Pub - Principles and Practice of Neuropathology

Principles and Practice
of Neuropathology,
Second Edition
JAMES S.NELSON, M.D. et al.,

Editors
OXFORD UNIVERSITY PRESS

Principles and practice
of neuropathology
This page intentionally left blank
PRINCIPLES AND PRACTICE
OF NEUROPATHOLOGY
Second Edition
Edited by
JAMES S. NELSON, M.D.

HERNANDO MENA, M.D.
JOSEPH E. PARISI, M.D.
and
SYDNEY S. SCHOCHET, JR., M.D.
1
2003
1
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Library of Congress Cataloging-in-Publication Data

Principles and practice of neuropathology /
[edited] by James S. Nelson . . . [et al.].—2nd ed.
p. ; cm. Includes bibliographical references and index.
ISBN 0-19-512589-4
1. Nervous system—Diseases. 2. Nervous system—Pathophysiology.
I. Nelson, James S., 1933–
[DNLM: 1. Nervous System Diseases—pathology. WL 140 P9566 2003]
RC347 .P743 2003 616.8047—dc21 2002029801
Materials appearing in this book prepared by individuals as part of their official duties as United States
government employees are not covered by the above-mentioned copyright, and any view expressed therein
do not necessarily represent the views of the United States government. Such individuals’ participation in the
Work is not meant to serve as an official endorsement of any statement to the extent that such statement
may conflict with any official position of the United States government.
987654321
Printed in the United States of America
on acid-free paper
The second edition is dedicated by the contributors
to Dr. Kenneth Earle
and to all of their neuropathology mentors
Preface
The second edition of Principles and Practice of Neu- Two colleagues have died since the publication of the
ropathology has been extensively revised to incorporate first edition—Dr. Kenneth Earle, to whom the first edi-
essential elements of the new and important neuro- tion was dedicated, and Dr. Julio Garcia, the senior au-
pathology information accumulated since publication thor of two chapters in the first edition. Their company
of the first edition in 1993. All of the chapters have and counsel continue to be missed. Dr. Hernando Mena
been edited or rewritten entirely. The contributors have completed the chapter on ischemic injury of the brain
been encouraged, wherever possible, to include relevant and spinal cord, and Dr. Elizabeth Rushing prepared a
genetic and imaging information. Alzheimer’s disease, new chapter on viral infections and prion diseases of
laboratory methods of brain tumor analysis, and tu- the nervous system for the second edition. As noted,
mors of the peripheral nervous system are covered in- the first edition was dedicated to Dr. Kenneth Earle.
dividually in separate chapters. The discussion of Lewy The contributors to that edition had either received
body disease has been expanded. The chapter on neu- their neuropathology training in Dr. Earle’s program
rocutaneous diseases in the first edition has been re- or were friends of Dr. Earle. In keeping with the di-
placed by the chapter on inherited tumor syndromes verse educational origins of the present list of contrib-
involving the nervous system, reflecting a more precise utors, the dedication has been expanded to include Dr.
separation and classification of these disorders based Earle and all of our teachers.
upon clinical, pathological, and genetic data. A new The editor thanks the co-editors, Drs. Mena, Parisi,
chapter with basic information on neuroimaging tech- and Schochet, for their help in assembling the second
niques has been added. The purpose of the book re- edition. A special acknowledgement of gratitude is ex-
mains unchanged: To present readers in the pathology tended to the staff of Oxford University Press for their
and neuroscience communities with a concise survey of excellent and timely assistance and advice concerning
general neuropathologic concepts and the major neu- the preparation and publication of this book.
ropathologic features of the neurologic disorders they
are likely to encounter. Honolulu, Hawaii J.S.N.
vii
Contents
Contributors, xi
1. Introduction to Neuropathology, 1
James S. Nelson and Gary S. Pearl
2. Elements of CT and MR Neuroimaging, 21
James S. Nelson
3. Developmental and Perinatal Neuropathology, 24
James S. Nelson
4. Bacterial, Fungal, and Parasitic Diseases of the Central Nervous System, 45
Steven C. Bauserman and L. Gill Naul
5. Viral Infections and Prion Diseases of the Central Nervous System (Excluding Retroviral Diseases), 78
Elisabeth J. Rushing
6. Neuropathology of Acquired Immunodeficiency Syndrome, 95
Carol K. Petito
7. Injuries to the Brain and Spinal Cord Associated with Ischemia, 112
Julio H. Garcia and Hernando Mena
8. Cerebrovascular Disease, 122
Carol K. Petito
9. Central Nervous System Trauma, 140
Mary E.S. Case
10. Intoxications and Metabolic Diseases of the Central Nervous System, 176
Suzanne Z. Powell and Sydney S. Schochet, Jr.
11. Neurodegenerative Diseases (Excluding Alzheimer’s Disease), 220
Lawrence A. Hansen
12. Alzheimer’s Disease, 238
James S. Nelson
13. Diseases of CNS Myelin, 246
Robert E. Schmidt
14. Introduction to Neurooncology, 267
James S. Nelson and Peter Burger
15. Laboratory Methods of Brain Tumor Analysis, 272
Paul E. McKeever
16. CNS Tumors (Excluding Pituitary, PNET, and Embryonal Tumors), 298
Joseph E. Parisi, Hernando Mena, and Bernd W. Scheithauer
17. Embryonal Tumors of the Central Nervous System, 383
Lucy B. Rorke
ix
x CONTENTS
18. Pituitary Tumors and Related Lesions, 396

Bernd W. Scheithauer
19. Tumors of the Peripheral Nervous System (Including the Craniospinal Nerve Roots), 425
Caterina Giannini and Bernd W. Scheithauer
20. Inherited Tumor Syndromes Involving the Nervous System, 448
James S. Nelson
21. Pathology of Non-Neoplastic, Regional Disorders of the Spinal Cord, 459
Ronald C. Kim
22. Non-Neoplastic Diseases of the Peripheral Nervous System, 497
Robert E. Schmidt
23. Neuromuscular Diseases, 525
Reid R. Heffner, Jr.
Index, 579
Contributors
STEVEN C. BAUSERMAN, M.D. RONALD C. KIM, M.D.

Senior Associate Pathologist Staff Neuropathologist
Austin Pathology Associates Long Beach DVA Medical Center
Austin, Texas Department of Veterans Affairs Medical Center
Clinical Professor of Pathology
PETER BURGER, M.D.
University of California Irvine
Professor of Pathology
Long Beach, California
Johns Hopkins University School of Medicine
Baltimore, Maryland PAUL E. MCKEEVER, M.D., Ph.D.
Professor and Chief of Neuropathology
MARY E. S. CASE, M.D.
Department of Pathology
University of Michigan Medical School
Chief Medical Examiner, St. Louis, St. Charles, Jefferson
Ann Arbor, Michigan
and Franklin Counties, Missouri
Professor of Pathology HERNANDO MENA, M.D.
St. Louis University Health Sciences Center Colonel, Medical Corps, United States Army
St. Louis, Missouri Chairman, Department of Neuropathology
Armed Forces Institute of Pathology
JULIO H. GARCIA, M.D. (DECEASED)
Washington, D.C.
Henry Ford Hospital L. GILL NAUL, M.D.
Detroit, ME Chairman, Department of Radiology
Case Western Reserve University Scott and White Clinic
Cleveland, Ohio Texas A&M University College of Medicine
Temple, Texas
CATERINA GIANNINI, M.D., Ph.D.
Consultant in Anatomic Pathology JAMES S. NELSON, M.D.
Assistant Professor of Pathology Neuropathologist-Investigator
Mayo Clinic Pacific Health Research Institute
Rochester, Minnesota Clinical Professor of Pathology
John A. Burns School of Medicine
LAWRENCE A. HANSEN, M.D.
University of Hawaii
Associate Professor of Pathology and Neurosciences
Honolulu, Hawaii
Departments of Neurosciences and of Pathology
University of California, San Diego JOSEPH E. PARISI, M.D.
La Jolla, California Professor of Pathology and Neuropathology
Division of Anatomic Pathology
REID R. HEFFNER, JR., M.D.
Departments of Laboratory Medicine and Pathology
Professor and Chairman
and Neurology
Mayo Clinic
School of Medicine and Biomedical Sciences
Rochester, Minnesota
State University of New York–Buffalo
Buffalo, New York GARY S. PEARL, M.D., Ph.D.
Orlando Regional Healthcare
Orlando, Florida
xi
xii CONTRIBUTORS
CAROL K. PETITO, M.D.

Professor
University of Miami School of Medicine
Miami, Florida
SUZANNE Z. POWELL, M.D.

Assistant Professor of Pathology/Neuropathology
Baylor College of Medicine
Houston, Texas
LUCY B. RORKE, M.D.

Senior Neuropathologist
Clinical Professor Pathology, Neurology and Pediatrics
The Children’s Hospital of Philadelphia
The University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania
ELISABETH J. RUSHING, M.D.

Colonel, Medical Corps, United States Army
Assistant Chairperson
Department of Neuropathology and Ophthalmic Pathology
Armed Forces Institute of Pathology
Adjunct Associate Professor
Georgetown University Medical Center
Washington, D.C.
BERND W. SCHEITHAUER, M.D.

Mayo Medical School
Department of Laboratory Medicine and Pathology
Mayo Clinic
Rochester, Minnesota
ROBERT E. SCHMIDT, M.D., Ph.D.

Director, Division of Neuropathology
Washington University School of Medicine
St. Louis, Missouri
SYDNEY S. SCHOCHET, JR., M.D.

Professor
Departments of Pathology, Neurology, and Neurosurgery
West Virginia University Health Sciences Center
Morgantown, West Virginia
Principles and practice
of neuropathology
1 Introduction to neuropathology
JAMES S. NELSON AND GARY S. PEARL
EVOLUTION OF NEUROPATHOLOGY Riggs, were certified (Abell, 1988, personal communica-

tion). The growth of clinical neurology, neurosurgery,
Neuropathology emerged as a distinct discipline dur- and the basic neurosciences that began after World War
ing the latter half of the nineteenth century. Stimulated II significantly increased the demands for neuropathol-
by the possibility of a clearer understanding of human ogy skills and led to the eventual creation of full-time
behavior, European neuroscientists, particularly in Ger- neuropathology positions at major medical institutions.
many and France, conducted systematic morphologic The need for accurate neuropathologic diagnosis in-
studies of the diseased human brain. The German ap- creased with the development of refined, expensive, and
proach, led by Weigert, Nissl, and Alzheimer, focused sometimes hazardous approaches to patient management
on the structural changes in neurons and glia associ- and therapy, particularly in regard to brain tumors. The
ated with various disease states and the etiologic and special requirements for residency training programs in
pathogenetic insights provided by these phenomena. neuropathology were first published in the 1971–1972
These scientists, followed by Jakob and Spielmeyer, Directory of Approved Internships and Residencies. The
supplemented the human data with experimental stud- first published list of accredited training programs in neu-
ies. In contrast, the French school, influenced by Char- ropathology appeared in the directory for 1972–1973
cot, emphasized the correlation between neurologic (Abell, 1988, personal communication).
signs and symptoms and the anatomic location of le- Neuropathology’s future course in the United States
sions. This information formed a basis for inferences is uncertain. During the initial phase of the specialty’s
regarding the function of tracts, nuclei, and other an- growth the National Institutes of Health provided con-
atomic components of the human brain (Greenfield, siderable financial support, chiefly through training
1958). Subsequently, diagnostic neuropathology be- grants. With the attenuation of these funds and the
came focused on a combination of the French and Ger- highly competitive research grant environment, few
man approaches. Successful practice of the discipline extramural dollars find their way into most neu-
involved not only a detailed understanding of anatomic ropathology budgets. Neuropathologic diagnostic stud-
pathology but also knowledge of clinical neurology and ies, although necessary and time consuming, are not of
neuroanatomy. In the last 20 years the ability to use sufficient volume at any institution to support even one
neuroimaging studies to enhance conventional mor- full-time neuropathologist. Although clinicians receive
phologic methods has become an important skill for and expect extensive teaching contributions from neu-
the neuropathologist (Burger et al., 1998). In the near ropathologists, such efforts lack corresponding finan-
future, changes in the traditional emphasis on mor- cial support. The future development of neuropathol-
phology as the basis for neuropathologic diagnosis are ogy in this country depends on solving the problem of
likely as more information is gained concerning genetic supporting, maintaining, and periodically repopulating
factors influencing the cellular expression of disease. a neuropathology cadre commensurate with the na-
In the United States the practice of neuropathology did tion’s medical requirements. In 1997 the American
not become a viable full-time occupation until the 1950s. Association of Neuropathologists held a workshop en-
Before that, neuropathology needs were met by clinicians, titled “Neuropathology in the 21st Century” that in-
usually neurologists, or by general anatomic pathologists cluded a discussion of these issues but provided no con-
on a part-time basis. Physicians devoting their profes- sensus regarding a strategy for the future (Wiley, 1997).
sional and scientific efforts exclusively to neuropathol- The difficulty in devising such a strategy may be re-
ogy could be found in only a few institutions. The Amer- lated to the notion that the responsibilities of a neu-
ican Board of Pathology gave the first subspecialty ropathologist include research, teaching, and clinical
examination in neuropathology in 1948. Two neu- neuropathology. Information and professional or sci-
ropathologists, Dr. Webb Haymaker and Dr. Helena entific demands have increased significantly in each of
1
2 PRINCIPLES AND PRACTICE OF NEUROPATHOLOGY
these areas. It may be necessary to recognize that one 4. The nervous system is a complex anatomic struc-
person can no longer be an acknowledged expert in all ture with widely divergent parts. In postmortem studies,
three areas. in contrast to the comparatively small number of histo-
logic sections required for adequate examination of
anatomically homogeneous organs such as the liver and
GROUND RULES OF NEUROPATHOLOGY kidney, microscopic examination of the major anatomic
subdivisions of the nervous system and, if indicated,
The principles of general anatomic pathology are rele- skeletal muscle, together with delineation of the ana-
vant to neuropathology. The following guidelines tomic distribution of the lesions is necessary for satis-
should be considered when those principles are applied factory neuropathologic evaluation. The College of
to the pathology of the nervous system. American Pathologists has recommended guidelines for
the autopsy examination of the brain, spinal cord, and
1. Neurologic diseases may be primary or secondary neuromuscular system (Powers, 1995). The selection of
disorders. Primary diseases, such as multiple sclerosis, specimens for microscopic examination is determined by
are those that develop initially within the parenchymal the neurologic symptoms and the lesions identified by
and supporting elements of the nervous system. Sec- macroscopic examination (Mirra et al., 1993; McKeith
ondary conditions, such as hepatic encephalopathy, are et al., 1996; National Institute on Aging, 1997). Sections
those that arise as complications of extraneural disor- of the superior frontal gyrus with the adjacent arterial
ders. Admittedly, the application of this distinction may boundary zone, hippocampus, corpus striatum, mid-
be debated in some cases. The important point, how- brain, pons with locus coeruleus, mid or caudal medulla,
ever, is that neurologic disturbances and lesions may cerebellar hemisphere and dentate nucleus, and cervical,
indicate either significant extraneural pathology or in- thoracic, and lumbar areas of the spinal cord are ex-
trinsic disease of the nervous system. amined routinely. The brain is then saved in formalin at
2. The diagnosis and classification of certain neuro- least until final disposition of the case. When the disease
logic diseases such as the neurodegenerative disorders process extends to peripheral nerve and skeletal muscle,
depend on a combination of clinical and pathologic cri- sections of the brachial and the lumbosacral plexuses,
teria, including the anatomic distribution of the lesions. sciatic nerve, sural nerve, and proximal and distal skele-
The diagnosis of amyotrophic lateral sclerosis, for ex- tal muscles from the upper and lower extremities are ex-
ample, is based on motor neuron loss, corticospinal amined. Specimens from the right and left sides of the
tract degeneration, and the clinical characteristics of the body should be included to determine the symmetry and
patient’s illness. distribution of the lesions. In cerebrovascular disorders
3. Neurologic signs and symptoms are influenced by the cervical arteries of the anterior and posterior circu-
the inciting disease, the part of the nervous system af- lation and the intracranial blood vessels (including the
fected, and the rate at which the disease evolves. Ob- dural venous sinuses) are examined for patency, steno-
viously, the clinical features of spinal cord infarction sis, and anomalies.
are very different from those of cerebral infarction. Fur- 5. The central and peripheral divisions of the ner-
thermore, the symptoms of cerebral infarction caused vous system have different regenerative capacities. In
by sudden vascular occlusion, such as embolism, may the central nervous system, repair and recovery involve
differ from those produced when the occlusion devel- chiefly an astrocytic and microglial reaction sometimes
ops more slowly, as in the case of thrombosis. These accompanied by proliferation of fibroblasts. Mature
considerations of location and rate of evolution are neurons do not replicate. Only limited regrowth of dis-
sometimes emphasized dramatically when a slowly rupted axons and collateral axonal sprouting may oc-
growing tumor such as a meningioma involves a part cur. Consequently, full functional recovery from larger
of the brain in which the lesion causes relatively few central nervous system (CNS) lesions is unlikely. Ab-
symptoms. By the time symptoms are recognized, the sent or only limited functional recovery, however, may
tumor may have become enormous by central nervous not be an inevitable result of central nervous system in-
system standards. Similarly, the early, subtle indications juries. Neurogenesis has been demonstrated in the hu-
of a slowly progressive degenerative disease may be un- man, adult CNS (Eriksson et al., 1998). In addition,
noticed until its extent causes obvious functional dis- recent studies show that the mature CNS expresses a
turbance. If this unmasking happens to coincide with number of the same substances that are involved in the
some chance event such as head trauma or emotional formation of neuronal networks during embryogenesis.
stress, etiologic importance may be erroneously attrib- The functional significance of these observations is as
uted to the event. yet unknown. They suggest, however, that the adult
1: INTRODUCTION TO NEUROPATHOLOGY 3
human CNS has the potential to replace damaged neu- 9. The central nervous system is described as a site
rons and remodel neuronal networks (Lowenstein and of immune privilege because tissue grafts implanted in
Parent, 1999). Axonal regeneration does occur in the the CNS appear to be exempt or protected from rejec-
peripheral nervous system after injury and may lead to tion. Other privileged sites include the anterior cham-
significant functional recovery. ber of the eye and the testis. The limited immunoreac-
6. Selective vulnerability is a concept often used to tivity at these sites was originally attributed to isolation
explain the preferential damage to certain regions or of the antigenic material from exposure to the immune
structures in the nervous system observed in generalized system because of blood–tissue barriers and the lack of
metabolic disturbances (hypoxia, intoxications), viral in- lymphatic pathways. Subsequent studies have shown,
fections, and degenerative diseases. When the pattern of however, that antigens from brain and other privileged
injury involves functionally related tracts and nuclei, the sites do come in contact with the immune system and
condition is referred to as a systematized disease. Ex- that immunoreactive lymphocytes can enter privileged
amples include amyotrophic lateral sclerosis and the sites. The basis for immune privilege is still under in-
spinocerebellar degenerations. Selective vulnerability vestigation In addition to the blood–brain barrier and
may involve discrete nuclei or groups of neurons, as is the passage of tissue fluids containing antigens directly
the case with hypoxic damage to the hippocampal cor- into the blood rather than through lymphatics, other
tex or hemorrhagic necrosis of the medial temporal lobes factors influencing immune regulation in the CNS in-
in herpes simplex type I encephalitis. The concept may clude immunosuppressive growth factors and limited
be extended to subcellular structures as in the case of expression of major histocompatibility complex mole-
the myelin sheath in multiple sclerosis. cules (Streilen, 1995).
The basis for the selectivity is often unknown. The
focal accentuation of lesions in cases of global ischemia
has been attributed to the vascular supply (distal arte- MORPHOLOGIC TECHNIQUES
rial perfusion bed) or the metabolic characteristics of USED IN NEUROPATHOLOGY
the affected region (energy reserves, sensitive enzymes).
Experimental studies indicate that excitotoxic injury Autopsy Procedures
(neuronal death caused by excessive release of excita- The autopsy procedure for removal of the brain de-
tory amino acid transmitters such as glutamate) may pends partly on whether the cranial sutures are open
be involved in selective ischemic damage to the CA1 or closed. The cranial cavity is opened either by cut-
region of the hippocampus (Whetsell, 1996; Auer and ting along suture lines or by sawing off the calvaria.
Benveniste, 1997). The spinal cord may be removed anteriorly after sec-
7. Neurons, astrocytes. axons, myelin sheaths, and tioning of the vertebral bodies or posteriorly after
other structures are unique to the nervous system. The laminectomy. The anterior method is generally more
study of neuropathology requires familiarity with the convenient except for dissection of the cervical cord,
normal morphology of these structures and their alter- segments of which are usually left behind when the an-
ations in response to injury. terior approach is used. Cranial and spinal nerve roots
8. The endothelial cells of CNS capillaries and the remain attached to the brain and spinal cord. Sensory
epithelium of the choroid plexus precisely control the ganglia are dissected as required. The College of Amer-
entry of cellular elements, ions, hormones, amino acids, ican Pathologists has published detailed guidelines for
and other substances from the blood into CNS paren- the autopsy examination of the brain, spinal cord, and
chyma or cerebrospinal fluid. The control mechanisms neuromuscular system (Powers, 1995). The presence or
involve a structural component, the tight junctions be- suspicion of infectious disease, particularly AIDS and
tween choroidal epithelial cells or CNS capillary en- Creutzfeldt-Jakob disease, necessitates special precau-
dothelial cells, as well as functional characteristics of tions (Brown, 1990; Ironside and Bell, 1996). In the
these cells, such as specific transport processes, limited case of Creutzfeldt-Jakob disease these extend to han-
pinocytosis, and other factors. Collectively, these con- dling of formalin-fixed tissue that can transmit the dis-
trol mechanisms are referred to as the blood–brain bar- ease (Brown, 1990).
rier or the blood–cerebrospinal fluid barrier. Besides
maintaining a constant microenvironment within the
Fixation Methods
CNS, the barriers influence CNS immunoreactivity
by selectively facilitating the passage of certain im- Various fixatives have been used in neuropathology
munoregulatory cells and molecules into the CNS while studies, most often to enhance the effects of a particu-
blocking the entry of others (Cserr and Knopf, 1997). lar stain. In the United States the best general fixative
for routine surgical and autopsy neuropathologic stud- (Chapters 15–20). The special procedures used for
ies is 10% neutral buffered formalin. For electron mi- peripheral nerve examination are summarized in the
croscopy, specimens are fixed in 3% phosphate- chapter on non-neoplastic diseases of the peripheral
buffered glutaraldehyde or buffered solutions of nervous system (Chapter 22).
paraformaldehyde and glutaraldehyde. The best fixa-
tion is obtained when intravascular perfusion of the
specimen is possible. Most human neural tissue is fixed GENERAL REACTIONS OF THE CENTRAL
by immersion, although some degree of perfusion fix- NERVOUS SYSTEM TO INJURY
ation can be achieved if postmortem brains are injected
with formalin through the major arteries at their base Pathologic conditions that accompany a variety of
(Adickes et al., 1997). The latter procedure may reduce central nervous system diseases are considered in this
the time needed for completion of the autopsy, which section.
may be necessary to meet current accreditation stan-
dards (Baker et al., 1996). Neural tissue may be em-
Brain Edema
bedded in either paraffin or celloidin for light micro-
scopic studies. The paraffin method is much faster and Brain edema is defined as an increase in the brain’s vol-
permits use of a wider range of stains than the celloidin ume because of an increase in its water and sodium con-
procedure. It is the technique employed most often in tent. A significant degree of brain edema may occur in
the United States. The celloidin method is valuable for head injury, stroke, infection, lead encephalopathy, hy-
the preparation of large specimens such as a coronal poxia, hypoosmolality, the disequilibrium syndromes as-
section of cerebrum to determine patterns of injury, for sociated with dialysis and diabetic ketoacidosis, and
the study of delicate normal and malformed fetal and some forms of obstructive hydrocephalus (Klatzo, 1987;
neonatal brains, and for morphometric investigations. Fishman, 1992). Brain edema has been classified ac-
Electron microscopy specimens are commonly embed- cording to its pathogenesis as either vasogenic or cyto-
ded in Epon, Epon-Araldite, or Spurr’s medium. Fresh toxic (Klatzo, 1967). A third type, interstitial or hydro-
or fixed tissues for histochemical studies involving en- cephalic edema, is sometimes added to the classification
zymes, lipids, carbohydrates, or antigens (immunohis- (Manz, 1974; Fishman, 1975).
tochemistry) are rapidly frozen in isopentane chilled at Vasogenic edema results from increased permeabil-
least to 80°C and sectioned without embedding in a ity of the cerebrovascular endotheliun that forms the
cryostat. blood–brain barrier to macromolecules, particularly
proteins (Klatzo, 1967). Consequently, protein tracers
such as Evans blue, trypan blue, and horseradish per-
Diagnostic Stains
oxidase can enter brain parenchyma after systemic in-
Special stains for selectively demonstrating neural struc- jection and indicate the sites of increased permeability.
tures, as well as stains for collagen. reticulin, carbohy- The change in permeability may be the consequence of
drates, microorganisms, and other tissue elements of defects in the tight junctions between endothelial cells,
interest are used in diagnostic neuropathology. Their increased vesicular transport across endothelial cells,
characteristics are summarized in Table 1.1. The spe- transendothelial passage through damaged or necrotic
cial stains traditionally associated with neuropatho- cells, or neovascularization with incomplete tight junc-
logic studies are being replaced by immunohistochem- tions or fenestrations in the newly formed endothelial
ical procedures, high-resolution light microscopy using cells (Fishman, 1992). The edema fluid biochemically
1-m-thick plastic sections stained with alkaline tolu- resembles a plasma filtrate with high sodium and serum
idine blue, and electron microscopy. More recently, protein concentrations. The fluid is located chiefly in
molecular techniques including polymerase chain re- the extracellular spaces of the white matter. Why va-
action (PCR), comparative genomic hybridization sogenic edema affects the white matter more severely
(CGH), and in situ hybridization (ISH) have gained than gray matter is unknown, but the lower capillary
importance in neuropathology, particularly in the density and cerebral blood flow in white matter may
study of neoplasms and infectious diseases (Bigner and be influential. Vasogenic edema probably is the most
Schrock, 1997; Muller et al., 1999; Kleinschmidt- common type of brain edema in humans. It complicates
DeMasters et al., 2001). Many of the important im- head injury, abscess, tumors, and hemorrhages. Both
munostains in diagnostic neuropathology apply to tu- vasogenic edema and cytotoxic edema occur with isch-
mors and are discussed in the chapters on that topic emic injury, including infarction.
TABLE 1.1 Common Neuropathology Stains
Stain Fixation Section Type Stain Type Application
A-beta amyloid Formalin Paraffin Immunostain Amyloid, senile plaque

Acid fast Formalin Paraffin Dye Mycobacteria
Alcian blue Formalin Paraffin Dye Mucin
Alpha beta crystallin Formalin Paraffin Immunostain Glial inclusions
Alpha synuclein Formalin Paraffin Immunostain Lewy bodies
Best’s carmine Formalin Paraffin Dye Glycogen
Modified Bielschowsky Formalin Paraffin Silver impregnation Neurites, senile plaques,
neurofibrils
Bodian Formalin Paraffin Silver impregnation Neurites, neurofibrils,
senile plaques
Cajal gold Formalin ammonium Frozen Gold impregnation Astrocytes
chloride sublimate bromide
CD 68 Formalin Paraffin Immunostain Macrophages
Chromogranin Formalin Paraffin Immunostain Neurosecretory granules
Congo red Formalin Paraffin Dye Amyloid
Fontana Formalin Paraffin Silver impregnation Melanin
Gallyas Zenker, B-5, formalin Paraffin Silver impregnation Neurofibrils, dystrophic neurites,
cytoskeletal inclusions
GFAP Formalin Paraffin Immunostain Astrocytes
Giemsa Formalin Paraffin Dye Toxoplasma
Gram Formalin Paraffin Dye Bacteria
Gridley Formalin Paraffin Dye Fungi
Ham 56 Formalin Paraffin Immunostain Macrophages
Hematoxylin & eosin Formalin Paraffin Dye General tissue stain
Hirsch-Peiffer Formalin Frozen Histochemical Cerebroside sulfate
Holzer Formalin Paraffin Dye Fibrillary astrocytes
Loyez Formalin Paraffin Dye Intact myelin (black)
Luxol fast blue (LFB) Formalin paraffin Dye Intact myelin (blue)
Methenamine silver Formalin Paraffin Silver impregnation Fungi
Movat pentachrome Formalin Paraffin Dye Collagen, elastic fibers, muscle,
fibrin, mucin
Mucicarmine Formalin Paraffin Dye Mucin
Myelin basic protein Formalin Paraffin Immunostain Intact myelin
Neurofilament protein Formalin Paraffin Immunostain Neurons, neurites
Neuron-specific Formalin Paraffin Immunostain Neuronal and neuroendocrine
enolase cells
Nissl Formalin Paraffin Dye Nerve cell bodies
Oil red O Formalin Frozen Dye Sudanophilic lipids including
neutral fat
PAS Formalin Paraffin Histochemical Glycogen, basement membrane
Perl’s prussian blue Formalin Paraffin Histochemical Ferric iron
PTAH Formalin Paraffin Dye Fibrillary astrocytes
Reticulin Formalin Paraffin Silver impregnation Reticulin fibers, basement
membrane
S-100 Formalin Paraffin Immunostain Glia and Schwann cells
Sevier-Munger Formalin Paraffin Silver impregnation Neurites, neurofibrils, senile
plaques
(continued)
5
TABLE 1.1 Common Neuropathology Stains (continued)

Stain Fixation Section Type Stain Type Application
Silver carbonate Formalin ammonium Frozen Silver impregnation Glia, especially astrocytes
(Hortega) bromide
Synaptophysin Formalin Paraffin Immunostain Neurons
Tau Formalin Paraffin Immunostain Neurofibrils, glial inclujsions
Thioflavine S Formalin Paraffin Fluorochrome dye Amyloid, neurofibrils,
senile plaques
Ubiquitin Formalin Paraffin Immunostain Glial and neuronal inclusions
van Gieson Formalin Paraffin Dye Collagen; may be used
with Verhoef
Verhoef Formalin Paraffin Dye Elastic fibers; may be used with
van Gieson
von Kossa Formalin Paraffin Histochemical Calcium
Warthin Starry Formalin Paraffin Silver impregnation Spirochetes
Source: Bancroft and Stevens (1996) and Carson (1997).
In cytotoxic edema, excessive amounts of water en- come dilated. These changes are reversible, including
ter one or more of the cellular elements in the central reestablishment of white matter volume after the ob-
nervous system, causing them to swell and reduce the struction is relieved either spontaneously or by shunt-
volume of the brain’s extracellular space. Neurons, glia, ing. The recovery mechanisms and their determinants
endothelial cells, and myelin sheaths may be affected. are not fully understood.
Water shifts into the cells because the cellular concen- The gross morphologic changes associated with brain
tration of osmotically active solutes is increased. This edema include softening and swelling of the affected
increase develops because of an injury impairing the parenchyma. The swelling increases the volume of the
cells’ capacity to maintain ionic homeostasis or in as- intracranial contents, leading to compression of the
sociation with systemic disturbances in fluid and elec- brain surfaces against the inner table of the skull. The
trolyte metabolism. The edema fluid consists of water compression causes flattening of cerebral gyri, nar-
and sodium. The endothelial barrier to macromole- rowing of intervening sulci, and accentuation of foram-
cules, including protein, is usually unaffected and inal and tentorial markings on the inferior cerebellar
plasma proteins are not a component of the cellular and medial temporal surfaces (Fig. 1.1). The cut sur-
edema. Both gray and white matter are affected. Cy- faces may be wet and shiny. If the edema is diffuse and
totoxic edema occurs in hypoxic or ischemic brain in- not of the hydrocephalic type, the ventricles become
jury, in osmotic disequilibrium syndromes associated smaller. In severe cases they are reduced to slitlike cav-
with hemodialysis or diabetic ketoacidosis, and in acute ities (Fig. 1.2).
plasma hypoosmolality states such as water intoxi- Microscopic changes vary in all forms of brain
cation and inappropriate secretion of antidiuretic edema. Routinely processed paraffin sections may ap-
hormone. pear normal. In the more severe forms of vasogenic
Interstitial or hydrocephalic edema is the accumula- edema the affected white matter is pale staining and
tion of cerebrospinal fluid in the extracellular spaces of vacuolated. The vacuoles may contain cell nuclei or
the periventricular white matter. This accumulation re- may appear to lie between parenchymal elements.The
sults from obstructed flow of cerebrospinal fluid in ei- distance between adjacent myelin sheaths or axons is
ther the ventricular system or the subarachnoid space increased. Eosinophilic droplets or acellular pink-
(Fishman, 1992). As fluid collects within the obstructed staining deposits are present around blood vessels. In
ventricles, pressure increases and the cerebrospinal fluid cases of cytotoxic edema, vacuoles can be seen in the
is forced across the ependymal lining into the adjacent affected parenchyma. These alterations require careful
extracellular spaces. Although an absolute increase in consideration and correlation with other gross and mi-
the volume of extracellular fluid occurs, the volume of croscopic observations before a definitive diagnosis of
the periventricular white matter is reduced (presumably edema can be made. In particular, decreased staining
because of loss of myelin lipids) and the ventricles be- intensity and parenchymal vacuolization can be in-
by successful treatment. These abnormalities, however,

might be caused by the same injury that led to the
edema or by the effects of incrcased intracranial pres-
sure rather than the simple accumulation of water and
sodium in the parenchyma. Further studies are required
to clarify the mechanisms of cerebral dysfunction in
brain edema.
The pathologic delineation of vasogenic, cytotoxic,
and interstitial forms of edema is based chiefly on con-
trolled experimental studies in previously healthy ani-
mals. Within the limits of these experimental protocols,
only one type of edema is induced. In humans, how-
ever, the pathogenesis of brain edema often involves
multiple mechanisms. Patients can have two or more
diseases, or complications of the primary disorder may
develop. These factors can lead to the occurrence of
more than one type of edema; for example, develop-
ment of acute hydrocephalus in a patient with a brain
tumor might be associated with both vasogenic and in-
terstitial brain edema.
FIGURE 1.1 Brain edema. Cerebral convexity. Flattened gyri and nar- Increased Intracranial Pressure and Brain Herniation
rowed sulci.
After closure of the sutures the volume of the cranial
cavity is fixed by rigid bony walls and compartmen-
duced as artifacts through improper fixation, dehydra- talized by partitions of bone and dura. The normal con-
tion, embedding, or staining of brain tissue. Morpho- tents of the cranial cavity (blood, brain, and cere-
logic evaluation is somewhat more precise when prop- brospinal fluid) are relatively incompressible. Under
erly fixed and stained, plastic-embedded sections, 1 m these conditions an increase in the volume of the cra-
thick, are examined by light microscopy or when thin nial contents can cause intercompartmental displace-
sections are studied by electron microscopy. These ment of brain, blood, or cerebrospinal fluid and in-
methods more convincingly show cellular swelling in creased intracranial pressure. As the intracranial
cytotoxic edema or enlargement of the extracellular contents expand, compression of the brain against the
space in vasogenic edema. These procedures are most inner surfaces of the cranial cavity and the edges of the
reliable when the tissue can be fixed rapidly after sep- dural septa produces flattening of gyri and narrowing
aration from its blood supply, as in experimental stud-
ies or brain biopsy specimens. Postmortem changes
such as swelling of cells and organelles or breakdown
of cell membranes begin quickly and can impede con-
clusive analysis of the observed alterations.
Questions about the possible deleterious effects of
edema on brain structure or function have not been
fully answered. The increases in intracellular or extra-
cellular space caused by the edema could affect the
timely availability of critical metabolites and disturb
cell function. Biochemical activity could be affected by
the elevated sodium levels. Reduced blood volume has
been described in edematous regions of brain (Penn and
Kurtz, 1977). Histologic examination shows occasional
lipid phagocytes and a reactive proliferation of
astrocytes in areas of chronic edema. Changes in
consciousness, seizure threshold, and the electroen- FIGURE 1.2 Brain edema. Note the slit-shaped outlines of the lateral
cephalogram accompany brain edema and are reversed and third ventricles.
of sulci over the convex surfaces of the cerebral hemi- tions of the ventral posterior hypothalamus (such as
spheres and accentuation of anatomical markings at the mammillary bodies) and rostral brain stem are dis-
base of the brain. Conditions which lead to an increased placed caudally. These alterations are often more evi-
volume of the cranial contents include brain edema, in- dent as seen by in situ imaging than by conventional
creased cerebral blood flow and blood volume (for ex- macroscopic examination of the brain. They are ac-
ample, in chronic pulmonary insufficiency with respi- companied by signs of diencephalic and upper brain-
ratory acidosis), or the development of space-occupying stem compression, including decreased level of con-
lesions such as tumors, abscesses, hematomas, and large sciousness, variations in pupillary size from small to
infarcts. The increase in volume caused by the space- midrange, and disturbances in respiratory rhythm.
occupying lesions involves not only the mass of the le- Uncal or medial temporal lobe herniation is caused
sion but also the edema which often accompanies the chiefly by asymmetric supratentorial space-occupying
lesion. Continuing expansion of the cranial contents lesions. As the medial temporal lobe herniates through
can cause obstruction of venous or cerebrospinal fluid the incisura, both the ipsilateral oculomotor nerve and
pathways with a further increase in intracranial the rostral brain stem are compressed, giving rise to ip-
pressure. silateral pupillary dilation, disturbed consciousness,
The displacement of brain from one intracranial and other signs of rostrocaudal deterioration of brain-
compartment to another caused by an increase in the stem function. In addition to the gyral flattening com-
volume of cranial contents is called brain herniation. If monly associated with increased intracranial pressure,
the volumetric increase takes place over a long period, the brainstem and adjacent basilar cerebral structures
as occurs with a slowly growing meningioma, consid- are displaced laterally away from the herniating tem-
erable displacement can develop asymptomatically and poral lobe (Fig. 1.3). If the displacement is severe, the
without a rise in intracranial pressure. In contrast, more rostral brain stem is forced against the edge of the op-
rapid expansion of cranial contents leads quickly to posite tentorial leaf, causing a wedge-shaped focus of
symptomatic brain herniations and increased intracra- tissue destruction involving the cerebral peduncle re-
nial pressure. ferred to as Kernohan’s notch (Fig. 1.4) (Kernohan and
The three herniations commonly encountered after Woltman, 1929). Its occurrence is characterized by the
rapid volumetric increase are transtentorial herniation development of hemiplegia on the same side as the her-
of the medial temporal lobe and brainstem, ventral
cerebellar herniation into the foramen magnum, and
subfalcial herniation of the cingulate gyrus. Less fre-
quently observed are herniations of the orbital gyri into
the temporal fossa, the hypothalamus into the hy-
pophyseal fossa, the anterior midline cerebellum up-
ward through the incisura of the tentorium, and por-
tions of the cerebral convexity through surgical or
traumatic defects in the calvaria.
Transtentorial herniation is caused by supratentorial
space-occupying lesions. It is sometimes separated into
two components: central herniation, which refers to the
rostrocaudal displacement of the hypothalamus and
rostral brain stem through the incisura of the tento-
rium, and uncal or medial temporal lobe herniation,
which involves herniation of the uncus and parahip-
pocampal gyrus over the free edge of the tentorium and
through the incisura (Plum and Posner, 1980).
Central herniation may be present without associ-
ated uncal herniation when both cerebral hemispheres
are enlarged equally, usually as a result of diffuse cere-
bral edema. In this circumstance, symmetric prominent
tentorial grooves are evident on the inferior surfaces of
both unci, the gyri are flattened, and the sulci are nar- FIGURE 1.3 Uncal herniation. Note sharp tentorial groove on the ven-
rowed over both cerebral convexities. Midline cerebral tral surface of the herniated uncus and parahippocampal gyrus with
structures, however, are not displaced laterally. Por- displacement of midline structures.
cerebellar displacement is commonly referred to as ton-

sillar herniation; however, the herniation includes the
biventral lobule as well as the tonsils (Fig. 1.6). Clini-
cal evidence of ventral cerebellar herniation includes
head tilt, stiff neck, paresthesias over the shoulders, and
eventual respiratory arrest resulting from medullary
compression. The pathologic diagnosis of tonsillar her-
niation is based primarily on macroscopic findings, in-
cluding identification of an inciting cause, evidence of
increased intracranial or posterior fossa pressure, a
prominent foraminal groove on the ventral surface of
the cerebellum, close approximation of the tonsils and
medulla, and edema of the medulla. Medullary edema
FIGURE 1.4 Kernohan’s notch. Wedge-shaped focus of necrosis on lat-
is indicated by bulges on the cut surface of the caudal
eral margin of cerebral peduncle. medulla where it was separated from the upper cervi-
cal spinal cord during removal of the brain post
mortem. Compression of the vascular supply to the ven-
niated temporal lobe. The posterior cerebral artery tral cerebellum can cause congestion, focal hemor-
crosses the ventral and medial surface of the temporal rhages, and infarction of the herniated parenchyma. In
lobe. As the medial temporal lobe herniates through some cases focal necrosis of the caudal medulla and up-
the incisura, the posterior cerebral artery is occluded per cervical cord is demonstrable. The pathologic le-
by compression against the tentorial edge, causing sions indicating tonsillar herniation may be bilaterally
infarction of the ipsilateral ventromedial occipital lobe. symmetric or asymmetric depending on the direction
The infarction produces a homonymous hemianopsia of force generated by the inciting lesion. In determin-
that becomes evident if the patient survives. Rostro- ing whether tonsillar herniation has occurred, the
caudal displacement of the brain stem causes stretch- pathologist must be aware of the normal variations in
ing and eventual disruption of the intrinsic vasculature foraminal markings on the ventral cerebellar surface
(chiefly arterioles) in the midbrain and pons giving rise and must find other anatomic evidence of tonsillar
to midline and lateral hemorrhages (sometimes called hemiation, in addition to a prominent foraminal
Duret hemorrhages) (Fig. 1.5). These hemorrhages pro- groove.
duce profound deterioration of brainstem function and Herniation of the cingulate gyrus beneath the falx is
can cause death through destruction and interruption not usually associated with any well-defined clinical
of cardiorespiratory centers and pathways. syndrome, probably because any symptoms produced
Herniation of the cerebellum into the foramen mag-
num is more often associated with space-occupying le-
sions in the posterior fossa. In addition, the herniation
can occur with supratentorial midline frontal masses,
in association with uncal herniation, and with gener-
alized increases in the volume of cranial contents. The
FIGURE 1.6 Ventral cerebellar herniation (tonsils and biventral lob-

FIGURE 1.5 Secondary brainstem hemorrhages (Duret hemorrhages) ule). The herniated cerebellum is closely approximated to the
involving midbrain and pons. medulla. A prominent foraminal groove is evident.
by the lesion are masked either by the lesion causing venous hypertension have been implicated as con-
the herniation or by the clinical effects of an accom- tributing factors in some cases of hydrocephalus.
panying uncal hemiation. In some cases, however, com- The lesions responsible for obstructive hydro-
pression of branches of the ipsilateral anterior cerebral cephalus include tumors and other masses, malforma-
artery against the free edge of the falx produces hem- tions, and inflammatory reactions involving the ven-
orrhagic infarction of the medial hemispheric surface tricular system or subarachnoid space. The ventricular
and lower-extremity weakness. Cingulate hemiation is system usually becomes obstructed at sites where the
caused by asymmetric, supratentorial space-occupying fluid pathway narrows, such as the foramen of Monro,
lesions, especially those involving the upper half of the the aqueduct of Sylvius, and the exit foramina of the
frontoparietal cerebral convexity. The cingulate gyrus fourth ventricle, or at the third or fourth ventricle when
is forced beneath the falx and across the midline. The the lumens become filled with tumor or blood clot. Sub-
ipsilateral corpus callosum is pushed ventrally, and the arachnoid pathways most often become blocked over
adjacent lateral ventricle is compressed. the cerebral convexities and around the rostral brain
External herniation may occur when edematous cere- stem (incisural block) as a result of inflammation or
bral cortex herniates through a craniotomy site or frac- hemorrhage. In the acute phase the blood clot or in-
ture. Pressure necrosis leads to further edema and vaso- flammatory exudate forms a barrier to flow. Subse-
congestion, causing continued herniation. quently, organization of the clot or exudate leads to fi-
brous obliteration of the subarachnoid space.
Obstructive hydrocephalus may be classified as
Hydrocephalus
communicating or noncommunicating depending on
Hydrocephalus is an abnormal increase in the in- whether or not the ventricular system remains in con-
tracranial volume of cerebrospinal fluid associated with tinuity (“communicates”) with the subarachnoid space.
dilatation of all or part of the ventricular system (Fig. In communicating hydrocephalus the obstruction is in
1.7) (Fishman, 1992). The condition usually results the subarachnoid space, and cerebrospinal fluid passes
from obstruction of cerebrospinal fluid pathways either freely through the entire ventricular system into the
within the ventricular system or in the subarachnoid subarachnoid space proximal to the obstruction. In
space: this is referred to as obstructive hydrocephalus. noncommunicating hydrocephalus the obstruction is
Increased production of cerebrospinal fluid causing hy- somewhere between the foramen of Monro and the exit
drocephalus has been demonstrated only in cases of foramina of the fourth ventricle, preventing free flow
choroid plexus papilloma with secretion of the excess of cerebrospinal fluid between all or part of the ven-
fluid by the tumor (Milhorat et al., 1976). Impaired tricular system and the subarachnoid space. The oper-
absorption of cerebrospinal fluid through arachnoid ational difference between these two types of obstruc-
villi and decreased venous drainage after occlusion or tive hydrocephalus orginally was based on detection of
a visible dye in the lumbar cerebrospinal fluid shortly
after injection of the dye into the lateral ventricle. The
presence of dye indicated communicating hydro-
cephalus, and the absence of dye indicated noncom-
municating hydrocephalus. The distinction between the
two types of obstructive hydrocephalus is important in
determining the location of surgical shunts used to by-
pass the obstruction and reduce ventricular size.
Compensatory increase in cerebrospinal fluid volume
and ventricular dilatation resulting from loss of brain
tissue through atrophy or other primary injuries to
brain parenchyma is called hydrocephalus ex vacuo. ln
this condition the flow of cerebrospinal fluid is unob-
structed and the intracranial pressure is normal.
Clinical evidence of hydrocephalus may be present
or absent. The head is enlarged in children when hy-
drocephalus develops before the cranial sutures close.
FIGURE 1.7 Hydrocephalus. Moderate, symmetric dilatation of lat- If the hydrocephalus is associated with increased in-
eral ventricles. tracranial pressure, then mental dullness, headaches,
nausea, vomiting, and papilledema may occur. The large, well-defined bodies and in others as small gran-
term normal pressure hydrocephalus refers to an im- ules or dustlike particles spread diffusely throughout
portatnt but incompletely understood form of commu- the cytoplasm. In Clarke’s column the normal concen-
nicating hydrocephalus in which a characteristic triad tration of Nissl substance at the periphery of neuronal
of clinical findings consisting of dementia, gait distur- perikarya is sometimes misinterpreted as chromatoly-
bance, and urinary incontinence is associated with im- sis, a neuronal reaction to injury. Postmortem autoly-
paired subararchnoid circulation and absorption of sis or fixation methods may induce artifactual changes
cerebrospinal fluid, and ventricular dilatation. Timely in neurons that may be misinterpreted as evidence of
and accurate diagnosis of this disorder is a matter of disease. One of the most common changes of this type
special importance because it is amenable to treatment is the dark, shrunken neuron seen in brain biopsies
with surgically placed shunts. fixed by immersion in formalin. The cytoplasm of these
Several alterations in the brain are common to all neurons is deeply stained. The cell body is shrunken,
forms of hydrocephalus. These include dilatation of the and the nucleus appears irregular, smaller, and uni-
ventricular system, reduction of the volume of the cere- formly basophilic with loss of detail. These features are
bral white matter, disruption and loss of the ependy- associated with immersion fixation and are not in-
mal lining, subependymal astrocytosis, accentuation of dicative of neuronal injury.
the primary, secondary, and tertiary cerebral sulci, and Pigments such as lipofuscin and neuromelanin are
perforation of the septum pellucidum. The lesions as- found in otherwise-normal nerve cells. Lipofuscin is
sociated with congenital and related forms of childhood present in many neurons throughout the central ner-
hydrocephalus are covered in Chapter 2. vous system of older persons and is sometimes referred
to as an age pigment, although it has been observed,
unassociated with neurologic disease, in the inferior oli-
CELLULAR CHANGES INDICATING CENTRAL vary and spinal cord neurons of some very young hu-
NERVOUS SYSTEM INJURY mans as well as in the inferior olivary, hypoglossal, and
trigeminal nuclei of 6-month-old Rhesus monkeys
Aside from alterations affecting supporting structures (Tomlinson, 1979; Mann and Yates, 1982). Melanin
such as blood vessels or meninges, the morphologic pigment is found in two types of cells in the central
changes in the central nervous system that have proven nervous system—leptomeningeal melanocytes and neu-
to be reliable indicators of nonneoplastic neural rons (neuromelanin). The leptomeningeal melanocytes
parenchymal injury chiefly affect neurons, astrocytes, are similar to melanocytes in the skin and eye. Melanin
and microglia. Reactions involving one or more of these is formed in these cells within cytoplasmic organelles
cells are present in almost every central nervous system called melanosomes. The process involves the tyrosi-
disease. In conditions such as the neurodegenerative nase-catalyzed oxidation of tyrosine, copolymerization
disorders where the etiology and pathogenesis are un- of the reaction products, and formation of melanin
known, the characteristics of the cellular reaction are pigment. Leptomeningeal melanocytes occur in great-
used together with their anatomic distribution and the est number along the ventral medulla and adjacent cer-
clinical findings to diagnose and classify individual vical cord. They are the cells that give rise to primary
diseases. melanomas of the central nervous system. The most
prominent groups of neurons containing neuromelanin
are in the substantia nigra and locus coeruleus; how-
Neurons
ever, the pigment can be seen in other neurons located
Familiarity with the diverse morphology of normal cen- along the floor of the fourth ventricle. Neuromelanin
tral nervous system neurons is necessary for accurate is biochemically and ultrastructurally distinct from the
identification of injured neurons. Nerve cell bodies melanin in the leptomeningeal melanocytes. Neurome-
range in size from very small, such as the Iymphocyte- lanin is not formed through the tyrosinase pathway. It
like granule cells of the cerebellar cortex, to large and appears to be a waste product of catecholamine me-
prominent, such as motor neurons in the precentral tabolism and is localized in subcellular structures re-
gyrus or anterior horns of the cervical and lumbar cord. sembling lysosomes rather than melanosomes (Gra-
The neuronal perikaryon may be multipolar, round, ham, 1979). Neuromelanin pigment is unaffected in
oval, pyramidal, or flask shaped. Nissl substance, the cases of albinism (Guillery et al., 1975).
histologic counterpart of clumped granular endoplas- Neuronal injury causes either cell death or progres-
mic reticulum, appears in some types of neurons as sive, sometimes reversible, morphologic alterations.
Nerve cell death ures should be viewed as approximations rather than

irrefutable doctrine. Dead neurons, especially those ad-
Two morphologic patterns of nerve cell death are cur-
jacent to areas of infarction or thalamic neurons in
rently recognized: eosinophilic neuronal necrosis (or
neonates with hypoxic–ischemic brain damage, may
simply neuronal necrosis) and neuronal apoptosis.
become encrusted with basophilic mineral deposits,
Macroscopically, the extent of either form of neuron
chiefly iron and calcium salts. This condition is referred
loss may be sufficient to produce an obvious decrease
to as ferrugination of neurons.
in the volume of the affected structure, which is re-
ferred to as atrophy. It is important to keep in mind
that some anatomic features used as indicators of brain Neuronal apoptosis
atrophy such as increased ventricular volume or ap-
This genetically regulated type of cell death may be ini-
parent increases in sulcal width are not always caused
tiated by either physiologic or pathologic processes
by parenchymal loss and may even reflect normal an-
(Hetts, 1998). Physiological processes involving apop-
atomic variations.
tosis include the scheduled elimination of excess cells
formed during embryogenesis in various organs in-
Eosinophilic neuronal necrosis cluding the central nervous system. The elimination
process is referred to as programmed cell death, and
This reaction is probably the most common morpho-
apoptosis is the mechanism by which the cells die.
logic expression of neuronal death in human neu-
Pathologic stimuli which may induce apoptotic cell
ropathology. It is characteristically associated with
death include ischemia, toxic disturbances, viral infec-
ischemic disturbances, such as severe systemic hy-
tion, and ionizing radiation. The affected cell becomes
potension with impaired cerebral perfusion or strokes
shrunken. In hematoxylin and eosin (H&E) stains the
caused by occlusive vascular disease, but it may be seen
cytoplasm is intensely eosinophilic. The chromatin con-
with other types of injuries. In sections stained with
denses along the nuclear membrane. Subsequently, the
hematoxylin and eosin the cytoplasm of the affected
nucleus fragments and cytoplasmic buds are formed
neurons has lost its usual slightly basophilic color and
which contain the nuclear fragments. The buds become
stains red. The nucleus is shrunken and darkly stain-
separated from one another forming apoptoic bodies
ing, and internal details are obscured (Fig. 1.8). These
which are phagocytosed by macrophages (Fig. 1.9). The
changes are evident in experimental animals killed 30
inflammatory response associated with necrotic cell
to 90 minutes after the ischemic event (Duchen, 1992).
death does not occur with apoptotic cell death. The
In humans the shortest survival time after the ischemia
role of apoptosis in human neuropathology is under in-
required for the appearance of unequivocal red neu-
vestigation. Evidence linking neuronal apoptosis with
rons is not known precisely. The evolution of
HIV encephalitis, brain infarction, and Alzheimer’s dis-
eosinophilic neurons commonly takes 6–8 hours in hu-
ease has been reported. Conclusive demonstration of
mans. Such changes, however, occasionally are seen af-
the occurrence and extent of apoptosis in human neu-
ter even shorter periods (Petito et al., 1987). These fig-
ropathologic conditions, however, is hampered by the
FIGURE 1.8 Eosinophilic neuronal necrosis. Slightly shrunken neurons

with loss of normal cyttoplasmic and nuclear details. The dark- FIGURE 1.9 Neuronal apoptosis. Cluster of apoptotic bodies. H&E,
staining nerve cell bodies are red in H&E stains. H&E, 240. 750.
difficulty in distinguishing apoptosis from other simi-

lar but unrelated cellular changes (Petito and Roberts,
1995; Baranaga, 1998).
The microscopic diagnosis of atrophy when the
necrotic or apoptotic process has ended requires con-
sideration of the normal histologic features of the cen-
tral nervous system. Nerve cell bodies are generally
arranged in vaguely defined groups rather than homo-
geneously in the gray matter of the brain and spinal cord.
This grouping gives rise to areas devoid of neurons that
may be mistakenly diagnosed as foci of nerve cell loss
or developmental absence. Accurate evaluation of these
foci can be difficult, particularly in regard to potential
developmental disturbances. The use of serial and con- FIGURE 1.10 Neuronal chromatolysis. Swollen neuron with central loss
trol sections and evidence of an astrocytic or microglial of Nissl substance and peripheral displacement of nucleus. H&E, 480.
reaction are helpful in resolving this type of problem.
ments belong to the family of intermediate filaments.

Progressive or reversible neuronal injuries
They are 10 nm in diameter and contain a distinctive
Morphologic evidence of progressive, sometimes re- protein composed of three polypeptides with approxi-
versible, neuronal injury includes central chromatoly- mate molecular weights of 68,000, 150,000, and
sis, neurofibrillary degeneration, neuronal storage of 200,000 daltons. Microfilaments range from 5 to 7 nm
metabolic products, and formation of inclusion bodies. in diameter and contain actin as their chief protein.
The physiologic functions of these fibrous elements
are not fully defined but are believed to involve main-
Central chromatolysis
tenance of cellular shape and intracellular transport of
The term central chromatolysis refers to the changes macromolecules and organelles. Increases in the num-
occurring in the nerve cell body after injury to its axon ber and changes in the morphology of neurofilaments
relatively close to the perikaryon or possibly to the cell and microtubules are associated with several human
body itself. The Nissl substance disappears beginning neurologic disorders, including Alzheimer’s disease,
in the center of the cell body around the nucleus and postencephalitic parkinsonism, progressive supranu-
extending peripherally. At the same time the nucleus is clear palsy. and the punch-drunk syndrome (dementia
displaced eccentrically and the cell body enlarges, caus- pugilistica), as well as experimental or therapeutic ex-
ing conversion of its contours from concave to convex posure to aluminum salts and the vinca alkaloids used
(Fig. 1.10). Depending on the severity of the injury and to treat hematologic malignancies. The term neurofib-
the regenerative capacity of the affected axon, the neu- rillary degeneration is applied to the light microscopic
ron may eventually recover or degenerate and disap- appearance of this alteration. Affected neurons contain
pear. This type of alteration can be seen in the motor prominent woven and convoluted masses or tangles of
neurons of the spinal cord in cases of anterior nerve neurofibrils that are most reliably demonstrated with
root compression. silver impregnation methods (Fig. 1.11). The ultra-
structure of the neurofibrillary tangle varies according
to which filamentous proteins are affected and the mor-
Neurofibrillary degeneration
phologic modifications they undergo. Some of these
Neurofibrils are the argyrophilic linear densities seen patterns are characteristically associated with a partic-
by light microscopy in nerve cell bodies and their pro- ular disease or group of disorders, such as paired heli-
cesses after silver impregnation. Ultrastructural studies cal filaments in Alzheimer’s disease. Recently, the bio-
have demonstrated that neurofibrils are a composite chemical classification of cytoskeletal pathology has
of three types of filamentous proteins—microtubules gained major significance (Dickson, 1997).
(neurotubules), neurofilaments, and microfilaments—
which are major components of the neuronal cy-
Neuronal storage
toskeleton (Goldman and Yen, 1986). Microtubules are
long, hollow structures measuring 25 nm in diameter. Characteristic morphologic evidence of neuronal dam-
The major protein component is tubulin. Neurofila- age occurs in some hereditary metabolic diseases caused
Inclusion bodies
Intracytoplasmic or intranuclear inclusions are impor-
tant indicators of neuronal injury. They occur in viral,
metabolic, and degenerative diseases. Viral infections
associated with intranuclear inclusions include those
caused by herpes simplex virus type 1, cytomegalovirus,
and measles virus (subacute sclerosing panencephali-
tis). Cytoplasmic viral inclusions are seen in rabies (Ne-
gri bodies) and occasionally in cytomegalovirus infec-
tions. Among the metabolic and degenerative diseases,
intracytoplasmic inclusions with characteristic (not
necessarily specific) associations are Pick bodies (Pick’s
FIGURE 1.11 Neurofibrillary degeneration. Prominent clusters of neu- disease), Lewy bodies (Parkinson’s disease), and Lafora
rofibrils fill the cell bodies of two neurons. Bodian, 600. bodies (Lafora’s disease). Pick bodies are rounded,
eosinophilic, argyrophilic, cytoplasmic masses made up
of 10–20 nm straight filaments, constricted fibrils, and
by enzymatic defects involving synthetic or degradative clumps of granular material. The straight filaments con-
pathways for lipids or carbohydrates. Interruption of tain neurofilament and microtubular epitopes that are
the pathway leads to cytoplasmic accumulation or stor- similar to those in Alzheimer paired helical filaments
age of intermediate substrates and their by-products. (Munoz-Garcia and Ludwin, 1984; Perry et al., 1987).
The cell body of the neuron enlarges, its contours Lewy bodies are homogeneous or concentrically lami-
change from concave to convex, and the nucleus is ec- nated structures with an eosinophilic core surrounded
centrically displaced (Fig. 1.12). In several neuronal by a clear halo (Fig. 1.13). They are composed of 7–8
storage disorders the cytoplasmic accumulations have nm straight filaments that have antigenic properties
distinctive histochemical and ultrastructural features. similar to neurofilaments (Goldman and Yen, 1986).
Identification of these characteristics in biopsy speci- Lafora bodies are round, homogeneous, or laminated
mens of brain and other tissues has been used as a structures between 10 and 30 m in diameter that are
means of confirrming and further categorizing clinically basophilic with hematoxylin and eosin and periodic
suspected cases of storage disorders (Greenwood and acid–Schiff (PAS) positive.They consist of a core of
Nelson, 1978). More recently, however, as the under- agranular and dense material surrounded by filamen-
lying metabolic disturbances have been delineated more tous structures that contain a glucose polymer called a
completely, biochemical tests on blood, leukocytes, and polyglucosan (Sakai et al., 1970; Gambetti et al., 1971;
other body fluids have supplanted the use of biopsy in Robitaille et al., 1980). Eosinophilic rods, referred to
several of these diseases. as Hirano bodies, and granulovacuolar degeneration,
FIGURE 1.12 Neuronal storage disorder (gangliosidosis). The cell bod-

ies are markedly enlarged with foamy cytoplasm. The nuclei and FIGURE 1.13 Two Lewy bodies in the cytoplasm of pigmented neu-
Nissl substance are displaced. H&E, 400. ron in the substantia nigra. H&E, 400.
one or more cytoplasmic vacuoles each containing a in the size, the number, or both the size and number
basophilic body, are intracytoplasmic neuronal inclu- of astrocytes; fibrillary astrocytosis is used for reactions
sions found chiefly in the cell bodies and processes of in which there is only a sparse population of astrocyte
neurons in the pyramidal cell layer of the hippocam- nuclei and astrocytic processes are the dominant his-
pus. Immunohistochemical studies have shown the as- tologic feature.
sociation of cytoskeletal proteins including actin and Secondary or reactive astrocytosis is one of the most
tau as well as the C-terminal fragment of the amyloid common and important neurocellular reactions to in-
precursor protein with the Hirano body: The granulo- jury (Fig. 1.14). It occurs as a response to injury of
vacuolar bodies also contain cytoskeletal proteins such other parenchymal elements such as neurons, axons, or
as tubulin, tau, and neurofilament proteins (Hirano, myelin sheaths and to distubances in CNS homeosta-
1997). Although Hirano bodies and granulovacuolar sis in the absence of structural damage (Kraig et al.,
degeneration occur in older persons without clinical ev- 1991; Norton et al., 1992). The morphologic charac-
idence of neurologic disease, they are more prevalent teristics of the reaction cannot be used to identify spe-
in certain degenerative disorders such as Alzheimer’s cific diseases. In this sense the reaction may be consid-
disease (DeArmond et al., 1997). Bunina bodies are ered nonspecific. Nevertheless, it is an indication that
eosinophilic. nonviral, intracytoplasmic inclusions that there has been some type of injury to the central ner-
may be observed in cases of familial or sporadic amy- vous system. Artifactual changes in the morphology
otrophic lateral sclerosis. Marinesco bodies (small, and staining characteristics of neurons, axons, and
eosinophilic intranuclear inclusions located chiefly myelin sheaths frequently are present in human surgical
in melanin-containing brainstem neurons) and eosino- and postmortem neuropathologic specimens. Recogni-
philic, intracytoplasmic inclusions in hypoglossal and tion of reactive changes involving astrocytes provides
anterior horn neurons are neuronal inclusions that have the neuropathologist with evidence for deciding if the
no known pathologic significance. alterations affecting neurons, axons, or myelin are in-
dicative of a disease process.
The early stages of reactive astrocytosis vary ac-
Astrocytes
cording to the acuteness and severity of the parenchy-
Two types of astrocytes, protoplasmic and fibrillary, mal damage as well as the extent of white matter in-
are distinguishable by light microscopy when metallic volvement. If the lesion develops rapidly with necrosis
impregnation techniques are used. Protoplasmic astro- or myelin destruction, the size of the astrocyte nuclei
cytes are located in gray matter, and fibrillary astro- increase and small but distinct amounts of cytoplasm
cytes are found chiefly in white matter. Ultrastructural may become visible around these nuclei in hematoxylin-
studies have demonstrated that both types contain and-eosin stained sections. Groups of two or more as-
10 nm intermediate filaments (glial fibrils); however, trocyte nuclei are seen within the lesion when the in-
the filaments are more numerous in fibrillary astro- jury involves cerebral cortex, basal ganglia, or other
cytes. Glial fibrillary acidic protein (GFAP) is a major gray matter structures.These nuclear groups were once
component of astrocytic intermediate filaments. Im-
munostains for detection of this protein are used reg-
ularly in diagnostic neuropathology to demonstrate as-
trocytes. Corpora amylacea are a form of polyglucosan
body similar to the Lafora body and occur in astrocytic
processes beneath the pia and around blood vessels in
the normal central nervous system. They are round,
vary from 10 to 40 m in diameter, stain basophilic
with hematoxylin-eosin, and are PAS positive.
The most important morphologic reactions of astro-
cytes to injury are the primary and secondary forms of
astrocytosis. Other disease-related astrocytic changes
include swelling, necrosis, and formation of inclusions.
The terms astrocytosis, astrogliosis, and gliosis are of-
ten used synonymously. Some authors use astrocytosis
in reference to an increase in the size or number of as-
trocytes and astrogliosis for increases in astrocytic pro- FIGURE 1.14 Reactive astrocytosis. Widespread hypertrophy of fib-
cesses. In this chapter astrocytosis refers to an increase rillary astocytes. Silver carbonate, 200.
interpreted to be evidence of amitotic division of as- and formation of a meshwork of astrocytic processes.
trocytes because mitotic figures are not seen in astro- The term fibrillary astrocytosis is applied to this stage
cytic reactions occurring in human brain tissue. With of the reaction. Eosinophilic masses called Rosenthal
the demonstration of mitotic division by reactive as- fibers can be seen within the processes, especially when
trocytes, however, this explanation has been discarded the lesion involves the white matter (Fig. 1.16). Ex-
(Latov et al., 1979; Miyake et al., 1988). The study by perimental studies of reactive astrocytosis have dem-
Cavanagh (1970) indicates that absence of mitotic fig- onstrated persistence of the glial changes in some mod-
ures in reactive postmortem astrocytes from humans els and their disappearnce in others (Norton et al.,
might reflect completion of the mitotic process during 1992). It is uncertain whether similar variations occur
the postmortem interval between death and fixation of in humans.
the tissue. Subsequently, experimental studies have pro- Reactive astrocytosis—that is, the astrocytic reaction
vided an additional reason for the absence of mitotic to injury of other parenchymal elements—is a gener-
figures. In several experimental models reactive astro- ally accepted concept with well-defined morphologic
cytosis involves chiefly hypertrophy of resting astro- features. In contrast, the occurrence and characteristics
cytes accompanied by intracellular accumulation of of primary astrocytosis—that is, the response of astro-
GFAP rather than proliferation of these cells (Norton cytes when they are the targets of sublethal injury—
et al., 1992). The impression of increased numbers of have not been completely defined. The astrocytic
astrocytes is produced by previously indiscernible rest- changes associated with hepatic encephalopathy and
ing astrocytes becoming conspicuous through hyper- other conditions in which blood ammonia levels are el-
trophy and synthesis of GFAP. Proliferation of astro- evated are viewed as possible examples of primary as-
cytes in the acute lesion is limited in extent or absent trocytosis. The altered astrocytes, referred to as Alz-
entirely (Norton et al., 1992; Eddleston and Mucke, heimer type II astrocytes, are found chiefly in gray
1993). matter. The nuclei are enlarged and vesicular and of-
As the reaction proceeds, the astrocytic cell body may ten contain nucleoli or glycogen inclusions. Their num-
continue to enlarge and become more conspicuous with bers appear increased, although the question of en-
the nucleus displaced toward the periphery. These enhanced prominence vs. absolute numerical increase is
larged astrocytes are referred to as gemistocytes or unresolved. The cell body does not appear to enlarge
gemistocytic astrocytes (Fig. 1.15). They are prominent and astrocytic processes do not increase in number (Fig.
in hematoxylin and eosin preparations because of their 1.17). Changes resembling Alzheimer type II astrocy-
enlarged pink-staining cell bodies. Creutzfeldt cells are tosis are sometimes seen in metabolic and toxic disor-
reactive astrocytes with multiple small nuclei. They are ders other than those associated with elevated blood
most frequently seen in demyelinating diseases and are ammonia levels (Norenberg, 1994).
significant because of the potential for misdiagnosis as Tau-positive, filamentous inclusions in astrocytes
a cell undergoing mitosis. are of significance in the diagnosis of degenerative
The later stages of human reactive astrocytosis in-
volve reduction in the size of the astrocyte perikarya
FIGURE 1.15 Gemistocytes. A group of reactive astrocytes with promi- FIGURE 1.16 Rosenthal fibers. Note the several sausage-shaped, dark-
nent cell bodies and eccentric nuclei. H&E, 400. staining, homogeneous bodies. Trichrome, 600.
The microglia respond to a variety of neuro-

parenchymal injuries by a process referred to as acti-
vation that involves expression of various antigens,
cell recruitment and proliferation at the site of injury,
formation of rod cells or macrophages, secretion of
cytokines, and release of cytotoxic substances
(Gehrmann et al., 1995; Dickson, 1997, 1999; Gon-
zalez-Scarano and Baltuch, 1999). Several of these
changes can be demonstrated only with special tech-
niques or have been observed chiefly in experimental
models. The microglial responses that are readily ob-
served in conventionally fixed and stained human
brain tissue are proliferation and formation of mac-
FIGURE 1.17 Alzheimer type 2 astrocytes. The astrocytes have en- rophages or rod cells. The proliferating microglia ac-
larged, optically clear nuclei and no visible cytoplasm. H&E, 400. cumulate at the site of injury forming a cluster of cells
with bean-shaped or twisted nuclei and little if any
visible cytoplasm. These clusters, referred to as glial
diseases (Chin and Goldman, 1996; Feany and Dick- stars or nodules, are frequently seen in cases of viral
son, 1996). Thorn-shaped astrocytes are seen in pro- encephalitis. Neuronophagia refers to the clustering
gressive supranuclear palsy, postencephalitic Parkin- of microglia around the cell body of a dead neuron
son’s disease, and dementia pugilistica. Tufted (Fig. 1.18). Microglia form macrophages in response
astrocytes are seen in progressive supranuclear palsy. to the death of tissue elements. In general if the de-
Astrocytic plaques are present in corticobasal gan- struction of tissue occurs with an intact blood–brain
glionic degeneration. Glial Pick bodies are present in barrier, the microglia are the source of the macro-
Pick’s disease. phages. Blood monocytes, however, are the primary
source of macrophages associated with acute inflam-
mation or necrotic lesions that disrupt the blood–
Microglia
brain barrier (Ulvestad et al., 1994). Rod cells are
In this chapter the term microglia is used in reference elongated bipolar cells with cigar-shaped nuclei that
to a distinct population of cells residing within the CNS develop characteristically in cerebral cortex as a re-
and distributed widely throughout the gray and sponse to subacute injuries in which necrosis is min-
white matter. Unlike astocytes, oligodendroglia, and imal or absent (Fig. 1.19). They are a characteristic
ependyma the microglia do not appear to be of neu- feature of general paresis, a form of tertiary neu-
roepithelial origin. Most investigators believe these cells rosyphilis, but they are also found in several other dis-
are relatives of the mononuclear phagocyte system and orders including subacute sclerosing panenecephalitis.
are derived from bone marrow cells that invade the
CNS during its development (Ling and Wong, 1993).
In normal adult CNS microglial cells are in a resting
state with a small, branched cell body that can be dem-
onstrated only with silver impregnation or immuno-
histochemical techniques following optimal fixation.
In the intact brain blood monocytes do not circulate
through or repopulate the parenchymal microglial. The
term perivascular microglia is sometimes used in refer-
ence to the mononuclear cells located between the outer
basement membrane of parenchymal blood vessels and
the glia limitans, the layer of astrocytic processes with
its own basement membrane that surrounds the blood
vessel. These cells are in circulatory continuity with the
mononuclear/phagocyte system of the blood and ap-
pear to be more closely related to that system than to
the parenchymal microglia (Hickey and Kimura, 1988; FIGURE 1.18 Neuronophagia. Phagocytosis of degenerated nerve cell
Dickson, 1997). body by reactive microglia. H&E, 400.
Oligodendroglial cytoplasmic inclusions have been

identified in several degenerative diseases (Chin and
Goldman, 1996; Feany and Dickson, 1996). Glial cy-
toplasmic inclusions, which are identified on Gallyas
silver stain or tau immunohistochemistry, are com-
posed of loosely packed filaments with a diameter of
20–30 nm. They also react positively for ubiquitin and
alpha, beta-crystallin. These are seen in sporadic mul-
tiple system atrophy. Coiled bodies are tau-positive
bundles of 15–20 nm filaments or tubules and are seen
in progressive supranuclear palsy, corticobasal gan-
glionic degeneration, Pick’s disease, and subacute scle-
rosing panencephalitis.
Other reactions of oligodendroglia to injury include
cell death by necrosis or apoptosis, formation of cyto-
FIGURE 1.19 Rod cell with cigar-shaped nucleus and a small amount
of visible cytoplasm. H&E, 400. plasmic inclusions associated with neurodegenerative
diseases, swelling of the cell body in hypoxic–ischemic
states, and proliferation around the margins of active
Oligodendrocytes and Ependymal Cells multiple sclerosis plaques (Ludwin, 1997).
Ependymal cells do not proliferate in response to
Both oligodendrocytes and ependymal cells have lim- injury and cell loss. Destruction of these cells is ac-
ited morphologic reactions to injury. Viral inclusions companied by proliferation of subependymal astro-
may occasionally be seen in either, but oligodendrocytes at the affected sites with formation of small col-
cytes are more frequently affected. In cases of progres- lections of nuclei and cell processes. This reaction is
sive multifocal leukoencephalopathy the nuclei of oligo- often visible macroscopically and referred to as gran-
dendroglia infected with the papovavirus undergo a ular ependymitis. Surviving ependymal cells may be
distinctive change that in its fully developed forrn es- overgrown by the astrocytic reaction and appear as
tablishes the diagnosis of this disease. The nucleus re- clusters or tubules buried within the proliferative foci
mains round but enlarges to approximately three times (Sarnat, 1995).
its normal size. As the nucleus increases in size, the
chromatin pattern is effaced. The nuclear contents ap-
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2 Elements of CT and MR neuroimaging
JAMES S. NELSON
Contemporary neuroimaging uses plain skull radiogra- 2.2). A scan produced after a contrast agent has been
phy, X-ray computed tomography (CT), and conven- injected is referred to as a contrast-enhanced CT. Le-
tional magnetic resonance imaging (MRI) to detect sions and tissues that show accumulation of the con-
anatomical features and single-photon-emission com- trast agent are described as contrast-enhancing and
puted tomography (SPECT), positron emission tomog- those that do not accumulate the agent are called
raphy (PET), and transcranial Doppler ultrasound to nonenhancing. A CT scan performed without the use
demonstrate physiological processes. Among these of a contrast agent is referred to as a nonenhanced CT.
techniques, CT and MR imaging have proven to be The most effective uses of CT scans include screen-
valuable aids to diagnostic surgical and autopsy neu- ing of acute head injuries, detection of subarachnoid
ropathologic examinations (Boyko et al., 1994; Burger hemorrhage, detection of calcified lesions, evaluation
et al., 1998). This chapter provides a brief summary of of lesions and injuries involving the skull or spine, im-
the imaging methods, terminology, and characteristics mediate postoperative studies, and in cases where MRI
of common normal and abnormal findings associated is contraindicated (Grossman and Yousem, 1994; John-
with CT and MR imaging of the central nervous sys- son and Becker, 1995; Burger et al, 1998).
tem (CNS). Two excellent sources of more detailed
information are the monograph by Grossman and
Yousem (1994) and the the website edited by Johnson MAGNETIC RESONANCE IMAGING
and Becker (1995). The complete citations for both are
included in the references at the end of this chapter. Although CT and MR images are somewhat similar in
appearance, MR imaging does not rely on X-rays or
other forms of ionizing radiation. MR images are the
COMPUTERIZED TOMOGRAPHY result of changes in the energy levels of tissue protons
(chiefly hydrogen nuclei) induced by pulses of electro-
Computerized tomography involves the use of a beam magnetic energy. The tissue protons initially are mag-
of parallel (highly collimated) X-rays (photons) that are netized and absorb energy from the electromagnetic
differentially absorbed (attenuated) by various tissue pulse. After completion of the energy pulse the protons
components as the X-rays pass through the CNS and release the absorbed energy and return to their equi-
its coverings. A digital image is produced by a computer- librium state. The released energy (echo) is the MR sig-
based detection system that reflects the pattern nal used to produce the final image.
of beam attenuation with gray-scale values between 1 The release of the energy by the excited protons and
(black) and 256 (white). In the CT image, tissues and their return to equilibrium (referred to as relaxation)
lesions of high attenuation (hyperdense) are white; takes place over time. It consists of two components
tissues and lesions of low attenuation (hypodense) are related to the geometry of the magnetizing energy pulse:
black. For example, bone and blood are hyperdense, relaxation of the component of proton magnetization
and air, fat, and water (edema) are hypodense. Normal parallel to the magnetic field and relaxation of the com-
brain tissue is intermediate between these two extremes ponent perpendicular to the magnetic field. The relax-
(Fig. 2.1). ation time for the parallel component is referred to as
Increased permeability or absence of the blood–brain T1 and the relaxation time for the perpendicular com-
barrier is demonstrated by intravenous injection of an ponent as T2. They are independent of one another.
iodinated contrast agent followed by CT. Accumula- The intensity of the MR signal depends on three fac-
tion of the hyperdense contrast agent within the pa- tors: the concentration of protons within the tissue, the
renchyma (e.g., vasogenic edema) or a lesion marks the duration of T1, and the duration of T2. Tissue char-
sites of barrier absence or increased permeability (Fig. acteristics may affect these factors and influence the
21
FIGURE 2.2 Same case as in Figure 2.1. Contrast-enhanced CT shows

FIGURE 2.1Left occipital metastasis contiguous with edematous white ring enhancement around metastasis indicating increased permeabil-
matter. Nonenhanced CT shows hypodense lesion in left occipital ity of blood–brain barrier.
contiguous with hypodense cerebral white matter.
less than 45 milliseconds are T1-weighted; scans with

strength of the signal. For example, a high density of a TR longer than 2000 milliseconds and a TE longer
protons is associated with increased signal strength. than 60 milliseconds are T2-weighted; and scans with
Both T1 and T2 are shortened by hard or highly vis- a TR longer than 2000 milliseconds and a TE shorter
cous tissues. More importantly, changes in the signal than 45 milliseconds are proton-density-weighted. TR
intensity and selective accentuation of tissue character-
istics or components can be induced by manipulating
the initial pulse sequence and signal collection so that
the eventual signal or image is more dependent
(weighted) on one of the three determinants of signal
intensity—for example, T1. The types of images pro-
duced by this manipulation include T1-weighted im-
ages (T1WI), T2-weighted images (T2WI), and proton-
density-weighted images (PDWI). Structures or lesions
with high signal intensity appear white or bright and
those with low signal intensity appear dark in MR
images. For example, in T1-weighted images, areas of
edema, infarcts, tumors, and calcified structures appear
dark while fat and protein-rich fluid appear white. In
T2-weighted images edema, tumor, and infarcts are
bright or white and calcified structures and protein-rich
fluid are dark (Figs. 2.3, 2.4).
Manipulation of the pulse sequence and signal col-
lection time to produce weighted images involves
changes in the time (in milliseconds) between repetition
of the exciting pulses referred to as “time to repeti-
tion,” or TR, and changes in the collection time (in mil-
FIGURE 2.3 Left frontoparietal glioblastoma and compression of left
liseconds) of the the energy released by the excited pro- lateral ventricle. T1-weighted, contrast-enhanced MRI shows ring en-
ton referred to as “time to echo,” or TE. In general, hancement indicative of increased blood–brain barrier permeability
scans with a TR less than 1000 milliseconds and a TE at tumor margin and left ventricular compression.
2: ELEMENTS OF CT AND MR NEUROIMAGING 23
the blood–brain barrier (Fig. 2.3). The contrast agent

consists of gadolinium, one of the rare earth elements,
chelated to diethylenetriamine pentaacetic acid (DTPA).
Gadolinium increases the relaxation rate of the hydro-
gen nuclei (protons) in the water around sites of bar-
rier absence or increased permeability (the paramag-
netic effect of gadolinium), causing a white signal to
appear at these sites in T1-weighted images.
MR imaging is best suited for detection of noncalci-
fied intra- or extraaxial CNS lesions except for sub-
arachnoid hemorrhage. MR imaging is not recom-
mended for evaluation of lesions involving bone cortex.
It cannot be used in patients with pacemakers, metal-
lic implants, or foreign bodies around the eyes or who
are claustrophobic (Grossman and Yousem, 1994;
Johnson and Becker, 1995; Burger et al., 1998).
FIGURE 2.4 Same case as in Figure 2.3. T2-weighted, nonenhanced REFERENCES

MRI shows areas of high signal intensity in the left cerebrum indi-
cating the site of the tumor and edema of the adjacent white matter. Boyko O.B., Alston S.R., Fuller G.N., Hulette C.M., Johnson G.A.,
A bright signal from the cerebrospinal fluid is evident within the lat- and Burger P.C. (1994). Utility of postmortem magnetic reso-
eral ventricles and subarachnoid space. nance imaging in clinical neuropathology. Arch Pathol Lab Med
118:219–225.
Burger P.C., Nelson J.S., and Boyko O.B. (1998). Diagnostic synergy
in radiology and surgical neuropathology: neuroimaging tech-
and TE values are printed on the film of the image. niques and general interpretive guidelines. Arch Pathol Lab Med
122:609–619.
usually in the lower left-hand corner.
Grossman R.I. and Yousem D.M. (1994). Neuroradiology, The
T1-weighted imaging and a gadolinium contrast Requisites. Mosby, St. Louis.
agent are used to demonstrate MR contrast enhance- Johnson K.A. and Becker J.A. (1995). The whole brain atlas. Avail-
ment indicative of increased permeability or absence of able from http://www.med.harvard.edu/AANLIB/home.html.
3 Developmental and
perinatal neuropathology
JAMES S. NELSON
TERMINOLOGY, CONVENTIONS, AND DEFINITIONS length or biparietal diameter directly or by ultra-

sonography and reference to tables correlating these
The prenatal period is divided into two phases: an em- meaurements with fetal age.
bryonic phase that extends from conception to the end The average length of prenatal life from ovulation to
of the eighth postovulatory week and a subsequent fe- birth is 264–270 days (38–381/2 weeks) with an esti-
tal phase that ends at birth. The embryonic phase is mated range of 250 to 285 days. Infants designated as
characterized by the appearance of a large number of preterm are those born less than 37 weeks after the first
new morpholgic features involving the nervous system day of the last menstrual perod (“postmenstrual
and other organs. The fetal phase is distinguished by weeks”). Term infants are those born between 37 and
an emphasis on the structural and physiological re- 42 postmenstrual weeks. The perinatal period extends
finement of these features. from the 28th postmenstrual week to 1 week after
Criteria used for assessing embryonic development birth. The neonatal period consists of the first 4 weeks
include morphologic staging, estimates of prenatal age, after birth. Viability refers to the age at which the in-
and body measurements such as the biparietal diame- fant has a reasonable chance of prolonged survival out-
ter and the greatest body length. Currently, staging cri- side the uterus. This age changes in accordance with
teria are available only for the embryonic phase. This technical advances. The age of viability currently is con-
phase comprises 23 Carnegie stages. As noted, the sidered to be 20 postovulatory weeks (O’Rahilly and
stages are based on morpholgic features and do not cor- Müller, 1996).
respond exactly to estimates of prenatal age or body
measurements. The staging procedure takes into ac-
NORMAL DEVELOPMENT OF THE
count the normal variation in the rate at which mor-
CENTRAL NERVOUS SYSTEM
phologic features develop. Consequently, all embryos
within a given stage have reached the same degree of
Formation and Development of the Neural Tube
morphologic development, but their prenatal ages may
differ by several days. Postovulatory age or its closely The human central nervous system is derived from ec-
related counterpart, postfertilizational age, in the em- toderm (O’Rahilly and Müller, 1996; Larsen, 1997).
bryonic phase may be obtained by assigning the em- The basic form of the brain and spinal cord is estab-
bryo to a Carnegie stage and referring to a table that lished during the embryonic period between the third
coordinates the approximate relationship between and eighth postovulatory weeks. The neural plate, the
stage and age. The length of the embryo as determined forerunner of the nervous system, appears during
by ultrasonography may also be used to estimate pos- the third week. Indentations in the neural plate indi-
tovulatory age. In clinical practice prenatal age is fre- cate the three major anatomic subdivisions of the brain:
quently estimated by assuming fertilization occurred 2 the forebrain or prosencephalon, the midbrain or mes-
weeks after the first day of the last menstrual period. encephalon, and the hindbrain or rhombencephalon.
The accuracy of this type of estimate can be enhanced The plate enlarges, folds dorsally, and fuses, forming
by measuring initial serum levels of the beta subunit of the neural tube. The folding of the neural plate to form
human chorionic gonadotropin. In the fetal phase, age the neural tube is referred to as primary neurulation.
may be estimated by using the menstrual dates as men- The prosencephalon, mesencephalon, and rhomben-
tioned above. More precise values can be obtained by cephalon and the expanded segments of the neural
determining body measurements such as greatest body tube enclosed by them are referred to as primary brain
24
3: DEVELOPMENTAL AND PERINATAL NEUROPATHOLOGY 25
vesicles. Primary neurulation is completed during trocytes, oligodendrocytes, radial glial cells (glioblasts),
the fourth week with closure of the rostral and caudal and ependymal cells (ependymoblasts). Processes of the
openings (neuropores) of the tube and separation of the ventricular cells extend outward forming the marginal
surface and neural ectodern. zone. After several periods of division, neurons and glia
Secondary neurulation involves formation of the differentiate and move peripherally out of the ventric-
most caudal segment of the spinal cord located caudal ular zone, forming the intermediate zone which lies be-
to the caudal neuropore. The process begins during the tween the ventricular and marginal zones. In most parts
fourth postovulatory week after closure of the caudal of the central nervous system cell proliferation is lim-
neuropore. A solid mass of neural tissue called the ited to the ventricular zone. In some areas, however, a
neural cord forms from the caudal eminence or end layer known as the subventricular zone develops be-
bud—a collection of undifferentiated cells located at tween the ventricular and intermediate zones and is the
the caudal end of the embryonic body. Subsequently, site of continuing neuronal and glial proliferation.With
continuity of the lumen of the neural tube is established few exceptions, virtually all mammalian neurons and
with the developing lumen of the neural cord. glial cells undergo at least one migration to arrive at
During development of the neural tube, cells from their definitive locations. Migration occurs before the
the neurosomatic junction (the region where the neurec- aggregation of cells to form nuclear groups or cortical
toderm of the neural plate joins the somatic ectoderm) layers. Cellular migration is usually radial and guided
and from the dorsolateral margins of the tube separate, by radially arranged glial processes extending from the
forming the neural crest. These cells migrate along well- ventricular zone internally to the surface of the mar-
defined pathways to a variety of locations, eventually ginal zone externally. After the migrating cells arrive at
giving rise to Schwann cells, melanocytes in all parts of their definitive locations, further developmental pro-
the body, the prevertebral and paravertebral sympa- cesses ensue, including the aggregation of cells to form
thetic ganglia and components of the cranial and spinal identifiable parts of the brain, differentiation of im-
ganglia, the amine precursor and uptake and decar- mature neurons, formation of connections with other
boxylation (APUD) system, and the leptomen inges. neurons, programmed death of certain neurons (apop-
The ectodermal placodes are an additional source of tosis ), and the elimination or stabilization of neuronal
neural tissue. This series of thickened foci in the ecto- connections formed previously. Cell adhesion mole-
derm overlying the neural tube contributes cells to ol- cules, growth factors, and steroid hormones are impli-
factory epithelium and ganglia associated with cranial cated in these processes. The precise mechanisms re-
nerves V and VII to X. sponsible for these changes, however, are not fully
The cervical, pontine, and mesencephalic flexures understood and represent one of the most important
form during the fourth and fifth postovulatory weeks areas of research in developmental neurobiology.
and are accompanied by formation of a primitive but
functioning cerebral circulation with identifiable arter-
Histogenesis of Major Anatomic Subdivisions
ies and veins. The cervical flexure develops at the junc-
tion of the spinal cord and rhombencephalon. The pon- The further development of the spinal cord, rhomben-
tine flexure divides the rhombencephalon into a caudal cephalon, mesencephalon, and prosencephalon is dis-
segment, the myelencephalon (future medulla oblon- cussed separately. These structures, however, are ex-
gata), and a rostral segment, the metencephalon (future tensively interconnected and their functions are closely
pons and cerebellum). The mesencephalic flexure marks integrated. Changes in one area, whether in the course
the site of the midbrain, which remains undivided. Dur- of normal development or because of noxious stimuli,
ing this same period, the prosencephalon separates into may induce structural or functional changes in other
the telencephalon and diencephalon. As a consequence parts of the nervous system not originally affected.
of the subdivsion of the prosencephlon and rhomben-
cephalon, there are now five “secondary” brain vesicles.
Spinal cord
At the time of neural tube closure the spinal cord con-
Neuronal and Glial Cytogenesis
sists of thick lateral walls with a thin roof and floor
In the course of the embryonic period, cell prolifera- plates enclosing a central canal. Masses of cells within
tion occurs in the walls of the neural tube with for- the dorsal and ventral halves of the lateral walls are
mation of a pseudostratified epithelium called the ven- separated by a longitudinal groove, the sulcus limitans,
tricular zone or germinal matrix. It is composed of cells into dorsal (alar) and ventral (basal) plates, which are
that are the precursors of neurons (neuroblasts), as- the forerunners, respectively, of the posterior and an-
terior horns. During the second and third months of Mesencephalon

embryonic and fetal life, differentiation of the spinal
The mesencephalon gives rise to the midbrain. Between
gray matter proceeds with formation of anterior and
the second and fifth months many of the morphologic
posterior nerve roots and development of connections
features that characterize the adult midbrain become
with other parts of the central nervous system. Changes
recognizable. The alar plate forms the tectum. The vol-
in the diameter of the spinal cord with formation of
ume of the original lumen of the neural tube is reduced
the anterior median fissure and posterior median sep-
to form the aqueduct. The nuclei of the third and fourth
tum accompany the parenchymal alterations. The gen-
cranial nerves are derived from the basal plates. The
eral form of the adult spinal cord is attained between
question of the alar or basal origin of the substantia
the third and fourth months.
nigra and of the red nuclei is unresolved.
Rhombencephalon
Prosencephalon
Development of the medulla, pons, cerebellum, and
fourth ventricle from the rhombencephalon and its lu- The diencephalon and telencephalon are the derivatives
men begins during the second prenatal month. The of the prosencephalon or forebrain. Rostrally, the sul-
lateral walls of the rhombencephalon are divided, as cus limitans does not extend beyond the midbrain. Con-
in the spinal cord, into alar and basal plates separated sequently, the prosencephalon is not usually separated
by the sulcus limitans. The cells within the basal plate into alar and basal layers. As is the case with other
are organized into medial, intermediate, and lateral parts of the central nervous system, many of the mor-
groups that give rise, respectively, to somatic efferent, phologic features that characterize the adult cerebrum
special visceral efferent, and general visceral efferent develop and become identifiable between the second
components of cranial nerve nuclei. Similarly, the alar and sixth prenatal months.
plate, in a medial-to-lateral direction, forms the The diencephalon develops from the lateral walls of
general visceral afferent, special visceral afferent, gen- the caudal forebrain. It encloses most of the original
eral somatic afferent, and special somatic afferent forebrain vesicle, which becomes the third ventricle. In
components. conjunction with an ingrowth of vascular mesenchyme,
The medulla is derived from the caudal or myelen- the roof plate of this structure forms the choroid plexus
cephalic portion of the rhombencephalon. The pons of the third ventricle. The caudal portions of the roof
and cerebellum develop from the rostral or meten- plate give rise to the pineal gland. The major subdivi-
cephalic segment of the rhombencephalon. Both alar sions of the diencephalic wall from dorsal to basal are
and basal sources contribute to the formation of the the epithalamus, dorsal thalamus, subthalamus, and hy-
medulla and pons. The cerebellum develops bilater- pothalamus. These divisions give rise to specific struc-
ally from dorsal regions of the alar plates referred to tures: the epithalamus to the habenular commissure,
as the rhombic lips. The ventricular, intermediate, the posterior commissure, and the habenular nuclei; the
and marginal layers present in other parts of the dorsal thalamus to the adult thalamus and geniculate
neural tube are identifiable within the rhombic lips. bodies; the subthalamus to the adult subthalamus; and
The rhombic lips give rise to the cerebellar plates, the hypothalamus to the adult hypothalamus (includ-
which unite, forming a small midline portion corre- ing the mammillary bodies), the infundibulum, and the
sponding to the cerebellar vermis and two lateral por- neurohypophysis.
tions corresponding to the cerebellar hemispheres. By The telencephalon is the most rostral portion of the
the end of the fourth month, the posterolateral, pri- forebrain and consists of the cerebral hemispheres and
mary, and secondary fissures and the flocculonodu- a medial portion, the lamina terminalis. The hemi-
lar lobe are delineated. spheres enclose the lateral ventricles, which are derived
The external changes in the cerebellum are accom- from the primitive telencephalic vesicles. The lateral
panied by histogenetic processes. Near the end of the ventricles communicate with the diencephalic third ven-
second prenatal month cells from the rhombic lip move tricle through the foramina of Monro. The cerebral
to the surface of the cerebellum to form the external hemispheres originate during the fifth postovulatory
granular layer. Eventually, cells from this layer migrate week as bilateral outpouchings of the prosencephalon.
inward to form the internal granular layer. The deep Subsequently the basal portions of the hemispheres en-
cerebellar nuclei, Purkinje cells, and Golgi neurons are large to form the corpus striatum (caudate nucleus and
derived from the ventricular zone of the rhombic lips putamen). The choroid plexus of the lateral ventricles
beginning in the fourth prenatal month. develops from vascular mesenchyme and the roof plate
where the hemispheres join the diencephalon. During Primary, secondary, and tertiary sulcation is well de-
the second prenatal month the caudate and putamen veloped over the surfaces of the cerebral hemispheres.
are separated by the appearance of the internal capsule. Primary sulci are the consistently located, easily recog-
The putamen and globus pallidus (a diencephalic de- nized sulci such as the central and the superior frontal
rivative) make up the adult lentiform nucleus. The sulci, which appear during the sixth and seventh pre-
amygdala is chiefly derived from the diencephalon. natal months. Secondary sulci are branches of the pri-
The thinner, dorsal portion of the cerebral hemi- mary sulci, and tertiary sulci are branches of the sec-
spheres, called the pallium, forms the primordium of ondary sulci. The appearance of secondary and tertiary
the cerebral cortex. The archicortex and the paleo- sulci begins before birth but after formation of the pri-
cortex are initially located on the dorsomedial aspect mary sulci. The pattern of secondary and tertiary sul-
of the pallium. Adult structures including the hip- cation is variable. Cerebral cortical lamination is dis-
pocampus; parts of the parahippocampal gyrus; the cernible. Nuclear masses and conduction pathways are
septal area; and the olfactory tubercle are derived evident. Neurons are closely packed and smaller than
from these areas, which are sometimes referred to as in the adult brain. Their nuclei are large in relation to
primitive cortex. The remainder of the pallium un- the size of the cell body. Basophilic particles. the fore-
dergoes extensive development, forming the neocor- runners of Nissl substance, can be seen in the neuronal
tex with displacement of the two more primitive cor- cytoplasm. The arborization of nerve cell processes is
tical areas onto the ventromedial aspect of the less extensive than in the adult brain (Larroche, 1977).
hemisphere. As a result of continued growth of the Myelination is incomplete in the full-term infant
hemispheres, sulci begin to appear during the sixth (Rorke and Riggs, 1969; Larroche, 1977). Myelinated
month. These sulci develop in an orderly fashion, and fibers are found within the spinal and cranial nerve
the principal sulci and gyri that form the characteris- roots, including the optic nerves and tracts. With the
tic pattern of the human cerebral cortex can be iden- exception of the lateral and anterior corticospinal
tified in the full-term infant (Chi et al., 1977; tracts, the principal ascending and descending path-
Dorovini-Zis and Dolman, 1977). ways in the spinal cord contain prominent, myelinated
In the adult the cerebral hemispheres are connected axons. Within the brain stem, myelinated axons are
across the midline by bundles of fibers called commis- present in the internal arcuate, spinocerebellar, and cor-
sures. The most important of these are the corpus cal- ticospinal tracts, the medial and lateral lemniscus, and
losum, the anterior commissure, the hippocampal com- the medial longitudinal fasciculus. Myelinated cerebel-
missure, the posterior commissure, and the habenular lar axons are seen both centrally and in folia, within
commissure. The first three are telencephalic deriva- the inferior and superior cerebellar peduncles, and to
tives, and the latter two originate from the dien- a lesser extent in the middle cerebellar peduncle. In the
cephalon. All begin developing at various times during cerebral hemispheres the thalamus, subthalamic nu-
the second and third month. cleus, globus pallidus, and internal capsule (posterior
limb), portions of the optic radiation, and the central
gyri contain myelinated axons in varying number. The
Characteristics of the Normal Brain in a
corpus callosum and fornix are unmyelinated.
Full-Term Infant
Difficulties may be encountered in determining the
Examination of the CNS from perinatal autopsies may presence of reactive astrocytosis because of the pres-
require procedures that differ from those used in the ence of myelination glia in the immature and full-term
examination of brains from older persons. Norman et human brain. Myelination glia are glial cells that oc-
al. (1995) have provided a practical and helpful dis- cur in large numbers in myelinating tracts but have not
cussion of techniques, diagnostic considerations, and acquired the morphologic features of mature oligoden-
problems associated with neuropathologic examination droglial cells. At this stage they may be confused with
of the infant CNS. reactive astrocytes.
The average weight of the brain in a full-term infant The presence of diffusely distributed sudanophilic
is approximately 400 g (Schulz et al., 1962). Accord- droplets in human neonatal white matter has been rec-
ing to Larroche (1977), the brain weight equals ognized for more than 100 years. All of the central ner-
10%–14% of the body weight in the mature full-term vous system white matter is affected, but the intensity
infant. The brain is soft at birth because up to 90% of of the process varies from tract to tract. Some of the
its weight consists of water. In contrast, the water con- droplets are located within glial cell bodies, whereas
tent of the adult brain is approximately 70%–75% of others are found in the neuropil without a discernible
the total weight (Katzman and Pappius, 1973). cellular localization. The significance of the the su-
danophilic droplets is controversial. They have been in- tions as morphologic defects involving an organ, part
terpreted as evidence of pathologic changes involving of an organ, or a larger region of the body resulting
white matter or glial cells and as accumulations of su- from an intrinsically abnormal developmental process
danophilic premyelin lipids in the cytoplasm of myeli- (Spranger et al., 1982). This definition distinguishes
nation glia (Friede, 1989). Ultrastructural studies on malformations from dysplasias, which affect tissues,
primates and humans suggest that the glia-related lipid not organs, and from disruptions and deformations, in
accumulation occurs primarily in either undifferenti- which the original developmental process is normal but
ated glial cells or astrocytes (Sumi, 1974, 1979; Schnei- extrinsic factors such as infection or mechanical forces
der, 1976). The studies in monkeys indicate that such interfere with the developmental process. The formu-
droplets occur in small numbers in control animals but lation of neuropathologic diagnoses based on these con-
are greatly increased in animals with anatomic evidence cepts, however, is complicated by several factors, in-
of hypoxic–ischemic brain injury. The sudanophilic cluding the lack of criteria with which to identify many
stains used to detect the droplets do not indicate the intrinsically abnormal developmental processes and the
type of sudanophilic lipid present. Possibly, the su- paucity of information concerning responses of the de-
danophilic changes in the control animals are the pre- veloping nervous system to injury. In practice and in
myelin lipids in myelination glia and the droplets in the this chapter, the term malformation is used in the sense
hypoxic–ischemic animals are lipids of another type re- suggested by Myrianthopoulos (1987): “any congeni-
flecting injury to the cells in which they are present. tal and developmental deviation from normality, gross
The adult pattern of the cerebral vasculature is pres- or microscopic, manifesting at birth or any time later,
ent at birth (Kaplan and Ford, 1966). The arteries form- if there is reasonable certainty that the malformation
ing the major branches of the circle of Willis are con- process began during the developmental continuum of
siderably smaller in diameter than those found in the form and function and exemplifies one of the accepted
adult brain. The functional capacity of the blood–brain malformation patterns: agenesis, aplasia, hypoplasia,
barrier in the normal full-term infant has not been fully and deformity.”
delineated. Ultrastructural studies, however, have dem- Data concerning the frequency of central nervous sys-
onstrated the presence of tight junctions between en- tem malformations vary because of differences in the
dothelial cells of cerebral capillaries in humans and design of epidemiologic studies, differences in diagnos-
animals very early in development (Mollgard and Saun- tic methods, and ethnic or geographic differences in in-
ders, 1986). cidence or prevalence. Based on the analysis of several
Other features of the nervous system, at term, in- studies, Myrianthopoulos (1987) estimated an inci-
clude a cavum septi pellucidi and the persistence of im- dence of 80–100 central nervous system malformations
mature neuroepithelium around the lateral ventricles per 10,000 births, both live and stillborn. The common
and over the cerebellum as the extemal granular cell malformations are anencephaly, microcephaly, hydro-
layer. These cells disappear during the 12–15 months cephalus, spina bifida, and Down syndrome. If central
following birth. The substantia nigra and locus nervous system malformations in spontaneous abor-
coeruleus are not grossly pigmented at birth. Micro- tions (chiefly exencephaly, encephalocele, and spinal
scopic examination. however, may show pigment gran- cord defects) are included, the incidence is 100–130 per
ules as early as midterm (Foley and Baxter, 1958; 10,000 conceptions with CNS malformations repre-
Lemire, 1975). senting 10% of all malformations. During the first year
of life approximately 100 deaths per 100,000 popula-
tion are caused by central nervous system malforma-
tions. At all ages these lesions account for 3 to 4 deaths
DEVELOPMENTAL DISORDERS
per 100,000 population annually. These numbers are
derived from surveys that are at least 15 years old. The
Malformations
current use of prenatal diagnosis and elective abortion
CNS malformations comprise a heterogeneous group may have induced changes in these data (Cragan et al.,
of structural abnormalities of varying severity that are 1995).
recognizable at or near birth. They indicate a distur- CNS malformations may be caused by genetic de-
bance of the developmental processes of the CNS by fects; chromosomal anomalies; environmental terato-
disease mechamisms that are often incompletely un- gens such as infectious agents, drugs, and chemicals;
derstood. There is no single, generally accepted, oper- and combinations of environmental and genetic factors.
ational definition of a malformation. An international The majority of CNS malformations, however, have no
working group has recommended defining malforma- known cause (Norman, 1996). The same type of mal-
formation can be caused by abnormal genes, chromo- with neural tube defects (Botto et al., 1999). Among
somal aberrations, or unknown factors. Consequently, the environmental influences that may affect neural
the morphological characteristics of the malformation tube closure are antiepileptic drugs such as valproic
may not be used to pinpoint specific causal processes acid (Robert et al., 1982) and carbamazapine (Rosa,
but may provide an indication of potential etiologic 1991), maternal hyperthermia early in the pregnancy,
agents. and maternal diabetes (Botto et al., 1999). Recent stud-
Experimental studies demonstrating a correlation be- ies have demonstrated that consumption of a daily 400
tween specific types of malformations and the devel- g supplement of folic acid by women during the peri-
opmental stage at which injury was induced have led conceptional period would reduce the incidence of
to the idea that timetables of developmental events can neural tube defects by at least 50% (Botto et al, 1999;
be used to determine when the teratogenic damage ac- Lumley et al., 2000).
tually occurred. Warkany reviewed the limitations in-
volved in assigning dates of origin for human malfor- Anencephaly. Many anatomic variants of anen-
mations based on these timetables. He pointed out that cephaly have been described. The basic defect is ab-
the developmental data may in some instances estab- sence of a major portion of the scalp, skull, and brain
lish the termination period or latest time at which a (Norman et al., 1995). In place of the neural structures
teratogen could have caused a particular malformation is an exposed mass of tissue, the area cerebrovasculosa
but not the exact time at which the teratogen acted. (Fig. 3.1). It is composed of thin-walled vascular chan-
Furthermore, termination periods are known for some nels, masses of neuroepithelial tissue, and structures re-
but not all malformations. Many, such as microcephaly sembling choroid plexus. The optic nerves and the eyes
and hydrocephalus, do not have known termination pe- are present. The caudal extent of the lesion varies. If
riods, and their time of inception cannot be established the occipital bones are present, portions of the brain
(Warkany, 1971). stem, cerebellum, and cranial nerves may be preserved.
When the bony defect involves the vertebrae the mal-
formation extends to the spinal cord. In some cases the
Neural tube defects
entire neural axis is affected, a condition referred to as
Neural tube defects (sometimes called failures of fusion craniorachischisis totalis.
or dysraphias) are characterized by a complete or re- The calvarial bones are small and deformed. Defor-
gional disturbance in the continuity of neural tube mities of the petrous temporal bone and the sphenoid
structures and their coverings. The defects are referred wings or abnormally fused bones may be present in the
to as neurulation, or open, defects when the neural tis- base of the skull. When the malformation extends into
sue is exposed to the environment or covered only by the spine, the extent varies but usually includes absence
a thin membrane. When the neural tissue is covered by of the vertebral arches. The anterior lobe of the pitu-
normal skin, the lesions are termed postneurulation, or itary is present, but the hypothalamus and posterior
closed defects. Anencephaly, open spina bifida (mye- lobe may be absent. The adrenal cortex is thin with an
locele; meningomyelocele), and cranioracischisis are
open defects. Postneurulation, or closed, defects include
iniencephaly, encephalocele, closed spina bifida (men-
ingocele; occult spina bifida), split cord malformations
(diastematomyelia; diplomyelia), and lipomyelomen-
ingocele. The pathogenesis of many of the closed de-
fects is uncertain. Some may reflect disturbed primary
or secondary neurulation while others may develop sec-
ondary to defects in the mesoderm surrounding the
neural tube or to other problems unrelated to neural
tube closure (Lemire, 1988; Norman et al., 1995; Hard-
ing and Copp, 1997; Botto et al., 1999).
The etiology of human neural tube defects is un-
known. Epidemiologic studies suggest that environ-
mental and genetic factors interact to cause these
lesions (Elwood et al., 1992). Chromosomal abnor- FIGURE 3.1 Anencephaly. The brain is replaced by the area cere-
malities, single gene mutations, and teratogens, how- brovasculosa, a disorganized collection of blood vessels and neu-
ever, have been identified in less than 10% of infants roepithelial tissue.
absent or reduced fetal zone. Abnormalities of other

