and protein levels if administered within 12 hours of
the LP (84). The sensitivity of the Gram stain in children and
adults with pneumococcal meningitis ranges between 69% and
95% and in meningococcal meningitis between 30% and 89%.
Blood cultures will be positive in 50% to 80% of patients, and
the CSF cultures will be positive between 80% and 90% of
cases (86). In general, the sensitivity of the Gram stain ranges
from 50% to 90%; however, the specificity approaches 100%
(61,86). In one study, only 22 (4%) out of 567 patients with
community-acquired meningitis and a negative Gram stain had
culture-proven bacterial meningitis (82).
Partially Treated Bacterial Meningitis
The diagnosis of patients that present with possible bacterial
meningitis who have received antibiotics remain a challenge
to clinicians. The acridine orange stain is a fluorochrome
stain that has been shown to improve detection of bacteria
in CSF specimens, especially in patients who have partially
treated bacterial meningitis (87). A more recent approach is
detection of Streptococcus pneumoniae C-polysaccharide,
which is found in the cell wall and is common to all serotypes,
in CSF by using rapid immunochromatographic membrane
assays (88,89). Two large, multicenter studies have shown
a sensitivity and specificity of 99% detecting S. pneumoniae
even in patients who have been pretreated with antibiotics that
have negative CSF cultures (90,91).

FIGURE 2.4 Gram stains of CSF from patients with bacterial men-
ingitis. A: Streptococcus pneumoniae. B: Neisseria meningitides.
C: Gram-negative meningitis.

Scheld_Ch02.indd 14 2/21/14 5:27 PM

 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
Cerebrospinal Fluid Bacterial Culture
Choice of culture media, methods of handling, and lengths of
time over which cultures are to be maintained are thoroughly
discussed in standard reviews and texts (92,93). The CSF
should be submitted to the laboratory immediately after the LP
and should be placed in culture promptly to avoid loss of fas-
tidious organisms such as Haemophilus influenzae, Neisseria
meningitidis, or anaerobes. CSF cultured for bacteria should,
at a minimum, be plated on a 5% sheep blood agar, chocolate
agar, and inoculated into an enrichment broth (93). A mini-
mum of 2 mL (ideally 5 mL or more) should be submitted for
Gram stain and bacterial culture.
Cerebrospinal Fluid Acid-Fast Bacilli Stains
and Cultures
A positive acid-fast stain for detection of M. tuberculosis is
highly suggestive of tuberculous meningitis, but positive results
occur in only 10% (94). The sensitivity of the acid-fast stain
depends greatly on the skill and persistence of the examiner and
the amount of fluid concentrated. In general, collecting four
serial samples and spinning of large volumes (20 mL) of CSF for
30 minutes enhances the rate of detection by smear microscopy,
but it is impractical (95). Isolating mycobacteria in culture is diffi-
cult with detection rates for M. tuberculosis between 10.2% and
55.8% for conventional Lowenstein-Jensen medium and from
4.3% to 48.9% for the automated commercial system BACTEC
Mycobacteria Growth Indicator Tube (MGIT) 960 (96).
Microscopic Detection of Anaplasma, Fungi,
and Protozoa in Cerebrospinal Fluid
In a few cases, intracellular morulae have been detected in CSF of
patients with meningitis due to Anaplasma infection (97). Fungi,
including C. neoformans, Blastomyces dermatitidis, C. immitis,
and Candida albicans, may occasionally be detected on Gram or
silver stains of concentrated CSF (98). In many cases of fungal
meningitis, however, organisms are too few to be readily detect-
able, and negative Gram or silver stains of CSF sediment in no
way excludes the possibility of fungal infection. India ink prepa-
rations, in which CSF sediment from 3 to 5 mL of CSF is mixed
with a drop of India ink, provide a useful means of outlining the
capsule of C. neoformans (Fig. 2.5). Sensitivity of the India ink
preparation is about 60% in patients who are not infected with
acquired immunodeficiency syndrome (AIDS) and more than
75% in patients with AIDS (98). Cryptococcal antigen detection
has replaced India ink preparations in most laboratories because
of its high sensitivity and specificity (99).
Wet mount preparations may be used to identify motile
trophozoites in the CSF of patients with primary amebic
meningoencephalitis (100). Search for motile organisms in
wet mounts may be made more reliable by the use of phase-
contrast microscopy.
C. neoformans is cultured from the CSF in approximately
72% of patients on the first LP and in more than 90% on
multiple attempts (101). Frequency of recovery of C. albicans
from CSF is also high (102). Isolation of other organisms such
as Histoplasma capsulatum or Brucella species often proves
difficult (103).
In most bacterial and fungal infections, extraneural sites
of possible infection should also be cultured. Depending on
the organism being sought, these sites may include blood,
urine, paranasal sinuses, ears, skin, oropharynx, sputum, bone
marrow, prostate, or abscess material.
Scheld_Ch02.indd 15
15
FIGURE 2.5 India ink preparation of CSF from a patient with
cryptococcal meningitis. The capsule of a cryptococcal organism is
clearly outlined by ink particles.
Viral Culture
Isolation of viral agents by tissue culture methods has been the
traditional means of diagnosis in cases of suspected viral men-
ingitis or encephalitis. Newer methods of virus isolation have
improved diagnostic yield; these include the incorporation of
multiple tissue culture cell lines and a combination of culture
and staining procedures (shell vial assay for early antigen
detection, enzyme immunoassays, and immunofluorescence
staining). Enteroviruses can be isolated in 43% to 77% of
patients, depending on the predominant viral serotype in a
particular community. In approximately half of these cases,
virus will be isolated by day 3 and in more than 80% by day 7
(104). Mumps virus and lymphocytic choriomeningitis virus,
the agents of western and eastern equine encephalitides, may
also be recovered from CSF. Herpes simplex virus (HSV) types
1 and 2 can be isolated from cases of meningitis but are rarely
recovered from CSF in cases of encephalitis. Varicella-zoster
virus; cytomegalovirus; and California, St. Louis, and Japanese
encephalitis viruses are rarely recovered (105).
ADJUNCTIVE AND
MOLECULAR STUDIES OF
CEREBROSPINAL FLUID IN
THE DIAGNOSIS OF CENTRAL
NERVOUS SYSTEM INFECTION
The need for rapidly available accurate diagnostic informa-
tion in CNS infections, the poor sensitivity of microscopic
examination of CSF sediment, and the delays inherent in
obtaining results of CSF culture have led to the development
of a wide variety of rapid diagnostic tests for CNS infections.
At present, PCR methods have largely replaced tissue culture
methods for enteroviruses, Herpetoviridae (herpes simplex,
herpes zoster, cytomegalovirus, Epstein-Barr virus), JC virus,
and West Nile virus. West Nile virus meningoencephalitis is
diagnosed largely by serology because the virus is only rarely
isolated by tissue culture methods at the time patients present
with neurologic symptoms (106).
2/21/14 5:27 PM
 16 Part I: Approach to the Patient and Diagnostic Evaluation
Bacterial Infections
Lactic Acid
Elevation of lactic acid levels in CSF occurs more frequently
in bacterial than in viral meningitis. A CSF lactate cutoff value
of more than 3.5 to 4.2 mmol/L provides supportive evidence
for a bacterial infection in untreated patients. Two large
metaanalyses have concluded that the determination of CSF
lactate level is better than the CSF WBC, glucose, or protein
in differentiating bacterial meningitis from aseptic meningitis
(sensitivity of 93% and 97% and specificity of 96% and 94%,
respectively) (107,108).
C-Reactive Protein
C-reactive protein (CRP) is an acute phase reactant released
from the liver in response to an inflammatory reaction, such as
meningitis. CRP is released within 6 hours of insult and peaks
after 36 hours. One of the functions of CRP is to bind to phos-
pholipid components of damaged cells or bacteria resulting in
activation of the classical complement pathway (109). Both
serum and CSF CRP have been studied as potentially useful
tools for discriminating bacterial meningitis from aseptic
or viral meningitis. A large retrospective study in children
showed a sensitivity of 93% and a specificity of 100% with
a CRP greater than 40 mg/L to detect bacterial meningitis
(110). Furthermore, a metaanalysis showed that a CRP level
greater than 20mg/L was conveyed significantly higher odds of
bacterial meningitis (odds ratio [OR] 9.9 [4.8 to 20.8]) (111).
Current literature supports the assertion that CRP may be
useful, but it should be used with caution as the sole criterion
in the differentiation of bacterial versus viral meningitis (61).
Procalcitonin
Procalcitonin (PCT) is a calcitonin propeptide synthesized
by C cells of the thyroid gland and released from leukocytes
of the peripheral blood (112). It has been used as a marker
of severe inflammation such as those caused by bacterial
infections, pancreatitis, burns, or trauma (113). In a prospec-
tive multicenter trial of 151 patients with a negative Gram
stain, 18 had confirmed bacterial meningitis; a serum PCT
greater than 0.5 ng/mL (sensitivity 87%, specificity 100%,
positive predictive value 1.0, negative predictive value 0.99)
had better diagnostic accuracy than serum CRP, CSF leukocyte
count, CSF/blood glucose ratio, CSF protein, and the physi-
cians assessment (109). A metaanalysis showed that a procal-
citonin level greater than 0.5 g/L was predictive of bacterial
meningitis with an OR 434 (95% confidence interval [CI]
57 to 1,000) (111). Procalcitonin in the CSF may also be
elevated in patients with probable Alzheimer disease, vascular
dementia, dementia with Lewy bodies, frontotemporal demen-
tia, and encephalitis (113).
Additional Biomarkers
Bacterial meningitis results in systemic and intrathecal inflamma-
tory reactions that may lead to significant morbidity and mortal-
ity. Several inflammatory markers (interleukin-1 [IL-1], IL-6
and -12, TNF-, soluble triggering receptor expressed on myeloid
cells-1 (sTREM1), cortisol, heparin-binding protein, and comple-
ment factor 3 and complement B) have all been evaluated in small
studies with adequate diagnostic accuracy (61).
Detection of Bacterial Antigens
Antigen-detection tests using latex agglutination assays are
available to rapidly detect meningitis caused by H. influenzae
type b, N. meningitidis serogroups A, B, C, Y, and W135,
Scheld_Ch02.indd 16
S. pneumoniae, E. coli K1, and Streptococcus agalactiae. In
general, these tests find little application; antigen-detection tests
are less sensitive than bacterial culture, offer no advantages over
the Gram stain, and their diagnostic reliability and usefulness
may vary from institution to institution (114,115). Situations
in which antigen-detection tests are not likely to be helpful
include cases in which the Gram stain is positive, in which the
CSF WBC count and chemistries are within normal limits, and
in which the CNS infection is hospital acquired (115).
Polymerase Chain Reaction
Molecular techniques such as polymerase chain reaction (PCR)
are well suited for the diagnosis of CNS infections because the
presence of microorganisms is highly suggestive of infection.
PCR has emerged as a novel technique for identifying viral,
bacterial, and mycobacterial causes of meningitis (116119).
Although CSF makes an ideal source to examine by PCR because
it is sterile and without contaminants, the presence of inhibitors,
assay contamination, and experimental conditions may some-
times alter its diagnostic value (118). There are a variety of PCR
methods used today including multiplex and nested PCR.
Multiplex PCR has the advantage of potentially detecting more
than one organism in the same PCR reaction. This is done by
using two or more primer pairs, each specific for a single agent.
In nested PCR, products from the first amplification are reampli-
fied from a second set of primers that is nested between the first
set. This essentially overcomes nonspecific amplification (i.e.,
assay contaminations) and increases the sensitivity of detection.
Bacterial Polymerase Chain Reaction. The use of PCR in
bacterial meningitis may serve a role in patients previously
treated with antibiotics or in the detection of difficult to
culture organisms such as Mycoplasma or Brucella. However,
molecular tests are not routinely available, and Gram stain
and culture of the CSF is still the gold standard for diagnosis.
Broad-range PCR amplifies the 16S ribosomal RNA (rRNA)
gene that is present in all bacterial species. Broad-range PCR
and organism-specific PCR have been used in detecting menin-
geal pathogens with sensitivities between 89% and 100% and
specificities of 95% to 100% (61). In a study of 409 patients
with bacterial meningitis in Burkina Faso, PCR was able to
make the diagnosis in a third of patients who had negative
bacterial cultures (120). The availability, expense, and time to
run these test may prove difficult, and positive results ideally
should be confirmed by species-specific PCR. Furthermore,
contamination of PCR specimens may cause false-positive
results, which can be encountered by improper handling or
contaminated work equipment from previous PCR reactions.
Viral Polymerase Chain Reaction. The use of PCR is the
preferred method of diagnosing patients with suspected
viral encephalitis such as those caused by HSV, enterovirus,
varicella-zoster virus, cytomegalovirus, or Epstein-Barr virus
(117). This is very important in cases of suspected HSV
encephalitis that can cause significant morbidity and mortality
if untreated. There are over 100 known viruses that may infect
the CNS although only a limited number of tests are available
for confirmation (117). The decision to perform molecular
tests is physician-driven and is often based on the clinical
presentation. In a study of 760 adult patients presenting with
meningitis and a negative Gram stain, only 44% had PCR in
the CSF performed for a viral pathogen (116).
Herpes simplex virus. Herpes simplex encephalitis (HSE)
is the most common cause of sporadic encephalitis in the
United States, and it is the most common cause of severe viral
encephalitis (121). In immunocompetent adults, 90% of HSE
2/21/14 5:27 PM
 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
is caused by HSV-1, with the remaining 10% caused by HSV-
2. In AIDS patients, the rate of HSV-2 may be higher (122).
Empirical antiviral therapy and prompt identification are of
crucial importance because of the high morbidity and mor-
tality associated with HSE. Early initiation of intravenous
acyclovir has been shown to reduce mortality in patients with
HSE (123). The availability of PCR has now become the diag-
nostic modality of choice for diagnosing HSE (117,121,123).
Numerous studies have shown sensitivities greater than 90%,
with specificities near 100% (117). Viral cultures are not rou-
tinely recommended because they are positive in less than 5%
of adults. Prior to PCR, the gold standard for diagnosing HSE
was brain biopsy (121). A negative PCR for HSV does not rule
out HSV encephalitis but rather makes it less likely (117).
Enterovirus. Enteroviruses are one of the most common causes
of aseptic meningitis in children and in adults (71). Enterovirus
PCR in the CSF has improved the detection rates compared to
viral cultures, and results can be available within 2 hours. The
Gene Xpert Enterovirus PCR had a sensitivity of 97.1% (95%
CI, 84.7% to 99.9%) and a specificity of 100% (95% CI, 94.6%
to 100%) for the diagnosis of enteroviral meningitis (124).
A rapid diagnosis of enteroviral meningitis could impact care by
avoiding hospitalization or empirical antibiotic therapy (71).
Mycobacterial Polymerase Chain Reaction
The diagnosis of tuberculous meningitis (TM) can be difficult
because culture sensitivities are low, and the organism may
take up to 6 weeks to grow (96). PCR has received interest in
hopes it may serve as a rapid, sensitive, and specific test for
TM. One of the more frequently used M. tuberculosis PCR
targets is IS61100 (125). Investigators prospectively studied
677 CSF samples in patients with clinically suspected TM
(125). All culture-positive samples (n 136) were positive
(100%) by the PCR assay. In those patients with clinically sus-
pected (culture negative) TM, the assay was positive in 70%
(n 541). Not all studies have shown as good of results, with
some sensitivities being reported as low as 33% (126) and as
high as 87% (127). Specificities also have a wide range from
88% to 100% (94). This discrepancy could be due to the
different types of measuring methods with the use of different
targets used in the laboratories (127).
Measurement of Adenosine Deaminase Levels
in Cerebrospinal Fluid
Adenosine deaminase is an enzyme that is widely distributed
in human tissues and is present in high concentrations in
lymphocytes. Elevation of CSF adenosine deaminase levels
may occur in a variety of neurologic disorders, including
bacterial meningitis, brain abscess, neurobrucellosis, cryp-
tococcal meningitis, and CNS lymphoma. Elevated levels of
lymphocyte adenosine deaminase are frequently present in the
CSF of patients with TM, and measurement of this enzyme has
been used to provide presumptive evidence of M. tuberculosis
infection and to evaluate response to treatment (128,129). The
test, though both sensitive and useful, is not specific because
it detects a component of host response and does not detect a
structural component of the organism itself.
Lyme Disease
The overall sensitivity and specificity of tests for diagnosis of
Lyme disease are still being determined, as is the accuracy of
tests used to diagnose CNS involvement. In the United States,
Scheld_Ch02.indd 17
17
the Centers for Disease Control and Prevention (CDC) recom-
mends using a two-step process for testing serum from patients
suspected of having Lyme disease (130). Step one involves
screening with a sensitive assay such as enzyme-linked immu-
nosorbent assay (ELISA) or immunofluorescence assay. Those
samples that are negative by such an assay are not tested further.
All equivocal or positive results are subsequently confirmed by
immunoblotting (Western blot) (131). Standardized criteria
for interpretation of both IgM and IgG are outlined elsewhere
(131). Antibody to B. burgdorferi may be absent early in the
course of infection, and seronegative Lyme disease, diagnosed
by T-cell proliferation to Lyme disease, has been reported
(132). False-positive test results for Lyme disease may be seen
in patients with infectious mononucleosis, positive serology for
syphilis, and autoimmune conditions.
In the acute form of neuroborreliosis, there is usually
pronounced synthesis of IgM antibody production (133). IgG
and IgA synthesis is seen in the chronic forms of disease (133).
Detection of intrathecal antibody production is considered
the most specific test for neuroborreliosis (134). However,
not all patients develop CSF antibodies. The CSF antibody
production in subtle CNS disease is inconsistent and may be
lacking in patients with only peripheral nerve involvement
(135). Detection of CSF antibody is not essential for diagnosis
(134,135). Accuracy and reliability of tests vary considerably
between laboratories; therefore, positive values reported by
laboratories unfamiliar to the physician must be approached
with caution and, if necessary, confirmed.
There is currently not a validated PCR method commercially
available (136). There are several parameters that can have sig-
nificant effects on the performance of the PCR such as sample
type and volume, extraction method (nested PCR, PCR followed
by hybridization, real-time PCR), target, primers, template DNA,
and PCR chemistry (136). A metaanalysis derived from published
PCR results irrespective of methods or targets from patients with
all stages of Lyme neuroborreliosis demonstrated an overall sensi-
tivity of 19% and a specificity of 100% (137). Other reports have
indicated that PCR is no more sensitive as a diagnostic tool than
the measurement of intrathecal antibody production and overall
is less useful (138139). PCR should not be considered a stand
alone test, and a negative result does not rule out neuroborrelio-
sis. At present, molecular assays may, at most, have a limited role
as adjunctive tests in patients who are seronegative and who have
a high likelihood of infection (e.g., as in the case of the immuno-
deficient patient). Elevated levels of CSF CXCL13 (C-X-C motif
chemokine 13) have been described in Lyme neuroborreliosis and
could serve as a diagnostic marker. Furthermore, CSF CXCL13
decreased with intravenous ceftriaxone and oral doxycycline
(140). As research tools, molecular assays may provide insight
into pathogenesis and clinical course when used prospectively
during the course of illness.
Fungal and Other Infections
Fungal Infections
Detection of cryptococcal antigen in spinal fluid is the most
practical diagnostic test for cryptococcal meningitis. The
test has a high degree of specificity and is positive in 83% to
98% of patients (141). Detection of cryptococcal antigen has
replaced India ink stains. Despite its sensitivity and specificity,
however, assays for cryptococcal antigen may occasionally
give false-negative results in both immunocompetent and
immunocompromised patients (142). Screening for cryptococ-
cal meningitis as a point of care test by using the cryptococcal
antigen in urine or plasma could help identify patients at high
risk sooner and possibly decrease mortality (143,144).
2/21/14 5:27 PM
 18 Part I: Approach to the Patient and Diagnostic Evaluation
Complement-fixing antibodies have been reported in CSF
in up to 95% of cases of meningitis caused by C. immitis
(145), although yield of detection has not been that high in
all series (146). Diagnosis of Histoplasma meningitis can be
extremely difficult, especially the chronic form of the disease,
which may occur in the absence of other manifestations of
disseminated infection (147,148). Detection of CSF antibodies
may be useful, but false-positive results have been reported
in patients with fungal meningitis caused by other organisms
and by diffusion of serum antibodies to H. capsulatum into
the CSF during other inflammatory conditions of the meninges
(149). Histoplasma polysaccharide antigen detection can be
detected in CSF, serum, or in urine. Small studies of less than
20 patients have documented sensitivities between 38% and
71% (149,150).
Development of molecular techniques for diagnosis of fun-
gal infections has lagged behind those assays for detection of
other pathogens. There are many reasons for this, but the most
compelling is the ubiquitous nature of fungi in the environment
and the difficulties with contamination control. Initial assays
used species-specific, single-copy genes (150). More recently,
investigators have evaluated the use of highly conserved,
multicopy genes that are universal to all or most fungal species
(150). Such targets have included 18S rRNA subunit genes,
28S rRNA genes, mitochondrial genes, and the intergenic
transcribed spacer (ITS) region of the rRNA gene (149,150).
Toxoplasmosis
Encephalitis is the most common presentation of toxoplasmo-
sis in the immunocompromised patient and most commonly
results from reactivation of latent infection (151). CSF antibody
titers have been used to diagnose and follow CNS infections
caused by Toxoplasma gondii in both patients with AIDS and
patients without AIDS (152,153). PCR may be useful in the
absence of typical serologic or radiologic studies and could po-
tentially decrease the need for a brain biopsy (154,155).
Whipple Disease
Whipple disease is a systemic illness caused by Tropheryma
whippelii. Illness is characterized by a predominance of intesti-
nal manifestations, but extraintestinal manifestations including
endocarditis, myocarditis, pericarditis, and CNS disease occur
with relative frequency (156). Although cultivation of the
organism has been reported (157), diagnosis is generally made
by a combination of cytologic analysis of tissue and fluids using
periodic acidSchiff (PAS) staining to demonstrate the presence
of macrophages laden with intracellular organisms and electron
microscopy (158). PCR has also been used to determine the
stage of disease and monitor response to therapy (158,159).
False-positive PCR results have been reported in asymptomatic
individuals, and for this reason, PCR cannot be recommended
in place of standard diagnostic techniques (159).
Viral Infections
PCR methods have had their greatest impact in the diagnosis
of viral meningitis and encephalitis and have replaced tissue
culture methods (117, 123). Additionally, before the advent
of PCR, CSF antibody titers and determination of CSF/serum
antibody ratios were routinely used as methods of acute viral
diagnosis. Determination of CSF antibody titers per se has
been found valuable in the diagnosis of chronic CNS infec-
tions such as tropical spastic paraparesis or subacute sclerosing
panencephalitis (160), but CSF antibody titers alone are of
limited value in most cases of acute viral encephalitis with the
exception of arboviruses such as West Nile virus where the PCR
Scheld_Ch02.indd 18
is less sensitive (117). Comparison of serum and CSF titers of
IgG and IgM antiviral antibodies has been proposed as a diag-
nostic test in encephalitis caused by HSV and other agents, but
the test, which is dependent on intrathecal antibody synthesis,
is of limited value at the time of presentation, and intrathecal
antibody may become detectable only as virus is cleared from
the CSF compartment (161). Most patients presenting with
West Nile virus infection already have CSF IgM antibodies to
the virus, making this the diagnostic method of choice (162).
Compared to viral culture (overall sensitivity, 14% to 24%),
the sensitivity of PCR ranges from 75% to 100% depending
on the virus (163175). Molecular detection of viral nucleic
acid sequences in CSF has not only improved diagnosis but
also has largely replaced invasive methods such as brain
biopsy, has shortened time to specific diagnosis, and particu-
larly in enteroviral CNS infections, has proven cost-effective
through decreased use of empirical antibacterial therapy and
reduction in hospital stay (163165). Finally, molecular assays
have added greatly to our understanding of the epidemiology
and pathogenesis of these infections (125,166,167).
Other Adjunctive Tests in the Diagnosis
of Central Nervous System Infections
Detection of Cytokines in Cerebrospinal Fluid
TNF, IL-1, and other cytokines have received increasing
attention as mediators of the inflammatory response during
bacterial meningitis and can help distinguish between bacterial
and viral meningitis (176180). Lopez-Cortez et al. (178) have
recently demonstrated that a TNF- level of more than 150 pg/
mL and IL-1 level more than 90 pg/mL showed sensitivities of
74% and 90%, respectively, in discriminating viral from aseptic
meningitis. Pinto Junior et al. (179) found that an elevated CSF
IL-8 level was higher in patients with acute bacterial meningitis
compared to aseptic meningitis and controls (100% of sen-
sitivity and 94% of specificity). Tang et al. (180) determined
the concentrations of IL-1 and TNF- in the CSF of 171
specimens of 144 patients whose cases were classified as fol-
lows: bacterial meningitis (n 23), aseptic meningitis (n 26),
and nonmeningitis (n 95). Significantly higher serum IL-1
and TNF- concentrations were detected in those with bacterial
meningitis than those with aseptic meningitis or among those
patients without meningitis (p 0.001). These findings, though
requiring both confirmation and amplification, suggest that
analysis of TNF and other cytokines, in particular IL-1, may
prove valuable in differentiating acute bacterial meningitis from
viral meningitis and possibly in detecting patients at particular
risk of adverse outcome. Their role in guiding adjunctive
therapy, such as corticosteroids and nonsteroidal treatment of
BBB injury, is also under investigation.
CHARACTERISTIC
CEREBROSPINAL FLUID FINDINGS
IN MAJOR CENTRAL NERVOUS
SYSTEM INFECTIONS
Bacterial Meningitis
Bacterial meningitis characteristically produces a neutrophilic
pleocytosis, hypoglycorrhachia (CSF glucose 45 mg/dL), and
an elevated protein level. Numbers of PMN leukocytes may
vary from a few to many thousand and usually range between
1,000 and 10,000 cells. A predominantly (50% of cells)
2/21/14 5:27 PM
 Chapter 2: Cerebrospinal Fluid in Central Nervous System Infections
lymphocytic pleocytosis has been reported in up to 14% of
patients (181), and atypical CSF profiles can especially be seen
in Listeria monocytogenes infection (182). A predominance
of lymphocytes may also be seen in neonatal gram-negative
meningitis (183). Leukocytes may be absent from CSF very
early in the course of infection, in neonatal meningitis, or in
severely immunocompromised patients (184).
Brain Abscess and Parameningeal Infection
Subdural empyema complicates community-acquired bacterial
meningitis in 2.7% of cases and is usually caused by S. pneu-
moniae in association with sinusitis or otitis (185). CSF
cultures are positive in 93% of these patients. In contrast, LP
in brain abscess is not helpful and has been complicated with
brain herniation in 4 out of 296 (1.3%) of patients (186). The
CSF findings are nonspecific and may include (a) a mixed, pre-
dominantly lymphocytic pleocytosis, (b) normal glucose level,
and (c) elevated protein level. Organisms are not present un-
less there is accompanying meningitis, in which case CSF find-
ings will be those of bacterial meningitis (187188).
Tuberculous Meningitis
Typical findings in tuberculous meningitis are (a) a pleocytosis
with lymphocytic predominance, (b) lowered glucose level,
and (c) elevated protein level (94,95). In approximately 70%
of patients, the cell count is between 100 and 400 cells (95).
However, as many as 1,000 to 1,200 cells may be present,
and in few patients, the CSF is acellular despite the presence
of organisms, elevation in protein, and hypoglycorrhachia.
Although most cells in the CSF are lymphocytes, relative
numbers of lymphocytes and PMN leukocytes may vary from
LP to LP. Protein levels are 100 to 500 mg/dL in 65% of
patients and may reach levels of 1,000 mg or more if treat-
ment is delayed (94,95). In 25% of patients, protein levels
are normal (94). Glucose levels are 30 to 45 mg/dL in 50%
of patients and may occasionally be less than 10 mg/dL. In
17% of patients, CSF glucose levels are normal (94). More
recently, clinical models that include a duration of symptoms
for more than 5 days, abnormal neurologic status, a CSF to
serum glucose ratio less than 0.5, a low CSF neutrophilic per-
centage (50%), and a CSF protein greater than 100 mg/dL
among others can aid clinicians distinguish between TM from
bacterial meningitis but need to be validated in other patient
populations (189).
M. tuberculosis may be extremely difficult to detect on
smear or to recover by culture. When tuberculous meningi-
tis is strongly suspected, obtaining more than 6 mL of CSF
and repeating LPs can be associated with a higher degree of
positive acid-fast bacilli smears and cultures (189). PCR may
provide a rapid means of diagnosis superior to acid-fast stain
(125127).
Fungal and Other Chronic Meningitides
Initial requirements for CSF analysis in suspected fungal infec-
tions are similar to those described for tuberculous meningi-
tis, and the same material may be sent for both mycobacterial
and fungal culture. CSF should be submitted for cryptococ-
cal antigen and, if the patient has a history of residence in
an endemic area such as the southwestern United States,
for complement-fixing antibodies to C. immitis. Additional
samples of CSF should be submitted for serologic studies for
Scheld_Ch02.indd 19
19
H. capsulatum, Brucella, or other organisms as indicated by
history and occupational exposure. Serum and CSF should be
frozen and held for future serologic studies. CSF findings in
fungal infections are similar to those described for tuberculous
meningitis, except that PMN leukocytes may be found less
often. The number of cells present may vary widely, and as
in tuberculous meningitis, CSF may be acellular in severely
immunocompromised patients, including those with AIDS
(190). An exception to this rule is seen in infections with
Mucorales, in which the extremely destructive nature of the
infection may result in large numbers of neutrophils (191).
As in tuberculous meningitis, CSF glucose level may return
toward normal before changes are seen in cell count and
protein.
Neurosyphilis
Suspicion of neurosyphilis is predicated on the presence of
reactive serum nontreponemal tests such as the rapid plasma
reagin (RPR) or the Venereal Disease Research Laboratory
(VDRL) and reactive serum treponemal tests such as the
fluorescent treponemal antibody-absorption (FTA-ABS),
Treponema pallidum particle agglutination (TPPA), or various
enzyme immunoassays. A serum RPR titer 1:32 or greater is
associated with a higher probability of neurosyphilis in both
HIV and nonHIV-infected individuals; a CD4 less than 350
cells/L is another predictor in HIV-infected patients (192).
A reactive CSF VDRL test confirms the diagnosis but it may
be insensitive, and a nonreactive test does not rule out neu-
rosyphilis (193,194). The CSF may contain variable numbers
of lymphocytes and an elevated protein level in asymptomatic
or symptomatic neurosyphilis (1). The findings are extremely
variable, however, and normal CSF cell count, protein, and
glucose values do not exclude active disease (193,194). Rarely,
syphilis may present as an acute meningitis, with CSF findings
similar to those of bacterial meningitis (1). The T. pallidum
PCR detection has been of value in primary syphilis, but the
utility in neurosyphilis is still under investigation (195).
Lyme Borreliosis
The CSF changes in Lyme neuroborreliosis are typically a
mild lymphocytic pleocytosis, modest elevation of protein
level, normal glucose level, and may mimic viral meningitis.
A clinical model named the rule of 7s can help distinguish
patients with Lyme meningitis from aseptic meningitis with a
sensitivity of 96%. If all the variables (7 days of headache,
70% CSF mononuclear cells, and absence of seventh or
other cranial nerve palsy) are absent, the patient has a low risk
of having Lyme meningitis (196).
Infections Caused by Mycoplasma, Rickettsia,
Ehrlichia, Anaplasma
CSF in meningoencephalitis associated with M. pneumoniae
infections may be normal but has also been characterized by
a usually lymphocytic pleocytosis, elevated protein level, and
mildly depressed glucose level (72). CSF in Rocky Mountain
spotted fever is usually acellular but may contain increased
protein concentration (197); typhus may be accompanied by
lymphocytic pleocytosis and elevation of protein concentra-
tion (198). Meningoencephalitis has been reported in human
granulocytic anaplasmosis (Anaplasma phagocytophilum)
in approximately 1% of cases and in human monocytic
2/21/14 5:27 PM
 20 Part I: Approach to the Patient and Diagnostic Evaluation
ehrlichiosis (Ehrlichia chaffensis and E. ewingii) in about 20%
of cases, and it usually has a mild lymphocytic pleocytosis
(199). One study has detected Ehrlichia morulae in CSF (97).
Viral and Other Acute Meningoencephalitis
Viral meningitis produces a lymphocytic pleocytosis, usually
in the range of 10 to 1,000 cells/mm3 with mildly elevated
protein and normal CSF glucose (25). PMN leukocytes may
at times constitute more than 50% of the cells during the first
24 to 36 hours of the infection, and this can change in a re-
peat LP (200,201) and in one series were shown to be present
for several days (202). In some patients with coxsackievirus
infections of the CNS, PMN leukocytes may constitute 90%
of cells at the onset of infection, and the predominance of
PMN leukocytes may persist for longer than 24 hours. There
are also reports of CSF samples with few or no cells yield-
ing enteroviruses on culture or by PCR (203). Protein is el-
evated in the range of 50 to 100 mg/dL but may sometimes
be higher. Glucose is usually normal, but depression of glu-
cose to levels approaching those of bacterial meningitis has
been reported in infections with HSV-2, herpes zoster virus,
mumps, and lymphocytic choriomeningitis virus (204,205).
CSF should be routinely sent for PCR analysis for entero-
viruses, including parechoviruses and for HSV. In patients
who have vesicular rashes, a varicella-zoster virus PCR
should also be sent. Both CSF and serum should be frozen for
future serologic testing.
Requirements for CSF analysis in cases of suspected viral
encephalitis are similar to those for viral meningitis, and CSF
findings are often similar. PMN leukocytes may be present
in large numbers in severe encephalitides accompanied by
extensive destruction of brain tissue. HSV classically produces
a hemorrhagic encephalitis. However, HSV is not unique
in its ability to produce hemorrhagic necrosis of brain, and
RBCs are often not detected; thus, the presence or absence of
RBCs cannot be used to differentiate HSV encephalitis from
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2/21/14 5:27 PM
 CHAPTER 3 IMAGING OF INTRACRANIAL
INFECTIONS
CARRIE P. MARDER AND KATHLEEN R. FINK
Intracranial infections are usually diagnosed by clinical assess-
ment and laboratory investigations, particularly cerebrospi-
nal fluid (CSF) analysis, combined with radiologic findings.
Imaging plays an important role by providing or narrowing
the differential diagnosis and occasionally identifying a par-
ticular entity that has a characteristic appearance, such as
herpes simplex virus encephalitis, pyogenic abscess, or empy-
ema. Imaging is also crucial for identifying complications of
disease and assessing response to treatment. Finally, imaging
contributes to the evaluation of opportunistic infections in
immunocompromised patients and other patients at high risk
for infection.
Here, we emphasize the overall strategy for imaging intra-
cranial infections and highlight specific entities in which imag-
ing findings contribute to diagnosis or management. We stress
the major complications of intracranial infections and address
special considerations for immunocompromised patients.
IMAGING STRATEGY
Patients suspected of harboring intracranial infection who
present with altered mental status, seizures, or focal neurologic
deficits should emergently undergo noncontrast computed
tomography (NCCT) to exclude life-threatening conditions.
In the acute setting, NCCT is the test of choice to assess for
hydrocephalus, cerebral edema, mass lesions, or hemorrhage
and is often performed prior to lumbar puncture (LP) to ex-
clude impending brain herniation. NCCT is widely available,
and the images are rapidly acquired, making the examination
well tolerated even by critically ill patients.
Clinically stable patients in whom immediately life-
threatening conditions have been excluded by NCCT often
require further evaluation with contrast-enhanced magnetic
resonance imaging (MRI), which has a greater sensitiv-
ity for leptomeningitis, ventriculitis, cerebral abscess, and
empyema as well as downstream complications of infec-
tion such as infarctions. MRI lacks ionizing radiation, so it
is relatively safe to perform, but specific contraindications
include pacemakers and other implanted metallic devices or
metallic foreign bodies. The risks and benefits of MRI should
be weighed carefully in pregnant patients. Studies have not
proven any negative effects of MRI to the fetus, but the
American College of Radiology recommends deferring MRI
until after pregnancy if possible (1). Because MRI acquisi-
tion time is much longer than CT, MRI may not be feasible
in critically ill patients who require intensive monitoring.
Additionally, if a patient is unable to lie still, motion artifact
may significantly degrade the images obtained.
Gadolinium contrast agents improve the sensitivity of
MRI but are generally avoided in patients with severe renal
dysfunction and a glomerular filtration rate of less than
30 mL/min/1.73 m2 due to the risk for nephrogenic systemic
fibrosis (2). Administration of gadolinium-based contrast
should be avoided in pregnancy due to the unknown effects of
exposure to free gadolinium ions on the developing fetus (1).
24
Scheld_Ch03.indd 24
According to the American College of Radiology Appro-
priateness Criteria for headache (3), both NCCT and contrast-
enhanced MRI of the head are usually appropriate for patients
presenting with new headache and suspected meningitis or
encephalitis, with the choice of test depending on local prefer-
ence and availability. When MRI is unavailable or contrain-
dicated, contrast-enhanced CT may be a suitable alternative.
Cerebrovascular complications of infection are relatively fre-
quent, and therefore magnetic resonance angiography (MRA)
and magnetic resonance venography (MRV), either with or with-
out contrast, may also be appropriate tests. Computed tomogra-
phy angiography (CTA) may be performed when there is strong
suspicion for vascular disease or to further evaluate abnormalities
detected by MRA. Other advanced imaging techniques such as
computed tomography perfusion (CTP) or magnetic resonance
perfusion (MRP), magnetic resonance spectroscopy (MRS), and
nuclear medicine studies such as single-photon emission com-
puted tomography (SPECT) and 18F-fluorodeoxyglucose posi-
tron emission tomography (FDG-PET) or PET/CT are usually
only performed for problem solving after the standard imaging
evaluation has been performed.
For evaluation of a new headache in an HIV-positive or
immunocompromised individual, MRI with or without con-
trast is usually appropriate as the initial imaging test (ACR
Appropriateness Criteria Headache [3]). For an indeterminate
cerebral mass in an immunocompromised patient, additional
problem-solving techniques such as FDG-PET/CT, SPECT, MRS,
and MRP may be helpful to narrow the differential diagnosis.
In neonates in whom the anterior fontanelle is patent, cra-
nial ultrasound may be used to evaluate for hydrocephalus,
subdural and epidural collections, and parenchymal masses (4).
Uncomplicated rhinosinusitis is usually managed clinically
without the need for imaging, but for suspected intracranial
or orbital complications of sinonasal disease, both NCCT and
contrast-enhanced MRI of the head, orbits, and paranasal
sinuses are usually appropriate, with CT and MRI serving as
complementary examinations (ACR Appropriateness Criteria
Sinonasal Disease [5]). Brain imaging is critical if there is a
concern for intracranial extension and is best accomplished
with contrast-enhanced MRI. If the patient is unable to tol-
erate gadolinium contrast, noncontrast MRI augmented with
contrast-enhanced CT of the head and sinuses is recommended.
Immunocompromised patients with acute or subacute rhino-
sinusitis are at high risk for developing intracranial or orbital
complications, and therefore the threshold for obtaining imag-
ing should be lower than for immunocompetent patients.
PYOGENIC INFECTIONS
Meningitis
Meningitis refers to inflammation of the pia and arachnoid
membranes. LP with CSF analysis is the test of choice for diag-
nosis (6), and imaging plays an ancillary role.
2/21/14 6:24 PM

FIGURE 3.1 Pyogenic (Streptococcus pneumoniae) meningitis. Contrast-enhanced CT (A) shows lepto-
meningeal enhancement (white arrows). MRI FLAIR sequence (B) shows subarachnoid hyperintensity
(black arrows).
Meningitis may be classified based on the pattern of involve-
ment. Pyogenic and viral meningitis typically involve the ce-
rebral cortices. Granulomatous or chronic meningitis typically
involves the basal surfaces of the brain (basilar meningitis) and
may be due to infectious or noninfectious causes. Pyogenic in-
fections may also produce a basilar pattern of meningitis.
The primary goals of imaging are to evaluate for contrain-
dications to LP and to exclude unexpected clinical mimics or
complications. NCCT can satisfy these goals, but not all patients
with suspected meningitis require CT. Reported risk factors for
an abnormal CT in patients with suspected bacterial meningitis
include age 60 years or older, immunocompromise, recent sei-
zure, focal neurologic deficits, and impaired consciousness (7). In
the absence of these clinical indicators, CT may not be necessary.
Five percent of patients with acute bacterial meningitis suffer
brain herniation, and herniation accounts for 32% of deaths (8).
A causal relationship between LP and brain herniation has not
been proven, but generally accepted imaging contraindications
to LP include midline shift, effacement of the basilar cisterns, and
posterior fossa mass effect (8, 9). Clinical signs of increased intra-
cranial pressure are also a contraindication to LP.
Imaging is usually normal in cases of bacterial meningi-
tis (10). Imaging findings supporting the diagnosis include
cerebral edema, inflammatory material in the subarachnoid
spaces, and leptomeningeal enhancement. Cerebral edema
manifests as narrowed or compressed sulci, ventricles, and
basilar cisterns. Inflammatory material in the subarachnoid
spaces manifests as hyperdense or enhancing material on CT
(Fig. 3.1A) and abnormal fluid-attenuated inversion recovery
(FLAIR) signal hyperintensity (Fig. 3.1B), enhancement, or
restricted diffusion (11) on MRI. Leptomeningeal enhance-
ment manifests as thin, linear enhancement extending along
the sulci and basilar cisterns in a gyriform pattern (12).
Leptomeningeal enhancement should not be confused with
pachymeningeal enhancement, which refers to enhancement
of the dura mater.
Scheld_Ch03.indd 25
Chapter 3: Imaging of Intracranial Infections 25
Imaging is also helpful to assess for complications of men-
ingitis, including extensive cerebral edema resulting in brain
herniation, infarcts, hydrocephalus, extraaxial pus collections,
ventriculitis, cerebritis, and cerebral abscess.
Sterile subdural effusions occur with meningitis but, unlike
infected extraaxial collections, generally resolve spontaneously.
Sterile subdural effusions may develop internal membranes or
septations and occasionally become infected, resulting in sub-
dural empyema (SDE) (13). Subdural effusions occur more
often in children with bacterial meningitis and typically de-
velop over the frontal and temporal lobes (13). Sterile effusions
appear similar to CSF in density or signal intensity or may be
mildly proteinaceous, resulting in slight signal hyperintensity
on FLAIR compared to CSF. They may be mistaken for promi-
nent subarachnoid spaces, a normal finding in infants. One
distinguishing feature is the finding of bridging vessels crossing
the collections, which are present in prominent subarachnoid
spaces but not subdural effusions (14).
Hydrocephalus is a potentially life-threatening complica-
tion of meningitis resulting from impaired resorption of CSF
by the arachnoid granulations or by diminished CSF outflow
due to viscous material in the ventricles or basilar cisterns.
Hydrocephalus may be the only imaging finding in patients
with meningitis, particularly those with basilar meningitis
(Fig. 3.2). In some cases, proteinaceous or enhancing material
may also be evident in the basilar cisterns on CT (Fig. 3.2A)
or MRI (Fig. 3.2B).
Cerebritis
Cerebritis refers to focal brain inflammation due to any cause,
including pyogenic infection (15). Unlike meningitis, which is
localized to the pia and arachnoid, cerebritis involves the brain
parenchyma and may occur adjacent to infected subdural or
epidural collections.
2/21/14 6:24 PM
 26 Part I: Approach to the Patient and Diagnostic Evaluation
FIGURE 3.2 Pyogenic basilar meningitis. NCCT (A) demonstrates hydrocephalus, with enlarged temporal
horns of the lateral ventricles (white arrow). Additionally, there is subtle effacement of basilar cisterns,
including the interpeduncular fossa (arrowhead). Contrast-enhanced MRI (B) shows corresponding en-
hancement in the interpeduncular fossa (arrowhead).
Cerebritis has a nonspecific imaging appearance. CT find-
ings include focal low attenuation (16) (Fig. 3.3A) without
enhancement or with nodular or peripheral enhancement,
which may resemble infarct or mass lesion. MRI findings in-
clude hyperintensity on T2 and FLAIR (Fig. 3.3B) with vari-
able enhancement (Fig. 3.3C). There may be hemorrhage or
restricted diffusion. MRI appearance may be similar to that
seen in status epilepticus, ischemia, or neoplasm.
If inadequately treated, cerebritis may develop into a cere-
bral abscess, following a well-described progression through
the stages of early cerebritis, late cerebritis, early abscess for-
mation, and late abscess formation (16,17) (Fig. 3.3C and D).
Features suggesting the formation of an abscess within an area
of cerebritis include development of a ring-enhancing mass
with restricted diffusion of the central cystic or necrotic core.
This is in contrast to the restricted diffusion that may be seen
with cerebritis, which affects the brain parenchyma itself.
Abscess
Cerebral abscess refers to a focal pus collection within brain
parenchyma with a surrounding capsule (15). Abscesses may
result from direct extension of local infection or from hema-
togenous spread. Local infections associated with cerebral
abscesses include otomastoiditis, sinusitis, and odontogenic
infections (18). Bloodborne infections may be associated
with intravenous drug use, bacterial endocarditis, pulmonary
infections, pulmonary arteriovenous malformations, congeni-
tal heart disease, and other causes (1821). Cerebral abscesses
may also occur after trauma or neurosurgical intervention.
Abscesses from bloodborne infections tend to be multiple
and located at the graywhite junction, most commonly in
the frontal lobes (1821). Abscesses arising from local spread
are often spatially related to the primary infection. For ex-
ample, a frontal abscess may develop adjacent to frontal si-
nusitis. In these cases, the primary infection is usually visible
on imaging.
Scheld_Ch03.indd 26
Regardless of etiology, abscesses share common imaging
features. On NCCT, abscesses appear as hypodense masses
with surrounding vasogenic edema, sometimes with a hyper-
dense rim corresponding to the abscess capsule (16) (Fig. 3.4A).
MRI also shows a localized mass with a T2-hyperintense ne-
crotic core and a markedly T2-hypointense rim surrounding
the collection that corresponds to the capsule (22) (Fig. 3.4B).
The central core demonstrates markedly restricted diffusion
(hyperintense on diffusion-weighted image [DWI] sequence
[Fig. 3.4C] and dark on apparent diffusion coefficient [ADC]
maps). Quantitative ADC values of the necrotic core are signifi-
cantly lower for abscesses than necrotic neoplasms (23).
On both CT and MRI, cerebral abscesses demonstrate thick
smooth rim enhancement, sometimes with thinning of the me-
dial wall. Focal wall rupture results in formation of a daugh-
ter abscess (22) (Fig. 3.4D). In immunocompromised patients,
ring enhancement may be absent and vasogenic edema may be
mild (15), requiring a high index of suspicion for diagnosis.
Complications of cerebral abscess include mass effect and
brain herniation. It is important to evaluate for intraventricu-
lar rupture of the abscess with resulting ventriculitis because
this is a marker of poor prognosis that requires aggressive
treatment (21). Imaging findings indicating ventricular rupture
include layering debris in the lateral ventricles and enhance-
ment of the ependymal lining.
The differential diagnosis of a ring-enhancing mass includes
high-grade glial neoplasm, metastasis, and less commonly,
tumefactive demyelination or subacute infarction. Usually, the
clinical scenario helps distinguish these entities, but in difficult
cases, MRP and MRS may be helpful.
MRP allows comparison of the cerebral blood volume of
the lesion with that of contralateral normal white matter, re-
sulting in a measure of relative cerebral blood volume (rCBV).
The enhancing component of high-grade tumors demonstrates
elevated rCBV (increased perfusion) compared to normal
white matter, whereas pyogenic abscesses demonstrate signifi-
cantly reduced rCBV, which is less than that of contralateral
normal white matter (23,24). It is important to evaluate the
2/21/14 6:24 PM
 Chapter 3: Imaging of Intracranial Infections 27

FIGURE 3.3 Cerebritis progressing to abscess. NCCT (A) and MRI (B, C) on presentation shows focal
parenchymal abnormality with decreased density on CT and increased FLAIR signal involving gray and
white matter (white arrows), with ill-defined central enhancement (C) (white arrowhead). Despite treat-
ment, contrast-enhanced MRI 2 weeks later demonstrated rim-enhancing abscess (D) (black arrowhead).
Notice also development of leptomeningeal enhancement (black arrow).

Scheld_Ch03.indd 27 2/21/14 6:24 PM

 28 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.4 Pyogenic (Streptococcus milleri) abscess. NCCT (A) shows right frontal mass with slightly
hyperdense rim (white arrow) and surrounding vasogenic edema. MRI T2 sequence (B) shows hypointense
rim corresponding to abscess capsule (black arrow) and extensive surrounding edema. C: Central necrotic
core demonstrates restricted diffusion (DWI). Postcontrast T1 sequence (D) shows thick rim enhancement
with daughter abscess (white arrowhead).

Scheld_Ch03.indd 28 2/21/14 6:24 PM


enhancing rim of these lesions rather than the central necrotic
regions, which do not statistically differ.
MRS evaluates the presence and relative ratios of metab-
olites present in a region of interest. Metabolites commonly
evaluated include choline, a marker of cell membrane turn-
over; N-acetylaspartate (NAA), a marker of neuronal integ-
rity; lactate, a marker of anaerobic metabolism; and lipid, a
byproduct of necrosis. Creatine, a marker for energy metabo-
lism, is often used as an internal control against which other
metabolite peaks are compared. In the central necrotic core of
both tumors and abscesses, the metabolite peaks of NAA, cho-
line, and creatine are all depressed or absent (25). In brain ab-
scesses, additional metabolite peaks may be present, including
amino acids, alanine, acetate, succinate, and lactate/lipid (26).
Although lactate and lipid may be present in necrotic tumors,
the other metabolites are more specific to abscesses (23,25,27).
Treatment alters the metabolite profile of the central abscess
cavity and must be considered in the evaluation.
Ventriculitis
Ventriculitis may result from intraventricular rupture of an
abscess, severe pyogenic meningitis (13), or as a complica-
tion after ventricular drainage procedures. Imaging findings
include layering debris within the ventricles, which appears
hyperdense on CT, hyperintense on FLAIR, and hypointense
on T2 compared to CSF (28). Infected ventricular debris may
also show markedly restricted diffusion, similar to the central
core of an abscess. Hydrocephalus is usually present, and there
may be enhancement of the ependymal lining. Ventricular sep-
tations may develop as a late sequela of ventriculitis (28).
Subdural Empyema
SDE refers to an infected subdural collection, occurring
between the dura and arachnoid membranes. SDE is often as-
sociated with direct spread of infection from sinusitis or otitis
media but also occurs as a complication of meningitis, trauma,
or neurosurgical procedures. Seeding of subdural effusions in
infants with meningitis, or seeding of subdural hematomas,
also leads to SDE (29,30). Early recognition of SDE is vital be-
cause urgent surgical decompression is usually required (31).
On CT, SDE appears as a hypo- or isodense crescentic
subdural collection (Fig. 3.5A) with rim enhancement (31),
which may be subtle. On MRI, SDE appears as a protein-
aceous subdural collection, hyperintense on T1 and FLAIR
relative to CSF (Fig. 3.5B). This is in contrast to a subdural
effusion, which follows CSF signal intensity on all sequences.
SDEs are usually hyperintense on DWI (11) (Fig. 3.5C) and
demonstrate rim enhancement (Fig. 3.5D), similar to other pus
collections. Sterile subdural effusions may demonstrate mild
rim enhancement but do not typically demonstrate restricted
diffusion (32). Complications of SDE include dural venous
sinus thrombosis (Fig. 3.5D), cerebral edema, cerebritis, and
cerebral abscess (Fig. 3.5B and C).
Epidural Abscess
Epidural abscesses are usually the result of direct extension of
adjacent infections, particularly sinusitis or otomastoiditis (33),
but may also occur after trauma (30) or neurosurgical proce-
dures. Infected material collects between the dura and calvarium.
Epidural abscesses may extend to involve the subdural space
and may be associated with cerebritis or cerebral abscesses.
Scheld_Ch03.indd 29
Chapter 3: Imaging of Intracranial Infections 29
Cranial epidural abscesses appear on NCCT as hypo- or
isodense extraaxial collections in the epidural space (33) that
may contain gas (Fig. 3.6A). On MRI, epidural abscesses are
T2 hyperintense and T1 iso- or hypointense relative to brain,
depending on the viscosity of the infectious material. There is
usually intense enhancement of the dura (Fig. 3.6B).
Coexistence of subdural and epidural collections is com-
mon, and differentiating them is sometimes difficult, particu-
larly by CT (31,34). MRI may help by allowing delineation
of the thickened or enhancing dura with respect to the col-
lection (34). Additionally, like epidural hematomas, epidural
abscesses tend to be lentiform and can freely cross dural reflec-
tions such as the falx but are bounded by the cranial sutures.
SPECIFIC ENTITIES
Tuberculosis
Tuberculous meningitis typically involves the basilar cisterns,
which become filled with a thick inflammatory exudate (35).
NCCT findings may be subtle and hydrocephalus may be the
only finding, although isodense material in the basilar cisterns
may be evident. Contrast-enhanced CT may demonstrate
enhancing material in the basilar subarachnoid spaces (36),
which may involve the pachymeninges. However, the absence
of basilar meningeal enhancement should not preclude the
diagnosis (37). Additional findings that support the diagno-
sis include infarcts and tuberculomas (36,37). HIV patients
with tuberculous meningitis are more likely to have tuber-
culomas and infarcts rather than basilar enhancement or
hydrocephalus (35).
MRI is useful in the assessment for tuberculous meningitis
and allows better visualization of basilar meningeal enhance-
ment (Fig. 3.7A), infarcts, pachymeningeal involvement, and
tuberculomas than CT (38). MRI may also show enhancement
of cranial nerves.
Tuberculomas are punctate or large granulomatous lesions
that have a variable appearance depending on the extent of cen-
tral caseation (39). On CT, tuberculomas may appear target-
like with central calcification surrounded by an enhancing rim.
On MRI, tuberculomas may be uniformly T2 hypointense or
may appear target-like, with a T2-hyperintense core surrounded
by a low T2 rim (39). Enhancement may be solid, nodular, or
ringlike.
Tuberculous abscesses are encapsulated masses contain-
ing pus and viable mycobacteria that occur more commonly
in immunocompromised patients (40). Unlike tuberculo-
mas, tuberculous abscesses are not primarily granulomatous
(35). By imaging, differentiating a tuberculoma with central
caseation from a tuberculous abscess is difficult. Tuberculous
abscesses also resemble pyogenic abscesses on conventional
imaging, with rim enhancement and a central necrotic core
demonstrating restricted diffusion. MRS may help differenti-
ate a tuberculous abscess from pyogenic abscess or necrotic
tumor. Metabolites specifically associated with tuberculous
abscesses include high lipid and lactate peaks (Fig. 3.7B).
Unlike pyogenic abscesses, amino acid, succinate, acetate, and
alanine peaks are absent (25,26).
Lyme Disease
Lyme neuroborreliosis refers to central nervous system (CNS)
involvement of Lyme disease. Although no specific imaging
findings exist, neuroborreliosis is often included in the dif-
ferential diagnosis for nonspecific white matter lesions and
2/21/14 6:24 PM
 30 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.5 Subdural empyema. NCCT (A) shows isodense left hemispheric subdural collection (white
arrows). MRI FLAIR sequence (B) shows collection is hyperintense to CSF (white arrows) and is associated
with cerebritis (white arrowhead), and these areas demonstrate restricted diffusion (C). Contrast-enhanced
MRI (D) confirms rim-enhancing collection (arrows) with collection deep to the enhancing dura (black
arrowhead), confirming subdural location. Note also the left sigmoid sinus thrombosis (black arrowhead)
complicating the subdural empyema.

Scheld_Ch03.indd 30 2/21/14 6:24 PM

 Chapter 3: Imaging of Intracranial Infections 31

FIGURE 3.6 Epidural abscess complicating maxillary sinusitis. Contrast-enhanced CT (A) shows left
maxillary sinus mucosal thickening and opacification (asterisk) with orbital subperiosteal rim-enhancing
collection (arrow) and intracranial extraaxial gas-containing collection (arrowhead). Contrast-enhanced
MRI (B) redemonstrates sinus disease (asterisk), subperiosteal abscess (black arrow), and enhancing
extraaxial collection (arrowhead), which can be localized to the epidural space by presence of the
overlying enhancing dura.

may share overlapping features with multiple sclerosis. Most Syphilis

patients with neuroborreliosis appear normal on MRI. When
imaging abnormalities exist, leptomeningeal enhancement and
cranial nerve root enhancement may be equally as common as
white matter lesions (41). The seventh cranial nerve is most
commonly involved, followed by the third and fifth cranial
nerves (42).
Neurosyphilis presents clinically in several discrete phases,
with variable imaging findings in each stage. A high index
of clinical suspicion is needed for diagnosis. Imaging may
be normal or may show cerebral atrophy, nonspecific white
matter lesions, parenchymal masses, or vascular complications

FIGURE 3.7 Tuberculosis: Postcontrast T1-weighted MRI (A) shows thick basilar enhancement (white
arrowhead) and enlarged temporal horns of the lateral ventricles, indicating hydrocephalus. MRS (B) of
the central necrotic core of a tuberculous abscess (white arrow) (yellow box) shows a marked lipid peak
(black arrowhead) and relative paucity of other metabolites.

Scheld_Ch03.indd 31 2/21/14 6:24 PM

 32 Part I: Approach to the Patient and Diagnostic Evaluation

TA B L E 3 . 1
PARENCHYMAL NEUROCYSTICERCOSIS:
IMAGING FINDINGS BY STAGE

Stage Description Imaging

Vesicular Cyst or cluster of Thin-walled cyst

cysts with scolex containing simple
fluid; no edema;
scolex may be
visible.
Colloidal Cyst degenerates; Cyst may become
vesicular incites dense on CT, T1
inflammatory hyperintense on
response MRI, with ring
enhancement;
vasogenic edema
Granular Cyst retracts; edema Cyst becomes
nodular begins to ebb. more solid and
smaller; decreasing
enhancement and
edema
Calcified Chronic Calcified nodules
nodular without edema
or enhancement;
FIGURE 3.8 Neurosyphilis. Postcontrast coronal T1-weighted MRI nodules dark on T2
shows left posterior parietal edema (dark area) (arrowhead), which is or gradient-echo
associated with parenchymal, leptomeningeal, and dural enhancement sequences.
(white arrow). (Case provided courtesy of James Fink, MD.)

including infarcts (43,44). T2/FLAIR-hyperintense lesions
measuring less than 1 cm occur in the deep periventricular and
subcortical white matter (43,44).
Syphilitic gummas are granulomatous lesions of the menin-
ges that subsequently involve brain parenchyma or dura or
both and that may contain Treponema pallidum. Gummas are
hypodense on CT and T1 hypointense and T2 hyperintense
on MRI, with mass-effect, enhancement, and surrounding va-
sogenic edema (44,45) (Fig. 3.8). Dural thickening indicates
dural involvement. Gummas typically occur in the cerebral
hemispheres but may also appear in unexpected locations,
such as the pituitary gland (45).
Meningeal syphilis may manifest as meningeal enhancement
on CT or MRI. Cranial nerve enhancement may also occur,
often involving cranial nerves VII and VIII (46). Syphilitic vas-
culitis (meningovascular syphilis) may affect medium and large
vessels (Heubner arteritis) or small vessels (Nissl-Alzheimer
type) (46). Infarctions can complicate either type. Angiographic
findings of infectious vasculitis are discussed further later in
this chapter.
Neurocysticercosis
Neurocysticercosis results from CNS invasion by the parasitic
organism Taenia solium and may involve brain parenchyma,
ventricles, or subarachnoid spaces. The imaging appearance
varies with location and stage of infection.
Parenchymal neurocysticercosis can be classified into
four stages from acute to chronic (47), as summarized in
Table 3.1. In the vesicular stage, a thin-walled cyst forms
containing the invaginated scolex, which may be visible on
FLAIR and contrast-enhanced sequences (48). During the
colloidal vesicular stage, the cyst degenerates, becomes pro-
teinaceous, and the scolex may disappear (Fig. 3.9AC). The
granular nodular stage occurs as the cyst retracts. Vasogenic
edema lessens, although nodular or ring enhancement per-
sists. Differentiating the colloidal vesicular stage from the
granular nodular stage may be difficult (47). Finally, dur-
ing the nodular calcified stage, edema and enhancement
subside, leaving a small calcified nodule (Fig. 3.9D). MRI
is best for identifying lesions in the vesicular, colloidal ve-
sicular, and granular nodular stages. CT is excellent at de-
tecting lesions in the nodular calcified stage (47), as is MR
gradient-echo sequence.
Intraventricular neurocysticercosis may occur alone or in
conjunction with parenchymal neurocysticercosis. Imaging
findings include cystic lesions within the ventricles, commonly
in the fourth ventricle (47). There may be associated noncom-
municating hydrocephalus. Cysts usually are thin walled and
contain CSF-like fluid, making them difficult to see on stan-
dard MRI sequences. High-resolution heavily T2-weighted
MRI sequences (MR cisternography) may help to delineate the
cyst walls.
Neurocysticercosis may also involve the subarachnoid spaces,
particularly the basilar cisterns, and appears as multilobular cys-
tic lesions (racemose neurocysticercosis) (Fig. 3.9E). The scolex
is often not visible.
Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob disease (CJD) is a prion disease that may
be sporadic, hereditary, or acquired from exposure to infected
CNS tissue. Variant CJD (vCJD) most commonly occurs
after consumption of meat from cows infected with bovine

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 Chapter 3: Imaging of Intracranial Infections 33

FIGURE 3.9 Neurocysticercosis. Colloidal vesicular phase on CT (A), FLAIR (B), and postcontrast T1
MRI (C) demonstrating central scolex (black arrows), thick rim enhancement (black arrowhead), and
surrounding vasogenic edema. D: Calcified nodular phase by CT (arrowheads). Subarachnoid neurocys-
ticercosis on T1 MRI (E), with multiple cysts (arrowheads) causing distortion of adjacent parenchyma.
(Cases provided courtesy of James Fink, MD.)

spongiform encephalopathy. Kuru occurs with cannibalism.
Iatrogenic CJD occurs with surgical exposures such as corneal
transplantation. Most cases of CJD are sporadic (sCJD) (49).
The imaging appearances of sCJD and vCJD have been best
described.
MRI is the preferred imaging modality (49) to sup-
port the diagnosis and exclude other etiologies. Criteria
to support the diagnosis of sCJD include DWI or FLAIR
signal hyperintensity in the caudate nucleus and putamen
(Fig. 3.10A), with involvement of at least one cortical
gyrus or involvement of more than three cortical gyri (50)
(Fig. 3.10B). The precentral gyrus is usually spared (51).
Globus pallidus, thalamus, and periaqueductal gray matter
may be involved (49). Cortical atrophy occurs with disease
progression.
vCJD is associated with the pulvinar signsymmetric
FLAIR signal hyperintensity in the pulvinar nuclei of the
thalamus (52). The dorsal medial nucleus of the thalamus may
also be hyperintense (hockey stick sign) (49,52), as may be
the tectal plate, periaqueductal gray matter, or cerebral cortex.
Cortical atrophy may occur but is usually less severe than with
the sCJD.

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 34 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.10 Sporadic Creutzfeldt-Jakob disease in two patients. DWI MRI (A) demonstrates restricted
diffusion in the caudate and anterior putamen (arrowhead). Cortex was also involved (not shown).
Predominantly cortical pattern of involvement in a second patient (B) showing restricted diffusion affect-
ing more than three gyri. (Case provided courtesy of James Fink, MD.)

VIRAL INFECTIONS
Viral infections of the CNS manifest variably as meningitis, en-
cephalitis, myelitis, radiculitis, postinfectious encephalomyeli-
tis, or various combinations thereof. Unlike most bacterial and
fungal infections, the intracranial imaging findings in viral en-
cephalitis may predict a specific causative organism (Table 3.2).
Viral Meningitis
Uncomplicated viral meningitis is usually diagnosed by clini-
cal presentation combined with CSF evaluation. Enteroviruses
are the most frequent cause (53). Imaging may be normal or
may show cortical leptomeningeal enhancement on contrast-
enhanced CT or MRI (12). Viral meningitis is less likely than
bacterial, fungal, or tuberculous meningitis to produce FLAIR
signal hyperintensity in the subarachnoid space (54), but this
finding is not reliable for distinguishing the entities.
Herpes Simplex Virus
Herpes simplex virus (HSV) type 1 is the most common
cause of sporadic acute viral encephalitis, and early diagnosis
and treatment are critical to limit morbidity and mortality.
Although all patients suspected of having HSV encephalitis
should receive prompt treatment regardless of imaging find-
ings, it is important to recognize the characteristic imaging
features because these may precede clinical suspicion of the
disease.
Infection usually begins in the anterior and medial aspects
of the temporal lobe(s) but may extend to the lateral temporal
lobes, inferior frontal lobes, insular cortex, and frontal and
parietal cingulate gyri. Findings may be unilateral or bilateral.
Extension to the pons may occur through retrograde viral
spread along the trigeminal nerve (55). CT may be normal
initially or may show low attenuation in the affected regions,
sometimes with associated mass effect, gyral enhancement,
or petechial hemorrhage (56,57) (Fig. 3.11A). MRI is more
sensitive for early disease and better demonstrates the edema-
tous changes as T2/FLAIR-hyperintense areas (Fig. 3.11B)
with concomitant decreased T1 signal intensity (55,58). DWI
may show restricted diffusion (Fig. 3.11C), which may pre-
cede findings on other sequences (5961). Hemorrhages occur
with disease progression and are demonstrated with high
sensitivity on MRI as petechial areas of intrinsic T1 signal
hyperintensity or as susceptibility artifact on gradient-echo se-
quences. Variable enhancement may also develop at this stage.
Progressive encephalomalacia occurs over several weeks, often

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 Chapter 3: Imaging of Intracranial Infections 35

TA B L E 3 . 2
CHARACTERISTICS OF VIRAL ENCEPHALITIS BY ENTITY

Viral Infection Pearls

Enteroviruses Normal or thin linear leptomeningeal enhancement

HSV Bilateral medial temporal and inferior frontal lobes, sparing basal ganglia
/ Abnormal DWI, enhancement, hemorrhages
Mass effect initially, followed by atrophy over several weeks

VZV Lesions at graywhite interface, white matter, gray matter

Vascular imaging may show vasculitis

Arboviruses Bilateral basal ganglia and thalami lesions

Can involve any brain area, including medial temporal lobes

ADEM Large, asymmetric lesions in supratentorial white matter

/ Deep gray nuclei, brainstem, spinal cord, optic nerves
Open ring sign of enhancement
Monophasic, with resolution on follow-up imaging

HIV Generalized cerebral atrophy

Symmetric periventricular white matter FLAIR hyperintensity with T1
isointensity

PML Asymmetric white matter signal abnormality (hyperintense T2,

hypointense T1) involving subcortical U-fibers
Cerebellar crescent-shaped lesions
Minimal mass effect and enhancement, except with IRIS
May see leading edge of abnormal DWI and enhancement
Progresses on follow-up; may lead to atrophy long-term

CMV Periventricular enhancement or calcification

Noteworthy features highlighted in bold text.

leading to marked temporal lobe atrophy (Fig. 3.11D) with
associated seizure disorder.
The differential diagnosis includes infarct, glioma, limbic
encephalitis (paraneoplastic syndrome), Rasmussen encephali-
tis (chronic viral encephalitis), and other viral infections, such
as arboviral encephalitis. Bilateral abnormalities, sparing of
the basal ganglia, and involvement of both medial and lateral
portions of the temporal lobes (posterior cerebral artery [PCA]
and middle cerebral artery [MCA] vascular territories) are all
features that increase the specificity for HSV.
Advanced techniques are not typically required for diagnosis
but may be helpful for problem solving. Both CTP (62) and SPECT
(63) show hyperperfusion of the involved areas acutely. MRS may
show decreased NAA and increased choline levels acutely, which
can mimic neoplasm (64). Follow-up conventional MRI usually
distinguishes these entities however, because HSV leads to atro-
phy, whereas infiltrating glioma persists or progresses (64,65).
Varicella-Zoster Virus
Neurologic manifestations of varicella-zoster virus (VZV) may
occur in the setting of primary infection (chickenpox) or reacti-
vation (shingles). Reactivation is usually associated with immu-
nosuppression or normal age-related declining immunity. VZV
infection is distinct among viral infections in that it causes a vas-
culopathy, which may involve either small or large vessels. Small
artery involvement may lead to monocular visual loss. Large artery
involvement classically leads to ischemic infarctions. Other mani-
festations of vasculopathy include subarachnoid hemorrhage,
aneurysm formation, and arterial dissection (66). Parenchymal
lesions in VZV infection characteristically occur at the graywhite
interface but may also occur in the cortical gray matter and deep
white matter. Multiple lesions at the graywhite interface should
specifically suggest VZV vasculopathy in the right clinical setting,
along with the differential diagnosis of emboli and metastases.
VZV vasculopathy may coexist with meningitis, radiculitis, and
myelitis and may occur with or without rash (66).
Arboviruses
Arthropod-borne viruses, also known as arboviruses, consti-
tute an important cause of viral meningoencephalitis world-
wide. Examples from this diverse group include the viruses
causing Eastern equine, Western equine, Venezuelan equine,
West Nile, Japanese, St. Louis, California, Murray Valley, and
tick-borne encephalitides. Affected patients may have normal
MRI findings or may have signal abnormalities on T2, FLAIR,
or DWI. Classically, lesions are located in the basal ganglia and
thalami bilaterally (Fig. 3.12), and this imaging pattern should
strongly suggest arboviral encephalitis in a potentially exposed
patient. The differential diagnosis includes anoxic or hypoxic
encephalopathy, toxic exposures such as carbon monoxide
poisoning, metabolic disorders such as Wilson disease and
mitochondrial abnormalities, and other entities such as CJD.
The basal ganglia and thalami are classically involved
in arboviral infections, but additional nonspecific areas of
involvement include the meninges, the brainstem and spinal
cord, the cortical gray matter, and the cerebral and cerebellar

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 36 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.11 HSV encephalitis. A: NCCT shows left temporal low density and volume expansion with
petechial areas of hemorrhage (arrowhead). B: Coronal FLAIR MRI in a different patient shows bilateral
involvement of the anterior and medial temporal lobes and insula. C: DWI shows restricted diffusion in
the corresponding areas, confirmed on ADC map (not shown). D: Axial NCCT in a third patient with
prior HSV encephalitis shows left temporal lobe atrophy.

white matter (65,67,68). Leptomeningeal or parenchymal
enhancement is variable. Isolated substantia nigra lesions have
been reported with St. Louis encephalitis (69). Arboviral en-
cephalitis commonly involves the mesial temporal lobes, but
involvement of the basal ganglia and thalami with relative
sparing of the anterior portions of the temporal lobes help to
distinguish arboviral infections from HSV (65).
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM), also known as
postinfectious or postvaccination encephalitis, is an inflamma-
tory autoimmune demyelinating condition that typically begins
abruptly 2 to 3 weeks following a viral illness or vaccination.
In contrast to multiple sclerosis, ADEM follows a monophasic
course lasting several weeks.
CT may be normal or may show nonspecific areas of low
attenuation (Fig. 3.13A). Lesions may show peripheral en-
hancement (7072). MRI is more sensitive, but lesions may not
be visible until several days after the onset of symptoms (73).
Like other demyelinating lesions, ADEM lesions have high T2
and FLAIR and low T1 signal intensity. They are located most
commonly in the supratentorial white matter (Fig. 3.13B)
and are often multiple, bilateral, and asymmetric, although
involvement of the deep gray structures may be symmetric (74).
Lesions may be small and round or large and irregular, some-
times with a central T2-hyperintense portion creating a fried

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 Chapter 3: Imaging of Intracranial Infections 37

egg appearance (75). Mass effect and surrounding edema

FIGURE 3.12 Eastern equine encephalitis. Symmetric hyperintense FLAIR
signal in the bilateral basal ganglia, including caudate, putamen, and glo-
bus pallidus. Bilateral thalamic involvement is also typical but not present
in this case. (Case provided courtesy of Mahmud Mossa-Basha, MD.)
are typically absent. Tumefactive demyelinating lesions and
rare hemorrhagic forms of ADEM may show surrounding
edema (74,75). A peripheral incomplete ring of enhancement,
the open ring sign, may occur in lesions that partially abut
white matter and cortex (Fig. 3.13C). In this situation, only the
white matter edge enhances, a sign that is highly specific for
demyelinating lesions and only rarely occurs with neoplasms
or abscesses (76,77). Other patterns of enhancement observed
in ADEM include closed ring, solid, nodular, or gyral enhance-
ment (74,75). Patterns of signal abnormality on DWI are vari-
able (78,79), and single lesions may have heterogeneous signal
intensity on DWI and ADC map (80).
MRS shows selective reduction of NAA initially, with nor-
mal levels of the other metabolites. NAA returns to normal
levels on follow-up imaging (81). Elevated choline and/or lac-
tate may also be observed (79,82) (Fig. 3.13D), resembling
other demyelinating conditions and brain tumors. MRP usu-
ally reveals hypoperfusion (Fig. 3.13E) (80), which may help
to distinguish ADEM from neoplastic lesions.
ADEM lesions usually either resolve or improve on follow-
up imaging, although sometimes there is residual gliosis.
Clinical resolution may precede radiographic resolution (73).
A subset of patients may have a relapsing form of the disease
resembling multiple sclerosis. The terms multiphasic or recur-
rent ADEM, however, should be reserved for cases in which

FIGURE 3.13 ADEM. NCCT (A) shows multiple large ill-defined areas of low attenuation bilaterally, which
are hyperintense on FLAIR (B). C: Postcontrast coronal T1-weighted image shows open ring signs (arrow-
heads) with incomplete peripheral enhancement abutting the white matter edge. Single voxel short echo time
MRS (D) of a left parietal lesion shows elevated choline:NAA ratio and a lactate peak (black arrows) mimick-
ing neoplasm. MRP (E) showing decreased perfusion in the lesions. Another patient with ADEM isolated to
the posterior fossa (F) demonstrating FLAIR hyperintense lesions in the pons and middle cerebellar peduncle.

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 38 Part I: Approach to the Patient and Diagnostic Evaluation
FIGURE 3.14 HIV. NCCT at presentation (A) and 5 years later (B) (obtained after trauma) demonstrate
progressive atrophy and patchy periventricular white matter hypoattenuation. B: Incidental right frontal
contusion and small intraventricular hemorrhage evident related to trauma. FLAIR (C) better shows
confluent periventricular white matter disease.
new MRI lesions develop or recur at least 3 months after the
initial demyelinating event and longer than 4 weeks after com-
pleting steroid therapy (74). These criteria help to distinguish
relapse from monophasic disease with a protracted course or
an incomplete response to treatment (83).
Supratentorial white matter lesions are most common in
ADEM, but lesions may also occur in the deep gray nuclei, in-
fratentorial white matter, spinal cord, and optic nerves (71,83).
Lesions may sometimes be isolated to the infratentorial white
matter (Fig. 3.13F).
HIV
Patients infected with HIV may have imaging findings related
directly to HIV infection in the CNS or related to opportunis-
tic infections. Associated opportunistic infections include viral
diseases such as progressive multifocal leukoencephalopathy
(PML) and cytomegalovirus (CMV) infections and fungal
infections such as Cryptococcus infection and coccidioidomy-
cosis. Tuberculosis and syphilis are also increasingly prevalent
in HIV-infected patients.
Direct effects of HIV infection include generalized cerebral
volume loss and symmetric patchy or confluent periventricular
white matter low attenuation on CT and signal hyperintensity
on T2 and FLAIR (Fig 3.14), with corresponding isointensity
on T1-weighted images. There is no contrast enhancement or
mass effect (40). HIV infection may be difficult to distinguish
from chronic microvascular ischemia and age-related volume
loss if comparison studies are not available. Symmetry, peri-
ventricular location, and T1 isointensity help to distinguish
imaging abnormalities due to HIV from those due to PML.
OPPORTUNISTIC INFECTIONS
Immune system compromise may affect humoral immunity
(B cells) or cell-mediated immunity (T cells) and may be due to
a primary immune deficiency or may be secondary to infections
Scheld_Ch03.indd 38
such as HIV, cancers such as leukemia, and medications such
as chemotherapy and immunosuppressive agents, which are
used following bone marrow or solid organ transplantation to
prevent rejection. Immunocompromised patients are prone to
frequent, severe, and long-lasting CNS infections that may be
caused by opportunistic pathogens. Neutropenic patients are
particularly susceptible to bacterial and fungal infections. The
most common CNS opportunistic infections to affect immuno-
compromised patients are discussed below.
Progressive Multifocal Leukoencephalopathy
PML is a progressive and frequently fatal demyelinating oppor-
tunistic infection caused by the JC virus, a ubiquitous patho-
gen that causes disease primarily in patients with impaired
T-cell immunity. The JC virus causes demyelination by directly
infecting the myelin-producing oligodendrocytes. Most cases
occur in the setting of HIV infection, hematologic disorders,
organ transplantation, and treatment with the monoclonal
antibody natalizumab for multiple sclerosis or Crohn disease.
The diagnosis is established by demonstrating JC viral DNA
in the CSF by polymerase chain reaction or by immunohisto-
chemical analysis of brain tissue, but characteristic findings on
MRI (Fig. 3.15) may first suggest the diagnosis.
PML appears as confluent areas of hypoattenuation on CT
and signal abnormality on MRI within the subcortical white
matter involving arcuate or U-fibers, sparing the cortex. MRI
shows confluent areas of T2 and FLAIR hyperintensity with
progressive hypointensity on T1-weighted images and little to
no mass effect or contrast enhancement. Scant peripheral en-
hancement as well as restricted diffusion is sometimes observed
at the leading edge of demyelination (84,85). More marked
enhancement and mass effect may be observed when PML is
associated with the immune reconstitution inflammatory syn-
drome (IRIS), further discussed below (8688).
Parietooccipital lobes and corpus callosum are typically
affected. Unlike multiple sclerosis, periventricular white
matter is relatively spared. Lesions are frequently multiple
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 Chapter 3: Imaging of Intracranial Infections 39

FIGURE 3.15 PML in a patient after autologous stem cell transplant. NCCT (A) shows a right frontal
hypodense lesion. MRI redemonstrates lesion (black arrowheads) as an area of subcortical T2 hyperin-
tensity (B) sparing the cortical ribbon. Restricted diffusion (C) and slight contrast enhancement (D) at
the posterior white matter margin corresponds to the leading edge of demyelination. There is hypo-
metabolism evident on FDG-PET (E). JC virus was confirmed by lumbar puncture. Posterior fossa PML
in a separate patient with advanced AIDS (F) shows a crescentic T1-hypointense lesion with minimal
enhancement (white arrow).

and asymmetric bilaterally and become increasingly conflu-
ent with progression to new areas on follow-up imaging.
Infratentorial lesions may occur, sometimes in isolation.
Cerebellar lesions often have a characteristic crescent-shaped
morphology (Fig. 3.15) (85,89,90).
Although PML lesions have a fairly characteristic ap-
pearance on conventional MRI, advanced techniques are
sometimes performed. MRS may show elevated choline and
depressed NAA peaks as well as lipid and lactate peaks (91).
This spectrum of metabolites reflects the underlying demyelin-
ating process and resembles other demyelinating conditions
such as ADEM but also resembles high-grade neoplasms.
MRP typically shows hypoperfusion in the affected areas, and
SPECT and FDG-PET or PET/CT studies show reduced meta-
bolic activity (Fig. 3.15), helping to differentiate PML from
lymphoma or a high-grade glioma.
The imaging features of PML can resemble ADEM, but
the two entities can usually be distinguished clinically. PML
occurs in immunocompromised patients and has a subacute
onset and progressive course of worsening neurologic im-
pairment and lesion enlargement on MRI. ADEM occurs in
immune competent individuals, usually children, following
a viral infection or vaccination and has an abrupt onset of
neurologic impairment followed by gradual improvement
clinically and radiologically during the course of steroid
treatment.
Cytomegalovirus Infection
CMV produces two distinct types of disease, one in newborns
related to in utero transmission of maternal infection and one in

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 40 Part I: Approach to the Patient and Diagnostic Evaluation
immunocompromised patients. Intracranial imaging findings
of congenital infection include periventricular calcifications,
migrational abnormalities, atrophy, and leukoencephalopathy
(55,65,92). In acquired CMV infections that occur in the set-
ting of immune deficiency, the intracranial imaging findings are
nonspecific but may include findings of meningoencephalitis,
ventriculitis, and/or leukoencephalopathy (40,55,65,92,93).
Rarely, acquired CMV infection manifests as a space-occupying
or peripherally enhancing mass (40,90). Extracranial imaging
findings of acquired CMV infection include chorioretinitis and
polyradiculitis.
The major differential diagnosis of CMV ventriculitis in
an immunocompromised patient is CNS lymphoma. Tuber-
culosis, toxoplasmosis, and bacterial ventriculitis are addi-
tional considerations. The pattern of contrast enhancement
may help distinguish these entities because smooth linear
enhancement favors viral or bacterial ventriculitis, whereas
nodular or mass-like enhancement favors lymphoma (94).
Involvement of the corpus callosum also suggests lymphoma
but can rarely occur with toxoplasmosis (95). Definitive diag-
nosis of CMV ventriculitis requires polymerase chain reaction
analysis for detection of viral DNA in the CSF. Lymphoma is
usually confirmed by detection of abnormal cells in the CSF
or by biopsy.
Toxoplasmosis
Cerebral toxoplasmosis usually presents clinically due to
reactivation of latent infection in immunocompromised pa-
tients (46). Toxoplasmosis appears as one or more ring- or
nodular-enhancing masses, corresponding to abscesses. T2
signal is heterogeneous and may vary according to the stage
of abscess formation and treatment effects (96). Unlike
FIGURE 3.16 CNS toxoplasmosis. Contrast-enhanced MR shows
ring-enhancing lesions, one of which demonstrates eccentric target-like
enhancement (arrowhead), a relatively specific sign for toxoplasmosis.
Note the second ring-enhancing lesion in the left thalamus (arrow).
Scheld_Ch03.indd 40
pyogenic abscesses, there is no central restricted diffusion
(97). Ring enhancement is common. The eccentric target
sign (Fig. 3.16) refers to an enhancing nodule along the
ring-enhancing wall of the lesion, which is highly specific,
but insensitive, for toxoplasmosis (98). Typical abscess
locations include the basal ganglia, thalamus, and cerebral
hemispheres at the graywhite junction (40). MRS typically
shows a large lipid and lactate peak, and perfusion studies
demonstrate decreased rCBV (98).
Differentiating toxoplasmosis from lymphoma in a patient
with AIDS remains a clinical conundrum (46). FDG-PET and
thallium-201 SPECT have both been used for differentiating
the two entities, but the utility of thallium-201 SPECT is vari-
able (99101). DWI MRI sequence may sometimes be helpful,
but there is significant overlap of ADC values between toxo-
plasmosis and lymphoma (102). Serial imaging confirming
expected response to antibiotic treatment, namely, resolution
of ring-enhancing lesions, may be the most helpful in diagnos-
ing toxoplasmosis (40).
Cryptococcus Infection
Cryptococcus CNS infection may affect immunocompe-
tent patients but is more common in immunocompromised
patients. Neuroimaging studies may be normal or may
demonstrate findings of meningitis, meningoencephalitis,
or vasculitis, better depicted with MRI than CT (103).
Meningitis findings include leptomeningeal enhancement
and subarachnoid space DWI hyperintensity (11). CNS
cryptococcal infection may also manifest as parenchymal
mass lesion(s) or hydrocephalus.
Cryptococcus infection often results in accumulation of
gelatinous exudate, which causes dilation of the perivascular
spaces and formation of pseudocysts (Fig. 3.17). These gelatinous
FIGURE 3.17 Cryptococcus. T2-weighted image demonstrates nodu-
lar lesions in the basal ganglia (black arrowhead) that are hyperintense
to brain but hypointense compared to CSF, consistent with gelatinous
pseudocysts.
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FIGURE 3.18 PML-IRIS. Initial FLAIR MRI (A) shows subtle right frontal hyperintense lesion
(white arrow). Follow-up scan 2 1/2 months later (B) shows interval enlargement of the FLAIR hyper-
intense lesion (white arrow) with mild mass effect. Postcontrast T1 images (C) shows new enhancement
with an open-ring configuration (black arrow), consistent with demyelination.
pseudocysts favor the basal ganglia and may have enhanc-
ing walls, particularly in immunocompetent patients (104).
Pseudocysts are hyperintense to CSF on FLAIR due to the pro-
teinaceous contents. Prominent perivascular spaces without
gelatinous exudate also occur, in concert with cerebral volume
loss, but should demonstrate the same signal characteristics as
CSF on all sequences.
Cryptococcomas may form, which are either granuloma-
tous lesions with few organisms or inflammatory lesions with
many organisms (40). Cryptococcomas appear as a cluster
of nodules that are non- or minimally enhancing in immuno-
compromised patients and enhancing in immunocompetent
patients (104). There is no central restricted diffusion, unlike
pyogenic abscesses. Most occur in the basal ganglia, thalamus,
and cerebellum (40).
Coccidioidomycosis
Coccidioidal meningitis may occur in both immunocompetent
and immunocompromised patients and presents as chronic
(basilar) meningitis. Associated hydrocephalus is common
(105,106). Vasculitis and infarctions may complicate the in-
fection (107). Focal-enhancing parenchymal brain lesions may
occur in severe disease as a result of direct extension of basilar
meningeal disease (105). The presence of either hydrocepha-
lus alone or hydrocephalus with infarction is associated with
higher mortality (106).
Immune Reconstitution Inflammatory
Syndrome
IRIS is a complication of highly active antiretroviral therapy
(HAART) that occurs in the setting of severe AIDS-related
immunodeficiency shortly after the initiation of therapy.
The syndrome is characterized by an exaggerated inflam-
matory response to dead, latent, or viable organisms or
self-antigens and may coexist with a variety of opportunis-
tic infections, most commonly JC virus and Cryptococcus
(108). The imaging findings might be confused with new or
Scheld_Ch03.indd 41
Chapter 3: Imaging of Intracranial Infections 41
worsening opportunistic infection. The diagnosis is usually
suspected when there is paradoxical clinical deterioration
with imaging findings that are atypical for a given oppor-
tunistic infection. For example, in IRIS-PML (Fig. 3.18),
there may be greater than expected enhancement or mass
effect (40,8688,108).
CEREBROVASCULAR
COMPLICATIONS OF INFECTION
Intracranial vascular complications of infections may be arte-
rial or venous and may occur in the setting of meningitis, head
and neck infections, or systemic infections. Examples include
infectious vasculitis, venous septic thrombophlebitis, septic
emboli, septic (mycotic) aneurysms, and disseminated intra-
vascular coagulation.
Infectious Vasculitis
Cerebral vasculitis may be primary and idiopathic, known
as primary angiitis of the central nervous system (PACNS),
or may be secondary to a variety of systemic vasculitides,
drugs, or infections. Infectious causes of cerebral vasculitis
are potentially treatable; therefore, patients with known or
suspected infections and new neurologic deficits warrant
evaluation with brain and cerebrovascular imaging. Vascular
complications of pyogenic bacterial meningitis are common
and outcomes are poor, with a high risk for stroke and asso-
ciated morbidity and mortality (109,110). Diagnosis of infec-
tious vasculitis is usually established by characteristic clinical
and radiologic signs combined with CSF analysis using cul-
ture, PCR, and serologic tests directed toward the most com-
mon pathogens.
Pathogens known to cause infectious cerebral vasculitis in-
clude bacteria such as Streptococcus pneumoniae (Fig. 3.19A
and B), Mycobacterium tuberculosis, and T. pallidum; vi-
ruses such as VZV (Fig. 3.19C and D); and a variety of fungi
(Fig. 3.19E and F) and parasites (66,107,111116). Any
cause of infectious basilar meningitis can potentially lead to
2/21/14 6:24 PM
 42 Part I: Approach to the Patient and Diagnostic Evaluation

FIGURE 3.19 Infectious vasculitis. A, B: Pyogenic (Streptococcus pneumoniae). T2-weighted MRI at

presentation (A) and 2 weeks later (B) demonstrate interval decrease in caliber of the basilar artery flow
void (open arrowhead) and new pontine infarcts (white arrow). C, D: Varicella-zoster vasculitis. Cerebral
angiography of the left internal carotid artery in the lateral (C) and PA (D) projection demonstrate
irregular narrowing of the posterior cerebral artery (C) (arrow) and middle cerebral artery (D, arrow).
E, F: Fungal (coccidioidal). Postcontrast T1 image demonstrates extensive basilar and subarachnoid en-
hancement (E, arrowhead) with evidence of subacute infarct in the posterior limb of the left internal
capsule (F, arrow) due to vasculitis affecting the lenticulostriate arteries.

Scheld_Ch03.indd 42 2/21/14 6:24 PM

 Chapter 3: Imaging of Intracranial Infections 43

vasculopathy involving the cerebral vessels at the base of the
brain either by inducing vasospasm or by inciting an inflam-
matory reaction within the vessel walls. In VZV vasculitis,
there is productive viral infection within the media of cerebral
vessel walls (66,117). It is controversial whether other viruses
such as HIV also cause cerebral vasculitis, because opportunis-
tic infections frequently coexist (66,115).
The vascular imaging findings of infectious vasculitis
are similar to other vasculitides and include segmental va-
soconstriction creating a beads-on-a-string appearance,
irregularities of the vessel wall, smooth vessel narrowing, dis-
sections, occlusions, or aneurysm formation. VZV vasculitis
may show contrast enhancement of the vessel walls, possi-
bly reflecting the underlying productive viral infection (114).
Leptomeningeal contrast enhancement on CT or MRI is vari-
able in basilar meningitis but, if present, may suggest infection
as the cause of vasculitis. Complications of vasculitis visible
on CT or MRI include infarcts and hemorrhages, including
subarachnoid hemorrhage.
Septic Thrombophlebitis
Cerebral venous septic thrombophlebitis represents an im-
portant pathway for intracranial spread of extracranial
infections from the paranasal sinuses, mastoid air cells,
orbits, and other facial structures (118,119) and may also
complicate meningitis (13). Septic thrombophlebitis can in-
volve dural venous sinuses, cavernous sinuses, or cortical
veins. High-risk patients include those with diabetes or
immunosuppression and those presenting with coalescent
mastoiditis or acute bacterial or fungal sinusitis involving
the frontal or sphenoid sinuses (119). Specific patterns of
septic thrombophlebitis include sigmoid dural venous sinus
thrombosis secondary to coalescent mastoiditis, superior
sagittal sinus thrombosis secondary to frontal sinusitis, and
cavernous sinus thrombophlebitis secondary to sphenoid
sinusitis or osteomyelitis (Fig. 3.20), orbital cellulitis, or
other facial infections.
Imaging signs of cavernous sinus thrombosis include fill-
ing defects, diminished enhancement, or an expanded con-
tour of the cavernous sinus (120,121). Indirect findings may
include proptosis; enlargement of the extraocular muscles;
and enlargement, nonenhancement, or filling defects within
the superior ophthalmic vein(s). Occasionally, gas bubbles are
present in the cavernous sinus due to dehiscence of the sphe-
noid sinus walls related to osteomyelitis. Secondary arterial
complications involving the cavernous internal carotid artery
may occur, including arteritis, thrombosis (Fig. 3.20A), and
aneurysm formation (Fig. 3.20B and C).
Imaging signs of dural venous sinus thrombosis include a
hyperdense venous sinus on NCCT, abnormal flow voids on
noncontrast MRI, absence of the normal flowrelated signal
on noncontrast MRV, and filling defects on contrast-enhanced

FIGURE 3.20 Septic thrombophlebitis and complications in two patients with sphenoid sinusitis.
A: Contrast-enhanced CT demonstrates mild expansion and nonopacification of the right cavernous
sinus (arrowhead) with thrombosis of the right cavernous carotid artery (white arrow). B: Contrast-
enhanced T1 MRI demonstrates patchy nonopacification of the cavernous sinuses bilaterally, with
abnormal left carotid artery flow void (black arrowhead). Cerebral angiogram (C) confirms mycotic
left cavernous carotid aneurysm (black arrowhead).

Scheld_Ch03.indd 43 2/21/14 6:24 PM

 44 Part I: Approach to the Patient and Diagnostic Evaluation
computed tomography venography (CTV) or MRV. Findings
on noncontrast MRI or MRV may be subtle in cases of in-
complete thrombosis or following partial recanalization.
Obstructive dural venous sinus thrombosis may lead to
secondary complications of venous hypertension and venous
infarction, visible on CT or MRI as vasogenic edema, paren-
chymal hemorrhages, ischemic or hemorrhagic infarcts, or
sometimes as isolated convexal subarachnoid hemorrhage.
Multiple infarcts or hemorrhages in a nonarterial distribu-
tion may suggest the diagnosis. Unlike arterial infarcts, which
show restricted diffusion, findings on DWI are variable in
venous infarctions.
Cortical vein thrombosis may be difficult to detect by imag-
ing. The characteristic finding on NCCT is the cord signa
hyperdense, serpiginous cortical structure corresponding to the
thrombosed vein, which does not opacify on CTV. MRI may
show abnormal susceptibility on gradient echo sequences, but
this finding is often obscured by susceptibility artifact from
the adjacent calvarium. Secondary complications related to
venous hypertension are similar to those of dural venous sinus
thrombosis.
Septic Emboli, Septic Aneurysms, and
Disseminated Intravascular Coagulation
Infectious endocarditis, as well as systemic sepsis from any
cause, can lead to intracranial complications from septic
FIGURE 3.21 Septic emboli. NCCT (A) demonstrates loss of graywhite differentiation consistent with
acute cortical infarct (arrowhead). Gradient-echo MRI sequence (B) demonstrates multiple small micro-
hemorrhages (arrow).
Scheld_Ch03.indd 44
emboli, septic (mycotic) aneurysms, or complex clotting
disorders such as disseminated intravascular coagulation
(DIC). Septic emboli may lead to multiple cerebral infarctions,
microhemorrhages, and microabscesses. The imaging find-
ings on NCCT include loss of graywhite differentiation or
hypoattenuation corresponding to acute infarcts (Fig. 3.21A).
MRI may show multifocal areas of FLAIR signal hyperinten-
sity or restricted diffusion at the graywhite interface, often
associated with small areas of abnormal susceptibility on
gradient-echo images (Fig. 3.21B). Contrast-enhanced im-
ages characteristically reveal multiple peripherally enhanc-
ing lesions at the graywhite interface, but this finding is
sometimes absent, especially early in disease. Multifocal sub-
arachnoid hemorrhage isolated to the cerebral convexities is
another presentation of septic emboli, possibly secondary to
focal arteritis or rupture of small vessels at the sites of em-
bolic occlusion. Convexal subarachnoid hemorrhage may be
visible on NCCT as peripheral areas of hyperdensity within
the cerebral sulci or as subarachnoid space FLAIR signal hy-
perintensity on MRI.
Septic aneurysms may form in association with septic em-
boli or as a consequence of systemic sepsis or spread from
local head and neck infections. Rupture of a septic aneurysm
may result in diffuse subarachnoid hemorrhage indistin-
guishable from saccular aneurysm rupture or a more local-
ized presentation of subarachnoid hemorrhage confined to
a sylvian fissure or a cerebral convexity. On angiography,
septic aneurysms often appear irregular in shape and arise in
2/21/14 6:24 PM

FIGURE 3.22 DIC. NCCT demonstrates multiple scattered areas of
convexal subarachnoid hemorrhage (SAH) (arrows).
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Scheld_Ch03.indd 45
Chapter 3: Imaging of Intracranial Infections 45
atypical locations, usually more distally in the vascular tree
compared to saccular aneurysms.
DIC usually occurs in the setting of systemic sepsis and
may also result in multiple cerebral infarcts and hemorrhages.
Multifocal convexal subarachnoid hemorrhage is another pre-
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The imaging findings are nonspecific and may share overlap-
ping features with septic emboli.
CONCLUSION
The spectrum of imaging findings in CNS infections includes
leptomeningeal enhancement, extraaxial collections, cerebri-
tis, encephalitis, white matter abnormalities, and enhancing
lesions. The pattern of these findings, however, may aid in
diagnosis of the underlying infectious agent and sometimes
predicts a specific organism. Additionally, imaging is key in
evaluating complications of CNS infections, including hydro-
cephalus, brain herniation, cerebral edema, infarcts, and other
vascular abnormalities.
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We gratefully acknowledge the contribution of some illustra-
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Scheld_Ch03.indd 48 2/21/14 6:24 PM
 PART II VIRAL INFECTIONS AND
RELATED DISORDERS
CHAPTER 4 PATHOGENESIS AND
PATHOPHYSIOLOGY OF VIRAL INFECTIONS
OF THE CENTRAL NERVOUS SYSTEM
KEVIN A. CASSADY AND RICHARD J. WHITLEY
Viral infections of the central nervous system (CNS) occur
infrequently and most often result in relatively benign, self-
limited disease. Nevertheless, CNS infections have tremendous
importance because of the potential for death and neurologic
damage. The highly specialized brain tissue is exquisitely sen-
sitive to metabolic derangements. Injured brain tissue recovers
slowly and often incompletely. Even in patients who recover
fully from viral encephalitis, months may be required for re-
turn to normal function (1). The brain and spinal cord pro-
vide diagnostic and therapeutic obstacles. On an anatomic
level, the brain is housed in a closed skull with the spinal cord
suspended within a bony columnar cage. A unique immuno-
logic surveillance system and the bloodbrain barrier further
distinguish infections of the CNS from those involving other
organ systems. Pathologic processes in the CNS have limited
clinical expressions and frequently share pathogenic mecha-
nisms. Tumors, infections, and autoimmune processes in the
CNS often produce similar signs and symptoms (2). Clinical
presentation and patient history, though frequently suggestive
of a diagnosis, remain unreliable methods for determining the
specific etiology of CNS disease (2,3). Understanding the path-
ogenic mechanism of a disease provides a rational basis for
the development of antiviral medications and strategies for the
prevention of viral CNS infections.
The pathogenesis of viral infections is multifactorial: age,
immune status, cultural practices, and genetic makeup can
influence the clinical manifestations of viral infection as read-
ily as viral load, gene polymorphisms, receptor preference, and
cell tropism. Although asymptomatic enteroviral infection pre-
dominates, some patients progress to viral meningitis or, rarely,
fulminant encephalitis (1,4). A detailed description of the
pathogenesis of the individual viral encephalitides is beyond the
scope of this chapter. Instead, general concepts of viral infec-
tion and the pathogenic mechanisms of viral CNS infection are
reviewed and specific examples developed where applicable.
DEFINITIONS
Viruses display tissue tropism and cause illness with a charac-
teristic temporal course. The definition of viral CNS disease
is often based on both viral tropism and disease duration.
Encephalitis refers to inflammation of parenchymal brain
tissue. Acute encephalitis occurs over a relatively short pe-
riod of time (days), whereas chronic encephalitis presents over
weeks to months. The temporal course of slow infections and
spongiform encephalopathies of the CNS (kuru, visna, variant
Creutzfeldt-Jakob disease) overlaps with that of the chronic en-
cephalitides. These progressive CNS diseases are distinguished
by a long incubation period, eventually resulting in death or
extreme neurologic disability over months to years (1,5).
Viral disease in the CNS can also be classified by pathogen-
esis. Neurologic disease is frequently categorized as either pri-
mary or postinfectious (1). A primary encephalitis results from
Scheld_Ch04.indd 49
direct viral entry into the CNS that produces clinically evident
cortical or brainstem dysfunction. Subsequent damage occurs
as a consequence of the host immune response, but invasion
by the pathogen initiates CNS damage (6). The parenchyma
exhibits neuronophagia, and viral antigen or nucleic acids can
be detected (6). Postinfectious or parainfectious encephalitis is
an acute demyelinating process temporally associated with a
systemic viral infection but without evidence of direct viral in-
vasion in the CNS and is included as one of the causes of acute
disseminated encephalomyelitis (ADEM) (6,7). Pathologic
specimens demonstrate demyelination and perivascular aggre-
gation of immune cells but no evidence of virus or viral antigen,
suggesting an immune-mediated etiology (1). The presence of
immune cells distinguishes primary and postinfectious enceph-
alitis from an encephalopathy.
Inflammation occurs at multiple sites within the CNS and
accounts for the myriad of clinical descriptors of viral neuro-
logic disease. Inflammation of the spinal cord, leptomeninges,
dorsal nerve roots, or nerves results in myelitis, meningitis,
radiculitis, and neuritis, respectively. Aseptic meningitis is
frequently used to refer to a benign, self-limited, viral infec-
tion causing inflammation of the leptomeninges (1). The term
aseptic meningitis is used instead of viral meningitis because
a pathogen fails to grow in conventional culture media and
reflects the historic ability to diagnose and treat only bacterial
and fungal CNS infections (6,8). This misnomer hinders epide-
miologic studies, because the definition fails to differentiate be-
tween infectious (fungal, tuberculous, viral, or other infectious
etiologies) and noninfectious causes of meningitis. Meningitis
and encephalitis can represent separate clinical entities; how-
ever, a continuum exists between these distinct forms of CNS
disease (1). A change in a patients clinical condition can reflect
disease progression, with involvement of different regions of
the CNS making it difficult to predict the extent of CNS infec-
tion early in the clinical course. A patient may present with
meningismus and be diagnosed as having viral meningitis and
then progress to meningoencephalitis with altered conscious-
ness and focal CNS changes (6). Epidemiologic data in many
cases provide clues to the viral etiology.
EPIDEMIOLOGY
Epidemiology studies of meningitis and encephalitis potentially
underestimate the true incidence of viral CNS infections. Even
when aseptic meningitis was a reportable disease, not all pa-
tients having a cerebrospinal fluid (CSF) pleocytosis or symp-
toms consistent with a viral meningitis had viral cultures or
other diagnostic studies performed. An overview is difficult,
because each pathogen fills a different ecologic niche with
unique seasonal, host, and/or vector properties (1) (Tables 4.1
and 4.2). Instead, it is useful to analyze the individual agents
responsible for viral brain infections in an effort to find popu-
lation patterns and trends.
49
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 50 Part II: Viral Infections and Related Disorders

TA B L E 4 . 1
TYPE OF DISEASE, EPIDEMIOLOGIC DATA, AND PATHOGENESIS OF VIRAL INFECTIONS
OF THE CNS: DNA VIRUS

Temporal Pathway Laboratory

Viral Agent CNS Disease Course Transmission to CNS Frequency Confirmation

Herpesviridae
Herpes simplex Encephalitis, meningitis, Acute Human Neuronal  Gold standardcell
virus type 1 meningoencephalitis Latent Blood culture brain biopsy
and type 2 reactivation sample; PCR has
replaced routine
brain biopsy.
Cytomegalovirus Encephalitis Acute Blood  Gold standardcell
(immunosuppressed culture, brain biopsy
and neonate) or CSF sample; PCR
may supplant this.
Epstein-Barr Encephalitis, meningitis, Acute  Serologic evidence.
virus myelitis, Guillain-Barr
Varicella-zoster Cerebellitis, Postinfectious Blood  Clinical findings,
virus encephalitis, Acute and latent Neuronal cell culture from a
meningitis, myelitis, reactivation lesion, brain biopsy
zoster ophthalmicus (zoster) or necroscopy.
Human herpes Encephalitis, febrile Acute ? ? ?PCR; high rate of
virus-6 seizures, latent form? Latent infection latent virus in
certain sites makes
interpretation
difficult
B virus Encephalitis Acute Animal bite Neuronal  Culture.
and human
Adenoviridae
Adenovirus Meningitis, encephalitis Acute Human Blood  Cell culture of CSF or
brain.
Poxviridae
Vaccinia Encephalomyelitis Postinfectious Vaccine Blood Extinct Recent

, frequent;  , infrequent; , rare; ?, unknown.

Historically, laboratory techniques for identifying neuro-
logic infections were insensitive, invasive, and required brain
biopsy. Over the last two decades, molecular detection tech-
niques have improved the detection of pathogens nucleic
acids in the CSF (8,9). Despite the improved sensitivity of
these techniques, the pathogen remains unidentified in the
majority of cases of encephalitis. Depending on the study
and diagnostic methods used, investigators fail to identify an
agent in the majority of presumed CNS infections (10,11).
CSF viral culture rates differ based on etiology. They can
often be diagnosed only presumptively by acute and conva-
lescent serologic testing or isolation of virus from another lo-
cation in the body (6,12). In a retrospective review of patients
who had positive bacterial CSF cultures, 1 of 20 had a con-
comitant virus isolated from the CSF (13,14). Historically,
the definitive method for virus detection in encephalitis was
brain biopsy and viral culture (1,2). Polymerase chain reac-
tion (PCR) techniques and other molecular biologic methods
from CSF samples have replaced culture and brain biopsy
as the standard for diagnosing encephalitis for some viruses
(herpes simplex virus [HSV], enterovirus, varicella-zoster
virus [VZV], and JC virus) (8,15,16). PCR has exquisite
sensitivity; however, the techniques sensitivity can lead to
erroneous diagnosis, because PCR may detect latent or in-
tegrated viral DNA potentially unrelated to the pathogenic
process (1). The introduction and testing of new antiviral
drugs will likely provide an impetus for accurate and timely
diagnosis.
Acute viral meningitis and meningoencephalitis represent
most viral brain infections and frequently occur in epidemics
(1). Enteroviruses cause an estimated 60% to 90% of cases,
whereas arboviruses constitute the majority of the remain-
ing reported cases (1,8). The Centers for Disease Control
and Prevention (CDC) received notification of approximately
7,200 to 14,500 cases of aseptic meningitis annually (1).
Most of these cases occurred from the late spring to autumn
months, reflecting the increased incidence of enteroviral and
arboviral infections during these seasons (17,18). The inci-
dence and etiology of encephalitis varies based on geography,
environmental factors, and frequency of exposure to vectors
responsible for viral transmission (19,20).
The CDC received 740 to 1,340 annual reports of per-
sons with encephalitis from 1990 to 1993 (1). Herpes sim-
plex virus infection of the brain occurs year round without

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 Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 51

TA B L E 4 . 2
TYPE OF DISEASE, EPIDEMIOLOGIC DATA, AND PATHOGENESIS OF VIRAL INFECTIONS OF THE CNS: RNA VIRUSES

Fatality Geographic Disease Pathway Laboratory

Viral Taxonomy CNS Disease Rate Vector Distribution Pattern to CNS Frequency Confirmation

TogaviridaeAlphavirus (arborvirus)
Western Meningitis, 310% Mosquito, U.S.west of Epidemic Blood  Serologic titers
equine encephalitis bird Mississippi (HI, CF,
encephalitis River NA, IFA),
virus viral antigen
detection in
brain. Rarely
culture.
Eastern 30% U.S.Atlantic Sporadic  Viral culture
equine and Gulf or antigen
encephalitis Coast states detection in
virus brain, serologic
titers (HI, CF,
NA, IFA), CSF
IgM ELISA.
Venezuelan 1% Mosquito, Central and Sporadic,  Serologic titers
equine horse South epidemic (HI, CF, NA,
encephalitis America, IFA), CSF IgM
virus southwestern ELISA.
U.S., and
Florida
FlaviviridaeFlavivirus (arbovirus)
Japanese Meningitis, 25% Mosquito, Japan, China, Epidemic, Blood  Peripheral blood
encephalitis encephalitis swine, Korea, endemic ELISA, serologic
virus bird Taiwan, titers (HI, CF,
Southeast NA, IFA), CSF
Asia, India, antigen tests.
Nepal
St. Louis 7% U.S.  CSF IgM ELISA,
encephalitis serologic titers
virus (HI, CF, NA,
IFA). Rarely
culture.
West Nile Rarely Uganda, Egypt,  Culture (rare),
fever virus Israel serology (HI,
IFA).
Murray Valley virus Encephalitis 2060% Australia  Viral culture,
serologic titer
(HI, CF, NA).
Tickborne 20% Tick, Eastern Epidemic,  Serologic titer
encephalitis unpasteur- Russia and sporadic (HI, CF, NA),
virus (TBE ized milk Central IgM ELISA.
complex) Europe
Bunyaviridae (arbovirus)
California Meningitis, 1% Mosquito, Northern Endemic Blood  Viral culture, CSF
(La Crosse) encephalitis rodent Midwest (LCV)  IgM ELISA,
encephalitis and (CEV) serologic titers
virus northeastern (HI, CF, NA,
U.S. IFA), CIE.
ReoviridaeOrbivirus (orvivirus)
Colorado Meningitis, 1% Tick, rodent Rocky Endemic Blood  Antigen detection
tick fever encephalitis Mountains, on RBC
Pacific membrane, viral
Coast states culture, serologic
titers (HI, CF,
NA, IFA).

(continued)

51

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 52 Part II: Viral Infections and Related Disorders

TA B L E 4 . 2
TYPE OF DISEASE, EPIDEMIOLOGIC DATA, AND PATHOGENESIS OF VIRAL INFECTIONS OF THE CNS:
RNA VIRUSES (CONTINUED)

Fatality Geographic Disease Pathway Laboratory

Viral Taxonomy CNS Disease Rate Vector Distribution Pattern to CNS Frequency Confirmation

Picornaviridae (enterovirus)
Poliovirus Meningitis 4.550%a Fecal-oral Worldwide Endemic Blood and  Viral culture
myelitis neuronal CSF or brain,
viral culture
from other
side. Serologic
testing for some
serotypes. PCR
becoming gold
standard.
Coxsackievirus Meningitis, Rarelyb Blood 
Echovirus Meningo- 
encephalitis,
myelitis

Paramyxoviridae (xanthematous virus)

Measles virus Encephalitis, 15% Postinfectious, Worldwide Sporadic Blood  Serology, ELISA,
SSPE blood clinically.
Mumps virus Meningitis, 1% Blood  CSF, viral culture.
encephalitis,
myelitis
Orthomyxoviridae (upper respiratory virus)
Influenza viruses Encephalitis 1% Postinfectious Worldwide Sporadic Blood  Viral culture from
another site.
Rhabdoviridae
Rabies virus Encephalitis, 100% Mammal Worldwide Sporadic Neuronal  Antigen detection
encephalo- in brain,
myelitis serologic tests
(IFA, CF, HI,
CIE), viral
culture.
Retroviridae
Human Encephalopathy, Ultimately Human Worldwide ? Blood  PCR autopsy
immunodeficiency encephalitis, 100% samples, MRI
virus type 1 leukoence- findings.
(HIV-1) phalopathy
Arenaviridae
Lymphocytic Meningitis, 2.5% Rodent Worldwide Sporadic Blood  CSF, blood culture,
choriomeningitis encephalitis urine culture,
virus serology.

CF, complement fixation; CIE, counterimmunoelectrophoresis; ELISA, enzyme-linked immunosorbent assay; HI, hemagglutination inhibition; IFA, immu-
nofluorescence antibody; NA, neutralizing antibody titer; SSPE, subacute sclerosing panencephalitis.
Frequency:   , frequent;  , infrequent; , rare; ?, unknown.
a
Case fatality from poliomyelitis is increased in sporadic cases. With vaccination, the epidemic forms of polio have decreased, as has morbidity. In turn, the
calculated case-fatality rate in the U.S. has increased in sporadic and vaccine-associated disease relative to the number of cases of disease.
b
Rarely fatal except in neonate and agammaglobulinemic patient in whom fatality rates can approach 50% even with treatment.

seasonal variation, affects all ages, and constitutes most
fatal cases of endemic encephalitis in the United States (21).
Arboviruses, a group of more than 500 arthropod-transmit-
ted RNA viruses, are the leading cause of encephalitis world-
wide and in the United States (1). Arboviral infections occur
in epidemics and show a seasonal predilection, reflecting the
prevalence of the transmitting vector (22). Asymptomatic
infections vastly outnumber those that are symptomatic.
Patients with symptomatic infections may develop a mild,
systemic febrile illness or a viral meningitis. Encephalitis oc-
curs in a minority of persons with arboviral infections, but
the case-fatality rate varies extremely from 5% to 70%, de-
pending on viral etiology, age of the patient, and unique host
differences (1,23).

52

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 Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 53

WNV 2011
Japanese B encephalitis and rabies constitute most cases of
encephalitis outside of North America. Japanese B encephalitis
virus, a member of the genus Flavivirus, occurs throughout
Asia and causes epidemics in China despite routine immuni-
zation for the virus (24,25). In warmer locations, the virus
occurs endemically (26). The disease typically affects children,
although adults with no history of exposure to the virus are also
susceptible (27). As with the other arboviral infections, asymp-
tomatic infections occur more frequently than symptomatic in-
fections. However, the disease has a high case-fatality rate and
leaves half of the survivors with a high degree of neurologic
morbidity (27). Of note, West Nile virus (WNV) encephalitis,
a member of the Flavivirus family, has increased in incidence
strikingly in the United States (28). In 2002 alone, the CDC
reported more than 3,989 cases and nearly 250 deaths. WNV
infection declined in the United States such that between 2008
and 2011, only 712 to 1,356 cases were reported. There was
an increase in cases (5,387) in the United States in 2012. Many
of the cases occurred in the Mississippi Valley and Southern WNV 2012
and Central United States, suggesting an evolving epidemi-
ology for this introduced pathogen (Fig. 4.1) (http://www
.cdc.gov/ncidod/dvbid/westnile/surv&controlCaseCount12_
detailed.htm). Rabies virus, a bullet-shaped RNA virus of the
family Rhabdoviridae, remains endemic around the world
(29). Human infections in the United States decreased over
the last decades to one to three cases per year because of the
immunization of domesticated animals. Bat exposure is in-
creasingly recognized as the source of infection. Fifteen per-
cent (685 of 4,470) of bats tested carried the rabies virus in
one study analyzing risk of bat exposure and rabies (30). In
most cases, (22 of 24) there was no evidence of bite; how-
ever, in half of the cases, direct contact (handling of the bats)
was documented (31). There is experimental evidence that
bat-associated rabies virus variants transmit across the dermis FIGURE 4.1 Cases of West Nile virus (WNV) in the United States
and potentially through hair follicles (29). Alternatively, bat 2011 (top panel) and 2012 as of December 11, 2012 (bottom panel).
bites may not have been recognized (1). In areas outside the Shaded area demonstrates counties where human WNV infection was
United States, annual cases of rabies encephalitis number in reported. (Courtesy of CDC Arboviral Branch.)
the thousands.
Postinfectious encephalitis, an acute demyelinating pro-
cess, accounts for approximately 100 additional cases of en-
cephalitis reported to the CDC annually in historical studies BSE cases, suggesting animal to human transmission (5). The
(32,33). The disease historically produced approximately report of atypical CJD (unique clinical and histopathologic
one third of the encephalitis cases in the United States and findings) affecting young adults (an age at which CJD rarely
was associated with measles, mumps, and other exanthema- has been diagnosed) led to the designation of a new disease,
tous viral infections (1). Postinfectious encephalitis is now variant Creutzfeldt-Jakob disease (vCJD). From 1996 to
associated with antecedent upper respiratory viral infection 2011, there have been 224 cases of vCJD reported, with 175
(noticeably with influenza virus) and varicella in the United of these occurring in Ireland and Great Britain (World Health
States (32). Measles continues to be a leading cause of postin- Organization [WHO] Web site: www.who.int). The numbers
fectious encephalitis worldwide. In addition to the postin- have declined since the ban in the use of bovine offal in fer-
fectious process, patients with paraneoplastic syndrome and tilizers, pet food, or other animal feed. Active monitoring is
autoantibodies to the N-methyl-d-aspartate (NMDA) auto- still important, and detection of BSE continues to be reported
antibodies have also been recently described (34). Recent in North America (Fig. 4.2) (CDC BSE Web site: http://www.
studies suggest that antigenic variation in the N-terminal do- cdc.gov/ncidod/dvrd/bse/).
main of the NMDA receptor may predispose these patients Environmental factors influence infections of the CNS.
to the autoimmune encephalitis (35). The slow infections Changes in behavior, cultural beliefs, and modification of
of the CNS and transmissible spongiform encephalopathies the environment result in changes in disease patterns and
(TSEs) occur sporadically worldwide (5). The prototypical exposure to new infectious agents. Arboviral infections will
TSE is Creutzfeldt-Jakob disease (CJD); it occurs at high likely increase as populations encroach on wilderness habi-
rates within families and has an estimated incidence of 0.5 tats and flood plains (1). Vaccination has further changed the
to 1.5 cases per million populations. In 1986, cases of a TSE character of viral CNS disease. In 1952, poliomyelitis affected
in cattle, bovine spongiform encephalopathy (BSE), were re- 57,879 Americans (1). Widespread vaccination has eradicated
ported in the United Kingdom. In addition to affecting other the disease currently from the Western Hemisphere. As so-
livestock throughout Europe that were fed supplements con- cial and environmental changes occur globally, the character
taining meat and bone meal, cross-species transmission of and prevalence of CNS viral infections will also change. CNS
BSE has been documented, leading to a ban in the use of infections must be examined in a geographic, cultural, and
bovine offal in fertilizers, pet food, or other animal feed (5). environmental context as well as at the cellular, molecular,
Increases in atypical CJD cases coincided with the peak of and genetic levels.

Scheld_Ch04.indd 53 2/21/14 5:30 PM

 54 Part II: Viral Infections and Related Disorders

7
N = 23
6

5

4

3

2

1
* #
0
1993 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
as of 04/24/2012
FIGURE 4.2 Monitoring and overview
U.S. Canada Canadaborn after 1997 feed ban Canadaunknown birth date
of BSE in North America. Columns rep-
resent number of cases of BSE in North
* Imported UK to Canada # Imported Canada to US

Born after March 1, 1999 America by country of origin and year.
(Courtesy of CDC and WHO.)

PATHOGENESIS be permissive, providing an adequate environment for viral

Viral Spread
Viruses use two basic pathways with fundamentally different
steps to gain access to the CNS: hematogenous and neuronal.
Viruses must survive and multiply at the cellular level effi-
ciently and in sufficient quantity to infect the CNS. The mech-
anism of spread to the CNS is in large part determined by viral
factors, site of entry, and successful replication in intermediate
cells (1). The local immune response at the site of entry, the
systemic immune responses, and the limited vascular access
afforded by the bloodbrain barrier further reduce the oppor-
tunity for viral neurologic infections (1). Differences in host
physiology and mechanism of spread to the CNS further influ-
ence the clinical manifestations of neurologic disease (1). For
example, adults with herpes simplex encephalitis (HSE) have
different presenting signs and symptoms than newborn babies
with HSV infection of the CNS. The route of viral spread and
areas of neurologic involvement differ based on the age of the
patient and mechanism of exposure (36). The subsequent neu-
rologic damage and poor outcome, however, are similar (1).
Subtle differences at the epidemiologic, host, tissue, cellular,
and genetic levels can alter this balance between viral exposure
and symptomatic infection.
replication. The initial steps involved in hematogenous spread
of virus to the CNS consist of replication at the local site of
entry and primary viremia (1). Infection of a secondary tissue
frequently ensues, permitting secondary replication and an ex-
tensive viremia that seeds the CNS. Not all viruses follow this
sequence, and genetic factors of both virus and host influence
the route of viral spread.
The cornified layers of dead skin cells provide a structural
defense for the greatest potential infective surface area of the
human body. Layers of keratin protect the underlying epi-
thelium from viral contact, thereby decreasing the incidence
of viral entry (1). Breaks in this defensive layer can result in
Mouth Conjunctiva
Respiratory
tract
Scratch,
injury
Alimentary
tract

Hematogenous Spread
Enteroviruses and arboviruses are prototypes for viremic
spread to the CNS. Although the location of viral entry dif-
fers for each family, both cause primary and secondary viremia
prior to infecting the CNS. Reviewing the necessary steps and Arthropod
Urogenital
the numerous barriers to hematogenous neurologic infection tract Capillary
explains the low incidence of symptomatic viral infection and
the even lower frequency of viral neurologic infections. A virus Anus
must first bypass or attach to and enter host epithelial cells to Skin
produce infection (37) (Fig. 4.3). In addition, the cell must FIGURE 4.3 Body surfaces as sites of virus infection and shedding.

Scheld_Ch04.indd 54 2/21/14 5:30 PM

 Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System
higher frequency of infection as well as more severe disease.
Some vector-borne viruses bypass the cornified epithelial layer
by inoculation into the subepithelial layer or directly into the
blood (1). The nonkeratinized epithelial layer that constitutes
the conjunctival, respiratory, oral, and nasopharyngeal sur-
faces provides an ideal entry point for aerosolized viruses or
pathogens transmitted by large droplets. Parainfluenza and
adenovirus, although uncommon, can cause primary encepha-
litis (1). More frequently, however, the respiratory viruses are
associated with postinfectious encephalitis (32). A mucous
layer composed of mucopolysaccharides, secretory immu-
noglobulins, and inflammatory cells provides a mechanical,
chemical, and cellular defense against pathogens (1). In the
gastrointestinal and urogenital systems, constant transit pro-
tects the mucosa. As in the respiratory mucosa, leukocytes
and secretory factors augment this mechanical defense. The
enteroviruses tolerate stomach acid, bile salts, proteolytic en-
zymes, and alkaline infusions to infect the host. Certain viruses
(coxsackievirus A9) actually require exposure to proteolytic
enzymes in the gut before they can infect select cell types (1).
Once virus breaches the epithelial barrier and finds a per-
missive cell, primary replication occurs. Virus then can spread
and replicate in the lymph node, or it can bypass the node
and enter the circulatory system, where it seeds other tissues
(arbovirus, enterovirus, measles virus, or varicella virus) (1).
Local immune responses are crucial in limiting systemic viral
infection. The generation of a swift inflammatory response
can limit viremia and symptoms of infection. Some viruses
resist phagolysosomal degradation, allowing them to circulate
and replicate within the protective sheath of a macrophage
(38,39). Antigenic changes and the sequestration of viral re-
ceptors provide additional mechanisms that enable viruses
to evade lymphocytes. For example, human rhinovirus 14,
influenza virus, and poliovirus have receptors embedded in a
recess or canyon in the viral membrane (1). The virus is
able to evade the immune response by altering the molecules
on the surface surrounding the highly conserved, immunologi-
cally inaccessible receptor molecules lining the canyon. Other
viruses have hypervariable sequences surrounding a small,
molecularly conserved binding sequence. The viral binding
site may be smaller than the antigenic sequence recognized by
the immunoglobulin. Changes in the hypervariable molecules
surrounding the binding site allow the virus to evade immune
responses without disrupting the fidelity of the receptor bind-
ing site (40,41).
Primary viremia allows virus to seed distant locations of
the body and frequently marks the onset of clinical illness.
Virus circulates in the vascular system attached to or within
host cells such or as free virus within the plasma (1). Viruses
have limited access to the CNS via cerebral vessels and re-
quire sufficient numbers of progeny to overcome the improb-
ability of contact and entry into a permissive cell. In rare
circumstances, such as disseminated neonatal herpes infec-
tion, virus infects the CNS after primary viremia. However,
most infect an intermediate tissue prior to reaching the CNS.
Viral genes may be as important as host physiology in de-
termining the route and degree of viral dissemination. For
example, the reovirus S1 gene determines the mechanism
of viral spread in the host. The S1 gene codes for a capsid
hemagglutinin, 1, that binds to neuron receptors. Serotypes
with an intact 1 gene spread to the CNS by neuronal path-
ways, whereas 1-deficient mutants gain access to the CNS
via the hematogenous route (42).
The liver and spleen provide ideal locations for secondary
viral replication because of their highly vascular structure.
The high degree of parenchymal contact and large number of
fixed mononuclear macrophage cells also provide an excellent
Scheld_Ch04.indd 55
55
opportunity for host eradication of viremia (1). Viruses infect
tissues other than the liver and spleen, such as muscle, endo-
thelium, and blood cells. These sites provide an environment
for viral replication in highly vascular locations that facilitate
extensive viremia. Secondary viremia produces high titers
of virus in the bloodstream for prolonged periods of time,
facilitating the seeding of target organs. Viral genetics and host
physiology determine the location and extent of infection at
these secondary sites (1).
Virus must localize in the vessels of the CNS before cross-
ing the bloodbrain or bloodCSF barrier, a network of tight
endothelial junctions sheathed by glial cells that regulate mo-
lecular access to the CNS (43). The pathophysiology of viral
transport from blood to brain and of viral endothelial cell tro-
pism is poorly understood. Virus infects endothelial cells, leaks
across damaged endothelium, passively channels through en-
dothelium (pinocytosis or colloidal transport), or bridges the
endothelium within migrating leukocytes (1). Cell-associated
and cell-free viruses can cross the endothelium and enter the
parenchyma or CSF. This bridging of the endothelium occurs
in choroid plexus vessels, meningeal blood vessels, or cerebral
blood vessels (1) (Fig. 4.4). Once in the CSF, virus may remain
limited to the meninges or may enter the brain parenchyma
across either ependymal cells or the pial linings.
Neuronal Spread
Rabies and HSV infection are prototypes of viral CNS infections
that access brain by peripheral neuronal spread. Historically,
the peripheral neural pathway was considered the only path-
way of viral neurologic infection. Experiments with HSV and
rabies virus performed in the nineteenth and early twentieth
centuries, combined with the discovery of the bloodbrain bar-
rier at the turn of the century, led most investigators to con-
clude that all viral neurologic infections occurred by neuronal
spread (1). Contemporary data, however, show that the blood-
stream provides the principal pathway for CNS infections in
humans. Some viruses (poliovirus and reovirus), previously
thought to infect the CNS by the hematogenous route, have
been detected in peripheral neurons in experimental models
(44). Viremia and neuronal spread to the CNS can occur con-
currently and are not mutually exclusive (1).
Neuronal spread occurs along peripheral or cranial
nerves. The nerve shields the virus from immune regulation
and allows access to the CNS. Rabies virus classically infects
by the myoneural route; however, infection has been docu-
mented from corneal transplantations, and aerosolized entry
has occurred following spelunking in caves contaminated
with infectious bat guano (29,45). These sources of infection
are infrequent and employ the same axonal mechanism of
spread within the nerve, albeit from a different location than
the myoneural route.
Rabies virus replicates locally in the soft tissue following a
rabid animal bite, although entry into sensory nerves prior to
soft tissue replication has also been documented (1). Protection
by antibody-mediated immune mechanisms in the soft tissue
provides the only known method of preventing neurologic dis-
ease and death (29). After primary replication, the virus en-
ters the peripheral nerve. Experimental evidence demonstrates
acetylcholine receptor binding as the mechanism of myocyte
entry (1). However, viruses have also been documented in cells
lacking these receptors. Once in the muscle, the virus buds
from the plasma membrane and may cross myoneural spin-
dles or enter the nerve by the motor endplate. The virus then
travels by anterograde and retrograde intraaxonal transport
to infect neurons in the brainstem and limbic system. Viruses
appear to cross the transsynaptic space between neurons by
2/21/14 5:30 PM
 56 Part II: Viral Infections and Related Disorders
Brain substance
CSF
Cerebral blood vessel
Nerve
CSF
From peripheral
nerve ending or
nasal mucosa
or dorsal CSF
root ganglion
passive transport rather than receptor-mediated transport.
Recent evidence suggests rabies virus enters projections in the
postsynaptic neuron that extend into invaginations on the pre-
synaptic side. These projections pinch off and fuse with the
presynaptic membrane, allowing the virus to spread along
motor or sensory neural pathways (1,45).
Paresthesias near the location of the animal bite and
change in behavior follow over the next weeks. These signs
and symptoms correlate temporally with the axoplasmic
transport of virus and infection of the brainstem and hippo-
campal region (1). The infection spares cortical regions during
this phase, allowing animals to vacillate between periods of
calm, normal activity and short episodes of rage and disorien-
tation (45). Eventually, the virus spreads from the diencephalic
and hippocampal structure to the remainder of the brain,
killing the animal. Experimental rabies infections in animals
demonstrate that the mode of acquisition influences the neu-
roanatomic location of initial infection (1).
Viruses also infect the CNS through cranial nerves. The
olfactory system is unique among cranial nerves in that the
neurons regenerate and have approximately a 1-month life
span. The olfactory neurons are not protected by the blood
brain barrier, theoretically providing direct neuronal access
to the brain (1). Animal studies have shown that HSV can
infect the brain through the olfactory system as well as the
trigeminal nerve. Moreover, the inferomedial temporal lobe,
the initial location of early HSV encephalitis, contains direct
connections with the olfactory bulb. The association of viral
latency in the trigeminal ganglia, the relative infrequency of
HSE, and the confusing data regarding encephalitis from HSV
reactivation suggest that the pathogenesis is more complex
than described earlier (1).
Host and Viral Factors Influencing
Neurotropism
As illustrated in Tables 4.3 and 4.4, viruses exhibit differences
in neurotropism (1). Strain and serotype differences influence
Scheld_Ch04.indd 56
Blood vessel in
choroid plexus
Ventricle
Pia
Ependyma
Meningeal blood FIGURE 4.4 Routes of viral invasion of
vessel the central nervous system. CSF, cerebro-
spinal fluid.
viral neuroinvasion and neurovirulence. For example, reovirus
types 1 and 3 produce different CNS diseases in mice based on
serotype differences in receptor affinities (1,42). Escape mutant
B4 of tick-borne encephalitis (TBE) virus also demonstrates
viral differences in mouse neuroinvasiveness. A single amino
acid substitution (Tyr to His) in domain 2 of viral surface
protein E eliminates viral neuroinvasiveness without affecting
neurovirulence (1). Receptor difference is only one determi-
nant of viral neurotropism. Other viral factors may influence
neurotropism. For example, enteroviruses in the same recep-
tor family produce very different diseases. Coxsackieviruses
B1 through B5 readily produce CNS infections, whereas type
B6 rarely produces neurologic infection. Viral genes influence
neurovirulence of HSV-1. Mutant HSV-1 viruses with either
134.5 gene deletions or stop codons inserted into the gene
have a decreased ability to cause encephalitis and death fol-
lowing intracerebral inoculation in mice as compared with
wild type virus (46,47). Upon entering mouse neuronal cells,
these 134.5 () mutants trigger the shutdown of protein syn-
thesis and elicit interferon signaling responses that limit ef-
ficient viral replication (48).
Host physiology is also important in determining the
extent and location of viral CNS disease. Age, sex, and ge-
netic differences between hosts influence viral infections and
clinical course. With respect to HSV infection, host muta-
tions in pattern recognition receptors important for type I
interferon production predispose patients to HSE (49). Host
age influences the clinical manifestations and sequelae of
a viral infection (50). Differences in outcome are twofold:
mature neurons resist virally induced apoptosis, and younger
patients can have more immature immune response to infec-
tion (51,52). Differences in macrophage function can alter
infections and disease. Moreover, macrophage processing
capacity can change with age in humans (1,38). Enteroviral
infections exemplify the difference that host physiology plays
in determining the extent of viral disease. Enterovirus infec-
tions in children younger than 2 weeks of age can produce
a severe systemic infection, including meningitis or menin-
goencephalitis (53). Ten percent of neonates with systemic
2/21/14 5:30 PM
 Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System 57

TA B L E 4 . 3
PROPOSED NEUROVIRULENCE FACTORS

Virus Viral Factor Effect

HSV-1 Viral 134.5 gene Decreased viral replication in neuronal tissue and
protein synthesis shutdown
Viral gE and gI glycoproteins Mutant viruses lacking these receptors do not
cause encephalitis
VZV Host cell-mediated immunosuppression Increased frequency of herpes zoster, visceral, and
disseminated cutaneous disease
CMV Viral Fc receptor protein Immune evasion: bind neutralizing antibodies
Virus binds 2-microglobulin Immune evasion
EBV Viral glycoproteins gp220 and gp350 Infect lymphocytes
Lassa fever virus Viral polymerase Changes the function of endothelium and platelets
Sindbis virus E2 envelope protein Neurovirulence receptor protein
Reovirus Viral proteins 1, 3, 1 Receptor proteins that influence CNS infection
Rabies virus Viral protein gG Major antigenic determinant, essential for
pathogenicity
Enterovirus Nucleotide 472 in the noncoding region Neurovirulence gene
Capsid proteins VP1 and VP3 Single amino acid changes in the capsid proteins
reduce neurovirulence
Measles virus M protein Deficiency of this protein inhibits release of virus
and is associated with SSPE
Tickborne encephalitis (TBE) virus Glycoprotein E (domain B) Neuroinvasiveness receptor domain
Murray Valley encephalitis virus Glycoprotein E (domain B) Neuroinvasiveness receptor domain
Louping ill virus Glycoprotein E (domain B) Neuroinvasiveness receptor domain

CMV, cytomegalovirus; SSPE, subacute sclerosing panencephalitis; VZV, varicella-zoster virus.

enteroviral infections die, and as many as 76% are left with
permanent sequelae (1). In older children, however, entero-
viral infections produce less severe disease. In addition to
age, physical activity may be another important host fac-
tor that determines the severity of infection. Exercise and
trauma have been associated with increased risk for paralytic
poliomyelitis and may result in an increased incidence of
enteroviral myocarditis and aseptic meningitis (1,54). The
frequency of infections in groups frequently reflects epidemi-
ologic differences in exposure. Increasingly, host differences
are recognized as equally important determinants of disease
at the cellular and molecular levels.

TA B L E 4 . 4
VIRAL NEUROTROPISM

Virus CNS Location

Herpes simplex virus (postnatal) Neurons in the inferomedial temporal lobe,

orbitofrontal areas
Varicella-zoster virus (postinfectious) White matter of the cerebellum
Cytomegalovirus Neurons, glial, ependymal, and subependymal cells
Epstein-Barr virus Cerebral blood vesselsvasculitis
Lassa fever virus Choroid plexus
Japanese encephalitis virus Brainstem and basal ganglia in humans, retinula cells
in mosquitoes
Rabies virus Neurons in the hippocampal, cerebellar,
mesencephalic areas
Mumps virus Ependymal and choroid plexus cells
Polyomavirus (immunosuppressed) Oligodendrocyte damage in subcortical white matter
Poliovirus Motor neurons in the anterior horn of the spinal cord
and brainstem

Scheld_Ch04.indd 57 2/21/14 5:30 PM

 58 Part II: Viral Infections and Related Disorders

Central Nervous System Physiology Arachnoid

The bloodbrain barrier limits chemical and environmental Subarachnoid

exposure to the CNS by a series of tight endothelial junctions
bound and maintained by glial cell foot processes. This barrier
provides a physiologic boundary between the metabolically
sensitive neuronal cells and the chemical changes outside the
CNS (43). In addition, the endothelial cells and tight junctions
provide a physical barrier to most pathogens, limiting viral
access to the CNS. As with most biologic systems, the blood
brain barrier is more complex and heterogeneous than previ-
ously imagined. The bloodbrain barrier was first described
during the late nineteenth and early twentieth century, when
scientists noted that various dyes administered intravenously
failed to penetrate the CNS (1). In the 1960s, experiments
certified that the tight junctions between endothelial cells
lining the cerebral vessels blocked the passage of small protein
molecules.
The tight junctions between endothelial cells provide
a relatively impermeable layer to most polar substances.
Unique transport systems and enzymes further distinguish
the CNS capillaries from blood vessels in other organs. The
asymmetric distribution of transport proteins in the endothe-
lial cell membrane creates a highly resistant, polarized cell
layer that limits paracellular diffusion (55). Hydrophilic sub-
stances cross the endothelial layer through receptor-mediated
endocytosis or through highly specific, saturable transport
systems. Respiratory gases and lipophilic chemicals passively
penetrate the layer of tight junctions readily. The cerebral
vessel endothelial cells also possess second-messenger mole-
cules that may regulate transmembrane permeability through
receptor binding (55). Substances produced during infection
or chemicals secreted by cells, such as histamine and inter-
leukins, change the permeability of the bloodbrain barrier,
thus modulating entry of viruses and immune cells into the
CNS. Astrocytes are metabolically important support cells
of mononuclear macrophage origin that surround cerebral
capillaries, induce tight junctions, and may regulate immune
cell entry (1).
space
Pia
Subpial
space
Blood vessel
Glia
limitans Perivascular
macrophage
Virchow-Robin
space
FIGURE 4.5 The relationship of the Virchow-Robin space to the sub-
pial and subarachnoid space.
The brain is an immunologically privileged site into
which immune cells do not readily enter. Increasingly, scien-
tists are discovering that immune cells reside in and circulate
through the Virchow-Robin space, a lymphatic channel lining
the perivascular space in the brain (1) (Fig. 4.5). Moreover,
many of the fixed glial support cells and pericytes surrounding
the vessels in the CNS can transform to monocyte/macrophage
antigen-presenting cells. The circulating lymphocytes act as
surveillance cells, detecting small amounts of antigen presented
by the macrophages in the perivascular space and initiating the
immune response either within the Virchow-Robin space or
peripherally at the lymph node. During periods of infection,
immune cells readily enter the CNS and fill the Virchow-Robin
space (1) (Fig. 4.6). The perivascular space provides a staging
area where lymphocytes interact chemically and differentiate
prior to entering the neuropil. Cells in the perivascular space
as well as cerebral capillary endothelial cells are capable of

Virchow-Robin space Enlarged Virchow-Robin

around CNS blood vessel- space around
resting state CNS blood vessel-
state during reaction
to intra-CNS immune
Some macrophages stimulation
containing antigen
migrate to lymph node
T cells stimulated
to respond
T and B
lymphocytes
activated

Virchow-Robin space Macrophage

T cells Plasma cells

Perivascular
macrophage

Rare Microglia
lymphocyte
Plasma cells

FIGURE 4.6 Illustration of the Virchow-Robin space as an immunologic space that can become expanded
with immunocompetent cells interacting together under conditions of immunostimulation in the brain.

Scheld_Ch04.indd 58 2/21/14 5:30 PM

 Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System
regulating T-helper cell subsets in vitro and may influence the
expression of the immune response, dictating which cells enter
the CNS. Different viruses may activate characteristic lympho-
cyte subsets for entry into the parenchyma. In some cases, the
immune response is instrumental in the pathogenesis of CNS
damage (1,51,56,57).
VIRAL REPLICATION IN THE
CENTRAL NERVOUS SYSTEM
The fundamental principles of viral replication and cell-to-cell
spread provide a framework for examining the pathogenesis
and clinical repercussions of neurologic infections. The clini-
cal manifestations and the severity of illness reflect the loca-
tion and extent of viral replication in the CNS. Once virus
accesses the CNS, it must introduce its genome and transport
proteins into the cytoplasm or the nucleus of the mammalian
cell. Once the viral genome has been uncoated, transcription
and translation proceed in a predictable and organized cas-
cade of gene expression, culminating in the replication of the
viral genome. Translation of late viral genes produces struc-
tural proteins essential for the construction of the next gen-
eration of viruses. Viral genomic material is packaged with
structural proteins and exits the cell (1) (Fig. 4.7). Viruses
exploit essential cell activities such as protein synthesis, in-
tracellular transport, and cellular communication to enter the
cell and replicate their genome. As in other biologic systems,
both divergent and convergent evolution has resulted in an
array of mechanisms for successful viral reproduction. As a
result, numerous strategies exist for viral entry, gene expres-
sion, replication, assembly, and egress (1). The relative speed
and efficiency with which the virus replicates determine the
progression of infection.
1 Attachment
2 Penetration (endocytosis)
3 Uncoating
4 Transcription of mRNA
5 Translation of early proteins
6 Replication of viral DNA
7 Transcription of mRNA
8 Translation of late proteins
9 Assembly of virions
10 Release by budding
FIGURE 4.7 The viral multiplication cyclea stylized and greatly
simplified diagram summarizing the key steps in the multiplication of
a typical DNA virus. (From Fenner F, White DO. Medical Virology.
2nd ed. Orlando, FL: Academic Press; 1986, with permission.)
Scheld_Ch04.indd 59
59
Attachment and Entry
Attachment is an essential first step in viral infection. Multiple
copies of proteins line the surface of a virus. These capsid or
envelope proteins create high-affinity bonds with host recep-
tors and initiate viral infection or a host cell response (58,59).
Classically, this response involves viral entry but may include
a change in cellular metabolism or generation of immune
responses by the cell. Temperature, pH, receptor affinity, and
the concentration of viral and host receptors influence the
hostviral receptor interaction similar to a receptor-ligand
reaction. The cell receptor consists of proteins, lipids, and/
or oligosaccharides. Receptor binding provides close contact
between virus and cell, facilitating but not ensuring viral entry
into the cell. Some viruses require specific chemical or proteo-
lytic conditions before entering the cell (6062). For example,
Semliki Forest virus requires the presence of cholesterol in the
cell membrane as well as a pH change in the endosome for
entry (63). The presence of one type of receptor for cell entry
does not preclude other mechanisms of entry into a host cell.
Viral entry into the cell is essential. Although receptors have
been identified, alternative entry mechanisms are being identi-
fied for viruses (64). Studies determining the structure of viral
glycoproteins and host receptor interactions as well as experi-
ments using viral recombinants and cell lines expressing cellular
receptors provide two methods used to characterize viral entry.
Viruses can bind nonspecifically to the cell surface; however,
these nonspecific interactions do not produce a biologic re-
sponse. Viruses frequently target essential and/or tightly con-
served host receptor domains. Some viruses appear to interact
with neurotransmitter receptors in the CNS. Experimental data
indicate that rabies virus binds to acetylcholine receptors on
mouse myocytes (1). Reovirus 3 binds to the -adrenergic recep-
tor. Viruses also bind to immunologic proteins on the surface of
cells. Poliovirus, HSV, and measles virus bind to receptors in the
immunoglobulin superfamily (65,66). Hormone and cytokine
receptors provide additional targets for viral cell entry. Viruses
can have more than one mechanism for entering a cell or differ-
ent receptors for different cell types (1). The number and distri-
bution of receptors help determine viral tissue tropism and the
extent of viral CNS disease. Receptor prevalence is not the only
determinant of viral tissue tropism (1). Transgenic mice, for
example, develop poliovirus infection only in limited tissue sites
despite the widespread expression of the receptor. Some viruses
require the presence of certain genes and transactivating factors
to infect a cell. While a cell may contain a certain receptor, a
permissive environment for viral replication may not exist. The
tissue, in such a case, is resistant to infection (67).
Enveloped viruses have different mechanisms than nonen-
veloped viruses for cell entry. Once the virus binds to the host
cell receptor domain, the virus can enter the cell by direct fu-
sion or receptor-mediated endocytosis. The receptor-bound
virus frequently becomes encased in a clathrin-coated pit during
endocytosis. Other modes of endocytosis exist, and virus has
been found in uncoated vesicles (1,68). Fusion proteins contain
hydrophobic regions and initiate the union of viral and cell mem-
branes in some enveloped viral infections. Nonenveloped viral
entry is more enigmatic. Conformational changes or proteolytic
cleavage may expose hydrophobic regions of capsid proteins,
enabling the protein capsid to fuse with or embed in the cell
membrane. The capsid then opens and releases the viral genome
into the cytoplasm. Endocytosis may provide the pH change or
enzymes necessary for viruscell fusion and ensures that the cell
is metabolically viable. Furthermore, it has been suggested that
endocytosis delivers the viral genome to the proper intracellular
location from which replication occurs. Viral fusion, in most
cases, occurs before the endosome fuses with the lysosome.
2/21/14 5:30 PM
 60 Part II: Viral Infections and Related Disorders
Replication and Egress
Viral replication begins after uncoating and delivery of the
genome to a satisfactory intracellular location (68). Viruses
replicating in the nucleus often contain nuclear targeting sig-
nals and can use existing cellular mechanisms to enter the
nucleus (1). Alternatively, viruses that replicate in the cyto-
plasm uncoat and deliver the genome to the perinuclear area
(68). The production of positive stranded viral messenger RNA
(mRNA) and the subsequent translation of gene products pro-
vide a unifying pathway for viral infections (Fig. 4.8). Viruses
use either host enzymes or specialized viral polymerases car-
ried with or encoded by the viral genome.
Host protein synthesis decreases at the start of viral protein
synthesis in most viral infections. Viruses have unique mecha-
nisms for inhibiting protein synthesis and can interfere with
the translation, transport, ribosomal binding, or stability of
host transcripts (1). With some viruses, premade proteins and
synthesized viral gene products decrease the transcription of
host mRNA (6971). Cellular transport of mRNA out of the
nucleus is inhibited late in adenovirus infections. Viral mRNA
copies can outnumber host mRNA or can be more efficiently
transcribed, thus restricting access to ribosomes (1). For ex-
ample, poliovirus inactivates the host cap-binding protein.
This alters the cells ability to modify transcripts and results
in less efficient translation of host proteins (1). Degradation
of host mRNA is another mechanism used by some HSV to
inhibit host protein synthesis (71). Some viral gene factors act
as repressors and inhibit host mRNA export (70).
Viral protein translation occurs in a stereotyped progres-
sion. Early gene expression regulates the transcription and
translation of the remaining viral genome, inhibits host pro-
tein and nucleic acid synthesis, and codes for enzymes neces-
sary for viral nucleic acid replication (1). After viral nucleic
acid replication, late viral genes are selectively expressed and
transcribe templates for capsid and structural proteins nec-
essary for virion assembly. Proteins synthesized from viral
transcripts can undergo posttranslational modification and
 DNA
Parvovirus
glycosylation (72). Viruses contain regulatory proteins and
promoter sequences that control the differential expression of
transcripts. Proteolytic modifications are made to the struc-
tural protein following attachment of fatty acids and oligo-
saccharides in the Golgi apparatus (1). In some cases, these
proteolytic changes are necessary for producing infectious
progeny. TBE virus, for example, requires cleavage of a mem-
brane-bound precursor protein (prM). The proteolytic change
produces a small, membrane-bound protein (M protein) that
protects another membrane-bound protein from conforma-
tional changes in the acidic secretory pathway. Viruses that
contain the uncleaved prM moiety lack fusion capability and
are noninfectious (1).
Replication of the viral genome involves the synthesis of
full-length, complementary genomic transcripts that act as
templates for replication of the viral genome. The efficiency
and fidelity of genomic replication influence the likelihood of
disease. Defects in the viral genome cause abortive replication
or result in conditionally defective viruses that multiply only in
the presence of cells or viruses carrying complementary genes.
The newly synthesized progeny genomes are transported
to capsid structures, where they enter viral capsid shells.
Enveloped viruses bud from the cell membrane, whereas non-
enveloped viruses exit the cell by lysis (1).
Viral Spread in the Central Nervous System
Viral disease of the CNS requires cell-to-cell spread of the
virus. The densely packed neuropil provides a unique envi-
ronment with limited extracellular space for viral dispersion.
Viruses can spread through the CNS in four prototypical ways:
(a) sequential cellular infection, (b) movement in the extracel-
lular space, (c) neuronal axoplasmic transport, or (d) transit
via migrating lymphocytes or glial cells. Viruses may spread
within the neural tissue using more than one mechanism.
Few viruses infect the CNS by contiguous cell-to-cell spread.
Sindbis virus provides one example of a virus that spreads
from ependymal cells directly to glial and neuronal cells in
experimentally infected mice (1). Viruses exhibit cell tropism,
frequently infecting one cell type more readily than another.
For example, HSV-1 infects neurons early during encephali-
tis but is not present in glial cells until late in the infection.
Herpesvirus spreads in the nervous system via axoplasmic
transport in neurons (73,74). Electron microscopy has dem-
 RNA  DNA  DNA onstrated togaviruses within extracellular space in the CNS.
Retrovirus Some viruses enter the CNS through a Trojan horse mecha-
Papovavirus nism via leukocytes (1,75).
Adenovirus
Herpesvirus
Poxvirus
Hepadnavirus Host Defense and Immunopathogenesis
Intrinsic and systemic antiviral defenses limit viral replica-
Picornavirus
 RNA
tion and infection (44,51,76). Viral replication can activate
Togavirus  mRNA
Coronavirus Reovirus enzymatic pathways that degrade viral nucleic acid tran-
scripts. Other cells undergo apoptosis, creating a nonviable
Orthomyxovirus environment for the virus (1). Interferon-mediated intrinsic
Paramyxovirus antiviral pathways within cells can retard viral penetration,
Arenavirus uncoating, transcription, translation, and assembly, represent-
Bunyavirus ing an important factor of host resistance to viral infection
Rhabdovirus (1,7779). Interferonstype I (interferon-
and interferon-),
type II (interferon-), and type III (interferon-)are secreted
by distinct cells, bind to different receptors, and represent
 RNA evolutionarily distinct molecules that limit viral replication
FIGURE 4.8 Six basic strategies for transcribing messenger RNA from (44,8084). Interferons activate a cascade of enzymes and ki-
different types of viral genome. (From Baltimore D. Expression of ani- nases that inhibit protein synthesis at different steps in the syn-
mal virus genomes. Bacteriol Rev. 1971;35:235, with permission.) thetic pathway. Interferons also modify the binding properties,

Scheld_Ch04.indd 60 2/21/14 5:30 PM

 Chapter 4: Pathogenesis and Pathophysiology of Viral Infections of the Central Nervous System
electrostatic charge, and receptor expression (major histocom-
patibility complex [MHC] antigen, 2-microglobulin, and Fc
receptor) of cellular membranes, further restricting viral access
and replication (1). These cytokines can enhance or suppress
expression of immune cell subsets (82,85). Although interferon
can protect host cells from viral infection, some pathogens
have developed resistance. Furthermore, the inflammatory re-
sponse in some cases causes damage to tissue and constitutes a
pathogenic mechanism for viral disease (57).
The presence of viral envelope proteins in the host cell
membrane elicits an immunologic response. The host immune
response targets and destroys the infected CNS cells, thus lim-
iting spread of the virus but potentially compounding disease.
For example, rabies virus causes metabolic derangement in the
neuron, usurps the cellular metabolic machinery, and inhibits
the synthesis of cellular proteins (1). The actual pathogenic
-helical form of the PrP protein results in a protease resis-
cause of neuronal cell death is not known but may involve
the synthesis of toxic metabolites by rabies virus. The immune
response changes the character of disease and the pathologic
findings. In paralytic or dumb rabies, patients have disease lim-
ited to the brainstem and demonstrate reduced B-cell, interleu-
kin, and cellular activity in response to rabies antigens (86,87).
Patients with furious or classic rabies generate brisk, late intra-
cranial immune responses to rabies antigens. An experimental
model, involving immunosuppression, demonstrates that this
late immune response compounds CNS damage in infected
animals (1).
In postinfectious encephalitis, the immune response is misdi-
rected against the brain itself. There is no evidence of direct viral
damage or viral antigens in the CNS (1). Viral antigens can share
homology with host proteins, and the ensuing immune reaction
can damage normal host tissue resembling virally infected cells
(7,88). Immune deregulation may cause immune-mediated
demyelination. For example, most patients with (post-Semple)
rabies vaccine encephalitis have antibodies against myelin basic
protein. Forty-seven percent of people with postinfectious
measles encephalitis have lymphocytes directed against myelin
basic protein, as compared with a 15% rate in nonencephalitic
patients with measles (1). The pathogenic mechanism of postin-
fectious encephalitis is not fully understood.
HIV infection is associated with a variety of CNS diseases.
Patients can develop a leukoencephalopathy with diffuse glio-
sis and loss of the cerebral white matter in addition to the
opportunistic infections and neoplasms associated with the
disease (51,56,89,90). Pathologic specimens show a multifocal
accumulation of giant cells with focal cerebral necrosis. PCR
in tissue samples demonstrates large amounts of HIV nucleic
acids in multinucleated giant cells. The viral structural and/
or regulatory proteins may be toxic to the CNS tissue (91).
Alternatively, macrophages and T lymphocytes may dam-
age the brain by aberrant secretion of interleukin and tumor
necrosis factor (1).
Transmissible Spongiform Encephalopathies
The TSEs produce clinical changes related to CNS dysfunc-
tion similar to the encephalitides (1). Unlike encephalitis, the
TSEs are slowly progressing noninflammatory CNS diseases
with long incubation periods involving the accumulation of
an abnormal form of a normal glycoprotein, the prion protein
(PrP) (92). Sporadic CJD occurs between the ages of 50 and
70 years and is characterized by dementia, tremors, and more
rarely abnormal movements and ataxia. Unlike sporadic CJD,
vCJD disease affects young adults and adolescents and pro-
duces cerebellar ataxia and sensory involvement (dysesthesias)
with florid amyloid plaques detected in the brain on autopsy
(5). Neurologic deterioration progresses relentlessly in the case
Scheld_Ch04.indd 61
61
of vCJD and most patients die less than a year after onset of
their neurologic manifestations.
These encephalopathies differ in mode of transmission.
Although most of the TSEs are experimentally transmissible
by direct inoculation in the CNS, this mode rarely occurs
except for iatrogenic transmissions (1). The scrapie agent
spreads by contact and lateral transmission. There is no evi-
dence for lateral transmission in the case of BSE or vCJD,
and all cases appear to have occurred following parenteral
or ingestion of affected materials. The transmissible agents
remain infectious after treatments that would normally in-
activate viruses or nucleic acids (detergent formalin, ionizing
radiation, nucleases). Most of the experimental work on TSEs
has involved analysis of the scrapie agent. The current work-
ing model is that posttranslational alteration of the normally
tant -pleated sheet structure that accumulates in neurons,
leading to progressive dysfunction, cell death, and subsequent
astrocytosis. In studies on the scrapie agent, gastrointestinal
tract involvement with infection of abdominal lymph nodes
occurs first, followed by brain involvement a year or more
later. Experimental subcutaneous inoculation in mice and
goats also lead to local lymph node involvement followed
by splenic spread and then CNS involvement. The mode of
transmission to the CNS (direct vs. hematogenous) or the in-
fectivity of body fluids at different stages of infection is not
known at this time.
The TSEs are currently only diagnosed by histologic ex-
amination, characteristic electroencephalography (EEG),
magnetic resonance imaging (MRI) changes, and the clini-
cal context. Most laboratory tests are of little value in the
diagnosis. CSF examination shows normal values or slightly
elevated protein levels. The EEG in classic CJD reveals gen-
eralized slowing early in the disease, punctuated by biphasic
or triphasic peaks late in the disease with the onset of myoc-
lonus. MRI changes late in the illness reveal global atrophy
with hyperintense signal from the basal ganglia (5). Fluid-
attenuated inversion recovery (FLAIR) MRI provides greater
sensitivity and demonstrates signal intensity changes in the
cortex that are undetectable by T2-weighted spin-echo MRI.
Histopathologic examination of the brain using a specific an-
tibody to the PrP-res protein confirms the disease. In addition,
evidence of gliosis, neuronal loss, and spongiform changes
support the diagnosis. In cases of vCJD, characteristic amy-
loid plaques (so-called florid plaques) microscopically define
the disease. The florid plaques are not seen in other TSEs and
consist of flower-like amyloid deposits surrounded by vacu-
olar halos. The detection of PrP-res in the tonsillar tissue by
immunohistochemical staining is also strongly supportive of
vCJD diagnosis (5).
Clinical Correlates to Disease
Patients with encephalitis have clinical and laboratory evidence
of parenchymal disease. Some viruses (rabies, B virus) produce
encephalitis without significant meningeal involvement; how-
ever, most patients with encephalitis have concomitant men-
ingitis (1). Most patients also have a prodromal illness with
myalgias, fever, and anorexia reflecting the systemic viremia.
Neurologic symptoms can range from fever, headache, and
subtle neurologic deficits or change in level of consciousness
to severe disease with seizures, behavioral changes, focal neu-
rologic deficits, and coma (93,94). Clinical manifestations
reflect the location and degree of parenchymal involvement
and differ based on viral etiology. For example, HSE infects
the inferomedial frontal area of the cortex, resulting in focal
seizures, personality changes, and aphasia. These symptoms
2/21/14 5:30 PM
 62 Part II: Viral Infections and Related Disorders
reflect the neuroanatomic location of infection with inflamma-
tion near the internal capsule, limbic, and Broca regions (1).
Paresthesias near the location of the animal bite and change in
behavior correlate temporally with the axoplasmic transport
of rabies and the viral infection of the brainstem and hippo-
campal region (94). Rabies has a predilection for the limbic
system, producing personality changes. The damage spares
cortical regions during this phase, allowing humans to vacillate
between periods of calm, normal activity and short episodes of
rage and disorientation (1). Alternatively, Japanese encephali-
tis virus initially produces a systemic illness with fever, malaise,
and anorexia, followed by photophobia, vomiting, headache,
and changes in brainstem function. Brainstem encephalitis
leads to difficulty with autonomic functions with increased
risk for cardiac and respiratory instability, reflecting infection
of brainstem nuclei (1,9597). Other patients have evidence of
multifocal CNS disease involving the basal ganglia, thalamus,
and lower cortex and develop tremors, dystonia, and parkin-
sonian symptoms.
Seizures are frequent during encephalitis. For example,
approximately 40% of patients with HSE develop seizures
(1). EEG patterns include focal slowing, spiking, and par-
oxysmal lateralizing epileptiform discharges. The cellular
mechanisms for seizures are incompletely understood. This
may result from dysfunction of the smaller, inhibitory, -
aminobutyric acid (GABA)secreting neurons. Although the
seizures encountered in patients with HSE could be directly
attributed to cellular destruction, an alternative hypothesis
for epileptogenesis in HSE centers on the uptake of virus in
the long projections of neurons. This uptake causes pertur-
bations in the cellular machinery necessary for the retention
of acetylcholine within the nerve terminal. As a result, the
excitatory neurotransmitter could leak from the cell and ul-
timately trigger a seizure focus. In addition to this mecha-
nism, suboptimal uptake of acetylcholine by malfunctioning
presynaptic and postsynaptic terminals can result in a rela-
tive excess of the neurotransmitter and abnormal electric dis-
charges. An excess of acetylcholine could also result from the
decreased synthesis of degradatory enzymes (such as acetyl-
cholinesterase) as viral replication proceeds. Finally, chronic
seizure foci are known to be hypermetabolic during interictal
periods. The first stage of viral cellular infection is the in-
hibition of the cells homeostatic mechanisms. The crippled
cell, unable to maintain homeostasis, may be predisposed to
disordered electric discharges (1).
Encephalitis, unlike meningitis, has higher mortality and
complication rates. Case-fatality rates differ based on the viral
etiology and host factors. For example, within the arthropod-
borne viral encephalitides, St. Louis encephalitis virus has an
overall case mortality rate of 10%. The mortality rate is only
2% in children but increases to 20% in the elderly (1). Similarly,
WNV meningoencephalitis produces greater mortality rates in
the elderly than in younger adults (98,99). Other viruses like
western equine and eastern equine encephalitis produce higher
mortality and morbidity in children than in adults (1).
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93. Sejvar JJ, Marfin AA. Manifestations of West Nile neuroinvasive disease.
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94. Laothamatas J, Sungkarat W, Hemachudha T. Neuroimaging in rabies.
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95. Jereb M, Lainscak M, Marin J, et al. Herpes simplex virus infection lim-
ited to the brainstem. Wien Klin Wochenschr. 2005;117(1314):495499.
96. Gelpi E, Preusser M, Garzuly F, et al. Visualization of Central European
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97. Ayukawa R, Fujimoto H, Ayabe M, et al. An unexpected outbreak of
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98. Murray K, Baraniuk S, Resnick M, et al. Risk factors for encephalitis
and death from West Nile virus infection. Epidemiol Infect. 2006;134(6):
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99. LaBeaud AD, Lisgaris MV, King CH, et al. Pediatric West Nile virus
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100. Padate BP, Keidan J. Enteroviral meningoencephalitis in a patient with
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101. Lee BE, Chawla R, Langley JM, et al. Paediatric Investigators Collaborative
Network on Infections in Canada (PICNIC) study of aseptic meningitis.
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102. Gorander S, Andersen O, Leiram B, et al. Multiphasic encephalomyelitis
in a patient with recurrent herpes simplex type 2 meningitis. Scand J Infect
Dis. 2006;38(10):942925.
103. Kupila L, Vuorinen T, Vainionpaa R, et al. Etiology of aseptic meningitis
and encephalitis in an adult population. Neurology. 2006;66(1):7580.
104. Tyler KL. Herpes simplex virus infections of the central nervous system: en-
cephalitis and meningitis, including Mollarets. Herpes. 2004;11(suppl 2):
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105. Kumar S, Kumar S, Kohlhoff SA. Recurrent HSV-2 meningitis in a 9-year-
old girl. Scand J Infect Dis. 2006;38(67):570572.
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plex virus type 2-induced meningitis. J Infect Dis. 1990;162(2):322330.
2/21/14 5:30 PM
 CHAPTER 5 VIRAL MENINGITIS AND
ASEPTIC MENINGITIS SYNDROME
JOS R. ROMERO

Viral meningitis can be characterized as a central nervous sys-
tem (CNS) viral infection with signs of meningeal irritation
(neck stiffness, Kernig and/or Brudzinski signs) and cerebro-
spinal fluid (CSF) pleocytosis but without neurologic dysfunc-
tion due to brain parenchymal involvement (1). It differs from
viral encephalitis where evidence of brain parenchymal dys-
function is manifested by an altered state of consciousness,
change in personality, or other objective signs of neurologic
dysfunction (e.g., seizures, cranial nerve palsies, abnormal
reflexes, paralysis, etc.). Although it is common to discuss the
two as wholly separate entities, it is important to note that
overlap between them (i.e., meningoencephalitis) does occur
following infection with many viral agents.
Almost 100 years ago, Wallgren (2) introduced the term
acute aseptic meningitis to describe a short-lived, self-limited,
benign CNS syndrome characterized by the acute onset of the
signs of meningeal irritation in which examination of the CSF
revealed a mononuclear pleocytosis and the absence of bacte-
ria on direct examination and by culture. In addition, no para-
meningeal process, acute/chronic systemic infectious disease,
or community infectious disease could be identified that could
produce the syndrome. With advances in diagnostic method-
ologies, it became evident that multiple infectious agents (e.g.,
Lyme disease), inflammatory conditions, drugs, environmental
agents, and so forth could cause the syndrome.
It is estimated that in the United States, the annual num-
ber of aseptic meningitis cases is at least 75,000. Viruses
account for the overwhelming majority of cases (Table 5.1).
Early reports indicated that mumps virus, lymphocytic cho-
riomeningitis virus (LCMV), and poliovirus (PV) were the
major identifiable causes of aseptic meningitis (3). As diag-
nostic techniques improved as a result of the development of
cell culture, the enteroviruses were shown to have a major
role in causation of syndrome (Table 5.2) (4,5). Nucleic acid

TA B L E 5 . 1
CAUSES OF THE ASEPTIC MENINGITIS SYNDROME AND CURRENT RELATIVE INCIDENCES

Common Rare
Viruses Viruses
Enteroviruses Herpes simplex virus type 1
Parechoviruses Varicella-zoster virus
Tick-borne encephalitis virusa Cytomegalovirus
Arbovirusesa Epstein-Barr virus
Herpes simplex virus type 2 Influenza A and B viruses
Bacteria Parainfluenza viruses
Borrelia burgdorferi (Lyme disease)a Human herpesvirus type 6
Partially treated bacterial meningitis (common pathogens) Measles virus
Parameningeal bacterial infection Rotavirus
Other Coronavirus
Kawasaki disease Encephalomyocarditis virus
Uncommon Parvovirus B19
Viruses Other
Mumps Brucella species
Lymphocytic choriomeningitis virus Mycoplasma hominis
Human immunodeficiency virus Mycoplasma pneumoniae
Bacteria Toxoplasma gondii
Mycobacterium tuberculosis Fungi (many)
Leptospira speciesa Autoimmune disorders
Other Behet syndrome
Fungi,a including Cryptococcus neoformans, Coccidioides Drugs (including immunomodulators, antibiotics)
immitis, Histoplasma capsulatum, Candida species, Malignancy
Blastomyces dermatitidis

a
Incidence varies greatly with geographic region.

65

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 66 Part II: Viral Infections and Related Disorders

TA B L E 5 . 2
VIRAL CAUSES OF ASEPTIC MENINGITIS IN SELECTED LARGE SERIES

Viruses Identified, %

Investigators No. Consistent

(Reference No.) Years Cases PV NPEV Arboviruses Mumps Herpes LCMV Other None Methodologya

Adair, Gauld, 194752 480 13.3 5.3 9.7 no 74.8 yes

and Smadel (3)
Meyer et al. (11) 195358 430 8.8 29.8 0.7 15.8 1.4 8.8 no 29.0 yes
Lennette, 1958 368 2.0 57.0 9.0 1.0 yesb 31.0 yes
Magoffin, and
Knouf (5)
Buescher, 195863 374 4.8 38.5 0.8 7.5 0.5 1.9 yesc 43.5 yes
Artenstein, and
Olson (12)
Berlin et al. (96) 198690 274 0.007 61.3 yesd 38.4 yes

LCMV, lymphocytic choriomeningitis viruses; NPEV, nonpolio enteroviruses; PV, polioviruses.

a
Virologic and/or serologic studies performed by a single laboratory with most or all specimens subjected to all tests.
b
1% adenovirus.
c
1% each measles, Epstein-Barr, influenza A.
d
1% adenovirus (1 case).

amplification tests (NAATs) have bolstered this finding and led
to the identification of novel causes (6).
The incidence of aseptic meningitis is influenced by many
factors, including effective vaccine programs, sanitation, pov-
erty, and regional endemic viruses (710). Previous significant
causes of viral meningitis such as PVs, mump virus, and LCMV
are now rare or infrequent as a result of effective vaccines, san-
itation, or improved housing (3,5,8,1113). Although many of
the infectious causes of aseptic meningitis are reportable (14),
the true incidence of the syndrome is unknown due to incom-
plete reporting, failure to test for specific agents, and because
aseptic meningitis is not a reportable condition. In Finland,
a 14-year birth cohort study found the annual incidence of
viral meningitis in children younger than 14 years of age to
be 27.8 per 100,000 (15). A more recent study from Greece
documented the annual incidence of aseptic meningitis to be
17 per 100,000 in children younger than 14 years of age (16).
Two studies from the United States give widely discrepant es-
timates of the incidence of aseptic meningitis. A 32-year (1950
to 1981) study from Olmsted County, Minnesota found that
the adjusted incidence rate of aseptic meningitis was 10.9 per
100,000 person-years (range 7.9 to 17.8 per 100,000) (8,13).
The Centers for Disease Control and Prevention reported that
the national incidence for aseptic meningitis ranged from 1.5
to 4.0 per 100,000 for the period spanning 1971 to 1981 (17).
The lower incidence in the latter report is most likely the re-
sult of passive surveillance and, therefore, underreporting. The
incidence of aseptic meningitis is greater in males and in chil-
dren, particularly those younger than 1 year of age (8,15,16).
ENTEROVIRUSES
Virology and Pathogenesis
The enteroviruses (EVs) are one of six genera (Enterovirus, Car-
diovirus, Cosavirus, Hepatovirus, Parechovirus, and Kobuvirus)
in the Picornaviridae (pico, small; rna, ribonucleic acid;
viridae, viruses) family of viruses known to cause disease in
humans. The original classification of the EVs, based on evidence
of human origin, pathology in animal models, patterns of replica-
tion in cell culture, and physicochemical characteristics, identified
72 serotypes (18). This schema, although initially useful, resulted
to the misclassification of several EV and inclusion of several non-
EV into the genus (19). The development of experimental and
computational methodologies for the study of the molecular biol-
ogy and genomic analysis of the EV allowed for refinement in the
classification of and identification of the EVs.
Currently, identification and classification of the EVs
is based on the nucleotide sequence of VP1, the largest and
most surface exposed of the viral capsid proteins containing
important neutralizing epitopes (2023). Using this approach,
the EVs have been speciated into four groups (enterovirus A
to D) containing more than 100 serotypes (Table 5.3) (24).
In addition, this approach has revealed that several of the
traditional EV serotypes are actually strains of the same se-
rotype or are not genetically related to the EVs (echoviruses 22
and 23) (20,21,2527).
The EVs are nonenveloped viruses 30 nm in diameter with
a buoyant density of 1.30 to 1.34 g/cm3 in caesium chloride
(CsCl) (19). The lack of an envelope confers to them relative
environmental stability where they can survive for days at
room temperature. Infectivity can be preserved for weeks at
20C or with little or no loss of infectivity for years when
stored at 70C. Similarly, the lack of a lipid envelope renders
them insusceptible to ether, chloroform, and alcohol. The EVs
are inactivated by heating to greater than or equal to 50C,
chlorine, and formaldehyde.
The capsid of all EVs is composed of 60 units each of four
structural or capsid proteins: VP1 to VP4, alternatively known
as 1A to 1D, arranged so as to give the virion icosahedral sym-
metry (2833). Each of proteins VP1 to VP3 is wedge-shaped
and composed of an eight-stranded antiparallel -barrel core.
Each of the stands is connected to the next by intervening loops
that determine antigenicity, receptor specificity, and confer cap-
sid stability (34). The basic structural element of the viral capsid,
the protomer, is initially composed of the proteins VP0, VP1,

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 Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 67

TA B L E 5 . 3
HUMAN ENTEROVIRUS AND PARECHOVIRUS SEROTYPES

Genus: Enterovirus

Species Serotype

Enterovirus A CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8,

(18 serotypes) CV-A10, CV-A12, CV-A14, CV-A16,
EV-A71, EV-A76, EV-A89, EV-A90, EV-A91, EV-A92, EV-A114
Enterovirus B CV-A9,
(59 serotypes) CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6,
E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20,
E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E-32, E-33,
EV-B69, EV-B73, EV-B74, EV-B75, EV-B77, EV-B78, EV-B79, EV-B80, EV-B81, EV-B82, EV-B83,
EV-B84, EV-B85, EVB-86, EV-B87, EV-B88, EV-B93, EV-B97, EV-B98, EV-B100, EV-B101,
EV-B106, EV-B107, EV-B110
Enterovirus C PV-1, PV-2, PV-3,
(21 serotypes) CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, CV-A24,
EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105,
EV-C109, EV-C113, EV-C116
Enterovirus D EV-D68, EV-D70, EV-D94, EV-D111
(4 serotypes)

Genus: Parechovirus

Human parechovirus HPeV- 1, HPeV-2, HPeV-3, HPeV-4, HPeV-5, HPeV-6, HPeV-7, HPeV-8, HPeV-9, HPeV-10, HPeV-11,
(16 serotypes) HPeV-12 HPeV-13, HPeV-14, HPeV-15, HPeV-16

CV, coxsackievirus; E, echovirus; EV, enterovirus; PV, poliovirus; HPeV, human parechovirus (24).

and VP3 (35). Five protomers self-assemble to form a pentamer.
Twelve pentamers, in turn, assemble around a single strand of
viral RNA to produce the immature virion. The cleavage of VP0
to yield VP2 and VP4 completes the formation of the mature vi-
rion. VP1 to VP3, and in particular VP1, have surface-exposed
amino acids which determine the antigenic diversity and the re-
ceptor specificity of the EV (20,33,36,37). VP4 is not surface ex-
posed but shares close association with the viral RNA and plays
a vital role in release of the genome after viral attachment (38).
The surface topographies of the various EVs share a num-
ber of similarities. These include a plateau or mesa located at
the fivefold axis of symmetry formed by the union of five pro-
tomers. Surrounding this plateau is a deep cleft or canyon into
which a viral receptor inserts when the EV encounters a sus-
ceptible host cell (36). Additionally, the host immune response
to EV infection generates serotype-specific antibodies directed
to antigenic sites around the fivefold axis and canyon walls,
thus blocking viral-host receptor interaction and infection.
Lastly, beneath the canyon floor exists a hydrophobic pocket
containing a lipophilic factor. This pocket has been the target
for the development of anti-EV drugs that result in altered re-
ceptor binding and viral uncoating (39,40).
The EV genome consists of single-stranded, positive
(messenger)-sense RNA of approximately 7,400 nucleotides
(nts) in length. The genome layout may be summarized as
follows: VPg5UTR[1A-1B-1C-1D/2A-2B-2C/3A-3B-3C-3D]
3UTR-poly(A) (24,41). The 5 end of the genome is covalently
linked to a small protein, VPg, essential for viral RNA repli-
cation. The genome is organized into a long 5 untranslated
region (5 UTR) of approximately 740 nts that immediately
precedes a single open reading frame (ORF). The ORF mea-
sures approximately 6,630 nts and is followed by a short (ap-
proximately 70 nts) 3 UTR and a terminal polyadenylated tail.
The 5 UTR contains multiple regions of predicted higher
order structure and highly conserved nucleotide identity
among the EV. This region of the genome contains elements
essential for viral RNA replication, translation of ORF, and, in
the PVs, determinants of neurovirulence. Because of the highly
conserved nucleotide sequences within the 5 UTR found
among all the EV, it serves as the target for NAATs for the
detection of the EV now in common use (42,43).
Translation of the ORF by host cell ribosomes is accom-
plished in a nonconical, cap-independent manner giving rise to
a single polyprotein that is posttranslationally cleaved by viral
and host proteinases to yield 11 viral proteins (four structural
and seven nonstructural) as well as several functional protein
intermediates. The ORF can be subdivided into three regions:
P1 to P3. The P1 region encodes for the four structural pro-
teins (VP1 to VP4 or 1A to 1D) that comprise the viral capsid.
These are organized 5 to 3 as VP4 (1A), VP2 (1B), VP3 (1C),
and VP4 (1D). The P2 and P3 regions code for seven non-
structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) that are
essential for the viral life cycle. The intermediate proteins play
roles in viral replication.
Immediately downstream of the ORF is a short 3 UTR fol-
lowed by a terminal poly(A) tract. Similar to the 5 UTR, the
3 UTR is predicted to have higher order structures and play a
role in genome replication (44).
Following binding of the EV to a host cell receptor, confor-
mational changes in the virion result in release of the viral ge-
nome into the cytoplasm of the host cell. The RNA genome is
replicated through a double-stranded RNA intermediate that
is formed by the EV RNA-dependent RNA polymerase (3D).
Despite more than 100 years of study of the pathogenesis of
EV infections, much still needs to be learned. Most of what is
known stems for the study of PV types 1 to 3 using information

Scheld_Ch05.indd 67 2/21/14 5:30 PM

 68 Part II: Viral Infections and Related Disorders
derived from human disease and nonhuman primate, murine,
and, most recently, transgenic (Tg) mouse models expressing
the PV receptor, PVR or CD155 (4550). It is likely that the
non-PV EVs share similar mechanisms of pathogenesis.
The majority of the EVs are transmitted via a fecal-oral
route. In addition to direct person-to-person or fecal-oral
transmission, experimental or clinical evidence exists for the
transmission of the EV via houseflies, housefly-contaminated
food, water, and sewage (5154). Bivalves have been found
to accumulate EV (55,56). However, their role in transmis-
sion has not been established. Notable exceptions to fecal-
oral transmission include coxsackievirus (CV)-A21, EV-D68,
and EV-D70, which may spread via contaminated fomites or
ocular and respiratory secretions. Evidence for transplacental
transmission exists, leading to congenital infection (5761).
Following ingestion of the EVs, infection of the cells of
the nasopharynx and, more significantly, the lower gastroin-
testinal (GI) tract occurs. The inherent acid-resistance of the
EV favors the latter. Replication in the lymphatic tissues of
these sites (i.e., tonsils and Peyer patches) leads to shedding
of the EV from the nasopharynx for 1 to 2 weeks and from
the GI tract in feces for several weeks to months (7). Seeding
of EV to the deep cervical and mesenteric lymph nodes ensues
and results in their spread to the systemic circulation via the
lymphatics. This primary or minor viremia leads to seeding
of various organs, including the CNS, liver, lungs, skin, and
heart. Further replication in the tissues of those organs results
in a major (secondary) viremia. If the CNS was not seeded
during the initial viremic episode, spread there may occur with
the major viremia. Viremia or presence of virus in the CNS
continues until the host develops type-specific neutralizing an-
tibodies directed to the capsid proteins, usually by day 7 to
10 postinfection. Immunoglobulin A (IgA) antibodies appear
in the respiratory and GI tracts 2 to 4 weeks after infection.
Unlike other viruses, which are largely contained by cellular
immune mechanisms, the EVs are cleared from the host pri-
marily by antibody-mediated mechanisms.
Great strides have been made in understanding the patho-
genesis of EV infections at a molecular level. The presence of
an EV receptor is the primary, but not the sole, determinant
for cellular infection (62). As stated previously, PVR has been
shown to be the receptor for the PVs (62) and maps to chro-
mosome 19. PVR is a member of the immunoglobin superfam-
ily and functions as an adhesion molecule. It helps to form
adherens junctions and is a recognition molecule for natural
killer cells. In addition to PVR, at least 11 other cell proteins
have been identified as receptors or coreceptors for other
EV serotypes (Table 5.2) (6366).
The exact identity of the cells in the upper and lower in-
testinal tract infected by the PVs is unknown. However, they
have been identified within the ileal wall and mesenteric nodes
in human infection (45,49,50). It is believed that the PV infect
either lower GI cells expressing the PVR or use transcytosis
through microfold (M) cells in the lower GI tract to gain access
to lymphoid tissue. Supporting this is the finding of PVR on the
surface of intestinal epithelium, M cells, and in the germinal
centers of Peyer patches (67). Support for the latter comes from
the finding that M cells can bind and endocytose PVs (68,69).
Why the majority of EV infections do not result in clinically
apparent infection (7073) comes for a number of studies that
suggest that replication of PV in extraneural tissues is inhibited by
the host interferon (IFN) response. PVR Tg mice that are IFN /
receptor deficient are highly susceptible to PV infection, and PV
replication in the small intestine is enhanced (74,75). Thus, IFN
responses may be crucial in limiting the spread of EV infection.
Lastly, the mechanism of EV entry into the CNS remains un-
clear. Evidence for two pathways exist for PV: transit through
Scheld_Ch05.indd 68
the bloodbrain barrier (BBB) or via retrograde axonal trans-
port. For the development of paralytic disease in chimpanzees,
viremia has been shown to be essential (76). This finding pro-
vided initial support that the BBB may be a route to the CNS.
Endothelial cells may express EV receptors that may influence
tissue susceptibility to the EV (77) and facilitate virus entry
into the CNS and other organs. Further buttressing of this hy-
pothesis came from the finding that cultured human brain mi-
crovascular cells can support PV replication (78,79). However,
in other studies, pharmacokinetic analysis of PV injected into
Tg and non-Tg mice indicated that PV was delivered to the
brain in significantly greater amounts than would be expected
from the vascular concentration (80). This suggests that PV
may enter the CNS via the BBB but without need of PVR.
Evidence in humans supports EV access to the CNS via
a neural route. Individuals inadvertently inoculated with an
incompletely inactivated PV vaccine developed initial paraly-
sis in the limb receiving the vaccine (81). Trauma to a limb
preceding PV infection has been associated with the develop-
ment of paralysis of that limb. Provocation poliomyelitis
following intramuscular injections into an extremity of a per-
son incubating wild type PV or those receiving live attenuated
PV vaccines has been well documented (82,83).
Substantial evidence from nonhuman primate and murine
models exists in support of EV access to the CNS via a neural
route. In monkeys, inoculation of the sciatic nerve with PV re-
sults in viral spread along the inoculated nerve and the spinal
cord (84). The initial limb to develop paralysis following in-
tramuscular inoculation of PV in monkeys and Tg mice is the
one injected (8587). If the sciatic nerve of the intramuscularly
inoculated lower extremity is frozen or transected, paralysis of
the limb is prevented (84,87). In Tg mice, it has been shown
that in provocation PV, there appears to be induction of retro-
grade axonal transport (88). PV may gain access to neurons at
the level of the neuromuscular junction.
The search for viral genomic determinants of neurotropism
and neurovirulence has focused on the PVs (89). After immu-
nization with live, neuroattenuated vaccine (Sabin) PV strains,
shedding of PV that has recovered the ability to cause pa-
ralysis (i.e., neurovirulent revertant strains) occurs routinely.
Comparison of wild type, vaccine, and revertant PV strains
has identified a 10-nucleotide region within the 5 UTR (nts
472 to 484 relative to PV type 3 Sabin strain) where neuroat-
tenuating mutations are found to cluster. Additional minor de-
terminants of virulence are localized to amino acids encoded
in the P1 and P3 regions. The search for determinants of neu-
rovirulence in other EV has been unsuccessful.
Histopathology
The benign nature of EV meningitis has made human patho-
logic data for this disease sparse. A report of a child who died
of CV-B5 myocarditis with concomitant meningitis describes
inflammation of the choroid plexus of the lateral and fourth
ventricles, fibrosis of the vascular walls with focal destruction
of the ependymal lining, and fibrotic basal leptomeninges (90).
Parenchymal findings were limited to moderate symmetric dila-
tion of the ventricles and an increase in the number and size of
subependymal astrocytes. The inflammatory reaction at the cho-
roid plexus supports the concept of viremic spread to the CNS.
An adolescent presenting with a similar constellation of findings
died of systemic CV-B3 infection (91). The dura was grossly
distended with swelling also of the pia, arachnoid, and brain
parenchyma. Microscopically, round cell infiltrates were noted
in the meninges overlying the cerebellum; the brain parenchyma
was congested with increased numbers of oligodendrocytes.
2/21/14 5:30 PM

Lymphocytic infiltration was most prominent around blood
vessels in the cerebral white matter and in the basal ganglia,
again suggesting viremic CNS access; focal areas of necrosis and
hemorrhage were also seen (91).
Epidemiology
The EVs have a ubiquitous worldwide distribution; humans
are their only natural reservoir (58,92). It is estimated that
they result in more than 1 billion annual infections worldwide
(22). In the United States alone, the non-PV EVs are estimated
to cause 30 to 50 million infections each year. Due to under-
reporting of EV infections (93), a well-grounded estimate of
the number of cases of EV meningitis that occurs each year is
not possible. However, conservative estimates place the annual
number to be between 30,0000 and 75,000 cases (22,94). The
EVs are responsible for 80% to 90% of identifiable causes of
viral meningitis (9497). Wild type PV were eradicated for the
West Hemisphere in 1991 (98) and are currently endemic only
in Afghanistan, Nigeria, and Pakistan (99). As such, they do
not contribute to the burden to EV in most of the world.
In regions with temperate climates, the non-PV EV exhibit
marked seasonality with the majority of infections occurring in
the summer and fall (Fig. 5.1) (92,100,101). This being said, EV
infections do occur during the winter, warranting their inclusion
in the diagnostic evaluation of aseptic meningitis during that time
of year (102106). In tropical and subtropical areas, EVs occur
year-round, but with higher incidence during the rainy season.
Despite the existence of more than 100 serotypes of EV,
only a limited number are responsible for the majority of dis-
ease observed annually in each geographic region (58,93,107
110). The rank of each serotype within the most frequently
isolated EVs varies annually and geographically. In the United
States, 15 serotypes accounted for approximately 80% of
all EVs reported from 1970 to 2005 (in descending order):
echoviruses (E)-9, -11, -30, CV-B5, E-6, CV-B2, CV-A9, E-4,
1.2
1.1
1.0
Reported Cases per 100,000 Population
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1986 1987 1988 1989 1990
Year (Month)
Scheld_Ch05.indd 69
Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 69
CV-B3, E-7, CV-B4, E-18, CV-B1, E-3, and -5 (93). Some se-
rotypes cycle with varying periodicity within a community
(58,93,109,110), a reflection of the availability of new sus-
ceptible host populations (especially children). Other sero-
types appear de novo as novel epidemic-associated viruses
(111). Around the world, the serotypes most commonly iso-
lated from the CSF and, therefore, from cases of meningitis
or meningoencephalitis, belong to the Enterovirus B species
(93,108,112,93,113,114). In the United States, the serotypes
most frequently isolated from CSF specimens over a 36-year
period, in descending order of frequency, are E-9, -11, -30,
CV-B5, E-6, CV-B2, CV-A9, E-4, CV-B4, E-7, -18, and -5 (93).
Outbreaks of EV meningitis are common. Large nation-
and community-wide outbreaks involving thousands of in-
dividuals have been well documented (115,116). Outbreaks
involving more localized venues such as neonatal units, nurs-
eries, daycare centers, orphanages, schools, pools, camps, and
sports teams occur (53,117122). Sequential episodes of EV
meningitis involving different serotypes have been reported to
occur within a month of each other (123125). Mixed infec-
tions involving EVs, other viruses, or bacteria have been well
described (102130).
Children represent the overwhelming majority of cases of
EV meningitis. An incidence peak among young infants and
school-aged children ages 5 to 10 years has been reported in
multiple studies (58,131133). Occasional outbreaks of EV
CNS infections occur predominantly among adults (134136).
A possible explanation for these findings may lie in the his-
tory of the particular serotypes in the geographic area studied.
Serotypes with endemic patterns, those occurring with sig-
nificant incidence annually, are most likely to affect only the
youngest children because of their absence of previous expo-
sure and immunity. Older children and adults are more likely
to predominate in an outbreak of a serotype that has not been
present in a community for several years, thereby creating a
reservoir of susceptible individuals among children born since
the last appearance of that serotype.
FIGURE 5.1 The seasonal occurrence
of aseptic meningitis in the United
States from 1986 to 1994, as reported
to the Centers for Disease Control and
Prevention. The striking predominance
of cases during the summer months
reflects the predominance of entero-
viruses as etiologic agents in aseptic
meningitis. (From Centers for Disease
1991 1992 1993 1994 Control and Prevention. MMWR Morb
Mortal Wkly Rep. 1993;42:69, with
permission.)
2/21/14 5:30 PM
 70 Part II: Viral Infections and Related Disorders
Host factors that predispose to EV meningitis, other than
young age and immunodeficiency, have been difficult to iden-
tify. A slight male-to-female predominance in the incidence
ratio for EV infections has been noted in large series. However,
in a recent report, male predominance was present only among
persons younger than 20 years of age (male/female ratio
1.4:0.9) (101). This most likely represents the larger number
of females exposed to young children who are principal source
of household exposure. Infection rates are higher among per-
sons of lower socioeconomic status, in areas of crowding, and
larger families (7).
Clinical Manifestations
The clinical manifestations of aseptic meningitis do not sig-
nificantly differ among the non-PV EVs causing the syndrome
(9,137). However, clinical manifestations do vary with the age
and immune status of the patient. Meningitis or meningoen-
cephalitis, singularly or in combination with other syndromes,
are common manifestations of symptomatic EV infection in
neonates and young infants. Two large retrospective reviews
have documented that 62% of infants younger than 3 months
of age with group B coxsackievirus infections and 27% of neo-
nates younger than 2 weeks of age with infections due to the
echoviruses had associated meningitis or meningoencephalitis
(60,138). In two prospective studies, clinical or laboratory
evidence of meningitis was found in 42% to 75% of neonates
with EV infection (139,140).
Early presentation of EV infection following birth suggests
transplacental, intrapartum, or immediate postpartum acqui-
sition of virus (60,138,139). Maternal illness (fever, symp-
toms of upper respiratory tract infection, abdominal pain)
has been reported to occur in 14% to 68% of infected neo-
nates (60,138141). In neonates, fever (38.0C) is almost
universal and accompanied by any or all of the following
nonspecific signs: irritability, lethargy, poor feeding, emesis,
DAYS 2 4 6 8
TEMPERATIURE
104
102
100
98
HEADACHE
NAUSEA & VOMITING
SYMPTOMS STIFF NECK
AND SIGNS (MYALGIA)
(RASH)
(MUSCLE WEAKNESS)
CSF
CELLS
PROTEIN
VIRUS ISOLATION
BLOOD
THROAT
FECES
CSF
ANTIBODIES
NEUTRALIZING
COMP. FIX.
Scheld_Ch05.indd 70
and upper respiratory tract findings (60,139,140,142). On
physical examination, the fontanelle may be full or bulg-
ing. Signs of meningeal irritation such as nuchal rigidity,
Brudzinski, and Kernig signs are generally absent. An exan-
them may be present. If encephalitis in addition to meningitis
(meningoencephalitis) is present, the neonate may present
with profound lethargy, seizures, and focal neurologic abnor-
malities that suggest herpes simplex virus (HSV) infection.
In some newborns, encephalohepatomyocarditis syndrome
may develop in which signs and symptoms of severe hepa-
titis and myocarditis are superimposed on those of menin-
goencephalitis (143). Disseminated intravascular coagulation
and other findings of sepsis result in an illness that may
be indistinguishable from that caused by overwhelming
bacterial infection.
In infants and children, following an incubation period
of 5 to 10 days, the onset of EV meningitis is usually abrupt
with fever (38 to 40C), the most common presenting sign
(137,143147). The natural history of EV meningitis is
depicted in Figure 5.2. The fever pattern may be biphasic, ini-
tially appearing in association with nonspecific constitutional
signs and symptoms followed by resolution and subsequently
reappearing with the onset of meningeal signs (137,148).
Headache is nearly always present in those individuals old
enough to report it. Interestingly, it may be ameliorated fol-
lowing the performance of a lumbar puncture, indicating
that it may be the result of increased intracranial pressure
(149,150). Photophobia is commonly reported. Infants and
young children may be irritable or, less commonly, lethargic
(142). Nonspecific findings, singly or in combinations, include
anorexia, exanthems, malaise, sore throat, abdominal pain,
nausea, emesis, and myalgias (144,147). In infants, the fonta-
nelle may be full or bulging. Less than 5% of infants younger
than 3 months of age have signs of meningeal irritation (142).
However, these become more common in older patients
(144,147,151,152). Seizures are noted in less than 5% of
children (142,146). Other uncommon complications include
10 12 14 16 18 20 22 24 26 28
50 1000
FIGURE 5.2 The clinical course of
enterovirus aseptic meningitis. CSF,
cerebrospinal fluid. (From Horstmann
DM, Yamada N. Enterovirus infec-
tions of the CNS. Res Public Assoc
Nerv Ment Dis. 1968;44:236253,
with permission.)
2/21/14 5:30 PM

coma, increased intracranial pressure, and inappropriate
secretion of antidiuretic hormone (142,153). The duration of
EV meningitis in infants and children is generally less than
1 week.
Fewer clinical reports exist documenting the presentation of
EV meningitis in adolescents and adults (134,136,154157).
Headache is the most frequently reported symptom and is
nearly uniformly present. The severity of the headache may
be such as warrant the use of narcotic analgesics in order to
control the pain (157). Photophobia, fever, signs of meningeal
irritation, nausea, emesis, and neck stiffness occur in more
than 60% of cases. Other less frequently encountered signs
and symptoms include myalgia, exanthems, and abdominal
pain. Full recovery takes longer in adolescents and adults and
may require up to 2.5 weeks (157).
In individuals with humoral immunodeficiencies (X-linked
agammaglobulinemia, X-linked hyper IgM syndrome, com-
mon variable immunodeficiency), EV infection may result in
chronic meningitis or meningoencephalitis that may last for
years and often have a fatal outcome (158161). In addition
to the common signs and symptoms of EV meningitis men-
tioned previously, neurologic manifestations include paraly-
sis/paresis, seizures, cognitive impairment, developmental
regression, sensorineural hearing loss, coma, dysarthria,
hydrocephalus, and aphasia. Extra CNS manifestations occur
singly or in combination in a significant number of cases and
include dermatomyositis, chronic hepatitis, arthritis, myocar-
ditis, and subacute lumbosacral polyradiculopathy. In patients
who have undergone repetitive, sequential lumbar punctures,
the cell culture detection of EV in CSF has been intermittent.
However, using NAATs, evidence of their persistence in CSF
has been documented (162). Treatment with antibody prepa-
rations intravenously and intrathecally or intraventricularly
TA B L E 5 . 4
TYPICAL CEREBROSPINAL FLUID PATTERNS DURING MENINGITIS
Pathogen Number of WBCs
Bacteria (common) 100s1,000s
Viruses
Leptospira
Lyme disease
Mycoplasma
Mollarets 10s100s Mononuclears
Kawasaki disease
Parameningeal focusa
Partially treated meningitisa
Mycobacteria
Brucella 10s100s
Fungal
Toxoplasmab
Connective tissue disease
Parameningeala 10s100s
Partially treateda
nl, normal; sl, slightly; WBCs, white blood cells; , decrease; , increase.
a
Either pattern may be seen.
b
Glucose usually normal.
Scheld_Ch05.indd 71
Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome 71
has resulted in stabilization of some of these patients; how-
ever, viral persistence has been documented during therapy
(159,162,163). With the availability of intravenous prepara-
tions of immune globulin and the early recognition of this
illness, fewer patients appear to be progressing to the classic
description of this disease, and atypical neurologic presen-
tations have appeared. The mortality rate in patients with
humoral immunodeficiencies may be as high as 50%.
The infected neonate is at greatest risk of severe morbidity
and mortality when signs and symptoms develop in the first
days of life (60,138,139,164). Neonates infected with CV-B4
were found to be higher risk of death than those infected with
other EV. The short-term prognosis of young children with EV
meningitis early in life appears to be good; however, there has
been some controversy over possible later sequelae. Neurologic,
cognitive, developmental, and language abnormalities have
been reported in controlled studies of long-term outcome in
children with EV meningitis during infancy (165168). In the
largest and most meticulously controlled study, however, no
differences between patients and controls could be demon-
strated in any of the neurodevelopmental parameters studied
(142). Less well studied are the ultimate outcomes of aseptic
meningitis cases in older children and adolescents; preliminary
data suggest possible school and learning difficulties, but con-
trol patients were not studied (169).
Laboratory Findings and Diagnosis
Salient among the laboratory analyses performed for the evalu-
ation of EV meningitis is the evaluation of the CSF. CSF analysis
can provide initial clues as to the etiology of the clinical syn-
drome (Table 5.4). Cytochemical analysis of the CSF typically
Pattern
Predominant Cell Glucose Protein
Neutrophils
nl/sl nl/sl
Mononuclears
Neutrophils nl/sl nl/sl
2/21/14 5:30 PM
 72 Part II: Viral Infections and Related Disorders
shows a mild to moderate lymphocytic pleocytosis ranging
from 10 to 1,000 cells/mm3 (136,139,141,142,145,149,160).
White blood cell (WBC) counts exceeding 1,000 cells/mm3 are
seen occasionally (60,103,147,170). Although pleocytosis is
almost always present, EVs have been isolated by cell culture
or detected by NAAT from the CSF of patients with clinical
evidence of meningitis without pleocytosis (171). This is par-
ticularly true in the young infant. If the CSF is examined early
in the course of the illness, a predominantly polymorphonu-
clear pleocytosis may be observed (136,139, 142,146,149).
Reexamination of the CSF several hours later will document
a typical lymphocytic pleocytosis (172174). The progres-
sion of an initially polymorphonuclear pleocytosis to one of a
more viral meningitis mononuclear pleocytosis has also been
observed with St. Louis encephalitis virus (175). The CSF pro-
tein concentration is mildly to moderately increased, whereas
the glucose concentration is generally normal. However, hypo-
glycorrhachia may occur, serving to confound the assessment
by suggesting a bacterial etiology (146,147,170).
Traditionally, the diagnosis of EV meningitis has relied on
isolation of the virus from CSF using cell culture or inocula-
tion of suckling mice (176). Although initially very useful, these
techniques have significant limitations. The sensitivity of tissue
culture for EVs is only 65% to 75% (177). The titer of EVs in
the CSF of patients with aseptic meningitis may be as low as
101 to 103 TCID50 (median tissue culture infectious dose) per
milliliter of CSF. This results in slower growth than is observed
with specimens of throat or rectal origin. The time to isolation
of EV from CSF ranges from 4 to 8 days (178) using traditional
cell culturetoo long to be clinically useful in patient man-
agement. Using shell vial culture, the time can be shortened
to 2 to 3 days, but sensitivity may be lost (179,180). Lastly,
optimum recovery of EVs from clinical specimens requires the
use of multiple cell lines, either individually or as mixtures, in
order to increase culture yield (181). Even using multiple cell
lines, some EVs, in particular the group A CVs and some of the
newer EVs, fail to grow in cell culture (182). The added cost
and technical expertise required for suckling mouse inoculation
makes it impractical for use in the modern diagnostic labora-
tory. Serologic confirmation of EV infection is also generally
impractical and not useful in acute management of the patient.
As mentioned previously, the 5 UTR contains regions of
conserved nucleotide identity among the EVs. These regions
have been exploited for the creation of primers and probes
that can be used in NAATs capable of detecting all EVs (43).
Compared to cell culture, NAAT detection of EVs in the
CSF has been shown to exhibit sensitivities that range from
86% to 100% and specificities ranging from 92% to 100%.
Furthermore, NAATs are capable of detecting EV genome in
CSF samples from individuals with syndromes clinically com-
patible with aseptic meningitis previously deemed negative by
cell culture or without pleocytosis (163,162,183). These assays
are also able to detect EV that cannot be grown in cell culture.
Lastly, NAAT can be performed rapidly, generally in a mat-
ter of hours. The results can be made available with sufficient
speed as to have an impact on patient management, resulting
in a reduction in hospital stay, antibiotic use, and ordering
of ancillary tests (184188). A confirmatory polymerase chain
reaction (PCR) test result obtained on a patient with clinical
aseptic meningitis can reassure the clinician that no further
diagnostic investigation is required. For these reasons, NAAT
detection has become the method of choice for the diagnosis
of CNS EV infection. Because of the lack of sensitivity of viral
culture for detection of the EV in CSF, it should be reserved for
instances when NAAT is not available.
Two caveats should be borne in mind when establishing
the diagnosis of EV meningitis. Confirmation of EV as the
Scheld_Ch05.indd 72
etiology for aseptic meningitis syndrome should rely on detec-
tion of the virus from the CSF. As previously discussed, follow-
ing EV infection viral shedding may occur from the throat and
GI tract for up to several weeks (7,92). Therefore, detection
of the EV from the stool or throat of an individual with asep-
tic meningitis may represent an infection that occurred weeks
previously and is unrelated to the present syndrome. Shedding
from a past infection cannot be ruled out unless the virus is
detected in nonpermissive sites (i.e., CSF, blood, tissue) (189).
Lastly, rare reports of co-infections of the CSF by bacteria
and EVs exist (102,126,129,130). In these patients, the clini-
cal and laboratory picture of bacterial meningitis dominated
and the virus was isolated incidentally. The patients were sick
enough that identification of a virus before identification of
the bacterium would have been unlikely to dissuade the cli-
nician from continued use of antibiotics. Thus, the detection
of an EV either by culture or NAAT must always be placed
in the context of the patients clinical picture and laboratory
findings. In the clinical presentation typical of viral meningitis,
co-infection with a clinically silent bacterium would be ex-
traordinarily unlikely.
Treatment and Prevention
No specific treatment exists for EV meningitis. Supportive
measures include bed rest, antipyretics, and analgesics, as
indicated. Administration of parenteral fluids for individuals
unable to take adequate fluids orally, especially infants, is
indicated. Seizures should be controlled with appropriate
anticonvulsant drugs.
Immune globulin preparations have been used for the treat-
ment of newborn infants with severe disease and immuno-
compromised individuals, but their efficacy is not established
(61,159,190). Intravenous, as well as intrathecal, administra-
tion may be necessary to ameliorate or prevent CNS infection
in immunocompromised patients.
The promising results from clinical trials of pleconaril
(39), an antiviral that inhibits EV binding and viral uncoat-
ing, were overshadowed by its adverse effects (40). In clini-
cal trials, pleconaril was found to induce cytochrome P450
3A, resulting in menstrual irregularities in women taking
hormonal contraceptives. This finding raised concerns that
it might increase the metabolism of some hormonal contra-
ceptives and anti-HIV drugs, thereby reducing their efficacy,
prompting the U.S. Food and Drug Administration not to
grant a license for its use.
The EVs are spread primarily through a lack of good
hygiene. Hand washing prevents the spread of the EVs and
should be encouraged in families and institutions (191).
In patients hospitalized with EV, meningitis infection con-
trol measures using standard precautions are sufficient.
Community measures for the prevention of EV infections rely
on the development and maintenance of sewage and potable
water systems. No vaccines exist for the non-PV EV. However,
recent early studies suggest that it may be possible to develop
an inactivated EV-A71 vaccine that can induce neutralizing
antibodies and is well tolerated in humans (192).
PARECHOVIRUSES
The first two members of the genus human parechoviruses
(HPeVs) were found in 1956 (193). However, it was not until
the turn of the century that they were accorded their own genus.
Originally classified as EVs and designated as echoviruses 22
and 23 (18) (currently designated HPeV 1 and 2, respectively),
2/21/14 5:30 PM
 Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome
it became evident early on that they exhibited characteristics
that differed from the other members of the genus (193,194).
The development of methodologies to probe the molecular
aspects of viral replication and viral genetics confirmed that
they differed substantively from the EV (2527,195,196) and
led to their reclassification in a separate genus (24).
Morphologically, HPeVs exhibit similar characteristics as
the EV: small size, lack of an envelope, a positive sense, and
single-stranded RNA genome of the length and organization
consistent with that of the EVs (6). Important differences
are the lack of maturational cleavage of VP0 to yield capsid
proteins VP2 and VP4. As a result, the HPeV capsid is
composed of three, rather than four, proteins. Differences
also exist in the function of two nonstructural proteins.
A detailed discussion of these and other differences is beyond
the scope of this chapter, and the reader is directed to a recent
review (6).
The genus is currently composed of 16 serotypes (Table 5.3)
(24). HPeVs have been reported worldwide. The epidemiology
of the HPeV continues to evolve as new serotypes are identified
and detection is improved using NAATs. Current data indicates
that the HPeVs account for approximately 2% of the EV iso-
lated using traditional cell culture in clinical laboratories (6).
HPeV1 followed by HPeV3 are the types most frequently iso-
lated. Infection with HPeV appears to occur early in life. In the
United States, 73% of HPeV1 and 67.6% of HPeV2 isolated
come from infants younger than 1 year of age. A longitudinal
study of Norwegian infants documented that the cumulative
incidence of HPeV infection by 24 and 36 months of age was
86% and 94%, respectively (197).
HPeV infections exhibit a strong seasonal epidemiology.
Worldwide, the peak incidence of infections occurs during the
summer and fall months (197204). A unique biennial pat-
tern of circulation has been reported for HPeV3 (205208).
As with the EVs, multiple HPeV serotypes circulate within a
community at the same time. The majority of cases of HPeV
meningitis occur in male infants younger than 3 months of
age. HPeV3 is the overwhelmingly dominant cause of HPeV
meningitis. Considerable variation in the annual prevalence of
HPeV meningitis is observed.
Transmission of the HPeV occurs via the fecal-oral and
respiratory routes. They may be shed from these sites for
weeks to months (197,201,209). The finding of HPeV in the
stool of healthy, asymptomatic infants indicates that many, if
not the majority, of infections are subclinical.
Irritability is present in nearly all cases of HPeV meningitis
(202,207,210). An exanthem is frequently present. Emesis,
diarrhea, and distention are reported in approximately one-
quarter to half of cases. Rhinorrhea, cough, tachypnea,
apnea, and wheezing may be present. Notably, findings of
increased intracranial pressure (bulging fontanelle) or men-
ingeal irritation (nuchal stiffness, Kernig or Brudzinski signs)
are absent. The CSF cytochemical evaluation reveals no or
minimal abnormalities in WBC count or protein and glu-
cose concentrations in the overwhelming majority of patients
(202,207,210).
Currently, NAAT is the methodology of choice for HPeV
detection because of its sensitivity and ability to detect all
known HPeV types in a clinically meaningful time frame (6).
Optimum diagnostic assays target the HPeV 5 UTR and
are not type-specific. They are designed for increased sen-
sitivity and to broadly detect all HPeV types from clinical
specimens.
The HPeV can produce cytopathic effect on appropriate
cell lines (211). However, cell culture detection is limited by
those factors discussed for the EV (see previous discussion)
(211,212).
Scheld_Ch05.indd 73
73
ARBOVIRUSES
The arboviruses are a group of more than 500 viruses from
various viral families that are transmitted by the bite of an
insect or tick (i.e., an arthropod vector) (213); hence, the
derivation of their name ararthropod, boborne, viruses.
Transmission to humans (epizootic transmission) occurs by
chance and is secondary to the natural enzootic cycle involv-
ing an arthropod vector and an avian or mammalian host.
Mosquitoes serve as the vectors for the majority of clinically
significant arbovirus endemic to North America. However,
Colorado tick fever virus, Powassan (POW) virus in North
America, and tick-borne encephalitis (TBE) virus in Eurasia
are transmitted by ticks (214,215).
Flaviviridae
West Nile Virus
West Nile virus (WNV) was first isolated in Uganda in 1937
(216). Its incursion into the United States in 1999 (217) pre-
ceded a rapid spread throughout the contiguous continental
United States as well as North and South America (218,219).
In the United States, WNV has displaced all autochthonous
arboviruses as the single major cause of CNS disease (220).
WNV is a member of the Flaviviridae family of RNA viruses,
within the genus Flavivirus (221). All members of the family
possess a host cellderived lipid envelope that is modified by
the insertion of viral proteins and a positive (message)-sense,
single-stranded RNA genome.
WNV is maintained in an enzootic cycle that involves pri-
marily avian hosts and mosquitoes (222). Culex mosquitoes are
important vectors in the United States (223). Mosquitoes are im-
portant in transgenerational and transseasonal maintenance of
the WNV enzootic cycle (224,225). WNV infections occur dur-
ing the summer months, generally from July through October in
the United States, coinciding with periods of increased activity
of its vectors. However, as WNV has spread southward in the
United States, reported transmissions to humans have occurred
as early as April and as late as December (223).
Transmission to humans (i.e., epizootic transmission) is
incidental and, with rare exception, results in a dead-end
infection without subsequent human transmission. The lat-
ter has occurred through transfusion of blood products and
organ transplantation (226229). In addition, confirmed or
suspected maternalfetal and maternalinfant vertical trans-
mission of WNV has been reported (230,231).
The majority of WNV infections in adults and children
result in subclinical disease. Infection of children results in
asymptomatic infection or milder disease more frequently
than in adults (232236). During one outbreak, children
were 4.5 times more likely to become infected with WNV
but 110 times less likely to develop West Nile neuroinvasive
disease (WNND) (237). In adults, age is the single most sig-
nificant risk factor for development of WNND (235,236,238).
The incidence of severe neurologic disease is 10 times higher
in persons aged 50 to 59 years and 43 times higher in those
aged 80 years or older compared with individuals 20 years
of age or younger. Other risk factors include hypertension,
diabetes mellitus, cardiovascular disease, alcohol abuse, and
immunosuppression. Approximately 80% of those infected
with WNV remain asymptomatic. The majority of the remain-
der develops an acute, self-limited febrile illness known as West
Nile fever. It is characterized by a sudden onset of fever (38 to
40C), accompanied by fatigue, malaise, anorexia, headache,
2/21/14 5:30 PM
 74 Part II: Viral Infections and Related Disorders
myalgias, and weakness. Ocular pain on eye movement has
been reported. A diffuse nonpruritic, macular, papular, macu-
lopapular, or morbilliform exanthem and diffuse lymphade-
nopathy may be seen (222,235,239241).
Less than 1% (1:140 to 320) of adults develop WNND: asep-
tic meningitis (WNV meningitis), encephalitis, or poliomyelitis-
like syndrome (241245). WNND may be even rarer in
children: approximately 1:4,200 infected children according to
one study (237,246). The median age of patients with WNV
meningitis is less than those with encephalitis (247). The per-
centage of individuals with WNV meningitis that comprise cases
of WNND varies by report. In an outbreak in Israel, 15.9%
of hospitalized patients with WNND had meningitis (233). In
the United States, WNV surveillance data from 1999 to 2008
found that 33% of WNND cases reported to the Centers for
Disease Control and Prevention (CDC) were meningitis (247).
Individuals 19 years of age or younger accounted for 8% of all
cases of meningitis. However, when cases of WNND in children
were analyzed for nearly the same time frame, 47% of all pe-
diatric cases were of meningitis as compared to encephalitis or
meningoencephalitis, which accounted for 37% of cases (236).
In adults and children, West Nile meningitis is clinically
indistinguishable from other causes of viral meningitis. The ill-
ness begins abruptly with fever, headache, nuchal rigidity, and
meningeal signs (222,235,244). Photo- and phonophobia may
be present. The headache may be so severe as to need the use
of narcotic analgesics to control. Weakness and dyskinesias in
the form of tremors, myoclonus, or parkinsonism may occur.
The outcome of West Nile meningitis is favorable, although it
may take 2 to 3 weeks to fully recover.
Analysis of the CSF shows a lymphocytic pleocytosis of
generally less than 500 cells/mm3 (235). If the CSF is exam-
ined early in the course of the illness, a polymorphonuclear
pleocytosis may be seen (248). The presence of plasma cells
may be indicative of WNV as the etiology (249).
The diagnosis of WNV infection relies on the detection
of WNV-specific antibodies in CSF or paired serum samples
(235,250). The most sensitive and commonly used diagnostic
assay is the IgM antibody-capture enzyme-linked immunosor-
bent assay (MAC-ELISA). It is capable of detecting CSF IgM
antibodies 3 to 5 days into the clinical illness and 3 or more
days earlier than detectable serum antibody (251). However,
a positive test should always be interpreted in the context of
clinical syndrome because the presence of WNV-specific IgM
has been detected in the CSF for up to 199 days after onset
of illness (252). The finding of WNV-specific IgM in the CSF
of an individual with a clinically compatible CNS syndrome
generally is considered diagnostic of WNND. If only serum is
used for establishing a diagnosis, a second convalescent serum
sample, obtained 2 or more weeks later, should be collected to
document a fourfold increase in specific antibody titers using
a functional assay such as neutralization or hemagglutination
inhibition (235). Because serologic cross reactions among
St. Louis encephalitis virus, WNV, and POW virus can occur,
serologic testing ideally should include a battery of region-
specific arboviral antigens (253).
St. Louis Encephalitis Virus
St. Louis encephalitis virus (SLEV) was first identified in 1933
following an epidemic of encephalitis in St. Louis, Missouri
(254). Like others of the genus, it is an enveloped, positive
(message)-sense, single-stranded RNA virus (221). It is recog-
nized as the cause of sporadic and epidemic encephalitis and
meningitis throughout the Americas. In the United States, most
cases are seen from July through September (255). In Florida,
epidemics have continued into December (256). Birds are
the reservoir, and four different species of Culex mosquitoes,
Scheld_Ch05.indd 74
each with a specific geographic distribution, are the principal
vectors (257). Younger patients tend to have milder forms of
SLEV-associated CNS disease (1,258). Approximately 15% of
all symptomatic cases of SLEV infection present as meningitis.
The frequency of SLEV meningitis in children is much higher:
approximately 40%. In contrast, patients older than 60 years
of age rarely (5% or less) present with aseptic meningitis.
No specific therapy is available.
Tick-Borne Encephalitis Virus
Tick-borne encephalitis virus (TBEV) is an important cause of
meningitis in Europe. Cases in returning travelers from Europe
and China have been seen in the United States (259). The disease
was first described in Austria in 1931 (260). TBEV is endemic
from Europe through far-eastern Russia, northern China, and
Japan. Three subtypes of the virus exist: European, Siberian, and
Far Eastern (10,215). It is maintained in enzootic cycles involving
Ixodid ticks and wild rodents (215). Humans may be infected
through the bite of an infected tick or, less commonly, the con-
sumption of virus-infected milk. The majority of cases occur from
March to November (10). The annual incidence of disease var-
ies widely by country: Latvia, Estonia, Lithuania, and southern
Germany30, 16.5, 11.2, and 2 cases per 100,000 inhabitants,
respectively (10). Aseptic meningitis is seen with infection due
to the European and Siberian viral subtypes. Meningitis is more
frequently seen in younger age-groups (10). Sixty-six percent of
cases in infants and children 15 years of age or younger are of
meningitis. This decreases progressively with advancing age such
that for individuals 60 years of age or older, 32% or less develop
meningitis. Diagnosis of TBEV infection is established by the
detection of virus-specific IgM and IgG in serum. Vaccines for the
prevention of TBEV-related disease are available in Europe and
Canada and are recommended for certain regions of the world
(10,215,261). No specific therapy is available.
Other flaviviruses such as POW virus (214,262) and
Japanese encephalitis virus (263,264) are far less commonly
identified as causes of meningitis.
Colorado Tick Fever Virus
Colorado tick fever (CTF) virus is an Orbivirus, a member of
the family Reoviridae. Orbiviruses are double-stranded, seg-
mented RNA viruses. The virion is nonenveloped, with an
outer diameter of 80 nm and an inner core of 50 nm diameter.
CTF virus is found mostly in western and mountainous regions
of the United States. Its tick vector is Dermacentor andersoni,
also known as the Rocky Mountain wood tick (265). After a
bite by an infected tick, a 3- to 6-day incubation period follows.
Hematopoietic cells, principally erythrocytes, are the major tar-
gets, wherein viral replication and dissemination occurs (265).
A biphasic illness is characteristic but is actually observed in
only half of patients (265). It consists of initial sudden onset of
high fever and headache with flulike constitutional symptoms.
Hepatosplenomegaly may occur, as well as GI symptoms. Stiff
neck and other meningeal signs occur in as many as 18% of
confirmed CTF cases (266). Meningoencephalitis and encepha-
litis can occur but less commonly than meningitis. The period
of illness is usually brief (2 to 3 days). A peripheral leukope-
nia with relative lymphocytosis is common. A lymphocyte-
predominant CSF pleocytosis and elevated protein level are
typically found in patients with neurologic manifestations.
Certain patients transiently improve (1 to 2 days), and then
a second phase of illness of equal or greater severity follows
(lasting an additional 2 to 3 days). Severe sequelae and death,
though rare, have been reported. Typically, recovery is rapid
and complete within 2 weeks. Laboratory diagnosis can be
made using PCR (within the first 5 days of illness) or IgM-based
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 Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome
serology (214). Virus may also be detected in peripheral blood
smears by indirect immunofluorescence. Paired acute and con-
valescent serology is useful for retrospective diagnosis.
Bunyaviridae
The California encephalitis group of viruses include five viruses
in the family Bunyaviridae. ThreeLa Crosse, Jamestown
Canyon, and snowshoe hareviruses have been associated
with aseptic meningitis (128,267). Numerically, La Crosse is
the most clinically relevant. From 1999 to 2007, La Crosse
virus was reported from 25 states. However, 87% of cases
came from 7 states: West Virginia, Ohio, North Carolina,
Tennessee, Wisconsin, Minnesota, and Illinois (255).
PARAMYXOVIRUSES
Mumps Virus
Mumps virus is a member of the genus Rubulavirus within the
subfamily Paramyxoviridae (268). It is an enveloped, pleomor-
phic virus possessing a single-stranded, negative-sense RNA
genome. Only a single serotype exists, although 13 genotypes
have been identified (269,270). In the United States, prior to
1967 and the introduction of an effective vaccine, mumps
infections are observed during the winter and spring, with epi-
demics occurring approximately every 3 to 5 years (271,272).
It was responsible for 2.5% to 15% of all cases of aseptic
meningitis and between 17.5% and 22% of known causes of
meningitis (5,8,9,11). As a result of mumps vaccine and effec-
tive vaccination programs, mumps cases have been reduced by
99% (273). However, mumps outbreaks continue to occur in
the United States (274,275).
Mumps is transmitted via respiratory droplets. Once infec-
tion occurs, viremia is the likely means of spread to distant
target organs, including the CNS (276). Meningitis is the most
common neurologic manifestation of mumps infection (277).
Mumps once was the leading identifiable cause of aseptic men-
ingitis. The widespread use of the attenuated live-virus vac-
cine in the United States has resulted in a dramatic drop in
incidence of mumps as well as its major role as a cause of
meningitis (278). Neurologic involvement is three times more
common in males. More than 50% of patients with mumps
parotitis have CSF pleocytosis (277); however, most are not
symptomatic of meningitis.
Clinically symptomatic meningitis occurs in up to 10%
of patients with parotitis (279). Symptoms of meningitis are
reported in cases of mumps parotitis by 4 to 10 days of illness
but may precede parotitis by as much as 7 days; half or more
cases of mumps meningitis may not be associated with par-
otitis at all (280,281). The clinical manifestations of mumps
meningitis are nonspecific and differ little from those of EV
cases. Fever is universal, usually lasting 3 days but occasion-
ally persisting for a week (280). Bradycardia, drowsiness, leth-
argy, and anemia are all reported. More significant neurologic
involvement can occur. Encephalitis is described concomi-
tantly with meningitis in as many as 35% of cases (280) or as
few as 4% (166).
Mumps virus meningitis and meningoencephalitis are usu-
ally benign and self-limited diseases (277,280). The prognosis
for rapid and full recovery from mumps meningitis is excellent
(277,280). The occasional fatalities demonstrate pathologic
findings of demyelination near blood vessels (277).
Most but not all cases of symptomatic mumps menin-
gitis have a primarily monocytic CSF pleocytosis, primarily
Scheld_Ch05.indd 75
75
mononuclear cells (277). Half of patients have 500 or fewer
cells/mm3, 75% of cases have 1,000 or fewer cells/mm3, and
the remainder have fewer than 5,000 cells/mm3. Exceptional
cases with more than 5,000 cells/mm3 have been reported.
Pleocytosis may persist for weeks. CSF protein level has been
reported as normal in more than half of patients with mumps
meningitis (280,282).
Several approaches exist for the diagnosis of mumps
virus meningitis: viral isolation, documentation of increased
antibody titers between serum acute and convalescent serum
samples obtained 2 to 3 weeks apart, documentation of
the presence of mumps-specific IgM antibodies, or NAAT
detection of mumps virus genome (283). Mumps virus can
be detected in saliva, blood, urine, and CSF. It is present in
saliva 9 days prior to and 8 days after the onset of parotitis.
In urine, it is detectable for up to 2 weeks after the onset of
symptoms. Mumps-specific IgM is present in the blood within
3 to 4 days of the start of symptoms and may persist for up
to 3 months. A sole serum sample demonstrating the presence
of mumps-specific IgM obtained within 10 days of the onset
of illness is sufficient to establish the diagnosis. IgG antibod-
ies are detectable 7 to 10 days after the start of symptoms
and persist for life. Antibodies to other paramyxoviruses may
cross-react with in mumps virus in serologic assays, leading to
false-positive results.
Other Paramyxoviruses
Measles infection may be associated with pleocytosis in as
many as 30% of uncomplicated cases in normal patients,
usually without signs or symptoms of meningitis (284). The
parainfluenza viruses have been associated with CNS infection
(285). The dominant serotype reported has been parainfluenza
virus type 3.
ARENAVIRUSES
Lymphocytic Choriomeningitis Virus
LCMV, a member of the family Arenaviridae, is an enveloped
virus with a genome consisting of two single-stranded, ambi-
sense RNA molecules (286). LCMV was one of the earliest
and significant viruses to be associated with aseptic meningitis
in humans (3) (Table 5.2). It is now rarely identified as a cause
of CNS infection in humans. The virus is endemic in wild
mice, which serve as its reservoir (287). In the United States,
the prevalence in wild mice is estimated to be 3.9% to 13.4%
(287). Seroprevalence studies in the United States suggest that
the 0.4% to 5% of patients sampled in three large cities had
evidence of LCMV infection (287289). The virus is trans-
mitted by rodents (hamsters, guinea pigs, rats, mice) via their
saliva, urine, feces, and nasal secretions (290). Individuals who
work with or own rodents as well as those living under impov-
erished and nonhygienic circumstances have traditionally been
at greatest risk (291294). Human-to-human transmission can
occur through transplantation (295,296). Approximately one
third of LCMV infections are asymptomatic. Clinically mani-
fest infections are usually mild and of brief duration. The infec-
tion frequently results in a biphasic illness characterized by an
initial flulike illness with fever, headache, malaise, myalgia,
anorexia, nausea, and emesis. A temporary, brief period of
improvement follows and precedes the onset of symptoms of
meningitis or encephalitis (291,292,297). Occasional severe
neurologic disease (meningoencephalitis, encephalitis) has
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 76 Part II: Viral Infections and Related Disorders
been reported (298). The course of meningitis and recovery are
often prolonged (299), but permanent neurologic impairment
is rare. CSF findings are indistinguishable from those of other
viral causes of aseptic meningitis: lymphocytic pleocytosis (up
to several thousand), mildly elevated protein, and usually nor-
mal or low glucose level. Other abnormalities include leukope-
nia, thrombocytopenia, elevations of transaminase levels, and
pulmonary infiltrates (297). Cell culture of CSF usually detects
the presence of LCMV. In severe disseminated infection, virus
may be found in the blood, urine, and nasopharyngeal secre-
tions. NAAT can be used to detect viral genome in CSF. Acute
and convalescent serum specimens can be tested for raising
antibody titers by enzyme immunoassays.
HUMAN HERPESVIRUSES
The majority of the human herpesvirusesHSV types 1 and
2, varicella-zoster virus (VZV) (300,301), Epstein-Barr virus
(EBV) (302,303), cytomegalovirus (CMV) (304), human her-
pesvirus (HHV)-6 (305308), and HHV-7 (308)have been
associated with reports of aseptic meningitis. Numerically,
HSV-1 and HSV-2, in particular the latter, are the major causes
of aseptic meningitis among this family for viruses.
HSVs appear to account for approximately 1% to 3%
of all cases of aseptic meningitis (Table 5.2). HSV-2 and,
much less commonly, HSV-1 have been associated with asep-
tic meningitis in patients with primary genital herpes infec-
tion (309311). HSV-2 meningitis following primary genital
infection is more frequently seen in women. Genital lesions
may not be present at the time of symptoms of aseptic men-
ingitis (310). Examination of the CSF demonstrates a lym-
phocytic pleocytosis, elevated protein, and normal glucose
concentrations.
Recurrent benign lymphocytic meningitis (RBLM), also
referred to as Mollaret meningitis, has been shown to be
associated primarily with HSV-2 and, much less so, HSV-1
(312315). The prevalence of RBLM is difficult to assess
because of its intermittent presentation, and it is not a report-
able condition. However, two reports place it between 1 and
2.2 cases per 100,000 population (316,317). The syndrome
is more frequently seen in young women and consists of
recurrent episodes of aseptic meningitis, lasting 2 to 5 days,
which resolve spontaneously and without sequelae (318). The
clinical presentation of RBLM is typical of viral meningitis.
However, approximately 50% of patients have transient neu-
rologic manifestations (seizures, hallucinations, diplopia, cra-
nial nerve palsies, altered consciousness). Lesions of genital
herpes are absent. Cytochemical analysis of the CSF reveals
a lymphocytic pleocytosis, mildly elevated protein, and nor-
mal glucose concentrations (318). Detection of HSV genome
is made by NAAT. The role of antiviral therapy in the manage-
ment of RBLM is debated. Administration of acyclovir has
been reported to result in rapid resolution of symptoms, and
suppressive therapy using valacyclovir or famciclovir may pre-
vent recurrences. In individuals with HSV-2 detected from the
CSF, counseling regarding prevention of transmission of geni-
tal HSV should be undertaken (318).
VZV-related meningitis is a recognized complication of
primary infection (chickenpox) and reactivation (zoster)
(300,301,319,320). Meningitis has been associated with
infection due to multiple different genotypes of the wild type
strain as well the vaccine strain (Oka strain) of VZV (321)
and may be seen in immunocompetent and immunocompro-
mised individuals. The clinical and CSF presentation is typical
of aseptic meningitis. However, in recent report, only half of
patients had fever, and nearly 25% had altered mental status or
Scheld_Ch05.indd 76
lethargy (321). In that study, all cases of meningitis occurred in
children. When meningitis complicates zoster, typical vesicu-
lar lesions restricted to dermatomal distribution are seen. The
use of NAAT has identified individuals with meningitis due to
reactivation of VZV but without skin lesions (301,321). The
benign course is typical of other aseptic meningitides.
Reports of meningitis with EBV and CMV infection are
far less common that those of the agents discussed previously.
Although HHV-6 and HHV-7 have been reported as causes
of CNS infection, including meningitis (305,307,308), these
reports must be interpreted with caution. HHV-6 has been
shown to establish persistence in the CNS and has been found
in the CSF of asymptomatic individuals (322).
OTHER VIRAL PATHOGENS
HIV
Aseptic meningitis is known to occur as part of the clinical
constellation of syndromes associated with primary HIV infec-
tion (323325). The symptoms and signs are typical of aseptic
meningitis and resolve rapidly. If the CSF is examined, a lym-
phocytic pleocytosis is present along with mildly elevated pro-
tein and normal glucose concentrations. HIV can be detected
in the CSF. Pleocytosis may also be seen in asymptomatic HIV-
infected individuals.
Occasional cases of aseptic meningitis or meningoencephali-
tis have been associated with adenoviruses in normal and immu-
nocompromised patients (326330), influenza A and B viruses
(331333), parvovirus (334), and rotavirus (335337).
NONVIRAL PATHOGENS
Multiple pro- and eukaryotic pathogens (bacteria, spirochete,
mycobacteria, fungi) can present with the classic features of
aseptic meningitis. The majority of these agents would not be
readily detectable by Gram stain of the CSF and may require
special culture techniques to identify. As originally noted by
Wallgren (2), parameningeal foci (sinusitis, otitis, mastoiditis,
trauma) can present similarly to viral meningitis and need to
be always considered in the differential diagnosis of aseptic
meningitis.
Spirochetes
Lyme Disease
In areas of the United States where Lyme disease is endemic
(338), CNS infection due to Borrelia burgdorferi may be
encountered in 10% to 15% of individuals infected by this
spirochete (339,340). B. burgdorferi is transmitted by Ixodes
species (scapularisEastern United States, or pacificus
Western United States) of ticks. Because the vector is so dimin-
utive, a significant number of infected individuals do not recall
a tick bite. The illness is commonly seen in the spring and
summer months and overlaps with EV and arboviral causes
of meningitis. Meningitis usually occurs in the early dissemi-
nated stage of infection. The clinical manifestations are similar
to viral meningitis and may occur in association with cranial
neuritis and radiculoneuritis (339343). The majority of chil-
dren have associated findings such as facial or sixth nerve
palsies, papilledema, and increased intracranial pressure of
erythema migrans. Analysis of the CSF reveals a lymphocytic/
monocytic pleocytosis (500 cells/mm3) and elevated protein
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 Chapter 5: Viral Meningitis and Aseptic Meningitis Syndrome
concentration. The CSF glucose concentration is usually nor-
mal but may be slightly decreased.
The diagnosis of Lyme meningitis requires documenting
B. burgdorferi infection using a two-step diagnostic approach
consisting of an initial enzyme-linked immunosorbent assay
(ELISA) followed by a specific Western blot assay. In addi-
tion, the CSF should be examined for the presence of intra-
thecal production of antibody to B. burgdorferi (339341).
Treatment with ceftriaxone, cefotaxime, or penicillin G for
2 to 4 weeks is recommended (340,342,343).
Other Spirochetes
Leptospirosis is an acute systemic vasculitic disease caused by
a number of spirochetes in the Leptospira genus. Acquisition
is via contact with infected animal body fluids. Although more
typically noted in the anicteric variety, meningitis is com-
mon in icteric leptospirosis (Weil disease) as well (344). The
CSF profile is indistinguishable from that caused by common
viruses, except that overall, more patients develop elevated
CSF protein than patients with common viral meningitis.
Aseptic meningitis is a relatively uncommon manifestation of
secondary and tertiary syphilis (345). Meningitis due to tick-
borne relapsing fever may be seen as frequently as with Lyme
disease (346).
Bacterial and Fungal Causes
The majority of tuberculous CNS infections are caused by
Mycobacterium tuberculosis. A small percentage is due to
bovine tuberculosis, Mycobacterium bovis. Children are par-
ticularly prone to develop tuberculous meningitis (347). The
presentation is often subacute, occurring over 1 to 3 weeks
(348). The clinical course consists of three stages. Personality
change, irritability, anorexia, listlessness, and occasional fever
characterize the first stage. Second stage signs and symptoms
reflect increased intracranial pressure and cerebral ischemia:
drowsiness, nuchal rigidity, cranial nerve palsies, anisocoria,
emesis, and seizures. In older children, adolescents, and adults,
headache and emesis may be the dominant features. The third
stage is characterized by coma, autonomic instability, fever, and
progressive cerebral dysfunction. Chest radiograph; tuberculin
skin testing; and, in older children, adolescents, and adults,
IFN gamma release assays should be performed, seeking evi-
dence of tuberculosis. The lumbar puncture reveals elevated
opening pressure. The CSF reveals a markedly elevated protein
and decreased glucose concentrations. A lymphocytic pleocy-
tosis of usually less than 500 cells/mm3 is seen.
CNS infections with Brucella species occur in less than 5%
of systemic brucella infections (349). Meningoencephalitis is
the usual presentation. Both acute and chronic forms have
been reported. Antibiotic therapy is usually curative; however,
some residual neurologic defects are the rule.
Fungal meningitis is more commonly seen in immunocom-
promised individuals; however, occasional cases have been
reported in immunologically normal individuals (350355).
Cryptococcus is the most commonly recognized cause of fungal
meningitis (352). Other causes include Candida, Histoplasma,
Coccidioides, Blastomyces, and Aspergillus (350,351,353355).
The clinical presentation is that of a subacute or chronic meningi-
tis with fever, headache, and altered consciousness. Meningismus
and focal neurologic findings are common findings. Evaluation
of the CSF reveals a lymphocytic pleocytosis in most cases
(a polymorphonuclear pleocytosis may be seen in some cases)
in association with an increased protein concentration and
Scheld_Ch05.indd 77
77
hypoglycorrhachia. In addition to fungal culture of the CSF,
evidence of infection should sought through detection of fungal
antigen, fungal wall constituents, or specific antibodies in CSF
and blood. When attempting to detect fungi through culture, it
is important to use 10 to 15 mL of CSF. Evidence of fungal infec-
tion in sites outside of the CNS should also be sought.
A variety of neurologic manifestations have been reported to
be associated with Mycoplasma pneumoniae infections (356).
Of these, aseptic meningitis and encephalitis are the most com-
mon. Clinically, mycoplasmal meningitis is impossible to dis-
tinguish from viral meningitis, and as in typical viral infection,
sequelae are not observed. Diagnosis is by serology or PCR
(356,357). Mycoplasma hominis has been associated with cases
of neonatal meningitis, usually in preterm infants (358).
Systemic Diseases
Kawasaki disease (KD) is an acute, self-limited vasculitis of
unknown etiology affecting children. In the United States, the
estimated overall annual incidence among children younger than
5 years of age is 20 cases per 100,000 population (359). The
incidence is higher among Asians and Pacific Islanders. Several
reports indicate that between 40% and 60% of children with
KD have a mild (usually 100 cells/mm3) mononuclear pleocy-
tosis on CSF examination (360,361). The incidence appears to be
highest in reports from Japan. The CSF protein and glucose con-
centration are normal in the overwhelming majority of children.
Many other systemic vasculitides (e.g., polyarteritis nodosa,
temporal arteritis, Takayasu arteritis, Wegener granulomatosis)
are associated with CSF pleocytosis (362). Meningitis has been
described as the initial manifestation of systemic lupus erythe-
matosus in several patients (363). Two percent to 4% of patients
with lupus may develop aseptic meningitis during the course of
their disease (363).
Medication-Induced Aseptic Meningitis
The clinical features of medication-induced aseptic meningitis
are not such that they set it apart from that caused by infectious
etiologies nor do they permit differentiation of the multiple
medication causes of the syndrome. A wide variety of medica-
tions, vaccines, or dyes, administered systemically or within the
CNS, have been associated with aseptic meningitis (364372).
The most common class of medications associated with asep-
tic meningitis is nonsteroidal antiinflammatory drugs (NSAIDs)
(364). Of the nonselective and selective inhibitors of cyclooxygen-
ase 1 and 2, ibuprofen is the most frequently associated NSAID
with aseptic meningitis. Ibuprofen-associated aseptic meningitis
is frequently seen in association with systemic lupus erythemato-
sus. The majority of cases are reported in women. The associated
pleocytosis is frequently polymorphonuclear in nature.
Antimicrobial agents have also been shown to cause
aseptic meningitis (364). Leading this group of medications
are trimethoprim and penicillin (penicillin, amoxicillin, or
amoxicillin-clavulanic acid). Intravenous immunoglobulin
is a well-recognized cause of aseptic meningitis (364). In
pediatric clinical trials using intravenous immunoglobulin,
the incidence of aseptic meningitis ranged from 6% to 32%.
Immunomodulators such as monoclonal antibodies against
CD3 or tumor necrosis factor- are important causes of
aseptic meningitis (364,368). Vaccine strains of mumps have
been the most frequently associated (364,373). Greater than
10 mumps vaccine strains are used around the world (373).
Although the Jeryl Lynn and related vaccine strains rarely, if
ever, cause aseptic meningitis, other vaccine strains have been
associated with varying incidences of this side effect (373).
2/21/14 5:30 PM
 78 Part II: Viral Infections and Related Disorders
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 CHAPTER 6 ENCEPHALITIS
CAROL GLASER AND ARUN VENKATESAN
Encephalitis is one of the most challenging syndromes for cli-
nicians to manage. Patients are often critically ill, and there
are many potential etiologies. Despite exhaustive testing, an
etiology is only identified in 40% to 70% of cases. Even when
a cause is identified, there may be no effective treatment (13).
Mortality rates vary substantially across studies and range
from 3% to 15% (4,5). The frequency of sequelae, including
cognitive and motor impairment as well as seizures, is also
variable; some case series report severe disability in 20% to
40% of patients (4,6,7). Not surprisingly, given the severity of
the disease as well as the complexity of diagnosis and clinical
management, substantial health care costs are associated with
encephalitis.
The term encephalitis generally refers to inflammation of
the brain parenchyma. However, without the identification
of a neurotropic agent or confirmation of inflammation in
brain tissue, the diagnosis of encephalitis is presumptive and
based on clinical features. Clinically, patients with encephalitis
often present with fever, headache, and altered mental status.
Seizures or focal neurologic deficits may also be present. In
principle, alteration in mental status distinguishes encepha-
litis from uncomplicated meningitis as meningitis symptoms
typically include fever, headache, and nuchal rigidity but lack
global or focal neurologic dysfunction. In practice, however,
the distinction between these two entities is not always readily
apparent, and in descriptions of central nervous system (CNS)
infections with mental status changes due to agents such as en-
teroviruses, rabies, West Nile virus or herpesviruses, the terms
encephalitis or meningoencephalitis are often broadly applied.
In contrast to encephalitis, encephalopathy refers to
any diffuse disease of the brain that results in changes in
function; the clinical hallmark of encephalopathy is an al-
tered mental state. Many entities including metabolic or
mitochondrial dysfunction, toxins, trauma, poor nutrition,
or lack of oxygen or blood flow to the brain can lead to
encephalopathy.
This chapter focuses predominantly on the immunocom-
petent host and pathogens in North America that either cause
encephalitis or an encephalitis-like syndrome. Moreover, many
patients with encephalitis also have meningeal inflammation,
thus demonstrating the overlap of encephalitis and menin-
goencephalitis. For the purposes of this chapter, the terms
encephalitis and meningoencephalitis are used interchangeably.
Other regions of the CNS may be variably affected, including
the spinal cord (myelitis), nerve roots (radiculitis), and nerves
(neuritis).
GENERAL: ETIOLOGIC AGENTS
AND EPIDEMIOLOGY
Although the term encephalitis is often used in conjunc-
tion with a viral etiology, many other infections and nonin-
fectious entities can cause encephalitis or encephalitis-like
symptomatology. The incidence of encephalitis varies through-
out the world and is contingent upon the population under
study, the geographic region, the availability of vaccines for
some causes of encephalitis, and differences in case definitions
84
Scheld_Ch06.indd 84
and surveillance activities. In tropical regions of the world,
the minimum estimated incidence of encephalitis is 6.3 per
100,000 (8). In the Western world, the incidence ranges
between 0.7 and 13.8 per 100,000 (810). Most reports find
the incidence of encephalitis higher in the pediatric age-group
than in adults. For example, a study in England of hospitalized
patients with encephalitis over a 10-year period demonstrated
an overall incidence of 1.5 per 100,000 population, a rate of
2.8 per 100,000 in children, and a rate of 8.7 per 100,000 in
infants (11). Somewhat higher rates in children were reported
from Finland (8.8 per 100,000 from 1973 to 1987) (12) and in
Slovenia (6.7 per 100,000 from 1979 to 1991) (13).
The epidemiology of encephalitis is a dynamic process. In
countries where vaccines are widely used for measles, mumps,
rubella, and varicella infections, the incidence of encephali-
tis due to these viruses has decreased (14,15). However, there
is a growing list of emerging and reemerging pathogens
such as Nipah virus, enterovirus 71, Balamuthia mandril-
laris, European tick-borne encephalitis virus, Hendra virus,
Baylisascaris procyonis, and Chandipura virus that can cause
encephalitis. Moreover, some agents are now identified in pre-
viously nonendemic regions of the world. Notable is West Nile
virus, which has expanded its geographic region from Africa to
North and South America, Europe, the Middle East, Western
Asia, and Australia (16). Chikungunya virus is yet another
striking example of a virus that has spread from its origin in
Africa to nearly 40 countries including a number of countries
adjacent to the Indian Ocean: La Reunion Island, Madagascar,
the Maldives, the Seychelles, and India. (17).
The increasing recognition of specific autoimmune causes,
as discussed later in this chapter, has also had a tremendous im-
pact on our understanding of the epidemiology of encephalitis.
INFECTIOUS CAUSES: SPECIFIC
EPIDEMIOLOGIC AND CLINICAL
FEATURES
Viruses
Many cases of viral encephalitis are either an uncommon
complication of a common infection, such as a herpesvirus or
enterovirus infection, or a predictable presentation of a rare
pathogen such as rabies or lymphocytic choriomeningitis virus.
The clinical manifestations of encephalitis are variable and
reflect the degree of brain involvement, host factors, and the
inherent pathogenicity of the offending agent. Most patients
with encephalitis have headache and fever, followed by altered
mental status. Seizures, behavioral changes, impaired cogni-
tion, aphasia, hemiparesis, and other focal neurologic signs
may be seen. Arboviruses are often associated with global CNS
dysfunction, whereas agents such as herpes simplex encepha-
litis typically result in focal manifestations. Although there is
significant overlap in the clinical presentation of various agents
and diagnosis can rarely be made on clinical grounds alone,
the most typical and/or characteristic features of some of the
causes are highlighted in the following sections.
2/21/14 5:31 PM

Herpes Simplex Virus
Herpesviruses are enveloped DNA viruses that are among the
most common causes of infections in humans. At least eight
herpesvirus types are known to infect humans. Herpes simplex
virus type 1 (HSV-1) is one the most common causes of spo-
radic encephalitis in the world (see Chapters 9 and 10). The
epidemiology and clinical features of neonatal herpes CNS
infections differ from children and adults and are not covered
in this chapter. The incidence of herpes simplex encephalitis
(HSE) caused by HSV-1 is estimated to be 4 per 1,000,000
(11,18). HSE is responsible for 10% to 20% of adult en-
cephalitis cases (3,19). HSE is less common in children than
in adults; in a large cohort of over 300 pediatric encephalitis
patients over a 12-year period, only 5% were due to HSE. In
the pediatric age-group, HSE is often a result of a primary in-
fection, whereas most HSE infections in adults are the result of
HSV reactivation. Importantly, the presence of herpes labialis
has no diagnostic specificity for encephalitis causality but does
serve as a marker of HSV infection.
The characteristic clinical presentation for HSE includes
altered mental status (97%), fever (90%), and headache
(81%) (20). Other common neurologic findings include per-
sonality change (85%), aphasia (40%), ataxia (40%), hemi-
paresis (38%), cranial nerve deficits (32%), and seizures
(31%) (4,21). Children are more likely to have extratempo-
ral involvement as manifested by clinical symptoms as well as
neuroimaging (22).
Unlike HSV-1, HSV-2 is more likely to cause disseminated
encephalitis and does not generally localize to the temporal
and inferior frontal regions of the brain (23). Most neuro-
logic CNS HSV-2 infections present with lymphocytic men-
ingitis. Relapsing meningitis, encephalitis, and myelitis can
also occur.
HSV-1 and HSV-2 can also cause brainstem encephalitis.
A recent comprehensive literature review of HSV brainstem
encephalitis identified 24 cases: 79% due to HSV-1 and 29%
due to HSV-2 (24). The most prominent features were neuro-
ophthalmologic manifestations; these were seen in over 80%
of patients and included nystagmus, impaired ocular move-
ments, anisocoria, ptosis, oscillopsia, or spasmodic move-
ments (24). Other cranial deficits, altered mentation, ataxia,
and corticospinal tract findings (e.g., hyperreflexia) were also
described. Although not common, quadriplegia was also pres-
ent in some (19%) of the patients (24).
Varicella-Zoster Virus
Both primary infections with varicella-zoster virus (VZV) and
endogenous reactivation (herpes zoster) can lead to encepha-
litis (25) (see Chapter 10). The most characteristic manifesta-
tion of VZV encephalitis in children is acute cerebellar ataxia
(e.g., nystagmus, dysarthria, and ataxia), which usually occurs
1 week after rash onset (26). VZV encephalitis, once a leading
cause of encephalitis in children, is much less common due to
the widespread use of VZV vaccine (27).
However, VZV encephalitis is relatively common in adults,
and its incidence rivals that of HSE (2831). The clinical pre-
sentation in adults is different than in children and includes
diffuse brain dysfunction, seizures, cranial nerve palsies, and
other focal neurologic signs (4,32). The presence of a diffuse
varicella rash or a vesicular rash in a dermatome distribution
can be an important clue to diagnosing VZV encephalitis.
Notably, however, as many as 44% of patients lack cutaneous
findings, a condition termed herpes sine zoster or preeruptive
varicella (3236). Although the pathophysiology of VZV-
associated encephalitis remains unclear, some cases appear to
be due to a medium and large vessel vasculopathy (25).
Scheld_Ch06.indd 85
Chapter 6: Encephalitis 85
Epstein-Barr Virus
Epstein-Barr virus (EBV), another herpesvirus, is most often
associated with mononucleosis but can also cause several
distinct neurologic syndromes including aseptic meningi-
tis, Guillain-Barr syndrome, Bell palsy, transverse myelitis,
cerebellitis, and encephalitis (37,38) (see Chapter 12). Most
neurologic complications due to EBV occur during primary
infection, typically in childhood. Importantly, many patients
with EBV-associated encephalitis do not have classic mononu-
cleosis symptoms (39,40). In a case series of 216 pediatric en-
cephalitis patients in Canada, 21 (9.7%) were identified with
EBV-associated encephalitis (40). Of these, only one patient
had classic mononucleosis symptoms; most others had a non-
specific prodrome of fever (81%) and headache (66%) (40).
Seizures occurred in almost half (48%) (40). Some individuals
with EBV-associated encephalitis experience micropsia, mac-
ropsia, and/or size distortion. This pattern of unusual images
of body and objects is referred to as the Alice in Wonderland
syndrome (41). There are sporadic reports in the literature
that reactivation of chronic EBV infection in adults may cause
neurologic manifestations, including encephalitis (42).
Human Herpesviruses 6 and 7
Human herpesvirus-6 (HHV-6), the primary cause of ro-
seola infantum in young children, has been identified as the
causal agent of 10% to 20% of febrile seizures and is also
occasionally associated with encephalitis (43,44) (see Chapter
13). Several studies of encephalitis in children have identified
HHV-6 as a causative agent, with the incidence of HHV-6
encephalitis ranging from 1% to 11% of cases (4549). In
one study of nine children with HHV-6 CNS infections,
characteristic clinical features included fever, gastroenteritis,
rash, seizures, and ataxia (50). Another case series reported
three pediatric patients with HHV-6associated rhomben-
cephalitis; clinical manifestations included encephalopathy,
seizures, ataxia, and myoclonus (51). HHV-7, a recently de-
scribed herpesvirus, is occasionally associated with roseola
and is typically acquired in the first few years of life. Recent
studies from the United Kingdom suggest HHV-7 may be an
important cause of febrile seizures and encephalitis in young
children (52).
Enteroviruses and Parechoviruses
Enteroviruses (EVs) are small, nonenveloped, single-stranded
RNA picornaviruses. Similar to herpesvirus infections, EV
infections are very common, and neurologic complications,
including encephalitis, represent a rare complication of EV
infection. Because EV infections occur frequently in children,
they are a leading cause of encephalitis in children and are
responsible for 10% to 15% of encephalitis cases for which an
etiology is identified (53). In general, EVs cause a milder clini-
cal illness than many other etiologies of encephalitis. In the
California Encephalitis Project, EV encephalitis patients had
less severe manifestations, including lower frequencies of coma
and shorter hospitalization stays than those due to other agents
(54). CNS infections with EV-71 are an important exception
to the decreased severity of EVs (55,56). In addition to caus-
ing acute flaccid paralysis (aka polio-like syndrome), EV-71
has also been associated with a distinctive form of encephalitis
initially described in Taiwan and Malaysia (55,57). Most cases
were in young children (younger than 5 years of age), with a
characteristic hand, foot, and mouth rash along with ataxia,
nystagmus, myoclonus, and oculomotor palsies (55). The
predominant neurologic presentations included myoclonus
(68%), vomiting (53%), and ataxia (35%) (57). Many of the
fatalities associated with EV-71 are due to pulmonary edema
2/21/14 5:31 PM
 86 Part II: Viral Infections and Related Disorders
and hemorrhage, which are thought to be a consequence of
pronounced autonomic instability due to lesions in the me-
dulla and spinal cord (58,59). Sporadic outbreaks involving
substantial numbers of EV-71 encephalitis cases have been ob-
served among young children in Europe and Asia over the past
several decades (6062).
The reclassification of former EVs, echovirus 21 and echo-
virus 22, resulted in the human parechovirus (HPeV) genus.
Echoviruses 21 and 22 are currently classified as HPeV-1 and
HPeV-2, respectively. At least 12 HPeV serotypes have been
described to date; nearly all have been associated with enceph-
alitis, typically in children younger than 2 years of age (63,64).
Clusters of HPeV-3 CNS infections have been reported (65).
Young children and infants with HPeV encephalitis develop
fever, seizures, irritability, feeding problems, and rash (66).
The relative frequency of HPeV encephalitis is unknown,
particularly because HPeV testing has only recently become
available.
Arboviruses
Arboviruses, viruses transmitted by an arthropod vector, are
well-recognized causes of encephalitis. The vast majority of
neurologic illnesses seen in humans are caused by three arbo-
virus families: Togaviridae, Flaviviridae, and Bunyaviridae (see
Chapter 15).
West Nile virus (WNV), a flavivirus, was first detected in
the Western Hemisphere in 1999 in New York City and rapidly
spread across North America from the Atlantic to the Pacific
coasts and into Mexico and Canada. It is the now the most
common cause of arboviral encephalitis in the United States
(67). Most individuals infected with WNV will experience
subclinical infection (70% to 80%) or febrile illness (20% to
30%). Less than 1% of infected individuals develop West Nile
neuroinvasive disease (WNND), which includes meningitis,
encephalitis, and/or acute flaccid paralysis.
WNND is more common in older individuals, with an inci-
dence of 1.35 per 100,000 in persons 70 years of age or older
compared with 0.05 per 100,000 in persons younger than
10 years of age (67). Other risk factors for WNND include
male gender, hypertension, diabetes, renal disease, and immu-
nosuppression (68,69). Characteristic presentations of WNND
include altered mental status or lethargy with or without move-
ment disorders (tremors, Parkinsonism, or myoclonus). Acute
flaccid paralysis is also a feature of WNV infection and can be
seen along with encephalitis or may occur in isolation (70,71).
Although the number of WNND cases has far surpassed the
number of cases due to other arboviruses in recent years, other
arboviruses in the United States cause seasonal outbreaks and
sporadic cases of neurologic disease. These include La Crosse
virus (LACV), eastern equine encephalitis virus (EEEV),
Powassan virus (POWV), and St. Louis encephalitis virus
(SLEV). In 2012, over 2,500 WNND cases were recognized
in the United States compared with 78 LAC cases (71 neuro-
invasive), 15 EEE cases (all neuroinvasive), 7 POW cases (all
neuroinvasive), and 2 SLE cases (1 neuroinvasive) (72).
LACV, primarily found in the upper Midwestern, mid-Atlantic,
and Southeastern regions of the United States, is the second most
common cause of arbovirus-associated CNS infections in the
United States. Unlike WNV, most neuroinvasive LACV cases
occur in the pediatric population rather than in adults; in 2012,
86% of cases were younger than 20 years of age (73).
Outside the United States, other arboviruses predominate.
Japanese encephalitis virus (JEV) is the most common cause of
mosquito-borne encephalitis worldwide. An estimated 50,000
cases of JEV clinical disease occur annually, primarily in chil-
dren younger than 10 years of age in Asia, South Asia (east of
Pakistan), and Southeast Asia (7476).
Scheld_Ch06.indd 86
Similar to many other arboviruses, most JEV infections are
asymptomatic, with less than 1% of infections leading to clini-
cal disease. When symptoms occur, encephalitis is the most
common presentation. After a characteristic febrile prodrome
including headache and vomiting, mental status changes,
seizures, focal neurologic deficits, and movement disorders
develop. Similar to patients with WNV, those affected by JEV
can also develop acute flaccid paralysis (77).
In Europe, tick-borne encephalitis virus (TBEV), another
flavivirus, is the most common cause of arboviral encephali-
tis (78). It is also found in China and Japan. Analogous to
WNV, neuroinvasive disease is more common in older popu-
lations (79). Growing numbers of cases have been recognized
in recent years as a result of improvements in diagnostics and
case reporting as well as increased recreational activities in
tick-infested areas (80). In Europe and Russia, there was an
average of 8,755 reported cases per year from 1990 to 2007
compared to an average of 2,755 cases per year from 1976 to
1989 (81). TBEV is characterized by three different subtypes:
European (TBEV-Eu), Siberian (TBEV-Sib), and Far Eastern
(TBEV-Fe). The TBEV-Eu subtype circulates predominantly
in Western, Central, Northern, and Eastern Europe; the
TBEV-Sib circulates predominantly in Asian parts of Russia;
and TBEV-Fe circulates predominantly in China, Japan, and
Eastern Russia. The clinical spectrum of disease ranges from
mild meningitis to severe meningoencephalitis with or with-
out paralysis (82). In individuals affected with the European
virus subtype, the illness is often biphasic, with the first stage
characterized by fever, fatigue, general malaise, headache,
and body pain. During the second phase of the illness, clini-
cal manifestations range from mild meningitis to severe en-
cephalitis, with or without myelitis and paralysis. Seizures
are uncommon. The disease associated with TBEV-Fe sub-
type is the most severe, with a case fatality of 20% to 40%
and higher rates of neurologic sequelae compared with other
subtypes (82).
Although JEV is recognized to cause more cases of enceph-
alitis than any other mosquito-borne virus worldwide, dengue
viruses are the most prevalent arboviruses that infect humans
and result in an estimated 390 million infections every year
(83). Infections with dengue typically result in dengue fever,
dengue hemorrhagic fever, and dengue shock syndrome.
Unlike many of the aforementioned arboviruses, neurologic
manifestations of dengue have traditionally been considered
to be the result of an encephalopathy rather than encephalitis.
However, detection of dengue viral RNA in brain tissue, virus
isolation in CSF, and the presence of dengue-specific CSF an-
tibody suggesting intrathecal synthesis have been described in
recent studies and strongly suggest the neuroinvasive potential
of dengue (8486).
Rabies
Rabies virus is one of the oldest known infectious diseases and
is considered to be the most deadly of all infectious diseases
(see Chapter 17). The number of rabies encephalitis cases in
the United States has declined dramatically from an average
of 100 or more cases per year before 1940 to only 2 to 3 cases
per year (87). Although rabies is rare in the United States, an
estimated 50,000 rabies cases occur annually worldwide; most
are acquired via rabid dog contact (88). In Asia, Africa, and
Latin America, animal rabies control programs and postexpo-
sure prophylaxis are limited. A recent report of 49 rabies cases
in the United States, from 1995 to 2011, identified 10 im-
ported and 39 cases acquired in the United States; of the cases
acquired in the United States, one was associated with a rac-
coon strain of rabies, and the rest were due to bat exposures.
The incubation period is generally between 20 and 60 days but
2/21/14 5:31 PM

can range from a few days to several years (89). Paresthesia
at the site of the bite is unique to rabies and can be an im-
portant clue to the diagnosis. Approximately 80% of human
rabies cases develop the encephalitic (furious) form charac-
terized by unusual behavior, extreme agitation, hydrophobia,
delirium, and seizures. The remainder of cases develops the
paralytic (dumb) form which is characterized by ascending
paralysis followed by confusion and coma. Patients generally
have a predominance of one form, but many affected individu-
als have components of both forms.
Lymphocytic Choriomeningitis Virus
Lymphocytic choriomeningitis (LCM) virus is an Old World
arenavirus that can be acquired from infected house mice,
hamsters, and guinea pigs. Humans become infected with
LCM virus when aerosolized saliva, respiratory secretions, or
urine from rodents or virus-contaminated dust are inhaled or
possibly ingested. Infections occur more frequently in the win-
ter months when rodents migrate indoors (90). The incidence
of LCM is unknown but appears to have decreased substan-
tially in the last several decades due to improvements in hous-
ing, which have resulted in less contact between house mice
and humans. However, it is likely that cases continue to occur
but are not recognized (91). LCM often results in a bipha-
sic illness with an initial phase of fever, anorexia, headache,
muscle aches, nausea, and vomiting. Several days later, CNS
symptoms can occur with either meningitis or encephalitis.
Extra-CNS manifestations may also be present, including or-
chitis, parotitis, arthritis, or alopecia (92,93).
Hendra Virus
Hendra virus is a paramyxovirus first recognized in Hendra,
Australia where it was associated with an outbreak of respira-
tory and neurologic disease in horses and humans in 1994.
The natural reservoir of the virus is thought to be flying foxes
(bats of the genus Pteropus). The virus is transmitted from
bats to horses and then transmitted to humans as a result of
direct contact with infected horses. More than 60 equine and
4 human fatalities have been reported (94). The high fatality
rate of this infection in horses and people, as well as the large
reservoir species, underscores the potential of this virus, and
other similar viruses, to emerge and cause outbreaks of severe
illness. Human illness due to Hendra virus is characterized by
influenza-like symptoms often followed by acute encephalitis.
A relapsing neurologic syndrome has also been described in a
few individuals (94).
Nipah Virus
Nipah virus, another emerging paramyxovirus, was first rec-
ognized in 1999 and associated with an encephalitis outbreak
among pig farmers in Malaysia. This virus has also caused
outbreaks in Singapore, Australia, Bangladesh, and India
(9597). Human infections can range from asymptomatic in-
fection to fatal encephalitis. When neurologic illness occurs,
individuals often experience influenza-like illness followed by
dizziness, excess drowsiness, and altered consciousness.
Measles Virus
Measles virus infection causes acute encephalitis in approxi-
mately 1 in 1,000 cases, often resulting in permanent brain
injury (see Chapter 8). Although indigenous transmission of
measles was eliminated in the United States in 2000, it is
still a common infection in much of the world. In addition
to acute encephalitis, measles is associated with subacute
sclerosing panencephalitis (SSPE), an indolent, progressive,
Scheld_Ch06.indd 87
Chapter 6: Encephalitis 87
and often fatal form of encephalitis that typically occurs 7
to 12 years after the initial infection and usually affects chil-
dren between 10 and 14 years of age (98,99). A history of
prior measles vaccination does not preclude the diagnosis of
SSPE because an unrecognized measles infection may occur
at an early age prior to immunization. This is supported
by molecular studies that have identified wild type measles
virus (rather than vaccine-type virus) from brain specimens
of SSPE cases (100). Early clinical features of SSPE include
personality and behavior changes, lethargy, decline in school
performance, and hyperactivity. More pronounced neuro-
logic manifestations such as aphasia, difficulty walking, and
involuntary movements (e.g., tremors, myoclonic jerks, and
choreoathetosis) later ensue. In the final stages, neurologic
deterioration resulting in a vegetative state occurs in most
affected patients (99).
Bacteria
While many infectious encephalitis cases have a viral etiol-
ogy, bacterial causes are important to consider in the diag-
nosis either as a mimicker of encephalitis or as an actual
cause of encephalitis. For example, Neisseria meningitidis and
Streptococcus pneumoniae do not cause encephalitis per se
but can cause clinical manifestations that are indistinguishable
from encephalitis. Mental confusion, drowsiness, convulsions,
and coma are not uncommon manifestations of N. meningiti-
dis and S. pneumoniae bacterial meningitides (see Chapter 24).
Mycobacterium tuberculosis
Although meningitis is the most common form of neurotu-
berculosis, Mycobacterium tuberculosis was the third leading
cause of encephalitis in a French study where it was identi-
fied in 15% of cases (101). In England, from 2005 to 2006,
M. tuberculosis was the causative agent in 12% of encephalitis
cases with an identified cause (29). Analogously, in a multi-
center study of encephalitis in Taiwan, M. tuberculosis was
the third most common cause of encephalitis in both pediat-
ric and adult patients (31). Of 20 patients with M. tubercu-
losis encephalitis referred to California Encephalitis Project
(CEP) between 1998 and 2005, many had features in common
with patients with viral encephalitis, including fever (75%),
altered consciousness (65%), personality change (45%), and
hallucinations (16%) (102). Because the base of the brain is
often affected by M. tuberculosis, signs referable to cranial
nerves are often seen along with fever, headache, irritability,
and drowsiness. Diffuse meningeal irritation may also result
in impairment of CSF resorption with accompanying hydro-
cephalus (see Chapter 29).
Listeria monocytogenes
Unlike S. pneumoniae and N. meningitidis that rarely cause
parenchymal brain infections, Listeria monocytogenes has tro-
pism for the brain parenchyma itself as well as the meninges
(103). The most common CNS manifestation of listeriosis is
of an isolated meningitis, but approximately 10% of patients
present with brainstem encephalitis, encephalitis, diffuse cere-
britis, or abscess in cerebral cortex or spinal cord (104). In the
French study cited earlier, L. monocytogenes was the fourth
most common etiology identified (101). Reported risk factors
for CNS Listeria include male gender, immunosuppression,
chronic illness, and advanced age (35,105108). Conversely,
an in-depth review of Listeria rhombencephalitis found that
it was reported primarily in healthy, nonimmunosuppressed
middle-aged adults and affected both genders equally (109).
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 88 Part II: Viral Infections and Related Disorders
Clinically, a biphasic disease course may be seen; a nonspecific
prodrome lasting several days is typical of the first phase. The
prodrome itself is similar to many viral illnesses with fever,
headache, nausea, and vomiting, but the duration of prodrome
is longer in CNS Listeria illnesses compared with viruses. The
second phase is characterized by progressive asymmetric cra-
nial nerve palsies, cerebellar signs (e.g., ataxia or dysmetria),
hemiparesis, and altered level of consciousness (109).
Treponema pallidum
Treponema pallidum, the cause of syphilis, is yet another bac-
terial infection that can potentially be confused with CNS viral
etiologies. Syphilis, also known as the great mimicker, can be
difficult to recognize; this is particularly true for neurologic pre-
sentations. Neurologic manifestations can occur during any stage
of the infection and include meningeal syphilis, meningovascular
syphilis, paretic neurosyphilis, and tabes dorsalis (see Chapter 38).
Borrelia Species
Borrelia burgdorferi, the causative agent of Lyme disease, is
primarily endemic to the eastern United States, although reser-
voirs are also present in the Pacific Northwest and Midwestern
states. Notably, the geographic range is expanding. Lyme dis-
ease can affect both the peripheral and central nervous system;
CNS involvement is typically characterized by meningitis, al-
though encephalitis can rarely occur (see Chapter 39).
Rickettsia
Rickettsial infections can also cause encephalitis. Of the rick-
ettsial diseases, Rocky Mountain spotted fever (RMSF) and
epidemic typhus are most commonly associated with neuro-
logic manifestations (110). In patients with RMSF, an intense
headache along with restlessness, irritability, confusion, and
delirium often occur. General or focal neurologic impairment
including vertigo, seizures, hemiparesis, and ataxia may also
be present (111). In a study of 92 children hospitalized with
RMSF in the southeastern and south central United States from
1990 through 2002, 33% had altered mental status, 18% pho-
tophobia, 17% seizures, and 10% coma (112). Ophthalmic
features including photophobia, conjunctivitis, petechiae of
the bulbar conjunctiva, exudates and retinal venous engorge-
ment, papilledema, and ocular palsies are frequently described
(113,114). Acute temporary hearing impairment may also
occur (115). Similar neurologic complications have also been
described for other rickettsial infections, although generally
are not as severe (116) (see Chapter 27).
Parasites and Free-Living Ameba
A number of parasites can cause encephalitis via direct in-
vasion of the brain. Helminthes including various ascaris,
hookworms, Gnathostoma spinigerum, Angiostrongylus canto-
nensis, Spirometra spp., Alaria spp., and others can cause larva
migrans, which refers to the prolonged migration and persis-
tence of helminth larvae in the tissues of humans (117,118).
Larva migrans can result in visceral (VLM), ocular (OLM),
neural (NLM), and cutaneous larva migrans (CLM) based on
the organ systems involved (118). VLM and NLM are usually
diseases of childhood, affecting children ages 1 to 8 years old.
B. procyonis, a common ascarid roundworm in raccoons,
causes an eosinophilic encephalitis in humans and other
animals. It is most commonly identified in children and,
although it is rare, often results in a severe and fatal illness.
Scheld_Ch06.indd 88
B. procyonis occurs in raccoons in North America, Europe,
and parts of Asia (119). More than 90% of juvenile raccoons
are infected in some areas of the United States (118). Humans
become infected by ingesting raccoon roundworm eggs in rac-
coon feces, by soil or water contaminated with raccoon feces,
or via contaminated hands. Small children are particularly vul-
nerable to infection because of their propensity to place dirt
and other objects in their mouths.
Other important neurotropic helminthes associated with
eosinophilic encephalitis or meningitis includes G. spinigerum
and Angiostrongylus species. Gnathostomiasis, most com-
monly caused by the nematode G. spinigerum, is a cause of
eosinophilic myeloencephalitis. G. spinigerum is endemic in
Southeast Asia and is increasingly being recognized in Central
and South America (120,121). Most cases are associated with
the ingestion of raw or undercooked fish, frogs, snakes, chick-
ens, or ducks. The median time from ingestion of infected food
to onset of symptoms may be several weeks to several months
(122). Common early symptoms may include sporadic epi-
sodes of cutaneous larva migrans (creeping eruption) with
localized pain and pruritus. When CNS involvement occurs,
it may result in the sudden onset of radicular pain or head-
ache. Paralysis of the extremities and loss of bladder control
may also occur (123). Cranial nerve abnormalities are also de-
scribed. Intermittent symptoms can occur for 10 to 15 years
after exposure because the larvae are long lived (124).
A. cantonensis, the rat lungworm, is the principal cause
of human eosinophilic meningitis worldwide, and although
many cases are self-limiting, severe forms of the disease
occur (125,126). Angiostrongylus spp. have been reported
in Louisiana and Hawaii as well as the South Pacific, Asia,
Australia, and the Caribbean (127,128). Humans become in-
fected by ingestion of the third stage larvae in the molluscan
intermediate host (e.g., snails, crabs, freshwater prawns) or
contaminated vegetables. Following ingestion, the larvae pen-
etrate the intestinal wall and reach the CNS via the blood-
stream. Clinical illness often consists of severe headache,
photophobia, meningeal signs, hyperesthesia, and paresthesia.
Coma, paralysis of extremities, and seizures are seen in the se-
vere forms of the disease (125,126). Conjunctivitis, periorbital
swelling, retinal hemorrhage, retinal detachment, or blindness
may occur if the eye is infected (129,130) (see Chapter 46).
Free-living ameba are ubiquitous in nature, and a few have
been associated with human disease. Those causing encephali-
tis are generally divided into two clinical entities: (a) primary
amebic meningoencephalitis due to Naegleria fowleri (also
known as the brain-eating ameba), and (b) granulomatous
amebic encephalitis.
Primary amebic meningoencephalitis (PAM) is a fulminant
disease occurring in children and young adults. The disease has
been reported in Australia, Europe, Asia, Africa, and North
America. In the United States, most of the cases have developed
in the southern tier of the country, where warm water condi-
tions are more likely to be encountered. Typically, humans be-
come infected with N. fowleri while swimming or washing in
warm, fresh water containing the ameba. Recent cases associ-
ated with the use of neti pots where N. fowlericontaminated
tap water were implicated as the source of infection have also
been described (131). The onset of PAM is usually within 2 to
3 days after exposure, and symptoms include severe headache,
fever, stiff neck, nausea, vomiting, diplopia, seizures, behav-
ioral changes, and coma (132135). Distortion of taste or smell
may also be a clinical feature (136,137). The case fatality rate
is very high; of 111 reported cases in the United States between
1962 and 2008, only one individual survived (131).
Two different closely related ameba cause granuloma-
tous encephalitis: Acanthamoeba spp. and B. mandrillaris.
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Acanthamoeba granulomatous encephalitis is an opportunistic,
chronic disease that may have a prodromal period of weeks to
months. Predisposing factors to acanthamebiasis include ste-
roid treatments, autoimmune conditions, organ transplants,
chemotherapy, radiation therapy, alcoholism, and pregnancy
(134,138). A small number of Acanthamoeba granulomatous
encephalitis cases have been described in immunocompetent
children. Clinical features of CNS Acanthamoeba infections
are variable but typically have a subacute to chronic presenta-
tion with fever, headache, seizures, personality change, leth-
argy, or confusion. Cranial nerve palsies, meningeal signs, or
hemiparesis may be seen on physical exam (138). Children
infected with Acanthamoeba have exhibited headache, stiff
neck, vomiting, abnormal behavior, fever, ataxia, and tonic-
clonic seizures (139141).
When first described, B. mandrillaris was considered
to be very rare, but recent reports suggest it may be more
common than previously recognized (142145). Symptoms
of Balamuthia granulomatous encephalitis include fever,
headache, vomiting, ataxia, hemiparesis, tonic-clonic sei-
zures, cranial nerve palsies (third and sixth cranial nerves),
and diplopia (146). Otitis media has preceded the onset of
Balamuthia granulomatous encephalitis in several pediat-
ric cases (146,147). Hydrocephalus develops in many cases
(147,148). Interestingly, two independent case reports involv-
ing Balamuthia encephalitis patients describe associated CNS
aneurysms (149,150) (see Chapter 45).
Fungi
Although fungal CNS infections do not cause encephalitis per
se and often manifest as meningitis and abscesses, some pa-
tients present with encephalitis-like symptoms. These illnesses
are more common in immunocompromised individuals, but
fungal neurologic infections can be seen in immunocompetent
individuals. Important fungal causes of CNS infections in the
United States include Cryptococcus neoformans, Coccidioides
immitis, Histoplasma capsulatum, and Blastomyces dermatiti-
dis. Cryptococcus gattii is an emerging fungal infection in the
United States, particularly in the Pacific Northwest, and has
a greater tendency to affect normal hosts than Cryptococcus
neoformans (151) (see Chapter 40).
Other Agents
Hundreds of other infectious agents have been associated with
encephalitis, but the frequency and significance of many of
them are unknown. This is especially true when a nonneu-
rotropic agent is found in a patient with encephalitis, par-
ticularly when the agent is identified outside the CNS. For
example, Mycoplasma pneumoniae is one of the most com-
monly diagnosed infections among children with encephalitis
(see Chapter 25). However, the significance of this association
is unclear, particularly as most of the diagnoses are based on
a positive immunoglobulin M (IgM) antibody to M. pneu-
moniae. M. pneumoniae is a ubiquitous pathogen, and there is
a high background incidence of acute infection. Furthermore,
there are many limitations of Mycoplasma serologic test-
ing (152). Other similar examples of nonneurotropic agents
implicated as causative agents include parvovirus B19, rotavi-
rus, and human metapneumovirus (153155).
Although the association of influenza viruses and en-
cephalitis is better documented and more accepted than
parvovirus B19, rotavirus, or human metapneumovirus, the
mechanism by which influenza leads to neurologic illness is
Scheld_Ch06.indd 89
Chapter 6: Encephalitis 89
poorly understood. Influenza-associated encephalitis (IAE)
and encephalopathy is typically characterized by a rapidly
progressive neurologic illness. Cases have been described
sporadically and follow the seasonal influenza pattern, with
illnesses typically occurring during winter months in temper-
ate climates. IAE is more common in the pediatric population
than in adults. Evidence of neuroinvasion by influenza is rarely
seen; these cases are better characterized as an encephalopathy
rather than encephalitis. Many cases of IAE, especially acute
necrotizing encephalopathy (ANE), have been reported from
Japan, but cases of encephalitis and encephalopathy have been
reported throughout the world, including the United States
(156,157). Several case reports and case series describe neu-
rologic illness associated with the pandemic H1N1 influenza
virus, including encephalitis/encephalopathy (158160).
Similarly, the neurologic illness associated with Bartonella is
often an encephalopathy rather than encephalitis. Cat-scratch
disease (CSD), typically caused by Bartonella henselae, is usu-
ally a self-limited infection associated with fever, regional
lymphadenopathy, and malaise. As the name implies, many
affected individuals have contact with a cat, often a kitten.
Atypical presentations can occur especially in children and
young adults and immunocompromised individuals. In a case
series of 130 CSD cases in Japan, 19 (15%) had encepha-
lopathy (161). Although lymphadenopathy is a hallmark of
CSD, it is not always present in encephalopathy cases (161).
Neuroretinitis can be an associated feature as well (162).
ACUTE DISSEMINATED
ENCEPHALOMYELITIS
The incidence of acute disseminated encephalomyelitis
(ADEM) is estimated to be 0.4 to 0.8 per 100,000 and it ac-
counts for 10% to 15% of encephalitis cases in the United
States (163165). It is more common in children than adults,
and many cases of ADEM have an identifiable trigger such
as a recent illness or vaccination. Neurologic symptoms typi-
cally develop 2 to 4 weeks after the trigger with rapid pro-
gression of symptoms (165). Prior to the widespread use of
vaccine-preventable diseases in the United States, measles and
mumps were common triggers of ADEM. In regions of the
world where vaccines are widely used to prevent measles and
mumps, such as the United States and Canada, upper respira-
tory infections are now the most commonly identified triggers
of ADEM.
ADEM affects multiple regions of the brain and spinal cord
and is characterized by the rapid onset of encephalopathy
along with multifocal neurologic deficits. Up to three quar-
ters of patients with ADEM will have altered mental status,
whereas seizures occur in 10% to 35% of patients (165).
Motor deficits (e.g., acute hemiparesis), ataxia, decreased ver-
bal output or mutism, cranial neuropathies, and urinary disor-
ders are common (166). Recovery can be complete, although
residual deficits can occur in up to 30% of patients.
NONINFECTIOUS ETIOLOGIES
There is growing recognition that immune-mediated condi-
tions result in a substantial proportion of cases of encephalitis.
AntiN-methyl-d-aspartate receptor (NMDAR) encephalitis,
a relatively newly recognized neuronal antibody-associated
encephalitis, deserves special mention because of the seemingly
high frequency of the syndrome. In the California Encephalitis
Project, the frequency of anti-NMDAR encephalitis surpasses
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 90 Part II: Viral Infections and Related Disorders
that of any single viral entity in the pediatric population and
also contributes to cases in adulthood (167).
Clinically, anti-NMDAR encephalitis is characterized by ab-
normal behavior, seizures, and movement disorders followed by
decreased level of consciousness and autonomic instability and
may be associated with ovarian teratoma (168). Importantly, the
development of prodromal symptoms of headache, low-grade
fever, or a nonspecific viral-like illness prior to the onset of neuro-
logic symptoms in many patients may initially suggest the diagno-
sis of an infectious, rather than autoimmune, encephalitis (168).
Another important cause of immune-mediated encephalitis
is antivoltage-gated potassium channel (VGKC) encephalitis.
Patients are typically older than 50 years of age, present with
symptoms of limbic encephalitis (memory dysfunction, be-
havioral changes, and seizures) and hyponatremia, and rarely
have an underlying neoplasm. Although antibodies were ini-
tially thought to recognize the VGKC receptor, subsequent
studies have demonstrated that the target of autoimmunity
is usually a different antigen (i.e., LGI1 or CASPR2) that is
tightly associated with the VGKC complex (168,169). Several
other antibodies are also associated with limbic encephalitis,
including those that recognize glutamic acid decarboxylase
(GAD), AMPA receptor, and the -aminobutyric acid (GABAb)
receptor. Intracellular onconeural antibodies associated with
paraneoplastic conditions (e.g., anti-Hu, Yo, Ma2, CV2,
amphiphysin, CRMP5, etc.) also need to be considered (170).
PATHOLOGY
Given the many different etiologies of encephalitis, the pathol-
ogy is highly variable and dependent not only on the under-
lying etiology but also the relative severity of the infection.
The characteristic histology of patients with viral encephalitis
includes perivascular mononuclear cell inflammation, phago-
cytosis of neurons, and microglial nodules. Distinctive char-
acteristic histopathologic features are seen with some viral
infections; intranuclear inclusion bodies are sometimes seen in
herpes simplex and varicella zoster, whereas Negri bodies (eo-
sinophilic cytoplasmic inclusions) are found within Purkinje
cells and are pathognomonic for rabies (Fig. 6.1).
EVs, parechoviruses, herpesviruses, arboviruses, and rabies
have well-established neurotropic potential where the virus di-
rectly invades the CNS and primarily affects the gray matter of the
brain. Other viruses, such as measles and rubella viruses, primarily
affect the white matter of the brain by triggering an autoimmune
reaction and result in a postinfectious encephalitis (e.g., ADEM).
Symptoms indistinguishable from viral encephalitis can be seen in
Scheld_Ch06.indd 90
patients with bacterial meningitis and rickettsial infections where
associated vasculitis and elaboration of toxins can lead to CNS
dysfunction. Intense inflammatory responses to fungi, free-living
ameba, and parasites can also lead to CNS dysfunction.
Organisms enter the CNS by different routes. Most enter via
the bloodstream, as is the case for EVs, HPeVs, and arboviruses as
well as several bacteria, rickettsia, and fungal agents (171). Once
the agent reaches the CNS, the bloodbrain barrier is penetrated
via the choroid plexus or through vascular endothelium (172).
The proposed mechanism for entry into brain of the ame-
bae varies by organism. For example, Balamuthia is thought to
enter the CNS via a hematogenous route, with ameba entering
the bloodstream either from the lungs or from cutaneous lesions.
Naegleria ameba, on the other hand, enter the nasal passages
and directly extend into the CNS by penetrating the olfactory
mucosa, entering the submucosal nervous plexus, migrating
along the olfactory nerves, and traversing the cribriform plate. A
distinct mechanism of entry via axon transport resulting in intra-
neuronal route is used by some viruses such as rabies and HSV-1.
Within the CNS, the pathogen often targets specific cells
and, depending on the brain region affected, variable clinical
manifestations ensue (173). Agents with specific predilection to
areas such as the brainstem (e.g., EV-71 and Listeria) can cause
rapid decompensation with coma or respiratory failure. Herpes
simplex encephalitis characteristically affect the temporal lobes
and cause hemorrhage and necrotizing lesions (174) (Fig. 6.2).
WNND has a predilection for the gray matter of the brain-
stem and spinal cord, but cerebellum, temporal lobe, basal gan-
glia, and thalamus may also be affected (175). Indeed, many of
the neuroinvasive flaviviruses such as JEV, TBEV, and WNV
have a predilection for specific regions of the brain, including
those regions important for motor control (thalamus, basal
ganglia, brainstem, and anterior horn cells of spinal cord) (176).
In other instances, the infectious agents do not necessarily in-
fect neurons. Nonneuronal cells, such as oligodendroglia, may
be infected, with resultant demyelination (177). Alternatively, an
infection may cause immune changes that result in damage. EBV-
associated encephalitis, for example, may be a result of an im-
munologic phenomena rather than acute neuroinvasion. There is
typically a 1- to 3-week delay in the onset of neurologic symptoms
after acute EBV infection (40). Further, the virus itself is often not
found in the CSF (40). In one cohort of five EBV encephalitis pa-
tients with CNS demyelination, four had prodromal symptoms
for 2 weeks or more and did not have EBV detected by polymerase
chain reaction (PCR) in CSF (40). Conversely, the development of
neurologic symptoms either in the absence of, or within a few days
of prodrome onset in the presence of, EBV in the CSF is suggestive
of direct invasion. In the pediatric series cited previously, one such
FIGURE 6.1 Rabies encephalitis. Purkinje cell in cerebellum
with eosinophilic, intra-cytoplasmic inclusion (Negri body).
(Courtesy of Dr. Andrew Bollen, University of California, San
Francisco.)
2/21/14 5:31 PM

patient had EBV detected by PCR in brain tissue, suggesting that
direct invasion of the brain may occur in some cases.
Viruses such as influenza are well known to be associated
with CNS manifestations, but the mechanisms by which they
cause neurologic signs and symptoms are not well under-
stood. The lack of viral detection in most IAE cases in the
CNS strongly points to a different pathogenesis; a number of
potential mechanisms have been invoked, including excessive
production of proinflammatory cytokines, vascular endothe-
lial dysfunction, and mitochondrial dysregulation (178).
As discussed earlier, Listeria may be associated either with
a pure meningitis or encephalitis. Pathologically, a suppurative
reaction is seen in the meningitic form, whereas a granuloma-
tous response is seen in the meningoencephalitis form (104).
Rickettsial agents invade and multiply in vascular endothe-
lial cells, leading to vasculitis both within and outside the CNS
(179,180). Vasculitis in the small vessels in the brain leads to
meningeal irritation with perivascular mononuclear infiltrates.
Characteristic pathologic lesions within the CNS include mul-
tifocal glial nodules and arteriolar microinfarctions (181).
In partially treated bacterial meningitis and in tuberculous
and fungal meningitis, a chronic basilar meningeal inflamma-
tion can cause a subarachnoid exudate, leading to obstruction
of CSF reabsorption with resultant communicating hydro-
cephalus and cranial nerve palsies. CNS vasculitis can also
lead to infarcts and focal neurologic deficits.
N. fowleri, a free-living ameba, causes destruction of gray
matter and devastation of the olfactory bulbs with purulent
meningitis and pronounced brain edema (182). In Balamuthia
and Acanthamoeba CNS infections, a granulomatous reaction
occurs with affected areas including the cerebrum, cerebel-
lum, and brainstem, where the amebae produce hemorrhagic
A B
Scheld_Ch06.indd 91
Chapter 6: Encephalitis 91
FIGURE 6.2 Herpes simplex encephalitis. Herpes simplex type
1 encephalitis with hemorrhage and necrosis of the right tempo-
ral lobe. (Courtesy of Dr. Andrew Bollen, University of California,
San Francisco.)
necrotic lesions. Multinucleated giant cells, focal necrosis,
and hemorrhage are seen in brain histopathology. In some
instances, large sheets of ameba can be found in the perivascu-
lar areas of brain tissue (Fig. 6.3).
B. procyonis and other nematodes that invade the CNS
cause damage by CNS larval migration, with histology demon-
strating inflammation and necrosis with track-like spaces.
Pathologic findings of fatal cases demonstrate necrosis and
inflammation with eosinophils, macrophages, lymphocytes,
and plasma cells concentrated in periventricular white matter
and leptomeninges in brain tissue. A characteristic of NLM/
Baylisascaris infection is a large number of eosinophils and eo-
sinophil granules surrounding the nematode migration track
and blood vessels (183).
DIAGNOSTIC APPROACH OF
PATIENTS WITH ENCEPHALITIS
Identification of a specific etiology, even if there is no available
treatment, is important for counseling of patients and fami-
lies, potential postexposure prophylaxis of contacts, and other
public health interventions. Additionally, the identification of
a specific agent may lead to withdrawal of unnecessary an-
timicrobial agents and reduce further testing. Knowledge of
limitations of testing, appropriate test selection, and timing of
sample collection is crucial to optimal diagnosis.
A thorough assessment of exposures highlighting ill contacts,
occupational exposures, vector and animal exposures, outdoor
activities, and ingestions should be ascertained. Both recent (e.g.,
for arbovirus) and remote (e.g., rabies, fungal) travel history are
important. Any recent or current respiratory, gastrointestinal,
FIGURE 6.3 Histopathology of B. mandril-
laris infections: (A) Brain tissue stained with
hematoxylin and eosin (100) showing B. man-
drillaris. Note that these B. mandrillaris organisms
may be mistaken for lymphocytes or macrophages.
(B) Higher magnification (1000) demonstrat-
ing trophozoites of B. mandrillaris in brain tis-
sue, some with single nucleolus (dotted arrow) or
double nucleoli (solid arrow). (Courtesy of Dr.
Govinda Visvesavara, Centers for Disease Control
and Prevention.)
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 92 Part II: Viral Infections and Related Disorders

TA B L E 6 . 1
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN ADULTS

Routine Studies

CSF

Collect at least 20 mL fluid, if possible; freeze at least 510 mL fluid, if possible

Opening pressure, WBC count with differential, RBC count, protein, glucose
Gram stain and bacterial culture
HSV-1/HSV-2 PCR (if test available, consider HSV CSF IgG and IgM in addition)
VZV PCR (sensitivity may be low; if test available, consider VZV CSF IgG and IgM in addition)
Enterovirus PCR
Cryptococcal antigen and/or India ink staining
Oligoclonal bands and IgG index
VDRL

Serum

Routine blood cultures

HIV serology (consider RNA)
Treponema testing (RPR, specific treponemal test)
Hold acute serum and collect convalescent serum 1014 days later for paired antibody testing

Imaging

Neuroimaging (MRI preferred to CT, if available)

Chest imaging (chest x-ray and/or CT)

Neurophysiology

EEG

Other Tissues/Fluids

When clinical features of extra-CNS involvement are present, we recommend additional testing (e.g., biopsy of skin lesions,
bronchoalveolar lavage and/or endobronchial biopsy in those with pneumonia/pulmonary lesions, throat swab PCR/culture in
those with upper respiratory illness, stool culture in those with diarrhea); also see below.