system organs such as the thyroid gland, thymus, and
lung may be observed.
Exencephaly and craniorachischisis are two malfor-
mations related to anencephaly. Exencephaly refers to
the absence or incomplete formation, chiefly, of the cal-
varial bones with relatively intact underlying neural
structures. This lesion is seen primarily in the course of
experimental studies on anencephaly before the neural
structures are destroyed. It is suggested that the even-
tual loss of the neural structures results from their ex-
posure, through the bony defect, to amniotic fluid,
which presumably has a toxic effect on the neural tis-
sue. Craniorachischisis refers to a bony defect that in-
volves both calvarium and the vertebral arches with ex- FIGURE3.2 Meningomyelocele. Section of cyst wall with disordered
neurons, glia, and meningeal tissue. H&E, 100.
posure of both brain and spinal cord to amniotic fluid.
Anencephaly is one of the more common human con-
genital anomalies of the central nervous system. Its in- ments. Abnormalities of the spinal cord such as hy-
cidence in the United States is approximately 4 to 10 dromyelia (dilation of the central canal) frequently
per 10,000 pregnancies (Palomaki et al., 1999; Botto occur adjacent to the main defect. Myelocele and
et al., 1999). When it is the only major anomaly, it oc- meningomyelocele are also associated with other con-
curs most commonly in females and in whites gener- genital lesions of the nervous system, including the
ally. Ninety-five percent of anencephalic infants are Chiari type Il (Arnold-Chiari) malformation causing
born in families with no history of neural tube defect. hydrocephalus. This lesion is discussed in a later sec-
After the birth of an anencephalic infant the risk of tion of the chapter.
similar defects in subsequent pregnancies increases to The term spina bifida cystica comprises two lesions,
between 2% and 5%. meningomyelocele and meningocele. The latter is a
During pregnancy, polyhydramnios is frequently closed form of neural tube defect in which a cystic mass
present (Medical Task Force, 1990). Most anencephalic of dura and leptomeninges covered by skin extends
infants are stillborn or die within a few days of birth. through the defect in the vertebral arches. The spinal
Some live for a week, and rare infants with a confirmed cord is in the spinal canal, but may have anatomical
diagnosis of anencephaly survive as long as 7–10 abnormalities.
months (McAbee et al., 1993). Although anencephalic Occult spina bifida refers to a group of axial skeletal
infants are unconscious, brainstem or other neurologic and spinal cord abnormalities usually classified as closed
functions including spontaneous respiration or move- neural tube defects and often less severe clinically than
ment of the extremities, withdrawal from noxious stim- open spina bifida. One or more vertebral arches are miss-
uli, and feeding reflexes may be present (Medical Task ing and other axial skeletal abnormalities may be pres-
Force, 1990). ent. Abnormalities of the spinal cord associated with oc-
cult spina bifida include hydromyelia, diastematomyelia,
Open spina bifida (myelocele and meningomyelo- and diplomyelia. Hydromyelia refers to dilatation of the
cele). Myelocele and meningomyelocele are the two central canal. In diastematomyelia the spinal cord and
types of open spina bifida. The incidence of open spina dura are divided in the midline into two halves by a bony
bifida in the United States is 6 to 10 per 10,000 preg- spur or fibrous band. The cord is joined together above
nancies (Palomaki et al., 1999; Botto et al., 1999). The and below the spur. Diplomyelia refers to duplication of
principal anatomical features of this malformation are a segment of the spinal cord with two anterior horns and
absent or unfused vertebral arches involving many ver- two posterior horns in each segment. Both segments lie
tebral levels and protrusion of malformed spinal cord, within a single dural sac (Norman et al., 1995; Harding,
nerve roots, and meninges through a portion of the ver- 1997).
tebral defect (Fig. 3.2). If the mass includes a cystic
component, it is referred to as a meningomyelocele.
Holoprosencephaly
When the cystic component is absent, the term myelo-
cele is used. These lesions may involve any level of the Holoprosencephaly comprises a group of malforma-
spinal cord but most commonly affect the lumbar seg- tions of varying severity that reflect disordered devel-
opment of telencephalic and diencephalic structures. In These structures are absent in holoprosencephaly, but
alobar holoprosencephaly, the most severe of these de- their absence or incomplete development may also oc-
fects, the cerebrum is a small, undivided spherical struc- cur in the absence of holoprosencephaly. These isolated
ture (Fig. 3.3). The cortical surface may be smooth or anomalies of the olfactory bulbs and tracts are referred
include irregularly disposed gyri that vary in size. Pos- to as olfactory hypoplasia or aplasia.
teriorly, a thin membrane is attached to the malformed Several etiologic factors have been associated with
cerebrum. This membrane covers the single ventricular holoprosencephaly. These include chromosomal ab-
cavity present in place of the lateral ventricles. The ol- normalities, especially trisomies 13–15, trisomy 18, and
factory bulbs and tracts are absent; abnormalities of other chromosomal disorders. Familial and hereditary
the optic nerves are common. The right and left cor- cases have been identified. Holoprosencephaly is also
pus striatum and thalamus are each fused, forming linked with maternal diabetes (Norman et al., 1995;
bilobed masses. Midline structures, including the cor- Harding, 1997; Golden, 1998).
pus callosum, septum pellucidum, and fornix, are ab-
sent. Facial and cranial deformities involving the eyes,
Migrational and dysplastic disorders
nose, and mouth, of which cyclopia is the most severe
form, accompany the brain lesion. Malformations are Disorders of migration include: (1) lesions such as het-
also commonly present in other organ systems. erotopic (ectopic) neurons and glial cells that are ab-
In the less severe forms of holoprosencephaly, semi- normally located in various parts of the CNS and indi-
lobar and lobar holoprosencephaly, the forebrain is cate interruption of the movement of these cells from
partly separated into two hemispheres by a longitudi- their origin along the lumen of the neural tube to the
nal fissure. In the depths of the fissure, however, thc positions they usually occupy in the adult nervous sys-
hemispheres are closely connected by gray matter or in- tem, and (2) lesions such as lissencephaly or agyria,
terdigitating gyri. The corpus callosum is absent, and pachygyria, and polymicrogyria that refer to various dis-
a single ventricle replaces the lateral ventricles. Portions orderly patterns in the arrangement of neurons and glial
of the isocortex are absent or poorly developed. The cells at their adult locations—chiefly in the cerebral cor-
accompanying facial and cranial malformations are tex, although polymicrogyria has been used in reference
similar to but less extensive than those associated with to lesions involving the cerebellar cortex. Dysplasia is a
alobar holoprosencephaly. disorder of cellular growth and development. Neurons
The term arhinencephaly is no longer acceptable as and glia that are abnormal in size or shape or express
a synonym for holoprosencephaly. Originally, it was paradoxical markers of cell lineage are frequently char-
used in reference to one of the features of holoprosen- acterized as dysplastic. Features of both disordered mi-
cephaly—absence of the olfactory bulbs and tracts. gration and cellular dysplasia may be evident in the same
lesion. Some authors refer collectively to the migrational
defects and cellular abnormalities as “dysplasias,” “dys-
plastic lesions,” or “cortical dysplasias.”
Heteropias and ectopias. Collections of neurons and

glia at abnormal locations in the centrum semiovale,
along the lateral ventricles, in the cerebellar white mat-
ter or elsewhere in the maturing CNS are called het-
erotopias or ectopias. The cerebral lesions may be large
or consist only of cells from the sixth cortical layer deep
in the subcortical white matter. In the newborn infant,
neurons normally may be found in the subcortical re-
gions. Heterotopias occur in the absence of gross de-
fects but also commonly accompany malformations.
Some disturbance of the cortical architecture may be
associated with cerebral or cerebellar heterotopias.
Foci of neural and glial tissue are sometimes found
in the subarachnoid space. Whether the cells migrate
into the subarachnoid space, are pinched off from the
FIGURE 3.3 Holoprosencephaly. The cerebrum is represented by an neural tube as a result of inflammatory states, or de-
undivided spherical structure with a few barely discernible sulci. velop in the subarachnoid space originally is unknown.
Lissencephaly, agyria/pachygyria, and polymicro-

gyria. In most cases these lesions are attributed to dis-
turbances in the cortical migration of nerve cells. One
form of polymicrogyria, however, may be the conse-
quence of neuronal injury after completion of migra-
tion to the cortex (Levine et al., 1974). These lesions
often occur in association with other, major cerebral
defects, but they may also occur in isolation.
The terms lissencephaly and agyria have been used
synonomously to designate total absence of cerebral
gyri. Pachygyria refers to broad cerebral gyri separated
by shallow sulci. Currently, the terms agyria or
agyria/pachygyria are used to describe brains that ei-
FIGURE3.5 Micropolygyria. Note the wrinkled and cobblestone ap-
ther lack cerebral gyri completely or have varying num- pearance of many gyral surfaces.
bers of broad flat gyri as well as large areas of the
cortical surface without gyri or sulci (Fig. 3.4).
Lissencephaly is used as a designation for a group of association with genetic and familial disorders (Nor-
disorders including the Miller-Dieker syndrome, the man et al., 1995).
Walker-Warburg syndrome, Fukuyama congenital
muscular dystrophy, and the isolated lissencephaly se- Cerebral dysplasias. As noted above, cerebral mal-
quence, in which agyria/pachygyria is a component of formations may comprise features of both migrational
the cerebral cortical malformation (Rorke, 1994; Nor- defect and cellular dysplasia. There is a tendency, how-
man et al., 1995), The areas of agyria/pachygyria may ever, to refer to lesions as dysplasias when morpho-
be widespread or focal. Microscopically, the cortex logically abnormal neurons or glia are the predominant
usually consists of only four layers. feature. Disorders that exemplify these features include
Polymicrogyria is a term sometimes applied to any focal or multifocal cerebral cortical dysplasia, hemi-
group of small gyri. More specifically it designates a megalencephaly, and tuberous sclerosis (Rorke, 1994;
lesion in which the gyral surfaces have a wrinkled ap- Norman, 1996).
pearance, although definitive secondary sulcation is
lacking (Fig. 3.5). The lesion may be widespread or fo-
Defects of the corpus callosum
cal. Microscopically, the cortex commonly appears as
a wavy band of cells. Adjacent molecular layers are not Complete (agenesis) or partial absence of the corpus
separated. Polymicrogyria may occur sporadically or in callosum occurs in association with other malforma-
tions, including familial conditions such as the Aicardi
syndrome, or as an isolated, asymptomatic lesion. In
partial defects the anterior body and genu are present
while the posterior body and splenium are absent. The
bodies of the lateral ventricles have a “bat wing” ap-
pearance with upward rotation of their bodies and
sharply pointed apices. The cingulate gyri are absent.
The other gyri on the medial surfaces of the hemi-
spheres have a radial arrangement. Collections of
myelinated fibers, called Probst’s bundles, resembling
incompletely formed lateral segments of the corpus cal-
losum are present adjacent to each of the lateral ven-
tricular apices (Fig. 3.6) (Norman, 1996).
Congenital Hydrocephalus
Congenital hydrocephalus may be communicating or
noncommunicating. Common causes include aqueduc-
FIGURE 3.4 Agyria/pachygyria. Lateral cerebral convexity with a com- tal obstruction, the Chiari type II (Arnold-Chiari)
bination of broad, flat gyri and agyric regions. malformation, and the Dandy-Walker malformation
sis, forking, and septum formation) were regarded as

malformations. The fourth (gliosis of the aqueduct)
was attributed to an inflammatory process. In prac-
tice, however, the morphological distinction between
these lesions may be difficult (Drachman and
Richardson, 1961). Furthermore, intracerebral inoc-
ulation of suckling rodents with myxovirus, para-
myxovirus, or reovirus type I produces infection of
the aqueductal ependyma followed by pathological
changes in the aqueduct resembling the presumed de-
velopmental and inflammatory forms of the congen-
ital human lesions described by Russell (Johnson and
Johnson, 1969; Margolis and Kilham, 1969). How
FIGURE 3.6 Agenesis of the corpus callosum. The bodies of the lat- frequently similar viral infections in humans cause
eral ventricles have a bat-wing configuration. Probst’s bundles are congenital hydrocephalus is unknown. Occasional
present bilaterally.
cases have been reported in children (Spataro et al.,
1976).
In cases of simple aqueductal stenosis the aqueduct
(Volpe, 1995). Less frequently, intrauterine infection,
is histologically normal but abnormally small. Forking
intraventricular hemorrhage, or other malformations
is characterized by replacement of the normal aqueduct
underlie the ventricular enlargement (Fig. 3.7).
with multiple ependymal channels separated by normal
parenchyma. The channels may communicate with each
Aqueductal obstruction other, enter the ventricles separately, or end blindly
(Fig. 3.8). Septum formation involves the presence of
In her landmark study, Russell (1966) recognized four
a glial membrane wholly or partially obstructing the
obstructive lesions of the aqueduct that cause con-
caudal aqueduct. Gliosis of the aqueduct is reduction
genital hydrocephalus. Three of these (simple steno-
of the lumen by a distinct collar of fibrillary astrocy-
tosis with remnants of the original ependymal lining
located at the periphery of the astrocytic reaction.
Ependyma is absent from its neoluminal margin (Fig.
3.9). The aqueduct may be affected segmentally or
throughout its length.
FIGURE 3.7 Hydrocephalus. Marked dilatation of the lateral ventri-

cles, thinning of the cerebral white matter, and disruption of the sep- FIGURE3.8 Forking of the aqueduct. Communicating and noncom-
tum pellucidum. municating channels lined by ependyma. H&E, 10.
hydromyelia (distension of the central canal of the

spinal cord) are almost always present in Chiari type
II malformations. Other central nervous system anom-
alies may also occur. The hydrocephalus is caused in
some cases by aqueductal obstruction, whereas in oth-
ers it may be related to blockage of subarachnoid cere-
brospinal fluid pathways at the foramen magnum by
the displaced cerebellum and brain stem (Daniel and
Strich, 1958; Peach, 1964; Harding and Copp, 1997).
The Chiari type I malformation may not cause symp-
toms until adolescence or adulthood, at which time
signs of increased intracranial pressure may appear
abruptly. Portions of one or both cerebellar tonsils
rather than vermis extend below the plane of the fora-
men magnum (Fig. 3.11). Syringomyelia and bony de-
formities of the foramen magnum may coexist with this
lesion. Spina bifida and meningomyelocele are rare
(Norman et al., 1995; Harding, 1997).
FIGURE 3.9 Aqueductal gliosis. The narrowed neolumen is sur-
rounded by astrocytic tissue and remnants of the original ependymal Dandy-Walker syndrome
lining. H&E, 10.
The Dandy-Walker syndrome involves the association
of hydrocephalus with a posterior fossa cyst, partial
or complete absence of the vermis, and dolicho-
Chiari malformations
cephaly (Fig. 3.12). The condition has been attrib-
Two of the Chiari group of malformations deserve par- uted to absence or closure of the fourth ventricular
ticular attention. The Chiari type II lesion is most com- exit foramina; however, these changes are not pres-
mon and is often referred to as the Arnold-Chiari mal- ent in many cases of the syndrome. According to
formation. In this condition the brain stem is displaced Harding (1997), developmental arrest of the hind-
caudally and slightly overrides the rostral spinal cord. brain is a better explanation for the pathogenesis of
An S- or Z-shaped curve is evident in longitudinal sec- the lesion. Hart et al. (1972) have suggested the fol-
tion at the cervicomedullary junction. A tongue of cere- lowing criteria for neuropathologic diagnosis: hydro-
bellar vermis extends for a variable distance caudally cephalus, partial or complete absence of the cerebel-
over the dorsal surface of the medulla into the spinal lar vermis, and posterior fossa cyst continuous with
canal (Fig. 3.10). Spina bifida, meningomyelocele, and the fourth ventricle.
FIGURE 3.10 Chiari type II malformation. Caudal elongation of the FIGURE 3.11 Chiari type I malformation. The prominent foraminal
vermis with caudal and dorsal displacemeny of the lower medulla groove marks the extension of both cerebellar tonsils below the plane
over the spinal cord. of the foramen magnum.
clude growth retardation, dysmorphic cranial or facial

features, and malformations of the central nervous sys-
tem and viscera. Mental retardation and microcephaly
are prominent features. The central nervous system le-
sions are among the most serious components of this
syndrome. Neuropathologic changes include micren-
cephaly, neuronal and glial migrational defects, hydro-
cephalus, holoprosencephaly, agenesis of the corpus
callosum, and neural tube defects (Swayze et al., 1997).
In addition to maternal alcohol consumption, other co-
existing factors such as drug abuse, poor nutrition, and
smoking can be etiologically related to the syndrome
(Kalter and Warkany, 1983). At least two epidemio-
logic studies, however, indicate a dose–response rela-
FIGURE 3.12 Dandy-Walker malformation. Sagittal section of brain
tionship between prenatal alcohol exposure, and cran-
stem and cerebellum. There is partial absence of the vermis and a
cyst communicates with the fourth ventricle. iofacial abnormalities (Ernhart et al., 1987; Werler et
al., 1991).
Syringomyelia Down Syndrome

The term syringomyelia is frequently applied to any The disorder called Down syndrome is relatively com-
spinal cord lesion that is tubular and cavitary and ex- mon, with an incidence of 1 in 600 to 1000 births. It
tends over several segments (Harding and Copp, 1997). was the first human disease shown to be associated with
When used in this way the term encompasses lesions chromosomal abnormalities, which include trisomy 21,
of different etiology, pathogenesis, and clinical impor- translocations, and mosaicism. Trisomy 21, present in
tance. The condition in which the cavity represents only 90–95% of cases, is associated with the sporadic form
a distention of the central canal is more precisely of Down syndrome. The risk of having children with
termed hydromyelia. Minor degrees of this lesion are trisomy 21 increases with advancing maternal age, es-
observed in routine autopsies; however, it has an im- pecially above 30–35 years. Robertsonian transloca-
portant association with the Chiari type II malformations involving chromosome 21q and 14 or 22q and
tion and meningomyelocele. The cavity is lined by 21q21q translocations occur in 4% of cases. The
ependymal cells and a meshwork of astrocytic pro- translocation type of Down syndrome is unrelated to
cesses. When used in a restricted sense, syringomyelia maternal age but is associated with an increased risk
refers to a cavitary lesion lined by an astrocytic mesh- of Down syndrome in subsequent pregnancies. Similar
work and devoid of ependymal cells except where the considerations apply to the mosaic form of this dis-
cavity may encroach on remnants of the central canal. order, which represents the remaining 1% of cases
The defect extends transversely across the cord and is
most extensive in the cervical segments (Fig. 3.13). Cau-
dally the lumbosacral segments are not usually in-
volved. The presence of histologically similar slitlike le-
sions in the brain stem is termed syringobulbia.
Although the lesion is believed to be a developmental
disorder, clinical symptoms often do not appear until
the second or third decade. The term secondary sy-
ringomyelia is sometimes used to designate tubular cav-
ities of obvious cause, such as tumors, trauma, and ad-
hesive arachnoiditis.
Fetal Alcohol Syndrome

The fetal alcohol syndrome comprises a group of con- FIGURE 3.13 Syringomyelia. Cervical cord. The transverse cavity has
genital disorders observed in the children of mothers an astrocytic lining without ependyma. It extends dorsally into the
who drink regularly during pregnancy. Anomalies in- posterior horns. H&E, 2.5.
(Thompson et al., 1991; Harding, 1997). Although no one-third of females with the chromosomal abnormal-
structural lesions in the central nervous system are spe- ity may be retarded (Cronister et al., 1991; Mandel and
cific for Down syndrome, certain gross abnormalities Heitz, 1992; Tsongalis and Silverman, 1993). Neu-
such as brain weight less than 1200 g, flattened occip- ropathologic findings include mild cerebral atrophy, to-
ital pole, and narrow superior temporal gyrus are of- gether with abnormalities of dendritic spines and im-
ten seen in this disorder (Fig. 3.14). Reduced numbers mature synapses in the cerebral cortex (Rudelli et al.,
of cerebral cortical neurons, morphologic irregularities 1985; Hinton et al., 1991). MRI studies have shown
of cerebral cortical dendrites, and indications of dis- reduction in the size of the cerebellar vermis and in-
turbed development of cerebral cortical synapses have crease in the volume of the fourth ventricle in both men
been reported, suggesting an underlying disturbance of and women with the fragile X syndrome. The reduced
cerebral cortical organization. Fibrillary astrocytosis of size of the vermis was attributed to hypoplasia rather
the cerebral white matter has also been described. Cere- than atrophy (Reiss et al., 1991a,b).
bral infarction or abscess may develop as a complica-
tion of the congenital heart defects commonly present
Sturge Weber Disease
in persons with Down syndrome (Harding, 1997).
Within the last two decades the frequent occurrence of The disease is characterized by a facial nevusflammeus
Alzheimer-type changes after 30 years of age in the or port-wine stain involving the upper face, including the
brains of patients with Down syndrome has been rec- forehead, eyelids, and conjunctive chiefly in the distribu-
ognized (Mann and Esiri, 1989). tion of the ophthalmic branch of the trigeminal nerve
accompanied by ipsilateral venous angiomas of the lepto-
meninges and choroid of the eye. In most cases, the lep-
Fragile X Syndrome
tomeningeal angioma overlies the occipital or occipito-
Fragile X syndrome is an X-linked dominant disorder parietal cortex. Bilateral meningeal angiomas, as.well as
with reduced penetrance and is one of the most com- angiomatosis of the dura, skull, and choroid plexus, have
mon forms of hereditary mental retardation (Warren been described. Evidence of a genetic predisposition in
and Nelson, 1994). Initially, the syndrome was associ- Sturge-Weber disease is lacking (deRecondo et al., 1972;
ated with a fragile site on the distal portion of the long Gomez, 1987, 1991; Baraitser, 1997).
arm of the X chromosome. Subsequently, the fragile X The clinical features of Sturge-Weber disease include
mental retardation (FMR1) gene associated with the seizures, motor and sensory deficits, mental subnor-
fragile X syndrome has been cloned and mapped to the mality, and congenital glaucoma (Gomez, 1987, 1991).
region of the fragile site. The mutations involve the ex- Imaging studies show a gyriform pattern of cortical cal-
pansion of an unstable CGG trinucleotide repeat within cification in the affected areas of the brain. Neu-
the gene (deVries et al., 1999). Affected males have ropathologic findings comprise venous angioma of the
varying degrees of mental retardation, mild dysmorphic subarachnoid space, subintimal calcification of sub-
features, and, in adults, enlarged testes. Approximately arachnoid arteries, and calcium deposition accompa-
nied by tissue destruction or atrophy affecting the
underlying cortex and white matter (Fig. 3.15). The
FIGURE 3.15 Sturge-Weber disease. Cerebral cortical resection. Ex-

FIGURE 3.14 Down syndrome. Small superior temporal gyrus and flat- tensive subarachnoid angioma and white streaks of parenchymal cal-
tened occipital pole. cification.
pattern of calcium deposition varies. Droplet incrusta- the edema extends across suture lines. Resolution usu-
tion of small blood vessels, coral-shaped masses, and ally occurs without consequence during the first 48
randomly distributed calcospherites may be seen. The hours postpartum.
parenchymal loss has been attributed to enlargement
of the calcium deposits and ischemic changes related to Subaponeurotic hemorrhage. This lesion is a more
seizures (Alexander and Norman, 1960). The course of severe form of caput succedaneum. Bleeding develops
the disease is a reflection of the severity and extent of deep to the epicranial aponeurosis but external to the
the ocular and cerebral lesions. Intractable seizures as- periosteum. The hemorrhage may extend across the en-
sociated with the cerebral lesions may be amenable to tire scalp. Extensive lesions may cause elevated levels
surgical treatment (Gomez, 1987, 1991). of serum bilirubin (Larroche, 1977).
Cephalhematoma. This hemorrhage is beneath the

PERINATAL BRAIN INJURY periosteum, usually over the parietal bones. The extent
is limited by periosteal attachments to bone margins.
The term perinatal brain injury refers to a group of he- Consequently the lesion does not cross suture lines.
morrhagic and necrotic lesions and their sequelae that Most cephalhematomas are without significance in re-
are believed to have their inception at or near birth gard to infant death.
(prenatal, intrapartum, or postnatal). Mechanical trauma,
asphyxia, and intoxications are among the mechanisms
implicated in their pathogenesis, often on the basis of Intracranial hemorrhage
incomplete evidence. Consequently, the influence and Extradural hemorrhage. Extradural hemorrhages are
importance of these mechanisms remain open to de- usually associated with skull fractures. The bleeding oc-
bate. The use of fetal monitoring, real-time ultrasound curs between the inner surface of the calvaria and the
scanning, other types of neuroimaging, and evoked po- periosteum. The extent of the hemorrhage may vary
tentials will add significantly to the understanding of and on occasion cause a mass effect. Extradural he-
perinatal brain injuries, particularly when these studies matomas are uncommon lesions in neonates, largely be-
are correlated with the results of careful neuropatho- cause skull fractures are rare in this age group.
logic examinations. These data should help resolve
some of the controversy surrounding the mechanisms Intradural hemorrhage. Intrafalcine and intratentor-
of perinatal brain injury (Sunshine, 1997; Edwards and ial hemorrhages occur in both premature and full-term
Nelson, 1998). infants. They have been attributed to asphyxia or me-
chanical trauma and appear to be without clinical sig-
nificance (Friede, 1989).
Hemorrhage
Extracranial hemorrhages involving the scalp and ad- Subdural hemorrhage. Among the clinically impor-
jacent periosteum, as well as intracranial hemorrhages, tant types of neonatal intracranial hemorrhage, sub-
are encountered in the neonatal neuropathologic ex- dural hemorrhage is the least common. It is usually
amination. The extracranial lesions are the caput suc- caused by intrapartum mechanical trauma related to
cedaneum, subaponeurotic hemorrhage, and cephalhe- one or more of the following risk factors: rigid or small
matoma. The location of intracranial hemorrhage birth canal; precipitous labor with insufficient dilation
may be extradural, intradural, subdural, subarachnoid, or stretching of pelvic structures; prolonged labor with
parenchymal, and periventricular/ intraventricular. excessive molding and compression of the head; breech,
Four of these have major clinical significance: subdural foot, face, or brow presentations that subject the head
hemorrhage, subarachnoid hemorrhage, parenchymal to unusually severe or deforming stresses or do not per-
hemorrhage, and periventricular/intraventricular hem- mit gradual adaptation of the birth canal to the head
orrhage (Rorke, 1992; Volpe, 1995; Wigglesworth, size; prematurity with excessive skull compliance: large
1996). size in full-term infants relative to the size of the birth
canal; and difficult deliveries such as forceps extrac-
tions or rotations (Volpe, 1995). The usual sources and
Hematomas of the scalp and adjacent periosteum
locations of the hemorrhage (Volpe, 1995; Wig-
Caput succedaneum. Hemorrhagic edema involving
glesworth, 1996) are as follows:
the skin and superficial subcutaneous tissue over the
calvaria of the presenting head is called caput suc- • Tears in bridging veins, most commonly those ves-
cedaneum. It results from vascular stasis caused by uter- sels extending from the subarachnoid space to the su-
ine or cervical pressure during labor. Characteristically perior sagittal sinus over the cerebral convexity. Blood
accumulates over one or both cerebral hemispheres. Parenchymal hemorrhage. Periventricular and intra-
This is the usual type of subdural hematoma encoun- ventricular hemorrhages are discussed separately in
tered in neonates. another section. The other types of parenchymal are
• Laceration of tentorium with extension to the vein related to a variety of causes, including coagulation
of Galen, straight sinus, lateral sinus, and infratentor- defects, trauma, vascular malformations, congenital
ial veins. Blood accumulates chiefly in posterior fossa tumors, and the use of extracorporeal membrane ox-
with possible extension over the basal surface of the genation techniques (Volpe, 1995; Kinney and Arm-
cerebrum. strong, 1997). Hemorrhagic lesions of the neonatal
• Occipital osteodiastasis (traumatic separation of cerebellum are usually the result of venous infarction,
squamous and lateral portions of occipital bone with extension of hemorrhage from intraventricular or sub-
laceration of occipital sinus). Blood accumulates in the arachnoid sources, primary intracerebellar bleeding,
posterior fossa. and traumatic lacerations in cases of occipital osteodi-
• Laceration of the falx with extension to the infe- astasis. The first three conditions account for most
rior sagittal sinus. Blood accumulates along the cere- cases (Volpe, 1995). Pathogenetic factors include diffi-
bral longitudinal fissure above the corpus callosum. cult delivery, hypoxic events, and prematurity. The oc-
currence of hemorrhagic venous infarction of the cere-
Major subdural hematomas in the newborn infant are
bellum in premature infants ventilated by face mask
life-threatening lesions. Most patients with extensive
has been associated with the use of occipital straps or
subdural bleeding caused by lacerations of the falx or
nets to attach the mask (Wigglesworth, 1996).
tentorium or occipital diastasis die or have a perma-
Prognostic data for parenchymal hemorrhage are
nent lesion such as hydrocephalus. With rapid diagno-
limited. Hemorrhagic lesions of the cerebellum in pre-
sis and intervention, however, some may survive. He-
mature infants are usually associated with a fatal out-
matomas over the cerebral convexity have a better
come, whereas full-term infants may survive. Infants
prognosis (Volpe, 1995).
treated with extracorporeal membrane oxygenation
methods have average mortality rates of 10%–15%.
Subarachnoid hemorrhage. The localized or diffuse Neurological deficits and developmental delay occurs
accumulation of blood in the subarachnoid space as a in 10%–20% of all survivors. Very small infants have
result of bleeding from leptomeningeal vessels is re- significantly higher rates for both death and neurolog-
ferred to as primary subarachnoid hemorrhage. In- ical disability (Volpe, 1995). Detailed information
volvement of the subarachnoid space by extension of concerning the overall prognosis for other types of
subdural, parenchymal, or intraventricular hemorrhage parenchymal hemorrhages is lacking.
is called secondary subarachnoid hemorrhage. Only
primary subarachnoid hemorrhage is considered in this Periventricular (germinal matrix)–intraventricular hem-
section. orrhage. Periventricular–intraventricular hemorrhage
Diffuse primary neonatal subarachnoid hemorrhage is a major cause of neurologic disability and death in
can vary from a few thin patches to prominent collec- the premature infant. Its prevalence based on imaging
tions of blood. It occurs in premature and full-term studies is 15%–20% among newborns of less than
infants. The cause is uncertain, but both hypoxia and 34 weeks’ gestation or with a birth weight less than
trauma have been implicated. The former mechanism 1500 g. The lesion occurs much less frequently in full-
is associated with premature infants and the latter with term infants. Clinical evidence of the hemorrhage de-
full-term babies. Thick, localized neonatal subarach- velops during the first 72 hours after birth. The respi-
noid hemorrhage usually occurs over the temporal and ratory distress syndrome is a major risk factor (Volpe,
occipital lobes. This type of subarachnoid hemorrhage 1995).
is associated with coagulation disorders and exchange Germinal matrix hemorrhages may be single or mul-
transfusions (Wigglesworth, 1996). tiple, unilateral or bilateral, and occur with or without
Volpe (1995) has identified three clinical groups of associated intraventricular hemorrhage. They develop
patients with subarachnoid hemorrhage: those with at any site along the ventricular borders where germi-
minimal or absent neurologic signs, those with seizures, nal matrix is present, such as the lateral margins of the
and those with catastrophic neurologic deterioration lateral ventricles (including the temporal and occipital
and a rapidly fatal course. Most of the patients in the horns) or the roof of the fourth ventricle. In some cases
first two categories appear to do well with little or no the matrix hemorrhage is contiguous with an area of
residual neurologic deficit, provided that no major hy- hemorrhagic necrosis in the cerebral parenchyma. This
poxic or traumatic brain damage is present. parenchymal lesion is considered to be a venous infarct
caused by venous obstruction induced by the matrix sound scan. The short-term mortality is related to the
hemorrhage (Gould et al., 1987). severity of the hemorrhage and varies from 10% to
In premature infants intraventricular hemorrhage 50% for moderate-to-severe grades. Among survivors
most often results from extension of the germinal ma- the frequency of major neurologic sequelae (motor
trix hemorrhage into the ventricular lumen (Fig. 3.16). deficits, intellectual retardation) varies from 5% to
Characteristically, the site of the matrix hemorrhage 35%. The mortality reaches 90% in cases with both
that is the source of the intraventricular hemorrhage is periventricular–intraventricular hemorrhage and ex-
either adjacent to the ventral head of the caudate nu- tensive hemorrhagic infarction of the cerebral paren-
cleus at the level of the foramen of Monro or along the chyma (Volpe, 1995).
body of the caudate nucleus. Less frequently, choroid The neuropathologic findings in survivors of
plexus hemorrhage is the source of the intraventricular periventricular–intraventricular hemorrhage have not
blood, and in some cases both matrix and choroid been extensively documented, chiefly because until re-
plexus hemorrhages are present (Wigglesworth, 1996). cently few infants lived more than 1 or 2 days after
In full-term infants relatively little of the germinal ma- onset of the hemorrhage. Improved medical manage-
trix remains; the intraventricular component of the ment has resulted in significant numbers of survivors.
hemorrhage usually originates from another site, most In an autopsy study Armstrong et al. (1987) observed
often the choroid plexus (Donat et al., 1978). The in- lesions related to periventricular–intraventricular
traventricular hemorrhage fills and distends all or part hemorrhage as well as necrotic parenchymal lesions
of the ventricular system. It may extend through the traditionally associated with hypoxia and ischemia.
fourth ventricular foramina into the cisterna magna and The principal hemorrhagic sequela was hydroceph-
subarachnoid space over the cerebellum and brain stem. alus. This form of posthemorrhagic hydrocephalus is
The pathogenesis of periventricular–intraventricular usually caused by organization of the subarachnoid
hemorrhage is complicated. Several factors are in- extension of the intraventricular hemorrhage with
volved, including disturbances in blood flow, pressure, obliteration of the subarachnoid space and foramina
and volume; asphyxia and respiratory distress; coagu- of the fourth ventricle. Less often the block occurs at
lation disorders; metabolic vulnerability of the matrix the aqueduct because of gliosis induced by intraven-
zone; and immaturity and fragility of vascular channels tricular bleeding (Larroche, 1977). In addition to ven-
(Volpe, 1995). tricular dilation, hemosiderin staining of the ependy-
Clinically, periventricular–intraventricular hemor- mal lining and leptomeninges is apparent. Other
rhage may be associated with a rapid (minutes to hours) hemorrhagic sequelae include hemosiderin-stained
or subacute (up to 24 hours) deterioration of neuro- subependymal cysts evolved from matrix hemorrhages
logic function, including alterations in consciousness that did not rupture into the ventricle and destruction
and tone, respiratory disturbances, and seizures. In of germinal matrix tissue.
some cases there is minimal evidence of a neurologic
disturbance. The diagnosis is confirmed with an ultra-
Hypoxic-Ischemic Lesions
The lesions described in this section are widely viewed
as developing against the background of a reduced oxy-
gen supply to the brain because of asphyxia leading to
inadequate vascular perfusion (ischemia) or diminished
circulatory transport of oxygen (hypoxemia). These
two disturbances, ischemia and hypoxemia, may occur
antepartum, intrapartum, or postpartum. Their princi-
pal associations include cardiac or circulatory insuffi-
ciency associated with intrauterine asphyxia, recurrent
apneic spells, congenital abnormalities of the heart or
great vessels, septic shock, respiratory insufficiency,
and severe right-to-left vascular shunts (Volpe, 1995).
Although perinatal asphyxial events are recognized as
significant risk factors associated with the development
of permanent neurologic disability, their occurrence
FIGURE 3.16 Periventricular/intraventricular hemorrhage. Bilateral does not lead inevitably to such an outcome. Infants
caudate hemorrhages with intraventricular extension. with documented evidence of perinatal asphyxia may
escape without lasting neurologic complications. Fur-

ther, several studies appear to indicate that the gener-
ally accepted view of intrapartum asphyxia as the ma-
jor cause of neonatal encephalopathy and cerebral palsy
is incorrect (Sunshine, 1997; Edwards and Nelson,
1998).
Both acute and chronic central nervous system le-
sions are attributed to hypoxic–ischemic injury. The
acute forms are periventricular leukomalacia and gray-
matter necrosis, which may involve structures in the
cerebrum, brain stem, or cerebellum. Chronic lesions
include ulegyria and status marmoratus. At least some
cases of the cavitary lesions mentioned below—
hydranencephaly, multicystic encephalomalacia, and
porencephaly—may also develop as a consequence of
hypoxic–ischemic parenchymal destruction.
Periventricular leukomalacia
Although periventricular leukomalacia was recognized
almost a century ago, this lesion received little atten-
tion until Banker and Larroche (1962) published their
FIGURE 3.17 Periventricular leukomalacia. Necrotic lesion involving
classic study delineating its pathologic characteristics,
the optic radiation.
including the distinctive anatomic distribution of the
lesions. Premature infants are affected most often, but
the disorder also occurs in full-term and stillborn in- clear. The former may represent a variant of the latter
fants (Volpe, 1995). (Gilles et al., 1977).
Macroscopically, the typical acute lesions appear
as one or more irregular white or yellow foci in the
Gray-matter necrosis
frontal centrum semiovale near the lateral angles of
the ventricles and in the optic radiations adjacent to Gray-matter necrosis occurs in both premature and full-
the ventricular trigones (Fig. 3.17). Some foci are he- term infants. It is also found in cases of periventricu-
morrhagic. Microscopically, the features are those of lar leukomalacia. If only a few cells are involved, no
coagulation necrosis with swollen axons accompa- gross changes may be evident. In the case of larger le-
nied by histiocytes, phagocytes, reactive astrocytes, sions, however, acutely affected areas are grossly
and vascular proliferation according to the age of the swollen and soft and appear pale, congested, or hem-
lesion. In older lesions fibrillary astrocytosis, mineral orrhagic. Histologic changes such as eosinophilic neu-
deposits, or even cavitation may be evident. Patho- ronal necrosis occur but may be difficult to recognize
genetic studies have focused on ischemia occurring because of the small size of the infant’s neuronal
after perfusion failure in arterial boundary zones or perikarya and the close packing of neurons in regions
end artery zones of the white matter as a basis for such as cerebral cortex. Nuclear karyorrhexis is one of
the necrotic lesions (DeReuck et al., 1972; Takashima the more reliable indicators of neuronal death in these
and Tanaka, 1978). circumstances. Subsequently, astrocytes and macro-
The term perinatal telencephalic leukoencephalopa- phages are activated, dead nerve cells disappear, and
thy has been applied to a group of cerebral white- the neuropil becomes vacuolated. Necrotic neurons,
matter changes comprising astrocytosis, amphophilic especially in the thalamus, may have intensely ba-
globules, and acutely damaged glia occurring alone, sophilic cell bodies that stain positively with periodic
together, or in combination with necrotic white matter acid–Schiff stain and with methods that reveal iron and
foci in neonatal autopsies. Clinical and experimental calcium. There may be regional accentuation of the
studies indicate that endotoxemia may play an impor- necrotic lesions with the most extensive lesions occur-
tant role in the induction of the alterations. The precise ring, for example, in the cerebral cortical arterial
relationship between perinatal telencephalic leukoen- boundary zones or the pons and subiculum (Wig-
cephalopathy and periventricular leukomalacia is un- glesworth, 1996). The factors that determine the re-
gional accentuation of the necrotic lesions are not

understood.
Ulegyria
The term ulegyria refers to a chronic lesion comprising
groups of atrophic, roughly mushroom-shaped gyri that
are found characteristically in the parietal and occipi-
tal convexities of infants and children who have sus-
tained perinatal episodes of hypoxic–ischemic injury
(Fig. 3.18). Perfusion failure in the distal arterial
beds supplying these areas and subsequent infarction,
parenchymal loss, astrocytosis, and atrophy appear to
be the mechanisms involved in the of these lesions. Mi-
croscopically, the parenchymal loss is greater along
FIGURE 3.19 Status marmoratus. Irregular bands of white tissue com-
sulcal valleys than over gyral crests, giving rise to the posed of myelin and astrocytic processes involve both caudate
mushroom configuration (Harding, 1997). nuclei.
Status marmoratus
been reported as an early stage in the development of
Status marmoratus is a chronic lesion occurring most of- status marmoratus (Friede and Schachenmayr, 1977).
ten in the thalamus, neostriatum, and cerebral cortex. Experimental studies have shown hypermyelination of
The term refers to the irregular intersecting bands of fetal neocortical transplants in either neostriatum or neo-
myelin and astrocytic fibers that develop abnormally cortex of adult rats. The histologic appearance of these
in these regions, most likely as a consequence of foci resembled the marbled lesions seen in humans
hypoxic–ischemic injury including small areas of infarc- (Deckel and Robinson, 1986). These observations sug-
tion. The gross and microscopic appearance of the le- gest that status marmoratus develops in myelinated
sion in myelin-stained sections recalls the variegated pat- structures following injury as part of the reparative pro-
terns seen on marble surfaces (Fig. 3.19). Several cess and may involve disorientation of myelinated fibers
mechanisms may be involved in the development of the or inadvertent myelination of axonal surrogates.
lesion. In some cases aberrant myelination of astrocytic
processes has been observed (Borit and Herndon, 1970).
Kernicterus
Disorientation of otherwise-normal bundles of myeli-
nated axons crossing glial scars in the basal ganglia has Kernicterus refers to the overt form of bilirubin enceph
alopathy in which there is selective staining of gray mat-
ter and neuronal necrosis. The disorder is caused by
relatively high serum levels of unbound, unconjugated
bilirubin that develops in the newborn period through
various processes including hemolytic disorders, re-
sorption of large hematomas, and congenital or ac-
quired defects in bilirubin conjugation. A serum biliru-
bin concentration in excess of 20 mg/dL is commonly
considered a clear indication for exchange transfusion
to prevent kernicterus. Other factors such as prematu-
rity, low serum albumin concentration, asphyxia, aci-
dosis, and sepsis may lower the serum bilirubin thresh-
old for kernicterus to a range of 10 to 15 mg/dL. Some
data indicate that there may be more subtle forms of
bilirubin encephalopathy with even lower serum biliru-
bin levels and without kernicterus (Volpe, 1995).
The pathogenesis of kernicterus involves movement
FIGURE 3.18 Ulegyria. Bilateral parietooccipital collections of at- of the bilirubin into the brain, most likely followed by
rophic gyri. The tissue loss is most marked along the sulcal valleys. intoxication and death of neurons. Increased perme-
ability of the blood–brain barrier resulting from endo- Porencephaly

thelial damage caused by asphyxia, intracranial infec-
The term porencephaly is generally used in reference to
tion, or increases in serum osmolality may facilitate en-
a circumscribed cavity involving one or both cerebral
try of bilirubin. The neuronal toxicity of bilirubin is
hemispheres. The superficial portions of the cavity are
believed to involve an effect on mitochondria, perhaps
covered by a membrane formed in part from lep-
enhanced by other concomitant neuronal injury such
tomeninges. Internally the lumen of the lateral ventri-
as hypoxia and hypoglycemia (Jew and Sandquist,
cle may communicate with the porencephalic cavity.
1979; Volpe, 1995). The basis for the selective in-
Dysplastic changes, such as micropolygyria, or distor-
volvement of specific nuclei and regions of gray mat-
tion of the gyral pattern, are evident in the cortical ar-
ter is uncertain. The explanation may involve vascular
eas adjacent to the defect (Fig. 3.20). The extent of the
factors, binding sites, or biochemical processes at the
astrocytic reaction in the parenchyma adjacent to the
affected sites.
defect may be minimal if the injury occurred relatively
The chief pathologic features of kernicterus are macro-
early in fetal life.
scopic, symmetric bilirubin staining of specific regions
of gray matter and and microscopic evidence of neuronal
necrosis at those sites. Most commonly affected are the Hydranencephaly
globus pallidus, thalamus, subthalamus, cranial nerve In hydranencephaly most or all of the cerebral cortex
nuclei, inferior olives, gracile and cuneate nuclei, and and white matter is replaced by translucent membra-
cerebellar roof nuclei. Less often the hippocampus, puta- nous sacs filled with cerebrospinal fluid and composed
men, lateral geniculate body, and anterior horns are in- of leptomeninges and glial tissue. In the less severe
volved. The yellow color of these structures is readily cases, gyri at the base of the brain can be identified.
apparent in the fresh brain and after formalin fixation.
Histologic examination of early lesions shows neurons
with vacuolated cytoplasm and pyknotic nuclei at the Multicystic encephalopathy
sites of gross staining. Bilirubin pigment is also dis- Multicystic encephalopathy is characterized by the
cernible even in paraffin sections, possibly reflecting tight presence of multiple cavities involving the white mat-
binding of the pigment to cell membranes. Evidence of
ischemic neuronal necrosis may be superimposed on the
pigmentary lesions. In the brains of infants who survive
the acute phase of kernicterus and die at a later date,
neuron loss and astrocytosis are evident in many of the
structures that stained during the acute stage (Hayashi
et al., 1991). During their first year, such children ex-
hibit hypotonia, brisk deep tendon reflexes, a persistent
tonic neck reflex, and slow development of motor skills.
Later the extrapyramidal signs and gaze disturbances
generally regarded as characteristic sequelae of ker-
nicterus appear (Volpe, 1995).
Cavitary Encephalopathies
Cavitary encephalopathies, including porencephaly,
hydranencephaly, and multicystic encephalopathy, are
characterized by the formation of one or more cavitary
lesions usually involving the cerebral hemispheres. The
cavities are sites of extensive parenchymal loss that ap-
pears to be the consequence of some type of cata-
strophic circulatory disturbance occurring in the latter
half of pregnancy or in the neonatal period. The patho-
genesis of these lesions remains obscure. They have
been associated with infectious agents, maternal expo- FIGURE 3.20 Porencephaly. The cavity extends from the cortical
sure to toxic gases, and genetic factors (Friede, 1989; surface to the ventricular lumen with dysplastic cortex along its
Rorke, 1992; Harding, 1997). margins.
ter and deeper cortical layers of the cerebrum. The cav- tailed assessment of specificity, critical period, and threshold. Am
ities are partly separated by glial septa containing lipid J Obstet Gynecol 156:33–39.
Foley J.M. and Baxter D. (1958). On the nature of pigment granules
phagocytes. The lesions occur chiefly in the distribu- in the cells of the locus coeruleus and substantia nigra. J Neu-
tion of the anterior and middle cerebral arteries. ropathol Exp Neurol 17:586–598.
Friede R.L. (1989). Developmental Neuropathology, 2nd ed.
Springer-Verlag, Berlin.
Friede R.L. and Schachenmayr W. (1977). Early stages of status mar-
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4 Bacterial, fungal, and parasitic
diseases of the central nervous system
STEVEN C. BAUSERMAN AND L. GILL NAUL
BACTERIAL INFECTIONS brospinal fluid (CSF) dynamics. When the meningitis

is acute, the brain is often markedly swollen. The
Bacterial infections of the nervous system continue to pathogenetic dynamics of this process have been stud-
be life threatening and often leave serious sequelae. As ied in great detail (Quagliarello and Scheld, 1992).
in our previous edition, we choose to discuss these var- Brain swelling results from a combination of vasogenic,
ious entities as infections of the meninges, focal puru- cytotoxic, and interstitial edema (Bell and McCormick,
lent accumulations, mycobacterial infections (predom- 1981; Saez-Llorens et al., 1990; Kirkpatrick, 1997).
inantly tuberculosis), other granulomatous diseases, Usually some degree of ventriculitis and choroid plexi-
and spirochetal infections. Additional brief discussions tis accompanies the meningitis with corresponding ab-
of the neuropathologic features of cat-scratch disease normalities demonstrated by neuroimaging (Fig. 4.2).
and Whipple’s disease are presented below. Powerful Phlebitis and arteritis are often present and lead to sec-
molecular techniques such as 16S PCR RNA have been ondary neuroparenchymal damage of an ischemic type.
applied to many of these diseases; some diagnostic and In some cases (especially those associated with dehy-
therapeutic monitoring breakthroughs have been made, dration), there is cortical vein and/or sagittal sinus
but the pathologic features are unchanged. thrombosis (Bell and McCormick, 1981).
Purulent Leptomeningitis Neonatal Meningitis

Purulent leptomeningitis is an acute suppurative infec- During the neonatal period from birth to 4 weeks,
tion of the pia–arachnoid and subarachnoid space meningitis has a high mortality rate, and severe seque-
(SAS). The causative organism(s) varies with geogra- lae are fairly common (Dodge and Swartz, 1965; Smith,
phy, patient age, and many socioeconomic factors. 1997). Neonatal meningitis has an incidence of ap-
Streptococcus pneumoniae (pneumococcus) continues proximately 0.13–2.24 cases per 1,000 births with the
to be the most common pathogen in adults (Schuchat, higher incidence in premature infants (Kroll and
1997). Age subdivisions in the pediatric population are Moxon, 1986), Group B Streptococcus (GBS) is the
used to predict predominant organisms, especially to most common causative organism, but it has recently
enable early diagnosis and therapeutic advantage. decreased in the United States (MMWR, 1997). Esch-
The gross and radiographic appearance of the brain erichia coli is second and Listeria monocytogenes is in
and spinal cord in this process is generally independent third place according to data from most developed
of the causative organism but is related to the stage of countries. (Remington et al., 1990; Smith, 1997). Pre-
the disease and to whether the person has been treated disposing factors in neonates include prematurity, pro-
with antibiotics and/or other agents. Exudate is most longed rupture of maternal membranes, traumatic
abundant in the subarachnoid space, especially along delivery (obstetric complications), and congenital mal-
vessels on the cortical surface and in the basal cisterns formations such as meningomyelocele and dermal si-
(Fig. 4.1B). Initially abundant neutrophils and fibrin nuses (Bell and McCormick, 1981; Kaplan, 1989;
are encountered in the subarachnoid space with radio- Klein, 1990; Smith, 1997). In addition, acquired respi-
logic findings related to that process. Later, macro- ratory, intestinal, and umbilical infections can lead to
phages become the predominant cells in the exudate. septicemia and meningitis (Kaplan, 1989). Neurologic
Organization of the exudate often leads to meningeal and neuropsychiatric sequelae are found in 30%–50%
fibrosis and may compromise vascular supply and cere- of the survivors (Dodge and Swartz, 1965). Hydro-
45
A B
FIGURE 4.1 (A) Bacterial meningitis. After T1-weighted axial images showed no abnormality, T1-weighted
axial images after contrast enhancement showed diffuse leptomeningeal enhancement consistent with
bacterial meningitis. (B) Bacterial meningitis from otitis. Acute bacterial meningitis in a child, originat-
ing from left otitis and mastoiditis (courtesy of Drs. McCormick and Schochet).
cephalus may result from occlusion of the aqueduct sec- The early onset, acute syndrome, is one of rather high
ondary to ventriculitis (Fig. 4.2) and obstruction of the mortality but mostly involves respiratory distress and
outlet foramina of the fourth ventricle, or impeded flow pneumonitis with sepsis occurring in the first 5 days of
of CSF through the subarachnoid space and arach- life. Meningitis is usually not the most predominant
noidal granulations (Kroll and Moxon, 1986). En- feature of this particular syndrome. Studies of the
cephalomalacia is seen especially in the vascular bor- serotypes strongly suggest that the disease results from
der zones (Friede, 1973) and in the white matter. intrapartum infection from maternal flora (Bell and
Seizures, learning disabilities, deafness, and focal neu- McCormick, 1981; Smith, 1997). The high mortality
rologic deficits of varying severity are common late se- rate in this syndrome ranges from 15% to 30% (Klein
quelae (Dodge and Swartz, 1965). 1990).
In many neonatal series the group B streptococcus The delayed form or late-onset syndrome is pre-
pathogen is “vertically” transmitted from maternal dominantly nosocomial in infants more than 10 days
vaginal flora with as many as 10%–35% of obstetric of age and is characterized by septicemia with resultant
patients harboring this organism in vaginal flora acute meningitis. Almost all of the cases of the delayed
(Smith, 1997). The “horizontal” transmission of this disease are associated with serotype III. The precise
organism accounts for delayed forms with nursery per- pathogenesis is unclear, but these organisms clearly
sonnel being the carriers in skin and nasopharynx. In have invasive properties with a predilection for in-
the neonates, two distinct syndromes with disparate volvement of the leptomeninges (Klein, 1990). This
clinical features are identified (Bell and McCormick, form of neonatal meningitis is somewhat less common,
1981; Smith, 1997). with a relatively low mortality rate of about 5%. Over-
4: BACTERIAL, FUNGAL, AND PARASITIC DISEASES OF THE CNS 47
mortality rate (Laavetter et al., 1971; Bell and Mc-

Cormick, 1981). Early diagnosis and therapy give some
chance for survival, however (Armstrong, 1995). The
delayed form may be nosocomial and has an onset be-
tween 5 and 8 days of age and a mortality rate of about
50%. One impediment to diagnosis is difficulty in iden-
tifying the agent in the CSF microscopically. Gram stain
preparations containing this organism may resemble
simple diphtheroids and be dismissed as insignificant
contaminants (Laavetter, 1971; Lorber, 2000).
A wide variety of other bacteria may cause neonatal
meningitis. In the developing countries Salmonella
species are common but are infrequently encountered
in the United States (Kaufman et al., 1975; Bell and
McCormick, 1981; Smith, 1997). Staphylococci are
important pathogens in certain settings such as surgi-
cal manipulations, use of indwelling catheters, shunts,
and other invasive procedures. Neisseria gonorrhoeae
has been known to cause meningitis as a complication
of gonococcal ophthalmia (Klein, 1990). Haemophilus
influenzae is a rare cause of neonatal meningitis as well.
Other bacteria that occasionally cause neonatal men-
ingitis include Citrobacter species, Flavobacterium
meningoscepticum, and a number of other unusual or-
ganisms, which are often nosocomial in origin (Bell and
FIGURE 4.2 Ventriculitis. Axial CT image after contrast enhancement
McCormick, 1981; Klein, 1990; Smith, 1997).
demonstrates prominent enhancement of the ventricular walls with
surrounding edema. Findings are consistent with bacterial ventri-
culitis. PATHOLOGY
The gross features of meningitis in neonates are simi-

all, GBS meningitis has become less common in recent lar to those seen in older individuals and consist of
years (MMWR, 1997). swollen brain with purulent exudate in the sulci along
E. coli is the most common cause of neonatal menin- the leptomeningeal veins, especially over the convexi-
gitis in some areas of the world including Latin Amer- ties, at the base, and over the vermis of cerebellum (Fig.
ica, where it is responsible for 40%–50% of cases in 4.1B). Exudate in these sites may be obvious when ex-
some series (Klein, 1990). Usually E. coli meningitis in udate elsewhere is very difficult to see grossly (Bell and
infants is due to organisms with the K1 capsular anti- McCormick, 1981; Smith, 1997). Secondary vascular
gen. This polysaccharide is thought to contribute to the complications are common in this age group. Result-
invasiveness of the agent (Klein, 1990; Smith, 1997). ing infarcts often produce the most serious sequelae
Listeria monocytogenes is a gram-positive bacterium (Friede, 1973). Neonatal meningitis is commonly ac-
transmitted transplacentally from the mother to fetus, companied by ventriculitis and choroid plexitis. Fenes-
causing abortion in many instances. Asymptomatic ges- tra in the vessels of the choroid plexus may be the
tational infection may result in stillbirth or prematu- portal of entry for CNS infection in patients with sep-
rity. The organism can produce neonatal meningitis or ticemia preceding purulent leptomeningitis (Bell and
a distinctive systemic granulomatous condition known McCormick, 1981; Saez-Llorens et al., 1990; Quagliarello
as granulomatosis infantiseptica which is quite striking and Scheld, 1992).
in its multiorgan involvement including hepatospleno-
megaly, myocarditis, and meningoencephalitis (Arm-
Childhood and Adult Meningitis
strong, 1995). The condition is often difficult to diag-
nosis clinically since the mother may be asymptomatic From 4 to 12 weeks of age meningitis is often caused
and the symptoms develop in the infant within the first by Streptococcus pneumoniae and delayed forms of
4 days of life. This early onset form has a nearly 100% some of the more common neonatal pathogens such as
Staphylococcus aureus and group B streptococcal in- croscopic feature, which may be marked in the early
fection of the delayed type. Immune compromise and stage, is endothelial and adventitial proliferation and
structural abnormalities such as shunt tubes and other reaction in small blood vessels of the leptomeninges.
neurosurgical procedures factor into this array of Later, between 2 and 4 weeks into the infection, there
agents (Kaufman, 1997). In developing countries Sal- may be cerebral cortical necrosis secondary to a num-
monella species are important pathogens in this age ber of events including vasculitis and subcortical white-
group. Neonatal tetanus is a worldwide infantile and matter degeneration and gliosis. In the rare chronic
childhood pathogen of significance in terms of mortal- meningitis cases, the ventricles are markedly dilated,
ity. Worldwide incidence is about 18 per 100,000 and large portions of the cortex are necrotic, and the white
neonatal tetanus represents half of all tetanus deaths in matter may be cystic (Roos et al., 1997).
developing countries (Bleck, 2000). Neuropathology is Subdural effusions or hygromas are commonly en-
mostly nonspecific, and toxin-mediated neuronal dam- countered as a complication of H. influenzae meningi-
age predominates. tis. The effusions may be bilateral and strikingly dem-
From the age of approximately 2–3 months to 3 years onstrated by neuroimaging. Organisms are rarely
the infant undergoes the transition from a state of pas- grown from cultures of this fluid. Permeability of dam-
sive immunity acquired from the mother to achieve long- aged blood vessels is involved in the pathogenesis (Roos
term immunity against many environmental pathogens. et al., 1997). Subdural hygromas in infants and chil-
During this particular age, H. influenzae has been the dren may be encountered with other types of meningi-
most common etiologic agent for meningitis with a peak tis and probably are related more to the young age
age between 6 and 18 months. Nearly all cases of H. in- of the patient than to the causative organism itself.
fluenzae meningitis occur before the age of 5 years. In S. pneumoniae is the leading cause of meningitis in
those instances beyond age 6 one must suspect possible adults and extends its clinical spectrum to all ages with
host susceptibility factors such as immune deficiency, highest mortality rates at the extremes of age (Durand
CSF leak, etc. The impact of conjugated vaccine on the et al., 1993; Kragsbjerg et al., 1994). The predisposing
prevalence of this type of meningitis has been profound: factors in addition to the very young and very old in-
a reduction of 76%–94% in certain surveys (Bisgard, dividuals include chronic alcoholism, especially related
1998; Van Alphen et al., 1997). to alcohol-induced defects in chemotaxis and impaired
H. influenzae is a gram-negative, pleomorphic rod phagocytosis. The age-dependent decline in immuno-
with somewhat variable staining properties. It requires competence further predisposes the elderly to this form
X and V growth factors for culture. Six serologic types, of meningitis and its complications and involves much
a–f, have been delineated. Of these, type b is responsi- higher mortality than in young adults and older chil-
ble for at least 85% of cases of meningitis (Roos et al., dren. Head trauma, especially when skull fracture has
1997; Moxon, 2000). Type b produces an endotoxin occurred with cerebrospinal fluid leak, puts people at
that is important for the organism’s virulence and con- high risk factor for recurring pneumococcal meningitis
tains a lipopolysaccharide on its surface. The usual se- at all ages. Pneumococci are often part of the flora
quence of events in such an infant is that of nasopha- of the nasal cavities, sinuses, ears, and mastoids
ryngeal colonization followed by hematogenous (Quagliarello and Scheld, 1992; Tunkel and Scheld,
dissemination and subsequent meningitis. This is re- 1997). Pneumococcal meningitis may be a complica-
flected by the fact that blood cultures are positive for tion of pulmonary infection, otitis, and sinusitis. Sep-
the organism in 65%–75% of cases (Roos et al., 1997). ticemia usually occurs prior to the meningitis. Circu-
Diagnosis of H. influenzae meningitis is aided by a lating encapsulated organisms place patients with
high index of suspicion. Meningitis occurs in this age hyposplenism, sickle cell disease, asplenism after
group and CSF studies support that interpretation. splenectomy in childhood, and related conditions at in-
Stains show gram-negative pleomorphic bacilli, but creased risk from this invasive organism (Saez-Llorens
morphologic misidentification is common (Roos et al., et al., 1990; Tunkel and Scheld, 1997). Immunocom-
1997). In the past, the rather demanding tests have been promised patients are at increased risk but can be par-
supplanted by rapid identification studies of CSF, tially protected by vaccination. Splenectomy in adults
which are highly sensitive in most instances (Greenlee, (unlike children) does not carry the same increased risk.
1997). Complications most common following bacterial
The neuropathology of H. influenzae meningitis is meningitis with this organism include sensorineural
similar to that of other forms of meningitis with a rather deafness, other cranial nerve palsies (Chu et al., 1990),
thick purulent exudate out of proportion to that seen hemiplegia, ataxia (secondary to hydrocephalus),
in other forms of bacterial meningitis. A peculiar mi- epilepsy, and decreased IQ (Gray, 1997).
Clinical diagnosis is often quickly established by Meningitis results from invasion of the central ner-
gram stain of cerebrospinal fluid sediment revealing vous system through the choroid plexus or other sites
gram-positive intracellular diplococci (Vetter et al., deficient in blood–brain barrier (sites of fenestrated
1993). This is confirmed by culture and immunodiag- capillaries) (Saez-Llorens, 1990; Kirkpatrick, 1997;
nostic techniques (Greenlee, 1997; Roos et al., 1997). Roos et al., 1997). The organisms may be seen within
Other diagnostic studies may include serotyping for epi- neutrophils when cerebrospinal fluid sediment is ex-
demiologic identification (Roos et al., 1997). amined. Sixty percent to 90% of cases are identified by
Brains from individuals who die of pneumococcal a rapid antigen identification technique applied to cere-
meningitis show gross pathologic features consistent brospinal fluid (Roos et al., 1997).
with the stage of the disease and its possible treat- Cutaneous eruptions are seen in 50%–65% of pa-
ment modifications. A variable amount of exudate tients. Smears from the cutaneous lesions often show
may be greenish over the convexities and in the ba- intracellular diplococci. Cardiac involvement can lead
sal cisterns. Some cases are complicated by sagittal to sudden death or cardiac decompensation (Hardman
sinus and/or cortical vein thrombosis, especially when and Earle, 1969) and may be seen in the absence of
dehydration supervenes (Bell and McCormick, 1981; meningitis. Several clinical syndromes are identified
Kirkpatrick, 1997; Roos et al., 1997). Radiographic with meningococcemia, with and without meningitis.
studies are often used to identify the complications Myocarditis is common in fatal cases with sustained
of bacterial meningitis due to this organism. Cortical septicemia (78% of cases reviewed at the Armed Forces
vein thrombosis often results in hemorrhagic infarcts, Institute of Pathology [AFIP] by Hardman and Earle)
which are strikingly demonstrated with appropriate (Hardman and Earle, 1969). Microvascular thrombi in
scans. the lungs may lead to core pulmonal (Dalldorf and
Neisseria meningitidis causes meningitis mainly in Jeanette, 1977). Arthritis and endophthalmitis have
children and young adults. Less than 10% of patients also been reported. Rarely, older adults, patients with
are over 35 years of age when contracting this infec- intercurrent infections, or patients with complement
tion. The organism is a gram-negative diplococcus usu- deficiencies develop chronic meningococcal infections.
ally seen intracellularly. Microbiologic features include Meningitis may develop in these individuals weeks or
fermentation of dextrose and maltose but not sucrose months after this recurrent illness (Roos et al., 1997).
(distinguished from other Neisseria species such as The Waterhouse-Friderichsen syndrome is defined as
N. gonorrhoeae). Multiple serogroups identify the fulminant meningococcemia associated with vasomo-
meningococci with serogroup A, which has been re- tor collapse, shock, and widespread hemorrhages in-
sponsible for past major epidemics worldwide (Api- cluding those in the adrenal glands (Roos et al., 1997).
cella, 1995). Serogroups B and C now cause most fa- Pathologic evidence suggests that disseminated in-
tal outbreaks and sporadic cases (Roos et al., 1997). travascular coagulation (DIC) produces these lesions.
The capsular polysaccharide enhances virulence and en- A comparable syndrome both clinically and patholog-
dotoxin release, leading to tissue injury, vascular col- ically including adrenal hemorrhages may be caused by
lapse, coagulopathy, and fatalities (Quagliarello and H. influenzae, pneumococcus, or staphylococcus (Bell
Scheld, 1992; Roos et al., 1997). and McCormick, 1981; Kirkpatrick, 1997; Roos et al.,
The pathogenesis is fairly well defined and the patho- 1997).
physiology is documented (Quagliarello and Scheld, Brains examined from patients who die rapidly of
1992). Nasopharyngeal colonization is followed by in- fulminant meningococcal disease may show marked
vasion and hematogenous dissemination. Deficiency of cerebral congestion and edema with minimal exudate
antimeningococcal antibodies usually represents lack of in the subarachnoid space (Dalldorf and Jeanette, 1977;
previous exposure (Roos et al., 1997). Late infant sus- Bell and McCormick, 1981). Others have hemorrhagic
ceptibility begins with loss of passively transferred ma- lesions reflecting the DIC in addition to the other vas-
ternal antibody. Crowded conditions contribute with cular edematous changes. Still others have microscopic
the mixing of individuals colonized and those without evidence of meningitis and foci of cerebritis. Abundant
previous exposure. This situation has been responsible exudate is exceptional in such cases and seen mainly in
for many epidemics in the military in basic training patients with a more chronic form of the disease (Roos
camps (Roos et al., 1997). Patients with deficiencies of et al., 1997). Complications of this disease are similar
the terminal component of complement such as those to those described in meningitis from other causes. Pre-
with lupus erythematosus are at special risk for dictors of sequelae include: EEG abnormalities with
meningococcal infections (Quagliarello and Scheld, seizures documented and decreased level of conscious-
1992; Roos et al., 1997). ness (including Glasgow coma score) during the clini-
cal course (27 of 29 cases predicted sequelae) (Chequer The diagnosis is best established by radiographic
et al., 1992). Application of neuroradiographic tech- techniques (Zimmerman, 1997) (Fig. 4.3A). Lumbar
niques often helps identify sequelae and complications puncture should be avoided in patients with possible
from bacterial meningitis (Ogilvy et al., 1992; Pfister brain abscess, since the procedure may precipitate her-
et al., 1993; Zimmerman, 1997). niation (Greenlee, 1997). Furthermore, cerebrospinal
fluid findings are not generally diagnostic for brain ab-
scess (Greenlee, 1997).
ABSCESS There are two main categories of pathogenesis: the
first involves the contiguous site of infection—for ex-
Brain abscesses are foci of suppuration within the ample, otitis, fronto-ethmoidal or sphenoid sinusitis,
neural parenchyma that may be subdivided into two or dental infection, and trauma (both surgical and non-
more stages. These include the early stage of cerebritis, surgical) (Wispelwey et al., 1997). The second category
with progression to cavitation, and the second stage of of pathogenesis is from a distant site, which especially
encapsulation that includes both early and late stages. includes: congenital heart disease with right-to-left
The signs and symptoms are nonspecific and similar to shunt (Kagawa et al., 1983); lung abscess, empyema,
those of other mass lesions, but headaches may be es- and/or bronchiectasis; bacterial endocarditis; and
pecially prominent. Manifestations of local or systemic compromised (immunosuppressed) host. Most patients
infection are often lacking (Pendelbury et al., 1989; with brain abscesses have either an extracerebral con-
Wispelwey et al., 1997). tiguous focus of suppuration, especially otitis, or si-
A B
FIGURE 4.3 (A) Bacterial abscess. T1-weighted postcontrast axial MR image of the brain shows irregu-
lar ring enhancing cystic mass in the right frontal–parietal region. There is surrounding vasogenic edema.
Findings are consistent with an abscess. Capsule is of intermediate signal intensity and enhances with
contrast. (B) Brain abscess, late stage, with organization in the parietal lobe. Note central suppuration
leaving artifactual defect with abscess wall containing neovascularity 1–2 mm thick (courtesy of Drs.
McCormick and Schochet).
nusitis. Blood-borne infections from distant sites, espe- rative focus, a zone of acute and chronic inflammation
cially dental infections, are responsible for a smaller and granulation tissue, and peripherally edematous, gli-
proportion of cases (Kaufman et al., 1975; Wispelwey otic parenchyma (Wispelwey et al., 1997; Kirkpatrick,
et al., 1997). 1997). The proliferating endothelial cells in the capsule
The causes are rather diverse in terms of etiologic or- do not form a competent blood–brain barrier and lead
ganisms, but certain organisms predominate, especially to continuing vasogenic edema (Dyste et al., 1988; Zim-
in certain settings (Wispelwey et al., 1997). Streptococci, merman, 1997).
both microaerophilic and anaerobic especially the Mortality from brain abscess is generally secondary
Streptococcus milleri group are recently more prevalent to herniation, and less commonly is due to rupture into
up to 70% of cases (Tunkel et al., 2000). Bacteroides the ventricular system. Over the years there has been
species and gram-negative bacilli are other frequent progress in reducing the mortality rate from 40% to
causes. In neonates, abscesses are often due to Cit- 50% to a level of less than 5% in a relatively recent
robacter species. Abscesses often show a mixed flora, series (Mampalan and Rosenblum, 1988). The greater
especially those in the temporal lobes arising as com- survival is attributed mainly to early diagnosis with
plications of otitis/mastoiditis. Staphylococcus is the neuroimaging techniques (Wispelwey et al., 1997; Zim-
most common pathogen in post-traumatic abscesses ex- merman, 1997).
cept where a sinus has been exposed to cerebrospinal Subdural abscesses or empyemas are usually exten-
fluid. In recent years abscesses due to Nocardia, fungi, sions from adjacent infections such as sinusitis (Kauf-
and parasites have been encountered more frequently, man et al., 1983), otitis, and osteomyelitis (Fig. 4.4A)
especially in patients with AIDS (Wispelwey et al., (Kaufman et al., 1983; Helfgott et al., 1997). Less com-
1997). Predisposing conditions to some extent predict monly they may result from infection of a preexisting
causative organisms as follows: decreased cell-mediated subdural hematoma. The infections tend to spread over
immunity is associated with Toxoplasma, Nocardia, the convexities but are usually unilateral because of the
Cryptococcus, Listeria, and mycobacterial species; neu- barrier of the falx (Fig. 4.4). Common causative or-
tropenia/neutrophilic functional defects are associated ganisms include Bacteroides species and mixtures of mi-
with aerobic gram-negative organisms, Aspergillus croaerophilic and anaerobic streptococci. Subdural ab-
species, Zygomycetes (mucor), and Candida species. scesses following surgical trauma or head trauma are
Post-transplant cases are most often mycotic (Hagensee often due to Staphylococci and gram-negative bacilli
et al., 1994) (see below). Multiple brain abscesses are (Helfgott et al., 1997).
identified in 10%–50% of cases since high-quality imag- Epidural abscesses are most commonly located in
ing studies have been available (Tunkel et al., 2000). lumbosacral or thoracic spine (Curling, 1990; Gellin,
The evolution of brain abscess as monitored by CT scan- 1997). They are frequently due to an extension from
ning has been well demonstrated (Brett, 1983; Zim- osteomyelitis, and many have arisen from hemato-
merman, 1997) (Fig. 4.3A). genous spread to that site. Causative organisms are
Brain abscesses typically arise in the white matter or predominantly staphylococci, streptococci, and gram-
at the gray–white junction. They are most common in negative bacilli, but in a significant proportion (espe-
the distribution of the middle cerebral artery zones in- cially in developing countries) they are due to tubercu-
volving frontal, temporal, and parietal lobes. Brainstem losis. One series reported 25% of cases being secondary
and ganglionic involvement is rare. Multiple abscesses to adjacent tuberculous infection (Kaufman, 1980). The
are found in apparently random distribution (Dyste et AIDS epidemic has contributed to this number as well
al., 1988; Pendlebury et al., 1989). Abscesses begin (Haas, 2000).
with focal cerebritis stage and hyperemic edges (Fig.
4.3B) which account for the imaging characteristics
of breakdown of blood–brain barrier (Zimmerman,
MYCOBACTERIAL INFECTIONS
1997). The neovascularization and appearance of fi-
broblasts herald the early organization/encapsulation
Tuberculosis
stage, with capsule being thinner on the deep aspect—
unfortunately promoting possible rupture into the ven- The prevalence of tuberculosis in the United States has
tricular system. The encapsulation, even at a late stage, generally been reduced by control methods since 1940.
is usually less than a few millimeters in thickness, de- The advent of AIDS and related immunocompromised
veloping at approximately 1 mm in a month’s time conditions has caused a significant increase in the past
(Wispelwey et al., 1997). Histologically three zones are few years, however (Haas, 2000). As a worldwide pub-
characterized in the mature abscess: the central suppu- lic health threat, tuberculous meningitis remains a com-
A rial infection are due to atypical mycobacteria (espe-

cially Mycobacterium avium-intracellulare), which may
cause parenchymal brain lesions especially in AIDS pa-
tients (Zuger and Lowy, 1997).
Tuberculous meningitis generally follows hemato-
genous dissemination from pulmonary lesions. The
meningitis usually spreads from a collection of small
granulomas on the surface of the cortex or in the lep-
tomeninges (Kirkpatrick, 1997; Zuger and Lowy, 1997;
Arvanitakis et al., 1998).
Cerebrospinal fluid typically shows a lymphocytic
pleocytosis (including some plasma cells when seen in
later stages) with moderate-to-marked reduction in glu-
cose and a marked elevation of cerebrospinal fluid pro-
tein up to 200 mg/dL. Acid-fast organisms are dem-
onstrated in less than 25% of cerebrospinal fluid
specimens (Greenlee, 1997). Culture is difficult and
slow, and new immunodiagnostic techniques including
PCR promise some help for more rapid and sensitive
diagnosis (Greenlee, 1997). A high level of clinical sus-
picion is most helpful in arriving at an early diagnosis.
The neuroimaging features of tuberculous infection of
the CNS are well recognized and reported (Kioumehr
et al., 1994; Zuger and Lowy, 1997) (Fig. 4.5A).
The gross pathologic changes include abundant thick
B exudate especially in basal cisterns (Fig. 4.5B) and small
miliary granulomas on the convexities of the hemi-
spheres (Fig 4.5B). Brains often show hydrocephalus
due to obstruction of outlet foramina and a striking
granular ependymitis especially on the floor of the
fourth ventricle (Fig. 4.5C). In addition, there may be
cerebral infarcts secondary to obliterative endarteritis
(Fig. 4.6). Vascular complications account for many of
the deaths and permanent sequelae (Dastur and Lalitha,
1972; Bell and McCormick, 1981; Zuger and Lowy,
1997).
Histologic examination of the granulomas and exu-
date shows caseation, infiltrates of lymphocytes and
plasma cells, and a variable number of Langhans giant
cells. The acid-fast bacilli are seen as short, rod-like
FIGURE 4.4 (A) Cerebritis and subdural empyema. Axial CT image bodies within the areas of caseation and occasionally
of brain after contrast enhancement shows mass effect on the right in the cytoplasm of giant cells. Antituberculous ther-
with shift of the midline structures and decreased density in the right
frontal lobe. In addition, there is a small extracerebral subdural fluid
apy may significantly alter their appearance, however
collection in the right frontal region. Findings are consistent with (Zuger and Lowy, 1997).
cerebritis and subdural empyema. (B) Subdural empyema (gross Tuberculomas are unusual manifestations of neuro-
brain). Note coating of brain surface due to purulent exudate, which tuberculosis in the United States but account for a large
is often associated with subarachnoid exudate. proportion of intracranial space-occupying lesions in
parts of the world where tuberculosis is more common
mon disease and often afflicts children in Asia, Africa, (Dastur and Lalitha, 1972; Gray, 1997; Zuger and
India (Dastur and Lalitha, 1972; Murthy and Yangala, Lowy, 1997). Their age-related distribution within the
1998), and South America. Virulence may vary with central nervous system is curiously similar to that of
certain strains of Mycobacterium tuberculosis (Arvan- primary CNS neoplasms; that is, among children, two-
itakis et al., 1998). Many of the cases of mycobacte- thirds are infratentorial. The lesions are solid, or rarely
A B
FIGURE 4.5 (A) Tuberculosis (MRI). T1-weighted coronal MR image

after contrast enhancement demonstrates thick and diffuse enhance-
ment of the dura. The diagnosis of tuberculous meningitis was con-
firmed by biopsy and laboratory studies. (B) Basilar tuberculous
meningitis (gross brain). A thick basilar exudate obscures the verte-
brobasilar arterial system and fills basal cisterns. Brain swelling and
vascular compromise are common associated findings. (C) Tuber-
culosis. T1-weighted sagittal MR image after contrast enhancement
shows generalized hydrocephalus and abnormal diffuse leptomeningeal
enhancement in the posterior fossa and around the brain stem.
53
volvement usually starts in the ulnar nerve at the el-

bow (Gelber and Swift, 1995).
The lepromatous form is associated with low host
resistance and is characterized by myriads of organisms
in plump histiocytes (lepra cells). The lepra cells are
filled with masses of acid-fast bacilli (globi). These cells
are found in the skin of the cooler portions of the body
(including the hands, feet, and head), peripheral nerves,
the anterior segment of the eyes, the upper airway, and
the testes. Infected peripheral nerves may be enlarged
and contain increased numbers of histiocytes and
Schwann cells harboring bacilli (Sabin and Swift,
1993). The fascicular structure of the nerve is main-
tained in this form of disease, and the lepromin skin
test is generally negative (Gelber and Rea, 2000).
The tuberculoid form is at the other end of the spec-
trum with maximal host resistance and is characterized
by localized areas of hypesthetic skin. Peripheral nerves
adjacent to the cutaneous lesions are enlarged and ex-
tensively disrupted by a granulomatous inflammatory
reaction. Caseation may lead to formation of abscesses
within these affected nerves, and acid-fast bacilli are
rarely demonstrable even when a sensitive modification
of the acid-fast stain (Fite-Farracca) is used (Bell and
McCormick, 1981; Sabin and Swift, 1993). In this form
of the disease the lepromin skin test is usually positive
consistent with strong host resistance. The pathology
FIGURE 4.6 Tuberculous vascular complications (photomicrograph). mostly depends on the host rather than the organism.
Microscopic section of leptomeningeal vessel showing marked fi- The dimorphous (borderline) form shows clinical and
brointimal thickening and stenosis in a 5-year-old child with basilar pathologic features of both the lepromatous and the tu-
tuberculous meningitis. Vascular complications constituted the most berculoid forms. The indeterminate form is difficult to di-
severe CNS damage in this instance.
agnose, because it is an early stage of the disease in which
skin changes are minimal and peripheral nerves are not
enlarged (Sabin and Swift, 1993; Gelber and Rea, 2000).
cystic, caseating granulomas containing acid-fast or-
ganisms. Some of the tuberculomas reported recently
in the United States have been related to AIDS and har- Other Granulomatous Diseases
bor atypical mycobacteria (Zuger and Lowy, 1997).
Sarcoidosis
Atypical mycobacteria often are associated with pa-
renchymal CNS lesions without meningitis. Sarcoidosis is a systemic granulomatous disease of un-
known etiology. It is often considered to be a patho-
logic response to diverse antigenic stimuli. The disease
Leprosy
commonly involves lymph nodes (especially hilar
Leprosy is a chronic infection of low communicability nodes), lungs, skin, eyes, salivary glands, and liver.
caused by Mycobacterium leprae. The disease occurs Neurologic manifestations, encountered in about 5%
primarily in tropical climates with endemic foci of cases (Stern et al., 1985; Scheld, 1997; Gripshover
throughout the world. In the United States most cases and Ellner, 2000) include cranial neuropathies (most
are found in Louisiana and Texas, where lepra bacilli often facial nerve palsy), aseptic meningitis, hypothal-
may be zoonotic in armadillos (Gelber and Rea, 2000), amic–pituitary dysfunction, and hydrocephalus (Manz,
and some have been seen in New York and California. 1983) (Fig. 4.7A). Widely dispersed, noncaseating gran-
The clinical manifestations vary widely and staging is ulomas often containing asteroid bodies (Fig. 4.7B) are
according to the host’s immune status (Sabin and Swift, found in the leptomeninges, most commonly at the base
1993; Gelber and Rea, 2000). Peripheral nerve in- of the brain. (Fig. 4.7B). These may extend into the ad-
A jacent neural parenchyma, particularly the hypothala-

mus. Rarely, larger confluent granulomas can mimic
intracranial neoplasms (Manz, 1983; Clark et al.,
1985). Neuroimaging studies may correlate well with
the neuropathology (Zimmerman, 1997) (Fig. 4.6B).
Sarcoid can also cause myelopathy, peripheral neu-
ropathies, and granulomatous myositis/myopathy, all
related to the noncaseating granulomatous process
without demonstrable organisms (Manz, 1983; Stern et
al., 1985; Gripshover and Ellner, 1997).
Whipple’s disease
Whipple’s disease is a chronic multisystem disease with
marked (6X) male predominance caused by Tro-
pheryma whippelii, an unusual, uncultured bacillary or-
ganism bearing some molecular similarity to Actino-
mycetes (Relman, 1992, 1997; Marth, 2000). The
clinical manifestations generally include weight loss,
abdominal pain, diarrhea, lymphadenopathy, and
B arthralgia. About 10% of the patients have neurologic
manifestations, and rarely, but recently more com-
monly, patients show central nervous system involve-
ment with little or no evidence of systemic or intesti-
nal disease. This may be due to “incidental” elimination
of the systemic disease by antibiotics that do not pen-
etrate the blood–brain barrier (Johnson and Diamone,
1980; Adams et al., 1987; Relman, 1997). Histopatho-
logic studies disclose foamy macrophages in the in-
testinal mucosa, lymph nodes, and occasionally other
tissues, including the heart. The macrophages are
faintly basophilic or amphophilic and stain intensely
with the periodic acid–Schiff reaction. Electron mi-
croscopy discloses degenerating bacillary organisms
and residual membranes in their cytoplasm (Fig. 4.8)
(Schochet and Lampert, 1969). In the nervous system
the characteristic macrophages are found as nodular
aggregates in gray matter and subependymal regions
(granular ependymitis), around blood vessels, and in
the leptomeninges (Schochet and Lampert, 1969;
Wilbert et al., 1976; Powers and Rawe, 1979; John-
son, 1980).
Spirochetal Infections
Neurosyphilis
FIGURE 4.7 (A) Neurosarcoidosis (MRI). T1-weighted sagittal MR The etiologic agent of syphilis, Treponema pallidum, is
image after contrast enhancement shows patchy enhancement in the usually transmitted sexually. The primary genital le-
inferior frontal lobe along with adjacent leptomeningeal enhance- sions appear about 3 weeks after mucous membrane
ment. (B) Neurosarcoidosis (photomicrograph). Noncaseating gran-
ulomatous inflammatory changes in the leptomeninges include an as-
inoculation. Secondary lesions develop several weeks
teroid body within a multinucleate giant cell characteristic of later, and in about 25%–30% of patients the organism
neurosarcoidosis. invades the central nervous system (Hook, 1997). Years
frontal and temporal lobes (Fig. 4.9). Striatal atrophy

is associated with hydrocephalus ex vacuo. The thick-
ened, fibrotic leptomeninges may adhere to the brain
surface. The brain parenchyma shows characteristic
histologic features including neuron loss, gliosis, and
proliferation of rod-shaped microglia that often con-
tain stainable iron. Spirochetes can be demonstrated
with appropriate silver stains. The intraparenchymal
and meningeal vessels are surrounded by perivascular
mononuclear cell infiltrates. The ventricles become di-
lated, and the ependymal surfaces are roughened be-
cause of the formation of ependymal granulations
(Goodman and Karakusis, 1988). Obliterative endar-
teritis leads to additional infarcts. Gummas are local-
ized nonsuppurative or necrotic inflammatory lesions
caused by the spirochetes (Kaplan et al., 1981). They
are rarely seen in the nervous system, but cases have
recently been reported with AIDS (Horowitz et al.,
1994).
Tabes dorsalis is a myelopathy thought to result from
meningeal fibrosis and involvement of the dorsal roots,
followed by degeneration of the posterior columns. The
dorsal aspect of the spinal cord becomes flattened, es-
pecially in the thoracic and lumbosacral levels (Fig.
4.10). Myelin stains usually show a distinctive
W-shaped area of demyelination, especially during the
earlier stages of the disease. Spirochetes cannot be dem-
FIGURE 4.8 Whipple’s disease (electron microscopy). Ultrastructural
onstrated in the tabetic spinal cords, but molecular
study of the characteristic histiocytes demonstrates altered bacillary methods show promise (Goodman and Karakusis,
organisms consistent with Tropheryma whippelii (Whipple’s disease 1988; Horowitz et al., 1994). Congenital syphilis may
organism). be produced by transplacental transmission of the
spirochetes within 2–5 years after initial maternal in-
fection. The older literature stated that the spirochetes
later, some of the patients display neurologic manifes-
tations of tertiary syphilis, including meningovascular
syphilis, general paresis, and tabes dorsalis as well as
combinations and complications of these (Goodman
and Karakusis, 1988; Davis, 1992).
Meningovascular syphilis is subacute or chronic
meningitis. Abundant spirochetes may be present in the
meninges. The inflammatory cells include lymphocytes,
plasma cells, and macrophages. These tend to aggre-
gate around blood vessels. The vessels show lympho-
plasmacytic infiltration, fibrous intimal proliferation,
and thinning of the media with preservation of the elas-
tica. This vaso-occlusive process, called Heubner’s ar-
teritis, leads to multiple small brainstem and cortical
infarcts (Kirkpatrick, 1997). The meninges undergo
progressive fibrosis.
Subsequent invasion of the brain parenchyma by the
FIGURE 4.9 Neurosyphilis (general paresis). Gross autopsy brain dem-
spirochetes can produce a chronic meningoencephalitis onstrates severe generalized cortical atrophy with widened sulci and
designated general paresis (GPI). The brain becomes narrow gyri, confirmed histologically and serologically to be neu-
markedly atrophic with maximal involvement of the rosyphilis (general paresis).
sought. Borrelia organisms have been recovered after

years (Steere et al., 1985), but no definite or consistent
etiologic connection to these neurologic diseases has
been established (Johnson, 1989; Finkel and Halperin,
1992). Ophthalmic involvement is well recognized with
many neuro-ophthalmic manifestations (Steere et al.,
1985; Balcer et al., 1997).
Lyme neuroborreliosis is difficult to diagnose with
certainty (Steere, 2000). The spirochetes are difficult to
demonstrate in tissue sections and fragile to grow in
culture. Biopsy specimens often fail to reveal the or-
ganisms, and the current serologic tests reflect expo-
sure to the agent but do not necessarily indicate active
FIGURE 4.10 Tabes dorsalis. A myelin-stained whole-mount section disease. New and promising diagnostic tests include
of lower cervical spinal cord shows flattened demyelinated dorsal Western blot and polymerase chain reaction (PCR)
columns characteristic of tabes dorsalis. techniques (Mouritsen, 1996; Nocton, 1996). Animal
models have helped in the understanding of pathogen-
esis and in developing a promising vaccine (Steere,
do not invade the fetus until the fifth month of gesta- 2000) based on outer surface protein A (OspA) (Sigal
tion, but more recent evidence suggests that passage et al., 1998).
through the placenta may occur much earlier (Davis, Relatively few histopathologic studies of human neu-
1992). The disease may remain dormant until late roborreliosis are available. Peripheral nerve biopsy
childhood or even adulthood. Some of the patients dis- specimens have shown axonal degeneration along with
play the so-called Hutchinson triad: notched teeth, epineurial and perineurial mononuclear inflammatory
eighth-nerve deafness, and interstitial keratitis. The cell infiltrates. Limited neuropathologic studies of pa-
neurologic manifestations of the congenital disease tients with borreliosis and encephalomyelitis have re-
are predominantly those of meningovascular syphilis vealed microglial nodules and perivascular lymphocytic
(Davis, 1992). infiltrates (Kuntzer et al., 1991; Duray, 1993). Occa-
sional vascular occlusions have been documented
(Steere, 2000).
Lyme borreliosis
Lyme borreliosis is a multisystem disease caused by the
Cat-scratch disease
tick-borne spirochete Borrelia burgdorferi. After infec-
tion by the tick, 60%–80% of patients with Lyme dis- CNS manifestations of this form of infection by Bar-
ease develop a characteristic skin lesion, erythema mi- tonella sp. (B. henselae, possibly Afipia felis, Bartonella
grans. Neurologic disorders subsequently develop in clarridgeiae) are recognized in approximately 2% of
10%–15% of untreated persons (Halperin et al., 1989; cases usually 2–5 weeks following the onset of
Halperin, 1990). These disorders include aseptic menin- adenopathy (Slater and Welch, 2000). They consist of
gitis, cranial neuritis, radiculoneuritis, peripheral several nonspecific symptom complexes, mostly en-
neuropathies, and encephalomyelitis (Camponovo and cephalopathy with myelitis, radiculitis, or neuroretini-
Meier, 1986; Davis et al., 1988). The cranial neuritis tis (Slater and Welch, 1997). Neuropathology material
most commonly involves the seventh nerve. In endemic is scant, but granulomas with necrosis in lymph nodes
areas up to 25% of cases of Bell’s palsy have been at- are the hallmark, with organisms stained by Warthin-
tributed to Lyme borreliosis (Halperin and Golightly, Starry silver stain (Lyon, 1971). There is a low yield of
1992). The radiculoneuritis may cause radicular pain positive staining and culture confirmation, however.
in the dermatome harboring the infecting tick bite. The
peripheral neuropathies are predominantly axonal de-
Actinomycete infections
generations. Both acute severe and chronic indolent
forms of encephalomyelitis have been described. Lyme The Actinomycetes are branched filamentous bacteria
neuroborreliosis may be the “great imitator” (Zaj- that are often discussed with the fungi because of their
kowska et al., 1998). Associations with chronic neu- appearance and staining characteristics (Robboy
rologic diseases such as multiple sclerosis, amyotrophic and Vickery, 1970). They include Nocardia and
lateral sclerosis, and Alzheimer’s disease have been Actinomyces.
Nocardiosis has been an uncommon disease, but the the brain (Brown, 1973). Brain abscess is the most
organism is recently encountered more frequently as an prevalent form of CNS disease (67%) (Wispelwey et
opportunistic pathogen. About 85% of cases in the al., 1997). Unlike Nocardia, Actinomyces is not acid
United States are due to N. asteroides (Sorrell et al., fast (Russo, 1995). A characteristic feature of actino-
2000). The lungs are most frequently involved, but dis- mycosis is the presence of “sulfur granules” in the sup-
semination to the central nervous system occurs in purative exudate. These are colonies of the filamentous
about 30% of cases, especially in severely immuno- bacteria that are surrounded by radiating eosinophilic
suppressed patients (Frazier et al., 1975; Adair et al., clublike structures (Hotchi and Schwartz, 1972). This
1987; Lerner, 1995; Wispelwey, 1997). In the brain, is known as the Splendore-Hoeppli phenomenon.
Nocardia usually produces multiple or multiloculated These organisms are well demonstrated by Gomori
abscesses (LeBlang et al., 1995), often with defective methenamine silver (GMS) or Brown-Bren stain (Russo,
encapsulation (Adair et al., 1987). The organisms ap- 1995).
pear as masses of branched filaments. They are diffi-
cult to see when stained with hematoxylin and eosin
but are gram positive and weakly acid fast. They are MYCOTIC INFECTIONS
best demonstrated with “overstained” methenamine
silver preparations (Fig. 4.11) (Robboy and Vickery, Mycotic infections of the central nervous system, once
1970). thought to be rare, are now much more common as the
Actinomycosis is most commonly caused by A. is- number of immunocompromised individuals has dra-
raelii or A. bovis. The infection usually involves the matically increased. This has been a result of wide-
head, neck, thorax, abdomen, or pelvis, and only rarely spread use of immunomodulating therapy, organ trans-
plantation (Hagensee et al., 1994), an aging population
with an increased number of malignancies, and the
spread of AIDS. According to recent taxonomy, one
might include Pneumocystis carinii in this group
(Bartlett and Hulette, 1997; Bennett and Bartlett,
2000). Mycotic infections of the central nervous sys-
tem are usually secondary to hematogenous dissemi-
nation from primary pulmonary infections and less of-
ten from other extracranial sites (Fetter et al., 1967).
Occasionally they result from direct extension from in-
fections of the sinuses or bone. The central nervous sys-
tem mycoses are difficult to diagnose with certainty in
living patients with the possible exception of crypto-
coccosis, for which the CSF cryptococcal antigen test
is extremely helpful. Most systemic fungi can cause
basilar meningitis or intraparenchymal abscesses. Oc-
casionally they are recognized at autopsy as the cause
of an otherwise-unexplained terminal illness (Perfect,
1991; Perfect and Durack, 1997). Candidiasis, crypto-
coccosis, aspergillosis, and mucormycosis have become
the most prevalent fungal infections of the central ner-
vous system with certain clinical settings predicting the
causative organism(s) (Perfect and Durack, 1997; Sep-
kowitz and Armstrong, 1997).
Candidiasis
Isolated CNS Candida infection was once rare, but in
the pre-AIDS era candidiasis became the most common
FIGURE 4.11 Actinomycosis. Methenamine silver stain shows branch-
mycotic infection of the central nervous system (Parker
ing, filamentous organisms characteristic of actinomycosis or nocar- et al., 1976; Lipton et al., 1984). Candida species are
diosis. normally found in the intestinal, genital, and cutaneous
flora. A wide variety of conditions promote invasion Histoplasmosis

and hematogenous dissemination of this organism.
These include long-term antibiotic and corticosteroid Histoplasma capsulatum is commonly found in the soil
therapy, indwelling catheters, hyperalimentation lines, in the Ohio, Mississippi, and St. Lawrence River val-
abdominal surgery, diabetes, burns, malignancies, neu- leys. A high proportion of individuals living in the en-
tropenia, and intravenous drug abuse, neutropenia be- demic areas have pulmonary lesions, but dissemination,
ing particularly important. Central nervous system in- especially to the central nervous system, is uncommon
fection can be caused by several species, but most are in immunocompetent individuals. Progressive dissemi-
due to Candida albicans (Parker et al., 1976, 1981; Lip- nated histoplasmosis (PDH) occurs in only 1 per 2000
ton et al., 1984). Involvement of the nervous system is cases of histoplasmosis in normal adult populations
usually in the form of multiple microabscesses (Fig. (Deepe, 2000). Nearly half of the patients with dis-
4.12) that may be accompanied by microgranulomas. seminated disease are immunosuppressed (Wheat et al.,
Meningitis is rare except in premature infants and 1990a; Perfect and Durack, 1997). Many of the pa-
neonates (Perfect and Durack, 1997). Both yeast forms tients with central nervous system involvement have
and pseudohyphae are encountered in the lesions (Fig. AIDS (Wheat et al., 1990b). In the nervous system,
4.12). They may be faintly basophilic when stained histoplasmosis usually causes basilar meningitis but
with hematoxylin and eosin but are intensely stained may produce intraparenchymal granulomas. The or-
by the periodic acid–Schiff reaction. They are also eas- ganisms are small ovoid yeasts, 2–4 m in diameter,
ily demonstrated with the methenamine silver reaction that are found within macrophages. In sections stained
(Fig. 4.12) (Edwards, 1995). with hematoxylin and eosin, shrinkage of the organ-
isms produces a halo and imparts the spurious ap-
pearance of a capsule (Fig. 4.13). They are readily seen
in Romanowsky-stained smears when disseminated
(e.g., in peripheral blood leukocytes) but are best dem-
onstrated and appear somewhat larger with methena-
mine silver stains (Fig. 4.13B) (Wheat et al., 1990a;
Deepe, 2000).
Blastomycosis
Blastomycosis is an uncommon mycotic infection. The
causative agent, Blastomyces dermatitidis, is a dimor-
phic fungus found in the soil and possibly in decaying
wood in the eastern United States. The lung is the most
commonly involved organ (Murphy, 1989; Chapman,
1995). Dissemination is infrequent but can lead to in-
volvement of skin, bones, and visceral organs, includ-
ing the prostate gland. The central nervous system is
involved in less than 5% of cases (Murphy, 1989). In-
volvement is usually in the form of abscesses (Roos et
al., 1987), but meningitis simulating bacterial menin-
gitis also occurs (Perfect and Durack, 1997). The or-
ganism in tissue appears as singly budding yeast with
a broad neck and thick retractile cell walls (Fetter et
al., 1967). B. dermatitidis characteristically elicits a
mixed granulomatous and suppurative reaction. Cere-
bral blastomycosis has rarely been encountered in pa-
tients with AIDS (Harding, 1991).
FIGURE 4.12 Candida sp. in CNS. Microgranulomas with giant cells Cryptococcosis
containing pseudohyphae and conidia characteristic of Candida sp.
in brain (GMS stain for fungus) (courtesy of Drs. McCormick and Cryptococcosis is currently the most common cause of
Schochet). fungal meningitis and may be the most common my-
A B
FIGURE 4.13 (A) Histoplasmosis. H&E-stained sections show multiple organisms in histiocytes with pale
zone suggesting capsule. Histoplasma capsulatum was documented. (B) GMS stain of Histoplasma. Sil-
ver stain of Histoplasma organisms stains the cell wall and does not demonstrate a capsule (courtesy of
Dr. Schochet).
cotic infection of the central nervous system, corticos- large or small granulomas (cryptococcomas or torulo-
teroid therapy and HIV infection being largely respon- mas) in the meninges, parenchyma, ependymal surfaces,
sible for this rise in frequency (Perfect and Durack, or choroid plexuses (Fig. 4.14B). The patients who have
1997). The causative agent, Cryptococcus neoformans cryptococcomas are rarely in an immunocompromised
(formerly Torula histolytica), is found in soil that has state (Sepkowitz and Armstrong, 1997). Several viru-
been contaminated with bird excreta. The primary hu- lence factors and strain differences in cryptococcus are
man infection is in the lung. More than 50% of the known (Jacobson and Tingler, 1994; Kozel, 1995).
patients in whom disseminated disease develops are Neurotropism may be due to catecholamines in the
immunocompromised. Predisposing conditions include CSF.
corticosteroid therapy, organ transplantation, collagen The organisms appear as singly budding yeast forms
vascular diseases, reticuloendothelial neoplasms, and in with a narrow neck or very rarely with short pseudo-
recent years AIDS (Chuck and Sande, 1989). hyphae. They stain faintly with hematoxylin and eosin.
For unknown reasons, almost all patients with dis- The cell walls stain strongly with the periodic
seminated disease have central nervous system in- acid–Schiff, mucicarmine, and methenamine silver
volvement, usually in the form of basilar meningitis. stains (Lazcano et al., 1993). Thick mucopolysaccha-
The meningitis may be subacute or chronic and may ride capsules that stain with Alcian blue and colloidal
lead to hydrocephalus. Cortical gray matter and basal iron surround these yeast forms. Tissue processing for
ganglia are often heavily affected. Definitive diagnosis paraffin-embedded sections often causes the capsular
can be established by CSF culture in about 75% of material to shrink onto the cell wall, leaving an empty-
cases, and cryptococcal antigen tests on CSF are posi- appearing halo around the stained organisms (Fig.
tive in more than 90% of cases. Examination of cere- 4.14B) (Chandler and Watts, 1987; Chimelli and
brospinal fluid with “India ink” is a time-honored Mahler-Araujo, 1997).
method but provides the diagnosis in only about 50%
of cases (Perfect and Durack, 1997). Cytospin, Milli-
Coccidioidomycosis
pore, or other cytologic preparations stained by the pe-
riodic acid–Schiff technique can sometimes be used as Coccidioidomycosis is a geographically restricted my-
the basis for diagnosis. In these preparations using Ro- cosis. The causative organism, Coccidioides immitis, is
manowsky stains, the organisms may be mistaken for found in semiarid soil in the southwestern United
leukocytes. Less commonly, cryptococcosis produces States, especially the San Joaquin Valley and Arizona.
multiple intraparenchymal pseudocysts that grossly Inhalation of spores frequently leads to self-limited pul-
look like small (2–3 mm) soap bubbles, especially in monary infections. The organism is both pathogenic
the superficial and deep gray matter (Fig. 4.14) (Laz- and an opportunistic pathogen. It has been estimated
cano et al., 1993). In rare cases the disease produces that disseminated disease develops in less than 0.2% of
A B
FIGURE 4.14 (A) Cryptococcus (MRI). T2-weighted axial MR image demonstrates increased signal in-
tensity in the basal ganglia producing “gelatinous pseudocysts” or “soap bubble” lesions in the stria-
tum. A diagnosis of cryptococcal disease was confirmed serologically. (B) Cryptococcus neoformans
(photomicrograph). Basilar exudate in this case contains negatively stained capsule around yeast forms
with abundant inflammatory exudate present (H&E stain).
infected patients. The disseminated form occurs more and eosin but are much better demonstrated with PAS
often in the nonwhite population and in pregnant, di- or methenamine silver stain (Fig. 4.15C) (Sobel et al.,
abetic, or immunosuppressed persons. Involvement of 1984; Stevens, 1995). The morphologic differential di-
the central nervous system occurs in about one-third of agnosis is extremely small, and includes Rhinosporid-
the cases of disseminated disease (Banuelos et al., 1996; ium seberi, which is larger and mucicarmine-positive
Chimelli and Mahler-Araujo, 1997; Perfect and Du- (Chandler and Watts, 1987; Stevens, 1995). Also, sim-
rack, 1997). In the central nervous system the disease ilar morphology is seen in protothecosis, which almost
can produce meningitis (Fig. 4.15), cerebritis, abscess, never involves the CNS. These involve infection with
or granulomas, alone or in various combinations (So- green slime mold.
bel et al., 1984; Mischel and Vinters, 1995; Banuelos
et al., 1996; Chimelli and Mahler-Araujo, 1997). En-
Aspergillosis
darteritis obliterans has been reported in CNS (Mischel
and Vinters, 1995). In tissue the fungi form distinctive Aspergillosis is the second or third most common my-
large sporangia (spherules) with a diameter of 60–70 cotic infection of the nervous system (Walsh et al.,
m. These become filled with small endospores (Fig. 1985; Sepkowitz and Armstrong, 1997). Several
4.15C). As long as the sporangia are intact, the tissue species can cause central nervous system infection,
reaction is predominantly granulomatous. When the but most cases are due to Aspergillus fumigatus or
enlarging sporangia rupture, the released endospores Aspergillus flavus. These mold organisms are found
elicit an acute inflammatory reaction. The organisms in soil, water, and decaying vegetation. Primary in-
are generally basophilic when stained with hematoxylin fections usually involve the lungs. Only while grow-
A B
FIGURE 4.15 (A) Coccidioidomycosis meningitis (MRI). T1-weighted

axial MR image of brain obtained after contrast enhancement shows
prominent diffuse leptomeningeal enhancement. (B) Coccidioidomy-
cosis meningitis (MRI). T1-weighted coronal MR image of brain ob-
tained after contrast shows prominent diffuse leptomeningeal en-
hancement. Diagnosis of coccidioidomycosis meningitis confirmed
histologically. (C) Coccidioidomycosis (photomicrograph). Giant cell
contains a spherule of Coccidioides immitis in a patient who died in
spite of systemic treatment for coccidioidomycosis meningitis (cour-
tesy of Scott & White Clinic Department of Pathology, Dr. Beissner).
ing in contact with air do the organisms produce sive therapy, neoplasms (especially lymphomas and
the distinctive sporangia resembling an aspergillum leukemias), neutropenia, hepatic failure, cardiovas-
(a container of holy water), from which the name is cular surgery, and intravenous drug abuse. Recent lit-
derived (Denning, 2000). Central nervous system in- erature has emphasized its frequency in organ trans-
volvement is usually the result of hematogenous plant patients (Torre-Cisneros et al., 1993; Bennet,
dissemination (Sepkowitz and Armstrong, 1997) al- 2000; Martinez, 1998). The diagnosis of central ner-
though some cases are due to direct extension from vous system involvement is infrequently established
the sinuses and ears or the result of head trauma. during life, but high clinical suspicion strongly favors
Conditions that predispose to hematogenous dissem- its early diagnosis and therapy (Walsh et al., 1985;
ination include corticosteroid and immunosuppres- Sepkowitz and Armstrong, 1997; Martinez, 1998).
Hematogenous dissemination generally leads to mul- Mucormycosis (Phycomycosis)

tiple lesions, whereas direct extension may produce
only one or a few lesions. The fungus is highly an- Although still uncommon, mucormycosis of the central
gioinvasive, and the early lesions are often recognized nervous system has been encountered more frequently
radiographically as foci of hemorrhagic cerebritis that in recent years (Chimelli and Mahler-Araujo, 1997).
resemble hemorrhagic infarcts (Fig. 4.16) (McCormick Alternative terms are phycomycosis and zygomycosis.
et al., 1975). Much less frequently the fungus produces The causative agents are several genera that belong to
intraparenchymal granulomas or even meningitis. In the family Mucoraceae, including Rhizopus, Mucor,
tissue the organisms form dichotomously branching and Absidia. These ubiquitous mold organisms are
septate hyphae of uniform (4–8 m) diameter (Chan- found in the soil and decaying vegetation. Several pat-
dler and Watts, 1987). They are only faintly visible with terns of disease with somewhat different predisposing
hematoxylin and eosin stain and are often weakly conditions have been delineated (Rangel-Guerra et al.,
stained with the periodic acid–Schiff technique. They 1985; Chimelli and Mahler-Araujo, 1997). The most
are most readily demonstrated with methenamine sil- common form is rhinocerebral (Fig. 4.17A), which is
ver stains. Because of the morphologic similarity to cer- encountered mainly in patients with poorly controlled
tain other hyphal organisms, a biopsy may be inter- diabetes and especially acidosis and dehydration. The
preted in a descriptive fashion suggesting aspergillosis patients usually have periorbital swelling, proptosis,
(Bennett, 2000). and a nasal discharge. Rhinocerebral disease results
from direct extension of the mycotic infection from the
nose or paranasal sinuses through veins to the orbit
and brain (Duplechain and White, 1989; Chimelli and
Mahler-Araujo, 1997).
Central nervous system involvement may also result
from hematogenous dissemination from extracranial
sites such as the lungs. Conditions that predispose to
hematogenous dissemination also include acidosis from
diarrhea and dehydration in children, organ transplan-
tation, immunosuppressive therapy for hematologic
malignancies, and intravenous drug abuse (Chimelli
and Mahler-Araujo, 1997). A few cases have been re-
ported in association with AIDS, but some of these pa-
tients were also IV drug abusers (Cuadrado et al.,
1988).
When the central nervous system involvement results
from hematogenous dissemination, the lesions often
produce isolated foci of hemorrhagic necrosis of deep
ganglionic structures (Cuadrado et al., 1988; Stave et
al., 1989; Siddiqi and Freedman, 1994). Mucormyco-
sis is very angioinvasive and often produces extensive
infarction of the neural parenchyma also in individu-
als with diabetes, diarrhea, and dehydration (Ostrow
and Hudgins, 1994; Sepkowitz and Armstrong, 1997).
Occasionally, multinucleate giant cells are present, but
granulomas are not typically encountered. The organ-
isms have fairly distinctive morphology and appear as
irregular broad (10–20 m diameter) hyphae (Fig.
4.17B) (Chandler and Watts, 1987). The hyphae are
nonseptate and branch at right angles. Folding of these
hyphae may simulate septate forms. They are relatively
well shown with hematoxylin and eosin but can be
FIGURE4.16 Aspergillus cerebritis (gross). Early acute cerebritis with
hemorrhagic changes is grossly obvious in right cerebellum and left demonstrated better with methenamine silver stains
midbrain tegmentum in this patient with severe chemotherapy- (Fig. 4.3). Small-vessel vasculitis is a common associ-
induced neutropenia. ated finding as well.
A B
FIGURE 4.17 (A) Mucormycosis (MRI). T2-weighted axial MR im-

age of brain shows prominent abnormal increased signal intensity
consistent with inflammatory changes in the left orbit, sinuses, and
inferior frontal lobe. There is also absence of the normal flow void
in the left internal carotid artery and middle cerebral artery. Find-
ings are consistent with invasive fungal infection and associated vas-
cular occlusion. (B) Mucormycosis. Photomicrograph showing non-
septate, broad fungus hyphae consistent with phycomycosis
(mucormycosis) seen without special stain. H&E, 125.
Other Cerebral Mycoses halation of spores. Rare cases of chronic meningitis and
cerebritis have been reported (Scott et al., 1987). Mul-
Many other mycotic infections exist but are geograph-
tifocal disease following hematogenous dissemination
ically restricted or rarely produce central nervous sys-
may involve ocular tissue and CNS especially in the im-
tem involvement. Morphologically, some of these fungi
munocompromised host (Rex and Okhuysen, 2000). In
resemble more common agents discussed above. This
tissue the fungus appears as small, budding, round-to-
emphasizes the need for cultures to establish a defini-
oval yeasts with short hyphae (cigar-shaped). These
tive diagnosis in mycotic infections, often for epidemi-
may be difficult to find.
ologic reasons. A few are mentioned briefly.
Pseudallescheria boydii is found in soil and water
Paracoccidioidomycosis, or South American blas-
and is a common cause of mycetomas. Rarely, it causes
tomycosis, is caused by Paracoccidioides brasiliensis.
meningitis or multiple brain abscesses (Kershaw et al.,
This fungus is endemic in parts of Central and South
1990; Bennett and Bartlett, 1995). In cerebrospinal
America, especially Brazil (Chimelli, 1997). The pri-
fluid and tissue the organism appears as septate hyphae
mary infection is in the lung. Rare cases of dissemi-
similar to Aspergillus.
nated disease with multiple intracerebral granulomas
have been attributed to this agent (Minguetti and
Madalozzo, 1983). The organisms appear as thick-
PARASITIC DISEASES
walled yeasts with multiple buds (unlike the single
buds of B. dermatitidis, aka North American blasto-
Nematodal Diseases
mycosis).
Sporotrichosis is caused by Sporothrix schenckii, A wide variety of nematodes or roundworms occa-
which is found in the soil and on plants. This fungus sionally involve the central nervous system, producing
generally produces skin infections by direct percuta- significant neurologic disease. Some examples are dis-
neous inoculation or occasionally lung infections by in- cussed.
Visceral larva migrans accompanied by fever, myalgia, and periorbital edema.