Conditional Studies

Host Factors

ImmunocompromisedCMV PCR, HHV-6/HHV-7 PCR, HIV PCR (CSF); Toxoplasma gondii serology and/or PCR;
Mycobacterium tuberculosis testing; fungal testing; WNV testing

Geographic Factors

Africamalaria (blood smear), trypanosomiasis (blood/CSF smear, serology from serum and CSF), dengue testing
AsiaJapanese encephalitis virus testing, dengue testing, malaria (blood smear), Nipah virus testing (serology from serum and CSF;
PCR, immunohistochemistry, and virus isolation in a BSL4 lab can also be used to substantiate diagnosis)
AustraliaMurray Valley encephalitis virus testing, Kunjin virus testing, Australian bat Lyssavirus (ABLV) testing
Europetick-borne encephalitis virus (TBEV) (serology); if southern Europe, consider WNV testing, Toscana virus testing
Central and South Americadengue testing, malaria (blood smear), WNV testing, Venezuelan equine encephalitis testing
North Americageographically appropriate arboviral testing (e.g., WNV, Powassan, La Crosse, eastern equine encephalitis viruses,
Lyme [serum ELISA and Western blot])

(continued)

Scheld_Ch06.indd 92 2/21/14 5:31 PM

 Chapter 6: Encephalitis 93

TA B L E 6 . 1
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN ADULTS (CONTINUED)

Conditional Studies

Season and Exposure

Summer/fallarbovirus and tick-borne disease testinga

Cat (particularly if with seizures, paucicellular CSF)Bartonella antibody (serum), ophthalmologic evaluation
Tick exposuretick-borne disease test a
Animal bite/bat exposurerabies testing
Swimming or diving in warm freshwater or nasal/sinus irrigationNaegleria fowleri (CSF wet mount and PCR)

Specific Signs and Symptoms

Psychotic features or movement disorderanti-NMDAR antibody (serum, CSF); rabies testing; screen for malignancy, Creutzfeldt-
Jakob disease
Prominent limbic symptomsautoimmune limbic encephalitis testing; HHV-6/HHV-7 PCR (CSF); screen for malignancy
Rapid decompensation (particularly with animal bite history or prior travel to rabies-endemic areas)rabies testing
Respiratory symptoms Mycoplasma pneumoniae serology and throat PCR (if either positive, then do CSF PCR); respiratory virus testing
Acute flaccid paralysisarbovirus testing, rabies testing
Parkinsonismarbovirus testing, Toxoplasma serology
Nonhealing skin lesionsBalamuthia mandrillaris, Acanthamoeba testing

Laboratory Features

Elevated transaminasesrickettsia serology, tick-borne diseases testinga

CSF protein 100mg/dL, or CSF glucose 2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset
M. tuberculosis testing, fungal testing
CSF protein 100 mg/dL or CSF glucose 2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and
recent antibiotic useCSF PCR for Streptococcus pneumoniae and Neisseria meningitidis
CSF eosinophiliaM. tuberculosis testing, fungal testing, Baylisascaris procyonis antibody (serum), Angiostrongylus cantonensis and
Gnathostoma sp. testing
RBCs in CSFNaegleria fowleri testing
Hyponatremiaanti-VGKC antibody (serum); M. tuberculosis testing

RBC, red blood cell; VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; EEG, electroencephalogram; CMV, cytomegalovirus.
a
Tick-borne disease testing should be tailored to specific geographic region and typically consists of serology (i.e., Borrelia, Ehrlichia, Rickettsia sp.,
Anaplasma phagocytophilum, TBEV) and blood PCR (Ehrlichia, Anaplasma).
Data from Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the
International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):11141128.

or rash illness should be investigated. Based on this information,
specific assays can be performed (Tables 6.1 and 6.2) (184).
A complete blood count, renal function tests, hepatic enzyme
levels, and coagulation studies should be included in the evalua-
tion of a patient with suspected encephalitis. An initial chest radio-
graph should also be performed as focal infiltrates are suggestive
of certain pathogens (e.g., fungal or mycobacterial infections) and
might lead to other diagnostic studies (e.g., bronchoscopy). A
thorough eye exam by an ophthalmologist may identify a migra-
tory nematode which would considerably narrow the differential.
Unless there is a specific contraindication, a lumbar puncture
(LP) with cerebrospinal fluid (CSF) analysis (cell count with dif-
ferential analysis, glucose and protein concentrations) and a mea-
surement of the opening pressure should be performed (185). A
simultaneous peripheral glucose should also be measured and is
particularly important in a diabetic patient because what appears
to normal CSF glucose might actually be low if the ratio of
CSF to serum glucose is not taken into consideration (102). The
CSF sample should be analyzed promptly, particularly because
neutrophils degrade within a few hours (186). Additionally, if
the CSF cell counts are performed by an automated cell counter,
eosinophils can be mistaken for neutrophils. Accurate identifica-
tion of eosinophils is best done by Giemsa or Wright stain of CSF
(128). The identification of CSF oligoclonal bands, representing
intrathecal antibody synthesis, is a nonspecific finding but can be
helpful in corroborating an infectious or inflammatory etiology.
The CSF profile offers important diagnostic clues on
whether a patient has an infectious or noninfectious etiology
and, within the infectious sphere, whether the cause is likely
viral, bacterial, fungal, or parasitic. The CSF profile in most
viral encephalitis patients demonstrates CSF mononuclear
cell pleocytosis, with cell counts ranging from 10 to 200 mg/
dL. However, several studies have shown that pleocytosis can
be absent or there may be an elevation in neutrophils early
in the course. Although many textbooks mention that poly-
morphonuclear leukocytes (PMNs) can predominate the first
24 hours of viral CNS infections and suggest that a shift to
mononuclear cells occurs after that time period, there have

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 94 Part II: Viral Infections and Related Disorders

TA B L E 6 . 2
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN CHILDREN

Routine Studies

CSF

Collect at least 5 mL fluid, if possible; freeze unused fluid for additional testing
Opening pressure, WBC count with differential, RBC count, protein, glucose
Gram stain and bacterial culture
HSV-1/HSV-2 PCR (if test available, consider HSV CSF IgG and IgM in addition)
Enterovirus PCR

Serum

Routine blood cultures

EBV serology (VCA IgG and IgM and EBNA IgG)
Mycoplasma pneumoniae IgM and IgG
Hold acute serum and collect convalescent serum 1014 days later for paired antibody testing

Imaging

Neuroimaging (MRI preferred to CT, if available)

Neurophysiology
EEG
Other Tissues/Fluids
M. pneumoniae PCR from throat sample
Enterovirus PCR and/or culture of throat and stool
When clinical features of extra-CNS involvement are present, we recommend additional testing (e.g., biopsy of skin lesions,
bronchoalveolar lavage and/or endobronchial biopsy in those with pneumonia/pulmonary lesions, throat swab PCR/culture in
those with upper respiratory illness, stool culture in those with diarrhea); also see below.

Conditional Studies

Host Factors

Age younger than 3 yearsparechovirus PCR (CSF)

ImmunocompromisedCMV PCR, HHV-6/HHV-7 PCR, HIV PCR (CSF); cryptococcal antigen; Toxoplasma gondii serology and/or
PCR; Mycobacterium tuberculosis testing; fungal testing; WNV testing

Geographic Factors

Africamalaria (blood smear), trypanosomiasis (blood/CSF smear, serology from serum and CSF), dengue testing
AsiaJapanese encephalitis virus testing, dengue testing, malaria (blood smear), Nipah virus testing (serology from serum and CSF;
PCR, immunohistochemistry, and virus isolation in a BSL4 lab can also be used to substantiate diagnosis)
AustraliaMurray Valley encephalitis virus testing, Kunjin virus testing, Australian bat Lyssavirus (ABLV) testing
Europetick-borne encephalitis virus (TBEV) (serology); if Southern Europe, consider WNV testing, Toscana virus testing
Central and South Americadengue testing, malaria (blood smear)
North Americageographically appropriate arboviral testing (e.g., WNV, Powassan, La Crosse, eastern equine encephalitis viruses,
Lyme [serum ELISA and Western blot])

Season and Exposure

Summer/fallarbovirus and tick-borne disease testinga

Cat (particularly if with seizures, paucicellular CSF)Bartonella antibody (serum), ophthalmologic evaluation
Tick exposuretick-borne disease testa
Animal bite/bat exposurerabies testing
Swimming or diving in warm freshwater or nasal/sinus irrigationNaegleria fowleri (CSF wet mount and PCR)

(continued)

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 Chapter 6: Encephalitis 95

TA B L E 6 . 2
DIAGNOSTIC ALGORITHM FOR INITIAL EVALUATION OF ENCEPHALITIS IN CHILDREN (CONTINUED)

Conditional Studies

Specific Signs and Symptoms

Abnormal behavior (e.g., new-onset temper tantrums, agitation, aggression), psychotic features, seizures, or movement disorder
anti-NMDAR antibody (serum, CSF), oligoclonal bands, IgG index, rabies testing
Behavior changes followed by myoclonic spasms/jerksmeasles IgG (CSF and serum)
Vesicular rashVZV PCR from CSF (sensitivity may be low; if test available, consider CSF IgG and IgM), VZV IgG and IgM from serum
Rapid decompensation (particularly with animal bite history or prior travel to rabies-endemic areas)rabies testing
Respiratory symptomschest imaging (chest x-ray and/or CT scan), respiratory virus testing, Mycoplasma pneumoniae PCR (CSF)
Acute flaccid paralysisarbovirus testing, rabies testing
Parkinsonismarbovirus testing, Toxoplasma serology
Nonhealing skin lesionsBalamuthia mandrillaris, Acanthamoeba testing
Prominent limbic symptomsautoimmune limbic encephalitis testing, HHV-6/HHV-7 PCR (CSF)

Laboratory Features

If EBV serology is suggestive of acute infection, perform EBV PCR (CSF)

Elevated transaminasesrickettsia serology, tick-borne diseases testinga
CSF protein 100 mg/dL, or CSF glucose 2/3 peripheral glucose, or lymphocytic pleocytosis with subacute symptom onset
M. tuberculosis testing, fungal testing, Balamuthia mandrillaris testing
CSF protein 100 mg/dL or CSF glucose 2/3 peripheral glucose and neutrophilic predominance with acute symptom onset and
recent antibiotic useCSF PCR for Streptococcus pneumoniae and Neisseria meningitidis
CSF eosinophiliaM. tuberculosis testing, fungal testing, Baylisascaris procyonis antibody (serum), Angiostrongylus cantonensis and
Gnathostoma sp. testing
HyponatremiaM. tuberculosis testing
M. pneumoniae serology or throat PCR positiveM. pneumoniae PCR (CSF)

RBC, red blood cell; VCA, viral capsid antigen; EBNA, Epstein-Barr nuclear antigen; EEG, electroencephalogram; CMV, cytomegalovirus.
a
Tick-borne disease testing should be tailored to specific geographic region and typically consists of serology (i.e., Borrelia, Ehrlichia, Rickettsia sp.,
Anaplasma phagocytophilum, TBEV) and blood PCR (Ehrlichia, Anaplasma).
Adapted from Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of
the International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):11141128.

been studies showing that PMNs may still predominate well
beyond this 24-time period (187). Therefore, a repeat LP a few
days following the first LP may be useful (188,189). In viral
encephalitis, the CSF protein generally is elevated but is typi-
cally less than 100 mg/dL, whereas the glucose level is almost
always normal with a few important exceptions (e.g., LCM
and mumps; Table 6.3).
As outlined earlier, viral infections can sometimes be associ-
ated with a neutrophilic predominance; however, when a neu-
trophilic pleocytosis is observed, particularly in cases where
CSF white blood cell (WBC) count is more than 1,000 cells/
mm3, protein more than 100 mg/dL, or CSF glucose level less
than 2/3 of serum levels, a nonviral entity should be strongly
considered. For most bacterial pathogens, the CSF shows a
WBC of 1,000 to 5,000 cells/mL with predominance of neu-
trophils (80% to 95%), glucose less than 40 mg/dL in over half
the cases, and a CSF glucose level less than 2/3 serum levels.
In fungal infections, moderate lymphocytic pleocytosis usually
is found along with elevated protein and low CSF glucose.
Eosinophils in the CSF are suggestive of a helminth infec-
tion (e.g., B. procyonis, Angiostrongylus spp., and G. spi-
nigerum). Eosinophils can also be seen in patients with
neurococcidiomycosis or neuro-Mycobacterium tuberculosis.
In patients with PAM, the CSF typically contains a very high
CSF cell count with a predominance of neutrophils, a slight
to pronounced decrease in glucose concentration, and an
increased protein content (75 to 970 mg/dL). The amebae
can sometimes be seen in wet-mount preparations of spinal
fluid (139,140,190). In patients with CNS Balamuthia infec-
tions, elevated CSF WBC is often seen along with mild to
markedly elevated protein (1,000 mg/dL) and normal or
slightly decreased glucose.
Although brain biopsy in the setting of suspected enceph-
alitis has become less common, examination of brain tissue
still has utility because of limitations in both molecular and
serologic methods. The use of targeted biopsy was recently
demonstrated by a report of 16 patients with undiagnosed
CNS illness where brain biopsy detected bacterial abscess (6),
toxoplasmosis (3), HSV (1), Aspergillus infection (2), and M.
tuberculosis infection (2). Biopsies can also be particularly
helpful for the diagnosis of noninfectious entities such as small
vessel vasculitis and intravascular lymphoma (191). An au-
topsy should be encouraged to determine the cause of death in
patients who die with unexplained encephalitis.
In addition to studies done acutely, an extra red top serum
tube should be drawn during the acute phase of illness and
held for later serologic studies. A convalescent serum should
be collected 10 to 21 days later. Similarly, extra spinal fluid
should also be frozen for future testing. Specific caveats of test-
ing are outlined in Table 6.3 and selected agents are outlined in
the following sections.
Text continues on page 100

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 96 Part II: Viral Infections and Related Disorders

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Viral Many CNS viral infections result in a mild CSF pleocytosis

(typically with a monocytic cell predominance but PMNs may
predominate, especially early in course); CSF protein normal to
mildly elevated (100 mg/dL) and normal glucose

Adenovirus
Arboviruses
Cytomegalovirus (CMV)a
Enteroviruses (EV)
Epstein-Barr virus (EBV)
Hepatitis C virus
Herpes simplex virus 1
(HSV-1)
CSF, respiratory, brain tissue PCR
or culture
Serology is the best assay for most
arboviruses: CSF IgM, serum IgM
and IgG (paired sera if possible)
for specific viruses as suggested
by geography:
West Nile virus (WNV)
California serogroup viruses (e.g.,
La Crosse virus [LACV])
Eastern equine encephalitis virus
(EEEV)
Powassan virus (POWV)
St. Louis encephalitis virus
(SLEV)
Western equine encephalitis virus
(WEEV)
CSF PCR
CSF PCR
Respiratory PCR
Stool PCR or culture
CSF PCR
Serum: anti-VCA IgM/IgG, anti-
EBNA
Heterophil
CSF PCR
CSF PCR
Intrathecal antibody if 1 week
of symptoms
Pathogen of unknown neurologic potential
CSF PCR testing rarely positive
PCR often negative due to acute viremia stage often completed
by the time of clinical presentation
PCR may be helpful in immunocompromised host or very early
in clinical course.
CSF IgG for specific arbovirus usually not helpful because
bloodbrain barrier integrity may be compromised; CSF blood
contamination can cause false-positive results for both IgM
and IgG.
IgM can persist for several months and sometimes 1 year;
more likely to persist in serum, but persistence has also been
described in CSF.
Serologic cross-reactivity among arbovirus of same family
(WNV, SLEV, and POWV antibodies cross-react; e.g.,
individual with prior dengue infection will test positive for
WNV IgG)
Antibody typically positive early in presentation but if
negative, repeat on later specimen
WNV: PMNs can persist in CSF.
WNV: Reactive lymphocytes in CSF (e.g., Mollaret-like cells)
have also been described.
EEEV: CSF WBC counts may be similar to bacterial meningitis
(e.g., counts up to 4,000/mm3 described).
POWV testing only available at CDC and a few state
laboratories
Serology can be problematic; false-positive IgM not uncommon
PCR: false positive (consider if viral load is low); CMV in CSF
also seen presumably because of latent infection
Atypical lymphocytes in CSF
Testing of EV PCR on CSF alone may miss infection because
EV present only transiently in CSF; test non-CNS site
(respiratory sample PCR, viral stool culture) to increase yield.
Both serology (serum) and PCR (CSF) for EBV is recommended.
Heterophil low sensitivity in children younger than 5 years of age
PCR false positives can occur if EBV-infected (latent)
mononuclear cells present
EBV CSF PCR can be negative in true cases because of
either timing of LP (late) or mechanism other than direct
neuroinvasion.
Atypical lymphocytes in CSF or peripheral blood is consistent
with EBV but not always present.
Pathogen of unknown neurotropic potential
HSV-1 causes the majority of HSE (outside neonatal period).
~5%10% of HSE patients have a normal CSF formula in the
first LP, particularly in children.
False-negative PCRs occur; if clinical suspicion for HSE,
consider repeat lumbar puncture early in the course of illness
to repeat CSF HSV PCR and intrathecal HSV antibody testing
Presence of either IgG or IgM may be indicative of CNS
infection; however, bloodbrain barrier integrity and CSF-
blood contamination needs to be considered when interpreting
results

(continued)

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 Chapter 6: Encephalitis 97

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES (CONTINUED)

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Herpes simplex virus 2 CSF PCR Presence of either IgG or IgM may be indicative of CNS
(HSV-2) Intrathecal antibody if 1 week infection; however, bloodbrain barrier integrity and CSF-
of symptoms blood contamination needs to be considered when interpreting
results
Human herpes virus 6 CSF PCR Pathogen of unknown neurologic potential
(HHV-6) (Quantitative blood PCR if Not all positive HHV-6 CSF PCR results correlate with disease;
CSF positive to determine when positive, important to consider chromosomal integration
chromosomal integration) or latent infection
Human herpes virus 7 CSF PCR Unknown frequency of CNS illness
(HHV-7) Pathogen of unknown neurologic potential; detection of virus
may represent acute disease but could also represent latent
virus.
HIV ELISA and Western blot (single
serum)
Plasma and CSF PCR
Human Respiratory tract (NP or throat) Pathogen of unknown neurologic potential
metapneumovirus PCR CSF PCR rarely positive
Influenza A/B virus Respiratory viral culture PCR of CSF rarely positive
Respiratory viral antigen test PCR on respiratory specimens more sensitive and specific than
Respiratory PCR (if above antigen assays
negative) Most cases are encephalopathy (vs. encephalitis).
JC virusa CSF PCR A positive result corroborates diagnosis; negative result does
not rule it out.
Lymphocytic CSF IgM/IgG CSF profile may resemble bacterial etiology (e.g., CSF WBC
choriomeningitis Serum IgM/IgG sometimes 3,000, PMNs predominance, low glucose and/or
(LCM) virus very elevated proteins).
One of the few viruses that can decrease glucose in CSF
Measles virusacute CSF antibodies CNS illness occurs ~1 week after fever/rash.
CSF PCR Measles PCR and antibody testing (serum and CSF)
Serum IgG/IgM (paired serumb
samples if possible)
Brain tissue PCR
Measles virusSSPEc CSF IgG antibodies Incubation period several years
Serum IgG antibodies Because SSPE is a result of long-standing infection, IgM will be
Brain tissue PCR negative; IgG levels in both CSF and serum very high
Measles CSF PCR rarely positive, PCR brain tissue positive
CSF formula generally unremarkable
Oligoclonal bands present in CSF
Mumps virus CSF culture or PCR One of few viruses that can cause low glucose in CSF
CSF IgM/IgM
Serum IgM/IgG (paired serumb
samples if possible)
Throat swab PCR
Parvovirus B19 Serum IgM Pathogen of unknown neurologic potential
CSF PCR
Rabies virus Antemortem: Coordinate testing with local and state health department and
Serum antibodies CDC.
Saliva PCR Antemortem testing is possible; multiple samples and different
Nuchal biopsy PCR and DFA assays are important to run. Negative tests antemortem do not
Brain tissue DFA rule out rabies.
Postmortem:
Brain tissue; viral isolation or
antigen detection
Respiratory syncytial RSV antigen Pathogen of unknown neurologic potential
virus (RSV) CSF PCR rarely positive
CSF profile often unremarkable

(continued)

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 98 Part II: Viral Infections and Related Disorders
TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES (CONTINUED)
Agent
Rotavirus
Rubella virus
Varicella-zoster virus
(VZV)
West Nile virus
Fungal
Coccidioides spp.c
Cryptococcus spp.c
Histoplasma capsulatumc
and Blastomyces sp.c
Free-living amebas and
parasites
Naegleria fowleri
Balamuthia mandrillarisc
Acanthamoeba spp.a,c
Baylisascaris procyonis
Toxoplasma gondiia
Scheld_Ch06.indd 98
Recommended Diagnostic Studies
Stool antigen
CSF PCR (testing available
specialized laboratories,
e.g., CDC)
Serology
CSF antibodies
CSF PCR
Intrathecal antibody if 1 week
of symptoms
Serum IgM/IgG
Skin lesions: DFA or PCR
See arboviruses (above)
CSF culture (large volume)
CSF-specific antigen
CSF-specific antibody
CSF India ink (for Cryptococcus
only)
Serum-specific antigen
Serum-specific antibody
Urine antigen (Histoplasma and
Blastomyces)
Wet mount of warm CSF
Brain histopathology
Serology
CSF and/or brain PCR
Brain histopathology (special
stains)
Serology (research laboratories)
CSF and/or brain PCR
Brain histopathology (special
stains)
CSF and serum antibodies
Older child: IgG, IgM, and PCR
Laboratory Findings; Limitations and Caveats
Pathogen of unknown neurologic potential
Typically young child with history of diarrhea; mechanism
unclear
CSF profile often unremarkable
One of viral causes of low CSF glucose
Because some CNS VZV infections are reactivation, IgM not
always positive
Positive VZV skin lesions do not prove CNS etiology but may
be suggestive of etiology.
Fungal CNS infections are often associated with CSF pleocytosis
with lymphocytic predominance, low glucose, and protein
100 mg/dL. EDTA-heat treated antigen test reported to
increase sensitivity for CSF and serum samples. Isolated CNS
disease can be difficult to diagnose because of insensitive
assays.
Note geographic locations of different fungal infections; order
antigen for each specific fungi.
Alert laboratory that coccidiomycosis is being considered if
fungal culture sent
Eosinophils sometimes present in CSF in coccidiomycosis
patients
Coordinate testing with local and state health department and
the CDC.
Demonstration of motile ameba on wet mount of CSF
LP often demonstrates very high WBC (often PMN
predominance), high protein (100 mg/dL), and low glucose
(50 mg/dL).
Coordinate testing with local and state health department and
the CDC.
Serology and PCR available at specialized laboratories (CDC)
Brain tissue may show necrotic and hemorrhagic
meningoencephalitis.
LP often shows high WBC (L or PMN) and protein 100 mg/
dL, resembling tuberculous meningitis.
Coordinate testing with local and state health department and
the CDC.
Serology and PCR available at specialized laboratories
Serology available in specialized laboratories (CDC)
Eosinophils almost always present in CSF and CBC
Often reactivation of disease, so IgM may not be positive; IgG
titers persistently high
(continued)
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 Chapter 6: Encephalitis 99

TA B L E 6 . 3
DIAGNOSTIC TESTING FOR INFECTIOUS ENCEPHALITIS WITH FOCUS ON PATHOGENS FOUND IN
IMMUNOCOMPETENT INDIVIDUALS IN THE UNITED STATES (CONTINUED)

Agent Recommended Diagnostic Studies Laboratory Findings; Limitations and Caveats

Bacteria

Bartonella henselae
Borrelia burgdorferi
Brucella spp.
Leptospira spp.
Listeria monocytogenes
Mycobacterium
tuberculosisc
Mycoplasma pneumoniae
Treponema pallidum
Serology (IFA) CSF PCR (if available) may also be useful to perform
PCR of lymph node CSF often negative
Serology (serial EIA and Western Test both serum and CSF for Borrelia antibody; may be
blot) delayed in CNS intrathecal synthesis
CSF antibody index CSF PCR rarely positive (in contrast to synovial fluid) but may
be useful in some cases
CSF IgG and IgM Serologyperform on both CSF and serum; culture increases
CSF culture sensitivity.
Serum IgG and IgM PCR available in some research settings; unknown sensitivity
False-positive IgM not uncommon
Serum IgM and IgG If serology negative on acute serum, important to repeat on
Urine culture convalescent serum
Routine bacterial culture on both CSF culture for Listeria relatively insensitive
CSF and blood CSF profile does not necessarily look bacterial, that is, can be
Multiple CSF cultures may be normal or have only a few hundred WBCs with predominance
helpful of lymphocytes; glucose and protein may be normal.
It may also be helpful to test CSF Listeria antibody because
detection of CSF antibody may be indicative of CNS infection.
CSF AFB smear, culture, PCR, CSF PCR is insensitive tool for detection of CNS M. tuberculosis;
direct examination important to test multiple samples.
Respiratory culture highly CNS M. tuberculosis should be considered in patients with
suggestive lymphocytic pleocytosis (but neutrophilic predominance can still
occur), CSF protein 100 mg/dL, and CSF glucose 50 mg/dL.
PCR of NP or other respiratory Pathogen of unknown neurologic potential
specimen Perform PCR on respiratory samples, serology on acute/
Serum IgM convalescent serum
Serum IgG paired CSF PCR rarely positive
Single IgG titer is not helpful.
CSF VDRL CSF VDRL specific but CSF FTA-ABS more sensitive
Serum PCR with confirmatory
FTA-ABS

Rickettsia In patients with rickettsial infections, low peripheral WBC, low

platelets, and increased liver function tests (LFTS) often present

Anaplasma Morulae in WBCs (granulocytes) If serology negative on acute serum, important to repeat on
phagocytophilum Whole blood PCR convalescent serum (seroconversion may occur a few weeks
Serology IgG/IgM (paired serab if after onset)
possible)
Coxiella burnetii Serology on paired serum samples Utility of Coxiella burnetii PCR in CSF unknown
Ehrlichia chaffeensis Morulae in WBCs (monocytes) If serology negative on acute serum, important to repeat on
Whole blood PCR convalescent serum (seroconversion may occur a few weeks
Serum IgG/IgM (paired serab if after onset)
possible)
Ehrlichia ewingii Morulae in WBCs (granulocytes) If serology negative on acute serum, important to repeat on
Whole blood PCR convalescent serum (seroconversion may occur a few weeks
Serum IgG/IgM after onset)
Rickettsia spp. Serology (IFA) If serology negative on acute serum, important to repeat on
Skin biopsy of rashPCR or convalescent serum (seroconversion may occur a few weeks
immunohistochemical staining after onset)

NP, nasopharyngeal; DFA, direct fluorescent antibody; EDTA, ethylenediaminetetraacetate; CBC, complete blood count; EIA, enzyme immunoassay; AFB,
acid-fast bacilli; VDRL, Venereal Disease Research Laboratory; FTA-ABS, fluorescent treponemal antibody-absorption; PMNs, polymorphonuclear cells.
a
Causes encephalitis primarily in neonate and/or immunocompromised host.
b
Testing should be done on acute serum and then later when acute and convalescent sera are available.
c
Typically presents as subacute chronic illness.
Data from Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the
International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):11141128.

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 100 Part II: Viral Infections and Related Disorders
TESTING OF SELECTED
ETIOLOGIES
Viral Testing
Specific studies for viral agents often employ molecular testing.
Molecular testing by nucleic acid amplification (e.g., PCR) test-
ing provides more timely and typically more sensitive results than
culture for viral CNS infections (116,192,193). However, the
limitations of these tests are often not recognized by physicians,
particularly false-negative and false-positive results as discussed
in the following sections for specific agents. Testing for intrathe-
cal antibody synthesis of specific pathogens such as arboviruses
and herpesviruses can be useful adjunct for diagnosis, particu-
larly in the later stages of disease (see the following discussion).
In patients with either preceding or concurrent respiratory
symptoms, a viral culture from the respiratory tract should be
performed early in the hospital course to optimize the virus
recovery. When a particular agent such as influenza or another
virus is suspected but the viral culture is negative, agent-specific
PCR testing should also be performed. Similarly, if there is a
history of preceding or concurrent diarrhea, a stool culture for
viral and, possibly, bacterial pathogens should be performed.
In children, a stool viral culture and/or EV PCR should be
routinely performed to enhance EV detection, regardless of the
presence of diarrhea.
Herpesviruses
The diagnostic test of choice for HSE is CSF HSV-1 DNA
nucleic acid (PCR) testing. If testing from the first LP is nega-
tive and HSE is still suspected (e.g., temporal lobe involvement
seen on neuroimaging), a second LP should be performed
within 24 to 48 hours as a number of studies have shown that
HSV PCR can be falsely negative, particularly early in course
of illness and in the pediatric age-group (22,189). For HSE,
intrathecal antibodies can be performed as a complement to
molecular testing, and this may be particularly helpful in es-
tablishing the diagnosis later in the course. Intrathecal synthe-
sis of HSV-specific IgG antibodies can often be detected 10 to
14 days after the onset of illness (194).
As mentioned in the clinical and epidemiology section, the
clinical spectrum of CNS infections associated with HSV-2
often differs from HSV-1. Molecular testing of CSF for the
presence of nucleic acid is the most reliable method for diag-
nosis for HSV-2; intrathecal antibody testing can be used as an
adjunct as described previously for HSV-1.
Because VZV encephalitis is one of the most common causes
of encephalitis in adults, VZV testing should be performed in
all adult patients, with or without skin lesions. Testing should
include both CSF VZV PCR and CSF VZV antibody (195).
Although detection of VZV antibody in the CSF can be more
sensitive than PCR, intrathecal synthesis may be delayed by a
week or more after onset of neurologic symptoms (196,197).
In the event of a traumatic tap, distinguishing intrathecal anti-
body synthesis versus blood contamination of CSF may be
accomplished by calculation of an antibody index (198).
For the diagnosis of EBV encephalitis, both serology and mo-
lecular testing is recommended (40). Quantitative viral load may
be helpful, as a high viral load supports a significant CNS infec-
tion, whereas a low positive PCR in CSF may represent latent virus
and may only be an incidental finding (199,200). Conversely, the
absence of a positive PCR in the setting of acute EBV serology
does not rule out acute infection, and a negative PCR may be a
result of the timing of LP (i.e., after virus has cleared from CSF)
or may reflect a mechanism other than direct infection.
Scheld_Ch06.indd 100
CSF PCR testing is recommended for the diagnosis of HHV-6
and HHV-7; however, the finding of a positive CSF PCR for
HHV-6 or HHV-7 is not necessarily equivalent to a diagnosis
of HHV-6 or HHV-7 encephalitis. This is because HHV-6 DNA
can be present in normal brain tissue and HHV-6 may be iden-
tified in CSF as an incidental bystander rather than a cause
of infection (201). Additionally, chromosomal integration must
be considered as a potential reason for a positive PCR in the
CSF. If a positive HHV-6 CSF PCR is obtained, an evaluation
of HHV-6 in the blood should be done to distinguish between
chromosomal integration and acute infection (48).
Enteroviruses and Parechoviruses
PCR testing of both CSF and a throat specimen should be per-
formed; if only CSF is tested, the diagnosis may be missed. For
example, in an outbreak of EV-71 in the United States, EV PCR
of CSF was positive in only 5 (31%) of 16 cases, whereas PCR
testing of throat specimens were uniformly positive (202,203).
Because EVs may be shed in the stool for weeks after infection,
culturing the stool for EV may increase the diagnostic yield; for
the same reason, a positive stool is suggestive, but not confir-
matory, of the diagnosis. Testing for parechoviruses should be
considered in all children younger than 3 years of age with the
same range of biologic samples tested as EVs. Parechoviruses
can only be detected by parechovirus-specific PCR assays.
Arbovirus
For most arboviruses, serologic testing of CSF and serum is
preferred to molecular testing because peak viremia gener-
ally occurs prior to symptom onset (204). The diagnosis of
WNV infection is typically made via detection of IgM cap-
ture enzyme-linked immunosorbent assay (MAC-ELISA) or
a fourfold or greater change in antibody titer on paired or
convalescent serum. Approximately 90% of patients with neu-
roinvasive disease will have detectable CSF IgM antibody by
days 8 to 10 after symptom onset (205). However, WNV IgM
may persist for prolonged periods, with detectable IgM titers
persisting more than 500 days after presentation in some indi-
viduals with neuroinvasive disease (206). Furthermore, there
is serologic cross-reactivity between the flaviviruses (SLEV,
dengue virus, yellow fever virus, or JEV), such that individuals
infected with, or vaccinated against, one of these agents could
test positive for WNV by IgM MAC-ELISA. Differentiation of
WNV from other flaviviruses is achieved by plaque reduction
neutralization testing (PRNT) (207).
For other arboviruses, the standard method for diagnosis
is similar, namely through detection of IgM or a fourfold or
greater change in antibody titer on paired acute and convales-
cent serum (208).
Other Viral Testing
The diagnosis of rabies should be considered in any rapidly
progressing encephalitis. Antemortem testing for rabies re-
quires highly specialized testing in a public health laboratory
using a combination of different assays and specimen types
(209). Whenever the diagnosis of rabies is entertained, consul-
tation with public health authorities is strongly recommended.
Testing for other viruses should be performed as suggested by
exposures or travel history.
Bacterial Testing
In most instances, detection of routine bacterial pathogens
via Gram stain and/or culture is fairly straightforward. The
CSF bacterial culture for L. monocytogenes, however, is rela-
tively insensitive compared with many other bacterial agents.
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Additionally, in contrast to many bacterial pathogens, the
CSF profile of CNS listeriosis patients, particularly those with
rhombencephalitis, can appear normal or similar to viral ill-
nesses with only a mild pleocytosis, a lymphocytic predomi-
nance rather than polynuclear predominance, and a normal to
minimal protein elevation (109) (see Table 6.3).
Neurotuberculosis can also be difficult to diagnose. The
sensitivity of CSF tuberculosis (TB) PCR is very poor; reported
sensitivity has been less than 25% in some studies (102). This
may be because of low bacillary load in the CSF, relatively
small CSF volumes submitted for testing, or PCR inhibitors
in samples (210). Testing from both CNS and extra-CNS sites
should be done for the workup of neuro-TB (see Table 6.3).
Fungal Testing
Fungal meningoencephalitis is typically a subacute illness.
Fungal culture of the CSF should be performed in individu-
als with indolent symptoms, immunocompromised persons, or
when the CSF findings are suggestive (e.g., CSF lymphocytic
pleocytosis, high protein, and low glucose). If a fungal etiology
is suspected, several different tests including culture, antigen
test, and serology on both CNS as well as non-CNS specimens
should be done (see Table 6.3) (211).
Rickettsial Testing
Diagnostic testing is similar for most rickettsial infections.
Serology is the most widely used method, and the indirect
fluorescent antibody (IFA) assay is considered the gold stan-
dard. Because serologic tests may be negative early in the ill-
ness, detection of the rickettsial agent in blood or tissues by
molecular assays (e.g., PCR) may be useful. Confirmation of
disease is best accomplished by evaluation of paired serum
specimens collected during the acute and convalescent phases
of the illness for a fourfold or greater change in antibody titer.
Immunohistochemistry of patients tissues (e.g., brain) is an-
other methodology that can be used to diagnose rickettsial
infection (212).
Parasitic and Free-Living Ameba Testing
The diagnosis of Baylisascaris is often suggested by a history of
exposure to raccoons (or their feces), clinical presentation, and
persistent eosinophilia in the blood and spinal fluid. Serologic
assays are available at the Centers for Disease Control and
Prevention (CDC). In patients with a history of travel outside
the United States with presence of CSF eosinophilia, both
gnathostomiasis and Angiostrongylus should be considered.
An ELISA test has been developed but is not widely available
(213). Molecular tests for Angiostrongylus are available at
the CDC.
Molecular technology is also available for the identification
of Balamuthia and Acanthamoeba DNA in tissues and CSF
(CSF PCR is less sensitive than brain tissue PCR) but is largely
limited to research laboratories and the CDC.
NEUROIMAGING MODALITIES
Neuroimaging plays a crucial role in the evaluation of patients
with suspected encephalitis, as it may support the diagnosis of
a specific etiology or identify alternate conditions that mimic
encephalitis (Table 6.4). Routinely available studies to evalu-
ate patients with suspected encephalitis include computed
Scheld_Ch06.indd 101
Chapter 6: Encephalitis 101
tomography (CT) and magnetic resonance imaging (MRI).
CT scanning involves the application of x-rays to produce to-
mographic images, resulting in excellent delineation of bony
structures; conventional MRI uses nuclear magnetic resonance
(MR) to detect hydrogen nuclei and provides good contrast
between soft tissues. Of the two, MRI is far more sensitive
and specific for the evaluation of infectious encephalitis (214
216). Conventional MRI imaging entails acquisition of vari-
ous sequences that provide complementary information. For
example, T1-weighted imaging (T1W) is well suited to define
structural abnormalities; T2-weighted imaging (T2W) and
fluid-attenuated inversion recovery (FLAIR) sequences may
identify areas of edema, demyelination, or inflammation; and
susceptibility-weighted imaging (SWI) is particularly useful
in identifying areas of hemorrhage. T1W imaging following
gadolinium administration can identify parenchymal or men-
ingeal regions where the bloodbrain barrier has been com-
promised, as occurs in active inflammation. Of particular note
is diffusion-weighted imaging (DWI), which identifies brain
regions where diffusion of water is restricted and may be more
sensitive than other conventional sequences for detection of
early abnormalities in encephalitis (217,218).
Several additional imaging modalities have emerged for
evaluation of encephalitis. MR spectroscopy can identify a
number of metabolites, including N-acetylaspartate (NAA),
choline, creatine, and lactate, based on unique proton chemi-
cal shifts. Quantification of the ratios of these metabolites
can provide information regarding inflammation, neuronal
loss, and demyelination. Both single-photon emission com-
puted tomography (SPECT) imaging and fluorodeoxyglucose
positron emission tomography (FDG-PET) involve detec-
tion of radioisotopes within the brain following injection
into the bloodstream and can provide information regarding
metabolism. Other MR-based techniques, including mag-
netization transfer and diffusion tensor imaging, as well as
molecular imaging techniques that allow for the detection of
disease-specific molecules, are currently being optimized and
may eventually show promise in evaluation of patients with
encephalitis (219).
Imaging of Selected Etiologies
Herpesviruses
The neuroimaging findings of encephalitis caused by HSV-1
reflect its predilection for the limbic system, with frequent in-
volvement of the mesial temporal and inferior frontal lobes
(Fig. 6.4).
In the acute stage, HSE typically results in edema, inflam-
mation, or hemorrhage. Although initial CT scans are nor-
mal in up to 25% of affected individuals, greater than 90%
of patients with HSE documented by CSF PCR will have MRI
abnormalities (220223). Abnormalities on conventional MRI
appear within 48 hours and include isointense or hypointense
lesions on T1W images and hyperintense lesions on T2W or
FLAIR images. Changes in DWI, which may reflect the rapid
accumulation of intracellular water in the setting of impaired
ion transport during acute infection, are seen even earlier
(218,224,225). MRI is superior to CT in the detection of sub-
acute (1 week) hemorrhage. Contrast enhancement on MRI
is typically in a cortical gyral pattern and often lags behind
symptom onset (226). Extratemporal abnormalities occur in
over half of cases and may involve the cerebral hemispheres,
thalamus, and brainstem (227229). Notably, in up to 15% of
patients, extratemporal involvement may be the sole-observed
neuroimaging abnormality (229) and is more likely to occur in
pediatric and immunocompromised populations (230232).
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 102 Part II: Viral Infections and Related Disorders

TA B L E 6 . 4
NEUROIMAGING IN ACUTE ENCEPHALITIS

Location Possible Etiologies Imaging Features Possible Etiologies

Basal ganglia Arboviruses Arteritis/ infarction Aspergillus spp.a

Enteroviruses Chikungunya virus
Epstein-Barr virus Nipah virus
Influenza virus (ANE) Treponema pallidum
Measles virus (acute infection) Varicella-zoster virus
Mycobacterium tuberculosis Mycobacterium tuberculosis
Respiratory viruses Other fungal infections
Anti-NMDAR encephalitis Calcifications Cytomegalovirus (neonate)
Brainstem Arboviruses Toxoplasma gondii (neonate;
Brucellosis periventricular)a
Enteroviruses Hemorrhage Herpes simplex virus 1
Epstein-Barr virus Influenza (ANE)
Herpes simplex virus 1 Varicella-zoster virus
Influenza virus (ANE)
Hydrocephalus Balamuthia mandrillaris
Japanese encephalitis
Coccidioides immitis
Listeria monocytogenes
Histoplasma capsulatum
Lyme
Mycobacterium tuberculosis
Mycobacterium tuberculosis
Toxoplasma gondii (neonate)a
Rabies
West Nile virus Microcephaly Cytomegalovirusa
Anti-NMDAR encephalitis Toxoplasma gondii (neonate)a
Cerebellum Epstein-Barr virus Space-occupying lesions Acanthamoeba spp.
Influenza virus (ANE) Balamuthia mandrillaris
Mycoplasma pneumoniae Mycobacterium tuberculosis
Varicella-zoster virus Toxoplasma gondiia
West Nile virus Fungal infections
Anti-NMDAR encephalitis White matter (different Balamuthia mandrillaris
Corpus callosum West Nile virus than ADEM) Baylisascaris procyonis
Epstein-Barr virus Borrelia burgdorferi
HPeV-3 (especially neonate)
Frontal lobe Enteroviruses
HIV
Herpes simplex virus 1
JC virusa
Herpes simplex virus 2
Measles virus (SSPE)
Treponema pallidum
West Nile virus
Spinal cord Arboviruses Cytomegalovirusa
Enteroviruses
Gnathostoma spp.
Rabies virus
Temporal lobeunilateral Enteroviruses
Herpes simplex virus 1
La Crosse virus
Treponema pallidum
Temporal lobebilateral Enteroviruses
Herpes simplex virus 1
Human herpesviruses 6/7/8a
Treponema pallidum
Anti-NMDAR encephalitis
Anti-VGKC encephalitis
Thalamus Arboviruses
Epstein-Barr virus
Influenza virus (ANE)

a
Causes encephalitis in immunocompromised and/or neonate host.

Scheld_Ch06.indd 102 2/21/14 5:31 PM


A hyperintensities in the dorsal brainstem, cerebellar dentate
B arboviruses, including SLE, EEE, TBE, and Murray Valley
FIGURE 6.4 Typical MRI findings in HSE on (A) coronal and (B) axial
FLAIR sequences.
MR spectroscopic findings have also been described, although
the clinical use of this imaging modality in the evaluation of
HSE remains undefined. Abnormalities, which typically in-
clude decreased NAA and increased choline, myoinositol, and
lactate, are thought to represent loss of neuronal integrity and
necrosis with accompanying macrophage infiltration and glio-
sis (233235).
In several case series of VZV encephalitis, the most notable
finding was the absence of brain imaging abnormalities in the
majority of patients. In a minority of patients, affected regions
included the temporal lobe and brainstem. A notable caveat is
that many patients in these series underwent CT scanning only
(32,236). VZV vasculopathy is often associated with T2W hy-
perintensities in the white matter and at the graywhite matter
junctions on MRI, with evidence of either ischemia or hemor-
rhage (25). The most commonly reported imaging abnormali-
ties in EBV-associated encephalitis include multiple, diffuse
hyperintensities on T2W and FLAIR imaging, often transient
and with involvement of the splenium of the corpus callosum
(237239).
HHV-6 associated limbic encephalitis typically involves
the mesial temporal lobe (hippocampus, entorhinal cortex,
and amygdala). Additional cortical and subcortical areas can
be involved and may be associated with specific clinical sub-
types (240,241). Involved areas are characterized by T2W
hyperintensity and variable degrees of enhancement. In addi-
tion, increased hippocampal uptake of glucose, suggestive of
increased metabolic activity, has been detected by FDG-PET
(242,243). Although both HSE and HHV-6 limbic encephalitis
Scheld_Ch06.indd 103
Chapter 6: Encephalitis 103
are associated with mesial temporal abnormalities, a recent
study suggested that early extratemporal involvement was
more likely in HSE (244). Rarely, HHV-6 infection of the CNS
has been associated with a syndrome similar to ANE (51,245).
Enteroviruses
Although poliovirus has almost completely disappeared in de-
veloped countries, nonpolio EVs are an important cause of dif-
fuse, generalized encephalitis. In such cases, neuroimaging is
typically normal. Certain EVs, however, may result in similar
clinical and radiographic manifestations as poliovirus. EV-71,
for example, is characterized by symmetric bilateral T2W
nuclei, and anterior horns of the cervical spinal cord on MRI
(246,247) (Fig. 6.5).
As in many cases of acute encephalitis, DWI appears to be
more sensitive than other conventional sequences for detection
of EV-71 lesions (248). Echovirus 7-associated encephalomy-
elitis is also associated with a similar topographical distribu-
tion on MRI (249). Isolated reports of unilateral and bilateral
hippocampal lesions in the setting of acute enteroviral infec-
tion have also been described (250,251).
Arboviruses
Neuroimaging abnormalities in WNV often involve the deep
gray matter, although findings are highly variable and up to
half of patients may have normal brain MRI (233,252,253). In
those who develop a flaccid paralysis, spinal cord imaging may
demonstrate T2W hyperintensities in the anterior cord and
gadolinium enhancement of the cauda equina, conus medul-
laris, and nerve roots (252,254). Limited studies of other
encephalitis, suggest involvement of the substantia nigra and
other deep gray structures, and the latter three viruses may
also resemble WNV acute flaccid paralysis both clinically and
radiographically (255,256). The considerable overlap in the
neuroimaging spectrum of these arboviruses prevents discrimi-
nation between these etiologies based on imaging alone.
JEV is most commonly associated with T2W hyperintensi-
ties on MRI in the thalami, with variable involvement of the
substantia nigra, basal ganglia, brainstem, cerebellum, and
cortex (257). Although the presence of thalamic abnormalities
is highly sensitive for JEV in the appropriate clinical setting,
their absence does not rule out JEV (258). Mesial temporal lobe
involvement has also been reported, although unlike herpes
FIGURE 6.5 Axial T2 MRI demonstrating symmetric hyperintensity
in the medulla in EV-71 encephalitis. (Courtesy of Philip Britton, The
Childrens Hospital, Westmead, NSW, Australia.)
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 104 Part II: Viral Infections and Related Disorders
encephalitis, the insula and anterior portion of the temporal
lobe are usually spared, while additional thalamic lesions are
typically present (259,260). In JEV cases with biphasic illness,
regression of prior lesions and the appearance of new lesions
in typical areas are described (261,262). In cases of dengue
encephalopathy, focal MRI abnormalities in a number of
brain areas have been found. In addition, generalized cerebral
edema has been reported and may be related to the prominent
metabolic disturbances observed in affected individuals (263).
Bilateral frontoparietal white matter lesions with restricted
diffusion, suggestive of subcortical strokes, have been reported
in two cases of Chikungunya encephalitis (264). However, in
another case series of children with various CNS manifesta-
tions including encephalitis, MRI abnormalities were only
rarely observed (265).
Rabies
The often rapid clinical course of rabies encephalitis presents
a challenge in obtaining neuroimaging. The limited available
data demonstrate diffuse T2W hyperintensities affecting both
the deep and cortical gray matter of the brain and spinal cord
in both the paralytic and encephalitic forms of rabies (266).
Although abnormalities may also be seen in the white mat-
ter, the predominant gray matter involvement distinguishes
rabies encephalitis from ADEM. Initially nonenhancing, the
gray matter lesions may demonstrate gadolinium enhancement
once the patient becomes comatose (267).
Nipah
In the acute phase, Nipah encephalitis is associated with small,
punctate T2W hyperintensities in the subcortical white mat-
ter, often restricting diffusion (268). This imaging evidence of
microinfarction is congruent with the main pathologic find-
ings of vasculitis-associated thrombosis and presence of Nipah
virus antigen in endothelial and smooth muscle cells of blood
vessels (269). For the subset of patients who suffer from a
relapse of neurologic symptoms, MRI shows patchy areas of
confluent cortical involvement on MRI and focal hypoperfu-
sion on SPECT imaging (270).
Hendra
In contrast to Nipah virus, the closely related Hendra virus
is associated predominantly with gray matter abnormalities
in the setting of meningoencephalitis. In three reported cases,
T2W hyperintense lesions involved the cortical gray matter,
with relative sparing of the deep white matter tracts and cer-
ebellum. Cortical lesions may be confluent or multifocal, and
restriction of diffusion can be seen on DWI (271).
Measles
Measles virus can cause differing CNS syndromes, including
acute measles encephalitis and SSPE. Neuroimaging in acute
measles encephalitis typically demonstrates bilateral, sym-
metric T2W hyperintense lesions involving the white matter
and deep gray matter structures in a pattern that can resemble
ADEM (272). Cortical gyral swelling may also be present in
the acute setting, and hemorrhage may develop in gray matter
areas over days to weeks (273).
The earliest stages of SSPE are often not characterized by
abnormalities on conventional MRI, although FDG-PET can
demonstrate cortical hypometabolism and MR spectroscopy
may show decreased NAA levels (274). As the disease pro-
gresses, T2W hyperintensities in the subcortical and periven-
tricular white matter can develop, as does brain atrophy. By
the late stages of SSPE, widespread changes in the cortex,
brainstem, and cerebellum can be seen (275).
Scheld_Ch06.indd 104
Mumps
Encephalomyelitis following mumps is associated with white
matter changes on brain MRI and a longitudinally extensive
myelopathy on spine imaging that may be indistinguishable
from ADEM; rarely, hemorrhagic white matter lesions have
been reported (276278).
Influenza
Neuroimaging findings in influenza-associated encephalopathy/
encephalitis are diverse. MRI can be normal or may demonstrate
diffuse brain edema or symmetric involvement of the thalami
(233,279,280). Severe cases of encephalitis are characterized by
T2W hyperintensities, hemorrhage, and restricted diffusion in
the thalami, basal ganglia, and cerebellum, consistent with ANE
(281). Milder cases may be associated with reversible lesions of
the splenium of the corpus callosum (282). Notably, imaging
abnormalities caused by the 2009 H1N1 virus do not appear
to differ significantly from other influenza strains (283285).
Mycobacterium tuberculosis
Cranial TB can present as tuberculous meningitis (TBM), tuber-
culomas, or abscesseseach of which have differing neuroim-
aging characteristics. TBM is associated with basal meningeal
enhancement, often accompanied by hydrocephalus, strokes
in the basal ganglia and internal capsule, and a focal or diffuse
pachymeningitis (286288). Intracranial tuberculomas consisting
of granulomatous tissue may have variable appearance on T2W
imaging depending on the pathologic stage of the lesion; nonca-
seating tuberculomas are T2W hyperintense, whereas those with
solid caseation are isointense or hypointense. When central lique-
faction ensues, tuberculomas may take on an appearance more
similar to that of an abscess. Such lesions exhibit T2W hyperin-
tensity surrounded by a peripheral rim of hypointensity and dem-
onstrate peripheral rim enhancement on contrast imaging (289).
Fungal Infections
Neuroimaging findings in the setting of CNS fungal infections
are often nonspecific and may be mistaken for TBM, pyogenic
abscess, or brain tumor (290,291). Fungal infections may result
in basilar meningitis, hydrocephalus, vasculitis, or abscess, and
any combination of these may be present on neuroimaging. In
immunocompetent individuals, fungal abscesses are hypoin-
tense on T1W imaging and hyperintense on T2W imaging, with
a well-defined rim enhancement on postcontrast images, simi-
lar to pyogenic or tubercular abscesses (290). Recent progress
has been made in distinguishing fungal abscesses from other
abscesses. In one study, all of the fungal abscesses showed intra-
cavitary projections directed centrally from the wall, a finding
not seen in the other abscess types. Overall, a ring-enhancing
lesion with irregular walls and nonenhancing intracavitary pro-
jections was likely to be a fungal abscess (292). Detection of the
disaccharide trehalose on MR spectroscopy may also distin-
guish fungal from nonfungal abscesses (292294).
MRI is frequently normal in the setting of cryptococcal menin-
gitis, although evidence of a basilar meningitis and/or hydroceph-
alus indistinguishable from TBM may be observed. The adjacent
brain parenchyma may also be affected, giving rise to cryptococ-
comas, most commonly seen in the midbrain and basal ganglia.
These lesions are of variable density on CT scan and, on MRI, are
hypointense on T1W imaging and hyperintense on T2W imag-
ing. Contrast enhancement is variable and more commonly seen
in immunocompetent individuals. Unlike pyogenic abscesses,
cryptococcomas typically do not demonstrate restricted diffusion
on DWI. MR spectroscopy demonstrates elevated lactate and
decreased NAA, choline, and creatine (26,290,295).
Imaging abnormalities in patients with CNS coccidioido-
mycosis may reflect strokes, granulomas, and white matter
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FIGURE 6.6 Listeria rhombencephalitis. Sagittal FLAIR MRI demon-
strates hyperintensity in the medulla.
disease, in addition to basilar meningitis and hydrocephalus.
Ischemia has been reported in over half of cases and typically
results in deep cerebral infarcts seen as areas of hyperintensity
on T2W imaging. Less commonly, focal enhancing lesions in
the white matter or deep grey matter representing granulomas
are observed (292,296,297).
Listeria monocytogenes
Rhombencephalitis in the setting of L. monocytogenes infec-
tion is characterized by the presence of multiple, small, medul-
lary T2W hyperintensities that demonstrate rim enhancement
on T1W imaging, reflecting a combination of microabscesses
and associated edema in the lower brainstem (298) (Fig. 6.6).
Borrelia Species
Acute CNS Lyme disease is associated with small T2W hyper-
intense and T1W isointense lesions in the subcortical white
matter, which may mimic those seen in multiple sclerosis
(299). Multifocal lesions may also be observed in the brain-
stem and spinal cord (300).
Treponema Pallidum
The clinical and MRI features of neurosyphilis are highly vari-
able. The MRI of patients with clinical encephalitis is charac-
terized by diffuse brain atrophy, evidence of subcortical white
A B
FIGURE 6.7 MRI abnormalities in ADEM. (A) Axial FLAIR shows
multiple subcortical T2 hyperintensities in both hemispheres. (B) T1
post gadolinium demonstrates incomplete rings of enhancement sur-
rounding the lesions.
Scheld_Ch06.indd 105
Chapter 6: Encephalitis 105
matter infarcts, or T2W hyperintensity in the mesial temporal
lobe (301,302).
Acute Disseminated Encephalomyelitis
MRI findings in ADEM typically include multiple, asymmetri-
cally distributed areas of T2W hyperintensity in the subcorti-
cal and deep white matter (Fig. 6.7).
Lesions in the deep gray matter, which are characteristic
of ADEM but atypical for multiple sclerosis and other demy-
elinating disorders, often have a symmetric appearance. In
approximately one third of cases, the cerebral cortex is also
involved. Infratentorial involvement occurs in over half of
cases, with lesions seen in the brainstem, middle cerebellar
peduncles, and cerebellar white matter (303305). The size
and morphology of lesions is highly variable, although they
tend to have poorer margination as compared to lesions in
other demyelinating diseases. In most cases, lesions appear si-
multaneously, and all lesions will exhibit a similar degree of
contrast enhancement. Restricted diffusion may be observed
on DWI sequences in the acute stage, potentially representing
swelling of myelin sheaths, myelin vacuolation, or infiltration
of inflammatory cells with concomitant free radical produc-
tion (306,307). Rare variants of ADEM include hemorrhagic,
necrotizing, and relapsing forms (308).
AntiN-Methyl-D-Aspartate Receptor Encephalitis
One third to one half of patients may have abnormalities on
brain MRI. Affected areas, seen as T2W or FLAIR hyperin-
tensities, include the mesial temporal lobes, periventricular
white matter, cortex, cerebellum, brainstem, or basal gan-
glia. Notably, on follow-up, many of these abnormalities
improve, although atrophy may develop. Less than 20% of
affected individuals will have evidence of contrast enhance-
ment (168,309).
AntiVoltage-Gated Potassium Channel Receptor
Encephalitis
The spectrum of diseases associated with antibodies to the
VGKC complex has been steadily growing. In the setting of
encephalitis, the most common finding is unilateral or bilat-
eral T2W hyperintensity in the mesial temporal lobe (169)
(Fig. 6.8).
Recent reports have suggested additional or exclusive in-
volvement of the basal ganglia (310,311).
FIGURE 6.8 Autoimmune limbic encephalitis. Coronal FLAIR MRI
demonstrates T2 hyperintensities in the bilateral mesial temporal lobes
(solid arrow) and cingulate gyrus (dashed arrow).
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 106 Part II: Viral Infections and Related Disorders
MANAGEMENT
Clinicians should focus first on treatable and common causes
of encephalitis. Empirical treatment for bacterial meningitis
(vancomycin plus a third-generation cephalosporin) should be
started because the clinical presentation may overlap with en-
cephalitis. Therapy with ampicillin should also be considered
when the demographics (i.e., older individuals), clinical pre-
sentation (i.e., rhombencephalitis), or CSF profile is suggestive
of Listeria infection. Antiviral therapy is generally restricted
to treatment of herpesviruses (especially HSV-1 and VZV) and
the unusual instance of HIV infection (312). Therapy with
acyclovir should be started and continued until HSV-1 has
been reasonably excluded as a diagnosis, which may require
testing serial CSF samples (see prior discussion). Therapy for
M. tuberculosis or fungal meningitis should be initiated when
clinical and laboratory testing is compatible. If rickettsial or
Ehrlichia infections are suspected, doxycycline should be initi-
ated empirically.
For IAE, oseltamivir may be beneficial (313). Corticosteroids
or intravenous immune globulin may also be helpful in some
IAE cases to combat the proposed hyperintense cytokine re-
sponse. There is no evidence that treatment of presumed CNS
Mycoplasma infection alters outcome.
In addition to directed therapy, aggressive supportive care
is critical, and minimizing secondary brain injury should be
made a high priority (314). Seizures, status epilepticus, and ce-
rebral edema are important complications of encephalitis and
encephalopathy and should be monitored closely in patients
who are not improving. An elevated CSF opening pressure
may serve as a harbinger for impending complications. Repeat
neuroimaging to monitor for cerebral edema is particularly
important in comatose patients. Typical indicators of elevated
intracranial pressure, such as poorly reactive dilated pupils,
decorticate or decerebrate posture, or Cushing triad (systolic
hypertension, bradycardia, and shallow respirations) are late
findings. Patients should also be monitored for the syndrome
of inappropriate secretion of antidiuretic hormone (SIADH).
SIADH and extrapontine myelinolysis (EPM) are important
examples by which acquired metabolic derangements can both
complicate, and mimic, encephalitis (315).
Conditions that mimic infectious encephalitis should be
considered, particularly if no etiology is identified in the first
week of hospitalization. Metabolic and toxic disorders caus-
ing encephalopathy and seizures should be excluded. Anti-
NMDAR encephalitis is of particular importance given its
apparently high incidence; when identified, immunotherapy
and removal of the tumor, if present, have been associated
with improvement.
OUTCOME
In general, the prognosis of encephalitis is highly dependent
on the underlying cause. Rabies and N. fowleri, for instance,
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 CHAPTER 7 POLIOMYELITIS, POLIO VACCINES,
AND THE POSTPOLIOMYELITIS SYNDROME
JOHN F. MODLIN AND DAVID J. COFFEY
Poliomyelitis is a systemic viral infection caused by any of three
human poliovirus serotypes that is characterized by acute men-
ingitis and lytic infection of motor neurons in the brainstem and
spinal cord resulting in cranial nerve dysfunction and transient
or permanent paresis of one or more extremities. In the United
States and other developed countries, poliomyelitis due to nat-
urally occurring polioviruses has been eliminated by routine
childhood immunization. Global eradication is a major prior-
ity of the World Health Organization (WHO) and other major
partners in the Global Poliomyelitis Eradication Initiative.
A BRIEF HISTORY
OF POLIOMYELITIS
Poliomyelitis has afflicted humans since antiquity (1). The
first acknowledged description in English is a biographical
narrative of the acute paralysis suffered by Sir Walter Scott
in the second year of his life, circa 1772, and the first medi-
cal description is recorded in the second edition of A Treatise
on Diseases of Children, published in 1789 by Michael
Underwood, a London pediatrician and obstetrician (2,3).
Major contributions to understanding the disease were made
by the German orthopedist Heine, whose 1840 monograph
describes the clinical features of acute poliomyelitis in young
children (4), by the French anatomist Charcot who showed
that paralysis was accompanied by a loss of motor nerve cells
within the anterior horns of the cord (5), and by Karl Oskar
Medin, a Swedish pediatrician who, in 1887, recorded the
natural history of poliomyelitis and developed a classification
that became widely used for decades afterwards. The eponym
Heine-Medin disease was widely used throughout Europe
and North America during the early twentieth century.
Up to this time, only sporadic cases of poliomyelitis were
recognized. The first recorded outbreaks of poliomyelitis
occurred in the mid- and late nineteenth century in northern
Europe and later in North America. Charles Caverly, a
Dartmouth College trained physician, described 132 cases with
18 deaths in the Otter Creek Valley near Rutland, Vermont,
the largest outbreak known to have occurred up to that time
in North America (6). These early outbreaks heralded larger
epidemics, including a countrywide epidemic of more than
1,000 cases in Sweden in 1905 (7) and 1,200 cases in New York
City in 1907 (1), and the spread of disease throughout Europe
and North America. The shift from endemic to epidemic dis-
ease has been ascribed to the improved hygienic conditions that
accompanied the increasing standards of living in the industrial-
ized world. In theory, extensive exposure to polioviruses during
infancy in the presence of passively acquired maternal antibody
results in harmless but immunizing infections. Conversely,
infections delayed beyond infancy as a result of higher sanitary
standards and reduced opportunities for exposure are associ-
ated with an increased risk of neurotropic infection (8).
In 1908, Landsteiner and Popper (9) demonstrated that the
etiologic agent of poliomyelitis was a filterable virus in a
112
Scheld_Ch07.indd 112
series of experiments in which they induced paralysis and spinal
cord lesions in a monkey by intraperitoneal injection of neural
tissue from a fatal human case; shortly thereafter, Flexner and
Lewis (10) at the Rockefeller Institute serially passed poliovi-
ruses in monkeys, fulfilling one of Robert Kochs postulates.
Serologic surveys in the 1930s and 1940s helped define the
basis for the observed differences in the behavior of epidemics in
different locations and social conditions. Evidence of immunity
was found in 80% to 100% of adults tested, with generally
lower levels in children (11). In time, it was shown that the
risk of infection was universal, but children living in poor sani-
tary conditions acquired infection at a much earlier age than
children from higher socioeconomic backgrounds, an observa-
tion that explained the enigmatic shift during the early twen-
tieth century from an endemic disease involving only young
infants to an epidemic disease that also affected older children
and young adults (12). Later studies conducted by Paul and
Riordan (13) in a remote Eskimo population 15 to 20 years
following outbreak of poliomyelitis showed that immunity per-
sisted for at least two decades and perhaps for life.
The existence of more than one type of poliovirus was first
inferred by Burnet and Macnamara (14) in 1931 when they dem-
onstrated that monkeys who had recovered from infection with
a strain recovered in Melbourne subsequently developed disease
when given the virulent MV strain and showed that the two
strains differed qualitatively in in vitro neutralization tests. These
results were confirmed by Paul and Trask (11) at Yale and the
two virus groups were respectively designated Lansing-like, or
Brunhilde-like, the latter in reference to the name of a labora-
tory chimpanzee (1). A third type was predicted by the studies of
Bodian (15), at Johns Hopkins in 1949. The existence of three
types, and not more, was verified by the testing of poliovirus
strains collected worldwide by a collaborative group organized
by the National Foundation for Infantile Paralysis (16).
The era of effective poliomyelitis treatment began in the
1920s with the invention of the Drinker negative pressure ven-
tilator or iron lung at the Harvard School of Public Health
(17) and its development at several Boston hospitals (18). The
earliest devices were powered by vacuum cleaners and were
fitted with boat portholes for access to the body of the patient.
Progress in the management of the persistently paralyzed
patient was also made during this period. The practice of rigid
immobilization of even mildly involved extremities for long
periods gave way to the influential practices of Sister Elizabeth
Kenny using warm, moist packs and prolonged physical
therapy (19).
In 1936, Sabin and Olitsky (20) produced the first un-
equivocal evidence that polioviruses could be grown in vitro
when they propagated the MV poliovirus strain in human
embryonic central nervous system (CNS) tissue, and a decade
later, Enders, Weller, and Robbins (21), succeeded in growing
Lansing strain poliovirus in human embryonic tissues. This
achievement is widely acknowledged as the landmark event
that opened the door to further characterization of the virus,
better understanding of the pathophysiology of poliomyelitis,
and development of successful vaccines.
2/21/14 5:32 PM
 Chapter 7: Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome
Building on these advances, Jonas Salk (22) developed the
first successful inactivated poliovirus vaccine (IPV), which was
first administered to paralyzed patients in a home for crippled
children in Pittsburgh in 1952. In 1954 to 1955, Salk IPV was
successfully tested in a monumental controlled trial involving
more than 1.8 million U.S. schoolchildren. In the meantime,
several investigators were studying live, attenuated polioviruses
that could be delivered orally and induce mucosal as well as
systemic immunity (23). Live attenuated poliovirus strains were
tested in humans in several countries and ultimately, three mon-
ovalent strains developed by Sabin were licensed for use in the
United States in 1961 and 1962. Over the next 2 years, more
than 100 million oral poliovirus (OPV) vaccine doses were dis-
tributed in the United States via community programs organized
Scheld_Ch07.indd 113
113
FIGURE 7.1 Incidence of poliomyelitis in the
United States, 1920 to 1960. (Data courtesy Dr.
Linda Quick, Centers for Disease Control and
Prevention.)
by health departments and medical societies. Trivalent OPV
vaccine was introduced in 1964 and remained the principal
poliovirus vaccine used in the United States until 1997.
Figure 7.1 illustrates the reported incidence of paralytic
poliomyelitis cases in the United States from 1920 to 1960.
A peak of 55,000 cases was reported in 1952. The introduc-
tion of IPV vaccine for general use in 1955 and OPV vaccine in
the early 1960s led to rapid and dramatic control of epidemic
poliomyelitis, and the incidence of paralytic poliomyelitis fell
from 13.9 cases per 100,000 in 1954 to less than 0.5 cases
per 100,000 in 1965. By the 1970s, sustained transmission
of naturally occurring polioviruses ceased and the last case
of domestically acquired poliomyelitis was reported in 1979
(Fig. 7.2). Rare cases acquired in other countries continued to
FIGURE 7.2 Incidence of poliomyelitis
and vaccine-associated paralytic polio-
myelitis (VAPP) in the United States,
1961 to 2002. (Data courtesy Dr. Linda
Quick, Centers for Disease Control and
Prevention.)
2/21/14 5:32 PM
 114 Part II: Viral Infections and Related Disorders
be imported into the United States in the 1980s, but control of
poliomyelitis in the Western Hemisphere by 1991 resulted in
virtual disappearance of imported cases. Approximately 8 to
10 vaccine-associated paralytic poliomyelitis (VAPP) cases fol-
lowing administration or transmission of OPV were observed
until OPV vaccine was discontinued in favor of IPV in 1997
(24). Since then, only very rare poliomyelitis cases attributed
to imported VAPP or to acquisition of OPV vaccine-derived
polioviruses (VDPV) by immunodeficient persons have been
reported in the United States (25,26).
VIROLOGY, TRANSMISSION,
PATHOPHYSIOLOGY,
AND IMMUNITY
Virology
The polioviruses are prototypical human enteroviruses (species:
Enterovirus C; family Picornaviridae). Three poliovirus sero-
types are distinguished from one another by in vitro neutral-
ization with type-specific antisera. The icosahedral virion of
approximately 27 nm in diameter is composed of a protein
capsid and an enclosed single-stranded RNA genome of ap-
proximately 7,500 bases in length. The genome functions as a
monocistronic message with a single open reading frame coding
a 250 kDa polyprotein, which is subsequently cleaved by both
viral coded and cellular proteases into capsid proteins, an RNA
polymerase, proteases, and other regulatory proteins. The four
capsid proteins (VP1 through VP4) combine to form the 60
structural subunits that are assembled into the viral capsid.
Like all picornaviruses, polioviruses exhibit substantial
genomic variability with up to 15% variation within the cap-
sid coding region for each serotype. The three Sabin OPV
vaccine strains differ from their naturally occurring parents
at fewer than 0.2% of positions across the full genome (27).
For all three serotypes, analogous nucleotide substitutions in
the 5 noncoding region appear to be associated with dimin-
ished ability to replicate in the gastrointestinal tract and with
diminished neurovirulence. Attenuating mutations also map
to capsid proteins for each of the individual serotypes.
All three poliovirus serotypes share a common cell mem-
brane receptor (poliovirus receptor [PVR]), a 67-kDa mem-
ber of the immunoglobulin superfamily coded on human
chromosome 19 (28,29). PVR-transgenic mice express PVR
in CNS and muscle tissue, endowing susceptibility to these tis-
sues but not on intestinal mucosal cells (30).
Transmission of Polioviruses
Before the introduction of poliovirus vaccines, naturally
occurring polioviruses circulated in temperate climates with
a marked seasonal variation resulting in peak activity from
July to October and low levels from December to May. All
three serotypes circulated concomitantly, although one or
two types often predominated within a defined community
during a single season. Horizontal transmission in the com-
munity occurred mostly among children 2 to 5 years of age,
and data from virus watch studies indicated that poliovirus
transmission was strongly associated with low socioeconomic
status and household contact. Once virus was introduced into
a household, 90% to 100% of susceptible persons became
infected, along with 20% to 50% of seropositive persons (31).
Adults were only slightly less likely to become infected than
young children. After the introduction of OPV vaccine, the
Scheld_Ch07.indd 114
attenuated vaccine viruses replaced the epidemiologic niche
inhabited by the naturally occurring viruses. The very low
levels of person-to-person transmission of naturally occurring
polioviruses during the winter and spring months probably
abetted the disappearance of naturally occurring viruses and
their replacement by OPV strains (32).
Pathophysiology
Ingested polioviruses implant in the oropharynx and small
bowel and penetrate the mucosa via specialized microfold cells
(M cells) and other epithelial cells overlying submucosal lym-
phoid tissues (33). In primate models, the most efficient site of
viral replication is detected in Peyer patches in the intestinal
submucosa (34,35). Spread to regional lymph nodes gives
rise to a transient and clinically silent minor viremia dur-
ing which virus spreads to systemic reticuloendothelial tissue
including lymph nodes, bone marrow, liver, and spleen (36).
For most poliovirus infections, viral replication is contained
at this stage, resulting in subclinical infection. In a minority
of infections, further replication of virus in reticuloendothelial
tissues leads to a major viremia, which coincides with the
onset of fever and other clinical symptoms (37).
The path by which polioviruses reach the CNS remains
unsettled. It is well established that viremia precedes paraly-
sis, but the precise mechanism by which the virus breaches the
bloodbrain barrier is not known (38,39). A study using trans-
genic mice bearing the PVR gene found that spinal cord involve-
ment can be blocked by sciatic nerve section after virus is injected
intramuscularly (40), suggesting that virus replication in skeletal
muscle precedes transport of virus to the cord via the peripheral
nerve (41,42), a concept consistent with the myotropic nature
of enteroviruses and the clinical observation of intense myalgias
preceding the onset of paralysis in affected patients.
Polioviruses are recoverable from the spinal cord for only
the first several days of paralysis. The necrotic lesions and
inflammatory infiltrates (Fig. 7.3C), which are distributed
within the gray matter of the anterior horn of the spinal cord,
the motor nuclei of the pons and medulla, and occasionally
other locations (Fig. 7.3A and B), may persist for months (43).
The severity of clinical paralysis depends more on the intensity
of the lesions, rather than their distribution.
Immunity
Immunity to poliovirus infection is type specific; cross pro-
tection between the three serotypes is low, if it exists at all.
Reinfection with the same serotype occurs upon exposure to
live poliovirus, regardless of whether prior immunity is based
on infection with naturally occurring polioviruses, infection
with live, attenuated viruses, or inactivated poliovirus vac-
cine administration. After household exposure to wild type
virus, 20% to 50% of naturally immune (31), 30% to 50% of
OPV immune, and 90% to 100% of IPV immune persons are
reinfected, as defined by virus excretion from the gastrointes-
tinal tract or rise in antibody titer. Reinfections are universally
asymptomatic and are rarely associated with oropharyngeal
virus excretion.
Passively acquired poliovirus antibody protects against dis-
ease, but not against infection (44). Preexisting humoral anti-
body prevents or reduces oropharyngeal shedding of poliovirus
upon reinfection but has only a minor effect on fecal shed-
ding (38,4547). Serum-neutralizing antibodies are made in
response to natural infection and to immunization with either
OPV or IPV vaccine. Antibodies made in response to natural
2/21/14 5:32 PM
 Chapter 7: Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome 115

A B

FIGURE 7.3 A: T2-weighted axial image demonstrates abnormal,

increased signal intensity in the cerebral peduncles (arrow).
B: Pathologic section shows areas of necrosis (arrows) in the region
of the substantia nigra, corresponding to the areas of abnormal sig-
nal intensity in (A). C: Photomicrograph shows cystic necrosis sur-
rounded by an area of macrophage infiltration. (From Wasserstrom R,
Mamourian AC, McGary CT, et al. Bulbar poliomyelitis: MR findings
with pathologic correlation. Am J Neuroradiol. 1992;13:371373,
C with permission.)

infection appear to persist for life (48), and it is presumed that
vaccine-induced protection is long term, if not lifelong.
Poliovirus secretory immunoglobulin A (IgA) appears in
nasopharyngeal and intestinal secretions 1 to 3 weeks after nat-
ural infection or administration of OPV vaccine (49). Secretory
IgA antibody persists for at least 5 to 6 years at low levels and,
unlike humoral antibody, is not boosted significantly upon
rechallenge with OPV vaccine (50). The degree of protection
conferred by local IgA antibody is relative. Upon rechallenge,
high secretory IgA titers inhibit virus replication, whereas
lower titers permit replication; virus shedding is dependent on
the challenge dose (46,51). Studies in the field show that child-
hood recipients of OPV are often reinfected and shed OPV
virus in feces despite multiple prior OPV doses (52,53).
CLINICAL FEATURES
OF POLIOMYELITIS
Acute Illness
More than 90% of naturally occurring poliovirus infections
are inapparent. Acute clinical poliomyelitis is traditionally
separated into two distinct phases: the minor illness with an
incubation period of 3 to 7 days and the major illness with
onset of symptoms generally 9 to 12 days after exposure (54).
The minor illness, coinciding with viremia, consists of nonspe-
cific symptoms such as fever, headache, sore throat, anorexia,
and listlessness. Overall, 4% to 8% of infected persons expe-
rience symptoms of the minor illness, and most resolve their
illness within 1 to 2 days without further symptoms.
The major illness is associated with CNS infection, which
has been variously estimated to occur in 0.1% to 1.0% of all
poliovirus infections (8,55). About one third of young children
who develop the major illness experience a biphasic illness
with symptoms of the minor illness preceding onset of CNS
disease; adults usually develop CNS disease without the pre-
ceding minor illness (37,56). The major illness is heralded by
the abrupt onset of fever, headache, vomiting, and meningis-
mus (Table 7.1). CSF pleocytosis is present at this early stage.
Approximately one third of cases of CNS disease are limited
to meningitis without detectable motor neuron impairment,
which resolves within 5 to 10 days (i.e., nonparalytic polio-
myelitis).
Muscle weakness is preceded by intense myalgias of
the involved limb(s) and the axial skeleton. The pain may
be relieved by exercise; patients may pace nervously in an
attempt to work off the pain. The hallmark of poliomy-
elitis is asymmetric motor paresis, which ranges from mild

Scheld_Ch07.indd 115 2/21/14 5:32 PM

 116 Part II: Viral Infections and Related Disorders
TA B L E 7 . 1
CLINICAL FEATURES OF ACUTE POLIOMYELITIS
Minor illness
Fever
Headache
Sore throat
Major illness
Abrupt onset of headache, vomiting, meningismus
Aseptic meningitis
Prodromal myalgias of involved muscles
Asymmetric motor weakness
Complications
Bulbar paralysis
Respiratory failure
Aspiration pneumonia
Myocarditis
Paralytic ileus and gastric dilatation
Bladder ileus
weakness of a single extremity to complete quadriplegia.
Proximal limb muscles are more involved than distal, and
legs are more commonly involved than arms. The deep ten-
don reflexes, which were initially brisk, become absent. The
pace of development of the paresis ranges from several hours
to several days; most commonly occurring over 2 to 3 days.
Cranial nerve involvement (i.e., bulbar poliomyelitis)
occurs in 5% to 35% of paralytic cases. Any of the motor
cranial nerves can be involved, with the ninth and tenth being
the most common.
Complications
Bulbar paralysis results in dysphagia, nasal speech, dyspnea,
difficulty managing secretions, anxiety, and respiratory com-
promise. Involvement of respiratory and vasomotor nuclei is
less common but may portend serious complications due to
hypoventilation, blood pressure lability, and cardiac arrhyth-
mias. Respiratory failure from paralysis of the diaphragm
and intercostal muscles represents the most serious compli-
cation of paralytic poliomyelitis. Aspiration pneumonia, pul-
monary edema, myocarditis, paralytic ileus, gastric dilation,
and ileus of the bladder may also complicate acute paralytic
disease.
Prognosis
Paralysis most often progresses for 1 to 3 days after onset,
rarely more than a week, halting about the time the patient
becomes afebrile (57). Most patients with limb paresis experi-
ence some recovery of function in the weeks to months after
acute disease. An estimate of the eventual outcome can be
made by a month after onset when most reversible weakness
will have resolved. Very little additional recovery of strength
can be expected after a period of 9 months. Residual motor
deficits remain in about two thirds of initially paralyzed
patients, ranging from minor debility to permanent, flaccid
paralysis.
Scheld_Ch07.indd 116
Overall mortality for spinal poliomyelitis is about 4% to
6%. During the poliomyelitis epidemics in the 1940s and
1950s, bulbar polio caused a mortality of 20% to 60% when
respiratory assistance was required. With modern intensive
care, deaths from temporary respiratory paralysis should be
less common.
Differential Diagnosis
Sporadic cases of paralytic disease due to the nonpolio entero-
viruses and West Nile virus is clinically indistinguishable from
poliomyelitis. Only two nonpolio serotypes have been known
to cause epidemic disease: coxsackievirus A7 virus, which
has caused small outbreaks of paralytic disease in the for-
mer Soviet Union (58), South Africa, and Scotland (59), and
enterovirus 71, which has caused large outbreaks in Eastern
Europe in the late 1970s and more recently in several countries
in Southeast Asia (6062).
Poliomyelitis must also be distinguished from other causes
of acute paralysis including the Guillain-Barr syndrome,
which is associated with paralysis that is classically ascend-
ing in nature, symmetric, and is accompanied by sensory
abnormalities in approximately 80% of cases. The CSF pleo-
cytosis that occurs during the major illness of poliomyelitis
is not characteristic of the Guillain-Barr syndrome, which is
associated with a normal CSF leukocyte count and an elevated
CSF protein concentration. Other conditions produce acute
paralysis, including transverse myelitis, botulism, tick paraly-
sis, epidural abscess, cord tumors, and hysteria; however, each
of these diseases has features that readily separate them from
acute poliomyelitis.
Risk Factors
Although it was once believed that adults are more susceptible
to paralytic complications, there is probably little correlation
of age with severity of disease after the decline of maternal
antibody (8,55). Studies during outbreaks suggest that infected
pregnant women have an increased risk of developing para-
lytic disease (63,64). There is no evidence that either naturally
occurring polioviruses (65) or attenuated vaccine polioviruses
(66) cause congenital defects.
Persons with B-cell immunodeficiency, primarily young
children with X-linked immunodeficiency syndromes, have
an increased risk of CNS disease when infected with either
naturally occurring or attenuated vaccine polioviruses. These
patients may develop acute paralysis or may have an atypical
course with an incubation period of several months, prolonged
febrile illness, chronic meningitis, and progressive neurologic
dysfunction that includes both upper and lower motor neuron
involvement (6770).
Strenuous exercise during the early stages of the major ill-
ness substantially increases the risk and severity of poliomy-
elitis. This effect has been well documented clinically (71,72);
and experimental infections with other enteroviruses provide
supportive evidence (73).
Paralytic poliomyelitis tends to localize in a limb that has
been the site of a recent intramuscular injection or injury
(7476). Observations in experimental poliomyelitis (39,40)
and after the administration of OPV vaccine (77) confirm this
association but do not fully explain the mechanism of the
provoking effect. Tonsillectomy during the incubation period
of poliomyelitis markedly increases the risk of bulbar disease
(78). The mechanism may be similar to the provoking effect of
injections on spinal poliomyelitis.
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 Chapter 7: Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome
POSTPOLIOMYELITIS SYNDROME
As many as 20% to 30% of patients who recover from para-
lytic poliomyelitis experience new onset of muscle weakness,
pain, atrophy, and fatigue many years after the acute illness.
With the eradication of acute poliomyelitis, the postpolio syn-
drome remains the sole polio-related clinical disease encoun-
tered by physicians in all but a few polio-endemic nations. It is
expected that the postpolio syndrome will ultimately decline in
incidence and disappear as poliomyelitis is controlled around
the globe.
History and Background of the
Postpoliomyelitis Syndrome
In 1875, Charcot (79) described a relationship between
acute poliomyelitis and late development of motor neuron
degeneration. By 1969, approximately 83 cases had been
described in which motor neuron degeneration occurred
decades after acute poliomyelitis (80), although the dis-
tinction between what we now describe as postpolio syn-
drome and other possible causes of late denervation, such
as amyotrophic lateral sclerosis (ALS), was not possible
in many of these cases. The hypothesis was advanced that
the incidence of late motor neuron disease might increase
as children affected during the epidemics of the 1950s
reached middle age (81,82). Initial concern that paralytic
poliomyelitis might increase the risk of subsequent ALS
was allayed by careful epidemiologic studies, suggesting
that prior infection with poliomyelitis might actually pro-
tect against the subsequent development of ALS (83). At
present, it seems clear that the etiology and natural his-
tory of the postpolio syndrome and ALS are quite differ-
ent. Postpolio syndrome is an indolent condition that rarely
leads to severe disability or death (84).
Nomenclature
Although the term postpolio syndrome has sometimes been
applied to all neurologic symptoms occurring as late mani-
festations of poliomyelitis, most authorities reserve this des-
ignation for a disorder characterized by new-onset muscle
weakness, fatigue, and pain, associated with loss of function
that occurs years after the original acute poliomyelitis epi-
sode (8587). Another term, postpolio progressive muscular
atrophy (PPMA) refers specifically to the weakness with or
without atrophy that results from late denervation of muscles
of patients (8891). Criteria for PPMA include a reasonable
past history of poliomyelitis with partial recovery of func-
tion and at least a decade of stabilization after recovery from
the initial illness. PPMA is then the development of progres-
sive muscular weakness following these antecedent criteria.
It is worth noting that atrophy probably occurs in only half
or fewer of the patients who develop new weakness (92).
Although the terms postpolio syndrome and PPMA are used
almost interchangeably, it should be recognized that postpo-
lio syndrome or postpoliomyelitis sequelae may include other
symptoms such as fatigue (undoubtedly the most common of
all symptoms), subjective alterations in attention or cogni-
tion, sleep disturbance, and alterations in pain perception.
Bulbar symptoms, including dysphagia and some pulmonary
disturbances, can occur and may be more common and severe
in those who had bulbar symptoms during their childhood
illness.
Scheld_Ch07.indd 117
117
Epidemiology and Risk Factors
Epidemiologic studies indicate that postpolio syndrome affects
a substantial proportion of the 250,000 to 640,000 polio survi-
vors estimated to live in the United States (83,86,93). A cohort
study of 300 persons living in Olmsted County, Minnesota, who
had contracted paralytic poliomyelitis between 1935 and 1955
found that 32 (64%) of 50 poliomyelitis survivors had symp-
toms consistent with postpolio syndrome, and in another ret-
rospective study of Allegheny County, Pennsylvania, residents
with a history of paralytic poliomyelitis noted a prevalence of
28% (94,95). In the latter study, female gender and permanent
impairment sustained at the time of acute polio infection seemed
to convey a higher risk of developing postpolio syndrome.
However, the strongest risk factor for developing postpolio syn-
drome was the interval from the original paralytic disease with
the incidence of postpolio syndrome peaking 30 to 34 years after
the original illness. Older age at the time of presentation with
postpolio syndrome has also been identified as a risk factor (86).
Etiology
Although the precise cause of postpolio syndrome remains
unknown, there is a consensus among authors that the cause
is probably related to exhaustion of motor units previously
overstressed by recovery from the acute denervation during
acute polio virus infection following which terminal elements
of surviving alpha motor neurons sprout to reinnervate adja-
cent myofibrils. After acute poliomyelitis, fewer anterior horn
cells innervate a relatively larger number of myofibrils, thereby
exaggerating the effects of the additional, physiologic cell loss
at a later date attributed to aging (92,96).
Other possible mechanisms have been considered, includ-
ing immunologic events and other virushost interactions.
Prime among these alternative theories is the conjecture that
polioviruses can persist for many years within the CNS of
patients with postpolio syndrome and cause recrudescent dis-
ease by direct viral infection or immunopathologic pathways
(97). Evidence in support of this theory includes the demon-
stration of oligoclonal immunoglobulin G bands (84,98) or
poliovirus-specific immunoglobulin M bands (99) in CSF, and
the demonstration of poliovirus-like RNA sequences in CSF
of postpolio syndrome patients by the polymerase chain reac-
tion (100). However, the presence of CSF oligoclonal bands
has been inconsistent across studies (101,102), and virologists
debate the likelihood of infectious virus, or even viral RNA,
persisting for long periods in immunocompetent hosts.
Pathophysiology
Physical fatigue may result from damage to motor units in
previously affected muscle (103106), perhaps associated with
a change in acetylcholine receptor sensitivity and/or number.
(This has a practical ramification for anesthesiologists who
may find it prudent to reduce the dose of paralytic agents for
patients with postpolio syndrome [107].) During exercise,
there is decreased maximal voluntary contraction of muscles
affected by postpolio syndrome, decreased tetanic force, and
delayed recovery. Based on these and other data, Sharma et al.
(106) hypothesize that muscle fatigue in postpolio syndrome
may be due to impaired activation beyond the muscle mem-
brane at the level of excitationcontraction coupling. Based on
neuropathologic studies of patients with poliomyelitis in the
1940s and 1950s, another hypothesis suggests that the fatigue
experienced by patients with postpolio syndrome has a central
2/21/14 5:32 PM
 118 Part II: Viral Infections and Related Disorders
FIGURE 7.4 T2-weighted axial MRI scan demonstrating one of three
hyperintense lesions (arrow) in the circum semiovale of a 42-year-old
patient with postpoliomyelitis syndrome. (From Bruno RL, Cohen
JM, Galaski T, et al. The neuroanatomy of postpolio fatigue. Arch
Phys Med Rehabil. 1994;75:498504, with permission.)
origin. These studies showed lesions in specific areas of the
brain whether or not clinical symptoms of encephalitis had
occurred, including the reticular formation in the brainstem,
vestibular nuclei, cerebellar nuclei, periaqueductal gray, hypo-
thalamic and thalamic nuclei, substantia nigra, locus ceruleus,
and median raphe nuclei (43,107,108). The reticular activat-
ing system, responsible for maintaining normal alertness and
attention, is composed of the brainstem reticular formation,
posterior hypothalamus, and thalamus. Specific injuries to
these structures from poliovirus infection could cause the acute
disorientation and depression of consciousness seen in acute
poliomyelitis and hypothetically could set the stage for late-
onset decompensation of arousal, attention, and subjective
cognition in postpolio syndrome (109,110). It has been sug-
gested that T2-weighted hyperintense areas observed on brain
magnetic resonance imaging (MRI) scans could represent these
areas of polio virusinduced damage (111) (Fig. 7.4). Injury to
the periaqueductal gray of the brainstem and substantia gela-
tinosa of the posterior horn of the spinal cord may explain the
hyperpathia that is reported by many polio survivors (111).
Clinical Features
Fatigue, which may be the most distressing and disabling
symptom, is also the most common complaint, occurring in
91% of polio survivors in national surveys (89,96,103,112).
Of these individuals, 41% experienced work limitation and
25% had interference with self-care (111). Patients also report
mental fatigue affecting attention and concentration (103).
The most common neurologic sign of postpolio syndrome
is new weakness, which may be accompanied by atrophy and
pain. Weakness occurs in those muscles previously weakened
during acute paralytic poliomyelitis or in muscles thought to
be previously unaffected and may increase with exertion. The
pain may be perceived in muscles or joints and can occur in
the presence or absence of weakness. Joint pain may occur
Scheld_Ch07.indd 118
because chronic residual weakness leads to abnormal joint
stresses. Scoliosis, poor mechanics, and abnormal postures
may all contribute. The degree of actual osteophytic change
may be less than one might anticipate given the amount of
residual weakness. Muscle pain may result from chronic
denervation or, if residual weakness is present, merely from
overuse of muscles. Secondary myopathy with elevation of
creatine kinase levels, usually of a mild degree, may occur in
some patients (95).
Postpoliomyelitis dysphagia, whether simply residual or
progressive could be a consequence of bulbar motor nerve
injury. Attention to the problems of dysphagia in patients with
postpolio syndrome was first drawn by Sonies and Dalakas
(113), who suggested that it was analogous to the postpolio
syndrome seen in the limbs, based on their series in which all
but 1 of the 32 patients studied had some abnormality in swal-
lowing function. Cinefluorography can demonstrate whether
there are impaired movements of the tongue, aspiration, or
pooling of material in the pyriform sinuses or valleculae.
Aspiration seems to be found only very infrequently and prob-
ably does not pose a severe risk in most instances (93,113).
Other symptoms that might be attributed to late-onset bulbar
dysfunction include the sleep-disordered breathing and chronic
alveolar hypoventilation that sometimes develop in patients
with postpolio syndrome (114). Sleep-disordered breathing
may include obstructive sleep apnea syndrome and may occur
more commonly in patients with postpolio syndrome who suf-
fered insult to respiratory control centers in the brainstem at
the time of their primary infection. Pulmonary function may
be further compromised if weakness of respiratory muscles,
impaired swallowing or cough mechanisms, chest wall defor-
mity, or poor thoracoabdominal interaction is present (115).
Electrophysiology
Conventional electromyography (EMG) demonstrates chronic
denervation and occasionally reveals new or ongoing denerva-
tion in the form of fasciculations, fibrillations, and positive
sharp waves (87,91,116). Both symptomatic and asymptom-
atic patients with postpolio syndrome show similar EMG
findings. Similarly, the chronic denervation and reinnerva-
tion signs (including both enlarged and polyphasic motor
unit potentials) and decreased interference patterns are seen
whether or not the muscle being tested was originally weak
(91,92,117). Enlarged motor units consistent with highly
increased fiber density can be demonstrated in 90% of patients
with postpolio syndrome with single-fiber EMG (90). Jitter and
neuromuscular blocking effects are also noted, which correlate
with the interval since acute poliomyelitis. Like conventional
EMG, single-fiber EMG is unable to distinguish symptomatic
and asymptomatic patients with postpoliomyelitis. In con-
trast, macro-EMG may distinguish muscles with new weak-
ness, because previously increased amplitudes decline with
new weakness and atrophy (90).
Although electrophysiologic studies in postpolio syn-
drome and PPMA have provided important pathophysiologic
information and supported the etiologic concept of overuse
or accelerated aging of overcompensated motor units, the pri-
mary clinical role for nerve conduction and EMG studies is to
exclude other causes for the patients complaints.
Psychologic Issues
Although the cardinal manifestations of postpolio syndrome
are neither caused nor modified by psychopathologic or
2/21/14 5:32 PM
 Chapter 7: Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome
personality factors, patients with postpolio syndrome may be
subject to characteristic psychologic symptoms (110,116,118).
Bruno et al. (112) argue that anxiety, depression, and com-
pulsive behavior occur frequently in polio survivors, resulting
from the experience of a disabling disease in childhood from
which recovery was achieved only by extreme effort (118).
Success in obtaining independence and in overcoming a dis-
ability was often accomplished by adopting very compulsive
behavior and demanding very high standards of themselves.
One of the goals that many individuals set was to overcome
the need for assistive devices such as braces, crutches, wheel-
chairs, and the like. In consequence, polio survivors achieved
higher than expected life goals.
Effects of Exercise
Unfortunately, the avoidance of assistive devices at the time
of acute weakness may be maladaptive in subsequently deal-
ing with postpolio syndrome (112). Overtaxing motor units
with exercise may contribute to irreversible damage to mus-
cle fibers and more severe weakness (88,119,120). Patients
with postpolio syndrome may benefit from rest periods, in-
creased sleep time, and other energy-conservation methods
to overcome fatigue (121). Compliance with appropriate
intervention to correct the overuse pattern appears to result
in improvement or resolution of new weakness and fatigue
(122). However, because disuse can also enhance weakness,
some moderation must be sought. Muscle strength may be im-
proved by nonfatiguing exercise (123). Specific protocols for
high-resistance exercise to improve isokinetic and isometric
strength for patients with postpolio syndrome have been de-
scribed (124,125).
POLIOVIRUS VACCINES
Inactivated Poliovirus Vaccine
IPV vaccine is prepared by inactivation of poliovirus seed
strains by formalin treatment for 12 to 14 days at 37C, the
method originally developed by Jonas Salk. However, con-
temporary IPV vaccines contain higher concentrations of
all three antigens compared with IPV vaccines introduced
in the 1950s. Three IPV formulations are now distributed
in the United States: trivalent IPV (IPOL, Aventis Pasteur)
and trivalent IPV combined with other recommended child-
hood vaccines (Pediatrix, GlaxoSmithKline and Pentacel,
Sanofi Pasteur). Most available IPV vaccines are produced
from wild type polioviruses grown in monkey kidney cells
and contain 40-, 8-, and 32-D antigen units, respectively, for
poliovirus serotypes 1, 2, and 3. IPV formulations produced
from Sabin OPV vaccine strains are under development in
China and elsewhere. The primary vaccination series for IPV
vaccine in the United States consists of four doses admin-
istered at 2 months, 4 months, 6 to 18 months, and 4 to
6 years of age (126). Since 2000, IPV vaccine has been used
exclusively in the United States for routine immunization
of infants against poliomyelitis and for all other recipients
including unimmunized adults, immunodeficient persons,
and anyone requiring polio vaccine boosters to travel to
poliovirus endemic regions (126).
Neutralizing antibodies are detectable to all three poliovi-
rus types in 99% of IPV vaccine recipients after two doses
and 100% after the third dose (127,128). A large boost
in antibody titer follows the third dose (127,128). After
three doses, mean titers to types 1 and 3 are higher than in
Scheld_Ch07.indd 119
119
OPV-immunized children, whereas mean titers to type 2 are
equivalent. Detectable antibody persists at protective levels
for at least 5 years, although mean titers decline considerably
(128). Vaccine efficacy for IPV distributed in the 1960s was
estimated to be 91% and 95% for 3 and 4 doses, respectively.
There are few data regarding vaccine efficacy of the current
IPV formulations. A casecontrol study in Senegal indicated
protection rates of 36% and 89% for recipients of one and
two doses, respectively (129). The efficacy for three doses is
assumed to be higher.
IPV-immunized children develop little or no measurable
secretory antibody (49). When challenged with live poliovi-
ruses, IPV-immunized children shed the challenge virus in their
feces at a higher rate, higher titer, and for a longer period than
OPV-immunized children (51), indicating a greater potential
for asymptomatic infection and transmission of circulat-
ing polioviruses to unimmunized contacts. Although this is
widely considered to be a disadvantage of IPV, there is strong
evidence that widespread use of IPV results in protection that
extends to unvaccinated persons in the community in devel-
oped nations with good sanitation (130,131). IPV vaccine
may reduce community transmission of polioviruses due to
reduction of pharyngeal shedding of poliovirus in reinfected
IPV vaccine recipients, which may be the important mode of
community spread (47), although there is little effect of IPV
vaccine in preventing spread within families in which fecal-
oral spread may be a more important mode of transmission
(132,133).
Live, Attenuated Poliovirus Vaccine
Live, attenuated trivalent (tOPV) vaccine remains the principal
vaccine used throughout the developing world. There are dif-
ferent manufacturers worldwide, but most follow a common
production method in which Sabin seed strains representing
each of the three poliovirus serotypes are individually grown
in monkey kidney cells and are combined for oral administra-
tion in concentrations of approximately 106.0 TCID50, 105.1
TCID50, and 105.8 TCID50 for poliovirus types 1, 2, and 3,
respectively. The unequal contribution of each type to the
trivalent preparation represents a balanced formulation
designed to account for the more efficient replication of type
2 OPV vaccine in the gastrointestinal tract (134). Because
type 2 virus regularly interferes with replication of types 1 and
3, a primary series of three doses are routinely administered
to enhance seroconversion to all three serotypes. Under con-
ditions of good hygiene, seroconversion rates of 50%, 85%,
and 30% to serotypes 1, 2, and 3, respectively, are achieved
following the first tOPV dose (135), and a second and third
tOPV dose induce neutralizing antibodies to all three types in
86% and 96%, respectively (127,136). Serum antibody to all
three types persists in 84% to 98% of vaccinees 5 years after
primary immunization (137), although reexposure to vaccine
viruses probably aids the maintenance of antibody levels in the
population. Secretory IgA poliovirus antibody appears in oro-
pharyngeal and duodenal secretions 1 to 3 weeks after OPV
immunization (49) and persists for at least 5 to 6 years (138).
Challenge studies suggest that the intestinal immunity induced
by OPV vaccine is similar to intestinal immunity following
natural infection (139).
The WHO Expanded Program on Immunization (EPI)
recommends one dose of tOPV at birth, a practice that
provides an opportunity to administer at least one dose of
vaccine to a child who may not present for routine health
maintenance care later, and three tOPV doses at 6, 10, and
14 weeks of age (140). Even though passively acquired
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 120 Part II: Viral Infections and Related Disorders
maternal antibody to polioviruses present in the infants
circulation and in breast milk reduces vaccine virus repli-
cation in the gastrointestinal tract and therefore blunts the
immune response in some infants, infants who receive OPV
at birth are more likely to have antibody to all three polio-
virus types at 4 months of age (141). Seroconversion rates
to tOPV are lower in many tropical countries compared to
seroconversion rates in developed countries (142144). Poor
responses to tOPV have contributed to outbreaks of polio-
myelitis in Oman, Israel, and Brazil despite relatively high
immunization rates existing before the appearance of epi-
demic disease (145147). Although the reasons for the lower
potency of tOPV vaccine in tropical areas remain incom-
pletely understood, concurrent diarrheal disease at the time
of immunization is an important factor (148,149).
Monovalent type 1 (mOPV1), monovalent type 3 (mOPV3),
and bivalent type 1 and type 3 (bOPV) were added to the
Global Polio Eradication Program in 2006 and 2009, respec-
tively to enhance seroconversion rates to type 1 and type 3
OPV in the absence of the type 2 vaccine virus (150). Studies
in Egypt and South Africa have confirmed the superior immu-
nogenicity of the monovalent vaccines compared to tOPV in
resource poor settings (151,152).
Nonimmune OPV recipients shed vaccine viruses in the
feces for 1 to 6 weeks and from the oropharynx for 1 to
3 weeks. The spread of OPV viruses to unimmunized children
is an advantage in areas in which immunization levels are low.
For example, a seroprevalence study in Houston and Detroit
found that 11% to 42% of 11- to 35-month-old children pos-
sessed poliovirus neutralization antibodies, despite receiving
no prior OPV vaccine (153).
Vaccine-Associated Paralytic Poliomyelitis
The only serious adverse reaction associated with OPV is
the rare occurrence of VAPP. The incidence of VAPP has
been estimated to be 2 to 4 cases per million individuals per
year in countries using OPV (154). In industrialized coun-
tries, the relative frequency of paralysis associated with the
first dose in the OPV series is about 10-fold higher than
with subsequent doses, whereas in developing countries,
this ratio is lower, probably due to lower vaccine effective-
ness (155). OPV virus types 3 and 2 were most common
causes of VAPP in the United States prior to discontinuation
of OPV use in 2000 (155). Approximately half of VAPP
cases are recent OPV vaccinees, most of whom develop
paralysis 7 to 21 days after the first feeding of OPV. A
similar number of cases occur among parents, other family
members, or other household contacts that develop paraly-
sis several weeks after the administration of OPV to a close
contact.
Persons who have transient or hereditary B-cell immuno-
deficiency, severe combined immunodeficiency syndrome, or
common variable immunodeficiency have an elevated risk of
VAPP (69,156). For immunodeficient VAPP patients, interval
between the last OPV dose and onset of neurologic disease
is unusually long, with a typical range of 1 to 8 months, and
has been documented to be as long as 7 years (70). The illness
may be protracted with chronic meningitis, progressive neu-
rologic dysfunction suggesting involvement of both upper and
lower motor neurons, progression of paralysis over several
weeks, and high mortality (67,68). Although fewer than 20%
of surviving VAPP patients excrete polioviruses for longer
than 6 months (70), fecal excretion of virus has been esti-
mated to occur for as long as 18 years in one immunodeficient
patient (157).
Scheld_Ch07.indd 120
GLOBAL CONTROL OF
POLIOMYELITIS
With some notable exceptions (158), paralytic poliomyeli-
tis affects mostly children between the ages of 6 months and
2 years in developing countries, and most cases are caused by
type 1 poliovirus. Lameness surveys of school-aged children in
more than 20 developing nations revealed lower limb paralysis
prevalence rates of 2 to 11 per 1,000 in the 1960s and 1970s,
prevalence rates that equal or exceed those of the peak epi-
demic years in the United States (159,160). Currently, OPV
vaccine is used almost exclusively in underdeveloped nations
because of lower cost, ease of administration, enhanced
mucosal immunity, and enhancement of population immunity
through transmission of vaccine viruses from immunized chil-
dren to nonimmune contacts.
Following the successful eradication of smallpox, an
international conference held in Bellagio, Italy in 1983
articulated the possibility of poliomyelitis eradication based
on the unique epidemiology of poliovirus infections and the
widespread availability of an inexpensive oral vaccine (tOPV)
(161,162). By 1991, the Pan American Health Organization
succeeded in eradicating polio in the Americas, and in 1988,
the World Health Assembly resolved to eradicate polio glob-
ally by the year 2000 (163165). The Global Poliomyelitis
Eradication Initiative (GPEI) is a consortium of international
partners led by the WHO (159,166). The principal strategies
employed by the GPEI include enhancement of routine infant
tOPV immunization, the conduct of large scale supplementary
immunization activities (SIAs) targeting all children younger
than 5 years of age, surveillance for poliomyelitis cases
through identification of persons with acute flaccid paralysis
(AFP), and maintenance of a global network of laboratories
capable of identification and characterization of polioviruses
in fecal specimens obtained from AFP cases. Seroconversion
rates during SIAs are higher than for routine immunization
(167), possibly because of spread of OPV or because they are
conducted during the dry season when diarrheal disease is less
prevalent. In the Americas, twice yearly mass campaigns were
credited with rapid cessation of poliovirus circulation and dis-
appearance of disease (168,169).
Although there has been a reduction of more than 99% in
the burden of paralytic poliomyelitis and circulation of type 2
polioviruses ceased in 1999, the goal of complete eradication
has proven to be more difficult to attain than originally an-
ticipated (170172). Progress stalled in the last decade due to
inability to stop transmission in some highly endemic areas,
exportation from these areas to previously polio-free nations,
social and cultural opposition to OPV immunization, civil
unrest, funding gaps, and the emergence of VDPV in areas
with low OPV coverage (173,174). Eventually, many of the
social, cultural, and political barriers were addressed, and in
the mid-2000s, the deployment of monovalent and bivalent
OPVs during SIAs led to improved seroconversion rates in
many countries affected by low tOPV potency. These new
formulations are now credited with the eventual elimination
of poliomyelitis in India and the marked reduction in case
load in some particularly challenging areas in sub-Saharan
Africa (166).
Vaccine-Derived Polioviruses
One unanticipated challenge to global poliomyelitis eradica-
tion is the emergence of virulent polioviruses derived from
OPV vaccine strains among underimmunized children living
2/21/14 5:32 PM
 Chapter 7: Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis Syndrome
in certain economically deprived regions (175,176). A retro-
spective laboratory investigation demonstrated previously
unrecognized type 2 VDPV isolates that circulated in Egypt
from approximately 1982 to 1993, and global surveillance
since 2000 has uncovered more than 15 subsequent VDPV
outbreaks representing all three poliovirus serotypes (177). All
VDPV strains have been isolated from regions with low OPV
coverage, permitting VDPV to circulate, and all have acquired
biologic properties that are indistinguishable from naturally
occurring wild type polioviruses, including neurovirulence in
monkeys and transgenic mice (178,179).
The discovery of the potential for reintroduction of viru-
lent polioviruses into previously polio-free areas via genera-
tion of VDPV has reinforced the necessity of maintaining high
immunization levels in all polio-free regions and has created
the necessity of discontinuing the use of all live, attenuated
poliovirus vaccines once eradication of naturally occurring
poliovirus disease is assured (180,181).
OUTLOOK
As of 2013, renewed commitment to eradication has reduced
the number of polio-endemic nations to threeNigeria,
Afghanistan, and Pakistanand the annual global case count
to less than 300, and there is hope that the mission to eradicate
will soon be met. The polio endgame now calls for replace-
ment of tOPV by bOPV once the threat from type 2 circulat-
ing vaccine-derived poliovirus (cVDPV) is diminished and the
ultimate discontinuation of all live OPV and a phased intro-
duction of IPV. IPV is known to be highly immunogenic when
administered to infants and children in resource-poor settings
(182185) and has shown promise as a supplement to OPV
in similar settings (147,186188). Furthermore, strategies are
being developed to overcome the higher costs associated with
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121
IPV production, delivery, and storage, including development
of dose reduction by intradermal injection, development of
new adjuvants, and combination of IPV with other vaccines
routinely administered to infants (174).
SUMMARY
Epidemic paralytic poliomyelitis is a disease that has both
appeared and disappeared during the past 120 years. Most
medical practitioners in industrialized countries have never
seen a case of acute poliomyelitis but may encounter patients
who are now developing the symptoms of postpolio syndrome.
The clinical, epidemiologic, and scientific foundations for the
control of poliomyelitis were laid in the first half of the twen-
tieth century. Now, eradication has been achieved through-
out the developed world by routine immunization programs
using two very effective vaccines, each of which possesses
unique advantages and disadvantages. In recent years, IPV has
become the preferred vaccine for developed countries because
of the risk of rare VAPP cases associated with OPV.
Attention is now focused on the few remaining locations
where polio remains endemic. Despite setbacks, new strate-
gies are being deployed and real progress has been made in
recent years. Hopefully, the goal of global poliomyelitis eradi-
cation will be achieved before the next edition of this text is
published. The posteradication phase will require continued
surveillance, maintenance of vaccine stockpiles for use should
virulent polioviruses reemerge, and containment of labora-
tory stocks of naturally occurring and attenuated polioviruses
(189). The discovery of VDPV in multiple locations has lim-
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2/21/14 5:32 PM
 CHAPTER 8 MEASLES AND RUBELLA
DIANE E. GRIFFIN
Measles and rubella are rash diseases of childhood that can
be complicated by neurologic disease. Measles virus (MeV)
induced neurologic disease is associated with community-
acquired infection of children, whereas the most important
rubella virus (RV)induced neurologic disease is associated
with congenital infection. For both diseases, effective and safe
vaccines exist. Despite wide distribution of measles vaccine,
measles remains a frequent cause of morbidity and mortality
worldwide, and even a low incidence of measles-associated
neurologic disease has a significant impact on society because
of the long-term neurologic disabilities that ensue (1). Rubella
vaccine is less widely distributed, but there is an intensifying
effort to increase coverage in developing countries and reduce
the worldwide incidence of congenital rubella syndrome (CRS)
(2). The World Health Organization has targeted both viruses
for elimination and potential eradication (3).
Neurologic complications may result from direct virus inva-
sion of the central nervous system (CNS) or from induction of
an autoimmune response to CNS antigens. For measles, there
are three distinct neurologic diseases that occur either at the
time of the acute disease or months to many years after appar-
ent recovery: acute disseminated encephalomyelitis (ADEM),
measles inclusion body encephalitis (MIBE), and subacute
sclerosing panencephalitis (SSPE). Rubella causes ADEM and
progressive rubella panencephalitis (PRP) less frequently than
measles but is also teratogenic and causes CRS.
BACKGROUND ON MEASLES
MeV, the etiologic agent of measles, is a member of the
Morbillivirus genus of the Paramyxoviridae family of nonseg-
mented, negative-stranded, enveloped RNA viruses. There are
several morbilliviruses and each has a relatively restricted host
Scheld_Ch08.indd 125
range. Nonprimate morbilliviruses cause respiratory disease in
dogs, horses, cows, goats, sheep, and marine mammals and
neurologic complications are common. Rinderpest, a disease
of cattle, has recently been eradicated (4,5).
Morbilliviruses have six structural proteins (Fig. 8.1). The
hemagglutinin (H) and fusion (F) are transmembrane proteins
present on the surface of the virus and infected cell. These pro-
teins are important for viral attachment and penetration of
the target cell. The matrix (M) protein is found on the inner
surface of the membrane and interacts with the cytoplasmic
tails of H and F and with the nucleocapsid for virion assem-
bly and budding. The nucleocapsid (N) protein surrounds and
encapsidates the viral RNA to form the helical nucleocapsid
structures. The phosphoprotein (P) and large (L) polymerase
protein are also associated with the nucleocapsid and com-
plete the viral elements necessary for RNA transcription. Two
nonstructural proteins, C and V, are encoded within the P gene
and regulate the host innate response to infection (612).
MeV transmission from person to person is by the respi-
ratory route. The virus spreads from the initial site of repli-
cation in the respiratory tract to local draining lymph nodes
(1315). Replication in lymphatic tissue produces virus that
then spreads through the blood to multiple organs including
skin, lung, liver, spleen, and lymph nodes. The viremia is cell
associated with infected B cells, T cells, and monocytes in cir-
culation (1618). MeV-infected leukocytes increase expression
and activation of the integrins lymphocyte function-associated
antigen (LFA)-1 and very late antigen (VLA)-4 that promote
adherence to the surface of endothelial cells and this interaction
is likely to facilitate the spread of infection to many organs
and tissues (19,20). In tissue, endothelial and epithelial cells
are also targets for infection (2123).
Three cellular receptors have been identified: membrane
cofactor protein or CD46 (24,25), signaling lymphocyte acti-
Nucleocapsid protein (N)
Phosphoprotein (P)
Matrix protein (M)
Fusion protein (F)
Attachment protein (H)
FIGURE 8.1 Schematic diagram of
Polymerase (L) measles virus. (Brindley and Plemper,
reproduced from Griffin DE. Measles
virus. In: Knipe DM, Howley PM, Griffin
DE, et al, eds. Fields Virology. 6th ed.
Philadelphia: Lippincott Williams &
Wilkins; 2013, with permission.)
125
2/21/14 5:33 PM
 126 Part II: Viral Infections and Related Disorders
rash
measles ADEM
virus MIBE
infection SSPE
7 14 21 1 3 6 9 1 3 6 9 12
days months years
FIGURE 8.2 Time after infection of the occurrence of the three major
neurologic complications of measles: acute disseminated encephalo-
myelitis (ADEM), measles inclusion body encephalitis (MIBE), and
subacute sclerosing panencephalitis (SSPE). (Reproduced from Griffin
DE. Measles virus. In Knipe DM, Howley PM, Griffin DE, et al, eds.
Fields Virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins;
2013, with permission.)
vation molecule (SLAM) or CD150 (26), and nectin 4 (27,28).
CD46 is a widely distributed human complement regulatory
protein expressed on all nucleated cells including the api-
cal surface of polarized epithelial cells. In the CNS, CD46
is expressed on choroid plexus epithelial cells, on cerebral
endothelium, and ependymal cells (29,30). SLAM/CD150 is a
membrane glycoprotein expressed on cells of the immune sys-
tem including immature thymocytes, activated T and B lym-
phocytes, activated monocytes, and mature dendritic cells
(31,32) but is not expressed by brain parenchymal cells (29).
Nectin 4 is an adherens junction protein expressed by epithe-
lial cells in the lungs, tonsils, and placenta (33,34). Studies of
different strains of MeV have shown that both vaccine and
wild type viruses can use CD150 and nectin 4 as a receptor.
However, although most vaccine strains use CD46 efficiently,
wild type strains do not (3537). The receptors used for neural
cell infection by wild type MeV and chick cell infection by vac-
cine virus (3840) have not been identified.
Through expression of the H and F proteins on the cell
surface, infected cells may fuse with nearby cells to form syn-
cytia or giant cells both in vitro and in the lungs and lymphoid
tissues of infected patients. However, MeV is not detectable
by usual pathologic or immunocytochemical techniques in
the brains of patients dying acutely with measles (21). Studies
using in situ hybridization have identified MeV infecting cere-
bral capillary endothelial cells during acute fatal disease (22).
In addition, electroencephalographic (EEG) abnormalities and
a cerebrospinal fluid (CSF) pleocytosis are common in acute
uncomplicated measles (4143), suggesting the possibility that
MeV infection of the CNS is common during uncomplicated
TA B L E 8 . 1
SUMMARY OF THE NEUROLOGIC COMPLICATIONS OF MEASLES
Age of
Disease Host Measles Onset
Acute disseminated Normal 2 yr
encephalomyelitis (ADEM)
Measles inclusion body Immunocompromised Any
encephalitis (MIBE)
Subacute sclerosing Normal 2 yr
panencephalitis (SSPE)
Scheld_Ch08.indd 126
infection. However, these changes are also observed after mea-
sles immunization, so it is not clear that they indicate virus
infection of the CNS (44).
The characteristic morbilliform rash of measles is due to
immune cell infiltration into sites of MeV infection of skin epi-
thelial cells and marks the onset of the immune response and
the initiation of virus clearance (45). It is a time of intense
immune activation (4648) which is accompanied by suppres-
sion of skin test responses to recall antigens such as tuberculin
(49,50) and decreased in vitro lymphoproliferative responses
to mitogens (51). This immune suppression contributes to an
increased susceptibility to secondary infections, the most com-
mon cause of death due to measles (52). The immune activa-
tion accompanying measles may contribute to the neurologic
complications as well.
Although clearance of infectious MeV is generally complete
after the rash has resolved, clearance of viral RNA requires
many months (53,54). This continued presence of MeV RNA
in lymphoid tissue and circulating mononuclear cells may con-
tribute to immune suppression and to development of acute
and chronic neurologic disease.
OVERVIEW OF THE NEUROLOGIC
COMPLICATIONS OF MEASLES
The neurologic complications of measles are uncommon and
occur at three distinct times in relation to the primary infection
and acute disease (Fig. 8.2). ADEM usually presents within
1 to 2 weeks of the appearance of the rash (55,56), MIBE
within a few months (57,58), and SSPE several years after ini-
tial infection (59). The age and general immune status of the
individuals susceptible to these complications are also distinct
(Table 8.1). ADEM occurs in individuals who have apparently
normal immune systems and are older than 2 years at the time
of primary infection (52). The incidence is 1:1,000 cases of
measles (52,60). MIBE occurs in immunosuppressed patients
of any age (6165). The incidence is approximately 1:10 cases
of measles in immunocompromised children (66,67). SSPE
occurs in immunologically normal individuals who have often
had measles at younger than 2 years (59,68,69). The incidence
is approximately 1:10,000 cases of measles (70).
MeV is easily demonstrable in the brains of patients with
MIBE and SSPE, but not ADEM (21). The current understand-
ing of these three neurologic complications of measles is that
ADEM is an autoimmune demyelinating disease triggered by
measles, MIBE is a progressive MeV infection of the brain in
patients unable to mount an effective immune response, and
SSPE is a slowly progressive MeV infection of the CNS that
is poorly controlled by the immune system and presents clini-
cally many years after infection.
Incidence Pathology Time Course
1:1,000 Inflammation, demyelination Monophasic, weeks
1:10 Inclusion bodies Progressive, months
1:10,000 Inclusion bodies, inflammation Progressive, years
2/21/14 5:33 PM

MEASLES INCLUSION-BODY
ENCEPHALITIS
History
Progressive MeV infection was reported first by Hecht (71)
in 1910 as a case of giant cell pneumonia. Hecht pneu-
monia was suspected to be a complication of measles and
this hypothesis was proven in 1959 when Enders et al. (72)
isolated MeV from the lungs and respiratory tract secretions
of three young children with compromised immune systems
and progressive pulmonary disease. Pathologic examination
of the lungs of these children showed giant cell pneumo-
nia. None had a history of rash or other classic signs or
symptoms of measles, but all had histories of exposure to
measles in the preceding months. Giant cells were found in
other organs (e.g., liver, lymph nodes), but neurologic symp-
toms were not reported and it is not clear that the brain was
examined (72).
Breitfeld and colleagues (73) first reported progressive
nervous system disease in 1973 as cases of SSPE. Two young
children with leukemia developed progressive neurologic dis-
ease and died approximately 6 months after exposure to mea-
sles. At autopsy, giant cells were not present in the CNS, but
there were intranuclear and intracytoplasmic inclusions now
recognized to be frequent pathologic features of persistent
MeV infection of the CNS. One also had Hecht pneumonia.
Subsequently, this neurologic disease, MIBE, was distinguished
from SSPE by its time of onset in relationship to measles, lack
of inflammatory response in the brain (74), and occurrence
in immunocompromised individuals. Recently, this disease has
also been described in adults who are immunocompromised
due to HIV infection (65) and after immunization with the live
attenuated MeV vaccine (75).
Pathogenesis and Pathology
The rash marks the onset of the immune response with the
appearance of MeV-specific antibody and cellular immu-
nity, and this immune response to MeV is normally effective
at clearing infectious virus from blood and tissues (53). In
individuals with severe acquired or genetic defects in cellular
immunity, a rash may not appear (72,73) and MeV infection
may not be controlled. These patients often develop progres-
sive pulmonary or neurologic disease due to unrestrained MeV
replication (66,73,74).
Virus infection of the CNS is presumed to begin with
infection of cerebral capillary endothelial cells or with in-
filtration of infected leukocytes into the brain (20,22,76).
Neurons or glial cells subsequently become infected and
virus spreads slowly within the CNS. Intranuclear and intra-
cytoplasmic eosinophilic inclusion bodies are seen primar-
ily in gray matter areas (73). There is focal necrosis, and
neurons often show signs of degeneration (74). The areas
of brain most frequently involved are the parietooccipital
areas, basal ganglia, and brainstem. Typically, there is little
evidence of an inflammatory response to the infection, al-
though proliferation of astrocytes and microglia is often ap-
parent (61,74).
On electron microscopic examination, inclusion bodies
contain the microtubular structures of MeV nucleocapsids
(58,74). MeV antigens (particularly N) can be identified by
immunocytochemical staining (77). However, the H, F, and
M proteins are undetectable (78) and often MeV cannot be
recovered in culture from brain tissue (61,64). Examination
Scheld_Ch08.indd 127
Chapter 8: Measles and Rubella 127
of viral RNA extracted from the brains of MIBE patients has
shown that messenger RNAs (mRNAs) for the envelope pro-
teins are limited in amount and that the virus has accumulated
many mutations, particularly in the M-protein gene, similar
to those found in SSPE (see later discussion) (79,80). These
mutations often preclude or severely limit productive replica-
tion (8183). These mutations may reflect positive selection
and adaption of the virus to growth in neurons or frequent
transcription errors, including biased hypermutation due to
the action of dsRNAdependent adenosine deaminase (84),
combined with a lack of selection for replication-competent
virus. Production of infectious virus may not be important
for virus replication and spread in the CNS, because neu-
rons can allow transsynaptic spread of viral RNAcontaining
nucleocapsids from cell to cell without production of infec-
tious virions (8588).
Clinical Manifestations
MIBE usually presents 1 to 6 months after exposure to mea-
sles with progressive neurologic deterioration in the absence
of fever. Signs and symptoms include altered mental status,
lethargy, slurred speech, focal motor seizures or epilepsia
partialis continua, weakness, and occasionally blindness or
hearing loss (57,62,65,77). Typically, the seizures are resis-
tant to control by anticonvulsant medications (62). Disease
progresses over days to weeks to coma and death and may
be accompanied by inappropriate secretion of antidiuretic
hormone (58,66,73).
Diagnosis
The diagnosis is often difficult because there may be no history
of a rash. History of exposure to measles or immunization in
the preceding months should be sought in immunosuppressed
individuals with progressive neurologic deterioration. Brain
biopsy with pathologic examination and reverse transcrip-
tase-polymerase chain reaction (RT-PCR) to detect MeV
RNA is often necessary for definitive diagnosis (62,65,89).
At the time of presentation, there is often no detectable
antibody to MeV, consistent with the poor immune response
to infection, although at later times antibody may be pres-
ent in serum or CSF (62,66,74). CSF examination is usually
within normal limits, but occasionally there is a moderate
elevation in the protein concentration (62). EEG findings are
usually abnormal, but nonspecific and nondiagnostic, with
diffuse slowing or periodic lateralized spike and wave activ-
ity (62,65,66,90). Computed tomographic (CT) scan and
magnetic resonance imaging (MRI) scans are often normal
at the time of presentation with later development of T2 sig-
nal abnormalities, edema, cortical atrophy, and ventricular
dilation (62,65,66).
Treatment and Prevention
Adequate measles immunization prior to the onset of leuke-
mia or other immunosuppressive illness undoubtedly pre-
vents many cases of MIBE (57). It is difficult to discern the
usefulness of postexposure immunoglobulin prophylaxis for
immunocompromised individuals. Several cases of MIBE
have occurred despite administration of immunoglobulin, but
many more may have been prevented. There is no established
antiviral treatment for MIBE and essentially all cases are fatal.
However, there are case reports of neurologic improvement
2/21/14 5:33 PM
 128 Part II: Viral Infections and Related Disorders
with prolonged intravenous ribavirin treatment (62) and
slowed disease progression with initiation of antiretroviral
therapy in patients with AIDS (65).
SUBACUTE SCLEROSING
PANENCEPHALITIS
History
SSPE was first described in 1933 by Dawson (91) in a 16-year-
old boy with progressive neurologic deterioration character-
ized by failing memory, slow and deliberate movements, and
myoclonus. The following year, he reported an additional case
of this subacute inclusion body encephalitis in a 5-year-old girl
(92). Histologic examination of the brains of these patients
showed inflammation with eosinophilic intranuclear and
intracytoplasmic inclusions in neurons. The disease became
known as Dawson encephalitis, and Dawson postulated that
the disease was of viral etiology, but he could not transmit the
disease to experimental animals. In 1945, van Bogaert (93)
described a similar condition, subacute sclerosing leukoen-
cephalitis with prominent white matter involvement. It was
appreciated subsequently that the same disease could involve
both gray and white matter (94). In 1966, paramyxovirus-like
particles suggestive of MeV were seen on electron microscopic
examination of the inclusions (95). Reports of these virus
particles were followed rapidly by observations of elevated
MeV antibody in serum and CSF, staining of the inclusions
with antibody to MeV antigens and culture of MeV from
brains (96100).
Epidemiology
SSPE is a rare (approximately 1 in 10,000) late complication
of measles (68,70,101). The mean time to onset of SSPE after
measles is 6 to 10 years (59,102,103) (Fig. 8.2). Children
with SSPE often have a history of acquiring measles at an
early age (59,6870,104107) when the immune system is
immature and maternal antibody may still be present. In most
parts of the world, the disease occurs preferentially in boys
(68,104,108,109). Exposure to birds has been identified as a
risk factor (69,105,108). How these factors increase the risk
of developing SSPE is unknown. There is no clustering of cases
to suggest that the virus causing the initial infection leading to
SSPE is different from the virus causing uncomplicated disease.
Pathogenesis and Pathology
SSPE is the most extensively studied of the neurologic com-
plications of measles. Nevertheless, the pathogenesis of this
rare complication remains obscure. It is not known whether
infection of the nervous system occurs at the time of primary
infection and progresses slowly with clinical evidence of dis-
ease apparent only after years or whether the infection is latent
at a site outside the CNS and then spreads to the brain. The
route of virus entry into the CNS is unknown, but infection of
cerebral capillary endothelial cells is a likely possibility (76,11).
Extensive sequence analysis of viral RNA from various parts
of the brain in SSPE suggests that the virus in the nervous sys-
tem is clonal (111), implying that virus entered the brain at
one time and then gradually spread throughout the nervous
system. This gradual spread has also been suggested by serial
MRI studies (112,113). Therefore, it is most likely that MeV
Scheld_Ch08.indd 128
enters the brain at the time of the original acute infection or
during the prolonged phase of circulating viral RNA and sub-
sequently spreads slowly through the CNS eventually infecting
a sufficient number of cells to produce dysfunction and clinical
evidence of infection.
At the time that neurologic symptoms are recognized, the
infection is extensive. Neurons and oligodendrocytes contain
nuclear and cytoplasmic viral inclusion bodies (114), antibody
responses are vigorous and evident both in serum and CSF
(115,116), and there is an extensive mononuclear inflamma-
tory reaction in the brain (92,93,117). Gray matter is most
prominently affected, but pathologic changes are present in
white matter as well (92,93). Retinitis is frequently present
with MeV antigen demonstrable in the retinal neuroepithe-
lium. At autopsy, MeV RNA or antigen can be detected in a
wide variety of tissues (118).
Pathologic examination of the brain shows intranuclear
and intracytoplasmic inclusions, in situ hybridization shows
MeV RNA, and immunocytochemical staining shows MeV
antigens (110). However, no virus is seen budding from the
surface of infected cells (119). Nuclear inclusions are filled
with smooth nucleocapsids (114,119) consistent with the
absence of the associated L and P proteins necessary for tran-
scription and replication of viral RNA. The cytoplasm con-
tains replication-competent fuzzy nucleocapsids that extend
into neuronal processes further suggesting that virus can
spread within the CNS by cell-to-cell synaptic transmission
of the ribonucleoprotein complex (85,87,88,113,120). The
observation that strains of MeV isolated from SSPE patients
are more likely than standard strains of MeV to cause neuro-
logic disease after intracerebral inoculation into small animals
and primates suggests that the virus has adapted to growth in
neural tissue.
Like MIBE, the virus present in the brain of SSPE patients
is replication defective and cannot usually be recovered
from SSPE brain in a cell-free form (99,100,121). Extensive
sequence analysis of viral RNAs has shown that SSPE viruses
are of the same lineage as viruses that cause acute measles but
distinguishable in the genes encoding the M, F, and H proteins
(112,122129). Studies of brain-associated viral proteins and
RNA in SSPE have revealed differences in the relative amounts
of the various viral mRNAs and proteins (127130), in the
antigenicity of viral proteins (131), and in RNA sequences cod-
ing for viral proteins (125127) between SSPE viruses and wild
type or vaccine strains of MeV. Because the disease cannot be
studied prospectively, it is not known for certain whether these
differences represent unique features of the original infecting
virus, selection for growth in the CNS, or selection for growth
in the presence of a vigorous antibody response.
In general, expression of M protein is low (130,132,133)
and the mRNA encoding M extracted from SSPE brain is
mutated throughout the gene. Construction of recombinant
viruses has shown that functional M is dispensable for virus
growth and spread in the CNS and may foster the formation
of nuclear and cytoplasmic inclusion bodies (83). Mutations in
the H and F envelope proteins that interfere with assembly and
budding of infectious virus are also associated with persistent
infection and SSPE (123,126,127,134).
The possibility that the development of SSPE represents
a defect in the immune response has led to investigations of
cellular and humoral immune responses to MeV and other
antigens. In contrast to patients with MIBE, there is often an
intense perivascular mononuclear inflammatory response in
brain and high levels of antibody to MeV in serum. There is
also significant production of MeV-specific antibody by plasma
cells residing in the CNS. This locally synthesized antibody
appears in the CSF leading to characteristic elevations in the
2/21/14 5:33 PM

level of CSF immunoglobulin much of which is MeV specific
(96,135137). Antibody produced in the CNS derives from
clones of resident antibody-secreting B cells and is therefore of
restricted heterogeneity leading to the appearance of oligoclo-
nal immunoglobulin bands on electrophoretic analysis of the
CSF from SSPE patients (138142). Antibodies against the N
and P proteins are particularly abundant and antibody against
the M protein is particularly deficient (132,143). Antibody to
CD9, a tetraspanin protein widely expressed in the CNS, is
also elevated, raising the possibility of an autoimmune com-
ponent to this progressive disease (144).
Experiments in small mammals have shown that treat-
ment with antibody after intracerebral infection with neuro-
adapted strains of MeV attenuates acute disease but increases
the incidence of persistent virus infection and subacute or
chronic encephalitis (81,145). Cases of SSPE have been associ-
ated with passive transfer of immunoglobulin and persistent
infection has been induced experimentally by passive transfer
of antibody (146). Therefore, antibody may contribute to the
establishment and maintenance of persistent nervous system
infection.
The mononuclear inflammatory response in the brain
includes CD4 and CD8 T cells as well as monocytes and
immunoglobulin-secreting B cells (103,136,147,148). Expression
of class I and class II major histocompatibility antigens is
increased in brain, and 2-microglobulin, interleukin (IL)-1, sol-
uble intercellular adhesion molecule (ICAM), soluble IL-2 recep-
tor, and soluble CD8 are increased in CSF (149,150). Thus, there
is no evidence for a global defect in immune responses, although
MeV induction of interferon- (IFN-) is reduced in some
individuals (151). It is likely that SSPE and MIBE are similar in
their pathogenesis, but that MeV replication and the appearance
of neurologic symptoms is slowed in SSPE by the presence of a
vigorous immune response (64). However, this immune response
is not able to clear the virus once parenchymal CNS infection has
been established and infection is progressive.
Clinical Manifestations
The age of initial MeV infection in individuals subsequently
developing SSPE is often younger than 2 years. The age of
onset of neurologic disease is typically between 2 and 20 years
of age but has been reported up to the age of 35 years
(59,68,102,109). The onset is insidious and the diagnosis is
often not suspected early in disease (152,153). The first symp-
toms are likely to be deterioration in school or work perfor-
mance and changes in personality (stage I). In adults, visual
impairment is often an early sign (112,154). Alteration in men-
tal status is followed by the onset of myoclonus, convulsions,
abnormal postures and movements, and autonomic dysfunc-
tion (stage II). Progressive neurologic deterioration is marked
by rigidity (stage III), optic atrophy, and akinetic mutism, end-
ing in coma (stage IV) and death months to years after onset
(155157). The course of SSPE is usually 1 to 3 years. More
rapid progression has been reported with perinatally acquired
infection (102,158,159). Occasionally, with good supportive
care, patients survive for longer periods of time and remis-
sions lasting weeks to years with total clinical courses of 10 to
16 years have been reported (119).
Diagnosis
The diagnosis of SSPE can be made by demonstration of
high levels of antibody to MeV in CSF in the setting of a
characteristic clinical picture. Typical EEG changes include
Scheld_Ch08.indd 129
Chapter 8: Measles and Rubella 129
a burst-suppression pattern often most easily demonstrable
during sleep (94,156,160), but this may not be present in
adult-onset disease (112). The CSF is often normal on routine
analysis of pressure, protein, glucose, and cells. However, the
immunoglobulin concentration is usually elevated, oligoclo-
nal bands are present on electrophoretic analysis, and MeV-
specific antibody is elevated (155). MeV RNA can be detected
in the brain and CSF by RT-PCR (112,161,162). CT and MRI
scans are generally unhelpful. CT scans often show evidence
of loss of parenchyma with ventricular dilation and cortical,
brainstem, and cerebellar atrophy accompanied by low paren-
chymal attenuation (163). MRI scans tend to show hyperin-
tense T2-weighted lesions in gray and white matter, with white
matter lesions becoming more prominent as disease progresses
(112,164166).
Treatment and Prevention
Numerous therapeutic agents including bromodeoxyuridine,
azaguanine, amantadine, interferon, isoprinosine, ribavirin,
and cimetidine have been used for the treatment of SSPE
(162,167170). Evaluation of the efficacy of any of these
regimens is difficult because the disease is rare, most reports
are anecdotal or uncontrolled, and the benefits at best are
short term. Therefore, there is no established treatment for
this disease.
Timely measles immunization is the most effective means
of prevention. The incidence of SSPE has decreased dramati-
cally since introduction of the live attenuated measles vaccine
and there is no evidence that the vaccine virus can cause SSPE
(70,101,102,104,160,171173).
ACUTE DISSEMINATED
ENCEPHALOMYELITIS
History
In 1790, James Lucas (174), an English surgeon, described the
first case of postmeasles encephalomyelitis in a 23-year-old
woman who developed paraparesis and urinary retention as
the measles rash was fading. ADEM can develop after a num-
ber of infections and is known under many names including
postinfectious and parainfectious encephalomyelitis (175).
Acute hemorrhagic leukoencephalitis or acute hemorrhagic
necrotizing encephalopathy probably represents a more severe
form of the disease. In 1960, Koprowski (176) hypothesized
that ADEM was an autoimmune (hyperergic) disease based
on the similarity of the pathology and clinical picture to
experimental autoimmune encephalomyelitis (EAE) and the
demyelinating disease that complicates immunization with the
brain-derived Semple rabies vaccine. This remains the lead-
ing hypothesis (55), but understanding of the pathogenesis of
ADEM is incomplete.
Epidemiology
ADEM occurs worldwide and complicates many infections
but is most frequent after measles (105,177). The overall
incidence of ADEM associated with measles is approximately
1 per 1,000 infections (52) but varies with age. ADEM is more
frequent in children older than 5 years of age and rare in those
younger than 2 years of age (52). It occurs equally in males
and females.
2/21/14 5:33 PM
 130 Part II: Viral Infections and Related Disorders
Pathogenesis and Pathology
ADEM occurs in close temporal association with acute measles
(Fig. 8.2) at a time of an active immune response to the infec-
tion (178). Brain pathology shows perivascular inflammation
and perivenular demyelination. During the acute phase, there
is patchy swelling in the walls of small cerebral vessels and
mononuclear cell infiltration. Later, perivenous inflammation
is more marked and demyelination is evident (60,179,180).
There is little evidence for direct infection of the brain by
MeV. Virus has rarely been recovered from the brain (56,181),
viral antigen is not detectable by immunocytochemical
staining (21,182), and viral RNA has not been detected by
in situ hybridization (21). Furthermore, there is no evidence
for a local virus-specific intrathecal antibody response as is
expected in diseases caused by direct virus infection of the
CNS (55). Therefore, there is no evidence that virus is pres-
ent in the CNS at the time of neurologic disease, but more
sensitive techniques such as RT-PCR have not been applied
and specimens from early in disease have not generally been
available for study. It is possible that virus in cerebral endothe-
lial cells plays a role in triggering the autoimmune disease or
allowing access of autoreactive cells (22). Thus, virus may no
longer be detectable by the methods used at the time that tissue
has been examined.
The pattern of loss of the myelin proteins, myelin-associated
glycoprotein, and myelin basic protein resembles that seen in
EAE, a disease induced in animals by inoculation of myelin
or myelin proteins (182). Furthermore, immunologic studies
of patients with ADEM have shown the presence of cellular
immune responses to myelin basic protein (55,181,183) and
antibody to myelin proteins similar to that seen in animals
with EAE and in humans with Semple rabies vaccine-induced
encephalomyelitis (55,184187). It is postulated that ADEM
is analogous to these autoimmune diseases, but the mecha-
nism by which an autoimmune response to myelin proteins
is induced during a systemic infection is not clear. The tim-
ing of this complication suggests that immune activation
associated with MeV infection may play a role in induction of
ADEM. Immune activation may increase presentation of self-
peptides and allow the proliferation of autoreactive clones of
cells (178,188). Patients with ADEM differ from patients with
uncomplicated measles by having more marked and prolonged
immunologic abnormalities. In particular, IgE is more persis-
tently elevated and soluble IL-2 receptor is lower in patients
with ADEM (47,189). IL-2 is one of the cytokines elevated
in plasma (190), and a similar disease has been reported as a
complication of IL-2 infusion (191).
The possibility of immunologic cross reactivity between
some component of myelin and a component of MeV has been
explored. Limited sequence homologies have been identified
but none for which biologic relevance has been shown (192).
Studies of MeV-specific antibodies and T cells have shown no
cross reactivity with myelin basic protein or galactocerebro-
side (193,194).
Clinical Manifestations
Typically, patients recovering from measles present with an
abrupt onset of renewed fever and obtundation accompanied
by neurologic signs and symptoms that can include menin-
gismus, seizures, altered mental status, multifocal neurologic
deficits, and coma (177,180). The onset is most often between
2 and 7 days after the appearance of the rash but occasion-
ally predates or appears up to 3 weeks after the rash (55).
Scheld_Ch08.indd 130
The disease has a monophasic course over 10 to 20 days.
Improvement is usually evident within a few days after onset.
Mortality ranges from 10% to 40% with substantial neuro-
logic residua in the majority of survivors (55,60,179). Prior
to widespread measles immunization, ADEM was a common
cause of chronic neurologic disability.
Diagnosis
The diagnosis is apparent on clinical grounds when neurologic
disease follows shortly after the rash. Routine laboratory tests
are not particularly helpful. There are no consistent abnor-
malities in blood or urine. CSF may be normal or contain a
modest elevation in protein and a mononuclear pleocytosis.
The EEG shows a nonspecific diffuse slowing. The CT scan
may be normal, but the MRI scan usually shows multiple foci
of demyelination most likely to be seen on T2-weighted and
fluid-attenuated inversion recovery (FLAIR) images in subcor-
tical and central white matter of the cerebral hemispheres, cer-
ebellum, brainstem, and spinal cord (166,177,195).
Treatment and Prevention
Measles vaccine is highly effective in prevention of ADEM and
neurologic complications after immunization are rare (196).
Treatment is not well established. Corticosteroids are widely
used, but the benefit is not clear (177,197199). One random-
ized study showed no benefit (200) and a retrospective study
found higher mortality and rates of sequelae in steroid-treated
patients (201). Intravenous immunoglobulin and plasma
exchange have also been used with some reported success
(177,202).
BACKGROUND ON RUBELLA
RV, the etiologic agent of the mild rash disease rubella or
German measles, is the only member of the Rubivirus genus
of the Togaviridae family. Togaviruses are single-stranded,
positive-sense, enveloped RNA viruses and all, except RV,
are in the Alphavirus genus and are transmitted by mosqui-
toes. No related animal viruses have been recognized. RV
has three structural proteins. The capsid protein surrounds
the RNA and the two envelope surface glycoproteins E1
and E2 are important for attachment and entry. E1 induces
neutralizing antibodies. Two clades and 10 genotypes are
recognized (203).
Like MeV, RV is a human virus that is transmitted between
individuals by respiratory droplets or aerosol and spreads
through the blood via a cell-associated viremia to skin and
other organs (204). RV can infect many types of cells, and
myelin oligodendrocyte glycoprotein has recently been iden-
tified as a cellular receptor (205). The immune response is
associated with the appearance of the rash. There is substan-
tial evidence of immune activation, leukopenia, and immune
suppression, as indicated by loss of skin test responses to recall
antigens (206,207).
The neurologic complications of postnatally acquired
rubella include ADEM, which is in every way similar to
ADEM complicating measles but occurs less frequently
(approximately 1:5,000 to 8,000 cases) (208), and PRP, a
disease similar to SSPE. However, the most important neu-
rologic complications occur when RV infection is acquired
prenatally (Table 8.2).
2/21/14 5:33 PM
 Chapter 8: Measles and Rubella 131

TA B L E 8 . 2
SUMMARY OF THE NEUROLOGIC COMPLICATIONS OF RUBELLA

Disease Host Incidence Time of Presentation

Congenital rubella syndrome First trimester fetus 1:2 Birth

(CRS)
Acute disseminated Normal child or adult 1:7,000 12 weeks after rubella
encephalomyelitis (ADEM)
Progressive rubella Prior CRS or rubella Very rare Years after CRS or rubella
panencephalitis (PRP)

CONGENITAL RUBELLA Pathogenesis and Pathology

SYNDROME
History
The first recognition of the connection between rubella and
birth defects was in 1941 when Norman Gregg (209), an
Australian ophthalmologist, noted an increase in cases of
congenital cataracts, frequently accompanied by cardiac
abnormalities, in babies born after an epidemic of rubella.
Subsequent studies documented the relationship between
maternal rubella early in pregnancy and multiple congenital
defects in the infants born to these mothers. The virus was iso-
lated in 1962 and an attenuated live virus vaccine was licensed
in 1969 (210,211).
Rubella Outcome
100
% infected
80
Percent of Fetuses
During the viremia in pregnant women, RV can infect the pla-
centa and spread to the fetus. Fetal infection is systemic, per-
sistent, and teratogenic. The most significant damage occurs
when infection occurs in the first trimester of pregnancy (212)
(Fig. 8.3). Spontaneous abortion is common during this period
(212). In infants who survive to term, common congenital
defects include cardiac abnormalities, hearing loss, low birth
weight, and cataracts. Neurologic complications that include
microcephaly, mental retardation, retinopathy, and meningo-
encephalitis are common (213215).
RV infects vessels and causes obstructive vasculopathy and
CNS lesions due to ischemia (216). Vascular lesions include
focal areas of destruction of the walls of arteries and veins,
pericapillary debris, thickening and proliferation of vessel
walls, and vascular constriction. Foci of parenchymal necrosis
follow the paths of damaged brain vessels and involve both
white and gray matter. In addition, RV infection of CNS cells
inhibits cell division leading to microcephaly (217).
Infection is persistent and RV can be isolated from tissues,
blood, CSF, and secretions for 6 to 30 months after birth, with
boys clearing virus more slowly than girls (218). Failure to clear
infection may be due to the immaturity of the immune system
at the time of infection (219) and is associated with a num-
ber of RV-specific and nonspecific immune deficits. RV-specific
IgM with neutralizing activity is present, but levels of IgG are
low and cellular immune responses are impaired (219221).

Peripheral blood mononuclear cells (PBMCs) do not proliferate

60
in response to mitogens (222) and responses to routine immuni-
zations are decreased compared to infants without CRS (218).

40
% with CRS
20
0 disease, typically patent ductus arteriosus, valvular stenosis
11 1112 1314 1516 1718 1922 2336 36
Weeks Gestation at Time of Maternal Rubella
FIGURE 8.3 Diagram showing the likelihood of fetal infection and
of congenital rubella syndrome (CRS) when rubella occurs in the
mother at various stages of gestation. (Graphed from data in Miller E,
Cradock-Watson JE, Pollock TM. Consequences of confirmed mater-
nal rubella at successive stages of pregnancy. Lancet. 1982;2:781784,
with permission.)
Clinical Manifestations
Infants at the time of birth typically show intrauterine growth
retardation and frequently have thrombocytopenia purpura,
hepatomegaly, and splenomegaly. Signs of neural involve-
ment include a bulging anterior fontanel, lethargy, irritabil-
ity, psychomotor retardation, and abnormal motor tone.
Other common manifestations of CRS are congenital heart
or pulmonary artery stenosis; eye disease, most often cata-
racts, glaucoma, or retinopathy; and sensorineural hearing
loss (213,214). As infants with CRS mature, psychomotor
retardation, behavioral disorders, psychiatric disturbances,
and autism, as well as endocrinopathies, ocular damage,
and hypertension may become apparent (223225). Prenatal
exposure to RV is also associated with subsequent diagnosis
of schizophrenia spectrum disorders, often accompanied by a
progressive cognitive decline (226,227).

Scheld_Ch08.indd 131 2/21/14 5:33 PM

 132 Part II: Viral Infections and Related Disorders
Diagnosis
Subependymal cysts and hypoechogenicity indicative of calci-
fication can be detected by cranial ultrasonography (228,229),
intraventricular and periventricular calcification is often evident
on CT scans, and parenchymal lesions are seen on MRI scans
(230,231). CSF protein is typically elevated and RV can often be
isolated from CSF as well as many other tissues, nasopharyngeal
secretions, and urine. RV RNA can also be detected by RT-PCR.
RV-specific IgM is usually present in serum.
Prevention and Treatment
Routine childhood, premarital, and postnatal RV immunization
programs prevent maternal infection and thus CRS (232,233).
Widespread vaccination has been successful in eliminating
rubella and CRS from the Americas (234,235). However,
introduction of rubella vaccine must be carefully planned to
avoid increasing the age of infection and thus the risk of CRS
(236238). When rubella is diagnosed in early pregnancy, ther-
apeutic abortion can be performed. Inadvertent immunization
of pregnant women can result in placental or fetal infection but
rarely results in congenital abnormalities (239,240) and is not
considered an indication for therapeutic abortion.
PROGRESSIVE RUBELLA
PANENCEPHALITIS
CRS is not usually progressive and virus is gradually cleared.
However, in a few individuals, progressive neurologic dete-
rioration begins many years later. This disease, PRP, was first
recognized in 1975 and is characterized by motor and mental
deterioration accompanied by high levels of RV-specific anti-
body in serum and CSF (241,242). The disease has also been
recognized as an occasional late complication of postnatally
acquired rubella (243).
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Scheld_Ch08.indd 132
On pathologic examination, white matter is preferentially
affected with mononuclear cell infiltration, microglial nodules,
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Rubella is one of the rash diseases associated with ADEM
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week after the onset of the rash and often include headache,
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Studies from the authors laboratory were supported by
research grants from the National Multiple Sclerosis Society,
the National Institutes of Health (AI23047), and the Bill &
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 CHAPTER 9 HERPES SIMPLEX VIRUS
RICHARD J. WHITLEY
Eight herpesviruses routinely cause human disease. The cur-
rent classification of herpesviruses into subfamilies serves the
purposes of identifying evolutionary relatedness and summa-
rizing unique properties of each member. The three subfam-
ilies are alpha that include herpes simplex virus 1 (HSV-1),
HSV-2, and varicella-zoster virus (VZV); beta consisting of
cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and
HHV-7; and the gamma herpesviruses, Epstein-Barr virus
(EBV), and Kaposi sarcoma herpesvirus (i.e., HHV-8). One
simian herpesvirus, B virus (Cryptotetia crypta), also an alpha
herpesvirus, can inadvertently infect humans, resulting in dev-
astating central nervous system (CNS) disease. These viruses
share similar molecular and biologic characteristics, including
the unique ability to establish latency and reactivate. These
agents, among the most common encountered by humans, are
common causes of CNS infections (1). Members of the alpha
herpesvirus subfamily are characterized by a very short repro-
ductive cycle, prompt destruction of the host cell, and ability
to establish latency, usually in sensory ganglia. Both HSV-1
and HSV-2 are routine causes of CNS disease and the subject
of this chapter.
GENERAL CHARACTERISTICS OF
HERPESVIRUSES
All members of the family Herpesviridae have a similar mo-
lecular structure. These viruses contain double-stranded DNA,
which is located at the central core. The DNA is surrounded
by a capsid, consisting of 262 capsomers and providing icos-
apentahedral symmetry to the virus. Tightly adherent to the
capsid is an amorphous tegument. Loosely surrounding the
capsid is a bilayered lipid envelope. The overall size of herpes
virions varies from 120 to approximately 300 nm, depending
on the virus. The envelope consists of polyamines, lipids, and
glycoproteins. The glycoproteins confer distinctive properties
to each virus, providing unique antigens to which the host is
capable of responding.
Herpesvirus DNA varies in molecular weight from approx-
imately 80 to 150 million and consists of 120,000 to 230,000
base pairs. Base composition of herpesvirus DNA varies be-
tween 31% and 75% of guanine plus cytosine. Of all the
herpesviruses, HSV-1 and HSV-2 are the most closely related,
with approximately 50% genomic homology. With the excep-
tion of HSV-1 and HSV-2, the structural and nonstructural
proteins coded by the DNA of the HHVs are not immuno-
logically related. However, HSV-1 and HSV-2 share common
types of proteins; therefore, cross-antigenic reactions do occur.
HISTORY
Infections caused by HSV have been recognized since the time
of ancient Greece. Greek physicians used the word herpes to
mean creeping or crawling in reference to observable skin
lesions. Likely, this word was used to describe various skin
conditions ranging from cancer to shingles and probably
Scheld_Ch09.indd 137
even fever blisters. The Roman scholar Herodotus associated
mouth ulcers and lip vesicles with fever (2). He called this event
herpes febrilis. Genital herpetic infections were described first
by a physician to the French royalty, Astruc (3).
The transmissibility of these viruses was established un-
equivocally by passage of virus from human lip and genital le-
sions to either the cornea or the scarified skin of the rabbit (4).
Goodpasture (5) further demonstrated that material derived
from the lesions of herpes labialis consistently produced en-
cephalitis when inoculated onto the scarified cornea of rabbits.
Since the first suggestions of herpes simplex encephalitis
(HSE) by the Mathewson Commission in 1926 (6) and subse-
quent description of the histopathologic changes (7), HSV is
reported as the most common cause of sporadic fatal encepha-
litis in the United States. Intranuclear inclusion bodies consis-
tent with HSV infection were first demonstrated in the brain
of a neonate with encephalitis (7) in 1941, as is described later
in this chapter. Virus was subsequently isolated from this brain
tissue (7). The first adult case of HSE providing similar proof
of viral disease (i.e., intranuclear inclusions in brain tissue and
virus isolation) was described in 1944 (8). The most striking
pathologic findings in this patients brain were apparent in the
left temporal lobe where perivascular cuffs of lymphocytes
and numerous small hemorrhages were found. This temporal
lobe localization subsequently has been determined to be char-
acteristic of adult HSE, and it differs from the patchy diffuse
encephalitis of neonates with HSV brain infection.
In the mid-1960s, Nahmias and Dowdle (9) demonstrated
two antigenic types of HSV. Viral typing allowed the demon-
stration that HSV-1 was historically primarily responsible for
infections above the belt (including brain disease in adults),
whereas HSV-2 was primarily responsible for infections
below the belt (brain disease in neonates). However, more
recent studies (10,11) indicate that either virus can infect the
mouth, genital tract, or brain.
INFECTIOUS AGENT
Recent detailed reviews highlight the importance of these or-
ganisms as models of viral replication and as pathogens for
human infection (11). Our current understanding of the struc-
ture of HSV indicates that the genome has a molecular weight
of approximately 100 million. The DNA encodes about 80
polypeptides. The DNA strands of HSV-1 and HSV-2 are co-
linear with reasonable but not identical matching of base pairs.
Of note, there is considerable overlap in the cross reactivity be-
tween the HSV-1 and HSV-2 glycoproteins, although unique-
ness can be demonstrated, as discussed later in this chapter.
Distinction between the two viral types can be demonstrated
by restriction enzyme analysis of viral DNA patterns. This
technique has been applied to epidemiologic investigations of
human HSV infections, as well.
Replication of HSV is characterized by the expression
of three gene classes: immediate early (alpha), early (beta),
and late (gamma), which are expressed temporally and in
a rolling-circle sequence (11). A few relevant events will be
137
2/21/14 5:33 PM
 138 Part II: Viral Infections and Related Disorders
noted. There are five immediate early genes, one of which
is necessary for initiating viral replication. The early gene
products include those enzymes necessary for viral replica-
tion (such as HSV thymidine kinase), as well as the regulatory
proteins. Current antiviral drugs with selective mechanisms
of action are activated at the level of early gene expression.
Acyclovir is an example of such a drug, being converted to its
active monophosphate derivative by HSV thymidine kinase.
Early gene expression coincides with an irreversible shutoff of
host cellular macromolecular protein synthesis, which results
in cell death. Structural proteins are usually of the late gene
class. Assembly of the virus begins in the nucleus, and the
envelope is acquired as the capsid buds through the inner la-
mella of the nuclear membrane, as shown in Figure 9.1. Virus
is transported through the cytoskeleton to the plasma mem-
brane, where lysis of the cell and release of progeny virions
occur. The replicative efficiency of HSV is poor, as indicated
by the ratio of infectious to noninfectious virions. With the
completion of replication, 11 glycoproteins are expressed on
the plasma membrane (12).
FIGURE 9.1 Maturation of herpes simplex virus (HSV). A: Electron
micrograph showing early vesiculation at the inner nuclear membrane
(INM). B: Electron micrograph showing development of an encapsi-
dated HSV at the INM. (Courtesy S. Chatterjee, PhD, Departments
of Pediatrics and Clinical Virology, University of Alabama at
Birmingham.)
Scheld_Ch09.indd 138
PATHOLOGY AND PATHOGENESIS
General Observations of Pathology
The pathologic changes induced by replicating HSV are similar
for both primary and recurrent infection and for both adults
and newborns but vary in the quantitative extent of cytopa-
thology. The histopathologic characteristics of a skin lesion
induced by HSV represent a combination of virus-mediated
cellular death and associated inflammatory responses. Changes
induced by viral infection include ballooning of infected cells
and the appearance of chromatin within the nuclei of cells;
this is followed by degeneration of the cellular nuclei, gener-
ally within parabasal and intermediate cells of the epithelium.
Cells lose intact plasma membranes and form multinucleated
giant cells. As host defenses are mounted, an influx of mono-
nuclear cells can be detected in infected tissue.
Pathology of Central Nervous System Disease
HSE results in acute inflammation, congestion, and/or hem-
orrhage, most prominently in the temporal lobes and usually
asymmetrically in adults (13) and more diffusely in the new-
born. Adjacent limbic areas show involvement as well. The
meninges overlying the temporal lobes may appear clouded or
congested. After approximately 2 weeks, these changes pro-
ceed to frank necrosis and liquefaction, as shown in Figure 9.2.
Microscopically, involvement extends beyond areas that
appear grossly abnormal. At the earliest stage, the histologic
changes are not dramatic and may be nonspecific. Congestion
of capillaries and other small vessels in the cortex and sub-
cortical white matter is evident; other changes are also evi-
dent, including petechiae. Vascular changes that have been
reported in the area of infection include areas of hemorrhagic
necrosis and perivascular cuffing (Fig. 9.3). The perivascular
cuffing becomes prominent in the second and third weeks of
infection. Glial nodules are common after the second week
(14,15). The microscopic appearance becomes dominated by
evidence of necrosis and eventually inflammation; the latter is
characterized by a diffuse perivascular subarachnoid mono-
nuclear cell infiltrate, gliosis, and satellitosis neuronophagia
(13,16). In such cases, widespread areas of hemorrhagic ne-
crosis, mirroring the area of infection, become most promi-
nent. Oligodendrocytic involvement and gliosis (as well as
astrocytosis) are common, but these changes develop very late
in the disease. Although found in only approximately 50% of
patients, the presence of intranuclear inclusions supports the
diagnosis of viral infection, and these inclusions are most often
visible in the first week of infection. Intranuclear inclusions
(Cowdry type A inclusions) are characterized by an eosino-
philic homogeneous appearance and are often surrounded by
a clear, unstained zone beyond which lies a rim of marginated
chromatin, as shown in Figure 9.4.
General Observations on the
Pathogenesis of Human Disease
The pathogenesis of human disease depends on intimate, per-
sonal contact of a susceptible individual (namely, one who is
seronegative) with someone excreting HSV. Virus must come
in contact with mucosal surfaces or abraded skin for infection
to occur. With viral replication at the site of infection, the cap-
sid is transported by neurons to the dorsal root ganglia, where
after another round of viral replication, latency is established.
2/21/14 5:33 PM
 Chapter 9: Herpes Simplex Virus 139

FIGURE 9.2 Gross pathologic

findings in herpes simplex encepha-
litis, illustrating hemorrhagic ne-
crosis of the inferior medial portion
of the temporal lobe.

FIGURE 9.3 A: Hemorrhagic necrosis on microscopic

examination. B: Perivascular cuffing on histopatho-
logic examination of a patient with herpes simplex
encephalitis.
A B

FIGURE 9.4 Intranuclear inclusions.

Scheld_Ch09.indd 139 2/21/14 5:33 PM

 140 Part II: Viral Infections and Related Disorders
These events have been demonstrated in a variety of animal
models (17). Transport of the virion is by retrograde axonal
flow (18). In some instances, replication can lead to severe
CNS infection; however, more often, the hostvirus interac-
tion results in latency. After latency is established, reactivation
can occur, with virus shedding at mucocutaneous sites appear-
ing as skin vesicles or mucosal ulcers or being totally asymp-
tomatic. Occasionally, primary infection can become systemic,
affecting other organ systems besides the CNS and the periph-
eral nervous system. Such circumstances include disseminated
neonatal HSV infection with multiorgan involvement, multi-
organ disease of pregnancy, and infrequently dissemination in
patients undergoing immunosuppressive therapy. Multiorgan
disease is likely the consequence of viremia in a host not
capable of limiting replication to mucosal surfaces.
Infection with HSV-1 is transmitted either by respiratory
droplets or through direct contact (to a susceptible individual)
with infectious secretions (such as virus contained in orolabial
vesicular fluid). Acquisition of HSV-2 infection is usually the
consequence of transmission via genital routes. Under these
circumstances, virus replicates in the vaginal tract or on penile
skin sites, with seeding of the sacral ganglia.
Pathogenesis of Latency
All of the herpesviruses have the ability to become latent, persist
in an apparent inactive state for varying durations, and be reac-
tivated by a provocative stimulus, as yet unidentified (11,19),
as recently reviewed. As a biologic phenomenon, latency has
been recognized since the beginning of the twentieth century
(2026). In 1905, Cushing (27) noted that patients treated for
trigeminal neuralgia (by sectioning a branch of the trigeminal
nerve) developed HSV lesions along the innervated areas of
the sectioned branch, as suggested previously by Goodpasture
(28,48). Several investigators have demonstrated that micro-
vascular surgery of the trigeminal nerve tract for tic doulou-
reux resulted in recurrent herpetic lesions in more than 90% of
seropositive individuals (2932). Axonal injury and attempts at
excision of lesions have been associated with recurrences (33).
Reactivation of latent virus appears to depend on an intact an-
terior nerve route and peripheral nerve pathways.
Recurrences occur despite both cell-mediated and humoral im-
mune responses and can be either symptomatic or asymptomatic.
Recurrences are spontaneous, but there have been associations
with physical or emotional stress, fever, exposure to ultraviolet
light, tissue damage, and immune suppression (25,34,35). Viral
DNA can be detected in neuronal tissue in the absence of cutane-
ous lesions (17,3639). Latent virus has been retrieved from the
trigeminal, sacral, and vagal ganglia of humans (2022,36,39).
Pathogenesis of Encephalitis
The pathogenesis of HSE in children (older than 3 months) and
adults is only partly understood. Both primary and recurrent
HSV infections can cause disease of the CNS. From studies
performed by the National Institute of Allergy and Infectious
Diseases (NIAID) Collaborative Antiviral Study Group (CASG),
approximately one third of the cases of HSE are the conse-
quence of primary infection. For the most part, the patients
with primary infection are younger than 18 years. The remain-
ing two thirds of cases occur in the presence of preexisting anti-
bodies, but only approximately 10% of patients have a history
of recurrent herpes labialis. Patients with preexisting antibod-
ies are considered to have HSE as a consequence of reactiva-
tion of HSV (40). A limited number of patients, approximately
Scheld_Ch09.indd 140
15%, have active herpes labialis and HSE, allowing compari-
son of the DNA by restriction enzyme analyses. The isolates
are usually identical; however, this is not always the case. The
virus isolated from the peripheral site can be different from that
retrieved from the CNS (41). Thus, the issues of reactivation
of virus directly within the CNS, the potential for enhanced
neurotropism of certain viruses, and the selective reactivation
and access of one virus by the trigeminal route or other routes
to the CNS remain for further elucidation.
The route of access of virus to the CNS in primary infection
is a subject of debate, especially in humans. Studies performed
more than five decades ago defined pathways for HSV access
to the brain in animals, including both the olfactory and tri-
geminal nerves among others (42). However, which of these
nerve tracts uniformly leads to HSV infection in the CNS of
humans is not clear. The anatomic distribution of nerves from
the olfactory tract into the limbic system, along with the recov-
ery of virus from the temporal lobe (the site of apparent onset
of HSE in the human brain), suggests that viral access to the
CNS via this route is a tenable hypothesis. Reports in the lit-
erature have found electron microscopic evidence that suggests
this has been the case in some individuals with HSE (4345).
Animal model data support the contention that the olfactory
tract provides one neurologic avenue for viral access to the
CNS and causes localization of the infection in brain regions
analogous to medial temporal structures in humans (46,47).
Definitive proof of such progression in humans is lacking.
Reactivation of HSV, leading to focal HSE, is a similarly
confusing problem from the standpoint of pathogenesis.
Evidence of latent virus within infected brain tissue exists
(48); however, virus reactivation at that site remains purely
hypothetical. Reactivation of virus peripherally (namely, in
the olfactory bulb or the trigeminal ganglion) with subse-
quent neuronal transmission to the CNS has been suggested
(42,49,50). Nevertheless, a relevant observation is that with
recurrent herpes labialis, whereby reactivation of virus from
the trigeminal ganglia occurs, HSE is a very uncommon event.
Furthermore, HSE does not occur more frequently in immuno-
compromised patients.
Host immunity plays an important, but undefined, role
in the pathogenesis of HSE. Possibly, the CNS is particularly
prone to HSV infection because intraneuronal spread may
shelter virus from host defense mechanisms. HSE is no more
common in the immunosuppressed host than in the normal
host; however, when it does occur, the presentation is atypical,
with a subacute but progressively deteriorating course.
More recently, a host genetic deficiency has been found to
play a role in recurrent HSE but certainly does not exist in all
patients (51).
EPIDEMIOLOGY
Herpes Simplex Virus, Type 1
The epidemiology of HSV infections is multifaceted. Because
the focus of this book is CNS infections, only a brief review of
non-CNS HSV infections follows. The reader is referred to more
complete reviews (11). HSV infections are distributed world-
wide and have been reported in both developed and developing
countries, including remote Brazilian tribes (52). Animal vec-
tors for human HSV infections have not been described; there-
fore, humans remain the sole reservoir for transmission of these
viruses to other humans during close personal contact. There
is no seasonal variation in the incidence of infection. Because
infection is rarely fatal, and because these viruses become
latent, more than two thirds of the worlds population can have
2/21/14 5:33 PM

recurrent HSV infections and, therefore, can transmit infection
during episodes of reactivation. HSV disease ranges from mild
(even indiscernible) in most patients to sporadic, severe, and
life-threatening disease in a few infants, children, and adults.
Children, particularly those younger than 5 years, are most
often infected; however, primary infections can also occur in
older individuals. With clinical illness, oropharyngeal disease,
namely gingivostomatitis, usually is the manifestation. Primary
infection in young adults has been associated with pharyngitis
and often a mononucleosis-like syndrome (53). Seroprevalence
studies have demonstrated that acquisition of HSV-1 infection
is related to socioeconomic factors, namely lower socioeco-
nomic populations acquire infection earlier in life than more
affluent individuals. The identification of primary gingivosto-
matitis that was proven to be caused by HSV infection (54,55)
led to the definition of the natural history of infection, includ-
ing the appearance of neutralizing antibodies (56), absence of
virus shedding in children younger than 6 months (57), and a
higher rate of occurrence among individuals of lower socioeco-
nomic status. Contemporary surveys document the viral shed-
ding data, ranging from 2% to 5% (5863).
Antibody surveys have helped clarify the epidemiology
of HSV infection. Geographic location, socioeconomic sta-
tus, and age all influence the acquisition of HSV infection
(54,6466). In developing countries, seroconversion occurs
early in life. In Brazilian Indians, HSV antibodies are detect-
able in more than 95% of children by the age of 15 years
(67). Similarly, serologic studies performed in New Orleans
demonstrated acquisition of antibodies in more than 90% of
children by the age of 15 years (68). In developing countries,
such as Uruguay, or in lower socioeconomic populations in the
central United States, the appearance of antibodies occurred
at similar but lower frequencies (6871). By 5 years of age,
approximately one third of patients had seroconverted; this
frequency increased to 70% to 80% by early adolescence.
Middle-class individuals of industrialized societies acquired
infection later in life. Seroconversion occurred during the first
5 years of life in 20% of children; there was no significant
increase until the second and third decades of life, at which time
the prevalence of antibodies increased to 40% and 60%, respec-
tively (72,73). One study of university students demonstrated
that seroconversion of susceptible individuals occurred at an
annual frequency of approximately 5% to 10% (53,74,75).
In summary, primary infection occurs very early in children of
underdeveloped countries and in those of lower socioeconomic
classes; however, in developed countries and more affluent
classes, primary infection is delayed until adolescence or, per-
haps, even adulthood. The frequency of direct person-to-person
contact is the major mediator of acquisition of infection.
Over the past decade, HSV-1 has been increasingly associ-
ated with primary genital herpes, reflecting a change in the
epidemiology of infection (11).
Herpes Simplex Virus, Type 2
Because HSV-2 infections are usually acquired through sexual
contact, antibodies to this virus are rarely found before the
age at onset of sexual activity. Although most genital HSV
infections are caused by HSV-2, an ever-increasing propor-
tion is attributable to HSV-1, as noted earlier, now as high as
50% of all new primary infections (10,7678). Approximately
1.5 million new cases of HSV-2 occur annually in the United
States (79). Genital HSV infections are not reportable in the
United States (80). Current estimates of infected individuals
with genital herpes in the United States range from 40 to
60 million (7678,81).
Scheld_Ch09.indd 141
Chapter 9: Herpes Simplex Virus 141
Women have the highest rates of infection, particularly
prostitutes and others with multiple sex partners, including
those with HIV infection. The incidence of genital HSV infec-
tions in both indigent women and those of middle and upper
socioeconomic classes is significantly lower than the incidence
found among women attending sexually transmitted disease
clinics (82). As with HSV-1 infections of the mouth, HSV-2
can be excreted in the absence of symptoms at the time of
primary, initial, or recurrent infection (83,84). The actual
frequency of asymptomatic excretion of HSV-2 in women by
culture is approximately 3% to 5% of all days, and by poly-
merase chain reaction (PCR) 15% to 20%. Furthermore, some
individuals can start and stop shedding multiple times during
the same day (85). Its occurrence creates a silent reservoir for
transmission of infection (86,87). The appearance of HSV-2
antibodies reflects the time of exposure or more simply the
acquisition of infection and is positively correlated with the
onset of sexual activity (70,71,88). However, crowded living
conditions may indirectly contribute to antibody prevalence
(89). If HSV-2 type-specific antibodies are sought in healthy
women, there is a wide discrepancy in prevalence, ranging
from averages of 10% in England and Italy to 25% in the
United States and 77% in Uganda (90,91). Up to 50% to 60%
of lower socioeconomic populations in the United States and
elsewhere develop antibodies to HSV-2 by adulthood. The
reader is referred to a review for worldwide seroprevalence
of HSV-2 (90). Seroprevalence is a function of age, number of
sexual partners, race, and marital status (9294).
Latent Genital Herpes
Simplex Virus Infections
Latent genital infection with subsequent reactivation is the
largest reservoir for transmission of HSV-2. As with HSV-1
infection, recurrent HSV-2 infection can be either symptom-
atic or asymptomatic; however, recurrence is usually associ-
ated with a shorter duration of viral shedding and fewer
lesions. Several studies have implicated a frequency of recur-
rence as high as 60% (88,95). The type of genital infection,
HSV-1 versus HSV-2, is predictive of the frequency of recur-
rence (9597), with HSV-1 infection recurring less frequently
than HSV-2 (98,99).
HERPES SIMPLEX ENCEPHALITIS
Background
HSV infections of the CNS are among the most severe of all
viral infections of the human brain. Currently, HSE is estimated
to occur in approximately 1 per 250,000 to 500,000 individu-
als per year. At the University of Alabama at Birmingham, the
diagnosis of HSE was proven by brain biopsy in an average of
ten patients per year, for an incidence of approximately 1 in
300,000 individuals, an incidence similar to those in Sweden
and England (100,101). With the advent of PCR, brain biopsy
is no longer used. In the United States, HSE accounts for 10%
to 20% of viral infections of the CNS (102).
The economic cost of HSE is considerable, as estimated
in 1983 for hospitalization alone of adults to be more than
$25 million (103). The total medical cost is considerably
higher because of the long-term care and support services
required for many of the survivors.
HSE occurs throughout the year and in patients of all
ages, with approximately one third of cases occurring in
patients younger than 20 years but older than 6 months and
2/21/14 5:33 PM
 142 Part II: Viral Infections and Related Disorders

approximately one half in patients older than 50 years (102). TA B L E 9 . 1

Caucasians account for 95% of patients with biopsy-proven
disease. Both sexes are affected equally. COMPARISON OF FINDINGS IN BRAIN-POSITIVE
The severity of disease is best determined by the outcome AND BRAIN-NEGATIVE PATIENTS WITH HERPES
of patients who have received either no therapy or an ineffec- SIMPLEX ENCEPHALITIS
tive antiviral medication, such as idoxuridine or cytosine arabi-
noside. In such situations, mortality is in excess of 70%; only No. (%) of Patients
approximately 2.5% of all patients with confirmed disease (9.1%
Brain Positivea Brain Negativea
of survivors) returned to normal function after recovery from
their illness (104108). Because brain biopsy with isolation of Historic findings
HSV from brain tissue was the method of diagnosis in these early
studies, a far broader spectrum of HSV infections of the CNS Alteration of 109/112 (97) 82/84 (96)
actually was thought to exist. However, with the more recent use consciousness
of PCR for diagnosis of HSE, virtually all patients have a focal Cerebrospinal fluid 107/110 (97) 71/82 (87)
neurologic disease, suggesting a limited spectrum of disease (109). pleocytosis
Fever 101/112 (90) 68/85 (78)
Headache 89/110 (81) 56/73 (77)
Diagnosis Personality change 62/87 (71) 44/65 (68)
Seizures 73/109 (67) 48/81 (59)
Several aspects relating to the diagnosis of HSE merit discus-
sion: (a) the clinical presentation in regard to the sensitivity and Vomiting 51/111 (46) 38/82 (46)
specificity of various clinical characteristics, (b) the historical Hemiparesis 33/100 (33) 19/71 (26)
use of brain biopsy to establish the diagnosis, (c) conditions Memory loss 14/59 (24) 9/47 (19)
that mimic HSE, and (d) noninvasive means of diagnosis. Data
Clinical findings at presentation
from the NIAID CASG compare presentation and outcome
for brain biopsypositive and brain biopsynegative patients Fever 101/110 (92) 84/79 (81)
(137). Of 202 patients who were evaluated for HSE because of Personality change 69/81 (85) 43/58 (74)
focal neurologic findings, HSV was isolated from brain tissue Dysphasia 58/76 (76) 36/54 (67)
of only 113. Only three of the remaining patients had combi-
Autonomic dysfunction 53/88 (80) 40/71 (58)
nations of serologic and clinical findings suggestive of HSE.
These patients were subsequently shown to have HSV DNA in Ataxia 22/55 (40) 18/45 (40)
their cerebrospinal fluid (CSF) by PCR. Hemiparesis 41/107 (38) 24/81 (30)
As shown in Table 9.1, most patients with biopsy-proven Seizures 43/112 (38) 40/85 (47)
HSE presented with a focal encephalopathic process, includ-
Focal 28 13
ing (a) altered mentation and decreasing levels of conscious-
ness with focal neurologic findings; (b) CSF pleocytosis and Generalized 10 14
proteinosis; (c) the absence of bacterial and fungal pathogens Both 5 13
in the CSF; and (d) focal electroencephalographic (EEG), com- Cranial nerve defects 34/105 (32) 27/81 (33)
puted tomographic (CT), and/or magnetic resonance image
(MRI) findings (102,110120). The frequency of headache Visual field loss 8/58 (14) 4/33 (12)
and CSF pleocytosis is higher in patients with proven HSE Papilledemia 16/111 (14) 9/84 (11)
than in patients with diseases that mimic HSE. Nearly uni-
a
formly, patients with HSE present with fever and personality Positive or negative findings from brain tissue culture.
change. Seizures, whether focal or generalized, occur in only Data from Whitley RJ, Soong S-J, Linneman C Jr, et al. Herpes sim-
approximately two thirds of all patients with proven disease. plex encephalitis: clinical assessment. JAMA. 1982;247:317320, with
permission.
Thus, the clinical findings of HSE are nonspecific and do not
allow for empirical diagnosis of disease predicated solely on
clinical presentation. Although clinical evidence of a localized
temporal lobe lesion is often thought to indicate HSE, various discharges, which arise from the temporal lobe (114118). Early
other diseases can mimic this condition. in the disease, the abnormal electric activity usually involves one
Examination of the CSF is indicated in patients with temporal lobe and then spreads to the contralateral temporal
altered mentation, provided it is not contraindicated because lobe as the disease evolves, usually over 7 to 10 days. The sen-
of increased intracranial pressure. In patients with HSE, CSF sitivity of the EEG is approximately 84%, but the specificity
findings are nondiagnostic, being similar in patients with con- is only 32.5%. CT scans initially show low-density areas with
firmed disease or diseases that mimic HSE. Both the CSF white mass effect localized to the temporal lobe, which can progress to
blood cell (WBC) count (lymphocytes predominance) and the radiolucent and/or hemorrhagic lesions (119,120). Bitemporal
CSF protein level are elevated. The average CSF WBC count is disease is common in the absence of therapy, particularly late in
100 cells/L; the protein averages approximately 100 mg/dL. the disease course (Fig. 9.5). When these neurodiagnostic tests
Sequential evaluation of CSF specimens from patients with are used in combination, the sensitivity is enhanced; however,
HSE indicates increasing cell counts and levels of protein. the specificity remains inadequate. None of these neurodiag-
The presence of CSF red blood cells is not diagnostic for HSE. nostic tests is uniformly satisfactory for diagnosing HSE. MRI
Approximately 5% to 10% of patients have a normal CSF detects evidence of HSE earlier than CT scan (111).
formula on first evaluation. A sensitive and specific means of diagnosis is the isolation of
Noninvasive neurodiagnostic studies support a presump- HSV from tissue obtained at brain biopsy (121). However, PCR
tive diagnosis of HSE. These studies have included EEG, CT, detection of HSV DNA in the CSF has become the diagnostic
and MRI. Focal changes of the EEG are characterized by spike procedure of choice. Brain biopsy is of value in confusing
and slow-wave activity and periodic lateralized epileptiform clinical presentations. Complications, either acute or chronic,

Scheld_Ch09.indd 142 2/21/14 5:33 PM

 Chapter 9: Herpes Simplex Virus 143

FIGURE 9.5 Sequential computed tomographic examination of a patient with confirmed herpes simplex
encephalitis.

occur in approximately 3% of patients. Fears of potentiating of therapy, including brain abscess, tuberculosis, cryptococ-
acute illness (by incising the brain in a diseased area) or of cal infection, and brain tumor. An additional 19 patients had
causing chronic seizure disorders have not been substantiated diseases that were indirectly treatable, and another 38 patients
by follow-up studies of patients in the NIAID CASG. had an alternative diagnosis established for which there was
no current therapy, usually other viral infections. Thus, those
diseases that mimic HSV infection of the CNS and that require
Serologic Evaluation immediate medical intervention should be considered if the
PCR is negative for HSV DNA.
Several strategies using antibody production as a means of diag-
nosing HSE have been utilized (58). Because most encephalitic
patients are HSV seropositive at presentation, seroconversion TA B L E 9 . 2
per se is usually not helpful because fever alone can reactivate DISEASES THAT MIMIC HERPES SIMPLEX
labial herpes, resulting in antibody elevations. A fourfold rise ENCEPHALITIS
in serum antibody was neither sensitive nor specific enough to
be useful. A fourfold or greater rise in CSF antibody occurred Nontreatable Diseases
significantly more often within a month after onset of dis- Treatable Diseases (N 46)a (N 49)a
ease in patients with biopsy-proven HSE: 85% versus 29%.
By 10 days after clinical presentation, however, only 50% of Abscess/subdural Vascular disease 11
brain biopsypositive patients had a fourfold rise in CSF anti- empyema Toxic encephalopathy 5
body. This test is useful only for retrospective diagnosis. The Bacterial 5 Reye syndrome 1
use of a ratio of serum to CSF antibody of 20 or less did not Listeria 1 Viral (N 40)
improve sensitivity during the first 10 days of disease. Fungal 2 Arbovirus infection
Mycoplasma 2 St. Louis encephalitis 7
Tuberculosis 6 Western equine 3
Polymerase Chain Reaction Detection of Cryptococcal 3 encephalitis
Viral DNA Rickettsial 2 California 4
Toxoplasmosis 1 encephalitis
PCR detection of HSV DNA in the CSF is the diagnostic Mucormycosis 1 Eastern equine 2
method of choice (121127). Data from the NIAID CASG Meningococcal 1 encephalitis
defined the sensitivity and specificity as 94% and 98%, meningitis Other herpesviruses
respectively. These CSF specimens were obtained from patients Other viruses Epstein-Barr virus 8
with biopsy-proven or biopsy-negative disease. Notably, the Cytomegalovirus 1 Others viruses
specificity would have been higher except that some tissue Influenza A 4 Mumps virus 3
specimens were fixed in formalin, which killed infectious Echovirus infectionb 3 Adenovirus 1
virus, prior to an attempt to isolate virus. HSV DNA persisted Tumor 5 Progressive multifocal 1
in 80% of tested CSF specimens for 1 week or more. Subdural hematoma 2 leukoencephalopathy
Systemic lupus 1 (JC virus)
erythematosus Lymphocytic 1
Adrenal 6 choriomeningitis
Diseases That Mimic Herpes Simplex leukodystrophy Subacute sclerosing 2
Encephalitis panencephalitis
In a compilation of the NIAID CASG data, 193 (45%) of a
Of 432 patients assessed.
432 patients undergoing brain biopsy for a focal encepha- b
Drug therapy under investigation.
lopathic process had HSE (128). As shown in Table 9.2, the From Whitley RJ, Gnann JW. Viral encephalitis: familiar infections
remaining patients were evaluated for diseases that mimic and emerging pathogens. Lancet. 2002;359:507513, with permission.
HSE (128). Thirty-eight had disease amenable to other forms

Scheld_Ch09.indd 143 2/21/14 5:33 PM

 144 Part II: Viral Infections and Related Disorders

Level of Consciousness
Associated Neurologic Syndromes
Lethargic Semicoma Coma
HSV obviously involves areas of the nervous system other N = 23 N=7 N=7
than the brain. Primary and recurrent genital herpes have been 100
associated with neuritis localized to one extremity or even
transverse myelitis. Neuritis evident in such patients can be 80
associated with altered sensation of the lower extremities, as
well as dysesthesias, shooting pain, and motor impairment.
60
Urinary and fecal incontinence have been reported in a few
patients. An aseptic meningitis syndrome is also common, fre-
quently being associated with a Mollaret syndrome, and not 40
without complications.
Guillain-Barr syndrome and localized dermatomal rashes 20

Percent of Patients
associated with acute neuritis have also been attributed to
HSV infections. 0
Acute retinal necrosis has been reported as a long-term
complication of HSE (129). N = 26 N = 13 N = 14
100

Therapy 80

The first antiviral drug reported as efficacious therapy of HSE 60

was idoxuridine; however, it was soon proven both ineffec-
tive and toxic (104). Subsequent therapeutic trials defined
vidarabine as a useful medication for the management of 40
biopsy-proven HSE (107,108); however, it has been replaced
by acyclovir in the physicians armamentarium. During these 20
studies, the variables of age, disease duration, and level of con-
sciousness at the onset of therapy were proven major deter- 0
minants of clinical outcome. Patients younger than 30 years
and with a more normal level of consciousness (lethargic as Returned to normal function Moderate debility
opposed to comatose) were more likely to return to normal Severe impairment Death
function than older patients, especially those who were semico-
FIGURE 9.6 Influence of level of consciousness and age on mortality
matose or comatose (Fig. 9.6). From these data, older patients
and morbidity.
(older than 30 years), whether comatose or semicomatose, had
mortality rates that approached 70%, a figure very similar to
that encountered in the placebo recipients of the previously Of acyclovir recipients, 10% experienced an increased
cited studies. If therapy is to be effective, it must be instituted BUN level, and 6% developed a creatinine level in excess
before the onset of hemorrhagic necrosis of a dominant tem- of 2 mg/dL. No clinical evidence of toxicity was detected.
poral lobe and significant deterioration of consciousness. The current therapy of choice for the management of HSE is
Acyclovir is superior to vidarabine for the treatment of HSE acyclovir. This drug is administered at a dosage of 10 mg/kg
(166). The NIAID CASG study defined a mortality of 55% at every 8 hours (30 mg/kg per day) for 14 to 21 days.
6 and 18 months after the initiation of treatment for vida-
rabine recipients versus 19% and 28%, respectively, for the
acyclovir group (Fig. 9.7). Late deaths were not a consequence 100
of either persistent or reactivated HSV infection but occurred
in patients who were severely impaired as a consequence of
their disease. Acyclovir decreases mortality to 19% 6 months 80 ACV (N = 32)
after therapy. Importantly, 38% of patients, irrespective of
age, return to normal function.
Percent Surviving

Previous studies indicated that age and level of conscious-

ness influenced long-term outcome. A more objective reflection 60
of level of consciousness is the Glasgow Coma Scale (GCS). ARAA (N = 37)
Scores that approached normal predicted enhanced survival.
When GCS score and age were assessed simultaneously 40
(Fig. 9.8), a GCS score of 6 or less predicted a poor therapeutic
outcome, irrespective of the agent administered or of the age
of the patient (130).
20
Regarding morbidity for acyclovir recipients, 38% of
p = 0.008
patients were normal or with minor impairment, 9% of patients
had moderate sequelae, and 53% of patients were left with
severe impairment or died. No patient entered into the NIAID 0
trials suffered a relapse after completion of therapy. Relapse of 0 3 6 9 12 15 18
HSE has been reported, though not well documented, in a few
Months
patients following the administration of vidarabine (131133)
and acyclovir (133,134). Many patients were not afebrile at FIGURE 9.7 Comparison of survival in patients with biopsy-proven
the conclusion of treatment, suggesting that a longer duration herpes simplex encephalitis treated with vidarabine (AraA) or
of therapy to a minimum of 14 to 21 days may be desirable. acyclovir (ACV); p .008.

Scheld_Ch09.indd 144 2/21/14 5:33 PM

 Chapter 9: Herpes Simplex Virus 145

N=4 N=5 N=7 N = 13 the newborn. Gross examination of the brain often reveals
100 100 encephalomalacia and hydranencephaly, which are likely the
1 consequence of extensive hemorrhagic necrosis. Porencephaly,
4 2 8 hydranencephaly, and multicystic lesions are often sequelae in
75 75 neonates who survive for several weeks or months following
neonatal HSV infection of the brain. The microscopic appear-
 30 ance of the brain is characterized by a mononuclear inflamma-
50 50 3 tion, necrosis, and hemorrhage.
3
3 Pathogenesis
25 25
2 In utero disease is likely a consequence of transplacental infec-
1 2 tion and usually involves skin, brain, eye, liver, and adrenals.
0 0 More commonly, the fetus comes in contact with infected
ARAA ACV ARAA ACV maternal genital secretions at the time of delivery. Viral rep-
6 6 lication in the newborn either remains limited to the portal
of entrynamely, the skin, eye, or mouthor progresses to
N=8 N=3 N = 18 N = 11 involve various other organs, including the brain (resulting
100 100 in encephalitis), causing life-threatening disease. Host mecha-
1 2 nisms responsible for control of viral replication at the site of
4 entry are unknown. For babies with encephalitis, intraneuro-
1 3
75 75 nal transmission of virus provides a privileged site that may be
1
2 impervious to circulating humoral and cell-mediated defense
4
mechanisms. Thus, transplacental maternal antibodies may be
 30 50 50 3 of less value in the prevention of encephalitic forms of neona-
tal HSV infections. Disseminated infection is a consequence of
5 viremia or secondary to extensive cell-to-cell spread, as occurs
25 25 9 with pneumonitis after aspiration of infected secretions.
1 4
Neonatal HSE illustrates the two major pathogenic routes
for virus access to the brain, namely, hematogenous and intra-
0 0 neuronal. For example, hematogenous spread of virus usually
ARAA ACV ARAA ACV
occurs with disseminated disease, and diffuse involvement of
6 6 the brain ensues in 60% to 80% of patients. In contrast, neu-
Normal and mild Moderate Severe ronal transmission probably results in the focal CNS disease
encountered in babies with encephalitis only when no distal
Dead Number of patients
organ involvement is documented (136).
FIGURE 9.8 Morbidity after vidarabine (AraA) or acyclovir (ACV)
treatment of biopsy-proven herpes simplex encephalitis, according to
age (younger than 30 years vs. older than 30 years) and the Glasgow Times of Transmission of Infection
Coma Scale score (6 vs. 6). The scale at the left side of each column
indicates percentages (0% to 100%). Neonatal HSV infection is acquired at one of three times: in
utero, intrapartum, or postnatally. Regardless of the time or
route of acquisition, the newborn is at risk of CNS disease.
Certainly, the mother is the most common source of infection
for the first two of these routes of transmission of infection to
NEONATAL HERPES SIMPLEX the newborn.
VIRUS INFECTIONS
Intrauterine Infection
History In utero acquisition of HSV infection is becoming increasingly
documented (137139). Manifestations of disease acquired
In 1941, Smith, Lennette, and Reames (7) reported the first in utero include chorioretinitis, cutaneous aplasia, hydran-
case of HSV infection of the CNS, as noted earlier. This case encephaly, and encephalomalacia (138) (Fig. 9.9). Risk fac-
occurred in a newborn with neonatal HSE. In 1952, Zuelzer, tors associated with intrauterine transmission of infection
Wolf, and Stulbery (135) reviewed eight cases of disseminated are unknown; however, both primary and recurrent maternal
HSV infection in neonates with involvement of most organs, infection can result in infection of the fetus in utero. In utero
including the brain in many instances. This report was fol- infection is the consequence of either transplacental or ascend-
lowed shortly by others indicating the association between ing infection.
HSV infection of the newborn and necrotizing encephalitis,
including the isolation of HSV in cell cultures from brain Intrapartum Infection
tissue.
The most common time of transmission of infection from
mother to the fetus is intrapartum. Transmission occurs when
the infant comes in contact with infected maternal genital
Pathology and Pathogenesis secretions at delivery, accounting for 85% of cases (140).
Prospective assessment of HSV excretion in the genital tract
at delivery indicates that shedding can occur in 0.5% to 1.3%
Pathology of women (141). Maternal primary versus recurrent infection
Although the pathology of HSE is discussed earlier in this influences the probability of neonatal infection, as discussed
chapter, a few characteristics appear more commonly in later in this chapter. With the increasing prevalence of HSV-2

Scheld_Ch09.indd 145 2/21/14 5:33 PM

 146 Part II: Viral Infections and Related Disorders
infection in the population at large, the probability of excret-
ing HSV at delivery should increase (142,143).
Factors that influence intrapartum acquisition of infection
by the fetus include the following: (a) type of maternal infec-
tion (primary vs. recurrent) (144), (b) maternal antibody sta-
tus (145,146), (c) duration of ruptured membranes (147), and
(d) placement of a fetal scalp monitor in a woman excreting
HSV (148,149).
Primary infection is associated with (a) larger quantities of
HSV replicating in the genital tract (more than 106 viral par-
ticles/0.2 mL of tissue culture inoculum) and (b) a period of
viral excretion that on average persists for 3 weeks. In con-
trast, in women with recurrent genital infection, HSV is shed
for an average of only 2 to 5 days and at lower concentrations
(approximately 103/0.2 mL of tissue culture inoculum). Because
of the larger quantity of virus and the longer period of viral
excretion, primary maternal infection is associated with a higher
rate of transmission to the fetusestimated between 30% and
50% (147). Reflecting the type of maternal infection, the deliv-
ery of transplacental maternal antibody to the fetus influences
both the severity of disease in the newborn and the likelihood of
fetal infection (145,146,150). Lastly, placement of a fetal scalp
monitor in women excreting virus has been shown to lead to
fetal infection. Monitor placement should be discouraged in
women with a history of genital herpes or visualized lesions.
The duration of ruptured membranes is reported to be
an important indicator of risk for acquisition of neonatal
infection. Cesarean section decreases the incidence of infection
in women with lesions present at delivery (147).
Postnatal Infection
The third route of transmission is postnatal acquisition
(151158). Documented sources include the mother (includ-
ing the breast as a source of virus [151,152]), the father
(labial lesions) (153,154), nosocomial transmission (nursery
FIGURE 9.9 Encephalomalacia resulting from in utero herpes simplex virus infection.
Scheld_Ch09.indd 146
personnel or other babies) (155157), and as a consequence
of the Jewish tradition of circumcision, known as metzitzah
bpeh (158).
Epidemiology of Maternal Infection
Disseminated Maternal Infection
HSV infections of pregnant women may extend beyond the
usual sites of disease, the oropharynx and the genital tract.
As first reported in 1969, dissemination can occur, leading
to cutaneous or visceral disease; fortunately, this is a rare
occurrence. In a limited number of cases (159162), dissemi-
nation following primary oropharyngeal or genital infection
has led to life-threatening diseases such as (a) hepatitis with
or without thrombocytopenia, (b) leukopenia, (c) consump-
tive coagulopathy, and (d) encephalitis. Although only a small
number of patients have been studied, the mortality among
pregnant women with disseminated infection has been greater
than 50%. Fetal deaths also occurred in more than 50% of
cases, though not necessarily associated with the death of the
mother.
Localized Maternal Infection
During the first 20 weeks of gestation, primary maternal geni-
tal HSV infection is associated with an increased frequency of
spontaneous abortion (approximately 25%), stillbirth, and as
noted earlier, congenital disease, particularly hydranencephaly
and chorioretinitis (138,163). Several studies have prospec-
tively evaluated the frequency and nature of viral shedding in
pregnant women with a known history of genital herpes. In
a predominantly white middle-class population, documented
recurrent infection occurred in 84% of pregnant women
(164). Moreover, asymptomatic viral shedding occurred in
2/21/14 5:33 PM

at least 12% of the recurrent episodes. Viral shedding from
the cervix occurred in only 0.56% of symptomatic infections
and in 0.66% of asymptomatic infections (84,165,166). For
asymptomatic pregnant women, an incidence of cervical shed-
ding as high as 3% has been reported (167). More than 60%
of women in various groups who give birth to infants with
neonatal HSV infection report no symptoms (168170).
Incidence and Presentation of
Neonatal Infection
The incidence of neonatal HSV infection is about 1 in 3,000
(0.03%) deliveries (136). Overall, two thirds of children with
neonatal HSV infection develop disease of the CNS, and the
disease may remain localized to the brain or become dissemi-
nated to involve various other organs. If untreated, newborns
with disseminated disease have a mortality of 80%, and new-
borns with disease limited to the CNS have a mortality of
approximately 50%.
Classification of newborns with HSV infection is manda-
tory for prognostic and therapeutic considerations (163).
Babies with congenital infection, by definition, must be identi-
fied within 48 hours of birth. Those babies who are infected
(either during delivery or postnatally) are divided into three
categories: (a) those with disease localized to the skin, eye,
or mouth; (b) those having encephalitis with or without skin,
eye, and/or mouth involvement; and (c) those having dissemi-
nated disease involving multiple organs, such as CNS, lung,
liver, adrenals, skin, eye, and/or mouth. This chapter focuses
on CNS disease and considers prospectively acquired data
obtained through the NIAID CASG. All babies, irrespective
of disease classification, should be considered at risk for CNS
complications of infection. The presentation and outcome of
infection (particularly prognosis after therapy) according to
category vary significantly with regard to both mortality and
morbidity.
Intrauterine Infection
Intrauterine infection is usually apparent at birth and is char-
acterized by a triad of findings: (a) skin vesicles and/or scar-
ring (cuteus aplasia), (b) eye disease (chorioretinitis, optic
atrophy), and (c) brain disease (microcephaly, encephaloma-
lacia, or hydranencephaly). Serial ultrasound examination of
the mothers of those babies infected in utero has occasionally
demonstrated hydranencephaly. Retinitis alone can be a pre-
senting sign and should alert the pediatrician to the possibility
of intrauterine HSV infection, although HSV infection is a less
common cause of chorioretinitis relative to other congenital
infections. The frequency of occurrence of intrauterine HSV
infection has been estimated to range between 1 in 100,000
(0.001%) and 1 in 200,000 (0.0005%) deliveries (138).
A small group of children will have skin vesicles or eye
lesions, which are present at the time of delivery. These
neonates are often born to women who have had prolonged
rupture of membranes. The babies have no other findings of
invasive multiorgan involvement; specifically, there is no cho-
rioretinitis, encephalitis, or evidence of other diseased organs.
Disseminated Infection
Table 9.3 summarizes the classification of 297 babies with
neonatal HSV infection from the NIAID CASG. Disseminated
HSV infection has the worst prognosis with regard to mor-
Scheld_Ch09.indd 147
Chapter 9: Herpes Simplex Virus 147
tality. Children with disseminated infection usually present to
tertiary medical centers for therapy between 9 and 11 days of
life; however, signs of infection are, on average, usually pres-
ent 4 to 5 days earlier.
The principal organs involved following disseminated
infection are the liver, brain, and adrenals; however, infection
can involve various other organs, including the larynx, tra-
chea, lungs, esophagus, stomach, lower gastrointestinal tract,
spleen, kidneys, pancreas, and heart. Constitutional signs and
symptoms include irritability, seizures, respiratory distress,
jaundice, bleeding diatheses, and shock, in addition to a char-
acteristic vesicular exanthem that is often considered pathog-
nomonic for neonatal HSV infection.
The vesicular rash, as described later in this chapter, is par-
ticularly important in the diagnosis of HSV infection. Notably,
about 20% of children with disseminated neonatal HSV infec-
tion will not develop skin vesicles during the course of their
illness (140,171). In the absence of skin vesicles, the diag-
nosis becomes exceedingly difficult because the clinical signs
are often vague and nonspecific, mimicking those of neonatal
sepsis. Mortality in the absence of therapy exceeds 80%; if
therapy is instituted before CNS disease ensues, outcome is
usually good. The most common cause of death in babies with
disseminated disease is either HSV pneumonitis or dissemi-
nated intravascular coagulopathy.
Evaluation of the extent of disease is imperative, as with
all cases of neonatal HSV infection. The clinical laboratory
should be used to define hepatic enzyme elevation (serum ala-
nine aminotransferase and AST), direct hyperbilirubinemia,
neutropenia, thrombocytopenia, and bleeding diatheses.
Unless contraindicated, examination of the CSF is imperative.
In addition, chest roentgenograms, abdominal x-rays, EEG,
and CT or MRI of the head can be judiciously and serially
employed to determine the extent of disease. The radiographic
picture of HSV lung disease is characterized by a diffuse inter-
stitial pattern that progresses to a hemorrhagic pneumonitis.
Pneumatosis intestinalis can be detected when gastrointesti-
nal disease is present. Encephalitis is a common component
of disseminated infection, occurring in about 75% of these
newborns. Serial evaluation of the CSF and noninvasive neu-
rodiagnostic tests, as defined later in this chapter, will help
assess the extent of brain disease.
Encephalitis
Infection of the CNS alone or in combination with dissemi-
nated disease presents with findings indicative of encephalitis.
Overall, nearly 90% of babies with brain infection caused by
HSV have evidence of an acute neurologic syndrome. Brain
infection can occur in one of two fashions: either as a com-
ponent of multiorgan disseminated infection or as encepha-
litis only, with or without skin, eye, and mouth involvement.
Nearly one third of all babies with neonatal HSV infection
have only the encephalitic component of disease.
Clinical manifestations of these two types of encephali-
tis include seizures (both focal and generalized), lethargy,
irritability, tremors, poor feeding, temperature instability,
bulging fontanel, and pyramidal tract signs. Whereas babies
with disseminated infection often have skin vesicles in asso-
ciation with brain infection, the same is not true for babies
with encephalitis alone. In this latter group, only approxi-
mately 60% have skin vesicles at any time during the disease
course (140,169171). Cultures of CSF yield virus in 25% to
40% of all patients. Anticipated findings on CSF examina-
tion include pleocytosis and proteinosis (as high as 500 to
1,000 mg/dL). Although a few babies with CNS infection,
2/21/14 5:33 PM
 148 Part II: Viral Infections and Related Disorders

TA B L E 9 . 3
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF INFANTS
ENROLLED IN NIAID COLLABORATIVE ANTIVIRAL STUDY

Disease Classification

Disseminated Central Nervous Skin, Eye, and

(%) System (%) Mouth (%)

No. of babies 94 (32) 101 (34) 102 (34)

No. of boys/number of girls 55/39 51/50 53/49
Race
No. of whites/number of others 60/34 76/25 76/26
No. of premature infants (36 weeks) 39 (41) 24 (24) 30 (29)
Gestational age (mean weeks SEM) 36.5 0.41 37.9 0.36 37.7 0.33
Enrollment age (mean days SEM) 11.7 0.68 17.0 0.79 12.0 1.1
Maternal age (mean years SEM) 21.7 0.50 23.1 0.46 22.7 0.52
Clinical findings (number)
Skin lesions 67 (71) 68 (67) 87 (85)
Brain involvement 50/83a (60) 101 (100) 0
Pneumonia 35/82 (43)a 0 0
Mortality at 1 yearb 58 (62) 15 (15) 0
Neurologic impairment of survivorsc
(number affected/total number)
Total 10/27b (37) 37/75 (49) 7/82b (9)
Adenine arabinoside 7/19 (37) 21/46 (46) 3/32 (9)
Acyclovir 2/6 (33) 14/26 (54) 1/43 (2)
Placebo 1/2 (50) 2/3 (67) 3/7 (43)

NIAID, National Institute of Allergy and Infectious Diseases.

a
Denominators vary according to number of patients who were evaluated.
b
Regardless of therapy.
c
Denominators vary according to number of patients with follow-up available.
From Whitley RJ. Herpes simplex virus infections. In: Remington J, Klein J, eds. Infectious Diseases of the
Fetus and Newborn Infants. 3rd ed. Philadelphia: WB Saunders; 1990:282305, with permission.

demonstrated by brain biopsy, have been reported to have Several points warrant reiteration. Clinical manifestations
no abnormalities of their CSF, certainly this is very uncom- of disease in children with encephalitis alone are virtually
mon. Serial CSF examinations provide a useful diagnostic identical to those findings that occur with brain infection in
approach because the infected newborn with brain disease disseminated cases, in spite of the presumed differences in
demonstrates progressive increases in its protein content. The pathogenesis. For babies with encephalitis only, approximately
importance of CSF examinations in all infants is underscored
by the finding that even subtle changes have been associated
with significant developmental abnormalities (172). An EEG,
CT, or MRI can be very useful in defining the presence of
CNS abnormalities. A characteristic MRI scan is shown in
Figure 9.10. Death occurs in 50% of babies with localized
CNS disease who are not treated, and it is usually related
to involvement of the brainstem. In the absence of antiviral
therapy, with rare exceptions, survivors are left with neuro-
logic impairment, and the long-term prognosis after either
disseminated infection or encephalitis alone is particularly
poor. Up to 50% of surviving children have some degree of
psychomotor retardation, often in association with micro-
cephaly, hydranencephaly, porencephalic cysts, spasticity,
blindness, chorioretinitis, or learning disabilities. Whether
visceral or CNS damage can be progressive after initial clear-
ance of the viral infection is unclear, but it is a possibility
suggested by long-term assessment of children with skin, eye,
or mouth disease (140,173) and more recently by a study of FIGURE 9.10 MRI scans of CNS neonatal herpes simplex virus infec-
a group of babies with more severe disease (174). tion (bitemporal disease).

Scheld_Ch09.indd 148 2/21/14 5:33 PM


60% develop evidence of a vesicular rash characteristic of HSV
infection. Thus, a newborn with pleocytosis and proteinosis
of the CSF but without a rash can easily be misdiagnosed as
having bacterial or other viral infection unless HSV infection
is carefully considered. In such circumstances, a history of
genital lesions in the mother or her sexual partner may be very
important in the incrimination of HSV as a cause of illness.
Skin, Eye, and/or Mouth Infection
Infection localized to the skin, eye, and/or mouth is associated
with virtually no mortality. When infection is localized to the
skin, the presence of discrete vesicles remains the hallmark of
disease. Clusters of vesicles (Fig. 9.11) often appear initially
upon the presenting part of the body that was in direct contact
with the virus during birth. With time, the rash can progress to
involve other areas of the body as well. Vesicles occur in 80%
of children with skin, eye, or mouth infection. Children with
disease localized to the skin, eye, or mouth generally present
at about 10 to 11 days of life. Those babies with skin lesions
invariably suffer from recurrences whether therapy is admin-
istered or not. Although death is not associated with disease
localized to the skin, eye, and/or mouth, approximately 30%
of these children eventually develop evidence of neurologic im-
pairment in the absence of antiviral therapy, which can result
in significant neurologic morbidity (140,173).
Infections involving the eye may manifest as keratocon-
junctivitis or later chorioretinitis. The eye can be the only
site of HSV involvement in the newborn. Findings include
keratoconjunctivitis, microphthalmia, or retinal dysplasia.
In the presence of persistent disease and no therapy, chorio-
retinitis can result. Chorioretinitis can be caused by either
HSV-1 or HSV-2 (175177). Keratoconjunctivitis, even in the
presence of therapy, can progress to chorioretinitis, cataracts,
and retinal detachment. Cataracts have been detected on
long-term follow-up of proven perinatally acquired HSV in-
fections (178).
Long-term neurologic impairment has been encountered
in children whose disease appeared localized to the skin, eye,
and/or mouth. The significant findings include spastic quad-
riplegia, microcephaly, and blindness. Despite normal clinical
and CSF examinations at the time these children completed
antiviral therapy, neurologic impairment became apparent
between 6 months and 1 year of life. In retrospect, when CSF
FIGURE 9.11 Characteristic vesicular rash.
Scheld_Ch09.indd 149
Chapter 9: Herpes Simplex Virus 149
from these babies was subjected to PCR analysis, evidence of
HSV DNA was detected in virtually all of these children, indi-
cating an asymptomatic infection of the CNS (179).
Diagnosis
The appropriate use of laboratory tools is essential if a diag-
nosis of HSV infection is to be achieved (180). Virus isola-
tion remains one of two definitive diagnostic methods. If skin
lesions are present, a scraping of skin vesicles should be made
and transferred (in appropriate virus transport media) to a
diagnostic virology laboratory. Clinical specimens should
be shipped on ice for prompt inoculation into cell culture
systems that are susceptible for the demonstration of the cy-
topathic effects characteristic of HSV replication. Specimen
shipping and processing should be expedited. In addition to
sampling vesicle fluid, other sites from which virus may be
isolated include the CSF, stool, urine, throat, nasopharynx,
and conjunctivae. In infants with evidence of hepatitis or
other gastrointestinal abnormalities, duodenal aspirates are
useful for HSV isolation. The virologic results of cultures
from these anatomic sites should be used in conjunction with
clinical findings to define the extent of disease in the new-
born. Typing of an HSV isolate must be done for prognostic
purposes.
Cytologic examination of cells from the maternal cer-
vix or from the infants skin, mouth, conjunctivae, or cor-
neal lesions has a sensitivity of only approximately 60%
to 70% and, therefore, should not be the sole diagnostic
determinant for infection in the newborn (11). Cellular mate-
rial obtained by scraping the periphery of the base of lesions
should be smeared on a glass slide and promptly fixed in cold
ethanol. The slide can be stained according to the methods
of Papanicolaou, Giemsa, or Wright before examination by
a trained cytologist. Deployment of Giemsa or, alternatively,
Tzanck smears likely will not demonstrate the presence of
intranuclear inclusions. Intranuclear inclusions and multinu-
cleated giant cells are indicative, but not diagnostic, of HSV
infection. The use of HSV monoclonal antibodies for rapid
diagnosis has gained widespread acceptance. These fluores-
cence studies should be performed by laboratories experi-
enced in the procedure.
Serologic diagnosis of HSV infection is not of great clini-
cal value. Therapeutic decisions cannot await the results of
2/21/14 5:33 PM
 150 Part II: Viral Infections and Related Disorders
serologic studies. The inability to differentiate transplacentally
acquired maternal immunoglobulin G from endogenously
produced antibodies makes the assessment of the neonates
antibody status both difficult and of little value during acute
infection. Commercially available serologic tests are now
capable of distinguishing HSV-1 from HSV-2 antibodies.
These assays are based on differences in glycoprotein gG1 and
gG2 (181). These are the only antibody assays that should be
used. Serial antibody assessments may be useful if a mother
without a history of HSV infection has a primary infection
late in gestation and, therefore, transfers little or no antibody
to the fetus.
The use of CT and MRI scans to define CNS disease is
essential, even in the child who appears normal.
Polymerase Chain Reaction to
Detect Viral DNA
The other definitive diagnostic method is PCR detection of
viral DNA, as discussed earlier in this chapter (121,179,182).
PCR has been applied to blood as an additional site for
diagnosis that is especially useful in babies with disseminated
disease.
Prevention
Cesarean Section
Mothers with active herpetic lesions should deliver their
child by cesarean section if delivery can be achieved within
4 hours of membrane rupture (147). Cesarean section is of
unproven benefit if membranes have been ruptured for more
than 4 hours. Recent data support this approach (147).
Furthermore, infection of the newborn has occurred in spite
of delivery by cesarean section (183), which was performed
specifically to prevent neonatal infection.
Vaccination
Though various strategies for prevention of neonatal infection
must be instituted, eventual control of HSV infection is most
likely to be achieved through vaccination, and there is consid-
erable research under way to design and test HSV vaccines,
in spite of a recent failure to prevent HSV-2 infections (85).
Several principles should be understood. First, the efficacy of
the vaccine must be sufficient to prevent transmission of infec-
tion. It is highly unlikely that any vaccine will totally prevent
infection. Second, high titers of antibody against HSV do not
protect humans from reactivation of latent infection. Third,
live virus vaccines tend to induce more potent and durable
humoral and cellular immune responses than subunit or puri-
fied glycoprotein vaccines.
Treatment
Background
Of all the perinatally acquired infections, the one most likely
to be amenable to successful therapy is that caused by HSV.
Because most babies acquire infection at the time of delivery or
shortly thereafter, successful antiviral therapy should decrease
mortality and improve long-term outcome. Inherent in these
presumptions is the recognition that diagnosis early after the
onset of clinical illness is essential, as is the case with peri-
natally acquired bacterial infections. Equally importantly, the
Scheld_Ch09.indd 150
Skin, eyes, or mouth, vidarabine (n = 31) or
acyclovir (n = 54)
1.0
0.9 CNS, vidarabine (n = 36)
0.8 CNS, acyclovir (n = 35)
Proportion Surviving
0.7
0.6
Disseminated, vidarabine (n = 28)
0.5
0.4
Disseminated; acyclovir (n = 18)
0.3
0.2
0.1
0
0 60 120 180 240 300 360
Survival (days)
FIGURE 9.12 Mortality in patients with disseminated disease and
CNS disease.
possibility of disease progression should encourage the early
institution of therapy. Of children presenting with disease
localized to the skin, eye, and/or mouth, approximately 70%
will progress to involve the CNS or result in disseminated
infection (169). When such events occur, the likelihood of an
adequate outcome, even with efficacious drugs, is not optimal
because many of these children will either die or be left with
significant neurologic impairment. The following paragraphs
summarize our knowledge of therapy.
First, the overall mortality rate for babies with encephali-
tis or disseminated infection 1 year after treatment with high
doses of acyclovir (20 mg/kg every 8 hours for 21 days) is
lower than that of prior studies of neonatal HSV infection
that used lower doses, as compared in Figure 9.12 (184,185).
There are no differences in either adverse effects or laboratory
toxicity.
Second, irrespective of the therapeutic modality employed,
there has been a significant increase in the number of babies
who returned to normal function. This can be accounted for
largely by the introduction of therapy before the develop-
ment of encephalitis or disseminated disease, as reflected by
Table 9.4 (185). Of the babies entered in the trial referenced in
Table 9.4, more than 48% have disease localized to the skin,
eye, and mouth (185). This represents a threefold increase in
the number of babies with skin, eye, and mouth involvement,
when compared with that of previous studies and historic data
(p .001). The change in spectrum of disease presentation is
most likely related to earlier diagnosis. The number of babies
with encephalitis has remained fairly constant at approximately
30%, whereas the number of babies with disseminated disease
has decreased to 22%. Nevertheless, improved morbidity by
disease classification is unchanged for encephalitis (Fig. 9.13).
Third, available data indicate that therapy has not been
initiated any earlier in the most recent neonatal HSV stud-
ies (186) as compared to earlier studies (185). However, the
mean duration of disease for all children (irrespective of dis-
ease classification) entered into these studies was 4 to 5 days;
therapy can, therefore, be instituted even earlier in the disease
course. This window for earlier administration of therapy
is significant if further advances in therapeutic outcome are to
be achieved.
2/21/14 5:33 PM
 Chapter 9: Herpes Simplex Virus 151

TA B L E 9 . 4
ASSESSMENT OF MORBIDITY AFTER 12 MONTHS IN INFANTS WITH NEONATAL HSV INFECTION TREATED
WITH VIDARABINE OR ACYCLOVIR

Morbidity After 12 Months (Number of Infants)

Alive After 12 Months; Dead within
Extent of Disease Normal Mild Moderate Severe Subtotal Morbidity Unknown 12 Months Total
Skin, eye, or mouth infection
Vidarabine 22 1 1 1 25 6 0 31
Acyclovir 45 0 1 0 46 8 0 54
Central nervous system
infection
Vidarabine 13 1 5 11 30 1 5 36
Acyclovir 8 5 6 9 28 2 5 35
Disseminated disease
Vidarabine 7 1 0 4 12 2 14 28
Acyclovir 3 1 0 1 5 2 11 18
Total 98 9 13 26 146 21 35 202

From Whitley RJ, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J
Med. 1991;324:444449, with permission.

The existing database from the NIAID CASG has provided
insight into those factors that influence outcome, as summarized
in Table 9.5 (187). Those factors that have a major impact on
outcome include disease classification, level of consciousness,
time of initiation of therapy, virus type (Fig. 9.14), and the
virus type and frequency of skin recurrences for babies whose
disease is localized to the skin, eye, and mouth. Our under-
standing of these data implies that limitation of disease before
there has been extensive multiorgan involvement or disease of
the CNS is associated with the best prognosis. This informa-
tion will be useful in developing therapeutic strategies and in
counseling parents of children with neonatal HSV infection.
From a laboratory perspective, a CSF that remains PCR
positive at the conclusion of therapy predicts a poor prognosis
and has resulted in prolonged therapy until the viral DNA can
no longer be detected at that site.
Long-Term Therapy with Oral Acyclovir
The use of oral acyclovir therapy for prolonged periods for
6 months has recently been shown to improve neurologic
outcome in children with encephalitis such that over 60%
of children with CNS disease returned to normal function
(188). This finding implies the chronic replication of HSV in
the brain.
Long-Term Follow-up
Children with neonatal HSV infection require frequent and
detailed long-term follow-up. Children with CNS or dis-
seminated disease are at risk for neurologic impairment.
Management of resultant seizure disorders is standard. Even
children with skin, eye, and/or mouth disease are at risk for
neurologic impairment and must be followed carefully.

n = 46 n=2 n = 28 n = 13 n=5 n = 18
100

80
Percentage

60

40

20

0
30 60 30 60 30 60
SEM Disease CNS Disease Disseminated
Disease FIGURE 9.13 Neonatal morbidity among
patients with known outcomes after
Severe Moderate Mild Normal 12 months of life.

Scheld_Ch09.indd 151 2/21/14 5:33 PM

 152 Part II: Viral Infections and Related Disorders

TA B L E 9 . 5
PROGNOSTIC FACTORS IDENTIFIED BY MULTIVARIATE ANALYSES FOR
NEONATES WITH HSV INFECTION

Relative Risk

Dominant Factors Mortality Morbidity

Total group (n 202)

Extent of disease
Skin, eyes, or mouth 1 1
CNS 5.8b 4.4b
Disseminated 33b 2.1b
Level of consciousness
Alert or lethargic 1 NSa
Semicomatose or comatose 5.2b NSa
Disseminated intravascular coagulopathy 3.8b NSa
Prematurity 3.7b NSa
Virus type
1 2.3c 1
2 1 4.9b
Seizures NS 3.0c
Infants with disseminated disease (n 46)
Disseminated intravascular coagulopathy 3.5b NSa
Level of consciousness
Alert or lethargic 1 1
Semicomatose or comatose 3.9b 4.0b
Pneumonia 3.6b NSa
Infants with CNS involvement (n 71)
Level of consciousness
Alert or lethargic 1 NSa
Semicomatose or comatose 6.1b NSa
Prematurity 5.2b NSa
Seizures NS 3.4b
Infants with infection of the skin, eyes, or mouth (n 85)
No. of skin-vesicle recurrences
3 NA 1
3 NA 21b
Virus type
1 NA 1
2 NA 14c,d

a
NS, not statistically significant (p .05); NA, not applicable (no baby with disease confined to the skin,
eyes, or mouth died).
b
p .01.
c
p .05.
d
Because of the correlation between virus type and skin-vesicle recurrence, virus type was not significant in
the multivariate model; however, it was significant as a single factor.
From Whitley RJ, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes
simplex virus infections. N Engl J Med. 1991;324:450454, with permission.

Scheld_Ch09.indd 152 2/21/14 5:33 PM


100
90
80
70
Percentage
60
50
40
30
20
10
0
HSV-1 HSV-2 HSV-1 HSV-2
SEM Disease CNS Disease
Dead Severe Moderate
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 CHAPTER 10 NEUROLOGIC MANIFESTATIONS
OF VARICELLA AND HERPES ZOSTER
JOHN W. GNANN, JR. AND RICHARD J. WHITLEY
Varicella-zoster virus (VZV) causes two clinically distinct diseases.
Varicella (chickenpox), which results from primary infection of
a susceptible individual, is a common, extremely contagious,
and usually benign acute illness that occurs in epidemics and is
characterized by a generalized vesicular rash. Like all other her-
pesviruses, VZV establishes latency following primary infection.
Reactivation of latent VZV results in a localized cutaneous erup-
tion termed herpes zoster or shingles, a common disorder among
the elderly. Both varicella and herpes zoster can be complicated
by central nervous system (CNS) involvement (1).
EPIDEMIOLOGY
Varicella
Humans are the only known reservoir for VZV. Primary
infection occurs when a susceptible individual is exposed to
airborne virus by the respiratory route. Patients with chicken-
pox are contagious for about 48 hours before and 4 to 5 days
after rash onset. Infection is usually acquired after exposure
to another individual with varicella but can also result from
exposure to a patient with herpes zoster. Varicella is highly
infectious; attack rates of 61% to 87% have been observed
following household exposure.
In the United States, varicella epidemics occur annually in
the late winter and early spring, with peak numbers of cases
reported in March. Before the availability of the varicella vac-
cine, about 3.8 million cases of chickenpox occurred each year
in the United States (15 cases per 1,000 population), which
approximately equaled the annual birth cohort (2). Varicella
was predominantly a disease of school-aged children. About
50% to 60% of varicella cases occurred in children between
5 and 9 years of age, and 90% of cases occurred in patients
younger than 15 years. Previous surveys indicated that more
than 90% of the U.S. population was VZV seropositive by
age 20 years (3). Mortality estimates for varicella in children
(ages 1 to 14 years) are 1.4 per 100,000 cases and in adults
31 per 100,000 cases (4).
Introduction of the varicella vaccine in the United States in
1995 resulted in striking changes in the epidemiology of chick-
enpox. By monitoring vaccine and disease activity at three
sentinel sites, the Centers for Disease Control and Prevention
(CDC) showed that vaccine coverage among preschool-
aged children increased from 40% in 1997 to 70% in 1999.
Between 1995 and 1999, varicella incidence declined 80% in
the surveillance areas, with the greatest decline seen in chil-
dren aged 1 to 4 years (5).
Herpes Zoster
Herpes zoster occurs as a result of reactivation of latent VZV.
The annualized incidence of herpes zoster is 1.5 to 3.0 cases
per 1,000 persons in the population (6,7). An incidence
Scheld_Ch10.indd 157
figure of 2.0 cases per 1,000 persons would predict about
500,000 cases of zoster annually in the United States.
Expressed another way, an individual has a 10% to 20%
risk of developing herpes zoster at some point during
his or her lifetime. Increasing age is the most important
risk factor for the development of herpes zoster. There is
an increase in the age-specific incidence of herpes zoster
beginning at around age 55 years; individuals older than
75 years have a zoster incidence of more than 10 cases per
1,000 person-years (7). Zoster occurs with equal frequency
in men and women, with no seasonal association. The
other well-defined risk factor for herpes zoster is altered
cell-mediated immunity. Patients with neoplastic diseases,
especially lymphoproliferative malignancies and organ
transplant recipients, are at very high risk for development
of herpes zoster. Approximately 15% to 30% of patients
with Hodgkin disease experience herpes zoster, compared
with 2% of patients with various solid tumors (8). The dis-
ease occurs in 3% to 10% of renal transplant recipients,
20% to 25% of cardiac transplant recipients, and 20% to
50% of allogeneic hematopoietic stem cell transplant re-
cipients (9). Herpes zoster is also seen with increased fre-
quency in persons infected with human immunodeficiency
virus (HIV) and often serves as an initial marker of disease
in that population (10). A longitudinal study of a cohort
of HIV-seropositive men in San Francisco demonstrated
an incidence of zoster of 29.4 cases per 1,000 person-
years, compared with 2.0 cases per 1,000 person-years in
a matched population of HIV-seronegative controls (11).
INFECTIOUS AGENT
VZV shares structural characteristics with other members
of the family Herpesviridae. The complete virion is approxi-
mately 180 to 200 nm in diameter. It is composed of an ico-
sahedral nucleocapsid measuring 90 to 95 nm in diameter, an
amorphous tegument, and a lipid-containing envelope with
glycoprotein spikes (12). The VZV genome consists of a lin-
ear, double-stranded DNA molecule containing 125,000 base
pairs with guanosine-plus-cytosine content of 46% (13).
The genome is organized in a manner similar to that of
other herpesviruses, having unique long (UL; 104.5 kb) and
unique short (US; 5.2 kb) regions flanked by inverted repeats.
VZV encodes approximately 69 polypeptides, including seven
glycoproteins.
VZV can be propagated in vitro in a limited number of
continuous and discontinuous cell culture monolayers, mostly
of human or simian origin. In human embryonic lung fibro-
blasts, cytopathic effects begin as a focal process with subse-
quent cell-to-cell spread. Approximately 8 to 10 hours after
infection, virus-specific immunofluorescence can be detected
in cells adjacent to the initial focus of infection. VZV is highly
cell associated, with very limited release of infectious virions
into the media.
157
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 158 Part II: Viral Infections and Related Disorders
PATHOGENESIS AND PATHOLOGY
Pathogenesis of Varicella
Varicella is transmitted via the respiratory route. Virus in air-
borne droplets enters the susceptible host via mucosal surfaces
of the conjunctiva, oropharynx, or upper respiratory tract.
VZV undergoes an initial round of replication, presumably in
cervical lymph nodes (14). When local immune responses are
overcome, a primary viremia occurs, with widespread dissemi-
nation of VZV to the reticuloendothelial system and possibly
to epithelial cells of other organs. VZV then undergoes mul-
tiple cycles of replication, resulting in a second viremic phase
(about 1 week after the initial viremia) that is accompanied
by the onset of clinical symptoms. VZV localizes to endothe-
lial cells of cutaneous capillaries and then extends to epithelial
cells of the epidermis, where replication results in formation of
the characteristic vesicles. Viremia and new vesicle formation
continue for 3 to 5 days and then terminate when humoral and
cellular immune responses appear.
Pathology of Varicella
The cutaneous manifestations of varicella begin with hema-
togenous infection of the endothelial cells of cutaneous blood
vessels. VZV then begins to replicate in the skin, leading to
ballooning degeneration of epithelial cells in the prickle cell
(malpighian) layer of the epidermis. Local collections of extra-
cellular edema fluid result in acantholysis, with elevation of the
stratum corneum to form a clear vesicle. Multinucleated giant
cells are found at the base of the lesion. Infected cells contain
eosinophilic intranuclear inclusion bodies (Cowdry type A
inclusions) surrounded by a clear zone. A perivascular infil-
tration of mononuclear cells is seen around cutaneous vessels.
The vesicular fluid becomes cloudy as it accumulates inflam-
matory cells and desquamated epidermal cells. The vesicular
fluid is resorbed, resulting in drying and crusting of the lesion.
Healing occurs with regeneration of the epithelial cell layers.
Pathogenesis of Herpes Zoster
As VZV replicates in the skin during acute varicella, some
virions are transported via sensory nerves to the correspond-
ing dorsal root ganglia (15). The virus establishes a latent
infection within the ganglion, preferentially infecting satellite
cells rather than neurons (16). An alternative explanation is
that VZV may reach the ganglion by viremic spread. VZV
may periodically reactivate and undergo limited replication,
but replication is suppressed by the immune response before
any clinical symptoms result (17,18). The specific immune
responses that limit reactivation of VZV from the sensory gan-
glia are poorly understood. The most important factor that
predisposes to the development of herpes zoster appears to be
decline or suppression of VZV-specific cellular immunity. This
may occur naturally with aging or be induced by immunosup-
pressive illness or therapy. Following reactivation and replica-
tion in the ganglion, virus travels along the sensory nerve to
the skin, where it again replicates in epithelial cells, produc-
ing the characteristic dermatomal vesicular rash of shingles.
Unlike the lesions of varicella, in which different stages are
seen simultaneously, most zoster lesions are in the same stage
of development. A limited viremia occurs during many epi-
sodes of herpes zoster, reflected by the appearance of a few
extradermatomal vesicles.
Scheld_Ch10.indd 158
Pathology of Herpes Zoster
Replication of VZV in the sensory ganglion results in intense
inflammation, neuronal destruction, and focal hemorrhage.
Less severe inflammatory changes often occur in the adjacent
ganglia. Occasionally, inflammation and necrosis also extend
to the anterior nerve root, resulting in localized motor neu-
ropathy. These changes are accompanied by lymphocytic
pleocytosis. Movement of virus from the ganglion down the
sensory nerve to the skin produces acute inflammation of the
nerve (19). Virus reaching the skin replicates in epithelial cells
of the epidermis, producing pathologic changes identical to
those described for varicella. Inflammatory changes in the sen-
sory nerve persist for months and may result in demyelination,
wallerian degeneration, and sclerosis.
CLINICAL MANIFESTATIONS
Natural History of Varicella
Varicella is generally a benign disease in healthy children,
although symptoms are often more severe in adolescents and
adults. Fewer than 5% of primary VZV infections are subclin-
ical. Symptoms develop after an incubation period of about
15 days (range, 10 to 20 days). A prodrome of fever, malaise,
headache, and anorexia is variably present, occurring more
commonly among older children and adults and lasting 1 to
2 days. A transient scarlatina-like rash is occasionally noted
just before or coincident with the appearance of the varicella
lesions. The lesions first appear on the head, then the trunk, and
finally the extremities. The greatest concentration of lesions is
on the trunk and proximal extremities. The rash of varicella is
characterized by rapid evolution of lesions over 8 to 12 hours
and by successive crops of new lesions. Consequently, lesions of
all stages are present simultaneously on involved skin surfaces.
Lesions begin as pink macules that quickly become papular
and evolve into fragile vesicles 1 to 4 mm in diameter sur-
rounded by a zone of erythema. As inflammatory cells migrate
into the vesicular fluid, the lesions become pustules; these are
often centrally umbilicated. The pustules become crusted and
the crusts detach after 1 to 3 weeks, usually healing without
scarring. Vesicles also appear on mucosal surfaces and rapidly
evolve into shallow ulcerations. New lesion formation contin-
ues for 2 to 4 days, accompanied by pruritus, fever (100 to
102F), headache, malaise, and anorexia. The rash peaks on
about the fifth day, with an average lesion count of 250 to 500;
fewer lesions are seen in children younger than 5 years (20).
Older children and secondary cases within a household tend to
have higher lesion counts and higher fever.
The most common complication of varicella in otherwise
normal children is bacterial superinfection (usually staphylo-
coccal or streptococcal infection) that can occasionally prog-
ress to serious necrotizing cellulitis (1). Varicella pneumonia is
rare in children but occurs more often in adults (21). Pregnant
women with chickenpox may be at especially high risk for
severe varicella pneumonia. Neonatal varicella can occur
when the mother develops chickenpox within a period of
5 days before to 2 days after delivery. The infected neonate can
develop severe disseminated varicella with a mortality of 20%
to 30%. Maternal varicella occurring during the first trimester
of pregnancy has been associated with congenital abnormali-
ties, but the risk appears low (about 1% to 2%) (1).
In immunocompromised children, varicella is a serious and
potentially fatal infection. Children at highest risk are those
with acute leukemia, although children with other malignan-
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 Chapter 10: Neurologic Manifestations of Varicella and Herpes Zoster
cies and those on cytotoxic or immunosuppressive medications
(including high-dose corticosteroids) can also develop compli-
cations. Immunocompromised children may develop severe
hemorrhagic or necrotic skin lesions (purpura fulminans or
hemorrhagic varicella) or severe bacterial superinfection.
Persistent viremia can result in dissemination of VZV, produc-
ing pneumonitis, hepatitis, or encephalitis. A chronic form of
varicella has been reported in HIV-infected children.
Neurologic Complications of Varicella
The incidence of CNS complications with varicella is reported
to be 1 to 3 per 10,000 cases (3,21). Because many uncompli-
cated cases of varicella do not come to medical attention, any
calculation of the frequency of complications is likely to be an
overestimation. The CNS manifestations most frequently asso-
ciated with chickenpox are cerebellar ataxia and encephalitis
(22,23). Uncommon neurologic complications include trans-
verse myelitis, aseptic meningitis, strokes, and Guillain-Barr
syndrome (23). Optic neuritis has been reported as a rare
complication of varicella in both pediatric and adult patients,
with good visual recovery expected in most cases (24). Reye
syndrome, a triad of acute hepatic failure, encephalopathy,
and hypoglycemia, was previously associated with varicella
(and with other viral infections) but is now known to be more
specifically related to salicylate therapy in febrile children.
However, many cases of Reye syndrome are included in older
reviews of varicella encephalitis, resulting in misleading esti-
mates of incidence and mortality.
Cerebellar Ataxia
Cerebellar ataxia, the most common neurologic abnormal-
ity associated with varicella, is diagnosed in approximately
1 per 4,000 cases of chickenpox (21). Children can develop
ataxia from several days before to 2 weeks after the onset
of the rash, although neurologic symptoms most often
occur simultaneously with the rash (23). Symptoms include
vomiting, headache, and lethargy accompanied by ataxia.
Fever, nuchal rigidity, and nystagmus occur in about 25%
of patients. Seizures are rare and suggest a more diffuse
encephalitis. In cases of ataxia presenting before the devel-
opment of rash, the correct diagnosis may not be clinically
apparent unless an association is made with recent varicella
exposure.
The extent of the diagnostic evaluation in patients with
varicella-associated cerebellar dysfunction should be gov-
erned by the severity of the illness and the degree of certainty
of the diagnosis. In uncomplicated cases, the clinical presenta-
tion alone is sufficient to establish the diagnosis, and no fur-
ther evaluation is necessary. In more complicated situations,
a cerebrospinal fluid (CSF) examination, an electroencephalo-
gram (EEG), and magnetic resonance imaging (MRI) scan of
the brain usually are warranted. The CSF is frequently nor-
mal, but a moderate lymphocytic pleocytosis (100 cells/L)
with mildly elevated protein and normal glucose levels may
occur in 20% to 30% of patients (23). The EEG demonstrates
diffuse slow-wave activity in approximately 20% of patients
and normalizes as the symptoms resolve (23). Few data are
available regarding the utility of computed tomographic (CT)
or MRI scan in diagnosing varicella-associated cerebellar
ataxia.
Cerebellar ataxia associated with chickenpox is self-
limited, and most abnormalities completely resolve within 1 to
3 weeks. Mortality is essentially zero, and deaths that occur
are usually attributed to the development of nonneurologic
complications such as pneumonia (22,23).
Scheld_Ch10.indd 159
159
The pathogenesis of this syndrome is unknown, partly
because of the lack of necropsy studies in this nonfatal illness.
The two pathogenic mechanisms that have been proposed are
direct viral involvement of the cerebellum or a parainfectious,
immunologically mediated demyelinating process analogous to
that seen with other viral infections. Recovery of VZV from
brain or CSF by culture has not been reported in varicella-
associated cerebellar ataxia. VZV antibodies have been detected
in the CSF of patients with CNS abnormalities in association
with varicella but were absent in children who had varicella
but no neurologic symptoms, perhaps reflecting intrathecal
antibody production (25). Analysis of CSF using polymerase
chain reaction (PCR) revealed VZV-specific DNA in three of
five children with varicella cerebellitis (26). These observations
suggest that VZV replication within the CNS does occur, but
detailed studies are lacking and the evidence for viral invasion
of the cerebellum is circumstantial.
Encephalitis
A less common but more severe CNS complication of chicken-
pox is encephalitis or cerebritis. The incidence of encephalitis
is estimated to be 1 to 2 cases per 10,000 cases of chicken-
pox (3). Most cases of encephalitis occur in children, but the
incidence is highest in adults (older than 20 years) and infants
(younger than 1 year). Neurologic symptoms may occur from
2 weeks before to several weeks after the varicella rash (most
often about 1 week after), and the onset may be abrupt or
gradual (22,27). Headache, fever, vomiting, and an altered
sensorium are the usual presenting symptoms (23,28). Seizures
occur in 29% to 52% of patients (23). Focal neurologic abnor-
malities can include ataxia, hypertonia or hypotonia, hyperre-
flexia or hyporeflexia, positive plantar reflexes, hemiparesis,
and sensory changes (23,28).
The CSF from patients with varicella-associated cerebri-
tis is frequently abnormal, with elevated opening pressure,
a mild to moderate lymphocytic pleocytosis (usually 100
cells/L), elevated protein (50 to 100 mg/dL), and normal
glucose (22). The EEG is often abnormal, showing slow-
wave activity consistent with a diffuse encephalitis. Focal
EEG abnormalities suggestive of epileptiform activity may
occur even without clinical seizures. In patients who do have
seizures, these EEG abnormalities tend to persist and are
present in 43% of follow-up studies at 1 year. Abnormalities
observed by CT in patients with varicella encephalitis have
included cerebral or cerebellar edema and areas of low at-
tenuation consistent with demyelination. MRI abnormalities
in children with postvaricella encephalitis have included dif-
fuse gray and white matter lesions or bilateral basal ganglia
lesions (29).
The reported mortality for varicella encephalitis has var-
ied from 5% to 35%, although many of these series included
cases of Reye syndrome (22,23,28). The actual mortality
rate for varicella cerebritis is probably less than 10%, with
complete or nearly complete recovery expected in most cases.
Long-term sequelae may be present in 10% to 20% of sur-
vivors (23). In a series of 59 cases of varicella with CNS
involvement, the mortality rate was 5% (22). Two of the three
deaths were associated with pneumonia, and 80% of the sur-
vivors were discharged from the hospital without detectable
sequelae.
The role of active viral replication in the CNS in varicella
encephalitis remains uncertain (30). Postmortem studies of
the brain have shown a wide range of histopathologic find-
ings (22,23,31). Diffuse cerebral edema is generally present.
Perivascular infiltration of mononuclear cells and demyelin-
ation have been seen in some cases, the latter suggesting a
postinfectious demyelinating process. Other cases have shown
2/21/14 5:34 PM
 160 Part II: Viral Infections and Related Disorders
focal hemorrhagic lesions. Intranuclear viral inclusions have
been observed only rarely in the brain following varicella, usu-
ally in immunocompromised patients (31).
Transverse Myelitis
On rare occasions, varicella has been associated with an isolated
weakness of the lower extremities, sphincter dysfunction, abnor-
mal deep tendon reflexes, and extensor-plantar reflexes (32). The
CSF is characterized by a lymphocytic pleocytosis and elevated
protein level with a normal glucose level. The completeness of
recovery is variable. The pathogenesis of varicella myelitis is
not known, although cases have been published in which VZV
DNA was detected in CSF by PCR, suggesting that active viral
invasion of the spinal cord may be involved (33).
Aseptic Meningitis
Aseptic meningitis has been reported as a complication of vari-
cella (23). Meningismus without evidence of cerebral or cere-
bellar dysfunction is suggestive of the diagnosis, and complete
recovery is expected. CSF findings are typical of viral meningitis,
with mild lymphocytic pleocytosis, slight elevation in the protein
content, and normal glucose level. VZV has not been cultured
from the CSF in this setting; PCR would be an appropriate diag-
nostic test. It is probably appropriate to consider CNS involve-
ment with varicella as a spectrum, with aseptic meningitis the
most benign manifestation and encephalitis the most serious.
Stroke Syndromes
Arterial ischemic strokes are a well-recognized complication
of herpes zoster ophthalmicus (HZO) but can also occur after
varicella (34,35). By some estimations, young children with ar-
terial ischemic strokes are threefold more likely than controls
to have recently had varicella. In a prospective cohort study, 22
(31%) of 70 children with arterial ischemic strokes had vari-
cella within the preceding 12 months, compared with 9% in
the healthy population (36). Children with strokes and recent
varicella infection had higher rates of basal ganglia infarction,
abnormal cerebral vascular imaging, and recurrent ischemic
attacks (p .05 for all) (36). The syndrome typically occurs
in otherwise healthy, immunocompetent children (median age,
5 years). The median interval between varicella infection and
the onset of neurologic deficits is 2 months (37). The children
usually present with hemiplegia, and angiography reveals vas-
culopathy of the branches of the middle cerebral artery (MCA).
A B
FIGURE 10.1 Anterior (A, left) and posterior (B, right) views of a patient with herpes zoster in the right
T3 dermatome. The vesicular eruption terminates at the midline.
Scheld_Ch10.indd 160
MRI typically demonstrates unilateral infarctions in the MCA
distribution (38,39). In one fatal case, histopathology revealed
active granulomatous arteritis of the MCA with lymphocytic
inflammatory infiltrate and VZV antigens in the smooth muscle
layer (37). Patients have been treated with intravenous acyclo-
vir and corticosteroids, but no data from controlled studies are
available to assess the efficacy of these treatments. Most chil-
dren with hemiplegia following varicella infection have good
neurologic recovery (which is a much better prognosis than
that associated with strokes in adults following HZO).
Natural History of Herpes Zoster
The inflammatory changes that occur in the sensory gan-
glion and nerve as VZV reactivates are manifested by pain
in the corresponding dermatome. The patient may report
sensations ranging from mild itching or tingling to severe
pain that precedes the appearance of the skin lesions by 1 to
5 days (or occasionally longer). Constitutional symptoms are
reported by fewer than 5% of patients during the prodromal
phase. The cutaneous eruption of herpes zoster is unilateral
and does not cross the midline. The rash appears in the skin
segment innervated by a single sensory ganglion (Fig. 10.1).
Overlap of lesions into adjacent dermatomes occurs in 20%
of patients. Scattered cutaneous vesicles beyond the primary
or adjacent dermatomes appear in about one third of patients
with herpes zoster infection and have no prognostic signifi-
cance. Disseminated VZV infection with visceral involvement
is extremely rare in immunocompetent patients with herpes
zoster infection, although occasional cases of encephalitis
and myelitis have been reported. Herpes zoster appears with
increased frequency in certain dermatomes, and this is thought
to reflect the distribution of skin lesions during varicella (18).
The most common sites for herpes zoster are the thoracic der-
matomes (50% of cases), followed by cervical (15%), lumbar
(15%), and sacral (5%) dermatomes (18). About 15% of zos-
ter cases occur in cranial nerve dermatomes, with most cases
involving the first division of the trigeminal nerve (HZO).
Ocular involvement can be a serious complication of HZO.
Conjunctivitis is common and benign, but more serious ocu-
lar manifestations, such as keratitis, scleritis, and iridocyclitis,
may develop in 50% to 70% of patients with HZO (40).
Skin changes begin with an erythematous maculopapular
rash, followed by the appearance of clear vesicles. New vesicle
formation typically continues for 3 to 5 days, followed by lesion
2/21/14 5:34 PM
 Chapter 10: Neurologic Manifestations of Varicella and Herpes Zoster 161

pustulation and scabbing. The extent of involvement can range cation of herpes zoster is chronic pain, or PHN, which occurs
from a few vesicles to a confluent eruption filling the entire with sufficient frequency that it can be considered a part of the
dermatome. Most lesions are crusted by day 10, but complete natural history of the disease (48).
skin healing may require 2 to 4 weeks. Unlike varicella, herpes
zoster is associated with a significant risk of skin scarring and Encephalitis
permanent pigmentation changes. Skin necrosis and gangrene
Herpes zoster can be complicated by acute encephalitis that usu-
in the involved dermatome can occur but are more commonly
ally occurs a few days after the onset of rash but has been re-
encountered in immunocompromised patients.
ported from days to weeks before or after the skin eruption (49).
During the acute phase of herpes zoster, most patients expe-
Encephalitis has occasionally been documented in the absence of
rience dermatomal pruritus and pain, which can be severe. The
apparent cutaneous zoster and in patients who received appro-
acute neuritis is variably described as an aching, burning, or
priate antiviral therapy during the acute episode of herpes zoster
stabbing pain. Many patients complain of headache, photopho-
(50,51). Immunocompromised patients are clearly at increased
bia, and malaise, but significant fever is rare. CSF examination
risk for the development of encephalitis (49,52). Other markers
(which is not routinely necessary) reveals a lymphocytic pleocy-
of increased risk for CNS involvement include zoster in a cranial
tosis and increased protein concentration; VZV can occasion-
nerve dermatome or the presence of cutaneous dissemination.
ally be cultured from the CSF. Although the skin usually heals
The mortality of herpes zosterassociated encephalitis has been
in 2 to 4 weeks, pain (postherpetic neuralgia [PHN]) persists for
reported to be from 0% to 25%, and the true incidence is prob-
longer than 1 month in 20% to 70% of patients with herpes
ably about 10% (49). The clinical presentation is most often an
zoster, with elderly patients experiencing the highest frequency
acute or subacute delirium accompanied by few focal neurologic
of chronic pain. Although herpes zoster is most common
signs (6,49,53). Other findings can include headache, meningis-
among older adults, the disease can occur in patients of any age.
mus, fever, ataxia, and seizures.
Immunocompetent children and young adults with herpes zos-
CSF examination reveals increased opening pressure,
ter tend to have less extensive cutaneous eruptions, less severe
increased protein, and a lymphocytic pleocytosis. Caution must
pain, and a much lower risk for chronic pain.
be used in interpretation of the spinal fluid findings, because
Patients with deficiencies in cell-mediated immunity have
pleocytosis is also present in about half of patients with
an increased incidence of herpes zoster and a higher risk for
uncomplicated herpes zoster (54). Positive VZV cultures have
complications. In immunocompromised patients, zoster causes
been obtained from CSF in patients with zoster encephalitis,
more severe skin involvement within the dermatome and may
and cells containing VZV-specific antigens have been identified
be accompanied by viremia with cutaneous or visceral dissemi-
in CSF. Serologic assays have revealed increased levels of VZV-
nation. Without antiviral chemotherapy, cessation of new vesi-
specific intrathecal antibodies (25). EEGs show diffuse abnor-
cle formation does not occur until about day 8, pustulation on
malities with an excess of slow-wave activity (53). Images
day 9, and scabbing on day 18 (41). Patients with herpes zoster
obtained by CT are generally nondiagnostic; published experi-
infection at highest risk for dissemination are those with lym-
ence with MRI in this syndrome is limited. PCR is the most
phoproliferative malignancies or those who recently received
sensitive diagnostic tool for zoster encephalitis. In one study
induction chemotherapy (8,42). Without antiviral treatment,
of seven patients with herpes zoster with neurologic symp-
the reported incidence of cutaneous dissemination in immuno-
toms (meningitis or encephalitis), PCR performed on CSF was
compromised populations is 6% to 26% (43). In most patients,
positive for VZV DNA in all cases (26). The frequency of PCR
dissemination is limited to the skin and does not substantially
positivity in CSF from patients with uncomplicated cutaneous
alter the prognosis. However, 10% to 50% of patients who
herpes zoster remains to be established.
develop cutaneous dissemination also have evidence of visceral
As with virtually all neurologic syndromes caused by VZV,
dissemination (such as pneumonitis, meningoencephalitis, or
there is controversy regarding the relative contributions of
hepatitis), which carries a much more serious prognosis. Even
direct viral replication and postinfectious immunopathologic
with the availability of antiviral chemotherapy, the mortality
changes in the pathogenesis of herpes zosterassociated
rate for zoster with visceral dissemination is 5% to 15%, with
encephalitis. Histologic studies have shown demyelination
most deaths attributable to pneumonitis (44). Visceral VZV
with mononuclear cell infiltrates, especially in white matter
infection occurring without any evidence of skin lesions is
(19,55). In brain tissue from patients who died with herpes
uncommon. However, several patients with acquired immu-
zosterassociated encephalitis, intranuclear inclusion bodies
nodeficiency syndrome (AIDS) and VZV myelitis or encepha-
were often evident, and viral particles have been visualized
litis but without clinically apparent zoster have been reported.
by electron microscopy (49). Supporting the hypothesis that
Another syndrome unique to the immunocompromised host is
active viral invasion and replication play a role, there are
chronic cutaneous VZV infection, sometimes associated with
many anecdotal reports of rapid clinical improvement after
acyclovir-resistant virus.
initiation of acyclovir therapy (52).
Chronic VZV encephalitis is seen almost exclusively in
immunocompromised patients, especially patients with AIDS
Neurologic Complications of Herpes Zoster with marked depletion of CD4 lymphocytes (56). The
onset of the encephalitis may occur months after an episode
Neurologic complications of herpes zoster can occur during of herpes zoster and 30% to 40% of these patients have no
the acute eruption (e.g., segmental motor paresis) or may ap- recognized history of cutaneous VZV infection, making the
pear weeks to months after the herpes zoster rash has resolved diagnosis more difficult. Pathologic studies reveal multifocal
(e.g., delayed contralateral hemiparesis) (45). Neurologic com- leukoencephalopathy, with lesions in the white matter near the
plications appear more often in immunocompromised patients, graywhite junction, small vessel vasculitis, and demyelination
including patients with HIV infection. Several pathologically (46). The clinical presentation is usually subacute with head-
distinct syndromes have been defined, including large and ache, fever, mental status changes, and seizures. Patients may
small vessel vasculopathies and ventriculitis (46). Investigators have focal neurologic defects including aphasia, hemiplegia,
have also described myelitis and polyradiculitis, as well as a and visual-field cuts (5759). MRI demonstrates plaquelike
variety of cranial and peripheral nerve palsies in association lesions in deep white matter, changes consistent with demy-
with herpes zoster (47). The most common neurologic compli- elination, and late development of ischemic or hemorrhagic

Scheld_Ch10.indd 161 2/21/14 5:34 PM

 162 Part II: Viral Infections and Related Disorders
infarcts of cortical and subcortical gray and white matter
(60,61). CSF examination reveals mild mononuclear pleocy-
tosis. VZV DNA has been amplified from the CSF of patients
with chronic encephalitis using PCR (62,63). Patients often
follow a clinical course of progressive deterioration and death,
although anecdotal reports have suggested some benefit from
high-dose intravenous acyclovir therapy (46,64). Other VZV-
induced neurologic disorders described in patients with AIDS
include multifocal leukoencephalitis (57), ventriculitis (65),
myelitis and myeloradiculitis (65,66), and focal brainstem
lesions (67).
Herpes Zoster Ophthalmicus with Delayed
Contralateral Hemiparesis
Hemiparesis is a rare but serious complication of herpes zos-
ter that has been reported in immunocompetent and immu-
nocompromised patients (68), including both children and
adults (69). The mean interval from rash to onset of neuro-
logic symptoms in adults is about 7 weeks, although intervals
of up to 6 months have been reported. The typical presenta-
tion is headache and hemiplegia occurring in a patient with
a history of recent HZO (70). The mortality rate is 20% to
25%. There is a high probability of permanent neurologic se-
quelae among survivors (71).
CSF examination reveals mononuclear cell pleocytosis (71).
Imaging studies (CT or MRI) show changes consistent with
brain infarction (72,73). Arteriography is usually diagnostic
and demonstrates inflammation, narrowing, and thrombosis
of the proximal branches of the anterior cerebral artery or
the MCA (74). Rare cases of posterior circulation strokes fol-
lowing herpes zoster infection involving a cervical dermatome
have been reported (75). The pathogenesis of this unusual dis-
order is thought to be direct VZV invasion of cerebral arteries
by extension along intracranial branches of the trigeminal
nerve. This results in inflammation of the internal carotid
artery or one of its branches on the side ipsilateral to the rash.
The local inflammatory response and thrombosis produce vas-
cular occlusion or distal embolization, resulting in infarction
and contralateral hemiparesis. Pathologic studies have demon-
strated a necrotizing arteritis of large and small cerebral vessels
with thrombosis in the proximal anterior cerebral artery or
the MCA (76). Although VZV has not been cultured from the
areas of inflammation, VZV-specific antigens and DNA have
been demonstrated in the smooth muscle cells of the media of
affected vessels (77).
Both acyclovir (78) and corticosteroids (79) have been used
in an effort to treat this syndrome, although no therapy has
been evaluated in a controlled or prospective fashion. Antiviral
therapy is warranted because of the demonstrated presence of
VZV in the inflamed vessels, but benefit of therapy is difficult
to assess, because irreversible cerebral infarction has usually
occurred by the time the diagnosis is made.
Myelitis
Herpes zosterrelated myelitis is thought to result from direct
invasion of the spinal cord by VZV, with unilateral motor and
posterior column dysfunction evolving into paraplegia (33).
The disorder most often follows thoracic herpes zoster, with
weakness developing in the same spinal cord segment as the
rash. Neurologic symptoms begin to develop an average
of 12 days after the onset of the rash (80). However, VZV
myelitis in patients with no history of antecedent zoster has
also been reported (81,82). Immunocompromised patients are
at increased risk for postzoster myelitis, and the syndrome is
well described in patients with AIDS (58,83). The most com-
mon initial manifestation is bladder dysfunction (e.g., urinary
Scheld_Ch10.indd 162
retention), often accompanied by weakness of the lower ex-
tremities, asymmetric reflexes, and sensory disturbances (80).
Prognosis for recovery of neurologic function has been vari-
able. In severe cases, the myelopathy can progress to a partial
Brown-Squard syndrome or total cord transection. MRI has
been useful in diagnosing myelitis, with abnormal signal evi-
dent in the cord at the level of inflammation (33,81,8486).
Pathologic studies have demonstrated necrosis of the spinal
cord, with posterior column involvement, focal demyelination,
and perivascular inflammation. The presence of intranuclear
inclusion bodies and positive immunofluorescence stains
for VZV antigens in spinal cord tissue are evidence for the
direct role of the virus in this disease (80). VZV DNA has
been amplified from the spinal fluid of patients with myeli-
tis by PCR techniques (33,81). Although there are anecdotal
reports of significant neurologic improvement with antiviral
treatment, this therapeutic approach has not been studied in a
prospective fashion (33,87).
Cranial and Peripheral Nerve Palsies
Segmental motor paresis complicates about 2% to 3% of cases
of dermatomal herpes zoster. Weakness, which may be abrupt
in onset, usually begins within a few days to 2 weeks after the
onset of the rash. The involved muscle groups are those whose
innervation corresponds with that of the affected dermatome.
Thus, thoracic zoster may be associated with paralysis of limb or
trunk muscles, while sacral zoster may result in bladder or anal
dysfunction. The peripheral motor neuropathy is caused by viral
invasion and inflammatory changes affecting motor neurons in
the anterior horn. Weakness is usually transient, and 75% to
85% of patients can expect total resolution, although a few pa-
tients experience prolonged paralysis with muscle atrophy.
Twelve percent to thirty percent of patients with herpes
zoster involving a cephalic dermatome develop oculomotor
or facial palsies. HZO can be associated with partial or com-
plete palsies of the third, fourth, or sixth nerve. Facial palsy
(sometimes including loss of taste on the anterior two thirds
of the tongue) may accompany otic zoster (Ramsay Hunt
syndrome) or zoster involving the second or third cervical
dermatomes (88,89).
Acute Retinal Necrosis
VZV-associated acute retinal necrosis (ARN) has been described
in both immunocompetent and immunocompromised persons.
Since the advent of the AIDS epidemic, a more aggressive variant
of this disease (sometimes termed rapidly progressive herpetic
retinal necrosis [RPHRN]) has been identified (90,91). Visual
changes are usually noted weeks to months after the antecedent
herpes zoster. ARN can follow either HZO or herpes zoster in
a remote dermatome. Furthermore, retinal involvement is bilat-
eral in more than half of cases, suggesting that VZV reaches the
CNS via hematogenous spread, possibly with extension along
nerve pathways within the anterior visual system (91). VZV ret-
initis presents with multifocal necrotizing lesions, often initially
involving the peripheral retina. The granular, nonhemorrhagic
lesions rapidly extend and coalesce, accompanied by relatively
little intraocular inflammation (92).
In patients with AIDS, VZV retinitis rapidly progresses to
full-thickness retinal necrosis, usually with retinal detachment,
resulting in blindness in 75% to 85% of involved eyes (91).
Because the involved eye is rarely salvageable in HIV-infected
patients with RPHRN, the goal is to try to prevent disease pro-
gression in the uninvolved eye. Intravenous acyclovir alone is
ineffective (92). Some experts recommend intravenous therapy
with ganciclovir or foscarnet (or a combination of the two) (93).
Anecdotal success with cidofovir or with intravitreal injections
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 Chapter 10: Neurologic Manifestations of Varicella and Herpes Zoster
of ganciclovir has also been reported (94). Results of antiviral
therapy for VZV retinitis in HIV-infected patients, regardless of
regimen, have been disappointing.
ARN in immunocompetent patients is a less virulent disease
and responds better to antiviral therapy. In this setting, acyclo-
vir is clearly beneficial for preserving useful vision (95). A sug-
gested antiviral regimen for ARN in the otherwise healthy host
is intravenous acyclovir 10 to 15 mg/kg every 8 hours for 10 to
14 days, followed by oral valacyclovir 1 g three times daily for
4 to 6 weeks, although this treatment approach has not been
studied in a controlled fashion.
Postherpetic Neuralgia
PHN is the term traditionally used to describe the chronic
dermatomal pain that persists after the cutaneous eruption of
herpes zoster has healed. PHN has been estimated to occur fol-
lowing 10% to 40% of zoster cases; some of the variability in
incidence calculations can be attributed to differing definitions
of PHN (6,18,96). Ragozzino et al. (6) reported that 9.3%
of the patients with herpes zoster in their study had PHN;
of these patients, 22% (or 2% of the total study population)
had pain that persisted for longer than 12 months. The inci-
dence (and possibly the duration) of PHN correlates directly
with patient age. Pain that persists for longer than 1 year
has been noted in 4%, 22%, and 47% of patients younger
than 20 years, older than 55 years, and older than 70 years
of age, respectively (6,97,98). Within the affected dermatome,
patients with PHN experience a variety of sensory abnormali-
ties (paresthesias, dysesthesias, allodynia) and neuralgic pain
of varying quality and severity. The pathogenesis of PHN
is not completely understood but apparently involves both
peripheral and central mechanisms. Experimental evidence
suggests that the damaged sensory nerve develops a lowered
activation threshold and superphysiologic responses to distal
stimuli. This excessive input from the peripheral sensory nerve
results in hyperexcitability of the dorsal horn, producing exag-
gerated central responses that are perceived as pain (99).
Successful treatment of PHN often requires a multifaceted
approach (48,100,101). Opioid analgesics are the mainstay
of therapy during the early phases of neuralgic pain. A clini-
cal trial with oxycodone for patients with PHN demonstrated
a significant level of pain reduction (67% of those receiv-
ing oxycodone vs. 11% receiving placebo), as measured by
a visual analog scale (102). Long-acting opioid preparations
(oral or transdermal) are preferable to short-acting analge-
sics for management of chronic PHN. Several randomized,
controlled clinical trials have shown tricyclic antidepressants
(including amitriptyline, nortriptyline, and desipramine) to
be effective in reducing the pain of PHN, either as a single
agent or in combination with other drugs (103,104). Because
tricyclic antidepressants are often associated with sedation
and anticholinergic side effects, treatment should begin with a
relatively low dose at bedtime, with a gradual increase in dos-
age as required and tolerated. Clinical trials have shown the
anticonvulsant gabapentin to significantly reduce established
PHN when used alone or in combination with other modali-
ties (105). For treatment of PHN, physicians should initiate
gabapentin at a dose of 300 mg three times daily and escalate
as required, watching for adverse effects such as somnolence,
dizziness, and ataxia. The adverse effects of these medica-
tions can be additive (such as sedation due to opioids, tricyclic
antidepressants, and gabapentin), especially in elderly patients.
Topical application of capsaicin provides relief of PHN for
some patients, but others find the local stinging and burning
associated with application of capsaicin cream to be intolera-
ble (106). Transdermal administration of lidocaine via patches
has been shown to reduce PHN in controlled trials (107,108).
Scheld_Ch10.indd 163
163
Topical treatments should be used only on intact, healed skin.
In a controlled clinical trial of 277 patients with intractable
PHN, intrathecal injection of 60 mg of methylprednisolone
acetate once weekly for 4 weeks resulted in significant pain re-
duction (109); these promising initial results await validation.
Zoster Sine Herpete
Clinicians occasionally encounter patients who present with
zoster-like neuropathic pain but never develop the character-
istic dermatomal rash (110,111). Recent detailed studies of
a few patients presenting with dermatomal pain have estab-
lished that some of these cases are due to VZV reactivation.
Patients with this syndrome, termed zoster sine herpete, have
rising titers of VZV-specific antibody in both serum and CSF
and have VZV DNA in CSF and peripheral blood mononu-
clear cells detectable by PCR (112,113). Because there is no
easy way to make the diagnosis, the incidence of zoster sine
herpete is not known. In anecdotal reports, responses to anti-
viral therapy have been inconsistent.
DIAGNOSIS
The appearance of varicella is quite distinctive, and in most
cases, a clinical diagnosis is accurate and reliable. The presenta-
tion of a child with mild constitutional symptoms, a diffuse ve-
sicular rash, and no prior history of chickenpox (or vaccination)
is strongly suggestive of the diagnosis, especially during an epi-
demic. Other infections that can occasionally mimic chickenpox
include vesicular exanthems caused by coxsackievirus, dissemi-
nated herpes simplex virus (HSV) infection, diffuse impetigo,
or rickettsialpox. Noninfectious cutaneous diseases that may
resemble varicella include contact dermatitis and dermatitis
herpetiformis. Herpes zoster, with its characteristic dermatomal
vesicular rash, is also readily diagnosed on the basis of clini-
cal appearance. The diagnosis may be less apparent in patients
who present with dermatomal neuralgia before the emergence
of skin lesions. The skin disease that is most commonly con-
fused with herpes zoster is zosteriform HSV infection (usually
in the sacral area), which can closely mimic the appearance of
shingles. Contact dermatitis can also occasionally resemble her-
pes zoster, but it tends to cross dermatomal boundaries.
There is no asymptomatic shedding of VZV, as there is with
HSV and cytomegalovirus. Therefore, identification of VZV
virions, antigens, or nucleic acids from cutaneous lesions or
nonneuronal tissues is diagnostic of active infection. VZV can
be cultured by inoculation of vesicular fluid into monolay-
ers of human fetal diploid kidney or lung cells (114). VZV is
very labile, and every effort should be made to minimize time
spent in transport and storage. Ideally, fluid should be aspi-
rated from a clear vesicle using a tuberculin syringe and inocu-
lated directly into tissue culture at the bedside. Characteristic
cytopathic effects are usually seen in tissue culture within 3
to 7 days. The culture process can be accelerated by use of
centrifugation in shell vials. Identification of the isolate can be
confirmed by direct immunofluorescent staining using VZV-
specific monoclonal antibodies. In general, viral culture for
VZV is highly specific but slow, insensitive, and expensive.
VZV infection can be demonstrated in infected tissue by his-
topathology or electron microscopy. However, visualization of
multinucleated giant cells with inclusion bodies or herpesvirus
virions does not distinguish between VZV and HSV. Direct
immunofluorescence staining using fluorescein-conjugated
monoclonal antibodies to detect VZV glycoproteins in infected
epithelial cells is highly sensitive and specific (115). Specimens
can also be stained with HSV-specific monoclonal antibodies
to distinguish VZV from HSV infection. This direct fluores-
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 164 Part II: Viral Infections and Related Disorders
cent antigen-detection method is rapid, simple, and more sen-
sitive than virus isolation (especially in late stages of infection,
when virus isolation becomes more difficult) and is especially
helpful for making a rapid diagnosis when the clinical presen-
tation is atypical.
The use of PCR to detect VZV nucleic acids in clinical speci-
mens holds great promise, but it is used primarily as a research
tool (116,117). PCR overcomes the difficulties inherent in cul-
turing labile VZV and has been useful in detecting VZV DNA in
CSF from patients with CNS infections (26,54,118120). In ad-
dition, the use of PCR makes it possible to distinguish between
disease caused by wild type VZV or by the VZV vaccine virus,
which is not routinely possible by culture (121).
Serologic techniques are used to determine susceptibility
of an individual to VZV infection and to document rising
antibody titers in patients with acute varicella or herpes zoster.
A serologic response is usually considered diagnostic if there is
a fourfold rise in antibody titer. Serum antibodies appear sev-
eral days after the onset of varicella and peak at 2 to 3 weeks,
meaning that serologic determinations usually deliver a retro-
spective rather than a real-time diagnosis. Acute infection can
be established by demonstration of VZV-specific serum immu-
noglobulin M titers. However, antigen-detection techniques
are usually faster and more reliable. Patients with herpes zos-
ter are VZV seropositive at the time of disease onset, but most
show a significant rise in titer during the convalescent phase.
Elevated antibody titers in CSF can support the diagnosis of
VZV encephalitis (25,54,122). Most laboratories have now
adopted an enzyme-linked immunosorbent assay (ELISA) or
a latex agglutination (LA) assay for VZV serodiagnosis (114).
TREATMENT
Varicella
For most immunocompetent children, chickenpox is a disease
associated with very low morbidity and mortality and support-
ive care alone is sufficient. Astringent soaks and nonaspirin anti-
pyretics improve comfort. Trimming the fingernails closely helps
prevent bacterial superinfections caused by scratching. If bacte-
rial cellulitis develops, antibiotics may be required. Oral acyclovir
has been evaluated for treatment of uncomplicated varicella in
immunocompetent children (20,123). Acyclovir therapy, initiated
within 24 hours of the onset of rash, resulted in shorter dura-
tion of fever, fewer skin lesions, and accelerated lesion healing.
Overall, oral acyclovir reduced the duration of symptomatic ill-
ness by about 24 hours. The populations studied in these con-
trolled trials were not sufficiently large to assess the impact of
acyclovir therapy on the incidence of varicella complications.
Oral acyclovir has also been evaluated in immunocompetent
adolescents and adults (124,125). As seen in the pediatric studies,
initiation of acyclovir therapy within 24 hours of onset of rash
resulted in reduction in time to cessation of new lesion formation,
reduced the number of lesions, and reduced constitutional symp-
toms, including fever. The dose of oral acyclovir for chickenpox
is 20 mg/kg (up to a maximum of 800 mg) five times daily for 5
to 7 days. Famciclovir and valacyclovir are likely to be at least
as effective as acyclovir for chickenpox but have not been exten-
sively studied. Oral antiviral therapy is optional in healthy chil-
dren with varicella, but it should definitely be used in adolescents
and adults because of their increased risk for more severe illness.
Few data exist to help address the question of antiviral ther-
apy for neurologic complications of varicella. In general, the
cerebellar ataxia syndrome is benign and self-limited, and there
is no evidence that antiviral therapy alters the natural history.
Varicella encephalitis is associated with a substantial degree of
Scheld_Ch10.indd 164
morbidity, and the availability of some specific therapy would
be useful. As discussed earlier in this chapter, there is consid-
erable controversy regarding what role, if any, active VZV
replication plays in the pathogenesis of varicella encephalitis.
However, because no other mode of therapy is available, and
because acyclovir is extremely safe and well tolerated, therapy
with acyclovir in patients with varicella encephalitis is war-
ranted. Corticosteroids have been proposed for use in varicella
encephalitis, but there are no reliable data to support their use.
In immunocompromised children, varicella is a serious
and potentially lethal infection that requires antiviral ther-
apy (126). Intravenous acyclovir was compared with placebo
in a small population of immunocompromised children with
chickenpox (127). In this trial, the administration of acyclo-
vir reduced the frequency of pneumonitis from 45% to 0%.
Despite the lack of data from large-scale controlled trials,
the safety and efficacy of intravenous acyclovir have led to
its acceptance as the drug of choice for varicella infection in
immunocompromised patients. For treatment of serious VZV
infections, intravenous acyclovir is given at a dose of 10 mg/kg
(or 500 mg/m2) every 8 hours.
Herpes Zoster
Appropriate supportive care can help make patients with her-
pes zoster more comfortable. The skin lesions should be kept
clean and dry to reduce the risk of bacterial superinfection.
Astringent soaks (e.g., Domeboro solution) may be soothing.
Most patients with acute herpes zoster infection have signifi-
cant pain and require therapy with opioid analgesics.
Three oral antiviral drugs are approved in the United States
for treatment of herpes zoster infection in the normal host. Oral
acyclovir, initiated within 72 hours of the onset of lesions at a
dose of 800 mg five times daily, reduces the duration of viral
shedding, accelerates the cessation of new lesion formation,
and accelerates the events of cutaneous healing (128130).
These clinical trials showed variable benefit from acyclovir
for reducing the duration of PHN. However, data from these
studies have been reexamined in a metaanalysis, which con-
clusively demonstrated that acyclovir was superior to placebo
for reducing the duration of zoster-associated pain, defined
as pain measured from the initial onset until final resolution
(131). Oral administration of valacyclovir (a prodrug of acy-
clovir) as a dose of 1 g three times daily produces plasma acy-
clovir levels that are approximately threefold to fivefold higher
than those achievable with acyclovir. Valacyclovir and acyclo-
vir have been compared in a controlled trial for treatment of
herpes zoster infection in the normal host (132). The two drugs
were equivalent in terms of accelerating events of cutaneous
healing; however, valacyclovir was superior in accelerating the
resolution of zoster-associated pain. When evaluated for treat-
ment of herpes zoster in the normal host, famciclovir (500 mg
orally three times daily) was significantly superior to placebo in
reducing the duration of viral shedding, limiting the duration
of new lesion formation, and accelerating the events of cutane-
ous healing (133). Most importantly, famciclovir was signifi-
cantly superior to placebo in reducing the duration of PHN.
A study comparing valacyclovir and famciclovir for herpes zos-
ter showed these drugs to be therapeutically equivalent (134).
All these compounds are safe and well tolerated for short-term
administration. Patients who are most likely to benefit from an-
tiviral therapy of herpes zoster are those who present for medi-
cal attention within 72 hours after onset of lesions, patients
with severe pain or large lesion surface area involvement at
the time of presentation, and elderly patients who are at high
risk for long-term complications, especially chronic pain (135).
2/21/14 5:34 PM
 Chapter 10: Neurologic Manifestations of Varicella and Herpes Zoster
HZO is a special situation in which antiviral therapy is clearly
beneficial and significantly reduces the risk for ocular compli-
cations (136). Consultation with an experienced ophthalmolo-
gist is also recommended for patients with HZO and ocular
involvement. Because of their convenience of administration,
famciclovir and valacyclovir are the preferred drugs for uncom-
plicated herpes zoster infection in the normal host.
Two large clinical studies have helped clarify the role of
corticosteroids in herpes zoster infection (137,138). Both
studies demonstrated benefit from corticosteroids in reducing
the duration of acute neuritis, but neither study showed any
reduction in the incidence or duration of PHN among steroid
recipients. Therefore, although corticosteroids (in combination
with antiviral therapy) can provide some symptomatic benefit
during the early phases of herpes zoster, corticosteroids will
not have an impact on the development of PHN.
Immunocompromised patients who develop herpes zos-
ter are at significant risk for morbidity and mortality related
to disseminated infection. Controlled trials have shown that
intravenous acyclovir substantially reduces the risk for cutane-
ous and visceral dissemination (44,139). In patients who are
less severely immunocompromised, it may be feasible to use an
oral antiviral drug for the treatment of zoster (140).
The role of antiviral drugs in the management of neuro-
logic complications of herpes zoster has not been evaluated in
a controlled fashion. For those diseases in which viral replica-
tion likely plays an important role in pathogenesis (e.g., zoster
myelitis), therapy with intravenous acyclovir is recommended;
this approach is supported by benefits noted in anecdotal
experience. For diseases such as delayed contralateral hemipa-
resis, in which the role of active viral replication is much less
clear, the value of antiviral therapy is uncertain, but in general
the potential benefits of antiviral therapy probably outweigh
any potential risks.
PREVENTION
A live, attenuated varicella vaccine containing VZVOKA strain
was developed in the 1970s in Japan and approved for use in the
United States in 1995 (141). At the standard dose, the protection
provided by the vaccine against VZV disease following house-
hold exposure was approximately 70%. Any case of chickenpox
occurring among vaccinated individuals was almost invariably
mild (median lesion count of 15 to 32) (142). The most com-
mon adverse event associated with the vaccine has been a mild
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ACKNOWLEDGMENTS
This project has been funded in whole or in part with Federal
funds from the National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Department of
Health and Human Services, under Contract (N01-AI-65306,
NO1-AI-15113, NO1-AI-62554, NO1-AI-30025), the General
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 CHAPTER 11 CYTOMEGALOVIRUS
PAUL D. GRIFFITHS
HISTORY
In the early years of the twentieth century, histopathologists
studying stillborn infants identified the characteristic intranu-
clear inclusions in fatal cases of what is now termed cytomegalic
inclusion disease (1). At first, the inclusion bodies were attributed
to a new protozoal infection (2). However, in 1921 Goodpasture
and Talbot (3) remarked on the similarity between these strange
bodies and the intranuclear inclusions produced in the skin
lesions of varicella (4). The viral etiology of the inclusions was
first proposed by von Glahn and Pappenheimer (5) in 1925. The
following year, Cole and Kuttner (6) were able to transmit the
guinea pig form of cytomegalic inclusion disease from salivary
gland material passed through a Berkefeld N filter. Later, three
laboratories simultaneously reported the isolation of the caus-
ative human virus in cell cultures: Smith (7) in 1956 from sali-
vary glands, Rowe et al. (8) in 1956 from adenoid tissue, and
Weller et al. (9) in 1957 from a liver biopsy specimen. In 1960,
Weller et al. (10) named the virus cytomegalovirus (CMV).
Since a characteristic feature of cytomegalic inclusion disease
is global mental retardation, scientists have known for more
than 50 years the basic nature of CMV and its tropism for cells
of the central nervous system (CNS). However, whether this
tropism resulted from the immature phenotype of cells dividing
to form the fetal CNS or whether CMV could also infect
terminally differentiated neural cells of adult origin was not
known. Although individual cases of CMV encephalitis have
been described in patients who were immunocompromised but
not infected with human immunodeficiency virus (HIV), such
cases are still the exception rather than the rule. For example,
CMV encephalitis was described in a renal transplant recipient
treated with augmented immunosuppression for graft rejec-
tion (11) and in a patient with Hodgkin disease who became
demented and died of pneumonia (12). The acquired immu-
nodeficiency syndrome (AIDS) epidemic changed this perspec-
tive; CMV infection was found so often at autopsy before the
advent of highly active antiretroviral therapy (HAART) that
it was the most common opportunistic infection of the CNS
in patients with AIDS (13). Both CMV infection and disease,
including of the CNS, have decreased dramatically in coun-
tries where HAART is readily available. This clinical benefit is
consistent with the possibility that CMV infection of the CNS
was a major and often unrecognized contributor to CNS dis-
ease. However, the clinical course of patients with AIDS is so
complex that it is not certain how much CNS disease could be
attributed to the presence of CMV as opposed to HIV, which
is also neurotropic and controlled by HAART. Interestingly,
CMV encephalopathy can predominate as the cause of death in
a child who acquires both CMV and HIV from its mother (14).
The aim of this chapter is to review what is known and how
much remains to be defined about CMV infection of the CNS.
INFECTIOUS AGENT
CMV has the largest genome (229 kb) of the viruses known to
infect humans. More than 200 potential open reading frames
were identified in strain Ad169 (15), with an additional 22 in
168
Scheld_Ch11.indd 168
wild type strains (16). Propagation in fibroblasts selects for this
and other genetic changes so viruses are now maintained in the
laboratory as bacterial artificial chromosomes with approxi-
mately 165 protein-coding genes in wild type strains (17). In
addition, the genome encodes approximately 10 micro-RNAs.
Recent results with ribosome profiling suggest that the genet-
ics of this virus may be even more complex than described so
far (18). Salient features of the molecular biology of the virus
are summarized later in this chapter, with a focus on genes
important for immune control or which are the targets of anti-
viral chemotherapy; for extensive details, readers are referred
elsewhere (19). By international agreement, proteins encoded
by the virus are described according to their map position (20)
(Fig. 11.1). For example, gpUL55, the glycoprotein known
as glycoprotein B, originates from the fifty-fifth open reading
frame of the unique long region, while ppUL82 is a tegument
phosphoprotein transactivator that maps to the eighty-second
open reading frame of the unique long region.
CMV encodes several transactivators. The major immediate-
early region maps to UL122/123. Alternative splicing produces
four major proteins, one of which interacts directly with TATA-
binding protein and downregulates its own promoter. This re-
gion contains upstream enhancers, is a strong regulatory region,
and is a major target of cell-mediated immunity. pUL69 is a
transactivator found in the virion. It synergizes with ppUL82 to
activate the major immediate-early promoter. These two proteins
together can thus be thought of as being functionally equivalent
to the -transinducing factor of herpes simplex virus (HSV).
A total of 11 genes are required for CMV replication (21).
These proteins together provide in trans the functions required
to allow replication of the lytic origin of replication (22). Some
of the functions are directly analogous to those required by
HSV, for example, DNA polymerase (UL54) and its accessory
protein (UL44), although an equivalent to the origin-binding
protein has not been identified.
Structural proteins of the virus include the major capsid
protein, UL86, and the minor capsid protein, UL46. The as-
semblin gene complex (UL80a) includes a protein important
for packaging DNA as well as a protease. Several phosphopro-
teins are found in the tegument (UL32, UL83, UL82, UL99).
ppUL83, known as the lower matrix protein, is the major
antigen detected in circulating leukocytes (23) and is the sec-
ond major target of the cell-mediated immune response (24).
Major envelope proteins exist on the plasma membrane
as multimolecular complexes and are major targets for hu-
moral immune responses. Glycoprotein complex I consists of
a homodimer of glycoprotein B (gB; gp UL55). Glycoprotein
complex II consists of gM (gp UL100) and gN (gp UL73).
Glycoprotein complex III consists of gH (gp UL75), gL (gp
UL115), and gO (gp UL74) in fibroblasts but gH, gL, and
three proteins (pUL128, pUL130, pUL131A) encoded within
the region of the genome which is deleted upon passage in
fibroblasts. This five-member complex of proteins mediates
viral entry into epithelial and endothelial cell lines (25).
CMV encodes a series of genes that interfere with immune
recognition of virus-infected cells. The product of US6 blocks
the transporter associated with antigen presentation, which
normally takes peptides from the cytosol into the lumen of the
2/21/14 5:34 PM
 Chapter 11: Cytomegalovirus 169

0 5 10 15 20 25 30

RL1 RNA2.7 RL5A RNA1.2 RL10 RL13 UL4 UL7 UL10 UL13 UL16 UL19 UL22A UL24
RL6 RL8A RL11 UL1 UL5 UL8 UL11 UL14 UL17 UL20 UL23
RL9A RL12 UL2 UL6 UL9 UL15A UL18 UL21A

30 35 40 45 50 55 60

UL25 UL27 UL29 UL30 UL31 UL32 UL33 UL34 UL35 UL36 UL37 UL40 UL43 UL45
UL26 UL30A UL38 UL41A UL44
UL42

60 65 70 75 80 85 90

UL46 UL47 UL48 UL49 UL50 UL52 UL53 UL54 UL55 UL56 UL57
UL48A UL51

90 95 100 105 110 115 120

ori RNA4.9 UL69 UL70 UL71 UL74 UL75 UL76 UL78 UL80 UL82
UL72 UL74A UL77 UL79 UL80.5
UL73

120 125 130 135 140 145 150

UL83 UL84 UL85 UL86 UL87 UL89 UL93 UL95 UL97 UL98 UL100 UL102
UL88 UL91 UL94 UL96 UL99
UL92

150 155 160 165 170 175 180

UL104 UL105 RNA5.0 UL112 UL115 UL119 UL122 UL124 UL128 UL132
UL103 UL111A UL114 UL116 UL120 UL123 UL130 UL148
UL117 UL121 UL131A

180 185 190 195 200 205 210

UL147A UL144 UL141 UL138 UL133 UL148D IRS1 US1 US3 US7 US9 US12 US14
UL147 UL142 UL140 UL136 UL148A UL150 US2 US6 US8 US10 US13 US15
UL146 UL139 UL135 UL148B UL150A US11
UL145 UL148C

210 215 220 225 230 235 kbp

US16 US18 US20 US22 US23 US24 US26 US27 US29 US32 US34A TRS1
US17 US19 US21 US28 US30 US33A
US31 US34

FIGURE 11.1 Consensus genetic map of Merlin strain human cytomegalovirus (HCMV), updated from
the publication by Dolan et al. 2004. The unique long (UL), unique short (US), terminal repeat long (RL),
terminal repeat short (TRS), and inverted repeat short (IRS) regions are shown, with a thicker format for the
genome termini. Introns are shown as narrow white bars. Colored arrows indicate protein-coding regions
as well as the direction of transcription. The colors indicate degrees of conservation of genes between
the Alpha-, Beta-, and Gammaherpesvirinae (core genes) or between the Beta- and Gammaherpesvirinae
(subcore genes). Various subsets of the remaining noncore genes are grouped into gene families. Note that
the micro-RNAs encoded within the genome are not shown. (Figure kindly provided by Dr. A. Davison.)

Scheld_Ch11.indd 169 2/21/14 5:34 PM

 170 Part II: Viral Infections and Related Disorders
endoplasmic reticulum. US3 binds to human leukocyte anti-
gen (HLA) heavy chains and retains them in the endoplasmic
reticulum. Genes US2 and US11 take HLA complexes from
the endoplasmic reticulum and export them back into the
cytosol for degradation in the proteasome. All of these effects
combine to decrease HLA display at the plasma membrane
and thus allow the virus to escape from cytotoxic T cells.
However, because HLA molecules also provide nonantigen-
specific signals to natural killer (NK) cells and macrophages,
their absence could trigger destruction of the virus-infected
cell via these innate immune effectors. To avoid this, CMV
has additional genes: UL18 to provide a negative signal to
macrophages and UL40 to provide a negative signal to NK
cells. In addition, the proteins encoded by UL16, UL141,
and UL142 block the recognition of a positive signal for NK
cells. In addition, a viral micro-RNA interferes with recogni-
tion of another of these host defense signals. In combination,
the function of these genes allows CMV to persist in the host
despite strong humoral and cell-mediated immune responses.
CMV encodes four sets of proteins that are predicted
G proteincoupled receptors (US27 and US28; UL33; UL78).
UL97 is a protein kinase homolog responsible for phosphory-
lating ganciclovir and acyclovir (2628).
EPIDEMIOLOGY
Humans are the only reservoir for CMV (29). Infection is
endemic worldwide and has no seasonal variation. The prev-
alence of CMV infection increases directly with age, with
significant variations according to geographic, ethnic, and
socioeconomic backgrounds. Antibodies of immunoglobulin G
(IgG) class against CMV can be found in approximately 60%
of adults in developed countries, and virtually 100% of adults
in developing countries (30). Within developed countries,
acquisition of CMV infection is increased in poor socioeco-
nomic environments and by sexual contact. The presence of
IgG antibodies indicates that infection has occurred some-
time in the past and that the virus should be presumed to be
latent. The sites of latency of CMV are not known, although
myeloid dendritic cells are clearly one of them, with reactiva-
tion of virus linked to cellular differentiation (3133). CMV
can be transmitted iatrogenically by all organ allografts and
at autopsy can be found in most tissues of the body. Thus,
whether CMV has a single site of latency or whether silent in-
fection can become established in multiple tissues is debatable.
Transmission of infection from one individual to another
requires direct contact. Sources of virus include saliva, blood,
vaginal secretions, semen, and breast milk (3436). Salivary
excretion of virus, particularly in association with mouthing
of toys, can lead to baby-to-baby transmission in the child care
setting (3739). Susceptible children can thus acquire CMV in
the day care environment and transmit infection to susceptible
family members in the home. Transmission of CMV from an
infant to his or her seronegative motheras well as from an
infant to pregnant caretakers, with subsequent transmission to
the fetushas been documented (40,41). Overall, in the United
States, contact with young children is a much more important
source of CMV for mothers than is sexual exposure (42).
Prospective studies in the United States and Europe have
established that pregnancy itself does not increase the risk of
acquiring CMV infection (4350). Primary CMV infections dur-
ing pregnancy are generally asymptomatic (43,4547,4951).
Among susceptible women, the risk of seroconversion during
pregnancy averages 1.7% (52). In primary CMV infection, an
innate barrier prevents in utero transmission; thus, primary
maternal CMV infection leads to transmission in only about 32%
Scheld_Ch11.indd 170
of fetuses (53). Moreover, only 12.7% of infected infants have
clinical manifestations at birth (from very mild to severe), and
the risk of subsequent sequelae averages 13.5% (54). Although
the rate of transmission of virus in utero appears lower, the risk
of neonatal disease with attendant sequelae appears to be higher
when the mother has acquired CMV infection during the first
trimester of pregnancy (55).
Maternal immunity to CMV neither prevents virus reac-
tivation nor controls the systemic spread of virus that can
produce congenital infection (44,48,5660). Studies that use
restriction endonuclease analysis of viral DNA to examine the
genetic relatedness between CMV strains isolated repeatedly
from mother and offspring indicate reactivation of an identi-
cal latent virus rather than reinfection with an exogenous one
(61). In other cases, there is evidence for exogenous reinfection
with a different strain (62,63). In a highly seropositive (82% of
persons) urban population of low socioeconomic background
in Alabama, recurrent CMV infection produced a 1.6%
(13/835 infants) rate of congenital infection, thus indicating
that most intrauterine infections in this population result from
this phenomenon (49). In contrast, the infants of immune
middle-class women with a seropositivity rate of 55% had a
lower rate of congenital infection (0.19%, i.e., 10/5,242). This
rate is not significantly different from that observed in Great
Britain and Sweden (44,48,57). Overall, the mothers of only
25% of babies born with congenital CMV infection in the
United States had primary infection during pregnancy (64).
Although maternal immunity is imperfect, congenital infec-
tions that result from recurrent infection are less likely to pro-
duce fetal damage than those resulting from primary infections
(49). However, the larger number of seropositive women in a
community may provide a number of infected neonates equal
to those born to seroconverting mothers (65).
During pregnancy and in the immediate postpartum period,
CMV can be shed at variable rates from one or more sites (49).
Rates of excretion are higher in younger, nonwhite women
from lower socioeconomic backgrounds. Most women who
excrete virus during pregnancy do so as a result of recurrent
infections (reactivation or reinfection) (61). There is little cor-
relation between CMV excretion from the cervix or in urine
during pregnancy and the subsequent birth of a congenitally
infected infant (47,50,66), but the presence of CMV in the
maternal genital tract at delivery and in the breast milk after
delivery is strongly associated with intrapartum/postpartum
transmission of infection to the infant (34,36). In full-term and
otherwise healthy infants, perinatal infection has little clinical
importance except for a small number of cases of interstitial
pneumonia (36,67,68). However, such children are a major
source of infection for other children in the day care environ-
ment (69,70) and represent an occupational risk to child care
personnel, particularly women of childbearing age (39,7173).
If a patient who is CMV IgG-seropositive becomes immuno-
suppressed, CMV reactivation is common, being found typically
in 50% of transplant recipients at some time after transplanta-
tion. The donor organ can also transmit CMV to seronegative
individuals (74) or to seropositive individuals (75), showing
that preexisting immunity to CMV does not provide protection
against infection. However, preexisting immunity does provide
moderate protection against CMV replication to high levels and
disease (76). Primary CMV infection can also be acquired from
blood transfusion (77).
In patients who are HIV positive, the same principles apply:
CMV infection becomes increasingly common as the immu-
nocompromised state progresses, although formal studies of
natural history have not been performed. However, CMV
disease, typically retinitis, clearly is uncommon before the
CD4 count declines to 100 106/L. It becomes increasingly
2/21/14 5:34 PM

common as such patients are followed, with typically 10%
of patients developing CMV disease within 2 years of follow-
up (78). Retinitis is associated with CMV encephalitis (79).
By itself, it represents approximately 85% of CMV disease in
patients with AIDS, with gastrointestinal tract infection rep-
resenting approximately 10% and CMV CNS disorders only
1% of total disease. Nevertheless, presentations in the CNS
(and peripheral nervous system) are being increasingly recog-
nized, as described later in this chapter.
ETIOLOGY
In cases of congenital CMV, one can be certain that the CNS
disease is attributable to CMV, as no other infectious agent is
present and the syndrome is characteristic. The same is prob-
ably true in the case of a female preterm infant born to an
HIV-positive mother who acquired congenital CMV and HIV
infection vertically. At 5 months, the child developed AIDS
and died at age 11 months of a rapidly progressive diffuse
encephalopathy. At autopsy, CMV encephalitis was seen, with
occasional inclusion bodies, yet there was no evidence for HIV
infection of the brain (14).
However, the same clear-cut picture is not seen in adult pa-
tients with AIDS, who typically have evidence for HIV involve-
ment of the CNS, with or without CMV infection (80). A case
definition for CNS conditions attributable to HIV has been
provided (81). However, it is not possible to exclude an HIV
contribution to CNS symptomatology in patients with CMV.
Indeed, in vitro there are multiple ways in which CMV and
HIV could interact so that each could enhance the replication
of the other; this has been reviewed by Griffiths (82). CMV
infection can also downregulate HIV (83). Other opportunistic
infections of the CNS are usually spatially distinct from CMV,
with the exception of HSV type 1 (HSV-1); superimposed CMV/
HSV-1 infection has been described (84,85). Interestingly, su-
perimposed CMV/HSV-1 infection of the brain has also been
described in a patient who does not have AIDS (86).
Cases have been described in which CMV appears to be the
cause of CNS dysfunction (8789). Until more is known about
the pathogenesis of CMV infection of the CNS, however, it is
not possible to guarantee that CMV infection is the sole cause
of the CNS dysfunction in an individual patient. Nevertheless,
populations of patients with AIDS can be examined to discern
patterns of clinical syndromes, with the strong presumption
that CMV is a candidate etiologic agent.
Animal experiments are not particularly helpful, because
human CMV is strongly species specific and replicates only in
humans. Animal CMVs, such as murine or guinea pig CMV,
can be studied; although they are different viruses, they do
have the advantage of occupying the same ecologic niche in
their species as human CMV does for humans. For example,
studies of the direct intracerebral inoculation of murine CMV
into mice of different ages show that the virus has a predilec-
tion to infect developing brain cells (90).
PATHOGENESIS
Results of preliminary studies indicate that the virulence
of congenital CMV infection is not strain dependent (61).
Although only a few infants have been studied, viruses iso-
lated from congenitally or perinatally infected siblings were
genetically identical. In two of the pairs of siblings assessed,
the first-born baby was severely affected, whereas the second-
born infant was only subclinically infected (60). Mechanisms
that possibly explain some of the CNS damage associated with
Scheld_Ch11.indd 171
Chapter 11: Cytomegalovirus 171
CMV infection include productive CMV replication leading
to destruction of individual cells (lytic infection) and indirect
damage mediated by action of components of the immune sys-
tem (immunopathology).
Lytic Infections
Continuous viral replication in affected organs could explain
why some infants are severely affected and others remain free
of symptoms. Longitudinal studies have demonstrated that
excretion of CMV into urine and saliva persists for years.
Chronic viral replication probably also occurs at other ana-
tomic sites that are less accessible to virologic examinations
(e.g., middle ear, brain).
The histopathologic hallmark of CMV CNS infection is the
characteristic intranuclear inclusion body (Fig. 11.2). This indi-
cates productive infection of the cell and represents a major site
of virus formation. Such cells are likely committed to die, so CNS
dysfunction could result from loss of their function. Inclusion-
bearing cells were seen in six fetuses with polymerase chain reac-
tion (PCR)positive amniotic fluids that were terminated at 19 to
35 weeks because of CNS lesions seen on ultrasound examina-
tions (91). Meningoencephalomyelitis and micronodular enceph-
alitis were seen in all, consistent with bloodborne dissemination
of virus. Diffuse periventricular microglial nodules were present.
Inclusions were seen in the stria vascularis, Reissner membrane,
and the organ of Corti as well as in epithelial cells of the saccule
and utricule. The authors suggested that CMV may gain access
to the inner ear via the highly vascularized stria vascularis and
damage the ability of this structure to maintain potassium ho-
meostasis, dissipate electric potentials, and support recirculation
of potassium within the perilymph.
Immunopathology
Studies of CMV polypeptides immunoprecipitated by IgG anti-
bodies indicate that symptomatically infected infants had a
delay (until 12 months of age) in the appearance of precipitating
FIGURE 11.2 Cytomegalovirus-infected cell showing the enlarge-
ment of the cell with two inclusion bodies, each surrounded by a
clear zone, within a pleomorphic nucleus. Hematoxylin-eosin stain;
magnification 252.
2/21/14 5:34 PM
 172 Part II: Viral Infections and Related Disorders

antibodies (92). However, when a humoral immune response

develops, antibodies to viral polypeptides are precipitated in
greater numbers and are maintained for longer periods. This
sustained humoral immune response to congenital CMV infec-
tion occurs in the presence of persistent viral replication, thereby
creating the potential for the formation of immune complexes
(93). During the first year of life, immune complexes circulate
in a large proportion of infants with congenital infection. The
molecular weight of these immune complexes is higher in symp-
tomatic infants than in asymptomatic infants. In a few fatal
symptomatic cases, deposition of immune complexes in renal
glomeruli has been demonstrated. Another factor in disease
pathogenesis is vasculitis, which may occur in utero or after
birth. Infants with congenital CMV infection who die soon after
birth usually have disseminated intravascular coagulopathy.
CMV pneumonitis in transplant recipients may be immu-
nopathologically mediated (94). Thus, the presence of the
virus is required for the syndrome, but the clinical disease may FIGURE 11.3 Cytomegalovirus-infected epithelial cell in the choroid
be caused by an abnormal, enhanced, cell-mediated immune plexus. Hematoxylin-eosin stain; magnification 252.
response. Immunopathology presumably also explains the im-
mune recovery vitreitis, which follows successful treatment
of CMV retinitis in patients with AIDS. Similarly, it has been cells and some astrocytes. In some cases, the microglial re-
suggested that the demyelinating component of the disease in sponse surrounds an inclusion-bearing cell. Other inclusion
the peripheral nervous system could be immunopathologi- body cells may be missed in the plane of section. In the series
cally mediated (95). It is unlikely that an identical scenario by Vinters et al. (85), CMV could not be found in every case
pertains in the CNS of patients with AIDS, because neurologic of microglial nodular encephalitis identified. Infected cells can
symptoms usually occur at profoundly low CD4 cell counts. likely be targets for microglial attack before reaching the stage
However, there are distinct possibilities that host cytokines, of bearing an inclusion body, because staining with monoclo-
released as a result of CMV infection, stimulated by CMV, or nal antibodies or the use of in situ hybridization reveals many
even encoded by CMV, could mediate extensive neural dam- more cells to be CMV infected (101,102).
age. For example, CMV activates tumor necrosis factor- and The second route of viremic spread is through the cere-
interleukin-6 (IL-6), both of which may induce HIV expres- brospinal fluid (CSF) following viral replication in infected
sion in macrophages (96). CMV replication is also enhanced epithelial cells of the choroid plexus (Fig. 11.3). Secondary
by IL-8. CMV infection induces production of messenger RNA seeding of the ependymal surfaces and internal spread pro-
(mRNA) of the IL-8 receptor, while IL-8 increases CMV rep- duce necroses of periventricular white matter (102). This con-
lication approximately fourfold (97). pUS28 has 33% amino dition, necrotizing ventricular encephalitis, may be extensive.
acid homology with the IL-8 receptor (97). Because IL-8 stim- Ependymal surfaces are replaced with CMV-infected cells,
ulates production of polymorphonuclear leukocytes, this is a infiltrating macrophages, inflammatory exudate, and necrotic
plausible explanation for the increased level of polymorpho- cells with or without hemorrhage (85,101).
nuclear leukocytes seen in the CNS in association with CMV, The histologic changes may be classified into one of five
particularly polyradiculopathy. The CMV genome encodes major groups: (a) nodular encephalitis, in which widely dis-
an -chemokine (UL146) and an IL-10 homolog (UL111A) seminated microglial nodules, only a minority of which may
whose function remains undefined in vivo. contain inclusion-bearing cells (Fig. 11.4), are seen dissemi-
nated over a wide area (103); (b) isolated inclusion-bearing

PATHOLOGY
CMV reaches the brain through viremic spread. In patients
with AIDS, viremia has been reported to have both a cel-
lular and a plasma component (98). In healthy individuals,
CMV can be found by PCR in monocytes (31). In transplant
recipients, ppUL83 (pp65) antigen has been demonstrated in
monocytes, polymorphonuclear cells, or endothelial cells (23).
Which, if any, of these cells are important for disseminating
CMV to the brain of patients with AIDS is not clear, but there
is evidence that microglia are derived from the peripheral
blood monocyte pool (99,100). Regardless, there is evidence
that CMV can spread through the brain by two routes.
The first route involves infection of the endothelial cells
of the brain, with spread to the contiguous astrocytes in foot
processes and their cognate neurons. This route of inoculation
is mirrored by the following histologic findings: (a) infection
of endothelial cells in the brain, which may sometimes be
associated with vascular thrombosis. Isolated endothelial cells
containing inclusion bodies may also be seen in the spinal cord
in association with a myelitis; (b) multiple foci of glial nodular FIGURE 11.4 A microglial nodule with an inclusion-bearing cell.
encephalitis. The glial nodules consist of multiple microglial Hematoxylin-eosin stain; magnification 160.

Scheld_Ch11.indd 172 2/21/14 5:34 PM

 Chapter 11: Cytomegalovirus 173

FIGURE 11.5 Isolated inclusion-bearing astrocyte in the subependyma.

Hematoxylin-eosin stain; magnification 252.

cells, which may be astrocytes (Fig. 11.5), neurons, or macro-

phages (104); (c) focal parenchymal necroses in an otherwise
normal neuropil, whose lesions are characterized by accumula-
tions of macrophages with axonal destruction and occasional
inclusion-bearing cells (105); (d) ventricular encephalitis,
characterized by inflammation and necrosis involving the ep-
endyma and subependymal glia (Fig. 11.6), often over a wide FIGURE 11.7 Radiculomyelitis involving the lumbar cord. Many
area of the ventricular lining (106); and (e) radiculomyelitis, darkly staining infected cells are seen. Immunoperoxidase for cyto-
megalovirus (Dako); 40.
in which inflammatory changes, often with a marked infiltrate
of polymorphonuclear neutrophils, are seen involving the cord
(Fig. 11.7), spinal roots, and dorsal root ganglia. To some
extent, the histologic changes mirror the portal of entry of the
virus into the CNS and its dissemination throughout the brain CLINICAL MANIFESTATIONS
and spinal cord, as discussed earlier.
The incidence of such findings in seven separate AIDS Clinical Presentation of Congenital Infection
autopsy series is shown in Table 11.1. The proportion of
patients in whom CMV infection of the CNS was documented
varied from 7.9% to 28%. In total, 161 (15.7%) of 1,026
Symptomatic Infection
patients in these studies had CMV involvement of the CNS. Disease in the symptomatic newborn is characterized by hepato-
An increasing number of viruses are being described that megaly, splenomegaly, microcephaly, direct hyperbilirubinemia,
produce similar clinical and pathologic changes in patients petechiae, and thrombocytopenia (108). Intracranial calcifica-
with AIDS (107). Indeed, the clinical and pathologic features tions and retinitis are demonstrable with regularity. Intrauterine
may reflect more the route of infection and the state of the growth retardation is often present. Diabetes insipidus has been
immune system than the nature of the virus. reported in a few infants with congenital infection (109).

FIGURE 11.6 An area of ventricular encepha-

litis involving the roof of the fourth ventricle.
Hematoxylin-eosin stain; magnification 40.

Scheld_Ch11.indd 173 2/21/14 5:34 PM

 174 Part II: Viral Infections and Related Disorders

TA B L E 1 1 . 1
COMPARISON OF INCIDENCE AND TYPE OF CYTOMEGALOVIRUS-INDUCED CENTRAL NERVOUS SYSTEM
LESIONS IN DIFFERENT AUTOPSY SERIES

Morgello and Klatt and Vinters McKenzie Artigas Chimelli

Findings Simpson (95) Shibata (103) et al. (85) et al. (104) et al. (105) et al. (106) RFH

Total no. 107 164 160 75 180 252 88

CMV (all organs) 81 31 61 91 53
CMV-induced CNS lesions 30 16 26 10/49 39 20 20
Microglial nodules 30 (100%)a 6 (38%) 29 (112%) 32 (82%) 17 (85%) 11 (55%)
Isolated inclusions 15 (50%) 6 (30%)
Necrosis 4 (13%) 2 (8%) 9 (23%) 4 (20%)
Necrotizing
leukoencephalopathy
Necrosis/infarcts
Necrotizing 3 (10%) 2 (13%) 7 (35%)
ventriculoencephalitis
Encephalitis 6 (38%)
Necrotizing 16 (41%) 2 (10%) 4 (20%)
radiculomyelitis
Myelopathy 1 (4%)
Leptomeningitis/ 5 (19%)
meningoradiculitis
Vasculitis 5 (31%) 4 (15%) 7 (18%)
Neuronal degeneration 4 (25%)
Meningitis 2 (13%)
Choroid plexusitis 2 (8%)

RFH, Royal Free Hospital; CMV, cytomegalovirus.

a
Percentage figures relate to total number of CMV-induced CNS lesions.

The mortality among congenitally infected infants may TA B L E 1 1 . 2

be attributed to hepatic dysfunction, bleeding, or secondary
bacterial infection (Table 11.2). Death after the first month of PUBLIC HEALTH CONSEQUENCES OF CONGENITAL
life is usually the consequence of hepatic dysfunction; how- CYTOMEGALOVIRUS INFECTION
ever, beyond the first year of life, death is usually the result of
complications in the neurologically handicapped child second- Variable Estimated Value
ary to malnutrition, aspiration pneumonia, or overwhelming
No. of livebirths per year 4,000,000
infection.
The CNS defects in these children of microcephaly and Average rate of newborns with 0.7%
intracranial calcifications are particularly striking. The CNS CMV infection
lesions of two children with intracranial calcifications evalu- Number of newborns with 28,000
ated by computed tomographic (CT) and magnetic resonance CMV infection
imaging (MRI) scans are shown in Figure 11.8. If calcifica- Number with symptomatic disease 3,556
tions are present on neurodiagnostic evaluation, long-term (rate, 12.7%)
neurologic impairment is unequivocal. Children with head
Number with fatal disease (rate, 0.5%) 18
circumferences less than the fifth percentile at birth may subse-
quently establish a normal brain growth pattern (110). Ocular Number of survivors with sequelae 1,769
and hearing defects are common in children with symptomatic (rate, 50%)
congenital CMV infection. The principal abnormality of the Number of asymptomatic infections 24,444
eye associated with congenital CMV infection is retinitis, with (rate, 87.3%)
optic atrophy being relatively uncommon (110). Retinitis in Number with sequelae (rate, 13.5%) 3,300
the newborn with CMV infection will usually resolve sponta-
Total number with sequelae or death 5,087
neously over the first several months of life, leaving residual,
characteristic pigmented scars. From a systematic review of the
literature (54), 50% of the survivors develop late-appearing CMV, cytomegalovirus.
Adapted from Dollard SC, Grosse SD, Ross DS. New estimates of
complications, such as hearing loss, mental retardation, delay the prevalence of neurological and sensory sequelae and mortality
in psychomotor development, chorioretinitis, optic atrophy, associated with congenital cytomegalovirus infection. Rev Med Virol.
seizures, expressive language delays, learning disabilities, and 2007;17(5):355363.
defects of dentition (48,56,108,110115).

Scheld_Ch11.indd 174 2/21/14 5:34 PM

 Chapter 11: Cytomegalovirus 175

Factors That Influence Disease

The type of maternal infectionthat is, primary or recurrent
has a direct impact on neurologic sequelae (Table 11.3). Any
neurologic impairment occurred in 25% of children of mothers
with primary infection, as compared to 8% among offspring
of women with recurrent disease. Importantly, the time to
documentation of neurologic impairment was also influenced
by type of infection (120), as shown in Figure 11.9. Among
women with primary infections, those occurring in the first tri-
mester had a greater association with both the incidence and
severity of sensorineural hearing loss and CNS sequelae (55).
However, damage was observed at all gestational ages, so the
timing of maternal infection cannot explain all of the variabil-
ity seen in clinical practice.
The quantity of CSF protein is a predictor of neurologic
outcome (121). Protein concentrations more than 120 mg/dL
were more commonly associated with microcephaly, abnormal
hearing, and multiple neurologic sequelae (121). Microcephaly
and an abnormality detected in the neonate by CT predict
future mental retardation and motor disability (122).

Asymptomatic Infection
Most newborns with congenital CMV infection will have no
symptomatology but are still at risk for neurologic and senso-
rineural impairment, which usually become apparent within
the first 2 years of life (118,123127). These observations
underscore the necessity for early diagnosis and intervention
in CMV infection.

FIGURE 11.8 Congenital cytomegalovirus infection. CT scans show

TA B L E 1 1 . 3
cortical atrophy and intracranial calcification. SEQUELAE IN CHILDREN WITH CONGENITAL
CYTOMEGALOVIRUS INFECTION ACCORDING
Of the 87.3% of infants with no clinical manifestations at TO TYPE OF MATERNAL INFECTION
birth, an average of 13.5% is at risk for the development of
Sequela Primarya Recurrenta p
similar abnormalities (54). The single most important late-
appearing sequela is sensorineural hearing loss (5% to 10% Sensorineural 15 (18/120) 5 (3/56) .05
of cases), which is bilateral in nearly half of the cases and hearing loss
substantial enough to interfere with learning and verbal com-
munication. The hearing impairment may become progressive Bilateral 8 (10/120) 0 (0/56) .02
only after the first year of life. hearing loss
Sensorineural deafness is probably the most common handicap Speech threshold 8 (9/120) 0 (0/56) .03
caused by congenital CMV infection, as first identified by Medearis 60 dBb
(114). CMV can replicate in the inner ear, as evidenced either by IQ 70 13 (9/68) 0 (0/32) .03
the cytopathology of Reissner membrane, stria vascularis, or semi- Chorioretinitisc 6 (7/112) 2 (1/54) .20
circular canals or by the presence of disease in the organ of Corti.
Hearing impairment in the child with symptomatic congenital Other neurologic 6 (8/125) 2 (1/64) .13
CMV infection can be progressive; it often becomes significant in sequelaed
infancy and early childhood but has been documented to occur in Microcephaly 5 (6/125) 2 (1/64) .25
some patients between 4 and 14 years of age (116). Congenital Seizures 5 (6/125) 0 (0/64) .08
CMV is second only to genetic defects in connexin proteins as a
Paresis or paralysis 1 (1/125) 0 (0/64) .66
known cause of sensorineural hearing loss (117).
Late-onset appearance of CMV retinitis has also been doc- Deathe 2 (3/125) 0 (0/64) .29
umented, although previously, CMV retinitis in the congeni- Any sequela 25 (31/125) 8 (5/64) .003
tally infected infant was not thought to relapse (118).
As techniques for neuroimaging improve, (119) isolated a
Percentages are given; numbers in parenthesis represent those with
lesions may be identified by cranial ultrasound or MRI which the sequela and the number evaluated.
b
were not part of the original case definitions of symptomatic For the ear with better hearing.
c
CMV infection given earlier. A current example is lenticulostri- Three of the seven children with retinitis (43%) in the primary
infection group had visual impairment.
ated vasculopathy, which some investigators consider a high d
Four of the eight children (50%) had more than one abnormality.
risk of future sensorineural hearing loss. There is a need for e
After the newborn period.
an internationally agreed case definition which takes account of From ref. 120.
changes in diagnostic practice.

Scheld_Ch11.indd 175 2/21/14 5:34 PM

 176 Part II: Viral Infections and Related Disorders
100
Recurrent infection (n = 64)
90
Children Free of Sequelae (%)
80 Primary infection (n = 125)
70
60
P = 0.02
50
40
30
20
10
0 extensive history of treatment of recurrent episodes of CMV
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Months Since Birth
FIGURE 11.9 Percentage of children with congenital cytomegalovi-
rus infection who remained free of sequelae, according to the type
of maternal infection. The p value was obtained by the log rank test.
(From ref. 120.)
Long-Term Follow-Up and Economic Impact
Long-term follow-up is mandatory in children with congenital
CMV infection because of late-onset hearing and ocular dis-
ease. The economic significance of this disease cannot be un-
derestimated, as reflected by a recent report from the Institute
of Medicine (128), which estimates that the present value of
the annualized health care costs of caring for individuals dam-
aged by CMV is $4 billion (mostly driven by congenital CMV).
Patients with Acquired
Immunodeficiency Syndrome
With the exception of polyradiculopathy, CMV infection
of the CNS produces no unique clinical features. Diagnosis
is often made at postmortem. Cell culture techniques were
used to test for CMV in brain tissue from 47 patients with
AIDS (13). A clinicopathologic association was seen between
the detection of CMV in the CNS and an antemortem diagno-
sis of undiagnosed encephalopathy, consistent with, but not
proof of, an etiologic role for CMV.
Encephalitis
CMV may cause encephalitis that is clinically indistinguishable
from HIV dementia and is often not diagnosed until autopsy
(129). When 14 autopsy-confirmed cases were compared with
17 controls with HIV dementia, the median survival of the
cases was shorter and they were more likely to have CMV dis-
ease outside the CNS (129). Typically, patients have a subacute
or chronic course, with cortical dysfunction leading to confu-
sion, lethargy, disorientation, and perhaps seizures. Brainstem
lesions, if present, may produce focal signs.
In six patients with necrotizing ventricular encephalitis,
chart review revealed distinctive clinical associations with
cranial nerve defects, nystagmus, and progressive ventriculo-
megaly detected by serial CT scans (130). This form of CMV
encephalitis is rapidly fatal.
Scheld_Ch11.indd 176
Polyradiculopathy
Patients present with a subacute onset of leg weakness and
numbness, leading to flaccid paraparesis. There may be pre-
ceding pain and paresthesias in the legs and perineum, and
areflexia with or without bladder dysfunction (131133).
CMV retinitis is also frequently found (131). A distinctive CSF
feature is the florid polymorphonuclear pleocytosis and low
glucose concentration.
Stem Cell Transplant Patients
Encephalitis caused by CMV is emerging as a late complication
in patients with severe and protracted T-cell immunocompro-
mise due to receipt of cord blood donation, T-cell depletion,
and/or antithymocyte globulin (134). These patients have an
viremia and often have strains of virus resistant to ganciclovir
and/or foscarnet before encephalitis develops. The mortality
is high.
Rasmussen Syndrome
There is some evidence that Rasmussen syndrome, with onset
in childhood following an infectious illness and characterized
by seizures and a progressive, unilateral cerebral atrophy and
neurologic deficits, may in some cases be associated with CMV
infection (135,136). However, detection of latent viral infec-
tion remains a possibility, and other investigators have not
been able to confirm a pathogenic role for CMV (137,138).
An uncontrolled case series of four cases reported benefit after
treatment with ganciclovir (139).
Peripheral Nervous System Syndromes
For completeness, distinctive clinical syndromes of the periph-
eral nervous system that have been associated with CMV in-
fection are described in the following sections.
Distal Symmetric Peripheral Neuropathy
Often termed painful peripheral neuropathy, distal symmetric
peripheral neuropathy has a subacute presentation, with pain
in the feet and clinical evidence of axonal atrophy (140). Some
of the early syndromes of the peripheral nervous system may
be the result of abnormal immune reaction.
Mononeuritis Multiplex
Patients with mononeuritis multiplex may present with sen-
sory and motor involvement of peripheral or cranial nerves.
Histologically, multiple peripheral nerves are involved in an
inflammatory process in which infiltrating polymorphonuclear
leukocytes and necrotizing vasculitis are seen (141).
DIAGNOSIS
The differential diagnosis of the clinical syndromes caused
by CMV is complex and discussed elsewhere (140,142).
Electromyography, nerve conduction studies, sural nerve biop-
sies, and MRI are frequently employed.
Evaluation of urine or saliva specimens from a child with
suspected congenital infection should lead to prompt detec-
tion of CMV. Classically, this was done by cell culture but is
2/21/14 5:34 PM

usually performed nowadays by PCR, which has equivalent
sensitivity and specificity (143). Repeat samples of urine and
saliva should then be tested to confirm the diagnosis, because
a positive saliva test can occasionally represent infected breast
milk imbibed by the baby rather than true congenital infection.
A blood sample should also be tested by PCR to detect viremia
which has a moderate association with the risk of developing
subsequent sensorineural hearing loss (144).
Diagnosis of CMV CNS infection is best made by PCR.
Several investigators have reported that PCR is a method of
high sensitivity and specificity for detecting CNS involvement
(145147). One exception to this is CSF samples collected at
autopsy, of which 70% were found to be PCR positive for
CMV with no clear correlation with histologic findings (148).
This indicates that CSF samples must be collected during life.
Cytospin preparations of CSF from 25 patients with AIDS
have been studied and stained with monoclonal antibodies
against pUL83 (pp65). Ten CSF samples were positive for
CMV with this technique, and it was reported that the poly-
morphonuclear leukocytes were hypersegmented, whether
or not they stained with the monoclonal antibody (149).
The same technique has also been shown to detect CMV in
13 cases of painful peripheral neuropathy, although these cells
are also found in cases of CMV retinitis (150).
Conventional cell culture for the propagation of CMV is far
too insensitive to detect the small amounts of CMV that are
found in the CSF, so this test is not recommended. Serology,
either of IgG or IgM antibodies, has no diagnostic value in the
investigation of these patients.
TREATMENT
Individual neonates with CMV disease have been given gan-
ciclovir, and inhibition of CMV has been reported. However,
ganciclovir has important potential toxicities in the neonate,
including neutropenia. The drug is also carcinogenic in animals
and has a cytostatic effect on the testes. It requires intravenous
administration, which may also produce significant morbidity.
To begin to study the potential safety and toxicity of ganciclovir
in neonates, Whitley et al. (151) conducted a randomized trial
comparing two doses of ganciclovir (4 mg/kg or 6 mg/kg given
intravenously twice daily for 6 weeks). The higher dose was tol-
erated as well as the lower dose, and so was taken forward into
a randomized trial of efficacy (152). The primary end point was
the proportion of children at 6 months with improved brain-
stem evoked potentials (or normal results if the baseline test
result was normal). This primary end point was met in 69%
of children given ganciclovir compared with 39% allocated to
no treatment. In addition, the proportion of children in whom
hearing worsened was 0% in the ganciclovir arm and 42% in
the no-treatment arm. Follow-up shows that these significant
changes are still present at 12 months of age. The neurologic
development of these children was worse in those not given
ganciclovir (153). This benefit is so important clinically that
a 6-week course of ganciclovir should now be considered to
be the standard of care for any child born with symptomatic
congenital CMV infection who would have met the entry cri-
teria for the trial described by Kimberlin et al. (152). The same
investigators showed that the prodrug valganciclovir could be
given to newborns (154). They are conducting a randomized
controlled trial comparing 6 weeks versus 6 months of valgan-
ciclovir given to symptomatic neonates with congenital CMV
infection, and the results are awaited with interest (http://www
.clinical trials.gov/show/NCT00466817).
Three drugs are used for the systemic treatment of CMV dis-
ease: ganciclovir, foscarnet, and cidofovir. Based on assessment
Scheld_Ch11.indd 177
Chapter 11: Cytomegalovirus 177
of CSF levels, ganciclovir and foscarnet do not penetrate the
CNS well, with estimates from animal experiments and small
studies in humans indicating that the CSF level is about one
third that found in plasma (155,156). Rather more patients
have been tested for foscarnet, whose CSF penetration appears
to be between one third and one half of plasma levels in most
patients (157,158). In addition to this pharmacologic disad-
vantage, all drugs have toxicities, discussed in the following
paragraphs. There are no reported double-blinded, placebo-
controlled trials of anti-CMV therapy in patients with AIDS
with CMV involvement of the CNS.
A case series examined the survival of two groups of AIDS
patients presenting with first-episode retinitis who had all been
treated with an intraocular device that released ganciclovir.
Some of the patients were given systemic ganciclovir treatment
in addition and had reduced mortality (159).
Five patients with CMV retinitis treated with maintenance
levels of ganciclovir have been described in whom abrupt pre-
terminal changes in mental status occurred. At autopsy, fulmi-
nant CMV encephalitis was found in all five, with prominent
ependymal and periventricular necrosis (160). These cases
demonstrate that prophylaxis with ganciclovir, in the doses
used for maintenance of CMV retinitis, cannot guarantee pro-
tection against CMV encephalitis. Furthermore, one patient
has been described who developed polyradiculopathy attrib-
uted to a ganciclovir-resistant strain of CMV after receiving
maintenance therapy for 8 months following a diagnosis of
CMV retinitis (161). Mathematical models of the replication
dynamics of CMV in vivo predicted that resistance should be
more common than was recognized clinically or by the use
of cell cultures for detecting CMV (162). This prediction has
been borne out by clinical cohort studies reporting that 15%
to 22% of transplant recipients or patients with AIDS given
long-term oral ganciclovir therapy develop CMV disease due
to resistant strains (163165).
Most patients given ganciclovir for polyradiculopathy do
not have clinical improvement (135,166,167). Some, however,
appear to respond (132,135,168). Some authorities use a com-
bination of ganciclovir plus foscarnet (each at full dose) but
again with disappointing results (169). There is no evidence for
synergy between ganciclovir and foscarnet in vivo, although
these drugs can be used in combination (each at half the nor-
mal dosage) to reduce the incidence of side effects (170).
The complications of ganciclovir include neutropenia and
thrombocytopenia. The drug is poorly bioavailable and is usu-
ally given by the intravenous route. Trials of high-dose oral
ganciclovir showed that maintenance doses can be provided
orally (171). This had the advantage of freeing the patient
from daily intravenous administrations, with the associated
risk of intravenous lines, but it did not overcome the problem
of subtherapeutic doses at the target organ, which facilitates
the emergence of resistant strains of CMV. More recently, the
valine ester prodrug, valganciclovir, has been licensed, which
provides the same area under the timeconcentration ganci-
clovir curve as does intravenous ganciclovir (172). It should
provide a more convenient and safer means of treating CMV,
especially because intravenous lines may predispose to bacte-
remias with a drug that causes neutropenia, and should reduce
the incidence of resistance.
Foscarnet is nephrotoxic and alters plasma levels of elec-
trolytes, particularly ionized calcium, which may precipitate
seizures. The drug also causes a fixed drug eruption on genital
skin. Although the incidence of nephrotoxicity can be reduced
significantly by adequate hydration, this drug remains second-
line therapy for the treatment of CMV disease. This is despite
the fact that a randomized comparison of ganciclovir and fos-
carnet for the treatment and maintenance of CMV retinitis in
2/21/14 5:34 PM
 178 Part II: Viral Infections and Related Disorders
HIV-infected individuals showed the drugs to be equipotent
for treating retinitis but that foscarnet had a significant sur-
vival benefit over ganciclovir (173). There are several possible
explanations for this finding including the potential efficacy of
foscarnet in treating HIV itself (174).
Cidofovir is nephrotoxic and must not be administered if
renal function is abnormal or if proteinuria is present. The
nephrotoxicity can be reduced by prehydration and adminis-
tration of probenecid.
A lipid prodrug of cidofovir (CMX001) is currently under-
going clinical trial (175).
Maribavir is a drug that directly inhibits CMV UL97. There
was evidence of antiviral activity in a phase 2 study of bone
marrow transplant patients where the need for preemptive
therapy was the primary end point (176). However, there was
no significant benefit when the lowest dose was compared to
placebo in a phase 3 study of bone marrow transplant patients
managed by preemptive therapy but where the end point was
CMV disease (177).
AiCuris 246 (Letermovir) inhibits the terminase enzyme
complex of CMV (responsible for packaging unit length
DNA into virions) and is currently in clinical trial in transplant
patients (178).
PREVENTION
Improved control of CMV disease of the CNS would be
expected if infection could be detected at an early stage and
treatment instituted promptly. However, in the absence of
natural history studies, it is not possible to design such trials
rationally. In my opinion, such trials should be organized so
that intervention studies, preferably prophylaxis of infection,
can be designed. Such studies should also include quantitative
measures of CMV load to determine whether a threshold value
exists above which CMV disease becomes more likely, as has
been reported for renal, liver, and marrow transplant recipi-
ents (179181). In transplant recipients, preemptive therapy
is given when CMV viremia is detected by PCR or antigen-
emia (182,183), although its relative merits compared with
prophylaxis are debated (184). A trial of preemptive therapy
in patients with AIDS (ACTG protocol 5030) failed to recruit
sufficient cases because HAART became available (185).
Controlled trials of antiviral chemotherapy for the prophy-
laxis of CMV disease in individuals infected with HIV have
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 CHAPTER 12 EPSTEIN-BARR VIRUS
SUSAN E. HOOVER, JEFFREY P. ROSS, AND JEFFREY I. COHEN
ETIOLOGY
Epstein-Barr virus (EBV) is a member of the herpesvirus family
(1) and, like other herpesviruses, contains a double-stranded
DNA core surrounded by a nucleocapsid. A tegument layer
containing several proteins envelops the nucleocapsid, which
is surrounded by an outer lipid envelope studded with viral
glycoprotein spikes.
EBV infects B lymphocytes and epithelial cells in the oro-
pharynx (2). Infection of epithelial cells results in lytic infec-
tion with production of virions, lysis of the cell, and release of
infectious virus. During virus replication, multiple EBV pro-
teins are expressed including the EBV early antigens (EAs),
DNA polymerase (the target of acyclovir), viral capsid antigen
(VCA), and viral glycoproteins. Infection of B lymphocytes
usually results in latent infection and immortalization of the
cells in vitro, without production of infectious virus. These
latently infected cells express only the EBV-encoded RNAs
(EBER-1 and EBER-2), nuclear proteins (EBNA-1, -2, -3A,
-3B, -3C, and LP), and latent membrane proteins (LMP-1,
-2A, and -2B).
EBV has a worldwide distribution, and the vast majority
of adults show serologic evidence of past infection. Primary
EBV infection is usually asymptomatic or mildly symptomatic
in early childhood; in contrast, symptomatic infectious mono-
nucleosis is more common in individuals who become infected
with EBV after the first decade of life. Transmission of EBV
probably occurs most often by exposure to saliva from asymp-
tomatic individuals who shed the virus. Serologic studies sug-
gest that EBV is commonly spread among susceptible siblings
within a family. EBV-associated infectious mononucleosis has
been transmitted by blood transfusion.
The incubation period for symptomatic infectious mono-
nucleosis is 30 to 50 days. During the first few weeks of the ill-
ness, peripheral lymphocytosis occurs, with a marked increase
in T cells and natural killer cells; many of these cells appear
as atypical lymphocytes on the peripheral blood smear.
Most of the clinical features associated with infectious mono-
nucleosis are manifestations of the vigorous cellular immune
responses to EBV infection rather than to direct cytotoxic ef-
fects of the virus. B cells are also increased in number, and up
to 20% may express EBV nuclear antigen during the first week
of illness.
DIFFERENTIAL DIAGNOSIS
Other infectious or noninfectious diseases can produce the
syndrome of infectious mononucleosis. Acute infection with
cytomegalovirus (CMV), Toxoplasma gondii, human immu-
nodeficiency virus type 1 (HIV-1), human herpesvirus type 6,
or hepatitis viruses can result in fever, lymphadenopathy, sore
throat, and atypical lymphocytes. Acute leukemia, lymphoma,
and reactions to certain drugs (e.g., phenytoin and sulfon-
amides) can also produce a syndrome resembling infectious
mononucleosis.
Other herpesviruses also produce neurologic symptoms
similar to EBV. Infection with varicella-zoster virus also can
Scheld_Ch12.indd 183
result in encephalitis, myelitis, or neuropathy in nonimmu-
nocompromised persons. Although encephalitis or radiculo-
neuropathy can occur in patients with CMV infection, these
patients are usually immunocompromised, and the disease is
progressive. Encephalitis due to herpes simplex virus (HSV) is
usually localized to the temporal lobes.
CLINICAL MANIFESTATIONS
Infectious Mononucleosis
EBV-associated infectious mononucleosis is an acute illness
characterized by fever, pharyngitis, lymphadenopathy, and
mononuclear leukocytosis with atypical lymphocytes (3).
Symptoms of infectious mononucleosis commonly include sore
throat, headache, and malaise in more than 50% of patients,
and myalgias, anorexia, nausea, and abdominal discomfort
in 10% to 20% of individuals. Physical examination shows
lymphadenopathy, pharyngitis, and splenomegaly in most pa-
tients, whereas 10% have hepatomegaly, jaundice, palatal enan-
them, or rash. Posterior cervical lymphadenopathy is most often
noted; however, any group of lymph nodes may be involved. A
pruritic maculopapular eruption develops in nearly all patients
after the administration of ampicillin. Important complications
of infectious mononucleosis include splenic rupture, autoim-
mune hemolytic anemia, thrombocytopenia, hepatitis, myocar-
ditis, airway obstruction from enlarged tonsils, and neurologic
abnormalities. Neurologic complications are cited as the lead-
ing cause of death resulting from infectious mononucleosis,
followed by secondary infection and splenic rupture. Fatalities
occur in fewer than 0.03% of cases of infectious mononucleosis.
Rare individuals infected with EBV develop a chronic ac-
tive infection, persisting 6 months and characterized by per-
sistent adenopathy and hepatosplenomegaly and involvement
of the lungs, eyes, or nervous system with EBV-infected lym-
phocytes. EBV infection of patients with the X-linked lympho-
proliferative disorder results in a fatal disease characterized
by lymphoid infiltration of organs, lymphomas, and opportu-
nistic infections. Immunocompromised patients may develop
EBV-associated lymphomas.
Neurologic Complications of Acute
Epstein-Barr Virus Infection
Involvement of the nervous system in infectious mononu-
cleosis is more common than generally appreciated. About
50% of patients have headache on presentation. Neck stiff-
ness without meningitis is a common finding. In one study,
about 25% of patients (43 of 162) had more than five cells
per cubic millimeter in the cerebrospinal fluid (CSF) (4). Many
of these patients had no symptoms of meningitis. Abnormal
Disclaimer: This chapter was prepared by Drs. Hoover, Ross, and Cohen
in their personal capacities. The views expressed herein do not necessarily
represent the views of the NIH, DHHS, or the federal government.
183
2/21/14 5:35 PM
 184 Part II: Viral Infections and Related Disorders

electroencephalograms (EEGs), which most often reveal dif-

fuse slowing patterns, have also been reported in patients with
infectious mononucleosis, but without clinically significant
central nervous system (CNS) disease (4).
Significant neurologic complications of acute infectious
mononucleosis are rare, occurring in fewer than 0.5% of more
than 4,300 cases of infectious mononucleosis in one review
(5). Neurologic complications, however, are an important
cause of morbidity in infectious mononucleosis and have been
reported in 6% to 7% of patients hospitalized with infectious
mononucleosis (6,7,7a). A study of children admitted to the
hospital with new neurologic symptoms found acute EBV in-
fections in 4% of patients and reactivated infections in 17%
of patients (8).
CNS symptoms may occur shortly before, during, or after
infectious mononucleosis or following acute EBV infection in
the absence of symptomatic infectious mononucleosis. Cases
of neurologic symptoms associated with infectious mono-
nucleosis before the 1970s, when EBV-specific serologic tests
were developed, must be regarded with caution because a
number of other infectious agents can produce the clinical
syndrome of mononucleosis. Only 1 of 14 cases of neurologic
complications associated with primary EBV infection reported
by Grose et al. (9) presented with clinical infectious mononu-
cleosis. Similarly, only 1 of 21 children with EBV encephalitis
identified prospectively at the Hospital for Sick Children in
Toronto had infectious mononucleosis; the others had nonspe-
cific symptoms of fever and headache (9a).
Examination of biopsy or autopsy specimens suggests that
immunologic mechanisms are probably more important in
the pathogenesis of neurologic complications than active viral
replication. Perivascular lymphocytic infiltrates, which may
include atypical lymphocytes, are often found in the leptomen-
inges, CNS parenchyma, nerve roots, and peripheral nerves
(10) (Fig. 12.1). Additional findings include parenchymal
edema and microglial proliferation (11). Inflammatory demy-
elinating lesions similar to those found in multiple sclerosis
or postinfectious encephalomyelitis or neuritis have also
been described (10,12). A report of antineuronal antibodies FIGURE 12.1 Brain biopsy from a 17-year-old girl with Epstein-Barr
in the serum of a patient with EBV-associated acute cerebellar virus encephalomyelitis. Top: Abnormal white matter showing peri-
ataxia, but not in patients with other neurologic diseases, pro- vascular infiltrates of inflammatory cells and foam cells. Some myelin
has been replaced by lipid-filled macrophages and hyperplastic astro-
vides support for an immune-mediated mechanism for CNS cytes. Hematoxylin-eosin stain; magnification 200. Bottom: Higher
disease (13). power view showing perivascular infiltrates and microglial reaction.
These studies indicate that the pathogenesis of EBV- Hematoxylin-eosin stain; magnification 400. (From Ambler M, Stoll
associated neurologic disease is different from that of HSV J, Tzamaloukas A, et al. Focal encephalomyelitis in infectious mono-
CNS disease. Although viral proteins are present in the brain nucleosis: a report with pathological description. Ann Intern Med.
of patients with herpes simplex encephalitis, brain biopsies 1971;75:579585, with permission.)
from patients with EBV encephalitis do not show viral nucleic
acids or proteins (14). Thus, autoimmune mechanisms are
probably responsible for the pathogenesis of EBV-associated
CNS disease.
Encephalitis
Patients having encephalitis associated with acute EBV infec-
Aseptic Meningitis tion may present with seizures, coma, personality changes,
distortions of perception, cerebellar ataxia, or focal brainstem
Aseptic meningitis is the most common neurologic complica- or cerebral findings. These complications usually occur 1 to 3
tion of primary EBV infection. Patients present with headache, weeks after the onset of clinical infectious mononucleosis, but
malaise, stiff neck, and occasionally photophobia (15). The they have occurred shortly before, during, or after other symp-
CSF usually shows a mild to moderate lymphocytic pleocyto- toms of infectious mononucleosis (15,16,17a). Alternatively,
sis, occasionally with atypical lymphocytes. The CSF protein they may be the only symptom of acute infection with EBV
concentration is normal or mildly elevated, and the glucose (6,18,19). Patients usually present with fever and headache
concentration is usually normal (15,16). Although the CSF progressing to encephalitis over a few days. Most cases occur
opening pressure is usually normal or slightly elevated, in in older children and young adults.
some patients, it is markedly increased, and repeated lumbar Generalized seizures, as well as coma and other signs of
puncture provides symptomatic relief (17). Aseptic meningitis diffuse encephalopathy, may occur without focal neurologic
associated with EBV has a good prognosis and usually resolves findings (5,7,15,16). Patients have presented with new onset
without CNS sequelae. of seizures and only later have been found by serology to have

Scheld_Ch12.indd 184 2/21/14 5:35 PM


recent EBV infection (20). EEGs in patients with diffuse en-
cephalopathy show generalized slowing with occasional sharp
wave activity, but they may reveal periodic discharges in pa-
tients with seizures (20).
Focal neurologic findings in EBV-associated encephalitis in-
clude localized seizures, hemiparesis, and unilateral Babinski
reflexes. In a large prospective study of encephalitis by the
Collaborative Antiviral Study Group, in which focal neuro-
logic findings were required for entry, 2% of patients (8 of
432) were found to have EBV encephalitis (21).
Although EBV encephalitis may involve any area of the
brain, the cerebellum is commonly involved. Numerous cases
of cerebellitis, usually manifested as acute cerebellar ataxia,
have been reported (13,21a). Most patients present with ab-
normalities of gait. A complete recovery is usual, but severe
cases with tonsillar herniation and death have been reported
(21b). Other commonly involved areas include the basal gan-
glia and cerebral hemispheres, with many patients having
involvement of multiple areas (21c21e). Several cases of in-
creased intracranial pressure associated with ischemic lesions
of the corpus callosum have been reported, two requiring
decompressive craniectomy (17a,21f,22). Encephalitis result-
ing from EBV infection has been reported as a cause of acute
hemiplegia in children and young adults (23). Some patients
present with a typical history of infectious mononucleosis fol-
lowed by psychosis and personality changes. Children with
EBV encephalitis may present with metamorphopsia, the so-
called Alice in Wonderland syndrome, in which affected in-
dividuals have perceptual distortions of personal body image,
size, and spatial relationships (8,18). Movement disorders in-
dicative of extrapyramidal involvement have been reported.
These include cogwheel rigidity and athetosis (24), Parkinson-
like syndrome (25,21d,21e), and Sydenham-type chorea (26).
Brainstem encephalitis with cranial nerve and long-tract signs
(27) and the locked-in syndrome have been described.
Acute psychosis (28) and transient global amnesia (29) may be
the only neurologic manifestation of EBV infection. Unusual
complications of EBV encephalitis include acute aqueductal
stenosis (30) and the syndrome of inappropriate antidiuretic
hormone secretion (31). Reye syndrome, acute fatty degenera-
tion of the liver accompanied by encephalopathy, has followed
primary EBV infection in a number of reported cases (32).
Rare cases of relapsing or chronic encephalitis associated
with acute EBV infection have been reported. Tolly, Wells, and
Sty (33) described a 10-year-old girl with waxing and wan-
ing neurologic symptoms associated with EBV infection that
A B
Scheld_Ch12.indd 185
Chapter 12: Epstein-Barr Virus 185
occurred over 3 months. Magnetic resonance imaging (MRI)
showed rapidly changing CNS lesions that correlated with the
fluctuating neurologic examination results (Fig. 12.2).
Myelitis
Spinal cord lesions can accompany encephalitis and present
as paraplegia, quadriplegia, or other motor or sensory losses
(5,34). The CSF shows a mononuclear pleocytosis with ele-
vated levels of protein, but the glucose level is often normal.
Isolated transverse myelitis with sensory and motor loss in the
absence of encephalopathy has also been reported (6,9), with
viral DNA being detected in the CSF (35,36). Most cases of
myelitis occur in older children and young adults and eventu-
ally resolve without residua, although several cases in older
adults have resulted in long-term sequelae such as muscle
weakness and sensory deficits (34).
Cranial and Peripheral Neuritis
Although any of the cranial nerves may be affected during
EBV infection, palsies of cranial nerve VII are most com-
mon. Numerous cases of unilateral or bilateral Bell palsy have
been reported in the setting of acute infectious mononucleosis
(5,6,15). With the advent of specific EBV serologic tests, in-
creased numbers of cases of Bell palsy have been attributed
to otherwise asymptomatic EBV infection (9). Other forms
of cranial nerve involvement include anosmia (37); Fisher
syndrome, involving multiple cranial nerves (38); bilateral
sensorineural hearing loss (39); unilateral hearing loss with
ipsilateral involvement of cranial nerves V and VII (40); ves-
tibular neuritis with oscillopsia; hypoglossal (XII) nerve palsy
(41); vocal fold paralysis due to vagal (X) nerve palsy (41);
extraocular muscle palsies involving cranial nerves III (42), IV,
or VI (6); and acute optic neuritis (15,43). Other ocular com-
plications include papilledema, retrobulbar neuritis, chiasmic
neuritis, ptosis, uveitis, episcleritis, and opsoclonus (44,45).
Among peripheral nerves that are affected during EBV in-
fection, the brachial plexus and its branches are most com-
monly involved. Brachial plexopathy in the setting of infectious
mononucleosis usually presents with shoulder pain followed
by paralysis of the serratus anterior for weeks to months
(7,46). Five patients with lumbosacral radicular plexopathy
and one patient with femoral neuropathy were described who
FIGURE 12.2 MRI scan of a 10-year-old girl
with a prolonged neurologic syndrome associated
with Epstein-Barr virus infection. T2-weighted im-
ages reveal a right cerebellar lesion (A) and bilat-
eral frontal lesions (B). These were two of several
transient lesions present on MRI scans that cor-
related with neurologic findings over a 3-month
period and resolved completely over subsequent
weeks. (From Tolly TL, Wells RG, Sty JR. MR
features of fleeting CNS lesions associated with
Epstein-Barr virus infection. J Comput Assist
Tomogr. 1989;13:665668, with permission.)
2/21/14 5:35 PM
 186 Part II: Viral Infections and Related Disorders

had serologic evidence of recent EBV infection (47). Acute au-

tonomic neuropathy has also been reported with acute EBV
infection (48).

Guillain-Barr Syndrome
Guillain-Barr syndrome, or acute inflammatory demyelin-
ating polyneuropathy, is characterized by progressive motor
weakness of more than one limb and areflexia. Guillain-
Barr syndrome usually presents several days to weeks after
the onset of infectious mononucleosis, or it may present in
patients with otherwise asymptomatic EBV seroconversion.
Grose et al. (9) found evidence of acute EBV infection in 12
of 24 patients with Guillain-Barr syndrome. None of these
patients had symptomatic infectious mononucleosis before the
onset of Guillain-Barr syndrome. Dowling and Cook (49) re-
ported that 8 of 100 patients with Guillain-Barr syndrome A
had an immunoglobulin M (IgM)positive test result for EBV,
indicative of recent infection. A prospective study found evi-
dence of acute EBV infection in only 2 of 99 patients with
Guillain-Barr syndrome, with a similar frequency (2%) in
age-matched controls (50). However, the lack of association
of Guillain-Barr syndrome with EBV may have been a conse-
quence of the older age of the patients studied, because most
older individuals are already seropositive for EBV. A case
control study from the Netherlands found evidence of acute
EBV infection in 16 (10%) of 154 patients with Guillain-
Barr, compared with 1% of age-matched controls with other
neurologic diseases (51).

Epstein-Barr VirusAssociated Central B

Nervous System Lymphoma
EBV has been associated with CNS lymphomas in patients
without any apparent immunodeficiency or, more commonly,
in patients with underlying immunodeficiencies. Although
some studies of immunologically normal individuals have
demonstrated EBV DNA in up to 46% (11/24 patients) of
B-cell CNS lymphomas by in situ hybridization (52), most
primary CNS B-cell lymphomas in nonimmunocompromised
persons do not contain EBV genomes.
EBV-associated CNS lymphomas have been reported in pa-
tients receiving solid organ or bone marrow transplants and in
patients with leukemia, X-linked lymphoproliferative disease,
and acquired immunodeficiency syndrome (AIDS) (53). From
10% to 25% of lymphomas in patients with heart, heartlung,
liver, kidney, or bone marrow transplants involve the CNS and
contain EBV genomes (54).
EBV has been detected in virtually 100% of CNS lym-
phomas in patients with AIDS (5456). Nearly all EBV-
positive lymphomas in human immunodeficiency virus
(HIV)positive patients express the EBV latency-associated
proteins EBNA-2 and LMP-1 (57,58) (Fig. 12.3). Viral
DNA is present in the lymphoma, not in neuronal cells (55).
EBV-associated CNS lymphoma in patients with AIDS oc-
curs more often in patients with very low CD4 cell counts.
HIV patients who later developed CNS lymphomas lacked
EBV-specific CD4 T cells (58a). CNS lymphomas are more
often monoclonal and lack c-Myc translocations when com-
pared with systemic (not involving the CNS) lymphomas in
patients with AIDS.
Early studies, prior to the era of highly active antiretroviral
therapy (HAART), showed that polymerase chain reaction (PCR)
detection of EBV DNA in the CSF was highly predictive for pri-
mary CNS lymphoma in patients with AIDS. Cinque et al. (59)
FIGURE 12.3 Immunohistochemical staining of a central nervous
system lymphoma from a patient with acquired immunodeficiency
syndrome. A: Staining with a monoclonal antibody to EBNA-2
shows nuclear staining in most of the tumor cells (closed arrow) but
not in cells lining a blood vessel (open arrows) (magnification 250).
B: Staining with a monoclonal antibody to latent membrane protein
shows cytoplasmic and membrane staining in several of the tumor
cells (closed arrows) (magnification 400). (From Bashir R, Luka J,
Cheloha K, et al. Expression of Epstein-Barr virus proteins in primary
CNS lymphoma in AIDS patients. Neurology. 1993;43:23582362,
with permission.)
used EBV DNA PCR to test CSF of patients with HIV and CNS
symptoms. They found that PCR for EBV had a sensitivity of
97% (35 patients PCR positive/36 with disease), specificity of
98% (180 patients PCR negative/183 without disease), and a
positive predictive value of 90% for the diagnosis of CNS lym-
phoma. Antinori et al. (60) showed a sensitivity of 85% and a
specificity of 100% for PCR of CSF in their evaluation of pa-
tients for CNS lymphoma. In some patients, EBV was detected
in CSF by PCR before CNS lesions were apparent on computed
tomographic (CT) or MRI scanning (59). However, more recent
studies in the era of HAART indicate that PCR alone is less
specific for a diagnosis of CNS lymphoma with a positive pre-
dictive value of 30% or less (60a,60b).
The combination of CSF EBV PCR and single-photon
emission computed tomography (SPECT) scanning has shown
promise for distinguishing CNS lymphoma from cerebral toxo-
plasmosis and other infections (61,62). A SPECT-to-thallium
uptake ratio is calculated as the amount of thallium-201 up-
take in the lesion divided by uptake in uninvolved brain or
scalp. Using SPECT scanning in HIV-infected patients with

Scheld_Ch12.indd 186 2/21/14 5:35 PM

 Chapter 12: Epstein-Barr Virus 187

focal brain lesions on CT or MRI, the sensitivity of a positive
scan for lymphoma ranged from 86% to 92%, and the speci-
ficity ranged from 83% to 89% (61,62). When both SPECT
scanning and CSF EBV PCR were performed, the sensitivity
increased to 100% (61).
Other Neurologic Syndromes Possibly
Associated with Epstein-Barr Virus
Epidemiologic data suggest an association between EBV and
multiple sclerosis (MS). Eight casecontrol studies found that
97% to 100% of patients with MS were seropositive for EBV,
whereas only 65% to 95% of age- and sex-matched controls
were seropositive (63). Compilation of these studies, involving
about 1,000 patients with MS and a similar number of controls,
yielded an odds ratio for MS in EBV-seropositive persons ver-
sus EBV-seronegative persons of 13.5 (95% confidence interval,
6.331.4). A casecontrol study of 305 persons who developed
MS and 610 matched controls found that all 10 of the EBV-
negative persons who subsequently developed MS became EBV
positive before MS onset, whereas only 10 of 28 controls who
never developed MS became EBV positive (64). Although a
metaanalysis showed a 2.2-fold relative risk of MS in persons
with infectious mononucleosis (65), the vast majority of patients
with MS have no history of infectious mononucleosis (66).
A nested casecontrol study of stored sera from more than 3
million military personnel found that serum levels of IgG VCA
or EBNA complex were proportionate to the risk of MS with
an average time of 4 years between serum collection and di-
agnosis of MS (67). The relative risk of MS was 20 and 34 in
those with the highest level of EBV VCA and EBNA complex
antibodies, respectively, compared with those with the lowest
titers of these antibodies. A follow-up study showed a similar
increase in risk with antibodies to EBV EBNA complex and
EBNA-1 antibodies (68). Wandinger et al. (69) reported an as-
sociation between EBV reactivation and MS disease activity. In
their study of 19 patients with MS followed monthly for 1 year,
patients with clinically documented relapses or progression of
MS had more frequent anti-EBV EA immunoglobulin A (IgA)
seroconversion or detectable EBV DNA in the serum com-
pared with those with stable MS. Several patients have been
reported who initially presented with acute EBV encephalitis
and developed new demyelinating CNS lesions over a period
of years, resulting in the diagnosis of MS (12,70). MS patients
have increased T-cell responses to EBV EBNA-1 which cross-
react with myelin antigens and result in production of inter-
feron (IFN)- (70a). Although one study reported finding EBV
RNA and protein in the brains from patients with MS (71),
EBV RNA has generally not been detected in MS plaques or in
CSF from patients with MS, and intrathecal anti-EBV antibody
synthesis did not differ in patients with MS and other controls
(72). EBV might be a cofactor for MS, or EBV infection and
MS may share a common genetic predisposition or a common
immunologic abnormality. The true role of the virus in the
pathogenesis of MS is unclear. Additional studies are needed,
particularly to look at CSF for EBV DNA or RNA, oligoclonal
bands specific for EBV, intrathecal synthesis of EBV antibody,
and EBV-specific T cells in patients with MS and controls.
In the mid-1980s, two small casecontrol studies reported
elevated antibody titers to EBV EA in patients with the chronic
fatigue syndrome (73,74). These patients presented with per-
sistent fatigue, myalgias, and mild cognitive impairment.
Other studies have shown that antibody titers to EBV EA
remain elevated in a substantial number of otherwise healthy
individuals. A study of 548 patients attending a referral clinic
found no differences in the seroprevalence or mean titers of
antibodies to EBV in patients with chronic fatigue compared
with healthy controls (75). Although some patients have per-
sistent fatigue lasting several months after acute infectious
mononucleosis, at present, there is no evidence for persistent
EBV infection as a cause of the chronic fatigue syndrome.
Several patients have been reported with the new onset of
depressive illness following acute infectious mononucleosis
(76). Subsequent casecontrol studies have yielded conflict-
ing results (77,78). Review of these studies indicates that EBV
does not play a significant role in the pathogenesis of depres-
sion. Three cases have been reported in which fatal subacute
sclerosing panencephalitis (SSPE), which is associated with
a measles-like agent, occurred concomitantly with infectious
mononucleosis (79). Whether EBV infection or its associated
immune alterations contributed to the development of SSPE in
these cases is not known.
LABORATORY AND
IMAGING STUDIES
The humoral immune response to EBV infection involves
both viral-specific and nonspecific antibodies (Table 12.1).
Detection of heterophile antibodies at a titer of more than 40,
along with symptoms of infectious mononucleosis and atypi-
cal lymphocytes, is diagnostic of acute EBV infection. The
titer of heterophile antibody is defined as the maximum serum
dilution after absorption with guinea pig kidney cells, which
can agglutinate sheep, horse, or beef erythrocytes. The com-
mercially available monospot test is based on the heterophile
test. False-positive results may occur in some patients with col-
lagen-vascular disease, lymphoma, or hepatitis; false-negative
results are more common in children younger than 5 years.
TA B L E 1 2 . 1
DIAGNOSTIC TESTS IN INFECTIOUS
MONONUCLEOSIS AND EBV-ASSOCIATED
NEUROLOGIC SYNDROMES
I. Serology
Antibody Onset Duration
VCA IgM Before or at time of symptoms 12 mo
VCA IgG Before or at time of symptoms Lifelong
EBNA 34 wk after onset of symptoms Lifelong
EA Peaks 34 wk after symptom onset; Months to
present in 70% of patients years
Heterophile Before or at time of symptoms; Weeks to
present in about 90% of patients months
II. Studies in EBV-associated neurologic syndromes
Cerebrospinal fluid: protein, lymphocytes, atypical
lymphocytes, VCA IgG, PCR for EBV DNA
Computed tomography
Magnetic resonance imaging
Single-photon emission computed tomography
Electroencephalography
EA, early antigen; EBNA, EBV nuclear antigen; PCR, polymerase chain
reaction; VCA, viral capsid antigen.

Scheld_Ch12.indd 187 2/21/14 5:35 PM

 188 Part II: Viral Infections and Related Disorders
Specific antibody responses directed against EBV are
more reliable than heterophile antibodies in making a diag-
nosis of EBV infection. Detection IgM antibodies to VCA,
which are usually present for 1 to 2 months after infection,
is particularly useful in the diagnosis of acute EBV infection.
Immunoglobulin G (IgG) antibodies to VCA are less helpful
for diagnosis, because they persist for life. EBV EA antibodies
develop later after infection and generally are not useful for
diagnosis of acute infection. Patients with chronic active EBV
infection may have elevated VCA IgG or EA antibody titers.
Antibodies to EBNAs are usually detectable 3 to 4 weeks after
onset of symptoms of infectious mononucleosis and persist
for life. Seroconversion to anti-EBNA positivity is evidence
for recent infection with EBV. Anti-EBNA antibodies may be
absent in immunocompromised patients.
Establishing the diagnosis of an EBV-associated neurologic
syndrome relies on an appropriate clinical neurologic diag-
nosis in the setting of serologic evidence of acute or rarely
chronic active EBV infection (Table 12.1). Examination of the
CSF often reveals a lymphocytic pleocytosis with an elevated
protein level, particularly in EBV encephalitis; atypical lym-
phocytes, if present, provide a clue to diagnosis. The CSF in
Guillain-Barr syndrome typically contains increased levels of
protein without a significant pleocytosis.
EBV has rarely been cultured from the mononuclear
cells obtained from the CSF of patients with neurologic
complications of EBV (80). EBV DNA has been detected by
PCR of CSF or neural tissue in patients with EBV-associated
neurologic conditions (14,26,81). Imai et al. (81) studied five
children with EBV-associated neurologic conditions diagnosed
by standard EBV serology. EBV DNA, but not other herpes-
virus DNA, was detected by PCR of the CSF from each case.
EBV DNA became undetectable by PCR as patients recovered
from their neurologic complications. Weinberg et al. (36) per-
formed quantitative PCR of the CSF and demonstrated that
patients with CNS lymphoma and encephalitis had high EBV
loads (104 EBV copies/mL); patients with encephalitis had
higher leukocyte counts than those with lymphoma. Two
patients with myelitis had lower EBV loads (103 EBV copies/
mL), but high leukocyte counts. Reverse transcriptase PCR
(RT-PCR) detected EBV lytic cycle messenger RNAs (mRNAs)
in the CSF of several patients with lymphoma or encephalitis.
EBV in the CNS declined in two patients with lymphomas
that responded to treatment, and increased in four patients with
Scheld_Ch12.indd 188
progressive disease (60). Because EBV is present in circulating
lymphocytes in asymptomatic seropositive individuals, culture or
PCR of cells from the CSF of EBV-seropositive patients with other
causes of CNS inflammation is an important negative control be-
fore a causal association with EBV can be shown. Measurement
of EBV DNA is frequently used for diagnosis, monitoring, and
prevention of lymphoproliferative disease after transplant (81a).
Intrathecal production of EBV-specific antibody is consid-
ered present when the ratio of the CSF-to-serum EBV antibody
titer is greater than the ratio of the CSF-to-serum -globulin
concentration. Production of EBV antibody in the CSF has
been demonstrated in several studies and suggests that active
virus replication may occur in the CNS (31,34,81).
CT may show changes typical of viral encephalitis or
acute disseminated encephalomyelitis with low attenuation,
nonenhancing cerebral lesions that may be associated with
mass effect, or edema in progressive disease (33). MRI is con-
siderably more sensitive and can reveal lesions, particularly
on T2-weighted images, when CT findings are normal (82)
(Fig. 12.4). SPECT brain scans show lesions with reduced
uptake in patients with EBV encephalitis (18) and increased
uptake in patients with EBV lymphomas (61,62). EEGs fre-
quently show generalized slowing with occasional bursts of
activity in patients with encephalitis.
TREATMENT AND OUTCOME
The treatment of neurologic complications associated with
acute EBV infection is generally supportive and may include an-
ticonvulsants, judicious use of fluids (to avoid cerebral edema),
and mechanical ventilation. Corticosteroids may be required
in cases of increased intracranial pressure. Steroid treatment in
cases of uncomplicated infectious mononucleosis reduces the
duration of fever and sore throat but does not reduce lymph-
adenopathy or splenomegaly (83). Corticosteroids have been
reported to be helpful in several anecdotes describing neuro-
logic complications related to EBV infection (including enceph-
alomyelitis, cerebellar ataxia, transverse myelitis, and cranial
and peripheral neuropathies) without intracranial hypertension
(24,38,47). Steroids, however, have also been associated with
the new onset of neurologic symptoms in patients with acute
infectious mononucleosis (84) and with a worse outcome in
Guillain-Barr syndrome (85). The limited experience with
FIGURE 12.4 Cerebral imaging from a 10-year-
old girl with Epstein-Barr virus encephalitis.
A: Findings of contrast-enhanced computed
tomographic scanning are normal. B: T2-weighted
MRI scan at the same level demonstrates bilat-
eral abnormalities in the posterior medial tempo-
ral areas (arrows). (From Bale JF, Andersen RD,
Grose C. Magnetic resonance imaging of the brain
in childhood herpesvirus infections. Pediatr Infect
Dis J. 1987;6:644647, with permission.)
2/21/14 5:35 PM

corticosteroids for EBV-associated CNS disease suggests that
they are useful in select cases; however, their potential benefits
must be balanced against their numerous risks.
Acyclovir inhibits EBV replication in vitro; however, a meta-
analysis of five clinical trials did not show any benefit of acyclovir
in the therapy of acute infectious mononucleosis (86). Although
acyclovir has been used in some cases of CNS disease associated
with EBV, it probably provides little or no benefit (87). Acyclovir
might be used in conjunction with corticosteroids for select cases
of EBV-associated CNS disease in an attempt to reduce viral rep-
lication in the setting of an immunosuppressing agent.
EBV-associated lymphomas involving the CNS in posttrans-
plant recipients are usually treated with cytotoxic chemotherapy
and/or radiation therapy. Immunosuppression is reduced when
possible. Newer treatments include monoclonal antibodies to
B-cell surface antigens (88,89), interferon- therapy (90), or
infusion of EBV-specific cytotoxic T cells (91). The incidence of
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Chapter 12: Epstein-Barr Virus 189
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2/21/14 5:35 PM
 CHAPTER 13 HUMAN HERPESVIRUS-6
MARY T. CASERTA
HISTORY
Human herpesvirus-6 (HHV-6) was first isolated from six
adults with acquired immunodeficiency syndrome (AIDS) or
lymphoproliferative disorders by Salahuddin et al. (1) in 1986.
Limited genomic analysis and morphologic studies suggested
that the new virus was a member of the herpesvirus family
and it was named human B lymphotropic virus (HBLV) based
on an apparent B-cell tropism (2). Further experiments dem-
onstrated the propagation of HBLV in various human cell
lines, including those of T-cell, B-cell, megakaryocytic, glial,
and endothelial origin, and the designation of HHV-6 was
proposed (3,4).
In 1988, Yamanishi et al. (5) were the first to report an etio-
logic role for HHV-6 in human disease. They isolated HHV-6
from the peripheral blood mononuclear cells (PBMCs) of four
Japanese children with exanthem subitum (roseola infantum)
and demonstrated seroconversion to HHV-6 in the patients
convalescent sera. Since its discovery, numerous other diseases
have been linked with HHV-6 in both immunocompromised
and immunocompetent hosts during primary or reactivated
infection, but a clear causal connection has not always been
proven. Diseases of the central nervous system (CNS) that
have been associated with HHV-6 include encephalitis, pri-
marily in immunocompromised hosts, seizures, and multiple
sclerosis (MS) (6). Chronic fatigue syndrome, Sjgren syn-
drome, and several lymphoproliferative disorders including
malignancies were all initially associated with HHV-6 but
have now been shown by further study to be unlikely due to
HHV-6 infection (79).
The syndrome of roseola has been well known among pedi-
atricians for generations. Most authors credit Zahorsky (10) in
1913 with the first definite description of the illness as a com-
mon, self-limited, febrile exanthematous disease of infancy. In
1941, Breese (11) described the epidemiologic, clinical, and
laboratory manifestations of roseola based on his experience
with 100 patients. Eight years later, Berenberg, Wright, and
Janeway (12) reported convulsions as the most common com-
plication of roseola, occurring in up to one third of children.
Kempe et al. (13) were able to document the infectious nature
of the illness in 1950 by directly transmitting disease via serum
and throat washings from an infected child to an uninfected
child and to rhesus monkeys (Macaca mulatta).
EPIDEMIOLOGY
Seroprevalence
Worldwide surveys have demonstrated ubiquitous infection
with HHV-6. Seroprevalence rates of more than 80% have
been reported consistently in various populations of adults by
several methods (1416). Age-specific studies have revealed
that antibody to HHV-6 is universally present in cord blood
and newborn sera at titers higher than in maternal sera, with
a gradual fall in geometric mean titers and seroprevalence
noted in the first 4 months of life, corresponding to the loss
Scheld_Ch13.indd 191
of transplacental antibody (17,18). Following this nadir, the
geometric mean titers increase steadily to reach a peak at
1 year of age (7,19,20). By 3 years of age, 100% of children
have acquired serologic evidence of infection with HHV-6. No
seasonal predilection for primary HHV-6 infection has been
noted in prospective studies, but small outbreaks of roseola
among infants documented by seroconversion to HHV-6 have
been reported (21,22). Seroprevalence rates remain stable
throughout childhood, adolescence, and adulthood until age
40 years, when a gradual fall in the prevalence and geometric
mean titer of antibody to HHV-6 is noted (23,24).
Transmission
The pattern of widespread and rapid acquisition of HHV-6
infection in infancy without contact with similarly ill individu-
als implies that the virus is spread readily from asymptomatic
children and adults to susceptible infants. HHV-6 DNA has
been frequently detected via polymerase chain reaction (PCR)
in saliva and throat swabs from healthy adults and children
both in cross-sectional studies and over time (25,26). Salivary
gland tissue specimens screened by in situ hybridization,
immunohistochemistry (IHC), and PCR have also been shown
to contain HHV-6, suggesting that saliva may be a major mode
of transmission and that the salivary glands are a site of persis-
tent infection (27,28). In a prospective, longitudinal study of
infants, the risk of acquiring primary HHV-6 infection in the
first year of life was greater among subjects whose parents re-
ported saliva-sharing practices, further supporting saliva as an
important mode of transmission (29). Recently, HHV-6 DNA
has been identified in a majority of nasal mucous and olfactory
tissue specimens suggesting that respiratory droplets may also
be a source of viral spread (30).
Evidence of primary HHV-6 infection in infants as young
as 14 to 21 days documented by viremia and rising antibody
titers demonstrates that the protection provided by maternal
antibody is incomplete and suggests the possibility of perina-
tal transmission of HHV-6 (21,31). These data are consistent
with reports of HHV-6 DNA in both the blood and the cer-
vical/vaginal samples from 12% to 25.8% of both pregnant
and nonpregnant women, implying possible sexual transmis-
sion of HHV-6 as well (3235). HHV-6 DNA was not detected
in 120 specimens of breast milk, making breast-feeding an
unlikely mode of transmission of HHV-6 (36).
Congenital infection with HHV-6, defined as the presence
of viral DNA in cord blood specimens, has been documented
in 1.19% (exact CI 1.02, 1.38) of newborns (37). Eighty-
six percent of congenital infections are due to chromosomal
integration. Transplacental HHV-6 infection accounts for the
remaining 14% of congenital infections (38). Chromosomal
integration is unique to HHV-6 among the human herpesvi-
ruses and has been identified in 0.85% of unselected subjects
(39). In individuals with chromosomal integration of HHV-6
(ciHHV-6), the entire viral genome is present in every nucle-
ated cell of the body, including the germline, and transmitted
via Mendelian genetics (40). Fluorescent in situ hybridization
has demonstrated that multiple chromosomes may harbor
191
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 192 Part II: Viral Infections and Related Disorder

FIGURE 13.1 Schematic comparing the genome structure of HHV-6 to inherited HHV-6 (iHHV-6).
A: The linear HHV-6 genome contains a unique long (UL) region of 143 kb with left and right direct
repeats (DR) of 8 kb at the termini. Perfect and imperfect telomere sequence (TTAGGG) positioned at
the end of DR play a role in HHV-6 chromosome integration into the telomere. B: Fluorescence in situ
hybridization (FISH) of PBMCs from a patient with iHHV-6A integrated into the telomere of chromo-
some 22q. Metaphase chromosomes counterstained with DAPI (blue), cy5-PNA telomere probe (red),
and FITC-conjugated HHV-6 cosmid probe (green). C: Genome structure of iHHV-6 in which HHV-6
DRR is fused with the telomere repeats near the chromosome subtelomere and the DRL fused with the
remaining telomere repeat array (TTAGGG)n. (From Arbuckle JH, Medveczky PG. The molecular biol-
ogy of human herpesvirus-6 latency and telomere integration. Microbes Infect. 2011;13:731741, with
permission. Copyright 2011 Elsevier Masson SAS. All rights reserved.)

integrated virus; however, the viral genome is always identi-
fied at the proximal end of the telomere with one site usually
identified per family (41,42). The HHV-6 U94 gene product
is thought to play a role in HHV-6 latency and in mediating
HHV-6 chromosomal integration via homologous recombi-
nation between the perfect telomere repeat sequences (TRS)
found in the direct repeat segments of the HHV-6 genome and
human telomeres (43) (Fig. 13.1).
Individuals with ciHHV-6 are notable for having persis-
tently high HHV-6 DNA viral loads in whole blood, serum,
plasma, and hair follicle specimens, with one or more genome
copies per cell (44). Although replicating virus can be induced
from cultured lymphocytes of individuals with ciHHV-6 via
treatment with histone deacetylase inhibitors, it is unknown
whether the production of infectious viral particles occurs in
vivo (41). The observation that infants with transplacental
HHV-6 infection have mothers with ciHHV-6 suggests that
integrated virus may be able to replicate as free virus and be
transmitted (45). No clinical manifestations have been rec-
ognized in infants with ciHHV-6 and the long-term clinical
significance of chromosomally integrated HHV-6 is unknown.
Preliminary data have demonstrated the rate of ciHHV-6
in groups of solid organ transplant patients and those with
malignancies to be approximately double that found in the
general population suggesting possible pathogenic potential;
however, this has yet to be confirmed (39).
Taxonomy
Soon after the initial description of HHV-6, two groups of
viruses were identified: HHV-6 variant A and variant B (46).
Both were included as members of the Roseolovirus genus
in the Betaherpesvirinae subfamily, along with HHV-7 and
human cytomegalovirus (CMV) (7). The two HHV-6 vari-
ants were found to be highly genetically related but could
be distinguished by the pattern of reactivity with monoclo-
nal antibodies, in vitro cellular tropism, nucleotide sequence
analysis, and restriction fragment length polymorphisms
(7,47,48). In North America, Europe, and Japan, HHV-6B
was found in approximately 97% of both healthy and immu-
nocompromised hosts and in infants during primary infection
(49,50). Recent PCR data have suggested that HHV-6A is the
predominant virus identified in children in sub-Saharan Africa
(51). In infants identified with ciHHV-6 in the United States,
approximately one third had HHV-6A, a frequency substan-
tially higher than in children with primary infection (21,38).
Dual infection with HHV-6A and HHV-6B has also been docu-
mented in both adults and children. Because of the differences
noted in epidemiology, tissue tropism, genome composition,
disease associations, and possible virulence between HHV-6A
and HHV-6B, the two were reclassified as separate species
in the genus Roseolovirus by the International Committee on
Taxonomy of Viruses in 2012. Further clarification of the epi-
demiology of HHV-6A and HHV-6B awaits the development
of reliable species-specific serologic assays (52,53).
VIRAL CHARACTERISTICS
HHV-6 contains a linear, double-stranded DNA genome of
160 to 170 kb that consists of a single unique sequence of
approximately 143 kb bounded by a single direct repeat (DR)
at both termini. The complete sequences of representative
isolates of both HHV-6A and HHV-6B have been published
and shown to be approximately 90% identical at the nucleo-
tide level (5456). The seven conserved gene blocks shared by
all HHVs are organized in an identical fashion in HHV-6A,
HHV-6B, HHV-7, and CMV, and the unique segment of both
the HHV6A and HHV-6B genomes are colinear with the long
unique segment of CMV (7). In addition, CMV, HHV-6A,
HHV-6B, and HHV-7 share a unique set of genes called beta
genes that are found only in CMV, HHV-6A, HHV-6B, and
HHV-7 (7).
HHV-6 displays the typical ultrastructural characteristics of
the herpesvirus family. It is an enveloped virus, approximately

Scheld_Ch13.indd 192 2/21/14 6:39 PM


FIGURE 13.2 An extracellular human herpesvirus type 6 virion.
c, capsid; d, DNA core; e, envelope; s, surface spikes; t, tegument.
(From Kramarsky B, Sander C. Electron microscopy of human herpes-
virus-6 [HHV-6]. In: Ablashi DV, Krueger GRF, Salahuddin SZ, eds.
Human Herpesvirus-6: Epidemiology, Molecular Biology and Clinical
Pathology. Amsterdam: Elsevier; 1992:5966, with permission.)
160 to 200 nm in diameter, and contains an electron-dense
core. The core is surrounded by a nucleocapsid with icosahe-
dral symmetry with a prominent tegument between the nu-
cleocapsid and outer lipid membrane (57) (Fig. 13.2). HHV-6
viral replication occurs in the nucleus of the infected cell. Viral
particles are initially released by exocytosis and then cell death.
Both HHV-6A and HHV-6B have the potential to encode
for approximately 97 proteins including those involved in reg-
ulatory functions, DNA replication, and structural proteins as
well as several unique genes not found in other herpesviruses.
Many of these gene products have been identified and re-
viewed previously and thus are not mentioned here (7,48,58).
One notable exception is HHV-6 U94, a protein that is homol-
ogous to the parvovirus adeno-associated virus type 2 (AAV-2)
Rep 68/78 gene that has been implicated in the maintenance
of latency and chromosomal integration as noted earlier (59).
PATHOGENESIS
Viral Growth Characteristics and
Cellular Tropism
All HHV-6 isolates can be grown in the laboratory in primary
cord blood mononuclear cell cultures that have been pretreated
with phytohemagglutinin (PHA) (60). HHV-6 has also been
propagated in adult PBMCs that have been stimulated with
monoclonal antibody to CD3 but not PHA (61). HHV-6 rep-
lication in vitro is augmented by T-cell activation and enhanced
in the presence of low concentrations of interleukin-2 (IL-2),
with increasing concentrations producing inhibition (62,63).
Following infection, HHV-6 reproducibly induces a cytopathic
effect characterized by large refractile mononucleated or binucle-
ated cells with intracytoplasmic and/or intranuclear inclusions
(64). Infected cells exhibit a slightly prolonged life span in PHA-
stimulated cultures compared with uninfected controls; however,
lytic infection of mononuclear cells has been the rule (65).
Scheld_Ch13.indd 193
Chapter 13: Human Herpesvirus-6 193
Santoro et al. (66) described CD46 (i.e., membrane cofac-
tor protein) as an essential cellular receptor for HHV-6. CD46
is also the receptor for the Edmonston strain of measles virus
and other bacterial microbes and functions as a complement
regulatory protein present on the surface of all nucleated cells.
This finding is in keeping with the observation that HHV-6
can infect a broad range of cell types in vitro including primary
T cells, monocytes, natural killer (NK) cells, dendritic cells,
oligodendrocytes, microglia, and astrocytes, with infection of
T-cell, B-cell, megakaryocytic, endothelial, glial, and epithelial
cell lines described (4,7,60,6774). Variability has been noted
in infectivity between HHV-6A and HHV-6B (69). HHV-6A
viruses are most efficiently propagated in the HSB2 or J-Jhan
T-cell lines, whereas HHV-6B isolates can be adapted to grow
in the Molt-3 T-cell line. A viral glycoprotein complex of gH,
gL, gQ1, and gQ2 has been demonstrated to be the viral li-
gand for many, but not all, laboratory isolates of HHV-6A
and HHV-6B (75). Given these observations, the possibility of
a second cellular receptor that could explain the differential
tropism between HHV-6A and HHV-6B has been postulated.
Ablashi et al. (60) studied the kinetics of host cell destruc-
tion in T-cell lines and reported that HHV-6A isolates demon-
strated enhanced cytopathogenicity compared with HHV-6B
isolates suggesting greater virulence of HHV-6A. Despite the
broad tropism of HHV-6 noted in vitro, viral replication in
nonlymphoid cell lines appears to be substantially restricted
with decreased production of infectious virus (58,76).
A previous study of PBMCs from children with roseola
suggested that HHV-6 acutely infects primarily mature CD4
T cells in vivo (77). However, higher viral loads and evidence
of viral gene transcription have been demonstrated in mono-
cytes and macrophages compared with CD4 T cells during
the acute phase of primary HHV-6 infection (78). Following
primary infection, the HHV-6 genome persists in PBMCs with
evidence suggesting that a true state of viral latency is induced
in cells of the myeloid lineage including CD34 stem cells,
which may function as a reservoir of latent virus (79,80).
The neuroinvasive potential of HHV-6 has been docu-
mented in several reports by the detection of HHV-6 DNA in
32% to 85% of brain tissue specimens from immunocompe-
tent adults at autopsy (8183). Chan et al. (84) sampled areas
of the cerebellum, frontal, temporal, parietal, and occipital
lobes bilaterally from 40 patients postmortem and found that
85% had one or more positive specimens. However, there was
no association between the presence of HHV-6 DNA and the
location of the sample, suggesting that HHV-6 may be widely
disseminated in the human brain (84). In addition, HHV-6
DNA has been found in gray matter and white matter samples
and in primary brain tumor tissue (82,85). Primary infection
with HHV-6 identified by viral isolation from PBMCs is due
almost exclusively to HHV-6B. In contrast, HHV-6A DNA
was detected in 12% to 70% of human brain tissue specimens
in the studies described previously, with up to 21% of patients
harboring both HHV-6A and HHV-6B in different regions of
the brain (81,82,84,86). In vitro studies have demonstrated
HHV-6A and HHV-6B infection of primary astrocytes and
oligodendroglia with the formation of multinucleated syncytia
(70,87). Attempts to infect neuronal cells have led to conflict-
ing results but generally suggest these cells are not a signifi-
cant source of productive infection (67,68,87). Enhanced
neurovirulence of HHV-6A has been suggested by several in
vitro studies examining the degree of cytopathic effect, DNA
replication, induction of apoptosis, and inhibition of cell pro-
liferation induced by HHV-6A compared to HHV-6B in both
primary glial cells and established cell lines (67,8891).
The clinical relevance of detecting HHV-6 DNA in cerebro-
spinal fluid (CSF) samples has not been fully clarified. HHV-6
DNA has been detected in the CSF of one quarter to one half of
2/21/14 6:39 PM
 194 Part II: Viral Infections and Related Disorder
children with primary infection, indicating that viral DNA may
be present in the CSF of a substantial number of immunocom-
petent children during primary infection (9294). In one report
of young febrile children with evidence of past HHV-6 infec-
tion, approximately 30% had detectable HHV-6 DNA present
in the CSF (92). The CSF was the only site of viral DNA detec-
tion in 29% of children, and these children were significantly
younger than those with HHV-6 DNA in both the CSF and the
PBMCs, indicating that the CNS may be a preferred site of la-
tency in younger children (92). Typing of CSF samples revealed
a greater frequency of HHV-6A in CSF (14%) than in PBMCs
(5%), also implying a greater neurotropism of HHV-6A (50).
These data imply that finding HHV-6 DNA in the CSF of nor-
mal hosts is not a rare event. However, in a single report of
bone marrow transplant (BMT) recipients, HHV-6 DNA was
identified in 22% of CSF samples from patients with symptoms
of CNS dysfunction compared with only 1% of control patients
with leukemia (95). Unfortunately, the cases and controls in this
study were not well matched by degree of immunosuppression.
Nevertheless, these data suggest that detecting HHV-6 DNA in
CSF may be a useful marker of disease in the proper clinical set-
ting. Part of the discrepancy between the results from studies of
children with primary infection and the BMT patients may be
due to the young age of the immunocompetent children studied
and the significant percentage with primary HHV-6 infection
compared to the older group of BMT patients. Given the recent
identification of ciHHV-6 and the fact that most subjects with
ciHHV-6 have no symptoms referable to the integrated virus,
caution should be used in interpreting the presence of HHV-6
DNA in CSF in order to avoid misdiagnosis of active HHV-6
infection in an individual with ciHHV-6 (39,93). Obtaining
HHV-6 viral load measurements in blood and CSF concur-
rently may be able to help distinguish between these different
clinical scenarios (93). Studies of healthy adults have demon-
strated the presence of HHV-6 DNA in saliva, PBMCs, urine,
and vaginal secretions, with evidence of continued presence of
the viral genome at these sites over several months consistent
with the broad in vitro tropism of HHV-6 (32,9698). Despite
initial reports of isolation of HHV-6 from adult saliva, sub-
sequent studies have shown that viral isolates obtained from
saliva are HHV-7 (99). Additionally, attempts at isolating infec-
tious HHV-6 from healthy subjects PBMCs have been gener-
ally unsuccessful. In contrast, isolates can be readily obtained
from immunocompromised hosts, demonstrating reactivation
of latent HHV-6 (100). Reactivation documented either by
HHV-6 viral isolation or by quantitative DNA PCR has also
been reported in immunocompetent children with measles or
dengue hemorrhagic fever and in adults with critical illness re-
quiring intensive care unit care or those with drug induced hy-
persensitivity syndrome (DIHS) or drug rash with eosinophilia
and systemic symptoms (DRESS) (101104). The cumulative
data support the concept of active HHV-6 viral replication in
mononuclear cells during primary infection, with the produc-
tion of abundant infectious particles. The virus then becomes
latent or persistent in the host PBMCs, salivary gland tissue,
the genitourinary (GU) tract, and the CNS, with the detection
of the HHV-6 genome in the absence of significant amounts of
infectious virus. Immune dysfunction allows for HHV-6 reacti-
vation, as evidenced by renewed viral isolation with subsequent
disease manifestations in a subset of patients.
Immune Response
Children with primary HHV-6 infection develop an immu-
noglobulin M (IgM) response on day 5 of illness, with the
appearance of immunoglobulin G (IgG) at approximately
Scheld_Ch13.indd 194
1 week (105). The IgM response is short lived, persisting for
only 2 to 3 weeks, and the IgG response lasts for extended
periods. Low level neutralizing antibody develops at approxi-
mately day 3 of illness, coincident with a falloff in the rate
of viral isolation, and peaks at 2 to 4 weeks into the illness
(106,107). Although the immune response to HHV-6 is gen-
erally sensitive and specific, IgM has also been detected in
approximately 5% of healthy adults and has been shown to
be cross reactive with HHV-7, limiting the usefulness of this
test for the diagnosis of HHV-6 infection or reactivation (108).
HHV-6specific CD4 and CD8 T-cell responses have also
been described, supporting a role for cellular factors in the
immune response to HHV-6 (109,110).
Following infection of PBMCs, HHV-6 interacts with the
immune system in several ways including downregulation of
CD3 and CD46 cell surface molecule expression, upregula-
tion of CD4, induction and suppression of cytokines and type
I interferons, and effects on NK cell activity (107,111114).
In vitro HHV-6 infection of dendritic cells has been described
with conflicting reports on the functional outcome of this
infection (115,116). Apoptosis of T cells both in vitro and in
vivo has been detected following HHV-6 infection, as well as
the previously well-described cell lysis (117,118). In addition
to the immune response generated to HHV-6, the viral genome
itself encodes several factors that have immunologic regulatory
activity including two chemokine receptor homologs (U12 and
U51) and two putative chemokines (U22 and U83) (111). It
has been postulated that through these proteins, HHV-6 may
either enhance viral replication in infected cells, enlarge the
pool of available virus susceptible cells, or circumvent the host
immune response to infection.
CLINICAL MANIFESTATIONS
Primary Infection
Roseola is an acute self-limited disease of infancy and child-
hood. It is characterized by the abrupt onset of high fever
lasting approximately 72 hours. The fever resolves by crisis
coincident with the appearance of a faint morbilliform rash
on the neck and trunk. Associated signs are notably sparse
but can include mild injection of the pharynx, palpebral con-
junctivae, or tympanic membranes and enlarged suboccipital
nodes (11).
Prospective studies have extended our knowledge of the
clinical manifestations of acute HHV-6 infection beyond that
of classic roseola. Hall et al. (21) identified 160 children with
primary HHV-6 infection by viremia and seroconversion from
a large number of children evaluated in a pediatric emergency
department. The mean age at primary HHV-6 infection was
9.4 months, with few cases occurring before 2 months or after
25 months of age (Fig. 13.3). High fever was the most con-
sistent manifestation of infection. All children had an acute
febrile illness, and 87% had fever of more than 39C. Fever
persisted for 6 days or longer in 15%. Associated clinical
symptoms and signs included irritability or a toxic appearance
in 72%, inflamed tympanic membranes in 46%, and upper
respiratory tract signs in 41%. Children with primary HHV-6
infection were significantly more likely to exhibit these signs
than matched controls. Cough and lower respiratory tract
signs were seen significantly less often in children with pri-
mary HHV-6 infection than controls. Only 17% of children
with primary HHV-6 infection developed a rash, making it
difficult to identify correctly the cause of the illness. Most chil-
dren were given a diagnosis of fever with otitis media, fever
2/21/14 6:39 PM

30%
Visits Due to HHV-6 (% of All Visits)
20%
10%
0%
02 35 68 911 1214 1517
of undetermined origin, or presumed sepsis, and 13% were
hospitalized. A more recent prospective study of an outpatient
cohort of infants with primary HHV-6 infection identified by
HHV-6 DNA detection in saliva confirmed that over 90% of
the infants had symptoms with fever, fussiness, and rhinorrhea
noted most often (119). Rash was identified in a little less than
one third of the cohort (119).
In a report from Japan of 176 children with roseola identi-
fied retrospectively, fever and rash were noted in 98% of the
patients (120). This study also detected a higher percentage
of children with gastrointestinal tract disturbances (68% with
diarrhea), in addition to edematous eyelids in 30%, erythema-
tous papules in the pharynx in 65%, cough in 50%, and mild
cervical lymphadenopathy in 31%. The differences between
these studies may be attributed in part to study design and case
definition. Also, the severity of the clinical symptoms associ-
ated with acute HHV-6 infection has been shown to be related
to the degree of viremia, which may contribute to the range
of reported manifestations of primary HHV-6 infection (121).
The laboratory evaluation of children with primary HHV-6
infection is generally nonspecific and reveals a depressed total
white blood cell count, with lymphopenia noted early in the
course of the infection. C-reactive protein levels have been
reported to be less than 10 mg/L in most patients (21,122).
Rarely reported complications of primary HHV-6 infection
include intussusception, Kawasaki disease, hepatitis, hemo-
phagocytic syndrome, and fatal multisystem disease (7,123).
A heterophil-negative mononucleosis syndrome has been associ-
ated with primary HHV-6 infection in immunocompetent adults
(124). However, most reports have relied on seroconversion as
evidence of HHV-6 infection, a method that is not optimal.
Central Nervous System Complications of
Primary Infection
Seizures have been reported as a complication of primary
HHV-6 infection. In the study from Japan noted earlier, 8% of
the children with roseola had seizures during the febrile phase
of the illness (120). Seizures were the most common complica-
tion of primary HHV-6 infection, occurring in 13% of chil-
dren with acute infection described by Hall et al. (21) from a
pediatric emergency department population. The highest inci-
dence of seizures was 36%, noted in children 12 to 15 months
of age. This rate was significantly greater than that of age-
matched controls with other febrile illnesses. In prospective
studies of children with first time febrile seizures, primary in-
fection with HHV-6 has been observed in 18% to 26% of the
Scheld_Ch13.indd 195
Chapter 13: Human Herpesvirus-6 195
50
Number with HHV-6 Infection
40
30 FIGURE 13.3 Number of children pre-
senting to the emergency department
with illness from primary HHV-6 infec-
20 tion (bars) and visits due to such infec-
tion as a percentage of all emergency
department visits for acute febrile ill-
10 nesses (curve) according to age. (From
Hall CB, Long CE, Schnabel KC, et al.
Human herpesvirus infection in chil-
dren. A prospective study of complica-
0 tions and reactivation. N Engl J Med.
1820 2123 24 1994;331:432438, with permission.)
patients (125,126). However, in the study by Zerr et al. (119)
noted earlier, no seizures were recorded among 81 ambulatory
children with primary HHV-6 infection. Although the exact
rate of seizures due to primary infection with HHV-6 has not
been precisely defined, a review of the viral causes of febrile
seizures examined almost 1,000 published cases of primary
HHV-6 infection and found seizures to be a complication in
16.5% (127).
Clinically, no differences have been identified between
children with febrile seizures associated with primary HHV-6
infection and those with febrile seizures not associated with
primary HHV-6 infection, including the height or duration of
fever or the recurrence rate of seizures in the first 24 hours
(125). Additionally, CSF analysis does not typically reveal
pleocytosis or abnormal glucose or protein levels in patients
with primary HHV-6 infection. Suga et al. (128) reported a
higher frequency of partial seizures, postictal paralysis, pro-
longed seizures, and clustering of seizures in 19 children
with primary HHV-6 infection compared with children with
seizures not associated with primary HHV-6 infection, sug-
gesting more significant CNS pathology and implying an in-
creased risk for the later development of epilepsy (92,129).
Early reports did suggest an increased risk of recurrent febrile
seizures in children due to HHV-6 infection, but a casecontrol
study of children with febrile seizures associated with primary
HHV-6 infection compared with children with febrile seizures
not associated with primary HHV-6 infection demonstrated
a statistically significant lower rate of seizures over the fol-
lowing 3 years in the children with primary HHV-6, casting
doubt on this association (130). However, more recent data
have suggested a link between chronic smoldering or reacti-
vated HHV-6 infection of the CNS and the later development
of medial temporal lobe epilepsy (MTLE) (131). One line of
evidence supporting this association comes from a prospec-
tive study of children with febrile status epilepticus (FSE), a
known risk factor for the development of MTLE that identi-
fied active HHV-6 infection in peripheral blood samples of
almost one third of the patients (132). Similar to the data
from children with simple febrile seizures, the children with
FSE associated with HHV-6 did not have CSF pleocytosis or
differences in peripheral white blood cell counts from pa-
tients with FSE not associated with HHV-6. There were also
no differences in the proportion of children with EEG ab-
normalities or acute hippocampal changes on MRI. Seizure
characteristics between children with FSE associated with
HHV-6 and those not associated with HHV-6 were similar
(Table 13.1), suggesting a shared pathogenesis of FSE among
different etiologies (132).
2/21/14 6:39 PM
 196 Part II: Viral Infections and Related Disorder

TA B L E 1 3 . 1
DESCRIPTIVE INFORMATION FOR CHILDREN WITH FSE WITH HHV6 OR HHV7 INFECTIONS (PRIMARY OR
REACTIVATED) AT BASELINE COMPARED TO CHILDREN WITH PRIOR OR NO HHV6 AND HHV7 INFECTIONS

HHV6 or HHV7 HHV6 and HHV7

Total or Reactivation or Prior Infections p
Feature (N 169) (n 58) (n 111) Value

Age (months)
Media (interquartile range) 15.8 (12.023.2) 14.8 (12.122.2) 17.4 (12.025.2) 0.67
Age 18 months 71 (42.0%) 20 (34.5%) 51 (46.0%) 0.15
Gender
Male 88 (52.1%) 30 (51.7%) 58 (52.2%) 0.95
Female 81 (47.9) 28 (48.3%) 53 (47.8%)
Development
Normal 148 (87.6%) 47 (81.0%) 101 (91.0%) 0.06
Suspect 10 (5.9%) 7 (12.1%) 3 (2.7%)
Abnormal 11 (6.5%) 4 (6.9%) 7 (6.3%)
Prior febrile seizures
Yes 35 (20.7%) 12 (20.7%) 23 (20.7%) 1.00
No 134 (79.3%) 46 (79.3%) 88 (79.3%)
Sick behavior before FSEa
Yes 78 (46.4%) 25 (43.1%) 53 (48.2%) 0.53
No 90 (53.6%) 33 (56.9%) 57 (51.8%)
Duration of recognized fever before FSE
1 h 74 (43.8%) 28 (48.3%) 46 (41.4%) 0.68
124 h 68 (40.2%) 21 (36.2%) 47 (42.3%)
24 h 27 (16.0%) 9 (15.5%) 18 (16.2%)
Peak temperature during illness
Mean peak temperature F (SD) 103.3 (1.3) 103.2 (1.0) 103.3 (1.5) 0.59
Mean ED peak temperature F (SD)a 102.2 (1.9) 102.4 (1.6) 102.0 (2.0) 0.22
Duration of FSE (min)
Median (interquartile range) 70.0 (47.0110.0) 67.5 (45.0105.0) 70.0 (50.0120.0) 0.30
Continuous versus intermittent FSE
Continuous 95 (56.2%) 29 (50.0%) 66 (59.5%) 0.50
Intermittent without full recovery 53 (31.4%) 21 (36.2%) 32 (28.8%)
in between
Intermittent with full recovery 21 (12.4%) 8 (13.8%) 13 (11.7%)
in between
Focal FSE
Yes (definitely or probably) 113 (66.9%) 44 (75.9%) 69 (62.2%) 0.07
No (maybe or no) 56 (33.1%) 14 (24.1%) 42 (37.8%)
Family history of FS or FSEa
Yes 52 (31.0%) 21 (36.2%) 31 (28.2%) 0.28
No 116 (69.0%) 37 (63.8%) 79 (71.8%)

FSE, febrile status epilepticus; FS, febrile seizure.

a
One with missing information.
From Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia.
2012;53:14811488.

Scheld_Ch13.indd 196 2/21/14 6:39 PM


Further data supporting a link between HHV-6 and MTLE
comes from a series of studies of adult and adolescent patients
undergoing epilepsy surgery. HHV-6B DNA was found in
28% to 63% of resected temporal lobe specimens in patients
with MTLE compared to zero specimens from patients with
other forms of epilepsy or 8% of specimens obtained from
trauma patients (133137). Active HHV-6 replication was
identified via the detection of higher viral loads of HHV-6 in
the hippocampus than the surrounding tissue, HHV-6 protein
expression via IHC, and HHV-6 messenger RNA (mRNA) pro-
duction in the hippocampus and temporal lobe tissue as well
as cultured astrocytes from the resected MTLE patient speci-
mens (133,134,136). Loss of glutamate transporter EAAT2
protein in infected astrocytes due to active HHV-6 infection
with a resultant inability to process extracellular levels of the
excitatory neurotransmitter glutamate is one proposed mecha-
nism of pathogenesis (131,134). Alternatively, increased lev-
els of expression of NFB have been detected in hippocampus
and temporal lobe specimens from MTLE patients suggesting
a role for inflammation in the development or progression of
MTLE (136).
Several older case reports have described encephalitis or
encephalopathy in children with roseola (138). Fever, de-
pressed level of consciousness, and seizures were the promi-
nent symptoms noted in these patients, with normal CSF
findings or mild pleocytosis with elevated protein levels.
Computed tomography (CT) was often normal at onset but
progressed to reveal hypodense lesions in multiple areas of
the cerebral cortex, including the frontal, parietal, temporal,
and occipital lobes, the putamen, and internal capsule (138
140). A single report including magnetic resonance imaging
(MRI) results demonstrated multiple lesions of demyelination
in the thalamus and parietooccipital deep white matter (141).
Electroencephalographic (EEG) findings were either normal
or nonspecific, with most studies remarkable only for dif-
fuse slowing following seizures. Single photon emission CT
(SPECT) performed in one patient showed diffuse hypoperfu-
sion of the left hemisphere that persisted for at least 50 days
(142). Although complete or near-complete recovery was
noted in several cases, mortality was also reported. More re-
cent reports of young children with probable primary infection
with HHV-6 have described a syndrome of rhombencephalitis
with progressive neurologic symptoms including ataxia and
cranial nerve deficits associated with imaging abnormalities of
the brainstem and cerebellum (143,144). Pleocytosis, HHV-6
DNA in the CSF, and elevated CSF total protein values were
found with identification of HHV-6 protein by IHC in a brain
biopsy sample from a single patient (143). Other reports from
single cases of encephalitis have not identified a unique patho-
logic description from brain tissue specimens and have re-
ported inconsistent results of DNA and IHC testing suggesting
a possible immune-mediated pathogenesis (145,146). In chil-
dren with primary HHV-6associated encephalitis or encepha-
lopathy with or without HHV-6 DNA in the CSF, significantly
greater concentrations of both interleukin (IL)-6 and IL-8 have
been identified in serum and CSF compared to values from
patients with HHV-6associated febrile seizures or normal
controls supporting this hypothesis (147149).
Reactivation
The lifelong consequences of infection with HHV-6 are still not
well known. Although HHV-6 DNA can be detected in several
body sites in adults years after primary infection, the occurrence
and frequency of reactivation, as well as the clinical relevance
of reactivation, have not been completely defined. As noted
Scheld_Ch13.indd 197
Chapter 13: Human Herpesvirus-6 197
earlier, HHV-6 reactivation has been reported in children with
measles or dengue hemorrhagic fever and in seriously ill adults
in an intensive care unit or with DIHS or DRESS. Evidence
of reactivation as determined by quantitative PCR of HHV-6
DNA in PBMCs in the critically ill adult patients was not asso-
ciated with any specific symptoms and did not have an impact
on mortality. However, it is notable that all but one of these
patients had HHV-6A detected, which may actually have been
due to ciHHV-6 and not true viral reactivation given the appar-
ent low prevalence of HHV-6A in the general U.S. population
(103). Reactivation of HHV-6 does occur in immunocompro-
mised hosts of all ages and has been associated with a range of
illnesses in this population. Following hematopoietic cell trans-
plantation (HCT), HHV-6 reactivation documented by viral
culture or quantitative PCR has been documented in 35% to
65% of patients (150,151). Several diseases including fever and
rash, encephalitis, interstitial pneumonitis, acute graft-versus-
host disease, delayed engraftment or myelosuppression, CMV
disease, and increased mortality have been associated with
HHV-6 reactivation in the HCT population (48,100,152). Two
of the best documented diseases linked to HHV-6 reactivation
in HCT recipients are fever with rash and encephalitis, occur-
ring from 2 to 4 weeks after transplantation (48,100).
HHV-6 reactivation has also been associated with both di-
rect and indirect clinical effects in approximately 1% of solid
organ transplant recipients including fever, rash, encephalitis,
bone marrow suppression, interstitial pneumonitis, gastroin-
testinal infections, CMV disease, fungal infections, and graft
rejection or dysfunction (153162). Many of these reports
provide conflicting results and older studies often relied on se-
rologic markers of reactivation. In prospective studies of HCT
recipients that have included both serology and viral culture or
quantitative PCR, the serologic results did not correlate with
viral assays, suggesting caution in diagnosing reactivation of
HHV-6 based on serology alone (163165).
Encephalitis associated with HHV-6 reactivation has been
reported in both immunocompetent and immunocompromised
hosts. Single case reports or small series have described disease in
previously healthy adults and children (166173). The quality of
these reports varies substantially and no clear group of symptoms
or unique clinical presentation has been identified. Clinical char-
acteristics have included both acute and subacute presentations,
diffuse headache, altered mental status, and seizures as well as
focal neurologic signs. Variable degrees of CSF pleocytosis and
protein elevations have been reported. Imaging studies have been
normal or with a range of findings including focal abnormalities
in the motor cortex, parietal lobe, temporal lobe, or white matter
disease in the pons, internal capsule, and midbrain (166174).
Outcomes have been mixed with both death and full recovery
reported. One point that appears consistent among these cases is
the identification of HHV-6 DNA in CSF as the main diagnostic
criteria. Given the relatively recent recognition of ciHHV-6 and
the persistent detection of HHV-6 DNA in all body fluids associ-
ated with viral integration, it is possible that several of the earlier
reports were confounded by ciHHV-6. Alternatively, individuals
with ciHHV-6 may develop encephalitis due to the integrated
virus as has been suggested in a prior report (175). The ques-
tion of whether HHV-6 reactivation can cause encephalitis in
immunocompetent individuals with ciHHV-6 or prior childhood
infection requires further careful study.
Encephalitis associated with HHV-6 reactivation in HCT
recipients has been well defined with the majority of reports
describing a syndrome of acute limbic encephalitis also re-
ferred to as posttransplantation acute limbic encephalitis
(PALE) (176181). In addition, HHV-6 reactivation has been
temporally associated with more common CNS symptoms
including delirium during the early posttransplant period and
2/21/14 6:39 PM
 198 Part II: Viral Infections and Related Disorder

neurocognitive decline measured at 12 weeks after transplant,
suggesting a significant impact on the clinical course of trans-
plantation (182).
The incidence of PALE among HCT recipients is es-
timated at 1.5% overall but may be as high as 28% in pa-
tients receiving two or more cord blood stem cell transplants
(176,177,179). PALE typically develops around the time of
neutrophil engraftment, usually from 2 to 6 weeks after trans-
plantation (176,179,181). Risk factors for the development of
PALE appear to be similar to the risk factors identified for
HHV-6 reactivation in HCT and include umbilical cord blood
as a donor source, human leukocyte antigen (HLA) mismatch,
time-dependent acute graft-versus-host disease, and the receipt
of corticosteroids during the first 4 weeks after transplanta-
tion (176,181,183). Hill et al. (176) have reported that all
patients who develop PALE have evidence of HHV-6 reactiva-
tion with positive DNA detection in plasma (176). In addi-
tion, patients with PALE have been found to have significantly
higher HHV-6 viral loads measured in plasma than patients
with HHV-6 reactivation without neurologic symptoms with
the peak viral load correlating with the time of development
of neurologic symptoms (176,183,184). Various plasma
viral load cutoff values have been proposed as a threshold
for predicting PALE with variable sensitivity and specificity
(176,183). However, not all studies have consistently noted
an association between HHV-6 viral loads and the develop-
ment of disease. Betts et al. (185) performed a prospective
surveillance study for HHV-6 reactivation following HCT
in 82 subjects and measured weekly whole blood viral loads.
They did not find an association between HHV-6 reactivation
and total CNS symptoms, including headache. Nor was there
an association between high level viremia (25,000 genome
copies/mL of whole blood) and CNS symptoms. Patients with
HHV-6 reactivation were more likely to have mental status
changes, and it is notable that the only patient who died with
neurologic complications had the highest level of HHV-6 vire-
mia among patients with CNS symptoms (185).
Wainwright et al. (180) were the first to describe five pa-
tients with limbic encephalitis associated with HHV-6 reactiva-
tion. Since then, multiple reports have confirmed the typical
clinical presentation of PALE as an acute onset of altered men-
tal status with confusion and prominent anterograde amnesia
(176,179,181,183). Fever, insomnia, hallucinations, agitation,
or emotional lability have also been described (179,186).
Seizures are frequently identified either clinically or via EEG
monitoring. Reported laboratory findings include the syndrome
of inappropriate antidiuretic hormone with minimally elevated
levels of CSF total protein (176,179181). CSF pleocytosis is
noted less commonly, probably due to the marked cytopenias
found posttransplantation (176,179181). MRI studies may
be normal early in the course of disease but typically show
focal nonenhancing abnormalities in the medial temporal lobe
often including edema in the hippocampus, uncus, and amyg-
dala either unilaterally or bilaterally on T2 fluid attenuation
inversion recovery (FLAIR) images with hypermetabolism in
these regions on positron emission tomography (PET) scan-
ning (186,187) (Fig. 13.4). Extension of abnormalities beyond
the medial temporal lobe into other limbic structures or ex-
tralimbic areas has also been described (176,186,188). A small
number of postmortem examinations have been performed
with neuronal loss and gliosis limited to the hippocampus and
amygdala regions (179,180). HHV-6B DNA has been identified

FIGURE 13.4 Matched level transverse slices showing acute (AD) and chronic (EH) phase morpho-
functional imaging in human herpesvirus 6 limbic encephalitis: postcontrast T1-weighted (A, E) and fluid-
attenuated inversion recovery (B, F) 3-T magnetic resonance imaging (MRI), fused MRI PET images
(C, G), and fluorodeoxyglucose positron emission tomography (FDG-PET) (D, H). On acute phase imag-
ing acquired 10 days after the beginning of neurologic signs and symptoms, FDG-PET shows bilateral in-
tense FDG uptake in both hippocampi and amygdalae (C, D). At the same time, MRI showed only a mild
increased signal on fluid-attenuated inversion recovery sequence (B) without contrast enhancement (A).
The follow-up study, done after 3 months, showed FDG hypometabolism (G, H) associated with a hippo-
campal sclerosis (E, F). (From Hubele F, Bilger K, Kremer S, et al. Sequential FDG PET and MRI findings
in a case of human herpes virus 6 limbic encephalitis. Clin Nucl Med. 2012;37:716717, with permission.)

Scheld_Ch13.indd 198 2/21/14 6:39 PM


in the CSF in the majority of patients with PALE and in one
autopsy specimen HHV-6 protein was detected within astro-
cytes and neurons in the hippocampal areas (180). A role for a
direct viral effect on disease pathogenesis is also supported by
data from a small study demonstrating that the viral load of
HHV-6 in CSF of HCT patients with encephalitis was signifi-
cantly greater than from children with primary infection (149).
However, similar to findings in children with primary HHV-6
infection and encephalitis or encephalopathy, elevated levels of
CSF IL-6, IL-8, and IL-10 have been identified in patients with
HHV-6 reactivation and associated limbic encephalitis com-
pared to controls suggesting neuroinflammation as one alter-
native pathogenic mechanism (149).
Mortality rates reported due to HHV-6associated PALE
have varied from 0% to 50% but do not appear to be differ-
ent than mortality in the general HCT population (176179).
Differences may become more apparent when patients with
cord blood transplantation are evaluated separately (176).
There does not appear to be an association between mortal-
ity and viral load measurements in the CSF or plasma, time
to antiviral treatment, or other clinical characteristics, sug-
gesting that although plasma viral loads may be useful as a
marker for disease development, they do not predict outcome
(176178). Morbidity is common following PALE with ap-
proximately 40% of patients reported to make a full recovery
(181). Most patients have persistent memory difficulties that
limit their day-to-day function, and symptomatic generalized
epilepsy has also been described (176179,181).
HHV-6 infection has also been etiologically linked to MS
and hypothesized to act as a trigger for disease development
(6,189). Studies have demonstrated a statistically significant
increased detection of HHV-6 proteins and both early and
late gene mRNA in oligodendrocytes from brain specimens
of patients with MS compared to control brains and from MS
plaques compared to normal-appearing white matter (189,190).
An increased frequency of detection of HHV-6 DNA in serum
and PBMC samples from patients with MS has also been de-
scribed, as well as an increased percentage of patients with MS
who have positive IgM antibody assay results to protein p41/38
(191,192). This last finding is tempered by a study that found
no difference in antibody reactivity to recombinant HHV-6 p41
protein between patients with MS and controls and suggested
that previous results may have been confounded by reactivity
to p38, a cellular protein (193). However, multiple reports have
continued to describe an increased frequency of detection of
HHV-6 DNA in the serum of patients with MS and a correlation
between clinical disease activity and HHV-6 DNA detection in
serum as well as mRNA detection in whole blood was noted
in a group of patients with relapsing and remitting MS over
time (194). Additionally, an increased prevalence of detection
of HHV-6A in serum has been reported in patients with MS,
suggesting a potential association between HHV-6A and this
disorder (194). These findings are in contrast to multiple studies
of CSF, serum, PBMCs, and brain tissue including demyelinated
plaques from patients with MS and controls demonstrating no
difference in the detection of HHV-6 DNA by PCR (195198).
The ability to compare results across studies is hampered by the
methodologic differences between these reports, making it dif-
ficult to form a conclusion about the strength of the association
between HHV-6 and MS.
DIAGNOSIS
The diagnosis of primary HHV-6 infection is confirmed by isola-
tion of the virus in culture coupled with seroconversion. Several
serologic methods have been developed for the detection of anti-
body to HHV-6 including an indirect immunofluorescence assay
Scheld_Ch13.indd 199
Chapter 13: Human Herpesvirus-6 199
(IFA), neutralization assay, immunoblot assay, and enzyme-linked
immunosorbent assay (ELISA) (199,200). Although antibody to
HHV-7 limits specificity at low titer, higher titer responses have
been shown to be reliable (200). IFAs that include the measure-
ment of antibody avidity have also been described and have the
added benefit of being able to provide an approximate timing of
primary infection (200). The IgM response to HHV-6 is short
lived, cross reactive with HHV-7, and can reappear after initial
infection diminishing the use of this test in the clinical diagnosis
of primary infection or reactivation (108).
Rapid diagnostic methods for the confirmation of HHV-6
infection are not available. The detection of HHV-6 DNA in
PBMC samples does not distinguish between latent infection
and active viral replication associated with primary infection
or reactivation. Secchiero et al. (201) detected HHV-6 DNA in
the serum of six of seven children with roseola, suggesting that
this method was both sensitive and specific for the timely detec-
tion of active viral replication if performed on cell-free speci-
mens. In a separate report of 47 plasma samples obtained from
children with roseola, HHV-6 could be isolated in culture from
only 21% of the samples, implying that plasma contained infec-
tious virus in only a minority of patients with primary HHV-6
infection (106). This was confirmed by Achour et al. (202) in a
study demonstrating that HHV-6 DNA in cell-free specimens is
primarily due to the presence of free DNA, not viral particles,
and that detection in plasma or serum correlates well with the
viral load in PBMC samples (202). However, the description
of ciHHV-6 and the recognition that asymptomatic individuals
with ciHHV-6 have HHV-6 DNA detectable in all body fluids
with high viral loads has limited the use of detecting HHV-6
DNA in plasma or serum as the sole test of active viral replica-
tion. Reverse transcriptase polymerase chain reaction (RT-PCR)
assays for HHV-6 have been developed to amplify mRNA cor-
responding to late structural proteins of the virus produced dur-
ing lytic infection in order to detect active replication (203,204).
The performance characteristics of each of these assays com-
pared to viral culture varies with the population being tested,
but in general, the detection of U90 and U100 mRNA is 90%
to 100% sensitive and 90% to 98% specific for primary and re-
activated HHV-6 infection (203205). Preliminary data suggest
that approximately 5% to 15% of samples of PBMCs from in-
dividuals with ciHHV-6 are positive in the U100 RT-PCR assay
slightly diminishing the discriminatory power of this test but
raising the possibility of viral protein production and or active
replication of the integrated genome (205). The measurement
of HHV-6 viral loads in whole blood has been suggested as a
means of differentiating between primary infection, reactiva-
tion, and ciHHV-6 with viral loads in individuals with ciHHV-6
often greater than 5.5 log10/mL or at least one genome equiva-
lent per cell with lower levels found in primary infection, reac-
tivation, and during latency (39,206). Additionally, individuals
with ciHHV-6 will have persistently high viral load measure-
ments in whole blood over time with HHV-6 DNA present in all
tissues including hair follicle specimens, which has been used in
research settings to identify subjects with integrated virus. From
a practical standpoint, it appears as though a combination of
DNA detection in plasma coupled with whole blood quanti-
tation may provide the best discriminatory power to identify
different types of infection with HHV-6 because both of these
assays are commercially available (39).
TREATMENT
In vitro studies have evaluated the susceptibility of HHV-6 to
available antiviral agents. Varying methods used in different
experimental systems make absolute comparisons between
reports difficult. In general, however, the pattern of antiviral
2/21/14 6:39 PM
 200 Part II: Viral Infections and Related Disorder
inhibition of HHV-6 resembles that of HCMV, with ganciclo-
vir, foscarnet, and cidofovir demonstrating effective in vitro
activity (48,58). This pattern of antiviral susceptibility is in
agreement with the results of in vitro assays and genomic anal-
yses that have failed to identify a virally encoded thymidine
kinase in HHV-6 and suggest that ganciclovir, foscarnet, and
cidofovir may be of use in the clinical setting, whereas acyclo-
vir- and thymidine kinasedependent drugs should have little
effect (207).
Randomized controlled clinical trials aimed at evaluating
the effectiveness of antiviral agents in patients with primary
or reactivated HHV-6 infections are lacking, and no drug is
currently licensed for the treatment of HHV-6 infection or dis-
ease. Case reports have described the successful treatment of
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207. Dewhurst S. Human herpesvirus type 6 and human herpesvirus type
7 infections of the central nervous system. Herpes. 2004;11(suppl
2):105A111A.
208. Cheng FW, Lee V, Leung WK, et al. HHV-6 encephalitis in pediatric un-
related umbilical cord transplantation: a role for ganciclovir prophylaxis?
Pediatr Transplant. 2010;14:483487.
209. Ishiyama K, Katagiri T, Ohata K, et al. Safety of pre-engraftment prophy-
lactic foscarnet administration after allogeneic stem cell transplantation.
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bone marrow transplantation: successful treatment with ganciclovir. Bone
Marrow Transplant. 1997;20:905906.
211. Phlmann C, Schetelig J, Reuner U, et al. Cidofovir and foscarnet for
treatment of human herpesvirus 6 encephalitis in a neutropenic stem cell
transplant recipient. Clin Infect Dis. 2007;44:e118e120.
212. Rapaport D, Engelhard D, Tagger G, et al. Antiviral prophylaxis may
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recipients. Transpl Infect Dis. 2002;4:1016.
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and treatment of human herpesvirus-6 in allogeneic stem cell transplantation.
Bone Marrow Transplant. 2002;29:595598.
2/21/14 6:39 PM
 CHAPTER 14 B VIRUS
RICHARD J. WHITLEY
HISTORY
Of the nearly 35 herpesviruses that have been isolated
from nonhuman primates, only oneB virus of Old World
monkeysis highly pathogenic for humans. In 1932, a young
physician (W.B.) bitten by a monkey developed localized ery-
thema at the site of the animal bite. This apparently local-
ized infection was followed by lymphangitis, lymphadenitis,
and ultimately transverse myelitis. The demise of W.B. was
ascribed to respiratory failure. Tissue specimens from W.B.
were obtained by two independent research groups. In 1933,
Gay and Holden (1) reported the identification of an ultra-
filterable agent that recreated in rabbits a disease similar to
that observed in W.B. This virus was recovered from the neu-
rologic tissues of W.B. The inoculation of this virus by either
intradermal or intracranial routes was lethal in the animal
model. These investigators thought that the virus was simi-
lar to herpes simplex virus (HSV) and referred to the isolate
as W. While attempts at transmission of this virus to rhesus
monkeys failed, infection of Cebus monkeys was successful.
In 1934, Sabin and Wright (2) reported the identification of a
similar filterable agent, which they identified as B virus, named
W.B. They isolated virus from several neurologic tissues as
well as from peripheral organs (spleen but not lymph nodes).
As with the isolate named W, B-virus infection resulted in
lethal disease when inoculated by either intradermal or intra-
cerebral routes into rabbits. However, the virus was avirulent
when inoculated by the same routes into a variety of other
species, including mice, dogs, and guinea pigs. Furthermore,
Sabin (3) recognized by immunologic characterization of the
isolate that it was related to both HSV and pseudorabies virus
(3,4). At the time when latinization of viral names was fash-
ionable, B virus acquired the name herpes simiae. The name
is a misnomer because nonhuman primates have yielded nu-
merous unrelated herpesviruses. According to the present no-
menclature, it is designated as the cercopithecine herpesvirus
type 1. In this chapter, the virus is designated by its common
name, B virus.
B virus is indigenous to Old World monkeys (5,6),
being enzootic in rhesus (Macaca mulatta) and cynomolgus
(Macaca fascicularis) monkeys, as well as in other Asiatic spe-
cies of the genus Macaca. Most reported human cases result
from bites by rhesus monkeys. Since the original reports of
human herpes B-virus infections, advances in our knowledge
about human disease caused by this virus have proceeded
slowly. Although B-virus infection of humans is not a com-
mon public health problem, the diagnosis of B virus in four
individuals living in Pensacola, Florida; two in Kalamazoo,
Michigan; and an animal handler at Yerkes Primate Center
has refocused medical and public health attention on the
neuropathogenicity of infection (7). Approximately 50 cases
have occurred, although only 26 are well documented (7).
Other cases are pending verification. Person-to-person trans-
mission of infection from one of the fatal cases to a relative
was documented for the first time. Additionally, a case has
been identified that led to infection, but without evidence of
life-threatening clinical disease (8). Lastly, ocular inoculation
of virus proved lethal (7).
204
Scheld_Ch14.indd 204
INFECTIOUS AGENT
B virus was propagated on the chorioallantoic membrane
of embryonated eggs in 1939 (8). Tissue culture isolation of
B virus did not occur until 1954, when it was recovered from
rhesus kidney tissue used for preparation of poliomyelitis vac-
cines (9). During vaccine production, suspended cell culture
systems from six kidneys elicited cytopathic effects similar to
those of HSV.
Notwithstanding numerous attempts at isolation of virus
from macaques, the first report of virus isolation is that of
Reissig and Melnick (10), who recovered B virus from tissue
cultures of purportedly normal rhesus monkeys. Further stud-
ies led to the realization that this virus was easily propagated
in monkey kidney and chick embryo cell lines (10, 11). B virus
also multiplies well in rabbit kidney cells and other established
cell lines such as BS-C-1 (12) and LLC-RK (13). Virus is stable
in tissue culture media when stored at 4C and viral infectivity
is maintained if the culture is stored at 72C.
Replication characteristics of B virus have been reported by
several laboratories (4,10,11,1416). The reproductive cycle
is relatively short. The virus inhibits host cell DNA and pro-
tein synthesis during the first 4 hours after infection. Infectious
virus is detectable approximately 6 hours after infection, and
both extracellular and intracellular virus levels reach a pla-
teau approximately 24 to 36 hours after infection and decline
thereafter (10,16).
PATHOLOGY AND PATHOGENESIS
Pathology
The characteristic cytopathic effect is similar to that of HSV.
Cells balloon, fuse into polykaryocytes, and form clusters as
focal areas of infection spread through the entire cell sheet. On
fixation and staining, Cowdry type A eosinophilic intranuclear
inclusions are demonstrable.
Pathologic findings in humans are indicative of the target
organs involved. As described later in this chapter, there is lit-
tle difference in the histopathologic findings encountered fol-
lowing either infection of humans or simians.
Pathogenesis of Human Infection
Disease in humans usually results from an animal bite or
scratch, although disease that is the consequence of respiratory
spread and reactivation has been reported (see later discus-
sion). Following exposure, replication of virus at the local site
of inoculation occurs. If the skin is the primary site of inocula-
tion, virus replicates in the skin; this leads to erythema and
calor at the initial site of involvement. A vesicular rash may ap-
pear in association with tingling and numbness. Usually, there
is evidence of local inflammation at the site of infection with
mononuclear infiltrate followed by evidence of lymphangitis
and subsequent lymphadenopathy. Although viremia has been
2/21/14 5:38 PM

documented in both rabbits and monkeys, this route of patho-
genesis has not been documented for humans. With lymphatic
involvement, it is possible for the virus to spread by lymphan-
gial routes. Visceral organs that are involved, including the
heart, liver, spleen, lungs, kidneys, and adrenals, demonstrate
evidence of congestion and focal hemorrhagic necrosis; how-
ever, the degree of involvement varies from one patient to the
next. A striking characteristic of human B-virus infection is the
propensity to involve the central nervous system (CNS) and
likely reflects spread via neuronal routes. Transverse myelitis is
a prominent neurologic finding, with ultimate progression of
infection to the brain. B-virus infection can involve all regions
of the brain without evidence of localization to any particular
region, in contrast to HSV infection of the CNS, which tends
to localize in the temporal lobe. Histopathologic findings of
the brain include hemorrhagic foci, necrosis, and inflamma-
tory changes, as evidenced by perivascular cuffing with mono-
nuclear infiltrates. Edema and degeneration of motor neurons
are prominent. Even with advanced disease, Cowdry type A
eosinophilic intranuclear inclusions can be found in only a
few cases. In addition, gliosis and astrocytosis are late histo-
pathologic findings. Thus, there can be evidence of myelitis,
encephalomyelitis, encephalitis, or combinations thereof (17).
Pathogenesis of Latency in Macaques
Like other herpesviruses, B-virus infection in macaques be-
comes latent and can recur. As is discussed later in this chap-
ter, prevalence of antibodies to B virus is widespread in Old
World rhesus monkeys. Rhesus monkeys captured in the wild
and shipped to primate centers develop vesicular lesions of the
oropharynx, suggesting a pattern of virus reactivation and re-
crudescence of lesions similar to that encountered with HSV.
Unequivocal evidence of latent B-virus infection in rhesus
monkeys evolved with the studies of the recovery of B virus in
monkey kidney cell culture systems. Thus, Wood and Shimada
(9) obtained six isolates from 650 pools of monkey kidneys,
suggesting that at least 1% of rhesus monkeys contain latent
virus that can be reactivated by culturing kidney cells. Virus
was isolated from rhesus tissues also by Boulter (18). B virus
was recovered by cocultivation from a variety of neuronal tis-
sues (including gasserian ganglia, trigeminal ganglia, and dor-
sal root ganglia) and the spinal cord (19). Latent virus was
also isolated by cocultivation of tissues from experimentally
infected rabbits (9).
As in the case of HSV infections in humans, the most prom-
inent factor associated with reactivation of B virus in rhesus
monkeys is stress, particularly stress associated with the cap-
ture and shipping of animals from the wild to captivity. To
date, the state of viral DNA during latency or on the molecular
or biochemical events associated with the establishment and
reactivation of latent virus are unknown.
EPIDEMIOLOGY OF
HUMAN INFECTION
B-virus infections of humans must be considered in the con-
text of the epidemiology of any infectious disease, including
the susceptibility of the host and quantity of virus to which
they are exposed. Importantly, the frequency of excretion of
B virus in infected animals averages 2% to 3% at most; thus,
if a human is bitten by an infected animal, the probability of
infection is low, albeit existent. Direct contact with a source of
virusnamely, an actively or latently infected animal (or cells
obtained from an infected animal)is the means by which an
Scheld_Ch14.indd 205
Chapter 14: B Virus 205
infection is transmitted. Virus cannot penetrate intact skin;
thus, a break in the skin is required for acquisition of infec-
tion. Sites that have been documented as initially infected in
humans include wounds, the eyes, and perhaps the respiratory
tract. Because it is well established that infected animals can
excrete virus in saliva, from the eyes, in vesicular fluid, and
perhaps in the stool, these must all be considered potential
sources for human infection. Furthermore, as has been well
documented in the history of the development of poliomyelitis
vaccine, infected cell culture tissues can also be a source of
viral infections for humans.
Person-to-person transmission of B virus has been docu-
mented (17). In this instance, the wife of an animal worker,
who subsequently died of B-virus infection of the CNS, ac-
quired vesicular lesions of her ring finger. She provided direct
care of her husbands vesicular lesions. Although she survived
infection without evidence of neurologic disease, the extent of
disease may have been limited by early intervention with acy-
clovir. Notably, individuals who developed B-virus infection
had either skin-to-skin or face-to-face contact with at least 40
other individuals during a cluster of cases in Pensacola, Florida.
Although these other individuals were under close surveillance,
none developed evidence of infection. Thus, casual contact can
be excluded as a method of transmission of B-virus infection.
This is particularly important from a public health standpoint.
Nonfatal infection has not been well documented in reports
of human disease. One recent animal bite resulted in localized
viral replication without systemic involvement (20). Serologic
assessment of humans for evidence of B virus as a marker of
subclinical infection is confounded by cross reactivity to HSV.
MANIFESTATIONS OF CENTRAL
NERVOUS SYSTEM DISEASE
Human B-virus disease is characterized by an ascending myeli-
tis or encephalomyelitis. To date, there are a limited number
of cases of human disease caused by B virus in the literature,
depending on the criteria for case definition (7). Several cases
have been cited in the literature but have not been docu-
mented. Regardless of the exact number of cases, the total
number of patients who have experienced disease is limited.
Probably thousands of animal workers have been exposed to
animals excreting virus, but very few have developed disease.
As noted earlier, casual transmission is unlikely. Nevertheless,
the lessons learned regarding the clinical manifestations of dis-
ease in individuals exposed to B virus, as well as the necessity
for methods of intervention and prevention, are reinforced by
the findings in these particular patients.
Infection can occur in one of four fashions. First, infection
may be asymptomatic. An animal worker exposed to a rhesus
monkey with conjunctivitis was stuck by a needle that had been
used for inoculation of this animal (20). Subsequent biopsy of
the needlestick site revealed evidence of multinucleated giant
cells. B-virus DNA was detected in the biopsy specimen, but
there was no evidence of clinical disease. This form of infec-
tion may be an underreported event for individuals exposed to
B virus. A second, and more common, route of infection is by
animal bite. Following a bite by a monkey excreting B virus, a
localized vesicular lesion associated with erythema and edema
develops at the site of viral inoculation. Subsequently, lym-
phangitis with spread to regional lymph nodes occurs, along
with the development of secondary lymphadenopathy. These
early stages of disease are generally accompanied by fever,
myalgia, vomiting, abdominal cramping, meningeal irrita-
tion, and such cranial nerve signs as nystagmus and diplopia.
Neurologic symptoms develop very rapidly. Altered sensation,
2/21/14 5:38 PM
 206 Part II: Viral Infections and Related Disorders
hyperesthesia, or paresthesia of the limbs usually precede evi-
dence of weakness, areflexia, and flaccid paralysis. Transverse
myelitis with urinary retention is likely to occur. With progres-
sive involvement of the CNS, decreased levels of conscious-
ness, altered mentation, respiratory depression, seizures, and
ultimately neurologic death ensue.
Although the incubation period for B virus has been de-
bated, most cases have a relatively short incubation period of
approximately 3 to 5 days; however, some cases have been
reported to occur as late as 24 days after an animal bite. The
onset of neurologic symptoms generally occurs 3 to 7 days
after the appearance of a vesicular rash. Time to death var-
ies and can occur as early as within 10 to 14 days or much
later. Improvements in intensive care for critically ill patients
probably have influenced these survival data. The progression
of infection is likely related to a variety of factors, including
host immunologic status quantity of neutralizing antibodies
to HSV, age of the patient, site of the bite, and quantity of
virus inoculated. Prolonged incubation periods, as well as the
mechanism for these prolonged incubation periods, have not
been well characterized (7).
Third, cases have been documented following exposure to
infected secretions by an ocular or respiratory route. An ani-
mal care provider was exposed to direct inoculation of saliva
into the eye. In spite of rigorous rinsing, she became infected
and subsequently died (7). Two other cases illustrate the po-
tential for respiratory spread. Symptoms in these individuals
were localized to the respiratory tract, including coryza, cough,
laryngitis, and pharyngitis. While associated with fever, these
symptoms progressed to respiratory distress, as evidenced by a
radiographic evidence of interstitial pneumonitis. One of these
two patients had virus isolated from a vesicle. Subsequently,
neurologic symptoms developed, ultimately leading to death
of these patients (5).
The fourth manifestation of human disease is recurrent in-
fection. At least two patients illustrate that a recurrent vesicu-
lar rash can occur as a consequence of B-virus infection. In one
case, infection was acquired as a consequence of person-to-
person transmission. In another case, an individual developed
lesions compatible with the diagnosis of herpes zoster; however,
B virus was isolated from these lesions. Of the well-described
cases of herpes B-virus infection, the majority developed en-
cephalitis (90%), with a documented mortality rate of 75%.
Survivors of B-virus infection of the CNS have a broad spec-
trum of neurologic impairment. Of those documented in the
literature before the availability of antiviral therapy, two had
mild or minimal impairment, one had moderate neurologic im-
pairment, and the remainder had severe impairment. The lit-
erature also documents three patients who were infected with
B virus and survived infection but did not develop encephalitis.
One had severe neurologic impairment (presentation of herpes
zoster), and two appeared normal on follow-up. With the use
of antiherpetic drugs, survivors who were treated early, even
if they had CNS disease, tended to survive without significant
impairment (2123). Thus, taken together, these cases serve to
emphasize the severity of B-virus disease.
DIAGNOSIS
Clinical
The total number of cases of B-virus infection is small. The
possibility of B-virus infection must be considered in any indi-
vidual having contact with Old World monkeys, particularly
Asiatic Macaca species. Because of the recent identification of
person-to-person transmission, individuals having intimate
Scheld_Ch14.indd 206
contact with workers exposed to these animals should be
considered as having B-virus infection if compatible clinical
findings occur. The suspicion of B-virus infection should be
reinforced in the presence of historical evidence of direct con-
tact with a rhesus monkey, either by bite, scratch, or labora-
tory accident. In addition, some cases have been acquired by
exposure to monkey tissues; consequently, this route of trans-
mission should not be excluded as a possibility for human
infection.
Clinical evidence of disease has been defined earlier. Of par-
ticular interest to the clinician is the presence of a vesicular
rash at a bite site with ipsilateral regional lymphadenopathy.
With a compatible incubation period, the progressive appear-
ance of neurologic symptomatologyparticularly altered sen-
sation in the extremities, weakness, hyporeflexia or areflexia,
and altered mentationin the presence of a wound should
suggest the possibility of B-virus infection.
Virus Isolation
Recovery of virus from humans suspected of having B-virus
infection must be attempted. Sources for retrieval of virus are
those indicative of the pathogenesis of disease. These include
vesicles, conjunctivae, pharyngeal swabs, and tissue biopsy
material. Furthermore, retrieval of virus from the cerebro-
spinal fluid (CSF) should be attempted, although the yield is
very low. Specimens for virus isolation should be processed
in cell lines that are susceptible to B virus. As noted earlier
in this chapter, these include primary vervet monkey kidney,
rabbit kidney cells, or established strains such as BS-C-1 or
LLC-RK-1. B virus replicates in all these cell lines, in contrast
to other simian viruses, which have a more limited spectrum of
susceptible cell lines (24).
Once viral isolation has been achieved, identification of
virus can be accomplished using either molecular methods
(25,26) or neutralization assays, although the latter assay is
cumbersome and tedious (5,27,28). Rapid identification of
isolates is essential for purposes of intervention with appropri-
ate therapeutic agents (29,30).
Serologic Evaluation
Serologic determination of B-virus infection is exceedingly
difficult because of its cross reactivity with HSV. Attempts
at antibody absorption are not satisfactory. The extensive
cross reactions of sera to simian viruses in the presence of
HSV antibodies have made diagnosis difficult (5,31,32).
Animal workers providing care for Macaca monkeys should
be serially bled for antibody determinations. Sera should be
banked for future reference. The standard serologic assays
that have been employed generally use either neutralization
assays or complement fixation (33). In general, complement-
fixing antibody titers to HSV are higher in humans than in
monkeys, whereas titers against B virus are higher in Macaca
monkeys than in humans. As previously mentioned, human
sera contain higher levels of neutralizing antibodies to HSV
than to B virus. Furthermore, sera derived from monkeys
with B-virus infection have been reported to neutralize
HSV better than they neutralize the endogenous virus. No
simple test exists to distinguish antibodies to HSV from
antibodies to B virus. Nevertheless, a variety of assays for
the rapid evaluation of human antibody response are under
development (29,34). The advent of these newer diagnostic
assays will be of value for prospectively evaluating patients
exposed to B virus.
2/21/14 5:38 PM
 Chapter 14: B Virus 207

TA B L E 1 4 . 1 animal workers (7,37). Although the risk of acquisition of in-

fection by B virus is extremely low, caution is indicated (37).
LABORATORIES THAT PERFORM TESTS FOR Guidelines for the management of macaques in captivity
B VIRUS (7) for research purposes include the following:
Physician, Laboratory, and 1. Macaque monkeys should be used only for research pur-
Contact Information Available Tests for B Virus poses and only when clearly indicated.
2. It is desirable to use macaques that are free of B-virus in-
Dr. Julia Hilliard Culture, serologic testing, fection. Thus, screening for B-virus infection before their
B Virus Research Resource and PCR analysis of use for research purposes is necessary. Furthermore, these
Laboratory specimens from humans animals should be maintained in a state that will prevent
Georgia State University or nonhuman primates acquisition of infection (5,6). Attempts are in progress to
P.O. Box 4118 establish B-virusfree colonies.
Atlanta, GA 30302-4118 3. All macaques should be considered infected unless proven
Tel.: (404) 651-0808 otherwise. This point warrants emphasis because it en-
E-mail: biojkh@panther.gsu.edu courages careful methods of handling these animals.
Dr. David Brown Culture, serologic testing, 4. Macaque handlers should be properly attired (arm-length
Central Public Health and PCR analysis of leather gloves, protective eyewear, and mask) and prepared
Laboratory specimens from humans to use proper restraints or anesthetic agents, such as ket-
Enteric, Respiratory, and or nonhuman primates amine, before manipulating animals.
Neurological 5. Cages and equipment for housing and transport of
Virus Laboratory macaques, as well as laboratory equipment with which
61 Colindale Avenue macaques have contact, should be thoroughly cleaned.
London NW9 5HT, England Sharp edges can lead to wounds in the macaques, which
Tel.: 44-208-200-4400 may ultimately be a source of infection.
E-mail: dbrown@phls.org.uk 6. Animal handlers, investigators, and support personnel
who handle macaques should be properly trained in the
Dr. Seymour S. Kalter Culture and serologic methods of animal restraint and manipulation. Every ef-
Esoterix testing of specimens fort must be made to educate personnel in bite prevention.
7540 Louis Pasteur Drive, from nonhuman Serial and prospective serologic evaluation of individuals
Suite 200 primates only who have continual contact with these animals should be
San Antonio, TX 78229 performed and sera specimens maintained at a repository
Tel.: (210) 614-7350 for future evaluation, if necessary. Knowledgeable medical
E-mail: sy.kalter@esoterix.com personnel should be readily available for consultation.
7. Any bite or scratch wound incurred from a macaque or as
From Cohen JI, Davenport DS, Stewart JA, et al. Recommendations a consequence of contact with a macaque cage should be
for prevention of and therapy for exposure to B virus (cercopithecine decontaminated as quickly as possible. Cleansing with soap
herpesvirus 1). Clin Infect Dis. 2002;35:11911203.
and water should be done for at least 15 minutes. If an eye
is involved, a sterile saline wash should be used. Cultures of
both the animal and the wound site should be obtained im-
mediately. Follow-up evaluation of these individuals should
include clinical and serologic evaluation. If there is evidence
Polymerase Chain Reaction Detection of suspected disease, assessments should proceed, with virus
isolation and further serologic evaluation. With evidence of
of B-Virus DNA disease, specific antiviral therapy should be instituted, as
noted in the next section, Prevention and Treatment.
Recently, a single-step polymerase chain reaction (PCR) assay
has been reported to be of value for diagnostic purposes (35). These recommendations have been provided as guidelines
Because of the rarity of disease, field performance character- for the management of macaques in captivity for research
istics need to be determined. Primate workers should carry a purposes (7,39). Variations from these guidelines can be dis-
card that indicates symptoms of B virus and contact informa- cussed with investigators at the CDC (Viral Exanthems and
tion for clinical and laboratory consultation regarding B virus Herpesvirus Branch, Division of Viral Diseases, Centers for
(Table 14.1). Disease Control and Prevention, 404-329-1338, www.cdc
.gov/ncidod/diseases/bvirus.htm).

CONTROL OF B-VIRUS
INFECTION
As with all other infectious diseases, the principal goal is to
prevent infection. Prevention has been stressed on numerous
occasions by the Centers for Disease Control and Prevention
(CDC) and in reviews published over the last 15 years (5
7,3638). Although a vaccine is not readily available for the
prevention of B-virus infections, one is under development
(37). Proper laboratory and animal breeding and handling
procedures will significantly decrease the risk of infection.
A CDC Advisory Committee has recommended procedures
for control and management of infected animals and exposed
PREVENTION AND TREATMENT
Treatment
Although vaccines have been evaluated in animal models,
none has proven efficacious in humans (17,4042). The use of
hyperimmune serum or -globulin has not been proven effec-
tive for the treatment of human infections caused by B virus
(43). Other investigators have demonstrated protection with
hyperimmune horse and rabbit sera for rabbit infection (44).
The use of other forms of hyperimmune sera has not been
proven effective.

Scheld_Ch14.indd 207 2/21/14 5:38 PM

 208 Part II: Viral Infections and Related Disorders
With the advent of antiviral therapy, nucleoside analogs
have been deployed for the management of B-virus infection
of humans. Four drugs have been used experimentally: vida-
rabine, acyclovir, valacyclovir, and ganciclovir. Each of these
drugs has been reported to have varying activity. Studies with
an acyclovir-based medication have attracted the most atten-
tion. In cell culture systems, acyclovir is active against B-virus
infection. One milligram of acyclovir decreased the yield of
virus by approximately 90% (45). Subsequent experiments in
animal models provided varying evidence of efficacy, depending
on the quantity of inoculation, delay in therapy, and duration
of treatment. Overall, a beneficial effect could be achieved in
animals (45). Smith et al. (46) have demonstrated that ganciclo-
vir is extremely active against B virus at concentrations of 0.55
mg/mL or less. These concentrations are achievable in humans.
More recently, animal model studies have shown the efficacy of
acyclovir and superiority of ganciclovir for disease therapy (15).
The use of acyclovir and its prodrug valacyclovir for ther-
apy of human disease has been more limited. The literature
includes several cases in which therapy instituted early in the
disease course may have slowed progression and led to a return
to normal function (20). Two of these cases were reported in
the Pensacola outbreak. The value of acyclovir under such cir-
cumstances cannot be unequivocally determined because of the
small number of patients who have this disease for evaluation
in controlled studies. If acyclovir is used initially for cutaneous
disease, some experts recommend a dose of 12.5 to 15.0 mg/
kg every 8 hours intravenously (IV) (7). With the availability
of the prodrug of acyclovir, valacyclovir, higher plasma levels
can be achieved (45). Thus, a recommendation for valacyclovir
therapy is made because of the severity of disease and its uni-
formly near-fatal outcome (7). The dose is 1 g every 8 hours.
Some experts recommend ganciclovir therapy for symp-
tomatic B-virus disease, particularly if the CNS is involved, for
References
1. Gay FP, Holden M. The herpes encephalitis problem. J Infect Dis.
1933;53:287303.
2. Sabin AB, Wright WM. Acute ascending myelitis following a monkey bite,
with the isolation of a virus capable of reproducing the disease. J Exp Med.
1934;59:115136.
3. Sabin AB. Studies on the B virus. I. The immunological identity of a virus
isolated from a human case of ascending myelitis associated with visceral
necrosis. Br J Exp Pathol. 1934;15:248268.
4. Sabin AB. Studies on the B virus. II. Properties of the virus and pathogenesis
of the experimental disease in rabbits. Br J Exp Pathol. 1934;15:269279.
5. Hull RN. The simian herpesviruses. In: Kaplan AS, ed. The Herpesviruses.
New York: Academic Press; 1973:389425.
6. Palmer AE. B virus, herpesvirus simiae: historical perspective. J Med
Primatol. 1987;16:99130.
7. Cohen JI, Davenport DS, Stewart JA, et al. Recommendations for preven-
tion of and therapy for exposure to B virus (cercopithecine herpesvirus
1). Clinical infectious diseases : an official publication of the Infectious
Diseases Society of America. Clin Infect Dis. 2002;35(10):1191203.
8. Burnet FM, Lush D, Jackson AV. The propagation of herpes B and pseudora-
bies viruses on the chorioallantois. Aust J Exp Biol Med Sci. 1939;17:3552.
9. Wood W, Shimada FT. Isolation of strains of virus B from tissue cultures of
cynomolgus and rhesus kidney. Can J Public Health. 1954;45:509518.
10. Reissig M, Melnick JL. The cellular changes produced in tissue cultures by
herpes B virus correlated with concurrent multiplication of the virus. J Exp
Med. 1955;101:341351.
11. Krech U, Lewis LJ. Propagation of B virus in tissue culture. Proc Soc Exp
Biol Med. 1954;87:174178.
12. Hopps HE, Bernheim BC, Nisalak A, et al. Biologic characteristics of a
continuous kidney cell line derived from the African Green Monkey. J
Immunol. 1963;91:416424.
13. Hull RN, Dwyer AC, Cherry WR, et al. Development and character-
istics of the rabbit kidney cell strain, LLC-RK. Proc Soc Exp Biol Med.
1965;118:10541059.
Scheld_Ch14.indd 208
a minimum of 14 days at dosages of 5 mg/kg every 12 hours
IV (7). The duration of therapy is not known but should con-
tinue until all CNS symptoms have resolved. Subsequent oral
administration of valacyclovir for suppression of latent infec-
tion is considered by many experts; however, there are no data
regarding the value of therapy for prolonged periods under
such circumstances. Furthermore, the value of valacyclovir for
life is recommended by some experts.
Prophylaxis
Valacyclovir should be used for prophylaxis in patients ex-
posed to B virus. The dosage is 1 g every 8 hours and should
be continued until the results of laboratory tests are available.
FUTURE DIRECTIONS
B-virus infection in humans should not occur. The proper
deployment of control procedures among animal handlers
should avoid all human infections. Regardless, the future will
allow for the development of more rapid and precise diagnos-
tic assays and the further definition of appropriate procedures
for handling infected animals and humans at risk for infection.
ACKNOWLEDGMENTS
Original studies performed by the investigators were sup-
ported by grants from the National Institute of Allergy and
Infectious Diseases (NO1-AI-62554, NO1-AI-30025), the
Division of Research Resources (RR0023) of the National
Institutes of Health, and the State of Alabama.
14. Benda R, Cinatl J. Isolation of two plaque variants from the prototype
strain of B virus (herpesvirus simiae). Acta Virol. 1966;10:178.
15. Falke D. Isolation of two variants with different cytopathic properties from
a strain of herpes B virus. Virology. 1961;14:492.
16. Hilliard JK, Eberle R, Lipper SL, et al. Herpesvirus simiae (B virus): repli-
cation of the virus and identification of viral polypeptides in infected cells.
Arch Virol. 1987;93:185198.
17. Whitley R, Hilliard J. Cercopithecine herpes virus 1 (B virus). In: Knipe
D, Howley P, Griffin D, et al., eds. Fields Virology. 5th ed. Philadelphia:
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18. Boulter EA. The isolation of monkey B virus (herpesvirus simiae) from the
trigeminal ganglia of a healthy seropositive rhesus monkey. J Biol Stand.
1975;3:279280.
19. Kalter SS, Weiss SA, Heberling RL, et al. The isolation of a herpesvirus
from the trigeminal ganglia of normal baboons (Papio cynocephalus). Lab
Anim Sci. 1978;28:705709.
20. Benson PM, Malane SL, Banks R, et al. B virus (herpesvirus simiae) and
human infection. Arch Dermatol. 1989;125(9):12471248.
21. Holmes GP, Hilliard JK, Klontz KC. B virus (herpes virus simiae) infec-
tion in humans; epidemiologic investigation of a cluster. Ann Intern Med.
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22. Davenport DS, Johnson DR, Holmes GP, et al. Diagnosis and management
of human B virus (herpesvirus simiae) infections in Michigan. Clin Infect
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23. Centers for Disease Control and Prevention. B virus infections in humans
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relationship in the herpes group. Br J Exp Pathol. 1974;55:471477.
25. Benda R, Prochazka O, Cerva L, et al. Demonstration of B virus (her-
pesvirus simiae) by the direct fluorescent antibody technique. Acta Virol.
1966;10:149154.
26. Hilliard JK, Kalter SS. Development of molecular probes for simian herpes-
virus detection. Dev Biol Stand. 1985;59:7986.
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27. Kalter SS. Virus studies on the normal baboon. In: Vagtborg H, ed. The
Baboon in Medical Research. Austin: Austin University Texas Press;
1965:416417.
28. Kalter SS, Hutt R. Serodiagnosis of herpesvirus infection in primates. Dev
Biol Stand. 1978;41:23540.
29. Heberling RL, Kalter SS. A dot-immunoblotting assay on nitrocellulose
with psoralen inactivated herpesvirus simiae (B virus). Lab Anim Sci.
1987;37:304308.
30. Hilliard JK, Munoz RM, Lipper SL, et al. Rapid identification of herpes-
virus simiae (B virus) DNA from clinical isolates in nonhuman primate
colonies. J Virol Methods. 1986;13:5562.
31. Boulter EA, Kalter SS, Heberling RL, et al. A comparison of neutralization
tests for the detection of antibodies to herpesvirus simiae (monkey B virus).
Lab Anim Sci. 1982;32:150152.
32. van Hoosier GL, Melnick JL. Neutralizing antibodies in human sera to
herpesvirus simiae. Tex Rep Biol Med. 1961;19:376380.
33. Gary WG, Palmer EL. Comparative complement fixation and serum neu-
tralization antibody titers to herpes simplex virus type 1 and herpesvirus
simiae in Macaca mulatta and humans. J Clin Microbiol. 1977;5:465470.
34. Katz D, Hilliard JK, Eberle R, et al. Elisa for detection of group-common
and virus-specific antibodies in human and simian sera induced by herpes
simplex and related simina viruses. J Virol Methods. 1986;14:99109.
35. Hirano M, Nakamura S, Mitsunaga F, et al. One-step PCR to distinguish B
virus from related primate alphaherpesviruses. Clin Diagn Lab Immunol.
2002;9:716719.
36. Estep RD, Messaoudi I, Wong SW. Simian herpesviruses and their risk to
humans. Vaccine. 2010;28(suppl 2):B78B84.
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Chapter 14: B Virus 209
37. Hirano M, Nakamura S, Mitsunaga F, et al. Efficacy of a B virus gD
DNA vaccine for induction of humoral and cellular immune responses in
Japanese macaques. Vaccine. 2002;20:25232532.
38. Liao G, Li R, Li C, et al. Safety and immunogenicity of inactivated polio-
virus vaccine made from Sabin strains: a phase II, randomized, positive-
controlled trial. J Infect Dis. 2012;205(2):237243.
39. Centers for Disease Control and Prevention. Updated CDC recommenda-
tions for the management of hepatitis B virus-infected health-care providers
and students. MMWR Recomm Rep. 2012;61(RR-3):112.
40. Buthala DA. Studies on herpesvirus simiae (B virus) inactivation and at-
tempts at vaccine production. J Infect Dis. 1962;111:95100.
41. Hull RN, Nash JC. Immunization against B virus infection. I. Preparation
of an experimental vaccine. Am J Hyg. 1960;71:1528.
42. Hull RN, Peck FB Jr, Ward TG, et al. Immunization against B virus infec-
tion. II. Further laboratory and clinical studies with an experimental vac-
cine. Am J Hyg. 1962;76:239251.
43. Boulter EA, Zwartouw HT, Thornton B. Postexposure immunoprophylaxis
against B virus infection. Br Med J (Clin Res Ed). 1982;284:746.
44. Buthala DA. Hyperimmunized horse anti-B virus globulin: preparation and
effectiveness. J Infect Dis. 1962;111:101106.
45. Boulter EA, Thornton B, Bauer EJ, et al. Successful treatment of exper-
imental B virus (herpesvirus simiae) infection with acyclovir. Br Med J.
1980;280:681683.
46. Smith KO, Galloway KS, Hodges SL, et al. Sensitivity of equine herpes-
viruses 1 and 3 in vitro to a new nucleoside analogue, 9-[{2-hydroxy-
1-(hydroxymethyl)ethoxy} methyl]guanine. Am J Vet Res. 1983;44:
10321035.
2/21/14 5:38 PM
 CHAPTER 15 ARTHROPOD-BORNE VIRAL
ENCEPHALITIDES
TOM SOLOMON, ADJANIE PATABENDIGE, AND RICHARD J. WHITLEY
Conventionally, viruses are placed within families and genera
according to the taxonomic system, based on morphologic,
biochemical, antigenic, and genetic similarities. However,
because the taxonomic system tells us nothing about how
a virus is transmitted or about the patterns of disease it
causes, it is of relatively little help to the practicing clini-
cian. For this reason, alternative groupings that incorpo-
rate these clinical and epidemiologic aspects are often used.
One such group is the arthropod-borne viral (or arboviral)
encephalitides that includes viruses transmitted by arthro-
pods (insect, ticks, sandflies, and biting midges) that are
important causes of central nervous system (CNS) disease
in humans. Altogether, there are more than 500 arthro-
pod-borne viruses, or arboviruses, that come from four
viral families (Togaviridae, Flaviviridae, Bunyaviridae, and
Reoviridae); only a relatively small number of these viruses
are responsible for human disease (Table 15.1). Within the
family Togaviridae, the Alphavirus genus contains eastern,
western, and Venezuelan equine encephalitis (EEE, WEE,
and VEE) virusesimportant causes of disease in horses and
humans in the Americasand chikungunya virus (CHIKV),
which caused major outbreaks associated with severe mor-
bidity in the Indian Ocean islands and in India during
2005 to 2007 (1). The flaviviruses (genus Flavivirus, fam-
ily Flaviviridae) include Japanese encephalitis virus (JEV),
which occurs across much of southern and eastern Asia and
is the most important cause of epidemic encephalitis world-
wide; West Nile virus (WNV), which has spread to cause
large encephalitis outbreaks in the United States; dengue
virus (DENV), which continue to be a global threat with
over 100 million infected annually; and tick-borne encepha-
litis (TBE) virusesimportant in Europe and Russia. Within
the family Bunyaviridae, the Bunyavirus genus includes La
Crosse virus (LACV) and other California serogroup viruses
that cause encephalitis, whereas the Phlebovirus genus
TA B L E 1 5 . 1
VIRAL FAMILIES AND GENERA CONTAINING ARBOVIRUSES
Family Arboviral Genera
Togaviridae Alphavirus (eastern equine encephalitis)
Flaviviridae Flavivirus (West Nile)
Bunyaviridae Bunyavirus (La Crosse)
Phlebovirus (Toscana)
Nairovirus (Crimean-Congo
hemorrhagic fever)
Tospovirus (tomato spotted wilt)
Reoviridae Coltivirus (Colorado tick fever)
An example from each genus is shown in parentheses.
210
Scheld_Ch15.indd 210
includes Toscana virus (TOSV), an important emerging
cause of CNS disease in southern Europe. The Reoviridae
family includes Colorado tick fever virus (CTFV) and similar
members of the Coltivirus genus that causes febrile illness
and CNS disease.
Arboviruses classically cause three disease patterns in
humans (Fig. 15.1): fever-arthralgia-rash syndromes, viral
hemorrhagic fevers (often associated with hepatitis), and neu-
rologic disease, which are the focus of this chapter. They con-
stitute some of the most important emerging and reemerging
infectious diseases. General principles of arboviral ecology,
epidemiology, and pathogenesis, as well as diagnosis, manage-
ment, and prevention of arboviral encephalitis, are discussed
before the more important diseases are considered in more
detail.
ECOLOGY OF ARBOVIRUSES
A basic understanding of the ecology of arboviruses is help-
ful in understanding the epidemiology of human disease.
For most of the arboviruses that cause neurologic disease
in humans, including many of the flaviviruses, alphaviruses,
and bunyaviruses, humans are not part of the natural cycle,
being incidental hosts (Fig. 15.2). In nature, these viruses
are typically transmitted between birds or small rodents
in enzootic cycles that use mosquitoes or ticks as vectors.
To be evolutionarily successful, arboviruses require immu-
nologically naive hosts, which is why most have evolved
to use rapidly reproducing animals. Humans are infected
when they encroach upon this natural enzootic cycle and
are bitten by the vector. This may be because they live in or
have entered areas where the virus circulates naturally or
because changes in ecologic or environmental circumstances
have caused the virus to move closer to areas inhabited
Nonarboviral Genera
Rubivirus (rubella)
Hepacivirus (hepatitis C)
Pestivirus (bovine viral diarrhea)
Hantavirus (sin nombre)
Rotavirus (rotavirus)
2/21/14 5:38 PM

FAR
CHK (a)
ONN (a)
RR (a)
VEE (a)
TOS (p)
CTF (c)
EEE (a) WN (f) DEN (f)
WEE (a)
JE (f)
LAC (b) SLE (f)
MVE (f)
CNS TBE (f) CCHF (n)
(a) Alphavirus genus (family Togaviridae) (f) Flavivirus genus (family Flaviviridae)
CHK = Chikungunya
ONN = Onyong nyong
RR = Ross river
VEE = Venezuelan equine encephalitis
EEE = Eastern equine encephalitis
WEE = Western equine encephalitis
(b) Bunyavirus genus (family Bunyaviridae)
LAC = La Crosse
(c) Coltivirus genus (family Reoviridae) (p) Phlebovirus genus (family Bunyaviridae)
CTF = Colorado tick fever
(n) Nairovirus genus (family Bunyaviridae)
CCHF = Crimean-Congo haemorrhagic fever
by humans. Sometimes a different mosquito carries the virus
to humans (a bridging vector), and sometimes there is an
intermediate vertebrate cycle that brings the virus closer to
humans (e.g., equines for some of the alphavirus encepha-
litides and swine for JEV). A large outbreak of disease in
animals is an epizootic. Whereas natural hosts have pro-
longed and high viremia, humans have transient and low
viremia, insufficient to transmit the virus further, and are
considered dead-end hosts. Most human infections are
asymptomatic or result in a mild nonspecific febrile illness,
but in a small proportion, the virus enters the CNS to cause
the syndrome for which the virus is known. The brief and
low viremia makes diagnosis of human infection by virus
isolation or nucleic acid amplification difficult, and for the
most part, serologic tests are used. Although humans are
dead-end hosts for most arboviruses, some arboviruses
are better adapted to replicate in humans, resulting in per-
sistent and high viremias, allowing for further transmission
to a biting insect. Examples include VEEV, TOSV, CTFV,
and DENV. These high viremias typically cause a charac-
teristic arboviral fever-arthralgia-rash syndrome in most
patients; CNS manifestations tend to be milder, for example,
aseptic meningitis. Because of the high viremias, virus isola-
tion and polymerase chain reaction (PCR) are more success-
ful for these viruses.
Scheld_Ch15.indd 211
Chapter 15: Arthropod-Borne Viral Encephalitides 211
RVF (p)
YF (f)
OHF (f)
KFD (f)
VHF
WN = West Nile
JE = Japanese encephalitis
SLE = St Louis encephalitis
MVE = Murray valley encephalitis
TBE = Tick-borne encephalitis
DEN = Dengue
YF = Yellow Fever
OHF = Omsk hemorrhagic fever
KFD = Kyasanur Forest disease
FIGURE 15.1 Medically important
arboviruses grouped according to
TOS = Toscana disease syndrome (top) and listed by
RVF = Rift Valley fever genus (bottom). FAR, fever-arthralgia-
rash; VHF, viral hemorrhagic fever;
CNS, central nervous system.
Arboviruses replicate in both the vertebrate host and
the vector in an extrinsic cycle. Whereas vertebrate hosts
typically mount an immune response and clear the virus,
the arthropod vectors are usually infected for life. Virus is
ingested by the vector with an infected blood meal, repli-
cates in the epithelium of the mesenteron (midgut), then
disseminates to the salivary glands, where it replicates fur-
ther and is excreted with each blood meal. The virus may
also be passed on from the adult mosquitoes and ticks to
their offspring, via transovarial transmission (Fig. 15.2).
For ticks, virus can also be transmitted vertically from the
larval to nymph then adult stages (transtadial transmission).
Vertical transmission is an important means of overwinter-
ing (i.e., surviving the cool winter months) for some viruses,
but for others, the means of overwintering is uncertain. An
exception to a typical arboviral cycle includes mechanical
transmission via the vectors mouth parts. More importantly,
some viruses, as well as being arthropod borne, can also
be directly transmitted between vertebrate hosts, bypassing
the arthropod vector, for example, humans can become in-
fected with Rift Valley fever virus (RVFV) from the body
fluids of infected animals (2), TBE virus can be transmit-
ted to humans via infected goats milk (3), and WNV can
be transmitted in infected blood products or transplanted
organs (4).
2/21/14 5:38 PM
 212 Part II: Viral Infections and Related Disorders

Vertical transmission
In transovarial transmission, the virus
is passed from the vector to its eggs.
For ticks, transtadial transmission
from larvae to nymphs, then to adults
also occurs.
Bridging vector
Sometimes, the vector carrying
the virus to humans differs from
that in the enzootic cycle. These
are usually anthropophillic
vectors i.e., they prefer biting
humans.

For some viruses, this provides

the means of overwintering
(surviving through the winter
months).

Dead end host

For most arbovirus, humans

do not transmit the virus
further. But there are few
Enzootic cycle
important exceptions.
Most arboviruses exist naturally in an
animal cycle (strictly the virus should
cause disease in animals to be
called enzootic). If these are wild
animals, the term Sylvatic cycle is Epizootic cycle
also used. Ornithophilic mosquitoes
prefer feeding on birds. A large outbreak of disease in animal is FIGURE 15.2 Overview of arboviral
an epizootic. Sometime, this also acts as ecology. A hypothetical arboviral cycle,
an amplifying/bridging cycle, bringing with an explanation of some commonly
the virus closer to humans. used terms.

PATHOGENESIS OF ARBOVIRAL
ENCEPHALITIS
Despite the wide range of arboviruses that cause encephalitis,
there are many similarities in the pathogenesis and pathology
(see Table 15.2 for an overview of the arboviral encephalitides).
Much of the data has come from rodent models of alphavirus
encephalitis. Following inoculation, usually during the bite of a
blood-sucking mosquito or tick, arboviruses typically replicate
in the skin and local lymph nodes, causing a viremia, before
entering the CNS (5). Langerhans cells in the skin have been
implicated as a site of replication for alphaviruses and some fla-
viviruses (68). Keratinocytes have also been shown to be one
of the initial targets for WNV replication and could be contrib-
uting to the persistence of WNV in the skin (9). Replication in
local skeletal muscle may also be important for alphaviruses.
Invasion of target organs appears to depend in part on the
extent of viremia, but also on other invasive viral characteristics
(10). The two peaks of the characteristic saddleback or bipha-
sic fever curve seen in many arboviral infections correspond to
production of interferon (IFN) and proinflammatory cytokines
during the initial viremia, and then a mononuclear inflamma-
tory response in infected target organs (11). IFN production is
induced when viral components are detected by cytoplasmic
proteins such as retinoic acid-inducible gene I (RIG-I) and mela-
noma differentiation-associated gene 5 (MDA5) during the
unwrapping of the viral RNA from the nucleocapsid to allow
replication. In addition, cells use toll-like receptors (TLRs)
to recognize pathogen-associated molecular patterns. TLR3,
TLR7, TLR8, and TLR9 are the main viral sensors in humans.
TLR7, TLR8, and TLR9 are localized in the endosomal com-
partments and signal through the MyD88 adapter, leading to
type 1 IFNs and inflammatory cytokine production. TLR3 is
located both on the cell surface and in endosomal compart-
ments and induces production of type 1 IFNs through toll/
interleukin-1 (IL-1) receptor (TIR) domain-containing adapter-
inducing IFN- (TRIF) adapter. Protein kinase R (PKR) and
2, 5-oligoadenylate synthetase (OAS) are two other cellular
viral sensors. Viral sensors activate IFN regulatory factors and
transcriptional induction of IFNs, which then signal through the
JAK/STAT pathway leading to transcription of many interferon-
stimulated genes (ISGs). The expression of ISGs and induction
of their products (e.g., RIG-I, MDA5, TLRs, OAS, PKR) are
critical for limiting replication of arboviruses. Many arbovi-
ruses encode nonstructural proteins to counter the host immune
response. The main function of these nonstructural proteins
is to antagonize the initial IFN response and is an important
adaptation that has helped arboviruses to establish themselves
in numerous vertebrate hosts (12).
The mechanisms of virus entering the CNS may include
infection of or transport across brain microvascular endothelial
cells that form the bloodbrain barrier (BBB) and infection of
olfactory neurons or of choroid plexus epithelial cells (1316).
However, the exact mechanisms of virus entry into the CNS
across the BBB and interactions of the virus with the BBB remain
incompletely understood, despite the critical role of the BBB in
preventing pathogen entry to the CNS (1720). In animal mod-
els, the term neuroinvasiveness is used to describe a virus abil-
ity to enter the nervous system following peripheral inoculation.

Scheld_Ch15.indd 212 2/21/14 5:38 PM

 Chapter 15: Arthropod-Borne Viral Encephalitides 213

TA B L E 1 5 . 2
OVERVIEW OF THE MAJOR ARBOVIRAL ENCEPHALITIDES

Main Vectors
Geographic (Mosquitoes Unless
Family/Genus Genus Virus Distribution Natural Hosts Otherwise Stated) Human Disease

Togaviridae Alphavirus Eastern equine North, Central, Freshwater swamp Culiseta melanura; High mortality; CSF
encephalitis and South birds in North Aedes species are may resemble
America America, rodents bridging vectors bacterial meningitis
and marsupials
in South America
Western Western Canada, Passerine birds Culex tarsalis; Aedes No human cases since
equine western and (sparrows, melanimon 1994, relatively low
encephalitis midwestern house finches); mortality
United States blacktail
jackrabbit
Venezuelan Central and Rodents, aquatic Culex FAR syndrome
equine South America, birds (Melanoconion) common; CNS disease
encephalitis occasionally species in enzootic rare. Humans have
extending cycle; Psorophora high viremias; virus
further north and Aedes species also isolated from
invoved in equine pharynx; Nonlicensed
epizootics, and live attenuated vaccine
epidemics (TC-83) available
Chikungunya Tropical and Non-human Aedes aegypti and FAR syndrome;
subtropical primates and Aedes albopictus polyarthralgia is
regions small mammals are main vectors. common; persistent
of Africa, (monkeys, bats) Aedes furcifer- arthralgia in some
Southeast Asia, taylori, Aedes cases; CNS disease
and Australia africanus, Aedes more common in
luteocephalus, and children; evidence of
Aedes neoafricanus vertical transmission
are enzootic vectors. from mother-to-child
Flaviviridae Flavivirus West Nile Africa, Middle Passeriform birds Culex pipiens and Nosocomial
East, Europe, (jays, blackbirds, others transmission also
Asia, America, finches, occurs; febrile
Australia warblers, syndrome common;
sparrows, crows) disease is more
severe in elderly and
immunosuppressed
Japanese Southeast Asia, Herons, egrets, Culex Most important
encephalitis Pacific Rim, migrating birds; tritaeniorhynchus, arboviral
Northern swine Culex gelidus and encephalitis; seizures
Australia, Asian others and parkinsonian
subcontinent features common;
inactivated vaccine
(Biken) is licensed;
live attenuated
vaccine in China
St. Louis North, Central, Passeriform and Culex tarsalis in Endemic disease
encephalitis and South columbiform the west; Culex in the western
America birds pipiens, Culex United States; large
quinquefasciatus, outbreaks in the
Culex nigripalpus eastern United States
in the east
Murray Valley New Guinea, Herons, egrets, Culex annulirostris, Mostly affects
Australia aquatic birds and others aboriginal children
Tick-borne Europe, Siberia, Small forest Ixodes ricinus, Poliomyelitis-like
encephalitis Far East rodents Ixodes persulcatus, paralysis of upper
and other ticks limbs is common.
Inactivated vaccines
are licensed

(continued)

Scheld_Ch15.indd 213 2/21/14 5:38 PM

 214 Part II: Viral Infections and Related Disorders

TA B L E 1 5 . 2
OVERVIEW OF THE MAJOR ARBOVIRAL ENCEPHALITIDES (CONTINUED)

Main Vectors
Geographic (Mosquitoes Unless
Family/Genus Genus Virus Distribution Natural Hosts Otherwise Stated) Human Disease

Dengue Almost every Humans, and Aedes aegypti and FAR syndrome (dengue
country nonhuman Aedes albopictus fever); syndrome of
between tropics primates vascular leak and
of Capricorn hemorrhage (dengue
and Cancer hemorrhagic fever);
neurologic disease
Bunyaviridae Bunyavirus La Crosse Midwestern and Chipmunks, Aedes triseriatus, Major pediatric
Eastern United squirrels Aedes albopictus arboviral encephalitis
States in United States;
fatalities are rare
Jamestown North America White tailed deer Aedes species, Culex Encephalitis in the
Canyon inornata elderly
California Western United Rabbits, other Aedes melanimon, Rare cause of human
encephalitis States, Canada rodents Aedes dorsalis disease
Tahyna Europe, Russia Domestic animals, Aedes vexans, Culex Newly recognized
rabbits annulata cause of febrile
illness with CNS
disease, especially in
Russia
Phlebovirus Toscana Mediterranean Not known Phlebotomus Mostly aseptic
countries perniciosus meningitis,
sandflies encephalitis rare
Rift Valley Africa, Middle Livestock Aedes and other Febrile illness with
Fever East mosquitoes; also retinitis hemorrhagic
direct transmission fever, encephalitis
from livestock (02%)
body fluids
Reoviridae Coltivirus Colorado tick Western United Squirrels, Dermacentor Meningitis in patient
fever States and chipmunks, andersoni ticks with leukopenia and
Canada other small thrombocytopenia
mammals

FAR, fever arthralgia rash.

Neurovirulence describes its ability to cause damage once
within the CNS (e.g., following invasion from the periphery
or following direct intracranial inoculation). Once inside the
nervous system, the pathogenesis may involve a combination
of infection and dysfunction of neurons, caused by direct viral
or indirect inflammatory damage and other mechanisms such
as programmed cell death. The immune response to alphavirus
infection has been characterized in experimental animals and
includes an early innate response with type I interferon (IFN-
and IFN-) production, followed by specific humoral and cel-
lular immune responses (21). Experiments with knockout mice
have shown type I IFN limits early viral replication, possibly
by production of MxA protein, a large cytoplasmic guanosine
triphosphatase that prevents accumulation of viral genomic and
subgenomic RNA (22). Tumor necrosis factor- (TNF-) and
other proinflammatory cytokines are produced, contributing to
the pathogenesis (23). Production of IFN- and other cytokines
and chemokines has been implicated in JEV in humans (2426).
The humoral immune response in human alphavirus and
flavivirus encephalitis includes early production of immuno-
globulin M (IgM), followed by immunoglobulin G (IgG) that
persists for years (2730). The failure of antibody production
is associated with a fatal outcome in human disease (3032).
Antibody appears to be protective by neutralization, nonneu-
tralizing binding, and complement-mediated lysis of infected
cells (33). In animal models of alphavirus encephalitis, anti-
body assists with nonlytic clearance of virally infected cells by
a mechanism that appears to be synergistic with the effects of
IFN- (34). This may be especially important for clearing virus
from the CNS, where limited expression of major histocom-
patibility class (MHC) antigens in mice (or human leukocyte
antigen [HLA] antigens in humans) may restrict the role of T
lymphocytes. Infiltration into the CNS of antibody-producing
B cells has been demonstrated in animal models (35). Cellular
immune responses to alphavirus infection include lymphopro-
liferative, cytokine, and cytotoxic. In alphavirus encephalitis,
there is infiltration of natural killer cells, B cells, CD4, CD8
T cells, and macrophages. CD8 T cells may be important in
virus clearance from infected macrophages (36). Studies on
humoral responses to flavivirus infection have shown protec-
tion of mice by passive transfer of antibodies against lethal
challenge by several flaviviruses (3739). Furthermore, B cell
deficient mice were shown to be highly susceptible to flavivirus
infection (37,4042). In contrast, the role of T cells during

Scheld_Ch15.indd 214 2/21/14 5:38 PM


flavivirus infection is less well characterized. A few studies
have shown a protective role for CD4 T cells by enhancing
antibody production and sustaining flavivirus-specific CD8
T-cell responses (43,44). CD8 T cells have been shown to be
important for clearance of virus and survival of mouse models
of WNV (4548), whereas cytotoxic T cells caused accelerated
and more severe pathogenesis in mice infected with MVEV
(49). In mice infected with JEV, CD8 T cells did not affect
the outcome of the infection. Therefore, a conflicting role for
CD8 T cells in flavivirus encephalitis is suggested (40).
PATHOLOGY OF ARBOVIRAL
ENCEPHALITIS
Few data are available for CNS infections caused by col-
tiviruses and phleboviruses because they are rarely fatal.
Pathologic studies of fatal human encephalitis caused by alpha-
virus, flavivirus, and bunyaviruses show many common find-
ings (5056). The leptomeninges are normal or slightly hazy,
and histologic examination shows an inflammatory infiltrate.
The brain parenchyma is congested with focal petechiae or
hemorrhage. Lesions are distributed through the gray matter
of the cerebral cortex, midbrain, basal ganglia, cerebellum,
brainstem, and spinal cord, providing the anatomic correlates
for many of the clinical features seen (see later discussion).
Microscopically, there is perivascular cuffing, with infiltration
of mononuclear and polymorphonuclear cells into the paren-
chyma, as well as neuronophagia of infected cells by glial cells.
Immunohistochemical analysis of the lymphocyte populations
typically shows CD4 and CD8 cells, which are presumed
to be cytotoxic T cells. Similar changes are seen in animal
models. Initially, there is perivascular infiltration of mono-
nuclear cells, with a few polymorphonuclear cells, which is
accompanied by perivascular extravasation of red blood cells
(RBCs), endothelial cell swelling, and hyperplasia (57,58).
This is followed by migration of lymphocytes and monocytes
toward virus-infected neurons. The inflammation is accompa-
nied by gliosis and by inflammatory and glial cell apoptosis
(59). Demyelination is seen in encephalitis caused by some
alphaviruses but does not seem to be important in the flavivi-
ruses (60). Although the cellular immunity and the inflamma-
tory response are important in most infections, some patients
die from virally induced neuronal cell death before there is
evidence of a cellular immune response and inflammation.
Various processes contribute to neuronal cell death includ-
ing apoptosis, cytoplasmic swelling, vacuolation, and mem-
brane breakdown (61). In some instances, alphaviruses are
inadequately cleared from the CNS, as illustrated by detection
of viral RNA in the brains of mice long after recovery (62,63).
Chronic progressive human disease with continuing brain in-
flammation long after the acute disease has been reported in
some alphavirus encephalitides (64). For example, persistent
symptoms such as joint and muscle pains can last for several
years post CHIKV infection (1). Chronic infection does not
appear to be important for most of the mosquito-borne flavivi-
ruses, but there is evidence of persistent infection and chronic
inflammation for humans infected with TBEV and in animal
models (65,66).
CLINICAL FEATURES
OF ARBOVIRAL ENCEPHALITIS
The clinical syndrome following neurologic infection with
an arbovirus depends on the site of attack. If the meninges
are involved, meningitis results; inflammation of the brain
Scheld_Ch15.indd 215
Chapter 15: Arthropod-Borne Viral Encephalitides 215
parenchyma causes encephalitis; and damage in the spinal
cord causes myelitis. The term meningoencephalomyelitis
encompasses the concept that all three components may be
affected. Despite the wide range of etiologic agents, there
are many similarities in the clinical presentations of arbovi-
ral encephalitis. After a brief incubation period, which typi-
cally is 4 to 8 days but may range from 1 to 28 days, patients
develop a nonspecific flulike illness with fever, headache, nau-
sea, and vomiting. Often, there are upper respiratory tract
symptoms, such as cough and sore throat, or abdominal pain
and diarrhea. Sometimes, a rash, conjunctival or pharyngeal
injection, or lymphadenopathy may give a clue to the diagno-
sis. This may be seen for the fever-arthralgia-rash viruses,
for example, WNV, DENV, CTF, TOSV, or VEEV. The febrile
phase usually lasts a few days and may immediately be fol-
lowed by continued fever with the development of neurologic
symptoms and signs, or there may be an intervening asymp-
tomatic period, thus giving a saddleback or biphasic fever
curve characteristic of some arboviral infections, such as TBE
or CTF. Neurologic disease may manifest as subtle changes
in behavior, or mutism, resulting in an initial misdiagnosis
of psychiatric illness. More often though, there is a profound
reduction in consciousness level, which in children may be
heralded by seizures. Seizures and status epilepticus are espe-
cially common in children with JEV and LACV encephalitis
(67,68). As well as obvious generalized tonic-clonic seizures,
subtle motor status epilepticus is being increasingly recog-
nized. A great range of focal neurologic signs may be seen in
arboviral encephalitis, including those of upper motor neu-
ron damage, such as a hemiparesis, and cranial nerve signs
indicative of brainstem damage. Flaccid limb weakness due
to destruction of the anterior horn cells in the spinal cord is
seen in flavivirus encephalitis and EEEV. Most flaviviruses can
also cause a poliomyelitis-like flaccid paralysis that typically
affects the lower limbs for mosquito-borne flaviviruses such
as JEV, WNV, and Murray Valley encephalitis (MVE), and
the upper limbs for TBE (6971). Extrapyramidal signs are
common in both alphavirus and flavivirus encephalitis and
are thought to be the clinical correlates of the basal ganglia
damage evident pathologically and radiologically, including
increased tone causing generalized axial and limb rigidity, or
rigidity/spasm such as opisthotonus, and tremors of the limbs,
eyelids, and tongue.
DIFFERENTIAL DIAGNOSIS OF
ARBOVIRAL ENCEPHALITIS
The differential diagnosis of arboviral encephalitis is broad
and includes other causes of viral encephalitis (Table 15.3),
as well as diseases that mimic viral encephalitis (Table 15.4).
Certain epidemiologic features may give a clue that a patient
has an arboviral infection. For example, in parts of Asia, epi-
demics of JEV occur with great predictability after the start
of the rainy season. In the Americas, the alphavirus equine
encephalitides are typically associated with illness in horses.
More recently, birds falling from the sky have heralded the
arrival of WNV. The age and occupation of the patient can
also point to epidemiologic risk factors. JEV tends to affect
children in rural parts of Asia, recent WNV encephalitis out-
breaks have affected the elderly or patients on immunosup-
pressive drugs, and LACV encephalitis tends to affect children.
A recent tick bite may suggest TBE in Europe, Russia, and the
Far East, or CTF in parts of North America, though other tick-
borne diseases, such as borreliosis, ehrlichiosis, and rickettsial
disease must be considered. A biphasic illness is characteris-
tic of some arboviral encephalitides. On examination, certain
2/21/14 5:38 PM
 216 Part II: Viral Infections and Related Disorders

TA B L E 1 5 . 3
VIRAL CAUSES OF ENCEPHALITIS

Encephalitis due to arboviruses, by geographic regiona Australasia

The Americas Murray Valley encephalitis, Japanese encephalitis, Chikungunya
West Nile, La Crosse, St. Louis, Rocio, Powassan Encephalitis due to other viruses, most of which are not geographically
encephalitis, restricted
Venezuelan, eastern and western equine encephalitis, Herpes viruses
dengue, Colorado tick fever
Herpes simplex virus, herpes zoster virus, Epstein-Barr virus,
Europe/Middle East cytomegalovirus
Tick-borne encephalitis, West Nile, Toscana, Dengue, Enteroviruses
Louping ill, Chikungunya
Poliovirus, coxsackieviruses, echoviruses, enteroviruses-70 and -71
Africa
Paramyxoviruses
West Nile, Chikungunya, dengue, (Rift Valley fever, Congo-
Measles virus, mumps virus, (Nipah virus, found only in Asia)
Crimean hemorrhagic fever)
Others
Asia
Rabies, influenza viruses
Japanese encephalitis, West Nile, dengue, Murray Valley
encephalitis, Chikungunya

a
Rarer or suspected arboviral causes are shown in parentheses.

TA B L E 1 5 . 4
DISEASES MIMICKING VIRAL MENINGOENCEPHALITIS

Central nervous system infections Parasites Neoplastic

Bacteria Cerebral malaria Primary brain tumor
Bacterial meningitis Toxoplasmosis Metastases
Tuberculosis Cysticercosis Paraneoplastic limbic encephalitis
Brain abscess Trypanosomiasis Metabolic
Typhoid fever Echinococcus Hepatic encephalopathy
Parameningeal infection Trichinosis Renal encephalopathy
Lyme disease Amoebiasis Hypoglycemia
Syphilis Rickettsiae Reye syndrome
Relapsing fever Rocky Mountain spotted fever Other
Leptospirosis Typhus Antibody-associated encephalitis
Mycoplasma pneumoniae Q fever - Voltage-gated potassium channels (VGKC)
Listeriosis Ehrlichiosis - N-methyl-d-aspartate receptor (NMDA-R)
Brucellosis Cat-scratch fever Drug reactions
Subacute bacterial endocarditis Parainfectious/postinfectious causes Subarachnoid hemorrhage
Whipple disease Guillain-Barr syndromea Cerebrovascular accidents
Nocardia Acute disseminated encephalomyelitisa Epilepsy
Actinomycosis Viral illnesses with febrile convulsions Hysteria
Fungi Shigella
Cryptococcus Viral infections associated with swollen
fontanelle
Coccidiomycosis Noninfectious diseases
Histoplasmosis Vasculitic
North American blastomycosis Behet disease
Candidiasis Cerebral systemic lupus erythematosus

a
Guillain-Barr syndrome and acute disseminated encephalomyelitis may follow viral or bacterial infections or vaccinations.

Scheld_Ch15.indd 216 2/21/14 5:38 PM


neurologic signs may suggest a patient has arboviral encepha-
litis rather than encephalitis caused by herpes or other viruses.
For example, in an unconscious patient, the presence of flaccid
limbs consistent with anterior horn cell damage, or the trem-
ors, increased tone, and rigidity spasms suggestive of basal
ganglia damage may suggest an arboviral cause.
INVESTIGATION AND DIAGNOSIS
OF ARBOVIRAL ENCEPHALITIS
A mild leukocytosis is common in many arboviral encepha-
litides, but leukopenia with thrombocytopenia is sometimes
seen in TBE and CTF. Hyponatremia due to a syndrome of
inappropriate antidiuretic hormone (SIADH) secretion is com-
mon, and in some infections, alanine transaminase may be
mildly elevated. In Western settings, lumbar puncture is often
delayed in severely ill patients until imaging has ruled out a
space-occupying lesion, or incipient brainstem herniation. In
many tropical settings where imaging is not available, lumbar
punctures are performed on most encephalopathic patients
who do not have signs of brainstem damage because of the
importance of excluding other treatable causes, particularly
bacterial infections (72,73). Lumbar puncture will often re-
veal mildly elevated cerebrospinal fluid (CSF) opening pres-
sures (up to 250 mm of CSF), a lymphocytic pleocytosis with
a normal CSF-to-plasma glucose ratio, and slightly elevated
protein level. However, an early lumbar puncture may reveal
no cells, or a neutrophil predominance, rather than a lympho-
cytic CSF. A low glucose ratio has been reported for EEEV and
CTF, whereas an elevated ratio has been reported for VEEVs.
Radiologic investigations may be helpful in excluding other
conditions and in highlighting changes such as the high sig-
nal intensity seen on magnetic resonance imaging (MRI) in the
thalamus and basal ganglia that characterizes both alphavirus
and flavivirus encephalitis (74). Computed tomography (CT)
scans may show low signal in the same areas or just edema.
Although they do not reveal diagnostic information, electro-
encephalograms (EEGs) can help identify seizures (particularly
the subtle motor seizures described earlier) and distinguish
focal seizures from tremors.
Percentage
100
of patients
positive
(Log scale)
10
CSF lgM antibody
1
Viraemia
Day of illness: 3 1 1 3 5 7 9 11 30
Infection
Clinical features: Fever CNS Disease
Diagnosis:
Virus detection Antibody detection
(limits of detection)
Real-time PCR 0.1 pfu lgM ELISA of CSF
Virus Isolation 1 pfu ~50% positive by hospital admission
RT-PCR 10 pfu ~95% positive by day 10 of illness
Scheld_Ch15.indd 217
Chapter 15: Arthropod-Borne Viral Encephalitides 217
For most arboviral infections of humans, viremias are so
low and brief that they are undetectable by the time a patient
comes to the hospital (75) (Fig. 15.3); exceptions are the viruses
for which humans are important natural or amplifying hosts,
such as DENV, VEEV, and TOSV. Virus may also sometimes
be isolated from the CSF, particularly for infections that prove
fatal, or from brain tissue at either biopsy or autopsy. The tradi-
tional method for virus isolation was inoculation into suckling
mice, but this has largely been replaced by continuous cell lines
(e.g., C6/36 cells derived from Aedes albopictus mosquitoes,
and Vero cells derived from African green monkey kidney).
Amplification by PCR of viral nucleic acid in the CSF or serum
tends to be more sensitive than virus isolation, particularly if
real-time Taq-Man PCR is used and has helped with diagnosis
of WNV and TOSV infections, although false-positive results
do occur. Immunohistochemistry of brain tissue may demon-
strate viral antigen in fatal cases, and antigen-capture enzyme-
linked immunosorbent assays (ELISAs) have been developed,
but they have limited utility.
Serologic methods to detect antiviral antibody are the main-
stay of the diagnosis of arboviral infections. The traditional
techniques such as hemagglutination inhibition, complement
fixation, indirect immunofluorescence, and neutralization tests
require the demonstration of a greater than fourfold rise in an-
tibody titer in samples taken several weeks apart and thus have
practical limitations; for example, they do not give a diagnosis
acutely and are not helpful in patients who die or are lost to
follow-up. However, they do have specific research uses. For
example, hemagglutinating antibodies are often broadly cross
reactive, so in a patient with an undiagnosed encephalitis, a
panel of antigens can be used to indicate whether a patient
was infected with a flavivirus, an alphavirus, a bunyavirus, or
other virus; this can then be followed by more specific tests
within that group. Neutralizing antibodies persist for life, so
they can be used for serologic surveys to indicate whether in-
dividuals have ever been infected with a virus. In recent years,
IgM and IgG capture ELISAs have become the most useful and
widely deployed tests for diagnosing arboviral encephalitis.
Depending on the virus, typically 50% of patients have anti-
body on admission to hospital, and more than 90% have anti-
body 1 week later, so in patients whose initial test results are
60 90
FIGURE 15.3 Diagnosis of arboviral
infections. As an example, the clinical
Recovery
course of West Nile encephalitis: viremia,
development of antibody, and the impli-
cations for diagnosis are shown. The
limits of virus detection are expressed
as plaque-forming units (pfu)/100 L;
human viremia is thought to be less than
10 pfu/100 L. The first day of fever is
taken as the first day of illness; most pa-
tients are not hospitalized until the third
to fifth day of illness.
2/21/14 5:38 PM
 218 Part II: Viral Infections and Related Disorders
negative, the test should be repeated after 1 week (Fig. 15.3).
Although they are the most useful tests, ELISAs too have their
limitations. For example, because closely related viruses have
many shared epitopes, there may be cross reactivity in IgM
and IgG capture ELISAs between the viruses. This problem
can usually be overcome by testing for the related viruses in
parallel, with the strongest reaction indicating the infecting
agent. However, sometimes a neutralization test, which is
more specific, may be needed. Importantly, antibody will be
detected in the serum of individuals who have had recent as-
ymptomatic or febrile infection but no neurologic disease. Its
detection in the CSF is usually taken as a better indicator of
viral replication in the CNS. Finally, some patients may make
antibody late or not at all. These patients are more likely to
die and to have virus detected by another means such as isola-
tion or PCR.
Newer approaches for detection of flaviviruses antibody
include the lateral flow assay and the microsphere immunoas-
say (MIA). The lateral flow device was recently approved by
the U.S Food and Drug Administration (FDA) for the diag-
nosis of WNV infection in humans, which can give a result in
15 minutes (76). In MIA, an antigen is attached to encoded
microbeads that will bind the target analytes during the assay
procedure. These can then be identified using a fluorescence-
activated cell sorting system (FACS). MIA is used by many
laboratories in the United States for WNV diagnosis as it is
highly sensitive compared to a standard ELISA. Furthermore,
one serum sample can be analyzed for reactivity to several an-
tigens in a single assay (77). Other approaches include high-
throughput rapid microneutralization assays, biosensor-based
assays, microfluidic systems based on virus-coated magnetic
beads, and multiplex real-time RT-PCR assays (7881).
TREATMENT OF ARBOVIRAL
ENCEPHALITIS
There are no established antiviral drugs for any arboviral en-
cephalitides. IFN-, ribavirin, and intravenous immunoglob-
ulins have been given to patients with flavivirus encephalitis,
based on in vitro and animal data. However, the few clini-
cal data available suggest that IFN- is not effective in JEV
(82). In the West, most patients with encephalitis will be
given acyclovir until herpes simplex virus type 1 (HSV-1) en-
cephalitis has been ruled out. The management of arboviral
encephalitis focuses on treating the complications of disease,
in particular hyponatremia, seizures, and increased intracra-
nial pressure (ICP). In most Western settings, severely ill pa-
tients will be electively ventilated and managed in intensive
care settings, allowing airway protection, seizure control,
optimal assessment of fluid balance, and hyperventilation to
reduce increased ICP. However, in many of the settings in
which arboviral encephalitis occurs, this is not possible. At a
minimum, patients at risk of raised ICP should be nursed at
30C, with the neck held straight to ensure the jugular venous
outflow is not impaired and with urine output monitored and
oxygen given.
Seizures are common, particularly in children with flavivi-
rus and bunyavirus infections. In addition to obvious tonic-
clonic seizures, subtle motor seizures may be indicative of
subtle motor status epilepticus (68). An EEG is advisable, par-
ticularly in patients with twitching of a finger, lip, or eyelid.
Simple or complicated seizures should be managed according
to local standard of care (8385) (see Chapter 1 where the
management of the critically ill patient with CNS infections is
discussed). A few specific notes relating to arboviral encepha-
litis are indicated. Attention to the etiology of increased ICP is
Scheld_Ch15.indd 218
of the greatest importance (86,87). In many encephalopa-
thies, if the blood pressure is well maintained, but increased
ICP is suspected, 20% mannitol (0.5 to 1.0 g/kg) is given,
although the little evidence available suggests the benefits, if
any, are only short term (68,88). Steroids are sometimes given,
although they were not shown to be beneficial in JEV (89).
Hypoglycemia is common in many tropical pediatric condi-
tions (90) and must be looked for and corrected.
PREVENTION OF ARBOVIRAL
ENCEPHALITIS
A consideration of the typical arboviral ecologic cycle
(Fig. 15.1) reveals points at which intervention might be effec-
tive. These can be divided into measures to interrupt the natu-
ral cycle, measures to stop humans being bitten by infected
vectors, and measures to stop infection resulting in disease (i.e.,
vaccination). For most of the arboviruses that cause encepha-
litis, because the natural cycle involves small wild birds and
rodents, interrupting this cycle is not possible. However, when
an intermediate or amplifying vertebrate host brings the virus
closer to humans, for example, equines for VEEV and swine
for JEV, measures can be taken. For example, vaccines that
protect horses against VEE probably also reduce the number
of human cases. Immunization of swine against JEV has been
practiced in Asia, though with limited success. However, relo-
cation of swine away from homes is probably a more effective
way of reducing transmission of JEV to humans. Surveillance
of mosquitoes, dead birds, and sentinel chickens (i.e., chickens
deliberately exposed to mosquito bites) for viral infection is
used in many Western settings as an indicator of viral activ-
ity and possible impending human disease, and antimosquito
measures are then implemented. Interventions to reduce the
number of circulating mosquitoes depend on the species and
the setting. Measures include removing stagnant water from
swampy areas, ditches, and drains favored by many Culex
species and removing the freshwater containers (car tires, tree
holes, litter) favored by Aedes species. Larvicides can also be
applied to potential breeding sites (either biologic larvicides
such as Bacillus thuringiensis variance israelensis or the chemi-
cal larvicide, metoprine). With continuing human cases, public
health authorities have practiced ground or aerosol spray-
ing with pyrethroid formulations that kill adult mosquitoes.
Newer interventions are under development including the
sterile insect technique and the Wolbachia-based strategies to
control Aedes species (9194).
For many of these measures, evidence of beneficial impact
is limited, but they demonstrate that public health authorities
are taking the situation seriously. Personal measures to reduce
the chance of being bitten by infected vectors are important.
These include using repellents that contain 10% to 30% DEET
(N, N-diethyl-3-methyl benzamide) on skin and clothing,
applying permethrin insecticides on clothes, and wearing long-
sleeved shirts and trouser. In areas where tick-borne viruses
circulate, regular inspection of the limbs ensures no ticks are
attached. Many of the Culex vectors bite at night, and the use
of impregnated bed nets is recommended. Public education is
an important part of any of these measures. For some flavi-
viruses (e.g., JEV and TBEV), inactivated or live attenuated
vaccines are available, although their use is limited by cost and
availability. The dramatic reduction in TBE in Austria follow-
ing widespread vaccination demonstrates feasibility. However,
because most of these viruses are enzootic, eradication by vac-
cinating humans is not possible. For other arboviral diseases,
the sporadic nature and low incidence mean that the vaccines
would not be economically viable, even if they existed.
2/21/14 5:38 PM

ALPHAVIRUSES
The alphavirus genus is one of two important genera in the
family Togaviridae (named after the cloak, or toga that envelops
the viruses) (11). Whereas alphaviruses are arthropod-borne
members of the other genus, the Rubivirus genus organisms
(e.g., rubella virus) are not arthropod borne and so are not con-
sidered further here (Table 15.1). Alphaviruses cause two clini-
cal syndromes. In Africa, Old World alphaviruses CHIKV and
onyong-nyong virus cause large outbreaks of fever arthralgia
and rash; a similar syndrome in which arthritis is predominant
is caused by Ross River virus in Australia. In the Americas,
New World alphaviruses EEE, WEE, and VEE viruses cause
outbreaks of encephalitis in horses and humans and are the
focus of this section (Table 15.2). EEE is notable for having
a higher case-fatality rate than other viruses in the group,
whereas WEE is remarkable because although it has caused
large outbreaks in the past, it has now virtually disappeared
as a disease of humans. Although VEEV causes encephalitis
in equines, in humans it causes a febrile disease, with only a
small proportion developing usually mild CNS disease. Two
other alphaviruses, Sindbis virus and Semliki Forest virus, have
animal models of the pathogenesis of alphavirus encephalitis.
Phylogenetic analyses suggest that the alphaviruses arose in the
New World with subsequent introductions into the Old World.
The WEE lineage appears to have derived as a recombinant of
an ancestral EEE-like and Sindbis-like viruses (95).
Infectious Agent
Alphaviruses consist of a single strand of positive-sense RNA
wrapped in a nucleocapsid and surrounded by a glycoprotein-
containing lipid membrane that is derived from host cell plasma
membrane (11). The virion is 60 to 70 nm in diameter. The 11- to
12-kb RNA has a 5 cap and a 3 polyadenylated tail. It consists
of message-sense RNA that is directly infectious. It codes from the
5 to the 3 end for four nonstructural proteins, nsP1, nsP2, nsP3,
and nsP4, and five structural proteinscapsid (C), envelope 3
(E3), E2, 6K (a 6-kd protein), and E1. The nonstructural proteins
are involved in replication of the viral RNA and production of
subgenomic RNA. The C protein has a conserved end with many
basic amino acids and is presumed to bind the viral genomic RNA
to form the nucleocapsid. This nucleocapsid is an icosahedron
with T 4 symmetry. The E1 and E2 glycoproteins project from
the lipid membrane, forming heterodimers that group as trimers
to form 80 knobs on the virion surface (96). Alphaviruses gain
entry into cells by attaching to the cell surface and entering via the
endocytic pathway to form vesicles. As the pH level of the vesicles
decreases, the E1/R2 heterodimer dissociates, revealing a highly
conserved hydrophobic sequence in E1. This is thought to act as
a fusion peptide, causing viral membrane and host cell membrane
to fuse, and thus releasing the viral nucleocapsid into the host
cytoplasm. Here the nucleocapsid is uncoated of its capsid protein
so that naked RNA is exposed to ribosomes for initiation of trans-
lation as the first step of viral replication. Virus is replicated in
association with the endoplasmic reticulum and Golgi apparatus,
and new virions are released by budding at the host cell surface.
Eastern Equine Encephalitis
Epidemiology
EEE virus was first isolated from the brain of a horse that
died during an epizootic of equine encephalitis in New Jersey
and Virginia in 1933 (97). The first human isolate was made
Scheld_Ch15.indd 219
Chapter 15: Arthropod-Borne Viral Encephalitides 219
5 years later. The geographical area affected by EEE extends
from Ontario and Quebec provinces in Canada, down the
eastern seaboard of the United States, and into South America
as far as Argentina. To the West, the area extends as far as
Wisconsin and eastern Texas. The virus is transmitted between
wading birds, passerines, and other swamp birds by Culiseta
melanura and other mosquitoes. It has also been isolated from
crows (98). These mosquitoes are strictly ornithophilic (bird
biting). However, other mosquitoes that feed on both birds
and mammals serve as bridging vectors carrying the virus to
horses, humans, and other mammals (Fig. 15.2, Table 15.2).
In South America, rodents and marsupials may be more im-
portant natural hosts than birds. Outbreaks of disease have
also occurred in commercial flocks of pheasants, partridges,
turkeys, and emus (99). In these circumstances, direct trans-
mission between birds because of preening and pecking and
transmission via the fecal-oral route have also occurred. The
means by which the virus persists during the winter is not
known, but persisting viremia in birds or vertical transmis-
sion into mosquito eggs has been postulated. Cases occur year
round but are more likely in the summer, especially when asso-
ciated with increased rainfall, which by creating a high water
table augments the breeding habitat of C. melanura.
EEE usually occurs as single cases and rarely as clusters
that may be preceded by disease in horses. The median annual
number of cases in the United States is three (range, 1 to 14),
and the reported incidence is less than 0.1 to 0.4 per 107.
Seroepidemiologic studies show that humans are only rarely
infected with the virus. Fewer than 7% of residents older than
45 years had antibody in one study (100). Most infected pa-
tients are asymptomatic with a ratio of symptomatic to asymp-
tomatic infections of about 1 in 30. However, the elderly and
young children are more likely to develop disease.
Clinical Features
After an incubation period, which is thought to range from 3 to
10 days, patients present with a few days of febrile prodrome
and then neurologic disease. Early symptoms include head-
ache, myalgia, photophobia, abnormal sensations, vomiting,
dizziness, and lethargy, followed by neck stiffness, a reduced
level of consciousness, and seizures. In infants, progression to
coma may be more rapid, occurring over 48 hours. On exami-
nation, a high pyrexia (39C) is common and one third of
patients have signs of meningismus. Clinical signs suggestive of
brainstem involvement include gaze deviation, nystagmus, and
papillary abnormalities. This may be because of inflammatory
lesions in the brainstem, but uncal and subtentorial hernia-
tion have been seen at autopsy. Hemiparesis and limb spastic-
ity suggest upper motor neuron involvement, whereas flaccid
limbs suggest involvement of lower motor neurons in the spi-
nal cord. Seizures may be generalized or focal. In patients who
remain conscious, aphasia and emotional lability may occur.
Limb dysesthesia and flaccid paralysis have also been reported
in a fully conscious patient, suggesting myelitis may occur
without brain involvement (101). Approximately one third of
patients die, but for those older than 60 years, the propor-
tion is 50%. One third of survivors have moderate or severe
sequelae (102).
Diagnosis
Peripheral leukocytosis, with neutrophil predominance can
occur. The CSF resembles that of acute bacterial meningitis
with a neutrophil pleocytosis (as high as 5,000 cells/mm3); the
RBC count and protein level are often elevated, and the glu-
cose ratio is less than 50% in half of the patients (102,103). CT
scans show diffuse cerebral edema in most patients. On MRI,
2/21/14 5:38 PM
 220 Part II: Viral Infections and Related Disorders
lesions that do not enhance with gadolinium are seen in the
basal ganglia, thalamus, and brainstem (102). EEGs show
background and focal slowing, as well as burst suppression.
High-voltage delta waves carry a poor prognosis (103).
Virus isolation from the blood is unusual, although it has
been reported for EEE early in the illness (101). In fatal cases,
virus may be isolated from brain tissue or detected by PCR or
immunohistochemical staining. In most cases, the diagnosis is
made serologically by detecting antibody in the blood. Older
serologic tests such as hemagglutination inhibition, comple-
ment fixation, and neutralization tests are being replaced by
IgM capture ELISAs, which detect antibody in a single blood
or CSF sample, thus providing an earlier diagnosis.
Treatment and Prevention
Because there are no antiviral drugs, treatment is focused
on the complications of infection, particularly seizures and
raised ICP and pneumonia. No vaccine against EEE is com-
mercially available, although an inactivated vaccine is used by
laboratory workers and others at high risk (104). Recently, a
chimeric Sindbis (SINV)/EEEV candidates have been shown
to be safe and effective against protecting mice against EEEV
(105). A similar vaccine is used to protect horses. Personal
protective measures against mosquito bites are described
earlier in this chapter.
Western Equine Encephalitis
Epidemiology
The isolation of WEE virus from the brain of horses dur-
ing an epizootic episode of unknown etiology in 1930 in the
San Joaquin Valley of California marked the first time an
arbovirus was isolated in the territorial United States (106).
Subsequently, in 1938, WEE virus was obtained from a child
who succumbed to encephalitis (107). Virus activity has been
reported from western Canada, the western and midwestern
United States, and as far south as Argentina. In the western
United States, WEE virus is transmitted between passerine
birds (sparrows and house finches) by Culex tarsalis mosqui-
toes. Epidemic and epizootic activity occurs mainly in the sum-
mer months. Highlands J virus, which is found in Florida, is
one of several related viruses in the WEE complex that do not
appear to cause disease in humans (108).
Clinical Epidemiology
Until recently, exposure to WEE virus was common, with up
to 20% of humans having antibodies in some areas. However,
a decline in the rural population and changes in land use have
meant that even in areas where the virus circulates, this fig-
ure is now less than 1% (109). The largest outbreak was in
1941, with more than 3,000 human cases and hundreds of
thousands of equine cases (110) and an estimated incidence of
167 per 100,000 in North Dakota, but since the 1990s, there
have been only a handful of reported cases each year. The ratio
of apparent to inapparent infections is estimated to be fewer
than 1 in 1,000 in adults and 1 in 60 in children.
Clinical Features
The clinical features of WEE tend to be milder than those
of EEE. After an incubation period, which ranges from 2 to
10 days, there is a nonspecific febrile prodrome before neu-
rologic disease. Meningismus is seen in half the patients, and
although weakness and tremors are common, fewer than 10%
of patients develop coma (111). Focal signs include cranial
Scheld_Ch15.indd 220
nerve palsies, hemipareses, hyporeflexia, spasticity, generalized
rigidity, and occasionally opisthotonus. The overall case-fa-
tality rate is approximately 4% to 10% (112), being higher
among the elderly. WEE virus is more severe in infants, with
rapid progression from nonspecific illness to convulsions
and coma. Transplacental infection has been reported (113).
The overall case-fatality rate is 3%, increasing to 8% for those
older than 50 years (114). Neurologic sequelae are common
in young children. Parkinsonian features including cogwheel
rigidity and tremors have also been reported (115).
Diagnosis
The peripheral white blood cell count is usually normal or
mildly elevated. Hyponatremia due to SIADH has been re-
ported. CSF opening pressures of more than 200 mm occur
in two thirds of patients. CSF white blood cell counts are usu-
ally less than 100 cells/mm3 but may range from less than 10
to 500 cells/mm3 with lymphocyte predominance, a slightly
elevated protein level, and a normal glucose ratio. CT scans
have been reported as normal, but EEGs show diffuse slowing
with focal delta activity in the temporal region, which may
mimic HSV-1 encephalitis (116). WEE virus is occasionally
isolated from the CSF or from diagnostic brain biopsies (117).
Detection of IgM in the CSF or serum is the preferred diagnos-
tic test (30).
Treatment and Prevention
There is no specific treatment, although equine immune serum
was used following laboratory exposure in one patient (118).
A nonlicensed inactivated vaccine is available for laboratory
workers and others at high risk (119). A recent study has shown
the potential of an adenovirus-vectored WEEV vaccine, Ad5-
WEEV, for development into an emergency vaccine during an
outbreak of WEEV (120). Furthermore, a human adenoviral
vector (Ad5-mIFN) expressing mouse IFN- was shown to
offer 100% protection against mice challenged with various
WEEV strains (121). Surveillance and vector control measures
are practiced in some areas where the virus circulates.
Venezuelan Equine Encephalitis
Epidemiology
VEEV was first isolated from the brains of dead horses in 1938
(122), and subsequently six antigenically related subtypes (I
through VI) have been identified based on serologic cross reac-
tivity (123). Tonate virus is a subtype IIIB VEE complex virus
that circulates in French Guiuan and has caused encephalitis
(124,125). Subtype I viruses were further subdivided serologi-
cally into IAB, IC, ID, IE, and IF. More recent molecular ge-
netic studies suggest a revision of some of these groups. VEEV
circulates in an enzootic sylvatic (forest) cycle (Fig. 15.2) and
emerges to cause major epizootics in horses and human epi-
demics every 10 to 20 years. Sylvatic VEEV is found in Central
and South America, and although most epizootics have oc-
curred in northern South America, particularly Venezuela and
surrounding countries, they have extended as far north as
Mexico and Texas (21,85,126). In its sylvatic cycle, VEEV is
transmitted between small mammals and aquatic birds mainly
by Culex melanoconion mosquitoes (Table 15.2). Sporadic
human cases occur when people enter the swampy and forested
locations where the viruses circulate or when bridging mosqui-
toes such as Aedes taeniorhynchus carry the virus to nearby
human habitats. In contrast, human epidemics occur at the
same time as equine epizootics when the virus emerges from
2/21/14 5:38 PM

its enzootic cycle and is transmitted between susceptible horses
by Aedes, Psorophora, Mansonia, and Deinocerites mosquito
species. Some studies suggest that the E2 protein encodes mos-
quito infection determinants for VEE, suggesting selection for
efficient infection of epizootic mosquito vectors may mediate
VEE emergence (127). Major epizootics and epidemics of VEE
have occurred every 10 to 20 years in cattle-ranching areas
of Venezuela, Peru, Colombia, and Ecuador. Although epizo-
otic viruses (subtypes IAB and IC) were originally thought to
be maintained in a separate transmission cycle from enzootic
viruses (subtypes 1D, 1E, or 1F), later studies have suggested
that epizootic IC viruses arise by mutation from sylvatic ID
viruses (128131). The 1C strains remain in the sylvatic cycle
until the ecologic factors support its emergence into the epi-
zootic cycle. Such outbreaks occur when heavy rainfall and
flooding expand the mosquito breeding habitats and support
expansion of the rodent population but also require a large
susceptible equine population. Outbreaks of VEE IAB subtype
that spread to Central America and Texas in the late 1960s and
early 1970s are thought to have originated from improperly
activated equine vaccine strains, as indicated by the fact that
the epizootic strains are genetically almost identical to the vac-
cine strains (132).
Seroprevalence studies indicate that up to 50% of the popula-
tion have antibody to VEEV in some sylvatic areas, whereas the
remainder of the population is immunologically naive until an
outbreak occurs. During the 1995 outbreak of VEE in Venezuela
and Colombia, an estimated 85,000 human cases occurred, of
which 3,000 had neurologic disease and 300 were fatal (128,133).
One third of the human population seroconverted, and 8% of the
equines died. Unlike most of the other arboviral encephalitides,
human viremias are sufficiently high to infect mosquitoes, sug-
gesting humans may not always be dead-end hosts. Isolation of
virus from the pharynx of up to 40% of patients suggests direct
spread between humans is possible (134). No epidemiologic evi-
dence of such spread has ever been demonstrated (133,134).
Clinical Features
Compared with the other alphavirus encephalitides, only a
very small proportion of symptomatic VEE infections results
in severe neurologic disease. The incubation period is brief
(1 to 5 days), and most patients then develop a febrile ill-
ness with severe headache, made worse by eye movements,
photophobia, facial flushing, conjunctival injection, myal-
gia, arthralgia, nausea, vomiting, and dizziness. Pharyngeal
inflammation and pain associated with cervical lymphade-
nopathy is common, and there may be subcostal tenderness
(133,135,136). Somnolence and tremulousness occur often.
More severe neurologic features occur in 4% to 14% of pa-
tients, particularly the young and elderly. Seizures, particu-
larly focal seizures, and raised ICP are common (133,137).
In 5% to 10% of hospitalized patients, cranial nerve palsies,
motor weakness, paralysis, or cerebellar signs are reported.
Respiratory tract infections, including interstitial pneumonia
and tracheobronchitis, are common and may result in second-
ary bacterial infection. Overall, 0.2% to 1.0% of symptomatic
VEE infections are fatal, but this increases to up to 10.0% to
25.0% of those with encephalitis. Children are estimated to
have ten times the risk of neurologic disease of adults, and
younger children have a greater case-fatality rate.
Diagnosis
Rather like the arboviral fever-arthralgia-rash syndromes,
VEEV infection is typically associated with a leukopenia and
elevated serum aspartate amino transferase levels (135). When
lumbar punctures are performed, the CSF reveals a lymphocyte
Scheld_Ch15.indd 221
Chapter 15: Arthropod-Borne Viral Encephalitides 221
pleocytosis that may reach several hundred cells/mm3 and is
reported to be associated with an elevated CSF glucose level.
As expected, given the relatively high viremias, VEEV can be
isolated from blood and pharynx up to the eighth day of ill-
ness and can be detected by PCR (134). VEEV antibody can
be detected by IgM capture ELISAs (138). A VEEV-specific
blocking ELISA that also identifies serotype-specific antibodies
against VEEV in sera of humans, equids, or rodents has been
reported (139).
Treatment and Prevention
There is no antiviral treatment for VEE. Supportive measures
include attention to seizures and increased ICP. Equine vaccines
for VEE interrupt transmission during outbreaks and prevent
epizootics. An inactivated vaccine has largely been replaced by
a live vaccine (TC-83), attenuated by serial passage in guinea
pig heart cells (140). VEEV is considered a useful agent for
biological warfare, because of its potential for droplet spread
and tendency to cause an incapacitating flulike illness, rather
than a fatal encephalitis, and for this reason, the vaccine was
produced by the U.S. military. TC-83 is given to laboratory
workers and produces neutralizing antibodies in more than
80% of recipients; however, it is associated with a high inci-
dence of adverse events including fever and aseptic meningitis
(37%). Most of those who do not respond immunologically
to the vaccine seroconvert when subsequently given a killed
vaccine (TC-84). An improved genetically engineered vaccine
V3526 is being developed (141,142). Another vaccine can-
didate in development is the recombinant, chimeric Sindbis/
VEEV (SIN-83) that is more highly attenuated than TC-83
(143,144). In addition, the use of antisense technology and
humanized monoclonal antibody has been shown to be effec-
tive against mice infected with VEEV (145,146).
Chikungunya Virus
Epidemiology
A large outbreak of a disease locally known as Chikungunya
in the Newala district of Tanganyika (now Tanzania) occurred
in 1952 to 1953 (147). However, CHIKV may have caused
outbreaks as early as 1779 as the disease was frequently mis-
taken with dengue (148). In the local language, Chikungunya
means the disease that bends up the bones. CHIKV was
first isolated in 1952 from the serum of a febrile human dur-
ing this outbreak (147,149). Although initially assessed as a
dengue outbreak, further characterization of the isolates by
serologic and antigenic techniques indicated that CHIKV was
an alphavirus (150). Since then, frequent outbreaks of CHIKV
have been reported from many African and Asian countries.
There are three CHIKV genotypes (West African, East/Central
African, and Asian) but only one CHIKV serotype, and there-
fore, infection with a given genotype should result in lifelong
immunity against any genotype (151).
In Africa, CHIKV typically circulates in a sylvatic, enzo-
otic cycle involving wild primates and forest-dwelling mosqui-
toes with sporadic infection of rural human populations. The
principle enzootic mosquito vectors include Aedes furcifer-
taylori (southern and western Africa), Aedes africanus (cen-
tral Africa), Aedes luteocephalus and Aedes dalzieli (Senegal),
Aedes cordellieri (South Africa) and Aedes neoafricanus.
Human migration has attributed to the introduction of CHIKV
to the urban setting, where human-to-human transmission oc-
curs through domestic and peridomestic mosquito vectors.
The main domestic vector, Aedes aegypti has been responsible
for the major outbreaks of CHIKV in Comoros, India, Kenya,
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 222 Part II: Viral Infections and Related Disorders
Seychelles, and Singapore during the early phases of the
global emergence of CHIKV during 2004 to 2011 (151,152).
However, during the later phases (2006 onward), genetic ad-
aptation of CHIKV to a new vector, A. albopictus led to major
outbreaks in several Indian Ocean islands (Reunion Island,
Sri Lanka), India, and Southeast Asian countries (Singapore,
Malaysia and Thailand) (153,154). The Indian outbreak re-
sulted in an estimated 1.4 million cases during 2006 to 2009,
whereas an estimated 266,000 cases (258 deaths) in the
Reunion Island were reported, with an overall attack rate of
34% during 2005 to 2006 (152,155). Later studies confirmed
that the epidemics in the Indian Ocean islands and in India
were associated with an amino acid substitution in the E1 en-
velop glycoprotein (E1-A226V) in CHIKV, which allowed the
virus to adapt for dissemination by A. albopictus. A further
mutation (E2-L210Q) has been described in the 2009 Indian
outbreak, which again resulted in an increase in the dissemi-
nation of CHIKV in A. albopictus (156). Autochthonous
transmission of CHIKV has been reported in Italy (2007) with
over 250 cases and in France (2010), signaling the emergence
of CHIKV in Europe for the first time (157,158). Imported
cases of CHIKV infection have now been reported in several
European countries, Australia, and the Americas (159161).
Clinical Features
The clinical features of CHIKV infection have some similari-
ties with dengue infection (162). Asymptomatic CHIKV infec-
tions are rare. After an incubation period that can range from
1 to 12 (average of 2 to 4) days, a sudden onset of high fever
followed by severe arthralgia and a skin rash develops. Almost
all CHIKV patients have symmetrical polyarthralgia. The most
affected joints are the fingers, wrists, ankles, elbows, toes, and
knees. The fever can reach as high as 40C and may last up
to 10 days. A transient maculopapular and erythematous rash
on the face, limbs, and torso is common and may last for 2 to
3 days. Other symptoms include myalgia, headaches, photo-
phobia, lumbar back pain, chills, weakness, malaise, nausea,
and vomiting (151,163). The acute phase of CHIKV infection
usually resolves within 1 to 2 weeks, but the arthralgia may
persist for many months or years in some patients (164,165).
Age and underlying joint disorders have been shown to in-
crease the likelihood of developing persistent arthralgia. The
case-fatality rate for CHIKV is about 0.1%, with most deaths
occurring in the elderly, neonates, and adults with an underly-
ing disorder. Heart failure, multiple organ failure, hepatitis,
and encephalitis are the most common causes of death (163).
CHIKV has not been generally considered to be a neuro-
tropic virus. However, reports from recent outbreaks have given
strong evidence of neurologic involvement of CHIKV. The
main neurologic manifestations of adults infected with CHIKV
are encephalopathy, acute flaccid paralysis, and Guillain-Barr
syndrome (166169). A recent study has reported that about
25% of adults admitted with atypical CHIKV infection during
the 2005 to 2006 Reunion Island had neurologic involvement
(mainly encephalitis, malaise, and meningoencephalitis) (170).
Neurologic manifestations were more common in children.
The most common manifestations were encephalitis, febrile
seizures, and acute encephalopathies (171). For the first time,
vertical transmission of CHIKV, from mother-to-child was
reported during the Reunion Island outbreak. Encephalopathy
was the most common neurologic manifestation among new-
borns infected by vertical transmission (172).
Diagnosis
A possible CHIKV case is suspected when a patient is pre-
sented with an acute onset of high fever and severe arthralgia
unexplained by other medical conditions. The case becomes
Scheld_Ch15.indd 222
probable if the patient is living or has visited an endemic area
within 15 days before onset of symptoms. The case is con-
firmed when the patient test positive for one of the diagnos-
tic laboratory tests for CHIKV (163). Diagnosis of CHIKV is
made during the acute phase of infection by detection of viral
RNA in serum samples by RT-PCR and by virus isolation. Viral
RNA can be detected in samples obtained from 1 day before
symptom onset to day 7. Real-time RT-PCR assays capable of
detecting a region of the nonstructural protein (nsp1) gene or
the envelope (E) gene are also used for diagnosis (173,174).
For later samples, indirect immunofluorescence and ELISA
can be used to rapidly and sensitively distinguish between IgG
and IgM antibodies. CHIKV antigen can be detected in serum
and CSF samples obtained 2 days after onset of symptoms by
antigen capture ELISA. Several commercial serologic assays as
well as in-house ELISA techniques have been used for CHIKV
diagnosis and have been shown to accurately distinguish
CHIKV from other alphaviruses (except onyong-nyong virus)
and flaviviruses (175177).
Treatment and Prevention
Nonsteroidal antiinflammatory drugs are the only recom-
mended treatment for arthralgia caused by CHIKV infection.
Ribavirin, chloroquine, and passive transfer of antibodies
are other potential treatments being investigated (163,178).
Vector control remains the main method of CHIKV prevention
(91,179). Several vaccine candidates are under development.
These include inactivated, whole-virus, DNA-based, viruslike
particle, and adenovirus-vectored vaccine approaches as well
as a chimeric alphavirus vaccine (105,180183).
FLAVIVIRUSES
Infectious Agent
There are three important genera in the family Flaviviridae: the
genus Hepacivirus, which includes hepatitis C virus, the genus
Pestivirus, which includes bovine viral diarrhea viruses, and
the genus Flavivirus (Table 15.1). This genus includes many
important causes of arboviral encephalitis, as well as arbo-
viral fever-arthralgia-rash and hemorrhagic fever syndromes,
such as dengue viruses and yellow fever virus (Fig. 15.1). The
genus and family are named after the Latin word for yellow
(flavus). Flaviviruses are thought to have evolved from a com-
mon ancestor as recently as 10,000 years ago and are rapidly
evolving to fill new ecologic niches (184,185). They consist of
a single strand of positive-sense RNA, wrapped in a nucleo-
capsid and surrounded by a glycoprotein-containing envelope.
The RNA comprises a short 58 untranslated region (UTR), a
longer 38 UTR, and between them a single open reading frame
(186). This codes for a single polyprotein, which is cotransla-
tionally and posttranslationally cleaved by viral and host pro-
teases into three structural proteins (core, or C, premembrane,
or PrM, and envelope, or E), and seven nonstructural (NS)
proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5).
The C protein is highly basic and combines with the RNA
to form the nucleocapsid. The PrM is closely associated with
the E protein, forming a heterodimer, and is thought to act as
a chaperone to it, impairing its function until after virion
release. Immediately before virion release, the PrM protein is
cleaved by a furin-like protease to its mature M protein form.
This allows the formation of E protein homodimers, which
are thus activated (187). The E protein is the largest struc-
tural protein, consisting of nearly 500 amino acids with up to
two potential glycosylation sites. It is the major target for the
2/21/14 5:38 PM

humoral immune response and is thought to be important in
viral entry into host cells. Studies with monoclonal antibodies
and more recently with x-ray crystallography have determined
the composition of the E proteins three domains (188,189).
Domain III is the putative receptor-binding domain (by which
virions attach to the yet-to-be-identified host cell receptor), do-
main II is the dimerization domain, and domain I has a central
beta barrel and is the hinge domain that links the other two
domains. Following viral attachment to the cell surface, fla-
viviruses enter cells by endocytosis. Subsequent fusion of the
virus lipid membrane with the endosome membrane allows
viral RNA to penetrate into the cytoplasm of the infected cell
(186). Recent cryoelectron microscopic studies have shown an
arrangement of 90 E-protein dimers lying flat on the surface
of the virion, which rearrange to form E homodimers as the
pH level decreases, exposing an internal fusion peptide and a
patch of viral membrane for fusion. Interestingly, recent stud-
ies have shown the E1 protein of alphaviruses has a striking
similarity to the flavivirus E protein, in terms of structure and
function (96). Together, they have been labeled class II fusion
peptides (190).
West Nile Virus
Epidemiology
WNV was first isolated from the blood of a febrile woman
in the West Nile region of northern Uganda in 1937 (191).
It was soon shown to be transmitted between vertebrate hosts
(especially birds) by mosquitoes. Sporadic cases and larger
outbreaks of febrile disease (West Nile fever) were reported in
Africa, the Middle East, and Asia (192). Although meningeal
irritation was noted in some patients with West Nile fever, the
first cases of encephalitis due to WNV occurred when the virus
was given as an experimental (and unsuccessful) treatment for
advanced cancer in 1951. The first naturally occurring West
Nile encephalitis cases were in the elderly residents of a nurs-
ing home in Israel (193). Outbreaks of equine and human
meningoencephalitis occurred in southern France during the
1960s, and a subtype of WNV (Kunjin virus) was isolated
in Australasia. Since the 1990s, the clinical epidemiology of
WNV appears to have changed with increasing frequency and
severity of outbreaks, including urban disease. These included
an outbreak with nearly 400 confirmed cases in Romania
in 1996, nearly 200 cases in the Volgograd region of Russia in
1999 and more than 200 cases in Israel in 2000 (194197). In
1999, the virus appeared in North America for the first time,
with 62 confirmed cases (198,199). It spread across the conti-
nent during 2000 and 2001, causing a largest encephalitis out-
break in 2002, with nearly 3,000 cases and 250 deaths (75).
WNV is now the leading cause of domestically acquired arbo-
viral disease in the United States of America and has spread
throughout Canada, the Caribbean, Colombia, and Mexico
(200,201). In 2010, WNV outbreaks occurred in Greece with
262 confirmed human cases with 197 cases of neuroinvasive
WNV and in Romania with 57 cases, out of which 54 was neu-
roinvasive (202,203). Another outbreak occurred in Greece in
2011 with 31 cases of neuroinvasive WNV (204).
Most human infections with WNV are asymptomatic. In
the 1998 to 1999 outbreaks, approximately 1 in 5 infections
resulted in West Nile fever and only about 1 in 150 developed
CNS disease (194,197). Over 75% of patients infected with
WNV had neuroinvasive disease (encephalitis, meningitis, or
acute flaccid paralysis) during the recent outbreak in Greece
and over 94% during the Romanian outbreak (202,203). In
contrast, the proportions were much lower in earlier outbreaks
in Africa (192,205). In outbreaks across Europe and America,
Scheld_Ch15.indd 223
Chapter 15: Arthropod-Borne Viral Encephalitides 223
the risk of febrile disease and of neurologic disease increased
with age, which may in part explain the differences compared
to parts of Africa. In Egypt, most of the population is infected
during childhood, and neurologic disease is rare (205). In a
South African outbreak of 18,000 people of all ages, only a
single encephalitis case was reported (192).
Recent molecular phylogenetic studies show that isolates of
WNV can be divided into seven lineages. Lineage 1 has been
subdivided into a further three clades: 1a, 1b, and 1c. Lineage
1b has spread to Australasia as Kunjin virus, whereas lineages
1a and 5 are found in India, and lineage 6 in Malaysia (206).
Lineage 2 strains have mostly been found in Africa, whereas
lineage 1 strains are more widely distributed and are responsi-
ble for all the large outbreaks during 1998 to 1999 (207,208).
This has led to the suggestion that they may be more virulent,
although neuroinvasive strains have been shown in both lin-
eages in animal models (209). However, lineage 2 was more
prevalent during the recent outbreaks in Europe (Greece,
Romania, and Italy) and therefore may disperse wider in the
future (210,211).
In nature, WNV is transmitted in an enzootic cycle between
birds by mosquitoes. WNV infects over 300 different bird
species and 50 mosquito species (1). Members of the order
Passeriformes (jays, blackbirds, finches, warblers, sparrows,
and crows) appear to be important in maintenance of the virus
in nature (because of viremias); the family Corvidae (crows,
blue jays) seems to be particularly susceptible Culex mosqui-
tos, particularly Culex pipiens, appear to be important in the
enzootic cycle, although different species may act as bridging
vectors transmitting the virus to humans.
How WNV is introduced to new areas is not completely
understood. Migratory birds are thought to be important for
the movement of WNV from Africa into southern Europe.
They may have been involved in the virus introduction into
the United States, although imported exotic birds, a viremic
human, or inadvertently transported mosquitoes seem more
likely (212). Molecular genetic evidence suggests there was a
single introduction into the United States of a strain closely
related to one isolated from a goose in Israel (207). A com-
plex interplay of viral, avian, mosquito, human, and cli-
matic factors may contribute to the large outbreaks that have
characterized the disease recently (Fig. 15.4). During the 2002
outbreak in the United States, transmission also occurred via
transplanted organs, infected blood products, and possibly
breast milk (213).
Clinical Features
After an incubation period, which is typically 2 to 6 days but
may extend to 14 days, patients with West Nile fever develop
a sudden onset of an acute nonspecific flulike illness, char-
acterized by high fever with chills, malaise, headache, back-
ache, arthralgia, myalgia, and retroorbital pain (86). Other
nonspecific features include anorexia, nausea, vomiting, diar-
rhea, cough, and sore throat. In epidemics of West Nile fever,
a flushed face, conjunctival injection, and generalized lymph-
adenopathy were common. A maculopapular or pale roseolar
rash was reported in about 50% of patients and was more
common in children. In one outbreak, 20% of patients with
West Nile fever had hepatomegaly and 10% had splenomegaly
(214). Myocarditis, pancreatitis, and hepatitis occur occasion-
ally in WNV infection.
Patients with neurologic disease due to WNV typically
have a febrile prodrome lasting 1 to 7 days that may be bi-
phasic, before developing neurologic symptoms. Although in
most cases, the prodrome is nonspecific, 15% to 20% of pa-
tients may have features suggestive of West Nile fever, includ-
ing eye pain, facial congestion, or a rash, though less than 5%
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 224 Part II: Viral Infections and Related Disorders

Behavioral factors Human immune response

Exposure to biting Impaired (e.g., immunocompromised

mosquitoes patients) allows virus to replicate
Avian hosts ? genetic susceptibility
Compromised blood brain barrier
Large population of
immunologically nave ? Allows virus to enter brain
susceptible hosts
e.g., cerebrovascular disease

Age

? impaired immunity
? coexisting disease
Enzootic vectors

Feed naturally on birds Bridging vectors

Breed in water with high Strain virulence determinants
Feed on birds and humans
organic content (ditches,
swamps) May be different to enzootic ? affect rate of viral replication
vectors ? some strains neuroinvasive
e.g., Culex pipiens and
others e.g., Culex salinarius and others

Climate

Increased temperature enhances virus replication in mosquitoes

Lack of rainfall increases organic content of water collections, and
enhances mosquito replication

FIGURE 15.4 Factors known or postulated to be involved in the enzootic cycle of West Nile virus, and
epidemics of human disease.

had lymphadenopathy (215). In the 1998 to 1999 outbreaks,
approximately two thirds of hospitalized patients had enceph-
alitis (with or without signs of meningeal irritation), and one
third had meningitis (194,196,199). Severe generalized muscle
weakness was a common feature in the 1999 New York out-
break and subsequent outbreaks in the United States (199).
In some patients, this affects only the limbs, but in others,
respiratory and bulbar musculature are affected, requiring
ventilation. Though initially ascribed to Guillain-Barr syn-
drome, the weakness was probably due to anterior horn cell
damage (myelitis), as is seen in other flavivirus infections (86).
Conscious patients with a polio-like flaccid paralysis due to
WNV were recognized in the 1970s and 2002 (70,216). In the
recent outbreaks in Greece, 85% of patients had encephalitis/
meningoencephalitis and 12% had meningitis, followed by
3% with acute flaccid paralysis (202).
Although seizures occurred in approximately 30% of pa-
tients in the early descriptions of West Nile encephalitis, they
did not appear to be an important feature in the Romania or
the New York outbreak (199). Other neurologic features in-
clude cranial neuropathies, optic neuritis, and ataxia. Stiffness,
rigidity, spasms, and tremors associated with basal ganglia
damage similar to that seen in JE (217) have also recently been
recognized in West Nile encephalitis (32).
Overall case-fatality rates for patients hospitalized with
West Nile encephalitis outbreaks ranged from 4% to 14% but
were higher in older patients (196,199). However, the overall
case-fatality rate during the recent Greece outbreak was much
higher at 17%, increasing to nearly 35% for those older than
80 years of age (202). Other risk factors for death include the
presence of profound weakness, deep coma, failure to produce
IgM antibody, impaired immunity, and coexisting illness such
as hypertension and diabetes mellitus (199,218). Neurologic
sequelae are common among survivors. In one study, half of
patients hospitalized still had a deficit at discharge and only
33% recovered fully at 1 year (219).
Diagnosis
Approximately 50% of patients have a peripheral leukocy-
tosis, and 15% have leukopenia (199,219). Hyponatremia
sometimes occurs in encephalitic patients. Examination of
the CSF typically shows a moderate lymphocytic pleocytosis,
although sometimes no cells or neutrophils may predominate.
The protein is moderately elevated and the glucose ratio is
typically normal. CT scans of the brain are usually normal.
MRI may show nonspecific enhancement of the meninges or
periventricular areas (199,220) or high signal intensities on
T2-weighted images in the thalamus and other basal ganglia
(32). Nerve conduction studies typically show reduced motor
axonal amplitudes consistent with anterior horn cell damage,
although there may also be some slowing of conduction velo-
cities and some changes to sensory nerves (86,216). The dif-
ferential diagnosis is broad and includes other causes of viral
encephalitis (Table 15.3) and other causes of fever and reduced
consciousness (Table 15.4).
Attempts at WNV isolation from serum or CSF are usu-
ally unsuccessful, because viremias are low, and the virus
has cleared by the time most patients present (Fig. 15.3).
Techniques include detection of viral antigen by ELISA or of
viral nucleic acid using reverse transcriptase PCR (RT-PCR)
or real-time PCR (Taq-Man). Real-time PCR, the most sensi-
tive of these techniques, detects only 55% of patients (221).
Newer real-time RT-PCR assays, including multiplex RT-PCR

Scheld_Ch15.indd 224 2/21/14 5:38 PM


assays are more sensitive and offer rapid detection of WNV
(81,210,222). The accepted standard for diagnosing WNV
infection is the detection of IgM-specific antibodies in CSF
and/or serum using IgM capture ELISAs (29). Whereas an-
tibody is detected in the serum of those with West Nile fever
or even asymptomatic infection, IgM in the CSF is specific for
CNS infection. Half of patients have antibody on admission,
and almost all have antibody by the seventh day of admission.
Those who do not are more likely to have virus isolated and
are more likely to die (32,223).
Treatment and Prevention
There is no established antiviral treatment for West Nile en-
cephalitis, although IFN-, ribavirin, and human immune
globulin have been used in some patients (196). Treatment for
patients with West Nile encephalitis is supportive. Mosquito
repellents are an identified prophylaxis being particularly
important for those in at-risk groups, such as the elderly
and the immunocompromised. There is no human vaccine for
WNV, although a crude formalin-inactivated vaccine and a
recombinant plasmidic DNA vaccine has been developed for
horses (224,225). Several new vaccine candidates for human
are being developed and evaluated with some vaccines in
phase I/II human trials (210,226,227).
Japanese Encephalitis
Epidemiology
Outbreaks of encephalitis have been described in Japan since
the 1870s (228). The virus was first isolated in 1935 and has
been recognized across much of eastern and southern Asia
since then. All of Southeast Asia, the western Pacific region,
most of the Asian subcontinent, and much of southern China
is now affected, and the virus recently reached Australia for
the first time (229). An estimated 35,000 to 50,000 cases and
10,000 deaths occur annually, making JEV numerically the
most important cause of epidemic viral encephalitis worldwide
(230). Approximately half the survivors have severe neuropsy-
chiatric sequelae, imposing a large socioeconomic burden in
the areas affected. JEV is transmitted naturally in an enzootic
cycle between birds, pigs, and other vertebrate hosts by mos-
quitoes, especially Culex tritaeniorhynchus, Culex gelidus,
and other species that breed in rice paddies. Humans become
infected when they encroach upon this enzootic cycle. Because
the virus is so ubiquitous, in rural areas almost all humans be-
come infected during childhood, but only a small proportion,
estimated at around 1 in 300 develop symptoms (230), which
may range from a nonspecific febrile illness through to a se-
vere meningoencephalomyelitis. In endemic areas, most cases
of JEV occur in children because by the time they reach adult-
hood, almost all individuals have been exposed to the virus
and will have developed neutralizing antibodies. However,
when immunologically naive adults are exposed to the virus,
for example, when the virus moves to new geographical areas
or when travelers or service personnel visit Asia, they too may
develop disease (231). In northern temperate parts of Asia,
JEV causes large summer epidemics, but in southern tropi-
cal areas, disease is year round, with a peak in the summer
months (232). There are at least four genotypes of JEV across
Asia; molecular phylogenetic studies suggest that the distribu-
tion of genotypes is best explained by the virus origin in the
Indonesia-Malaysia region and spread from here (233235).
A recent molecular phylogenetic study has identified the Muar
strain of JEV as the fifth genotype of JEV with approximately
20% divergence from other JEV strains (236). Furthermore,
Scheld_Ch15.indd 225
Chapter 15: Arthropod-Borne Viral Encephalitides 225
recently isolated strains from C. tritaeniorhynchus in China
and from Culex bitaeniorhynchus in Republic of Korea have
been identified as genotype V, suggesting that this genotype
may be reemerging in Asia (237,238).
Clinical Features
After a 4- to 14-day incubation period, most patients develop
a brief nonspecific febrile illness and then neurologic disease,
manifesting as a reduction in the level of consciousness and
seizures. Seizures occur in approximately 85% of children
and 10% of adults with JEV (68,239). Multiple seizures and
status epilepticus are associated with a poor outcome. Subtle
motor status epilepticus, in which the only clinical manifesta-
tion might be the twitching of a finger or eyebrow, is important
in JEV (68). Multiple uncontrolled seizures may be associated
with increased ICP and clinical signs of brainstem herniation
syndromes (68). Movement disorders are common in JEV, both
in the acute stages of infection and as part of the spectrum of
neuropsychiatric sequelae. One quarter of patients showed acute
manifestations in one series (68). A characteristic parkinsonian
syndrome includes masklike facies, tremors, and cogwheel rigid-
ity. Other movement disorders include generalized rigidity, jaw
dystonias, opisthotonus, choreoathetosis, orofacial dyskinesias
(involuntary tongue protrusions), myoclonic jerks, and opsoclo-
nus myoclonus (68,217). These disorders are thought to be the
clinical correlate of the inflammation often seen in the basal gan-
gliaparticularly the thalamus and substantia nigraon MRI
and at autopsy (217,240). In some patients, intention tremors
and ataxia reflect cerebellar involvement. Other focal neurologic
signs include cranial nerve palsies, upper motor neuron weak-
ness (in 30% to 50% of patients), and flaccid limb weakness,
with reduced or absent reflexes, which is often associated with
respiratory or bulbar paralysis (241). The combination of upper
and lower motor neuron damage can lead to bizarre mixtures
of clinical signs that can change hourly during the acute stages
of infection. In addition to causing flaccid weakness in coma-
tose patients with encephalitis, JEV can cause a poliomyelitis-
like acute flaccid paralysis in fully conscious patients (69). Acute
retention of urine, due to an atonic bladder, may be an early clue
that paralysis is due to a flavivirus (69). Overall, 20% to 30%
of hospitalized patients die, and half the survivors have neuro-
psychiatric sequelae. Poor prognostic signs include a depressed
level of consciousness, decerebrate posturing, multiple seizures,
increased ICP, isolation of virus from the CSF, and low levels of
JEV-specific IgM and IgG in CSF and serum (31,68,239,242).
Other nonspecific indicators include elevated admission temper-
ature, absent abdominal reflexes, hyponatremia, low serum iron
level, and elevated CSF white blood cell counts and protein level
(68,126,239,243,244).
Diagnosis
A peripheral polymorphonuclear leukocytosis is common.
CSF examination reveals an elevated opening pressure in 50%
of patients and usually a lymphocytic pleocytosis with a nor-
mal glucose ratio and slightly elevated protein. MRI may show
high signal intensity on T2-weighted scans in the thalamus,
other basal ganglia, midbrain, brainstem, and sometimes an-
terior spinal cord. EEGs may reveal seizure activity, including
periodic lateralized epileptiform discharges (PLEDs) as occurs
with HSV encephalitis. This is usually on a background of
slow-wave activity. Nerve conduction studies typically show
reduced motor amplitudes, consistent with damage to the
lower motor neurons in the anterior horns of the spinal cord
(69,241), as is seen at autopsy (240). JEV is confirmed by IgM
and IgG capture ELISAs, revealing antibody in the serum and
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 226 Part II: Viral Infections and Related Disorders
the CSF (27,245,246). A robust and user- friendly rapid IgM
capture ELISA (JEV Chex) has been developed with similar
sensitivity as conventional ELISAs (247). Virus isolation and
PCR from serum are usually negative; they may be positive in
the CSF of fatal cases and in postmortem brain tissue (31,248).
Treatment and Prevention
A number of antiviral compounds against JEV have shown
promise in vitro or animal models, including nitric oxide,
ribavirin, and IFN- (249251). IFN- showed promise Eastern strains are associated with greater epidemic potential,
in open clinical trials (252), but in a randomized placebo-
controlled trial in Vietnamese children, it failed to make any
difference to the outcome (82). Treatment of JEV focuses on
controlling the complications of infection such as seizures
and ICP. High-dose dexamethasone failed to show any ben-
efit (89). Recent studies on mice have shown protective ef-
fects of pentoxifylline and minocycline against JEV challenge
(253255).
Given that the vectors of JEV breed in rice paddies, vector
control may seem an impossible task, but measures that may
have an impact include intermittent irrigation of the rice pad-
dies and use of natural larvicides, such as larvivorous fish and
the plant neem (Azadirachta indica) (256). Personal protection
with insect repellents and by using mosquito netting is also
recommended. However, the most effective prevention is with
vaccines. A mouse-brainderived formalin-inactivated vac-
cine (JE-Vax) has been available for many years, produced by
the Japanese under the Biken label and by the Korean Green
Cross. Efficacy was demonstrated in a double-blind trial in
Thailand (257), and it is used by travelers and service per-
sonnel and in some of the wealthier Asian countries (231).
Earlier crude preparations of the vaccine were associated with
adverse events, and in the early 1990s, there were reports of
hypersensitivity reactions, although the risk of serious neuro-
logic adverse events is low, at about 1 in 1 million (258). JE-
Vax is no longer manufactured and all existing stocks expired
in May 2011 (259). A live attenuated vaccine (SA14-14-2),
developed by passage through primary hamster kidney cells,
has been used in China since the 1980s and was shown to
be safe and efficacious (260262). It is also relatively cheap
and has been licensed to use in Korea, Nepal, and Sri Lanka.
However, regulatory approval for its wider use has been de-
layed because of concerns about its production, in particular
whether it meets international good manufacturing practice.
A new inactivated Vero cell culturederived vaccine (IC51 or
IXIARO) using the attenuated SA14-14-2 strain for adults is
now approved for use in the United States, Europe, Canada,
Australia, Hong Kong, and Switzerland. Clinical trials are on-
going to determine the safety and efficacy of this vaccine for
use in children (259). Newer vaccines in clinical trials include
a chimeric vaccine (JE-CV or IMOJEV) in which the prM and
E genes of JEVSA14-14-2 strain are inserted into the genome
of the yellow fever 17D backbone containing the yellow
fever nonstructural gene, which has been used safely for many
years (226,263).
St. Louis Encephalitis
Epidemiology
Before West Nile encephalitis in New York in 1999, St. Louis
encephalitis (SLE) was the most important flavivirus in North
America. Outbreaks compatible with SLE were described
from the 1920s, but the disease was first recognized in Paris,
Illinois and then St. Louis and Kansas City, Missouri in the
1930s. The virus was isolated from the brain of a fatal case
Scheld_Ch15.indd 226
in 1931 (264) and is transmitted in nature between passeri-
form and columbiform birds by Culex mosquitoes. The area
affected by SLE extends from Canada through the United
States to Central and South America. Strains of virus circu-
lating in the United States are genetically distinct from those
in Central and South America, forming two major clades,
within which there are subgroups. Strains in the western
United States, which are transmitted by C. tarsalis mosqui-
toes, differ from those found in the east that are transmitted
by C. pipiens/Culex quinquefasciatus and Culex nigripalpus.
being more readily transmitted by mosquitoes, causing higher
viremias in sparrows (one of the major vertebrate hosts)
and a higher case-fatality rate in humans (265). However,
between epidemics in the east, there may be long intervals
during which no cases are seen. In contrast, in the western
United States, transmission is endemic and sporadic cases are
seen every year, but the case-fatality rates are lower. The in-
cidence rates are highest in the Ohio and Mississippi River
basins and the Gulf Coast. The annual reported incidence has
fluctuated from 0.003 to 0.752 per 100,000, with a median
of 35 cases reported each year (265). However, larger num-
bers have occurred in some years. In 1975, the largest out-
break recorded caused 2,800 cases in 31 states, and in 1990,
there were 222 cases during an epidemic in Florida. Serologic
surveys suggest that on average approximately 1 in 300 in-
fections is symptomatic. This rises with age, from 1 in 800
among children younger than 10 years to 1 in 85 for adults.
Human immunodeficiency viruspositive individuals appear
to be at greater risk of acquiring SLE (266). More recently, an
outbreak of SLE occurred in Argentina with 47 laboratory-
confirmed cases and nine deaths (267,268).
Clinical Features
After an incubation period, which is usually around 4 days
but may extend to 21 days, patients present with fever, head-
ache, malaise, myalgias, and other nonspecific features such as
diarrhea, nausea, vomiting, cough, and sore throat. Dysuria,
urgency, and incontinence are early features in some patients.
In patients younger than 20 years, about 55% have encephali-
tis, and 40% have meningitis, but in those older than 60 years,
more than 90% have encephalitis (269). The most common
manifestation of encephalitis is a reduced level of conscious-
ness, which may range from mild confusion to deep coma.
Tremulousness of the eyelids, tongue, lips, and extremities
is one of the most common neurologic signs. More marked
involuntary movements such as myoclonus, nystagmus, and
opsoclonus are less common. About 25% of patients have
cranial nerve palsies, usually unilateral. Cerebellar ataxias are
also common. Seizures occur in children and in more severe
adult cases and are a poor prognostic sign (270). Subtle motor
seizures have also been reported (271). About 17% of patients
die (269), and neuropsychiatric sequelae including emotional
disturbances, forgetfulness, tremor, unsteadiness, and visual
disturbances occur in about 33% of patients.
Diagnosis
The peripheral white blood cell count is normal or slightly
elevated. In some patients, microscopic hematuria, protein-
uria, and pyuria have been reported. Hyponatremia due to
SIADH secretion occurs in more than one third of patients,
and alanine aminotransferase and creatinine phosphokinase
levels may be slightly elevated. One third of patients have an
elevated CSF opening pressure, and there is typically a moder-
ate mononuclear pleocytosis, with an elevated protein level.
EEGs show diffuse slowing and occasional spike-and-wave
activity, including PLEDs. The MRI may show high signal
2/21/14 5:38 PM

intensity in the substantia nigra (269). The diagnosis is usu-
ally made by IgM capture ELISA or immunofluorescence, with
nearly 100% of CSF samples being positive by day 7 of illness
(272). Antibody can also be measured in the serum, but there
may be problems with cross-reactive antibody in patients pre-
viously exposed to other flaviviruses, such as dengue. Virus
can sometimes be cultured from the brain tissue of fatal cases
or occasionally demonstrated by electron microscopy. Viral
antigen detection and PCR results may be positive but are not
reliable for routine diagnosis.
Treatment and Prevention
There is no antiviral treatment; thus, care is supportive. There
is no vaccine. Measures to reduce the risk of being bitten by an
infected mosquito are described earlier in this chapter.
Murray Valley Encephalitis
Epidemiology
Outbreaks of encephalitis in Australia in 1917 and 1922, la-
beled Australian X disease, or an aberrant form of polio-
myelitis (273), have subsequently been attributed to MVEV,
which was first isolated from the brain of a fatal case in 1951
(274). The virus has been found across parts of Australia and
New Guinea and is transmitted between herons, egrets, and
other aquatic birds, by Culex annulirostris, and other mos-
quitoes. The overwintering mechanism and factors responsible
for the intermittent epidemics are not known. MVEV is en-
zootic in the Kimberley region of Western Australia and the
Northern Territory and is thought to only reach southeast-
ern Australia during extreme weather conditions (275). Only
about 1 in 1,000 to 1 in 2,000 infections result in disease,
and the number of cases is small, 25 between 1990 and 1998.
Most cases are in aboriginal children living in areas where they
are exposed to the virus, but cases have also occurred in travel-
ers to these areas (276). More recently, the number of MVEV
cases increased (16 cases and three deaths) in endemic areas
of Australia and reemerged in southeastern Australia. This
outbreak in 2011 was followed after heavy rainfall and flood-
ing resulting in increased numbers of C. annulirostris mosqui-
toes and widespread seroconversion among sentinel chicken
flocks (277).
Clinical Features, Diagnosis, and Treatment
After a brief nonspecific febrile illness, milder cases develop
meningism and tremulousness, whereas in more severe cases,
there are seizures, flaccid paralysis requiring mechanical ven-
tilation, and coma (276). Infants may deteriorate rapidly and
die within 24 hours. Approximately one fourth of hospital-
ized cases die and one fourth have severe sequelae. Typically,
there is a CSF pleocytosis, with mildly elevated protein and
normal glucose levels. MRI may show high signal intensities in
the basal ganglia (278). Virus has been isolated by inoculating
postmortem brain tissue into chick embryos, but the diagnosis
is usually made serologically with an ELISA, hemagglutina-
tion inhibition, complement fixation, or neutralization test.
Treatment is supportive, because there is no antiviral drug.
Patients with MVE have been treated with corticosteroids but
the effectiveness has not been assessed in controlled clinical
studies (277). No vaccine is available, and the low incidence of
disease makes it unlikely that one will be developed. However,
recent studies in mice have shown that the live chimeric JEV
vaccine offered cross protective immunity against lethal chal-
lenge with MVEV (279).
Scheld_Ch15.indd 227
Chapter 15: Arthropod-Borne Viral Encephalitides 227
Tick-Borne Encephalitis
Epidemiology
Descriptions of a disease compatible with TBE appeared from
the 1930s, and the virus was first isolated by Russian scientists
in the Far East in 1937 (280). Three closely related subtypes
of TBE virus exist, whose names reflect the geographical areas
they principally affect: European/Western, Siberian, and the
Far East. However, across this vast geographical area, the dis-
ease was given a range of different names (central European
encephalitis, Russian spring/summer encephalitis, Far East
Russian encephalitis, biphasic milk fever, Taiga encephalitis,
Kumlinge disease, Fruhsommer meningoenzephalitis) before it
was realized that they are essentially the same disease. The TBE
group serocomplex (recently renamed the mammalian group
of tick-borne flaviviruses) also includes Powassan virus (a rare
cause of encephalitis in Canada); louping ill virus (a very rare
cause of CNS disease in the British Isles and Scandinavia);
and viruses that cause hemorrhagic disease, such as Kyasanur
Forest disease virus (in India) and Omsk hemorrhagic fever
virus (in Siberia) (Fig. 15.1). TBE virus is naturally transmit-
ted between small rodents by hard Ixodes ticks (particularly
Ixodes ricinus and Ixodes persulcatus). Because ticks may live
for months or even years, and because they can pass the virus
to their offspring transovarially and transtadially, they act as
important reservoirs. Following the bite of an infected tick,
small mammals become viremic, and subsequent biting ticks
then become infected. In addition to this classic arboviral
transmission cycle, virus may also be transmitted from tick
to tick via infected reticuloendothelial and inflammatory cells
(Langerhans cells, neutrophils, monocytes, and macrophages)
in the skin of the vertebrate host without the need for the ani-
mal to become viremic (8). Adult ticks tend to feed on larger
mammals and thus infect humans walking through dense for-
est between spring and autumn. Across the large geographical
area where TBE occurs, the virus tends to circulate in small
natural foci where the vegetation, temperature, moisture,
and presence of appropriate mammalian hosts supports
their existence. Humans can also become infected by drink-
ing the unpasteurized milk or cheese of infected goats, cows,
and sheep, causing biphasic milk fever. There has been a
dramatic increase in the number of cases of TBE in humans
following drinking TBEV-infected milk in Russia and Europe
(281). The incidence of TBE varies according to location and
year (282). TBE is endemic in 27 European countries. The
endemic area spans from central and Eastern Europe to Siberia
and some parts of Asia, including China and Japan. Nearly
170,000 clinical cases of TBE have been reported in Europe
and Russia between 1990 and 1999. In Europe, there have
been on average about 3,000 cases annually in the last 5 years
(281). Following the collapse of the former Soviet Union and
reduced use of pesticides and vaccine against TBE, the annual
incidence rose to more than 10,000 cases (3). Serologic sur-
veys indicate that in endemic regions, 70% to 95% of infec-
tions are subclinical.
Clinical Features
Three fourths of patients recall a tick bite, a median of 8 days
(range, 4 to 28 days) before symptoms develop (283). A cou-
ple days of headache, fatigue, and pain in the neck, shoulders,
and lower back precede the onset of high fever, nausea, and
vomiting. In three fourths of patients, the illness is biphasic,
with this febrile prodrome of several days, followed by an
afebrile period of about 8 days (range, 1 to 33 days) before
neurologic disease develops (283,284). In the mildest form of
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 228 Part II: Viral Infections and Related Disorders
diseaselabeled the febrile form by Russian cliniciansthe
febrile phase lasts from 1 to 5 days, sometimes with severe
muscle pains and sometimes numbness and fasciculations,
before resolving with no residual deficit (3). In the menin-
geal form of disease, there is neck stiffness and photopho-
bia. The meningoencephalitic form is characterized by a
reduced level of consciousness, which may range from drowsi-
ness and hallucination to deep coma, focal neurologic signs,
including hemiplegia, and seizures. There may also be cardiac
arrhythmias. A poliomyelitic form with poliomyelitis-like
flaccid paralysis is common in TBE virus infection. This usu-
ally affects the neck and upper limbs to cause pain, sometimes
with periodic muscle contractions and numbness, then upper
limb weakness with winging of the scapula, wristdrop, or a
hanged head due to neck extensor weakness. Muscle atro-
phy begins after the second or third week and persists. In con-
trast, some patients develop a polyradiculoneurotic form of
disease: neuropathy occurs 1 to 2 weeks after the initial febrile
phase and is associated with a recurrence of fever, but there is
usually complete recovery. Finally, in Russia, a chronic form
of TBE has been described and is believed to be caused only
by the Siberian subtype of TBEV. In some patients, deteriora-
tion continues long after the acute disease, postmortem ex-
amination suggests chronic inflammation, and viral RNA may
be detected by nucleic acid hybridization. Other patients are
asymptomatic following the initial tick bite but present years
later with a progressive form of disease, with virus being iso-
lated at autopsy (65). Spontaneous regular contractions (myo-
clonic jerks) of the limbs are seen in about 25% of patients
with all neurologic forms of TBE disease and may persist as
epilepsia partialis continua (Kozhevnikov epilepsy).
Traditionally, disease caused by the Far East subtype of
TBE virus is thought to be more severe than that caused by the
European subtype, with case-fatality rates of 20% to 60% com-
pared with 1% to 3%, respectively. Differences in criteria for
hospitalization may account for much of this apparent differ-
ence, although differences in virulence have been found in animal
models. The case-fatality rate of the Siberian subtype appears
to be similar to that of the European subtype, with neurologic
sequelae reported for 30% to 60% of survivors. Interestingly,
in biphasic milk fever following oral ingestion of infected milk,
TBE virus typically causes only the febrile form of disease.
Although there is sometimes mild meningism, encephalitis and
paralysis are not seen, and recovery is the rule (3).
Diagnosis
During the initial febrile stage, leukopenia and thrombo-
cytopenia are common (285), but by the time patients have
neurologic disease, many have a leukocytosis (283). CSF ex-
amination usually reveals a mild pleocytosis with elevated pro-
tein level. EEGs of patients with encephalitis show slowing
with or without focal activity (283). On MRI, abnormalities
have been shown in about one fourth of patients with enceph-
alitis, usually in the thalamus but sometimes in the caudate,
cerebellum, and brainstem. The diagnosis is usually suspected
because of the history of tick bite, although other tick-borne
febrile illnesses including borreliosis and ehrlichiosis should
be considered. The diagnosis is confirmed by detection of
IgM antibodies in CSF and/or serum using an ELISA (286),
although during the early viremic phase, virus may also be
cultured from the blood. PCR assay have also been shown to
be useful in detecting TBEV in the first phase of illness (287).
Treatment and Prevention
There is no antiviral treatment, but an anti-TBE immune globu-
lin has been used for postexposure prophylaxis in those bitten by
ticks in areas where the virus circulates. It is licensed under the
Scheld_Ch15.indd 228
FSME-Bulin label by Baxter in Austria, and the Encegam label
by Chiron/Behringwerke in Germany. An intramuscular dose of
0.2 mL/kg is recommended up to 4 days after the tick bite (288).
Prophylaxis later than this is not recommended because of the
theoretical potential of antibody aggravating inflammation in
patients with established neurologic disease. Postexposure pro-
phylaxis is not recommended for children. The preparations
have also been used (at 0.4 mL/kg) as short-term preexposure
prophylaxis for those about to visit areas at risk.
A formalin-inactivated vaccine based on an Austrian virus
isolate (TBEV-Eu strain Neudoerfl) grown in chick embryo
cells has been commercially available in Europe since 1976. It
had a relatively high rate of side effects (fever, headache, mal-
aise) but has been replaced by a highly purified form, prepared
by ultracentrifugation (289). This vaccine (FMSE-Immun,
Baxter), which contains aluminum hydroxide as an adjuvant,
has an efficacy of about 98%. Vaccination is recommended for
those living, traveling, or working in areas at risk, as well as
laboratory workers. Mass vaccination since 1981 in Austria
resulted in a marked decline in the number of TBE cases (290).
Another formalin-inactivated vaccine, based on the TBEV-Eu
strain K23 (Encepur, Novartis) manufactured in Germany
is also used in Europe. This vaccine was initially withdrawn
from pediatric use because of allergic reactions related to poly-
gelin, which was removed in 2001 (291). Children are given
half the adult dose to reduce the high fever that was observed
when given the full dose (292). Two other formalin-inactivated
vaccines, TBE-Moscow vaccine (based on the Far-Eastern
Sofjin strain) and EnceVir vaccine (based on the Far-Eastern
205 strain), are widely used in Russia and several Asian coun-
tries. EnceVir is not currently recommended for pediatric use
because of high rates of fever and allergic reactions observed
in 2010 and 2011. These two vaccines are produced similar to
the vaccines used in Europe except the TBE-Moscow vaccine,
which is finally lyophilized. All four vaccines are produced
according to the World Health Organization (WHO) manu-
facturing standards (293). Live attenuated vaccines against
TBEV are currently under development (294). In 2011, the
WHO published its first position paper on TBE vaccines, giv-
ing recommendation for TBE vaccination (295).
Neurologic Dengue Disease
Epidemiology
Most patients affected by one of the four dengue viruses
(dengue 1, 2, 3, and 4) present with a fever-arthralgia-rash
syndrome or a viral hemorrhagic fever (296). The cause and
even existence of neurologic manifestations of dengue has
been a long-standing controversy (297302). However, more
recent studies have given strong evidence to support neuro-
invasion of DENV (303306). Most authorities now accept
that dengue viruses can cause a nonspecific encephalopathy
and occasionally encephalitis, even if the mechanism is not
yet clear (307,308). The four types of dengue virus were iso-
lated from febrile patients in the 1940s, and dengue is unusual
among arboviruses in that humans are the main natural host,
although a sylvatic cycle exists in primates in Southeast Asia
and West Africa (309). The virus is transmitted between hu-
mans by A. aegypti and A. albopictus mosquitoes that breed
in small collections of fresh water around the home (e.g.,
collected in rubbish, water containers, and tires). Dengue is
very widely distributed, being found in almost every country
between the tropics of Capricorn and Cancer (310). According
to the WHO, over 50 million cases of dengue occur every year.
Three outbreaks of dengue occurred during 2001 and 2011
in the United States, and the reemergence of autochthonous
2/21/14 5:38 PM

dengue transmission within Europe has also been described
(311,312). Neurologic disease has been reported from virtu-
ally every country where dengue occurs (297). It is now rec-
ognized that in parts of Southeast Asia, dengue is responsible
for 1 in 20 patients admitted with a suspected CNS infection
(300) and as many as 1 in 5 of those with a clinical diagnosis
of encephalitis (299).
Clinical Features
Most patients with neurologic dengue present with a reduced
level of consciousness and other signs of severe dengue infec-
tion, including the shock, vascular leakage, and hemorrhage
that characterize dengue hemorrhagic fever (DHF). They may
also have metabolic disturbances such as hyponatremia and
acidosis, and in many patients, the encephalopathy is thought
to be secondary to these complications. However, in other
patients with no rash, hemorrhage, or other signs of dengue
fever or DHF, viral invasion across the BBB causing encephali-
tis is thought to occur. In support of this is virus isolation, PCR
detection, and detection of anti-dengue IgM antibody in the
CSF of some patients (300,313315). A recent study on 150
CSF samples from fatal cases during a dengue epidemic pe-
riod in Brazil found evidence of DENV in 41 CSF samples out
of 84 dengue-positive patients (306). Clinically, these patients
present with a brief febrile illness followed by a reduction in
consciousness level, which may range from lethargy, drowsi-
ness, and irritability to deep coma. Seizures are also common,
particularly in young children (316,317). These may be sim-
ple febrile seizures or those associated with prolonged coma.
Pyramidal or long tract signs also occur, but the extrapyra-
midal tremors and tone abnormalities that characterize other
arboviral encephalitides such as JEV and West Nile encepha-
litis (86) are less common in dengue, although they have been
described (318,319). Presentations consistent with acute dis-
seminated encephalomyelitis have also been described, some
time after a dengue infection (320). Meningismus occurs in
up to 30% of patients, usually as part of an encephalopathic
illness. Uncomplicated viral meningitis due to dengue viruses
is rare. Other neurologic manifestations include mononeu-
ropathies, polyradiculopathies, Guillain-Barr syndrome, and
acute neuromuscular weakness due to myositis and hypokale-
mia (303,307,321,322).
Diagnosis
Patients with dengue often have leukopenia and thrombocy-
topenia, as well as mildly elevated hepatitic transaminases. In
patients with DHF, an elevated hematocrit is found because of
fluid loss from blood vessels due to increased vascular perme-
ability (301,323). Hyponatremia is common, particularly once
fluid resuscitation has begun. CSF examination reveals a mod-
erate lymphocytic pleocytosis in up to 30% of patients with
neurologic disease. CT and MRI may show diffuse cerebral
edema, although focal abnormalities have also been reported
(300,313,319,324). Dengue can be confirmed by isolating the
virus from serum or CSF, PCR detection, or demonstrating
IgM antibodies. Because dengue is so common in many parts
of the world, and because IgM antibody may persist in the
blood for up to 3 months, confirmation of antibody or virus
in the CSF provides stronger evidence that dengue was the
cause of the neurologic symptoms (307). In addition, rigorous
efforts must be made to rule out other causes.
Treatment and Prevention
No effective drugs against dengue are available. Because pa-
tients with DHF are particularly likely to develop shock, fluid
management is critical, and detailed guidelines are available
Scheld_Ch15.indd 229
Chapter 15: Arthropod-Borne Viral Encephalitides 229
(325). No vaccines are available yet, but several vaccine
candidates are currently undergoing preclinical development
and some in clinical trials (326,327). Currently, the most ad-
vanced dengue vaccine in phase III clinical trials is ChimeriVax,
the chimeric tetravalent live vaccine (yellow fever 17D back-
bone) manufactured by Sanofi Pasteur (226). Several other
chimeric and live attenuated vaccines are also in clinical trials
(326,328,329). There is no important enzootic cycle, and be-
cause the disease is spread by peridomestic mosquitoes, vector
control measures can have an impact. These include educating
people to remove Aedes breeding sites, treating stored water
with larvicide (e.g., temephos), or the copepod Mesocyclops
that feeds on A. aegypti larvae, covering water storage contain-
ers, and ultralow volume spraying of organophosphorus insec-
ticides during epidemics (330). In some settings, legislation and
fines for those who fail to remove Aedes breeding sites from
the home have been effective. Personal protection with insect
repellents is also recommended. The evidence for the efficacy of
these measures is variable. The only undoubtedly effective vec-
tor control measure was the near eradication of A. aegypti from
South America, using DDT, during the yellow fever campaign
of the 1950s to 1970s. Since that campaign ended, Aedes has re-
infested South America (331). Worldwide, A. aegypti continues
to spread, and dengue is increasing as a global health problem
(332). In 2007, sequencing of the A. aegypti genome was com-
pleted and has led to the development of transgenic mosquitoes
that could be useful in preventing dengue transmission to hu-
mans (333). These include development of sterile mosquitoes,
interfering with mosquito feeding and reproduction and the use
of Wolbachia to infect mosquitoes (9294).
BUNYAVIRIDAE
The Bunyaviridae family is the largest family of animal viruses,
with more than 350 members. It is named after Bunyamwera
Village in Uganda where the prototype virus was isolated. The
family consists of five genera, the first two of which contain
important arboviral causes of CNS disease. Within each genus
of the family, viruses are placed into serogroups according to
their cross reactivity in serologic tests.
The Orthobunyavirus genus contains the mosquito-borne
LACV and other members of the California encephalitis
serogroup of viruses.
The Phlebovirus genus includes the sandfly-borne TOSV,
which is emerging as an important cause of CNS disease
in southern Europe, and RVFV, which is transmitted by
mosquitoes and causes febrile, hemorrhagic, and occasional
CNS disease.
The Nairovirus genus includes Crimean-Congo hemor-
rhagic fever virus, which is transmitted by ticks.
The Hantavirus genus, whose members are not arthropod
borne, includes viruses that cause hantavirus pulmonary
syndrome, and hemorrhagic fever with renal syndrome.
The Tospovirus genus contains only plant viruses transmitted
by thrips (woodworm), and no human pathogens.
Infectious Agent
All members of the family Bunyaviridae are 90 to 120 nm
in diameter and are spherical in shape, except hantaviruses,
which are either spherical or rod-shaped particles. These en-
veloped viruses have glycoprotein spikes assembled from the
glycoproteins Gn and Gc, and enclose three circular nucleo-
capsids, containing three linear segments of single-stranded
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 230 Part II: Viral Infections and Related Disorders
negative-sense RNA, designated L (large), M (medium), and
S (small) (334,335). These range in size from 1 to 2.2 kb for
the S, 3.5 to 6 kb for the M, and 6.3 to 12.0 kb for the L. The
L segment codes for a single L protein, RNA-dependent RNA
polymerase (RdRp) protein. The M segment codes for surface
glycoproteins G1 and G2, and for a nonstructural protein
NSm. The S segment codes for nucleocapsid protein N (forms
the ribonucleoprotein [RNP] complex by encapsidating the
viral RNA replication products) and for a nonstructural pro-
tein NSs, although for hantaviruses, the nonstructural proteins
NSm and NSs have not been detected (335,336).
Attachment of G1 and/or G2 glycoproteins to an as yet
unidentified cell receptor is thought to be the first step in viral
replication. However, some studies suggest that integrins are
involved in hantavirus attachment, and phebovirus entry into
dendritic cells involves DC-SIGN (337,338). Entry into the
cell by endocytosis is followed by uncoating and release of
the three nucleocapsids into the cytoplasm, possibly mediated
by pH-dependent fusion of the viral envelope and host endo-
somal membrane. A recent study suggests that after clathrin-
independent endocytosis, phleboviruses pass through early
and late endosomes, followed by late endosomal acidification
and release of RNPs and accumulation in the Golgi (339).
Replication of viral RNA occurs via a positive-sense comple-
mentary RNA (cRNA) intermediate. Transcription of viral
RNA to messenger RNA (mRNA) is followed by translation
to produce viral proteins. For Phlebovirus and Tospovirus,
the SA segment is transcribed in both positive and negative
directions (ambisense). The G1 and G2 proteins are glycosyl-
ated, and viral particles assemble by budding into the Golgi
vesicles. These are transported to the cell surface, and fu-
sion of the cytoplasmic vesicles with the plasma membrane
results in virion release through exocytosis. Although this
mechanism of viral release applies to most viruses in the fam-
ily Bunyaviridae, RVFV can also bud off directly at the cell
surface.
La Crosse and Other California
Serogroup Viruses
The California serogroup viruses are the only major cause of
CNS disease in the Bunyavirus.
Epidemiology
California encephalitis virus was isolated from mosquitoes
by Reeves and Hammon in 1941 (340) and was shown to
be associated with three cases of encephalitis. Although the
serogroup was named after this virus, human disease is rare
(341). LACV, which was isolated from the brain of a fatal en-
cephalitis case in 1960 (342), is the most important member
of the group and was probably the most common cause of
arboviral encephalitis in the United States until the arrival of
WNV. Other members of the California serogroup include
Jamestown Canyon virus, which is also a relatively common
cause of CNS disease, and snowshoe hare virus, which is not
(Table 15.2). California serogroup viruses are typically trans-
mitted in nature between rodents by Aedes mosquitoes. LACV
is transmitted between chipmunks and squirrels by Aedes tri-
seriatus, a forest-dwelling tree-hole breeding mosquito that
breeds in rainwater collected in artificial containers in urban
settings. Evidence is accumulating that the recently introduced
mosquito species A. albopictus may be involved in the emer-
gence of LACV infection (343). During the winter months,
the virus overwinters by vertical transmission into Aedes eggs
(344). For Jamestown Canyon virus, the white-tailed deer is
Scheld_Ch15.indd 230
thought to be an important amplifying host. In Europe and
Russia, the California encephalitis virus serogroup Tahyna
virus is a cause of fever, respiratory symptoms, and occasion-
ally CNS disease (345,346).
Most encephalitis cases due to California serogroup viruses
occur during the summer and early fall, particularly among
residents of the Mississippi and Ohio River basins (347); how-
ever, 31 states have now reported cases, with 130 cases (116
neuroinvasive cases) reported from 14 states in 2011. Nearly
95% of patients were younger than 18 years of age (348).
The recent spread of LACV to Tennessee, North Carolina,
and West Virginia has been attributed to invasive mosqui-
toes including A. albopictus (349). The incidence of LACV
encephalitis is estimated at up to 30 per 100,000 in endemic
areas (67). Most cases occur in children living close to wooded
forests or visiting them for recreation; risk factors include the
time spent outdoors and proximity of homes to tree holes
(343). Approximately 75 encephalitis cases are reported each
year. The ratio of asymptomatic to symptomatic infections is
about 1,000:1, and in endemic areas, 20% of the population
is seropositive by age 60 years. Jamestown Canyon virus is
distributed across the northern United States. Encephalitis
due to Jamestown Canyon virus occurs mostly in the elderly.
Seroprevalence is 4% to 10% in some areas (350).
Clinical Features
Children with LACV encephalitis typically present with fever,
headache, malaise, nausea, and vomiting, which are often ac-
companied by meningeal signs (67,351353). Seizures, which
often include a focal component, occur in approximately 50%
of children, one third of whom have status epilepticus. Half
the patients have altered consciousness, and 10% are coma-
tose. Focal neurologic signs include hemiparesis, aphasia, dys-
arthria, chorea, and in about 10% clinical signs of raised ICP.
Poor prognostic indicators include reduced plasma sodium
level, increased body temperature, and a Glasgow Coma Scale
score of less than 13 out of 15, and possibly increased number
of seizures. Although fatalities are rare, approximately 10%
of patients have sequelae at hospital discharge. About 20% of
those with seizures in the hospital develop epilepsy. Jamestown
Canyon virus causes a similar clinical pattern (354).
Diagnosis
A peripheral leukocytosis is common, and although there is
usually a CSF lymphocytic pleocytosis up to 600 cells/mm3,
an early lymphocytic pleocytosis may be normal. CSF pro-
tein is elevated in about 30% of patients, but the glucose
level is usually normal. Low sodium level due to SIADH se-
cretion is reported in about 20% of patients. Diagnosis is
usually serologic because attempts to isolate virus from CSF
or blood are negative, although virus has been isolated from
brain tissue.
Treatment and Prevention
There is no antiviral treatment for California serogroup vi-
ruses, or indeed any members of the Bunyavirus genus. A
recent study investigated the safety and pharmacokinetics
of intravenous ribavirin treatment for children with LACV
encephalitis, but the results did not support the use of riba-
virin for LACV encephalitis (355). Attention should focus on
treating the complications of infection, particularly hypona-
tremia and seizures. There is no vaccine. Preventive measures
include environmental measures to decrease breeding sites, for
example, removing tree holes, tires, and litter, which provide
pools of water favored by Aedes mosquitoes for breeding.
2/21/14 5:38 PM

Phleboviruses Causing Central Nervous
System Disease
Most members of this genus are transmitted by phlebotomine
sandflies, although RVFV, which causes epidemics of febrile
illness, and occasional hemorrhagic disease, retinitis, or neu-
rologic disease, across sub-Saharan Africa, is a notable excep-
tion, being transmitted principally by Culex mosquitoes.
Sandfly Fever Viruses
A febrile illness associated with sandfly bites was recognized
since the early twentieth century. During outbreaks in World
War II, Albert Sabin isolated sandfly fever Sicilian virus and
sandfly fever Naples virus from U.S. troops (356). Both vi-
ruses decreased or disappeared after the 1940s in countries
performing insecticide spraying for malaria eradication. More
recently, an outbreak occurred among Greek soldiers stationed
in Cyprus with 256 out of 581 soldiers infected with sandfly
fever Sicilian virus (357). In 1971, TOSV, a new virus antigeni-
cally closely related to sandfly fever Naples virus, was isolated
in Italy from the sandfly Phlebotomus perniciosus (358,359).
It has since emerged as the most important cause of pediatric
CNS infections in some parts of Italy, causing up to 80% of
cases during the summer (360). Children from rural or semi-
urban areas are especially vulnerable. TOSV has also been rec-
ognized in other Mediterranean countries, including Cyprus,
France, Greece, Portugal, Spain, and Turkey (361,362). In af-
fected areas, seroprevalence levels of 10% to 25% have been
found (361,363). The viruss natural cycle has not been fully
determined. In particular, although it has been shown that the
virus replicates in sandflies and can be passed vertically to off-
spring via transovarial and transtadial transmission, no natu-
ral vertebrate host has yet been identified. However, humans
have sufficiently long and high viremias to transmit sandfly
viruses to biting sandflies, which contributed to some urban
outbreaks.
Clinical Features, Investigation, and Diagnosis
Aseptic meningitis is the most common presentation of TOSV,
but encephalitis has also been described (363367). In one
series, all 14 patients had neck stiffness and 3 were encepha-
lopathic, including 1 with repeated seizures (360). Peripheral
white blood cell counts are usually normal, and the CSF shows
a lymphocytic pleocytosis with normal glucose and mildly el-
evated protein levels. The outcome is generally good, with no
deaths or severe sequelae reported. Enterovirus infections are
high on the differential for patients with aseptic meningitis in
the summer months, and a duplex PCR has been developed
to distinguish between these infections (368). TOSV can be
isolated from the serum and CSF by inoculation into suckling
mice or cell lines. Because humans have high viremias, virus
isolation and PCR from serum and CSF is often successful
(369). IgM ELISAs have also been developed (368,370,371).
Treatment and Prevention
There is no established antiviral treatment for TOSV infection
or other CNS Phlebovirus infections, although ribavirin may
be effective in RVF (250). Widespread use of DDT was effec-
tive in controlling sandfly fevers in the past, particularly re-
sidual spraying of internal walls in homes where sandflies rest.
Although sandflies are small enough to penetrate mosquito net-
ting, impregnated bed nets are a deterrent, and the application
of insecticides on the skin is recommended.
Scheld_Ch15.indd 231
Chapter 15: Arthropod-Borne Viral Encephalitides 231
Rift Valley Fever Virus
RVF virus was first isolated in 1930, during an investigation of
a large epizootic of disease causing abortion and death in sheep.
Originally found in the Rift Valley of Kenya, the virus is dis-
tributed across sub-Saharan Africa, Egypt, Saudi Arabia, and
Yemen (332,372,373). Disease in animals follows the explosive
increases in mosquito populations caused by heavy rains or new
irrigation projects. Humans become infected by mosquitoes or
contact with animal blood or other products. In humans, the
virus causes epidemics of febrile illness with hemorrhagic mani-
festations in about 1% to 2% (2). About 0.5% to 1.0% of pa-
tients develop retinal vasculitis or encephalitis as a late sequelae
1 to 4 weeks after the acute illness (374). Encephalitis mani-
fests as headache, meningismus, and clouding of consciousness,
sometimes with a recrudescence of fever. In fatal cases, focal
necrosis is seen pathologically, which may be due to viral cell
damage. However, the late presentation after viral clearance and
development of antibodies suggest an immunopathologic pro-
cess may be responsible, possibly due to a delayed hypersensi-
tivity reaction (375). Because this virus is directly transmissible
to humans from the body fluids of livestock, abattoir workers
in affected areas should wear protective clothing. There are no
human vaccines against phleboviruses, but vaccines are available
to protect livestock against RVFV and are the main countermea-
sure against eliminating the source of human infection (376).
COLTIVIRUSES
The genera of the family Reoviridae include the Rotavirus genus
and three genera of arboviruses, Orbivirus, Coltivirus, and the re-
cently designated Seadornavirus. The orbiviruses include animal
pathogens such as bluetongue virus and African horse sickness
virus, but no important human pathogens, and so are not consid-
ered further here. The most important coltivirus is CTFV, which
because of similarities in its geographical distribution, vector and
symptoms were not distinguished from the rickettsial disease
Rocky Mountain spotted fever until the 1930s. Its viral etiology
was demonstrated in the 1940s. Eyach virus is a coltivirus iso-
lated from ticks in central Europe, where patients with CNS dis-
ease have been shown to have antibodies against the virus (377).
Banna virus was isolated from the CSF and blood of patients
with encephalitis in China (378,379). It had been classified as a
coltivirus, but following genome sequencing, it has been placed
with Kadipiro virus in the new genus, Seadornavirus (380,381).
Infectious Agent
Like other Reoviridae, coltiviruses are nonenveloped particles
consisting of a double-capsid structure with icosahedral symmetry
containing double-stranded RNA. The 29-kb genomes are divided
into 12 segments of double-stranded RNA (ranging from 0.3 to 3.7
thousand base pairs), which can undergo resortment (382). Based
on comparisons with other Reoviridae, each segment is thought to
encode the mRNA for a single gene product, which in the case of
VP1 is thought to be the RNA-dependent RNA polymerase.
Epidemiology
CTFV is transmitted between ground squirrels, chipmunks, and
other small mammals by Dermacentor andersoni (wood ticks).
The geographical distribution of cases is limited by the distri-
bution of the vectors and host to mountainous areas between
4,000 and 10,000 feet in the western United States and Canada
2/21/14 5:38 PM
 232 Part II: Viral Infections and Related Disorders
(383). CTFV or a closely related virus may be transmitted by
Dermacentor variabilis in parts of California. Larval, nymphal,
or adult ticks may be infected. The virus persists transtadially
between the maturing tick forms but is not passed transovari-
ally (Fig. 15.2). Ticks are infected for life, which may be up to
3 years. The vertebrate hosts usually have subclinical viremias
that can last for months or even longer in hibernating animals,
possibly providing one means for viral overwintering. Whereas
immature ticks feed on small mammals, adults feed on larger
mammals, deer, elk, and occasionally humans. Human cases of
CTF occur in the summer months, when the number of ticks
and vertebrate hosts is increased, as is human exposure to the
ticks, because of recreational and occupational activities.
Pathogenesis and Clinical Features
CTFV infects hematopoietic cells, resulting in persisting in-
fection of erythrocytes, leukopenia, and thrombocytopenia
(384). The relative contributions of viral cytopathology and
the host immune response in the pancytopenia is not certain
(385). Because CTF is rarely fatal, there are few reports of the
pathology, but hyaline membrane disease, endothelial swell-
ing, and focal necrosis of the brain, liver, and spleen have been
reported, similar to the changes seen in animal models (386).
IFN- levels in the plasma are high during the first 10 days
of infection. After this neutralizing antibody, titers raise, but
despite this, viremias persist in nearly half the patients (383).
Transplacental transmission has been recorded, but most
patients present with a history of exposure to ticks in an area
where the virus circulates, and many will recall a tick attach-
ment. Following 3 to 5 days of incubation (range, 1 to 14
days), there is fever, headache, malaise, and gastrointestinal
disturbances. After 2 to 3 days, the fever may subside for a
couple of days, before recurring, illustrating the biphasic or
saddleback fever pattern (50% of patients with CTF). There
is sometimes mild conjunctivitis, lymphadenopathy, and a faint
maculopapular rash, or petechiae (383). Neurologic features
include neck stiffness, photophobia, and mildly reduced con-
sciousness. Rarely, there is encephalitis hepatitis, perimyocar-
ditis, and pneumonitis. Intravascular coagulopathy has been
reported; only three deaths, all in children, are noted (387).
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2/21/14 5:38 PM
 CHAPTER 16 MENINGITIS AND ENCEPHALITIS
CAUSED BY MUMPS VIRUS
JOHN W. GNANN, JR.
Mumps is an acute systemic human infection caused by a
paramyxovirus. Mumps virus is highly transmissible and, in
unimmunized populations, causes epidemics of mumps among
school-aged children. Although salivary gland enlargement,
especially parotitis, is the most readily recognized clinical
manifestation of mumps, the infection involves many other
organs, including the central nervous system (CNS). In the
past, nonsuppurative parotitis was considered the sine qua
non of mumps, and involvement of any other organ system
was viewed as a complication. However, studies conducted
over the last 60 years have made it clear that CNS involve-
ment during mumps occurs with such high frequency that it
should be considered a part of the natural history of the infec-
tion and not as an aberrant manifestation or complication.
Indeed, some virologists have classified mumps virus as pri-
marily neurotropic.
The spectrum of CNS diseases associated with mumps
ranges from mild aseptic meningitis, which is very common, to
fulminant and potentially fatal encephalitis, which is very rare.
The literature describing CNS involvement with mumps can be
difficult to assess critically because some authors have grouped
all cases of mumps neurologic disease under the label mumps
meningoencephalitis. Although this term is convenient, its
use obscures the fact that the clinical course and prognosis
of mumps aseptic meningitis differs markedly from that of
mumps encephalitis, although there is considerable overlap
between the two syndromes. It is important for the clinician to
establish whether an individual patient with mumps has clear
evidence of encephalitis because that diagnosis has important
implications for management and prognosis.
EPIDEMIOLOGY
In unvaccinated urban populations, mumps (or epidemic par-
otitis) is a disease of school-aged children with a worldwide
distribution. Mumps infrequently occurs in infants younger
than 1 year of age, presumably because of transplacentally ac-
quired antibody. Most mumps cases occur in children between
4 and 7 years of age (1). By age 15 years, over 90% of children
have antibodies against mumps virus.
Prior to the release of the live attenuated mumps vaccine in
the United States in 1967, mumps was an endemic disease with
a seasonal peak of activity occurring between January and May
(2). The largest number of cases reported in the United States
occurred in 1941, when the incidence of mumps was 250 cases
per 100,000 population (3). In 1968, when the live attenu-
ated vaccine was first being put to clinical use, the incidence of
mumps was 76 cases per 100,000 population. In 1985, a total
of only 2,982 cases of mumps were reported, an incidence of
1.1 cases per 100,000 population, representing a 98% decline
from the 185,691 cases reported in 1967 (4). Sporadic out-
breaks of mumps in secondary schools occurring in the United
States were attributed to primary vaccine failure (5). Between
1988 and 1993, 36% of all mumps cases in the United States
were in patients older than 15 years of age (6). In 1989,
Scheld_Ch16.indd 239
the Centers for Disease Control and Preventions Advisory
Committee on Immunization Practices recommended that all
children receive a second dose of the measles-mumps-rubella
(MMR) vaccine at the time of school entry, which reduced the
rate of primary vaccine failure (4). The incidence of mumps in
the United States declined steadily after 1987; only 387 cases
were reported in 1999 (7). By testing sera from the 1999 to
2004 U.S. National Health and Nutrition Examination Survey
(NHANES), the overall age-adjusted seroprevalence of immu-
noglobulin G (IgG) to mumps virus was shown to be 90% (8).
However, a series of outbreaks in the United States and
Canada in 2005 to 2006 reemphasized the potential for
mumps virus to cause localized epidemics even in highly vac-
cinated populations (9,10). In 2006, a total of 6,584 cases of
mumps were reported, with a national incidence of 2.2 cases
per 100,000 population (9). The U.S. outbreak was centered
in the Midwest and peaked in April 2006; 34% of the cases
occurred in Iowa. The highest age-specific age rate was in per-
sons aged 18 to 24 years (median age 22 years), many of whom
were college students (11). Among the Iowa cases, 7% were
unvaccinated; 14% had received one dose of MMR; 49% had
received two or more doses of MMR; and 30% had unknown
vaccine status. Although some cases can be attributed to fail-
ure to vaccinate, most represented primary (insufficient initial
immune response) or secondary (waning immune response)
vaccine failure (12). These findings suggest the need for a
mumps vaccine with a longer duration of protection or modifi-
cation in vaccination policy, perhaps focusing on young adults
(9,13). In selected outbreaks, a third dose of mumps vaccine
has been administered for outbreak control, which appears to
be a safe and effective measure (14,15).
The importance of immunization of adolescents and young
adults was emphasized by a large outbreak (over 56,000 re-
ported cases) of mumps in the United Kingdom in 2004 to
2005 (16,17). Many of the cases occurred in university students
who were too old to have been vaccinated in childhood but too
young to have been exposed to epidemic natural infection (18).
Conversely, a large mumps outbreak (3,500 cases) occurred
in 2009 to 2010 in New York and New Jersey, causing disease
primarily among adolescent boys attending Orthodox Jewish
schools (19). Mumps transmission in this highly vaccinated
population was apparently facilitated by the close face-to-face
interactions among the students. The propensity for mumps to
spread among vaccinated adolescents in schools and commu-
nal living environments raises the question of whether a revised
vaccination schedule should be considered (2022).
In unimmunized populations, mumps is one of the most
common causes of aseptic meningitis and encephalitis (23). In a
survey conducted in Minnesota from 1950 to 1981, mumps
was identified as the cause of encephalitis in 6 of 189 cases and
the cause of aseptic meningitis in 7 of 283 cases (24). In that
series, mumps was the second most common cause of both
encephalitis and aseptic meningitis (behind California virus
and enteroviruses, respectively). Meyer et al. (25) reviewed
713 cases of encephalitis and aseptic meningitis treated at U.S.
military hospitals between 1953 and 1958. In those patients in
239
2/21/14 5:38 PM
 240 Part II: Viral Infections and Related Disorders
whom a specific etiology was established, mumps was identi-
fied in 91 cases, poliomyelitis in 156, coxsackievirus B in 80,
lymphocytic choriomeningitis virus in 58, and echovirus in 53.
In an analysis of 191 cases of acute encephalitis occurring in
adults in Finland between 1967 and 1978, mumps virus was
found to be the second most common etiologic agent (following
herpes simplex virus), accounting for 6.8% of the cases (26).
The frequency with which CNS manifestations occur during
acute mumps has varied tremendously (from 1% to 70%)
among published series (27,28). A more realistic estimate of
the frequency of symptomatic CNS involvement during mumps
appears to be 10% to 30%. Potential causes for this variability
in reported incidence include the interest and skill of the ob-
server, the population studied (e.g., schoolchildren vs. military
recruits, outpatients vs. hospitalized patients), the case defini-
tions used, and the frequency of use of lumbar puncture for
diagnosis. Symptomatic encephalitis is observed much less fre-
quently than aseptic meningitis, probably occurring in fewer
than 0.1% of cases of acute mumps (2931). Cerebrospinal
fluid (CSF) pleocytosis occurs in 40% to 60% of patients with
acute mumps, although only 10% to 30% of patients with
mumps have clinical evidence of meningeal irritation. That is,
about half of the patients with mumps with CSF pleocytosis
do not have CNS symptoms (28,32). Bang and Bang (27) per-
formed lumbar punctures on 371 patients with mumps paroti-
tis and found that 235 (63%) had elevated CSF white blood
cell counts; of these 235 patients, 129 showed no clinical evi-
dence of meningitis or encephalitis. Similarly, Finkelstein (33)
found elevated CSF white blood cell counts in 16 of 40 patients
(40%) with mumps parotitis; 6 of these had no clinical evi-
dence of CNS involvement. Clearly, mumps CNS disease can
also occur in patients without evidence of parotitis; indeed,
40% to 50% of patients with mumps meningitis have no evi-
dence of salivary gland enlargement (34,35). If we accept that
CSF pleocytosis occurring during acute mumps is indicative of
CNS infection, then we must conclude that CNS involvement
during mumps is quite common and frequently asymptomatic.
Although male and female patients have the same risk for
mumps parotitis, there is a distinct male predominance (70%
to 80%) with respect to development of CNS disease among
children with mumps. In virtually every published series, the
ratio of boys to girls is between 3:1 and 4:1 (28,3032,3639).
This striking difference in the incidence of mumps CNS disease
between the sexes has not been satisfactorily explained. Among
young adults with mumps and CNS involvement, the ratio of
men to women is closer to 1:1 (39). The peak incidence of CNS
involvement in mumps occurs at about age 7 years in both
sexes (31,39,40). Of all cases, 60% to 70% occur in children
between 5 and 9 years of age (28,30,37,38,41). Several authors
have reported seasonal differences in the frequency of mumps
meningoencephalitis, with and without parotitis (34,35,4044).
INFECTIOUS AGENT
Mumps virus is classified as a member of the family
Paramyxoviridae and the genus Rubulavirus (45). In gen-
eral, members of the family Paramyxoviridae possess nonseg-
mented RNA genomes, bind to neuraminic acid receptors on
host cells, replicate in the cytoplasm, are inactivated by ether,
and cause respiratory infections in humans (46). Serologic
testing with hemagglutination inhibition (HI) or neutraliza-
tion assays has identified only one serotype of mumps virus,
although minor antigenic differences among mumps virus
isolates can be detected using panels of glycoprotein-specific
monoclonal antibodies (47). Infection can be prevented by
vaccination with a single strain of mumps virus. Mumps virus
Scheld_Ch16.indd 240
shares some serologic cross reactivity with other paramyxovi-
ruses, especially parainfluenza viruses, which can complicate
interpretation of serodiagnostic assays (48).
Mumps virions are pleomorphic, irregularly spherical, en-
veloped particles with an average diameter of about 200 nm.
Glycoprotein spikes project from the outer surface of the lipid
envelope, which encloses a helical nucleocapsid composed of
RNA and nucleoproteins. The mumps virus genome consists
of a linear molecule of single-stranded, negative-sense RNA
approximately 15.3 kilobases in size that encodes seven major
proteins and several minor proteins. The three proteins con-
tained in the ribonucleoprotein complex are the nucleocapsid
protein (NP), which is the major structural protein of mumps
virus, plus the phosphoprotein (P) and large (L) protein, which
are thought to function as the RNA-dependent RNA poly-
merase (49). Full-length transcription of the V/P gene yields
the V protein (also known as NS1), whereas RNA editing dur-
ing the transcription of V/P produces the phosphoprotein as
well as the nonstructural I protein (also known as NS2) (50).
The V protein blocks host antiviral responses by inhibiting the
interferon signal transduction pathway and interleukin (IL)-6
expression and may serve as a virulence factor (5153). The
function of the I protein is not known. The envelope contains
the matrix (M) protein and the two surface glycoproteins that
mediate hemagglutinin-neuraminidase (HN) and fusion (F)
activities. The HN glycoprotein is responsible for attachment
of mumps virus to the receptors on the host cell, and the F
glycoprotein induces the fusion of lipid membranes neces-
sary for penetration of the virus nucleocapsid into the cell. In
traditional complement fixation (CF) assays, HN and NP are
known as V antigen and S antigen, respectively.
The function of the membrane-associated protein encoded
by the small hydrophobic (SH) gene has not been fully defined,
although it does not appear to be essential for viral replication
(54). Characterization of the genetically divergent SH region
is a useful tool for distinguishing wild type and vaccine strains
of mumps virus (55). Furthermore, studies employing reverse
transcriptase polymerase chain reaction (RT-PCR) methodol-
ogy have demonstrated 13 distinct viral genotypes (designated
A to M) based on sequence of the SH gene (5658). These
molecular tools will allow more precise studies of mumps
transmission and population genetics (5962). In the Western
hemisphere, genotypes A, C, D, E, and H are more common,
whereas genotypes B, F, and I predominate in Asia. Although
there is only a single mumps serotype, some investigators have
found that cross-neutralization between mumps virus geno-
types is reduced (63,64). Some studies have suggested that
infection with certain genotypes (e.g., C, D, H, or J) may result
in enhanced neuropathogenicity (60,65), but this observation
was not confirmed by other investigators (58).
Humans are the only known natural hosts for mumps virus,
although infection can be experimentally induced in a variety
of mammalian species. In vitro, mumps virus can be cultured
in many mammalian cell lines, including primary Rhesus
monkey kidney, human embryonic kidney, BSC-1, Vero, and
HeLa cells, as well as in embryonated hens eggs (66). In tis-
sue culture, the cytopathic effects caused by mumps virus
appear within 3 to 6 days and are highly variable. They in-
clude development of rounded cells, formation of eosinophilic
intracytoplasmic inclusions, and fusion of cells to form giant
multinucleated syncytia. Guinea pig or chick erythrocytes will
adhere to mumps virusinfected cells, a phenomenon medi-
ated by hemagglutinins present on the surface of infected cells.
Traditionally, verification of the isolate as mumps virus has been
accomplished by a hemadsorption inhibition assay, in which
mumps virusspecific antiserum is used to block the adherence
of erythrocytes to mumps-infected cells. Most laboratories
2/21/14 5:38 PM
 Chapter 16: Meningitis and Encephalitis Caused by Mumps Virus
now use direct or indirect immunofluorescence methods to
identify mumps virus in tissue culture (66). Molecular methods
based on PCR have also been described (67).
PATHOGENESIS AND
PATHOPHYSIOLOGY
Mumps is highly contagious, although some studies have sug-
gested that it is less contagious than varicella or measles (68).
This clinical observation may be skewed by the fact that up to
30% of all mumps infections are subclinical and asymptom-
atic (69). Over 90% of adults who give negative histories for
mumps are, in fact, seropositive when tested for mumps anti-
bodies, indicating prior subclinical infection (70).
Mumps can be experimentally transmitted to humans by in-
oculation of virus onto the nasal or buccal mucosa, suggesting
that most natural infections result from droplet spread of upper
respiratory secretions from infected to susceptible individuals.
Virus can be isolated from saliva for 5 to 7 days before and 5
to 8 days after the onset of clinical symptoms, meaning that an
infected individual is potentially able to transmit mumps for a
period of up to 2 weeks (71,72). The average incubation period
for mumps is about 18 days (range 14 to 28 days) (73,74).
During this interval, primary viral replication is thought to take
place in epithelial cells of the upper respiratory tract, followed
by spread of virus to regional lymph nodes and then viremic
dissemination to glandular and neural tissue (75,76).
Mumps virus is delivered to the CNS either via free plasma
viremia or by infected host mononuclear cells (77,78). Virus is
thought to spread across the endothelium of the choroid plexus
and to infect choroidal epithelial cells. Replication of mumps
virus then takes place in the choroidal epithelium, and progeny
virus is shed into the CSF. In support of this model is the observa-
tion that mumps virus can be easily recovered from CSF during
the early phases of mumps meningitis in humans. Additionally,
choroidal and ependymal epithelial cells containing mumps an-
tigens can be recovered from the CSF of patients with mumps
meningoencephalitis (79). Replication of mumps virus in the
choroid plexus and ependyma (the tissue that lines the cerebral
ventricles and covers the choroid plexus) has been demonstrated
in rodent (77) and primate (80) models of mumps CNS infec-
tion. When mumps encephalitis develops, it is presumed that
virus replicating in ependymal cells spreads by direct extension
into neurons within the brain parenchyma, as has been observed
in the hamster model of mumps encephalitis (81).
PATHOLOGY OF MUMPS
CENTRAL NERVOUS SYSTEM
INFECTION
Autopsy reports of patients who have died with acute encepha-
litis caused by mumps virus have been reviewed by Donohue
(82) and Schwarz et al. (83). Many of these cases occurred
prior to the availability of modern virologic or serologic meth-
ods for confirmation of the diagnosis, and some were likely
caused by pathogens other than mumps virus. Among those
cases in which mumps virus was the probable cause of the fatal
encephalitis, neuropathological findings were quite variable
(28,8284). The most commonly recorded features were dif-
fuse edema of the brain, limited mononuclear cell infiltration of
the meninges, perivascular infiltration with mononuclear cells,
glial cell proliferation, focal areas of neuronal cell destruc-
tion, and localized demyelinization. These histologic changes
were seen in the white matter of the cerebral hemispheres and
Scheld_Ch16.indd 241
241
cerebellum and in the white and gray matter of the brainstem
and spinal cord. Because of the pattern of perivascular demy-
elinization, Donohue (82) and Schwarz et al. (83) suggested
that these findings were more suggestive of a postinfectious or
parainfectious encephalopathy rather than of tissue destruction
caused directly by mumps virus. Conversely, other authors have
interpreted the findings of cellular destruction as consistent
with primary mumps virus cytopathic effect (85). In most cases
of fatal mumps encephalitis that have been carefully studied,
there has been histologic evidence of both cellular destruction
(suggestive of direct virus effect) and demyelinization (sugges-
tive of an autoimmune process). The pathogenesis of mumps
encephalitis remains incompletely understood.
Investigations using the hamster model have made major con-
tributions to our understanding of the pathogenesis of mumps
CNS disease. CNS mumps infections have been produced exper-
imentally by the intracerebral or intraperitoneal inoculation of
newborn hamsters with a neuroadapted strain of mumps virus
(77,86). About 9 to 12 days after intracerebral inoculation with
mumps virus, suckling hamsters developed wasting, ruffled hair,
and arched backs; they usually died within 24 hours. Maximum
titers of mumps virus were detected in hamster brains at 5 days,
and the virus titer declined as neutralizing antibodies appeared.
The clinical symptoms occurred 3 to 5 days after the decline
in virus titers and the concurrent development of neutralizing
antibody (86). During the first week after virus inoculation, the
neuropathologic appearance of the brain was characterized by
intense perivascular mononuclear cell infiltrates. During the sec-
ond week, microglial cell proliferation and small areas of necro-
sis were observed. Notably, no foci of demyelinization (as has
been observed in human brains) were apparent.
Immunofluorescence studies of suckling hamster brains fol-
lowing intracerebral inoculation with mumps virus showed that
mumps virus antigens were present in endothelial cells of the cho-
roid plexus, in ependymal cells, and in neurons of the brainstem,
hippocampus, and cerebral cortex. Most of the infected neurons
were morphologically normal, and there was little correlation be-
tween the major sites of neuronal infection and the observed sites
of perivascular inflammation (86). The histologic appearance
of mumps encephalitis in suckling hamsters is more consistent
with direct virus-induced pathology than with immunologically
mediated pathologic changes. Studies using the suckling hamster
model have also demonstrated an association of mumps CNS
infection with the development of stenosis of the aqueduct of
Sylvius and with granular ependymitis (87). These findings sug-
gest a possible (but unproven) linkage between mumps CNS in-
fections and aqueductal stenosis in children (88,89).
The ability of mumps virus to establish chronic infections
in tissue culture systems is well known (90,91). In the ham-
ster model, cell-associated mumps virus can be recovered
from brain explant cultures for up to 50 days after infection,
well after the appearance of specific humoral immunity (77).
In humans with mumps meningoencephalitis, the persistence
of leukocytes and oligoclonal mumps-specific immunoglobu-
lins in the CSF for months after the acute infection suggests
the possibility of ongoing antigenic stimulation from chronic
mumps CNS infection (92,93). Sufficient data do not yet exist
to confirm or refute a potential for mumps virus as a cause of
chronic CNS infection in humans, but chronic infection, if it
occurs at all, is uncommon (92,94).
IMMUNE RESPONSES
Specific humoral and cell-mediated immune responses develop
during the course of acute mumps infection, but the relative
contributions of antibody and cellular immunity to viral
2/21/14 5:38 PM
 242 Part II: Viral Infections and Related Disorders

clearance have not been precisely determined. Interestingly,

mumps does not often cause unusually severe or prolonged CLINICAL COURSE AND
infections in immunocompromised patients, although severe NATURAL HISTORY
nephritis due to mumps virus has been reported in renal trans-
plant recipients (95). Mumps usually begins with a short prodromal phase charac-
Within 10 days of infection, mumps-specific immunoglobu- terized by low-grade fever, malaise, headache, and anorexia.
lin M (IgM) appears in serum and immunoglobulin A (IgA) Young children may initially complain of ear pain. The patient
can be detected in saliva (96,97). Serum IgM titers begin to then develops the characteristic salivary gland enlargement
wane shortly after the acute illness and are usually undetect- and tenderness (113). The parotid glands are most commonly
able after 6 months (96,98). A mumps-specific IgG response is involved, although other salivary glands (e.g., submandibu-
detectable during the first week of the acute infection, peaks lar and sublingual) may be enlarged in about 10% of cases.
about 3 to 4 weeks after the onset of the infection, and persists Parotitis may initially be unilateral, with swelling of the con-
for decades (99). Using the CF assay, a fourfold rise in mumps- tralateral parotid gland occurring 2 to 3 days later; bilateral
specific IgG can usually be demonstrated within 10 to 14 days parotitis eventually develops in over 80% of patients with
after the onset of the disease (100). Lifelong immunity follows symptomatic salivary gland involvement. Painful parotid gland
natural infection. Symptomatic mumps virus reinfections have enlargement progresses over the course of 2 to 3 days, lifting
been reported, but most patients who report more than one the earlobe outward and obscuring the angle of the mandible
episode of mumps probably had parotitis caused by infection (Fig. 16.1). The orifice of Stensen duct is often red and edema-
with a different pathogen (101). tous. Lymphatic obstruction resulting from bilateral glandular
Mumps-specific immunoglobulins are also detectable enlargement can occasionally result in presternal edema (114).
in CSF of patients with mumps meningoencephalitis (102). Fever and parotid gland swelling peak on about the third
Using a sensitive enzyme-linked immunoadsorbent assay day of the illness, followed by defervescence and resolution
(ELISA) method, mumps-specific IgG was detected in almost of parotid pain and swelling within about 7 days. Long-term
all CSF specimens from patients with mumps meningitis, and sequelae of parotitis are uncommon. Children with mumps
mumps virus IgM was detected in about 50% of patients
(103). By measuring the levels of immunoglobulin in serum
and CSF and then comparing this ratio with that of an index
antibody (such as measles antibody), intrathecal synthesis of
mumps-specific immunoglobulin was shown to occur during
mumps CNS infection. There was no apparent correlation
between the severity of clinical disease and the presence or
absence of mumps IgM in the CSF (104). Furthermore, no
correlation between the CSF leukocyte count and the CSF
mumps antibody titer was demonstrated (104). Infection
(or vaccination) with mumps virus also elicits a cell-mediated
immune response (105). Peripheral blood lymphocytes that
proliferate when stimulated with mumps S and V antigens can
be detected by an in vitro blastogenesis assay following natu-
ral infection or immunization (106). Lymphocytes recovered
from the CSF of patients with mumps meningitis also prolif-
erate when stimulated with mumps antigens (107). Human
leukocyte antigen (HLA)restricted cytotoxic T lymphocytes
(CTLs) are detectable in peripheral blood following mumps
infection or immunization and in CSF of patients with mumps
CNS infection (108). Kreth et al. (109) demonstrated that
T lymphocytes from CSF and from blood from 10 children
with mumps meningitis were cytotoxic to autologous mumps
virusinfected target cells. Lymphocyte-mediated toxicity was
present during the acute phase of mumps meningitis, declined
over 2 to 3 weeks after the onset of symptoms, and was no lon-
ger apparent after 50 days. Fleischer and Kreth (110) cloned
mononuclear cells directly from the CSF of a patient with
mumps meningitis and demonstrated that 90% of the cells
were T lymphocytes and that 60% were CD8 suppressor/
cytotoxic T cells. A high percentage of the T-cell clones
showed specificity for the autologous mumps virusinfected
target cells. In patients with self-limited mumps meningitis,
CSF interferon disappeared within a week, whereas interferon
levels remained elevated in the CSF from those patients who
had persistent CSF pleocytosis (111). These findings suggest
that the recruitment of CTLs into the CNS in mumps menin-
gitis is highly antigen specific and that mumps-specific CTLs
could play a role in the immunopathologic changes observed
in human brains after fatal mumps encephalitis. Recent stud- FIGURE 16.1 Child with mumps demonstrating neck swelling due
ies have also demonstrated increased levels of IL-8, IL-10, to salivary gland enlargement. (Provided by the Centes for Disease
IL-12, IL-13, and interferon (IFN)-gamma in CSF from chil- Control and Prevention [CDC] Public Health Image Library, Patricia
dren with mumps meningitis (112). Smith and Barbara Rice, image #1861.)