This phase in histologically correlated with acute in-
Visceral larva migrans results from accidental human
flammation in the affected muscle sites. Initially the lar-
infection with various nematodes that are usually found
vae are small and found within the parasitized my-
in nonhuman hosts. The disease is relatively common
ofibers (nurse cells). Later they enlarge, encyst, and can
in the southern United States where it is generally due
remain dormant for years (Gould, 1971; Taratuto and
to the dog ascarid, Toxocara canis (Nelson et al., 1990;
Venturiello, 1997a; Cameron and Durack, 1997). Oc-
Cameron and Durack, 1997). Less commonly, visceral
casionally the larvae migrate to the heart, where they
larva migrans is due to the cat ascarid, Toxocara cati,
may produce a lethal myocarditis. In some cases they
or rarely the raccoon ascarid, Bayliascaris procyonis.
invade the central nervous system (10%–24% in one
Children acquire the infection by ingesting ova in con-
report) (Taratuto and Venturiello, 1997a) where they
taminated soil or from puppies. The larvae are released
may produce meningitis or encephalitis with focal
and migrate through the intestine to involve other or-
deficits (Kramer and Aita, 1972; Taratuto and Ven-
gans, especially the liver and lungs. The resulting man-
turiello, 1997a). The lesions that have been observed
ifestations include malaise, cough, and wheezing ac-
in the central nervous system in fatal cases have in-
companied by a leukocytosis with a relatively high
cluded petechial or focal hemorrhages, perivascular in-
proportion of eosinophils (Fox et al., 1985; Cameron
flammation, and very rarely granulomas around larvae
and Durack, 1997).
(Eltrodt et al., 1987).
Occasionally the larvae migrate into the eye, pro-
ducing ocular larva migrans. This may lead to visual
impairment. Funduscopic examination may disclose en- Eosinophilic meningitis
dophthalmitis and retinal detachment or may show a
Eosinophilic meningitis is most commonly caused by
mass lesion that can be mistaken for retinoblastoma
infection with larvae of the rat lungworm, An-
(Gutierrez, 1990; Hotez, 1993; Grossniklaus, 1997).
giostrongylus cantonensis. This infection is found most
Rarely, the larvae migrate to the central nervous sys-
commonly in Southeast Asia and in the Pacific. The
tem, where they produce small necrotic and granulo-
parasite has a complicated life cycle with various snails
matous lesions (some following their tract of migration)
and slugs as intermediate hosts. Humans generally ac-
containing macrophages, mononuclear inflammatory
quire the infection from accidental or intentional in-
cells, polymorphonuclear leukocytes, and eosinophils.
gestion of intermediate or transport hosts. The larvae
The larvae, especially when dead, are partially engulfed
have an unexplained predilection to migrate to the cen-
by giant cells, some containing so-called asteroid bod-
tral nervous system, also including some cases of vis-
ies (see sarcoid above) (Schochet, 1967; Nelson et al.,
ceral larva migrans (Gutierrez, 1990; Cross, 1997).
1990). The larvae of T. canis and T. cati are nearly in-
The life cycle cannot be completed in the accidental
distinguishable, and the larvae of B. procyonis are
human hosts. The resulting clinical syndromes include
somewhat larger (Fox, 1985).
mild meningitis and a somewhat more serious radicu-
lomyeloencephalitis (Kuberski and Wallace, 1979).
These are characterized by an abundance of eosinophils
Trichinosis
in the cerebrospinal fluid. Pathologic studies are lim-
Trichinosis is caused by infection with Trichinella spi- ited but have revealed subarachnoid hemorrhage, in-
ralis, which can occur in both humans and animals flammatory cell infiltrates (including eosinophils) in the
(Gould, 1971; Taratuto and Venturiello, 1997a). The subarachnoid space and neural parenchyma, and the
prevalence of trichinosis is declining, with most cases presence of identifiable nematodes (Nye et al., 1970;
currently in Eastern Europe and the former Soviet Kliks et al., 1982).
Union. In the United States fewer than 100 cases are Rarely, eosinophilic meningitis and intraparenchy-
reported each year. mal hemorrhages can result from central nervous sys-
The infection is acquired by ingestion of under- tem involvement by another nematode, Gnathostoma
cooked meat, usually pork, that contains the encysted spinigerum (Kawamura et al., 1983).
Trichinella. The adult nematodes are found in the duo-
denum and jejunum. Heavy infections may produce
Strongyloidiasis
gastrointestinal symptoms. Newly formed motile lar-
vae migrate from the intestine to various tissues but can Strongyloidiasis is caused by Strongyloides stercoralis.
mature only in skeletal muscle. Invasion of muscle is Filariform larvae enter through the skin, pass through
the lungs, and mature in the duodenum and jejunum. Cysticercosis

The parasitized individuals excrete rhabditiform and
Cysticercosis is now considered the most common par-
occasionally filariform larvae. In some cases the ex-
asitic disease of the nervous system worldwide (Davis
creted filariform larvae reinfect (autoinfect) the host for
and Kornfield, 1991; Cameron and Durack, 1997). It
many years. This can lead to hyperinfection in chron-
develops when a human serves as intermediate host for
ically ill or immunosuppressed individuals. Central ner-
the pork tapeworm, Taenia solium. Humans are the
vous system involvement may occur in patients with
definitive hosts and usually become parasitized by con-
the hyperinfection syndrome. The major neurologic
suming pork containing encysted larvae. The adult
manifestation is meningitis resulting from bacteria that
worm develops in the small intestine, producing mini-
are carried into the subarachnoid space with the larvae
mal symptoms. Periodically, proglottids containing ova
or enter the circulation through colonic ulcerations.
are shed from the terminal segment of the adult tape-
Rarely, larvae can be found in the neural parenchyma
worm. If these are ingested by a suitable intermediate
(Wachter et al., 1984).
host, usually a pig, the embryos are disseminated
throughout the body and develop into encysted larvae.
Cysticercosis occurs when a human serves as the in-
Platyhelminth Infection
termediate host. This usually results from ingestion of
The cestodes (tapeworms) and the trematodes (flukes) ova in fecally contaminated food or water. Although
are two major groups of the Platyhelminthes, or flat- cysticercosis is relatively uncommon in the United
worms, that may cause significant human parasitic dis- States, it is an important infection in California (Scharf,
ease of the central nervous system. Some of the more 1988) and states bordering Mexico, as well as in other
important examples are discussed. parts of the world (Gutierrez, 1990; Cameron and Du-
A B
FIGURE 4.18 (A) Cysticercosis. Axial CT image demonstrates a cystic mass in the right basilar cisterns.
This is consistent with the racemose form of cysticercosis. (B) Cysticercosis. Gross photograph of mid-
brain showing leptomeningeal involvement by cysticercosis in the racemose form involving the interpe-
duncular fossa and dorsal to the tectum (courtesy of Drs. McCormick and Schochet).
rack, 1997; Pittella, 1997). In addition, individuals who ducek, 1978), meninges (Sotelo and Margin, 1987), or
harbor the adult tapeworms may develop autoinfection ventricular system, where the second form, C. race-
from fecal contamination or possibly reverse peristalsis. mosus, is more common (Fig. 4.18A). The viable in-
The cysticerci are of two types: C. cellulosae, which traparenchymal cysticerci are usually 1–2 cm in diam-
is called cysticercus, is found especially in the subcuta- eter (Fig. 4.19A & B) and contain a single invaginated
neous tissues, skeletal muscles, nervous system, and eye. scolex (Fig. 4.19C). Each scolex has a rostellum with
One to several hundred cysts may be found in the neural four suckers and a double row of 22–32 hooklets (Fig.
parenchyma (especially gray matter) (Fig. 4.18) (Gaj- 4.19C). The larva contain a bladder which may help
C D
FIGURE 4.19 (A) Cysticercosis (MRI). T2-weighted axial MR image shows edema around solitary left
temporal lobe cyst. A second, less distinct lesion in pons. Biopsy was proven as Cysticercus cellulosae
(cysticercosis). (B) Cysticercosis. Gross autopsy brain from 13-year-old with 3-year history of epilepsy
and massive infestation of brain. Note selective involvement of gray matter in the frontal lobes at the
genu of corpus callosum. Note the inflammatory changes surround cysts where larvae have died (cour-
tesy AFIP). (C) Multiceps multiceps. Larva head with four sucking disks and armed hooklets on rostel-
lum. Morphology is similar to the Cysticercus organisms and to that of mature Taenia solium head. (D)
Cysticercosis. Microscopic section of bladder area of larva from stereotactic brain biopsy of degenerat-
ing cortical larva in a case of cysticercosis.
in identification (Fig. 4.19D). The cyst wall is sparsely tral nervous system. The cysts grow progressively and
cellular, surrounded by an eosinophilic cuticle, and of- may become quite large. The wall is thick, multilami-
ten contains fine mineral concretions. While the en- nated, and acellular and covers a thin germinative layer.
cysted larvae are viable, the surrounding neural paren- Small brood capsules and numerous minute protosco-
chyma shows minimal reaction (immune tolerance). lices with distinctive hooklets bud into the interior from
When the cysticerci degenerate and die, there is mas- the germinative layer (Taratuto and Venturiello,
sive antigen exposure eliciting an intense inflammatory 1997b). These constitute the so-called hydatid sand
reaction including vasculitis and development of glio- (Sparks et al., 1976). Rupture of the cyst can lead to
sis and granulation tissue in the surrounding neural pa- anaphylaxis, massive inflammatory reaction, and for-
renchyma. This leads to their distinctive image with mation of additional cysts from further development of
MR scan (Fig. 4.19A) (Davis and Kornfield, 1991; Sil- the protoscolices (Gutierrez, 1990; Taratuto and Ven-
bert et al., 1993; Pittella, 1997b). Eventually some of turiello, 1997b).
the cysts undergo mineralization. Manifestations of
neurocysticercosis include seizures, mass effects, and
Schistosomiasis
obstruction of the cerebrospinal fluid pathways (Sparks
et al., 1976b; Pittella, 1997). Serologic studies of CSF Schistosomes are trematodes that have complex life cy-
may confirm the diagnosis. cles with various snails as intermediate hosts. Several
Racemose cysticerci due to C. racemosus are large species, including Schistosoma japonicum, S. mansoni,
multiloculated cysts that lack an invaginated scolex. and S. haematobium, are important causes of parasitic
They are usually found in the basilar cisterns (Fig. disease in various parts of the world (Cameron and Du-
4.18A&B) and within the ventricular system, especially rack, 1997; Pittella, 1997a). As adults, the schistosomes
the fourth ventricle. The intraventricular lesions com- inhabit blood vessels. S. japonicum and S. mansoni are
monly cause hydrocephalus (Davis and Kornfield, found predominantly in the superior and inferior
1991). Arachnoiditis and vasculitis commonly result mesenteric veins, respectively, whereas S. haematobium
from degeneration and death of racemose cysticerci in is found predominantly in the veins around the urinary
the subarachnoid space (Sotelo and Margin, 1987). Co- bladder (Gutierrez, 1990). Involvement of the central
existence with C. cellulosae is observed in 10% of cases nervous system is an infrequent but important compli-
(Pittella, 1997b). cation (Pittella, 1997a). The spinal cord is more com-
monly involved by S. haematobium and S. mansoni, a
prevalent form of CNS disease in Puerto Rico and in
Coenurosis
New York Puerto Ricans. Cerebral involvement is most
Coenurosis is a rare parasitic disease of humans caused commonly caused by S. japonicum. The neuropatho-
by larvae of various dog tapeworms, especially Multi- logic changes result from the presence of ova in vessels
ceps multiceps (Taenia multiceps). The definitive hosts and tissue, and the subsequent granulomatous inflam-
are dogs, and the usual intermediate hosts are sheep. mation and fibrosis (Gutierrez, 1990; Pittella, 1997a).
Human infection results from accidental ingestion of The pathologic lesions are at least partly mediated
ova with life cycle and pathogenesis similar to cys- through immune mechanisms and may include focal
ticercosis (Cameron and Durack, 1997). The cystic lar- and diffuse vasculitis (Cameron and Durack, 1997).
vae have a propensity to develop in the nervous sys-
tem, subcutaneous tissue, muscle, and eye. The cysts
Paragonimiasis
are similar to those of cysticercosis but contain multi-
ple scolices (Gutierrez, 1990; Cameron and Durack, Paragonimiasis is caused by the oriental lung fluke,
1997; O’Neill and Connor, 1997). Paragonimus westermani, and related species. The dis-
ease is encountered predominantly in Korea, Japan, and
Taiwan. The parasite has a complex life cycle and hu-
Echinococcosis (hydatid disease)
man pulmonary infection is quite common in these ge-
Echinococcosis or hydatid disease is caused by larvae ographic areas. The adult flukes reside in the lung, and
of Echinococcus granulosa and related species, which ova are excreted in the sputum and feces. Various snails
are small tapeworms found primarily in dogs. The usual and crustaceans are intermediate hosts. Occasionally,
intermediate hosts are sheep. Human infection results cerebral involvement is encountered in individuals who
from accidental ingestion of the ova, usually from close have pulmonary parasitism, the brain being the most
contact with dogs. The larval cysts develop primarily frequent ectopic site. The flukes are thought to migrate
in the liver and lungs and only rarely involve the cen- to the brain through various basilar foramina (espe-
cially the jugular foramen) (Cameron and Durack,

1997). In the neural parenchyma the flukes produce ab-
scesses and granulomas. The characteristic operculated
ova can be found in the cerebral lesions (Gutierrez,
1990; Cameron and Durack, 1997).
Protozoal Diseases
Several protozoa are important human pathogens.
A few of the more common causes of disease are
discussed.
Toxoplasmosis
Toxoplasmosis is caused by infection with the coccid-
ian, Toxoplasma gondii. The definitive hosts for this
parasite are domestic cats and other feline species. Hu-
man infections are usually acquired from consumption
of undercooked or raw meat containing parasitic cysts
or from contaminated cat feces (Frenkel, 1974). The
prevalence of antibodies indicative of prior infection
varies widely among populations but ranges from 20%
to 40% in the United States (Duke et al., 1997). Most
primary infections in immunocompetent humans are
asymptomatic. However, lymphadenopathy develops
in some individuals, as does, very rarely, central ner-
vous system disease (Bach and Armstrong, 1983).
Primary infections in pregnant women are potentially FIGURE 4.20 Congenital toxoplasmosis. Gross autopsy brain from in-
more significant, since they can cause congenital toxo- fant with congenital toxoplasmosis. Note massive cortical degenera-
plasmosis by transplacental infection of the fetus. The tion and calcification, especially in periventricular white matter sites.
severity of the congenital disease is highly variable,
ranging from nearly asymptomatic to devastating dis-
ease affecting especially the central nervous system. The degrees of chorioretinitis and may be severely damaged.
risk of congenital infection is greater during the latter Infants who appear less severely affected at birth may
part of the pregnancy (Duke et al., 1997). However, develop significant neurologic deficits later in life, mak-
infections during the earlier months lead to more se- ing etiologic diagnosis more difficult (Duke et al.,
vere involvement of the central nervous system and eyes 1997). Such late and subtle cases have not generally
(Desmonts and Couvreur, 1974; Townsend et al., been studied pathologically.
1975). Although most primary infections are asymptomatic,
Brains from infants with severe congenital toxoplas- the encysted organisms can remain dormant for many
mosis may contain multifocal or confluent areas of ne- years. They can become reactivated and cause signifi-
crosis that are most extensive in the periventricular re- cant neurologic disease in immunocompromised pa-
gions (Fig. 4.20). The brains may show hydrocephalus tients. The precise mechanism for the reactivation
or even hydranencephaly, the latter resulting from re- remains unclear (Duke et al., 1997). Formerly, reacti-
sorption of necrotic tissue, especially white matter. Pro- vation was relatively uncommon and was seen pre-
liferating organisms are especially numerous trapped dominantly in individuals with lymphoreticular malig-
within the ventricular cavities but may be difficult to nancy and in organ transplant recipients (Best and
demonstrate in the necrotic tissue. Some of the tissue Finlayson, 1979). In recent years toxoplasmosis has be-
destruction may be due to vasculitis mediated by anti- come one of the most common causes of cerebritis and
gens that diffuse into the tissues from the ventricular cerebral abscesses in patients with AIDS (Navia, 1986;
cavities and react with passively transferred maternal Duke et al., 1997) (Fig. 4.21A & B). The pathologic
antibodies. Eventually the areas of necrosis may un- features and radiographic changes are of acute necro-
dergo mineralization. The eyes often develop varying tizing encephalitis (Fig. 4.21A & B) (Smirniotopoulos
A B
FIGURE 4.21 (A) Acquired toxoplasmosis (MRI). T1-weighted axial MR image after contrast enhance-
ment demonstrates multiple small enhancing masses in both cerebral hemispheres consistent with dis-
seminated toxoplasmosis. (B) Toxoplasmosis in AIDS. Gross specimen of cerebellum showing multifo-
cal necrotizing lesions of CNS toxoplasmosis in a patient with AIDS (courtesy of Dr. Schochet). (C)
Toxoplasmosis. Photomicrograph of H&E-stained cysts and tachyzoites in a case of cerebral toxoplas-
mosis in the setting of AIDS.
et al., 1997). The interior of the lesions often consists meningoencephalitis (Butt, 1966; Martinez et al., 1977;
of amorphous necrotic tissue with few organisms. The Martinez and Visvesvara, 1997). The organisms are
inflamed periphery contains numerous cysts and free free-living thermophilic amoebae found in soil and wa-
tachyzoites (Fig. 4.21C). The free organisms are slightly ter whose growth is enhanced by hot climate and wa-
elongated and measure approximately 3 by 6 m. They ter warmed by power plants (Martinez and Visvesvara,
can be seen reasonably well when stained with hema- 1997). Most of the patients who acquire the disease
toxylin and eosin. Their identity can be confirmed by have a recent history of swimming or diving (or other
immunoperoxidase staining techniques (Sun et al., water sports) in fresh contaminated water. The motile
1986). The eyes of an infected patient may also show organisms enter the nervous system along olfactory
reactivated chorioretinitis especially in AIDS or other nerves through the cribriform plate. They spread
immunosuppressed individuals (Duke et al., 1997; through the subarachnoid space and into brain paren-
Frenkel, 1997). chyma. Their neurotropism remains unexplained but
dramatically demonstrated in experimental models as
well (Durack, 1997; Martinez and Visvesvara, 1997).
Amebic meningoencephalitis
Brains at postmortem show hemorrhagic meningitis
Naegleria fowleri is a rare cause of primary amoebic with thin exudate that is maximal in the basal sub-
encephalomyelitis (PAM), a severe, lethal hemorrhagic arachnoid space. The olfactory bulbs and tracts and the
basal portions of the frontal and temporal lobes con- a primary severe keratitis/keratoconjunctivitis in indi-
tain areas of hemorrhagic necrosis. The amoebae can viduals who wear certain types of contact lenses (es-
be seen within the subarachnoid space and around ves- pecially those who prepare their own saline solution
sels in the necrotic neural parenchyma. The organisms from salt tablets and tap water) (Margo, 1987) or
(trophozoites without flagellates or cysts) resemble individuals who have corneal trauma (Martinez
macrophages but can be distinguished by their promi- and Visvesvara, 1997). The pathogenesis relates to
nent central round nucleoli (Fig. 4.22A and C) (Mar- entry through corneal epithelial defects. Freshwater
tinez and Visvesvara, 1997). swimming/water sports while wearing contact lenses is
Various species of Acanthamoeba, including Lepto- discouraged due to this particular risk (Martinez and
myxid (Balamuthia sp., especially B. mandrillaris), an- VIsvesvara, 1997).
other genus of free-living amoeba, may cause granulo- Entamoeba histolytica is a common intestinal para-
matous amebic encephalitis (GAE) (Ma et al., 1990; site in many parts of the world. Trophozoites are found
Martinez and Visvesvara, 1997; Karpinski and Visves- in the colon, and cysts are passed in the feces. The in-
vara, 1997). GAE is encountered predominantly in im- fection may be asymptomatic or cause colitis associ-
munosuppressed individuals, including patients with ated with amoebic invasion of the bowel wall and oc-
AIDS (Gardner et al., 1991; Martinez, 1991; Sison et casionally disseminated disease. Liver abscesses and,
al., 1995; Martinez and Visvesvara, 1997). This form very rarely, brain abscesses develop in patients with in-
of amoebic meningoencephalitis shows multifocal vasive amebiasis (Durack, 1997). The brain (secondary
parenchymal lesions involving cerebrum, cerebellum, amebic) abscesses are often multiple and appear as foci
and brain stem resembling abscesses by MRI scans (Fig. of hemorrhagic necrotic neural parenchyma, often lo-
4.22B) (Schumacher et al., 1995; Falcone et al., 1994; cated at the junction between cortex and white matter,
Kidney and Kim, 1998). Acanthamoeba can also cause strongly suggesting hematogenous disseminations (Du-
A B
FIGURE 4.22 (A) Granulomatous amebic encephalitis (GAE). Micro-

scopic section of innumerable organisms in a case of (GAE). Similar
histologic appearance is seen in meningoencephalitis due to Naegle-
ria sp. (PAM). Note similarity to histiocytes. Special stains may be
used to identify histiocytes and to identify organisms specifically. (B)
Granulomatous amebic encephalitis (GAE) due to Balamuthia sp.
T2-weighted MR axial image of patient with multifocal granuloma-
tous amoebic encephalitis most obvious in the left frontal lobe. Di-
agnosis confirmed at autopsy as Balamuthia mandrillaris. (C) Gran-
ulomatous amebic encephalitis (electron microscopy). Trilaminar cyst
wall is distinctive by electron microscopy in this case of granuloma-
tous amoebic encephalitis due to Balamuthia sp. (same case as
Fig. 4.22A).
rack, 1997). They are composed of inflamed, necrotic tis- firmed by immunohistochemical stains) (Turner, 1997).
sue in which the amoebae may be difficult to distinguish The erythrocytes often appear to adhere to the endo-
from macrophages. The histology reflects the stage of the thelial cells. Foci of endothelial cell damage, necrosis,
abscess with somewhat milder degrees of inflammation and/or reaction occur. The vessels are often surrounded
in proportion to necrosis (Bauerjee et al., 1983). by petechial and ring hemorrhages (Oo et al., 1987;
Turner, 1997). Other neuropathologic features include
focal ischemia, brain edema, and heavy pigment depo-
Cerebral malaria
sition. Patients with a longer survival may harbor small
Malaria remains a major cause of morbidity and mor- demyelinated foci containing collections of microglial
tality in many parts of the world. The Anopheles mos- cells and astrocytes, the so-called Dürck nodules/
quito acts as the vector. Cerebral involvement, which granulomas. Pigment phagocytosis is often present
occurs in 1%–10% of cases, accounts for the majority (Turner, 1997).
of fatalities from malaria (Toro and Roman, 1978;
Cegielski and Warrell, 1997; Turner, 1997; Krogstad,
2000). Cerebral malaria is an acute encephalopathy Trypanosomiasis
that occurs predominantly if not exclusively in patients
Trypanosomes are hemoflagellates that are important
infected with Plasmodium falciparum. The clinical
causes of disease in large but geographically restricted
manifestations include fever, a decreased level of con-
areas of the world (Pentreath, 1995). African try-
sciousness, seizures, and motor dysfunctions (Cegielski
panosomiasis is caused by subspecies of Trypanosoma
and Warrell, 1997). The pathogenesis of cerebral
brucei (Cegielski and Durack, 1997; Chimelli, 1997;
malaria emphasizes the marked sequestration of para-
Hanly, 1997). Both forms are transmitted to humans
sitized red blood cells (PRBCs) resulting in cerebral hy-
and animals by the tsetse fly and cause a meningoen-
poxia from blockage of cerebral microvasculature by
cephalitis, the so-called African sleeping sickness. In-
PRBCs (Aikawa et al., 1990; Roman, 1991).
fection with Trypanosoma b. rhodesiense is often some-
At postmortem, the brain is usually swollen. The cor-
what more fulminant and is found in eastern and
tex may have an abnormal pink color as a result of
southeastern Africa. Infections with Trypanosoma b.
congestion of the leptomeningeal and intracortical
gambiense are found predominantly in western and
vessels or a slate gray color because of the presence of
sub-Saharan regions and tend to be more chronic.
abundant intravascular malarial pigment. The white
Pathologic studies have usually demonstrated subacute
matter often contains diffuse petechial and ring hem-
or chronic meningoencephalitis. Rarely, trypanosomi-
orrhages (Turner, 1997). Microscopic examination
asis produces a hemorrhagic leukoencephalitis with
shows small vessels that are congested and contain
vascular endothelial damage (especially in later stages)
pigment-laden and PRBCs (Fig. 4.23) (may be con-
(Cegielski and Durack, 1997). On histologic study the
subarachnoid and perivascular spaces contain abun-
dant mononuclear cells, including B lymphocytes and
numerous plasma cells. The plasma cells may contain
multiple intracytoplasmic droplets of immunoglobulin.
These cells are characteristic but not diagnostic of the
disease and have been described as “morular cells”
(Hanly, 1997). The trypanosomes are rarely demon-
strated in this particular setting.
American trypanosomiasis, or Chagas disease, is
found predominantly in South America (especially
Brazil) and Central America. The infection is caused by
Trypanosoma cruzi and transmitted by reduviid bugs
(Lack and Filie, 1997). The major complications are
cardiomyopathy and megacolon largely secondary to
involvement of the autonomic nervous system (Chimelli
and Scaravilli, 1997). Involvement of the central ner-
FIGURE 4.23 Cerebral malaria. Photomicrograph of H&E-stained sec-
tion of brain showing well-preserved neuron and intravascular para-
vous system is rare in adults and occurs most often in
sitized red blood cells due to falciparum malaria. Sequestration in brain infants as the result of congenital infection. Rare cases
is pathogenetic, and vascular complications are most significant. of meningoencephalitis have occurred in the immuno-
suppressed either as a result of blood transfusions (Lei- origin in a case of Garin-Bujadoux-Bannworth syndrome with
guarda et al., 1990) or via latent infection in patients positive Borrelia antibody response. J Neurol 233:69–72.
Cegielski J.P. and Warrell D.A. (1997). Cerebral malaria. In: Infec-
with AIDS (Rosemberg et al., 1992; Pantreath, 1995; tions of the Central Nervous System (W.M. Scheld, R.J. Whitley,
Chimelli, 1997). In these cases amastigotes (Leishma- and D.T. Durack, eds.). Raven Press, New York, pp. 807–829.
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rons, and glia. Immunohistochemical stains may help tions of the Central Nervous System (W.M. Scheld, R.J. Whitley,
in identifying the organism (Chimelli and Scaravilli, and D.T. Durack, eds.). Raven Press, New York, pp. 807–829.
Chandler F.W. and Watts J.C. (1987). Pathologic Diagnosis of Fun-
1997). gal Infections. American Society of Clinical Pathologists, ASCP
Press, Chicago.
Chapman S.W. (1995). Blastomyces dermatitidis. In: Principles and
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5 Viral infections and prion diseases
of the central nervous system
(excluding retroviral diseases)
ELISABETH J. RUSHING
The past decade has witnessed a rapid growth in our of viral diseases. The present review focuses on the ba-
knowledge of how to diagnose and treat viral diseases. sic patterns of disease and selected advances regarding
In particular, the advent of effective antiviral treatment the most common agents, as well as a brief survey of
options has focused new attention on the prompt and important emerging causes of viral infections of the ner-
accurate diagnosis of nervous system viral infections. vous system. In addition, special consideration will be
The routine availability of antibody testing of the cere- given to a discussion of the so-called “slow virus in-
brospinal fluid (CSF) and more recently, of polymerase fections” or prion diseases.
chain reaction (PCR) analysis has facilitated early de-
tection of many viral infections (DiBiasi and Tyler,
1999). Despite these advances, viral infections of the BASIC CONCEPTS
nervous system remain an important source of global
morbidity and mortality. In general, most acute viral Viruses are highly specialized obligate intracellular par-
infections are benign and self-limited and clinically sig- asites that exploit the host cell for protein synthesis and
nificant central nervous system (CNS) disease is an production of energy. The simpler viruses—essentially
uncommon complication of systemic viral infection. transmissible genomes—consist of a single type of nu-
In other instances, as exemplified by the notorious cleic acid (either a single- or double-stranded DNA or
1918–1919 influenza pandemic, the tragic aftermath RNA genome) surrounded by one or more proteins. Vi-
included worldwide outbreaks of viral encephalitis with ral nucleic acid is almost always wrapped in a protein
debilitating morbidity and over 25 million deaths (Reid package called a capsid composed of integral protein
et al., 2001). Furthermore, in a variety of diseases in- subunits known as capsomeres. The entire structural
cluding multiple sclerosis and schizophrenia, viruses are unit of nucleic acid, nucleoprotein(s), and capsid is
once again under scrutiny as potential pathogens (John- called a nucleocapsid (Melnick, 1982). For some
ston et al., 2001; Stohlman and Hinton, 2001; Pearce, viruses, the capsid directly mediates contact with un-
2001). What role will the pathologist play in the in- infected cells. Other more complex viruses form an
vestigation and diagnosis of CNS viral diseases? In the outer envelope derived from membranes of the infected
future, pathologists will probably rely less on their cell as the preliminary step to entering the host cell. In
knowledge of morphology and will instead be called general, the classification of viruses into orders and
upon to integrate molecular diagnostic tools with tra- families is based on nucleic acid composition, nucleo-
ditional histopathologic methods (Gressens et al., capsid size and symmetry, and envelope status. Al-
1993). The reasons are twofold: the lack of diagnostic though viruses come in a wide variety of sizes and
specificity of morphologic features in most viral infec- shapes and chemical composition, it is not essential for
tions, and secondly, the fact that the presence of a the pathologist to commit to memory all the nuances
viral agent in infected tissue is not always coupled of viral taxonomy. The major categories of neurotropic
with specific pathologic change. Nonetheless, classic viruses are presented in Table 5.1 (Whitley, 1997).
histopathologic study will continue to complement From a clinicopathologic perspective, viral diseases
newer molecular diagnostic methods and provide use- can be classified by the areas of the nervous system that
ful insight into both the recognition and pathogenesis bare the brunt of the infection—for example, meninges
78
5: VIRAL INFECTIONS AND PRION DISEASES OF THE CNS 79
TABLE 5.1 Major Neurotropic Viruses (Whitley, 1997). However, prion diseases, or “slow
virus infections”—actually a misnomer—represent a
Herpesviridae
unique class of CNS degenerative diseases caused by
Herpes simples virus (HSV) I and II
infectious proteins that can be initiated either geneti-
Cytomegalovirus (CMV) cally by somatic mutations or by exposure to infectious
Varicella-zoster (VZV) material (Prusiner, 2001).
Arbovirus (alphavirus)
Hematogenous spread is the most common portal of
entry for viral infections. The relatively common en-
Western equine encephalitis (WEE)
teroviruses and arboviruses gain access to the CNS
Eastern equine encephalitis (EEE)
through viremic spread (Hinson and Tyler, 2001). Af-
Venezuelean equine encephalitis (VEE)
ter invasion of the host and a few rounds of replica-
Arbovirus (flavivirus) tion, transient viremia leads to seeding of distal sites
Japanese encephalitis including the nervous system. As exemplified by the
St. Louis encephalitis (SLE)
herpes simplex virus, viruses can gain entry to the ner-
vous system by a peripheral, retrograde neuronal route
West Nile fever virus
along cranial nerves. Rabies is an example of intra-
Tickborne encephalitis complex
neuronal transmission of a virus that spreads cen-
Arbovirus (Bunyaviridae) tripetally along peripheral nerves from the initial inoc-
California (LaCrosse) encephalitis virus ulation site to ultimately involve the limbic system,
spinal cord, and cerebellum.
Picornavirus (enterovirus) Finally, the clinicopathologic expression of any given
Poliovirus CNS viral infection is a complex interplay between vi-
Coxssackie virus ral pathogen and host factors. In general, CNS viral in-
fections are more frequent in childhood. The severity of
Paramyxovirus
CNS viral disease tends to increase with age, however.
Measles virus
Needless to say, integrity of the immune system, the in-
Mumps virus fecting dose and virulence of the viral agent, and as-yet-
Rhabdoviridae to-be-identified genetic factors are among the multitude
Rabies virus of conditions that modify the course of the disease.
Arenavirus
Lymphocytic choriomeningitis (LCM) virus ACUTE VIRAL INFECTIONS OF
THE NERVOUS SYSTEM
Aseptic Meningitis
(meningitis), brain parenchyma (encephalitis), or in- In the United States, the number of cases of viral menin-
volvement of both areas simultaneously (meningoen- gitis far exceeds the number of cases of meningitis of
cephalitis), or cerebral white matter (viral leucoen- all other causes. The term aseptic meningitis refers
cephalopathy). In addition to this site-specific feature to the clinical syndrome of self-limited episodes of
or tissue tropism, viral diseases often display a charac- inflammation of the leptomeninges without evidence
teristic temporal course. Based on different virus–cell of brain parenchymal (encephalitis) or spinal cord
interactions, viral infections may be defined as acute, (myelitis) involvement. Since the absence of bacterial
subacute, or chronic (Rushing and Burns, 2001). Her- or fungal etiologies is implicit in the term aseptic, it is
pes simplex and varicella-zoster are prototypes of a spe- often considered synonymous with viral etiology (Jack-
cial category of chronic viral infection known as latent son and Johnson, 1989). Routine laboratory studies
infections (Wainwright et al., 2001). In latent infec- typically show cerebrospinal fluid pleocytosis with nor-
tions, the virus remains dormant without giving rise to mal values of protein and glucose (except for low lev-
signs of infection, and then it later reemerges as an acute els of glucose in lymphocytic choriomeningitis and
infectious process. Finally, CNS viral diseases can be mumps) (McDonald et al., 1989; Connolly and Ham-
designated as primary, resulting from direct viral entry mer, 1990). The few pathologic studies of viral menin-
into the CNS, or postinfectious, signifying CNS infec- gitis have shown nonspecific mononuclear infiltrates in
tion temporally associated with systemic viral infection, the meninges, ependyma, and choroid plexus without
but without direct evidence of CNS viral invasion involvement of the underlying brain parenchyma.
Enteroviruses (coxsackievirus, poliovirus, echovirus, cephalomyelitis) or nerve roots (encephalomyeloradi-

and human enteroviruses 68–71) account for 75%– culitis) (McAbee and Kadakia, 2001). The most im-
90% of aseptic meningitis (Rotbart, 1995). They are portant viruses causing acute sporadic encephalitis in
small RNA viruses of the picornavirus family with nu- immunocompetent adults are HSV-1, accounting for up
merous serotypes that are transmitted by the hand– to 95% of the cases, VSV, and less commonly, en-
fecal–oral route (Grist et al., 1978). Using a variety of terovirus (Koskiniemi et al., 2001). Epidemics of en-
diagnostic methods, including serology, culture, and cephalitis are commonly associated with arbovirus in-
PCR genomic amplification of enteroviral RNA, a spe- fection, which includes members of several different
cific viral cause can be identified in up to 90% of cases taxonomic groups (Hinson and Tyler, 2001). Since the
(Rotbart et al., 1998). Enterovirus should be consid- number of viruses reported to cause encephalitis is le-
ered the leading candidate during the summer months, gion, new causes of viral encephalitis are constantly ap-
especially in children (15 years), although sporadic pearing, sometimes in unexpected locations, as illus-
cases of enterovirus meningitis are seen year-round trated by the recent outbreak of encephalitis in New
(Rotbart, 1995; Kleinschmidt-DeMasters and DeBiasi, York City due to West Nile virus (Johnson 1994; Nash
2001; Wong, 2000). Overall, herpes simplex virus 2 et al., 1999; Marra, 2000; Solomon and Malawa,
(HSV-2) is probably second only to enterovirus as a 2001).
cause of viral meningitis. It occurs most frequently in PCR amplification of viral nucleic acid is now the
the clinical setting of genital herpes. Confirmed by PCR diagnostic procedure of choice for many types of viral
amplification of HSV-2 DNA from CSF, it is responsi- encephalitis, since attempts to culture viruses from the
ble for recurrent attacks of lymphocytic meningitis in CSF are often disappointing. In cases where CSF PCR
20% of patients (Picard et al., 1993). Arboviral menin- studies fail to lead a to a specific diagnosis, brain bi-
gitis should be suspected when clusters of meningitis opsy is indicated (Kleinschmidt-DeMasters et al.,
occur in a restricted geographic region during the late 2001). Biopsies are more likely to yield positive results
summer months, especially when there is a history of if they are obtained from sites that appear to be sig-
a tick bite or travel to an endemic area. In patients with nificantly involved on the basis of clinical and neu-
concurrent chickenpox or shingles, varicella-zoster roimaging criteria. When adequate biopsy tissue is har-
(VSV) meningitis should be considered, although the vested, it should be cultured for virus and examined by
increasing utilization of attenuated varicella vaccine has routine light and electron microscopy (Garcia et al.,
contributed to a declining incidence (Koskiniemi et al., 1984).
2001). Similarly, with widespread use of the live at-
tenuated mumps vaccine, the incidence of mumps
Arbovirus encephalitis
meningitis has fallen precipitously. Viral meningitis
caused by lymphocytic choriomeningitis (LCM) virus As noted, arbovirus (arthropod-borne viruses) infec-
is another candidate for consideration in the late fall tions are common causes of sporadic and epidemic
or winter in individuals with a history of exposure to acute encephalitis in the United States. The geo-
small rodents in the house (mice, hamsters) or labora- graphic and seasonal incidence of arbovirus infection
tory setting. The various strains and isolates of LCM relates to the life cycle of the arthropod vectors, to
are considered to be a genus within the family Are- animal reservoirs, and the potential for arthropod
naviridae, viruses containing two single-stranded RNA vector contact with humans. Viruses in this group are
segments. Important laboratory clues to the diagnosis enveloped RNA viruses, which belong to different
of LCM include marked CSF pleocytosis and hypogly- families, including togavirus, flavivirus, bunyavirus,
corrhachia (Barton and Mets, 2001). and reovirus. The natural reservoirs of arboviruses
are birds and small mammals. Humans and horses,
in the case of the equine encephalitides, are inciden-
Viral Encephalitis
tal or “dead-end” hosts. Arbovirus is transmitted to
Viral encephalitis is a more severe inflammation that humans by blood-sucking arthropods, including mos-
primarily involves the brain parenchyma, resulting in quitoes, sandflies, and ticks. After replication at the
diffuse or localizing signs of cerebral dysfunction. Typ- inoculation site, the virus spreads to regional lymph
ical symptoms include a flulike prodrome followed by nodes where it proliferates before hematogenous dis-
seizures, focal neurological deficits, and an impaired semination. In most instances, arboviral infection is
level of consciousness. Many patients with encephalitis subclinical, and severe CNS involvement occurs only
also have evidence of meningitis (meningoencephalitis) in a small fraction of persons infected (Hinson and
and, in some cases, involvement of the spinal cord (en- Tyler, 2001).
The genus alphavirus of the Togaviridae family in- cephalitis and West Nile viruses. Wild birds are the nat-
cludes three important causes of mosquito-borne en- ural reservoir of the virus, which is transmitted to hu-
cephalitis: eastern equine encephalitis (EEE), western mans by Culex mosquitoes. Epidemics occur in sum-
equine encephalitis (WEE), and Venezuelan equine en- mer and early fall, mainly in the midwestern and
cephalitis (VEE). Eastern equine encephalitis is the most southern United States (Day, 2001). As in other en-
severe and fortunately least common form of arbovirus cephalitides, the disease is more severe in the elderly,
encephalitis. The disease occurs mainly on the eastern whose fatality rate may be as high as 20%. Significant
seaboard of the United States, with a few inland foci neurologic disability may be a consequence of the dis-
as far removed as Michigan, especially in swampy ar- ease (Downs, 1982). Japanese encephalitis is the most
eas, and it is more common during the late summer common cause of epidemic encephalitis worldwide and
and early fall. Among patients with EEE the mortality a serious health problem in the Far East (Umenai et al.,
may be as high as 70%, and many survivors are left 1985). It is commonly a severe disease, with a fatality
with severe neurologic sequelae. Western encephalitis rate of about 50% and frequent serious disabilities in
occurs on the west coasts of Canada, the United States, survivors. The disease is transmitted by Culex mos-
and Central America and the northern part of South quitoes, which breed in rice fields. In cooler northern
America. In contrast to EEE, neurological involvement climes, ticks are more important vectors of flavivirus
in WEE is mild and there is an increased attack rate encephalitis. Tick-borne encephalitis caused by fla-
and morbidity in the young—particularly children un- vivirus is seasonal, corresponding to peak summertime
der 2 years of age—and in the elderly. VEE is usually vector populations, and occurs in Scandinavia, Russia,
a self-limited flulike syndrome that is prevalent in Cen- and Central Asia. Of note, in Europe the disease is rel-
tral and South America, but cases have been reported atively mild, but in the Far East, it tends to be severe,
in Texas and Florida. Mosquitoes transmit VEE, and with a case fatality rate of 20%–25% (Downs, 1982;
horses are an important reservoir of disease. Generally Garcia et al., 1984).
mild encephalitis occurs in adults and older children; For the most part, the pathologic changes in ar-
however, the case-fatality rate in children under 5 years bovirus encephalitis are similar to those observed in
approaches 35% (Shope, 1980). other viral encephalitides (Table 5.2). Morphologic fea-
tures include a predominantly mononuclear inflamma-
tory infiltrate within the leptomeninges and brain pa-
California group of viruses
renchyma, which is often evident as mononuclear
The California virus and other related agents, which “cuffing” around blood vessels. In severe cases, neu-
include the LaCrosse virus, represent different sero- rons are destroyed and surrounded by mononuclear
groups of the bunyavirus genus. Undoubtedly often un- cells and microglial cells (neuronophagia). In infants,
derreported, the LaCrosse virus is responsible for as pathologic examination reveals massive parenchymal
many as 20% of cases of encephalitis in children. The destruction, whereas in older children and adults, WEE
disease is common in the north-central states and is is characterized by extensive lesions within the basal
transmitted by woodland mosquitoes. In addition to ganglia, thalamic nuclei, and deep cerebral white mat-
the common vertical mode of infection in mosquitoes, ter. In the case of EEE, polymorphonuclear inflamma-
horizontal transmission involving small mammals is tion often dominates early in the infectious process. Fo-
also probable. Most cases affect children under 15 years cal vasculitis and thrombus formation are frequently
of age during the months of July through September.
The clinical spectrum varies from mild meningeal irri-
tation to severe and occasionally fatal encephalitis. TABLE 5.2 Histologic Hallmarks of CNS
Neurological or psychiatric sequelae occur in up to Viral Infections
15% of survivors (Weaver et al., 1958). Microglial nodules
Neuronophagia
Flaviviruses Intranuclear inclusion bodies (e.g., Cowdry type A)
Perivascular lymphocytic cuffing
Flaviviruses are among the most important emerging
Mononuclear inflammation
neurotropic viruses known. Many are spreading to new
Leptomeninges (aseptic meningitis)
geographical areas and causing increased cases of en-
Brain parenchyma (encephalitis)
cephalitis. St. Louis encephalitis (SLE) is an important
encephalitis caused by arboviruses in the United States. Spinal cord [poliomyelitis (gray matter) or myelitis (white
matter)]
It shares antigenic relationships with Japanese en-
noted. The areas most commonly affected include the ture that is characterized by a double-stranded DNA
basal ganglia, thalamus, hippocampus, and frontal and central core packaged in a capsid that consists of cap-
occipital cortices. Pathologic changes in SLE are most someres arranged in icosahedral symmetry. HSV is one
pronounced in the substantia nigra, thalamus and hy- of the largest and most complex viruses, and its en-
pothalamus, basal ganglia, and cerebral and cerebellar veloped double-stranded DNA codes for about 50 dif-
cortices. Microglial nodules are small collections of ferent proteins (McKendall, 1989). The human her-
elongated, rod-shaped microglial cells that represent a pesviruses elicit a spectrum of acute, subacute, and
characteristic but not pathognomonic finding of viral chronic infections of the central and peripheral nervous
encephalitis. Because of typically mild CNS involve- system. An important observation concerning all hu-
ment in VEE, the neuropathologic features are poorly man herpesviruses is that they are able to persist in a
documented. Typical viral inclusions are not generally latent physical state within ganglionic neurons and
found in tissues of patients dying of arbovirus en- within blood T or B cells (Warren et al., 1977). The
cephalitis, and the specific virus involved must be iden- mechanisms that control reactivation are currently un-
tified by viral cultures and serologic or molecular der investigation by combining pathologic study with
studies. Nonspecific astroglial proliferation usually ac- PCR technology (Hukkanen and Vuorinen, 2002).
companies viral encephalitis (Weaver et al., 1958). While there are many overlapping clinicopathologic
The West Nile (WN) virus recently reached the features among the infections HSV-1 and -2, CMV,
Americas and shares the flavivirus phylogenetic group VZV, EBV, and HHV-6, major differences exist, espe-
of viruses with SLE. It is one of the most ubiquitous of cially between immunosuppressed and immunocompe-
human arbovirus infections, being found throughout tent individuals (Kleinschmidt-DeMasters et al., 2001).
Africa, Asia, and parts of Europe. The WN virus is har- In children and young adults, HSV-1 enters the body
bored in birds, although the virus is able to infect a va- through the olfactory mucosa, while most adults with
riety of domestic and wild animals as well as humans HSV-1 encephalitis give a history of previous mucocu-
and subhuman primates. The principal vectors consist taneous HSV infection (O’Meara and Ouvrier, 1996).
of a variety of mosquitoes (Nash et al., 2001). The large The virus reaches the central or peripheral nervous sys-
proportion of infections is asymptomatic, a striking and tem through the peripheral nerves, where it presumably
remarkably consistent feature among other flavivirus remains shielded from the host’s immune system. HSV
encephalitides—for example, SLE and Japanese en- viremia may occur in newborns, but usually not in im-
cephalitis. In each of these infections, the virus enters munocompetent adults. The virus remains latent until
the CNS from the blood by permeating vascular endo- reactivated by a variety of circumstances, such as
thelial cells into brain parenchyma or, alternatively, trauma and immunosuppression.
through the olfactory epithelium. Pathologic features Contrary to previous reports of a uniformly high
include encephalitis and meningoencephalitis, some- mortality rate, PCR CSF studies have documented
times with compromise of the cranial nerve roots. The milder forms of HSV-1 encephalitis. In neonates and
inflammatory process may show a predilection for the young children, imaging studies indicate that the dis-
brain stem, especially the medulla (Sampson et al., ease is more often diffusely bilateral or multifocal. Le-
2000). Neuronal necrosis, microglial nodules, neu- sions occur along a vascular distribution pattern, sug-
ronophagia, perivascular infiltrates of activated T cells gesting a hematogenous route of spread. The typical
and macrophages, and microglial nodules are promi- pathologic appearance of HSV encephalitis includes
nent in the affected areas. Viral antigen has been iso- multiple small sites of hemorrhagic necrosis involving
lated from neurons, and macrophages and other tissues the basal frontal lobes, the cingulate gyrus, and the
from human and animal cases (Steele et al., 2000; mesial portion of the temporal lobes (Fig. 5.1). The di-
Sampson et al., 2000). agnosis can be suspected based on the classic topogra-
phy of the lesions and is readily recognizable by MRI.
Since the advent of reliable PCR CSF analysis for HSV-
Herpesvirus encephalitis
1, the use of brain biopsy for diagnosis is declining
Members of the Herpesviridae family show well- (Kleinschmidt-DeMasters et al., 2001). With biopsy,
defined antigenic and biologic characteristics that fa- HSV encephalitis can be demonstrated by viral cultures,
cilitate identification and viruses that are pathogenetic histologic studies, electron microscopy, and immuno-
for humans include herpes simplex virus (HSV) types histochemical studies. The preferred biopsy site is the
1 and 2, human herpesvirus type 6 (HHV-6), Epstein- anterior part of the inferior temporal gyrus. Typical ho-
Barr virus (EBV), cytomegalovirus (CMV), and varicella- mogeneous eosinophilic viral inclusions within affected
zoster virus (VSV). Herpesviridae share a virion struc- neurons, glia, and endothelial cells are demonstrated
Cytomegalovirus Infection
CMV is a linear double-stranded DNA virus, and the
largest and most complex of the human herpesvirus
family. Like other members of the herpes viruses it ex-
hibits primary infection, latency, and recurrent infec-
tion. CMV is a widespread agent that infects people of
all ages, though there is increasing evidence of high ac-
quisition rates during early childhood, adolescence, and
the child-bearing years. Serological studies indicate
varying patterns of antibody status worldwide, reflect-
ing different prevalence according to geography and so-
cioeconomic status (Bale, 1984). Recent CSF PCR stud-
ies indicate that CMV is occasionally responsible for
encephalitis and myelitis in immunocompetent adults.
For the most part, CMV infections of the brain are
more common in HIV-infected individuals but they can
also be acquired through blood transfusion and organ
transplants (Ho, 1982).
Congenital CMV infection, often acquired transpla-
FIGURE 5.1 Herpes encephalitis. Bilateral hemorrhagic lesions of the centally, is common and often asymptomatic. The risk
temporal lobes. of fetal complications is highest when the infection oc-
curs during the first trimester. Neurological manifesta-
tions can range from isolated deafness to diffuse, se-
vere encephalopathy. More specifically, CNS anomalies
only during the first days. Inflammation may be absent
associated with congenital CMV include microcephaly,
in cases associated with compromise of the immune sys-
hydrocephalus, chorioretinitis, and microphthalmia.
tem (Schiff and Rosenblum, 1998).
Necrotizing meningoencephalitis, more pronounced in
Although HSV-2 usually causes aseptic meningitis in
subependymal areas, occurs in many cases (Fig 5.2A).
adults, it also accounts for a small percentage of cases
The brain lesions also include subependymal calcifica-
of frontotemporal encephalitis in immunocompetent
tions and microgyria, attributable to a poorly under-
patients. In adults, HSV-2 infection has been confirmed
stood decrease in blood perfusion. In addition to mi-
in cases of transverse myelitis, brainstem encephalitis,
croglial nodules and mononuclear infiltrates, the
and benign meningoencephalitis. In neonates, HSV-2 is
histologic appearance of classic cytomegalic changes in-
more common than HSV-1 and is responsible for seri-
cludes the presence of large “owl-eye” inclusions
ous neurologic sequelae including cases of fatal en-
(Cowdry type A) within greatly enlarged nuclei of
cephalitis. Using PCR, HSV-2 has now been associated
neuronal, glial, or ependymal cells (Fig. 5.2B). Intra-
with Mollaret’s meningitis, a rare disease characterized
cytoplasmic inclusions can also be present. In im-
by recurrent, benign episodes of aseptic meningitis
munocompetent adult brains, CMV produces a menin-
(Kleinschmidt-DeMasters et al., 2001).
goencephalitis in which, although microglial nodules
HHV-6 is the etiologic agent of exanthema subitum
are frequent, diagnostic intranuclear inclusions are less
(roseola) and is now recognized as an important cause
common than in the congenital form. In the absence of
of febrile seizures in children, especially in Japan
typical inclusions, the diagnosis of CMV must rest with
(Yoshikawa, 2000). Case reports have linked HHV-6
viral culture, demonstration of viral DNA by in situ
to rapidly fatal encephalitis, to focal brain necrosis in
hybridization, or immunohistochemical studies.
immunocompetent patients, and to meningoen-
cephalitis and demyelination in immunocompromised
individuals (Navia et al., 1987). Preliminary research
Varicella-Zoster Virus Infection
suggests that HHV-6 infection may act synergistically
with other viral pathogens (Ito et al., 2000). The Varicella-zoster virus (VZV) is the etiologic agent of two
demonstration of HHV-6 in asymptomatic individu- distinct clinical diseases, varicella (chickenpox) and
als suggests that caution should be exercised in im- zoster (shingles). The CNS may be involved either dur-
plicating HHV-6 as the etiologic agent in the above ing the primary infection (varicella) or during the reac-
conditions. tivation of latent (Gilden and Vafai, 1989) virus (herpes
A lain-Barré syndrome; and some cases of granulomatous

angiitis of the central nervous system. Paralysis can oc-
cur either as a consequence of the involvement of ante-
rior horn cells or secondary to an infarct from VZV ar-
teritis. The range of histopathologic changes in typical
cases includes lymphocytic inflammation and hemor-
rhagic necrosis of dorsal root ganglia, degeneration of
motor and sensory roots, and eosinophilic intranuclear
inclusions within dorsal root ganglia neurons (Mc-
Cormick et al., 1969). In immunodeficient patients,
ventriculitis, demyelinating lesions, and deep white-
matter hemorrhagic infarcts are reported. Viral particles
are demonstrable by electron microscopy and VZV
antigens are demonstrable by immunofluorescence or
immunoperoxidase studies. PCR appears to be the sen-
sitive and rapid method of demonstrating VZV DNA
(Stroop and Baringer, 1982; Strauss, 1984; Tyler, 1994;
Kleinschmidt-DeMasters et al., 2001).
Rabies
B
Rabies, also known as hydrophobia or aquifuga, is
one of the oldest communicable diseases on record.
The term rabies is derived from the ancient Indian
word rabh, meaning, “to make violent” (Beran,
1981). It is a fulminating, usually fatal, infection in-
volving the CNS in humans and other mammals. A
single-stranded RNA virus belonging to the genus
Lyssavirus within the rhabdovirus family causes the
disease. The enveloped bullet-shaped viral genome
replicates within the cytoplasm of infected cells, pro-
ducing the characteristic eosinophilic cytoplasmic in-
clusions known as Negri bodies (Chopra et al., 1980).
FIGURE 5.2 (A) Coronal section of brain discloses granular ependy- Rabies virus possesses a capsule with surface projec-
mal surface due to CMV meningoencephalitis. (B) Microscopic sections containing a glycoprotein that elicits the pro-
tion reveals “owl-eye” intranuclear viral inclusions.
duction of neutralizing and hemagglutination-in-
hibiting antibodies and stimulates T-cell immunity.
Transmission of the disease to humans is commonly
zoster). A benign, self-limited cerebritis and VZV menin- propagated through the bite of unimmunized dogs
goencephalitis represent CNS manifestations of varicella and cats (urban) and wild animals (sylvatic), includ-
infection. At the time of initial varicella infection, the ing skunks, raccoons, coyotes in the United States,
virus reaches cranial or dorsal root ganglia, where it re- and foxes, an important wild reservoir in Europe. In
mains latent until it is reactivated and produces the char- general, infection in domestic animals represents
acteristic cutaneous vesicular eruption in the affected “spillover” from sylvatic reservoirs of infection.
dermatome. Herpes zoster is common and often more Other less frequent forms of transmission are through
severe among immunosuppressed individuals (including inhalation of aerosolized rabies virus in bat-infested
those with AIDS) and in the elderly (Roizman, 1985). caves, ingestion, and, in laboratory settings, through
Neurologic complications of VZV infection include postexposure of an open wound or mucous membranes
herpetic neuralgia, especially common in the elderly; to infected material (Noah et al., 1998). Isolates of
meningoencephalitis, which may occur during primary rabies virus from different animal species and locales
infection (varicella) or during reactivation (zoster), with differ in their antigenic and biologic properties. In
or without cutaneous lesions; transverse myelitis, a rare rare instances, human-to-human transmission by in-
complication that may follow varicella or zoster; Guil- fected corneal transplants has been reported.
The initial introduction of the live virus occurs tion of the virus in the limbic system, with cortical spar-
through the epidermis or mucous membranes. The in- ing, correlates clinically with behavioral and emotional
cubation period is usually 2–8 weeks, although it varies changes seen in an alert and cognitively intact patient.
with the type of infecting strain, and is found to be in- Gross pathologic specimens of the brain in rabies
versely related both to the size of the inoculum and to show scattered hemorrhages, necrosis, and surround-
the proximity of the site of the bite to the CNS. The ing edema in the cerebral deep gray matter. The basic
passage of the virus centripetally from the peripheral microscopic neuropathology of rabies resembles that of
nervous system to the CNS occurs through retrograde other viral infections of the CNS. The histopathologic
axoplasmic flow of approximately 12–24 mm per day hallmark of rabies encephalitis is neuronal necrosis
until the virus reaches the next neuronal cell body. (Dupont and Earle, 1965). Whenever there is severe
Once the virus reaches the CNS, it replicates almost ex- neuronal necrosis there is often accompanying hyper-
clusively within the gray matter and then passes cen- emia, with petechial hemorrhages, especially within the
trifugally along autonomic nerves to other tissues (Jack- thalamus and subependymal region (Mrak and Young,
son et al., 1999). Passage of the virus into the salivary 1994). Negri bodies, found in approximately 80% of
glands and viral replication in acinar cells facilitates humans with rabies, are large, round or oval, discrete
further transmission through infected saliva. After the intracytoplasmic acidophilic inclusions especially com-
prodromal phase, human disease presents in either of mon in neurons in the pyramidal cells of hippocampus,
two clinical forms: encephalitic and paralytic, analo- cerebral cortex, and Purkinje cells of the cerebellum
gous to the “furious” and “dumb” rabies seen in dogs. and occasionally found in the brain stem and spinal
In encephalitic rabies, the initial symptoms are non- dorsal ganglia (Fig. 5.3). Some neurons contain less
specific, such as fever, malaise, pain, or anesthesia at well-defined cytoplasmic inclusions termed lyssa bod-
the bite site. Subsequently, patients rapidly progress ies. They may be anywhere in the cytoplasm or in its
from symptoms of hydrophobia, hypersalivation, and dendrite, and there may be more than one in a single
hyperirritability to neurologic symptoms, such as agi- cell. Inflammatory infiltrates and microglial nodules
tation, mood swings, and seizures. Paralytic rabies en- may also be present throughout the brain, although
cephalitis often presents with a confusing diagnostic there is usually a disparity between the abundance of
picture of flaccid paralysis resembling Guillain-Barré virus and presence of inflammation (Mrak and Young,
syndrome. The pathogenesis of paralytic rabies is 1994). Finally, when rabies encephalitis is suspected,
poorly understood but appears to correlate with the ab- special handling of tissue obtained for histopathologic
sence of an adequate immune response to the infection study is necessary. Use of face masks, gowns, and gloves
and diminished numbers of peripheral blood B lym- by all personnel in contact with tissue and body fluids
phocytes. Both forms of the disease are invariably fa- such as saliva and CSF is advised. In addition, all
tal and usually progress to coma and death within 2–25 known or suspected human contacts should receive
days after onset of neurologic symptoms. Patients usu- postexposure prophylaxis.
ally succumb to failure of central vegetative functions,
although death may also be due to concomitant rabies
myocarditis (Hattwick et al., 1972).
Because the disease has a fulminating course, ante-
mortem diagnosis is often difficult. More than a third
of the cases are diagnosed postmortem. Antemortem
diagnosis can be confirmed by isolating the virus from
the saliva, cerebrospinal fluid, or urine; by demonstra-
tion of the antigen by immunofluorescence studies in
nuchal skin biopsies, corneal impression or salivary
smears; or in a brain biopsy (Negri bodies) (Blenden et
al., 1986). In the CNS, there is an initial localization
of the infection in deep gray matter, and there is evi-
dence for involvement of glial cells along with the neu-
rons. In paralytic rabies, the medulla and spinal cord
bear the brunt of extensive neuronal injury and in-
flammation, whereas in the encephalitic form, it is the FIGURE 5.3 H&E section of cerebellum from a case of rabies en-
brain system and the cerebrum, particularly the limbic cephalitis shows a Purkinje cell containing a bullet-shaped cytoplas-
system, that are especially targeted. The early localiza- mic inclusion Negri body.
Poliovirus, Acute Myeloradiculitis

The manifestations of infection by poliovirus range
from inapparent illness to paralysis and death. Humans
are the only natural host and reservoir of poliovirus.
Polioviruses are members of the genus Enterovirus and
family picornavirus. The genome of poliovirus is com-
posed of single-stranded RNA and is not surrounded
by a lipid envelope. Three main serotypes of the po-
liovirus are recognized. Lifelong immunity and cross-
protection exists between types 1 and 2, but there is
less between these two serotypes and type 3. Before the
introduction of poliovirus vaccine, most paralytic dis-
ease was due to type 1 (Goldblum et al., 1984). Po- FIGURE 5.4 Atrophy and cavitation of the anterior horn of the spinal
liomyelitis remains a serious health problem in many cord in chronic poliomyelitis.
areas of the world, but fewer than 10 cases of para-
lytic poliomyelitis, most of them vaccine associated,
were reported annually in the United States in the last Presenting many years after the acute illness, the
decade. Most of the infections remain asymptomatic postpolio syndrome is recognized as new-onset weak-
and only about 10% of infected individuals have ness, fatigue and fasciculations, and pain with pro-
viremia. The central nervous system infection is a rare gressive atrophy of muscles involved during the initial
complication of enteric infections. CNS involvement paralytic disease (Jubelt and Agree, 2000). The syn-
may take the form of acute aseptic meningitis, en- drome is more common among women and with in-
cephalitis, or paralytic disease (Ren and Racaniello, creasing time after acute disease. Weakness may also
1992). Paralytic disease is more common among older slowly progress to involve muscles not previously af-
individuals, pregnant women, persons exercising stren- fected. Although the pathogenesis of this syndrome is
uously, and persons undergoing trauma at the time of incompletely understood, it is thought to be due to pro-
infection. A remote risk of vaccine-associated paralytic gressive loss of residual motor neurons that remained
disease exists following administration of the live, oral after the initial attack. There is no evidence to support
attenuated vaccine; this is especially true in im- persistent or reactivated poliovirus infection.
munosuppressed or immunocompromised children and
adults. Poliovirus mainly affects motor and autonomic
Coxsackievirus and Echovirus
neurons. The selective vulnerability of anterior horn
cells of the spinal cord appears to be related to the large Coxsackievirus and echovirus may produce aseptic
number of viral receptors on the surface of these cells. meningitis and encephalitis, and, overall, enteroviruses
Other neurons, including cerebellar roof nuclei, Betz cause most of the viral central nervous system infec-
cells of the precentral gyrus of the cerebral cortex, and tions in the United States. In contrast to polioviruses,
neurons of brainstem (mesencephalon, pons, and coxsackievirus and echovirus can be recovered from
medulla) nuclei and reticular formation, can also be in- cerebrospinal fluid early in the disease. In children with
fected by the polioviruses. The dorsal root ganglia are deficits of humoral immunity, these viruses may pro-
commonly involved pathologically, but this seldom reduce progressive, chronic encephalitis (McAbee and
sults in clinical disease. In approximately 10%–25% of Kadakia, 2001). Certain enteroviruses may also par-
cases, brainstem nuclei are extensively involved, lead- ticipate in the pathogenesis of polymyositis (Fox et al.,
ing to the bulbar form of the disease. In this form of 1994). There are no specific pathologic features asso-
the disease, the ninth and tenth cranial nerve nuclei are ciated with these infections.
by far the most severely involved. Microscopic changes
in the acute phase are nonspecific and include destruc-
Mumps
tion of involved neurons, hemorrhage, neuronophagia,
microglial nodules, and perivascular mononuclear in- Mumps is an acute, systemic, highly communicable vi-
filtrates. In the chronic phase, changes include atrophy ral infection that involves the meninges in approxi-
and cavitation of the anterior horns (Fig. 5.4) and at- mately 10% of patients with clinical parotitis. The
rophy of ventral spinal nerve rootlets. Viral inclusions mumps virus is an enveloped pleomorphic RNA virus
are not found within the infected cells and the virus is that belongs to the paramyxovirus group. There is only
seldom recovered from the cerebrospinal fluid. one antigenic type of mumps virus. After the intro-
duction of the mumps vaccine in 1967, the incidence measles virus. The incidence of SSPE has dramatically
of mumps declined significantly in the United States. declined in the United States since the introduction of
Prior to that time, mumps was principally a disease of measles vaccine; however, it remains endemic in much
children, although today more than 50% of cases of the developing world (Gascon, 1996). Most patients
occur in young adults. Epidemics tend to occur in con- give a history of primary measles infection before the
fined populations such as those in schools and the mil- age of 2 years, which is followed after a latent interval
itary services (McDonald et al., 1989). Mumps menin- of 6–8 years by the development of a progressive neu-
gitis, encephalitis, myelitis, polyradiculitis and cranial rologic disorder. Initial manifestations include declin-
neuritis are now well known and may occur without ing school performance and mood and behavioral
clinical parotitis. Based on a hamster model of mumps changes. Typical signs of CNS infection, including fever
meningoencephalitis, viral entry into the CNS is thought and headache, are not evident. As the disease pro-
to be via mumps-infected mononuclear cells across the gresses, patients develop ataxia, myoclonus, seizures,
choroid plexus epithelium, which then spreads to intellectual deterioration, visual disturbances and mo-
meningeal surfaces by the normal routes of CSF tor disabilities. The EEG shows a characteristic peri-
flow (Narayana et al., 1987). Aseptic meningitis may odic “burst and slow-wave” pattern, and CSF anti-
develop before, during, after, or in the absence of measles antibodies are often present (Dyken, 1985).
parotitis. The glucose level in the CSF may be abnor- Neuroimaging studies show multifocal white matter le-
mally low, and this finding may arouse suspicion of sions, cortical atrophy and ex vacuo hydrocephalus
bacterial meningitis. At the other end of the spectrum, (Tsuchiya et al., 1988). Measles virus can be cultured
mumps encephalitis may leave severe sequelae in sur- from brain tissue and viral antigen can be identified by
vivors. These complications include cerebellar ataxia, immunocytochemistry, and the viral genome can be de-
facial palsy, transverse myelitis, Guillain-Barré syn- tected by in situ hybridization or PCR amplification.
drome, chronic headaches, seizures, aqueductal steno- Oligoclonal IgG bands in cerebrospinal fluid and serum
sis, and hydrocephalus (O’Meara and Ouvrier, 1996). are another characteristic finding in SSPE (Dyken,
2001). More recently, techniques utilizing phage-
displayed antigen libraries have identified IgG extracted
CHRONIC AND SUBACUTE VIRAL INFECTIONS from patients with SSPE (Burgoon et al., 2001).
OF THE CNS Macroscopic examination of the brain in patients
with SSPE usually reveals variable atrophy of the cere-
Measles Virus Infections Including Subacute bral cortex (Fig 5.5A), changes in color and consistency
Sclerosing Panencephalitis of the white matter (Fig 5.5B), and dilatation of the
ventricles (ter Meulen et al., 1972). Histopathologic
The most common neurologic complications of measles
evaluation reveals variable involvement of the cerebral
are aseptic meningitis, followed by acute disseminated
cortex, white matter, basal ganglia and thalamus char-
encephalomyelitis. Much less commonly, CNS in-
acterized by neuronal loss, perivascular inflammation,
volvement produces either subacute or chronic en-
astrocytosis, and neuronophagia and patchy demyeli-
cephalitis. Measles inclusion-body encephalitis occurs
nation. Although not as common as in measles inclu-
months after onset or recovery from the infection, usu-
sion body encephalitis, similar intranuclear and intra-
ally in patients with impaired immunity. The disease is
cytoplasmic inclusions are found within infected
postinfectious and is probably immune mediated and
neuroglia (Fig 5.5C) (Jabbur et al., 1969; Townsend et
not the result of direct central nervous system infection
al., 1975). Alzheimer-type neurofibrillary tangles are
by the measles virus. Inclusion-body encephalitis is a
also present in cases of prolonged duration. Immuno-
disorder of uncertain pathogenesis that occurs within
fluorescence or immunohistochemical stains reveal
months of the initial infection (Schneider-Schaulies et
measles virus antigen in a large number of neurons and
al., 1999). Morphologically, measles inclusion-body
glial cells (McQuaid et al., 1994).
encephalitis is characterized by eosinophilic inclusions
filling the nuclei of neurons and glia, CD-68 immuno-
reactive microglial nodules, and, in contrast to SSPE,
Progressive Multifocal Leukoencephalopathy
abundant immunohistochemical evidence of viral anti-
gen (Mustafa et al., 1993). Progressive multifocal leukoencephalopathy (PML) is a
Subacute sclerosing panencephalitis (SSPE) is a rare, relentlessly progressive subacute disorder characterized
progressive, frequently fatal demyelinating disease of pathologically by multifocal areas of demyelination
the CNS that attacks children and adolescents and is a throughout the CNS. The etiologic agent known as
more delayed manifestation of brain infection with papovavirus (papilloma, polyoma, vacuolating agent)
A rare condition usually complicating lymphoprolifera-

tive disorders, myeloproliferative disease, and chronic
infectious or granulomatous disease. Since the onset of
the AIDS epidemic, its incidence has increased consid-
erably and HIV infection has become, by far, the ma-
jor risk factor. The diagnosis of PML is often suggested
by neuroimaging studies which show widespread in-
volvement of white matter, with nonenhancing, multi-
focal, asymmetric, coalescing lesions without mass ef-
fect, most often periventricularly, in the centrum
semiovale, in the parietal-occipital region and cerebel-
lum (Greenlee, 1998). In many cases, PCR appears to
be a reliable technique for demonstrating viral genome
B in the CSF. Diagnostic confirmation can be made with
histopathological examination of the brain either by
cerebral biopsy or postmortem.
Macroscopic changes in PML include, in severe cases,
mulifocal softening, discoloration, and crumbling of the
hemispheric white matter (Fig. 5.6A). The microscopic
changes of PML are characteristic and include multi-
focal areas of demyelination of varying size distributed
throughout the CNS (Figure 5.6B). In addition to de-
myelination, there are characteristic cytologic alter-
ations including, tremendous enlargement of astro-
cytes, often displaying irregular, hyperchromatic, and
bizarre nuclei, and pronounced loss of oligodendrocytes
C (Brooks and Walker, 1984). Surviving oligodendro-
cytes often show enlarged, densely staining nuclei with
basophilic, homogeneous, and glassy chromatin (Fig.
5.6C). With electron microscopy these infected cells
show characteristic intranuclear round viral particles,
singly or forming crystalline arrays (Fig. 5.6D). Fila-
mentous inclusions may also be present. Immunofluo-
resence or immunoperoxidase studies show viral spe-
cific antigens within infected oligodendrocytes, and in
situ hybridization studies demonstrate papovavirus
DNA sequences within oligodendrocytes, astrocytes
with bizarre nuclei, and endothelial cells (Fig 5.6E). Al-
though PCR amplification of JC virus DNA from CSF
FIGURE 5.5 (A) Lateral aspect of the brain from a case of SSPE shows has become an important diagnostic tool, patients with
atrophy. (B) The coronal section reveals atrophic, discolored white negative CSF PCR studies may require brain biopsy for
matter. (C) Intranuclear viral inclusion. definitive diagnosis. In biopsy or autopsy specimens, JC
virus can be detected by immunocytochemistry, in situ
hybridization, or PCR amplification. Detection of JC
possesses a supercoiled DNA genome and is nonen- virus genome should be considered diagnostic only in
veloped (Small et al., 1986). Patients often present with the appropriate clinical setting, since both the antigen
visual deficits, personality changes, mental impairment and genomic material have been identified in normal
progressing to dementia, and motor deficits late in the brains.
course of the disease. Although a few antiviral treat- The pathogenesis of PML is incompletely under-
ments have been tried, their efficacy is unproven. The stood. In the majority of cases, the causative agent is
course of the disease is invariably fatal. the polyoma virus JC (JCV). In the United States, four
Almost all patients have an underlying immunodefi- main types of the JCV have been identified, each one
ciency. Prior to the HIV epidemic, PML used to be a associated with a specific region of origin: JCV1 is one
A B
C D
FIGURE 5.6 Progressive multifocal leukoencephalopathy (PML). (A)

Coronal section shows granularity and cavitation of cerebral white
matter. (B) LFB stain highlights patchy areas of demyelination. (C)
Enlarged oligodendrocyte containing amphophilic intranuclear viral
inclusions. (D) Intranuclear crystalline polyoma viral structures on
electron microscopy. (E) Positive in situ hybridization with the J-C
probe.
of European origin, type 2 is Asian, type 3 is African, gen, an early protein of JCV replication. Few cases of
and type 4 most probably represents a recombination PML are related to the SV40 virus and BK virus
of types 1 and 3. Infection with JC virus is common in (Kuchelmeister et al., 1993).
the general population, but usually it does not produce
disease and the virus remains latent in the kidney. Af-
ter immunosuppression, lymphocytes may transport PRION DISEASES
the virus to the brain, where oligodendrocytes become
infected. Studies in transgenic mice in which the JC Prions (protein infectious agents) are infectious parti-
virus has been incorporated into the genome show cles (DeArmond and Prusiner, 1995). Prion diseases,
widespread central nervous system demyelination, also known as “slow virus” diseases (Sigurdson, 1954)
which correlates with the expression of the JCV T anti- and transmissible spongiform encephalopathies (TSE)
(Gibbs et al., 1968) are a group of rare, fatal neu- of the brain. Kuru, the prototype of human prion dis-
rodegenerative diseases with distinctive clinical and eases, is confined to the Fore people in New Guinea,
pathologic features that are recognized in humans and who once practiced ritual cannibalism. Briefly, patho-
other mammalian species. The human prion diseases logic features include neuronal dropout, spongiform
include kuru, sporadic and familial Creutzfeldt-Jacob change, and characteristic dense core amyloid deposits
disease, Gerstmann-Sträussler-Scheinker disease, fatal (Fig 5.7), found primarily within the cerebellum. With
familial insomnia (FFI), and more recently, variant the decline of cannabalism, kuru has become extinct
Creutzfeldt-Jacob disease (vCJD) (DeArmand et al., (Gajdusek, 1977; Chesebro, 1991).
1985; Prusiner, 1993). The enigmatic infectious agent,
called a prion, is a unique kind of protein that, unlike
Creutzfeldt-Jakob Disease
all other agents known to cause infectious diseases, con-
tains neither DNA nor RNA (Prusiner, 1982). Although Creutzfeldt-Jacob disease (CJD), first described in the
details of the pathogenesis of these disorders are still 1920s, and in its sporadic form, is the most common
unfolding, compelling arguments have been made that and hence the most familiar of this family of diseases.
transmissible proteins are triggered when normal mem- In the United States approximately 400 people devel-
brane-associated proteins undergo post-translational oped CJD in the year 2000 (Prusiner, 2001). It is esti-
conformational changes (Safar et al., 1993). The prion mated that the incidence of sporadic CJD is about 1
protein is a normal component of cellular membranes million per year (Masters et al., 1981). CJD usually af-
of neurons and glial cells. Specifically, the normal cel- fects individuals between 50 and 70 years of age, al-
lular prion protein (PrPc) is converted into the disease, though isolated cases have been reported in younger
causing scrapie isoform (PrPSc) (Prusiner, 1991). This and older patients. Most patients eventually develop a
initial transformation may occur in organs such as constellation of neurologic abnormalities including
spleen, lung, and gastrointestinal tract. PrPc has a high cognitive impairment, behavioral abnormalities, visual
content of helix relative to -pleated sheet, while disturbances, and cerebellar, pyramidal and extrapyra-
PrPSc is rich in -pleated sheet content and has little midal signs. During the course of the disease, the EEG
helix (DeArmand and Prusiner, 1993). The reversal of exhibits periodic paroxysms of triphasic or sharp waves
this ratio, resulting in a different three-dimensional against a slow background. The average duration of
structure, is thought to be the fundamental event in the disease is 4–5 months (Johnson and Gibbs, 1998).
the pathogenesis of prion diseases (DeArmond and The gross brain abnormalities vary among patients
Prusiner, 1997). A chromosomal gene located on the with CJD, but most patients do not have recognizable
short arm of chromosome 20 encodes both normal and macroscopic abnormalities; patients with longer sur-
scrapie isoforms. Prion diseases may manifest as vival may have diffuse cerebral atrophy. On micro-
sporadic, infectious, or inherited disorders (Prusiner, scopic examination, the defining pathology in all cases
2001). Most cases are sporadic (85%). An infectious of CJD is the presence of vacuolation of gray matter
transmission in humans has been documented through
cannibalism (kuru), accidental inoculation during a
therapeutic procedure including corneal transplanta-
tion, use of contaminated EEG electrodes, dura mater
grafts, use of preparations of growth hormone and hu-
man pituitary gonadotropin contaminated with prion
protein (Prusiner, 2001), and more recently, the con-
sumption of prion-tainted beef (variant Creuzfeldt-
Jacob disease) (DeArmond and Prusiner, 1997). In 15%
of cases, prion diseases are inherited in an autosomal
dominant fashion (Deslys et al., 1994).
The five rarely encountered clinical conditions are
united by the following characteristics: an often-
protracted incubation phase followed by rapidly pro-
gressive neurological deterioration, a characteristic pat-
tern of pathologic changes in brain tissue, and a uni-
formly fatal prognosis. Because of these protean clinical
manifestations, definitive diagnosis is often delayed and FIGURE 5.7 Section of cerebellum demonstrating a kuru plaque (ar-
may not be confirmed until postmortem examination row).
structures termed spongiform change (Fig. 5.8). The velop progressive dementia. Myoclonus is not a promi-
characteristic distribution of vacuolar change is within nent clinical feature nor are periodic discharges on the
the cerebral neocortex, subiculum of the hippocampus, EEG commonly observed in CJD. Onset is earlier in
caudate, putamen, thalamus, and the molecular layer life, generally before 50 years of age. Familial cases ex-
of the cerebellum. The 1 to 5 m vacuoles observed by hibit autosomal dominant transmission. Germline mu-
light microscopy throughout the neuropil represent tations in the gene coding PrP have been described in
swollen axonal and dendritic processes associated with affected families (Prusiner, 2001). Pathologic findings
loss of synaptic organelles and the accumulation of ab- include “kuru” plaques that consist of a dense core of
normal membranes, as visualized by electron mi- amyloid deposits surrounded by smaller globules—
croscopy. Vacuoles are also observed in the cytoplasm especially common in the cerebellum. These plaques are
of neurons, and to a lesser extent in astrocytes and immunoreactive to PrP. Other features include white
oligodendrocytes (Gajdusek, 1977). Reactive astrocy- matter degeneration, involving the spinocerebellar tracts
tosis is usually quite prominent, whereas inflammation and the posterior columns; spongiform changes, usu-
is conspicuously absent. Between 5% and 10% of pa- ally not as well developed in CJD; and neurofibrillary
tients with CJD have amyloid (kuru) plaques, which tangles similar to those described in Alzheimer’s dis-
stain with antisera against PrP proteins. These plaques ease. Extracts of brain tissue in GSS produce spongi-
appear as discrete eosinophilic, glassy masses with ra- form changes when inoculated into laboratory animals
diating amyloid fibrils at the periphery (DeArmand and (Masters et al., 1981).
Prusiner, 1997).
Familial CJD is defined by a dominantly inherited
Variant Creutzfeldt-Jacob Disease
mutation of the PRNP gene. GSS-type plaques do not
accompany the pathologic features of spongiform Recent evidence links the appearance of new variant
change. Familial CJD tends to have a mean age of on- Creutzfeldt-Jacob disease (vCJD) in humans to the con-
set about 12 years earlier than sporadic CJD. Neu- sumption of bovine-spongiform-encephalopathy con-
ropathologic features with respect to distribution and taminated cattle-derived products (Brown, 1997).
degree of spongiform change vary within and among Fewer than 100 cases have been described. The clini-
families. cal phenotype differs notably from CJD: it occurs pri-
marily in younger individuals and is commonly associ-
ated with psychiatric symptoms. Prominent ataxia is
Gerstmann-Sträussler-Scheinker Disease
another distinguishing clinical feature of vCJD. The
Gerstmann-Sträussler-Scheinker (GSS) was first de- neuropathologic hallmarks of vCJD are confluent
scribed as a familial disorder, but sporadic cases have spongiform change in the cerebellum, basal ganglia,
also been reported (DeArmand and Prusiner, 1997). and thalamus with marked thalamic gliosis (Ironside,
The disease is heralded by symptoms of ataxia, 1998). Amyloid plaques, called “florid plaques,” are
dysarthria, and hyporeflexia. Some patients may de- present in the cerebral cortex, especially in the occip-
tal lobe and cerebellum (Ironside, 1998). These struc-
tures are composed of a central core of PrP amyloid
surrounded by vacuoles suggesting petals of a flower
(Will, 2000).
Fatal Familial Insomnia

Familial and sporadic cases of this unusual prion dis-
ease have been identified throughout the world (Budka,
1998). In the most classic presentation, clinical symp-
toms and signs include insomnia dysautonomia, early
impairment of attention and vigilance, and memory and
motor deficits. The disease starts between 35 and 60
years of age, is inherited as an autosomic dominant
trait, and leads to death within 7–32 months. Neu-
FIGURE 5.8 Spongiform change in the cortex in a case of CJD. H&E
ropathologic examination reveals prominent neuronal
section shows vacuolation of the neuropil affecting all layers of the loss and gliosis involving the anterior ventral and
cerebral cortex. mediodorsal thalamic nuclei, with additional cerebral
cortical involvement in two cases (Mastrianni and DeArmond S.J., and Prusiner S.B. (1993). The neurochemistry of
Roos, 2000). The discrete topography of the lesions in prion diseases. J Neurochem 61:1589–1601.
DeArmond S.J., Mobley W.C., DeMott D.L., Barry R.A., Beckstead
fatal familial insomnia underscores the role of the thal- J.H., and Prusiner S.B. (1985). Identification of prion amyloid fil-
amus in the regulation of the sleep–wake cycle. Spon- aments in scrapie-infected brain. Cell 41:221–235.
giosis, which is usually found in prion diseases, is usu- DeArmond S.J. and Prusiner S.B. (1995). Etiology and pathogenesis
ally absent in fatal familial insomnia. An abnormal of prion diseases. Am J Pathol 146:785–811.
prion protein (PrPsc) is detected in the brain (Medori DeArmond S.J. and Prusiner SB. (1997). Prion diseases. In: Green-
field’s Neuropathology, 6th ed. (P. Lantos and D. Graham, eds.)
et al., 1992). There is a mutation at codon 178 of the Edward Arnold, London, pp. 235–280.
gene encoding this protein (Scaravilli, 2000). DeBiasi R. and Tyler K.L. (1999). Polymerse chain reaction in the
diagnosis and management of central nervous system infections.
Arch Neurol 56:1215–1219.
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and its topographic distribution. Acta Neuropathol 89:368–373.
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researchers and pathologists for nearly a century. In re- ceptibility in iatrogenic and sporadic Creutzfeldt-Jacob disease. J
cent years, unprecedented advances from diverse fields of Gen Virol 75:23–27.
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6 Neuropathology of acquired
immunodeficiency syndrome
CAROL K. PETITO
RETROVIRUS INFECTION OF THE CENTRAL CXCR4 (Border and Collman, 1997). Macrophage-
NERVOUS SYSTEM tropic (M-tropic) virus utilizes the CCR5 coreceptor
whereas T-lymphocyte-tropic (T-tropic) virus utilizes
Retroviruses are RNA viruses that contain a reverse tran- the CXCR4 chemokine coreceptor. Specific sequences
scriptase (RNA-dependent DNA polymerase) by which in the V3 loop of gp120 determine the coreceptor us-
they replicate and persist in cells as intermediate DNA age (Hoffman et al., 1999). The initial binding site for
proviruses. In humans and experimental animals, infec- viral gp 120 in astrocytes and neurons is unknown since
tions by these viruses are associated with neoplasms and both lack CD4 receptors (Kozlowski et al., 1991; Hao
a variety of neurologic disorders resulting from direct or et al., 1997). Galactosyl ceramide is one potential re-
indirect involvement of the central nervous system (CNS) ceptor since it binds to gp 120 in vitro and since its an-
(Johnson and McArthur, 1987). tibodies block HIV entry into astrocytes in vitro
Human T-cell lymphotropic virus type I (HTLV-1), (Harouse et al., 1989). A recent observation with im-
the retrovirus responsible for T-cell lymphomas and leu- portant implications for the mechanisms of neuronal
kemias, is associated with a chronic, slowly progressive injury is the identification of neuronal chemokine core-
myelopathy characterized by spastic paraparesis or ceptors (principally CXCR4 receptors) (Horuk et al.,
paraplegia, extensor plantar reflexes and hyperreflexia, 1997; Lavi et al., 1997), activation of which by T-tropic
and urinary incontinences; sensory disturbances are in- gp120, in culture, causes neuronal apoptosis (Hes-
frequent (Cartier et al., 1997). HTLV-1-associated selgesser et al., 1998).
myelopathy (HAM) is endemic in certain parts of the Viral tropism varies according to disease state and
tropics (Vemant et al., 1987) and Japan (Osame et al., tissue. In plasma, M-tropic, CCR5-using viruses pre-
1987a). Maternal, hereditary, and transfusion-acquired dominant until late-stage AIDS, when T-tropic viruses
transmissions may occur (Osame et al., 1987b; Gout et are more common. M-tropic viruses also are the pre-
al., 1990). HTLV-1 antigens and DNA, as well as anti- dominant subtypes in brain isolates.
HTLV-1 antibodies, are found in patients’ sera and cere- In the brain, productive infection is essentially con-
brospinal fluid (Bhagavati et al., 1988). Pathologic stud- fined to microglia and cells of monocytic lineage but
ies demonstrate lymphocytic inflammation of meninges, absent in neuroectodormal cells (Wiley et al., 1986;
perivascular spaces, and parenchyma of the spinal cord Koenig et al., 1986; Gabzuda et al., 1986). Astrocytes,
with loss of myelin and axons in the lateral and ante- and possibly neurons, may harbor a restricted, non-
rior columns (Akuzuki et al., 1988). productive or latent infection by HIV (Nuovo et al.,
Human immunodeficiency virus (HIV) is a member 1994; Saito et al., 1994; Tornatore et al., 1994; Ranki
of the lentivirus subfamily of retroviruses. Viral RNA, et al., 1995; Sharer et al., 1996; Brannagan et al., 1997;
reverse transcriptase, and structural core proteins form Torres-Muñoz et al., 2001). Such cells contain provi-
its inner core which, in turn, is surrounded by an outer ral DNA with or without limited expression of viral
bilipid membrane composed of viral transmembrane protein. Formation of new virions is absent.
(gp4l) and external membrane (gp120) glycoproteins
and components of the host plasma membrane (Hasel-
Clinical Manifestations of Human Immunodeficiency
tine et al., 1988). In most cells, HIV entry depends not
Virus Infection
only on the well-known interaction between viral
gp120 and host CD4 cell-surface molecules but also on Neurologic complications are common in patients with
host chemokine coreceptors—principally, CCR5 and HIV infection (Snider et al., 1983; Belman et al., 1985;
95
Epstein et al., 1985; Levy et al., 1985b; Brew et al., mentia (Achim et al., 1994; Wiley and Achim, 1994).
1988) and as many as 50% of patients have signs and Although HIV encephalitis may not be detected in all
symptoms of CNS dysfunction during the course of demented patients (Navia et al., 1986b; Glass et al.,
their illness. Myopathies and neuropathies also de- 1995; Brew et al., 1995), its absence may represent a
velop, although their clinical incidence is less clear. false-negative finding rather than implying alternative
Acute or subacute CNS syndromes are uncommon at mechanisms. Neuronal injury may be due to latent vi-
the time of seroconversion or before the onset of the ral infection or to indirect methods. Potential neuro-
acquired immunodeficiency virus syndrome (AIDS). toxins include viral proteins and cytokines, especially
Opportunistic infections, primary lymphoma, and tumor necrosis factor alpha (Price et al., 1988; Gen-
AIDS dementia complex (currently termed HIV-1-as- delman et al., 1994; Lipton, 1996). A common under-
sociated cognitive-motor disorder, or HIV-associated lying mechanism may be excitotoxicity due to activa-
dementia) are late manifestations of AIDS. tion of glutamate receptors and excessive Ca2 influx
HIV-associated dementia (HAD) is an AIDS-defining (Dreyer et al., 1990; Magnuson et al., 1995; Lipton,
illness and also an independent mortality risk factor in 1996; Muller et al., 1996). Alternatively, activation of
AIDS patients (Ellis et al., 1997). A triad of cognitive neuronal chemokine coreceptors, either by gp120 or
dysfunction, behavioral disturbances, and motor im- their respective cytokines, may lead to injury and death.
pairment is characteristic (Navia et al., 1986; McArthur Selective vulnerability to neuronal injury correlates
et al., 1993) and initial mental slowing, confusion, and with expression of neuronal chemokine coreceptor
memory loss proceed to frank dementia. Patients may CXCR4, which increases with AIDS and with HIVE
have organic psychoses and hallucinations. Motor im- (Petito et al., 2001).
pairment includes paraparesis or quadriparesis, gait
ataxia, incoordination, and postural tremor. In adults,
Pathological Manifestations of Human
some or all of the motor dysfunction may be related to
Immunodeficiency Virus Infection
coexistent vacuolar myelopathy, whereas in children,
in whom vacuolar myelopathy is rare, the motor dys- During the first decade of the HIV epidemic, central
function is more likely due to HIV leukoencephalopa- nervous system abnormalities were encountered in up
thy in the centrum semiovale. Its anatomical localiza- to 80% of all autopsies. Encephalitis due to HIV or cy-
tion is likely to be subcortical regions including basal tomegalovirus (CMV) predominated and other oppor-
ganglia and, in some cases, the centrum semiovale. tunistic infections (OIs), lymphoma, and metabolic dis-
Dementia was present in approximately one-third of orders also were seen. Table 6.1 outlines their autopsy
patients in Snider’s initial report of the neurologic com- incidence between 1983 and 1986 (Petito et al., 1986),
plications of AIDS (1983) and subsequent studies have the distribution of which is similar to that in other post-
found an incidence as high as 50%. It is rare in asymp- mortem studies performed during that time (Anders et
tomatic HIV-infected patients and only a few cases have al., 1986). Current therapies have altered the incidence
been described in which HAD is the first manifestation of CNS disease. Brain lymphomas have increased and
of HIV infection and AIDS (Mirra et al., 1986; Petito HIV encephalitis has decreased (Gray et al., 1991;
et al., 1986; Navia and Price, 1987). The current effi- Rhodes, 1993; Nicolato et al., 1995) and our own ex-
cacy of highly active antiretroviral therapy (HAART) perience at a large county hospital confirms these ob-
has reduced the incidence of HAD but this reduction servations (Table 6.2). However, Baldeweg et al. (1998)
may only be temporary and disappear with the emer- suggest that the beneficial effects of antiretroviral ther-
gence of resistant virus. apies on HIVE are transient since reduced incidences
Children with HAD have a gradual loss of develop- of HIV dementia and opportunistic infections occur
mental milestones, psychomotor retardation, and spas- only during the first 18 months of therapy.
tic paraparesis or quadriparesis (Belman et al., 1985; Neurosurgical biopsies primarily include those dis-
Epstein et al., 1985). Symptoms and signs are unusual orders causing focal lesions; thus toxoplasmosis, pri-
before 6 months of age. Microcephaly and facial dys- mary CNS lymphoma, and progressive multifocal
morphism also have been noted. Basal ganglia calcifi- leukoencephalopathy (PML) predominate (Iacoangeli
cation can be visualized on head CT scans (Belman, et al., 1994). Children with AIDS have HIVE and HIV-
1986). Like adults, HIV-infected children have cerebral related psychomotor retardation or dementia. Oppor-
atrophy and mild ventricular dilation. tunistic infections are infrequent and primary brain
The pathogenesis of HAD is not entirely understood. lymphoma or cerebrovascular disorders are the usual
Productive viral infection (i.e., HIV encephalitis cause of focal brain lesions (Burns, 1992). Large ves-
[HIVE]) is important and viral load correlates with de- sel arteropathies, possibly related to HIV, appear to be
6: NEUROPATHOLOGY OF ACQUIRED IMMUNODEFICIENCY SYNDROME 97
TABLE 6.1 Neuropathology of Acquired Immunodeficiency Syndrome (1980–1985)

Autopsy Series (%) Surgical Biopsies (%)
(153 patients) (57 biopsies in 55 patients)
Virus
Human immunodeficiency virus 28
Cytomegalovirus 26
Progressive multifocal leukoencephalitis 2 16
Varicella-zoster virus 2
Herpes simplex virus 2
Microglial nodule encephalitis 17
Toxoplasma gondi 10 16
Fungus
Cryptococcus 3
Candida 1
Histoplasma 1
Neoplasm
Primary lymphoma 6 19
Secondary (systemic) lymphoma 2
Vacuolar myelopathy 30
Normal, metabolic, or non-specific changes 20 19
Inflammation, necrosis 17
Source: Modified from Petito et al. (1986).
confined to the pediatric population (Dubrovsky et al., nosis may not be possible even with the help of com-
1998). mercially available antisera and circular DNA (cDNA)
For a number of reasons, the pathological diagnosis probes that work well in formalin-fixed paraffin-
of the HIV-related disorders may be difficult, especially embedded tissue. The location of the microglial nod-
on small tissue samples obtained for surgical biopsy. ules (see later discussion) may suggest an etiology but,
First, the CNS response to many of these infections is by itself, is insufficient for a diagnosis. The differential
similar. Microglial nodules composed of activated mi- diagnosis between inflammation and lymphomas can
croglial cells (rod cells), macrophages, reactive astro- be difficult on small biopsy fragments since chronic in-
cytes, and chronic inflammation in the leptomeninges flammation is typically seen in CNS lymphomas and
and perivascular spaces of the brain are seen with in- since viral infections can be accompanied by some nu-
fection with HIV, herpes viruses, and toxoplasmosis. If clear atypia in the lymphocytic infiltrates. Studies with
the characteristic multinucleated cells, viral inclusions, cell surface markers for B and T lymphocytes and for
or microorganisms are not present, a definitive diag- IgG kappa and lambda chains are useful, especially if
TABLE 6.2 Autopsy Incidence of CNS Disease in AIDS over Time

Year HIV VM CMV Toxo Lymph PML Fungi
1984–1985 25% 7% 13% 12% 4% 2% 13%

(n 52)
1992–1996 24% 11% 10% 14% 11% 1% 5%
(n 160)
1997–1998 12% 6% 9% 9% 12% 6% 6%
(n 33)
1999–2001 8% 0 1% 11% 6% 0 11%
(n 65)
HIV, human immunodeficiency virus; VM, vacuolar myelopathy; CMV, cytomegalovirus; Tox, toxoplasmosis; Lymph, lymphoma; PML, progressive multifo-
cal leukoencephalopathy.
frozen tissue is available. Gene rearrangement studies

from frozen or paraffin-embedded material can help
distinguish lymphoma from inflammation. Lastly, the
specimen received for histological examination, espe-
cially if small, may not contain diagnostic tissue
(Hirschfeld et al., 1994).
Human Immunodeficiency Virus Encephalitis

In 1983, Snider et al. (1983) described a subacute en-
cephalitis in patients with HAD that was characterized
by cerebral atrophy, ventricular dilation, diffuse or
perivascular myelin loss, occasional multinucleated
cells, and multiple poorly circumscribed microglial nod-
ules in subcortical locations. The relationship between FIGURE 6.1 Cortical atrophy and ventricular dilation in 45-year-old
this subacute encephalitis and HIV infection in brain woman with 4 year history of AIDS.
was firmly established within 2 years when virus was
detected in the CNS by Southern blot in situ hy-
bridization (Shaw et al., 1985), direct isolation (Levy erally encountered in viral infection. The inflammatory
et al., 1985a; Ho et al., 1985), and by detection of anti- nodules may lie within brain parenchyma (Fig. 6.3A)
HIV IgG in cerebrospinal fluid (Resnick et al., 1985). or in paravascular regions (Fig. 6.3B). In addition,
Electron microscopy, in situ hybridization, and im- HIVE has characteristic multinucleated or multinucle-
munohistochemistry have detected HIV in macro- ated giant cells, the presence of which is sufficient to
phages and multinucleated cells (Epstein et al., 1985; establish a diagnosis of HIV encephalitis (Sharer et al.,
Sharer et al., 1985; Koenig et al., 1986; Wiley et al., 1985; Budka et al., 1991) (Fig. 6.3B, 6.4A). Immuno-
1986; de la Monte et al., 1987; Budka, 1990; Sharer, reactivity for viral antigens such as gp41 (Fig. 6.4B)
1992). or p24 assists in establishing the diagnosis of HIV
HIV enters the CNS around the time of seroconver- encephalitis.
sion and can be cultured from the CSF in up to 80% The microglial nodules, multinucleated cells, and HIV
of cases. It is likely that actual brain infection does not antigen are numerous in the basal ganglia (Petito et al.,
occur until the onset of AIDS and immunodeficiency 1986; Achim et al., 1994) although a subset of patients
since autopsy studies rarely or never detect amplified have HIV-related lesions concentrated in the subcortical
HIV DNA or HIV encephalitis in brains of HIV- white matter (HIV leukoencephalitis) (Kleiheus et al.,
infected asymptomatic patients (Davis et al., 1992; Bell 1985). In severe cases, HIVE is associated with focal re-
et al., 1993; Sinclair et al., 1994). A high frequency of
HIV-infected dendritic cells in the choroid plexus
stroma of AIDS pateints suggests that this structure
could be a site of hematogeneous dissemination and the
identification of HIV-infected cells in the choroid
plexus of HIV-infected asymptomatic patients supports
this hypothesis of a CNS reservoir of HIV (Falangola
et al., 1995; Chen et al., 2000).
Gross examination of brains with HIVE often reveals
cortical atrophy with widened sulci and ventricular di-
lation (Fig. 6.1). A gray discoloration of the centrum
semiovale occasionally may be encountered. In chil-
dren, white matter atrophy can be severe and associ-
ated with grossly visible atrophy of the corpus callo-
sum and internal capsule (Fig. 6.2). Microscopically,
multiple microglial nodules in subcortical locations and FIGURE 6.2 Marked atrophy of centrum semiovale and corpus callo-
a sparse lymphocytic infiltrate in leptomeninges and sum and mild atrophy of cerebral cortex in 4-month-old child with
perivascular spaces are typical and similar to those gen- maternally acquired AIDS.
A A
B B
FIGURE 6.3 Inflammatory infiltrates of HIV encephalitis include mi- FIGURE 6.4 (A) Multinucleated giant cell in human immunodeficiency
croglial nodules (A) or paravascular infiltrates (B). Multinucleated virus (HIV) encephalitis. (B) Positive immunoreactivity for HIV gp41
cells are common, as seen in B. in monocytes and multinucleated cells of a microglial nodule.
gions of myelin pallor or necrosis in the white matter

(Fig. 6.5) and diffuse or focal neuronal loss and reactive
astrocytosis in the gray matter. Calcifications of blood
vessels and adjacent parenchyma develops in the basal
ganglia in children with AIDS and rarely may be en-
countered in brains of adults as well (Fig. 6.6). Microglial
nodules also can be encountered in the brain stem, the
cerebellum and, less frequently, the spinal cord. Al-
though the cerebral cortex appears normal with mild dis-
ease, neuronal loss and gliosis are prominent in cases of
widespread HIVE, and a diffuse synaptic and dendritic
loss in the cerebral cortex has also been described (Wi-
ley et al., 1991; Masliah et al., 1997). Diffuse myelin
pallor is common and associated with astrocytosis, mi-
croglial cell proliferation, perivascular macrophages, and
sparse lymphocytic infiltration.
Some of the pathologic changes that are associated
with HIVE may be seen in its absence. Gray and FIGURE 6.5 Focal myelin loss in human immunodeficiency virus en-
coworkers (1992) described 11 HIV-positive asympto- cephalitis. Luxol fast-blue and hematoxylin and eosin.
TABLE 6.3 Spinal Cord Diseases in 178 Patients*

with Acquired Immunodeficiency Syndrome
(%)†
Vacuolar myelopathy 29
Gracile tract degeneration 1
Microglial nodule myelitis 10
HIV myelitis 5
Herpes virus myelitis 7
Cytomegalovirus 5
Herpes simplex virus 2
Varicella-zoster virus 1
Infectious myelitis (others) 7
FIGURE6.6 Basal ganglia calcification in blood vessels and paren- Fungal 4
chyma in human immunodeficiency virus encephalitis. Bacterial 2
Lymphoma 2
Normal 52
matic patients in whom granular ependymitis, lym-
Source: Modified from Petito (1993).
phocytic meningitis with perivascular inflammation, *Eight of the patients were children.
myelin pallor with reactive astrocytosis, and mi- †The total percentage is greater than 100% because some patients had more
than one disease.

croglial proliferation were common. It is possible that
the inflammatory infiltrates were related to asymp-
tomatic HIV meningitis. In contrast, the myelin pal-
lor and gliosis may be caused by an open blood–brain occurred in tandem with brain infection (Table 6.3).
barrier found in AIDS patients without other CNS le- The current autopsy incidence of spinal cord lesions is
sions, including HIVE (Petito and Cash, 1992; Power less than 5%.
et al., 1993).
Like many infectious, metabolic and degenerative
diseases of the CNS, neuronal death in HIV infection Vacuolar Myelopathy
develops by apoptotic mechanisms (Adle-Biassett et al., Vacuolar myelopathy (VM) is characterized by spongy
1995; Gelbard et al., 1995; Petito and Roberts, 1995; vacuolation of myelin sheets in the posterior and lat-
An et al., 1996). Potential stimuli include tumor ne- eral columns (Fig. 6.7) (Goldstick et al., 1985; Petito
crosis factor and viral glycoproteins, including gp120 et al., 1985). The mid- to lower thoracic spinal cord
and tat, all of which cause neuronal apoptosis under is most severely involved. In many cases, the fascicu-
experimental conditions.
Spinal Cord Diseases

The clinical incidence of myelopathies in HIV infection
and AIDS is low, and large series outlining neurologic
complications in AIDS describe myelopathies in less
than 10% of patients. (See Petito, 1993, for review.)
Vacuolar myelopathy is the most common spinal cord
disorder and often is symptomatic. Necrotizing myelitis
due to cytomegalovirus (CMV), herpes simplex virus
(HSV)-CMV, or varicella-zoster virus (VZV) cause neu-
rologic dysfunction, but these disorders are less fre-
quent than vacuolar myelopathy.
In early autopsy studies, the incidence of spinal cord
disease in AIDS was high and 30% or more of patients
had vacuolar myelopathy. Not surprising, infections, FIGURE 6.7 Severe vacuolar myelopathy involving entire white mat-
including HIV myelitis, were second in frequency and ter of spinal cord as illustrated in Petito et al. (1985).
FIGURE 6.8 Scattered lipid-laden macrophages within vacuoles in pa- FIGURE6.9 Gracile tract degeneration in AIDS. Luxol fast-blue and
tient with moderately severe vacuolar myelopathy. hematoxylin and eosin.
lus gracilis is more severely involved than the lateral Gracile Tract Degeneration
or anterior columns. Vacuolation is confined to cen-
Gracile tract degeneration (GTD) was first described at
tral myelin and, when present at the posterior nerve
autopsy in four patients with a distal sensory polyneu-
root entry zone, abruptly terminates at the junction
ropathy (Rance et al., 1988). It is characterized patho-
between central and peripheral myelin. Macrophage
logically by loss of myelinated axons in the medial fas-
infiltration and reactive astrocytosis are sparse and are
ciculus gracilis (Fig. 6.9). It is an uncommon disorder;
proportional to the severity of the disease (Fig. 6.8).
in our autopsy series, GTD alone had an incidence of
Axons are relatively preserved in mild cases. With
approximately 2%. Localization to the fasciculus gra-
more severe involvement, occasional axonal spheroids
cilis suggests disease in the posterior roots, dorsal root
are encountered and Wallerian degeneration can be
ganglia, or peripheral nerves at lumbosacral levels.
present at distal cord segments. Clinical symptoms of
vacuolar myelopathy correlate with the anatomic lo-
cation of the lesions and with the severity of the vac-
DISEASES OF PERIPHERAL NERVE AND MUSCLE
uolation (Table 6.4).
IN AIDS
The etiology of vacuolar myelopathy has been con-
troversial. Since HIV antigen or nuclear acids in mac-
Peripheral Neuropathies
rophages and multinucleated cells of HIV are absent
(Rosenblum et al., 1989; Petito et al., 1994), the close A variety of peripheral neuropathies occur in AIDS pa-
pathological resemblance to the myelopathy of vitamin tients. Their clinical prevalence is not clear but ranges
B12 deficiency suggest a metabolic disorder and have from 5% to 38% (Simpson and Bender, 1988) and in-
promoted recent trials with methionine (DiRocco et al., creases with disease state. Gastaut et al. (1989) found
1998). Initial studies show a beneficial response, sup- electrical evidence of nerve damage in 40% of asymp-
porting the hypothesis that VM is a metabolic rather tomatic HIV-infected patients, 90% of AIDS-related
than an infectious disease. complex, and 100% of AIDS patients. The pathologic
TABLE 6.4 Clinical Features in 20 Patients with Vacuolar Myelopathy*

Upper Motor
Disease Severity Leg Weakness Neuron Signs Ataxia Incontinence
Mild (8) 1 1 3
Moderate (7) 5 4 3 5
Severe (5) 5 4 4 4
Total (20) 11 8 8 12
Source: Modified from Petito CK et al. (1985).

*Numbers in parentheses refer to total number in each category of disease severity.
changes of the demyelinating neuropathies, sensory ax- al., 1993). Since AIDS patients with a proximal my-
onopathies, and vasculitic neuropathies are similar to opathy often have both inflammation and AZT-related
those seen in non-AIDS patients. Distal symmetrical mitochondrial changes, the therapeutic decision to
polyneuropathy (painful sensory neuropathy) is rela- withhold AZT or institute steroid therapy can be dif-
tively common and its severity correlates with plasma ficult (Simpson and Wolfe, 1991).
viral load (Simpson et al., 2002). In addition, a dose-
related neuropathy has been associated with some an-
tiretroviral therapy (Moyle and Salder, 1998). OPPORTUNISTIC INFECTIONS AND
LYMPHOMAS IN AIDS
Myopathies
Many neurologic disorders in AIDS patients are sec-
Muscle weakness is common in AIDS patients: one se- ondary to the overwhelming immunosuppression that
ries found an incidence of 20% in patients without azi- develops in these patients with the onset of AIDS. Com-
dothymidine therapy (Simpson and Bender, 1988). mon opportunistic infections include CMV, toxoplas-
Pathologic findings include polymyositis, noninflam- mosis, Cryptococcus neoformans, and progressive
matory myopathy with muscle necrosis, and severe type multifocal leukoencephalopathy (PML). Tuberculosis,
II muscle atrophy, related perhaps to disuse atrophy varicella-zoster virus (VZV), herpes simplex virus
(Fig. 6.10). Nemaline rods, vesicular changes, and cy- (HSV), syphilis, and others also have been described.
toplasmic bodies are common albeit nonspecific The following section highlights several of the more
changes. CD8 lymphocytes and macrophages, the common opportunistic infections and lymphoma seen
major inflammatory components in HIV-related myosi- with AIDS. The reader is referred to other chapters in
tis, surround and invade muscle fibers expressing ma- this book for additional information concerning infec-
jor histocompatibility complex type I antigens (Illa et tions and lymphomas of the CNS.
al., 1991).
Zidovudine (AZT) can cause a mitochondrial my-
Central Nervous System Toxoplasmosis
opathy with impaired cytochrome c oxidase activity
(Dalakas et al., 1990; Mhiri et al., 1991). Staining with Toxoplasmosis is the most frequent cause of focal or
modified trichrome stain on frozen sections reveals ac- multifocal symptoms and signs in AIDS patients. For-
cumulations of red dots representing mitochondria in tunately, unlike most AIDS-associated diseases of the
the subsarcolemmal region or filling the atrophic fibers CNS, it successfully responds to appropriate therapy. It
(Fig. 6.11A). Ultrasound examination reveals pro- usually is due to reactivation of a previously acquired
liferation, abnormal shapes, and intramitochondrial infection of Toxoplasma gondii rather than to newly
paracrystalline inclusions (Fig. 6.11B). Cytochrome c acquired infection (Scrittmatter et al., 1992). Thus, the
oxidase histochemistry reveals variable numbers of incidence of cerebral toxoplasmosis depends in part on
muscle fibers lacking the enzyme activity (Chariot et the regional prevalence of acquired infection. Patients
A B
FIGURE 6.10 Polymyositis in AIDS. (A) Atrophy, increased endomysial connective tissue and inflamma-
tion. (B) Phagocytosis and chronic inflammation.
A who fail to respond to treatment. The usual cause is an-

other lesion, typically CNS lymphoma, although drug-
resistant organisms can also be responsible.
The gross and microscopic appearance of untreated
toxoplasmosis varies, in part, with the immune status
of the patient (Falangola et al., 1994). When cerebral
toxoplasmosis is the AIDS-defining illness, inflamma-
tion and even fibrous capsule formation are prominent
and mimic bacterial or fungal abscesses. Since this ap-
pearance is more frequent in surgical biopsy than au-
topsy material, and since organisms may be difficult to
detect, immunohistochemical studies for Toxoplasma
gondii may be warranted when the etiology of a brain
abscess is not otherwise determined. This may have spe-
B cial importance when the HIV status of a patient is un-
known. When untreated toxoplasmosis is present in a
severely immunocompromised patient, poorly circum-
scribed regions of necrosis are present and predominate
in gray matter structures (Fig. 6.12A). Hemorrhage is
variable but may be extensive. Cortical lesions usually
communicate with the overlying subarachnoid space.
Microscopic examination shows regions of necrosis
with or without hemorrhage and associated with sparse
inflammation, usually mononuclear, and lipid-laden
macrophages. Some patients have a prominent hyper-
trophic vasculitis that may contribute to the necrosis
and hemorrhage (Fig. 6.13B) (Huang and Chou, 1988).
Extracellular tachyzoites in the parenchyma (Fig.
FIGURE 6.11 (A) Ragged red fibers in AZT myopathy (modified
6.14A) and cell cytoplasm (pseudocysts) are numerous
trichrome stain). (B) Electron microscopy of paracrystalline inclu-
sions within mitochondria. although occasional encysted bradyzoites are found at
the periphery of the necrotic regions and in adjacent
brain. Immunohistochemical detection of Toxoplasma
generally present with focal neurological signs and antigens is useful in demonstrating the organisms (Fig.
imaging studies demonstrate multiple, usually contrast- 6.14B). Untreated toxoplasmosis also can be manifest
enhancing, lesions in the cerebral cortex, basal ganglia, as multiple compact microglial nodules containing ex-
and cerebellum (Navia et al., 1986c). Rarely, CNS toxo- tracellular or encysted organisms (Gray et al., 1989) or
plasmosis is confined to the choroid plexus (Falangola as a primary infection of the choroid plexus (Falangola
et al., 1993; Eggers et al., 1995). Utilization of thallium- et al., 1993).
201 brain single-photon-emission computed tomogra- Organization of the lesions and eradication of the or-
phy (SPECT) assists in differentiating toxoplasmosis ganisms follow appropriate therapy (Navia et al.,
from lymphoma (Ruiz et al., 1994; Villringer et al., 1986c). Gross examination shows well-circumscribed
1995; Lorberboym et al., 1996). Gene amplification of areas of firm, yellow–white necrosis surrounded by a
CSF is positive in half of the cases provided it is per- thin yellow rim (Fig. 6.12B) composed of lipid-laden
formed prior to or within 1 week of therapy (Cingolani macrophages and thin-walled blood vessels. Such or-
et al., 1996). Serum toxoplasmosis IgG antibody titers ganization develops within several weeks of therapy.
are elevated, although rarely they are low or fail to rise Tachyzoites are sparse although encysted bradyzoites
during the course of the CNS illness. In the setting of may be encountered. With time, the necrotic center is
suspected toxoplasmosis, a therapeutic trial of pyri- absorbed and is replaced by a cystic cavity surrounded
methamine and sulfadiazine is instituted (Israelski and by fibrillary astrocytes (Fig. 6.12C). At this point, the
Remington, 1988). If the lesions are due to toxoplas- differential diagnosis between a healed cerebral infarct
mosis, they will readily respond to therapy and clini- and a healed Toxoplasma abscess arises since both are
cally and radiographic improvement is apparent within cystic cavities surrounded by gliotic brain and since
several weeks. Cerebral biopsy is reserved for patients Toxoplasma organisms are usually absent. Dystrophic
A Cytomegalovirus Encephalomyelitis
Cytomegalovirus (CMV) infection of the CNS is com-
mon in patients with AIDS but is rarely symptomatic.
During the initial 10 years of the epidemic, it was seen
at autopsy in one-third of all AIDS patients, appearing
as a microglial nodule encephalitis (Morgello et al.,
1987; Vinters et al., 1989). In contrast to the microglial
nodules of HIV, those due to CMV are compact and
frequent in the cerebral cortex. Viral inclusions are
found in about 10% of the microglial nodules. Both
Cowdry type A intranuclear inclusions and small ba-
sophilic cytoplasmic inclusions are present in an en-
larged cell, which can be either astrocytic or neuronal
B (Fig. 6.15).
A minority of patients with CMV in the CNS de-
velop hemorrhagic necrotizing lesions that present as a
ventriculitis (Fig. 6.16, 6.17), rhombomyelitis or focal
lesions (Morgello et al., 1987; Moulignier et al., 1996).
CMV myelitis often is associated with cranial and
FIGURE 6.12 Toxoplasma gondii abscess. (A) Untreated, right cere-

bellum. (B) Organizing, left thalamus. (C) Cystic lesions in cerebral
cortex, communicating with overlying subarachnoid space.
calcifications in and adjacent to the cystic regions are

not unusual. In contrast to chronic bacterial and fun-
gal abscesses, fibrous encapsulation is rare, although it FIGURE 6.13 Toxoplasmosis. (A) Necrosis with mild inflammation
may be seen in patients whose initial manifestation of and solitary Toxoplasma gondii cyst. (B) Endarteritis and marked
AIDS is CNS toxoplasmosis. adventitial fibrosis and inflammation.
A B
FIGURE6.14 Toxoplasmosis. (A) Encysted bradyzoites and extracellular tachyzoites. (B) Positive in-
imunoreactivity of cysts and tachyzoites.
spinal radiculitis (Grafe and Wiley, 1989). Coinfection patients and coexisted with CMV infection. These pa-
with HSV is common when CMV lesions are hemor- tients had hemorrhagic necrotizing ventriculitis associ-
rhagic and necrotizing. ated with encephalomyeloradiculitis. Large wedge-
CMV may infect the central nervous system via mul- shaped regions of acute necrosis were present in brain
tiple mechanisms. Hematogeneous spread is the prob- stem and spinal cord and were associated with the
able initial mode of entry, whereas secondary cere- CMV inclusions as well as with the more typical
brospinal fluid spread is likely in the patients with Cowdry type A intranuclear inclusions of HSV. HSV
diffuse ventriculomyelitis. Retrograde spread from also can be associated clinically and pathologically with
CMV infection of peripheral nerves is another mecha- myelitis alone.
nism of entry and may be present in patients with CMV Varicella-zoster virus damages the central nervous
neuritis and radiculitis. system in several ways. It can produce a multifocal de-
myelinating leukoencephalitis (Fig. 6.18) (Morgello et
al., 1987) mimicking the multifocal demyelinating le-
Infection with Other Herpes Viruses
sions of PML. This is similar to the VZV leukoen-
HSV and VZV are infrequent in patients with AIDS cephalitis initially described in immunosuppressed non-
but, when present, usually are symptomatic. In our AIDS patients by Horten et al. (1981). VZV can infect
early autopsy series, HSV was present in 2% of blood vessels and produce a vasculopathy with sec-
FIGURE 6.15 Cytomegalovirus. Microglial nodule with enlarged cell FIGURE6.16 Cytomegalovirus ventriculitis. Hemorrhagic necrosis of
containing cytomegalovirus intranuclear inclusion. ependymal lining.
A B
FIGURE 6.17 (A) Numerous cytomegalovirus inclusions in subependymal region. (B) Immunoreactivity
for CMV antigens.
ondary infarction (Amlie-Lefond, et al., 1995). VZV sions are infrequent. Inflammation can be prominent
causes a myelitis in patients with cutaneous herpes when PML develops early in the course of AIDS, when
zoster. Finally, trigeminal VZV involving the conjunc- the immune system is less compromised (Hair et al.,
tiva can cause retinitis, optic neuritis, and a secondary 1992), and may account for those cases with contrast
transsynaptic infection of the lateral geniculate bodies enhancement.
and optic radiations (Rostad et al., 1989).
Primary Central Nervous System Lymphoma
Progressive Multifocal Leukoencephalopathy
Primary brain lymphoma is present in approximately
The gross and microscopic features of PML in AIDS 5% of AIDS patients examined at autopsy. Its clinical
are similar to those found in immunocompromised and pathologic features are similar to those found in
non-AIDS patients with PML, although the viral in- non-AIDS patients (So et al., 1986). Gross appearance
clusions tend to be more numerous and necrosis and is variable and includes: diffusely infiltrating lesions re-
perivascular inflammation may be more pronounced sembling infiltrating gliomas (Fig. 6.19A); carcinomas
(Kleiheus et al., 1985; Aksamit et al., 1990). CT and or Toxoplasma abscesses; or poorly demarcated ne-
MRI scans characteristically show multifocal regions of crotic regions (Fig. 6.19B) that may be intensely hem-
demyelination. Contrast-enhanced lesions or mass le- orrhagic. Camilleri-Broet et al. (1997) studied 51 AIDS-
A B
FIGURE 6.18 Varicella-zoster virus leukoencephalitis, with peripheral demyelination and central necro-
sis. (A) Luxol fast blue and hematoxylin and eosin. (B) Intranuclear Cowdry type A inclusions of
varicella-zoster virus.
A B
FIGURE 6.19 Central nervous system lymphoma. (A) Diffuse infiltration with expansion of centrum semi-
ovale. (B) Poorly circumscribed regions of necrosis in cortex and basal ganglia.
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7 Injuries to the brain and spinal cord
associated with ischemia
JULIO H. GARCIA AND HERNANDO MENA
In many neuropathology textbooks the chapter enti- in the young are also covered in separate sections of
tled “Cerebrovascular Diseases” includes a description this chapter.
of three interrelated groups of diseases: ischemic in- Stroke is a term used in the Anglo-Saxon literature
juries, spontaneous parenchymal–subarachnoid hem- with two distinct meanings:
orrhages, and diseases of the blood vessels. The latter
1. Strokes are the third most common cause of death
two topics are covered in a separate section of this
and the leading cause of disability in the United States.
book. This chapter only contains information on the
In this context, stroke means any of a large group of
neuropathology of ischemic disorders of the central
diseases of the CNS that have a “vascular” etiology.
nervous system (CNS). Circulatory disorders charac-
Regardless of geographic location the proportional dis-
terized by ischemia can be separated according to their
tribution of strokes is very similar: nearly 75% are of
etiology into two large categories: (1) those affecting
ischemic origin; the rest are hemorrhagic and primar-
the CNS in a global manner and (2) those produced
ily originate either in the brain parenchyma or in the
by the occlusion of one artery. The former condition
subarachnoid space.
is referred to as global cerebral ischemia whereas the
2. Clinicians use the word stroke to mean that the
occlusion of a single vessel creates a condition of fo-
usually sudden, abrupt appearance of a discrete or fo-
cal ischemia or a situation in which the circulatory ab-
cal neurological deficit such as monocular blindness,
normality primarily affects the territory normally
dysphasia, or localized motor/sensory deficits has a pre-
supplied by the occluded vessel. The clinical manifes-
sumptive “vascular” etiology.
tations of focal ischemia (secondary to an arterial oc-
clusion) are commonly known as a stroke, a designa- Two facts justify the use of stroke as an admitting
tion that is not appropriate for the clinical expressions or initial diagnosis: (1) Clinical evaluation alone can-
of global cerebral ischemia. Instead of the localized not distinguish between ischemic and hemorrhagic le-
neurologic deficit (such as monomelic paresis, for ex- sions; this makes neuroimaging of stroke victims es-
ample) that accompanies an arterial occlusion, patients sential before the diagnosis and appropriate treatment
suffering severe hemodynamic crises may complain of of the individual patient can be started. (2) However,
“light-headedness” or may become unconscious. The several hours must elapse before the lesions produced
pathologic features of the injuries affecting the brain by ischemia become fully visible on neuroimaging eval-
and produced by deficient blood flow (or by insuffi- uations based on the application of conventional CT
cient oxygenation) vary according to the etiology of or MRI. Therefore, during the very early stages of the
the ischemic event (hemodynamic versus vascular), the disease process (or stroke) the main application of CT
age of the person, and the type of vessel involved scanning is to rule out intracranial bleeding. In contrast
(artery, arteriole, veins/sinuses). Also, the severity of to the subtle changes produced by ischemia, in the ini-
the ischemia (measured in terms of percentage decrease tial hours hemorrhages (even small ones) can be easily
of blood flow) and duration of the event influence the detected with CT scan.
resulting patterns of tissue injury.
This chapter describes selected features of lesions af-
fecting the brain and spinal cord as a consequence of DEFINITION OF ISCHEMIA: CLASSIFICATIONS
hemodynamic crises, arterial occlusions, and venous/
sinus thromboses. The topics of subcortical leukoen- Ischemia describes the condition characterized by a sup-
cephalopathy, spinal cord ischemic injury, and stroke ply of blood that is insufficient to maintain cellular
112
7: ISCHEMIC CNS INJURIES 113
functions. The normal average cerebral blood flow, or TABLE 7.1 Conditions Associated with Global
CBF (55 mL/100 g of tissue per minute) can be modi- Ischemic/Hypoxic Injury to the Brain
fied in a manner such that only moderate ischemia (15
Transient cardiac arrest
mL/100 g of tissue per minute) develops. This condi-
Arterial hypotension (to levels lower than the limits of
tion is compatible with functional restitution following autoregulation)
the recovery of the normal CBF. Severe ischemia (10
Strangulation
mL/100 g of tissue per minute) leads to irreversible cell
Near drowning
injury within a few minutes of its inception. A chrono-
Carbon monoxide poisoning
logic difference exists between the time when the func-
tional deficit (secondary to ischemia) appears and the Increased intracranial pressure (as occurs after closed-head trauma)
time when the irreversible damage to the tissue becomes Vasospasm (following subarachnoid hemorrhage)
demonstrable. The more moderate the degree of isch-
emia, the more prolonged this chronological difference
becomes.
The mechanism responsible for inducing ischemia ischemia in survivors of serious hemodynamic crises.
may affect only one area or region of the brain (local Despite the global or systemic nature of the ischemic
ischemia) or may simultaneously affect the entire brain injury, specific sites of the brain are selectively or pref-
(global ischemia). The most common causes of global erentially injured in many of these cases. This discrim-
ischemia are conditions characterized by hemodynamic inating pattern of injury can be partly explained by the
crises such as arterial hypotension and transient car- architecture of the arterial blood supply, which creates
diac arrest. Focal ischemia, secondary to an arterial oc- arterial border zones or regional watersheds. At these
clusion, results in severe tissue injury to areas that are sites the levels of blood flow (during the hypotensive
topographically distant from the site of the collateral crisis) are lower than in the rest of the brain and this
anastomoses (core or center of the arterial territory) explains their selective involvement. Arterial boundary
and in moderate tissue injury to regions where the CBF (or border) zones (ABZs), also called watersheds, exist
is better preserved (penumbra or margin of the isch- on the dorsal surface of the cerebral hemispheres. These
emic area) as a reflection of the proximity of these re- watersheds correspond to the terminal territories of the
gions to collateral anastomoses. anterior, middle, and posterior cerebral arteries. ABZs
also exist in the cerebellum and in the spinal cord.
Given a situation in which the vessels are symmetri-
cally intact, an episode of severe hypotension will re-
BRAIN INJURIES SECONDARY TO CONDITIONS sult in brain damage that is more pronounced at these
CAUSING GLOBAL ISCHEMIA ABZs.
Additional variations in the topography of brain sites
Clinical situations in which the whole brain is affected that become selectively injured following global isch-
by ischemia are those characterized by either transient emia cannot be explained by regional differences in the
cardiac arrest or by a decrease in mean arterial blood blood flow because these sites (e.g., the Purkinje cell
pressure (MABP) to levels below the limits necessary layer of the cerebellum) are not included in one single
to maintain autoregulation. This term applies to mech- arterial territory. The selective involvement of neurons
anisms that maintain CBF constant despite changes in located at these vulnerable sites is attributed to some
systemic pressure; in normotensive persons, autoregu- as-yet-undefined intrinsic attributes of the cell, which
latory mechanisms remain effective at MABP of 45–170 in some textbooks are covered under the term patho-
mmHg. Some of the conditions in which autoregula- klysis.
tory mechanisms are expected to become inadequate to In addition to the ABZs, brain areas that are selec-
maintain brain perfusion at normal levels are listed in tively vulnerable to the effects of global ischemia are
Table 7.1. located in the hippocampus (CA1 and CA4 areas), in
Despite the fact that under conditions of hemody- the cerebellum (Purkinje’s cell layer), in the cerebral
namic crises or hypoxia the entire brain and spinal cord neocortex (layers 3-4), in the basal ganglia (globus pal-
are simultaneously exposed to the same insult, selected lidus), and in the thalamus (reticular nucleus) (Ross and
portions of the brain undergo earlier and more severe Graham, 1993). The increased vulnerability of the thal-
damage compared to the rest of the brain. amic reticular nucleus to the effects of global ischemia
Selective vulnerability applies to the predictable topo- is frequently reflected in persistent cognitive deficits, in
graphic distribution of brain sites that are injured by attentional processes which are apparent among sur-
vivors of cardiac arrest, as well as in patients subjected

to open-heart surgery (Ross and Graham, 1993). Neu-
roimaging studies reveal, in most survivors of global
ischemic episodes, bilateral and usually symmetrical le-
sions that are particularly prominent as hyperintense
areas (on T2-weighted MR images) located in the ba-
sal ganglia, thalamic nuclei, and substantia nigra. En-
larged subarachnoid spaces, secondary to the atrophy
of the cortical ribbon, become easily apparent in pa-
tients who survive for several weeks the hemodynamic
crisis (Fujioka et al., 1994).
The neurological syndromes associated with global
ischemic injury to the brain correlate with the topo-
graphic distribution and severity of the lesions. The FIGURE 7.1 Microscopic section of cerebral cortex showing necrosis
most frequent syndrome is associated with injury to the of deep cortical layers in a laminar pattern. Hematoxylin and eosin
tissues located in the ABZ that exists between the ter- stain.
minal branches of the middle and anterior cerebral ar-
teries (MCA and ACA). The neurologic deficits affect-
ing these patients include bilateral brachial paralysis
with maximal involvement of the muscles in the prox- Delayed death of neurons (DDN) is the designation
imal limbs. This has prompted the designation of “man- given to the changes induced in the hippocamus of rats
in-a-barrel” syndrome (Marti-Vilalta et al., 1994). subjected to transient (5 min) bilateral carotid clamp-
Anatomical abnormalities visible in the brains of pa- ing followed by several days of reperfusion. Under these
tients who are resuscitated but who require a mechan- conditions, necrotic neurons were absent or scarce in
ical ventilator to support their breathing are sometimes experiments terminated after 1 day. The numbers of
erroneously called “respirator brain.” Obviously, the dead hippocampal neurons peaked in experiments in
respirator is not the cause of the changes induced by which reperfusion lasted 4 days (Ito et al., 1975). A
global ischemia. The ischemic episode caused by either comparable observation has been made in human au-
cardiac arrest or hypotension triggers prompt and mas- topsies. Increasing numbers of dead neurons were de-
sive swelling of the brain. This enlargement of the brain tected in the human hippocampus among survivors of
volume leads to a marked increase in intracranial pres- severe hemodynamic crises. Numbers of necrotic neu-
sure that in turn leads to decreased perfusion pressure rons at this site correlated with the length of the sur-
with the development of further ischemia and addi- vival period, or reperfusion, suggesting that some un-
tional brain swelling. The nearly complete cessation of defined biological event, loosely called maturation
the intracranial circulation has been documented in phenomenon, may continue to exert its lethal effects
some of these patients by using intraarterial injections on neurons hours or days after the circulation is
of isotopes that do not circulate beyond the base of the reestablished (Petito et al., 1987). Excessive concentra-
skull. This type of injury constitutes one of the instances tions of interstitial glutamate, an excitatory neuro-
of brain death, or a condition in which the function of transmitter that promotes the intracellular entry of
most organs is preserved while the perfusion and there- Ca2, frequently are mentioned as one of the mecha-
fore the vitality of the brain is irreversibly lost several nisms responsible for the death of many neurons in ar-
days before the patient is pronounced dead. At autopsy, eas of the brain that are known to be selectively vul-
an extremely swollen and softened brain shows evi- nerable to the effects of global ischemia.
dence of maceration (or aseptic necrosis) that appears Hippocampal sclerosis describes a pattern of injury
incongruous with the relative good preservation of to Ammon’s horn in which most neurons of the pyra-
other organs. midal cell layer of the hippocampus are replaced by a
Laminar and pseudolaminar necroses are terms used glial scar. This lesion characteristically involves Som-
to describe an injury to the neocortex in which the su- mer’s sector (CA1) and is the most common finding in
perficial and deep layers of this structure are relatively patients who suffer chronic epileptic seizures as part of
preserved following global ischemia. (Fig. 7.1). This the syndrome of mesial temporal sclerosis. In addition
pattern of damage is the result of a selective injury to to epileptic seizures, selective neuronal injury to the
a layer or lamina of the cortex where most parenchy- CA1 sector of the hippocampus also can be induced by
mal cells and blood vessels are destroyed. global ischemia and hypoglycemia.
Leukoencephalopathy of Probable Ischemic Origin TABLE 7.2 Angiopathies as Potential Causes of Focal
Ischemic Injury to the Brain
Subcortical leukoencephalopathy (SLC), cerebral white
matter rarefaction, or leukoaraiosis, as it is sometimes Large arteries
described in the neuroimaging literature, defines struc- Atherosclerosis
tural abnormalities involving the subcortical cerebral Fibromuscular dysplasia
white matter that are detected on CT in the form of ei- Arterial dissection
ther diffuse periventricular areas of decreased density Moyamoya syndrome
or patchy hypodense areas in the immediate subcorti- Small blood vessels
cal region. In the T2-weighted images of MR the white Arteriolosclerosis
matter (WM) lesions appear as hyperintense.
Amyloid angiopathy
Some authors associate these changes in the density of
CADASIL*
the WM with the name of Otto Binswanger. This prac-
Sneddon’s syndrome
tice is discouraged because the definition of Binswanger’s
disease is uncertain and because leukoaraiosis exists in Noninfectious angiitis
otherwise-normal persons. Thus, applying the term dis- Behçet’s syndrome
ease to the neuroimaging changes in these individuals is Primary angiitis of the CNS
incongruous (Pantoni and Garcia, 1995). The gross fea- Polyarteritis nodosa
tures of SLC include sparing of U fibers, slight granular- *Cerebral autosomal dominant arteriopathy with subcortical infarcts and
ity, and change in the color of the cerebral WM (Fig. 7.2). leukoencephalopathy.
SLC is detected with increasing frequency among per- Source: Adapted from Garcia J.H. and Ye Z.-R. (2000).
sons older than 60 years who are otherwise neurolog-
ically intact. However, SLC may be clinically associ-
ated with cognitive disorders and attention deficits of presence of occasional macrophages accompanied by
moderate severity as well as with subtle gait distur- small cavitary lesions called lacunar infarcts.
bances. The pathogenesis of SLC is unknown. Based
on the analysis of epidemiological data, several authors
attribute the condition to the effects of moderate isch- BRAIN INJURIES CAUSED BY FOCAL ISCHEMIA
emia. The mechanisms responsible for the ischemic in-
jury among patients with SLC are thought to be either Most syndromes of ischemic stroke are attributed to
repeated brief hemodynamic crises or occlusive disease the occlusion of an artery. Occlusion of intracranial
of the brain’s small blood vessels or a combination of veins or sinuses does not manifest itself as a stroke in
both (Pantoni and Garcia, 1997). The histologic fea- most instances.
tures of SLC are nonspecific and include rarefaction of Intracranial arteries can become occluded as a con-
myelinated fibers, decreased numbers of oligodendro- sequence of diseases of the blood vessels (Table 7.2)
cytes, increased numbers of reactive astrocytes, and the and as a result of embolism either from the heart (Table
7.3) or from atheromatous plaques of the carotid artery
TABLE 7.3 Potential Sources of Cardiac Embolism to

the Brain
High-risk sources
Atrial fibrillation
Prosthetic heart valves
Rheumatic mitral stenosis
Myocardial infarction (recent)
Aneurysmal scar in the left ventricle of the heart
Mural thrombus
Cardiac myxoma
Dilated cardiomyopathy
Valvular vegetations
FIGURE 7.2 Subcortical leukoencephalopathy associated with discol-
oration and cavitation of the parietal white matter on the left. Source: Adapted from Poole and Chimowitz (1996).
and aortic arch. Intravascular coagulation secondary to tus (Bryan et al., 1991). The clinical syndromes pro-
a variety of hematologic disorders (Table 7.4) and, in duced by the occlusion of one intracranial artery vary
patients with subarachnoid hemorrhage, sustained va- according to the topography of the area affected by the
sospasm are additional causes of arterial occlusions. ischemia and the extent of the injury. The evolution of
The parenchymal lesion produced by an arterial oc- the deficit is unpredictable. Some patients recover com-
clusion is called an infarct once it reaches the state of pletely within 24 hours of the stroke, usually in about
coagulation necrosis. This general statement must be 30 minutes. Others may improve gradually but are left
tempered by these caveats: (1) there is a delay of sev- with residual neurologic deficit. Still, a significant num-
eral hours or days between the time when the artery ber (up to 43% in some series) experience neurologic
becomes occluded and the time when the entire terri- deterioration over a period of several days or weeks af-
tory is affected by coagulation necrosis, (2) the arter- ter the initial episode. Neither the reasons for im-
ial occlusion must be sustained for a minimal period of provement nor the causes of chronic detrioration are
about 3 hours (in experimental subjects) before the le- known (Fisher and Garcia, 1996).
sion becomes an infarct 2–3 days later, and (3) brain Neuroimaging studies of patients with ischemic
lesions produced by transient arterial occlusions dis- stroke: Most brain lesions of ischemic origin (secondary
play morphological features that are entirely different to an arterial occlusion) are identified on CT as areas
from those typical of an infarct. of hypodensity that first become apparent 4–12 hours
after the stroke. Sequential neuroimaging studies of a
large group of patients with ischemic stroke revealed,
Anemic (Bland) or White Infarct
after 24 hours, abnormalities that originally had been
This lesion is the outcome of a prolonged (several undetectable; in addition, many of the initially visible
hours) arterial occlusion; the neuroimaging abnormal- lesions were larger and more conspicuous after 24
ities induced by an arterial occlusion are of a diverse hours (Bryan et al., 1991). Sequential evaluations of
nature and do not become detectable by conventional the focal ischemic brain lesions visible on CT also dis-
CT and MR methods until several hours after the ic- closed, in approximately 43% of the patients with large
supratentorial lesions, spontaneous hemorrhagic trans-
formation (HT) of the ischemic lesion. This HT usu-
ally corresponds to petechiae confined to the gray mat-
TABLE 7.4 Hematological Causes of Occlusive
Arterial Disease ter of the infarct (Toni et al., 1996). In a small minority
of cases the ischemic brain lesions become totally ef-
Natural anticoagulant deficiency faced by a large hematoma. Marked neurological de-
Heparin, cofactor II, antithrombin III (AT-III), protein C, protein S terioration and even death have been observed in as-
sociation with large intracerebral hemorrhages or
Defects in the fibrinolytic system hematomas that develop at the site of an ischemic brain
lesion (del Zoppo and Mori, 1992).
Elevated fibrinogen levels, plasminogen deficiency, elevated tissue
plasminogen activator inhibitor (PAI-1), decreased tissue Anatomic pathology of anemic (pale) infarcts: The
plasminogen activator (tPA), hereditary dysfibrinogenemia traditional description of the brain changes initiated by
the occlusion of a large artery includes four stages: (1)
Presence of antiphospholipid antibodies In the very early period (days 3–4) gross changes are
minimal and include subtle blurring of the gray–white
Erythrocyte disorders matter demarcation accompanied by decreased tissue
Polycythemia vera, sickle cell anemia, paroxysmal nocturnal consistency (i.e., encephalomalacia). (2) The second
hemoglobinuria stage (days 4–7) is characterized by a marked increase
in the volume of the injured tissue with displacement,
Platelet disorders or herniation, of neighboring structures; sometimes this
is called the “mass effect” (Fig. 7.3). In cases of large-
Essential thrombocytopenia, thrombotic thrombocytopenic purpura
(TTP), heparin-associated thrombocytopenia artery occlusion this swelling may be severe enough to
cause the death of the patient through the herniation
Miscellaneous
of the uncinate gyrus and the secondary interference
with the blood supply of the upper brain stem. Simul-
Disseminated intravascular coagulation (DIC), malignant
taneously, at the same time as this swelling, coagula-
neoplasms
ton necrosis affects the territory irrigated by the oc-
Source: Adapted from Tatlisumak and Fisher (1996). cluded artery. (3) During the third stage (days 7–14)
following sequence has been suggested based on the

evaluation of a limited number of samples obtained at
autopsy: (1) Eosinophilic (necrotic) neurons and pyk-
notic (necrotic) oligodendrocytes predominate between
days 1 and 4 after the stroke. (2) In addition to the fea-
tures visible in the initial period, abundant macro-
phages and newly formed blood vessels appear between
days 5 and 7. (3) Neuronal ghosts, macrophages, and
gemistocytes characterize the next period during days
8 through 14. (4) Both neurons and oligodendrocytes
become unrecognizable in the fourth period, days 5
through 27 (Chuaqui and Tapia, 1993). Neither the
cause nor the duration of the arterial occlusion was
FIGURE 7.3 Anemic infarct in the territories supplied by the left an- known in most of the cases in which this study was
terior and middle cerebral arteries associated with edema and com- based.
pression of ventricles. In experimental models of ischemic stroke, induced
by occluding one MCA through the insertion of a ny-
lon monofilament into the carotid artery, the very early
swelling disappears, the lesion becomes more readily (30 minutes) changes include the following: swelling of
demarcated, and the beginning of cavitation may be glial cells (in particular, astrocytes), pyknosis and nu-
visible at isolated small regions of the infarct. (4) The clear fragmentation of oligodendrocytes, changes in de-
terminal stage (sometimes, called liquefactive necrosis) pendent microvessels, and shrinkage/swelling of neu-
consists of the formation of a fluid-filled cavity at the ronal perikarya with arrival of polymorphonuclear
site of the original necrotic lesion (Fig. 7.4). The for- leukocytes and monocytes beginning as early as 30 min-
mation of this cavity is the result of the removal of utes after the arterial occlusion. Tissue swelling peaks
necrotic tissue by macrophages. This outcome is dif- about 72 hours after the arterial occlusion, and coag-
ferent from that observed when coagulative necrosis af- ulation necrosis becomes apparent in the entire terri-
fects other organs such as the heart in which necrotic tory of the occluded artery after about 3 and 4 days.
myocardium is replaced by a fibrocollagenous scar. Removal of the necrotic debris by monocytes/macro-
The four sequential patterns described above can be phages begins on days 10 through 14 and formation of
reproduced in experimental animals only when the a fluid-filled cavity is the final outcome of brain in-
artery remains permanently occluded. As described be- farcts associated with prolonged arterial occlusions.
low, the features of the brain lesion (secondary to fo- Cavitary infarct is the designation given to the end stage
cal ischemia) are substantially modified by reopening of brain injuries in which ischemia was the result of a
the artery. The correlation between the duration of the prolonged arterial occlusion accompanied by a severe
arterial occlusion and the type of anatomical changes
affecting the human brain is made difficult by the fact
that in most human ischemic strokes the existence of
an arterial occlusion can be only inferred. Moreover,
the duration of an arterial occlusion, in an individual
case, is seldom if ever known. Nevertheless, repeated
(serial) angiography has shown that the percentage of
demonstrable arterial occlusions (in the same groups of
stroke patients) drops precipitously from 74% to less
than 40% between 12 and 24 hours after the begin-
ning of symptoms (Solis et al., 1977). This study dem-
onstrates the efficiency of the endogenous fibrinolytic
systems and suggests that in many instances of human
ischemic stroke, the brain lesions are caused by tran-
sient arterial occlusions.
The evolution of the histologic abnormalities that be-
gin with an arterial occlusion and evolve into a brain FIGURE 7.4 Cavitary infarct involving left basal ganglia and internal
infarct is difficult to outline in human specimens. The capsule.
decrease in the local CBF. The features described above latter group, only 24% had evidence of hemorrhagic
are consistently reproduced in the experimental animal transformation (Lodder et al., 1988). Both autopsy and
only if the artery remains occluded for a minimum of neuroimaging studies suggest that the best predictor of
3 to 4 hours. HT in a human focal ischemic lesion is its volume. The
larger the lesion the more likely it is that HT will de-
velop. In several instances a persistent arterial occlu-
Hemorrhagic (Red) Infarct
sion has coexisted with the hemorrhagic transforma-
Ischemic brain lesions (of arterial occlusive etiology) tion of an otherwise “ischemic” brain lesion. Repeated
that have a grossly visible component of petechiae are CT-scan evaluations of patients with ischemic strokes
called hemorrhagic (red) infarcts (Fig. 7.5). These punc- reveal that a significant percentage of focal “ischemic
tate hemorrhages are more common in the gray than brain lesions” (about 43%) spontaneously develop pe-
in the white matter and in some patients multiple petechiae within 5 hours of the initial event and in the
techiae may coalesce into a large intracerebral hemor- absence of any change in the clinical condition of the
rhage (or hematoma). We presume that all brain lesions patient (Toni et al., 1996).
caused by an arterial occlusion begin as pale or anemic Two different patterns of HT have been documented
lesions that later undergo secondary hemorrhagic trans- at the site of the brain lesions that accompany focal
formation (HT). These HTs of ischemic brain lesions ischemic injuries; the most frequent consists of multi-
and the de novo appearance of a brain hemorrhage ple petechiae that in the cerebrum predominantly in-
have been associated with the administration of throm- volve the cortex and the basal ganglia. Less frequently,
bolytic agents for the treatment of occlusive disease af- a single large hemorrhage may completely efface the
fecting either coronary or intracranial arteries (Pessin original ischemic lesion. Both patterns of HT may oc-
and del Zoppo, 1995). Based on observations made in cur in the absence of treatment with either fibrinolytic
autopsy specimens, Fisher and Adams (1951) suggested or antithrombotic agents. However, administering tPA
that the hypothetical reperfusion of the ischemic terri- for the treatment of either coronary or intracranial
tory or reestablishment of the anterograde flow (via the artery occlusion is associated with an increased risk
spontaneous reopening of the occluded artery) could of intraparenchymal brain bleeding (Pessin and del
account for the development of hemorrhages observed Zoppo, 1995). This suggests that, depending on the
at the site of white (bland) infarcts. This mechanism timing of the arterial reopening and the histologic fea-
may indeed precede the hemorrhagic transformation of tures of the brain lesion, reopening an occluded artery
some ischemic brain lesions, but arterial reopening is may or may not be beneficial to patients with ischemic
not essential for the hemorrhagic transformation of a stroke. The mechanisms through which ischemic brain
brain ischemic infarct. Recent autopsy studies have re- lesions undergo HT are incompletely understood. Some
vealed a higher (76%) proportion of hemorrhagic brain authors suggest that multiple factors, such as necrosis
infarcts among patients who had a source of embolism of the microvessels, changes in arterial blood pressure,
from the heart when compared with those in whom the and extent of the collateral anastomoses, are important
arterial occlusion was judged to be thrombotic. In this in promoting bleeding at the site of an ischemic brain
lesion (del Zoppo and Mori, 1992). Histologically, the
main differences between the features of hemorrhagic
and anemic infarcts include the presence of numerous
hemorrhages accompanied by infiltrates of polymor-
phonuclear (PMN) leukocytes and large multifocal col-
lections of extravasated plasma that are more common
in the cases in which there is a hemorrhagic compo-
nent. Both lesions are characterized by coagulation ne-
crosis.
Incomplete Infarction
The term incomplete infarction was suggested by
Lassen (1982) to designate brain lesions produced by
arterial occlusions that create ischemia of moderate
FIGURE 7.5 Hemorrhagic infarct in the territory supplied by the left severity and that result in the death of a limited num-
middle cerebral artery associated with cortical petechial hemorrhages. ber of cells, mostly neurons. Moderate ischemia exists
whenever the arterial occlusion is of short duration,

or—in cases of persistent occlusion—whenever the col-
lateral connections that exist distal to the site of the ar-
terial occlusion are abundant and efficient. The tissue
abnormalities that prevail at sites injured by moderate
ischemia include destruction of a limited number of
neurons with survival of astroglial and vascular ele-
ments. As a result, and in contrast with the patterns
observed at sites of severe ischemia, the typical abnor-
mality affecting the ischemic brain area includes preser-
vation of tissue architecture, increased tissue density,
and absence of cavitation (Fig. 7.6). Moderate ischemia
exists in situations in which the compensatory circula-
tion is adequate to maintain a local blood flow of 15–20 FIGURE 7.7 Lacunar infarct involving white matter in the right frontal
mL/100g of tissue per minute. Two cases have been re- lobe.
ported in which imaging studies, calculations of local
CBF, and histopathological evaluation of the brain con-
firmed the existence of an arterial occlusion, the degree Based on the observations made on humans and an-
of focal ischemia affecting a part of the brain, and the imals, incomplete infarctions can be defined as brain
“loss” of a significant percentage of neurons at same lesions induced by arterial occlusions that lead to tis-
site affected by moderate ischemia (Lassen et al., 1983). sue destruction within the territory of the occluded
Incomplete infarcts have been created in rats with MCA artery involving only a limited number of neurons. Co-
occlusion by reopening the artery within 60 minutes. agulation necrosis (pannecrosis) either affects small foci
In these experiments, the brain lesion was primarily or does not occur, and cavitation does not develop even
confined to the striatum; at this site, the most promi- after several months. Histological features of incom-
nent feature was, in addition to necrosis of a selected plete infarcts include “loss” of some neurons, micro-
group of neurons, marked reactive astrogliosis (Garcia glial activation (without formation of macrophages),
et al., 1997a). and marked hypertrophy of astrocytes.
A significant percentage of patients with transient
neurologic deficits of probable ischemic origin, or TIAs,
have neuroimaging evidence of brain lesions that may
represent incomplete infarcts (Fazekas et al., 1996).
Lacunar Infarcts
The term lacunar infarct or lacune is reserved for brain
lesions of presumed ischemic origin that have a cavi-
tary appearance on neuroimaging studies and that mea-
sure 1.5 cm in diameter. In order of frequency la-
cunes have been found in these locations: the putamen,
the thalamus, the internal capsule, the basis pontis,
and the subcortical cerebral white matter (Fig. 7.7). La-
cunae are thought to be the result of occlusions in-
volving one or more of these vessels: lenticulostriate
branches of the anterior and middle cerebral arteries,
thalamoperforating branches of the posterior cerebral
arteries, paramedian branches of the basilar artery, and
penetrating arteries of the cerebrum.
The clinical syndromes most commonly observed
among patients with lacunae are: pure motor hemi-
FIGURE 7.6 Incomplete infarct in area supplied by a leptomeningeal
paresis (55%), pure hemisensory stroke (18%), and
artery occluded by an embolus. The architecture of the tissue is pre- sensorimotor syndrome (15%) (Arboix et al., 1990).
served with absence of cavity formation. Lacunar syndromes are highly predictive of lacunar in-
farcts, which are attributed to one of four different eti- 20. Ischemic injury in the neonate is discussed in Chap-
ologic mechanisms: (1) diseases of the small or pene- ter 3. Cerebrovascular accidents or strokes among chil-
trating blood vessels, in particular arteriolosclerosis, (2) dren and persons up to 20 years of age display several
narrowing of the ostium of arterioles at their site of important differences compared to the strokes observed
origin from a large artery, (3) atheromatous narrow- in adults: (1) Risk factors are different and include con-
ing of the arteriole’s lumen, and (4) embolism from ei- genital heart diseases, inherited angiopathies (e.g., mi-
ther the cardiac chambers or the aorta and carotid ar- tochondrial encephalomyopathy and lactic acidosis),
teries. Cardiac disorders that may become a source of inherited coagulopathies (e.g., protein C deficiency),
embolism to the brain include atrial fibrillation, recent sickle cell hemoglobinopathy and structural abnormal-
myocardial infarct, bacterial endocarditis, cardiac myx- ities of the blood vessels—in particular, arteriovenous
oma, valvular vegetations, and valvular prostheses. malformations. (2) Most strokes in children are hem-
orrhagic rather than ischemic. (3) Most parenchymal
hemorrhages, in children, have a superficial location on
VENOUS INFARCTS the cerebrum or cerebellum. (4) Subcortical and lacu-
nar infarcts are extremely uncommon in children. (5)
Brain lesions secondary to the thrombotic occlusion of Young patients show a greater capacity for functional
dural sinuses or veins are characterized by fluid retention recovery attributed to the “plasticity” of the develop-
(i.e., brain edema) and by bleeding at the site of the le- ing brain (Garcia and Pantoni 1995).
sion. Most venous infarcts exhibit topographic patterns In a comparative study in which the subtypes of
different from those seen in brain lesions caused by an ar- stroke were classified as atherothrombotic (AT), car-
terial occlusion; for example, hemorrhagic lesions on both dioembolic (CE), small-vessel occlusion (SV), and un-
sides of the midline are common in cases of superior sagit- known (U), the distribution of the number of cases
tal sinus thrombosis. The hemorrhages of venous infarcts among children/adults was as follows: AT 0/16 (P
are not restricted to the gray matter, as is the case in hem- 0.001), CE 15/14 (P 1.0), SV 0/3 (P 0.26), and U
orrhagic arterial infarcts, and the topographic distribu- 36/23 (P 0.04). (Williams et al., 1997). This study,
tion of the lesion is incompatible with that of an arterial in agreement with many others, emphasizes the diffi-
territory. Moreover, the clinical expressions of venous in- culty that exists in a significant percentage of stroke
farcts are, in most instances, different from those consid- cases in identifying the etiology of the ischemic condi-
ered characteristic of an ischemic (arterial) stroke. Some tion.
of these features include chronic dull headaches, papil-
ledema, and seizures (Table 7.5). The histologic features
of venous infarcts include large, edematous, hemorrhagic ISCHEMIC INJURIES TO THE SPINAL CORD
areas of softening with numerous PMN leukocytes dis-
tributed throughout the lesion, and absence of coagula- Most ischemic lesions to the spinal cord are associated
tive necrosis (Garcia and Mena, 1997b). with structural abnormalities of the aorta, in particu-
lar atherosclerosis of the abdominal segment of this
artery. Embolism of atheromatous material is probably
STROKES IN THE YOUNG the most common cause of occlusion involving the
spinal arteries. Medical procedures that may become
Ischemic injuries in the young have different manifes- complicated by ischemic injury to the spinal cord in-
tations in the newborn and in persons under the age of clude thoracolumbar sympathectomy, surgical repair of
the abdominal aorta, pneumonectomy, aortography,
TABLE 7.5 Main Clinical Signs and Symptoms and spinal angiography. Among 44 cases of spinal
Associated with Cerebral Venous Thrombosis stroke diagnosed over a period of 10 years at two uni-
versity hospitals, the etiology of the spinal stroke was
Signs n 71 n 110
listed as follows, in decreasing order of frequency: ab-
Headache 91% 75% dominal aortic atheromatous disease with fusiform
Papilledema 27% 49% dilatation, aortic dissection, aortic rupture, hemo-
Focal neurologic deficits 66% 34%
dynamic crises, anterior spinal artery occlusion, repair
of spinal arteriovenous malformation, hematomyelia,
Seizures 48% 37%
epidural hemorrhage, cervical osteophytes, celiac plexus
Altered consciousness 56% 30%
block, systemic lupus erythematosus, coagulopathies,
Source: Adapted from Bousser (1997). and decompression sickness (Cheshire et al., 1996).
The patterns of injury to the spinal cord induced by Garcia J.H., Liu K-F., Ye Z-R., and Gutierrez J.A. (1997a). Incom-
the ischemic events include: (1) transverse myelopathy plete infarct and delayed neuronal death after transient middle
cerebral artery occlusion in rats. Stroke 28:2303–2310.
(also called spinal apoplexy), (2) anterior spinal artery Garcia J.H. and Mena H. (1997b). Vascular diseases. In: Neu-
syndrome, and (3) central myelopathy. The clinical ex- ropathology: The Diagnostic Approach (J.H. Garcia, H. Budka,
pressions of these injuries include: P. McKeever, H.B. Sarnat, and A.A. Sima, eds.). Mosby, St. Louis,
pp. 263–320.
1. Transverse myelopathy: flaccid paraplegia or Garcia J.H. and Pantoni L. (1995). Strokes in childhood. Semin Ped
quadriplegia, sphincter paralysis, and complete loss of Neurol 2:180–191.
sensation below the level of the lesion. Motor paraly- Garcia J.H. and Ye Z-R. (2000). Epidemiology and pathology of oc-
sis frequently is preceded by acute pain of radicular clusive cerebrovascular disease. In: Neurosurgery, 3rd ed. (A.
Crockard, R. Hayward, and I. Hoff, eds.). Blackwell Science, Ox-
character. ford (in press), pp. 704–726.
2. Anterior spinal syndrome: in addition to motor Ito U., Spatz M., Walker J.T. and Klatzo I. (1975). Experimental
and sphincter paralysis many patients have dissociated ischemic in monogolian gerbils. Light microscopic observations.
sensory loss involving pain and temperature sensation Acta Neuropathol 32:209–215.
but sparing vibration and position sense. Lassen N.A. (1982). Incomplete cerebral infarction: focal incomplete
ischemic tissue necrosis not leading to emollision. Stroke 13:522–
3. Centrospinal ischemic injuries result in a clinical 524.
syndrome closely similar to that typical of transverse Lassen N.A., Losen T.S., Hojgaard K., and Skriver, E. (1983). In-
myelopathy (Barth and Bogousslarsky, 1996). complete infarction: a CT-negative irreversible ischemic brain le-
sion. J Cereb Blood Flow Metab 3:S602–S603.
Magnetic resonance imaging is the most valuable tool Lodder J., Krijne-Kubat B., and Van der Lugt P.J. (1988). Timing of
in the direct, noninvasive identification of ischemic autopsy-confirmed hemorrhagic infarction with reference to car-
hemorrhagic lesions involving the spinal cord. dioembolic stroke. Stroke 19:1482–1484.
Marti-Vilalta J.L., Arboix A., and Garcia J.H. (1994). Brain infarcts
in the arterial border zones: clinico-pathologic correlations. J
Stroke Cerebrovasc Dis 4:114–120.
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8 Cerebrovascular disease
CAROL K. PETITO
Cerebrovascular diseases are a broad category of dis- or internal carotid arteries. Stroke is a general term used
orders that affect the cerebral circulation. They en- to describe a sudden or rapid onset of neurologic
compass not only diseases of the intraparenchymal and deficit(s) caused by infarction, intraparenchymal hem-
extraparenchymal cerebral blood vessels but also ab- orrhage, or subarachnoid hemorrhage. The temporal
normalities in the systemic vasculature, especially the profile of strokes may be divided into improving, wors-
carotid arteries and heart, and systemic illnesses that ening, or stable. Most are due to cerebral infarcts
alter blood coagulation or blood flow. The end result caused by thrombi, emboli, or hemodynamic alter-
of these cerebrovascular abnormalities is cerebral hem- ations. Symptoms and signs depend on infarct site and
orrhage or cerebral ischemia. The risk factors for cere- the degree of infarct-related edema. Certain risk fac-
brovascular disease include environmental hazards tors, such as hyperglycemia, may influence the brain’s
such as cigarette smoking, metabolic disorders such as response to ischemia and worsen the outcome (Parsons
diabetes, and genetic factors such as protein S defi- et al., 2002).
ciency (Natowicz and Kelley, 1987). Brain hemorrhages are caused by hypertension, amy-
The following discussion reviews clinical disorders of loid angiopathy, brain tumors, blood dyscrasias, vas-
cerebrovascular diseases (Whisnant, 1990), briefly dis- cular malformations, and vasculitis. The location of the
cusses the pathology and etiology of infarcts and hem- hemorrhage and the age of the patient correlate, in part,
orrhage, and then describes specific disorders of the with its etiology. Hypertensive hemorrhages, for ex-
cerebral blood vessels. ample, are common in the basal ganglia, whereas those
caused by amyloid angiopathy are common in the
parieto-occipital lobes. The incidence of intracerebral
CLINICAL DISORDERS hemorrhage increases with patient age (Broderick et al.,
1993), related in part to amyloid angiopathy in the el-
Cerebrovascular diseases are asymptomatic when an in- derly. Hemorrhages in the subarachnoid spaces are usu-
farct or hemorrhage is in a “silent” region of the cen- ally caused by rupture of a saccular aneurysm of the
tral nervous system or when arterial occlusion is com- circle of Willis. Clinical symptoms include a sudden on-
pensated by adequate collateral flow. Such collateral set of severe headache, alterations of consciousness, and
pathways include the circle of Willis, communications vomiting. Hemorrhages that involve both the sub-
between the external and internal carotid arteries via arachnoid space and the brain parenchyma (“mixed”
the ophthalmic artery, and reversed flow from the an- hemorrhages) are classically due to arteriovenous mal-
terior spinal artery into the vertebral artery. formations, although other causes such as amyloid an-
Focal brain dysfunction due to cerebrovascular dis- giopathy, tumor, and infection may produce a similar
ease includes transient ischemic attacks (TIAs), re- distribution of bleeding.
versible ischemic neurological deficits (RINDs), and Cerebrovascular disease rarely may cause dementia
strokes. A TIA is defined as a transient focal loss of due to multiple infarcts (vascular dementia, multi-
brain function that can be attributed to a specific vas- infarct dementia) or global ischemia. Since the preva-
cular supply which usually lasts for 2–15 minutes but lence of both dementia and stroke increases with age,
no more than 24 hours. In contrast, RINDs last for they often are found together. The usual causes of
more than 24 hours but less than 1–3 weeks. They leave multi-infarct dementia are hypertension and cerebral
no persistent deficit and often are multiple. In both, emboli. Intravascular lymphoma, cerebral autosomal
pathologic examination of the appropriate brain region dominant arteriopathy with subcortical infarcts and
may show a small infarct, but usually no lesions are leukoencephalopathy (CADASIL), and vasculitides are
found. TIAs are attributed to platelet–fibrin emboli rarer etiologies. Global ischemia after cardiorespiratory
from ulcerative atherosclerotic plaques in the common arrest occasionally results in dementia or recent mem-
122
8: CEREBROVASCULAR DISEASE 123
ory loss when the insult produces selective neuronal ne-

crosis of hippocampus and adjacent temporal lobe
structures (Volpe and Petito, 1985; Corey-Bloom et al.,
1997). Cardiopulmonary bypass surgery and sickle cell
disease are other examples of diffuse ischemia produc-
ing mild cognitive defects (Sotaniemi et al., 1986; Steen
et al., 1998).
Hypertensive encephalopathy in patients with
chronic, poorly controlled hypertension is related to
loss of autoregulation with secondary vasospasm and
vasodilatation (Skinhoj and Stranctgaard, 1973). It is
manifested by headaches, obtundation, seizures, and,
at times, transient neurologic deficits. Pathologic de-
scriptions include petechiae, cerebral edema, fibrinoid
necrosis, and thrombosis of intraparenchymal vessels FIGURE 8.2 Multiple cystic infarcts caused by emboli from ipsilateral
(Chester et al., 1978). common carotid artery.
NEUROPATHOLOGY OF INFARCTS AND 1995; Brown et al., 1999). The distribution of the em-
HEMORRHAGES: REVIEW bolic infarcts may assist in identifying their source. For
example, multiple infarcts in the distribution of the an-
A cerebral infarct is a well-circumscribed area of ne- terior and middle cerebral arteries in one hemisphere
crosis in the distribution of a specific vascular territory suggest embolic origin from a plaque in the ipsilateral
and results from occlusion or severe hypoperfusion in carotid artery, whereas bilateral cerebellar infarcts may
the feeding artery (Fig. 8.1). Atherosclerosis of ex- indicate origin from the basilar artery.
tracranial neck arteries is its most common cause. Em- Lacunar infarcts (lacunes) are small cystic infarcts
bolic infarcts are usually multiple (Fig. 8.2) and typi- less than 1.5 cm in diameter that are located in basal
cally hemorrhagic. Sources of emboli include mural ganglia, thalamus, or cerebral white matter (Fig. 8.3).
thrombi or valvular heart disease, paradoxical emboli Lacunes can have a number of causes, including hy-
through a patent foramen ovale even in the absence of pertensive changes in penetrating arteries as well as em-
elevated right heart pressure atherosclerotic plaques boli of local or cardiac origin (Tuszynski et al., 1989;
from the ascending aorta or neck vessels, and, rarely, Horowitz et al., 1992). Basal ganglia lacunes may be
tumor or infectious emboli from pulmonary lesions due to systemic emboli as well as intrinsic hypertensive
(Lechat et al., 1988; Masuda et al., 1994; Sitzer et al., cerebrovascular disease, whereas white matter lacunes
FIGURE 8.1 Well-circumscribed cortical infarct with embolus in over- FIGURE 8.3 Lacunar infarcts in basal ganglia and centrum semiovale
lying meningeal artery. of patient with chronic hypertension.
FIGURE 8.4 Thrombosis of superior sagittal sinus.
correlate well with aging and hypertension (Uehara et

al., 1999). FIGURE 8.5 Recent (2-day-old) infarct in distribution of right middle
Ischemic white matter disease includes demyelination cerebral artery.
and infarction. Perhaps its best-known example is Bin-
swanger’s disease, a dementing illness associated with
hypertension, lacunes, or demyelination in the centrum The evolution and organization of cerebral infarct
semiovale, and with arteriolar sclerosis of white mat- follow an orderly sequence of events (Table 8.1) the ra-
ter blood vessels (Olszewski, 1965; Babikean and Rop- pidity of which is proportional to the size of the infarct
per, 1987; van Swieten et al., 1992; Pantoni and Gar- (Chuaqui and Tapia, 1993). Initially the infarcted brain
cia, 1995). Global ischemia also may produce white is slightly soft, swollen, and dusky (Fig. 8.5). Enhanced
matter demyelination and infarction in conditions such vascular permeability, caused first by increased vesicu-
as periventricular leukomalacia of infancy or delayed lar transport but later by vascular necrosis (Petito et
white matter damage after cardiorespiratory arrest or al., 1982), results in cerebral edema (Fig. 8.6) that is
carbon monoxide intoxication (Plum et al., 1962; Gins- grossly apparent by 24–48 hours. With time, the
berg et al., 1974). Rarer causes of focal white matter necrotic material is removed by macrophages and re-
ischemia and dementia include CADASIL and other placed by a cystic cavity (Fig. 8.7). In general, a 1 cm3
cerebral vasculitidies (Jen et al., 1997). infarct requires 3 months to become cystic.
Venous infarcts result from thrombosis of the dural Microscopic identification of an infarct is not ob-
sinuses and cerebral veins (Fig. 8.4) (Bousser et al., 1985; served until 12–24 hours in postmortem material (Fig.
Lefkowitz, 1989; Jacobs et al., 1996). Pathologic exam- 8.8), although as little as 1 hour may be sufficient for
ination of venous infarcts reveals hemorrhagic regions the histologic detection of ischemic neuronal necrosis
of necrosis in the territory of the underlying cerebral cor- (Petito et al., 1987). Polymorphonuclear leukocyte in-
tex and white matter. In contrast to arterial infarcts, ve- filtration is scant (Fig. 8.9A) unless sepsis is present.
nous infarcts are more hemorrhagic and may involve the After 3 days, axonal retraction balls (Fig. 8.9B) develop
white matter more than the cerebral cortex. in adjacent brain, especially when the infarct involves
TABLE 8.1 Sequential Organization of Cerebral Infarcts

Time Morphologic Changes
24 hours Well-circumscribed area of necrosis, softening, and discoloration in an arterial territory. Circumscribed pallor and
acute neuronal necrosis, often at edge of infarct (“penumbral zone”)
Days 1–2 Minimal polymorphonuclear leukocyte infitrate
Days 2–5 Blood–brain barrier breakdown and cerebral edema
Days 3–5 Axonal retraction balls at edge of infarct, usually in white matter
Days 5–7 Appearance of lipid-laden macrophages (“gitter cells”) at periphery; hyperplastic blood vessels
Day 14 Sheets of lipid-laden macrophages
Days 10–20 Surrounding rim of gemistocytic astrocytes
3 months Cystic space surrounded by fibrillary astrocytes
FIGURE 8.6 Acute cortical infarct showing blood–brain barrier break- B

down to serum proteins detected by positive immunoreactivity for
fibrinogen.
white matter structures. Macrophages, derived from

blood-borne monocytes, appear around day 5 and are
responsible for the neovascularization that also is ap-
parent at this time. Gemistocytic astrocytes, with plump
eosinophilic cell bodies, are difficult to see before 2
weeks, although gemistocytic and fibrillary astrocyto-
sis is prominent around subacute or cystic infarcts (Fig.
8.9C). Preservation of the outer cortical layer (Fig.
8.9D) helps distinguish old infarcts from contusions or
other lesions communicating with the subarachnoid FIGURE 8.8 Hyperacute infarcts caused by bone marrow emboli
space, such as healed toxoplasmosis. caused by cardiac resuscitation 12 hours before death. (A) Low-
Wallerian degeneration of distal axons begins almost power image showing well-circumscribed regions of pallor. (B) High
magnification of ischemic neuronal necrosis.
immediately but usually cannot be appreciated on gross
examination or with hematoxylin and eosin stains for
approximately 2 weeks. Following large cerebral in-
farcts, Wallerian degeneration is most readily seen in
the ipsilateral medullary pyramid, which is enlarged
and whiter than usual. Microscopic examination shows
vacuolation of the pyramid, slightly retractile myelin,
and, rarely, gitter cells. In a few months, tracts under-
going Wallerian degeneration are shrunken and slightly
gray.
Hemorrhages in the brain are well-circumscribed le-
sions that compress adjacent structures (Fig. 8.10A).
Blood–brain barrier breakdown and cerebral edema in
the adjacent brain parenchyma usually accompany
them. Organization of the hemorrhage is accomplished
at its periphery (Fig. 8.10B) where microscopic exam-
ination shows collections of hemosiderin-laden macro-
phages and proliferated capillaries (Fig. 8.11). With
time, the hematoma organizes into a slitlike cavity with
a slightly firm, yellow–brown lining due to gliosis and
FIGURE 8.7 Cystic infarct of left cerebral hemisphere. Sparing of ba- persistence of hemosiderin-laden macrophages (Fig.
sal ganglia indicates occlusion distal to lenticulostriate arteries. 8.10C).
A B
C D
FIGURE 8.9 Cerebral infarct. (A) Sparse polymorphonuclear leukocyte infiltration at 2 days. (B) Axon
retraction balls of edge of infarct at 5 days. (C) Gitter cells (left) and gemistocytic astrocytes (right) at
4 weeks. (D) Cystic change with sparing of outer cortical layer at 3 months.
ATHEROSCLEROSIS occluded artery, and emboli. Sources of emboli are

multiple.
Atherosclerosis is the major cause of cerebral infarcts.
Common risk factors include smoking, diabetes, and
hypertension although other factors, such as radiation HYPERTENSIVE CEREBROVASCULAR DISEASE
and cerebral amyloid angiopathy, may also be en-
countered (O’Connor and Mayberg, 2000; Cadauid et Acute increases in arterial blood pressure cause
al., 2000). blood–brain barrier breakdown via enhanced pinocyto-
Atherosclerotic disease of the extracranial arteries of sis within the cerebral capillaries and arterioles (Fig.
the neck, particularly the common and internal carotid 8.12) (Nag and Robertson, 1977). When the increase is
arteries, is the primary site of atherosclerotic cere- chronic, serum proteins accumulate in the basement
brovascular disease. Most studies suggest that carotid membrane of cerebral arterioles and eventually are or-
endarterectomy is an effective mode of preventing ganized into collagen. These chronic changes, similar to
stroke when the stenosis is greater than 70% of the arteriolar sclerosis in systemic organs of hypertensive pa-
carotid lumen (Gorelick, 1999). Brain infarcts due to tients, are most prominent, and generally confined to,
intracranial atherosclerosis are usually encountered in the intraparenchymal arterioles of the basal ganglia, cen-
the vertebrobasilar system (Amarenco and Caplan, trum semiovale, pons, and occasionally cerebellum. The
1993; Amarenco et al., 1996). The mechanisms of involved vessels display medial hyalinization, loss of
atherosclerotic-induced infarcts include thrombosis muscularis, vascular dilation, and stenosis (Fig. 8.13A).
hemodynamic reductions of blood flow in a partially Fatty deposits and lipid-laden macrophages are seen in
B FIGURE8.11 Organizing hematoma (right) surrounded by rim of he-

mosiderin and lipid-laden macrophages.
lenticulostriate arteries of hypertensives (Russell, 1963),

other studies suggest that true microaneurysms are rare
(Challa et al., 1992).
Brain changes in hypertension include dilated peri-
vascular spaces (Fig. 8.14A); etát lacunairé or criblé,
lacunes (lacunar infarcts), and hemorrhage. Etát lacu-
nairé (in centrum semiovale) and etát criblé (basal gan-
glia) refer to rarefaction and gliosis in perivascular neu-
ropil (Fig. 8.14B). These alterations can be severe and
even apparent on magnetic resonance imaging or com-
C puted tomographic scans. However, they are unassoci-
ated with clinical symptoms and signs. Lacunar infarcts
may be asymptomatic, may be associated with charac-
teristic focal neurologic deficits, and rarely may be the
cause of multi-infarct dementia. Though traditionally
thought to be due to intrinsic arteriolar sclerosis of in-
traparenchymal vessels, some may be secondary to car-
diac emboli (see above).
FIGURE 8.10 Intraparenchymal hemorrhages accompanying chronic

hypertension. (A) Recent. (B) Organizing. (C) Remote.
severely hyalinized vessels (the lipohyalinosis of C. Miller

Fisher, 1979). Although postmortem injection studies FIGURE 8.12 Acute hypertension causing enhanced vesicular trans-
have shown multiple microaneurysms, known as Charcot- port and blood–brain barrier breakdown of intravascularly injected
Bouchard aneurysms (Fig. 8.13B), on the penetrating electron-dense horseradish peroxidase.
A B
FIGURE 8.13 Hypertensive vascular alterations in basal ganglia. (A) Tortuous artery with marked hyalin-
ization and thickening of its wall. (B) Microaneurysm of Charcot-Bouchard (courtesy Dr. Bruce Horten,
New York). Verhoef–Van Gieson stain.
Intraparenchymal hemorrhages in hypertension may CEREBRAL ANEURYSMS AND

be due to the rupture of Charcot-Bouchard micro- SUBARACHNOID HEMORRHAGE
aneurysms or of weakened arteriolar sclerotic vessels
(Challa et al., 1992). The distribution of these hemor- Saccular (berry) aneurysms of the circle of Willis are
rhages follows the distribution of the hypertensive vas- the most common intracranial aneurysms. Arterial di-
cular changes in the cerebral blood vessels. Thus, most lation (ectasia) or fusiform aneurysms may be caused
are in the basal ganglia (Fig. 8.10); approximately 10% by atherosclerosis, especially in the vertebrobasilar sys-
of each may be found in the pons and the cerebellum. tem; by infection, including by Treponema pallidum or
Binswanger’s disease (subcortical arteriosclerotic en- by vasculitis. Mycotic aneurysms are usually secondary
cephalopathy) features white matter ischemic lesions to bacterial infection; despite their name, a fungal ori-
that are caused by hypertensive vascular disease. Typ- gin is rare. These small arterial aneurysms are located
ically, this term is restricted to cases involving demen- in the distal branches of the leptomeningeal arteries.
tia and subcortical arteriosclerotic encephalpathy and Consequently their rupture gives rise to subarachnoid
not having other causes of dementia such as Alzhei- hemorrhages over the cerebral convexities rather than
mer’s disease. at the base of the brain. Often a systemic site of infec-
A B
FIGURE 8.14 Hypertension. (A) Dilated perivascular spaces in cerebral white matter. (B) Rarefaction of
perivascular neuropil (état criblé).
tion is not apparent until after rupture of the mycotic

aneurysm. Dissecting aneurysms are rare and usually
involve the extracranial rather than the intracranial ar-
teries. They may be continuous with a dissecting aor-
tic aneurysm or may be confined to the cerebral or ver-
tebral arteries. Causes include trauma, infections, and
cystic medial necrosis (Nedwich et al., 1963; Sasaki et
al., 1991). They tend to occur in younger patients and
may cause infarcts or subarachnoid hemorrhages.
Saccular (berry) aneurysms occur at the bifurcations
of the arteries at the base of the brain (Fig. 8.15). The
majority (roughly 70%–90%) develop on the anterior
portion of circle of Willis at three sites: the bifurcation
or trifurcation of the middle cerebral artery in the Syl-
vian fissure, the junction of the posterior communicat-
ing artery with the internal carotid artery, and the an-
terior communicating artery complex. Aneurysm repair
is by application of surgical clips to the neck of the an-
eurysm or by endovascular coil embolization (Johnston
et al., 2000). Studies by McCormick and Acosta-Rue
(1970) suggest that rupture correlates in part with an-
FIGURE 8.16 Giant aneurysm of basilar artery with recent thrombo-
eurysm size (6 mm to 5 cm) and location (internal
sis and rupture.
carotid–posterior communicating artery junction or
anterior communication artery complex). Giant an-
eurysms of the circle of Willis (Fig. 8.16) are less com-
mon than the saccular ones. Because of their size, they
may occur as space-occupying lesions. Rupture occurs in approximately 25%–50% (Brill, 1969) and has a
higher incidence of poor outcome when compared with
rupture of aneurysms 10 mm in diameter (Roos et al.,
2000).
The risk factors for saccular aneurysm rupture (Rinkel
et al., 1998) include cigarette smoking, hypertension, fe-
male sex, atherosclerosis, heavy alcohol consumption,
aging, polycystic kidney disease type 3, and aortic coarc-
tation in adults. Ruptured aneurysms are slightly more
common in women than in men and usually occur be-
tween the fourth and sixth decades. The association be-
tween rupture and hypertension is controversial.
The pathogenesis of saccular aneurysms was origi-
nally attributed to “medial defects” of the elastic lam-
ina at bifurcation sites. They are now thought to be ac-
quired lesions, since reports of saccular aneurysms
before 20 years of age are rare and degenerative
changes are present at the site of aneurysm formation
(Stehbens, 1975; Lipper et al., 1978).
Microscopic findings include a loss of internal elas-
tic lamina and muscularis at the junction of artery with
aneurysm (Fig. 8.17). The aneurysm wall itself is com-
posed of hyalinized connective tissue, and its lumen
may be partly obliterated by organizing thrombus. Sac-
cular aneurysms usually rupture into the subarachnoid
FIGURE 8.15 Saccular aneurysm arising from the anterior communi- space (Fig. 8.18). However, intraparenchymal or in-
cating artery. traventricular rupture may occur, especially if prior
CEREBRAL AMYLOID ANGIOPATHY
Cerebral amyloid angiopathy (CAA) is confined to in-

tracranial arteries and arterioles in the leptomeninges
and the superficial cortex of the cerebral (and cerebel-
lar) hemispheres, although the amyloid protein itself
may be found in systemic vessels as well (Joachim et
al., 1989). It is a sporadic disease in patients over 70
years of age (Mandybur, 1986; Vinters, 1987) but may
be familial in younger patients (Gudmundsson et al.,
1972). Microscopically, involved vessels are dilated and
their walls thickened and replaced by pink amorphous
material (Fig. 8.19A). The amyloid has a yellow–green
dichroism when stained with Congo red stain and
FIGURE 8.17 Junction of cerebral artery (bottom) and saccular aneu-
viewed under polarized light (Fig. 8.20A). Rupture at
rysm (top) demonstrating absence of muscularis and elastic lamina
in aneurysm wall. Masson stain.
sites of aneurysmal dilations (Fig. 8.19B) or areas of
fibrinoid degeneration (Challa et al., 1992) may be re-
sponsible for the lobar hemorrhages seen with CAA.
Cerebral amyloid angiopathy has been described in a
number of disorders. In some, the protein composition
bleeding has caused fibrous adhesions between the an- of the amyloid has been identified (Table 8.2). The ma-
eurysm and adjacent brain. jor protein of sporadic CAA is the amyloid beta pro-
Vasospasm is the major complication of subarach- tein (ABP) of Alzheimer’s disease (Fig. 8.20B), although
noid hemorrhage. It can be detected by arteriogram in cystatin C has been recently identified as well (Ghosi,
30%–70% of patients at 4–12 days after aneurysm rup- et al., 1996; Coria et al., 1987).
ture and causes symptoms in 20%–30% of patients Both sporadic and familial CAA produce lobar hem-
(Heros et al., 1983). Approximately half of these pa- orrhages that may be multiple and repetitive. Since the
tients die or have severe neurologic deficits resulting involved vessels are in the leptomeninges and superfi-
from cerebral ischemia. The pathogenesis of vasospasm cial layers of the cerebral cortex, the hemorrhages oc-
is obscure. Endogenous substances such as serotonin
and prostaglandins derived from red blood cells; me-
chanical distortion or compression by the subarachnoid
blood; and hypersensitivity of sympathetic nervovaso-
rum to circulating catecholamines have all been impli-
cated as causes for the vasospasm accompanying sub-
arachnoid hemorrhage.
Other complications of subarachnoid hemorrhage in-
clude cerebral edema, acute and chronic ventricular ob-
struction, rebleeding, and cerebral infarcts. Rebleeds
develop in 8%–12% of patients, with 30% of the
episodes occurring within the first 2 weeks. Infarcts can
be caused not only by vasospasm but also by direct
pressure from the hematoma, vascular compression
produced by brain herniation, and hypoperfusion re-
lated in part to systemic hypotension and elevated in-
tracranial pressure. Acute hydrocephalus following
subarachnoid hemorrhage results from blockage of the
foramina of Lushka and Magendie, whereas chronic
hydrocephalus results from organization of the blood
with resultant fibrosis in the subarachnoid spaces at the
base of the brain, over the cerebral convexities, or
around the pacchionian granulations of the superior FIGURE 8.18 Fresh subarachnoid hemorrhage at base of brain fol-
sagittal sinus. lowing rupture of saccular aneurysm.
A tiple classification schemes abound. A recent proposal

suggests dividing vascular lesions of the cord into vas-
cular neoplasms (hemangioblastoma and cavernous
malformations), spinal aneurysms (rare), arteriovenous
fistulas and arteriovenous malformations and describes
the clinical and surgical characteristics of each (Spet-
zler et al., 2002).
Arteriovenous Malformations
AVMs are composed of thin- and thick-walled vascu-
lar channels filled and distended with blood (Fig.
8.22A). More than 90% are in the cerebral hemi-
spheres. When viewed microscopically, the vessel walls
B have a thin muscularis (venous component) or muscu-
laris and elastic lamina (arterial component) (Fig.
8.22B), which may be replaced by hyalinized connec-
tive tissue or even focal collections of amyloid. In-
travascular thrombi of varying stages of organization
FIGURE 8.19 Cerebral amyloid angiopathy. (A) Dilated and thickened

arterial wall. (B) Aneurysmal dilation.
cur in the cortex, extend into its centrum semiovale,

and frequently involve the subarachnoid space (Fig.
8.21). Indeed, CAA is the major cause of lobar hem-
orrhages in elderly patients without metastatic carci-
noma. CAA also can cause cerebral ischemia and thus
may be accompanied by small cortical scars, infarcts, B
or perivascular gliosis. Finally, CAA is closely linked
to Alzheimer’s disease and the incidence of dementia is
high in these patients.
VASCULAR MALFORMATIONS
Vascular malformations are congenital lesions of cere-

bral vessels and include arteriovenous malformations
(AVMs), cavernous hemangiomas, capillary telangiec-
tasias, and venous angiomas (Challa et al., 1995). They
arise during early fetal life when the usual division into
arteries, veins, and capillaries is interrupted, resulting
in the formation of direct arterial–venous communica- FIGURE 8.20 Cerebral amyloid angiopathy. (A) Characteristic yel-
tions. They may be associated with chromosomal de- low–green dichromism with polarized light. (B) Positive immunore-
fects and hereditary patterns. In the spinal cord, mul- activity for amyloid beta protein.
TABLE 8.2 Protein Composition of Amyloid in A

Cerebral Amyloid Angiopathy of the Brain
Cerebral Amyloid Angiopathy Protein
Sporadic, elderly ABP

Hereditary (Iceland, Netherlands)
cystatin C variant (Icelandic)
Senile dementia of Alzheimer type ABP
Down syndrome ABP
Spongiform encephalopathy protein Prion
Trauma (dementia puglisitica) ABP
Vasculitis, vascular malformations
Radiation necrosis
ABP, amyloid beta protein.