Scheld_Ch16.indd 242 2/21/14 5:38 PM

 Chapter 16: Meningitis and Encephalitis Caused by Mumps Virus
are usually isolated for about 5 days after the appearance of
parotitis, although this practice is of dubious benefit to class-
mates, because the virus is excreted for several days prior to
the onset of clinical symptoms (115).
Epididymoorchitis is rare in boys with mumps, but it
occurs in 25% of postpubertal men with mumps infection
(19,116,117). Orchitis is caused by replication of mumps
virus in seminiferous tubules, with resulting lymphocytic
infiltration and edema (118120). Orchitis is most often uni-
lateral, but bilateral involvement occurs in 10% to 30% of
cases (121). Orchitis typically develops within 1 week after
the onset of parotitis, although orchitis can develop prior to
or even in the absence of parotitis. Mumps orchitis is char-
acterized by marked testicular swelling and severe pain,
accompanied by fever, nausea, and headache (121123). The
pain and swelling resolve within 5 to 7 days, although residual
testicular tenderness can persist for weeks. Testicular atrophy
may follow orchitis in about 35% to 50% of cases, but steril-
ity is an uncommon complication, even among patients with
bilateral orchitis. Orchitis occurring in vaccinated males who
develop breakthrough mumps tends to be less clinically
severe (124).
Mumps can cause inflammation of other glandular tissues,
including pancreatitis (125) and thyroiditis (126). Investigators
in the 1970s proposed an epidemiologic association between
mumps and juvenile diabetes mellitus (127); however, the
dramatic decline in the incidence of mumps has not been
reflected by a similar decline in the occurrence of juvenile-
onset diabetes. Oophoritis and mastitis have been reported
in postpubertal women with mumps (113,128). Renal func-
tion abnormalities are common in mumps and virus can be
readily isolated from urine, but significant or permanent renal
damage is rare (129,130). Other infrequent manifestations of
mumps include arthritis (131,132), myocarditis (133,134),
and thrombocytopenia (135).
Maternal mumps infection during the first trimester of
pregnancy results in an increased frequency of spontaneous
abortions (136). However, no clear association between con-
genital malformations and maternal mumps has been demon-
strated (137). An etiologic relationship between gestational
mumps and endocardial fibroelastosis has been postulated
(138). Mumps occurring during the perinatal period is usually
benign, perhaps due the partial protective effect of transpla-
cental antibody (139).
TA B L E 1 6 . 1
PRESENTING SIGNS AND SYMPTOMS OF PATIENTS WITH MUMPS INFECTION OF THE CENTRAL NERVOUS SYSTEM
Kravis et al. (36) Murray et al. (37)
(N 74) (N 50)
Fever NR 88%
Vomiting 68% 76%
Headache 47% 72%
Parotitisa 53% 54%
Neck stiffness 43% 76%
Lethargy 28% 34%
Abdominal pain 15% 16%
Seizures 14% NR
NR, not reported.
a
Or swelling of other glands.
Scheld_Ch16.indd 243
243
Central Nervous System Manifestation
of Mumps
CNS infection is the most common extrasalivary manifesta-
tion of mumps and may precede, accompany, or follow the
development of parotitis (35). There is no association between
the severity of the parotitis and the likelihood or severity of
meningitis (27). Most frequently, CNS symptoms follow the
onset of parotitis by about 5 days (140). In a study of 41 cases
of mumps encephalitis reported by Koskiniemi et al. (31),
parotitis appeared 3 to 14 days prior to CNS involvement in
15 patients, was coincident with encephalitis in 9 patients,
occurred 1 to 4 days after the onset of CNS symptoms in
2 patients, and was absent in 15 patients. In another series
of 24 patients with mumps parotitis and meningoencephalitis,
11 patients had parotitis for 6 to 21 days before the onset of
the CNS symptoms, 9 patients had neurologic symptoms pre-
ceding the parotitis by 1 to 8 days, and 4 patients had parotitis
and CNS symptoms that occurred simultaneously (42). Levitt
et al. (30) noted a mean interval of 2.7 days between the onset
of parotitis and the development of CNS symptoms, but the
range was wide, with parotitis developing from 20 days before
to 7 days after CNS disease. These data clearly indicate that
the development of CNS disease in mumps does not depend
on prior development of parotitis. The physician examining a
patient with suspected meningoencephalitis may not exclude
the possibility of mumps simply because the patient does not
have clinically apparent salivary gland involvement.
The common presenting signs and symptoms seen in patients
with mumps CNS infection are summarized in Table 16.1. The
most frequently reported presentation is a triad of fever, vom-
iting, and headache. Salivary gland enlargement is present in
only 50% of patients with mumps CNS disease. The fever is
frequently high (39C to 40C) and lasts for 72 to 96 hours.
The headache and vomiting may also be quite severe and usu-
ally persist for about 48 hours (32,141). Other frequently
noted clinical findings include neck stiffness, lethargy or som-
nolence, and abdominal pain. Most patients with mumps with
CNS involvement have signs of meningitis (e.g., headache
and nuchal rigidity), but no evidence of cortical dysfunction.
Defervescence is usually accompanied by overall clinical recov-
ery, and the total duration of illness in uncomplicated cases is
7 to 10 days (40,41).
McLean et al. (44) Azimi et al. (42) Levitt et al. (30)
(N 30) (N 51) (N 64)
100% 94% 100%
79% 84% 78%
62% 47% 88%
62% 47% 53%
77% 71% 93%
31% 69% NR
23% 14% NR
18% 18% NR
2/21/14 5:38 PM
 244 Part II: Viral Infections and Related Disorders
The presence of seizures, pronounced changes in level of
consciousness, or focal neurologic findings are indicative of
significant encephalitis (30). Koskiniemi et al. (31) reviewed
41 cases of mumps encephalitis occurring in Helsinki, Finland
between 1968 and 1980 and reported high fever (39) in
83%, vomiting in 88%, headaches in 71%, difficulty walking
in 37%, nuchal rigidity in 27%, seizures in 24%, psychiatric
disturbances in 22%, and significantly depressed levels of con-
sciousness in 20% of patients.
Mumps meningitis is a benign disease with essentially no risk
of mortality or long-term morbidity. It is difficult to judge accu-
rately the true incidence of neurologic sequelae following mumps
CNS disease from published reports because of the variability
of the populations studied. Patients who develop permanent se-
quelae following mumps with CNS involvement are presumed
to have had mumps encephalitis. However, the mortality rate for
patients with mumps encephalitis is 1.5% or less, and perma-
nent sequelae are rare. As with many childhood viral infections,
the mortality rate for mumps appears to be substantially higher
among adults than among children. Between 1982 and 1991,
14 mumps-associated deaths were reported in the United States,
and more than half occurred in patients older than 20 years of
age. Even among patients who are profoundly encephalopathic,
the probability for complete recovery is high; sustained seizures
and focal neurologic deficits (both of which are uncommon) may
predict a less favorable outcome (31). In many large series of
patients with mumps CNS infection, no long-term neurologic
sequelae were identified (28,42,44,141). Ataxia, behavioral
changes, and electroencephalographic abnormalities have been
noted in children in the immediate postencephalitis period, but
these usually resolve within a few weeks (42).
A wide variety of other neurologic complications have been
observed following mumps encephalitis. Among the reported
sequelae are behavioral disturbances and personality changes
(31,34,36,142), seizure disorders (40,143), cranial nerve palsies
(especially facial and ocular palsies) (36,144), muscle weakness
including hemiparesis (34,37), cerebellitis and ataxia (31,145),
acute hydrocephalus (146), and chronic headaches (143,147).
Myelitis and polyneuritis have also been reported as sequelae
of mumps (148,149).
Sensorineural hearing loss is an uncommon but well-rec-
ognized complication of mumps that occurs with an estimated
frequency of 0.5 to 5.0/100,000 cases (143,147,150,151). In a
recent survey conducted in Japan, the incidence of hearing loss in
children with mumps was reported to be much higher (7 in 7,400
cases, or approximately 1/1,000 cases) (152). Deafness may be
either transient or permanent and probably results from direct
damage to the cochlea by the mumps virus (154). Rare ocular
complications of mumps include keratitis, iritis, and central reti-
nal vein occlusion (154,155).
DIAGNOSIS AND LABORATORY
FINDINGS
The presentation of a febrile child with parotitis strongly sug-
gests the diagnosis of mumps, particularly if the individual is
known to be susceptible and has been exposed to mumps dur-
ing the preceding 2 to 3 weeks. However, the reduced frequency
of mumps in countries where vaccination is routine may result
in physician inexperience and reduced accuracy of clinical diag-
nosis (156). An atypical clinical presentation (e.g., meningitis or
orchitis without parotitis) will usually require laboratory con-
firmation. Culturing for mumps virus is the definitive diagnostic
test but is frequently not available and has largely been replaced
by polymerase chain reaction (PCR) assays. Testing of paired
acute and convalescent sera should demonstrate a diagnostic
Scheld_Ch16.indd 244
fourfold rise in mumps antibody titer, providing a retrospective
diagnosis. Parotitis can occasionally be caused by other viruses
(e.g., Epstein-Barr, adenovirus, influenza A, parainfluenza,
coxsackievirus, lymphocytic choriomeningitis) or by bacteria
(e.g., Staphylococcus aureus) (157,158). Noninfectious causes
of parotid gland enlargement include Sjgren syndrome, sar-
coidosis, thiazide ingestion, iodine sensitivity, tumor, or salivary
duct obstruction (159,160). Parotid gland enlargement has been
described in patients with AIDS, especially children (161,162).
A careful physical examination should permit parotitis to be
distinguished from lymphadenitis or lymphadenopathy.
When aseptic meningitis occurs in the context of parotitis,
the diagnosis of mumps is usually obvious. The cause of the
meningitis may be obscured, however, if there is no accompa-
nying salivary gland enlargement. Mumps meningoencephalitis
has been confused with nonparalytic poliomyelitis, especially
when it occurs during the summer (34). In general, the CSF leu-
kocyte count is higher in mumps than in poliomyelitis, and the
clinical findings of neck stiffness and fever resolve more quickly
in cases of mumps than in polio (28). Lennette et al. (163) re-
ported 11 cases of encephalitis with mild local muscle weakness
that were all clinically considered to be polio but that were sero-
logically demonstrated to be caused by mumps virus.
Confirmation of CNS involvement in patients with mumps
is based on examination of the CSF. CSF pleocytosis (5
white blood cells/mm3) occurs in 40% to 60% of patients
with mumps parotitis (27,32). The spinal fluid opening pres-
sure is normal in virtually all cases (28). The CSF white blood
cell count is usually in the range of 200 to 600 cells/mm3
(Table 16.2), although cell counts of 1,000 to 2,000 cells/mm3
are not uncommon. In the series of 45 patients with mumps
meningoencephalitis reported by Wilfert (38), the CSF white
blood cell count on the initial lumbar puncture was less than
100 cells/mm3 in 13% of patients, 100 to 500 in 53%, 500 to
1,000 in 29%, and more than 1,000 cells/mm3 in 5% of pa-
tients. The differential count of CSF leukocytes demonstrates
more than 80% lymphocytes in 80% to 90% of patients
(28,30,36,38). A small number of neutrophils are commonly
seen, but neutrophil predominance in the initial CSF sample
occurs in fewer than 5% of patients with mumps CNS infec-
tion (28,38,42). The CSF protein is normal in about one half
the patients and moderately elevated (100 mg/dL) in the re-
mainder (31,38,40,41). The CSF glucose is normal in most
patients, but moderate hypoglycorrhachia (20 to 40 mg/dL)
may be present in 10% to 20% of patients with mumps men-
ingitis (30,31,41,42). In the series reported by Wilfert (38), 14
of 45 patients had CSF glucose of less than 40 mg/dL. Marked
hypoglycorrhachia (10 mg/dL), as can be seen in pyogenic
bacterial meningitis, is very uncommon in mumps meningitis.
An abnormally low CSF glucose is an unusual finding in viral
meningitis and has been reported most often in meningitis
caused by mumps virus, lymphocytic choriomeningitis virus,
or herpes simplex virus.
No clear association has been established between the mag-
nitude of the CSF pleocytosis and the clinical course. The CSF
white blood cell count may be higher in patients with parotitis
and signs of meningitis than in patients with parotitis alone
(27). However, there is no correlation between the level of CSF
pleocytosis and severity of illness (40). CSF findings do not
differ significantly between those patients with meningitis only
and those with mumps encephalitis (30). The magnitude of the
spinal fluid abnormalities is not predictive of the risk for long-
term sequelae following mumps encephalitis (31).
Studies employing sequential lumbar punctures have dem-
onstrated that the CSF white blood cell count frequently
increases during the first 2 to 3 days after the onset of CNS
symptoms and then begins to decline (34,38,164). Even 2 weeks
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 Chapter 16: Meningitis and Encephalitis Caused by Mumps Virus
TA B L E 1 6 . 2
INITIAL CEREBROSPINAL FLUID FINDINGS IN PATIENTS WITH
MUMPS INFECTION OF THE CENTRAL NERVOUS SYSTEM
Russell and
Kilham (226) Donald (164)
(N 22) (N 19)
WBC (per mm3)
Mean 503 416
Range 1002,920 41,260
Differential (% lymphs)
Mean 96 69
Range 89100 2898
Protein (mg/dL)
Mean 56 79
Range 17145 20240
Glucose (mg/dL)
Mean NR 53
Range NR 3469
WBC, white blood cell; NR, not reported.
after the onset of CNS symptoms, when most patients with
mumps meningoencephalitis are asymptomatic or substantially
improved, the CSF white blood cell count may still be in the
range of 100 to 500 cells/mm3. Complete normalization of the
spinal fluid and disappearance of CSF pleocytosis may require
several weeks (28,40,165).
Laboratory confirmation of the clinical diagnosis depends on
isolation of mumps virus, nucleic acid amplification, or dem-
onstration of an appropriate serologic response (166). Mumps
virus can be isolated from saliva from virtually all patients with
acute mumps parotitis (34). Virus can also be recovered from
the urine for up to 2 weeks after the onset of illness. Virus can be
isolated from 30% to 50% of CSF samples collected early during
the course of mumps CNS infection (28,39,44). Wolontis and
Bjrvatn (167) attempted virus isolation from CSF specimens
of 655 patients with mumps and CSF pleocytosis and were suc-
cessful in 33% of cases. Interestingly, no significant association
between the magnitude of the CSF pleocytosis and the probabil-
ity of viral isolation could be demonstrated (34,167).
Widespread availability of molecular diagnostic techniques
such as RT-PCR has replaced viral culture in many settings
and may eventually replace serology (67,168,169). Detection
of mumps virus RNA is diagnostic of infection; sequence
analysis of the amplified SH gene can be used for molecular
epidemiologic studies. Quantitation of viral RNA is readily
accomplished using real-time RT-PCR methods (170172).
RT-PCR appears to be more sensitive than culture or immuno-
histochemical staining for detection of mumps virus in CSF or
oropharyngeal swabs (168,173).
A variety of assays have been developed to measure the
humoral immune responses to mumps virus infection (66).
To greater or lesser degrees, all these serologic tests are lim-
ited by cross reactions between mumps virus and other human
parainfluenza viruses (48). The neutralizing antibody assay
has been considered the gold standard test, but it is techni-
cally demanding. The HI assay is simple and sensitive, but re-
agents may not be commercially available. In the past, the most
widely used serologic test has been the CF assay, which detects
Scheld_Ch16.indd 245
245
Ritter (40)
(N 30)
357
151212
89
30100
49
17140
NR
NR
antibodies directed against the V (HN) and S (nucleocapsid)
antigens. Highly sensitive ELISAs that can be readily auto-
mated have now largely replaced CF as the preferred method
for serodiagnosis (174,175). All these assays are designed to
measure a fourfold increase in mumps-specific IgG between the
acute serum (collected at the time of clinical disease) and the
convalescent serum (collected 2 to 4 weeks later). Alternatively,
demonstration of mumps-specific IgM by ELISA is indicative of
recent infection and is widely used for serodiagnosis of acute
disease (176). An IgM response is detectable during the first
week of illness and persists for at least 6 weeks (177179).
In cases of mumps meningoencephalitis, involvement of the
CNS can be confirmed by demonstration of IgM or elevated
ratios of mumps-specific IgG in CSF (103,180). Presence of IgG
by a standard serologic test provides presumptive laboratory
evidence of prior infection, but there is no universally accepted
surrogate immunologic marker of protection (181). The mumps
skin test is not a reliable indicator of immune status.
Other routine laboratory studies are not generally helpful.
The average peripheral white blood cell count in patients with
mumps is 10,000 to 12,000 cells/mm3, with a differential of
30% to 40% lymphocytes (36,40,42). Approximately 30%
of patients have an elevated serum amylase, reflecting inflam-
mation of the salivary glands or pancreas (42). During acute
mumps encephalitis, the electroencephalogram characteristi-
cally shows moderate to severe slowing without spikes or later-
alizing signs (31,182). Little information is available regarding
the utility of modern imaging methods (computed tomography
or magnetic resonance imaging) in the diagnosis and manage-
ment of mumps CNS infections (183). Scrotal ultrasonography
may help with the evaluation of orchitis (184).
THERAPY
Clinical management of patients with mumps consists of con-
servative measures to provide symptomatic relief and ensure
adequate rest, hydration, and nutritional support. There is
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 246 Part II: Viral Infections and Related Disorders
currently no established role for antiviral chemotherapy or pas-
sive immunotherapy in mumps. Treatment of orchitis includes
bed rest, scrotal support, analgesics, and ice packs. In anec-
dotal reports, men with mumps orchitis were said to improve
and have a lower frequency of testicular atrophy after admin-
istration of interferon--2B, but this therapy has not been
adequately studied in a controlled fashion (121,185188).
Patients with clinical evidence of significant CNS involvement
(altered mental status, seizures, or focal neurologic findings)
require hospitalization for observation. Supportive care for
patients with mumps encephalitis includes hydration, fever
control, antiemetics, and anticonvulsants as required. Lumbar
puncture has been reported to relieve the headache associated
with mumps meningitis in some patients. There have been an-
ecdotal reports of the use of corticosteroids in patients with
mumps encephalitis, but no benefits have been proven (40).
In the series of patients with mumps meningoencephalitis
reported by Ritter (40), the average duration of hospitaliza-
tion was 9.1 days, with a range of 5 to 19 days.
PREVENTION
The cornerstone of mumps prevention is active immuniza-
tion with the live attenuated mumps vaccine (189,190). The
U.S. Public Health Service recommends administration of the
MMR vaccine by subcutaneous injection in two doses, with
the first dose given at 12 to 15 months of age and the second
at ages 4 to 6 years, prior to school entry (191). In 2011 to
2012, median coverage of children with two doses of MMR in
the United States was 94.8% (192). Clinical trials conducted
during vaccine development indicated a vaccine efficacy rate
of 97% (193). However, studies conducted during more re-
cent mumps outbreaks have suggested that the vaccine is 80%
to 90% effective in preventing clinical mumps (26,194198).
Vaccine efficacy may be lower among household contacts
(65 to 75%) (198). In countries where universal vaccination
is practiced, mumps outbreaks due to failure to vaccinate con-
tinue to occur among immigrants and in specific groups where
vaccination is not accepted (199202). Furthermore, large-
scale mumps outbreaks in highly vaccinated populations con-
tinue to occur and can be attributed to primary (inadequate
immune response) or to secondary (waning immunity after
successful immunization) vaccine failure (1922,203,204).
Asymptomatic mumps virus infection has been demonstrated
in vaccinated children (with an attack rate of 7% to 10%)
and may contribute to epidemic spread (205). Because wild
type mumps virus is always genetically distinct from vaccine-
strain virus, concerns have been raised that vaccine-induced
immunity might not provide protection against some wild-
type variants (206). However, in vitro studies have shown that
genetically diverse mumps virus isolates collected during out-
breaks were all effectively neutralized by sera from vaccinated
children, arguing against immune escape (207).
Administration of the live mumps vaccine is contraindi-
cated in pregnant women (208). Vaccination is also not rec-
ommended in persons who have received immunoglobulin
therapy within the preceding 3 months (which might interfere
with the immune response to the vaccine) or in persons with
severe systemic immunosuppression caused by disease or med-
ical therapy. Mumps immunization (using MMR) is recom-
mended for children infected with human immunodeficiency
virus (HIV) who do not have evidence of severe immunosup-
pression (defined as CD4 count less than 200 lymphocytes/
mm3 or CD4 less than 15% (209). Since mumps vaccine is
produced in cell cultures of chick embryos and may contain
trace amounts of egg protein and neomycin, immunization is
Scheld_Ch16.indd 246
not recommended for persons with a history of anaphylac-
tic reactions to those substances. Desensitization protocols to
permit safe administration of the vaccine to egg-allergic chil-
dren have been described (210).
Questions regarding prevention often arise when an indi-
vidual with no history of mumps (typically a male adult) is
exposed to a patient with active mumps. The immune status of
the exposed individual can be determined by ELISA, although
this may involve some delay (98). Mumps vaccine can be
safely administered to an individual of unknown immune sta-
tus (211). However, vaccine given to a susceptible individual
after exposure to mumps may not provide protection. The vast
majority of adults born in the United States before 1957 have
been naturally infected and are therefore immune, although
susceptibility rates among younger adults are higher (212).
Widespread use of the mumps vaccine has had a major im-
pact on the incidence of mumps and mumps meningoenceph-
alitis (190). Through the mid-1960s, mumps was a leading
cause of viral encephalitis (213). By the mid-1980s, however,
mumps had been reduced to the seventh most common cause
of viral encephalitis in the United States, accounting for only
0.5% of cases of viral encephalitis. This trend was documented
in Minnesota, where mumps was the second most common
cause of encephalitis between 1950 and 1972, but where no
cases of mumps CNS infection were noted in 1972 to 1981
(24). Similarly, mumps and measles disappeared as leading
causes of encephalitis in children in Finland after institution of
a nationwide MMR vaccination program in 1982 (214). Not
surprisingly, the resurgence in mumps over the last decade has
been accompanied by increased numbers of cases of mumps-
associated meningitis and encephalitis.
The Jeryl Lynn strain of attenuated mumps virus used in
the United States since 1967 is a very well-tolerated vaccine,
although rare instances of fever, parotitis, orchitis, or asep-
tic meningitis following immunization have been reported
(215). Other attenuated mumps viruses used for vaccina-
tion in various countries include RIT 4385, Urambe Am9,
Rubini, Leningrad-3, Leningrad-Zagreb, Hoshino, and Torii
strains (216). Beginning in 1988, an increased frequency of
vaccine-related mumps meningitis cases (rates as high as 1 to
3/1,000 vaccinations) was recognized in Japan (217), Canada
(218), Brazil (219), and the United Kingdom (220). These
cases followed administration of an MMR vaccine containing
the Urabe Am9 strain of mumps virus. In several instances,
mumps virus was recovered from the CSF (221). A similar
situation was reported from Yugoslavia following adminis-
tration of the Leningrad-3 mumps vaccine (222). The clini-
cal presentation and CSF findings of the vaccine-related cases
are similar to those of naturally occurring mumps meningitis,
with onset of symptoms about 3 weeks after vaccination. In
general, the patients with vaccine-related meningitis were not
seriously ill, and long-term sequelae have not been noted. This
adverse effect of vaccination was presumed to result from in-
adequate attenuation of the vaccine virus. However, nucleo-
tide sequencing of the mumps virus HN gene from the Urabe
vaccine showed that the vaccine was actually a mixture of wild
type and variant mumps viruses with identifiable genetic dif-
ferences, which appear to confer differences in neurovirulence
(223,224). For example, most isolates recovered from patients
who developed postvaccination parotitis or meningitis were
wild type (Lys335) rather than variant (Glu335) virus (223).
In some countries, the highly immunogenic Urabe mumps
vaccine strain was replaced by the highly attenuated Rubini
strain, which appears to provide unacceptably low levels of
clinical protection (190,225). These problems have not been
recognized in the United States, where the Jeryl Lynn mumps
vaccine is still used.
2/21/14 5:38 PM
 Chapter 16: Meningitis and Encephalitis Caused by Mumps Virus
Selected Readings
Barskey AE, Schulte C, Rosen JB, et al. Mumps outbreak in Orthodox Jewish
communities in the United States. N Engl J Med. 2012;367:17041713.
Carr MJ, Moss E, Waters A, et al. Molecular epidemiological evaluation of the
recent resurgence in mumps virus infections in Ireland. J Clin Microbiol.
2010;48:32883294.
Centers for Disease Control and Prevention. Prevention of measles, rubella, con-
genital rubella syndrome, and mumps, 2013: summary recommendations
of the Advisory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2013;62(RR-04):134.
Dayan GH, Quinlisk MP, Parker AA, et al. Recent resurgence of mumps in the
United States. N Engl J Med. 2008;358:15801589.
Hviid A, Rubin S, Muhlemann K. Mumps. Lancet. 2008;371:932944.
Krause CH, Eastick K, Ogilvie MM. Real time PCR for mumps diag-
nosis on clinical specimenscomparison with results of conventional
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2/21/14 5:38 PM
 CHAPTER 17 RABIES
ALAN C. JACKSON
Rabies is an acute viral infection of the central nervous sys-
tem (CNS) that also involves the peripheral nervous system
both in its pathogenesis and clinical manifestations. Rabies is a
zoonotic disease affecting mammals that is usually transmitted
to humans by bites from animal vectors. Rabies virus infec-
tion causes most cases of rabies, although nonrabies virus
lyssaviruses have been recognized to very rarely cause disease
with identical clinical and pathologic features, but not in the
Americas. Physicians in geographic regions where rabies is
rare must consider the diagnosis based on the clinical picture
alone, because there may not be a history of an animal expo-
sure. Rabies can nearly always be prevented after a recognized
exposure with initiation of appropriate prophylactic therapy.
Once rabies develops, the disease is almost invariably fatal
with rare exceptions, and survival has usually been associated
with the administration of rabies vaccine prior to the onset of
the disease.
HISTORY
Rabies has a long and colorful history going back to antiq-
uity. Perhaps the earliest reference to rabies was in the pre-
Mosaic Eshnunna Code of Mesopotamia in about 2300 bc
(1). Rabid dogs were recognized in China centuries before
the birth of Christ (2). The works of Democritus, Aristotle,
Hippocrates, and Celsus made reference to rabies in both hu-
mans and animals (3). In 100 ad, Celsus described human
rabies and used the term hydrophobia, which is derived from
the Greek words meaning fear of water. Celsus recognized
that the saliva of the biting animal contained the poisonous
agent, and he recommended the practice of using caustics,
burning, cupping, and also sucking the wounds of individu-
als bitten by rabid dogs in order to prevent the subsequent
development of rabies (3).
In the early nineteenth century, Zinke (4) demonstrated
experimentally that the infectious agent causing rabies was
transmitted in the saliva by painting saliva from a rabid dog
into incisions made in healthy animals. In 1879, Galtier, who
was working at a veterinary school in Lyon, France, used rab-
bits in his rabies experiments and noted that it was technically
much less difficult and dangerous than experiments using dogs
and cats (5). Subsequently, Louis Pasteur took up this experi-
mental rabbit model of rabies. He transmitted rabies virus by
inoculating CNS tissues of rabid animals into the brains of
other animals and noted that sequential brain passages led to
attenuation for peripheral inoculation (6). In 1885, Pasteur (7)
successfully immunized a 9-year-old boy, Joseph Meister, who
had been severely bitten by a rabid dog, with a series of inocu-
lations of infected rabbit spinal cord tissues that had been par-
tially inactivated after variable periods of desiccation. Joseph
Meister never developed rabies and, subsequently, many peo-
ple were immunized with nervous system vaccinations in Paris
and other locations throughout the world.
In 1903, Adelchi Negri (8) described eosinophilic cytoplas-
mic inclusions in infected neurons, which are now called Negri
bodies. Negri bodies proved to be useful for a pathologic di-
agnosis of rabies. In 1958, fluorescent antibody staining was
Scheld_Ch17.indd 251
applied in order to demonstrate rabies virus antigens in tissues
(9), which became very useful for rabies diagnosis and also
for early rabies pathogenesis studies in animals performed by
Richard Johnson (10) and Frederick Murphy (11,12) and their
colleagues.
RABIES VIRUS
Rabies virus is in the family Rhabdoviridae and genus
Lyssavirus and is a nonsegmented negative-strand (antisense)
RNA virus consisting of 11,932 nucleotides that code for five
viral proteins: nucleocapsid protein (N), matrix protein (M),
phosphoprotein (P), glycoprotein (G), and large polymerase
protein (L) (13) (Fig. 17.1). Helical genomic RNA forms a ri-
bonucleoprotein (RNP) core associated with the N, P, and L
proteins. The RNP serves as a functional template for viral
transcription and replication. The G and M proteins are as-
sociated with a lipid bilayer envelope that surrounds the RNP
core. The G protein forms spikelike projections on the sur-
face of the viral envelope and serves as the major surface an-
tigen of the virus and binds viral neutralizing antibodies and
is important for immunity. Rabies virus belongs to genotype
1 of lyssaviruses, which includes wild type rabies virus strains
(also called street rabies viruses) and also laboratory-adapted
strains, including vaccine strains. The nonrabies virus lyssavi-
ruses that have been recognized to rarely cause human disease,
which is indistinguishable from rabies, include Mokola virus
(genotype 3), Duvenhage virus (genotype 4), European bat lys-
savirus 1 (genotype 5), European bat lyssavirus 2 (genotype 6),
Australian bat lyssavirus (genotype 7), and Irkut virus (geno-
type pending) (14).
PATHOGENESIS
Rabies virus is usually transmitted in the saliva to humans and
animals via a bite, although a scratch or abrasion with salivary
contamination can also result in viral transmission. Aerosol
transmission in a laboratory accident (15,16) and in a cave
containing millions of bats (17) has also been documented but
only occurs very rarely. Organ and tissue (corneal and vascu-
lar conduit) transplantation are also well-documented causes
of transmission of rabies virus in humans, which account for
a total of 16 well-documented cases (14,18,19). Much has
been learned about the steps involved in rabies pathogenesis
(Fig. 17.2) from experimental studies in animals. Usually, the
incubation period lasts about 20 to 90 days after the time
of the exposure (e.g., bite), although it may vary from a few
days to over a year. Based on studies in animals, the virus is
thought to remain close to the site of viral entry during most
of this incubation period. After an exposure involving muscle,
rabies virus is known to bind to nicotinic acetylcholine recep-
tors (20), which are located in the postsynaptic membrane
of the neuromuscular junction. The virus spreads across the
synaptic cleft and then spreads centripetally toward the spi-
nal cord in motor nerve fibers of peripheral nerves by retro-
grade fast axonal transport (21). Bats cause more superficial
251
2/21/14 5:39 PM
 252 Part II: Viral Infections and Related Disorders

Glycoprotein (G)
505 a.a. Lipid membrane

Phosphoprotein (P)
297 a.a. (-) viral RNA
12 kb

Matrix protein (M)

RNA-dependent
Nucleoprotein (N) 202 a.a
RNA-polymerase (L)
2130 a.a. 450 a.a.

FIGURE 17.1 Schematic representation of the rabies virus particle. Viral proteins: N for nucleoprotein,
P for phosphoprotein, M for matrix protein, G for glycoprotein, and L for large protein; their length in
amino acids are indicated. The viral membrane is covered by the glycoprotein G, whereas M is located
beneath the membrane. N is bound to the genomic RNA and together with P and L forms the ribonu-
cleoprotein, which constitutes the active viral replication unit. (Reproduced from Albertini AAV, Ruigrok
RW, Blondel D. Rabies virus transcription and replication. Adv Virus Res. 2011;79:122, with permis-
sion. Copyright Elsevier.)

exposures with their bites involving cutaneous and subcuta-

neous tissues, but experimental studies have not yet examined
the detailed pathways of viral spread in animal hosts. After
infecting spinal cord neurons (e.g., ventral horn neurons), ra-
bies virus spreads within axons of the CNS by fast axonal
transport along neuroanatomic connections. After CNS infec-
tion is established, there is centrifugal spread of rabies virus
to multiple organs along sensory and/or autonomic nerves. In
rabies vectors, viral spread to the salivary glands is important,
and saliva is secreted containing infectious rabies virus, which
is important for transmission to new hosts via bite exposures.
Viral spread also occurs to multiple organs, including the skin
(important for rabies diagnosis using a skin biopsy), heart
(with myocarditis in some cases), adrenal medulla, and gas-
trointestinal tract (22).
PATHOLOGY
Characteristic microscopic features of rabies encephalomyeli-
tis include mild mononuclear inflammatory changes involving
the leptomeninges, perivascular regions, and the parenchyma.
There are microglial nodules called Babes nodules in the pa-
renchyma, which were described by Babes (23), that consist
of activated microglia and monocytes. Degenerative neuronal
changes are not usually prominent in rabies. However, neu-
ronophagia can be observed with accumulations of activated
microglia/macrophages in the process of phagocytosing de-
generating or dying neurons (24). Infected neurons may con-
tain characteristic eosinophilic inclusions called Negri bodies
(Fig. 17.3), which were described by and named after Adelchi
Negri (8,25). Electron microscopy has demonstrated that
Negri bodies are composed of large aggregates of granulofila-
mentous matrix material and variable numbers of viral par-
ticles (24).
EPIDEMIOLOGY
Worldwide, about 99% of human rabies cases are related to
transmission from dogs related to the presence of endemic dog
rabies, particularly in Asia and Africa. Although the means of
controlling dog rabies are very well established, for a variety
of economic, cultural, and political reasons, dog rabies persists
in many countries, and people in these regions are at a con-
tinued risk of transmission via dog bites. In other countries,
rabies is endemic in wildlife, and this poses the main risk for
transmission of rabies virus. Rabies virus variants can be iden-
tified with molecular techniques, including monoclonal anti-
body characterization and reverse transcriptase polymerase
chain reaction (RT-PCR) amplification with sequencing. Bats
are the most important wildlife rabies vectors, and in the
United States, bat rabies is present in every state except Hawaii
(Fig. 17.4). Because of their small size, bat bites may not be
recognized, leaving no opportunity for initiating effective pre-
ventive measures. Patients infected by bat rabies virus variants
may not even be aware that they have had contact with bats
(Table 17.1). A bat rabies virus variant associated with silver-
haired bats and tricolored bats are most frequently associated
with human rabies in the United States and Canada. A variant
associated with Brazilian (Mexican) free-tailed bats is the sec-
ond most common variant associated with human rabies cases
in the United States. Although big brown and little brown bats
are often found in houses and they are commonly found to be
infected with rabies virus, they are not frequently responsible
for human rabies cases.
Terrestrial animals that are vectors of rabies in North
America include raccoons, skunks, and foxes (30) (Fig. 17.5).
Raccoon rabies is endemic along the entire eastern coast of
the United States. In the 1940s, raccoon rabies was present in
Florida, and over a period of decades, it gradually spread north

Scheld_Ch17.indd 252 2/21/14 5:39 PM


and the first incursion occurred into Ontario, Canada in 1999.
There are only two documented cases of human rabies due to
a raccoon rabies virus variant (19,31). Skunk rabies is present
in midwestern states, the prairie provinces of Canada, and in
California. Fox rabies is now uncommon in North America
because it has been well controlled, particularly in Ontario
(red fox) and Texas (gray fox), and in Europe with oral vac-
cination programs. Companion animals, especially dogs and
cats, are also at risk of developing rabies transmitted from
wildlife vectors, and they may then pose a danger to humans.
CLINICAL FEATURES
Typically, the incubation period from the time of the expo-
sure until the time of the onset of clinical disease is between
20 and 90 days but may be as short as only a few days or
exceed a year. There is a well-documented report of rabies
Scheld_Ch17.indd 253
Chapter 17: Rabies 253
FIGURE 17.2 Schematic diagram
showing the sequential steps in the
pathogenesis of rabies after an animal
bite/peripheral inoculation of rabies
virus. (Reproduced from Jackson AC,
Fu ZF. Pathogenesis. In: Jackson AC,
ed. Rabies: Scientific Basis of the Disease
and Its Management. 3rd ed. Oxford:
Elsevier Academic Press; 2013:299349;
Copyright Elsevier.)
with an incubation period as long as 6 years (32). Prodromal
symptoms in rabies are nonspecific and include fever, chills,
malaise, fatigue, insomnia, anorexia, headache, anxiety, and
irritability. They may last for up to 10 days prior to the onset
of neurologic symptoms. The earliest neurologic features of
rabies include paresthesias, pain, and pruritus at or close to
the site of exposure, which likely reflects infection and inflam-
matory changes in local sensory ganglia (e.g., dorsal root gan-
glia or cranial sensory ganglia). By this time, the wound may
have completely healed. There are two clinical forms of disease
in rabies: encephalitic rabies (in 80% of cases) and paralytic
rabies (in 20% of cases). The main burden of the infection
in encephalitic rabies involves the brain, whereas in paralytic
rabies, the main burden likely involves the spinal cord, nerve
roots, and peripheral nerves. Fever occurs in both forms.
In encephalitic rabies, there may be episodes of generalized
arousal or hyperexcitability, which are separated by lucid pe-
riods (33). Patients may have aggressive behavior, confusion,
2/21/14 5:39 PM
 254 Part II: Viral Infections and Related Disorders
and hallucinations. Features of autonomic dysfunction are
common, and these may include hypersalivation, piloerection
(gooseflesh), sweating, priapism, and cardiac arrhythmias.
Hydrophobia is a characteristic clinical feature of encepha-
litic rabies and occurs more frequently with infections due
to rabies virus variants associated with dogs than with bats.
Patients may initially experience pain in the throat or have
Scheld_Ch17.indd 254
FIGURE 17.3 Hematoxylin and eosinstained
sections showing Negri bodies in the perikarya of
(AC) cerebellar Purkinje cells and (D, E) pyrami-
dal neurons in the cerebral cortex of human rabies
cases. The arrow in (C) indicates a Negri body
in an apical dendrite. (Magnifications: A, 355;
B, 515; C, 615; D, 820; E, 970). (Adapted
from Rossiter JP, Jackson AC. Pathology. In:
Jackson AC, ed. Rabies: Scientific Basis of the
Disease and Its Management. 3rd ed. Oxford:
Elsevier Academic Press; 2013:351386; Copyright
Elsevier.)
difficulty swallowing. When they attempt to swallow, they ex-
perience contractions of the diaphragm and other inspiratory
muscles, typically lasting for 5 to 15 seconds. Subsequently,
this may become a conditioned reflex and the sight, sound,
or even mentioning water (or other liquids) may trigger the
spasms. Aerophobia is the occurrence of these same spasms
precipitated by a draft of air on the skin. There is progressive
FIGURE 17.4 Reported cases of ra-
bies involving bats, by county, in 2011.
Histogram represents the number of
counties in each category for total
number of bats submitted for testing
(excluding Oklahoma). (Reproduced
from Blanton JD, Dyer J, McBrayer
J, et al. Rabies surveillance in the
United States during 2011. J Am Vet
Med Assoc. 2012;241:712722, with
permission.)
2/21/14 5:39 PM

TA B L E 1 7 . 1
INDIGENOUSLY ACQUIRED CASES OF HUMAN
RABIES FROM BATS IN THE UNITED STATES AND
CANADA, 19502011a
Type of Case Number of Cases
Bite or scratch 23 (36.5%)
Direct contact with no 11 (17.5%)
recognized bite
House exposure but no 8 (12.7%)
direct contact
No history of bat contact 21 (33.3%)
Total 63
a
Data from De Serres et al. (26), Pue et al. (27), and
Blanton et al. (2830).
Adapted from Jackson AC. Update on rabies. Res Rep Trop Med.
2011;2:3143, with permission from Dove Medical Press.
neurologic deterioration with worsening in the level of con-
sciousness to coma and the development of paralysis.
In paralytic rabies, there is early prominent weakness that
usually initially involves the bitten extremity and progresses
to involve the other extremities and facial muscles. Sphincter
involvement, pain, and sensory disturbances also occur.
Hydrophobia is unusual in paralytic rabies, although weak-
ness of bulbar and respiratory muscles also develops. Patients
with paralytic rabies later develop neurologic deterioration
with progression to coma, and they typically survive longer
than patients with encephalitic rabies.
Medical complications are common in rabies patients
treated aggressively in a critical care unit. Cardiac and respi-
ratory complications are common. Cardiac disorders include
heart failure, hypotension, a variety of arrhythmias, and car-
diac arrest. Both cardiac ganglia and the myocardium may
FIGURE 17.5 Distribution of the major rabies virus variants among
wild terrestrial reservoirs in the United States and Puerto Rico, 2008
to 2012. *Potential host shift event. (Reproduced from Dyer JL,
Wallace R, Orciari L, et al. Rabies surveillance in the United States
during 2012. J Am Vet Med Assoc. 2013;243:805815.)
Scheld_Ch17.indd 255
Chapter 17: Rabies 255
become infected with rabies virus, and in some cases, there
is an associated myocarditis (3436). Respiratory complica-
tions include hyperventilation, hypoxemia, respiratory depres-
sion with apnea, atelectasis, and aspiration pneumonia (37).
Hyperthermia or hypothermia may occur, likely secondary
to hypothalamic infection. Endocrine complications include
inappropriate secretion of antidiuretic hormone and diabetes
insipidus (37,38). Multiple organ failure commonly occurs in
patients treated aggressively in critical care units.
DIFFERENTIAL DIAGNOSIS
The diagnosis of rabies may be difficult without a history of an
animal exposure. Physicians may not ask about animal expo-
sures, and the patient may not recall an exposure or may not
be able to provide this information at the time of presentation.
In early phases, encephalitic rabies may be misdiagnosed as a
psychiatric disorder and paralytic rabies as Guillain-Barr syn-
drome. Rabies hysteria is a conversion disorder (somatoform
disorder) that likely occurs as a psychologic response to the
fear of developing rabies (39). It is characterized by a shorter
incubation period than rabies, aggressive behavior (not com-
mon in humans), inability for the patient to communicate, and
a long clinical course with recovery.
Other viral encephalitides may show behavioral changes
with fluctuations in the level of consciousness. Hydrophobic
spasms are not observed, and the presence of brainstem signs
is unusual in conscious patients in most of the other viral
encephalitides. Herpes simiae (B virus) encephalomyelitis,
which is transmitted by monkey bites, is usually associated
with a shorter incubation period and recovery may occur (40)
(see Chapter 14). Tetanus has a shorter incubation period
(3 to 21 days) than rabies and is characterized by sustained
muscle rigidity involving paraspinal, abdominal, masseter
(trismus), laryngeal, and respiratory muscles with superim-
posed brief recurrent muscle spasms (41) (see Chapter 37).
In tetanus, consciousness is preserved, there is no cerebrospi-
nal fluid (CSF) pleocytosis, and the prognosis is much better
than in rabies. In Africa, rabies is commonly misdiagnosed
as cerebral malaria (42). Anti-N-methyl-d-aspartate recep-
tor (anti-NMDA) encephalitis occurs in young patients (es-
pecially females) and is characterized by behavioral changes,
autonomic instability, hypoventilation, and seizures, and it has
recently been recognized that this autoimmune disease rivals
viral etiologies as a cause of encephalitis (43). Postvaccinal
encephalomyelitis is an important differential diagnosis in pa-
tients immunized with a vaccine derived from neural tissues
(e.g., Semple vaccine), which is currently used in only a few
resource-poor countries. Patients with paralytic rabies may
resemble the Guillain-Barr syndrome, and the pathologic fea-
tures may also be similar (44). Local symptoms at the site of
the bite, piloerection, early or persistent bladder dysfunction,
and fever are all more suggestive of paralytic rabies.
INVESTIGATIONS
Routine blood tests and computed tomography (CT) head
scans are typically normal in rabies. Magnetic resonance
(MR) imaging may be normal or show signal abnormalities
in the brain, spinal cord, and nerve roots/plexuses, but these
findings are not specific for rabies and the main usefulness of
MR imaging is to exclude other diagnostic possibilities (45).
CSF analysis usually shows a mononuclear pleocytosis with a
cell count of less than 100 cells/L. Serum-neutralizing anti
rabies virus antibodies may develop in unvaccinated patients
2/21/14 5:39 PM
 256 Part II: Viral Infections and Related Disorders
but may not appear for a week or more during the clinical
course of disease, and some patients never develop antibodies
prior to death. Neutralizing antirabies virus antibodies may
also develop in the CSF, whereas CSF antibodies are not pres-
ent in vaccinated patients who do not have rabies encephali-
tis. Specific laboratory tests for confirmation of a diagnosis
of rabies include a full-thickness skin biopsy taken from the
posterior region of the neck at the hairline. Rabies virus anti-
gen may be detected in nerve fibers around hair follicles with
direct fluorescent antibody staining. A recent advance in the
laboratory diagnosis of rabies is detection of rabies virus RNA
in fluids or tissues using RT-PCR amplification. Detection of
rabies virus RNA in saliva is the most useful. RT-PCR can
also be used on skin biopsies (46) and CSF but is much less
sensitive on CSF. A negative laboratory test for rabies never
excludes rabies unless performed on brain tissues, and the tests
may need to be repeated for diagnostic confirmation of a ra-
bies diagnosis. Brain tissues are only very rarely obtained by
biopsy antemortem but are routinely evaluated postmortem by
direct fluorescent antibody staining and by culture techniques.
PREVENTION OF RABIES
Rabies can be very effectively prevented after recognized ex-
posures. Detailed guidelines that are periodically updated are
available from the Centers for Disease Control and Prevention
(47) and from the World Health Organization (48), and these
documents are available on the Morbidity and Mortality
Weekly Report (http://www.cdc.gov/mmwr/) and World
Health Organization (http://www.who.int/en/) Web sites.
Algorithms can be very useful in making decisions concerning
postexposure rabies prophylaxis (Fig. 17.6). The first step is to
determine whether there is a real risk of rabies virus transmis-
sion, which depends on obtaining the details of the exposure,
the species of animal involved, and also on knowledge about
the local epidemiologic situation. Advice from local public
health officials can be very helpful in determining whether
postexposure rabies prophylaxis measures should be initiated.
Laboratory testing on brain tissues from an animal is needed
for a definitive diagnosis of rabies, which is usually performed
by an antigen detection method using the fluorescent antibody
technique. If a dog, cat, or ferret remains healthy for a 10-day
period after an exposure, then a confident conclusion can be
made that rabies virus transmission did not occur during the
exposure because the brainstem infection associated with the
salivary excretion of infectious virus would have progressed
to overt clinical signs within the period. Of course, unwanted
animals may be tested without an observation period. Other
animals must not be observed after an exposure because there
is uncertainty about the period of time for clinical disease to
develop, and this period may substantially exceed 10 days. If
an animal escapes after an exposure, then it should be consid-
ered rabid unless information from public health officials indi-
cates that this is unlikely. Current recommendations indicate
that the physical presence of a bat may warrant postexposure
prophylaxis when a person such as a small child or sleeping
adult is unable to reliably report contact that could have re-
sulted in a bite (47). However, in light of the low risks and
high costs, recommendations for bedroom exposures to a bat
while sleeping and without known physical contact have been
questioned (49).
Postexposure rabies prophylaxis in previously unvacci-
nated persons includes wound cleansing and active immu-
nization with rabies vaccine and passive immunization with
human rabies immune globulin (HRIG). All animal bite
wounds should be thoroughly cleaned with soap and water
Scheld_Ch17.indd 256
and, if available, a virucidal agent (e.g., povidone) should be
used to irrigate the wounds. In the United States, four doses
of rabies vaccine, which was recently reduced from five doses,
are recommended on days 0, 3, 7, and 14 (50), and for each
dose, 1.0 mL of vaccine should be given intramuscularly in
the deltoid muscle. Two rabies vaccines are currently licensed
in the United States and Canada: purified chick embryo cell
vaccine (PCECV) (RabAvert) and human diploid cell vaccine
(Imovax). Pregnancy is not a contraindication for immuniza-
tion. Local and mild systemic adverse effects are common.
Local reactions include pain, erythema, edema, and pruritus;
systemic reactions include fever, myalgias, headache, and nau-
sea. Antiinflammatory medications and antipyretics may be
used, but immunization should not be discontinued. The dose
of HRIG is based on weight (20 IU/kg), and HRIG should
be infiltrated into and around the wound and the remaining
portion of the dose can be given intramuscularly in a differ-
ent location (e.g., gluteal muscles) than the vaccine is given. If
there are multiple or extensive wounds and a large volume of
HRIG is needed for infiltration, then HRIG can be diluted as
required for satisfactory wound infiltration. HRIG should not
be given later than 7 days after the first dose of rabies vaccine.
Adverse effects of HRIG include local pain and low-grade
fever. If HRIG is not available, then purified equine rabies im-
mune globulin, which is much more readily available in some
rabies-endemic countries (e.g., Thailand), may be used in the
same manner at a dose of 40 IU/kg.
In persons at risk of rabies exposures, including laboratory
workers, veterinarians, and travelers to places with endemic
dog rabies (e.g., Asia and Africa), preexposure rabies immuni-
zation should be considered. Three doses of vaccine are given
on days 0, 7, and 21. When prolonged protection is needed,
booster doses of rabies vaccine can be given periodically as re-
quired based on a serum-neutralizing antirabies antibody titer.
After a rabies exposure in preimmunized individuals, in addi-
tion to wound cleansing, two doses of rabies vaccine should be
given on days 0 and 3 and HRIG should not be given.
THERAPY OF HUMAN RABIES
There is no effective therapy for human rabies, and the disease
is virtually always fatal. In all except a single case, survivors
have received rabies vaccine prior to the onset of the clinical
disease. In 2003, a viewpoint article was published outlining
the therapeutic options for consideration of an aggressive ap-
proach for a patient with rabies (51). Young and previously
healthy patients with an early clinical diagnosis of rabies were
felt to be the best potential candidates for aggressive therapy
(51). Therapies suggested for consideration include rabies vac-
cine, HRIG, monoclonal antibodies (for the future), ribavirin,
interferon-, and ketamine. It was felt that a combination of
therapies might improve efficacy in situations in which specific
therapies used individually had failed in the past, similar to the
situation for current therapies of a variety of infectious and
other noninfectious diseases.
In 2004, a 15-year-old female who had been bitten on her
finger by a bat and did not receive postexposure prophylaxis
therapy survived rabies (52). She developed typical clinical fea-
tures of rabies encephalitis about a month after the bite. On
arrival at a tertiary care hospital in Milwaukee, Wisconsin, neu-
tralizing antirabies virus antibodies were detected in sera and
CSF (initially at titers of 1:102 and 1:47, respectively). Nuchal
skin biopsies were negative for rabies virus antigen, and rabies
virus RNA was not detected in saliva or in the skin biopsies
using RT-PCR. She was intubated and put into a drug-induced
coma, which included the noncompetitive NMDA antagonist
2/21/14 5:39 PM
 Chapter 17: Rabies 257

Did an exposure to rabies occur?

Did an animal bite the patient, or did
a potentially unrecognized exposure occur?
Was there direct contact of the patients open
bleeding wound, broken skin, or mucous
membranes with potentially infectious Yes
Was the animal a mammal?
material such as animal saliva or central
nervous system tissue?
No Yes
No

Yes
No PEP Was the animal a small rodent or rabbit?

No

Observe the animal for Yes Yes

Is the animal available
10 days. Does it exhibit Was the animal a dog, cat, or ferret?
for observation?
signs of rabies?

No
No

Yes
Was the animal domestic livestock?
No Yes Consult public health
officials for local
rabies epidemiology.
Was the animal No
a bat, or is
terrestrial rabies
present? No
Is the animal (brain) available for testing?

Yes

No Yes

Did the animal Negative for Positive for

exhibit any rabies rabies
signs of rabies?

No Yes

No PEP PEP No PEP PEP No PEP PEP

FIGURE 17.6 Algorithm for rabies postexposure prophylaxis (PEP) in the United States. (Reproduced
from Rupprecht CE, Gibbons RV. Prophylaxis against rabies. N Engl J Med. 2004;351:26262635, with
permission.)

ketamine at 48 mg/kg/day as a continuous infusion and intra-
venous midazolam for 7 days. A burst-suppression pattern on
her electroencephalogram was maintained, and supplemental
phenobarbital was given as needed. She also received antivi-
ral therapy, including intravenous ribavirin and amantadine
200 mg per day administered enterally. She improved and was
discharged from hospital with neurologic deficits, and she sub-
sequently demonstrated further neurologic improvement (53).
This patient is the first documented rabies survivor who
did not receive any rabies vaccine prior to the onset of clini-
cal rabies (Table 17.2). It remains uncertain if therapy with
one or more specific agents played a significant role in her fa-
vorable outcome (60). Since that time, there have been over
25 cases in which the main components of this approach (the
Milwaukee protocol) have been used, and the therapy failed
with fatal outcomes (61). The induction of coma per se has no

Scheld_Ch17.indd 257 2/21/14 5:39 PM

 258 Part II: Viral Infections and Related Disorders
TA B L E 1 7 . 2
CASES OF HUMAN RABIES WITH RECOVERY
Age of
Location Year Patient Transmission
United States 1970 6 Bat bite
Argentina 1972 45 Dog bites
United States 1977 32 Laboratory (vaccine strain)
Mexico 1992 9 Dog bites
India 2000 6 Dog bites
United States 2004 15 Bat bite
Brazil 2008 15 Vampire bat bite
a
Patient died less than 4 years after developing rabies with marked neurologic sequelae (Dr. L. Alvarez, personal communication, 1997).
b
Patient died about 2 years after developing rabies with marked neurologic sequelae (Dr. S. Mahusudana, personal communication, 2005).
(Adapted from Jackson AC. Therapy of human rabies. In: Jackson AC, ed. Rabies: Scientific Basis of the Disease and Its Management. 3rd ed. Oxford:
Elsevier Academic Press; 2013:573587; Copyright Elsevier.)
established benefit for the management of infectious diseases
of the nervous system, and there is no evidence to date sup-
porting this approach in rabies or other viral encephalitides.
Hence, therapeutic coma should not become a routine therapy
for the management of rabies. Recent experimental evidence
does not support a mechanism of excitotoxicity in a mouse
model of rabies and also in rabies virus infection of cultured
neurons, and there was also a lack of efficacy of ketamine ther-
apy in cultured neurons and in the mouse model (62). Even in
situations in which there is very strong experimental evidence
of excitotoxicity in animal models, numerous clinical trials in
humans have failed to demonstrate efficacy of neuroprotec-
tive agents in stroke (63). Hence, a neuroprotective effect of a
therapy given to a single patient without a credible scientific
rationale is highly doubtful. It is likely that this patient would
also have recovered with only good supportive therapy.
Neutralizing antirabies virus antibodies are an important
marker of an adaptive immune response that is essential for
clearance of rabies virus and recovery (64). The presence of
serum-neutralizing antirabies virus antibodies early in a pa-
tients clinical course probably occurs in less than 20% of pa-
tients with rabies and is likely an important factor contributing
to a favorable outcome in this patient. There have been six sur-
vivors of rabies who received rabies vaccine prior to the onset
of their disease and only one without vaccine. This suggests
that an early immune response is associated with a positive
outcome. Recovery of cases with atypical clinical features of
rabies without the development of antirabies virus neutraliz-
ing antibodies (65,66) were probably not actual cases of rabies
and should not be considered survivors. Bat rabies virus vari-
ants are probably less neurovirulent than canine virus variants
or other variants that are responsible for most human cases of
rabies (67), and human rabies due to canine rabies virus vari-
ants likely has a reduced chance of a favorable outcome than
cases caused by bat rabies virus variants. One previous sur-
vivor of rabies, who was also infected with a bat rabies virus
variant received rabies vaccine prior to the onset of disease
and made an excellent neurologic recovery (54). It is unknown
if the causative bat rabies virus variant in the Milwaukee case
was attenuated and had different biologic properties than other
isolated variants because there was no viral isolation in this
case. However, in rabies survivors, diagnostic laboratory tests
are usually negative for rabies virus antigen and RNA in fluids
Scheld_Ch17.indd 258
Immunization Prior to Onset Outcome Reference
Duck embryo vaccine Complete recovery (54)
Suckling mouse brain vaccine Mild sequelae (55)
Preexposure vaccination Sequelae (16,56)
Postexposure vaccination Severe sequelaea (57)
(combination)
Postexposure vaccination Severe sequelaeb (58)
(combination)
None Mild sequelae (52,53)
Postexposure vaccination Severe sequelae (59)
and tissues, and brain tissues have not been tested. This may
reflect effective viral clearance in which centrifugal spread of
the infection to peripheral organ sites is reduced or very rapid
clearance occurs through immune-mediated mechanisms.
Pathologic data from a number of human rabies cases treated
with the Milwaukee protocol indicate that the therapy is inef-
fective in clearing rabies virus infection from the brain and from
preventing neuronal injury. A case from Edmonton (Canada)
was treated with the Milwaukee protocol and after termination
of the therapeutic coma remained in a brain deathlike state for
about 4 weeks (68). At autopsy, there was complete loss of neu-
rons in the cerebral cortex, and positive staining for rabies virus
antigen was observed in both brainstem and cerebellar neurons,
indicating a failure of clearance of the viral infection from the
brain and also failure of protection against neuronal injury and
loss (68). In Germany, lung and kidney/pancreas recipients from
a rabies virusinfected donor developed rabies and were treated
with major components of the Milwaukee protocol, including
intravenous midazolam, ketamine, and phenobarbital (in one)
(19). One patient died within 2 days, whereas the other survived
64 days after the onset of clinical rabies. At autopsy, the two
patients had 1.2 to 2.3 109 RNA copies per mg of CNS tis-
sue, indicating ineffective viral clearance. The long surviving pa-
tient showed viral clearance from systemic organs and peripheral
nerve. Hence, Milwaukee protocol therapy has proved ineffective
in promoting viral clearance from the CNS in rabies. It remains
highly doubtful that the Milwaukee protocol will prove to be
useful in the management of human rabies. Unfortunately, pro-
motion and repetition of this flawed therapy has likely already
impeded progress in the development of new effective therapies
for rabies. A better understanding of basic mechanisms underly-
ing rabies pathogenesis in humans and animals is needed, which
may prove to be very helpful in the development of novel thera-
peutic approaches for the management of this dreaded disease.
OTHER LYSSAVIRUS INFECTIONS
Nonrabies virus lyssaviruses may cause fatal neurologic ill-
nesses that are clinically and pathologically indistinguishable
from rabies. Mokola virus has been isolated from shrews,
although the reservoir is unknown. In 1971, a 6-year-old girl
died with Mokola virus infection (69); another case with mild
2/21/14 5:39 PM

illness was more likely due to cross-contamination of specimens
in the laboratory (70). The index case of Duvenhage virus infec-
tion was transmitted by a bat and occurred in South Africa (71),
and two additional cases were recently reported (72,73). There
have been two cases reported due to European bat lyssavirus 1
(74,75) and another two cases due to European bat lyssavirus 2
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 CHAPTER 18 HUMAN PRION DISEASES
SERGGIO C. LANATA, SVEN FORNER, AND MICHAEL D. GESCHWIND
The transmissible spongiform encephalopathies (TSEs) are a
group of closely related fatal neurodegenerative diseases that
affect humans and several other mammals (Tables 18.1 and
18.2). TSEs have a few characteristics in common: (1) they are
transmissible in nature and/or experimentally; (2) they invari-
ably lead to brain dysfunction or encephalopathy, which
manifests clinically as cognitive, behavioral, sensory, and/or
motor dysfunction; (3) they are uniformly fatal; and (4) they
currently can only be diagnosed definitively by neuropathol-
ogy (or genetically in certain cases).
TSEs are caused by prions (for proteinaceous infectious
particles), misshapen forms of the endogenous prion protein,
in the central nervous system (1); hence, TSEs are now referred
to as prion diseases, which is the term that will be used
for this chapter. Prion (pree-ahn) diseases are unique in medi-
cine in that they occur in three forms: sporadic, infectious/
acquired, and genetic. All three mechanisms occur in humans.
Prions are considered infectious because they rarely can be
transmitted from person to person (iatrogenically) or even less
commonly by ingestion. When they are transmitted into, or
develop in, the nervous system, they cause the conversion of
normal-shaped prion proteins into an abnormal, pathogenic
conformation. This conversion process becomes exponen-
tial and leads to the spread of prions throughout the brain,
causing neuronal dysfunction and cell death and, ultimately,
neurodegeneration. Prions are intrinsically different from all
other naturally occurring infectious agents, however, in that
they do not rely on nucleic acid to replicate within the host
organism. Furthermore, the presence of sporadic and heritable
forms of prion disease also differentiates prions from all other
infectious agents. This chapter will focus primarily on human
prion diseases, with the caveat that most of our knowledge of
the pathophysiologic mechanisms of prion disease has been
obtained from animal and cell culture studies.
TA B L E 1 8 . 1
PRION DISEASES IN HUMANS
Class Disease Abbreviation
Sporadic Sporadic Jakob-Creutzfeldt sJCD
disease
Fatal insomnia sFI
Variably protease-sensitive VPSPr
prionopathy
Genetic Genetic Jakob-Creutzfeldt gJCD
Disease
Gerstmann-Strussler-Scheinker GSS
Fatal familial insomnia FFI
Acquired Iatrogenic Jakob-Creutzfeldt iJCD
disease
Variant Jakob-Creutzfeldt disease vJCD
Kuru Kuru
Scheld_Ch18.indd 261
SCRAPIE, KURU, AND THE
DISCOVERY OF PRIONS
The history of the discovery of prions is an inspiring journey
of multidisciplinary scientific collaboration that profoundly
changed our understanding of infectious and neurodegenerative
diseases. This journey began with the careful study of the prion
disease called scrapie, which primarily affects sheep and goats.
Scrapie is probably the earliest described prion disease,
with the first reports published in 1750, but the disease was
probably recognized as early as 1732 in Great Britain. The
clinical signs of scrapie are variable; the most frequently ob-
served clinical signs are emaciation, repetitive head rubbing,
hyperesthesia, and pruritus. Pruritus is often severe enough
to make the affected animal rub and scrape (hence the term
scrapie) its body against rough surfaces, leading to wool
loss and skin abrasions (2). Affected animals often become hy-
persensitive to outside stimuli, including noises, sudden move-
ments, or handling by humans, to the extent some stimuli will
cause the animal to startle violently or convulse. Other com-
mon signs include tremor and ataxia leading to impaired gait
and falls. Behavioral changes are prominent and common. A
nibbling response of the mouth is often evoked by scratching
the animals back (positive scratch response). Scrapie has a
long incubation period, ranging between 2 and 5 years, and
affected animals live up to 6 months after symptom onset.
Scrapie is transmissible both naturally and experimentally.
The natural means of transmission is a matter of debate, with
both environmental and genetic susceptibility factors influenc-
ing transmission (3). Experimental transmissibility of scrapie,
however, was firmly demonstrated in 1936 when Cuill and
Chelle (4) showed that healthy sheep inoculated with scrapie-
infected spinal cord tissue developed the disease. At the time,
however, the infectious agent of scrapie was unknown.
Puzzled by scrapies long incubation period and devastat-
ing course, Bjorn Sigurdsson, an Icelandic veterinarian, first
proposed the notion of slow viral infections in the 1950s
TA B L E 1 8 . 2
PRION DISEASES IN NONHUMAN MAMMALS
Disease Abbreviation Animal Hosts
Scrapie Sc Sheep, goat
Transmissible mink TME Mink
encephalopathy
Bovine spongiform BSE Cattle
encephalopathy
Chronic wasting CWD Mule deer, elk,
disease moose
Feline spongiform FSE Cats
encephalopathy
Exotic ungulate EUE Nyala, greater kudu
encephalopathy
261
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 262 Part II: Viral Infections and Related Disorders
regarding a paralytic encephalitis of sheep called rida (5). In
his view, these neurologic diseases were caused by unknown
viruses with prolonged incubation periods (years to decades)
that led to death after a short and progressive clinical course.
Sigurdssons ideas shed light on the etiology of many diseases
that were poorly understood at the time (6). For example,
maedi, a deadly form of pneumonitis in sheep, and visna, a
slowly progressive encephalitis, were found to be caused by
the same virus, now known as the maedi-visna lentivirus (7).
The suspected viral cause of scrapie, on the other hand, still
remained elusive.
Concurrently, in the 1950s, D. Carleton Gajdusek, an
American physician and virologist, initiated the scientific
study of a human neurologic disease known as kuru in Papua
New Guinea. Papua New Guinea is one of the most culturally
diverse countries in the world, with more than 800 languages
spoken among roughly 6.3 million people segregated in differ-
ent tribes. The kuru epidemic emerged in the early twentieth
century among the Fore tribe that inhabits one of the highland
provinces. Kuru means to shiver from fever or cold in the lan-
guage of the Fore people (8). The disease is characterized clini-
cally by the insidious onset of progressive cerebellar ataxia,
eventually leading to inability to walk. A typical early feature
of the disease is the presence of unusual laughter, giving rise to
the phrase the laughing death to describe kuru (9). In later
stages, brainstem findings typically manifesting as eye move-
ment abnormalities and severe dysarthria are also common.
Like scrapie, the incubation period for kuru is long, as long as
50 years (10), and disease duration is relatively short, usually
less than 12 months.
Early anthropologic studies of the Fore people described
a ritualistic form of cannibalism that prevailed across all age
groups. Fore people consumed the bodies of their deceased
relatives (endocannibalism), including those who died of
kuru (11). This was done with the hope of maintaining the
spirit of the deceased within the village community. Perhaps
partly for this reason, Gajdusek and his team initially sus-
pected an infectious, probably viral, etiology to kuru, bor-
rowing from Sigurdssons concept of slow viral infections
(12). It soon became clear, however, that kuru was not a typ-
ical infectious disease, in that victims did not exhibit fever
or other clinical signs of infection, including no signs of
meningoencephalitis, no obvious cerebrospinal fluid (CSF)
abnormalities, and patients did not respond to antibiotic
medications. Furthermore, autopsy studies of brains affected
by kuru did not demonstrate the inflammatory changes
typically seen in many forms of nervous system infections.
Additionally, it was not transmissible to small laboratory
animals and no infectious agent had been identified (8). This
led Gajdusek and others to conduct an exhaustive search of
environmental factors that could explain the transmissible
and seemingly infectious nature of kuru (13,14), but none
were found. The absence of an environmental cause for kuru
coupled with the well-described tribal and familial distribu-
tion of the disease led some to believe that kuru was a genet-
ically inherited condition (15). Large epidemiologic studies
showed that the incidence of kuru dramatically decreased
among members of tribes who abolished endocannibalism,
thus pointing toward a transmissible disease mechanism
rather than a genetic one (8).
A major breakthrough came when William J. Hadlow, a
veterinarian pathologist, made note of the neuropathologic
similarities between kuru and scrapie and postulated that
a similar infectious agent was the cause of both diseases
(16). This was an important conceptual contribution to the
study of prion diseases in general, as prior to the 1950s,
the efforts to understand scrapie and kuru were disjoined
Scheld_Ch18.indd 262
(1). This observation further motivated scientists to take
on the challenge of identifying the causative agent of these
diseases.
Toward this goal, a series of careful experiments done on
scrapie-infected brains demonstrated that the scrapie agent
was resistant to conditions that normally inactivated other
infectious organisms like viruses and bacteria, such as expo-
sure to formalin (17), very high temperatures (18), and other
solvents (19). Scrapie, and presumably kuru, was beginning
to show properties that distinguished it from other infectious
diseases.
Siggurdsons and Hadlows hypotheses were eventually
supported experimentally in 1966, when the transmission
of kuru was demonstrated by Gajdusek and colleagues (20)
through the intracerebral inoculation of diseased brain tissue
in the chimpanzee. The proven transmissibility of kuru helped
solidify the natural transmissibility theory that had already
been gaining momentum based on anthropologic and epide-
miologic observations: kuru was transmitted through endo-
cannibalism (21). Furthermore, neuropathologic similarities
between kuru and Jakob-Creutzfeldt disease (JCD) had been
clearly recognized in the late 1950s (22). And the same group
of investigators that demonstrated transmission of kuru to
chimpanzees also demonstrated transmission of JCD to the
chimpanzee in 1968 (23). This was an important experimental
discovery, as JCD had previously been regarded as a human
neurodegenerative disease of unknown etiology. Taken to-
gether, these observations led to the introduction of the term
transmissible spongiform encephalopathies to highlight the
many neuropathologic and clinical characteristics shared by
these three diseases.
Still, although experimental transmissibility had been
proven for scrapie, kuru, and JCD, and natural transmissi-
bility had been shown for scrapie and kuru, the infectious
substrate of these diseases remained unknown. As mentioned
earlier, the scrapie agent did not share basic biochemical and
biophysical properties with other known infectious organ-
isms. This notion was strengthened in 1966, when Alper
and colleagues (24) showed that extracts of scrapie-infected
brains retained their infective nature even after exposure to
large doses of ultraviolet light that were known to irrevers-
ibly damage the DNA and RNA molecules, thus implying
that the scrapie agent lacked nucleic acid. Later, similar stud-
ies were conducted on tissue containing the agent responsible
for kuru and JCD (25).
The idea of an infectious agent lacking nucleic acid was
considered outlandish at the time. It implied that the agent
that transmitted these diseases was, at its core, unlike any
other known infectious agent. This idea captured the curi-
osity of neurologist Stanley Prusiner and other researchers.
Through a series of careful experiments using animal models,
Prusiner confirmed that the scrapie agent indeed resists inacti-
vation by procedures that hydrolyze, modify, or shear nucleic
acids; furthermore, Prusiner and colleagues demonstrated that
the scrapie agent was inactivated by treatments that denatured
protein (26). Based largely on this line of evidence, Prusiner
postulated that a protein, which he named prion (pree-ahn)
for proteinaceous infectious particle, was the principal car-
rier of scrapie (27).
The discovery of prions (PrP, for prion protein) shattered
the concept that nucleic acids are the sole carriers of trans-
missible infectious disease. Alternative theories to explain
the nature of the scrapie agent were proposed for years after
Prusiners postulate (28,29), but none of these theories has
been proven experimentally and the prion model has become
widely accepted over the last two decades, supported by a vast
body of evidence.
2/21/14 5:39 PM
 Chapter 18: Human Prion Diseases 263

NORMAL AND PATHOGENIC The Prion Protein Gene (PRNP)

PRION PROTEINS: PrPC AND PrPSc
After PrP was found to be the disease-producing substrate in
concentrates of scrapie-infected brain tissue (27), the question
arose whether PrP was acquired exclusively from the environ-
ment via an infectious mechanism or if it was also produced
endogenously by the diseased animal.
In 1986, for the first time, researchers were able to isolate
PrP-related genomic clones in normal hamsters using comple-
mentary DNA (cDNA) obtained from PrP messenger RNA
(mRNA), thus demonstrating that mammalian cells carry the
gene responsible for encoding PrP (30). Similar experiments
were performed in mice (31) and other mammals including
humans (32). The gene that encodes PrP is known as PRNP.
PRNP encodes a normal form of PrP with incompletely under-
stood cellular functions. The misshapen, pathogenic form of
PrP, on the other hand, has unique biochemical properties that
distinguish it from its normal counterpart (as will be discussed
in the following sections). This distinction led to the current
designation of cellular PrP (PrPC) to describe PrP in its nor-
mal form and scrapie PrP (PrPSc) to describe the misfolded,
pathogenic form of PrP. The terms PrPC and PrPSc will be used
accordingly in this chapter.
The prion gene, PRNP, is located in the short arm of chromo-
some 20 in humans. It is composed of two exons and one in-
tron, and the protein-coding region is located in exon 2. PRNP
encodes the 253 amino acid PrP. A schematic of PRNP and
the prion gene in other species is shown in Figure 18.1. There
are more than 30 autosomal dominant mutations of PRNP
that lead to inherited forms of prion disease in humans. These
occur primarily in the form of point mutations as well as some
insertion, and possibly deletion mutations. Point mutations
normally occur in the central and C-terminal portions of PrP.
Insertion mutations occur in the N-terminal end of the pro-
tein, which is normally composed of a nonapeptide followed
by four octapeptide repeats. Different mutations lead to varied
familial forms of the disease (33,34).
Historically, clinically-based studies of the heritable forms
of prion disease in humans led to the identification of three
classic phenotypes: Gerstmann-Strussler-Scheinker disease
(GSS), familial Jakob-Creutzfeldt disease (fJCD), and fatal fa-
milial insomnia (FFI). These three forms of familial JCD were
described based on clinicopathologic features, prior to the
identification of PRNP. The classification of familial (genetic)
prion diseases, however, has changed with the division of fa-
milial forms based on specific PRNP mutations. Genetic prion

FIGURE 18.1 Mutations and polymorphisms of the prion protein gene; PrP mutations of the prion pro-
tein gene; PrP mutations causing genetic human prion disease; and PrP polymorphisms found in humans,
mice, sheep, elk, and cattle. Above the line of the human sequence are mutations that cause gPrD. Below
the lines are polymorphisms, some, but not all, of which are known to influence both the onset and the
phenotype of disease. Residue numbers in parentheses correspond to the human codons. (Much of the
data were compiled by J.-L. Laplanche.) (From Knipe DM, Howley PM, eds. Fields Virology. 5th ed.
Philadelphia: Lippincott Williams & Wilkins; 2007:3072.)

Scheld_Ch18.indd 263 2/21/14 5:39 PM

 264 Part II: Viral Infections and Related Disorders
diseases (gPrDs) are discussed in detail in the section, Human
Genetic Prion Diseases.
Polymorphisms in the PRNP gene have been shown to in-
fluence prion disease susceptibility and the clinical phenotype.
The most important polymorphism in humans is at amino acid
129 of PRNP, which can be methionine (M) or valine (V). As
every person has two copies of each gene, humans can be ei-
ther MM, MV, or VV. Homozygosity (either MM or VV) at
codon 129 increases susceptibility to sJCD (35,36), for exam-
ple. Likewise, in patients with gPrD, the cis codon 129 poly-
morphism (i.e., the codon 129 allele on the same DNA strand
as the mutation) can greatly influence how a disease presents
(37). The phenotypic influence of these polymorphisms will be
discussed further under the gPrDs section.
The Function of Cellular PrP
PrPC is expressed mostly in the brain, but it has also been de-
tected in a wide variety of mammalian tissues, including leu-
kocytes, heart, skeletal muscle, lung, intestinal tract, spleen,
and reproductive organs (38). The role of PrPC in the nervous
system remains elusive and controversial. PrPC is a cell-sur-
face glycoprotein that forms part of cell membrane structures
known as lipid rafts (39). In the nervous system, lipid rafts
are heavily involved in cellular signal transduction pathways,
including neurotrophic factor signaling, cell adhesion and mi-
gration, axon guidance, myelin genesis, and synaptic trans-
mission (40). It is therefore not surprising that most of the
cellular functions of PrPC that have been described over the
past two decades relate to a wide range of signal transduction
pathways (41) involving molecular interactions with multiple
cellular proteins (42), some of which are vital for normal neu-
ronal function. For example, in mouse neuroblast brain cells,
PrPC overexpression enhances cell proliferation and cell cycle
reentrance, whereas PrPC silencing slows down the cell cycle;
these effects are mediated via PrPC interactions with epidermal
growth factor receptor (EGFR) in the plasma membrane (43).
Similarly, PrPC expressed in pluripotent human embryonic
stem cells have been shown to induce and modulate cell cycle
dynamics and partly determine cell differentiation (44). PrPC
has also been shown to be essential for myelin maintenance,
as depletion of PrPC in neurons triggers a form of chronic
demyelinating neuropathy in mice (45). PrPC has been impli-
cated in neuroprotective and neurotoxic signaling cascades
(46). Furthermore, there is an expanding body of evidence
that supports clear interactions between PrPC and metal ions
in different signaling pathways, particularly copper, zinc, and
iron (47).
Despite the role of PrPC in a variety of important cellular
functions (48), however, some PrPC knockout mice have been
shown to develop normally and do not have signs of neuro-
logic disease (49), thereby suggesting that the absence of PrPC
is not a sufficient cause of neurodegeneration or neurodevel-
opmental abnormalities.
Structural Differences Between PrPC and PrPSc
All mammalian proteins are composed of a specific structure of
amino acids (primary structure) that are arranged into identifi-
able repeating structures held together by hydrogen bonding
(secondary structure), which in turn cause protein molecules to
adopt specific three-dimensional conformations (tertiary and
quaternary structures). Via their three-dimensional structure,
Scheld_Ch18.indd 264
cellular proteins are able to interact with each other and
thereby dictate an organisms physiology.
The primary structure of PrPC across different mamma-
lian species is highly conserved (50) and is nearly identical to
that of PrPSc (51). PrPSc and PrPC also share important post-
translational modifications, including the presence of two
N-glycosylation sites, a single disulfide bond between cysteine
residues, and a glycosylphosphatidylinositol membrane an-
chor at the C-terminus (this is the site of attachment of PrPC to
the cell membrane) (52).
The biochemical and biophysical differences that exist be-
tween PrPC and PrPSc are the result of specific posttranslational
modifications that affect the secondary, tertiary, and quaternary
structures of these proteins. In this respect, the most important
difference between PrPC and PrPSc relates to their response upon
exposure to detergents and proteases. PrPC is soluble in nonde-
naturing detergents and degrades when exposed to proteases.
PrPSc, on the other hand, forms amyloid structures (prion rods
that show the typical fluorescence birefringence of amyloids)
when exposed to detergents and is highly resistant to cellular
proteases, particularly proteinase K (PK) (52). It is important
to note that PrPSc is not fully resistant to PK, however, and this
will be discussed further in the following texts. The insolubility
of PrPSc to detergents, on the other hand, is universal, and this
property is used in the laboratory to accurately diagnose the
presence of prion disease.
Our knowledge of the structural differences that exist be-
tween PrPSc and PrPC at an atomic level has been obtained via
careful studies on different transgenic animal models using
nuclear magnetic resonance (NMR) and infrared (IR) spec-
troscopy and x-ray crystal diffraction. IR spectroscopy stud-
ies have shown that PrPC has a high alpha-helix content and
virtually no beta-sheet content, whereas PrPSc is characterized
by roughly equal amounts of alpha-helices and beta-sheets
(53). Alpha-helices and beta-sheets are secondary protein
structures. NMR spectroscopy studies also reveal that PrPC
forms a unique three-dimensional structure in its C-terminus,
consisting of three alpha-helices bundled with two short
antiparallel beta-sheets (52), whereas the N-terminus does
not arrange into a specific conformation. These findings
have been largely replicated using x-ray crystal diffraction
methods (54).
Possible Mechanisms of PrPC Conversion and
PrPSc Propagation
The infectious nature of prions in animals was perhaps
most influentially demonstrated by Legname and colleagues
(55) in 2004, when they inoculated fibrils of N-terminally
truncated recombinant mouse PrP made in Escherichia coli
into the brains of transgenic PrP knockout mice expressing
N-terminally truncated PrP and showed that these mice devel-
oped neurologic dysfunction between 380 and 660 days after
inoculation, with neuropathologic findings consistent with
prion disease. When brain extracts from these mice were then
inoculated into the brains of wild-type mice, these mice devel-
oped a prion disease. Many other similar experiments have
confirmed that prions have the ability to replicate and propa-
gate within the nervous system.
As stated previously, the mode of propagation of prions
is unique among infectious agents, in that prions do not ap-
pear to use nucleic acid to replicate within the host species.
Instead, according to the protein-only hypothesis of prion
spread, the presence of PrPSc by itself induces endogenous
2/21/14 5:39 PM

PrPC to misfold into PrPSc via the modification of the second-
ary and tertiary structures of PrPC in a process referred to as
template-directed misfolding. In other words, PrPSc acts as a
template that guides PrPC misfolding: one molecule of PrPSc
induces the conversion of one molecule of PrPC into PrPSc,
two molecules of PrPSc induce the transformation of two new
molecules of PrPC, and so PrPSc accumulates in an exponential
fashion (see Figs. 18.2 and 18.3. The progressive accumula-
tion of pathogenic PrPSc in the nervous system leads to the
clinical manifestations and neurodegeneration seen in prion
disease (1).
The exact mechanisms by which PrPSc leads to the mis-
folding of PrPC are yet to be determined. It has been demon-
strated experimentally that the first step in prion infectivity
involves the successful cellular uptake of PrPSc in susceptible
host cells (56,57), thereby allowing the physical interac-
tion between PrPC and PrPSc that is required for misfolding.
Although it is widely accepted that the presence of cel-
lular PrPC is required for the propagation of prion disease
(58,59), the initial cellular uptake of PrPSc occurs without
participation of PrPC (60). Instead, several cell membrane
Scheld_Ch18.indd 265
Chapter 18: Human Prion Diseases 265
FIGURE 18.2 Molecular pathogen-
esis of prion disorders. In sJCD, PrPC
spontaneously misfolds into PrPSc.
In gPrD, mutations in the prion gene
make it easier for PrPC to misfold into
PrPSc. In iatrogenic forms of prion
disease, PrPSc is accidentally transmit-
ted into the brain of a person, causing
their PrPC to misfold into PrPSc by a
templating mechanism. Conversion of
PrPC to PrPSc becomes exponential and
results in neurodegeneration or spongi-
form encephalopathy. (From Rubin R,
Strayer DS, Rubin E. Rubins Pathology.
6th ed. Baltimore: Lippincott Williams
& Wilkins; 2011:1334.)
receptors have been implicated in the initial steps of trans-
formation of PrPC into PrPSc. Among these, the low-density
lipoprotein receptorrelated protein 1 (LRP1) might be an
important player (61) as well as glycosaminoglycan (62) and
laminin receptors (63). There are likely other cellular recep-
tors involved in this process.
Once incorporated to the host cell, PrPSc leads to PrPC mis-
folding within minutes. This was elegantly demonstrated in in
vitro experiments using epitope-tagged PrPC in neuroblastoma
cell lines (64). Moreover, it appears that PrPC misfolding oc-
curs largely within the cell surface, from where PrPSc is then
endocytosed and either recycled back to the plasma membrane
or deposited within the Golgi system (65).
Several biochemical and biophysical factors have been
shown to facilitate the misfolding of PrPC into PrPSc in vitro,
including the presence of acidic and/or salt solutions and inter-
actions between PrPC and metal ions (66). The cellular mecha-
nisms of PrPC misfolding remain elusive, however, and there is
mounting evidence suggesting that there are several different
cellular structures and cofactors mediating the transformation
of PrPC to PrPSc (67,68).
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 266 Part II: Viral Infections and Related Disorders
FIGURE 18.3 One proposed mechanism for reproduction of the
infectious prion protein (PrP). PrPC, noninfectious PrP; PrPSc, infec-
tious PrP. (From Harvey RA, Cornelissen CN. Microbiology. 3rd ed.
Baltimore: Lippincott Williams & Wilkins; 2012:328.)
Scheld_Ch18.indd 266
SPORADIC HUMAN PRION
DISEASE: JAKOB-CREUTZFELDT
DISEASE, FATAL INSOMNIA, AND
VARIABLY PROTEASE-SENSITIVE
PRIONOPATHY
Sporadic Jakob-Creutzfeldt Disease
The disease that we now recognize as sporadic Jakob-
Creutzfeldt disease (sJCD) clinically and neuropathologically
was first described by Alfons Maria Jakob (69,70) in the
early 1920s. The single case that his mentor Hans Gerhard
Creutzfeldt (71) described in 1920, on the other hand, was nei-
ther clinically nor neuropathologically representative of sJCD
or what we now know as prion disease (72,73). Therefore,
some authors prefer the more correct eponym Jakobs or
Jakob-Creutzfeldt disease rather than Creutzfeldt-Jakob dis-
ease (CJD) when referring to prion disease. The authors of this
chapter prefer the name Jakob-Creutzfeldt over Creutzfeldt-
Jakob. Thus, the term should probably be Jakob-Creutzfeldt
disease (or even Jakobs disease [JD]). Of note, some physicians
have mistakenly thought prion disease was due to the JC virus
and incorrectly sent the JC virus PCR as a test for prion dis-
ease. In this chapter, we use the term Jakob-Creutzfeldt disease.
Most studies have shown that about 85% of human prion
diseases are sporadic, 10% to 15% are genetic, and less than 1%
is acquired. In a large prospective systematic study of human
prion disease in Europe, Australia, and Canada from 1993
to 2002, which included more than 4,400 pathology-proven
cases, the incidence of sporadic prion disease was approxi-
mately 85%, genetic was about 10%, and acquired were about
6% (74). The larger percentage of acquired cases than many
other studies is likely due to the emergence of vJCD primar-
ily in the United Kingdom and France during this time period
(75) as well as the emergence of human pituitary hormone
cases from prior exposure in the United Kingdom, France, and
Australia (76). The incidence of sporadic human prion diseases
in most populations is about 1 per million, of gPrD about 1 per
10 million, and even less for acquired prion disease (77).
Before recent advances in molecular biology were applied to
study human prion disease, sJCD was subdivided into separate
phenotypes based on clinical and histopathologic character-
istics. Classic subtypes of sJCD described in the early litera-
ture include the Heidenhain variant of sJCD, characterized
by prominent early visuospatial symptomatology, sometimes
leading to cortical blindness (78); the Jakob variant or spas-
tic pseudosclerosis, which presents with prominent frontal,
pyramidal, and extrapyramidal symptoms; and the Brownell-
Oppenheimer variant, characterized by early cerebellar dys-
function and late dementia. Other clinical variants exist in the
literature.
It is now known that the clinicopathologic variability of
sJCD is in part due to two factors: the polymorphisms at
codon 129 of PRNP (36) and at least two distinct species
of PrPSc (PrPSc type 1 and type 2). In the laboratory, the two
types of PrPSc are distinguished by their mobility on Western
blot transfers after exposure to PK (Fig. 18.4) (79). Taken
together, this line of evidence suggests that the different sJCD
phenotypes are an expression of interactions of the host PRNP
genotype and PrPSc type, and this notion forms the basis of our
current classification of sJCD.
Large studies have been carried out comparing molecular,
neuropathologic, and clinical characteristics of sJCD subjects
(80). Results of these studies prompted a classification scheme
2/21/14 5:39 PM

FIGURE 18.4 Western blot. Western blot analysis of brain homog-
enates from cerebral cortex and probed with antibody 3F4 (against
PrP) after digestion with PK. In each column there are three bands,
representing from top to bottom: diglycosylated, monoglycosylated,
and unglycosylated PrPSc. Type 1 PrPSc has an unglycosylated band
running at a molecular weight of 21 kDa. Type 2 PrPSc has an ungly-
cosylated band running at a molecular weight of 19 kDa. The electro-
phoretic migration of the unglycosylated PK-resistant PrPSc in lane 1 is
from an sJCD MM1 case and shows type 1 PrPSc, whereas lane 2 from
an MM2 sJCD case shows type 2 PrPSc, with a 19 kDa unglycosylated
PK-resistant PrPSc. (From Tartaglia M, Thai J, See T, et al. Pathologic
evidence that the T188R mutation in PRNP is associated with prion
disease. J Neuropathol Exp Neurol. 2010;69[12]:12201227.)
that included six molecular subtypes based on PRNP codon
129 polymorphisms (M/M, M/V, or V/V) and PrPSc type (type
1 or 2). There is considerable overlap between classic sJCD
clinical phenotypes and the clinical phenotypes associated
with each molecular subtype to the extent that five combined
sJCD subtypes were initially recognized: MM1/MV1, VV1,
VV2, MV2, and MM2 cortical and MM2 thalamic (the lat-
ter of which corresponds to sporadic fatal insomnia) (79,81).
The discovery that many patients have both type 1 and type 2
prions has complicated this earlier molecular classification and
expanded the subtypes of sJCD (79,82). It is beyond the scope
of this chapter to describe the clinicopathologic characteristics
of each subtype in great detail. The main characteristics of
each subtype are shown in Table 18.3 (79).
The clinical presentation of sJCD in general is protean, how-
ever. Studies show that 40% to 60% of affected individuals
initially develop cognitive symptoms (8385), generally mani-
festing as memory, executive, and language dysfunction and/or
confusion. Other early clinical manifestations include cerebel-
lar dysfunction, constitutional symptoms, and behavioral/per-
sonality changes (e.g., depression, irritability) in around 20%
of pathology-proven cases of sJCD. Furthermore, impaired vi-
sion (blurred vision, diplopia, and visual hallucinations) has
been reported as an initial complaint in 9% to 15% of cases
(8486). Myoclonus, which is anecdotally considered to be a
sensitive sign of sJCD by many clinicians, is a late feature of
the disease in up to 90% of cases (84). Other movement dis-
orders are often seen in patients with sJCD, either early or late
in their disease course, including dystonia (fixed posturing of
a body part), choreoathetosis (slow, writhing or quick dance-
like movements), parkinsonism (slowed movements, tremor
at rest, etc.), and supranuclear gaze palsy (inability to move
eyes volitionally) (87). Other rare initial manifestations of
Scheld_Ch18.indd 267
Chapter 18: Human Prion Diseases 267
sJCD include seizures (including status epilepticus) (88); these
have been reported in some studies in up to 10% of cases, but
usually later in the disease course. In our experience, seizures
are far less common than this (84,86,88). Clinically evident
peripheral neuropathy (including cranial neuropathy) is very
uncommon in sJCD (89,90) but is seen more commonly in
some gPrDs (9195).
The average age of onset of sJCD is 65 years, with a peak
incidence in the 7th decade. The average disease duration is 4
to 7 months. The great majority of patients (90%) die within
1 year of diagnosis, but up to 5% of patients may survive for
2 or more years (36,84,96). Certain factors such as younger
age at onset, female gender, and heterozygosity at codon 129
have been associated with longer survival in sJCD (36,77,79).
Invariably, however, sJCD leads to a relatively rapidly progres-
sive dementia (RPD) (compared to most other neurodegenera-
tive diseases), with varied clinical manifestations, depending
on which areas of the brain are affected by prion neurode-
generation. Regardless of pattern of prion spread, most cases
develop akinetic mutism prior to death (87). Death is usually
due to aspiration pneumonia.
Brain magnetic resonance imaging (MRI) is the most sen-
sitive and specific diagnostic test for sJCD, with published
sensitivity of approximately 91% to 96% and specificity of
approximately 92% to 94% (79,97,98). The high diagnos-
tic sensitivity of brain MRI is largely a reflection of its ability
to detect changes very early in the disease course (98). The
most sensitive MRI sequences for the diagnosis of sJCD are
diffusion-weighted imaging (DWI) and apparent diffusion
coefficient (ADC) sequences; indeed, DWI has been shown
to be more sensitive than fluid-attenuated inversion recovery
(FLAIR)/T2 sequences abnormalities (98,99).
The radiographic hallmark of sJCD is the presence of DWI
MRI hyperintensities in the neocortex, basal ganglia, and/or
thalamus, often associated with corresponding ADC map hy-
pointensities, suggesting restricted flow of water molecules in
these regions (97), probably due to pathological changes oc-
curing in prion disease, particularly vacuolation (spongiform
change), prion deposition, and/or gliosis (astrocyte prolifera-
tion) (100). These MRI findings have been included in various
criteria for sJCD (101), although some criteria allow T2 or
FLAIR and do not require DWI abnormalities (102), which
might lead to false-positive diagnoses (97). An example of the
typical brain MRI findings seen in sJCD is shown in Figure
18.5. Three major patterns of DWI MRI hyperintensities have
been identified in sJCD: neocortical and subcortical (approxi-
mately 68% of cases), predominantly neocortical (24% to
30%), and predominantly subcortical (mostly striatal hyperin-
tensities, with or without thalamic involvement) (2% to 5%)
(97,103) (Fig. 18.6). Cortical hyperintensities (or cortical rib-
boning) can be unilateral or bilateral but typically spares the
precentral cortex (97,104). Striatal involvement often begins
unilaterally, but eventually becomes bilateral, and typically
has a decreasing anterior-posterior gradient (i.e., the anterior
caudate appears more hyperintense than the posterior puta-
men) (97). Moreover, up to 90% of sJCD cases demonstrate
involvement of limbic and paralimbic cortical structures (i.e.,
insula, anterior cingulate, hippocampus), visualized as hyper-
intensities and hypointensities of these regions on DWI and
ADC sequences, respectively. In our experience, isolated lim-
bic involvement is atypical for sJCD, however, and should
alert the clinician toward alternative diagnoses (97).
Cortical ribboning is not 100% sensitive and specific for
sJCD, however, as it is also seen in cases of viral and/or autoim-
mune encephalitis, hypoglycemia, seizures and status epilepticus,
hyperammonemic encephalopathy, hypoxic injury, mitochondrial
encephalopathy, vasculitis, and other conditions (97,98,105).
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 268 Part II: Viral Infections and Related Disorders

TA B L E 1 8 . 3
MAIN CLINICOPATHOLOGIC CHARACTERISTICS OF sJCD SUBTYPES

Average Age of Average Disease Characteristic Clinical DWI MRI

sJCD Subtype Onset (years) Duration (months) Features at Onset Findings234,235 PrPSc Neuropathology

MM1/MV1 66 (4291) 4 (124) Cognitive decline is by Primarily cortical Predominantly non-

far the most common hyperintensities in amyloid synaptic
initial manifestation; frontal, parietal, PrPSc deposition
ataxia, visual temporal, or
impairment, aphasia, insular regions
and psychiatric
features can be initial
manifestations in
around 1/3 of patients.
MM2-cortical 66 (4982) 14 (324) Nearly all patients Widespread cortical Perivacuolar PrPSc
present with cognitive hyperintensities deposits
decline; aphasia
may be initial
manifestation in up
to 1/3 of patients.
Ataxia and psychiatric
manifestations are far
less frequent at onset.
MM2-thalamic 46 (2474) 16 (1073) Cognitive decline and Often normal Mild PrPSc deposition
(sporadic fatal ataxia occur in nearly in the thalamus
insomnia) half of patients at
onset; insomnia,
psychiatric symptoms,
and visual signs
occur in around
1/3 of patients at
onset. Dysautonomia
is a rare initial
manifestation.
MV2 62 (4081) 17 (443) Ataxia is most common Predominant signal Kuru-like plaques
initial manifestation, increase in the
followed closely basal ganglia and
by cognitive thalamus
decline. Psychiatric
manifestations
occur in up to 1/3
of patients at onset.
Aphasia is a rare
initial manifestation.
VV2 64 (4183) 6 (318) Nearly all patients Predominant signal Focal plaque-like
present with ataxia; increase in the PrPSc deposits
cognitive decline basal ganglia and
occurs in up to cingulate gyrus
1/3 of patients.
Psychiatric symptoms,
visual impairment,
and aphasia are
uncommon at onset.
VV1 43 (1971) 19 (472) Cognitive decline Cortical Mild synaptic
is most common hyperintensities PrPSc deposition
initial manifestation; in the cingulate,
psychiatric signs are insular cortex, and
initial manifestation in hippocampus
up to 1/3 of patients.

From refs 36, 81, and 233.

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 Chapter 18: Human Prion Diseases 269

FIGURE 18.5 Three common variations of sporadic Jakob-Creutzfeldt disease presentation on MRI.
A: Neocortical (solid arrow), limbic (dashed arrow), and subcortical gray matter (dotted arrow).
B: Neocortical and limbic cortex. C: Limbic and subcortical. Note that the DWI shows the hyperintensities
much more than the corresponding FLAIR sequences, and that DWI hyperintensities often have correspond-
ing ADC hypointensity. Pattern A was found in 54% of cases, pattern B in 27% of cases, and pattern C in
9% of cases. Note that the abnormalities are more readily seen on DWI than on FLAIR. ADC hypointensity,
indicating restricted diffusion, corresponds to most DWI hyperintensities. ADC abnormalities are most eas-
ily identified in the basal ganglia. (From Vitali P, Maccagnano E, Caverzasi E, et al. Diffusion-weighted MRI
hyperintensity patterns differentiate CJD from other rapid dementias. Neurology. 2011;76[20]:17111719.)

Hence, clinicians should consider these and other conditions in
the presence of cortical ribboning on brain MRI. Likewise, stria-
tal and diencephalic DWI hyperintensities with ADC hypointen-
sities should not be considered pathognomonic of sJCD, as these
changes have been observed in extrapontine myelinolysis, Wilson
disease, Wernicke encephalopathy, and hyperglycemia with
seizures (97,105). These DWI hyperintensities might decrease in
late stages of the disease due to brain atrophy, particularly in pa-
tients with disease duration of over 1 year (97). Despite the high
sensitivity and specificity of MRI DWI and ADC sequences for
the diagnosis of sJCD in the right clinical setting, there is evidence
to suggest that radiologists often miss the diagnosis of sJCD
because they fail to recognize these changes (106,107).
Electroencephalogram
The diagnostic value of electroencephalography (EEG) has less-
ened to some extent due to the high sensitivity and specificity
of brain MRI for the diagnosis of sJCD (98). Still, the presence
of periodic sharp wave complexes (PSWCs), often biphasic or
triphasic, occurring every 0.5 to 2 seconds (Fig. 18.7) remains
a useful finding that helps rule in sJCD in the right clinical
setting (77,108). This EEG finding is found only in about two
thirds of sJCD patients, however, and is most often present
late in the disease course and may require repeated EEG test-
ing (108). In general, compared to brain MRI, EEG probably
provides little value for diagnosis early in the disease course.
Furthermore, the presence of PSWCs rarely is seen in other
neurologic conditions such as Alzheimer disease, dementia
with Lewy bodies, toxic-metabolic and anoxic encephalopa-
thies (e.g., hepatic), progressive multifocal leukoencephalopa-
thy, and Hashimoto encephalopathy (109,110).
Cerebrospinal fluid
Routine CSF analysis is typically normal in sJCD, although
sometimes a mild elevation in the total protein level can be seen
(typically less than 75 mg/dL). CSF pleocytosis (10 cells/L
white blood cells [WBCs]), an elevated immunoglobulin G (IgG)
index, and/or the presence of oligoclonal bands are unusual in
sJCD and should lead the clinician to consider other conditions,
particularly infectious or autoimmune disorders (111,112).
The clinical use of several CSF biomarkers is quite contro-
versial, with evidence showing varying degrees of sensitivity and

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 270 Part II: Viral Infections and Related Disorders

FIGURE 18.6 Brain MRI of a patient with pathology-proven sJCD showing three key sequences for
prion disease diagnosis: FLAIR, DWI, and ADC. Note that the abnormal hyperintensities (bright areas)
in the deep nuclei (solid arrows) and cortex (dotted arrows; cortical ribboning) are more evident on the
DWI than the FLAIR MRI, which is typical of JCD. The hyperintense regions on DWI have correspond-
ing hypointense (dark) regions on the ADC sequence showing that the DWI and FLAIR hyperintensities
are due to restricted diffusion of water molecules.

specificity for the diagnosis of sJCD. The 14-3-3 protein, for
example, which is one of the first CSF proteins reported to be
elevated in sJCD, and initially reported to have 100% sensitivity
and 96% specificity for the diagnosis of sJCD (113), has been
subsequently found to have more limited sensitivity and specific-
ity when studied in larger patient cohorts (114,115). A more re-
cent analysis in the United Kingdom showed CSF 14-3-3 protein
sensitivity of 86% and specificity of 74% in a pathologically con-
firmed cohort (116). Similarly, an analysis of data obtained from
the U.S. National Prion Disease Pathology Surveillance Center
(NPDPSC) showed the 14-3-3 protein Western blot only had
a receiver operating characteristic area under the curve (ROC
AUC) value of 0.68 (117), which is poor considering that a test
with perfect sensitivity and specificity would be 1.0. Some stud-
ies on the clinical use of CSF 14-3-3 protein suggests it should
be considered a general marker of neuronal injury and death.
Indeed, 14-3-3 protein is ubiquitously present in the intracellu-
lar compartment of brain neurons and is released into the CSF
compartment due to neuronal injury from varied causes. Thus,
14-3-3 protein can be elevated in many non-prion neurologic
conditions, such as multiple sclerosis, acute stroke, Alzheimer
disease and other neurodegenerative dementias, HIV-related
neurodegeneration, seizures, and many others (118122). In this
respect, a large multicenter European study found that the speci-
ficity of 14-3-3 protein is lowered when used to differentiate sJCD
from acute neurologic disorders (such as vascular, inflammatory,
or seizures) versus neurodegenerative dementias (82% to 87%
vs. 95% to 97% respectively). This suggests taking the differen-
tial diagnoses into consideration is important when interpreting
the test result (123). In summary, a positive 14-3-3 protein does
not necessarily equate with prion disease. Regardless, recent rec-
ommendations from the American Academy of Neurology sug-
gest ordering CSF 14-3-3 protein when there is a strong clinical
suspicion of JCD (pretest probability of 20% to 90%) in order
to reduce diagnostic uncertainty (124).
Total-tau (t-tau), neuron-specific enolase (NSE), and the as-
trocytic protein S100 are also used as CSF biomarkers for sJCD
diagnosis. The sensitivity and specificity of these biomarkers var-
ies greatly among studies. In a large multicenter, retrospective
European study (115), the combined sensitivity and specificity
of the four main sJCD biomarkers (14-3-3 protein, t-tau, NSE,
and S100) was found to be higher than the individual sensitiv-
ity and specificity. Not all patients in this study underwent all
four tests nor were the tests performed in the same CSF samples,

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 Chapter 18: Human Prion Diseases 271

FIGURE 18.7 Periodic complexes associated with Jakob-Creutzfeld disease. A 65-year-old woman with
history of rapid cognitive decline, myoclonus, and gait ataxia. Her EEG showed bilaterally synchronous
and independently sharp wave discharges. Her CSF 14-3-3 prion protein was positive, further supportive
of Jakob-Creutzfeld disease. (From Greenfield LJ, Geyer JD, Carney PR, eds. Reading EEGs: A Practical
Approach. Philadelphia: Lippincott Williams & Wilkins; 2010:253.)

however; hence, this study did not permit a fair comparison be-
tween biomarkers. Nevertheless, the study found the sensitivity
and specificity of the 14-3-3 protein to be 85% and 84%, t-tau
(cutoff 1,300 pg/mL) 86% and 88%, NSE 73% and 95%, and
S100 82% and 76%, respectively (115). Other studies, how-
ever, have shown sensitivity and specificity values higher than
90% for t-tau in sJCD (125,126), although there is still no agree-
ment over its cutoff value (usually higher than 1,150 pg/mL).
In reviewing all of the data, the opinion of the authors of
this chapter is that among 14-3-3, t-tau and NSE, the single
best CSF biomarker is the t-tau, although NSE has somewhat
higher specificity, whereas the 14-3-3 protein is overall the
least clinically useful. There probably is not sufficient data to
make a determination of the clinical utility of S100B (beta).
At our center, we send all three biomarkers when looking for
evidence of rapid neuronal injury. In summary, these CSF bio-
markers are likely markers of rapid neuronal injury and do not
equate with prion disease, but might be helpful in some cases,
yet have overall less diagnostic use than brain MRI (97,98).
New CSF diagnostic tests, such as real-time quaking-induced
conversion reaction (RT-QuIC), that are relatively specific for
prions (and not just biomarkers) are under development (127).
Two Uncommon Forms of Sporadic Human
Prion Disease: Fatal Insomnia and Variably
Protease-Sensitive Prionopathy
The MM2 thalamic form of sJCD is sometimes referred to as
sporadic fatal insomnia (sFI), the least common of the six forms
of sJCD based on molecular classification (36,81). It is similar
clinically and pathologically to the rare gPrD FFI, as described
under gPrDs section. It is the rarest form of sporadic human
prion disease, with approximately 31 cases reported in the lit-
erature. On average, affected patients are 46 years old at dis-
ease onset, mean survival is 24 months (79). Clinicians should
consider this form of sporadic prion disease in patients with
rapidly progressing dementia associated with sleep abnormali-
ties and dysautonomia. Unlike sJCD, EEG, CSF, and brain MRI
investigations have not been shown to be helpful for the diag-
nosis of this disorder (79). Instead, polysomnography, which
shows impaired sleep-related wave forms (such as K-complexes
and spindles), and brain positron emission tomography (PET)
examinations, which consistently show thalamic hypometabo-
lism, have proven to be more useful diagnostic tools (79).

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 272 Part II: Viral Infections and Related Disorders

The variably protease-sensitive prionopathy (VPSPr) is the
latest addition to the list of sporadic human prion diseases
introduced into the literature in 2008 (128). The term vari-
ably protease-sensitive prionopathy is derived from the fact
that prions extracted from brain tissue from such cases pro-
duces a distinctive electrophoretic profile on Western blot due
to sensitivity to protease digestion, which distinguishes it from
other forms of prion diseases. As most laboratory techniques
for diagnosis of prion disease (e.g., Western blot and immu-
nohistochemistry) rely on identification of protease-resistant
PrPSc, as described previously, detecting this form of prion dis-
ease can be quite difficult (129). VPSPr has certain distinctive
clinical, molecular, and pathologic characteristics (79,129).
Clinically, patients generally present with prominent psychi-
atric manifestations and rapid cognitive decline (primarily
aphasia), followed by motor manifestations (ataxia and par-
kinsonism). Clinical presentations, however, vary according
to codon 129 genotype (79). Based on the cases identified
through 2010, cases associated with methionine homozygosity
(VPSPr-129MM) seem to not have prominent psychiatric fea-
tures, whereas VPSPr-129MV and VSPr-129VV cases usually
lack parkinsonism and ataxia. As is the case in sJCD MM2-
thalamic form, MRI, CSF, and EEG investigations often do not
show the typical features diagnostic for sJCD. It is not clear if
VPSPr is as transmissible as other prion diseases, as the prions
in VPSPr are more sensitive to proteases and thus might be
more easily degraded.
Basic Neuropathology of Human Prion Diseases
At a macroscopic level, atrophy is the only gross neuroana-
tomic finding in sJCD brains. Atrophy can be mild to moderate,
localized to the cerebral cortex, basal ganglia, and cerebel-
lar regions. As in other neurodegenerative diseases, atrophy
is most pronounced in patients with a long clinical course.
Unlike what is seen in other neurodegenerative diseases, how-
ever, prominent hippocampal atrophy is usually not seen in
human prion disease (130).
Microscopically, the histopathologic hallmarks of human
prion disease are the presence of neuronal loss, astrocytic glio-
sis, vacuolation (or spongiform changes), and deposition of
prions (PrPSc) in the brain (Fig. 18.8) (131). These changes

FIGURE 18.8 Photomicrographs from right (side relatively spared radiologically and pathologically)
and left (side affected radiologically and pathologically) cortex of a patient with sJCD with very asym-
metric brain involvement. A and D show hematoxylin and eosin (H&E) stains, B and E show CD68
immunostaining for glia (astrocytic gliosis), and C and F show a synaptic pattern of staining for PrPSc
using the 3F4 antibody (against PrP) after hydrolytic autoclaving (which degrades PrP, but not PrPSc).
(From Geschwind M, Potter CA, Sattavat M, et al. Correlating DWI MRI with pathologic and other
features of Jakob-Creutzfeldt disease. Alzheimer Dis Assoc Disord. 2009;23[1]:8287.)

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 Chapter 18: Human Prion Diseases 273

occur without signs of inflammation in the brain, other than
those seen typically with neuronal loss in neurodegenerative
disease, such as microglia activation, astrocytosis, and re-
lease of cytokines (132134). The distribution of vacuola-
tion changes seen in human prion disease vary between cases
and disease subtypes (77), although the head of the caudate
nucleus is most often involved, whereas the brainstem is
relatively spared (130). More than 95% of sJCD cases show
vacuolation and the remaining cases are diagnosed by immu-
nohistochemistry to PrPSc. PrPSc deposition in sJCD is usually
in a nonamyloid form, with frequent synaptic or punctate
deposition in the cortex as well as perivacuolar PrPSc deposi-
tion in brain regions containing vacuolation.
Amyloid plaques of PrPSc are very common in kuru and
the gPrD GSS (see the following texts) but are only found in
about 10% or less of sJCD cases. More specifically, GSS is
usually characterized by multicentric plaques, composed of
a dense core of amyloid surrounded by smaller globules of
amyloid. A different type of plaque known as florid plaque
is commonly seen in vJCD (see the following texts); it con-
sists of an amyloid core surrounded by a halo of spongiform
change, giving it a flower (florid) appearance. This is a find-
ing strongly suggestive for vJCD, as it is rarely seen in other
prion diseases. FFI (see the following texts), a gPrD, is charac-
terized by severe neuronal loss and gliosis in thalamic nuclei,
whereas vacuolation and amyloid deposition are minimal or
even absent (130). Small amounts of PrPSc are usually found
but often restricted to the thalamus, temporal lobe, or other
regions (77).
The Differential Diagnosis of
Sporadic Jakob-Creutzfeldt Disease
Because of the protean manifestations of sJCD, it is often
confused with many other conditions. Table 18.4 shows the
breakdown of non-prion diagnoses of patients referred to

TA B L E 1 8 . 4
DIAGNOSTIC BREAKDOWN OF NONJAKOB-CREUTZFELDT DISEASE RAPIDLY PROGRESSIVE DEMENTIA
REFERRALS TO TWO JAKOB-CREUTZFELDT DISEASE CENTERS

University of California, San Francisco German Cohort n 124

Cohort n 104 (21 Pathology-Proven)136 Total (37 Pathology-Proven)135 Total

Unclassified dementia 14 Alzheimer disease 34

Psychiatric 12 Unclassified dementia 20
Dementia with Lewy bodies 8 Cerebrovascular disease (vascular dementia, 11
cerebrovascular accident)
Encephalitis 8 Encephalitis (chronic), unknown 10
Frontotemporal degeneration (FTD) or FTD motor 7 Parkinson disease 6
neuron disease
Corticobasal degeneration 6 Psychiatric 6
Autoantibodya 4 Motor neuron disease 3
Metastatic encephalopathy 4 Multiple sclerosis 3
Primary CNS lymphomab 4 Paraneoplastic 3
Alzheimer disease 3 Intoxication 3
Encephalopathy 3 Alcohol-induced atrophy 2
Leukoencephalopathy 3 Brain tumord 2
Progressive supranuclear palsy 3 Chronic epilepsy 2
Vasculitis 3 Corticostriatonigral degeneration 2
Alzheimer disease/dementia with Lewy bodies 2 Familial spastic paraplegia 2
Cerebrovascular (vascular dementia, 2 Hashimoto encephalopathy 2
cerebrovascular accident)
Paraneoplastic 2 Hereditary ataxia 2
Otherc 8 Huntington disease 2
Metabolic disorder 2
Primary CNS lymphoma 2
Otherc 5

CNS, central nervous system.

a
One antiglutamic acid decarboxylase, 65 isoform (GAD65), voltage-gated potassium channel, and two novel antineuronal antibodies.
b
One lymphomatosis cerebri.
c
Other University of California, San Francisco Cohort: hydrocephalus, mesial temporal sclerosis, vertigo, germinoma, methylmalonic acidemia,
mulsclerosis, methotrexate toxicity, pathology-proven sarcoid.
d
Gliomatosis cerebri and astrocytoma.
Other German Cohort: leukodystrophy, congophilic angiopathy, fatal familial insomnia, hypoxia, and Niemann-Pick lipoid histiocytosis.
Modified from Geschwind MD. Rapidly progressive dementia: prion diseases and other rapid dementias. Continuum (Minneap Minn). 2010;
16(2 Dementia):3156.

Scheld_Ch18.indd 273 2/21/14 5:39 PM

 274 Part II: Viral Infections and Related Disorders

two large prion referral centers. Many cases initially mis-

diagnosed as prion disease had other neurodegenerative
diseases, encephalitis, or autoimmune (antibody-mediated)
encephalopathies (135138). Among 1,106 brain autopsies
from patients referred with potential JCD to the NPDPSC,
32% (342 cases) were negative pathologically for prion dis-
ease. Among the 304 cases with adequate tissue for diagno-
sis, 51% had Alzheimer disease, 12% had vascular disease,
but almost 25% had possibly treatable conditions, most
commonly autoimmune, neoplastic, or infectious condi-
tions (139). Unfortunately, the reverse is also true in that
prion diseases are often misdiagnosed as other conditions.
In our own recent study of 163 pathology-proven sJCD sub-
jects, patients were an average of two thirds of the way
through their disease course before sJCD was diagnosed
clinically. Infections (non-prion) was the third most com-
mon misdiagnosis category; the top two diagnostic misdi-
agnosis categories were other neurodegenerative diseases
and autoimmune encephalopathies (91). The authors of
this chapter have written several papers on the workup and
evaluation of patients with RPD, including prion disease
(112,140,141). Some suggested diagnostic tests for a pa-
tient with suspected JCD or another form of RPD is shown
in Figure 18.9.
ACQUIRED HUMAN PRION
DISEASES: KURU, IATROGENIC
JAKOB-CREUTZFELDT
DISEASE, AND VARIANT JAKOB-
CREUTZFELDT DISEASE
By far, the most efficient route of transmission of prion dis-
eases is through direct intracerebral inoculation, yet acquired
forms of prion disease would be virtually nonexistent in nature
if this were the only mode of transmission. Indeed, similarly to
viruses, bacteria, and parasites, prions have been shown to in-
vade host mammalian organisms via parenteral and oral routes.
Oral transmission of prion disease has been demonstrated in
humans as well as several animal prion diseases (142,143).
More specifically, in humans, variant Jakob-Creutzfeldt disease
(vJCD) and kuru are acquired via oral transmission (although
vJCD can also be transmitted by blood products; see the follow-
ing section on vJCD). Acquired prion diseases can also occur
iatrogenically via neurosurgical manipulation with contami-
nated instruments, from contaminated corneal and dura mater
grafts, through EEG electrodes, and from intramuscular injec-
tion of cadaveric-derived human pituitary hormones (144,145).

Blood tests CSF Imaging Urine/Other

Basic panel of tests

- Complete blood count - Cell count and - Brain MRI - Urine analysis
- Basic metabolic panel (Ca,P,Mg) differential (including FLAIR, (and culture if
- Liver function tests (including ammonia) - Protein DWI and ADC indicated)
- Renal function tests - Glucose sequences), at - EEG
- Thyroid function tests - lgG index least one scan with
- Oligoclonal bands and without
- Anti-TG and Anti-TP antibodies
contrast
- Vitamin B12/MMA/homocysteine - VDRL
- Rheumatologic screen (ANA, ESR, CRP, - 14-3-3/NSE/total
RF, ANCAs, SSA, SSB) tau
- Rapid plasma reagin (RPR)
- HIV serology
- Paraneoplastic/autoimmune antibodies

Tests to consider in selected cases

- Lyme disease (in endemic areas) - Bacterial, fungal, - Cancer screen (CT - Heavy metal screen
- Cancer screen acid-fast bacilli chest, abdomen, (24h urine)
- Blood smear stains and cultures and pelvis with and - Copper (24h urine)
- Cytology without contrast;
- Coagulation profile - Porphobilinogen
- Flow cytometry mammogram;
- Hypercoagulability testing (PBG)/delta-
body PET scan)
- Whipple PCR aminolevulinic acid
- Copper and ceruloplasmin - MR angiography (ALA) in urine (24h)
- Additional rheumatologic tests - Cryptococcal or brain
antigen - EMG/nerve
(complement, dsDNA, anti-Sm, anti-RNP, angiogram
- Viral PCRs and conduction study
anticardiolipin, anti-SCL 70, Anti-Jo, anti- - MR spectroscopy
cultures - Brain biopsy
centromere antibodies) - Carotid ultrasound
- Echocardiogram

FIGURE 18.9 Suggested diagnostic tests for initial rapidly progressive dementia evaluation. anti-TG,
antithyroglobulin; anti-TP, antithyroperoxidase; MMA, methylmalonic acid; ANA, antinuclear antibody;
ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; RF, rheumatoid factor; ANCA, antineutro-
phil cytoplasmic antibody; VDRL, Venereal Disease Research Laboratory; NSE, neuron-specific enolase;
PCR, polymerase chain reaction. (From Paterson RW, Takada LT, Geschwind MD. Diagnosis and treat-
ment of rapidly progressive dementias. Neurol Clin Pract. 2012;2[3]:187200.)

Scheld_Ch18.indd 274 2/21/14 5:39 PM


Prions Invade the Host Organism
Analogously to Other Infectious Agents
A basic understanding of the mechanisms of spread of pri-
ons after oral inoculation in animal models serves to high-
light the infectious nature of prions. Owing to the unique
biochemical and biophysical properties of PrPSc, prions are
able to resist the low pH and proteolytic environment of
the upper gastrointestinal tract. Indeed, even direct intra-
gastric inoculation of PrPSc, in which it is exposed to the
low pH of stomach acid, leads to the development of prion
disease (146). Once prions reach the small intestine, they
enter the gut-associated lymphoid tissue (GALT), accumu-
lating in Peyer patches (147,148). The exact mechanisms of
absorption of PrPSc from the gut lumen into Peyer patches is
a matter of debate (149); there is strong evidence to suggest
that microcytic cells (M cells), which are specialized cells
within follicle-associated epithelia that overlie organized
mucosa-associated lymphoid tissues (MALTs), are key play-
ers for the transportation of PrPSc across the gastrointes-
tinal epithelium (150,151). Recent studies also suggest M
cellindependent routes of PrPSc transportation (149,152).
Once inside enterocytes, prions are transported into Peyer
patches mainly by dendritic cells, which are bone marrow
derived antigen-presenting cells (153), with macrophages
also playing a somewhat unclear role in this process (154).
Accumulation of PrPSc within Peyer patches is a crucial step
in allowing efficient spread of prions from the gastrointesti-
nal system into the central nervous system. Indeed, the ab-
sence of Peyer patches impairs neural invasion of PrPSc in
animals (155).
After PrPSc accumulates in GALT, and in Peyer patches
in particular, prions infiltrate the enteric nervous system.
Evidence for direct spread from GALT to the enteric nervous
system is most clearly supported by the fact that the regions
of myenteric (Auerbach) plexuses with the most robust accu-
mulation of PrPSc are those closest to Peyer patches harboring
PrPSc (151). Clinicopathologic studies in animals show that
after entering the enteric nervous system, prions reach the
brain via the autonomic peripheral nervous system (primarily
the sympathetic nervous system) and spinal cord or by direct
spread into the medulla oblongata through vagal nerve efferent
fibers. In mice infected intraperitoneally with PrPSc, prion ac-
cumulation occurred first in the splanchnic autonomic (mostly
sympathetic) fibers, which served as conduits for prion spread
to the midthoracic spinal cord, from where prions ascended
into the brain via the intermediolateral cell columns (156). A
similar pattern of spread has been described in a hamster ani-
mal model (157). Furthermore, PrPSc inoculated into the sci-
atic (158) and optic (159) nerves of mice leads to prion-related
brain degeneration, further proof that the peripheral nervous
system can serve as a conduit for prion spread. Moreover,
sympathectomy delayed or prevented neural invasion of PrPSc
from GALT. (160)
Interestingly, other experiments that probed the temporo-
spatial spread of PrPSc using immunohistochemical methods
showed an alternative, direct route of spread from the enteric
nervous system to the medullary dorsal motor nucleus in the
medulla oblongata, from where prions ascend into the brain
(161,162). Similar patterns of neural invasion of prion disease
have been described in other animals, including cattle (163).
Together, these experiments suggest that the vagus nerve serves
as conduit of prion spread.
There is also experimental evidence suggesting that prions
spread from GALT into more distant lymphoid organs before
reaching the central nervous system. In several animal forms
Scheld_Ch18.indd 275
Chapter 18: Human Prion Diseases 275
of prion disease, as well as in vJCD, the spleen and lymph
nodes have been shown to be the first sites of PrPSc replication
after peripheral inoculation. This notion is supported by the
fact that splenectomy delays the onset of orally transmitted
prion disease in mice (164), whereas athymia does not (165),
thus indicating that the B cell immune system plays a major
role in prion disease spread, as has been shown experimentally
(166168). Moreover, prions accumulate in the appendix of
patients with vJCD before they become symptomatic (169),
and tonsil biopsy has been used to diagnose vJCD in the pre-
clinical phases (170). As discussed previously, PrPSc requires
the presence of PrPC for infectivity (171,172). Therefore, in
order for prion disease to propagate within the lymphoid sys-
tem, it must express PrPC; this has been shown experimentally
(173). Taken together, this evidence suggests that lymphoid or-
gans influence the hosts susceptibility to peripheral infection
and serve as foci of propagation and spread to the CNS via the
hemopoietic system.
Aside from direct transmission of prions occurring from
the autonomic nervous system into the central nervous system,
there is also considerable evidence to suggest that prions are
carried to the brain through the blood by crossing the blood
brain barrier (BBB). Prions can be detected in blood plasma
in animals (174), and vJCD can be transmitted via blood
transfusion (175), thus suggesting that blood has the ability
to harbor and transmit disease. Furthermore, PrPC has been
shown to participate in the transport of molecules across the
BBB (176), and radioactively labeled PrPC has been shown to
cross the BBB in both the brain-to-blood and blood-to-brain
directions (177).
Kuru
As discussed in detail previously in the section on the histori-
cal background of prion diseases, kuru is an acquired form of
prion disease due to endocannibalism, confined to the Fore
ethnic group in Papua New Guinea. It has largely become ex-
tinct after the cessation of endocannibalism by missionaries.
Due to an incubation period as long as 50 years or greater,
very rare cases are still being identified (10).
Variant Jakob-Creutzfeldt Disease
vJCD was first identified in the United Kingdom in 1995 (178)
and quickly garnered global media and epidemiologic atten-
tion due to its association with bovine spongiform encepha-
lopathy (BSE) (mad cow disease) and that it was affecting
young persons. BSE is unique in that it is the only form of
nonhuman prion disease known to be transmissible directly
to humans. It is hypothesized that BSE in bovine populations
occurred through contamination of cattle feed with scrapie-
infected sheep products (179181). Worldwide, more than
180,000 cattle are thought to have been infected with BSE, and
the vast majority of these were in the United Kingdom (182).
Due to heightened awareness and more rigorous screening of
livestock, however, the incidence of BSE has been dramatically
reduced since 1992 (182). Two new vJCD cases were identi-
fied in the United Kingdom in 2011, and to our knowledge,
no new cases of vJCD were reported in the United Kingdom
in 2012 or 2013. As of November 2013, 228 cases have been
reported worldwide (183). The relationship between the num-
ber of BSE and vJCD cases over time in the United Kingdom is
shown in Figure 18.10.
2/21/14 5:39 PM
 276 Part II: Viral Infections and Related Disorders

FIGURE 18.10 Annual frequency of bovine spongiform encephalopathy (BSE) and variant JCD in Great
Britain, 1988 to 2010. (From Engleberg NC, Dermody T, DiRita V. Schaechters Mechanisms of Microbial
Disease. 5th ed. Baltimore: Lippincott Williams & Wilkins; 2013:557.)

Although vJCD shares many features with sJCD, the clinical has focused heavily on T2-weighted sequences (i.e., proton
presentation of vJCD differs in several salient ways. Patients density, T2 and FLAIR imaging), primarily because the pre-
infected with vJCD are often younger, with a median age of ponderance of data has been collected in the United Kingdom,
onset around 27 years (range 12 to 74 years) (184) and a lon- where the acquisition of DWI sequences is uncommon. Thus,
ger median disease duration of about 14.5 months (184) than the sensitivity and specificity of DWI for the pulvinar sign is
patients with sJCD. The PRNP codon 129 polymorphism has not yet known.
been identified as a critical susceptibility factor for the acquisi-
tion of vJCD, with nearly every reported case thus far having
been found to be homozygous for methionine at this location
(185,186). Psychiatric symptoms are often an early, prominent
feature, occurring as long as 6 months before obvious neuro-
logic impairments manifest. As a result, many patients with
vJCD are often initially thought to have psychiatric etiologies
for their illness (184). Sensory symptoms (dysesthesias), often
painful; cerebellar signs; and involuntary movements such as
dystonia, myoclonus, and chorea often become more evident
later on in the disease course (184,187).
Diagnostic test results are often also divergent with those
seen in sJCD. CSF tests are often less revealing, with lower
sensitivity and specificity than they are in the differential
diagnosis of sJCD (188). Patients with vJCD rarely exhibit
the classic PSWCs seen in sJCD on EEG, and if so, only in
the final stages of disease progression (189). The brain MRI
hallmark of vJCD is the pulvinar sign, in which bilateral
hyperintensity in the pulvinar nucleus in the posterior region
of the thalamus is brighter than in the anterior putamen
FIGURE 18.11 Magnetic resonance imaging of a patient with vari-
on T2-weighted, FLAIR, or possibly other MRI sequences ant Jakob-Creutzfeldt disease (vJCD). A: Increased signal intensity
(Fig. 18.11). In 85% of patients with vJCD, the pulvinar sign in the pulvinar (arrows; pulvinar sign). B: Increased signal intensity
is seen on their first exam (190). This is a finding rarely exhib- in the pulvinar and dorsomedial thalamus (arrow; double hockey
ited in other forms of human prion disease (191), although it stick sign). (From Engleberg NC, Dermody T, DiRita V. Schaechters
has been reported in sJCD (192). The literature investigating Mechanisms of Microbial Disease. 5th ed. Baltimore: Lippincott
the use of brain MRI in the differential diagnosis of vJCD Williams & Wilkins; 2013:558.)

Scheld_Ch18.indd 276 2/21/14 5:39 PM


As with other forms of non-gPrD, the definitive diagnosis
of vJCD relies on neuropathologic evidence of the presence of
PrPSc in the central nervous system. In vJCD, there is typically
abundant PrPSc deposition and vacuolation in the neuropil as
well as the presence of florid plaques composed of multiple
fibrillary PrP plaques surrounded by spongiform vacuoles.
These are seen most commonly in the molecular layer of the
cerebellum (130). Because vJCD is acquired peripherally, PrPSc
accumulation often is identified in tonsillar tissue and other
parts of the lymphoreticular system (see Fig. 18.12) (193).
Importantly from an infectious disease perspective, it was re-
cently discovered that vJCD could also be acquired from trans-
fusion of vJCD-contaminated blood products (194,195). Three
cases of vJCD have been reported in patients who received
(contaminated) blood transfusions prior to 1999 and developed
symptoms from 6.5 to 7.8 years after the date of implicated
transfusion; all cases clinically and neuropathologically were
similar to other cases of vJCD (196). Two additional patients,
both heterozygous at codon 129 in PRPN (129MV), received
contaminated blood products (nonleukodepleted red blood cells
and factor VIII, respectively) and died of nonneurologic causes
but had positive prion testing in their lymphoreticular system
but without clinical signs of vJCD and without vJCD prions in
their brains; it is not known if they would have ever developed
clinical vJCD (145,186). Of great concern is that these cases
show that vJCD was transmissible by blood product donation
years before the donors became symptomatic.
In order to determine the number of persons in the United
Kingdom who might be harboring latent vJCD, and be po-
tential transmissible carriers of vJCD prions, a few stud-
ies have analyzed anonymized U.K. appendix and/or tonsil
samples. An initial large study found a prevalence of 1 per
4,000 appendices positive for vJCD prions (197), whereas
a follow-up larger study found a higher prevalence of 1 per
2,000 appendices positive, leading to assumptions that there
are subclinically infected persons in the population who might
be transmissible carriers (198); their risk of either develop-
ing symptomatic vJCD and/or passing it on to others through
Scheld_Ch18.indd 277
Chapter 18: Human Prion Diseases 277
FIGURE 18.12 Human tissues and blood involved
in propagation and transport of prions in vJCD.
Orally ingested prions are intestinally absorbed and
transported to the blood and lymphoid fluids. After a
peripheral replication step in the spleen, appendix, ton-
sils, or other lymphoid tissues, prions are transported
to the brain primarily by peripheral nerves. Direct
penetration into the brain across the bloodbrain bar-
rier is conceivable. (From Aguzzi A, Heikenwalder M.
Pathogenesis of prion disease: current status and future
outlook. Nat Rev Microbiol. 2006;4[10]:765.)
medical/surgical procedures or blood products is not known.
Measures were taken in the United Kingdom to prevent trans-
mission of vJCD through blood products with donor selection,
leukodepletion of blood (WBCs carry a majority of prions in
blood), and efforts toward developing methods to detect PrP
in blood (182). It is important to note that although trans-
mission through blood products has been reported in vJCD,
there are no known cases to date of transmission from sJCD
patients through blood transfusion.
Iatrogenic Jakob-Creutzfeldt Disease
To date, with the exception of kuru, human-to-human trans-
mission of prion disease has only occurred iatrogenically. The
first reported case of suspected iatrogenic prion disease was
published in 1974 of a 55-year-old female who developed
RPD beginning 18 months after receiving a corneal transplant
from a donor who later was found to have autopsy-confirmed
JCD. The patient died of JCD 8 months later (199).
Multiple other cases of suspected iatrogenic Jakob-
Creutzfeldt Disease (iJCD) have been reported in the litera-
ture since the 1970s. These have been carefully reviewed by
Paul Brown and colleagues up to 2012 (76,144,200). Several
other vectors of transmission have been implicated in iJCD:
dura mater grafts, EEG leads, neurosurgical instrumentation,
human pituitary hormone extracts, and packed red blood
cells. These modes of transmission will be reviewed briefly.
Since the original report of iJCD via corneal transplanta-
tion, only two other similar cases have been published in the
literature. The first occurred in Japan and the second case in-
volved a German patient (201). Neither case is very conclusive
for a causal relationship, however, as the medical history of
the donor of the Japanese case is unknown and the German
patient developed JCD 30 years after receiving corneal trans-
plants from a donor who died of JCD. Nevertheless, potential
donors of any tissue, including corneas, should be screened for
dementia, particularly prion disease.
2/21/14 5:39 PM
 278 Part II: Viral Infections and Related Disorders
Three years after the first case of iJCD was published
in 1974, Bernoulli and colleagues (202) reported on two
patientsa 23-year-old woman and a 17-year-old boywho
developed JCD within 2 years of having depth electrodes placed
as part of an EEG study for epilepsy. It was later found that
the same electrodes had been previously used in a 69-year-old
woman who died from JCD. Transmission occurred despite
standard sterilization procedures at the time (70% alcohol
and formaldehyde vapor). More than 2 years later, and after
repeated sterilizations, the same electrodes were implanted in
the cortex of a chimpanzee: the animal became symptomatic
18 months later and subsequently died of JCD, confirming
the cases were iatrogenic (203). To date, this represents the
only case of experimentally proven iJCD. A handful of other
cases of JCD have been associated with neurosurgical instru-
mentation, but not proven, with a mean incubation period of
17 months (range 12 to 28 months).
By far, the most common sources of iJCD has come from
cadaveric prion-contaminated growth hormone extracts and
dura mater grafts. The first published case associated with
cadaveric human growth hormone (hGH) extracts involved a
20-year-old man with congenital idiopathic hypopituitarism
who had been treated for approximately 14 years with growth
hormone extracts obtained from pooled human cadaver pitu-
itary glands (204). He developed ataxic gait and dysarthria,
followed by cerebellar dysfunction, myoclonus, and dementia
that progressed rapidly to death due to JCD. Concurrently,
two similar cases were reported to the Centers for Disease
Control and Prevention (CDC): one involved a 22-year-old
man with long-standing growth hormone deficiency who had
been treated with cadaveric hGH for approximately 8 years
and the other case involved a 34-year-old man with congenital
hypopituitarism who had received cadaveric hGH for approx-
imately 6 years; the former case died of autopsy-confirmed
CJD and the latter case died after a course of RPD highly sus-
picious for CJD (205) (http://www.cdc.gov/mmwr/preview/
mmwrhtml/00000563.htm).
The hormone extracts used to treat these patients was pro-
duced and distributed by the National Hormone and Pituitary
Program (NHPP). Approximately 10,000 U.S. patients re-
ceived cadaveric hGH through the NHPP between 1963 and
early 1985 from different hGH batches derived from a pool of
approximately 16,000 cadaver pituitary glands. The average
duration of therapy was 4 years. Each patient received extracts
from up to three different batches per year. Since the original
reports of hGH-associated iJCD, a total of 226 similar cases
have been reported throughout the world, with most originat-
ing in France (119 cases), in the United Kingdom (65 cases),
and in the United States (29 cases). In the United States, all re-
ported cases have occurred in patients who received cadaveric
hGH prior to 1977, before a column chromatography step was
added to the manufacturing purification process of cadaveric
hGH extracts (206). It is estimated that around 2,700 people
received NHPP extracts prior to 1977, and to our knowledge,
the last case in the United States was reported in 2009. In the
United Kingdom, on the other hand, cases continue to appear
at a rate of approximately 2 per year, the most recent case was
reported in 2011. In France, all cases are thought to have arisen
within a 20-month period between December 1983 and July
1985, when up to 50% of hormone extracts produced became
contaminated due to faulty manufacturing processes (206).
It is important to note that the vast majority of pituitary
hormoneassociated iJCD cases have been associated with
hormone extracts produced and distributed by the NHPP.
There are at least two case reports, however, of iJCD asso-
ciated with commercially available cadaveric hGH extracts,
which were produced in different laboratories from those used
Scheld_Ch18.indd 278
to produce the NHPP-distributed hGH (207). The first case in-
volved a 39-year-old Austrian man who died of JCD approxi-
mately 22 years after receiving commercial cadaveric hGH in
the mid-1980s. The second case was a 33-year-old man who
developed rapid dementia approximately 26 years after the
midpoint of commercial hGH treatment and died 9 months
later from probable sJCD. His clinical syndrome and CSF and
brain MRI findings were consistent with JCD, but autopsy
was not performed. Both patients were treated with different
extracts of commercial cadaveric hGH, but it appears that they
received some extracts from the same brand in the same year
(Crescormon, by Kabi Pharmaceuticals, Sweden) (207). More
than 10,000 people, mostly outside the United States, received
commercial cadaveric hGH produced by different companies.
Many details regarding sourcing and production methods of
these extracts are lacking.
Incubation periods for hGH-associated iJCD range from 5
to 42 years (mean 17 years) from the midpoint of treatment
duration (206). Clinically, iJCD secondary to hGH therapy
tends to produce a clinical syndrome that is reminiscent of
kuru, with prominent early cerebellar signs and late cognitive
dysfunction. Although there is not much data on MRI findings
in hGH-associated iJCD, they appear to range from isolated
cerebellar involvement (208) to appearing similar to sJCD,
often with deep nuclei involvement (207).
Susceptibility to infection is influenced by the methio-
nine/valine polymorphism at codon 129 of the PRNP gene.
Methionine homozygosity is present in 55% of affected U.S.
and French individuals (compared to 40% methionine homo-
zygosity in the general population), whereas valine homozygos-
ity is far more common in the U.K. cohort. Moreover, patients
who were heterozygous at codon 129 tend to have longer incu-
bation periods (30 years) than normal (mean 17 years) (209).
Dura materassociated iJCD is as common as hGH-associ-
ated iJCD worldwide. As of 2012, there are 228 reported cases
of dura materassociated JCD, and 142 of these have occurred
in Japan (200,210). The remaining cases have been reported
in Argentina, Australia, Canada, and Europe. Most iJCD cases
due to dura mater graft contamination have been traced back
to grafts manufactured by one German company, which was
a global provider of dura mater grafts in the 1980s (manufac-
turing ceased in 1987, but patients received grafts until 1993)
(200). The main reason why so many cases have been reported
in Japan relates to the high frequency of use of these grafts in
Japan compared to other countries; it is estimated that 20,000
Japanese patients received contaminated grafts annually dur-
ing the 1980s, often for nonlife-threatening conditions. Other
factors, however, may have contributed to the high incidence,
such as longer survival, and hence longer incubation times,
among Japanese recipients (210).
In most cases the clinical and neuropathologic features of
dura materassociated iJCD appear similar to those of sJCD
(200). In Japan, however, there is evidence suggesting that
dura materassociated iJCD may have distinctive clinical and
molecular features. In Japanese patients with dura materas-
sociated iJCD, two distinct phenotypes were identified: a
dominant type, comprising nearly two thirds of cases, that is
pathologically and clinically nearly identical to sJCD and an
atypical type with prominent plaque formation in the brain
and other atypical clinical features such as slower disease pro-
gression. Both of these types were associated with methionine
homozygosity at codon 129 of the PRNP gene. These differ-
ences have led some investigators to postulate contamination
of the dura mater grafts with different prion strains (211).
Worldwide, the mean incubation period of dura materassoci-
ated iJCD is 12 years, with the shortest and longest reported
incubation times being 16 months and 30 years (200).
2/21/14 5:39 PM

The emergence of dura materassociated iJCD occurred
almost concurrently to that of hGH-related iJCD, and the inci-
dence of both peaked in the mid-to-late 1990s and has steadily
declined since the institution of recombinant growth hormone
extracts (growth hormone extracts and gonadotropins have
been manufactured in vitro since 1987) and synthetic dura
mater grafts (77). Nevertheless, given the long incubation
times reported for both modes of transmission, it is expected
that additional cases might still occur from past exposure.
Likewise, the medical community across different specialties
has adopted effective infection control measures that have de-
creased the risk of iJCD significantly. Patients with suspected
JCD are excluded as blood, tissue, or organ donors. Clinicians
evaluating patients with suspected JCD should always ask
about any prior human pituitary hormone use, ophthalmo-
logic surgery, and neurosurgical procedures.
Measures to prevent iJCD vary by country and by health
care institution. Our institutions infection control guide-
lines for managing suspected human prion cases are avail-
able online at http://infectioncontrol.ucsfmedicalcenter
.org/ICMANUAL2007/Section4/Sec%204.2%20
Human%20Prion%20Policy_5-31-2012.pdf. The World
Health Organization and the CDC have published iJCD
prevention guidelines as well as information on the dis-
tribution of tissue infectivity (212,213) (http://www.who
.int/csr/resources/publications/bse/whocdscsraph2003.pdf,
http://www.cdc.gov/ncidod/dvrd/cjd/qa_cjd_ infection_
control.htm).
HUMAN GENETIC PRION
DISEASES: FAMILIAL JAKOB-
CREUTZFELDT DISEASE,
GERSTMANN-STRUSSLER-
SCHEINKER DISEASE, AND FATAL
FAMILIAL INSOMNIA
gPrDs account for approximately 10% to 15% of all cases of
prion disease. They are associated with autosomal dominant
mutations in the human PrP gene, PRNP, on the short arm of
chromosome 20. PRNP mutations are of different kinds, in-
cluding point mutations, insertions, truncations, and deletions
(34,214,215). There are presently more than 30 PRNP muta-
tions associated with gPrD, all of which lead to disease via the
production of a mutant PrP molecule (PrPSc) (34,214,215).
Some gPrDs have been shown to be transmissible to laboratory
animals, although most have not been tested for transmission
and a few have failed to transmit (216). Genetic forms of prion
disease can be diagnosed through DNA testing of blood in
vivo or through autopsy tissue. Most known PRNP mutations
have very high penetrance (nearly 100%), yet more than 60%
of patients with gPrD do not report a positive family history
of prion disease. This is likely due to a combination of factors,
including misdiagnosis. Some mutations, such as the E200K
mutation, however, have reduced penetrance (217). Patients
with gPrD are typically younger at onset (approximately 40s
to 60s) and have a slower and longer disease course compared
to sJCD patients, although there is great clinical variability
among different mutations, in part due to other genetic (codon
129 polymorphisms) and epigenetic factors that influence phe-
notypic expression (34,214).
As stated previously in the basic prion genetics section of
this chapter, there are three main forms of gPrD in humans:
Gerstmann-Strussler-Scheinker disease, familial Jakob-
Creutzfeldt disease, and fatal familial insomnia. Before discuss-
Scheld_Ch18.indd 279
Chapter 18: Human Prion Diseases 279
ing these three familial presentations of gPrD, it is important
to mention that all three forms were described prior to the
identification of the PRNP gene, hence the description of these
diseases is primarily based on clinicopathologic observations
(214). After the identification of PRNP and its mutations, a
much wider spectrum of phenotypes associated with gPrD is
emerging. In a recent study, for example, researchers identified
a consistent phenotype of chronic diarrhea with autonomic
failure and a length-dependent axonal, predominantly sensory,
peripheral polyneuropathy associated with a specific PRNP
mutation (PRNP Y163X truncation mutation) (218). These
patients begin to develop peripheral neurologic symptoms in
early adulthood, whereas cognitive decline does not occur
until their 40s or 60s, thereby suggesting that genetic forms
of prion diseases can affect the peripheral nervous system be-
fore leading to encephalopathy and dementia. Furthermore,
a recent case of atypical parkinsonism was linked to a spe-
cific mutation in the PRNP gene, the D202N mutation, that
had previously only been associated with GSS (219). Indeed,
the phenotypic heterogeneity associated with PRNP muta-
tions is certainly not encompassed by the three classic forms
of gPrD mentioned previously. Clinical features of each gPrD
can be highly variable, not only within the same mutation but
also within a single family (215). In order to help categorize
gPrDs more easily, however, we will briefly discuss each one
of these forms.
Familial Jakob-Creutzfeldt Disease
For most mutations causing fJCD, the clinical presentation usu-
ally is indistinguishable to that of sJCD, with RPD, ataxia, and
other motor manifestations. More than 15 mutations have been
associated with fJCD, most are point (missense) mutations but
some are insertion mutations and a deletion (34,214). The most
common fJCD mutation worldwide is E200K (214) found most
commonly among Libyan Jews and Slovakians (220). Similarly
to sJCD, brain MRI is helpful for the diagnosis of fJCD, and
both fJCD and sJCD have overlapping findings on MRI. The
MRI appearance of fJCD seems to vary according to mutation
type, however. For example, fJCD patients due to E200K muta-
tion typically show symmetric, prominent striatal hyperinten-
sities on MRI, with less prominent cortical ribboning (221),
whereas patients with V180I mutations often shows cortical
ribboning with minimal or absent basal ganglia hyperintensities
(222). An MRI of a patient with fJCD due to E200K is shown in
Figure 18.13A. Also, depending on the mutation, the EEG often
shows PSWCs in fJCD, particularly in late stages. CSF biomark-
ers (14-3-3 protein, NSE, t-tau) in fJCD often are elevated, but
with typically lower sensitivity than in sJCD (115).
Gerstmann-Strussler-Scheinker Disease
Patients with GSS often become symptomatic earlier than pa-
tients with sporadic prion disease (disease onset is typically in
the 50s or younger). Clinically, GSS often manifests with the
insidious onset of movement abnormalities, including progres-
sive ataxia or parkinsonism. Cognitive impairment is usually
a late feature, although some mutations present with early
dementia and/or behavioral abnormalities. Among all forms
of human prion disease, patients with GSS are perhaps the
most likely to be misdiagnosed as having other neurodegen-
erative diseases or even non-neurodegenerative neurologic and
psychiatric illness. This occurs largely because GSS may have
an unusually long survival compared to other forms of prion
disease (214,223,224).
2/21/14 5:39 PM
 280 Part II: Viral Infections and Related Disorders

FIGURE 18.13 Axial MRI from representative cases of familial Creutzfeldt-Jakob disease (fCJD)
(A), Gerstmann-Strussler-Scheinker (GSS) (B), and non-prion causes of rapidly progressive dementia
(npRPD) (C). A: An fCJD case (E200K mutation) showing neocortical (solid arrow) involvement more
evident in the right hemisphere, especially in the right frontal lobe; limbic involvement (dashed arrow)
more evident in the right anterior cingulate and right insula; and subcortical (dotted arrow) hyperintensi-
ties, greater in DWI than in FLAIR images. Note the subcortical ADC hypointensity in bilateral striatum.
The image was read as Creutzfeldt-Jakob disease (CJD). B: A GSS case (F198S mutation) with bilateral
limbic hyperintensity in the anterior cingulate, insula, and subtle involvement in the mesiotemporal cor-
tex, equally evident in DWI and FLAIR images. Image read as not CJD. C: An npRPD patient with limbic
encephalopathy due to anti-AMPAR with anti-Sox2 antibodies and small cell lung cancer. Note signifi-
cant bilateral hyperintensity in mesiotemporal cortex (including hippocampus and amygdala), insula, and
cingulate, greater on FLAIR than on DWI images. MRI read as not consistent with CJD. (From Vitali
P, Maccagnano E, Caverzasi E, et al. Diffusion-weighted MRI hyperintensity patterns differentiate CJD
from other rapid dementias. Neurology. 2011;76[20]:17111719.)

There is considerable phenotypic variability in GSS within
and between mutations and families (34,225,226). There are
at least 10 PRNP mutations associated with GSS, these include
several missense mutations, a stop mutation, and insertion
mutations (octapeptide repeat insertions [OPRIs]). In general,
OPRI mutations with 5 or more additional octapeptide repeats
(repeats of 24 base pairs) are associated with a long duration
(several years), GSS phenotype, whereas OPRI mutations with
4 or fewer repeats may present as sJCD (34,214). An 8-octa-
peptide repeat insertion mutation (OPRI-8) of PRNP results in a
GSS phenotype with prominent early neuropsychiatric features,
often in the late 20s, with a long disease course of several years.
These patients have ended up hospitalized in psychiatric institu-
tions for management of manic manifestations (223). Likewise,
patients with 6-OPRI mutations may demonstrate psychologic
and/or personality changes (irritability, short temper, aggres-
sion, antisocial behavior, and aggression) years before the onset
of GSS (33). Neuropsychologic testing of these cases almost in-
variably shows frontal executive impairment as well as frequent
visuospatial, language, and memory impairments (224).
EEGs of patients with GSS usually reveal slow waves, not
the PSWCs seen in sJCD. Likewise, CSF biomarkers that offer
some diagnostic use in sJCD (protein 14-3-3, NSE, and t-tau)
are typically not elevated in GSS (115). Given that these CSF
biomarkers are thought to be released into the CSF as a result
of rapid neuronal injury or neurodegeneration, it is possible
that the slow course of GSS is preventing the accumulation of
these markers in the CSF of affected patients (121). Finally,
brain MRI investigations in patients with GSS usually do not
reveal the cortical ribboning or deep nuclei hyperintensities

Scheld_Ch18.indd 280 2/21/14 5:39 PM


seen in sJCD and in other forms of prion disease, although
patients with some PRNP mutations associated with GSS do
have brain MRI findings characteristic of prion disease (97).
An MRI of a GSS patient due to an F198S mutation is shown
in Figure 18.13B.
Fatal Familial Insomnia
FFI is a very rare form of gPrD caused by a single PRNP point
mutation, D178N, with codon 129 having methionine (129M)
on the same chromosome (cis). Curiously, patients with the
D178N mutation with the cis codon 129 being valine (129V)
usually present with an sJCD clinicopathologic phenotype.
Thus, codon 129 can have a profound effect on the expres-
sion of human prion disease. The codon 129 polymorphism
on the trans or normal (without the mutation) allele also af-
fects disease presentation; for example, FFI patients with
codon 129 methionine homozygosity have shorter disease
durations than those with a trans valine at codon 129 (227).
Patients with FFI usually become symptomatic in their late 40s
(48 to 49 years; range 20 to 72 years), usually with severe,
progressive insomnia over several months, followed by other
manifestations such as dysautonomia (e.g., tachycardia, hy-
perhidrosis, and hyperpyrexia) as well as motor and cognitive
manifestations appearing later in the illness. Mean survival is
about 18 months (range 7 to 33 months), which is slightly
longer than most sJCD patients (34,77). Similarly to patients
with GSS, EEG investigations in patients with FFI usually
show generalized slowing, not PSWCs. Brain MRI is usually
unremarkable, but fluorodeoxyglucose positron emission to-
mography (FDG-PET) imaging reveals thalamic and cingulate
hypometabolism, often even before disease onset (228) CSF
biomarkers in general have very low sensitivity in FFI (115).
The infectious nature of human gPrDs is not clear, but over-
all they appear very difficult to transmit and the risk of trans-
missibility is presumed to be very low. There are no known
cases of transmission of gPrD from human to human. Because
of the theoretical risk of transmission through blood products,
persons with sJCD, gPrD, or at risk for gPrD (asymptomatic
either with a mutation or have not had PRNP testing) should
not donate blood products. The American Red Cross does
not accept blood product donations from blood relatives of
someone who has died from JCD (http://www.redcrossblood
.org/donating-blood/eligibility-requirements/eligibility-criteria-
alphabetical-listing); their presumed reasoning is that there is a
chance that the JCD patient had gPrD and thus blood relatives
are at risk for also carrying a mutation and thus being potential
transmissible carriers. Realistically, if a patient with JCD does
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2/21/14 5:39 PM
 CHAPTER 19 HUMAN IMMUNODEFICIENCY
VIRUS
CHRISTINA M. MARRA

HIV can directly infect the cerebrospinal fluid (CSF) and the
brain. Infection of the CSF is a notable feature of the acute
retroviral syndrome, and CSF pleocytosis is common in HIV
infection, particularly among individuals with high peripheral
blood CD4 T-cell counts, detectable plasma HIV RNA,
and in those not on antiretroviral therapy (1). Infection of
the brain likely is the substrate for dementia in HIV infec-
tion. The immunodeficiency caused by HIV predisposes indi-
viduals to secondary or opportunistic central nervous system
(CNS) infections or neoplasms (Table 19.1). The incidence
of dementia and most CNS opportunistic infections has de-
clined in the developed world with widespread use of com-
bination antiretroviral therapy (CART). However, although
the incidence may be decreasing, the prevalence of cognitive
impairment is increasing (24). In addition, treatment of HIV
itself may be associated with neurologic complications. The
clinical findings and treatment of CNS opportunistic infec-
tions seen in HIV-infected individuals are covered in several
chapters of this book. In particular, a detailed discussion of
cerebral toxoplasmosis is provided in Chapter 43, and neu-
rosyphilis is covered in Chapter 38. This chapter addresses
two opportunistic infections not covered elsewhere: primary
CNS lymphoma, which is considered with infections because
of its association with Epstein-Barr virus infection, and pro-
gressive multifocal leukoencephalopathy (PML) caused by the
JC virus. In addition, the most common CNS complications
associated with HIV itself are discussed, including newly rec-
ognized syndromes.

TA B L E 1 9 . 1
CENTRAL NERVOUS SYSTEM INFECTIONS ASSOCIATED WITH HIV

Type of Infection Organisms Focal Lesion Encephalitis Meningitis

Protozoal Toxoplasma gondii X X (rare)

Trypanosoma cruzi X
Amoebae (rare) X X X
Viral Cytomegalovirus X X X
Herpes simplex type 1 X
Herpes simplex type 2 X X
Varicella zoster X X X
JC virus (causes PML) X X (rare) X (rare)
Epstein-Barr virus (associated X
with primary CNS lymphoma)
Bacterial Mycobacterium tuberculosis X X
Treponema pallidum X X
Mycobacterium avium complex X X
Listeria monocytogenes X X
Salmonella sp. X
Streptococcus pneumoniae X
Nocardia sp. X
Bartonella sp. (rare) X X
Mixed (pyogenic brain abscess) X
Fungal Cryptococcus neoformans X X
Candida sp. X X
Aspergillus sp. X X
Coccidioides immitis X
Histoplasma capsulatum X
Pneumocystis jirovecii (rare) X

286

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 Chapter 19: Human Immunodeficiency Virus 287

FOCAL BRAIN DISEASE Differential Diagnosis

Opportunistic infections, neoplasms, and cerebrovascular dis-
ease are the most common causes of focal findings referable
to the brain in HIV-infected patients. In such individuals, the
presence or absence of contrast enhancement and mass effect
on cranial neuroimaging studies helps to narrow the differen-
tial diagnosis. Lesions associated with contrast enhancement
and mass effect are most commonly due to toxoplasmosis, pri-
mary CNS lymphoma, or tuberculoma. Lesions with minimal
or no contrast enhancement and no mass effect are most com-
monly due to PML.
Primary Central Nervous
System Lymphoma
Etiology
Primary CNS lymphomas in HIV-infected patients are typically
of B-cell origin and are classified as diffuse large cell or immu-
noblastic (5). Epstein-Barr virus (EBV) is detectable in these
tumors in virtually all HIV-infected patients (5). Prolonged im-
mune suppression and EBV-induced B-cell stimulation likely
contribute to tumor development (6).
As noted earlier, the most common causes of brain lesions as-
sociated with contrast enhancement and mass effect are toxo-
plasmosis, primary CNS lymphoma, and tuberculoma. Other
causes are listed in Table 19.1.
Clinical Symptoms and Findings
The presenting clinical features of HIV-associated primary
CNS lymphoma include confusion, lethargy, memory loss,
hemiparesis, speech and language disorders, seizures, and cra-
nial nerve palsies (7,8).
Laboratory and Imaging Studies
HIV-infected patients with primary CNS lymphoma typi-
cally have peripheral blood CD4 T-cell counts less than 50/
L (9). Brain computed tomography (CT) or magnetic reso-
nance imaging (MRI) show ring- or homogeneously enhanc-
ing lesion(s), often located periventricularly or in the frontal
lobes, although other locations may be seen (Fig. 19.1). These
lesions may cross the midline in the corpus callosum and may

FIGURE 19.1 Paired contrast-enhanced T1-weighted (top) and fluid-attenuated inversion recovery
(FLAIR) (bottom) magnetic resonance images in HIV-associated primary CNS lymphoma showing a
single well-circumscribed lesion with contrast enhancement and surrounding edema. Biopsy showed dif-
fuse large B-cell lymphoma. (With permission from Claire Beiser, MD.)

Scheld_Ch19.indd 287 2/21/14 5:40 PM

 288 Part II: Viral Infections and Related Disorders
be associated with patchy nodular ventricular enhancement
(10). Thallium-201 (201Tl) single-photon emission computed
tomography (SPECT) may be helpful in distinguishing be-
tween CNS infections and primary CNS lymphoma in HIV-
infected individuals. Focal areas of increased 201Tl uptake are
seen in patients with lymphoma, whereas no brain uptake
is seen in patients with CNS infections such as Toxoplasma
encephalitis or tuberculoma (11,12). Delayed imaging and
calculation of a retention index increase the specificity of
the test (12).
Although the diagnosis of primary CNS lymphoma can
only be proven by histopathology, examination of CSF for
EBV DNA by polymerase chain reaction (PCR) may be sensi-
tive and specific for establishing the diagnosis (13) when it is
used in the appropriate clinical setting: an HIV-infected patient
with a focal brain lesion with mass effect and enhancement.
The positive predictive value of the test is highest in patients
with a low likelihood of CNS toxoplasmosis, such as those
who are Toxoplasma seronegative or who have been taking
trimethoprim-sulfamethoxazole for prophylaxis against toxo-
plasmosis. When the test is used more broadly in clinical set-
tings, the positive predictive value of detection of EBV DNA
in CSF is lower (14,15).
Treatment and Prevention
HIV-associated primary CNS lymphomas are sensitive to
radiation therapy. In a retrospective analysis conducted be-
fore the availability of CART, median survival was about 3
to 4 months with radiation therapy and dexamethasone and
untreated survival was 3 to 4 weeks (16). Death was usually
due to opportunistic infection rather than lymphoma (7,8).
Absence of opportunistic infection, younger age, higher
Karnofsky performance status, and delivery of higher biologi-
cally effective doses of radiation were associated with longer
survival (17).
More modern studies show that whole brain radiation
therapy (at least 30 Gy) (1820) and CART (18,20,21) are
associated with better survival in HIV-infected patients with
primary CNS lymphoma, often with best survival seen in
those who receive both modalities. Prolonged survival has
also been reported in HIV-infected patients with primary
CNS lymphoma who only received CART (2224). Some
have suggested that whole brain radiation be reserved for
patients who do not respond to antiretrovirals to avoid the
morbidity, particularly leukoencephalopathy, associated with
this treatment modality. Because of the association with EBV,
some investigators have advocated combination therapy for
HIV-associated primary CNS lymphoma that targets this virus
with agents such as ganciclovir or foscarnet. Individual re-
ports of success with these regimens can be difficult to eval-
uate because patients are often also treated with radiation,
CART, and immune modulators (2530). Overall, treatment
data for HIV-associated primary CNS lymphoma are mostly
from retrospective case reports and series and are limited by
selection bias. The best treatment for HIV-associated primary
CNS lymphoma is not known because a randomized trial has
not been conducted, and, given the low incidence of the disor-
der, may never be feasible.
Prior to the advent of CART, primary CNS lymphoma oc-
curred in 1% to 4% of HIV-infected persons. Since CART has
become widely available, the incidence of this disorder has
declined (31,32) and survival has improved (18,33). Thus,
prevention lies in antiretroviral treatment to prevent pro-
longed immunosuppression.
Scheld_Ch19.indd 288
Progressive Multifocal
Leukoencephalopathy
Etiology
PML is caused by a polyoma virus called JC virus. This
virus is usually acquired in childhood. It remains latent in
kidney and perhaps in brain, reactivates in the setting of
immunosuppression, and infects oligodendrocytes and less so
astrocytes. Death of oligodendrocytes leads to demyelination.
Differential Diagnosis
The diagnosis of PML should be considered in patients with
dementia, particularly if there are also focal neurologic find-
ings. Varicella-zoster encephalitis may cause demyelination
and should also be considered (34). Cytomegalovirus (CMV)
encephalitis is sometimes accompanied by focal lesions that
could mimic PML (35). Substance abuse, particularly a form
of heroin use called chasing the dragon, can cause clinical
and radiographic abnormalities similar to PML (36). A se-
vere form of HIV-associated leukoencephalopathy charac-
terized pathologically by extensive perivascular macrophage
infiltration and demyelination and high levels of brain and
CSF HIV RNA has been described (37). Patchy or confluent
white matter high signal intensity is seen on brain MRI. The
syndrome occurs in patients failing CART and is accompa-
nied by cognitive abnormalities. Leukoencephalopathy has
been described in individuals whose HIV is successfully
treated, and has been attributed both to CNS immune
reconstitution (3840) and to CNS escape in individu-
als with suppressed plasma HIV RNA but detectable CSF
HIV RNA (41). The latter two diagnoses may be distin-
guished from PML because they may be associated with
CSF pleocytosis.
Clinical Findings
Patients with PML typically experience insidious onset of
progressive neurologic deficits, most commonly cognitive dys-
function, limb weakness, gait disturbance, coordination dif-
ficulties, and visual loss. Headache is a complaint in about
one fourth of patients. Neurologic examination shows focal
deficits, particularly hemiparesis or visual field abnormali-
ties (42,43). Less common manifestations of CNS JC infec-
tion include cerebellar granule cell neuronopathy (44) and JC
infection of cortical pyramidal neurons, causing an acute en-
cephalopathy (45).
Laboratory and Imaging Studies
HIV-infected patients with PML typically have peripheral
blood CD4 T cells less than 200/L, although even before
the advent of CART, about 10% of patients had CD4 counts
above this threshold (43). In the current treatment era, indi-
viduals with PML and much higher or even near-normal pe-
ripheral blood CD4 T cell concentrations have been reported
(46,47).
Brain CT in patients with PML may sometimes be normal.
More often, it shows multiple, often confluent, white matter
lesions that are most commonly located in the parietooccipital
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 Chapter 19: Human Immunodeficiency Virus 289

FIGURE 19.2 Paired T1-weighted (top) and fluid-attenuated inversion recovery (FLAIR) (bottom) mag-
netic resonance images in HIV-associated PML. Most notable is the large left frontal white matter lesion
that crosses the midline in the corpus callosum. This abnormality is seen on both the T1-weighted and
FLAIR images but is better seen on the FLAIR images. Another smaller lesion is evident in the right fron-
tal white matter. None of the lesions has associated mass effect.

regions. These lesions are low density and have little, if any,
mass effect (43). Enhancement may be seen in 10% of CT
scans and is usually faint and peripheral (43). Brain MRI
shows more lesions than CT (48). In contrast to the white mat-
ter lesions seen in HIV-associated dementia, which are visible
only on T2-weighted images, PML lesions are low intensity
on T1-weighted and high intensity on T2-weighted images
(Fig. 19.2); about 15% show faint contrast enhancement (43).
Contrast enhancement is more likely to be seen in the setting
of immune reconstitution (see the following discussion). In ad-
dition to the abnormalities seen on T1- and T2-weighted MRI,
restricted diffusion may be seen; additional examples of MRI
abnormalities in PML are shown in Chapter 3.
Diagnostic criteria for PML have been recently published
(49). In patients with characteristic clinical and neuroimaging
findings, histologic examination or identification of JC virus
DNA by PCR in CSF can confirm the diagnosis. However,
a negative PCR does not exclude the diagnosis. Individuals
who develop PML while receiving CART as well as those with
higher peripheral blood CD4 T cell concentrations are more
likely to have a negative diagnostic PCR (50).
Treatment and Prevention
Recent studies suggest that the current incidence of PML has
declined approximately three- to fourfold compared to before
1996, with estimates among HIV-infected individuals ranging
from 0.6 to 1.3 per 1,000 person-years (51,52). Treatment
with potent antiretrovirals has also resulted in significantly
improved survival in patients with PML (5153).
Several prognostic factors have been identified in HIV-
associated PML. Mass effect on MRI (54) and brainstem and
cerebellar involvement (55,56) are associated with poorer out-
come. Higher peripheral blood CD4 T-cell count at diagnosis
(48,51,5760), PML as the AIDS-defining illness (58), lower
concentration and decline in CSF JC virus DNA concentration
during antiretroviral therapy (5964), and the presence of JC
virus-specific cytotoxic T cells in blood (6567) are associated
with improved survival.
All HIV-infected patients with PML should be treated with
CART aimed at complete suppression of plasma HIV viremia.
Whether certain types of antiretroviral regimens are more

Scheld_Ch19.indd 289 2/21/14 5:40 PM

 290 Part II: Viral Infections and Related Disorders
effective than others remains a matter of debate because few
prospective studies have been conducted. Two retrospective
analyses suggest that a regimen that includes a protease inhibitor
may be more effective than one that does not (68,69). Gasnault
and colleagues (60) conducted a multicenter, prospective, open-
label trial of an individualized regimen of five antiretrovirals,
including enfuvirtide for the first 6 months, in 28 HIV-infected
patients with PML. The 1-year survival was 75%, significantly
higher than the historically reported survival of 45% at the
time the trial was planned (63,7072). In this trial, all deaths
occurred within the first 4 months of treatment (60).
As a consequence of an immune reconstitution inflamma-
tory syndrome (IRIS), PML may develop (unmasking or simul-
taneous IRIS) or worsen (paradoxical or delayed IRIS) after
beginning antiretroviral therapy. In an observational study
in Spain of 61 patients with PML, 14 (23%) developed PML
IRIS, of which 8 were unmasking IRIS and 6 paradoxical IRIS
(53). In a case series and retrospective review, PML IRIS devel-
oped 1 week to 26 months (median 7 months) after beginning
antiretroviral therapy, with a shorter latency, greater number
of MRI-defined brain lesions, and poorer outcome in paradox-
ical compared to unmasking IRIS (73). A retrospective case se-
ries showed that peripheral blood CD4 T cells 50/L at the
time of initiating antiretroviral therapy significantly increases
the risk of PML IRIS and that the prognosis of patients with
PML IRIS is no different than PML patients without IRIS (74).
Paradoxical IRIS is characterized by clinical worsening and
progression of previously defined MRI lesions or development
of new lesions, often, but not always, with evidence of contrast
enhancement. In the absence of new enhancement, paradoxi-
cal IRIS can be difficult to distinguish from progressive dis-
ease, although the onset of clinical worsening in IRIS may be
more acute. Both fatal and benign courses have been described
(73,7577) as well as individuals that do and do not respond
to immunosuppression with steroids (73,78). A single case of
rapid improvement in paradoxical PML IRIS after treatment
with the CCR5 inhibitor, maraviroc, but not treatment with
methylprednisolone, has been reported (79). The authors specu-
lated that blocking of CCR5 leukocyte recruitment to the CNS
might have been the underlying mechanism of improvement.
No specific therapy for HIV-associated (or nonassociated)
PML has been identified. Cytosine arabinoside (Ara-C) given
intravenously (IV) or intrathecally did not confer a survival
benefit in a clinical trial conducted before the availability of
CART (80). A metaanalysis of cidofovir showed no benefit
beyond that of CART (72). Mefloquine showed anti-JC activ-
ity in an in vitro assay (81), but an open-label randomized
trial was stopped early because of lack of efficacy (64). Based
on the observation that the cellular receptor for JC virus is the
5-HT2A serotonin receptor (82), mirtazapine has been used for
PML treatment with anecdotal reports of success (83,84), but
no clinical trial has been conducted.
HIV-infected patients with PML who survive generally
have persistent neurologic deficits, although some regain in-
dependence. In the trial by Gasnault and colleagues referenced
earlier, the median modified Rankin scale at 12 months in the
21 survivors was 3 (moderate disability). Eight patients had
only slight disability and were independent (60). In contrast,
in the Swiss HIV Cohort Study, among 47 individuals who
survived more than 1 year, only 8 (17%) had clinical improve-
ment (52). In a convenience sample of 23 HIV-infected pa-
tients with PML who survived at least 5 years, 9 remained
neurologically stable, 10 had partial improvement, and 4 had
marked improvement; 8 had only slight disability and lived in-
dependently (55). In a population-based study from Denmark,
5 of 11 patients followed for 3 years (from an original group of
47 patients) returned to their pre-PML level of function (51).
Scheld_Ch19.indd 290
DIFFUSE CENTRAL NERVOUS
SYSTEM DISEASE
HIV-Associated Neurocognitive Disorders
Cognitive impairment due to HIV infection was first character-
ized by Navia et al. (85) in 1986 and termed AIDS dementia
complex or ADC to emphasize a triad of cognitive, motor,
and behavioral abnormalities: (a) forgetfulness and loss of
concentration; (b) apathy, social withdrawal, and irritability;
and (c) loss of balance and leg weakness. On neurologic ex-
amination, such patients typically demonstrated slowed ver-
bal and motor responses, reminiscent of neurologic findings in
Parkinson disease. Not every patient with ADC had all three
components of the triad at onset of disease, and not all patients
with mild disease progressed to more severe disease. As will be
discussed further in the following section, with the advent of
CART, the incidence of HIV-associated dementia (HAD) has
decreased, but the incidence and prevalence of less severe forms
of cognitive impairment have increased. In 2006, a working
group addressed the criteria for diagnosis of HIV-associated
neurocognitive disorders (HAND) (86). These criteria are com-
monly referred to as the Frascati criteria, because the work-
ing group met in Frascati, Italy. Three categories of impairment
were established: asymptomatic neurocognitive impairment
(ANI), mild neurocognitive disorder (MND), and HAD. The
diagnosis of all three disorders is based on results of neuro-
psychologic (NP) tests covering at least the domains of verbal/
language, attention/working memory, abstraction/executive,
memory (learning, recall), speed of information processing,
and sensoryperceptual or motor skills, in combination with
an assessment of everyday functioning. In all categories, cogni-
tive or functional impairment cannot be explained by delirium,
opportunistic CNS disease, systemic illness, psychiatric illness,
substance use, or medications with CNS effects (Table 19.2).
Although these categories were intended for research purposes,
they have become increasingly applied to clinical settings.
Epidemiology and Risks
Estimates early in the HIV epidemic suggested that at least
60% of patients with AIDS developed overt or subclini-
cal HAD (85,87). The proportion decreased to about 7% in
the first years after antiretrovirals became available (88,89).
Several studies in the CART era show that the prevalence of
HAD is low but the prevalence of milder impairment (MND
and ANI) is surprisingly high. For example, in the multi-
center U.S. CNS HIV Antiretroviral Therapy Effects Research
(CHARTER) study, among 1,316 participants without severe
confounding disorders that could independently explain cog-
nitive impairment, 2% had dementia, 12% had MND, and
33% had ANI (90). In a study of 100 Italian patients with
undetectable plasma HIV RNA, 2% met criteria for HAD,
17% for MND, and 50% for ANI (91), and in a study of
400 French patients, 7% had HAD, 31% had MND, and
21% had ANI (92). Although symptomatic HAND (MND
and HAD) remains a risk factor for poorer survival (4), the
relevance of an ANI diagnosis has been questioned for sev-
eral reasons. These include concerns that (a) normative NP
data are from nonconfounded normal individuals rather
than background-matched controls; (b) in a normally distrib-
uted population, 16% will score 1 SD below the norm on a
given test; and (c) no published study has demonstrated that
ANI confers a risk for subsequent dementia (93,94). In addi-
tion, patients frequently transition from mild impairment to
normal cognition and vice versa despite stable CART regimens
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 Chapter 19: Human Immunodeficiency Virus 291

TA B L E 1 9 . 2
DIAGNOSTIC CRITERIA FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS

Disorder Neuropsychologic Testing Available Neuropsychologic Testing Not Available

Asymptomatic neurocognitive Impairment (1 SD below a Mental status exam (MSE) impairment

impairment (ANI)
Mild neurocognitive disorder (MND)
HIV-associated dementia (HAD)
Note: Severity of NP impairment and
functional decline must both meet
these standards in order to diagnose
the person as having HAD. If either
NP impairment or functional decline
is mild, the condition should be
classified as MND.
demographically appropriate normative
mean) in 2 cognitive domains
No reported or demonstrated functional
decline
Mild NP impairment (1 SD below a
demographically appropriate normative
mean), involving 2 cognitive domains
Reported or demonstrated mild functional
decline
Moderate NP impairment (2 SD below a
demographically appropriate normative
mean) on 2 cognitive domains.
Alternatively, one domain could be more
severely impaired (2.5 SD below the
mean) and another less severely impaired
(1 SD below the mean)
Reported or demonstrated major functional
decline
(1 SD below a demographically
appropriate normative mean) involving
2 cognitive domains
No reported or demonstrated functional
decline
Mild MSE impairment (1 SD below a
demographically appropriate normative
mean), involving 2 cognitive domains
Reported or demonstrated mild
functional decline
Moderate MSE impairment (2 SD
below a demographically appropriate
normative mean), involving 2
cognitive domains
Reported or demonstrated major
functional decline

Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology.
2007;69(18):17891799.

(95,96). Whether this reflects diagnostic imprecision, practice
effects or normal variation remains undefined (97).
Low current, and in particular low nadir, CD4 is a risk fac-
tor for prevalent neurocognitive impairment in the CART era
(90,95,98,99). However, the association between HIV-related
factors and incident cognitive impairment is less clear. Although
current but not nadir CD4 remained a significant predictor of
incident dementia in the Concerted Action on Seroconversion
to AIDS and Death in Europe (CASCADE) cohort (100), in the
AIDS Clinical Trials Group Longitudinal Linked Randomized
Trials (ALLRT) study, neither current nor nadir CD4 or plasma
HIV RNA predicted incident cognitive impairment (95). In a
population-based study of 1,320 HIV-infected patients in
Canada, incident symptomatic cognitive impairment was
more common with lower nadir CD4 and plasma HIV RNA
greater than 1 million copies/mL (101). In this study and in the
CASCADE study, longer estimated duration of HIV infection
conferred greater risk of incident impairment (100,101).
Etiology
HIV can be recovered from CSF (102) or brain (103) early in
the course of infection, and acute meningitis or encephalitis
may be part of the acute retroviral syndrome (102,104,105).
Moreover, brain inflammation and injury is evident in primary
HIV infection in some, but not all, patients (106108). Most
experts agree that productive brain HIV infection is restricted
to perivascular macrophages and less so microglia (109).
Infection of the CNS may be driven by activation of peripheral
monocytes as a consequence of microbial translocation from
the gut early in infection (110). Activated monocytes are bet-
ter able to support productive HIV infection (111), and HIV
DNA concentration in activated monocytes is higher in pa-
tients with cognitive impairment than in those with normal
cognition (112). Astrocytes may be infected but do not sup-
port viral replication (113). The prevailing view is that HIV
causes brain injury and subsequent cognitive impairment via
indirect mechanisms (114116). Proposed models suggest that
HIV-infected mononuclear phagocytes release toxic viral gene
products such as gp120 or tat. Alternatively, infected brain
macrophages or microglia may release cell-derived toxins such
as quinolinic acid; cytokines, including tumor necrosis factor-
(TNF-); eicosanoids; platelet-activating factor; or nitric
oxide. This hypothesis is particularly compelling because the
neuropathology of HAD is characterized by increased num-
bers of activated macrophages, and the severity of dementia
correlates better with the degree of macrophage staining in
brain than with the number of HIV-infected cells in brain
(117). Toxic substances released by activated macrophages
may injure neurons directly, may injure astrocytes or oligoden-
drocytes and interfere with their supporting functions, or may
stimulate astrocytes or oligodendrocytes to release toxic prod-
ucts that may augment neurotoxicity. Nonproductive HIV in-
fection of astrocytes may contribute to macrophage activation,
a 180 augmenting neurotoxicity.
The relationship between brain HIV infection and clini-
cally evident cognitive impairment may be changing in the
current treatment era, particularly among patients with mild
impairment. A recent pathologic study of 589 individuals with
advanced disease showed no relationship between brain HIV
infection and HAND (118), and, as discussed in the follow-
ing section, although detectable CSF HIV was associated with
prevalent dementia and predicted it in the pre-CART era, these
associations are less robust in the era of CART. Moreover, the re-
lationship between lower nadir CD4 and cognitive impairment

Scheld_Ch19.indd 291 2/21/14 5:40 PM

 292 Part II: Viral Infections and Related Disorders

suggests that CNS injury may have occurred in the past, and
that although impairment may be persistent, it may not reflect
the effect of ongoing CNS infection, inflammation, or injury.
This legacy, however, might lessen cognitive reserve. As
HIV-infected patients live longer, aging (119), vascular disease
(120122), metabolic abnormalities (123), and CART toxicities
(124126) may increasingly contribute to cognitive impairment.

Differential Diagnosis
Before the advent of highly active antiretroviral therapy, HAD
was a disease of those with advanced immunosuppression,
and CMV encephalitis was an important alternative diagnosis
to consider. In the current treatment era, patients with HAD
may present with peripheral blood CD4 T cells more than
200 cells/L (2,3) and CMV encephalitis is rare. The differ-
ential diagnosis includes psychiatric disease, particularly de-
pression; adverse effects from prescription or illicit drugs; and
cerebral opportunistic infections including toxoplasmosis, tu-
berculosis, cryptococcal meningitis, and neurosyphilis. Rarely,
PML may present solely with cognitive changes, but focal neu-
rologic findings and neuroimaging almost always distinguish
patients with PML from those with HAD (127).

Clinical Symptoms and Findings

Patients with HAD generally present with subacute onset of
cognitive impairment, often with complaints of mental and
physical slowness. Neurologic examination typically is re-
markable for slowed verbal and motor responses. Ataxia and
hyperreflexia may also be seen. A staging system for HAD has
been used to characterize clinical severity (128,129). It is based
on functional disability and ranges from normal cognitive and
motor function (stage 0), to mild impairment (stage 1) with
preserved ability to perform all but the more demanding tasks
of work or daily activities, to end-stage disease (stage 4) dis-
tinguished by rudimentary comprehension and responses. Not
all patients with mild disease progress to more severe stages.
Laboratory and Imaging Studies
The diagnosis of HAD is based on clinical findings and re-
mains one of exclusion. There is no specific test that estab-
lishes the diagnosis. However, CSF studies may be the most
informative. Conventional CSF evaluation helps exclude other
disorders. Data from the Multicenter AIDS Cohort Study sug-
gest that a CSF 2-microglobulin concentration more than
3.8 mg/dL in a CSF specimen with a normal white blood cell
(WBC) count is specific, but not sensitive, for the diagnosis of
HAD (130). In the pre-CART era, among patients with AIDS,
CSF HIV RNA levels were elevated in those with cognitive
impairment (131); they correlated with severity of dementia
(132,133) and predicted incident impairment (134). In the
CART era, CSF HIV RNA does not distinguish between those
with and without cognitive impairment (135,136). However,
in the clinical setting, measurement of CSF HIV RNA can be
useful. A CSF concentration higher than plasma suggests, but
does not prove, that cognitive impairment is due to ongoing
CNS HIV infection and is one definition of CNS escape (see
the following discussions).
Neuroimaging is useful in excluding other disorders but
does not establish the diagnosis of HAD. Cranial CT may be
normal or show atrophy or patchy white matter attenuation
(85). Cranial MRI is more sensitive than CT for demonstrating
white matter abnormalities and may show high T2 signal in
FIGURE 19.3 T2-weighted brain magnetic resonance images in HIV-
associated dementia show patchy and diffuse increased signal inten-
sity in the white matter.
the periventricular regions and in the centrum semiovale that
are not seen on T1-weighted sequences (Fig. 19.3). However,
atrophy and focal white matter abnormalities may be seen in
HIV-infected individuals without cognitive changes (137).
Treatment and Prevention
Early studies showed that even zidovudine monotherapy im-
proved cognition and survival in patients with HAD (138,139).
Studies early in the CART era showed that decline in CSF HIV
RNA and improvement in NP test performance could be seen
in individuals treated with CART (140142), and CART is
also associated with increased survival in patients with HAD
(143). Improvement in cognition after starting CART may lag
behind improvement in CD4 or decline in plasma HIV RNA;
in one study, improvement peaked at 24 to 36 weeks after
beginning CART (144). That CART may also play a role in
preventing development of cognitive impairment is shown
by a recent study demonstrating that HIV-infected patients
who initiated CART early in the course of disease had a low
prevalence of cognitive impairment that was comparable to
matched HIV-uninfected individuals (145).
In the last few years, much attention has been given to
whether antiretroviral regimens with good CNS penetration
are more effective in decreasing CSF HIV RNA concentra-
tion and in improving cognitive function than regimens with
poorer penetration. Letendre and colleagues (146,147) have
published two versions of the CNS Penetration Effectiveness
(CPE) rank, which estimates CNS drug penetration based on
virologic and pharmacologic data. The most recent version
uses four categories (14), with higher values assigned to drugs
with better predicted penetration (147). The score for a given
regimen is calculated as the sum of the scores of its component
drugs. Higher CPE regimens convey increased likelihood of

Scheld_Ch19.indd 292 2/21/14 5:40 PM


suppressed CSF HIV RNA (146,147). However, the relation-
ship between regimen CPE and improvement in cognition is
less clear. Although several studies suggest that regimens with
higher CPE improve cognitive function more than regimens
with lower scores, this finding is not universal (148). A recent
study suggested that the revised CPE rank is superior to the
original, which might explain some, but not all, discrepan-
cies between different studies (149). An observational study
showed that higher CPE conveyed an increased risk of cogni-
tive worsening in patients with advanced HIV (124), and a
small randomized trial of three CART regimens showed that
although patients in the arm with the highest CPE had greater
cognitive improvement, these patients also had greater evi-
dence of brain inflammation by neuroimaging (150).
Shikuma and colleagues (151) have proposed a monocyte
efficacy (ME) score as a means of determining the effectiveness
of an antiretroviral regimen in treating CNS HIV infection.
The ME score is defined as the summed reciprocal ( 1,000)
of each agents median effective concentration (EC50) in a rest-
ing macrophage acute infection model (151). The relationship
between cognitive impairment and ME score was examined
in a cohort of 139 individuals on stable CART for at least
6 months; those who were taking atazanavir or lopinavir were
excluded because of lack of EC50 data. Patients whose regi-
mens had higher ME scores had lower odds of symptomatic
cognitive impairment. Of note, the CPE rank and ME score
of individual regimens may not be congruent. For example, an
acceptable regimen of abacavir, lamivudine, and nevirapine
yields a high CPE of 9 but a low ME of 73 (152).
Several adjunctive agents have been investigated for the
treatment of HAD. Their rationale is based on data reviewed
above suggesting that neuronal damage is a downstream event
triggered by release of toxic viral gene products or inflamma-
tory mediators from infected mononuclear cells. None have
proved to be beneficial, including nimodipine (153), CPI-1189
(an antioxidant that blocks TNF- in animal models) (154),
selegiline (155,156), memantine (157,158), minocycline
(159161), and rivastigmine (162).
Encephalitis in the Setting of Combination
Antiretroviral Therapy: Central Nervous
System Immune Reconstitution Inflammatory
Syndrome, Central Nervous System Escape,
and CD8 T-Cell Encephalitis
Just as there are reports of IRIS in patients with CNS opportu-
nistic infections treated with CART, CNS IRIS due to HIV it-
self has been reported after CART initiation (3840). Typically,
patients develop diffuse or focal neurologic symptoms and
signs usually accompanied by CSF pleocytosis in the absence of
an identifiable infectious agent. Such patients need to be distin-
guished from those with CNS escape in the setting of apparently
effective CART. These patients develop diffuse or focal neuro-
logic symptoms while on CART, with detectable CSF HIV RNA
in the setting of suppressed peripheral viremia or with CSF HIV
RNA concentrations higher than simultaneous plasma levels
(163165). Canestri and colleagues (166) described CNS escape
in 11 patients defined as CSF HIV RNA more than 200 copies/
mL with corresponding plasma HIV RNA less than 50 copies/
mL or CSF HIV RNA more than 1 log higher than plasma.
Clinical syndromes included meningitis, encephalitis, and my-
elitis. Based on genotypic analysis, CSF virus was not sensitive
to the CART regimen in five patients (166). Asymptomatic low-
level CNS escape with CSF HIV RNA concentrations ranging
from 52 to 860 copies/mL has been described in a small series
of patients (167). Compared to patients with undetectable CSF
Scheld_Ch19.indd 293
Chapter 19: Human Immunodeficiency Virus 293
HIV RNA, those with CNS escape had a longer duration of
CART and had experienced more treatment interruptions, rais-
ing the question of whether CSF viral blips, similar to what
has been described in plasma, may occur. A review of the lit-
erature shows overlap between CNS IRIS and CNS escape. The
distinguishing feature should be detection of CSF HIV RNA,
which is not seen in IRIS, but that is an integral part of the
diagnosis of CNS escape. Reports describe successful treatment
of CNS IRIS with steroids, whereas reports of successful treat-
ment of CNS escape usually entail changes in CART based on
genotypic analysis of CSF viral sensitivity or by substitution or
addition of agents thought to have good CNS drug penetration.
Of note, the pathogenesis of CNS IRIS and CNS escape may be
similar. Lescure and colleagues (168) describe 14 HIV-infected
patients who were initially diagnosed with encephalitis of un-
known etiology. Two patients had CNS IRIS, two had CNS
escape, one had viral rebound after stopping CART, and six
had a minor infection a few days before onset of their neuro-
logic illness. Brain MRI showed diffuse T2 and fluid-attenuated
inversion recovery (FLAIR) signal intensities in gray and white
matter with punctate or linear gadolinium enhancement that
was best seen with T1-weighted spin-echo sequences combined
with magnetization transfer. Histology showed intense perivas-
cular infiltration of polyclonal CD8 lymphocytes.
SPINAL CORD DISEASE
HIV-Associated Myelopathy
Several processes can affect the spinal cord in HIV-infected pa-
tients (Table 19.3). HIV-associated myelopathy (HAM) is likely
the most common cause of spinal cord dysfunction in this pop-
ulation in the U.S. Most of what we know about the disorder
comes from studies conducted before the advent of CART, and
the overall incidence of the disease is now low.
Etiology
The pathogenesis of HAM, pathologically termed vacuolar
myelopathy, is poorly understood. Detection of HIV in spinal cord
is not associated with presence or severity of vacuolar changes
(169). Activated macrophages can be identified in the posterior
and lateral columns of spinal cords from HIV-infected individu-
als with and without vacuolar myelopathy (170), and degree of
myelin damage is proportional to the number of infiltrating mac-
rophages (171). Thus, the pathogenesis of HAM may be simi-
lar to that proposed for HAD. Because of pathologic similarities
between HAM and myelopathy associated with vitamin B12 or
cobalamin deficiency, nutritional or vitamin deficiencies have
also been suggested as a cause of HAM. In autopsy-based series,
vitamin B12 levels in patients with vacuolar myelopathy are not
low (170,172). However, cobalamin is a cofactor for conversion
of homocysteine to methionine, which is subsequently converted
to S-adenosylmethionine (SAM). SAM is needed for myelin for-
mation and repair. In a small study, CSF SAM levels were sig-
nificantly lower in patients with HAM compared to HIV-infected
patients without myelopathy and normal controls (173). These
results support the hypothesis that HAM may be due to abnor-
malities of a B12-dependent metabolic pathway.
Differential Diagnosis
Differential diagnosis of myelopathy in HIV-infected patients
includes extrinsic cord compression from tumor such as lym-
phoma, infection, such as bacterial or mycobacterial osteomy-
elitis, or hemorrhage (174). These entities usually have a rapid
course and associated back pain and sensory level, which
2/21/14 5:40 PM
 294 Part II: Viral Infections and Related Disorders

TA B L E 1 9 . 3 are uncharacteristic of HAM (see the following discussion).

Intrinsic cord abnormalities due to tumor or abscess, particu-
SPINAL CORD DISEASES ASSOCIATED WITH HIV larly lymphoma, toxoplasmosis, or tuberculosis, should also
be excluded. Human T-lymphotropic virus (HTLV) type 1 or
Extrinsic lesions type 2 infection may be indistinguishable from HAM. Myelitis
Tumors due to syphilis or herpes viruses (varicella-zoster virus [VZV],
Metastatic lymphoma herpes simplex virus [HSV], or CMV) and nutritional disor-
ders should also be considered (Table 19.3).
Other metastases
Infections due to conventional bacteria, Mycobacterium
tuberculosis, or fungi
Clinical Findings
Vertebral osteomyelitis
Epidural or subdural abscess Patients with HAM complain of slowly progressive lower
Epidural or subdural hemorrhage extremity weakness and stiffness, trouble walking, and urinary
frequency and incontinence. Men may note erectile dysfunction.
Intrinsic lesions HAM typically coexists with distal sensory peripheral neuropa-
Tumors thy, with concomitant complaints of lower extremity numbness,
Lymphoma pain, or dysesthesia (175). Neurologic examination shows spas-
Glioma tic paraparesis or paraplegia; gait dysfunction; sensory ataxia;
hyperreflexia, often with absent ankle reflexes in the setting of
Infections concomitant neuropathy; impaired vibration and position senses;
Toxoplasmosis extensor-plantar responses; and sphincter dysfunction (172,175).
M. tuberculosis
Cryptococcosis
Myelopathy Laboratory and Imaging Studies
HTLV types 1 and 2 HAM is a diagnosis of exclusion. MRI of the spinal cord should
Syphilis be undertaken to exclude extrinsic or intrinsic cord lesions. In
HAM, MRI is usually normal. When abnormalities are seen,
HIV-associated myelopathy
they typically involve the thoracic spinal cord with or without
Transverse myelopathy involvement of the cervical cord and include atrophy or increased
Multiple sclerosis intramedullary signal intensity (176,177). Abnormal tibial so-
Stroke matosensory-evoked potentials with prolonged conduction time
are considered by some to be diagnostic (173). Analysis of CSF
Myelitis
is indicated to exclude alternative diagnoses; in HAM, the CSF is
HIV typically acellular with mild to moderate elevation in protein con-
Herpesviruses centration (175). One study showed that CSF HIV-1 RNA con-
Human cytomegalovirus centrations were not increased in patients with HAM; however,
these individuals were all on stable antiretroviral therapy (178).
Varicella-zoster virus
Herpes simplex virus types 1 and 2
Metabolic Treatment and Prevention
Vitamin B12 deficiency
Copper deficiency There is no proven treatment for HAM. Case reports describe
improvement after beginning CART (179182), and this is cur-
Folate deficiency rently the therapy of choice. A controlled trial of L-methionine
Portosystemic shunt (183) and an open-label study of IV immunoglobulin for HAM
showed no benefit (184). The association between advanced
HIV disease and HAM suggests that earlier treatment for HIV
is the best preventative strategy.

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 CHAPTER 20 GUILLAIN-BARR SYNDROME
TONY M. MCGRATH

Since the decline in cases of poliomyelitis, the Guillain-Barr
syndrome (GBS) has emerged as the most frequent cause of
acute flaccid paralysis. The spectrum of GBS includes classi-
cal acute inflammatory demyelinating polyneuropathy (AIDP),
acute motor axonal neuropathy (AMAN), acute motor sen-
sory axonal neuropathy (AMSAN), and variants such as Fisher
syndrome (1,2). AIDP, the most common form in the Western
Hemisphere, is characterized by rapidly progressive, usually
ascending, and symmetric paralysis of the extremities, variable
involvement of bulbar, facial, and ocular muscles, and loss of
deep tendon reflexes (3). Although the disorder is often pre-
ceded by a bacterial or viral illness, no evidence presently exists
to indicate that GBS is caused by direct infection of nervous tis-
sue. Current research implicates an autoimmune mechanism.
HISTORY
Landry is credited with the first modern description of a dis-
order similar to GBS. In 1859, he reported a patient with par-
esthesias and subjective weakness. Unlike present definitions
of GBS, objective weakness did not occur until 1 month after
symptom onset but was then severe and rapidly progressive,
leading to death 8 days later (4). Although Oslers account in
1892 (5) of acute febrile polyneuritis was remarkably similar
to the illness we now term GBS, the development of the lumbar
puncture in the late nineteenth century permitted a more pre-
cise characterization of the disorder and its differentiation from
poliomyelitis and other neuropathies (6). In 1916, Guillain
et al. (7) detailed a clinical syndrome in two individuals char-
acterized by motor weakness, paresthesias, areflexia with pres-
ervation of cutaneous reflexes, and increased cerebrospinal
fluid (CSF) albumin without pleocytosis (albuminocytologic
dissociation). Both recovered fully. Similar descriptions soon
followed, but controversy arose regarding diagnostic criteria.
In 1976, following an apparent increase in GBS associ-
ated with the swine flu vaccine, the National Institute of
Neurological and Communicative Disorders and Stroke
(NINCDS) was directed by the Centers for Disease Control
and Prevention (CDC) and the National Institute of Allergy
and Infectious Diseases to develop clear diagnostic criteria for
GBS to assist in epidemiologic studies. These criteria (NINCDS
criteria) were reported in 1978 (3) and, though intentionally
somewhat restrictive, are now generally accepted. The clinical
section of this chapter contains a summary of these criteria.
EPIDEMIOLOGY
Epidemiologic studies of GBS are inherently troublesome (8).
The major difficulty is the lack of definitive diagnostic markers
for GBS. Because diagnosis must rely on clinical criteria, inci-
dence may be over- or underestimated if criteria are too broad
or stringent or if atypical variants are counted or excluded. Also,
the results of studies employing dissimilar criteria may not be
comparable. A dilemma arises in regard to whether persons with
an underlying condition known to produce a neuropathy, such
as diabetes mellitus, should be included when one is attempting
a survey of a pure neuropathy such as GBS. Moreover, GBS dis-
plays a wide range of clinical severity. Because many epidemio-
logic studies rely on hospital-based reporting, mild cases not
requiring hospitalization could be lost. Despite these difficul-
ties, numerous epidemiologic investigations of GBS have been
performed. Ten of these are summarized in Table 20.1.
Incidence rates in studies using NINCDS criteria (914,15)
range from 0.4 to 2.0 per 100,000 persons. In the population-
based Olmstead County survey (9), 15% of GBS cases were mild
and did not require hospitalization. Therefore, hospital-based
studies (10,11,13,14) may underestimate the true rate by as
much as 15%. Nevertheless, incidence rates are similar among

TA B L E 2 0 . 1
REGION SURVEYED, PERIOD OF SURVEY, TOTAL, MALE, AND FEMALE GUILLAIN-BARR SYNDROME
INCIDENCE RATE PER 100,000 PEOPLE, AND NUMBER

Average Annual Incidence Rate

Region Surveyed Time Period Total Male Female Cases (n)

Olmstead County, Minnesota (9) 46 yr (19351980) 1.7 2.3 1.2 48

Hordaland, Western Norway (10) 26 yr (19571982) 1.14 1.45 0.83 109
Sardinia (11) 12 yr (19691980) 0.4 0.41 0.39 120
Stockholm, Sweden (12) 19 yr (19731991) 1.84 2.15 1.57 556
Western Australia (13) 6 yr (19801985) 1.35 1.49 1.2 109
Benghazi, Libya (14) 3 yr (19831985) 1.74 1.62 1.86 27
Ontario, Canada (16) 7 yr (19831989) 2.02 1,302
Quebec, Canada (16) 7 yr (19831989) 2.3 1,031
Spain (17) 13 yr (19851997) 0.85 1.14 0.58 337
Ferrara, Italy (15) 8 yr (19942001) 1.97 2.25 1.71 26

299

Scheld_Ch20.indd 299 2/21/14 5:40 PM

 300 Part II: Viral Infections and Related Disorders

TA B L E 2 0 . 2 60% of the infections, followed by gastrointestinal ailments and

nonspecific febrile illnesses. Elderly persons with GBS experience
DIAGNOSTIC CRITERIA PROPOSED BY a similar incidence of antecedent infections (27,28). However,
GUILLAIN-BARR SYNDROME STUDY GROUP they may be less likely to complain of preceding gastrointestinal
symptoms (27). As many as 70% of children with GBS experi-
Features required for diagnosis ence an infectious disease within 28 days of neurologic symptom
Progressive motor weakness of more than one extremity onset, with nonspecific upper respiratory illnesses being respon-
Areflexia or marked hyporeflexia sible in nearly 80% (2023). Yet, gastrointestinal prodromic
symptoms may vary. A recent study found that vomiting was
CSF cell counts of no more than 50 monocytes or
more common in children with AIDP compared with AMAN
two polymorphonuclear leukocytes
(28.1% vs. 6.5%), and diarrhea was more common in AMAN
Features strongly supportive of the diagnosis compared with AIDP (32.6% vs. 12.5%) (19). Persons with
Progression for days to a few weeks severe GBS resulting in tetraparesis and prolonged mechanical
Relative symmetry of weakness ventilation are generally no more likely than mildly or moder-
ately affected patients to have an antecedent infection (2931).
Mild sensory signs or symptoms
Neurologic symptoms usually begin within 2 weeks after
Cranial nerve involvement the infectious illness (9,13,16,26,27,30,31) but may occur
Onset of recovery 24 wk after cessation of progression more acutely (31). Shorter periods between the prodromal
Autonomic dysfunction illness and neurologic symptoms seem to follow antecedent
upper respiratory infections, but a longer delay may occur in
Initial absence of fever
patients with preceding gastrointestinal symptoms (32,33).
Elevated CSF protein after 1 wk of symptoms In the majority, an infectious agent responsible for the prodro-
Abnormal electrodiagnostic tests with slowed conduction mal illness is never identified.
or prolonged F-waves Many viruses and bacteria (Table 20.3) have been impli-
cated as antecedent triggering factors in GBS (16,21,28,3236),
Modified from ref. 25. although many of the proposed causal agents and GBS may
simply represent a chance association. Winer et al. (26) tested
the proposition in serologic studies on 100 persons with GBS
and age- and sex-matched controls. Evidence of cytomega-
lovirus (CMV) and C. jejuni infection was significantly more
studies conducted in different decades, ethnic groups, races, and frequent in GBS patients (11% and 14%, respectively) than
geographic areas. These findings are consistent with the hypoth- among controls. Although positive Epstein-Barr virus (EBV),
esis that the triggering agents responsible for GBS are widespread
and numerous, and susceptibility is similar among populations.
Most studies of GBS have revealed higher incidence
among men (911,13) and no significant seasonal differences TA B L E 2 0 . 3
(9,13,16). Incidence increases with advancing age beyond PROPOSED INFECTIOUS ANTECEDENTS OF
40 years, commonly peaking in the seventh and eighth decades GUILLAIN-BARR SYNDROME
(10,11,13,14,16,17). Autumn clustering of GBS following
Campylobacter jejuni infection has occurred (18,19). Viruses Bacteria
Four epidemiologic surveys have examined the incidence
of GBS in children (2023). Two (21,23) used NINCDS crite- Adenovirus Brucella
ria, and two (20,22) used criteria outlined in Table 20.2 (24). Coronavirus Campylobacter jejuni
Although children with clinical variants of GBS were identified,
they were not included in the results. Annual incidence rates of Coxsackievirus Haemophilus influenzae
GBS in children were lower (0.4 to 1.1 per 100,000 children) Cytomegalovirus Helicobacter pylori
than rates obtained in the general population (see Table 20.1). Epstein-Barr virus Listeria monocytogenes
No difference in frequency between boys or girls occurred in
Echo virus Mycoplasma pneumoniae
California (20) and Finland (22), whereas male-to-female ratios
of 1.5:1 were observed in Paraguay (21) and Taiwan (23). Hepatitis A, B, and C Pasteurella tularensis
Although a seasonal preponderance was not apparent in three Herpes simplex Salmonella typhosa
studies (20,22,23), 76% of affected children in Paraguay (21) Herpes zoster Shigella
had onset of symptoms during the summer months.
Human herpesvirus type 6 Yersinia
When childhood GBS in California (20) was analyzed by
age at onset, frequency was significantly greater in 2-year-old Human immunodeficiency virus
children than among other age groups. This finding may reflect Influenza A and B
the higher incidence of triggering infections in this age group. Japanese encephalitis virus
In Paraguay (21), a similar increase in children younger than
Measles
4 years of age was seen, but in Finland (22) and Taiwan (23),
age distribution was evenly dispersed. Mumps
Parainfluenza
Respiratory syncytial virus
Antecedent Events Vaccinia
Clinically apparent antecedent infections occur within 28 days Variola
of onset in approximately 50% of persons with GBS (914,16, West Nile virus
25,26). Minor upper respiratory symptoms account for about

Scheld_Ch20.indd 300 2/21/14 5:40 PM


parvovirus B19, and Mycoplasma pneumoniae serologies were
identified in GBS, controls demonstrated similar results. Hankey
(13) obtained acute and convalescent serum from 62 persons
with GBS and found evidence of recent viral infection in 50%.
Parainfluenza virus type 3, CMV, and adenovirus titers were
identified in five, six, and seven specimens, respectively, whereas
EBV, herpes simplex, herpes zoster, parainfluenza type 1 and 2,
measles, coxsackie, echovirus, coronavirus, and influenza A and
B titers were each present in one or two samples. Infection with
M. pneumoniae was encountered in five. Despite these various
reports, convincing evidence of causality exists for only CMV,
EBV, human immunodeficiency virus (HIV), herpes zoster, C.
jejuni, and M. pneumoniae. Measles-associated GBS may occur,
but only rarely. Although variola (smallpox) and vaccinia have
been conclusively linked with GBS, the eradication of smallpox
and the discontinuation of vaccinia immunization make any
association with GBS of historic interest only. However, since
the September 11, 2001 terrorist attack and the threat of bio-
terrorism, the expected increase in smallpox vaccinations could
lead to an increase in vaccine-related GBS.
Dowling and Cook (36) detected immunoglobulin M (IgM)
antibody directed against CMV in 15% of 220 persons with
GBS. Those with CMV antibodies were primarily young
women (average age, 25.6 years) in whom only 80% had a
clinically apparent preceding infection. CMV-associated GBS
appeared in three separate 10- to 16-week clusters over 3 years.
Abnormal liver enzymes were present in 50% of the CMV sero-
positive cases. Evidence of recovery was associated with a fall in
CMV IgM antibody titer. No correlation has been demonstrated
between primary infection with CMV and severity or outcome
of GBS (26,33). CMV-associated GBS has occurred following
transplant of a CMV-infected heart in a CMV-negative recipi-
ent (37) and may occur with CMV reactivation after autolo-
gous bone marrow or organ transplantation (37,38).
EBV (like CMV, a herpesvirus) infection may precede
neurologic symptoms in 2% to 8% of GBS (20,26,28).
It may present as hepatitis or mononucleosis or, like CMV,
may be clinically silent prior to GBS onset. Clinical or sub-
clinical encephalopathy may complicate EBV-associated GBS
(36). Antecedent primary herpes zoster infection may occur
in 3% to 4% of children with GBS (20,23). GBS may also
develop in association with reactivated herpes zoster infection
(13,25,30). In contrast, recent herpes simplex virus infection
is uncommonly identified in GBS (34). The most recently iden-
tified herpesvirus, human herpesvirus type 6 (HHV-6), has
been proposed as an etiologic agent in GBS. Antibody against
HHV-6 was demonstrated in a significantly greater number of
GBS patients than among blood donors in Italy (35).
GBS has been described early in the course of HIV infection
(3941). In 1987, HIV was the most common infection associ-
ated with GBS at the University of Miami School of Medicine
(41). In Zimbabwe, 55% of 29 consecutive persons with
GBS were HIV seropositive (39). HIV infection did not pro-
duce a higher incidence of prodromal illness in GBS. In each
seropositive individual, GBS was the initial manifestation of
HIV infection. Generalized lymphadenopathy, coincident en-
cephalopathy, and CSF pleocytosis were significantly more
likely with HIV infection. Mean CSF white blood cell counts in
HIV-associated GBS were 14/mm3 (range of 0 to 63 cells) (39).
HIV seropositivity has not been associated with poor recov-
ery following GBS (40,41). GBS in HIV-infected individuals is
probably secondary to disordered immune regulation charac-
teristic of the infection.
Several mosquito-borne infections have been reported with
GBS. Japanese encephalitis virus (JEV) may be an important an-
tecedent infection in endemic areas. JEV is the most frequently
recognized cause of mosquito-borne encephalitis and typically
Scheld_Ch20.indd 301
Chapter 20: Guillain-Barr Syndrome 301
occurs in epidemics in endemic areas. Ravi et al. (34) detected
high titers of IgM antibody specific to JEV in serum and/or CSF
in 62% (21 of 34) of consecutive cases in southern India. None
had signs of encephalitis, and all satisfied NINCDS criteria (see
later discussion) for GBS. Clinical course and outcome were
similar in JEV-seropositive and -seronegative individuals. The
JEV antigen was demonstrable in the CSF of one person, and
virus was isolated from CSF in another. Pathologic examination
in one autopsied case demonstrated discrete necrotic lesions at
the cerebral graywhite matter junction and demyelination of
ventral and dorsal nerve roots. West Nile virus (WNV) was
reported in an individual with GBS during the 1999 outbreak
in New York City (42). During the summer of 2002, six cases
of acute flaccid paralysis syndrome associated with WNV were
reported in Mississippi and Louisiana (43). The individuals,
however, had asymmetric weakness and CSF pleocytosis, sug-
gesting a polio-like syndrome. Falciparum malaria has also
been reported with GBS (44,45). Sokrab et al. (45) reported a
mortality rate of 40% in 10 individuals with acute falciparum
malaria and GBS during a seasonal exacerbation.
In 1982, Rhodes and Tattersfield (46) reported the first case
of GBS following C. jejuni enteritis. Subsequently, C. jejuni
has been recognized as the most common bacterial antecedent
infection in GBS. Serotyping of C. jejuni is accomplished by
examination of heat-labile antigens (Lior method) and/or heat-
stable antigens (Penner method) (47). Several Penner and Lior
serotypes of C. jejuni have been isolated from GBS patients, but
Penner serotype 19 and Lior serotype 11 predominate (4858).
These serotypes are uncommon in uncomplicated gastroenteri-
tis (47). Winer et al. (26) and Boucquey et al. (33) found sero-
logic evidence of recent C. jejuni infection in approximately
14% of GBS, and Mishu et al. (18) and Kaldor and Speed (59)
reported C. jejuni infection in 37% of GBS. No history of pre-
ceding gastrointestinal symptoms has been reported in some
GBS patients with serologic evidence of recent C. jejuni infec-
tion (33,59). The incidence of C. jejuni infection in the United
States peaks from August through October (56), whereas the
peak incidence for children in Mexico is from July through
September (19). Statistically significant summer and autumn
clustering of C. jejuniassociated GBS has occurred (18).
Stool cultures after onset of GBS with C. jejuni seroposi-
tivity are often negative (33,49,52,54,59), because C. jejuni
excretion lasts an average of 16 days (60), and GBS symptoms
may be delayed until 3 weeks after gastrointestinal symptoms.
Appropriate antibiotic treatment of C. jejuni enteritis does not
prevent GBS (46,49).
Although Boucquey et al. (33) and Enders et al. (54)
reported no association between C. jejuni seropositivity and
GBS severity or outcome, severe disease and poor prognosis
in C. jejuniassociated GBS is well recognized (26,46,59,61).
In one series of 21 C. jejuniinfected persons with GBS, 90%
required mechanical ventilation (59). Severe involvement may
occur because of a tendency of C. jejuniassociated GBS to
damage axons rather than myelin (62). Of 11 children in China
with AMAN, 90% demonstrated serologic evidence of recent
C. jejuni infection (63). Conversely, Enders et al. (54) reported
no greater electrophysiologic evidence of axonal involvement
in C. jejuniassociated GBS, and although Vriesendorp et al.
(61) demonstrated severe disease and poor recovery more
commonly in C. jejuniseropositive GBS, electrophysiologic
evidence of primary axonal involvement was not apparent.
The mechanism by which C. jejuni infection triggers GBS
is now better understood. Antigenic cross reactivity occurs
between C. jejuni and components of peripheral nerves (PNs)
(64,65). Host factors may determine whether infection with
C. jejuni produces GBS. Although Hillert et al. (66) found no
common human leukocyte antigen (HLA) class II antigens in
2/21/14 5:40 PM
 302 Part II: Viral Infections and Related Disorders
GBS, and Winer et al. (67) demonstrated no association be-
tween HLA class I antigen and GBS and only a weak associa-
tion between HLA class II antigen DR2 and severe GBS, Yuki
et al. (52) reported HLA class I antigen B35 in seven Penner se-
rotype 19 C. jejuniassociated cases of GBS. The authors con-
cluded that the combination of HLA B35 antigen and Penner
serotype 19 C. jejuni infection could precipitate an autoim-
mune response culminating in GBS. This is due to molecular
mimicry between lipooligosaccharides (LOSs) of C. jejuni and
gangliosides in PNs (68). The sialyltransferase gene (cst-II) has
been identified to produce ganglioside-like LOS. The gene con-
sists of 291 amino acids; the 51st determines its enzymatic ac-
tivity. Cst-II (Thr51) produces GM1-like and GD1a-like LOSs,
whereas Cst-II (Asn51) produces GT1a-like and GD1c-like
LOSs which mimic GQ1b (69,70).
Evidence of M. pneumoniae infection has been confirmed
in 1% to 5% of GBS (13,23,26,34). Currently, it is the second
most commonly identified nonviral pathogen associated with
GBS. An influenza-like syndrome may precede the onset of
neurologic symptoms.
Mori et al. (71) reported elevated antiHaemophilus influ-
enzae antibodies in 6 of 46 (13%) Japanese patients with GBS
but none of the 49 controls. Western blot analysis performed
on the H. influenzaepositive patients immunoglobulin G
(IgG) confirmed recognition both of lipopolysaccharides of
H. influenzae and the ganglioside, GM1 (72).
In 1998, Chiba et al. (73) detected antibodies against
Helicobacter pylori in the CSF from 4 of 7 patients with GBS.
In 2002, Chiba et al. (74) examined CSF from 13 patients with
GBS (8 AIDP, 4 AMAN, 1 unexcitable nerve conduction) and
8 control patients. Six of the AIDP patients had a specific IgG
antibody to the VacA of H. pylori.
Rabies vaccine and the A/New Jersey/76 swine influenza
vaccine (swine flu vaccine) have been reliably linked with GBS
(32). Early rabies vaccine was made of desiccated brain and spi-
nal cord of rabies-infected animals. Both acute demyelinating
encephalomyelitis (ADEM) and GBS sometimes followed vacci-
nation. A proliferative lymphocytic response and antibodies to
myelin basic protein (MBP), a constituent of central and periph-
eral nervous system myelin, have been demonstrated in persons
with rabies vaccineassociated GBS (75). An immune response
against MBP has been proposed as the cause of ADEM and
GBS in these individuals. The discontinuation of rabies vaccine
prepared from infected animal brain and spinal cord has virtu-
ally eliminated rabies vaccineassociated ADEM and GBS.
In 1976 and 1977, an increase in GBS in the United States
was temporally associated with the A/New Jersey/76 swine
influenza vaccination campaign. The original CDC study
demonstrated a statistically significant increase in the risk of
developing GBS within 6 weeks of swine flu vaccine adminis-
tration in persons 18 years of age and older (76). This study has
been criticized because uniform GBS diagnostic criteria were
not used, records were reviewed by nonphysician casework-
ers, no standardized method of record assessment was used,
and follow-up evaluations were not performed (77). Safrenek
et al. (78) reviewed all GBS cases in Michigan and Minnesota
from October 1, 1976 through January 31, 1977. Diagnostic
criteria were developed, and a neurologist reviewed all medical
records blindly. Although mistakes in the original CDC study
were uncovered, these authors also demonstrated a significant
increase in the relative risk of adults developing GBS within
6 weeks of swine flu vaccine. Four manufacturers produced
the swine flu vaccine administered to the civilian population
in 1976. All were associated with an increased risk of GBS
(79). GBS has not been linked to previous or subsequent influ-
enza vaccinations. Military personnel who received swine flu
vaccine developed by the United States military in 1976 did
Scheld_Ch20.indd 302
not experience an increased frequency of GBS (80). The fac-
tor associated with the civilian vaccine that was responsible
for the increased risk of GBS has never been determined; how-
ever, in 2008, Nachamkin et al. showed that the 1976 swine
flu vaccine contained contaminating moieties which elicited
anti-GM1 antibodies after inoculation into C3H/HeN mice.
Vaccine samples from 11 unopened vaccine lots containing
A/New Jersey/76 swine influenza antigen from three different
manufactures were found to induce IgG and IgM antibodies
to GM1, but no to C. jejuni, after immunization in mice. This
response was also observed in both the 1991 to 1992 and 2004
to 2005 vaccines. No vaccines were found to contain bacterial
DNA (81).
GBS has been reported following other vaccinations, but
clear evidence of causality is lacking. Hankey (13) recorded
recent vaccination in 5% of GBS, and of 100 individuals with
GBS studied by Winer et al. (26), 6 had received a vaccination
within 3 months of GBS onset. Ten vaccines were involved,
and the rate of vaccination was similar in a control population.
The latter study illustrates the importance of discovering the
frequency of vaccination in the background population before
assigning significance to a case of GBS following vaccination.
Several reports of GBS following vaccination against polio-
myelitis have been recorded. In 1984, an outbreak of poliomy-
elitis in Finland resulted in an intensified vaccination program
with oral poliovirus vaccine (OPV) (82). Subsequently, an
unexpected rise in GBS occurred, precipitating epidemiologic
surveys attempting to link OPV with GBS. Although an unex-
pectedly high rate of GBS occurred within 10 weeks following
OPV administration, a small number of persons were involved,
and an unexpectedly high rate of GBS also occurred in the
weeks prior to the vaccination program.
Five percent to ten percent of GBS cases occur following
intracranial, thoracic, abdominal, and orthopedic surgical
procedures (6,13,26,29,30,33,37). This could be secondary to
primary CMV infection following blood transfusion, although
many reports exist of persons who did not receive transfusion.
Other sources of iatrogenic infection associated with surgery
or hospitalization could be responsible. Possibly, the surgery
itself elicits a disordered immune response culminating in GBS.
GBS may also occur during pregnancy or the postpartum
period (11,13,30,32). Unlike infants of mothers with myas-
thenia gravis, infants of mothers with GBS are unaffected.
Whether the pregnancy or an associated infection, such as
CMV, precipitates GBS is uncertain. Clinically and patho-
logically typical cases of GBS have also been associated with
malignancy, especially Hodgkin and non-Hodgkin lymphoma
(13,33,83). GBS is rarely associated with other autoimmune
disorders (32).
PATHOLOGY
The pathologic findings in GBS are remarkably uniform
irrespective of the antecedent illness or precipitating event.
Lesions usually occur as discrete foci of abnormality and have
been observed along the entire length of PNs. Areas of pref-
erential involvement are the nerve roots, sites of ligamentous
entrapment, and distal terminal branches (32). Kanda et al.
(84) noted a relative absence of lesions in the initial few mil-
limeters of anterior and dorsal nerve roots. This sparing of
the transitional region between central and peripheral nervous
systems (CNS and PNS) may be attributable to the marginal
blood supply in this location. The pathologic process may
involve autonomic, motor, and sensory systems simultane-
ously, but in individual cases, abnormalities may predominate
in one. Areas of maximal pathologic change usually parallel
2/21/14 5:40 PM

clinical involvement, although this association is imperfect.
Generally, motor involvement exceeds sensory changes, but in
most patients, pathologic lesions do not preferentially or more
severely involve the anterior roots or motor nerves (32,8488).
In a subset of GBS patients primarily manifesting motor dys-
function, relative sparing of dorsal roots and sensory nerves
has been noted (63,85). The pathologic hallmark of GBS is a
perivenular mononuclear cell infiltrate with segmental demy-
elination. In 1969, Asbury et al. described multifocal, peri-
venular mononuclear cell infiltration involving motor, sensory,
autonomic, and cranial nerves (85). The invading lymphocytes
and monocytes were derived from blood. Even in diffusely
involved nerves, inflammatory cell concentration was great-
est around blood vessels of the endoneurium, the connective
tissue surrounding individual nerve fibers. Infiltration about
vessels of the epineurium, the connective tissue sheath of the
entire nerve, was present but less commonly observed.
Small and medium-sized lymphocytes were the predomi-
nant inflammatory cells recognized early; macrophages were
the more prominent cell type in older lesions with considerable
myelin destruction. Polymorphonuclear leukocytes were infre-
quently observed and then only in early, extensively affected
areas, apparently in response to tissue necrosis. Plasma cells
appeared in some chronic processes. Lesions of various ages
were present within specimens from individual cases. Indeed,
reparative processes were apparent in areas still presenting evi-
dence of ongoing myelin breakdown (85).
Alterations of the myelin sheath occurred in the areas of inflam-
matory cell infiltration (85). Retraction at the node of Ranvier
was seen in early lesions; more advanced changes included a
complete dissolution of the myelin sheath. Myelin disintegration
appears to evolve from the nodal region toward the centrally
located Schwann cell. These areas of segmental demyelination
were bounded by intervals of normal-appearing myelin. Active
phagocytosis of myelin was evident. Axonal damage with resul-
tant wallerian degeneration was present almost exclusively in
areas with extensive inflammation. Asbury et al. (85) concluded
that axonal degeneration was a secondary phenomenon induced
by the severe inflammation and demyelination.
Schwann cell proliferation was present in lesions from
patients surviving longer than 2 weeks. Although demon-
strated in areas with segmental demyelination but preserved
axons, Schwann cell proliferation was most common in nerves
that had undergone wallerian degeneration. The proliferat-
ing Schwann cells were arranged in columns, forming a tube
to guide the regenerating axons. Patients surviving several
months with incomplete recovery of motor function demon-
strated evidence of imperfect remyelination: myelin sheaths
were thin and pale, internodes were shorter, and Schwann cell
numbers were increased (85).
Subsequent examinations have supported many of the orig-
inal findings of Asbury et al., but marked variability in the
pathologic lesions of GBS is now commonly reported. These
reports have described, even in early lesions, less conspicuous
or absent lymphocytic infiltrate (63,84,8691). Treatment with
steroids or other immunomodulatory therapies may alter the
degree of lymphocytic infiltration. Immunohistochemical anal-
ysis of biopsy material has demonstrated T-cell lineage in most
of the invading lymphocytes with only a few B cells present
(80,83). Although CD4 helper/inducer and CD8 cytotoxic/
suppressor T cells are present, CD4 cells may predominate in
early lesions (88). Like Asbury et al. (85), Hanovar et al. (86)
were unable to identify the origin of the larger mononuclear
cells present in more advanced lesions.
Pathologic reports of GBS have confirmed the invariable pres-
ence of macrophages in areas of demyelination. Electron micro-
scopic (EM) studies have demonstrated macrophages existing as
Scheld_Ch20.indd 303
Chapter 20: Guillain-Barr Syndrome 303
two types (8894). One type consists of actively phagocytic mac-
rophages that occur in an extratubal location within the endoneu-
rial space and in an intratubal location beneath the Schwann cell
basement membrane. Focal lysis of the outermost myelin lamellae
occurs in the areas contacted by the macrophage. The cytoplas-
mic projections of the macrophage then penetrate through the
myelin gaps, insinuate themselves between the myelin lamellae,
and peel away layers of myelin from the axon. These invading,
actively phagocytic macrophages express major histocompatibil-
ity complex (MHC) class II antigens (86,88,9598).
The manner in which macrophages accomplish myelinoly-
sis is not understood. Arstila et al. (92) demonstrated increased
acid phosphatase and acid proteinase activities in GBS lesions.
These lysosomal enzymes may be derived from macrophages.
However, the macrophage processes observed in GBS lesions are
devoid of organelles, including lysosomes (90). The second type
of macrophage, the foamy macrophage, is postphagocytic, con-
tains myelin debris and lipids, and does not express MHC class
II antigen (95). In GBS lesions, MHC class II antigen expression
has also been observed on endothelial and Schwann cells (98).
Macrophages have also been observed within the axon cyl-
inder (63). This location might explain some cases of axonal
degeneration that apparently ensue in the absence of severe
demyelination. McKhann et al. (63) reported pathologic findings
on 10 autopsies from individuals with acute flaccid paralysis in
China, a syndrome clinically indistinct from GBS. Although two
of the patients had pathologic findings similar to those described
by Asbury et al. (85), five were dominated by selective involve-
ment of motor axons with absence of inflammation and little
evidence of demyelination. Numerous macrophages were pres-
ent in the areas of axons undergoing wallerian degeneration. The
macrophages were located within both endoneurium and degen-
erating axons. The authors have designated this entity AMAN.
Immunoglobulin and activated complement deposits have
been described in GBS nerve biopsy specimens. Nyland et al.
(96) detected activated complement C3b receptor along nerves
in GBS. Positive staining for C3 was observed along nerve fibers,
and IgG and IgM were apparent in the region of the myelin
sheath. Other investigators have failed to demonstrate immuno-
globulin within the myelin sheath (8890,94). Immunoglobulin
staining of the endoneurium has occasionally been noted
(89,90). Deposition of IgM on perineurium is a normal find-
ing (89,90). Deposits of C3d were present in the myelin sheath
of a single patient (94). In mice models of GBS, deposition of
complement at the presynaptic motor nerve terminus has been
reported (99,100,101). This in turn leads to a blockage of syn-
aptic transmission at the neuromuscular junction (102).
Axonal degeneration in the absence of demyelination or
inflammation has also been observed by Feasby et al. (88).
Macrophages were not seen within the axon cylinder, and no
evidence of inflammation or macrophage-associated demy-
elination was encountered. Axonal degeneration of motor and
sensory nerves was severe. Electrophysiologic studies demon-
strated inexcitability of motor nerves, a pattern seen primar-
ily in axonal degeneration. The authors named this variant
AMSAN. Prognosis for recovery is poor with axonal degen-
eration, whether it is a primary event or secondary to intense
inflammation and demyelination.
PATHOGENESIS OF
GUILLAIN-BARR SYNDROME
The most compelling evidence for a T-cellmediated mechanism
in the pathogenesis of GBS is the finding of T-cell infiltration in
affected nerves (32,85,87,88,90,91). Another indicator of T-cell
involvement is the presence of lymphoblasts in blood during
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 304 Part II: Viral Infections and Related Disorders
early GBS and a possible correlation between their number and
disease severity (103). Increases in HLA-DR antigen and trans-
ferrin receptor, both present with T-cell activation, have been
observed on the surface of T cells in GBS (104108). Serum
levels of interleukin-2 (IL-2), a T-cell growth factor, and serum-
soluble IL-2 receptor (sIL-2R), shed from activated T cells, are
increased in GBS (104107). Levels are maximal at onset and
decrease during recovery. Serum levels of IL-2 do not correlate
with maximal functional disability. However, concentration of
sIL-2R may predict severity (107). Activated T cells may me-
diate injury in GBS by (a) stimulation of B-cell proliferation
and antibody production against myelin components, (b) mac-
rophage recruitment, (c) activation of the complement system,
or (d) direct cytotoxic damage of myelin or Schwann cells (97).
Consistent alterations in T-cell subpopulations have not
been demonstrated (104,108110). Dahle et al. (108) noted
normal total lymphocyte counts in acute GBS but a decrease in
the proportion of CD4 helper/inducer T cells and an increase
in the proportion of CD8 cytotoxic/suppressor T cells. Within
the CD4 population, helper/inducer cells predominated over
suppressor/inducer cells, known to be decreased in diseases
of autoimmune mechanism. Winer et al. (110) demonstrated
decreased numbers of CD8 T cells in GBS patients with sero-
logic evidence of recent C. jejuni infection and decreased num-
bers of CD4 T cells in GBS patients with serologic evidence
of recent CMV infection. Specific activation of T cells against
myelin proteins has not been consistently observed with the
sera from those with GBS. Two series (111,112) found no evi-
dence of T-cell sensitivity to myelin P2 protein. Several reports
have demonstrated T-cell clonal proliferation against proteins
P2 and P0 and their peptides (113115). However, similar
results have been obtained in normal controls and controls
with other neurologic diseases (113,115).
Macrophage involvement in GBS is evidenced by demon-
stration of macrophages in affected nerves in GBS pathologic
specimens (32,8588), electron microscopic observation of mac-
rophage-mediated myelin stripping and phagocytosis (8994),
and indications of macrophage activation and their possible
role as antigen presenters through the surface expression of
MHC class II antigens. Neopterin is produced by macrophages
in response to T-cell activation. Serum levels of neopterin are in-
creased in GBS and fall as clinical involvement improves (116).
In vitro, monocytes from GBS patients have demonstrated a
greater ability to generate reactive oxygen species, indicative of
cytokine activation, than monocytes from controls (104). Thus,
available data indicate that macrophage activation, probably by
activated T cells or their byproducts, occurs in GBS.
MHC class II marker expression is necessary for antigen pre-
sentation. Invading, actively phagocytic macrophages in GBS
express MHC class II markers on their surface (86,88,89,95).
Although MHC class II marker has been detected on the Schwann
cell surface in GBS (98), these markers have also been observed
on the Schwann cell surface in degenerative, toxic, and metabolic
neuropathies (117). Tumor necrosis factor- (TNF-) is a cytokine
elaborated by both activated T cells and macrophages. Increased
serum levels of TNF- occur in GBS (118). Although TNF- may
play a role in the immune-mediated injury in GBS, recombinant
TNF- alone will not produce myelin destruction in vitro (119).
The mechanism by which activated T cells and macro-
phages gain access to PN is not fully understood but appar-
ently involves two adhesion molecules, E-selectin (ELAM-1)
and intercellular adhesion molecule-1 (ICAM-1) (97). ELAM-1
is expressed on endothelial cells activated by IL-2, TNF-, and
endotoxin. It aids in the binding of lymphocytes, monocytes,
eosinophils, and neutrophils to the blood vessel wall. Like IL-2
receptor, ELAM-1 enters the circulation and can be measured
in serum. Elevated ELAM-1 serum levels have been observed
acutely in GBS (120,121).
Scheld_Ch20.indd 304
In recent years, the humoral immune system has been
implicated in the pathogenesis of GBS because of (a) the dem-
onstration of immunoglobulin and complement deposition in
GBS nerve biopsy specimens (89,90,94,95), (b) the therapeu-
tic effect of plasmapheresis and intravenous immunoglobulin
(IVIG) (see later discussion), (c) the ability of GBS sera to cause
demyelination of nerve in tissue culture and possibly in vivo,
and (d) the demonstration of antibodies against PN constituents
in GBS sera. Whole serum or IgM antibody from some patients
with early GBS will produce complement-dependent demyelin-
ation of PN tissue cultures (122124). Electron microscopic
studies have disclosed damage to cultured Schwann cells and
vesicular myelin degeneration after exposure to GBS sera in
the absence of leukocytes, lymphocytes, or macrophages (122).
A lesser degree of in vitro demyelination occurs in PN tissue
culture after exposure to control sera, GBS patients during
recovery, or persons with other neurologic diseases (123).
A humoral mechanism in the pathogenesis of GBS has
focused on the detection of antibodies to PN constituents, espe-
cially gangliosides and related glycolipids. Complement-fixing
antibodies directed against PN myelin are demonstrable in the
sera of some persons with early GBS (120,125). AntiPN-myelin
antibodies are highest at presentation, significantly increased
over levels from normal and diseased controls, and decrease
with improving clinical symptomatology (125). Production of
antiPN-myelin antibodies in GBS is predominantly extrathe-
cal, although measurable amounts are present in CSF (126).
In GBS, activated complement components are detectable
in serum and CSF. AntiPN-myelin antibodies peak prior to
activated complement levels, providing evidence of an antibody-
mediated complement attack on PN myelin (127,128).
Characterization of antiPN-myelin antibodies has disclosed
increased levels of circulating antibody to galactocerebroside
(GalC) (110) and P2 protein (112). Antibody levels to these my-
elin constituents were low and, in the case of P2 protein, only
marginally increased over those of control sera. Koski et al.
(129) discovered antiPN-neutral glycolipid antibodies in GBS
sera. Antigenic cross reactivity was demonstrated between this
PN neutral glycolipid and Forssman antigen, a component of
some viral and bacterial cell membranes.
Gangliosides are sialylated glycosphingolipids located on
mammalian cell plasma membranes. Ganglioside function is not
known precisely, but gangliosides are implicated in cell differ-
entiation, cellcell interactions, and receptor functions such as
binding of viruses, bacterial toxins, hormones, growth factors,
and interferons (130). IgG and IgA antibodies to GM1, GD1b,
and GQ1b have been shown to activate leukocytes, which may
contribute to the pathogenesis of GBS (131). The major gangli-
osides of PN are GM3 and GD3, and the major ganglioside of
PN myelin is LM1. GM1, although a major component of CNS
myelin, is only a minor constituent of PN. GM1 has been local-
ized to both nerve plasma membrane and the myelin sheath and
appears to accumulate in the paranodal region (132). Antibody
to gangliosides is present in low amounts in normal human
plasma (133). In 1988, Ilyas et al. (134) detected significantly
increased levels of antibodies to the gangliosides GD1a, GD1b,
and GT1b and to two associated glycolipids in serum from pa-
tients with acute GBS compared to controls.
High IgG antibody titers against GQ1b, a minor ganglioside
of PN that has been localized to the paranodal region of human
ocular motility nerves, was detected in 90% of 41 persons with
Fisher syndrome (FS) (135137), a GBS clinical variant manifest-
ing primarily as ophthalmoplegia and ataxia. Anti-GQ1b anti-
body decreases as clinical symptoms improve and may be absent
in people with mild FS (135137). High anti-GQ1b antibody
titers have also been demonstrated in Bickerstaff brainstem en-
cephalitis, a syndrome that bears some clinical resemblances to
FS (138), and in typical GBS with prominent ophthalmoplegia
2/21/14 5:40 PM

(137). High-titer anti-GQ1b antibody is not usually detectable
in typical GBS lacking ophthalmoplegia or in normal controls
(137). The pathogenetic role of anti-GQ1b antibodies in FS is
not known. Lipopolysaccharide of C. jejuni isolated from FS
does cross-react with epitopes of anti-GQ1b antibody (56).
Subsequent to the original observation of high antiganglio-
side antibody titers in GBS (134), antiganglioside antibodies
(AGA) have been detected in 10% to 60% of patients with
GBS (61,97,139145). The AGA titers may correlate with
GBS severity and decrease with clinical improvement (143).
Antibodies to many known gangliosides and unidentified glyco-
lipid fractions have been demonstrated in association with GBS,
but antibody to GM1 is most frequently cited, especially in cases
with mainly motor symptoms (139,141144,146). Both IgM
and IgG antibodies to gangliosides are present, but IgM antibod-
ies predominate early (142). The early presence of IgG or IgA
antibodies to GM1 has been associated with severe, prolonged
GBS (139) and may predict poor recovery (141,144,147149).
AGA have also been detected in individuals with hyperreflexia
and impaired central motor conduction in association with
acute paralysis, acute ataxia, or chronic paralysis (150).
Anti-GM1 antibodies have been reported in up to 58% of pa-
tients with GBS showing serologic evidence of preceding C. jejuni
infection (139,149). Yuki et al. (62) described anti-GM1 anti-
body in association with C. jejuni infection in severe GBS with
electrophysiologic evidence of primary axonal degeneration and
poor recovery. Immunogenic cross-reactivity between GM1 and
C. jejuni isolates from GBS patients has been described (53,57).
GM1 antibodies recognize a carbohydrate sequence that is pres-
ent in several gangliosides and on bacterial cell walls. GM1 gan-
gliosides may also be important for nerve growth factor signaling.
Tanaka et al. reported that GM1 antibodies interfered with
the neurotrophic action of nerve growth factor and TrkA auto-
phosphorylation signaling in PC12 cells, a sympathetic nerve cell
line (151). Nakatani et al. reported GM1 antibodies of patients
with AMAN inhibit the current action of Cav2.1 (P/Q-type)
voltage-dependent calcium channel in Purkinje cells of rats (152).
Elevated titers to GM1 and GD1b occur in C. jejuni infec-
tion without GBS (153). However, research now shows that
elevated antibodies to GM1, GD1a, GM1b, and GalNAcGD1a
occur with higher frequency in AMAN, whereas elevated GQ1b,
GT1a, GD3, and GD1b antibodies occur in the majority of FS
(154). In 32 Japanese children with GBS, Nishimoto et al. (155)
reported the frequency of IgG antibodies to gangliosides: GM1
(34%), GM1b (22%), GD1a (25%), and GalNAc-GD1a (13%).
In addition, antibodies to ganglioside complexes (GSCs) are
associated with severe GBS. Patients with GBS requiring mechan-
ical ventilation may have antibodies to GD1a/GD1b and GD1b/
GT1b complexes, and patients with FS may have antibodies to
GQ1b/GM1 and GQ1b/GD1a GSC (156,157,158,159). GM1/
GalNAc-GD1a GSC have also been reported in 10 patients with
GBS (160). Other antibodies associated with GBS have been iden-
tified (Table 20.4) (65,162164). Immunogenic cross reactivity
between GalC and M. pneumoniae has also been described (165).
TA B L E 2 0 . 4
ANTIBODIES ASSOCIATED WITH GUILLAIN-BARR
SYNDROME
GD1a GM1
GD1b GM1b
GD3 GT1a
LM1 GT1b
GQ1b GalNAcGD1a
Scheld_Ch20.indd 305
Chapter 20: Guillain-Barr Syndrome 305
The IgG subclasses 1 and 3 predominate in IgG antibodies
to both GM1 and GQ1b. These subclasses are usually seen in
immune responses to protein antigens rather than to carbohy-
drates such as gangliosides. This suggests that the primary anti-
body response in GBS is against a protein. The antibody simply
cross-reacts with gangliosides (161). The IgG subclass may be
a predictor of severity and outcome. Jacobs et al. reported pa-
tients with only IgG1 AGA had a worse prognosis compared
to patients with both IgG1 and IgG3 AGA. This may be in part
due to the longer serum half-life of IgG1 (21 days) compared to
the relative shorter half-life of IgG3 (7 days) (166).
CLINICAL MANIFESTATIONS
An ad hoc committee of the NINCDS proposed diagnostic cri-
teria for GBS in 1978 (3). These criteria, further reaffirmed and
elaborated by Asbury in 1980 (167) and Asbury and Cornblath
in 1989 (168), are summarized in the following paragraphs
along with additional comments. Electrodiagnostic criteria are
discussed in the subsequent section.
The diagnosis of GBS is based on (a) progressive motor
weakness of more than one extremity and (b) areflexia,
although proximal hyporeflexia with distal areflexia may be
seen. Weakness may precede reflex changes by 2 or 3 days (168)
and typically spreads from the lower extremities to involve the
upper extremities, trunk, and cranial nerves (6,7). Weakness
usually ascends from the thighs to the upper arms, although
hands and feet are initially involved in some cases (6). Muscle
wasting may eventually occur in 50% of patients (168).
Features strongly supportive of the diagnosis include
(a) rapid progression of motor weakness reaching a plateau
in 4 weeksin one study, the average time elapsing from
onset of weakness to its maximum was 12 days, with 98%
of patients reaching maximal weakness by 4 weeks (25);
(b) relative symmetry of motor weakness; (c) mild sensory
symptoms. GBS is often heralded by paresthesias in the toes
and fingers (6). Sensory symptoms are eventually present in
70% of GBS patients (9,11,13). Subjective sensory complaints
commonly exceed objective sensory findings (6,11). When
objective sensory loss occurs, proprioception and vibration
are primarily involved (169), presumably because the fibers
involved in their conduction are myelinated to a greater extent
than are the fibers conducting temperature, pinprick, and light
touch; (d) cranial nerve involvement. Data in one study of
100 consecutive GBS patients revealed facial palsy (frequently
bilateral) in 53% of patients, bulbar weakness in 13%, and
extraocular muscle palsy in 9% (169). Rarely, all brainstem re-
flexes may be lost simulating brain death; (e) recovery ensues.
This usually begins 2 to 4 weeks after cessation of progression
but may be delayed months (6). Little improvement is seen
after 1.5 to 2 years (25,29); and (f) autonomic dysfunction.
Sympathetic and parasympathetic systems may be involved,
producing cardiovascular, gastrointestinal, urinary, pupillary,
and sudomotor symptoms. Autonomic involvement is recog-
nized in about 20% of GBS cases, although the actual figure
is probably much higher (13,20,21). Minor cardiovascular
abnormalities in GBS include sinus tachycardia and postural
hypotension. Malignant arrhythmias secondary to autonomic
dysfunction remain a leading cause of death in GBS patients.
Hypertension, hypotension, and sensitivity to vasoactive drugs
also occur. Urinary retention, constipation, gastroparesis, and
loss of pupillary responses are less frequent (25). Disordered
sympathetic function can produce both excessive sweating and
anhidrosis (170). Impotence may persist in a few men (6).
Variant clinical features include (a) fever at the onset of
neurologic symptoms; (b) severe sensory loss with pain. Severe
pain may be the presenting complaint in some GBS patients,
2/21/14 5:40 PM
 306 Part II: Viral Infections and Related Disorders
particularly in children, in whom the diagnosis of GBS may
be difficult initially. Painful symptoms may include myalgias
and arthralgias, paresthesias and dysesthesias, meningismus,
radicular and back pain, and abdominal discomfort (9,25,171);
(c) progression may continue beyond 4 weeks or show a minor
relapse. Approximately 3% to 9% of patients will have one
or more relapses (9,32); (d) no significant recovery. Complete
recovery occurs in approximately 60% of patients, but mild
disability persists in 30%, and significant handicap remains in
5% to 10% (6,9,25,169). Children experience a better outcome
(2023); (e) sphincteric dysfunction may occur; urinary reten-
tion is rare but may occur secondary to autonomic involve-
ment (169); and (f) CNS involvement. Although controversial,
occasional GBS patients demonstrate cerebellar ataxia, exten-
sor plantar responses, and ill-defined sensory levels (25).
CSF findings that are strongly supportive of the diagno-
sis include (a) elevated CSF protein. Increases in CSF protein
concentrations are thought to arise from the severe nerve root
involvement. CSF protein elevations are usually not present until
after 1 week of symptoms and peak during the nadir and early
recovery period (6,11). CSF protein concentrations may reach
levels of 2 g/dL, though much lower levels are typical (11,14,32);
a CSF protein concentration greater than 2.5 g/dL should alert
one to the possibility of cord compression (6). No correlation
exists between protein values and mode of onset or progression,
severity, or outcome of GBS (9,25,32). However, elevated heavy
chain neurofilament (NfH), a marker of axonal damage, may in-
dicate a worse prognosis (172). Papilledema noted in some cases
of GBS has been attributed to impaired CSF absorption second-
ary to increased protein levels (13,25,169). However, papilledema
and increased intracranial pressure have been seen in GBS with
normal CSF protein, and papilledema is not consistently present
in patients with extremely high protein values (32); and (b) ten or
fewer mononuclear leukocytes per cubic millimeter.
CSF variants include (a) normal CSF protein in the period
1 to 10 weeks following the onset of neurologic symptoms
normal CSF protein values may be present in 20% of GBS pa-
tients (6,9,11,32)and (b) 11 to 50 mononuclear leukocytes
per cubic millimeter. In the presence of HIV infection, CSF
pleocytosis in GBS is expected. Cornblath et al. (40) noted a
mean of 23 cells/mm3 in nine HIV-infected persons with GBS.
Clinical variants of GBS include (a) FS with ophthalmo-
plegia, ataxia, and areflexia; (b) polyneuritis cranialis (173);
(c) pharyngealcervicalbrachial weakness (174); (d) parapare-
sis with areflexia (32); (e) sensory loss with areflexia (32,168);
(f) pure pandysautonomia (175); (g) pure motor weakness
(32); (h) AMAN (63); and (i) AMSAN (88). Paraparesis with
areflexia can be included as a variant of GBS only if spinal
cord compression and transverse myelitis have been excluded
and electrophysiologic studies are consistent with demyelinat-
ing polyneuropathy (32). Sensory loss with areflexia is most
commonly secondary to a neuronopathy associated with
malignancy, particularly small cell carcinoma of the lung and
lymphoma. Rather than a demyelinative process, dorsal roots
are destroyed by intense inflammation (32). Although pure
pandysautonomia may result from an autoimmune pathogen-
esis similar to that of GBS, pathologic evidence of demyelin-
ation is lacking (32,167,175). GBS with motor weakness in
the absence of subjective or objective sensory loss may occur
(32). However, such patients should be distinguished from
those with AMAN (63), a syndrome clinically similar to a pre-
dominantly motor form of GBS but pathologically and prob-
ably pathogenetically distinct. AMSAN as described by Feasby
et al. (88) is also pathologically different from GBS and should
be considered a separate entity as well.
Radiologic studies are generally not helpful in the diagno-
sis of GBS. However, contrast-enhanced magnetic resonance
imaging may demonstrate enhancement of nerve roots.
Scheld_Ch20.indd 306
Clinical and laboratory features that should alert one to the
possibility of alternative diagnoses are (a) conspicuous asym-
metry of extremity weakness; (b) persistent bladder or bowel
dysfunction or bladder or bowel dysfunction at onset; (c) more
than 50 mononuclear leukocytes/mm3 in CSF or the presence
of polymorphonuclear leukocytes in CSF; (d) protein concen-
tration greater than 2.5 g/dL; and (e) distinct sensory level.
The differential diagnosis of GBS includes ADEM present-
ing transverse myelitis, or spinal cord compression presenting
as flaccid paralysis, myasthenia gravis, diphtheritic neuropa-
thy, vasculitic neuropathy, lead neuropathy, and arsenic poi-
soning. Weakness related to enteroviral infection (including
poliovirus), botulism, and hysterical paralysis may occasion-
ally be confused with GBS. Weakness secondary to enteroviral
infection is associated with a CSF pleocytosis and electrophys-
iologic evidence of motor neuron injury. A history of prodro-
mal constipation and poor feeding in infants or the ingestion
of contaminated food in adults, preservation of reflexes in
some patients, and the presence of a presynaptic defect on elec-
trophysiologic studies can differentiate weakness secondary to
botulism from GBS. Acute intermittent porphyria is excluded
by the absence of urinary excretion of porphobilinogen and
-aminolevulinic acid. The presence of cells in the CSF should
alert one to the possibility of lymphomatous, carcinomatous,
or sarcoid meningitis as well as Lyme disease. Extremity and
respiratory muscle weakness mimicking GBS can occur 12 to
96 hours after organophosphate exposure (176), secondary to
blockade of nicotinic receptors by excess acetylcholine. Basilar
artery occlusion and tick paralysis may mimic MFS (6).
ELECTROPHYSIOLOGIC FEATURES
Electrophysiologic studies have significantly increased our
understanding of GBS and improved diagnostic accuracy.
The symptoms and signs in GBS are attributed to abnormali-
ties in nerve conduction. Although the diagnostic criteria of
GBS described in 1978 (3) report normal studies of nerve
conduction in up to 20% of GBS, more recent series have
identified electrophysiologic abnormalities in 90% to 100%
(169,177180). Because of the multifocal nature of pathologic
lesions in GBS, the likelihood of detecting electrophysiologic
abnormalities increases with the number of nerves tested (177).
Generally, three or more motor nerves should be examined
(168). Early in the course of GBS, nerve conduction may be
normal or minimally abnormal. Repeat testing may be neces-
sary in inconclusive cases. Abnormalities in motor nerve con-
duction, sensory nerve conduction, mixed nerve conduction,
and late motor responses (H-reflex study and F-wave study)
may occur alone or in any combination.
In 1990, Asbury and Cornblath (168) proposed electro-
diagnostic criteria for demyelinating neuropathies, including
GBS. These criteria require three of the following to be pres-
ent: (a) decreased conduction velocity in two or more motor
nerves; (b) conduction block or abnormal temporal disper-
sion in one or more motor nervesperoneal nerve between
ankle and below fibular head, median nerve between wrist and
elbow, or ulnar nerve between wrist and below elbow; (c) pro-
longed terminal motor latency (TML) in two or more motor
nerves; and (d) absent F-waves or prolonged F-wave latency.
In early GBS, electrophysiologic evidence of demyelination
is apparent primarily in proximal nerve plexuses and in the
distal nerve twigs (31,181,182). During the first 5 weeks,
motor conduction abnormalities are more common than
sensory nerve conduction abnormalities (169,178). Slowed
motor nerve conduction is present at some point in 60% to
80% of those with GBS with maximal slowing detected in the
third week (167,168,177,180). Electrophysiologic evidence
2/21/14 5:40 PM

of motor nerve demyelination (conduction block or temporal
dispersion) is present in approximately 60% of GBS patients
within 2 weeks of illness onset (177,179,183). Markedly
slowed motor conduction velocity has been associated with
a poor long-term prognosis (169,182). In a given nerve, con-
duction block may be generalized, or predominantly proxi-
mal or distal. Abnormal temporal dispersion is evident in only
20% (183). Abnormal TML occurs in 40% of GBS (177,182)
and may be present in nerves with normal motor conduction
velocity between the proximal and distal sites (31). The nadir
of abnormalities of sensory conduction is reached in the fourth
week (169). The delay in sensory electrophysiologic abnor-
malities is felt to reflect, in part, secondary involvement of
sensory nerves related to intraneural edema accentuated by
compression at sites of anatomic vulnerability.
When the motor nerve is inexcitable, either severe distal de-
myelination with complete conduction block or axonal degen-
eration is responsible (184,185). Inexcitable motor nerves may
be present in up to 20% of GBS (182). Although some authors
have reported that inexcitable motor nerves within 2 weeks of
symptom onset is uniformly associated with a poor long-term
prognosis (185), Triggs et al. (184) found complete recovery
by 1 year in 50% of such individuals. Abnormal temporal dis-
persion with reduced distal compound motor action potential
(CMAP) is due to demyelination. Whether secondary to axonal
loss or severe distal demyelination, the absence or marked re-
duction (0% to 20% of the lower limit of normal) of the distal
CMAP amplitude appears to be the strongest electrophysiologic
predictor of prolonged disease and incomplete recovery follow-
ing GBS (31,169,178,182,185). In those with reduced distal
CMAP amplitude, if improvement in CMAP amplitude occurs
on sequential studies or if plasma exchange is performed, bet-
ter outcome results (184). In one series of 23 children in whom
reduced distal CMAP amplitude was the most common electro-
physiologic abnormality, no correlation between distal CMAP
amplitude and degree of recovery following GBS was evident
(179). However, the absence of a distal CMAP abnormality
early in GBS does not predict a good outcome (186).
Prolonged F-wave latency, indicating abnormal conduction
in the proximal motor nerve, is the most common electro-
physiologic abnormality in GBS, occurring in approximately
90% of patients during the course of the illness (169,177).
Indeed, prolonged F-wave latency may be the only detectable
electrophysiologic abnormality in some patients (187). F-wave
latency does not predict outcome.
The occurrence of spontaneous fibrillation potentials dur-
ing EMG in GBS, an indication of muscle denervation, has
also been associated with incomplete recovery following GBS
(188,189). It generally appears between the second and fourth
weeks after onset. In some cases, particularly in children,
the presence of fibrillation on EMG is not predictive of poor
recovery (178,179).
In AMAN, sensory and motor nerve conduction velocity
and TML are normal, but CMAP is reduced and F-waves are
either absent or normal. Unlike GBS with CMAP abnormali-
ties, the outcome in AMAN is good with only mild distal weak-
ness and atrophy present at 1 year (63). Electrophysiologic
studies in FS differ from those in typical GBS by predominant
abnormalities in sensory rather than motor nerves (190,191).
TREATMENT
Despite recent successes of immunomodulatory therapies in
GBS, meticulous nursing and medical care remain essential.
Most individuals with GBS require in-hospital observation.
Patients with mild disease may not require treatment but
must be monitored closely until progression has ceased (6).
Scheld_Ch20.indd 307
Chapter 20: Guillain-Barr Syndrome 307
Rapidly progressive weakness, respiratory embarrassment or
infection, progressive bulbar dysfunction, or cardiovascular
abnormalities warrant intensive care monitoring (6,192).
Respiratory failure occurs in approximately 20%, necessitat-
ing careful respiratory monitoring, especially during the progres-
sive stage of illness. Vital capacity should be measured every 4 to
6 hours, and elective intubation should be performed when the
vital capacity falls to 15 mL/kg of body weight (6,192195).
Patients should be observed for clinical signs of respiratory fatigue
such as diaphoresis, tachycardia, and paradoxical movement of
abdominal muscles during inspiration. Respiratory rate is vari-
able in persons with GBS and impending respiratory failure (195).
Blood gas studies and oxygen saturation are unreliable predictors
of respiratory failure. Significant respiratory compromise can be
present before hypoxia and hypercarbia occur. Oropharyngeal
weakness may warrant earlier intubation (6,192). Newton-John
(196) demonstrated fewer pulmonary complications with early
assisted ventilation (before the vital capacity fell below 21 mL/
kg) compared to late assisted ventilation (after the vital capacity
fell below 15 mL/kg). The use of immunomodulatory therapies
(see later discussion) in ventilated GBS patients has decreased the
mean time of ventilation to 16 to 24 days from 26 to 48 days
(24,197,198). Weaning from mechanical ventilation should not
begin until vital capacity is greater than 7 mL/kg; extubation can
be safely attempted when the vital capacity is 15 mL/kg (197).
Because of the prominence of autonomic disturbances in
GBS, continuous electrocardiographic and possibly arterial
blood pressure monitoring is necessary in those requiring inten-
sive care (6,192,193). The majority of cardiovascular irregu-
larities occur during peak motor weakness, but episodes during
convalescence have also been reported (170,194,199201).
Cardiovascular dysfunction in GBS include sinus tachycar-
dia, postural hypotension, minor ECG changes, hypertension,
episodic hypotension, bradyarrhythmia, tachyarrhythmias,
and sensitivity to vasoactive drugs (188,194,199,201). Drugs
producing hypotension in GBS include phentolamine, nitro-
glycerin, hexamethonium, edrophonium chloride, thiopental
sodium, morphine sulfate, and furosemide. Phenylephrine,
ephedrine, dopamine, and isoproterenol have been associated
with hypertension (170). Carbamazepine precipitated asystole
in a man recovering from GBS (200). Atropine and glycopyr-
rolate should be used cautiously in GBS because of a risk of
tachyarrhythmias. Some authors advocate insertion of a car-
diac pacemaker in any patient with a nonsinus arrhythmia
(170). Vagal stimulation such as occurs with tracheal suction-
ing, intubation, extubation, Valsalva, and distention of a hol-
low viscus may produce hypotension and bradyarrhythmias
in GBS (192,194). Severe tachyarrhythmias have been termi-
nated with verapamil and pindolol (194).
Infection of the urinary tract or lung occurs in almost 25%
of those requiring intensive care (202). Intravenous line or gen-
eralized sepsis occurs less commonly. Chest physiotherapy and
incentive spirometry are essential to prevent sputum retention,
bronchial obstruction, and segmental collapse. In individuals re-
quiring long-term urinary drainage, intermittent catheterization
may be less problematic than a chronic indwelling catheter (194).
Gastrointestinal hemorrhage complicates the course of 2%
to 8% of those in intensive care units (194). The best prophy-
laxis against gastritis is regular feeding. If feeding is not possible
because of gastric paresis, gastric emptying may be improved
with metoclopramide or cisapride and isotonic, low-fat enteral
formulas, and avoidance of sedatives and narcotics. When
feeding is impractical, sucralfate or magnesium-containing
antacids may provide adequate gastric bleeding prophylaxis
(193). Individuals with GBS have increased nutritional needs
from hypercatabolic states and the metabolic demands of
regenerating myelin and atrophied muscles and must be closely
followed (193).
2/21/14 5:40 PM
 308 Part II: Viral Infections and Related Disorders
Early physical and occupational therapy in GBS may aid
in the prevention of joint contractures and pressure nerve
palsies and may also hasten the return of limb control, walk-
ing, and balance during the recovery period. Frequent posi-
tion changes and soft bedding are needed to prevent decubiti
(192). Subcutaneous low-dose heparin is commonly employed
for prophylaxis against deep vein thrombosis (192,194).
Successful treatment of pain and dysesthesias associated
with GBS is highly individualized. Painful symptoms are usu-
ally worse at night and may preclude intensive physiotherapy.
Proper positioning and splinting, socks or gloves, massage, and
hot or cold packs can provide relief in many (171). Nonsteroidal
antiinflammatory drugs may alleviate musculoskeletal pain.
Tricyclic antidepressants and carbamazepine are popular
choices for neurogenic pain but should be used cautiously in
those who have cardiovascular irregularities or urinary retention
(171,200). Quinine and capsaicin or lidocaine salve have proved
beneficial (171,192). Low-dose methylprednisolone may benefit
some individuals (192). Narcotic analgesics may be required for
adequate pain relief but should be used cautiously because of
secondary hypotension and risk of ileus. Some authors advocate
the use of epidurally administered opioids for severe pain (171).
Transcutaneous nerve stimulation has received mixed commen-
tary as an adjunct to other forms of pain management (171).
Acute GBS can be a frightening experience. Severe GBS is
susceptible to anxiety and depression. Reassurance that the
disorder is self-limited and that the majority of patients make
a full recovery is beneficial. Visits from individuals who recov-
ered from GBS may also be helpful (193,194).
Individuals with GBS are at risk for hyperkalemia fol-
lowing succinylcholine chloride (203). Muscle membrane
changes after nerve injury result in the proliferation of cholin-
ergic receptors. Succinylcholine interacts with the cholinergic
receptor, producing depolarization with the influx of sodium
and release of potassium. Normally, depolarization does not
release enough potassium to increase serum levels. However,
after diffuse PN injury such as occurs in GBS, the increase in
cholinergic receptors may cause enough potassium release to
increase serum potassium levels sufficient to produce arrhyth-
mias and cardiac arrest. It is not known when, if ever, succinyl-
choline can be safely administered to patients recovered from
GBS (203). Nondepolarizing neuromuscular blocking agents
may also result in prolonged paralysis (204).
Immune Modulation
Immune modulation has now emerged as a promising adjunct
to general medical care in GBS. Corticosteroids were used in
the treatment of GBS for many years. Their use was based
largely on their antiinflammatory effects and the results of a few
uncontrolled trials. Three randomized, controlled trials showed
little, if any, benefit from corticosteroids (205207). In fact,
steroids may have a detrimental effect (205). One study com-
paring 21 prednisolone-treated subjects and 19 untreated indi-
viduals demonstrated slower improvement in the treated group
at 1, 3, and 12 months. Six of the treated groups had disabling
weakness compared to one control. Three relapses occurred in
the treated group. A nonrandomized study of GBS suggested
that coincident administration of methylprednisolone and IVIG
was more effective than treatment with IVIG alone (208).
Plasma exchange (PE) appeared in the 1980s as a beneficial
treatment for GBS (209). Enthusiasm for its use was based on
three sets of observations: (a) case reports showing improve-
ment following PE; (b) efficacy of PE in chronic inflammatory
demyelinating polyneuropathy; and (c) reports of in vivo demy-
elination by GBS sera (25). Four randomized controlled trials
employing PE have been performed (24,210,211). Because it
Scheld_Ch20.indd 308
was considered unethical to carry out sham PE, none of the
trials was blinded. These studies included 263 in the PE-treated
group and 269 treated with conventional methods alone. Only
individuals who required assistance walking were included.
The greatest benefit was seen in those who began PE within
1 week of onset. PE 14 days or more after onset observed little
benefit in those treated. Duration of mechanical ventilation
was significantly shorter, and time to onset of motor recov-
ery, independent walking, and length of hospitalization were
shorter. Outcome at 6 months and 1 year was better compared
to those receiving conventional therapy. In one large series (24),
a 12-year-old boy with GBS died of inflammatory myocarditis
after two PE treatments. Otherwise, no deaths in the PE-treated
group could be attributed to PE, and the number of deaths in
each group was similar.
IVIG has recently proved efficacious in the treatment of
GBS. IVIG is pooled human IgG from 5,000 to 10,000 blood
donors. Side effects of IVIG occur in fewer than 5% of re-
cipients and are summarized in Table 20.5 (212). The most
common adverse reactions are systemic and include nausea,
vomiting, headache, fever, chills, myalgias, tachycardia, and
hypotension. These reactions are believed to be secondary to
impurities in the preparation and can usually be managed by
slowing the infusion rate. Fatal anaphylaxis may occur during
IVIG administration in IgA-deficient individuals. Preparations
with very low levels of IgA should be used in IgA deficiency
and in those for whom determination of IgA levels is not pos-
sible (213). Patients with impaired renal function have rarely
developed renal failure following IVIG administration. With
current preparations of immune globulin, the remaining
adverse reactions listed in Table 20.5 are extremely rare (213).
The early justification for treatment of GBS with IVIG
was based on its efficacy in other immune-mediated disorders
(214). The mechanism by which IVIG exerts its effectiveness in
immune-mediated diseases such as GBS is unknown but could
be related to the presence of antiidiotypic antibodies (215).
Antiidiotypic antibodies are normally circulating antibodies
that bind other antibodies and serve as immunoregulators.
Treatment with IVIG exposes circulating autoantibodies to
antiidiotypic antibodies in IVIG and may result in clearance
of the autoantibodies (215). Other possible beneficial effects
of IVIG in GBS include inhibition of complement-binding and
cytokine secretion, blockade of antibody receptors, reduction
in autoantibody synthesis, amplification of suppressor cell
activity, and inhibition of lymphocyte proliferation (215).
Treatment of GBS with IVIG may have several therapeutic
advantages over PE. It is readily available, may be given in any
hospital without delay, and can be used in those patients with
cardiovascular instability. Also, IVIG administration does not
remove medications or plasma proteins as PE does and rarely
requires placement of a central venous catheter. Treatment
cost is comparable to that of PE.
TA B L E 2 0 . 5
SIDE EFFECTS OF INTRAVENOUS IMMUNE GLOBULIN
Systemic effects
Anaphylaxis
Hemolytic anemia
Viral infection
Aseptic meningitis
Renal failure
Thrombotic events
2/21/14 5:40 PM
 Chapter 20: Guillain-Barr Syndrome 309

TA B L E 2 0 . 6 onset, 29 of 33 examined children had achieved clinical motor

function 1 or 0 (220,223,224,226,227). Two of the remaining
CLINICAL GRADING OF MOTOR FUNCTION four children had no residua at 1 and 2 years (208). These
IN GUILLAIN-BARR SYNDROME reports support the notion that PE can be safely performed in
seriously ill children with GBS and that they benefit from PE
0 Healthy therapy.
1 Minor signs and symptoms but capable of working IVIG is an attractive treatment for childhood GBS for rea-
2 Able to walk 10 meters without assistance sons similar to those in adults. Also, central venous access
required for PE is rarely necessary in IVIG. This is particu-
3 Able to walk 10 meters with assistance
larly advantageous in infants and small children. Sixty-seven
4 Bedridden or chairbound children administered IVIG for GBS have been described
5 Requires assisted ventilation (212,225,227233). All treated children were clinical motor
6 Dead function grade 3 or worse and ranged in age from 1.7 to 16
years. IVIG was administered in doses of 400 mg/kg body
weight on 5 consecutive days, 1 g/kg body weight on 2 con-
secutive days, or a single dose of 2 g/kg body weight. Thirty-
five children were treated within 2 weeks of symptom onset,
A randomized trial comparing IVIG and PE treatment of GBS
1 child was treated 19 (232) and 30 days (230), respectively,
was performed by the Dutch Guillain-Barr Study Group (216).
after onset, and time of treatment was not available in 30 chil-
Individuals with typical GBS of less than 2 weeks duration with
dren (225,229,231). Side effects of IVIG treatment occurred
a clinical motor function grade of 3 or greater (Table 20.6) (24)
in three children. Two complained of headache during treat-
were included. PE of 200 to 250 mL/kg of body weight in five ses-
ment, and one developed macroscopic hematuria. Sixty-five of
sions was performed in 73 subjects, and 400 mg of IVIG/kg body
the 67 children (97%) demonstrated a significant response to
weight was administered on five consecutive days to 74 subjects.
IVIG therapy, usually within 1 week. Improvement attributed
PE was interrupted one or more times in 16% of the PE group,
to IVIG therapy was seen as late as 19 days (212). One of
primarily because of hypotension and difficulties with venous
the nonresponders began IVIG treatment on day 3 of her ill-
access. IVIG infusion was not interrupted in any. Although this
ness but developed respiratory failure on day 7 and required
study did not establish superiority of IVIG over PE in GBS, it
mechanical ventilation for 28 days. She eventually recovered
did demonstrate equal effectiveness. IVIG treatment was signifi-
(227). The course of the other nonresponder was not described,
cantly better in the median time of improvement by one clinical
but all of the children in that series completely recovered in
grade (41 days in the PE group and 27 days in the IVIG group).
4 months (229). Interestingly, both of the nonresponders re-
Significantly fewer subjects receiving IVIG required mechani-
ceived the shorter 2-day course of IVIG rather than the 5-day
cal ventilation compared to the PE-treated group. In the Dutch
course administered in the Dutch Guillain-Barr study (216).
Guillain-Barr study, 8 of 74 (11%) patients treated with IVIG
The results obtained in these 67 IVIG-treated children with
experienced a relapse of symptoms after the treatment ended
GBS are similar to results obtained in the 62 children treated
(217). Clinical deterioration following PE or IVIG may occur be-
with PE. The nonresponder rate in the PE-treated children was
cause early treatment ends before natural progression has ceased
10% versus 3% in the IVIG-treated children. In both groups,
or the pathogenic process is reactivated after treatment is com-
improvement was usually evident within 1 week of begin-
pleted (218). Most authors advocate retreatment only if clinical
ning therapy. Comparisons of the two treatments for time
grade 3 or worse is reached. One trial found no significant differ-
to achieve independent walking and final outcome are not
ences in secondary outcome measures of PE alone compared to
reliable because information is not available for many of the
PE followed by IVIG (219). No data exist to support changing
patients. One of the series compared IVIG administration and
treatment in those who do relapse.
PE in children with GBS (227). This study was not randomized
The treatment of GBS in children is similar to treatment in
or blinded, and the attending neurologist made the treatment
adults. Despite the apparent effectiveness of immunomodula-
choice. Five children underwent PE, and 10 received 1 g of
tory therapies in children with GBS, meticulous nursing and
IVIG/kg body weight on two consecutive days. All children
medical care remain the mainstay of therapy. Children who
receiving PE responded, whereas 9 of 10 children in the IVIG
are too young to perform forced vital capacity measurements
group responded. The PE group improved two functional
must be monitored closely for signs and symptoms of impend-
grades in a mean of 48 days versus 17 days in the IVIG group.
ing respiratory failure.
The outcome at 6 months was similar. Although it appears
No randomized trials have been performed to assess effi-
that IVIG resulted in quicker improvement, the groups were
cacy and safety of PE or IVIG in pediatric GBS. A review of
not equal. Mechanical ventilation was necessary in 60% of
the literature reveals 62 children treated with PE (220227).
the PE group but in only 30% of the IVIG group. Patients in
The children ranged in age from 1.2 to 16 years. Grade 3 or
the IVIG group began treatment one day earlier than those
greater disability (Table 20.6) was present in all treated chil-
in the PE group, and their average age was 2 years younger.
dren. Mild hypotension responsive to fluid administration was
Certainly, one can conclude from the available reports that
the most frequent complication of PE in the 49 children for
both PE and IVIG can favorably alter the course of GBS in
whom information was available (220,221,223,224,226,227).
nonambulatory children, but whether one treatment is supe-
Systemic reactions occurred in four children who received
rior will have to be answered by a randomized trial.
fresh frozen plasma as a replacement fluid. Two children
displayed emotional upset at the end of a PE session, possi-
bly secondary to hypocalcemia (224). Only 1 of 58 reported
children began PE more than 2 weeks after symptom onset PROGNOSIS
(15 days) (224). Fifty-four of the 62 reported children (87%)
receiving PE improved significantly after beginning PE; most Despite the considerable progress made in the treatment of
within 1 week. Two children responded partially, and six did GBS in recent decades, the mortality rate remains 5% to 10%
not respond. One PE nonresponder improved after a single (6,9,14,24,25,28,30,169). In some geographic locations, mor-
IVIG dose of 1.5 g/kg body weight (225). Six months after tality as high as 21% has been recorded (11). Causes of death

Scheld_Ch20.indd 309 2/21/14 5:40 PM

 310 Part II: Viral Infections and Related Disorders
directly attributable to GBS include cardiac arrest related to
dysautonomia and respiratory failure (9,14). Mortality sec-
ondary to assisted ventilation and paralysis occurs following
accidental disconnection from ventilation, pneumonia, adult
respiratory distress syndrome, septicemia, and hemorrhagic or
thrombotic events.
Approximately 60% recover fully. Minor residua such as
footdrop or mild distal numbness remain in approximately
20%, and 5% to 10% will retain permanent disability
(6,9,14,25,33). GBS may recur years after the initial event in
5% of individuals (9,23). The lack of uniform recovery has
prompted a search for clinical, laboratory, and electrophysi-
ologic features predictive of prognosis.
Most authorities agree that older age, rapid progression
to quadriparesis, and need for ventilatory assistance predict
severe disease and prolonged or incomplete recovery (6).
Underlying malignancy may also be predictive of poor out-
come. Treatment with PE has a beneficial effect on duration of
disease and speed of recovery but may not influence the final
degree of recovery in GBS (210,211). However, the French
Cooperative Group demonstrated a significant increase in the
percentage of fully recovered GBS patients in the PE versus
conventional therapy groups (71% vs. 52%). PE did not influ-
ence the incidence of severe residual disability following GBS
(234). The Dutch Guillain-Barr study found advanced age to
be the only clinical predictor of slowed or incomplete recovery
(216). However, older age has not been associated with poor
outcome in several series (13,27,28,48,235). Beghi et al. (9)
found an association between age and GBS severity only in
persons older than 70 years of age, and Winer et al. (169)
noted poor outcome more often in those older than 40 years
of age.
In one series, 50% of GBS patients with rapid progression
to quadriparesis in 2 to 5 days were nonambulatory 2 years
after onset (29). Loss of ambulation in 7 days was predictive
of poor outcome in the large multicentered trial comparing
PE and conventional therapy of GBS (235). However, other
series have not related rapid progression to outcome (9).
A prolonged plateau period before onset of recovery (23 days)
has also correlated with incomplete recovery (48).
The need for ventilatory support may be a negative prog-
nostic feature in GBS (6,48,169,235), but Hankey (13) found
no difference in outcome among individuals requiring ventila-
tion shorter or longer than 28 days.
Laboratory features predictive of severe disease and incom-
plete recovery include serologic evidence of C. jejuni infec-
tion (26,46,59,61) and the early presence of IgG or IgA AGA
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SUMMARY AND FUTURE
DIRECTIONS
GBS is a demyelinating disorder of PN occurring in all ethnic
groups and geographic locations. Men and older individuals
appear to be more frequently affected. A variety of preceding
events may incite GBS, but minor infections are implicated
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 CHAPTER 21 ACUTE VIRAL MYELITIS
J. DAVID BECKHAM AND KENNETH L. TYLER
Viral infections of the spinal cord occur as part of more exten-
sive infection of the central nervous system (CNS) or periph-
eral nervous system. When myelitis occurs in association
with encephalitis or meningitis, the resulting syndromes are
referred to as encephalomyelitis or meningoencephalomyelitis.
Myelitis associated with involvement of spinal nerve roots or
peripheral nerves is referred to as myeloradiculitis or myelo-
radiculoneuritis. This chapter focuses on acute viral infections
in which spinal cord involvement is the dominant feature.
Acute myelitis associated with rabies virus and HIV infection
is discussed elsewhere (see Chapters 17 and 19), as are cases of
chronic viral myelitis due to infection with retroviruses includ-
ing HIV and human T lymphotropic viruses (HTLVs). In addi-
tion to directly infecting and injuring the spinal cord, viruses
can trigger postinfectious immune-mediated tissue injury.
Spinal cord involvement is a common but rarely dominant
feature of acute disseminated encephalomyelitis (ADEM) (see
Chapter 22). Transverse myelitis (TVM) is an acute syndrome
defined by the nature and extent of the anatomic injury to the
spinal cord, often associated with antecedent viral infections.
Specific causes of TVM are discussed under the individual vi-
ruses involved, and the idiopathic syndrome is briefly reviewed
at the end of this chapter.
The term myelitis means inflammation of the spinal cord
and refers to disease of the spinal cord caused by a direct in-
fectious process, a postinfectious process, or another indirect
mechanism of injury. The clinical features are determined to
a large degree by the location and extent of the process both
in the craniocaudal and the transverse axes of the spinal cord
rather than by the inciting agent.
The clinical features of myelitis provide important clues
to the anatomic location of the lesion but do not enable my-
elitis to be separated from other causes of intramedullary
spinal cord injury. The clinical features of myelitis caused
by different viruses overlap substantially, and identification
of a specific viral etiology typically depends on the results
of laboratory tests. The characteristic features of myelitis
include variable combinations of weakness; sensory loss;
and bowel, bladder, and sexual dysfunction, typically evolv-
ing over days. Apoplectic or hyperacute (hours) evolution of
symptoms is occasionally seen in viral myelitis but is more
typical of vascular spinal cord disease (1) (e.g., infarction
resulting from atherosclerosis, arteritis, emboli or hemor-
rhage, or even venous thrombosis [Foix-Alajouanine syn-
drome]). Viral causes of chronic myelitis or myelopathy in
which symptoms evolving over weeks or months are largely
limited to HIV and HTLV.
Weakness in viral myelitis may be either of the upper motor
neuron type with associated spasticity, hyperreflexia, and ex-
tensor-plantar reflexes or of the lower motor neuron type with
flaccid weakness and decreased or absent deep tendon reflexes.
Lower motor neuron involvement in the absence of significant
sensory signs or symptoms is often referred to as acute flac-
cid paralysis or poliomyelitis-like illness, although the latter
term is best reserved for cases in which pathology is limited
to the anterior horns of the spinal cord. Involvement of motor
neurons in the anterior horns or involvement of the anterior
roots can result in prominent clinical and electrophysiologic
Scheld_Ch21.indd 315
evidence of denervation, including the presence of fascicula-
tions and fibrillations. Sensory loss in myelitis can be radicular,
dermatomal, or both. Depending on the transverse localiza-
tion of the lesion(s), either loss of position and vibration sense
or loss of pain and temperature may occur. Finding a sensory
level below which sensory functions are lost is a classic hall-
mark of spinal cord disease. Either relative or absolute spar-
ing of sensation in sacral dermatomes (sacral sparing) may
occur when an intramedullary process such as viral myelitis
leaves the most peripheral fibers in the spinothalamic tract
relatively unharmed.
Patients with acute onset of signs and symptoms sugges-
tive of spinal cord dysfunction are a medical emergency. Initial
clinical and laboratory studies should be directed at trying to
identify whether a compressive lesion is present and whether it
is intramedullary or extramedullary in location. An algorithm
for the immediate diagnostic approach to patients with acute
myelopathy is shown in Figure 21.1(2). Table 21.1 summarizes
key diagnostic tests that may be useful in evaluating a patient
with suspected acute viral myelitis. In the following sections,
viral etiologies of acute myelitis are discussed individually.
HERPESVIRUSES
Herpes Simplex Virus
Both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2)
can cause myelitis. HSV-2 most commonly causes myelitis
in adults and HSV-1 most commonly in children (1,3). The
clinical presentation ranges from mild forms of disease with
full recovery to severe necrotizing myelitis with permanent
sequelae. Most cases are monophasic, although about 20%
of patients experience recurrent episodes of myelitis, a feature
common to infection with several herpesviruses (47). In pa-
tients with recurrent disease, the interval between recurrences
may vary between 1 week and several months, with three or
more discrete recurrences being noted (5,7). Up to two thirds
of patients with HSV myelitis have an ascending pattern of
spinal cord involvement, with the remainder having TVM (5).
Most cases of monophasic HSV myelitis are due to
HSV-2 (5). Patients with HSV-2 myelitis often have a history
of genital herpes. However, in one series, only two of seven
patients with HSV-2 myelitis had known genital herpes, and
lesions, when present, often preceded spinal involvement
(5). Clinical features of HSV myelitis include paresis or pa-
ralysis, more commonly involving the legs than the arms.
Patients may have either reduced and/or absent tendon
reflexes or hyperreflexia with extensor-plantar responses.
Decreased sensation to pain, temperature, and touch is com-
mon and tends to be more severe in sacral dermatomes.
Patients can have decreased anal tone and urinary incon-
tinence with overflow. HSV-2 can also cause a lumbosacral
radiculomyelitis characterized by urinary retention associ-
ated with constipation, dull pain in the anogenital region,
paresthesias, loss of sensation, or flaccid paresis of the leg
muscles (8).
315
2/21/14 5:40 PM
 316 Part II: Viral Infections and Related Disorders

Presentation: Neurologic dysfunction consistent with a spinal cord injury at a specific level

History and physical examination

Confirm acute myelopathy
Elicit time course and extent of deficits
Determine signs, symptoms or prior history suggesting infection, systemic inflammatory disease, vascular/ischemia,
neoplasia, multiple sclerosis, radiation exposure, neuromyelitis optica, or trauma
Determine if recent history of vaccination or systemic illness

First priority: Rule out a compressive etiology

Gadolinium enhanced MRI of the spinal cord within 4 hours

Sufficient to cause Yes Structural abnormality (spondylolisthesis) or

compressive myelopathy? spinal mass

Yes No No

Urgent surgical evaluation Second priority: Define presence/absence of spinal cord inflammation
Consider intravenous
methylprednisolone

Lumbar Puncture
Consider non-inflammatory causes of myelopathy
Ischemia-arterial, venous, watershed or
arteriovenous malformation
Radiation No CSF pleocytosis or gadolinium
Epidural lipomatosis enhancement or elevated igG index
Fibrocartilaginous embolism
Consider early inflammatory myelopathy, false Yes
negative CSF (repeat LP in 27 days)
Third priority: Define extent
of demyelination

Check Brain MRI with gadolinium

and visual evoked potential

Brain/Brain Yes
Site of demyelination? Demyelination?
and optic tract

No
Optic Nerve/Tract

Possible diagnosis Acute Transverse Myelitis (ATM):

Multiple Sclerosis Idiopathic or Disease-Associated
ADEM Possible Neuromyelitis Optica (use standard criteria to distinguish
Disease-Associated ATM (Devics Disease) and initiate appropriate treatment)

FIGURE 21.1 An algorithm illustrating the immediate diagnostic approach to a patient presenting with
a suspected acute myelopathy or myelitis. LP, lumbar puncture. (From Transverse Myelitis Consortium
Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology.
2002;59:499505, with permission.)