B
may be prominent and at times may prevent arterio-

graphic visualization (“cryptic” AVM) (Becker et al.,
1979). Use of presurgical embolization produces char-
acteristic histology of embolic material and its in-
travascular organization (Schweitzer et al., 1993; Kepes
and Yarde, 1995). Adjacent brain parenchyma shows
the effects of ischemia and repeated hemorrhages; at-
rophy, reactive gliosis, and hemosiderin-laden macro-
phages are common. Calcification may occur within
blood vessels or parenchyma. AVMs may remain un-
changed, regress, or enlarge (Stein and Wolper, 1980;
FIGURE 8.22 Arteriovenous malformation (AVM). (A) The AVM in-
Ondra et al., 1990).
volves both leptomeninges and brain. (B) Multiple thick and thin-
The initial presentation of AVMs is hemorrhage in walled vascular channels with transitions between arterial and ve-
most (71%) patients. They generally involve the brain nous components.
and the overlying subarachnoid space (mixed hemor-
rhage). Seizures and headaches are common early signs
and symptoms. The incidence of bleeding of AVMs is
2%–4% per year, and bleeding will recur in 6% of
these within the first year (Stein and Wolper, 1980). A
association between AVMs and brain tumors may ex-
ist. In a review of 31 case reports of AVMs and menin-
giomas occurring in the same patients, the AVM was
adjacent to or intermixed with the brain tumor in 18
(Soria et al., 1990).
AVMs of the vein of Galen produce massive dila-
tion of that vessel (so-called aneurysms of the great
vein of Galen). Symptoms correlate with the age at
onset (Gold et al., 1964; Norman and Becker, 1974).
Neonates develop cyanosis and heart failure, brain
infarcts or periventricular leukomalacia; infants gen-
erally present with seizures and obstructive hydro-
cephalus; and children usually develop a subarach-
noid hemorrhage.
FIGURE 8.21 Cerebral amyloid angiopathy causing multiple superfi- Spinal cord AVMs may be intramedullary or ex-
cial hemorrhages in 73-year-old man. tramedulIary (Hurst et al., 1995). When thrombosis oc-
curs, they may be associated with acute or subacute pro- A

gressive myelopathy, as originally described by Foix and
Alajouanine (1926) as subacute necrotizing myelitis.
Cavernous Hemangiomas
Cavernous hemangiomas are composed of collections
of closely packed, large, thin-walled blood vessels with
no intervening normal brain parenchyma. Their
propensity for spontaneous thromboses may limit or
prevent visualization by angiogram, with the inclusion
of other mass lesions in the differential diagnosis. Be-
cause of the associated calcifications, this often includes
oligodendroglioma. Cavernous hemangiomas may be
incidental findings at autopsy, may be found as mass B
lesions, or may rupture and cause intraparenchymal
hemorrhages. Familial forms have been reported (Rig-
amonti et al., 1988). Grossly, the lesion has a gross
spongy appearance (Fig. 8.23A). On microscopic ex-
amination, focal calcifications, hemosiderin-laden mac-
FIGURE 8.24 (A) Capillary hemangioma at junction of pontine

tegmentum and basis pontis. (B) Thin-walled vascular channels are
separated by normal brain parenchyma.
rophages, gliosis with Rosenthal fibers, and recent

hemorrhage admixed or adjacent to a cavernous he-
mangioma are characteristic (Fig. 8.23B).
B
Capillary Telangiectasias
Capillary telangiectasias are incidental findings at au-
topsy and often are encountered in the centrum semio-
vale or basis pontis. They are composed of dilated thin-
walled vascular spaces separated from one another by
normal brain parenchyma. Grossly, these lesions are
slightly firm and hemorrhagic but do not have mass ef-
fect (Fig. 8.24A). Brain parenchyma within and adjacent
to the dilated capillary channels is normal and gliosis and
evidence of old hemorrhage is not common (Fig. 8.24B).
Venous Angiomas
FIGURE8.23 (A) Cavernous hemangioma of corpus callosum. (B) Venous angiomas are composed of dilated veins sepa-
Thin-walled vessels with focally hyalinized walls. rated from one another by brain parenchyma that usu-
ally is unremarkable. A large varicose draining vein is SLE is rare (Weiner and Allen, 1991). Neurologic symp-
often found. A “varix” refers to a single, anomalous, toms and signs in patients with SLE, often erroneously
large, tortuous vein and is a variant of a venous an- diagnosed as lupus cerebritis, are related to multifocal
gioma. cerebral ischemia arising from emboli from heart valves
(Libman-Sacks endocarditis) or intravascular thrombi
secondary to circulating antiphospholipid antibodies
VASCULITIS OF THE CENTRAL NERVOUS SYSTEM (Devinsky et al., 1988; Levine et al., 1990b). Ischemic
transverse myelitis may accompany SLE, and post-
Vasculitis of the intracranial blood vessels may be of mortem studies have shown thromboses of spinal ar-
infectious or noninfectious origin, as reviewed below. teries in some patients (Andrianakos et al., 1975).
Complications include focal atrophy with neuronal loss Primary vasculitis confined to the central nervous
and gliosis, infarcts, or hemorrhage. An additional system has been reported occasionally. Pathologic stud-
complication of infectious vasculitis, especially if due ies, when available, usually reveal a granulomatous
to a septic embolus, is the development of mycotic an- angiitis with variable giant cell formation involving
eurysm, as described above. leptomeningeal and parenchymal blood vessels (Lie,
1992). Special stains fail to reveal microorganisms, and
there is no evidence of sarcoidosis in these patients. Al-
Infectious Vasculitis
though the cause of granulomatous angitis is unknown,
Infectious causes of vasculitis include bacteria, fungi, an association with cutaneous herpes zoster suggests a
parasites, or virus and often are secondary to possible etiologic role of that virus.
meningeal infection. The vasculitis generally involves
leptomeningeal veins but arteries also may be affected,
Cranial (Temporal) Arteritis
and their occlusion, either by inflammation or throm-
bosis, results in cerebral infarcts. Septic emboli typi- Cranial (temporal) arteritis, an autoimmune disease of
cally lodge in intraparenchymal vessels but may affect extracranial arteries, develops in the sixth or seventh
the leptomeningeal vessels and be the cause of cere- decade (Huston and Hunder, 1990). Early symptoms
bral infarcts, arteritis, or mycotic aneurysms. Viral in- typically include a low-grade fever, malaise, and a
fections causing CNS vasculitis include varicella- throbbing unilateral or bilateral headache. These may
zoster virus (VZV), cytomegalovirus, herpes simplex be preceded or accompanied by proximal muscle pain
virus (HSV), and human immunodeficiency virus (polymyalgia rheumatica). The disorder responds well
(HIV). VZV can cause a proliferative arteriopathy of to steroids, but prolonged therapy with low-dose pred-
larger leptomeningeal vessels or a primary granulo- nisone is needed to prevent recurrence of the arteritis.
matous vasculitis of intraparenchymal vessels in the Important complications arise when the disease in-
apparent absence of VZV encephalitis. In these set- volves other extracranial arteries such as the oph-
tings, atrophy, demyelination, infarcts, and hemor- thalmic artery. The arteritis involves the extracranial
rhage may arise (Amlie-Leford et al., 1995). Infectious portions of the internal carotid or vertebral circulation,
vasculitides due to CMV, HSV, and HIV are uncom- but the intracranial portions are unaffected (Wilkenson
mon complications of their respective encephalitis or and Russel, 1972). Postmortem examinations demon-
nerve root infections. strate abrupt transitions between inflamed extracranial
As in any vasculitis, pathologic changes include in- vessels and uninvolved internal carotid or vertebral ar-
flammation within the vessel wall, necrosis, disruption teries as they enter the cranial cavity. Cerebral infarc-
or reduplication of the elastic lamina, and fibrointimal tion occurs if the affected arteries become occluded by
proliferation. Special stains, immunohistochemistry, thrombus or give rise to emboli.
and in situ hybridization are useful tools to identify mi- Microscopic findings include a mild-to-moderate
croorganisms and viruses. mononuclear cell inflammation of all three layers of the
artery (Fig. 8.25A). Characteristic multinucleated giant
cells (Fig 8.25B) often accompany the inflammatory in-
Noninfectious Vasculitis
filtrates, but their presence is not required for the di-
Systemic vasculitides rarely involve the CNS. When this agnosis. Fragmentation and reduplication of the elas-
does occur, it is more common with polyarteritis notic lamina is always present. Ingestion of elastic lamina
dosa than with systemic lupus erythematosus (SLE), hy- fragments by the giant cells has suggested that the dis-
persensitivity angiitis or Wegener’s granulomatosis ease has an autoimmune origin with autoantibodies di-
(Moore and Cupps, 1983). Cerebral vasculitis due to rected against the external elastic lamina of extracra-
B FIGURE8.26 Intravascular lymphoma, leptomeningeal artery. Lym-

phoma cells infiltrate vessel wall and occlude the lumen.
Clinically, patients present in their seventh decade

with multifocal neurological signs and symptoms; de-
mentia eventually develops in approximately 75% of
patients and is due to multiple cerebral infarcts. Fever
is encountered in 73%, skin lesions in 33%, and
organomegaly in 20%. Because the skeletal muscle and
peripheral nerves may be involved, biopsies of these
sites may avoid the need for a brain and leptomeningeal
biopsy.
Less common causes of neoplastic cerebrovascular
FIGURE 8.25 Temporal arteritis. (A) Thickened artery with intimal diseases include brain tumors with hemorrhages or the
thickening, inflammation, and giant cells. (B) Inflammatory infiltrate
production of pseudo-aneurysmal dilatations due to tu-
of lymphocytes and giant cells.
mor infiltration of leptomeningeal arteries. Systemic
tumor emboli occasionally can be seen at postmortem
examination, but clinical manifestations are rare.
nial arteries. Fibrointimal proliferation is prominent
and leads to occlusion of the lumen. Since skip lesions
are common, deeper sections throughout the tissue GENETIC DISEASES OF THE
block should be made if initial biopsy slides show only CEREBRAL VASCULATURE
normal artery.
Genetic diseases that result in direct damage to cere-
bral vessels are rare. One of the most common and best
NEOPLASTIC CEREBROVASCULAR DISEASES understood is the entity known as cerebral autosomal
dominant arteriopathy with subcortical infarcts and
Intravascular lymphoma is the principal neoplastic leukoencephalopathy; fortunately, this disorder also is
disease of consequence to the cerebral vasculature known by its initials—CADASIL (Bousser and Tournier-
(Sheibani et al., 1986; Demirer et al., 1994). This is a Lasserve, 1994; Ruchoux and Maurage, 1997). This
B-cell lymphoma with a predilection for the intracra- disorder is a mendelian autosomal dominant disease
nial and intraspinal leptomeningeal arteries (Fig. 8.26). due to a mutation in the notch 3 gene on chromosome
Subsequent vascular occlusion causes multiple infarcts 19q12 (Tournier-Lasserve et al., 1993). It is character-
of brain and spinal cord. Although the cerebral vessels ized by familial migraines, early onset stroke, and de-
bear the brunt of the disease, lymphomatous infiltrates mentia (Desmond et al., 1999). Notch 3 mutations also
and intravascular lymphoma appear also in systemic are associated with genetic migraines, hereditary parox-
organs including adrenals, kidneys, heart, stomach, pe- ysmal ataxia, and certain human and murine tumors
ripheral nerves, and skeletal muscle. (Gray et al., 1999).
Desmond et al. (1999) summarized the clinical find- duces a dissecting aneurysm of the carotid or vertebral
ings in 105 reported cases of CADASIL. Strokes or arteries. Radiation injury also affects cerebral blood
TIAs (43%) and migraines (42%) were the usual pre- vessels (O’Connor and Mayberg, 2000). Acutely, there
senting symptoms and signs. The overall average age is enhanced pinocytosis and blood–brain barrier break-
of symptom onset was 36.7 12.9 years although down with cerebral edema. Later stages may be asso-
those with migraine as the presenting illness had a ciated with delayed vascular necrosis. Radiation injury
lower age of onset than those whose initial symptoms to the neck vessels can result in fibrointimal prolifera-
were strokes or TIAs (28.3 11.7 years vs. 41.2 9.2 tion and accelerated atherosclerosis.
years). Other presenting symptoms included cognitive
impairment in 6% and depression in 8.6%. As the dis-
ease progressed, the overall incidence of migraines was THROMBOSES OF DURAL SINUSES AND
essentially unchanged (43%) but that of stroke/TIA CEREBRAL VEINS
(82%), cognitive impairment (18%), and depression
(20%) increased and overt dementia appeared in 42%. Thromboses of the dural sinuses and cerebral veins are
In the 22 of the 105 patients who died, the mean age generally divided into two groups (Bousser et al., 1985;
of death was 54.8 10.6 years. Nineteen of the 22 had Jacobs et al., 1996). Primary aseptic thromboses usu-
strokes or TIAs and 19 were demented. ally are associated with hypercoagulable states or cir-
The centrum semiovale bears the major burden of culatory slowing in conditions such as dehydration,
the disease and myelin pallor, demyelination, and in- pregnancy, oral contraceptives, hemolytic anemias, and
farcts are common. Arterioles are thickened and a gran- the postoperative period. Secondary or septic venous
ular deposit is present in their media, which is thrombi are seen with pyogenic infection of the face or
eosinophilic with Masson trichrome stain, stains posi- sinuses, subdural abscesses, and meningitis. Pathologi-
tively for elastic fibers, and is osmophilic on electron cally, the involved sinus or cortical vein is distended
microscopy. Its origin is uncertain but may represent and occluded by antemortem thrombus material (Fig.
degenerated elastic fibers. Small infarcts are also seen 8.4). Lines of Zahn and peripheral infiltration of the
in the basal ganglia, thalamus, and brain stem. The thrombus by fibroblasts assist in distinguishing ante-
gross and microscopic pathology of CADASIL bears a mortem from postmortem clot. When the venous
striking resemblance to hypertensive cerebrovascular thrombosis results in brain infarct, the necrotic brain
disease although the arteriolar sclerosis of hypertension is usually hemorrhagic and its location is dependent on
fails to display the granular osmophilic material in the the site of thrombosis. Infarcts are parasagittal with su-
media of the involved vessels. An accompanying sys- perior sagittal sinus thromboses and thalamic with
temic arteriopathy indicates the potential value of skin straight sinus thromboses. Thrombosis of the cavernous
biopsies in arriving at the diagnosis of CADASIL al- sinus results in periorbital edema and pupillary dilata-
though electron microscopy may be required to iden- tion, facial numbness, and visual loss.
tify the vascular abnormality (Ruchoux et al., 2000).
Other genetic vasculopathies include hereditary cere- BLEEDING DIATHESES
broretinal vasculopathy, hereditary encephalopathy
with retinopathy, nephropathy and stroke (HERNS), Microhemorrhages, or petechia, are the hallmarks of a
and mitochondrial angiopathy, which is seen in MELAS group of diverse diseases which include thrombotic
syndrome (mitochondrial myopathy, encephalopathy, thrombocytopenia purpura, disseminated intravascular
lactic acidosis, and strokelike episodes). (See review by coagulopathy, fat emboli, air (or nitrogen) emboli, arsenic
Jen et al., 1997.) poisoning, and cyanide intoxication. Thrombocytopenia
purpura tends to concentrate in the gray matter and the
TRAUMATIC ANGIOPATHIES remainder tend to concentrate in the white matter.
Physical trauma can rupture (1) the bridging veins be-

MISCELLANEOUS DISORDERS OF CEREBRAL
tween the cerebral hemisphere and the superior sagit-
BLOOD VESSELS
tal sinus, resulting in subdural hematomas; (2) the
epidural arteries, typically the middle meningeal artery,
Crack Cocaine Abuse
resulting in epidural hematoma; or (3) small intra-
parenchymal or leptomeningeal vessels in association Cerebral hemorrhages occasionally may accompany
with brain contusions. Rarely, physical trauma pro- crack cocaine abuse (Levine et al., 1990a). The fre-
quency is low and this complication certainly occurs Amarenco P., Heinzlef O., Lucas C., Touboul P.J., et al. (1996). Ath-
less often than myocardial infarction in this patient erosclerotic disease of the aortic arch as a risk factor for recur-
rent ischemic stroke. New Eng J Med 334(19):121–1221.
population. Although crack-cocaine-related brain hem- Amlie-Lefond C., Kleinschmidt-DeMasters B.K., Mahalingam R.,
orrhages initially were thought to be caused by a CNS Davis L.E., and Gilden D.H. (1995). The vasculopathy of
vasculitis with vessel wall inflammation, other studies varicella-zoster virus encephalitis. Ann Neurol 37:784–790.
suggest that hypertension, vasospasm, or a bleeding Andrianakos A.A., Duffy J., Suzuki M., and Sharp J.T. (1975). Trans-
diathesis may be causative (Merkel et al., 1995; verse myelopathy in systemic lupus erythematosus. Ann Intern
Med 83(5):616–624.
Kibayashi et al., 1995; Nolte et al., 1996; Aggarwal et Babikean V. and Ropper A.H. (1987). Binswanger’s disease: a re-
al., 1996). view. Stroke 8:2–12.
Becker D.H., Townsend J.J., Kramer R.A., and Newton T.H. (1979).
Occult cerebrovascul armalformations: a series of 18 histological
Snedden’s Syndrome verified cases with negative angiography. Brain 102:249–287.
Bousser M.G., Chiras J., Bories J., and Castaigne P. (1985). Cere-
Snedden’s syndrome is a rare disorder that combines bral venous thrombosis: a review of 38 cases. Stroke 16:199–213.
the dermatological finding of a livedo reticularis with Bousser M.G. and Tournier-Lasserve E. (1994). Summary of the Pro-
a progressive vascular dementia due to multiple cere- ceedings of the First International Workshop on CADASIL.
bral infarcts. Its onset is during early adult life. Other Stroke 25:704–707.
Brill J. (1969). Massive aneurysms at the base of the brain. Brain
clinical findings may include acrocyanosis, cardiac
92:535–570.
valvular anomalies, and hypertension. A family his- Broderick J.P., Brott T., Tomsick T., Miller R., and Huster G. (1993).
tory of the disease may be encountered. The etiology Intracerebral hemorrhage is more than twice as common as sub-
and the presence of an actual systemic or intracere- arachnoid hemorrhage. J Neurosurg 78:188–191.
bral vasculitis are uncertain and in situ thrombi or Brown W.R., Moody D.M., and Challa V.R. (1999). Cerebral fat
embolism from cardiopulmonary bypass. J Neuropath Exp Neu-
cardiac emboli may be important (Gerschwind et al.,
rol 58:109–119.
1995). Cadauid D., Mena H., Kodler K., and Frommelt R.A. (2000). Cere-
bral amyloid angiopathy is a risk factor for cerebral ischemia
infarcts. J Neuropath Exp Neurol 59:768–773.
Dego’s Disease Challa V.R., Moody D.M., Dixon M.D., and Bell M.A. (1992). Char-
cot-Bouchard aneurysm controversy: impact of a new histologic
Dego’s disease is a multisystem vasculopathy with pro- technique. J Neuropathol Exp Neurol 51:264–271.
gressive occlusion of small and medium-sized arteries Challa V.R., Moody D.M., and Brown W.R. (1995). Vascular mal-
of the skin and viscera. The nervous system occasion- formations of the central nervous system. J Neuropathol Exp
ally is involved (Subbiah et al., 1996) and venous si- Neurol 54:609–621.
nus thrombosis, subdural or intraparenchymal hemor- Chester E.M., Agamanollis D.P., Bankar B.Q., and Victor M. (1978).
Hypertensive encephalopathy: a clinicopathological study of 20
rhages, and infarcts may occur. Rarer conditions cases. Neurology 28:928–939.
include spinal cord infarcts, myopathies, and radicu- Chuaqui R. and Tapia J. (1993). Histologic assessment of the age of
loneuropathies. recent brain infarcts in man. J Neuropath Exp Neurol 52(5):
481–489.
Comu S., Verstraeten T., Rinkoff J.S., and Busis N.A. (1996). Neu-
Acute Posterior Multifocal Placoid rological manifestations of acute posterior multifocal placoid pig-
Pigment Epitheliopathy ment epitheliopathy. Stroke 27(5):996–1001.
Corey-Bloom J., Sabbagh M.N., Bondi M.W., Hansen L., Alford
APMPPE is another rare multisystem vasculopathy that M.F., Masleah E., and Thal L.J. (1997). Hippocampal sclerosis
usually presents as a chorioretinal disease of young contributes to dementia in the elderly. Neurology 48:154–160.
adults. Rarely, it is associated with strokes. Its average Coria F., Castano E., and Frangione B. (1987). Brain amyloid in nor-
mal aging and cerebral amyloid angiopathy is antigenically re-
age of onset is 24 years and the male:female ratio is 4:1.
lated to Alzheimer’s disease protein. Am J Pathol 129:422–428.
The etiology is unclear. In one review (Comu et al., Demirer T., Dail D.H., and Aboulafia D.M. (1994). Four varied cases
1996), arterial narrowing was seen with a cerebral an- of intravascular lymphomatosis and a literature review. Cancer
giogram in five of eight cases; arteriolar vasculitis was 73(6):1738–1745.
seen in one of one muscle biopsy; and granulomatous Desmond D.W., Moroney J.T., Lynch T., Chan S., Chin S.S., and
Mohr J.P. (1999). The natural history of CASASIL: a pooled anal-
angitis of the brain was seen in one of one autopsy.
ysis of previously published cases. Stroke 30:1230–1233.
Devinsky O., Petito C.K., and Alonso D.R. (1988). Clinical and neu-
ropathological findings in systemic lupus erythematosus: the role
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9 Central nervous system trauma
MARY E.S. CASE
Head injuries account for half of all trauma deaths and EXTERNAL EXAMINATION OF THE HEAD AND NECK
for more cases of permanent disability than any other
type of trauma (Kraus, 1993). Head injury statistics The examination of the head begins with inspection of
vary markedly depending upon how the head injury is the external surfaces of the head, face, and neck. Ar-
defined and whether the data come from hospitals, eas of wet or dried blood should call attention to sites
medical examiners’ reports, or police reports; data on of possible underlying injury. To properly examine in-
admissions for head injury are not collected uniformly juries in the scalp at autopsy, any hair surrounding the
in the United States. Many hospitalized patients who injury should be shaved away to provide better visibil-
have other severe injuries in addition to their head in- ity. Diagramming the injuries is useful if injuries are
jury do not have the diagnosis of head injury recorded numerous or complex in appearance. Standard points
in the hospital record, so those injuries are lost from of reference should be used to describe the location of
the database (Moss and Wade, 1996). In a series of the lesions in relation to such landmarks as the ante-
49,143 patients from 95 trauma centers, the overall rior midline, auditory meatus, vertex, occipital protu-
mortality of patients with head injury was 18.2%, three berance, and supraorbital rim.
times higher than in patients with no head injury
(Gennarelli et al., 1989). U.S. mortality data from 1979
to 1986 recorded 315,328 deaths associated with head BLUNT TRAUMA: ABRASIONS,
injury, representing 2% of all deaths, 26% of injury CONTUSIONS, LACERATIONS
deaths, and an annual death rate of 16.9 per 100,000
residents (Sosin et al., 1989). The head injury death An abrasion is a superficial injury produced when a
rate varies among different population settings up to a blunt impact scrapes away a portion of the skin sur-
high of about 32 per 100,000 residents, and urban pop- face (Fig. 9.1). Examples of abrasions are scratches and
ulations have the higher rates. The most common brush burns. An abrasion may have a recognizable pat-
causes of these head injuries are traffic accidents tern that suggests the mechanism or object that pro-
(⬃50%), gunshot wounds (20%–40%), falls (10%), duced it. A pattern frequently found on the face of a
and assaults (5%–10%). Head injury is a major cause traffic accident victim is the dicing abrasion, which con-
of mortality and morbidity at all ages. The death rate sists of very small edged or angled linear markings
for head injury in children is about 10 per 100,000, where the skin surface was struck by pieces of tem-
five times the mortality rate for leukemia, the next lead- pered automobile door glass, which shatters into cubes
ing cause of death (Kraus et al., 1986). The annual head when broken. These injuries are significant because
injury rate for children in San Diego was found to be they indicate a point of impact and may suggest the
185 per 100,000. The most common causes of child- mechanism of that impact.
hood head injury were falls (35%), recreational activ- A contusion or bruise is an area of discoloration, vis-
ities (29%), and traffic accidents (24%). The mecha- ible at the skin surface, that occurs when blunt force
nism of children’s head injuries varies with the age of strikes the body and causes small blood vessels beneath
the child. In some series, falls account for as many as the skin surface to rupture and bleed. As blood from
75% of head injuries in those under the age of 3 years the torn vessels enters the subcutaneous fat or deeper
(Jamison and Kaye, 1974; Hanhn et al., 1988; Luerssen soft tissues, it pools in the area of injury and imparts
et al., 1988). Many studies find that children have a initially a purple or blue color visible on the surface
lower mortality rate and better outcome than adults af- (Fig. 9.2). With the passage of time, the accumulated
ter severe head injury, although this trend does not hold blood is removed by phagocytes and the blood pigment
for the very young child who sustains abusive head in- is broken down; the color visible at the surface changes
jury (Berger et al., 1985; Alberico et al., 1987). to varying hues of green, brown, and finally yellow be-
140
9: CENTRAL NERVOUS SYSTEM TRAUMA 141
extravascular site to another. The external appearance

of the ecchymosis is similar to the discoloration of a
bruise, but an area of ecchymosis should be distin-
guished from a contusion because of the difference in
pathogenesis. Two types of ecchymosis are particularly
associated with head trauma.
Periorbital ecchymoses, or “raccoon eyes,” refers to
bluish or purple discoloration and swelling of the up-
per and lower eyelids (Fig. 9.3). The swelling may be
severe enough to preclude lifting the eyelid. Periorbital
ecchymoses are caused by fractures in the orbital roofs
of the anterior cranial fossae, which allow blood to
move downward from the fracture sites into the orbital
fat and subcutaneous tissue of the eyes. These ecchy-
moses do not indicate that a direct impact to the eye
region has necessarily occurred. Gunshot wounds of the
head in which a bullet passes through the calvarium
may result in orbital roof fractures and periorbital ec-
chymoses. A fall in which the back of the head strikes
a surface may result in contrecoup fractures of the or-
FIGURE 9.1 Acute abrasions on forehead, nose, cheek, and chin.
bital roofs and periorbital ecchymoses (Hirsch and
Kaufman, 1975) (Fig. 9.4).
fore fading away. Contusions indicate points of impact Mastoid ecchymosis—or the Battle sign—is a bluish
and may have patterns that are useful in identifying the discoloration of the skin overlying the mastoid area be-
striking object. Bruises can be easily seen on the face hind the ear. This ecchymosis is caused by fracture of
but may not be readily visible in the scalp even in very the petrous portion of the temporal bone, resulting in
young individuals. The scalp of an adult may absorb bleeding into the adjacent tissues. As the blood becomes
as much as 35% of the energy of an impact, dissipat- visible at the surface behind the ear, it is seen as the
ing the force of the impact before it reaches the un- Battle sign.
derlying structures. Although the scalp in infants is thin,
it is very elastic, so impacts, particularly broad-based
ones, may not leave a bruise on the surface. Contusions
on the neck may be of importance because they may
point to possible underlying vascular damage.
An ecchymosis is discoloration visible at the skin sur-
face that is caused by blood which has moved from one
FIGURE 9.3 Periorbital ecchymosis of left eye in patient with fracture

of left orbital roof caused by gunshot wound through left side of
FIGURE 9.2 Two areas of contusion on occipital scalp of infant. forehead.
Sharp Wounds
Incised wounds are made with cutting instruments such
as knives or scalpels. The edges of incised wounds are
sharply made and lack the marginal abrasion or con-
tusion found in the laceration. The depth of an incised
wound is uniform throughout its extent and lacks the
tissue bridges which are found in the laceration. Incised
wounds of the face, scalp, and neck do not differ greatly
from such wounds elsewhere. Stab wounds may pene-
trate the skull but are relatively uncommon. The areas
most easily penetrated by sharp instruments are the or-
bits and the thinner bone of the temporal calvarium.
Gunshot Wounds
Gunshot wounds that involve relatively loose, poorly
supported areas of the face, such as the nose, eyelids,
lips, and ears, may have unusual appearances, which
may make them difficult to identify as gunshot
FIGURE 9.4 Bilateral orbital roof fractures from impact to back of head.
wounds because these wounds often lack the charac-
teristic features that distinguish entrance and exit gun-
Lacerations are produced by a blunt object striking shot wounds. Entrance wounds in these sites are more
the skin surface and tearing open or splitting apart the likely to resemble an exit wound and often resemble
skin or scalp. The margins of a laceration tend to be tears with marked bruising at the margins. Intraoral
abraded or contused (Fig. 9.5). Within the depths of entrance wounds may present difficulty in examina-
the laceration can be seen strands of unevenly torn tis- tion because of the presence of rigor in the jaws after
sue or vessels bridging the gap of the wound. Blunt ob- death. After the calvarium has been opened and the
jects and forces commonly produce recognizable pat- brain has been removed, intraoral wounds can be ex-
terns in the lacerations they create. Linear objects amined by tracing the pathway downward from the
produce linear tears, and a round hammer head tends defect through which the missile entered the cranial
to produce a crescent pattern. cavity (Fig. 9.6).
FIGURE 9.5 Lacerations of scalp with marginal abrasions and tissue FIGURE 9.6 Intraoral entrance of gunshot wound passing upward
bridging. Patient was hit on head with crowbar. through clivus.
examination if determining the age of these hemor-

rhages is warranted.
EXAMINATION OF THE SKULL
The examination of the skull begins with inspection of

the calvarium to detect any wound or fracture that might
be present. In many head injuries the periosteum lying
over the calvarium is suffused with blood. Fractures are
best demonstrated by removing the periosteum in the
vicinity of fractures (Fig. 9.8). In young children the pe-
riosteum is particularly thick over the calvarium and may
obscure underlying fractures. The temporalis muscles
FIGURE 9.7 Large area of fresh subgaleal hemorrhage in left parietal should also be removed to adequately view the under-
scalp from head of young child. lying bone. Wounds or fractures should be described in
relation to standard landmarks, and diagrams are fre-
quently helpful to supplement photographs.
INTERNAL EXAMINATION OF THE SCALP As the calvarium is being opened, it is prudent to
saw around the areas of injury when possible. When
A mastoid-to-mastoid incision to open the head at au- the calvarium is lifted off, the presence of any epidural
topsy allows reflection of the scalp forward and back- or subdural blood should be noted because such blood
ward and permits close inspection of the undersurface will be lost during manipulation and removal of the
of the scalp (Fig. 9.7). Injuries that were visible exter- brain and it is important to note even very small quan-
nally can be viewed more fully from the undersurface, tities of such blood. The fit of the brain should be as-
and impacts to the head that did not produce an ex- sessed as the brain sits inside the cranial cavity (Fig.
ternal mark may be appreciated from the undersurface. 9.9). An atrophic brain appears to fit loosely, whereas
The location and size of subgaleal hemorrhages should a markedly swollen brain fits tightly. Fit is particularly
be noted, and diagramming these hemorrhages is often significant in infant brains and may be the best indi-
helpful. Tissue sections should be taken for microscopic cator of marked swelling.
A B
FIGURE 9.8 (A) Heavy periosteal bleeding over entire calvarium. (B) Hemorrhagic periosteum removed
to demonstrate gunshot wound surgically altered and linear fracture.
of force of the impact and is affected by the skull’s an-

atomic characteristics. Sites where fracture lines de-
velop depend upon certain anatomic features such as
the greater thickness of the frontal and occipital bones
as well as the petrous ridges contrasted to the thin tem-
poral bones. Computed tomography (CT) scanning per-
formed on patients with minor head injuries admitted
to a non-neurosurgical hospital found that 10% of
adult patients with a linear fracture had surgical in-
tracranial lesions, primarily epidural hematomas (Ser-
vadei et al., 1988a,b). Linear fractures account for 75%
of skull fractures of children (Rosman et al., 1979). A
late complication of linear fractures in childhood is the
growing fracture, which usually occurs before 3 years
of age. In a growing fracture, the fracture line is eroded
along the margin by a leptomeningeal cyst that pro-
trudes through a tear in the dura, causing the fracture
width to increase or grow with time.
FIGURE 9.9 Markedly swollen infant brain fits tightly inside cranial Basilar skull fractures
cavity.
Basilar skull fractures may be linear, depressed, or com-
minuted (Fig. 9.11). Fractures of the skull base may be
After the brain is removed from the cranial cavity, limited to the area of the base or may spread into the
the dura should be gently removed from the cranial fos- base from the calvarium. Several characteristic patterns
sae so that fractures and other wounds can be thor- of basilar fracture can be described. Comminuted frac-
oughly examined. Too vigorous pulling on the dura tures of the orbital roofs, which produce the raccoon
may create artifactual fractures. Wounds and fractures eyes previously described, are frequently associated
should be described in relation to standard landmarks. with gunshot wounds of the head, particularly from
temple to temple, and with falls in which the back of
the head forcefully strikes a surface. Deep linear frac-
Skull Fractures
tures extending from side to side across the middle cra-
A skull fracture indicates that sufficient force has been nial fossae through the petrous ridges and pituitary
applied to the head to exceed the bone’s ability to bend fossa, the hinge or rocker fracture, are commonly found
without breaking. A number of variables determine the in association with a massive impact to the side of the
ease with which bone will fracture, including the age, head, usually resulting from a traffic accident (Fig.
sex, and race of the patient, certain disease states, and
the anatomic location of the bone. Skull fractures can
be classified using a variety of schemes but generally
include the following types.
Linear fractures
A linear fracture is a simple fracture line or crack that
tends to radiate outward away from a point of impact
and extends through bone until the impact’s energy is
dissipated (Fig. 9.10). Extensions of the fracture line
travel the path of least resistance. Linear fractures may
originate in the calvarium and extend into the base of
the skull or may originate in the base. Linear fractures
are commonly produced by broad-based forces such as
the impacts that occur in traffic accidents and falls. The FIGURE 9.10 Linear fracture of left frontal and parietal calvarium
direction of the fracture line corresponds to the lines crossing coronal suture.
the skull base can result from damage to the structures

that reside in, enter, or leave the base. Tears of vessels
or venous sinuses, laceration of nerves, or damage to
the pituitary gland, inner ears, or paranasal sinuses may
complicate a basilar fracture.
Depressed fractures
Depressed fractures are produced by a forceful impact
that strikes the skull over a small surface area, result-
ing in a portion of bone being pushed inward, where
it may impinge upon the brain (Fig. 9.13). Examples
of such forces are homicidal assaults with hammers,
crowbars, or metal bars and impacts with protruding
pointed objects in vehicular collisions. The most com-
mon circumstances in which children sustain depressed
fractures are home accidents and traffic accidents. Chil-
dren with compound depressed fractures are much
more likely to have dural lacerations than children with
FIGURE 9.11 View of base of skull showing comminuted fractures of simple depressed fractures (Stahlhammer, 1986; Stein-
right and left anterior cranial fossae resulting from multiple blows bok et al., 1987).
to the head.
Comminuted fractures
9.12). Ring fractures extending through the posterior Comminuted fractures result from forceful heavy im-
and middle fossae to encircle the foramen magnum are pacts striking the head over a wide surface area with
caused most frequently by forceful hyperextension of the bone breaking into fragments (Fig. 9.14). Examples
the neck in traffic accidents or less commonly when the of these types of forces are a homicidal assault with a
spinal column is driven upward in falling from a height meat cleaver or a brick falling from a height to strike
and landing on the feet. Complications of fractures of the top of the head.
Diastatic fractures
Diastatic fractures occur when a fracture line extends
into a suture and causes the suture to open (Fig. 9.15).
These fractures result from forceful impacts and are
FIGURE 9.12 Deep hinge fracture across petrous ridges of middle cra- FIGURE 9.13 Deeply depressed fracture of right occipital bone sus-
nial fossae resulting from traffic accident. tained in fall down stairs.
several stories up, structural collapse of buildings, and

other devastating situations, all of which are readily
verifiable by examination of the scene (Jamison and
Kaye, 1974). A large literature currently exists that doc-
uments more than 1000 children who have been ex-
amined for head injury after trivial falls in or around
the home or from hospital beds witnessed by unbiased
observers (Kravitz et al., 1969; Helfer et al., 1977; Ivan
et al., 1983; Billmire and Meyers, 1985; Garrettson and
Gallagher, 1985; Nitnityongskul and Anderson, 1987).
Following these trivial falls, none of these children was
found to have sustained neurological deficit or lethal
injury, although about 1% do have skull fractures that
may occasionally be complicated by epidural hemor-
FIGURE 9.14 Comminuted fracture of left temporoparietooccipital rhage and increasing intracranial pressure secondary to
calvarium from blows with crowbar. the hemorrhage. When skull fractures occurred in these
trivial accidents, the fractures were found to be linear,
most common in childhood before the sutures are narrow, parietal, and uncomplicated with the excep-
firmly ossified. tion of the occasional epidural hemorrhage (Meservy
et al., 1987). Hobbs studied a group of children under
2 years of age who had sustained skull fractures in ei-
Compound fractures ther accidental or nonaccidental circumstances (Hobbs,
Compound fractures are those in which the overlying 1984, 1989). Based on his investigation of these chil-
scalp is lacerated. Compound fractures may occur with dren, Hobbs suggested that skull fractures after an al-
any of the other types of fracture. leged minor accident indicate abuse if one or more of
the following are present:
Childhood fractures 1. Multiple or complex fracture

2. Depressed fracture
Skull fractures in children have a number of unique fea- 3. Maximum fracture width greater than 3 mm
tures (Harwood-Nash et al., 1971). Head injuries are 4. Growing fracture
common abusive injuries and account for up to 80% 5. Involvement of more than one cranial bone
of deaths from inflicted or abusive trauma in children 6. Nonparietal fracture
(Case, 1997). Fifty percent of children with fatal in- 7. Associated intracranial injury
flicted head injuries have skull fractures. Accidents in
children that can result in serious head injury or death
include traffic accidents, falling out of windows from BRAIN DAMAGE RELATED TO TRAUMA
Traumatic brain injury is classified in the following sec-

tions based partly on Adams’s scheme for “brain dam-
age in fatal non-missile injury” with the addition here
of penetrating injuries (Adams et al., 1980a).
Immediate-Impact Injury
Immediate-impact injuries are traumatically caused le-
sions that are generated at the time of impact and are
produced by the direct damage of the impact itself rather
than arising as a complication of the traumatizing force.
Contusions
FIGURE 9.15 Diastatic fracture of lambdoid suture resulting from mul- A contusion is a bruise of the brain’s cortical surface
tiple blunt impacts with linear blunt object. in which tissue is disrupted and devitalized and bleed-
ing in the contusion is caused by torn vessels within the A

cortex. Depending on the forcefulness of the impact
that caused the contusion, the bruise may occupy only
a portion or the entire depth of the cortical layer with
the lesion extending from the subpial zone inward (Fig.
9.16). Contusions tend to be wedge shaped, with their
base lying along the crest of the gyrus and the apex di-
rected toward the subcortical white matter.
Continued bleeding within a contusion may extend
down into the subcortical white matter, producing a
contusion hemorrhage. In contusions the subpial layer
is studded with small hemorrhages, an appearance
which distinguishes contusions from early infarction,
which spares the subpial layer. Contusions are focal
damage, and even in severe cases they may be associ-
ated with complete clinical recovery although the con-
tused tissue will be permanently lost. The necrotic cor-
tical tissue of the contusion is removed by the usual
inflammatory processes, accompanied by macrophages
and reactive gliosis, eventually resulting in a sunken
orange–brown scar. Contusions large enough to pro- B
duce subcortical hemorrhage may heal to form a cys-
tic cavity containing glial trabeculae with remnants of
hemorrhage visible as brown–orange hemosiderin
staining within the cyst (Fig. 9.17).
Contusions tend to be larger and more hemorrhagic
in patients who are alcoholic or hypertensive or who
have bleeding diatheses. Adams and associates devel-
oped a contusion index in which the depth and extent
of contusions were graded in the frontal, temporal,
parietal, and occipital lobes, in the cortex above and
below the Sylvian fissures, and in the cerebellum
(Adams, 1980b). The indices reflected the severity of
contusion at each site and were used to assess other
FIGURE 9.17 (A) Large area of old contusion involving right frontal
types of head injury such as skull fracture or diffuse pole, right orbital surface, and right temporal pole from a motorcy-
axonal injury. cle accident 25 years previously with comminution of frontal skull.
(B) Coronal sections of old contusion shown in (A). Contusion cav-
ity extending deep into right basal ganglia and lateral ventricle.
A number of theories have been proposed to explain

the phenomenon of contusion in relationship to certain
movements of the head. Holbourn’s rotational shear
force theory to some extent explains the contrecoup
pattern that contusions often assume (Holbourn, 1943,
1945). Holbourn studied the two components of iner-
tial loading—translatory movement, or the movement
of the brain in a straight line within the cranial cavity,
and rotatory movement, in which the brain rotates as
if on an axis. Holbourn found translational movement
to be relatively benign in the mechanics of brain injury.
FIGURE9.16 Acute cortical contusions with punctate and streak hem- His theory suggests that rotational movements of the
orrhages within cortex. brain generate shearing forces that produce contusions
in a distribution described as the contrecoup pattern. common contusions and occur in a variety of falls. Typ-
Shearing forces are those forces that act on the surface ical falls in which such a pattern of contusion would be
of a body to try to change that body’s shape. Com- expected occur when (1) an upright individual falls
pressive forces are forces that act to compress a body. backward or to the side or (2) jumps from a moving
Holbourn and others have found the brain to be more vehicle, (3) when an individual seated in a high upright
susceptible to shearing forces than to compressive position (a bar stool, for instance) falls and strikes their
forces. Parts of Holbourn’s theory are helpful in ex- head, or (4) when an upright individual falls down the
plaining contusional patterns in relation to movement stairs. Falls from a height greater than about one story
of the brain. The anterior and middle cranial fossae of may result in skull fractures but do not produce con-
the skull base have the rigid projections of the sphe- trecoup contusions. In falling from these greater heights,
noid wings and the petrous ridges. Either impact or im- the brain and head both fall at the same rate without
pulse to the head that causes the brain to rotate within developing the brain lag that accompanies the falling
the cranial cavity will cause the frontal and temporal head that has angular acceleration, which results when
portions of the brain to sweep across these bony pro- the body is closer to the surface from which the indi-
tuberances, creating shearing forces and possibly bruis- vidual falls and the body rotates about a fixed point of
ing those surfaces of the brain. contact (Dawson et al., 1980). The contrecoup pattern
of contusion is the pattern of contusion expected when
a moving head strikes a surface in a fall involving an
Coup contusions
angular acceleration in an individual older than about
Coup contusions are produced by an impact to the sta- 4 years of age. In younger children, a variety of anatom-
tionary head that deforms but doesn’t fracture the skull ical and developmental differences affect the outcome
and imparts energy to the underlying brain, damaging of falling and these differences will be discussed in the
the cortical surface beneath the impact. Precisely how section “Head Injuries of Infants and Young Children.”
the energy of the impact damages the cortical surface As aging occurs and brain atrophy develops, elderly
is unknown. Coup contusions are relatively uncommon adults sustaining falls with angular acceleration do not
contusions, although they are frequently mistakenly di- demonstrate contrecoup patterns of contusion with the
agnosed in contusions adjacent to fractures that should same frequency as the younger adult, although these
be considered fracture contusions. The extent and contusions may occur in some elderly patients. More
severity of the coup contusion tend to be much less ex- frequently, the elderly person who sustains a fall that
tensive than the contrecoup contusion. Occasionally, produces a significant neuropathological outcome will
the impacting force striking the stationary head is so have subdural hemorrhage.
massive that rotational movement of the brain occurs Contrecoup contusions demonstrate the same patho-
resulting in a contrecoup pattern of contusion, but such logic features as do other contusions but commonly
cases are rare. Coup contusions appear grossly and mi- tend to be more severe in terms of depth and breadth.
croscopically identical to other bruises of the brain. These contusions occur over the frontal and temporal
They are located most commonly over the convex and poles, over the orbital surfaces of the frontal lobes, and
lateral cerebral surfaces. The blow to the head that along the ventral and lateral surfaces of the temporal
causes a coup contusion commonly produces contusion lobes (Fig. 9.18). The point of impact to the head tends
of the scalp, which appears as subgaleal hemorrhage at to be approximately opposite the most severe extent of
the overlying site. the contusion complex, although contusions may also
appear elsewhere in the frontotemporal zones. Contre-
coup contusions tend to extend deeply into the brain
Contrecoup contusions
so that much or all of the cortical layer is occupied by
Contrecoup contusions are produced when the moving contusion with some extension into the subcortical
head strikes a surface that imparts a massive force to white matter. The surface of these contusions is dis-
the head. According to Holbourn’s theory, the head in rupted, pulped cortex that resembles raw meat. Con-
motion as it falls develops a brain lag with the brain trecoup contusions may be so severe that the lep-
trailing further away from the leading margin of the tomeninges are torn, exposing the underlying cortex.
skull. On impact, the brain rotates within the cranial Blood can easily leave the subarachnoid space through
cavity and damage occurs over the frontal and tempo- the torn leptomeninges and can enter the subdural
ral regions of the brain as these areas rub along the bony space, producing subdural hemorrhage. “Burst lobe”
prominences of the anterior and middle cranial fossae refers to such a pulped frontal or temporal pole with
(Holbourn, 1945). Contrecoup contusions are relatively overlying subdural hemorrhage (Fig. 9.19).
A complete loss of balance, but few people fall so freely

forward. The compressible air-filled energy-absorbing
facial bones also provide a cushion that protects the in-
tracranial structures (Lee et al., 1987). An exceptional
frontal impact fall victim is shown in Figure 9.20. Af-
ter this very intoxicated man was arrested and had his
hands handcuffed behind him, he staggered and fell for-
ward, striking the right side of his forehead on a curb.
Autopsy showed a fracture of the right orbital roof with
fracture contusion of the right orbital gyri. There was
very heavy contrecoup contusion over the left lateral
temporal surfaces. Because this man’s arms were hand-
cuffed behind him, they were unavailable to break his
fall. The location of the contusions in this patient in-
cludes that portion of the brain which sweeps over the
bony prominences of the anterior and middle cranial
fossae and lies almost directly opposite the point of im-
pact. The point of impact was far forward and the con-
trecoup contusions are seen much farther behind the
B usual contused sites because these areas rotated much
further forward than usual.
Contusions in infants and children

Contusions are rare in infants and young children.
Courville studied 48 children under 5 years old to de-
termine at what age the lesions typical of coup–
contrecoup contusions appear (Courville, 1965). Eigh-
teen of these children had a fatal brain injury whose
mechanism indicated a possibility of contrecoup le-
sions. Two children under 3 years of age were consid-
ered to have contrecoup contusions. One of these was
a 6-week-old infant said to have fallen from its crib
FIGURE 9.18 (A) Massive contrecoup contusions of bilateral orbital onto the right side of the head who was found at au-
surfaces and frontal poles from impact to occipital region in fall from
moving van. (B) Sagittal section through cerebral hemispheres with
massive frontal contrecoup contusions shown in (A).
The classic contrecoup contusion occurs when the

moving head strikes the occipital or lateral surface and
contusions are produced over the frontotemporal zones
almost in a direct line opposite the point of impact. Im-
pacts to the front of the head occurring in a fall do not
produce contrecoup contusions in the occipital poles.
The smooth curvature of the posterior fossa does not
have ridges that can produce shearing forces as the oc-
cipital lobes sweep across that surface. Falls in which
the front of the head forcefully and freely strikes a hard
surface are fairly rare because people falling forward
usually land on the knees or extend the arms to break FIGURE 9.19 Close-up view of contrecoup contusions of orbital sur-
the fall. Many people hit the head very forcefully when faces shown in Figure 9.18A with rupture of blood through arach-
falling directly backward or sideways as a result of a noid into subdural space. “Burst” lobe.
A explain why the morphology of brain injuries is dif-

ferent in this age group from those later in life will be
discussed in the section “Head Injuries of Infants and
Young Children.” Studies of contusions in children
done more than 25 years ago must now be viewed with
the possibility in mind that many of the older cases
studied were unrecognized abusive injuries.
Lindenberg and Freytag described a lesion that they
termed a “contusion tear” in the brains of 16 infants
under 5 months of age (Lindenberg and Freytag, 1969).
These infants sustained their injuries as a result of al-
leged falls or impacts to the head. Tears involving the
cerebral white matter appeared as grossly evident slits
or irregularly shaped clefts. Some of these tears ex-
tended into the cortex or the lateral ventricles. They
occurred most often in the orbital and temporal lobes
and in the first and second frontal convolutions. The
tears contained small amounts of blood when fresh,
B
and older lesions were smooth-walled defects with faint
brown–yellow staining of the walls. In addition to the
tears visible grossly, microscopic tears were found in
which the outer zone of the first layer of the cortex was
separated from the underlying cortex in a horizontal
tear running parallel to the surface of the convolution.
Lindenberg and Freytag explained that the white mat-
ter tears resulted from an indentation of the skull on
impact that deformed the brain by flattening the con-
volution and generating shearing forces in the subja-
cent white matter. Tears away from points of impact
were related to shifting of the brain. The tears in the
external layer of the cortex were explained as resulting
from shearing forces acting parallel to the brain sur-
face either at impact or as the brain shifted. Calder et
FIGURE 9.20 (A) Handcuffed intoxicated man fell and struck right
side of forehead on curb, sustaining fracture contusions of right oral. suggested that the smooth lining of the inner table
bital gyri. (B) Left lateral cerebral surface with contrecoup contu- of the skull in infants facilitates the transfer of shear-
sions over left temporoparietal surfaces from right frontal impact. ing forces into the white matter, where tears then oc-
cur (Calder et al., 1984). Since the advent of CT, many
children have undergone cranial examinations for acute
topsy to have extensive contusion of the left temporal head injury. Occasional reports have described contu-
lobe. Today, the mechanism of this infant’s injuries sions in young infants observed by CT, but most stud-
would probably be interpreted as abusive impacts to ies fail to find contusion as a common lesion (Cohen
the head rather than a fall. The other child was 21 et al., 1986; Ellison et al., 1978; Zimmerman et al.,
months old and was said to have fallen from a ladder, 1978a). These injuries in young children will be con-
height unknown, and to have hit the back of the head. sidered in “Head Injuries of Infants and Young Chil-
This child at autopsy had minimal contusions of the dren.”
subfrontal and anterior temporal regions that were de-
scribed as “marked only by miliary hemorrhages in the
Fracture contusions
cerebral cortex.” Among the children less than 3 years
old, Courville found contrecoup contusions in only Fracture contusions are contusions that occur immedi-
25% of those whose reported mechanism of injury ately adjacent to a skull fracture. The edges of the frac-
would suggest contrecoup lesions. After 4 years of age tured bone may directly strike the adjacent convolu-
the frequency increased to 70% of the expected. Char- tions, bruising an area considerably larger than the
acteristics of the infant and young child’s head that may fracture. Many of the lesions described as coup contu-
sions are actually fracture contusions. When fragments are driven into the brain resulting in fracture contu-
of bone extend into the cortical surface, there is tear- sions and lacerations of the brain. Contusions do not
ing of the leptomeninges and brain and the lesion behave either a coup or a contrecoup pattern. The edges
comes a laceration (Fig. 9.21). Fracture contusions can of the lacerated brain may be relatively nonhemor-
be found in any part of the brain wherever the skull is rhagic or may have fairly heavy fracture contusions.
fractured. Gunshot wounds of the skull often produce The brain may lose much of its normal contour and is
fracture contusions around the entrance and exit best described as macerated. Occasional injuries of this
wounds of the brain. Fracture contusions do not de- type are produced by homicidal assaults with heavy in-
note any information about movement of the head or struments such as hammers or cleavers.
brain in relationship to one another. Repeated blows to the head shatter the skull, often
exposing the brain directly to the impacts. Amazingly,
some victims of these injuries remain conscious during
Herniation contusions
the assault, although the brain damage will be ulti-
Herniation contusions are produced by explosive forces mately lethal as brain swelling and increased intracra-
thrusting a portion of brain against a firm bony ridge nial pressure develop. Failure to lose consciousness de-
or dural boundary. These contusions occur on the ven- spite massive brain injury is related to the lack of
tral surfaces of the hippocampal, parahippocampal, acceleration of the brain in these injuries, and con-
and occipitotemporal gyri remote from the site through sciousness can be maintained as long as the deep gray
which a missile passes as it travels through the cerebral structures and brain stem are intact (Ommaya and
hemispheres. Herniation contusions can also occur over Gennarelli, 1974).
the ventral surface of the cerebellar hemispheres when
a missile passes near that area.
Falls from a great height
In a fall from a height greater than about the first story,
Other Impact Injuries
the body tends not to rotate about a point of contact,
Crushing head injury the head will not develop angular acceleration, and at
impact, both the skull and the brain will be traveling
Crushing head injuries occur when the stationary head
at the same rate of speed (Dawson et al., 1980). Be-
is struck by a massive object that crushes the skull
cause the skull and brain of a freely falling head im-
(Duhaime et al., 1995). Examples of such injuries in-
pact at the same moment, no rotation of the brain oc-
clude the pedestrian whose head is run over by the
curs within the cranial cavity. Without rotation of the
wheel of a vehicle and industrial accidents in which a
brain, the pattern of contrecoup injuries does not de-
mechanical apparatus accidentally closes on a worker’s
velop. The injuries to the brains in falls from great
head with great compressive force. As the skull frac-
heights resemble the injuries created by a crushing head
tures into fragments and collapses inward, bone shards
injury. Massive fracturing of the skull and laceration
of the brain are produced, and any contusions seen are
fracture contusions
Diffuse axonal injury

Diffuse axonal injury was first described as diffuse de-
generation of the white matter by Strich in 1956 and
has been described by others as inner cerebral trauma
and shearing injury (Strich, 1956; Peerless and Rew-
castle, 1967; Grcevic, 1982). Brains with this injury of-
ten appear relatively normal to the unassisted eye.
Brains with the most severe degrees of diffuse axonal
injury have focal lesions in the corpus callosum, focal
lesions in one or both dorsolateral quadrants of the ros-
tral brain stem, and diffuse injury to axons. The lesions
FIGURE 9.21 Fracture contusions and cortical lacerations along left
in the corpus callosum and dorsolateral quadrants of
lateral and convex and right convex cerebral surfaces resulting from the rostral brain stem are recognizable grossly in a well-
blows to head from crowbar. fixed brain but may be difficult to readily observe in
fresh specimens. In the early stage of injury (days), the injury such as victims of traffic accidents who are dead
lesions are small hemorrhages—either streaks of hem- at the scene obviously have very significant brain in-
orrhage or small punctate intraparenchymal hemor- jury yet the brain lesions may not be grossly evident or
rhages. In the corpus callosum, the lesions tend to be may be very sparse because the appearance of the gross
horizontal linear streaks of hemorrhages usually situ- lesions is dependent upon hemorrhage, and these vic-
ated more laterally, although they may be seen also tims may expire before there is much bleeding into their
midline in more severe cases. The brainstem lesions lesions even though the axonal damage is lethal. The
consist of small punctate hemorrhages along the lateral amount of subdural hemorrhage and subarachnoid
margins of the tegmentum of the midbrain and pons. hemorrhage may also be very sparse for the same rea-
In addition to the lesions in the corpus callosum and sons. The hemorrhagic lesions as well as the subdural
rostral brain stem, similar hemorrhagic lesions may be and subarachnoid hemorrhages are markers of the un-
found in the subcortical white matter, fornix, tela derlying axonal injury in cases of persons dying from
choroidea, walls of the third ventricle, basal ganglia, closed-head trauma in whom there is no mass lesion to
and hippocampal regions (Fig. 9.22). Large streak hem- account for their neurological deterioration or death.
orrhages of the frontal subcortical white matter are seen On microscopic examination the diffuse injury of ax-
in severe cases, and this lesion appears to be identical ons appears as damage to nerve fibers, which in the
to the gliding contusion described by Lindenberg and early stage takes the form of numerous axonal retrac-
Freytag (1957; Adams and Doyle, 1986). Individuals tion bulbs in the white matter of the cerebral hemi-
who have sustained diffuse axonal injury also demon- spheres, the cerebellum, and the brain stem (Fig. 9.23).
strate bleeding within the subdural space which is fre- The retraction bulbs may be visible by light microscopy
quently midline and posterior and will have small foci after 18–24 hours as accumulations of axoplasm which
of subarachnoid hemorrhage on the cerebral convexi- appear on H&E staining as pink bulbs where axons
ties. Victims who die very quickly from diffuse axonal have been severed and the axoplasm of the disrupted
A B
FIGURE 9.22 (A) Diffuse axonal injury in coronal section of brain

from traffic fatality with streak and ball hemorrhages of right sub-
cortical white matter (gliding contusion), left centrum semiovale, and
left side of corpus callosum and basal ganglia. (B) Punctuate hem-
orrhages in pontine tegmentum in diffuse axonal injury in same pa-
tient as (A). (C) Streak hemorrhages in cerebellar white matter in dif-
fuse axonal injury.
1977; Zimmerman et al., 1978; Van Dongen and

Braakman, 1980; Levi et al., 1990).
Magnetic resonance imaging (MRI) can be used to
identify the gross lesions of diffuse axonal injury, par-
ticularly after the early stage. Levin and associates ob-
served that patients with the most severe diffuse axonal
injury had deeper parenchymal lesions identified by
MRI than patients with less severe damage (Levin et
al., 1988).
Diffuse axonal injuries (DAIs) result most commonly
from traffic accidents and occur less often in falls and
assaults to the head, although lesions of diffuse axonal
injury are seen also in these patients in association with
other injuries (Adams et al., 1989; Imajo, 1996). When
FIGURE 9.23 Section of pons with numerous retraction balls. Hema- compared with other head-injured patients, patients
toxylin and eosin, 400. with diffuse axonal injury have fewer skull fractures
and a lower incidence of cerebral contusions, intracra-
nial hematoma, and elevated intracranial pressure. Pa-
axons leaks out the severed end and creates a bulbous tients with moderate-to-severe diffuse axonal injury are
enlargement of the end. Immunocytochemical stains rendered immediately unconscious by their injury; the
such as amyloid precursor protein may enable the cause of the unconsciousness is axonal injury as deep
demonstration of axonal injury after survival as short as the deep gray matter of the basal ganglia and thal-
as 2 hours (Sheriff and Bridges, 1994). Although ax- amus. Many of these latter patients who survive for
onal processes are usually the designated site of injury long periods following these injuries do so in persistent
in diffuse axonal injury, axons are taken to include all vegetative states. DAI patients survive longer than se-
the processes of the neurons and include the dendrites verely head-injured patients without diffuse axonal in-
also (Folkerts et al., 1998). In patients who have sur- jury (Adams et al., 1982).
vived for several weeks, the damaged areas demonstrate Strich concluded that axonal damage is produced by
breakdown of myelin with vacuolation of the neuropil mechanical forces engendered at the moment of impact
and small clusters of microglia in the white matter of and which physically disrupt axons (Strich, 1961).
the cerebral hemispheres, the cerebellum, and the brain Some investigators have suggested that the damage to
stem. In patients dying many months after the injury, the white matter is a secondary event and is due to hy-
Wallerian degeneration is present in the long tracts poxic brain damage, edema, or herniation compression
throughout the cerebral hemispheres, the brain stem,
and the spinal cord. Gross findings include a reduced
bulk of the white matter of the cerebral hemispheres,
an increased size of the ventricles, and old sunken
scarred defects where tissue was lost or small hemor-
rhages resolved (Adams et al., 1980) (Fig. 9.24).
Lesions of diffuse axonal injury can be recognized by
CT and correspond to the gross autopsy findings. In
the acute stage, bilateral cerebral swelling with ven-
tricular and cisternal compression, eccentric hemor-
rhage in the corpus callosum, and the absence of a fo-
cal mass lesion are the most frequent findings on cranial
CT. Less often identified are small areas of hemorrhage
adjacent to the third ventricle or within the white mat-
ter of the cerebral hemispheres. Small amounts of sub-
dural and subarachnoid hemorrhage are frequently de-
scribed. Within 2–3 weeks following the injury, FIGURE 9.24 Old lesions of diffuse axonal injury—in a patient in a
persistent vegetative state for 7 years following a traffic accident—
atrophic enlargement of the lateral ventricles can be showing marked thinning and discoloration of corpus callosum, small
identified and focal areas of decreased density within cavities from old punctate hemorrhages in basal ganglia, reduction
the cerebral white matter may be seen (Dublin et al., of bulk of white matter, and moderate ventricular dilatation.
of the brain stem; however, the pathology of the le- swelling was formed. Recent investigations by Povli-
sions of diffuse axonal injury do not appear similar to shock and his colleagues on nondisruptive axonal in-
the pathology of those lesions (Jellinger and Seitel- jury distinguished morphologically between axonal
berger, 1970). swelling and axonal bulbs where the most severely in-
Gennarelli and associates produced diffuse axonal jured axons are torn at the time of injury and the ma-
injury in monkeys using only controlled angular head jority of axons enter a pathologic sequence of changes
acceleration in the sagittal, oblique, or lateral direc- leading to secondary axotomy (Povlishock, 1992, 1995;
tion without the necessity of impact to the head Maxwell et al., 1997).
(Gennarelli, 1982a). The Penn II device developed by The mechanism postulated to account for the lesions
those investigators is a head-accelerating machine that of diffuse axonal injury is rotational movement of the
uses a nonimpact, distributed acceleration load to brain within the cranial cavity either in response to im-
move the head in a controlled pathway. A 60° angu- pact to the head or to nonimpact inertial mechanisms
lar movement was allowed for each direction acceler- such as shaking of the head or body. As the skull turns
ated. Monkeys were placed in the apparatus with their or rotates in response to such an impulse, the brain also
heads in a helmet that could move the head sagittally moves to follow the movement of the skull and has to
(posterior to anterior), obliquely (head turned 30° to rely on its rigidity to avoid being left behind the skull.
the left and moving posterior to anterior), or laterally Because the brain is not very rigid, it does lag to a con-
(head turned 90° to the left and moving left to right). siderable degree behind the skull. In the rotation of the
Diffuse axonal injury was found in 18 of the 26 ani- brain, the most peripheral layers of the brain generally
mals and was classified into three grades of increas- rotate further than the inner deeper layers. Due to the
ing severity from axonal abnormalities only in the nonuniformity and different consistencies of the brain
parasagittal white matter (grade 1), to a focal lesion structures, strains result at the junctures between the
in the corpus callosum in addition to axonal damage various structures, resulting in tears of axonal processes
in the parasagittal white matter (grade 2), to axonal occurring at the interfaces. Lesser forces act to disrupt
damage in the white matter, a focal lesion in the cor- the most external junctures while greater forces disrupt
pus callosum, and a focal lesion in the region of the deeper and deeper junctures down to the deep gray mat-
superior cerebellar peduncle (grade 3). The lesions ter of the basal ganglia and thalamus and, most deeply,
found in the corpus callosum and rostral brain stem to the rostral brain stem. Loss of consciousness is as-
were similar to those seen in humans with diffuse ax- sociated with disruption of axonal processes within the
onal injury. The presence and extent of diffuse axonal deep gray structures.
injury correlated highly with a lateral direction of ac-
celeration. Gennarelli’s model has provided a repro-
Brainstem avulsion
ducible animal model for diffuse axonal injury. He
concluded that prolonged coma and diffuse axonal in- Very forceful hyperextension injuries of the head which
jury do not result from an object striking the head but are most often sustained in traffic accidents may pro-
are due to the movements imparted to the head. Ax- duce a complete or partial tear or avulsion transversely
onal injury in the brain is proportional to the degree across the brain stem. These tears develop most often
of coronal motion, and the amount of diffuse axonal at the pontomedullary junction or occasionally at the
injury parallels the severity of injury as measured by cervicomedullary junction. The tear or avulsion grossly
duration of coma, neurologic signs, and outcome. consists of an irregular separation arising on the ven-
Studies by Povlishock and coworkers have identified tral surface of the brain stem and extending to variable
and elucidated the axonal changes that precede for- depths toward the dorsal surface at the pontomedullary
mation of the axonal retraction bulbs (Povlishock et junction (Fig. 9.25). The disruption may be partial or
al., 1983). Using light and electron microscopic stud- it may completely separate the two portions of brain
ies of the intraaxonal anterograde transport of horse- stem. The torn brain stem looks pasty and usually is
radish peroxidase in animals with minor head injury accompanied by little bleeding with small streaks of
over a 24 hour period, these authors found that shear- hemorrhage in the adjacent brain stem. A small-to-
ing forces did not tear axons but initiated a progres- moderate amount of subarachnoid blood lies over and
sive axonal change. Retraction bulbs formed from adjacent to the laceration. Most of these victims die im-
swelling of the axon, which resulted from accumula- mediately, but short-term survival has been described
tion of organelles as axoplasmic transport was impaired in a few (Pilz et al., 1982). Whether such brainstem
in the injured axon. The separation of the proximal and avulsion can occur without diffuse damage elsewhere
distal axonal segments did not occur until the reactive in the brain is still debated by a few investigators but
caliber, the bullet construction, and the range of fire.

For shotgun wounds of the head, the behavior depends
mainly on the range of fire; if the gun is fired at short
range, the wound will usually be perforating. Gunshot
wounds of the head caused by high-velocity missiles
also tend to be perforating. Of gunshot wounds to the
head caused by handguns, about 30% perforate the
head and about 30% perforate the skull. As the caliber
of the bullet increases, the tendency to perforate the
head increases. The construction of the bullet affects
its behavior; bullets that are fully jacketed with copper
perforate more readily than other forms. At the closer
ranges of fire, the bullet is more likely to perforate (Di-
Maio, 1999). A common behavior for a low-velocity
FIGURE 9.25 Complete transection of pontomedullary junction from missile is for it to enter the head, pass through the brain,
traffic accident. bounce off the inner table of the skull, and then either
ricochet back into the brain to create a secondary track
or skim along the surface of the brain adjacent to the
is thought by many not to occur without diffuse dam-
skull. The position of an intracranial bullet does not
age elsewhere (Ommaya and Gennarelli, 1974).
necessarily indicate that the bullet took a direct path-
way from its point of entry to the final resting site. A
Penetrating Injuries second common behavior for a low-velocity missile is
for it to pass through the brain and, lacking the nec-
Gunshot wounds of the head
essary energy to exit the skull, to come to rest at the
The wounding capacity of a missile depends on the en- dura–inner table juncture. Lastly, a low-velocity mis-
ergy which is transferred from the bullet to the tissue sile may partially exit the skull and be recovered just
through which the bullet passes. The velocity of the under a raised-up bone flap or it may exit the skull
missile is the primary determinant of the amount of en- fully and come to rest just under the scalp.
ergy the missile can transfer. Low-velocity missiles are Gunshot wounds can be classified on the basis of the
those which travel slower than 1500–2000 feet per sec- distance between the muzzle and the point at which the
ond and include bullets fired by most civilian hand- bullet enters the body surface. Contact gunshot wounds
guns. The damage produced by a missile passing are wounds made with the muzzle of the gun in con-
through tissue is caused by both the permanent track tact with the body surface. The edges of a contact
of the bullet and the temporary cavity that follows the wound are burned by the hot gases and flame that ac-
bullet. The size and appearance of the missile tract are company the bullet into the wound so that the wound
not helpful in determining the direction of travel of the margins are burned, blackened, and seared. Soot, which
missile, its caliber, or its velocity. The temporary cav- is the black carbonaceous gas discharged along with
ity created in the wake of the bullet lasts only 5–10 the bullet, is also deposited on the edges of the wound
milliseconds but causes damage along the bullet path and within the underlying tissues. As the muzzle’s po-
by stretching and destruction of the surrounding tis- sition changes from tight contact with the body surface
sues. The temporary cavity resulting from a low- to looser contact or angled contact, soot-laden gas can
velocity missile is small, possibly four to five times the escape from around the edge of the muzzle and be de-
size of the bullet, whereas high-velocity missiles pro- posited farther out onto the adjacent skin surface (Fig.
duce a temporary cavity which may be up to 30 times 9.26). Close wounds and near-contact wounds are
the diameter of the bullet (DiMaio, 1999). made with the muzzle out of contact with the skin sur-
Gunshot wounds of the head are common injuries; face but close to it. Soot is deposited around the wound
32%–40% of fatal gunshot wounds are to the head. in a wider area, and the shape of the soot deposit varies
Penetrating wounds are gunshot wounds in which the depending on the muzzle’s angulation. Intermediate-
missile enters the head and does not exit. Perforating range wounds are wounds made beyond the range of
wounds are gunshot wounds in which the missile en- soot deposition but close enough for burned and un-
ters the head, passes through the brain, and exits the burned powder grains to strike the skin surface and
head. Generally the behavior of missiles in passing cause tiny abrasions on the skin called the “powder tat-
through the head depends on the type of weapon, its too” (Fig. 9.27). Since these abrasions are actually
FIGURE 9.26 Loose contact gunshot wound of right lateral forehead

with soot deposited along margins of wound.
wounds of the skin surface, they cannot be washed off

the skin, although soot can be washed away. Distant FIGURE 9.28 Distant gunshot wound of back of head with abrasion
gunshot wounds are wounds in which the muzzle is far rim surrounding wound.
enough from the skin surface so that no deposit of
residue is left on the skin surface. The hole through
which the bullet passes is surrounded by an abrasion the diploe tends to fracture wider than the first. An en-
ring of raw or dried abraded skin. The abrasion ring trance wound tends to have a broader bevel on the in-
varies in shape depending on features of the bullet, its ner table than on the outer table, whereas an exit wound
angle of entry, and the location on the body (Fig. 9.28). has a broader bevel on the outer table than on the inner
As a bullet passes through the skull, there is frequently table. This pattern is common but not invariable (Baik
evidence of the bullet’s direction of travel to be seen in et al., 1991). Occasionally a bullet strikes the head tan-
the manner in which the bone fractures. The skull tends gentially so that part of the bullet enters the head
to fracture in a broadening cone, and the second part of and part of the bullet passes on. This may create a key-
hole defect in which part of the wound in the skull looks
like an entrance wound with a wider bevel on the inner
table and part of the wound looks like an exit wound
with a wider bevel on the outer table.
High-velocity wounds of the head are extremely
damaging at any distance (Fig. 9.29). When high-
FIGURE 9.27 Intermediate-range gunshot wound of left cheek with FIGURE 9.29 High-velocity missile entering left parietal skull with ex-
heavy deposit of stipple, or “powder tattoo,” surrounding wound. tensive fracturing of calvarium.
velocity wounds are made when the weapon is in con-

tact with the head, such explosive forces are created
that the entrance wound frequently consists of a large
gaping defect whose entry site may not be identifiable
because it is torn open or split apart and the skull is
extensively fractured. The cerebral hemispheres are of-
ten extruded from the head, leaving the brain stem and
cerebellum sitting in a severely fractured skull base.
Shotgun wounds at contact or close range are also
extremely destructive and result in splitting open of the
head, extensive fracturing of the skull, and often ex-
trusion of the cerebral hemispheres.
The missile pathway through the brain consists of
macerated brain mixed with blood and bone fragments
which are carried along from the entrance site as sec- FIGURE 9.31 Entrance of medum-caliber gunshot wound through
ondary missiles. The track itself may be poorly hem- right inferior frontal gyrus surrounded by contused edges and torn
leptomeninges suffused with blood that extends out into the sub-
orrhagic, although most are intensely hemorrhagic (Fig. arachnoid space. Bullet exited left inferior frontal gyrus and was re-
9.30). Fracture contusions surround both the entrance covered beneath scalp outside bone.
and exit bullet wounds of the brain and are accompa-
nied by subarachnoid hemorrhage spreading outward
from the wounds (Fig. 9.31). Contusions may be seen
as contusions at a distance because they are away from
in some cases over the ventral surfaces of the tempo-
the direct path through which the bullet travels.
ral and occipital lobes as a result of the downward
thrust of these surfaces onto the underlying dura and
bone in response to a bullet passing through the head. Stab wounds
These herniation contusions are sometimes referred to
Knives and other sharp objects may enter the head, al-
though wounds from these instruments are much less
common than gunshot wounds. The most common sites
of stab wounds are through the orbits or through the
squamous portions of the temporal bones, where
the bone may be more easily penetrated (Fig. 9.32). The
effect of a stab wound entering the head depends on
the damage done directly by the penetrating object in
passing through vascular structures, nerves, or brain
and the complications that may arise from these
wounds, such as infection or bleeding. Stab wounds are
much less disruptive to tissue than gunshot wounds be-
cause they are caused by an object traveling at a much
lower velocity than those that cause gunshot wounds
(Haworth and deVilliers, 1988; Sarvesvaran, 1991).
Primary Complications
Intracranial hemorrhage
Epidural hemorrhage. Epidural hemorrhage occurs
in about 3% of head injuries and its incidence is high-
est in people between the ages of 10 and 30 years
FIGURE 9.30 Small-caliber gunshot wound (suicide) in which the mis- (Baykaner et al., 1988). Epidural hemorrhages occur
sile entered the right temporal area and passed through lateral wall infrequently in the elderly—only 2%–4% occur in pa-
of right anterior fossa and then through right and left frontal lobes
tients over 60 years old—and they are uncommon un-
to partially exit lateral wall of left anterior fossa. Bullet was recov-
ered half out of bone beneath scalp. Missile pathway measures up der 2 years of age (Campbell and Cohen, 1951;
to 2 cm in width and contains macerated brain mixed with clotted Jamieson and Yelland, 1968; Phonprasert et al., 1980).
blood. At both these extremes of age, the dura is firmly ad-
A hemorrhages occur in association with a skull fracture.

In Rivas and coworkers’ series of 161 patients with
epidural hematomas, 80%–85% of the hematomas
were associated with skull fractures (Rivas et al., 1988).
Baykaner and colleagues looked at 95 patients with
epidural hematomas and found linear fractures in 51%
and depressed fractures in 42% (Baykaner et al., 1988).
Twenty-seven percent of the patients under 15 years of
age did not have skull fractures. Fractures of the skull
may lacerate branches of the middle meningeal artery
where these small vessels lie in grooves on the inner
table of the skull. In children an impact to the head
may produce a skull deformity that strips the dura off
the inner table of the skull and tears the adjacent small
vessels without fracturing the skull (Freytag, 1963). The
grooves in which these vessels travel along the inner
table do not develop until age 4 years, when the diploe
develops, and this characteristic affects the ease with
which these vessels tear in young children.
Epidural hemorrhage requires a direct impact to the
B
head and the formation of an epidural hemorrahage
usually indicates that a significant force has been ap-
plied to the head. The impact to the head frequently
produces a lesion in the overlying scalp, which may
be either a laceration or a subgaleal hemorrhage
(McKissock et al., 1960) (Fig. 9.33). Head injuries that
produce epidural hemorrhage most commonly result
from traffic accidents, falls, and direct blows to the
head (Phonprasert et al., 1980; Baykaner et al., 1988;
Lobato et al., 1988a; Rivas et al., 1988). Epidural hem-
orrhages do not have as frequent an association with
abusive injuries in children as do subdural hemor-
rhages. In about 1% of the trivial falls in and about
FIGURE 9.32 (A) Bilateral stab wounds of eyes. Each wound passes
through lower eyelid and under globe to enter orbits. (B) Close-up
the home that children sustain by accident, small lin-
view of sphenoid bone. Stab wound on left shows forceps passed ear skull fractures result which are occasionally fol-
through defect just beneath lesser wing of sphenoid bone through lowed by epidual hemorrhages (Shugerman et al.,
left middle fossa and passed into left inferior temporal gyrus at pole. 1996).
Stab wound on right passed through horizontal 1.3 cm defect on Epidural hemorrhages are most commonly located
lesser wing of sphenoid bone into right gyrus rectus.
over the cerebral convexities. Rivas and colleagues
found that 16% of their 161 patients’ hematomas were
in the frontal region, 19% in the temporal, 31% in
herent to the inner table of the skull and difficult to the temporoparietal, 27% in the parietal, and 7% in the
strip away. Hahn and associates studied 738 head- occipital-posterior fossa (Rivas et al., 1988). Brambilla
injured children under 16 years of age and found that and coworkers also found a 7% incidence of epidural
epidural hemorrhages accounted for 44% of the in- hematomas in the posterior fossa (Brambilla et al.,
tracranial hemorrhages and that 75% of these epidural 1986). Occasionally a frontal impact may cause bilat-
hemorrhages occurred in children over 3 years of age eral frontal epidural hematomas by lacerating a frontal
(Hahn et al., 1988). branch of the middle meningeal artery (Frank et al.,
The bleeding in an epidural hemorrhage lies between 1982). Epidural hemorrhages usually demonstrate a
the skull and the dura and usually arises from lacera- lenslike configuration because they are confined more
tion of a branch of the middle meningeal artery, al- discretely above the dura in contrast to the crescent
though a few such hemorrhages arise from tears of a shape usually demonstrated by a subdural hematoma,
dural sinus or diploic vein (Hill, 1961). Most epidural where the blood may spread out over the convexities
A B
FIGURE 9.33 Epidural hemorrhage in 6-month-old child. (A) Large area of subgaleal hemorrhage in right
occipital scalp overlying 7.2 cm linear fracture of right occipital bone. (B) Six to 8 mL of epidural blood
over right posterior fossa. (C) Brain has markedly flattened right occipital lobe.
and run down into the sulci. The epidural hematoma (Jamieson and Yelland, 1968a). Lobato and associates
exerts pressure through the dura, which uniformly com- found that 75% of their patients with acute epidural hem-
presses the underlying brain and creates a markedly orrhages had one or more associated intracranial lesions
flattened contour to the underlying ipsilateral cerebral (Lobato et al., 1988a). Rivas and colleagues found that
surface. The flattening of the ipsilateral cerebral con- 43% of their patients with epidural hemorrhages had as-
vexity by an acute epidural hematoma is much more sociated intracranial lesions on the initial or subsequent
pronounced than the flattening seen underlying an CT scans and that the incidence of associated lesions was
acute subdural hematoma (Fig. 9.34). significantly higher in comatose patients than in those
The brain surface which lies immediately beneath an who were conscious (Rivas et al., 1988). Regarding the
epidural hemorrhage frequently demonstrates contusions associated lesions, Baykaner and associates described
and subarachnoid hemorrhage caused by an adjacent temporal subdural hemorrhages in 13%, intracerebral
skull fracture, although the cortical surface may be free hemorrhages in 2%, and brain lacerations in 2%
of injury. Patients who have epidural hemorrhages fre- (Baykaner et al., 1988).
quently also have other intracranial injuries, which are The volume of an epidural hematoma can vary from
not necessarily at the site of the epidural hemorrhage a few milliliters, which may be significant in a young
A child, to 150 mL or more. In Rivas and associates’ se-

ries of 161 patients with epidural hematomas, hema-
tomas larger than 150 mL were found in 23% of co-
matose patients and 3% of conscious patients and
hematomas smaller than 90 mL were found in 56% of
comatose patients and 86% of conscious patients (Ri-
vas et al., 1988). They concluded that the volume of
an epidural hematoma correlated with the severity of
the clinical presentation and influenced the final out-
come, since the mortality rate was significantly higher
in patients with clots larger than 150 mL. The average
volume for comatose patients under 20 years of age
was 68 mL and over 20 years was 115 mL and for con-
scious patients under 20 years of age was 50 mL and
over 20 years was 51 mL.
The rate of evolution of an epidural hematoma is an
important factor in determining the clinical outcome.
Patients in whom clinical signs develop later tend to do
better when their hematomas are surgically evacuated
than do patients in whom the clinical signs develop
B
early, indicating those cases with rapidly bleeding he-
matomas (Gallagher and Browder, 1968). Lobato and
associates found that the patients who were operated
on soonest after injury and in whom the clinical signs
of the hematoma had developed the quickest had larger,
more rapidly developing hematomas which were more
likely to adversely affect the patients’ outcomes (Lo-
bato et al., 1988a). Rivas and associates found in their
series that in both the conscious and unconscious
groups of patients, those whose symptoms developed
later had a better outcome (Rivas et al., 1988). More
slowly developing or delayed epidural hematomas are
now being diagnosed more frequently than they were
in the past because CT scanning has become a routine
C
procedure, and it is particularly informative in this re-
gard when it is done sequentially. Sakai and associates
described a group of 37 patients who had either no
epidural hemorrhage or only a small epidural hema-
toma on the initial CT scan; in 65% of these patients,
hematomas subsequently developed and enlarged, in
51% they reached 25 mm or greater in thickness on
repeat CT scan 24 hours later (Sakai et al., 1988). Ri-
vas and associates reported that delayed epidural he-
matomas developed in 8% of their 161 patients and
were found on CT scans from 5 hours to 6 days after
the injury (Rivas et al., 1988).
The routine performance of CT scanning has im-
proved the outcome of patients with epidural hemato-
FIGURE 9.34 Two-year-old child struck on head with hairbrush with mas by improving the accuracy of the initial diagnosis,
fracture of right parietal skull. (A) An 80 mL epidural hematoma by permitting recognition of hematoma reaccumulation
over the right temporoparietal region. (B) Brain has markedly flat-
tened right parietal cerebrum with fracture contusions of right su-
or incomplete removal, and by allowing identification
perior and middle temporal gyri. (C) Coronal section of brain show- of associated intracranial lesions. Sequential CT scan-
ing markedly flattened right parietal lobe. ning in addition to the initial scan is necessary to iden-
tify these lesions. The neurological status of the patient 30%, whereas in those operated on more than 6 hours
with an epidural hematoma at the time of surgery is an after injury the mortality rate was 95%. Doppenberg
important determinant of the outcome. Mortality in pa- and associates found that subdural hemorrhage resulted
tients with epidural hematomas that require surgical in a significant increase in free radical production in
evacuation is virtually limited to those patients who are rats, which may provide insight into why even rapidly
comatose (Rivas et al., 1988). The current mortality evacuated subdural hemorrhages frequently have a dev-
rate for epidural hematomas diagnosed by CT scan is astating outcome (Doppenberg et al., 1998).
10%–12%, compared with a 30% mortality rate be- Large, clinically significant subdural hemorrhages are
fore CT scanning was available (Baykaner et al., 1988; probably always traumatic, although smaller amounts of
Lobato et al., 1988). The mortality rate in tertiary-care subdural bleeding can result from nontraumatic pro-
neurosurgical centers for patients with epidural hema- cesses such as a hypertensive intracerebral hemorrhage
tomas who are not comatose on initial presentation ap- or subarachnoid hemorrhage from a ruptured berry an-
proaches zero (Bricolo and Pasut, 1984; Brambilla et eurysm or ruptured vascular malformation that breaks
al., 1986). The mortality rate for epidural hematomas through the arachnoid membrane and bleeds into the
is not correlated with age, but the presence of associ- subdural space. In contrast to the epidural hemorrhage,
ated intracranial lesions worsens the prognosis (Rivas subdural hemorrhage does not require a direct blow or
et al., 1988). Diffuse axonal injury may coexist with impact to the head. The bleeding in a subdural hem-
an epidural hematoma and adversely affects the out- orrhage most often arises from tears of the cortical
come (Lobato et al., 1988a). bridging veins and lies between the dura and arachnoid
membrane. To tear or avulse a bridging vein requires
Subdural hemorrhage. The two lesions responsible only that the brain be accelerated to a critical rate
for more head injury deaths than all other lesions com- within the head. Either impact to the head or move-
bined are acute subdural hemorrhages and diffuse in- ment of the head or body that shakes the brain around
juries that are associated with coma of longer than 24 within the cranial cavity may result in tearing of bridg-
hours (Gennarelli et al., 1982b). The acute subdural ing veins. Gennarelli and associates carried out exper-
hematoma presents the most devastating problem of all iments with monkeys that simulated closely the way in
nonmissile brain injuries. In Gennarelli’s multicenter which subdural hematomas are produced in humans
study of outcome of severe head injury, acute subdural (Gennarelli and Thibault, 1982). These studies dem-
hematoma was associated with death in 74% of pa- onstrated that the bridging veins are more liable to tear
tients and good recovery in only 8%. In that same when the head undergoes a rapid acceleration or high
study, the most common single lesion in patients with strain, such as occurs during a fall or an assault, than
severe head injury was the acute subdural hematoma, during low-strain incidents such as traffic accidents.
which accounted for 29% of the entire population and These authors have isolated the parameters of angular
was responsible for 45% of all the deaths (Gennarelli acceleration and pulse duration and have produced sub-
et al., 1982b). Sahuquillo-Barris and coworkers found dural hemorrhages with angular acceleration alone
that acute subdural hemorrhage occurred in 10%–30% without any impact to the head.
of patients with severe head injury and in a number A small number of cases of spontaneous subdural
of studies was responsible for mortality rates of hemorrhage of arterial origin have been reported. These
50%–90% (Sahuquillo-Barris et al., 1988). Hahn and hemorrhages have a high mortality, and the arteries at
colleagues found that acute subdural hematomas ac- operation have been identified as cortical branches of
counted for 36% of the intracranial hematomas in 738 the middle cerebral artery near the Sylvian fissure
children under 16 years old with head injury (Hahn et (Tokoro et al., 1988).
al., 1988). Other studies of acute subdural hemorrhage Subdural hemorrhages are classified into subgroups
have found mortality rates ranging from 40% to 60% based on the length of time between the injury and the
(Fell et al., 1975; Gennarelli and Thibault, 1982). Tim- onset of symptoms. The acute subdural hemorrhage is
ing of surgery for evacuation of subdural hematoma is one which is immediately symptomatic, the subacute
a determining factor in the outcome. Seelig and his col- subdural hemorrhage becomes symptomatic after 1 to
leagues described a marked reduction in mortality and 2 weeks, and the chronic subdural hemorrhage becomes
an improvement in outcome in patients with acute sub- symptomatic after 2–3 weeks. This is a classification
dural hematomas who were operated on less than 4 merely for purposes of naming these hemorrhages and
hours after injury (Seelig et al., 1981). In patients with has resulted in a considerable confusion as to the mean-
acute subdural hematomas who were operated on ing of timing of these injuries. The scheme is an artifi-
within 4 hours of injury the mortality rate was less than cial classification and should not be taken too literally,
nor should one expect much precision in these deter-

minations.
Skull fractures accompany about 50% of acute sub-
dural hemorrhages and if a fracture is present, the frac-
ture does not necessarily correspond to the site of the
hemorrhage. There is a significant association between
acute subdural hemorrhage and diffuse axonal injury,
and as demonstrated by Gennarelli’s multicenter study
of outcome in severe head injury, these two lesions con-
tribute a large share of the mortality rate in severe head
injury (Gennarelli et al., 1989). The amount of sub-
dural blood which must accumulate to create a signif-
icant collection depends on the patient’s age, the de-
gree of brain atrophy, and the rapidity with which the
blood accumulates. In infants even a very small collec-
tion of a few milliliters of subdural blood is a signifi-
cant finding because even small amounts can result in
a very tight fit of the brain within the cranial cavity.
In shaken infants, the amount of subdural blood is fre-
quently quite small but the presence of subdural blood
FIGURE 9.36 Adult with thin layer of acute subdural blood over the
is highly significant as a marker of brain acceleration,
left cerebral convexity resulting from vehicular accident.
which may also produce diffuse axonal injury (Fig.
9.35). In children between 1 and 3 years of age, 30–50
mL of subdural blood represents a significant amount.
In older children and adults, significant amounts of sub- ing veins travel makes these individuals particularly sus-
dural blood may vary from 100 mL up to as much as ceptible to tears of the bridging veins but also provides
250 mL. As the brain undergoes atrophy in the elderly an increased space for the subdural collection to oc-
or the alcoholic patient, the greater distance between cupy before symptoms arise.
the dura and the cortical surface across which the bridg- Acute subdural hemorrhages are of special interest
in child abuse. Of children who die from abusive or in-
flicted injuries, 40%–80% die of head injuries and
greater than 90% of children with inflicted head in-
juries have acute subdural hemorrhage. The association
between subdural hemorrhage and child abuse has been
recognized for many years (Kempe et al., 1962;
Guthkelch, 1971; Caffey, 1972; Hadley et al., 1989).
The association of inflicted head injuries and subdural
hemorrhage is indicative of the severity of the acceler-
ative forces which are applied to the child’s head in
abusive injuries and will be more fully discussed in a
later section “Head Injuries of Infants and Young Chil-
dren.”
Subdural hemorrhage may be unilateral or bilateral
with a tendency to be more commonly unilateral (Fig.
9.36). Subdural hemorrhages frequently lie over the
cerebral convexity in the frontoparietal region, al-
though very large hemorrhages may cover the entire
cerebral surface on one side. Varying amounts of sub-
dural blood commonly also lie over portions of the cra-
nial fossae (Fig. 9.37). The brain surface underlying an
FIGURE 9.35 Twenty-month-old shaken infant with 10 mL of subacute subdural hemorrhage is less flattened than the
dural blood over right cerebral convexity and a smaller amount on cortical surface underlying an epidural hemorrhage.
the left. The degree of gyral flattening may actually be more
dergoes aging changes to become a chronic subdural

membrane. In most cases of severe head injury to in-
dividuals with previously normal brains, acute subdural
blood is rather readily resolved or rapidly organized.
The chronic subdural hematoma is primarily a delayed
hemorrhage that develops in particular categories of
patients who have either brain atrophy (the elderly or
the alcoholic) or a low intracranial pressure (patients
with hydrocephalus who have been treated with
shunts). Brain atrophy creates an extended distance of
travel for the bridging veins, which appears to increase
the ease with which these veins tear. Patients who have
hydrocephalus that has been treated by the surgical
placement of a shunt have both a low intracranial pres-
sure with a reduced resistance to the extracerebral ac-
cumulation of fluid and a brittle skull—both factors
that contribute to the ease of subdural bleeding. Rather
minor trauma in these special categories of patients may
result in tearing of the bridging veins and small
amounts of subdural bleeding, which induce an in-
FIGURE 9.37 View of base of skull in 37-year-old man kicked in right
growth of granulation tissue from the dural side. This
side of head; heavy acute subdural blood is present over right mid-
dle and posterior fossae. granulation tissue contains fragile macrocapillaries
which may produce microbleeds and gradually lead to
enlargement of the hematoma. The further evolution
marked on the gyri of the contralateral hemisphere than of these hematomas is most determined by the nature
on the ipsilateral hemisphere, although if herniation is of the vascular neomembrane formed in these particu-
produced, it will occur on the same side as the hemor- lar (atrophic brain or shunted) patients. The expansion
rhage. The cortical surface beneath a subdural hemor- of these hematomas also appears to be related to the
rhage frequently demonstrates foci of subarachnoid excessive activation of both the clotting and fibrinolytic
hemorrhage because tearing of the bridging veins also systems in the subdural fluid (Lofgren, 1986).
results in tearing of underlying arachnoidal vessels Determining the age of subdural blood depends upon
where the bridging veins have passed through the both the gross and microscopic features. Fresh subdural
arachnoid and been disrupted. Other injuries may be blood remains liquid for about the first 4 days and then
present on the cortical surface beneath a subdural hem- becomes clotted and looks somewhat like reddish-black
orrhage. Acute subdural hemorrhage is commonly cranberry gel. Fibroblasts and capillaries begin to grow
found adjacent to the “burst” frontal or temporal poles, into the hematoma from the dural side, and as these
which accompanies severe degrees of contrecoup con- proliferations continue, the clot begins to adhere to the
tusion if the arachnoid is torn. undersurface of the dura. By the second week, the clot
Subacute subdural hematoma reflects a less severe in- begins to liquify as a result of fibrinolysis. As erythro-
jury than the acute subdural hematoma. Since these cytes are lysed and pigment is removed from the he-
hemorrhages take longer than the acute subdural hem- matoma, the clot changes from dark red to an orange
orrhages to become symptomatic, the underlying in- brown. During this period, a membrane of granulation
juries are usually less severe and the evolution of the tissue covers the dural undersurface and grows along
hematoma is slower. These differences are reflected in the circumference of the arachnoidal side of the hema-
a mortality rate one-third that of acute subdural he- toma to lay down a membrane of granulation tissue
matomas. over that surface. By the third week, there is a neomem-
The chronic subdural hemorrhage is not simply a brane over each surface of the hematoma. The liqui-
subdural hemorrhage which takes a longer period of fied clot progressively loses pigment and volume. Red
time to become symptomatic. Chronic subdural hema- blood cells may remain microscopically intact for many
tomas are a distinctive and unique type of hemorrhage. weeks. Portions of the clot may come to resemble mo-
These hematomas very rarely result from severe head tor oil or may appear as gray gelatinous bulges in the
injury in individuals whose brain was previously nor- membranes. The capillaries that develop in the granu-
mal and in which an acute subdural hemorrhage un- lation tissue of the neomembranes are fragile and may
be easily ruptured as a result of minor trauma or be-

cause of changes in the volume of the hematoma. Tear-
ing of these capillaries results in foci of rebleeding,
which probably do not greatly increase the volume of
the hematoma but do give it patches of variable color
in contrast to the depigmented areas of the hematoma.
Between the first and the third month, the neomem-
branes on both sides of the hematoma become mature.
As the liquid center grows smaller and eventually dis-
appears, the two membranes merge and adhere to the
undersurface of the dura. This mature layer consists of
fibrous tissue with hemosiderin-laden macrophages
scattered throughout. After 3–4 months, depending on
its size, the hematoma is completely organized and no
further estimation of its age can be made. (The evalu-
ation of subdural membranes in infants and young chil-
dren will be discussed in “Head Injuries in Infants and
Young Children.”)
Kawakami and associates proposed a hypothesis to
explain the development of chronic subdural hemato-
FIGURE 9.38 Forty-year-old man struck repeatedly on the head with
mas based on studies of coagulation and fibrinolysis a blunt object causing skull fractures with underlying fracture con-
factors in the hematoma contents (Kawakami et al., tusions and lacerations. Subarachnoid hemorrhage surrounds the cor-
1989). They found an excessive activation of the clot- tical injuries.
ting and fibrinolytic systems in these hematomas. At
the time of head injury, damage to the cerebral capil-
lary endothelium and brain tissue releases tissue throm- distribution similar to the hemorrhage from a ruptured
boplastin. The clotting systems are excessively acti- berry aneurysm. These hemorrhages are relatively rare,
vated, and there is marked consumption of clotting usually are followed by immediate collapse, and are al-
proteins. The outcome is defective clot formation, re- most uniformly fatal within the first 2 days. These hem-
sulting in recurrent hemorrhage in the neomembrane. orrhages are most frequently produced by a laceration
As the process is repeated, the dura reacts to the fibrin of a vertebral artery at the level of C1, or less often of
to gradually form the outer membrane and the extrin- an intracranial segment of a vertebral artery, the pos-
sic fibrinolytic system is activated. This cycle is repeated terior inferior cerebellar artery, or the basilar artery
and the hematoma enlarges. (Coast and Gee, 1984; Deck and Jagadha, 1986; Dol-
man, 1986). Most of the lacerations reported have been
Subarachnoid hemorrhage. Subarachnoid hemor- in the vertebral artery at the level of the first cervical
rhage is bleeding beneath the arachnoid membrane in vertebra and have been related to an impact to the neck
the space normally occupied by the cerebrospinal fluid. or jaw that often had occurred in a barroom fight (Si-
Massive subarachnoid hemorrhage may result from monsen, 1967; Contostavlos, 1971). Such an impact to
nontraumatic causes such as ruptured berry aneurysms the neck or jaw produces a lateral displacement of the
or vascular malformations. Trauma, however, is the atlas and in some cases has been associated with a frac-
most common cause of subarachnoid hemorrhage be- ture of the transverse process of the atlas. In the
cause injury of almost any significant magnitude results anatomical course of the vertebral artery, on leaving
in some degree of subarachnoid bleeding. Subarachnoid the foramen transversarium of C1 in its path to enter
hemorrhage is found overlying contusions, spreading the cranial cavity, the vertebral artery travels posteri-
outward from lacerations (Fig. 9.38), and around gun- orly and medially a distance of 1.3 cm before reaching
shot wounds. Subarachnoid hemorrhage tends to lie un- the atlanto-occipital membrane. As the vertebral artery
der areas of subdural hemorrhage where the traction passes through the foramen magnum, the adventitia of
that tears bridging veins also tears adjacent vessels in the vertebral arterial wall joins with the basilar dura
the arachnoid. and at that point the vessel is fixed or tethered. A lat-
The traumatic basilar subarachnoid hemorrhage is a eral movement of the atlas may cause the fixed upper
unique injury consisting of massive subarachnoid hem- segment of the vertebral artery to stretch, since it can-
orrhage over the ventral surface of the brain stem in a not move freely at that point. The stretching of the
artery may be forceful enough to produce a laceration.

These lacerations are not usually complete transactions
of the artery but are frequently dissections within the
tunicae of the vessel wall resulting in blood separating
the intima, media, and adventitia of the arterial wall
(Fig. 9.39). The blood dissects upward toward the
atlanto-occipital membrane where the arachnoid mem-
brane of the base of the brain is also attached to the
dura. When the dissecting blood reaches that point, it
ruptures into the subarachnoid space. Identifying lac-
erations of this type requires removal of the fresh sub-
arachnoid blood clot under running water to enable
examination of the circle of Willis to exclude the pos-
sibility of aneurysm. The vertebral artery is then ex-
amined by a posterior dissection of the upper cervical
vertebrae. Injection of the vertebral artery at its origin
with contrast media demonstrates some of these injuries
but not all of them, since many of the injuries are dis-
sections and not transections. A useful marker is the
presence of a contusion externally on the jaw or neck
FIGURE 9.40 Lateral view of posterior neck dissection demonstrating
at the point of impact and an area of internal hemor-
contusion in splenius capitis overlying mastoid. Transverse process
rhage in the muscle overlying C1 (Fig. 9.40). of C1 lies deep between angle of mandible and mastoid. This man
slid into first base and struck the right side of his neck on the first
Intraventricular hemorrhage. Intraventricular hem- baseman’s knee. He was immediately unconscious and died shortly
orrhage is the accumulation of blood within the ven- after.
tricles which may pass out into the subarachnoid space
but is not simply a reflux of predominantly subarach-
noid blood into the ventricles from the basal cisterns. liliter up to large hemorrhages of 40–60 mL. The av-
Nontraumatic intraventricular hemorrhage may result erage hemorrhage is about 10–15 mL. Although intra-
from the extension of a hypertensive hemorrhage in the ventricular hemorrhage was thought in the past to be
ganglionic region into the ventricle or from bleeding of associated only with severe intracranial injury, high-
a vascular malformation of the choroid plexus. Trau- resolution CT scans have demonstrated that traumatic
matic intraventricular hemorrhage occurs frequently in intraventricular hemorrhages occur more commonly
association with other intracranial injury. The volume than previously recognized (Kim et al., 1981). Fujitsu
of intraventricular blood can vary from less than a mil- and associates studied 26 patients with intraventricu-
lar hemorrhage and by analysis of the CT scans were
able to determine the origin of 15 of the hemorrhages
(Fujitsu et al., 1988). These hemorrhages were found
to arise in contusional hemorrhage in the frontal or
temporal lobes, in hemorrhages in the caudate nucleus,
and in hemorrhages in the thalamus. The authors were
able to distinguish differences in the impact directions
for these various subgroups, and they proposed that
the mechanism producing the hemorrhages in the ba-
sal ganglia was shearing injury between the basal nu-
clei and the perforating vessels.
Intracerebral hemorrhage. Traumatic intracerebral

hemorrhages vary in size from small hemorrhages of
less than 0.5 cm up to large parenchymatous hemor-
rhages of 6–7 cm or greater in dimension. These hem-
FIGURE 9.39 Section of vertebral artery demonstrating blood from lu- orrhages can be divided into two major subgroups on
men dissecting through media of vessel wall. the basis of their mechanism of development. The
largest parenchymatous traumatic hematomas are lesions and the hypertensive hemorrhage is character-
found most often in the frontal and temporal lobes and ized by its ganglionic location and is not connected to
are associated with adjacent cortical contusion or lac- adjacent foci of contusion or laceration. Patients with
eration (Gurdjian, 1976) (Fig. 9.41). These hematomas hypertensive hemorrhages also have other evidence of
may extend deeply into the white matter but most of- hypertensive cardiovascular disease such as left ven-
ten have a cortical connection. Large parenchymatous tricular hypertrophy and lacunar infarcts of the brain.
hemorrhages may extend into the ventricle but are usu-
ally above and lateral to the basal ganglia at the point Burst lobe. The term burst lobe refers to a severely
at which the hemorrhages breach the ventricle. The ad- contused frontal or temporal pole whose cortical sur-
jacent areas of contusion and laceration tend to be face is pulped and lacerated with the extension of the
closely related to the parenchymatous hemorrhage, and cortical hemorrhage through the arachnoid into the
often these are seen to connect at one or more points. subdural space. Burst lobes occur most commonly in
The second subgroup of traumatic intracerebral hem- association with contrecoup contusions. The amount
orrhages are those associated with diffuse axonal in- of subdural hemorrhage produced by this mechanism
jury. The ring and ball, punctate, and streak hemor- varies from insignificant collections to large hemor-
rhages caused by diffuse axonal injury in the white rhages.
matter and basal ganglia are attributed to tearing of
small vessels by the same shearing stresses that dam- Delayed traumatic intracerebral hemorrhage. A de-
age the axons. These small hemorrhages may continue layed traumatic intracerebral hematoma is one that
to bleed and enlarge over several days, and their evo- arises in an area of brain that has been previously in-
lution into larger hemorrhages can often be observed jured by impact, usually resulting in a contusion. The
on serial CT scans. The gliding contusion described by hemorrhage is delayed for hours or days beyond the
Lindenberg and Freytag is a hemorrhagic lesion in the time of the initial injury. Vessels within the contused
parasagittal white matter that was thought to be re- area of brain may have been weakened by the injury,
lated to traction on the bridging veins as the brain and if autoregulation fails and systemic hypertension
moved or “glided” in relation to the attached dura (Lin- develops, bleeding can ensue from the damaged capil-
denberg and Freytag, 1957). More current views on laries. Most of these hematomas develop in the frontal
these lesions attribute them to the shearing forces of or temporal lobes, but the location depends on the na-
diffuse axonal injury and consider them to be a form ture of the injury. CT scans at the time of injury can
of this type of damage to the brain (Adams et al., 1982). appear normal or may demonstrate a cortical contu-
The distinction between a traumatic intracerebral sion, and later CT scans demonstrate the evolving he-
hemorrhage and a nontraumatic hypertensive hemor- matoma. The hemorrhage is heralded by the sudden
rhage should not create any dilemma, since the trau- onset of neurologic deficit, and the mortality rate is
matic hematoma occurs in relation to other traumatic quite high (44%–46%) (Gudeman et al., 1979; Nin-
choji et al., 1984; Young et al., 1985).
Brain swelling. Brain swelling is an increase in the

size of one or both cerebral hemispheres. The distri-
bution of the swelling depends on a number of factors,
including the patient’s age and the nature of the injury.
Localized swelling occurs adjacent to the site of any in-
jury, such as a contusion. Brain swelling was classified
into cytotoxic and vasogenic types by Klatzo (Klatzo,
1967). In head injury, much of the interest has been in
vasogenic edema. Vasogenic edema results from injury
to the capillary endothelial cell junction, the site of the
blood–brain barrier, which then allows for the passage
of plasma proteins and electrolytes into the brain ex-
tracellular space. Edema fluid flows from the site of
capillary damage in the white matter toward the ven-
FIGURE 9.41 Forty-six-year-old man who was struck on head with a
blunt object and sustained right frontal pole contusions. Intracere-
tricles under the hydrostatic force of the circulation
bral hemorrhage of right frontal lobe is connected to the overlying (Ruelen et al., 1977). In the cortical gray matter, edema
contusions of the frontal pole. fluid does not extravasate into the extracellular space
and the astrocytes take in fluid and swell. Edema fluid terion of whether intracranial pressure had been raised
in the white matter moves into the ventricles and en- to a significant level (Fig. 9.42). This marker does not
ters the cerebrospinal fluid, the pathway by which the appear if the intracranial pressure was elevated for a
edema fluid can leave the system. The presence of short time or if the pressure was elevated in the in-
edema contributes to increases of the intracranial pres- fratentorial compartment (Adams and Graham, 1976).
sure and may depress cerebral blood flow and impair The most common causes of increased intracranial
autoregulation (Van Dongen and Braakman, 1980). pressure in head trauma patients are intracranial he-
Cerebral hyperemia also contributes to brain swelling matomas and brain swelling. Hemorrhage or infarction
(Hanigan et al., 1987). Cerebral hyperemia is an in- in the brain stem as a result of tentorial herniation is
crease in the cerebral blood volume or cerebral blood the type of brain damage that usually results in death
flow as a result of impaired autoregulation. Zimmer- in these cases. The exact sequence of events resulting
man and colleagues described the CT findings in pedi- in elevated intracranial pressure is not fully understood.
atric patients with acute general cerebral swelling Studies of intracranial pressure dynamics indicate
(Zimmerman et al., 1978). The CT findings demon- that three parameters contribute to the level of pres-
strated absence or compression of the lateral and third sure: the rate of fluid formation, the outflow resistance,
ventricles and basal cisterns, and this was the most and the vascular contribution (Marmarou et al., 1987).
common pattern seen on CT scans in children with se- The greatest proportion of the intracranial pressure ap-
vere head injuries. These authors suggested that the pears to be related to the vascular contribution. The
swelling was largely due to hyperemia. They proposed onset of vasomotor paralysis may mark the point at
a hypothesis to explain the hyperemia as vasodilatation which brain swelling is no longer reversible (Langfitt
of the cerebral arterial bed following injury and caus- and Gen, 1982).
ing increased cerebral blood flow and cerebral blood
volume. Increased blood volume reduces intracranial
Hypoxic brain damage
compliance by forcing cerebrospinal fluid out of the
ventricles and subarachnoid spaces and results in the The incidence of ischemic damage to the brain in pa-
CT pattern of acute general cerebral swelling. Of 87 tients dying from head injury is high. Ischemic brain
children between 2 years and 15 years of age studied damage is more common in patients who have had a
by Graham and associates, 70% had the CT findings clinical episode of hypoxia, either as hypotension or
of acute general cerebral swelling, which has also been hypoxemia, and in patients who have had elevated in-
termed diffuse cerebral swelling (Graham et al., 1989). tracranial pressure. Several neuropathologic patterns of
Lobato and coworkers described 55 adult patients hypoxic brain damage can be observed in patients with
with severe head injury and bulk enlargement of one head injuries. A common distribution of ischemic dam-
cerebral hemisphere which developed within a few age occurs in the arterial boundary zones or watershed
hours of trauma (Lobato et al., 1988). This group had zones, particularly between the anterior and middle
the highest mortality rate and shortest survival time cerebral artery territories. Ischemic damage can also oc-
among the 520 head-injured patients these authors
studied. Eighty-five percent of these patients had a large
subdural hematoma ipsilateral to the swelling. In 20%
of the patients the hematoma was evacuated within 4
hours, but this did not significantly change the out-
come. The authors suggested that the hemispheric
swelling was the dominant factor in determining the
patients’ course.
Secondary Complications
Increased intracranial pressure
Increased intracranial pressure is a common cause of
death in head injury, particularly in the group of pa-
tients who survive long enough to be hospitalized for
some period of time Pressure necrosis in one or both FIGURE 9.42 Coronal section from swollen brain with compressed
parahippocampal gyri at autopsy may be used as a cri- ventricles and necrosis of right parahippocampal gyrus.
cur throughout the cerebral cortex, particularly in the and violently shaking the child back and forth so that
hippocampus and in the basal ganglia and cerebellum. the head forcefully oscillates from front to back.
Vascular spasm can reduce cerebral blood flow into an During the violent shaking of the child, the arms and
area of injury and produce hypoxic damage (Adams et legs of the shaken child are also violently flung about
al., 1980a). and whiplashed and injury may be found in the un-
Rose et al. studied 116 head-injured patients who derlying long bones. The bones most frequently affected
had talked following their injury and then died (Rose are the tibia, distal femora, and proximal humeri, al-
et al., 1977). Their ability to speak was taken as evi- though any long bone may be injured (Kleinman,
dence that they had not sustained irreversible impact 1990).
brain injury and that death could have been prevented The concept of shaken baby syndrome has further
if secondary damage had been avoided or treated. De- evolved over the three decades since its original de-
lay in the treatment of intracranial hematomas was scription. These are common injuries, and some cases
found to be the most common avoidable problem that are not diagnosed because the pathological findings
caused death. Seelig and associates reported a mortal- may be fairly subtle and may be missed or not recog-
ity rate of 30% for patients with acute subdural he- nized clinically or at autopsy. Children as old as 4 or
matomas who underwent surgery within 4 hours and 5 years may be fatally shaken although the great ma-
a mortality rate of 90% for patients operated on after jority are under 2 years old and most are under 12
4 hours (Seelig et al., 1981). What the mechanism is months. Even adults may sustain shaken head injuries
which is triggered by the delay in removing these he- with findings identical to those found in shaken infants.
matomas, which increases morbidity and mortality, is Pounder described a 30-year-old prisoner who was vi-
not known precisely but one possibility is an increase olently shaken, and when he died 3 days later, his
in hypoxic damage. Experimental production of in- autopsy demonstrated subdural, subarachnoid, and
tracerebral hemorrhage in rats by injection of autolo- retinal hemorrhages with diffuse axonal injury. The de-
gous blood into the caudate nucleus results in ischemic ceased was short and slightly built (151 cm and 44.3
damage to the overlying cortex (Nath et al., 1987). In kg) and was grasped by the shoulders and shaken
a related experiment, a microballoon was inserted into (Pounder, 1997).
the caudate nucleus of rats, inflated, and, after 10 min- Infants may be shaken to less than fatal outcome but
utes, deflated. These animals demonstrated a persistent may sustain injuries to the brain that will later be re-
reduction in cerebral blood flow to the region and isch- flected in varying degrees of mental retardation or slow-
emic damage in the overlying cortex. The findings sug- ness, learning disorders, seizures, blindness, and irri-
gest that ischemic damage occurs at the time of for- tability. Of infants that are shaken, about 7%–30%
mation of the hematoma and is not prevented by the die, 30%–50% have severe cognitive or neurological
early removal of the hematoma (Sinar et al., 1987). In- deficits, and 30% have a chance of full recovery
jection of blood into the subdural space of rats pro- (Rosenthal et al., 1990; Bruce, 1978).
duced ischemic damage to the cortex underlying the Appreciation of the unique characteristics of young
hematoma from 4 hours to 24 hours after a volume of children’s head injuries requires an understanding of
blood was introduced which amounted to 14%–16% the developmental differences which exist in the brain
of the hemispheric volume (Miller et al., 1990). and skull at these early ages. Injuries to the young
child’s brain are unique because the trauma occurs to
an organ that is in the process of maturing; the mech-
HEAD INJURIES OF INFANTS AND anisms, the thresholds of injury, and the types of in-
YOUNG CHILDREN jury differ from those which affect the older child or
adult. At birth, the brain is enclosed in a pliable skull,
Caffey’s description of whiplash shaking of infants in a feature which assists the head’s passage through the
the early 1970s introduced the concept that serious and birth canal as well as accommodating the rapidly grow-
even fatal head injury could be done to infants by shaking brain. The skull is pliable because of the unfused
ing them (Caffey, 1972, 1974). The injuries Caffey de- sutures, because of the open fibrous fontanelles, and
scribed were characterized by subdural and/or sub- because the skull is thin and unilaminar. No other or-
arachnoid hemorrhages and retinal hemorrhage in the gan grows as rapidly as the brain; the brain reaches
absence of bruises to the face or scalp or of skull frac- 75% of its adult weight by age 2 years and attains adult
tures which would point to impact injuries. The type weight by 5 or 6 years. The brain of the young child
of shaking in which significant brain injury results usu- is very soft and has the approximate consistency of un-
ally involves holding the child by the thorax or arms set gelatin for two reasons: first, the process of myeli-
nation is just beginning in the cerebrum at birth and skull base allows the young child’s brain to rotate more
then rapidly progresses during the first 2 years of life, readily in response to head acceleration or deceleration
although the new myelin sheaths are thin; second, the than occurs once the skull base has developed its bony
young brain has a much greater water content than do ridges and concavities (Duhaime et al., 1987; Kriel et
those of older children and adults: by weight, 87% of al., 1988).
the cortex and 89% of the white matter is water at The mechanical forces which are of most importance
birth compared to 83% and 69%, respectively, in the in blunt head injury are primarily those of translational
second decade. The infant’s head at birth is dispro- and rotational forces. Translational forces are those
portionately large compared to the rest of the skeleton. forces generated by a direct blow or impact to the head
The largeness of the infant’s head is due primarily to which may produce focal contact injury to the skull or
the calvarium, which must grow rapidly to accommo- brain, but the major effect on the brain is to produce
date the brain’s very rapid growth rate. The facial skele- linear movement of the brain within the cranial cavity,
ton of the child, by contrast to the calvarium, is small a type of brain movement which is quite benign (Om-
and is in proportion to other parts of the skeleton. The maya et al., 1968; Gennarelli et al., 1982a). The triv-
facial skeleton remains small until the secondary den- ial home falls that children sustain in falling from fur-
tition erupts and teeth begin to fill the mouth and evoke niture and even down stairs seem to generate primarily
development of the maxillae and mandible around age translational forces, and although such falls may occa-
6 years and thereafter. At birth, the weight of the child’s sionally result in a skull fracture, these incidents gen-
head is about 10%–15% of its body weight compared erally tend to be very benign and do not result in loss
to about 2%–3% in adult life; the young child’s head of consciousness, neurological deficit, or death (Om-
is a large, heavy head. The bone of the young calvar- maya and Gennarelli, 1974; Wilkins and Rengachary,
ium is thin and the double layer of the diploe does not 1985; Stahlhammer, 1986).
develop until after the fourth year. The base of the skull Rotational forces are those forces generated by ei-
of the infant is relatively flat and shallow and lacks the ther impact or nonimpact inertial mechanisms which
pronounced concavities which will develop in later produce a sudden acceleration or deceleration of the
childhood as a result of the growth and maturation of head. Whiplash shaking is a nonimpact inertial mech-
the orbital roof shelf, the sphenoid bones, and the anism which produces an acceleration and deceleration
petrous ridges of the middle cranial fossae. Once de- of the head. Rotational forces result in rotational move-
veloped, these bony compartments prevent ready rota- ment of the brain within the cranial cavity, causing the
tional movement of the brain within the cranial cavity. brain to turn abruptly on its axis or at its attachment
As a result of the flatter, smoother skull base in the in- at the brainstem–cerebral junction. Such rotational
fant and young child, the brain is more free to rotate movements of the brain result in the type of injury re-
in the cranial cavity if significant force is applied. Fi- ferred to as shearing injury or diffuse axonal injury
nally, the weak, undeveloped neck muscles of the child (Ommaya and Gennarelli, 1974; Wilkins and Ren-
do not provide much resistance to abrupt head move- gachary, 1985; Stahllhammer, 1986; Hanigan et al.,
ment on either shaking or impact (Williams, 1995). 1987; Margulies and Thibault, 1989; Duhaime et al.,
Because of these unique features of the young child’s 1992). In young children, both impact and shaking re-
brain and skull, children under age 4 or 5 years are sult in the same brain injury, diffuse axonal injury or
particularly vulnerable to diffuse or shearing injuries of shearing injury, because both these mechanisms may
the brain. Impact to the immature brain is more likely cause rotation of the brain. After about the age of 4 or
to produce shearing injury than brain contusions, 5 years, the most common cause of diffuse axonal in-
which might result on impact in older children and jury is the motor vehicle accident.
adults. The undeveloped or incomplete degree of myeli- There is some experimental evidence which suggests
nation and the small axonal size predispose the young that shaking alone may not be forceful enough to pro-
brain to shearing injury: a soft brain simply tears more duce the angular acceleration necessary to create shear
readily. Impact force is more effectively transferred injury (Duhaime et al., 1987). Many forensic patholo-
through the thin, pliant skull and across the shallow gists and clinicians who have responsibility for the care
subarachnoid space of a young child’s head to produce of head-injured children have experience contrary to
shearing brain injury. The large, heavy head mounted that experimental evidence and believe that a young
on the weak neck of the young child produces insta- child can be shaken to death based both on confessions
bility of the head, which in turn will result in greater by perpetrators as to how they injured a child as well
movements of the head and brain when acted upon by as autopsies in which no impact site is found on the
acceleration–deceleration forces. Finally, the shallow scalp or skull and shaking was presumed. Not all im-
pacts are reflected on the scalp, however, because a arachnoid hemorrhage occurs in patches especially over
child’s scalp is very elastic and stretches on impact, and the parasagittal cerebral convexities and may be very
not all impacts are evidenced by hemorrhage in the sparse and difficult to appreciate because some or all
galea. It is not possible or necessary to attempt to dis- of the subarachnoid blood may be present on the mesial
tinguish children’s head injuries as due to either impact surfaces between the cerebral hemispheres.
or shaking because the brain pathology is identical in Retinal hemorrhages are found in 70%–85% of the
both. If there are focal injuries such as skull fractures, cases of rotational brain injuries in young children. The
scalp bruises, or subgaleal hemorrhage, certainly im- mechanism which causes these hemorrhages is not pre-
pact can be assumed. In the absence of such marks of cisely understood but their presence correlates highly
impact, however, shaking alone should not be pre- with a rotational head injury and they are greatly over-
sumed as there may well have been impact that cannot represented in cases of nonaccidental head trauma in
be discerned. young children. Mechanisms that may account for reti-
The pathology of young children’s head injuries of nal hemorrhages include increased pressure transmit-
the rotation or acceleration–deceleration type consists ted to the central retinal vein from increased intratho-
of the markers of shearing injury—subdural hemor- racic or intracranial pressure, direct trauma to the
rhage, subarachnoid hemorrhage, and retinal hemor- retina from being struck by the vitreous moving within
rhages. The subdural hemorrhage results from tearing the eye, and traction upon the retina by the movement
of the bridging veins which pass from the cortical sur- of the vitreous pulling away from the retina. The reti-
face to the dural venous sinuses; these veins tear as they nal hemorrhages seen in abusive head injuries are sim-
are stretched as the brain moves within in the cranial ilar to the retinal hemorrhages which frequently occur
cavity (Gennerelli et al., 1982b; Wilkins and Ren- in full-term neonates after vaginal delivery. In these
gachary, 1985; Yason et al., 1986; Vowles et al., 1987). neonates, the mechanism which has been suggested is
Subdural hemorrhage is evident in 90%–98% of cases increased intrathoracic pressure caused by squeezing
of inflicted head injury in children at autopsy. Most the infant’s thorax as it passes through the birth canal.
frequently the subdural hemorrhage is located over the Neonates who have these retinal hemorrhages have not
cerebral convexities, where it may be unilateral or bi- been found to have any intracranial injury. Most of the
lateral, and there is a tendency for the subdural blood neonatal retinal hemorrhages resolve after 5 or 6 days
to extend into the posterior interhemispheric fissure. By although a few last longer and none has been corre-
CT scan, small amounts of interhemispheric subdural lated with later developmental delays or strabismus
blood can be detected which may be missed at autopsy (Levin et al., 1980; Berger and Margolis, 1985). In chil-
because of its location, but the CT is less sensitive than dren older than 30 days who have retinal hemorrhages,
autopsy in detecting small-convexity subdural hemor- the great majority have abusive head injuries. Oph-
rhages (Kleinman, 1990). The amount of subdural thalmological findings in children with inflicted head
blood at autopsy may consist of only 2–3 mL and will injury include retinal hemorrhages involving the pe-
be not be appreciated if the prosector does not imme- riphery of the retina associated with retinal detach-
diately view the cranial cavity as the calvarium is be- ments, retinal tears, and large numbers of retinal hem-
ing removed. Once the brain is removed from the cra- orrhages. There may be additional internal eye injuries
nial cavity, the opportunity to view small amounts of in these same children consisting of vitreous bleeding
subdural blood on the convex cerebral surfaces may be and retinal folds. In children with very severe acciden-
lost. The amount of subdural hemorrhage may be as tal traumatic head injuries, an occasional instance of
much as 100 mL or more but usually is much less, but retinal hemorrhage is found. Nontraumatic causes of
the presence of subdural blood is important as a marker retinal hemorrhages include bleeding disorders, sepsis,
of shearing injury. The importance of the subdural meningitis, vasculopathies, increased intracranial pres-
hemorrhage is not necessarily or primarily as a space- sure, and very rarely if ever cardiopulmonary resusci-
occupying mass lesion producing increased intracranial tation (Goetting and Sow, 1990; Wilbur, 1992, 1994;
pressure and the consequences of tentorial herniation, Gilliland and Luckenback, 1993; Johnson et al., 1993;
although some hemorrhages will be large enough to Guilliland and Folber, 1996).
have these complications. Subdural bleeding may con- While the subarachnoid hemorrhage, subdural hem-
tinue to enlarge to some extent if the child survives for orrhage, and retinal hemorrhages are markers of the
several days in the hospital. The presence of even a rotational or shearing injury to the brain, the under-
small amount of subdural blood indicates that brain lying pathology of the shear injury is diffuse axonal
rotation has been produced, and such rotation may injury. Diffuse axonal injury, which has been more
have caused some amount of diffuse axonal injury. Sub- fully discussed in an earlier section, consists of tears
of axonal processes and small blood vessels and,