Scheld_Ch21.indd 316 2/21/14 5:40 PM

 Chapter 21: Acute Viral Myelitis 317

TA B L E 2 1 . 1
POTENTIALLY USEFUL DIAGNOSTIC STUDIES FOR EVALUATING PATIENTS WITH SUSPECTED ACUTE MYELITIS

MRI of spinal cord and brain Serum

CSF examination Complete blood cell and differential, platelet count, hemoglobin
Cell count and differential and hematocrit
Cytology ESR
Glucose C-reactive protein
Protein Serum calcium, albumin
IgG, IgG index BUN, creatine
Electrophoresis and oligoclonal bands Aspartate aminotransferase, alanine aminotransferase, alkaline
Myelin basic protein phosphatase
CSF stains Creatine kinase, aldolase
Gram stain Amylase, lipase
Acid-fast bacilli stain (for mycobacteria) Vitamin B12 level
India ink stain Thyroid function tests
CSF serology Serum protein electrophoresis
VDRL Angiotensin-converting enzyme
Cryptococcal antigen ANA, anti-ds-DNA, anti-SS-A (Ro), anti-SS-B (La), anti-Sm
CSF cultures (Smith), anti-RNP
Bacterial Total complement, C3, C4 complement levels
Fungal Monospot and heterophile tests
Mycobacterial Cold agglutinins (for mycoplasma)
Viral HIV serology
CSF PCR: Mycoplasma IgG, IgM antibodies
HSV-1, HSV-2 Hepatitis A IgG, IgM; hepatitis B serology, hepatitis C serology
EBV RPR, FTA-ABS
VZV Lyme serology (IgG, IgM)
CMV Toxoplasma serology
HHV-6 Miscellaneous test
Enterovirus Chest x-ray
HIV Urinalysis
(WNV) Stool cultures for enteroviruses
(Rabies) Throat cultures for enteroviruses, mumps (selected cases)
(Mycoplasma) Urine cultures for CMV, mumps (selected cases)
(Mycobacterium tuberculosis) PPD
CSF and serum antibody studies EMG/NCV in patients with suspected muscle, peripheral nerve
WNV IgG, IgM or root involvement
HSV IgG, IgM Urodynamic studies in patients with bladder signs or symptoms
CMV IgG, IgM Visual and somatosensory evoked responses
VZV IgG, IgM Special tests for selected cases
EBV VCA IgG, IgM Spinal and/aortic arteriography in cases of suspected infarction
EBV EA IgG or embolus
EBV EBNA IgG Neck skin biopsy with direct fluorescent antibody analysis for
HHV-6 IgG, IgM rabies antigen
HTLV-1 IgG
Measles, mumps, rubella serology (selected cases)
Rabies IgG, IgM (selected cases)
Mycoplasma IgG, IgM complement-fixing antibodies
Borrelia burgdorferi (Lyme)

ANA, antinuclear antibody; ESR, erythrocyte sedimentation rate; FTA-ABS, fluorescent treponemal antibody absorption; PPD, purified protein
derivative; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.

The most severe form of HSV myelitis is an acute necro-
tizing myelopathy, which occurs predominantly in patients
with underlying diseases including HIV infection (9), malig-
nancy (10), and diabetes (11,12), although rare cases occur
in the absence of associated disease (13). All cases to date
have been associated with HSV-2. At autopsy, these patients
often show areas of necrosis in the gray and white matter
of the spinal cord associated with perivascular lymphocytic
cuffing. Cowdry type A inclusions are found in neurons,
viral antigen can be demonstrated by immunocytochemis-
try, and herpesvirus-like particles have been seen by electron
microscopy (913). Some cases have a prominent necrotiz-
ing arteritis associated with myelomalacia with Cowdry A
inclusion-bearing cells seen in the wall of the anterior spinal
artery (9).
In HSV myelitis, the cerebrospinal fluid (CSF) typi-
cally shows a lymphocytic pleocytosis and normal glucose
concentration. Patients with recurrent attacks may have a
progressive reduction in the degree of pleocytosis with suc-
ceeding attacks (7). Typical cell counts range between 10 and

Scheld_Ch21.indd 317 2/21/14 5:40 PM

 318 Part II: Viral Infections and Related Disorders
200 cells/mm3, although rare cases with normal cell counts
have been reported (5,14). The CSF profile in patients with
acute necrotizing myelopathy may show striking pleocyto-
sis with up to 5,750 cells and a predominance of polymor-
phonuclear (PMN) leukocytes rather than lymphocytes (12).
Surprisingly, some reported patients have had no or minimal
pleocytosis (9,11). The CSF protein concentration is almost in-
variably elevated (range, 50 to 430 mg/dL). Oligoclonal bands
were found in one of nine patients in one series (5) and have
been noted in other case reports (7,15).
HSV is only rarely cultured from CSF in patients with
myelitis (15), and diagnosis depends on demonstration of HSV
DNA in CSF by polymerase chain reaction (PCR) (46,1517).
In one series of nine patients, all had PCR amplifiable HSV
DNA in CSF, with six cases due to HSV-2, two cases due to
HSV-1, and one case indeterminate. In this series, HSV-2 DNA
was found in six of six cases with ascending myelitis, whereas
HSV-1 DNA was found in two of the three patients with nona-
scending TVM (5). In an HSV CSF PCR-negative patient, a
presumptive diagnosis can be made by demonstrating intra-
thecal synthesis of HSV-specific antibodies (7). Antibody stud-
ies may be particularly useful in cases in which CSF is only
available late in infection (e.g., 14 days), when HSV DNA
is likely to have disappeared. Evidence of intrathecal synthesis
of HSV-specific antibodies can be based on (a) the presence in
CSF of immunoglobulin M (IgM) anti-HSV antibodies (these
antibodies cross the bloodbrain barrier poorly and their de-
tection in CSF is generally indicative of intrathecal synthesis);
(b) the detection of HSV-specific oligoclonal bands present
in CSF but not in serum; (c) the comparison of HSV-specific
immunoglobulin G (IgG) levels in CSF and serum with correc-
tion for bloodbrain barrier leak using either the CSF/serum
albumin ratio or the ratio of antibody titers in CSF to that
in serum for an irrelevant virus (5,14,16,18). Basic labora-
tory studies usually add little to the diagnosis, although some
patients have elevations in erythrocyte sedimentation rate and
C-reactive protein (6,18).
Magnetic resonance imaging (MRI) is exceedingly impor-
tant for its role in both excluding other potential diagnoses
and in establishing the presence of an intramedullary process.
The typical appearance of HSV myelitis is of an intramedullary
fusiform or spindle-shaped area of an increased T2-weighted
signal (5,7,14,16). The spinal cord is often enlarged or swollen
in the area of the lesion. Areas of an increased T2-weighted
signal may also have T1-weighted signal hypointensity. In rare
cases, areas are both T1 and T2 hyperintense, a finding sug-
gestive of hemorrhagic necrosis (5). Contrast (gadolinium)
enhancement may be seen in the area of the lesion and the
adjacent meninges and nerve roots (6,7,16,17). Lesions are
most commonly in the upper thoracic and cervical cord (5,6)
but can also involve the lower cord including the conus medul-
laris and cauda equina (7,1517).
No controlled clinical trials of antiviral therapy for HSV
myelitis are available. Based on anecdotal reports, patients
should be treated with intravenous acyclovir for at least
14 days (10 mg/kg three times per day). This can be followed
by oral antiviral drugs (e.g., valacyclovir at 1 g three times per
day) until symptoms resolve. The utility of adding steroids is
unproven. When given, steroids should be used only in com-
bination with antiviral therapy. A typical regimen involves
intravenous methylprednisolone (500 to 1,000 mg per day for
3 to 5 days) followed by oral prednisone (100 mg per day)
with doses tapered over 2 weeks (5,7,17).
The prognosis of HSV myelitis is extremely variable. In
one series of nine patients, one third (n 3) made a complete
recovery, and the remaining two thirds (n 6) had residual
sequelae including paraplegia and tetraplegia (5).
Scheld_Ch21.indd 318
Varicella-Zoster Virus
Myelitis is an unusual complication of varicella-zoster virus
(VZV) infection, with most cases occurring in immuno-
compromised individuals (1921). Myelitis can also occur
as a complication of primary varicella infection or chicken-
pox (20,22,23). In immunocompromised patients, common
underlying diseases include HIV infection (19,20,21,24,25),
Hodgkin and non-Hodgkin lymphoma (19), and immunosup-
pressive therapy (26,27). In a recent review of 31 cases of VZV
myelitis, 55% of patients with VZV myelitis were immuno-
compromised, and the majority of the remaining patients had
an underlying comorbidity such as malignancy or autoimmune
disease (28). Cases of VZV myelitis in immunocompetent pa-
tients are reported but uncommon (29). Many patients have
antecedent zoster, although several cases without rash (myeli-
tis sine herpete) have been reported (3032). When zoster is
present, it can involve virtually any dermatome, but myelitis
is often associated with disseminated zoster in immunocom-
promised patients (19). Cord dysfunction typically follows the
onset of zoster with a median of 12 days (range, 5 to 21 days),
but symptoms of myelitis may follow rash by up to 3 months
or myelitis symptoms may precede the appearance of rash
(19,24). Cases of TVM following zoster have also occurred
in patients who have previously received zoster vaccine (33).
Patients with zoster myelitis present with subacute onset
of asymmetric leg weakness which progresses to bilateral leg
weakness with paraparesis in up to 85% of patients (19).
Sensory loss is common (75%), with involvement of pain
and temperature more common than position and vibration
sense. A Brown-Squard syndrome may occur, with poste-
rior column signs (loss of position and vibration sense) ipsi-
lateral to the rash and spinothalamic tract signs (loss of pain
and temperature sense) contralateral (19). Approximately one
third of patients will have a level to all sensory modalities,
urinary incontinence occurs in about 50%, and bowel incon-
tinence can also occur. In a few cases, VZV myelitis may show
a relapsing and remitting pattern (20,25,34), a feature also
seen in some cases of HSV-2 myelitis (see earlier discussion).
Atypical presentations of VZV myelitis including cases not
associated with rash (zoster sine herpete), skin lesions devel-
oping after myelopathy, or lack of correspondence of zoster
lesions to spinal cord injury level occur more frequently in
immunocompromised patients (28).
In VZV myelitis, CSF shows a mononuclear pleocytosis
in about 75% of patients with an increase in PMN predom-
inance in patients with rapid onset and severe disease (19).
Recurrent episodes of CSF PMN pleocytosis with recurrent
episodes of VZV myelitis have been reported (30). CSF protein
concentration is elevated in 70%, but glucose concentration is
almost always normal. It is important to recognize that at least
50% of immunocompetent patients with a zoster rash in the
absence of myelitis have a CSF lymphocytic pleocytosis with
cell counts from 5 to 1,440 cells/mm3 and exceeding 100 cells/
mm3 in 30% of those with pleocytosis (35).
Approximately 25% of patients with a zoster rash will also
have evidence of CSF anti-VZV IgG and detectable VZV DNA
by PCR, but CSF anti-VZV IgM is usually not detectable and
the CSF VZV IgG index is usually normal, suggesting that
intrathecal synthesis of VZV-specific antibody does not occur
in uncomplicated herpes zoster reactivation (35). By contrast,
patients with zoster myelitis often have a positive CSF VZV
PCR and intrathecal VZV-specific IgG synthesis, even VZV
specific CSF oligoclonal bands (36).
Patients with VZV myelitis frequently have abnormalities
on spinal MRI (Fig. 21.2). These can include diffuse swelling
2/21/14 5:40 PM

FIGURE 21.2 T1-weighted sagittal spinal MRI scans following admin-
istration of gadolinium from a 27-year-old woman with varicella-
zoster myelitis. Enhancing lesions are present at the cervicomedullary
junction (open arrow) and in the cervical region of the spinal cord
(closed arrows). (From Gilden DH, Beinlich BR, Rubinstien EM, et al.
Varicella zoster myelitis: an expanding spectrum. Neurology. 1994;44:
18181823, with permission.)
of the cord and areas of high T2-weighted signal with or with-
out associated T1 hypointensity and contrast enhancement
(20,22,27,32,3739). MRI lesions in the brainstem and cervi-
cal cord may also occur in immunocompetent patients with
zoster myelitis (35).
The diagnosis of VZV myelitis is generally suspected
when signs of myelitis develop following a typical zos-
ter eruption in an immunocompromised patient. Definitive
diagnosis depends on isolation of virus from CSF (24,31),
demonstration of intrathecal synthesis of VZV-specific anti-
body (20,36,37,40), or PCR amplification of VZV DNA from
CSF (20,27,37,4042). Comparative studies of the sensitiv-
ity and specificity of these tests are lacking, although clinical
experience suggests that PCR is likely to be the most sensitive,
and culture the least. Antibody and PCR test results should
be viewed as complementary rather than mutually exclusive;
as in other viral infections, antibodies typically develop later
than detectable nucleic acid. The duration for which VZV
DNA remains detectable in CSF following varicella myelitis
is unknown. In patients with relapsing-remitting myelitis, CSF
VZV DNA may persist, as two patients had positive CSF PCR
results 8 and 11 months after onset of disease (20).
No controlled clinical trials of treatment for VZV
myelitis are available. Treatment typically involves intrave-
nous acyclovir given alone or in combination with steroids
(19,31,37,39,4244), although the paucity of cases and the
variability in treatment regimens make efficacy difficult to
access (20). In several patients who received intravenous acy-
clovir after myelopathy was established, treatment seemed to
be without effect (24,39,44). By contrast, there are also reports
of complete recovery in AIDS patients with VZV myelitis
following acyclovir therapy (10 mg/kg every 8 hours) for 21 to
35 days (42) and improvement in patients treated with either
Scheld_Ch21.indd 319
Chapter 21: Acute Viral Myelitis 319
acyclovir alone (20,37) or a combination of acyclovir and
high-dose steroids (31). One patient apparently responded to
oral famciclovir (500 mg every 8 hours), who had not previ-
ously responded to steroids, acyclovir, or foscarnet (37).
Pathologic studies of VZV myelitis are limited (19,25,32).
In a comprehensive review of nine fatal cases, there was
extensive hemorrhagic necrosis with necrotizing vasculitis
and thrombosis in the dorsal root ganglia associated with
Cowdry type A intranuclear inclusions in both ganglion and
satellite cells (19). Almost all cases had abnormalities in the
posterior roots and the posterior horns of the spinal cord, al-
though severity varied. Inclusion bodies were seen in about
50%, and patients could have demyelination and signs of
necrotizing vasculitis and hemorrhagic spinal cord necrosis
(19,32). A similar necrotizing process with demyelination and
Cowdry type A inclusions was described in an AIDS patient
with chronic zoster myelitis (25). In a recent review of five
postmortem cases of VZV myelitis, tissue necrosis and inflam-
matory cell infiltration were the primary findings, but other
pathologic changes were noted as well, including vasculitis,
thrombosis, hemorrhagic transformation, and Cowdry type
A inclusions (28).
Cytomegalovirus
Cytomegalovirus (CMV) involvement of the spinal cord
either can result in a pure TVM or can produce myeloradicu-
litis, or radiculomyelopathy. Most cases of CMV-associated
myeloradiculopathy occur in HIV-infected patients (4548),
and this can be the initial manifestation of AIDS (49). Myelitis
can be a complication of both adult and pediatric HIV infec-
tion (50). Although CMV myelitis is predominantly a disease
of immunocompromised individuals, there have been isolated
reports of both TVM and myeloradiculopathy in immuno-
competent individuals (5157). Isolated cases of dual infec-
tion of the cord with both HSV and CMV have been reported
in patients with AIDS (58). The incidence of CMV-associated
myeloradiculopathy has declined dramatically since the
introduction of highly active antiretroviral therapy (HAART).
Myeloradiculopathy occurs with approximately equal fre-
quency as an isolated manifestation of CMV infection and
in systemic CMV disease (59). Patients present with rapidly
progressive flaccid paralysis of the legs with hyporeflexia or
areflexia (60). Urinary retention occurs in almost all patients
(60). Pain, often involving the perianal region and low back,
is a common initial symptom. Sensory loss usually involves
small-fiber modalities (pain, temperature) more than vibration
or proprioception, although both can occur. The symptoms
are typically progressive, although some patients have a more
indolent course.
One of the unusual features of CMV myeloradiculitis is the
common occurrence of a PMN rather than a lymphocytic CSF
pleocytosis (61,62). This feature is distinctive enough that its
presence in an HIV-infected patient with myeloradiculopa-
thy should always suggest the possibility of CMV infection
(63). Cell counts exceeding 1,000/mm3 can occur (46,6466),
although median values of 150 to 650 cells/mm3 are more typi-
cal (60,61). In addition to pleocytosis, the CSF typically shows
an elevated protein concentration. Severe hypoglycorrhachia
may occur (46), although a CSF glucose concentration of less
than 50% of the coincident plasma value has been reported in
only about 30% of patients (62).
Imaging studies are useful in demonstrating the location
and extent of lesions. Typical findings on spinal MRI include
areas of increased T2-weighted signal within the spinal cord,
associated with enhancement of the pial lining of the cord,
2/21/14 5:40 PM
 320 Part II: Viral Infections and Related Disorders
conus, cauda equine, and lumbosacral nerve roots on contrast-
enhanced T1-weighted images (66,67). The presence of promi-
nent radicular enhancement in association with myelitis occurs
more often with CMV infection than in other forms of viral
myelitis and may provide a clue to the diagnosis.
Clinical electrophysiologic studies may be helpful in dem-
onstrating the presence of radicular and peripheral nerve
involvement in association with myelitis, especially because this
component of the disease may be clinically obscured when the
myelitis is severe. Both slowed conduction velocities consistent
with demyelination and reduced amplitude of motor and sensory
action potentials consistent with axonal injury occur (59,68).
PCR tests to amplify CMV DNA from CSF are the diagnos-
tic procedure of choice (59,6972). The diagnostic sensitivity
of CSF PCR in CMV myelitis is more than 80%, with a speci-
ficity of more than 90% (59). It is important to emphasize that
CSF PCR is often positive when cultures are negative (69,72).
Quantitative PCR studies of CMV DNA in CSF suggest that
extremely high DNA levels, exceeding 10 million copies of
CMV DNA per milliliter of CSF can be found in patients with
myeloradiculopathy (59,69,73).
CMV may be cultured from CSF in cases of radiculomyeli-
tis (59). The high seroprevalence rate of anti-CMV antibodies
in serum generally renders serologic studies of limited value.
However, the demonstration of specific intrathecal synthesis of
anti-CMV antibodies or the presence of detectable CSF anti-
CMV IgM antibodies can be considered presumptive evidence
for CNS infection.
Controlled clinical trials of antiviral therapy in CMV-
associated neurologic disease are lacking, and most reports
of treatment of CMV-associated neurologic disease involve
isolated cases (59,69,74,75). Response to treatment of my-
eloradiculopathy is variable. Improvement or stabilization of
symptoms has followed treatment with ganciclovir, foscarnet,
or a combination of the two agents (60,62,64,68,7680).
Disease has been associated with ganciclovir-resistant strains
(81,82), and this risk may be enhanced in patients whose dis-
ease developed during ganciclovir treatment for CMV infec-
tion elsewhere. As a general rule, the presence of myelitis is
an extremely poor prognostic indicator, with one review cit-
ing mean survival times of 5.4 1.8 weeks in patients not
receiving ganciclovir and 14.6 9.4 weeks in those receiving
ganciclovir therapy (76).
Successful treatment is usually associated with disappear-
ance of CMV DNA from CSF, whereas viral DNA persists
in nonresponders (74). A typical induction regimen for gan-
ciclovir involves 14 to 21 days of intravenous therapy with
doses of 5 mg/kg every 12 hours. Intravenous foscarnet at
a dose of 90 mg/kg every 12 hours provides an acceptable
alternative. Patients who fail to respond to either foscarnet
or ganciclovir alone may respond to combined therapy with
the two drugs (79). A third agent, cidofovir, has been shown
to be efficacious in treatment of CMV retinitis, but experi-
ence with this agent in CMV-associated neurologic disease
is limited (83). A typical dosing regimen is 5 mg/kg intrave-
nously every week for 2 weeks followed by infusions of 5 mg/
kg every 2 weeks. Fourteen to twenty-one days of ganciclo-
vir or foscarnet therapy is likely to be sufficient for immuno-
competent patients. In most organ transplant recipients, 14
to 21 days of therapy is also likely to be adequate assuming
clinical and virologic response has occurred. Maintenance
therapy is usually not required for CMV myelitis in organ
transplant recipients, although maintained vigilance for recur-
rent disease is essential. In patients with HIV infection, it is
critical that HAART be initiated or optimized concomitantly
with anti-CMV therapy. HIV-infected patients invariably
require maintenance therapy with an orally bioavailable valine
Scheld_Ch21.indd 320
ester of ganciclovir (valganciclovir). Induction and mainte-
nance doses of intravenous and oral ganciclovir, intravenous
foscarnet, and intravenous cidofovir require adjustment in
patients with renal insufficiency. Neutropenia is the major
dose-limiting side effect with ganciclovir, and nephrotoxicity
with foscarnet and cidofovir. Nephrotoxicity can occur with
ganciclovir but is less common. Neurotoxicity can occur with
ganciclovir and foscarnet and in the case of foscarnet is often
related to electrolyte alterations (especially hypocalcemia).
Patients whose HIV infection responds to HAART and who
consistently (6 months) demonstrate nondetectable HIV
viral loads and CD4 cell counts of more than 100 cells/mm3
may be able to discontinue maintenance therapy.
Few detailed pathologic studies of CMV myeloradiculitis
have been performed. There is often a prominent PMN and
mononuclear cell infiltrate involving the sacral spinal cord,
cauda equina, and lumbosacral nerve roots associated with
both demyelination and axonal destruction. CMV antigen is
detectable in the spinal cord and in involved roots and endo-
thelial cell (47,59).
Human Herpesvirus-6 and
Human Herpesvirus-7
Human herpesvirus type 6 (HHV-6) causes exanthema subitum
(roseola infantum). Most individuals are infected in early child-
hood (age 6 to 12 months). Although primary HHV-6 infection
is usually benign, there have been isolated reports of meningo-
encephalitis. Myelitis appears to be extremely rare in patients
with HHV-6 infection. HHV-6 neuroinvasive disease including
encephalitis and/or myelitis are most commonly reported as
a complication in bone marrow transplant recipients (84,85)
and occur with a frequency of about 3% in allogeneic hema-
topoietic stem cell transplantation and up to 16% in patients
receiving cord blood transplantation from an unrelated donor
(86). Median onset of clinical symptoms is 23 days after trans-
plant, and limbic encephalitis is the most common presenting
syndrome with or without associated myelitis. Very rare cases
of HHV-6 myelitis in immunocompetent individuals have been
reported (87). HHV-6 may also be responsible for rare cases of
chronic myelitis presenting as spastic paraparesis (88).
There is one reported case of combined encephalitis and
acute flaccid paralysis in an immunocompetent 19-year-old
man infected with HHV-7 (89). The CSF had a lymphocytic
pleocytosis, an elevated protein concentration, and a nor-
mal glucose. HHV-7 DNA was amplified from CSF by PCR.
Serologic studies were also consistent with acute HHV-7 infec-
tion. Virus was not cultured from either blood or CSF, and
serum PCR studies, in contrast to those in CSF, were negative.
Epstein-Barr Virus
Neurologic complications of Epstein-Barr virus (EBV) infection
have been estimated to occur in 1% to 5% of patients with
severe infectious mononucleosis (90). EBV-associated neuro-
logic disease can also occur in the absence of, or even precede,
symptoms of infectious mononucleosis (91,92). CNS and pe-
ripheral nervous system manifestations of EBV infection include
meningoencephalitis, cerebellitis, Guillain-Barr syndrome, and
TVM. The spinal cord manifestations of EBV infection are
generally considered among the more unusual neurologic com-
plications of EBV infection, although exact data about their
frequency are not available (9195). Many cases of EBV myeli-
tis have occurred in apparently immunocompetent individuals
and often present as a meningoencephalomyeloradiculopathy
2/21/14 5:40 PM

(96,97). Isolated reports of myelitis in immunocompromised
patients, including a case in a bone marrow transplant recipi-
ent, have appeared (98).
TVM typically develops 1 to 2 weeks after the onset of
infectious mononucleosis. It is important to recognize that the
symptoms of mononucleosis may be mild (e.g., pharyngitis
alone). Patients present with flaccid weakness with absent or
decreased reflexes (91,92,98101). Most patients have a sen-
sory level, often associated with some radicular sensory signs
and symptoms. Urinary retention is common (101). Less typi-
cally, the acute onset of paraparesis or tetraparesis is associated
with spasticity, hyperreflexia, and extensor-plantar reflexes
(91). A more indolent course in which weakness is preceded
by back pain and radicular sensory symptoms has also been
reported (91). A lower motor neuron pattern of asymmet-
ric flaccid weakness resembling poliomyelitis can occur with
absence of associated sensory or bladder symptoms (102).
In some patients, even though myelitis is the dominant fea-
ture, associated radicular and encephalitic symptoms coexist,
and the syndrome has been referred to as encephalomyelora-
diculopathy (103), encephalomyelitis (101), meningoencepha-
lomyelitis, meningomyeloradiculitis, and encephaloradiculitis
(96). When signs and symptoms suggesting involvement of
multiple areas of the CNS occur, they can appear concomi-
tantly (98) or sequentially (104). One reported patient had
associated bilateral optic neuritis, suggestive of Devic disease
(neuromyelitis optica [NMO]) (99).
Spinal MRI in EBV myelitis typically shows an area of in-
creased intramedullary T2-weighted and decreased T1-weighted
signal with enhancement of the lesion and adjacent meninges
after administration of gadolinium (91,96,98,99,101). The
affected area of the spinal cord may appear widened or swol-
len (91,98). Nerve root enhancement has also been noted in
patients with myeloradiculitis (96). A patient who presented
with a poliomyelitis-like syndrome had no abnormal intramed-
ullary signal but did show meningeal enhancement around the
cauda equina (102). Myelitis can occur with a normal MRI
scan (93,103).
In patients with a prominent radicular component, results
of clinical electrophysiologic tests may be abnormal with pro-
longed F-wave latencies on electromyography (EMG) and
increased spontaneous activity consistent with denervation
(100102). Laboratory studies can provide clues to the diag-
nosis. Complete blood cell count may show lymphocytosis and
atypical lymphocytes (93). The presence of significant numbers
of atypical lymphocytes in blood or CSF should prompt con-
sideration of EBV infection but can occur with other infections
(101). Older serologic tests, including the heterophil antibody
test (the Paul-Bunnell test), have been largely replaced by com-
mercial spot and slides tests (e.g., Monospot test) to detect het-
erophil antigens. It is important to recognize that heterophil
tests are often negative in patients with EBV-associated TVM
(91,92). Serologic tests measuring antibodies against distinct
virus-specific antigens, including the viral capsid antigens
(VCAs), early antigens (EAs), and Epstein-Barr nuclear an-
tigen (EBNA), provide more sensitive and specific confirma-
tion of diagnosis. Serodiagnosis of EBV infection is made by
demonstrating serum IgM VCA, which is generally present
acutely then declines over 1 to 3 months (99). Detection of
IgM antibodies to VCA is both sensitive and specific for di-
agnosis of recent EBV infection and can be found in about
90% of patients. The presence of IgG antibodies to VCA, IgG
antibodies to EA, and no antibodies to EBNA in convalescent
sera provides evidence of recent EBV infection (91,92,99).
A fourfold increase in titer of anti-VCA IgG antibody between
acute and convalescent sera is also presumptive evidence of
acute infection. However, IgG VCA antibody titers are often
Scheld_Ch21.indd 321
Chapter 21: Acute Viral Myelitis 321
elevated in the acute sera, and seroconversion is demonstrable
only in a few patients (about 10% to 20%). IgG VCA and
EBNA antibodies can persist for life, and their presence, in
the absence of other serologic signs of acute infection, reflect
past rather than active infection. In rare cases, seroconversion
may be delayed for up to 2 months after onset of illness (92),
further complicating diagnosis.
In patients with EBV myelitis, the CSF typically shows a
mild lymphocytic pleocytosis (25 to 500 cells), mildly elevated
protein concentration, and normal or mildly depressed glu-
cose concentration (91,93,98,99,101104). EBV can be
cultured from oropharyngeal washings and circulating lym-
phocytes in patients with infectious mononucleosis. However,
virus is only rarely isolated from CSF in patients with neuro-
logic disease (105), although EBV DNA has been amplified
from brain tissue by PCR (106,107). Virus may be shed by
asymptomatic patients or as a result of reactivation induced
during other diseases which limits the specificity of culture.
In patients with serologic evidence of systemic EBV infec-
tion, CSF studies can assist in definitively establishing the
presence of associated CNS infection. Demonstration of EBV
IgM VCA antibodies in CSF provides evidence of intrathecal
antibody synthesis and presumptive evidence of associated
CNS infection (99). Sequential studies of CSF EBV-specific
IgM have only rarely been performed. In one reported case,
CSF IgM was detected at 2 weeks after onset, was equivo-
cal at 4 weeks, and absent at 8 weeks (99). Intrathecal syn-
thesis of IgG antibodies can be demonstrated by measuring
concomitant CSF and serum IgG VCA levels and correcting
for CSF/serum albumin ratio (96,104). Amplification of EBV
DNA by PCR from CSF provides strong evidence of CNS
infection (93,96,98,101,102,104), although cases with nega-
tive CSF PCR and positive serology results have been reported
(91,103). The duration for which PCR-amplifiable EBV DNA
persists in CSF is unknown, although one immunocompro-
mised patient treated with ganciclovir and hyperimmunoglob-
ulin was PCR positive after 1 month but became PCR negative
at 2 months after onset of symptoms (98). A second patient
was found to have positive CSF PCRs at 1 and 4 weeks postin-
fection, with a negative result at 7 weeks postinfection (108).
Semiquantitative PCR can be used to evaluate EBV genome
copy numbers in different forms of EBV infection, including
CNS disease, and to a more limited degree to evaluate the
effects of therapy (109,110) Genome copy number has gener-
ally been in the range of 500 to 2,000 copies/mL, although
one immunocompromised patient had 100,000 copies/
mL (98,110). PCR and antibody tests should be considered
complementary, with nucleic acid frequently detected acutely
and then clearing over approximately the first 2 weeks, and
antibody production appearing after the first week or two of
infection.
Acyclovir inhibits EBV replication and viral shedding
but does not significantly reduce clinical symptomatol-
ogy associated with uncomplicated infectious mononucle-
osis (90). Studies of the effects of antiviral therapy in EBV
myelitis are anecdotal, and no controlled clinical trials have
been performed. Intravenous acyclovir (10 mg/kg three times
a day for 14 to 21 days) has been associated with clinical
improvement in some patients (93,101). Whereas ganciclovir
is more active in cell culture against EBV than acyclovir, only
anecdotal experience exists. A 16-year-old boy who developed
TVM following a bone marrow transplantation was success-
fully treated with a combination of ganciclovir (10 mg/kg per
day intravenously for 4 weeks followed by 60 mg/kg per day
orally for 4 weeks) and CMV hyperimmunoglobulin (400 mg/
kg three times a week for 1 month then twice weekly for an
additional month) (98). The role of steroids as adjunctive
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 322 Part II: Viral Infections and Related Disorders
treatment in EBV infections remains controversial, although
their use has been advocated for severe complications of
infectious mononucleosis. In one multicenter double-blind
controlled trial, the use of steroids in uncomplicated infectious
mononucleosis was without clinical benefit and increased
the risk of cardiac and neurologic complications (90,111).
However, steroids, in combination with acyclovir, have been
used in individual cases of EBV myelitis, and some patients
have experienced rapid improvement after their institution
(91). Doses have been extremely variable, with one typical
regimen using intravenous methylprednisolone (1,000 mg
every 12 hours for 7 days) followed by prednisone (60 mg per
day) for an additional week followed by a tapering dose over
several months (91). Although studies are limited to isolated
cases, some reports indicate that the number of genomic copies
of EBV in CSF declines with antiviral therapy (109).
Pathologic studies of fatal cases of EBV-associated myelitis
are extremely limited. In some patients, both anterior horn cell
degeneration and inflammatory infiltration of nerve roots have
been described (100). Clear prognostic information is diffi-
cult to obtain because of the paucity of reported cases. Many
patients make a significant recovery, although mild residual
weakness and sensory loss often persist (91). Other patients
have improved to a more modest degree, with substantial
residual weakness and hyperreflexia (92,93,96).
Herpesvirus simiae (Monkey B Virus,
Cercopithecine Herpesvirus-1)
B virus is considered at length in Chapter 14 and is not further
discussed here.
PICORNAVIRUSES (POLIO AND
OTHER ENTEROVIRUSES)
Poliovirus infection was previously the worlds most com-
mon cause of acute flaccid paralysis. In 1988, an estimated
350,000 cases of polio occurred worldwide in 125 countries.
In 1988, the Global Polio Eradication Initiative was launched
by the World Health Organization (WHO). Thanks to an
aggressive campaign of immunization, the number of cases of
wild type (nonvaccine-associated) polio has declined by more
than 99.8% worldwide. In 2013 (through 10 December),
359 cases of poliovirus have been reported and all were due
to serotype 1 viruses. The cases have occurred predominantly
in countries with ongoing civil strife and weakened gov-
ernmental and public health institutions including Somalia
(183), Pakistan (74), Nigeria (50), Syria (17), Kenya (14),
Afghanistan (11), Ethiopia (6), and Cameroon (4). In 1994,
the WHO was able to certify the region of the Americas as
polio free, followed by the western Pacific region in 2000,
and the European region in 2002 (www.polioeradication.org).
The last known case of indigenous wild type polio infection
in the Western Hemisphere occurred in Peru in 1991 (112).
Given the reemergence of poliovirus in countries of previous
eradication, the American Academy of Pediatrics recommends
continued vigilance in the United States to maintain vaccina-
tion with the inactivated poliovirus vaccine (113). A few cases
of poliomyelitis still occur in several countries in association
with the use of the live attenuated (Sabin) polio vaccine
(114). In 2002, 13 such cases, all from countries in Africa,
were reported to the WHO. Vaccine-associated poliomyelitis
can occur at a rate of 1 in 2.7 million vaccines in either vacci-
nated individuals, nonimmunized, or incompletely immunized
Scheld_Ch21.indd 322
individuals exposed to circulating vaccine strain viruses and
often is associated with an undiagnosed immune deficiency
(115). A recent case of vaccine-derived poliomyelitis infection
was recently described in a 44-year-old woman with common
variable immune deficiency that was infected when her child
was immunized 11.9 years earlier with type 2 vaccine-derived
poliovirus (116). In some cases, low vaccine coverage is associ-
ated with mosaic recombinant poliovirus lineages that include
genetically distinct vaccine-derived strains of poliovirus (117).
An outbreak of vaccine-associated poliomyelitis occurred in
children in the Dominican Republic and Haiti in 2000/2001
and involved 21 confirmed cases, with two fatalities (118).
All the affected individuals were unvaccinated or incompletely
vaccinated, with disease being caused by a derivative of the
poliovirus type 1 oral vaccine strain.
Ninety percent to ninety-five percent of patients infected
during an epidemic with poliovirus remain asymptomatic.
A small percentage (4% to 8%) develop a minor illness last-
ing 1 to 4 days and characterized by pharyngitis, gastrointesti-
nal symptoms, fever, malaise, and headache. This corresponds
to the period during which virus is replicating in the nasophar-
ynx and gastrointestinal tract (119). Only approximately 1%
to 2% of individuals develop neurologic signs and symptoms
(major illness). Major illness typically begins with fever,
malaise, and headache, followed within 24 hours by signs of
meningeal irritation indistinguishable from other forms of
viral meningitis. Within 2 to 5 days of onset of meningitis,
weakness appears, often associated with muscle pain and ten-
derness. Infection may predominantly involve the spinal cord
(spinal poliomyelitis), brainstem (bulbar poliomyelitis), or
cerebrum (polioencephalitis). Spinal poliomyelitis accounts for
66% to 75% of neurologic cases (120). Weakness manifests
as a flaccid areflexic paralysis, which is typically more severe
proximally than distally, affects the legs more severely than the
arms, is asymmetric, and progresses for 3 to 5 days after onset.
Atrophy appears rapidly, usually within 5 to 7 days, and can
progress over several weeks.
CSF studies show a lymphocytic pleocytosis, normal or
mildly elevated protein concentration, and normal glucose
concentration (120). More than 90% of patients have 20 to
300 cells/mm3. During the first 72 hours, PMN cells may pre-
dominate, but they are subsequently replaced by lymphocytes.
The results of electrophysiologic tests are consistent with an
anterior horn cell process and include reduced amplitudes of
compound muscle action potentials (CMAPs) with normal
sensory amplitudes and no significant alteration in conduction
velocity beyond that explained by the degree of axonal loss.
MRI studies in classic polio have only rarely been reported but
show increased T2-weighted signal in the substantia nigra and
spinal cord anterior horns and cord swelling (121,122).
The pathologic substrate of spinal poliomyelitis is injury
predominantly affecting the motor neurons of the anterior
horns (120). Injury is typically more severe in the lumbar and
cervical enlargements and can extend transversely to involve
the posterior and intermediate horns, intermediolateral cell
column, and even dorsal root ganglia.
Diagnosis is similar to that of other enteroviruses (EVs) and
can be made based on virus isolation, amplification of viral
RNA, or serologic studies. Stool cultures have the highest yield
for isolation of virus and are often positive for weeks to months
after onset of illness. Amplification of viral RNA from CSF by
reverse transcriptase PCR (RT-PCR), using the generally avail-
able EV probes, confirms the presence of an EV, but not
specifically polio. Poliovirus-specific primers for RT-PCR are
available but are not generally used by hospital diagnostic lab-
oratories. A fourfold increase in poliovirus-specific neutralizing
or complement-fixing antibody in serum confirms diagnosis.
2/21/14 5:40 PM

There is no specific treatment for spinal poliomyelitis.
The experimental antiviral agent pleconaril is unfortunately
not currently available from the manufacturer (ViroPharma)
but was of benefit in treatment of two of three patients with
vaccine-associated paralytic poliomyelitis in an uncontrolled
open-label study (123). Pleconaril acts by integrating into a
hydrophobic pocket on the capsid of picornaviruses such as
polio and thereby inhibiting both viral uncoating and receptor
binding (123). Vaccination using either the inactivated Salk or
live attenuated Sabin vaccines or a combination of both pro-
vides effective protective immunity and has been the mainstay
of the worldwide poliovirus eradication campaign.
Mortality from poliomyelitis was about 8% in the last pre-
vaccination polio epidemics in the United States, with deaths
occurring predominantly in patients with bulbar or encepha-
litic forms of the disease. Patients with spinal poliomyelitis
rarely die. Most patients with weakness show some improve-
ment within the first several weeks after onset, with 60% of
eventual recovery being achieved by 3 months and 80% by
6 months (124).
Twenty-nine percent to sixty-five percent of patients sur-
viving paralytic poliomyelitis will subsequently experience
new onset of fatigue, weakness, and increasing muscle atro-
phy decades after recovery from their initial illness, termed the
postpolio syndrome (125,126). The most common symptoms
of postpolio syndrome include generalized fatigue (62% to
89%), weakness in previously affected muscles (54% to 87%),
weakness in previously unaffected muscles (33% to 77%),
myalgia (39% to 80%), and increasing atrophy (28% to 39%)
(125,127). Some patients experience new respiratory insuffi-
ciency, bulbar dysfunction, or sleep apnea (125).
The pathogenesis of postpolio syndrome remains unknown
and some aspects remain controversial (125,127). There is no
known therapy for postpolio syndrome that has been shown
to be of efficacy in randomized controlled trials (128).
Nonpolio Enteroviruses
Rare cases of myelitis due to EVs other than poliovirus have
been reported. Most cases have been attributed to coxsacki-
evirus A7, A9 (129), B1, B3, and B4 (130133); ECHO virus
types 2, 5, 11, 18, 19, and 25 (134139); and EV type 71
(see later discussion). Most patients have been immunocom-
petent, although myelitis has been described in a patient
with X-linked agammaglobulinemia (132). The clinical syn-
drome can be indistinguishable from that caused by poliovi-
rus. Most patients have asymmetric muscle weakness, usually
involving the legs. The deep tendon reflexes are diminished
or absent, and muscle tone is decreased or flaccid. Weakness
can occur with dramatic suddenness, even evolving over sev-
eral hours. Sensory abnormalities are not present in classic
poliomyelitis. In patients with TVM, the typical picture is
of a flaccid paralysis either with decreased or absent or less
commonly with increased deep tendon reflexes combined with
the presence of a sensory level, urinary retention, and in some
cases decreased anal sphincter tone (129,134,135,139).
Because of their rarity, laboratory studies of patients with
nonpolio EV myelitis are limited. CSF usually shows a mild
lymphocytic pleocytosis with normal or mildly elevated pro-
tein and normal glucose concentrations (129,137), although
cases with entirely normal CSF parameters occur (131,132).
Electrophysiologic studies do not distinguish between ante-
rior horn cell disease and a motor axonopathy. In both cases,
there is evidence of denervation and reduction in amplitude of
CMAPs with preserved conduction velocities and normal sen-
sory action potentials (132). MRI can show areas of increased
Scheld_Ch21.indd 323
Chapter 21: Acute Viral Myelitis 323
T2-weighted signal predominantly localized to the gray matter
(121,131), although studies may also be normal (129,132).
In addition to abnormal intramedullary signal, some patients
have cord swelling and gadolinium enhancement of affected
areas on T1-weighted images (139).
Diagnosis depends on amplification of enteroviral RNA
from CSF by RT-PCR (132), isolation of virus from CSF
(129,132), or demonstration of a more than fourfold increase
in specific antibody titer between acute and convalescent sera
(129,131). Isolation of virus from throat or stool provides
supportive evidence (137), but because of the potential for
viral shedding for up to several months, cultures from these
sites cannot be considered definitive evidence of enteroviral
CNS infection.
No controlled trials of therapy are available. As noted ear-
lier, pleconaril, although not currently available, was reported
to be of benefit in two of three treated patients with para-
lytic poliomyelitis associated with the polio vaccine (123). In
one adult patient with acute flaccid paralysis due to echovirus
19, clinical and laboratory evidence of improvement occurred
following combined therapy with pleconaril and intravenous
immune globulin (IVIG) (138).
PCR and in situ PCR (IS-PCR) have been used to search for
evidence of enteroviral infection in patients with amyotrophic
lateral sclerosis (ALS). One study reported that 88% of
patients with ALS (vs. 3% of controls) had enteroviral nucleic
acid detected by IS-PCR in spinal cord specimens. The ampli-
fied RNA had high homology with ECHO virus 7 (140). The
same group reported isolating enteroviral RNA by RT-PCR
in 60% of spinal cord specimens from Japanese patients with
ALS as compared to 14% of controls. Amplification of nucleic
acid from two cases indicated the sequences had high homol-
ogy with ECHO viruses 7, 9, and 30 (141). Unfortunately,
these studies have not been confirmed by other investigators.
One important study using real-time RT-PCR failed to detect
any ECHO sequences in 20 spinal cord and 10 motor cortex
samples from patients with ALS (142). As a result, the evi-
dence linking enteroviral infection to ALS must be considered
unconfirmed and extremely suspect.
Enterovirus-71
EV-71 is endemic worldwide and causes periodic epidemic
outbreaks of both hand, foot, and mouth disease (HFMD) and
neurologic illness (143145). The largest known outbreak to
date involved 100,000 to 300,000 cases in Taiwan in 1998
(146,147). A small outbreak of 45 cases of EV-71 infection,
including 7 cases of poliomyelitis-like paralysis, occurred in
the United States in 1987 (148). Overall, the most common
CNS manifestations of EV-71 include aseptic meningitis,
brainstem encephalitis, and poliomyelitis-like flaccid paraly-
sis, with children younger than 4 years of age at higher risk
for neurologic complications. Most patients will have a 1- to
7-day prodromal illness that precedes the onset of neurologic
disease. Prodromal symptoms include rash, headache, fever,
coryza, and diarrhea.
EV-71 spinal cord involvement can result in either polio-
myelitis or TVM (144,145,149152). In some patients, spinal
cord disease is combined with encephalitis (encephalomyelitis).
The frequency of spinal cord involvement has varied in differ-
ent outbreaks between 1% and 21% (149,153). Sporadic cases
of EV-71 poliomyelitis-like illness can also occur (148,152).
CSF studies usually show a lymphocytic pleocytosis with
normal or slightly elevated protein and normal glucose concen-
trations. MRI can show areas of increased T2-weighted signal
within the cord, cord swelling, and increased signal in the ven-
2/21/14 5:40 PM
 324 Part II: Viral Infections and Related Disorders
tral roots and in the conus medullaris associated with dorsal
brainstem involvement (154). In patients with poliomyelitis-
like illness, increased signal can occur predominantly in the
anterior horns (147,150). Definitive diagnosis depends on iso-
lation of virus from CSF, amplification of viral nucleic acid from
CSF by RT-PCR, or documentation of seroconversion between
acute-phase and convalescent-phase sera. Unfortunately, CSF
viral cultures are only rarely positive. In one recent series, no
positive CSF cultures were found among 27 tested patients
(146). The sensitivity of CSF RT-PCR is also uncertain. Virus
is isolated from throat and/or stool cultures in only approxi-
mately 20% of patients, but EV-71 RNA can be amplified from
these specimens in approximately 50% of patients, suggesting
that RT-PCR is more sensitive than culture (146).
No controlled clinical trials of treatment are available.
IVIG was without effect in one study (103). The antiviral drug
pleconaril, which has activity against many enteroviral strains,
does not have significant inhibitory activity against EV-71 in
vitro but has not been tested clinically in EV-71 myelitis or
CNS infection. It is no longer available in the United States.
Hepatitis A
TVM is a rare complication of hepatitis A infection. All cases
reported to date have been in immunocompetent individu-
als, including both adults and children (57,155,156). Several
patients have had associated brainstem involvement (57,156).
The usual presentation for myelitis is flaccid weakness and a
sensory level (57,155,156). CSF shows a lymphocytic pleocyto-
sis, elevated protein concentration, and normal glucose concen-
tration (155). Liver function test results are abnormal and can
provide an important clue to diagnosis. MRI studies are limited,
but in one report, increased T2-weighted signal was noted in the
cervical cord in association with cord swelling (155). Diagnosis
depends on demonstration of seroconversion (155).
ARBOVIRUSES
West Nile Virus
West Nile virus (WNV) is an arbovirus belonging to the
Flaviviridae family and the Japanese encephalitis (JE) virus
serocomplex, a group that includes JE, St. Louis encephalitis,
and Murray Valley viruses. WNV was identified as the cause of
a cluster of encephalitis cases in New York City in August, 1999
(157). This marked the first emergence of this virus as a cause
of encephalitis in the Western Hemisphere, although major
outbreaks of WNV encephalitis had occurred in Romania
(1996), Russia (1999), and Israel (2000) (158). The geographic
distribution of the virus spread progressively across the United
States and now causes annual epidemic outbreaks of neuro-
invasive viral infection throughout the United States. In 2013
(through 3 December), 2,318 cases of WNV were reported to
the Centers for Disease Control and Prevention (CDC), includ-
ing 1,171 cases of neuroinvasive disease and 105 deaths (http://
www.cdc.gov/westnile/statsMaps/). Serosurveys following the
initial outbreak in New York suggest that asymptomatic cases
outnumber symptomatic ones by about 150:1. Symptomatic
disease can take the form of West Nile fever, aseptic meningi-
tis, meningoencephalitis with or without weakness, or acute
flaccid paralysis. In the initial New York outbreak, 63% had
encephalitis, 29% aseptic meningitis, and 8% fever and head-
ache alone (158). Encephalitis occurred predominantly in older
individuals. One of the striking features in encephalitis cases
Scheld_Ch21.indd 324
was the presence of weakness in 32%, flaccid paralysis in 11%,
and 40% of encephalitis cases had hyporeflexia (157).
The pathogenesis of the weakness associated with WNV
is multifactorial. Early reports suggested that some patients
had electrophysiologic findings consistent with Guillain-Barr
syndrome (159). However, most cases of weakness following
WNV infection are secondary to a poliomyelitis-like syndrome
attributable to WNV-associated injury to anterior horn cells
(160168). Acute flaccid paralysis can vary in extent from a
single limb to tetraparesis in some cases with associated se-
vere respiratory impairment (160,161,169). Although WNV
neuroinvasive infection is much more common in adults and
in the elderly in particular, cases of WNV poliomyelitis are
also reported in children (170). Uncommon presentations of
WNV acute flaccid paralysis include isolated upper extremity
brachial monoplegia or diplegia as well as reports of delayed
and recurrent limb weakness (171,172).
Patients with WNV-associated myelitis typically have a CSF
lymphocytic or PMN pleocytosis with elevated protein (75 to
234 mg/dL) and normal glucose concentrations (160163).
However, cell counts were normal in 20% of patients in one
series (160,163). When CSF pleocytosis is present, the range
has typically been between 50 and 350 cells/mm3, although
counts as high as 2,600 cells/mm3 have been reported (160).
Large studies of MRI changes for WNV myelitis are not avail-
able. A recent small study of 17 patients with WNV encepha-
litis or meningoencephalomyelitis found that 50% of patients
had an abnormal MRI in the deep gray matter or brainstem,
and two patients had increased T2 intensity in the ventral horn
of the spinal cord (173). This data is consistent with prior
studies showing that 38% of MRIs were abnormal (162), with
one patient exhibiting enhancement of the cauda equina and
two patients with areas of increased T2-weighted signal within
the cord as well as abnormal gradient and spin-echo signals.
Electrophysiologic studies in these cases are consistent with
injury to anterior horn cells or their axons and have shown
reduced motor amplitudes, from 25% to 50% of normal, with
preserved sensory responses, conduction velocities, and distal
latencies. On EMG testing, motor units are normal, but re-
cruitment is severely reduced (160,162,163).
Pathologic studies on patients with acute poliomyelitis-like
flaccid paralysis are limited. Histopathologic changes reported
include acute parenchymal and perivascular inflammatory
changes in the spinal cord with associated loss of anterior horn
cells (162,165).
Diagnosis of WNV infection depends predominantly on
serology (158). In patients with fever and neurologic manifes-
tations, diagnosis of WNV CNS infection can be made by (a)
detection of anti-WNV IgM in CSF by capture enzyme-linked
immunosorbent assay (ELISA), (b) demonstration of both IgM
and IgG antibody in a single serum sample, (c) detection of
WNV RNA in CSF by RT-PCR, or (d) isolation of virus from
CSF, blood, or brain tissue. Of these methods, the CSF IgM
assay is the most sensitive and specific. CSF RT-PCR is highly
specific but considerably less sensitive than serology. Serologic
cross reactions can occur with other members of the JE virus
serocomplex and can often be distinguished by performing
neutralizing antibody tests. IgM antibodies in both serum and
CSF can persist for 6 months or longer, providing another
potential source of confusion in endemic areas (158).
Currently no known effective treatment of WNV infec-
tion is available. Both ribavirin and interferon alpha, alone
or in combination, have been utilized in non-controlled stud-
ies. A phase I/II randomized placebo-controlled double-blind
trials to evaluate the efficacy of an Israeli IVIG preparation
(Collaborative Antiviral Study Group [CASG210]) and a
phase II/III randomized, placebo-controlled, double-blinded
2/21/14 5:40 PM

trial to evaluate the safety and efficacy of a humanized mono-
clonal antibody (MGAWN1) were both discontinued due to
low enrollment.
The prognosis of patients with West Nile flaccid paralysis
or poliomyelitis is not fully understood, but studies suggest
that morbidity and mortality are substantial (174). A wide
range of presentation and degrees of limb weakness may
occur. In cases of bulbar involvement and acute flaccid paraly-
sis, the mortality may be as high as 70% (175,176). In gen-
eral, respiratory failure is associated with fatality rates greater
than 50%. Of patients who survive West Nile flaccid paralysis,
most strength recovery occurs in the first 6 to 8 months fol-
lowing weakness onset. However, initial severity of paralysis
does not predict strength outcome (175,176).
Japanese Encephalitis (B) Virus
JE virus is the most common cause of epidemic viral encepha-
litis worldwide, typically causing in excess of 50,000 cases per
year. As with other arboviruses, asymptomatic cases outnum-
ber cases of encephalitis by at least 100:1. The virus is endemic
in many parts of Southeast Asia, China, and the Indian sub-
continent. Myelitis can occur in conjunction with encephali-
tis or more rarely as the predominant clinical manifestation.
Most cases of JE virus myelitis present as a poliomyelitis-like
acute flaccid paralysis, but cases of acute TVM following JE
virus infection are also reported (177).
In a survey of 22 cases of acute flaccid paralysis in chil-
dren occurring in a Vietnamese hospital, 12 (55%) cases
were due to JE virus (178). Patients typically presented with a
febrile illness followed by acute onset of asymmetric areflexic
weakness, typically involving legs more than arms. Seven of
twelve patients had associated acute urinary retention. Muscle
pains in the affected limbs, back stiffness, and nuchal rigid-
ity were common. Respiratory tract muscle involvement lead-
ing to respiratory failure occurred in one third of patients.
Two patients had findings suggestive of associated brainstem
involvement. Objective sensory findings did not occur in this
series, although two patients had sensory symptoms. Patients
typically had a CSF lymphocytic pleocytosis with normal or
mildly elevated protein concentration and normal glucose
concentration. Electrophysiologic studies in patients with dis-
tal weakness typically showed reduced amplitude of motor
action potentials with normal conduction velocities and distal
latencies, although study results were often normal in patients
without distal weakness.
Diagnosis of JE virus infection depends on demonstration
of antiJE virus IgG antibodies in serum. Detection of CSF
antiJE virus IgM is a specific marker of CNS disease, because
CSF IgM antibodies do not occur in asymptomatic individuals.
CSF PCR can be performed by the CDC, and if positive also
allows for definitive diagnosis of neurologic disease.
No specific therapy for JEV myelitis is available. An
effective formalin-inactivated JEV vaccine has been avail-
able since the early 1950s. Neurologic complications follow-
ing vaccination for JE virus are rare. Three cases of myelitis
associated with the formalin-inactivated killed vaccine have
been reported (179182). These patients typically present 1
to 2 weeks after vaccination with a TVM. Typical symptoms
include paraparesis, a sensory level, and urinary retention.
Weakness is usually initially flaccid and associated with hy-
poreflexia or areflexia. CSF studies typically show a pleocy-
tosis with elevated protein concentration. One patient had a
PMN predominance (950 cells/mm3, 90% PMN). Elevated
CSF myelin basic protein has been detected in several patients
(180,182). MRI scan can show cord swelling, with areas of
Scheld_Ch21.indd 325
Chapter 21: Acute Viral Myelitis 325
high T2-weighted and reduced T1-weighted signal with asso-
ciated gadolinium enhancement (179,180,182). Two patients
improved dramatically after intravenous or oral steroid treat-
ment (180,182).
Tick-Borne Encephalitis Virus
Tick-borne encephalitis (TBE) virus is another member of the
family Flaviviridae. Human infection can occur either from
exposure to the virus-carrying tick vector or from ingestion
of raw milk or cheese from infected goats, sheep, or cows.
Illness is often biphasic, with neurologic symptoms appear-
ing following an acute febrile illness and defervescence fol-
lowed by recurrent fever associated with possible neurologic
symptoms. Asymmetric paralysis of single or multiple limbs
commonly occurs in conjunction with meningoencephalitis,
but myelitis can also occur as the predominant presentation of
infection with either Central European TBE virus or Russian
spring-summer encephalitis virus. The most common myelitic
presentation is an acute flaccid paralysis resembling paralytic
poliomyelitis (183185). Diagnosis is made by demonstration
of specific IgM antibody in serum or CSF. No specific therapy
is available, although immune globulin has been utilized in
non-controlled trials (186). Rare cases of myelitis have also
occurred following vaccination against TBE virus (187).
Symptoms develop days to a few weeks following immuniza-
tion and usually take the form of a TVM with weakness, a
sensory level, and urinary retention. Although patients may
initially have a flaccid paralysis with hyporeflexia or areflexia,
this usually evolves into a hyperreflexic spastic paralysis with
extensor-plantar responses (187). MRI has been reported to
show increased T2-weighted signal within the spinal cord
(187). One patient improved following immunosuppressive
therapy with cyclophosphamide (187).
ORTHOMYXOVIRUSES AND
PARAMYXOVIRUSES (INFLUENZA,
MEASLES, AND MUMPS)
Myelitis has been reported as a rare complication of influ-
enza A infection (188,189). Patients typically present with
initial respiratory symptoms and fever. Myelitis manifests
as weakness usually with depressed or absent deep tendon
reflexes, although extensor-plantar responses may be present
(189). Cases of TVM associated with H1N1 infection were
recently reported (190). One case of TVM was reported fol-
lowing vaccination with the H1N1 live attenuated influenza
vaccine; but it was unclear whether TVM was vaccine-related
or a consequence of a concomitant mycoplasma infection
(191,192). One reported case of influenza myelitis pro-
gressed to complete tetraparesis with associated dysarthria
and dysphagia (189). CSF shows a pleocytosis with elevated
protein and normal glucose concentrations. MRI of the spi-
nal cord shows cord swelling with intramedullary increased
T2- and decreased T1-weighted signal (189). Diagnosis of
influenza myelitis is based on serology. Demonstration of
intrathecal synthesis of antibody against influenza A pro-
vides strong supportive evidence for direct CNS viral infec-
tion (193). TVM has also been reported as a complication
of seasonal influenza vaccination (193). MRI in one patient
showed fusiform cord enlargement and increased intramed-
ullary T2-weighted signal, but no gadolinium enhancement
on T1-weighted images. Recovery from vaccine-associated
myelitis can be complete.
2/21/14 5:40 PM
 326 Part II: Viral Infections and Related Disorders
Isolated cases of myelitis have been reported in association
with both wild type rubella (164,165) and the live attenuated
vaccine strain (194), measles (195), and mumps (196).
OTHER VIRUSES
Isolated examples of myelitis caused by other viruses include
lymphocytic choriomeningitis virus, adenovirus, parvovirus
B19, and hepatitis B (197203).
TRANSVERSE MYELITIS
TVM is an anatomic diagnosis that refers to a focal inflamma-
tory disorder of the spinal cord (myelitis) that affects motor,
sensory, and autonomic pathways (hence, transverse)
(204208). In adults, the incidence of TVM ranges from 1.3
to 8 cases per million population with a bimodal peak in
incidence at ages 10 to 19 years and 30 to 39 years (209213).
As noted earlier, TVM can be caused by viral infections. It can
also occur after an infection or vaccination and is likely due to
a postinfectious or parainfectious immune-mediated response.
The general term TVM should be reserved for those patients
in whom no specific etiology is identified. When a specific eti-
ology is known, this is best included in the designation (e.g.,
EBV TVM).
TVM may selectively involve the conus and epiconus of
the spinal cord (214). A progressive myelopathy with evidence
of spinal cord necrosis with features resembling Devic disease
(NMO) may occur (215,216). Relapsing forms of TVM
have also been described (217); distinguishing these cases from
predominantly spinal forms of relapsing-remitting multiple
sclerosis is problematic. Finally, a subset of patients with a domi-
nant clinical picture of TVM with encephalitic and/or radicular
signs and symptoms (encephalomyeloradiculopathy) has
been reported (218).
Patients develop weakness typically maximal in the legs with
50% progressing to complete paraplegia. Virtually all patients
have sensory signs and symptoms including paresthesias, numb-
ness, or radicular/bandlike dysesthesias (2). Most will have an
associated sensory level. Autonomic symptoms are variable and
can include constipation, bowel or bladder incontinence, and
voiding difficulties, particularly urinary retention (2). Deficits
can develop in as little as 4 hours, although in most patients,
progression occurs over days to several weeks. Patients who
take more than 1 month to progress to maximum deficit are
unlikely to have TVM. Most patients will have a CSF pleo-
cytosis, and it has been suggested that evidence of spinal cord
inflammation, as documented either by CSF pleocytosis, by
abnormal IgG index, or by gadolinium-enhancing lesions,
should be part of the diagnostic criteria for TVM (2).
Diagnosis of TVM depends on clinical features and sup-
portive laboratory study results. In most patients, abnormali-
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ACKNOWLEDGMENTS
Dr. Tyler is supported by grants from the National Institute
of Neurological Disorders and Stroke (NINDS) (NS076512),
National Institute of Allergy and Infectious Diseases (NIAID)
(AI01064), the Department of Veterans Affairs (BX000963),
and by the Reuler-Lewin Family Professorship of Neurology
at the University of Colorado Health Sciences Center.
Dr. Beckham is supported by the NIAID U54 AI065357 Rocky
Mountain Regional Center of Excellence.
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2/21/14 5:40 PM
 CHAPTER 22 POSTINFECTIOUS
ENCEPHALOMYELITIS
KAREN L. ROOS AND AUGUSTO MIRAVALLE

Postinfectious encephalomyelitis is an acute monophasic dis- Although postinfectious encephalomyelitis can occur sponta-
order of the central nervous system (CNS) that occurs within neously, most often it follows a precipitating event (Table 22.1).
days to weeks of a viral illness or a vaccination. The antecedent As stated, the major preceding event is either a viral infection or a
viral illness is typically either an upper respiratory tract infec- vaccination. Measles, varicella, rubella, mumps, and influenza A
tion or a nonspecific febrile illness. In the past, most cases were and B viruses have all been associated with the development of
associated with the exanthematous diseases (vaccinia, measles, postinfectious encephalomyelitis. The other major inciting event
varicella, and rubella) (1). Although postinfectious encepha- is vaccination, particularly in cases involving enveloped viruses
lomyelitis has a clear temporal relationship with infection such as smallpox (vaccinia virus) and rabies. In addition to viral
or immunization, it is not the result of primary neural tissue infection and vaccination, other less common etiologies associ-
invasion by an organism. Infectious agents are rarely identified ated with postinfectious encephalomyelitis are bacterial infec-
or recovered from neural tissue (2). The disease is instead an tions and autoimmune and hematologic disorders (5,1133).
immune-mediated disease triggered by an infectious agent or
an immunization.
TA B L E 2 2 . 1
HISTORY CAUSES OF POSTINFECTIOUS/POSTVACCINAL
ENCEPHALOMYELITIS
One of the earliest descriptions of postinfectious encephalitis
was recorded in 1790 of a 23-year-old woman who developed Viruses
symptoms of encephalitis following smallpox (3). This was
Measles
followed by reports of several neurologic disorders following
smallpox infection (4). In 1905, a case of encephalitis after Varicella
the jennerian cowpox inoculation was reported in France, Rubella
and another case was observed in the London Hospital in Vaccinia
1912 (5). The disease was recognized as a well-defined entity
in 1922, when 11 fatalities due to postinfectious encephalitis Mumps
were reported in Great Britain (4). Influenza A and B
Paralysis and encephalitis is a well-known complication of Hepatitis C
animal brain tissuederived rabies vaccine. In developed coun- Human immunodeficiency virus
tries, these have been replaced by the use of commercial tissue
culture rabies vaccines, but animal brain tissuederived rabies Vaccinations
vaccines continue to be used in many areas of the world. Smallpox
In 1941, Weston Hurst (6) described a syndrome with similar Rabies
clinical presentation to postinfectious encephalomyelitis but with Measles
a worse prognosis. This entity was characterized by the presence
of petechial hemorrhages around blood vessels, intense numbers Rubella
of polymorphonuclear leukocytes, perivenular demyelination, Oral poliovirus
necrosis, and fibrin deposits on pathologic examination. This dis- Japanese encephalitis
ease was called acute hemorrhagic leukoencephalomyelitis (6). Recombinant hepatitis B
On the basis of the preceding illness, postinfectious encephalo-
myelitis has also been called parainfectious, postexanthematous, Tetanus toxoid
postvaccinal, and postinfluenzal encephalomyelitis. In reference to Bacterial infections
the pathology, this illness is also known as acute disseminated en- Streptococcus pyogenes
cephalomyelitis (ADEM), perivascular myelinoclasis, perivenous Legionella pneumophila
encephalitis, acute demyelinating encephalomyelitis, immune-
mediated or hyperergic encephalomyelitis, and disseminated vas- Legionella cincinnatiensis
culomyelinopathy (7). These terms are used interchangeably. Leptospira interrogans
Rickettsia rickettsii
ETIOLOGY Mycoplasma pneumoniae
Plasmodium falciparum
The incidence of postinfectious encephalomyelitis from differ- Immune disorders
ent causes has been reported to be between 0.4 and 0.8 per
Autologous peripheral blood stem cell
100,000 of population, with a median age of onset of 4.5 to
7.5 years in pediatric studies and 33.5 years in a study of adult Lupus
patients (8). The disease has a seasonal peak in winter and Autoimmune hemolytic anemia
spring, consistent with its putative infectious etiologies (9,10).

331

Scheld_Ch22.indd 331 2/21/14 10:48 PM

 332 Part II: Viral Infections and Related Disorders
Viral Etiologies
Postmeasles encephalomyelitis is the most common CNS com-
plication of measles virus infection, with an estimated incidence
of 1 to 2 in 1,000 cases of measles. The onset of symptoms of
postmeasles encephalomyelitis is variable. Typically, after the
rash is fading, fever suddenly returns, associated with head-
aches, vomiting, and signs of meningeal irritation. Headache is
invariably an early feature and often relieved by lumbar punc-
ture. If the spinal cord is involved, there is backache, progres-
sive lower extremity weakness, and urinary retention (13).
Postinfectious encephalomyelitis as a complication of vari-
cella virus infection is rare and occurs in about 1 in 10,000 cases
of chickenpox. The onset of symptoms is usually between 4 and
14 days after the appearance of the rash, with sudden fever,
ataxia, seizures, drowsiness, stupor, and obtundation (13).
Postinfectious encephalomyelitis is thought to occur in
approximately 1 out of 5,000 children with rubella infection.
Signs and symptoms of neurologic involvement occur within the
first week after the onset of the rash. The presentation is usually
very severe with convulsions and sudden loss of consciousness.
Headache and meningeal signs are also common (13).
Postinfectious encephalomyelitis has been reported in associ-
ation with hepatitis C virus infection and as a primary manifesta-
tion of human immunodeficiency virus (HIV) infection (1416).
Vaccination
At present, less than 5% of all postinfectious encephalomyeli-
tis cases follow immunization. Postvaccinal encephalomyelitis
has been associated with immunization for rabies, hepatitis B,
influenza, Japanese B encephalitis, diphtheria/pertussis/tetanus,
measles, mumps, rubella, pneumococcus, polio, smallpox, and
varicella (Table 22.1) (34). Postvaccinal encephalomyelitis usu-
ally occurs 7 to 14 days after vaccination, but cases have been
reported as early as 1 day and as late as 23 days following vac-
cination (35). The risk is usually increased directly with increasing
age of primary vaccination after the first year of life (36). In gen-
eral, postvaccinal encephalomyelitis occurs more frequently in
primary vaccinees than in revaccinees. Complications in revaccin-
ees occur in individuals who have not been vaccinated for many
years, and therefore react like primary vaccinees, or in individuals
who have acquired immunodeficiency disorders (37). During the
1947 smallpox outbreak in New York City, the reported incidence
of postvaccinal encephalomyelitis was 1 in 100,000 (35). In 1968,
5,594,000 primary smallpox vaccinations and 857,400 revac-
cinations were given in the United States. The overall incidence
of postvaccinal encephalomyelitis was 2.9 per 1 million primary
vaccinations. None of the revaccinees developed postvaccinal
encephalomyelitis. The case-fatality rate of postvaccinal encepha-
lomyelitis between 1959 and 1966 was approximately 25% in the
United States (38) and 30% to 50% in Europe (4,39).
The incidence of encephalitis associated with the live
attenuated measles virus vaccine is thought to be 1.16 per
1,000,000 doses, with most cases occurring in the second week
after immunization (19). Postvaccinal encephalomyelitis has
been associated with the poliovirus vaccine (19), the Japanese
encephalitis vaccine (20), the tetanus toxoid vaccine (21), and
the recombinant hepatitis B vaccine (24).
Other Infectious Agents
Streptococcus pyogenes has been reported as a causative agent
of postinfectious encephalomyelitis associated with acute glo-
merulonephritis (23). Postinfectious encephalomyelitis has been
reported as a complication of Legionella pneumophila infection
Scheld_Ch22.indd 332
(24), following leptospirosis (25), typhoid fever (26), and in the
recovery phase from Rocky Mountain spotted fever (28).
A postmalaria neurologic syndrome has been described, charac-
terized as acute onset of convulsions, acute confusional state, dys-
phasia, acute psychosis, tremor, myoclonus, and ataxia in patients
recovering from Plasmodium falciparum malaria. Giemsa-stained
smears of peripheral blood must be negative at the time of symp-
tom onset, distinguishing this syndrome from cerebral malaria,
which occurs during parasitemia. The development of the syn-
drome can be up to 9 weeks (median, 4 days) from eradication
of the systemic parasitemia (29). Postinfectious encephalomyelitis
has been reported as a complication of Mycoplasma pneumoniae
infection (30), after autologous stem cell transplantation (31), and
in association with lupus (32) and autoimmune hemolytic anemia
(33). Whether this is simply a chance association or these diseases
have a specific role in the pathogenesis is unclear.
CLINICAL PRESENTATION
The presentation of postinfectious encephalomyelitis is usually
characterized by abrupt onset of neurologic symptoms days to
weeks after a viral illness or vaccination. Nevertheless, a clear
preceding infection or vaccination cannot be found in up to one
third of children and half of adults presenting with disease (8,40).
In those cases, systemic symptoms, including fever (43% to 52%),
headache (45% to 58%), malaise, and myalgias may occur shortly
before the appearance of neurologic signs and symptoms (41).
Because of the widespread involvement of the optic nerves,
brain, and spinal cord, postinfectious encephalomyelitis usu-
ally presents as a polysymptomatic, monophasic, multifocal
neurologic demyelinating disease. Obtundation and depressed
consciousness, in addition to unilateral or bilateral long tract
signs (85%), acute hemiparesis (76%), and ataxia (59%), are
the most common presentations. Cranial nerve deficits may
be present because of involvement of the corticobulbar fibers
to the motor nuclei of the cranial nerves. These signs may be
associated with an altered level of consciousness ranging from
lethargy to coma (42). Focal or generalized tonic-clonic sei-
zures and psychosis may also be part of the initial presentation
(43). Postinfectious encephalomyelitis can be distinguished
clinically from acute viral encephalitis by the predominance of
subcortical white matter involvement. In contrast, viral enceph-
alitis usually presents with predominantly cortical features,
including confusion, aphasia, and convulsions. Other com-
mon presenting signs and symptoms are listed in Table 22.2.
TA B L E 2 2 . 2
COMMON PRESENTING SYMPTOMS IN
POSTINFECTIOUS ENCEPHALOMYELITIS
Fever
Headaches
Meningismus
Encephalopathy
Coma
Focal neurologic deficits (hemiparesis, cerebellar ataxia,
cranial neuropathies)
Seizures
Transverse myelitis
Aphasia
Movement disorders
Psychosis
2/21/14 10:48 PM

Interestingly, presenting symptoms may vary in pediatric
versus adult-onset postinfectious encephalomyelitis. Motor
deficits can occur in both adult and pediatric cases. However,
sensory deficits and polyradiculoneuropathies are more fre-
quently found in adults, whereas seizures predominate in
pediatric cases.
Even though postinfectious encephalomyelitis usually dis-
plays a monophasic disease course, rare cases of relapsing
postinfectious encephalomyelitis have been described. In order
to fulfill definition of recurrent postinfectious encephalomy-
elitis, the second clinical event should occur at least 3 months
from the initial event, without involvement of new clinical areas
or magnetic resonance imaging (MRI) evidence of dissemina-
tion in time. It has also been suggested that in order to distin-
guish recurrent postinfectious encephalomyelitis from multiple
sclerosis (MS), the second event should not occur while the
patients is receiving steroid treatment (44). Multiphasic postin-
fectious encephalomyelitis is a term that has been assigned
to recurrent postinfectious encephalomyelitis cases where the
second event represents a polysymptomatic presentation with
involvement of a different anatomic area. In those cases, MRI
must show new areas of involvement with complete or partial
resolution of previous lesions (10,44). Long-term clinical and
imaging follow-up has shown the resolution of lesions with
no long-lasting neurologic impairments in most of these multi-
phasic cases (41).
There is a long-standing controversy about whether a sec-
ond episode of postinfectious encephalomyelitis should be
called MS and treated accordingly. As a general rule, patients
who develop clinical evidence of dissemination in space and
time along with evidence of chronic demyelination in the CNS
will likely develop MS. The classic scenario is the patient, typi-
cally a child, who is diagnosed with postinfectious encepha-
lomyelitis following a viral infection, recovers, and then after
some time develops recurrent symptoms with or without an
antecedent viral infection. Two criteria are helpful in making
the correct diagnosis: (a) The development of new symptoms
representing distinct areas of demyelination not involved in
the original episode favors the diagnosis of relapsing-remitting
MS, and (b) the appearance of new lesions on neuroimaging
supports the diagnosis of MS (45). It is worth remembering that
brain lesions of MS patients usually increase in size and num-
ber during the course of the illness (41). In addition, chronic
MS lesions appear as black holes on T1-weighted images,
whereas black holes are not seen on T1-weighted images in
patients with postinfectious encephalomyelitis. As patients re-
cover from postinfectious encephalomyelitis, there is evidence
of complete or partial resolution of lesions on neuroimaging.
Oligoclonal bands should not persist in the cerebrospinal fluid
(CSF) of patients with postinfectious encephalomyelitis, but
will either persist or appear over time in the CSF of patients
with MS (41).
Acute hemorrhagic leukoencephalitis is considered a hyper-
acute form of postinfectious encephalomyelitis and has been
reported to occur in 2% of pediatric cases (46). On physi-
cal examination, there may be meningismus, obtundation,
and lethargy, in addition to upper motor neuron signs, brain-
stem findings, transverse myelitis, and cranial neuropathies.
In general, maximum deficits are reached in the first week
from onset. Recovery usually starts to become clinically evi-
dent after the first week, with complete resolution of deficits
and MRI lesions within 3 months (10). Although the progno-
sis is in general favorable, as high as 30% of patients require
intensive care, with an estimated mortality rate of 20% (10).
Despite the neuropathologic differences between postinfec-
tious encephalomyelitis and acute hemorrhagic leukoencepha-
litis, it is possible that they represent a gradient of severity of
the same pathologic process.
Scheld_Ch22.indd 333
Chapter 22: Postinfectious Encephalomyelitis 333
PATHOGENESIS
The pathology of postinfectious encephalomyelitis can be repro-
duced in the animal model of experimental allergic encephalo-
myelitis. This is a demyelinating disorder of the CNS induced
in animals by immunization with myelin extracts, proteins, or
peptides found in myelin. In an effort to reproduce in animal
models the lesions described in postvaccinal encephalomyelitis,
Rivers and colleagues (47) in 1933 injected homogenates of nor-
mal rabbit brains into monkeys. After 6 months, several mon-
keys developed a lymphocytic infiltration and demyelination of
the CNS tissue (47).
Experimental allergic encephalomyelitis can be passively
transferred to healthy animals by immune lymphocytes (48).
These activated T cells assume a novel functional phenotype
after transfer into a recipient animal that allows them to migrate
to the CNS and pass through the bloodbrain barrier. This mi-
gration briefly precedes the onset of clinical experimental allergic
encephalomyelitis. There is a minimal interval of 3 days between
the intravenous administration of pathogenic T cells and the
onset of clinical experimental allergic encephalomyelitis (49).
T cells can potentially react with a wide variety of molecular
structures, but normally they do not react against self-antigens.
However, some encephalitogenic CD4 and CD8 T lymphocytes
can be found in the blood, thymus, and secondary lymphoid
tissues of apparently healthy individuals, but through the action
of suppressive cytokines, they usually do not attack the CNS.
T cells become pathogenic only if activated. One possible sce-
nario to explain the development of postinfectious encephalo-
myelitis is that an infecting microbe expresses a peptide that is
structurally similar to myelin basic protein (MBP). This epitope
can trigger the activation of self-reactive T cells by a mechanism
known as molecular mimicry. Once activated, these cells can
multiply and mature into effector T cells, producing mediators
and cytokines that can react to normal self-antigens. In addition,
some T cells express more than one specific antigen receptor.
One receptor type could be specific for the myelin antigen and
the other for the microbial antigen. Exposure to the microbial
antigen could activate the T cell, which by virtue of its myelin-
specific alternative receptor could attack the CNS (49).
Another mechanism proposed to explain the pathogenesis
of postinfectious encephalomyelitis is the activation of self-
reactive immune cells by the release of cytokines by virus-
mediated death of host cells. Penetration of these self-reactive
immune cells into the brain or spinal cord leads to the charac-
teristic pathology of postinfectious encephalomyelitis.
The role of circulating humoral factors in the pathogen-
esis of postinfectious encephalomyelitis is still unclear, but
several lines of evidence suggest that antibody production by
the host may aid in limiting or preventing the disease presum-
ably by binding to MBP and inhibiting the access of autoreac-
tive T lymphocytes. Prostaglandins of the E series secreted by
blood monocytes and cerebral glial cells inhibit the immune
response in experimental allergic encephalomyelitis by down-
regulation of monocytes and T cells and reduce the clinical
and histologic abnormalities of experimental allergic encepha-
lomyelitis in rats (12).
DIAGNOSIS
The diagnosis of postinfectious encephalomyelitis is based on
clinical history, the findings on neurologic examination, neu-
roimaging abnormalities of demyelination, and CSF analy-
sis. Several attempts have been made to establish a series of
clinical features that will increase the likelihood of the diag-
nosis of postinfectious encephalomyelitis. The International
2/21/14 10:48 PM
 334 Part II: Viral Infections and Related Disorders

TA B L E 2 2 . 3
DIAGNOSTIC CRITERIA OF POSTINFECTIOUS ENCEPHALOMYELITIS

Clinical Features

First clinical attack of inflammatory or demyelinating disease in the CNS

Acute or subacute onset
Affects multifocal areas of the CNS
Polysymptomatic presentation
Must include encephalopathy; acute behavioral change such as confusion or irritability and/or alteration in consciousness ranging
from somnolence to coma
Attack should be followed by improvement on clinical and/or neuroradiologic (MRI) measures.
Sequelae may include residual deficits.
No other etiologies can explain the event.
Relapses (with new or fluctuating symptoms, signs, or MRI findings) occurring within 3 months of the inciting episode are considered
part of the same acute event. In addition, relapses that occur during a steroid taper or within 4 weeks of completing a steroid taper
are considered part of the initial inciting episode.

MRI Features

Large (12 cm in size) multifocal, hyperintense, bilateral, asymmetric lesions in the supratentorial or infratentorial white matter
Rarely, brain MRI shows a single large (12 cm) lesion predominantly affecting white matter.
Gray matter, especially basal ganglia and thalamus, may be involved.
Spinal cord MRI may show confluent intramedullary lesion(s) with variable enhancement, in addition to the abnormalities on brain MRI.
No radiologic evidence of previous destructive white matter changes.

Encephalopathy is a required feature for the diagnosis of postinfectious encephalomyelitis but is not a typical feature of multiple sclerosis. In addition,
a cerebrospinal fluid pleocytosis 50 white blood cells per mm can be observed in postinfectious encephalomyelitis, whereas this finding is highly
atypical for multiple sclerosis.
From Krupp LB, Banwell B, Tenembaum S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology.
2007;68(16)(suppl 2):S7S12, with permission.)

Pediatric Multiple Sclerosis Study Group has developed a
series of criteria for the diagnosis of postinfectious encepha-
lomyelitis (Table 22.3). These criteria have been developed
based on selected review of the literature and expert panel
discussion. The specificity, sensitivity, and biologic validity to
the diagnosis of postinfectious encephalomyelitis when using
these guidelines have not been evaluated to date.
Due to the broad spectrum of differential diagnosis in pa-
tients presenting with a monophasic demyelinating CNS disorder
(Table 22.4), the diagnosis of postinfectious encephalomyelitis

TA B L E 2 2 . 4
DIFFERENTIAL DIAGNOSIS IN PATIENTS PRESENTING WITH A DEMYELINATING
CENTRAL NERVOUS SYSTEM DISORDER

Diagnosis Characteristics

MS Relapses and remissions, optic neuritis, INO, history of fatigue, sensory symptoms, MRI
showing dissemination in time and space, presence of inflammatory markers on CSF
MS variants (Marburg variant, Tumefactive demyelinating lesions on brain MRI, polysymptomatic presentation
Bal concentric sclerosis)
NMO Optic neuritis, acute myelitis, contiguous spinal cord MRI lesion, presence of anti-
aquaporin-4 antibodies
Viral encephalitis (HSV, VZV, EBV, Encephalopathy, seizures, coma, cortical/brainstem symptoms, systemic manifestations
JC, HIV, Japanese encephalitis virus, (fever, vomiting, myalgias, cutaneous rash), lower motor neuron symptoms
WestNile virus) (poliomyelitis like syndromes associated with WNV)
SSPE Behavioral changes, myoclonic jerks, hemiparesis, cogwheel rigidity, dementia
PML/PML-IRIS Progressive cognitive decline, cortical symptoms, seizures, encephalopathy, history of
immunosuppression, widespread enhancement on T2/FLAIR high signal lesions on
brain MRI, lack of spinal cord involvement

INO, internuclear ophthalmoplegia; PML-IRIS, progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome.

Scheld_Ch22.indd 334 2/21/14 10:48 PM

 Chapter 22: Postinfectious Encephalomyelitis 335

TA B L E 2 2 . 5 Imaging
COMMON PRESENTING SYMPTOMS OF The typical computed tomography findings are areas of dis-
MULTIPLE SCLEROSIS seminated hypoattenuation in the subcortical white matter
of the brain that enhance after the administration of contrast
Optic neuritis (35). They may or may not be surrounded by edema. MRI is
History of fatigue a useful tool to aid in the diagnosis of postinfectious encepha-
lomyelitis. In general, patients with postinfectious encephalo-
Sensory symptoms myelitis have a higher frequency of large confluent bilateral
Lhermitte sign symmetrically oriented diffuse T2/fluid-attenuated inversion
Diplopia/INO recovery (FLAIR) high signal lesions, ventral brainstem lesions,
Uhthoff phenomenon as well as the presence of monophasic pattern of enhancement
(Fig. 22.1) (50). T2-weighted and FLAIR MRI scans demon-
Vertigo strate areas of increased signal in the subcortical white matter,
Gait disturbance brainstem, cerebellum, and periventricular white matter (43).
These may have the appearance of large globular lesions (Fig.
INO, internuclear ophthalmoplegia. 22.1). Periventricular lesions are less frequently seen in postin-
fectious encephalomyelitis than MS, and if present, there is
usually homogeneous contrast enhancement. The lesions are
typically bilateral and asymmetric, vary in size and number,
usually requires a comprehensive, thorough investigation. The and could enhance in a nodular, spotty, ring, or heterogeneous
most common disorders in the differential diagnosis are MS pattern after the administration of intravenous gadolinium.
(both pediatric as well as adult presentation), viral encephali- There may be lesions in gray matter as well. Involvement of the
tis, transverse myelitis, and neuromyelitis optica. Common deep gray matter may help distinguish postinfectious encepha-
symptoms of MS are listed in Table 22.5. Other disorders in- lomyelitis from MS (43). More advanced imaging techniques,
cluding CNS infections, neurometabolic CNS disorders (includ- such as magnetic resonance spectroscopy, have demonstrated
ing mitochondrial disorders), neurosarcoidosis, systemic lupus elevation of lipids and reduction of the myoinositol:creatinine
erythematosus, primary CNS angiitis, NMO, anti-N-methyl- ratio during the acute phase, followed by reduction in lipids
d-aspartate-receptor (anti-NMDA) encephalitis, chronic lym- and increased myoinositol:creatinine ratios in the chronic set-
phocytic inflammation with pontine perivascular enhancement ting (51). Fluorodeoxyglucose positron emission tomography
responsive to steroids (CLIPPERS), Bickerstaff encephalitis, scans usually show marked hypometabolism in the affected
and CNS malignancies should be considered. areas of the brain (45).

A B

C D

FIGURE 22.1 A: Multiple lesions of postinfectious encephalomyelitis on T2-weighted MRI scan. B: The
lesions enhance after the administration of gadoliniumdiethylenetriamine pentaacetic acid due to altered
bloodbrain barrier permeability from the inflammatory process. C: T2-weighted MRI scan showing classic
distribution of lesions seen in an MS patient. There is clear predominance of ovoid-shaped periventricular
lesions, which appear to be perpendicular to the long axis of the lateral ventricle. D: T1-weighted MRI scan of
the same MS patient showing hypointense signal along most of the lesions, suggestive of chronic axonal loss.

Scheld_Ch22.indd 335 2/21/14 10:48 PM

 336 Part II: Viral Infections and Related Disorders

TA B L E 2 2 . 6
MAGNETIC RESONANCE IMAGING FEATURES THAT ASSIST IN THE DISTINCTION BETWEEN
MULTIPLE SCLEROSIS AND POSTINFECTIOUS ENCEPHALOMYELITIS

Positive Predictive
MRI Features That Suggest Multiple Sclerosis Diagnosis Sensitivity (%) Specificity (%) Value (%)

Callen criteria (at least 2 out of 3 features suggest MS over ADEM) 75 95 96

Absence of a diffuse bilateral lesion pattern
Presence of T1 hypointensities
Two or more T2/FLAIR periventricular lesions
Barkhof criteria (at least 3 out of 4 features suggest MS over ADEM) 61 91 90
9 T2/FLAIR-weighted lesions or 1 Gd-enhancing lesion
3 periventricular lesions
1 juxtacortical lesion
1 infratentorial lesion

Gd, gadolinium.

A recent review suggested that the use of Callen MS-ADEM
criteria resulted in a high sensitivity (75%) and specificity
(95%) for distinguishing MS at first attack from postinfec-
tious encephalomyelitis (Table 22.6) (52). The authors also
concluded that these MRI-based criteria were predictive of the
diagnosis of MS versus postinfectious encephalomyelitis even
in the absence of encephalopathy.
and lack of IL-17. However, more concrete studies will need to
be performed to determine this. In order to facilitate the initial
steps in the diagnosis of postinfectious encephalomyelitis, we
propose a list of basic CSF studies that are useful in the differen-
tial diagnosis of postinfectious encephalomyelitis, MS, and viral
encephalitis (Table 22.7).

Laboratory Investigations PATHOLOGY

Given the possible similarities between postinfectious encepha-
In rare circumstances, pathologic evaluation of involved tis-
lomyelitis and MS, similar laboratory tests are performed as part
sue can assist in the diagnosis. Consistent with postinfectious
of the workup of both conditions. MS is classically diagnosed
encephalomyelitis clinical presentation, focal, perivenous,
by multiple lesions on MRI as well as the presence of oligoclo-
and subependymal changes dominate the pathologic pattern.
nal IgG bands in the CSF (53). Unfortunately, in the majority
of postinfectious encephalomyelitis cases, there are minor and
nonspecific changes that occur that make diagnosis based on the
standard of care laboratory testing difficult. However, there are TA B L E 2 2 . 7
some distinguishing features that do differentiate this disease
from patients with MS and with healthy controls. These include CEREBROSPINAL FLUID IN THE DIFFERENTIAL
elevated levels of total protein concentration (usually above DIAGNOSIS OF POSTINFECTIOUS
100 mg/dL) and increased cell count (usually more than 50 cells/ ENCEPHALOMYELITIS, MULTIPLE SCLEROSIS,
mm3) (54,55). It has been shown that the presence of certain cyto- AND VIRAL ENCEPHALITIS
kines, such as tumor necrosis factor (TNF)-, interleukin (IL)-2,
IL-4, IL-5, IL-6, IL-8, IL-10, and interferon (IFN)-, are more Cell count with differential
common in postinfectious encephalomyelitis than MS (56,57). Glucose and protein concentration
IL-17 has been reported to be increased in the CSF and blood Myelin basic protein
of MS patients (58,59); however, this is not observed in pa- Oligoclonal bands
tients with postinfectious encephalomyelitis. A study performed
measuring 18 different chemokines in the blood and CSF of IgG index
patients with suspected postinfectious encephalomyelitis, MS, Viral culture
or healthy controls revealed a distinct pattern of increased ex- PCR for HSV-1 DNA
pression of specific chemokines in postinfectious encephalo- PCR for West Nile virus
myelitis patients not observed in patients with MS or controls.
These changes were only observed in the CSF and not in the PCR for HIV RNA
blood. Mean concentration of the chemokines (postinfectious PCR for JC virus DNA
encephalomyelitis, MS, healthy controls) CXCL7 (522 / PCR for EBV DNA
115 vs. 197 / 37 vs. 158 / 53), CCL1 (28.7 / 6.8, PCR for VZV DNA
18.5 / 3.4, 10.0 / 1.7), CCL22 (75.7 / 38.5, 9.4 /
1.8, 4.3 / 0.8), and CCL17 (18.6 / 3.4, 1.8 / 0.6, VZV IgG and IgM
7.2 / 0.6) were distinctly higher in the CSF from postinfec- HSV IgG and IgM
tious encephalomyelitis patients. Based on these data, it may
be possible to distinguish postinfectious encephalomyelitis pa- PCR, polymerase chain reaction.
tients from MS patients based on increased chemokine levels

Scheld_Ch22.indd 336 2/21/14 10:48 PM


Similar to MS, postinfectious encephalomyelitis lesions are
mostly in the white matter at the corticalsubcortical junc-
tion but may also be seen in the cerebellum, spinal cord,
and brainstem (43,60). Contrary to MS, early postinfectious
encephalomyelitis involves infiltration of adaptive immune
cells, mostly T lymphocytes, followed by innate monocytic
cells. Inflammatory lesions in postinfectious encephalomyelitis
spread radially outward from the vessels, whereas in MS, they
border the plaques (43). Additionally, axons in areas of de-
myelination are relatively preserved in postinfectious encepha-
lomyelitis, whereas in MS, there can be significant axonal
loss. The major pathologic distinguishing factor is irregular
borders observed in postinfectious encephalomyelitis lesions,
whereas lesions from MS patients exhibit sharp distinct bor-
ders. Postinfectious encephalomyelitis is also distinguished
from acute viral encephalitis by its pathology. Postinfectious
encephalomyelitis is predominantly a disease of white mat-
ter, but gray matter may also be affected, particularly basal
ganglia, thalami, and brainstem (42). Acute viral encephalitis
is predominantly a disease of gray matter. The lesions charac-
teristic of postinfectious encephalomyelitis are around small
veins, in the cerebral white matter, brainstem, and spinal cord,
and are composed of mononuclear cells and lymphocytes.
Luxol fast blue stains that stain myelin reveal well-demarcated
areas of loss of myelin. Staining for axons in the same areas
that have loss of myelin reveals that the axon cylinders are rel-
atively preserved. The neurons in the area show minor changes
(4). The degree of the preservation of axon cylinders and the
extent of the involvement of neurons determine prognosis.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis is that of inflammatory, demyelinat-
ing diseases of the CNS. These include MS, viral encephalitis,
transverse myelitis, and neuromyelitis optica (Devic syndrome)
as the most common disorders. Table 22.7 provides a list of
CSF studies to determine the etiology. The leading disease in
the differential diagnosis is MS. The first attack of MS can be
difficult to differentiate from postinfectious encephalomyelitis.
The specific neurologic symptoms are often very helpful in dis-
tinguishing between the two diseases, as is the history of the
onset of symptoms within 2 to 31 days of a viral illness or vacci-
nation. Although typical of postinfectious encephalomyelitis, a
confusional state, headache, a decreased level of consciousness,
and convulsions are also quite atypical of MS. MS is more likely
than postinfectious encephalomyelitis to have a monosymp-
tomatic presentation of optic neuritis, a brainstem syndrome,
a cerebellar syndrome, or a transverse myelitis. The presence
of bilateral optic neuritis is more suggestive of postinfectious
encephalomyelitis than MS (41). Although both syndromes are
primarily demyelinating diseases, the lesions of postinfectious
encephalomyelitis are larger, more extensive, homogeneously
enhance with contrast, and can involve gray matter, whereas
the classic lesions of MS are ovoid-shaped, may or may not
enhance, and usually involve the periventricular white matter,
particularly the trigone and body of the lateral ventricle (41).
The Marburg variant of MS is a fulminant form of MS.
Neuroimaging abnormalities may distinguish the Marburg
variant from postinfectious encephalomyelitis, but more often
it is the clinical course.
The viral encephalitides that may have a similar presen-
tation and similar neuroimaging and CSF abnormalities to
postinfectious encephalomyelitis include flavivirus infections
(Japanese encephalitis virus, St. Louis encephalitis virus, and
West Nile virus), herpesvirus infections (varicella-zoster virus
[VZV], Epstein-Barr virus [EBV], herpes simplex virus [HSV],
Scheld_Ch22.indd 337
Chapter 22: Postinfectious Encephalomyelitis 337
and other nonserotypable herpesviruses), progressive multifo-
cal leukoencephalopathy due to JC virus, and HIV encephali-
tis. Japanese encephalitis virus classically infects the thalamus,
brainstem, basal ganglia, substantia nigra, spinal cord, cerebral
cortex, and cerebellum. The clinical presentation is character-
ized by fever, vomiting, convulsions, and coma. During the acute
illness, patients may have movement disorders due to lesions in
the basal ganglia and substantia nigra or flaccid paralysis due
to lesions in the spinal cord (61,62). Hyperintense lesions on
T2-weighted images in the substantia nigra and thalami can
be seen in Japanese encephalitis (61,63). The diagnosis is made
by demonstrating intrathecal production of specific antibodies.
West Nile virus encephalitis presents with fever, head-
ache, and confusion and may have associated weakness in a
poliomyelitis-like syndrome. The diagnosis is made by either
the demonstration of West Nile virus nucleic acid in CSF, West
Nile virus immunoglobulin M (IgM) antibody in CSF, or a
fourfold increase in serum West Nile virus immunoglobulin G
(IgG) antibodies between acute and convalescent sera.
VZV encephalitis presents with headache, malaise, and con-
fusion days to weeks after the cutaneous eruption of zoster. The
neuroimaging abnormalities of VZV encephalitis can be strik-
ingly similar to those of postinfectious encephalomyelitis. VZV
encephalitis may manifest as spherical subcortical white matter
lesions with the typical appearance of demyelination (64).
In addition, there may be large and small ischemic and
hemorrhagic infarctions of the cortical and subcortical gray
and white matter. The diagnosis is made by demonstrating
either VZV DNA in CSF, VZV IgM antibodies in CSF, or a
positive CSF viral culture.
EBV may cause a meningoencephalitis during the course
of mononucleosis. Following primary infection, the virus
establishes latent infection in the CNS and can reactivate,
causing encephalomyelitis. The clinical presentation includes
fever, headache, focal neurologic deficits, an altered level of
consciousness, and convulsions. This is a monophasic illness
with neuroimaging evidence of lesions throughout the CNS.
Diagnosis is made by demonstrating EBV DNA in CSF.
HSV-1 may reactivate from latent infection in the trigeminal
ganglia and present as a brainstem encephalitis instead of caus-
ing the classic presentation of frontoorbital and temporal lobe
dysfunction. There are also reports of HSV DNA in the CSF of
patients with a clinical syndrome of encephalomyelitis and neuro-
imaging evidence of multiple hyperintense lesions in the thalamus,
corpus striatum, pons, and deep white matter on T2-weighted
MRI scans (65,66). The diagnosis of brainstem encephalitis or
encephalomyelitis due to HSV-1 is made by the demonstration
of HSV-1 DNA in CSF by polymerase chain reaction or by the
demonstration of intrathecal production of HSV antibodies.
Progressive multifocal leukoencephalopathy is a demyelin-
ating disease occurring in patients with severe cellular immu-
nosuppression caused by a reactivation of latent JC virus likely
acquired during childhood. This disease is progressive to death
over the course of a few months. HIV patients and patients re-
ceiving immunosuppressive therapies are at higher risk of de-
veloping progressive multifocal leukoencephalopathy (PML).
HIV encephalitis occurs in immunosuppressed individuals and
presents with cognitive, motor, and behavioral abnormalities.
T2-weighted MRI scans show areas of increased signal inten-
sity in the subcortical white matter.
Subacute sclerosing panencephalitis (SSPE) is a degenera-
tive disease of the brain due to measles virus, which presents
after a latent period of several years or more from acute measles
infection (67). This disease manifests with visual complaints,
behavioral changes, and myoclonic jerks followed by hemipare-
sis, cogwheel rigidity, and dementia. There are elevated antibody
titers against measles virus in CSF specimens and histopathologic
2/21/14 10:48 PM
 338 Part II: Viral Infections and Related Disorders
evidence of extensive demyelination, glial proliferation, and neu-
ronal and glial intranuclear inclusions (67,68). Although initially
this disease may be a consideration in the differential diagnosis,
SSPE is not a monophasic disorder, but a progressive illness.
Transverse myelitis is an inflammatory condition of the spi-
nal cord due to a number of infectious and autoimmune eti-
ologies. The thoracic cord is most commonly affected. There
is a progressive weakness of lower extremities over the course
of several hours to several days. Back pain may be present.
Typically, there is a sensory level and bowel and bladder dys-
function. The maximum deficit is reached by definition within
4 weeks. Spinal MRI demonstrates swelling of the cord at the
level of involvement. Devic syndrome refers to the combina-
tion of optic neuritis and myelitis and is now more commonly
referred to as neuromyelitis optica.
Posttransplantation lymphoproliferative disease and leuko-
encephalopathies after chemotherapy and radiotherapy may
have neuroimaging abnormalities that resemble those of postin-
fectious encephalomyelitis but are distinguished by the clinical
setting in which they occur.
TREATMENT AND PREVENTION
Vaccination of infants against measles, mumps, and rubella has
had a significant effect on decreasing the incidence of postin-
fectious encephalomyelitis caused by these viruses. Despite the
inherent risk of acute neurologic complications following vac-
cination, the incidence of naturally occurring encephalomyeli-
tis is still greater.
Currently, the only agent with proven efficacy in the preven-
tion of postvaccinal encephalomyelitis is antivaccinia -globulin
(AGG). The first clinical trial to prevent postvaccinal encepha-
litis was performed in 1956. At the time of primary smallpox
vaccination, 53,630 Dutch military recruits were given an injec-
tion of 2 mL of 16% AGG, and 53,044 were given placebo.
The donors of the AGG were healthy volunteers from the Royal
Netherlands Army and the Royal Netherlands Air Force who
had recently been vaccinated. Only 3 cases of postvaccinal en-
cephalitis occurred in the treated group, compared with 13 cases
in the control group (69). AGG is not effective in treating post-
vaccinal encephalitis once this complication has occurred.
Therapeutic recommendations for postinfectious encepha-
lomyelitis are complicated by the lack of double-blind pla-
cebo-controlled clinical trials and the fact that postinfectious
encephalomyelitis improves spontaneously. Several case series
suggest that early high-dose corticosteroid therapy is beneficial
(70,71). Early series used adrenocorticotropic hormone (ACTH)
or dexamethasone (1 mg/kg per day), but recent series use in-
travenously administered methylprednisolone in a daily dose of
1,000 mg per day for 3 to 5 days based on the experience with
treating an acute exacerbation of MS. No firm guidelines exist
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A randomized, sham-controlled clinical trial of plasma ex-
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21(2):583586.
75. Keliman M BP. Acute disseminated encephalomyelitis: response to intrave-
nous immunoglobulin. J Child Neurol. 1995;10:481483.
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Scheld_Ch22.indd 340 2/21/14 10:48 PM
 PART III BACTERIAL AND MYCOPLASMAL
INFECTIONS
CHAPTER 23 PATHOGENESIS AND
PATHOPHYSIOLOGY OF BACTERIAL INFECTIONS
PHILIPP AGYEMAN, DENIS GRANDGIRARD, AND STEPHEN L. LEIB
The brain not only is a normally sterile site but also is pro-
tected from infection by specialized barriers, including the
bony skull and the bloodbrain barrier (BBB). Consequently,
infections of the central nervous system (CNS) in general and
bacterial infections of the CNS in particular are comparatively
rare. In the United States, the incidence of bacterial meningitis
decreased to 1.38 per 100,000 population in 2007 (1). The
incidence of brain abscesses is not known precisely but is esti-
mated to be approximately 1 per 100,000 population (2,3). In
contrast, the incidence of severe sepsis in the United States in
2007 was 303 cases per 100,000 population (4).
To establish bacterial CNS infections, pathogens must gain
access either to the subarachnoid space (in the case of meningitis)
or to the brain parenchyma (in the case of brain abscess). Many
of the complex processes involved in the transition of pathogens
from outside the host into the CNS have been elucidated, par-
ticularly for meningitis. Most cases of bacterial meningitis likely
arise from bacteremia, which is caused by invasion of the blood-
stream by the pathogen after colonization of the nasopharyngeal
and intestinal mucosa. Similarly, in the pathogenesis of brain
abscess, the hematogenous route is important in a substantial
number of cases. However, the mechanisms by which pathogens
gain access to the site of infection from the bloodstream likely
differ substantially between meningitis and brain abscess. This is
suggested by the fact that organisms typically causing bacterial
meningitis (e.g., Streptococcus pneumoniae, Haemophilus influ-
enzae, Neisseria meningitidis) very rarely cause brain abscess,
whereas pathogens typically found in brain abscess (e.g., aerobic
and anaerobic Streptococcus species and Staphylococcus aureus)
are rarely the cause of bacterial meningitis. Further elucidation
of the molecular events leading to CNS invasion is likely to
allow a better understanding for these differences.
Not all bacterial infections of the CNS are the result of
bacteremia. This is most obvious when bacterial meningitis
occurs as a consequence of infection of a cerebrospinal fluid
(CSF) shunt or when a brain abscess results from breaching
of the skull and meninges by trauma or a neurosurgical pro-
cedure. Similarly, in patients in whom brain abscess or men-
ingitis originates from a focal infection in the vicinity of the
brain (i.e., sinusitis, otitis media, dental abscess), contiguous
spread rather than bacteremia represents the likely route by
which the pathogen gains access to the CNS. Again, the patho-
gen causing the focal infection seems to determine whether the
secondary infection is meningitis (in the case of S. pneumoniae
or H. influenzae) or brain abscess (in the case of streptococci
other than S. pneumoniae), suggesting pathogen-dependent
differences in pathogenesis.
Multiple processes occur from the time a pathogen has
reached the site of infection until the full manifestations of
the disease have developed. These include the induction of
cytokines and chemokines, activation of inflammatory media-
tors such as nitric oxide (NO), reactive oxygen species (ROS),
or matrix metalloproteinases (MMPs), recruitment of white
blood cells to the site of infection, and cytotoxic events. Many
of these events have been analyzed in detail in bacterial menin-
gitis, whereas less is known in the case of brain abscess.
Scheld_Ch23.indd 341
This chapter focuses on the pathogenesis of bacterial men-
ingitis and the subsequent development of brain damage.
Aspects of the pathogenesis of brain abscess are discussed in
detail in Chapter 31.
PATHOGENESIS OF
BACTERIAL MENINGITIS
The development of bacterial meningitis progresses through
four interconnected phases: (a) bacterial colonization and in-
vasion of the host with subsequent infection of the CNS, (b)
bacterial multiplication and induction of inflammation in the
subarachnoid and ventricular space, (c) progression of inflam-
mation with associated pathophysiologic alterations, and (d)
damage to the CNS (Fig. 23.1).
Bacterial Invasion of the Host and
Penetration of the BloodBrain Barrier
Figure 23.2 shows the pathogenic steps involved in the devel-
opment of bacterial meningitis.
Colonization
Before a meningeal pathogen can cause invasive disease, it has
to successfully colonize the host first. S. pneumoniae, N. men-
ingitidis, and H. influenzae type B, which most frequently
cause bacterial meningitis in humans, colonize the nasophar-
ynx and are transmitted from person to person by the respira-
tory route. On the other hand, group B Streptococcus (GBS)
(Streptococcus agalactiae), Escherichia coli, and Listeria
monocytogenes, which cause meningitis at the vulnerable ex-
tremes of age and in immunocompromised persons, colonize
the gastrointestinal tract and are transmitted through the oral,
vaginal, or fecal-oral route.
Colonization of the nasopharyngeal mucosa is established
by evasion of mucosal host defense mechanisms, for example,
ciliary clearance and secretory immunoglobulin A (IgA), suc-
cessful competition with other organisms in the aerobic envi-
ronment of the upper respiratory tract, and adherence to the
mucosal epithelium. Specialized surface components, such as
components of the polysaccharide capsule, or pili, and the
production of bacterial enzymes are crucial for the various
steps necessary to establish colonization.
The mucociliary escalator is the main mechanical defense
machinery of the respiratory tract. It constantly propels par-
ticles, including bacteria, to the outside. In order to gain access
to the mucosa and establish themselves in the respiratory tract,
S. pneumoniae, N. meningitidis, and H. influenzae type B have
to overcome the mucociliary escalator. As exemplified by S.
pneumoniae, there are several means by which bacteria may
avoid being trapped and flushed away by mucus. The polysac-
charide capsule of S. pneumoniae is almost exclusively nega-
tively charged. This could increase electrostatic repulsion from
341
2/21/14 5:41 PM
 342 Part III: Bacterial and Mycoplasmal Infections

Nasopharyngeal
colonization

Bloodstream
invasion

Systemic
Bacteremia
hypotension

Meningeal invasion

Bacterial multiplication
and lysis

Ventricular and
Loss of vascular
subarachnoid space Bacterial factors
autoregulation
inflammation

Vasculitis
Breakdown of the CSF outflow Neurotoxic
blood-brain barrier obstruction environment

Vascular spasm,
thrombosis

Cerebral Intracranial Brain

ischemia hypertension edema

Necrosis Apoptosis

Cortical brain damage Hippocampal

e.g., cerebral palsy, brain damage FIGURE 23.1 Selected mechanisms
sensorimotor deficits, e.g., learning disabilities that contribute to the pathogenesis of
cortical blindness bacterial meningitis and the develop-
ment of brain injury.

the likewise negatively charged sialic acid residues of mucus
(5). Additionally, deglycosylation of mucus by secreted exogly-
cosidases (e.g., neuraminidase A [NanA], beta-galactosidase
B, etc.) may decrease its viscosity and lessen entrapment
(6). Furthermore, pneumolysin, a major virulence factor of
S. pneumoniae that is released by autolysis, inhibits ciliary
beating (7,8). Pneumolysin has been shown to be necessary for
successful colonization of the nasopharynx (9). Ciliostasis has
also been documented in H. influenzae infection (10), whereas
nasopharyngeal colonization of N. meningitidis entails cyto-
toxicity for ciliated epithelial cells (11).
Besides its mechanical action, respiratory mucus also har-
bors several soluble antibacterial agents. Secretory IgA antibod-
ies inhibit microbial adherence and penetration into the mucosa.

Scheld_Ch23.indd 342 2/21/14 5:41 PM

 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections 343

Opaque phenotype
Nasopharynx (encapsulated pathogen)

Colonization
Transparent phenotype

Mucin layer

Nasopharyngeal

Host invasion
epithelial
cell layer

Extracellular matrix

Endothelial cells

Survival in the bloodstream

Monocyte

Bloodstream
MMPs
Neutrophils Cytokines
Chemokines
Integrins
Selectins
Blood brain barrier

Infection of the CNS

Brain microvascular
endothelial cells
Basal membrane
Tight
CNS junction
MMPs
Cytokines
Glia cell Chemokines

FIGURE 23.2 Schematic representation of pathogenetic steps involved in the development of bacte-
rial meningitis: (a) bacterial colonization of the nasopharynx and invasion of the host; (b) bacteremia
with subsequent transgression of the bloodbrain barrier (BBB); and (c) bacterial multiplication, induc-
tion of inflammation, and invasion of blood-derived neutrophils into the subarachnoid and ventricular
space. Colonization of the nasopharyngeal mucosa is established by adherence to the mucosal epithelium
and affected by phase variation in colonial morphology. Bacteria then penetrate the mucosal barrier
through or between epithelial cells. The capsule is the primary survival factor in the bloodstream, operat-
ing against circulating antibodies, complement-mediated bacterial killing, and neutrophil phagocytosis.
Pathogens must cross the BBB to induce bacterial meningitis. Once attachment to cerebrovascular endo-
thelial cells has occurred, several strategies can be employed by the pathogen to migrate across the BBB
and gain access to the CSF space. These include (a) paracellular passage by disruption of the intercellular
endothelial connections or endothelial injury; (b) transcellular transport by active or passive transcytosis;
and (c) invasion within white blood cells during diapedesis. The entry of blood-derived neutrophils into
the CSF requires tethering and rolling of leukocytes along the endothelium, which is mediated by the
interaction of members of the selectin family, followed by firm adhesion to endothelium and subsequent
emigration through the vessel wall. The transmigration of leukocytes through vessel walls occurs along
a chemotactic gradient mainly dependent on chemokines. Neutrophils appear to also use certain MMPs,
such as MMP-8 and MMP-9, to digest ECM components and thus facilitate the process of extravasation.

N. meningitidis, S. pneumoniae, and H. influenzae, as well as
some members of the resident oral flora, secrete highly specific
endopeptidases that cleave the heavy chain of human IgA1,
including its secretory form (sIgA1), thus separating the mo-
nomeric antigen-binding fragments (Fab) from the secondary
effector functions of the IgA1 antibody (Fc) (12). IgA1 prote-
ases exist as three different classes of proteinases. IgA1 prote-
ases of H. influenzae and N. meningitidis are genetically related
serine proteinases, those of S. pneumoniae are metalloprotein-
ases. Cleavage of IgA1 by proteases impairs specific mucosal
immunity in the upper respiratory tract, thus allowing bacteria
to colonize. IgA1 proteases may also contribute to the patho-
genesis of invasive infections by leading to the coating of bacte-
ria with Fab fragments, which mask epitopes and thus protect
them from subsequent recognition by intact immunoglobulin
(13). Lysozyme is an important component of the innate im-
mune system and abundantly present in the saliva, airway fluid,
and lysosomal granules of neutrophils. Its muramidase activity
leads to hydrolyzation of the bacterial cell wall polymer pep-
tidoglycan. Modification of peptidoglycan by N-deacetylation
and O-acetylation and the production of lysozyme inhibitors are
bacterial strategies to fend off lysozyme action (14). The gene
coding for the enzyme responsible for N-deacetylation, peptido-
glycan N-acetylglucosamine deacetylase A (PdgA), is present in
S. pneumoniae and L. monocytogenes (15). Genes encoding for
peptidoglycan O-acetyltransferases have also been found in S.
pneumoniae (attenuator of drug resistance [adr]) and N. men-
ingitidis (peptidoglycan acetylase A [pacA] and pacB) (16). For

Scheld_Ch23.indd 343 2/21/14 5:41 PM

 344 Part III: Bacterial and Mycoplasmal Infections
S. pneumoniae, it has been shown that expression of PdgA and
Adr is necessary to provide lysozyme resistance and provide col-
onization advantage in the mouse model (17). Finally, apolacto-
ferrin, the iron-depleted form of lactoferrin, is bacteriostatic or
bactericidal for bacteria. The pneumococcal surface protein A
(PspA) protects against the bactericidal effect of apolactoferrin,
probably by binding to the active sites of apolactoferrin (18).
Bacterial adherence to epithelial cells is mediated by adhes-
ins on the bacterial surface binding to epithelial cell receptors.
Based on their structure, fimbrial and afimbrial adhesins can
be distinguished in meningeal pathogens. Fimbriae (or pili) are
filamentous structures, first identified in Gram-negative bacte-
ria, that protrude from the outer cell membrane. Fimbriae are
composed of several subunits that form rodlike structures and
carry a specific adhesive subunit at their tip (19,20). Fimbriae
have been associated with the early steps of adhesion mostly,
but not exclusively, in Gram-negative meningeal pathogens.
Several afimbrial adhesins have been identified in all meningeal
pathogens and will be discussed with the respective pathogens.
Adherence of pneumococci to mammalian cells and pneu-
mococcal virulence is facilitated by regulated expression levels
of the polysaccharide capsule in a process called phase varia-
tion. Capsular phase variation of S. pneumoniae is marked by
changes in colonial morphology from opaque to transparent
and correlates with differences in virulence. The transparent,
less capsulated phenotype is more capable of colonizing the
nasopharynx, whereas the opaque phenotype shows increased
virulence during systemic infections (21,22). Masking of
underlying adhesion molecules by the polysaccharide capsule
is a possible explanation for the inferior colonization capabili-
ties of opaque strains. Adherence of S. pneumoniae in itself is
thought to involve binding to glycoconjugates on the surface
of the respiratory epithelium, although the exact mechanisms
have not been completely elucidated (23). Recognition of these
binding sites is enhanced by cleavage of the terminal sialic acid
by NanA and other glycosidases (24,25). Further putative
roles of NanA during the colonization process are its involve-
ment in the formation of biofilm (26) and competition with
other meningeal pathogens (27). A specific function as adhe-
sin has been shown for the choline-binding protein A (CbpA;
also called PspC or SpsA), which binds to the polymeric im-
munoglobulin receptor (pIgR) on human mucosal epithelial
cells and complement factor H (23). Importance of CbpA
has been demonstrated in an infant rat model where CbpA-
deficient pneumococci were significantly restricted in their
ability to colonize the nasopharynx (28). CbpA is a member
of the family of choline-binding proteins. This family of pro-
teins shares phosphorylcholine, a component of lipoteichoic
and teichoic acids, as common cell wall anchor. Interestingly,
phosphorylcholine also binds to activated platelet-activating
factor receptor (PAFr) on epithelial cells and C-reactive pro-
tein (CRP) (29). Inflammation enhances this process, as ex-
pression of PAFr on lower respiratory tract epithelial cells,
and thereby PAFr-dependent adhesion and transcytosis of S.
pneumoniae, are increased by rhinovirus, acid, fossil fuel
derived particulate matter, and cigarette smoke (30). On the
other hand, phosphorylcholine expression itself can be modu-
lated by the pneumococcal phosphorylcholine esterase. This
may allow the bacterium to limit CRP-binding and consecu-
tive complement activation (23). Eventually, cellcell adhesion
molecules have been identified as important adhesion targets
for viruses, bacteria, and parasites (31). For S. pneumoniae, it
has been shown that pneumococcal surface antigen A (PsaA)
attaches to E-cadherin, an adhesion receptor it shares with L.
monocytogenes (32). CbpA and PsaA are produced by virtu-
ally all clinical isolates of S. pneumoniae and contribute to
their virulence (33). It has also been shown in children that
Scheld_Ch23.indd 344
pneumococcal carriage and infection induce salivary and
serum antibodies against NanA, CbpA, and PsaA, among
other pneumococcal antigens (34,35). Also, levels of PsaA and
NanA antibodies in the serum were inversely correlated to fre-
quency of respiratory tract infections (35).
Primary adherence of N. meningitidis depends on the bind-
ing of type 4 pili on the bacterial cell surface to nonciliated
epithelial cells. Thereby, N. meningitidis induces rearrange-
ments of the cellular cytoskeleton leading to protrusion of
microvilli and formation of cortical plaques in epithelial cells
(10). Clusters of bacteria are then embraced by microvilli,
increasing stability of the adhesion. Further physical proxim-
ity of the bacterial and epithelial cell surfaces accompanied
by the loss of fimbriae and downregulation of capsule allows
other adhesins to attach to their respective receptors (36).
Most notably, opacity-associated (Opa) proteins, a family of
phase-variable outer membrane proteins of N. meningitidis,
bind to carcinoembryonic antigen-related cell adhesion mol-
ecules (CEACAM), cell surfaceexpressed heparan sulfate
proteoglycans, and extracellular matrix (ECM) proteins (37).
CEACAMs are further involved in the invasion process of
N. meningitidis (discussed below). While fimbriae protrude
from the polysaccharide capsule, the capsule interferes with
the function of other adhesins of N. meningitidis (38,39).
Downmodulation of the capsule or inducing the upregulation
of adhesion receptors (e.g., CEACAMs) are proposed mecha-
nisms by which invasive N. meningitidis overcome this disad-
vantage (38).
Although structurally different, fimbriae are also important
adhesion molecules of H. influenzae (40). They mediate adhe-
sion to mucin, ECM, and epithelial cells (41). Besides fimbriae,
the protein Hsf is a major adhesin of H. influenzae. Hsf is
anchored in the outer membrane of H. influenzae and forms
fiber-like structures on the cell surface (41). Similar to N. men-
ingitidis, the outer membrane protein P5 of H. influenzae
binds to CEACAM-1 and intercellular adhesion molecule-1
(ICAM-1) (42,43).
E. coli and GBS are the main pathogens of neonatal menin-
gitis but, like L. monocytogenes, may also cause meningitis in
the elderly and immunocompromised persons. Transmission
from the asymptomatically colonized mother or the environ-
ment can lead to the colonization of the intestinal tract of the
infant, the first step in the pathogenesis of neonatal E. coli and
GBS meningitis. The food-borne pathogen L. monocytogenes
disproportionately affects pregnant women and is transmitted
to the fetus through the placenta (44).
Similar to N. meningitidis, adherence of E. coli to host cells
depends primarily on fimbriae. For example, the type I fim-
briae in E. coli harbor the adhesive FimH subunits on their tip
(45). FimH binds mannose-containing residues on the host cell
and has been implicated in the tissue tropism of pathogenic
E. coli (46). Additionally, type S fimbriae are expressed by E.
coli that have been isolated in neonatal meningitis and sep-
sis cases (47). Another heterogenous family of adhesins that
may be assembled into fimbriae-like structures are the Afa/Dr
adhesins that have been reported to adhere to the decay-ac-
celerating factor (DAF) expressed on cells exposed to plasma,
complement proteins, CEACAMs, and type IV collagen (19).
The expression of adhesins on E. coli differs between the dif-
ferent pathogenic and nonpathogenic subtypes and likely de-
termines the organ tropism. Accordingly, the majority of E.
coli isolates found in neonatal meningitis exhibits the capsular
serotype K1 and a limited repertoire of different O antigens
(48). The reason for the neurotropism of these specific sero-
type combinations is not yet completely understood, although
the K1 capsule seems to be the decisive factor for meningitis
development (49).
2/21/14 5:41 PM
 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections
Akin to neonatal E. coli meningitis, epidemiologic analysis
of GBS in neonates with GBS meningitis shows a predomi-
nance of the capsular serotype III and the clonal complex ST-17
(50). Recently, a novel virulence factor has been described in
bacteria belonging to the ST-17 complex. The hypervirulent
GBS adhesin is anchored to the cell wall and in vitro signifi-
cantly enhances adhesion to intestinal epithelial cells, resulting
in increased colonization of the intestine in the in vivo mouse
model (50). Other adhesins involved in the attachment of GBS
to the gastrointestinal epithelium primarily bind to compo-
nents of the ECM. For example, the cell surface protein SepB
binds to fibronectin but also mediates cleaving of complement
factor C5a. Attachment to laminin is mediated by the adhe-
sin Lmb, whereas the surface-anchored protein FbsA binds to
fibrinogen (51). Finally, fimbriae have also been involved in
GBS adherence and biofilm formation (52).
For adherence and internalization of L. monocytogenes at
the intestinal mucosa level, the interaction of the internalin A
(InlA) with the cell-junction protein E-cadherin is paramount
(53,54). E-cadherin is normally located below the tight junc-
tion and not available as a receptor to intraluminal bacteria.
However, it has been demonstrated that E-cadherin is pres-
ent on the luminal surface of mucus-secreting goblet cells and
may be temporarily accessible at the tips of intestinal villi due
to constant shedding of dead enterocytes (55,56). Whereas
adherence to the intestinal epithelium is important for the
pathogenesis of L. monocytogenes in the elderly and immuno-
compromised persons, transmission of L. monocytogenes to the
neonate occurs via the transplacental route. Histopathologic
analysis of placentas from women with fetoplacental listeriosis
and in vitro analysis indicate that L. monocytogenes targets
E-cadherin on the surface of syncytiotrophoblasts in a similar
way as in the intestine (57).
Invasion of the Bloodstream
The functional integrity of the respiratory tract mucosa is criti-
cal in protecting the host from bacterial invasion. Viral infec-
tions of the respiratory tract may lead to a decrease in ciliary
function and associated mechanical clearance of bacteria, up-
regulation of different host cell receptors involved in bacterial
adherence, and alteration of host immune response (58,59),
and are associated with an increased risk of invasive bacterial
disease. Epidemic outbreaks of meningitis due to N. meningiti-
dis in the sub-Saharan meningitis belt coincide with the dry
periods of the year, when the protective barrier of the mucous
membrane is compromised (60).
Bacteria can penetrate the mucosal barrier through or be-
tween epithelial cells, and both routes seem to be employed
depending on the pathogen. Presence of a capsule or sialylated
lipooligosaccharides, factors that are instrumental for the sur-
vival of meningeal pathogens in the bloodstream, hinders the
process of transcytosis (10,61). Most of the identified mecha-
nisms by which these pathogens directly invade human na-
sopharyngeal mucosal cells take advantage of a ubiquitous
cellular endocytosis mechanisms. In clathrin-mediated endo-
cytosis, a ligand-receptor interaction initiates the formation of
a clathrin-coated pit, which eventually forms a vacuole that
engulfs particles (62,63). Additionally, actin rearrangements
are induced and further enhance bacterial internalization.
On the other hand, paracellular migration of bacteria might
be facilitated by toll-like receptor (TLR)dependent down-
regulation of tight junction components (64) or degrada-
tion of intercellular junctions mediated by bacterial enzymes
or bacteria-bound plasmin (6568). So far, several host cell
factors have been identified as targets of bacterial invasion
mechanisms.
Scheld_Ch23.indd 345
345
The transmembrane receptor pIgR is necessary for trans-
port of IgA and IgM across epithelial cells. After binding of
the immunoglobulins at the basolateral surface of the epithe-
lial membrane, the pIgR-immunoglobulin complex is taken up
into endosomes and transported across the epithelium in vesi-
cles to the apical mucosal surface, where it is released into mu-
cosal secretions (69). S. pneumoniae is capable of exploiting
this mechanism for its own transcytosis across mucosal cells.
As previously mentioned, binding of S. pneumoniae to human
pIgR is mediated by CbpA. This interaction allows S. pneu-
moniae to hijack the recycling pathway of pIgR from the api-
cal to the basal cell surface by retrograde transport, thereby
facilitating transmucosal invasion of pneumococci (70,71).
The CEACAM proteins, a family of proteins involved in in-
tercellular adhesion, have been identified as target of adhesion
molecules of N. meningitidis, H. influenzae, and E. coli (72).
Of the CEACAMs that have been associated with bacterial
binding, CEACAM-1 is most widely distributed on different
human cell types. Other CEACAMs that have been shown to
bind to Opa of N. meningitidis are CEACAM-3, CEACAM-5,
and CEACAM-6 (73). Interestingly, binding to CEACAM-1
does not only allow N. meningitidis to adhere and invade epi-
thelial cells by endocytosis (74) but may also downregulate
the host immune response on several levels (72). On the other
hand, binding of N. meningitidis to CEACAM-3 on neutro-
phils has been shown to enhance engulfment and killing of
bacteria (73).
E-cadherin is the cell surface protein responsible for estab-
lishment of adherens junctions between neighboring cells (31).
In the intestine, the interaction of listerial protein InlA with
E-cadherin leads to the rearrangement of the actin skeleton
of the host cell and ensuing engulfment of the bacteria into a
vacuole that is transported to the basolateral cell surface (56).
Persistence in the vacuole until release into the lamina propria
is in contrast to intracytosolic release and replication of L.
monocytogenes in other human cells. Although interaction of
InlA with E-cadherin is also involved in the invasion process
of L. monocytogenes in the placenta, additionally, binding of
InlB to its host receptor Met is necessary (75).
The exact mechanisms by which E. coli K1 and GBS invade
human mucosal cells have not been elucidated. One adhesin/
invasin that has been identified in E. coli K1 is the Hek outer
membrane protein, which mediates binding to proteoglycan
on the epithelial cell surface (76). Additionally, a role for outer
membrane protein A (OmpA) and IbeB, better studied in BBB
crossing, has been suggested (76). Altogether, akin to other
meningeal pathogens, this points to an endocytosis-like pro-
cess which is enabled by rearrangement of the epithelial cell
cytoskeleton (77).
Between epithelial cells and mesenchymal cells lies the base-
ment membrane, providing a final mechanical barrier before
the invading pathogen can disseminate throughout the host.
Attachment to ECM components is an important property
of bacterial infection pathogenesis, and ECM adhesins have
been identified in most meningeal pathogens (e.g., PavA of
S. pneumoniae [23], Opc of N. meningitidis [78], fimbriae of
H. influenzae [79], and ScpB of GBS [51]). To cross the base-
ment membrane, meningeal pathogens have devised several
strategies: degradation of the basement matrix by secretion
of proteolytic enzymes, use of the hosts plasminogen-plasmin
system, and possibly crossing of the basement membrane in
phagocytic cells. Hyaluronidase is an endoglycosidase that
degrades hyaluronic acid, a component of the ECM. S. pneu-
moniae strains demonstrate a strong correlation between
hyaluronidase activity and the capacity to induce menin-
gitis (80). Intranasal instillation of pneumococci together
with hyaluronidase was followed by meningitis in 50% of
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 346 Part III: Bacterial and Mycoplasmal Infections
inoculated mice, whereas mice inoculated without hyaluroni-
dase failed to develop meningitis (65). Plasminogen is the key
proenzyme of the fibrinolytic system, which after activation
becomes the broad-spectrum protease plasmin. Although
fibrin is its main substrate, plasmin can cleave several com-
ponents of the basement membrane and ECM (81). Binding
of plasminogen has been shown for N. meningitidis, S. pneu-
moniae, and H. influenzae (82) and enhances invasiveness of
S. pneumoniae and H. influenzae (67,83,84). Phagocytic cells
targeting colonizing pathogens on the mucosal surface move
freely between the mucosal surface and the intraluminal space
of the mucosal microvasculature. This movement of phago-
cytic cells can be exploited by bacterial pathogens that are able
to survive in phagocytic cells (85). For L. monocytogenes, it
has been shown that dendritic cells are an important transport
vehicle from the mucosa to lymphatic organs (86).
Intravascular Survival
Once in the bloodstream, meningeal pathogens are immediately
attacked by the host immune defense. To establish successful
bacteremia, meningeal pathogens need to overcome the differ-
ent effector systems of the immune defense. Clearance of the
classical meningeal pathogens S. pneumoniae, H. influenzae,
and N. meningitidis relies on antibody-mediated opsonization
followed by activation of the complement system. In the case
of S. pneumoniae and H. influenzae, this is followed by phago-
cytosis and finally intracellular killing, whereas the membrane
attack complex is important for control of N. meningitidis (87).
In neonates with E. coli and GBS meningitis, immune defense re-
lies especially on innate immunity, with the complement system
being the first line of defense. The importance of the complement
system for the clearance of meningeal pathogens is underlined by
the fact that patients with impaired complement activation (i.e.,
sickle cell disease, anatomical or functional asplenia, or poly-
morphisms in the complement components) are predisposed to
invasive pneumococcal infections, whereas patients with defi-
ciencies in the terminal complement components are prone to
invasive infections with N. meningitidis (8891).
The complement system may be activated by the classical
pathway, the mannose-binding lectin (MBL) pathway, or the
alternative pathway, all converging at the deposition of acti-
vated complement factor C3b on the pathogen surface, which
catalyzes the downstream effectsopsonization and phago-
cytosis or bacteriolysisof the complement system (87). The
meningeal pathogens have developed several mechanisms to
evade deposition of C3b on the cell surface. The polysaccharide
capsule, although hindering adherence to the mucosal surface
and entry into epithelial cells, is the primary survival factor in
the bloodstream, operating against circulating antibodies, com-
plement-mediated bacterial killing, and neutrophil phagocytosis
(49). Accordingly, encapsulation is a shared feature of the major
hematogenous meningeal pathogens (H. influenzae, N. menin-
gitidis, S. pneumoniae, E. coli K1, and GBS). Sialic acid, which
is present on most human cells and blocks activation of com-
plement, is also found in the capsule of meningeal pathogens,
for example, GBS (type III), E. coli (K1), and meningococci
(groups B and C). Thereby, the polysaccharide capsule may pre-
vent complement-mediated bacteriolysis (92). Also, in S. pneu-
moniae, the capsule is thought to interfere with the activation
of the classical complement pathway by limiting binding of im-
munoglobulin and CRP to subcapsular antigens (93). Binding of
immunoglobulin may further be hindered by the action of IgA1
proteases. IgA1-proteases cleave IgA1 in the hinge region and
liberate monomeric Fab-a fragments, which block the access of
intact immunoglobulin G (IgG) or immunoglobulin M (IgM) to
the pathogen (94). Several host defense mechanisms counteract
Scheld_Ch23.indd 346
the antiphagocytic activity of the bacterial capsule. Most effec-
tive are antibodies against capsular components, which permit
optimal opsonization of bacteria and ensure efficient phago-
cytosis by polymorphonuclear (PMN) leukocytes and macro-
phages. The efficacy of this mechanism is underscored by the
more than 95% decrease of H. influenzae type b meningitis after
the introduction of conjugate vaccines, which induce high anti-
capsular antibody titers even in young children (95).
The first step in the classical complement pathway is the
association of C1-complex to antibodies bound to the bacte-
rial surface. The pneumococcal protein PspA has been shown
to limit this step (96). C1-complex (classical complement path-
way) or MBL-associated serine protease 2 (MBL pathway) then
activate the C3-convertase C4b2a, which in turn activates C3
to C3b. As with any enzyme cascade, activation of the comple-
ment system needs to be balanced carefully to avoid damage
to host cells. Regulators of complement activation include
C4-binding protein (C4BP), factor H, and DAF, which accel-
erate the dissolution of C3-convertases (97). E. coli K1, N.
meningitidis, S. pneumoniae, GBS, and H. influenzae may all
inhibit the classical and MBL complement pathway by bind-
ing of C4BP (98,99). Also, S. pneumoniae, N. meningitidis,
and GBS can bind factor H and downregulate the alternative
complement pathway (100102). In particular, meningococcal
factor Hbinding protein has received considerable attention
because this molecule is a key component of group B menin-
gococcal vaccines (103,104). The result of C3 activation is the
generation of C5 convertase. C5 convertase cleaves C5 into
C5a, a strong chemoattractant and anaphylatoxin, and C5b,
member of the membrane attack complex (MAC). GBS ex-
press an endopeptidase that cleaves C5a (105). The final step
of complement cascade is the generation of the MAC, which
mainly affects Gram-negative pathogens. Vitronectin regulates
this last step of the complement cascade by interfering with
MAC assembly. H. influenzae and N. meningitidis have been
shown to bind vitronectin through Hsf and Opc, respectively,
and thereby limit bacteriolysis (106). Although evasion of the
complement system also impedes opsonic phagocytosis, the
polysaccharide capsule of the classical meningeal pathogens
additionally allows for direct evasion of bacterial uptake and
killing by professional phagocytes (107,108).
In contrast, the intracellular pathogen L. monocytogenes
depends mainly on its ability to evade intracellular killing in the
phagolysosome to evade the host immune system. After uptake
into the cell, L. monocytogenes can rupture the vacuole through
the action of two phospholipases and listeriolysin and escape into
the cytosol (109). Concurrently, N. meningitidis and S. pneu-
moniae have been shown to escape the oxidative burst in leu-
kocytes by guarding themselves against ROS by the production
of glutathione (110,111). Another important virulence factor of
L. monocytogenes is the actin assemblyinducing protein ActA,
which catalyses polar actin assembly and autophagy escape,
thereby enabling intracellular motility and spread to adjacent
cells (109). Although bacterial clearance by phagocytosis is an
important early step in listeriosis, the ability of L. monocytogenes
to survive intracellularly in macrophages allows it to travel to
target organs, thereby evading innate immune mechanisms.
In summary, the intricate defense mechanisms of bacteria
against the host immune system only need to safeguard the
survival of one (or a few) organism(s), which may then gain
access to the subarachnoidal space and cause meningitis (112).
Meningeal Invasion
To enable efficient neuronal signaling, the CNS is a tightly
regulated space protected from its surroundings by differ-
ent barriers. The boundary to the blood is provided by the
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 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections
BBB, the bloodcerebrospinal fluid barrier (BCSFB), and the
arachnoid (113). The BBB is composed of brain endothelial
cells, closely connected through adherens and tight junctions;
a basal membrane; astrocytic and microglial processes; and
pericytes. The close interconnection of endothelial cells, low
pinocytic activity, and specific transport mechanisms allow
for a selective permeability (113). Bloodborne pathogens must
cross the BBB or the BCSFB from the bloodstream to induce
bacterial meningitis. Clinical observations and experimental
studies demonstrate a relationship between the magnitude of
bacteremia and the development of meningitis for most menin-
geal pathogens (89,114,115). However, high bacteremia alone
is not sufficient for the development of bacterial meningitis,
but expression of selective bacterial adhesion and invasion fac-
tors is necessary (116).
Attachment to the brain microvascular endothelial cells is
facilitated by receptors for meningeal pathogens found on the
endothelium in cerebral capillaries and the choroid plexus.
The laminin receptor, a cell surface protein involved in binding
to ECM components, has been suggested as common adhesion
target for S. pneumoniae, N. meningitidis, and H. influenzae
and also supports invasion of cytotoxic necrotizing factor 1
(CNF1) expressing E. coli K1 (117,118). Adhesion to brain
endothelial cells via the laminin receptor is mediated by CbpA
in pneumococci, outer membrane proteins PilQ and PorA in
meningococci, and the porin OmpP2 in H. influenzae (117).
Further, fimbriae are important structures in bacterial adhe-
sion to human cells (see earlier discussion). Fimbriae are es-
sential for binding of N. meningitidis to brain endothelial
cells (119). Binding of E. coli K1 to brain endothelial cells is
also mediated by FimH on type 1 fimbriae binding to CD48
and OmpA association with glycoproteins on the cell surface
(116). For GBS as well, several adhesins are required for bind-
ing to brain endothelial cells, including the pilus tip adhesin
PilA (120122).
Once attachment has occurred, pathogens may employ
several strategies to migrate across the BBB and gain access
to the CSF space. These include (a) transcellular traversal
by transcytosis, (b) paracellular passage by disruption of the
intercellular endothelial connections or endothelial injury,
and (c) invasion within white blood cells during diapedesis.
Causative organisms of bacterial meningitis have mainly been
shown to migrate into the CSF by transcellular or paracellular
migration (116). However, L. monocytogenes also accesses the
CSF space inside leukocytes (123).
Direct invasion of endothelial cells by meningeal pathogens
involves ligand-receptor interactions between bacteria and
host cells and rearrangement of the endothelial actin cytoskel-
eton, which ultimately leads to the uptake of the pathogen in
a vacuole and transcellular transport (116,124). For S. pneu-
moniae, the interaction of phosphorylcholine with PAFr and
expression of NanA are important for invasion of the BBB
(125). PAFr is a transmembrane receptor expressed by several
different cell types across the human body and involved in the
pathogenesis of different inflammatory diseases, atherogen-
esis, embryo implantation, and CNS signaling (126). PAFr is a
G proteincoupled receptor and the ligand-receptor complex
can be taken up into a vacuole that either recycles back to
the cell surface or fuses with lysosomes to terminate signaling
(126). Similarly, pneumococci bound to PAFr via phosphoryl-
choline are taken up into vacuoles but may then avoid fusion
of the vacuole with lysosomes. Instead, they are transported
to the basolateral surface of the endothelial cell and released
out of the cell (127). Likewise, IbeA and CNF1 proteins are
involved in the invasion of brain endothelial cells by E. coli
K1, ultimately leading to the uptake of E. coli into a vacuole
(116,128). An important aspect of transcytosis of meningeal
Scheld_Ch23.indd 347
347
pathogens is the ability of bacteria to avoid fusion of the vacu-
ole with lysosomes as demonstrated for E. coli K1 (129).
Interaction of bacterial adhesins with ECM proteins may
enhance invasion of meningeal pathogens. In vitro evidence
has been brought forward for the exploitation of the integrin
receptormediated mechanism of ECM protein internalization
by N. meningitidis and GBS (122,130). On the other hand, for
N. meningitidis, experimental evidence indicates that the for-
mation of cortical plaques, induced by microcolonies on brain
endothelial cells, and the ensuing reorganization of the intra-
cellular cytoskeleton lead to the opening of intercellular junc-
tions followed by paracellular penetration of the BBB (119).
Receptor-mediated signaling as well as local inflammation
with recruitment of leukocytes may further modify tight junc-
tions and allow bacteria to penetrate paracellularly (119,122).
Transcellular invasion of brain endothelial cells by L. mono-
cytogenes is thought to be mediated by InlA and InlB in similar
fashion as in the intestine and placenta, although conflicting
experimental evidence exists (123,131). Additionally, the ef-
fective intracellular trafficking of L. monocytogenes across the
BBB in phagocytic cells has been shown in a mouse model
(132,133).
In humans, invasion of the CSF by bacteria can occur in-
dependently of bacteremia. This happens typically when focal
infections occur in structures in immediate proximity to the
brain (e.g., otitis media, mastoiditis, sinusitis) or when the in-
tegrity of the skull and meninges surrounding the brain is dis-
rupted (e.g., malformations, trauma, neurosurgery). In a case
series of 87 patients with pneumococcal meningitis, more than
half of the patients had radiologic signs of otitis or sinusitis
(134), whereas in a larger observational study, otitis and si-
nusitis were reported as predisposing conditions in 25% of
patients (135). In a model of pneumococcal respiratory tract
infection, meningitis occurred without detectable bacteremia,
suggesting that pneumococci are able to invade the brain by
bypassing the bloodstream (136). Similarly, a galU mutant
and its parent pneumococcal strain both caused meningitis fol-
lowing otitis media infection in gerbils, despite the mutants
impaired ability to disseminate to the bloodstream following
infection (136).
For L. monocytogenes, S. pneumoniae, and N. meningitidis,
retrograde access to the CNS via the neural route has also been
documented (123,137,138). However, for L. monocytogenes,
this mechanism is likely only important in ruminants. These
observations support the notion that meningeal pathogens
can gain access to the subarachnoid space by several routes.
The relative importance of hematogenous versus nonhematog-
enous routes of infection in humans is not exactly known.
Meningeal Infections Associated with
Foreign Bodies
Pathogenesis of foreign bodyassociated meningeal infection
differs in several important aspects from bacterial meningitis
described earlier. First, at the time of foreign body insertion
and due to local tissue damage, access of bacterial pathogens
to the CSF space is facilitated. Second, bacteria may organize
on the foreign body in form of biofilm, thereby defying the
hosts immune system and systemically administered anti-
microbials. Finally, foreign body-associated meningitis fre-
quently brings forth only low-grade inflammation, with fever,
irritability, and shunt malfunction being the most prevalent
clinical findings (139,140). CSF shunt infections develop into
clinical ventriculitis or meningitis only in approximately 30%
of patients. In patients with hydrocephalus, CSF shunts con-
vey CSF from the lateral cerebral ventricles to the peritoneum
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 348 Part III: Bacterial and Mycoplasmal Infections
or right cardiac atrium or transiently to an external collec-
tion system. Shunt infection is one of the main complications
associated with CSF shunts. The reported incidence of CSF
shunt infection is in the range of 5% to 15% (141144),
with pediatric patients being more affected than adults (143).
Shunt infections occur primarily as an early postoperative
event, which manifests itself within a few days or weeks after
surgery (139,142,143). Due to the close association with the
operative procedure and the prevalence of bacteria belonging
to the skin flora, intraoperative inoculation is thought to be
the most likely cause of infection in early CSF shunt infection.
However, late shunt infections can occur several years after
implantation, likely due to hematogenous infection or associ-
ated with intraabdominal infection (139,143). Shunt coloniza-
tion with bloodborne pathogens such as H. influenzae or S.
pneumoniae has also been found, and one study reported five
cases of meningitis due to N. meningitidis, H. influenzae, and
S. pneumoniae out of a series of 289 patients with CSF shunt
followed for 10 years (145). Nevertheless, most shunt infec-
tions are caused by staphylococci, in particular S. epidermidis,
which causes half of all cases (143,144,146). The characteris-
tic feature of CSF shunt infection is the adherence of bacteria
to the inner surface of the shunt tubing. Insertion of a CSF
shunt leads to local inflammation and deposition of ECM pro-
teins, that is, fibronectin or fibrinogen, on the shunt surface
(147). Binding of ECM proteins via fibrinogen-binding pro-
tein (148), fibronectin-binding protein (149), and vitronectin-
binding proteins (150) enhances adherence of S. epidermidis
to the shunt surface. In an experimental model of catheter-
associated infection, presence of a foreign body reduced the
number of bacteria needed to establish infection (151). Once
attached to the shunt surface, S. epidermidis rapidly organizes
into a biofilm, characterized by bacteria embedded in a self-
generated polysaccharide matrix (152,153). Although shunt
infection does elicit an inflammatory response in the CNS
(154), staphylococci forming a biofilm are relatively protected
from the host immune defense mechanisms (151,155,156).
Additionally, bacteria organized in a biofilm have a greatly
increased resistance to systemic antimicrobial therapy. This
is likely due to the diversity of metabolic states of bacteria
inside the biofilm combined with the physical protection by
the extracellular polysaccharide matrix (153,157). Penetration
of most antimicrobials through the BBB does not suffice to
reach the necessary concentrations needed to kill bacteria in-
side a biofilm (158), therefore intraventricular administration
of antibiotics and shunt removal are frequently necessary to
treat CSF shunt infection.
The pathogenesis of Gram-negative CSF shunt infection
is not well understood. Retrograde infection in which bowel
perforation may lead to distal colonization of the shunt with
subsequent retrograde migration to the ventricles is frequently
suggested as the most likely mechanism for Gram-negative
shunt infections.
The several times higher risk of patients after cochlear
implantation to develop bacterial meningitis was first appreci-
ated in 2002. Depending on the type of cochlear implant used,
there was a 16 to 30 times higher incidence in bacterial menin-
gitis than in the general U.S. population (159). S. pneumoniae
accounted for 60% of the cases with known etiology (159).
Incidence of bacterial meningitis in this special population has
since then decreased, but it is still at least twice as high as in
the general population (160). Cochlear implants are designed
for people with profound bilateral sensorineural deafness in
whom the auditory nerves are intact but hearing aids are inef-
fective. In animal studies, the insertion of an electrode array
into the scala tympani reduced the number of bacteria needed
to induce meningitis in animals challenged with S. pneumoniae
Scheld_Ch23.indd 348
by the hematogenous or otogenic route, whereas sole cochle-
ostomy surgery did not (161). The exact impact of the foreign
body in this setting has not been elucidated. To reduce the
risk of postcochlear implantation meningitis, it is suggested
that patients are thoroughly evaluated for accompanying inner
ear malformations, which may increase the risk for CSF leaks,
and completion of their vaccination status. At surgery, mea-
sures should be taken to minimize communication between
the middle and inner ear, as this is thought to be the mode of
bacterial entrance in a sizable portion of meningitis cases in
patients with cochlear implant (162).
Bacterial Multiplication in the
Cerebrospinal Fluid
Host defense mechanisms in the CNS are tightly regulated.
Peripheral immune cells and plasma proteins are largely excluded
from the brain parenchyma by the BBB and BCSFB, and the
brain parenchyma additionally features anti-inflammatory
properties. Therefore, under physiologic conditions, microglia
and astrocytes provide basic immune functions in the brain (rec-
ognition of pathogen-associated molecular patterns [PAMPs],
initiation of inflammation), whereas peripheral leukocytes cross
the BBB only in low numbers and stick to the perivascular space
of CNS microvessels (163). In bacterial meningitis, the perivas-
cular space and the meninges are the interface where cellular
recognition of PAMPs and danger-associated molecular patterns
elicits a strong inflammatory reaction and leads to the recruit-
ment of peripheral immune cells to the CNS (164,165). In con-
trast to the peripheral blood, where cellular and soluble factors
of the innate immune system are present in abundance and may
act immediately on bacterial challenge, innate immune defense
in the perivascular and meningeal space needs to be scaled up
first (166,167). This delay in immune activation favors the sur-
vival of pathogens once they have reached the CSF. Bacteria can
multiply within the CSF almost as efficiently as in vitro (168),
reaching titers of up to 109 CFU/mL, spread over the entire sur-
face of the brain and spinal cord, and extend into the Virchow-
Robins space along penetrating vessels. Interestingly, presence
or absence of leukocytes in the CSF does not affect bacterial
multiplication in experimental meningitis models (169,170).
In contrast, the complement system has been found to be in-
strumental to the control of bacterial multiplication in the CSF,
supporting leukocyte influx, cytokine expression, and bacterial
phagocytosis (171,172). Consistent with this, negative outcome
in bacterial meningitis has been associated with depletion of
complement factors in the CSF (166,173).
Gene expression analyses of S. pneumoniae have shown
that, with exception of capsule genes, classical virulence genes
(i.e., encoding for pneumolysin, autolysin, and pyruvate oxi-
dase) are downregulated in the CSF (174176). In contrast,
upregulation of genes involved in amino acid acquisition/
synthesis and energy metabolism has been documented in
S. pneumoniae growing in CSF due to the scarcity of nutrients
in the CSF (175,176).
Induction of Inflammation
Autolysis or exposure of bacteria to lytic antibiotics in the CSF
leads to the release of subcapsular components (fragments of
cell wall, lipopolysaccharide, teichoic and lipoteichoic acid,
peptidoglycans, bacterial DNA, and other cytosolic factors)
that trigger the inflammatory response in the subarachnoid
space. Different cells from the tissues lining the CSF (epen-
dymal and endothelial cells, perivascular macrophages) and
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 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections
brain-resident cells (mostly microglia, but also astrocytes and
neuronal cells) are able to recognize these bacterial compo-
nents. Distinct and often overlapping sets of specialized extra-
cellular (i.e., TLRs) or intracellular (i.e., NOD-like receptors
[NLR]) receptors are used by these cells to sense the major
meningeal pathogens (177179). Genetic variations related to
these receptors are associated with negative outcome during
bacterial meningitis (180182). In response to bacterial stim-
uli, cells equipped with these specialized receptors produce
cytokines, chemokines, and other proinflammatory molecules,
leading to the recruitment of leukocytes to the site of infection
(183,184).
Cytokines and Chemokines
A large variety of cytokines and chemokines have been de-
tected in the brain parenchyma or the CSF during bacterial
meningitis in patients or in experimental models (185188).
The pattern of cyto-/chemokines produced in response to the
different meningeal pathogens has been shown to vary in in
vitro and in experimental infection models. These differences
are presumably related to pathogen-specific activation of pat-
tern recognition receptors (189192). They may contribute to
the differences in outcome observed in patients affected by the
different pathogens.
Early in the course of bacterial meningitis, tumor necrosis
factor- (TNF-), interleukin (IL)-1, and IL-6 are released,
which then trigger, often in synergy, a cascade of inflammatory
mediators, including other cytokines, chemokines, platelet-
activating factor (PAF), antimicrobial peptides, prostaglan-
dins, MMPs, NO, and ROS. The expression of TNF- and
IL-1 is detected first in the ependyma and the meninges and
later in the parenchyma in experimental meningitis (194).
Increased CSF concentrations of TNF-, IL-1, IL-6, IL-8,
and IL-10 are characteristic for bacterial meningitis. These cy-
tokines are predominantly proinflammatory with the excep-
tion of IL-10, which downmodulates the production of TNF-
and other proinflammatory cytokines (194196).
High concentrations of TNF- in CSF were detected
within 3 hours after injection of live H. influenzae in an
experimental meningitis model (197). Intracisternal injection
of S. pneumoniae led to a peak concentration of TNF- in CSF
approximately 12 to 24 hours after infection, with persistently
elevated levels for at least 24 hours (198,199). The sustained
TNF- activity in the CSF may be explained by continuous
stimulation by products released from bacteria in the CSF or
by a positive feedback loop in the inflammatory cascade (198).
TNF- leads to nuclear factor-B (NF-B) activation, which
regulates the expression of many proinflammatory genes (e.g.,
IL-1, TNF-, IL-6, IL-8, macrophage inflammatory protein-1,
inducible NO synthase [iNOS], cyclooxygenase-2, ICAM-1)
(200,201).
Administration of TNF- into the CSF results in patho-
physiologic changes characteristic of bacterial meningitis,
including BBB breakdown, neutrophil influx, and increase of
cerebral metabolism, oxygen consumption, and cerebral blood
flow (CBF), which in part are mediated through cyclooxygen-
ase activity (202207). Antibiotics cause rapid lysis of micro-
organisms and an associated brisk release of bacterial cell wall
products, resulting in significantly higher TNF- concentra-
tions in CSF shortly after initiation of antimicrobial therapy
(208,209).
The proinflammatory cytokine IL-1 is released by
mononuclear phagocytes, glial cells, and endothelial cells in
the CNS. Upon recognition of intracellular pathogens, the
precursors of IL-1 or IL-18 are activated by caspase-1 in
the inflammasome complex (179, 210212). IL-1 is present
Scheld_Ch23.indd 349
349
in CSF samples of patients with bacterial meningitis, and
its concentration is significantly correlated with inflamma-
tory parameters, TNF- concentrations, and adverse disease
outcomes (213). IL-1 appears in the CSF of rats as early
as 30 minutes after intracisternal injection of H. influenzae
lipooligosaccharide (214) and 6 to 12 hours after injection
of live S. pneumoniae in infant rats (199). When injected
directly into the CSF of rabbits, IL-1 triggers a meningeal
inflammation without detectable TNF- activity, suggesting
an independent mechanism of action, whereas simultaneous
administration of TNF- and IL-1 results in a synergistic
increase in leukocyte influx into the CSF. TNF- and IL-1
induce other secondary cytokines such as IL-6, IL-8, and
IL-10 (213).
IL-6 is produced by monocytes, endothelial cells, and
astrocytes, essentially in response to IL-1. IL-6 is present in
the CSF during meningitis later than TNF- and IL-1 and re-
mains present longer than the latter cytokines. Although IL-6
can be detected in the CSF of patients with bacterial menin-
gitis, its presence is not correlated with any of the indices of
meningeal inflammation or with severity of disease (215). IL-6
has a predominantly proinflammatory effect and is a potent
inducer of acute-phase proteins, fever, leukocytosis, and acti-
vation of the complement and clotting cascades (216). Some
antiinflammatory effects of IL-6 include inhibition of TNF-
and IL-1 production in vitro and induction of IL-1 recep-
tor antagonist (217). Accordingly, knockout mice lacking IL-6
display an increase in pleocytosis and in the inflammatory
response (218).
IL-8 (CXCL8) was the first identified member of a large
family of chemokines shown to regulate the migration of leu-
kocyte subsets toward the CNS during bacterial meningitis
(187). Similar to most chemokines, its primary action is to
activate and attract leukocytes, mainly neutrophils, to sites of
inflammation. Cells shown to produce IL-8 upon stimulation
with TNF, IL-1, or bacterial products include monocyte-mac-
rophages, neutrophils, endothelial cells, astrocytes, microg-
lia, and neurons. IL-8 is present in the CSF of patients with
bacterial meningitis (187) and enhances neutrophil adhesion
to endothelial cells, a prerequisite for the invasion of leu-
kocytes into the brain. Belonging to the same chemokine
subfamily as IL-8, the concentrations of CXC5 (ENA-78)
and CXCL-1 (GRO-) increase in the CSF of patients with
bacterial meningitis, inducing neutrophil chemotaxis (119).
To a lesser extent, another subfamily of chemokines, includ-
ing monocyte chemoattractant protein-1 (MCP-1, CCL2),
MIP-1 (CCL3), and MIP-1 (CCL3) is upregulated in the
CSF of patients with bacterial meningitis and attracts mono-
nuclear leukocytes (220).
IL-10 is an antiinflammatory cytokine that inhibits the
production of TNF-, IL-1, IL-6, and IL-8 in vitro and
attenuates brain edema during meningitis. High levels of
IL-10 have been found in the CSF of patients with bacte-
rial meningitis, and in rabbits with experimental meningi-
tis, administration of IL-10 downmodulated subarachnoid
space inflammation (221). In an experimental rat model of
pneumococcal meningitis, systemically, but not intrathe-
cally, administered IL-10 reduced CSF pleocytosis and the
concentration of proinflammatory cytokines (222). The in-
flammatory responses of IL-10 genedeficient and wild type
mice were compared in a mouse model of meningitis induced
by intranasal inoculation of S. pneumoniae. Although anti-
bacterial defense and survival were not influenced, the ab-
sence of IL-10 was associated with an increased immune
response, as reflected by a more pronounced inflammatory
subarachnoid infiltrate and higher concentrations of proin-
flammatory cytokines and chemokines in brain tissue (223).
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 350 Part III: Bacterial and Mycoplasmal Infections
In experimental neonatal E. coli meningitis in mice, IL-10
favors the immune response by increasing the phagocytic
activity of immune cells to clear the pathogen more rapidly
and reduce the inflammatory response (224). In addition to
IL-10, transforming growth factor- (TGF-) has also been
shown to have antiinflammatory properties in experimental
meningitis by reducing cerebral edema, intracranial pressure
(ICP), and CBF (225). Conversely, by specifically blocking
TGF- signaling on neutrophils and macrophages, neutrophil
influx and bacterial clearance were increased in experimental
pneumococcal meningitis, which resulted in less secondary
brain damage and improved survival (226).
Matrix Metalloproteinases and Related Proteases
The MMPs comprise endopeptidases that serve as effectors
of cell migration, tissue remodeling, and cytotoxicity by
degradation of ECM components. MMPs are synthesized as
inactive zymogens and can be activated by conformational
changes that disrupt a Zn2 binding cysteine switch. MMPs
not only function as effectors of tissue remodeling but
also interact with the cytokine network. Cytokines such as
TNF- , IL-1, and IL-2 modulate the expression and regula-
tion of MMPs. In return, MMPs and related metalloprotein-
ases can act as sheddases or convertases as they transform
membrane-bound cytokines, cytokine receptors, and adhe-
sion molecules to their soluble forms. TNF- converting
enzyme (TACE/ADAM-17) is a member of the ADAM (a
disintegrin and metalloproteinase) family of membrane pro-
teins and is a highly efficient sheddase of TNF- and TNF
receptors. These have an integral role in the network of
MMPs and cytokines (227).
Most MMPs are expressed only on demand through the
action of cytokines, eicosanoids, growth factors, and com-
ponents of infectious pathogens, among others. The most
prominent of these inducers are the proinflammatory cyto-
kines IL-1 and TNF-. MMP-2, in contrast to other MMPs,
lacks a classic promoter sequence and is constitutively ex-
pressed. Tissue inhibitors of metalloproteinases (TIMPs),
the specific endogenous inhibitors of MMPs, form com-
plexes with pro- and active forms of MMPs and inhibit the
enzymatic activity. Similar to MMPs, TIMPs are also regu-
lated by a network of different signaling molecules (228).
MMPs appear to play a central role in the development of
bacterial meningitis (e.g., breakdown of the BBB, intrathecal
production of cytokines, and accumulation of blood-derived
leukocytes in the CSF) (229,230). Levels of MMP-1, -3, -7,
-8, -9, and -10 have been found to be upregulated in the
CSF of patients with bacterial meningitis, whereas TIMP-1
and TIMP-2 may be slightly upregulated. Interestingly, in
the same patients, TIMP-4 was downregulated in the CSF
(231233). Immunohistochemical analysis of the brain tis-
sue of patients with purulent meningoencephalitis revealed
endothelial cells and infiltrating leukocytes with an increased
staining signal for MMP-9, TIMP-1, and TIMP-2 (234). CSF
levels of MMP-9 were significantly higher in those children
who developed neurologic sequelae than in those who re-
covered fully, thus identifying high CSF concentrations of
MMP-9 as a risk factor for the development of neuronal
damage (235).
Studies in a rat model of pneumococcal meningitis docu-
mented a 100-fold to 1,000-fold transcriptional induction of
MMP-3, -8, -9, -12, -13, and -14, but not of MMP-2 and -7,
in brain parenchymal tissue (198,236). In CSF cells, messen-
ger RNA (mRNA) of MMP-8 and -9 were 10-fold to 100-
fold increased, whereas MMP-2 and -7 remained at basal
levels (198). The cortical brain damage in this experimental
model is associated with changes in MMP-9/TIMP-1 ratio
Scheld_Ch23.indd 350
and an increase in collagen degradation (237). In experi-
mental meningitis, treatment with MMP inhibitors led to a
significant reduction of mortality and seizure incidence and
reduced the extent of cortical damage (236,238). In addi-
tion to this effect, combined inhibition of MMP and TACE
led to a reduction of hippocampal apoptosis and preserved
learning capacity of animals that recovered from bacterial
meningitis (198).
Neutrophil Invasion
Neutrophil migration into the CSF is a distinctive feature of
bacterial meningitis and contributes to the deleterious effects
of inflammation on the brain. In response to cytokines, che-
mokines, and other chemotactic stimuli, neutrophils penetrate
the microvascular basement membrane, leaving the blood-
stream to accumulate in the CSF, where they produce the pro-
found CSF pleocytosis characteristic of bacterial meningitis
(239241).
The entry of blood-derived neutrophils into the CSF is
facilitated by a cascade of events (Fig. 23.2). The initial step
in the adhesion cascade is the tethering and rolling of leu-
kocytes along the endothelium, which is mainly mediated by
the interaction of members of the selectin family and their
glycoprotein ligands (242,243). E-selectin and P-selectin,
upregulated on the endothelial cell surface in response to
proinflammatory stimuli, bind to P-selectin glycoprotein
ligand-1 and other glycosylated ligands (243). The rapid
formation and breakup of these bonds on the neutrophil sur-
face enable the rolling motion along the vessel wall (244).
Further, the hydrodynamic drag forces close to the vessel
wall induce the flattening of the rolling neutrophil. This re-
duces hydrodynamic drag and increases the area where se-
lectin-ligand bonds may be established (245). Consequently,
in mice deficient in P-selectin, partial reduction of neutro-
phil influx was observed after cytokine-mediated induction
of sterile meningitis, whereas mice deficient in P-selectin
and E-selectin showed almost complete inhibition of neu-
trophil influx in the same experimental model (246). The
polysaccharide fucoidin is a selectin blocker that inhibits
leukocyte rolling and subsequent leukocyte transendothe-
lial migration. Treatment with fucoidin intravenously has
been shown to attenuate the pleocytosis in experimental
pneumococcal meningitis (247249). Rolling of leukocytes
along a chemotactic gradient is followed by firm adhesion
to the endothelium. Halting of the rolling motion is induced
by the activation of integrins on the neutrophil surface by
chemokines (e.g., IL-8, C5a) (250). Activated leukocyte 1-
and 2-integrin (i.e., LFA-1) demonstrate higher affinity to
members of the immunoglobulin-like superfamily on the
endothelium, including ICAM-1 and vascular cell adhe-
sion molecule-1 (VCAM-1) (251). After firm adhesion to
the vessel wall, neutrophils crawl, mediated by a different
2-integrin (i.e., Mac-1), to a suitable transmigration site
(252). Transgenic deletion of ICAM-1 in a mouse model of
brain inflammation and trauma led to a significant reduc-
tion in the number of granulocytes infiltrating the brain tis-
sue (253). Also, antibody-mediated blocking of integrins or
ICAM-1 was shown to decrease leukocyte influx in experi-
mental meningitis models, confirming an important role for
these molecules in assisting leukocyte entry into inflamed
neural tissue (254256).
Finally, the transmigration of leukocytes across the BBB may
occur by the paracellular or transcellular route (243,257,258).
Intracellular signaling induced by the interaction of integ-
rins with their ligands leads to remodeling of endothelial cell
actin cytoskeleton and facilitates paracellular or transcellular
migration of leukocytes (257).
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 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections 351

Histologic examination shows that the exudate in acute bac-

TARGETS OF DAMAGE
IN MENINGITIS
Figure 23.3 shows the histopathology of experimental pneu-
mococcal meningitis and group B streptococcal meningitis.
Cerebral Vasculature
Very early in the pathogenesis of meningitis, the cerebral vas-
culature is at the center of processes that lead to the develop-
ment of meningitis and CNS damage. Processes at the level of
the cerebral vasculature include activation of endothelial cells
by inflammatory mediators produced during bacteremia, dis-
ruption of endothelial function by the traversal of meningeal
pathogens and inflammatory cells from the bloodstream into
the CSF, and involvement of the vasculature by the granulo-
cytic inflammation in the subarachnoid space. Important con-
sequences of these processes are the disruption of the BBB,
brain edema, loss of CBF autoregulation, and focal and global
changes of CBF resulting in cerebral ischemia.
Pathology
Subarachnoid space inflammation appears as a gray-yellow
to green exudate covering the base and convexities of the
brain with obvious involvement of cerebral arteries and veins.
terial meningitis consists predominantly of granulocytes,
whereas there is a mixture of lymphocytes, macrophages, and
granulocytes in subacute to chronic forms of meningitis (259).
Infiltration of vessel walls by these inflammatory cells, often in
a focal pattern, is observed. Inflammatory alteration of the ves-
sel wall is often associated with permanent thrombosis of the
vessel lumen and vascular occlusion (260). Vascular occlusion
may also occur in absence of local inflammatory infiltrate (261).
Vascular complications have been shown to be a frequent occur-
rence in children and adults with bacterial meningitis (262,263).
In fatal cases of neonatal meningitis, inflammatory vasculitis is
uniformly present, possibly indicating that the cerebral vascula-
ture of the neonate is particularly susceptible to inflammatory
damage (264). Some of the severe structural damage in the neo-
natal brain following meningitis may be related to this suscepti-
bility of the vasculature to inflammatory damage.
Disruption of the BloodBrain Barrier
Under physiologic condition, the BBB and BCSFB act as bar-
riers to the brain, selectively limiting the entry of macromol-
ecules and cells. Access of leukocytes to the CNS is therefore
tightly regulated, and in the healthy individual, only very few
leukocytes transmigrate the BBB and BCSFB (163). In men-
ingitis, however, the permeability of these brain barriers in-
creases as a result of functionally relevant alterations induced
by the disease process.

FIGURE 23.3 Histopathology of experimental pneumococcal meningitis (AD) and group B

streptococcal meningitis (E). A: Extensive cortical injury consisting of confluent areas of cortical
necrosis. Areas with markedly reduced neuronal density occur in a wedge-shaped distribution
(black arrowhead) suggestive of ischemic damage. The hippocampal dentate gyrus is also shown
(white arrowhead) (cresyl violet, magnification 10). B: Focus of cortical neuronal loss on the
right contains neurons with morphologic features of necrosis, including cell swelling and fading
of cytoarchitecture and is sharply demarcated from preserved neurons on the left (cresyl violet,
magnification 40). C: Subarachnoid space inflammation consisting of bacteria and inflamma-
tory cells extending into the Virchow-Robin space around the penetrating cortical vasculature.
D: Hippocampal dentate gyrus histology of an infant rat suffering from pneumococcal meningitis
at 42 hours after infection. Apoptotic cells are characterized by the presence of round or oval
apoptotic bodies consisting of two or more round, regularly shaped, dark chromatin clumps
(inset). The occurrence of apoptosis is characteristically observed in the inner rim (i.e., the sub-
granular zone) of the dentate gyrus (arrowheads) (cresyl violet, magnification 40). E: Dentate
gyrus of the hippocampus with a sharply demarkated (arrowheads) zone of injury containing
clustered cells with dense and shrunken nuclei demonstrating the appearance of uniformly pyk-
notic nuclei throughout the entire blade (lower right quadrant). (cresyl violet, magnification 40).

Scheld_Ch23.indd 351 2/21/14 5:41 PM

 352 Part III: Bacterial and Mycoplasmal Infections
In this respect, enhancement of BBB permeability due to
an increase in paracellular leakage has been particularly stud-
ied. Tight junctions and the corresponding intracellular actin
cytoskeleton are the most important components of the BBB
that regulate paracellular transport pathways. Remodeling of
the actin cytoskeleton, reorganization of tight junctions, and
enzymatic degradation of tight junctions and basement mem-
brane components may all lead to increased BBB permeability
(257,265). These changes are mediated by direct damage to
endothelial cells by the infecting pathogen, alterations induced
by signaling and effector molecules released during the inflam-
mation process, and changes induced by the interaction of in-
flammatory cells with the brain barriers.
In vitro cytotoxic damage to brain endothelial cells has
been seen with S. pneumoniae, mainly mediated by pneu-
molysin (266268), and N. meningitidis, mainly mediated
by NO (269). Pneumolysin was also shown to lead to as-
trocyte cytoskeleton remodeling in vitro (270), which might
also support BBB disruption. Nevertheless, the importance of
direct cytotoxic damage to the brain endothelial cells in vivo
is not known.
Different proinflammatory molecules produced by endo-
thelial cells, circulating leukocytes, microglia, or astrocytes
may induce disruption of the BBB (271). Some of the cyto-
kines that have been associated with disruption of the BBB
are TNF-, IFN-, IL-1, and IL-6 (218,272). Mechanisms disruption of the BBB leads to alterations in the brains micro-
by which cytokines may increase permeability of endothelial
tissue include rearrangement of cellular cytoskeleton and tight
junction organization, activation of metalloproteinases, and
increased generation of ROS. In vitro evidence for a direct
effect of TNF- and IFN- on the endothelial cytoskeleton
and intercellular tight junctions mainly stems from non-CNS
endothelial models (273), whereas direct effects on brain en-
dothelial cells are disputed (274276). A direct effect of IL-1
on BBB permeability via protein kinase C theta mediated phos-
phorylation of zona occludens-1 has been demonstrated (277).
MMP-3 and MMP-9 are, via NF-B upregulation, some
of the main downstream effector molecules in BBB disrup-
tion triggered by the cytokines TNF- and IL-1, but MMP-9
may also be activated by NO or MMP-3 (278). MMPs may
increase BBB permeability by breakdown of basement mem-
brane and tight junctions. Significantly increased CSF levels of
MMP-8 and MMP-9 have consistently been found in human
meningitis cases (230232,235). Further, in a rat model of
meningococcal meningitis, disruption of the BBB, increased
ICP, and CSF pleocytosis were paralleled by the occurrence of
MMP-9 activity in the CSF 6 hours after bacterial challenge
(229). Besides MMPs, ROS and NO have been identified in
experimental studies as key mediators in the pathophysiology
of bacterial meningitis (279282). Both molecular mediators
contribute to the development of increased ICP, BBB disrup-
tion, and CSF leukocytosis (283). Inhibition of the biologic
effects of ROS and NO by radical scavengers in experimental
meningitis prevented cerebral damage including BBB break-
down (279,282,284,285). There are several pathways by
which ROS and NO may induce BBB/BCSFB disruption. Cell
membrane dysfunction mediated by lipid peroxidation and
oxidative damage to cell membrane proteins, tight junction
and cytoskeletal reorganization, and MMP activation may
all contribute to BBB disruption (286). In clinical and experi-
mental studies, markers for lipid peroxidation were elevated
in the CSF in bacterial meningitis (287,288). Furthermore, in
experimental studies, pharmacologic inhibition of lipid perox-
idation reduced ICP and cerebral edema (289), whereas phar-
macologic ROS inhibition lowered the level of peroxidation
markers in the CSF (280,290). Vascular endothelial growth
factor (VEGF) is also involved in the disruption of the BBB
Scheld_Ch23.indd 352
in traumatic brain injury and multiple sclerosis (291,292).
Interestingly, experimental and clinical evidence does not sup-
port a role for VEGF in the disruption of the BBB in bacterial
meningitis (186,291,293).
Besides their chemoattractant properties, chemokines also
exert a direct effect on BBB permeability. For example, the
chemokines IL-8 and MCP-1 lead to cytoskeleton rearrange-
ments (294).
Massive neutrophil pleocytosis in the CSF space is a hall-
mark feature of bacterial meningitis (see previous discussion).
Both the paracellular and transcellular route are accepted for
the diapedesis of leukocytes across the BBB (257,258). The
effect of neutrophils on BBB permeability may be divided in
release of effector molecules like MMP-9 and ROS and direct
opening of paracellular pathways. Downstream signaling
induced by adhesion of leukocytes to ICAM-1 and VCAM
induces remodeling of the endothelial cytoskeleton and reor-
ganization of tight junctions, ultimately increasing paracellu-
lar permeability of the BBB (257).
As a result of the increased BBB permeability during menin-
gitis, molecules in the blood, including antibiotics, penetrate at
increased rates into the CSF. This facilitates therapy, because
the CSF/serum ratio of antibiotic concentration is often higher
than without inflammation (295). Other molecules penetrating
the BBB may, however, be harmful. It is hypothesized that the
environment that contribute to neuronal demise, for example,
by leading to higher concentrations of excitatory amino acids
(EAA) (see later discussion) and other potentially harmful
molecules present at high concentrations in the bloodstream.
Alterations of Cerebral Blood Flow
Bacterial meningitis is associated with marked changes in CBF.
Early in the course of the disease, an increase in blood flow is
observed, whereas in advanced meningitis, CBF is reduced
(262,279,280,296299). Focal changes in the vasculature, loss of
CBF autoregulation, ICP, and systemic hypotension may all lead
to perturbation of CBF in bacterial meningitis. Cerebrovascular
changes documented in patients with vascular complications in-
clude segmental narrowing of vessels and irregularities of vessel
walls (134,300). Additionally, arterial and venous thrombo-
ses are frequently documented (261,301). Vasculitis (301) and
vasospasms (299) likely explain segmental alteration of vessel
wall diameter in meningitis, whereas a procoagulable disposi-
tion caused by the bacterial infection may additionally explain
vascular thrombosis (261). The middle and anterior cerebral ar-
teries or the basilar artery are frequently affected during stroke
associated with bacterial meningitis (134,262). Sequelae are
most devastating when large vessels at the base of the brain are
affected, resulting, for example, in hemiparesis or quadriparesis
(264,302,303).
Impairment of CBF autoregulation has been documented
in bacterial meningitis, both in experimental models and in
clinical studies (279,298,299,304308). As a result of loss of
CBF autoregulation, systemic hypotension, which may arise in
patients with meningitis as a result of sepsis or severe dehydra-
tion, cannot be compensated and may lead to cerebral ischemia.
Conversely, systemic hypertension may then augment vaso-
genic edema and ICP. Elevated ICP has been associated with
an increase in CBF in experimental pneumococcal meningitis
(309,310). Ultimately, in the rigid framework provided by the
cranium, an excessive increase in ICP may limit CBF. Factors
leading to increased ICP in bacterial meningitis are cerebral
edema (see later discussion) and increased blood volume in the
brain resulting from hyperemia or from venous congestion pre-
cipitated by thrombotic occlusion of inflamed veins (304).
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 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections
In addition to global cerebral hypoperfusion, brain regions
with focal hypoperfusion caused by vasculitis of large and
small arteries traversing the inflamed subarachnoid space are
frequently observed. This form of vasculitis is thought to be
mainly responsible for ischemic damage leading to perma-
nent neurologic sequelae (Fig. 23.3A and B) (279,303). NO
plays a crucial albeit complex role in modulating CBF during
meningitis. In experimental models of bacterial meningitis,
inhibition of NO formation by a nonselective, competitive
inhibitor of NOS reduced the hyperemia observed early in
the disease (279,311,312). In more advanced disease, inhibi-
tion of iNOS significantly increased the extent of ischemia
and neuronal injury in the brain (296). These studies suggest
a dynamic role of NO at the level of the cerebral vascula-
ture during meningitis. Early in the disease, the vasodilatory
effect of NO contributes to the hyperemia induced by the
subarachnoid space inflammation. Later, when CBF progres-
sively declines under the influence of vasoconstrictive factors
(see later discussion), NO produced in the vasculature has
some protective effects against ischemia. Thus, attempts to
downmodulate NO production during meningitis are poten-
tially dangerous, despite the evidence that NO contributes to
some of the potentially harmful changes in bacterial menin-
gitis, such as CSF inflammation, brain edema, and ICP (see
later discussion).
ROS also play a critical role in modulating CBF during men-
ingitis (280,289,312,313). During the early phases of pneu-
mococcal meningitis in rats, scavenging of O2 and of H2O2
by superoxide dismutase and catalase prevented the develop-
ment of hyperemia and increased ICP (312,313). Generation
of ROS is localized primarily to the cells of the subarachnoid
and ventricular inflammation and to the cerebral vasculature,
as shown in infant rats with experimental meningitis (280).
The likely cellular sources of ROS include granulocytes,
endothelial cells, and activated microglial cells. Interestingly,
the cerebral vasculature shows evidence of marked oxidative
alterations during experimental pneumococcal meningitis in
infant rats, whereas oxidative damage to the brain paren-
chyma itself has not been yet documented conclusively (314).
The oxidative damage to the vasculature can be inhibited by
treatment with antioxidants. The same antioxidants have been
shown to reduce cerebral ischemic damage in these models
and prevent the decline in CBF (280,281). These data suggest
that the cerebral vasculature is exposed to significant oxida-
tive stress during meningitis, which in turn contributes to CBF
reduction and cerebral ischemia.
NO and ROS can chemically react and form peroxyni-
trite, which is a strong oxidant that exerts cytotoxic effects
(283,315). In addition, the reaction leads to the loss of the
vasodilatory biologic effect of NO. Nitrotyrosine residues on
proteins as a marker for the presence of peroxynitrite were
detected in the meninges, the cortical blood vessels penetrating
the subarachnoid space, and inflammatory cells in the brains
of patients with bacterial meningitis and corresponding ani-
mal models (283,316). Furthermore, pretreatment with the
peroxynitrite scavenger urate attenuated meningeal inflamma-
tion, BBB disruption, and intracranial hypertension (316).
Endothelins, potent vasoconstrictor peptides produced in
the CNS by vascular endothelial cells, astrocytes, and neurons,
are also involved in CBF dysregulation. Increased endothelin
levels are found in the CSF of patients with bacterial men-
ingitis (317). Endothelin synthesis is triggered by cytokines,
that is, TNF- (318320), and inhibited by NO (321). In
experimental pneumococcal meningitis, therapy with an endo-
thelin antagonist significantly prevented the reduction of CBF
induced by the infection and concomitantly reduced the extent
of cerebral ischemia (322).
Scheld_Ch23.indd 353
353
Inner Ear
Unilateral or bilateral hearing impairment is the most com-
mon neurologic sequelae following bacterial meningitis and is
found in 5% to 30% of survivors (323326). S. pneumoniae
meningitis is associated with the highest risk of developing
sensorineural hearing loss (327330). Onset of hearing loss
during bacterial meningitis is progressive rather than abrupt
and the magnitude of hearing loss is related to the duration
of untreated infection (324). Hearing loss consecutive to bac-
terial meningitis can be transient or permanent. Studies in
models of meningitis indicate that hearing loss is the result of
direct involvement of the inner ear by the inflammation dur-
ing the acute phase of the disease. However, no close correla-
tion could be found between the extent of hearing loss and the
magnitude of CSF pleocytosis or CSF bacterial concentrations
(324). Magnetic resonance imaging (MRI) studies in humans
with meningitis have documented inflammatory involvement
of the inner ear, suggesting that the animal models reflect the
clinical situation (331). In survivors of meningitis, progressive
cochlear ossification and spiral ganglion loss is observed years
after the disease (332,333).
Pathology
During the acute stage of meningitis, suppurative labyrinthitis
is a common feature observed in the human temporal bone
of patients with bacterial meningitis, often accompanied by
pus in the perilymphatic duct (334). Similarly, histopathologic
examination of the temporal bone from rats with bacterial men-
ingitis showed a dense inflammatory cell infiltrate throughout
the subarachnoid space extending to the inner ear. Studies in
experimental meningitis revealed that in the earliest stages of
pneumococcal infection, bacteria and inflammatory cells are
already present within the cochlea (335,336). Inflammation
in the inner ear is primarily confined to the perilymphatic
space (scala tympani) (337,338). Inflammatory infiltration
of the cochlea was shown to progress via the cochlear aque-
duct to the perilymphatic space and via the spiral ligament to
the endolymphatic space during experimental pneumococcal
meningitis (336). During this phase, which is characterized by
high inflammation, damage to the bloodlabyrinth barrier, the
hair cells, and the spiral ganglion is observed (339). Damage
begins at the base of the cochlea and progresses to the apex,
corresponding to hearing loss first at high then at low frequen-
cies. Studies in experimental meningitis caused by E. coli and
S. pneumoniae revealed that both pathogens invaded the scala
tympani and triggered the development of lesions including
craters in the apical surface of inner supporting cells and dis-
ruption of the inner hair cell stereocilia. Pneumococcal men-
ingitis produced more pronounced lesions and induced breaks
in the junctions between inner hair cells and their adjacent
supporting cells, as well as ballooning and rupture of the api-
cal surface of outer hair cells (340). Spiral ganglion neuronal
loss is observed later than the first signs of hair cell damage
and hearing loss. In the early stage of inflammation, hearing
threshold changes are associated with nonlethal structural
changes in cochlear hair cells and are potentially reversible.
Conversely, in more advanced experimental infection, irrepa-
rable ultrastructural inner ear damage, especially the loss of
spiral ganglion neuronal cells, is associated with severe to pro-
found deafness (335,341).The more severe cochlear lesions
induced by S. pneumoniae may explain the higher incidence
of deafness after pneumococcal meningitis. Toxic effects of
the meningeal pathogen (e.g., pneumolysin from S. pneu-
moniae [342]) and inflammatory mediators appear to be
responsible for the cytopathic effects (340,343). In particular,
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 354 Part III: Bacterial and Mycoplasmal Infections
the production of ROS seems to be crucial for the pathogen-
esis of cochlear damage and hearing loss in bacterial meningi-
tis (339). Inducible and endothelial NO synthase expression
and tyrosine nitration have been documented in the cochlea
of rats with pneumococcal meningitis (344). Treatment with
peroxynitrite scavengers or antioxidants resulted in reduced
hearing loss and protection of spiral ganglion neuronal cells
(345,346). Upon microperfusion in cochleas, NO donors have
been demonstrated to damage hair cells and supporting neu-
ronal cells (347,348). Furthermore, in vitro, exposure to NO
causes irreversible morphologic changes in isolated outer hair
cells (349). A direct neurotoxic effect of ROS on hair cells
or spiral ganglion cells seems therefore plausible, but other
possible points of action may also exist, like damage to the
bloodlabyrinth barrier (339).
Damage to the cochlea and hearing loss is prevented
by antioxidants or NO synthase inhibitors in experimen-
tal studies (344346). Similarly, strategies to limit the host
inflammatory reaction by using doxycycline (350) or non-
lytic antibiotics (351) are promising adjuvant therapies
reducing sensorineural hearing loss. Conflicting results have
been published concerning the use of dexamethasone in both
experimental and clinical studies. Whereas some experimen-
tal models showed an improvement in hearing capacity by
dexamethasone (352354), others did not (355). Similarly,
the beneficial use of dexamethasone in clinical practice is
inconsistent (356360) and may differ depending on the
causative agent, the age of the patient, comorbidity, and
socioeconomic factors.
Central Nervous Tissue
Neurologic Sequelae
Apart from the high mortality, bacterial meningitis often
causes brain damage of both cortical and subcortical struc-
tures. The neurologic sequelae resulting from brain damage
include hearing impairment (see previous discussion), obstruc-
tive hydrocephalus, and damage to the brain parenchyma
with focal sensorimotor deficits, mental retardation, seizure
disorders, and cortical blindness. In a meta-analysis, hearing
loss was the most frequent sequelae, almost three times more
frequent than seizures and motor deficits, respectively (323).
Less frequent were cognitive impairment, hydrocephalus, and
visual disturbance. Any sequelae after discharge was present
in 19.9% of patients with bacterial meningitis. The risk for a
major sequelae after bacterial meningitis (i.e., cognitive deficit,
bilateral hearing loss, motor deficit, seizures, visual impair-
ment, hydrocephalus) was at least twice as high in African
and Asian countries compared to European countries (323).
Bacterial meningitis caused by S. pneumoniae has consistently
been associated with higher rates of disabilities than infection
with H. influenzae or N. meningitidis (135,323,361). Lately,
behavioral and cognitive sequelae in children and adults after
bacterial meningitis have been increasingly and accurately ap-
preciated (362367). This is of special concern in childhood
meningitis, as it was shown that neurologic sequelae of child-
hood meningitis may persist for more than 10 years, thus im-
pairing learning during the entire time children attend school
(363,365,368,369). In adults tested 0.5 to 13.5 years after
acute bacterial meningitis, 32% of 155 meningitis survivors
suffered from relevant impairment of psychomotor perfor-
mance, speed of cognitive processes, and concentration and
memory functions (366). Overall, these studies emphasize the
substantial neurologic damage and functional impairment re-
sulting from bacterial meningitis in children and adults.
Scheld_Ch23.indd 354
Pathology
The neuropathology of bacterial meningitis includes subarach-
noid space inflammation, inflammatory involvement of the
cerebral vasculature (see previous discussion), and evidence
of parenchymal brain damage. Damage to the brain paren-
chyma is evidenced by the presence of brain edema, including
signs of cerebral herniation (see later discussion), by areas of
cerebral infarction resulting from ischemia, and by histologic
changes (370374). The latter show loss of neurons, often in
a focal pattern (Fig. 23.3A and B), which is most prominent in
patients who survive acute meningitis for several days before
succumbing to the disease. MRI performed on newborn or
children affected by bacterial meningitis showed infarctions
in the frontal, temporal, and parietal lobes; the basal gan-
glia; and the thalamus, as well as periventricular white mat-
ter injuries, leading to cerebral atrophy and hydrocephalus
(263,375377). In adult patients with bacterial meningitis,
the temporal lobe and the limbic system also displayed struc-
tural changes (367). Neuronal loss is associated with a marked
reaction of astrocytes and microglia (378) as well as axonal
injury (379,380). Furthermore, meningitis induced by Gram-
negative bacteria is often characterized by the development of
brain abscesses (381,382).
In the dentate gyrus of the hippocampus, special forms of
cell death have been observed during meningitis (280,383,384)
(Fig. 23.3D and E). The first form of injury is defined as apop-
tosis based on morphologic criteria in cresyl violetstained
brain sections (condensed, fragmented nuclei) (Fig. 23.3D,
inset) and the detection of fragmented DNA (i.e., TUNEL
stain) (385). Furthermore, activated caspase-3, an effector cas-
pase that is responsible for executing the cell death program,
has been documented in apoptotic neurons of the hippocam-
pal dentate gyrus in experimental meningitis (384,385). The
specific role of caspase-3 in this form of neuronal apoptosis
was documented in infant rats with pneumococcal meningitis,
where enzymatic caspase-3 activity was significantly increased
and intracisternal administration of the caspase-3specific
inhibitor Ac-DEVD-CHO significantly reduced apoptosis
in the hippocampus of infected animals (385). In a different
approach, caspase-3 activation and hippocampal damage was
prevented by treatment with a pan-caspase inhibitor, which
exhibits antiinflammatory activity through blocking of inter-
leukin-converting enzyme (386).
The apoptotic injury in the hippocampus is of particular
significance because experimental data suggest that it is related
to learning impairment following meningitis (198,387,388).
Such an association is also supported by the observation that
activated caspase-3 and morphologic evidence of apoptosis is
primarily localized to immature progenitor cells in the subgran-
ular zone of the dentate gyrus, cells that have been implicated
in the acquisition of new memory (384,385,389). Damage
to the dentate gyrus of the hippocampus may thus represent
an anatomic substrate for cognitive impairment and learning
disabilities following meningitis (198,387,388,390). As a con-
sequence of apoptotic damage, hippocampal neurogenesis is
impaired after bacterial meningitis (391). Furthermore, hip-
pocampal cell death associated with inflammatory conditions
results in a dysregulation of hippocampal neurogenesis, with a
transient increase in cell proliferation (392394) and changes
in the transcriptional profile in the stem cell population of the
dentate gyrus (i.e., the neurogenic niche) (395).
Confirming the findings in animal models, brain sections
of 20 patients who died from bacterial meningitis showed
apoptotic neurons with immunoreactivity for precursor and
active forms of caspase-3 in the dentate gyrus (396). In a study
in patients surviving meningitis, volumetric measurements
of the hippocampus by MRI techniques showed unilateral
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 Chapter 23: Pathogenesis and Pathophysiology of Bacterial Infections
and bilateral hippocampal atrophy, potentially reflecting the
apoptotic loss of neurons observed by histopathology (397).
Furthermore, cell proliferation in the hippocampus was also
found to be dysregulated in human patients who succumb to
bacterial meningitis (398).
The second form of hippocampal neuronal damage is
characterized morphologically by uniformly shrunken nuclei,
forming clusters of damaged cells predominantly in the lower
blade of the dentate gyrus, spanning the entire width of the
dentate gyrus band (Fig. 23.3E). This form of hippocampal
damage is the preferential pattern of neuronal injury observed
in experimental meningitis caused by GBS (280,384). Criteria
for classical apoptosis, such as formation of apoptotic bodies
and positive staining for activated caspase-3, as well as mor-
phologic criteria for necrosis, for example, cell swelling, loss
of cellular structures, are absent (384). However, this form of
neuronal injury may be linked to apoptosis-inducing factor
(AIF) (399,400), more reminiscent of ischemia-related neuro-
nal damage (401). Therefore, both forms of damage may be
temporally distinct and caused by distinct mediators (402).
Brain Edema and Cerebral Herniation
The development of cerebral edema is a hallmark of the ce-
rebral involvement during meningitis (403). Cerebral edema
may be classified as vasogenic, cytotoxic, interstitial, or
osmotic (404). Cerebral edema in bacterial meningitis may be
a combination of all four forms. Vasogenic cerebral edema is
primarily a consequence of increased BBB permeability, which
leads to extravasation of plasma proteins into the brain pa-
renchyma (see earlier discussion) and mainly affects the white
matter (404). Cytotoxic edema results from an increase in
intracellular water following intracellular accumulation of
osmotically effective ions (i.e., sodium, potassium, or gluta-
mate). Cytotoxic mechanisms include ischemia and the effect
of EAAs (404406). Cytotoxic edema affects gray and white
matter in the brain. Interstitial edema occurs by an increased
influx of CSF across the ventricular ependyma into the peri-
ventricular white matter, either through increased CSF produc-
tion (increased blood flow in the choroid plexus) or decreased
resorption secondary to increased CSF outflow resistance
across the arachnoid villi system of the sagittal sinus (407). In
obstructive hydrocephalus after meningitis, chronic interstitial
edema may lead to destruction of brain tissue (408). Osmotic
edema might be caused by inappropriate secretion of antidi-
uretic hormone during the course of bacterial meningitis. The
observed hypoosmolality of serum results in a net influx of
water into the brain (404,409).
Brain edema contributes substantially to the acute fatal
outcome of bacterial meningitis (134,410,411). The major
dangers of extensive brain edema during meningitis are herni-
ation of brain tissue and compression of the brainstem due to
increased ICP, which can cause complete cessation of cerebral
circulation. But increased ICP alone may compromise cerebral
perfusion and lead to ischemia. In addition to brain edema
itself, other factors associated with bacterial meningitis can
contribute to excessive intracerebral hypertension, including
the development of obstructive hydrocephalus, meningitis-
associated cerebritis, cerebral infarction, cerebral venous
thrombosis, and status epilepticus (412,413).
Impaired regulation of water transport underlies the patho-
physiology of brain edema. Aquaporins (AQP) are pore-form-
ing membrane proteins ubiquitously present in living organisms
(414). AQP-1, AQP-4, and AQP-9 have been documented in
the primate brain and are involved in water homeostasis of
the brain (415). The major aquaporin in the brain, AQP-4,
shows contradictory effects in several forms of brain edema. In
cytotoxic edema, AQP-4 was shown to support brain edema
Scheld_Ch23.indd 355
355
formation by increasing transcellular influx of water across
the BBB, whereas in vasogenic and interstitial brain edema,
lack of AQP-4 leads to more severe brain edema by limiting
outflow of CSF (404,416). In a mouse model of pneumococ-
cal meningitis, AQP-4 was significantly upregulated and as-
sociated with increased cytotoxic brain edema (417). AQP-4
upregulation was also found in the brain of a patient with
bacterial meningitis (418), but not in the CSF of patients with
bacterial meningitis (419).
Severe brain edema results in a caudal shift of midline struc-
tures, leading to their entrapment in the tentorial notch or fo-
ramen magnum. The most common type of brain herniation
occurs when a portion of the temporal lobe is displaced (uncal
herniation), which compresses cranial nerve III, the midbrain,
and the posterior cerebral artery, leading to coma and respi-
ratory arrest. Caudal shifts produce herniation of the para-
hippocampal gyri and/or cerebellum, which occurs when part
of the cerebellum is displaced through the foramen magnum.
These intracranial processes are manifested clinically in altered
consciousness and postural reflexes. Caudal displacement
of the brainstem causes palsy of the third and sixth cranial
nerves. Ultimately, these changes can result in decortication or
decerebration with rapid progression to respiratory and car-
diac arrest. Cerebral herniation is occasionally precipitated by
lumbar puncture in the setting of brain edema and increased
ICP. The highest risk for cerebral herniation is in patients in
whom there is a focal brain lesion leading to midline shift and
intracranial hypertension. In these patients, performance of a
lumbar puncture is contraindicated (420).
Factors other than brain edema and intracranial hyperten-
sion that may lead to acute death from bacterial meningitis
include extensive cerebral infarction resulting from vasculitis
and coagulation disturbances and/or circulatory failure result-
ing from septic shock (421).
Mediators of Cell Death in Neuronal Tissue
EAAs including glutamate have been proposed as mediators
of brain damage by inducing either apoptosis or necrosis and
appear to mediate neuronal injury in a variety of brain disor-
ders. In ischemia, the best studied example of EAA-mediated
injury, increased concentrations of EAA in the brain intersti-
tial fluid result from an increased release by ischemic neurons
and reduced uptake by glial cells (422). Studies in experimen-
tal models of bacterial meningitis and inference from clinical
studies point to ischemia and EAA as likely mediators of direct
neuronal toxicity (378,406).
A role for EAA in mediating neuronal injury in meningi-
tis is supported by the following evidence. Glutamate con-
centrations in the CSF of patients with bacterial meningitis
were significantly elevated compared to those in patients with
viral meningitis and noninflammatory neurologic diseases
and correlated with the severity of the disease as scored by
the Glasgow Coma Scale (423,424). In a rabbit model, gluta-
mate concentrations in the brain interstitial fluid, as measured
by microdialysis probes, were significantly increased in pneu-
mococcal meningitis (424). The source of the increased EAA
concentrations in the brain during meningitis has not been
identified but may be related to BBB disruption. Furthermore,
in an infant rat model of neonatal meningitis, kynurenic acid,
a nonselective inhibitor of the neurotoxic effect of EAA,
significantly attenuated brain injury, both in the cortex and
in the hippocampus (378,406). However, adjuvant treat-
ment with dextromethorphan, a noncompetitive N-methyl-
d-aspartate (NMDA) receptor antagonist, was found to
aggravate hippocampal apoptosis in the infant rat model of
pneumococcal meningitis (425). Furthermore, accumula-
tion of endogenous kynurenic acid by combined inhibition
2/21/14 5:41 PM
 356 Part III: Bacterial and Mycoplasmal Infections
of kynurenine 3-hydroxylase and kynurenine kinase resulted
in an aggravation of apoptotic neuronal death in the hippo-
campal dentate gyrus in the same experimental model; in this
case, nicotinamide adenine dinucleotide depletion, observed as
a result of the intervention, may have caused an energy failure
responsible for the increase in apoptosis (426).
Inflammatory factors such as cytokines, metalloproteinases,
and ROS are produced by leukocytes, monocytes, and microg-
lia as a result of the host immune response. The intensity and
duration of this response are responsible for the development
of neuronal damage. Reducing the intensity by the use of anti-
inflammatory corticosteroids or nonlytic antibiotics may be a
therapeutic option (427). Some pathogens have been shown
to interfere with the activation-induced cell death of immune
cells, possibly prolonging in a detrimental way the extent of
inflammation. For example, N. meningitidis inhibits apopto-
sis in neutrophils (428) or macrophages (429). Similarly, GBS
interfere with TLR-2mediated activation-induced cell death
in macrophages and microglia (430). Therefore, modulating
the lifespan of the cells producing neurotoxic factors may be a
beneficial treatment during bacterial meningitis (431). Because
neutrophils produce different presumably neurotoxic factors
(cytokines, metalloproteinases, ROS), often modulating each
other, it is difficult to determine which really directly triggers
neuronal cell death (432).
The marked increase in ROS production during certain
pathologic conditions, such as during acute and chronic
inflammation, ischemia/reperfusion, or trauma, can lead
to oxidative cell and tissue injury. The brain is believed to
be particularly vulnerable to oxidative damage because
of its high concentrations of unsaturated fatty acids, high
rate of oxygen consumption, and relatively low concentra-
tions of antioxidants (433). Compatible with an important
role of ROS in experimental meningitis, the use of radical
scavengers prevented BBB breakdown, attenuated lipid per-
oxidation and ischemia in the brain parenchyma, and pro-
tected neurons from injury in experimental meningitis models
(434). Furthermore, the neurotoxic effect of EAAs has been
shown to involve ROS (435). Despite these observations, a di-
rect neurotoxic effect of ROS in the brain parenchyma during
meningitis has been difficult to document conclusively. In the
infant rat model of pneumococcal meningitis, there was only
a moderate loss of soluble antioxidants (ascorbate, glutathi-
one) in the brain parenchyma and CSF and no evidence for in-
duction of antioxidant defenses (290). Furthermore, most of
the beneficial effects of ROS scavengers in experimental men-
ingitis are compatible with a beneficial effect primarily at the
level of the cerebral vasculature (314) (see previous discus-
sion). In the same model, marked loss of adenosine triphos-
phate in the brain parenchyma was positively correlated with
the extent of neuronal injury (436). Oxidative alterations of
cerebral vasculature and subsequent reduction of CBF leading
to cerebral ischemia are plausible mechanisms for neuronal
damage during meningitis.
Theoretically, NO may act as a neuroprotective or neu-
rotoxic molecule in meningitis depending on its redox state;
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ACKNOWLEDGMENTS
This work was supported in part by grant no. 138094 (to SLL)
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2/21/14 5:41 PM
 CHAPTER 24 ACUTE BACTERIAL MENINGITIS
KAREN L. ROOS, ALLAN R. TUNKEL, DIEDERIK VAN DE BEEK, AND W. MICHAEL SCHELD
The meningitis syndrome has been recognized for centu-
ries. Hippocrates realized the important intracranial conse-
quences of otitic infection, and clear clinical descriptions of
meningitis have been found dating from the sixteenth cen-
tury. However, the syndrome of epidemic meningitis with a
purpuric rash was not identified until 1805, when Viesseux
wrote about an epidemic of malignant purpuric fever sur-
rounding Geneva, Switzerland, the first clinical description of
meningococcemia with meningitis. The pathologic hallmark
of the condition, inflammation within the subarachnoid space
(SAS), was described in autopsy reports in the French liter-
ature the following year. Danielson and Mann (1) recorded
the first observations of meningococcemia and meningitis in
the United States in 1806. Many of these early descriptions
were collated in a treatise by Elisha North of Connecticut in
1811 and summarized in references 1 and 2. Then, as now,
the disease could present dramatically in a fulminant form.
The epidemic nature of meningococcemia was frightening to
physicians and lay persons alike. For example, Dr. Samuel
Woodward, of Torrington, Connecticut, wrote the following
in The American Mercury, Hartford, in 1807:
The violent symptoms were great lassitude, with universal pains in
the muscles, chills; heats, if any, were of short duration; unusual
prostration of strength; delirium, with severe pain in the head;
vomiting, with indescribable anxiety of stomach; eyes red and
watery, and rolled up, and the head drawn back with spasm; pulse
quick, weak, and irregular; petechiae and vibices all over the body,
and a cadaverous countenance and smell; death often closed the
scene in ten or fifteen hours after the first attack . . . the body, near
the fatal period, and soon after, became as spotted as an adder. . . .
Similarly, the following was written by the Reverend Festus
Foster of Petersham, Massachusetts, as a letter to the editor of
The Worcester Spy, dated March 6, 1810:
I hasten to give you a sketch of the spotted fever in this place.
It made its first appearance about the beginning of January last;
but the instances were few and distant from each other, until last
week. Although it had proved fatal in most instances, seven only
had died belonging to this town, previous to the 25th of February.
Since that time the disorder has come upon us like a flood of
mighty waters. We have buried eight persons within the last eight
days. About twelve or fifteen new cases appeared on Thursday last;
many of them very sudden and violent. This was the most melan-
choly and alarming day ever witnessed in this place. Seven or eight
physicians were continually engaged in the neighborhood north of
the meeting house, and I believe not one half hour passed in the
forenoon without presenting a new case. Pale fear and extreme
anxiety were visible in every countenance. . . .
It is inconceivable that this fulminant form of meningococ-
cemia had been previously unrecognized, especially given the
excellent clinical descriptions of rashes in the literature from
the period. One must speculate that the virulence of menin-
gococci for humans changed in the early nineteenth century.
Meningococci were first isolated in 1887 by Anton
Weichselbaum in Vienna; they were obtained from the cerebro-
spinal fluid (CSF) of six patients with meningitis and were ini-
tially named Diplococcus intracellularis meningitidis. All three
of the major meningeal pathogens (Neisseria meningitidis,
Streptococcus pneumoniae, and Haemophilus influenzae) were
Scheld_Ch24.indd 365
isolated and described in the last two decades of the nineteenth
century. Quincke introduced lumbar puncture (LP) in 1891,
and the major CSF alterations associated with meningitis
(pleocytosis, hypoglycorrhachia, and elevated protein concen-
tration) were well recognized by the turn of the century.
The treatment of bacterial meningitis in the early years of
this century was dominated by methods for removal of large
volumes of CSF and/or direct instillation of substances (e.g.,
dyes, enzymes) into the SAS. After early leads from European
investigators, the first truly significant therapeutic modality
for this disorder on a large scale, the systemic and intrathecal
administration of antimeningococcal antisera raised in horses,
was documented by Simon Flexner in 1913. Though toxic,
antisera therapy reduced the mortality of meningococcal men-
ingitis (from approximately 80% to 30%) during World War
I and for decades thereafter. The principles of serum therapy
were applied by Dr. Hattie Alexander and others to meningitis
caused by H. influenzae in the 1940s.
The approach to the patient with bacterial meningitis was
profoundly altered by the advent of antimicrobial therapy. The
first successful account of the therapy of meningococcal men-
ingitis with an antimicrobial agent in this country was pub-
lished by Schwentker et al. (3) in 1937; nine patients survived
after receiving subcutaneous and intraspinal injections of sul-
fanilamide, and the sole death occurred after eradication of the
organism from CSF. The introduction of penicillin and other
antimicrobial agents (e.g., streptomycin and chloramphenicol)
ushered in the modern antimicrobial era, likened to an indus-
trial revolution (4). These developments led to the widespread
belief that serious bacterial infections were solved. Despite
the introduction of myriad new antimicrobial agents and the
development of newer diagnostic techniques, the mortality
from meningitis caused by the three major bacterial patho-
gens has not changed appreciably in the last four decades.
However, the use of the third-generation cephalosporins dur-
ing the 1980s for therapy of gram-negative aerobic bacillary
meningitis has substantially reduced the mortality of this con-
dition. Recent years have revealed an explosion of new knowl-
edge on the pathogenesis and pathophysiology of bacterial
meningitis (see later discussion), with attendant ramifications
on the use of adjunctive therapy (e.g., corticosteroids, nonste-
roidal antiinflammatory agents, and monoclonal antibodies)
for this disease.
EPIDEMIOLOGY
During 2003 to 2007, approximately 4,100 cases of bacte-
rial meningitis occurred annually in the United States (5), but
this disease is much more common in developing countries
(see later discussion). In addition, the relative frequency with
which each of the various bacterial species causes meningitis
is age related. Gram-negative bacilli (principally Escherichia
coli K1), group B streptococci, other enteric bacilli, and much
less commonly, Pseudomonas species are the major causative
agents during the neonatal period. Meningitis in children and
adults is primarily caused by meningococci and pneumococci,
365
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 366 Part III: Bacterial and Mycoplasmal Infections
although disease caused by aerobic gram-negative bacilli is in-
creasing in frequency, especially in the elderly. N. meningitidis
is the only major cause of epidemics of bacterial meningitis.
The development of meningitis depends on a complex array
of factors, including virulence properties of the organisms, the
carrier state, and the hosts humoral immune response. These
factors differ among the major pathogens, for which reason epi-
demiology, carrier state, and host immunity are considered sepa-
rately for each of the three major etiologic agents in this section.
The classification of the pathogens, putative virulence fac-
tors, and the clinical settings associated with less prevalent
agents are discussed later (see the section Etiology, later in
this chapter).
Haemophilus influenzae
H. influenzae type b (Hib) was previously the leading cause of
bacterial meningitis in the United States but now accounts for
only approximately 7% of cases (5). Meningitis caused by Hib
displays an interesting bimodal seasonal pattern in northern
Europe and the northern United States, with peaks in June and
September through November (6,7).
The overall annual incidence of serious Hib disease dif-
fers between geographic locales and among populations.
Significant interannual variations in the incidence of meningi-
tis caused by Hib have also been reported within a single geo-
graphic area over time (8). This is an important consideration
in assessing the efficacy of Hib vaccines. Before the advent of
conjugate vaccines (see later discussion), the overall rate of
Hib meningitis in the United States was approximately 60 per
100,000 children younger than 5 years of age (9), greater than
the figures from other countries in northern Europe. These
incidence rates differ markedly among age-groups (see later
discussion) and in children younger than 6 years. In a 3-year
nationwide prospective study on pediatric meningitis in Israel,
the incidence of Hib meningitis during the first year of life was
67.1 per 100,000, and in children younger than 5 years of age,
it was 18.5 per 100,000 (10). Some studies report a higher
incidence in nonwhites (7,11). For example, the incidence rate
for Hib meningitis for the total population of Washington
State was 2.2, 3.4, and 13.5 per 100,000 for whites, blacks,
and Native Americans, respectively (11). In contrast, others
have found no differences between rates for blacks and whites
younger than 1 year of age (12).
Before the availability of the current Hib vaccines, 1 in
every 200 children developed invasive Hib disease by 5 years
of age. Meningitis caused by Hib in the first 2 months of life
is rare, presumably because of placental transfer of protective
concentrations of maternal bactericidal antibody. Most cases
occur between 4 months and 2 years of age. The highest rate
of illness occurs in children 6 to 17 months of age; children
older than 2 years of age have a lower incidence (6,8,9,1117).
Approximately 80% of cases develop in unvaccinated children
younger than 2 years of age in this country, but this propor-
tion varies by geographic locale. The proportion of cases is ap-
proximately 20% lower in this age-group in northern European
countries. These differences in age distribution may directly
influence the efficacy of candidate Hib vaccines. Nontypeable
strains of H. influenzae are commonly carried in the nasophar-
ynx of asymptomatic individuals. Carriage of encapsulated
strains (usually type b) is rare: rates are less than 5% in children
and less than 1% in adults. However, the carriage rates among
household contacts of an index case are much higher: 20% to
25% overall and more than 50% among children younger than
5 years of age. This varies with the clinical disease. For exam-
ple, carriage rates among children 5 years old are 20% and
Scheld_Ch24.indd 366
55% for household contacts of epiglottitis and meningitis cases,
respectively. This prevalence is reflected in the increased risk
for serious Hib disease among household contacts of the index
case, which is age dependent: 4% for children 2 years of age,
2% for children 2 to 3 years old, and 0.1% for children 4 to
5 years of age. The risk for Hib infection among household con-
tacts is approximately 600-fold greater than the age-adjusted
risk for the population at large and is the basis for chemopro-
phylactic strategies. Carriage is usually asymptomatic and may
occur despite the presence of circulating anticapsular antibod-
ies or effective eradication of meningitis following antibiotic
therapy. The Hib carrier state may persist for weeks to months.
The occurrence of Hib meningitis is inversely proportional to
the age-related concentration of type-specific anticapsular anti-
bodies (18). Finnish studies, measuring antipolyribosylribitol
phosphate (anti-PRP) antibodies by radioimmunoassay, con-
firm the age-related susceptibility to systemic Hib disease:
90% of children (3 to 12 months old) had concentrations of
less than 150 ng/mL, whereas adults had higher concentra-
tions (19). These anti-PRP antibodies, in concert with comple-
ment, are (a) opsonic and bactericidal against Hib in vitro and
(b) protective in vivo. Antibodies to Hib outer membrane pro-
teins (Omps) also appear protective, but only against the ho-
mologous subtype. The anti-PRP response to infection is age
related, being poor in infants; older children and adults de-
velop higher titers. It is also dependent on PRP concentrations
and clearance rates. PRP antigenemia may persist for weeks in
younger children with Hib meningitis, delaying the antibody
response. Approximately 80% of children with Hib meningitis
develop an antibody response within 3 months. The antibody
response is blunted in children with agammaglobulinemia or
immunoglobulin G2 (IgG2) subclass deficiency, as well as in
all children younger than 24 months of age receiving the Hib
PRP vaccine, because this polysaccharide is a poor immunogen
in this age-group (9). The age-related acquisition of protective
anticapsular antibodies is too rapid to be accounted for by
the low incidence of carriage or disease caused by Hib alone.
Cross-reacting antigens from E. coli and other bacteria within
the gut are postulated to serve as the primary immunogen.
Acquisition of Hib (nasopharyngeal carriage) and the con-
centration of circulating anticapsular antibody are the two
main factors that determine risk for disease in most patients.
Some of these risk factors have been alluded to (e.g., immuno-
globulin or complement deficiency, household contacts of an
index case). Other conditions that also may be important in in-
creasing susceptibility to invasive Hib infection include sickle
cell anemia, postsplenectomy states, CSF fistulas, chronic pul-
monary infections, alcoholism, and probably lower socioeco-
nomic status (e.g., Eskimos and American Indians). Day care
outside the home and the presence of young siblings increases
the risk for invasive disease, whereas breast-feeding is pro-
tective. The risk is highest for children younger than 2 years
of age in day care but is not apparent for older children, is
equally high for those in a family day care setting or those in
a professional day care center (mean group size, 4 and 12 chil-
dren, respectively), and is significantly higher (p  .02) within
the first month of attendance, especially among younger chil-
dren (20). The risk ratio doubles with each additional sibling
younger than 7 years of age and is higher in twins (20). New
associations have also suggested that the childs previous state
of health, especially a history of otitis media and/or previ-
ous hospitalization, increases the risk for serious Hib disease.
Otitis media remains significant, especially for younger chil-
dren, even after controlling for confounding variables such
as day care attendance (21). Pharyngitis and otitis media are
associated with Hib meningitis in approximately one half and
two thirds of the cases, respectively.
2/21/14 5:42 PM

Because of the bimodal seasonal occurrence of Hib menin-
gitis, at least in northern latitudes, it has been suggested that
preceding viral upper respiratory tract infections predispose to
the acquisition of Hib and subsequent disease, but this issue
remains controversial (22). Recent studies comparing the at-
tack rates of meningitis between two ethnic groups living to-
gether in one geographic area (Jews and Bedouins in the Negev
region of Israel) suggested that community-acquired bacterial
meningitis is associated more strongly with the type of mor-
bidity most prevalent in the region at any given time (e.g.,
upper respiratory tract or gastrointestinal infections) rather
than any specific type of infection (23).
There has been a profound reduction (from 76% to 90%) in
the incidence of invasive infections caused by Hib in the United
States, specifically in young children (2427), attributed, in
part, to the widespread use of conjugate vaccines against Hib
that were licensed for routine use in all children beginning at 2
months of age. In a study of Hib disease rates in Los Angeles
County, California, Hib disease was nearly eradicated in a
fully immunized population, demonstrating the importance of
promotion of widespread use of these conjugate vaccines (28).
Similar results have been observed outside the United States.
In Finland, there has been a marked decrease in the number of
cases of Hib meningitis from a peak of 43 cases per 100,000
population in the late 1970s to no cases in 1991 in the greater
Helsinki area (29). Similarly, during a prospective study of bac-
terial meningitis in the northeast Thames region of the United
Kingdom, there was an 87% decline in the number of cases
of Hib meningitis in 1993 (7 cases) compared with 1991 and
1992 (50 cases) (30). Widespread usage beginning at 2 months
of age has nearly eliminated serious invasive Hib disease in chil-
dren in North America, Western Europe, Japan, and in many
areas of Latin America. Unfortunately, for reasons of cost, Hib
conjugate vaccines are used sparingly in many resource-limited
settings, and Hib meningitis remains common in children
in these areas. For example, Hib still accounted for 32% of
FIGURE 24.1 The meningitis belt of sub-Saharan Africa, comprising areas of Africa that experience
repeated epidemics of serogroup A meningococcal meningitis. (From Centers for Disease Control and
Prevention. CDC Health Information for International Travel 2014. New York: Oxford University Press;
2014.)
Scheld_Ch24.indd 367
Chapter 24: Acute Bacterial Meningitis 367
cases in children younger than 5 years of age in Bulgaria in the
mid-1990s (31). In addition, there was a report of emergence of
cases in Nottingham, United Kingdom of invasive Hib disease
in those previously vaccinated against the disease (32). Several
explanations were put forth to explain this increase, most nota-
bly that the vaccination schedule in the United Kingdom was at
2, 3, and 4 months of age, and no booster dose was given (33).
In areas in the developing world, declining rates of Hib men-
ingitis have been reported since introduction of Hib conjugate
vaccines, with effectiveness ranging from 88% to 94% (3437).
The occurrence of meningitis caused by Hib in individuals older
than 6 years of age should prompt efforts to exclude common ac-
companying conditions, such as otitis media, sinusitis, epiglottitis,
CSF leaks, an immunodeficiency state, splenectomy or asplenic
states, other parameningeal foci of infection, diabetes mellitus,
and alcoholism (38,39). Although the incidence in children has
dramatically declined, the incidence of invasive H. influenzae dis-
ease in adults is more complex. In one population-based study of
the epidemiology and outcome caused by typeable and nontype-
able H. influenzae among adults in Utah during 1998 to 2008,
there was an increase in incidence over the study period from 0.14
per 100,000 person-years in 1998 to 1.61 per 100,000 person-
years in 2008 (40); patients older than 65 years of age accounted
for 51% of the cases and 67% of the deaths.
Neisseria meningitidis
Meningococcal infections continue to pose serious problems on
all continents. They are influenced by multiple factors, including
geography, season, climate, meningococcal serogroup, and pop-
ulation demographics (2,41). Although worldwide in distribu-
tion, the incidence of epidemic meningococcal meningitis and/
or meningococcemia exhibits high geographic variability. The
meningitis belt of sub-Saharan Africa represents a classic en-
demic area (Fig. 24.1). Although meningococcal infections were
2/21/14 5:42 PM
 368 Part III: Bacterial and Mycoplasmal Infections
not recorded in the area until the 1880s, large outbreaks still
occur regularly. Although the precise effects of climatic condi-
tions on the incidence of meningitis are unresolved, the belt lies
within the 300- and 1,100-mm rainfall lines. At least 390,000
cases with 53,000 deaths occurred within the seven countries
of the belt in the 10-year period 1951 through 1960. The aver-
age annual incidence since 1950 has been estimated as approxi-
mately 70 cases per 100,000 population by the World Health
Organization (WHO) (41). In 1988, more than 57,000 cases
of meningococcal disease were reported from the African con-
tinent; in 1989, the number of cases increased to more than
70,000, with more than 40,000 reported from Ethiopia (42).
Because reporting is often delayed and may be incomplete, this
figure likely underestimates the actual number of cases. More
than 180,000 cases were reported by the WHO for the regions
in 1996, the highest yearly total in more than 40 years. Similarly,
within a 1-month period (October 1974), 4,865 patients with
meningococcal meningitis were treated at the major infectious
diseases hospital in Sao Paulo, Brazil. The overall mean an-
nual incidence of meningitis caused by N. meningitidis reached
370 cases per 100,000 population in the greater Sao Paulo area
in that year. The attack rate was 517 cases per 100,000 inhabit-
ants during a group C epidemic in Upper Volta (now Burkina
Faso) in 1979, and recent studies documented an attack rate
of 400 to 450 per 100,000 children up to 8 years of age in the
Faeroe Islands (43). In contrast, the mean annual attack rate
in the United States (1975 to 1980) was approximately 1.2
per 100,000 persons but was, again, age dependent: 17.1 per
100,000 in children younger than 1 year of age, 5.2 per 100,000
in 1- to 4-year-old children, and 0.3 per 100,000 among adults.
Approximately 2,500 to 3,000 cases of meningococcal infection
were reported annually in the United States between 1984 and
2003. In a multistate surveillance project conducted between
1989 and 1991 in the United States, the average annual inci-
dence of meningococcal disease was 1.1 per 100,000; 46% of
cases occurred in children 2 years of age, and the highest age-
specific incidence was in children younger than 4 months of age
(44). A similar figure of approximately 2 per 100,000 popula-
tion was reported from Finland from 1976 through 1980.
The peak incidence of meningococcal meningitis in indus-
trialized nations occurs in winter through early spring in both
epidemic and endemic periods. Similar seasonal trends may also
occur in tropical areas. For example, both the group C and group
A meningococcal epidemics in the Sao Paulo area from 1971 to
1974 began in May or June, the point of transition from the rainy
TA B L E 2 4 . 1
ETIOLOGY OF BACTERIAL MENINGITIS IN THE NORTHERN HEMISPHERE AMONG PATIENTS AGED 16 YEARS
AND OLDER
Organism United States 19621988
Haemophilus influenzae 4 5
Streptococcus pneumoniae 38
Neisseria meningitidis 14
Listeria monocytogenes 11
Othera 20
Unknown 13
a
Includes nonpneumococcal streptococci, gram-negative bacilli, enterococci, Staphylococcus aureus, anaerobes, and diphtheroids.
Adapted from refs. 69, 477, and 478.
Scheld_Ch24.indd 368
to the dry season. African outbreaks occur during the dry season
from December to June. Annual outbreaks in the sub-Saharan
meningitis belt tend to peak in late April and early May, when the
dry desert wind (harmattan) has ceased and temperatures are high
throughout the day, and terminate abruptly with the onset of the
rainy season (41). Low humidity may alter the pharyngeal muco-
sal barrier, thereby predisposing it to infection. Although the in-
troduction of a new virulent strain into a susceptible population
may contribute to the epidemics, many other factorsincluding
crowding, the presence of other respiratory pathogens, poor hy-
giene, and poorly defined environmental featurescontribute to
the initiation of a meningococcal epidemic (45).
Although meningococcal meningitis may be more prevalent
in men and boys, the reports are often skewed by the inclusion
of military recruits and chronic alcoholics. Meningitis caused
by N. meningitidis is primarily a disease of children and young
adults: fewer than 10% of cases occur in patients older than
45 years of age. In the United States and Finland, children younger
than 5 years of age account for approximately 55% of cases dur-
ing nonepidemic conditions, whereas in Zaria, Nigeria, the peak
incidence occurs in 5- to 9-year-olds (43). Major epidemics are
heralded by a shift to the right toward older age-groups (i.e.,
adolescents instead of children), a predictive feature of epidem-
ics in the meningitis belt identified by prospective surveillance.
Although meningococcal meningitis is unusual in adults, 33%
of sporadic meningococcal disease occurred in adults in a 5-year
population-based study in Atlanta (46). Underlying conditions
such as congestive heart failure, multiple myeloma, and infec-
tion with human immunodeficiency virus (HIV) were prevalent
in adults older than 24 years of age with meningococcal infec-
tion but unusual in the 18- to 24-year-old group.
Large-scale epidemics caused by serogroup A meningo-
cocci have occurred at 20- to 30-year intervals throughout the
world in the last and this century and continue at approxi-
mately 8- to 12-year intervals in the African meningitis belt,
where approximately 1% of the population is affected. These
strains infrequently cause disease in the United States, but se-
rious outbreaks caused by serogroups A, B, or C continue in
many areas (Table 24.1). A predominant serogroup circulating
in the African meningitis belt since 2000 is W135, an unusual
occurrence (see later discussion). Serogroups B and C now
cause most focal outbreaks and endemic disease in many areas
(see the section Etiology later in this chapter).
N. meningitidis disease is exclusive to humans. No inter-
mediate host, reservoir, or animal-to-human transmission has
Percentage of Total Cases
Iceland 19751994 Canada 19851995 United States19701998
8 4
20 53 48
56 2 14
6 25 7
12 27
8
2/21/14 5:42 PM

been proved. The nasopharynx is the natural reservoir for
meningococci; transmission is facilitated by airborne drop-
lets or close contact. The definition of close contact has not
been clearly elucidated but generally refers to persons who
have had prolonged (8 hours or longer) contact while in close
proximity (3 feet or less to the patient) or direct exposure to
the patients oral secretions (through kissing, mouth-to-mouth
resuscitation, endotracheal intubation, or endotracheal tube
management) within 1 week before the onset of the patients
symptoms until 24 hours after initiation of appropriate an-
timicrobial therapy (47). Meningococcal colonization may
result in an asymptomatic carrier state (which is most com-
mon) or in endemic, hyperendemic (e.g., a meningitis belt
between epidemics at 10 to 50 cases per 100,000 per year),
or epidemic disease. Although there is no clear relationship
between carriage rate and overt disease, the development of
the carrier state and the host immune response are, as for Hib
meningitis, important variables in the epidemiology of menin-
gococcal infections.
Approximately 6% of the population develops nasopharyn-
geal colonization with N. meningitidis yearly. Nasopharyngeal
carriage rates vary with age and the population under study.
The carriage rate is markedly influenced by age: 0.5% to 1%
in children 3 to 48 months old, approximately 5% in adoles-
cents 14 to 17 years old, and 20% to 40% in young adults.
Analogous to Hib, carriage rates are higher in close contacts
of an index case. Carriage rates of meningococci of approxi-
mately 40% have been documented in close family contacts
of meningococcal cases. In closed populations (e.g., military
barracks during early training), carriage rates of 20% to 60%
are commonplace and may reach 90% during epidemics of me-
ningococcal disease. Nasopharyngeal carriage usually persists
for weeks to months, similar to Hib carriage. Spread of menin-
gococcal disease is usually carrier mediated (i.e., not spread by
case-to-case contacts) and largely accounts for the increased
risk for disease (500- to 1,000-fold above the background en-
demic rate) in household contacts of an index case. The organ-
ism is often introduced into the home environment by an adult
family member, with subsequent transmission to others; infants
are colonized last of all. Although uncharacterized host and
environmental factors contribute to containment of infection
to the nasopharynx (thereby preventing disseminated disease),
host immunity also plays an important role. Nevertheless,
those individuals most recently colonized with meningococci
appear to be at the greatest risk for invasive disease. Secondary
systemic meningococcal disease often develops within 5 days
of recognition of the index case, with 70% to 80% of second-
ary cases occurring within 14 days of the primary case.
As with Hib disease, the age-specific incidence of menin-
gococcal infection is inversely proportional to the presence of
serum bactericidal antibodies against serogroups A, B, and
C. More than 50% of infants possess bactericidal antibody
at birth as a result of transplacental transfer. The specifics of
the antibody response may be responsible for the occurrence
of meningococcal meningitis during the neonatal period. The
group B capsular polysaccharide is a polymer consisting of two
to eight linked sialic acid residues but is immunologically iden-
tical to the oligosaccharides of several human glycoproteins,
including brain gangliosides. Immunologic tolerance thus ex-
ists in this age-group; although IgM antibody can be induced,
the usual switch to IgG antibody production does not occur
(43). Because IgM does not cross the placenta, IgG antibody
to the serogroup B polysaccharide is lacking in neonates, con-
tributing to the occurrence of group B meningococcal disease
in this patient population. In addition, group B meningococcal
capsular antigen is identical to the capsular polysaccharides
of E. coli K1 and certain types of group B streptococci, major
Scheld_Ch24.indd 369
Chapter 24: Acute Bacterial Meningitis 369
causes of neonatal sepsis and meningitis. The prevalence of
antimeningococcal capsular antibodies is lowest between
6 and 24 months of age, increasing to approximately 70%
by early adulthood. The inverse link between occurrence of
invasive disease and bactericidal antibody was first docu-
mented during an outbreak of serogroup C meningococcal
meningitis among army recruits in 1968 (48). In this study, the
sera of only 5.6% of the recruits who developed meningococ-
cal disease had bactericidal activity before the onset of illness,
compared with 82.2% of control sera. Notably, 5 (38.5%) of
13 recruits without bactericidal antibody developed systemic
illness after colonization with the group C strain.
Although recovery from invasive meningococcal disease
generally confers lifelong immunity against the homolo-
gous serogroup, this is not the major immunizing process.
Nasopharyngeal colonization, particularly with serogroups B,
C, or Y, may elicit the development of bactericidal activity, pri-
marily directed against the colonizing strain but also against
heterologous organisms within 5 to 12 days of acquisition.
Colonization with nongroupable meningococci or Neisseria
lactamica may elicit protective immunity, especially in young
children. N. lactamica is virtually nonpathogenic, but nasopha-
ryngeal carriage rates of this organism are highest (4% to 20%)
in children between 3 months and 12 years of age, whereas the
age-adjusted carriage rates for N. meningitidis are only 0.5%
to 2%. As with Hib, the carriage rates of pathogenic menin-
gococci are too low in children to account for antibody for-
mation, and the importance of other cross-reacting organisms
has also been proposed: Bacillus pumilus for group A poly-
saccharide and E. coli for group C organisms. Paradoxically,
an exuberant IgA response to meningococci may actually
enhance the development of systemic disease. When a large
proportion of induced anticapsular antibodies are of the IgA
class, complement-mediated immune bacteriolysis by IgM is
blocked, thus enhancing susceptibility to invasive disease. This
peculiar immunologic phenomenon is transient, lasting only a
few days following asymptomatic nasopharyngeal acquisition
of N. meningitidis or closely related organisms.
In addition to antibody, an intact complement system is
also a component of host defense against invasive meningo-
coccal disease. Studies of extreme phenotypes have identified
genetic correlates of increased susceptibility in the complement
system (49). Recurrent or chronic neisserial infections have
been associated with rare isolated deficiencies of late comple-
ment components (C5, C6, C7, or C8, and perhaps C9), occa-
sionally in concert with failure to produce antimeningococcal
antibodies. Recurrent episodes of neisserial infections may
occur in these patients without an increase in susceptibility
to other pathogens (50), and screening for complement de-
fects is useful in patients with these syndromes. Complement
deficiency also appears to predispose to meningitis caused by
nongroupable meningococci and Neisseria-related bacteria
(i.e., Moraxella and Acinetobacter species) (51). In addition,
complement deficiency or depletion of early components (C1,
C3, or C4) because of an underlying disease such as nephrotic
syndrome, hepatic failure, systemic lupus erythematosus, pres-
ence of C3 nephritic factor, or multiple myeloma may predis-
pose to the first episode of invasive meningococcal disease.
An association between homozygous C4b deficiency (present
in approximately 3% of the population) and the develop-
ment of childhood meningitis was demonstrated. Up to 30%
of patients with invasive meningococcal syndromes display
decreased complement function. Properdin deficiency, or dys-
function with normal concentrations, also predisposes to me-
ningococcal infections; this defect is reversible by vaccination
(52). The mortality associated with meningococcal meningitis
in patients with complement component deficiencies is actually
2/21/14 5:42 PM
 370 Part III: Bacterial and Mycoplasmal Infections
lower than the general population (3% versus 19%, respec-
tively). However, since invasive meningococcal infection oc-
curs in 39% of patients with deficiency of terminal complement
components and about 6% of those with properdin deficiency,
a screening test (e.g., CH50) has been suggested (53) for all
individuals with serious meningococcal disease, with further
consideration for determination of specific complement and/
or properdin concentrations if documented. Asplenic states
increase the risk for serious infections by encapsulated organ-
isms, especially Hib or S. pneumoniae but also meningococci.
In genetic casecontrol studies, invasive meningococcal dis-
ease was associated with the IL1RA  2018T C polymor-
phism, with susceptibility increased in homozygous IL1RA 
2018C carriers (49). CFH, SFTPA2, CEACAM3, and
CEACAM6 polymorphisms were significantly associated with
an increased susceptibility to meningococcal disease, whereas
other CEACAM6 and SFTPA2 polymorphisms showed a pro-
tective effect (49). A genome-wide association study identified
variants in the CFH region associated with host susceptibility
to meningococcal disease (54). Further studies are needed to
confirm these associations before a definite conclusion can be
drawn on their role because of the limited sample size and lack
of correction for multiple testing.
Although all the aforementioned factors (particularly
recent colonization with a pathogenic strain in a nonimmune
host) undoubtedly contribute to the pathogenesis of meningo-
coccal disease, the precise determinants contributing to overt
clinical illness (as opposed to the usual outcome of asymp-
tomatic carriage) are poorly defined. Even during epidemics,
only 1 in 1,000 to 5,000 colonized patients develop disease
(43). Various predisposing factors, including crowding, lower
socioeconomic status, and poor general health, have been pro-
posed to explain the increased incidence among blacks in the
United States and among alcoholics in Finland or Alaska (41).
However, the influence of such conditions (e.g., overcrowding)
has not been supported by studies in Nigeria. An antecedent
viral infection has been suggested as another predisposing
factor, because approximately one third of meningococcal
cases follow symptoms referable to the upper respiratory tract.
An outbreak of meningococcal disease followed a large influ-
enza epidemic in Texas in 1981, and simultaneous outbreaks
of meningococcal and influenza A2 infections have been
described in institutional settings. Although meningococcal
pneumonia may complicate influenza (e.g., the 1918 to 1919
pandemic), the role of viral infections in the enhancement of
meningococcal dissemination is unproved (22).
The time from nasopharyngeal acquisition to bloodstream
invasion is short (usually approximately 10 days). The incu-
bation period may also be short, because secondary cases
commonly occur within 1 to 4 days of the index case. Once
the organism is bloodborne, more than 90% of meningococcal
disease is manifested as meningitis and/or meningococcemia.
Although a single case of meningococcemia or meningitis in
a college student engenders alarm, invasive disease due to this
organism is no more common in such students when compared
with nonstudent age-matched 18- to 22-year-old controls but
is increased threefold in freshmen living in dormitories, a tar-
get of some vaccine recommendations. Active or passive smok-
ing and binge alcohol consumption also appear to increase the
risk of meningococcal disease in this age-group. The first quad-
rivalent meningococcal conjugate vaccine against serogroups
A, C, Y, and W135 was licensed in January 2005 in the United
States for routine use, starting at age 11 to 12 years; recent
recommendations are for one vaccine in this age-group, with
a booster dose given at age 16 years (55,56). A two-dose pri-
mary series administered 2 months apart is recommended for
those age 2 to 54 years with persistent complement component
Scheld_Ch24.indd 370
deficiency or functional or anatomic asplenia and for adoles-
cents with HIV infection. A two-dose primary series is also
recommended for children 9 to 23 months of age at increased
risk for invasive meningococcal disease (57). Lack of a vac-
cine against serogroup B meningococcus is a significant issue,
although recent investigations of a multicomponent serogroup
B vaccine (4CMenB) demonstrated that this vaccine was im-
munogenic (5861); 84% to 100% of infants who were ad-
ministered the vaccine developed bactericidal antibodies.
Streptococcus pneumoniae
Although pneumococcal meningitis occurs in all age-groups,
pneumococci remain the most common cause of bacterial
meningitis in adults. The annual incidence of pneumococcal
meningitis has remained relatively stable in the United States
for the past three decades until recently with introduction of
the heptavalent pneumococcal conjugate vaccine (see later
discussion). In seven studies analyzing data from diverse geo-
graphic areas in this country from 1959 to 1978, the annual
incidence was 0.3 to 2.3 per 100,000 population, with a mean
of 1.3 per 100,000. An identical infection rate of 1.3 per
100,000 persons annually was recorded from the Oklahoma
City area in 1984 and extrapolated from several states and Los
Angeles County in a relatively recent (1995) national survey
conducted by the Centers for Disease Control and Prevention
(CDC) (62,63); higher rates of invasive pneumococcal disease
were reported at the extremes of age (see later discussion),
in men and boys, and among blacks and American Indians
as compared with whites. Nearly identical incidence figures
(1.2 to 1.4/100,000 population annually) were reported from
the Gteborg, Sweden area from 1975 through 1980 (64)
and from rebro county in Sweden (1.0/100,000 popula-
tion annually) from 1981 through 1992 (65). Pneumococcal
meningitis was, again, more common in men and boys, and
most cases occurred from December through May. However,
higher incidence rates have been reported from other areas.
For example, surveillance studies from 1980 to 1986 among
the Alaskan native population in the Yukon-Kusko-Kurin delta
region of southwestern Alaska documented an extremely high
frequency of invasive pneumococcal disease; the annual rate
for pneumococcal meningitis was 13.2 per 100,000 persons
overall (66). Perhaps more importantly, the annual incidence
rate was 216 per 100,000 children younger than 2 years
18 times higher than that reported from Sweden (64) and 36-
to 37-fold greater than United States rates derived from both
passive and active surveillance (7,62,66). These rates of bac-
teriologically confirmed invasive pneumococcal disease were
the highest reported for any population worldwide. Although
most cases of invasive pneumococcal disease occurred during
the Arctic summer, pneumococcal meningitis cases clustered in
the winter (66), as described in other reports (7).
The risk for pneumococcal meningitis is age dependent,
with increased incidence rates occurring at the extremes of age.
For example, the number of cases per 100,000 persons per year
in the Gteborg, Sweden area for 1970 through 1980 were as
follows: 12.0 for infants younger than 12 months old, 0.4 to
0.9 for children and adults 2 to 39 years old, 1.2 to 1.6 for per-
sons 40 to 70 years old, and 2.2 for those older than 70 years
of age (64). The dramatic incidence among Alaskan native
children younger than 2 years of age (216/100,000 annually)
are noted earlier in this chapter. Similarly, the annual incidence
rates for all invasive pneumococcal infections (including bac-
teremic pneumonia) in the Oklahoma City area in 1984 were
97 per 100,000 for infants younger than 1 year of age and 87
per 100,000 for elderly adults older than 80 years of age.
2/21/14 5:42 PM

As with disease caused by the other major meningeal patho-
gens, pneumococcal meningitis follows recent nasopharyngeal
colonization by a virulent strain. The rate of asymptomatic car-
riage varies with age, environment, geographic locale, and the
presence of an upper respiratory tract infection. Pneumococci
have been isolated from the upper respiratory tract of 5% to
70% of normal adults; approximately 25% acquire a new
strain annually. Carriage rates decline with age (30% to 35%
for children ages 6 to 11 years and 18% to 19% in adults) and
are higher in closed populations (e.g., 27% to 58% in schools
and orphanages, 50% to 60% in closed military populations).
The duration of pneumococcal carriage varies from weeks to
months and is longer in children than in adults. Most carrier
strains in the normal population are of higher numbered cap-
sular types and only infrequently are associated with invasive
disease (see later discussion). Carriage is prolonged in indi-
viduals with low serum antibody concentrations against the
homologous capsular type before colonization. Spread of this
organism within the family unit is influenced by crowding, the
season (greater in fall and winter), and the presence of pneu-
mococcal disease (particularly pneumonia and otitis media).
The precise relationship between pneumococcal carriage and
the development of protective immunity is poorly defined.
More than 50% of children develop a rise in type-specific
antibody concentrations following colonization; this is rarely
observed in adults, perhaps because of the relatively high an-
tibody concentrations already present in adults. Nevertheless,
otitis media often occurs in colonized infants despite the pres-
ence of type-specific antibodies. Antibody concentrations gen-
erally decline with time despite persistent carriage of a given
strain (67). In addition, antibody responses to different capsu-
lar types vary considerably and are generally poor in infants
younger than 2 years of age. Specific antibody responses tend
to be higher after intermittent periods of nasopharyngeal car-
riage than after continuous ones. The antibody response after
pneumococcal colonization, its influence on subsequent dis-
ease, and the impact of other environmental antigens require
further study.
Studies of extreme phenotypes among patients with inva-
sive pneumococcal disease have identified genetic correlates
of increased susceptibility in the complement system and the
signalling cascade after toll-like receptor pathways (49). Case
control studies showed that invasive pneumococcal disease was
associated with certain MBL and C3-variant genotypes (49,68).
Several factors predispose to pneumococcal meningitis
(69,70):
Pneumonia (15% to 25% of patients)
Otitis media
Sinusitis
CSF fistulas, leak
Head injury
Cochlear implants with positioners
Alcoholism, cirrhosis
Sickle cell disease, thalassemia major
Other splenic disease
Wiskott-Aldrich syndrome
Multiple myeloma
Pneumonia coexists much more commonly with pneumo-
coccal meningitis than with the other two major pathogens.
Acute otitis media is seen in approximately 30% of patients
with pneumococcal meningitis; acute sinusitis may also be an
important antecedent event. Pneumococci are the most com-
mon cause of recurrent meningitis in the setting of CSF leaks.
Recent or remote head trauma is found in about 10% of pa-
tients with pneumococcal meningitis. Alcoholism, cirrhosis,
and spontaneous bacterial peritonitis are underlying disorders
Scheld_Ch24.indd 371
Chapter 24: Acute Bacterial Meningitis 371
in approximately 20% to 35% of patients with this disease.
Pneumococci are the most common cause of meningitis in chil-
dren with sickle cell anemia and commonly cause meningitis
in other asplenic states or in the setting of primary or acquired
immunodeficiencies (71). S. pneumoniae causes 87% of pyo-
genic meningitis cases in sickle cell disease; cases in the 2- to
3-year-old group occur at a rate of 12 per 1,000 patient-years.
The risk for pneumococcal meningitis in this age-group of chil-
dren with sickle cell anemia is increased 36-fold as compared
with that observed in control groups of black children, and it is
increased 314-fold over that observed in whites. Pneumococcal
meningitis also occurs with increased frequency in persons with
the Wiskott-Aldrich syndrome, thalassemia major, childhood
nephrotic syndrome, multiple myeloma, and chronic lympho-
cytic leukemia. Defects in immunoglobulin concentration or
function, as well as poor alternative complement pathway
mediated opsonization of pneumococci, are common in many
of these disorders. Pneumococcal meningitis is approximately
450-fold more common in patients with acquired immuno-
deficiency syndrome (AIDS) when compared with the general
population (71), often despite prophylaxis with trimethoprim-
sulfamethoxazole (TMP-SMX) to prevent other opportunistic
infections. In one study of 352 episodes of community-acquired
pneumococcal meningitis in adults, 245 (70%) were associ-
ated with an underlying disorder and the overall in-hospital
mortality rate was 30% (72); death in patients younger than
60 years of age was more often caused by neurologic compli-
cations; in patients 60 years or older, death was more likely
secondary to systemic complications. In children with cochlear
implants with positioners who are beyond 24 months after im-
plantation, the incidence of bacterial meningitis was 450 cases
per 100,000 person-years compared with 0 cases in children
without positioners (73); the updated overall incidence was
189 cases per 100,000 person-years, with most cases caused
by S. pneumoniae (74). Outbreaks of pneumococcal meningi-
tis have also been described during African outbreaks of me-
ningococcal meningitis (75). In children who develop second
episodes of pneumococcal meningitis, screening for congenital
immunoglobulin deficiencies should be performed (53).
The rates of pneumococcal meningitis have decreased
in children and adults since introduction of the heptavalent
pneumococcal conjugate vaccine (from 1.13 to 0.79 cases
per 100,000 between 1998 to 1999 and 2004 to 2005), al-
though the increase in disease caused by serotypes not in the
vaccine (19A, 22F, and 35B) is concerning (76). The Advisory
Committee on Immunization Practices now recommends use
of the 13-valent pneumococcal conjugate vaccine (77), which
not only offers protection against the serotypes in the heptava-
lent vaccine (4, 6B, 9V, 14, 18C, 19F, 23F) but also protection
against additional serotypes (serotypes 1, 3, 5, 6A, 7F, 19A).
ETIOLOGY
In a review of 296 episodes of community-acquired meningitis
in adults reported from the Massachusetts General Hospital
from 1962 through 1988, the most common pathogens were
S. pneumoniae (37%), N. meningitidis (13%), and L. mono-
cytogenes (10%) (78).
The epidemiology of bacterial meningitis changed dramati-
cally in areas that have embraced Hib conjugate vaccines starting
in the late 1980s. The influence of these vaccines from the four
largest and most recent surveys conducted in the United States
(7,62,79) is shown in Table 24.2. Hib was responsible for 45%
to 48% of cases from 1978 through 1986 but only 7% of cases
in a surveillance study (62) conducted in 1995 in laboratories
serving all acute-care hospitals in 22 counties from four states
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 372 Part III: Bacterial and Mycoplasmal Infections

TA B L E 2 4 . 2
Haemophilus influenzae
ETIOLOGY OF BACTERIAL MENINGITIS IN THE
UNITED STATES, 19781995 Haemophilus species are small, gram-negative, pleomorphic
coccobacilli. They are facultative anaerobes that grow best an-
Percentage of Total Cases aerobically with 5% to 10% CO2 on blood-enriched media.
H. influenzae requires both X factor (hematin) and V factor
19781981 1986 1995 20062007 (nicotinamide adenine dinucleotide, nicotinamide adenine dinu-
Organism (7) (79) (62) (5) cleotide phosphate, or nicotinamide nucleoside) for growth under
aerobic conditions and is nonhemolytic. Chocolate agar is most
Haemophilus 45 48 7 7 commonly employed for the initial isolation of H. influenzae.
influenzae H. influenzae strains are either encapsulated (typeable) or un-
Streptococcus 13 18 47 58 encapsulated (nontypeable). Encapsulated strains are classified
pneumoniae into six types, designated a through f, according to specific reac-
Neisseria 20 14 25 14
tions with antisera directed against epitopes on capsular antigens.
meningitidis
Methods for grouping include counterimmunoelectrophoresis,
latex particle agglutination of culture supernatants, immunofluo-
Streptococcus 3 6 12 18 rescence, and the production of halos surrounding colonies on
agalactiae media containing antisera. Nearly all invasive H. influenzae infec-
Listeria 2 3 6 3 tions are caused by serotype b (Hib). The capsule is a repeating
monocytogenes polymer of PRP, an important virulence determinant of this or-
Other 8 14 ganism (see later discussion). Hib also contains a lipooligosaccha-
ride (here, designated lipopolysaccharide [LPS] for convenience)
Unknown 6
in the outer membrane, an additional virulence determinant. Hib
strains have been further classified into subtypes based on electro-
phoretic mobility differences among Omps. Although the patho-
(10 million population). The incidence of Hib meningitis de- genic role of these Omps is uncertain, subtype analysis is useful
clined from 2.9 to 0.2 per 100,000 population from 1986 to for epidemiologic studies. For example, in a survey of 256 in-
1995, respectively. The median age of patients with bacterial vasive isolates from 22 states representing a variety of clinical
meningitis rose from 15 months to 25 years during this inter- settings, about 70% of cases were caused by strains of three sub-
val, perhaps the most dramatic change in the epidemiology of types (1H, 2L, and 3L) among the 21 Omp subtypes identified. In
any bacterial infection in recent decades. As a result, approxi- contrast, 84% of 80 invasive isolates studied in the Netherlands
mately 70% of bacterial meningitis in the United States is due had the same Omp subtype pattern (type 1, identical to subtype
to pneumococci or meningococci. In the early pivotal trial in 3L in the Granoff classification system), and no strains of subtype
California, invasive (e.g., bacteremia and meningitis) pneumo- 1H, 1L, or 2H were found.
coccal disease was virtually eliminated in infants vaccinated It has been recognized, largely on the basis of multilocus en-
with the heptavalent conjugate vaccine at 2, 4, and 6 months of zyme electrophoretic analysis by Musser et al. (80), that the natu-
age. Although targeted to children, recent data support a herd ral populations of Hib from widely divergent geographic areas are
immunity phenomenon, similar to that experienced with Hib clonal as a consequence of infrequent recombination of chromo-
conjugate vaccines, leading to a decline in pneumococcal bac- somal genes. For example, 32 distinct multilocus enzyme geno-
teremia and/or meningitis in the population (including adults) types, referred to as electrophoretic types (ETs), were apparent
following introduction of conjugate pneumococcal vaccine in among 177 U.S. isolates by analysis of 16 metabolic enzymes, but
infancy. In another surveillance study among residents in eight 73% of invasive disease episodes were caused by strains belonging
surveillance areas representing 17.4 million persons from 1998 to only three ETs. In the largest and most comprehensive analy-
to 2007, the impact of the heptavalent pneumococcal conju- sis (80), 2,209 encapsulated H. influenzae strains (including 1975
gate vaccine was appreciated in which the incidence of men- Hib) from 30 countries on six continents collected over a 40-year
ingitis caused by vaccine serotypes decreased from 0.61 cases period were studied by multilocus electrophoresis of 17 chromo-
per 100,000 population in 1998 to 1999 to 0.05 cases per somally encoded metabolic enzymes, Omp subtyping, and the
100,000 population in 2006 to 2007, although the number of pattern of restriction fragment length polymorphism in the cap
cases of bacterial meningitis caused by nonvaccine serotypes region (the chromosome region responsible for capsular expres-
increased by 61% (5); the mean age of all patients with menin- sion). On the basis of allele profiles at the enzyme loci, 280 distinct
gitis increased from 30.3 years in 1998 to 1999 to 41.9 years ETs in two phylogenetic divisions were identified: the population
in 2006 to 2007. However, despite the declining incidence of structure is definitely clonal. Currently, nearly all invasive disease
bacterial meningitis in the United States, the overall case-fatality worldwide is caused by nine clones of Hib. One genetically distinct
rates did not change significantly (15.7% in 1998 to 1999 com- clone complex occurs with considerable frequency worldwide,
pared with 14.3% in 2006 to 2007; p  .50). but marked geographic variation occurs for other clones or clone
As shown in Table 24.1, the responsible organisms for families. Based on an extensive analysis, it appears that this distri-
community-acquired bacterial meningitis in adults older than bution of clones on an intercontinental scale is largely accounted
16 years of age are somewhat different, but S. pneumoniae, for by the patterns of racial/ethnic composition and historical de-
N. meningitidis, and L. monocytogenes predominate. Similar mographic movements of the human host populations (80).
recent (e.g., after 2000) surveys for resource-limited settings
are lacking and sorely needed to guide vaccine strategies in
this age-group. Neisseria meningitidis
In the following sections, each of the major meningeal
pathogens is considered, including relevant classification Neisseria species are nonspore-forming, nonmotile, oxidase-
schemes. In addition, the potential virulence characteristics of positive, gram-negative cocci (measuring approximately 0.8 
each organism are briefly discussed. 0.6 m) that usually appear as biscuit- or kidney-shaped

Scheld_Ch24.indd 372 2/21/14 5:42 PM


diplococci on smears of infected fluids. Because other organ-
isms (e.g., Moraxella species) are similar morphologically,
identification rests on biochemical or immunologic tech-
niques. All Neisseria species are oxidase positive, and sugar
fermentation reactions are usually sufficient for speciation
within the genus. Gonococci ferment glucose (but not malt-
ose or lactose) to acid, whereas meningococci ferment both
glucose and maltose to acid. N. lactamica, a related organ-
ism occasionally present in throat cultures, ferments glucose,
maltose, and lactose. Maltose-negative variants of meningo-
cocci have been isolated; these strains may be differentiated
from gonococci by fluorescent antibody tests, coagglutination
tests, or electrophoretic analysis of hexokinase isoenzymes.
These strains usually acquire the ability to ferment maltose
on subculture; true maltose-negative variants are rare, but
this property is genetically linked to sulfadiazine resistance.
Meningococci grow rapidly on blood, chocolate, gonococcal,
or enriched Mueller-Hinton agar in a moist, 3% to 10% CO2
environment at 35C to 37C. A modified Thayer-Martin me-
dium is employed for meningococcal isolation from contami-
nated sites, as in detection of the carrier state. The transoral
approach for obtaining specimens is more practical and is at
least as sensitive as older transnasal approaches for carrier
detection. Because this organism is susceptible to drying and
chilling, all specimens should be inoculated promptly.
As in other gram-negative bacteria, the ultrastructural char-
acteristics of meningococci are complex. The surface compo-
nents include capsular polysaccharide, fimbriae or pili, LPS, and
Omp; several of these structures are important virulence deter-
minants. Meningococci are classified by serogroups based on
structural differences among capsular polysaccharides and ag-
glutination reactions with specific antisera, and they are further
defined by serotypes based on analysis of the Omp. Capsular
polysaccharide detected by positive agglutination with refer-
ence antisera is uniformly present among invasive isolates, but
20% to 50% or more of carrier strains are unencapsulated
(nongroupable). The serogroups have important epidemiologic
and prevention-related implications. Thirteen serogroups are
recognized (43), designated as follows: A, B, C, D, H, I, K,
L, X, Y, Z, 29E, and W135. Most meningococcal disease is
caused by organisms in serogroups A, B, C, and Y, although
the proportion of cases caused by serogroup W135 is increas-
ing. Although serious outbreaks of serogroup A, B, or C disease
have occurred worldwide, most focal outbreaks and endemic
disease in many countries are caused by serogroups B and C.
For example, in the United States from 1975 to 1980, the dis-
tribution of serogroups among 12,980 cases was as follows:
B, 56%; C, 19%; Y, 11%; W135, 10%; and A, 3%. Similar fig-
ures were reported for the period 1978 to 1981 (7). Serogroup
W135 disease, especially among adults, has been increasing
in the United States and apparently elsewhere (e.g., Senegal)
since 1981. Group B organisms, especially B:15:P1.16, have
emerged as important pathogens in northern Europe, caus-
ing serious local outbreaks peaking in the 10- to 20-year-old
group. The continued high prevalence of serogroup B menin-
gococcal disease has important implications because of the lack
of an effective, widely available vaccine against this serogroup.
An outbreak of serogroup C disease occurred in California in
1987 (81). Serious outbreaks caused by serogroup A continue
in Nepal, Saudi Arabia, Chad, Sudan, Burkina Faso, and else-
where. Approximately 40,000 cases of serogroup A disease
occurred in Ethiopia in the spring of 1989 (Fig. 24.1).
There have been increases in the incidence of serogroup
C disease in North America to equal or surpass the incidence of
disease caused by serogroup B (42). From 1985 through 1992, a
clonal serogroup C meningococcal strain (designated ET-15 and
defined by multilocus enzyme electrophoresis) was associated
Scheld_Ch24.indd 373
Chapter 24: Acute Bacterial Meningitis 373
with an increase in both the incidence and the mortality of
meningococcal disease in Canada (82). This and four other
closely related clonal strains were also implicated in a marked
increase in outbreaks of serogroup C meningococcal disease in
the United States (83). These studies suggested the emergence of
a clonal group of virulent serogroup C meningococcal strains
in North America, leading to an increase in the rate of menin-
gococcal disease in some regions, an increased number of out-
breaks, and a higher case-fatality rate (84).
In an analysis from the United States (85), part of an active
and ongoing laboratory-based population-based surveillance for
meningococcal infection from 1992 to 1996, the serogroup dis-
tribution for the three most common isolates was as follows:
C, 35%; B, 32%; and Y, 26%. Similar results were noted in
New York City through 2000 (86). In contrast, serogroup B
accounted for 75% of meningococcal isolates in Italy (87).
More than 98% of cases of invasive meningococcal disease
are sporadic (88). From 1998 to 2007, a total of 2,262 cases
of meningococcal disease were reported to the Active Bacterial
Core surveillance sites, with an annual incidence of 0.53 cases
per 100,000 population (89). The incidence decreased from
0.92 cases per 100,000 population in 1998 to 0.33 cases per
100,000 population in 2007; the incidence decreased to this
historic low before the introduction of the quadrivalent menin-
gococcal conjugate vaccine. Infants younger than 1 year of age
had the highest incidence (5.38 cases per 100,000 population),
although the distribution of serogroups is also different in this
population (serogroup B, 3.08 per 100,000 population; sero-
group C, 0.53 per 100,000 population; serogroup Y, 1.50 per
100,000 population). A recent outbreak of serogroup C disease
was reported in New York City among men who have sex with
men (90). During the outbreak of meningococcal disease coin-
ciding with the Hajj pilgrimage in March 2000, the attack rate
of W135 disease was 25 cases per 100,000 pilgrims (91); all out-
break-associated isolates of serogroup W135 were members of a
single clone of the hypervirulent ET-37 complex, which occurred
as the result of expansion of a clone that had been in circulation
since 1970 (92). A high incidence of serogroup X cases was re-
ported in Niger (93), representing 51% of 1,139 confirmed cases
of meningococcal meningitis in 2006; serogroup X disease also
emerged in Togo and Burkina Faso during 2006 to 2010 (94).
Serotypes within a serogroup of N. meningitidis are clas-
sified largely on analysis of Omp profiles in the cell enve-
lope. At least 20 serotypes are recognized (95), resulting in
a classification scheme that is useful in epidemiologic studies.
Physicochemical characterization of the Omps, which might
be candidate antigens for vaccines, has led to the designation
of five major classes. Class 2 and 3 proteins are the major po-
rins responsible for aqueous channels in the outer membrane.
Class 5 proteins are surface exposed and may have a role in
virulence, but the function of class 1 and 4 proteins is poorly
defined. The serotype designation has important epidemiologic
uses and may identify virulence characteristics among menin-
gococci. For example, serotype 2 (2a, 2b) strains are respon-
sible for approximately 50% of serogroup B disease (in which
15 serotypes have been described), followed by serotypes 15
and 9; in contrast, serotypes 4 and 6 have been isolated only
from carriers. Serotype 2 is also responsible for about 80% of
invasive serogroup C disease and is an important marker for
serogroups Y and W135 pathogenic strains as well (95). All
serogroup A meningococci, in contrast, are homogeneous with
respect to Omp and show no homology to serotypes within
other serogroups. Serotype analysis has also been linked to
certain clinical characteristics (96). However, this technique
is available only in research or reference laboratories. In addi-
tion, at least eight immunotypes of meningococci, classified by
differences among LPS subtypes, are known to exist and may
2/21/14 5:42 PM
 374 Part III: Bacterial and Mycoplasmal Infections
play a role in pathogenesis and disease expression. LPS im-
munotype analysis may also be useful in the further character-
ization of the epidemiology of meningococcal disease (41,43).
The recent availability of monoclonal antibodies to detect
variations in Omp and/or LPS will improve the resolution of
these typing systems for epidemiologic analysis.
In addition to classification by serogroup, serotype, and
LPS subtype, many reports have focused on multilocus enzyme
electrophoresis for the characterization of the chromosomal
genome of isolates and for estimation of the genetic relatedness
among strains (97). These studies, similar to the analysis of
Hib (80), have identified the clonal nature of N. meningitidis
and have been useful for epidemiologic purposes. For example,
electrophoretic variation (defined as 17% genetic distance
between isolates) in seven metabolic enzymes and two Omp in
423 isolates of serogroup A strains recovered from 23 epidem-
ics or outbreaks occurring in 38 countries on six continents
over a 70-year period since 1915 identified 21 clones (des-
ignated A I-1 through A IV-4) containing 34 ETs (97). This
technique has been useful for delineating similarities and dif-
ferences among isolates from cases and carriers before, during,
and after epidemics (98). It has also been useful for tracing
movements of epidemic strains geographically over time (81).
For example, following an epidemic in Nepal (1983 to 1984),
a single clonal complex of serogroup A meningococci (III-1,
representing 11 closely related ETs) was introduced into Saudi
Arabia in 1987 by Muslim pilgrims traveling to Mecca for the
annual hajj (98). The same strain was then introduced into
sub-Saharan Africa following the hajj, causing an explosive
outbreak in Chad in 1988. An analysis of 109 isolates of se-
rogroup B meningococci in Norway has also revealed differ-
ences among carriers and cases (99). Although 78 ETs were
identified, 91% of the cases of systemic disease in 1984 were
caused by strains from the ET-5ET-37 complex, whereas
these isolates were recovered from only 7% and 9%, respec-
tively, of healthy carriers. The most common clonal complex
found among carriers was never isolated from patients with
invasive disease, suggesting a low virulence potential for these
clones. Two clones, ET-15 and ET-508, have been associated
with outbreaks of meningococcal infection in North America
(82,83,100). Clonal analysis will undoubtedly continue to
contribute important information on the epidemiology of me-
ningococcal infection, and it may prove useful in an analysis
of virulence properties. As noted earlier, serogroup W135 has
been circulating, particularly among pilgrims to Mecca during
the hajj since 2000 in Africa, the Middle East, and worldwide
(attack rate 25/100,000); all isolates were members of a single
hypervirulent ET-37 complex (91,92). This occurred through
the expansion of a clone that had been circulating since 1970.
Vaccination with quadrivalent vaccine in hajj pilgrims from
several areas (e.g., North America, Western Europe) appears
to have reduced transmission of W135 meningococci to close
contacts upon return (101,102).
The putative meningococcal virulence characteristics are as
follows:
Capsular polysaccharide
-hemolysis occurs under anaero-
Pili
IgA protease
LPS (endotoxin)
Omps
Outer membrane vesicles, or blebs
Metabolic pathways (e.g., iron)
As noted earlier, all isolates from invasive infections are en-
capsulated (serogroup positive), but 20% to 90% of isolates
from carriers are unencapsulated (nontypeable). The capsu-
lar polysaccharide appears to be essential for meningococcal
Scheld_Ch24.indd 374
virulence, probably because of its antiphagocytic properties
that allow the organism to escape host phagocytic clearance
mechanisms within the bloodstream and/or CSF. Pili are pro-
tein surface appendages composed of identical pilin-repeating
subunits. Pili from meningococci and gonococci are morpho-
logically and chemically similar. Cross-reacting antibodies bind
to a short peptide sequence (residues 69 to 94) of gonococcal
pili that is essential for receptor-binding function. Fresh menin-
gococcal isolates from carriers and cases contain 7 to 40 pili
per diplococcus. Pili are important mediators of meningococ-
cal adhesion to human nonciliated columnar nasopharyngeal
epithelial cells, an important early step in the development of
the carrier state. Extracellular proteases that cleave the IgA1
heavy chain in the hinge region are elaborated by pathogenic
Neisseria species (i.e., meningococci and gonococci). Although
the role of IgA proteases in the pathogenesis of disease is con-
troversial, these enzymes are produced by only a few organisms
(e.g., N. meningitidis, Neisseria gonorrhoeae, H. influenzae,
S. pneumoniae, and Streptococcus sanguinis), many of which
are important meningeal pathogens and may promote invasion
at the pharyngeal portal of entry. Meningococcal LPS resem-
bles H. influenzae LPS by a lack of the O-antigenic polysac-
charide side chains found in enteric bacilli despite a smooth
phenotype and proven virulence. LPS is clearly important in
the genesis of an array of the clinical manifestations of menin-
gococcemia and/or meningitis (see later discussion). Although
the specific role for Omp in meningococcal virulence is unclear,
these organisms release substantial amounts of cell surface ma-
terial (in the form of outer membrane vesicles containing Omp
and LPS) during growth in vitro and in vivo in the absence of
cell lysis, a process exacerbated by antimicrobial agents. These
outer membrane vesicles, or blebs, represent relevant vehicles
for central nervous system (CNS) tissue damage during menin-
gococcal infection (see later discussion). Tissue invasion may
also be facilitated by the ability of meningococci to obtain iron
from transferrin.
Streptococcus pneumoniae
Pneumococci are nonspore-forming, nonmotile, small (ap-
proximately 0.8 m), gram-positive streptococci that typically
appear as lancet-shaped diplococci with the tapered ends in
juxtaposition in clinical specimens. They tend to associate in
pairs rather than in short chains, although the latter morphol-
ogy is facilitated by broth culture. Pneumococci are facultative
anaerobes that flourish in a variety of supplemented artificial
media. Optimal growth occurs in various media supplemented
with serum or blood and glucose, at a pH level of 7.8 and a
temperature of 37C in an enriched CO2 environment. The
organisms are catalase negative and relatively fastidious.
Colonies on blood agar are initially dome shaped, but they
become umbilicated with time as a result of the activity of au-
tolytic enzymes (l-alaninemuramylamidase). Pneumococci are
-hemolytic (i.e., a greenish discoloration surrounds colonies
on blood agar), although
bic conditions. S. pneumoniae must be separated from other
-hemolytic streptococci in the laboratory; this is usually ac-
complished with a disk susceptibility test using the unique sus-
ceptibility of pneumococci to Optochin (ethylhydrocupreine
hydrochloride). Pneumococci, but not other streptococci, are
also sensitive to bile or bile salts (e.g., 10% deoxycholate),
but the bile solubility test is now rarely performed in hospital
laboratories.
Pneumococci are classified within serotypes on the basis of
antigenic differences among capsular polysaccharides. These
capsular substances are complex polysaccharides that form
2/21/14 5:42 PM

hydrophilic gels on the surface of the organism. At present,
at least 90 serotypes have been identified, classified by two
systems of nomenclature (American and Danish). Capsular
polysaccharides are identified by agglutination; the Neufeld
quellung reaction, characterized by capsular swelling and in-
creased refraction in the presence of antisera, also useful for
identifying pneumococci in clinical specimens (e.g., CSF); pre-
cipitation; and counterimmunoelectrophoresis. It is important
to emphasize that cross reactions exist between individual
pneumococcal serotypes, as well as with other bacteria (e.g.,
E. coli, Klebsiella pneumoniae, Hib, and S. sanguinis). For
example, serotype 14 pneumococcal capsular polysaccharide
cross-reacts with type III group B streptococci and with certain
human ABO blood group isoantigens.
Capsular polysaccharide is essential for pneumococcal vir-
ulence, and a few serotypes are associated with most invasive
infections. Encapsulated organisms (smooth colonies on agar)
are virulent for humans and experimental animals, whereas
unencapsulated (rough colonies on agar) strains are avirulent.
Capsular polysaccharide enhances virulence through its anti-
phagocytic properties, as in Hib and meningococci.
Of the more than 90 known pneumococcal serotypes, only
a few (usually the lower number types rather than the higher
number types commonly found in the carrier state) account
for most invasive pneumococcal infections. The predominant
capsular types were types 1, 2, and 3 in the preantibiotic era.
A different pattern has emerged in the past 40 years, and it dif-
fers between adults and children. A few capsular types cause
the majority of bacteremic cases among adults: types 1, 3, 4, 7,
8, 9, 12, and 14, and less commonly types 6, 18, and 19 (these
are not listed in rank order). Approximately 65% of cases are
caused by eight serotypes, although no single serotype predom-
inates among bacteremic adults. Capsular types 14, 6, 18, 19,
23, 1, 4, and 9 cause approximately 85% of serious infections
in children, a pattern different from that observed in adults.
Perhaps more important with respect to this discussion, there
is a very strong correlation between serotypes causing pneu-
monia (or bacteremia) and those responsible for pneumococ-
cal meningitis (69). For example, 76% to 86% of blood and
CSF isolates were included among the 14 serotypes represented
in the original pneumococcal vaccine. However, marked geo-
graphic variations exist among pneumococcal serotypes caus-
ing invasive disease, and the serotype distribution may change
over time in a given locale. Furthermore, some serotypes may
be more virulent than others and associated with less favor-
able outcomes, including death. Older studies of pneumococ-
cal meningitis in the 1950s (summarized by Scheld [69]) noted
an increased mortality with disease caused by serotypes 2, 8,
and 12. Although type 12 caused only 2.5% of cases, it was
responsible for 30.7% of the deaths. Similarly, serotype 6 was
associated with four of eight deaths in a more recent survey.
The role of other cell surface components (such as
C-polysaccharide antigens, cell wall antigens, M- or R-protein
antigens) and putative toxins (such as hemolysin, neur-
aminidase, purpura-producing principle) in the pathogenesis
and pathophysiology of pneumococcal meningitis remains
poorly defined. Nevertheless, CSF inflammation is induced
by pneumococcal cell wall and its constituents (particularly
lipoteichoic acid) but not by purified pneumococcal capsular
polysaccharide (see later discussion).
Gram-Negative Bacilli
Approximately 84% of cases of neonatal meningitis and sepsis
attributable to E. coli are caused by strains bearing the K1
capsular polysaccharide antigen; this capsular type serves as
Scheld_Ch24.indd 375
Chapter 24: Acute Bacterial Meningitis 375
a marker of neurovirulence. In addition to the K1 capsule,
multiple other potential virulence factors for bloodbrain bar-
rier (BBB) traversal and meningitis have been documented in
E. coli from phylogenetic groups A, D, and B2 (e.g., O45:K1
and O18:K1 strains) (103).
Aerobic gram-negative bacilli have become increasingly
important in patients with bacterial meningitis (104). Beyond
the neonatal period, aerobic gram-negative bacillary men-
ingitis occurs in three major clinical settings: head trauma
(approximately 30% of cases, especially in conjunction with
CSF rhinorrhea or otorrhea); after neurosurgical procedures
(approximately 50% of cases); and in association with other
conditions (approximately 20% of cases), including strongy-
loidiasis, gram-negative bacteremia, ruptured brain abscess,
or impairment of host defense mechanisms (e.g., steroids or
AIDS). Many of these infections are nosocomial in origin,
although community-acquired gram-negative bacillary menin-
gitis is increasing in frequency, particularly in the elderly older
than 71 years and in debilitated, alcoholic, or diabetic adults
(105107). The most common causes of gram-negative aero-
bic bacillary meningitis beyond the first month of life include
Klebsiella species (about 40% of cases), E. coli (roughly 15%
to 30%), and Pseudomonas aeruginosa (about 10% to 20%).
In a recent study from Korea of 91 adult patients with noso-
comial meningitis, Acinetobacter species accounted for 32.5%
of cases (108).
Streptococcus agalactiae
Group B streptococci are the most common cause of invasive
neonatal disease in the United States, accounting for approxi-
mately 11,000 cases of meningitis and/or bacteremia yearly.
The incidence of group B streptococcal neonatal infections has
remained relatively stable in this country until recently (109).
The use of antimicrobial agents (e.g., ampicillin) in pregnant
women with vaginal colonization with group B streptococci
at the time of delivery has led to a decline in the incidence
of neonatal invasive group B streptococcal disease, perhaps,
as suggested by one study, with an increase in ampicillin-
resistant E. coli early-onset sepsis in low-birth-weight infants
(110). However, it appears to be increasing in frequency in the
developing world.
Group B streptococci are classified into six main serotypes
(designated Ia, Ib/c, Ia/c, II, III, and IV) based on the expression
of type-specific capsular polysaccharide antigens and various
surface proteins as additional antigenic markers (111); addi-
tional candidate serotypes are under evaluation. Although all
serotypes have been isolated from neonates with invasive dis-
ease, type III is responsible for the vast majority of meningeal
infections, suggesting a high virulence potential and/or CNS
tropism for this serotype. The chromosomal genetic diversity
of S. agalactiae was studied and the clonal nature of the native
bacterial populations was again demonstrated (112). A collec-
tion of 128 isolates representing all six serotypes, including
44 type III isolates from invasive episodes (18 recovered from
CSF), were subjected to multilocus enzyme electrophoresis,
an analysis based on electrophoretically demonstrable allelic
profiles at 11 metabolic enzyme loci, all encoded at the chro-
mosome level. Nineteen distinct ETs were identified in two
primary phylogenetic divisions, each representing a multilocus
clonal genotype. A single ET (ET-1), comprising 40 isolates of
serotype III group B streptococci, formed the first phylogenetic
division. These strains produced greater amounts of neur-
aminidase and were more virulent than the other type III iso-
lates found in several of the 18 ETs in the second division. This
newly evolved clone (ET-1) is responsible for most invasive
2/21/14 5:42 PM
 376 Part III: Bacterial and Mycoplasmal Infections
disease episodes caused by group B streptococci type III in the
United States (112). Overall, approximately 52% of group B
streptococcal meningitis cases in the United States occur dur-
ing the first month of life. In one recent review of 444 cases
of neonatal bacterial meningitis over a 7-year period, group
B streptococcus was the most common etiology in early-
onset (occurring between day 0 to 4 of birth) and late-onset
(occurring between day 5 and 28 of birth) disease, respon-
sible for 77% and 50% of cases, respectively (113). In the
United States, the overall mortality rate ranges from 7% to
27%. Survivors of group B streptococcal meningitis also have
substantial long-term morbidity (114), indicating the need for
ongoing developmental follow-up and the development of pre-
ventive strategies (see later discussion).
In addition to the common conditions of neonatal men-
ingitis and postpartum fever and/or bacteremia in parturi-
ent women caused by group B streptococci, these organisms
also cause serious infections in adults, including meningi-
tis (115,116). Risk factors in adults include age older than
60 years, diabetes mellitus, parturition, cardiac disease, colla-
gen-vascular diseases, malignancy, alcoholism, hepatic failure,
renal failure, corticosteroid therapy, decubitus ulcers, neuro-
genic bladder, previous stroke, and AIDS. No underlying ill-
nesses were found in 43% of patients in one review (116).
Listeria monocytogenes
L. monocytogenes remains an important cause of neonatal
meningitis; the source is the genital tract or subclinical infec-
tion of the mother. Although L. monocytogenes may cause
meningitis in normal adults, most patients are diabetic, alco-
holic, elderly, or immunosuppressed. L. monocytogenes had
been the major cause of bacterial meningitis among renal
transplant recipients, but this is decreasing in frequency as a
result of the use of TMP-SMX prophylaxis.
L. monocytogenes is widespread. Although clusters of nos-
ocomial cases and focal outbreaks are reported, most cases
of human listeriosis are sporadic. The incidence of L. mono-
cytogenes infections is difficult to quantitate. Many countries
in northern Europe have reported annual incidence figures of
approximately 2 to 3 per million. After a large (142 cases)
food-borne outbreak in Los Angeles County, California, in
1985, mandatory reporting of L. monocytogenes isolates by
clinical laboratories was instituted. During the first year of
active surveillance, 94 cases of listeriosis were reported (117),
for an annual crude incidence of 11.7 per million persons, sim-
ilar to figures (11.3 per million annually) reported from France
in 1984. Listeriosis is undoubtedly underreported.
Approximately one third of cases in the United States are
in neonates and/or their mothers (39% in the Los Angeles
survey) (117). The proportion of perinatal infections in Europe
is higher. Among the nonperinatal cases, various risk factors
for listeriosis were identified, including immunosuppression as
a documented history of steroid ingestion or chemotherapy
(35% of cases, the single most important risk factor); age
older than 75 years; renal disease; cancer; alcoholism and/or
cirrhosis; and AIDS. Nevertheless, serious Listeria infections,
including meningitis, remain uncommon in patients with
AIDS (118,119), but diagnosis of Listeria meningitis in any-
one younger than 50 years of age should prompt testing for
HIV, if not done previously. Of the nonperinatal cases, only
2 of 57 had no definable underlying risk factor; 21 of 57 had
meningitis (117). As stated earlier, L. monocytogenes remains
a distinctly unusual cause of meningitis in developing coun-
tries. Listerial infection is most common in infants younger
than 1 month of age (up to 10% of cases), adults older than
60 years of age, alcoholics, cancer patients, those receiving
Scheld_Ch24.indd 376
corticosteroid therapy, and immunosuppressed adults (e.g.,
renal transplant recipients) (120122). In one recent study,
patients with chronic lymphocytic leukemia had a greater than
1,000-fold risk of acquiring listeriosis (123). Other predispos-
ing conditions include diabetes mellitus, liver disease, chronic
renal disease, collagen-vascular diseases, pregnancy, and con-
ditions associated with iron overload. Listeria meningitis has
also been reported with use of antitumor necrosis factor-
(TNF- ) agents, such as infliximab in patients with Crohn dis-
ease (124) and ulcerative colitis (125), and etanercept in a pa-
tient with adult Still disease (126). Meningitis can also occur
in immunocompetent children and adults (127,128). In non-
perinatal cases, the route of transmission is often unknown.
At least 1% of normal individuals excrete the organism in
their stools, but contacts of symptomatic patients have much
higher excretion rates (approximately 25%). Nevertheless, the
true carriage rate, its duration, and its relationship to invasive
disease are poorly defined. Although often considered a zoo-
nosis, most patients do not report animal exposure. Reports
have emphasized food-borne transmission of L. monocy-
togenes, a route of transmission that accounts for the over-
whelming majority of sporadic cases. Many foods have been
implicated, including coleslaw, Mexican-style cheese, raw veg-
etables, seafood, pasteurized milk, Swiss cheese, raw hot dogs,
undercooked chicken, alfalfa sprouts, cantaloupe, diced celery,
hog head cheese (a meat jelly made from hog heads and feet),
and processed meats, thus pointing to the intestinal tract as
the usual portal of entry (120,122,129134). In one outbreak,
57 cases of listeriosis occurred in western Switzerland in as-
sociation with the consumption of soft cheese (135); 40% of
these cases were meningitis and 39% were meningoencepha-
litis. Some studies report a higher frequency of listeriosis in
summer, opposite to the seasonal pattern seen with most
other forms of bacterial meningitis. However, the incidence
of invasive listeriosis has been decreasing, likely a result of a
decrease in the prevalence of L. monocytogenes contamina-
tion of ready-to-eat food (136); this has been associated with
a decrease in nonperinatal listeriosis-associated deaths (137).
L. monocytogenes is a gram-positive, nonspore-forming,
catalase-positive, aerobic rod that may be difficult to culture
on initial isolation but that, once grown, passes readily on a
variety of laboratory media. The organisms may appear coc-
coid on Gram stains of clinical specimens, particularly CSF,
and are often mistaken for pneumococci. More importantly,
L. monocytogenes resembles diphtheroids and may thus be
dismissed as a contaminant, a grave error. The presence of
-hemolysis and a characteristic tumbling motility at room
temperature are used to separate L. monocytogenes from
similar diphtheroid-like organisms. A hemolytic and cytolytic
toxin (listeriolysin 0) of 52 kd appears essential for virulence;
the toxin is expressed under conditions of low pH and low iron
concentration and may facilitate phagolysosomal disruption
and growth within mononuclear phagocytes. At least 11 sero-
types are recognized, but more than 90% of invasive infections
are caused by three serotypes: Ia, Ib, and IVb. The rate of un-
favorable outcome among adults with Listeria meningitis was
recently found to increase over a 14-year period from 27% to
61%, with the emerging L. monocytogenes serotype ST6 iden-
tified as the main factor leading to a poorer prognosis (138).
Staphylococcus epidermidis
Coagulase-negative staphylococci are very rare causes of bac-
terial meningitis in children and adults, except in the setting
of an indwelling CSF shunt, where these organisms are the
most prevalent pathogen. Therefore, this group is discussed
elsewhere in this volume.
2/21/14 5:42 PM

Staphylococcus aureus
Meningitis caused by Staphylococcus aureus is relatively
unusual; this organism was responsible for 0.8% to 8.8%
of cases in various surveys (139,140). S. aureus is the second
most common cause of CSF shunt infections, accounting for
12% to 36% of cases. This organism is also frequently isolated
from patients with nosocomial meningitis and is responsible
for approximately 20% of such cases. Although secondary
meningitis in the setting of infective endocarditis is an uncom-
mon event, most of these infections are caused by S. aureus.
Other important associated conditions have been recognized,
including head trauma, neurosurgical procedures, various ab-
scesses (cerebral, epidural, oral, abdominal), sinusitis, osteo-
myelitis, decubitus ulcers, pneumonia, cellulitis, injection drug
use, malignancy, and infected intravascular grafts or shunts.
Several other predisposing factors have been proposed. In a
retrospective review of 28 cases of S. aureus meningitis seen
from 1972 to 1982 at three North Carolina teaching hospi-
tals, 22 occurred beyond the neonatal period (140). Among
the adult patients (n  20; mean age 52 years), 45% had an
underlying condition (diabetes mellitus, malignancy, renal
failure, immunosuppression), 35% had had head trauma or
undergone neurosurgery (ventriculoperitoneal shunt, crani-
otomy), and about 20% developed meningitis in association
with endocarditis or a paraspinal infection. Mortality was
high (50% in adults), especially when S. aureus meningitis
complicated a distant extracranial focus of infection (five of
the six patients with purulent meningitis during active endo-
carditis died) (140). The prognosis for S. aureus infections of
CSF shunts is more favorable. In a review of clinical and bac-
teriologic data from 61 postoperative and 43 hematogenous
cases of S. aureus meningitis from Denmark, postoperative
cases had a lower mortality rate (18%) than cases resulting
from hematogenous spread (56%); hematogenous S. aureus
meningitis had a higher mortality rate related to age, pres-
ence of shock, and infections with strains of phage type 95
(141). Hospital-acquired cases are often caused by methicil-
lin-resistant strains (142). In one series from 1999 to 2008
(143), S. aureus accounted for approximately 5% of cases of
culture-proven bacterial meningitis in adults; since 2005, more
than 75% of all cases were caused by methicillin-resistant
Staphylococcus aureus (MRSA) and 52% (11 of 21 cases) of
hematogenous cases were seen in injection drug users. In a
multicenter review of 86 cases of MRSA meningitis in adults
(144), the infection was nosocomial in 93% of cases; in those
patients with postoperative meningitis, the most common pre-
disposing conditions were the presence of CSF devices, neuro-
surgery, CSF leaks, and head trauma.
Anaerobic Bacteria
Meningitis caused by anaerobic bacteria is rare, accounting
for fewer than 1% of pyogenic cases, except following the in-
traventricular rupture of a brain abscess. Anaerobic meningitis
may be underrecognized because CSF is not routinely cultured
anaerobically. Enriched media and proper transport of CSF to
the laboratory, which are essential for isolation of anaerobes,
-lactam agents.
are not uniformly performed. Only five cases caused by strict
anaerobes were reported among 18,642 patients analyzed by
the CDC in one study (7).
Anaerobic meningitis is associated with a variety of clinical
conditions, including rupture of brain abscess or extension to
the surface of the brain; chronic otitis, mastoiditis, or sinus-
itis; head trauma; neurosurgical procedures (e.g., craniotomy,
laminectomy); congenital dural defects; abdominal trauma
Scheld_Ch24.indd 377
Chapter 24: Acute Bacterial Meningitis 377
or surgery; gastrointestinal disease; head and neck cancer;
suppurative pharyngitis; CSF shunts; and immunosuppression
(particularly corticosteroid administration) (145,146). Most
cases arise from spread of infection secondary to a contigu-
ous focus of disease; anaerobic meningitis rarely complicates
bacteremia from a distant extracranial focus.
A variety of bacterial species are responsible for anaerobic
meningitis. Only nine cases of Bacteroides fragilis meningitis
unaccompanied by a brain abscess had been reported in the
modern era through 1987 (147). Seven occurred in premature
infants or neonates (median age, 20 days), thereby complicat-
ing congenital defects or gastrointestinal disease such as necro-
tizing enterocolitis (148). Meningitis caused by Fusobacterium
species, usually Fusobacterium necrophorum, generally occurs
in older children (median age, about 5 years) or adults as a
complication of acute or chronic otitis media (148). A vari-
ety of anaerobic gram-positive cocci have been isolated in a
few cases, particularly peptostreptococci. Meningitis caused
by Clostridium species almost always develops following head
trauma or a neurosurgical procedure. For example, in a sum-
mary of 17 cases caused by Clostridium perfringens (149), only
3 were not associated with CNS trauma or surgery. Although
the disease course is highly variable, some cases of clostridial
meningitis are characterized by intracranial gas formation,
visible on plain skull radiographs or computed tomography
(CT); CSF white blood cell (WBC) concentrations exceeding
20,000/mm3; and death within hours of presentation. A few
cases of meningitis caused by Actinomyces species (in the
absence of brain abscess formation) and Propionibacterium
acnes (usually subacute with a predominantly monocytic CSF
pleocytosis) have also been reported. In approximately one
eighth of patients, the infection is mixed, with anaerobic plus
aerobic or microaerophilic organisms recovered from CSF.
Unusual Etiologic Agents
CNS infections caused by higher bacteria (e.g., Mycobacterium
species, Nocardia species, Actinomyces species), spirochetes
(e.g., Treponema pallidum, Borrelia burgdorferi, Leptospira
species), Brucella species, and so on, are discussed elsewhere in
this volume. A plethora of bacteria have been documented as the
cause of meningitis in isolated case reports or in small numbers
of patients, including group A streptococci usually in associa-
tion with pharyngitis, otitis media, and/or sinusitis (150); non-
pneumococcal -hemolytic streptococci such as Streptococcus
mitis (151); enterococci (152,153); Streptococcus gallolyticus;
diphtheroids (although P. acnes is an important etiologic agent
in patients with CSF shunt and drain infections); N. gonor-
rhoeae (approximately 30 cases reported in the past 20 years);
Neisseria subflava; Gardnerella vaginalis (one case report);
many members of the Enterobacteriaceae in addition to E. coli
and Salmonella species; Flavobacterium meningosepticum;
Haemophilus species other than H. influenzae; and many oth-
ers. Fewer than 0.5% of adult cases of bacterial meningitis
are caused by group C streptococci but may occur in humans
after contact with domestic animals (especially horses) or their
unpasteurized products (154,155); however, mortality is high,
perhaps because of the unpredictable susceptibility of this
organism to
Despite the frequency with which the viridans strepto-
cocci cause bacteremia, they are unusual causes of meningitis
(0.3% to 5% of culture-proven cases) (156). Streptococcus
salivarius meningitis has been reported following spinal an-
esthesia (157,158) and myelogram procedures (159), sup-
porting the importance of appropriate infection control
practices (i.e., masks, proper aseptic technique, and safe
injection practice) in those who perform spinal procedures.
2/21/14 5:42 PM
 378 Part III: Bacterial and Mycoplasmal Infections

Streptococcus suis is the most frequent cause of bacterial

meningitis in southern Vietnam and is associated with sig-
nificant morbidity attributable to hearing loss (160); the pig
is the natural reservoir of this microorganism and the main
source of human infection. Risk factors for S. suis meningitis
include eating high-risk dishes (such as undercooked pig
blood or pig intestine) popular in parts of Asia, occupational
exposure to pigs, and exposures to pig or pork in the pres-
ence of skin injuries (161).
Polymicrobial bacterial meningitis, with simultaneous re-
covery of two or more bacterial species from CSF, is unusual.
Mixed infections account for about 1% of bacterial meningitis
cases. In a review of 34 series encompassing 11,281 cases of
bacterial meningitis, 116 cases (1%) were mixed (162). This
condition appears to be evolving in the antibiotic era. Before
1950, nearly all cases occurred in children and were caused
by combinations of bacteria commonly associated with men-
ingitis (the three major meningeal pathogens). Since 1950,
most cases have occurred in adults, with a wider spectrum of
etiologic agents, particularly gram-negative aerobic bacilli. FIGURE 24.2 Infiltration of the meninges by neutrophils.
Approximately one third of cases were nosocomially acquired.
Common predisposing conditions in the older population af-
fected since 1950 include contiguous foci of infection, tumors
in close proximity to the neuraxis (e.g., head and neck), rectal and the pathophysiology of associated complications have sub-
carcinoma, or fistulous communications with the CNS. The sequently allowed for a more complete understanding of the
mortality rate is 63% for cases occurring after 1950. Several pathologic processes operating in this disorder.
cases of meningitis caused by mixed bacterial and mycobacte- Bacteria reach the meninges through one of the following
rial or fungal agents have also been reported. pathways: (a) hematogenous dissemination from a distant
Simultaneous isolation of viruses and bacteria from the site (e.g., nasopharynx, lung, skin, and genitourinary tract);
CSF is rare; only seven well-documented cases were reported (b) spread from an adjacent suppurative focus of infection
prior to 1988 (163). However, in a 1-year retrospective review (e.g., otitis media, sinusitis, and mastoiditis); and (c) a con-
from the Ohio State University published in 1986, 5 (2.8%) of genital or an acquired structural defect (176).
176 children with CSF enteroviral isolates also had bacterial Once bacteria gain access to the SAS, an inflammatory
meningitis (163). Conversely, CSF samples from 5 (4.8%) of process ensues (Fig. 24.2). Neutrophils migrate into the SAS,
105 children with bacterial meningitis also grew an entero- producing a purulent exudate. On gross examination, the exu-
virus. All the patients presented in late summer at the peak date has a gray-yellow or yellow-green appearance (Fig. 24.3).
of the enterovirus season, and each case was caused by a dif-
ferent bacterial pathogen. Because the CSF formula was in-
distinguishable from that of patients with typical bacterial
meningitis, and because the clinical course and response to
therapy were similar to those of patients with typical bacte-
rial meningitis, this condition may be underrecognized, as CSF
viral cultures are rarely performed when bacterial meningitis
is the likely diagnosis.

PATHOGENESIS AND
PATHOPHYSIOLOGY
Despite the availability of effective antimicrobial therapy,
bacterial meningitis continues to be a potentially fatal ill-
ness. Several investigators have examined the pathogenic and
pathophysiologic mechanisms operating in meningitis, with
the aim of improving the outcome of patients with this disor-
der. These pathogenetic and pathophysiologic mechanisms are
discussed in detail in Chapter 23 and are detailed in a number
of excellent reviews (164174).

PATHOLOGY
Adams et al. (175) described the pathology of bacterial menin-
gitis in 1948 based on examination of autopsy material from
patients with H. influenzae meningitis. Experimental models of FIGURE 24.3 Purulent exudate in subarachnoid space over cerebral
bacterial meningitis, knowledge of host defense mechanisms, hemispheres.

Scheld_Ch24.indd 378 2/21/14 5:42 PM


FIGURE 24.4 Purulent exudate in the cerebral sulci.
It is most abundant in the cisterns at the base of the brain
and over the convexities of the hemispheres in the rolandic
and sylvian sulci (175) (Fig. 24.4). The tendency for exudate
to accumulate in the cisterns at the base of the brain is ex-
plained by the anatomy of the SAS, which is deepest at the
base of the brain. The various cisterns are expansions of the
SAS, with the largest of these areas lying between the cerebel-
lum and medulla and extending downward below the foramen
magnum, the so-called cisterna magna or cerebellomedullary
cistern (177). Purulent exudate accumulates in this cistern and
extends into the other basal cisterns and onto the posterior
surface of the spinal cord (Figs. 24.5 and 24.6). The exudate
also extends into the arachnoidal sheaths of the cranial nerves
and into the perivascular spaces of the cortex. A small amount
of exudate may be found in the ventricular fluid and attached
to the ventricular walls and choroid plexus; thus, the appear-
ance of the ventricular fluid is usually cloudy by the end of the
first week of the infection (175).
Microscopic examination of the subarachnoid exudate
in the early stages of infection demonstrates large numbers
of neutrophils and bacteria (lying either free in the exudate
or within neutrophils) (Fig. 24.7) (176). The role of the
FIGURE 24.5 Purulent exudate surrounding the temporal poles,
optic chiasm, and pons.
Scheld_Ch24.indd 379
Chapter 24: Acute Bacterial Meningitis 379
FIGURE 24.6 Purulent exudate (arrow) covering spinal cord and
nerve roots.
neutrophil in eradicating infection at this stage is unknown.
The presence of free-living bacteria in the exudate suggests
that phagocytosis by neutrophils is incomplete as a result of
deficient opsonic activity in CSF; however, low CSF leukocyte
concentrations in the presence of high CSF bacterial concen-
trations have been associated with a poor prognosis in both
experimental and human meningitis (178). These observa-
tions suggest that the neutrophils have a beneficial role in par-
tial control of the early stages of the infection. The presence of
large numbers of neutrophils in the SAS and vessel walls may,
however, also be detrimental to the host, as is discussed in the
previous section.
Within the first 48 to 72 hours of infection, there is
evidence of inflammation in the walls of the small and
medium-sized subarachnoid arteries (Fig. 24.8). The endo-
thelial cells swell and multiply, narrowing the lumen. The
adventitia is infiltrated by neutrophils, and neutrophils and
lymphocytes form a layer beneath the intima (Fig. 24.9).
Subintimal arterial infiltration by neutrophils and lympho-
cytes is relatively unique to infection of the meninges, and
it may be related to the anatomy of the meningeal arter-
ies. It is only rarely observed in inflammatory processes in
other organs (175). The adventitia of the subarachnoid ves-
sels, as they enter the brain parenchyma, is formed by the
arachnoid membrane. As arteries and veins enter the brain
parenchyma, they carry with them a sleeve of arachnoid im-
mediately surrounding the vessels and a sleeve of pia mater
FIGURE 24.7 Diplococci. Red-stained cells are polymorphonuclear
leukocytes.
2/21/14 5:42 PM
 380 Part III: Bacterial and Mycoplasmal Infections
FIGURE 24.8 Aggregation of white blood cells in the arterial
intima.
external to this. Between these two layers lies an extension
of the SAS, known as the perivascular space or Virchow-
Robin space, which is filled with CSF (177) (Fig. 24.10).
Because the vessel wall is enveloped by the arachnoid mem-
brane, it is affected early by any inflammatory process in
the meninges. However, as shown in animal models of
bacterial meningitis, the arachnoid membrane generally
remains intact.
The meningeal veins become distended and develop mural
inflammation during bacterial meningitis. There may be
focal necrosis of the vessel wall, along with mural thrombus
formation in the lumen of the vein or in the dural sinus (175)
(Fig. 24.11). Hemorrhagic cortical infarction is the result of
cortical venous and dural sinus thrombosis.
Toward the end of the first week of meningeal infection,
there is a change in the cellular composition of the subarachnoid
exudate. Neutrophils begin to degenerate and are removed
Scheld_Ch24.indd 380
FIGURE 24.10 Inflammatory cell extension from the subarachnoid
space into a space of Virchow-Robin. Note the infiltrate around the
arterial wall and on the intimal surface.
by macrophages, which are derived from meningeal histio-
cytes. Lymphocytes and fibroblasts proliferate in the exudate.
Microscopic changes in the brain parenchyma may also be
present. The nuclei of neurons and glial cells become shrunken,
pyknotic, and darkly staining (Fig. 24.12). Rod-shaped mi-
croglial cells and astrocytes increase in number in the cerebral
and cerebellar cortex, brainstem, and spinal cord (Fig. 24.13).
Astrocytic processes become swollen (Fig. 24.14). There is a loss
of myelinated fibers in the subcortical white matter, cerebellum,
and brainstem (175). Similar morphologic changes are seen in
ischemic and hypoxic cortical injury, suggesting that ischemia
and/or hypoxia may contribute to the pathologic changes from
bacterial meningitis at this stage.
Also at the end of the first week of the infection, there
is infiltration of the subependymal tissues and perivascular
spaces by neutrophils and lymphocytes. The ependymal and
subependymal tissues become edematous, and cells begin to
FIGURE 24.9 Small artery with inflammatory
infiltration of the vessel wall and mural thrombus.
2/21/14 5:42 PM

FIGURE 24.11 Inflammatory infiltrate in the wall of a cerebral vein
with thrombosis. Note inflammatory cells in thrombus.
FIGURE 24.12 Shrunken red neurons.
FIGURE 24.13 Marked proliferation of microglial cells (arrow).
Scheld_Ch24.indd 381
Chapter 24: Acute Bacterial Meningitis 381
FIGURE 24.14 Reactive gemistocytic astrocytes (arrow).
die; desquamation of the ependymal lining also occurs. Rod-
shaped microglial cells and swollen astrocytes proliferate and
overgrow the remnants of the ependymal lining. An inflamma-
tory infiltrate in the walls of the subependymal arteries may
occlude the vessel, leading to tissue necrosis (175).
As the infection progresses, the subarachnoid exudate
continues to accumulate. In some areas, it may become sev-
eral millimeters thick (Fig. 24.15). Toward the end of the sec-
ond week, the exudate separates into two layers. The outer
layer, just beneath the arachnoid membrane, is composed of
neutrophils and fibrin. The inner layer, which is contiguous
with the pia, is composed of lymphocytes, plasma cells, and
macrophages (175). As the subarachnoid exudate continues
to accumulate, the flow of CSF may become obstructed.
The dynamics involved in obstruction of CSF flow are as
follows: the bulk of CSF is formed by the choroid plexus
in the lateral and third ventricles, and it flows through the
cerebral aqueduct into the fourth ventricle. CSF leaves the
fourth ventricle through the midline foramen of Magendie
and the lateral foramina of Luschka to reach the SAS (177).
When the foramina of Magendie and Luschka are blocked by
exudate, the spinal fluid cannot circulate to the convexities of
FIGURE 24.15 Purulent exudate in the sylvian fissure and covering
the cerebellum in the brain of a premature infant with meningitis.
2/21/14 5:42 PM
 382 Part III: Bacterial and Mycoplasmal Infections

in the subcortical white matter. Cytotoxic edema is caused

by an accumulation of intracellular water and sodium with
subsequent swelling of cells. Membrane polyunsaturated fatty
acids and other toxic factors released from leukocytes contrib-
ute to the development of cytotoxic edema (69). Interstitial
edema is a result of obstruction to CSF resorption, as discussed
earlier in this chapter.
Cerebral edema leads to an increase in ICP, and increased
ICP adversely affects cerebral perfusion pressure (CPP), defined
as the difference between the systemic mean arterial pressure
(MAP) and the ICP: CPP  MAP  ICP (180). Cerebral blood
flow may be maintained at normal or near-normal levels in the
presence of increased ICP, provided that the CPP is maintained
at a range of at least 50 to 60 mm Hg. As ICP continues to rise,
or if systemic arterial pressure decreases, cerebral ischemia and
infarction may result.
Experimental evidence exists for a loss of autoregulation
of cerebral blood flow in bacterial meningitis (181). This is
FIGURE 24.16 Hydrocephalus. another potential contributing factor to the development of
cerebral ischemia in this infection. Cerebral blood flow is
normally constant within a range of mean systemic arterial
the brain, where it is normally absorbed. The flow of CSF is
pressure from 50 to 150 mm Hg. When autoregulation is
blocked at the level of the fourth ventricle, resulting in non-
disturbed, systemic hypotension results in decreased cerebral
communicating or obstructive hydrocephalus (Fig. 24.16).
blood flow and cerebral ischemia (182).
From the fourth ventricle, CSF normally flows to the SAS at
Cerebral edema may lead to herniation of brain tissue.
the base of the brain. From here, CSF flows up over the convex-
Herniation may compress intracerebral arteries, leading to
ity of the hemispheres to be absorbed by the arachnoid villi in
ischemia and infarction; it may also compress the surface of
the intracranial venous sinuses (177). The presence of a fibrino-
the brain against the dura, leading to necrosis of brain tis-
purulent exudate in the SAS interferes with the absorption of
sue. Tonsillar herniation, the downward displacement of the
CSF by the arachnoid villi. This obstruction to CSF resorption
cerebellar tonsils through the foramen magnum, can result in
resulting from inflammatory changes in the arachnoid granula-
apnea, hemodynamic instability, coma, and death (177,183).
tions results in communicating hydrocephalus. When the sub-
The pathologic lesions described are typical of meningi-
arachnoid exudate has been present for several weeks, there
tis caused by bacteria, but some distinctions among lesions
are (a) marked fibrosis of the arachnoid villi and (b) pockets of
caused by H. influenzae, N. meningitidis, and S. pneumoniae
exudate walled off by adhesions between the arachnoid mem-
infection have been observed. The subarachnoid exudate
brane and dura (175). These fibrotic changes produce further
in H. influenzae meningitis is very thick and purulent, with
mechanical obstruction to the resorption of CSF by the arach-
loculated pockets of pus in the basilar cisterns and cerebral
noid villi. The end results are (a) transependymal movement of
sulci. In contrast, the exudate in pneumococcal meningitis
CSF from the ventricular system into the brain parenchyma and
tends to be more extensive over the convexities of the hemi-
(b) the development of interstitial cerebral edema.
spheres than in the basilar cisterns (Fig. 24.18). In menin-
The development of diffuse cerebral edema and increased
ICP further complicates the pathologic changes already
described. Cerebral edema is defined as an increase in the
volume of the brain resulting from an increased water con-
tent (179) (Fig. 24.17). The cerebral edema in meningitis is
a combination of vasogenic, cytotoxic, and interstitial edema
(170). Vasogenic edema is a result of increased permeabil-
ity of brain capillaries with the subsequent accumulation of
water and protein molecules in the extracellular space, mainly

FIGURE 24.17 Specimen demonstrating the characteristic changes of FIGURE 24.18 Purulent exudate over the cerebral convexities sec-
cerebral edema-flattened gyri and narrowed ventricles. ondary to pneumococcal meningitis.

Scheld_Ch24.indd 382 2/21/14 5:42 PM


FIGURE 24.19 Petechial hemorrhages in gray matter secondary to
meningococcal meningitis.
gococcal meningitis, the pathologic changes depend on the
severity and duration of the infection. In acute fulminating
meningococcemia, death may occur before pus can accumu-
late in the SAS. At autopsy, severe hyperemia and swelling
of cerebral tissue are evident, with petechial hemorrhages
in the gray and white matter (Fig. 24.19) and in the sub-
ependymal regions of the lateral ventricles. A hemorrhagic
ependymitis is typical of severe lethal meningococcal infec-
tion (Fig. 24.20). The presence of pus in the SAS may be evi-
dent only by microscopic examination (183). The pathologic
changes in meningococcal meningitis of longer duration are
similar to those described for meningitis caused by pyogenic
organisms in general.
Cranial and spinal nerve deficits, focal neurologic deficits,
seizure disorders, and subdural effusions are well-recognized
complications of meningitis. The cranial and spinal nerve
deficits are usually transient and caused by exudate in the
SAS surrounding the nerves. Focal neurologic deficits and sei-
zure activity arise from cortical and subcortical ischemia and
infarction (bland and hemorrhagic), which are the result of
inflammation and thrombosis in arteries and veins. Subdural
effusions are relatively common in the course of bacterial
meningitis in children; they are the result of an increase in
the permeability of the thin-walled capillaries and veins in
the inner layer of the dura, with leakage of fluid into the
subdural space.
FIGURE 24.20 Hemorrhagic ventriculitis complicating meningitis.
Scheld_Ch24.indd 383
Chapter 24: Acute Bacterial Meningitis 383
Bacteremia also contributes to the pathologic features of
this disease. Bacteremia is present in 30% to 90% of cases
of bacterial meningitis. It can be either the primary event
leading to development of meningitis or a secondary event
arising from the clearance of bacteria from the SAS through
the arachnoid villi to the bloodstream. Pneumococcal cell
walls activate the alternative complement pathway, with
the generation of chemotactic peptides in the systemic
circulation and in CSF. The principal component of this
activity is C5a, a highly chemotactic peptide that is a
stimulus for an intense CSF accumulation of neutrophils.
By this process, neutrophils also become sequestered in
the pulmonary vascular bed, leading to cardiopulmonary
dysfunction, neutrophil-mediated vascular damage, and the
development of the acute respiratory distress syndrome and
thereby further contributing to the morbidity and mortality
of meningitis (69).
CLINICAL MANIFESTATIONS
Neonates
Clinical clues to the presence of meningitis in neonates are
temperature instability (hypothermia or hyperthermia), list-
lessness, high-pitched crying, fretfulness, lethargy, refusal to
feed, weak suck, irritability, jaundice, vomiting, diarrhea, or
respiratory distress (184,185). Nuchal rigidity is not typically
found in the neonate. A change in the childs affect or state
of alertness is one of the most important signs of meningitis.
A bulging fontanelle (seen in one third of cases) usually occurs
late during the course of illness; seizures are observed in 40%
of neonates with bacterial meningitis.
Infants and Children
The symptoms and signs of acute bacterial meningitis in
infants and children depend on the age of the child, duration
of illness, and host response to infection (186); the clinical fea-
tures can be subtle, variable, nonspecific, and even absent. The
initial symptoms of bacterial meningitis in infants and chil-
dren may be any of the following: fever, stiff neck, headache,
lethargy, irritability, nausea, vomiting, and photophobia
(Table 24.3). In children 1 to 4 years of age, fever (94%), vom-
iting (82%), and nuchal rigidity (77%) are the most common
initial symptoms.
Although the symptoms are nonspecific, the combination
of one or more of these symptoms with signs of meningeal
irritation should suggest the diagnosis of meningitis. The classic
signs of meningeal irritation are nuchal rigidity and Brudzinski
and Kernig signs. Brudzinski actually described several signs of
meningeal irritation, including the nape-of-the-neck sign, the
identical contralateral reflex sign, and a reciprocal contralateral
reflex sign, as well as others (187,188). The nape-of-the-neck
sign is Brudzinskis best-known sign and is universally recog-
nized today as Brudzinski sign. The nape-of-the-neck sign
is positive when passive flexion of the neck results in flexion
of the hips and knees. The identical contralateral reflex sign
is elicited with the patient in the supine position by passively
flexing the hip and knee on one side. This sign is positive when
the contralateral leg flexes with this maneuver. The reciprocal
contralateral reflex sign is positive when the leg that has flexed
in response to passive flexion of the other leg begins to extend
spontaneously, resembling a little kick. The identical and re-
ciprocal contralateral reflex signs are not elicited as often as the
2/21/14 5:42 PM
 384 Part III: Bacterial and Mycoplasmal Infections

TA B L E 2 4 . 3 meningitis, 70 of viral meningitis, and 12 of unknown etiol-

ogy. Lethargy was more common in children with bacterial
SYMPTOMS AND SIGNS OF BACTERIAL MENINGITIS meningitis than in children with viral meningitis: 50% of the
BY AGE-GROUP children with bacterial meningitis were lethargic, and 32%
of the children with viral meningitis were lethargic (p .14).
Age-Group Symptoms Signs Although vomiting is a symptom of meningeal irritation, it
is a nonspecific symptom in children. Vomiting occurred in
Child Fever Nuchal rigidity 336 children, 84 of whom had bacterial or viral meningitis.
Lethargy or altered level Purpuric or Fever was present in every child with meningitis. The tempera-
of consciousness petechial rash ture elevations were higher in bacterial meningitis than in viral
Headache Seizures meningitis; 80% of the children with bacterial meningitis had
Irritability Ataxia temperatures of 38.8C or higher. In children with viral men-
Nausea and vomiting Focal neurologic ingitis, 40% had temperatures of 38.8C or greater (193). The
Respiratory symptoms deficits, including possibility of meningitis in a child who does not or cannot
Photophobia cranial nerve complain of headache or stiff neck and who does not have
palsies meningeal signs should be suspected when fever accompanies
Adult Fever Nuchal rigidity changes in behavior, changes in mental status, or new onset
Headache Altered level of of seizures.
Lethargy, confusion, or consciousness In one recent review of children aged 2 months to 15 years
coma Seizures who presented with suspected meningitis, the classic clinical
Nausea and vomiting Focal neurologic signs had limited value in establishing the diagnosis (194).
Photophobia deficits, including Clinical examination revealed nuchal rigidity in 65% of
Respiratory symptoms cranial nerve those with meningitis; Brudzinski and Kernig signs were elic-
palsies ited in 51% and 27% of those with meningitis, respectively.
Elderly Fever Nuchal rigidity Therefore, physicians should have a low threshold for LP in
Confusion or coma Altered level of patients at high risk for bacterial meningitis, given the serious
Headache consciousness nature of this disease.
Respiratory symptoms Seizuresstatus In a review of 1,064 cases of bacterial meningitis in infants
epilepticus and children, there were no signs of meningeal irritation in
16 patients (1.5%). Eight patients were older than 2 years
of age. LP was performed because of unexplained fever as-
sociated with an altered level of consciousness, behavioral
changes, seizure activity, or petechial skin lesions. Meningitis
was caused by N. meningitidis in seven patients, H. influenzae
nape-of-the-neck sign (188). The manner in which Kernig sign in six, S. pneumoniae in two, and Salmonella enteritidis in one.
is elicited and the interpretation of the results of the maneuver Most patients had a peripheral leukocytosis with a left shift.
as it is done today are different from those originally described The peripheral WBC count was greater than 10,000 cells/mm3
by Kernig (189). The maneuver as described by Kernig was in 12 patients and greater than 20,000 cells/mm3 in 7 patients
performed with the patient in a seated position while the phy- (195). The results of this review suggest that although menin-
sician attempted to extend the knee passively. In the presence gitis may occasionally occur without meningeal signs, there
of meningitis, knee extension was resisted so that a contrac- will usually be other signs or symptoms of intracranial infec-
ture of the extremities was maintained (188,189). Today the tion and a peripheral leukocytosis.
sign is elicited with the patient in a supine position. The thigh Observational data that are useful in predicting the pres-
is flexed on the abdomen, with the knee flexed. The leg is then ence of serious illness (e.g., meningitis) in a febrile child in-
passively extended. When meningeal inflammation is present, clude the following: (a) quality of cry, (b) reaction to parent
the patient resists leg extension (190). Nuchal rigidity and stimulation, (c) level of consciousness, (d) color, (e) hydra-
Brudzinski and Kernig signs are observed in fewer than 50% tion, and (f) response to social stimulation. These six items
of children with bacterial meningitis. were identified as significant and independent predictors of
The possibility of bacterial meningitis should be considered serious illness from a list of 14 observational items, scored
in every child with fever, vomiting, nuchal rigidity, and lethargy by pediatricians, for 312 febrile children 24 months of age or
or an altered mental status. In a review of 110 cases of culture- younger (196). The quality of the cry in a child with a serious
proven bacterial meningitis in children, fever (38.5C) was illness was weak, moaning, or high pitched. A healthy child
the most common symptom, being present in 94% of patients. was either not crying or had a strong cry with normal tone.
The absence of fever, particularly hypothermia, was associated Reaction to parental stimulation was judged based on the par-
with a worse prognosis, perhaps related to the slower rate of ent holding the child, talking to the child, or giving the child
bacterial replication in CSF when temperatures are elevated. a bottle. The child with a serious illness did not stop crying or
Apart from fever, the most common symptoms were (a) vomit- barely responded to stimulation by its parent. Consciousness
ing (82%) and nuchal rigidity (77%) in 1- to 4-year-old chil- was impaired in children with serious illnesses. They were le-
dren and (b) headache (92%) in children ages 5 to 12 years. thargic, stuporous, or obtunded. Sick children were described
Vomiting and nuchal rigidity were present in 80% of the as pale, cyanotic, or ashen. Signs of dehydration were present.
children who were 12 months or older. Nuchal rigidity is a The response to social stimulation was judged according to
classic sign of meningitis but can be absent early in the course whether the child would smile when talked to or smiled at.
of this illness; therefore, the absence of nuchal rigidity should Sick children did not respond to social stimulation. These six
not exclude the diagnosis of bacterial meningitis (191). items, when used together, had a specificity of 88% and a sen-
In a review of 709 LPs done on children in an outpatient sitivity of 77% for the presence of serious illness. When com-
setting in which there was a concern for meningitis, the CSF bined with history and physical examination, the sensitivity of
was abnormal in 16% (192). There were 30 cases of bacterial the six-item model increased to 92%. If all six of the observa-

Scheld_Ch24.indd 384 2/21/14 5:42 PM

 Chapter 24: Acute Bacterial Meningitis 385

tion items were normal in a child, the probability of that child an LP is very low. If, however, there are clinical signs of menin-
having a serious illness was only 4.7% (196). gitis, an LP is indicated. If the seizure has a focal onset or there
The possibility of meningitis in a febrile child may also is a focal neurologic deficit on examination, CT is indicated
be suggested by the tempo of the illness. The presentation of before LP is performed. All children with new-onset febrile
meningitis in children is that of either a subacute infection or convulsions in whom LP is not performed should be reexam-
an acute fulminant illness. Children with a subacute presenta- ined 1 to 4 hours after the initial examination to be sure that
tion have fever, lethargy, and nuchal rigidity that progresses serious disease is not present (203).
over 1 to several days and is usually preceded by an upper The presence of a diffuse erythematous maculopapular
respiratory tract infection or otitis media (197). Children rash may be an early manifestation of meningococcemia or
with meningitis may also present with an illness that has been may represent a viral illness. The presence of a purpuric or
progressive over 24 to 72 hours or a fulminant illness that petechial rash on the trunk and lower extremities is sugges-
develops over several hours. tive of meningococcemia, although petechiae are sometimes
Children with a more rapidly progressive illness have signs seen in echovirus type 9 meningitis, acute staphylococcal en-
and symptoms of meningeal irritation and increased ICP on docarditis, and rarely pneumococcal or H. influenzae men-
initial presentation. CSF pressures exceeding 300 mm H2O ingitis (198,204). Petechiae are found in the skin, mucous
are common in acute bacterial meningitis, and ICPs exceeding membranes, or conjunctivae, but never in the nailbeds, of pa-
500 to 600 mm H2O are not unusual (197,198). Increased tients with meningococcemia; they usually fade in 3 or 4 days
ICP in bacterial meningitis in children is the consequence, in (205). Petechiae and/or purpura occurs in 50% to 75% of
part, of vasogenic and cytotoxic cerebral edema, altered CSF children with meningococcal meningitis. Children with fulmi-
resorption, and the inappropriate secretion of antidiuretic nating meningococcal septicemia may have the Waterhouse-
hormone (199) (see Chapter 23). The clinical manifestations Friderichsen syndrome, characterized by the following: (a)
of increased ICP include (a) an altered level of consciousness; sudden onset of a febrile illness, (b) large petechial hemor-
(b) dilated, poorly reactive or nonreactive pupils; (c) abnor- rhages in the skin and mucous membranes, (c) cardiovascu-
malities of ocular motility; (d) pathologically brisk lower ex- lar collapse, and (d) disseminated intravascular coagulation.
tremity reflexes; and (e) bradycardia and hypertension, also Of all patients with a meningococcal infection, 10% to 20%
known as Cushing reflex. The development of elevated ICP have a fulminant meningococcal septicemia (206) (Color
should be anticipated and monitored in a child with bacte- Figs. 24.21 to 24.26).
rial meningitis. The absence of papilledema does not exclude Focal neurologic signs, such as cranial nerve palsies with
the presence of increased ICP. Papilledema is rarely observed abnormalities of ocular motility, hemiparesis, visual field
early in the course of increased ICP and is usually not evident defects, and ataxia, may occur early or late in the course of
until increased ICP has been present for at least several hours bacterial meningitis in approximately 15% of children (197).
(197,198). For this reason, the presence of papilledema at the Cranial nerve palsies likely develop as the nerve becomes
time of the initial presentation should raise suspicion of a focal enveloped by exudate in the arachnoidal sheath surrounding
intracranial process such as a brain abscess or other localized the nerve. Alternatively, cranial nerve palsies may be a sign
mass lesion, and it is an indication for CT prior to LP. of increased ICP. The presence of bilateral palsies of the sixth
Seizures occur in 30% to 40% of children with acute bacte- cranial nerve, manifested as weakness of lateral rectus muscles,
rial meningitis, usually during the first 3 days of illness (200). is a well-recognized sign of increased ICP.
In one review of 52 cases of H. influenzae meningitis in chil-
dren, seizures occurred in 44% (23 cases) (198). There has
been a long-standing controversy about whether to do an LP
in febrile children with new-onset seizures. The vast majority
of children who present with a new-onset seizure associated
with fever and who have a normal neurologic examination do
not have meningitis. One series reviewed the results of LP per-
formed on 328 children presenting with their first febrile con-
vulsion. None of the children had meningeal signs. Meningitis
was diagnosed by LP in four children (1.2%). Three of the
children had viral meningitis, and one had H. influenzae men-
ingitis. All four children were younger than 18 months of age.
All the children in this series who were older than 18 months
of age had unequivocal signs of meningitis (201). A similar ob-
servation was made in a review of LP performed on 304 chil-
dren for evaluation of new-onset seizures associated with
fever. There were 15 cases of meningitis, and in only one case
were there no meningeal signs. In that case, the child had viral
meningitis and recovered fully without treatment (202). These
studies suggest that LP should not necessarily be routinely per-
formed in children for evaluation of simple febrile convulsions
in the absence of meningeal signs.
Convulsive seizure associated with fever is a problem
unique to young children. A simple febrile seizure, as defined
by the Consensus Development Meeting on Long-term
Management of Febrile Seizures (1980), occurs between ages
3 months and 5 years in association with fever and is of brief
duration (15 minutes), nonfocal, nonrepetitive, and without
associated neurologic deficits. If the seizure fits this definition FIGURE 24.21 Early appearance of rash in a patient with acute me-
and the child is awake and alert after the seizure, the yield of ningococcemia.

Scheld_Ch24.indd 385 2/21/14 5:42 PM

 386 Part III: Bacterial and Mycoplasmal Infections

FIGURE 24.22 Close up of rash in a patient with acute meningo- FIGURE 24.23 Fulminant petechial/purpuric rash in patient with
coccemia. meningococcemia.

FIGURE 24.24 Examples of severe purpura fulminans and peripheral gangrene in two patients with
acute meningococcemia.

FIGURE 24.26 Gross pathologic specimen showing intraventricular

FIGURE 24.25 Gross pathologic specimen depicting adrenal hemor- hemorrhage from a patient with acute meningococcemia and dissemi-
rhage in fulminant acute meningococcemia (Waterhouse-Friderichsen nated intravascular coagulation. Note marked right-to-left herniation
syndrome). (fatal in this case) and periventricular white matter edema.

Scheld_Ch24.indd 386 2/21/14 5:42 PM


Hemiparesis may be caused by vasculitis and cerebral
infarction or may be a sign of the presence of a large sub-
dural effusion. Subdural effusions commonly develop in the
course of bacterial meningitis in children and are not usually
associated with clinical symptomatology. Subdural effusions
develop when the infection in the adjacent SAS leads to an
increase in the permeability of the thin-walled capillaries and
veins in the inner layer of the dura. The result is leakage of al-
bumin-rich fluid into the subdural space, usually a self-limited
process. When the inflammatory process subsides, fluid for-
mation usually ceases and the fluid in the subdural space is re-
sorbed (197). Some subdural effusions are, however, clinically
significant. The development of a hemiparesis or increased
ICP may be the consequence of an enlarging subdural effusion
causing mass effect. The presence of a prolonged fever in a
child with a subdural effusion suggests that the effusion has
become infected.
Ataxia may be the presenting sign of bacterial meningitis
in a child. Ataxia is a sign of vestibular dysfunction, and in
this clinical setting, it suggests the presence of labyrinthitis.
In most children, it is a transient symptom; however, it has
implications for prognosis, because auditory and vestibular
disturbances usually occur together. As such, ataxia is associ-
ated with postmeningitic hearing loss (207).
Children with meningitis may develop hyponatremia and
the syndrome of inappropriate secretion of antidiuretic hor-
mone (SIADH) (208). The symptoms of hyponatremia and/
or SIADH are lethargy, stupor, confusion, and/or seizure ac-
tivity. When the following criteria are met, the diagnosis of
SIADH should be considered: (a) serum sodium level less
than 135 mEq/L, (b) serum osmolality less than 270 mOsm/L,
(c) urine osmolality greater than two times the serum osmolal-
ity, (d) urine sodium greater than 30 mEq/L, and (e) no clinical
evidence of hypovolemia or dehydration (209). SIADH is not
the only cause of hyponatremia in children with bacterial men-
ingitis. Hyponatremia may also develop when fluid therapy is
too aggressive or as a result of the syndrome of cerebral salt
casting. Regardless of the reason for hyponatremia, the serum
sodium level should be monitored frequently in every child
with bacterial meningitis. This is discussed in greater detail
later in this chapter (see the section Therapy).
Ocular complications, including fundal abnormalities, cra-
nial nerve palsies (see earlier discussion), pupillary dysfunc-
tion, and corneal or conjunctival lesions, are actually quite
common during the course of bacterial meningitis in children,
but only one case of transient cataract formation has been
reported in association with meningococcal meningitis.
Bacterial meningitis is at least 30-fold more common in chil-
dren with cochlear implants to address profound hearing loss
than in controls (210). The major pathogen is S. pneumoniae
and risk factors include use of a positioner to improve trans-
mission of the electrical signal by pushing the electrode against
the medial wall of the cochlea (voluntarily withdrawn from
the market by the manufacturer in July 2002); and joint ra-
diographic evidence of inner ear malformation and CSF leak.
More cases occurred within 30 days of surgery, but sporadic
cases were observed 24 months after implantation (210).
Adults
The typical presentation of bacterial meningitis in an adult
is that of an upper respiratory tract infection during which
a meningeal symptom, such as headache, nuchal rigidity,
vomiting, or an altered level of consciousness, develops (211)
(Table 24.3). The clinical signs and symptoms of bacterial
meningitis in an adult are very similar to those in children,
Scheld_Ch24.indd 387
Chapter 24: Acute Bacterial Meningitis 387
with a few exceptions. The most common bacterial cause of
meningitis in adults is S. pneumoniae. The clinical presenta-
tion of meningitis caused by S. pneumoniae is somewhat dif-
ferent from that of meningitis caused by the meningococcus
or H. influenzae. Adults with pneumococcal meningitis usu-
ally have an altered mental status on admission and rapidly
become stuporous or comatose. In addition, recurrent seizure
activity and focal neurologic deficits are more common in the
early stages of pneumococcal meningitis than in meningo-
coccal or H. influenzae meningitis. These and other factors
may contribute to the continued high mortality rate in pneu-
mococcal meningitis. S. pneumoniae is associated with the
highest mortality rate of the major meningeal pathogens. For
example, a mortality of 36.8% was reported from one series
of 55 cases of community-acquired pneumococcal meningitis
(212). Death is more likely to occur in patients of advanced
age, in the absence of meningismus, and in the presence of
pneumonia, other extraneural complications, or a prolonged
duration of illness prior to therapy (7 days). Nevertheless, it
appears that most deaths occur later in the disease course as
a consequence of cardiorespiratory insufficiency (213). They
are not usually caused by early overwhelming CNS damage.
A classic description of the clinical presentation of bac-
terial meningitis in adults was presented by Carpenter and
Petersdorf (211) in 1962. This review includes 209 cases of
bacterial meningitis: 53 cases were caused by meningococci,
63 by pneumococci, 35 by H. influenzae, and 58 by other bac-
terial organisms. A reliable history of the onset of symptoms
was obtained in 134 patients. Thirty-six patients (27%) had
sudden onset of headache, confusion, lethargy, and loss of con-
sciousness and sought hospitalization within the first 24 hours.
Only 3 of these 36 patients had symptoms of respiratory tract
infection. In contrast, 71 (53%) of the 134 patients had more
slowly progressive symptoms of meningitis for 1 to 7 days be-
fore admission. Of these, 26 patients (37%) had respiratory
symptoms. In 27 (20%) of the 134 patients, an infection in
the respiratory tract developed 1 to 3 weeks before the first
symptom of meningitis. The results of physical examination
for meningeal signs were recorded in 199 cases. Either nu-
chal rigidity, Kernig signs, or Brudzinski signs were present in
161 patients (81%). Studies suggest that the latter two signs
are less common in adults with meningitis than previously
reported (214). Level of consciousness on admission was re-
corded in 191 patients (96%); only 9 (5%) patients were alert,
48 (24%) were lethargic, 44 (22%) were confused, and the re-
mainder were obtunded or comatose (211). Patients with me-
ningococcal meningitis were most often alert, and those with
pneumococcal meningitis were more often obtunded.
Geiseler et al. (215) made observations of altered con-
sciousness at presentation in bacterial meningitis, similar to
those of Carpenter and Petersdorf (211). They recorded level
of consciousness at the time of admission in 1,289 patients
with community-acquired bacterial meningitis. Overall, 230
(17.8%) were alert, 672 (52.1%) were irritable or lethargic,
262 (20.3%) were stuporous or obtunded, and 125 (9.7%)
were comatose and/or convulsing (215). In adults, as in chil-
dren, lethargy or an altered mental status is the strongest indi-
cator of bacterial meningitis.
Durand et al. (78) reviewed the charts of all cases of acute
bacterial meningitis in individuals 16 years or older at the
Massachusetts General Hospital from 1962 through 1988.
The most common pathogen of community-acquired menin-
gitis was S. pneumoniae. Ninety-five percent of patients had
fever (temperature 37.7C) on presentation. Neck stiffness
was present in 88% of patients on initial physical exami-
nation. At the time of admission, 61 (22%) were alert, 142
(51%) were confused or lethargic, 61 (22%) were responsive
2/21/14 5:42 PM
 388 Part III: Bacterial and Mycoplasmal Infections
only to pain, and 17 (6%) were unresponsive to all stimuli.
On presentation or during the first 24 hours, 81 (29%) had
focal seizures or focal neurologic findings. The most common
predisposing factors for community-acquired meningitis were
pneumonia, sinusitis, acute otitis media, altered immune state,
alcoholism, and diabetes mellitus (78).
In another review of 696 episodes of community-acquired
bacterial meningitis, the triad of fever, neck stiffness, and
altered mental status was present in only 44% of episodes
(216), although almost all patients (95%) presented with at
least two of four symptoms (i.e., headache, fever, stiff neck,
and altered mental status). Cerebrovascular complications
may manifest at any time during the course of pneumococcal
meningitis. In an observational study of 696 patients with
community-acquired bacterial meningitis, cerebral infarction
occurred in 174 (25%) episodes and was seen in 128 (36%) of
352 patients with pneumococcal meningitis (217).
Pneumonia is present on admission in 25% to 50% of adults
with pneumococcal meningitis (211). Acute and chronic oti-
tis media are also predisposing conditions for pneumococcal
meningitis. In one series of 178 patients with pneumococcal
meningitis, acute otitis media was present in 59 (33.1%) (215).
When pneumonia or otitis media is not present, the possibility
of a dural sinus fistula should be considered. S. pneumoniae
is the most common causative agent in meningitis following
head trauma (basilar skull fracture) or meningitis associated
with a structural defect (either congenital or traumatic in
origin) that creates a communication between the paranasal
sinuses, nasopharynx, or middle ear and the SAS (218).
In adults aged 15 to 60 years, underlying host factors may
increase the risk for meningitis while simultaneously blunt-
ing its presenting signs. Such predisposing factors include
malignancy, alcoholism, sickle cell disease, diabetes, organ
transplantation, splenectomy, high-dose steroid therapy, and
long-term dialysis. In these clinical settings, the symptoms of
meningitis may include altered sensorium, persistent head-
ache, or new-onset seizures. Fever or nuchal rigidity may not
develop (219).
The occurrence of H. influenzae meningitis in an adult
should prompt consideration of the presence of (a) otitis
media, (b) paranasal sinusitis, (c) other parameningeal foci of
infection, (d) CSF leak from previous head trauma, or (e) a
concurrent pneumonia, pharyngitis, or immunodeficiency dis-
ease. The clinical presentation of H. influenzae meningitis in
adults is typical of bacterial meningitis and includes headache,
fever, altered mental status, and nuchal rigidity (220).
Elderly
Meningitis should be suspected in every elderly patient who
is febrile and either disoriented, stuporous, or comatose
(Table 24.3). In a review of 54 cases of bacterial meningitis
in the elderly, confusion was present in 92% (12 of 13) of the
patients with pneumococcal meningitis and in 78% (7 of 9) of
those with gram-negative meningitis on initial presentation.
This review compared the clinical presentation of bacterial
meningitis in the elderly (patients aged 50 years and older)
with that in younger patients (aged 15 to 49 years). On initial
presentation, the incidence of more severe abnormalities of
mental status in the older age-group with bacterial meningitis
was statistically different from that of the younger group, and
concurrent pneumonia was present more often in the older
2-transferrin.
patients than in the younger group (221). In another review
of CNS infections in patients older than 65 years of age at
the Mount Sinai Hospital in New York from 1970 through
1985, 28 cases of bacterial meningitis were identified (222).
Although fever (often of low grade) was uniformly present,
Scheld_Ch24.indd 388
only 57% had meningismus and only 21% complained of
headache. Pneumococci were the most common etiologic
agent, and these cases were often (58%) accompanied by
pneumonia, sinusitis, or otitis media; the overall mortality was
approximately 40%.
Most elderly patients with meningitis have nuchal rigidity,
that is, resistance to passive flexion of the neck. Resistance to
passive movement of the neck is a common physical finding
in elderly patients because of the presence of cervical spon-
dylosis. It is important to be able to distinguish between the
cervical rigidity of cervical spondylosis and nuchal rigidity
resulting from meningitis. In nuchal rigidity, the neck resists
flexion but can be passively rotated from side to side. In ri-
gidity consequent to cervical spinal disease, lateral rotation,
extension, and flexion of the neck are all associated with
resistance. Similarly, hypertonicity of the neck muscles result-
ing from disease of basal ganglia, such as parkinsonism, can be
distinguished from true nuchal rigidity.
Specific comments should be made about the presentation
of nontraumatic, spontaneous gram-negative bacillary men-
ingitis in the elderly or debilitated patient. In these patients,
the classic signs and symptoms of meningitis may be subtle
at initial presentation. They may have only low-grade fever
and altered mental status without headache or nuchal rigid-
ity; however, patients with spontaneous gram-negative bacil-
lary meningitis tend to have a rapidly progressive fulminant
course associated with bacteremia, shock, and coma (223).
The elderly patient with gram-negative meningitis may rapidly
become comatose after presenting with what at first appeared
to be a minor illness. Once coma develops, nuchal rigidity may
not be present, because this sign is lost during deep coma.
In a recent 30-year study of 185 patients 65 years of age
and older, the diagnosis of community-acquired bacterial
meningitis was more difficult because of the absence of char-
acteristic meningeal signs (224); compared with adult patients
younger than 65 years of age, the older patients showed greater
neurologic severity with a high number presenting with coma
on admission, seizures, and hemiparesis.
Posttraumatic Meningitis
Bacterial meningitis may develop following a traumatic head
injury that produces a dural fistula between the SAS and the
nasal cavity, paranasal sinuses, or middle ear. The infection
may develop shortly after the injury or may not occur until
months to years later (225). Traumatic head injury is the most
common cause of recurrent meningitis in the adult (220).
Conversely, congenital fistulous connections to the CNS, often
via the middle ear in association with Mondini dysplasia, are
the most common underlying process in children with recur-
rent bacterial meningitis (226). An immunodeficiency state
may also be instrumental in the development of this syndrome.
A dural fistula develops when the force of the injury is suf-
ficient to fracture bone and tear the dura. The most common
site for dural fistula is in the anterior cranial fossa, in the area
of the cribriform plate. Here, the bone is very thin and the
dura is tightly adherent to the bone. A fracture in this area
allows CSF to leak through torn arachnoid and dura into the
nasal cavity, resulting in CSF rhinorrhea (225). There may also
be loss of the sense of smell, or anosmia. CSF rhinorrhea can
be distinguished from nasal secretions by testing the fluid for
Physical signs indicating a basilar skull fracture with the
potential for development of a dural fistula and meningitis in-
clude periorbital ecchymoses, bruising behind the ear (Battle
sign), hemotympanum, and/or blood in the external auditory
canal (225).
2/21/14 5:42 PM

In most patients, CSF rhinorrhea ceases spontaneously.
Approximately one in four patients with CSF rhinorrhea de-
velops meningitis (225); the reported frequency ranges from
9% to 36%. Surgery is indicated in patients who develop
meningitis with persistent rhinorrhea. The management of
meningitis occurring in this setting and the approach to dem-
onstration of the location of the dural fistula is discussed later
in this chapter.
Meningitis Following
Neurosurgical Procedures
Meningitis complicating a neurosurgical procedure, such as a
craniotomy, is usually insidious in onset and difficult to dis-
tinguish clinically from the neurologic abnormalities expected
in the postoperative period. Although an altered level of con-
sciousness and signs of meningeal irritation may be expected
in the postoperative period, the presence of fever or prolonged
obtundation should prompt an examination of the CSF.
Approximately 60% to 70% of all cases of meningitis com-
plicating a neurosurgical procedure, with the exception of a
shunting procedure, are caused by gram-negative bacilli (223).
The remainder is caused by staphylococci, predominantly
S. aureus. In the postneurosurgical patient, K. pneumoniae,
Acinetobacter baumannii, and E. coli are the most common
infecting gram-negative organisms. Craniotomy for trauma
or for tumor represents the most common surgical proce-
dure associated with postoperative gram-negative bacterial
meningitis (227).
Although the surgical insertion and subsequent constant
presence of an indwelling ventriculoperitoneal (VP) or ventric-
uloatrial (VA) shunt catheter for decompression of hydroceph-
alus allow bacteria to enter the CSF space, signs of meningitis
usually do not accompany these infections in the early stages.
The bacteria involved in early shunt infection gain entry to
the lumen of the shunt from a contaminated wound or from
the patients skin surface at the time of operation (228). The
initial symptoms of shunt infection are nonspecific and include
fever, nausea, vomiting, and lethargy. Fever is the most com-
mon manifestation of shunt infection. Virtually all patients
have temperatures greater than 37.8C, and most have tem-
peratures of 38.8C or more (229). Fever is often the sole
manifestation of infection in patients with VA shunts, whereas
patients with infected VP shunts are more likely to present
with signs of shunt malfunction and/or signs of inflammation
around the shunt reservoir or along the course of the tub-
ing (229,230). Signs of shunt malfunction are secondary to
progressive hydrocephalus and, in children, include enlarg-
ing cranial circumference, tense nonpulsatile fontanelle, and
papilledema. Signs of shunt malfunction may be associated
with signs of meningitis. Results of examination of CSF from
the lumbar area may be negative; therefore, CSF should be
obtained by aspiration from the infected shunt reservoir.
Infections of the CNS may also develop when subcuta-
neous CSF reservoirs, such as Ommaya and Rickham reser-
voirs, are placed for therapeutic purposes. These and other
types of indwelling intraventricular catheters may lead to
meningitis with coagulase-negative staphylococci, S. aureus,
Corynebacterium species, or gram-negative bacilli. Infections
usually occur within the first 3 months after insertion of the
device and, as with infections of VP or VA shunts, are prob-
ably the consequence of contamination by skin flora during
implantation or subsequent use for therapeutic purposes.
In these patients, signs of meningitis are usually not present,
but most will complain of fever, lethargy, headache, or nausea
and vomiting (231).
Scheld_Ch24.indd 389
Chapter 24: Acute Bacterial Meningitis 389
Immunosuppressed Hosts
The risk for development of bacterial meningitis in an im-
munocompromised patient depends on a number of factors,
such as the underlying disease and its treatment, the duration
of immunosuppression, and the type of immune abnormality
(232). There are four major types of host defense abnormali-
ties in the immunocompromised patient: (a) defects in T-
lymphocytemacrophage function (cell-mediated immunity);
(b) defects in humoral immunity; (c) defects in the number and
function of neutrophils; and (d) loss of splenic function from
surgery, disease, or radiotherapy, resulting in the inability to
remove encapsulated bacteria. Knowledge of the type of host
defense abnormality is often helpful in predicting the infecting
organism (233,234).
Patients with defects in cell-mediated immunity include
(a) those with lymphomas, particularly Hodgkin disease;
(b) organ transplant recipients; (c) patients treated with daily
corticosteroid therapy; and (d) patients with AIDS. These
patients are most susceptible to CNS infection by microorgan-
isms that are intracellular parasites, the eradication of which
depends on an intact T-lymphocytemacrophage system (233).
L. monocytogenes is a causative organism of bacterial menin-
gitis in patients with defective cell-mediated immunity due to
hematologic malignancies, organ transplantation, pregnancy,
chronic corticosteroid therapy, alcoholism, and advanced age
(235). The incidence of L. monocytogenes meningitis in HIV-
infected individuals is low due to pneumocystis prophylaxis
with TMP-SMX. The clinical presentation of L. monocyto-
genes meningitis includes fever and headache, as well as an
increased tendency for focal neurologic deficits and seizures
during the initial presentation. Meningitis caused by this
organism may also present with a clinical picture suggestive of
an acute brainstem disorder or rhombencephalitis, with signs
of ataxia, cranial nerve deficits, and nystagmus (236).
Patients with defective humoral immunity are unable to
mount an antibody response to bacterial infection, and they
are, therefore, unable to control infection caused by encap-
sulated bacteria. Patients with this type of host defense ab-
normality include those with chronic lymphocytic leukemia,
multiple myeloma, or Hodgkin disease following chemother-
apy and radiotherapy, among others. These patients are at par-
ticular risk for meningitis caused by S. pneumoniae, Hib, and
less commonly N. meningitidis. The presentation of meningitis
in these patients is often that of a fulminant illness resulting in
death in several hours.
Patients with splenectomy may develop (a) overwhelming
bacteremia and fulminant meningitis with the same organ-
isms, resulting from loss of the filtering function of the splenic
sinusoids in removing encapsulated bacteria from the blood-
stream, and (b) a reduced ability to produce IgM opsonizing
antibodies (233,234).
Patients with neutropenia are at particular risk for meningitis
caused by P. aeruginosa and members of the Enterobacteriaceae
family (234). The clinical presentation of bacterial meningitis in
patients with neutropenia may be subtle, consisting of low-grade
fever and lethargy or a change in headache pattern (233). Signs
of meningeal irritation depend on the hosts ability to mount
an inflammatory response; therefore, in the neutropenic patient
they are often minimal.
DIFFERENTIAL DIAGNOSIS
Although the diagnosis of meningitis is usually made by
examination of the CSF, the decision to perform spinal fluid
analysis is based on the clinical presentation. When the signs
2/21/14 5:42 PM
 390 Part III: Bacterial and Mycoplasmal Infections
and symptoms suggest meningitis, and the decision is made
to examine the CSF, the next step is to be certain that a focal
intracranial mass lesion does not exist that may predispose
to brain herniation following LP. If the history and neuro-
logic examination suggest a focal mass lesion, then LP should
be delayed until a neuroimaging procedure, either a cranial
CT scan, without and with contrast enhancement, or a cranial
magnetic resonance imaging (MRI) scan is obtained.
LP is relatively contraindicated in the presence of a focal
mass lesion because of the danger of brain herniation. However,
it has become common practice to delay LP until a CT or MRI
scan has been obtained despite the absence of focal neurologic
deficits by history or examination. The time involved in waiting
for a CT or MRI scan significantly delays treatment, and delay
in treatment is the most critical factor in determining morbid-
ity and mortality in bacterial meningitis. Therefore, if a CT or
MRI scan is to be performed, antimicrobial therapy should be
initiated promptly, pending results. In the absence of an altered
level of consciousness, focal neurologic signs, and/or papill-
edema, an LP can be safely performed without first obtaining
a CT or MRI scan. Although CT is commonly performed be-
fore LP in adults with suspected meningitis, the vast majority
of scans are unnecessary and unlikely to reveal abnormalities,
and clinical characteristics can be used rapidly to exclude pa-
tients that are unlikely to have abnormal findings on CT (237).
Focal infectious lesions that have clinical presentations similar
to those of meningitis and that can result in significant morbid-
ity if LP is unknowingly performed include brain abscess, sub-
dural empyema, and epidural abscess. The clinical presentation
of each of these disorders has similarities and distinguishing
features when compared with that of meningitis.
The most common symptom of a brain abscess is a hemicra-
nial or generalized headache, generally seen in 70% to 75% of
patients (238242). A brain abscess presents as an expanding
intracranial mass lesion rather than as an infectious process; as
such, fever is present in only 45% to 50% of patients and usually
is not prominent. More than 50% of patients have focal neuro-
logic deficits, and one third of patients present with new-onset
focal or generalized seizure activity. The findings on neurologic
examination are related both to the site of the abscess and to
the presence of raised ICP caused by an expanding mass lesion.
Hemiparesis is the most common sign of a frontoparietal lobe
abscess. A disturbance of language or behavior or an upper hom-
onymous quadrantanopia is the sign of a temporal lobe abscess.
Ataxia is the most common sign of a cerebellar abscess. Nuchal
rigidity rarely occurs until the abscess has ruptured into the ven-
tricle or until infection has spread to the SAS. Sudden worsening
of the headache, accompanied by new-onset meningismus, may
signify rupture of the abscess into the ventricular space (243).
Most patients with a subdural empyema initially complain
of headache that is localized to the side of the subdural in-
fection. The headache becomes increasingly more severe and
generalized, and it is followed by an alteration in the level of
consciousness. Fever, chills, and nuchal rigidity are present in
most cases. Focal neurologic deficits are present in 80% to
90% of patients, and they include hemiparesis or hemiplegia,
paralysis of horizontal gaze to the side opposite the lesion,
and focal or generalized seizures (244). The diagnosis should
be considered in patients with acute bacterial sinusitis in com-
bination with severe intractable headache, varying degrees of
altered level of consciousness, focal neurologic deficits, and/or
signs of meningeal irritation (245,246). The presentation of a
posterior fossa subdural empyema includes severe headache,
vomiting, marked nuchal rigidity, cranial nerve deficits, and
pupillary abnormalities (247); cerebellar signs were elicited in
only 40% of patients in one study (248).
A typical presentation of an intracranial epidural abscess
is an unrelenting hemicranial headache and fever that have
Scheld_Ch24.indd 390
developed during or after treatment for frontal sinusitis, mas-
toiditis, or otitis media. If the abscess is large, mild alterations
of consciousness may occur; however, focal neurologic defi-
cits, seizures, and signs of increased ICP do not develop until
the infection has extended into the subdural space or a deeper
intraparenchymal complication has occurred (244).
The decision to delay LP until CT or MRI scan is obtained
may be made when the patient does not appear to be seriously
ill or when there is uncertainty about the findings of neurologic
examination. Patients with viral meningitis usually do not ap-
pear as ill as patients with bacterial meningitis and often have
had symptoms for several days. When the history suggests a
focal onset to the headache or a transient neurologic symptom,
LP is best delayed until a CT or MRI scan has been obtained.
The initial symptoms of viral meningitis are fever, headache,
lethargy, myalgias, and nuchal rigidity. There are several distin-
guishing clinical features of viral meningitis: (a) viral meningi-
tis has a more insidious onset and a slower progression than
bacterial meningitis; (b) patients with viral meningitis often
complain of an incapacitating headache that is not relieved by
analgesics, but they are otherwise awake and alert; (c) the fever
is usually higher in bacterial meningitis than in viral meningitis;
and (d) although generalized malaise may be present, stupor,
obtundation, and coma do not occur in viral meningitis (219).
Altered level of consciousness, focal neurologic deficits, and
new-onset seizure activity are symptoms of a viral encephalitis,
meningoencephalitis, or bacterial meningitis. The presentation
of herpes simplex virus (HSV) encephalitis is often subacute
and on examination is characterized by (a) fever, confusion,
or a change in behavior; (b) new-onset seizure activity; and/or
(c) focal neurologic deficits. A history of hemicranial headache
of several days duration, preceding the onset of the confusional
state, is a classic presentation of this illness. HSV has a predi-
lection for the temporal and orbitofrontal areas; therefore, a
change in mentation or behavior is a common finding (249).
Signs and symptoms of meningitis represent the most com-
mon neurologic presentation of Lyme disease. Patients have
headache, stiff neck, low-grade fever, a unilateral or bilateral
(in 25% of cases) facial nerve palsy, or a radiculitis. The char-
acteristic skin lesion of Lyme disease, erythema migrans (EM),
precedes the symptoms of meningitis in approximately 80% to
90% of patients. Signs and symptoms of meningitis occur weeks
to a few months after the initial infection, or they may be the
first manifestation of the disease without antecedent EM (250).
The presence of a rash with meningitis suggests meningococ-
cemia. As has been discussed, the classic lesions associated with
fulminating meningococcal septicemia are large petechial hem-
orrhages in the skin and mucous membranes. Between 50% and
75% of children with meningococcal meningitis have a purpu-
ric or petechial rash, principally on the trunk and lower ex-
tremities. Petechiae are found in the skin, mucous membranes,
and conjunctivae, but not in the nailbeds, in meningococcemia.
Petechiae are also sometimes seen on the trunk and extremi-
ties in echovirus type 9 meningitis, acute staphylococcal endo-
carditis, and rarely pneumococcal or H. influenzae meningitis
except in asplenic patients (198,204). Petechiae may be found
in the nailbeds in acute staphylococcal endocarditis. Petechial
rashes should be promptly examined microscopically in the
initial evaluation of meningococcemia after aspiration or after
making a touch preparation on a glass slide; approximately
70% of these preparations will reveal the organisms, usually
within vacuolated neutrophils. In fulminant meningococcemia,
the organisms may be visualized in the peripheral blood smear.
Although the sensitivity of this method is low, this simple test
should always be performed in suspected meningococcemia.
Headache, fever, rash, and altered mental status are symp-
toms of rickettsial infections (see Chapter 27) and, as such, enter
into the differential diagnosis of meningitis. A petechial rash
2/21/14 5:42 PM

is characteristic of Rocky Mountain spotted fever (RMSF),
which is caused by Rickettsia rickettsii. The rash of typhus is a
faint macular-papular pink rash (251). The rash of RMSF con-
sists initially of 1- to 5-mm pink macules that are often noted
first on the wrist and ankles and then spread centrally to the
chest, face, and abdomen. The rash of RMSF usually does not
involve the mucous membranes. Petechial lesions in the axillae
and around the ankles, accompanied by lesions on the palms
and soles of the feet, are characteristic of RMSF, but this clas-
sic pattern is often absent. The macules will initially blanch
with pressure, but after a few days they become fixed and turn
dark red or purple. Diagnosis can be made by biopsy of the
lesions and staining of the specimen with fluorescent antibod-
ies to R. rickettsii (252). A negative result does not exclude
RMSF, because sensitivity of this test is only 70%.
The characteristic rash caused by an enterovirus consists of
erythematous macules and papules on the face, neck, trunk,
and to a lesser degree the extremities. Rarely, the rash associ-
ated with enteroviral infection may become petechial in nature.
The rash of Lyme disease, EM, begins as a red macule or
papule at the site of the tick bite. It then expands centrifugally
as an erythematous lesion with central clearing. This may be
the only lesion, or the disease may disseminate to form mul-
tiple secondary ringlike lesions. Symptoms of meningitis may
develop while the skin lesions are still present, or they may
begin 1 to 6 months after the skin lesions have resolved (250).
Noninfectious neurologic disorders that have clinical presen-
tations similar to those of meningitis are subarachnoid hemor-
rhage, neuroleptic malignant syndrome, and posterior fossa
tumors. The classic presentation of a subarachnoid hemorrhage
is the sudden onset of a severe, excruciating headache, or a sud-
den transient loss of consciousness followed by a severe head-
ache. Most patients complain of vomiting. Syncope accompanies
the explosive onset of headache in about 50% of cases. Nuchal
rigidity develops within a few hours of the onset of a subarach-
noid hemorrhage and is usually associated with a change in the
level of consciousness. Low-grade fever may develop within sev-
eral days. When an intracranial aneurysm ruptures into the brain
parenchyma, a focal neurologic deficit is usually present. A uni-
lateral palsy of the third nerve, with a dilated, nonreactive pupil,
is suggestive of third nerve compression by an aneurysm at the
junction of the posterior communicating artery and the internal
carotid artery. The triad of headache, neck stiffness, and vomiting
should raise suspicion of a warning leak from an aneurysm (252).
The symptoms of neuroleptic malignant syndrome (NMS) are
fever, generalized lead-pipe rigidity (including cervical rigidity),
fluctuating level of consciousness (ranging from agitation to stupor
and coma), and autonomic instability. The latter is characterized
TA B L E 2 4 . 4
TYPICAL CEREBROSPINAL FLUID FINDINGS IN BACTERIAL VERSUS ASEPTIC MENINGITIS
CSF Parameter Bacterial Meningitis
Opening pressure 180 mm H2O
Glucose 40 mg/dl
Chapter 24: Acute Bacterial Meningitis 391
by pallor, unstable blood pressure, diaphoresis, tachycardia, and
arrhythmias. A leukocytosis of 15,000 to 30,000 cells/mm3, with
a shift to the left, is common. Liver function abnormalities are
usually seen, but the most specific laboratory abnormality in this
disorder is marked elevation in the serum creatine kinase (CK)
concentration, usually exceeding 10,000 IU/L (253).
Signs of a posterior fossa tumor are stiff neck, cranial nerve
abnormalities, gait disturbance, vomiting, cerebellar deficits,
and occasionally an altered level of consciousness.
A cranial CT or MRI scan and examination of the CSF
will narrow the differential diagnosis. The possibility of the
presence of increased ICP should be considered before LP.
Increased ICP is an expected complication of bacterial menin-
gitis and is not a contraindication to LP.
The clinical signs of increased ICP are (a) a dilated, nonreac-
tive pupil; (b) drowsiness; (c) abnormalities of ocular motility,
the most common of which are the consequence of unilateral or
bilateral palsies of the sixth cranial nerve; and (d) bradycardia
and hypertension, the Cushing reflex. Pupillary dilation is usu-
ally secondary to parenchymal midbrain distortion from either
raised ICP or transtentorial herniation. Drowsiness or stupor
is often the first sign of increasing ICP and is caused by inter-
ference with the reticular activating system in the brainstem.
If raised ICP appears likely and a focal intracranial mass lesion
has been excluded by CT or MRI scan, LP can usually be safely
performed. When the decision is made to delay LP until a CT or
MRI scan has been obtained, blood cultures should be obtained
and intravenous antibiotics and dexamethasone therapy begun
while awaiting results of CT or MRI scan (see later discussion).
Intravenous antibiotics usually do not sterilize the CSF in the time
it takes to obtain a CT or MRI scan and spinal fluid. Blood cul-
tures may identify the infecting organism in 50% to 80% of cases
of bacterial meningitis (although this frequency varies with the
causative organism), and they are more often positive in patients
who have not received prior treatment with oral antibiotics (189).
LABORATORY DIAGNOSIS
Cerebrospinal Fluid
The typical CSF findings of bacterial and aseptic meningitis
are compared in Table 24.4.
Opening Pressure
The first step in examination of the CSF is measurement of
the opening pressure with an air-water manometer. This step
Aseptic Meningitis
Normal or slightly elevated
45 mg/dl
CSF-to-serum glucose ratio 0.4 0.6
Protein 50 mg/dl Normal or elevated
White blood cells 10 to 10,000/mm3neutrophils predominate 502,000/mm3lymphocytes predominate
Gram stain Positive in 7090% of untreated cases Negative
Lactate 3.8 mmol/L Normal
C-reactive protein 100 ng/mL Minimal
Limulus lysate assay Positive indicates gram-negative meningitis Negative

Scheld_Ch24.indd 391 2/21/14 5:42 PM

 392 Part III: Bacterial and Mycoplasmal Infections
is often neglected, but knowledge of the presence of raised
ICP is important in management of the patient. Normal CSF
pressure, with the patient in the lateral recumbent position, is
usually defined as less than 180 mm H2O (254). However, nor-
mal opening pressure can be as high as 250 mm H2O in obese
patients (255). CSF pressure should not be measured with the
patient in a seated position. If the spinal needle is inserted with
the patient seated, the patient should then be moved to a lat-
eral recumbent position and the opening pressure recorded.
Elevated CSF pressure in the range of 200 to 500 mm H2O is
common in bacterial meningitis.
Appearance
Normal CSF is clear. The presence of more than 200 WBCs/
mm3, more than 400 red blood cells (RBCs)/mm3, bacteria
(105 CFU/mL), or an elevated protein concentration makes
the fluid appear cloudy or turbid. When the LP is traumatic
and the initial CSF sample appears bloody, the fluid should
clear as flow continues. Xanthochromia refers to a yellow or
yellow-orange color in the supernatant of centrifuged spinal
fluid; it may be used to distinguish CSF that is bloody second-
ary to subarachnoid hemorrhage from CSF that is bloody as
a result of a traumatic LP. When CSF is bloody secondary to
traumatic LP, the supernatant of the centrifuged fluid is clear.
In subarachnoid hemorrhage, the supernatant is xanthochro-
mic within 2 hours after the hemorrhage. Elevated CSF pro-
tein concentrations (150 mg/dL) also cause xanthochromia
(254,256) and are the usual reason for xanthochromia in
bacterial meningitis.
Glucose
The normal CSF glucose concentration is greater than 45 mg/
dL. A glucose concentration of less than 40 mg/dL occurs in ap-
proximately 58% of patients with bacterial meningitis (257).
However, the CSF glucose may be falsely low in the presence
of hypoglycemia, or it may be erroneously interpreted as nor-
mal in the presence of CNS infection when the serum glucose
is elevated. An accurate interpretation of the CSF glucose con-
centration is done by determining the CSF-to-serum glucose
ratio. A normal CSF-to-serum glucose ratio is about 0.6 (257).
Values less than 0.31 are an indication of low CSF glucose,
and they are observed in approximately 70% of patients with
bacterial meningitis (257). A decreased CSF-to-serum glucose
ratio is also consistent with fungal or tuberculous meningitis,
carcinomatous meningitis, mumps encephalitis, subarachnoid
hemorrhage in 15% to 20% of patients, and several other
conditions (258).
Protein
Any process that disrupts the BBB results in an elevated
CSF protein concentration. Values greater than 50 mg/dL in
CSF obtained from the lumbar SAS, as well as ventricular CSF
protein concentrations greater than 15 mg/dL, are considered
abnormal. When the LP is traumatic and there is blood in
the CSF, the true protein concentration is corrected by sub-
tracting 1 mg of protein per deciliter for every 1,000 RBCs in
CSF (258).
White Blood Cell Count
The CSF abnormalities characteristic of bacterial meningitis in-
clude a polymorphonuclear (PMN) pleocytosis, a low glucose
concentration, and an elevated protein concentration. The
CSF should be examined promptly after it is obtained, because
WBCs in the CSF begin to disintegrate after about 90 minutes.
The normal WBC count in the CSF of adults and children is 0
Scheld_Ch24.indd 392
to 5 mononuclear cells (lymphocytes and monocytes)/mm3; a
WBC count of greater than 10 cells indicates a pathologic pro-
cess such as infection. Normal CSF does not contain PMN leu-
kocytes; however, following centrifugation, an occasional PMN
leukocyte may be seen. It has been stressed that for the CSF to
be considered normal, no more than a single PMN leukocyte
should be seen in the differential count, accompanied by a total
WBC count of less than 5 cells/mm3 (254,256). However, most
CSF differential counts are now performed on cytocentrifuged
specimens in hospital laboratories. In these preparations, a few
PMN leukocytes may be seen even in the absence of disease
(i.e., when minimal blood contamination is present) or in as-
sociation with a high peripheral leukocyte concentration (258).
A traumatic puncture or an intracerebral or subarachnoid
hemorrhage introduces RBCs and WBCs into the CSF. The
correction factor for the WBC count in the presence of blood
in the CSF is as follows: (a) If the peripheral RBC and WBC
counts are normal, then 1 WBC/700 RBCs can be subtracted
from the total WBC count in CSF; and (b) in the presence of
an abnormal peripheral WBC or RBC count, the following
formula can be used (258), although valid studies on the diag-
nostic accuracy in meningitis are lacking:
True WBC (CSF)  Actual WBC (CSF)  WBC (Blood)
 RBC (CSF)/RBC (Blood)
Generalized seizures may induce a transient CSF pleocyto-
sis consisting predominantly of PMN leukocytes. However, to
attribute a CSF pleocytosis to seizure activity, the following
criteria should be met: (a) The fluid should be clear and color-
less, (b) the opening pressure should be normal, (c) the CSF
glucose concentration should be normal, (d) the WBC count
should not exceed 80 cells/mm3, (e) there should be no men-
ingeal signs or other evidence of infection, and (f) Gram stain
results should be negative (259). Even if these conditions are
met, patients should usually be treated with antibiotics until
the results of bacterial cultures are known. There also remains
the possibility that a viral encephalitis, with a predominance
of PMN leukocytes in CSF, is the cause of the seizure activity.
In large reported series of bacterial meningitis, in 90% of
cases, there are greater than 100 WBCs/mm3 in the CSF, and
in 65% to 70% of cases, there are greater than 1,000 WBCs/
mm3 (211,215,260,261). The differential count usually shows
a predominance of PMN leukocytes. In about 10% of cases of
bacterial meningitis, there may be a predominance of lympho-
cytes early in the infection, especially if the total WBC concen-
tration is less than 1,000/mm3. In one series, 32% (13 of 41) of
patients with bacterial meningitis with a CSF WBC concentra-
tion of 1,000 cells/mm3 or less had a predominance of lympho-
cytes (262). In addition, in about 20% to 75% of patients with
viral meningitides, the CSF may initially have a predominance
of PMN leukocytes, with an eventual shift (over the course of
several hours) to a monocytic predominance. This has led to
controversy about the necessity for repeated LP and the time
period in which a repeated LP should be obtained to demon-
strate a shift in cell type. It is our feeling that a repeated LP is
usually not necessary unless there is further clinical deteriora-
tion. In the presence of a lymphocytic pleocytosis, the results
of CSF chemistries, Gram stain, and other tests (see later dis-
cussion) suggest the diagnosis. If bacterial meningitis is sus-
pected, even though there is a predominance of lymphocytes,
the patient should be treated with antibiotics until the results
of bacterial cultures are known.
Gram Stain and Culture
Examination of CSF by Gram stain allows for rapid, accurate
identification of the infecting organism. If the CSF is cloudy,
2/21/14 5:42 PM

smears should be obtained from fresh, uncentrifuged fluid for
Gram stain. If the CSF is clear, smears should be obtained
from the centrifuged sediment. The Gram stain is positive in
identifying the organism in 60% to 90% of cases of bacterial
meningitis (257,263). However, the probability of detecting
bacteria on a Gram-stained specimen depends on the number
of organisms present. Most smears will be positive when the
CSF bacterial concentration is greater than 105 CFU/mL. Only
25% of smears are positive when the bacterial concentration
is 103 CFU/mL or less (197).
Cerebrospinal Fluid Lactate
The lactic acid concentration in CSF has been reported to be
useful in differentiating between bacterial and viral meningitis,
especially in those patients who have been partially treated with
antibiotics prior to examination of the CSF, as well as in those
patients with low CSF WBC concentrations. In a European
study, the lactic acid in CSF was measured in 50 patients with
acute bacterial meningitis. In 46 patients (92%), the CSF lac-
tate concentration was 3.5 mmol/L or greater. The investigators
in this study concluded that CSF lactate was useful in the diag-
nosis of acute bacterial meningitis if it was 3.5 mmol/L or more
(264). Other studies have demonstrated that in most cases of
acute bacterial meningitis, the CSF lactate concentration is
3.8 mmol/L or more (254). Although the sensitivity of the CSF
lactate level is high for bacterial meningitis, its specificity is low.
In a review of the lactic acid concentrations in 493 samples
of CSF from 434 adults with various CNS conditions, the
lactate concentration was greater than 35 mg/dL in 50 cases.
Only 19 of the 50 cases of infective meningitis were caused by
either bacterial or viral pathogens. Although the lactic acid
concentration was elevated in most cases of bacterial menin-
gitis in this study, the CSF samples with elevated lactic acid
concentrations had cell counts and chemistries suggestive of
bacterial meningitis; therefore, the elevated lactate concentra-
tion provided little additional information (265). In this re-
view, as in others, an elevated CSF lactic acid concentration
was nonspecific. Other causes of elevated CSF lactate concen-
trations include recurrent seizure activity, cerebral ischemia,
hypocapnia, closed head injury, neoplasms, and craniotomy
(254,265). Although the source of the CSF lactate is debated,
cerebral hypoxia/ischemia, anaerobic glycolysis, vascular
compromise, and metabolism of the CSF leukocytes are all
potentially important factors (266).
Additional studies have examined whether elevated CSF
lactate concentrations are useful in differentiating bacterial
from nonbacterial meningitis in patients who have not received
prior antimicrobial therapy (267). Two metaanalyses, one in-
cluding 25 studies with 1,692 patients (adults and children)
(268) and the other including 31 studies with 1,885 patients
(269), concluded that the CSF lactate concentration is useful
in the differentiation of bacterial from aseptic meningitis. In
another study of adult patients, the CSF lactate concentration
had a negative predictive value 99% and positive predictive
value 82% for bacterial meningitis when it was 3.8 mmol/L or
higher (270). However, in patients who received antimicrobial
therapy prior to LP, CSF lactate concentrations had a substan-
tially lower sensitivity compared to those who had not been
treated with antimicrobial agents (269), such that the useful-
ness of CSF lactate in patients pretreated with antimicrobial
therapy is probably limited.
Other Tests
The CSF concentration of several other substances also in-
creases in the presence of bacterial meningitis, including
various enzymes (e.g., lactate dehydrogenase and creatine
Scheld_Ch24.indd 393
Chapter 24: Acute Bacterial Meningitis 393
phosphokinase) and fibrin-degradation products; however,
the elevations are nonspecific. Tests for these compounds are
rarely, if ever, performed in hospital laboratories.
Combinations of Cerebrospinal Fluid Tests
Although many of the aforementioned tests commonly per-
formed on CSF may suggest the diagnosis of bacterial men-
ingitis, none is irrefutable evidence of this disease, except a
positive culture and/or positive stains. Combinations of test
results with clinical parameters may permit a more accurate
assessment of the probability of bacterial versus viral
meningitis. This approach appears to have merit, as empha-
sized in a retrospective review of 422 patients with acute
meningitis at Duke University (271). The following CSF pa-
rameters were individual predictors of bacterial meningitis
with greater than 99% certainty: glucose level of less than
34 mg/dL; CSF-to-blood glucose ratio less than 0.23; leuko-
cyte counts more than 2,000/mm3 or neutrophil counts more
than 1,180/mm3. Although any one of these results predicted
bacterial meningitis with high probability, none could rule it
out. A multiple regression model using four parameters (age,
month of onset, CSF-to-blood glucose ratio, and CSF neu-
trophil concentration) proved highly reliable in separating
bacterial from viral meningitis. Although the model requires
further validation, a nomogram is included in the article and
should be consulted for more precise analysis of gram-negative
cases (271).
A number of other studies have examined combinations
of clinical features, with or without test results, to develop
models in an attempt to accurately predict the likelihood of
bacterial meningitis compared to other potential etiologies
(most often viruses) (272). In several retrospective studies of
immunocompetent patients older than 1 month of age with
acute bacterial or viral meningitis, a CSF glucose concentra-
tion less than 34 mg/dL, a CSF-to-blood glucose ratio less than
0.23, a CSF protein concentration greater than 220 mg/dL,
more than 200 leukocytes per cubic millimeter of CSF, and
more than 1,180 neutrophils per cubic millimeter of CSF were
found to be individual predictors of bacterial rather than viral
meningitis, with 99% certainty or better. Many other pre-
diction models have been developed. In a recently published
metaanalysis of bacterial meningitis score validation stud-
ies in which 5,312 patients were identified from eight stud-
ies, 4,896 (92%) had sufficient clinical data to calculate the
Bacterial Meningitis Score, which identifies children with CSF
pleocytosis who are at very low risk of bacterial meningitis
(low-risk features were negative CSF Gram stain, CSF abso-
lute neutrophil count 1,000 cells/mm3, CSF protein 80 mg/
dL, and peripheral absolute neutrophil count 10,000 cells/
mm3) (273). The combined sensitivity was 99.3%, specificity
62.1%, and negative predictive value 99.7%, indicating that
this scoring system could be used to assist clinical decision
making for the management of children with CSF pleocytosis.
If used, these models should be limited to the age cohort in
which they were developed. Despite the positive results of this
metaanalysis and other studies, clinical judgment should con-
tinue to be used in decisions about the need for administration
of empirical therapy in patients with suspected bacterial men-
ingitis (272). Prediction models may be most useful in doubt-
ful cases, when they can be used to suggest a reconsideration
of the diagnosis.
Partially Treated Meningitis
The effect of oral antibiotic therapy on CSF analysis was studied
in two prospective studies of 281 children with Hib meningitis.
Ninety-four (33%) children had been treated with more
2/21/14 5:42 PM
 394 Part III: Bacterial and Mycoplasmal Infections
than one dose of antibiotics within 1 week before admission.
Compared with results in untreated children, the results of CSF
analysis in children pretreated with antibiotics showed sig-
nificant decreases in the percentage of neutrophils (p  .03),
protein concentration (p  .001), and percentage with a posi-
tive Gram stain or culture (p  .05). Differences in total WBC
count, glucose concentration, CSF-to-serum glucose ratio, and
blood culture results were not statistically significant. When
adjustment was made for duration of illness before admission,
only the difference in CSF protein concentration remained sta-
tistically significant (p  .01) between children who were pre-
treated as compared with untreated children. The duration of
illness preceding admission was significantly longer in children
who had been treated with antibiotics compared with that in
untreated children. These observations suggested that the natu-
ral progression of illness in the pretreated group was less rapid
than that in the untreated group and possibly accounted for the
differences in numbers of WBCs and bacteria in the pretreated
group, in whom infection was less fulminant (274).
Intravenous antibiotic therapy, even for as long as several
days prior to initial LP, does not markedly alter the chemical
or morphologic characteristics of the CSF in cases of bacterial
meningitis (197). CSF was examined in 68 children with acute
bacterial meningitis on admission and 44 to 68 hours after
intravenous antibiotic therapy. Initial antibiotic therapy in all
cases consisted of ampicillin (200 mg/kg daily in six divided
doses) in combination with chloramphenicol (100 mg/kg daily
in four divided doses). In those cases in which meningococci,
pneumococci, or group A streptococci were isolated from
CSF culture, aqueous penicillin G (400,000 U/kg daily in six
divided doses) was substituted. In 65 children with meningi-
tis caused by Hib, pneumococci, group A streptococci, and
meningococci, intravenous antibiotic therapy did not signifi-
cantly alter the CSF protein, glucose, or WBC concentrations.
However, bacteria were not evident on smear and did not
grow in culture from CSF obtained after intravenous antibi-
otic therapy of this duration (275).
In general, bacteria should not be seen on Gram stain or
grow in culture from CSF examined 24 hours after treatment
has begun with appropriate antibiotic therapy. The CSF glu-
cose concentration approaches normality by the third day of
antibiotic therapy in 80% of patients, but it may remain low
for as long as 10 days. The CSF protein concentration remains
elevated for at least 10 days. The WBC count in CSF remains
elevated in more than 50% of cases after a standard 7- to
10-day course of antibiotic therapy, but it typically decreases
when compared with the value obtained prior to therapy or
early in the course of bacterial meningitis (256).
Rapid Diagnostic Tests
Several techniques have been developed for the rapid detec-
tion of bacterial antigens in the CSF, including the latex
agglutination test, the staphylococcal or other coagglutina-
tion tests, and counterimmunoelectrophoresis, among many
others (276). These techniques use serum containing bacterial
antibodies or commercially available antisera directed against
the capsular polysaccharide to detect the presence of bacte-
rial antigens in CSF. Counterimmunoelectrophoresis requires
specialized equipment and expertise and is rarely performed
in hospital laboratories. Due to unacceptably poor sensitivity
, tumor necrosis factor- , com-
of latex agglutination for the diagnosis of bacterial meningitis
in CSF samples with a negative Gram stain (277), this test
has been abandoned in most hospital laboratories and cannot
be routinely recommended, although might be considered for
patients who have been pretreated with antimicrobial therapy
and when CSF Gram stain and culture results are negative,
where available (278).
Scheld_Ch24.indd 394
The limulus amebocyte lysate test can detect minute quantities
of endotoxin (e.g., 10 ng/mL) in the CSF. It is reported to have a
sensitivity of 77% to 100%, with some studies reporting sensi-
tivities of 97% to 99% for detecting gram-negative endotoxin.
It has been recommended as a useful method for the detection of
gram-negative bacterial meningitis (279). It is occasionally em-
ployed in the setting of an abnormal CSF following neurosurgery
or head trauma. Nevertheless, the results of the test rarely change
patient management because physicians should employ antimi-
crobials with activity against gram-negative aerobic bacilli in this
clinical setting, even if the limulus lysate test result is negative.
C-Reactive Protein and Procalcitonin
The C-reactive protein (CRP) is an acute-phase reactant that, when
present in concentrations greater than 100 ng/mL in CSF, is quite
sensitive for differentiating bacterial from viral meningitis. The
CRP response is minimal in viral meningitis. CRP concentrations
in CSF may be elevated in other CNS inflammatory or necrotic
conditions and thus are not specific for bacterial meningitis; how-
ever, when cell counts and chemistries suggest meningitis, the
CRP concentration is useful in distinguishing between bacterial
meningitis and viral meningitis (280,281). In this circumstance,
a negative CSF CRP result excludes bacterial meningitis with
99% certainty. Because CRP is produced in the liver, serum CRP
may be useful in differentiating bacterial from viral meningitis
as well. A normal serum CRP has a negative predictive value of
about 99% for acute bacterial meningitis. Thus, in patients where
the CSF Gram stain is negative and the differential diagnosis is
between acute bacterial (or partially treated bacterial) and viral
meningitis, a normal serum CRP concentration excludes bacterial
meningitis with about 99% certainty and these patients may be
safely observed in the absence of antibacterial therapy.
A normal serum procalcitonin (another acute-phase reac-
tant) concentration has nearly identical predictive value to the
CRP (282284). In one study, a serum procalcitonin concen-
tration of more than 0.2 ng/mL had a sensitivity and specificity
of up to 100% in the diagnosis of bacterial meningitis (285),
although false-negative results have been reported (286). In
another study, serum procalcitonin, at a cutoff of 0.28 ng/mL,
had a sensitivity of 95%, specificity of 100%, negative predic-
tive value of 100%, and positive predictive value of 97% in the
diagnosis of bacterial meningitis (270). In patients with menin-
gitis in whom the CSF Gram stain is negative and analysis of
other parameters is inconclusive, serum concentrations of CRP
or procalcitonin that are normal or below the limit of detection
have a high negative predictive value in the diagnosis of bacte-
rial meningitis, so that these patients (i.e., with a presumptive
diagnosis of viral meningitis) can be carefully observed with-
out initiation of antimicrobial therapy (278,284).
Other Diagnostic Markers
Other markers that have been studied as markers for acute
bacterial meningitis in children and adults include CSF
concentrations of cortisol, heparin-binding protein, soluble
triggering receptor expressed on myeloid cells 1, interleukin-6,
interleukin-12, interleukin-1
plement component B, and complement component 3 (272).
Most of these studies included low numbers of patients, limit-
ing their generalizability. In one study, heparin-binding protein
had a sensitivity of 100% and specificity of 99.2% in the dif-
ferentiation of bacterial from aseptic meningitis (287).
An immunochromatographic test for detection of S. pneu-
moniae in CSF was found to be 100% sensitive and specific for
2/21/14 5:42 PM

diagnosing pyogenic pneumococcal meningitis (288), although
more studies are needed to demonstrate the usefulness of this
test in the diagnosis of pneumococcal meningitis; the overall
sensitivity of the test is 95% to 100% (289).
Polymerase Chain Reaction
Polymerase chain reaction (PCR) assays that use specific bacterial
primers to detect the nucleic acid of S. pneumoniae, N. meningit-
idis, H. influenzae, E. coli, S. agalactiae, and L. monocytogenes
in CSF are available. These assays are reported to be highly sensi-
tive (290295). In clinical practice, culture results are often re-
ported before the results of the PCR assay are known limiting the
usefulness of this assay. A broad-range bacterial PCR that can
be performed in 2 hours and that can detect small numbers of
viable and nonviable organisms in CSF has been developed. This
could be useful as a screening test for bacterial meningitis and
in patients who have been treated with antimicrobial therapy in
whom CSF culture is often negative (296); in this study, the test
characteristics for broad-based bacterial PCR demonstrated a
sensitivity of 100%, a specificity of 98.2%, a positive predictive
value of 98.2%, and a negative predictive value of 100%. In
another study with use of a multiplex PCR assay for detection of
N. meningitidis, S. pneumoniae, and Hib, the overall specificity
and positive predictive value were 100% and the negative pre-
dictive value was 99.1% to 99.5% (297). Multiplex assays for
detecting genes of meningeal pathogens were 100% specific for
detecting its target organisms or serogroups, and the lower limit
of detection was similar to that for the singleplex assays (298).
In another study, the sensitivity of broad-range PCR was higher
than that of culture (59% versus 43%), whereas the specificity
was 97% for both methods of diagnosis (299). Therefore, broad-
based bacterial PCR can be used to detect the most common
microorganisms in only one test and has adequate sensitivity
and excellent specificity (272). The broad-based bacterial PCR
can be done within 2 hours in most industrialized countries,
although they are scarce in resource-poor countries. PCR may
be particularly useful in patients with bacterial meningitis who
have received prior antimicrobial therapy and are more likely to
have negative CSF cultures (300). The sensitivity and specificity
of PCR in CSF for the diagnosis of pneumococcal meningitis are
92% to 100% and 100%, respectively (289). Real-time PCR has
also been used for the diagnosis of L. monocytogenes menin-
goencephalitis (301). Problems with false-positive results arise
when using PCR, although further refinements in this technique
may lead to its usefulness in the diagnosis of bacterial meningi-
tis, particularly when CSF Gram stain and cultures are negative.
Another potential application of PCR is rapid detection of the in
vitro susceptibility of meningeal pathogens to specific antimicro-
bial agents. In one report, a novel real-time PCR-hybridization
assay was developed for the rapid detection of penicillin sus-
ceptibility in S. pneumoniae; when applied to 24 pneumococcal
DNA-positive CSF extracts, penicillin-sensitive S. pneumoniae
was detected in all instances (302). Further studies may establish
the usefulness of this rapid technique in allowing clinicians to
decide on the use of specific antimicrobial therapy in patients
with bacterial meningitis (see later discussion).
Neuroimaging
In the acute stage of bacterial meningitis, the CT scan may be
normal or it may demonstrate enhancement of the meninges and
ependyma with widening of the cisterns at the base of the brain
and the cortical sulci, a result of the accumulation of purulent
exudate in the basal cisterns and over the convexities of the hemi-
spheres (303). However, the presence of these abnormalities on
Scheld_Ch24.indd 395
Chapter 24: Acute Bacterial Meningitis 395
CT scan contributes very little to the diagnosis of meningitis.
The diagnosis is made by the clinical presentation and analysis
of the CSF. The extent of meningeal enhancement on CT also
does not influence management or prognosis. The value of CT
in suspected bacterial meningitis is in the exclusion of other CNS
pathologic processes and in the investigation of the complications
of this infection, including (a) prolonged fever for several days
after the initiation of antibiotic therapy, (b) fever that develops
after an afebrile period during therapy (secondary fever), (c) pro-
longed obtundation or coma, (d) new or recurrent seizure activ-
ity, (e) signs of increased ICP, and (f) focal neurologic deficits.
The most common causes of prolonged fever in patients
with bacterial meningitis are subdural effusions, drug fever,
and concomitant arteritis or pneumonia. In published series,
9% to 13% of patients with Hib or with pneumococcal or me-
ningococcal meningitis had fever for 10 days or longer after the
initiation of appropriate antibiotic therapy. In approximately
25% of these patients, the fever was attributed to the presence
of a subdural effusion. The most common causes of secondary
fever are nosocomial infections and subdural effusions (304).
Although the intracranial complications of meningitis are dem-
onstrated well by CT scan, the results of the CT scan rarely
influence the management of children with meningitis and pro-
longed fever in the absence of other clinical features suggesting
CNS complications (305). In one review of 107 children with
bacterial meningitis who underwent CT scan, one or more ab-
normalities were found in 52% of cases (306). However, the
majority of findings did not require specific intervention.
Subdural effusions are a relatively common complication
of bacterial meningitis, being reported in 20% to 50% of in-
fants and children with meningitis. Only a small percentage is
clinically significant (307310). In most cases, the fluid in the
subdural space is sterile and is resorbed when the inflammatory
process subsides; however, when a subdural effusion is demon-
strated by CT in a patient with prolonged fever, the possibility of
the development of a subdural empyema is raised. Subdural effu-
sions are typically low-density collections of fluid adjacent to the
inner border of the skull that are hypodense to brain and nearly
isodense to spinal fluid (Fig. 24.27). They are often bilateral and
may flatten and displace the frontal horns posteriorly. When
a subdural effusion becomes purulent, its density on CT scan
FIGURE 24.27 Contrast-enhanced CT scan demonstrating subdural
effusion.
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 396 Part III: Bacterial and Mycoplasmal Infections

A B

FIGURE 24.28 A: CT scan demonstrating extraaxial fluid collection suggestive of subdural effusion as
opposed to subdural empyema. B: After administration of contrast, the medial border of the subdural
fluid collection enhances; therefore, it is a subdural empyema.

appears higher than that of CSF. After the administration of an
intravenous contrast agent, there is significant enhancement,
when the effusion is an empyema, at the border between the ex-
traaxial fluid collection and the underlying cortex (Fig. 24.28).
Sterile subdural effusions do not typically demonstrate contrast
enhancement of the medial border (303) (Fig. 24.29).
The possibility of raised ICP secondary to diffuse cerebral
edema or obstructive or communicating hydrocephalus should
be considered in patients with a progressive or prolonged
alteration of consciousness. The CT abnormalities consistent
with diffuse cerebral edema include (a) loss of differentiation
between gray matter and white matter; (b) compression of
the ventricles, giving the frontal horns a slitlike appearance;
(c) loss of sulcal markings; and (d) lack of visualization of the
perimesencephalic, suprasellar, or quadrigeminal cisterns (303)
(Fig. 24.30). The CT appearance of communicating hydroceph-
alus is an enlargement of the entire ventricular system, including
the fourth ventricle, with periventricular lucencies surrounding
the frontal horns (Fig. 24.31). The latter abnormality repre-
sents transependymal movement of CSF from the ventricular
system into the brain parenchyma as a result of blockage in
the normal CSF resorption pathways (303). The development
of an obstructive hydrocephalus secondary to blockage of CSF
flow by exudate at the foramina of Magendie and Luschka has
the CT appearance of dilated lateral and third ventricles, with
nonvisualization of the fourth ventricle.

A B

FIGURE 24.29 A: CT scan of subdural fluid collection before contrast enhancement. B: CT scan after
contrast enhancement. The medial border of the subdural fluid collection does not enhance; therefore,
it is a subdural effusion.

Scheld_Ch24.indd 396 2/21/14 5:42 PM


A B
FIGURE 24.30 A and B: CT scans demonstrating diffuse cerebral edema. There is loss of differentiation
between gray matter and white matter, and the sulci are markedly less prominent.
The development of seizure activity and/or focal neurologic
symptoms and signs during the course of meningitis are clear-cut
indications for neuroimaging. The cause of these abnormalities
may be cerebritis, brain abscess, cortical infarction, enlarging
subdural effusions, or empyema. Areas of cerebritis can easily be
missed by CT scan. When they are visualized by CT, they appear
as low-density lesions on the noncontrasted scan; after contrast ad-
ministration, they are surrounded by an inhomogeneous halo.
There may also be diffusion of contrast medium into the low-
density center of an area of cerebritis. As the abscess matures and
a capsule is formed, it becomes a low-density lesion with a sharply
demarcated dense ring of contrast enhancement, surrounded by a
variable hypodense region of edema (311) (see Chapter 25).
Cortical infarctions complicating bacterial meningitis are the
result of vasculitis. The CT appearance of a cortical infarction is
that of a hypodense lesion that conforms to a vascular territory.
FIGURE 24.31 CT scan demonstrating enlargement of the entire
ventricular system, including the fourth ventricle, characteristic of
communicating hydrocephalus.
Scheld_Ch24.indd 397
Chapter 24: Acute Bacterial Meningitis 397
Following the administration of contrast, cortical infarctions
have a gyriform, nodular, or ring pattern of enhancement (306)
(Fig. 24.32). Hemorrhagic infarctions are characteristically as-
sociated with hyperdense areas on noncontrasted scans (303).
MRI scanning, like CT, is useful for evaluating the compli-
cations of bacterial meningitis. Subdural empyemas, cortical
infarctions, and areas of cerebritis are more readily imaged by
MRI than by CT, but in a sick patient an MRI scan is more dif-
ficult to obtain than a CT scan. It is considerably more difficult
to manage a critically ill patient in an isolated MRI scanner
suite than in the CT scanner.
The extent and degree of leptomeningeal enhancement from
bacterial meningitis are well demonstrated by MRI scan after the
intravenous administration of the paramagnetic contrast agent
gadolinium (Fig. 24.33). Paramagnetic contrast agents produce
local alterations in magnetic environments that directly affect the
MRI signal obtained from protons. The image that is obtained
after the administration of the contrast agent visualizes this ef-
fect on proton relaxation. The contrast agent itself is not visual-
ized. Areas of active breakdown in the BBB are enhanced when
scans are obtained after the administration of gadolinium (312).
Pathologic examination of animals with experimental bacterial
meningitis demonstrated that areas of contrast enhancement on
both CT and MRI scans correlated with inflammatory cell infiltra-
tion, and gadolinium-enhanced T1-weighted MRI scans revealed
inflammatory meningeal and ependymal lesions more effectively
than did contrast-enhanced CT. Unenhanced T1- and T2-weighted
MRI scans did not detect meningeal inflammation (313).
Subdural effusions can sometimes be distinguished from
subdural empyemas by their MRI appearance. Subdural effu-
sions are low-protein collections; therefore, they appear isoin-
tense to spinal fluid on MRI (Fig. 24.34). Subdural empyemas
are more proteinaceous and therefore appear to have higher
signal intensity than CSF on T2-weighted MRI scans (314).
MRI is superior to CT scan in visualizing a cortical infarc-
tion. Ischemia and/or infarction are common causes of focal
neurologic deficits in bacterial meningitis. On T2-weighted
MRI images, areas of infarction appear as areas of abnor-
mal, increased signal intensity. An acute infarction is often
not visualized on CT scan within the first 24 hours unless the
infarction is large or associated with edema and mass effect.
MRI is the most sensitive modality for these complications,
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 398 Part III: Bacterial and Mycoplasmal Infections

A B

C D

FIGURE 24.32 A and B: CT scan before and after contrast enhancement. High ventricular level. C and D:
CT scan before and after contrast enhancement. Low ventricular level. Hypodense lesion characteristic
of cortical infarction in a patient with Hib meningitis. Following the administration of contrast, there is
a gyriform pattern of enhancement.

particularly with regard to infarction, especially when seen
on diffusion-weighted imaging, and ventriculitis (315). MR
angiography and perfusion-weighted imaging may show vas-
cular complications, including focal stenosis and irregularity
of major intracranial arteries. CT angiography is more sensi-
tive than MR angiography for demonstrating focal stenosis of
small cerebral arteries.
INITIAL MANAGEMENT
The initial management of a patient with presumed bacterial
meningitis is to obtain blood cultures, initiate antimicrobial
and dexamethasone therapy if indicated, and obtain spinal
fluid analysis to determine whether the CSF formula is con-
sistent with that diagnosis (see earlier discussion) (278,316).
Empirical antimicrobial therapy should be initiated based on
the patients age and underlying disease status (Table 24.5).
Although no prospective data are available on the timing of
administration of antimicrobial therapy in patients with bac-
terial meningitis, a retrospective cohort study in patients with
community-acquired bacterial meningitis demonstrated that a
delay in initiation of antimicrobial therapy after patient ar-
rival in the emergency department was associated with an ad-
verse clinical outcome when the patients condition advanced
to a high stage of prognostic severity (317), thus supporting
the assumption that treatment of bacterial meningitis before
it advances to a high level of clinical severity improves clini-
cal outcome. This concept has also been supported by two
retrospective studies: one demonstrated a reduction in mortal-
ity with early administration of antimicrobial therapy (318),
and the other showed a benefit in terms of neurologic out-
come and survival in patients who received antimicrobial
therapy before the patients level of consciousness deteriorated
to a score lower than 10 on the Glasgow Coma Scale (319).
In another retrospective case study, delay in administration

Scheld_Ch24.indd 398 2/21/14 5:42 PM


FIGURE 24.33 Gadoliniumdiethylenetriamine pentaacetic acid
enhanced T1-weighted magnetic resonance scan demonstrating diffuse
meningeal enhancement in a patient with meningitis.
of antimicrobial therapy was associated with death; in the
multivariate analysis, a delay of longer than 6 hours in antimi-
crobial administration after presentation conferred an 8.4-fold
greater risk of death (320). An additional retrospective cohort
study of 286 patients with community-acquired bacterial men-
ingitis confirmed these results, in which early and adequate
administration of antimicrobial therapy related to onset of
overt signs of meningitis was independently associated with
favorable outcome (odds ratio [OR]  11.19) (321).
Some patients should have a noncontrast CT scan of the head
performed before LP to rule out the presence of brain shift (as a
result of an intracranial mass lesion or generalized brain edema)
because of the potential risk of herniation (278). However, the
time involved in waiting for a CT scan significantly delays the
FIGURE 24.34 T2-weighted magnetic resonance scan demonstrating
subdural effusion.
Scheld_Ch24.indd 399
Chapter 24: Acute Bacterial Meningitis 399
TA B L E 2 4 . 5
EMPIRICAL THERAPY FOR PURULENT MENINGITIS
Predisposing Factor Antimicrobial Therapy
Age
Neonate Ampicillin plus cefotaxime; or
ampicillin plus an aminoglycoside
Infant (123 mo) Vancomycin plus a third- or fourth-
generation cephalosporina
Children and adults Vancomycin plus a third- or fourth-
(250 yr) generation cephalosporina,b
Adults 50 yr Vancomycin plus ampicillin plus
a third- or fourth-generation
cephalosporina
Immunocompromised Vancomycin plus ampicillin plus
state either cefepime or meropenem
Basilar skull fracture Vancomycin plus a third- or fourth-
generation cephalosporina
Head trauma; Vancomycin plus either ceftazidime
postneurosurgery or meropenem
a
Cefotaxime or ceftriaxone or cefepime.
b
Add ampicillin if meningitis caused by Listeria monocytogenes is
suspected.
initiation of antimicrobial therapy, with the potential for in-
creased morbidity and mortality in patients with bacterial men-
ingitis. Therefore, emergency empirical antimicrobial therapy
and adjunctive dexamethasone therapy if indicated, after ob-
taining blood cultures, should be initiated before sending the
patient to the CT scanner. Although CSF cultures may be sterile
after the initiation of antimicrobial therapy, pretreatment blood
cultures and the CSF formula or Gram stain will provide evi-
dence for or against a diagnosis of bacterial meningitis. In one
retrospective review of 177 patients (39 of whom had received
prior antimicrobial therapy) with CSF cultureproven bacterial
meningitis (322), the combination of blood culture and CSF
Gram stain, with or without latex agglutination, identified the
causative bacterium in 92% of patients. Although some clini-
cians routinely order CT scans of the head before performance
of an LP in adults with suspected bacterial meningitis, this is not
necessary in most patients. In a study of 301 patients with bac-
terial meningitis (237), the clinical features at baseline that were
associated with an abnormal finding on CT scan of the head
were an age of at least 60 years, immunocompromised status,
a history of CNS disease, a history of seizure within 1 week be-
fore presentation, and neurologic abnormalities (an abnormal
level of consciousness, an inability to answer two consecutive
questions correctly or to follow two consecutive commands,
gaze palsy, abnormal visual fields, facial palsy, arm drift, leg
drift, and abnormal language). It is reasonable to proceed with
LP without CT scan of the head if the patient does not meet any
of the following criteria: new-onset seizures, an immunocom-
promised state, signs that are suspicious for space-occupying
lesions (papilledema or focal neurologic signs, not including
cranial nerve palsy), or moderate to severe impairment of con-
sciousness (278,323). Although the decision to perform a CT
before LP must be individualized, these guidelines are useful
in determining the patient groups that are more likely to have
abnormal findings on neuroimaging studies.
Once the infecting meningeal pathogen is isolated and sus-
ceptibility testing known, antimicrobial therapy can be modi-
fied for optimal treatment (Tables 24.6 and 24.7) (278,316).
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 400 Part III: Bacterial and Mycoplasmal Infections

TA B L E 2 4 . 6
RECOMMENDED ANTIMICROBIAL THERAPY FOR ACUTE BACTERIAL
MENINGITIS

Microorganisma Antimicrobial Therapy

Haemophilus influenzae type b Third-generation cephalosporinb

Neisseria meningitidis Third-generation cephalosporinb
Streptococcus pneumoniae Vancomycin plus a third- or fourth-generation cephalosporinb
Listeria monocytogenes Ampicillin
Streptococcus agalactiae Ampicillin or penicillin G or a third-generation cephalosporin

a
Pathogen presumptively identified by positive Gram stain.
b
Cefotaxime or ceftriaxone or cefepime.

TA B L E 2 4 . 7
SPECIFIC ANTIMICROBIAL THERAPY FOR ACUTE MENINGITIS

Microorganism Standard Therapy Alternative Therapiesa

Bacteria
Haemophilus influenzae
-Lactamase negative
-Lactamase positive
Neisseria meningitidis
Penicillin MIC 0.1 g/mL
Penicillin MIC 0.11.0 g/mL
Streptococcus pneumoniae
Ampicillin Ceftriaxone, cefotaxime, cefepime,
chloramphenicol, aztreonam, fluoroquinolone
Ceftriaxone or cefotaxime Cefepime, chloramphenicol, aztreonam,
fluoroquinolone
Penicillin G or ampicillin Ceftriaxone, cefotaxime, chloramphenicol
Ceftriaxone or cefotaxime Chloramphenicol, fluoroquinolone, meropenem
Penicillin MIC 0.06 g/mL Penicillin G or ampicillin Ceftriaxone, cefotaxime, chloramphenicol
Penicillin MIC 0.12 g/mL b

Ceftriaxone or cefotaxime MIC 1.0 g/mL Ceftriaxone or cefotaxime Meropenem, cefepime

Ceftriaxone or cefotaxime MIC 1.0 g/mL Vancomycinc plus Vancomycin plus moxifloxacind
ceftriaxone or cefotaxime
Enterobacteriaceaee Ceftriaxone or cefotaxime Aztreonam, fluoroquinolone, trimethoprim-
sulfamethoxazole, meropenem, ampicillin
Pseudomonas aeruginosa Ceftazidimef or cefepimef Aztreonamf, fluoroquinolonef, meropenemf
Acinetobacter baumanniie Meropenem Colistin (usually formulated as colistimethate
sodium)b, polymyxin Bb
Listeria monocytogenes Ampicillin or penicillin Gf Trimethoprim-sulfamethoxazole
Streptococcus agalactiae Ampicillin or penicillin Gf Ceftriaxone, cefotaxime, vancomycin
Staphylococcus aureus
Methicillin-sensitive Nafcillin or oxacillin Vancomycin, linezolid, daptomycin
Methicillin-resistant Vancomycinc Trimethoprim-sulfamethoxazole, linezolid, daptomycin
Staphylococcus epidermidis Vancomycinc Linezolid

a
There may not be clinical data to support all recommendations for alternative antimicrobial agents in patients with bacterial meningitis, but specific
agents are suggested based on CSF penetration in experimental animal models and in vitro activity against the offending pathogen.
b
Might also need to be administered by the intraventricular or intrathecal routes.
c
Addition of rifampin may be considered; see text for indications.
d
Would recommend moxifloxacin given its excellent CSF penetration and in vitro activity against S. pneumoniae, although there are no clinical data to
support its usefulness in patients with pneumococcal meningitis; if used, many authorities would combine moxifloxacin with vancomycin or a third-
generation cephalosporin such as cefotaxime or ceftriaxone.
e
Choice of a specific antimicrobial agent must be guided by in vitro susceptibility testing.
f
Addition of an aminoglycoside should be considered.
Adapted from van de Beek D, Brouwer MC, Thwaites GE, et al. Advances in treatment of bacterial meningitis. Lancet. 2012;380:16931702.

Scheld_Ch24.indd 400 2/21/14 5:42 PM

 Chapter 24: Acute Bacterial Meningitis 401

TA B L E 2 4 . 8 Recommended dosages of antimicrobial agents for children

with infections of the CNS are shown in Table 24.8, and those
RECOMMENDED DOSES OF ANTIBIOTICS FOR for adults are presented in Table 24.9. In addition, certain
CHILDREN patients should receive adjunctive dexamethasone therapy
when presenting with suspected or proven bacterial meningitis
Dosing (185,186,278,316). This is discussed in more detail in the sec-
Antibiotic Daily Dose Interval (hr) tion Adjunctive Therapy.
Penicillin G 250,000400,000 U/kg 46
Ampicillin 300 mg/kg 46 TREATMENT
Chloramphenicol 75100 mg/kg 6
Ceftriaxone 80100 mg/kg 1224a General Principles of Therapy
Cefotaxime 225300 mg/kg 68
Ceftazidime 150 mg/kg 8 Bacteriologic cure of meningitis is defined as the eradica-
tion of bacteria from CSF. Effective antimicrobial therapy of
Cefepime 150 mg/kg 8 bacterial meningitis depends on attaining adequate bacteri-
Meropenem 120 mg/kg 8 cidal activity in the CSF. Several factors, largely elucidated
Nafcillin 200 mg/kg 6 in experimental animal models of meningitis, determine
Vancomycinb 60 mg/kg 6 whether bactericidal activity is achieved, including (a) the
ability of an antibiotic to penetrate the BBB, (b) the activ-
Rifampin 1020 mg/kg 1224 ity of the antibiotic within purulent CSF, and (c) the rate of
Gentamicin 7.5 mg/kg 8 metabolism of an antibiotic and its rate of clearance from
Amikacin 2030 mg/kg 8 CSF (324328).
Trimethoprim- 1020 mg/kg (based 612
The BBB poses physiologic restrictions, allowing only
sulfamethoxazole on trimethoprim)
highly lipid-soluble substances or substances transported by
carrier-mediated facilitated diffusion to traverse it under nor-
a
mal conditions (324,329). The ability of an antibiotic to pen-
If a once-daily regimen is used, we recommend that on the first day,
a dose of 80 mg/kg be given at diagnosis, at 12 and 24 hr, and then
etrate the BBB depends on several factors: (a) degree of lipid
every 24 hr thereafter. solubility, (b) degree of ionization at physiologic pH, (c) pro-
b
Maintain serum trough concentrations of 15 to 20 g/mL. tein binding in serum, (d) molecular size and structure of the
antibiotic, and (e) status of the BBB. The BBB acts physiolog-
ically like a lipid bilayer. In general, the greater the lipid solu-
bility of an antibiotic, the better its penetration into CSF. For
example, chloramphenicol is a highly lipophilic substance
TA B L E 2 4 . 9 that easily penetrates the BBB. The
-lactam antibiotics have
poor lipid solubility, which limits their entry into CSF under
RECOMMENDED DOSES OF ANTIBIOTICS normal conditions (324). The un-ionized form of a drug pos-
FOR BACTERIAL MENINGITIS IN ADULTS sesses greater lipid solubility than the ionized form. Thus,
(15 YEARS OF AGE AND OLDER) a lesser degree of ionization at the pH of serum and CSF
increases entry of antibiotics into CSF by increasing their
Antibiotic Total Daily Dose (Dosing Interval)
lipid solubility. Penicillin G has a high degree of ionization
Penicillin G 2024 miU (every 4 h) at the pH of plasma and CSF. This, combined with its low
lipid solubility, may explain the poor penetration of penicil-
Ampicillin 12 g (every 4 h) lin G across intact meninges. The normal plasma-to-CSF pH
Ceftriaxone 4 g (every 1224 h)a gradient is approximately 0.1 pH unit (330). The plasma-
Cefotaxime 812 g (every 46 h) to-CSF pH gradient is altered, however, by purulent men-
Ceftazidime 6 g (every 8 h)b ingitis. The accumulation of lactate in CSF during bacterial
meningitis decreases the pH of CSF, increases the gradient,
Cefepime 6 g (every 8 h) and enhances the penetration of some antibiotics into CSF.
Meropenem 6 g (every 8 h) Conversely, as metabolic acidosis develops, the pH gradi-
Vancomycin 3060 mg/kg (every 812 h)c ent is reversed and the penetration of antibiotics into CSF is
Nafcillin, oxacillin 912 g (every 4 h)d reduced (324).
Protein binding and molecular size limit the ability of an
Chloramphenicol 4 g (every 6 h)e antibiotic to enter the CSF. Only the free nonprotein-bound
Rifampin 600 mg (every 24 h) portion of an antibiotic in serum can enter the CSF; therefore,
Gentamicin, tobramycin 5 mg/kg (every 8 h) highly protein-bound antibiotics have lower CSF concentra-
Amikacin 15 mg/kg (every 8 h) tions than antibiotics with a lower degree of protein binding,
other factors being equal. Increased binding to plasma pro-
Trimethoprim- 1020 mg/kg (every 612 h) teins reduces the amount of antibiotic penetration into CSF;
sulfamethoxazole (based on trimethoprim) however, it is the concentration of free antibiotic in CSF rela-
tive to its minimum bactericidal concentration (MBC) that de-
a
Actual dose studied was 50 mg/kg, every 12 h. termines its therapeutic effectiveness (329).
b
Not enough patients studied to make firm recommendation. Although the pharmacokinetics of an antibiotic greatly in-
c
Maintain serum trough concentrations of 15 to 20 g/mL.
d
Higher doses associated with leukopenia. fluence its ability to penetrate the BBB, the most important
e
Use 6 g/d for pneumococcal meningitis. factor appears to be the presence of meningeal inflamma-
Data from refs. 479 and 181. tion. A moderate degree of meningeal inflammation results
in a marked increase in the penetrability of most antibiotics.

Scheld_Ch24.indd 401 2/21/14 5:42 PM

 402 Part III: Bacterial and Mycoplasmal Infections
In many instances, altered BBB permeability is essential
for an antibiotic to be effective in bacterial meningitis.
The morphologic alterations of the BBB observed in an adult
rat model of experimental meningitis consist of an early and
sustained increase in pinocytotic vesicles with a progressive
separation of intercellular tight junctions in the cerebral mi-
crovasculature (331). These features may contribute to anti-
microbial entry into purulent CSF.
Once the antibiotic penetrates into CSF, several factors
influence its ability to eradicate the infection: (a) sufficient
-lactamaseproducing isolates are still
concentrations of free active drug must be achieved in CSF,
-
because this form of the antibiotic is necessary for bactericidal
effect. The high protein concentrations in purulent CSF limit
the concentration of free, unbound antibiotic; (b) an antibi-
otic must achieve concentrations in CSF in vivo exceeding the
MBC of the infecting organism by 10- to 20-fold for optimal
efficacy (173); (c) the bactericidal activity of an antibiotic
may be diminished by the coadministration of a bacteriostatic
agent. For example, chloramphenicol inhibits the bactericidal
effect of aminoglycosides against gram-negative aerobic bacilli
within the CSF (332). Conversely, antimicrobial combinations
may exert an enhanced, synergistic improvement in the rate
of bactericidal activity within the CSF in vivo (e.g., ampicil-
lin plus gentamicin versus L. monocytogenes or S. agalactiae);
(d) early in the course of bacterial meningitis, there may be
very large numbers of bacteria in CSF (i.e., 108 CFU/mL).
Some antibioticsin particular the
-lactam antibiotics increasing in incidence worldwide. In Ontario, Canada, the
demonstrate an inoculum effect in vitro, such that the mini-
mum inhibitory concentration (MIC) increases dramatically
as the inoculum of the test strain is increased from 105 to
107 CFU/mL under standardized in vitro conditions (324).
The inoculum effect may explain the failure of certain anti-
biotics in vivo, as the in vitro activity of an antibiotic is rou-
tinely determined in standard growth media using a bacterial
concentration of 105 CFU/mL (325); (e) an antibiotic must
remain physically stable in the presence of bacterial inacti-
vating enzymes, such as
-lactamase and chloramphenicol for serious meningococcal infection, including meningitis.
acetyltransferase (329).
The effectiveness of an antibiotic in eradicating bacterial
meningitis is also determined by its rate of metabolism and
the activity of its metabolites. For example, cephalothin is
metabolized in vivo to desacetylcephalothin, which is less ac-
tive in vitro than the parent compound (324). In contrast, the
metabolite of cefotaxime (desacetylcefotaxime) is as active in
vitro as the parent compound. Antibiotics are removed from
CSF either by simple resorption through arachnoid villi or by
an energy-dependent active transport process that removes
the antibiotic from the CSF to the intravascular compartment
across the epithelium of the choroid plexus. This exit pump
is inhibited by weak organic acids, such as salicylates and pro-
benecid, and to some extent by meningitis itself.
-Lactam 0.06 g/mL or lower and 0.12 g/mL or greater, respectively
antibiotics are cleared from the CSF by this process. The third-
generation cephalosporins (e.g., ceftriaxone and cefotaxime)
possess decreased affinity (as compared with penicillin G) for
the choroid plexus exit pump, so that they remain in CSF
for a longer time (329).
There have also been investigations to determine whether
continuous infusion of antimicrobial therapy improves out-
come in patients with bacterial meningitis. In one study of
-lactam antibi-
723 African children with bacterial meningitis randomly as-
signed to receive bolus or continuous infusion of cefotaxime
for the first 24 hours of therapy, 272 children died, but the
mode of administration did not significantly affect the propor-
-lactam antibiotics and thus a
tion of children who died or were severely disabled at the time
of hospital discharge (333); children with pneumococcal men-
ingitis given continuous cefotaxime infusion were significantly
less likely to die or have sequelae, however.
Scheld_Ch24.indd 402
Antimicrobial Therapy for Specific Organisms
Neisseria meningitidis
Penicillin G and ampicillin are the preferred antibiotics
for the treatment of meningitis caused by N. meningitidis
(197,219,334). A 7-day course of therapy is adequate for
most cases of uncomplicated meningococcal meningitis. There
are reports of strains of N. meningitidis resistant to penicil-
lin (335). However,
rare (336). Penicillin-resistant strains that do not produce
lactamase appear, instead, to have a reduced affinity for peni-
cillin-binding proteins (e.g., PBP-2 and PBP-3) and have been
reported from Spain, the United Kingdom, and other countries
(335,337339). In Spain, the number of relatively penicillin-
resistant meningococcal isolates reached 20% in 1989 (340).
However, in the United States in 1991, MICs of penicillin of
0.125 g/mL were noted for only 3 of 100 isolates submit-
ted to the CDC (341). Routine susceptibility testing of menin-
gococcal isolates is recommended. Meningococcal meningitis
caused by the relatively penicillin-resistant strains has, how-
ever, been successfully managed with penicillin therapy, and
thus the clinical significance of this partial resistance is unclear
at present (173). Nevertheless, this situation must be carefully
monitored, because meningococci showing relative resistance
to penicillin (i.e., MICs in the range of 0.1 to 1.0 g/mL) are
prevalence of invasive meningococcal disease caused by strains
with decreased in vitro susceptibility to penicillin was much
higher (21.7%) in 2006 (342), although it did not change in
frequency between 2000 and 2006. Cefotaxime or ceftriaxone
should be used when relatively penicillin-resistant strains of
meningococci are isolated and when a patient is allergic to
penicillin (343). Because of potent in vitro activity and ease
of administration (e.g., every 12 hours and perhaps effective
at every 24 hours), ceftriaxone may well be the drug of choice
Chloramphenicol is also generally effective and widely used in
developing countries.
Streptococcus pneumoniae
Initial therapy of pneumococcal meningitis includes a combi-
nation of a third- or fourth-generation cephalosporin (either
ceftriaxone, cefotaxime, or cefepime) plus vancomycin until
the results of antimicrobial susceptibility testing are known.
The Clinical and Laboratory Standards Institute has recently
redefined the in vitro susceptibility breakpoints for pneumo-
coccal isolates from patients with meningitis as either suscep-
tible or resistant, with intravenous penicillin breakpoints of
(344). A pneumococcal isolate with an MIC for cefotaxime
or ceftriaxone of less than 0.5 g/mL is considered suscep-
tible, 1.0 g/mL intermediate, and more than 2.0 g/mL
resistant (345). In the United States, approximately 34% of
pneumococcal isolates are penicillin nonsusceptible (MICs
in the intermediate and resistant ranges) and approximately
14% are resistant to ceftriaxone (346). The mechanisms by
which S. pneumoniae develop resistance to
otics (penicillin and extended-spectrum cephalosporins) is
through alterations of one or more penicillin-binding proteins
(347). Alterations in the penicillin-binding proteins lead to a
decrease in their affinity for
decreased susceptibility to the antibiotic (346). In Brazil, peni-
cillin resistance was mainly detected in isolates of serotypes 14
(61%), 23F (16%), 6B (10%), and 19F (3%) (348). Results
of recent surveillance studies in the United States show that
2/21/14 5:42 PM

the prevalence of penicillin-nonsusceptible S. pneumoniae
ranges from 25% to more than 50% (349); rates are as high
as 60% in some parts of Latin America and as high as 80%
in some countries in Asia. Factors reported to predispose to
resistance include the patients age (younger than 10 or older
than 50 years); immunosuppression; prolonged hospital stay;
children in day care settings; infection by serotypes 14 and
23; and frequent, prolonged, or prophylactic use of antimicro-
bial therapy. However, penicillin nonsusceptible strains have
been isolated even when no risk factors or comorbidities are
identified (350).
In view of the increasing number of strains resistant to
penicillin, all CSF isolates of S. pneumoniae should be tested
for sensitivity to penicillin and the third-generation cephalo-
sporins by in vitro susceptibility testing. A third- or fourth-
generation cephalosporin (i.e., cefotaxime or ceftriaxone
or cefepime) is recommended for strains of pneumococci
resistant to penicillin (MIC 0.12 g/mL) but sensitive to
the third-generation cephalosporins (MIC 1 g/mL). For
-
strains resistant to penicillin and the cephalosporins, van-
comycin plus a third- or fourth-generation cephalosporin is
the antimicrobial regimen of choice (351,352). The addition
of rifampin or a ceftriaxone-rifampin regimen has also been
recommended by some authorities, but rifampin may dem-
onstrate indifference or slight antagonism when combined
with
-lactam agents in standardized in vitro assays (353),
although rifampin, without bacteriolytic activity, may protect
against neuronal damage (354). Although concerns have been
raised about use of vancomycin in patients with pneumococ-
cal meningitis who are also receiving adjunctive dexametha-
sone, appropriate CSF concentrations of vancomycin may be
attained as long as appropriate dosages of vancomycin are
used. In a study of 14 patients, administration of intravenous
vancomycin (at a continuous infusion of 60 mg/kg per day,
after a 15 mg/kg loading dose) led to mean serum and CSF
vancomycin concentrations of 25.5 g/mL and 7.2 g/mL,
respectively (355). These data indicate that appropriate CSF
concentrations can be attained when appropriate doses are
used. Trough serum concentrations of 15 to 20 g/mL are
recommended (356). Intrathecal or intraventricular vancomy-
cin is a reasonable consideration in patients not responding to
parenteral therapy.
Vancomycin-resistant strains of pneumococci have not
been seen, but strains of S. pneumoniae tolerant to vancomy-
cin have been reported. Tolerance is the ability of a bacteria to
survive in the presence of an antibiotic, neither growing nor
being eradicated by the antibiotic. Tolerance may be a precur-
sor for the development of antimicrobial resistance because it
creates survivors of antibiotic therapy (357359).
Imipenem has been utilized in the therapy of penicillin-
resistant pneumococcal meningitis, although its proconvulsant
activity may limit its usefulness; meropenem, a carbapenem
with less seizure proclivity than imipenem, may be an effec-
tive alternative (360). However, in a study of 20 cefotaxime-
resistant S. pneumoniae isolates (361), 4 were of intermediate
susceptibility and 13 were resistant to meropenem, suggest-
ing that meropenem may not be a useful alternative agent for
the treatment of pneumococcal isolates that are highly resis-
tant to penicillin and cephalosporins. Chloramphenicol is one
agent that has been studied for the treatment of pneumococcal
meningitis. However, clinical failures with chloramphenicol
have been reported in patients with penicillin-resistant iso-
lates, probably because of the poor bactericidal activity of
chloramphenicol against these strains; 20 of 25 children had an
unsatisfactory outcome (i.e., death, serious neurologic deficit,
poor clinical response) in one study (362). Chloramphenicol
resistance was also found in 27% of pneumococcal isolates in
Scheld_Ch24.indd 403
Chapter 24: Acute Bacterial Meningitis 403
Malawi during 2004 to 2006 (363) and in 43% of isolates in
Papua New Guinea (364).
Fluoroquinolones have shown efficacy in some small series
or randomized trials in patients with gram-negative meningi-
tis. In recent years, in response to drug-resistant pneumococci
in particular, newer fluoroquinolones with improved activ-
ity against gram-positive cocci have been introduced. These
agents (e.g., gatifloxacin, moxifloxacin, gemifloxacin, and
garenoxacin) penetrate well into CSF and have produced ex-
cellent results in experimental models of multidrug-resistant
pneumococcal meningitis, including vancomycin-tolerant
strains (365370). Pharmacodynamic analysis suggests that a
Cmax CSF-to-MBC ratio of at least 5 and CSF concentrations
above the MBC for the test strain for the entire dosing interval
are necessary for optimal bactericidal activity. Furthermore,
newer antipneumococcal fluoroquinolones demonstrate syn-
ergistic activity in vitro and in vivo in experimental models of
pneumococcal meningitis and combination therapy appears to
prevent quinolone resistance among pneumococci (370). A
lactam (e.g., ceftriaxone)potent antipneumococcal quinolone
regimen is very promising (371,372) and may well supplant
the currently favored ceftriaxone (or cefotaxime or cefepime)
(373)vancomycin in the future, pending evaluation in ran-
domized controlled trials.
Gram-Negative Bacilli
The results of clinical trials in patients with gram-negative
bacillary meningitis favor the use of a third- (or fourth-)
generation cephalosporin over conventional aminoglycoside-
containing regimens (219,223,374). Cefotaxime, ceftizoxime,
ceftriaxone, and ceftazidime penetrate well into inflamed CSF
and are highly active against gram-negative enteric bacilli
(223,375). Cure rates of 78% to 94% have been achieved with
the cephalosporins, compared with previous mortality rates of
40% to 90% with predominantly aminoglycoside-containing
regimens (173).
However, given the emergence of strains of gram-negative
bacilli that are resistant to the third-generation cephalosporins
(376), the use of other intravenous agents, with or without in-
traventricular antimicrobials, may need to be considered and
several have been used in patients with meningitis caused by
aerobic gram-negative bacilli (278). In general, the aforemen-
tioned third-generation cephalosporins appear to be equally
efficacious for the treatment of gram-negative bacillary menin-
gitis, with the exception of meningitis caused by P. aeruginosa.
Ceftazidime or cefepime is recommended when P. aeruginosa
is suspected (377). Clinical trials suggest the efficacy of ceftazi-
dime alone for Pseudomonas meningitis, but a combination of
ceftazidime and an aminoglycoside may be used if response is
delayed (173).
Although clinical experience is scant, the fluoroquinolones
have demonstrated efficacy in animal models of gram-negative
bacillary meningitis. Intravenous pefloxacin has shown good
efficacy with bacteriologic eradication from the CSF in nine of
ten patients with gram-negative aerobic bacillary meningitis
failing conventional therapy in one study (378). However, the
quinolones should be considered only for gram-negative bacil-
lary meningitis caused by multiresistant strains or in patients
unresponsive to standard therapies (379).
Although extended-spectrum penicillins (e.g., ticarcillin-
clavulanate, temocillin) and aztreonam have proved effec-
tive in the therapy of experimental models of gram-negative
bacillary meningitis in animals, their use is not recommended
because the clinical experience with third-generation cephalo-
sporins in humans is far more extensive. Meropenem has been
successfully used in patients with gram-negative meningitis
2/21/14 5:42 PM
 404 Part III: Bacterial and Mycoplasmal Infections
(including P. aeruginosa), and further investigations may
confirm its efficacy in the therapy of bacterial meningitis (380).
The worldwide database on the use of meropenem in the ther-
apy of bacterial meningitis is quite extensive and encouraging,
including cases of gram-negative bacillary meningitis failing
third-generation cephalosporin therapy (e.g., Enterobacter
species).
For empirical treatment of Acinetobacter meningitis,
intravenous meropenem with or without an aminogly-
coside administered by the intraventricular or intrathe-
cal route has been recommended (381); if the organism is
later found to be resistant to carbapenems, colistin (usu-
ally formulated as colistimethate sodium) or polymyxin B
should be substituted for meropenem and may also need to
be administered by the intraventricular or intrathecal route
(382). Intravenous colistin (5 mg/kg per day) was success-
fully used to treat a patient with meningitis caused by a
multidrug-resistant A. baumannii (383); intrathecal colistin
was also efficacious in other cases of meningitis caused by
this same multidrug-resistant organism (384,385) and in-
trathecal polymyxin E has also been used in a patient with
Acinetobacter meningitis (386). In a summary of treatment
of multidrug-resistant A. baumannii, a total of 14 patients
-lactamase,
were treated for CNS infection (ventriculitis or meningitis)
with colistin given intravenously and/or either intrathecally
or intraventricularly (387); sterilization was achieved in all
cases and cure in 13 of 14 cases. In the presence of meningi-
tis, CSF concentrations of colistin were shown to be 0.5 g/
mL (34% to 67% of serum concentrations) (388). Two cases
of A. baumannii meningitis were also successfully treated
with tigecycline (389).
-lactamase enzyme and the chlor-
Haemophilus influenzae type b
A third-generation cephalosporin, either cefotaxime or cef-
triaxone, is recommended for the initial therapy of H. influ-
-lactamasepositive Hib isolate should be tested for sus-
enzae meningitis (334). There are few differences between
cefotaxime and ceftriaxone for therapy of bacterial menin-
gitis. Both are generally very active against the major men-
ingeal pathogens, rapidly sterilize CSF cultures, and are safe
and effective (390). The long half-life of ceftriaxone allows
for twice-daily (or even once-daily) administration of this
antibiotic. Several studies have documented that once-daily
administration of ceftriaxone is safe and efficacious for the
treatment of bacterial meningitis (336). However, this is not
yet recommended as standard therapy for adults; a twice-
daily dose is preferred (173). Ceftriaxone has shown prom-
ise as once-daily therapy for completion of the therapeutic
course in the home setting in stable children with menin-
gitis following an uncomplicated hospital stay. A 7- to 10-
day course of antibiotics is generally recommended for Hib
meningitis.
Despite initial enthusiasm, cefuroxime, a second-
generation cephalosporin, is not recommended for the treat-
ment of Hib meningitis. The in vitro bactericidal activity of
this drug has been shown to be inferior to that of the third-
generation cephalosporins, and there have been reports of an
unusually high incidence of positive Gram stain and cultures
in CSF obtained several days into treatment. In a prospective,
multicenter study, 106 children with acute bacterial menin-
gitis were randomly assigned to receive either ceftriaxone
or cefuroxime (391). Delayed sterilization of CSF was more
common among six patients given cefuroxime than in one
patient given ceftriaxone (p  .112). When all children with
positive CSF cultures (Hib, N. meningitidis, S. pneumoniae, S.
agalactiae) were included in the analysis, ceftriaxone therapy,
as compared with cefuroxime therapy, resulted in (a) more
Scheld_Ch24.indd 404
rapid sterilization of the CSF at follow-up LP at approxi-
mately 24 hours (2% versus 12% positive cultures; p  .11);
(b) less moderate to profound sensorineural hearing loss at
the 2-month follow-up examination (4% versus 17%; p 
.05); and (c) reversible biliary pseudolithiasis on serial ab-
dominal ultrasonography (16 of 35 versus 0 of 35; p  .001)
(391). In another comparative trial, ceftriaxone also led to a
more rapid clinical response as compared with cefuroxime
(392). The third-generation cephalosporins, cefotaxime and
ceftriaxone, are clearly preferable to cefuroxime in the treat-
ment of Hib meningitis. Resistance of Hib to the third-gen-
eration cephalosporins and fluoroquinolones in vitro has not
been described (393). A combination of chloramphenicol and
ampicillin was at one time the recommended therapy for Hib
meningitis. The use of a third-generation cephalosporin, ei-
ther cefotaxime or ceftriaxone, has the following advantages
over therapy with a combination of ampicillin plus chlor-
amphenicol: (a) the need to monitor serum chloramphenicol
concentrations is eliminated; (b) the potential toxicities of
chloramphenicol are avoided; (c) the number of daily doses
of antibiotics is decreased (199); (d) approximately 29% of
Hib strains causing meningitis in the United States are re-
sistant to ampicillin, through the production of
although a smaller number of strains are resistant to ampicil-
lin because of reduced affinity for penicillin-binding proteins.
An increasing number of Hib strains are resistant to chloram-
phenicol, through the production of chloramphenicol acetyl-
transferase (199). More than 50% of ampicillin-resistant H.
influenzae CSF isolates from Spain are also chloramphenicol
resistant (394). Thus, in some countries, Hib isolates resistant
to both ampicillin and chloramphenicol are common (199).
DNA coding for both the
amphenicol acetyltransferase enzyme can reside on plasmids,
although chromosomally mediated resistance, as, for exam-
ple, to trimethoprim, has been described (395). Therefore,
any
ceptibility to chloramphenicol. In addition, therapy with the
third-generation cephalosporins may result in a more rapid
sterilization of the CSF as compared with therapy with ampi-
cillin plus chloramphenicol.
The pharmacokinetics of chloramphenicol are highly vari-
able among individuals; therefore, serum concentrations of this
antibiotic must be monitored to ensure therapeutic concentra-
tions while avoiding potential toxic concentrations, especially
in infants. Therapeutic serum concentrations are in the range
of 15 to 25 g/mL, obtained 60 to 120 minutes after the com-
pletion of an intravenous or oral dose. Concentrations in ex-
cess of 30 g/mL are associated with an increased incidence of
bone marrow suppression, and levels exceeding 50 to 80 g/
mL may depress myocardial contractility (396). The pharma-
cology of chloramphenicol is altered in patients in shock or
with liver disease. In either clinical situation, excessive serum
concentrations of chloramphenicol could potentially decrease
cardiac contractility. Chloramphenicol should, therefore, be
avoided in patients with these conditions (396).
When chloramphenicol is used in combination with phe-
nobarbital and phenytoin, serum concentrations of all three
drugs must be monitored. Chloramphenicol inhibits hepatic
microsomal enzymes and therefore prolongs the half-life
of phenytoin in serum, resulting in toxic concentrations of
phenytoin. Phenytoin, conversely, interferes with hepatic
metabolism of chloramphenicol, resulting in toxic serum con-
centrations. Phenobarbital induces hepatic microsomal en-
zymes, increases chloramphenicol metabolism, and decreases
serum chloramphenicol concentrations. These drug interac-
tions interfere with the eradication of the infection as well as
with the management of seizure activity (263,397).
2/21/14 5:42 PM

As discussed, fluoroquinolone-resistant H. influenzae
have not emerged, and these agents penetrate well into the
CSF. Trovafloxacin was compared with ceftriaxone (
van- rifampin has been successfully used in patients with MRSA
comycin) in a multicenter, randomized comparative trial con-
ducted in 11 countries and enrolling children 3 months to
12 years of age (398). The major pathogens were Hib, 39%;
N. meningitidis, 32%; and S. pneumoniae, 21%. The overall
efficacy was similar in both groups (prompt CSF sterilization
in 94% to 96%); fluoroquinolones may be an excellent al-
ternative for Hib meningitis in patients with
-lactam allergy.
Streptococcus agalactiae
Penicillin G or ampicillin or a third-generation cephalospo-
rin has been standard therapy for neonatal meningitis caused
by group B streptococci (GBS) and is the recommended ther-
apy for treatment of S. agalactiae meningitis in adults (278).
Additionally, the number of penicillin-resistant strains of
GBS appears to be increasing (399). Infection with strains of
S. agalactiae resistant to tetracycline, erythromycin, lincomy-
cin, and clindamycin has been reported; therefore, the use of
these penicillin substitutes in patients with GBS infections is
not recommended (399).
The therapy of GBS meningitis in patients with life-threatening
penicillin allergy presents a problem. If third-generation cephalo-
sporins must be avoided, then vancomycin or teicoplanin may be
tried, but clinical experience is almost nonexistent.
Listeria monocytogenes
Ampicillin is the drug of choice (often combined with gentami-
cin during the initial phase of treatment) for meningitis caused
by L. monocytogenes. In addition, in a recent retrospective
review of patients with listeriosis (58% with primary bactere-
mia and 42% with meningitis), differences in mortality were
not seen in those treated with ampicillin or with the combina-
tion of ampicillin and gentamicin. An alternative agent in a
penicillin-allergic patient is TMP-SMX, which is bactericidal
against Listeria in vitro. In one retrospective series, therapy
with TMP-SMX plus ampicillin was associated with a lower
failure rate and fewer neurologic sequelae than the combi-
nation of ampicillin plus an aminoglycoside (122), although
more data are needed before this combination can be recom-
mended. Oral therapy with TMP-SMX has been used in some
patients with Listeria meningitis and may be considered in
patients who demonstrate a rapid clinical response to intrave-
nous therapy and in whom good adherence is expected (400).
The third-generation cephalosporins are inactive against this
organism (173). Intravenous vancomycin is not efficacious, al-
though intraventricular vancomycin was successful in one case
of recurrent L. monocytogenes meningitis (401). Meropenem
may be a useful alternative as it is highly active against listeriae.
Staphylococci
Meningitis caused by S. aureus (MSSA) is treated with nafcil-
lin or oxacillin (139,140,402,403). Vancomycin is the drug of
choice for methicillin-resistant staphylococci and for patients
allergic to penicillin. The CSF should be monitored during
therapy, and if the spinal fluid continues to yield viable or-
ganisms after 48 hours of intravenous treatment, then either
intrathecal or intraventricular vancomycin, 20 mg once daily
(in adults), can be added (402404). The role of adjunctive
rifampin therapy is unclear, although the addition of rifampin
or TMP-SMX should be considered in patients not responding
to therapy and if the organism is susceptible (144). Linezolid
has been used successfully in some patients with MRSA CNS
infections (405,406). Daptomycin has been shown to have
Scheld_Ch24.indd 405
Chapter 24: Acute Bacterial Meningitis 405
similar antibacterial activity to vancomycin in an experimen-
tal model of MRSA meningitis (407), and daptomycin plus
meningitis (408410).
Anaerobes
A combination of chloramphenicol and penicillin G has been
recommended for meningitis caused by anaerobes. Penicillin G
has excellent activity against most anaerobes, with the excep-
tion of Bacteroides fragilis. Chloramphenicol is active against
most B. fragilis isolates. Analogous to the experience in patients
with brain abscess, we prefer metronidazole for the therapy of
the rare cases of anaerobic meningitis. Penicillin G should be
used in addition pending culture results. Metronidazole is bac-
tericidal against virtually all strict anaerobic organisms and
penetrates into the CSF and brain well.
Empirical Antimicrobial Therapy by
Age-Group and Underlying Condition
Neonates
Enteric gram-negative bacilli, streptococci (in particular
S. agalactiae), and L. monocytogenes are the most com-
mon causative organisms of bacterial meningitis in neonates.
A third-generation cephalosporin plus ampicillin is recom-
mended as initial therapy in this age-group.
Children
A combination of cefotaxime or ceftriaxone or cefepime and
vancomycin has become the antibiotic of choice for the initial
treatment of acute meningitis in children in whom the etio-
logic agent has not been identified. The empirical therapy of
bacterial meningitis in children should include coverage for
S. pneumoniae, Hib, and N. meningitidis, which is provided
by the third-generation cephalosporins; vancomycin is added
for pneumococcal meningitis pending in vitro susceptibility
testing. The recommended doses of these antibiotics are listed
in Table 24.8.
Adults (Ages 15 to 50 Years)
S. pneumoniae and N. meningitidis are the causative organ-
isms of approximately 85% of cases of bacterial meningitis in
otherwise healthy adults (411). Empirical therapy of meningi-
tis in adults should, therefore, be directed toward these organ-
isms. Ceftriaxone (4 g per day in divided doses every 12 hours)
or cefotaxime (up to 8 to 12 g per day in divided doses every
4 to 6 hours) or cefepime (6 g per day in divided doses every
8 hours) is effective therapy for meningitis caused by either
of these organisms (412); vancomycin should be added until
the results of antimicrobial susceptibility testing are known.
The recommended doses of these antibiotics are listed in
Table 24.9. All CSF isolates of pneumococci and meningococci
should be tested for penicillin or cephalosporin resistance.
Older Adults
The most common organisms causing meningitis in adults
older than 50 years are S. pneumoniae and enteric gram-
negative bacilli; however, meningitis caused by Listeria and
H. influenzae is increasingly recognized. For initial therapy of
meningitis in elderly patients, either ceftriaxone or cefotaxime
or cefepime plus vancomycin, in combination with ampicillin,
is recommended (219,221,263). Meropenem may be an attrac-
tive candidate for monotherapy in this age-group in the future.
2/21/14 5:42 PM
 406 Part III: Bacterial and Mycoplasmal Infections
Duration of Therapy
The standards for the duration of therapy of bacterial men-
ingitis have been derived from clinical experience rather than
rigid scientific analysis (413). They are basically empirical.
Although shorter courses of therapy may be equally effica-
cious, we recommend the following duration of treatment
as general guidelines, not rigid standards, when the etiologic
agent is known: N. meningitidis, 5 to 7 days; H. influenzae, 7
to 10 days; S. pneumoniae, 10 to 14 days; GBS, 14 to 21 days;
and gram-negative aerobic bacilli and L. monocytogenes, 3
to 4 weeks. Nevertheless, it must be stressed that the patients
response, as assessed by clinical and laboratory parameters,
is the most important criterion in the decision to terminate
therapy within this discretionary range. In a double-blind ran-
domized trial of 5 or 10 days of therapy with ceftriaxone for
bacterial meningitis in children beyond the neonatal period,
it was determined that ceftriaxone could be discontinued in
those patients who were stable after 5 days of treatment (414),
although the uncertainties around organism-specific data
(especially for S. pneumoniae) and the need for clinical judg-
ment at day 5 should lead to caution in reducing treatment
duration (415).
Meningitis Following Trauma
S. pneumoniae is the most common cause of meningitis follow-
ing traumatic head injury in association with the formation of
a dural sinus fistula (218). H. influenzae is a less common, but
also important, pathogen in this setting. A third- or fourth-
generation cephalosporin plus vancomycin is recommended
for empirical treatment of meningitis in patients with closed
head injury. The regimen can subsequently be modified based
on the results of CSF cultures.
Meningitis Following
Neurosurgical Procedures
The most common organisms causing meningitis in the patient
who has undergone a neurosurgical procedure, with the ex-
ception of a shunting procedure, are gram-negative bacilli and
339
staphylococci (223). Initial therapy of meningitis in the post-
15 pg/mL) in patients in septic shock.
neurosurgical patient should be directed against gram-negative
bacilli, but also against P. aeruginosa and S. aureus (219). A
third- or fourth-generation cephalosporin is recommended for
the treatment of gram-negative bacillary meningitis (223,374).
Ceftazidime or cefepime should be used. Cefepime is a fourth-
generation cephalosporin that is also active against pseudo-
monads. Vancomycin should be added until infection with
staphylococci is excluded.
Coagulase-negative staphylococci and S. aureus are the
most common pathogens causing CSF shunt infections.
Unless the organism is clearly susceptible to methicillin,
vancomycin is recommended for shunt infections caused by
staphylococci (139,402,403). Therapy of methicillin-resis-
tant staphylococcal shunt infections should include a com-
bination of intravenous vancomycin and either oral rifampin
or intrashunt or intraventricular vancomycin (403,416).
Although cefuroxime may enter ventricular fluid in the pres-
ence of an infected CSF shunt, the concentrations are quite
variable (417). This agent is not, therefore, recommended for
shunt infections.
Immunosuppressed Hosts
As has been discussed, the risk for development of bacterial
meningitis in an immunocompromised patient depends on a
number of factors, such as (a) the underlying disease and its
treatment, (b) the duration of immunosuppression, and (c) the
Scheld_Ch24.indd 406
type of immune abnormality. Knowledge of the latter helps pre-
dict the infecting organism (233,234). Patients with defects in
cell-mediated immunity are most susceptible to CNS infections
by microorganisms that are intracellular parasites, the eradica-
tion of which depends on an intact T-lymphocytemacrophage
system. L. monocytogenes is the most common cause of bac-
terial meningitis in patients with defective cell-mediated im-
munity (234). Patients with defective humoral immunity are
unable to mount an antibody response to a bacterial infection,
and they are therefore unable to control infection caused by
encapsulated bacteria. These patients are at particular risk for
meningitis caused by S. pneumoniae, Hib, and, less commonly,
N. meningitidis. Patients with neutropenia are at particular
risk for meningitis caused by P. aeruginosa and members of the
Enterobacteriaceae family (233). The choice of antibiotic for
empirical treatment of bacterial meningitis in the immunosup-
pressed patient should be made based on the type of immune
abnormality.
Adjunctive Therapy
As is discussed in Chapter 23, the generation of bacterial cell
wall components in CSF during treatment of meningitis with
antibiotics contributes to increased inflammation in the SAS
(18). Bacterial cell wall components stimulate the release of
inflammatory cytokines in the CNS, such as TNF, IL-1, and
prostaglandins (173). It may be possible to reduce the inflam-
matory response in the SAS and thus improve the outcome
of this infection by administering antiinflammatory agents in
conjunction with antibiotics (172,418).
TNF is a macrophage-secreted hormone that is released in
response to bacterial endotoxin. The injection of small doses
of purified endotoxin into healthy volunteers causes the
appearance of elevated serum concentrations of TNF within
90 minutes after the infusion, accompanied by symptoms
of headache, fever, rigors, and myalgia (419). Endogenous
TNF release has been observed in patients with sepsis and
in those with meningococcemia. Damas et al. (420) detected
very high serum concentrations of TNF (mean, 701
pg/mL; normal, 75
Waage et al. (421) found elevated serum TNF concentra-
tions in patients with meningococcal disease. The patients
with the highest concentrations (0.1 ng/mL) died. Ming
et al. (422) found elevated concentrations of TNF in CSF
during bacterial meningitis in both mice and humans. None
of the CSF samples from patients with viral (echovirus, cox-
sackievirus, or mumps virus) meningitis or other neurologic
diseases (e.g., multiple sclerosis) in this study contained
measurable concentrations of TNF (422). This suggests that
the presence of TNF in CSF may be specific for bacterial
meningitis (173).
TNF induces IL-1 release from endothelial cells and mac-
rophages (423). IL-1 represents a family of polypeptides that
are both beneficial and detrimental to the host. The primary
sources of IL-1 are monocytes and macrophages, but IL-1
is also produced by brain astrocytes and microglia. IL-1
is a potent chemoattractant for neutrophils, monocytes, B
cells, and T cells; it has an important role in B-cell prolifera-
tion and antibody production, as well as in T-cell activation
(424). IL-1 may, however, also be detrimental to the host.
IL-1 released into tissue induces a proliferative response.
IL-1 released by astrocytes into brain tissue may contribute
to brain gliosis and scar formation (424). IL-1 increases the
concentration of metabolites of arachidonic acidmost no-
tably PGE2 and leukotriene B4, which are potent mediators
of inflammation (423).
2/21/14 5:42 PM

Possible therapeutic approaches to decrease the harmful ef-
fects of TNF and/or IL-1 might include (a) drugs or procedures
to decrease their production, block their biologic activity, or
enhance removal from the circulation, (b) passive immuni-
zation with antibodies against TNF and IL-1, and (c) drugs
that interfere with IL-1induced arachidonic acid metabolites.
Corticosteroids are highly effective in reducing IL-1 produc-
tion in vitro and in vivo. Many of the biologic activities of
IL-1 are inflammatory; aspirin, acetaminophen, and nonste-
roidal antiinflammatory agents can reduce fever, muscle PGE2
production, leukocyte chemotaxis, and so on. Therapeutic
concentrations of nonsteroidal antiinflammatory agents and
antipyretic blood levels of aspirin do not, however, reduce IL-1
production, IL-1mediated lymphocyte activation, or IL-1
synthesis of acute-phase proteins (424).
Passive immunization with monoclonal antibodies directed
against TNF and IL-1 may be a future therapeutic option.
Beutler et al. (425) passively immunized mice with antiserum
to murine TNF and protected them from the lethal effects of
gram-negative bacteremia. A major limitation, however, of
monoclonal antibody therapy for meningitis is the BBB. Even
during active inflammation, the BBB is an effective barrier of
antibody penetration into the CSF. To achieve sufficient anti-
body concentrations within the CSF, it would be necessary to
produce serum concentrations of antibodies at least 20- to 100-
fold higher than the expected protective concentration in serum
or to administer the antibody by intrathecal injection (426).
Despite aggressive supportive care and the administration
of appropriate antimicrobial agents, the outcome for patients
with fulminant meningococcemia is often poor. Serum TNF
concentrations correlate directly with outcome in this condi-
tion. Activated protein C (drotrecogin alfa activated) reduces
mortality in patients with severe sepsis (427) but has been
withdrawn from the worldwide market. Plasmapheresis has
been attempted, although on an extremely limited scale, in
meningococcemia and may lead to a rapid decrease in serum
TNF concentrations and/or improved mortality and morbidity
(428). Despite the lack of a controlled clinical trial, this ap-
proach definitely deserves further study.
Clinical trials suggest a beneficial effect from dexametha-
sone in the treatment of bacterial meningitis in children and
adults. In a prospective, randomized trial, 429 patients with
bacterial meningitis were treated with either (a) dexametha-
sone, ampicillin, and chloramphenicol or (b) ampicillin and
chloramphenicol only. Dexamethasone was administered in-
tramuscularly with the first dose of antibiotic, at a dose of
8 mg to children younger than 12 years and 12 mg to adults
every 12 hours for 3 days. There were 56 cases of Hib men-
ingitis, 106 cases of pneumococcal meningitis, and 267 cases
of meningococcal meningitis. The case-fatality rate was sig-
nificantly lowered in patients with pneumococcal meningitis
receiving dexamethasone; only 7 of 52 patients died, com-
pared with 22 of 54 patients not receiving dexamethasone
(p  .01). Dexamethasone therapy also significantly reduced
the incidence of hearing loss in patients with pneumococcal
meningitis. None of the 45 surviving patients in the dexa-
methasone-treated group developed hearing loss, whereas
4 of 32 patients treated with antibiotics alone became deaf
(p  .05) (429). However, there were no significant differences
between groups in time to afebrility or improvement in CSF
parameters, there was no documentation of possible adverse
effects, an extraordinarily high percentage of patients pre-
sented in a comatose state, most patients (370 of 429) received
inadequate therapy for 3 to 5 days before hospitalization, the
antibiotics were administered intramuscularly, and no differ-
ences in mortality were noted in patients with meningococcal
or Hib meningitis.
Scheld_Ch24.indd 407
Chapter 24: Acute Bacterial Meningitis 407
The results of a double-blind placebo-controlled trial of
200 infants and children with bacterial meningitis demon-
strated a beneficial effect of dexamethasone therapy in reduc-
ing the incidence of sensorineural hearing loss. Patients were
treated with ceftriaxone or cefuroxime, with either dexa-
methasone (0.15 mg/kg every 6 hours for 4 days) or placebo.
Of 84 patients in the placebo-treated group, 13 (15.5%) had
moderate or more severe bilateral hearing loss as compared
with 3 (3.3%) of 92 of the dexamethasone-treated children
(p  .01) (430). The beneficial effects of dexamethasone were
observed only in the children receiving concurrent cefuroxime
(which may be suboptimal therapy) and not in those treated
with ceftriaxone, thus rendering interpretation difficult.
Dexamethasone appeared to be of particular benefit in chil-
dren with milder cases of Hib meningitis (430).
Similar trends suggesting a beneficial effect of dexametha-
sone were observed in a third randomized, placebo-controlled
trial by the Dallas group for children receiving cefuroxime
(431). Once again, patients receiving dexamethasone became
afebrile sooner, and the CSF glucose concentration rose more
rapidly during the first day of therapy. Although the small
sample size precluded a significant result from an analysis of
hearing loss, the data combined with the data of the previous
study (430) continued to reveal an advantage for corticosteroid
therapy (432). The use of cefuroxime, a suboptimal agent (see
earlier discussion) (338), in approximately 160 of 260 patients
in these trials had led some investigators to question the rou-
tine use of dexamethasone as adjunctive therapy based on
the results of these clinical trials (433). A metaanalysis of 11
randomized clinical trials (as of 1988) of dexamethasone for
adjunctive therapy confirmed benefit for H. influenzae type b
meningitis, especially for hearing outcomes, and suggested
benefit for pneumococcal meningitis in children if begun with
or before parenteral antibiotics (434).
Another trial, from Costa Rica, randomized infants and
children with bacterial meningitis to receive cefotaxime with
either dexamethasone or placebo (435). In this study, the
dexamethasone or placebo was administered 15 to 20 minutes
before the first dose of cefotaxime in an attempt to attenu-
ate the SAS inflammatory response maximally. When patients
were monitored for a mean of 15 months, those who had re-
ceived adjunctive dexamethasone had a significantly decreased
incidence of one or more neurologic sequelae, although there
was only a trend in reduction of audiologic impairment.
A review of the medical records of 97 infants and children
with pneumococcal meningitis (treated from 1984 to 1990)
demonstrated a beneficial effect of dexamethasone therapy in
infants and children with fulminant meningeal infection, as
defined by laboratory studies, altered level of consciousness,
and the presence of septic shock and cerebrovascular instabil-
ity. They accounted for two thirds of the deaths and had a
significantly increased incidence of seizures and permanent bi-
lateral moderate or greater hearing loss. Of the survivors, 1 of
8 steroid-treated patients, as compared with 7 of 13 nonste-
roid-treated patients, had moderate or severe bilateral hearing
loss (436). However, this was a retrospective review and there
were no data on differences in outcome with regard to specific
antibiotic used.
In a prospective, placebo-controlled double-blind trial of
dexamethasone (given at a dosage of 0.4 mg/kg every 12 hours
for 2 days) in 115 children with acute bacterial meningitis,
Hib was the infecting organism in 30 (55%) of 55 patients
in the placebo group, and in 37 (62%) of 60 patients in the
dexamethasone-treated group. N. meningitidis was the infect-
ing organism in 12 (22%) of 55 patients in the placebo group
and in 16 (27%) of 60 patients in the dexamethasone-treated
group. At follow-up examination 3, 9, and 15 months after
2/21/14 5:42 PM
 408 Part III: Bacterial and Mycoplasmal Infections
discharge, 3 (5%) of 60 dexamethasone-treated patients had
one or more neurologic or audiologic sequelae, compared with
9 (16%) of 55 placebo recipients (p  .065) (437).
Other studies questioned the routine use of adjunctive
dexamethasone in infants and children with bacterial meningi-
tis. In one trial, there were no significant reductions in audio-
logic and neurologic sequelae with adjunctive dexamethasone
therapy, although dexamethasone was given within 24 hours
of antimicrobial therapy (median, 11 hours) and the study
was stopped prematurely because the standard of care became
early administration of dexamethasone (438). Similarly, in the
second trial, adjunctive dexamethasone was not associated
with significant improvements in neurologic sequelae, devel-
opmental outcome, or unilateral or bilateral deafness (439).
Dexamethasone was given within 4 hours of the first anti-
microbial, and there was a lack of follow-up for 13% of the
study population. In a very large study from Malawi, dexa-
methasone again failed to improve outcome in children with
bacterial meningitis, but the evaluation of hearing loss was
suboptimal and still suggested a steroid benefit (440).
The American Academy of Pediatrics recommends con-
sideration of dexamethasone therapy in infants and children
2 months and older with proven or suspected bacterial meningi-
tis. A daily dose of 10 to 12 mg/m2 (0.6 mg/kg) in four divided
doses is recommended for 3 to 4 days (441). Therapy for 2 days
may also be efficacious (437,442). Children should, however, be
carefully monitored for potential complications of corticosteroid
use, specifically gastrointestinal hemorrhage and hyperglycemia.
The concomitant use of an intravenous H2 receptor antagonist is
recommended to prevent gastrointestinal tract bleeding. If cor-
ticosteroids are used, they should definitely be administered
early, that is, before or simultaneously with the first dose(s)
of parenteral antimicrobial agents. This is particularly impor-
tant, because administration of currently available bacteriolytic
agents (e.g., ceftriaxone) leads to rapid release of free endotoxin
from gram-negative organisms into CSF, with an attendant ex-
aggeration of the hosts inflammatory response (443).
The results of a prospective, randomized, double-blind trial
of adjunctive dexamethasone therapy for bacterial meningitis
in 301 adults in five European countries over 9 years demon-
strated that dexamethasone improves the outcome in adults
with acute bacterial meningitis. The benefits were most striking
in the patients with pneumococcal meningitis (444). In another
clinical trial, patients with pneumococcal meningitis who were
treated with dexamethasone had a lower fatality rate than
those that were not treated with dexamethasone (429). There
has been concern that dexamethasone would decrease the pen-
etration of vancomycin into the CSF. In a prospective study of
11 adults with community-acquired pneumococcal meningitis
that were treated with a combination of dexamethasone and
vancomycin at a dose of 15 mg/kg every 8 hours or 7.5 mg/kg
every 6 hours, there were four therapeutic failures (445). The
dose of vancomycin was well below the recommended dose of
60 mg/kg per day. In a prospective randomized clinical trial of
the bactericidal activity of vancomycin against cephalosporin-
resistant pneumococci in CSF of children with acute bacterial
meningitis, vancomycin in a dose of 60 mg/kg per day pen-
etrated reliably into the CSF when the children were treated
concomitantly with dexamethasone (0.6 mg/kg per day divided
into four doses for 4 days) (446). The recommended dosage of
dexamethasone for adults is 8 to 10 mg intravenously every
8 hours for 2 to 4 days. Dexamethasone therapy should not
adversely affect the outcome of viral meningitis (447).
Many other clinical trials were undertaken to determine the
effects of adjunctive dexamethasone on outcome in patients
with bacterial meningitis (173,278). On the basis of previous
data, and the apparent absence of serious adverse outcomes in
Scheld_Ch24.indd 408
adult patients who received dexamethasone, the routine use
of adjunctive dexamethasone (given concomitant with or just
prior to the first dose of an antimicrobial agent for maximal
attenuation of the SAS inflammatory response) is warranted
in most adults with pneumococcal meningitis (448). A recent
study demonstrated a favorable trend toward reduced rates for
death and hearing loss and no evidence that dexamethasone
was harmful in patients with meningococcal meningitis (449).
Adjunctive dexamethasone should not be used in patients
who have already received antimicrobial therapy for several
hours. Despite these positive benefits in terms of morbidity
and mortality, there were some concerns regarding cognitive
long-term outcome in patients treated with dexamethasone.
However, a follow-up study of 87 eligible patients in which
46 were treated with adjunctive dexamethasone and 41 with
placebo, neuropsychologic evaluation showed no significant
differences between patients treated with dexamethasone or
placebo (450). In an evaluation of 357 episodes of pneumo-
coccal meningitis from 2006 to 2009 in the Netherlands since
implementation of adjunctive dexamethasone on a large scale
basis, the prognosis has improved with mortality rates de-
creasing from 30% to 20% (451).
Despite these positive benefits, the routine use of adjunc-
tive dexamethasone in patients with bacterial meningitis in the
developing world has been controversial. In one randomized,
double-blind, placebo-controlled study in adolescents and
adults in Vietnam with confirmed bacterial meningitis (452),
patients who received adjunctive dexamethasone experienced
a significant reduction in the risk of death at 1 month (relative
risk [RR], 0.43) and the risk of death or disability at 6 months
(RR, 0.56); the highest proportion of cases in this study were
caused by S. suis, followed by S. pneumoniae. In contrast, in
a randomized, double-blind, placebo-controlled study from
Malawi, there were no significant differences in mortality at
40 days in the intention-to-treat analysis (56% in the dexa-
methasone group versus 53% in the placebo group) or when
the analysis was restricted to patients with proven pneumococ-
cal meningitis (53% in the dexamethasone group versus 50%
in the placebo group) (453). However, in this trial, almost
90% of the patients were infected with HIV and most likely
had advanced disease; delayed presentation was also associ-
ated with a poorer outcome, although adjusting for this factor
in the analysis had no effect. These data suggest that adjunc-
tive dexamethasone is not beneficial in resource-poor coun-
tries where a substantial number of patients are infected with
HIV (454). In a Cochrane metaanalysis of 24 studies involving
4,041 participants, adjunctive dexamethasone did not reduce
overall mortality, but there was a trend to lower mortality in
adults; corticosteroids were associated with lower rates of se-
vere hearing loss, any hearing loss, and neurologic sequelae,
although these benefits were only seen in studies from high-
income countries (455). In a subgroup analysis based on caus-
ative microorganism, corticosteroids reduced severe hearing
loss in patients with H. influenzae meningitis and mortality in
patients with S. pneumoniae meningitis.
The use of adjunctive dexamethasone is of particular con-
cern in patients with pneumococcal meningitis caused by
penicillin- and cephalosporin-resistant strains, in which case
patients may require antimicrobial therapy with vancomycin
(173,278). A diminished CSF inflammatory response after
dexamethasone administration might significantly reduce
vancomycin penetration into CSF and delay CSF sterilization,
as shown in an experimental rabbit model of penicillin-and
cephalosporin-resistant pneumococcal meningitis. This re-
sult was confirmed in another rabbit model of pneumococ-
cal meningitis in which significantly lower CSF vancomycin
concentrations and differences in bacterial killing were found
2/21/14 5:42 PM

in the dexamethasone-treated rabbits. However, CSF van-
comycin penetration was not reduced by dexamethasone in
a study in children (446), and in another study in which a
continuous infusion of vancomycin was used (60 mg/kg per
day), adequate CSF concentrations (7.2 g/mL) were achieved
despite the concomitant administration of adjunctive dexa-
methasone (355). CSF concentrations of ceftriaxone are not
significantly altered in animals or patients treated with adjunc-
tive dexamethasone (456,457). In contrast, in an experimental
rabbit model of cephalosporin-resistant pneumococcal men-
ingitis (458), concomitant use of dexamethasone with ceftri-
axone resulted in higher CSF bacterial counts and a higher
number of therapeutic failures. For any patient receiving
adjunctive dexamethasone who is not improving as expected
or who has a pneumococcal isolate for which the cefotaxime
or ceftriaxone minimal inhibitory concentration (MIC) is
2.0 g/mL or greater, a repeat LP 36 to 48 hours after initia-
tion of antimicrobial therapy is recommended to document the
sterility of CSF (278). In the study cited earlier, only 78 (72%)
of 108 CSF cultures that were positive for S. pneumoniae were
submitted for in vitro susceptibility testing, and all were sus-
ceptible to penicillin (444), a finding that is unusual in many
areas of the world. In patients with pneumococcal meningitis
caused by strains that are highly resistant to penicillin or ceph-
alosporins, careful observation and follow-up are critical to
determine whether use of adjunctive dexamethasone is associ-
ated with adverse clinical outcome in these patients (278,448).
In addition to corticosteroids, several other adjunctive ap-
proaches to the therapy of bacterial meningitis may be useful
(418,459). These include (a) bactericidal but nonbacteriolytic
antibiotics to reduce endotoxin and other injurious substance
(e.g., outer membrane vesicle) release into CSF (a theoretical
but as yet impractical method); (b) nonsteroidal antiinflam-
matory agents; (c) other prostaglandin inhibitors; (d) anti
endotoxin-binding agents; (e) monoclonal antibodies directed
against complement factor 5 (460), endotoxin, cytokines, or
leukocyteendothelium adhesion molecules; (f) pentoxifylline;
(g) cytokine antagonists; (h) nitric oxide synthase (NOS) in-
hibitors (i.e., aminoguanidine); (i) thalidomide, by blocking
TNF release from microglia (461); (j) osmotic dehydrating
agents (e.g., mannitol, glycerol); (k) scavengers of peroxyni-
trite; and (l) inhibitors of matrix metalloproteinases (MMPs).
Treatment of Complications
Raised Intracranial Pressure
ICP is usually increased in bacterial meningitis; therefore, this
complication should be anticipated and treated promptly. The
clinical signs of increased ICP are (a) an altered level of con-
sciousness ranging from drowsiness to coma; (b) a dilated,
poorly reactive, or nonreactive pupil; (c) abnormalities of
ocular motility; and (d) bradycardia and hypertensionthe
Cushing reflex. Increasing ICP may be associated with only
one or a combination of these clinical signs. Papilledema does
not develop until increased ICP has been present for several
hours; therefore, the absence of papilledema should not be
used to exclude the presence of increased ICP. Increased ICP
may lead to herniation. Signs of impending herniation in-
clude (a) midposition, nonreactive pupils; (b) unequal or di-
lated, nonreactive pupils; (c) skew deviation or dysconjugate
eye movements; (d) decorticate or decerebrate posturing; and
(e) bradycardia and abnormal respiratory patterns.
Patients who are awake and alert can be watched clinically
for signs of advancing increased ICP. Patients who are stupor-
ous or comatose may benefit from an ICP monitoring device.
Scheld_Ch24.indd 409
Chapter 24: Acute Bacterial Meningitis 409
TA B L E 2 4 . 1 0
TREATMENT OF INCREASED INTRACRANIAL
PRESSURE
1. Head of the bed elevated 30 degrees
2. Hyperventilation to maintain Paco2 between 27 and
30 mm Hga
3. Mannitol
a. Children: 0.52.0 g/kg infused over 30 min and repeated
as necessary
b. Adults: 1.0-g/kg bolus injection or 0.25 g/kg every 23 hr
4. Pentobarbital
a. Initial dose: 510 mg/kg at a rate of 1 mg/kg/min
b. Maintenance dosage: 13 mg/kg/hr
a
Although hyperventilation is beneficial (for about 1224 hr) in low-
ering intracranial pressure, caution is advised, as Paco2 values below
25 mm Hg may produce cerebral ischemia.
ICP exceeding 20 mm Hg is abnormal and should be
treated; however, outcome may be improved if pressures
greater than 15 mm Hg are treated. The rationale for treating
the smaller elevations in pressure is to avoid large elevations,
or so-called plateau waves, that can lead to herniation and
irreversible brainstem injury (180,263). Plateau waves are sus-
tained elevations in ICP that may occur spontaneously or as
the result of small increases in cerebral blood volume from hy-
poxia, fever, or intratracheal suctioning. When ICP is already
high, plateau waves may be reached quickly and lead to brain
death (182,263). The treatment of increased ICP is outlined in
Table 24.10.
Nonetheless, in one study of 15 patients with bacterial
meningitis in whom intracranial pressure was measured (462),
intracranial pressure was successfully lowered in most patients
by a broad range of measures, which consisted of sedation,
steroids, normal fluid and electrolyte homeostasis, blood
transfusion, albumin infusion, decrease of MAP, treatment
with a prostacyclin analog, and eventually thiopental, ven-
triculostomy, and dihydroergotamine. In nonsurvivors, mean
intracranial pressure was significantly higher and CPP was
markedly lower than in survivors despite treatment; however,
this was not a comparative study and the results should be
interpreted with caution.
Elevating the head of the bed 30 degrees reduces the
ICP. Turning the head to the side (particularly to the left)
or hyperextending the neck may trigger an increase in ICP.
Intratracheal suctioning or endotracheal intubation may in-
crease ICP (182,263,463).
Hyperosmolar agents, such as mannitol, decrease ICP by
decreasing cerebral edema. Mannitol remains almost entirely
in the extracellular intravascular space, making this compart-
ment hyperosmolar to brain tissue. The result is movement of
water from brain tissue into the intravascular space. Mannitol
can be given either as a bolus intravenous injection of 1 g/kg
over 10 to 15 minutes or in small frequent doses of 0.25 g/
kg every 2 to 3 hours. A bolus injection can be repeated at 3-
to 4-hour intervals to maintain the serum osmolality between
315 and 320 mOsm/L (180,182,263,463).
Dexamethasone appears to be beneficial in reducing ICP
and cerebral edema in animal models of bacterial meningitis
(464,465). However, its efficacy for reducing cerebral edema
in patients with bacterial meningitis has not been established.
Steroids are known to be beneficial in reducing cerebral edema
2/21/14 5:42 PM
 410 Part III: Bacterial and Mycoplasmal Infections
surrounding tumors. In this situation, cerebral edema is largely
vasogenic in origin. Steroids reduce vasogenic edema by re-
ducing the permeability of cerebral capillary endothelial cells
(466). There is experimental evidence to suggest that steroids
reduce interstitial edema in meningitis (467). Cerebral edema
in meningitis is a combination of vasogenic, cytotoxic, and
interstitial edema (170). The evidence that steroids decrease
vasogenic and interstitial edema suggests a role for cortico-
steroids in the management of this complication, which may
contribute to raised ICP.
The use of steroids to reduce cerebral edema in meningitis
also has disadvantages. Steroids decrease inflammation in the
meninges. As has been discussed, a moderate degree of inflam-
mation in the meninges is required for the CSF penetration
of many antibiotics. By reducing meningeal inflammation, the
concentration of antibiotics in CSF is reduced. This may be
most important several days into treatment, when meningeal
inflammation has been reduced substantially by antibiotic
treatment. Steroids should, therefore, be discontinued within
approximately 4 days of treatment (441).
High-dose barbiturate therapy is useful when other modal-
ities have failed to control ICP. Barbiturates decrease the cere-
bral metabolic demand for oxygen and thus decrease cerebral
blood flow. The result is a decrease in ICP. Pentobarbital is
administered in an initial dose of 5 to 10 mg/kg at a rate
of 1 mg/kg per minute, followed by a dose of 1 to 3 mg/
kg per hour. This therapy requires an intracranial monitor-
ing device or an electroencephalogram (EEG) to monitor
cerebral activity, because the clinical examination is severely
limited by the depressive effects of barbiturate. Pentobarbital
is administered until the ICP is reduced below 20 mm Hg
or until the EEG demonstrates a suppression-burst pattern.
Recommended serum concentrations of pentobarbital to re-
duce ICP are 20 to 40 g/dL. A Swan-Ganz catheter should
be in place to monitor cardiac output. High-dose barbiturates
are associated with significant cardiac toxicity, including de-
creased cardiac output, decreased contractile force, arrhyth-
mias, and hypotension. Pentobarbital is the recommended
barbiturate when barbiturate coma is desired, because this
drug has a relatively short half-life. The half-life of pento-
barbital is 24 hours, compared with the longer half-life of
phenobarbital (5 days). The use of pentobarbital allows for
a more rapid reversal of barbiturate coma than does the use
of phenobarbital. Pentobarbital coma is maintained until the
ICP has been below 20 mm Hg for 24 hours. The dosage of
barbiturate is then slowly decreased to prevent a rebound in-
crease in ICP (263,463,468).
Seizures
Seizures occur in 30% to 40% of children with acute
bacterial meningitis (200). They occur in more than 30% of
adults with pneumococcal meningitis in the first few days of
illness (218). In a nationwide prospective study on adults with
community-acquired bacterial meningitis, seizures occurred
in 17% of patients and were associated with severe CNS and
systemic inflammation, structural CNS lesions, pneumococ-
cal meningitis, and predisposing conditions (469). The high
associated mortality rate warrants a low threshold for start-
ing anticonvulsant therapy in those with clinical suspicion
of a seizure. If not managed quickly and aggressively, status
epilepticus may develop. Severe or prolonged seizure activity
can produce permanent damage resulting from anoxic isch-
emic changes in areas of the temporal lobe, cerebellum, and
thalamus (263,468). The increased energy requirements of
discharging neurons cannot be met by cerebral blood flow
during sustained seizure activity. The result is ischemic necro-
sis and loss of cortical neurons (441). Status epilepticus that
Scheld_Ch24.indd 410
is continuous for 90 minutes or longer can cause permanent
neurologic sequelae.
For early termination of seizure activity, a short-acting an-
ticonvulsant with a rapid onset of action (such as lorazepam
or diazepam) is recommended. Lorazepam is administered
intravenously in 1- to 4-mg doses in adults and in an initial
dose of 0.05 mg/kg in children. Lorazepam has a duration
of action three to four times longer than that of diazepam in
adults (441); 4 mg of lorazepam is therapeutically equivalent
to 10 mg of diazepam (470). Diazepam is administered in a
dose of 0.25 to 0.4 mg/kg (maximum, 10 mg) at a rate of 1 to
2 mg per minute. The 10-mg dose may be repeated up to three
times at intervals of 15 to 20 minutes (471). Diazepam has
a half-life of 15 minutes; therefore, the blood level decreases
rapidly. A long-acting anticonvulsant should be administered
immediately after lorazepam or diazepam. The long-acting
anticonvulsant of choice in children and adults is phenytoin
or fosphenytoin. Phenytoin is administered in a dose of 18 to
20 mg/kg at a rate no faster than 50 mg per minute. Phenytoin
can prolong the QT interval or lead to hypotension. If either
of these side effects is observed, the rate of administration is
decreased. Fosphenytoin is a water-soluble prodrug of phe-
nytoin that is converted to phenytoin by nonspecific phos-
phatases. Doses of fosphenytoin are expressed as phenytoin
equivalents. Infusion side effects are less common with fos-
phenytoin than with phenytoin (472). Fosphenytoin is admin-
istered in a dose of 18 to 20 mg/kg at a rate no faster than
150 mg per minute. Phenytoin is very effective in controlling
convulsions without depressing consciousness or respiration
(263). Intravenous phenytoin reaches peak brain and blood
concentrations within 15 minutes (473). The half-life of phe-
nytoin following a loading dose is approximately 36 hours
(470). Serum concentrations greater than 25 g/mL are usu-
ally necessary to terminate status epilepticus. If an 18- to
20-mg/kg dose of phenytoin fails to control seizure activity, an
additional 500 mg of phenytoin can be given. A maintenance
dose of 100 mg every 6 hours (in adults) should be started
after the loading dose.
If fosphenytoin fails to control seizure activity, the patient
can be treated with intravenous levetiracetam or valproic
acid or intubated, mechanically ventilated, and treated with
phenobarbital. For adults, phenobarbital is administered
intravenously at a rate of 100 mg per minute until seizure
activity stops, or to a loading dose of 20 mg/kg (263). The
loading dose of phenobarbital in children is 20 mg/kg, ad-
ministered intravenously at a rate of 30 mg per minute (474).
The most common adverse effects of phenobarbital loading
are hypotension and respiratory depression. If these compli-
cations are managed and seizure activity continues, an addi-
tional 10 mg/kg can be given (474). The primary reason for
failure to control seizures is that anticonvulsants are admin-
istered in subtherapeutic doses or that the rate of administra-
tion is too slow.
The combination of phenytoin and phenobarbital controls
seizure activity in the vast majority of patients. When they fail
to do so, general anesthesia with pentobarbital can be tried.
The dose of pentobarbital is the same for children and adults:
a loading dose of 3 to 5 mg/kg and a maintenance dose of 1 to
2 mg/kg per hour (263,474). In the past, paraldehyde or a
continuous intravenous diazepam drip was used to treat status
epilepticus; however, paraldehyde is no longer available, and a
diazepam drip is no longer recommended.
Fluid Management
Most children with bacterial meningitis are hyponatremic
(serum sodium concentration 135 mEq/L) early in the course
of their illness (441). Fifty percent of children have evidence of
2/21/14 5:42 PM

SIADH on admission to the hospital (208). Restriction of flu-
ids to correct serum sodium is potentially important, because
the degree and duration of hyponatremia correlate with the
development of neurologic sequelae. However, a rigid adher-
ence to fluid restriction, a time-honored practice in the treat-
ment of hyponatremia in children with bacterial meningitis, is
no longer recommended because of the adverse effects of hy-
povolemia on cerebral perfusion pressure. A Cochrane review
on fluid therapy for acute bacterial meningitis concluded that
there is some evidence that supports maintaining intravenous
fluids rather than restricting them in the first 48 hours, in set-
tings with high mortality rates and where patients present late.
However, where children present early and mortality rates are
lower, there is insufficient evidence to guide practice.
The initial rate of intravenous fluid administration should
be approximately three fourths of normal maintenance re-
quirements, or about 1,000 to 1,200 mL/m2 daily. A 5%
dextrose solution with one-fourth to one-half normal saline
and 20 to 40 mEq/L potassium is recommended. The serum
sodium concentration and urine specific gravity should be
measured every 6 to 12 hours (441). The mean duration of
hyponatremia in children with Hib meningitis in one study
was 20 hours (range, 0 to 240 hours) (475). The volume of
fluids administered can be gradually increased when the
serum sodium concentration rises above 135 mEq/L. In most
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Chapter 24: Acute Bacterial Meningitis 411
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 CHAPTER 25 MYCOPLASMAL AND
UREAPLASMAL INFECTIONS
ARI BITNUN AND SUSAN RICHARDSON
Mycoplasmas and ureaplasmas (class Mollicutes) are the
smallest known bacteria (1,2). They are adapted to life in
humans, animals, insects, and plants and cannot survive free
living in nature due to their dependence on host cells for
nutrients. Of the more than 200 known species, about 17 have
been associated with human mucous membrane colonization.
ThreeMycoplasma pneumoniae, Mycoplasma hominis, and
Ureaplasma urealyticum/Ureaplasma parvumaccount for
most reports of central nervous system (CNS) disease in
humans. Rare cases of CNS disease due to other species have
been reported, most often in association with immunocom-
promising or other predisposing conditions (35).
Mycoplasmas and ureaplasmas have a cell volume less
than 5% that of a typical bacillus such as Escherichia coli
and one-sixth the number of genes (about 800,000 base pairs
for M. pneumoniae vs. 4.6 million base pairs for E. coli)
(1,6). It is thought that they evolved from gram-positive
eubacteria by a process of degenerative evolution typified
by gradual reduction in genome size (6,7). Due to the lack
of a cell wall, they are pleomorphic in shape, are highly sus-
ceptible to adverse environmental conditions, and are resis-
tant to -lactam and glycopeptide antibiotics. Because they
do not synthesize folic acid, they are also resistant to the
sulfonamides. Their small size allows them to pass through
0.45-m pore filters commonly used to filter-sterilize media.
This trait, coupled with challenges in detection, has earned
FIGURE 25.1 Scanning electron microscopy of Mycoplasma pneumoniae cells. There are large aggre-
gates of cells shown; the isolated spindle and filamentous shapes in between are individual cells with
typical morphology. (Courtesy J. Carr, Centers for Disease Control and Prevention.)
420
Scheld_Ch25.indd 420
them wide notoriety for contamination of continuous cell
lines. The small genome size also translates into less syn-
thetic capacity and the need for specially enriched media for
laboratory cultivation (6).
This chapter covers CNS diseases attributable to M. pneu-
moniae (Mp), M. hominis (Mh), and Ureaplasma species (Uu).
Because the presence of infection or disease in sites other than
the nevous system can be helpful in diagnosis, these are discussed
as well. In the section on Mp, information related to Guillain-
Barr syndrome is included due to overlapping pathogenetic
mechanisms. The section on diagnosis includes some basic in-
formation on laboratory detection and collection of specimens
as a resource for interacting with the clinical laboratory.
MYCOPLASMA PNEUMONIAE
Etiology
Mp is primarily an extracellular pathogen of the respiratory
tract. It was first isolated in culture from the sputum of a patient
with atypical pneumonia in 1944 (8). Initially referred to as
the Eaton agent, it was classified as a pleuropneumonia-like
organism in 1961 and received its current taxonomic name in
1963 (9). Mp is filamentous in structure (Fig. 25.1), measuring
2/21/14 5:43 PM
 Chapter 25: Mycoplasmal and Ureaplasmal Infections 421

1 to 2 m in diameter and 0.1 to 0.2 m in width. It attaches

to human epithelial cells primarily by means of a highly spe-
cialized organelle that contains a network of adhesion proteins
including the P1 and P30 adhesins (1,6,10). Gliding motility
plays an important role in its ability to colonize fully differenti-
ated mucus-producing tissues of the respiratory tract (11,12).
It is capable of invading and surviving within cells in vitro
(13,14), but whether this occurs to a meaningful extent in vivo
is not known. Human-to-human transmission requires close
contact and occurs by the droplet contact route.
Epidemiology
Respiratory tract infection due to Mp is extremely common;
the incidence of pneumonia is highest in school-aged children
(15,16). The proportion of pneumonia cases attributable to
Mp increases from about 20% in children between 10 and
16 years of age to about 50% in young adults (1719). Many
infections, however, are subclinical, particularly in those
younger than 5 years of age (20,21). There is no particular
seasonal distribution. Epidemics occur every 3 to 7 years su-
perimposed on low level but constant endemicity (17).
The incidence of neurologic disease attributable to Mp
has been estimated at 0.1% or less (22). Among hospitalized
patients with serologically confirmed Mp infection, the inci-
dence is higher, between 1% and 10% (2325). Neurologic
complications are most often sporadic, but clusters of cases
have been observed during epidemics of respiratory tract
disease (26,27). Children account for 50% to 70% of those
diagnosed with neurologic complications of Mp (23,28,29).
Furthermore, in Europe and North America, Mp is a lead-
ing cause of acute encephalitis in children, responsible for
5% to 13% of all cases (23,28,29). There is no apparent sex
predilection (29).
Pathogenesis of Neurologic Disease
The pathogenesis of Mp-associated neurologic disease is
incompletely understood. Three broad mechanisms have been
proposed with varying levels of supportive evidence (30,31):
(a) direct invasion of the brain parenchyma; (b) autoimmu-
nity, or other immune-mediated processes; and (c) vascular
occlusion. Neurotoxin-mediated CNS disease, as seen with
Mycoplasma gallisepticum in turkeys and Mycoplasma neuro-
lyticum in mice (32,33), has not been demonstrated in humans
with Mp-associated neurologic disease.
Several lines of evidence support the concept of direct infec-
tion of the brain by Mp. Mp has, albeit rarely, been cultured
from or detected by various indirect microbiologic techniques
at autopsy from the brain of several fatal cases of suspected
Mp neurologic disease (Fig. 25.2) (3437). It has also been
cultured from or detected in the cerebrospinal fluid (CSF) by
polymerase chain reaction (PCR) of over 50 subjects, 80%
of whom had meningitis, meningoencephalitis, or encepha-
litis (28,3853). A cerebrovascular vasculopathy character-
ized by antimycoplasmal immunostaining of endothelial cells
and electron microscopic demonstration of Mycoplasma-like
structures within endothelial cells has been observed (54,55).
Finally, by analogy to other species, there is conclusive evi-
dence from both natural and experimental infection of rodents,
turkeys, and alligators by Mycoplasma pulmonis, M. gallisep-
ticum, and Mycoplasma alligatoris, respectively, for the direct
infection hypothesis (5658).
Autoimmunity due to antigenic mimicry and production
of antineuronal antibodies has been implicated in the patho-
genesis of Mp-associated neurologic syndromes, including
postinfectious encephalitis, acute disseminated encephalomy-
elitis (ADEM), transverse myelitis, and Guillain-Barr syn-
drome (30,31). Glycolipid epitopes of Mp cross-react with
several gangliosides, and anti-galactocerebroside antibodies

FIGURE 25.2 Histopathology from fatal cases of Mycoplasma pneumoniaeassociated polyradiculo-

neuropathy in previously healthy 45-year-old man. M. pneumoniae was detected in tracheobronchial
secretion by PCR and M. pneumoniae serology was reactive in serum by the complement fixation test
with a titer of 1,280. A: Subcortical cerebral white matter with numerous perivascular foci of demyelin-
ation and necrosis (hematoxylin and eosin stain, original magnification 40); B: Immunohistochemical
evidence of M. pneumoniae antigen inside macrophages present in the perivascular inflammatory
infiltrate (immunohistochemical assay performed by using the monoclonal antiM. pneumoniae antibody
and naphthol fast red as counterstain, original magnification 50). (From Stamm B, Moschopulos M,
Hungerbuehler H, et al. Neuroinvasion by Mycoplasma pneumoniae in acute disseminated encephalomy-
elitis. Emerg Infect Dis. 2008;14(4):641643, with permission.)

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 422 Part III: Bacterial and Mycoplasmal Infections

(anti-GalC) have been demonstrated in the sera of individuals
with postinfectious neurologic syndromes due to Mp (5962).
In one study, serum anti-GalC was detected in 3 of 3 indi-
viduals with postinfectious CNS disease attributed to Mp
as compared to 8 of 32 with Mp infection restricted to the
respiratory tract and 2 of 52 healthy controls (61). Among
patients enrolled in several Guillain-Barr syndrome treat-
ment trials in Europe, 11 of 16 subjects with anti-GalC had
serologic evidence of Mp infection; anti-GalC was present
not only in 78% of Mp-associated Guillain-Barr syndrome
patients but also in 58% of Mp infections without neurologic
disease (63). The antigen mimicry hypothesis is further sup-
ported by the observation that the anti-GalC activity in serum
of patients with Mp-associated Guillain-Barr syndrome is
inhibited by preincubation with Mp antigens (59,60). Among
subjects with Mp-associated encephalitis in the California
Encephalitis Project, anti-GalC was detected in the CSF of
50% of subjects in whom there was neuroimaging evidence of
demyelination (64). Whether anti-GalC causes disease or is an
epiphenomenon is uncertain.
With respect to Mp encephalitis, current data suggest that
pathogenesis is multifactorial, involving both direct infection
and immunologically mediated processes. Several investiga-
tors have observed that Mp DNA is detected in serum or CSF
of subjects with a prodrome of less than or equal to 7 days
but not in those with a longer prodrome (28,48,49). This sug-
gests two distinct patterns of Mp encephalitis: (a) an early-
onset syndrome caused by direct invasion and (b) a late-onset
syndrome in which the presence of the organism in the CSF
or brain is not necessary to cause disease. The CSF cytokine
profile of both early- and late-onset forms of Mp encephalitis,
consisting of elevated interleukin-6 (IL-6) and IL-8 and nor-
mal interferon- and tumor necrosis factor-, suggests a dif-
ferent pathophysiology to that associated with other bacterial
and viral pathogens (31,65). The elevated proinflammatory
cytokine IL-18 in late-onset, but not early-onset, encephalitis
suggests this cytokine may play an important role in the patho-
genesis of the late-onset form of disease (31,65).
The pathogenesis of Mp-associated stroke is poorly under-
stood (30,31). A procoagulable state has been implicated in
a minority of cases (6670), whereas in others, a systemic or
focal vasculitis appeared to be responsible (71,72). The obser-
vation that the mean interval between the onset of respiratory
illness and stroke is about 10 days (range 3 to 21 days) is con-
sistent with an immune-mediated process (30).
Clinical Manifestations
Respiratory and Spectrum of Nonneurologic
Systemic Manifestations
Mp is primarily a pathogen of the respiratory tract. Clinical
disease is typified by an insidious onset of fever, headache,
malaise, sore throat, and dry cough. In most, disease remains
confined to the upper respiratory tract. Progression to tracheo-
bronchitis or pneumonia occurs in fewer than 10% of cases.
Walking pneumonia, the hallmark of Mp respiratory disease,
derives its name from the relatively mild clinical disposition of
most of those afflicted. Rales and wheezes may occasionally be
heard, but physical examination is often unrevealing despite
radiographic evidence of pneumonia. Widespread mottled,
diffuse nodular densities are characteristic (Fig. 25.3); pleu-
ral effusions occur in 5% to 20% of cases. Although rare,
fulminantand even fataldisease can occur.
Extrapulmonary manifestations of Mp infection have been
described for almost every organ system (1,73). Neurologic
complications, followed by those affecting the skin and
mucous membranes, are most common. The prototypical
dermatologic complication, erythema multiforme minor and
Stevens-Johnson syndrome, are seen most often in children
and young adults (7476); in some cases, isolated mucosal

A B

FIGURE 25.3 Posteroanterior (A) and lateral (B) chest radiographs of a 20-year-old patient with culture-
proven Mycoplasma pneumoniae pneumonia. Streaky, nodular densities are present in the right middle
and left lower lobe areas. (From Clyde WA Jr. Infections of the respiratory tract due to Mycoplasma
pneumoniae. In: Chernick V, Kendig E, eds. Disorders of the Respiratory Tract in Children. 5th ed.
Philadelphia: WB Saunders; 1990:403412, with permission.)

Scheld_Ch25.indd 422 2/21/14 5:43 PM

 Chapter 25: Mycoplasmal and Ureaplasmal Infections
involvement can occur (75). Myalgia, arthralgia, and polyar-
thropathy are relatively common; septic arthritis is restricted
primarily to those with immunocompromising conditions
(77,78). Cardiac complications include myocarditis, pericar-
ditis, and pericardial effusion. Other extrapulmonary com-
plications include acute glomerulonephritis, tubulointerstitial
nephritis, immunoglobulin (Ig) A nephropathy, renal failure,
autoimmune hemolytic anemia, thrombocytopenic purpura,
and intravascular coagulation (1).
Neurologic Manifestations
The clinical manifestations of Mp-associated neurologic dis-
ease are protean and generally indistinguishable from those
due to other viral and bacterial pathogens. Syndromes ascribed
to Mp, selected key clinical features, strength of the microbio-
logic evidence supporting the association, and references for
each are provided in Table 25.1. It is important to empha-
size that for most of the neurologic syndromes associated with
Mp infection, proof of causality is lacking. The association
is strongest for encephalitis, meningitis, meningoencephalitis,
ADEM, transverse myelitis, Guillain-Barr syndrome, and
acute striatal necrosis.
A history of respiratory tract infection preceding or
accompanying neurologic symptoms is an important clue to
the diagnosis of Mp-associated neurologic disease. However,
the absence of a respiratory illness does not preclude Mp as a
cause; between 35% and 75% of those with Mp-associated
acute encephalitis have no history of respiratory symptoms
(23,28,29,40,7981). In those with respiratory symptoms,
tracheobronchitis or pneumonia is more typical of adolescents
and adults, whereas children younger than 5 years of age often
have upper respiratory tract disease characterized by rhinitis,
mild cough, or sore throat. In individuals with demyelinating
conditions, bilateral striatal necrosis, Bickerstaff brainstem
encephalitis, opsoclonus myoclonus syndrome, and stroke,
respiratory symptoms are almost universal, preceding neuro-
logic symptom onset by 1 to 4 weeks.
Acute encephalitis is the most common neurologic compli-
cation attributable to Mp. Common clinical features include
fever (50% to 100%), reduced or altered consciousness (45%
to 100%), symptoms or signs of meningeal irritation (20%
to 80%), seizures (40% to 60%), focal neurologic deficits
(20% to 60%), and ataxia (10% to 25%) (28,40,79). A mild
lymphocytic pleocytosis averaging less than 100 cells/L or a
slightly elevated CSF protein is demonstrated in 30% to 60%
of cases (28,40,79,81). Nonspecific electroencephalographic
(EEG) abnormalities, such as diffuse slowing or findings indica-
tive of an epileptic focus, are observed in 80% to 100% of cases
(28,40,79). Periodic lateralizing epileptiform discharges (28)
and extreme spindles (82) have been seen rarely. Computed
tomography or magnetic resonance imaging abnormalities sug-
gestive of focal edema, ischemia, or inflammation are evident
in 35% to 60% of cases (Figs. 25.4 to 25.6) (28,40,81). Mp
encephalitis is a severe entity with a mortality of up to 10%
(23,79,81) and residual sequelae that include cognitive impair-
ment, seizure disorder, or focal motor deficits in 40% to 60%
of survivors (28,79,81,83). In a study of 462 children with
encephalitis, those due to Mp were seven times more likely to
die or have severe neurologic sequelae than other children in
the cohort, second only to herpes simplex virus (84).
Diagnosis
Mp should be considered in the differential diagnosis of
any subject presenting with one of the syndromes associ-
ated with Mp regardless of clinical manifestations, CSF
Scheld_Ch25.indd 423
423
profile, and EEG and neuroimaging findings. Current or
recent upper or lower respiratory tract infection or pneu-
monia, whether of undetermined cause or confirmed to be
due to Mp, should raise the index of suspicion for Mp as
a possible cause. It is worth emphasizing again, however,
that the absence of respiratory disease does not preclude
the diagnosis, particularly in young children. The presence
of nonneurologic extrapulmonary features compatible with
Mp may also serve as a clinical clue. The presence of cold
hemagglutinins, often used as a quick screen for Mp infec-
tion, should not be relied upon due to poor sensitivity and
specificity (167).
Microbiologic diagnosis of Mp infection is based on
serology and detection of the pathogen by culture or PCR
in clinical samples. Culture is of limited use and not rou-
tinely available in most clinical laboratories due to its
low sensitivity compared to PCR and because it is labor
intensive, expensive, and requires up to 3 to 12 weeks of
incubation for positive results. The sensitivity of PCR (1 to
10 colony forming units) is 100-fold higher than culture.
As Mp neurologic disease can be either due to direct infec-
tion of the brain or immunologically mediated, PCR testing
or culture of both CSF and respiratory samples is recom-
mended. In one prospective 5-year study, Mp was detected
in the CSF of 6 of 11 (54%) children and in the respira-
tory tract of 5 of 11 (46%) children with probable Mp en-
cephalitis (28). CSF samples intended for Mp PCR should
be tested or frozen promptly because the stability of Mp
DNA is adversely impacted by storage at room or refrigera-
tor temperatures (168). An important potential limitation
of both culture and PCR is that a positive result from a
respiratory sample may reflect infection acquired as much
as 3 to 7 months earlier and therefore may not be relevant
to the acute illness (15,16,169171). For this reason, com-
bining PCR testing with acute and convalescent serologic
testing is encouraged.
Numerous commercial serologic assays are available for
the diagnosis of Mp infection (172). Most use a crude culture
extract, which contains glycolipid antigens that cross-react
with other mycoplasmal, bacterial, human, or plant antigens
(173). Better performance (sensitivity and specificity) has been
observed when recombinant antigens are used or the antigen
is enriched for cytadhesin protein P1, although these assays
are generally not commercially available (174,175). In the ap-
propriate clinical context, detection of IgM or IgA in acute
sera, seroconversion from negative to positive, or a fourfold
rise in titer between acute and convalescent sera is indicative
of acute infection (1,6). A negative result, however, does not
exclude Mp infection; in a study of 12 commercially available
kits in a predominantly adult population with PCR-proven
Mp respiratory tract infection, anti-Mp IgM was detected in
only 16% to 42% of acute sera and 32% to 84% of convales-
cent sera (176). Negative serology has also been observed in
patients with culture or PCR-proven CNS disease due to Mp
(28,34,38).
False-positive serologic results are also a significant
concern. For a cohort of children with encephalitis in
whom the prevalence of Mp infection is about 7% (28),
a false-positive serologic test rate of approximately 50%
is expected for an assay with a sensitivity of 90% and a
specificity of 94% (30). The observation that 80% of chil-
dren with encephalitis and reactive Mp IgM in acute sera, in
whom the organism was not detected by PCR in either CSF
or respiratory samples, had compelling evidence implicating
other pathogens as the cause of encephalitis, reinforce this
observation and the downside of relying solely on serology
for diagnosis (28).
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 424 Part III: Bacterial and Mycoplasmal Infections

TA B L E 2 5 . 1
SELECTED CLINICAL FEATURES OF MYCOPLASMA PNEUMONIAEASSOCIATED
NEUROLOGIC SYNDROMES

Clinical Syndrome Selected Clinical and Investigative Features

Encephalitis and Most common neurologic syndrome associated with Mp; children account for 60%80% of cases
meningoencephalitis (23,29)
(24,25,28,34,35,37, Protean clinical features generally indistinguishable from encephalitis due to other etiologies; death or
3941,4345, neurologic sequelae occur in 40%60% (23,28,29,79,83,91)
4749,53,79,83, Respiratory symptoms prior to or concurrent with neurologic symptom onset in 25%65% of cases
85100) (23,28,29,79,83)
Mp detected in CSF or brain tissue by PCR or culture in significant number of cases
(28,34,35,39,41,4345,4749,52,53,8587,100)
Detection of Mp in blood or CSF most often in absence of prodrome, or prodrome 7 days in duration;
in those with a prodrome 7 days at time of neurologic symptom onset, Mp often detected in the
respiratory tract, but not in blood or CSF (28,48,49)
Antibiotic therapy is recommended; corticosteroids may be of benefit (101)
Meningitis Intermediate in frequency; majority of cases in children and young adults
(2325,29,52,94,102) Clinical features and CSF findings typical of aseptic meningitis; benign clinical course
Onset usually within 7 days of respiratory symptom onset
Implicated on basis of serology alone in most cases; occasionally detected in CSF by PCR or culture (52)
Potential benefit of antimicrobial therapy unknown
Acute disseminated Intermediate in frequency; no age predilection
encephalomyelitis Polysymptomatic with encephalopathy, focal neurologic deficits, and neuroimaging evidence of
(28,36,46,51,103113) multifocal asymmetric demyelination presenting 14 weeks after respiratory illness
Mp implicated on basis of serology alone in most reported cases; occasionally detected by PCR in
respiratory samples (28,36,108) or CSF (46,51)
Anti-ganglioside antibodies demonstrated occasionally (105)
Primary treatment with corticosteroids, IVIG, or plasmapheresis; role of antimicrobial therapy
uncertain
Acute hemorrhagic Rare; fewer than 10 reports; no age predilection
leukoencephalitis Hyperacute form of ADEM characterized by rapid progression from confusion and muscle weakness
(Hurst disease) to stupor and coma 14 weeks after respiratory tract illness
(114117) Mp implicated on the basis of serology alone in all reported cases
Treatment with plasmapheresis (115,116) or corticosteroids (114,116,117) with partial response in some
Neurologic sequelae common in survivors (114,116)
Transverse myelitis Moderate in frequency (3550 reported cases); most cases in children and young adults
(38,42,111, Focal motor, sensory, or autonomic deficits and neuroimaging evidence of focal spinal cord
118120) demyelination 14 weeks after respiratory illness
Mp implicated on basis of serology alone in most reported cases; occasionally detected by PCR in
respiratory samples (38) or CSF (38,42)
Primary treatment with corticosteroids, IVIG, or plasmapheresis; role of antimicrobial therapy
uncertain
Bickerstaff brainstem Rare; 2 case reports involving children; no reported adult cases
encephalitis (121,122) External ophthalmoplegia, ataxia, and altered consciousness 12 weeks after respiratory illness
Mp implicated on the basis of serology and, in one case, detection of Mp in the respiratory tract by
PCR (121)
Elevated anti-GQ1b antibody titers in serum
Treatment with IVIG or immune adsorption associated with full recovery
Acute bilateral striatal Intermediate in frequency (1020 reported cases); children and adolescents, no reported adult cases
encephalitis (striatal Encephalopathy and extrapyramidal features most often 14 weeks after respiratory tract illness (124)
necrosis) (123140) Mp implicated on the basis of serology in most cases; detected by PCR in respiratory sample of one
case (124) and CSF of one case (123)
Anti-GM1 ganglioside antibody demonstrated in one case (136)
Treatment with corticosteroids (135,136), IVIG (124,136,140), or plasmapheresis (135) associated
with apparent response in some
Gradual but full recovery in most cases; residual movement disorder in some (127,129,132,137)
Acute bilateral thalamic Rare; fewer than 5 reports all children
necrosis (141143) Acute onset of encephalopathy and symmetric thalamic abnormality on imaging within 7 days of
respiratory symptom onset
Mp implicated on the basis of serology alone in all reported cases
Residual sequelae such as dystonia and tremor

(continued)

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 Chapter 25: Mycoplasmal and Ureaplasmal Infections 425

TA B L E 2 5 . 1
SELECTED CLINICAL FEATURES OF MYCOPLASMA PNEUMONIAEASSOCIATED
NEUROLOGIC SYNDROMES (CONTINUED)

Clinical Syndrome Selected Clinical and Investigative Features

Opsoclonus-myoclonus Rare; fewer than 10 reports, predominantly involving children

syndrome (144148)
Guillain-Barr syndrome
(GBS) (83,149155)
Cerebellar ataxia
(39,98,158,159)
Stroke (50,6672,
160164)
Cerebral vasculopathy
(54,55,165,166)
Opsoclonus, myoclonus, and ataxia 14 weeks after respiratory tract illness
Mp implicated on the basis of serology and selectively PCR detection in respiratory tract samples (145)
Anti-glutamate receptor antibodies detected in CSF of one case (148)
Corticosteroid and/or IVIG prescribed in all cases; dramatic response to plasmapheresis in one case (146)
Full recovery in all reported cases
Moderate in frequency; Mp implicated in 5%15% of GBS cases (149152)
Onset of neurologic symptoms 14 weeks after respiratory illness
Mp implicated on basis of serology alone in most reported cases; occasionally detected by PCR or
culture in respiratory samples (153,155157) or CSF (153)
Anti-ganglioside antibodies often detected (152,157)
Primary treatment with IVIG or plasmapheresis; role of antimicrobial therapy uncertain
Rare; reported in both children and adults
Onset of cerebellar manifestations 13 weeks after respiratory illness; in some, but not all, associated
with a more generalized encephalitic picture (39,158)
Mp implicated on the basis of serology in most cases; detected in throat sample and CSF in one case (39)
Potential benefit of antimicrobial therapy or immune-modulating therapies unknown
Rare; no age predilection
Neurologic symptoms usually develop 13 weeks after onset of respiratory illness
Hypothesized to be related to hypercoagulable state (6670) or vasculitis (71,72)
Mp implicated on the basis of serology alone in most reported cases; detected in respiratory tract
sample and CSF in one reported case (50)
Antiphospholipid and anticardiolipin antibodies demonstrated in some cases (50,70)
Potential benefit of antimicrobial therapy, corticosteroids, or IVIG unknown
Rare; 4 reported cases, all adults
Limited evidence implicating Mp; diagnosis based on immunostaining and electron microscopy
Subacute presentation with cognitive decline, weakness, ataxia

PCR, polymerase chain reaction; IVIG, intravenous immune globulin; ADEM, acute disseminated encephalomyelitis.

FIGURE 25.4 Neuroimages of an 8-year-old girl who presented with acute left-sided hemiplegia sub-
sequent to a 5-day history of fever, headache, and vomiting; Mycoplasma pneumoniae was detected in
the CSF by PCR. A: Magnetic resonance angiogram shows prominence of the vessels of the right middle
cerebral artery distribution in keeping with loss of autoregulation (arrows). The caliber of the arteries
in the left middle cerebral artery distribution is normal. B: T2-weighted coronal image (TR5700, TE90)
shows extensive cortical swelling and increased signal intensity within the gray matter of the right frontal
and temporal lobes. The white matter is relatively spared. (From Bitnun A, Ford-Jones E, Blaser S, et al.
Mycoplasma pneumoniae ecephalitis. Semin Pediatr Infect Dis. 2003;14:96107, with permission.)

Scheld_Ch25.indd 425 2/21/14 5:43 PM

 426 Part III: Bacterial and Mycoplasmal Infections
FIGURE 25.5 Magnetic resonance image demonstrating pronounced
edema of the cortical gray matter in the left hemisphere with exten-
sion to involve the subjacent white matter. The ventricles are large,
but there is no periventricular edema. This 14-month-old female pre-
sented with a right-sided focal seizure and encephalopathy following
a respiratory illness of 7 days duration. Mycoplasma pneumoniae
was implicated as the likely culprit on the basis of a complement
fixation titer of 1:128. (From Bitnun A, Ford-Jones E, Blaser S,
et al. Mycoplasma pneumoniae ecephalitis. Semin Pediatr Infect Dis.
2003;14:96107, with permission.)
Treatment
The most appropriate therapeutic interventions for suspected
or proven CNS disease due to Mp depend largely on the patho-
genesis of the syndrome in question. Key considerations are
the need for antimicrobial therapy and/or immune-modulating
therapies such as corticosteroids, intravenous immune globulin
(IVIG), or plasmapheresis (177,178). Because controlled trials
evaluating these treatments have not been conducted, recom-
mendations are based on anecdotal evidence from case reports
and case series and, in reference to immunologically mediated
entities such as ADEM, transverse myelitis, and Guillain-Barr
syndrome, extrapolated from data relating to these syndromes
irrespective of the infectious trigger. A multidisciplinary care
approach is important; for patients with increased intracranial
pressure, urgent neurosurgical consultation should be sought
as hemicraniectomy may be lifesaving (179).
Antibiotic therapy should be considered for all patients
with neurologic disease attributed to Mp, despite the pau-
city of efficacy data, because of the potential for significant
neurologic sequelae. It should be noted, however, that the
impact of such therapy on outcome is unknown; full recov-
ery has been observed with (38,39,41,44,51,52,61,83,85,8
6,97,100,112,155) and without (47,48,61,106) antibiotic
therapy, as has an apparent lack of response to such therapy
Scheld_Ch25.indd 426
FIGURE 25.6 Magnetic resonance image of a 10-year-old female
with Mycoplasma pneumoniaeinduced ADEM. On this T2-weighted
axial (TR2800, TE90) image, multiple foci of increased signal inten-
sity within deep gray structures and white matter are present. Upper
respiratory symptoms of 2 weeks duration had resolved 1 to 2 weeks
prior to the onset of encephalitis. M. pneumoniae was implicated on
the basis of positive serology (positive IgM by enzyme immunoassay
and acute/convalescent complement fixation titers of 1:128/1:512)
and detection of the organism by PCR in the throat. (From Bitnun
A, Ford-Jones E, Blaser S, et al. Mycoplasma pneumoniae ecephalitis.
Semin Pediatr Infect Dis. 2003;14:96107, with permission.)
(23,25,52,53,61,83,87,112). In adults and children 8 years of
age or older, in whom direct infection of the brain is proven
or possible, antibiotics with good in vitro and in vivo activ-
ity against Mp capable of traversing the bloodbrain bar-
rier and achieving therapeutic levels within the CNS such
as azithromycin, doxycycline, or a fluoroquinolone such as
moxifloxacin or levofloxacin are preferred (100,180184).
Chloramphenicol is another option as it achieves excellent
CSF levels (184) and has good activity against Mp, but the
risk of idiosyncratic bone marrow aplasia is of concern. For
those with immunologically mediated conditions in whom the
CSF tests negative for Mp by PCR, eradication of the patho-
gen from the respiratory tract using erythromycin or clarithro-
mycin may be appropriate. In children younger than 8 years
of age, doxycycline and tetracycline should be avoided due to
the risk of enamel hypoplasia and irreversible darkening of
permanent teeth.
Immune-modulating therapies are frequently used in the
management of demyelinating conditions. Corticosteroids
and IVIG, used alone or in combination, have been associated
with temporal clinical improvement in some (28,46,51,110
112,114,118120,185), but not all (36,103,107,186), patients
with ADEM and transverse myelitis. IVIG is preferred in
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 Chapter 25: Mycoplasmal and Ureaplasmal Infections 427

Guillain-Barr syndrome (155,156,187). Plasma exchange is

reserved for patients (with all three conditions) who fail to
respond to corticosteroids or IVIG (103,109,114).
Corticosteroids may also have a role in the treatment of
Mp-associated encephalitis. In a case report and retrospective
review of severe Mp encephalitis, treatment with corticoste-
roids was associated with complete or near-complete recovery
in 78% of cases (101). By comparison, full recovery was evi-
dent in only 52% of children not treated with steroids (79).
A prolonged taper over several weeks may be warranted in
severe cases to prevent symptomatic relapse (101). The role
of immune-modulating therapies in less common forms of
Mp neurologic disease is uncertain. Corticosteroids and IVIG,
sometimes in combination, have been associated with temporal
clinical improvement in several patients with Mp-associated
bilateral striatal necrosis (124,135,136) and opsoclonus myoc-
lonus syndrome (145,147,148). IVIG and immune adsorption
therapy have been used with apparent success in Bickerstaff
brainstem encephalitis (121,122).
OTHER MYCOPLASMA SPECIES
Mh and Uu are rare causes of CNS disease but neverthe-
less account for the vast majority of mycoplasmal CNS dis-
ease not attributable to Mp. Both are commensals of the
genitourinary tract. The Ureaplasma genus contains 14 dis-
tinct serovars divided into two separate species: U. parvum
(serovars 1, 3, 6, and 14) and U. urealyticum (serovars 2, 4,
5, and 7 through 13) (188). It is not known if there are any
differences between the two species with respect to pathoge-
nicity, and at present, they can only be differentiated by sero-
typing or PCR (2,189). For purposes of this review, they are
considered together. Rare case reports of CNS disease due to
Mycoplasma salivarium, Mycoplasma faucium, Mycoplasma
genitalium, and Mycoplasma maculosum have been reported
(35,190,191). A summary of the salient features of CNS
infections due to mycoplasmal species other than Mp is pro-
vided in Table 25.2.

TA B L E 2 5 . 2
CENTRAL NERVOUS SYSTEM INFECTIONS ATTRIBUTABLE TO MYCOPLASMA AND UREAPLASMA SPECIES
OTHER THAN MYCOPLASMA PNEUMONIAE

Species Syndrome Salient Clinical Features

Mycoplasma Meningitis and Sole pathogen in reported cases; diagnosis by culture or molecular detection
hominis meningoencephalitis techniques
(192205) Premature and term neonates predominantly; older individuals with head trauma
or neurosurgical procedures (192,205) or immunocompromising conditions (192)
Targeted antibiotic therapy recommended, although recovery without such
therapy noted in some neonates (200,201)
Brain abscess Sole pathogen in most reported cases, polymicrobial in others (190); diagnosis
(190,192,206209) by culture or molecular detection techniques
Predominantly premature and term neonates; rare reports of adults and older
children (190,192,206)
Most adult cases associated with head trauma or neurosurgical procedures
(192,206)
Ureaplasma Meningitis Sole pathogen in most reported cases; diagnosis by culture or molecular
urealyticum/ (200,201,210220) detection techniques
Ureaplasma Premature neonates predominantly; one reported case of immunocompromised
parvum adult following a neurosurgical procedure (221)
Targeted antibiotic therapy recommended, although recovery without such
therapy noted in many neonates (200,201,214)
Mycoplasma Brain abscess (5) Polymicrobial; detected in culture or by PCR
salivarium Poor dental hygiene in 55-year-old male with history of alcohol abuse and
prior pulmonary tuberculosis; second case involved 26-year-old male with no
underlying conditions
Antibiotic therapy included moxifloxacin in both cases
Residual neurologic deficit in one case
Mycoplasma Brain abscess (190,191) Polymicrobial; to date, detection only using molecular techniques
faucium Immunologically normal adults; association with sinusitis, dental abnormalities (191)
Need for targeted antimicrobial therapy uncertainfull recovery with antibiotic
therapy not targeting M. faucium reported in all cases (191)
Mycoplasma Brainstem encephalitis (4) Five-year-old previously healthy girl; full recovery
genitalium Detected by PCR in CSF
Mycoplasma Meningitis (3) Fifteen-year-old with common variable immune deficiency
maculosum Repeatedly detected by PCR and cultured from CSF
Likely acquired from pet dog (M. maculosum is a canine Mycoplasma species)
Failed treatment with doxycycline and ciprofloxacin; responded to prolonged
course of valnemulin hydrochloride (pleuromutilin antibiotic)

PCR, polymerase chain reaction; CSF, cerebrospinal fluid

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 428 Part III: Bacterial and Mycoplasmal Infections
MYCOPLASMA HOMINIS
Epidemiology
Mh colonizes the genital tract of 0% to 20% and 10% to 30%
of otherwise healthy sexually active men and women, respec-
tively (222224). Higher rates occur in men with urethritis
and in women with bacterial vaginosis, urethritis, or cervicitis
(225,226). Between 5% and 10% of newborns are asymptom-
atically colonized at the time of birth (227,228). Colonization
is transient, only rarely being detected in prepubertal children
beyond 3 months of age (228). Colonization rates increase
with the onset of sexual activity (222,229,230).
Clinical Features
Mh has been associated with nongonococcal urethritis in both
men and women and with bacterial vaginosis and pelvic in-
flammatory disease in women. Wound infections subsequent to
trauma or surgery and septic arthritis in association with a pros-
thetic joint or an immunocompromised state such as malignancy
and hypogammaglobulinemia have been reported (3,192,205).
The majority of CNS infections due to Mh occur in neo-
nates (193). Premature and term infants have both been af-
fected. Meningitis and meningoencephalitis are the most
common entities (193204); brain abscess and subdural em-
pyema also occur (207209). Colonization of the respiratory
or genitourinary tract during the birthing process followed by
hematogenous dissemination is the likely pathogenesis. Onset
of symptoms in reported cases ranged from day 1 to day 32 of
life, the majority during the first 2 weeks of life (193). Clinical
and laboratory features are indistinguishable from those due
to other bacterial pathogens. CSF pleocytosis, elevated CSF
protein, and hypoglycorrhachia have all been observed (193);
a predominance of polymorphonuclear leukocytes is charac-
teristic. Adverse outcome is seen in approximately 50% of
cases, death in 28%, and neurologic sequelae in 28% (193).
In older children and adults, Mh has been implicated as a
cause of brain abscess subsequent to neurosurgical procedures
(192,206) and meningitis in the context of immune suppres-
sion related to cancer chemotherapy (192). Fever and focal
neurologic manifestations are typical. Mh has also been de-
tected by multiple 16S ribosomal DNA sequencing in poly-
microbial brain abscesses (190); the significance of Mh in
pathogenesis of these brain abscesses and, by extension, the
need for Mh-targeted antimicrobial therapy is unknown.
Diagnosis
Because of the rarity of Mh CNS infection and the difficulty in
culturing the organism, diagnosis requires a high index of sus-
picion. It should be considered in any neonate with meningitis,
encephalitis, or brain abscess when CSF cultures are negative
and there is no clinical response to standard neonatal sepsis
treatment, such as a combination of -lactams (e.g., ampicillin
plus cefotaxime) or a -lactam with an aminoglycoside.
As the organism is extremely sensitive to environmental con-
ditions, specimens should ideally be inoculated into appropri-
ate transport media, such as 10B or SP4 broth, at the bedside.
The preferred culture medium is SP4 broth and agar (pH 7.5)
supplemented with arginine. Mh may occasionally grow as
pinpoint translucent colonies after 2 to 3 days incubation on
conventional blood or chocolate agar plates. Failure of these
colonies to enlarge and the inability to visualize organisms by
Scheld_Ch25.indd 428
Gram stain of a colony sample should lead to consideration of
mycoplasmal infection. Molecular diagnosis using PCR offers
superior sensitivity and improved turnaround time compared
to culture (231,232). Serology is of no value in diagnosis.
Treatment
Mh is usually susceptible to the tetracyclines (tetracycline,
doxycycline, minocycline), chloramphenicol, lincosamides
(clindamycin), quinupristin-dalfopristin, and selectively to the
fluoroquinolones (233). Tetracyclines are considered the drugs
of choice (192,193). Doxycycline has been used most exten-
sively, including in neonates despite the potential for bone and
dental toxicity (194,196,197,199,201,208). Chloramphenicol
has been used alone or in combination with other antibiotics
(193,195,197199,203,209); in one case, it had to be discon-
tinued due to presumed toxicity that included hypotension and
pancytopenia (199). Several recent Mh meningitis cases have
been successfully treated with moxifloxacin or gatifloxacin
(193,202,206). The in vitro efficacy of these fourth-generation
fluoroquinolones is superior to that of the older generation
fluoroquinolones ciprofloxacin and levofloxacin (193,233).
Potential advantages of the fluoroquinolones include their bac-
tericidal activity and excellent CSF penetration (193,202,206).
A 2- to 3-week course of antibiotic therapy is usually sufficient
for Mh meningitis. In those with brain abscesses, 6 weeks of
such therapy should be given; surgical drainage needs to be
considered in all cases.
It is paramount that susceptibility testing be performed on
all sterile site isolates of Mh due to increasing rates of antibi-
otic resistance (234). For example, over a 20-year period in
Germany, resistance to tetracycline, doxycycline, and cipro-
floxacin rose from 2.1% to 14.5%, 0% to 14.5%, and 0% to
15.4%, respectively (234).
UREAPLASMA SPECIES
(UREAPLASMA UREALYTICUM
AND UREAPLASMA PARVUM)
Epidemiology
Asymptomatic colonization of the genital tract occurs in 40%
to 80% of sexually active women (2,222,225); among sexually
active men, approximately 25% to 50% are similarly colonized
(223,225). Approximately half of newborn infants of colonized
mothers acquire the infection perinatally, the vast majority
asymptomatically (235237). Colonization rates decline during
early infancy, and in children 2 to 13 years of age, the organism
can rarely be detected (228,230). As is the case with Mh, genital
colonization rates increase with onset of sexual activity (230).
Clinical Features
In adults, Uu is primarily associated with nongonococcal ure-
thritis in men and complications of pregnancy in women (238).
Maternal urogenital colonization with Uu is associated with
histologic chorioamnionitis, stillbirth, preterm birth, and ad-
verse neonatal outcomes including neonatal pneumonia, bron-
chopulmonary dysplasia, intraventricular hemorrhage, and
lower psychomotor development scores at 2 years of age (239).
High levels of the proinflammatory cytokines IL-1, tumor
necrosis factor-, IL-6, and IL-8 in amniotic fluid correlate
with preterm premature rupture of membranes (pPROM) and
2/21/14 5:43 PM
 Chapter 25: Mycoplasmal and Ureaplasmal Infections
isolation of Uu, which suggests that Uu is truly pathogenic in
this setting. Extragenital non-CNS infections reported rarely
in older children and adults include postoperative wound and
prosthetic joint infections and systemic infections such as septic
arthritis in patients with common variable immune deficiency
and other immunocompromising conditions (3,240243).
CNS disease due to Uu occurs primarily in premature
infants (200,201,208,210220). Meningitis is the most com-
mon syndrome. There is one report of a brain abscess, from
which both Uu and Mh were isolated, in a 3-week-old term
infant (208). An association between Uu infection and intra-
ventricular hemorrhage has been noted in some (201,220),
but not all, studies (244). In one study, the risk of grade 3 to
4 intraventricular hemorrhage among very-low-birth-weight
premature infants was fivefold higher when Uu was detected
in serum by PCR and serum IL-1 was elevated; of note,
U. parvum was the only Uu species detected in the serum of
these patients (220). Despite these suggestive data, a causal
link is uncertain because very-low-birth-weight premature in-
fants are at high risk of intraventricular hemorrhage for many
reasons irrespective of Uu colonization or infection status.
In adults, CNS disease due to Uu is exceedingly rare. The only
published report was that of a 38-year-old male who developed
Uu (biovar 2) meningitis 10 weeks after renal transplantation and
4 weeks after placement of a ventricular drain for management
of increased intracranial pressure (221). He was successfully
treated with a combination of doxycycline and chloramphenicol.
Diagnosis
Unlike Mh, Uu cannot be cultured from routine bacterio-
logic media. Its specific transport and culture requirements
are similar to those of Mh (239). Growth usually occurs in
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 CHAPTER 26 BARTONELLA INFECTIONS,
INCLUDING CAT-SCRATCH DISEASE
MICHAEL GILADI, MOSHE EPHROS, AND DAVID F. WELCH
The bacterial genus Bartonella is named for Dr. A. L. Barton,
who described the erythrocyte-adherent Bartonella bacilli-
formis in 1909. It is the etiologic agent of Oroya fever, an
acute bacteremic infection characterized by sepsis and hemo-
lysis, and of verruga peruana, principally a cutaneous nodular
vascular eruption representing chronic infection. The previ-
ously suspected link between the two conditions was tragi-
cally confirmed in 1885 by Daniel Carrin, a medical student
who injected himself with bloody material from a verruga and
subsequently died of Oroya fever. This form of bartonellosis is
thus known as Carrin disease and South American bartonel-
losis because it is limited to the Andean mountain regions of
Peru, Ecuador, and Colombia. It affects the local population
and, rarely, travelers to these countries. Bartonellosis garnered
little attention outside its endemic zone in recent years until
related bacteria, then named Rochalimaea species, were found
to be important pathogens, primarily in patients with acquired
immunodeficiency syndrome (AIDS).
TAXONOMY
The now supplanted genus Rochalimaea was formerly clas-
sified with Bartonella in the order Rickettsiales and con-
sisted of only two species, Rochalimaea (Rickettsia) vinsonii,
the Canadian vole agent, and Rochalimaea (Rickettsia)
quintana, the agent of trench fever. The latter is a debilitating
but self-limited human illness so named after it affected many
military personnel in World War I. Except for sporadic out-
breaks, trench fever had all but disappeared from the clinical
scene in recent decades. However, the 1990s saw the reemer-
gence of R. quintana as a pathogen of considerable interest
(15), coincident with the discovery of two related species
that also cause human disease, originally named Rochalimaea
henselae and Rochalimaea elizabethae (69).
Bartonella species are alphaproteobacteria, which also
contains Afipia, Agrobacterium, and Brucella. Unlike mem-
bers of the order Rickettsiales, Bartonella species have been
cultured on cell-free media. Sequencing of 16S ribosomal RNA
(rRNA) genes to determine phylogenetic relationships among
these organisms revealed high levels of relatedness between
B. bacilliformis and the former Rochalimaea species (10) and
confirmed that all of them are more closely related to Brucella
and Agrobacterium than to members of the rickettsiae. Based
on DNA hybridization and 16S rRNA similarity, the former
Rochalimaea species were combined with Bartonella in 1993
(11), and the members of the family Bartonellaceae were
removed from the order Rickettsiales. A further proposal was
made in 1995 to merge into the genus Bartonella a number
of species of the genus Grahamella, which are intraeryth-
rocytic pathogens of rodents, birds, fish, and other animals
(12). Recently, an increasing number of Bartonella species
have been identified and characterized. Currently, the genus
Bartonella consists of at least 27 recognized species or subspe-
cies, of which at least 13 have been recognized as confirmed or
potential human pathogens. Others have been isolated from
434
Scheld_Ch26.indd 434
nonhuman wild and domestic mammals, including rodents,
cervids, and cattle, without associated identifiable human ill-
ness (13). Comparison of phylogenetic data, inferred mainly
from 16S rDNA, 16S-23S rRNA intergenic spacer, citrate
synthase and 60-kd heat shock protein gene sequences have
identified six evolutionary clusters within the genus Bartonella
(14). Cat-scratch disease (CSD)causing B. henselae are classi-
fied into two serotypes, Houston-1 and Marseille, which cor-
respond to two genotypes based on 16S rRNA gene sequences,
genotype I and genotype II. The significance of this and other
classifications with respect to pathogenesis and clinical mani-
festations has not been established (15,16).
EPIDEMIOLOGY
Infections with B. bacilliformis are geographically limited to
middle altitudes of the Andes mountains, probably because of
the distribution of species of the genus Lutzomyia (formerly
Phlebotomus), its sandfly vectors. B. quintana is globally dis-
tributed; there have been reports of focal, but widely separated,
outbreaks of trench fever, also known as quintan or 5-day
fever. Outbreaks commonly have been associated with condi-
tions of poor sanitation and personal hygiene that predispose
to exposure to the human body louse Pediculus humanus, the
only identified vector of B. quintana. Although B. quintana
has also been identified in the human head louse P. humanus
capitis, there is no strong evidence that head lice are vectors
of this organism between human hosts (17). Nonhuman verte-
brate reservoirs have not yet been identified for either B. bacil-
liformis or B. quintana.
Cats bacteremic with B. henselae constitute the major res-
ervoir of this pathogen. B. henselae has been documented
to cause bacteremia (18,19) in seemingly healthy domestic
cats, including some that have been specifically associated
with bacillary angiomatosis (19) or typical CSD (18) in their
human contacts. B. henselae bacteremia has been globally
reported among pet, impounded, or stray cats. Rates of
bacteremia can vary and may be as high as 89% (1825).
Other animals, particularly dogs, have been implicated as a
possible reservoir for B. henselae, but reports are anecdotal
and evidence essentially circumstantial. Fleas and ticks are
arthropod vectors of B. henselae, based on epidemiologic as-
sociations (26,27) and reports of identification of B. henselae
by both culture and DNA amplification from cat-associated
fleas (18,19). Cat-to-cat transmission by infected fleas has
been shown to occur (21), although evidence of cat-to-human
transmission by fleas is lacking. Like B. quintana, B. henselae
infection is globally endemic. However, regional variations in
the prevalence of either B. henselae or B. quintana may occur.
Transmission to humans has been linked to cats by serologic
and epidemiologic studies (27,28), its recovery from cases of
human lymphadenitis consistent with CSD (18,29), and the
identification of B. henselae DNA by polymerase chain reac-
tion (PCR) in CSD lymphadenitis and other affected tissues
(3033).
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 Chapter 26: Bartonella Infections, Including Cat-Scratch Disease
OVERVIEW OF CLINICAL/
PATHOLOGIC MANIFESTATIONS
Oroya Fever and Verruga Peruana
Bartonella bacilliformis
Oroya fever, the bacteremic illness of primary B. bacilliformis
infection, develops 2 to 14 weeks (mean 3 weeks) after in-
oculation by the sandfly Lutzomyia verrucarum (34). Bacteria
invade blood vessel endothelium, proliferate, and upon re-
entry into blood vessels replicate and destroy erythrocytes.
Microvascular thrombosis results in end-organ ischemia. In its
milder form, the febrile illness often remits in a week. When
abrupt in onset, high fever, chills, diaphoresis, headache, and
mental status changes are associated with a rapidly developing
severe hemolytic anemia (3538). Lymphadenopathy, throm-
bocytopenia, severe myalgia and arthralgia, and complications
such as delirium, coma, dyspnea, and angina can occur during
this stage. Without antimicrobial treatment, mortality rates
up to 40% to 80% have been reported (39,40); however, a
disease milder in severity and with a low (0.7%) case-fatality
rate may occur (41). Convalescence is associated with a de-
cline of fever and disappearance of bacteria on blood smears
as well as increased susceptibility to intercurrent opportunistic
infections such as salmonellosis (42) or toxoplasmosis (43).
Usually within months of acute infection, verruga peruana
may become evident. This late-stage manifestation of infec-
tion is characterized by crops of nodular skin lesions; mucosal
and internal lesions can also occur. Their histology typically
contains neovascular proliferation with occasional bacte-
ria evident in interstitial spaces. B. bacilliformis invasion of
endothelial cells, which was described by Rocha-Lima and
believed to be the etiology of cytoplasmic inclusions, is rare
(44). Verruga peruana lesions may develop at one site while
receding at another. They may persist for months to years and
eventually become fibrotic with involution. Asymptomatic
persistent bacteremia with B. bacilliformis infection can occur
in up to 15% of survivors of acute infection (45) who may
serve as the organisms reservoir.
Bacteremic Illness and Endocarditis
Bartonella quintana, Bartonella henselae,
and Other Bartonella Species
The natural course of trench fever includes a spectrum of self-
limited clinical patterns (46). Incubation may span days to
weeks before the typical sudden onset of fever. The febrile ill-
ness may be brief (lasting 4 to 5 days), prolonged (uninterrupted
for 2 to 6 weeks), or most commonly, paroxysmal (three to five
episodes, each of about 5 days). Fever may be accompanied
by other nonspecific symptoms and signs such as headache,
vertigo, retroorbital pain, conjunctival injection, nystagmus,
myalgia, arthralgia, hepatosplenomegaly, rash, leukocytosis,
and albuminuria. B. quintana has reemerged as a cause of
bacteremic illness (designated also as urban trench fever) in
human immunodeficiency virus (HIV)uninfected homeless
patients with chronic alcoholism (5,47,48). B. quintana was
also identified in body lice from these patients. Clinical char-
acteristics include headache, sweats, severe leg pain, and low
platelet counts. Many bacteremic patients were afebrile and
some were asymptomatic. Chronic bacteremia, as indicated by
positive blood cultures up to 78 weeks, and intermittent bac-
teremia were found to occur.
Scheld_Ch26.indd 435
435
B. quintana or B. henselae bacteremia in HIV-infected per-
sons is often characterized by insidious development of fatigue,
malaise, body aches, weight loss, progressively higher and lon-
ger recurring fevers, and sometimes headache. Hepatomegaly
may occur. Although there is evidence implicating Bartonella
species in some cases of HIV-associated encephalopathy, menin-
goencephalitis, and neuropsychiatric disease, lumbar puncture
during acute bacteremia in HIV-infected persons can be unre-
vealing (6,9). Rarely, fever without localizing symptoms or signs
in association with B. henselae bacteremia has been reported in
immunocompetent patients (6,9). Aseptic meningitis concurrent
with bacteremia has been documented in an immunocompetent
host (26). B. henselae bacteremia can evolve into long-term
asymptomatic persistence (26).
Both B. quintana and B. henselae are considered important
pathogens of endocarditis, accounting for approximately 3%
of all patients with infective endocarditis, and a much larger
proportion, up to 28%, of patients with culture-negative
endocarditis (1,4,4951). B. elizabethae, B. vinsonii subspe-
cies berkhoffii, B. alsatica, and B. koehlerae have rarely been
isolated from patients with endocarditis (8,5254). Patients
with B. quintana endocarditis often have been homeless and
alcoholic, whereas patients with B. henselae endocarditis have
commonly reported being in contact with a cat. The typical
clinical presentation is that of subacute bacterial endocarditis,
including neurologic manifestations such as stroke. In a ret-
rospective study of 101 patients with Bartonella endocarditis,
embolic phenomena were reported in 43% of patients. A sig-
nificant number of patients were afebrile at presentation, 12 of
the 101 patients died, 2 relapsed, and 76 underwent valvular
surgery (55).
Bacillary Angiomatosis and Peliosis
Bartonella quintana and Bartonella henselae
Bacillary angiomatosis (BA), also termed epithelioid angio-
matosis or bacillary epithelioid angiomatosis, is a disorder of
neovascular proliferation originally described involving skin
and regional lymph nodes of HIV-infected persons (5658).
It has since been demonstrated to involve a variety of inter-
nal organs (5961), including the brain (62), and to occur
in other immunocompromised (59,63) and immunocompe-
tent hosts (6466). B. quintana infections have a predilection
for causing subcutaneous and deep soft tissue disease and
lytic bone lesions, whereas B. henselae infections are associ-
ated with lymph node disease and parenchymal peliosis of
the liver and/or spleen. B. henselae and B. quintana (2,9,67)
equally cause BA of the skin, the most common manifesta-
tion of this illness. Risk factors for B. quintana infection
are low income, homelessness, and body louse infestation,
whereas B. henselae infection is associated with cat or cat
fleas contact (67).
Skin lesions often arise in crops, but their timing and gross
appearance can vary. They can be remarkably similar to the
lesions of verruga peruana. However, most cases of BA have
been identified outside the region of endemic B. bacilliformis.
Thus, the most important differential diagnoses are Kaposi sar-
coma and pyogenic granuloma. Studies addressing the poten-
tial association between pyogenic granuloma and Bartonella
infection have resulted in conflicting results (68,69). The his-
tologic distinction of BA from other neovascular tumors has
been clearly described (70,71).
Bacillary peliosis (BP), originally described involving the
liver and sometimes spleen in HIV-infected persons (72), has
since been identified in other immunosuppressed persons
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 436 Part III: Bacterial and Mycoplasmal Infections
and found to involve lymph nodes as well (59,73). Involved
organs contain numerous blood-filled, partially endothelial
celllined cystic structures and surrounding clumps of bacilli
(identified by Warthin-Starry silver staining) in the midst of
inflammatory cells.
Cat-Scratch Disease
Bartonella henselae (Possibly Bartonella clarridgeiae,
Bartonella quintana, and Afipia felis)
B. henselae is the major etiologic agent of CSD (18,19,2832).
B. clarridgeiae, B. quintana, and Afipia felis have rarely been asso-
ciated with CSD in humans (7476). The various manifestations
that comprise CSD have been recognized over the past 100 years,
but the syndrome per se was not really defined until 1950 (77).
In typical CSD (about 90% of cases), a cutaneous papule or
pustule usually develops within a week after an animal contact
(more commonly a kitten) at a site of inoculation (usually a
scratch or bite) (7880). Regional adenopathy (mostly involv-
ing head, neck, or upper extremity) develops in 1 to 7 weeks
(Fig. 26.1). About one third to one half of patients have fever,
and about one sixth develop lymph node suppuration. The
histopathology of nodes includes a mixture of nonspecific in-
flammatory reactions including granulomas and stellate necro-
sis. Bacilli may be demonstrable by Warthin-Starry staining.
Atypical CSD (about 10%) occurs as extranodal or compli-
cated disease in the absence or presence of lymphadenopathy
and includes Parinaud oculoglandular syndrome, encephalop-
athy, neuroretinitis and other neurologic syndromes, fever of
unknown origin, hepatic and splenic abscesses, granulomatous
hepatitis, debilitating myalgia, arthritis or arthralgia (affect-
ing mostly females older than age 20 years), osteomyelitis and
other musculoskeletal manifestations, and erythema nodosum
(79,8184). Other manifestations and syndromes (e.g., pneu-
monitis, myocarditis, and thrombocytopenia) have also been
associated with CSD (8588).
In most cases, whether typical or atypical, spontaneous
resolution occurs in 2 to 4 months. The prolonged course
of CSD lymphadenopathy, which is often accompanied by
fever, night sweats, weight loss, and liver or spleen involve-
ment, may resemble lymphoma or other malignant processes.
Consequently, this may lead to unnecessary, extensive, costly,
and sometimes invasive diagnostic procedures (8991).
FIGURE 26.1 Cat-scratch disease lymphadenopathy in a 10-year-old
previously healthy male.
Scheld_Ch26.indd 436
NEUROLOGIC MANIFESTATIONS
OF BARTONELLA INFECTIONS
Associated with Oroya Fever
Acute B. bacilliformis infection (Oroya fever) has long been
recognized to have associated neurologic manifestations (34).
Acute onset of severe headache is usually coincident with
onset of fever and development of hemolysis. Characteristics
of the meningoencephalitis that occurs in about 1 in 10 cases
include diffuse neurologic impairment that may result in sei-
zures, hallucinations, delirium, and/or reduced consciousness,
which can progress to obtundation and coma. Diminished
level of consciousness is associated with a poorer prognosis.
Meningeal findings without encephalitis also can occur and
vice versa. Less commonly, localized findings in the form of
cranial or spinal nerve palsies occur, with the latter sometimes
causing a meningomyelitis with flaccid or spastic paralysis.
Cerebrospinal fluid (CSF) protein elevation and mild mono-
nuclear leukocytosis can occur, and bacteria may be identi-
fied within these leukocytes. Peripheral nerve palsies that
occur during the later eruptive verruga stage are usually due to
granulomatous inflammatory lesions within peripheral nerves;
such impediments are usually chronic but associated with
gradual resolution.
The often fatal course of Oroya fever has allowed his-
topathologic correlation with clinically evident neurologic
manifestations (92,93). Most of the neurologic manifesta-
tions appear to be the result of the vascular endothelial cell
damage that develops. In the leptomeninges, capillary and
venous congestion and thrombosis are common, associated
with microhemorrhages, adventitial proliferation, perivascu-
lar edema, and rarely, formation of new microvasculature.
As a consequence of profound hemolytic anemia (hemoglo-
bin concentration 4 g/L has been reported in Oroya fever)
and microvascular thrombosis, resulting in ischemia, there
can be subacute neuronal degeneration. Reactive glial prolif-
eration is usually diffuse but in some cases may be nodular.
Occasionally, granuloma-like nodules composed of microglial
cells and histiocytes, named verrucomas, are found in the cho-
roid plexus, ependyma, and brain parenchyma. Ultimately, the
meningoencephalitis associated with Carrin disease appears
to be more a consequence of the damage done to the hosts
microvasculature, complicated by the associated profound
anemia, than the result of a primary neurotropic affinity on
the part of B. bacilliformis.
Associated with Trench Fever
and Other Manifestations of
Bartonella quintana Infection
Although trench fever is often associated with headache, specific
neurologic manifestations of this form of B. quintana infection
are uncommon. Few cases of B. quintana infection with distinct
central nervous system (CNS) pathology have been described.
A 19-year-old HIV-uninfected patient with hypogammaglobu-
linemia presented with fever, left hemiparesis, slurred speech,
urinary incontinence, blurred vision, and behavioral changes,
which developed over 2 months due to a necrotizing granulo-
matous process involving the right thalamus and surrounding
tissues. B. quintana was identified in brain tissue, bone marrow,
and serum specimens from this patient by PCR and nucleotide
sequencing. B. quintana DNA was also amplified from the CSF
of an 8-year-old immunocompetent child with encephalitis and
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 Chapter 26: Bartonella Infections, Including Cat-Scratch Disease
axillary adenitis (94). A previously healthy 16-month-old girl
was admitted to the intensive care unit with encephalopathy
complicated by Guillain-Barr syndrome and hydrocephalus,
which necessitated placement of a ventriculoperitoneal shunt.
She had serologic and molecular evidence of central nervous
system infection by B. quintana (95).
Associated with Cat-Scratch Disease
The most commonly recognized neurologic manifestations
associated with B. henselae infection are those of CSD, pre-
dominantly encephalopathy and neuroretinitis. Isolated cranial
and peripheral neuropathies (e.g., facial palsy), polyneuropa-
thy, transverse myelitis, and other manifestations uncommonly
occur (96145). CSD vertebral osteomyelitis may rarely present
with neurologic complications, including intraspinal extension
(146150). Encephalopathy probably occurs in 2% to 4% of
all recognized CSD cases, although estimates range from 1%
to 7% (115). Extrapolating from an estimated U.S. CSD case
rate of 9.3 per year per 100,000 population, 2% to 4% would
represent between 500 and 1,000 annual CSD encephalopathy
cases in the United States. The California Encephalitis Project
reported Bartonella species as the causative agent in 7 (2%) of
334 patients with encephalitis, making it the most common bac-
teria associated with encephalitis (151). In contrast, Bartonella
cases were found neither among 203 patients with encephali-
tis in a multicenter prospective study from England nor among
253 patients in a national prospective study conducted in France
(152,153). However, the diagnosis of Bartonella encephalitis in
the latter study may have been underrepresented because the
authors excluded survivors hospitalized for more than 5 days
because these patients were assumed to have aseptic meningi-
tis rather than encephalitis. Patients with encephalitis due to
Bartonella species may have a fulminant presentation but often
recover fully within several days after onset and thus could have
been excluded from the study (154). Such diagnoses can easily
be overlooked if the clinician fails to obtain an adequate history.
With domestic cats representing the single largest category of
companion animals in the United States, the importance of an
accurate history regarding animal exposure cannot be overem-
phasized when evaluating a patient with findings consistent with
one of these syndromes. A common pitfall in history taking is to
inquire about a cat scratch or a cat bite rather than cat contact,
as a significant proportion of CSD patients report cat contact
without injury. Though less established, one must also keep an
open mind to the possibility of transmission of B. henselae from
other animals such as dogs.
CSD encephalopathy remains predominantly a clinical
diagnosis, now subject to laboratory confirmation by tech-
niques described later in this chapter (predominantly anti-
body testing). Adolescents and adults may represent a greater
proportion of cases of CSD encephalopathy than they do of
CSD overall (81). Encephalitis was also reported to be more
common in elderly patients (older than 60 years of age) with
CSD than in younger patients (155). The pathogenesis of CSD
encephalopathy and other CNS manifestations associated
with CSD remains unclear. Whether these rare complications
are attributable to direct invasion of the CNS by B. henselae or
to other mechanisms such as vasculitis or immune response is
unknown. B. henselae has been shown to infect feline microg-
lial cells in vitro and survive intracellularly for up to 4 weeks;
however, no ultrastructural abnormalities were identified
within infected brain cells by electron microscopy (156).
In most patients, encephalopathy usually follows lymph-
adenopathy, by a period of days up to 2 months, although it
has also been reported to precede lymph node involvement or
Scheld_Ch26.indd 437
437
to occur in its absence. Persistent generalized headache is a
common part of the history, but fever is an inconsistent find-
ing. Patients may become restless and combative. Nearly half
of patients develop seizures, which may range from focal to
generalized and from brief and self-limited to status epilep-
ticus. Short-term anticonvulsant therapy may be required,
as may be supportive therapy in the face of obtundation or
coma. Nuchal rigidity, pathologic reflexes, or pupillary dila-
tion may be present transiently. Neurologic deficits such as
aphasia, cranial nerve palsy, paresis, hemiplegia, and ataxia
are usually self-limited, although time to resolution may span
weeks to months to as long as a year. Persistence of intel-
lectual impairment, ataxia, and seizures have been reported
(81,112,118,125,128), as well as rare cases of death due to
CSD meningoencephalitis in two previously healthy children,
aged 4 and 6 years (157,158).
Laboratory studies in the setting of CSD encephalopathy do
not add specific positive diagnostic findings to the clinical pic-
ture, but they serve to exclude other processes. CSF measure-
ments fit no consistent pattern, except that hypoglycorrhachia
is rare. Elevation of CSF protein concentration and pleocytosis
with lymphocytic predominance occur in only about one third
of patients (but not necessarily in the same patients) (151).
Peripheral blood leukocytosis occurs as well in only about one
third of patients. CSF cultures have been consistently negative.
Studies of the brain with computed tomography (CT) and/
or magnetic resonance imaging (MRI) usually show no abnor-
malities. Transient nonspecific abnormalities are occasionally
identified, but a few cases of persistent structural abnormali-
ties have been reported (128,159). Electroencephalography
during the acute phase of CSD encephalopathy commonly
reveals diffuse slowing, yet another nonspecific feature that
resolves with clinical recovery. Brain biopsy is usually not in-
dicated because of the self-limited nature of CSD encephalopa-
thy, and thus little is known about the histologic correlates
of the clinical manifestations. At autopsy of a fatality due to
CSD encephalomeningitis, there was marked cerebral edema
with no gross evidence of acute meningitis. Microscopic ex-
amination revealed multiple granulomatous lesions, meningi-
tis, and encephalitis. Warthin-Starry silver stain of the brain
and liver revealed pleomorphic rod-shaped bacilli consistent
with B. henselae infection. Analysis of brain tissue with PCR
confirmed the presence of B. henselae DNA (157). Histologic
examination of the second fatality showed extensive diffuse
perivascular lymphocytic infiltrates with microglial nodules
scattered throughout the frontal, parietal, and occipital lobes
and the pons. In some foci, the nodules appeared vaguely
granulomatous (158). Biopsy of concurrent lymphadenopathy,
when done, reveals features typical of CSD.
The neuroretinitis associated with CSD (96,108,116,117,
120,121,124,129,133,160164) has been confirmed by se-
rology and culture to be related to B. henselae infection.
Neuroretinitis in association with B. henselae bacteremia (96),
aseptic meningitis (165), and encephalopathy (166) have been
reported in patients with CSD. Chorioretinitis and multiple
hypodense areas within the spleen and liver parenchyma have
been described in a 10-year-old previously healthy boy several
weeks after a cat scratch (167). Although long-term prognosis
is usually good, some individuals may develop mild postin-
fectious optic neuropathy, and few may develop permanent
visual disturbances. Vitrectomy is only rarely indicated. With
the refinement of techniques for identification of Bartonella
infection, diagnostic accuracy has improved, broadening
the spectrum of CSD-associated retinal manifestations and
identifying new Bartonella species as possible pathogens
in neuroretinitis. B. grahamii was identified by PCR ampli-
fication and sequence analysis in the intraocular fluid of an
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 438 Part III: Bacterial and Mycoplasmal Infections
FIGURE 26.2 Left eye neuroretinitis in a previously healthy 35-year-old
male cat owner with cat-scratch disease. Disc edema with macular exu-
dates in a star formation (macular star; arrow) are seen. Macular star
retinopathy is thought to result from leakage of lipid-containing exudate
from capillaries in the optic head with subsequent extension into the
subretinal space and macular region. (Courtesy Ehud Zamir, MD.)
HIV-seronegative patient with bilateral neuroretinitis and be-
havioral changes, and B. elizabethae infection was diagnosed
serologically in another patient with neuroretinitis (168,169).
The typical clinical scenario of CSD neuroretinitis, a pro-
cess first described as Leber idiopathic stellate retinopathy
(116,170), is that of painless, fairly sudden loss of visual acuity,
usually unilaterally, and sometimes preceded by an influenza-
like syndrome or development of regional lymphadenopathy.
Neuroretinitis is characterized by papilledema often associated
with macular exudates in a star formation (Fig. 26.2). In a ret-
rospective study among 24 patients with CSD with 35 affected
eyes, isolated foci of retinitis or choroiditis were the most com-
mon ocular manifestation identified in 83% of eyes and 83%
of patients. Optic disk swelling was the second most common
finding (46% of eyes, 63% of patients), followed by a macu-
lar star (43% of eyes, 63% of patients) and vascular-occlusive
events (14% of eyes, 21% of patients). Final visual acuity was
20/25 or better in 26 (74%) of 35 eyes and was similar in both
treated and untreated patients (161). Optic disk edema asso-
ciated with peripapillary serous retinal detachment has been
described as an early sign of ocular CSD. The typical macular
star may or may not follow these early manifestations (171).
Other types of ocular CSD manifestations include optic neu-
ritis, anterior uveitis, panuveitis, vitreitis, pars planitis, focal
retinal vasculitis, retinal white spot syndrome, branch retinal
arteriolar or venular occlusions, central retinal artery and vein
occlusion, focal choroiditis, vitreous and retinal hemorrhages,
and a process associated with peripapillary angiomatosis
(172181). The pathophysiology of neuroretinitis is thought
to be leakage of lipid-containing exudate from capillaries in the
optic head with subsequent extension into the subretinal space
and macular region. This type of process has been recognized
as a secondary phenomenon in most circumstances, occur-
ring in association with traumatic injuries of the eye or brain,
ocular vascular disturbances, toxins, autoimmune states (e.g.,
Behet syndrome), or a variety of infections (e.g., influenza-
like syndromes, syphilis, leptospirosis, tularemia, tuberculosis,
psittacosis, endemic mycoses, and parasites). Thus, although
this process can be considered characteristic of CSD neuroreti-
nitis, it is not pathognomonic and many other causes must be
included in the differential diagnosis.
Scheld_Ch26.indd 438
Associated with HIV Infection
Intracerebral bacillary angiomatosis was first recognized in
1990 (62) in a man with AIDS. In 1994, antibody and DNA
amplification evidence of Bartonella infection was reported
in the setting of neurologic manifestations complicating HIV
infection (182), and epidemiologic studies have confirmed an
association between the presence of serum anti-Bartonella anti-
bodies and increased risk of development of neuropsychologic
decline or dementia over 5 years. An estimated 4% of new
cases of HIV-associated dementia or neuropsychologic decline
might be ascribed to Bartonella infections and therefore are
potentially treatable with antibiotics. Subsequent small num-
bers of case reports have added anecdotal evidence suggesting
the potential utility of antimicrobial therapy in reversing
Bartonella-associated neuropsychiatric abnormalities.
Chronic Neurologic and
Neurocognitive Manifestations
A few recent studies, originating mostly from one group of
investigators, reported the detection of various Bartonella
species, including B. henselae, B. vinsonii subsp. berkhoffii,
B. koehlerae, Candidatus B. melophagi, or coinfection with
more than one Bartonella spp. in blood samples, using a novel
enrichment blood culture technique, followed by PCR and
DNA sequencing. Patients were apparently immunocompe-
tent individuals who presented with various chronic neuro-
logic or neurocognitive syndromes, including seizures, ataxia,
memory loss, tremors, fatigue, insomnia, headache, arthralgia,
myalgia, hallucinations, and other symptoms. Many individu-
als had extensive arthropod and animal exposure. It has been
suggested that because the duration of illness in these patients
ranged from months to many years, these Bartonella species
may induce a chronic intravascular, persistent, or relapsing
infection. More studies are needed to evaluate the role of these
pathogens in patients with chronic neurologic and neurocog-
nitive dysfunction (183188).
Infections Caused by Other Species
B. vinsonii subsp. arupensis was isolated from the blood of
a 62-year-old cattle rancher who was admitted to a hospital
with acute onset of confusion, emotional liability, difficulty in
walking, facial numbness, slurred speech, diplopia, headache,
and myalgias. He was discharged 7 days later with a signifi-
cant improvement in neurologic symptoms (189).
A case of meningitis attributed to Bartonella washoensis,
isolated from a patients blood using routine blood culture sys-
tem, was described in a 47-year-old previously healthy woman
with exposure to pet and farm animals. Oropsylla montana
fleas were implicated as the vector for disease transmission in
this case (190).
LABORATORY CONFIRMATION
OF CLINICAL DIAGNOSIS
The laboratory diagnosis of Bartonella-associated diseases can
be achieved through modified conventional bacteriologic cul-
ture methods, co-culture with endothelial cells, immunosero-
logic or immunocytochemical means, or DNA amplification.
These approaches are described in current diagnostic micro-
biology references (191). Serologic testing has become the
2/21/14 5:44 PM
 Chapter 26: Bartonella Infections, Including Cat-Scratch Disease
mainstay of diagnosis, particularly when the involved tissue is
less accessible for biopsy sampling such as CSD patients with
CNS infection. Early lymph node biopsy or fine-needle aspira-
tion (before spontaneous resolution of lymphadenitis occurs)
for histopathology, PCR, and culture should be encouraged
in patients with serious complications such as encephalitis or
neuroretinitis, when CSD is a likely diagnosis and B. henselae
serology is negative or equivocal.
Detection and Identification of the Agent
Bartonella species usually do not grow under the conditions
used for standard bacteriologic cultures. If culture is attempted,
freshly prepared media provide optimal recovery. Heart infu-
sion agar with 5% to 10% defibrinated rabbit or horse blood
supports better growth of most strains than chocolate or 5%
sheep blood agars. Plates sealed after 24 hours of incubation
to preserve moisture content usually can be incubated up to
30 days without notable deterioration. Even when these tech-
niques are strictly applied, recovery of B. henselae from lymph
nodes and other specimens of patients with CSD is extremely
rare. Moderate success in the recovery of isolates has been
achieved using alternate techniques (192,193). The combina-
tion of enrichment culture and PCR amplification may opti-
mally detect Bartonella species with respect to sensitivity and a
clinically relevant time frame, although this approach is gener-
ally not available in the majority of clinical laboratories.
Colonies of Bartonella species are sticky, autoadherent, and
of two morphologic types: (a) irregular, raised, whitish, rough,
and dry appearing or (b) smaller, circular, tan, and moist
appearing. Both types are often present in the same culture.
The degree of colonial heterogeneity varies by species, with
B. henselae typically having a greater proportion of rough colo-
nies than B. quintana. Repeated subcultures cause most strains
of B. henselae to revert to smooth cultures. Gram stain of a col-
ony reveals small, gram-negative, slightly curved rods (which
may mimic Haemophilus, Campylobacter, or Helicobacter),
and a wet mount usually demonstrates twitching motility.
B. bacilliformis and B. clarridgeiae possess flagella, whereas
B. henselae, B. elizabethae, and to lesser extent, B. quintana
have twitching motility believed due to pili. Presumptive identi-
fication of B. henselae or B. quintana can be made on the basis
of these features, plus a lengthy (7-day) period of incubation
before appearance, negative catalase and oxidase reactions,
and absence of acid production from carbohydrates.
Confirmatory identification is usually by referral to a labo-
ratory experienced with Bartonella species. Newer methods
have been applied to identification of Bartonella species in-
cluding mass spectrometry (194), in addition to PCR-based
and DNA hybridization techniques that can be used to dis-
tinguish species and for direct detection in clinical material
(30,31,90,195199). DNA fragments of B. henselae can be
amplified from various clinical specimens including fresh
lymph nodes and other tissues (including brain), CSF, freshly
aspirated pus, minute amounts of tissue obtained from lymph
node fine-needle aspiration, and paraffin-embedded material.
Molecular subtyping of strains can be performed using PCR-
based sequence analysis (15) or restriction fragment length
polymorphism, and repetitive extragenic palindromic PCR.
Serology
Because culture of Bartonella species remains technically dif-
ficult with a low success rate, alternative means of diagnosis
are important. Serology is the most commonly used test for
Scheld_Ch26.indd 439
439
diagnosis, replacing the skin test that was poorly standardized
and carried a potential risk for transmission of infectious agents.
An immunofluorescence assay (IFA) and several enzyme immu-
noassays (EIAs) have been described for B. henselae and B. quin-
tana detection. They have been used primarily to demonstrate
anti-Bartonella antibodies in persons with CSD (28,129,200)
and in some cases of HIV-associated aseptic meningitis, en-
cephalopathy, or neuropsychiatric disease (96,182). The IFA
described by Regnery et al. (28) in 1992 generally performs
well, but it was not designed for detecting immunoglobulin M
(IgM) antibodies. In studies in which this assay was performed
at the U.S. Centers for Disease Control and Prevention, with
reciprocal titers of more than 64 as the cutoff value, both sen-
sitivity (84% to 95%) and specificity (94% to 98%) were high.
It has been less consistent in studies performed in Europe (201).
A high seroprevalence of antiB. henselae immunoglobulin G
(IgG) in Europe due to exposure to nonB. henselae species
may result in inferior performance of the IFA compared with
the United States. EIA studies in some HIV-infected persons
with encephalopathy or neuropsychiatric findings have demon-
strated antibodies reactive with a formalin-fixed whole bacterial
cell antigen preparation of B. henselae but have not satisfacto-
rily demonstrated B. henselae specificity (182). An EIA using
N-lauroyl-sarcosineinsoluble outer membrane antigen from
agar-grown B. henselae to test sera from 84 patients with CSD
defined by PCR (82 patients) or skin test (6 patients) determined
the EIA sensitivity to be 75% for antiB. henselae IgG alone,
48% for IgM alone, and 85% overall when positive IgG, IgM,
or both were accepted as diagnostic. EIA specificity was 98%
(200). The same EIA was used to study antibody kinetics in pa-
tients with CSD. AntiB. henselae IgM remained positive for
3 months or less and its presence indicated acute disease. IgG
titers also declined over time but may last for longer than 2 years.
Serologic cross reactivity is among the limitations of both
IFA and EIA. Neither adequately discriminates between anti
B. henselae and antiB. quintana antibodies. Cross reactivity
has also been demonstrated between Bartonella and others in-
cluding Coxiella burnetii and Chlamydia species. Data regard-
ing the clinical significance of such cross reactivity are limited,
and this represents a potential concern because all of these
microorganisms are causative agents of endocarditis and may
have similar clinical presentations.
Treatment of Bartonella-Related
Neurologic Manifestations
Antibiotic regimens for Bartonella infections have been de-
termined empirically, based on clinical experience, as well as
published case reports and clinical studies, which are mostly
uncontrolled with limited follow-up (202). One of the most
intriguing aspects of nonB. bacilliformis infections is the
clinical observation that antimicrobial therapy seems to have
a much greater impact on immunocompromised patients with
systemic disease (e.g., patients with AIDS with bacteremia
and BA) than on immunocompetent patients with localized
disease (e.g., patients with CSD with regional lymphadenitis).
This perhaps reflects the different pathologic processes in-
volved. The recommended therapy for acute B. bacilliformis
infection, Oroya fever, is either chloramphenicol (0.5 g PO/IV
four times a day for 2 weeks) plus another antibiotic, (prefer-
ably a -lactam), or ciprofloxacin 0.5 g twice a day for 10
days. CNS involvement with impaired consciousness neces-
sitates parenteral therapy. Because of ease of administration,
low cost, and observed clinical effectiveness, the initial ther-
apy of choice for uncomplicated bacteremia and BA caused by
B. henselae or B. quintana in immunocompromised patients
2/21/14 5:44 PM
 440 Part III: Bacterial and Mycoplasmal Infections
is oral erythromycin (e.g., 0.5 g four times a day as stearate).
Other macrolides, doxycycline (100 mg twice daily), or other
tetracyclines may serve as alternatives (67,202,203).
The role of antimicrobial therapy for CSD-associated neu-
roretinitis is controversial. In a small retrospective case series,
doxycycline and rifampin appeared to shorten the course of
disease and hasten visual recovery in seven patients with CSD
neuroretinitis compared to historic cases. The demonstration
of B. henselae bacteremia associated with neuroretinitis adds
weight to the argument for treatment with antibiotics (96,160).
There is no definite evidence of the utility of antibiotic therapy
in shortening or altering the course of CSD encephalopathy.
However, because of anecdotal reports of apparent efficacy
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2/21/14 5:44 PM
 CHAPTER 27 RICKETTSIOSES, ANAPLASMOSES,
AND Q FEVER
DIDIER RAOULT

Bacteria in the order Rickettsiales are gram-negative micro-
organisms that grow in association with eukaryotic cells. They
do not grow in axenic media but require living hosts such as
cell cultures, embryonated eggs, or susceptible animals. With
the exception of Rickettsia prowazekii, the agent of epidemic
typhus, and possibly Rickettsia felis in sub-Saharan Africa,
these bacteria infect humans incidentally as zoonoses. On the
basis of molecular phylogeny, the bacteria causing rickettsial
diseases have been reclassified (Table 27.1). Rickettsioses are
emerging infectious diseases, with many new rickettsial dis-
eases having been described in the past 15 years. Rickettsioses
can be grouped as follows: Q fever, ehrlichioses, and diseases
caused by Rickettsia and Orientia species.
The genus Rickettsia is subdivided into the typhus group,
containing Rickettsia typhi and R. prowazekii, and the spotted
fever group (SFG) that includes 24 species of organisms patho-
genic for humans (Table 27.1). Rickettsiae are associated with
arthropods. They are mainly transmitted to humans by bites
from infected arthropods, but infections from aerosols of infected
insect feces and blood transfusions have also been described
(1). Ixodid or hard ticks are the vectors of SFG rickettsiae and
have a specific geographic distribution. Mites are the vectors
of Rickettsia akari (worldwide) and Orientia tsutsugamushi
(linked to Asia), lice are the vectors of R. prowazekii, and fleas
are the vectors of R. typhi and perhaps mosquitoes for Rickettsia
felis (2) (Table 27.2).
The main clinical signs and symptoms of rickettsioses include
fever, headache, a rash that is maculopapular or sometimes pete-
chial or vesicular, inoculation eschars at the site of the arthropod
bite, and local lymphadenopathies. Neurologic involvement is

TA B L E 2 7 . 1
GENETIC CLASSIFICATION OF RICKETTSIAE PATHOGENIC FOR HUMANS

Genus Group Species Serotype

Alpha proteobacteria
Rickettsiaceae Rickettsia Typhus R. prowazekii
R. typhi
Spotted fever R. conorii Malish
Isral
Astrakhan
Indian
R. rickettsii
R. sibirica
R. mongolotimonae
R. slovaca
R. honei
R. japonica
R. heilongjianghensis
R. aeschlimannii
R. helvetica
R. australis
R. felis
R. akari
R. parkeri
R. africae
R. raoultii
R. philipii (364D)
R. massiliae
Orientia Scrub typhus O. tsutsugamushi
Anaplasmataceae Ehrlichia E. chaffeensis
E. ewingii
Ehrlichia sp. Wisconsin
Anaplasma A. phagocytophilum
Neorickettsia N. sennetsu
Wolbachia W. pipientis
Gamma proteobacteria
Coxiella C. burnetii

444

Scheld_Ch27.indd 444 2/21/14 6:58 PM

 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever 445

TA B L E 2 7 . 2
SPOTTED FEVERS

Year of
Regional Micro-
Arthropod Eschar Lymph High Fatality organism
Disease Organism Host Geographic Area Rash Tche Noire Node Fever Rate Isolation

Rocky Mountain R. rickettsii Dermacentor America (north, Yes, may be Very rare No Yes High 1919
spotted fever andersoni, central, and purpuric
Dermacentor south)
variabilis,
Amblyomma
cajennense
Mediterranean R. conorii Rhipicephalus Mediterranean, Yes, papular, Common No Yes Moderate 1932
spotted fever, sanguineus Africa, Asia may be
Kenya tick purpuric
typhus
Siberian tick R. sibirica Dermacentor Siberia, China Yes Common No Yes Low 1946
typhus nuttalli
Rickettsial pox R. akari Liponyssoides Worldwide Yes Common Yes Yes Low 1946
sanguineus vesicular
Queensland tick R. australis Ixodes Eastern Yes, may be Common ? Yes Moderate 1950
typhus holocyclus Australia vesicular
Israel spotted R. conorii idem R. Isral, south Yes Rare No Yes Low 1974
fever serotype conorii Europe
israel
Flinders Island R. honei Ixodes Flinders Island, Yes Common Yes Yes Low 1991
spotted fever granulosus Eastern
Australia,
Thailand
Astrakhan R. conorii R. pusillus Caspian sea, Yes Rare No Yes Low 1991
fever serotype Balkans
astrakhan
Japanese R. japonica Ixodes ricinus Japan (China ?) Yes Common No Yes Low 1992
spotted fever
African tick- R. africae Amblyomma Sub-Saharan, Yes (half of Frequently Yes No Low 1992
bite fever hebraum, Africa, cases); multiple
Amblyomma West Indies may be
variegatum vesicular
Lymphangitis- R. sibirica Hyalomma Mongolia, Africa, Yes Common Yes Yes Low 1996
associated mongolotimo- species, Mediterranean
rickettsiosis nae Rhipicephalus area
pusillus
Scalp eschar R. slovaca Dermacentor Europe, Pakistan Very rare May be Yes, No Low 1997
and neck R. raoultii marginatus, Europe, Asia, erythem- painful Unknown 1999
lymphadenop- Dermacentor North Africa atous
athy (SENLAT), reticularis
tick-borne
lymphadenop-
athy (TIBOLA)
Chinese spotted R. heilonji- China Yes Common No Yes ? 1998
fever anghensis
Unnamed R. helvetica Ixodes ricinus Europe, Asia No, Yes No No Sudden 2000
erythema death
Flea-borne R. felis Ctenocephalides Worldwide Sometimes Sometimes Unknown Yes Unknown 2001
spotted fever felis
Unnamed R. aeschlimannii Hyaloma Africa Yes Yes Yes Yes Unknown 2002
marginatum
Indian tick typhus R. conorii Rhipicephalus India Yes Yes No Yes ? 2002
serotype
Indian

(continued)

Scheld_Ch27.indd 445 2/21/14 6:58 PM

 446 Part III: Bacterial and Mycoplasmal Infection

TA B L E 2 7 . 2
SPOTTED FEVERS (CONTINUED)

Year of
Regional Micro-
Arthropod Eschar Lymph Fatality organism
Disease Organism Host Geographic Area Rash Tche Noire Node High Fever Rate Isolation

American R. parkeri Amblyomma North, Central, Yes Common Yes Low to Unknown 1939
boutonneuse maculatum, and South moderate
fever Amblyomma America
triste

Spotted fever R. massiliae Rhipicephalus North and South Yes Common No Yes Unknown 1992
species America,
Europe, North
and sub-Saharan
Africa
Spotted fever R. philipii Dermacentor North America No Yes Yes Yes Unknown 1975
364 D occidentalis

mainly associated with severe forms of disease where it is part
of a multiple organ dysfunction syndrome (MODS). The main
pathologic mechanism in rickettsioses is a vasculitis following
infection of the vascular endothelial cells (Fig. 27.1). Apart from
the known pathogens, many other rickettsial strains have been
found in arthropods, in particular ticks (1), but their roles as
human pathogens have yet to be determined.
The first name given to a rickettsial disease, typhus, is in-
dicative of central nervous system (CNS) involvement because
it derives from (typhos) meaning cerebral confusion.
Rickettsioses are seasonal and the arthropod host determines
their epidemiology and geographic distribution. Rickettsia
species were divided into three taxonomic groups:
The typhus group comprises R. typhi, the agent of flea-
borne, murine typhus, and R. prowazekii causing louse-
borne epidemic typhus, Brill-Zinsser disease, and American
sylvatic typhus linked to flying squirrels.
The SFG rickettsiae, which cause tick-transmitted diseases
such as Rocky Mountain spotted fever (RMSF) (caused by
R. rickettsii), Mediterranean spotted fever (MSF) (Rickettsia
conorii), and African tick-bite fever (Rickettsia africae);

FIGURE 27.1 Rickettsia rickettsii in a human

endothelial cell. Five rickettsiae are present, vis-
ible as electron-dense structures surrounded by
a capsular halo in the peripheral cytoplasm, at
1-, 6-, 8-, 11-, and 12-oclock positions. Note
that the rickettsia at the 1-oclock position is
clearly a rod-shaped bacterium with a cell wall.
Electron microscope; magnification 11,400.
(Courtesy Dr. D. Silverman, Department of
Microbiology and Immunology, University of
Maryland at Baltimore.)