rarely, actual tissue tears in certain areas of the brain
(Adams, 1989, 1980a). The areas of predilection for
axonal injury are the corpus callosum, subcortical
white matter (especially of the superior frontal gyri),
the periventricular areas, and the dorsolateral quad-
rants of the rostral brain stem. Axonal tears are very
difficult to see in young children because of the small
size of the axonal processes. Calder et al. described
diffuse axonal injury in two infants, both over 5
months of age (Calder et al., 1984). In one infant, re-
traction bulbs were identified microscopically in the
corpus callosum but none was found in the dorsolat-
eral quadrants of the rostral brain stem. In a second
infant retraction balls were found in the dorsolateral FIGURE 9.43 Two-month-old female infant with abusive head injury
quadrants of the rostral brain stem but none was with subgleal hemorrhage of left parieto-occipital scalp, fractures of
right and left temporal bones and diastasis of the lambdoid suture,
found in the corpus callosum. These authors could not and bilateral subdural and subarachoid hemorrhages demonstrating
find any evidence of diffuse axonal injury in infants large contusion tear of right occipital lobe.
under 5 months old. Vowles et al. (1987) studied a
group of infants under 5 months of age who were ei-
ther shaken or struck directly on the head to produce It is not usually possible to establish the existence of
fatal head injuries. By using Naoumenko and Feigin’s diffuse axonal injury in young children by demon-
silver method to stain axonal processes (1967), dif- strating the classic pathological changes of retraction
fuse axonal injury was demonstrated in the white mat- bulbs, tissue tears, or intraparenchymal hemorrhages,
ter of the cerebral hemispheres and in the corpus although all these findings have been demonstrated on
callosum but not in the brain stem. The staining tech- occasion (Vowles et al., 1987; Case, 1997; Case et al.,
nique permitted the study of very fine axons. In ad- 2001). For this reason, it is important to appreciate the
dition to retraction balls, some cases demonstrated markers of shearing injury, the subarachnoid/subdural
varicosities or swellings along the axons (Vowles et hemorrhages and retinal hemorrhages, to identify these
al., 1987). The blood vessel tears of diffuse axonal in- cases as diffuse axonal injury.
jury are usually described as grossly evident linear The shearing injuries of young children are accom-
streaks or punctate hemorrhages which may vary from panied by brain swelling of various degrees. Initially,
less than 1 mm up to many centimeters in patients CT scans may demonstrate brain swelling and de-
who survive for several days and whose bleeding con- creased ventricular size without other lesions being vis-
tinues. Blood vessels in young children are very elas- ible. The swelling is probably related both to direct in-
tic and do not tear readily even when adjacent axonal jury to the axonal processes, causing localized edema,
processes are torn, so the streak and punctate hem- as well as to generalized swelling caused by changes in
orrhages grossly evident in many examples of diffuse vascular permeability and autoregulation (Kleinman,
axonal injury are very seldom found in young chil- 1990).
dren with diffuse axonal injury. Recognition of diffuse brain injury in young children
The tissue tears are gross lesions seen with the naked is important in establishing the timing of the injury be-
eye and usually are found in children under the age of cause diffuse injuries become symptomatic immediately
1 year as the lesion which Lindenberg described as if there is a moderate to severe degree of diffuse axonal
contusion tears (Lindenberg and Freytag, 1969) (Fig. injury, as would be expected if there is a significant
9.43). These are small, cleftlike tears which occur at neurological outcome or death (Ommaya and Gennarelli,
the cortex–white matter junction or within the layers 1974; Adams et al., 1982, 1989). Studies on children
of the cortex and are due to the differential movement with accidental head injuries in which they sustained
of the brain as some portions of the brain shear or slip diffuse axonal injury find that these children demon-
apart as the brain rotates. Contusion tears are rare le- strated an immediate decrease in the level of their con-
sions and in those cases in which they are seen, they sciousness (Willman et al., 1997; Duhaime et al., 1998).
are accompanied by subarachnoid and subdural hem- Correlations of clinical and experimental observations
orrhage and do not constitute isolated features of the on cerebral concussion and traumatic unconsciousness
shearing injury. demonstrate that progressively deeper disconnections
of axonal processes affecting the deep gray matter and tional forces necessary to develop tearing of bridging
rostral brain stem are the cause of the unconsciousness veins which would produce subdural hemorrhage or
in these children and not increasing intracranial pres- shearing injury (Kravitz et al., 1969; Helfer et al., 1977;
sure or hypoxia. The symptoms demonstrated by these Nitnityongskul and Anderson, 1987; Chadwick et al.,
severely injured children are those of an immediate de- 1991; Williams, 1991; Lyons and Oates, 1993).
crease in the level of consciousness, either lethargy or The problem of rebleeding in a chronic subdural
unconsciousness; respiratory irregularity, difficulty, or membrane is sometimes postulated to have caused sub-
apnea; and frequently seizures. The respiratory diffi- sequent acute subdural bleeding accompanied by an
culty which occurs in these children may be related to abrupt loss of consciousness following a minor or triv-
damage to lower brainstem medullary centers of respi- ial injury. In these cases, the children have appeared
ratory control which are damaged by the same axonal clinically normal, following the alleged initial injury
injuries which damage the upper brain stem. The tim- which caused the alleged chronic subdural membrane,
ing with which respiratory difficulty develops is not until the time of the alleged trivial trauma, but then
very precise and except to say that it follows the loss they become suddenly symptomatic because of the re-
of consciousness and that these children cannot survive bleeding. As discussed in the earlier section, “Subdural
for many hours outside medical care in which ventila- Hemorrhage,” the type of chronic subdural hemor-
tory support is available, it is not possible currently to rhage which would be at any risk of rebleeding would
predict the exact length of time such an injured child be expected only in those patients in whom there was
could survive. brain atrophy or surgically shunted hydrocephalus. In
Children who sustain repetitive episodes of mild in- a child who appears normal clinically until the time
jury of the shearing type gradually accumulate brain that acute subdural bleeding occurs, there is no reason
damage and may acquire neurological deficiencies. The to suspect that rebleeding in a preexisting chronic mem-
exact timing of such mild additive injuries is not pos- brane is responsible for the new hemorrhage. Certainly
sible to determine. The presence of old shearing lesions the presence of a chronic subdural membrane of the
does not make the brain more susceptible to new shear- type which would represent a rebleeding risk would
ing injury. Mild injuries not accompanied by loss of render the child symptomatic. The dura of young chil-
consciousness are not usually brought to medical at- dren, particularly along the basilar skull sutures, is a
tention. Some mild shearing injuries are manifested very cellular structure which contains growing fibrous
clinically by seizures and present difficult diagnostic tissue along with numerous hematopoietic cells, in-
problems as there is no currently available method to cluding macrophages many of which normally contain
demonstrate the underlying pathology of the shear in- hemosiderin. The appearance of these normal dura may
jury until more severe degrees of diffuse axonal dam- be misinterpreted as having a thin chronic subdural
age have been done and the injuries can be recognized membrane by microscopists who are not familiar with
by the markers of the subdural or subarachnoid hem- looking at these young duras and who may incorrectly
orrhage on CT scan or MRI. believe these membranes to be the cause of acute sub-
The distinction between nonaccidental and acciden- dural hemorrhage. Cases in which preexisting chronic
tal head injuries in children is an area of concern for subdural membranes are suspected of having caused
many physicians. The injuries described above as shear- new bleeding should certainly have grossly evident
ing or diffuse injuries require such extremes of rota- chronic membranes which would be readily visible at
tional force that they occur in accidental head injuries autopsy and not be diagnosed solely on the basis of the
only in obvious accidents such as motor vehicle acci- microscopic finding of a cellular and hemosiderin-laden
dents. Besides vehicular accidents, other fatal acciden- dura.
tal childhood head injuries tend to be crushing head in-
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10 Intoxications and metabolic diseases
of the central nervous system
SUZANNE Z. POWELL AND SYDNEY S. SCHOCHET, JR.
This chapter is an eclectic collection of topics includ- as zinc content and lactic dehydrogenase activity, have
ing hypoxia, selected intoxications, certain vitamin de- been demonstrated among these areas, some workers
ficiencies, and selected metabolic diseases. Many of still attribute these regional variations to the distribu-
these conditions show selective vulnerability. This term tion of blood vessels within the hippocampus. In the
has been used to describe the regional variations in the cerebral cortex (Fig. 10.2), injury is often most severe
nervous system’s response to the injurious effects of in the parietal and occipital lobes, and especially in the
various conditions. The pathophysiologic basis for se- depths of sulci reflecting perfusion patterns. In less se-
lective vulnerability has been the subject of study for a verely affected areas, neuronal loss is maximal in the
long time. Many years ago the Vogts introduced the third and fifth cortical layers. Among the basal ganglia,
term pathoclisis to describe the similarity of the re- the outer portions of the head and body of the caudate
sponse in various areas designated as topistic units. nuclei, the outer portions of the putamena, and the ba-
They assumed that some unknown biochemical char- solateral portions of the amygdalae are considered
acteristics accounted for the common response in dis- more vulnerable areas. The pallida are commonly
parate areas of the nervous system. Their hypothesis affected. Selective injury to this region has been attrib-
was challenged by others who attempted to explain the uted to impaired perfusion through the pallidal
regional variations on a vascular basis. Included among branches of the anterior choroidal arteries. In the brain
the vascular factors were the lack of continuity of the stem of an adult the substantia nigra, inferior colliculi,
capillary bed in arterial border zones and compression and inferior olivary nuclei are considered to be the more
of vessels by cerebral edema and herniation. Currently, vulnerable sites remove. In infancy the oculomotor,
many of the features of selective vulnerability have been trigeminal, ambiguual, vestibular, cochlear, gracile, and
attributed to the effects of excitotoxic amino acids and cuneate nuclei may be affected.
the distribution of receptors for these amino acids (Auer At the cellular level, the sequential neuronal changes
and Sutherland, 2002). have been studied in detail in laboratory animals. Four
stages have been delineated. The first is microvacuola-
tion. Most of the intracellular vacuoles are due to di-
HYPOXIA lated mitochondria; some result from dilated rough and
smooth endoplasmic reticulum. The second stage is the
A commonly encountered nervous system injury results simple ischemic cell change. These shrunken, hyper-
from an inadequate supply or utilization of oxygen and chromatic cells have swollen endoplasmic reticulum and
glucose. The brain normally receives about 15% of the aggregated ribosomes. The third stage is the ischemic
cardiac output, utilizes about 20% of the blood oxy- cell change with “incrustations.” The shrunken neurons
gen, and catabolizes about 15% of the blood glucose. appear to have small, dense bodies applied to their sur-
Areas traditionally considered to be especially vulner- face. They are actually portions of hyperchromatic cy-
able to hypoxia are the hippocampi, cerebral cortex, toplasm protruding from the surface of the shrunken
portions of the basal ganglia (particularly the pallida), neurons. The fourth and final stage is the homogenizing
and the Purkinje cell layer of the cerebellum. cell change. The affected neurons are shrunken, angu-
Within the hippocampus, the CA1 area, or Sommer’s lar, and hyperchromatic. This is the stage that is most
sector (Fig. 10.1), and CA3, the end plate, are gener- reliably identified in human material and is generally
ally more severely affected than CA2, the so-called re- seen 6–12 hours after injury. In the past, these changes
sistant sector. Although biochemical differences, such have been attributed simply to failure of energy pro-
176
10: INTOXICATIONS AND METABOLIC DISEASES OF THE CNS 177
INTOXICATIONS
Carbon Monoxide
Carbon monoxide is a colorless, odorless, nonirritating
gas produced by the incomplete combustion of carbon-
containing fuels. The toxic effects result mainly from im-
paired transport of oxygen by the blood. Although re-
versible, hemoglobin has a 250-fold greater affinity for
carbon monoxide than for oxygen. Furthermore, carbon
monoxide increases the oxygen-binding affinity of he-
moglobin and impedes the release of oxygen from he-
moglobin to other tissues. Therefore, carboxyhemoglo-
binemia produces more severe tissue hypoxia than a
FIGURE 10.1 Section showing hypoxic changes in neurons in the CA1
comparable degree of anemia. Additional toxic effects
sector (Sommer’s sector) of the hippocampus. result from the binding of carbon monoxide to other
iron-containing proteins such as myoglobin, cytochrome
P450, catalases, peroxidases, and cytochrome oxidase.
A major histotoxic effect on mitochondrial respiration
duction. In more recent years, it has been suggested that may be due to the binding of carbon monoxide to the
these neuronal changes may be attributed to a cascade cytochrome oxidase complex (Dolan, 1985).
of injurious metabolic events following abnormal re- The manifestations of acute carbon monoxide intoxi-
lease of excitatory neurotransmitters (Auer and Suther- cation correlate with the concentration of carboxy-
land, 2002). hemoglobin in the blood. This concentration is deter-
Although less extensively discussed, glial cells mined by the duration of exposure and concentration
also respond to hypoxia. In the acute phase, astro- of carbon monoxide in the ambient environment. An
cytes undergo rapid swelling and may accumulate otherwise healthy individual can be expected to have se-
glycogen. Disruption of the membranes of the vere headache and dizziness at 20%–30% saturation; im-
swollen astrocytes during tissue processing produces paired vision, hearing, and mentation at 40%–50% sat-
the appearance of enlarged perineuronal and perivas- uration; coma and convulsions at 50%–60% saturation;
cular spaces. Eventually, the reactive astrocytes con- and death from cardiorespiratory failure when saturation
tain increased numbers of intracytoplasmic fila- is over 70%. An atmospheric concentration of 0.5%–1%
ments. Oligodendrocytes are less affected and show can bring the saturation level to 75% in 2–15 minutes.
cytoplasmic swelling. The microglia give rise to rod Lower saturation levels may prove fatal in individuals
cells and participate in the phagocytosis of cellular with cardiovascular disease. Deaths in acute intoxication
debris. are often the result of cardiac arrhythmias. Elevated
carboxyhemoglobin levels are seen in smokers—often
5%–6% and occasionally up to 13% saturation in heavy
smokers.
Patients with acute carbon monoxide intoxication
may appear flushed, pallid, or even cyanotic. The clas-
sic cherry red color of skin, blood, and viscera is ob-
served more often as a postmortem phenomenon than
in living patients. The skin may show extensive blister
or bulla formation. Petechiae, mucosal and retinal
hemorrhages, and pulmonary edema may develop.
Brains from individuals who die within a few hours
from carbon monoxide intoxication generally show
congestion and edema, an abnormal red color, and rare
petechial hemorrhages. The cherry red color of the fresh
brain may become less prominent as a result of pro-
FIGURE 10.2 Section showing hypoxic changes in isocortical neurons. longed formalin fixation.
For comparison, note the single relatively normal neuron in the cen- Delayed neurological manifestations may appear a
ter of the illustration. few days to a few weeks after acute intoxication. Choi
(1983) found delayed neurological sequelae in 65 of Hemorrhagic and necrotic lesions are commonly en-
2360 victims of acute carbon monoxide poisoning. countered in the cerebral cortex and hippocampi.
These patients demonstrated their sequelae after lucid Lapresle and Fardeau (1967) found foci of cortical ne-
intervals of 2–40 days following the acute intoxication. crosis in 12 of 22 cases and varying degrees of hip-
The most common symptoms were mental deteriora- pocampal injury in 10 of 20 cases. Basal ganglia in-
tion, urinary or fecal incontinence, gait disturbance, volvement has been reported producing Tourette’s
and mutism. The most common signs were masked syndrome (Pulst et al., 1983) and a parkinsonian syn-
face, glabella sign, grasp reflex, increased muscle tone, drome (Klawans et al., 1982). The cerebellum may
short-step gait, and retropulsion. Brains from patients show loss of Purkinje cells and of internal granular
who die after 1–7 days often show numerous petechial layer cells.
hemorrhages. Necrosis of the pallidum is classically as- Lesions of the white matter are encountered equally
sociated with delayed deaths from carbon monoxide as often as gray matter lesions in individuals with de-
intoxication. At autopsy, grossly discernible foci of pal- layed death from carbon monoxide intoxication and
lidal necrosis are encountered most often in individu- are felt by some to be responsible for the neurological
als who survive for 6 or more days. Microscopic foci sequelae (Ginsberg, 1985; Parkinson et al., 2002). Four
of ischemic or hemorrhagic necrosis may develop categories of white matter lesions have been described,
sooner. Lapresle and Fardeau (1967) observed pallidal but the groups overlap (Lapresle and Fardeau, 1967).
necrosis in 16 of 22 patients who survived 1–139 days The lesions may consist of multiple small necrotic foci
following intoxication. The lesions are usually bilateral found predominantly in the anterior deep central white
but may be unequal in severity. The necrosis usually matter and anterior portion of the corpus callosum and
involves the inner segment of the pallidum but may ex- also involve the periventricular regions (Parkinson et
tend into the outer segment or dorsally into the inter- al., 2002). The lesions are centered around small blood
nal capsule (Fig. 10.3). These lesions have also been vessels that contain swollen endothelial cells with vesic-
demonstrated antemortem by computed tomography ular nuclei. Some of the endothelial cells may even con-
(CT) and magnetic resonance imaging (MRI) (Sawada tain mitotic figures. A second category of lesions con-
et al., 1983; Silverman et al., 1993; Parkinson et al., sists of large confluent areas of necrosis that may
2002). Although characteristic of delayed death from extend from the frontal to the occipital poles within
carbon monoxide, the lesions are not restricted to this the deep periventricular white matter and through the
condition. They have also been seen in a wide variety corpus callosum. These lesions are sharply demarcated
of other conditions accompanied by hypoxia or anoxia and tend to spare the arcuate fibers. Still other lesions
(Auer and Sutherland, 2002). The notion that the pal- consist of demyelination with relative preservation of
lidal necrosis is due to direct cellular toxicity has been axons in the deep periventricular white matter. These
disputed. Many authors regard these lesions as the re- lesions may be small and discrete, extensive, or even
sult of hypotension and impaired circulation in the pal- confluent. Arcuate fibers tend to be spared. This pat-
lidal branches of the anterior choroidal arteries. tern of demyelinative lesions may be encountered in pa-
tients with delayed neurological deterioration, the so-
called biphasic myelinopathy of Grinker. Finally, in
some patients, the lesions consist of very small necrotic
foci limited to the hemispheric white matter. Although
direct toxic effects of carbon monoxide may contrib-
ute to the production of white matter lesions, identical
lesions can be seen in other anoxic or hypoxic states.
Combinations of hypoxemia—particularly due to the
generation of free radicals, lipid peroxidation, and the
binding of CO to heme in cytochrome c oxidase (Crys-
tal and Ginsberg, 2000)—systemic hypotension, and
acidosis may be contributory factors.
Cyanides
Cyanide poisoning can occur from either ingestion or
FIGURE 10.3 Delayed death from carbon monoxide poisoning. Note inhalation. Inhalation of smoke containing cyanide de-
the necrosis of the pallidum bilaterally. rived from the thermal decomposition of nitrogen-
containing materials may cause or significantly considerable individual variation. Fatalities are often the
tribute to deaths from residential fires (Baud et al., result of ingesting alcohol in combination with other
1991). The toxicity is due to the reversible but strong drugs. The brains from individuals dying of acute eth-
bonding between the cyanide ion and ferric iron of in- anol intoxication usually show little more than cere-
tracellular cytochrome oxidase. This bonding leads bral edema.
rapidly to cessation of cellular respiration. Thus, Cerebral atrophy and ventricular enlargement have
cyanides are considered histotoxic or cytotoxic agents. been described in patients with chronic alcoholism. The
In cases of acute cyanide intoxication, death occurs role of the neurotoxic effects of alcohol and its catabo-
rapidly from respiratory arrest but may be preceded by lites in producing these changes apart from associated
seizures. A characteristic bitter almond odor may be nutritional deficiencies has been controversial (Harper,
evident in individuals who have ingested the poison. 1998). A recent study showed that well-nourished
The blood develops a cherry red color. Brains from chronic alcoholics had a significantly greater degree of
these individuals may show edema, and occasionally brain shrinkage associated with increasing age than did
focal subarachnoid hemorrhages. If death is delayed, control subjects. The magnitude of these changes cor-
the brains may show petechial hemorrhages, foci of ne- related with the lifetime dose of ethanol consumed
crosis in the basal ganglia and white matter, and loss (Nicolás et al., 1997). The atrophy and ventricular en-
of Purkinje cells. Rarely, parkinsonism (Utti et al., largement in chronic alcohol abusers is due predomi-
1985; Rosenberg et al., 1989) and a syndrome charac- nantly to a reduced volume of cerebral white matter
terized by extrapyramidal motor and cerebellar symp- (de la Monte, 1988). Neuronal loss occurs but tends to
toms (Rosenow et al., 1995) has been reported in in- be confined to specific areas such as the superior frontal
dividuals who have survived acute cyanide poisoning. convolutions (Harper, 1998). The wide spectrum of
Optic nerve and tract degeneration also has been re- cortical neuronal changes previously described in alco-
ported but is not well documented. holic patients—including swelling, “pigmentary atro-
Cyanide intoxication may also result from degrada- phy,” pyknosis, and loss of small pyramidal cells—is
tion of cyanogenic glucosides. At least one death has now regarded as nonspecific or artifactual.
been reported following the ingestion of amygdalin in
the form of laetrile (Braico et al., 1979). Chronic con-
Alcoholic cerebellar degeneration
sumption of insufficiently processed cassava that con-
tains cyanogenic glucosides has been implicated in caus- In patients with chronic alcoholism, atrophy may de-
ing an ataxic neuropathy and nonprogressive spastic velop in the rostral vermis and adjacent areas on the
paraparesis in central Africa (Tylleskär et al., 1994). superior surface of cerebellar hemispheres. This type of
cerebellar degeneration may be encountered as an iso-
lated lesion or in association with other alcohol-related
Ethanol
lesions such as Wernicke’s encephalopathy. The clini-
Ethanol has many direct and indirect effects on the cen- cal manifestations evolve slowly over months or years
tral nervous system (Brust, 1993). Intoxication in- and include truncal instability, leg ataxia, and a wide-
creases the risk for various forms of traumatic injuries. based stance and gait. The vermal atrophy can be dem-
Alcoholism predisposes individuals to infections, in- onstrated antemortem by CT and MRI but does not
cluding meningitis and cerebral abscesses, and is an im- correlate well with the severity of clinical manifesta-
portant cause of peripheral neuropathy. Consumption tions (Hillbom, 1986).
of alcohol has been claimed to increase the risk of cere- At autopsy, folia in the rostral vermis (Fig. 10.4) and
brovascular accidents, especially hemorrhagic strokes. to a lesser extent on the superior surface of the cere-
This idea remains controversial. bellar hemispheres are narrowed and separated by
Impairment of function can be seen with blood eth- widened interfolial sulci. The crests of the folia are
anol levels of only 50 mg/dL. Acute intoxication with more severely affected than the depths of the interfo-
large quantities of alcohol can lead to cardiorespira- lial sulci. This is in contrast to the pattern of alteration
tory depression and death. Blood ethanol levels greater resulting from hypoxia. The fully developed lesion
than 450 mg/dL are generally considered potentially shows loss of Purkinje cells, patchy loss of granular
lethal. However, individuals have survived much higher cells, and atrophy of the molecular layer. In addition,
levels (Lindblad and Olsson, 1976). This is due in part the Bergmann glia have proliferated. The cerebellar
to the increased tolerance found in chronic alcoholism. white matter remains relatively unaffected. The earlier
Children are often considered more vulnerable than stages of this degenerative process have not been well
adults to acute intoxication but here too there is con- documented morphologically.
(Kawamura, 1985). The clinical manifestations are highly

variable. The patients often display only features of
chronic alcohol abuse and withdrawal. Others show de-
mentia, emotional disorders, gait disturbances, apraxias,
and aphasias. Some have displayed an interhemispheric
disconnection syndrome (Rosa et al., 1991). The etiol-
ogy of Marchiafava-Bignami disease remains unknown
although speculations abound regarding nutritional defi-
ciencies and toxicities.
Grossly, the lesion appears as a discolored or even
partially cystic demyelinated region in the corpus cal-
losum. The demyelination and necrosis are maximal in
the genu and body of the corpus callosum. The lesion
is maximal in the interior of this structure and reveals
characteristically spare, thin layers of myelinated fibers
FIGURE 10.4 Superior vermal atrophy secondary to chronic alcohol along the dorsal and ventral surfaces of the corpus cal-
abuse. losum. In some cases additional demyelinative lesions
have been seen in the optic chiasm, anterior commis-
sure, centrum semiovale, and middle cerebellar pedun-
The pathogenesis of this process has not been estab- cles. Similarities between the lesions of Marchiafava-
lished. Generally, it is attributed to direct toxic effects Bignami disease, experimental cyanide intoxication,
of alcohol or associated nutrition deficiencies, espe- and central pontine myelinolysis have been emphasized.
cially thiamine deficiency (Victor et al., 1989; Harper Microscopic examination of the lesions shows ex-
and Butterworth, 2002). A direct neurotoxic effect of tensive demyelination with relative sparing of axis
alcohol is less likely, since development of degenera- cylinders. Oligodendrocytes are reduced in number,
tion does not correlate well with the magnitude of al- and lipid-laden macrophages are abundant. Reactive
cohol consumption (Estrin, 1987). Alternatively, it may astrocytes may be prominent in the more destructive
be due to electrolyte imbalances. Experimental studies lesions with cyst formation. Blood vessels in and
have suggested that excessively rapid correction of hy- around the lesions show endothelial proliferation and
ponatremia may be responsible for this lesion, as well mural hyalinization.
as central pontine myelinolysis (Kleinschmidt-DeMas-
ters and Norenberg, 1981). Some authors feel that a
Central pontine myelinolysis
similar but generally milder form of cerebellar atrophy
can occur as an age-related phenomenon independent Central pontine myelinolysis is an uncommon form of
of alcoholism. demyelination that is encountered predominantly in the
basis pontis. This disorder was first described in detail
by Adams et al. in 1959. Three of their four patients
Marchiafava-Bignami disease
suffered from chronic alcoholism, and all had serious
Marchiafava-Bignami disease is a rare disorder charac- malnutrition. In subsequent reports, the spectrum of
terized by demyelination of the corpus callosum. It was underlying disorders has been expanded (Sterns et al.,
described originally in malnourished Italian men who 1986) including reports of patients with severe liver dis-
were addicted to the consumption of crude red wine. Sub- ease, especially post orthotopic liver transplantation
sequently the disorder was described in other groups with (Wijdicks et al., 1996), severely burned patients (Mc-
more diverse preferences in alcoholic beverages (Koep- Kee et al., 1988), in AIDS (Miller et al., 1998) and even
pen and Barron, 1978). A few cases have even been re- childhood cases have been reported (Estol et al., 1989).
ported in poorly nourished individuals who abstained Although the pathogenesis remains incompletely delin-
from alcohol (Leong, 1979). In several instances, Marchi- eated, electrolyte imbalances, especially the excessively
afava-Bignami disease has been found in association with rapid or overcorrection of hyponatremia, has received
Wernicke’s encephalopathy, and in rare cases, there has much support from review of clinical material and ex-
been concurrent central pontine myelinolysis (Ghatak perimental studies (Sterns et al., 1986; Rojiani et al.,
et al., 1978) or cerebellar degeneration (Romero-Lopez 1994). Individuals who have been chronically hypona-
et al., 1997). Although the disease is usually diagnosed tremic appear to be especially susceptible although re-
at autopsy, the lesions can be seen by CT and MRI cent experimental studies have shown that azotemia
and an uremic state are protective against the devel-

opment of myelinolysis (Soupart et al., 2000). Alter-
natively, it has been suggested that the lesion is caused
by a relative or absolute hyperosmolality or hyper-
tonicity rather than specifically the alteration in the so-
dium level (McKee et al., 1988; McComb et al., 1989;
Riggs and Schochet, 1989).
The pathophysiologic basis for the preferential in-
volvement of the pons and the cause of the demyeli-
nation remain unsettled. Some authors have attributed
the preferential pontine localization to the detrimental
effects of edema in areas where gray matter is inter-
posed between bundles of longitudinally and trans-
versely oriented myelinated fibers (Messert et al.,
1979). In such areas, including the basis pontis, a larger
proportion of oligodendrocytes is in close proximity to
the more vascular gray matter (Riggs and Schochet,
1989). It has been postulated that the edema results
from opening of the blood–brain barrier from osmotic
injury to the vascular endothelium (Norenberg, 1983;
McKee et al., 1988). Most recently, several cases of
CPM were examined immunohistochemically utilizing
both apoptotic (Bax, Bak and the death receptor (DR)3) FIGURE 10.6 Macrosection of central pontine myelinolysis. Note the
and anti-apoptotic (Bcl-2) markers which suggested rim of preserved myelin.

that apoptosis may be a mechanism of oligodendrocyte
death (DeLuca et al., 2002) in the disease.
The clinical manifestations of central pontine myeli- to the pontine lesions are obscured by obtundation or
nolysis are determined in part by the size of the lesion. coma from the associated illness. In only a small
Often, the lesions are too small to be clinically symp- proportion of cases do the findings of quadriparesis,
tomatic and are detected only at the time of autopsy pseudobulbar palsy, or pseudocoma substantiate a
(Newell and Kleinschmidt-DeMasters, 1996). In other purely clinical diagnosis of central pontine myelinoly-
cases, signs and symptoms that might be attributable sis. The diagnosis may be assisted by the use of com-
puterized tomography and magnetic resonance imag-
ing (Brunner et al., 1990). In one case, T2 hypointense
signal abnormalities preceded the development of clin-
ical manifestations of central pontine myelinolysis
(Rouanet et al., 1994).
On gross inspection the typical lesion of central pon-
tine myelinolysis appears as a discolored, demyelinated
area that may be centrally cavitated in the basis pon-
tis (Fig. 10.5). The lesions are often triangular or dia-
mond-shaped and vary from a few millimeters in di-
ameter to extensive lesions that involve almost the
entire cross section of the basis pontis. Occasionally,
the lesions are bifid, involving the lateral portions but
sparing the midline of the pons. Generally at least a
thin rim of intact myelin is present at the lateral and
ventral margins of the pons (Fig. 10.6). Extension into
the pontine tegmentum is variable. Demyelination is
usually maximal in the middle and rostral portions of
the pons. Rarely, the lesions extend rostrally into the
FIGURE 10.5 Central pontine myelinolysis. Note the demylinated, par- midbrain. Caudally, the lesions generally stop at the
tially necrotic region of the basis pontis. pontomedullary junction. The cerebellar peduncles may
be involved along with the pons (Weissman and Weiss- pairment, paresis, and ataxia (Menger and Jorg,
man, 1989). In some cases, the lesion can be seen only 1999).
in stained sections.
On histologic study, central pontine myelinolysis is
Fetal alcohol syndrome
characterized by demyelination with relative preserva-
tion of axons and neuronal perikarya (Fig. 10.7). The Fetal alcohol syndrome encompasses a broad spectrum
acute lesions contain numerous lipid-laden macro- of neurological and somatic lesions in the fetus that re-
phages but few or no perivascular inflammatory cell insult from the adverse effects of chronic maternal alco-
filtrates. Oligodendrocytes are markedly reduced in holism. The syndrome is regarded as a leading cause of
number or even absent. Occasionally foci of necrosis mental retardation and birth defects (Streissguth et al.,
and cavitation are present in the center of the more se- 1991) with a recently estimated incidence of 0.33 cases
vere lesions. These foci may be surrounded by reactive per 1000 in the Western world (Abel and Sokol, 1991).
axons. Astrocytes in and around the lesions show re- The risk for fetal malformations appears to be greatest
active changes and proliferate. Occasionally, Alzheimer shortly after conception, but exactly how little mater-
type II astrocytes may be seen in the demyelinated por- nal alcohol consumption is necessary to cause the fetal
tion of the basis pontis and in the overlying pontine alcohol syndrome remains uncertain (Ernhart et al.,
tegmentum. 1987). In fact, it has been determined that the ethanol
Sometimes, especially in more severe cases, central toxicity is greatest during synaptogenesis in the last
pontine myelinolysis (CPM) is accompanied by ex- trimester of gestation (Goodlet and West, 1992), which
trapontine lesions. These have been encountered in has been shown to occur concomitantly with decreased
the subcortical white matter; striatum; internal, ex- bcl-2 expression (Yachnis et al., 1997). Apoptosis, in-
ternal, and extreme capsules; thalami; lateral genicu- duced by ethanol (a known N-methyl-D-aspartate
late bodies; anterior commissure; fornices; and white [NMDA] agonist) and also gamma-aminobutyric acid
matter of cerebellar folia (Gocht and Colmant, 1987; (GABA)ergic agents (benzodiazapenes), has been re-
McComb et al., 1989). Extrapontine lesions have cently reported during synaptogenesis in rats (Ikono-
been recently described in children with involvement midou et al., 2000), supporting the idea that late ef-
of the hippocampi (Brown and Caruso, 1999). As in fects of alcohol in the pregnant woman can produce
the pons, these sites of extrapontine demyelination fetal alcohol syndrome. Furthermore, whether the syn-
are characterized by close apposition of gray and drome results from the direct toxicity of alcohol and
white matter. its catabolites or from a reduction in intrauterine blood
Clinical outcome of patients with CPM ranges from flow is not well understood.
complete recovery (approximately 25% in a recent Clarren and Smith (1978) grouped the resulting ab-
report) to continued memory and/or cognitive im- normalities into four categories: central nervous system
dysfunction and malformations; prenatal and postna-
tal growth retardation; craniofacial abnormalities; and
variable malformations of other organs. Of these, the
involvement of the central nervous system is the most
serious. The nervous system dysfunction includes men-
tal retardation, a weak grip, poor hand–eye coordina-
tion, tremulousness, irritability in infancy and hyper-
activity in childhood, seizures, hypotonicity, and
cerebellar dysfunction. The facial anomalies are dis-
tinctive and include mild-to-moderate microcephaly,
short palpebral fissures, epicanthal folds, maxillary hy-
poplasia, a low nasal bridge with a short or upturned
nose, and a hypoplastic upper lip with a narrow ver-
milion border. The growth retardation tends to affect
body length more than weight.
Despite the frequency of this syndrome, detailed neu-
ropathological studies are relatively limited. The most
FIGURE 10.7 Microsection of central pontine myelinolysis. Note the consistent described neuropathologic lesions have in-
relative preservation of neurons despite the demyelination (Luxol fast cluded microcephaly, reduction in cerebral white mat-
blue stain). ter, enlargement of the ventricular system, cerebellar
hypoplasia, and neuroglial heterotopias. The neuroglial slowly by hepatic alcohol dehydrogenase to form
heterotopias may be periventricular and project into the formaldehyde, which is about 30 times more toxic than
cavities of the ventricular system or may be in the lep- methanol, and then to formic acid. The formic acid and
tomeninges. These lesions are thought to reflect ab- formates, which block cellular respiration, contribute
normal neuronal and glial migration during the early to the development of a severe metabolic acidosis.
part of gestation. Peiffer and coworkers (1979) studied The ocular pathology of methanol intoxication has
brains in three fetal and three childhood cases. They been investigated extensively. Older reports described
found a wide spectrum of lesions ranging from mild degeneration of the retinal ganglion cells and photore-
dysplasia to severe malformations including sy- ceptors. In more recent studies, edema of the optic disc
ringomyelia, the Dandy-Walker malformation, poren- and demyelination and necrosis of the retrolaminar op-
cephaly, agenesis of the corpus callosum, and hydran- tic nerve have been the principal findings (Sharpe et al.,
encephaly. Another report described severe anomalies 1982). In a case reported by Naeser (1988), there was
that included features of incomplete holoprosencephaly bilateral central necrosis of the optic nerves from be-
and septo-optic dysplasia (Coulter et al., 1993). Of par- hind the lamina cribrosa to the orbital apex. The prox-
ticular interest is a 4-year-old girl with this syndrome imal parts of the nerve and the optic tracts showed no
who died as the result of an accident. She had a small necrosis. The retrolaminar localization of the injury has
brain with reduced cerebral white matter, ventricular been attributed to high regional concentration of the
dilatation, and neuronal heterotopias along the lateral formates in a watershed area between cerebral and op-
ventricular surfaces. This case may provide a more ac- tic nerve circulations (Sharpe et al., 1982). Most re-
curate picture of the neuropathologic lesions in the nu- cently, a rodent model was developed that showed
merous milder cases of fetal alcohol syndrome (Clar- mitochondrial disruption and vacuolation in retinal
ren, 1981). pigment epithelium, photoreceptor inner segments and
the optic nerve. These findings suggest that ocular tox-
icity in methanol intoxication results from mitochon-
Methanol
drial damage induced by formates (Eells et al., 2000).
Methanol is used in the manufacture of formaldehyde, The brains of individuals dying of acute methanol in-
as a component of certain antifreeze solutions, and as toxication show only cerebral edema. When death is
a flammable heating compound. Formerly it was used delayed for a few days, necrosis of the lateral portion
as an adulterant of alcoholic beverages. The toxicity of of the putamen and the claustrum develops in about
methanol was not fully appreciated until the 1920s. one-third of the victims (Fig. 10.8). The lesions in the
When originally produced from destructive distillation putamen are often hemorrhagic, while those in the
of wood, “wood alcohol” contained unpleasant- claustrum and intervening external capsule tend to be
smelling and tasting contaminants that discouraged hu- ischemic. With still longer survival, the necrotic areas
man consumption. After production methods im- can undergo cystic transformation. In some cases, the
proved, methanol was included in alcoholic beverages, putaminal necrosis can be demonstrated antemortem
cosmetics, and medicinals as a cheap substitute for eth-
anol. Methanol intoxication has continued to occur,
most often as the result of consumption of adulterated
“moonshine” or various methanol-containing fluids
not intended for oral consumption.
Individual susceptibility to ingested methanol varies
widely. A few hours may elapse before the onset of
symptoms, which include drowsiness, headache, nau-
sea, vomiting, abdominal pain, dyspnea, and visual dis-
turbances. Blindness has followed the ingestion of as
little as 4 mL of pure methanol. The usual lethal dose
is in the range of 70 to 100 mL but as little as 30–60
mL has been reported to be lethal. Intoxication also
can result from inhalation of methanol vapors or ab-
sorption through the skin.
Methanol itself produces central nervous system de-
pression, but the more serious effects are produced by FIGURE 10.8 Delayed death from methanol intoxication. Note the
the catabolites of this alcohol. Methanol is oxidized hemorrhagic necrosis of the putamen.
by CT (McLean et al., 1980) (Fig. 10.9). Extensive ne-

crosis of cerebral and cerebellar white matter also may
develop in patients with especially prolonged survival
following severe methanol intoxication. This too has
been demonstrated antemortem by CT (McLean et al.,
1980). The pathogenesis of the putaminal lesions is un-
known. Sharpe and associates (1982) have suggested
that the cerebral white matter lesions as well as the
retrolaminar optic nerve lesions result from the myelin-
oclastic histotoxicity of formates.
Ethylene Glycol
Ethylene glycol is commonly used as an industrial sol-
vent and as a component of various antifreeze and cool- FIGURE 10.10 Ethylene glycol poisoning. Note the mild perivascular
inflammation and refractile crystals in the vessel wall.
ing agents. Intoxication with ethylene glycol results
most often from its consumption as an ill-advised sub-
stitute for ethanol or as a vehicle for suicide. The min-
imum lethal dose is estimated to be in excess of 100 Ethylene glycol intoxication is manifest clinically in
mL; it is rapidly absorbed from the gastrointestinal three fairly distinct stages. Central nervous system dys-
tract and peak serum levels are detected in as little as function predominates during the first 12 hours after
1, and up to 4, hours after ingestion (Saladino, 1991). ingestion and is usually accompanied by severe meta-
Ethylene glycol is progressively oxidized by hepatic al- bolic acidosis. This is followed during the next 12–24
cohol dehydrogenase to a series of more toxic com- hours by cardiorespiratory manifestations that include
pounds including glycolaldehyde, glycolic acid, and gly- tachypnea, tachycardia, and congestive heart failure. If
oxylic acid. A small proportion is eventually oxidized the patient survives for 3–4 days, renal failure becomes
to oxalic acid. a significant problem (Linnanvuo-Laitinen and Hut-
tunen, 1986). Shortly after ingestion, the patients may
appear to be drunk but lack the expected odor of
alcohol. The early cerebral manifestations including
drowsiness, stupor, and coma. These features coincide
with the period of maximal aldehyde formation. A wide
variety of other neurologic complications, including al-
tered consciousness, meningismus, ocular abnormali-
ties, cranial nerve dysfunction, seizures, and movement
disorders, has been tabulated by Berger and Ayyar
(1981). The acidosis is attributed primarily to the for-
mation of glycolic acid. The oxalic acid is responsible
for the hypocalcemia and calcium oxalate crystalluria
that does not occur until 24–72 hours after ingestion
of this intoxicant.
On gross examination the brains of individuals dying
from ethylene glycol intoxication show cerebral edema,
meningeal congestion, and occasionally petechial hem-
orrhages. Microscopic examination shows acute inflam-
matory cell infiltrates in the meninges and around in-
traparenchymal blood vessels. Crystalline deposits of
calcium oxalate may be seen in and around vessels in
the meninges, neural parenchyma (Fig. 10.10), and cho-
roid plexus. These crystals are best seen when the tissue
sections are examined with polarized light. Although
FIGURE 10.9 CT scan showing bilateral putaminal necrosis in a pa- previously implicated in causing the coma, the crystals
tient with methanol intoxication. probably do not contribute directly to it.
Isopropyl Alcohol
Isopropyl alcohol is another compound that can cause
serious intoxication when consumed as a substitute for
ethanol by alcohol abusers, when ingested accidentally
by children, or when used as a vehicle for suicide. The
most common source is rubbing alcohol, which com-
monly contains 70% isopropyl alcohol. This material is
absorbed rapidly and the major catabolite is acetone. In
contrast to methanol and ethylene glycol, isopropyl al-
cohol intoxication does not cause severe metabolic aci-
dosis. Abdominal pain, nausea, vomiting, hematemesis,
and hypotension may develop. Neurologic manifestations
include confusion, dizziness, incoordination, dysarthria,
hyperreflexia, stupor, and coma (Rich et al., 1990). The FIGURE 10.12 Section of cerebellum showing severe loss of Purkinje
usual lethal dose in adults who are not alcoholics is about cells and mild loss of internal granular layer cells from a patient main-
tained on high-dose phenytoin.
250 mL. Neuropathological findings are nonspecific. In
a fatality we examined, early necrosis of the putamena
and caudate nuclei was present. and the superior cerebellar peduncles. Ultrastructural
study showed that the spongy degeneration resulted
Hexachlorophene from intramyelinic edema. Adults and older children
rarely have any systemic effects from the use of hexa-
Hexachlorophene is a chlorinated bisphenol that is used chlorophene emulsion on intact skin, but toxic effects
as a bacteriostatic topical germicide. Some of the drug have followed the application of this compound to mu-
is absorbed through the skin. In sufficient quantities, it cous membranes, diseased skin, and burns. In addition,
can cause a neurotoxic reaction manifesting as tremu- rare fatalities have resulted from oral ingestion of hexa-
lousness, seizures, lethargy, and coma. Neurotoxicity chlorophene.
was encountered in low-birth-weight, premature in- The intramyelinic edema has been reproduced ex-
fants who were bathed repeatedly in a hexachlorophene perimentally in laboratory animals intoxicated with
emulsion (Powell and Lampert, 1979). These infants hexachlorophene. In addition, these animals show vac-
were especially susceptible because of the increased per- uolation of peripheral nerve myelin and degeneration
meability of their skin and the lesser ability of their liv- of retinal photoreceptor cells. The mechanism by which
ers to detoxify and excrete the drug. Spongy degener- hexachlorophene exerts its toxic effect on the lipid-rich
ation of white matter is found in the brain stem, membranes of the myelin sheath and photoreceptor
especially the medullary reticular formation, the medial cells has not been determined.
longitudinal fasciculus, the medial lemniscus (Fig. 10.11)
Phenytoin
Cerebellar atrophy, loss of Purkinje cells and granular
cell layer neurons, and gliosis of the cerebellar cortex
have been observed in patients with seizure disorders
who have undergone long-term therapy with pheny-
toin. The role of phenytoin in producing these lesions
is controversial and difficult to assess, since similar
changes may result from hypoxia during seizures (Ney
et al., 1994). In a comparative study of epileptic pa-
tients, Gessaga and Urich (1985) suggested that lesions
attributable primarily to phenytoin were distributed
diffusely throughout the cortex of the hemispheres and
vermis and consisted of subtotal loss of Purkinje cells
and rarefaction of the granular cell layer (Fig. 10.12).
FIGURE 10.11 Microsection of brain stem showing intramyelinic By contrast, they found that the lesions resulting from
edema from repeated exposure to hexachlorophene. postictal anoxia affected the lateral lobes of the cere-
bellum more than the vermis and were more severe in Chemotherapeutic Agents
the depths of interfolial sulci. However, the most per-
Methotrexate
suasive evidence for the neurotoxicity of hydantoin or
one of its catabolites comes from the demonstration of Both central and peripheral nervous system complica-
cerebellar degeneration in patients with few or no tions have been encountered in the course of systemic
seizures. Lindvall and Nilsson (1984) demonstrated or intrathecal chemotherapy with various antineoplas-
marked cerebellar atrophy by CT in a man treated pro- tic agents (Kaplan and Wiernik, 1984). Methotrexate
phylactically with phenytoin for 21/2 months following is one of the most commonly used chemotherapeutic
a subarachnoid hemorrhage. Similarly, Masur and as- agents. The adverse effects of this folic acid antagonist
sociates (1989) demonstrated cerebellar atrophy by se- on the bone marrow, gastrointestinal tract, liver, re-
rial tomograms after an attempted suicide with 7 g of productive organs, and fetal tissues are well known.
phenytoin. Comparable morphologic data are scanty. The drug also can cause neurotoxicity under various
Ghatak and coworkers (1976) observed cerebellar at- circumstances. Acute or subacute chemical meningitis,
rophy with total loss of Purkinje cells throughout the meningoencephalitis, and even transverse myelitis have
entire cerebellum and mild loss of granular layer cells occurred after intrathecal administration of methotrex-
in a patient who had only rare seizures. Experimental ate. The meningitis is accompanied by cerebrospinal
studies in laboratory animals have yielded conflicting fluid pleocytosis, but the histopathologic features are
results and have not resolved the question of pheny- unknown. Spinal cords from patients with transverse
toin’s neurotoxicity. myelitis usually show no morphological abnormalities
The use of anticonvulsants including diphenylhy- or only demyelination of spinal nerve roots and small
dantoin during pregnancy has been implicated in pro- regions of superficial spinal white matter. Rarely, acute
duction of various congenital anomalies. The risk that encephalomyelopathy has followed the repeated in-
an infant exposed to hydantoin in utero will develop trathecal administration of methotrexate.
the full fetal hydantoin syndrome is approximately In rare cases acute neurologic deficits have followed
10% with at least some effects in 33% of those ex- intravenous administration of methotrexate. Transient
posed (Jones, 1997). Measurement of amniotic fluid hemiplegia and focal seizures have been observed in
epoxide hydrolase may be useful in determining patients being treated with high-dose intravenous
whether infants are at increased risk for congenital methotrexate followed by leucovorin rescue. Multiple
malformations induced by maternal anticonvulsant hemorrhagic infarcts with fibrinoid necrosis and throm-
drugs (Buehler et al., 1990). The classic features of bosis of small vessels have complicated intracarotid in-
the syndrome include prenatal and postnatal growth fusion of methotrexate in high doses. Necrotic lesions
retardation, mental retardation, craniofacial anom- in a predominantly periventricular distribution have
alies, and limb defects. Craniofacial gene expression been observed in patients treated with intraventricular
has been recently examined in experimental animals methotrexate. Obstruction of the cerebrospinal fluid
treated with phenytoin. Expression of retinoic acid pathways is regarded as essential in the development
receptors (RAR) were significantly increased after of these lesions. Focal intraparenchymal lesions have
phenytoin exposure. Gene expression of laminin beta occurred when misplaced ventricular catheters have de-
1, and several growth factors was also elevated in livered methotrexate directly into the neural paren-
the craniofacial regions of the exposed embryos sug- chyma.
gesting that derangements at critical points during Among the most widely recognized neurological
development may be responsible for the described complications are the delayed encephalopathies fol-
craniofacial anomalies (Gelineau-van Waes, 1999). lowing a combination of high-dose, long-term systemic
Microcephaly, hydrocephalus, and neural tube defects or intrathecal methotrexate therapy and cranial irradi-
are among the more severe nervous system malfor- ation in children with leukemia (Kaplan and Wiernik,
mations that have been reported in this condition 1984). The clinical manifestations usually appear in-
(Trice and Ambler, 1985). A case of lobar holopros- sidiously and include confusion, mental deterioration,
encephaly has also been reported in this condition ataxia, seizures, and eventually stupor or coma. Neu-
(Kotzot et al., 1993). In other reports, the neuropathologic studies have disclosed various patterns of
ropathologic findings have been much more subtle. injury. The most common form is a subacute necrotiz-
The possibility of prenatal exposure to other terato- ing leukoencephalopathy. These lesions consist of mul-
gens and the role of intrauterine infections must be tiple discrete or confluent foci of coagulative necrosis
considered before lesions can be attributed solely to within the white matter. Some of the necrotic foci may
the maternal use of anticonvulsants. be surrounded by petechial hemorrhages. In the more
severe cases the lesions are roughly symmetric, bilat- Pathologic studies have shown loss of myelin, micro-
eral, and especially prominent within the central white vacuolation, and axonal degeneration in the spinal cord.
matter of the cerebral hemispheres. Microscopic study
of the lesions shows coagulative necrosis with miner-
Cisplatin
alization of reactive axons and cellular debris. Lipid-
laden macrophages are often abundant, but inflamma- Cisplatin (cis-diamminedichloroplatinum II) is a plat-
tory cells are sparse. The lesions may be surrounded by inum compound used in the therapy of patients with
areas of demyelination and reactive astrocytosis. Other various malignant neoplasms, including brain tumors.
patients show predominantly a noninflammatory min- The most common major side effects are renal, gas-
eralizing angiopathy. These vascular alterations are trointestinal, and hematologic toxicity. Cisplatin has
most severe in the gray matter, especially the putam- also been reported to have toxic effects on both the
ina, and the cerebral cortex in the depths of sulci. His- central and the peripheral nervous system. Neurosen-
tologic examination reveals heavy mineralization of the sory hearing loss is the most common form of neuro-
walls of small blood vessels leading to luminal occlu- toxicity. Intraarterial administration of the drug for
sion. The vascular lesions are accompanied by variable treatment of brain tumors has been complicated by
degrees of parenchymal necrosis and mineralization. hearing loss and by visual loss from retinopathy, de-
Magnetic resonance imaging studies have shown hy- generation of the optic nerves, and cataracts (Shima-
poplasia of the cerebellar vermis in children who had mura et al., 1990). The optic toxicity does not appear
been treated with radiation and intrathecal methotrex- to be dose dependent and may be bilateral despite
ate for acute lymphoblastic leukemia (Ciesielski et al., unilateral infusion of the agent (Maiese et al., 1992).
1994). Experimental studies have implicated the astro- Cisplatin has also caused occasional cases of demyeli-
cytes as the primary target for methotrexate neurotox- nation of the posterior columns of the spinal cord, cor-
icity. This is thought to be mediated by inhibition of tical blindness, and multifocal necrotizing leukoen-
purine and ribonucleic acid synthesis (Bruce-Gregorios cephalopathy (Bruck et al., 1989). Morphologic studies
et al., 1991). are limited and difficult to interpret because of the un-
Delayed leukoencephalopathy, similar to subacute derlying disease and concurrent use of other chemother-
necrotizing leukoencephalopathy, has occurred in apeutic agents.
adults after prophylactic cranial radiation and treat- The peripheral neuropathies associated with use of
ment with systemic chemotherapeutic agents for small- cisplatin are predominantly sensory and autonomic
cell carcinoma of the lung (So et al., 1987). neuropathies. Sural nerve biopsy specimens show loss
of large fibers with axonal degeneration and demyeli-
nation (Roelofs et al., 1984).
Cytosine arabinoside
Cytosine arabinoside (AraC) is a pyramidine analogue
Vincristine
that is commonly used in the treatment of acute leu-
kemia. Neurotoxic reactions have been reported with Vincristine, an alkaloid derived from the periwinkle
high-dose intravenous regimens (Hwang et al., 1985). plant (Vinca rosea), is commonly used as an antineo-
Most often these have been cerebellar dysfunction. plastic agent. Development of a peripheral neuropathy
Other complications include encephalopathy, seizures, is often the dose-limiting factor when this agent is em-
and leukoencephalopathy. Some of the reactions are re- ployed (Kaplan and Wiernik, 1984). The initial mani-
versible upon discontinuation of the drug therapy. festation of the neuropathy is usually suppression of
Pathological studies on patients with the cerebellar dys- the Achilles tendon reflex. This is followed by pares-
function have shown loss of Purkinje cells and prolif- thesias, distal motor weakness, and cranial nerve
eration of Bergmann glia, especially in the depths of in- palsies. Constipation and colicky abdominal pain re-
terfolial sulci. The changes tended to spare the caudal flect involvement of the autonomic nervous system. The
portions of the vermis, flocculus, and tonsils (Winkle- neurotoxic effects result from the binding of vincristine
man and Hines, 1983). Postmortem examination of a to microtubule proteins and disruption of fast axonal
patient with necrotizing leukoencephalopathy revealed transport. Histologic studies of peripheral nerve speci-
extensive coagulation necrosis, hemorrhage, demyeli- mens have shown predominantly axonal degeneration.
nation, and reactive gliosis (Hwang et al., 1985). The blood–brain barrier generally spares the central
Intrathecal administration of cytosine arabinoside nervous system from the neurotoxicity of this drug.
has been complicated by manifestations ranging from Nevertheless, inappropriate antidiuretic hormone se-
meningismus to paraplegia (Kaplan and Wiernik, 1984). cretion and seizures have been reported occasionally.
On a few occasions, vincristine has been inadver-

tently administered intrathecally (Slyter et al., 1980).
This has been followed by ascending paralysis, sensory
deficits, respiratory failure, and death 3–14 days later.
Spinal cord examination has disclosed swollen motor
neurons with disrupted Nissl granules and aggregates
of neurofilaments. One patient also had prominent
eosinophilic crystals (Fig. 10.13) in the cytoplasm of
anterior horn motor neurons. These were thought to
be derived from reaggregation of microtubule proteins
(Schochet et al., 1968).
Nitrosourea compounds
BCNU (1,3-bis[2-chloroethyl]-1-nitrosourea) is a ni-
trosourea compound currently used in chemotherapy
FIGURE 10.14 Section of sural nerve biopsy specimen from a patient
for certain brain tumors. Although systemic therapy is with acquired giant axonal neuropathy. Note the axonal swelling.
complicated by bone marrow suppression and pul-
monary fibrosis, neurotoxic effects are usually minimal.
However, use of high-dose systemic BCNU for ex-
tracranial neoplasms has led to necrotizing en- crosis of neural parenchyma, gliosis, and fibrinoid ne-
cephalomyelopathy (Burger et al., 1981). Two types of crosis of vessels resembling delayed radiation necrosis
lesions were encountered. One type was small foci of (Kleinschmidt-DeMasters, 1986; Di Chiro et al., 1988).
swollen axons and vacuolated myelin. These were
found predominantly in the white matter, especially the
Hexacarbon
brain stem, spinal cord, and corpus callosum. The sec-
ond type consisted of large symmetric foci of necrosis Methyl-N-butyl-ketone and N-hexane are aliphatic hy-
involving both gray and white matter. The lesions were drocarbons that have been employed extensively as or-
further characterized by thrombosis of small vessels and ganic solvents. Following industrial exposure or abu-
fibrinoid necrosis of vessel walls. BCNU is often ad- sive inhalation, these two compounds, and their
ministered intraarterially for regional perfusion of cere- common catabolite, 2,5-hexanedione, are capable of
bral neoplasms. Occasionally this has been complicated producing a mixed sensory and motor neuropathy. The
by a severe leukoencephalopathy with coagulative ne- patients often show continued progression of the neu-
ropathy for a several months, even after removal from
exposure to the toxic hexacarbon (Schaumburg and
Berger, 1993). Histologically the neuropathy is char-
acterized by the formation of focal enlargements on ax-
ons (Fig. 10.14) similar to those seen in hereditary giant
axonal neuropathy. The enlargements are proximal to
nodes of Ranvier and are filled with accumulations of
neurofilaments (Fig. 10.15). In the case of the hexacar-
bon neuropathy the axonal enlargements are thought
to result from partial impairment in the transport of
neurofilaments at the nodes of Ranvier. This has been
attributed to abnormal cross links among the intraax-
onal neurofilaments that are caused by the 2,5-hexa-
nedione. The formation of the axonal enlargements is
followed by degeneration and secondary demyelination
of the distal segments of the affected nerves. The cen-
tral nervous system is involved to a lesser extent. The
FIGURE 10.13 Photomicrograph of anterior horn motor neurons
showing clumping of neurofilaments and presence of eosinophilic in-
distal segments of long tracts such as the fasciculus gra-
tracytoplasmic crystal (arrow) following intrathecal administration cilis contain axonal enlargements similar to those in the
of vincristine. peripheral nerves.
Hayward, 1967). The brain stem showed severe loss of

neurons in the corresponding motor nuclei. Degenerative
neuronal changes also occurred in the globus pallidus,
substantia nigra, and hypothalamus. Reactivation of a
latent herpes simplex virus infection has been suggested
as an explanation for the preferential trigeminal in-
volvement (Cavanagh and Buxton, 1989).
Toxic Metals
Many metals in appropriate form and sufficient concen-
tration are toxic to humans. Most adversely affect mul-
tiple organ systems. In this chapter, space permits only
brief consideration of a few especially neurotoxic metals.
FIGURE 10.15 Electron micrograph showing a portion of one of the ax-
onal swellings. The interior of the axon is distended by neurofilaments.
Arsenic
At the present time, most cases of arsenic intoxication
result from occupational exposure or ingestion as a re-
Toluene
sult of homicidal or suicidal intent. It is used in wood
Toluene is an aromatic hydrocarbon that is widely used preservatives, weed killers, and pesticides and in the
as a solvent. Inhalation of solvent vapors including manufacture of glass. In the past, cases also resulted
toluene has become a common abusive practice, and from the therapeutic use of arsenical compounds and
when chronic, it causes a neurotoxic syndrome (Rosen- consumption of illicit liquor contaminated with arsenic.
berg et al., 1988; Filley et al., 1990). The clinical mani- Acute arsenic poisoning is characterized by colicky ab-
festations include cognitive impairment, cerebellar ataxia, dominal pain, nausea, vomiting, and diarrhea. Renal
pyramidal tract dysfunction, deafness, visual impairment, failure, shock from endothelial injury with plasma tran-
abnormal ocular movements (including bilateral inter- sudation, and death may occur in severe cases. Chronic
nuclear ophthalmoplegia) (Hunnewell and Miller, 1998), arsenic intoxication is manifested by malaise, gastroin-
and anosmia. Abnormal brainstem auditory evoked re- testinal disturbances, and skin lesions including in-
sponse (BAER) and EEG findings have been reported creased pigmentation and hyperkeratosis of the palms
(Hormes, 1986). MRI studies have shown cerebral atro- and soles of the feet. In some patients Mees’ lines de-
phy (cortical) (Schikler et al., 1982), loss of gray–white velop on nails (Fig. 10.16). Hematologic manifestations
differentiation, and increased periventricular signal in-
tensity on T2-weighted images (Filley et al., 1990). Lim-
ited neuropathologic studies have shown atrophy, wide-
spread demyelination of cerebral and cerebellar white
matter, and perivascular collections of macrophages that
stained by the periodic acid–Schiff technique. Electron
microscopy performed on one case disclosed intracyto-
plasmic trilaminar lipid leaflets similar to those in
adrenoleukodystrophy (Kornfeld et al., 1994).
Trichloroethylene
Trichloroethylene is a chlorinated hydrocarbon that has
also been employed extensively as a solvent. It has also
been administered as an inhalation anesthetic and at one
time was used in the treatment of trigeminal neuralgia.
The compound is neurotoxic with prominent involve-
ment of the optic, facial, and especially trigeminal nerves.
A postmortem study described demyelination and axonal FIGURE 10.16 Chronic arsenic intoxication. Note the white lines on
degeneration of trigeminal root and nerves (Buxton and the fingernails (Mees’ lines).
include anemia, thrombocytopenia, leukopenia, and chew on items coated with lead paint. Children
basophilic stippling of erythrocytes. with lead encephalopathy have excessive irritability,
A mixed sensory and motor peripheral neuropathy seizures, an altered state of consciousness ranging from
is a prominent feature of both acute and chronic ar- drowsiness to coma, and evidence of increased in-
senical intoxication. The histopathologic changes en- tracranial pressure. Deaths are now rare and usually
countered in peripheral nerve biopsy specimens are pre- occur in young children between the ages of 18 months
dominantly those of axonal degeneration (Fig. 10.17) and 3 years. Those who survive the acute intoxication
with secondary demyelination (Goebel et al., 1990; may have mental retardation, behavioral abnormalities,
Windebank, 1993; Greenberg, 1996). visual loss, and seizures.
Encephalopathy has been observed with both acute Brains from patients who succumb to the acute en-
and chronic arsenic intoxication. However, recent re- cephalopathy are swollen with flattened gyri and com-
ports do not discuss the morphological features of this pressed ventricles. Uncal and tonsillar herniation may
clinical manifestation. Older reports described cerebral be present. The histopathological changes include con-
edema and petechial hemorrhages in the corpus callo- gestion, petechial hemorrhages, and foci of necrosis.
sum, periventricular white matter, internal capsule, and Some of the capillaries are obliterated, whereas others
brain stem following arsphenamine therapy. Whether are dilated and unusually prominent. Some are
these lesions resulted from arsenic intoxication or surrounded by a proteinaceous exudate. Periodic
because of a hypersensitivity reaction to the drug is acid–Schiff staining may reveal small globules within
unknown. the perivascular astrocytes (Clasen et al., 1974). Dif-
fuse astrocytosis of both gray and white matter has
been reported even in the absence of capillary changes.
Lead
Many authors have attributed the encephalopathy to
Although many occupational, domestic, and environ- vascular injury, especially in the immature nervous sys-
mental sources of lead have been eliminated or reduced, tem (Goldstein, 1984).
unacceptably high blood levels are still present in many Lead peripheral neuropathy, the usual manifestation
children, especially among lower socioeconomic groups of lead neurotoxicity in the adult, is a remarkably pure
in urban areas. Lead can enter the body through the motor neuropathy that often is most severe in the ra-
gastrointestinal and respiratory tracts, and, when in or- dial nerves, producing wrist and finger drop. Few re-
ganic compounds, through the skin. Many body sys- cent histopathologic studies on patients with this dis-
tems, including the hematopoietic, genitourinary, and order have been reported. Behse and Carlsen (1978)
nervous systems, are adversely affected by lead. mentioned sural nerves in eight men who had 1–8 years
Lead neurotoxicity may be manifested by en- of occupational exposure to lead but no clinical man-
cephalopathy, neuropathy, or both. In recent years, ifestations of neuropathy. The sural nerves merely
lead encephalopathy has become relatively rare and is showed a slightly increased incidence of paranodal de-
encountered predominantly in young children who myelination and an increased incidence of degeneration
among the unmyelinated fibers. By contrast, numerous
studies of experimental lead neuropathy have been re-
ported. These have shown segmental demyelination and
endoneurial edema. Recent studies have suggested that
the initial peripheral nerve injury is due to the direct
toxic effect of lead on the Schwann cells and mem-
branes comprising the myelin sheaths rather than en-
doneurial edema (Windebank and Dyck, 1985).
Manganese
The neurotoxicity of manganese has been studied most
extensively in miners who have had chronic exposure
to manganese dioxide in the form of pyrolusite. It has
also been studied in metal workers. The clinical mani-
festations include transient psychiatric disturbances
FIGURE 10.17 Epoxy section from sural nerve biopsy specimen show- (so-called manganese madness), headaches, and a hy-
ing axonal degeneration secondary to chronic arsenic intoxication. pokinetic parkinsonian syndrome. The parkinsonian
manifestations persist even after exposure has been ter- posure to inorganic mercury have shown localization
minated and much of the manganese has been cleared of the metal in motor neurons, shrinkage of axons
from the body (Hochberg et al., 1996; Huang et al., (Pamphlett and Png, 1998), take up by the olfactory
1998) and apparently do not respond to treatment with tracts, and deposition in olfactory bulbs in animal mod-
levadopa (Pal et al., 1999). Human pathological stud- els (Henriksson and Tjalve, 1998).
ies are limited (Yamada et al., 1986). Degenerative Organic mercury compounds have been responsible
changes were found predominantly in the pallidum and for major outbreaks of poisoning in recent years.
subthalamic nucleus and to a lesser extent in the stria- Chronic organic mercury intoxication from fish con-
tum. The substantia nigra was rarely involved. Intra- taminated by methyl mercury developed in large num-
venous injections of manganese chloride in nonhuman bers of individuals living in the Minimata Bay and Ni-
primates produced degeneration primarily in the globus igata districts of Japan (Tokuomi et al., 1982) with
pallidus and the pars reticularis of the substantia nigra subsequent reports of the neurologic findings of 77 pa-
(Olanow et al., 1996). It has also been suggested that tients at autopsy (Uchino et al., 1995) which included
manganese accumulation in the brain may account for sensory loss predominantly in the extremities, con-
the MRI abnormalities and contribute to the neuro- striction of visual fields, and retrocochlear hearing loss
logical dysfunction in patients with chronic liver dis- and no correlation between the degree of cerebellar dys-
ease (Hauser et al., 1994) largely due to the reduction function and the concentration of methyl mercury in
in the expression of the astrocytic glutamate trans- the cerebellar tissue. Other large outbreaks have re-
porter, which leads to increased levels of glutamate sulted from the consumption of grain treated with an
(Hazell and Butterworth, 1999). Additionally, the neu- organic mercury fungicide. More recently Davis and
rotoxicity of manganese is reportedly multifactorial and colleagues (1994) reported severe methyl mercury poi-
relates to the balance of iron, aluminum, and calcium soning in four children resulting from consumption of
and their interactions with dopaminergic systems and mercury-contaminated pork for 3 months. The clinical
mitochondria (Verity, 1999). manifestations included cortical blindness or con-
stricted visual fields, impaired proprioception, choreoa-
thetosis, mental retardation, attention deficits, and
Mercury
quadriparesis. MRI showed atrophy of calcarine cor-
Metallic mercury and all mercury compounds, both in- tices, parietal lobes, and cerebellum. Another recent
organic and organic, are potential sources of human in- case of organic mercury intoxication resulted from a
toxications. Intoxication as a result of elemental and single accidental laboratory exposure to dimethyl mer-
inorganic mercury is now rarely seen since occupational cury. This resulted in delayed cerebellar disease and
exposure has been reduced and the medicinal use of eventually death (Nierenberg et al., 1998).
mercury and mercury compounds has been sharply cur- Neuropathologic studies have shown cerebral atro-
tailed. Acute inorganic mercury poisoning most often phy that is most pronounced in the anterior portions
causes gastrointestinal tract and renal tubular injury. of the calcarine fissures and to a lesser extent in the
Pulmonary injury can occur from inhalation of metal- precentral and postcentral gyri. The areas of cerebral
lic mercury vapors. Neurotoxicity was a prominent atrophy are characterized by neuronal loss, especially
manifestation of chronic inorganic mercury poisoning. from the outer cortical layers, and gliosis. Cerebellar
When this condition was more common, the initial atrophy is encountered almost as frequently as the at-
symptoms were often bizarre behavioral changes called rophy of the calcarine cortex. Microscopy shows loss
“erethism.” Other common findings included intention of neurons from the internal granular cell layer, pro-
tremor and movement disorders. Occasionally, periph- liferation of Bergmann glia, and mild loss of Purkinje
eral neuropathy developed. This was also a major man- cells. The apparent differences between the lesions
ifestation of acrodynia, or “pink disease,” a disorder caused by inorganic and organic mercury may result
resulting from chronic mercury poisoning in infants from differences in the rate of entry into the nervous
and young children. The mercury was acquired from system.
teething powders and antihelminthic agents. There are
few recent reports of the neuropathology of inorganic
Thallium
mercury poisoning. Davis and colleagues (1974) de-
scribed cerebellar atrophy with loss of internal granu- Although thallium compounds are highly toxic, they
lar layer cells and some Purkinje cells in two women are included in pesticides used for insect and rodent
who had used a laxative containing calomel (mercurous control. Pesticides are the major source of thallium in
chloride) for many years. Experimental studies of ex- accidental ingestions. In the past, thallium compounds
were used for the control of night sweats from tuber- acterized by asterixis, speech difficulties, seizures, and
culosis and as depilatory agents. Oral ingestion of thal- dementia. Although the brain aluminum content may
lium compounds can produce a wide spectrum of toxic be quite high, neurofibrillary tangles characteristic of
manifestations. Acute intoxication causes gastrointesti- Alzheimer’s disease (AD) are generally not present al-
nal disturbances manifesting as nausea, vomiting, di- though some have reported their presence and regional
arrhea, and abdominal pain. These may be followed by distribution (Crapper et al., 1976). Laser microprobe
cardiopulmonary dysfunction. In some cases death re- analyses have shown only small increases of aluminum
sults from myocardial necrosis. in neurons both with and without neurofibrillary tan-
Peripheral neuropathy is a major feature of thallium gles in patients with AD (Reusche et al., 1992; Lovell
intoxication. Initially, this is manifested as limb pain et al., 1993). Therefore, aluminum’s role in Alzheimer’s
occurring predominantly in the legs and localized to disease (AD) is unclear and remains a topic of heated
the joints. Distal sensory loss and muscle wasting may debate (Forbes and Hill, 1998; Munoz, 1998).
follow. Proximal tendon reflexes tend to be preserved.
Peripheral neuropathy may be the initial manifestation
Cadmium
in milder cases. Alopecia is the most widely recognized
manifestation of thallium intoxication but does not be- Recently, cadmium, a known occupational and envi-
come evident for several weeks and does not occur in ronmental toxin with a very long half-life (15 years),
all patients. Involvement of the autonomic nervous sys- has been reported in nickel-cadmium battery factory
tem has been implicated in the development of the workers to cause polyneuropathy (Viaene et al., 1999)
alopecia and cardiac dysfunction, which may be de- and olfactory disorders (Rydzewski et al., 1998;
layed and be caused by involvement of small unmyeli- Sulkowski et al., 2000) due to chronic exposure to this
nated axons (Nordentoft, 1998). Most descriptions of metal. Parkinsonism has also been reported after acute
the peripheral nerve pathology have emphasized axonal exposure (Okuda et al., 1997).
degeneration (Limos et al., 1982; Windebank, 1993).
Skeletal muscle has been reported to show myopathic
changes including necrosis of individual myofibers, in-
VITAMIN DEFICIENCIES
ternal nuclei, and fiber splitting (Limos et al., 1982).
Mees’ lines similar to those resulting from arsenic in-
General Deficiencies
toxication may develop in some patients.
Behavioral changes (McMillan et al., 1997), seizures, An important group of neurologic disorders is caused
and movement disorders have been reported, especially by vitamin deficiencies. These disorders are seen in
in cases of chronic intoxication. Diverse neuropatho- many parts of the world among malnourished individ-
logical changes including cerebral congestion and uals with inadequate food supplies. In the more highly
edema, neuronal loss, chromatolysis, neuronal vac- developed countries with abundant food, vitamin defi-
uolization, and degeneration of the posterior columns ciencies are encountered most often among alcohol
of the spinal cord have been described (Kennedy and abusers, especially when the alcohol consumption is not
Cavanagh, 1976). However, Davis and associates accompanied by other foods. Less commonly, vitamin
(1981) studied a patient who died about 9 days after deficiencies are seen in food faddists, in individuals with
ingesting 5–10 g of thallium nitrate. They found no gastrointestinal diseases, and in individuals receiving
histopathological abnormalities in the brain and only parenteral fluid maintenance without inadequate vita-
questionable chromatolysis of scattered neurons in the min supplementation.
anterior horns of the spinal cord. Nevertheless, the cere-
bral gray matter contained some of the highest con-
Thiamine Deficiency
centration of thallium in the body.
The Wernicke-Korsakoff syndrome and certain poly-
neuropathies are caused by thiamine deficiency. Al-
Aluminum
though these disorders are encountered most often in
For many years, the neurotoxicity of aluminum has patients with chronic alcoholism, at least some cases of
been controversial. Dialysis dementia or encephalopa- Wernicke’s encephalopathy have been associated with
thy has been attributed to exposure to aluminum in the other conditions. These include gastrointestinal neo-
dialysate of chronic hemodialysis patients (Alfrey et al., plasms, chronic dialysis, treatment with tolazamide,
1976) and to the use of oral phosphate-binding com- prolonged intravenous therapy without vitamin sup-
pounds that contain aluminum. This disorder is char- plementation, in pregnancy with hyperemesis gravi-
darum, and gastric plication for morbid obesity (Nadel

and Burger, 1976; Mukherjee et al., 1986; Abarbanel
et al., 1987; Jagadha et al., 1987; Ihara et al., 1997;
Togay-Isikay et al., 2001; Ogershok et al., 2002).
Conjugate gaze and lateral rectus palsies, nystagmus,
ataxia, and mental confusion are the classic features of
Wernicke’s encephalopathy. Recent criteria that have
been proposed for the diagnosis of Wernicke’s en-
cephalopathy require the presence of two of the fol-
lowing four features: dietary deficiency, oculomotor ab-
normalities, cerebellar dysfunction, and altered mental
status or mild memory impairment (Caine et al., 1997).
However, significant proportions of patients do not dis-
play the full spectrum of classic abnormalities (Harper
et al., 1986). Stupor, coma, hypotension, and hy- FIGURE 10.19 Acute Wernicke’s encephalopathy. Note the petechial
pothermia may be the major features in some patients hemorrhages in the mammillary bodies and walls of the third ven-
with atypical manifestations (Charness et al., 1989). tricle.
Morphologic evidence of Wernicke’s encephalopathy
was reported in 0.8%–2.7% of consecutive cases in
four large autopsy series (Cravioto et al., 1961; Harper stant (Torvik, 1987; Victor et al., 1989). The mam-
et al., 1986; Torvik, 1987; Victor et al., 1989). This millary bodies and other affected areas typically dis-
far exceeds the prevalence of clinically diagnosed Wer- play a gray-to-brown discoloration. A narrow band of
nicke’s encephalopathy. The pathological features vary tissue immediately adjacent to the ventricular system
with the stage and severity of the disease process and around the aqueduct generally remains unaffected.
(Harper and Butterworth, 2002). Patients who die in Occasionally the lesions contain petechial hemor-
the acute stages may have lesions in the mammillary rhages. Only rarely are the hemorrhages large and con-
bodies, hypothalamus, and periventricular region of the spicuous (Fig. 10.19). Even among acute cases, patho-
thalamus, around the aqueduct, and beneath the floor logical changes may not be discernible grossly. Patients
of the fourth ventricle. The mammillary bodies, espe- with more chronic or previously treated disease may
cially the medial nuclei, are the most frequently affected have only mildly discolored and mildly atrophic mam-
structures and are involved in virtually all cases (Fig. millary bodies. The lesions in periventricular and peri-
10.18). Involvement of the other locations is less con- aqueductal regions may be inconspicuous. Atrophy of
the mammillary bodies has been demonstrated by CT
and MRI in patients with chronic Wernicke’s en-
cephalopathy (Charness et al., 1987; Sullivan et al.,
1999; Park et al., 2001).
The histopathologic findings also vary with the
stage and severity of the disease. Acute lesions dis-
play edema, petechial hemorrhages, demyelination,
and reactive astrocytosis with relative preservation of
neurons. Capillaries are abnormally prominent be-
cause of swelling and hyperplasia of the endothelial
cells (Fig. 10.20). Lipid-laden macrophages may be
present in enlarged perivascular spaces. When pe-
techial hemorrhages are present, extravasated eryth-
rocytes and hemosiderin-laden macrophages may be
seen. The reactive astrocytes may be enlarged and ab-
normally conspicuous. Rarely, unusually prominent,
chromatolytic-appearing neurons may be encoun-
tered in the mammillary bodies. In the chronic stages
of the disease and in treated patients the affected re-
FIGURE 10.18 Coronal section showing shrinkage and discoloration gions may show little more than mild loss of neurons
of the mammillary bodies due to Wernicke’s encephalopathy. and gliosis.
vate dehydrogenase complex, ketoglutarate dehydro-

genase, and transketolase. However, the precise neuro-
chemical basis for the lesions in Wernicke’s enceph-
alopathy has not been fully elucidated. The mammillary
bodies, which are almost invariably affected in Wer-
nicke’s encephalopathy, have the highest regional ac-
tivity of transketolase in the normal human brain. It
has also been suggested that abnormal release of exci-
totoxic neurotransmitters may contribute to the devel-
opment of Wernicke’s encephalopathy and that a defi-
ciency of serotonin may be found in Korsakoff’s
psychosis (Charness et al., 1989).
The relatively infrequent and inconsistent develop-
ment of the Wernicke-Korsakoff syndrome even among
individuals with severe alcoholism has been attributed
FIGURE 10.20 Photomicrograph of mammillary bodies from a patient to genetically determined differences in the binding
with Wernicke’s encephalopathy. Note the presence of macrophages, of thiamine pyrophosphate by transketolase (Blass and
unusually prominent endothelial cells, and gliosis. Neurons are rel- Gibson, 1977). This finding has been correlated with
atively well preserved.
the observation that Wernicke-Korsakoff syndrome
occurs most often among individuals of European ex-
traction. Recently, an age-dependent parameter for de-
Retrograde amnesia and an impaired ability to ac- termination of transketolase activation has been devel-
quire new information are considered the classic fea- oped that identifies marginal thiamine deficiency
tures of Korsakoff’s psychosis. This disorder is usually (Rooprai et al., 1996) in this group of patients.
encountered in alcoholic patients with Wernicke’s en- Thiamine deficiency also produces peripheral neu-
cephalopathy. Rarely, Korsakoff’s psychosis can occur ropathies including beriberi neuropathy (Ohnishi et al.,
independently, even in nonalcoholic individuals with 1980; Kril, 1996) and at least some cases of so-called
other diencephalic lesions. alcoholic polyneuropathy. Most histopathologic stud-
Lesions in the medial dorsal nuclei of the thalamus ies on nerve specimens from patients with alcoholic
(Fig. 10.21) have been regarded as the morphological neuropathy have disclosed axonal degeneration with
substrate of the Korsakoff component of the Wer- secondary demyelination.
nicke-Korsakoff syndrome (Victor et al., 1989). Sup-
port for this interpretation is derived from cases of
Korsakoff’s psychosis associated with hemorrhages
and neoplasm in this anatomic location. However,
Torvik (1987) and others have described patients with
the Wernicke-Korsakoff syndrome in whom lesions
were restricted to the mammillary bodies and midline
region of the thalamus but sparing the medial dorsal
nuclei. Most recently, Harding et al. (2000) described
unbiased stereologic examination of the hypothalamic
mamillary nuclei and the anterior and mediodorsal
thalamic nuclei in patients with Wernicke’s enceph-
alopathy identifying extensive neuronal loss in mam-
millary and mediodorsal thalamic nuclei in both am-
nesic and non-amnesic patients but finding consistent
loss in the anterior thalamic nuclei only in the sub-
group with Korsakoff’s psychosis. These findings pro-
vide evidence that damage to anterior thalamic struc-
tures may be important in the memory disorder.
Thiamine in the form of thiamine pyrophosphate is FIGURE10.21 Acute Wernicke’s encephalopathy. Note the petechial
a cofactor for various enzyme systems such as the pyru- hemorrhages in the dorsomedial nucleus of the thalamus.
Leigh’s Disease not et al., 2001; Ogawa et al., 2002; Powers and De-
Vivo, 2002) and in patients with abnormalities of both
Subacute necrotizing encephalopathy (Leigh’s syn- SURF-1 and SCO2 located on 22q13 (Sue et al., 2000).
drome) is a metabolic disorder affecting predominantly However, patients with SCO2 mutations had a com-
infants and children (Victor et al., 1989). Weakness, bination of encephalopathy, cardiomyopathy and neu-
hypotonia, respiratory difficulties, seizures, and abnor- ropathologic findings that were atypical for Leigh’s syn-
mal eye movements are among the more common clin- drome and a more severe COX deficiency suggesting
ical manifestations. Acidosis is often present. The neu- that although there is a defect in COX activity, there
ropathologic lesions are similar to those encountered is phenotypic variation. Additionally, SURF-1 gene mu-
in Wernicke’s encephalopathy, but the distribution is tations are not exclusive to Leigh’s syndrome; a case of
somewhat different. Most notably, the mammillary leukdystrophy has also been described (Rahman et al.,
bodies are usually spared. Relatively symmetric areas 2001). A myriad of other mutations include those the
of partial necrosis are found in the periaqueductal gray flavoprotein gene in the respiratory chain complex II
matter, posterior colliculi, substantia nigra, inferior oli- (Parfait et al., 2000) and of the mtDNA COIII gene
vary nuclei, and dentate nuclei. Less frequently, the cau- (Tiranti et al., 2000). Characteristic paracrystalline in-
date nuclei, putamina, optic nerves, and spinal cord are clusions of muscle identified in these diseases ultra-
involved. structurally have also been identified in Leigh’s disease
Over the years, Leigh’s syndrome has been attributed (Crosby and Chou, 1974). However, examination of
to diverse metabolic abnormalities, including the pres- spongy lesions of brain has shown splitting of myelin
ence of a glycoprotein that inhibits the synthesis of thi- (Kimura et al, 1991), and nonviral intraneuronal in-
amine triphosphate, defective activity of the pyruvate clusions in a suspected case of Leigh’s disease (Lew et
dehydrogenase complex (PDHC), deficiency of pyru- al., 1989), and immunohistochemical analysis of inner
vate carboxylase, and deficiency of cytochrome c oxi- mitochondrial membranes showed increased staining in
dase (COX) (Di Mauro et al., 1987; Miranda et al., glial, mesodermal, and some neurons in cases of Leigh’s
1989; Rahman et al., 1996; Dahl, 1998, De Vivo, disease (Paulus and Peiffer, 1990).
1999). The syndrome may be the result of any of sev-
eral metabolic defects rather than a single biochemical
Vitamin B12 Deficiency
derangement. The disease process had historically been
assumed to be inherited as an autosomal recessive al- Vitamin B12 is obtained principally from meats and
though X-linked and maternal inheritance occur. It is dairy products. The vitamin must be bound to intrin-
caused by mitochondrial DNA abnormalities with mi- sic factor, a glycoprotein produced by gastric parietal
tochondrial failure of oxidative metabolism and is re- cells, prior to absorption in the ileum. Most cases of
lated to other mitochondrial encephalomyopathies, vitamin B12 deficiency result from inadequate gastric
including Kearns-Sayre, mitochondrial myopathy, en- production of intrinsic factor. An autoimmune atrophic
cephalopathy with lactic acidosis and strokelike gastritis is responsible for the failure of intrinsic factor
episodes (MELAS), and myoclonic epilepsy with ragged production in patients with pernicious anemia (Toh et
red fibers (MERRF). Although typically not involving al., 1997). Rarely, inadequate production of intrinsic
muscle, approximately 30% of the time a biochemical factor production is due to gastric neoplasms or fol-
defect in cytochrome c oxidase (COX) is identified (Na- lows gastrectomy. The vitamin deficiency can also re-
gai et al., 1992; Powers and DeViro, 2002). Leigh’s sult from diseases that impede intestinal absorption
syndrome (LS) is genetically heterogeneous with nu- including malabsorption syndromes, intestinal tuber-
merous different mitochondrial defects. A mutation in culosis, regional enteritis, and lymphomas. Some cases
the pyruvate dehydrogenase complex E1-alpha-subunit have resulted from competitive uptake of the vitamin
gene has been identified indicating that some cases are by fish tapeworm infestation or bacterial overgrowth
indeed X-linked (Mathews et al., 1993). A point mu- in blind loops and diverticula of the small intestine.
tation at position 8993 of mtDNA is a common cause The deficiency has major effects on the hematopoi-
(Santorelli et al., 1994; Carelli et al., 2002); other abetic, gastrointestinal, and nervous systems. The hema-
normalities include large scale deletions and point mu- tologic abnormalities range from macrocytosis and hy-
tations in NDUFVI and NDUFS1 genes in mitochon- persegmentation of polymorphonuclear leukocytes to
drial complex I of the respiratory chain (Loeffen et al., classic megaloblastic anemia. Effects on the gastroin-
1998; Benit et al., 2001) and mutations in COX as- testinal tract include glossitis, anorexia, diarrhea, and
sembly genes, SURF-1 on chromosome 9p34 (Pequig- weight loss. The neurologic complications result from
a combination of myelopathy and peripheral neuropa-

thy. The manifestations include weakness, paresthesias,
an unsteady gait, and loss of vibration and position
sense. Reflexes, especially in the lower limbs, may be
hyperactive from the myelopathy or hypoactive because
of the neuropathy. Vitamin B12 deficiency can also pro-
duce visual impairment and changes in mental function
ranging from apathy or irritability to psychosis. The
various neurologic and psychiatric manifestations may
occur in the absence of macrocytosis or anemia (Lin-
denbaum et al., 1988; Karnaze and Carmel, 1990).
Vitamin B12 is known to be a coenzyme for only
two reactions in humans, conversion of L-methyl-
malonyl–CoA (coenzyme A) to succinyl–CoA and methy-
lation of homocysteine to methionine. The precise bio-
chemical basis for the detrimental effects of vitamin B12 FIGURE 10.22 Photomicrograph of spinal cord showing intramyelinic
deficiency upon the nervous system has not been eluci- edema and demyelination in the posterior column due to vitamin B12
dated. In recent years it has been recognized that nitrous deficiency.
oxide inactivates vitamin B12. Myeloneuropathy has been
reported in patients with marginal B12 deficiency who Recently, serum levels of tumor necrosis factor
have been given nitrous oxide anesthesia (Holloway and (TNF)-alpha have been found elevated combined with
Alberico, 1990), and both myelopathy and psychosis decreased amounts of neurotrophic epidermal growth
have been reported in individuals who abusively inhale factor (EGF) in patients with B12 deficiency when
nitrous oxide (Stabler et al., 1991). compared to unchanged levels in patients with iron de-
In patients with longstanding severe disease the ficiency anemia (Peracchi et al., 2001).
spinal cord may be mildly shrunken with discolored
posterior and lateral columns. On histologic examina-
Vitamin E Deficiency
tion, coalescent patchy lesions displaying varying
degrees of demyelination, spongiosis, and gliosis are Over the years, there has been increasing evidence that
found in the posterior and lateral columns. In especially vitamin E (alpha-tocopherol) deficiency adversely af-
severe cases the anterior columns are also involved. The fects the human nervous system. Among the lesions
lesions are generally most prominent in the lower cer- noted are dystrophic axons in the fasciculus gracilis and
vical and thoracic portions of the spinal cord but may cuneatus. Dystrophic axons are terminal or pretermi-
extend rostrally into the medulla. The earliest lesions nal, spherical-to-fusiform enlargements that may be
consist of vacuolar distension of myelin sheaths. The many times larger than the axons from which they are
vacuolation imparts the characteristic spongy appear- derived. Most dystrophic axons are homogeneous or
ance to the affected white matter (Fig. 10.22). De- granular, although some may be vacuolated or appear
myelination ensues, and lipid-laden macrophages be- as spiked balls. They can be seen with hematoxylin and
come scattered throughout the lesions. At least some eosin but are better demonstrated with trichrome and
of the axons undergo Wallerian degeneration. Initially silver stains (Fig. 10.23). Ultrastructural studies have
astrocytosis is not marked, but dense gliosis can be seen shown that the dystrophic axons contain accumulations
in longstanding cases. of filaments, membranes, tubules, altered mitochon-
Occasionally, mixed demyelinative and destructive dria, and osmiophilic granular material.
lesions are seen in the cerebral white matter. These le- Large numbers of dystrophic axons were found in the
sions have been designated Lichtheim plaques. They gracile nuclei of children and young adults with biliary
may involve the optic pathways, affecting particularly atresia and cystic fibrosis, diseases that impair the ab-
the papillomacular bundles. Relatively few morpho- sorption of this fat-soluble vitamin. Furthermore, they
logic studies of peripheral nerves in patients with vita- were more numerous in the patients who had not received
min B12 deficiency have been carried out. Earlier re- supplemental vitamin E (Sung et al., 1981). In two other
ports emphasized a reduction in the number of large large series of patients with cystic fibrosis, some of the
myelin sheaths, suggesting segmental demyelination, cases showed degeneration or demyelination of the fas-
whereas more recent reports (Kosik et al., 1980) have ciculus gracilis in addition to dystrophic axons (Geller et
described predominantly axonal degeneration. al., 1977; Cavalier and Gambetti, 1981).
Sphingolipidoses
Lipids constitute 50%–70% of the white matter and
30%–40% of the gray matter. The major myelin lipids
are cerebrosides, cholesterol, and phospholipids, in-
cluding sphingomyelin. Gray matter contains a greater
proportion of gangliosides and less phospholipids. The
sphingolipids are lipids with sphingosine (an 18-carbon
unsaturated aminodiol or closely related compound) as
their common base. Acylation of sphingosine with long-
chain fatty acids gives rise to ceramides. Substitution
of the terminal hydroxyl group on ceramide by phos-
phoylcholine gives rise to sphingomyelin. Similarly,
substitution by single hexoses gives rise to the cere-
FIGURE 10.23 Photomicrograph showing dystrophic axonal swellings
in the fasciculus gracilis (Bodian silver stain). brosides. More complex glycosphingolipids that con-
tain one or more sialic acid (N-acetyl-neuraminic acid)
residues on oligosaccharide chains are gangliosides. De-
More recently, varying combinations of weakness, rangements in the catabolism of sphingolipids due to
ataxia, loss of proprioception, areflexia, ophthalmo- the deficiency of specific enzymes or obligate activator
plegia, pigmentary retinopathy, neuropathy, and my- proteins are responsible for various storage diseases and
opathy have been observed in patients with chronic leukodystrophies (Kolter and Sandhoff, 1998); thera-
cholestastic liver disease, various forms of intestinal peutic trials of bone marrow transplantation and stem
malabsorption, abetalipoproteinemia, and selective vi- cell transplants have been recently employed (Brady,
tamin E deficiency without malabsorption (Krendel et 1998; Krivit et al., 1999; Kolodny, 2000).
al., 1987). These clinical observations have been ac-
companied by relatively limited neuropathological
Niemann-Pick disease
studies. Dystrophic axons, demyelination of the poste-
rior columns of the spinal cord, excessive neuronal pig- Niemann-Pick disease is now considered to be a het-
mentation, and pigmentation of glial cells in the zona erogeneous group of autosomal recessive disorders
reticularis of the substantia nigra, pallidum, and puta- characterized by the abnormal accumulation of sphin-
men have been seen in some of the cases (Weder et al., gomyelin, cholesterol, and various other lipids. As bio-
1984). Peripheral nerves have shown loss of large chemical data have been accumulated, the four forms
myelinated fibers and rare dystrophic axons (Brin et of Niemann-Pick disease delineated in the traditional
al., 1985; Muller and Goss-Sampson, 1990). Muscle Crocker classification have been regrouped into two
biopsy specimens have shown fiber-type grouping and separate categories. The first category consists of cases
intracytoplasmic deposits of lipopigment (Neville et al., with marked sphingomyelinase deficiency and includes
1983). Most recently, Vitamin E deficiency and a mu- Crocker types A and B. The sphingomyelinase gene re-
tation in the alpha-tocopherol transfer protein (alpha- sponsible for these two alleic conditions has been
TTP) gene have been associated with a spinocerebellar mapped to chromosome 11 p 15.1 to 15.4 (Schuchman
ataxia, ataxia with vitamin E deficiency (AVED). Al- and Desnick, 1995). The second category consists of
though alpha-TTP had been described previously only cases that are now considered to be primarily a cho-
in the liver, neuropathologic findings in a case of lesterol lipidosis that is due in large part to the in-
AVED, patients with cholestatic liver disease and tralysosomal sequestration of endocytosed cholesterol
abetalipoproteinemia have localized alpha-TTP to cere- (Pentchev et al., 1995; Vanier and Suzuki, 1998). This
bellar Purkinje cells (Copp et al., 1999). Further stud- category includes cases formerly described as Crocker
ies are needed to determine the spectrum of pathological types C and D.
changes directly attributable to the vitamin E deficiency. Crocker type A Niemann-Pick disease is the classi-
cal infantile form of the disease and accounts for about
METABOLIC DISEASES 75% of all cases. Many of the patients are Ashkenazic
Jews. The disease becomes evident early in infancy with
Since only a few selected diseases can be covered in a hepatosplenomegaly and psychomotor retardation.
short chapter, major emphasis is given to the sphin- One-third to one-half of the infants have cherry red
golipid storage diseases and related leukodystrophies. spots in their maculae. Death usually occurs by the age
of 5 years. Sphingomyelin and cholesterol accumulate

in the brain and visceral organs. These patients have a
severe deficiency of sphingomyelinase activity. Neu-
ronal storage (Fig. 10.24) is especially prominent in
brainstem nuclei, cerebellum, and spinal cord gray mat-
ter. The liver shows vacuolation of both hepatocytes
and Kupffer cells. The lungs, spleen, lymph nodes, and
bone marrow contain numerous large macrophages
with foamy cytoplasm (the so-called Niemann-Pick
cells). Such cells, if not treated with lipid solvents, will
show birefringence when viewed with polarized light.
In paraffin-embedded sections, the lipid-laden cells
stain variably with the periodic acid–Schiff technique.
On ultrastructural study the stored material appears
partly as small myelin figures with a lamellar period- FIGURE 10.25 Electron micrograph showing bone marrow macro-
icity of about 5 nm. phage from a patient with type C Niemann-Pick disease. Note the
loose myelin figures within the cytoplasm.
Crocker type B Niemann-Pick disease is a subacute
or chronic visceral form without obvious central ner-
vous system involvement. Initially the spleen is en- Carstea et al., 1997) has led to transgenic mouse mod-
larged, and hepatomegaly and pulmonary involvement els, which have been utilized to study cholesterol-low-
occur somewhat later. Sphingomyelinase activity is de- ering agents. A second gene, NPC2, has also been
ficient, and sphingomyelin and cholesterol accumulate recently cloned (Naureckiene et al., 2000). Liver cho-
in visceral organs. In addition to Niemann-Pick cells, lesterol storage was decreased, but there was no no-
bone marrow from these patients may contain numer- table effect on the onset or progression of neurologic
ous lipofuscin-laden macrophages. These cells stain symptoms (Erickson et al., 2000). The clinical mani-
blue with the Giemsa or Wright stain. Thus, type B festations are diverse. The course of the disease is sub-
Niemann-Pick disease is an important cause of so-called acute or chronic with onset of hepatosplenomegaly and
sea-blue histiocytosis. psychomotor retardation between the ages of 2 and 4
Cases formerly classified as Crocker types C and D years. Involuntary movements develop in some pa-
Niemann-Pick disease are now considered to be genet- tients, as does a supranuclear paresis of vertical gaze
ically heterogeneous disorders primarily of intralyso- that is considered highly characteristic of this disease
somal sequestration of unesterified cholesterol (Vanier (Higgins et al., 1992). Brains from these patients may
and Suzuki, 1998). Recent cloning of the NPC1 gene, show mild cerebral and cerebellar atrophy. In addition
located on chromosome 18q11 (Carstea et al., 1993; to neuronal storage, the cerebral white matter may con-
tain dystrophic axonal spheroids. Neurofibrillary tan-
gles have been reported in some cases with an espe-
cially protracted clinical course (Vanier and Suzuki,
1998). Viscera, especially the spleen and liver, contain
a mild excess of sphingomyelin and other sphingolipids
in addition to the cholesterol storage. The foamy cells
in bone marrow aspirates from these patients are more
pleomorphic than in type A Niemann-Pick disease. On
ultrastructural study they contain loosely compacted
myelin figures and lipofuscin (Fig. 10.25). Type D
Niemann-Pick disease is now considered to be a
subset of type C that is restricted to individuals of
Nova Scotian descent.
Gaucher’s disease
Gaucher’s disease is the most common of the sphin-
FIGURE 10.24 Photomicrograph showing distended neurons, reflect- golipidoses. It is an autosomal recessive disorder char-
ing intraneuronal storage, in a patient with Niemann-Pick disease. acterized by an abnormal accumulation of glucocere-
broside resulting from deficient glucocerebrosidase ac-

tivity (Beutler and Grabowski, 1995). The gene coding
for this enzyme, which is alternatively designated as
lysosomal acid -glucosidase, is located on chromo-
some 1q21 with over 60 mutations identified (Balicki
and Beutler, 1995). Rarely, the disease is due to defi-
ciency of saposin, a cofactor required for normal en-
zyme activity. Three clinical phenotypes have been de-
lineated (Brady et al., 1993).
Type 1 Gaucher’s disease, also called “adult” or
chronic non-neuronopathic Gaucher disease, is by far
the most common form. Over half of the patients are
Ashkenazic Jews with X1226Y mutation although it is
not found in patients from Japan (Ida et al., 1999). The
severity of the disease varies considerably. Most of the FIGURE 10.26 Epoxy section of bone marrow from a patient with
glucocerebroside stored in visceral organs is derived Gaucher disease. The intracytoplasmic glucocerebroside imparts a
from phagocytosis and degradation of senescent eryth- striated appearance to the cytoplasm.
rocytes and leukocytes. The clinical manifestations may
become apparent at any age but usually during late
childhood. Major manifestations include splenomegaly, olism of endogenous gangliosides. The neuronal death
hypersplenism (thrombocytopenia and anemia), he- has been attributed to the accumulation of minute
patomegaly, skin pigmentation, and bone involvement quantities of cytotoxic glucosphingosine.
(Erlenmeyer flask deformity of the femurs, aseptic ne- Type 3 Gaucher’s disease, alternatively designated as
crosis, and fractures). Control of the hypersplenism “juvenile” or subacute neuronopathic Gaucher disease,
may require splenectomy, after which the bone in- is the least common form of the disease with the most
volvement often becomes more severe. Although the common mutation identified as X444Y that may be
central nervous system is not directly involved by type found in the other two types of the disease. Clinical
1 Gaucher disease, a small number of patients with this manifestations, including hepatosplenomegaly and neu-
form of the disease have neurological symptoms as a rologic manifestations, generally appear during late
result of the skeletal and hemorrhagic complications of childhood or early adulthood. In type 3b, horizontal
the disease (Grewal et al., 1991). supranuclear gaze palsy is the sole neurologic sign (Pat-
The glucocerebroside accumulates within Kupffer terson et al., 1993). Glucocerebroside accumulates in
cells and in macrophages, especially in the spleen, all tissues, including brain, but to a lesser extent than
lymph nodes, and bone marrow. The stored gluco- in type 2 Gaucher’s disease.
cerebroside imparts a characteristic appearance of
wrinkled tissue paper to the affected cells (so-called
Fabry’s disease
Gaucher cells) (Fig. 10.26). The cells also stain strongly
with the periodic acid–Schiff technique. Ultrastruc- Fabry’s disease is a rare, X-linked (q22 region), reces-
turally, the stored material appears as aggregates of sive sphingolipidosis. In the affected patients, ceramide
large, twisted tubules. trihexoside, globotriaosylceramide, and related com-
Type 2 Gaucher’s disease, alternatively designated as pounds accumulate in various tissues as the result of
“infantile” or acute neuronopathic Gaucher’s disease, deficiency of -galactosidase A activity (Desnick et al.,
is quite rare. Clinical manifestations appear between 3 1995), which is heterogeneous with numerous muta-
and 6 months of age and include hepatosplenomegaly, tions recently delineated (Topaloglu et al., 1999;
spasticity, and severe psychomotor retardation. The Rosenberg et al., 2000).
disease progresses rapidly and death ensues within 1–2 The full expression of the disorder is encountered in
years. Brains from these patients show widespread neu- hemizygous males. The onset of clinical manifestations
ronal loss from the cerebral cortex and basal ganglia, often occurs during adolescence with episodes of pain
perivascular collections of cerebroside-laden macro- and mild fever. Somewhat later, cutaneous telangiec-
phages, and occasionally neuronal storage. Biochemical tases (so-called angiokeratomas) may appear (Fig.
studies have shown intracerebral storage of glucocere- 10.27). These are most numerous on the lower ab-
broside. In type 2 Gaucher’s disease, the intraneuronal domen, genitalia, and upper legs. The patients also may
glucocerebroside is thought to be derived from catab- have decreased sweating, abnormally tortuous con-
barrier regions (Kaye et al., 1988). This would also ac-

count for the prominent deposits in the leptomeningeal
blood vessels and choroid plexuses. In all locations, the
lipid deposits are stained by the periodic acid–Schiff
and Luxol fast blue techniques. In fresh tissue, the de-
posits are birefringent. On ultrastructural examination
the lipids appear predominantly as osmiophilic inclu-
sions composed of concentric, stacked, or curved lipid
lamellae.
The characteristic pain may be due to neural in-
volvement. Preferential loss of small myelinated and un-
myelinated nerve fibers has been demonstrated in pe-
ripheral nerves. Spinal ganglia show loss of small
neurons.
FIGURE 10.27 Patient with Fabry disease. Note the numerous cuta-
neous angiokeratomas. Tay-Sachs disease
Three biochemically distinct forms of the GM2 gan-
gliosidoses affect infants. These are designated as type
junctival vessels, and corneal opacifications. Corneal B or true Tay-Sachs disease; type O or Sandhoff’s dis-
opacification may be the only finding in the heterozy- ease; and the AB variant, in which an activator protein
gous female carriers. Renal involvement is manifested is deficient. Type B or true Tay-Sachs disease results
by lipiduria, proteinuria, hypertension, and eventual re- from mutations of the HEXA gene located on chro-
nal failure. Vascular involvement leads to myocardial mosome 15 and results in deficient activity of hex-
and cerebral infarcts. The prothrombotic state has been osaminidase A but normal activity of hexosaminidase
recently investigated and serum levels of leukocyte in- B. Furthermore, missense mutations of two codons in
tegrins have been implicated in the etiology of endo- HEXA cause the specific biochemical phenotype, the
thelial vascular injury. In patients with Fabry’s disease, B-1 variant (Mahuran, 1999). Type O—Sandhoff’s
serum levels of plasminogen activator inhibitor are disease—is caused by mutations of the HEXB gene lo-
higher and thrombomodulin levels are lower than in cated on chromosome 5 and results in deficient syn-
normal controls (DeGraba et al., 2000). The cere- thesis of both hexosaminidase A and B. The gene for
brovascular disease results from the predominant in- the activator protein is also located on chromosome 5
volvement of the vertebrobasilar circulation and may (Gravel et al., 1995). Single missense mutations in each
be associated with dolichoectasia of these vessels (Mit- HEXB and GM2A (activator protein) have also been
sias and Levine, 1996). Rarely, patients with atypical identified (Mahuran, 1999).
hemizygous Fabry’s disease may have manifestations
limited to cardiac disease in the form of left ventricu-
lar hypertrophy. Death usually occurs from renal fail-
ure or cardiac or cerebrovascular disease during the
fourth or fifth decade.
Prominent sphingolipid deposits are present in the
walls of blood vessels (Fig. 10.28), cardiac myofibers,
the cornea, and renal tubular epithelium and glomeruli.
Lesser quantities are present in reticuloendothelial cells,
especially in the bone marrow. Neurons in the amyg-
dala, hypothalamus, reticular formation of the brain
stem, the intermediolateral column of the spinal cord,
and in dorsal root and autonomic ganglia may be dis-
tended by intracytoplasmic sphingolipid. The basis for
the highly selective pattern of neuronal involvement re-
mains unclear. It has been suggested that the accumu- FIGURE 10.28 Photomicrograph showing stored ceramide trihexoside
lation of ceramide trihexoside in certain regions of the in the wall of meningeal vessels in a patient with Fabry disease (Luxol
brain is due to proximity to permeable blood–brain fast blue stain).
Tay-Sachs disease is the most common of the GM2

gangliosidoses. The deficiency of hexosaminidase A re-
sults in massive accumulation of GM2 ganglioside (nor-
mally a minor ganglioside) and its asialo derivative. The
disease is encountered predominantly among Ashke-
nazic Jews. The onset of clinical manifestations gener-
ally occurs between 3 and 6 months of age. The early
manifestations include psychomotor retardation, weak-
ness, visual impairment, and an exaggerated startle re-
sponse (so-called hyperacusis). The children often have
doll-like facial features and cherry red spots in their
maculae. Cherry red spots are found in virtually all
cases of Tay-Sachs and Sandhoff’s disease and about
half the patients who have Niemann-Pick disease and
generalized gangliosidosis. Late in the course of these
diseases, the cherry red spots fade as ganglion cells de-
FIGURE 10.30 Epoxy section of cerebral cortex from an infant with
generate (Kivlin et al., 1985). Patients with Tay-Sachs
Tay-Sachs disease. The intracytoplasmic stored material appears as
disease have no visceromegaly but have an enlarged numerous spherical bodies.
head late in the course of the disease. They generally
die by 3 or 4 years of age.
Early in the course of Tay-Sachs disease, the brain is
morphic inclusions in astrocytes. Astrocytosis becomes
small and abnormally firm. Later it enlarges and be-
prominent as cerebral neurons are lost.
comes edematous. The cerebral white matter may show
linear areas of subcortical necrosis, demyelination, and
cystic degeneration. Ganglioside storage is prominent Sandhoff’s disease
in cortical neurons, Purkinje cells, retinal ganglion cells,
Sandhoff’s disease is a less common form of infantile
and autonomic ganglia. The affected neurons are en-
GM2 gangliosidosis due to deficiency of both hex-
larged and have rounded contours. The Nissl granules
osaminidase A and B. These deficiencies result in an
and nuclei are displaced by the intracytoplasmic mate-
accumulation of GM2 and asialo-GM2 in neural tissues
rial, which appears somewhat foamy in paraffin-em-
and an accumulation of globoside, an aminoglycolipid,
bedded sections (Fig. 10.29). In epoxy sections, the cells
in viscera. Clinical manifestations of the disease are
appear to contain numerous intracytoplasmic spherical
similar to Tay-Sachs disease, but there is no ethnic
inclusions (Fig. 10.30). Electron microscopy reveals
predilection.
concentrically laminated intracytoplasmic inclusions,
the so-called membranous cytoplasmic bodies, in the
affected neurons (Fig. 10.31) and somewhat more pleo-
FIGURE10.31 Electron micrograph of cortical neuron from an infant