Scheld_Ch27.indd 446 2/21/14 6:58 PM

 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever
TA B L E 2 7 . 3
TRANSMISSION OF RICKETTSIAL DISEASES
Tick borne (tick is both vector and reservoir)
Transmitted through tick saliva after tick bite (depending
on prevalence of local tick):
R. rickettsii, R. conorii, R. sibirica, R. africae
R. australis, R. honei, R. slovaca, R. mongolotimonae
R. aeschlimannii, R. japonica, R. heilongjianghensis,
R. parkeri? R. philipii (364D)? etc.
Mite borne (mite is both vector and reservoir)
Transmitted through mite bite:
R. akari (mouse mite)
O. tsutsugamushi (chiggers)
Flea borne (flea is both vector and reservoir)
Transmitted through flea feces by autoinoculation or by
aerosol:
R. felis (cat fleas)
R. typhi (rat fleas)
Louse borne (louse is only vector)
Transmitted through infected feces by autoinoculation or
by aerosol:
R. prowazekii
a mite transmitted disease, rickettsialpox (R. akari); and a
spotted fever caused by R. felis that may be transmitted by
fleas or mosquitoes (Tables 27.2 and 27.3).
The scrub typhus group includes O. tsutsugamushi, a mite
(chigger)-borne disease.
Coxiella burnetii, the agent of Q fever, belongs to the
-Proteobacteria phylum. It causes a zoonosis in many
mammal species, including domestic animals and wild un-
gulates, and is excreted in birth products and milk. Humans
are usually infected by aerosols and may develop an acute
primary infection eventually followed by a chronic disease
when predisposing factors are present. Many acute infec-
tions cause neurologic signs; meningitis, meningoencephali-
tis, and Guillain-Barr syndrome have been associated with
C. burnetii.
Ehrlichioses and anaplasmoses are zoonoses (3). Ehrlichia
species grow in blood cells in a cytoplasmic vacuole, forming
clusters or morulae. The bacteria in this large group are in-
creasingly recognized as potential human pathogens, and their
current taxonomy has been changed recently to match current
phylogenic knowledge. Four genera are described, as follows:
One apparently associated with a helminth vector and named
Neorickettsia contains only one human pathogen recognized
in Japan and Laos (Neorickettsia sennetsu); two are trans-
mitted by ticks, Ehrlichia (including the three human patho-
gens, Ehrlichia chaffeensis, Ehrlichia ewingii, and Ehrlichia
sp. Wisconsin) and Anaplasma (with Anaplasma phagocyto-
philum being the only currently identified human pathogen).
The fourth genus, Wolbachia, has one recognized species,
Wolbachia pipientis, which could be associated with arthro-
pods or nematodes. When associated with filaria, in human
filariasis, it appears to be a pathogenic factor and a treatment
target. The two most common ehrlichioses, the human mono-
cytic ehrlichiosis (HME) caused by E. chaffeensis and human
granulocytic anaplasmosis (HGA) caused by A. phagocyto-
philum may cause neurologic pathology such as meningitis or
meningoencephalitis.
Scheld_Ch27.indd 447
447
RICKETTSIOSES
Historical Background and
Emerging Rickettsioses
Epidemic typhus was differentiated from typhoid in the six-
teenth century (4) because of the existence of a rash in the rick-
ettsial disease. Some authors suspected an American origin for
typhus because of the American sylvatic flying squirrel reservoir.
At the beginning of the twentieth century, Ch Nicolle proved
the role of lice in typhus transmission, and Ricketts (5) proved
that the wood tick, Dermacentor andersoni, was involved in
the transmission of RMSF in Montana. In the Old World in
1910, Conor reported the first cases of MSF in Tunis. The role
of Rhipicephalus sanguineus was established in 1930 (2).
Recently, several new tick-borne diseases have been identi-
fied. Of the rickettsial diseases, only five that are transmitted by
ticks were known before 1991 (1), and subsequently, many new
diseases have been reported, including Astrakhan (6); Flinders
Island spotted fever (7); African tick-bite fever (8); Japanese
spotted fever (9); American Boutonneuse Fever (Rickettsia
parkeri); and, in Europe, infections caused by Rickettsia sibirica
mongolotimonae (10), Rickettsia slovaca (11), Rickettsia raoul-
tii, Rickettsia helvetica (12), and Rickettsia aeschlimannii (13)
(Table 27.2).
New rickettsial species have frequently been found when
arthropod vectors have been studied, that is, ticks, mites, or
insects (fleas, lice, etc.). For example, C. burnetii, R. africae,
R. conorii caspia, R. felis, R. sibirica mongolotimonae, R.
slovaca, R. helvetica, and R. aeschlimannii were first isolated
from arthropods and later from people.
Recently, new diseases have been discovered using combina-
tions of isolation, serologic testing, and polymerase chain reac-
tion (PCR) amplification. However, to definitively establish a
disease, one should obtain an isolate of the presumptive agent
from clinical patients. When this is not possible, an association
of serology, immunologic detection of antigens in tissues, and
PCR amplification of two different target genes may be used
to establish an etiologic relationship between a disease and an
organism. Morphologic recognition of rickettsia-like bodies
by electron microscopy is of little value (14). Microorganisms
found in ticks (15) should be suspected of being human patho-
gens, because isolates of unknown pathogenicity have errone-
ously been considered nonpathogenic for years (1).
Diseases
Rocky Mountain Spotted Fever
Epidemiology. RMSF is the most severe of the rickettsioses.
It is caused by R. rickettsii and is currently the main tick-
transmitted rickettsiosis recognized in America along with R.
parkeri (with R. africae in West Indies). It was described first
in the nineteenth century in the Western United States but is
now known to be prevalent in 44 states in the United States
and in Central and South America (Brazil, Argentina, Costa
Rica, Columbia, and Mexico).
The main tick vectors are Dermacentor andersoni (the
Rocky Mountain spotted wood tick) in Western United
States and Dermacentor variabilis (the American dog tick) in
the East, the Midwest, and the South. In Central and South
America, Amblyomma cajennense is the major identified vector.
The duration of attachment is critical for infections, and trans-
mission is unlikely when the tick feeds for less than 20 hours.
2/21/14 6:58 PM
 448 Part III: Bacterial and Mycoplasmal Infection

The tick bite is painless and frequently goes unnoticed. The epi- TA B L E 2 7 . 5
demiology of RMSF undergoes yearly variations that are largely
unexplained but probably mainly due to variations in tick activ- DIFFERENTIAL DIAGNOSIS OF ROCKY MOUNTAIN
ity and human encounters with ticks. There are 500 to 1,000 SPOTTED FEVER
cases annually in the United States, with 90% reported from
April to September, during late spring and summer. The disease With a rash
is relatively more prevalent in children younger than 10 years. Measles
Rubeola
Clinical Manifestations. The incubation period of RMSF Adenovirus
ranges from 2 to 14 days. Initially, patients have a sudden onset Coxsackie virus
of fever and headache, nonspecific signs with a broad list of Dengue
possible differential diagnoses. This has led to the recommenda- HIV infection
tion that in areas endemic for RMSF, primary care physicians Infectious mononucleosis
should treat individuals presenting with unexplained fever, with Mycoplasma pneumoniae
or without other manifestations of RMSF, as if they had the Disseminated Neisseria gonorrhoeae infection
disease (16,17). A rash usually appears 3 to 5 days after the Staphylococcus aureus
onset of symptoms but is not seen in 10% of patients, especially Streptococcus pyogenes
in dark-skinned patients. It is diffuse and involves palms and Treponema pallidum (especially in patients with AIDS)
soles; it is maculopapular and can be purpuric. Skin necrosis or Purpura fulminans (Meningococci, Haemophilus,
gangrene involving the digits or limbs may be observed in severe Pneumococci, Capnocytophaga canimorsus or various
cases (18). Renal failure is common in severe cases (19) and is Babesia sp. in splenectomized patients)
related to acute tubular necrosis or hypovolemia. Pulmonary With central nervous system involvement
manifestations of RMSF range from cough to respiratory dis- Meningitis
tress from pulmonary edema. Retinal abnormalities seen on Enteroviruses
funduscopic examination include venous engorgement, retinal Meningococci
edema, hemorrhages, papilledema, and arterial occlusion. HIV
Abnormalities in routine laboratory screens are nonspe- Mumps
cific; the white blood cell (WBC) count is generally normal, Pneumococci
anemia is uncommon, but thrombocytopenia is observed in Leptospirosis
one third to one half of patients. Hyponatremia and eleva- Listeriosis
tions in serum transaminases (e.g., aspartate aminotransferase Lyme disease
[AST]) occur commonly. Encephalitis and meningoencephalitis
Analysis of fatal cases of RMSF has shown that older age, Eastern or western equine encephalitis
hospitalization, and lack of treatment or treatment with chlor- St. Louis encephalitis
amphenicol are significantly correlated with death. Treatment West Nile virus
with tetracyclines, however, lowered the mortality rate (20). Japanese encephalitis
Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is a Other viral encephalitidies (e.g., Nipah, Hendra) etc.
risk factor for fulminant disease (21). Herpes simplex virus
Cytomegalovirus (in patients with AIDS)
Neurologic Involvement. The frequency and the severity of Q fever
neurologic abnormalities depend on the severity of the illness Leptospirosis
(22). Neurologic complications are often the cause of death. Any multiorgan dysfunction syndrome
Headache is often severe and diffuse or bifrontal (2328) Toxic shock syndrome
(Table 27.4). In one study, 23% of patients had serious CNS S. pyogenes

TA B L E 2 7 . 4
NEUROLOGIC FINDINGS IN ROCKY MOUNTAIN complications, including stupor, seizures, delirium, ataxia,
SPOTTED FEVER focal neurologic deficits, papilledema, and coma (19). Coma
is more likely to occur in fatal cases (28). Cranial and periph-
Finding Occurrence
eral nerve abnormalities can occur, with hearing loss being the
most common. Neck stiffness, which is common, is usually
Headache 80%
related to neck muscle myalgia. The incidence of meningeal
Stupor 20% signs is about 20% and a diagnosis of bacterial or viral men-
Meningismus 20% ingitis is often considered (27) (Table 27.5). It was found that
Neck stiffness 20% 21 (66%) of 32 patients with RMSF who had undergone a
lumbar puncture had abnormalities of the cerebrospinal fluid
Ataxia 10%20%
(CSF) and abnormal CSF findings have now been documented
Coma 10%20% in 63 patients (19). There was a pleocytosis in 38%, the pro-
Seizures 10% tein concentration was increased in 35%, and there was a
Decreased hearing 10% moderate decrease in glucose concentration in 8%. The WBC
count in the CSF is rarely more than 100 cells/mm3. Usually
Meningitis 10%
lymphocytes predominate.
Focal neurologic signs 2% A wide variety of focal neurologic deficits have been described
Papilledema 2% including cranial nerve palsies, aphasia, and ataxia, hemiplegia,
complete paralysis, spasticity, and neurogenic bladder (29).

Scheld_Ch27.indd 448 2/21/14 6:58 PM

 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever
FIGURE 27.2 Cerebral petechiae in RMSF. These lesions are com-
monly found in the gray matter, but in this specimen, they are promi-
nent in the white matter. (From Binford CH, Connor DH. Pathology
of Tropical and Extraordinary Diseases. Washington, DC: Armed
Forces Institute of Pathology; 1976, with permission.)
Patients with encephalitis may have Rocky Mountain spotless
fever (30) and two patients have been described who developed
a rash only after a brain biopsy was obtained (22). Therefore,
in endemic areas, doxycycline may be added to acyclovir in the
treatment of encephalitis. There is very little information on
computed tomography (CT) findings in RMSF, but low-density
areas and edema have been described (29). The electroencepha-
logram (EEG) usually shows diffuse cortical dysfunction, espe-
cially in comatose patients (19).
The gross pathologic findings in RMSF involving the CNS
include edema and hemorrhage (Fig. 27.2). Microscopically,
perivascular accumulations of inflammatory cells, glial nod-
ules, and arteriolar thrombonecrosis with small infarcts have
been seen. Microorganisms are readily demonstrated in the
endothelial cells of blood vessels using either immunofluores-
cence (31) or immunoperoxidase techniques (Fig. 27.3).
Residual neurologic deficits are common following RMSF.
They include learning disabilities, deafness, behavioral distur-
bance, depression, transverse myelitis, aphasia, and impair-
ment of fine motor skills (20,3235). It was reported in one
series that 1 to 8 years after recovery, 57% of patients had
neurologic abnormalities, including headaches, mild defects in
intellectual functioning, and EEG abnormalities (34).
In America, it was believed that RMSF for decades was the
only tick-borne rickettsiosis, but a discrepancy appears in the
increasing number of reported cases and a lowering fatality
rate (35). Because several tick-borne SF were identified such as
R. parkeri that causes a mild disease with an inoculation eschar
Scheld_Ch27.indd 449
449
FIGURE 27.4 Plantar rash in a patient with Mediterranean spotted fever.
and a rash, R. massiliae infecting Rhipicephalus ticks has been
found to cause spotted fever in Europe, R. amblyommii has
been linked to fever and rash in Southeastern United States,
and a spotted fever with inoculation eschar in California was
linked to a new rickettsia (Rickettsia philipii 364D). Finally,
R. africae is prevalent in West Indies and reported in American
travelers to Africa. However, these diseases are generally mild
with rare involvement of the CNS.
Other Tick-Borne Rickettsioses
Tick-transmitted rickettsioses have limited geographic distri-
butions that are determined by their tick vectors. In Europe,
MSF is caused by R. conorii and is also known as bouton-
neuse fever, Marseilles fever, Astrakhan fever, Israeli spotted
fever, Indian tick typhus, or Kenyan tick typhus. It resembles
RMSF but has specific features. The disease is milder, but a
fatality rate of 1.5% to 2.5% of hospitalized patients is still
found. A malignant form of the disease with purpuric rash,
shock, and MODS has been described in alcoholic, diabetic,
human immunodeficiency virus (HIV)infected, and old, or
debilitated patients. The typical clinical presentation is that
of a patient with fever, a rash (which may involve the palms
and soles [Fig. 27.4]), and a tche noire, that is, a black es-
char at the site of the tick bites. The tche noire is found in
50% to 80% of patients. The rash is often papular, which led
to one of the names of the disease (boutonneuse fever). Israel
tick-bite fever and Astrakhan fever appear milder than typical
MSF, and a tche noire is often lacking.
R. slovaca and R. raoultii causes a newly described dis-
ease that appears to be common in Europe. The tick vectors,
FIGURE 27.3 A characteristic endovasculitic lesion from the
skin of a patient with RMSF, showing mononuclear infiltration
of the blood vessel wall with hemorrhage and thrombus forma-
tion. Similar lesions are found throughout the body, including the
brain. (From Walker DH. Rickettsial and chlamydial diseases.
In: Kissane JM, ed. Andersons Pathology. 9th ed. St. Louis: CV
Mosby; 1990:348361, with permission.)
2/21/14 6:58 PM
 450 Part III: Bacterial and Mycoplasmal Infection
Dermacentor marginatus and Dermacentor reticulatus, feed
mainly in the cold months and tend to attach on the scalp of
people, preferring haired sites. The disease is more prevalent in
children and women, contrary to other tick-borne rickettsio-
ses. It is rarely exanthematic, with the typical clinical picture
including an erythematous skin lesion ranging from 2 to 8 cm
in diameter at the site of the tick bite on the scalp and regional
lymphadenopathy (which may be painful). Rarely, patients
have fever and a rash, and a deep postinfectious asthenia and
residual alopecia at the site of the tick bite can be observed.
A case of meningoencephalitis has been reported. The occur-
rence of this rickettsiosis without rash may stimulate research
on other new rickettsial diseases with only localized manifesta-
tions (36). This disease has been named successively TIBOLA
(for tick-borne disease), DEBONEL (for Dermacentor-borne
eschar and lymphadenopathy) and SENLAT (scalp eschar and
neck lymphadenopathy after tick bite) (36a).
In Africa, African tick-bite fever may be the most com-
mon tick-borne rickettsiosis worldwide. It is due to R. africae,
which is transmitted by African ticks, Amblyomma hebraeum,
and Amblyomma variegatum. They usually feed on ungulates
but also feed readily on human beings and cause a high preva-
lence of infection in rural Africa (60% of tested patients ex-
hibit antibodies) and in travelers. More than 50% of patients
have more than one tche noire (Fig. 27.5), which are
most often on the lower limbs and are often associated with
regional lymphadenopathy in the groin. The disease differs
from the other milder rickettsioses in that fever is frequently
absent; a rash is present in only half of the patients with the
disease; and the rash may be vesicular (which has never been
FIGURE 27.5 Inoculation eschar in a patient with African tick-bite fever.
Scheld_Ch27.indd 450
reported in confirmed MSF) in half of the cases. An aphthous
stomatitis can be associated with the disease. In Asia, Japanese
spotted fever (caused by Rickettsia japonica), Siberian tick
typhus (caused by Rickettsia sibirica), and infections caused
by R. mongolotimonae comprise commonly and ropelike lym-
phangitis between the inoculation eschar and a lymph node.
Rickettsia australis (Queensland tick typhus) and Rickettsia
honei (Flinders Island spotted fever) cause diseases resembling
MSF, but their rash can be vesicular. The neurologic involve-
ment of the other tick-borne spotted fevers is comparable
to that of RMSF. MSF has been associated with meningitis,
meningoencephalitis, deafness, stupor, and coma (often with
MODS) (37). Meningoencephalitis was reported in two pa-
tients with Japanese spotted fever (38).
The spotted fever caused by R. felis is a new incompletely
defined disease. The bacterium is found in fleas in the United
States, Peru, Europe, and Africa and in mosquitoes in Africa.
It has been grown only recently (39,40). Seven cases have been
reported from Texas, Mexico, Brazil, France, and Germany.
All had fever, six of seven had a rash, and an inoculation es-
char was present in some patients (39,41). A diagnosis can
be based on serology using specific R. felis antigen or PCR
of blood or skin biopsies. The most effective treatment has
not been established, but the bacterium is highly susceptible
to doxycycline (42). Recently, it was reported commonly
associated with fever in Kenya and Senegal where malaria is
endemic, causing as much as 6% of fevers (2a). The infection
in children in Africa consists of fever and vesicular rash and
was named Yaaf (42a).
Rickettsialpox (Rickettsia akari)
Rickettsialpox was first described in New York City, where it is
still prevalent (43). The recent terrorism events (of September
11, 2001) have led physicians to pay increased attention to skin
eschars (as might be seen with anthrax) and vesicular rashes
(which might be seen with smallpox), and this has led to an
increase in the cases of rickettsialpox diagnosed in New York
City between 2001 and 2002 (44). R. akari, the causal agent,
is an SFG rickettsia transmitted by the bite of the mouse mite
(Liponyssoides sanguineus). Serologically, it cross-reacts with
other SFG rickettsia. The prevalence of infections is probably
underestimated, although cases have also been reported from
Arizona, Utah, and Ohio and a high seroprevalence was found
in intravenous drug users in Baltimore. Cases have also been
diagnosed in Russia, Ukraine, Slovenia, and Korea (1). Ten
days after the mite bite, the beginning of the illness is marked
by fever, headache, and myalgia. A careful examination will
reveal an inoculation eschar and regional lymphadenopathy.
Two to six days later, a rash appears consisting of 5 to 40
macular then papular to vesicular (or even pustular) lesions.
The name of the disease was derived from the latter, and it is
often mistaken for chickenpox. The disease is usually mild (1).
Epidemic Typhus
Typhus is transmitted by the human body louse, which lives
in clothes and multiplies rapidly when cold weather and lack
of hygiene allow it to. Its prevalence reflects the low socio-
economic status of certain members of a society (45) and
rises during war, in poor countries in refugee camps, and
in homeless people in rich countries, including the United
States and Europe. Recent reports of cases have been made in
Burundi (46), Rwanda, Russia, Peru, the United States, and
Algeria (47).
Humans are the reservoirs of R. prowazekii and lice are
the vectors. They are infected by ingesting R. prowazekii in a
blood meal. The organism multiplies in the gut and is released
2/21/14 6:58 PM
 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever 451

in feces (48), where R. prowazekii can survive for weeks.

Patients are infected by aerosols or by inoculation of infected
feces into the skin during scratching. Patients who recover
from typhus may have latent infections and relapse years later
with stress. The relapsing form is named Brill-Zinsser disease
and is associated with bacteremia that might lead to lice be-
coming infected and the start of a new outbreak (1). In the
United States, the eastern flying squirrel (Glaucomys volans)
and its fleas, lice, and mites can be infected. They constitute a
sylvatic reservoir and generate cases of domestic typhus (49).
Typhus begins abruptly with fever, headache, and myalgias.
Coughing is also common, as is neurologic involvement, ev-
idenced by stupor, confusion, or coma (Figs. 27.6 to 27.8).
A rash is observed in 20% to 80% of patients but may be
difficult to observe in dark-skinned people. It usually starts
in the axilla and then spreads. It is usually macular but may
be purpuric in severe cases. Diarrhea and jaundice are often
reported. Splenomegaly is found only infrequently. In severe
cases, shock is observed and the spontaneous fatality rate is
20% to 30%. Abnormal laboratory results might include leu-
kopenia, thrombocytopenia, anemia, and increased serum he-
patic enzymes. The disease should be considered in patients
with high fever and confusion and in patients exposed to lice.
In tropical countries, epidemic typhus might be confused with
typhoid, malaria (50), hemorrhagic fevers, and dengue. This
could have fatal consequences because the prescribed treat-
ments for typhoid (-lactams, co-trimoxazole, and quino-
lones) are ineffective in typhus. In people with lice, it can be
confused with trench fever and relapsing fever, in which the FIGURE 27.7 Illustration of a typhus nodule of the cerebral cortex in
same treatment can be prescribed (46). a patient with epidemic typhus. Note the proliferative character of the
Brill-Zinsser disease is the late relapsing form of typhus that is lesion and the absence of necrosis. (rom Wolbach SB, Todd JL, Palfrey
frequently undiagnosed as a rash and recent exposure to lice are FW. The Etiology and Pathology of Typhus. Cambridge, MA: The
Belknap Press of Harvard University Press; 1922. Copyright 1922
commonly not present (51). Interviewing the patient may reveal
by the President and Fellows of Harvard College.)
previous exposure to lice, associated, or not, with a previous
diagnosis of typhus. The disease is mild and the prognosis is good.
Sylvatic typhus in the United States is caused by an R. Murine Typhus
prowazekii variant and is a milder disease. The most promi-
Murine typhus is associated with rat and opossum fleas.
nent clinical features are neurologic, with meningitis being the
Humans are infected when contaminated flea feces are in-
clinical manifestation (49). Few cases have been described and
oculated into the skin during scratching at the sites of flea
nearly all occurred in areas east of the Mississippi, where the
bites. The disease is more prevalent in hot and humid areas,
eastern flying squirrel is found. In these areas, cases may be
specifically when rats proliferate. In the United States, 50 to
observed in winter and sylvatic typhus should be considered in
100 cases are reported yearly, mainly in southern California
patients with a rash.
and southern Texas. Recently, cases have been described in
Mexico, Indonesia, Southern Europe, and Africa (52,53).
The incubation period ranges from 8 to 16 days. The dis-
ease begins abruptly with fever, myalgias, arthralgias, nausea,
vomiting, and headache. A discrete rash is observed in 40% to
50% of patients, on average, 6 days after the onset of signs. It
is detected less often in dark-skinned patients. The rash usu-
ally consists of pink macules but may become maculopapular
(54). It begins in the axilla and generalizes to the trunk but
usually does not involve the face, palms, and soles. It can be-
come purpuric in severe cases. One third of patients have a
cough and one fourth of the patients have nonspecific intersti-
tial pneumonia sometimes associated with pleural effusion. In
severe forms, respiratory distress might require intubation and
artificial ventilation. Neurologic symptoms range from confu-
sion and stupor to coma and seizures in severe forms. Cerebral
hemorrhages may occur. Digestive involvement can manifest
as vomiting, abdominal pain, jaundice, and in severe cases,
hematemesis (52,55).
Laboratory abnormalities include leukopenia, which may
FIGURE 27.6 A hemorrhagic lesion in the superficial cerebral cortex
in a patient with epidemic typhus. Macrophages have ingested ex-
be followed by leukocytosis. There might also be thrombo-
travasated red blood cells. (From Wolbach SB, Todd JL, Palfrey FW. cytopenia and anemia, especially when hemolysis is observed
The Etiology and Pathology of Typhus. Cambridge, MA: The Belknap (often in patients with G6PD deficiency). A moderate increase
Press of Harvard University Press; 1922. Copyright 1922 by the in serum liver enzymes is common. In patients with severe dis-
President and Fellows of Harvard College.) ease, hyponatremia and hypoalbuminemia are observed.

Scheld_Ch27.indd 451 2/21/14 6:58 PM

 452 Part III: Bacterial and Mycoplasmal Infection
The prognosis is usually favorable, but 10% of pa-
tients require intensive care and 1% die. The neurologic
complications of murine typhus usually manifest during
the second week of illness (56). Aseptic meningitis occurs
in 2% to 5% of patients (56). Meningoencephalitis, which
is rare, occurs in older patients. Such patients usually have
seizures. Papilledema rarely occurs (57). The CSF WBC
count rarely exceeds 150 cells/mm3 and mononuclear cells
predominate (56).
Scrub Typhus (Orientia tsutsugamushi)
Scrub typhus is transmitted by the bite of trombiculid mite
larvae infected by O. tsutsugamushi. It is prevalent in a tri-
angle extending between northern Japan, eastern Australia,
and eastern Russia, and including the Far East, China, and
the Indian subcontinent. Altogether, 1 billion people may be
exposed. Seasonality is determined by emergence of larvae. In
temperate zones, it occurs mainly in autumn and to a lesser
extent in spring. O. tsutsugamushi species have a wide hetero-
genicity. The more common serotypes are Kato, Karp, Gilliam,
and Kawasaki (58).
The incubation period in rural or urban scrub typhus is
10 days or more. The onset of signs is usually sudden and
associated with fever, headache, and myalgias. With care-
ful examination, an inoculation eschar may be found at the
site of the mite bite and draining lymph nodes may be ten-
der. Generalized lymphadenopathies and rash may be ob-
served. The symptoms vary according to organ involvement.
Neuromeningeal symptoms are relatively common. Severe
forms can occur, associated with septic shock.
The fatality rate in untreated patients is 6% to 10%. In
a study of scrub typhus in Thailand, 9 (13%) of 72 patients
presented with meningitis or encephalitis syndromes, or both
(59). One of the nine had cerebellitis and another had papill-
edema (59). Focal neurologic signs may predominate (60). The
CSF contains mainly mononuclear WBCs (59). Laboratory
abnormalities may include leukopenia, thrombocytopenia,
and increased levels of hepatic enzymes. Interestingly, scrub
Scheld_Ch27.indd 452
FIGURE 27.8 Two examples of typhus nodules in
the gray matter of a patient with epidemic typhus.
Such lesions typically show marked inflammatory
reaction with infiltrating macrophages and lympho-
cytes. (From Ash JE, Spitz S. Pathology of Tropical
Diseases. Philadelphia: WB Saunders; 1945, with
permission.)
typhus is not more severe in HIV-infected patients and an
HIV-suppressive factor appears to be produced during infec-
tion. Relapses of the disease may occur (61,62). Diagnosis
may be difficult because the clinical presentation is often
nonspecific and identifying epidemiologic factors is criti-
cal. Infectious mononucleosis is commonly confused with
scrub typhus.
Diagnostics
Serology
Serologic assays are the simplest diagnostic tests to perform
(Table 27.6). The Weil-Felix test was the first to be used and
involves antigens from three Proteus strains: Proteus vulgaris
OX-2, P. vulgaris OX-19, and Proteus mirabilis OXK. It was
used widely to detect rickettsioses based on serologic cross re-
actions (63), but the test lacks sensitivity and specificity.
Today, the most commonly used serologic test is microim-
munofluorescence (MIF). It is reliable but does not allow dif-
ferentiation of infections within the different SFG rickettsiae
(64,65). The Western blot immunoassay (63) can be used to
differentiate between infections with the various SFG rick-
ettsiae, provided that acute-phase serum samples are used.
The test detects two types of antigens, high-molecular-weight
outer membrane protein (rOmpA and rOmpB) and lipo-
polysaccharide-like antigen. The proteins are species specific
(63,66) and provide the basis for rickettsial serotyping (67).
If serum samples are collected very early in infection, strong
homologous reactions are often observed, making a spe-
cific diagnosis possible (68). However, because such serum
samples are not always available, more specific methods are
needed. Cross-absorption studies are useful, especially if com-
plemented by Western blotting (68). This is particularly the
case with typhus, in which in 50% of patients, serum samples
have the identical antibody titers to both R. prowazekii and
R. typhi (69).
2/21/14 6:58 PM
 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever 453

TA B L E 2 7 . 6
DIAGNOSTIC TESTS FOR RICKETTSIAL DISEASES

Smears Serology Immunodetection PCR Culture Xenodiagnosis

Rickettsioses
RMSF (R. rickettsii) NA MIF (cross reaction Yes (skin biopsy) Yes (skin) Yes Tick by PCR
with other MSF)
MSF (R. conorii) NA MIF (cross reaction Yes (skin biopsy) Yes (skin) Yes Tick by PCR
with other MSF)
R. africae NA MIF (often late) Yes (skin biopsy) Yes (skin, blood) Yes Tick by PCR
R. slovaca NA MIF (often negative) NA Yes (skin, Yes (blood) Tick by PCR
lymph nodes)
R. akari NA MIF Yes (skin) Yes Yes (skin) No
R. felis NA MIF NA Yes (blood) NA NA
R. prowazekii NA MIF (cross reactions Yes (skin biopsy) Yes (blood) Yes (blood) Louse by PCR
with R. typhi)
R. typhi NA MIF (cross NA? Yes (blood) Yes NA
reactions with
R. prowazekii)
O. tsutsugamushi NA MIF (use strains: Yes Yes (skin, Yes NA
Kato, Gillian, blood)
Karp, Kawasaki)
Ehrlichioses
E. chaffeensis Yes (morula in MIF (cross reactions Yes (in tissues) Yes Yes ?
monocytes) with E. ewingii)
A. phagocytophilum Yes (morula in MIF Yes (in tissues) Yes Yes NA
PMN)
E. ewingii Yes (morula in MIF (cross NA Yes NA NA
PMN) reactions with
E. chaffeensis)
Q fever
C. burnetii NA MIF (phase II Yes (valve, Yes (valve) Yes NA
and phase I for placenta)
chronic diseases)

NA, not applicable.

PCR-Based Detection of Rickettsiae
PCR amplification can be used to detect rickettsiae in blood,
skin biopsies, skin swabbing, and arthropods (70,71). Blood
should be centrifuged and PCRs for rickettsiae should be car-
ried out on the leukocyte-rich buffy coat. Although heparinized
blood can be used for isolation of rickettsiae into cell culture, it
is preferable to use blood collected in ethylenediaminetetraac-
etate (EDTA) or sodium citrate for PCR amplification, because
heparin inhibits PCR and is difficult to neutralize. PCR am-
plifications must be performed before the initiation of antibi-
otic treatment and before antibodies become detectable. Fresh
tissues are preferred for PCRs, but paraffin-embedded tissues
and even slide-fixed specimens may be used (72). Although not
always present, the tche noire is the most useful sample to
biopsy or to swab (72a) to detect SFG rickettsiae by PCR assay
(73), and using this technique, we have characterized several
species in our laboratory (10,74). PCR amplification of tche
noires or blood samples can be very useful because they enable
earlier diagnoses of infections than cell culture or serology.
PCR-based methods for the detection of rickettsiae are attrac-
tive because they not only circumvent the need for culture but
also possibly offer a more sensitive and specific alternative.
Rickettsial DNA can also be detected in ticks (7578), fleas
(40), or mosquitoes (2a) and lice (47) by PCR-based amplifica-
tion methods (79). Detection strategies based on recognition of
sequences within the 16S rRNA gene (80,81) and those encod-
ing a 17-kd protein (8284), citrate synthase (41,46,85), and
the rOmpB (46,86) and rOmpA (for SFG rickettsiae) (10,87)
have been described. Because none of the PCR assays to date
is specific for individual rickettsial species, reaction products
must be further analyzed to identify the species detected.
Approaches involving either restriction endonuclease analysis
or base sequence determination have been described.
Immunologic Detection of Rickettsiae
Skin biopsy specimens have been used in the diagnosis of rick-
ettsioses since the early work of Woodward et al. (88). Samples
can be tested fresh or after fixation and paraffin embedding.
Samples obtained at autopsy can be tested in the same manner
as skin biopsy specimens (89,90).
The use of methods incorporating specific polyclonal anti-
bodies or monoclonal antibodies allows the detection of rick-
ettsiae in blood or other tissues (91). This approach enables
diagnosis of infections in patients before they seroconvert and

Scheld_Ch27.indd 453 2/21/14 6:58 PM

 454 Part III: Bacterial and Mycoplasmal Infection
hence early administration of specific treatment. The method
can also be used to diagnose rickettsial infections in retrospec-
tive studies using fixed tissues.
Isolation of Rickettsiae
Isolation of rickettsiae is difficult and dangerous and should
be attempted only in specialized laboratories. Rickettsiae have
been isolated by several methods. Although laboratory animals,
originally guinea pigs and subsequently rats and voles, and
embryonated eggs have been widely used, cell culture is the most
commonly used system for primary isolation. Tick or mamma-
lian cell lines can be used. We have used a microculture system to
isolate rickettsiae from human blood and other sources (9294).
The shell vial assay was adapted from a commercially available
method for cytomegalovirus culture and early antigen detection.
Isolation of rickettsiae by cell culture is now performed routinely
in our laboratory from heparinized blood (leukocyte-rich buffy
coat) and skin biopsies collected from patients before they have
received antibiotic therapy and from arthropods (93,94).
Treatment
Doxycycline is the main drug used to treat rickettsioses. In
vitro, SFG rickettsiae are susceptible to doxycycline, chlor-
amphenicol, clarithromycin, ketolides, fluoroquinolones, and
rifampicin (42,95). Typhus group rickettsiae are also suscep-
tible to erythromycin (96).
Doxycycline is the main drug used to treat RMSF, and it
should be prescribed in suspected cases. It is used in both children
and adults, but not in pregnant women and allergic patients. In
rickettsioses such as MSF, murine typhus, and epidemic typhus,
a single day of treatment with doxycycline (200 mg) is effec-
tive, but this has not yet been determined for RMSF. The drug
should be given orally except in patients with gastric intoler-
ance or coma, in whom it should be given intravenously. The
usual dose is 200 mg daily in two doses. The required duration
of treatment in RMSF is not yet fully determined, but because
of the lack of relapse, it can be stopped 3 days after apyrexia.
In pregnant women, chloramphenicol is the only available
alternative to doxycycline, but the drug has been shown to be
less effective than doxycycline in treating RMSF (97). Failure
has been reported when patients with murine typhus or epi-
demic typhus were treated with quinolones (98), and the drug
should be avoided in these diseases despite its in vitro activity.
Preliminary reports indicate the new macrolides such as azithro-
mycin and clarithromycin are effective in the treatment of chil-
dren with MSF (99). Severely ill patients should be treated in
intensive care units and fluid administration should be carefully
TA B L E 2 7 . 7
EHRLICHIOSES: GEOGRAPHIC DISTRIBUTION
Agent Disease
E. chaffeensis Human monocytic ehrlichiosis
A. phagocytophilum Human granulocytic
anaplasmosis
E. ewingii Unnamed
Ehrlichia sp. Wisconsin Unnamed
N. sennetsu Japanese monocytic ehrlichiosis
Scheld_Ch27.indd 454
monitored. Mechanical ventilation is used in cases of respira-
tory distress, and antiseizure drugs in patients with seizures. In
patients with gangrene of the extremities, amputation may be
necessary. Glucocorticoids have not proven useful.
Prevention is based on the prevention of tick, louse, and
flea bites by using repellents and/or protective garments. It is
also useful to check for ticks after exposure. Careful examina-
tion of the scalp, groin, and axilla is recommended. Ticks can
be removed with forceps and the skin should be disinfected.
ANAPLASMOSES
Anaplasmataceae species comprise four genera. They multiply
in their hosts blood cells, including red blood cells (in animals
Anaplasma marginale), platelets (in dogs Ehrlichia platys), mono-
cytes (E. chaffeensis), and neutrophils (A. phagocytophilum). Two
are tick-transmitted diseases: Anaplasma and Ehrlichia, whereas
two are helminth-borne diseases: Neorickettsia and Wolbachia.
The index case of modern ehrlichioses was reported in the
United States in 1987 (100). The patient developed a fever after
being bitten by a tick in Arkansas, despite receiving chlorampheni-
col. The patient had, on blood smears, morulae in polymorpho-
nuclear (PMN) cells and antibodies to Ehrlichia canis. Since then,
three human erhlichial agents have been discovered (3). The first
agent of human ehrlichiosis identified in the United States was
E. chaffeensis. This infects monocytes and causes HME. The sec-
ond is A. phagocytophilum causing HGA and infects PMN. The
third is E. ewingii, an agent transmitted by A. americanum, which
is prevalent in Arkansas and infects neutrophils. It cross-reacts
serologically with E. chaffeensis and infects mainly immunocom-
promised people. It has yet to be cultured and has been identified in
dogs and patients by PCR. A recently identified Ehrlichia sp. was
detected in four patients in Minnesota (100a) and is yet unnamed.
Human Monocytic Ehrlichiosis
(Ehrlichia chaffeensis)
Epidemiology
E. chaffeensis has been isolated or identified by PCR mainly
in the United States, in southeastern, south central, mid-
Atlantic States, and California. Its vector is the American tick,
A. americanum (lone-star tick) (Table 27.7), and white-tailed
deer are the mammalian reservoir. Immature ticks are infected
by feeding on blood from persistently bacteremic reservoirs.
E. chaffeensis is transmitted transtadially in the tick and infects
its next host (deer or human) during its next blood meal. The dis-
ease epidemiology reflects the ticks biology because most cases
Vector Geographic Distribution
Amblyoma americanum South central, southeastern, mid-Atlantic,
coastal states (United States)
Ixodes ricinus Ixodes Europe, eastern and northern United States
scapularis
A. americanum South, central, southeastern, mid-Atlantic,
coastal states (United States)
I. scapularis Minnesota or Wisconsin (United States)
Fluke of the gray mulet? Japan
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 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever
are contracted in the south of the United States, in rural areas
where the tick is most prevalent, and from April to September
when the ticks are most active. In highly endemic areas, the
incidence of HME can reach 100 cases per 100,000 inhabitants.
Older patients are more susceptible to infection. Case reports
from South America and Asia have been provided (100b).
Clinical Findings
The incubation period is 7 to 10 days, and tick exposure is re-
ported by 80% of patients. Common presenting signs are fever,
headache, nausea, malaise, and anorexia. If untreated, patients
may develop severe signs and require intensive care. Digestive
tract involvement is common with nausea, vomiting, diarrhea,
and abdominal pain. CNS infection manifests in many forms,
from confusion to coma (101). A rash is observed in 30% of
patients, and lymphadenopathies in 25%. In severe forms, shock
may be observed with hypotension, tachycardia, respiratory
distress, seizures, renal insufficiency, myocardial failure, and
coma. CNS involvement is common (3). Patients may develop
confusion, photophobia, stupor, hallucinations, and eventually
seizures and coma. Changes in mental status, ataxia, blurred
vision, and cranial palsy have also been reported (101). CSF
examination often reveals pleocytosis, with a predominance of
lymphocytes or neutrophils, and elevated protein levels.
Full blood cell counts typically show leukopenia, due
to lymphopenia and neutropenia, and thrombocytopenia.
Coagulopathies may be observed in severe forms. Increases in
AST, alanine aminotransferase (ALT), and lactate dehydroge-
nase are common. The prognosis of HME improves with early
antibiotic treatment, but the fatality rate is still high, at 2.5%. In
people concurrently infected with HIV, the disease may be most
severe, and in a recent study, 6 of 13 patients with coinfections
died. The diagnosis of HME should be strongly considered in
patients with a history of tick exposure and unexplained fever.
Laboratory Diagnosis
Careful examination of blood and CSF smears may help to
identify typical morulae. Treatment should be started in any
suspected case. Diagnosis can be confirmed by culture, but
PCR is used more commonly. A confirmatory PCR using a sec-
ond target gene is useful. Most cases are currently diagnosed
serologically by demonstrating a fourfold or greater increase
in antibody titers or by seroconversion. The reference tech-
nique is immunofluorescence antibody (IFA). A single titer of
25 is indicative of the diagnosis. There are cross-reactive anti-
bodies among Ehrlichia species and with A. phagocytophilum.
Treatment
Doxycycline is the recommended treatment in adults and chil-
dren. Only rifampin also shows in vitro activity, but the drug
has been used only in a few pregnant patients. The treatment
is given empirically for 2 weeks, or it should be continued for
3 to 5 days after fever subsides (101a).
Human Granulocytic Anaplasmosis
(Anaplasma phagocytophilum)
Epidemiology
A. phagocytophilum was identified in ungulates in the 1930s
as an agent causing chronic neutropenia. The first human case
was recognized in 1990 and the disease has now been reported
from America and Europe. It is transmitted by Ixodes scapularis
(eastern North America), I. pacificus (western North America),
I. ricinus (Europe), and I. persulcatus (Asia). These ticks are
Scheld_Ch27.indd 455
455
FIGURE 27.9 Human granulocytic anaplasmosis: Anaplasma phago-
cytophylum. (May-Grunwald-Giemsa [MGG] stain 60.)
also vectors of Lyme disease, and the epidemiology of the
diseases is similar. Concurrent infections may also occur. The
temporal distribution of the disease parallels that of nymph
stage activity, with two peaks in spring and autumn. Ticks
are infected while feeding on bacteremic rodents. Deer play
a major role as hosts of adult ticks and reservoirs. In highly
endemic areas in the United States, incidences of infection can
reach 50 per 100,000 inhabitants per year. Men are at higher
risk of infection than women or children (3).
Clinical Findings
The incubation period is around 10 days and a history of tick
exposure is reported by 80% of patients. Signs of the disease fre-
quently begin abruptly with fever, headache, malaise, and myal-
gias that may be particularly severe. Rash is found in fewer than
10% of patients. Visceral involvement may be observed and diges-
tive symptoms such as nausea, vomiting, and diarrhea have been
reported. Neurologic symptoms may include confusion, meningi-
tis, and meningoencephalitis. Brachial plexopathy and demyelin-
ating polyneuropathy have also been reported (102104).
The prognosis is favorable in most patients, even without
specific therapy, but some patients may develop septic shock.
Most deaths are the consequence of induced immunosuppres-
sion and patients may die of invasive aspergillosis, candidiasis,
cryptococcosis, and herpes esophagitis (104a).
Laboratory findings often include thrombocytopenia with
leukopenia (lymphopenia and/or neutropenia). Increased
serum transaminases are also common. A diagnosis can be
made by the observation of morulae within PMN cells in blood
smears. Culture from blood is possible (Fig. 27.9) (105), but
PCR is used more commonly to identify A. phagocytophilum.
Most cases are diagnosed by serology using IFA. Treatment
is similar to that of HME except that in vitro A. phagocyto-
philum is susceptible to fluoroquinolones. Response to these
agents has not been tested in patients.
Human Ewingii Ehrlichiosis
(Ehrlichia ewingii)
Canine granulocytic ehrlichiosis, reported in the United States in
1972, is caused by the yet uncultured E. ewingii. The bacterium
has been characterized by amplification and sequencing of the
16S rRNA gene. E. ewingii is vectored by A. americanum, which
also transmits E. chaffeensis. Of 60 cases of human ehrlichioses
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 456 Part III: Bacterial and Mycoplasmal Infection
in Missouri in 1999, 4 were caused by E. ewingii (105); sub-
sequently 4 other cases have been reported by the Centers for
Disease Control and Prevention (106,107). The disease is prev-
alent in immunocompromised hosts (7/8), those also infected
with HIV or receiving immunosuppressive drugs. Patients, who
report tick exposure, present with fever, thrombocytopenia, leu-
kopenia, and various symptoms including meningitis. Morulae
may be seen in PMN cells in blood smears. The prognosis in
reported cases has been good and patients respond dramatically
to doxycycline. Patients have antibodies that cross-react with
E. chaffeensis and PCR of blood samples has been shown to be
useful in the diagnosis of the disease. Infections with E. ewingii
should be considered when ehrlichiosis is suspected in immuno-
compromised patients exposed to A. americanum ticks.
Other Anaplamoses
Neorickettsia senetsu
This bacterium is associated with fish flukes and can cause
fever and mononucleosis syndrome in humans eating raw fish.
First described in Japan, it has been reported since in Korea
and recently in Laos (107a).
Wolbachia
Wolbachia can infect the nematode causing filariasis in humans
in which they control the reproduction rate of the worm. They
cause some of the inflammatory responses of filariasis specifi-
cally at the initiation of treatment. Doxycycline has been shown
useful in the treatment of filariasis following this discovery,
which is much less toxic than other current therapies (107b).
Candidatus Neoehrlichia mikurensis
This rare disease found in Europe and Asia can cause fever in
immunocompromised hosts.
Q FEVER
Q fever is a worldwide zoonosis caused by C. burnetii. Ungulates
and pets are the major reservoirs. The infection in humans is
variable in severity, clinical expression, and natural course and
may be acute or chronic. C. burnetii, a gram-negative bacte-
rium, multiplies in acidic vacuoles within the monocytes of its
host. Growing in vitro, C. burnetii becomes a deleted avirulent
mutant, which is named phase II and is useful in serologic diag-
nosis of acute infections (108). Coxiella organisms survive for
long periods in the environment and can be wind borne.
C. burnetii infection is incompletely eliminated after acute
infection in some hosts, for example, immunocompromised
patients and those with cardiac valve lesions. C. burnetii
organisms continue to multiply despite high antibody titers
and cause chronic infection. In patients with endocarditis,
interleukin-10 (an antiinflammatory cytokine) is increased and
monocytes are unable to control growth of C. burnetii (109).
Epidemiology
C. burnetii infects a wide range of animals, especially ungulates
and cats, which are the most important vectors for people who
are usually infected by aerosols, or less frequently by ingesting
milk products. Interhuman spread of infections during sexual
intercourse, parturition, and blood transfusions has been re-
ported (108). In the past few years, major outbreaks have been
related to sheep and goats in the United States and Canada (108)
Scheld_Ch27.indd 456
FIGURE 27.10 Typical lesions on liver biopsy during acute Q fever:
a central lipid vacuole surrounded by a fibrinoid ring and an inflam-
matory granuloma with mainly macrophages and neutrophils. This
histologic feature is called the doughnut aspect.
and a giant outbreak was observed in the Netherlands (109a).
The current geographic distribution is largely unknown. As
C. burnetii is considered a potential bioterrorism agent, diag-
nostic tools have been developed rapidly in the United States.
Adult men are the predominant group (110).
Clinical Manifestations
In several series, 60% of infected patients seroconvert without
apparent disease, 38% experience self-limiting mild disease
(111), and only 2% require exhaustive diagnostic procedures
and hospitalization. Months to years after initial infection,
0.2% to 0.5% of patients develop cardiovascular infection
manifestations, usually those suffering from immunosuppres-
sion or a cardiac valve or vascular lesion (109a,112).
Patients diagnosed with acute infections present with a variety
of symptoms. Most common are isolated prolonged fever (14%)
(113), pneumonia (37%), and as the only symptom in 17%.
Hepatitis is found in 60% of patients and is the only sign in
40%. Some hepatitis cases are associated with an inflammatory
syndrome and autoantibodies and may be resistant to antibiotic
treatment. When liver biopsies are performed, typical lesions are
lipid vacuoles surrounded by a fibrinoid ring in the form of a
doughnut (Fig. 27.10). Patients may have a rash in 1.5% of cases.
Patients may also have other cardiovascular manifestations such
as pericarditis or more rarely myocarditis (1% to 2%).
Neurologic Manifestations
Severe headache is the most common CNS symptom. The neu-
rologic manifestations of Q fever (Table 27.8) also include toxic
confusional states, encephalitis, dementia, cerebellar symp-
toms, cranial nerve palsies, psychoses, and motor and sensory
neuropathies (22,114). A few cases of encephalitis, meningo-
encephalitis, and encephalomyelitis have been reported late in
the course of acute Q fever (115117). Meningoencephalitis is
present in approximately 1% of patients with Q fever (118).
Seizures and coma may accompany the meningoencephali-
tis of Q fever. A study (114) reported an incidence of neuro-
logic complications among 22% of 103 patients, in which 46
had acute Q fever, 5 chronic Q fever, and 52 past infections.
Six of the forty-five patients with acute Q fever had residual
neurologic impairment, weakness, blurred vision, recurrent
meningismus, residual paresthesias, and sensory loss involving
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 Chapter 27: Rickettsioses, Anaplasmoses, and Q Fever 457

TA B L E 2 7 . 8 oligoamnios, intrauterine fetal death (IUFD), and premature

delivery (123a,123b).
NEUROLOGIC SYMPTOMS AND SYNDROMES Patients with Q fever endocarditis have a very chronic
ASSOCIATED WITH Q FEVER infection with low-grade fever, progressive deterioration of
valve function, and progressive heart failure. Fever is inter-
Symptoms/Syndromes Situation mittent and vegetations are frequently absent with echocar-
diography. If not diagnosed, the disease progressively worsens
Meningitis (aseptic) Acute Q fever and emboli (mainly cerebral) may be observed associated with
Encephalitis Acute Q fever renal insufficiency, splenomegaly, and hepatomegaly. Digital
Meningoencephalitis Acute Q fever clubbing may also be observed (108).
Guillain-Barr syndrome Acute Q fever Laboratory abnormalities include increases in hepatic
enzymes and leukopenia and thrombocytopenia, which are
Miller-Fisher syndrome Acute Q fever common. Circulating anticoagulant associated with antiphos-
Myelitis Acute Q fever pholipid may be observed, as may antismooth muscle
Fever and coma Acute Q fever antibodies. With endocarditis, antinuclear antibodies, micro-
Fever and seizures Acute Q fever hematuria, and serum rheumatoid factor are often found.
Cranial nerve palsy Acute Q fever
Pseudo herpetic encephalitis Acute Q fever
Diagnosis
Acute dementia Acute Q fever
Cerebellitis Acute Q fever Diagnosis is based mainly on serology. Direct detection of
Optic neuritis Acute Q fever
C. burnetii by culture, PCR, or immunochemistry in valve,
liver, or blood samples is useful, but serology by IFA is the
Hemiplegia Endocarditis reference method. Two antigens (phase I and phase II) can
Behavioral disturbance Postinfection be used in the IFAs. Acute Q fever is diagnosed when there is
Chronic fatigue Postinfection seroconversion or a fourfold increase is seen to phase II an-
tigen. A single serum sample with immunoglobulin G (IgG)
antibodies more than 200 and immunoglobulin M (IgM)
more than 50 against phase II is also diagnostic (124). In
the left leg (114). Behavioral disturbance, cerebellar symp- chronic Q fever, antibodies are at higher titers and directed
toms, cranial nerve palsies, extrapyramidal disease, and the against both phase I and II. IgG to phase I at a titer of 800
Miller-Fisher variant of the Guillain-Barr syndrome (areflexia or 1,600 is diagnostic of chronic infection, as is IgA of more
and ophthalmoparesis) have been reported as complications of than 100.
acute Q fever. The most common residual disorder of Q fever
meningitis is a disturbance of vision (119). In the series re-
ported by Derrick (120), 1 (0.3%) of 273 patients examined Treatment
had encephalomyelitis. In a report of neurologic involvement
in acute Q fever in 29 patients, we found 17 with meningoen- In vitro, several antimicrobials are bacteriostatic with mini-
cephalitis or encephalitis, 8 with meningitis and myelitis, and mum inhibitory concentrations compatible with clinical use.
4 with peripheral neuropathy (121). A review of 16 patients These include co-trimoxazole, doxycycline, rifampin, fluoro-
with Q fever meningoencephalitis (116) revealed that 8 pa- quinolones, and newer macrolides (but not erythromycin). All
tients had an elevated CSF WBC level, ranging from 18 to these compounds have been used with anecdotal success. Only
1,392 cells/mm3. In all but one case, mononuclear cells pre- doxycycline for acute Q fever (108) and co-trimoxazole for a
dominated. The EEG showed nonspecific abnormalities in five Q fever during pregnancy (125) have been proven effective.
of the six patients tested. None of these compounds is bactericidal in vitro, but doxy-
PostQ fever chronic fatigue was first reported in Australia. cycline together with chloroquine (which alkalinize the acidic
Patients presented with prolonged fatigue, arthralgia, myalgia, pH of the vacuole where C. burnetii organisms multiply) is
muscle fasciculation, blurred vision, sweats, and enlarged pain- bactericidal and has been proven the best antibiotic therapy
ful lymph nodes. A casecontrol study was conducted more for chronic Q fever (125a).
recently in the United Kingdom in 102 patients from a 1989 Treatment is straightforward in patients with acute Q fever,
Q fever outbreak, and pneumonia patients were used as con- but when patients spontaneously resolve, treatment is of un-
trols (122). Chronic fatigue syndrome was found more often in certain benefit. Doxycycline, the most effective antibiotic,
patients convalescing from acute Q fever. In some patients, the should be given for up to 2 weeks. The use of fluoroquino-
symptoms persisted for many years. Thus, human C. burnetii lones for patients with neurologic involvement was suggested
infection may induce a persistent debilitating syndrome in because of the good CSF penetration by the drugs, but this
convalescing patients, as is occasionally observed in patients is not supported by convincing clinical data. Some patients
with chronic typhoid fever or chronic brucellosis. However, with hepatitis do not respond well to antimicrobial therapy
this clinical manifestation is extremely rare in my experience because of an excessive immunologic response. They do, how-
in France. Whether this reflects differences in strains or other ever, improve rapidly with a short course of glucocorticoids
specificities is unknown (123). In the Netherlands, many cases (108). In pregnant women, it has been shown that taking
have been reported since the beginning of a large outbreak; co-trimoxazole for the duration of pregnancy avoids unfavor-
preliminary data suggest that behavioral psychotherapy may able outcomes (125).
be helpful in these cases. Bactericidal drugs are necessary in patients with endo-
Prognosis is usually favorable even without treatment, carditis (126,127). In vitro, antibiotic efficacy is impaired
except in certain patients. In pregnant women, with or with- by the low pH of the vacuole in which C. burnetii organ-
out symptoms, Q fever compromises the pregnancy, includ- isms reside. Hydroxychloroquine increases the pH of this
ing spontaneous abortion, intrauterine growth retardation, vacuole and restores the bactericidal effect of doxycycline.

Scheld_Ch27.indd 457 2/21/14 6:58 PM

 458 Part III: Bacterial and Mycoplasmal Infection
In patients with endocarditis, the recommended treatment
is the concurrent use of doxycycline (200 mg daily) and OH
chloroquine (600 mg daily, then adjusted to reach a 1-mg/
mL plasma concentration). This regimen is given for 18 to
36 months, depending on serologic responses. The major
problem with this treatment is photosensitivity and expo-
sure to the sun should be avoided. Alternative treatment is
the concurrent use of doxycycline and ofloxacin for 3 years
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Hughes JM, eds. Emerging Infections 3. Washington, DC: ASM Press;
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 CHAPTER 28 WHIPPLES DISEASE
MATTHIAS MAIWALD AND DAVID A. RELMAN
In a seminal autopsy report in 1907, George H. Whipple pro-
vided a thorough and articulate description of the disease that
now bears his name (1). His publication illustrated nearly all
the key features that define this clinical entity. However, there
was no mention of neurologic manifestations, and no postmor-
tem examination of the central nervous system (CNS). More
than 50 years later, the incidence and significance of CNS in-
volvement in Whipples disease began to be appreciated (2).
We now know that Whipples disease is a systemic disorder
that typically affects the gastrointestinal tract and that the CNS
is one of the most common sites of extraintestinal involvement,
along with the lymphatic system and the heart (3,4). In addi-
tion, the CNS is the most common site of relapse after anti-
microbial treatment of non-CNS disease (5). Furthermore, it
has been suggested that early CNS infection occurs in most
or all patients with Whipples disease, although only a subset
of patients develop symptomatic or radiologically apparent
CNS disease (6).
Classical Whipples disease primarily affects middle-aged
men and usually presents with arthralgias, abdominal pain,
fever, diarrhea, malabsorption, and weight loss (4,712). A fas-
tidious bacterium, Tropheryma whipplei, is the causal agent of
the disease; it is an actinomycete (class Actinobacteria) on the
basis of molecular phylogenetic analysis (1316). Whipples
disease can present with protean manifestations, especially in
the setting of symptomatic CNS involvement. Thus, delays
or failures in the diagnosis of this disease are common. The
prognosis of CNS Whipples disease is generally serious and is
worsened by delays in, or withholding of appropriate antimi-
crobial therapy (5,17).
This chapter focuses on the CNS aspects of Whipples disease.
Relatively little attention is given to the systemic (non-CNS) fea-
tures of this disorder. These have been well described in a num-
ber of other reviews (4,10,1821). Because it is an extension of
the CNS, a discussion of Whipples disease involving the eye is
included (see the section Clinical Manifestations).
ETIOLOGY
George Whipple concluded from histology and special stains
that the subject of his case report suffered from a disorder
of lipid metabolism (1). Although he observed bacilliform
structures in silver-stained sections of a lymph node, he did
not interpret this finding as related to the pathogenesis of the
disease. However, beginning in the 1950s and 1960s, evidence
started to accumulate that Whipples disease is caused by a
distinct species of bacterium. First, bacteria with a charac-
teristic uniform morphology are consistently seen by electron
microscopy in pathologically affected tissues (2225). These
organisms are usually numerous, are recognized and phago-
cytosed by tissue macrophages, and undergo binary fission in
areas of pathology. Second, patients with clinical manifesta-
tions of Whipples disease respond to antibacterial therapy
(4,26). Third, intact bacteria disappear with clinical response
to antibiotics and reappear during clinical relapse (27).
Fourth, specific bacterial DNA sequences from T. whipplei
are consistently detected in and have been shown to hybridize
Scheld_Ch28.indd 461
to areas of pathology (14,28). Finally, after several decades of
unsuccessful attempts, the bacterium was isolated in culture,
first from a heart valve specimen (29) and subsequently from
other clinical specimen types, including intestinal tissue (30)
and cerebrospinal fluid (CSF) (31).
The Whipples disease bacterium (T. whipplei) is rod-
shaped, measures about 0.2 m by 1 to 2 m, and is sur-
rounded by a 20-nm-thick cell wall. The outermost layer
surrounding the bacterium consists of a symmetric membrane
that morphologically resembles those of eukaryotic origin
(25). An inner electron-dense layer within the wall reacts
strongly with periodic acidSchiff (PAS) reagent and accounts
for the PAS-positive staining pattern of the bacteria and their
remnants within macrophage vacuoles. The organism stains
weakly gram positive and is not acid fast. Examples of typi-
cal morphology, when viewed by electron microscopy, are
shown in Figure 28.1 and in several references (24,25,27).
Characterization of the bacterium at the molecular level was
initially achieved by broad-range 16S ribosomal DNA (rDNA)
polymerase chain reaction (PCR): a unique bacterial 16S ribo-
somal RNA (rRNA) gene sequence was found directly in af-
fected tissues (13,14). Phylogenetic analysis indicated that the
bacterium belongs to the actinomycetes (13,14); however, its
relationships to the other known actinomycetes are relatively
distant (15). The name Tropheryma whipplei (initially pro-
posed as Tropheryma whippelii) is based on the Greek words
trophe, nourishment, and eryma, barrier, because of the mal-
absorption in classical Whipples disease and to honor George
Whipple as the discoverer of the illness (14,16,32).
Cultivation of T. whipplei in the laboratory was finally
successful in prolonged co-culture with human fibroblast
FIGURE 28.1 Electron micrograph of Whipple bacillus undergoing
binary fission within the vitreous of a patient with chronic uveitis.
(From Rickman LS, Freeman WR, Green WR, et al. Brief report: uve-
itis caused by Tropheryma whippelii [Whipples bacillus]. N Engl J
Med. 1995;332:363366, with permission.)
461
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 462 Part III: Bacterial and Mycoplasmal Infections
cells (29). In the initial culture setup, a bacterial generation
time of about 18 days was observed (29), but subsequent re-
ports estimated the doubling time at between 28 hours and
4 days (31,33,34). In any case, this is among the slowest
growth rates ever reported for a medically relevant bacterium.
Subsequently, a cell-free culture medium was designed, con-
sisting of tissue culture medium supplemented with amino
acids which the bacterium cannot synthesize on its own (34),
and additional strainsboth in cell culture and in cell-free me-
diumhave been cultivated from various other clinical speci-
men types (35,36). Of relevance for the neurologic aspects of
Whipples disease is the successful isolation of T. whipplei from
CSF specimens; this includes CSF from neurologically symp-
tomatic as well as asymptomatic patients and from a patient
in the treatment-free period after prolonged antibiotic therapy
(31,37). These findings indicate that T. whipplei is viable and
presumably is able to replicate in the CNS. Nevertheless, at
the present time, culture is not a suitable tool for routine diag-
nostic purposes in the workup of possible Whipples disease.
Two T. whipplei isolates from culture, one from CSF and
another from an infected heart valve, served as the basis for
genome sequencing projects (38,39). It is now established that
the genome of T. whipplei is quite small, slightly less than 1
Mbp, and bears the features of a reduced-genome organism
that is dependent on a host for synthesis of amino acids and
for energy metabolism. At the same time, there is a relative
abundance of predicted surface molecules, and this includes
a unique protein family, termed the WiSP family (for T. whip-
plei surface proteins). The genome also possesses a number of
built-in mechanisms to create genetic and antigenic varia-
tion, and these are predicted to generate considerable variabil-
ity among the organisms surface molecules. It is hypothesized
that these features are linked to immune evasion and thus to
the organisms ability to sustain a chronic infection.
The natural occurrence and reservoirs of T. whipplei are
a topic of ongoing research and debate. The first record of
the bacteriums occurrence outside diseased human tissues was
provided by the detection of specific sequences in wastewater
from sewage treatment plants (40), suggesting that T. whip-
plei may have an environmental reservoir and reside within
polymicrobial communities. Several diagnostic PCR studies
only rarely found positive results in pathologically unaffected
human tissues (4144). However, several other studies found
T. whippleispecific DNA sequences in saliva, gastric juice, in-
testinal biopsies, and stool of asymptomatic persons (4549),
prompting debate as to the reliability and generalizability of
these findings (20,50). More recent studies have reported posi-
tivity rates of 2% to 4% in stool and 0.2% in saliva of healthy
adults and 8% in stool and 2% in saliva of sewage workers,
both in France, and the results were confirmed by a second
PCR assay (48,49). Further evidence was provided with the
detection of T. whipplei in stool and saliva of asymptomatic
household members of patients with Whipples disease, includ-
ing some of the same bacterial genotypes as in the respective
patients (51). As a consequence, it has been postulated that
there is an asymptomatic carrier state with T. whipplei and
that the organism is a commensal bacterium of humans that
causes Whipples disease only in a subset of predisposed indi-
viduals (20,36,50).
Differences between T. whipplei strains were first detected
in the 16S-23S rRNA intergenic spacer sequence, and up to
seven different spacer sequence types have been described
(5254). Subsequent analyses found several highly variable
genomic sequences (HVGS) that formed the basis for an im-
proved strain typing system (55); this genotyping system has
been used in several epidemiologic investigations in France and
in Senegal (51,56,57). However, although some geographical
Scheld_Ch28.indd 462
differences in strain distribution have been noticed, so far, no
specific associations between different T. whipplei strains and
particular disease manifestations or carrier states have been
identified (36).
EPIDEMIOLOGY
Classical Whipples disease with intestinal involvement is a
rare entity. It has been estimated that about 20 to 30 cases of
Whipples disease are reported each year in the literature (4)
and that the total number of published cases since Whipples
original description is less than 2,000 (12). Available epidemi-
ologic data indicate that the disease almost exclusively affects
Caucasians, that the mean age at diagnosis is 50 to 60 years,
that there is a strong proclivity for males, and that people in
the farming trades and other outdoor professions are propor-
tionately overrepresented (4,1012,58). However, available
incidence estimates almost certainly underrepresent the true
number of cases and tend to exclude cases with nonclassical
pathology or purely extraintestinal disease. In fact, recent re-
ports indicate that the involvement of T. whipplei in culture-
negative endocarditis without intestinal manifestations may be
more common than would be expected from the incidence of
classical Whipples disease, suggesting that endocarditis might
follow a different epidemiologic pattern (59,60). Other re-
ports implicate T. whipplei in acute transient illnesses, such as
episodes of febrile illnesses in Senegal (61) and acute diarrhea
in children in France (56), although the causative role of the
organism in these instances is uncertain.
Epidemiologic assessment of CNS Whipples disease is
hampered by frequent uncertainties surrounding the diagnosis
of cases. Often, investigators diagnose CNS Whipples disease
on the basis of CNS clinical manifestations plus confirmed di-
agnosis of Whipples disease pathology at other anatomic sites,
typically in the small intestines or mesenteric lymph nodes. In
cases with positive histopathology in the small intestine and
confirmed by either electron microscopy or a well-validated
PCR test, the diagnosis is firm (4,18,62). However, there is
an increasing number of reports and case series of presumed,
isolated CNS Whipples disease in the absence of other organ
manifestations (6366). In a considerable fraction of these
published cases, the diagnosis has been made solely on the
basis of positive PAS staining results and/or insufficiently vali-
dated PCR tests. As discussed in the section Diagnosis and
Differential Diagnosis (later in this chapter), such diagnostic
approaches lack the necessary specificity to be able to confirm
CNS Whipples disease.
Current literature suggests that the demographics of CNS
Whipples disease are roughly similar to those of Whipples
disease cases involving all sites, although relevant informa-
tion is limited. In the large review by Dobbins (4), among
28 patients with CNS Whipples disease for whom an age is
listed, the mean is 40 years. A published series of 11 cases
of CNS Whipples disease lists a 9:2 male:female ratio and a
mean age at onset of 49 years (67). Another review of CNS
Whipples disease (68) provides a mean age of 50 years and a
male:female ratio of 8:2 among a group of 70 patients with
predominant but not exclusive neurologic presentation, and
a mean age of 42 years and a male:female ratio of about 1:1
among a group of 21 patients with presumed isolated neuro-
logic manifestations.
Among several published case series of systemic and/
or classical intestinal Whipples disease, the proportion of
patients with neurologic manifestations ranges between
slightly less than 10% and slightly more than 40% (712).
Three case series (810) list neurologic symptoms as the
2/21/14 8:10 PM

presenting symptomsalthough that does not mean sole or
isolated CNS diseasein 4% of cases each. The overall in-
cidence and the proportion of truly isolated CNS Whipples
disease are too rare and too small to allow for any meaningful
estimates. Patients who are symptomatic may be only a small
subset of those with bacterial infection in the CNS or with
CNS pathology. This follows from two types of observations.
First, a PCR-based study (69) demonstrated positive results
for T. whipplei in CSF in 7 out of 10 (70%) neurologically
asymptomatic patients at the time of diagnosis of intestinal
Whipples disease. Second, autopsy cases from the preantibi-
otic era had a high proportion of pathologic findings in the
brain. Sieracki et al. (2) described extensive CNS involvement
at autopsy in two patients with Whipples disease who never
reported CNS symptoms. In a series of postmortem examina-
tions on patients with Whipples disease described by Enzinger
and Helwig (3), 10 of 11 patients had characteristic brain
lesions associated with this disease. It has been suggested
that isolated CNS manifestations as primary presentations
of Whipples disease may be increasing in frequency and that
this may be attributed to the incidental use of antibiotics that
suppress early, presymptomatic non-CNS disease but do not
penetrate well enough into the CNS to halt progression there
(70). Again, the numbers of isolated CNS cases are insuffi-
cient for a careful analysis of this issue, and increasing disease
awareness may be an alternative explanation.
PATHOGENESIS AND
PATHOPHYSIOLOGY
The pathogenesis of Whipples disease and of T. whipplei in-
fection is an evolving field. A number of immunologic abnor-
malities have been identified in patients with Whipples disease,
and these are presumed to play a role in pathogenesis by way
of increasing host susceptibility to infection. However, so far
these abnormalities are all of a quantitative nature: No clear
genetic defects or dichotomous presence or absence of any
defined phenotypic markers have been described. Identified
abnormalities include (a) diminished ability of macrophages
of Whipples disease patients to degrade intracellular micro-
organisms (7173); (b) reduced interleukin-12 production by
patients peripheral blood monocytes upon stimulation with
bacterial antigens (74); (c) dysregulation of mononuclear cell
function such that the components of a T helper 1 (Th1) im-
mune response are reduced and those of a T helper 2 (Th2)
immune response increased (75); (d) diminished Th1 reactiv-
ity of peripheral and duodenal CD4 T cells upon stimulation
with specific T. whipplei antigens (76); (e) a transcriptional
pattern of M2/alternatively activated macrophageswhich
is associated with a Th2 immune responseas detected in
duodenal tissue of one patient with Whipples disease (77);
(f) a lack of an inflammatory response and a predominance
of an M2/alternative activation phenotype in peripheral and
duodenal macrophages, in combination with reduced nitrite
production in duodenal tissue and an impaired capacity of pe-
ripheral monocytes to perform oxidative burst upon exposure
to T. whipplei (78); and (g) a paradoxically higher immu-
noglobulin G (IgG) antibody response against T. whipplei in
asymptomatic carriers as compared to patients, indicating a
diminished serologic response to infection (79,80).
There are a few reports of secondary or opportunistic infec-
tions in patients with Whipples disease (81), but apart from
Giardia duodenalis infection, which has been reported in 8%
and 12% of patients, respectively, in two case series (82,83),
these are not commonly observed phenomena, and humoral
immune responses against other pathogens are largely intact (4).
Scheld_Ch28.indd 463
Chapter 28: Whipples Disease 463
Also, there is no significantly increased incidence of Whipples
disease in patients with known primary immunodeficiencies
or immunosuppressive therapies and instead only reports that
immunosuppressive therapy may hasten the onset of clinically
apparent Whipples disease in patients with prodromal articular
manifestations (84,85). Surprisingly, one sequence-based study
of the lung microbiome (i.e., the lungs microbial content and
composition) (86) found T. whipplei DNA in HIV-infected in-
dividuals. Furthermore, in 11 of the 82 HIV-positive subjects,
T. whipplei sequences dominated the microbial community
(50% of sequence reads). The clinical significance of these
findings is unclear because none of the individuals suffered
from respiratory complaints or known lung pathology, but
these findings also suggest that T cellbased immunity is impor-
tant in controlling the organism.
Based on the detection of T. whipplei in acute self-limited
illnesses and also in asymptomatic people, it has been proposed
that T. whipplei may be transmitted from infected hosts or
the environment, possibly in early childhood; may cause acute
primary infections in some; may go on to be carried by some;
and may cause classical Whipples disease only in those who
lack the immune response to contain the organism (87,88).
However, at this point, available data are not sufficient to be
able to confirm these proposals. Taken together, there is good
evidence that immunologic factors play an important role in
pathogenesis, but the abnormalities identified so far are com-
paratively modest and mainly manifest as immunologic dys-
regulation between a Th1 and Th2 response.
Current concepts hold that the disease process is initiated
by translocation of the bacterium from the intestinal lumen
into the intestinal mucosa, possibly via invasion of intestinal
epithelial cells or through epithelial intercellular junctions,
followed by crossing of the basement membrane and replica-
tion in the intestinal lamina propria (24,89). There, the bac-
teria are ingested by macrophages and appear to spread via
blood vessels or via lymphatics into mesenteric lymph nodes
and into the systemic circulation. Infected blood monocytes
are possible vehicles for dissemination to other organs (90).
Uncertainty still exists concerning the preferred compartment
for bacterial multiplication. Earlier electron microscopic stud-
ies indicated that most intact bacterial structures in untreated
intestinal Whipples disease are extracellular, just beneath the
intestinal basement membrane, whereas ingested bacteria
in macrophages exist both with intact shapes and in vary-
ing stages of degradation (24,25). In situ hybridization local-
ized the 16S rRNA of T. whipplei (corresponding to intact
bacteria) to the extracellular spaces of the intestinal lamina
propria, most concentrated underneath the basement mem-
brane, but not in macrophages (28). However, some investi-
gators also report intracellular replication in a monocyte and
macrophage cell culture model and enhanced replication after
addition of interleukin-16 (91).
Once T. whipplei disseminates, the brain is one of the fa-
vored sites for metastatic infection. The mechanisms by which
the bacteria cross the bloodbrain barrier and infect brain
parenchyma are unknown. Entry by extracellular bacteria
or by bacteria within monocytes both are possibilities. The
perivascular and subependymal distribution of macrophage
nodules suggests bloodborne bacterial dissemination. The
distribution of microorganisms and histologic lesions within
the CNS is relatively widespread and therefore argues against
highly localized microbial tropism. The size and multifocal
nature of the microglial nodules in CNS Whipples disease
is compatible with neurologic deficits described in patients.
For example, microscopic lesions in the oculomasticatory
segments of the midbrain and upper pons might explain the
unusual features of oculomasticatory myorhythmia (OMM)
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 464 Part III: Bacterial and Mycoplasmal Infections
or oculofacial-skeletal myorhythmia (OFSM), both findings
that are nearly pathognomonic for CNS Whipples disease
(9294). However, the degrees to which CNS manifestations
are directly due to the bacteria or to immunologic or cellular
responses are not known. In cases with extensive CNS dis-
ease, bacteria are found within neurons and in macrophages
(see the next section), and neuronal loss and reactive astrocy-
tosis are seen during later stages of the disease process.
PATHOLOGY
In 1936, Ford and Walsh (95) described the case of a 47-year-
old man who died after a 10-month history of sleep distur-
bance, progressive paralysis of ocular movements, keratitis,
bulbar palsies, and what would later be called OMM (92). They
did not recognize this as a case of Whipples disease. Notable
findings at postmortem examination included cerebral atrophy,
swelling of basal ganglia, and widespread degenerative changes
of the cerebral gray matter with encephalitis, especially involv-
ing the corticobulbar tracts. In some areas, there was neuronal
cell death; other neurons were swollen with a granular blu-
ish purple cytoplasm. More than 50 years later, these tissues
were reexamined with a variety of histologic techniques, in-
cluding the PAS stain (96). The encephalitis involved extensive
mononuclear cell infiltration of gray and white matter with
perivascular cuffing, microglial proliferation, and marked as-
trocytosis. Foamy macrophages formed nodules and contained
PAS-positive accumulations. Some neurons and astrocytes were
PAS positive as well. These are all features that are typical of
Whipples disease pathology in the brain. In addition, electron
microscopy confirmed the presence of bacillary structures in
the cerebral cortex as well as in retinal tissue.
Other cases of CNS involvement in Whipples disease have
probably gone unrecognized (2,3). For example, 3 of the
34 patients with Whipples disease that were reported in the
literature between 1907 and 1948 had symptoms referable to
the CNS at the time of death, including confusion and somno-
lence (97); however, CNS Whipples disease was not formally
discussed before 1960. The development of PAS reagents and
electron microscopy greatly facilitated this discussion. Sieracki
et al. (2) were the first to address CNS pathology in Whipples
disease directly. Two postmortem examinations revealed nu-
merous and widespread periventricular, subependymal, and
subcortical nodules, containing PAS-positive sickle-form
particle-containing (SPC) cells. These SPC cells corresponded
to the same foamy macrophages that had been traditionally
associated with Whipples disease in intestinal tissues. They
noted less consistent involvement of the choroid plexus and
leptomeninges. In the autopsy review by Enzinger and Helwig
(3) of Whipples disease 3 years later, 10 of 11 cases in which
CNS tissue was available displayed the characteristic lesions
described earlier.
The gross and microscopic pathology of CNS Whipples
disease has been summarized by a number of investigators
(98101). In many cases, chalky yellowish white 1- to 2-mm
nodules are distributed diffusely throughout the cortical and
subcortical, cerebral and cerebellar gray matter, and in sub-
ependymal locations. They demonstrate a special predilection
for temporal, periventricular, and periaqueductal gray matter,
hippocampus, hypothalamus, and basal ganglia. Less com-
mon sites include the cerebellum and the thalamic and olivary
nuclei. They tend to be perivascular. Other common gross
pathologic findings in CNS Whipples disease include cortical
atrophy and ventricular dilation.
On microscopic examination, nodules are aggregates of
primarily macrophages (microglia) that stain strongly positive
Scheld_Ch28.indd 464
FIGURE 28.2 Histology of CNS Whipples disease (periodic acid
Schiff [PAS] reaction). Clumps or plaques of PAS-positive material
within neuropil of the cortical gray matter. The most intense stain-
ing involves macrophages (arrows). Less intense lacy staining patterns
may correspond to the location of extracellular bacteria (magnifica-
tion 200). (Courtesy Dr. Donald Regula, Department of Pathology,
Stanford University School of Medicine, Stanford, California.)
with the PAS reagents (Figs. 28.2 and 28.3). Reactive and hy-
pertrophic astrocytes are common at the periphery of these
nodules; lymphocytes and plasma cells are uncommon. Dual
staining with PAS reagent and antibodies directed against
glial fibrillary-associated protein (GFAP) indicates astrocytes
(Fig. 28.3). In cases with more extensive involvement, individ-
ual PAS-positive cells are more diffusely distributed and may
infiltrate overlying subarachnoid space (100) and white mat-
ter (Fig. 28.4). High-power examination of PAS-stained tissue
reveals intracellular and extracellular material with variable
appearance, from lacy strands to darker specks and larger ir-
regular granules or clumps (Fig. 28.5). Occasionally, a bacilli-
form particle can be discerned. In areas with more substantial
collections of PAS-positive material, there tends to be neuro-
nal loss and demyelination with vacuolization. Smaller (mi-
croscopic) microglial nodules have been described that stain
less intensely with the PAS reagents (99). Some reports have
described microinfarcts that occur most often in the frontal
or occipital lobes (100); it is hypothesized that such infarcts
may be caused by small emboli released from cardiac valvular
vegetations that were found commonly in Whipples disease
patients in earlier autopsy series (3,4). The phagocytes associ-
ated with these infarcts are not PAS positive.
Bacilli were first seen in the brain in 1969 with electron
microscopy and resembled those previously described in non-
CNS cases of Whipples disease (101,102). The distribution of
bacteria and bacterial remnants corresponds well with areas
of PAS-positive staining. Large numbers of extracellular bac-
teria can be detected within neuropil and near macrophages.
Intact intracellular bacteria, as well as bacilli undergoing vari-
ous stages of degradation, are found within the widely distrib-
uted PAS-positive macrophages (98,101,103105). Evidence
of bacillary binary fission suggests that microbial replication
does take place within the CNS (98,101). Macrophages with
degraded bacilli found at the center of older lesions stain more
strongly with PAS than macrophages with intact bacilli at the
periphery (99). Late stages of bacterial degradation produce
intracellular accumulations of serpiginous bacterial mem-
branes that create the large, homogeneous, and more strongly
staining PAS-positive granules. Whipples disease pathol-
ogy can be focal; involvement of the brain, as with the small
2/21/14 8:10 PM
 Chapter 28: Whipples Disease 465

FIGURE 28.3 Cellular distribution of periodic acidSchiff (PAS)positive material in CNS Whipples
disease (dual staining with PAS and antibody directed against glial fibrillary-associated protein [GFAP]).
Left: PAS-positive material is localized to GFAP-negative cells (macrophages) in this section of cortical
gray matter. GFAP-positive cells are predominantly astrocytes (arrows) (magnification 400). Right:
Astrocytes (brown) are seen in the vicinity of extracellular and intracellular PAS-positive material (magni-
fication 600). (Courtesy Dr. Lysia Forno, Department of Pathology, VA Palo Alto Health Care System,
Palo Alto, California.)

intestine, may be patchy (106); thus, a negative random biopsy
result does not rule out the disease (see also section Diagnosis
and Differential Diagnosis).
CLINICAL MANIFESTATIONS
Neurologic manifestations of Whipples disease occur in three
scenarios: (a) accompanied by intestinal and/or other systemic
disease manifestations at the time of diagnosis, particularly
when the disease is diagnosed at an advanced stage; (b) in the
setting of clinical relapse after antibiotic treatment of intestinal
or other manifestations; and (c) as primary or isolated neuro-
logic disease without other apparent manifestations. Among
these scenarios, neurologic relapse after treatment (b) is most
commonly encountered. This scenario was particularly com-
mon before the 1980s, when tetracyclineswhich do not cross
the bloodbrain barrier wellwere typically used for treat-
ment. In one review of 88 mostly tetracycline-treated patients,
31 relapsed after initial treatment, and relapses in 13 patients
(15% of all patients) affected the CNS (5). CNS relapses
generally have a poor prognosis, and some are refractory to
renewed antibiotic treatment (4,5,17,107). However, more re-
cent case series (10,12,108,109) show a much lower incidence
of CNS relapses, particularly when initial intravenous induc-
tion therapy with -lactams and/or oral long-term treatment
with trimethoprim-sulfamethoxazole (TMP-SMX)which
cross the bloodbrain barrier better than tetracyclineshave
been used.
Presentation with isolated CNS Whipples disease is an
extremely rare clinical event. However, this may be difficult
to differentiate from CNS disease combined with other sys-
temic manifestations; for example, a history of migratory
arthralgias or chronic cough might represent extraintestinal

FIGURE 28.5 Histology of CNS Whipples disease (periodic acid

FIGURE 28.4 Histology of CNS Whipples disease (periodic acid
Schiff reaction). Less intense lacy staining patterns may correspond to
the location of extracellular bacteria (arrow) (magnification 1,500).
(Courtesy Dr. Donald Regula, Department of Pathology, Stanford
University School of Medicine, Stanford, California.)
Schiff reaction). High-powered view of neurons with faint positive
material (arrow). Neurons are less commonly involved than are mac-
rophages (microglia), except in severe disease (magnification 2,000).
(Courtesy Dr. Donald Regula, Department of Pathology, Stanford
University School of Medicine, Stanford, California.)

Scheld_Ch28.indd 465 2/21/14 8:10 PM

 466 Part III: Bacterial and Mycoplasmal Infections
Whipples disease, but these complaints are quite nonspecific
and may not be viewed as significant during the time leading
up to more prominent manifestations. Even cases with clas-
sic features of Whipples disease may be missed because of
the drawn-out time course of the illness. Nonetheless, there
are a number of notable reports in this context. Some reports
represent primary presentation with isolated CNS Whipples
disease where examination of other organs yielded negative
results (65,99,110,111). Several other cases represent primary
neurologic presentation where other organs were not inves-
tigated (112,113) or where involvement of other organs was
also found but was not prominent (92,96,98,114119). A
few published cases represent CNS relapses years after initial
treatment, at a time when the non-CNS findings had become
completely negative (120122). Several combined case reports
and literature reviews specifically dedicated to primary or iso-
lated CNS Whipples disease have been published (6365); the
most recent one by Mohamed et al. (65) discusses 24 cases.
However, these published cases should be interpreted with
caution, because a significant number of these diagnoses were
based solely on PAS-positive histologic findings that have
not been confirmed with either electron microscopy or well-
validated PCR assays. As discussed (see Epidemiology and
Diagnosis and Differential Diagnosis), PAS-positive histo-
logic findings are not entirely specific for Whipples disease.
Another report (37) summarizes 20 cases (authors own and
cases from the literature) that are described as T. whipplei
chronic encephalitis, but the case definition used would also fit
the description of primary or isolated CNS Whipples disease
as commonly used by other authors; similar caution concern-
ing the certainty of diagnoses is also indicated with this series.
Common neurologic manifestations of Whipples disease are
dementia (or cognitive impairment), ophthalmoplegia, myoclo-
nus, altered level of consciousness, psychiatric abnormalities, hy-
pothalamic dysfunction, and ataxia (4,37,67,68,93) (Table 28.1).
The first three are considered a characteristic triad that should
suggest the diagnosis of CNS Whipples disease, although only a
minority of patients (approximately 15%) has all three signs to-
gether (4,93). Headache is a common but nonspecific complaint.
The dementia is slowly progressive and manifest by memory im-
pairment, confusion, personality change, paranoia, emotional la-
bility, and depression. Approximately 71% of patients with CNS
Whipples disease show signs of cognitive impairment, and nearly
half of these patients also demonstrate psychiatric disturbances
(93). Patients have sometimes been misdiagnosed with Alzheimer
disease. Nearly all cases of ophthalmoplegia are supranuclear,
usually in the form of vertical volitional ophthalmoplegia with
preserved involuntary extraocular movements in response to
head movements. OMM and OFSM constitute a peculiar mix-
ture of synchronized eye movements and myoclonus that are re-
ported in about 20% of patients; both may be pathognomonic
for CNS Whipples disease (see later discussion) (93), but other
forms of myoclonus can occur without eye involvement or in a
dyssynchronous fashion. In a particularly severe case of myoc-
lonus, a patient suffered from synchronized 1-Hz jerks of the
right face, pharynx, arm, diaphragm, and calf, causing her entire
body to shake (114). Segmental myoclonus involving the facial
nerve is also described in the setting of Whipples disease (123).
Hypothalamic signs reported in this disease include polydipsia,
polyphagia, insomnia, and hypersomnia (111,120,121,124).
In their review of 28 patients, including 12 with CNS manifes-
tations, Fleming and colleagues (8) found headache, diplopia,
depression, confusion, and other forms of altered personality
to be common at the time of presentation. A subsequent review
of CNS Whipples disease cases from the same institution (67)
found cerebellar ataxia (6 of 11 cases, 55%) to be more common
than described in other series.
Scheld_Ch28.indd 466
TA B L E 2 8 . 1
CLINICAL MANIFESTATIONS OF CNS WHIPPLES
DISEASE
More common
Dementia (or cognitive impairment)
Ophthalmoplegia
Myoclonus
Altered level of consciousness
Psychiatric abnormalities
Hypothalamic dysfunction
Ataxia
Less common
OMM or OFSMa
Seizures
Aphasia
Cortical visual defect
Dysarthria
Tinnitus
Meningitis
a
Oculomasticatory myorhythmia (OMM) or oculofacial-skeletal myo-
rhythmia (OFSM); both may be pathognomonic.
Less common clinical manifestations of CNS Whipples
disease include aphasia, paresis, impaired vision due to cor-
tical lesions, seizures, dysarthria, auditory impairment, tin-
nitus, vertigo, trigeminal neuralgia, hydrocephalus, and
meningitis (68,93,110,116,125128). Syndromes and pathol-
ogy suggestive of cerebrovascular stroke have been reported
in patients with Whipples disease (129,130). In addition to
cognitive impairment, behavioral disturbances may be promi-
nent (131). In the setting of disease relapse with neurologic
presentation, the most common clinical features are demen-
tia, ataxia, hypothalamic dysfunction, ophthalmoplegia, and
seizures (4,5). Although uncommon, the spinal cord and
peripheral nerves may also be involved in Whipples disease
(68,110,132,133), and although not directly affecting the
nervous system, infectious spondylodiscitis with T. whipplei
(134,135) and myopathy (136) have also been reported.
OMM was originally described by Ford and Walsh (95)
in 1936 and by Van Bogaert et al. (137) in 1963, but the
diagnosis of Whipples disease was not made until reexamina-
tion of these cases years later (96,104). Though rare, OMM
may be unique to Whipples disease and for this reason war-
rants appreciation by clinicians. OMM is manifest by smooth
convergent-divergent pendular oscillations of the eyes with
synchronous rhythmic (approximately one per second, 1 Hz)
contractions of the jaw (92,93,138,139). It can be continuous
during the day, persist during sleep, and remain unaffected by
environmental stimuli (92). In one patient, it led to permanent
bruxism (140). Similar clinical findings, such as convergent
nystagmus, may be related to OMM and are equally sugges-
tive of Whipples disease. In addition, OMM may be a form
(or subset) of OFSM (93,141143), which is also associated
with Whipples disease and is manifest by synchronous rhyth-
mic movements of the face and extremity muscles. It can also
involve eyelids, palate, tongue, and cervical muscles and is also
seen rarely in ocular pontocerebellar atrophy.
2/21/14 8:10 PM

Early observations on the natural course of untreated
Whipples disease suggested three clinical phases (3,7): (a) an
initial prolonged phase with insidious onset, marked by ar-
thralgias, fatigue, occasional cough, and anemia; (b) a sec-
ond phase characterized by abdominal pain, diarrhea, fever,
lymphadenopathy, and weight loss; and (c) a terminal phase
marked by cachexia, congestive heart failure, and death. In
retrospect, CNS findings were often evident but unrecognized
during the second phase. Nonetheless, even today, the diagno-
sis of Whipples disease is made in some cases only after death.
Untreated CNS disease usually leads to progressive dementia,
decline in level of consciousness, coma, and death within a
period of months to several years.
The eye is a site of significant and probably underappre-
ciated involvement by Whipples disease (93,116,144149).
Ocular manifestations include (a) CNS disturbances affecting
the eye, as described earlier, and including ophthalmoplegia,
cranial nerve III, IV, or VI palsies, OMM/OFSM, pupillary
abnormalities, and ptosis (93); and (b) direct peripheral in-
volvement of the eye and ocular structures, mostly by infec-
tious processes (147,148). The latter, in general, occurs in
individuals with preexisting evidence of gastrointestinal and/
or neurologic involvement; however, a few reported cases of
ocular disease have been diagnosed without or with minimal
extraocular manifestations. In one of these cases, T. whipplei
DNA was detected in the duodenal mucosa, despite normal
duodenal histology (144). The most common eye manifes-
tations of Whipples disease are visual loss, uveitis, vitreitis,
retinitis, optic neuritis, and papilledema. Anterior chamber
findings have included keratitis with corneal precipitates and
iris nodules. These latter findings may suggest a diagnosis of
sarcoidosis. Ocular disease is usually bilateral. Histologic or
cytologic examination may reveal typical PAS-positive mac-
rophages (SPC cells) within the vitreous humor, lens capsule,
and inner retina (116,145,149,150). Whipples bacilli have
also been visualized with electron microscopy, and their DNA
can be detected in vitreous fluid and ocular tissues by PCR
(144,149,150). In a large series of microbiologic investigations
on 1,520 anterior chamber and vitreous fluid specimens from
cases of uveitis of unknown etiology in France, infections were
diagnosed in 147 cases, and among other fastidious bacteria,
possible T. whipplei infection was diagnosed by PCR in 8 cases
and definite T. whipplei infection in 2 cases (151). Thus, when
investigating inflammatory eye manifestations suspected to
be due to Whipples disease, a combination of PAS staining
and PCR may be a useful diagnostic approach. Antimicrobial
treatment usually arrests progression of ocular disease and
may lead to clinical remission (149).
DIAGNOSIS AND DIFFERENTIAL
DIAGNOSIS
The diagnosis of CNS Whipples disease remains a clinical
challenge, mainly because of its rarity and because most signs
and symptomsexcept presumably OMM and OFSMcan
also be observed in other clinical entities. The diagnosis re-
quires astute attention to the overall clinical history and
physical findings, and this includes CNS findings as well as
other relevant details, such as joint problems, low-grade fever,
unusual skin pigmentation, changes in bowel habits, weight
loss, and abdominal and peripheral lymphadenopathy. Any
diagnostic workup for possible CNS Whipples disease should
always include upper gastrointestinal endoscopy, including
multiple (about five) small intestinal biopsies, as well as an as-
sessment of a patients lymph nodes. Results of routine labora-
tory studies are often nonspecific. Anemia, hypoalbuminemia,
Scheld_Ch28.indd 467
Chapter 28: Whipples Disease 467
steatorrhea, increased erythrocyte sedimentation rate and
C-reactive protein, and low serum carotene levels are relatively
common in patients with Whipples disease (3,4,7,8,1012).
Standard CSF analysis may be unremarkable or may display
mild abnormalities such as elevated pressure, elevated protein
concentration, and mild pleocytosis (4,68,93,128). The CSF
glucose content is almost always normal. The electroencepha-
logram (EEG) may be unremarkable or show diffuse slowing
(65,68,115).
Neuroimaging studies have not revealed any specific or
characteristic patterns for CNS Whipples disease; imaging re-
sults may even be normal (10,68,93,152). Computed tomog-
raphy (CT) scans may reveal cortical atrophy and ventricular
dilation; low-density, contrast-enhancing mass lesions are also
well described (105,110,126,153). Magnetic resonance imag-
ing (MRI) probably offers greater sensitivity than CT scan-
ning in detecting CNS Whipples disease pathology (68,93).
Various reports describe lesions with increased T2-weighted
signal intensity in the subcortical white matter, hypothalamus,
uncus, medial temporal lobes, and amygdala with variable de-
grees of enhancement (103,111,112,132,139,154) (Fig. 28.6).
Adler and Galetta (139) provide gadolinium-enhanced T1-
weighted images with evidence of bloodbrain barrier leakage
that resolved with treatment. Positron emission tomography
(PET) scanning may also be used to detect areas of pathology
with increased glucose uptake (65). Focal lesions as detected
by neuroimaging may be targeted for stereotactic brain biop-
sies, if this becomes necessary (65,105,110,112,113).
Diagnostic testing includes studies based on histology, cy-
tology, electron microscopy, and PCR. Histology is the tra-
ditional diagnostic approach for Whipples disease and may
reveal PAS-positive inclusions in macrophages in intestinal,
brain, and other tissues (62). Some investigators supplement
histologic examination with immunohistochemistry using T.
whippleispecific antibodies, although this test is not widely
available (37). Cytologic examination, involving PAS stain-
ing of a cytocentrifuge pellet, is useful for CSF and vitreous
fluid (69,120,149,153). When positive, cytology shows mono-
nuclear cells with PAS-positive inclusions, also termed sickle-
form particle-containing cells (Fig. 28.7). Electron microscopy,
which has been in use since the 1960s, serves as the traditional
confirmatory test for PAS-positive histologic findings (24,25).
PCR testing has been available since the 1990s; various assays
have targeted sequences such as the 16S rRNA gene, the 16S-
23S rDNA intergenic spacer, and genomic repetitive sequences
(14,41,49,155157). In recent years, most PCR assays have
been transferred to a real-time platform (44,158,159). PCR
can serve as a confirmatory or supplementary test for intes-
tinal biopsies and as a primary or supplementary test for ex-
traintestinal tissues or body fluids (19,21). The possibility of
serology for diagnostic purposes has been explored but has
not yet reached a stage of wider availability for routine diag-
nostic use (29,79,80).
In the setting of suspected CNS Whipples disease, a rea-
sonable primary approach is to pursue a diagnosis with upper
gastrointestinal endoscopy and small intestinal biopsies, in
combination with lumbar puncture to obtain CSF for cytology
and/or PCR testing (21). Cytologic examination requires co-
ordination with the receiving laboratory because CSF must be
fresh (preferably 1 hour old) (69). Some investigators have
proposed PCR testing of saliva and stool for first-line screen-
ing to diagnose classical intestinal Whipples disease, but this
approach lacks sensitivity for extraintestinal manifestations
and may be positive in asymptomatic carriers (49). Secondary
approaches should be guided by clinical judgment and should
target suspected pathologically affected sites, such as lymph
nodes, ocular fluids, or brain. Like the intestinal mucosa, brain
2/21/14 8:10 PM
 468 Part III: Bacterial and Mycoplasmal Infections

A B
FIGURE 28.6 Magnetic resonance images revealing posterior subcortical white matter lesions in a
59-year-old man with biopsy-proved Whipples disease of the duodenum and brain, before (A) and after
(B) 10 months of antibiotic therapy. (From Cooper GS, Blades EW, Remler BF, et al. Central nervous sys-
tem Whipples disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with
cefixime. Gastroenterology. 1994;106:782786, with permission.)

FIGURE 28.7 Light microscopic images from cytologic examination of CSF from patients with Whipples
disease, using the periodic acidSchiff (PAS) stain. A: Typical sickle-form particle-containing (SPC) cell
from a patient before antibiotic therapy. B: Cell with PAS-positive material in the cytoplasm that does not
resemble that of typical SPC cells (indeterminate finding) from a patient undergoing antibiotic therapy.
Original magnification: A, 196; B, 158. (From von Herbay A, Ditton HJ, Schuhmacher F, et al.
Whipples disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebro-
spinal fluid. Gastroenterology. 1997;113:434441, with permission.)

Scheld_Ch28.indd 468 2/21/14 8:10 PM


involvement may be localized and/or patchy, and therefore
brain biopsies should be guided by neurophysiologic examina-
tion and imaging results (68,93). Apart from positive results
for standard brain histology (using the PAS stain) and electron
microscopy, T. whipplei rDNA has been amplified from brain
tissue (37,65); however, the common practice of prolonged
fixation may hinder PCR-based amplification from archival
specimens, and controls for the presence of amplifiable DNA
are a necessity (160). Although a rare occurrence, PCR may
detect T. whipplei DNA in histologically unaffected sites, such
as the duodenal mucosa in a case of T. whipplei uveitis (144).
Also, apart from being useful for establishing a diagnosis, PCR
and cytologic examination of CSF initially and at regular in-
tervals during treatment may be useful for staging and moni-
toring disease in order to detect and respond to the threat of
CNS relapses in classical and CNS Whipples disease (69).
Reactivity to the PAS stain is not specific for Whipples
disease. The PAS reagent stains other microorganisms, includ-
ing a number of actinomycetes and fungi, as well as nonmi-
crobial glycoprotein and some cellular debris (4,18,62). As a
consequence, it is necessary to confirm PAS-positive findings
by electron microscopy (showing bacteria of the typical size
and shape of T. whipplei) or by PCR. Some investigators have
indeed documented instances of PAS-positive brain histol-
ogy that were not confirmed to be due to Whipples disease
(37,160). Two microorganisms to consider in the differential
diagnosis of PAS-positive findings are Mycobacterium avium
complex and Histoplasma capsulatum, both of which are
found within macrophages and both of which may involve the
brain. These organisms are particularly relevant in the setting
of HIV infection; in such instances, attempts should be made
to distinguish these organisms from T. whipplei by culture,
PCR, and other staining procedures. In this context, it is rel-
evant that CNS and other systemic T. whipplei infections have
been documentedalthough rarelyin patients with AIDS
(161,162), and Whipples diseaselike syndromes can be in-
duced by M. avium complex and Rhodococcus equi in patients
with AIDS (163,164).
Similarly, PCR testing requires attention to detail; false-
positive results may arise from PCR contamination as well
as from amplification of nontarget sequences (20,165,166).
When PCR results are solely judged by agarose gel electropho-
resis, bands of presumably the right size may be seen that nev-
ertheless do not correspond to T. whipplei DNA (M. Maiwald
and D. A. Relman, unpublished results). As a consequence,
it is recommended that one employ strict anti-contamination
practices and use PCR assays that have been validated with ad-
equate positive and negative clinical samples, that one include
adequate negative as well as inhibition controls, and confirm
the identity of PCR products by sequencing. Some investiga-
tors propose confirmation of positive results by a second PCR
with a different target sequence (157).
The differential diagnosis of CNS Whipples disease in-
cludes other forms of subacute or chronic encephalopathy
(e.g., Wernicke encephalopathy, heavy-metal poisoning, and
storage diseases in children), Alzheimer disease, Parkinson
disease, prion diseases, cerebral vascular infarcts, CNS vascu-
litis, paraneoplastic syndromes, neurosyphilis and other CNS
infections, and chronic demyelinating disorders (167). In ad-
dition, hypothalamic presentations of Whipples disease may
resemble Kleine-Levin syndrome (120). A history of alcohol-
ism and a response to thiamine may help to identify Wernicke
encephalopathy. Some presentations of CNS Whipples disease
may resemble multiple sclerosis (MS), but supranuclear oph-
thalmoplegia, myoclonus, and seizures are unusual in MS.
Also, MS may be associated with myorhythmias and rarely
with pendular ocular oscillations, but they are usually of a
Scheld_Ch28.indd 469
Chapter 28: Whipples Disease 469
higher frequency (4 to 5 Hz) than those seen in CNS Whipples
disease. Isolated myorhythmias are also sometimes seen in
brainstem vascular disease and in cerebellar degeneration sec-
ondary to chronic alcoholism. Creutzfeldt-Jakob disease and
CNS Whipples disease share some features, including patient
age at onset, dementia, and myoclonus. Subacute sclerosing
panencephalitis can also resemble CNS Whipples disease;
however, the former typically occurs in a younger age-group.
CNS Whipples disease can be distinguished from slow virus
infections or prion diseases on the basis of brain pathology.
OMM and OFSM are mimicked by at least three neuro-
logic clinical entities, although generally, they are differenti-
ated from other forms of pendular nystagmus by their smooth
continuous nature, high amplitude, and slow frequency.
First, OFSM occurs rarely in ocular pontocerebellar atrophy.
Second, oculopalatal myoclonus can appear similar to OMM,
although there are no convergent ocular oscillations in oculo-
palatal myoclonus, and there is no olivary pseudohypertrophy
in Whipples disease. Third, OMM can be confused with con-
vergence nystagmus of Parinaud, but the latter is episodic and
is usually provoked by attempted upward gaze (92).
TREATMENT
Therapy for Whipples disease has been largely guided by
empirical observations and retrospective literature reviews
(5,810,108). Before the 1980s, when tetracyclines were com-
monly used for treatment, relapse rates were high and CNS
relapses occurred frequently (5). Even though recent case se-
ries show much lower relapse rates (10,12,109), CNS relapses
continue to pose a real and very serious threat to patients.
In two remarkable published cases, CNS relapse occurred 8
and 12 years, respectively, after treatment and presumed cure
of intestinal Whipples disease (121,122). Earlier case series
showed that patients who received initial intravenous induc-
tion therapy with penicillin and streptomycin followed by oral
maintenance therapy with tetracyclines (the Duke regimen)
had a more favorable clinical outcome (5). Supplemented by
the fact that TMP-SMX shows better clinical outcomes than
tetracycline-based regimens (108) and even penetrates a rela-
tively intact bloodbrain barrier well, several recent recom-
mendations for treatment suggest initial intravenous induction
therapy for 2 weeks with a -lactamcontaining regimen (e.g.,
either penicillin G plus streptomycin, a third-generation ceph-
alosporin, or a carbapenem) followed by oral maintenance
therapy with TMP-SMX for at least 1 year (1921).
Despite the use of these induction and maintenance regi-
mens, instances of treatment failure, including worsening
of CNS symptoms, have been observed under TMP-SMX
therapy, and this includes cases of apparently acquired TMP-
SMX resistance in T. whipplei (103,108,139,168170). Some
patients with worsening CNS symptoms have benefitted from
a change in regimen or from cycles of intravenous salvage
therapy. Relevant case reports describe intravenous treatment
periods with ceftriaxone (69,139); switches to the oral third-
generation cephalosporin, cefixime (103); and addition of ri-
fampin, which is also known for excellent CNS penetration, to
the regimen (171).
In vitro studies with cultivated T. whipplei have shown that
in co-culture with fibroblasts, the organism appears susceptible
to doxycycline, macrolides, penicillins, rifampin, teicoplanin,
and TMP-SMX and variably susceptible to imipenem (172); in
axenic medium, the organism also appears susceptible to cef-
triaxone and vancomycin (173). Furthermore, genome analy-
sis has suggested that T. whipplei is inherently resistant to the
trimethoprim component in TMP-SMX (174). Thus, some
2/21/14 8:10 PM
 470 Part III: Bacterial and Mycoplasmal Infections
have proposed that the TMP-SMX combination can be safely
replaced by sulfadiazine alone (175); the latter also penetrates
the bloodbrain barrier well. In vitro studies have further sug-
gested that the combination of doxycycline and hydroxychlo-
roquine is bactericidal for T. whipplei, presumably because
hydroxychloroquine enhances tetracycline activity by raising
the pH value of phagolysosomes (172). Encouraging initial
treatment results in patients have been reported with this regi-
men (19,176). As a consequence, it has been suggested that
patients with CNS involvement may benefit from treatment
with doxycycline plus hydroxychloroquine, plus either TMP-
SMX or sulfadiazine (175). To improve on CNS penetration
of the tetracycline-chloroquine combination, one group (177)
treated a patient with persistent infection of the CSF using a
combination of minocycline and chloroquine (minocycline has
better CNS penetration than doxycycline) and successfully
eradicated T. whipplei from the CSF. A randomized clinical
trial of initial intravenous ceftriaxone followed by 1 year of
oral TMP-SMX versus initial meropenem followed by 1 year
of TMP-SMX in 40 patients (109) did not show any signifi-
cant difference between the two regimens, and apart from one
patient with persistent T. whipplei in the CSF, there were no
relapses within a median observation period of 89 months.
Some patients may experience clinical deterioration, often
accompanied by fever and other systemic manifestations,
weeks to months after initiation of treatment. In these pa-
tients, the deterioration has been attributed to a phenomenon
akin to immune reconstitution inflammatory syndrome (IRIS),
as described in patients with HIV infection (178). This phe-
nomenon may be clinically serious. Although patients often
respond favorably to corticosteroid treatment, one patient
apparently failed steroid treatment and responded instead to
thalidomide (179).
In summary, the treatment of Whipples disease, and its
CNS manifestations in particular, remains difficult. It is unclear
how much weight should be assigned to in vitro susceptibility
data. One should continue to rely on clinical studies or case
series as a major source of information on which to base treat-
ment decisions. Initial intravenous therapy with a -lactam,
either alone or in combination with another agent, and subse-
quent extended oral treatment with drugs that penetrate well
into the CNS appear to be most effective.
PREVENTION
Whipples disease in its classic form is a rare disorder. Our
present understanding of the risk factors for this disease is
insufficient to allow for any recommendations for preventive
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FUTURE DIRECTIONS
Although significant progress has been made in the last 10
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179. Lagier JC, Fenollar F, Lepidi H, et al. Successful treatment of immune
reconstitution inflammatory syndrome in Whipples disease using thalido-
mide. J Infect. 2010;60:7982.
2/21/14 8:10 PM
 CHAPTER 29 TUBERCULOUS MENINGITIS
DOROTHEE HEEMSKERK, JEREMY FARRAR, AND MAXINE CAWS

Yea, I have known inflammations, Imposthumes, whelks, scirrhus the disease in four different stages, according to the pulse of the
Tumors growing to the Meninges, with the Skull, and other patient. He emphasized that the terminology Dropsy upon the
Diseases of an evil conformation, excited in the Membranes of brain (-

[hydrocephalus]  [on] 


the Brain; by which at first for a long time, frequent headache,
and most cruel, and then afterwards a sleepy and deadly distemper
hath been induced; the cause of the Disease not detected, but
after Death by the Anatomy; and indeed it is to be suspected that
inveterate and pertinacious pains in the Head, which return, and
daily become more tormentive, in spight of all Remedies depend
upon some such invincible Cause.
Thomas Willis (16211675), from De Anima Brutorum
(1672) (1)
HISTORY
Tuberculosis
Tuberculosis (TB) has been a part of everyday human life since
ancient times. There is evidence of TB in man dating back to
4000 bc, but the disease may have been present even earlier.
Before the discovery of the causative agent (Mycobacterium
tuberculosis), TB, in its many forms, has had many different
syndromal descriptions: phthisis, consumption, scrofula, Pott
disease, or others less well known such as yaksma (Indian)
and Chaky Onkay (Incan). The term tubercle was first used
by Franciscus de la Boe, also known as Sylvius of Leyden
(16141672). He stated that tubercles were often seen in the
lungs of consumptives (2). He was also accredited with dis-
covering a cleft in the brain consequently named the sylvian
fissure, which we now know to be a preferential site for
exudates formed in tuberculous meningitis (TBM).
The Origin of Tuberculous Meningitis
The earliest descriptions of intracranial TB date back to the
seventeenth century. Physicians frequently used the term acute
hydrocephalus or dropsy of the brain for a condition in
children of which the etiology was unknown but presented with
fever, headache, vomiting, and rapid death. Some of the his-
torical descriptions vividly illustrate the despair of both patient
and doctor; some pathologic descriptions were punctilious and
very archetypal.
Nec minus a phlegmone et abcessu quam hujasmodi meningitis et
tuberculis, cephalgiae lethales et incurabiles oriuntur (Sometimes
the headaches, fatal and incurable, follow abscesses and swellings
of the envelopes of the brain, as well as placques and tubercles of
these membranes). (Willis, 1672 [1])
Willis was far ahead of his time as it was not until 150 years
later that the tubercles found upon autopsy were regarded as a
distinguishing aspect of the clinical syndrome, which was only
then proposed to be tubercular meningitis.
Attempts were made to define this disease entity based
on clinical and autopsy findings, but due to the multiform
presentation both clinically and pathologically, consensus was
not reached until Robert Whytt (1714 to 1766) lifted the disease
out of obscurity with his treatise Observations on the dropsy in
the brain. He gives a detailed account of 20 patients, dividing
474
Scheld_Ch29.indd 474
[the brain] as described by Hippocrates [460 to 377 bc] in his
De Morbis Popularibus) is in these cases incorrect, because the
accumulated fluid is not found between the skull and the dura
mater but most frequently in the ventricles. The antediluvian
technique proposed by Hippocrates to make a perforation in the
upper part of the cranium to evacuate the fluid Whytt concluded
was of no use (3). This publication gave an impetus to scientists
to study this condition systematically and many contributions
followed with different views on the origin of the disease. Some
considered the arachnoid the seat of the pest, others lesions in the
brain parenchyma, the ventricles, until finally Penn in 1825, who
thought the origin was in the pia mater, called it meningitis (1).
The term tubercular meningitis was first used in 1836
by P.H. Green in the Lancet. Green introduced the term tu-
bercular meningitis to describe the condition of the cerebral
membranes, which were affected by tubercular lesions in nine
tenths of the cases in a series of 45 children, who at the same
time had tubercular deposits in the lungs or the abdomen.
Green argued that these findings were a more essential
characteristic of the disease than the accumulation of cerebro-
spinal fluid (CSF) (4,5). The condition was uniformly lethal.
Elucidating Pathogenesis
By the end of the nineteenth century, attempts were made
to relieve symptoms from raised intracranial pressure and
hydrocephalus. Walter Wynter (1860 to 1945) had devised a
crude technique to puncture the lumbar subarachnoid space.
He successively performed this archaic form of lumbar punc-
ture on four patients with TBM to relieve symptoms but
with short-lived improvement (widening of the pupils and
temporary improvement of sensorium), but all four patients
died (6,7). Morton (1891) describes the clinical findings of
a series of patients during illness and the pathologic findings
in the brain postmortem to further explore whether there
would be a rationale for Wynters procedure. Although failing
to clearly associate the extent of the hydrocephalus to the
observed clinical picture, he concluded:
The operation does no harm, and as the patient is already comatose
no anaesthetic is required. But in any efforts we may make to
remove the more serious symptoms of tuberculous meningitis by
draining the intraventricular fluid we must remember it is nearly
always only part of general tuberculosis, which may, and prob-
ably will, prove fatal in other ways, though if in this rapidly fatal
meningitis we can prolong life it may be some time longer before
the general tuberculosis does its deadly work. (8)
Tuberculous meningitis remained universally fatal.
It was not Wynter but Heinrich Quincke who began to
popularize the lumbar puncture for both therapeutic and
diagnostic purposes in the late nineteenth and early twentieth
century. With the discovery of M. tuberculosis by Robert Koch
in 1892 and the development of x-rays by Wilhelm Roentgen
in 1895, diagnosis before death was now achievable, although
effective treatment remained elusive.
The disease was still thought to develop in a manner analo-
gous to other meningitides until a meticulous serial autopsy
2/21/14 8:21 PM

study of 82 patients by Rich and McCordock (9) in 1933
provided the basis of what still now is considered to be the
establishment of pathogenesis. In guinea pigs and rabbits,
Rich and McCordock (9) could only provoke inflammation
of the meninges by the direct inoculation of bacilli into the
central nervous system (CNS) and not by peripheral injec-
tion and consequent hematogenous spread. In human autopsy
studies, they described that the tubercles found in the brain
were seldom of the same age as those found in other organs
and that vasculitis found in the brain was rather a process
originating from the adventitia inward, more likely to be the
result of a focus within the brain rather than caused by di-
rect hematogenous spread of bacilli. These findings led them
to form a coherent hypothesis in which they postulated that,
after inhalation of the pathogen, a short-lived bacteremia fol-
lowed, during which bacilli spread throughout the body and
seeded the surface of the brain, forming small granulomas
known as Rich foci. These can exist without causing symp-
toms for an unknown period but may rupture; upon release
of the mycobacteria, meninges become inflamed, giving rise to
a multitude of possible pathologic tuberculous conditions in
the CNS (9).
Treatment Development
The discovery of the causative pathogen was met with eu-
phoria, as new hopes were raised of a cure. Experimental
treatment was attempted with tuberculin, originally a glyc-
erin extract of M. tuberculosis developed by Koch, but with
catastrophic results. Other therapies raised hopes but proved
ineffective, including sanocrysin (gold therapy) (10). In 1944,
the first effective antituberculous agent, streptomycin, was dis-
covered by Salman Waksman, a discovery for which he would
win the Nobel Prize for Medicine in 1950. By 1948, dozens of
cases of successfully treated TBM with intrathecal and intra-
muscular streptomycin were reported in the literature. Rich
and Samuels (11) reviewed these cases while giving a striking
account of a case involving a 2-year-old boy who at the height
of his disease was in a vegetative state but within 6 months
recovered with residual weakness of his left arm and minor
mental impairment. Many publications followed on successful
streptomycin treatment. However, by 1950, numerous strepto-
mycin resistance reports appeared (1217). Paraaminosalicylic
acid (PAS) was added to the regimen; although a weak antitu-
berculous agent, it prevented development of resistance. With
the introduction of isoniazid (1952), a major improvement in
treatment of all forms of TB was seen. It became clear that
intrathecal administration was no longer necessary. With the
introduction of pyrazinamide (1954) and rifampicin (1963),
treatment regimens for all presentations of drug-susceptible
TB could be shortened to 6 to 8 months. The relative con-
tributions of the first-line TB drugs to the efficacy of TBM
treatment were comprehensively reviewed by Donald in 2010
(18). Fifty years on these drugs isoniazid, pyrazinamide, rifam-
picin, and streptomycin remain the mainstay of treatment for
the vast majority of patients with TB globally. It is difficult to
think of another common infectious disease whose treatment
regimen has remained largely unchanged for over 50 years.
Vaccine Development
Despite failing to find a cure, Koch continued experimenting
with tuberculin hoping to develop an effective vaccine; how-
ever, it proved not to be effective. Clemens van Pirquet (1874
to 1929), after observing a hypersensitivity reaction to a sec-
ond inoculation with smallpox vaccine, was led to the idea that
Kochs tuberculin might cause a similar reaction in patients
previously exposed to mycobacteria. Charles Mantoux (1877
Scheld_Ch29.indd 475
Chapter 29: Tuberculous Meningitis 475
to 1947) expanded on these ideas and developed the Mantoux
diagnostic test in 1907, which is still in use today. During 1902
to 1920, Albert Calmette and his assistant Camille Gurin de-
veloped a vaccine by serial passage of Mycobacterium bovis
(which can cause TB in both cattle and humans). After 13 years
and 230 passages, the bacille Calmette-Gurin (BCG) strain
was considered attenuated and was first used as a vaccine in
humans in 1921 (2).
The accomplishments in the first half of the twentieth cen-
tury in diagnosis, treatment, and understanding of pathogenesis
seemed to offer the opportunity of eradication. However, the
next 60 years has been fraught with setbacks and TB remains
a huge global public health problem. The first cases of AIDS
came to light in the early 1980s. Since then, it has become clear
that the interaction of TB and HIV has had a severe impact
on both pandemics, while complicating the management of
both diseases. HIV-infected individuals are more susceptible
to both active TB disease and all extrapulmonary forms of TB.
The HIV epidemic has therefore generated significant increases
in the number of adults presenting with TBM in high HIV
prevalence areas. Drug-resistant strains of M. tuberculosis
have continued to increase in prevalence, including multidrug-
resistant (MDR) and extensively drug-resistant (XDR) TB,
which are now present in every region of the world. Huge
advances have been made in unravelling immunology, and
genetics has deepened our understanding of the immunopa-
thology underlying disease; however, vaccination, diagnosis,
and treatment are still reliant on antiquated techniques, which
are inadequate to control the continued pandemic.
BURDEN OF DISEASE
Tuberculosis Epidemiology
In the nineteenth century, TB was highly prevalent in Europe,
with an annual incidence estimated to be greater than 1,000
per 100,000. Mortality was high because patients were only
treated with bed rest or ineffective therapies and it is thought
that over 50% of sufferers died. In the time of Robert Koch,
one out of seven Germans died of TB. In the late nineteenth and
early twentieth century, incidence declined in more developed
countries due to economic development, improved living con-
ditions, hygiene, and the introduction of sanatoria in which
patients were isolated from the general population. After the
introduction of antimycobacterial treatment, the decline in
incidence and mortality accelerated. The initial response was
euphoric, and expectations to extinguish this blazing epidemic
were high.
Despite the initial achievements during the twentieth cen-
tury, global TB burden remains enormous. Worldwide, approx-
imately 2.4 billion people are infected with M. tuberculosis, of
whom 10% will develop active disease during their lifetime.
People infected with HIV with latent TB are 20 to 30 times as
likely to develop active forms of TB (19).
A systematic analysis for the global burden of disease study
in 2010 including mortality data from 187 countries from
1980 to 2010 ranked TB as the 10th leading cause of death
globally. Of the 52.8 million deaths of all causes globally in
2010, 1.2 million were attributable to TB (20). According
to the World Health Organization (WHO), 8.7 million new
cases were reported in 2011 and an estimated 1.4 million died
(21). The Millennium Development Goals aimed to achieve a
50% reduction in prevalence and death rates of TB relative to
1990 levels by the year 2015. According to the WHO, from
1990 to 2011, a reduction of 41% in mortality was observed.
According to the WHO, if the current trend is preserved, the
2/21/14 8:21 PM
 476 Part III: Bacterial and Mycoplasmal Infections
set target for 2015 will be met (21). However, this is depen-
dent on the continued commitment of national TB programs
and policy makers. The TB epidemic is highly pluriform, with
22 developing countries carrying more than 80% of the bur-
den of TB. Demographic factors such as poverty, crowding,
and malnutrition play an important role, as does availability
of good quality TB drugs. The impact of the HIV pandemic
is illustrated by the huge increase in the contribution of HIV/
TB to cause of death patterns among young adult men and
women; by 2010, HIV/TB and injuries combined caused more
than half of deaths among men aged 20 to 39 years (20).
Together with HIV, MDR and XDR TB continue to fuel the
pandemic (21). The goal to eliminate TB as a public health
problem by 2050 seems quixotic without renewed and sus-
tained commitment from international donors and the global
health community.
Burden of Tuberculosis of the Central
Nervous System
The burden of extrapulmonary TB is tightly associated with
the general pandemic and accounts for more than 10% of all
TB cases (21). Of these, about 5% are forms of TB in the CNS.
These estimates are crude because diagnosis of extrapulmonary
TB in general and CNS TB in particular is challenging, and
according to WHO definitions, a patient who has both signs
of pulmonary and extrapulmonary TB should be classified as
having pulmonary TB (21).
In endemic settings, TB is often the leading cause of child-
hood bacterial meningitis (22). In 2009, 7% of all annual
cases of bacterial meningitis and septicemia in the United
Kingdom were caused by TB, being the third leading cause
after meningococcal and pneumococcal disease (23). With
the introduction of meningococcal C (1999) and pneumococ-
cal (2006) vaccines in the routine immunization schedule in
the United Kingdom (and in the absence of an effective TB
vaccine), TBM may well become the lead cause.
In high TB-burden countries, young children aged 0 to
4 years are mostly affected, however, rarely, younger than
3 months of age (24). The age range from 5 to 15 years old is
often referred to as the favored age as this population has
the lowest rate of TB of all forms (25). In countries with a low
prevalence of TB, most cases of TBM are in adults. Commonly
reported risk factors are alcoholism, diabetes, recent cortico-
steroid use, malignancy, and immunosuppression (26). The
advent of HIV has dramatically changed the dynamics of the
TB pandemic.
Mortality and Morbidity
Mortality among TBM cases remains high and varies depend-
ing on age, risk group (HIV), stage of disease upon diagno-
sis, drug sensitivity of the infecting organism, time between
onset of symptoms and initiation of effective antibiotics,
and the sophistication of health care infrastructure and fa-
cilities. Mortality in children ranges between 10% and 20%
(24,25,27,28). Neurologic sequelae are frequent and reported
in more than half of surviving children. In a retrospective sur-
vey of 554 children in South Africa, 74% of patients suffered
long-term disabilities or death (13%), including hearing or
vision impairment (14% and 16% respectively), motor deficits
(44%), and cognitive impairment (77%) (29).
For HIV-uninfected adult patients presenting early (stage I
disease), mortality is approximately 20% (30). Mortality
increases with delayed presentation and advanced stage of
disease (Table 29.1). For patients in stage II, mortality is
approximately 30% and in stage III, 55%. As in children, in
Scheld_Ch29.indd 476
TA B L E 2 9 . 1
TUBERCULOUS MENINGITIS SEVERITY GRADING
ACCORDING TO MEDICAL RESEARCH COUNCIL 1948
Early Patients with mainly nonspecific symptoms, with
little or no clinical signs of meningitis, with no
pareses, in good general condition, and fully
conscious. Diagnosis established mainly on
findings in cerebrospinal fluid (CSF).
Advanced Patients obviously extremely ill, deeply
comatose, or with gross pareses
Medium Patients in a condition between those of the first
two groups
From Medical Research Council. Streptomycin treatment of tubercu-
lous meningitis. Lancet. 1948;1:582596.
adults, permanent neurologic disability affects over half of the
survivors (30). Co-infection with HIV has a major impact on
mortality. In Vietnam, mortality for the corresponding grade
groups in a trial of immediate versus delayed antiretroviral
therapy (ART) for HIV-associated adult TBM was stage I,
40%; stage II, 52%; and stage III, 75% (31). In HIV-infected
children in India, 6-month mortality has also been reported
to be drastically higher than in HIV-negative children (36%
vs. 10%) (32). These mortality figures are a reflection of the
severe immunosuppression in these HIV-infected patients,
illustrating the importance of commitment of policymakers to
invest in accessible integrated TB/HIV care.
The Influence of HIV
The HIV epidemic has undoubtedly fuelled the TB epidemic.
Worldwide, an estimated 34 million people are infected with
HIV (33). An estimated one third of these patients are thought
to be co-infected with M. tuberculosis. HIV-infected patients
with latent TB have a 50% lifetime risk of progressing to active
forms of TB versus HIV-negative patients with latent TB who
have a 10% lifetime risk of developing disease (34). HIV pa-
tients are more likely to develop extrapulmonary forms of TB,
including TBM, and have a higher mortality. Diagnosis of TB
can be more challenging in HIV patients due to a less specific
presentation, wider differential diagnosis, and lower sensitiv-
ity of sputum smear microscopy. However, in contrast, CSF
smear is more likely to be positive in HIV-infected individuals
with TBM due to higher bacillary loads (35). Patients with low
CD4 levels and smear-negative results may have atypical CSF
findings, immunologic tests are not reliable, and neuroimag-
ing may not reveal typical lesions and includes a wider differ-
ential diagnosis (36). Polypharmacy may prove problematic,
with higher toxicity from combined ART and antitubercu-
lous regimens and drug interactions. ART-naive patients who
commence ART treatment during their treatment of TBM may
present with immune reconstitution inflammatory syndrome
(IRIS), which may be particularly detrimental if it presents
intracranially (37).
Drug Resistance
WHO estimates 20% of M .tuberculosis infections worldwide
are now resistant to at least one first-line drug (38). MDR
TBM is resistant to at least rifampicin and isoniazid, the two
most effective first-line agents. MDR TBM has been associated
with very high mortality in both children and adults (3941).
Drug resistance in TBM is rarely diagnosed in time to make
2/21/14 8:21 PM

appropriate treatment adjustments. The difficulties of access
to rapid TB drug susceptibility testing (DST) in much of the
world are compounded by the rarity of a positive isolation
of M. tuberculosis from the CSF. Drug resistance prevalence
among TBM cases will generally follow similar patterns to
those observed regionally for pulmonary TB.
Isoniazid resistance in the absence of concomitant rifam-
picin resistance is more prevalent than MDR TB; 7% of M.
tuberculosis strains globally are now resistant to isoniazid (38).
Because isoniazid is the most effective drug in decreasing the
bacterial load in the first two days of anti-TB treatment, early
recognition of resistance is of great importance, particularly in
TBM cases where rapid killing of bacilli is likely to be crucial. In
Vietnam, isoniazid resistance alone or combined with resistance
to other drugs was found in a third of culture-positive samples
in adult HIV patients with TBM, with 4.3% MDR TBM (40).
In a cohort with predominantly HIV-negative patients, isonia-
zid resistance was found in 37.1% of samples of which 21%
were MDR (overall MDR rate was 5.6%) (39). Mortality from
MDR TBM was 100% in the absence of available second-line
therapy. In children with a culture-proven diagnosis of TBM,
MDR TB or rifampicin monoresistance was identified in 5%
of cases in South Africa. Multidrug resistance, not surprisingly,
was associated with very high mortality (83%) (42).
Isoniazid resistance without rifampicin resistance also has a
significant impact on mortality. An initial analysis of a cohort
of TBM patients in Vietnam failed to find a significant im-
pact of isoniazid resistance (/ streptomycin resistance) on
mortality (43), but a larger study in Vietnamese HIV-positive
patients showed a significant reduction in survival (adjusted
hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.18 to
2.66) among patients infected with isoniazid-resistant, rifam-
picin-susceptible strains compared to those with fully suscep-
tible isolates (40). In a retrospective cohort study in the United
States, researchers also found a significant increase in risk of
death associated with isoniazid resistance (odds ratio [OR],
1.61; 95% CI, 1.08 to 2.40) (44). Among Vietnamese HIV-
positive adult patients, the adjusted hazard ratio for mortality
of MDR TBM patients compared to patients with isolates sus-
ceptible to all agents or streptomycin monoresistant was 5.21
(95% CI, 2.38 to 11.42) (Fig. 29.1).
Long-Term Disability
Very little is known about long-term outcome and disability
for both children and adults. Antituberculous chemotherapy
has been unsuccessful in completely preventing long-term
sequelae; in many cases, diagnosis may be too late, but in
others, significant neurologic damage occurs subsequent to
initiation of treatment. Especially in children, neurocogni-
tive impairment can jeopardize development, education, and
quality of life and place a great burden on families, schooling,
and medical systems. A recent long-term follow-up study on
a South African cohort of pediatric TBM patients who were
severely ill on presentation (stage II or III) reported only 20%
of children to be functionally normal at follow-up (median
6 years after TBM treatment completion). The main areas
of functional deficit were cognitive impairment (80%), poor
scholastic progress (43%), and emotional disturbance (40%).
A smaller proportion of children (25%) had evidence of
motor impairment (45). In a Danish nationwide, population-
based cohort study with up to 30 years follow-up, TBM was
associated with an almost twofold increased long- term risk of
dying compared to a background population (mortality risk
ratio [MRR], 1.79; 95%, CI, 1.09 to 2.95). In this study, the
underlying cause of long-term death was most frequently TBM
itself rather than secondary to the most commonly reported
neurologic sequelae (46).
Scheld_Ch29.indd 477
Chapter 29: Tuberculous Meningitis 477
Neurologic sequelae most frequently described in adults are
cognitive impairment, motor deficits, cranial nerve palsy, and
optic atrophy (47). A 5-year follow-up on Vietnamese adults
with TBM who took part in a randomized controlled trial on
the effect of dexamethasone on survival could only demonstrate
an overall benefit of dexamethasone up to 2 years following
treatment. Five years after treatment completion, there was
no difference in overall survival or disability outcome in both
groups. In the group receiving dexamethasone, 48.4% (vs.
52.7% in placebo group) of patients had died at 5 years (31%
at 9 months), 6.8% (vs. 7.4% in the placebo group) were se-
verely disabled, 17.2% (vs. 14.8% in placebo group) had inter-
mediate disability, and only 27.6% (vs. 25.1% in the placebo
group) had good outcome (48). However, the beneficial effect
of dexamethasone was preserved at 5 years for patients with
stage I TBM at presentation, demonstrating that, contrary to
preceding medical wisdom, patients with stage I TBM are the
group who gain the greatest benefit from corticosteroids.
Vaccination with Bacilli Calmette-Guerin and
Protection Against Tuberculous Meningitis
The controversies surrounding the protection that the BCG vac-
cine confers to adult pulmonary and meningeal TB still exist. In
adults, reported efficacy against all forms has ranged from as
high as 80% to 0%. It is proposed that the vaccine establishes
immunity by inducing effector memory T cells in the lungs that
gradually wane after 10 to 15 years rather than building a lon-
ger lasting central memory (49). Various theories have been
proposed for the differences observed in efficacy, including dif-
ferences in the circulating M. tuberculosis strains, BCG vaccine
strains, or preimmunization exposure to environmental myco-
bacteria. Nonetheless, consensus on the benefit of prevention of
severe forms of childhood TB including TBM and miliary TB is
established. The vaccine is thought to be 52% to 86% protec-
tive against developing the severe complications of childhood
TB such as miliary TB and TBM (50). It has been estimated that
the 100.5 million BCG vaccinations given to infants in 2002
would have prevented 29,729 cases of TBM in children during
their first 5 years of life, or 1 case for every 3,435 vaccinations,
and 11,486 cases of miliary TB, or 1 case for every 9,314 vac-
cinations. Based on these data, it is considered a cost-effective
intervention in Southeast Asia, Africa, and the Western Pacific,
where TB infection rate and vaccine coverage are highest (50).
In BCG-vaccinated children in India who do develop TBM, the
clinical spectrum of disease does not seem to be ameliorated
(51). The BCG is the most widely used vaccination globally.
IMMUNOPATHOGENESIS
Mycobacterium tuberculosis
Transmission of TB occurs when a person inhales mycobacteria-
laden droplet nuclei. One to five bacilli are sufficient to cause in-
fection. M. tuberculosis is the causative agent of almost all cases
of TBM. M. tuberculosis is an obligate aerobic, intracellular
bacterium. On the cell surface, it has a waxy coating. The high
lipid content of the cell wall renders these bacilli imperceptible
to the Gram stain. The organisms are slow growing with a gen-
eration time of 15 to 20 hours, contrasting with that of some
pyogenic bacteria, such as Streptococcus pneumoniae, Neisseria
meningitides, and Staphylococcus aureus, with generation times
of less than an hour. The complex antigenic structure of the
cell wall includes polysaccharides, proteins, peptides, lipids,
and glycolipids with specific immunologic properties. Other
2/21/14 8:21 PM
 478 Part III: Bacterial and Mycoplasmal Infections

A Survival by resistance group B Survival by resistance category

1.00 1.00
Survival Probability

Survival Probability
0.75 0.75

Sensitive/SM mono-resistant
Fully sensitive
0.50 0.50
SM mono-resistant
INH+/-SM resistance
0.25 INH mono-resistant 0.25

MDR INH+SM resistant MDR

0.00 0.00
0 3 6 9 0 3 6 9
Months Since Randomization Months Since Randomization
No. at risk No. at risk
Fully sensitive 98 52 41 35 Sensitive 126 66 53 47
STR mono-resistant 28 14 12 12 INH+/-STR resistance 52 25 11 8
INH mono-resistant 12 6 2 2 MDR 8 0 0 0
INH+STR resistant 40 19 9 6
MDR 8 0 0 0

C Survival by lineage D Survival by lineage of patients infected with

fully susceptible M. tuberculosis strains only
1.00 1.00
Survival Probability

Survival Probability

0.75 0.75
East Asian/Beijing

0.50 East Asian/Beijing 0.50

Euro-American Euro-American
0.25 0.25
Indo-Oceanic
Indo-Oceanic
0.00 0.00
0 3 6 9 0 3 6 9
Months Since Randomization Months Since Randomization
No. at risk No. at risk
Indo-Oceanic 18 5 3 3 Indo-Oceanic 14 3 2 2
Euro-American 22 10 6 5 Euro-American 14 7 6 5
Beijing 82 43 30 26 Beijing 55 33 26 23

FIGURE 29.1 Survival by drug-resistance pattern of pathogen of an HIV-positive cohort. SM,

streptomycin; INH, isoniazid; MDR, multidrug resistant. (Tho DQ, Trk ME, Yen NT. Influence of
antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated
tuberculous meningitis. Antimicrob Agents Chemother. 2012;56[6]:30743079.)

antigens are contained within the cytoplasm. These molecules
determine the characteristic immune response to tuberculous
infection and its resultant pathology.
Macrophages and Granuloma Formation
In pulmonary TB, the alveolar macrophage has a central role
in the initial innate immune response to M. tuberculosis as
well as in initiating the adaptive T-cell immunity. If upon
recognition and ingestion of bacteria, the macrophages fail to
eradicate M. tuberculosis, T cells are recruited to the site of
infection and generate a chronic inflammation and granuloma
formation in order to contain the infection (52). The granu-
loma is pivotal to tuberculous disease and characterized by the
formation of central necrosis of the lesion, often referred to as
caseation. In solid necrosis, mycobacterial growth is inhibited,
and the infection can be contained and can remain dormant.
Granuloma with liquefied central necrosis provides an optimal
environment for extracellular mycobacteria and may rupture,
allowing the spread of bacilli to other parts of the lung, the
bloodstream, or the exterior environment (53).

Scheld_Ch29.indd 478 2/21/14 8:21 PM


The onset of the adaptive immune response to M. tuberculosis
is delayed compared to other infections. This delay allows for
an exponential growth of the mycobacteria before it is slowed
or arrested by the host defenses (54). For the adaptive immune
response in TB, CD4 T cells are essential. CD4 T cells exert
their protective effect by the production of cytokines, primar-
ily interferon- (IFN-) and tumor necrosis factor-
(TNF-
). however, immunologic interpretation is imperfect. Murine
IFN- is a central protective cytokine in mycobacterial infection
proposed to protect by mediating the induction of nitric oxide
synthase (NOS), enhancing the microbicidal system within mac-
rophages (55). TNF-
plays a key role in granuloma formation current knowledge on pathogenesis of CNS TB is based on
and macrophage induction and has immunoregulatory prop-
erties (53). Other cytokines involved in mycobacterial disease
control are interleukin (IL)-1B, IL-6, IL-12, IL-15, IL-18 (proin-
flammatory) and IL-10, IL-4, and transforming growth factor-
(TGF-) (antiinflammatory) (53,56). In addition to the complex
regulatory meshwork of cells and immune mediators that con-
trol the innate and adaptive immune response, different compo-
nents may be negatively influenced by microbe-specific virulence
factors. The virulence of the mycobacteria is thought be founded
in their ability to regulate macrophage chemotaxis, necrosis, and
apoptosis, facilitating a beneficial environment within the mac-
rophage or extracellularly in the granuloma and consequently
their own proliferation and possibly also facilitating egress to
other sites of infection, including the CNS (57).
Immune Response in Tuberculous Meningitis
TNF-
is thought to have a crucial but controversial role in
pathogenesis of TBM. TNF-
is a proinflammatory cytokine
produced by monocytes, macrophages, and dendritic cells upon
stimulation with mycobacteria or mycobacterial products and
plays an essential role in granuloma formation and mainte-
nance (58). Whereas in pulmonary TB, TNF-
-neutralizing
drugs can lead to progression to (fatal) disease, in TBM, an
elevated production of TNF-
has been proposed to be associ-
ated with more severe disease, but it has not been established
if this is merely a marker of advanced disease or if dispro-
portionate TNF-
responses mediate disease progression. It is As a result of this infection, a dense gelatinous fibrinocellular
probable that protective immunity is dependent on a delicate
balance between pro- and antiinflammatory factors and that
individuals with responses at the extremities of the spectrum
are both at risk of more severe disease.
In vitro infection of microglial cells (macrophages of the
brain) results in the production of robust amounts of TNF-
, IL-6, IL-1B, CCL2, CCL5, and CXCL10 (59). In rabbits spinal cord and cerebellum, often into the sylvian fissures. It can
infected intracisternally with M. bovis, oral thalidomide
treatment led to reduction of TNF-
levels and clinical may develop, giving rise to ischemic events. Hydrocephalus can
improvement (60). In vivo in TBM, TNF-
levels show a peak develop by blockage of CSF circulation when exudates cover
in the early phase of disease but drop soon after initiation
of treatment (61). Some researchers found an association in
disease severity and CSF levels of IFN- and TNF-
in both of the aqueduct and third ventricle (66,69). Exudate, vasculi-
HIV-positive and HIV-negative patients (62). This was not
supported in a Vietnamese cohort, in which the only cytokine
independently associated with severe disease was IL-6. HIV
co-infection was associated with attenuated levels of several
immune mediators in CSF, in whom low levels of IFN- did
show an association with death, implying a protective role for
IFN-. Interestingly, the addition of dexamethasone to treat-
ment was not associated with an attenuation of inflammatory
indices but did lead to a decreased mortality rate (61).
The brain provides a unique immunologic environment to
pathogens. We know most of the inflammatory mediators are
produced locally at the site of infection. Immunologic studies
usually involve cells from peripheral blood or CSF. Compared to
the infected tissue, even in pulmonary TB, low proportions of M.
tuberculosisspecific effector cells are found in the blood (63).
Scheld_Ch29.indd 479
Chapter 29: Tuberculous Meningitis 479
Central Nervous System Pathology
Unfortunately, current postmortem studies are scant (64,65)
but would contribute a great deal to our understanding of the
disease. Rabbit models are thought to mimic human disease;
studies are not of use in directly studying neuropathogenesis
in TBM although are widely used in understanding suscep-
tibility and protective responses to mycobacteria (66). Our
the hypothesis promulgated over 70 years ago. Even though
later researchers have expressed criticism (67), their view
has been carried forward by most recent experts; in short,
small intracranial granulomas are formed after seeding of ba-
cilli in the brain during a short-lived bacteremia. These Rich
foci may rupture during periods of relative immunosuppres-
sion or other unknown stimuli, releasing mycobacteria in the
subarachnoid space or ventricular space which may give rise to
the various forms of CNS TB: meningitis, tuberculoma, tuber-
culous abscess, encephalitis, or spinal cord TB. Incorporating
more recent pathologic data, Donald and colleagues (68) have
proposed the following classification of pathogenesis in TBM:
1. The hematogenous dissemination of bacilli from the pri-
mary complex establishes a cortical or meningeal focus.
Soon after its establishment, this proceeds to caseate
and discharge its contents into the subarachnoid space.
In young children, this hematogenous dissemination is
particularly likely to take the form of miliary TB.
2. In a small minority of cases, hematogenous dissemination
may establish a caseating focus in the choroid plexus or in
the walls of the ventricles from which TBM may develop.
3. Hematogenous dissemination at the time of primary infection,
or later, establishes a cortical or meningeal focus. This is ini-
tially controlled but may, at any time thereafter, undergo case-
ation and discharge its contents into the subarachnoid space.
4. A caseous process extends from adjacent structures such as
the vertebrae or middle ear to involve the CNS (very rare).
leptomeningeal exudate is formed. Microscopically, this exudate
contains small and large mononuclear cells, including epitheli-
oid cells, which also act as macrophages. The exudate typically
centers around the interpeduncular fossa. When substantial, the
exudate may extend anteriorly to the suprasellar region, and it
may extend through the prepontine cistern and surround the
envelope and compress cranial nerves and arteries. Vasculitis
the choroid plexus and the basal subarachnoid cisterns around
the midbrain and pons or when tuberculoma cause narrowing
tis, and hydrocephalus can cause changes in brain parenchyma.
Border-zone encephalitis describes a tissue reaction com-
monly seen in brain tissue adjacent to zones of thick adher-
ent exudate. The brain tissue softens, showing signs of edema,
perivascular infiltration, and microglial reaction (66,70). In the
following paragraphs, we will briefly discuss other forms of
CNS TB; the rest of the chapter will focus on TBM.
Tuberculoma in the Central Nervous System
CNS tuberculoma can be encountered separate from TBM, as
it is estimated only 10% of patients with tuberculoma develop
meningitis (71,72). Conversely, in some radiologic studies,
tuberculomas were observed either at presentation or developed
2/21/14 8:21 PM
 480 Part III: Bacterial and Mycoplasmal Infections
during treatment in over 60% of patients with TBM (73). In
endemic areas, tuberculoma represents the cause of up to 30%
of patients presenting with intracranial masses. Tuberculoma
can be solitary or multiple, with some reporting hundreds of
lesions in one patient, dubbed tuberculomatosis cerebri (71).
In general, tuberculomas in the context of TBM, although de-
pending on the location, are not associated with worse out-
come and will resolve on antituberculous treatment (74).
Rarely, tuberculomas coalesce and liquefy to cause tuberculous
cerebral abscess, which may necessitate surgery (75).
Tuberculous Encephalopathy
Tuberculous encephalopathy (TBE) was first described in 1966
in Indian children who presented with symptoms of a diffuse
cerebral involvement (coma, convulsions, movement disorders)
in the context of disseminated TB but normal cerebrospinal find-
ings (76). As there was no clear evidence of TB infection within
the brain, the authors proposed an alternative pathogenetic im-
mune-/hypersensitivity-mediated explanation for this syndrome,
pathologically characterized by white matter, myelin loss with
commensurate axonal loss, and focal necrosis. The principal
pathogenetic factor in the group of cases was said to be an allergic
cerebral edema leading to an edematous leukoencephalopathy
similar to acute disseminated encephalomyelitis (ADEM) (77).
However, use of steroids for these patients had proven ineffec-
tive. Careful review of the original publication and the literature
of the following 40 years led South African experts to reappraise
this entity in 2007, concluding that the patient population joined
under the umbrella of TBE was clinically and histopathologi-
cally heterogenous. According to the authors, other plausible
factors may have caused the typical findings of TBE, including
hypoxic ischemia and toxic or drug-related complications of TB
infection (78). TBE has not been reported in adults.
Tuberculosis of the Spinal Cord
Tuberculous radiculomyelitis (TBRM) has been used as a generic
term to include arachnoiditis, intramedullary tuberculoma, and
spinal cord complications of TBM (79). Currently, it is thought
that TBRM may develop in alternative ways, either (1) as a pri-
mary lesion, (2) as an extension from TBM, or (3) secondary to
vertebral TB (80). Intramedullary tuberculomas are rare. The
pathogenesis is parallel to CNS TB: via bloodborne seeding of
bacilli, granuloma formation follows, drainage persists into the
subarachnoid space which may lead to an inflammatory reac-
tion in the pia-arachnoid, which may lead to secondary men-
ingitis (81). Clinical presentation may vary, usually presenting
with symptoms of a subacute intramedullary space-occupying
lesion (82). Early recognition of this form of CNS tuberculoma
is important because early surgical intervention and decom-
pression followed by long-term antituberculous chemotherapy
may significantly improve morbidity. Accurate diagnosis can be
helped by magnetic resonance imaging (MRI) (83).
Vascular Events
Secondary to the infection with M. tuberculosis and resultant
intracerebral immunologic response, stroke may develop. In the
late nineteenth and early twentieth century, vascular involvement
in TBM was recognized and extensively studied. Still the vas-
cular events in TBM are a pressing subject in TBM research,
because the damage caused by stroke is often irreversible and the
occurrence of stroke is associated with worse outcome (84,85).
Scheld_Ch29.indd 480
Stroke was reported in 13% to 57% of Indian patients with
TBM (85). In Vietnam, serial MRI revealed stroke in only 9%
of patients upon diagnosis, but after 60 days of treatment,
41% of patients had developed stroke (73). This may be even
more prevalent in children, with infarcts reported in 76% of
systematically scanned children in South Africa (86). Most in-
farcts occur in the region of the arteria cerebri media (middle
cerebral artery [MCA]), particularly in the medial lenticulostri-
ate and thalamoperforating vessels, causing the characteristic
basal ganglia infarcts (84). It is thought that this vascular in-
volvement follows the distribution of the meningeal exudates,
which causes local vasculitis, particularly at the base of the
brain and along the sylvian fissures. The proposed mechanisms
by which the vessels occlude resulting in ischemia are multi-
form. Meticulous histopathologic descriptions of the vascular
changes in TBM were published by Hektoen (87) in the late
nineteenth century. He concluded that the changes could be ei-
ther explained by an endarteritis with subendothelial tubercles,
proposed to be caused by direct hematogenous invasion of ba-
cilli in the vessel wall, or tuberculous proliferation affected the
arteries from the adventitia inward to reach the media and the
intima (87). Currently, largely based on the findings of Rich
and McCordock (9), the widely accepted view is that the in-
flammation is spread from outward (adventitia) in rather than
reversed. Other stenosing or damaging mechanisms are thought
to be intimal proliferation, vessel wall necrosis, or vasospasms.
The role of vessel thrombosis is unclear. There is some evidence
that strokes early in the course of disease are caused by vaso-
spasms and later strokes involve proliferative intimal disease,
raising the prospect for therapeutic interventions for the pre-
vention of thrombotic and vasospasm-associated stroke (9,84).
The Role of Miliary Tuberculosis
Rich and McCordock (9) did not assign a role for miliary TB
in the pathogenesis of TBM as the Rich foci found in their
subjects were often older than the miliary lesions, and there-
fore military TB was deemed to be an incidental occurrence
rather than part of the etiology. Even though this is the view
carried forward in most textbooks, some researchers claim
that, particularly in children and possibly in immunocompro-
mised patients, the disseminated state of miliary TB increases
the likelihood of the formation of leptomeningeal granuloma
(Rich foci) (68). This may well explain the frequent asso-
ciation of TBM with miliary TB (Fig. 29.2). In children, the
FIGURE 29.2 Chest x-ray showing miliary TB of the lungs.
2/21/14 8:21 PM
 Chapter 29: Tuberculous Meningitis 481

prevalence of miliary TB of the leptomeninges is much higher TA B L E 2 9 . 2

than in adults. Younger children most often develop both TBM
and miliary TB within 3 months of primary infection. Children PRESENTING CLINICAL FEATURES IN ADULTS AND
with concomitant miliary TB and TBM are also significantly OLDER CHILDREN
younger than those with TBM only (24). The immune system
of these young children and the immunocompromised may SYMPTOM FREQUENCY/RANGE
not be robust enough to prevent an overwhelming bacteremia,
exemplified by the miliary character of disease. In these indi- Headache 50%80%
viduals, TBM may be the result of a more direct spread of the Fever 60%95%
pathogen to the meninges and subarachnoid space. Vomiting 30%60%
Photophobia 5%10%
CLINICAL PRESENTATION Anorexia/weight loss 60%80%

CLINICAL SIGN
General Symptoms on Presentation
Neck stiffness 40%80%
TBM typically presents in a subacute manner. Presenting signs,
Confusion 10%30%
symptoms, CSF findings, and frequencies according to the British
Infection Society guidelines are shown in Table 29.2. In adults, Coma 30%60%
the majority of patients present with fever, headache, nuchal Cranial nerve palsy 30%50%
rigidity, vomiting, meningism, abnormal mental stage, and pho- VI 30%40%
tophobia (75,88,89). Weight loss, night sweats, lethargy, and
III 5%15%
cough have also be reported (90). The mean duration of symp-
toms is typically more than 5 days. A longer duration of history VII 10%20%
is associated with worse symptomatology on presentation. Hemiparesis 10%20%
In 1948, the British Medical Research Council first pub- Paraparesis 5%10%
lished a classification of TBM patients according to the severity
Seizures adults 5%
of disease (see Table 29.1). Over the years, these stage groups
have been refined and are published in different formats. In Children 50%
general, both adult and pediatric patients in stage I are fully
conscious and may have nonspecific symptoms; in stage II, CEREBROSPINAL FLUID
patients will have signs of meningitis, lethargy, or cranial FINDINGS
nerve palsies; in stage III, TBM is accompanied by stupor,
severe illness, gross paralysis, or paresis, convulsions, and or Clear appearance 80%90%
involuntary movements (51). In clinical practice and research, Opening pressure 25 cm H2O 50%
it would be more useful to have a Glasgow Coma Scale (GCS) Leucocyte count (103/mL) 51,000
guided staging system. An example is shown in Table 29.3.
Typical findings upon neurologic examination are VI cere- Neutrophils 10%70%
bral nerve palsy (present in up to 40% of patients) but also Lymphocytes 30%90%
nerves III and VII are often involved (5% to 20%). Hemiparesis Protein (g/L) 0.453.0
and paraparesis may be present upon presentation (in 5% to
Lactate (mmol/L) 5.010.0
20% of patients) (75,88) but may also develop during treat-
ment secondary to infarction. Seizures are rarely a presenting Glucose CSF/Blood 0.5 95%
symptom in adults, however in children are reported in around
50% of patients (28,29).Visual disturbances, decreased vision, Thwaites G, Fisher M, Hemingway C, et al. British Infection Society
and diplopia may have a variety of causes, including primary guidelines for the diagnosis and treatment of tuberculosis of the central
nervous system in adults and children. J Infect. 2009;59(3):167187.
involvement of optic nerve by tuberculous lesion leading to
optic neuritis, optochiasmatic arachnoiditis (OCA), and
tuberculoma in the chiasmatic region or in the optic pathways
(91). More often, visual disturbances are secondary to raised
intracranial pressure or ethambutol toxicity. A rare cause of TA B L E 2 9 . 3
visual loss in TBM is neuroretinitis (92). Tuberculoma can
cause a wide array of neurologic symptoms associated with MEDICAL RESEARCH COUNCIL GRADING SYSTEM
space-occupying lesions depending on their location within the FOR TUBERCULOUS MENINGITIS
CNS. Urinary retention is common which may indicate spinal
cord involvement. Movement disorders are associated with TBM Grade Diagnostic Criteria
basal ganglia involvement, mostly tremor, but also chorea,
Grade I Glasgow coma score 15, no focal neurology
ballismus, and myoclonus have been reported (88).
The initial symptoms of TBM may be nonspecific, but Grade II Glasgow coma score 1114 or
within the context of prolonged symptoms, a previous history Glasgow coma score 15 with focal neurology
of TB, or a chest x-ray consistent with recent or past TB Grade III Glasgow coma score 10
infection, this history must raise heightened suspicion with the
treating physician. In many textbooks, TBM is described as
From Heemskerk D, Day J, Chau TT, et al. Intensified treatment
chronic or subacute meningitis; however, this terminology is with high dose rifampicin and levofloxacin compared to standard
unhelpful. Once a patient with TBM seeks medical care, he treatment for adult patients with tuberculous meningitis (TBM-IT):
or she should be treated as a medical emergency as with any protocol for a randomized controlled trial. Trials. 2011;12:25.
other meningitis.

Scheld_Ch29.indd 481 2/21/14 8:21 PM

 482 Part III: Bacterial and Mycoplasmal Infections
Children may have a more protracted and nonspecific
presentation. In TB-endemic settings, it is often the most com-
mon cause of childhood bacterial forms of meningitis (22).
Prodromal symptoms include fever, headache, anorexia, and
vomiting in older children, whereas failure to thrive, poor
appetite, vomiting, and sleep disturbances are more com-
mon in younger children or infants. Cough and weakness
may also be reported (28,29).As these symptoms are non-
specific, children tend to present to the hospital only when
the clinical situation has deteriorated and they are already in
the later stages of disease (29). Similar to adults, when ini-
tial nonspecific symptoms are associated with a history of
recent contact with a case of documented TB, TBM should
be suspected. A prolonged history of more than 5 days, focal
neurologic deficit, and abnormal movements have been found
to be independently predictive of TBM (27). Examination
may reveal nonspecific signs of meningism, failure to thrive,
and in younger children, a bulging fontanel or increased head
circumference. Funduscopy may reveal signs of papilledema
or retinal involvement. In a retrospective study of 554 South
African children, 97% presented in stage II or III, with a
median duration of symptoms of 9 days. Meningeal irritation
was the most frequent finding (98%). Convulsions (47%) and
mono-/para-/quadri-/hemiplegia (63%) were also frequently
observed. Cranial nerve palsies were less common (27%) than
in adults, as was raised intracranial pressure (23%) (29).
The emergence of HIV has changed the epidemiology of TB
and particularly the clinical outcome of disease. HIV-infected
patients are more likely to develop extrapulmonary forms of
the disease. TBM is considered an AIDS-defining condition.
Research studies do not suggest that HIV greatly alters the
clinical presentation of TBM, especially in patients with higher
CD4 counts; the clinical presentation may mirror that seen
in HIV-negative individuals. Patients with lower CD4 counts
may have a more atypical course of disease, with less specific
and more subtle signs and wider differential diagnosis, render-
ing diagnosis more challenging (36). Therefore, HIV-infected
patients may present later during the course of disease, with
altered consciousness, and consequently more often in the
advanced stages of disease (35). HIV patients are more likely
to have impaired cognition, generalized lymphadenopathy,
and hepatosplenomegaly (32). A retrospective study compar-
ing clinical presentation and outcome in children with and
without HIV infection surprisingly found that HIV-uninfected
children were more likely to present with a decreased level
of consciousness; this may be related to the poor immune
response in immunocompromised children. Similar to adults,
HIV-infected children had a longer history of being unwell,
poorer nutritional state, more commonly had accompanying
hepatosplenomegaly, lymphadenopathy, and otorrhea (93).
Despite the similarity in presentation, outcome is significantly
worse for HIV-infected adults and children with TBM.
Progression During Treatment
Paradoxical responses during antituberculous treatment are
frequently reported despite appropriate chemotherapy with
susceptible bacilli. This can be encountered in all tissues but
most often in the lungs, lymph nodes, and the brain (94). In the
brain, tuberculoma may develop or enlarge during treatment
for pulmonary TB, TBM, or miliary TB. Either discovered on
routine brain imaging or accompanied by worsening of symp-
toms, signs of a space-occupying lesion, or convulsions. This
generally occurs within 1 to 4 months of starting treatment,
often after initial improvement. Antituberculous therapy
should be continued; the addition of systemic corticoste-
roids may be considered (95). Within the context of a sound
diagnosis and microbiologic confirmation of a susceptible
Scheld_Ch29.indd 482
pathogen, paradoxical response can be diagnosed clinically;
however, incorrect diagnosis, drug resistance, and cerebral
infarction may be alternative causes of deterioration despite
treatment. Early recognition of these alternative causes is
important as they warrant urgent intervention.
In TBM, vascular events are most often ischemic in nature.
Vascular involvement is more frequently seen in chronic men-
ingitides than in treated acute bacterial forms of meningitis
(96). Other infective causes of stroke in tropical regions may
include malaria, syphilis, Chagas disease, cysticercosis. Events
can go unnoticed, as they occur silently or in severely ill pa-
tients already in deep coma. The most common signs of TBM-
associated stroke are mono- or hemiplegia but also may present
as lowered consciousness, disorders of movement, seizures,
cranial nerve palsies, papilledema, and decerebration (84).
Clearly, neurologic deterioration also can have its origin in a tu-
berculoma, cerebral edema, or infiltrating exudate (97). Unlike
hypertensive or atherothrombotic stroke, transient ischemic at-
tacks (TIAs) and lacunar lesions are rare in TBM (84). Patients
may present with symptoms of stroke but more often develop
stroke later in the course of disease, typically during the first
weeks of treatment (73,84). It is not currently possible to pre-
dict which patients will develop stroke and it is associated with
higher mortality and morbidity. Initial imaging studies may not
be sensitive enough to detect the early changes of an ischemic
event. Antithrombotic therapies such as aspirin and dipyridam-
ole which prevent or reduce the incidence of stroke may im-
prove outcomes in TBM and warrant further clinical study.
DIAGNOSIS
Clinical Case Definition
Early recognition of TBM is pivotal, because prompt initiation
of treatment greatly increases chances of survival and reduces
disability. However, early symptoms are nonspecific and
diagnostic confirmation has hardly improved since the early
twentieth century. Ziehl-Neelsen smear for acid-fast bacilli is
central to diagnosis because it gives rapid results; however, the
reported sensitivity is low. Sensitivity estimates depend on the
criteria used for gold standard and range widely from 10%
to 60%. This wide variation is likely to depend on many fac-
tors including laboratory performance, workload, technician
diligence and experience, time from taking the sample to stain-
ing in the laboratory, and volume of CSF examined. Liquid
culture of M. tuberculosis is considered the gold standard for
diagnosis, but due to the slow growing nature of mycobacteria,
the time to a positive result may range from 2 to 8 weeks. This
renders the test ineffective for clinical decision making regard-
ing treatment initiation, although a positive result can confirm
the decision to continue therapy (although a negative result
should not automatically lead to stopping) and provides an
isolate for drug susceptibility evaluations. A suggestive history
must raise clinical suspicion. A clinical diagnostic algorithm
based on prospective data and validated against a second
data set is available based on clinical and laboratory features
(98,99). Different clinical algorithms are published through-
out the literature; those of most use are based on simple
clinical and laboratory criteria and can be used in resource-
limited settings, where disease burden is highest. Table 29.4
shows an example.
In order to address the heterogeneity in clinical diagno-
sis among published research studies of TBM, a consensus
score-based case definition, based on expert opinion, has been
published for use in the research context, with an alternative
scoring if imaging is not available. This case definition is not
2/21/14 8:21 PM

TA B L E 2 9 . 4
DIAGNOSTIC CRITERIA OF TUBERCULOUS
MENINGITIS USED IN CLINICAL TRIALS
Classification Diagnostic Criteria
Definite TBM Clinical meningitis plus acid-fast bacilli seen
in the CSF or
Mycobacterium tuberculosis cultured from
the CSF
Probable TBM Clinical meningitis plus one of the following
criteria:
Radiographic evidence of pulmonary
tuberculosis
Acid-fast bacilli seen in sputum or
gastric fluid
Evidence of extrapulmonary tuberculosis
CT or MRI brain scan features
consistent with TBM
Possible TBM Clinical meningitis plus 2 of the following
criteria:
History of previous tuberculosis
Illness duration 5 days
Glasgow coma score 15
Focal neurologic signs
and 2 of the following criteria:
Yellow CSF
50% lymphocytes in the CSF
CSF glucose 50% blood glucose
From Heemskerk D, Day J, Chau TT, et al. Intensified treatment
with high dose rifampicin and levofloxacin compared to standard
treatment for adult patients with tuberculous meningitis (TBM-IT):
protocol for a randomized controlled trial. Trials. 2011;12:25.
intended to determine treatment decisions and may be less
practical in the clinical setting. In particular, it should not be
used to exclude a diagnosis of TBM (100) (Table 29.5).
Without the context of a suggestive clinical history, TBM
can mimic other chronic meningoencephalitides. Notably, in
HIV-infected patients, the chief obstacle in clinical practice
is the distinction from other chronic forms of meningitis, in
particularly cryptococcal meningitis, cerebral toxoplasmosis,
cytomegalovirus encephalitis, and CNS lymphoma. Because
diagnostic yield from smear is generally low, careful exclu-
sion of other diagnoses is imperative. As soon as suspicion
is raised, history taking and additional investigations should
be directed toward the exposure to TB and ruling out other
treatable causes.
Cerebrospinal Fluid Analysis
Fundamental to diagnosis is the lumbar puncture and conse-
quent CSF analysis. CSF pressure is raised (20 cm H2O) in
approximately 50% of adults and 40% to 75% of children
(10 cm H2O). Typically, the CSF is straw colored. The
results can be equivocal. The white cell count (WCC) is generally
lower (10 to 1,000  106 cells/mL) than in bacterial meningitis,
predominantly lymphocytic, with a low serum to CSF glucose
ratio (50%). Lactate is usually raised, reflecting intracerebral
metabolic disturbances or ischemic processes. Raised total protein
levels (0.5 g/L) are an indication of bloodbrain barrier disrup-
tion or increased intracerebral production of immunoglobulins.
Scheld_Ch29.indd 483
Chapter 29: Tuberculous Meningitis 483
In children, CSF modifications are similar to adults; however,
smear and culture are less sensitive.
In HIV-positive patients, atypical findings are encoun-
tered in a considerable proportion of patients, which may
lead to delay in diagnosis and treatment. Normal levels of
lactate, glucose, protein, and WCC are more often reported
in HIV; even completely normal CSF findings can be found
particularly in patients with severe immunosuppression (CD4
count 50 cells/L). In the context of HIV, neutrophils often
predominate in the CSF cell population (37).
Essential to the search for acid-fast bacilli is the volume of
the CSF sample, the time spent on microscopic examination,
and the efficiency with which the microbiology, biochemistry,
and hematology laboratories use the precious CSF sample.
Increasing the volume (to a minimum of 6 mL) and slide
examination time to a standard time (preferably 30 minutes)
can improve the yield to more than 60% of clinically diag-
nosed cases (101). Particularly for pediatric patients, it can be
difficult to obtain large volumes of CSF, but drawing of larger
volumes should be encouraged to improve the confirmation
rate, where not contraindicated. It should be remembered that
the major safety issue relates to the decision on whether to
perform a lumbar puncture; the volume of CSF then taken is
of secondary consequence. Hence having made the decision
to perform a CSF, it is only ethical to then take a volume of
CSF that will give a good chance of improving the care of the
patient. The CSF should be concentrated prior to examina-
tion of the deposit, either by centrifugation or filtration (102).
Direct smear examination of CSF is rarely positive.
Chest X-Ray
The chest x-ray may reveal active or previous infection with
M. tuberculosis. In children, signs of primary infection may
be noted on chest x-ray. In adults, the chest x-ray is often
normal, but all typical lesions can be found including apical
scarring, calcified Ghon complex, upper lobe infiltration, and
nodular and cavitating disease. Miliary TB is frequently asso-
ciated with TBM (see Fig. 29.2) found on chest x-ray in 25%
to 50% of adults and 15% to 25% of children with TBM
(103,104).
Mycobacterial Culture
As for CSF smear, sensitivity of culture of M. tuberculosis
from the CSF is increased by using a larger volume of CSF,
which should be concentrated prior to inoculation of the
deposit wherever possible. Previously, Lowenstein-Jensen
(LJ) media and later agar media (Middlebrook 7H10, 7H11)
were recommended; however, liquid culture techniques show
increased sensitivity and more rapid turnaround times for the
isolation of mycobacteria and should be used where possible.
Commercial liquid culture systems include BACTEC MGIT
960 system (Becton Dickinson Microbiology Systems, Sparks,
MD) and MB/BacT system (BioMrieux, Durham, NC) and
have reduced the time to results for both isolation and DST of
mycobacteria (105). CSF cultures generally become positive
between 10 and 21 days on commercial liquid culture systems,
although late positives may occur after 35 days due to the low
bacillary load (106,107).
The microscopically observed drug susceptibility
(MODS) assay is a noncommercial liquid culture technique
with minimal technical requirements that can detect both
mycobacteria and drug resistance (108). In TBM, MODS
culture has shown comparable sensitivity to mycobacteria
2/21/14 8:21 PM
 484 Part III: Bacterial and Mycoplasmal Infections

TA B L E 2 9 . 5
UNIFORM CASE DEFINITION

CLINICAL CRITERIA DIAGNOSTIC SCORE

Maximum category score  6

Symptom duration of more than 5 days 4

Systemic symptoms suggestive of tuberculosis (one or more of the following): 2
weight loss (or poor weight gain in children), night sweats, or persistent cough
for more than 2 weeks
History of recent (within past year) close contact with an individual with 2
pulmonary tuberculosis or a positive TST or IGRA (only in children younger
than 10 years of age)
Focal neurologic deficit (excluding cranial nerve palsies) 1
Cranial nerve palsy 1
Altered consciousness 1

CSF CRITERIA Maximum category score  4

Clear appearance 1
Cells: 10500/L 1
Lymphocytic predominance (50%) 1
Protein concentration greater than 1 g/L 1
CSF-to-plasma glucose ratio of less than 50% or an absolute CSF glucose 1
concentration less than 2  2 mmol/L

CEREBRAL IMAGING CRITERIA Maximum category score  6

Hydrocephalus 1
Basal meningeal enhancement 2
Tuberculoma 2
Infarct 1
Precontrast basal hyperdensity 2

EVIDENCE OF TUBERCULOSIS ELSEWHERE Maximum category score  4

Chest radiograph suggestive of active tuberculosis: signs of tuberculosis  2; 2/4

miliary tuberculosis  4
CT/ MRI/ultrasound evidence for tuberculosis outside the CNS 2
AFB identified or Mycobacterium tuberculosis cultured from another sourcethat 4
is, sputum, lymph node, gastric washing, urine, blood culture
Positive commercial M. tuberculosis NAAT from extraneural specimen 4
Exclusion of alternative diagnoses
An alternative diagnosis must be confirmed microbiologically (by stain, TST, tuberculin skin test. IGRA, interferon-
culture, or NAAT when appropriate), serologically (e.g., syphilis), or release assay; NAAT, nucleic acid amplification
histopathologically (e.g., lymphoma). The list of alternative diagnoses that test. AFB, acid-fast bacilli. The individual
should be considered, dependent on age, immune status, and geographical points for each criterion (1, 2, or 4 points)
region, include pyogenic bacterial meningitis, cryptococcal meningitis, were determined by consensus and by
syphilitic meningitis, viral meningoencephalitis, cerebral malaria, parasitic considering their quantified diagnostic value
or eosinophilic meningitis (Angiostrongylus cantonensis, Gnathostoma as defined in studies.
spinigerum, toxocariasis, cysticercosis), cerebral toxoplasmosis and bacterial
brain abscess (space-occupying lesion on cerebral imaging), and malignancy
(e.g., lymphoma)

(continued)

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 Chapter 29: Tuberculous Meningitis 485

TA B L E 2 9 . 5
UNIFORM CASE DEFINITION (CONTINUED)

Clinical entry criteria

Symptoms and signs of meningitis include one or more of the following: headache, irritability, vomiting, fever, neck stiffness,
convulsions, focal neurologic deficits, altered consciousness, or lethargy.
Tuberculous meningitis classification
Definite tuberculous meningitis
Patients should fulfill criterion A or B:
A. Clinical entry criteria plus one or more of the following: acid-fast bacilli seen in the CSF, Mycobacterium tuberculosis
cultured from the CSF, or a CSF-positive commercial nucleic acid amplification test.
B. Acid-fast bacilli seen in the context of histologic changes consistent with tuberculosis in the brain or spinal cord with
suggestive symptoms or signs and CSF changes or visible meningitis (on autopsy).
Probable tuberculous meningitis
Clinical entry criteria plus a total diagnostic score of 10 or more points (when cerebral imaging is not available) or 12 or more
points (when cerebral imaging is available) plus exclusion of alternative diagnoses. At least 2 points should either come from
CSF or cerebral imaging criteria.
Possible tuberculous meningitis
Clinical entry criteria plus a total diagnostic score of 69 points (when cerebral imaging is not available) or 611 points
(when cerebral imaging is available) plus exclusion of alternative diagnoses. Possible tuberculosis cannot be diagnosed or
excluded without doing a lumbar puncture or cerebral imaging.
Nontuberculous meningitis
Alternative diagnosis established, without a definitive diagnosis of tuberculous meningitis or other convincing signs of dual
disease

From Marais S, Thwaites G, Schoeman JF, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis.
2010;10(11):803812.

growth indicator tube (MGIT) for CSF culture, however with
a median turnaround time of 6 days versus 15.5 days (106).
This study did not evaluate direct DST using MODS or MGIT.
MODS is increasingly used in low-resource countries for the
diagnosis of pulmonary MDR TB; however, it is still not
widely used for TBM, although that should change. WHO has
endorsed both commercial and noncommercial liquid culture
systems for TB diagnosis (109).
MDR TB is defined as M. tuberculosis with resistance
to at least rifampicin and isoniazid. XDR TB is defined as
M. tuberculosis with resistance to at least isoniazid and rifam-
picin, any fluoroquinolone, and at least one of three injectable
second-line drugs (amikacin, capreomycin, or kanamycin).
Whereas MDR pulmonary TB can be effectively treated with
second-line antituberculous drugs, evidence on effective treat-
ment of MDR TBM is limited to small series or single case
reports and mortality is extremely high (39). The majority of
deaths from TBM occur within the first month of treatment
(30,31,110). If the CSF is culture positive for mycobacteria,
molecular diagnostic tests can be used to establish resistance to
rifampicin or isoniazid (111,112). If only conventional pheno-
typic DST is available, the results of the drug susceptibility test
will be returned to the treating physician at the earliest after
4 to 6 weeks but more often after at least 8 weeks of treat-
ment. The majority of TBM patients infected with rifampicin-
resistant strains will have succumbed before the decision can
be made to change to a second-line regimen; for this reason,
molecular tests for rifampicin resistance should be applied in
all cases of TBM, but especially where there is a high suspicion
of MDR TBM (previous treatment history, known exposure
to an MDR or chronic TB case, HIV patient, or failure to
respond to first-line therapy). Currently, there is no evidence
base to support treatment regimens for patients with MDR
TBM, but the principle of TB treatment to never add a single
drug to a failing regimen should be applied. Experience from
pulmonary TB and pharmacokinetic data support the use of a
fluoroquinolone (levofloxacin, gatifloxacin, or moxifloxacin)
(113,114). Ciprofloxacin should not be used because it is less
active against M. tuberculosis; resistance develops rapidly and
may cause selection of strains resistant to more active fluoro-
quinolones (113).
Tuberculin Skin Testing
The Mantoux tuberculin skin test (TST) is performed by
intracutaneously injecting a small dose of purified protein
derivative (PPD). After 48 to 72 hours, an induration of 15 mm
or more is considered positive in all persons (115). The value
of this diagnostic test is highly dependent on the background
prevalence of TB, age of the patient, and the co-infection with
HIV. Up to 10% to 15% of immunocompetent children with
culture-documented TB do not initially show TST reactivity.
Sensitivity can be decreased by host factors, such as young
age, poor nutrition, immunosuppression, other viral infections
(such as measles, varicella, and influenza), recent TB infec-
tion, and disseminated TB diseases (116). In culture-proven
TBM patients in Egypt, only 19% of patients had tubercu-
lin positivity on admission. The yield improved when the test
was repeated after 60 days, with 62% positivity (117). Severe
immunosuppression will also suppress skin test reactivity
(118). False-positive TST results may also occur in BCG-
vaccinated individuals and those exposed to environmental
nontuberculous mycobacteria (116). In the United Kingdom,
Heaf testing was preferred to Mantoux. It follows the same
principles as the Mantoux test, however a special Heaf gun
with multiple small needles is used, which is thought to be less
painful in children and has an easier readout (119).

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 486 Part III: Bacterial and Mycoplasmal Infections
Developments in Diagnostics
Biochemical tests
Biochemical tests can detect features of the infecting organism or
products of the host immune response. Of the biochemical tests,
adenosine deaminase (ADA) assays are still of interest world-
wide, particularly in low-income settings. The test is relatively
cheap and easy to perform. It is an attractive candidate for the
diagnosis of TBM because it has been shown to be of value in
the distinction of tuberculous pleural effusions (120). ADA is re-
leased by T cells during cell-mediated immune response to bacilli
(121). A recent metaanalysis reviewed 10 publications on ADA
for the diagnosis of TBM and concluded that the mean values of
the sensitivity and specificity of the ADA assays were respectively
79% and 91% compared to culture as the gold standard, with
an inability particularly to distinguish TBM from bacterial men-
ingitis (122). However, publication bias and spectrum bias in
included cases may have resulted in overestimation of diagnostic
accuracy. Inclusion of inappropriate controls will result in an
overestimation of diagnostic accuracy, particularly if the test is
poor at discriminating the common differential diagnoses; raised
levels may also be seen in sarcoidosis, meningeal lymphoma,
subarachnoid hemorrhage, and neurobrucellosis. Although
ADA may be of use within diagnostic algorithms, the probability
that a patient has TBM with a negative result is still too high to
rule out the diagnosis using ADA values. Furthermore, in HIV-
infected individuals, the test is not of use (123).
Immunoassays
Various immunoassays have been evaluated for diagnosis of TBM,
with highly variable sensitivity and specificity between studies,
again commonly due to spectrum bias among controls. WHO
issued the first ever negative policy recommendation against
using existing commercial serologic assays for the diagnosis of
pulmonary TB in 2011, following a systematic evaluation (124).
Immunoassays may not distinguish between acute infection and
previous exposure, and cross reactivity of antibodies may further
decrease specificity. The detection of lipoarabinomannan (LAM)
has been evaluated for the diagnosis of TB and current interest is
heightened since the development of a point of care lateral flow
urine assay, which has shown value in the diagnosis of pulmonary
TB in HIV patients with severe immunosuppression (CD4 100
cells/L) (125,126). However, this is a relatively distinct subset
of patients and a CD4 assay is first required to determine if the
LAM test is applicable. LAM is a cell wall component of M. tu-
berculosis, has immunoregulatory and antiinflammatory effects,
and serves as a virulence factor of the mycobacteria (127). Earlier
studies on ELISA directed toward detection of IgG antibodies to
LAM antigens have reported promising sensitivity and specificity
in small studies, but highly variable results are published for dif-
ferent clinical populations with TB, reflecting the spectrum bias
in evaluation of serologic tests for TB. A standardized LAM an-
tigen detection ELISA test, showing results within 2 to 3 hours
(Clearview TB ELISA, Inverness Medical Innovations, Waltham,
MA), has been assessed on CSF of 150 patients in an HIV high-
prevalence setting. With a disappointingly low sensitivity of 31%,
but specificity of 94%, it has the potential to be a rapid rule-in
test for TBM for HIV-infected patients with advanced immuno-
suppression when used in combination with a clinical prediction
rule (128), but optimized CSF smear is likely to have a higher di-
agnostic yield. Other immunologic tests that have been evaluated
are interferon- release assays (IGRA), including peripheral blood
IgG ELISPOT response to PPD, CFP-10, and ESAT-6; however, all
showed poor sensitivity in patients with TBM (129,130). One of
the commercially available IGRA tests, QuantiFERON-TB Gold
Scheld_Ch29.indd 486
In-Tube test (QFT-GIT) uses enzyme-linked immunosorbent assay
(ELISA) technique to measure cell-mediated immunity in response
to proteins specific for M. tuberculosis complex. When assessed
for TBM in India, the whole blood IGRA had sensitivity of 44.4%
and specificity of 62.5% for diagnosing TBM with positive pre-
dictive value (PPV) of 72.7%. IGRA on CSF had 88% indetermi-
nate results in TBM patients (131).
Nucleic Acid Amplification Tests
Amplification of mycobacterial DNA by polymerase chain
reaction (PCR) has turned away attention from immunologic
techniques. Systematic review on commercial nucleic acid
amplification tests (NAATs) for TBM summarized the perfor-
mance as having potential to rule in or confirm diagnosis (speci-
ficity 98%), but low sensitivity (56%) precludes the use of these
tests to rule out (132). NAAT should be used as an adjunct to
conventional microscopy, culture, and clinical algorithms.
The most recent advance in diagnosis is the GeneXpert MTB/
RIF (Cepheid, Sunnyvale, CA), an easy-to-use desktop machine
that simultaneously detects the presence of M. tuberculosis and
rifampicin resistance using real-time PCR, giving results within
2 hours. Risk of contamination and consequent false-positive
results is reduced by the use of sealed disposable cartridges.
The rapid turnover time may lead to an important improve-
ment in the management of MDR TB. The test has been en-
dorsed by the WHO in 2010 for the use in pulmonary TB (112).
GeneXpert is more sensitive than smear, compared to culture.
In smear-negative, culture-positive sputum samples, detection
of M. tuberculosis showed 76.9% sensitivity and 99.0% speci-
ficity in a decentralized low-income setting. Sensitivity for
rifampicin resistance was 94.4% and specificity 98.3%, regard-
less of HIV infection (133). These results are clearly promis-
ing and roll out of the GeneXpert MTB/RIF test has been
impressive globally (http://who.int/tb/laboratory/mtbrifrollout/
en/). The GeneXpert test has been shown to be more sensitive
than smear on extrapulmonary samples in reports combining
analysis of all extrapulmonary samples with a small number
of CSF samples (134137). In June 2013, the WHO Strategic
and Technical Advisory Group (STAG) reviewed the evidence
for use of GeneXpert on extrapulmonary samples. 15 pub-
lished and 7 unpublished studies, involving 5,922 samples,
were included in the review which endorsed GeneXpert for use
on extrapulmonary samples, including CSF. The report recom-
mended Xpert MTB/RIF should be used in preference to con-
ventional microscopy and culture as the initial diagnostic test
in testing cerebrospinal fluid specimens from patients presumed
to have TB meningitis (strong recommendation given the ur-
gency of rapid diagnosis, very low quality of evidence). Pooled
sensitivity and specificity against a clinical gold standard were
estimated to be 55.6% and 98.8%, respectively (138).
Data from 265 consecutive patients with suspected TBM
presenting at Hospital for Tropical Diseases, Ho Chi Minh City,
Vietnam showed GeneXpert detected M. tuberculosis in 56.7%
(n  97/171 [95% CI, 48.9; 64.2%]) of pretreatment CSF sam-
ples of patients clinically diagnosed with TBM (specificity was
100%, n  94/94). Detection was only marginally lower than
MGIT culture at 60.8% (n  104/171) and similar to detection
rates in CSF reported for other commercial nucleic acid ampli-
fication tests, with the advantage that rifampicin resistance is
also detected by GeneXpert (139). Three cases of rifampicin re-
sistance were detected and confirmed by MGIT DST. Although
the numbers of MDR cases are too small to draw robust conclu-
sions regarding accuracy in CSF, rifampicin resistance detection
by GeneXpert MTB/RIF has been shown to be accurate in spu-
tum samples. For MDR TBM, this test will be of great impor-
tance, as detection of drug resistance within hours rather than
days will allow research into optimal treatment of MDR TBM.
2/21/14 8:21 PM
 Chapter 29: Tuberculous Meningitis 487

Further multicenter evaluation of this novel GeneXpert assay

may lead to significant improvement in the diagnosis and treat-
ment of TBM in general and MDR TBM in particular.

Central Nervous System Imaging

Radiologic results can add additional evidence for diagnosis while
also potentially serving as the missing link between epidemiol-
ogy, etiology, and pathophysiology, especially given the paucity of
postmortem studies. Presenting findings are pluriform and during
treatment, progressive changes may appear. Contrast-enhanced
MRI is the modality of choice because it has a higher resolution
over computed tomography (CT) scanning. However, in many
endemic settings, MRI is too expensive or not readily available.
The typical initial findings are hydrocephalus, basal menin-
geal enhancement, and tuberculoma. Hydrocephalus (Fig. 29.3)
is the most common finding. Hydrocephalus is also seen in bacte-
rial meningitis, although less frequent (140). Generally, in TBM,
hydrocephalus is of the communicating type (141). Occasionally,
obstructive hydrocephalus can be diagnosed by imaging, when
narrowing of the aqueduct of Sylvius is noted or when a
parenchymal mass is demonstrated obstructing the flow of CSF.
If neurosurgical interventions (shunting, endoscopic third ven-
triculostomy) are available and contemplated, air encephalogra-
phy can be helpful in excluding patients with communicating FIGURE 29.4 Basal meningeal enhancement in an adult with TBM.
hydrocephalus from undergoing unnecessary procedures (142). Gadolinium-enhanced T1-weighted magnetic resonance image show-
Basal meningeal enhancement (Fig. 29.4) in the advanced stage ing TBM-associated basal meningeal enhancement extending toward
the sylvian fissures.
can, although rarely, be demonstrated on noncontrast CT scans,
when obliteration of the interpeduncular cisterns is observed. After
contrast administration, there is typically diffuse enhancement of
have been reported to occur in 5% to 40% of patients presenting
the basal subarachnoid cisterns; occasionally, meningeal enhance-
with TBM (74,144). The typical features on MRI imaging de-
ment is seen over the cerebral convexities, the sylvian fissures, and
pend on whether the granuloma is noncaseating, caseating with
the tentorium (143). In the early stages, CT or MRI imaging with-
a solid center, or caseating with a liquid center. The noncaseat-
out the use of contrast may show little or no abnormalities.
ing tuberculoma is usually hypointense on T1-weighted images
Tuberculomas (Fig. 29.5) are characteristic for TBM and can
and hyperintense on T2-weighted images and shows homoge-
involve the parenchyma of the brain, spinal cord, subarachnoid,
neous enhancement after contrast administration. The caseating
and subdural or epidural space; may be multiple or solitary; and
tuberculoma with solid caseation looks hypointense or isoin-
tense on T1-weighted images and isointense to hypointense on
T2-weighted images, with rim enhancement on contrast admin-
istration. Caseating granuloma with a liquid center looks hypoin-
tense on T1-weighted images and hyperintense on T2-weighted
images, with rim enhancement after contrast administration (74).
On imaging, a (tubercular) abscess may be difficult to distinguish
from tubercular granulomas with a liquid center. Tuberculous
abscesses are generally more rapidly progressive, larger, have a
thinner wall, and can be loculated and irregular in shape.
During treatment, tuberculoma may develop paradoxically;
however, in a prospective serial MRI study, this phenomenon was
observed in 60% of patients, suggesting that it is part of the natural
course of disease on treatment rather than being discordant (73).
Ischemic events most commonly occur during treatment rather
than being a presenting sign, mostly located in the basal ganglia
(Fig. 29.6), which is in line with the severe basal infection, exu-
dates formation, and consequent vasculitis. In a serial MRI study,
dexamethasone reduced the proportion of patients who developed
infarcts during treatment; however, the difference was not statisti-
cally significant, possibly due to insufficient sample size (73).
Using contrast-enhanced MRI in children in Turkey, pre-
senting findings were meningeal enhancement (90.9%), hydro-
cephalus (63.6%), infarction (45.5%), tuberculomas (27.2%),
cranial nerve involvement (27.2%), and severe cortical atro-
phy (9.1%) (145). Retrospectively, miliary involvement of
the leptomeninges was present in a very large (88%) propor-
FIGURE 29.3 Hydrocephalus associated with TBM. Gadolinium- tion of young South African children scanned for TBM (146).
enhanced T1-weighted magnetic resonance image showing gross However, rare miliary CNS involvement is also reported in some
hydrocephalus associated with TBM. adult patients (Fig. 29.7). This discrepancy between adults and

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 488 Part III: Bacterial and Mycoplasmal Infections

FIGURE 29.5 Tuberculoma in an adult with TBM. Gadolinium-enhanced T1-weighted MRI showing
multiple tuberculoma in the cerebral peduncle extending to the hypothalamus.

young children may be an indication that direct hematogenous
spread to the meninges plays a larger role in the young, pos-
sibly due to immature innate and adaptive immunity.
The same diagnostic imaging criteria apply to children with
HIV infection, however cortical atrophy is a more common
finding (86) (Fig. 29.8). In adults with AIDS, radiologic find-
ings are reported to be similar to patients without HIV; how-
ever, the differential diagnosis will include other opportunistic
infections and primary or metastatic lymphoma of the CNS
(32,37,147). Some have observed that hydrocephalus and
meningeal enhancement are a less common radiologic finding
in HIV patients (36). Infarcts, tuberculous abscess, tubercu-
lous encephalitis, and optochiasmatic arachnoiditis on imag-
ing have all been associated with poor outcome.
With the advent of newer more sensitive imaging tech-
niques, our ability to detect abnormalities will improve.
Magnetic resonance angiography (MRA) may have a role in
predicting the chance of infarction in TBM (148). 3-Tesla
magnetic resonance neurography imaging may carry improved
sensitivity and ability to detect cranial nerve involvement, for
example. Still, the obvious obstacles in low-resource settings,
where rapid diagnosis is needed the most, remain.

FIGURE 29.6 Basal ganglia infarct in an adult with TBM. CT image FIGURE 29.7 Miliary lesions in an adult with TBM. Gadolinium-
without contrast showing infarction of the left capsula interna and enhanced T1-weighted MRI showing multiple miliary lesions and
caudate head. small tuberculoma in an adult patient with TBM.

Scheld_Ch29.indd 488 2/21/14 8:21 PM

 Chapter 29: Tuberculous Meningitis 489

A B C

D E F

G H I

FIGURE 29.8 Common MRI findings in children with TBM. A: Contrast-enhanced axial T1-weighted
image reveals thick leptomeningeal enhancement in suprasellar cistern extending into interpeduncular
cistern. B: Contrast-enhanced coronal T1-weighted image reveals leptomeningeal enhancement with
marked basal leptomeningeal enhancement. C: Axial T1-weighted image reveals several enhancing
nodules in parenchyma. D: Axial T2-weighted image reveals infarction of right caudate head and puta-
men. E: Gadolinium-enhanced T1 axial imaging showing extensive basal leptomeningeal enhancement
in suprasellar, interpeduncular, and ambient cisterns. F: Unenhanced sagittal T1-weighted image reveals
massive hydrocephalus. G: Contrast-enhanced axial T1-weighted image reveals thick leptomeningeal
enhancement in suprasellar cistern extending into interpeduncular and ambient cisterns and small tu-
berculoma in left brainstem. H: Contrast-enhanced axial T1-weighted image reveals basal meningeal
enhancement and both dilated temporal horns. I: Contrast-enhanced coronal T1-weighted image reveals
thick leptomeningeal enhancement of interhemispheric fissure. (continued)

Scheld_Ch29.indd 489 2/21/14 8:21 PM

 490 Part III: Bacterial and Mycoplasmal Infections

J K L

FIGURE 29.8 (continued) J: Contrast-enhanced axial T1-weighted image shows tuberculoma in the left
temporal lobe. K: Contrast-enhanced axial T1-weighted image shows small tuberculomata in brainstem
and basal meningeal enhancement of both sylvian fissures. L: Contrast-enhanced axial T1-weighted
image shows small tuberculoma in left brain peduncle and temporal lobe, both dilated temporal horns
and meningeal enhancement of left sylvian fissure. (Courtesy of Dr. Nguyen Duc Bang, Pham Ngoc Thach
Hospital for Tuberculosis and Lung Diseases, Ho Chi Minh City, Vietnam.)

similar; however, for children, often higher dosages are used

TREATMENT
The treatment of TBM may be divided into four comple-
mentary areas: specific antituberculous therapy, adjunctive
immunomodulatory therapy, anticoagulant therapy, and man-
agement of intracranial pressure. In addition, treatment of
HIV-associated TBM requires consideration of drug interac-
tions and IRIS.
Specific Antituberculous Treatment
Treatment guidelines for TBM treatment are not uniform.
In general, global guidelines recommend 9 to 12 months
treatment with rifampicin, isoniazid, pyrazinamide, and strep-
tomycin (or ethambutol) in the intensive phase, followed by a
combination of rifampicin and isoniazid in the continuation
phase (75,149151). These treatment regimens are based on
the early trials in pulmonary TB involving the introduction
of the new first-line antituberculous drugs. The drug dos-
ages and duration of treatment recommended for TBM are
derived from pulmonary regimens and are not based on phar-
macokinetic principles. Regimens for children and adults are
(Table 29.6).
In this section, we would like to put emphasis on the
statement that the CNS should be regarded as a unique
therapeutic compartment (152) and pharmacokinetic and
pharmacodynamic data should be considered in the construc-
tion of more effective treatment schedules. The majority of
deaths from TBM occur in the first 2 months of treatment,
indicating that effective antimycobacterial killing is most
critical in the intensive phase. However, prevention of relapse
and the prevention of emerging resistance are additionally im-
portant principles of effective multidrug treatment.
The ability of the different first-line antituberculous drugs
to penetrate the CSF is variable and few of the second-line
drugs are effective in reaching the brain. A summary of
antimycobacterial activity and CSF penetration of the first-line
drugs used in the intensive phase is appropriate. We will also
briefly review some of the second-line agents with favorable
CSF levels. Of note, little is known about the levels of antimy-
cobacterial drugs in the brain tissue. Drugs may need to over-
come both bloodCSF barrier, consisting of the choroid plexus
and the lining epithelial cells, and the bloodbrain barrier, made
up of endothelial tight junctions in capillaries and surrounding

TA B L E 2 9 . 6
RECOMMENDED DAILY DOSAGE OF FIRST-LINE ANTITUBERCULOUS DRUGS IN
CHILDREN AND ADULTS WITH TUBERCULOUS MENINGITIS

Drug Daily Dose Children (12 years) Daily Dose Adult

Isoniazid (INH) 10 mg/kg (range 615 mg/kg) 5 mg/kg (range 46 mg/kg)

Rifampicin (RIF) 15 mg/kg (range 1020 mg/kg) 10 mg/kg (range 812 mg/kg)
Pyrazinamide (PZA) 35 mg/kg (range 3040 mg/kg) 25 mg/kg (range 2030 mg/kg)
Streptomycin (SM) 17.5 mg/kg (range 1520 mg/kg) 15 mg/kg (range 1218 mg/kg)
Ethambutol (EMB) 20 mg/kg (range 1525 mg/kg) 15 mg/kg (range 1520 mg/kg)

From Donald PR. The chemotherapy of tuberculous meningitis in children and adults. Tuberculosis
(Edinb). 2010;90(6):375392.

Scheld_Ch29.indd 490 2/21/14 8:21 PM


glial cells. The level of drugs in the two compartments, CSF
and brain tissue, may not be equal. A third hurdle may be
the penetration and action of drugs in the relatively anaerobic
conditions within the tuberculoma.
Streptomycin and Ethambutol
The initial drug to be introduced for TBM treatment was
streptomycin. This aminoglycoside must be given intramus-
cularly. Streptomycin is a protein synthesis inhibitor. The
minimal inhibitory concentration (MIC) in fully susceptible
clinical isolates is in the range 0.5 to 2.0 g/mL (153). With
the commonly used dosages in adults, the early bactericidal
activity (EBA; generally defined as the fall in counts per mil-
liliter sputum per day during the first 2 days of treatment) of
streptomycin, however, is low (0.1 log10 colony-forming unit
[CFU]/mL sputum per day) (154). With a poor penetration in
CSF, the contribution of streptomycin to multidrug regimens
for TBM is probably very limited. In the absence of meningeal
inflammation, penetration does not occur. However, in menin-
gitis, the penetration can be up to 20% of simultaneous serum
levels. In the early course of disease, when bloodbrain barrier
disruption is prominent, levels above the MIC may be found in
CSF (3 to 16 g/mL). However, when clinical improvement is
noted, CSF levels barely reach the MIC (0 to 1.25 to 4 g/mL)
(155). Because TBM may reflect a general state of dissemi-
nated TB, it appears appropriate to maintain streptomycin in
treatment schedules, however at the cost of increased toxicity.
For HIV patients, ethambutol should be substituted for strep-
tomycin because injection should be avoided when possible in
HIV-infected individuals. Ethambutol is bacteriostatic against
actively growing TB bacilli by obstructing the formation of
the bacterial cell wall. Ethambutol is slightly more efficient
in penetrating the CSF, with levels compared to serum in the
range of 0% to 54%. In healthy adults, despite an oral dose of
50 mg/kg which was twice the usual therapeutic dose, and in
the presence of proportionally high blood levels, ethambutol
did not appear in the CSF of healthy adults. After oral doses
of 18.6 to 25 mg/kg levels, ethambutol did appear in the CSF
of patients with active meningitis (0.74 to 1.98 g/mL) (155).
Still, with an MIC of 0.5 to 2.0 g/mL, there may be a limited
role for ethambutol in TBM treatment. Both streptomycin and
ethambutol have been shown ineffective in sterilizing sputum
in pulmonary TB, so their role in TBM may be limited to re-
sistance prevention. It is possible that by increasing the dose
of these drugs, therapeutic levels could be achieved in the CSF,
but this would come at the cost of increased toxicity.
Isoniazid
After the introduction of isoniazid, a major improvement
was seen in the outcome for patients with all grades of TBM.
Isoniazid exerts its antimycobacterial activity by inhibiting
the synthesis of mycolic acid required for the mycobacterial
cell wall. It is the most bactericidal TB drug and kills ap-
proximately 95% of rapidly multiplying organisms in sputum
samples within 48 hours (156). Isoniazid has the highest EBA
of the first-line TB drugs ranging from 0.4 to 0.8 log10 CFU/
mL sputum per day (154). MIC in liquid media is low: 0.02
to 0.04 g/mL (153). A Cmax of 3 to 5 g/mL is needed for
optimal action against sensitive M. tuberculosis and isoniazid-
resistant strains with relatively low MICs (157). It has good
penetration in the CSF in both children and adults. Peak levels
are reached at approximately 6 hours after dose (155). With
an oral dosage of about 9 mg/kg, isoniazid rapidly diffused
into the CSF. By 4 hours, mean CSF isoniazid concentrations
measured were 3.2 g/mL, well over the MIC and in the range
of optimal Cmax for sensitive strains (158). Isoniazid is effective
Scheld_Ch29.indd 491
Chapter 29: Tuberculous Meningitis 491
in preventing resistance when used with companion drugs.
It is less efficient in eradicating slow-growing organisms.
Some advocate the administration of higher doses because
resistance is increasingly abundant and higher intracerebral
Cmax may lead to killing of strains with low-level resistance,
which do not carry mutations in the katG gene. Additionally,
the N-acetyltransferase-2 genotype of an individual (NAT2)
influences the EBA of isoniazid at a given dose, and faster
isoniazid acetylators consistently have a lower EBA (154).
Conversely, slow acetylators may have increased susceptibility
to hepatotoxicity (159).
Rifampicin
Rifampicin is a key drug in the treatment for TBM, illustrated
by the high mortality in MDR TBM patients compared to
isolated isoniazid resistance. In contrast, in a review of the lit-
erature, Donald (18) found little effect on mortality in adults
after the introduction of rifampicin and pyrazinamide to the
TBM treatment schedule but a significant effect on survival in
children. Still, based on the drug resistance data, rifampicin
seems to have a pivotal role in treatment; it may well be that
doses in adults are not sufficient to reach adequate levels in the
CSF. An Indonesian phase 2 clinical trial, establishing the safety
of high-dose intravenous (13 mg/kg/day) rifampicin with or
without (high dose) moxifloxacin, did not show increased tox-
icity and moreover showed a 50% reduction in mortality for
patients receiving high-dose rifampicin (160). However prom-
ising, this trial was not powered for a clinical outcome, and the
results of a current randomized controlled trial comparing an
intensified 2-month regimen of high-dose (15 mg/kg/day) oral
rifampicin and levofloxacin are awaited (161).
Rifampicin inhibits bacterial RNA synthesis by inhibiting
RNA polymerase. Rifampicin is highly bound to plasma pro-
teins, which leaves only 20% of total drug freely diffusible. This
is reflected in the ability of rifampicin to penetrate the CSF, with
a CSF/plasma ratio of maximally 20% found in early TBM and
no drug detectable in CSF in the absence of meningeal inflam-
mation (155). After an oral dosage of approximately 11 mg/kg,
serum Cmax averaging 11.5 g/mL were obtained at 2 hours.
Rifampicin penetrated very slowly into the CSF, and concentra-
tions only slightly in excess of its MIC against M. tuberculosis
(approximately 0.3 g/mL) maintained throughout the period
(158). In general, low serum levels of rifampicin are reported,
particularly in HIV-positive patients, in whom absorption of
all TB drugs may be impaired (162). It is suggested that ri-
fampicin serum concentrations 2 hours post dose between 8
and 24 g/mL are required for optimal treatment of pulmo-
nary TB. Serum levels below 4 g/mL are defined as very low
(163). In Indonesia, 70% of TB patients had 2-hour plasma
concentrations (Cmax) below 4 g/mL (164). Increasing the
dose of rifampicin from 10 mg/kg to 13 mg/kg led to a dis-
proportionate (65%) increase in plasma levels and significantly
increased the proportion of patients with rifampicin peak
plasma concentrations above the reference value of 8 g/mL
(165). The EBA and bactericidal activity of rifampicin (0.2 to
0.6 log10 CFU/mL sputum per day) may be enhanced with an
increased dose.
Pyrazinamide
The mechanism of action of pyrazinamide is not completely
understood. It is known for its ability to kill semidormant
M. tuberculosis bacilli in low pH milieu that are not killed by
the other TB drugs, possibly by disrupting membrane energetics
and inhibiting membrane transport function in M. tuberculosis
(166). In pulmonary TB, addition of pyrazinamide to a
6-month regimen significantly reduced relapse rate to less than
2/21/14 8:21 PM
 492 Part III: Bacterial and Mycoplasmal Infections
5% (18,156). Pyrazinamide is very efficient in penetrating the
CSF. Generally high levels are found comparable to those in
serum (167). The EBA in the first few days of treatment is low
but at days 4 to 14 matches that of rifampicin and isoniazid
and is probably also active against extracellular bacilli (18).
Because rifampicin penetration in CSF is limited and isoniazid
resistance is frequent, the role of pyrazinamide in TBM should
not be underestimated.
Drug-Resistant Tuberculous Meningitis
The general principles for treating multidrug-resistant TB
are as follows: (a) use at least three previously unused drugs,
one of which should be a fluoroquinolone; (b) streptomycin
resistance does not confer resistance to other aminoglycosides,
therefore amikacin or kanamycin can be used; and (c) treat
for at least 18 months (168). There is no uniform guideline
for treatment of drug-resistant TBM. No clinical trials have
been conducted. Our ability to diagnose drug-resistant TBM
more rapidly with PCR-based techniques will warrant an
expeditious introduction of protocols for practitioners in
all settings. Such guidelines should be based on our existing
pharmacokinetic and pharmacodynamic knowledge in order
to minimize toxicity and maximize efficacy. Most second-line
TB drugs have limited bactericidal capacity and do not diffuse
easily to the CSF (41).
Second-Line Agents
Of the second-line drugs, fluoroquinolones are an attractive
option for the treatment of TB meningitis because of their
demonstrable in vitro activity, intracellular penetration, toler-
ability, good bioavailability, and ease of administration. With
the exception of ciprofloxacin, the mycobactericidal activity is
comparable to that of isoniazid. The EBA of levofloxacin, gati-
floxacin, and moxifloxacin in pulmonary TB were compared
to that of isoniazid by Johnson and colleagues (169). This
study reported levofloxacin to have the greatest EBA, compa-
rable to that of isoniazid. The EBA 02 of INH (0.67 log10
cfu/ml/day) was greater than that of moxifloxacin and gati-
floxacin [both 400 mg daily] (0.33 and 0.35 log10 cfu/ml/day,
respectively), but not of levofloxacin 1000 mg daily (0.45 log10
cfu/ml/day) (169). The diffusion to the cerebral compartment
is excellent. A pharmacokinetic study comparing ciprofloxa-
cin, levofloxacin, and gatifloxacin in patients with TBM found
levofloxacin to have excellent CSF penetration, with a ratio
of area under the curve (AUC) in CSF to AUC in plasma of
75%. This compared favorably with gatifloxacin (35%) and
ciprofloxacin (14%) (170). For moxifloxacin, the penetration
has been reported to be 71% and 82% of plasma levels with
doses of 800 mg and 400 mg, respectively (171).
In serum, median free AUC024/actual MIC90 in plasma was
180.99 for levofloxacin, 179.77 for gatifloxacin, and 58.35 for
moxifloxacin. Cmax was 15.55 g/mL for levofloxacin, 4.51 g/
mL for gatifloxacin, and 6.13 g/mL for moxifloxacin (172).
These pharmacokinetic data suggest that the fluoroquinolones,
levofloxacin and moxifloxacin in particular, have the poten-
tial to be highly effective sterilizing agents in the treatment of
TBM.
Of the remaining second-line drugs, only ethionamide and
cycloserine have considerable ability to diffuse to the CSF. In
TBM, serum to CSF penetration ratio of 40% to 100% were
reported, with peak CSF concentrations ranging from 1.0 to
2.6 g/mL achieved 3 hours after administration of a 250-mg
dose (155). The reported MIC was 0.25 to 0.5 g/mL (157).
Scheld_Ch29.indd 492
Ethionamide may be a valuable drug for the management of
both susceptible and drug-resistant TBM. Ethionamide is a
structural analog of isoniazid. If isoniazid resistance is con-
ferred by mutations in the KatG gene, these isolates may still
be sensitive to ethionamide; however, inhA mutations for
isoniazid resistance confer cross-resistance to ethionamide
(173,174). Cycloserine is only moderately bactericidal and
has an MIC of 25 to 75 g/mL; however, penetration in CSF
is good (157). None of the second-line drugs have been sub-
jected to clinical trials for the use in TBM treatment with the
exception of moxifloxacin and levofloxacin (160,161).
Of the new agents, a diarylquinoline (bedaquiline or Sirturo,
previously known as TMC207) was approved for the treat-
ment of MDR TB by the U.S. Food and Drug Administration
in December 2012. It has a novel mode of action specifically in-
hibiting mycobacterial adenosine triphosphate (ATP) synthase
(175). When added to a background regimen of second-line
drugs in patients with MDR pulmonary TB, TMC207 led to
more rapid sputum culture conversion and possibly prevented
resistance formation in companion drugs without adding to
toxicity of the regimen (176). Its MIC against M. tuberculosis
is very low (0.06 g/mL) (177). The EBA in the first 3 days
of treatment is not optimal, but from days 4 to 7, TMC207
induced similar reduction in CFUs to rifampicin and isoniazid
over the same period (178). The ability of this new compound
to cross the bloodbrain barrier has not been established yet;
however, it has favorable pharmacokinetic properties and is an
attractive candidate for future studies in patients with TBM.
In view of the severity of TBM, generally, higher toxicity
of treatment may be acceptable if accompanied by improved
clinical outcomes. The most common reason for treatment
interruption is hepatotoxicity. Especially isoniazid, rifampi-
cin, and pyrazinamide are implicated in drug-induced hepa-
titis (DIH); however, when carefully monitored, gross hepatic
failure can be prevented. Streptomycin can cause oto- and
nephrotoxicity, and ethambutol optic neuritis. Cardiac tachyar-
rhythmias are reported for the fluoroquinolones, moxifloxacin
in particular, but are very rare. Key to favorable outcome is
early initiation of effective anti-TB treatment. Clinical trials
are needed to develop more effective treatment guidelines for
both drug-susceptible and resistant TBM. General manage-
ment guidelines have been published by the British Infection
Society and may be helpful for clinicians to make individual
treatment decisions (Fig. 29.9) (75).
Adjunctive Treatment
Corticosteroids
Global guidelines now recommend the use of corticosteroids
as an adjunct to treatment. Addition of dexamethasone to the
antibiotic regimen used in TBM has been proven to reduce
mortality in TBM in both adults and children (30,179).
A Cochrane review concluded that the adjunctive use of
corticosteroids reduce the risk of death (risk ratio [RR], 0.78;
95% CI, 0.67 to 0.91; 1140 participants, 7 trials) in patients
with TBM. Data on disabling residual neurologic deficit
showed that corticosteroids additionally reduce the risk of
death or disabling residual neurologic deficit (RR, 0.82; 95%
CI, 0.70 to 0.97; 720 participants, 3 trials) (180). This has
not been proven or refuted for HIV-positive patients. The
beneficial effect of steroids may not be homogenously distrib-
uted among different patient populations. Across the different
severity groups, the beneficial effect of dexamethasone may
be more pronounced in the less severe grades (30,48). More
recently, it has been reported that the immune response can
be modulated through the leukotriene A4 hydrolase (LTA4H)
2/21/14 8:21 PM
 Chapter 29: Tuberculous Meningitis 493

FIGURE 29.9 Management of TBM (British Infection Society guidelines).

Scheld_Ch29.indd 493 2/21/14 8:21 PM

 494 Part III: Bacterial and Mycoplasmal Infections
gene. Indirectly, this gene regulates TNF-
levels, and pro- Immune Reconstitution with Antiretroviral Therapy
moter polymorphisms can lead to either a hyperinflammatory
state, inadequate inflammation, or an intermediate response.
Patients with TBM, who were homozygous for the LTA4H-
high polymorphism (T/T), had higher levels of TNF and high
leukocytes in CSF. Among patients not receiving glucocorti-
coids, mortality was highest among patients with a T/T geno-
type. However, these patients showed the greatest reduction in
mortality in the group treated with adjunctive dexamethasone,
suggesting that the dexamethasone may reduce excessive in-
flammatory response in this group. By contrast, patients who
were homozygous for the polymorphism causing low expres-
sion of LTA4H (C/C) showed increased mortality when treated
with dexamethasone, probably due to further suppression of
an inadequate immune response. The patients who were het-
erozygous at this locus (C/T) had the lowest mortality and the
use of dexamethasone did not appear to influence mortality in
this group (181).
These results suggest that disease severity in humans can be
caused either by an exaggerated or a deficient immune response
and, perhaps more importantly, that treatment with cortico-
steroids may only benefit those with a certain predisposition
to hyperinflammation and may be detrimental in those with
deficient immune responses. This needs prospective assessment
and
and if proven may necessitate more tailored use of corticoste-
roids according to individual genotyping or phenotyping of
the immune response in the future.
Thalidomide
Thalidomide is a drug with immunomodulatory properties
through the inhibition of TNF-
(182). In animal studies, Stroke is associated with poor outcome in TBM. Infiltrative
TNF-
levels in the CSF produced during TBM were shown and proliferative vasculitis and necrotizing vessel pathologies
to correlate with the extent of pathogenesis, although this has
been difficult to replicate in humans with TBM (84). In rabbits
infected intracranially with TB, an antitubercular regimen
that included thalidomide led to reduction of TNF-
levels in earlier pathologic studies (64,87). Severe pulmonary TB is
in CSF and prevented death (183). The same group has used
a thalidomide analogue (IMiD3) for the treatment of experi-
mental animals infected with TBM as an adjunct to standard
antituberculous treatment. IMiD3 has comparable immuno-
modulatory action to thalidomide, but unlike thalidomide,
IMiD3 is not teratogenic. The additional use of IMiD3 in
rabbits resulted in marked improvement in survival, reduced
CSF leukocytosis, lower levels of TNF, and attenuated inflam-
mation of the meninges on histologic examination. The ben-
eficial effect on survival and severity of symptoms of IMiD3
was markedly greater than that of thalidomide in this animal
model (184).
Conversely, increases of TNF-
concentrations have been received corticosteroids, which may have biased the results.
reported during thalidomide treatment, raising more ques-
tions about the interaction between TNF-
and thalidomide. lish the role of aspirin (and dipyridamole) in the management
A clinical study in 15 adults with TB, including HIV-positive
and HIV-negative patients, showed a reduction in disease
severity with the use of thalidomide, which was correlated
with an increase in TNF-
levels. By contrast, those patients reversed by aggressive therapy with oxygen, fluid resuscita-
with poor outcome who were not designated to receive
thalidomide continued to demonstrate clinical progression of
the disease and remained with low levels of TNF-
and type pathogenesis of TBM vascular disease are necessary to guide
1 cytokines (185).
In children with TBM, a randomized placebo controlled
study of adjunctive thalidomide was stopped early because of
an increased risk of death and adverse events in the treatment
arm (186). The role of TNF-
in TB is complex and has yet Hydrocephalus
to be fully elucidated. Currently, there is no role of TNF-
inhibition in the treatment for TBM; however, the potential
role for IMiD3 in the management of TBM in patients may be
a subject of future pharmacokinetic research.
Scheld_Ch29.indd 494
The mortality for HIV-infected patients with TBM is alarmingly
high. CD4 counts of patients with TBM are characteristically
very low (35). For these patients, the question of timing of initi-
ation of ART is critical. Initiation should be as early as possible
to support the immune response; however, toxicity, pharmaco-
kinetic interactions, IRIS, and pill burden may complicate early
treatment. Two recent clinical trials on initiation of ART in
HIV-associated TB showed that severely immunocompromised
(CD4 200 cells/L) patients with (mostly pulmonary) TB
may benefit from early initiation of ART with lower rates of
AIDS-defining illnesses or death, but at the cost of a higher oc-
currence of IRIS (187,188). In TBM, mortality is much higher
and intracranial IRIS may be detrimental (189). A randomized
controlled trial in Vietnam showed no reduction in mortality
with immediate initiation of ARTs; instead, the study suggested
that it may be safer to defer the initiation of ART to 8 weeks
of TBM treatment in patients with TBM, as delayed treatment
was associated with fewer adverse events (31). TBM IRIS has
been reported to be a frequent occurrence in ART-naive pa-
tients who started ART treatment 2 weeks after initiation of
TBM treatment (16/34, 47%). High CSF neutrophil counts,
culture positivity, and a combination of high CSF TNF-
low IFN- concentrations on presentation was associated with
development of IRIS (190). For a more elaborate review and
guideline of ART and TB drug interactions, we refer to the
National Institutes of Health (NIH) guidelines (191).
Aspirin and Dipyridamole
have been implicated in the pathogenesis. The relative contri-
bution of thrombosis to the development of ischemic events is
unknown. Tuberculous thrombophlebitis has been described
characterized by impaired fibrinolysis and a hypercoagulable
state (192). In children with TBM, changes were found in
procoagulation, antithrombotic factors, fibrinolysis, platelet
counts, and vascular endothelium functions, all contributing
to an increased risk of thrombosis (193). Aspirin has been sub-
jected to clinical trials in TBM because it is antithrombotic and
possibly neuroprotective. However, a clinical trial in 146 chil-
dren with TBM showed no significant effect on either mortality
or neurologic deficits with low-dose or high-dose aspirin regi-
mens (194). One open-label randomized study in 118 adults
on the role of aspirin showed a beneficial effect on mortality
and MRI results (195). In this study, some patients selectively
Larger appropriately randomized studies are needed to estab-
of TBM-related ischemic events. In an intensive neurosurgi-
cal care setting in South Africa, cerebral tissue oxygenation
was monitored in two children. A decline in oxygenation was
tion, inotropic support, and blood transfusion, which possibly
prevented infarction (196). More profound insights into the
rational therapeutic interventions.
Raised Intracranial Pressure and
Furosemide with or without acetazolamide can be used for
treating communicating hydrocephalus in TBM to decrease
CSF production by the choroid plexus. Some institutions favor
2/21/14 8:21 PM

daily lumbar punctures with intracranial pressure monitoring
through manometry to assess the response to medical therapy.
An external ventricular drain, ventriculoperitoneal shunting,
or endoscopic third ventriculostomy may be indicated for
patients not responding to conservative measures and noncom-
municating hydrocephalus (197). Patients for these procedures
should be carefully selected, as the success rate depends on the
correct diagnosis, the severity of disease, and the expertise of
the neurosurgical teams. Outcome is better in patients with
early intervention in the better grades (198). Some institutions
use osmotic agents, such as mannitol or hypertonic saline,
however there have been no studies establishing the effective-
ness in TB of the CNS.
Hyponatremia
TBM accompanied by hyponatremia is associated with a worse
outcome. Mostly, it is caused by the syndrome of inappropri-
ate antidiuretic hormone secretion (SIADH) or cerebral salt-
wasting (CSW) syndrome. CSW is probably underdiagnosed
in TBM, and the distinction between the two entities is often
difficult in endemic settings. Treatment should be directed to
avoid both hypoosmolality and hypovolemia. Fluid restriction
can be detrimental and is not recommended. Generally, it is
advised to treat all hyponatremic patients cautiously with
hypertonic saline with or without fludrocortisones (197,199).
Correction should be gradual in order to avoid pontine
myelinolysis.
Pathogen Genetics and Virulence
M. tuberculosis strains were shown to vary in virulence in the
1960s when Mitchison et al. conducted experimental infection
of Guinea pigs with strains from South India and Britain
(200,201). Many epidemiologic in vitro and in vivo stud-
ies have since attempted to establish differences in virulence
with regard to dissemination and disease severity but no
consensus has yet been established due to often contradic-
tory findings and the difficulty of interpretation (202,203).
There is wide variation in experimental technique in vitro
or the comparative strains in both laboratory and epidemio-
logic studies. Evolutionarily, TBM represents a dead end for
the pathogen and therefore propensity to cause TBM is not
directly advantageous but may be a by-product of increased
pulmonary virulence causing greater transmission (204). The
standard laboratory strain, H37Rv, which was the first M.
tuberculosis strain sequenced in 1997 (205), is laboratory
adapted and exhibits low virulence in vitro and in animal
models in comparison with almost all clinical strains (206),
therefore demonstration of increased virulence in comparison
with H37RV does not represent a hypervirulent strain.
Analysis of large sequence polymorphisms within the
M. tuberculosis genome has defined six major global lineages,
which are largely geographically restricted within the
eponymous region; Indo-Oceanic, Euro-American, East Asian,
East African-Indian, and two Mycobacterium africanum lin-
eages. Within the modern East-Asian lineage, the Beijing
genotype has been defined by its characteristic spoligotype
and extensively investigated, as it has been associated with
increased virulence and drug resistance in several regions
(207212). Introduction of the Beijing genotype into some
regions also resulted in rapid increases in prevalence of this
strain (212). In Vietnam, among TBM cases, it shows sig-
nificant association with HIV status, drug resistance, and
multidrug resistance (213) compared with Euro-American
Scheld_Ch29.indd 495
Chapter 29: Tuberculous Meningitis 495
and Indo-Oceanic strains. HIV-negative patients infected
with the Beijing-strain had shorter duration of illness before
presentation to hospital and fewer CSF leukocytes, suggesting
that mycobacterial genotype may affect disease progression
and the nature of the intracerebral inflammatory response
(214). Studies in South African children have also shown an
association between Beijing genotype and extrapulmonary TB
(208). A recent retrospective cohort study of TBM patients
in Thailand supported the theory that the Beijing genotype is
the most pathogenic strain of M. tuberculosis and associated
with TBM, whereas the Euro-American lineage was much less
commonly linked with TBM. Results showed that modern
sublineages of Beijing genotype were associated with higher
CSF WCC and more severe (stage III) disease but not with
mortality rate (215). Conversely, among HIV-positive patients
in Vietnam, those infected with the modern Beijing lineage
strains had lower mortality than patients infected with the
ancient Indo-Oceanic lineage (HR, 0.29; 95% CI, 0.14; 0.61)
(214). This contradictory finding might be explained by the
proinflammatory properties of the modern Beijing lineages,
which although detrimental to the immunocompetent host
may be conversely protective in the immunocompromised. It is
known that protective immunity in TB disease is a delicate bal-
ance of pro- and antiinflammatory cascades. However, studies
in other regions have found no association between Beijing
genotype and dissemination (216218). Within each region,
the M. tuberculosis genotypes circulating vary significantly as
do the genotyping divisions applied to analysis and therefore
the pathogen populations being compared are not identical.
Wider studies synthesizing global data are required to estab-
lish definitive interpretation.
Host-Genetics
It has long been known that there is a genetic element to TB
susceptibility. Of those exposed to M. tuberculosis, approxi-
mately 10% establish an infection and, of those, 10% will
develop active disease while the remaining individuals will
harbor a latent infection. Approximately 1% of active TB
cases develop into TBM. Susceptibility to the different forms
of TB (latent, active, disseminated) is a complex interplay
between host genetics, pathogen genetics, and environmental
factors (such as smoking, malnutrition, comorbidities).
Protective immunity to TB depends on innate immunity
and an effective TH1 response, as evidenced by the dramatic
increase in susceptibility shown by HIV-infected individuals.
Many candidate genes have been proposed to be associated
with susceptibility to pulmonary TB (219222), but fewer
studies have looked at the association between host genetics
and susceptibility to severe and disseminated disease. The
toll-like (TLR) receptor pathway has been implicated in TB
progression. The human TLR family has 12 members that can
recognize pathogen-associated molecular patterns (PAMPs)
and upon activation initiate an innate immune response,
cytokine production, and the formation of the adaptive
immune response. The TLRs known to be involved in M.
tuberculosis recognition are TLR2, TLR4, TLR9, and possibly
TLR8 (223). One of the few host genetic studies to investigate
susceptibility factors for TBM as distinct from pulmonary TB
showed an association between a polymorphism in the TLR2
gene (SNP T597C) and the development of TBM and miliary
TB, indicating the TLR2 pathway plays a role in the ability to
disseminate of M. tuberculosis (214). However, this polymor-
phism is itself synonymous, and the causative single nucleotide
polymorphism (SNP) in linkage disequilibrium has not yet
been identified. Further studies investigating the interaction
2/21/14 8:21 PM
 496 Part III: Bacterial and Mycoplasmal Infections
between host and pathogen in TBM susceptibility have shown
that individuals with the TLR2 polymorphism are more likely
to be infected with the Beijing genotype of M. tuberculosis
and that this association is strongest in those with TBM (214).
Polymorphisms in the toll-interleukin 1 receptor domain-con-
taining adaptor protein (TIRAP) gene have also been shown
to be associated with susceptibility to TBM in Vietnam and
South Africa (224,225). TIRAP is a protein further down the
TLR pathway, which mediates signals from the TLR receptors,
activating macrophages and dendritic cells.
Recently a SNP in the promoter region of the LTA4H gene
has been identified to play a role in susceptibility to myco-
bacteria which is discussed in more detail in the section on
corticosteroid treatment. Future research on host genetic
susceptibility to TB and TBM will need to explore the poten-
tial of genetically tailored adjunctive therapies.
CONCLUSION
CNS TB is a devastating form of TB. In resource-limited
settings, it places a high burden on patients, their fami-
lies, society, and health care systems. Disease incidence is a
direct reflection of the TB epidemic and complicated by the
MDR/XDR TB and HIV epidemic. The current develop-
ments in TBM research have advanced our understanding
of the disease; however, they have not led to acceptable im-
provements in clinical outcomes. Early diagnosis and treat-
ment initiation are essential to a good outcome. The recent
endorsement of the GeneXpert test for pulmonary TB may
impact the management of MDR TBM in particular, which
is highly lethal, and offers the potential for improved diag-
nostics for TBM. However, more robust evidence must be
generated to validate the specificity for rifampicin resistance
on CSF, because withholding rifampicin from treatment regi-
mens for sensitive strains may be detrimental. Little is known
about the optimal second-line treatment regimen for MDR
TBM and this may pose TB programs and clinicians with a
problem when confronted with a rifampicin-resistant positive
result on GeneXpert, without an elaborate drug sensitivity
spectrum. Both first- and second-line treatment will need to
be optimized for TBM according to the ability of antimyco-
bacterial drugs to penetrate the brain. Still, there is a pressing
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Scheld_Ch29.indd 496
need for the development of a rapid, sensitive, point of care
diagnostic that can be used in decentralized settings. This will
lead to a reduction in frequently encountered disastrous treat-
ment delays.
Currently, the TB drug pipeline has 10 compounds in the
clinical development phase for both MDR and drug-sensitive
TB (http://www.newtbdrugs.org/pipeline.php). Because the
pipeline is aimed to create affordable, tolerable, active new
antimycobacterials for pulmonary TB, CSF penetration is
not necessarily an attribute that these candidate compounds
have been developed for. Assessing any new drug that emerges
from the pipeline will need to be subjected to well-designed,
adequately powered clinical trials for TBM, which are
resource consuming and difficult to achieve and will require
multisite involvement. Other areas of future research for TBM
treatment should include the benefit of adjunctive drugs such
as aspirin or immune-modulating drugs, which may reduce
sequelae. In general, future trials should be aimed at efficiency
by using innovative trial designs, making more efficient use
of existing drugs, and by basing the trial rationale on existing
pharmacokinetic/pharmacodynamic data, in particular, the
ability to penetrate the brain. Protection conferred by BCG
vaccine is insufficient. The TB vaccine pipeline has 11 vac-
cine candidates entered in clinical trials. (http://www.tbvi
.eu/fileadmin/user_upload/Documenten/News/TB_Vaccine_
Pipeline_2011_FINAL03042012.pdf). Most are preexpo-
sure vaccines aimed to prevent TB disease intended to either
replace BCG (recombinant live vaccines) or to be given after
BCG prime as boosters (either protein adjuvant formulations
or recombinant viral carriers) (226). Recently, MVA85A, a
booster vaccine for BCG, was subjected to the first efficacy
trial since BCG; however, it failed to prove a statistically sig-
nificant effect (227). The development of an effective vaccine
has the potential to greatly influence the TB epidemic, how-
ever requiring renewed funding incentives, appropriately
structured trials, and eventually government commitment to
support vaccination strategies. It is a less popular notion, but
fundamental to the control of both the TB and HIV pandemics
is the commitment of policymakers to address socioeconomic
issues, such as poverty, crowding, lack of education, failing
health care infrastructure, and lack of access to health care
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 CHAPTER 30 INFECTIONS DUE TO
NONTUBERCULOUS MYCOBACTERIA
JEANA L. BENWILL AND RICHARD J. WALLACE, JR.
Mycobacteria other than Mycobacterium tuberculosis have
established themselves as human pathogens. By 1960, most
of the common species of nontuberculous mycobacteria
(NTM) had been described, including Mycobacterium kansa-
sii, Mycobacterium avium, Mycobacterium intracellulare, and
Mycobacterium fortuitum (1). More than 140 species have now
been recognized and characterized in the genus Mycobacterium
(25), more than 70 of them in the past 20 years (4,5). Much
of this taxonomic explosion relates to the use and availability
of 16S ribosomal (rRNA) gene sequencing, 65 kDa heat shock
protein (hsp65), -subunit of RNA polymerase (rpoB), and
large public DNA databases (25).
Two general groups of NTM can be delineated on the
basis of microbiologic, clinical, and epidemiologic character-
istics: the slowly growing and rapidly growing mycobacteria
(RGM). Characteristics of the species included in these groups
are shown in Table 30.1 (see later discussion). The incidence
of disease due to NTM has increased substantially in the past
20 years, in part because of better knowledge of its diseases,
in part because of improved laboratory techniques, and in
part because of the pandemic of human immunodeficiency
virus (HIV). The most commonly recovered species or spe-
cies complex is M. avium complex (MAC), which commonly
TA B L E 3 0 . 1
CLASSIFICATION OF MYCOBACTERIAL SPECIES
COMMONLY CAUSING HUMAN DISEASE
Mycobacterium tuberculosis complex
Mycobacterium tuberculosis
Mycobacterium bovis
Mycobacterium africanum
Mycobacterium leprae
Slowly growing mycobacteria
Mycobacterium kansasii
Mycobacterium marinum
Mycobacterium avium complex
Mycobacterium avium
Mycobacterium intracellulare
Mycobacterium malmoense
Mycobacterium simiae
Mycobacterium ulcerans
Mycobacterium xenopi
Rapidly growing mycobacteria
Mycobacterium fortuitum group
Mycobacterium chelonae
Mycobacterium abscessus complex
Mycobacterium mucogenicum
Scheld_Ch30.indd 501
caused disseminated disease in patients with advanced HIV
infection before the advent of effective antiretroviral therapy
(ART). Among the slowly growing mycobacteria: MAC,
M. kansasii, M. genavense, M. malmoense, and M. simiae
have been identified with central nervous system (CNS) dis-
ease. In addition to the slowly growing NTM, the RGM
organisms that have been associated with CNS disease have
been M. fortuitum group (primarily M. fortuitum) and the
M. abscessus complex. This chapter summarizes the epidemi-
ology, diagnosis, and treatment of each of the NTM reported
to cause CNS disease.
GENERAL OVERVIEW
NTM are generally free-living organisms that are ubiquitous
in the environment. They have been recovered from surface
water, household water and biofilms, soil, and domestic and
wild animals (16). Studies have demonstrated that mycobac-
teria easily become aerosolized from aqueous sources and that
more easily aerosolized strains also more commonly cause pul-
monary infections.
During the 1950s, the ability of NTM to cause human disease
became increasingly clear as a consequence of several landmark
publications. In 1959, Runyon (7) proposed a classification sys-
tem that divided human isolates of NTM into four groups on
the basis of growth rates, colony morphology, and pigmentation
in the presence and absence of light. This allowed mycobacterial
laboratories to more readily identify individual species of NTM,
allowing clearer characterization of distinct diseases and syn-
dromes associated with these organisms. In 1979, Wolinsky (1)
published an exhaustive review of the clinical and laboratory
features of these organisms. This provided one of the first refer-
ence sources for physicians to review the clinical significance of
the wide variety of species grouped as NTM and the clinical dis-
ease syndromes they produce. The number of cases of NTM dis-
ease has dramatically increased, as has knowledge about these
mycobacteria, in the more than 30 years since this publication
appeared. Subsequent major reviews that have updated newer
species since the study by Wolinsky (1) in 1959 were by Wayne
and Sramek (2) in 1992, Brown-Elliott and Wallace (3) in 2002,
and Tortoli (4,5) in 2003 and 2006.
The frequency of disease due to the different species of NTM
is unknown. By the early 1990s, laboratories informally reported
that more than 50% of evaluated mycobacterial species were
NTM. Much of this increase is related to the high incidence of
disseminated MAC disease in patients with acquired immunode-
ficiency syndrome (AIDS). Among 41,439 cases of AIDS reported
to the Centers for Disease Control and Prevention (CDC) from
1981 to 1987, disseminated NTM infection occurred in 5.5%,
and 96% of these were due to MAC (8). As a consequence, CNS
infections due to NTM have increased in frequency.
Prior to describing NTM infections of the CNS in patients
with HIV, it may be useful to briefly review disseminated NTM
infection in these patients. With the exception of rare cases
that might occur by direct extension or from trauma, infection
501
2/21/14 5:45 PM
 502 Part III: Bacterial and Mycoplasmal Infections
of the CNS is likely to occur from hematogenous dissemina-
tion. Therefore, these patients may approximate the patient
population from which CNS disease arises. Horsburgh and
Selik (8) summarized the epidemiology of disseminated NTM
infection in the pre-ART era in the United States from 1981
to 1987 based on data reported to the CDC. As stated pre-
viously, disseminated NTM infection was reported in 5.5%
(2,269 cases) of patients with AIDS over this 7-year period and
96% of these were MAC. The remaining 4% included M. kan-
sasii (2.9%), M. gordonae (0.6%), and M. fortuitum complex
(0.3%). The number of patients with NTM disease increased
in parallel with the incidence of AIDS, and the overall propor-
tion in the pre-ART era remained nearly constant at 5.5%.
Significant regional variations in this figure, from 3.9% to
7.8%, were noted. NTM disease occurs primarily in patients
with AIDS, generally in patients with fewer than 50 CD4
cells/L (9). Patients with disseminated NTM infection had
significantly shorter survival (median, 7.4 months) than pa-
tients with AIDS without disseminated NTM infection (me-
dian, 13.3 months). Disseminated NTM infection is diagnosed
after AIDS in nearly one half (47.2%) of patients. In short, the
early AIDS epidemic has been accompanied by an epidemic of
disseminated NTM disease as severely immunocompromised
patients were exposed to these ubiquitous but relatively less
virulent organisms. With the advent of ART, however, the re-
covery rate of MAC and other NTM in patients with AIDS has
fallen dramatically since the mid to late 1990s.
In the absence of HIV infection, on the other hand, the dis-
tribution of infections due to the different NTM species was re-
ported by Swiss investigators who reviewed all 513 HIV-negative
patients from whom NTM were isolated at the University of
Zurich from 1983 to 1988 (9). In this study, 34 patients were
thought to have clinical disease due to these infections, 21 had
pulmonary disease, 10 had soft tissue disease, and 1 had dis-
seminated disease. There were no instances of CNS involve-
ment. The most common isolates were MAC in 16 patients
and M. kansasii in 9 patients. M. terrae complex, M. fortuitum
group, M. marinum, and M. malmoense were also involved.
NTM disease in children before the AIDS era was reviewed
by Lincoln and Gilbert (10). In contrast to adults, cervical
lymphadenitis due to M. scrofulaceum and MAC, as well as
cutaneous disease due to M. marinum and M. ulcerans, pre-
dominated. Twelve cases of disseminated disease were re-
ported. Six patients were reported with definite CNS disease
and one additional case was highly probable. Of these seven
patients, M. kansasii was the pathogen in three patients (one
was a dual infection with M. tuberculosis), scotochromogens
were reported in two patients, and MAC in two patients.
Three patients were Asian and two patients each were from
Europe and the United States. Cerebrospinal fluid (CSF) re-
sults reported in five of seven patients were typical of myco-
bacterial infection, that is, lymphocytic pleocytosis, elevated
protein level, and depressed glucose levels. One definite case,
however, had a neutrophilic pleocytosis. Treatment was not
detailed and four patients died. A 2-year prospective surveil-
lance study of children in Netherlands with NTM demon-
strated that MAC was the most common pathogen, but no
disseminated or CNS disease was reported (11). Jensen et al.
(12) conducted a retrospective review of mycobacterial dis-
ease in HIV-infected children in Spain from 1997 to 2008. Of
1,307 HIV-infected children, 42 had mycobacterial disease
of which 22 had NTM. Nine had disseminated disease, but
CNS involvement was not reported. Overall, a reduction of
mycobacterial infection decreased from 5.9 to 1.6 events per
1,000 HIV-infected children-year. NTM disease rates were
2.3, 3.4, and 0.3 per 1,000 HIV-infected children-year for
1997 to 1999, 2000 to 2002, and 2003 to 2008, respectively.
Scheld_Ch30.indd 502
The authors attribute the increase of NTM disease during the
2000 to 2003 period to increased awareness and diagnostic
consideration of NTM (12).
The review by Wolinsky (1) serves as a convenient and au-
thoritative starting point for a discussion of NTM infections
of the CNS prior to 1979. One case each of meningitis due to
M. kansasii, MAC, and M. gordonae were described. The pa-
tient with M. kansasii was a 34-year-old woman who died of
disseminated infection. The patient with MAC was a 13-year-
old boy with disseminated disease who had MAC isolated from
CSF and had granulomatous meningitis on postmortem exami-
nation. The patient with M. gordonae infection was a hydroce-
phalic infant who had undergone multiple shunt procedures with
infection of the peritoneal fluid and CSF. Wolinsky (1) also men-
tioned one case of MAC meningitis from his own experience.
In addition, he noted two instances in which other pathogens
were also present: M. kansasii was isolated from the meninges at
postmortem examination in a 2-year-old with miliary and men-
ingeal M. tuberculosis, and M. intracellulare was isolated from
the CSF of a 46-year-old woman with cryptococcal meningitis
(a subsequent smear of the CSF for acid-fast bacilli [AFB] was
positive, but cultures were negative with the patient receiving
chemotherapy). Because two pathogens were isolated, the role
of NTM in these patients diseases was difficult to determine.
The following sections of this chapter review the epidemiol-
ogy, microbiology, and chemotherapy of the NTM implicated
in CNS disease and summarizes reported cases to date. The
chapter is organized by species of mycobacterium divided into
slowly and rapidly growing species. Several case series de-
scribed more than one species. Investigators from Brooklyn,
New York described 11 years of experience at Kings County
Hospital with NTM from 1980 through 1990 infections of the
CNS in patients with AIDS (13). Sixteen CSF cultures were
positive for NTM. Fifteen grew MAC and one grew M. fortui-
tum group. Three patients concurrently had CNS toxoplas-
mosis. Ten of the fifteen died during hospitalization. Japanese
workers accumulated 109 cases of NTM disease by nationwide
investigation from 1955 to 1965; 6 involved the CNS, but the
NTM isolates were not speciated (14). A report from Malaysia
identified a 9-month-old admitted with meningitis and CSF
from which AFB with yellow-orange colonies were cultured
from a cisternal puncture but not from a lumbar puncture (15).
Wolinskys view of these reports raised the important issue of
acceptable criteria for the diagnosis and reporting of CNS dis-
ease due to NTM. Given a compatible clinical situation, isola-
tion of multiple colonies of NTM in pure culture from repeated
specimens of CNS tissue or fluid would constitute strong evi-
dence for NTM as a cause of the patients CNS disease (16).
Clinical and microbiologic response to specific therapy and the
absence of other pathogens would virtually seal the diagnosis.
SLOWLY GROWING
NONTUBERCULOUS
MYCOBACTERIA
Mycobacterium avium Complex
Epidemiology
MAC includes ubiquitous, free-living organisms (1). MAC iso-
lates are readily recovered from natural reservoirs including
soil and water, and organisms similar to those causing human
disease have been recovered from aerosols near natural waters.
Recent environmental studies have shown that the major reser-
voir for M. avium is household water and pipe biofilms but that
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 Chapter 30: Infections Due to Nontuberculous Mycobacteria
M. intracellulare is absent and presumably acquired from envi-
ronmental exposure outside the household (17). The geographic
distribution of the organism, however, is not uniform. A survey
of skin-test reactivity within the United States to an antigen pre-
pared from MAC was published in 1969 (18). The skin-test
reagent, called PPD-B or Battey antigen (Battey State Hospital,
Rome, Georgia), was applied to approximately 275,000 naval
recruits who had lived their entire lives in a single county. Skin-
test reactivity was most common among recruits from the
southeastern and Gulf Coast states. In these areas, more than
70% of individuals had been exposed to or infected with MAC
or an antigenically similar organism. MAC lung disease appears
to be relatively more prevalent in these same areas.
The incidence of MAC infections in selected groups of HIV-
infected patients before the advent of effective ART was measured
by Nightingale et al. (9). They followed 1,006 patients at one
institution during a 3-year period with monthly blood cultures
from the date of AIDS diagnosis and determined the incidence of
MAC bacteremia to be 21% at 1 year and 43% at 2 years (9).
The incidence of MAC bacteremia was inversely related to CD4
lymphocyte counts, occurring in only 3% of patients with CD4
lymphocytes of 100 to 199 cells/L increasing progressively to
39% for patients with fewer than 10 CD4 lymphocytes/L.
Pathogenesis
MAC is likely to disseminate to the CNS hematogenously from
a respiratory or gastrointestinal source. In rare cases, CNS dis-
ease may occur following trauma, direct extension from an
adjacent focus of infection such as the paranasal or mastoid
sinuses and with implantable foreign material (1922).
Early experience with MAC disease in HIV-infected pa-
tients indicated that heavy bacteremia, widespread disease,
and a high tissue burden of organisms were typical. Subsequent
study suggests that these early observations focused on patients
with relatively far advanced disease. Torriani et al. (23) studied
44 patients with MAC bacteremia who eventually had com-
plete autopsies over 5 years in California. No tissue involve-
ment could be identified in 30% of patients, whereas 70% of
patients had one to nine different tissue sites involved (median
of four). CNS involvement was seen in one patient who had
both cerebral and spinal cord infection with MAC. The likeli-
hood of detectable tissue involvement increased directly in pro-
portion to the length of survival after the first positive blood
culture: 43% in patients dying within 2 months, 72% among
patients dying in 2 to 10 months, and 90% among patients
dying after 10 months. This suggested that mycobacteremia
preceded disseminated MAC disease. These workers hypoth-
esized that mycobacteria infect a mucosal surface (gut or lung),
multiply locally, and eventually enter the bloodstream and dis-
seminate, seeding other organs and tissues. CNS involvement is
likely to be a natural consequence of this pathogenic sequence.
Some understanding of the pathogenesis of CNS infection by
MAC in immunocompromised patients is provided by a murine
model reported by Wu et al. (24). Following intravenous ad-
ministration of M. avium, numerous mycobacteria were pres-
ent in macrophages within granulomatous lesions in the brain
by 6 months. Interestingly, none of the mice exhibited clinical
signs of meningitis or encephalitis, a finding similar to many
HIV-infected patients with CNS involvement with M. avium.
Mycobacterium avium Complex Infection of the
Central Nervous System in HIV-Infected Patients
CNS disease due to MAC in HIV-infected patients has been
documented through case reports, case series, and reviews of
medical records associated with laboratory isolates of MAC
(Table 30.2). Interestingly, of the five patients in the initial
Scheld_Ch30.indd 503
503
description of AIDS from Los Angeles (25), all five eventually
developed disseminated MAC disease and two of the five had
CNS disease due to MAC (26).
Hawkins et al. (27) reported the experience of the Memorial
Sloan-Kettering Cancer Center with disseminated MAC infec-
tion in patients with AIDS from 1981 to 1984. Of 366 patients
with AIDS, 67 (18.3%) were diagnosed with disseminated MAC
infection. CNS involvement was not identified before death in
any of these patients. Autopsies were performed in 45 of these
patients, and 12 (39%) of 31 whose brain tissue was cultured
had positive cultures for MAC from brain tissue. In another re-
port from the same institution focusing on the neuropathology
of AIDS, Snider et al. (28) described 50 patients (of 160 patients
with AIDS from 1980 to 1983) who developed neurologic dys-
function. Twenty patients had complete autopsies. MAC was
cultured from the brains of two patients with disseminated
MAC disease, and AFB were seen microscopically in the brain
tissue in one of these. AFB were seen in brain tissue of a third
patient with disseminated MAC disease, but cultures were nega-
tive. These patients had impaired cognition, psychomotor retar-
dation, fevers, sweats, anorexia, malaise, and gastrointestinal
complaints. CSF showed a mild pleocytosis (7 to 36 white blood
cells [WBCs]/L, 90% polymorphonuclear [PMN] in one pa-
tient, and 70% lymphocytes in a second) but normal protein and
glucose concentrations. Pathologically, two had gray and white
matter changes of subacute encephalitis with nodular collections
of microglial cells, without inflammatory changes and reactive
astrocytosis and small foci of demyelination in the white matter.
Levy and Bredesen (29) reviewed the neurologic manifesta-
tions of 1,286 patients with AIDS in San Francisco, of whom
474 had diseases affecting the CNS. Included were four patients
with MAC infection of the CNS. Computed tomographic (CT)
scan of the head revealed single hypodense lesions in two cases, a
single contrast-enhancing lesion in one, and no abnormalities in
one. Biopsy of the contrast-enhancing lesion revealed toxoplas-
mosis and lymphoma, in addition to MAC infection. In the CSF,
there was a mild pleocytosis (12 to 15 WBCs/L) and mild el-
evations of protein but normal glucose values. CSF culture grew
MAC in two patients. Brain biopsy yielded MAC in one patient,
and postmortem examination identified MAC in the CNS in the
fourth patient. In reviewing the published literature to that point,
the authors identified 14 cases of CNS infection with MAC.
Most patients had disseminated MAC infection before present-
ing with diffuse encephalitis. Meningitis, cranial neuropathy, and
peripheral neuropathy were also reported in association with
MAC infection of the CNS. Survival was uniformly poor.
In these severely immunocompromised patients, more than
one opportunistic pathogen may be isolated from the CNS es-
pecially in the era of more sensitive tests like polymerase chain
reaction (PCR) assays. Two AIDS patients were reported by
Sharma et al. (32) in which one patient had altered sensorium,
fever, and meningismus who in the CSF had 20 WBCs/L
(100% lymphocytes) and mild elevation of protein with nor-
mal glucose. CSF culture and multiplex PCR grew M. avium
and M. tuberculosis. The second patient had prior pulmonary
tuberculosis (TB) and had severe headache. CSF contained
110 WBCs/L (70% lymphocytes), 600 mg/dL protein, and
glucose 63 mg/dL. Cultures of CSF were negative for M. avium
and M. tuberculosis, but multiplex PCR was positive for both
species. In addition, CSF cryptococcal antigen was positive.
At Kings County Hospital in New York, Jacob et al. (13)
reviewed all positive CSF cultures for NTM over 11 years,
from 1980 to 1990. Of the 16 patients with positive cultures,
14 occurred from 1987 to 1990, 15 were MAC, and 1 was
M. fortuitum group (see later discussion). Twelve patients had
a previous diagnosis of AIDS and the remaining four had at
least one major risk factor for HIV infection. All 15 patients
2/21/14 5:45 PM
 504 Part III: Bacterial and Mycoplasmal Infections

TA B L E 3 0 . 2
REPORTED MYCOBACTERIUM AVIUM COMPLEX INFECTIONS OF THE CENTRAL NERVOUS SYSTEM IN
PATIENTS WITH AIDS

No. of Age State or

Reference Cases (yr) Sex Country Diagnosis Culture Source Source Population of Cases

23 1 NR NR CA Encephalomyelitis Blood, PM: 44 pts. with blood cultures positive for

brain, spinal MAC and autopsies at University of
cord California, San Diego, 19881992
26 2 30 M CA Meningoencephalitis CSF, PM: brain Initial report of AIDS from Los Angeles,
30 M CA NR PM: brain 5 pts.
27 12a NR NR NY NR PM: brain 67 pts. with disseminated MAC of
366 total pts. with AIDS at Sloan-
Kettering, 19811985, 12/45 with
PM cultures of brain but 0/50 with
cultures antemortem
28 3b 39 M NY Encephalitis PM 8 pts. with disseminated MAC of
50 pts. with CNS involvement at
Sloan-Kettering, 19801983
29 4 NR NR CA Encephalitis Brain biopsy 482 pts. with CNS involvement
NR NR CA Meningitis PM of 1,286 total pts. with AIDS
at University of California, San
NR NR CA Meningitis CSF
Francisco to 1986
NR NR CA Meningitis CSF
30 3 NR NR Italy Encephalitis NR 30 pts. who developed disseminated
MAC of 350 pts. followed
prospectively 19851993
31 1 NR NR France Rhombencephalitis CSFa Single case report
32 2 58, 38 M India Meningitis CSF Pts. with positive CSF for NTM and
TB. 1 pt. with positive CSF culture
for NTM and TB
33 2 NR NR CA NR CSF 100 consecutive MAC isolates from
89 pts. at San Francisco General
Hospital
13 15 33 4 9M:6F NY Meningitis CSF, PM 16 pts. with NTM isolated from CSF at
Kings County Hospital 19801990
34 1 38 M TX Meningitis CSF 32 pts. who had CSF cytology at M.D.
Anderson 19821986
35 2 Adult NR France Encephalitis PM 125 autopsied pts. at 1 hospital
19821986
36 2 Adult NR Zaire Meningitis CSF 43 pts. with CNS manifestations of 104
consecutive HIV-positive admitted
pts. in Kinshasa
37 1 42 M Germany Meningoencephalitis CSF Single case report
38 1 32 M Australia Epidural abscess Abscess Single case report
39 1 Adult Epidural abscess Single case report
40 2 Adult 1M:1F Spain Meningoencephalitis; CSF Pts. with positive CSF cultures for NTM
brain abscess between 19821994
41 1 Adult M Australia Brain abscess Brain Single case report
42 1 34 F France Brain abscess Brain biopsy Single case report
43 1 40 M France Brain abscess Brain biopsy Single case report
44 1 38 M Canada Brain abscess Brain biopsy Single case report
45 1 33 M Michigan Brain abscesses Brain biopsy Single case report
46 1 42 F India Brain abscess Abscess Single case report
47 1 23 M Taiwan Meningoencephalitis CSF Single case report
and myelitis

NR, not reported; PM, postmortem cultures and/or histopathology; pts., patients; M, male; pt., patient; TB, Mycobacterium tuberculosis; F, female.
a
Cytomegalovirus also isolated from CSF.
b
Cases may overlap.

Scheld_Ch30.indd 504 2/21/14 5:45 PM

 Chapter 30: Infections Due to Nontuberculous Mycobacteria 505

FIGURE 30.1 Magnetic resonance scan of the brain and spinal cord demonstrating numerous tiny nod-
ules scattered diffusely in an AIDS patient with MAC isolated from CSF. (From Lee YC, Lu CL, Lai CC,
et al. Mycobacterium avium complex infectionrelated immune reconstitution inflammatory syndrome
of the central nervous system in an HIV-infected patient: case report and review. J Microbiol Immunol
Infect. 2013;46:6872, with permission.)

with MAC disease had widespread dissemination, and in 3 pa-
tients, autopsies demonstrated extensive MAC disease of CNS,
bone marrow, liver, gastrointestinal tract, and lymph nodes,
but no other CNS disease.
The number of additional cases of CNS disease due to MAC
over the years has declined dramatically with better ART and
the decline in cases of disseminated MAC (3346). However,
MAC involving the CNS has been increasingly reported with
immune reconstitution (41,42,44,47). Lee et al. (47) reported
an interesting case of diffuse nodules of the brain and spinal
cord (Fig. 30.1) of a patient with AIDS whose treatment for
disseminated MAC had been discontinued after immune re-
constitution. MAC was isolated from blood and CSF cultures
and responded well with reinitiation of MAC drug therapy.
Most cases in the literature describe one to three brain lesions,
but Verma and Dhamija (45) reported a case of disseminated
M. avium-intracellulare infection in an AIDS patient with mul-
tiple brain lesions (Fig. 30.2).

FIGURE 30.2 Magnetic resonance scan of the brain with multiple ring-enhancing lesions with MAC isolated
from brain biopsy. (From Verma R, Dhamija R. Disseminated Mycobacterium avium-intracellulare infection
presenting as multiple ring-enhancing lesions on brain MRI. Mayo Clin Proc. 2009;84:394, with permission.)

Scheld_Ch30.indd 505 2/21/14 5:45 PM

 506 Part III: Bacterial and Mycoplasmal Infections

Mycobacterium avium Complex Infection of the
Central Nervous System Not Associated with
HIV Infection
MAC infection of the CNS has also been reported in the ab-
sence of HIV infection, both in patients with another immu-
nocompromising process and in patients without identifiable
immunologic deficits (Table 30.3). The frequency with which
this occurs is difficult to determine because it is relatively rare,
generally not reported, and no surveillance system for NTM
infection exists. At Mt. Sinai Hospital in New York, mycobac-
teria were recovered from CSF specimens from 21 patients be-
tween 1970 and 1983 (16). Three isolates were NTM and 19
were M. tuberculosis. Two patients had high colony counts of
MAC recovered on both inoculated slants. The third had a sin-
gle colony of M. gordonae, probably a contaminant, isolated
from otherwise normal CSF. The first patient was previously
healthy and presented with meningitis clinically. Her CSF had
471 WBCs/L (84% lymphocytes), 234 mg/dL of protein, and
41 mg/dL of glucose. Both MAC and M. tuberculosis were
isolated from the CSF. The second patient had chronic myelog-
enous leukemia (CML) in blast crisis and MAC was isolated in
pure culture with high colony counts on both slants.
These cases raise the critical issues of interpreting positive
CSF cultures of NTM and reasonable criteria to diagnose NTM
infection of the CNS. These authors suggest that to ascribe
CNS disease to NTM, multiple colonies of the NTM should
be demonstrated on repeated cultures of CSF in the absence of
other pathogens. None of these three patients met these crite-
ria, but the high colony counts and pure culture of MAC from
the single CSF specimen of the second patient make contamina-
tion unlikely. However, these criteria may focus too narrowly
on CSF alone as a specimen source. For example, isolation of
MAC from a biopsy of brain, meninges, aspirate of a brain ab-
scess, or from a postmortem specimen in an appropriate clini-
cal setting would be strong microbiologic evidence of MAC
disease. In addition, these criteria do not allow for the pos-
sibility of dual infection with NTM and another pathogen. A
case report illustrates these points (48). A 48-year-old woman
presented with fever, a shift in her leukocyte differential toward

TA B L E 3 0 . 3
REPORTED MYCOBACTERIUM AVIUM COMPLEX INFECTIONS OF THE CENTRAL NERVOUS SYSTEM IN
PATIENTS WITHOUT HIV INFECTION

No. of State or Diagnosis

Reference Cases Age Sex Country (Culture Source) Comorbidity Source Population of Cases

1 1 NR NR U.S.A. Meningitis (NR) Immunosuppressed Single case reported in extensive

review of NTM
16 2 58 M New York Meningitis (CSF) CML in blast crisis, 21 pts. with mycobacterial
40 F New York Meningitis (CSF) M. tuberculosis meningitis (19 TB), Mt. Sinai
(CSF), previously Hospital, New York City
healthy 19701983
48 1 48 F U.S.A. Meningitis, brain C. neoformans (CSF), Single case report
abscess (CSF) previously healthy
49 1 31 F Switzerland Meningitis, brain Previously healthy Single case report
abscess (CSF) (? corticosteroids)
50 NR NR Colorado Meningitis (NR) Disseminateda MAC 13 pts. with disseminated MAC
at National Jewish Hospital,
Denver, 19401984
51 1 47 F Japan Meningitis (CSF) Disseminated MAC, Single case report
CML, pulmonary
alveolar proteinosis
52 1 50 M Brain abscess (tissue) Systemic lupus Single case report
53 1 38 M Brain abscess (tissue) Sarcoidosis Single case report
54 1 52 M U.S.A. Brain abscess (tissue) Lung carcinoma s/p Single case report
lobectomy and
radiotherapy
55 1 63 M Canada Brain abscess (tissue) Sarcoidosis Single case report
56 1 29 M Ohio Bone marrow, liver Hodgkin disease Single case report
57 1 73 F Japan Meningitis (CSF) Previously healthy Single case report
59 1 38 M U.S.A. Brain abscess (tissue) Sarcoidosis, Single case report
corticosteroids
107 1 5 F Denmark Meningitis (CSF) NR Single case report
107 1 13 M U.S.A. Meningitis (CSF, PM) Disseminated MAC Single case reported in textbook
on NTM

NR, not reported; M, male; F, female; PM, postmortem.

a
Granulomatous meningitis at PM examination.

Scheld_Ch30.indd 506 2/21/14 5:45 PM

 Chapter 30: Infections Due to Nontuberculous Mycobacteria
immature forms, and a posterior fossa mass lesion. A ventricu-
loatrial shunt was placed and CSF from this procedure con-
tained 32 mg/dL of glucose, 38 mg/dL of protein, and 83 WBCs/
L (all mononuclear). Two days later, CSF obtained by lumbar
puncture (opening pressure 300 mm) had 14 mg/dL of glucose,
107 mg/dL of protein, and 44 WBCs/L (75% mononuclear).
India ink and culture demonstrated Cryptococcus neoformans.
The patient was treated with amphotericin B and 5-fluorocyto-
sine and gradually improved. After 6 weeks, CSF from the orig-
inal lumbar puncture grew M. intracellulare. Lumbar puncture
was repeated and several AFB were seen on direct smear, but
no further cultures grew the organism. Isoniazid and rifampin
were added to her therapeutic regimen and she eventually re-
covered. She was free of relapse at a 3-year follow-up but had
significant neurologic sequelae. The role of M. intracellulare in
producing disease in this patient was difficult to determine, but
based on careful evaluation of the circumstances, the authors
concluded that the organism was unlikely to be a contaminant.
Another case of MAC infection of the CNS in a previously
healthy person was reported by Uldry et al. (49). A 31-year-old
woman presented with a 2-year history of progressive head-
aches that suddenly became worse associated with lethargy,
confusion, vomiting, and a grand mal seizure. On examination,
the patient had depressed consciousness, a stiff neck, decorti-
cate posturing, and bilateral flexor-plantar reflexes. CT of the
head showed hydrocephalus due to compression of the fourth
ventricle and meningeal enhancement with contrast. A ventric-
uloatrial shunt was placed and the CSF contained 453 WBCs/
L (80% lymphocytes). The patient was treated with isoniazid,
rifampin, and pyrazinamide for TB and steroids for sarcoid-
osis, but all cultures were negative. Immunologic evaluation
was negative. The patient improved clinically, and repeated
immunologic parameters, HIV serology, and chest radiography
remained normal. Over the subsequent 2 years, however, the
patient fluctuated clinically, the CSF profile remained abnor-
mal, and cultures were repeatedly negative. After 2 years, head-
ache recurred and a left hemiparesis developed. Repeated CT
scans showed a right temporal mass with surrounding edema.
Craniotomy revealed a hemorrhagic necrotic mass, which on
microscopic examination had granulomas, multinucleated giant
cells, and few AFB. The tissue grew MAC. This case is notewor-
thy because it illustrates the difficulty of diagnosing and treating
MAC infection of the CNS. However, an alternative explana-
tion is possible, based on the long duration of disease before the
diagnosis of MAC. The patient may have had an undiagnosed
cause for her CNS disease initially and then developed a MAC
cerebral abscess as a consequence of chronic steroid therapy.
Additional cases of CNS infection due to MAC have been re-
ported in the context of disseminated MAC disease by workers
at National Jewish Hospital (Denver, Colorado)in a review
of 13 cases of disseminated MAC infection in HIV-negative
patients from 1940 through 1984 (50). The criteria for dissem-
inated disease by which they selected cases required isolation
of MAC from at least one nonpulmonary site and microbio-
logic or histopathologic evidence of granulomatous disease at
a second anatomically distinct site. By this case definition, one
patient with meningeal involvement was identified. No details
were provided. It is now presumed that all these patients had
a genetic abnormality that predisposed them to NTM disease.
One case of disseminated MAC infection with CNS in-
volvement was reported by Japanese workers in a patient with
pulmonary alveolar proteinosis and CML (51). A 47-year-old
woman with CML who had been treated with busulfan for
2 years developed a recurrent cough and had an abnormal chest
radiogram. AFB smears of expectorated sputum were positive.
Transbronchial lung biopsy revealed pulmonary alveolar pro-
teinosis. Cultures of sputum, bone marrow, and CSF grew MAC.
Scheld_Ch30.indd 507
507
Four interesting cases of brain abscess mimicking spindle
cell tumors have been described. Di Patre et al. (52) reported
a 50-year-old patient with systemic lupus erythematosus who
presented with a dural-based meningioma-like mass in the
right frontal lobe. The mass resembled a meningioma with fas-
cicular arrangement of spindle cells without caseation or giant
cells but by AFB stains consisted of large numbers of AFB in
histiocytes (52). A very similar case was reported by Morrison
et al. (53) of a 38-year-old man with sarcoidosis who also
presented with a spindle cell pseudotumor. It had minimal
necrosis but was loaded with AFB. Arkun et al. (54) reported
a 52-year-old with history of lung carcinoma, left upper lobec-
tomy, and radiotherapy with complex, multiloculated, ring-
enchancing cystic lesion of the left tentorium with compression
of the fourth ventricule resulting in hydrocephalus. The tis-
sue consisted of spindle cells arranged in bands, fascicles, and
ill-defined nodules with a single giant cell. Ziehl-Neelsen and
Fite staining was positive, and MAC was identified by DNA
probe (54). Sadek et al. (55) described a case with underlying
sarcoidosis with headache and word-finding difficulties with
a left frontal ring-enchancing lesion. Tissue revealed multiple
foci of spindle cell pseudotumor formation with large num-
ber of AFB. Similar pseudotumors have been described with
M. tuberculosis in immunosuppressed patients, but these are
some of the first to be described due to NTM.
Gyure et al. (56) presented the case of a patient with un-
derlying Hodgkin disease who presented with signs of me-
ningoencephalitis that included seizures, confusion, nuchal
rigidity, and extensor-plantar responses. The patient died and
at autopsy was found to have focal aggregates of lymphocytes,
macrophages, and AFB located predominantly in a perivas-
cular location. Cultures of CSF and brain were positive for
MAC. Okada and Yoshioka (57) reported a case of acute dis-
seminated encephalomyelitis associated with meningitis in a
73-year-old female who had fever, meningism, disorientation,
left eye eversion, muscle weakness, and ataxic gait. Magnetic
resonance imaging (MRI) showed multifocal and asymmetric
increased T2 signals of the white and cortical graywhite mat-
ter junction of cerebral hemispheres, cerebellum, and brain-
stem. CSF contained WBCs of 1,295/L (60% PMNs) and
protein of 60 mg/dL with normal glucose. M. intracellulare
was isolated from CSF by PCR. The patient was treated with
rifampicin, streptomycin, clarithromycin, and steroids with
resolution of symptoms.
Immune defects involving interleukins (IL) 10 and 12 and
tumor necrosis factor- (TNF-) and interferon- (IFN-) are
risk factors for pulmonary and disseminated NTM. Browne
et al. (58) reported adult-onset immunodeficiency in Thai and
Taiwanese patients associated with autoantibodies to IFN-.
One hundred five patients had NTM isolated, with 52 having
disseminated disease, but no details of CNS involvement were
reported. Two cases of immunodeficiency with CNS NTM in-
volvement have been reported. Dickerman et al. (59) reported
a case of a 38-year-old male with sarcoidosis who underwent
MRI due to possible seizure activity which demonstrated right
frontal, left parietal, and right cerebellar lesions. M. avium was
cultured from resected frontal and parietal lesions. Despite
therapy, the cerebellar lesion increased in size and total resec-
tion of the cerebellar mass was performed. Histopathology
showed encapsulated abscess with mixture of plasma cells,
lymphocytes, and macrophages with AFB. The patient was
found to have low concentrations of IFN- and TNF-. The
case described by Sadek et al. (55) as previously discussed on
further analysis showed TNF- and IL-12 defect in response
to MAC antigens but high levels of IFN-. These cases demon-
strate the complex and fascinating IL, TNF, and IFN immune
response in NTM disease.
2/21/14 5:45 PM
 508 Part III: Bacterial and Mycoplasmal Infections
Laboratory
MAC is readily identified in the laboratory by acid-fast smear
and culture using techniques for CSF and tissue standard-
ized for TB. The organisms grow well in broth medium and
on Middlebrook 7H10 agar, typically producing small, flat
transparent smooth colonies on agar that often have a pale
yellow color. Their colony morphology readily distinguishes
them from M. tuberculosis. Commercial nucleic acid probes
(AccuProbe, Gen-Probe, Inc.) are available that identify
MAC isolates with greater than 99% accuracy 1 day after the
colonies have grown, a technique used in most laboratories.
M. avium and M. intracellulare are separate species, but their
separation has no clinical value for the individual patient with
lung disease and, hence, is generally not done. Specific DNA
probes that recognize only M. avium or M. intracellulare are
commercially available, however, MAC is also readily identi-
fied by high-performance liquid chromatography (HPLC) by
analysis of mycolic acid patterns, a technique used by many
large state laboratories and the CDC.
Antimicrobial susceptibility testing of NTM based on the
American Thoracic Society (ATS) and the 2011 Clinical and
Laboratory Standards Institute (CLSI) guidelines currently
recommend reporting primary susceptibility to only clarithro-
mycin with secondary testing of linezolid and moxifloxacin
(60,61). It recognized that the only drug for MAC for which
susceptibility testing has been shown to be predictive of clini-
cal outcome was clarithromycin. Studies have shown that un-
treated strains of MAC were all clarithromycin susceptible,
with minimum inhibitory concentrations (MICs) of less than
8 g/mL, whereas strains that relapsed or failed therapy had
one of two mutations in the 23S rRNA gene, with MICs gener-
ally more than 32 g/mL. Susceptibility to other drugs such as
ethambutol, rifampin, rifabutin, streptomycin, and amikacin
provided no information about clinical responses to therapy.
However, recently, Brown-Elliott et al. (62) proposed amika-
cin MIC breakpoints reporting 96.2% of clinical isolates had
MICs of less than 32 g/mL and prolonged exposure corre-
lated with development of 16S rRNA mutation with MICs
more than 64 g/mL.
Treatment
Therapy of disease due to MAC, like susceptibility testing, is
more difficult and more controversial than that for M. tuber-
culosis. There have been few prospective controlled treatment
trials (6367). Treatment of CNS disease must be extrapo-
lated from cumulative experience and data on treatment of
MAC lung disease in HIV-negative patients and disseminated
disease in patients with AIDS. Recommendations for therapy
generally follow ATS guidelines last updated in 2007 (60). The
regimen recommended by the ATS for the treatment of MAC
lung disease is a three-drug regimen. The daily regimen con-
sists of clarithromycin (500 mg twice daily) or azithromycin
(250 mg daily), rifampin (600 mg), and ethambutol (15 mg/kg
daily). The same three drugs can also be given intermittently.
The doses then are clarithromycin at 1,000 mg or azithromy-
cin 500 mg, ethambutol at 25 mg/kg, and rifampin at 600 mg
given three times weekly (Monday, Wednesday, and Friday).
Rifabutin at 150 mg can be substituted for rifampin in the
daily regimen, and at 300 mg in the three-times-weekly regi-
men for severe disease. Aminoglycoside therapy with either
streptomycin or amikacin is usually reserved for cavitary, ex-
tensive disease or macrolide-resistant cases. Patients requiring
long-term parenteral therapy should receive a dose of 8 to
10 mg/kg two to three times per week.
These macrolide-based regimens appear to have good ac-
tivity in the therapy of disseminated MAC disease in patients
Scheld_Ch30.indd 508
with AIDS (6871) and in MAC lung disease in HIV-negative
patients (60,6365). Their usefulness and role in the therapy
of MAC disease of the CNS have not been studied, but they
offer exciting potential for therapy of a very difficult disease.
Treatment of MAC lung disease is continued until cultures
remain consistently negative for at least 12 months.
For the treatment of MAC in AIDS, a joint panel between
the CDC, the National Institutes of Health, and the HIV
Medicine Association of the Infectious Diseases Society of
America published recommendations (72). The basic princi-
ples for therapy included the necessity of regimens containing
at least two drugs, one of which should be either clarithromy-
cin or azithromycin. Most commonly, ethambutol and either
rifampin or rifabutin would be the second and third drugs.
Clofazimine was once considered among the possible agents
to treat these infections. However, studies now show increased
mortality when this drug is used in this setting, so it should
not be used for treatment of disseminated MAC. Treatment
should be continued for at least 12 months and discontinuing
treatment is based on the absence of ongoing MAC disease
and appropriate and sustained immune response due to ART.
Treatment of CNS infection is complicated by the lack
of therapeutic data and by the preference for parenteral
therapy in critically ill patients with altered mental status.
Clarithromycin, rifampin, and ethambutol penetrate relatively
well into the CNS. With inflamed meninges, the aminoglyco-
sides and the newer quinolones penetrate into the CNS to a
limited extent. Intrathecal therapy with aminoglycosides has
been well described in other conditions, especially meningitis
due to gram-negative bacteria. At present, the standard agents
for treatment of pulmonary or disseminated MAC disease
would appear to be the best available agents for MAC CNS
disease.
Mycobacterium kansasii
The major reservoir for M. kansasii is likely commercial or
household water, and clinical disease predominates along the
southeastern and southern coastal states and the central plains
states. Unlike other NTM, M. kansasii has never been found
in soil or natural water supplies but has been recovered con-
sistently from tap water in cities where M. kansasii infection
is endemic. Previous studies in Texas show that M. kansasii
disease is concentrated in urban areas, supporting a pos-
sible association between clinical disease and potable water
supplies. M. kansasii infection causes pulmonary nodular
disease in patients with bronchiectasis, fibrocavitary pulmo-
nary disease resembling TB, and, rarely, disseminated disease
in immunocompromised hosts including patients with AIDS
(1,8). The most common extrapulmonary sites are lymph
nodes, bone marrow, bone, joints, and skin. Only 10 cases
of CNS disease have been described, 7 of whom occurred in
patients with AIDS.
Mycobacterium kansasii Infections of the
Central Nervous System
The 10 cases of CNS disease due to M. kansasii that have
been reported are listed in Table 30.4. The first description of
M. kansasii disease in the CNS was reported by Wood et al.
(73) in 1956 in the context of disseminated M. kansasii infec-
tion and was just discussed. In the second report of M. kansasii
disease of the CNS in the literature (1966), both M. kansasii
and M. tuberculosis were isolated from a 2-year-old girl with
meningitis (74). The patient presented with signs of meningi-
tis and her father was subsequently discovered to have active
pulmonary TB. Lumbar puncture on two occasions had
2/21/14 5:45 PM
 Chapter 30: Infections Due to Nontuberculous Mycobacteria 509

TA B L E 3 0 . 4
REPORTED MYCOBACTERIUM KANSASII INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

Reference No. of State/ Diagnosis

No. Cases Age Sex Country (Culture Source) Comorbidity Source Population of Cases

73 1 34 F U.S.A. Meningitis (CSF) Disseminated M. 15 pts. with M. kansasii

kansasii pregnancy infection, not HIV infected
74 1 2 F KY Meningitis (PM) M. tuberculosis Single case report
meningitis (CSF)
76 1 NR NR DC Meningitis (CSF) AIDS, disseminated 12 AIDS pts. with disseminated
M. kansasii M. kansasii at George
Washington University Hospital
77 1 NR NR TX Meningitis (CSF) AIDS, C. neoformans 9 pts. with disseminated
(CSF), MAC, M. kansasii of 1,100 AIDS
(CSF, blood) pts. at Parkland Hospital,
Dallas
79 1 NR NR NY Meningitis (CSF) AIDS 121 AIDS pts. with neurologic
complications in New York City
80 1 Adult M TX Brain abscess (tissue) AIDS, HCV 12 AIDS pts. with M. kansasii
infection at UTMB Galveston
19902001
81 1 22 F NY Meningitis (CSF) AIDS 86 AIDS pts. with NTM at Kings
County Hospital, Brooklyn
19811990
82 1 40 F GA Brain abscess AIDS, disseminated Single case report
(abscess aspirate) M. kansasii
83 1 42 M FL Brain abscess AIDS, disseminated Single case report
(abscess aspirate) M. kansasii
84 1 13 M U.S.A. Meningitis (CSF, PM) Disseminated Single case report
M. kansasii

F, female; pts., patients; NR, not reported; M, male; HCV, hepatitis C virus; PM, postmortem examination.

pleocytosis (200 to 313 WBCs/L, with a lymphocytic pre-
dominance), elevated protein level (59 mg/dL), and depressed
glucose levels (22 to 27 mg/dL). The second specimen had one
AFB on direct microscopy and grew M. tuberculosis. Despite
treatment with isoniazid and streptomycin, the patient died. At
autopsy, the CSF grew M. tuberculosis, but the leptomeninges
grew M. kansasii in pure culture. This highly unusual report,
the first of its kind, raises the possibility of mixed infection by
M. tuberculosis and M. kansasii.
In patients with advanced HIV infection, M. kansasii often
produces disseminated infection. Among patients with AIDS
reported to the CDC from 1981 to 1987, disseminated M. kan-
sasii was reported in 0.44% of patients from areas endemic for
M. kansasii and in 0.08% in patients from nonendemic areas
(8). Several retrospective studies have examined disseminated
M. kansasii infection in HIV-infected patients (7580). In two
of these reports, M. kansasii was isolated from CSF in one
patient each, but few clinical details were provided (79,80).
A report from New York reported 121 patients with AIDS
of whom one had M. kansasii isolated from the CSF (79).
Symptoms included fever, weight loss, hypoadrenalism, and
hematemesis. Lumbar puncture was performed before treat-
ment and three times over the next month because of neuro-
logic deterioration. All CSF specimens had normal cell counts,
protein values, and glucose values, and negative cultures until
the fourth specimen grew M. kansasii several weeks after the
patients death. Smith et al. (80) reported a retrospective re-
view of the pathologic features of M. kansasii in patients with
AIDS during 1990 to 2001. Twelve patients were identified
with only one patient having CNS involvement. Little details
were provided, but brain biopsy revealed granulomatous in-
flammation with AFB and the patient recovered on therapy.
The sixth case of M. kansasii CNS disease was reported
by Shafer and Sierra (81) in 1992. They summarized the ex-
perience with NTM (excluding MAC and M. gordonae) over
a 10-year period (1981 to 1990) at Kings County Hospital
in Brooklyn, New York. Seven patients had M. kansasii. Six
of the seven M. kansasii isolates were from respiratory speci-
mens. The seventh was isolated from the CSF of a 22-year-old
HIV-infected Haitian woman who had a brain lesion visual-
ized by contrast-enhanced CT scan but no other details of this
case were provided.
In 1992, Gordon and Blumberg (82) reported a 40-year-old
woman with a 5-day history of right-sided headaches and left-
sided weakness. Physical examination disclosed fever, oral thrush,
right Horner syndrome, and gait ataxia. CD4 lymphocyte count
was 118 cells/L. CT scan of the head revealed two ring-enhanc-
ing lesions in the right frontal lobe and thalamus. Fine-needle as-
piration of the right frontal lobe mass revealed focal necrosis and
perivascular inflammation, but no organisms were visible micro-
scopically. Cultures grew only M. kansasii. The patient survived
20 weeks after the initiation of treatment.
A mass lesion with associated meningitis due to M. kansasii
infection was reported from Florida in 1993 (83). A 42-year-
old man with AIDS presented with 2 weeks of headaches,
1 week of confusion and fever, and 1 day of loss of balance.