FIGURE10.29 Cerebral cortex from an infant with Tay-Sachs disease. with Tay-Sachs disease. The stored material appears as the so-called
Note the distended neurons that contain ganglioside. “membranous cytoplasmic bodies.”
The neuropathological findings are nearly identical

to those in Tay-Sachs disease, but the visceral organs
show additional abnormalities. The heart shows endo-
cardial fibrosis and valvular thickening. Prominent vac-
uoles have been seen in pancreatic acinar cells, hepa-
tocytes, and renal tubular epithelium. Granules that
stain with Luxol fast blue and periodic acid–Schiff
stains have been seen in the heart, bronchial epithe-
lium, fibroblasts, smooth muscle cells, and histiocytes
in the spleen and lymph nodes. Electron microscopy
has revealed membranous cytoplasmic bodies, zebra
bodies, and pleomorphic membranous structures in he-
patocytes, heart muscle, and renal tubular epithelium.
FIGURE 10.32 Photomicrograph of medulla from an infant with GM-
Other GM2 gangliosidoses 1 gangliosidosis. Note the distended neurons containing stored gan-
glioside.
Another form of infantile GM2 gangliosidosis is due to
deficiency of an activator protein rather than deficiency
of hexosaminidase A or B. Rare cases of juvenile and phic deposits. Fine vacuoles are present in the renal
adult forms of GM2 gangliosidoses have been de- tubular epithelium, hepatocytes, Kupffer cells, and en-
scribed. In some of these patients the disease mimics dothelial cells. Foamy-appearing macrophages are pres-
spinal muscular atrophy or motor neuron disease in as- ent in numerous visceral organs including the liver,
sociation with stuttering speech, dementia, or psychosis spleen, kidneys, lungs, and bone marrow. Lymphocytes
(Specola et al., 1990). Brain imaging may show cere- may contain prominent intracytoplasmic vacuoles. Au-
bellar vermal atrophy in these patients (Streifler et al., topsy examination of two children, each approximately
1993). 15 months old, showed impairment of myelination for
age in addition to neuronal storage (Folkerth et al.,
2000).
GM1 gangliosidoses
Juvenile and adult forms of GM1 gangliosidosis also
The GM1 gangliosidoses are rare diseases caused by a have been described. They differ from the infantile form
deficiency of acid -galactosidase activity. The gene for in having a later onset of manifestations, which include
this enzyme has been mapped onto chromosome 3. As extrapyramidal signs and dystonia, and less prominent
a result of the enzyme deficiency, there is storage of dysmorphic changes.
GM1 ganglioside in the nervous system and visceral
storage of a keratan-sulfate-like mucopolysaccharide
Neuronal Ceroid–Lipofuscinosis
(Suzuki et al., 1995b).
Clinical manifestations of the usual infantile form be- Neuronal ceroid–lipofuscinosis (NCL) or the Batten-
come evident shortly after birth and include psy- Vogt syndrome, is a group of at least four closely re-
chomotor retardation, seizures, and blindness. Cherry lated diseases with additional variant forms that are
red spots are present in the maculae of about half of inherited as autosomal recessive diseases (Zeman and
the patients. The children have rather coarse facial Dyken, 1969; Goebel, 1995; Goebel and Sharp, 1998;
features and numerous skeletal abnormalities. He- Suzuki and Suzuki, 2002). All are characterized by the
patomegaly appears after about 6 months. Death gen- accumulation of lipopigments in various tissues. The
erally occurs by the age of 2 years. lipopigments are yellow to brown, autofluorescent, and
The brains from patients with GM1 gangliosidosis stained by the periodic acid–Schiff and Sudan reactions.
are of normal size or mildly atrophic in contrast to the The pathogenesis of these diseases is incompletely de-
megalencephaly that may be seen in Tay-Sachs disease. lineated but to date, genes designated CLN1-8 have
Neurons in the cortex, brain stem, cerebellum, and been identified (Bennett and Hoffman, 1999; Mole and
spinal cord are distended by intracytoplasmic deposits Gardiner, 1999). Defects in lipid peroxidation, abnor-
of ganglioside (Fig. 10.32). As shown by electron mi- malities in dolichol metabolism, and defective protease
croscopy, the material stored in neurons resembles the inhibitors had been implicated in the pathogenesis of
membranous cytoplasmic bodies seen in Tay-Sachs dis- these disorders, but these findings have not been sub-
ease. The astrocytes contain somewhat more pleomor- stantiated by more recent studies. The lipopigments
that accumulate in the late infantile, juvenile, and adult

forms of the disease contain subunit c of mitochondrial
adenosine triphosphate (ATP) synthase. The lipopro-
tein in the infantile form appears to contain sphin-
golipid activator proteins.
Haltia-Santavuori type
The infantile, Haltia-Santavuori, type (INCL) of the
disease has been reported primarily from Finland
(Hagberg et al., 1968). This disease is characterized by
an onset of manifestations that usually is seen before 2
years of age. The patients display rapidly progressive
psychomotor retardation and early blindness with op-
tic atrophy and retinal dystrophy. Seizures are rare, but FIGURE 10.34 Coronal section of the brain from a child with Jansky-
Bielschowsky form of neuronal ceroid-lipofuscinosis. Note the cere-
all patients have myoclonus. Patients may linger in a
bral atrophy and ventricular dilatation.
decorticate state for years. The gene responsible for this
form of neuronal ceroid-lipofuscinosis has been mapped
to chromosome 1p32 causing palmitoyl protein thio- of rapidly progressive psychomotor retardation and nu-
esterase (PPT) deficiency (Vesa et al., 1995; Mitchison merous, often intractable, seizures. Visual impairment
et al., 1995); eight new mutations have been recently is usually minimal until late in the disease. Recently,
reported by Salonen et al. (2000), making a total of 31 the gene responsible for at least some cases of late in-
different mutations that have been discovered to date. fantile neuronal ceroid–lipofuscinosis (LINCL) has
The brain is severely atrophic. The cerebral cortex been located on chromosome 11p15 (Sleat et al., 1997;
shows severe loss of neurons and gliosis and contains Goebel and Sharp, 1998), and the LINCL gene (CLN2)
numerous pigment-laden macrophages. The white mat- has been found to code for a lysosomal protease with
ter shows extensive loss of myelin and axons. On ultra- deficient activity in these patients. Two cases of suc-
structural examination the pigment in the brain and cessful prenatal screening have been performed for
other tissues appears predominantly as osmiophilic LINCL (Berry-Kravis, 2000).
granular material (“Finnish snowballs”) with occa- The brain is moderately atrophic (Figs. 10.33,
sional lamellar structures. 10.34), and the cerebral cortex shows neuronal loss
with pigment storage in the remaining neurons. The
Jansky-Bielschowsky type cerebellum shows even more severe neuronal loss and
gliosis; immunohistochemical staining for BCL-2 sug-
The late infantile (LINCL), Jansky-Bielschowsky type
gests that neuronal loss may be mediated by apoptosis
of disease is characterized by onset in early childhood
(Puranam et al., 1997). Especially massive pigment ac-
cumulations, appearing as large, compact intracyto-
plasmic inclusions, may be found in the thalamus, sub-
stantia nigra, inferior olivary nuclei, and dentate nuclei.
Although visual impairment is a late manifestation of
this disease, the retinal ganglion cells show massive
storage of the lipopigment (Schochet et al., 1980). On
ultrastructural examination, the pigment in the brain
and other tissues appears predominantly as membrane-
bound aggregates of curvilinear profiles (Fig. 10.35).
Tissues such as muscle, peripheral nerve, and even pe-
ripheral blood buffy coat contain the characteristic
curvilinear profiles and can be used for diagnosis (Fig.
10.36).
A Finnish variant of late infantile neuronal ceroid–
FIGURE 10.33 Exterior of the brain from a child with the Jansky-
lipofuscinosis has a slightly later onset of clinical man-
Bielschowsky form of neuronal ceroid-lipofuscinosis. Note the cere- ifestations and features especially severe cerebellar at-
bral and severe cerebellar atrophy. rophy. The lipopigment that accumulates in this form
tered, are a late manifestation. The CLN3 gene is lo-

calized on chromosome 16 in the 16p11, 2-12.1 region
and has been implicated as the loci for this autosomal
recessive disease. The function of the proteins are un-
known (Hoffman et al., 1999).
The brain is usually only moderately atrophic. The
cerebral cortex contains numerous rounded, pigment-
laden neurons (Fig. 10.37). The cerebellum may be
normal sized, and there may be only a moderate loss
of neurons. On ultrastructural study the pigment de-
posits in the brain and other tissues appear as mem-
brane-bound aggregates of both fingerprint and curvi-
linear profiles. Lymphocytes are commonly vacuolated.
FIGURE 10.35 Electron micrograph of cortex from a child with the

Jansky-Bielschowsky form of neuronal ceroid-lipofuscinosis. Note Kufs type
the intracytoplasmic curvilinear profiles.
The adult, Kufs, type (ANCL) of the disease is rare
(Goebel and Braak, 1989). Onset is generally during
of the disease contains subunit c of ATP synthase and adult life and the disease progresses very slowly. Men-
minor amounts of sphingolipid activator proteins. The tal deterioration, behavioral changes, ataxia, and extra-
gene responsible for this form of the disease has been pyramidal signs are major clinical manifestations.
localized to chromosome 13 (Tyynelä et al., 1997). On Seizures are infrequent and vision is typically unim-
ultrastructural study, the stored material is similar paired. Sporadic, autosomal recessive, and autosomal
to juvenile neuronal ceroid–lipofuscinosis; however, dominant cases have been reported. The location of the
lymphocytes are not vacuolated. gene or genes responsible for this form of neuronal
ceroid–lipofuscinosis is unknown, but the putative gene
has been designated NCL4.
Spielmeyer-Sjögren type The brain is only mildly atrophic. Pigment accumula-
The juvenile (JNCL), Spielmeyer-Sjögren, type is the tions are present in neuronal perikarya and meganeu-
most common form of neuronal ceroid–lipofuscinosis. rites. On ultrastructural study the pigment is variable in
The disease is characterized by slowly progressive psy- configuration. Some resembles lipofuscin, but granular
chomotor retardation and severe visual impairment
that have their onset later in childhood. The course of
the disease is protracted and seizures, when encoun-
FIGURE 10.37 Photomicrograph of brain from a child with the

FIGURE 10.36 Electron micrograph of buffy coat lymphocyte from a Spielmeyer-Sjögren form of neuronal ceroid-lipofuscinosis. Note the
child with the Jansky-Bielschowsky form of neuronal ceroid-lipofus- moderately enlarged neurons containing finely granular intracyto-
cinosis. Note the membrane-bounded mass of curvilinear profiles. plasmic material.
deposits and curvilinear, rectilinear, and fingerprint pro-

files also have been reported. Involvement outside of the
central nervous system is less prominent than in the other
forms of neuronal ceroid–lipofuscinosis.
Mucopolysaccharidoses
The mucopolysaccharidoses (MPS) are a group of rare
systemic metabolic diseases that result from deficient
activity of various lysosomal enzymes involved in the
degradation of glycosaminoglycans (Neufeld and
Muenzer, 1995; Suzuki and Suzuki, 2002). Currently,
six major forms with several subtypes are recognized.
All are inherited as autosomal recessive traits except
Hunter’s disease, which is an X-linked recessive disor- FIGURE 10.39 Electron micrograph of brain from a child with Hurler
der. Excessive amounts of mucopolysaccharides accu- disease. The stored gangliosides appear as so-called “zebra bodies.”
mulate in visceral organs and somatic tissues, and par-
tial degradation products are excreted in the urine. In
some of the diseases, gangliosides also accumulate in
neurons. accumulate in the connective tissues, blood vessels,
corneas, and liver. Cells, other than basophils, in the
adenohypophysis are markedly and distinctively vac-
Hurler’s disease (MPS I H)
uolated. The meninges are often thickened and fibrotic,
Hurler’s disease is often considered the paradigm of the and the Virchow-Robin spaces are enlarged. Meningeal
mucopolysaccharidoses and has an incidence of about cysts and hydrocephalus are common. Neurons are en-
1:100,000. The disease is inherited as an autosomal re- larged and distended because of intracytoplasmic ac-
cessive trait. The clinical diagnosis generally becomes cumulation of various gangliosides (Fig. 10.38). On ul-
apparent between 6 and 24 months of age. The affected trastructural study the intraneuronal deposits appear as
children have gargoyle facies, severe mental retarda- lamellated osmiophilic profiles, the so-called zebra bod-
tion, hearing loss, corneal opacities, cardiac dysfunc- ies (Fig. 10.39). By contrast the mucopolysaccharide
tion, and numerous skeletal abnormalities, including an deposits appear as vacuoles that are empty or filled with
enlarged J-shaped sella turcica. Mucopolysaccharides faintly osmiophilic granular material. The disease is
caused by deficient activity of alpha-L-iduronidase. The
gene encoding this enzyme has been localized to chro-
mosome 4p16. Both dermatan sulfate and heparan sul-
fate are excreted in the urine.
Scheie’s syndrome (MPS I S)

Scheie’s syndrome is a mild form of MPS I. This is a
rare disease with a prevalence of about 1:600,000. The
affected patients have corneal clouding and cardiac
valvular disease but only mild bone and somatic in-
volvement. Intelligence is normal, and the cortical neu-
rons show no histologic evidence of intracytoplasmic
storage. The patients may have cervical spinal cord
compression from thickened dura. This is even more
common in the intermediate phenotype known as the
Hurler-Scheie syndrome (MPS I H/S) (Kaufman et al.,
1982). The syndrome is caused by the same enzyme de-
FIGURE 10.38 Photomicrograph of spinal cord from a child with ficiency as that which causes Hurler’s disease; MPS I
Hurler’s disease. Note the enlarged anterior horn motor neurons that H, MPS I S and also MPS IH-S (Harles-Scheie) are al-
contain stored gangliosides. lelic (Mueller et al., 1984).
Hunter’s syndrome (MPS II) Morquio’s syndrome (MPS IV)

Hunter’s syndrome is unique among the mucopolysac- Morquio’s syndrome is a rare disorder with an inci-
charidoses because it is transmitted as an X-linked re- dence of about 1:300,000. Two forms have been rec-
cessive disorder localized to Xq27-28. The disease has ognized, both of which are characterized by normal in-
an incidence of about 1:80,000 males. Two forms are telligence but severe skeletal deformities including short
recognized. The severe phenotype is similar to Hurler’s trunk dwarfism and ligamentous laxity. Neurons may
disease except for the lack of corneal clouding and a be moderately swollen and contain periodic acid–
somewhat slower progression. These patients may have Schiff–positive globular inclusions. On electron mi-
ventricular enlargement, and some have compressive croscopy the intraneuronal inclusions appear as wavy
myelopathy. A mild phenotype has also been identified. membranes accompanied by lipid droplets (Koto et al.,
These patients have normal intelligence and survive into 1978). Hypoplasia of the odontoid process commonly
adulthood. Both forms may have a characteristic peb- leads to a compressive cervical myelopathy. Morquio’s
bling of the skin in which papules or small nodules co- disease is caused by deficient activity of galactose 6-
alesce to form ridges on the upper trunk, especially the sulfatase localized to chromosome 16q24 (Baker et al.,
scapular regions. Both forms also may have multiple 1993) in the more severe type A form of the disease
peripheral nerve entrapment syndromes. Retinal de- and a similar deficiency of beta-galactosidase in the
generation is present in both forms but is more pro- type B form of the disease has been localized by fluo-
nounced in the severe phenotype. The disease is caused rescence in situ hybridization (FISH) to 3p21.33
by deficient activity of iduronate sulfatase. Dermatan (Takano & Yamanouchi, 1993); and additional point
sulfate and heparan sulfate are excreted in the urine. mutations have been recently identified (Paschke et al.,
2001). Keratan sulfate is excreted in the urine.
Sanfilippo’s syndrome (MPS III)
Sanfillippo’s syndrome is a group of four diseases that Maroteaux-Lamy disease (MPS VI)
can be distinguished only by their corresponding enzyme Maroteaux-Lamy disease is a rare disease with a wide
deficiencies. All are inherited as autosomal recessive range of severity. Although the somatic lesions in the
traits. The incidence has not been determined. The af- severe form are similar to those in Hurler’s disease, in-
fected children have severe mental retardation, atheto- telligence is usually normal. Compressive myelopathy
sis, and seizures. In contrast to the other mucopoly- may be a serious complication even in the milder forms
saccharidoses, they have milder skeletal deformities, (Young et al., 1980). The disease is caused by deficient
minimal hepatomegaly, and no corneal opacification. It activity of arylsulfatase B. The gene for this enzyme has
has been suggested that Sanfilippo’s disease is under- been mapped to chromosome 5q13-14 (Litiens et al.,
diagnosed because the mental retardation is not ac- 1989) with multiple subsequent mutations identified
companied by prominent somatic manifestations. The (Isbrandt et al., 1994; Voskoboeva et al., 1994; Villani
brains may show mild-to-moderate atrophy. Neurons et al., 1999). Only dermatan sulfate is excreted in the
are enlarged and distended by various gangliosides. On urine.
ultrastructural examination the ganglioside deposits
may be similar to the zebra bodies seen in Hurler’s dis-
Sly’s syndrome (MPS VII)
ease or more pleomorphic, including forms that closely
resemble membranous cytoplasmic bodies (Hadfield et Sly’s syndrome is an extremely rare disorder of vari-
al., 1980). The various forms are caused by deficient able severity characterized by somatic abnormalities,
activity of four different enzymes: heparan-N-sulfatase, corneal clouding, prominent inclusions in leukocytes,
alpha-N-acetylglucosaminidase, acetyl-CoA:alpha-glu- and moderate-to-no mental retardation. Postmortem
cosamine acetyltransferase, and N-acetylglucosamine- studies on a young adult disclosed dystosis multiplex,
6-sulfatase. The gene for the first of these enzymes, atrial stenosis, and fibrous thickening of the atrioven-
heparan-N-sulfatase, has been identified and located tricular and aortic valves. Microscopic evidence of lyso-
on chromosome 17q25 (Scott et al., 1995) and the last somal storage was evident in many tissues including the
of these enzymes, has been N-acetylglycosamine-6- central nervous system. The intraneuronal storage de-
sulfatase has been localized to chromosome 12q14. The posits were finely granular and membrane bounded ag-
gene for alpha-N-acetylgucosaminidase has been re- gregates of whorled filamentous material and lipid
cently cloned and identified on chromosome 17q21 droplets (Vogler et al., 1994). The disease is caused by
(Zhao et al., 1996; Schmidt & Chen et al., 1998). Only deficient activity of beta-glucuronidase activity. The
heparan sulfate is excreted in the urine. gene for this enzyme has been mapped to chromosome
7 and multiple mutations (Fukuda et al., 1991; Wu and described. These patients have diverse clinical manifes-
Sly, 1993; Yamada et al., 1995) and pseudogenes have tations including hemiparesis, spastic paraparesis, cere-
been identified (Shipley et al., 1993). Dermatan sulfate, bellar ataxia, cortical blindness, and varied neuroradi-
heparan sulfate, and chondroitin 4,6-sulfate are ex- ological findings (Satoh et al., 1997).
creted in the urine. The brain from infantile cases is generally small and
very firm. The gray matter and the arcuate fibers tend
to be relatively well preserved. The central white mat-
LEUKODYSTROPHIES ter is generally discolored. The corpus callosum, inter-
nal capsules, pyramidal tracts, and cerebellar white
The leukodystrophies are rare metabolic diseases in matter may show cavitation in addition to discoloration
which the major manifestations involve the white mat- (Fig. 10.40).
ter of the central and peripheral nervous systems. In The microscopic findings include a paucity of intact
some patients, pathologic changes are also evident in myelin and oligodendrocytes, numerous globoid cells,
extraneural tissues. Bone marrow transplantation pro- gliosis, and a variable loss of axons. The globoid cells
tocols for globoid cell leukodystrophy, adrenoleukody- are large mononucleated or multinucleated macro-
strophy, metachromatic leukodystrophy, and Hurler’s phages that tend to cluster about blood vessels (Fig.
syndrome (above) have been employed with varying de- 10.41). Their cytoplasm contains abundant galacto-
grees of success (Krivit, 1999). cerebroside, which is responsible for intense staining
with the periodic acid–Schiff technique. On ultrastruc-
tural study the galactocerebroside within the globoid
Krabbe’s Disease
cells appears as either elongated, multiangular crys-
Krabbe’s disease, or globoid cell leukodystrophy, is an talline arrays (Fig. 10.42) or as striated, twisted tubules
autosomal recessive disorder resulting from deficient (Fig. 10.43). Both configurations probably represent
activity of galactosylceramidase. The gene for this en- stacks of narrow, elongated plates. Much of the stored
zyme has been mapped to chromosome 14q31 and the material appears to be free in the cytoplasm of the
cDNA cloned (Chen et al., 1993; Sakai et al., 1994). globoid cells and not confined to secondary lysosomes.
Several families have been identified with particular The peripheral nerves show a variable degree of de-
novel mutations in the galactocerebrosidase (GALC) myelination with accumulation of cerebroside in
gene (Bernardini et al., 1997; DeGasperi et al., 1999). Schwann cells and endoneurial macrophages. However,
This enzyme deficiency leads to impaired catabolism of typical globoid cells are rarely seen in peripheral nerves.
galactocerebroside, an important constituent of the Biochemical studies have shown a marked deficiency
myelin sheath (Suzuki et al., 1995). Although the pre- of galactosylceramidase (galactocerebroside beta-galac-
cise incidence is unknown, the disease is rare. An inci-
dence as high as 2:100,000 has been reported from
Sweden, but the disease seems to be more common in
Scandinavia than elsewhere. No ethnic predilection has
been demonstrated.
The onset of clinical manifestations is generally be-
tween 3 and 6 months of age. The initial stage is char-
acterized by cessation of psychomotor development,
extreme irritability, stiffness, and episodes of fever
without demonstrable cause. The second stage is char-
acterized by rapid neurological deterioration with
seizures, hypertonia, and opisthotonic posturing. The
terminal stage is characterized by decerebration and
blindness. Patients rarely survive beyond 2 years of age.
The infants generally have a small head, elevated pro-
tein concentrations in their cerebrospinal fluid, and
slowed nerve conduction velocities. MRI and CT have
shown distinctive, symmetric dense lesions in the deep
nuclear gray matter in addition to the expected lesions FIGURE 10.40 Coronal section of the brain of a child with Krabbe’s
of the white matter (Farley et al., 1992). Very rare cases disease. The white matter is reduced in volume and abnormally firm.
with a later onset and longer survival also have been The internal capsules are focally cavitated.
FIGURE 10.41 Photomicrograph of cerebral white matter from a child FIGURE 10.43 Electron micrograph of globoid cell showing the in-
with Krabbe’s disease. Note the collections of globoid cells, enlarged tracytoplasmic deposits of galactocerebroside in the form of twisted,
macrophages, that contain galactocerbroside. striated tubules.
tosidase). This prevents the normal degradation of accumulation of sulfatides (Kolodny and Fluharty,
galactocerebroside during the period of rapid myelin 1995). These compounds are important constituents of
turnover. The undegraded galactocerebroside accumu- myelin. In smaller quantities and with a slightly differ-
lates in macrophages and induces the formation of the ent chemical composition, they are also found in other
globoid cells. Deficiency of the same enzyme results in tissues, such as the kidney, spleen, and hepatobiliary
the accumulation of small quantities of a highly toxic system. At least four forms of metachromatic leukody-
compound, psychosine. This material is probably re- strophy can be delineated. Current evidence suggests
sponsible for the death of oligodendrocytes and the ces- that all forms of the disease are transmitted as autoso-
sation of further myelin formation. As a result, the mal recessive traits. The degradation of sulfatides re-
brain content of galactocerebroside and sulfatide is acquires the enzymatic action of arylsulfatase A and a
tually lower than normal. nonenzymatic activator protein, saposin B. The gene
for arylsulfatase has been mapped to chromosome 22.
Metachromatic Leukodystrophy Multiple mutations have been described. The I and O
mutations produce no active enzyme, while the A and
Metachromatic leukodystrophy, or sulfatide lipidosis, R mutations have low enzymatic activity. Homozygos-
is a group of sphingolipidoses resulting from abnormal ity for the I-group alleles is associated with the late in-
fantile form of metachromatic leukodystrophy, while
homozygosity for the group A alleles is associated with
the adult form of metachromatic leukodystrophy. Com-
pound heterozygosity for both groups of alleles is found
in the juvenile form (Polten et al., 1991). Rarely, the
disease has been found in individuals with normal aryl-
sulfatase A activity who are deficient in the nonenzy-
matic activator protein. In addition, mutations in the
arylsulfatase A pseudodeficiency gene are common and
can result in clinically normal individuals with low aryl-
sulfatase A activity (Kappler et al., 1991; Hageman et
al., 1995).
The late infantile form is the most common variant
of metachromatic leukodystrophy. A prevalence of
1:40,000 has been reported most often. Most patients
initially appear normal but show the onset of clinical
FIGURE 10.42 Electron micrograph of globoid cell showing the in-
manifestations between 1 and 2 years of age. Early
tracytoplasmic deposits of galactocerbroside in the form of multian- manifestations include hypotonia, weakness, and gait
gular crystalline profiles. disturbance. Later there is mental regression and loss
of speech, and hypertonia replaces the hypotonia. Even-

tually the children are blind and decerebrate. Many pa-
tients have abnormal gray maculae with red centers.
Gallbladder function may be impaired but is rarely
demonstrated. The cerebrospinal fluid contains in-
creased protein, and nerve conduction velocities are
slowed. There is excess urinary excretion of sulfatide.
Abnormalities of the white matter have been demon-
strated by CT and MRI imaging. Death occurs 2–10
years after the onset of symptoms.
The juvenile form of metachromatic leukodystrophy
shares many features in common with the late infan-
tile form. However, the onset of symptoms occurs
somewhat later. The course of the disease is variable.
The adult form of metachromatic leukodystrophy is
rare. By definition, onset of clinical manifestations oc- FIGURE 10.45 Electron micrograph of peripheral nerve biopsy speci-
curs later, often when the person is over 21 years of men from a child with metachromatic leukodystrophy. Note the
age. Personality changes and dementia may precede the lamellar configuration of the stored sulfatide.
onset of motor signs. Other features include nystagmus,
ataxia, tremor, increased deep tendon reflexes, and in-
continence. Nerve conduction velocities are usually stained strongly by periodic acid–Schiff techniques. The
slowed. CT and MRI studies show evidence of diffuse most characteristic histochemical procedure is the so-
demyelination, especially in the frontal lobes. The dis- called Hirsch-Peiffer reaction. Acidified cresyl violet
ease may be protracted over decades (Hageman et al., used in this reaction imparts a distinctive brown color
1995). to the sulfatide deposits. Furthermore, the reaction
The cerebral white matter is abnormally firm, gray product appears green when viewed with polarized
to brown, and focally cavitated. The central white mat- light. On ultrastructural study the sulfatides have sev-
ter is more severely affected than the arcuate fibers. Mi- eral configurations, of which stacks of lamellae are the
croscopy shows loss of myelin and a marked reduction most characteristic (Fig. 10.45).
in the number of oligodendrocytes. The most striking In addition to the white matter lesions, neuronal stor-
abnormality is the presence of numerous rounded gran- age may be seen in the basal ganglia, thalamus, brain
ular masses of sulfatide (Fig. 10.44). These are pre- stem, and spinal cord. This is less pronounced than in
dominantly within macrophages. The sulfatide deposits the form with multiple sulfatase deficiency. Peripheral
stain metachromatically with a number of dyes and are nerves show segmental demyelination and accumula-
tion of sulfatides in Schwann cells and endoneurial
macrophages. Visceral organs such as kidney and gall-
bladder also contain excess sulfatide.
The precise mechanism by which the sulfatide accu-
mulation damages myelin remains controversial. The
excess sulfatide may impede the normal remodeling of
myelin or lead to the formation of a metabolically un-
stable myelin. The formation of a toxic compound,
sulfogalactosphingosine, analogous to psychosine in
Krabbe’s disease, has also been suggested.
Metachromatic leukodystrophy with multiple sulfa-
tase deficiencies combines features of late infantile
metachromatic leukodystrophy and the mucopolysac-
charidoses (Kepes et al., 1988; Guerra et al., 1990).
Some authors classify this rare disease as a mucolipi-
dosis. The onset of clinical manifestations is generally
FIGURE 10.44 Photomicrograph of cerebral white matter from a child between 1 and 2 years of age. The clinical manifesta-
with metachromatic leukodystrophy. Note the Schiff-positive de- tions are similar to the late infantile form of metachro-
posits of sulfatide. matic leukodystrophy, but in addition, some patients
also have hepatomegaly, coarse facial features, ich-

thyosis, and bony abnormalities. Leukocytes may con-
tain Alder-Reilly granules. Biochemical studies have
shown accumulation of sulfatides and mucopolysac-
charides. Neurons may also contain excess ganglio-
sides. This disease is due to marked deficiencies of aryl
sulfatases A, B, and C. Neuronal storage is most pro-
nounced in this form of the disease. The stored mate-
rial may consist of gangliosides.
Adrenoleukodystrophy
Adrenoleukodystrophy and adrenomyeloneuropathy
together form a group of rare, X-linked recessive dis-
orders resulting from abnormal beta-oxidation of lipids
in peroxisomes (Moser et al., 1995a,b). The genetic ab-
FIGURE 10.47 Electron micrograph of white matter from a patient
normality involves a peroxisomal membrane protein
with adrenoleukodystrophy. Note the trilaminar profiles in the cy-
(Powers and Moser, 1998) and is localized to the Xq28 toplasm of a macrophage.
region encoding the ALD protein (ALDP) (Moser,
1995a; Moser, 1997; Smith, 1999; Powers et al., 2000).
As a result, very long-chain fatty acids accumulate in
The classic, juvenile form of adrenoleukodystrophy
blood plasma and tissues in the form of cholesterol es-
affects boys between the ages of 5 and 15 years of age.
ters and gangliosides. The precise mechanisms by which
Manifestations include behavioral abnormalities, intel-
the cellular damage is produced remains incompletely
lectual deterioration, impaired vision and hearing, and
elucidated. Myelin containing abnormally high pro-
gait abnormalities. The patients also may have periph-
portions of very long-chain fatty acids may be unsta-
eral neuropathy and seizures as late manifestations. In
ble and lead to the myelin breakdown. In addition, the
addition to the neurologic complications, patients may
abnormal lipids may initiate cytokine and T-cell–
have adrenal insufficiency. This form of the disease usu-
mediated inflammatory demyelination (Ito et al., 2001).
ally is rapidly progressive and leads to death in 3–5
Several forms of the disease have been delineated. The
years.
phenotypic variability may be caused by modifier genes
The cerebral white matter has a gray–brown translu-
or environmental factors.
cent appearance and may become cavitated in more se-
vere cases. The changes are generally most pronounced
in the parieto-occipital regions. By CT the affected ar-
eas show decreased attenuation with irregular foci of
enhancement. In contrast to the cerebrum, the spinal
cord is typically uninvolved. Histologic findings include
demyelination, loss of oligodendrocytes, and gliosis.
Axons are relatively spared except when cavitation en-
sues. There are perivascular infiltrates of mononuclear
inflammatory cells and macrophages (Fig. 10.46). Some
of the macrophages are weakly periodic acid–Schiff
positive and have a distinctive striated appearance ow-
ing to lipid lamellae composed of two osmiophilic
leaflets separated by a narrow clear space (Fig. 10.47).
The adrenal cortex may be hypertrophied or atrophic
and infiltrated by mononuclear inflammatory cells.
Cells in the zona fasciculata and reticularis become en-
larged and may display a striated appearance. Similar
FIGURE 10.46 Photomicrograph of cerebral white matter from a pa-
changes may be seen in the Leydig cells of the testis.
tient with adrenoleukodystrophy. Note the perivascular inflamma- Adrenomyeloneuropathy generally affects men in
tory cells, foamy macrophages, and reactive astrocytes. their 20s. When initially examined they often have spas-
tic paraparesis and peripheral neuropathy. They may Balicki D. and Beutler E. (1995). Gaucher disease. Medicine (Balti-
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Baud F.J., Barriot P., Toffis V., Riou B., Vicaut E., Lecarpentier Y.,
This form of the disease generally pursues a more in- Bourdon R., Astier A., and Bismuth C. (1991). Elevated blood
dolent course than childhood adrenoleukodystrophy. cyanide concentrations in victims of smoke inhalation. N Engl J
Female heterozygotes may have similar but milder Med 325:1761–1766.
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11 Neurodegenerative diseases
(excluding Alzheimer’s disease)
LAWRENCE A. HANSEN
Alzheimer’s disease bestrides the narrow world of neu- eases. Table 11.1 is a traditional neuroanatomically
rodegeneration like a colossus, casting so giant a shadow based classification, arranging diseases according to
that other entities receive comparatively little light when which portions of the central nervous system bear the
all neurodegenerative conditions are considered collec- brunt of neuron loss and fibrous gliosis. Clinical man-
tively. To remedy this insufficient illumination, the pres- ifestations can be deduced from such a scheme by
ent chapter attempts to disenthrall the reader of Alzhei- knowing the normal function of the degenerating part
mer’s disease by excluding it. Such a solution comes at of the central nervous system. Diseases of archicortex
the cost of an awkwardly qualified title and runs the risk and neocortex cause dementia; those of basal ganglia
of inviting jocular comparison with the apocryphal in- result in movement disorders, loss of anterior horn cells
quiry, “Other than that, Mrs. Lincoln, how did you like in the spinal cord produces weakness; etc. Neurologists
the play?” Nevertheless, other than Alzheimer’s disease, revel in such a neuroanatomic classification since their
what are neurodegenerative disorders? forte is determining where a disease is in the central
nervous system, without necessarily knowing what the
disease is.
COMMON DENOMINATORS OF Table 11.2 is an inclusion based classification of neu-
NEURODEGENERATIVE DISEASES rodegeneration. From the pathologist’s perspective,
such a scheme brings us closer to the essence of a dis-
Neurodegenerative diseases consist of neuron loss with
ease, since it focuses upon morphologic manifestations
reactive fibrous gliosis distributed symmetrically in spe-
of perturbed cytoskeletal metabolism, which seem
cific neuroanatomic systems. Most neurodegenerative
likely to be related to disease pathogenesis. Neurolo-
diseases also display more or less pathognomonic in-
gists rightly object, however, to an exclusively inclu-
clusions in persisting neurons, glia, or their processes.
sion based definition of a neurodegenerative disease,
Such inclusions are usually derived from altered cy-
since clinical manifestations may vary widely within a
toskeletal elements. In most disorders, it is undeter-
single category. For example, some patients with Lewy
mined whether pathologic inclusions cause neuronal
bodies have only motor parkinsonism and no demen-
dysfunction and death or merely signal that it has oc-
tia while others are demented without parkinsonism.
curred, recapitulating the macabre but innocent rela-
Similarly, some diseases now considered tauopathies
tionship of a tombstone to a corpse. Neuron loss in
predominantly affect the brain stem causing rigidity,
neurodegenerative diseases lacking inclusions is even
while other afflict the neocortex and result in demen-
more enigmatic, since the neuron in such conditions ap-
tia. Characterizing a specific disease according to both
pears to merely “melt, thaw, and resolve itself into a
neuroanatomic location (Table 11.1) and diagnostically
dew” leaving little trace beyond fibrous gliosis except
specific inclusions (Table 11.2) constitutes the time
in instances of rapid neurodegeneration when activated
honored marriage of neuroanatomy and pathology that
microglia may surround and engulf doomed neurons.
is neuropathology.
Molecular biologists have further advanced our un-
CLASSIFICATION SCHEMES FOR derstanding of neurodegeneration by identifying not
NEURODEGENERATIVE DISEASES only which cytoskeletal proteins comprise particular in-
clusions but, in the tauopathies at least, which alter-
Both legitimate and pettifogging objections are raised natively spiced isoforms of proteins accumulate in spe-
to all classification schemes for neurodegenerative dis- cific diseases. Neuropathologists view this development
220
11: NEURODEGENERATIVE DISEASES (EXCLUDING ALZHEIMER’S DISEASE) 221
TABLE11.1 Neuroanatomic Classification of netic ménage a trios into a marriage of neuroanatomy

Neurodegenerative Diseases and pathology (Table 11.4). The most common genetic
error, causing many diseases, consists of expanded
Diseases of archicortex and neocortex
three basepair sequences, referred to as triplet repeats.
Alzheimer’s disease (see Chapter 12) The mechanisms by which expanded triplet repeats and
Dementia with Lewy bodies other mutations finally cause disease are not yet un-
Frontotemporal dementia derstood, but it makes satisfying sense that a faulty ge-
Corticobasal degeneration netic recipe ultimately results in a bad biological soup.
Pick’s disease
Senile dementia with tangles
TABLE11.2 Inclusion-Based Classification of
Dementia with grains Neurodegenerative Diseases
Neurofibrillary tangles
Diseases of basal ganglia
Alzheimer’s disease (see Chapter 12)
Parkinson’s disease
Senile dementia with tangles
Huntington’s disease
Progressive supranuclear palsy
Striatonigral pattern of multiple systems atrophy
Corticobasal degeneration
Hallervorden-Spatz disease
Lewy bodies
Diseases of brain stem and/or cerebellum
Parkinson’s disease
Dementia with Lewy bodies
Olivopontocerebellar pattern of multiple systems atrophy
Olivopontocerebellar atrophies
Ballooned neurons
Dentatorubropallidoluysian atrophy
Pick’s disease
Diseases of spinal cord Corticobasal degeneration
Motor neuron disease/ALS and its variants

Tau-positive neuronal and/or glial inclusions
Spinal muscular atrophy
Friedreich’s ataxia Alzheimer’s disease (see Chapter 12)
Corticobasal degeneration
ALS, amyotrophic lateral sclerosis.
Pick’s disease
somewhat wistfully since it seems to portend the diag- Dementia with grains
nostic ascendancy of gels and blot over slides and Frontotemporal dementia linked to chromosome 17
stains. Parkinson–dementia complex of Guam
Biochemically based classifications divide neuro- Senile dementia with tangles
degenerative disease into two major categories, tauop-
athies and synucleinopathies, as shown in Table 11.3. Ubiquitin-positive glial or neuronal inclusion
This arrangement results in a clinically promiscuous
Multiple systems atrophy (glial cytoplasmic inclusions)
mixing of movement disorders and dementias, reflect-
Striatonigral form
ing variable involvement of subcortical and cortical
Olivopontocerebellar form
neuroanatomic structures by the same aberrant bio-
chemical pathways. Such a classification is inspired by Shy-Drager syndrome
the enigmatic symmetry of diverse brain proteins (tau, Motor neuron diseases (neuronal inclusions)
synuclein, beta amyloid, and prion) all accumulating as
abnormal filaments in different diseases. It is hoped that Diseases lacking cytoplasmic inclusions
this proteinaceous and filamentous common denomi- Huntington’s disease
nator will prove to be a pathogenetic Rosetta stone. Olivopontocerebellar atrophies
The heritability of many neurodegenerative diseases Friedreich’s ataxia
has long been known. Molecular biologists have now Dentatorubropallidoluysian atrophy
identified the mutations responsible for a host of these
Hallervorden-Spatz disease
disorders, introducing a spicy etiologic element of ge-
TABLE11.3 Filamentous Protein-Based Classification a movement disorder without dementia. Dementia with
of Neurodegenerative Diseases Lewy bodies, however, typically presents with cogni-
tive impairment and only subtle or absent accompany-
Tauopathies
ing parkinsonism. Yet the Lewy body and the neu-
3-repeat and 4-repeat tau isoforms roanatomic structures showing neuron loss and gliosis
Alzheimer’s disease constitute a tie that binds these seemingly disparate en-
Senile dementia with tangles tities (Fig. 11.1). Clinical distinctions between Parkin-
Frontotemporal dementia linked to chromosome 17 son’s disease and dementia with Lewy bodies appear
Others initially obvious to most neurologists. But the neu-
4-repeat tau isoforms ropathological overlapping of Parkinson’s disease and
Corticobasal degeneration dementia with Lewy bodies is often mirrored by the de-
Progressive supranucleur palsy velopment of dementia in Parkinson’s disease patients
Frontotemporal dementia
and the appearance of motor parkinsonism subsequent
to an initial presentation with dementia in patients di-
Others
agnosed as having dementia with Lewy bodies. In short,
3-repeat tau isoforms
these entities frequently morph into one another both
Pick’s disease
clinically and neuropathologically.
Frontotemporal dementia linked to chromosome 17 In 1996, an international consortium produced con-
Others sensus guidelines for the clinical and pathologic diag-
nosis of dementia with Lewy bodies. In order to sepa-
Synucleinopathies rate Parkinson’s disease with dementia from dementia
Lewy body disorders with Lewy bodies these experts stipulated that “If de-
Parkinson’s disease mentia occurs within twelve months of the onset of ex-
Dementia with Lewy bodies trapyramidal motor symptoms, the patient should be
Multiple system atrophy
TABLE11.4 Genetic Causes of

Irritatingly, as is so often the case with medicine and Neurodegenerative Diseases
molecular biology, there is an inverse relationship be- Triplet repeat mutations
tween how common a disease is and how much we un-
Cytosine–adenine–guanine
derstand about its ultimate causation at the molecular
level. The big three of neurodegenerative disease—that Huntington’s disease
is, Alzheimer’s disease, Lewy body diseases, and motor Spinocerebellar atrophies types 1, 2, 3, 6, 8
neuron disease—are slow to surrender their subtle se- Spinal and bulbar muscular atrophy
crets since these disorders are genetically determined in Dentatorubropallidoluysian atrophy
only a small minority of cases. Perhaps as genetic de- Guanine–adenine–adenine
fects responsible for specific diseases are discovered, such Friedreich’s ataxia
entities should be removed from the neurodegenerative
list and shifted to a more appropriate category of dis- Mutations other than triplet repeats
eases of genetic etiology. Until then, locating a disease
Trisomy 21, APP, PS1, PS2 genes
along all three axes tells us where it is occurring (neu-
Alzheimer’s disease (see Chapter 12)
roanatomy, Table 11.1), what is happening to cells at
Cu/Zn superoxide dismutase gene
that site (inclusions and biochemistry, Tables 11.2 and
11.3), and why, if a genetic cause has been uncovered Motor neuron disease
(etiology, Table 11.4). Such triangulation may serve to Survival motor neuron gene
fix the position of a disease in the reader’s memory. Spinal muscular atrophy
Tau gene mutations
Frontotemporal dementia linked to chromosome 17
LEWY BODY DISEASES Familial progressive supranucleur palsy
Missense mutations in alpha-synuclein protein
Lewy body diseases exemplify the difficulties encoun- A53T familial parkinson’s disease
tered in classifying neurodegenerative disorders. The A30P familial parkinson’s disease
prototypical Lewy body disease, Parkinson’s disease, is
FIGURE 11.1 Loss of pigmented neurons, gliosis, and extraneural neu- FIGURE 11.2 Concentrically laminated intracytoplasmic eosinophilic
romelanin with Lewy bodies in persisting pigmented neurons of the subcortical Lewy bodies are obvious in pigmented neurons of the
substantia nigra characterize Lewy body diseases. Hematoxylin and brain stem. Hematoxylin and eosin stain. Photograph courtesy of
eosin stain. Photograph courtesy of Ronald Hamilton, M.D. Ronald Hamilton, M.D.
assigned to a primary diagnosis of possible dementia ment epitopes. Electron microscopic examination of ni-
with Lewy bodies. If the clinical history of Parkinson- gral Lewy bodies discloses a dense central core of cir-
ism is longer than twelve months, Parkinson disease cular profiles surrounded by a peripheral rim of radi-
with dementia will usually be a more appropriate diating 7–20 nm filaments. Neocortical Lewy bodies are
agnostic label” (McKeith, 1996). Such a procrustean composed of amorphous material and 10–20 nm fila-
solution, with the clinician employed as deus ex ments with irregular contours. The filamentous ultra-
machina, belies complex interactions of motor parkin- structure of the Lewy body and its immunohistochem-
sonism, Lewy body pathology, and dementia, but it cur- ical profile have been interpreted as suggesting that
rently constitutes the state of the art. disturbed neurofilament metabolism or transportation
is at the core of Lewy body formation.
Alpha-synuclein is also clearly implicated in the
Lewy Bodies
pathogenesis of the Lewy body. Alpha-synuclein is an
Lewy bodies are intracytoplasmic eosinophilic neuronal incompletely understood protein found primarily in
inclusions. Lewy bodies in pigmented neurons of the neurons, where it is localized predominantly at axon
brain stem typically appear as dense eosinophilic cores terminals or synapses (Trojanowski and Lee, 1998).
surrounded by less densely staining peripheral halos
(Fig. 11.2). Neocortical Lewy bodies are more subtle
and appear in the perikarya of pyramidal neurons in
layers V and VI as spherical, homogeneous, slightly
eosinophilic inclusions lacking a concentric laminar
structure (Fig. 11.3). Neocortical Lewy bodies have
long been literally overlooked because they are so sub-
tle with hematoxylin and eosin stains. Ubiquitin anti-
bodies label Lewy bodies, enhancing their recognition
(Fig. 11.4). Ubiquitin is a highly conserved protein in
evolution, and its function is to target other proteins
for breakdown by cytosolic proteases. Like the red
stickers appearing on windshields of abandoned cars
along the freeway, ubiquitin labels objects destined for
hauling away.
Lewy bodies are formed, at least in part, from al-
FIGURE 11.3 Neocortical Lewy bodies peripherally displacing neu-
tered neuronal cytoskeletal elements, and immunohis- ronal nuclei are often subtle, poorly defined, and only slightly
tochemical studies of these inclusions have identified eosinophilic. Hematoxylin and eosin stain. Photograph courtesy of
neurofilament, microtubular, and paired helical fila- Ronald Hamilton, M.D.
stead that Lewy bodies Parkinson’s disease, clini-

cal parkinsonism, dementia, Alzheimer’s disease
pathology. According to such extreme lumpers, there
is no such thing as Lewy body disease other than
parkinson’s disease. Since demented parkinson’s dis-
ease patients invariably have at least a few neocortical
as well as subcortical Lewy bodies (Hughes et al.,
1992), they could literally be construed as examples of
dementia with Lewy bodies. However, as discussed
above, the 1996 International Consortium on Demen-
tia with Lewy Bodies separated Parkinson’s disease
with dementia from dementia with Lewy bodies on the
basis of clinical presentation and recommended the
FIGURE 11.4 Neocortical Lewy bodies are more readily visualized by
nomenclature “dementia with Lewy bodies.”
labeling with antibodies to ubiquitin (anti-ubiquitin immunoperoxi- Dementia with Lewy bodies (DLB) is the second lead-
dase stain). Photograph courtesy of Ronald Hamilton, M.D. ing cause of dementia, trailing only Alzheimer’s disease
(Hansen and Crain, 1995). Dementia with Lewy bod-
ies accounts for 15%–25% of the cognitively impaired
Alpha-synuclein is the same protein previously desig- elderly, most of whom have received diagnoses of Alz-
nated NACP, the precursor protein of the non-A-beta heimer’s disease during life. Only a minority of DLB
component of senile plaques (Ueda et al., 1993). Ni- patients meet clinical criteria for Parkinson’s disease in
gral and neocortical Lewy bodies and dystrophic addition to dementia, and their parkinsonian motor
nigral neurites in Parkinson’s disease and dementia with symptoms are mild—usually lacking a resting “pill
Lewy bodies contain alpha-synuclein immunoreactivity rolling” tremor—or absent altogether. When arche-
(Irizarry et al., 1998). An alanine to threonine muta- typal, cognitive dysfunction in dementia with Lewy
tion at residue 53 of alpha-synuclein caused by a sin- bodies differs distinctively from dementia in Alzhei-
gle basepair change at position 209 from guanine to mer’s disease. Visual hallucinations, fluctuations in
adenine was found in four chromosome four-linked mental status, attentional impairments, and dispropor-
families with autosomal dominant Parkinson’s disease tionately severe problem solving and visuospatial diffi-
(Polymeropoulos et al., 1997). A second missense mu- culties typify dementia with Lewy bodies (Salmon and
tation (A3OP) was subsequently discovered to cause Galasko, 1996).
familial Parkinson’s disease in a German family. Spo- A minority of dementia with Lewy bodies brains have
radic cases of Parkinson’s disease, however, are not as- only Lewy body–related pathology. This consists of neu-
sociated with mutations in the alpha-synuclein gene. ron loss and gliosis with Lewy body formation in re-
Since both neurofilaments and alpha-synuclein have maining neurons in the substantia nigra, locus
been detected immunohistochemically within Lewy coeruleus, and nucleus basalis of Meynert. Neocortical
bodies, it seems reasonable to speculate that aberrant Lewy bodies occur in medium size pyramidal neurons
interactions of one with the other might lead to ab- of the deeper cortical layers, especially in the limbic cor-
normal accumulation of these proteins into pathologi- tex. Many cases also display ubiquitin, neurofilament,
cal Lewy bodies. and alpha-synuclein–positive Lewy neurites in CA2-3 of
the hippocampal formation, the amygdala, the nucleus
basalis of Meynert, and in brainstem nuclei (Dickson et
Dementia with Lewy Bodies
al., 1991; Kim et al., 1995). Dementia with Lewy bod-
Eighteen different labels have been affixed to Lewy ies brains with only Lewy body pathology can be con-
body diseases characterized by dementia and varying strued as pure diffuse Lewy body disease, and patho-
degrees of motor parkinsonism, including diffuse Lewy logically resembles idiopathic Parkinson disease, which
body disease, senile dementia of the Lewy body type, has been shown to feature neocortical Lewy bodies in
cortical Lewy body disease, Lewy body variant of Alz- almost all cases, and Lewy neurites in many (Church-
heimer’s disease, and Alzheimer’s disease plus Parkin- yard and Lees, 1997). It may be that such pure diffuse
son’s disease. Such nomenclature diversity reflects a Lewy body disease patients are less demented than those
complex interplay of Lewy body pathology, Alzhei- whose brains have both Lewy body and Alzheimer’s dis-
mer’s disease pathology, parkinsonism, and dementia. ease pathology, but unequivocal dementia does occur
A contrary, minimalist nosologic camp contends in- in brains with only Lewy bodies and Lewy neurites. De-
mentia in DLB correlates with neocortical Lewy body to neuron loss in the nucleus basalis of Meynert. Other
counts. Such correlations have been found in studies of cholinergic deficits affect intrinsic striatal cholinergic
the Lewy body variant of Alzheimer’s disease (Samuel neurons in the caudate, and the reticular nucleus in the
et al., 1996), dementia with Lewy bodies (Samuel et al., thalamus, which receives cholinergic projections from
1997a), diffuse Lewy body disease, and even Parkin- both the basal forebrain and brainstem pedunculopon-
son’s disease with dementia. Lewy neurites in the hip- tine nuclei. Loss of striatal dopamine is comparable to
pocampus may contribute substantively to cognitive im- that seen in Parkinson’s disease and greatly exceeds any
pairment, but they are also found in some nondemented such loss in Alzheimer’s disease (Langlais et al., 1993).
Parkinson’s disease patients. Neuropsychiatric compli- It’s reasonable to attribute motor parkinsonism, and
cations in neuropathologically pure Parkinson’s disease perhaps visual hallucinations, in dementia with Lewy
overlap those of dementia with Lewy bodies, diffuse bodies to disruptions of striatal dopaminergic input.
Lewy body disease, Lewy body variant, and senile de- Most, but not all, dementia-with-Lewy-bodies brains
mentia of the Lewy body type, and may in fact differ have more Alzheimer’s disease pathology than age
only in the timing of their onset relative to motor parkin- matched controls (Hansen and Samuels, 1997). This
sonism (Churchyard and Lees, 1997). fact is invariably entangled with questions about how
Many dementia-with-Lewy bodies brains display a much Alzheimer’s disease pathology is necessary to
striking spongiform vacuolization of the neuropil which warrant a diagnosis of Alzheimer’s disease and how
strongly resembles that seen in Creutzfeldt-Jakob dis- much can be attributed to normal aging, or so called
ease at both light and electron microscopic levels of “pathologic aging.” This question is addressed, but not
magnification (Hansen et al., 1989). This vacuolar ab- resolved, in Chapter 12. The complicated character of
normality is negative for antiprion antibodies and is the Alzheimer’s disease overlap will persist as long as
nontransmissible. The spongiform vacuolization is usu- there are differences of opinion about the neuropatho-
ally confined to the entorhinal cortex, temporal neo- logic definition of Alzheimer’s disease.
cortex, amygdala, and sometimes the cingulate gyrus Most dementia-with-Lewy-bodies brains not only
(Fig. 11.5). These vacuoles may derive from degenera- have as much neocortical amyloid as Alzheimer’s dis-
tion of terminal axons of large pyramidal neurons res- ease specimens when measured immunocytochemically
ident in layers IIIC and V of the transentorhinal cor- (Gentleman et al., 1992) but typically have as many
tex and with disappearance of their ubiquitin-positive neuritic plaques as Alzheimer’s disease brains (McKen-
granular processes (Iseki et al., 1997). zie et al., 1996) and far more than age-matched con-
Neocortical cholinergic activity (choline acetyltrans- trols. These neuritic plaques usually lack tau-positive
ferase) is far more severely depleted in dementia with neurites, unlike those in Alzheimer’s disease (Samuel,
Lewy bodies than in Alzheimer’s disease (Ince et al., 1997b). Apolipoprotein E (ApoE) 4 is overrepresented
1998). The extent of neocortical choline acetyltrans- in dementia with Lewy bodies, just as it is in Alzhei-
ferase loss correlates well with dementia in dementia mer’s disease and is related to increased amyloid plaque
with Lewy bodies (Samuel, 1997a) and is attributable pathology in both conditions (Gearing et al., 1995;
Olichney et al., 1996). Apolipoprotein E (ApoE) 4 is
not increased in Parkinson’s disease or in neuropatho-
logically pure diffuse Lewy body disease lacking amy-
loid plaques (St. Clair, 1997).
Some authorities are dismissive of the amyloid over-
lap in dementia with Lewy bodies and Alzheimer’s dis-
ease since they interpret such pathology as pathologi-
cal aging. These experts contend that only abundant
microtubule associated protein tau abnormalities in the
neocortex constitute conclusive evidence of Alzheimer’s
disease (Strong et al., 1995) and therefore insist upon
the presence of numerous neocortical neurofibrillary
tangles, neuropil threads, or tau-positive swollen neu-
rites in neuritic plaques for a diagnosis of Alzheimer’s
disease. Even if only tau pathology is ruled admissible
FIGURE 11.5 Spongiform vacuolization of the neuropil is encountered as evidence for concomitant Alzheimer’s disease, how-
in the temporal lobe in many cases of dementia with Lewy bodies. ever, the situation is still complicated by the presence
Hematoxylin and eosin stain. of more tau pathology in the medial temporal lobes of
most, but not all, dementia with Lewy bodies brains

than in age matched controls (Hansen and Samuels,
1997). Most, but not all, dementia-with-Lewy-bodies
brains occupy higher Braak and Braak stages of Alz-
heimer’s disease neurofibrillary pathology than do age
matched controls, but lower stages than brains with
pure Alzheimer’s disease. Since Braak staging is based
on entorhinal and hippocampal neurofibrillary tangles
and neuropil threads (Braak and Braak, 1991), it seems
that most, but not all, of these specimens have more tau
pathology than controls but less than Alzheimer’s dis-
ease. Correlational studies of dementia in Lewy body
variant, dementia with Lewy bodies, and Parkinson’s
disease with dementia have all shown statistically strong FIGURE 11.6 Gross pallor of the substantia nigra and locus coeruleus
relationships between cognitive impairment and Braak in Parkinson’s disease compared to a control reflects loss of pig-
stages of Alzheimer’s disease pathology (Jellinger, 1996; mented neurons. Photograph courtesy of R.D. Terry, M.D.
Samuel, 1997a). Still, a minority of dementia-with-
Lewy-bodies brains lack Alzheimer’s pathology alto-
gether and yet come from clinically demented patients. The cause of Parkinson’s disease is unknown except
in a tiny minority of patients with autosomal dominant
versions who have mutations in the -synuclein gene
Parkinson’s Disease
(Polymeropoulos et al., 1997). Sporadic Parkinson’s
The brunt of neurodegeneration in Parkinson’s disease disease not linked to a genetic abnormality is most com-
is borne by the pars compacta of the substantia nigra mon in the fifth and sixth decades and shows a male
where neuron loss and gliosis is accompanied by ex- predilection. Prevalence figures vary from 30 to 190
traneural neuromelanin and single or multiple Lewy per 100,000 population (Lowe et al., 1997).
bodies in persisting pigmented neurons. Consequent
dopamine depletion in the neostriatum causes the clas-
sical extrapyramidal movement signs of Parkinson’s NON-ALZHEIMER’S, NON-LEWY BODIES
disease: rigidity, bradykinesia, and often resting tremor. DEMENTIAS/TAUOPATHIES
Neuron loss, gliosis, and Lewy bodies are not con-
fined to the substantia nigra in Parkinson’s disease. Alzheimer’s disease and dementia with Lewy bodies, ei-
Other affected nuclei include the locus coeruleus, the ther in pure form or more typically accompanied by
dorsal motor nucleus of the vagus, the nucleus basalis modestly severe Alzheimer’s disease pathology, account
of Meynert, and sometimes the intermediolateral cell for about 80% of dementia among the elderly. The
column of the spinal cord. As in dementia with Lewy non-Alzheimer’s, non-Lewy body degenerative demen-
bodies, neocortical Lewy bodies can be found if sought, tias encountered in the remaining 20% include the fron-
typically in the limbic cortex. Lewy neurites in CA2-3 totemporal dementias, some of which are linked to
of the hippocampal formation, amygdala, nucleus chromosome 17, corticobasal degeneration, Pick’s dis-
basalis of Meynert, and brainstem nuclei are also seen ease, progressive supranuclear palsy presenting with de-
in some cases. The only gross abnormality in these mentia, senile dementia with tangles, and dementia
brains is pallor of the substantia nigra and locus with argyrophilic grains. Most of these neurodegener-
coeruleus (Fig. 11.6). ative diseases feature neuronal and glial accumulations
While James Parkinson’s original account stipulates of phosphorylated tau protein, and some categorical
“senses and intellect were uninjured,” it is now known minimalists contend that they should all be construed
that as many as 20%–40% of Parkinson’s disease pa- as variations on the theme of “tauopathies.” Compli-
tients ultimately become demented. The neuropatho- cating this category of dementias is the realization that
logic substrate of dementia in Parkinson’s disease is some of these disorders were traditionally classified as
complex. A third of demented Parkinson’s disease pa- “subcortical” diseases—that is, progressive supranu-
tients have Alzheimer’s disease pathology, 10% have clear palsy and corticobasal degeneration.
widely distributed Lewy bodies in the neocortex, and Tau is a microtubule-associated protein which acts
the remaining 55% have only the typical pathology of to assemble polymers of tubulin into microtubules. Mi-
Parkinson’s disease (Hughes et al., 1992). crotubules are responsible for neurite extension and
serve as tracks for intracellular transport (Buee and mentia (Mann, 1998). This disease (or all these dis-
Delacourte, 1999). In the tauopathies, hyperphospho- eases) is likely to present clinically with personality
rylated tau proteins aggregate into abnormal intracy- changes, disturbances of memory and executive func-
toplasmic filaments. Six tau isoforms are derived from tion, and stereotypical compulsive behavior.
a single tau gene on chromosome 17. These are pro- Despite the seemingly nonspecific histopathology of
duced by alternative mRNA splicing of exons 2, 3, and frontotemporal dementias when evaluated with routine
10. This allows for six combinations with from 352 to hematoxylin and eosin stains, genetic and immunohis-
441 amino acids and molecular weights ranging from tochemical balkanization asserts itself in this category
45 to 65 kDa. Microtubule binding domains in the tau as in so many others. Approximately 60% of the fron-
protein are called repeats, and the six alternatively totemporal dementias are hereditary, and most of these
spiced isoforms have either three (3-R tau) or four are linked to the tau gene on chromosome 17q 21-22.
(4-R tau) such domains in their carboxy terminal ends. More than 10 exonic and intronic mutations in the tau
The fourth repeat domain is encoded by exon 10. Nor- gene have been found in about 20 frontotemporal de-
mal cerebral cortex has slightly more 3-R tau than mentia families (Hong et al., 1998). Since many of these
4-R tau, but the ratio is nearly one to one. families also exhibit parkinsonism, it has been proposed
Tauopathies can be categorized according to which that they be grouped under the rubric of frontotempo-
isoforms. 3-R tau, 4-R tau, or both aggregate into fil- ral dementia and parkinsonism linked to chromosome
amentous inclusions in neurons and glia, as detected by 17 (FTDP-17) (Spillantini et al., 1998). Immunohisto-
immunoblotting. In Alzheimer’s disease all isoforms of chemical studies of FTDP-17 brains reveal numerous
tau are hyperphosphorylated and aggregate to form intracytoplasmic tau-positive inclusions in frontal,
paired helical filaments. Consequently, both 3-R tau temporal, insular, and cingulate cortex as well as
and 4-R tau are found in Alzheimer’s disease im- hippocampus, brain stem, and spinal cord. The tau-
munoblots. In progressive supranucleur palsy and cor- positive inclusions occur in neurons, oligodendroglia,
tiobasal degeneration only 4-R tau aggregates as in- and astrocytes. This tau pathology is reminiscent of that
clusions, while in Pick’s disease only 3-R tau isoforms seen in progressive supranuclear palsy and corticobasal
aggregate. Frontotemporal dementias are more com- degeneration, again suggesting that all these disorders
plicated since some versions accumulate 3-R tau, oth- are forms of “tauopathies.” Depending upon which tau
ers 4-R tau, and still other both 3-R and 4-R tau. Fi- gene mutation is responsible for the disease, 3-R tau
nally, one form of frontotemporal dementia shows a isoforms, 4-R tau isoforms, or both accumulate in the
selective loss of all six tau isoforms, but not tau mRNA, filamentous inclusions.
suggesting a post-transcriptional biochemical blockage Sporadic frontotemporal dementia is by definition
(Zhukareva et al., 2001). This tauopathy sans tau seems not linked to chromosome 17 and does not show ab-
analogous conceptually to aleukemic leukemia. normal tau deposits in neurons and glia. Sporadic fron-
totemporal dementia may be combined with motor
neuron disease, producing both dementia and signs and
Frontotemporal Dementia
symptoms indistinguishable from those of amyotrophic
Frontotemporal dementias are first negatively defined lateral sclerosis. These cases feature ubiquitin im-
by their lack of Alzheimer’s disease plaques or tangles, munoreactive inclusions similar to those seen in motor
Lewy bodies, Pick bodies, abundant ballooned neurons, neuron disease lacking cortical atrophy and dementia.
subcortical tangles, and argyrophilic grains. The fron- The label “motor neuron disease inclusion dementia”
totemporal dementias show a histologically nonspecific has been advanced by some experts who emphasize the
atrophy of the frontal and temporal lobes accompanied importance of ubiquitin-positive inclusions in dentate
by varyingly severe neuron loss and fibrous gliosis in granule cells and layer 2 neocortical neurons (Lowe,
the corpus striatum, substantia nigra, and medial thal- 1998).
amus. While not pathognomonic, a characteristic fea-
ture of the frontotemporal lobe atrophies is spongy vac-
Corticobasal Degeneration
uolization primary affecting cortical layer 2 in the
frontal and temporal lobes. Thus defined, the fron- Corticobasal degeneration (CBD), as the name implies,
totemporal dementias either overlap with or subsume affects both neocortex and basal ganglia. More specif-
other nosologic entities including hereditary dysphasic ically, the substantia nigra pars compacta component
dementia, primary progressive aphagia, progressive of the basal ganglia is depigmented, showing extensive
subcortical gliosis, dementia lacking distinctive histo- neuron loss, fibrous gliosis, and extraneural neurome-
pathologic features, and nonspecific frontal lobe de- lanin deposition while the neostriatum and globus pal-
lidus are more mildly and variably afflicted. Because Corticobasal degeneration is of unknown etiology,
the neurodegenerative accent falls so heavily on the sub- although familial cases have been reported, and in these
stantia nigra in CBD, a now obsolete alternative label suspicion falls again on the tau gene previously impli-
for this entity, corticonigral degeneration, is descrip- cated in families with frontotemporal dementia linked
tively more apt. Neocortical atrophy in CBD provides to chromosome 17. Sex incidence is equal and the av-
a rare exception to the rule of bilateral symmetry in erage age of onset is 60 with a disease duration run-
neurodegenerative disease, at least in its early stages. ning from 6 to 10 years (Lowe et al., 1997). Patients
Initial descriptions of CBD emphasized unilateral gyral with dementia rather than motor CBD may be older,
narrowing and sulcal widening of the peri-Rolandic however.
frontal and parietal lobes accompanied by depigmen-
tation of the substantia nigra. These gross neu-
Pick’s Disease
ropathologic abnormalities correlated well with clini-
cal descriptions of CBD as an adult-onset akinetic rigid Pick’s disease is most famous for not being Alzheimer’s
syndrome presenting in one arm or leg with involun- disease. Invariably contrasted with Alzheimer’s disease,
tary movements and late-developing dementia. How- despite being less common by an order of magnitude,
ever, more recently, a pattern of frontotemporal de- Pick’s disease has historically been extolled as the neu-
mentia has been reported as the most prominent or only rodegenerative “other” cause of dementia. As demen-
clinical manifestation of CBD, and in some series CBD tia with Lewy bodies, frontotemporal dementia, and
is now the second most common form of non-Alzhei- corticobasal degeneration have emerged from the noso-
mer’s, non-Lewy-body dementia after frontotemporal logic fog of dementing disorders, Pick’s disease has been
dementia (Bergeron et al., 1998). Brains from CBD pa- progressively bumped further down the list of diag-
tients with dementia rather than movement distur- nostic alternatives to Alzheimer’s disease. Recently rec-
bances are more likely to show a pattern of cortical at- ognized entities such as dementia with tangles and de-
rophy with frontal predominance and involvement of mentia with grains threaten Pick’s disease with further
the temporal lobe rather than the classic peri-Rolandic demotion.
atrophy of motor CBD. The Pick’s disease brain shows circumscribed corti-
Neocortical neuron loss and gliosis in the affected cal atrophy classically affecting both frontal and tem-
gyri of CBD varies from mild with microvacuolization poral lobes (Fig. 11.7). While such frontotemporal at-
of the superficial cortical layers to moderate or even rophy is archetypal, some Pick’s cases show only frontal
severe pancortical atrophy. An accompanying histo- or only temporal atrophy. Pick’s disease brains are
pathologic hallmark of CBD is the “ballooned” neu- more shriveled than those of typical Alzheimer’s dis-
ron. These are swollen chromatolytic cells with pe- ease, and brain weights often decline to 750–900 g. The
ripherally displaced nuclei. While balloon neurons circumscribed lobar atrophy is often severe, described
typify CDB, they are not pathognomonic, since a few with some metaphorical license as “knife edge.” One
can also be found in frontotemporal dementia and striking gross feature of Pick’s disease is abrupt termi-
many occur in Pick’s disease. Nigral neurodegeneration nation of this severe atrophy in the superior temporal
in CBD is accompanied by inclusions in some residual
pigmented neurons. These swollen cells have slightly
basophilic cytoplasmic filaments which peripherally
displace nuclei and neuromelanin. Such inclusion bear-
ing neurons are indistinguishable from the pigmented
cells with globose tangles found in the substantia nigra
of progressive supranuclear palsy.
Immunohistochemical stains of CBD brains reveal
extensive accumulation of abnormal tau protein in cell
bodies of neurons and glia. Tau staining also reveals
cortical neurofibrillary tangles in all cases (Bergeron et
al., 1998). Tau-positive astrocytic plaques and oligo-
dendroglial coiled bodies are especially numerous in the
atrophic peri-Rolandic cortex and its underlying white
matter. Only 4-R tau isoforms aggregate into filaments FIGURE 11.7 The Pick’s disease brain shows severe circumscribed
in CBD, just as in progressive supranuclear palsy (PSP) frontotemporal lobar atrophy with sparing of the posterior superior
(Buee and Delacourte, 1999). temporal gyrus.
gyrus, with sparing of its posterior third. Accompany- Senile Dementia with Tangles
ing caudate atrophy can be so pronounced as to mimic
Huntington’s disease. Neurodegeneration in the sub- Senile dementia with tangles (tangle predominant se-
stantia nigra is variable, severe in some cases and mild nile dementia) is a recently recognized neuropathologic
in others. Microscopy discloses argyrophilic spherical correlate of cognitive impairment among the elderly,
intracytoplasmic neuronal inclusions in the granule and predominantly afflicting females over 80 (Jellinger and
pyramidal cell layers of the hippocampus and in small Bancher, 1998). Dementia may be severe, but some of
neurons of the upper neocortical layers of the atrophic these patients have only mild-to-moderate global cog-
lobes (Fig. 11.8). Ballooned neurons, also called nitive impairment with disproportionally severe mem-
swollen chromatolytic neurons or Pick cells, are more ory disturbances. Brains in this condition are moder-
common in the middle and lower cortical layers. ately to severely atrophic, averaging around 1100 g.
Pick bodies are filamentous proteins composed of an The histopathologic essence of this disease is neurofib-
abnormal form of the microtubule-associated protein rillary tangles and neuropil threads restricted to the
tau. Abnormal tau protein in Pick’s disease differs from transentorhinal cortex, entorhinal cortex, hippocam-
that in Alzheimer’s disease, corticobasal degeneration, pus, and amygdala. Both intraneuronal and extracellu-
or progressive supranuclear palsy. Specifically, only lar “ghost” tangles occur, the extracellular forms pre-
3-R tau isoforms aggregate into Pick bodies. Ballooned dominating in the entorhinal cortex. These tangles are
neurons in Pick’s disease contain neurofilament pro- identical to those in Alzheimer’s disease. Unlike Alz-
teins (Dickson et al., 1998). heimer’s disease, however, neocortical tangles are ab-
Neurologic manifestations of Pick’s disease are often sent or sparse and neocortical neuritic plaques are lack-
satisfyingly consistent with the distribution of selective ing. Only minority of cases have even a few diffuse
cortical atrophy. Patients with medial temporal lobe amyloid plaques without swollen neurites. This exclu-
pathology affecting the amygdala have a Kluber-Bucy sively or predominantly allocortical neurofibrillary
syndrome. Those with more frontal pathology have a pathology corresponds to the “limbic” stages III and
frontal lobe syndrome with personality changes and IV of neuritic Alzheimer’s disease as defined by Braak
disinhibition. Visuospatial abilities may persist despite and Braak (see Chapter 12). The prevalence of the
overt dementia, reflecting preservation of parietal and ApoE
4 alleles is very low in senile dementia with tan-
occipital neocortex. gles, while the frequencies of ApoE
3 and
2 are higher
Most Pick’s disease (80%) is sporadic, but familial than in controls. Since the ApoE 4
4 allele is linked
cases have been described with an autosomal dominant with amyloid deposition in both Alzheimer disease and
pattern of inheritance. Some of these reportedly in- dementia with Lewy bodies, the absence or paucity of
herited cases, however, probably represent genetic amyloid deposits in this condition may be related to
forms of frontotemporal dementia with tau gene the lack of an
4 allele. Neither the etiology of dementia
mutations rather than true Pick’s disease, since they with tangles nor an explanation for its female pre-
lack Pick bodies. dominance is known. The highest reported incidence
for this entity was nearly 8% in a group of mildly de-
mented older patients. Another study found senile de-
mentia with tangles in about 6% of a consecutive au-
topsy series of 350 cases clinically thought to be
probable Alzheimer’s disease (Jellinger and Bancher,
1998).
Dementia with Grains

Dementia with grains, also called argyrophilic grain
disease or dementia, is yet another newly discovered
category of dementia among the elderly (Jellinger,
1998). Dementia with grains is also a member of the
family of tauopathies since it’s pathognomonic small
spindle- or comma-shaped argyrophilic grains in the
hippocampus and adjacent limbic cortex are tau im-
FIGURE 11.8 Pick bodies. Many neurons contain rounded, argy- munoreactive. These brains also show argyrophilic tau-
rophilic intracytoplasmic inclusions. Bielschowsky silver stain. Pho- positive oligodendroglial inclusions called coiled bod-
tograph courtesy of James S. Nelson, M.D. ies in the white matter. Dementia with grains may
underlie the small percentage of grossly and micro- in the putamen proceed from dorsal to ventral. Smaller
scopically “normal” brains encountered in large clini- striatal neurons drop out before larger ones, and in-
copathologic dementia series, since the argyrophilic creasingly compacted striate fiber bundles lose myelin.
grains are invisible with routine hematoxylin and eosin The selectively vulnerable cells are medium-sized spiny
preparations and fairly subtle even with silver staining neurons which contain gamma-aminobutyric acid
techniques. Not surprisingly, as with so many tauop- (GABA), enkephalin, and neuropeptide Y. Similarly
athies, electron microscopy reveals filaments. The inci- sized aspiny neurons and large aspiny neurons are rel-
dence of argyrophilic grain dementia is difficult to as- atively spared (Kowall et al., 1987). Aficionados of neu-
sess, since in some cases these abnormal, presumably rochemically defined subcompartments in the neostria-
dendritic, inclusions are found in isolation and can be tum further stipulate that the most extensive pathologic
invoked as a cause of dementia, while in other instances changes in Huntington’s disease involve matrix as op-
they accompany Alzheimer’s disease pathology. posed to striosomal or patch components (Hedreen and
Folstein, 1995). A grading scheme for evaluating the
severity of atrophy in Huntington’s disease assesses
DISEASES OF THE BASAL GANGLIA neuron loss and gliosis on a scale of 0 to 4 (Lowe et
(EXCLUDING PARKINSON’S DISEASE) al., 1997). As with all grading protocols in pathology,
such an approach belabors the observation that any
Huntington’s Disease pathology is bad, and more is worse.
While overshadowed by the dramatic shrinkage of
Neuron loss, fibrous gliosis, and consequent atrophy
the neostriatum, Huntington’s disease brains also show
of the caudate and putamen are the neuropathologic
less spectacular atrophy of neocortex, thalamus, and
essence of Huntington’s disease. This neostriatal de-
white matter. Dementia in Huntington’s disease may
generation can manifest clinically as chorea, rigidity, or
therefore be attributable to either neocortical atrophy
dementia. Depending on patient age when symptoms
or to disruption of connections between the caudate
and signs manifest, Huntington’s disease can be divided
nucleus and frontal association cortex.
into juvenile, midlife, and late-onset forms (Ellison et
Huntington’s disease is transmitted as an autosomal
al., 1998d).
dominant trait caused by a triplet repeat of cytosine–
Caudate atrophy in Huntington’s disease follows a
adenine–guanine (CAG) in the Huntington gene on
medial-to-lateral progression. As the disease evolves,
chromosome 4. Increasing lengths of the causal triplet
the caudate’s characteristically convex contour first
repeat result in the phenomenon of anticipation—that
flattens and eventually becomes concave. The frontal
is, earlier onset of the disease in succeeding generations
horns of the lateral ventricles enlarge commensurately
of afflicted patients. The CAG repeat is the codon for
(Fig. 11.9). Neuron loss, fibrous gliosis, and atrophy
glutamine. The gene product, huntingtin, is conse-
quently burdened with longer and longer polyglutamine
sequences proportional to the redundancy of the trip-
let repeat. CAG repeats of 29 or less seem not to man-
ifest themselves clinically while those of 40 or more
will both express and transmit Huntington’s disease
(Young, 1998). Sporadic cases, presumably due to
spontaneous mutations, also occur. Affected striatal
neurons in Huntington’s disease have no cytoplasmic
inclusions but their nuclei accumulate the abnormal
huntington protein. A recent study of normal striatum
found that neuronal immunostaining for the huntingtin
protein is primarily confined to medium-sized spiny
neurons, while similarly sized aspiny neurons show lit-
tle or no immunopositivity. These results echo the se-
lective vulnerability of specific neuronal populations
FIGURE 11.9 Right cerebrum, Huntington’s disease (right), compared
encountered in Huntington’s disease (Ferrante et al.,
with right cerebrum of age-matched control case without neurologi-
cal disease. Huntington’s disease is characterized by gross atrophy of 1997). Coincidence? Probably not. The frequency of
the caudate and putamen with enlargement of the frontal horns of the Huntington’s disease varies from 4 to 7 per 100,000
lateral ventricles. Photograph courtesy of James S. Nelson, M.D. population (Lowe et al., 1997).
Multiple Systems Atrophy fects the oligodendroglial–myelin–axon–neuron com-

plex with resulting secondary loss of neuronal
Multiple systems atrophy (MSA) seems to belong perikarya. A tubular morphology at the ultrastructural
among diseases of the basal ganglia when it manifests level provides a refreshing departure from the filamen-
as neuron loss and gliosis in the putamen and substantia tous appearance of most neurodegenerative intracyto-
nigra, a form of MSA termed striatonigral degenera- plasmic inclusions. Surprisingly, the GCI is composed
tion (Fig. 11.10). If the cerebellum, basis pontis, and of alpha-synuclein (Trojanowski and Lee, 1999). Why
inferior olives are preferentially affected, however, a neuronal protein found in synaptic terminals should
MSA appears more akin to disorders of the brain stem turn out to be the hallmark inclusion of oligodendroglia
and cerebellum—i.e., olivopontocerebellar atrophies. in MSA is a mystery.
When the putamen, substantia nigra, inferior olives, ba- While GCIs are diagnostically specific for MSA,
sis pontis, and cerebellum are all involved, often along other alpha-synuclein–based inclusions also occur.
with the intermediolateral cell column of the spinal Specifically, neuronal cytoplasmic inclusions, neuronal
cord, attempts to concisely categorize MSA according nuclear inclusions, glial nuclear inclusions, and neu-
to neuroanatomically linked systems collapse of their ropil threads can all be found with appropriate im-
own weight. Immunohistochemically demonstrable munohistochemical techniques (Dickson et al., 1999).
glial cytoplasmic inclusions, however, constitute a neu- Clinical manifestations of MSA mirror the neuro-
ropathologic linchpin uniting the varied expressions of anatomic distribution of neuron loss, gliosis, and GCIs.
MSA (Ellison et al., 1998). Atrophy of the putamen and substantia nigra, the stri-
The glial cytoplasmic inclusions (GCIs) requisite for atonigral pattern of MSA, causes parkinsonism. Cere-
the diagnosis of MSA occur in the cytoplasm of oligo- bellar ataxia results from neurodegeneration in the
dendrocytes in both gray and white matter. Initially rec- olivopontocerebellar systems. Anatomic failure, most
ognized with immunohistochemical stains for ubiqui- dramatically encountered as Shy-Drager syndrome with
tin, GCIs are also argyrophilic. Of variable size and orthostatic hypotension, is attributable to neuron loss
shape, GCIs may be conical, oval, or triangular and in the sympathic preganglionic intermediolateral cell
when large, completely occupy the cytoplasm and pe- columns of the spinal cord.
ripherally displace oligodendroglial nuclei. GCIs in Patients with MSA usually present between the
MSA are widely but not randomly distributed. They fourth and sixth decades of life. Its cause is unknown
occur in high density in the gray and white matter of and its incidence is difficult to determine, since earlier
the frontal cortex, lentiform nuclei, mesencephalon, studies didn’t stipulate the presence of the now diag-
pons, medulla oblongata, spinal cord, and cerebellum. nostically requisite GCIs (Ellison et al., 1998b). Most
Some authorities speculate that this oligodendroglial patients with MSA are probably diagnosed with
pathology drives the neurodegeneration of MSA, hy- Parkinson’s disease during life.
pothesizing that the formation of GCIs adversely af-
Hallervorden-Spatz Disease
Hallervorden-Spatz disease (HSD) involves the globus
pallidus and pars reticularis of the substantia nigra
and so is considered here among the neurodegenerative
diseases of the basal ganglia. But, in a larger sense,
HSD represents a regionally restricted expression of a
broader category of neuroaxonal dystrophy. Axonal
swellings, termed spheroids, characterize both HSD and
infantile neuroaxonal dystrophy. In the latter, dys-
trophic neuroaxonal swellings are widespread in the
CNS, involving both white and gray matter. In HSD,
spheroids are essentially confined to the globus pallidus
and zona reticularis of the substantia nigra, where they
are accompanied by neuron loss, fibrous gliosis, and
FIGURE 11.10 The striatonigral pattern of multiple system atrophy conspicuous iron pigment deposition free in the neu-
shows gross shrinkage of the putamen and pallor of the substantia ropil, around blood vessels, or in microglia, astrocytes,
nigra. Photograph courtesy of James S. Nelson, M.D. or spheroids. Gross changes include shrinkage and rust
brown coloration of the globus pallidus and substan-

tia nigra. Both Lewy bodies and neurofibrillary tangles,
presumably incidental, have been associated with HSD.
Unlike all the diseases dealt with previously in this
chapter, HSD is a neurodegenerative condition of the
young. Onset is typically before age 15 with signs rang-
ing from chorea or athetosis to rigidity, dysarthria, and
mental deterioration. These patients usually die by age
35, but a second incidence peak involves older individ-
uals in whom extrapyramidal disorders and dementia
are typical presentations. Some familial cases of HSD
have shown an autosomal recessive pattern of inheri-
tance, but no causal gene is known (Lowe et al., 1997).
FIGURE 11.11 A tegmental neuron in the brain stem of a patient with
progressive supranuclear palsy contains a globose neurofibrillary tan-
gle. Bodian silver stain. Photograph courtesy of James S. Nelson,
DISEASES OF BRAIN STEM AND/OR CEREBELLUM M.D.
Progressive Supranuclear Palsy