Scheld_Ch30.indd 509 2/21/14 5:45 PM

 510 Part III: Bacterial and Mycoplasmal Infections
CT of the head revealed a 4-cm mass in the right occipitopa-
rietal region, which enhanced with intravenous contrast. CSF
contained no cells, no organisms microscopically, and normal
glucose level, but protein level was 690 mg/dL. Aspiration of
the intracranial mass yielded pus, which was smear positive
for AFB. Blood, sputum, and CSF cultures grew M. kansasii
and PCR of the abscess aspirate was positive for M. kansa-
sii. Treatment with isoniazid, rifampin, and ethambutol led
to resolution of symptoms and negative blood cultures within
1 month and clearing of the lesion on CT by 3 months.
Thus, disseminated M. kansasii disease occurs in a small
but consistent fraction of patients with AIDS, and CNS in-
volvement occurs rarely. The majority of published CNS infec-
tions with M. kansasii have occurred in HIV patients. CNS
disease may be a manifestation of hematogenous spread of this
microorganism.
Laboratory
M. kansasii is seen on smear and recovered in culture by tech-
niques designed for M. tuberculosis. It grows readily in broth,
as well as on Middlebrook 7H10 agar and Lowenstein-Jensen
agar. The organism typically produces rough large colonies that
turn bright yellow with exposure to light (photochromogen). A
species-specific DNA probe for M. kansasii has been described
and is commercially available (AccuProbe, Gen-Probe, Inc.).
The organism is readily identified by biochemical tests as well
as by HPLC. On acid-fast smears, M. kansasii typically ap-
pears as a large, long bacillus that has unusual beading when
stained with Ziehl-Neelsen or Kinyoun stains. This often al-
lows an initial suspicion that one is dealing with this organism,
as opposed to M. tuberculosis.
Current 2011 CLSI recommendations for susceptibility
testing of M. kansasii are for rifampin and clarithromycin only
given the concentration problems with isoniazid and to do ad-
ditional testing for other drugs such as amikacin, ethambutol,
ciprofloxacin, moxifloxacin, linezolid, rifabutin, and sulfon-
amides only if the isolate is rifampin resistant (61).
Treatment
Treatment of M. kansasii disease of the CNS is extrapolated
from the treatment of M. kansasii lung disease in HIV-negative
patients and from the case reports summarized herein.
Treatment of M. kansasii was dramatically improved by the
additions of rifampin and ethambutol to the pharmacopeia,
as the success rate for regimens containing these two drugs
approach 100% (84,85). The current 2007 ATS recommenda-
tion for treatment of pulmonary disease due to M. kansasii
includes isoniazid (300 mg per day), ethambutol (15 mg/kg
per day), and rifampin (600 mg per day) for a duration that
includes 12 months of negative cultures (60).
However, the British Thoracic Society reported 155 pa-
tients who were treated with ethambutol and rifampicin (86).
Sputum conversion was reported in 99.4% of patients. In ad-
dition, Griffith et al. (87) reported 15 patients treated with
standard MAC therapy three times weekly. The sputum con-
version and long-term success rates were excellent with no
treatment failures or relapses, but the study was too small to
change the current ATS recommendations. Thus, clarithromy-
cin in combination with rifampin and ethambutol is believed
to be the best regimen based on excellent in vitro activity, mini-
mal toxicity, clinical performance against other NTM, and an-
ecdotal experience (78,88,89). For patients with HIV disease
on ART regimens for which rifampicins are contraindicated,
a macrolide may substitute for the rifampicin if the ART regi-
men cannot be adjusted (63). Tompkins and Witzig (90) retro-
spectively reviewed M. kansasii infection in 137 HIV patients
Scheld_Ch30.indd 510
grouped pre-ART era and ART era. Clarithromycin-treated
patients survived a median of 8 months (2 vs. 10 months) lon-
ger compared to those treated without clarithromycin.
In place of isoniazid, which has marginal activity, sulfa-
methoxazole-containing regimens have been used successfully
in the treatment of rifampin-resistant disease, but these studies
antedated the availability of clarithromycin (91,92). In a study
of 40 patients, Ahn et al. (84) demonstrated that the addition
of streptomycin at 1 g twice weekly for the first 3 months to a
12-month regimen of the recommended three-drug daily com-
bination resulted in a long-term success rate of 97%.
Treatment for CNS disease should be based on optimal
regimens for this infection at other body sites where sufficient
numbers of cases provide a more solid understanding of the
chemotherapy of this disease, combined with pharmacologic
principles of the treatment of CNS infections. One additional
drug that offers potential for treatment of CNS disease due
to M. kansasii is linezolid (Zyvox). All isolates of M. kansa-
sii have MICs of less than 4 g/mL (peak serum levels are
15 to 20 g/mL) (93) and the drug has excellent CNS pen-
etration. Because of the large number of drugs available for
M. kansasii and the cost of linezolid, there is no reported
experience with other clinical forms of M. kansasii or with
CNS disease. Linezolid has proven effective for the treatment
of Mycobacterium chelonae (94) and Nocardia species (95),
including patients with brain abscesses (95).
Mycobacterium simiae
This species of mycobacteria was first reported in 1965 when it
was isolated from Macacus rhesus monkeys (96). M. simiae are
slow-growing organisms that may produce pigmented and non-
pigmented colonies. It has been rarely associated with human
disease but has been described to cause lung disease in the set-
ting of structural lung disease (bronchiectasis). M. simiae is usu-
ally reported from Israel and the southwestern United States
based on clinical samples (60). The epidemiologic source of
M. simiae is not well established but has been reported in sev-
eral pseudo-outbreaks in the southwestern United States attrib-
uted to hospital water and has been recovered from tap water
sources derived from large aquifers (97). Four cases of CNS
infection of M. simiae have been reported. Valero et al. (98)
reported 137 clinical isolates of M. simiae in 75 patients in San
Antonio, Texas over an 11-year period (1983 to 1993). One
hundred twenty-eight (93%) isolates were from respiratory
sources, four blood, one skin, one urine, one lymph node, and
one bone marrow. Only one case involved the CNS, a 38-year-
old man with AIDS who presented with fever, night sweats,
and falls. CT of the head revealed three brain lesions with brain
biopsy reported as B-cell lymphoma that was AFB stain posi-
tive with no granulomas. Tissue culture grew M. simiae, but the
patient refused therapy and 10 weeks after brain biopsy died.
The second case of M. simiae occurred in a 40-year-old
man with AIDS who developed right hemiparesis, progressive
truncal ataxia, vertigo, and horizontal binocular diplopia with
fever and weight loss (99). MRI demonstrated multiple en-
hancing isointense nodular lesions at the left cerebral peduncle
and medulla involving the leptomeninges. Lumbar puncture
on two occasions revealed 10 to 20 mononuclear cells/L,
glucose of 47 to 72 mg/dL, and protein of 49 to 135 mg/
dL. Partial surgical resection of the medullary lesion revealed
dense proliferation of spindle cells with histiocytes, lympho-
cytes, and mononuclear cells. Ziehl-Neelsen staining was AFB
positive and tissue culture grew M. simiae that was confirmed
using 16S rRNA PCR gene sequencing. M. haemophilum was
also isolated from blood cultures, and the authors attribute
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 Chapter 30: Infections Due to Nontuberculous Mycobacteria
the negative tissue culture for M. haemophilum due to lack of
hemin or ferric ammonium citrate in culture medium that is
essential for its growth (61). He received isoniazid, rifampin,
pyrazinamide, ethambutol, and clarithromycin for treatment
and improved with only residual neurologic deficits. This is
the fifth case of CNS NTM infection forming spindle cell pseu-
dotumors (5255,99).
Balkis et al. (100) reported the third case of M. simiae in
an 83-year-old HIV-negative man who developed fever, confu-
sion, and agitation 2 days after surgery for a right hip fracture
secondary to a fall who had complained of feeling ill for
several weeks prior to the fall. Bilateral interstitial infiltrates
were seen on chest radiography. His level of consciousness
deteriorated along with respiratory failure requiring intuba-
tion. Brain CT scan showed small vessel ischemic disease and
CSF specimen showed 1 WBC/L, normal glucose and pro-
tein levels. Bronchoalveolar lavage was performed and 1 week
later grew M. simiae in culture. One week after lumbar punc-
ture, CSF culture grew M. simiae. Both isolates were identi-
fied using 16S rRNA gene sequencing. The patient developed
cardiopulmonary arrest and died. The authors contend that
because cultures were recovered from two different sterile sites
and no other mycobacteria was isolated in any other culture
during hospitalization, M. simiae was a true pathogen.
The final case of M. simiae was reported in a 39-year-old
with a 4-month history of fever, night sweats, and weight loss
who was diagnosed with AIDS (101). Physical exam revealed
hepatosplenomegaly, and liver biopsy showed AFB with mini-
mal disruption of the liver tissue and was treated empirically
for TB with rifampicin, isoniazid, ethambutol, and pyrazin-
amide. CSF specimen showed no WBCs, normal protein,
and glucose. After hospital discharge, blood and CSF culture
grew M. simiae and antimycobacterial therapy was changed
to moxifloxacin, rifabutin, ethambutol, and azithromycin and
ART was started 10 days later. Three months after ART, fever
and malaise returned with negative microbiologic workup,
and immune reconstitution inflammatory syndrome was diag-
nosed and resolved with steroid therapy.
M. simiae is highly drug resistant, including ethambutol and
rifabutin. The best antimycobacterial drugs are the macrolides
(clarithromycin or azithromycin), trimethoprim-sulfamethoxazole
(TMP-SMX), moxifloxacin, and amikacin (102).
Mycobacterium gordonae
M. gordonae organisms are ubiquitous in the environment,
but their recovery has been most closely identified with water.
M. gordonae are slow-growing, rarely pathogenic organisms
that are occasionally encountered in the microbiology labora-
tory and usually considered an environmental contaminant.
Weinberger et al. (103) reviewed all reported cases of disease
due to M. gordonae to 1992 and identified 23 cases, of which
13 had sufficient information to be judged definite. Eight had
pulmonary disease, seven had soft tissue infection of an ex-
tremity, five had disseminated disease, three had peritonitis,
and one had corneal infection. The CNS was involved in two
cases, both of whom involved CSF shunts (see following sec-
tion). In most of these patients, the infection was treated with
three antimycobacterial drugs including isoniazid, rifampin,
ethambutol, and/or an aminoglycoside. Overall, 6 of 24 pa-
tients died. These cases and all reported cases of M. gordonae
infection involving the CNS were in the premacrolide era, and
no isolates were confirmed by molecular methods.
The first case was a hydrocephalic child who had two ven-
triculoatrial shunts placed at 18 days and 7 months of age (104).
The child had an elevated CSF protein level (106 mg/dL) and
Scheld_Ch30.indd 511
511
increased intracranial pressure necessitating a ventriculoperito-
neal (VP) shunt. The patient underwent several shunt revisions
complicated with the development of ascites. CSF specimens
grew M. gordonae, and shunt valve was loaded with AFB.
The meningitis and ascites resolved with shunt removal and
antimycobacterial therapy. The second case of M. gordonae
meningitis occurred in a 23-year-old woman, who underwent
a VP shunt following excision of a cerebellar medulloblastoma
9 years prior, who presented with fever, hematuria, and progres-
sive renal insufficiency (105). Nine months before admission,
she had been placed on prednisone for presumed hypersensi-
tivity pneumonitis and hepatitis. Cultures of lung biopsy ob-
tained 9 months prior revealed 2 growth of M. gordonae. CSF
was tapped from the shunt and showed numerous AFB. CSF
analysis showed normal glucose and slightly elevated protein.
M. gordonae were cultured from CSF, urine, renal biopsy, and
the shunt that had been removed.
Although one cannot generalize from two reported cases,
it remains prudent to consider a mycobacterial etiology in
chronically febrile patients who have had shunting procedures
including infection of the shunt itself. Treatment with antimy-
cobacterial agents and removal of the foreign body was effec-
tive in these two cases.
Mycobacterium genavense
This species of mycobacteria was first reported by Bottger et al.
(106) in 1992 who described it in 18 patients with AIDS present-
ing with fever, diarrhea, and marked weight loss. Two subsequent
reports on M. genavense described similar symptoms in patients
with AIDS, with a 68% mortality by 12 months (107,108).
In terms of CNS disease, two cases have been reported.
Berman et al. (109) reported a 50-year-old man with AIDS. The
patient was admitted with a 1-month history of memory prob-
lems, confusion, and episodic tremor of the right arm, as well
as a 2-week history of right-sided weakness and paresthesias.
The patient had mild right-sided motor and sensory deficits and
slurred speech. CT revealed cerebral edema and a mass effect in
the left parietal region. The patient was treated empirically for
toxoplasmosis with pyrimethamine and sulfadiazine but had a
grand mal seizure after 1 week. MRI at that time showed a
left parietal mass abutting the dura with meningeal enhance-
ment and a large zone of surrounding edema. CT-guided needle
biopsy revealed a patchy lymphocytic infiltrate without granu-
loma formation but with clusters of AFB on Ziehl-Neelsen stain.
Treatment was started with five drugs to cover M. tuberculosis
and MAC, and then was changed to clarithromycin, cipro-
floxacin, and ethambutol when the organism was identified as
M. genavense. The patient did well clinically and repeat imag-
ing demonstrated complete resolution at 12 months.
Uchino et al. (110) reported a 50-year-old man with primary
immunodeficiency who presented with dysarthria, aphasia, and
right hemiparesis. MRI revealed multiple intracranial masses in
the subcortical regions. CSF cultures were negative for NTM.
Brain biopsy was perfomed, which confirmed M. genavense
infection. These reports, as well as the previous reports on
M. genavense, describe significant difficulties culturing this organ-
ism using standard techniques for mycobacteria. Identification to
the species level, in most cases, requires molecular methods.
Mycobacterium terrae Complex
The M. terrae complex initially included only M. terrae and
M. nonchromogenicum. The species has now been expanded
to multiple other species, with the most common isolate being
2/21/14 5:45 PM
 512 Part III: Bacterial and Mycoplasmal Infections

M. arupense. The M. terrae complex are rare, slowly grow-

ing nonpigmented mycobacteria that are present in tap water
presumed to be nonpathogenic in the lung but are a recognized
cause of posttraumatic tenosynovitis and local osteomyelitis
of the extremities. Two cases involving the CNS have been
reported (111,112). Woods and Washington (111) reviewed
the microbiology and clinical aspects of NTM and described
the Cleveland Clinic Foundations experience with NTM,
from 1982 to 1985. Of 140 patients with mycobacteria iso-
lated from clinical specimens, 93 were NTM, primarily MAC
(124 specimens). M. gordonae (75 specimens), M. kansasii
(59 specimens), and M. fortuitum group (58 specimens) ac-
counted for most of the remainder. Whereas most of these iso-
lates were from respiratory tract specimens, one patient who
had an acoustic neuroma removed several months previously
developed meningitis due to M. terrae complex. Details of the
case were not published. Lai et al. (112) described a 65-year-old
HIV-negative man who had radiotherapy for nasopharyngeal
carcinoma 6 years prior to presentation. He was admitted with
a 2-month history of headache and 5-day history of fever, nau-
sea, and poor appetite. Physical exam revealed meningismus
and CT disclosed dilated ventricles with diminished sulci. Two
lumbar punctures were performed revealing pleocytosis, 140
to 488 WBCs/L (77% to 81% PMNs), elevated protein of
131 to 267 mg/dL, and glucose 11 to 37 mg/dL. Microbiologic FIGURE 30.3 Magnetic resonance imaging, convalescent phase
CSF analysis showed negative Gram stain and culture, AFB axial fluid-attenuated inversion recovery (FLAIR) demonstrates dif-
stain, and cryptococcal antigen. Fever and headache persisted, fuse white matter high signal from a patient that M. malmoense and
M. interjectum was identified from CSF. (From ODwyer JP, OConnor
and MRI revealed leptomeningeal enhancement of the right
JG, McDermott H, et al. Meningoencephalitis associated with non-
temporal region and premedullary areas of the brain stem. tuberculous mycobacteria [published online November 22, 2009].
Empirical therapy for TB meningitis was initiated, but neuro- BMJ Case Rep, with permission.)
logic status worsened to coma. Repeat CT demonstrated hy-
drocephalus necessitating external ventricular drainage. Five
weeks after CSF AFB cultures were obtained, both yielded
treatment, encephalopathy improved, enabling the patient to
M. nonchromogenicum.
be discharged home. Specific antimycobacterial therapy was
not described further.
Mycobacterium malmoense
M. malmoense is a slow-growing pigmented species first re- Mycobacterium triplex
covered in Malmo, Sweden. It can cause a variety of diseases
M. triplex is a rare slowly growing nonpigmented species.
such as chronic pulmonary disease or cervical lymphadenitis
Most clinical cases have had underlying immune deficien-
in children. It is second only to MAC in many areas of north-
cies, especially advanced HIV disease. Zeller et al. (115)
ern Europe as a cause of NTM disease and is rarely seen in
described a 41-year-old man from Nigeria with AIDS with
the United States. Two cases with CNS disease have been re-
positive cultures of blood, sputum, and ascitic fluid with the
ported. Florakis et al. (113) described a patient with chronic
organism shown to be related to M. triplex by partial 16S
mastoiditis who was found to have pituitary insufficiency sec-
rRNA gene sequencing. The patient developed signs of left
ondary to mycobacterial infection due to M. malmoense. The
hemiballism-hemichorea. An MRI showed a lesion in the
disease was proven by surgical biopsy and 16S rRNA gene
subthalamic lesion. Cultures of CSF also grew M. triplex.
sequencing. The second case was a 49-year-old woman with
The patient initially responded to antimycobacterial therapy
a 6-month history of deteriorating vision, anorexia, anxiety,
but did poor clinically and died 5 months after the start of
and poor memory with a change in behavior manifested as
the therapy.
disinhibition and aggression (114). Physical exam revealed
Thus, it appears that less commonly encountered species of
poor cognitive performance, bilateral papilledema, and gen-
mycobacteria also cause CNS disease on occasion. Diagnosis
eral hyperreflexia and extensor plantar reflexes. CSF analy-
of mycobacterial disease of the CNS requires, ideally, that the
sis revealed pleocytosis, 37 WBCs/L (monocytes), elevated
involved tissue be examined microbiologically for AFB and
protein of 949 mg/dL, and 1:3 CSF:serum glucose ratio with
histopathologically specifically for mycobacteria and chronic
negative AFB stain. MRI demonstrated periventricular white
(often granulomatous) inflammation. Treatment of CNS dis-
matter changes and enhancement in the basal ganglia. CSF
ease due to these organisms must be based on published find-
culture grew M. malmoense and M. interjectum based on
ings and clinical experience, largely in other organs, as well as
the Hain PCR method. Empirical therapy with rifampicin,
principles of pharmacotherapy of CNS disease.
isoniazid, ethambutol, and pyrazinamide with steroids was
initiated. Over the next 3 months, the clinical course wors-
ened with development of myoclonus, vision loss, sleepwake
Transverse Myelopathy and Radiculomyelopathy
cycle disturbance, and agitation. Repeat CSF analysis revealed One study described two cases of transverse myelopathy and
elevated protein of 541 mg/dL and bilateral optic atrophy by radiculomyelopathy associated with pulmonary disease due to
funduscopic examination. MRI demonstrated development of M. kansasii and M. malmoense (116). The fact that only one
secondary white matter changes (Fig. 30.3). After 8 weeks of such report exists suggests it is a rare event with NTM.

Scheld_Ch30.indd 512 2/21/14 5:45 PM

 Chapter 30: Infections Due to Nontuberculous Mycobacteria
RAPIDLY GROWING
NONTUBERCULOUS
MYCOBACTERIA
RGM include four clinically relevant species, including M. for-
tuitum, M. mucogenicum, M. chelonae, and the M. absces-
sus complex. The proper taxonomy and nomenclature of
M. abscessus complex that now includes M. abscessus (sensu
stricto), M. massiliense, and M. bolletti will be a continual and
dynamic process as more detailed genomic sequencing occurs.
The RGM are generally considered environmental saprophytes
widely distributed in nature, including tap water (1,60).
Mycobacterium fortuitum
The M. fortuitum group includes a variety of species that in-
clude M. fortuitum, M. porcinum, M. senegalense, M. mag-
eritense, M. peregrinum, and M. houstonense. M. fortuitum
was originally described as a cause of a postinjection site
abscess and principally causes primary skin and soft tissue
infections, surgical wound infections, and central venous cath-
eterrelated infections (117). Rarely, other infections such as
pulmonary disease, prosthetic valve endocarditis, and cervical
lymphadenitis can occur.
The relative frequency of CNS infection due to the M. for-
tuitum group is unknown but is probably rare. Most cases
were reported before the recognition of the earlier noted new
species, which require molecular methods for identification.
Hence, all early isolates are listed as M. fortuitum group un-
less clearly delineated from these other species by molecular
methods. Reported experience with this disease is summa-
rized in Table 30.5. It has been associated with spinal cathe-
ters, ventricular shunts, and mastoiditis. Indirect information
in this regard can be gleaned from reported cases such as the
1983 report by Wallace et al. (117). During a 4-year period,
these workers were involved in the care of 125 patients with
disease due to RGM. One of these patients had M. fortuitum
meningitis.
Hand and Sanford (118) reported the first case of a CNS
infection due to the M. fortuitum group. They described an
8-year-old boy with 12 days of fever, stiff neck, back and leg
pain, lethargy, and disturbed gait. Eight days before admis-
sion, a lumbar puncture revealed 3,025 WBCs/L (74% PMN
cells), 237 mg/dL of protein, and 51 mg/dL of glucose. Smears
and cultures were negative, and the boy was diagnosed with
aseptic meningitis. On admission, the boy was febrile and
had a stiff neck. Repeated lumbar puncture was essentially
unchanged. On the sixth hospital day, however, attempted
lumbar puncture yielded frank pus. Myelography revealed
a complete block to contrast material at T12. At surgery, a
cauda equina abscess was drained and an Ommaya reservoir
was placed. Cultures of the pus obtained at attempted lumbar
puncture and the material from surgery grew an M. fortuitum
group, which was resistant to all antibiotics tested. Multiple
subsequent cultures of CSF and reservoir grew M. fortuitum
group and the reservoir was eventually removed. The organ-
ism based on in vitro susceptibility testing was only sensitive
to oxacillin and kanamycin, and the patient was treated with
these antibiotics for 25 days. Six months after discharge, the
patient was ambulating without crutches but with persistent
gait disturbance.
Four cases of M. fortuitum group CNS infection have been
reported occurring after surgical procedures (20,21,119,120).
Meningitis developed in a 19-year-old woman following
Scheld_Ch30.indd 513
513
lumbar discectomy (119). CSF was sampled repeatedly over a
10-month period. Two initial cultures of CSF were positive for
M. fortuitum group and eight subsequent cultures during a 10-
month period were negative with the patient on treatment. CSF
leukocyte counts ranged from approximately 100 to 800 cells/
L, peaking 1 month after presentation. Dbridement of the
infected site revealed granulomatous reaction with AFB in
the bony tissue. Treatment was primarily with doxycycline,
amikacin, and capreomycin once the identity of the organism
was established. The next case involved a 57-year-old woman
who developed recurrent fever and headache for 1 year fol-
lowing surgery for meningioma (120). Repeated CSF analysis
was indicative of bacterial meningitis with negative microbio-
logic cultures. One year after surgery, repeat CSF culture grew
M. fortuitum group, which was treated with clarithromycin
and levofloxacin. Symptoms and CSF analysis improved on
therapy.
The remaining two cases involved children. A 9-year-old
female underwent tympanomastoidectomy and 1 month later
developed a mastoid fluid collection (20). Fluid collection was
drained and culture grew M. fortuitum group with subsequent
development of osteomyelitis of the right temporal bone with
meningeal enhancement by MRI. Lumbar puncture was nega-
tive for organisms. The patient underwent a modified radical
mastoidectomy and histopathology revealed granulomas with
central necrosis, chronic inflammation with lymphocytes, and
AFB stain negative. Tissue sent to the CDC for culture and
susceptibilities identified M. fortuitum/M. peregrinum group
with reported sensitivity to doxycycline and meropenem. The
patient was treated with doxycycline and meropenem and
1 month later developed fever, headache, and back pain. MRI
demonstrated a subdural fluid collection in the cerebellopon-
tine angle that was surgically excised. Histopathology revealed
inflammatory tissue and negative stain for AFB. Quinn and
Steele (21) reported a 12-year-old male with Arnold Chiari
type I malformation diagnosed at 8 years of age who under-
went posterior cranial fossa decompression with dural graft-
ing. Fever and severe headaches followed immediately after
surgery with CSF showing lymphocytosis with negative bac-
terial and fungal cultures. Two weeks postoperatively, he de-
veloped a CSF leak requiring surgical revision, but fever and
headaches continued, in addition to nausea, vomiting, and
photophobia. Three weeks postoperatively, he developed per-
sonality changes that progressed to deteriorating mental status
and 5 weeks postoperatively, CT demonstrated obstructive
hydrocephalus. Ventriculostomy with subsequent VP shunt
placement was performed. CSF obtained during ventriculos-
tomy demonstrated AFB and he was empirically treated for
TB. When AFB was identified as M. fortuitum group, antimy-
cobacterial therapy was changed to amikacin, cefoxitin, and
clarithromycin. The VP was not removed due to the patient
being shunt dependent. Over the next 2 months, fevers, de-
creased appetite, and abdominal pain with VP obstruction
requiring multiple revision and externalization of the shunt
occurred. Ventricular and peritoneal fluid grew M. fortuitum
group several times. Up to this point, the patient had received
2 months of cefoxitin, 4 months of amikacin and clarithro-
mycin, 1 month of ciprofloxacin, and 3 weeks of merope-
nem. Based on in vitro susceptibility, he was continued on
ciprofloxacin, clarithromycin, and TMP-SMX with minimal
planned therapy of 6 months. However, subsequent chest CT
demonstrated multiple pulmonary nodules, and CSF grew
M. fortuitum group. The authors concluded that the VP
shunt seeded the vasculature resulting in pulmonary infection.
Antimycobacterial therapy was changed to linezolid, azithro-
mycin, amikacin, ciprofloxacin, and TMP-SMX with clinical
improvement. After 12 months from initial presentation, the
2/21/14 5:45 PM
 514 Part III: Bacterial and Mycoplasmal Infections

TA B L E 3 0 . 5
REPORTED MYCOBACTERIUM FORTUITUM GROUP INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

Reference No. of Age State or Source Population

No. Cases (yr) Sex Country Diagnosis (Culture Source) Comorbidity of Cases

117,126 1 10 M Texas Subdural empyema Chronic otitis media 125 pts. with RGM
meningitis, posterior disease over 4 years
fossa abscess, mastoiditis, (most from Texas);
(CSF, abscess) case summarized in
detail in reference (126)
118 1 8 M Texas Cauda equina abscess, Motor vehicle accident 6 pts. with RGM disease
meningitis (abscess, CSF) over 3 years, Dallas
119 1 19 F Louisiana Meningitis, deep wound Lumbar discectomy 8 pts. with RGM
infection (CSF, biopsy) disease over 6 years,
New Orleans
120 1 57 F Japan Meningitis Meningioma Single case report
20 1 9 F Michigan Mastoiditis, temporal bone Otitis media, Single case report
osteomyelitis, subdural myringotomy,
fluid collection tympanoplasty
21 1 12 M Louisiana Meningitis Arnold Chiari Single case report
malformation,
ventriculoperitoneal
shunt
121 1 60 F Hong Kong Ventriculitis (CSF) Ventriculoatrial shunt Single case report
122 1 13 F Florida Meningitis Ventriculoperitoneal Single case report
shunt
123 1 Adult U.S.A. Ventriculitis (CSF) Spinal epidural catheter Single case report
22 1 60 M North Meningitis, infected pump Intrathecal drug Single case report
Carolina delivery device
124 1 16 M Spain Meningitis, infected wound Motor vehicle accident Single case report
(CSF, wound)
125 1 Adult M Texas Meningitis, dural abscess Motor vehicle accident 123 pts. with RGM
nonpulmonary disease
13 1 28 M ? Meningitis AIDS Single case report
127 1 28 M Texas Meningitis AIDS, disseminated Single case report
disease
128 2 28 M Thailand ? Hydrocephalus 103 pts. with NTM
disease in Thailand
54 F
129 1 33 F Germany Meningoencephalomyelitis None Single case report
130 1 Meningitis Prosthetic valve Single case report
endocarditis
131 1 NR NR India Brain abscess (abscess) NR 50 pts. with brain
abscess admitted to
neurosurgical unit

M, male; pts., patients; F, female; NR, not reported.

shunt was obstructed again and CSF remained culture positive
for M. fortuitum group. Intraventricular injection of amikacin
(4 mg) and linezolid (1 mg) were initiated due to failed oral
and intravenous therapy. Based on new in vitro susceptibil-
ity, antimycobacterial therapy with ciprofloxacin, TMP-SMX,
and twice-weekly intraventricular amikacin and linezolid was
initiated with subsequent sterile CSF cultures.
Two additional cases involving ventricular shunts have been
reported. Chan et al. (121) described a 60-year-old woman in
which a ventriculoatrial shunt was inserted for obstructive hy-
drocephalus from spontaneous cerebellar hematoma. At the
time of shunt placement, the CSF was normal except for the
presence of blood. From the time of shunt placement, how-
ever, the patient had persistent fever. Routine studies of the
CSF were normal except for a slightly elevated protein level.
AFB smears, however, were positive and cultures grew M. for-
tuitum group. The CSF studies were repeated and the results
were the same. The only drugs to which the organism was
susceptible in vitro were amikacin and ofloxacin. Treatment
with these antibiotics was ineffective, and the patient deterio-
rated until the shunt was removed. Intraventricular amikacin
(20 mg on alternate days) was initiated through a Rickham

Scheld_Ch30.indd 514 2/21/14 5:45 PM

 Chapter 30: Infections Due to Nontuberculous Mycobacteria
reservoir. After 1 week of intraventricular plus systemic ther-
apy, the patient defervesced. Smears and cultures of the CSF
became negative after 3 weeks of this therapy, and therapy was
continued for 10 weeks. The other case involved a VP shunt
for hydrocephalus (122). Two additional reports involving an
epidural spinal catheter and intrathecal drug delivery device
have been described (22,123).
Two cases of M. fortuitum group meningitis followed local
penetrating trauma. In 1984, Santamaria-Jauregui et al. (124)
reported a 16-year-old boy who developed relapsing M. for-
tuitum group meningitis following a motor vehicle accident.
A minor skin wound in the right sacral region from the ac-
cident necessitated excision and drainage 3 days later. Two
weeks later, the boy developed fever, headache, and a stiff
neck. Lumbar puncture revealed cloudy CSF with 1,085 WBC
(80% neutrophils) with normal biochemistry and negative
microbiologic analysis. Radiographic studies were negative
including head CT scan and myelography. The patient was
treated with two courses of multidrug antibacterial therapy
but relapsed both times when the drugs were discontinued.
Repeated lumbar puncture after the second relapse showed the
CSF contained 2,100 WBCs/L (75% neutrophils), 100 mg/dL
of protein, and 45 mg/dL of glucose. The patient developed
signs of meningitis and repeated CSF examination showed
1,200 WBCs (75% PMN), glucose level of 10 mg/dL, and pro-
tein level of 1.5 g/dL. CSF from both relapses grew M. fortui-
tum group. The original sacral wound became fluctuant and
pus from the wound grew M. fortuitum group. An abscess
and fistula that reached the sacrum were surgically excised and
drained and a piece of glass was found in the dbrided tissue.
However, the fistula could not be demonstrated to communi-
cate with the spinal canal. M. fortuitum group was isolated
from the dbrided tissue and glass fragment. Treatment with
isoniazid and trimethoprim-sulfamethoxazole produced clini-
cal improvement and normalization of the CSF. Wallace et al.
(125) reported a similar case that also followed a motor vehi-
cle accident and recovered after prolonged antibiotic therapy
and multiple surgeries.
Dalovisio et al. (126) reported 10 patients with disease due
to M. fortuitum group and M. chelonae. One was a 10-year-old
boy with chronic otitis media. A CT scan of the head showed
a right cerebellopontine angle mass. At surgery, the patient
had a subdural empyema and abscess, which grew M. fortui-
tum group. The patient was treated with erythromycin, iso-
niazid, and kanamycin for 2 weeks without success. Clinical
deterioration led to reexploration of the posterior fossa but
only partial resection of the abscess due to extensive disease.
Subsequent treatment with doxycycline and ethionamide for
several months did not resolve the fever, and after 8 months,
he developed obstructive hydrocephalus requiring VP shunt
placement. A culture obtained at that time grew M. fortuitum
group susceptible to amikacin. The patient was treated with
amikacin with gradual improvement, and all signs of the in-
fection eventually cleared; however, the patient developed per-
manent partial hearing loss from the amikacin. The authors
concluded that aggressive surgical dbridement and treatment
with antibacterial drugs based on in vitro susceptibility results
(often including amikacin and doxycycline) were critical com-
ponents of successful therapy.
Two patients with AIDS developed M. fortuitum group
meningitis with no precipitating cause (13,127). Both were
28-year-old men with far advanced HIV disease presenting with
clinical meningitis. One patient was lost to follow-up (13) and
one patient died with proof of the meningitis at autopsy (127).
Saritsiri et al. (128) reviewed NTM infection of 103 patients
in a Thai hospital. Seventy-one patients were HIV-infected
and only two cases involved the CNS. Both patients were HIV
Scheld_Ch30.indd 515
515
negative, had hydrocephalus, and M. fortuitum group was iso-
lated from the CSF.
Kell et al. (129) reported M. fortuitum group CNS infection
in a 33-year-old HIV-negative patient with recurrent double
vision, paresthesia, and vertigo for 2 years following an appen-
dectomy. MRI demonstrated multiple-enhancing leptomenin-
geal and intraparenchymal lesions in the cervical spinal cord
and brainstem. CSF contained 100 WBC/L (lymphocytes),
CSF/serum glucose ratio of 0.4, total protein of 2,500 mg/dL,
and positive AFB stain. However, microbiologic cultures and
PCR were repeatedly negative. The authors assumed infec-
tion was due to slowly growing NTM, and antimycobacterial
therapy was initiated with clarithromycin, ethambutol, and ri-
fabutin. The patient improved until several months later when
Lhermitte phenomenon, neck stiffness, recurrent hiccups, and
unsteady gait developed. MRI demonstrated increased num-
bers of lesions disseminated in the basilar cisterns, subarach-
noidal space of the vermis, and meninges and lumbar puncture
proved disease progression. Therapy was changed to etham-
butol, isoniazid, and levofloxacin with improved symptoms.
Two months later, this patient developed cranial nerve pal-
sies and MRI revealed hydrocephalus requiring VP shunt and
therapy was changed to rifampicin, ethambutol, isoniazid, and
levofloxacin for 1 month without improvement. Open biopsy
(approximately 1 year after initial presentation) of a menin-
geal lesion at C5/C6 demonstrated caseating granulomas with
negative Ziehl-Neelsen stain for AFB. Tissue by PCR analy-
sis identified M. fortuitum group. Tissue culture remained
negative (on chemotherapy). Amikacin and meropenem were
started when M. fortuitum group was identified, and later, ti-
gecycline was added and amikacin was stopped. The patient
had improved at 18 months and therapy was continued.
The remaining two reported cases of M. fortuitum group
CNS infection included a patient with fatal prosthetic valve
endocarditis with secondary meningitis (130). A study from
Hyderabad, India reviewed 50 cases of brain abscesses that
were diagnosed by CT scan and confirmed surgically in all cases
(131). One specimen grew M. fortuitum group but no other
microorganisms. No other details of this case were published.
Laboratory
RGM are the most difficult of the NTM to be recognized by
standard staining and culture techniques used for M. tubercu-
losis. The organisms do not always stain well with the Ziehl-
Neelsen or Kinyoun method and may not be recognized readily
with the fluorochrome method. For example, it is not uncom-
mon to see a sputum sample that is AFB smear negative but
with a heavy growth of an RGM species such as M. abscessus,
suggesting that the organisms did not stain. Though not per-
tinent to CSF specimens, RGM are also highly susceptible to
the decontamination procedures that are used to remove other
bacteria from specimens. Hence, quantitation of the amount
of RGM organisms present by smear or culture can be difficult
and should be assessed carefully. Separation of M. fortuitum
from the M. chelonae and M. abscessus group is done fairly
readily in the laboratory if molecular methods are used (132).
M. fortuitum is the more drug susceptible of the RGM
group, and essentially all isolates are susceptible or interme-
diate in vitro to achievable serum levels of amikacin, imipe-
nem, sulfonamides, and fluoroquinolones, and approximately
50% are susceptible to doxycycline and cefoxitin (102). Most
isolates are susceptible to linezolid (133), an oxazolidinone
that has excellent CNS penetration with high serum and CSF
levels (95). Macrolide therapy for the RGM group is compli-
cated by inducible erythromycin ribosomal methylase (erm)
gene that confers resistant by methylating an adenine in the
2/21/14 5:45 PM
 516 Part III: Bacterial and Mycoplasmal Infections
peptidyltransferase regions of the 23S rRNA (102). Erm gene
sequencing and extended incubation with clarithromycin of
the mycobacteria for 14 days, compared to routine 3-day in-
cubation, will detect inducible resistance.
Treatment
In general, patients with serious M. fortuitum group disease
are given parenteral therapy with amikacin plus cefoxitin or
imipenem combined with one or more oral agents and then
are treated with oral agents alone. For most diseases, the total
duration of therapy has been 6 months. Success rates with
M. fortuitum group skin and soft tissue infections and in lung
disease are quite high. Wallace et al. (125) prospectively stud-
ied treatment outcomes of 76 patients with extrapulmonary
disease due to M. fortuitum group who were treated on the
basis of in vitro drug susceptibility results once these became
available. Thirty-three patients had extensive or serious disease
requiring inpatient combination chemotherapy and surgical d-
bridement (31 patients). Almost all patients were treated suc-
cessfully despite that these studies antedated the availability of
clarithromycin, the fluorinated quinolones, and imipenem. No
single regimen for M. fortuitum group CNS disease has been es-
tablished. Multiple drugs would appear to have potential; and
three to four drugs should probably be used, at least initially.
Mycobacterium chelonae
M. chelonae was previously grouped as the M. chelonae/ab-
scessus complex and M. abscessus was not officially recognized
as a separate species until 1992. Thus, literature prior to that
date makes the nomenclature difficult to interpret. M. chelonae
causes predominately skin, soft tissue, and bone infection and
rarely pulmonary disease. M. chelonae is more likely to cause
disseminated cutaneous disease compared to the M. fortuitum
group (117,134,135). Wound infections and abscesses are gener-
ally the consequence of trauma, surgery, or immunosuppression.
Wallace et al. (134) characterized clinical disease due to
100 isolates of M. chelonae associated with extrapulmonary dis-
ease. No case involved CNS disease. One case of M. chelonae CNS
infection has been reported involving a 39-year-old man who de-
veloped a spontaneous extradural abscess with associated psoas
abscess due to M. chelonae who recovered after multiple surgeries
and prolonged antibiotic therapy over a 33-month period (136).
M. chelonae organisms are more susceptible based on in
vitro susceptibility to tobramycin than to amikacin, and it is
the preferred aminoglycoside for this species. Macrolide ther-
apy, either with clarithromycin or azithromycin, is an option
for treatment because M. chelonae does not possess an erm
gene. M. chelonae are uniformly resistant to cefoxitin, and ap-
proximately 60% of isolates are susceptible to imipenem; how-
ever, susceptibility testing with imipenem is problematic due
to lack of reproducibility (102). Linezolid penetrates into the
CNS, and approximately 50% of isolates are susceptible (102).
Mycobacterium abscessus Complex
The M. abscessus complex includes M. abscessus (sensu
stricto), M. massiliense, and M. bolletti. The proper taxonomy
surrounding these closely related RGM is currently in debate.
M. abscessus (sensu stricto) is predominately isolated in the
southeastern United States and has similar endemic geographic
distribution as MAC. It is the predominate RGM causing pul-
monary disease (approximately 80%) and similar to MAC is
usually superimposed on preexisting lung disease, especially
Scheld_Ch30.indd 516
bronchiectasis. The natural epidemiology and pathogenicity of
M. massiliense and M. bolletti is less known.
Eleven cases of CNS disease with M. abscessus complex have
been reported. Maniu et al. (137) described a 59-year-old woman
with a stab wound to the neck 6 months before her admission
with meningitis. Despite multiple antibiotics that included
clarithromycin, the patient died of her disease. A 27-year-old
man with secondary pulmonary alveolar proteinosis associated
with myelodysplastic syndrome developed a subcutaneous ab-
scess and meningitis after video-assisted thoracic surgery (138).
The patient died of graft versus host disease and M. abscessus
complex sepsis after transplantation. Liebeskind et al. (139) de-
scribed a 35-year-old man with 5 months of fever, fatigue, night
sweats, anorexia, jaundice, and difficulty concentrating found to
have M. abscessus complex bacteremia with a vegetation of the
posterior leaflet of the mitral valve. Lumbar puncture revealed
80 WBC/L, glucose 41 mg/dL, and total protein 88 mg/dL.
Punctate lesions of the left basal ganglia, right thalamus, and
diploic space of the right parietal bone were seen on MRI.
Ciprofloxacin, amikacin, and meropenem for antimycobacte-
rial therapy was started. On hospital day 18, CSF cultures from
admission grew M. abscessus complex and therapy based on in
vitro susceptibilities was switched to clarithromycin, imipenem,
and amikacin. During hospitalization, the patient had intermit-
tent tonic-clonic seizures and on day 44 had a seizure; repeat
MRI revealed left frontoparietal hemorrhage and subsequently
developed brain herniation and respiratory distress on day
69 and died. Autopsy demonstrated disseminated granulomas
with AFB in meninges and subcortical structures.
Talati et al. (140) reported a 28-year-old woman with left
eye enucleation and ocular prosthesis placement after trauma
10 years previously. The patient underwent prosthesis replace-
ment due to failure and within 1 year developed extrusion of
the implant with purulent drainage. The prosthesis was removed
and surgical cultures grew M. abscessus complex. The patient
was placed on clarithromycin and presented several months later
with headache, meningismus, and nausea. MRI revealed en-
hancement of the left orbit, inferior portion of the left cavernous
sinus, and infratemporal fossa. CSF analysis showed pleocytosis,
411 WBC/L, glucose 30 mg/dL, and total protein 111 mg/dL
with negative bacterial and fungal cultures. The patient was
treated with amikacin and meropenem for 2 weeks followed by
cefoxitin monotherapy for 6 weeks. Fever and headaches per-
sisted, and an Ommaya reservoir was placed for intraventricular
amikacin therapy and cefoxitin was changed to tigecycline. After
1 month of therapy, seizures developed and MRI demonstrated a
cerebral abscess surrounding the Ommaya reservoir, prompting
shunt removal. At that time, therapy was changed to cefoxitin
and tigecycline. At this point, the patient had received 4 months
of intravenous antibiotic therapy with persistent symptoms.
Repeat CSF analysis revealed 450 WBC/L (82% PMN) and
total protein 548 mg/dL. Repeat MRI (Fig. 30.4) demonstrated
basilar meningitis, resolving brain abscess, and multiple micro-
abscesses. CSF cultures grew M. abscessus complex. The patient
was treated with a variety of antibiotics including amikacin, tige-
cycline, linezolid, meropenem, moxifloxacin, and co-trimoxazole
and received approximately 21 months of therapy with marked
improvement of her symptoms and functional status.
Lee et al. (141) reviewed 15 patients with CNS NTM infec-
tion in a Taiwanese hospital from 2000 to 2010. M. abscessus
complex was identified in 8 patients, MAC in 6 patients, and
M. kansasii in 1 patient. The MAC and M. kansasii patients
were not described in detail. Six out of the 8 patients with
M. abscessus complex had preserved isolates that were ana-
lyzed using 23S rRNA and erm (41) PCR gene sequencing. All
six isolates were determined to be M. massiliense. Underlying
disease identified 2 patients to have otomastoiditis, 1 patient
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 Chapter 30: Infections Due to Nontuberculous Mycobacteria 517

FIGURE 30.4 Magnetic resonance imaging of the brain of patient with M. abscessus complex. The top
left panel is an axial section FLAIR image showing marked nodular enhancement in the orbit and intra-
temporal fossa. The bottom left panel is a second axial section flair image showing an abscess in the fron-
tal lobe also caused by M. abscessus complex infection. The follow-up images show significant interval
improvement in nodular basilar disease and decrease in size and enhancement of the frontal lobe abscess.
(From Talati NJ, Rouphael N, Kuppalli K, et al. Spectrum of CNS disease caused by rapidly growing
mycobacteria. Lancet Infect Dis. 2008;8:390398, with permission.)

Scheld_Ch30.indd 517 2/21/14 5:45 PM

 518 Part III: Bacterial and Mycoplasmal Infections
chronic otitis media, and 4 patients steroid use. Five patients de-
veloped infection postneurosurgery, and 2 patients had dissemi-
nated disease. Clarithromycin-based therapy combined with
imipenem, amikacin, levofloxacin, and moxifloxacin were the
most common regimens with treatment courses ranging from
4 months to 1 year. Five patients died.
Treatment
M. abscessus (sensu stricto) is the most drug-resistant organ-
ism of the RGM which makes treatment difficult. Most iso-
lates are susceptible to amikacin. Approximately 50% are
sensitive to linezolid and imipenem based on in vitro suscepti-
bilities (102). Seventy percent are susceptible to cefoxitin, and
commonly, tigecycline therapy is used, but there are no estab-
lished breakpoints. M. abscessus (sensu stricto) has a func-
tional erm gene in contrast to M. massiliense and M. bolletti
causing macrolide-based therapy a rare exception. In contrast,
M. massiliense and M. bolletti lack a functional erm gene,
and macrolide-based therapy is the main treatment. These
organisms otherwise have similar in vitro susceptibilities as
M. abscessus (sensu stricto) (102). No single regimen has
been established for CNS infection with M. abscessus (sensu
stricto), M. massiliense, or M. bolletti.
Mycobacterium mucogenicum
M. mucogenicum, formerly known as a Mycobacterium
chelonaelike organism, is an RGM common in tap water. It
has been associated with outbreaks linked to water contami-
nation and central venous catheter infections remain the most
common clinical infection due to this organism. Four cases of
CNS infection due to M. mucogenicum have been reported.
Wallace et al. (142) reviewed 87 isolates of which 20 (23%)
were determined to be clinically significant. Only two cases
involved the CNS with limited clinical data. The one case with
clinical disease occurred in an AIDS patient who had a lum-
bar puncture 3 weeks prior for an unrelated reason. M. mu-
cogenicum was isolated from multiple CSF cultures that were
also AFB smear positive. Two fatal cases of M. mucogenicum
were reported by Adkambi et al. (143). The first patient was a
23-year-old man with 2-week history of headache, vertigo, and
neck pain who presented with fever. A CSF specimen revealed
24 WBC/L (26% PMN), normal glucose and protein lev-
els, and negative Ziehl-Neelsen stain. The patient died 3 days
after admission. Microbiologic analysis was negative except
for positive CSF PCR analysis yielding M. mucogenicum using
16S rRNA and rpoB gene sequencing. CSF culture confirmed
M. mucogenicum. The second case was an 82-year-old man
with diabetes and chronic renal failure with femoral vascu-
lar graft who was admitted for fever, cough, and confusion.
Chest radiography demonstrated alveolar pneumonia. CSF
analysis demonstrated no WBCs, normal glucose level, and
elevated protein level of 67 mg/dL. CT scan showed extensive
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2/21/14 5:45 PM
 CHAPTER 31 BRAIN ABSCESS
MATTHIAS KLEIN, HANS-WALTER PFISTER, ALLAN R. TUNKEL, AND W. MICHAEL SCHELD
DEFINITION
Brain abscess is a focal intracerebral infection that begins as
a localized area of cerebritis and develops into a collection
of pus surrounded by a well-vascularized capsule. It con-
tinues to be a diagnostic and therapeutic challenge to the
clinician.
HISTORY
The first reference to a brain abscess is attributed to
Hippocrates in the fifth century bc (1). He described a
syndrome of purulent otorrhea and fever associated with
cerebral symptoms and stressed that the chances of survival
depended on the external draining of purulent material:
Chills, pain, and fever throughout the head, especially in
the ear, temples, and bregma. . . . If anyone moves him, he
vomits copiously and easily. . . . If, in this patient, a wa-
tery discharge breaks out through the nostrils or ears, it runs
out mixed with pus, and he recovers; if not, he usually dies
in seven days. The Corpus Hippocraticum even advocated
surgical therapy: Then incise the head at the bregma; bore
right through to the brain, and heal the wound as you would
one made by sawing. The first documented successful drain-
age of a brain abscess (of otitic origin) is attributed to the
French surgeon S.F. Morand in 1752 (2). In 1872, the army
surgeon J. F. Weeds reported on the successful drainage of a
traumatic frontal brain abscess and reviewed the American
and European medical literature (2). Of 214 cases of brain
abscess on record, only 4 cases resulted in recovery. Weeds
noted that not a single case recovered without the abscess
being opened and its contents evacuated, either by nature or
by the knife of the surgeon. In 1893, Sir William MacEwen
published his famous monograph Pyogenic Infective Diseases
of the Brain and Spinal Cord (2). Nineteen patients oper-
ated on for a cerebral or cerebellar abscess were reported in
that work; eighteen of these recovered and only one patient
died. This publication established MacEwen as the father
of modern brain abscess management. Diagnostic delay was
the major obstacle in the success of therapeutic intervention,
as Victor Horsley put it in 1888, These cases are fortunately
simple, perhaps the simplest, examples of intracranial sur-
gery, but there remains yet the method of diagnosis (3).
In the twentieth century, refined surgical techniques, intro-
duction of antibiotics, and finally the advent of computed
tomography (CT) have contributed to a significant improve-
ment in the mortality and morbidity rates associated with
brain abscess (e.g., 4% mortality from 1981 to 1986 in a
study by Mampalam and Rosenblum [4]). Among the major
problems in the twenty-first century are postoperative intra-
cranial infections due to antimicrobial-resistant bacteria and
growing numbers of immunosuppressed patients who have
an increased risk of developing a brain abscess, mostly due to
atypical pathogens such as fungi, and excessive mortality
rates of up to 97% (5,6). Further progress in the therapy of
brain abscess is therefore necessary.
522
Scheld_Ch31.indd 522
EPIDEMIOLOGY
The incidence of brain abscess is estimated at 0.3 to 1.3 cases
per 100,000 people per year (7,8) with a male-to-female ratio
of 2:1 to 4:1 (4,9,10). One important factor in the incidence
of brain abscess (as is true for most infectious diseases) seems
to be the general health status of the population: In a study on
973 patients from South Africa with brain abscess from 1983
to 2002, the incidence dropped by 50% from 1983 to 2002,
mainly due to improvements of socioeconomic standards and
increased availability of primary health care services (9). In the
total population, the incidence of brain abscess is relatively
low; however, the risk is markedly elevated in certain patient
groups (Table 31.1).
ETIOLOGY
In the preantibiotic era, analysis of intracranial pus revealed
Staphylococcus aureus in 25% to 30% of patients, strepto-
cocci in 30%, coliforms in 12%, and no growth in approxi-
mately 50% (11,12). With proper attention to techniques, the
role of anaerobic agents in brain abscess has become appar-
ent. In one earlier study (13), 14 of 18 abscesses grew anaer-
obes on culturepredominantly streptococci in 66%, with
Bacteroides species in 60%. Series from the United Kingdom
have stressed the role of anaerobic bacteria in brain abscesses,
especially of otitic origin (11,12). The results of seven studies
(in adults and children) demonstrate a particularly important
role for streptococci, Enterobacteriaceae (in particular Proteus
species), and Bacteroides species (Table 31.2). The organisms
and their frequency of isolation in exclusively pediatric-based
series of brain abscess are similar to these figures except in
the neonatal setting: In a large study on neonatal brain ab-
scess, Proteus mirabilis was identified in 27 (90%) of 30 cases,
Escherichia coli in two, and Serratia marcescens in another
newborn (14).
The location of a given brain abscess or its predisposing
cause often suggests the most likely etiologic agents (Table 31.3).
Bacteria
The streptococci represent a diverse group of organisms;
however, those most frequently isolated in patients with brain
abscess belong to the Streptococcus milleri group (Streptococcus
anginosus, Streptococcus constellatus, Streptococcus interme-
dius), which has a recognized predilection for causing focal
suppurative disease (1517). Streptococci from this group
are often microaerophilic. Streptococcus pneumoniae, despite
being the leading cause of bacterial meningitis in adults, is
only rarely cultured from patients with brain abscesses (18).
S. aureus is the most common cause of traumatic and post-
operative brain abscesses, often isolated in pure culture (9).
After craniotomy, S. aureus accounted for almost 50% and
Staph. epidermidis for 5% of intracranial infections in a large
prospective study of 2,944 patients (19) and the proportion
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 Chapter 31: Brain Abscess 523

TA B L E 3 1 . 1
PATIENTS WITH AN INCREASED RISK OF DEVELOPING A BRAIN ABSCESS (SELECTED STUDIES WITH HIGH
NUMBERS OF PATIENTS)

Underlying Condition/Predisposing Factor Risk of Developing a Brain Abscess Reference No.

Acute or chronic sinusitis 1.7% 281

Chronic otitis media 0.14% 25
Lifetime risk for a 30-year-old patient: 0.5% 282
Penetrating craniocerebral trauma 3.0% and 4.2% after missile or fragment injury 283, 284
Craniotomy 0.58% risk of developing abscess or empyema 19
Cyanotic congenital heart disease 2.1% 285
Single pulmonary AVM 3.1% and 7.7% 152, 286
Multiple pulmonary AVMs 6.6% and 16.4% 152, 286
Diffuse pulmonary AVMs 37.5% 280
Acute infective endocarditis 4.1% and 7.1% 287, 147
Solid organ transplant recipients Heart or heartlung transplantation: 1.05% and 2.16% 5, 288, 289
Kidney transplantation: 0.36% 5
Liver transplantation: 0.63%, 0.64%, and 2.4% 5, 290
Allogeneic, syngeneic, and autologous BMT 1.77% and 4.0% (77% patients with toxoplasmosis, 23% 291, 292
and peripheral blood SCT with fungal brain abscesses, results of a German studya)
Allogeneic BMT 0.9% and 1.6% 293, 294
Allogeneic hematopoietic SCT 2.7% (toxoplasmosis, results of a German studya) 295
Human immunodeficiency virus infection 0.22% (United States), 1.0% (Francea), and 2.2% 296298
(on antiretroviral therapy) (Germanya) incidence of toxoplasmosis per year

AVM, arteriovenous malformation; BMT, bone marrow transplant; SCT, stem cell transplant.
a
The incidence of toxoplasmic encephalitis is lower in the United States due to the lower endemicity (seropositivity) compared with Europe (292).

TA B L E 3 1 . 2
BACTERIOLOGIC RESULTS OF ABSCESS PUS CULTURES FROM 491 PATIENTS REPORTED IN SEVEN STUDIES
FROM THE UNITED STATES (122), GREAT BRITAIN (28,154), SWITZERLAND (132), SWEDEN (299), CHINA (218),
AND TAIWAN (300)

Etiologic Pathogen Frequency (%) Etiologic Pathogen Frequency (%)

Streptococci 40.3 Pasteurellaceae 5.5

Unspecified aerobic streptococci 9.0 Haemophilus species 4.1
Viridans streptococcia 15.5 Eikenella species 0.6
Streptococcus pneumoniae 1.4 Pasteurella species 0.4
Unspecified anaerobic streptococci 14.5 Actinobacillus actinomycetemcomitans 0.4
Staphylococci 12.6 Bacteroides speciesc 21.8
Staphylococcus aureus 11.4 Fusobacterium species 4.9
Coagulase-negative staphylococci 1.2 Propionibacterium species 2.4
Enterococci 1.2 Corynebacterium species 1.8
Peptostreptococci 5.9 Pseudomonas species 1.2
Enterobacteriaceae 25.3 Veillonella species 0.6
Proteus speciesb 12.9 Actinomyces species 0.6
Escherichia coli 6.3 Lactobacillus species 0.6
Klebsiella species 4.1 Clostridium species 0.4
Citrobacter species 0.8 Nocardia asteroides 0.4
Salmonella species 0.6 Prevotella intermedia 0.2
Enterobacter species 0.4 Acinetobacter species 0.2
Serratia marcescens 0.2 Bacillus species 0.2

Cultures were positive in 402 cases (82%). A single organism was detected in 72% of these patients and 28% had mixed cultures. The percentages refer
to the total number of positive cultures (n 402). Because of the presence of mixed cultures, the total of the percentage numbers exceeds 100%.
a
Mostly Streptococcus milleri.
b
Mostly Proteus mirabilis or Proteus fragilis.
c
Mostly Bacteroides fragilis or Bacteroides melaninogenicus.

Scheld_Ch31.indd 523 2/21/14 5:46 PM

 524 Part III: Bacterial and Mycoplasmal Infections

TA B L E 3 1 . 3
MOST PROBABLE LOCATION AND MICROBIAL FLORA OF BRAIN ABSCESSES ACCORDING TO THE SOURCE OF
INFECTION OR UNDERLYING CONDITION

Underlying Condition Most Probable Site of Abscess Most Common Microbial Flora References

Paranasal sinus
Otogenic infection
Odontogenic infection
Bacterial endocarditis
Pulmonary infection (abscess,
empyema, bronchiectasis)
Right-to-left shunt (congenital
cyanotic heart disease,
pulmonary arteriovenous
malformation)
Penetrating trauma or
postoperative
Immunosuppressed patients:
e.g., bone marrow, stem cell,
or solid-organ recipients
Patients with acquired Frequently multiple abscesses,
immunodeficiency syndrome any lobe can be involved
Frontal lobe
Temporal lobe, cerebellum
Frontal lobe
Frequently multiple abscesses,
any lobe can be involved
Frequently multiple abscesses,
any lobe can be involved
Frequently multiple abscesses,
any lobe can be involved
Depends on site of wound
Frequently multiple abscesses,
any lobe can be involved
Streptococci (in particular, S. milleri), 11, 20, 120,
Bacteroides species, Staph. aureus, 121, 154,
Haemophilus species 281, 301, 302
Proteus species, streptococci, Bacteroides 20, 24, 28, 154,
species, Pseudomonas species, Staph. aureus 303306
Streptococci, staphylococci, Actinomyces 23, 28, 307
species, Actinobacillus species, Bacteroides
species, Fusobacterium species
Staph. aureus, viridans streptococci 148, 227
Streptococci, staphylococci, Bacteroides species, 227
Fusobacterium species, Enterobacteriaceae
Streptococci, staphylococci, Peptostreptococcus 161, 162, 285,
species, Haemophilus species 302, 308
Staph. aureus (methicillin-resistant Staph. 19, 28, 116,
aureus), Staph. epidermidis, streptococci, 154, 277
Enterobacteriaceae (multiresistant strains),
Clostridium species
Aspergillus species, Candida species, Nocardia 5, 6, 289, 290,
species, Toxoplasma gondii, Cryptococcus 293295, 309
neoformans, Listeria monocytogenes,
Mycobacterium species
Toxoplasma gondii, Mycobacterium species, 90, 92, 203,
Cryptococcus neoformans, Aspergillus 310, 311
species, Candida species, Nocardia species,
L. monocytogenes

of methicillin-resistant Staph. aureus (MRSA) was very high
(41%). In a recent study from Argentina, MRSA was even
identified in 10% of 80 patients with brain abscess (15).
Enterococcus faecalis has been reported as a rare cause of oto-
genic, metastatic (e.g., due to endocarditis), meningitis-associated,
and neonatal brain abscess (2022). Peptostreptococci, which are
a common oropharyngeal flora, have been occasionally found in
odontogenic, otorhinogenic, postoperative, and metastatic (e.g.,
following esophageal dilation) brain abscess (20,23).
Enterobacteriaceae are usually found in mixed cultures.
Proteus species are the most commonly isolated organism;
they exhibit a particular association with otogenic disease
(17,24,25) and neonatal brain abscess (26). Brain abscesses
due to Proteus species have also been reported after neuro-
surgical procedures (27). E. coli is sometimes found in oto-
genic or metastatic brain abscesses (28). It is also a cause of
neonatal brain abscesses (29). In two studies from Taiwan
(30,31), Klebsiella species (mostly Klebsiella pneumoniae,
less often Klebsiella oxytoca) were common (some with a
gas-forming appearance) in patients with debilitating dis-
eases (in particular, diabetes mellitus). Citrobacter species,
especially Citrobacter diversus, are often implicated in brain
abscesses that arise as a complication of neonatal meningitis
(32,33), but they are very rare in adults with brain abscesses
(34). Salmonella (S. typhi, S. typhimurium, and S. enteritidis
of group B, C, or D) brain abscess is also uncommon (35).
This disease is most likely to occur in adults with certain
predisposing factors like meningitis, tumor, ischemia, trauma,
intracranial hematoma, and human immunodeficiency virus
(HIV) infection (3638). Enterobacter species, though an-
other rare cause of brain abscess (39), must be considered in
postoperative cases (27). Serratia marcescens is another rare
cause of neonatal brain abscess (40,41). In adults, only few
cases with opportunistic S. marcescens brain abscess are re-
ported (42,43). In general, Enterobacteriaceae must be taken
into account especially in postoperative deep brain infections
(9,19,35).
Aggregatibacter aphrophilus and Aggregatibacter paraphro-
philus are most often isolated in brain abscesses due to
Haemophilus species (16,17,44,45). Brain abscess secondary
to H. influenzae is rare (46). Eikenella corrodens, which be-
longs to the oropharyngeal flora, has been occasionally detected
in particular in otorhinogenic or odontogenic brain abscess
(47,48). Pasteurella multocida brain abscess has been reported
as a rare complication of animal scratches or bites (4951).
Actinobacillus actinomycetemcomitans is sometimes encoun-
tered in polymicrobial odontogenic brain abscesses, often in
conjunction with Actinomyces infection (52,53).
Pseudomonas aeruginosa is mainly associated with oto-
genic brain abscess but has also been detected as a postop-
erative, posttraumatic, or as a hematogenous complication
(9,20,35,54). Anaerobes are significant causative pathogens
of brain abscess, often found in mixed culture (16,35).
Bacteroides and Fusobacterium species are most frequently

Scheld_Ch31.indd 524 2/21/14 5:46 PM


isolated. Brain abscesses due to Clostridium species (typically
with a gas-forming appearance) may develop in particular
after penetrating head trauma with soil or fecal contamination
of the wound. Clostridium infections must also be considered
postoperatively (55). In particular, cases due to Clostridium
welchii, Clostridium perfringens, Clostridium septicum,
Clostridium tertium, and Clostridium bifermentans have been
reported (5658). Propionibacterium acnes has also gained at-
tention as a cause of postoperative and posttraumatic brain
abscess, being reported to occur up to 10 years after surgery
(5961). Few cases of a brain abscess due to corynebacteria
have been reported (6264). Actinomyces species are anaero-
bic human commensals of low pathogenicity, which have been
repeatedly recovered from brain abscesses (65). Two thirds of
the patients with central nervous system (CNS) actinomyco-
sis have an obvious primary site of infection distant from the
CNS, most commonly the lung or cervicofacial region. When
no obvious source is apparent, occult dental infection is often
suspected (66).
Especially in immunocompromised hosts with brain abscess,
Listeria monocytogenes or Nocardia species can be found as
causative pathogens (more than 90% of patients with listerial
brain abscess and 34% with nocardial brain abscess are im-
munocompromised [9,30,35,67]). N. asteroides was isolated
in 98% of nocardial brain abscesses; single cases were due to
N. farcinica and N. caviae (67). N. asteroides infections of the
brain often had evidence of a pulmonary portal of entry (38%
of cases). Bacillus cereus (68,69), Rhodococcus equi (70,71),
and Gordona terrae (72) are other recognized pathogens of
brain abscess in immunocompromised hosts. In approximately
5% to 10% of cases of meningitis due to Mycobacterium tuber-
culosis, tuberculous granulomas (tuberculomas) can be found
(73,74); they usually resolve with medical therapy. When the
caseous core of a tuberculoma liquefies, a tuberculous abscess
results; tuberculous brain abscesses are usually larger and less
common than tuberculomas, may be multiloculated, and often
have greater mass effect and edema (73). Depending on the
prevalence of tuberculosis, a considerable proportion of focal
FIGURE 31.1 Cerebral aspergillosis. A: Space-occupying brain lesion (asterisk) with contrast enhance-
ment on MRI in a 60-year-old patient. B: Histologic evaluation revealed a predominantly granulocytic
infiltration with the detection of Aspergillus fumigatus (arrow).
Scheld_Ch31.indd 525
Chapter 31: Brain Abscess 525
intracranial infections may be due to M. tuberculosis (9,30),
reaching 56% in a Saudi Arabian study (75). In addition to
M. tuberculosis, other mycobacteria were observed to cause
focal CNS lesions; these include Mycobacterium bovis (bacille
Calmette-Gurin) in an immunocompromised child (76),
Mycobacterium kansasii in patients with acquired immuno-
deficiency syndrome (AIDS) (77), and Mycobacterium avium
complex in patients with and without AIDS (78).
Yeasts and Fungi
Fungi have assumed an increasing role as the etiologic agents
of focal intracranial infections. Many pathogenic fungi, such
as Cryptococcus neoformans, Candida species, Sporothrix
schenckii, Aspergillus species, and Zygomycetes species are
ubiquitous (79). Others are geographically restricted, such as
Coccidioides immitis (southwest United States, northern Mexico,
and Argentina), Histoplasma capsulatum (greater Mississippi
Valley, along the U.S.Mexico border, in multiple regions of
Central and South America, and in scattered areas around the
world), and Blastomyces dermatitidis (midwestern and mideast-
ern United States, along the St. Lawrence River, and in certain
countries in Africa, the Middle East, and India). Most cases occur
in immunocompromised patients, and mortality remains high.
Cerebral aspergillosis occurs in 10% to 20% of all cases
of invasive aspergillosis (Fig. 31.1) and only rarely is the
brain the sole site of infection (80). Without therapy, mor-
tality is high, but survival rates of up to 31% are reported
in patients receiving voriconazole therapy (81,82). Among
the most important risk factors for invasive aspergillosis are
immunosuppressive therapy (including high-dose steroids),
hematologic malignancies, solid-organ and bone marrow
transplantation, and HIV infection (80,83). A report of brain
abscesses in bone marrow transplant recipients observed
that 33 (58%) of 62 cases were due to Aspergillus species
(mostly Aspergillus fumigatus, with a few cases of Aspergillus
flavus and Aspergillus terreus) (6). Fungi of the Zygomycetes
2/21/14 5:46 PM
 526 Part III: Bacterial and Mycoplasmal Infections
(formerly Phycomycetes) class can also invade the CNS.
Rhino-(orbital-)cerebral mucormycosis usually affects immu-
nocompromised patients, in particular patients with diabetes
mellitus, hematologic malignancies, or stem-cell and solid
organ transplantation (8486). Isolated cerebral mucormy-
cosis has been observed mostly in injection drug users with
or without AIDS (87), but also in patients with hematologic
malignancies (88) or pharmacologic immunosuppression
(89). Candidiasis is the fungal infection most often observed
at autopsy to be involving the CNS (90). Cases of diffuse
cerebritis with miliary microabscesses, large parenchymal ab-
scesses, meningitis, and cerebrovascular complications have
been described (90). Risk factors for the development of CNS
candidiasis are immunosuppression, treatment with antibiot-
ics or corticosteroids, intravascular catheters, recent abdomi-
nal surgery, prematurity (in neonates), recent neurosurgery or
cerebrospinal fluid (CSF) diversion, and injection drug abuse
(90). Cryptococcus neoformans usually causes meningitis
when it invades the CNS, but mass lesions due to this organ-
ism have been observed. Neuroradiologic studies have shown
cryptococcoma (granuloma) in 11% of patients with crypto-
coccal meningitis studied by CT (91) and in 50% of patients
studied by magnetic resonance imaging (MRI) (92).
Scedosporium apiospermum (formerly known as Allescheria
boydii, Pseudallescheria boydii, and Petriellidium boydii) has re-
ceived increased attention as a potential cause of CNS infection
(93). In addition to immunosuppression, near drowning in pol-
luted water and rarely direct inoculation (orbital trauma, lum-
bar puncture) were reported as predisposing conditions (94,95).
Cladosporium trichoides (Xylohypha bantianum, Cladosporium
bantianum) is the most common cause of cerebral phaeohypho-
mycosis, accounting for 28 of 53 reviewed cases (96).
Protozoa and Helminths
Various protozoa and helminths may cause brain abscesses,
with their incidence varying with geographic location.
Toxoplasmosis is one of the most common parasitic infec-
tions of the brain, particularly in the setting of AIDS (97) (see
later discussion) but also in patients after bone marrow trans-
plantation (98,99). Entamoeba histolytica infections rarely
involve the brain (100). The lesions are usually multiple and
are most often associated with another focal site of infec-
tion, usually hepatic. Free-living amebas (Naegleria species,
Acanthamoeba species, and Balamuthia species) are prefer-
entially neurotropic (101,102). CNS infection with Naegleria
fowleri typically presents as acute fulminant meningoenceph-
alitis (primary amebic meningoencephalitis) in immunocom-
petent children and adults after exposure to polluted water
(water-related sport activities in the tropical and subtropical
climates) (102). Balamuthia mandrillaris and Acanthamoeba
species cause granulomatous amebic encephalitis, which has
a subacute or chronic course and is usually seen in immu-
nocompromised individuals (in particular, in patients with
AIDS) (102,103). Amebic CNS infections are usually fatal.
Neurocysticercosis (due to Taenia solium larvae) is the
most common parasitic infection of the human nervous system
(104107). It is endemic in many parts of the world, particularly
Latin America, Africa, and Asia, and still relatively common in
Portugal, Spain, and Eastern European countries. In many de-
veloped countries with high rates of immigration from endemic
areas, neurocysticercosis is an imported disease (107,108).
Cysticercosis is probably the single most important cause of ac-
quired epilepsy in the developing world (109). Focal brain lesions
in neurocysticercosis usually present as (solid-enhancing) granu-
lomas, calcified nodules, or (ring-enhancing) cystic lesions with
Scheld_Ch31.indd 526
or without a scolex (109). Other helminthic infections that occa-
sionally lead to focal intracranial lesions include schistosomiasis
(110), echinococcosis (111), paragonimiasis (112), trichinosis
(113), sparganosis (114), and infections due to Angiostrongylus
cantonensis (115) or Strongyloides stercoralis (116).
PATHOGENESIS
Brain abscesses occur most commonly in association with one
of three distinct clinical settings: (a) a contiguous focus of
infection, (b) cranial trauma or neurosurgical procedures, or
(c) hematogenous spread from a distant focus. No predispos-
ing factors are recognized in approximately 10% to 25% of
reported cases (Table 31.4).
Contiguous Infectious Foci
Most patients with brain abscess demonstrate a contiguous
focus of infection, usually sinusitis or otitis.
Otitis/Mastoiditis
The incidence of otogenic brain abscess (Tables 31.1 and 31.4)
seems to decrease in developed countries. However, in areas
where otitis media continues to be neglected or where therapy
is delayed, intracranial complications of this process still present
a particularly serious threat (117). Chronic otitis media and/or
mastoiditis leads to intracranial extension much more often
than acute disease. In particular, cholesteatoma is a common
associated finding in otogenic brain abscesses, being found in
38% to 98% of patients (24,25). Most otogenic brain abscesses
are solitary lesions. The majority of otogenic brain abscesses
(55% to 75%) are located in the temporal lobe (24,25). The cer-
ebellum is the next most commonly affected area (20% to 30%),
and it has been observed that approximately 90% of cerebellar
abscesses are secondary to otogenic infections (118). Otogenic
intracranial suppuration most often develops in patients younger
than 30 years and shows a male predominance (24,25).
Sinusitis
Sinugenic brain abscesses are almost exclusively located in
the frontal lobe (Fig. 31.2), reflecting the distribution of the
associated sinusitis (119121). Most cases are in the setting of
frontoethmoidal disease followed by maxillary disease (122).
TA B L E 3 1 . 4
UNDERLYING CONDITIONS IN 1,730 PATIENTS WITH
BRAIN ABSCESS (AFTER [20,28,122,126,127,154,312])
Underlying Condition Mean Frequency (Range)
Otitis/mastoiditis 33% (1466%)
Hematogenous spread 23% (1734%)
Trauma/neurosurgery 14% (323%)
Sinusitis 9% (120%)
Dental infection 2% (013%)
Unknown (cryptogenic) 17% (1025%)
Othersa 3% (09%)
a
Other causes were in particular meningitis and infections of the
scalp or skull. The total is 101% because of the presence of multiple
predisposing conditions in some patients.
2/21/14 5:46 PM

FIGURE 31.2 Sinusitis and brain abscess. MRI of a brain abscess (asterisk) located in the frontal lobe
caused by frontal sinusitis (arrow). A: T2-weighted sequence. B: T1-weighted with contrast. C: Diffusion-
weighted imaging.
Sphenoid sinusitis, despite its relative rarity (approximately
3% of all sinusitis cases), has a relatively high rate of intra-
cranial complications (123). Intracranial suppuration second-
ary to sinusitis predominates in men in their second or third
decade of life (119,120).
Dental Infection
Dental infections have less often been documented as a predis-
posing cause of a brain abscess in the past (Table 31.4), but a
recent study indicated an important role for dental infection as
a source of brain abscess in up to 12% of patients (16). Given
the frequency of dental infections, however, intracranial compli-
cations of this process are rare. The site of an associated brain
abscess is most commonly the frontal lobe, but temporal lobe
localization can also occur by direct extension. A large majority
of intracranial infections in this setting follow a recent tooth ex-
traction or dental manipulation. Bacteremia has been observed
in 100% of patients after dental extraction, in 70% after den-
tal scaling, in 55% after third molar surgery, and in 20% after
endodontic treatment (124). Another study reported that 9% of
children with extensive tooth decay were bacteremic before treat-
ment (125). Hygiene procedures such as brushing of the teeth
increased the prevalence of bacteremia to 40%, and anesthetic
and surgical procedures increased it to 97%. In both studies, the
bacteria isolated from the blood were mostly facultative species
indigenous to dental plaque, in particular viridans streptococci
(124,125). Many cases of cryptogenic brain abscess are believed
to be secondary to asymptomatic dental foci of infection.
Facial and Scalp Infections
Facial and scalp infections were reported in 1% to 4% of pa-
tients with brain abscess (126,127). Septic thrombosis of the
cavernous sinus is a possible link, and Staph. aureus is the
most common pathogen in this setting (128).
Meningitis
Brain abscess rarely complicates bacterial meningitis; however,
it should be strongly considered as an associated possibility in
the neonate with purulent meningitis, particularly when men-
ingitis is due to gram-negative organisms (29). The vast major-
ity of neonatal brain abscesses that complicate meningitis are
Scheld_Ch31.indd 527
Chapter 31: Brain Abscess 527
due to P. mirabilis or C. diversus. Neonatal meningitis due to
Enterobacter species or Serratia species is also often compli-
cated by brain abscesses (39,40). Although P. mirabilis is a rare
cause of neonatal meningitis, 27 of 30 neonatal brain abscesses
diagnosed over a 12-year period were due to this organism (14).
Additionally, abscess formation has been associated with more
than 70% of cases of C. diversus meningitis in the infant (129).
The increased propensity for these two organisms to cause a
brain abscess is incompletely understood (130,131).
Cranial Trauma and Neurosurgical
Procedures
Penetrating Cranial Injury
The risk of a brain abscess is increased in the setting of a penetrat-
ing cranial injury. Combat series reported a risk of 3% to 4.2%
of developing a brain abscess after missile or fragment injuries
(Table 31.1). Risk factors were extensive brain injury, coma,
trajectory through an air sinus, wound infections, CSF fistula,
inadequate initial dbridement, retained (bone or metallic) frag-
ments, and incomplete dural closure. Several series have noted
the role of head trauma as the cause of brain abscess in civilians.
Thus, head trauma was reported as an underlying cause of brain
abscess in 3% to 11% of patients in most series (4,28,132,133).
Whereas the incidence of brain trauma as the cause for cerebral
abscess formation declined in a study from the United Kingdom
(16), it was found to be the most common cause (33%) for brain
abscess in 973 patients from South Africa (9), reflecting the inci-
dence of brain trauma (due to accidents or violence) in a society.
Various types of cranial trauma have been implicated, including
compound depressed skull fractures (133,134), dog bites (135),
injuries due to rooster pecking (136), and cranial penetration
with lawn darts, pencil tips, or paint brushes (137,138). Several
cases of brain abscess as a complication of cervical traction with
tongs or halo fixation have been described (139,140). Associated
pin-site cellulitis is usually observed.
Craniotomy
Brain abscess after neurosurgery is common (Fig. 31.3).
In a series of 2,944 patients who underwent neurosurgery,
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 528 Part III: Bacterial and Mycoplasmal Infections
neurosurgical site infections developed in 117 (4%) (19).
Forty-four patients (1.5%) had incisional infections (30 with
scalp infections and 14 with bone flap osteitis), and seventy-
three (2.5%) had deep wound infections (meningitis in 56
and mass lesions in 17 patients). Given the high number of
neurosurgical operations at certain centers, it was reported
among the most frequent causes for brain abscess in some
series (16,141). Risk factors for deep wound infections were a
Glasgow Coma Scale score of less than 10 on admission, total
hair removal, emergency surgery, CSF drainage, CSF leak-
age, and early subsequent operations. Interestingly, wound
contamination, surgical duration, and the absence of antimi-
crobial prophylaxis were not significant risk factors for deep
wound infections (19). The authors, therefore, hypothesized
that the risk of contaminating CSF or brain parenchyma be-
gins during surgery but persists in the postoperative period
if a CSF drainage or leakage is present. This hypothesis was
supported by a predominance of hospital-acquired antibiotic-
resistant bacteria in deep wound infections.
Hematogenous Spread
Hematogenous brain abscesses often share the following char-
acteristics: (a) a distant focus of infection, most often within
the chest; (b) location in the distribution of the middle cerebral
artery (Fig. 31.4), (c) initial location at the gray matterwhite
matter junction, (d) poor encapsulation, and (e) high mortality.
FIGURE 31.4 Pathology of brain abscess. A: Deep white matter abscess (asterisk) adjacent to the body of
the lateral ventricle. B: Multiple brain abscesses at the junction between gray and white matter (arrows).
C: Gross photograph of a large, chronic temporal lobe abscess (asterisk). The location of this abscess is
immediately above the petrous temporal bone.
Scheld_Ch31.indd 528
FIGURE 31.3 Brain abscess complicating
brain surgery. MRI of a brain abscess
(asterisk) in a 28-year-old patient who
had been operated on a cyst of the lateral
ventricle by occipital craniotomy (arrow).
A: Fluid-attenuated inversion recovery
(FLAIR). B: T1-weighted imaging with con-
trast enhancement. Pseudomonas aerugi-
nosa and coagulase-negative staphylococci
were identified as causative pathogens.
These abscesses are more often multiple and multiloculated as
compared with those that have an origin from a contiguous
focus of infection. Thirty-seven percent to 50% of multiple
brain abscesses were of hematogenous origin in several studies
(142144), whereas metastatic spread accounted only for
17% to 34% of all brain abscesses (Table 31.4).
Pulmonary Infections
Pyogenic lung diseases, especially lung abscess and bronchi-
ectasis, accounted for 7% to 18% of total brain abscess cases
in four studies (4,9,122,127). Underlying chronic pulmonary
diseases such as cystic fibrosis, however, are surprisingly infre-
quently complicated by a brain abscess (145). When observed,
it most often occurs in older adolescents or adults (146).
The organisms cultured from the sputum only occasionally
matched those cultured from the brain abscess and in some
patients, associated sinus disease was found. These observa-
tions suggest that the lung is not necessarily the source of brain
abscess in patients with cystic fibrosis and that contiguous
spread of infection should also be considered.
Endocarditis
Brain abscess occurs in 5% to 7% of patients in the setting
of bacterial endocarditis (Table 31.1) (147,148), despite the
presence of persistent bacteremia (see Chapter 34). The high-
est incidence of brain abscess (5.4%) was reported in infective
endocarditis of the left-sided valves due to Staph. aureus (148).
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 Chapter 31: Brain Abscess 529

FIGURE 31.5 Brain abscess in endocarditis. MRI of Staphylococcus aureus endocarditisassociated brain
abscess in a 75-year-old patient. A: The FLAIR-sequence shows perifocal edema (arrow) and (B) contrast
enhancement indicates the capsule of the abscess (arrow). C: The diffusion-weighted imaging shows
increased signal intensity within the abscess cavity (arrow).

The development of a brain abscess depends on the level and
duration of the bacteremia, the virulence of the organism, and
the occurrence of preceding emboli. A greater incidence of
brain abscess or meningitis is observed in cases of acute, rather
than subacute bacterial endocarditis (Fig. 31.5).
Right-to-Left Shunt
Abnormal venous-arterial channels which increase the risk of
developing a brain abscess probably because of septic micro-
emboli that can escape the pulmonary capillary filter (right-
to-left shunt) include pulmonary arteriovenous malformations
(AVMs), congenital cardiac defects, patent ductus arterio-
sus, and patent foramen ovale (PFO) (149,150). Hereditary
hemorrhagic telangiectasia (Rendu-Osler-Weber disease) is
complicated by brain abscess, with striking regularity (151).
Approximately 25% of patients with this condition have
pulmonary AVMs and 70% of the patients with pulmonary
AVMs have hereditary hemorrhagic telangiectasia (152). The
incidence of brain abscess seems to increase with the num-
ber of pulmonary AVMs (Table 31.1). Clinical findings, such
as cyanosis, clubbing, polycythemia, and hypoxemia, may
be absent (asymptomatic AVMs). The diagnostic workup of
patients with brain abscess should therefore include a search
for pulmonary AVMs (153). Congenital cyanotic heart disease
(CCHD) was found in 0% to 10% of patients with brain ab-
scess (122,154). Some pediatric series suggest that CCHD is
the most common cause of brain abscess in children (150,155).
In many studies, 50% or more of all brain abscesses were at-
tributed to CCHD in this age-group (155160), and in two
large series of brain abscess in those with cyanotic heart dis-
ease, more than 50% of patients were younger than 10 years
of age (161,162). Tetralogy of Fallot is consistently the most
commonly cited defect (161,162). Transposition of the great
arteries, double outlet right ventricle, single ventricle, tricuspid
atresia, Ebstein disease, and Eisenmenger complex were the
next most frequently observed disorders in the largest series
(161). Several reports showed PFO in patients with brain ab-
scesses (163). However, the prevalence of PFO in adults is high
(20% to 35%). Therefore, a population study will be neces-
sary to document whether the prevalence of PFO is higher in
patients with brain abscess with a presumed spread from a
distant infectious focus than in the general population.
Other Foci of Metastatic Spread
Other distant foci of infection may be associated with brain
abscess and have included wound and skin infections, osteomy-
elitis, pelvic infection, cholecystitis, and other forms of intraab-
dominal sepsis. Brain abscess has also been described as an
unusual complication of esophageal dilation of caustic strictures
and endoscopic ligation of varices (164,165). Brain abscess in
these cases is probably due to bacteria of the oropharyngeal
flora that entered into the circulation through lesions of the mu-
cous membrane. Transient bacteremia develops in up to 100%
of cases of esophageal dilation (mostly due to viridans strepto-
cocci, Staph. aureus, and Staph. epidermidis) and in up to 50%
of cases involving sclerotherapy (mostly due to Pseudomonas
species and -hemolytic streptococci) (164,166).
Location
In approximate decreasing order of frequency, a solitary abscess
may involve the following brain regions: frontal, temporal,
parietal, and occipital lobes and cerebellum (Table 31.5). This
TA B L E 3 1 . 5
LOCALIZATION OF BRAIN ABSCESSES (ACCORDING
TO SELECTED STUDIES FROM THE COMPUTED
TOMOGRAPHY ERA [20,122,132,154,218,313])
Localization Mean Frequency (Range)
Frontal lobe 37% (1949%)
Temporal lobe 24% (1841%)
Parietal lobe 22% (746%)
Occipital lobe 10% (326%)
Cerebellum 7% (010%)
Sella 1% (04%)
Basal ganglia 1% (07%)
79% (range 6290%) of the 495 patients had single and 21% (range
1038%) had multiple abscesses. Therefore, the total exceeds 100%.

Scheld_Ch31.indd 529 2/21/14 5:46 PM

 530 Part III: Bacterial and Mycoplasmal Infections
distribution reflects the associated, often contiguous, focus of
infection (Table 31.3). Intrasellar, brainstem, basal ganglia,
and thalamic abscesses are rare.
Pituitary Abscesses
Pituitary abscess is caused either by hematogenous seeding of
the pituitary gland or by direct extension of an adjacent infec-
tion, such as meningitis, sphenoid sinusitis, cavernous sinus
thrombophlebitis, or a contaminated CSF fistula (167). Besides
infection by pyogenic bacteria, pituitary infections have been
caused by Treponema pallidum, M. tuberculosis, Entamoeba
histolytica, and a variety of fungi, including Histoplasma
capsulatum, Blastomyces dermatitidis, Sporothrix schenckii,
Candida species, and Aspergillus species (167,168).
Brainstem Abscesses
Brainstem abscesses (Fig. 31.6) often arise from hematogenous
spread or, less frequently, in association with a contiguous infec-
tion, such as otitis (169,170). Brainstem abscesses have a rela-
tively poor prognosis. This is primarily because their anatomic
location can lead to catastrophic neurologic complications and
often preclude definitive drainage. Brainstem abscesses tend to
elongate in the brainstem rather than expand laterally (170).
Therefore, the clinical findings can be confusing.
Abscesses in the Thalamus and Basal Ganglia
Inflammatory lesions (especially when solitary) of the thala-
mus and basal ganglia are also somewhat unusual (Table 31.5).
Most often they are hematogenous (171) and they are fre-
quently associated with hydrocephalus, most likely due to close
proximity to the ventricles (172).
General Pathogenetic Considerations
The final common pathway for brain abscess development in
the preceding conditions appears to require a compromised
area of brain. Experimental data suggest that infection is
extremely difficult to establish in normal brain tissue (173).
Brain abscess may develop from a contiguous infection via di-
rect extension through areas of associated osteitis or osteomy-
elitis and retrograde thrombophlebitic spread via diploic or
emissary veins into the intracranial compartment. Additional
possibilities in the case of otogenic infection include spread
through preexisting channels (the internal auditory canal,
Scheld_Ch31.indd 530
FIGURE 31.6 Brainstem abscess. Brainstem abscess
which presents (A) as a ring-enhancing lesion (arrow)
on T1-weighted image with contrast enhancement.
B: On diffusion-weighted imaging, the lesion appears
hyperintense (asterisk). Fusobacterium nucleatum
was isolated from specimen collected by stereotactic
biopsy.
cochlear, and vestibular aqueducts) or between temporal su-
ture lines. Hematogenous dissemination is occasionally im-
plicated with contiguous foci, particularly in cases of sinus
or odontogenic origin. None of these hypotheses explains the
relative rarity of intracranial infection with sinusitis or oti-
tis, how bacteria traverse an intact dura, or what determines
the form of intracranial complication that eventually evolves
(e.g., meningitis, epidural abscess, subdural empyema, or
brain abscess) in the individual with the same predisposing
condition.
The development of a brain abscess in the setting of neo-
natal meningitis deserves special comment. The pathogenesis
appears to follow the initiation of a necrotizing vasculitis
(particularly in the small penetrating vessels), leading to sub-
sequent hemorrhagic necrosis and liquefaction of the subcor-
tical white matter, an area highly susceptible to changes in
cerebral perfusion (174). Others disagree with this formula-
tion, contending that the evidence favors an initial ventricu-
litis followed by ependymal disruption and subsequent direct
extension of the infection into the brain parenchyma. Similar
findings have been noted in an infant rat model of Citrobacter
diversus meningitis and brain abscess (175) and support the
latter hypothesis.
In hematogenous cases, the polycythemia and systemic hy-
poxia observed in CCHD and hereditary hemorrhagic telangi-
ectasia increase blood viscosity, with an associated reduction
in brain capillary flow, perhaps leading to microinfarction and
reduced tissue oxygenation in the brain. Septic microemboli
that escape the pulmonary capillary filter through right-to-left
shunts during bacteremic episodes might then seed already
compromised brain tissue. This hypothesis is in good agree-
ment with the development of abscesses in focal brain damage
due to, for example, brain tumor, hemorrhage, or ischemia.
In 1997, a review reported 15 cases of abscess formation in
brain neoplasms (176). Six of the brain abscesses developed in
a meningioma, glioma, or craniopharyngioma and were asso-
ciated with bacteremia due to Salmonella typhi, Staph. aureus,
Bacteroides oralis, or E. coli (most of the other abscesses de-
veloped in pituitary tumors or craniopharyngiomas and were
attributed to contiguous spread from an adjacent infected
sinus). It was proposed that tumor-associated bloodbrain
barrier breaching favored the development of hematogenous
brain abscesses as eight such cases of abscess development at
the site of an intracerebral hemorrhage were reported (21).
A similar mechanism has been proposed for the observation of
brain abscess formation in ischemic brain tissue (177,178) and
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 Chapter 31: Brain Abscess 531

after endovascular treatments of cerebral aneurysms, AVMs,

or dural arteriovenous fistulas (38,179,180).
The immune response that is elicited to combat the invad-
ing pathogen is an essential part of abscess formation as it also
destroys surrounding normal brain tissue (181). This is sug-
gested by the finding that lesions of the brain are much greater
than the area of bacterial growth in experimental brain ab-
scesses (182,183). The most extensive work on the pathogen-
esis of brain abscess has been performed in a mouse model of
S. aureus brain abscess. S. aureus has been shown to activate
parenchymal microglia and astrocytes (in a toll-like receptor
2 [TLR2], TLR4, and MyD88-dependent fashion [184,185]).
In turn, they produce a variety of cytokines and chemokines
such as interleukin-1, tumor necrosis factor- (TNF-), and
macrophage inflammatory protein-2 (MIP-2) (186189) that
attract peripheral inflammatory cells. If the initial immune re-
sponse is unable to clear the infection (which can be related
to the presence of bacterial virulence factors such as -toxins
in S. aureusrelated brain abscess or the result of an insuffi-
cient immune responses), a continuing inflammatory response
is initiated and upheld. Among the stimuli for such an on-
going inflammation are bacterial toxins (pathogen-associated
molecular patterns [PAMPs]) and endogenous agents that are
set free as a consequence of tissue damage (damage-associated
molecular patterns [DAMPs]) and stimulate the immune re-
sponse (189,190). As a consequence, the development of a
chronic disruption of the bloodbrain barrier and final abscess
formation is found. These experimental findings support the
idea that an intervention with both antiinfective and antiin-
flammatory compounds might be an effective strategy to mini-
mize damage to brain parenchyma in brain abscess (181). FIGURE 31.8 Histology of advanced brain abscess. A: Photomicrograph
of an abscess wall during a later stage of abscess development. Thick
collagen fibers (arrows) are seen within the capsule wall. B: Trichrome
PATHOLOGY stain photomicrograph of abscess wall. Thick collagen fibers (arrows)
are seen above the inflammatory mass.

Histopathologic Stages of Brain Abscess

Development
The evolution of a brain abscess includes four histopathologic
stages (191). This staging process, described in animal mod-
els of brain abscess, correlates well with human brain abscess
evolution (192).
The first stage is an early cerebritis (days 1 to 3 following
intracerebral inoculation in animals), which progresses to a
perivascular inflammatory response surrounding the developing
necrotic center by the third day. Profound edema in the sur-
rounding white matter develops concurrently (Fig. 31.7).
In the second stage of late cerebritis (days 4 to 9), develop-
ment of a well-formed necrotic center reaches its maximum
size. Additionally, fibroblasts appear, setting the stage for
capsule formation and a marked increase in neovascularity at
the periphery of the necrotic zone. These newly formed capil-
laries often lack tight junctions and leak proteinaceous fluid.
Surrounding this is the beginning of a reactive astrocyte re-
sponse, along with persistent white matter edema.
The third stage, early capsule formation (days 10 to 13),
is characterized by a slight decrease in the size of the necrotic
center (Fig. 31.8). At this point, there is a well-developed layer

FIGURE 31.7 Histology of early brain abscess. A: Wall of brain abscess. Normal white matter is seen
to the left, and there is an intermediate area of edematous brain (asterisk) adjacent to the abscess wall.
B: Higher magnification showing periabscess inflammatory exudates (asterisk). There is relatively little
encapsulation at this early stage. C: Higher magnification of abscess wall. Note the combination of
increased gliosis and inflammatory cells (asterisk) adjacent to the abscess.

Scheld_Ch31.indd 531 2/21/14 5:46 PM

 532 Part III: Bacterial and Mycoplasmal Infections
of fibroblasts, with significantly more reticulin deposition on
the cortical side than on the ventricular side of the lesion.
Outside this developing capsule is a region of persistent cere-
britis and neovascularity, with a further increase in reactive
astrocytes.
These processes continue in the fourth and final stage, late
capsule formation (day 14 and later). The capsule continues
to thicken, with an abundance of reactive collagen present by
the third week.
Some studies have criticized the preceding models util-
ity in describing a uniform mode of brain abscess evolution
(193). These authors, using the same dog model and inocu-
lum, could not detect viable organisms in the brain lesions
after 3 days and, in all animals, the lesions spontaneously
resolved. Further work is necessary to reconcile this debate.
Nonetheless, a brain abscess model in rats supports the pre-
viously mentioned histologic progression (194). Two other
experimental models of brain abscess using organisms other
than -hemolytic streptococci also indicate that this view
of abscess evolution is either overly stereotyped or affected
by inadequate growth of the microorganisms. In a model
of Bacteroides fragilis (inoculated with Staph. epidermi-
dis) brain abscess (195), the same stages of evolution were
observed; however, the early and late capsule stages could
not be differentiated, because of a delay in encapsulation
when compared to abscesses following streptococcal chal-
lenge. These abscesses enlarged more quickly, were prone
to early ventricular rupture (25%), and exhibited incom-
plete encapsulation. This suggests the extreme virulence of
B. fragilis, an important pathogen in brain abscess, in brain
tissue when part of a mixed infection. In an experimental
model using S. aureus (196), there were quantitative and
qualitative differences in abscess evolution when compared
with inoculation of -streptococci. S. aureus inoculation
resulted in larger lesions, earlier ependymitis, and delayed
progress toward healing, with longer periods required for
the infection to reach a stable size. The same approximate
stages were present, but their separation was also not as
distinct as previously described. The white matter appeared
more susceptible to destruction than the gray matter, and
the spread of infection was centrifugal, rather than along
particular white matter tracts. In contradistinction, a model
of E. coli brain abscess exhibited expansion of the abscess
along white matter tracts (197). In addition, results from
the S. aureus experimental model raised some questions
regarding the previously held assumption that the capsule
serves to contain infection. The abscess reached its maxi-
mum size in the late cerebritis stage, before any significant
capsule formation had taken place, suggesting that the host
was able to contain the infection before capsule formation.
Also, even in the late capsule stage, inflammation, necrosis,
and edema extended well beyond the well-formed capsule.
Two observations regarding encapsulation deserve special
attention: (a) capsule formation is usually more complete on
the cortical side of the abscess than on the ventricular side
(191), and (b) encapsulation is less extensive in abscesses
resulting from hematogenous spread than in those arising
from a contiguous focus of infection (198). The preferential
deposition of collagen on the outer edge of the abscess is
thought to be due to the better vascularization of the gray
matter (197). This discrepancy probably explains the pro-
pensity for abscesses to rupture medially rather than into the
subarachnoid space. Similarly, cerebral ischemia from a sep-
tic embolus might impede optimal collagen formation (198).
Therefore, brain abscess formation is a continuum from
cerebritis to a collagen-encapsulated necrotic focus; however,
its maturity is dependent on many factors, including local
Scheld_Ch31.indd 532
oxygen concentration, the offending organism, and the hosts
immune response.
CLINICAL MANIFESTATIONS
Signs and Symptoms
The clinical manifestations of a brain abscess (Table 31.6)
can vary greatly among patients. Additionally, symptoms
from the primary site of infection (i.e., otitis, sinusitis, or
distant suppurative foci) may predominate. The evolution
of symptoms of a brain abscess may range from indolent to
fulminant; the average duration of symptoms until hospital
admission is 11 to 12 days (range, hours to several weeks)
(122,132). The classic triad of fever, headache, and a focal
neurologic deficit is present in less than 50% of patients.
In most patients, the prominent clinical manifestations of
brain abscess are due to an expanding intracerebral mass
rather than infection; neurologic signs, such as headache and
hemiparesis, predominate in patients with multiloculated
brain abscess as compared with patients with uniloculated
brain abscess (199). The clinical presentation of patients with
cerebellar abscesses is different, because signs of raised in-
tracranial pressure (ICP) (e.g., headache, vomiting, and pap-
illedema, 90%), fever (90%), meningismus (70%), and
depressed consciousness (50%) are particularly common
(118,200). Cerebellar signs are present in 25% to 50% of
patients, whereas hemipareses are evident in only 10% of pa-
tients. The clinical presentation of frontal lobe abscesses is
often dominated by headache, drowsiness, inattention, and
a generalized deterioration in mental function. Hemiparesis
with unilateral motor signs and a motor speech disorder are
the most common focal findings. A temporal lobe abscess
may present with early ipsilateral headache. If the abscess
is in the dominant hemisphere, an aphasia or dysphasia may
be present. An upper homonymous hemianopia may also be
demonstrated and may be the only sign of a right temporal
lobe abscess. Intrasellar abscesses often simulate a pituitary
tumor, presenting with headache (90%), abnormal pitu-
itary function (50%), and visual field defects (50%) (167).
The clinical presentation of brainstem abscess is usually a
rapidly progressing neurologic deficit involving cranial nerves
and long tracts.
TA B L E 3 1 . 6
PRESENTING SIGNS AND SYMPTOMS IN 968
PATIENTS WITH BRAIN ABSCESS (AFTER [20,122,126,
127,218,234,299])
Sign or Symptom Frequency Range (Mean)
Headache 5597% (77%)
Impaired consciousness 2891% (53%)
Fever 3262% (53%)
Nausea with vomiting 3585% (51%)
Papilledema 956% (39%)
Hemiparesis 2344% (36%)
Seizures 1335% (24%)
Neck stiffness 541% (23%)
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 Chapter 31: Brain Abscess 533

FIGURE 31.9 Cerebral metastasis as differential diagnosis of brain abscess. Cystic lesion in a 66-year-
old patient that appears (A) hyperintense on T2-weighted imaging (asterisk) and (B) shows only a very
distinct contrast enhancement of the rim (arrow). C: Diffusion-weighted imaging is negative (asterisk).
The lesion was diagnosed as a metastasis of a pulmonary adenocarcinoma.

diagnosis is primary CNS lymphoma, followed by brain ab-

Differential Diagnosis
Because of their nonspecific presentation and frequent lack of
fever, brain abscesses can be confused with several other pro-
cesses. The major differential diagnoses of a brain abscess in-
clude primary (glioblastoma) or metastatic malignancies of the
CNS (Figs. 31.9 and 31.10). Furthermore, differential diagnoses
may include other infectious diseases, including viral encephali-
tis (especially due to herpes simplex virus), subdural empyema
and epidural abscess, or mycotic aneurysms in the setting of in-
fective endocarditis. Cerebral venous sinus thrombosis, cerebral
infarction, resolving hematoma, arterial infarction in the stage
of luxury perfusion, AVM, neurosarcoidosis, and tumefactive
multiple sclerosis may also be confused with a brain abscess,
both symptomatically and occasionally radiographically (201).
In patients with AIDS, the most common cause of intracranial
mass lesions is toxoplasmosis; the most important differential
scesses due to pathogens other than Toxoplasma (Table 31.3),
metastatic tumors, and cerebrovascular disease (202).
APPROACH TO A DIAGNOSIS
Laboratory Investigations
Examination of the blood is rarely helpful in the diagnosis of a
brain abscess (Table 31.7). The serum C-reactive protein (CRP)
values are more commonly elevated than the blood leukocyte
counts or erythrocyte sedimentation rate (ESR). However, up to
23% of patients in previous studies had a normal CRP serum con-
centration. Blood cultures are infrequently positive (about 10%) at
the time of presentation. However, blood cultures were reported to
be positive in 86% of patients with listerial brain abscesses (203).

FIGURE 31.10 Glioblastoma multiforme as differential diagnosis of brain abscess. Two cerebral lesions
in a 56-year-old HIV-positive patient with a CD4 count of 1000 cells/L and negative anti-Toxoplasma
antibodies. A: The lesions are hyperintense on the T2-weighted image (arrows) and (B) show ring-shaped
contrast enhancement (arrows). C: Diffusion-weighted imaging is isointense in the center of the lesion
(arrows). Glioblastoma multiforme was diagnosed after biopsy.

Scheld_Ch31.indd 533 2/21/14 5:46 PM

 534 Part III: Bacterial and Mycoplasmal Infections

TA B L E 3 1 . 7
APPROACH TO A DIAGNOSIS OF BRAIN ABSCESS AND POSSIBLE UNDERLYING CONDITIONS

Method Possible Results References

Cranial CT/MRI Cerebritis: focal area of edema (high signal on T2-, low signal on T1-weighted 190, 220, 261
with contrast images, hypodense on CT) with mass effect (sulcal effacement or ventricular
administration compression) and minimal/heterogeneous enhancement
Abscess: necrotic center (pus) is usually isodense with CSF on CT and
hyperintense on MRI; capsule can be iso- or hyperintense on T1- and
hypointense on T2-weighted images; edema around the abscess cavity; mass
effect, ring-enhancement on CT or MRI
Complications: edema, hemorrhage, hydrocephalus, ventricular rupture?
Evidence for source of infection: sinusitis, otitis, mastoiditis, fracture, osseus
dehiscence, congenital malformation, intracranial foreign body?
Diffusion-weighted Abscess fluid is hyperintense on DW MRI (neoplastic cystic brain lesions are 190
(DW) MRI hypointense); apparent diffusion coefficient values are decreased in brain
abscesses (and increased in neoplastic cystic brain lesions)
Stereotactic abscess Microscopy; aerobic and anaerobic cultures: positive in 84% (mean, range 28, 122, 132, 154, 218, 299
aspiration 6997%); fungal, mycobacterial, and nocardial cultures (on indication)
Blood cultures Aerobic and anaerobic cultures: positive in 3 (11%) of 27 patients in one study 122
Laboratory studies Blood leukocyte count: elevated in 47% (mean, range 3057%) 4, 122, 132, 218, 299
Erythrocyte sedimentation rate: elevated in 59% (mean, range 4865%) 4, 218, 299
Serum C-reactive protein: elevated in 82% (mean, range 7790%) 204, 314316
Serologic test for HIV (on indication)
Echocardiography Right-to-left shunt, valvular vegetations (endocarditis)
Chest x-ray/CT of Pulmonary infection: abscess, pneumonia, empyema, bronchiectasis,
the chest aspergilloma
Pulmonary arteriovenous malformation
Dental (panoramic) Dental infection
radiography

Lumbar puncture is also of very limited value for the
diagnosis, most often reveals nonspecific CSF alterations, and
carries a considerable risk of cerebral herniation; therefore, it
should not be performed in patients with a space-occupying
brain abscess. Cerebral herniation developed immediately
after lumbar puncture in 2.1% of patients (mean, range 0%
to 4.2%) (126,127,132,204,205), and neurologic deteriora-
tion was observed in 13.5% of 193 patients with brain abscess
who received a lumbar puncture (9). Positive CSF cultures,
however, were reported in only 6% of patients (mean, range
0% to 10%) (4,122,127,132), unless there has been a rup-
ture of abscesses into the ventricles or subarachnoid space, in
which case up to 20% may be positive (122). The CSF cell
count can range from 0 to more than 100,000 cells/L, the
protein level from normal to more than 500 mg/dL, and CSF
glucose concentration can be normal or severely depressed
(122,132).
Neuroimaging Studies
Neuroimaging is the most important first step in establish-
ing the diagnosis of brain abscess. Cranial CT (Table 31.7,
Figs. 31.11 to 31.14) and in particular MRI (Table 31.7,
Figs. 31.2, 31.3, 31.5, and 31.15 to 31.17) are very sensitive
neuroimaging modalities for the detection of brain abscesses
and yield precise anatomic information. However, this is not
paralleled by an equivalent specificity; a similar appearance is
occasionally seen with other cystic brain lesions, in particular
neoplasms (201). Cranial CT is widely available and often fa-
cilitates early detection of brain abscess. For the detection of
a brain abscess, the CT must be performed with intravenous
contrast administration. During early brain abscess, a nonen-
hancing hypodensity is usually found. However, it has to be
kept in mind that in the earlier phases of brain abscess, CT
may show only low attenuation abnormalities with mass effect
(Fig. 31.11) or even fail to detect a lesion at all (Fig. 31.14).
This is especially true in brainstem abscesses. During later
stages, when bloodbrain barrier breaching progresses, con-
trast enhancement and finally a thick ring-enhancing lesion is
found on CT, representing the development of an inflamma-
tory capsule (Figs. 31.12 and 31.13). During later stages, the
contrast-enhancing ring becomes thinner. Features thought to
discriminate abscesses from malignant tumors (thinner, more
regular contrast-enhancing rim and homogeneous enhance-
ment of the capsule after infusion of contrast medium) do not
always permit a precise diagnosis.
The value of MRI in differentiating brain abscess from
other cystic lesions of the brain, such as tumor, has increased
in the past years. Compared to CT, MRI is more sensitive in
the detection of early cerebritis and small satellite lesions.
Furthermore, MRI allows estimation of the degree of central
necrosis, ring enhancement, and surrounding cerebral edema
more accurately than CT. MRI is also better suited for the de-
tection of brain abscess in the brainstem. In contrast to tumors,
increased signal in diffusion-weighted imaging (DWI) at re-
duced apparent diffusion coefficient (ADC) values are found
in brain abscesses (Figs. 31.9 and 31.10) (206209). In a study

Scheld_Ch31.indd 534 2/21/14 5:46 PM

 Chapter 31: Brain Abscess 535

FIGURE 31.11 Frontotemporoparietal space-occupying brain abscess. A: Unenhanced CT scan showing

a large right frontotemporoparietal mass lesion (asterisk) that is causing marked right-to-left shift of mid-
line structures and effacement of the ipsilateral lateral ventricle. B: Contrast-enhanced CT scan showing
a thin-rimmed, homogeneous enhancement (arrow) surrounding an area of decreased attenuation within
the center of the abscess. C: Unenhanced CT scan, performed 6 weeks after surgical aspiration of the
abscess and antibiotic therapy, showing resolution of the mass effect. D: Enhanced scan showing minimal
contrast enhancement in the temporal lobe (arrow).

FIGURE 31.12 Multiloculated brain abscesses in sepsis. Multiple

cerebral abscesses due to hematogenous spread of Staphylococcus
aureus in a patient with sepsis. Lesions are seen in periventricular
locations (A, white arrow), in the centrum semiovale (B, white
arrow), and at the junction between gray and white matter (B,
dotted arrow).

FIGURE 31.13 Occipital lobe abscess. A: Unen-

hanced axial CT scan showing a hypodense occip-
ital lesion (arrow). B: After contrast enhancement,
a ring-enhancing lesion (arrow) was found on
T1-weighted MRI. Furthermore, an additional
cortical contrast enhancing lesion was found
(arrowhead).

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 536 Part III: Bacterial and Mycoplasmal Infections

FIGURE 31.14 Presentation of differ-

ent stages of brain abscess on CT. On
CT, during the early stage of a brain
abscess, (A) a hypodense area is seen
(asterisk) with (B) only slight contrast
enhancement (arrow). Three weeks
later, (C) the hypodense area has in-
creased in size (asterisk) and (D) the
abscess wall can be seen after admin-
istration of contrast (arrow). Causative
pathogen: Staphylococcus aureus.

FIGURE 31.15 Presentation of brain abscess on CT and MRI. Parietooccipital brain abscess in a 42-year-
old female appears (A) as a hypodense lesion (asterisk) on native CT. On MRI, (B) the edema (arrow) sur-
rounding the abscess appears hyperintense and (C) contrast enhancement visualizes the capsule (arrow).
D: On diffusion-weighted imaging, the abscess cavity appears hyperintense (arrow). Streptococcus inter-
medius and Aggregatibacter aphrophilus were identified as causative pathogens.

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 Chapter 31: Brain Abscess 537

perfusion-weighted MR measurements (of the peripheral re-

gions of cystic lesions of the brain) to distinguish brain abscess
from tumor (214). Possibly, a combination of MR spectros-
copy, DTI, and perfusion-weighted MR might be helpful to
further increase specificity of MR in diagnosing brain abscess
in the future.

FIGURE 31.16 Nocardia farcinica brain abscess. T1-weighted MRI
with contrast shows multiple parenchymal ring-enhancing lesions in
a 39-year-old patient after kidney transplantation. Nocardia farcinica
was isolated from brain biopsy material.
of 147 cystic lesions of the brain in 115 patients, the sensitivity
and specificity of DWI for the differentiation of brain abscesses
from non-abscesses were 96% each (208). This does not hold
true for all cases of cerebral toxoplasmosis where MRI, and
especially DWI, findings differ depending on the stage of the
disease (Fig. 31.17) (210). Although less readily available, an
increased fractional anisotropy (FA) was found in the cavity of
abscesses using diffusion tensor imaging (DTI), allowing dis-
crimination of abscesses from tumors (211). Using magnetic
resonance (MR) spectroscopy, resonances for acetate, lactate,
alanine, succinate, and pyruvate as well as valine, leucine,
and isoleucine were found elevated in brain abscess but not in
tumors (212,213). Recent studies suggest an additional role of
Biopsy
The most important diagnostic measure in the establishment
of the diagnosis of brain abscess is histologic and microbio-
logic assessment of tissue from the suspicious lesion. This
not only allows differentiation between tumor and abscess
but also identification of the causative pathogen. Thus, a
specimen obtained from biopsy of cystic lesions should (a) be
sent for histologic evaluation and (b) be evaluated by Gram
stain and aerobic, anaerobic, mycobacterial, and fungal cul-
tures (Fig. 31.18). Furthermore, staining for mycobacteria,
Nocardia, and fungi should be performed. In recent studies,
16S ribosomal DNA polymerase chain reaction amplification
was shown to increase the number of bacterial species isolated
from brain abscesses (215217), but further data are needed
to determine its use in identification of important causative
pathogens in patients with brain abscess. Identification of the
causative organism(s) is especially crucial for further therapy
(see the following discussion).
TREATMENT
Treatment of brain abscess is based on the following principles:
(a) surgical therapy of brain abscess, (b) antibiotic therapy, and
(c) surgical therapy of the primary infectious focus. Therefore,
optimal medical care of brain abscess requires the cooperation
between an infectious disease specialist, neurologist, neurora-
diologist, neurosurgeon, microbiologist, and sometimes an ear,
nose, and throat specialist, surgeon, dentist, or maxillary sur-
geon. Cranial CT or MRI allows a precise localization of the
abscess or, when multiple abscesses are present, identification of

FIGURE 31.17 Cerebral toxoplasmosis. A: T2-weighted image shows a left frontal lesion (asterisk) with
large edema causing midline shift (arrow). A smaller hyperintense lesion was found in the occipital lobe
(dotted arrow). B: The large frontal lesion shows contrast enhancement of the capsule wall (arrow).
C: Diffusion-weighted imaging is isointense at the area of the frontal lesion (asterisk) and hyperintense
at the small occipital T2-weighted hyperintense lesion (arrow). Toxoplasma gondii was identified as
causative pathogen in this HIV-positive 35-year-old patient (CD4 count: 50 cells/L).

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 538 Part III: Bacterial and Mycoplasmal Infections

FIGURE 31.18 Diagnostic abscess aspiration. A 56-year-old HIV-positive patient with a CD4 count
of 40 cells/L presented with fever and somnolence. A: T1-weighted MRI showed multiple contrast-
enhancing lesions that (B) were hyperintense on diffusion-weighted imaging. The largest lesion (asterisk)
was chosen for diagnostic stereotactic aspiration. After computed calculation of the most suitable approach
to avoid bleeding complications, (C) a stereotactic frame (pound sign) was attached to the patients head.
The skin at the area for the calculated access (arrowhead) was disinfected and prepared for a 1-cm long in-
cision. D: A burr hole of 2 mm in diameter was drilled. A perfect position of the drill (arrow) was ensured
through attachment of the drill to the stereotactic frame. E: Guided through a precalculated position on
the stereotactic frame, the abscess was carefully punctured with a needle (arrowheads) measuring 1 mm
in diameter. F, G: The cavity of the lesion was found liquid, and fluid was aspirated (o). Microbiologic
studies of the specimen revealed Aspergillus fumigatus. (CG courtesy of Prof. Dr. Friedrich-Wilhelm
Kreth, Department of Neurosurgery, Ludwig Maximilians University of Munich.)

the lesion that is most suited for stereotactic aspiration. In addi-

tion, sources of infection (e.g., otitis or sinusitis) can be detected.
Randomized controlled studies of therapies for brain abscess do
not exist. Treatment recommendations are, therefore, based on
retrospective analyses and clinical experience. Although doubted
by some authors (132), some major series have demonstrated
that the administration of preoperative antibiotics reduces the
yield of positive cultures (4,218). However, antimicrobial ther-
apy can be withheld until surgery only if the operation can be
performed within a short time (hours) and the abscess does not
show a significant mass effect (risk of herniation). The risks of
stereotactic aspiration are probably less than the risks of incor-
rect diagnosis and choice of antibiotics; therefore, the decision to
use empirical therapy alone should be made with great caution.
Surgical Therapy
The timing of surgery and type of surgical procedure selected
remain controversial and prospective studies are lacking.
Usually, aspiration or excision is used. Retrospective series
failed to detect any significant difference in mortality (or
functional neurologic outcome) between patients treated by
aspiration or excision (4,28,218,219). Nevertheless, the type
of care (stereotactic aspiration plus medical treatment vs. op-
eration plus medical treatment vs. medical treatment alone)
in these studies was often not based on clear and explicit
data. However, there is consensus that bacterial brain abscess
should be treated by surgery if larger than 2.5 cm and causing

Scheld_Ch31.indd 538 2/21/14 5:46 PM


significant mass effect. However, it remains unclear what
type of operation should be favored. Interestingly, outcome
was more associated with clinical presentation and the speed
of operation rather than the type of operation (14,132,220).
The choice of surgical treatment should, therefore, depend
on the patients clinical status, the location and accessibility
of the abscess(es), the techniques available, and the surgeons
expertise.
Stereotactic Aspiration
Because stereotactic aspiration causes less tissue damage than
excision, CT (or MRI)-guided stereotactic aspiration through
a burr hole is usually considered the method of choice in pa-
tients with brain abscess (Fig. 31.18). Stereotactic aspiration is
particularly valuable for deep-seated abscesses (brainstem, cer-
ebellum, and basal ganglia), multiple abscesses, and abscesses
in critical locations (Figs. 31.6 and 31.19), where high precision
is necessary (221223). In addition, patients who are poor can-
didates for general anesthesia might better be treated by aspi-
ration rather than operation. With large superficial abscesses
of the cerebral hemispheres, CT-guided freehand burr-hole
aspiration may be performed as an emergency measure (in those
with impending cerebral herniation). It requires less preparation
but is less precise than stereotactic aspiration.
Compared with excision, the disadvantage of aspiration
is that repeated aspirations or even excision may become
necessary. Another considerable risk is intracranial bleeding;
Scheld_Ch31.indd 539
Chapter 31: Brain Abscess 539
therefore, abnormal results of clotting studies or thrombocy-
topenia are particular contraindications for burr-hole aspira-
tion and must be corrected.
Excision
Open craniotomy and total excision of the abscess may be-
come necessary in all lesions that fail to respond to repeated
aspirations and medical therapy (Fig. 31.20). Excision is also
necessary in brain abscesses secondary to foreign bodies, and
some authors advocate that abscesses exhibiting gas by CT or
on plain film should also be completely excised, because an
open craniotomy will allow for the detection and treatment of
an extracranial communication (224). Furthermore, patients
with abscesses in the posterior cranial fossa are often prefera-
bly treated by excision (223,225,226). Patients with posttrau-
matic or postoperative brain abscess have also been considered
candidates for excision by most authorities (222,225).
Medical Therapy
Antibiotic therapy, usually in combination with surgery, is
important in the management of brain abscess. Because the
chance to detect the causative pathogen from specimens col-
lected during aspiration or excision of the abscess decreases
in a time-dependent manner after antibiotic therapy has been
started, immediate surgery followed by empirical antibiotic
FIGURE 31.19 Successful aspiration of
a cerebellar brain abscess. The 38-year-
old patient with a history of long-
standing injection drug abuse presented
with impaired consciousness and fever.
A: Diffusion-weighted MRI showed a
hyperintense lesion in the cerebellum
(asterisk) B: Histologic studies of brain
biopsy specimen showed a massive infil-
tration of inflammatory cells (arrows),
predominantly granulocytes (hematoxylin
and eosin [H&E] staining). C: Gram stain
revealed gram-positive cocci that pre-
sented in clusters (arrows). Microbiologic
investigations identified Streptococcus
anginosus. D: Follow-up MRI 18 days
after aspiration showed disappearance of
the hyperintensity on diffusion-weighted
imaging. (B, C courtesy of Prof. Dr. Armin
Giese, Center for Neuropathology and
Prion Research, Ludwig Maximilians
University of Munich.)
2/21/14 5:46 PM
 540 Part III: Bacterial and Mycoplasmal Infections

FIGURE 31.20 Open surgery in temporal brain abscess. A: T1-weighted MRI with contrast enhance-
ment shows right temporal brain abscess (asterisk) in a 52-year-old patient. Initial stereotactic aspiration
failed to identify a causative pathogen (possibly due to pretreatment of the patient). Despite broad antibi-
otic therapy, the size of the abscess increased, requiring open surgery. During surgery, (B) a hard abscess
wall (asterisk) was found. For orientation, please note the sylvian vein (black arrow). C: After the abscess
was opened, the hard abscess wall can be seen from inside (arrow) as well as pus (asterisk) inside the
abscess cavity. (B, C courtesy of Dr. Jan Mehrkens, Department of Neurosurgery, Ludwig Maximilians
University of Munich.)

therapy is recommended. However, if surgery is delayed,
empirical antibiotic therapy needs to be started before sur-
gery. Despite a lack of data, medical therapy alone might be
an option in certain situations. However, by not performing
surgery, confirmation of the diagnosis and identification of the
causative pathogen is important to be able to select the cor-
rect antimicrobial therapy. In consequence, only few patients
are treated by medical therapy alone; for example, only 19 of
973 patients received nonsurgical treatment in a study from
South Africa (9). In retrospective case series, candidates that
seemed suitable for antibiotic therapy alone were patients with
small abscesses (2.5 cm), in good clinical condition (Glasgow
Coma Scale 12), and in whom the etiology of the abscess
was established (170,227). Medical therapy alone can also
be considered in patients with a lesion in the cerebritis stage
(which are much more likely to respond to antibiotic therapy
alone because of lack of a capsule) or surgically inaccessible
abscesses (in particular brainstem abscesses) (170). These pa-
tients should be treated with high-dose broad-spectrum intra-
venous antibiotics for at least 6 to 8 weeks and perhaps longer.
If the patient shows neurologic deterioration or serial CT
scans show that the abscess does not decrease in size within
several weeks or even grows, a surgical procedure should be
reconsidered to confirm the diagnosis, collect material for cul-
ture, and remove as much pus as possible (220,228).
Suitable Antimicrobial Agents
Randomized controlled studies that compared the efficacy of
different antibiotic regimens are lacking in patients with brain
abscess. Antibiotics used for the treatment of brain abscess
should be administered intravenously, be active against the
pathogens that have been identified as causative agents of the
abscess or are likely in a given clinical scenario, penetrate into
the abscess fluid (and into the site of the underlying infection)
in adequate concentrations, and have bactericidal activity
(220). Additional therapeutic concerns include the effect of the
abscess environment on the activity of the antibiotic and the
possibility of negative drug interactions when multiple agents
are administered. In 32 patients with brain abscess, penicillin
G was detectable consistently if the dose exceeded 24 million
units daily (in adults) (229). Fusidic acid entered the brain
abscess readily, but concentrations of various cephalosporins
and cloxacillin were low. Metronidazole attains high concen-
trations in brain abscess pus (230), often exceeding serum
concentrations after a dose of 400 to 800 mg every 8 hours.
Because of these results and the bactericidal activity of metro-
nidazole against strict anaerobes, this agent is an important
component of antimicrobial regimens for brain abscesses.
Vancomycin attained acceptable concentrations (for aerobic
streptococci and staphylococci) in the single brain abscess
studied (231). Cefotaxime, ceftazidime, ceftriaxone, and
ampicillin/sulbactam were shown to be efficient in the treat-
ment or to have an adequate penetration into brain abscesses
(232236). Imipenem/cilastatin has also been demonstrated to
penetrate at sufficient levels into brain abscess pus and to be
effective (237240). However, because of the reported neu-
rotoxicity (increased incidence of seizures) of imipenem, me-
ropenem is preferred; a successful outcome using this agent in
the treatment of a brain abscess due to a multidrug-resistant
Enterobacter cloacae was shown (241). In the search for
newer antibiotics, linezolid has been shown to be a promis-
ing agent for the treatment of CNS infections, having good
penetration into the CSF (242,243). Quinolones, which have
been used with success, should be used with caution in the
treatment of cerebral abscesses, because they can also lower
seizure thresholds (244).
Empirical Antimicrobial Therapy
The antimicrobial regimens commonly recommended for the
therapy of brain abscess are empirical and reflect the consider-
ations already noted, as well as the in vitro activity of the com-
ponent agent(s) against the usual pathogens. No controlled
trials on the relative efficacy of various regimens have been
performed. Interpretation of the success or failure of a given
regimen is further confused by the various surgical procedures,
which may be used concomitantly.
In patients with community-acquired brain abscesses
(Tables 31.8 and 31.9), third-generation cephalosporins,
such as ceftriaxone or cefotaxime, which are directed against
streptococci and a broad range of gram-negative bacteria are
preferred for first-line empirical therapy. In addition, cover-
age of anaerobes (e.g., by metronidazole) and staphylococci
(e.g., by flucloxacillin, nafcillin, or vancomycin) should be
considered in appropriate circumstances. If meropenem is

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 Chapter 31: Brain Abscess 541

TA B L E 3 1 . 8
EMPIRICAL ANTIMICROBIAL THERAPY OF BRAIN ABSCESS

Underlying Condition Recommended Antimicrobial Regimen

Community acquired (immunocompetent patients) Third-generation cephalosporina,b metronidazole

Postoperative or posttraumatic Meropenem (or cefepime) vancomycin

a
Ceftriaxone or cefotaxime; for Pseudomonas species: ceftazidime aminoglycoside, meropenem aminoglycoside, cefepime aminoglycoside,
or ciprofloxacin.
b
If staphylococci are suspected: plus vancomycin (alternatives: rifampicin, nafcillin). Linezolid (1200 mg per day in 2 divided doses [600 mg IV every
12 hours] intravenously in adults) has an activity comparable to that of vancomycin but has a much better bloodCSF penetration (however, clinical
reports on the use of linezolid in CNS infections are very limited). It needs to be kept in mind that administration of linezolid for the prolonged periods
required for brain abscess therapy may lead to significant side effects such as bone marrow suppression, optic neuropathy, and polyneuropathy.

used, the addition of metronidazole is not necessary because TA B L E 3 1 . 9

meropenem is active against anaerobic bacteria itself. Patients RECOMMENDED DOSAGES FOR ANTIMICROBIAL
with otogenic brain abscesses should be treated initially with THERAPY OF BRAIN ABSCESSES IN ADULTS
ceftazidime or cefepime, because these cephalosporins are also (DOSING MAY NEED ADJUSTMENT IN PATIENTS
effective against Pseudomonas aeruginosa (Table 31.8). WITH UNDERLYING RENAL OR LIVER DISEASE)
Because patients with posttraumatic brain abscess or noso-
comial brain abscess are at risk for infection with MRSA and Antimicrobial Agent Dosage
multiresistant Enterobacteriaceae, meropenem or cefepime
plus vancomycin is the recommended empirical treatment in Amphotericin B 0.61.25 (to 1.5) mg/kg i.v.a
such cases (Table 31.8). Bone marrow, stem cell, and solid deoxycholate q24h
organ transplant recipients with brain abscesses often require
Liposomal amphotericin B 5 mg/kg i.v. q24h
initial polypragmatic therapy including meropenem, vanco-
mycin, voriconazole, and anti-Toxoplasma therapy to treat a Ampicillin 2 g i.v. q4h
wide variety of potential infectious pathogens. In all cases, the Cefepime 2 g i.v. q8h
empirical treatment should be modified or extended, if labora- Cefotaxime 34 g i.v. q8h
tory, clinical, or radiologic findings are suggestive of a specific
Ceftazidime 2 g i.v. q8h
pathogen. After culture results are obtained, therapy needs
to be modified according to the identified pathogen(s) and in Ceftriaxone 2 g i.v. q12h
vitro susceptibility testing. Clindamycin 600 mg i.v. q6h
The usual treatment of choice for CNS candidiasis is the Nafcillin 2 g i.v. q4h
combination of intravenous liposomal amphotericin B and oral
Fluconazole 400800 mg i.v. or p.o. q24h
flucytosine (90,245). Cryptococcal CNS disease, best studied in
patients with cryptococcal meningitis, is usually treated with a Flucytosine 25 mg/kg p.o. q6h
combination therapy consisting of liposomal amphotericin B Fosfomycin 5 g i.v. q8h
and flucytosine (induction therapy). After 2 weeks, consolida- Itraconazole 200400 mg p.o.b q12h
tion therapy with fluconazole (400 mg per day) should be given
Linezolid 600 mg i.v. q12h
for an additional 8 to 10 weeks. Then, immunosuppressed pa-
tients should receive fluconazole (200 to 400 mg per day) for an Meropenem 2 g i.v. q8h
additional 6 to 12 months (suppression) (246). In HIV-positive Metronidazole 500 mg i.v. q68h
patients, suppressive therapy is continued until CD4 cells are Nafcillin 2 g i.v. q4h
maintained above 150 to 200 cells/L for more than 6 months
in patients on antiretroviral therapy. CNS coccidioidomycosis Penicillin G 4 106 U i.v. q4h
should be treated with fluconazole or, alternatively, itraconazole Pyrimethamine 50 mg p.o. q24hc
(247), and patients with CNS blastomycosis should be treated Sulfadiazine 68 g p.o. q24h
with liposomal amphotericin B (248). CNS histoplasmosis Rifampin 10 mg/kg i.v. (up to 600 mg) q24h
should be treated initially with amphotericin B for 3 months,
then with itraconazole for 12 months (249). In the treatment of Trimethoprim 160 mg i.v. q68h
cerebral mucormycosis, amphotericin B is the only antifungal ( sulfamethoxazole)
agent with proven in vivo activity (250). Actinomycosis of the Voriconazole 4 mg/kg i.v. q12hd
CNS is often treated with high-dose intravenous penicillin for 2 Vancomycin 15 mg/kg i.v.e q812h
to 6 weeks, followed by oral therapy with amoxicillin, ampicil-
lin, or penicillin V for 6 to 12 months. Doxycycline, erythro- i.v., intravenously; p.o., orally.
mycin, and clindamycin can be given alternatively according to a
High dosages are recommended in particular for the treatment of
sensitivity test results. aspergillosis.
b
Instillation of antibiotics into the abscess cavity during Possible alternative to amphotericin B; poor penetration of the
aspiration has been employed, but the efficacy of this practice bloodCSF barrier.
c
Loading dose: 50200 mg p.o., 1015 mg/day folinic acid should be
has never been established. Antibiotics given in this manner given to decrease bone marrow suppression from pyrimethamine.
may diffuse into surrounding brain tissue in high concentra- d
Loading dose 2 6 mg/kg on the first day.
tions, causing seizures. It should, therefore, be used with cau- e
Need to monitor serum concentrations and maintain at 1520 g/mL.
tion and is not recommended.

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 542 Part III: Bacterial and Mycoplasmal Infections
Management of Nocardial Brain Abscesses
A study of 131 patients with nocardial brain abscesses (67)
recommended that (a) if an extraneural nocardial infection
(present in 70% of patients) is documented in a clinically sta-
ble immunocompetent patients with a brain abscess less than
2 cm in diameter, empirical treatment with trimethoprim-
sulfamethoxazole should be given (possible alternatives are
meropenem, ceftriaxone, ampicillin, linezolid, vancomycin,
or amikacin) and (b) if the patient deteriorates clinically,
or if the abscess does not decrease in size within 4 weeks,
stereotactic aspiration should be performed to confirm the
diagnosis and to decompress the lesion. However, several re-
cent reviews challenged this view and recommended that an
open or stereotactic biopsy should be performed early in the
patients course, because it facilitates an early and accurate
diagnosis (251253). Another series of 11 patients confirmed
that aspiration is an effective treatment of nocardial brain
abscesses with considerable mass effect (254). Nine of these
patients were treated only with aspiration and long-term
chemotherapy (intravenous chemotherapy for 4 to 6 weeks
and subsequent oral drug therapy for 6 to 12 months; nine
patients were treated with trimethoprim-sulfamethoxazole)
and two patients underwent craniotomy and lesion excision.
Four of the nine patients needed only one aspiration, three
patients needed two aspirations, and three or four aspirations
were necessary in one patient each. There were no fatalities
in this series.
Management of Cerebral Aspergillosis
A prospective unblinded study on 277 patients with inva-
sive aspergillosis showed that voriconazole therapy was as-
sociated with a lower mortality than amphotericin B during
the first 12 weeks of treatment but the number of patients
with cerebral aspergillosis was low (n 5 in each treat-
ment group) (82). Nevertheless, in a retrospective study of
81 patients with cerebral aspergillosis, treatment with vori-
conazole was associated with a complete or partial response
in 35% of patients (81). In comparison, cerebral aspergil-
losis was reported to be fatal in more than 90% of patients
despite therapy with amphothericin B. Thus, voriconazole
is recommended as the treatment of choice for cerebral as-
pergillosis. Furthermore, multifactorial analysis revealed
that additional neurosurgical treatment such as craniotomy,
abscess resection, abscess drainage, or shunting/placement
of an Ommaya reservoir were associated with improved
outcome (81). To date, whether excision or aspiration is
the better treatment for cerebral aspergillosis is not clear.
However, an early diagnostic stereotactic aspiration, if fea-
sible, is warranted in cases of suspected cerebral aspergil-
losis (80,255).
Management of Brain Abscess in Patients with AIDS
The following procedures have been proposed for the evalu-
ation and treatment of intracranial lesions in patients with
AIDS (202): (a) empirical treatment for toxoplasmosis should
be instituted in all cases (pyrimethamine plus sulfadiazine
or pyrimethamine plus clindamycin), except when a single
intracranial mass lesion accompanies negative serology for
toxoplasmosis; and (b) a stereotactic biopsy is indicated if
serology is negative or the patient deteriorates clinically or
radiologically during antitoxoplasmic therapy, although large
lesions may require immediate surgical decompression. In
HIV-infected children, proceeding directly to stereotactic bi-
opsy may be considered, because toxoplasmosis is rare in this
patient population.
Scheld_Ch31.indd 542
Management of Patients with Multiple Abscesses
For patients with multiple brain abscesses, it has been recom-
mended that all abscesses larger than 2.5 cm in diameter or
with significant mass effect should be stereotactically aspirated
(or excised) (220,221). If the abscesses are all smaller than
2.5 cm in diameter, the largest and/or most accessible lesion
should be aspirated for diagnostic purposes. In the case of en-
largement of an abscess after a 2-week interval or a failure of
an abscess to diminish in size after 3 to 4 weeks of antibiotics,
further surgical drainage is recommended.
Duration of Antimicrobial Therapy and Follow-up
In general, the appropriate duration of antimicrobial therapy
for brain abscess is not completely clear, but duration of antibi-
otic therapy for shorter than 4 weeks are not reported. Usually,
4 to 8 weeks of intravenous therapy is reported suitable, pro-
vided that the pathogens are susceptible, a clear clinical and
radiographic response is observed, and the treatment is well
tolerated by the patient. Some favor an additional 2 to 4 weeks,
others a several months course of oral antimicrobial therapy
to prevent relapse. However, clinical evidence for that recom-
mendation is lacking. Drugs used for oral treatment include
trimethoprim-sulfamethoxazole, amoxicillin/clavulanic acid,
moxifloxacin, linezolid, and rifampin (220), although rifampin
should not be used as single-agent therapy. Follow-up should
include clinical examinations and serial CT scans or MRI to
document resolution of the abscess (Fig. 31.19). However, even
a cured brain abscess may continue to exhibit areas of con-
trast enhancement on neuroimaging for several months after
completion of successful therapy (256). Follow-up DWI might
be of help in assessing treatment responses in brain abscess in
the future (257).
Corticosteroids
The use of corticosteroids in brain abscess is problematic
because it might interfere with the CNS penetration of anti-
biotics (258). In summary, there is no data favoring a routine
use of steroids in the treatment of brain abscess. Adjunctive
therapy with corticosteroids should, therefore, be restricted
to patients with a progressive neurologic deterioration or
impending cerebral herniation and radiologic evidence that the
abscess is causing significant cerebral edema and mass effect.
Furthermore, in patients with abscesses in areas where edema
might quickly become critical (cerebellum), the use of cortico-
steroids should be considered. Whenever corticosteroids are
used, a rather quick reduction of dosage is recommended once
the patient has had a clinical response.
TREATMENT OF COMPLICATIONS
The most important complications of brain abscesses are (a)
seizures, (b) obstructive hydrocephalus, (c) intraventricular
rupture of the abscess resulting in ventriculitis and/or menin-
gitis, and (d) brain edema.
Seizures
On admission, seizures are reported in up to 34% of patients
with brain abscess (9,16,32,259). Acute seizures should be ter-
minated with administration of intravenous benzodiazepines,
such as lorazepam or midazolam, or by intravenous fosphe-
nytoin. For the prevention of further seizures, carbamazepine
and fosphenytoin are recommended; in addition to phenytoin,
valproate and levetiracetam are available for intravenous
2/21/14 5:46 PM

administration. Patients without seizures but with epileptic
discharges on the electroencephalogram (EEG) should also be
treated with antiepileptic drugs. Interestingly, a reduced fre-
quency of seizures in brain abscess was reported in patients
treated with aspiration in comparison to those treated with
excision, but studies were retrospective (260). The prophylac-
tic treatment of patients without EEG abnormalities, however,
still is a matter of debate, and there are no conclusive studies
of seizure prophylaxis in patients with brain abscess. For brain
abscesses, some authors propose seizure prophylaxis for all
patients with a duration of at least 1 year (190,227). Others
recommend reevaluation of initially treated patients by neu-
rologic and EEG examination several weeks after treatment
of the abscess is initiated and withdrawal of the medication if
no seizures occurred and EEG does not show signs typical for
epilepsy (261). In patients with EEG abnormalities that are
indicating epileptic activity, however, the treatment should be
continued.
Obstructive Hydrocephalus
Unilateral or bilateral external ventricular drainage (in cases
with obstruction at the foramen of Monro, especially in cases
with basal ganglia or thalamic abscess [171]) may become
necessary in brain abscesses complicated by obstructive hy-
drocephalus. Placement of an external ventricular drain is es-
pecially important in patients with abscess formation in the
posterior cranial fossa. In a series of 77 patients with cerebel-
lar abscesses, hydrocephalus was diagnosed in 79.2% (118).
In these patients, hydrocephalus was found to be a significant
adverse prognostic factor. With a policy of aggressive CSF di-
version (immediate ventricular drainage in any patient with
a cerebellar abscess and an overt or incipient hydrocephalus,
even in patients that were fully conscious), the authors were
able to reduce the mortality from 29% to 11.6% (118). Besides
acute hydrocephalus, persistent disturbances of CSF circulation
are common in patients with brain abscess: 10 of 20 survivors
of intraventricular rupture of brain abscesses in the study by
Takeshita et al. (262) required permanent CSF shunting.
Ventricular Rupture
The encapsulation of a brain abscess often is more complete on
the cortical than on the ventricular side (191). Thus, brain ab-
scesses are more likely to rupture into the ventricles rather than
laterally into the subarachnoid space (262). Intraventricular
rupture of brain abscesses affects approximately 15% to 25%
of patients with brain abscess (127,262,263) and results in ven-
triculitis, meningitis, and disturbances of the CSF circulation,
causing an additional increase of ICP. Accordingly, intraven-
tricular rupture of brain abscess is associated with an unfa-
vorable outcome (127,263). Because intraventricular rupture
of brain abscesses often affects drainage of CSF, placement of
external ventricular drains (sometimes even bilaterally) might
be necessary in such patients.
Brain Edema
The edema around the abscess cavity is usually very pro-
nounced; it may be greater in volume than the abscess itself
(201). To reduce the surrounding edema, corticosteroids are
frequently recommended. Controlled prospective studies on
adjunctive therapy with corticosteroids for brain abscesses
have not been performed. Retrospective studies failed to show
Scheld_Ch31.indd 543
Chapter 31: Brain Abscess 543
a beneficial effect of corticosteroids on outcome (122,132).
However, the analysis is complicated because corticosteroids
are given mostly to severely obtunded and comatose patients
who are known to have a dismal prognosis (4,218). The use of
corticosteroids should be restricted to patients with a progres-
sive neurologic deterioration or impending cerebral herniation
and radiologic evidence that the abscess is causing significant
cerebral edema and mass effect. Prolonged use of corticoste-
roids cannot be recommended in view of animal experimental
findings of delayed capsule formation and reduced bacterial
clearance. Therefore, high-dose corticosteroid therapy (e.g.,
intravenous dexamethasone at 8 mg every 8 hours) should be
given when necessary and should then be tapered off over a few
days after the patients condition has stabilized. Severe brain
edema and impending cerebral herniation may necessitate fur-
ther measures to reduce the increased ICP, such as osmotherapy
(e.g., mannitol), sedation, and moderate hyperventilation.
Meningitis
A brain abscess can rarely complicate bacterial meningitis
and vice versa; also, both can develop from contiguous or
hematogenous spread from an extradural focus. The associa-
tion of brain abscess and meningitis is particularly common
in neonates. In older children and adults with brain abscess,
meningitis is probably the result of rupture of the abscess into
the ventricles or into the subarachnoid space in most cases.
Meningitis is also more common in patients with a brain
abscess due to L. monocytogenes: 38% of these patients were
reported to have positive CSF cultures (203).
Lumbar puncture should not be performed in patients
with a proven brain abscess. However, one should be aware
of meningitis as a complication of brain abscess, because
meningitis-associated systemic and CNS complications (such
as vascular complications) may contribute to an adverse out-
come. For the management of acute bacterial meningitis and
its complications, see Chapter 24.
Hyponatremia
Like other intracranial diseases, a brain abscess can be com-
plicated by hyponatremia; its incidence in patients with brain
abscess, however, is unknown. Two different syndromes caus-
ing hyponatremia are particularly important, the syndrome of
inappropriate antidiuretic hormone secretion (SIADHS) and
that of cerebral salt wasting (CSW). SIADHS is character-
ized by water retention, leading to dilutional hyponatremia.
By comparison, CSW is due to primary natriuresis, leading to
hypovolemia and sodium deficit. SIADHS should be treated by
volume restriction; the treatment of CSW consists of sodium
and water replacement (264).
Hemorrhage
Bleeding into the abscess cavity, the surrounding brain paren-
chyma, into the ventricular system, or the subarachnoid space
has been reported as a rare complication of brain abscesses
(265267). It may lead to a stroke-like presentation and the
neuroradiologic diagnosis of the brain abscess may be con-
fused by a hemorrhage. The underlying mechanism is not
clear. However, the bleeding seems likely to occur from newly
formed fragile blood vessels in the wall of the abscess cavity.
There are no specific recommendations for the treatment of
hemorrhage associated with brain abscess.
2/21/14 5:46 PM
 544 Part III: Bacterial and Mycoplasmal Infections
PROGNOSIS
Mortality
The mortality of brain abscess was 40% to 80% in the pre-
antibiotic era with a decline in numbers after the introduc-
tion of penicillin (268). An adverse prognosis previously was
associated with (a) delayed or missed diagnosis, (b) poor
localization, (c) multiple, deep, or multiloculated lesions,
(d) ventricular rupture, (e) coma on admission, (f) fungal eti-
ology, and (g) inappropriate antibiotics. Additional negative
factors often cited are extremes of age, large abscesses, pres-
ence of metastatic abscesses, and rapidly progressive disease
(4,132,218,262,269). Since the introduction of CT scanning,
the mortality has decreased substantially (4,16,270). Thus,
in recent studies, the mortality of brain abscess was between
10% and 19% (9,1517,30). Easier detection of underlying
conditions (e.g., sinusitis or osseous dehiscence), monitoring
of the therapeutic progress, and recognition of complications
by CT and MRI have probably contributed to the improved
prognosis. Furthermore, CT-guided stereotactic aspiration has
greatly improved in particular the treatment of deep-seated
and brainstem abscesses.
Seizures
Among the long-term complications of brain abscess, seizures
have been particularly well studied. Older follow-up stud-
ies showed a prevalence of 50% (mean, range 34% to 72%)
(269,271273). However, most of the patients included in these
studies had been treated in the pre-CT era and the figures might
be lower today. By comparison, studies in the CT era (though
with fewer patients and much shorter follow-up) reported
seizures in 12% of the survivors (mean, range 10% to 16%)
(4,132,234). Seizures were reported to have manifested within
1 year after discharge in 86% (269), within 2 years in 78%
(272), or in 41% within 1 year and in 76% of patients within
4 years (273); however, intervals of more than 10 years have
also been observed. Also, the amount of spike and sharp waves
on EEG showed a marked increase during the first 4 years both
in patients with and in those without seizures (273). Neither sei-
zures nor EEG abnormalities before treatment of the abscess are
predictive for a later epilepsy (269). Seizures are common fol-
lowing frontal, parietal, or temporal abscesses, but they are rare
after abscesses located in the cerebellum or the occipital lobe
(272,273). The impact of the surgical method on the frequency
of seizures is not clear. After burr-hole aspiration alone com-
pared with craniotomy and total excision of the abscess, some
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2/21/14 5:46 PM
 CHAPTER 32 EPIDURAL ABSCESS
HANS-WALTER PFISTER, MATTHIAS KLEIN, ALLAN R. TUNKEL, AND W. MICHAEL SCHELD

less often than in the thoracic or lumbar regions (Table 32.1).

SPINAL EPIDURAL ABSCESS In recent years, the increasing use of spinal interventions for
pain management has caused a relative increase of lumbar
First described by the Italian anatomist Morgagni in the epidural abscesses (2,10). A recent series of 40 cases reported
eighteenth century, a spinal epidural abscess is a suppurative that 11 of 16 patients who were injection drug users had epi-
infection in the space around the spinal cord located between dural abscesses in the cervical region (6). It was postulated
the dura mater and the vertebral periosteum (1). It is both a that this may reflect the venous and lymphatic drainage of the
medical and a surgical emergency, requiring prompt and ac- upper extremity. Whereas the rich circulation ensures ample
curate diagnosis and treatment to prevent irreversible spinal blood supply to the spinal cord, it may also act as a conduit
cord dysfunction, paralysis, and death. along which infection may spread. Infection tracking along
these pathways is the likely explanation for the longitudinal
extension of spinal epidural abscesses that usually affect mul-
Epidemiology tiple adjacent spinal segments. On average, 3.3 2.7 (mean
standard deviation [SD]) spinal cord segments were re-
Although spinal epidural infections are uncommon, recent ported to be involved in five clinical studies with 133 patients
studies suggest that the incidence of this infection is increasing (11,12,1416); however, infections of the entire length of the
(2). Although incidence rates of spinal epidural abscesses have spinal epidural space have been reported (panspinal infection)
not been calculated from population-based data, estimates (3,7,17). Of note, spinal epidural abscesses can also be found
from recent case series noted an increase from 0.2 to 1.2 cases at noncontiguous sites, such as the cervical and lumbar spinal
per 10,000 admissions in the mid-1970s (3) to significantly cord (18).
higher incidence rates of up to 1.96 (4), 2.8 (5), or 11.31 cases
(6) per 10,000 admissions to large tertiary care centers in
the 1980s and early 1990s. The reasons for the increasing
incidence of epidural spinal infections seem to be an aging
population, increased use of spinal procedures, and a rising
rate of injection drug use (47). However, a change in refer-
ral patterns or a greater recognition (more widespread use of
magnetic resonance imaging [MRI]) must also be considered.
Approximately 70% of patients with spinal epidural
abscess are between 31 and 70 years of age, with no obvious
predilection for any given decade (1). The youngest patient in
the literature was 10 days of age and the oldest was 87 years
of age (1). Almost all large case series observed a preference
for the male gender, with an average male-to-female ratio of
1.0:0.56 (1). The reasons for this male predominance are not
apparent. However, some risk factors associated with spinal
epidural abscesses are more common in males, such as alcohol
abuse, injection drug usage, and trauma (1).

Pathogenesis and Pathophysiology

Below the foramen magnum, the epidural space extends the
length of the spine. It is composed of two compartments:
(a) a true space posterior and lateral to the spinal cord con-
taining a cushioning layer of fat embedded with penetrating
arteries and an extensive venous plexus, and (b) a potential an-
terior space where the dura adheres to the posterior surface of
the vertebral body (8,9) (Fig. 32.1). The epidural space is cir-
cumferential around the spinal cord distal to the second sacral
segment, the terminal point of its anterior attachment. Given
these anatomic considerations, it is not surprising that spinal
epidural abscesses are located posteriorly in most cases (3,5). FIGURE 32.1 Vertebral body and sub-/epidural space. Transverse
In addition to the boundary imposed by the anterior at- section of a vertebral body showing the location of the epidural and
tachment to the vertebral canal, the dimensions of the epidural subdural spaces. (a) vertebral body, posterior arch; (b) vertebral body,
space vary from segment to segment. In the cervical region anterior arch; (c) dura mater; (d) arachnoid; (e) pia mater; (f, beige) epi-
where the epidural space is smallest, epidural abscesses occur dural space; (g, yellow) subdural space; (h, blue) subarachnoid space.

550

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 Chapter 32: Epidural Abscess 551

TA B L E 3 2 . 1 TA B L E 3 2 . 2
LOCATION OF SPINAL EPIDURAL ABSCESSES SELECTED IMPORTANT RISK FACTORS AND
IN 889 PATIENTS SOURCES OF INFECTION IN 1,005 PATIENTS WITH
SPINAL EPIDURAL ABSCESS
Location No. of Patients (%)
Risk Factors and/or Sources of Infection No. of Patientsa (%)
Cervical 172 (19.4)
Cervicothoracic 60 (6.8) Immunocompromising conditions
Thoracic 294 (33.0) Diabetes mellitus 178 (15.4)
Thoracolumbar 59 (6.6) Alcoholism 52 (4.5)
Lumbar 150 (16.9) Malignancy 26 (2.3)
Lumbosacral 140 (15.7) Chronic kidney disease 24 (2.1)
Sacral 3 (0.3) Corticosteroid therapy 20 (1.7)
Cervicothoracolumbar 8 (0.9) Trauma and invasive procedures
Thoracolumbosacral 3 (0.3) Spinal trauma 55 (4.8)
TOTAL 889 (100) Extraspinal trauma 41 (3.5)
Epidural anesthesia 43 (3.7)
Data from references 1, 1113, 35, 36. Extraspinal operations 42 (3.6)
Spinal operations 39 (3.4)
Paravertebral injections 12 (1.0)
Lumbar puncture 1 (0.1)
Source of Infection Other sources of infection
Infection may be introduced into the epidural space by direct Skin infections 133 (11.5)
extension from a contiguous infection (about 1/3 of cases) or Injection drug use 98 (8.5)
by hematogenous seeding from a remote site (about half of Vertebral osteomyelitis/discitis 59 (5.1)
cases); in the remaining cases, the source of infection is not
Pulmonary/mediastinal infections 45 (3.9)
identified (7) (Table 32.2). Contiguous infections include (1)
vertebral osteomyelitis/discitis; retropharyngeal, perinephric, Sepsis 39 (3.4)
paraspinal, or psoas abscesses; decubitus ulcers; and persistent Urinary tract infection 23 (2.0)
dermal sinus tracts (Fig. 32.2). Local invasion from superficial Vascular access 17 (1.5)
infections can also occur following penetrating injuries, in-
Paraspinal abscess 14 (1.2)
cluding prior surgery or spinal procedures including placement
of catheters or stimulators; epidural drug injections; paraver- Degenerative spinal disorders 50 (4.3)
tebral injections; computed tomography (CT)guided needle Other risk factors or sources of 149 (12.9)
biopsy; and, very rarely, lumbar puncture (1). Metastatic seed- infectionb
ing may result from any bacteremic infection. Skin and soft TOTAL 1,155
tissue infections are typically found, but sources have also in-
cluded endocarditis and infected intravascular catheters, respi- a
Multiple risk factors were present in many patients.
ratory tract infection, urinary tract infection, dental abscesses, b
For example, pharyngitis, wound infection, endocarditis, sinusitis
abdominal infections, and complications from gastrointes- or upper respiratory tract infection, HIV infection, dental abscess,
tinal surgery (1). In contrast to spinal epidural abscesses in retropharyngeal abscess, psoas abscess, liver disease, adrenal insuffi-
adults (Fig. 32.3), adjacent vertebral osteomyelitis is distinctly ciency, ulcerative colitis, Crohn disease, systemic lupus erythematosus,
uncommon in children with this infection; thus, most spinal dermal sinus, herpes zoster neuralgia, decubitus ulcer, pregnancy, and
delivery.
epidural abscesses in children have been attributed to hema- Data from references 1, 12, 16, 19, 20, 35.
togenous seeding from a distant focus (21).
One possible explanation for the development of an epi-
dural abscess after a recent or remote trauma including prior
spinal surgery is that a small hematoma or area of damaged and 16% for cesarean sections) reported only a single case
tissue may provide a fertile area for subsequent hematogenous of an epidural abscess (23). Another mostly retrospective
seeding (22). Whether antecedent trauma is indeed a true risk study estimated the risk at approximately 1 per 5,000 cath-
factor for the subsequent development of a spinal epidural eters (24). A recent prospective study identified nine patients
abscess or whether patient recall bias has influenced this his- with epidural abscess after 17,372 epidural catheters (1 per
tory has not been systematically examined. Of course, spinal 1,930 catheters), with a mean catheterization time of 11 days
trauma may also contribute to the development of an infection (25). Immunocompromise and longer duration of catheter-
by creating a site of entry for microorganisms into the epidural ization were associated with an increased risk of an epidural
space (disruption of anatomic barriers). abscess in that study: only one of the nine patients had no
The reported risk of an epidural abscess after epidural complicating disease (four had malignancies, two had diabe-
catheterization varies widely in the literature. Prolonged use tes mellitus, one had multiple trauma, and one had chronic
of epidural catheters, significant comorbidity, older age, injec- obstructive airway disease); furthermore, all patients with
tion drug use, and diabetes mellitus contribute to the rate of abscess had epidural catheters in situ for 3 days or longer. This
infection (2). A retrospective analysis of 505,000 extradural is best illustrated by the relatively high risk of long-term epi-
blocks in obstetric practice (84% for relief of pain in labor dural treatment of chronic pain (mostly patients with cancer),

Scheld_Ch32.indd 551 2/21/14 8:29 PM

 552 Part III: Bacterial and Mycoplasmal Infections

FIGURE 32.2 Congenital dermal sinus as a risk factor for intraspinal infection. T2-weighted MRI
(A, sagittal; B, transversal) of this 26-year-old patient shows a dermal sinus (arrows, incidental finding)
extending to the intraspinal region (C6C7). The patient had a previous surgical decompression of an
Arnold-Chiari malformation.

which was complicated by an epidural abscess in 3%, 4%,
or even 12% of patients in three recent studies (13,26,27).
In another study, none of 1,062 patients who had epidural
anesthesia for a period of less than 14 days developed a serious
infectious spinal complication (28).
Underlying medical conditions that have been associated
with spinal epidural abscesses include degenerative joint disease,
diabetes mellitus, injection drug use, alcoholism and cirrhosis,
malignancy, renal failure and hemodialysis (2931), pregnancy,
ulcerative colitis and Crohn disease (both immunosuppressive
treatment and enteroepidural fistulas may be relevant), systemic
lupus erythematosus, chronic granulomatous disease, cortico-
steroid therapy, and acquired immunodeficiency syndrome (1).
Compared with the damage produced by spinal tumors
and cysts, the damage produced by bacterial spinal epi-
dural abscesses is often out of proportion to the size of the
inflammatory mass, that is, the lesion of the spinal cord can
be more extensive than can be accounted for by mechani-
cal effects of compression alone (3). This important feature
may be attributed to many factors including thrombosis and

FIGURE 32.3 Pyogenic osteomyelitis and epidural abscess. The 51-year-old patient, with 1 month of back
pain, presented with fever and cauda equina syndrome. A: On T1-weighted MRI, ventral presacral (arrow)
and epidural (arrowheads) contrast enhancement correspond with abscess formation. B, C: In addition to
the presacral abscess (arrow), T2-weighted sequences reveal hyperintensities of the os sacrum (asterisk) and
the paraspinal muscle (section sign), indicating osteomyelitis and infection of the muscle. Staphylococcus
aureus was identified as the causative pathogen from blood culture.

Scheld_Ch32.indd 552 2/21/14 8:29 PM

 Chapter 32: Epidural Abscess 553

thrombophlebitis of veins draining the spinal cord with resul-

tant edema and venous infarction (3); compression of the arte-
rial supply to adjacent cord segments with local ischemia and
infarction; focal areas of vasculitis induced by the adjacent in-
flammatory mass; or bacterial exotoxin production, especially
by Staphylococcus aureus.
Still, a rabbit model of spinal epidural abscess has demon-
strated that the damage to the spinal cord is more consistent
with mechanical compression than with ischemia or infarction
(32,33). This model, using a clinical isolate of Staph. aureus,
also demonstrated many of the pathologic features seen clini-
cally in spinal epidural abscesses: preservation of gray mat-
ter, white matter edema, vacuolization, liquefaction, myelin
degeneration, and axonal swelling. This pattern is consistent
with compressive damage, as spinal cord ischemia is typically
characterized by necrosis of the gray matter and relative pres-
ervation of the white matter (33). Furthermore, the posterior
spinal arteries and the anterior spinal artery were patent mi-
croangiographically in paraplegic animals with minimal and
moderate cord compression and even in some cases of large
epidural abscesses with severe degrees of compression (32).
Dorsal and anterior spinal veins and the anterior epidural
venous plexus were also patent in animals with minimal or
moderate compression. Only in rabbits with severe cord com-
pression, the dorsal spinal vein and the perforating arterioles
were occluded ipsilaterally to the abscess. With profound
compression, all blood flow was noted to cease. The authors,
therefore, concluded that the initial neurologic deficit results
from compression and that vascular compromise (as a result
of compression and probably not due to vasculitis or throm-
bosis) is an important factor in the final pathogenesis of spinal
epidural abscess. Although these rabbit experiments (32,33)
suggested a primary role for mechanical compression, other
animal models favored an additive adverse effect of compres-
sion and ischemia on neurologic function (7).
Microbiology
A microbiologic diagnosis is usually made from blood and/
or intraoperative cultures. Polymicrobial spinal epidural
abscesses are a rarity, blood cultures are positive in about
60% of the patients (7), and pathogens identified by blood
culture are almost always identical with the infectious agents
cultured from abscess pus. This situation is, therefore, com-
pletely different from that in patients with brain abscesses.
In the latter, blood cultures are positive in only about 10%
of patients, and even if the blood cultures are positive, they
do not allow for firm conclusions on the microbial spectrum
of the brain abscess because brain abscess pus often grows
mixed cultures (see Chapter 31). The microbial spectrum
of spinal epidural abscesses also differs greatly from that of
brain abscesses, as Staph. aureus (Fig. 32.4) is the most com-
mon etiologic agent in children and adults (responsible for
about two thirds of spinal epidural abscesses). Coagulase-
positive and negative (mostly Staph. epidermidis) staphylo-
cocci cause approximately 70% of spinal epidural abscesses
(note that in some studies, up to 15% of the isolates were
methicillin-resistant Staphylococcus species [34] with a fre-
quency up to 40% in some studies [7,35]). The remaining
30% of cases are caused by a wide spectrum of infectious
agents (Table 32.3). Most streptococcal spinal epidural ab-
scesses are due to viridans streptococci and Streptococcus
pneumoniae (1,45). Escherichia coli is responsible for most
infections due to Enterobacteriaceae. Much less frequently
Proteus, Enterobacter, Salmonella, Serratia, Citrobacter,
and Klebsiella species have been reported (1). Spinal epidural
infections due to Pseudomonas aeruginosa are relatively
uncommon but require particular attention because of this
TA B L E 3 2 . 3
MICROBIOLOGY OF SPINAL EPIDURAL ABSCESS:
CULTURE RESULTS (ABSCESS PUS, BLOOD,
AND/OR CSF) FROM 934 PATIENTS WITH
SPINAL EPIDURAL ABSCESSES

Infectious Agent No. of Patients (%)

Staphylococcus aureus 611 (65.5)

Coagulase-negative staphylococci 40 (4.3)
Streptococci 71 (7.6)
Enterobacteriaceae 48 (5.1)
Pseudomonas speciesa 18 (1.9)
Mycobacterium tuberculosis 17 (1.8)
Other bacteriab 15 (1.6)
Mixed bacterial infections 33 (3.5)
Fungic 13 (1.4)
Parasitesd 3 (0.3)
No growth or agent not specified 65 (6.9)

a
Mostly Pseudomonas aeruginosa.
b
For example, Neisseria, Acinetobacter, Actinomyces (37), Actinobacillus,
Brucella (3840), Listeria (41), Clostridium, Propionibacterium, Nocardia
(42), Bacteroides, Morganella, Eikenella, and Haemophilus (43,44) species.
c
Mostly Aspergillus fumigatus, single cases due to Sporothrix schenckii
or Candida species.
d
FIGURE 32.4 Staphylococcus aureus. Gram stain reveals violet (gram- Two cases due to Dracunculus medinensis, one due to Echinococcus
positive) bacteria, which typically present in clusters (arrows). (Courtesy granulosus.
of Dr. Andreas Wieser, Max von Pettenkofer-Institute for Hygiene and Data from references 1, 11, 12, 16, 19, 20.
Microbiology, Ludwig Maximilians University of Munich.)

Scheld_Ch32.indd 553 2/21/14 8:29 PM

 554 Part III: Bacterial and Mycoplasmal Infections

pathogens resistance to many antibiotics. Anaerobes, such
as Bacteroides, Peptostreptococcus, or Fusobacterium spe-
cies are also an uncommon cause of spinal epidural abscesses.
Spinal epidural abscess is rarely caused by agents of actino-
mycosis or nocardiosis (1,46). The incidence of mycobacterial
epidural infections (Fig. 32.5) varies greatly geographically.
Although they are very rare, for example, in studies from
North America or Western Europe, mycobacteria were re-
sponsible for 8 (28%) of 29 cases of spinal epidural abscesses
in a series from Taiwan (19) and 19 (53%) of 36 cases in a
Turkish investigation (47).
Fungal etiologies of spinal epidural abscesses include
Aspergillus species (48,49), Candida species (50), Blastomyces
dermatitidis (51), Coccidioides immitis (52), Cryptococcus
neoformans (53), mucormycosis (54), Sporothrix schenckii
(14), and Pseudallescheria boydii (55). Recently, an outbreak
of fungal meningitis after epidural or paraspinal glucocorti-
coid injection with contaminated methylprednisolone has
been described (48,49). The outbreak is ongoing and involves
multiple states. Clinical data from 66 patients showed that 47
(71%) had meningitis alone, 11 (17%) suffered from cauda
equina syndrome or focal infection nearby the injection site
(4 of whom had documented epidural abscess) with or with-
out meningitis, and 8 (12%) had posterior circulation stroke
(with or without meningitis). The median time from the
last epidural glucocorticoid injection to symptom onset was
18 days. Eight patients (12%) died, and 7 of them had stroke.
A total of 22 patients had laboratory confirmation of fungal
infection, either Exserohilum rostratum infection (21 patients)
or Aspergillus fumigatus infection (1 patient) (49).
Parasitic causes of epidural abscesses have also been reported,
including Echinococcus (56), guinea worm (Dracunculus medi-
nensis) (57), and Schistosoma mansoni (58).
The microbiology of spinal epidural abscesses in children
does not differ substantially from that in adults. In 2001, a
review of the literature summarized 34 cases of childhood
spinal epidural abscesses (21): Staph. aureus was cultured in
21 patients (62%), streptococci in 2 (6%, S. agalactiae in one
and viridans streptococci in another), Salmonella enteritidis
in 2 (6%), E. coli in 1 (3%), Pseudomonas aeruginosa in 1
(3%), Mycobacterium bovis in 1 (3%), Candida tropicalis in
1 (3%), and Aspergillus flavus in 1 (3%). Multiple organisms
were isolated in one patient and no organisms were isolated in
three children (9%).

FIGURE 32.5 Tuberculous discitis, osteomyelitis, and epidural abscess. A: Plain film in the lateral projec-
tion of the thoracolumbar junction demonstrates narrowing of the disc space, rarefaction and erosion
of the cortical margins of the subjacent vertebrae (arrows), and early gibbus formation. CT scans at the
level of (B) T12 and (C) L4 after intravenous contrast demonstrate osseous destruction of T12 with an
associated epidural abscess (arrows) causing compression of the thecal sac. Note the left-sided psoas
abscess in part C (asterisk). Sagittal (D) and axial (E) T1-weighted MRI scans 3 days later demonstrate
near-complete dissolution of the disc space between T11 (number sign) and T12 (section sign), extensive
osseous destruction, and paraspinal and epidural (arrows) inflammatory disease. F: Sagittal and (G) axial
T1-weighted MRI scans after intravenous administration of gadoliniumdiethylenetriamine pentaacetic
acid demonstrate abnormal enhancement in the T11T12 disc space (F, arrowheads), in the subjacent
vertebrae (F, arrows), and in the paraspinal and epidural compartment (G, arrowheads), indicative of
active inflammatory disease. H: CT-guided percutaneous needle (arrows) aspiration of the psoas abscess
with the patient in the prone position. Cultures yielded Mycobacterium tuberculosis.

Scheld_Ch32.indd 554 2/21/14 8:29 PM


Clinical Manifestations
The initial clinical signs and symptoms of a spinal epidural ab-
scess, characteristically including fever, back pain, and malaise,
may be subtle. A spinal epidural abscess is often not suspected
on admission. The most common initial misdiagnoses are menin-
gitis, intervertebral disc prolapse, vertebral osteomyelitis, lumbar
degenerative joint disease, spinal neoplasm, transverse myelitis,
spinal ischemia, and urinary tract infection (1). The duration of
symptoms is variable; they may be present for just a few days or up
to several months before the patient presents for evaluation (4,59).
The four-stage clinical progression of a spinal epidural
abscess was first described by Rankin and Flothow (60) more
than 50 years ago. In addition to fever and malaise, the first
localizing symptoms are backache and focal vertebral pain and
tenderness on examination. This is followed by root pain
manifested by radiculopathy and/or paresthesias, which often
may be described as electric shocks. Spinal cord dysfunc-
tion, the third stage, is characterized by motor and sensory
deficits or by bladder or bowel dysfunction. This is followed
by the final stage of complete paralysis (Table 32.4).
Although early symptoms of backache may be indolent and
persist for weeks or months, back pain usually progresses to
root pain within 3 to 4 days followed by early signs of spinal
cord dysfunction within the subsequent 4 to 5 days. The neuro-
logic deficits at this stage are usually reversible; however, rapid
surgical intervention at this point may be crucial because pro-
gression to complete paralysis may occur within a few hours
regardless of the chronicity of the process up to this point.
Specific neurologic signs depend on the level of spinal cord
involvement and is another factor that influences the differen-
tial diagnosis at the time of presentation.
The presentation of a spinal epidural abscess has historically
been described as acute (symptoms persisting for 2 weeks at (3,59). The CSF leukocyte count was 40 cells/L (median, range
the time of presentation) or chronic (symptoms for 2 weeks at 0 to 27,000 cells/L) in one study (59) and 60 cells/L (mean,
the time of presentation) (3,5). The rate of progression of the ini-
tial stages may suggest the route of infection: acute presentations
often represent hematogenous seeding and rapid expansion of
the inflammatory mass, whereas chronic presentations are more
likely the result of a gradually expanding contiguous infection.
TA B L E 3 2 . 4
PRESENTING SIGNS AND SYMPTOMS IN
942 PATIENTS WITH SPINAL EPIDURAL ABSCESS
Signs and Symptoms No. of Patients (%)
Fever 617 (66)
Initial pain symptom:
Back pain 679 (72)
Local tenderness 190 (20)
Radicular pain 209 (22)
Beginning neurologic deficit:
Muscle weakness 226 (24)
Incontinence 232 (25)
Sensory deficit 128 (14)
Advanced neurologic deficit:
Paraparesis/paraplegia 313 (33)
Tetraparesis/tetraplegia 34 (4)
Data from references 1, 16, 20.
Scheld_Ch32.indd 555
Chapter 32: Epidural Abscess 555
Although the prognostic significance of distinguishing
acute from chronic spinal epidural abscesses has recently been
questioned, patients with acute presentations may have higher
peripheral leukocyte concentrations (mean values ranging
from 12,300 to 16,700 cells/L [35]) and higher tempera-
tures when compared to those of patients with long-standing
symptoms who may have only mild elevations in these two
parameters (mean peripheral leukocyte concentrations rang-
ing from 7,100 to 11,900 cells/L). Other authors, however,
reported similar peripheral leukocyte concentrations in acute
and chronic cases (6). In both presentations, the erythrocyte
sedimentation rate (ESR) is generally elevated (25 to 30 mm
per hour); however, the magnitude of the ESR is not a reliable
clinical clue as to the chronicity of the infection (5,6). Serial
ESR measurements showed good correlation between resolu-
tion of clinical signs and decreases in ESR (34). Regardless of
the clinical course, the average peripheral leukocyte concen-
trations were 15,700 cells/L in 218 patients from the litera-
ture (range, 1,500 to 42,000 cells/L) and the average ESR
was 77 mm (range, 2 to 150 mm) in 117 patients from the
literature (1). Recent studies have also reported elevated serum
C-reactive protein (CRP) levels in patients with spinal epidural
abscesses, 15.0 9.5 mg/dl in one study (20). Serum CRP
levels were also shown to respond more quickly to therapeu-
tic interventions than, for example, the ESR (61). Similarly, a
persistent strong elevation of the CRP value after 8 days post-
surgery was shown to be associated with a poor outcome (20).
Blood cultures will be positive on average in 72% of patients
(mean, range 64% to 82% in three recent studies [4,16,59]).
Cerebrospinal fluid (CSF) examination is typically that of a
parameningeal focus of infection with elevated protein levels
and increased leukocytes. The CSF leukocytes may be a mix-
ture of polymorphonuclear leukocytes and mononuclear cells or
predominantly polymorphonuclear leukocytes in most patients
range 0 to 820 cells/L) in another report (3). Extremely elevated
leukocyte counts in the CSF may indicate that the spinal needle
has entered a lumbar epidural abscess (3,59). CSF protein values
are elevated in approximately 90% of patients (59). Markedly
elevated CSF protein levels (350 mg/dL) are often predictive
of a complete block of the spinal canal; however, an elevated
protein level of lesser magnitude is found in patients with spinal
block in nearly two thirds of cases (5). CSF glucose concentra-
tions were reported to be decreased (50 mg/dL) in more than
half of the cases (59). Except when there is concomitant menin-
gitis, CSF Gram stains rarely demonstrate organisms, and spinal
fluid cultures are positive in only 15% of patients (mean, range
7% to 25% [4,5,59,62]), also similar to other parameningeal
infections. Most authors recommend against performing a lum-
bar puncture in patients with an adjacent spinal epidural abscess
because of the possibility of inducing meningitis or subdural in-
fection if the needle traverses the epidural space or the potential
risk of neurologic deterioration if performed below the spinal
block (59). Perhaps the principal reason not to perform lumbar
puncture is the meager information that this test provides. The
CSF alterations are nonspecific and when CSF cultures are posi-
tive, so usually are the blood cultures (59).
At the time of surgery, findings may range from frank pus
to granulomatous tissue. Whereas acute cases are more likely
to have purulent material, this correlation was not found con-
sistently in other case series (4,63). Overall, intraoperative
cultures have the greatest chance of yielding a microbiologic
diagnosis; on average 86% of all cases have positive cultures
(mean, range 82% to 90% [35,16,19,59]). However, when a
patient has been receiving antibiotics for more than 1 week be-
fore culture, diagnostic cultures are unlikely to be positive (5).
2/21/14 8:29 PM
 556 Part III: Bacterial and Mycoplasmal Infections
Differential Diagnosis
Signs of fever and back pain should raise suspicion of a spinal
epidural abscess, especially when spinal tenderness or radicu-
lar signs are demonstrated on physical examination. However,
these signs and symptoms may not always be present and lack
specificity for this diagnosis. About half of the patients with
spinal epidural abscess are initially misdiagnosed (7), particu-
larly when patients present in early clinical stages (35,59,62).
One review documented that spinal epidural abscesses took
significantly longer to diagnose in patients when it was not in-
cluded among the differential diagnoses at admission: 6.6 days
versus 1.9 days (59). The main differential diagnoses include
intervertebral disc prolapse, spinal tumors, transverse myelitis,
epidural hematoma, vertebral osteomyelitis, spinal subdural
or intramedullary abscess, spinal arteriovenous malformation,
and spinal arterial ischemia. The clinical picture of spinal epi-
dural abscess can also be mimicked by acute spinal cord dys-
function due to myelitis during bacterial meningitis (64).
Approach to Diagnosis
The imaging method of choice for diagnosis of spinal epidural
abscess is contrast-enhanced MRI (6570). However, availabil-
ity, contraindications (e.g., heart pacemaker), or insufficient co-
operation of the patient sometimes requires the use of the other
methods, such as (postmyelography) CT. Plain films of the spine
will not directly visualize the spinal epidural abscess but may
demonstrate certain findings that can be an indication of the
presence of infection in the spinal canal (66,67). These findings
include intervertebral disc space narrowing in discitis and loss
of definition or destruction of both the inferior cortical margin
of one vertebral body and the superior cortical margin of the
contiguous vertebral body in osteomyelitis. Rarefaction and loss
of bony trabeculae can also be seen. In advanced or rapidly pro-
gressive cases, vertebral body collapse (or dissolution) and gibbus
formation may be seen on plain films. In general, osteomyelitis
Scheld_Ch32.indd 556
most commonly occurs in the lumbar spine, and the bodies of
the vertebrae are affected more often than the posterior elements.
Helpful ancillary plain film findings include a mass effect or dis-
placement of the larynx in a retropharyngeal abscess or scoliosis
and displacement of bowel loops in a lumbar paraspinal abscess.
Normal plain films do not exclude the presence of a spinal epi-
dural abscess, particularly in acute presentations. In this setting,
additional radiographic examinations are almost always needed
for further evaluation. Similar to plain films, bone scans often
provide clinically not useful information that may be misleading
in this setting.
Myelography, which will not directly visualize a spinal epi-
dural abscess, will demonstrate the associated mass effect on
the spinal cord, thecal sac, or nerve roots. A spinal epidural
abscess can result in a complete extradural obstructive block to
the flow of water-soluble contrast. However, in patients with a
prominent ventral epidural space in the lower lumbar spine due
to abundant epidural fat, an epidural abscess may not be de-
tected on myelography if it causes indentation or obliteration
of the epidural fat without indenting the opacified thecal sac.
Both CT and MRI can directly visualize an epidural in-
flammatory mass (6568,70). As is true in the neuroimag-
ing of many diseases of the brain and spinal canal, MRI has
proven superior to CT for evaluation of patients with epi-
dural abscesses. MRI obviates the need for myelography and
CT in most cases. The advantages of MRI include its ability
to image long segments of the spinal canal in multiple planes
(Figs. 32.6 and 32.7), thereby enabling precise delineation of
all loculations of inflammatory tissue; its ability to image all
compartments around the spinal canal into which an inflam-
matory process might extend; its ability to directly visualize the
neural elements with high-contrast resolution without the need
for intrathecal contrast; its noninvasiveness, which is a particu-
lar advantage over myelography, because of the desire to avoid
inadvertent puncture of the abscess or iatrogenic spread of in-
fection from the epidural to the subarachnoid space following
introduction of a needle into the spinal canal. Furthermore,
with MRI, patient follow-up is facilitated and assessment of
response to therapy is readily performed. The ability of MRI
FIGURE 32.6 Spinal epidural abscess in a
73-year-old patient. T1-weighted MRI shows
epidural lesions (arrow) with surrounding
contrast enhancement located (A) at C3/C4
and (B) T7T9. Insets show corresponding
axial sections. Staphylococcus aureus was
identified in blood and cerebrospinal fluid.
2/21/14 8:29 PM

to distinguish active inflammatory tissue from chronic granu-
lation tissue is further enhanced by intravenous administra-
tion of gadolinium. MRI demonstrates epidural inflammatory
disease to be a soft tissue mass, which compared to the spinal
cord is isointense on T1-weighted images and hyperintense on
T2-weighted images. Diffusion-weighted imaging may show a
signal abnormality within the spinal abscess (70,71). The extra-
dural location of disease and the associated mass effect on the
thecal sac, spinal cord, or cauda equina are generally readily
appreciated on MRI, as is the extradural location of disease
and the associated mass effect on the thecal sac. The presence of
concomitant paraspinal abscesses is easily identified (Fig. 32.8).
FIGURE 32.8 Epidural spinal abscess. Transverse T1-weighted MRI in
this 82-year-old patient shows a contrast-enhancing space-occupying epi-
dural lesion (arrow) and contrast enhancement (asterisk) in the paraspinal
muscles. Enterococcus faecium was identified from the paraspinal muscles.
Scheld_Ch32.indd 557
Chapter 32: Epidural Abscess 557
FIGURE 32.7 Epidural spinal abscess. The
82-year-old patient, with 4 weeks of back
pain, presented with fever and progres-
sive paraparesis. Sagittal T1-weighted MRI
shows a contrast-enhancing space-occupying
lesion (arrowheads) ranging from (A) T4
to (B) L3 and contrast enhancement in the
paraspinal muscles (asterisk). Insets show
corresponding axial sections. Staphylococcus
aureus was isolated from blood culture and
surgical material.
In the presence of discitis, a characteristic finding on MRI is
abnormal high signal intensity in the disc on T2-weighted im-
ages (Fig. 32.9). This is in contradistinction to degenerative
disc disease, which demonstrates low signal intensity. Vertebral
osteomyelitis is seen as low signal intensity on T1-weighted im-
ages in the involved marrow cavity, with high signal intensity
on T2-weighted images. These osseous changes are usually ob-
served in conjunction with inflammatory disease of the subja-
cent intervertebral disc as described.
Treatment
A spinal epidural abscess is a neurosurgical emergency. The
neurologic deterioration to severe spinal cord dysfunction can
occur in just a few hours, making the diagnosis and treatment
imperative (Fig. 32.10). The initial treatment usually consists
of decompressive surgery and drainage of the abscess, eradica-
tion of the primary underlying infectious focus (if detectable),
and parenteral antibiotic therapy.
Posterior epidural abscesses are usually treated by decom-
pressive laminectomy, removal of pus or granulation tissue, and
postoperative irrigation with sterile saline through extradural
drains for several days. Percutaneous, CT-guided needle aspira-
tion might be a rational alternative to surgical decompression
in selected patients with posteriorly located abscesses, which
extend across multiple spinal segments, exhibit minimal cord
compression, and demonstrate stable neurologic examination
results with minimal or no neurologic deficits (72). For the
treatment of anterior epidural abscesses, an anterior approach
may be necessary. Adjacent sources of infection should also be
cured surgically (e.g., vertebrectomy for severe osteomyelitis
with vertebral body destruction).
2/21/14 8:29 PM
 558 Part III: Bacterial and Mycoplasmal Infections

FIGURE 32.9 Spondylodiscitis. The 65-year-

old patient presented with fever and a history
of back pain for 4 weeks. Clinical exami-
nation revealed dysaesthesia of the left leg,
corresponding to dermatome L5. In compari-
son to (A) plain T1-weighted sagittal MRI,
(B) contrast enhancement of the vertebra L4
and L5 and the intervertebral space L4/L5
was noted. C: On T2-weighted MRI, a hyper-
intense signal of the intervertebral space was
found. CT-guided puncture (L4/L5) revealed
granulocytic inflammatory changes. Isolation
of bacteria was not successful. For A, B, and
C: L4 (asterisk), L5 (number sign), and L4/L5
intervertebral disk space (arrow).

Parenteral antibiotic therapy should be directed against
the etiologic agents most likely to be involved: Staph. aureus,
coagulase-negative staphylococci, streptococci, and gram-
negative rods. A combination of a third-generation cephalo-
sporin (e.g., ceftriaxone) with another antimicrobial showing
antistaphylococcal activity (e.g., nafcillin) is recommended (for
dosages, see Table 32.5). If methicillin-resistant staphylococci
are suspected or isolated, vancomycin should be used. Linezolid
or daptomycin may become alternative antibiotic agents to
cover methicillin-resistant staphylococci in the therapy of an
epidural spinal abscess; however, clinical experience with these
agents in this disease is limited. A nosocomial spinal epidural
abscess may be initially treated with meropenem or cefepime
plus vancomycin. When the etiologic agent has been identi-
fied in cultures, the antibiotic regimen should be modified ac-
cording to the antibiogram. Minimum treatment duration of
4 to 6 weeks is usually recommended; this period should be
extended to 6 to 8 weeks or more if osteomyelitis is present.
The administration of corticosteroids (e.g., intravenous dexa-
methasone) is controversial. Their benefit has not been proven

FIGURE 32.10 Early epidural and paravertebral abscess. The 74-year-old patient presented with subacute
paraparesis and high-grade fever. A: T2-weighted MRI showed hyperintensities of the L3/L4, L4/L5, and L5/S1
intervertebral disc spaces (arrows) and the L3 and L4 vertebral bodies. B: T1-weighted images showed subtle
contrast enhancement of the L3 and L4 vertebral bodies (arrowheads) and (C) epidural material with contrast
enhancement (arrows) as well as contrast enhancement of the paravertebral muscles (asterisk). D: Material ob-
tained during surgery revealed few gram-positive cocci (Gram stain, arrowheads). Microbiologic investigations
identified Staphylococcus aureus, which was also found in blood cultures. (D, Courtesy of Prof. Dr. Armin
Giese, Center for Neuropathology and Prion Research, Ludwig Maximilians University of Munich.)

Scheld_Ch32.indd 558 2/21/14 8:29 PM


TA B L E 3 2 . 5
RECOMMENDED DOSAGES FOR ANTIMICROBIAL
THERAPY OF EPIDURAL ABSCESSES IN ADULTS
(DOSING MAY NEED ADJUSTMENT IN PATIENTS
WITH UNDERLYING RENAL OR LIVER DISEASE)
Antimicrobial Agent Dosage Per Day
Cefotaxime 34 g i.v. q8h
Ceftriaxone 2 g i.v. q12h
Fosfomycin 5 g i.v. q8h
Linezolid 600 mg i.v. q12h
Meropenem 2 g i.v. q8h
Metronidazole 500 mg i.v. q68h
Nafcillin 2 g i.v. q4h
Rifampin 10 mg/kg (up to 600 mg)
i.v. q24h
Vancomycin 15 mg/kg i.v. q812ha
a
Need to monitor serum concentrations and maintain at 15 to 20 g/mL.
and controlled studies do not exist. They may be beneficial in
reducing local edema in patients with progressive neurologic
compromise who are awaiting surgical decompression (7).
Nonsurgical management using antibiotic therapy alone
may be considered in selected patients without significant
neurologic deficit, with complete paralysis for more than
3 days, and in patients refusing surgery, with panspinal infec-
tion or in poor medical condition with a high surgical risk.
Identification of the causative pathogen may be attempted by
CT-guided needle aspiration in conservatively treated patients
with negative blood cultures and with posteriorly located
abscesses. Conservatively treated patients without signifi-
cant neurologic deficit need close neurologic monitoring in a
hospital with facilities for emergency decompressive surgery.
Retrospective analyses suggest that the outcome is compa-
rable to that of surgically treated patients, if these guidelines
are followed (11,16,73,74). In the future, MRI criteria may
also be helpful when selecting patients for conservative treat-
ment. A recent study (75) suggested that a good outcome was
associated with abscesses shorter than 3 cm cephalocaudally,
less than 50% narrowing of the sagittal diameter of the spi-
nal canal, and homogenous contrast enhancement (suggestive
of phlegmonous or granulomatous tissue, opposed to the
peripheral enhancement of a frank abscess containing pus).
The authors, therefore, suggested that only patients fulfilling
at least two of these criteria should be treated conservatively.
However, definite conclusions can be drawn only from con-
trolled studies, which are still lacking and are unlikely to be
performed.
In patients with tuberculous spinal epidural abscess
(Fig. 32.5), antituberculous chemotherapy (usually with four
agents pending susceptibility testing) has diminished the need
for surgical intervention except when stabilization of the spine
is required. Because bony changes may progress radiographi-
cally for an average of 4 months following the initiation of
chemotherapy, it has been emphasized that clinical parameters
rather than radiographic changes should be followed to moni-
tor therapy during the early stages of treatment. However, if
neurologic signs and symptoms develop, decompression of a
tuberculous spinal epidural abscess may be required to prevent
permanent neurologic deficits (76). (For the recommended
antituberculous chemotherapy, see Chapter 29.)
Scheld_Ch32.indd 559
Chapter 32: Epidural Abscess 559
TA B L E 3 2 . 6
OUTCOME OF 244 PATIENTS WITH SPINAL EPIDURAL
ABSCESSES TREATED BETWEEN 1991 AND 2000
Outcome No. of Patients (%)
Complete recovery 100 (41)
Minor neurologic deficits 68 (28)
Paresis/paralysis 39 (16)
Death 37 (15)
TOTAL 244 (100)
Data from references 1, 20.
Prognosis
The outcome of a spinal epidural abscess seems to be directly
related to several independent variables (Table 32.6). When the
diagnosis is made early in the course of their illness and before
the development of significant neurologic deficit, patients fare
better than when a delay in diagnosis has occurred (1). Complete
recovery with the return of full neurologic function is most likely
to occur in patients without a neurologic deficit at the time of
diagnosis and treatment or when neurologic signs are present
for less than 24 hours (3). All large case series of the literature
have shown that more severe preoperative neurologic deficits are
generally associated with a worse prognosis (1,19,20). If weak-
ness or paralysis exists for more than 36 to 48 hours, complete
recovery is less likely (1). In some series, patients with cervical or
cervicothoracic epidural abscesses had more profound sequelae
than those with lumbar, lumbosacral, or sacral abscesses (16,74).
Other parameters such as older age, underlying disease, septice-
mia, and higher degree of thecal sac compression were also asso-
ciated with an adverse outcome in several studies (1,5,12,16,74).
INTRACRANIAL EPIDURAL
ABSCESS
Epidemiology
The true incidence of intracranial epidural abscesses is not
known. In one hospital-based series, it was the third most com-
mon localized intracranial infection, following brain abscesses
and subdural empyemas (77), and in a recent South African
series of 82 patients, epidural abscess accounted for 1.8% of all
intracranial infections (78). Intracranial epidural abscesses have
been reported in a wide age range, from 1 month to 71 years
of age (7779). In contrast to recent studies from develop-
ing countries and earlier studies from the developed world in
which intracranial epidural abscesses were principally sequelae
of sinusitis, mastoiditis, and otitis media, recent case series
from developed countries document that they are more likely
to complicate neurosurgical procedures because up to 2% of
craniotomies may be complicated by this infection (78,80).
Pathogenesis and Pathophysiology
Above the foramen magnum the dura is essentially the adher-
ent inner lining of the skull. Here the epidural space represents
only a potential space, which is created when it is violated by
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 560 Part III: Bacterial and Mycoplasmal Infections

FIGURE 32.11 Chronic intracranial epidural abscess. The 19-year-old patient had a history of acute sinusitis
followed by recurrent episodes of mild headache and intermittent fevers responsive to oral antibiotics over
a 4-year period. A: Noncontrast CT scan demonstrates left maxillary sinus inflammatory disease (asterisk).
B: Noncontrast CT section of the brain obtained at the same time as part A demonstrates a hypodense mass
(number sign) overlying the left frontal lobe associated with edema and mass effect. The hyperdense rim
(arrows) represents calcification, indicative of the long-standing nature of the inflammatory process. C: T1-
weighted MRI scan obtained after the intravenous administration of gadoliniumdiethylenetriamine penta-
acetic acid demonstrates a hypointense mass (number sign) with a thick enhancing rim (arrows). Left frontal
craniotomy revealed a purulent collection that was negative by Gram stain and culture.

an encroaching mass (tumor, adjacent infection, or hematoma)
or as a result of trauma. As a consequence, infections of the in-
tracranial epidural space primarily result from the extension of
contiguous infections, in particular, sinusitis (Fig. 32.11) and
otitis/mastoiditis (8184). Other common risk factors for intra-
cranial epidural abscesses are recent transnasal, transmastoid, or
intracranial surgical procedures (Figs. 32.12 and 32.13); post-
traumatic infection; congenital osseous defects of the anterior
cranial fossa that facilitate communication between the epidural
space and the paranasal sinuses; and, rarely, dental infection
(78,84,85). The abscess expands as the pressure generated by
the growing inflammatory mass dissects the dura away from the
skull. As a result, an intracranial epidural abscess is a slowly
growing mass, the property that accounts for its insidious clini-
cal presentation. Intracranial abscesses rarely dissect beyond the
base of the skull because there the dura is even more tightly fixed.

FIGURE 32.12 Intracranial epidural abscess. Epidural frontal

abscess in a 41-year-old patient 5 months after meningioma
operation. The patient suffered from headaches, fever, and
(A) a supraorbital swelling (arrow). B: Using computed tomog-
raphy (bone window), the swelling (arrow) could be allocated
in close proximity to the clips (arrowhead) that were inserted
to hold the reinserted bone after trepanation. C: Although
native CT only revealed the extracranial swelling, (D) extra-
(arrow) and also intracranial (black arrowhead) inflammation
were observed after contrast enhancement was administered.
Histologic assessment of material gained from surgery revealed
granulocytic inflammation; a causative pathogen could not be
identified. (A, Courtesy of Dr. Nicole Terpolilli, Department of
Neurosurgery, Ludwig Maximilians University of Munich.)

Scheld_Ch32.indd 560 2/21/14 8:29 PM


Microbiology
The etiology of intracranial epidural abscesses is frequently
polymicrobial with the most common organisms includ-
ing anaerobic gram-positive cocci, Staphylococcus species,
Streptococcus species (in particular Streptococcus angino-
sus), and anaerobic gram-negative bacilli (84). Anaerobic
bacteria are cultured from many sinus-associated intra-
cranial epidural abscesses. Streptococci and staphylococci
(including Staphylococcus epidermidis and methicillin-resistant
Staphylococcus aureus) are the leading pathogens in postop-
erative epidural abscess (78,84).
Other organisms isolated from localized intracranial epi-
dural abscesses include Peptostreptococcus species, Salmonella
species, Klebsiella species, Proteus species, E. coli, Providencia
species, Citrobacter species, Serratia marcescens, Proteus
mirabilis, Haemophilus influenzae, Eikenella corrodens,
Bacteroides species, Propionibacterium acnes, Enterobacter
cloacae, Mycobacterium tuberculosis, Aspergillus fumigatus,
Pseudallescheria boydii, and Rhizopus species (mucormycosis)
(55,80,84,8688).
Clinical Manifestations
The slow-growing intracranial epidural abscess may cause few
symptoms other than fever, localized skull tenderness, dull
headache, nausea, vomiting, and lethargy (79). Papilledema
may develop with increasing intracranial pressure. When cra-
nial osteomyelitis is present, edema and cellulitis of the face and
scalp also may develop. Thus, although attention is focused on
the primary process such as sinusitis, cellulitis, skull fracture,
or a recent neurosurgical or otorhinologic procedure, a devel-
oping intracranial abscess may remain undetected. A recent
paper on 82 patients with cranial epidural abscess reported
that the prominent clinical features were fever (57%), frontal
subgaleal abscess (Pott puffy tumor, 46%), periorbital edema
(40%), headache (37%), meningismus (35%), and seizures
(11%) (78). In 23 cases of postoperative epidural abscess, the
most common sign was wound infection (95.7%), followed
by encephalopathy (44.7%), fever (34.8%), and headache
(17.4%) (80). Symptoms may be present for several weeks or
months before the diagnosis is made (78).
Scheld_Ch32.indd 561
Chapter 32: Epidural Abscess 561
FIGURE 32.13 Intracranial epidural abscess.
The 61-year-old patient had a history of previ-
ous meningioma operation and postoperative
bleeding within the operation site. A: T1-
weighted imaging shows a space-occupying
lesion (asterisk) with surrounding contrast
enhancement (arrows) and adjacent posterior
edema (number sign). B: Diffusion-weighted
imaging was hyperintense at the margin of
the lesion (asterisk). Enterobacter aerogenes
was isolated from surgical material.
Depending on the location of the abscess, focal neurologic
signs may develop as a result of continued expansion of the
inflammatory mass. However, in the aforementioned series of
82 patients, focal neurologic signs were present in only 4.9%
of patients (78). Involvement of the apex of the petrous tem-
poral bone and cranial nerves V and VI may lead to unilateral
facial pain and lateral rectus weakness (Gradenigo syndrome)
(89). Although the gradually expanding intracranial abscess
may remain localized, more often the dura cannot contain
the expanding epidural abscess. This may result from the
development of thrombosis of the valveless emissary veins that
run between the skull and meninges or it may result from direct
penetration through the necrotic dura. When this occurs, the
intracranial epidural abscess may be complicated by subdu-
ral empyema, brain abscess, or meningitis. The process may
be further complicated by venous sinus thrombosis, which,
though uncommon, is a serious complication (90). Because the
uncomplicated epidural abscess grows slowly, it is often the
striking manifestations of the complicationsmeningismus,
seizures, changing mental status, or comathat may be the
first indication of an intracranial process.
Approach to Diagnosis
In contrast to spinal epidural abscess, in an intracranial
epidural abscess, a microbiologic etiology is established far
more reliably from intraoperative cultures than from blood
cultures (80). Diagnosis is made by contrast-enhanced CT
or MRI. CT can detect a low-attenuation extraaxial mass
(84). Contrast CT in epidural abscesses reveals a thick me-
dial rim enhancement, which represents inflamed displaced
dura (Fig. 32.12). The degree of rim enhancement is usually
thicker and more irregular in an epidural abscess than in sub-
dural empyema. Calvarial osteomyelitis, subgaleal or sub-
periosteal abscesses, and frontal sinus inflammatory disease
are typically associated with intracranial epidural abscesses.
Large epidural abscesses can cause mass effect on the under-
lying brain (Fig. 32.14); however, in contradistinction to the
clinically more significant subdural empyema, an intracranial
epidural abscess rarely demonstrates parenchymal abnor-
malities on CT (Fig. 32.12C). As noted, it is important to
appreciate that an intracranial epidural abscess often coexists
2/21/14 8:29 PM
 562 Part III: Bacterial and Mycoplasmal Infections
with a subdural empyema, so presence of the former should
prompt a careful search for the latter.
Patients with postoperative and posttraumatic extraaxial
abscesses often present months to years following surgery or
head trauma, respectively (80). These patients may have signs
of local wound infection, but they generally show neither
systemic signs of infection nor neurologic changes. Patients
with postoperative and posttraumatic abscesses usually have
underlying structural brain lesions that may lead to the persis-
tence or the reaccumulation of these collections. Postoperative
abscesses occupy the cavity created by the craniotomy defect,
whereas posttraumatic abscesses are often an iatrogenic com-
plication of evacuation of a preexisting subdural or epidural
hematoma. Both postoperative and posttraumatic abscesses
are visualized as hypodense extraaxial collections with me-
dial rim enhancement on CT. Edema and mass effect on
the underlying brain are usually minimal and parenchymal
abnormalities are rare (91). The indolent clinical course and
the relatively benign radiographic findings are due to the pres-
ence of a discrete limiting membrane from prior surgery or
trauma, which serves to shield the underlying cerebral cortex.
Abscesses in these two clinical circumstances can be very dif-
ficult, if not impossible, to differentiate from noninfected ster-
ile effusions or chronic extraaxial hematomas. A change in
density of these collections on serial CT scans, associated with
subtle mass effect on adjacent brain, may be the first indica-
tion of an intracranial infection.
The morphology of posttraumatic intracranial epidural
abscesses on MRI corresponds to that seen on CTthat
is, lentiform or crescentic collections overlying a cerebral
Scheld_Ch32.indd 562
FIGURE 32.14 Intracranial epidural abscess.
Intracranial epidural abscess in a 55-year-
old patient 6 weeks after surgical interven-
tion necessary because of chronic subdural
hematoma. A: T1-weighted MRI showed a
contrast-enhancing (arrows) space-occupying
lesion (number sign) with (B) an increased
signal intensity on diffusion-weighted imag-
ing (number sign). C: Histology of surgical
material revealed mainly polymorphonuclear
granulocytes (arrows) and few lymphocytes
(arrowhead) (hematoxylin and eosin [H&E]
staining). D: On Gram stain, gram-positive
bacilli were detected that were later identified
as Propionibacterium species (arrow). E: In
Propionibacterium species cultures, Gram
stain typically reveals violet (gram-positive)
bacteria which can occur singularly (arrow-
head), in pairs (arrow), or in groups (dotted
arrow). (C, D, Courtesy of Prof. Dr. Armin
Giese, Center for Neuropathology and Prion
Research, Ludwig Maximilians University of
Munich; E, Courtesy of Dr. Andreas Wieser,
Max von Pettenkofer-Institute for Hygiene and
Microbiology, Ludwig Maximilians University
of Munich.)
convexity and/or in the interhemispheric fissure (Fig. 32.15).
MRI offers several advantages over CT in the evaluation of
patients with intracranial epidural abscesses. Specifically,
in otorhinologically induced abscesses, MRI can accurately
identify and delineate the collections (including small locu-
lations) early in the stage of disease, when the findings on
CT can be subtle (92). This ability of MRI is attributable to
the inherent high degree of contrast between the purulent
collections and the subjacent calvaria, brain, and CSF, com-
bined with the absence of streak artifacts from bone. The di-
agnosis of an intracranial epidural abscess can be confirmed
by diffusion-weighted imaging restriction (Figs. 32.13 and
32.15) (84,93). In postoperative and posttraumatic abscesses,
MRI can readily differentiate these collections from sterile
effusions and chronic extraaxial hematomas based on signal-
intensity differences, a distinction that is usually subtle or
undetectable on CT. Intracranial abscesses are usually mildly
hyperintense to CSF on T1-weighted images and more mark-
edly hyperintense to CSF on T2-weighted images (Figs. 32.5C
and 32.6). In contrast, sterile effusions are isointense to CSF
(92,94). Posttraumatic abscesses are hypointense on both T1-
weighted and T2-weighted images in contrast to most chronic
hematomas (94).
Lumbar punctures contribute little to the diagnosis of epi-
dural abscess, because the CSF findings are nonspecific, cul-
tures are usually negative, and there is a considerable risk of
neurologic deterioration following lumbar puncture because
of transtentorial or foraminal herniation (78). A lumbar punc-
ture should, therefore, not be performed in patients with sus-
pected or proven epidural abscess.
2/21/14 8:29 PM

FIGURE 32.15 Intracranial epidural abscess. The 59-year-old patient developed brain abscess 5 weeks
after surgery for meningioma. A: Transverse T1-weighted MRI showed a contrast-enhancing lesion
(asterisk) with (B) perifocal edema (number sign) on T2-weighted sequences. C: Diffusion-weighted
imaging revealed an increased signal intensity (asterisk).
Treatment
Therapy consists of surgical drainage of the epidural abscess
(formal craniotomy or drainage through burr holes or an ex-
tended craniectomy), surgical therapy of underlying infections,
and medical therapy. The medical therapy is that of brain
abscess (see Chapter 31). In brief, empirical antibiotic ther-
apy should usually include a third-generation cephalosporin
(e.g., ceftriaxone) and metronidazole in cases of community-
acquired epidural abscesses. Postoperative or posttraumatic
epidural cranial abscesses can be treated empirically with a
combination of vancomycin and meropenem. After culture
results, the therapy should be modified according to the
antibiogram.
The surgical therapy of an intracranial epidural abscess is
primarily aimed at drainage of the collection to prevent further
accumulation and neurologic damage while obtaining material
for culture. Burr holes may suffice, but craniotomy or craniec-
tomy may be required, particularly if overlying bone is involved.
Nathoo et al. (78) reported that they could adequately drain
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 CHAPTER 33 SUBDURAL EMPYEMA AND
SUPPURATIVE INTRACRANIAL PHLEBITIS
BARRY J. HARTMAN AND DAVID C. HELFGOTT
CRANIAL SUBDURAL EMPYEMA
Empyema is an important form of intracranial suppura-
tion, accounting for 15% to 25% of pyogenic intracranial
infections (13,97). It represents an infectious process that
occupies the space between the dura mater and arachnoid
surrounding the brain. Left undiagnosed and untreated, sub-
dural empyema is rapidly fatal, so early recognition is criti-
cal. In older children and adults, subdural empyema is most
often a complication of otorhinologic infection (1,419,98).
Subdural empyema may also occur as a result of head trauma
or surgery, osteomyelitis of the skull, or bacteremic spread
from a distant focus of infection. In infants, leptomeningi-
tis is the most common predisposing cause of subdural em-
pyema (11,20,21,97). Males predominate over females, and
about 70% of patients are in their second or third decade of
life (35,710,12,13,15,2226). Patients will present with
fever and headache in more than 90% of cases and many
will have associated neurologic abnormalities (1,39,12,13,
1519,21,23,24,2630,99,100,101). The diagnosis of subdu-
ral empyema is confirmed using computed tomography (CT)
or magnetic resonance imaging (MRI) scanning techniques.
However, a strong clinical suspicion despite the lack of evidence
for subdural empyema on scans warrants more invasive inves-
tigation. Definitive therapy consists of surgical drainage and
systemic antibiotics, yet mortality remains as high as 40% in
some series (14,21). Spinal subdural empyema also has been
described; however, it is quite rare, with fewer than 150 cases
reported in the literature (31,102). This condition is addressed
briefly later in the chapter. Suppurative intracranial phlebitis
is a serious complication of cranial and facial infections and
results in thrombosis of the major dural venous sinuses. This is
discussed at the end of this chapter.
Historical Perspective
The first comprehensive clinicopathologic descriptions of subdu-
ral empyema as a distinct entity were published in the 1940s,
although the first definitive report of subdural empyema dates
back to 1861 (32,33). This initial report was followed by sev-
eral more around the turn of the century, with a compilation of
44 cases by Blegvad (32) in 1910. Early names for this disease in-
cluded pachymeningitis interna, purulent pachymeningitis,
pia-arachnoid abscess, phlegmonous meningitis, and sub-
dural abscess, but these were rejected by Kubik and Adams in
favor of subdural empyema (8,32). Interestingly, early publica-
tions reported a preponderance of subdural empyema secondary
to otogenic infections (32). However, because of the compila-
tion of 42 confirmed cases resulting from frontal sinusitis by
Courville (33), it has become clear that paranasal sinusitis is the
most important causative factor in the development of subdural
empyema in older children and adults. During the past 50 years,
much has changed in the areas of therapy and diagnosis of sub-
dural empyema. Before the development of antibiotics, subdural
empyema was almost always fatal (32,33). Antibiotics, improved
566
Scheld_Ch33.indd 566
diagnosis, and newer surgical techniques have combined to lower
the mortality rate to 10% to 40% (1,4,5,715,21,22,24,28,29).
Physicians depended on their clinical skills and plain roentgeno-
grams of the sinuses and skull to direct their attention to the
possibility of intracranial suppuration, until the development
of cerebral angiography in the early 1960s, which proved an
extremely sensitive method of detecting a subdural collection
(13,34). The emergence of CT in the 1970s provided a noninva-
sive rapid means of visualizing the cranial contents; its reliability,
safety, and ease of operation made it the first choice for diagnosis
of suspected subdural empyema (2,10,26,35). Recently, MRI has
proven even more sensitive than CT (36).
Pathogenesis and Anatomic Considerations
The clinical features of subdural empyema are easily understood
if one considers the anatomy of the subdural space with respect
to its surrounding structures (Fig. 33.1). The subdural space is
normally a potential space rather than an actual space because
the dura mater follows the contours of the skull and lies adjacent
to the arachnoid and pia mater (37). The ability to form an actual
space with fluid collection is greater around the convexities of the
cerebral hemispheres where the brain does not approximate the
skull as closely as it does around the basal areas (15,22,33).
Posteriorly, the tentorium cerebelli is a reflection of dura
separating the cerebellum from the cerebral cortex (38). It is an
effective barrier to the passage of subdural collection infraten-
torially, except at its free anterior margin where fluid may seep
into the subdural space of the posterior fossa. Only about
10% of subdural empyemas are infratentorial (15,39,40).
Medially, the falx cerebri is a reflection of dura extending the
length of the cerebrum that separates the cerebral hemispheres
(38). Subdural fluid that accumulates between the falx and
the arachnoid are known as parasagittal, interhemispheric,
or parafalcine subdural empyemas and are usually second-
ary to surface subdural collections but rarely may be primary
(4143). A subdural empyema may communicate with the
contralateral side via the inferior free margin of the falx.
It therefore follows that infections or trauma of the head are
the usual causes of subdural empyema. Table 33.1 reviews the
conditions predisposing to subdural empyema in series reported
during the past two decades (excluding series of only infants).
Paranasal sinusitis overwhelmingly predominates as the precipi-
tating factor for the development of subdural empyema (101).
The sinusitis almost always involves a frontal sinus, often with
other sinuses affected as well. The incidence of subdural empy-
ema following frontal sinusitis is 1% to 2% (45). The frontal
and sphenoid sinuses are intimately associated with the dura
mater, separated from the dura only by a thin plate of bone.
These sinuses communicate with the maxillary and ethmoid
sinuses, which are more anteriorly placed. Because of its posi-
tion, the frontal sinus is almost always involved in paranasal
sinus infection that spreads to the subdural space. In addition,
the growing posterior wall of the frontal sinus during puberty
has been offered as a possible explanation for the striking
2/21/14 5:47 PM
 Chapter 33: Subdural Empyema and Suppurative Intracranial Phlebitis 567

Subarachnoid Superior
space sagittal sinus Arachnoid granulations
Calvaria Diploic vein
Epidural space (potential)
Skin
Dura mater (gray)
Galea aponeurotica
Subdural space
Pericardium Arachnoid
Superior cerebral vein mater (purple)
Cerebral artery Pia mater
(yellow)
Cerebral hemisphere
Falx cerebri

FIGURE 33.1 Diagram of the cranial cavity showing the location of the subdural and epidural spaces.
(From Moore KL, Agur AMR, Dalley AF. Clinically Oriented Anatomy. 7th ed. Baltimore: Lippincott
Williams & Wilkins; 2014.)

age susceptibility for the development of subdural empyema
(7,26,46).
Two modes of extension have been proposed for the spread
of infection from a frontal sinus to the subdural space: direct and
indirect (33). Direct extension involves erosion of the posterior
bony wall of the frontal sinus by infection, with further erosion
of the underlying dura mater (33). In teenagers primarily, fron-
tal bone osteomyelitis with subperiosteal abscesses (a Pott puffy
tumor) can extend directly into the subdural space (47,103).
The more likely route is indirect, with extension of infection
and associated thrombophlebitis through the mucosal veins of
the sinus to the emissary veins that link the facial and dural ve-
nous systems (15,33,48). From the dural sinuses, the infection
establishes itself in the subdural space at the frontal pole and
may spread posteriorly over the convexity, medially into the in-
terhemispheric region, and contralaterally. This extension may
create significant pressure on a large area of underlying brain
tissue (15,22,49). As stated previously, it is unusual but possible
for the empyema to spread infratentorially (15). Further retro-
grade thrombophlebitis often occurs, involving the valveless,
deeper veins of the cerebrum, which in turn may lead to necrosis
and infection of brain tissue (10,13,32,33). Subdural empyema

TA B L E 3 3 . 1
PREDISPOSING CAUSES OF SUBDURAL EMPYEMA

Reference No. No. of Patients Sinusitis Otogenic Head Trauma/Surgery Hematogenous Othera

Bradley and Shaw (1) 47 55% 13% 4% 4% 23%b

Mauser et al. (4) 37 59 12 15 0 15
Miller et al. (5) 23 35 30 26 4 4
Weisberg (6) 8 88 0 0 0 12
Hodges et al. (7) 4 100 0 0 0 0
Khan and Griebel (8) 15 40 7 27 13 13
Hockley and Williams (9) 42 74 12 0 2 12
Zimmerman et al. (10) 49 41 2 31 2 23
Smith and Hendrick (11) 25 32 12 28 4 24b
Bannister et al. (12) 66 68 21 3 3 5
Kaufman et al. (13) 17 41 6 24 6 24b
Le Beau et al. (14) 37 43 0 16 0 41b
Bhandari and Sarkari (15) 37 54 32 5 3 5
McIntyre et al. (16) 14 57 21 14 0 7b
Hoyt and Fisher (17) 17 53 12 0 0 35b
Dill et al. (18) 32 56 0 28 3 13b
Nathoo et al. (44) 699 67 9 8 0 16b
Cole et al. (100) 25 52 0 12 26b
total 1192 62 10 11 1 16
range 32100 032 031 013 041

a
Includes facial infections, local osteomyelitis, unknown.
b
Includes infants with meningitis.

Scheld_Ch33.indd 567 2/21/14 5:47 PM

 568 Part III: Bacterial and Mycoplasmal Infections
secondary to an otogenic source of infection differs only in the
site at which pus enters the subdural space. The tympanic cavity
is bounded superiorly by the tegmen tympani, a thin plate of
bone forming part of the temporal bone of the skull separating
the tympanic cavity from the brain (37). Perforating veins pass
through this plate of bone to communicate with the superior
petrosal venous sinus of the dura (37). In addition, mastoid air
cells within the temporal bone surrounding the middle ear com-
municate with the tympanic cavity and may lie very close to
the posterior cranial fossa separated from the dura by slivers of
bone (37). Otitis or mastoiditis may, therefore, extend directly
into the subdural space via erosion of the tegmen tympani or
bone adjacent to the air cells and dura mater or spread infection
indirectly by way of a progressive thrombophlebitis of the per-
forating veins (27,32). Because the venous sinuses into which
the veins from the middle ear and mastoid bone drain are within
or beneath the tentorium (38), otogenic infection may result in
posterior fossa subdural empyema (27). As opposed to subdural
empyema secondary to frontal sinusitis, otitis-induced subdural
empyema is initially localized posteriorly or on the tentorium
(50). Hematogenous spread of bacteria to the subdural space
from a distant site of infection is an uncommon cause of subdu-
ral empyema, accounting for fewer than 5% of all cases in most
series (Table 33.1). Several reports describe the development
of subdural empyema via hematogenous spread to a preexist-
ing subdural hematoma (51,52). Subdural empyema is a rare
complication following cranial surgery; in one series, subdural
empyema occurred in slightly more than 1 in 1,000 cranioto-
mies (53). In a large series of 16,540 craniotomy procedures
from 1997 to 2007, only 0.5% had intracranial infection (only
7 cases were pure subdural infections) (104).
In adults, the extension of a subdural empyema from acute
purulent meningitis is very unusual. Although there is a sub-
arachnoid inflammatory exudate, the arachnoid is fairly im-
permeable to the bacterial process occurring adjacent to it
(22). Bacterial meningitis in adults is a very unusual cause
of subdural empyema, occurring in less than 1% of cases
(21,105). However, in infants, meningitis is an important pre-
disposing condition for the development of a subdural empy-
ema (11,20,21,97,100). Subdural empyema occurs in about
2% of infants with bacterial meningitis (54). The pathogenesis
is presumably infection of an initially sterile subdural effu-
sion (13,20,21). Such sterile effusions are variably reported as
occurring in up to 60% of infants with meningitis (13,20,97).
Clinical Features
A high clinical suspicion and rapid diagnosis of subdural
empyema are critical for a successful outcome. Certainly, an adult
with a recent history of sinusitis and a new presentation sugges-
tive of central nervous system (CNS) infection warrants an inves-
tigation to exclude subdural empyema. However, in some cases,
the antecedent infection is subtle enough to be unrecognized. In
others, the concurrent complication of sinusitis with a subdural
empyema delays the diagnosis of the latter because symptoms are
attributed to the sinusitis. In other cases, the subdural empyema
is not suspected because the precipitating cause for the subdural
empyema is unknown or arises from a distant focus of infection.
Although the clinical presentation may vary, there are key clinical
features of subdural empyema that if present should result in its
inclusion in ones initial differential diagnosis. The sex and age dis-
tributions of patients with subdural empyema are striking. There
is an overrepresentation of men reported in series of patients
(mostly adults) with subdural empyema published during the last
two decades. In those that report only children, males also pre-
dominate. However, in infants, this sex discrepancy may not be
so marked (35,710,12,13,15,16,18,19,2226,54,99,100,106).
Scheld_Ch33.indd 568
50
Percent of Patients
40
30
20
10
0
1 2 3 4 5 6 6
Decade of Life
FIGURE 33.2 Age distribution of patients reported with subdural
empyema.
Figure 33.2 displays the age distribution of patients reported in
series of consecutive patients with subdural empyema. It is clear
that most cases occur during the second and third decades of
life. As stated earlier, the significant growth of the frontal sinus
during puberty has been proposed as an explanation for the un-
even age distribution (7,26,46). However, confirmatory analyses
comparing patients sex, age, and source of infection have not
been reported.
The clinical features of adults with subdural empyema are
presented in Table 33.2. Generally, patients have a nonspecific
illness for a few days to a few weeks before presentation to the
hospital acutely ill (1,5,12,13). However, if the infection is a re-
sult of head trauma or surgery, the symptoms may be milder and
present more subacutely (10,23,55,56,104). The most common
symptoms and signs are headache, fever, neurologic deficit, and
stiff neck. Vomiting and malaise are often reported as well (8,15).
Seizures, papilledema, and altered level of consciousness ranging
from drowsiness and disorientation to coma also occur frequently.
These neurologic changes may be presenting signs or, as is often
the case, may develop during the course of the illness (6,7,15,28).
Diffuse neurologic signs such as altered level of conscious-
ness, papilledema, and generalized seizures are a result of
increased intracranial pressure (ICP) (33,57). Focal neurologic
abnormalities such as hemiparesis, jacksonian seizures, dys-
phasia, and cranial neuropathies may be secondary to local
pressure on the underlying cortex by the subdural process
(21,27,32,33,41,49,58) and may be precipitated by cortical
venous thrombosis with accompanying brain inflammation
and infarction (21,22,57). Such focal neurologic signs may
help to localize the empyema. This is particularly true in cases
of infratentorial subdural empyema that occurs infrequently,
but that is easily suspected if cerebellar signs such as ataxia and
nystagmus are present (27). Interhemispheric (parasagittal,
parafalcine) subdural empyema, usually associated with dis-
ease over the convexities but uncommonly occurring alone
(43), characteristically produces contralateral leg symptoms,
including weakness and focal seizures (41,43,49,58). As the
interhemispheric suppuration extends backward over the ten-
torium and below the occipital lobes, homonymous hemiano-
pia may result (49,58). Subdural empyema overlying one or
both convexities yields the most nonspecific neurologic signs.
Clues to the involved areas can be (a) contralateral paresis or
seizures, (b) aphasia or dysphasia associated with left-sided
infection, or (c) cranial neuropathies (32,33,49). The clinical
signs of subdural empyema in infants are similar to those in
adults. In addition, a bulging anterior fontanelle is a common
finding in infants (11,20,54).
2/21/14 5:47 PM
 Chapter 33: Subdural Empyema and Suppurative Intracranial Phlebitis
TA B L E 3 3 . 2
CLINICAL SIGNS OF SUBDURAL EMPYEMA
Signs/Symptoms % No. of Patientsa
Fever 78
Headache 74
Hemiparesis 71
Altered consciousness 69
Nuchal rigidity 60
Seizures 49
Papilledema 33
Altered speech 22
b
Other focal deficits 46
a
Total number of patients in whom finding was assessed.
b
Includes cranial neuropathies, hemianopia, other.
Differential Diagnosis
The cardinal features of headache, fever, stiff neck, and neuro-
logic signs are not specific for subdural empyema. The differ-
ential diagnosis also includes brain abscess, epidural abscess,
meningitis, meningoencephalitis, subdural hematoma, and in-
tracerebral thrombophlebitis (21,48). Of these, the presence of
focal neurologic signs makes meningitis much less likely. The
presence of nuchal rigidity is unusual in brain abscess and sub-
dural hematoma. Unfortunately, clinical grounds alone do not
allow the exclusion of most of these possibilities. Therefore,
more specific testing should be undertaken as soon as the diag-
nosis of subdural empyema is suspected.
Diagnostic Studies
Routine studies such as blood tests and plain roentgenograms
are of very little value in patients with suspected subdural em-
pyema. Most patients are found to have a peripheral blood
leukocytosis (3,11,13,27,30,33). Plain films of the skull are
not useful except to demonstrate a sinusitis or mastoiditis or
to show widened sutures in infants (21). In infants, cranial
ultrasonography can detect a subdural collection and may
differentiate a reactive effusion from a subdural empyema
(107). Before the development of CT, cerebral arteriography,
with a diagnostic accuracy of 80% to 90%, was the proce-
dure of choice to diagnose subdural empyema (13,15,21,27).
Although nearly perfect for the detection of hemispheric and
parafalcine subdural collections, the sensitivity of carotid
angiograms for posterior fossa subdural empyema was not
as great (27). Presently, the safety, ease of application, and
reliability of CT and MRI make them the modalities of choice
to diagnose subdural empyema.
Computed Tomography and Magnetic
Resonance Imaging
The radiologic evaluation of patients with subdural and epi-
dural empyemas has been revolutionized by the advent of CT
in 1972 and MRI in 1984. The introduction of CT has had a
major impact on the management and prognosis of subdural
and epidural empyemas because CT allows (in a noninvasive
manner) earlier and more accurate detection, delineation, and
Scheld_Ch33.indd 569
569
References
451 3, 4, 69, 13, 1519, 21, 23, 26, 27, 30, 99
467 39, 13, 1519, 21, 23, 24, 26, 27, 30
389 35, 79, 13, 17, 18, 21, 23, 24, 26, 28, 30
544 1, 39, 12, 13, 15, 1719, 21, 23, 27, 30
416 4, 68, 13, 1519, 21, 23, 24, 26, 27, 29, 30
607 49, 13, 1519, 21, 23, 24, 26, 28, 29, 30,99
238 69, 13, 15, 17, 18, 21, 24, 26, 27, 30
364 36, 8, 9, 15, 18, 24, 26, 28
296 59, 13, 15, 18, 24, 26, 28, 30, 99
characterization of these extraaxial (extraparenchymal) inflam-
matory lesions and their associated intraaxial (parenchymal)
sequelae when compared to carotid arteriography (10). In ad-
dition, CT provides an important adjunct to standard clinical
parameters in the assessment of the adequacy of patient re-
sponse to therapy. The CT, findings during the early stages of
development of a subdural empyema may be subtle and easily
overlooked (10). Noncontrast CT scans typically demonstrate a
crescentic hypodense collection over one or both cerebral con-
vexities and/or around the interhemispheric tissue (Fig. 33.3A).
Contrast-enhanced CT increases the conspicuity of the collec-
tions that represent active inflammatory disease either in the
leptomeninges or in the subjacent cerebral cortex (Fig. 33.3B).
Thick, irregular enhancement of the falx in association with
a spindle-shaped collection is seen in interhemispheric subdu-
ral empyemas (43) (Fig. 33.4). Parenchymal changes at this
early stage include thickening and hyperdensity of the underly-
ing cortical gray matter and hypodensity of the white matter
on noncontrast CT images; these changes indicate the presence
of edema, hyperemia, and ischemia (10). Additionally, gyral
enhancement subjacent to an extraaxial empyema on con-
trast CT scans is a common finding, indicative of meningitis,
cerebritis, and/or venous thrombosis (Fig. 33.3B). Extensive
mass effect on the ipsilateral cerebral hemisphere that is out
of proportion to the small size of the extraaxial collection is
invariably present, and it is manifested as ventricular compres-
sion, sulcal effacement, and midline shift. It is important to
examine the paranasal sinuses, middle ear cavity, and orbits
for the presence of inflammation, which may reflect the origin
and extent of the intracranial abnormalities (26,29) (Figs. 33.5
and 33.6A).
Unrecognized and untreated, the subdural empyema rap-
idly grows and develops loculations and the parenchymal
abnormalities progress to cortical infarction and abscess
formation. MRI is proving to have a greater sensitivity and
specificity in the workup of patients with an extraaxial
empyema; this is attributed to several inherent advantages of
MRI over CT (36,59,60). MRI uses several standard pulse
sequences referred to as T1 weighted, proton-density
weighted, and T2 weighted (61). T1-weighted images
emphasize contrast between the brain and cerebrospinal fluid
(CSF), and proton-densityweighted and T2-weighted images
emphasize contrast between brain and pathologic processes
(61) (Fig. 33.6B and C).
2/21/14 5:47 PM
 570 Part III: Bacterial and Mycoplasmal Infections

A B

FIGURE 33.3 Subdural and epidural empyemas due to

paranasal sinus inflammatory disease. A: Noncontrast
computed tomographic (CT) scan of the brain demonstrat-
ing right hemispheric edema with compression of the right
lateral ventricle. No definite empyema is seen. B: Contrast-
enhanced CT scan demonstrating a right convexity sub-
dural empyema with a thin rim of marginal enhancement
(large arrows) and gyral enhancement (small arrows).
Note the disproportionate degree of mass effect on the
underlying brain with ventricular compression when com-
pared to the size of the empyema.

MRI has been found to have six inherent advantages over
CT. First, MRI permits excellent visualization of superficial
brain anatomy, precise localization of extraaxial empyemas
(Fig. 33.4C), and more definitive separation of extraaxial col-
lections from their associated intraaxial complications such
as edema, cerebritis, and venous thrombosis, which are more
readily visualized on MRI than on CT (36,62). Second, streak
artifacts from the bony calvaria, which are particularly prob-
lematic on CT, are not limitations on MRI. Third, MRI is su-
perior to CT in differentiating noninfected subdural effusions
and hygromas from infected empyemas. As with other protein-
aceous fluids, the T1- and T2-weighted values of purulent col-
lections are smaller than those of CSF. These collections are,
therefore, mildly hyperintense to CSF on T1-weighted images
and markedly hyperintense to CSF on T2-weighted images
(36). Fourth, the unprecedented sensitivity of MRI to subtle
changes in tissue water content is uniquely suited to the goal
of early detection of the parenchymal abnormalities that can
occur secondary to a subdural empyema. Fifth, MRI is more
specific than CT in differentiating a subdural from an epidural
empyema (36,63). A hypodense medial rim, representing in-
flamed displaced dura, is seen on MRI of an epidural empyema
but not on that of a subdural empyema. Finally, the delineation
of extraaxial inflammatory disease, leptomeningeal disease,
and parenchymal abnormalities is improved with the use of
the MRI contrast agent, gadolinium diethylenetriamine pen-
taacetic acid (64), and diffusion-weighted imaging (108,109).
CT and MRI play a role in the follow-up of patients
with extraaxial empyemas (10,36,59). Residual or recur-
rent collections that may necessitate reexploration are par-
ticularly prone to occur in the parafalcine or subtemporal
regions. These locations are well imaged on MRI because
of its ability to obtain direct coronal sections of the brain.
Long-term follow-up CT or MRI examinations frequently
demonstrate cortical atrophy adjacent to a previous extra-
axial empyema.

A B C

FIGURE 33.4 Otorhinologically induced subdural empyema. A: Contrast-enhanced computed tomo-

graphic scan demonstrating subtle right hemispheric empyema. B: Interhemispheric subdural empyema
(arrows) delineated by the falx medially and with early membrane formation laterally. C: T2-weighted
MRI scan taken the same day. Note the improved visualization of the right convexity compared to that of
A (long arrows); also note the interhemispheric subdural empyema (short arrows) and the inflammatory
disease in the frontal sinus (arrowheads).

Scheld_Ch33.indd 570 2/21/14 5:47 PM

 Chapter 33: Subdural Empyema and Suppurative Intracranial Phlebitis 571

In addition to providing no valuable diagnostic informa-

tion, lumbar puncture is a potentially dangerous procedure
in patients with signs of increased ICP (66). Several deaths
from cerebral herniation have been reported in patients with
subdural empyema shortly after undergoing lumbar puncture
(13,25,26,40,44). Certainly, patients with papilledema or a
focal neurologic abnormality or patients with suspected in-
creased ICP should not undergo a lumbar puncture.

FIGURE 33.5 Contrast-enhanced computed tomographic scan of the
paranasal sinuses demonstrating extensive maxillary, ethmoid, and
sphenoid sinus inflammation (arrows).
Lumbar Puncture
Lumbar puncture is often performed in patients who are sub-
sequently diagnosed with subdural empyema, but it is neither
sensitive nor specific for this disease. Recovery of a causative
organism in the CSF is rare, except in infants in whom men-
ingitis preceded the development of the subdural empyema
(11,20,21,54). The CSF formula in children and adults with
subdural empyema is unpredictable, as shown in Table 33.3.
Typically, the white blood cell (WBC) count is elevated; how-
ever, many series report patients with zero to five CSF leu-
kocytes per cubic milliliter (13,25,26,29,30). The differential
cell count on the CSF is highly variable: although a polymor-
phonuclear pleocytosis is more common, the mononuclear cell
predominates in close to 40% of patients. A normal protein
concentration suggests the absence of a subdural empyema be-
cause there is an inflammatory response by the arachnoid to
the overlying subdural process. However, because the arach-
noid is generally impermeable to the infectious agent, CSF
Gram stain and culture almost never demonstrate the bacterial
cause of the subdural empyema and are, therefore, not helpful
in choosing antibiotic therapy.
Bacteriology
The microbiologic etiology of subdural empyema is established
by Gram stain and culture of evacuated pus from the subdural
space. Unfortunately, cultures of subdural pus are sterile in
about one third of patients (25) because patients are almost
always receiving antibiotics preoperatively. It has been sug-
gested that the high number of negative cultures is also related
to the lack of proper handling and culture for anaerobes (25).
In one study in which paranasal sinus cultures and subdural
cultures were compared, three of the four sinus isolates did
not correlate with the subdural isolates (26). Blood cultures
may provide additional diagnostic information in about 10%
of cases in which the subdural fluid is sterile (11,21,26). The
organisms cultured most often from subdural infections are
aerobic and anaerobic streptococci. Staphylococci are cultured
less often, followed by aerobic gram-negative bacilli and non-
streptococcal anaerobes (Table 33.4). In most patients, a single
organism is responsible for subdural empyema. However, sev-
eral series have included cases in which multiple organisms
have been cultured (3,5,7,16,17,19,21,22,25,27).
Generally, the causative organism is predictable based
on the anatomic focus from which the infection originated
(3,5,8,13,45,55,56,100). Otorhinogenic subdural empyemas
are most often due to aerobic and anaerobic streptococci and
are less often due to coagulase-positive staphylococci and
other anaerobes. Infections secondary to head trauma, sur-
gery, or an indwelling foreign device are most often caused
by coagulase-positive and coagulase-negative staphylococci
and gram-negative bacilli. Four cases of postneurosurgical

A B C

FIGURE 33.6 Subdural empyema in the setting of orbital and paranasal sinus inflammatory disease. A,
left: Contrast-enhanced computed tomographic (CT) scan demonstrating a right orbital abscess (long
arrows) and ethmoid sinusitis (short arrows). Proton-density MRI scan (B, center) and T2-weighted
MRI (C, right) taken the same day as for A, demonstrating a small right convexity subdural collection
(arrows), which is brighter than CSF in B and which is, therefore, not a sterile effusion or hygroma. Note
that the conspicuity of the empyema on MRI is greater than that on CT.

Scheld_Ch33.indd 571 2/21/14 5:47 PM

 572 Part III: Bacterial and Mycoplasmal Infections

TA B L E 3 3 . 3
CEREBROSPINAL FLUID FINDINGS IN SUBDURAL EMPYEMA

CSF Parametera No. of LPs with Parameter Reported Number (%) References

5 WBCs 108 11 (10%) 68, 13, 21, 23, 2527, 29, 30, 57, 65
6499 WBCs 94 63 (67) 8, 13, 21, 23, 2527, 29, 30, 57, 65
500999 WBCs 94 8 (9) 8, 13, 21, 23, 2527, 29, 30, 57, 65
1,000 WBCs 94 15b (16) 8, 13, 21, 23, 2527, 29, 30, 57, 65
50% polys 64 43 (67) 8, 13, 21, 23, 2527, 29, 30, 57, 65
Elevated proteinc 93 76 (82) 7, 8, 13, 23, 2527, 29, 30, 57, 65
Normal glucosed 72 66e (92) 7, 8, 13, 21, 23, 25, 26, 29, 57, 65
Positive Gram stain 34 2 (6) 68, 25, 27, 65
Positive CSF culture 156 14b (9) 68, 13, 16, 19, 21, 23, 2527, 29, 30, 65, 100

LP, lumbar puncture.

a
From series with more than three lumbar punctures reported.
b
Two with preceding bacterial meningitis.
c
Reported as elevated or 50 mg/100 mL.
d
Reported as normal or 50 mg/100 mL.
e
Four of six with decreased glucose with bacterial meningitis or preceding neurosurgery.

subdural empyema caused by Propionibacterium acnes, a Treatment and Outcome

gram-positive anaerobic bacillus, were reported often occur-
ring several weeks after the surgical procedure (67,68). The clinical suspicion of subdural empyema requires the im-
Subdural empyemas originating from distant foci of infection mediate institution of parenteral antibiotic therapy. Antibiotics
are caused by a variety of organisms. In infants with leptomen- should be chosen based on the suspected source of the infec-
ingitis, subdural empyema is caused by the same organism re- tion and on the organisms known to commonly cause subdural
sponsible for the meningitis, usually Streptococcus pneumoniae empyema. Although no prospective comparisons of antibiotic
or Haemophilus influenzae (21,54). Many organisms other than regimens for subdural empyema have been conducted, an
those mentioned have been reported to cause subdural empy- acceptable empirical therapy includes a -lactamasestable
ema. These include Salmonella species (69,70), Campylobacter penicillin, a third-generation cephalosporin, and metroni-
fetus (52), Serratia marcescens (71), Neisseria meningitidis dazole. Depending on the prevalence of methicillin-resistant
(72,73), Pasteurella multocida (52,74), Actinomyces israelii, Staphylococcus aureus or the likelihood of coagulase-negative
and Actinobacillus actinomycetemcomitans (new genus name staphylococci, vancomycin may be used in place of the
Aggregatibacter) (75). In the Far East, a greater percentage of bac- -lactamasestable penicillin. Although there is no consensus,
terial pathogens are gram-negative aerobes (Enterobacteriaceae), some advocate irrigation of the subdural space with antibiotics
particularly Klebsiella pneumoniae (110). (2,8,9,12,14,49). No current data support a specific duration
of antibiotic therapy; however, most patients are treated for 3
to 4 weeks after drainage (21). Empirical therapy for seizure
TA B L E 3 3 . 4 prophylaxis has been advocated (8,13,28,45), and steroids
and mannitol have been used successfully to decrease ICP in
MICROBIOLOGY OF ADULT SUBDURAL EMPYEMA
individual cases (5,13,24).
Organism Incidencea Although anecdotal cases have been successfully treated with
antibiotics alone (76,77), surgical drainage of a subdural empy-
Streptococci ema is imperative. Disagreement exists, however, over the opti-
mal mode of surgery. The comparative efficacy of multiple burr
Aerobicb 36%
holes versus craniotomy is complicated by clinical factors that
Anaerobic 10% may contribute to outcome. Several parameters have been sug-
Staphylococci gested to be important in predicting patient mortality, includ-
Coagulase positive 9% ing age of patient (12), source of infection (12), microbiology
(12), time from presentation to surgery (13), management of
Coagulase negative 3% the primary source of infection (1), extent of spread of empy-
Aerobic gram-negative bacillic 10% ema (4), level of consciousness at presentation (1,4,79,12,27),
Other anaerobes 6% and surgical technique (4,5,79,12,14,22,24,27). Analysis of
the few reviews that correlate the primary source of infection
Sterile 29%
with ultimate outcome suggest that subdural empyema second-
a
ary to paranasal sinusitis is associated with less overall mortality
Over 200 evaluable cases from references 35, 7, 8, 12, 13, 1619, compared to other primary sources of infection (1,3,1214,18).
2123, 2527, 30; total greater than 100% because of multiple
isolates from single cases. However, level of consciousness at presentation and surgi-
b
Includes -, -, nonhemolytic. cal technique have correlated better with outcome in several
c
Mostly enteric bacilli. studies. Table 33.5 compares patient mortality with level of
consciousness at presentation. Those patients presenting awake

Scheld_Ch33.indd 572 2/21/14 5:47 PM

 Chapter 33: Subdural Empyema and Suppurative Intracranial Phlebitis 573

TA B L E 3 3 . 5
ASSOCIATION OF LEVEL OF CONSCIOUSNESS WITH MORTALITY IN SUBDURAL EMPYEMA

Grade

I II III IV
Reference No. Deaths No. Deaths No. Deaths No. Deaths

Bradley and Shaw (1) 20 0 18 9 0 0 5 5

Mauser et al. (4) 16 1 36 5 22 6 24 10
Hodges et al. (7) 0 0 5 0 7 0 2 2
Khan and Griebel (8) 2 0 8 0 4 1 1 1
Hockley and Williams (9) 7 1 22 1 0 0 13 5
Bannister et al. (12) 22 2 30 10 6 1 8 6
Dill et al. (18) 13 0 12 0 5 2 2 1
Morgan and Williams (27) 1 1 4 1 0 0 2 2
total 81 5 135 26 44 10 57 32
% Deaths 6% 19% 23% 56%

I, awake and alert; II, drowsy and disoriented; III, responsive to painful stimuli; IV, unresponsive to pain.

and alert (grade I) have the greatest chance of survival and those
presenting unresponsive to pain (grade IV) are least likely to
survive. Patients who are drowsy and disoriented (grade II) or
responsive only to painful stimuli (grade III) have intermediate
survival statistics. Of the survivors, decreased level of conscious-
ness at presentation correlates with more severe neurologic
sequelae (4,7,8).
Several groups have advocated craniotomy over burr-hole
drainage, citing increased survival in the group treated by
craniotomy (4,5,79,12,14,22,24,27,44) (Table 33.6). The
advantage of craniotomy is considered to be related to the
greater ease of evacuating pus from a larger area. Few inves-
tigators, however, have considered the level of patients con-
sciousness when evaluating mortality of the surgical groups.

TA B L E 3 3 . 6
COMPARATIVE SURVIVAL RATES FOR SURGICAL APPROACHES TO SUBDURAL EMPYEMAS

Burr Holes Craniotomy

Reference No. Deaths % No. Deaths %

Mauser et al. (4) 46 11 24 47 10 21

Miller et al. (5) 18 4 22 4 1 25
Hodges et al. (7) 11 1 9 2 0 0
Khan and Griebel (8) 9 1 11 5 1 20
Hockley and Williams (9) 22 6 27 20 1 5
Bannister et al. (12) 15 7 47 24 2 8
Le Beau et al. (14) 11 8 73 26 6 23
Dill et al. (18) 8 1 12 22 2 10
Bok and Peter (19) 44 3 7 45 4 9
Feuerman et al. (22) 11 2 18 7 0 0
Borzone et al. (24) 2 0 0 12 2 17
Morgan and Williams (27) 3 3 100 4 1 25
Skelton et al. (30) 3 0 0 7 0 0
Nathoo et al. (44) 90 21 23 322 26 8
Matt Nayan et al. (111) 50 2 4 40 4 10
Liu et al. (97) 18 15
total 361 70 19 602 60 10
range 0100 025

Scheld_Ch33.indd 573 2/21/14 5:47 PM

 574 Part III: Bacterial and Mycoplasmal Infections

In several studies in which both the level of consciousness and
the mode of surgery are established, it is notable that patients
with grades III and IV coma were more likely to undergo burr-
hole drainage (5,7,22,27). In fact, Mauser et al. (4) report a
higher death rate in the craniotomy group when patients pre-
senting with grades III and IV consciousness are considered
but lower mortality in the craniotomy group among patients
with grades I and II consciousness. Hence, the increased sur-
vival with craniotomy may be related, in part, to its more
frequent use in a patient population starting with a better
prognosis. A study by Nathoo et al. (44) of 699 patients with
subdural empyema reported improved mortality rates using
craniotomy rather than burr holes or limited craniectomy re-
gardless of severity of disease. However, a good outcome was
achieved in 71% of those undergoing burr-hole drainage and
86% undergoing craniotomy. Nathoo et al. (44) suggest that
craniotomy provides the best decompression of the brain and
the most complete evacuation of pus. The optimal treatment
for all patients remains unclear; however, regardless of the
initial surgical approach (multiple burr holes vs. craniotomy),
several studies report a number of patients requiring reopera-
tion (4,7,9,98). Several studies have documented increased
reoperation rates in those patients treated with burr holes
compared to craniotomy, with one study having a reoperation
rate of 50% with burr holes compared to only 20% in the
craniotomy group (4,98).
The overall mortality of subdural empyema and the extent
of neurologic sequelae reported in survivors are summarized in
Table 33.7. In the past, mortality rates averaged 11% to 12% and
morbidity rates were 17% to 45% (98). Some recent studies with
aggressive antibiotic and surgical approaches have reduced the
mortality to less than 5% and morbidity to less than 13% (98).
The potential extent of neuroanatomic sequelae is illustrated by
necropsy studies (33). Venous sinus thrombosis is a common
finding in patients with subdural empyema because the route
of infection to the subdural space is generally via these venous
sinuses. As a result of the absence of valves in the venous system
of the brain, thrombophlebitis may extend to the cortical and
subcortical veins of the cerebrum. Thrombosis of these vessels
results in venous stasis and subsequent congestion and softening
of adjacent brain tissue. Brain infarction and necrosis (Fig. 33.7),
with or without abscess formation, may ensue. Therefore, clini-
cal neurologic sequelae may be a consequence of brain abscess or
brain infarction secondary to increased ICP or venous thrombo-
sis. More than 10% of patients with subdural empyema develop
venous sinus thrombosis or brain abscess (13,33,45).

TA B L E 3 3 . 7
MORTALITY AND NEUROLOGIC SEQUELAE OF SUBDURAL EMPYEMA

% Sequelae in Survivors

References Total Cases % Mortality Severea Mild/Moderateb Seizures

Bradley and Shaw (1) 47 32

Mauser et al. (4) 102 26 18 18 29
Miller et al. (5) 23 17 5 11 37
Hodges et al. (7) 14 14
Khan and Griebel (8) 15 15 15 31 46
Hockley and Williams (9) 42 17
Zimmerman et al. (10) 49 12
Smith and Hendrick (11) 22 1
Bannister et al. (12) 66 29
Kaufman et al. (13) 17 35
Le Beau et al. (14) 37 40
Bhandari and Sarkari (15) 37 34 16 32
McIntyre et al. (16) 14 21
Hoyt and Fisher (17) 17 12
Dill et al. (18) 32 9 38 10 3
Bok and Peter (19) 90 8 5 10
Farmer and Wise (21) 17 41 0 33 11
Feuerman et al. (22) 22 14 25 48 8
Borzone et al. (24) 14 14 8 42 37
Cowie and Williams (28) 89 27 0 23 34
Renaudin and Frazee (29) 23 22
Skelton et al. (30) 10 0 0 20 20
Matt Nayan et al. (111) 90 7 0 11
Cole et al. (100) 42 5 20
Legrand et al. (98) 23 4 13

a
Disabling hemiparesis or aphasia.
b
Sequelae not inhibiting activity.

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 Chapter 33: Subdural Empyema and Suppurative Intracranial Phlebitis
A gens were Mycobacterium tuberculosis and Echinococcus
B commonly suppurative intracranial phlebitis of the dural
FIGURE 33.7 Two-year-old child with Haemophilus influenzae men-
ingitis. A, top: Contrast-enhanced computed tomographic (CT) scan
demonstrating extraaxial collections over both frontal convexities and
in the anterior aspect of the interhemispheric fissure (arrows). Note
the similarity of these collections to the CSF in the ventricular sys-
tem, making it difficult to distinguish them from sterile effusions and
prominent subarachnoid spaces. Spinal tap revealed purulent men-
ingitis. B, bottom: Follow-up CT scan 2 months later demonstrates
extensive zones of infarction and hydrocephalus.
SPINAL SUBDURAL EMPYEMA
Spinal subdural empyema is a rare condition, with fewer
than 80 cases previously reported in the literature, with most
reports from the Western Hemisphere in patients in their
sixth and seventh decade of life. In 2013, Sandler et al. (112)
reported 11 cases of spinal subdural empyema in children
throughout the world and reviewed 73 additional cases. The
median age was 6.5 years with 38% of cases younger than
3 years of age and 15% younger than 1 year of age. Most
of the children were male (2:1 ratio) and 53% were associ-
ated with spinal congenital abnormalities. Fifty-six percent
of cases lived in the Eastern Hemisphere with only 17% from
the United States.
In adults, signs and symptoms include fever, back pain,
and subsequent signs of spinal cord compression (7880).
Scheld_Ch33.indd 575
575
It can be distinguished from spinal epidural abscess by the
absence of tenderness to palpation in most cases of spinal
subdural empyema (78,79,81,102). In children, however,
spinal tenderness is more common (112). Therefore, in chil-
dren, the clinical presentation may be difficult to differenti-
ate from acute transverse myelitis. Spinal subdural empyema
most commonly occurs in the thoracolumbar spine, although
subdural infection of the cervical spine has been reported
(31,80,8285,112).
Spinal subdural empyema most often arises as a result
of hematogenous spread of infection to the spinal subdural
space, with S. aureus being the most common etiologic agent
(78,102). Other reported pathogens include streptococci
(31,86), coagulase-negative staphylococci (79,87), and gram-
negative bacilli (78,80). Occasionally, this may arise from local
trauma or surgical procedures including incidental dural tears
(113,114) and even acupuncture (115). In a series of child-
hood spinal subdural empyema, the most common patho-
granulosis (112).
Diagnosis is best accomplished by MRI with gadolinium
with decreased signal on T1 and increased signal on T2. Fat-
suppressive techniques with MRI help define the subdural
space (112). Metrizamide-enhanced spinal CT can be used
in areas where MRI is not available or is contraindicated.
Treatment consists of empirical antibiotic therapy initially
directed against S. aureus, streptococci, and gram-negative
enteric bacilli, in association with laminectomy for drainage
of the empyema. Antibiotics can then be adjusted based on
specific culture results for a duration of 2 to 4 weeks.
SUPPURATIVE INTRACRANIAL
PHLEBITIS
Infections within the sinuses or facial structures can lead to
intracranial complications that include subdural empyema,
cerebral abscesses, epidural abscesses, meningitis, and less
veins. Suppurative phlebitis can occur as a primary complica-
tion or as a secondary complication to other intracranial infec-
tions such as subdural empyema (Table 33.8).
Pathogenesis
Infection usually spreads to the dura via venous drainage
from the sinuses (91), middle ear, face, or scalp. Within the
dura mater are seven paired venous sinuses and five unpaired
sinuses, all of which are spaces between two layers of dura.
They collect blood from the veins of the brain, skull, and
face, and they empty into the internal jugular veins (38).
Emissary (perforating) veins allow the passage of blood
from the larger veins of the face and scalp into the dural
venous sinuses, serving as a potential communication for
more superficial infection of the head with the venous system
of the brain (37). The venous system of the head and brain
is valveless, allowing retrograde spread of thrombophlebitis
from infected venous sinuses into dural and cortical venous
channels (21,37,116).
Suppurative intracranial phlebitis can lead to infarction or
brain inflammation (21,22,57) with subsequent neurologic
sequelae such as seizures, hemiparesis, or cranial neuropathies.
Cavernous sinus thrombosis is more commonly associated
with ethmoid and sphenoid disease, whereas occasionally,
ophthalmic vein thrombophlebitis may extend posteriorly to
cause cavernous sinus thrombosis (91).
2/21/14 5:47 PM
 576 Part III: Bacterial and Mycoplasmal Infections

TA B L E 3 3 . 8
MAJOR SITES OF SUPPURATIVE INTRACRANIAL PHLEBITIS

Dural Venous Sinus Source of Blood Flow Predisposing Site of Infection Clinical Presentation Miscellaneous

Cavernous sinus Superior or inferior Sphenoid and ethmoid Headache Acute onset
ophthalmic vein sinusitis Fever Most common site of
Facial infections Proptosis suppurative phlebitis
Otitis media Ptosis 30% mortality
Dental infection Chemosis 39% complete recovery
Cranial nerve dysfunction
(III, IV, VI; rarely V1, V2)
Decreased visual acuity
Lethargy/coma
Superior sagittal Ethmoid veins Bacterial meningitis Hemiparesis Largest venous sinus
sinus Frontal parietal veins Frontal and maxillary Intracranial hypertension 78% mortality
Occipital superior sinusitis (rarely ethmoid
cerebral vein sinusitis)
Diploic veins Subdural or epidural Headache Rare patient with
empyema Nausea and vomiting complete recovery
Seizures
Confusion/coma
Lateral sinuses Superior sagittal sinus Acute or chronic otitis media Unilateral headache Subacute presentation
Straight sinus Mastoiditis Earache 012% mortality
Pharyngitis Papilledema 75% complete
Facial pain recovery
Diplopia
Vertigo
Cranial nerve dysfunction (V, VI)

Data from references 8890.

to the pathogens involved in chronic otitis media, which is

Clinical Features
Most patients present with headache and fever associated with
a toxic appearance and leukocytosis. Increased ICP and pap-
illedema are present in 53% to 65% of cases of cavernous
and lateral sinus thrombosis but less commonly with superior
sagittal thrombosis (88,89). Focal neurologic findings involve
cranial nerves primarily based on the location of some cra-
nial nerves to the venous sinuses. Cranial nerves III, IV, and
VI controlling the extraocular muscles are primarily involved
with cavernous sinus thrombosis as they pass through or near
the inflamed cavernous sinuses (89). Lateral sinus thrombosis
is most often associated with unilateral sixth nerve palsy. On
rare occasions, the ophthalmic and maxillary branches of the
trigeminal nerve (V1 and V2, respectively) are involved with
cavernous sinus thrombosis and less commonly with lateral
sinus thrombosis. Hemiparesis may occur in up to 61% of pa-
tients with superior sagittal sinus thrombosis due to cerebral
infarcts (88).
Microbiology and Pathogenesis
S. aureus is the most common bacterial pathogen, occurring
in more than 60% to 70% of cases of cavernous sinus throm-
bosis (8890). Other gram-positive bacteria such as strepto-
coccal species and pneumococci also can be associated with
acute suppurative intracranial phlebitis. In septic lateral sinus
thrombosis, gram-negative bacteria such as Proteus mirabilis
and Escherichia coli as well as anaerobes such as Bacteroides
fragilis and anaerobic streptococci may play a larger role due
often its predisposing condition (88). Immunosuppression and
hematologic malignancies may be associated with fungal infec-
tions such as mucormycosis (92). A study from Pakistan and
the Middle East reviewed 109 cases of cerebral venous throm-
bosis of which 20 (18%) had infectious causes ranging from
tuberculous meningitis, rhino-orbital fungal infection, bacte-
rial meningitis, mastoiditis, malignant otitis, and others (117).
Diagnosis
High-resolution contrast-enhanced CT scans with fine cuts
through the suspected areas have been used most extensively
over the years. However, MRI has now become the modality of
choice for diagnosing suppurative intracranial phlebitis, par-
ticularly cavernous sinus thrombosis, using thin-section coro-
nal images as well as magnetic resonance angiography (MRA)
and magnetic resonance venography (MRV) (91,93,117120).
In a recent review of cerebral venous thromboses (118), the ad-
vantages and disadvantages of CT and MRI modalities are dis-
cussed. Although the exact sensitivity and specificity for MRI
techniques are unknown, it is estimated that CT/computed to-
mography venography (CTV) shows 95% sensitivity and 91%
specificity and that MRI/MRV is equal or better than CT/CTV
(118). In cases where MRI is not available or contraindicated,
CT techniques are fairly accurate.
Cerebral angiography and venography are used only rarely
(121) since the advent of CT and MRI. Lumbar puncture with
CSF evaluation always is abnormal with neutrophilic pleocy-
tosis and elevated pressure but is generally not diagnostic and
may pose some risk in patients with severely elevated ICP.

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 Chapter 33: Subdural Empyema and Suppurative Intracranial Phlebitis
Treatment
All intracranial suppurative infections require the use of
appropriate high-dose antibiotics with good penetration of
the bloodbrain barrier. Appropriate surgical intervention to
drain the sinuses or subdural collections is usually manda-
tory. In addition, anticoagulants may be added to the regi-
men for cavernous and sinus thrombosis using heparin or
low-molecular-weight heparin followed by warfarin for a
6-week course or until the thrombus resolves radiographi-
cally (119). The use of anticoagulants, however, is contro-
versial because of the risk of bleeding from carotid artery
rupture or cerebral venous infarction (94). Direct throm-
bolytic therapy has been used for refractory cerebral sinus
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2/21/14 5:47 PM
 CHAPTER 34 COMPLICATIONS OF INFECTIVE
ENDOCARDITIS
STEFANO GIULIERI, RETO ANTOINE MEULI, AND MATTHIAS CAVASSINI
Central nervous system (CNS) complications of infective endo-
carditis (IE) occur in about 30% of patients, with the highest
incidence among patients referred to tertiary care centers and in-
tensive care units, as well as patients with mitral valve endocar-
ditis and IE due to virulent microorganisms (e.g., Staphylococcus
aureus, gram-negative bacilli, fungi). Ischemic stroke accounts
for up to two thirds of CNS complications, followed by intra-
cranial hemorrhage, meningitis, brain abscess, intracranial in-
fectious aneurysm (ICIA), and encephalopathy. Embolization
of infected vegetations is the main pathogenetic mechanism.
Imaging (both computed tomography [CT] and magnetic reso-
nance imaging [MRI], coupled with noninvasive angiography)
plays a pivotal role in the diagnosis of CNS complications.
Optimal management includes early institution of antimicro-
bial treatment, which has the highest impact on the risk of fur-
ther emboli. Anticoagulation should be cautiously continued
in patients with established cardiac indications (e.g., prosthetic
valve). In the presence of an established indication, patients with
IE and ischemic stroke should undergo cardiac surgery without
delay, whereas it should be postponed for at least 4 weeks in
case of intracerebral hematoma. Unruptured ICIA may be man-
aged medically with radiologic follow-up, whereas enlarging or
ruptured ICIA should be treated surgically or by an endovascu-
lar approach. Despite improvement in the management, patients
with CNS complications generally carry a worse prognosis com-
pared to patients without neurologic complications.
HISTORY
Infective endocarditis (IE) was probably recognized as early
as 1646 by Rivire, but the full clinical spectrum of malig-
nant endocarditis was first comprehensively described by
Sir William Osler (1) in his Gulstonian lectures at the Royal
College of Physicians in London in 1885. He not only de-
scribed the different modes of onset, and the extraordinary
diversity of symptoms which may arise, but carefully ana-
lyzed the pathophysiology of distant complications, particu-
larly of central nervous system (CNS) manifestations such
as meningitis: The meningeal complications of endocarditis
have not received much attention, considering the frequency
with which it has occurred . . . somewhat over 12 per cent (1).
He also related IE and mycotic aneurysms to a common infec-
tious etiology and later emphasized the central importance of
blood cultures in diagnosis (2).
EPIDEMIOLOGY
In developed countries, the reported incidence of IE is 3 to 7 per
100,000 per year (36). This rate has remained fairly constant
over time (7). Incidence of IE increases sharply with age, with
a peak of 15 episodes per 100,000 per year in patients older
than 70 years (4,8). The male:female ratio is 2:1. In-hospital
and 6-month mortality in recent series are 15% to 20% and
25%, respectively (9). These apparently stable overall rates of
Scheld_Ch34.indd 579
incidence and mortality mask the continually evolving spec-
trum of IE and the contrasts that exist between various types
of IE. For instance, subacute IE due to viridans streptococci
has an early mortality rate of only 5% to 10%, whereas acute
prosthetic valve endocarditis (PVE) in an elderly patient with
congestive heart failure can be fatal in up to 70% of patients.
The overall figures reflect shifting frequency of predisposing
factors. In developed countries, the decreasing prevalence of
chronic rheumatic heart disease is counterbalanced by an in-
creased number of patients with prosthetic valves and intra-
vascular devices, injection drug use, and elderly patients with
degenerative heart disease (10). The mean age of patients pre-
senting with IE has increased, from 34 to 43 years in the early
antibiotic period to 52 to 55 years more recently, and has even
passed 60 years in some reports (3,11,12).
PREDISPOSING FACTORS
Degenerative valve disease has replaced rheumatic heart dis-
ease as the main underlying condition in patients with IE (10).
Degenerative valvular disease with calcified atheromatous
deposits is associated with IE in a proportion of cases that
increases with age and may be a predisposing factor in up to
50% of the IE cases in elderly patients (13). Mitral valve pro-
lapse (MVP) associated with valve dysfunction is another rec-
ognized risk factor for IE, found in 10% to 30% of patients
(14). In a casecontrol study, the risk of IE was eight times
higher among patients with MVP (15), but, given the high in-
cidence of MVP (5%) in the general population, the absolute
risk per patient is low, estimated to be 0.0175% per year (14).
Although it remains a common predisposing condition in
developing countries, rheumatic heart disease is associated
with IE in less than 5% of cases in the Western countries (16).
Congenital lesions are found in 6% to 20% of cases (17), mostly
ventricular septal defect, bicuspid aortic valve, patent ductus
arteriosus, and tetralogy of Fallot. A bicuspid aortic valve is an
important factor in elderly persons in whom it may be present
in up to 20% of IE cases; this is probably because of associated
valvular sclerosis and abnormalities of blood flow (18).
Prosthetic valves account for 7% to 25% of the cases of
IE and the annual incidence of IE in patients with prosthetic
valves is approximately 1% (19). In-hospital mortality rate
ranges from 20% to 30% (20).
IE related to hospitalization and ambulatory invasive
treatments (health care associated) now accounts for one
third of cases (21). The proportion of IE associated with
other intracardiac devices such as pacemakers or implant-
able cardioverter-defibrillators was 6.4% in the ICE-PCS (22).
Nosocomial bacteremias (mainly Staphylococcus aureus) rep-
resents as many as 25% of the cases in certain series (23,24).
IE is reported in 2% to 6% of patients undergoing long-term
hemodialysis (25). Intravenous drug users (IVDUs) are at high
risk for IE. Moreover, 20% to 40% of IVDUs suffering from
IE have preexisting cardiac lesions, often caused by previous
infection (26).
579
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 580 Part III: Bacterial and Mycoplasmal Infections
PATHOGENESIS
Certain lesions of the endothelium of the valve or heart cavities
can easily be infected should a bacteremia occur. This has been
shown in animal models: An intravascular polyethylene cathe-
ter placed across the aortic or the tricuspid valve will induce the
deposition of platelets and fibrin and lead to the formation of
nonbacterial thrombotic endocarditis (NBTE) (27). Many fac-
tors can induce endothelial lesions, which promote the forma-
tion of NBTE. The most important are valvular organic lesions
with associated perturbations of blood flow and prosthetic
valves. Even microscopic lesions are prone to infection by circu-
lating bacteria (28), so not surprisingly, up to 50% of patients
with IE have no known predisposing heart condition at the time
of diagnosis (29). Transient asymptomatic bacteremias occur
frequently, often following minor mucosal trauma induced by
daily domestic activities such as chewing or tooth brushing.
Bacteremia may also be triggered by various iatrogenic proce-
dures. Among the many bacterial species that can be recovered
during transient bacteremias, streptococci account for most IE
cases, probably because of the frequency with which they enter
the bloodstream and the adherence properties of their surfaces.
Circulating bacteria readily attach to NBTE. The attachment
process is probably mediated on the host side by receptor-like
structures such as fibronectin, fibrinogen, laminin, or collagen,
which interact with the surface of bacteria (8). Platelets also play
a role in these initial events (30,31). On the microbial side, only
bacteria with the ability to adhere to valvular lesions can pro-
duce IE. Gram-positive cocci (e.g., staphylococci, streptococci)
adhere more strongly than enterobacteria to heart valves (32).
Once microorganisms have attached to NBTE, they start to
multiply and stimulate further deposition of fibrin and platelets
through the activation of tissue factors or procoagulant activ-
ity. This thrombotic process buries some bacterial colonies deep
within the vegetation where they are protected from circulating
neutrophils. This has led to the concept of the vegetation as an
area of localized agranulocytosis. Bacteria deeply seated in the
vegetation are metabolically inactive and thus resistant to the ac-
tion of some antibiotics. Furthermore, some antibiotics do not
fully penetrate into the vegetation. This combination of factors
favors the bacteria and helps explain why cure of endocarditis
requires the prolonged administration of bactericidal antibiotics.
Because the infected vegetation is located within the blood-
stream, persistent bacteremia is a hallmark of bacterial endocar-
ditis, permitting the diagnosis through blood cultures in most
patients. Moreover, further deposition of platelets, fibrin, and
circulating bacteria will compensate for the fragmentation, em-
bolism, and/or resorption of the vegetation by the inflammatory
response, in a delicate and complex balance. IE also induces im-
munologic responses that contribute to some clinical manifesta-
tions of IE such as glomerulonephritis or vasculitis (30).
ETIOLOGIC AGENTS
The list of microorganisms that can cause IE includes most
human pathogenic bacteria, as well as rickettsiae, Bartonella,
chlamydiae, and fungi (19). However, gram-positive cocci pre-
dominate. The pattern of distribution of these etiologic agents
differs profoundly according to underlying risk factors, the
valve type (native vs. prosthetic), and geography (33).
Native Valve Endocarditis
S. aureus is now as common as streptococci as a causative
pathogen of native valve endocarditis (NVE) in developed
Scheld_Ch34.indd 580
countries (6). In the International Collaboration on
Endocarditis-Prospective Cohort Study (ICE-PCS), S. aureus
and streptococci both accounted for 32% of 1,881 cases of
definite NVE (16). The increase in frequency of S. aureus IE
is explained by several invasive medical procedures associated
with S. aureus bacteremia (e.g., hemodialysis, long-term intra-
venous catheters) (24). The clinical course of S. aureus IE is
usually acute and complicated. In-hospital mortality rate was
22% in a recent prospective study (24). Coagulase-negative
staphylococci rarely cause NVE but appear to be increasing
in frequency and can pursue an aggressive clinical course (34).
Special attention has been drawn to Staphylococcus lugdunen-
sis, being commonly associated with valve destruction (35).
In a recent French series of 497 patients with definite IE
(79% with NVE), streptococci, although less frequent com-
pared to a previous study (4), were still the most common
cause of IE and were responsible for 48% of cases (6). The
viridans group (e.g., Streptococcus sanguis, Streptococcus ora-
lis, Streptococcus mutans, and Streptococcus mitis) accounts
for at least two thirds of these cases. The clinical course is gen-
erally subacute and an underlying cardiac condition is often
present. Streptococcus milleri, an occasional cause of IE, has
a peculiar propensity to cause distant abscesses and local peri-
valvular invasion (36). Streptococcus bovis group (including S.
gallolyticus subsp. gallolyticus, S. gallolyticus subsp. pasteria-
nus, and S. infantarius subsp. coli) accounts for up to 20% of
streptococcal IE (37) and is often associated with neoplasms
of the gut, of which it may be the first manifestation (38,39).
Streptococcus pneumoniae and streptococci of the Lancefield
groups A, B, C, G may also occasionally cause endocarditis
(40,41). Enterococci account for 10% of all IE (42); these
strains are particularly resistant to the bactericidal activity of
antibiotics. Older people are usually affected and outcome can
be fatal in approximately 16% of patients (42).
Numerous other bacteria are well known but uncom-
mon causes of NVE, for example, Coxiella burnetii, Brucella,
and bacteria of the HACEK group (Haemophilus species,
Actinobacillus actinomycetemcomitans, Cardiobacterium hom-
inis, Eikenella corrodens, Kingella species) (43). Actinobacillus
actinomycetemcomitans has now been reclassified as
Aggregatibacter actinomycetemcomitans (44). Bartonella is an
unusual cause of endocarditis in homeless people (45).
Prosthetic Valve Endocarditis
PVE cases with onset within 2 months after surgery are called
early PVE (46). Early PVE cases are presumably related to
intraoperative contamination. S. aureus is responsible for
35% of early PVE cases; coagulase-negative staphylococci are
found in 17% of cases. The frequency of gram-negative bacilli
(10% to 20%), diphtheroids (0% to 3%), and fungi (5% to
10%) is higher in PVE than in NVE (47), and they are usually
isolated in early PVE.
Cases occurring 2 months or more after surgery are called
late PVE and are largely community acquired. As compared to
early PVE, streptococci are more common and are responsible
for approximately 20% of late PVE cases (46).
Intravenous Drug Users
S. aureus accounts for more than 50% of IVDU cases probably
because of its high frequency on the skin in local infections at the
injection site (cellulitis, abscesses, suppurative thrombophlebitis)
and on drug paraphernalia (48). In some regions, methicillin-
resistant S. aureus (MRSA) have been responsible for IE among
2/21/14 5:47 PM
 Chapter 34: Complications of Infective Endocarditis 581

IVDUs. Several other bacterial species such as Pseudomonas
aeruginosa, enterococci, and Serratia species or fungi are all more
common in addicts than in the general population (49). In 40%
to 70% of the cases, the tricuspid valve is affected (50). Right-
sided IE among IVDUs has a mortality rate of less than 10% (48).
findings (59). Based on the number of major and minor criteria,
any case of suspected IE is classified as definite, possible, or
rejected IE. These criteria have been primarily developed for
research purpose, but they can help integrate diagnostic findings
(Table 34.1)

TA B L E 3 4 . 1
Culture-Negative Infective Endocarditis
CRITERIA AND DIAGNOSIS OF INFECTIVE
Patients with a clinical presentation suggestive of IE but with ENDOCARDITIS
negative blood cultures account for 5% to 10% of the cases
(8). The most common cause for culture-negative IE is prior Criteria
administration of antibiotics. In the absence of prior antibiotic
Major
administration and with appropriate blood culture media, most
bacteria will eventually grow but may require repeated blood 1. Blood culture Two separate blood cultures with
culture and prolonged incubation periods (51). Some micro- typical microorganism
organisms, such as Aspergillus species, C. burnetii, Legionella Persistently positive blood cultures
species (usually Legionella pneumophila), or Tropheryma (12 hours apart or three of three
whippelii, cannot be recovered from the blood, so diagnosis or more)
relies on other methods such as tissue culture, in situ hybrid- Single positive blood culture for
ization, polymerase chain reaction (52), or special serologic Coxiella burnetii or antiphase I
tests (53). By applying a standardized diagnostic algorithm, IgG antibody titer 1 : 800
Fournier et al. (33) were able to identify an etiologic agent
2. Endocardial New regurgitant murmur
among 476 out of 759 (63%) patients referred for blood
involvement
culturenegative IE. C. burnetii (229 cases) and Bartonella sp.
(86 cases) were the most common etiologic agents. A noninfec- Positive echocardiogram for IE
tious origin of culture-negative IE (e.g., marantic endocarditis, (oscillating mass, abscess, new
systemic lupus erythematosus) was diagnosed in 19 patients. dehiscence of PV)
Minor
1. Predisposition, predisposing heart condition, or
CLINICAL MANIFESTATIONS injection drug use
2. Fever, temperature 38C
The signs and symptoms of IE are extremely variable because of
the diversity of the etiologic agents and the various organs in- 3. Vascular phenomena: emboli, infectious aneurysm,
volved. Clinical presentation may range from a chronic disease intracranial hemorrhage
with unspecific systemic symptoms to acute life-threatening 4. Immunologic phenomena: glomerulonephritis, Osler
sepsis. Fever with a heart murmur is the most common clinical nodes, Roth spots, RF
presentation; it may be the only clue to the diagnosis, especially 5. Microbiology: positive blood culture but not meeting
early during the course of the disease and with microorgan- major criteria, serological evidence of active infection
isms of low virulence. In a prospective study of 109 episodes with organism consistent with IE
of IE, fever was present in 98% of cases (54). A new murmur Diagnosis
and skin lesions were found in 59% and 32%, respectively.
Splenomegaly and musculoskeletal manifestations were pres- Definite
ent in 16% (54). Congestive heart failure complicates one third Pathology or bacteriology of vegetations
of episodes in recent studies (4,16,54). Distant complications or
such as major emboli, lumbar pain, or rupture of a infectious
Two major criteria
aneurysm may be the first presenting manifestations of IE. All
the various clinical manifestations of IE arise from one or more or
of four main mechanisms: bacteremia, embolization (55), im- One major and three minor criteria
munologic manifestations (56), and local complications (57). or
Five minor criteria
Possible
DIAGNOSIS
One major criterion and one minor criterion
The diagnosis of IE requires the integration of clinical, mi- or
crobiologic, and echocardiographic data. Hematologic ab- Three minor criteria
normalities are frequently observed: Anemia, leukocytosis,
and thrombocytopenia are present in 66%, 50%, and 18% of Rejected
cases, respectively. Urinalysis shows abnormalities in 30% or Firm alternative diagnosis
more of patients, mainly evidence of proteinuria or microscopic or
hematuria, one third of patients has elevated creatinine (54). Resolution on 4 days of antibiotics
Circulating immune complexes may be detected, but they are
nondiagnostic (56). Repeated electrocardiography can reveal
PV, prosthetic valve; RF, rheumatoid factor.
new atrioventricular block, particularly in the setting of aortic From Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the
valve endocarditis, suggesting perivalvular invasion (58). Duke criteria for the diagnosis of infective endocarditis. Clin Infect
The Duke criteria combine predisposing factors to IE, the blood Dis. 2000;30:633638, with permission.
culture isolate or histologic examination, and echocardiographic

Scheld_Ch34.indd 581 2/21/14 5:47 PM

 582 Part III: Bacterial and Mycoplasmal Infections

Echocardiography has proven to be a valuable diagnostic
tool in patients with suspected IE. Transesophageal echocar-
diography (TEE) has substantially better ability to detect vege-
tations, perivalvular extension, and myocardial abscesses than
transthoracic echocardiography (TTE). TTE has a sensitivity
of 40% to 63% for detecting vegetations in NVE (60). TEE
increases the sensitivity for detecting vegetations in NVE to
more than 90% (61). TEE is particularly useful in PVE, with
which vegetations are detected in more than 80% of the cases
compared with less than 30% with TTE. A negative TEE has a
negative predictive value for IE of 86% to 97%.
TREATMENT AND PREVENTION
Once the diagnosis of IE has been made, antibiotic treatment
should be started promptly to eradicate the infecting mi-
croorganisms as soon as possible. It is well established that
a prolonged course of antibiotics is needed for cure even if
the microorganisms are highly sensitive to the drug used. The
antibiotic agent must be bactericidal and should be selected
according to in vitro susceptibility test results and the experi-
ence gathered from experimental and clinical studies (10,62).
Surgery has an important role in the management of IE, as an
optimal therapeutic approach requires operative intervention
during the course of medical treatment in almost 50% of pa-
tients with IE (63). In the ICE-PCS, the rate of surgical inter-
vention (48%) was comparable among patients with NVE and
PVE (16). Nearly all patients with fungal endocarditis require
combined surgical and medical treatment (64). Hemodynamic
deterioration, local complications, and uncontrolled infection
are the major indications for surgery (10,65). Although the
need for surgery in patients presenting with hemodynamic
deterioration and uncontrolled infection is widely recognized
(66), it remains controversial whether surgery is indicated for
prevention of systemic embolism. In a randomized study from
Korea, patients at high risk for systemic embolism (i.e., with
severe valvular regurgitation and large vegetations) had signifi-
cantly less systemic embolic events if operated early during the
course of disease (67). Figure 34.1 summarizes current indica-
tions for valve surgery in patients with IE. Other interventions
that should be considered in patients with IE are the removal
of intravascular devices (e.g., pacemakers, intracardiac car-
dioverter defibrillators, central venous catheters) (68), and the
drainage of extracardiac infections (e.g., septic arthritis).
Attempted prevention of IE is aimed at patients with
known underlying predisposing factors who undergo a proce-
dure that may result in bacteremia. Possible portals of entry,
such as oral and dental lesions or urinary or gastrointestinal
tract pathology, should be sought and treated if necessary.

HIGH EMBOLIC RISK PERSISTENT SEPSIS

HEART FAILURE (large vegetation >10 mm, (periannular abscess,
previous embolic event) difficult microorganism)

YES NO YES NO YES NO

Severe Controlled Other poor prognostic features

by medical treatment (difficult organism,
severe valve regurgication)

Severe
valve regurgitation
YES NO

YES NO

Emergency/ Urgent/ Medical Urgent Individual Medical Urgent Medical

urgent surgery elective surgery management surgery decision* management surgery management

*based on size and mobility of vegetation,

affected valve, previous embolism, duration
of antibiotic treatment

FIGURE 34.1 Indications and timing of valve surgery in patients with IE. (Adapted from Prendergast
BD, Tornos P. Surgery for infective endocarditis: who and when? Circulation. 2010;121:11411152.)

Scheld_Ch34.indd 582 2/21/14 5:47 PM

 Chapter 34: Complications of Infective Endocarditis
Recommendations for use of prophylactic antibiotics have
been updated, and indications for prophylaxis have been
considerably restricted to four high-risk conditions: prosthetic
cardiac valve, history of previous IE, some forms of congenital
heart disease (CHD) (e.g., unrepaired CHD), and heart trans-
plantation recipients with valvulopathy (69).
CENTRAL NERVOUS SYSTEM
COMPLICATIONS OF INFECTIVE
ENDOCARDITIS
Among the various manifestations of IE, neurologic complica-
tions are particularly important for three main reasons: They
occur often, they may be the first or the predominant manifes-
tation of the disease, and they are a leading cause of death and
complications due to IE (70).
Incidence
The reported overall incidence of CNS complications of IE
varies greatly. In most series, the incidence of CNS involve-
ment during the course of IE ranges between 20% and 40%,
with an average of 30%. The incidence has not changed much
over time, despite wide differences in the diagnostic criteria
employed in various studies and many evolutionary changes
that have occurred in the natural history of IE over the past
60 years. Among 743 patients pooled from seven series pub-
lished before the advent of antibiotics, 176 (24%) were noted
to have neurologic manifestations (1,7176). Among 1,622
patients from eight studies reported between 1947 and 1978,
457 (28%) had such complications (7785). Among 1,329
episodes of IE from seven series published between 1981 and
1993, 437 (33%) were accompanied by neurologic manifesta-
tions (11,8693). And among 2,162 episodes of IE from eight
series published between 1996 and 2007, 512 (24%) were
complicated by neurologic events (70,94101). Recent studies
may indicate a lower rate of neurologic complications: The in-
cidence of stroke in a French cohort of 390 patients and in the
ICE-PCS was 18% and 17%, respectively (4,16). However,
data on other neurologic complications were not reported.
Finally, among 513 patients presenting with complicated
native-valve IE, focal neurologic findings, and altered mental
status were described in 18% and 16%, respectively (9).
Incidence of asymptomatic CNS events is much higher. By
systematically using resonance imaging of the brain, Snygg-
Martin et al. (102) identified cerebrovascular complications
in 65% of patients; about half of them were asymptomatic.
In another study of systematic brain imaging in IE, radiologic
evidence of brain embolism was detected in 80% of patient,
whereas 25% had clinical stroke (103).
Factors Influencing the Incidence of Central
Nervous System Complications
The reported incidence is understandably higher in stud-
ies devoted primarily to the neurologic aspects of IE and
in studies based on autopsies, because brain damage often
causes or contributes to death in IE (11,78,79). In one au-
topsy series of 69 cases of IE, cerebral emboli were found
in up to two thirds of the young adults and in 46% of the
total cases (104). Frequency of CNS complications also tends
to be higher in series gathered from referral centers (105)
or specialized units. For example, among 198 patients with
Scheld_Ch34.indd 583
583
IE hospitalized in 33 intensive care units (ICUs) in France,
108 (55%) presented with neurologic complications (106).
In contrast, the rate of CNS complications was only 22% in
a series of IE observed in a large community hospital (11).
This referral bias would alter not only the number but also
the type and severity of the complications because referral is
often precipitated by CNS involvement. On the other hand,
in a series gathered from six hospitals of different types (uni-
versity, private, and Veterans), the frequency of CNS compli-
cations was very similar (92).
Age and Sex
In many studies of adults with IE, the age of the patients did not
appear to greatly influence the overall frequency of CNS com-
plications. In a recent series, however, major neurologic events
were recorded in 22%, 28%, and 34% of patients younger
than 40 years, 40 to 60 years, and older than 60 years, re-
spectively. In elderly patients, neurologic manifestations tend
to be more common as a presenting clinical sign of IE (107);
as many as one fourth to one third of them may present with
neurologic signs (86), compared with 5% to 17% in the gen-
eral population. If disorientation is included as a neurologic
finding, the figure can be as high as 45%. Neurologic compli-
cations in children reported in five series ranged from 15% to
32% (108). Because major neurologic events are uncommon
in children or young adults, everyone should recall the dictum,
In hemiplegia in young adults or children, always think of
infective endocarditis.
Generally, the sex distribution of the patients with or with-
out neurologic complications appears to be similar in both
sexes (83).
Location of Vegetations in the Heart
Neurologic complications are a hallmark of left-sided valvular
abnormalities. This association was noted as early as 1852,
before IE was recognized as a clinical entity (109). The inci-
dence of neurologic complications is markedly lower in iso-
lated right-sided IE. In a series of 40 IVDUs with tricuspid IE
due to S. aureus, none presented with cerebral manifestations,
whereas 2 of 5 of those with left-sided involvement had cere-
bral septic emboli (110). Of 97 episodes of IE in drug addicts,
none of the nine major CNS events that were present on initial
evaluation occurred in the 32 cases that involved the right side
of the heart (111), although the infection was caused by highly
virulent organisms such as S. aureus. CNS complications were
observed in 54 (41%) of 133 patients with aortic and/or mitral
valve involvement and in only 4 (12%) of 33 of those with tri-
cuspid IE (92). When neurologic manifestations occur in right-
sided IE, they present as meningitis, cerebral abscesses, or
encephalopathy, rather than as strokes, and are most often re-
lated to virulent pathogens such as S. aureus or S. pneumoniae
(112). Systemic embolization is rare in right-sided IE but does
occasionally occur either from septic thrombi arising in the
pulmonary veins or via paradoxical embolization through a
patent foramen ovale, which is present in 18% of the normal
population.
Mitral valve endocarditis is associated with a higher rate
of neurologic complications (83,106,113,114). For example,
in a recent French study of 198 patients with IE, mitral valve
involvement was independently associated with neurologic
complications (OR 1.54, CI 1.07 to 2.21) (106). A study
from Duke University including 707 patients with IE found a
twofold risk of stroke among patients with mitral valve endo-
carditis as compared to aortic valve endocarditis (114). This
association was not reported by older studies (115), probably
because of small size (88).
2/21/14 5:47 PM
 584 Part III: Bacterial and Mycoplasmal Infections

Neurologic complications in the context of PVE are of spe- 100

cial concern because of the threat of superimposed intrace-
rebral hemorrhage, which might be caused or promoted by
anticoagulation. Most published data are derived from PVE
complicating mechanical prosthetic valves. The overall inci-
dence of focal neurologic events associated with PVE varies
from 11% to 44% (46,116122), which is considerably higher 50
than the overall thromboembolic rate of 1% to 4% per year
observed for anticoagulated patients with uninfected pros-
thetic valves (123).
Studies comparing the incidence of CNS complications
between NVE and PVE have given conflicting results. In
one study, 11 (13%) of 82 patients with NVE, compared to
6 (33%) of 18 with PVE, presented with such complications 0
(117); however, another study reported 40 (35%) of 113 for

3
4

90

08
4

5
16
13

=8

=5
patients with NVE and 24 (39%) of 62 for those with PVE

n=

=1
n=
n=

n'

n'

n'
(88). Other series did not report any statistically significant
difference regarding the number of NVE and PVE CNS com- Pruitt, 1978 Heiro, 2000 Sonneville, 2011
plications (46,98,124).
It is unclear whether the incidence of embolic events is af- Culture negative Other Enterococci
fected by the time of onset of PVE in relation to the placement Viridans Coagulase-negative S. aureus
of the prosthetic valve. In one study, CNS embolic episodes streptococci staphylococci
were reported in 0% to 11% of patients with early onset PVE
and in 23% to 28% of those with late-onset PVE (120). The FIGURE 34.2 Microbiology of infective endocarditis in patients with-
higher rate in late-onset PVE was confirmed in another study out (n) and with (n) CNS complications.
in which peripheral manifestations occurred in 10% of early
onset PVE cases, compared to 34% in late-onset PVE cases
(125). However, in a recent prospective study of 78 cases of
observed with some other bacteria, particularly group D and
PVE, the rate of CNS complications did not differ between
nongroup D streptococci, which ranged from 25% to 47%
early and late PVE (126).
(83,88,92,97,113).
The incidence of CNS complications in PVE is influenced
Some species of bacteria other than S. aureus, such as
by anticoagulant therapy. In patients insufficiently anticoagu-
Enterobacteriaceae or anaerobic bacteria, have been associ-
lated, CNS complication rates of 38% to 71% were noted,
ated with a high rate of neurologic complications (83,128).
compared to only 8% to 10% in patients on appropriate an-
Moreover, certain microorganisms are prone to a high rate
ticoagulant therapy (116,119). In one series of 61 patients,
of certain types of neurologic involvement. For example, al-
there was no difference in the rate of embolism or risk of
though S. pneumoniae has become rare in IE, causing only
bleeding between patients receiving no anticoagulation or sub-
1% to 3% of cases (129), in these few cases, associated pneu-
therapeutic doses and those who were adequately anticoagu-
mococcal meningitis is common, being found in 40% to 60%
lated (121). When anticoagulated patients develop neurologic
(130,131). Purulent complications are also frequently encoun-
complications, they are at high risk for major hemorrhage
tered with S. aureus IE, either as meningitis or as brain abscess.
(83,120,127).
Certain bacteria such as the Haemophilus species, members of
The type of prosthetic valve may influence the rate of CNS
the genus Abiotrophia (formerly nutritionally variant strepto-
manifestations. Of 33 patients with bioprosthetic valve in-
cocci), or fastidious organisms have been associated with large
fection gathered from three studies, 4 (12%) had neurologic
emboli; these emboli may occlude major vessels including
events (117,120,121), a figure lower than that with mechani-
cerebral arteries. In patients with culture-negative IE, major
cal valves. However, in another study of 62 patients with PVE,
embolic phenomena, including those to the brain, were noted
there was no statistical difference when the type of prosthetic
twice as often as in patients with culture-positive IE. Cases due
valve involved was compared among patients with and with-
to Candida spp. are also associated with large vegetations and
out neurologic complications (88).
a high rate of embolic phenomena (132,133). Of 27 patients