Neurodegeneration in progressive supranuclear palsy phosphorylated tau isoforms with the amino acid se-
(PSP) targets multiple brainstem nuclei, the subthala- quence encoded by exon 10—that is, 4-R tau iso-
mus, basal ganglia, and the cerebellar dentate. Many forms—aggregate into filaments in PSP, whereas tau
affected nuclei in PSP are neuroanatomically linked— isoforms without exon 10 (3-R tau) are not detected.
for example, globus pallidus–subthalamus, dentate–red Paralleling this subtle distinction, PSP tangles by elec-
nucleus–inferior olive, pontine nuclei–dentate, and tron microscopy consist primarily of straight filaments
neostriatum–substantia nigra, but others are not. Of all while those in AD are paired helical filaments.
the structures which can show neuron loss and fibrous Tau-immunoreactive glia in PSP are found in all de-
gliosis in PSP, those most reliably and severely affected generating nuclei. Affected astrocytes are described as
are the globus pallidus, subthalamus, colliculi, peri- “tufted” or “thorn-shaped” and are considered highly
aqueductal gray matter, oculomotor nucleus, red nu- characteristic but not specific for PSP since a few such
cleus, substantia nigra, dentate, locus coeruleus, pe- lesions can also be seen in Pick’s disease. White mat-
dunculopontine nucleus, and cranial nerve nuclei X and ter associated with involved nuclei in PSP contains tau-
XII. Other frequently but less invariably involved gray immunoreactive oligodendroglia termed coiled bodies.
matter includes the inferior olives, neurons of the ba- Because 4-R isoforms of tau form glial inclusions, sub-
sis pontis, neostriatum, nucleus basalis of Meynert, cortical globose neurofibrillary tangles, neocortical tan-
hippocampus, entorhinal cortex, and neocortex. De- gles, and ballooned neurons can all be seen in both PSP
spite such widely distributed pathology, gross neu- and CBD; differentiating these sometimes clinically,
ropathologic changes in the PSP brain are typically neuropathologically, and biochemically overlapping
undramatic. Slight shrinkage and subtle brown discol- entities can be a diagnostic challenge.
oration of the globus pallidus is accompanied by more Clinical onset of PSP is typically between ages 50 and
obvious pallor of the substantia nigra, and often the 77. Initial presentation often includes postural insta-
locus coeruleus. The mesencephalon appears slightly bility, falls, and abnormal gait. Parkinsonism with
miniaturized, while its aqueduct of Sylvius is dilated. rigidity may precede the ocular motility problems
Neuropathologic hallmarks of PSP are globose neu- which give PSP its name. Impaired downgaze usually
rofibrillary tangles in persisting neurons of atrophic nu- occurs before difficulties with upgaze. Variably severe
clei, best seen with silver stains (Fig. 11.11), and glial dysarthria, dysphagia, and cognitive impairment some-
accumulations of tau protein, disclosed by immuno- times progressing to dementia are also encountered in
histochemistry. The globose neurofibrillary tangles of PSP. A small percentage of PSP patients present with
PSP contain abnormally phosphorated tau protein, but dementia and never develop supranuclear gaze palsy.
the tau in PSP differs from that in neurofibrillary tan- Most victims die within 8 years of disease onset.
gles of AD. Specifically, western blots of tau from PSP PSP is rare, with an incidence of only 1.5 per 100,000
show only doublet bands, while those of Alzheimer’s population (Lowe et al., 1997). While the cause of spo-
disease tangles have triplet bands (Bergeron, 1998). radic PSP is unknown, a genetic polymorphism in the
This banding pattern reflects the fact that only hyper- tau gene is associated with a greater than chance fre-
quency of PSP. A dinucleotide polymorphism in the olivopontocerebellar atrophy, neuron dropout in the
gene somehow influences exon 10 splicing and thus the basis pontis with secondary degeneration of the mid-
proportion of 4-R tau isoforms. dle cerebellar peduncle results in marked atrophy of the
pontine base. Friedreich’s ataxia (see below) spares the
cerebellar cortex, olives, and basis pontis but severely
Olivopontocerebellar Atrophies
affects ascending spinal cord sensory fiber tracts and
Some appreciation for the complexity of olivoponto- the dentate. Because it is now clear that differing pat-
cerebellar degeneration can be gleamed from a glimpse terns of cerebellar cortical, olivary, pontine, and spinal
at current classification tables, which include autoso- cord degeneration can occur in single genetically de-
mal dominant cerebellar ataxias types I–IV and spino- termined diseases, no less an authority than Green-
cerebellar ataxias types 1–5 before even arriving at field’s Neuropathology recommends that the term
dentatorubropallidoluysian atrophy, episodic ataxias, olivopontocerebellar atrophy be regarded as a patho-
x-linked cerebellar ataxias, and six variants of autoso- logical description and not a diagnosis (Fig. 11.12).
mal recessive cerebellar ataxias (Ellison et al., 1998c).
Clinical, rather than inheritance-based, classifications
Friedreich’s Ataxia
often correlate poorly with the neuroanatomic distri-
bution of atrophy revealed at autopsy and are heavily Employing a neuroanatomically based classification
contaminated with eponyms. Converging clinical, neu- system, Friedreich’s ataxia (FA) is primarily a neu-
roanatomic, and inheritance based classification crite- rodegenerative disease of the spinal cord, but because
ria intertwine to tie a Gordian knot. New insights de- it affects cerebellar afferents and the dentate, it is clin-
riving from molecular biology have, Alexander-like, cut ically considered a form of spinocerebellar ataxia. This
through this categorical complexity by revealing a be- autosomal recessive disorder is caused by a guanine–
guilingly simple genetic error underlying the bewilder- adenine–adenine triplet repeat in a gene on chromo-
ing varieties of inherited cerebellar ataxies. In short, some 9 encoding for a 210-amino-acid protein called
these diseases are caused by triplet repeats, most often frataxin. Frataxin is a mitochondrial protein encoded
cytosine–adenine–guanine, in different genes on vari- by the nuclear genome. Its function relates to iron ho-
ous chromosomes (Lowe et al., 1997; Ellison et al., meostasis, but how its deficiency causes selective neu-
1998c). The currently known spinocerebellar ataxias ron loss and cardiomyopathy is unknown (Koeppen
with CAG repeats, like Huntington’s disease, produce 1998).
defective proteins with expanded polyglutamine se- The spinal cord in FA shows myelin pallor secondary
quences. The proteins are called ataxins and, again as to axonal degeneration in the posterior columns, pos-
in Huntington’s disease, longer repeats cause earlier on- terior and anterior spinocerebellar tracts, and corti-
set of symptoms. Specific pathogenetic mechanisms cospinal tracts (Fig. 11.13). These changes reflect a dy-
deriving from these genetic miscues which result in
anatomically linked neuron loss and gliosis are, to char-
itably understate the case, incompletely worked out.
Unlike most neurodegenerative diseases, those caused
by triplet repeats lack cytoplsmic inclusions and instead
feature intranuclear accumulations of the mutant genes’
abnormal protein products.
Older neuroanatomically based classification schemes
for the cerebellar ataxias emphasized varyingly severe
involvement of the cerebellar cortex, inferior olives, nu-
clei of the basis pontis, and fiber tracts afferent to the
cerebellum in the spinal cord. Autosomal dominant
cerebellar ataxias now known to be caused by triplet
repeats manifest as Purkinje cell loss and Bergman’s
gliosis with a lesser component of granule layer neu-
ron dropout and consequent atrophy of cerebellar fo-
lia and pallor of cerebellar white matter. Cerebellar cor-
FIGURE 11.12 Gross atrophy of the cerebellar hemispheres, basis pon-
tical degeneration is accompanied by secondary loss of tis, and middle cerebellar peduncles is accompanied by more subtle
inferior olivary neurons with shrinkage of the olive and shrinkage of the inferior olivary nuclei—in this case, by olivoponto-
pallor of its hilum—that is, olivocerebellar atrophy. In cerebellar atrophy. Photograph courtesy of R.D. Terry, M.D.
ing back axonopathy attributable to neuron loss and

gliosis occurring in the dorsal root ganglia, nucleus dor-
salis of Clark, posterior horns of the spinal cord, and
motor cortex, respectively. While FA spares the cere-
bellar cortex, pons, and olives, there is severe neuron
dropout and gliosis in the dentate with consequent ax-
onal loss and myelin pallor in the superior cerebellar
peduncles.
Friedreich’s ataxia is the most common of the spin-
ocerebellar degeneration with a prevalence of 1–2 per
100,000, usually presenting before age 15 (Ellison et
al., 1998c). Signs and symptoms correlate well with the
degenerating spinocerebellar systems since these pa-
tients have gait ataxia, loss of joint position and vi- FIGURE 11.14 The spinal cord in motor neuron disease/amyotrophic
bration senses, and cerebellar ataxia. Cardiomyopathy lateral sclerosis shows myelin pallor in both lateral and one anterior
is common. corticospinal tract reflecting axonal degeneration consequent to neu-
ron loss occurring in the primary motor cortex (myelin stain). Pho-
tograph courtesy of the Ronald Hamilton, M.D.
DISEASES OF SPINAL CORD
Motor Neuron Disease/Amyotrophic Lateral Sclerosis however, expressly communicates the essence of the
pathology in this disease, since both muscle atrophy
Degenerative loss of motor neurons is called amy-
and tract degeneration are merely consequences of
otrophic lateral sclerosis (ALS) in America and motor
lower and upper motor neuron loss. The European
neuron disease (MND) in Europe. Both names have ad-
nomenclature “motor neuron disease” is more exact
vantages. “Amyotrophic” focuses attention on the mus-
and explicit, although less information rich. With a
cle weakness and eventual neurogenic atrophy in this
knowledge of neuroanatomy and pathology, however,
condition resulting from loss of lower motor neurons
the amyotrophic and lateral sclerosis components de-
in the spinal cord anterior horns and brain stem. “Lat-
riving from motor neuron disease can be deduced. Mo-
eral sclerosis” refers to the myelin pallor and gliosis
tor neuron disease as a rubric has an additional ad-
seen in the lateral corticospinal tracts attributable to
vantage in that some variant expressions of this
dying back distal axonopathy caused by dropout of up-
disorder do not involve upper motor neurons. The ab-
per motor neurons in the precentral gyrus primary mo-
sence of lateral sclerosis in such cases renders the term
tor cortex. Neither amyotrophic nor lateral sclerosis,
amyotrophic lateral sclerosis something of a misnomer,
while the designation motor neuron disease remains lit-
erally accurate. The American eponym “Lou Gehrig’s
disease” baffles Europeans but carries powerful emo-
tional connotations for those who remember the
stricken Yankee first baseman proclaiming himself “the
luckiest man on the face of the earth” while standing
in the shadow of death from ALS at age 39.
When fully expressed, MND/ALS shows loss of large
lower motor neurons in the spinal cord anterior horns,
motor nuclei of cranial nerves V, VII, X, and XII in the
brain stem, and upper neurons in the precentral gyrus.
The upper motor neuron loss causes secondary axonal
degeneration and consequent myelin pallor in the lateral
and anterior corticospinal tracts (Fig. 11.14), while
lower motor neuron dropout in the ventral horns is re-
flected in gross atrophy, shrinkage, and brown discol-
FIGURE 11.13 The spinal cord in Friedreich’s ataxia shows myelin
pallor in the posterior columns, posterior and anterior spinocerebel- oration of anterior nerve roots compared to posterior
lar tracts, and corticospinal tracts (myelin stain). Photograph cour- ones. The precentral gyrus may be perceptively
tesy of R.D. Terry, M.D. shrunken, but this is rare. Affected muscles show neu-
rogenic atrophy. Neurodegenerative disease involving ized by loss of large motor neurons in the anterior horns
only lower motor neurons, termed progressive muscular and the motor nuclei of cranial nerves in the brain stem.
atrophy (PMA), and that which affects only motor nu- Upper motor neurons are spared, and hence there is no
clei in the brain stem, called progressive bulbar palsy lateral sclerosis. Neuron loss and fibrous gliosis, best
(PBP), are variants of MND/ALS. Most patients pre- seen in the cervical and lumbar enlargements of the
senting with PBP progress to straightforward MND/ALS spinal cord, maybe be accompanied by neurofilamen-
eventually. Primary lateral sclerosis (PLS) with loss of tous swelling of persisting neurons. The ubiquitin-pos-
only upper motor neurons is construed nosologically as itive intracytoplasmic skeins of MND/ALS are lacking.
a distinct entity since it alone spares all lower motor neu- Anterior nerve roots may be shrunken and brown.
rons (Ellison et al., 1998a). All forms of SMA are autosomal recessive. The great
Routine hematoxylin and eosin stains in MND/ALS majority (more than 90%) either lack a gene termed
reveal motor neuron dropout and fibrous gliosis, some- survival motor neuron gene or have a mutated form.
time accompanied by diagnostically nonspecific Bunina Other genes, however, have also been reported as ab-
bodies, hyalin inclusions, or ballooning of persisting normal or absent in high percentages of SMA popula-
motor neurons. Neuronophagia may be encountered in tions (Ellison et al., 1998a).
rapidly progressive cases. Characteristic inclusion bod- SMA is divided into three types based on age of on-
ies in remaining anterior horn cells are disclosed by im- set. SMA 1 is the acute infantile form, also called Werd-
munohistochemical staining for ubiquitin, which shows nig-Hoffman disease. SMA 1 is the most ominous ex-
intracytoplasmic threadlike structures termed skeins. planation for neonatal hypotonia, in which patients
Electron microscopy, predictably, reveals a filamentous present as “floppy babies,” sometimes with congential
ultrastructure. arthrogryposis. Veteran childbearers may report di-
Most MND/ALS is sporadic, and hence of unknown minished intrauterine fetal movement compared to that
cause, but 5%–10% is transmitted as an autosomal experienced with preceding healthy siblings. Death by
dominant familial trait. A quarter of familial MND/ age 2 months is usually attributable to respiratory fail-
ALS cases are linked to chromosome 21 in the region ure. SMA 2, the chronic infantile form, has a later on-
of the Cu/Zn superoxide dismutase gene. Mutations in set during the first year of life, and the patients often
this gene have been found, but this tantalizing clue to survive until late adolescence. SMA 3, the chronic prox-
the etiology of MND/ALS occurs in only a minority of imal form of spinal muscular atrophy, commences dur-
familial cases (Ellison et al., 1998a). ing childhood and may mimic limb-girdle muscular
Males are more likely to be stricken with MND/ALS dystrophy or a dystrophinopathy. These victims often
than females. The incidence is 2 per 100,000 (Lowe et live to early adulthood.
al., 1997). Most patients are about 60 when they be- Muscle biopsies from infants with SMA 1 or SMA 2
come ill. Muscle weakness and wasting and bulbar dys- show a characteristic pattern of neurogenic atrophy.
function reflect pathology in the anterior horns and Large groups or entire fascicles of very small round my-
brain stem. Upper motor neurons signs are attributable ofibers are juxtaposed to greatly hypertrophied but still
to the “lateral sclerosis” in the corticospinal tracts. On- round myofibers, most of which are type 1.
set to death averages 5 years. Only a minority of
MND/ALS patients become demented, but frontotem-
poral dementia with MND/ALS-type ubiquitin-positive AMYOTROPHIC LATERAL
intraneuronal inclusions has recently been recognized SCLEROSIS/PARKINSONISM DEMENTIA
as a not-uncommon form of non-Alzheimer’s/non- COMPLEX OF GUAM
Lewy-body dementia. These patients have ubiquitin-
positive inclusion in neurons of the internal granule cell Amyotrophic lateral sclerosis/parkinsonism dementia
layer in the hippocampus and in layer 2 of the neo- complex of Guam (ALS/PDC) needs its own diagnos-
cortex, as well as in motor neurons of the anterior tic category, since otherwise it would have to be cross
horns. Cognitive impairment predominates clinically, referenced under MND/ALS, diseases of archicortex
and many of these patients don’t exhibit signs or symp- and neocortex, diseases of basal ganglia, diseases of
toms of MND/ALS prior to death (Mann, 1998). brain stem and cerebellum, neurofibrillary tangle dis-
eases, and tauopathies. ALS/PDC of Guam also occu-
pies a solitary niche as a uniquely geographically and
Spinal Muscular Atrophy
ethnographically restricted neurodegenerative disorder.
The spinal muscular atrophies (SMAs) are genetically It occurs almost exclusively in the Western Pacific Mar-
determined forms of motor neuron disease character- iana Islands of Guam and Rota among the Chamorro
people, although a similar neurodegenerative condition Dickson D.W., Davis A., and Lang A.E. (1998). Corticobasal gan-
has also been found in the Kii peninsula of Japan and glionic degeneration and progressive supranuclear palsy present-
ing with cognitive decline. Brain Pathol 8:355–365.
in New Guinea (Esiri et al., 1997). Dickson D.W., Davis A., and Lang A.E. (1991). Hippocampal de-
Florid, extensively distributed neurofibrillary tangle generation differentiates diffuse Lewy body disease (DLBD) from
formations with accompanying neuron loss and gliosis Alzheimer’s disease: light and electron microscopic immunocyto-
characterize ALS/PDC. Parkinsonism can be traced to chemistry of CA 2–3 neurites specific to DLBD. Neurology
neuron loss, gliosis, and tangles in the substantia nigra 41:1402–1409.
Ellison D., Love S., Chimelli L., Harding B., Lowe J., Roberts G.W.,
and basal ganglia. Dementia is attributable to tangles and Vinters H.V. (1998a). Motor neuron disorders. In: Neu-
and neuron dropout in the archicortex and neocortex ropathology. Mosby, Barcelona, pp. 27.1–27.10.
in a pattern resembling that of Alzheimer’s disease, but Ellison D., Love S., Chimelli L., Harding B., Lowe J., Roberts G.W.,
lacking senile plaques. Patients with symptoms of and Vinters H.V. (1998b). Parkinsonism and akinetic–rigid dis-
MND/ALS have neuron loss, gliosis, and small num- orders. In: Neuropathology. Mosby, Barcelona, pp. 28.1–28.16.
Ellison D., Love S., Chimelli L., Harding B., Lowe J., Roberts G.W.,
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All this is much, and yet ALS/PDC can show more. Mosby, Barcelona, pp. 29.1–29.8.
Neurofibrillary tangles and neuron dropout also are Ellison D., Love S., Chimelli L., Harding B., Lowe J., Roberts G.W.,
seen in the thalamus, hypothalamus, and many brain- and Vinters H.V. (1998d). Hyperkinetic movement disorders. In:
stem nuclei. Interestingly, although some tangles occur Neuropathology. Mosby, Barcelona, pp. 30.1–30.5.
Esiri N.M., Hyman B.T., Beyruther K., and Masters C.L. (1997). Ag-
in the dentate, the Purkinje and granule cell layers of ing and dementia. In: Greenfield’s Neuropathology (D.I. Grahm
the cerebellar hemispheres are spared. The tangles of and P.L. Santos, eds.). Arnold, London, pp. 153–233.
ALS/PDC are identical to those of Alzheimer’s disease, Ferrante R.J., Gutekunst C.A., Persichette F., McNeil S.M., Kowall
but far more widely distributed. As in Alzheimer’s dis- N.W., Guesella J.F., MacDonald M.E., Beal M.F., and Hersch
ease, these tangles consist of paired helical filaments at S.M. (1997). Heterogeneous topographic and cellular distribution
of huntingtin expression in the normal human neostriatum. J Neu-
the ultrastructural level. The few tangles encountered rosci 17:3052–3063.
in the spinal cord anterior horns, however, are com- Gearing M., Schneider J.A., Rebeck G.W., Hyman B.T., and Mirra
posed of straight tubules. The tangles in ALS/PDC stain S.S. (1995). Alzheimer’s disease with and without co-existing
positively with antibodies to tau protein. Tau- Parkinson’s disease changes: apolipoprotein E genotype and neu-
immunopositive coiled bodies in oligodendroglia simi- ropathologic correlates. Neurology 45:1985–1990.
Gentleman S.M., Williams B., Royston M.C., Jagoe R., Clinton J.,
lar to those seen in CBD are encountered in the motor Perry R.H., Ince P.G., Allsop D., Polak J.M., and Roberts G.W.
cortex, thalamus, mesencephalic tegmentum, and spinal (1992). Quantification of A 4 protein deposition in the medial
cord in ALS/PDC. temporal lobe: a comparison of Alzheimer’s disease and senile de-
The cause of ALS/PDC is unknown. Both genetic and mentia of the Lewy body type. Neurosci Lett 142:9–12.
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12 Alzheimer’s disease
JAMES S. NELSON
Alzheimer’s disease (AD) is a neurodegenerative disor- tem symmetrically, and have a symptomatology
der characterized clinically by progressively severe de- characterized by loss of neurological function—for ex-
mentia and, eventually, development of limb rigidity ample, paresis and intellectual impairment. Some neu-
with impaired mobility. AD occurs in both sporadic rodegenerative diseases are familial. Examples of neu-
and familial forms. In the United States the highest age- rodegenerative disorders include AD, Huntington’s
specific incidence of dementia occurs from 65 to 95 disease, Parkinson’s disease, the spinocerebellar degen-
years of age. An estimated 6%–10% of persons in this erations, and amyotrophic lateral sclerosis. The patho-
age range are severely demented; 50%–75% of these logical changes involve a progressive loss of neurons
individuals have Alzheimer’s disease (Kawas and Katz- and their processes that may be systematized (selec-
man, 1999). Women are at higher risk of developing tively involve anatomically or functionally related nu-
AD than men. The odds ratios for women to develop clei and tracts—e.g., motor system disease).
dementia and AD relative to men are 1.18 and 1.56, According to the Diagnostic and Statistical Manual
respectively (Gao et al., 1998). The course of the AD of Mental Disorders (DSM IV), the criteria for the di-
from onset to death may vary from a few months to agnosis of dementia include the development of multi-
several years. The reported mean duration is 6–12 years ple cognitive defects manifested by both memory im-
(Molsa et al., 1986; Schofield and Mayeux, 1998). In- pairment and one or more of the following cognitive
fection, usually bronchopneumonia, is the most com- disturbances: aphasia, apraxia, agnosia, and distur-
mon cause of death. bance in executive functioning. These cognitive deficits
The neuropathology of AD involves the cerebral cor- must cause significant impairment in social or occupa-
tex, including the hippocampus and entorhinal cortex tional functioning and represent a significant decline
most severely, but subcortical and brainstem struc- from a previous level of functioning. The deficits should
tures—for example, the basal nucleus of Meynert, lo- not occur exclusively in the course of delirium. Further,
cus coeruleus, and brainstem raphe nuclei—are also af- clinical or laboratory evidence should show that the
fected. The cortical lesions include varying degrees of deficits are related to a specific organic factor or fac-
atrophy accompanied by the accumulation of senile tors. In the absence of such evidence, an etiologic or-
plaques chiefly of neuritic type in the neuropil and for- ganic factor can be presumed if the deficits cannot be
mation of neurofibrillary tangles in nerve cell bodies. accounted for by any nonorganic mental disorder—for
Cerebral amyloid angiopathy involving subarachnoid example, a major depression causing cognitive impair-
and cortical blood vessels occurs in at least 85%–90% ment (American Psychiatric Association, 1994).
of AD cases.
Until the 1970s the diagnosis of Alzheimer’s disease
was often restricted to cases where the dementia began EPIDEMIOLOGY
before 65 years of age. A dementing disorder occurring
after 65 yrs of age with neuropathology qualitatively The peak age-specific prevalence of AD in the United
similar to AD neuropathology was called senile de- States is between 65 and 95 years of age. The preva-
mentia. Cases of Alzheimer’s disease with onset before lence of dementia including AD doubles every 5 years
65 years of age and cases of senile dementia are now after age 60. Currently, the estimated prevalence of AD
widely recognized as a single disease referred to as Alz- in the United States is 2.32 million (range, 1.09 to 4.58
heimer’s disease (Amaducci et al., 1986). million). A fourfold increase in the prevalence of AD
The term neurodegenerative disorder refers to a is projected over the next 50 years with the disease
group of neurological diseases of uncertain etiology eventually affecting 1 in 45 Americans (Brookmeyer et
that usually begin without obvious cause, typically but al., 1998; Kawas and Katzman, 1999; Cummings and
not always involve the affected parts of the nervous sys- Cole, 2002).
238
12: ALZHEIMER’S DISEASE 239
Risk factors that have been identified or implicated ysis took into account the predicted distribution of pro-
for AD include advancing age, female gender, the portions of surviving first-degree relatives without Alz-
apolipoprotein E (ApoE)-epsilon4 allele, head injury, heimer’s disease or DAT. The authors suggested that
low serum levels of folate and vitamin B12, raised lev- the concordant twin pairs had a heritable form of the
els of plasma and total homocysteine, family history of disease while Alzheimer’s disease or DAT in the dis-
AD or dementia, thyroid disease, fewer years of formal cordant twin pairs may have resulted from environ-
education, lower income, and lower occupational sta- mental influences or from a somatic chromosomal
tus. Suggested protective factors are higher educational change following zygotic division.
level; daily, moderate consumption of wine; and diets Approximately 5% of AD cases begin before 60 years
with higher than average amounts of fish (Kawas and of age and occur as clusters within families. These cases
Katzman, 1999; Cummings and Cole, 2002). are referred to as early onset familial AD. They are au-
The presence of the ApoE-epsilon4 allele is one of the tosomal dominant disorders (Tanzi, 1998; Rosenberg,
most important risk factors for AD—chiefly for spo- 2000). Mutations of the amyloid precursor protein gene
radic, late-onset AD (onset at 60 years of age). The (APP) on chromosome 21q, and the presenilin 1 and
ApoE gene is located on the long arm of chromosome 2 genes (PS1, PS2) on chromosomes 14q and 1q, re-
19. Of its three variants (epsilon 2, 3, and 4) the ep- spectively, account for 50% of the early onset autoso-
silon4 allele is particularly associated with an increased mal dominant cases. The genes associated with the re-
likelihood of developing AD. The epidemiologic–actu- maining 50% of autosomal dominant cases have not
arial lifetime risk for an individual without a family his- been identified (Rosenberg, 2000). Information con-
tory of AD and without an ApoE-epsilon4 allele is ap- cerning the functions of the abnormal gene products is
proximately 9%. The risk of developing AD by 75 years incomplete; however, all three mutations are associated
of age for individuals who are heterozygous for ApoE- with increased accumulation of A beta amyloid in brain
epsilon4 is increased threefold and increased eightfold parenchyma.
for those who are homozygous for ApoE-epsilon4 com-
pared with heterozygous ApoE-epsilon3 individuals (Se-
shadri et al., 1995; Rosenberg, 2000). The epsilon4 vari- NEUROPATHOLOGY
ant, however, does not cause AD; homozygous epsilon4
individuals may not develop AD while many with other The principal macroscopic finding is cerebral cortical
ApoE genotypes—for example, homozygous epsilon3— atrophy with widened sulci and narrowed gyri. The
do develop AD. The epsilon4 allele also appears to severity of the atrophy varies from case to case and
increase the risk of AD more in white and Asian popu- may be minimal. When atrophic changes are evident,
lations than in African-American and Hispanic popula- the most prominently affected sites are the medial tem-
tions (Cummings and Cole, 2002). poral cortex and the frontal, temporal, and parietal cor-
tex over the cerebral convexities (Fig. 12.1). Frontal
HEREDITARY GENETIC FACTORS
Most cases of AD with onset at or after 60 years of

age (late onset AD) appear to be sporadic forms of the
disease. AD, however, has been shown to occur in first-
degree relatives in approximately 50% of these cases.
These data suggest that the pathogenesis of some ap-
parently sporadic late-onset AD cases involves both ge-
netic and nongenetic factors (Breitner et al., 1988;
Hofman et al., 1989). The possibility of sporadic forms
of AD is supported by a study of monozygotic twin
pairs concordant and discordant for proven Alzhei-
mer’s disease or dementia of the Alzheimer type (DAT)
reported by Rapoport et al., (1991). The concordant
monzygotic twin pairs had a significantly higher fre-
quency of a positive family history for Alzheimer’s dis- FIGURE 12.1 Alzheimer’s disease. Macroscopic atrophy (narrowing
ease or DAT in at least one first-degree relative than of gyri, widening of sulci) especially affecting the frontal, temporal,
the discordant monozygotic twin pairs. The data anal- and parietal cortex.
FIGURE12.2 Neuritic plaques and neurofibrllaey tangles. Hip- FIGURE 12.4 Neocortical neurons with neurofibrillary tangles. Frozen
pocampal cortex. Sevier-Munger silver stain. section. Classical Bielschowsky silver stain.
and temporal accentuation of the atrophy resembling mass may be flame-shaped or rounded (globose) de-
Pick’s disease is apparent in some cases. The lateral ven- pending on the shape of the nerve cell body in which
tricles, especially the temporal horns, may be dilated. it is located. An occasional NFT can be seen with hema-
The volume of the central cerebral white matter (cen- toxylin and eosin staining. (Figs. 12.3–12.5). The ac-
trum semiovale) is reduced. The substantia nigra is curate assessment of the prevalence of NFTs requires
normally pigmented unless some form of Lewy body the use of silver methods such as the Bodian,
disease accompanies the AD. The locus coeruleus ap- Bielschowsky, or Gallyas techniques or the thioflavine
pears pale even in the absence of Lewy body disease. S fluorochrome stain. Extracellular NFTs, referred to
The most important microscopic lesions are the neu- as “ghost tangles,” occur when the neuron in which
rofibrillary tangle (NFT) and the senile plaque (Fig. the NFT was located dies and disintegrates. Ghost tan-
12.2). Both occur chiefly in the cerebral cortex; how- gles are seen most frequently in CA1 of the hip-
ever, they are also found in the gray matter in other pocampus and the entorhinal cortex.
parts of the brain. The NFT is not specific for AD. It Ultrastructural studies show that the NFT consists
occurs in other neurodegenerative disorders, in CNS chiefly of paired helical filaments (PHFs) and occa-
trauma caused by boxing, and in some viral infections sional straight filaments (Figs. 12.6, 12.7). The PHF is
(Morris, 1997; Terry et al., 1999). composed of two filaments each approximately 20 nm
The NFT is a mass of argyrophilic fibrils that forms in diameter that periodically constrict to 10 nm occur-
in the cytoplasm and apical dendrites of neurons. The ring at intervals of 80 nm. The major protein compo-
nent of the PHF is hyperphosphorylated tau protein.
FIGURE 12.3 Part of a neurofibrillary tangle is evident as an intracy-

toplasmic, dark, fibrillar band at the periphery of the nerve cell body
opposite to the nucleus. Hippocampal cortex. Hematoxylin and eosin FIGURE 12.5 Brainstem tegmental neurons with rounded or globose
stain. neurofibrillary tangles. Bodian silver stain.
FIGURE 12.8 Components of neuritic plaque evident in a section
FIGURE 12.6 Electron micrograph. Dystrophic neurite with paired he- stained with hematoxylin and eosin.
lical filaments. The beaded configuration of the better-preserved fil-
aments is indicative of the periodic constrictions of these structures.
silver stain or the thioflavine S fluorochrome stain are
necessary for consistent, reliable detection of senile
Normally occurring tau is a microtubule-associated plaques (Fig. 12.8). There are two major types of senile
protein that is involved in the assembly and stabiliza- plaques: neuritic plaques and diffuse plaques (Figs. 12.9,
tion of microtubules. The PHF is immunoreactive to 12.11). Neuritic plaques are composed of fibrillar A
antibodies against tau epitopes and to Alz-50, a mono- beta amyloid, dystrophic neurites (as the name implies),
clonal antibody against the A68 protein. The A68 pro- reactive astrocytes, and microglia (Morris, 1997; Terry
tein is a phosphorylated form of tau and is a major et al., 1999). The amyloid may form a central core with
protein subunit of the PHF (Lee et al., 1991). radiating dystrophic neurites and astrocytic processes
Senile plaques are rounded deposits of A beta amy- (Figs. 12.6, 12.9, 12.12). Typically, the dystrophic neu-
loid, a specific amyloid composed of A beta peptides rites contain paired helical filaments (PHFs), dense bod-
derived from amyloid precursor protein (APP), a nor- ies, and tau protein (Figs. 12.6, 12.12). Dystrophic neu-
mally occurring cell membrane protein (Figs. 12.8– rites without paired helical filaments and lacking
12.12). The plaques are are located in the neuropil. They immunoreactivity for tau protein are found in some neu-
vary in size from 5 to 200 m in diameter. Some may ritic plaques. The term burnt-out plaque is used in ref-
be evident with hematoxylin and eosin staining; how- erence to neuritic plaques composed chiefly of an amy-
ever, special stains such as the modified Bielschowsky loid core with few or no remaining neurites (Fig. 12.10).
FIGURE 12.9 Neuritic plaque with dense amyloid core surrounded by

FIGURE 12.7 Electon micrograph. Paired helical filaments. Note the enlarged, dystrophic neurites and occasional neuropil threads. Neu-
wavy appearance of the filaments indicative of the periodic con- rons with neurofibrillary tangles are adjacent to the plaque. Hip-
strictions. pocampal cortex. Modified Bielschowsky silver stain.
FIGURE 12.10 Burnt-out neuritic plaque with residual dense amyloid

core and a few dystrophic neurites. Frozen section. Classical
Bielschowsky silver stain.
FIGURE 12.12 Electon microgroph. Neuritic plaque with dense, stel-
late amyloid core, astrocytic processes, and cross sections of dys-
Diffuse plaques consist only of irregularly rounded trophic neurites with dense bodies and degenerating organelles.
deposits of A beta peptides with little or no fibrillar
amyloid (Fig. 12.11). Dystrophic neurites, reactive as-
trocytes, and microglia are absent. Diffuse plaques are (Fig. 12.9). They may reflect a degenerative process or
immunoreactive for A beta peptides but do not stain an aberrant form of sprouting. The threads contain
with Congo red. The problem of the pathogenesis of PHF and are immunoreactive to antibodies against tau
neuritic plaques and their possible origin from diffuse and ubiquitin (Terry et al., 1999).
plaques remains unsolved (Morris, 1997; Terry et al., Cerebral amyloid angiopathy refers to the deposition
1999). of A beta amyloid in the walls of subarachnoid and
Additional microscopic findings include neuropil cortical blood vessels (chiefly arteries) in the cerebrum
threads, cerebral amyloid angiopathy (CAA), granulo- and cerebellum (Fig. 12.13). The angiopathy is present
vacuolar degeneration, Hirano bodies, synaptic loss, in at least 85%–90% of AD cases. Approximately 15%
and cortical status spongiosis. of affected AD cases have a severe form of the an-
Neuropil threads are slender, curled or straight, ar- giopathy. CAA appears to be a risk factor independent
gyrophilic neurites lying within the neuropil. Most ap-
pear to be dendritic; however, a few resemble axons
FIGURE 12.13 Subarachnoid arteries with cerebral amyloid angiopa-

thy. The media stains homogeneously and is devoid of cellular de-
FIGURE 12.11 Diffuse plaque. Argyrophilic granular deposits form- tails. Intimal changes indicating development of the characteristic
ing an irregular profile in the neuropil and partially surrounding neu- double-barreled lumen are evident in one of the larger-caliber arter-
rons. Modified Bielschowsky silver stain. ies. Periodic acid–Schiff–hematoxylin stain.
of APOE genotype for parenchymal vascular lesions in

AD including small cortical infarcts and microinfarcts
(Olichney et al., 2000).
Granulovacuolar degeneration refers to the presence of
clear vacuoles containing 3–5 m granules in tne cyto-
plasm of neurons chiefly in the pyramidal cell layer of the
hippocampus (Fig. 12.14). The alteration is readily ap-
parent with hematoxylin and eosin staining. The granules
are immunoreactive to antibodies against tubulin, neuro-
filament protein, and tau protein (Terry et al., 1999).
Hirano bodies are rod-shaped eosinophilic structures
lying in the cytoplasm of neurons, although in con-
ventional histologic sections they appear to be extra-
cellular (Fig. 12.15). They occur most often, but not FIGURE 12.15 Rod-shaped Hirano body adjacent to hippocampal
neuron. Hematoxylin and eosin stain.
exclusively, in the pyramidal cells of the hippocampus
and are easily identified with hematoxylin and eosin
staining. Hirano bodies are immunoreactive to anti-
tical layers while the C-J lesion involves the deeper
bodies against actin (Terry et al., 1999).
cortical layers (Morris, 1997).
Loss of cortical synapses in AD demonstrated by
quantitative morphometric analyses of various synap-
tic proteins including synaptophysin correlates with the DIAGNOSTIC NEUROPATHOLOGIC CRITERIA
accompanying degree of cognitive impairment. The loss
is accentuated around neuritic plaques (Terry et al., Starting with the National Institute on Aging/American
1999). Association of Retired Persons (NIA/AARP) workshop
In some cases of AD, neuron loss in the outer layers in 1984 (Khachaturian, 1985), there have been three
of the cortex is severe and associated with vacuoles in sets of criteria proposed for the neuropathologic diag-
the neuropil, particularly in the temporal lobe (Fig. nosis of AD in the United States. The original NIA cri-
12.16). The vacuolar change is referred to as status teria (commonly referred to as the Khachaturian crite-
spongiosis. Status spongiosis is not related to the ria) based the diagnosis on a correlation between the
spongiform encephalopathy occurring in Creutzfeld- number of senile plaques (diffuse and neuritic) per cu-
Jakob (CJ) disease but may be confused with the C-J bic millimeter of neocortex and the age of the individ-
lesion. The vacuolar change in AD affects the outer cor- ual according to the following formula:
50 years of age: 2–5 senile plaques and
NFT anywhere in the neocortex
FIGURE 12.16 Focus of vacuolar change (status spongiosis) in super-

FIGURE12.14 Granulovacuolar degeneration. Hippocampal neurons ficial temporal cortex. The amyloid cores of two neuritic plaques are
with multiple, clear intracytoplasmic vacuoles containing small, evident on the opposite borders of the focus. Hematoxylin and eosin
rounded, darkly staining bodies. Hematoxylin and eosin stain. stain.
50–65 years of age: 8 or more neocortical senile PRECLINICAL ALZHEIMER’S DISEASE

plaques; there may be some NFT
66–74 years of age: 10 or more neocortical senile The criteria for definitive diagnosis of AD include clin-
plaques; there may be some NFT ical evidence of dementia. Recently, the occurrence of
a preclinical form of AD has been inferred based upon
The Khachaturian criteria were an important first examination of brains from persons with the mildest
step in the development of reliable criteria. They have form of clinically recognizable dementia and from non-
been supplanted by the CERAD (Consortium to Es- demented persons in the same age group (Price and
tablish a Registry for Alzheimer’s Disease) criteria Morris, 1999). Because the brains from the cases of
(Mirra et al., 1994) and the NIA/Reagan consensus cri- minimal dementia already contain large numbers of NP
teria (Anonymous, 1997). and NFT, the development of the AD process with for-
The CERAD criteria involve determination of a neu- mation of NP and NFT must begin before any clinical
ritic plaque score of “absent,” “sparse,” “moderate,” evidence of dementia is apparent. Consequently, some
or “frequent” for each of three histologic sections rep- of the brains from a group of nondemented persons
resenting middle frontal, superior and middle tempo- with detailed cognitive studies should have minimal or
ral, and inferior parietal neocortex by comparing a 1 no AD-related lesions while other brains from this
mm2 microscopic field of maximum neuritic plaque group might be the site of significant AD-related
density in the section with published cartoons of the pathology and represent preclinical forms of AD (Price
four grades of neuritic plaque density. NFT density in and Morris, 1999). Several studies of brains from el-
the same areas is also graded but is not included in derly patients with detailed cognitive studies confirm
the eventual determination of the age related plaque the occurrence of these two general types of neu-
score. The single highest neuritic plaque score among ropathologic findings and lend support to the concept
the three neocortical sections is correlated with the of preclinical AD (Hulette et al., 1998; Davis et al.,
age of the patient to obtain an age-related plaque score 1999; Price and Morris, 1999).
of A, (uncertain histological evidence of AD), B (his-
tological findings suggest AD), or C (histological find-
ings indicative of AD). Other parts of the brain—for NEUROTRANSMITTERS
example, cingulate gyrus, hippocampus, and substan-
tia nigra—are also examined in addition to the neo- Neurochemical changes involving decreases in neuro-
cortical sections to determine the presence or absence transmitters such as acetylcholine, norepinephrine, and
of comorbid neuropathology. The final diagnosis is serotonin occur as a result of neuronal loss affecting
determined by correlating the age-related plaque score the basal nucleus of Meynert, locus coeruleus, and
with any other neuropathologic findings—for exam- brainstem raphe nuclei, respectively. The basal nucleus
ple, vascular lesions, cortical Lewy bodies, and clini- of Meynert is the principal source of cholinergic input
cal information concerning the mental status of the to the cerebral cortex. Recognition of the progressive
patient. cholinergic deficit occurring in AD has led to the ther-
The NIA/Reagan consensus criteria involve com- apeutic use of cholinesterase inhibitors to conserve the
bining CERAD criteria with an assessment of neu- available supply of acetylcholine and delay certain as-
rofibrillary pathology in the entorhinal cortex, hip- pects of the neurological deterioration (Cummings and
pocampus, and neocortex according to the staging Cole, 2002).
procedure developed by Braak and Braak (1991). The
continued use of CERAD criteria supported by ex-
amination of the hippocampus and neocortex for NFT PATHOGENESIS OF ALZHEIMER’S DISEASE
was recommended for routine diagnostic evaluation
by pathologists and neuropathologists. The consensus Although NFT density correlates significantly better
panel pointed out that AD is a heterogeneous clini- than neuritic plaque density with impaired mental sta-
copathologic entity and that neither the clinical his- tus, the formation and deposition of A beta amyloid is
tory nor the neuropathology can, by itself, predict its currently regarded by many as a key step in the patho-
counterpart. The panel also recognized that any AD- genesis of AD. Evidence for this view is based in part
associated pathology including diffuse plaques, neu- on the effects of the genetic mutations involving the
ritic plaques, and NFT is abnormal and should be APP and presenilin genes that underlie autosomal dom-
noted even if they appear to be incidental (Anony- inant forms of AD. Although there is incomplete
mous, 1997). information concerning their specific functions, each
is associated in some way with increased accumulation Lameris A.J., Otten V.M., and Saan R.J. (1989). History of de-
of A beta amyloid in brain. Further support for the mentia and Parkinson’s disease in 1st-degree relatives of patients
with Alzheimer’s disease. Neurology 39:1589–1592.
amyloid hypothesis is provided by studies of Down Hulette C.M., Welsh-Bohmer K.A., Murray M.G., Saunders A.M.,
syndrome. Patients with this disorder have three copies Mash D.C., and McIntyre L.M. (1998). Neuropathological and
of the APP gene with an appropriate increase in neuropsychological changes in”normal” aging: evidence for pre-
APPmRNA. During the third and fourth decades of life, clinical Alzheimer disease in cognitively normal Individuals. J
these patients consistently develop the neuropatho- Neuropathol Exp Neurol 57:1168–1174.
Kawas C.H, and Katzman R.(1999) Epidemiology of dementia and
logic features of Alzheimer’s disease including diffuse Alzheimer disease. In: Alzheimer Disease, 2nd ed. (R.D. Terry,
plaques, neuritic plaques, and NFT. The amyloid hy- R.K.L. Katzman, and S.S. Sisodia, eds.). Lippincott William &
pothesis suggests that the A beta amyloid deposits are Wilkins, Philadelphia, pp. 95–116.
neurotoxic and cause parenchymal injury by activating Khachaturian Z.S. (1985). Diagnosis of Alzheimer’s disease. Arch
apoptosis, oxidative stress, inflammation, and, possi- Neurol 42:1097–1105.
Lee V.M., Balin B.J., Otvos L. Jr., and Trojanowski J.Q. (1991).
bly, increasing NFT formation (Rosenberg, 2000; Cum- A68: a major subunit of paired helical filaments and derivatized
ings and Cole, 2002). forms of natural tau. Science 251: 675–678.
Mirra S.S., Gearing M., and Heyman A. (1994) CERAD Guide to
the Assessment Alzheimer’s Disease and Other Dementias.
ACKNOWLEDGMENTS CERAD, Durham, NC.
The author thanks Dr. Suzanne Mirra and Dr. Lawrence Hansen for Molsa P.K., Marttila R.J., and Rinne U.K. (1986). Survival and cause
their helpful comments regarding the contents of this chapter. of death in Alzheimer’s disease and multi-infarct dementia. Acta
Neurol Scand 74:103–107
Morris J.H. (1997). Alzheimer’s disease. In: The Neuropathology of
Dementia (M.M. Esiri and J.H. Morris, eds.). Cambridge Uni-
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13 Diseases of CNS myelin
ROBERT E. SCHMIDT
Myelin is an evolutionary development that increases oligodendroglial cytoplasm is found external to the
the speed of conduction of the action potential and myelin sheath in comparison to the relatively large
also results in its improved metabolic efficiency. This amount of Schwann cell cytoplasm in PNS myelin.
is accomplished by excitation and, eventually, energy- Oligodendroglia do not produce a basal lamina. In con-
requiring repolarization of discrete foci of the axon at trast to those of the PNS, CNS nodes of Ranvier are
the nodes of Ranvier rather than by involvement of naked and exposed directly to the extracellular space.
the entire axolemma as in nonmyelinated axons. Al- Oligodendroglial cells or their precursors proliferate in
though myelin is frequently portrayed as multiple response to some types of clinical and experimental in-
wrappings of an otherwise-ordinary plasma mem- jury; however, the amount of regenerated myelin that
brane of the Schwann cell, it is actually organized dif- can be demonstrated in most of the processes to be dis-
ferently along lines specialized for its function. Myelin cussed here is rarely capable of normalizing large foci
contains relatively more lipid than does hepatic of demyelination.
plasma membrane, particularly increased amounts of Myelin is bluish green in the CNS and purple in the
galactolipids and plasmalogens, and is provided with PNS (Color Figure 13.3 in separate color insert) when
a limited number of specialized proteins critical for stained with Luxol fast blue and periodic acid–Schiff
the organization and maintenance of its compact (LFB-PAS), a histochemical stain routinely used for
structure features that distinguish it from the routine myelin. The difference in color, which reflects the dif-
plasmalemma. ferential extraction of some central oligodendroglia-
Peripheral nervous system (PNS) myelin is synthe- derived myelin periodic acid–Schiff–positive glycolipid
sized and maintained by Schwann cells. Each Schwann constituents during histologic processing, is only one
cell myelinates only one myelin internode on one sin- of many biochemical differences between CNS and PNS
gle axon. Ultrastructural examination demonstrates a myelin. CNS and PNS myelin also differ in the nature
collar of Schwann cell cytoplasm surrounding the of their myelin-associated proteins (proteolipid protein
myelin sheath, which is in turn surrounded by a promi- predominantly in the CNS, P2 and P0 proteins pre-
nent basal lamina (Fig. 13.1). Nodes of Ranvier on pe- dominantly in the PNS, and myelin basic protein in
ripheral nerve axons consist of myelin-free, imbricated both sites), lipid composition, and periodicity of the
Schwann cell processes and basal laminae that isolate lamellae. Such differences may contribute to the selec-
the node from the extracellular endoneurial space. tivity of some myelinopathies, particularly those with
Damage to PNS myelin typically results in robust an immune-mediated pathogenesis, for PNS or CNS
Schwann cell proliferation and substantial, at times targets.
nearly complete, regeneration of myelin.
Central nervous system (CNS) myelin is produced
and maintained by the oligodendroglial cell, which is DEFINITIONS
seen typically in formalin-fixed hematoxylin-and-
eosin–stained cerebral white matter as a small hyper- Experimental and clinical diseases of myelin include
chromatic nucleus surrounded by a clearing or halo, conditions in which myelin itself or the myelin-
giving the cell a “fried egg” appearance (Fig. 13.2). forming cell, either the Schwann cell in the peripheral
Oligodendroglia support numerous internodes of nervous system or the oligodendrocyte in the central
myelin (as many as 30–50 in some sites) on multiple nervous system, is the primary focus of the pathogenetic
axons, and, therefore, the loss of a single oligoden- process. In primary demyelination the primary target
droglial cell may result in more diffuse injury than the of the pathologic process is the myelin-forming cell or
loss of a single Schwann cell. Only a small tongue of myelin itself. Segmental demyelination results in myelin
246
13: DISEASES OF CNS MYELIN 247
DEMYELINATIVE DISEASES OF THE CENTRAL

NERVOUS SYSTEM
Immune-Mediated Processes
Multiple sclerosis
The most typical form of multiple sclerosis (MS) in the
United States is a chronic relapsing and remitting form
(Charcot type) chiefly affecting young adults. MS is
characterized by visual symptoms, paralysis, ataxia,
and motor and sensory disturbances involving any level
of the central nervous system and may result in the
progressive development of permanent disability. The
pathogenesis of MS remains incompletely known, al-
FIGURE 13.1 Typical appearance of myelin. Electron micrograph of
though a variety of hereditary, infectious, and autoim-
small myelinated axon from the sural nerve. Peripheral myelin is in- mune mechanisms are thought to contribute (McFarlin
timately associated with the Schwann cell nucleus, surrounded by a and McFarland, 1982a,b; Hallpike et al., 1983).
considerable amount of cytoplasm, and enclosed in an enveloping
basal lamina (arrow).
Gross pathologic findings
The neuropathologic hallmark of MS is the plaque (Fig.
13.4), a grossly visible focus of demyelination, which
loss with preservation of axonal integrity. Processes in
typically is pinkish (recent, active) to gray (remote, in-
which primary axon or neuron loss secondarily result
active), gelatinous in appearance, and firm (“sclerotic”)
in loss of myelin, as, for example, in descending corti-
to the touch. In the most common MS patterns (de-
cospinal tract degeneration following rostral spinal
scribed in detail in the next section), many plaques ap-
cord transection, are not typically considered demyeli-
pear to be centered on small vessels, typically venules,
native and are not further discussed here. Although the
and may grossly extend from the edges of plaques along
demyelinative processes to be discussed are myelin di-
vessels as “Dawson’s fingers.” Demyelinative plaques
rected and selective, in a practical sense there are few
in typical MS have a predilection for certain sites within
myelinopathic processes in which axons are not dam-
the central nervous system:
aged to some degree, including processes with either a
rapid or protracted course. 1. Periventricular white matter, particularly the lat-
eral aspects of the lateral ventricles (Fig. 13.5), but also
periventricular or periaqueductal areas of the brain
stem
FIGURE 13.2 Central nervous system white matter. Oligodendroglial

cells exhibit a perinuclear halo, giving them a “fried egg” appear- FIGURE 13.4 Multiple sclerosis. Inactive gray shrunken plaque ex-
ance. H&E. hibits sharp borders with adjacent white matter.
FIGURE 13.7 Multiple sclerosis. These horizontal sections of optic

FIGURE 13.5 Multiple sclerosis. A typical location of cerebral hemi- nerves and chiasm show multiple gray gelatinous plaques (arrows).
spheric MS plaques is immediately adjacent to the lateral ventricles.
2. Subcortical, at the junction of the cerebral cortex Microscopic findings

and digitate white matter (Fig. 13.6), which may ex-
tend into the cortex proper (the cortex does have a Plaques in a typical case of relapsing and remitting
complement of myelinated axonal targets) chronic MS (Charcot type) often exhibit different de-
3. Optic nerves, chiasm, and tracts (Fig. 13.7), in- grees of inflammation, gliosis, and remyelination based
volved to some degree in almost all cases of remitting/ on their age and activity. Although plaques are some-
relapsing MS times designated as early or late, they are better iden-
4. Brainstem descending and ascending tracts, in- tified as active or inactive, since the margins of a long-
cluding the cerebellar peduncles. The brain stem, par- standing plaque may show active demyelination
ticularly the pons, is one site in which white matter is (chronic active plaque) while its center may differ, ex-
external to gray matter and therefore, plaques may be hibiting little inflammation. An active plaque margin
visible externally in a subpial distribution (Fig. 13.8) typically is not as sharply demarcated from the adja-
5. Spinal cord, especially the subpial region, which cent white matter as is an inactive plaque and it is
may result in patchy involvement which does not re- markedly cellular and heterogenous (Fig. 13.10). An
spect tract boundaries (Fig. 13.9). active plaque is characterized by:
FIGURE 13.8 Multiple sclerosis. Subpial brainstem plaques (arrows)

FIGURE 13.6 Multiple sclerosis. Subcortical and intracortical MS are visible on the external surface of the pons and the cerebral pe-
plaques may be numerous. duncles in the midbrain.
FIGURE 13.10 Multiple sclerosis. The margin of an active plaque

FIGURE 13.9 Multiple sclerosis. The distribution of MS plaques in the shows markedly increased cellularity and absence of a sharp border
spinal cord may extend across tract boundaries with islands of patchy with adjacent white matter. LFB-PAS.
preservation of myelin or, at other levels, affect its entire cross
section.
myelin from axons (patterns I and II, Fig. 13.11) rem-
iniscent of experimental autoimmune demyelination;
1. Loss of myelin and/or oligodendroglia. Myelin (2) ligand–receptor complexes with pinocytosis of
loss results from damage to oligodendroglia or myelin myelin fragments by macrophages containing clathrin-
itself; however, the precise target and detailed mecha- coated pits and evidence of immunoglobulin deposition
nism are rapidly evolving topics of investigation. A re- within the pit (pattern II); and (3) dying-back oligo-
cent series of investigations (Lucchinetti et al., 1996, dendrogliopathy (Rodriguez and Scheithauer, 1994)
1998, 2000; Lucchinetti and Rodriguez, 1997; Winger- characterized by selective damage to the distalmost as-
chuk et al., 2001) of active MS lesions suggests that pect of oligodendroglial processes (pattern III). It has
several different mechanisms may be operative (Table been thought that the most common primary patho-
13.1), producing distinct patterns of injury, although genetic process in multiple sclerosis is directed against
in any single patient active lesions tend to be of the myelin itself with relative sparing (at least early) and
same pattern. These patterns may be grossly separated reactive proliferation of oligodendroglial cells (Fig.
into immune-mediated inflammatory perivascular de- 13.12) or their progenitors particularly at the plaque
myelinative processes (patterns I and II) and those in- margins in chronic active plaques. However, recently
volving primary injury to the oligodendrocyte (patterns it has been reported that active MS lesions show vari-
III and IV). Ultrastructural examination of active MS able reduction of oligodendroglia (Lucchinetti et al.,
plaques has shown several patterns of injury to myelin 1999) followed by their reappearance, presumably aris-
or oligodendroglia including: (1) macrophages engag- ing from mobile oligodendroglial precursor cells. One
ing in phagocytosis of normal-appearing or vesicular of the earliest alterations in inflammatory demyelina-
TABLE 13.1 Patterns of Multiple Sclerosis Neuropathology

I II III IV
Frequency* 15% 70% 10% 10%

Macrophages/T cells Yes Yes Yes Yes
Myelin proteins lost All All MAG others All
Perivascular plaques Yes Yes No No
IgG/C deposition No Yes No No
Remyelination Yes Yes No No
Oligodendrocyte fate Preserved/proliferation Preserved/proliferation Dying-back oligodendro- Death in periplaque
gliopathy and apoptosis white matter
MAG, myelin associated glycoprotein.

*Based on autopsies and surgical biopsies.
FIGURE 13.11 Multiple sclerosis. An attenuated myelin sheath is sep-

arated and engulfed by an adjacent microglial cell (M). (From Raine
FIGURE 13.13 Multiple sclerosis. Perivascular macrophages engorged
CS, 1983 with permission)
with myelin debris (arrows) accumulate in an active multiple sclero-
sis plaque. LFB-PAS.
tion may be the demonstration of clusters of activated
microglia (strongly upregulated CD68, CD45,
HLA-DR) and scattered intravascular and perivascu- 2. Macrophages containing myelin debris within the
lar lymphocytes, in edematous, but otherwise normal parenchyma or in a perivascular distribution (Fig.
appearing, white matter. VCAM-1 immunoreactive mi- 13.13) are the pathologic hallmark of plaque activity
croglia appear to target and intimately surround oligo- in all patterns. Initially phagocytosed LFB-PAS-stained
dendrocytes at borders of developing MS plaques (Pe- myelin often retains its blue color (LFB) but later stains
terson et al., 2002). Patterns may vary between early red (PAS) as it is catabolized.
and late stages of MS as well as between different pa- 3. Relative sparing of axons and neurons within de-
tients (Lucchinetti et al., 1996). myelinative plaques. Recently, investigators (Trapp et
al., 1998; Peterson et al., 2001) have returned to this
issue, initially addressed by Charcot and others—that
active plaques, and even chronic inactive plaques, ex-
hibit significant axonopathy which is typically mani-
fest as axonal spheroids or axon loss. Axonopathy may
underlie clinical residua, limit the potential for recov-
ery, and result in the progressive disability which may
develop with time. Alternatively, results of recent in-
vestigations suggest that axon loss may be an early and
substantial alteration in multiple sclerosis lesions which
may even be demonstrable in areas lacking myelin loss
(Bjartmar et al., 2001). Although the bulk of the ax-
onopathy may reflect a bystander effect, axonal tar-
geting may be more selective.
4. A prominent mononuclear cell infiltrate within the
parenchyma and in the perivascular region (Fig. 13.14),
consisting predominantly of T and, to a lesser extent, B
lymphocytes that vary in number and type with the le-
sion’s activity, although some details are still debated
(Reinherz et al., 1980; Hauser et al., 1986; Morimoto
et al., 1987; Zweiman and Lisak, 1986). In active le-
sions or at the active margin of chronic plaques, the
parenchymal lymphocytic cells have been considered to
belong predominantly to the CD4 T cell subtype,
FIGURE 13.12 Multiple sclerosis. Oligodendroglial cells (arrows) are
whereas those constituting the perivascular cuffs are
relatively preserved in area of active demyelination. (From Raine et composed of CD8 T-cell subtype and B cells, although
al., 1981 with permission) this is also an area of controversy (Lucchinetti and Ro-
flammatory demyelination, as well as IFN, IFN, IL-4,

IL-10, and TGF, which, in parallel with their role in
EAE, are thought to downregulate the process (Cannella
and Raine, 1995; Brosnan and Raine, 1996; Navikas and
Link, 1996; Ledeen and Chakraborty, 1998). A signifi-
cant role for TNF, in particular, has been advanced in
the pathogenesis of MS plaques and recent evidence has
supported the presence of receptors for TNF on oligo-
dendrocytes in MS lesions (Bonetti and Raine, 1997).
Matrix metalloproteinases may be important to optimize
the entry of inflammatory cells and macrophages into the
parenchyma. A role for oxidative damage resulting from
reactive oxygen species and liberation of nitric oxide and
peroxynitrite has also been considered.
FIGURE 13.14 Multiple sclerosis. Perivascular cuffs of lymphocytes
are characteristic of active plaques. LFB-PAS. 9. Endothelial cell activation with upregulation of
adhesion molecules ICAM-1 and VCAM-1 on endo-
thelial cells and their ligands on circulating leukocytes
driguez, 1997). Recently, a more substantive role for (Hartung et al., 1995).
CD8 cytotoxic lymphocytes has been proposed (Neu-
mann et al., 2002). CTLs amy be clonally expanded in The cellular and molecular pathogenesis of the MS
MS lesions and substantially outnumber CD4 cells in plaque is indeed complex and a consensus has not
some settings (e.g., primary progressive MS) and may cor- emerged in many areas despite intense ongoing research.
relate with the extent of axonal damage. Oligodendroglial
cells and neurons can express MHC class I molecules and,
in presenting antigens to cytotoxic CD8 cells, may be Remyelination
directly damaged by activated T cells. Th1 subpopulations Scattered foci of apparent subtotal myelin loss (shadow
of T cells, which are important for cell-mediated immune plaques), which are occasionally found in the brain
processes, are thought to have a prominent role in in- stem (arrow, Fig. 13.15), are currently thought to rep-
flammatory demyelination, although much of this work resent partial remyelination (and partial demyelina-
is based on experimental allergic encephalomyelitis (EAE) tion) of small plaques (chiefly in patterns I and II).
and is not as precisely worked out in MS, where Th1 and Shadow plaques show ultrastructural evidence of re-
Th2 cells are not as clearly defined. Variable numbers of myelination (Fig. 13.16), as evidenced by the presence
plasmacytoid cells can also be demonstrated. Class II ma- of shorter, more thinly myelinated internodes, as well
jor histocompatibility complex antigens can be demon- as other more subtle morphologic features. An unusual
strated on macrophages, although they are apparently not
associated with oligodendrocytes themselves. Many T
cells within lesions do not recognize myelin; rather, they
are nonspecific recruits to plaques and may follow, rather
that initiate, myelin destruction.
5. Reactive astrocytic proliferation.
6. Edema in variable amounts, chiefly reflecting
leakage from the damaged blood–brain barrier.
7. Increased immunoglobulin, complement, and
complement activation products (pattern II). Macro-
phages may engage in Fc-receptor-mediated myelin
phagocytosis. The clonal expansion of B cells and their
differentiation into plasma cells in CNS lesions of MS
(Colombo et al., 2000) suggests an antigen-driven lo-
cal antibody response.
8. A complex mixture of cytokines which may include
FIGURE 13.15 Multiple sclerosis. This section of medulla shows a
lymphotoxin, tumor necrosis factor (TNF), interferon
shadow plaque (arrow) adjacent to the remaining portion of the com-
(IFN), and several interleukins—(IL)-1, IL-2, IL-12— pletely demyelinated plaque (arrowhead) from which it arose (myelin
which are proinflammatory cytokines that promote in- basic protein immunohistochemistry).
droglia may be followed by remyelination in an ex-

perimental setting (Duncan and Milward, 1995). In
patterns III and IV, in which oligodendroglia are the
apparent targets of the demyelinative process, sub-
stantial remyelination is not identified.
Inactive plaques
The quiescent plaque (“chronic silent plaque”) exhibits
little residua of its inflammatory pathogenesis. Rarely,
a few perivascular mononuclear cells or macrophages
are found. The margins of the plaque are sharp, rela-
tively acellular compared to active plaques, and con-
tinue to show relative axon sparing as demonstrated by
sequential sections of a hemispheric plaque stained for
myelin (Fig. 13.17A) and axons (Fig. 13.17B). Oligo-
FIGURE 13.16 Multiple sclerosis. The margin of a shadow plaque dendroglia are absent or substantially decreased in
demonstrates a few normally myelinated axons as well as axons with
disproportionately thin, presumably regenerating myelin sheaths.
number in the center of inactive plaques (Fig. 13.18)
Several oligodendroglial nuclei are admixed. (From Raine, 1983, with with the exception of the plaque margin. Within the
permission) plaque naked axons and astrocytes and their processes
form of remyelination, occasionally encountered in the

spinal cord in MS, consists of patches of remyelination
which are typically adjacent to the dorsal root entry
zone. In these sites myelin, previously produced and
maintained by oligodendroglia, is derived from
Schwann cells that have proliferated and migrated into
the demyelinated spinal cord from adjacent dorsal
roots, presumably in response to mitogenic and trophic
signals derived from myelin debris within the cord. Re-
myelination is a complex process which may differ be-
tween individual patients. For example, patients with
the APO 2 allele show significantly decreased re-
myelination compared to patients with other alleles
(Carlin et al., 2000). In all the preceding scenarios, the
extent of plaque remyelination generally has not been
regarded as clinically significant; however, recent stud-
ies are more optimistic (Blakemore and Keirstead,
1999; Chari and Blakemore, 2002). The identification
of oligodendrocyte precursors, even in adult brains,
and the effect of various growth factors (e.g., fibro-
blast growth factor, neuregulin, brain-derived neu-
rotrophic factor, insulinlike growth factor–1 and
platelet-derived growth factor) on oligodendrocyte
growth, proliferation, and maturation suggests the
possibility of harnessing the remyelinative process. Re-
myelination plays a larger role in the resolution of de-
myelinative insults in experimental animal models.
Significant remyelination accompanies myelinopathy FIGURE 13.17 Multiple sclerosis. (A) Margin of a chronic inactive
caused by cuprizone, barbotage, ethidium bromide, plaque (p) is sharply demarcated from surrounding myelinated tracts
and shows no evidence of inflammatory infiltrate or debris-laden
experimental allergic encephalomyelitis, canine dis- macrophages. LFB-PAS. (B) An adjacent section stained for axons
temper myelitis, X-ray damage, and cyanide poison- shows relative axonal sparing within the plaque (p). Bielschowsky
ing. Transplantation of Schwann cells or oligoden- axon stain.
of perivascular mononuclear cells and macrophages

(Fig. 13.19A). Significant numbers of axonal spheroids
(Fig. 13.19B) may be demonstrated, attesting to con-
comitant axonopathy, which may culminate in frank
parenchymal necrosis. Acute MS is relatively more
common in Japan than in the United States.
Acute inflammatory demyelinative mass presenting

as neoplasm (“tumefactive MS”)
A group of patients has been identified (Kepes, 1993)
who present with a single large mass lesion, usually in
the cerebral hemispheric white matter, which is clini-
FIGURE 13.18 Multiple sclerosis. A chronic inactive plaque (p) con- cally thought to represent glioma. Upon biopsy these
tains few, if any, oligodendroglia compared to adjacent white mat- patients demonstrate an acute inflammatory demyeli-
ter and only scattered astrocytic nuclei. LFB-PAS. native process with myelin loss and relative axonal
sparing, which has similarities to multiple sclerosis and
are demonstrable. Immunohistochemical studies iden- acute disseminated encephalomyelitis. The admixture
tify only scattered residual B and T cells. of reactive astrocytes and the cellularity of the process
may result in the mistaken diagnosis of a glioma, par-
Variants of Multiple Sclerosis ticularly at the time of frozen section when the cyto-
plasm of foamy macrophages may adopt an apparent
Acute multiple sclerosis (Marburg type) fibrillary appearance. The recognition of the distinctive
Acute MS is a monophasic illness which may be rapidly histologic appearance of the process, the application of
fatal. Areas of demyelination are large and confluent; special stains for myelin and axons, and the determi-
the discrete locations characteristic of the chronic re- nation of the immunophenotype of the constituent cells
lapsing form of MS are less common. When examined usually result in the correct diagnosis. The subsequent
microscopically, lesions show preferential loss of large clinical course of such patients is unclear since only a
amounts of myelin accompanied by the apparent death subpopulation of such patients described in the litera-
and/or proliferation of a population of oligodendroglial ture has developed classical MS on follow-up; others
cells, edema, gemistocytic astrocytes, and the presence may eventually develop CNS lymphoma (Bender and
Schapiro, 1989; Alderson et al., 1996).
Devic’s disease
Devic’s disease is generally accepted as a variant of
acute MS in adults. Marked involvement of optic nerves
and spinal cord may be accompanied by large areas of
hemispheric myelin damage, often with a rapid onset
(Jen Chou et al., 1984). Demyelinative foci in Devic’s
disease are typically more destructive than spinal cord
and optic nerve involvement in the chronic relapsing
forms of MS. The destructive component may reflect
the effect of prominent local edema or release of cyto-
kines, resulting in superimposition of ischemic changes.
Like other acute patterns of MS, Devic’s disease occurs
with relatively increased frequency in Japan. The rapid
course ends with the patient’s death in a significant
number of cases.
FIGURE 13.19 Acute multiple sclerosis. (A) The margin of a conflu-
ent area of demyelination shows an admixture of lymphocytes, mono- Balo’s concentric sclerosis
cytes, macrophages, reactive astrocytes, and oligodendroglia. LFB-
PAS. (B) An adjacent section stained for axons (Bielschowsky stain)
Balo’s concentric sclerosis is a rare variant of acute MS
demonstrates scattered axonal spheroids, signifying axonal that occurs in children and young adults (Moore et al.,
injury. 1985). It is characterized by concentric wavelike pat-
of myelin loss in MS. The incidence of MS shows

prominent geographic variation with latitude, particu-
larly corresponding to areas of residence during
childhood, with those in temperate climates generally
displaying a greater risk than those in the tropics. De-
mographic studies also have provided evidence for
small epidemics of MS in the Faroe Islands after the in-
flux of British troops during World War II (Kurtzke
and Hyllested, 1986). A large number of infectious
agents have been touted over the years as the cause of
MS currently Chlamydia pneumoniae (Sriram et al.,
1998), endogenous retroviruses and HHV-6 (Challoner
et al., 1995)—but, to date, none has been definitively
proven (Larner, 1986; Boman et al., 2000; Strupp,
2001). The parallels with EAE (Lassmann, 1983) and
studies of populations of various types of lymphocytes
during acute exacerbations of the clinical disease, and
the types of lymphocytes within lesions of various dis-
ease activities have suggested an autoimmune mecha-
nism (Raine, 1984; Waksman and Reynolds, 1984;
Hohlfeld et al., 1995; Genain and Hauser, 1997; Con-
lon et al., 1999). The tendency of MS to occur in fam-
ilies also suggests a genetic component. The increased
frequency of certain HLA markers in patients with MS
FIGURE 13.20 Balo’s concentric sclerosis. This variant of acute multiple
sclerosis is characterized by a distinctive pattern of concentric rings of
(Engell et al., 1982; Sriram et al., 1985) with different
demyelination. (From Prineas and McDonald, 1997, with permission.) subtypes reported in different ethnic groups also has
been interpreted as evidence for a genetic etiology.
Interesting insights into the pathogenesis of some
terns of myelin loss alternating with myelinated zones forms of MS have been provided by the laboratory dis-
(Itoyama et al., 1985) which are thought to represent ease EAE, which is an experimental animal model of
remyelination (Fig. 13.20). Inflammation often is not immune-mediated demyelination. EAE, particularly a
prominent. Lesions may be quite destructive with sig- chronic relapsing form that develops in mice and some
nificant axonopathy. strains of juvenile guinea pigs (Fig. 13.21), exhibits a
number of interesting parallels with MS (Raine, 1997).
Schilder’s disease
Schilder’s disease is a form of myelinopathy in which
large confluent areas of mostly hemispheric white
matter inflammatory demyelination are accompanied
by significant axonal damage (Poser et al., 1986). Its
resemblance to acute MS and the demonstration of
scattered small discrete plaques in some cases sug-
gests that it may be an MS variant with a monopha-
sic continuous presentation. Originally, the term re-
ferred to a group of heterogeneous conditions that
were characterized by confluent areas of myelin loss
and a perivascular inflammatory infiltrate. Some
of the early cases appear to have been a form of
adrenoleukodystrophy.
FIGURE 13.21 Chronic relapsing experimental allergic encephalo-
Pathogenetic mechanisms of multiple sclerosis myelitis (CREAE). The pattern of demyelination in this guinea pig
EAE model exhibits a number of pathologic similarities to chronic
Many intriguing epidemiologic observations (Kurtzke, multiple sclerosis. (From Lassmann and Wisniewski, 1979, with
1980) have provided insights into potential mechanisms permission.)
Animals injected with homogenized central nervous a viral illness or exposure in children (Alter et al., 1986)
system tissue suspended in Freund’s adjuvant or se- with an appropriate genetic background sensitizes the
lected subpopulations of activated T cells sensitized to immune system to a viral antigen which is cross reac-
various myelin constituents develop a paralytic syn- tive with some constituent of white matter (“molecu-
drome which may be acute and monophasic or char- lar mimicry”). Subsequently an unknown trigger in
acterized by a remitting and relapsing course with an- adulthood initiates an autoimmune attack on central
atomic distribution and microscopic neuropathologic nervous system myelin.
findings similar to lesions of human MS. Recently, im-
munization of rats with myelin oligodendrocyte glyco-
Acute disseminated encephalomyelitis
protein (MOG) is reported to result in the histopathol-
ogy of classical MS as well as variants such as Devic’s Acute disseminated encephalomyelitis ([ADEM]; also
disease, Balo’s concentric sclerosis, and the Marburg called postinfectious, perivenous, or postvaccinial en-
type of acute MS (Storch et al., 1998). EAE may be cephalomyelitis) is an acute, classically monophasic, de-
passively transferred from one animal to another with myelinative disease of children and adults that may fol-
T lymphocytes but not with humoral antibodies, evi- low mumps, measles, varicella, or other viruses (often
dence for a necessary but not exclusively cell-mediated as the viral syndrome is waning); immunization against
immune mechanism. Nonetheless, individual demyeli- rabies using the old Pasteur procedure in which the
native foci show immunohistochemical evidence of im- virus was grown in and harvested from the central ner-
munoglobulin deposition, perhaps locally synthesized. vous system or smallpox vaccination (Fenichel, 1982;
EAE may begin with CNS antigen-specific CD4 T Hemachudha et al., 1987) can cause it. ADEM may
cells, presumably generated and activated in the pe- also occur without an identified predisposing cause.
riphery, which encounter a myelin antigen in an ap- The course is short and occasionally fatal, but most pa-
propriate setting in the CNS. T-cell subsets are involved tients recover.
and interplay in the determination of the activity of in- The gross appearance of the brain may be unre-
dividual plaques. Th1 cells, a functional phenotype of markable, or it may exhibit edema and slight discol-
CD4 T cells which mediate delayed-type hypersensi- oration of the white matter. Neuropathologic findings
tivity, or their products IL-2, TNF/, and IFN, pro- typically involve the white matter of the cerebral hemi-
mote EAE. Surprisingly, EAE can still be induced in spheres, but they may be found at any level of the cen-
mice with targeted null mutations (i.e., knockout) of tral nervous system. Indeed, different primary insults
some of the genes (e.g., TNF, lymphotoxin ) neces- may result in different targeted regions of the central
sary for the synthesis of critical cytokines (Frei et al., nervous system. Lesions typically consist of perivenous
1997). The Th2 phenotype of CD4 T cells, which foci of demyelination (Figs. 13.22, 13.23A) with rela-
have a role in humoral immunity and produce IL-4, IL- tive axonal sparing (Fig. 13.23B), lipid-containing mac-
6, IL-10, and IL-13, downregulate EAE. Both popula- rophages, and a mononuclear cell infiltrate. Recovery
tions may be found in the inflammatory demyelinative may be followed by resolution of the symptoms, and
lesions of human MS. Antigen-presenting cells in the there is evidence for apparent remyelination.
CNS in conjunction with upregulation of adhesion
molecules on the microvasculature result in recruitment
of macrophages and T and B cells, with eventual
blood–brain barrier breakdown. The microenviron-
ment in the EAE lesion is further developed with the
liberation of TNF, proteases, nitric oxide, edema, and
antimyelin antibodies. Studies of EAE have suggested
that T cells may be sensitized to myelin proteins, espe-
cially myelin basic protein, and that B cells may be sen-
sitized to a lipid component, particularly galactocere-
broside.
Evidence therefore exists for immune-mediated in-
fectious and genetic elements in the etiology of MS
(Scheinberg and Raine, 1984; Poser, 1986; Hickey,
1999; Raine et al., 1999). Probably all three mecha- FIGURE 13.22 Acute disseminated encephalomyelitis. The character-
nisms participate and interact in the pathogenesis of istic perivascular pattern of demyelination is striking in this low-
this interesting disease. One attractive hypothesis is that magnification micrograph of the spinal cord (Loyez stain for myelin).
FIGURE 13.24 Acute hemorrhagic leukoencephalitis. Numerous pe-

techial hemorrhages in the white matter of the cerebral hemispheres
appear confluent in some sites.
FIGURE 13.23 Acute disseminated encephalomyelitis. Perivenous foci

show myelin loss (A, LFB-PAS) with relative preservation of axons
(B, Bielschowsky stain). The gross appearance of acute hemorrhagic leukoen-
cephalitis consists of edema and petechial hemorrhages
Even though the disease may follow a number of vi- that occur within the white matter of the cerebral hemi-
ral illnesses, viruses are not routinely recovered from spheres (Fig. 13.24) but that may extend into the brain
the lesions or immunolocalized within the lesions. stem and cerebellum. On microscopic examination the
Rather, the occurrence of the illness after immuniza- disease is characterized by a pathologic process similar
tion, particularly when central nervous system tissue to the perivenous demyelinative appearance of ADEM
was used to make the inoculum (as in the old Pasteur with the apparent superimposition of an additional com-
rabies treatment), strongly suggests an immune- ponent of vascular (usually venular) necrosis, typically
mediated mechanism. Possible sensitization to some al- with fibrin leakage and a polymorphonuclear leukocytic
tered central nervous system antigen during the initial infiltrate (Fig. 13.25). In some cases microscopic areas of
viral infection or cross-reactivity between a viral anti- infarction are seen in the territories of involved vessels.
gen and central nervous system white matter may pro- Addition of pertussis vaccine to Freund’s adjuvant in
vide the trigger for the process (Lisak et al., 1974; Lam- the EAE model reproduces this “hyperacute” patho-
pert, 1978). logic pattern experimentally. Interestingly, vaccination
Once again, a form of ADEM serves as an appro- against pertussis has occasionally resulted in the
priate model. The acute monophasic form of ADEM in clinical development of acute hemorrhagic leukoen-
rodents to a degree resembles ADEM. This form of EAE
may be transmitted by T cells from symptomatic ani-
mals as well as by injecting animals with T cells ini-
tially sensitized to select myelin constituents and sub-
sequently grown in vitro to remove all available
sensitizing antigens before injection into a recipient an-
imal. Rare clinical cases appear to form a continuum
with features of both ADEM and MS.
Acute hemorrhagic leukoencephalitis

Acute hemorrhagic leukoencephalitis (Weston-Hurst
disease), which may appear after a prodrome of upper
respiratory infection, is a monophasic, rapid, frequently
fatal disease. It may accompany several viral exan-
thems, occur after exposure to a variety of drugs, or FIGURE 13.25 Acute hemorrhagic leukoencephalitis. Prominent
follow immunization (Behan et al., 1973; Byers, 1975; perivenous myelin loss is accompanied by angionecrosis, polymor-
Graham et al., 1979). phonuclear leukocytes, and focal hemorrhages. H&E.
FIGURE 13.26 Progressive multifocal leukoencephalopathy. White FIGURE 13.28 Progressive multifocal leukoencephalopathy. Multiple
matter involvement in the cerebral hemispheres ranges from mild dis- foci of demyelination are not accompanied by significant inflamma-
coloration to focal cavitation. tory infiltrate. LFB-PAS.
cephalitis. The occurrence of the disease after rabies AIDS. A few cases occur without known immunosup-
immunization and the hyperacute EAE findings suggest pression. The 3–6 month course is characterized by pro-
an immune-mediated mechanism, perhaps coupled gressive visual, motor, and sensory symptoms, promi-
with immune complex deposition within vascular walls nent personality change, and eventual dementia. A
resulting in subsequent complement activation and vas- short course culminating in death is the typical out-
cular necrosis. come, although antiviral agents may have an effect.
Pathologic changes in PML occur at all levels of the
central nervous system, although they tend to be con-
Infectious Demyelinating Disease
centrated in the white matter of the cerebral hemi-
Progressive multifocal leukoencephalopathy spheres (Astrom et al., 1958). The gross appearance
ranges from subtle discoloration of the white matter to
Progressive multifocal leukoencephalopathy (PML) usu-
substantial tissue loss (Fig. 13.26). Histopathologic
ally develops in adults. Patients have a variety of
findings consist of multiple foci of demyelination (Fig.
underlying disease processes, including lymphoprolif-
13.27) with a distinctive microscopic appearance:
erative diseases (lymphoma, chronic lymphocytic leu-
kemia), chronic infections (tuberculosis), immunosup- 1. Multiple foci of myelin and oligodendroglial cell
pressive therapy associated with transplantation, or loss are usually accompanied by a minimal inflamma-
FIGURE 13.27 Progressive multifocal leukoencephalopathy. This whole FIGURE 13.29 Progressive multifocal leukoencephalopathy. A nucleus
mount of cerebral cortex and underlying white matter shows numer- of an infected oligodendroglial cell (arrow) is markedly enlarged in
ous foci of demyelination, which do not spare subcortical U fibers and comparison to adjacent uninfected oligodendroglia (arrowhead,
extend into deeper portions of the overlying cortical mantle. LFB-PAS. H&E).
FIGURE 13.30 Progressive multifocal leukoencephalopathy. This elec- FIGURE 13.32 Progressive multifocal leukoencephalopathy. In situ hy-
tron micrograph of an infected oligodendroglial nucleus shows nu- bridization for the viral genome demonstrates swollen oligoden-
merous “stick and ball”-shaped virions of papovavirus (electron mi- droglial nuclei (arrowheads) and markedly enlarged atypical astro-
crograph). cytes (arrows).
tory infiltrate (Fig. 13.28). These lesions are typically 3. Atypical astrocytic cells are often bizarre and sig-
in the white matter, although they may overlap areas nificantly enlarged with multilobate or multiple nuclei,
of cortical gray matter. superficially resembling neoplastic cells (Fig. 13.31). In-
2. Hyperchromatic enlarged oligodendroglial nu- terestingly, although productive infection of astrocytes
clei are found at the margin of the lesions (Fig. 13.29). by JC virus is not typical, evidence suggests that the vi-
Ultrastructural examination (ZuRhein and Chou, ral genome is incorporated into astrocytes as seen by
1965) shows filamentous and round (“stick and ball”) in situ hybridization (Fig. 13.32). Administration of JC
viral particles in oligodendroglial nuclei (Fig. 13.30), virus to newborn experimental animals has induced a
which have the typical structure of papovavirus, a variety of central nervous system neoplasms. Rare clin-
double-stranded DNA virus. Most viruses cultured ical reports of astrocytic neoplasms arising in progres-
to date have been JC virus (the initials refer to the sive multifocal leukoencephalopathy have been pub-
patient from whom the agent was first identified). lished.
The viruses may also be demonstrated using in situ
A similar infectious demyelinative disease in experi-
hybridization or immunolocalization for JC-virus-
mental animals involves the infection of oligoden-
associated proteins.
droglia of mouse central nervous system by the JHM
strain of mouse hepatitis virus, although the distinctive
pathology of PML is not present.
Metabolic Demyelinative Diseases (Leukodystrophies)

Most of the diseases in this section represent inborn er-
rors of metabolism. They are often hereditary with on-
set in the first decade of life (although metachromatic
leukodystrophy may not become symptomatic until
adulthood) (Alves et al., 1986). The diagnosis is es-
tablished by molecular genetics if an abnormal gene has
been characterized, by the biochemical analysis of an
enzyme defect if known, by the clinical presentation,
or by its distinctive neuropathologic appearance (see
Kaye, 2001, for a recent review). Pathologic findings
FIGURE 13.31 Progressive multifocal leukoencephalopathy. Unusual
include widespread and confluent areas of myelin loss,
bizarre astrocytic nuclei (arrows) are frequently demonstrated in de- astrocytosis, and, often, late in the course of the dis-
myelinated foci. H&E. ease, a significant degree of axon loss. Inflammation is
minimal with the exception of adrenoleukodystrophy.

Surprisingly, in leukodystrophies in which all oligo-
dendroglia might be expected to share in the same bio-
chemical defect, there may be significant sparing of
white matter U fibers which run immediately adjacent
to the cortex and consist of myelinated axons commu-
nicating between individual gyri.
Krabbe’s disease
Krabbe’s disease (globoid cell leukodystrophy) is an au-
tosomal recessive inherited disease that arises in in-
fancy, usually within 6 months of birth, resulting in
progressive motor and mental retardation and periph- FIGURE 13.34 Krabbe’s disease. Numerous perivascular collections of
eral nerve dysfunction. The gross pathology (Andrews “globoid cells” (arrows) accompany gliotic white matter. H&E.
et al., 1971) consists of large confluent areas of dis-
colored gelatinous white matter and U-fiber sparing (ar-
row, Fig. 13.33). Patients lack the enzyme galacto- cells in peripheral nerves exhibit repeated demyelina-
cerebrosidase and as a result accumulate large amounts tion and remyelination, which results in onion-bulb for-
of galactocerebroside, a myelin constituent, as the re- mation. The accumulation of increased amounts of
sult of myelin turnover, initially in oligodendroglia and galactocerebroside usually does not result in the for-
Schwann cells. Oligodendroglial cells eventually die, mation of globoid cells in peripheral nerve. The stored
perhaps as a result of the metabolism of accumulated material has a distinctive ultrastructural appearance
galactocerebroside along normally minor biochemical consisting of aggregates of lucent tubular crystalloids
pathways, resulting in the production of psychosine, a (Shaw and Carlson, 1970). Twitcher and saposin A mu-
toxic by-product (Igisu and Suzuki, 1984). Degenerat- tant mice are animal models of Krabbe’s disease.
ing oligodendroglia are engulfed by macrophages,
which accumulate the liberated galactocerebroside and Metachromatic leukodystrophy
myelin debris but also lack the ability to eliminate it
metabolically. These monocyte–macrophage cells often Metachromatic leukodystrophy is an autosomal reces-
form multinucleated “globoid cells” with a parenchy- sive disease resulting in large confluent areas of dis-
mal and perivascular distribution (Fig. 13.34). Schwann colored gelatinous white matter with U-fiber sparing
similar to Krabbe’s disease. Gray matter is relatively
spared, as illustrated by the preservation of the dentate
nucleus in the midst of profound demyelination of the
cerebellar hemispheric white matter (Fig. 13.35). The
FIGURE 13.33 Krabbe’s disease. A coronal section of the cerebral

hemisphere shows marked gelatinous discoloration of confluent ar- FIGURE 13.35 Metachromatic leukodystrophy. Neuronal sparing, il-
eas of white matter, although the subcortical U fibers (arrow) are lustrated by the preserved dentate nucleus in this cerebellar section,
spared in contrast to deeper white matter. contrasts with adjacent areas of marked myelin loss.
FIGURE 13.36 Metachromatic leukodystrophy. Marked loss of myeli- FIGURE 13.38 Metachromatic leukodystrophy. In sural nerve, promi-
nated axons is accompanied by oligodendroglial cell loss and large nent demyelination, remyelination, and rudimentary onion-bulb for-
numbers of sulfatide-laden macrophages (arrows, LFB-PAS). mation accompany endoneurial macrophages engorged with sulfatide
(plastic section, toluidine blue).
disease is caused by a deficiency of the enzyme aryl-

sulfatase A, which is necessary for the degradation of matic; that is, binding of acidified cresyl violet dye to
sulfatide, a myelin constituent. In metachromatic the structured sulfatide deposit alters the way the dye
leukodystrophy, oligodendroglial and Schwann cells interacts with light, resulting in a brown hue. The
lack the ability to degrade sulfatide, which is produced chronic process eventually leads to significant axon loss
continually as a function of the normal turnover of in the cerebral hemispheric white matter. Although
myelin constituents. Sulfatide progressively accumu- Schwann cells also fail to degrade sulfatide, their pro-
lates in oligodendroglia, eventually killing them and re- liferative ability and/or resistance to killing results in
sulting in prominent myelin loss (Fig. 13.36), and is re- ongoing cycles of myelin degeneration and regenera-
leased into the extracellular space. Subsequently, tion in peripheral nerve, eventually causing onion-bulb
sulfatides are taken up by and accumulate in macro- formation and substantial axon loss (Fig. 13.38). The
phages, which also are unable to complete the degra- accumulation of sulfatide in Schwann cells and mac-
dation of sulfatide and as a result accumulate large rophages (Fig. 13.39) within the endoneurium of the
amounts of the material. Distinctive prismatic (Fig.
13.37) or tuffstone inclusions, which represent lysoso-
mal collections of sulfatide, can be seen in many cell
types, including oligodendroglia, Schwann cells, and
macrophages. The accumulated material is metachro-
FIGURE 13.39 Metachromatic leukodystrophy. Electron micrograph

of the sural nerve shows axons with thinned or absent myelin sheaths
FIGURE 13.37 Metachromatic leukodystrophy. As seen in this elec- (black arrows) and cytoplasmic storage of sulfatide in Schwann cells
tron micrograph of a macrophage, sulfatide storage is characterized (white arrow) and macrophages (black arrowhead, electron micro-
by distinctive prismatic inclusions (arrow, electron micrograph). graph).
sural nerve permits (Martin et al., 1982; Yudell et al.,

1967) diagnosis of metachromatic leukodystrophy by
a peripheral nerve biopsy, although biochemical tests
are typically sufficient.
Adrenoleukodystrophy
The classic form of adrenoleukodystrophy (ALD) is in-
herited as an X-linked recessive trait; however, a num-
ber of subtypes have been described (Moser et al., 1984;
Goldfischer et al., 1985; Goto et al., 1986). In the clas-
sic type, young boys present with intellectual and be-
havioral problems and deteriorate progressively over the
course of a few years. Adrenal dysfunction may develop
FIGURE13.40 Adrenoleukodystrophy. Characteristic perivascular in-
before or after the onset of central nervous system flammation accompanies marked myelin loss and astrocytosis. LFB-PAS.
difficulties, or not at all, and may dominate the clinical
picture or, alternatively, represent only a minor prob-
lem. The accumulation of very long-chain fatty acids Gross demyelination preferentially involves the poste-
(VLCFA) has been reported in various tissues and cul- rior portions of the cerebral hemispheres, chiefly occip-
tured cells (O’Neill et al., 1982; Rizzo et al., 1984) and ital and parietal lobes and portions of the temporal lobes,
may relate to a deficiency or dysfunction of peroxisomes the corpus callosum, anterior commissure, and internal
(Dubois-Dalcq et al., 1999)—small, dense organelles that capsule (Schaumburg et al., 1975); sites in which ALDP
contain a variety of enzymes related to oxidant status is highly expressed may be particularly at risk. ALDP
and long chain fatty acid metabolism. The frank absence expression differs in subpopulations of oligodendrocytes
of peroxisomes, reflecting deficiency in assembly, is seen and, in combination with modifier genes, may underly
in the infantile connatal form of adrenoleukodystrophy; the age, severity, and distribution of pathology in
however, peroxisomes are present in the typical X-linked adrenoleukodystrophy/adrenomyeloneuropathy. The his-
form. Neonatal ALD is now thought to share common tologic appearance of the CNS (Fig. 13.40) is similar to
gene defects with Zellweger’s syndrome and infantile that in the other leukodystrophies except that perivas-
Refsum’s disease (Powers and Moser, 1998). A defi- cular cuffing by lymphocytes (chiefly CD8 cytotoxic
ciency of the enzyme VLCFA-CoA (coenzyme A) syn- lymphocytes) (Ito et al., 2001) is unique among leuko-
thetase, which catalyzes the formation of CoA deriva- dystrophies and may superficially resemble MS. Cleft-
tives of very long-chain fatty acids in anticipation of their like lucent lamellar inclusions (Schaumburg et al., 1974;
degradation, has been identified in X-linked ALD and Powell et al., 1975), presumably containing long-chain
was initially thought to represent the genetic defect in fatty acids, may be found in Schwann cells, oligoden-
this form of the disease. Recent work on the molecular droglia, macrophages, and testicular and adrenal corti-
genetics of X-linked ALD, surprisingly, did not demon- cal cells. Axon loss may be substantial.
strate a gene defect in VLCFA-CoA synthetase; rather,
the defective gene in X-linked ALD codes for a peroxi-
Alexander’s disease
somal membrane protein (ALDP) with homology to an
ATP-binding cassette transporter superfamily. At this In this leukodystrophy, cases tend to be sporadic, rep-
time, the relationship of the enzyme defect and ALDP is resenting de novo mutations, and they occur more of-
not completely understood (Aubourg and Dubois-Dalcq, ten in males. The initial symptoms may be intellectual
2000) but may result from the failure of the substrate and motor deterioration, or the disease may present as
or a cofactor needed for enzymatic activity to gain ac- an apparent mass lesion. Demyelination involves the
cess to the peroxisomal environment. It is proposed that cerebral hemispheres, extending to the rostral brain
the presence of VLCFA in myelin induces a degree of stem. The microscopically distinctive feature of Alexan-
myelin instability and results in the recruitment of an der’s disease (Alexander, 1949; Herndon and Rubin-
immune T-cell- and cytokine-mediated process in which stein, 1968) is the development of a large number of
presentation of a lipid antigen may result in substantial Rosenthal fibers, which are eosinophilic cigar-shaped
myelin destruction. Adrenomyeloneuropathy, a milder structures composed predominantly of B-crystallin,
form of the disease, may reflect the contribution of a which occur in association with collections of glial fil-
modifier gene. aments rich in glial fibrillary acidic protein (GFAP), and
spread loss of myelin in the cerebrum and cerebellum

and “spongy degeneration” of the white matter—that
is, development of numerous microscopic white matter
vacuoles in which oligodendroglia are relatively nu-
merous (Fig. 13.42). Ultrastructural examination dem-
onstrates (1) focal fluid-filled areas of splitting of
myelin lamellae between two major dense lines and (2)
swelling of astrocytes; both of these underlie the light
microscopic spongy appearance. In addition, there is
an accumulation of glia resembling Alzheimer type II
astrocytes. A mutation in the gene for the enzyme as-
partoacylase, a poorly understood white matter en-
zyme, has been reported. Peripheral nerve is spared
FIGURE 13.41 Alexander’s disease. Proliferation of large numbers of from the process.
Rosenthal fibers (arrows) in degenerated white matter, particularly
in a perivascular or subpial distribution, is characteristic. H&E.
Vanishing white matter disease (childhood ataxia
with diffuse hypomyelination)
which develop in areas of intense astrocytosis. They are This leukodystrophy has an abrupt childhood or ado-
particularly prominent in subpial, periventricular, and lescent onset and is inherited in an autosomal recessive
perivascular locations (arrows, Fig. 13.41), in which fashion (Van der Knaap et al., 1997; Francalanci et al.,
they preferentially accumulate. Recent work has estab- 2001). Markedly deficient white matter is accompanied
lished the presence of point mutations in the GFAP gene by unusual swollen foamy oligodendroglia which con-
in many patients with Alexander’s disease (Brenner et tain myelin proteins and focally increased numbers of
al., 2001; Messing et al., 2001). Transgenic mice which oligodendroglia in areas of relative myelin sparing
overexpress human GFAP have resulted in an animal (Wong et al., 2000). Molecular genetic studies have re-
model (Eng et al., 1998). cently demonstrated a defect in the translation initia-
tion factor eiF2B (Leegwater et al., 2001; van der
Knaap et al., 2002).
Pelizaeus-Merzbacher disease
An X-linked leukodystrophy, of which a number of
Other rare types of leukodystrophy
types and inheritances have been defined, is character-
ized in some forms by a “tigroid” pattern of myelin A variety of rare diseases exist in which white matter
loss in the cerebral hemispheres with widespread, fre- damage is prominent, and they are classified by some
quently perivascular, islands of preserved myelin (Ze- investigators as leukodystrophies. Such diseases include
man et al., 1964). Macrophages with sudanophilic de-
bris are not conspicuous. The genetic defect in
Pelizaeus-Merzbacher disease, at least for a percentage
of cases, involves defective synthesis of myelin proteo-
lipid protein (PLP) (Koeppen et al., 1987; Saugier-
Veber et al., 1994). Animal models (e.g., jimpy mouse)
with discrete defects in the PLP gene have been re-
ported.
Canavan’s disease
Canavan’s disease is an autosomal recessive disease
with typical onset in infancy and a rapidly fatal course
(Adachi et al., 1973). The gross appearance of the brain
consists of confluent gelatinous discoloration of the
cerebral and cerebellar white matter, which resembles
the other leukodystrophies (Goodhue et al., 1979; Luo FIGURE 13.42 Canavan’s disease. Affected white matter shows nu-
and Huang, 1984). Microscopic findings include wide- merous vacuoles and large numbers of intact oligodendroglia. H&E.
Questionably Iatrogenic Demyelinating Disease

Central pontine myelinolysis
Central pontine myelinolysis may arise in a variety of
diseases or conditions (e.g., alcoholism, malnourish-
ment, inappropriate secretion of antidiuretic hormone
as a paraneoplastic process) (Adams et al., 1959;
Messert et al., 1979) that have in common the clinical
setting of rapid correction of sodium imbalance in hy-
ponatremic states (Laureno, 1982; Norenberg et al.,
1982). Shortly after correction of the ionic imbalance,
FIGURE 13.43 Central pontine myelinolysis. The loss of myelin in the an area of demyelination develops in the basis pontis;
central pons is accompanied by relative axonal preservation in typ-
however, it typically does not extend to the periven-
ical cases of central pontine myelinolysis; however, in some cases,
significant destruction may supervene, resulting in cavitation. tricular and subpial sites favored by MS. Although
myelin loss is preferentially greater than axon loss, se-
vere cases may demonstrate significant axonal destruc-
tion, even cavitation (Fig. 13.43). Less frequently, sim-
sialuria, homocystinuria, 5,10 methylene tetrahydro- ilar histopathologic findings can be demonstrated in
folate reductase deficiency, cytochrome oxidase defi- extrapontine sites. Areas of extrapontine involvement
ciency, pyruvate dehydrogenase deficiency, 2-hydroxy- are those in which gray and white matter are intimately
glutaric aciduria, glutaric aciduria type II, and the apposed, such as the lateral geniculate nucleus and
Sjogren-Larsson syndrome (a defect in fatty alcohol me- cortex/digitate white matter. In the illustrated case (Fig.
tabolism). Cases of apparent leukodystrophies which 13.44) there is preferential involvement of pencil fibers
are characterized by macrophages containing debris penetrating gray matter of the basal ganglia. There is
staining with sudan black dye with no further classifi- little evidence of perivascular or parenchymal inflam-
cation or identification of an enzyme defect may be des- mation, and the appearance of the lesion is not histo-
ignated as sudanophilic leukodystrophy. logically distinctive. Study of animal models suggests
that the most immediate pathogenetic mechanism may
be localized edema which results from osmotic injury.
SUMMARY
Diseases of myelin range from self-limited processes to

devastating illnesses with fatal outcomes. The key to
designing therapeutic or preventive stratagems is pre-
cise knowledge of the detailed mechanisms responsible
for the pathologic findings and identification of the dis-
ease early in the active phase rather than solely at au-
topsy. Recent advances in immunology and molecular
techniques may soon result in the clinical ability to tar-
get and destroy select subpopulations of T cells re-
sponsible for a variety of immune-mediated myelin dis-
eases, especially MS. Experimental animal models of
demyelinating diseases, such as chronic relapsing EAE,
permit the continuing detailed study of new preventive
and therapeutic approaches. Increased understanding
of the processes controlling remyelination of demyeli-
nated axons offers promise for the recovery of estab-
lished lesions, as occurs spontaneously in many exper-
FIGURE 13.44 Central pontine myelinolysis. This disease may affect
imental animal model systems. The sparing of certain
nonpontine sites, particularly those in which white matter borders
gray matter, as in this case of involvement of pencil fibers (arrows) anatomic sites in some myelin diseases resulting from
in the basal ganglia. LFB-PAS. inborn errors of metabolism suggests that much re-
mains to be learned about basic processes underlying remyelination associated with possession of the APOE epsilon2
myelin synthesis, maintenance, and degradation. allele. J Neuropathol Exp Neurol 59:361–367.
Challoner P.B., Smith K.T., Parker J.D., MacLeod D.L., Coulter
S.N., Rose T.M., Schultz E.R., Bennett J.L., Garber R.L., and
Chang M. (1995). Plaque-associated expression of human her-
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14 Introduction to neurooncology
JAMES S. NELSON AND PETER BURGER
CNS tumors may be primary or secondary. Primary mors, the focal signs may be accompanied by evidence
CNS tumors develop initially within the brain, spinal of increased intracranial pressure.
cord, optic nerves, cranial or spinal nerve roots, lep- • Both primary and metastatic tumors behave as
tomeninges, and dura. Pituitary tumors are primary in- space-occupying lesions, compressing neural paren-
tracranial tumors and are sometimes classified as pri- chyma, increasing intracranial pressure, and causing
mary CNS tumors. Secondary tumors originate from brain herniations. The growth of the tumor may ob-
primary neoplasms arising in organs, structures, and struct the circulation of the cerebrospinal fluid through
tissues outside the CNS and reach the CNS either by the ventricles or subarachnoid space, causing hydro-
direct extension when the primary tumor is located in cephalus and further increasing intracranial pressure.
a contiguous structure such as the base of the skull or In very young children before closure of the cranial su-
by metastasis, indicated by absence of continuity be- tures, the rising pressure causes widening of the sutures
tween the CNS tumor deposit and its primary source and eventually an increase in head size.
outside the CNS. Primary CNS tumors are generally
classified according to their cellular origin (glioma, as-
trocytoma), their tissue of origin (meningioma, nerve
INCIDENCE AND PREVALENCE
sheath tumors), or their organ of origin (pinealoma).
The craniopharyngioma is an exception to this scheme.
Statistics related to the incidence and prevalence of cen-
tral nervous system tumors are derived from popula-
tion-based studies in which an attempt is made to de-
DISTINCTIVE CHARACTERISTICS OF CNS TUMORS
termine the number of new cases annually (incidence)
and the number of existing cases (prevalence) among
Although similar to systemic neoplasms in some re-
all persons living within a geopolitical region or a rep-
spects, tumors involving the central nervous system
resentative sample of that population. Data from au-
have the following distinctive characteristics.
topsy or institutional series cannot be used to deter-
• Primary central nervous system tumors rarely mine incidence and prevalence because the cases in
metastasize outside the CNS. Malignancy is indicated these series have not been selected randomly and may
by rapid growth, invasion of adjacent structures, and not be representative of the general population. Inci-
spread to other parts of the central nervous system dence and prevalence rates from population-based stud-
along anatomic pathways such as the ventricular sys- ies reported by brain tumor registries may differ from
tem or subarachnoid space. Even apparently benign tu- one another because different criteria are used to de-
mors may cause considerable morbidity or death be- fine brain tumors or data collection is limited only to
cause they involve major blood vessels or other vital malignant tumors.
structures and cannot be safely excised. Such tumors Secondary tumors involving the CNS are, in fact, the
are categorized more appropriately as slowly growing most common type of CNS neoplastic lesion. In the
rather than benign. They are sometimes described as year 2000 over 185,000 persons in the United States
“malignant by position.” will be diagnosed with a primary or secondary brain
• The anatomic location of the neoplasm is one of or spinal cord tumor. Approximately 35,000 (19%)
the principal determinants of the accompanying neu- will be primary and 150,000 (81%) secondary (Yung
rologic signs and symptoms. A tumor involving major et al., 1996; CBTRUS, 2000; Greenlee et al., 2000).
motor pathways may cause prominent symptoms, The most common identified origins for metastatic
whereas a lesion of the same size and type beneath the CNS tumors, including those involving the spinal cord,
nondominant frontal lobe may give rise to barely per- are the respiratory system, breast, gastrointestinal tract,
ceptible clinical effects. In the case of intracranial tu- genitourinary tract, melanoma, and lymphoma. Ap-
267
proximately 10% of CNS metastases have an uniden- The age-specific incidence rates for most primary
tified primary site (Nelson et al., 2000). CNS tumors increase with age and peak between 65
In regard to primary CNS tumors, the database of and 85 years of age. Exceptions are pilocytic astrocy-
the Central Brain Tumor Registry of the US (CBTRUS) toma, medulloblastoma, and germ cell tumors that have
contains population-based data on all primary benign peak incidence rates during the first two decades of life,
and malignant brain and CNS tumors reported by can- and ependymoma and craniopharyngioma that have
cer registries from 14 states with a combined popula- peak rates during the first two decades of life and be-
tion equal to approximately 23% of the entire U.S. pop- tween 45 and 65 years of age. The incidence rate for
ulation. As noted previously, tumor registries categorize meningioma is two times higher in women than in men.
brain tumors differently. CBTRUS defines brain and Otherwise, the general incidence rates of all primary
CNS tumors as those primary tumors arising at the fol- CNS tumors combined and of most individual histo-
lowing sites: brain, meninges, spinal cord, cranial logic types are somewhat higher in men than in women
nerves and other parts of the CNS, the pituitary, and (CBTRUS, 2000).
the pineal gland. All primary tumor morphologies and The principal location and frequency of the different
all behavioral types (benign, uncertain, and malignant) histologic types of CNS tumors vary according to age.
located at these sites are included in the database. In persons over 20 years of age, the most common pri-
CBTRUS reports an incidence rate of 12.7 per mary intracranial and intraspinal tumors in order of
100,000 person-years for primary, benign, and malig- frequency are: meningioma, glioblastoma, astrocytoma
nant brain and CNS tumors (including pituitary and (all types), nerve sheath tumors, pituitary tumors, oligo-
pineal gland) in the United States from 1992–1997 ad- dendroglioma (all types), malignant glioma nos, and
justed to the year 2000 U.S. standard population. (Pre- ependymoma (all types). Most of these are located most
viously, cancer incidence rates in the United States have often at intracranial, supratentorial sites. Among the
been adjusted to the year 1970 United States standard primary supratentorial tumors in this age group the
population. The use of the year 2000 U.S. standard most common are: meningioma, glioblastoma, and
population that has recently become available provides anaplastic astrocytoma (CBTRUS, 2000).
a better representation of the current age distribution The most common primary intracranial and in-
in the U.S. population.) Overall, the diagnosis in 82% traspinal tumors in persons under 20 years of age in
of these cases was confirmed histologically. Approxi- order of frequency are: medulloblastoma/primitive neu-
mately 62% were considered malignant and 38%, be- roectodermal tumor (PNET), pilocytic astrocytoma,
nign (CBTRUS, 2000). other tumors of astrocytic lineage (anaplastic, glioblas-
Annually in the United States, primary malignant toma, nos), malignant glioma nos, ependymoma (all
brain tumors account for 2%, or 13,000, of the types), mixed neuronal and glial tumors, germ cell tu-
deaths due to cancer. They are the second most com- mors, and craniopharyngioma. Most of these tumors
mon cause of cancer death during the first two occur most often at intracranial, infratentorial sites.
decades of life and the third most common cause of The common infratentorial tumors in this age group
cancer death in persons 20–39 years of age (Green- are: medulloblastoma/PNET, pilocytic astrocytoma
lee et al., 2000). The 5 year survival rate for all pri- (both cerebellar), ependymoma ( fourth ventricle), and
mary malignant CNS tumors combined is 25%–27% brainstem astrocytoma (CBTRUS, 2000).
(CBTRUS, 2000). The common spinal cord tumors in persons over 20
Between 80% and 90% of CNS tumors are in- years of age are schwannoma, meningiorna, metastatic
tracranial and 10%–20% are intraspinal (Fogelholm et tumors, and glioma, chiefly ependymoma and astro-
al., 1984). Specifically, in the CBTRUS database, 61% cytoma. These tumors have characteristic but not in-
of primary CNS tumors were located within the brain variable anatomic locations: glioma, intramedullary;
(cerebrum, brain stem, cerebellum, ventricles); 31% in schwannoma and meningioma, extramedullary and in-
the meninges, nerve roots, and spinal cord; and 8% in tradural; and metastases, extramedullary space. In-
the pituitary or pineal gland. The most common mor- tramedullary metastases are rare (Helseth and Mork,
phologies in order of frequency were glioma (all types), 1989).
meningioma, nerve sheath tumor (schwannoma and Spinal cord tumors in persons under 20 years of age
neurofibroma), and pituitary adenoma. Meningioma are uncommon. Statistics concerning the frequency of
followed by glioblastoma were the two most common individual types in this age group vary. In addition to
individual histologic types. Tumors of astrocytic lin- gliomas, schwannomas, meningiomas, and metastases,
eage (astrocytoma and glioblastoma) were the most such tumors as dermoids, teratomas, and lipomas, are
common types of glioma. encountered in this age group.
14: INTRODUCTION TO NEUROONCOLOGY 269
ETIOLOGY Among the patient characteristics with prognostic

significance are age, degree of neurologic impairment,
The cause for the majority of primary human central and Karnofsky performance status at the time of diag-
nervous system tumors is unknown. Similar neoplasms nosis. In studies of patients with supratentorial anaplas-
have been induced experimentally in laboratory ani- tic astrocytomas and glioblastomas, for example, as
mals with viral and chemical carcinogens such as the both age and the degree of neurologic or general phys-
SV 40 and JC papovaviruses and the nitrosoureas. The ical impairment increased, the prognosis became poorer
etiologic relationship of these agents, as well as other (Nelson et al., 1985). The extent of the surgical resec-
putative risk factors such as trauma and a variety of tion also appears important with regard to length of
occupational chemical exposures, to primary tumors in survival. In general, prognosis improves as larger
the human central nervous system remains uncertain amounts of tumor are removed.
(Inskip et al., 1995; Davis and Preston-Martin, 1998). A variety of morphologic features have been used as
The development of meningiomas, fibrosarcomas, prognostic indicators for central nervous system tu-
and gliomas following diagnostic X-ray exposure or ra- mors. Supratentorial astrocytic tumors have been stud-
diation therapy for fungal disease of the scalp or for ied extensively in this regard. In histologically malig-
an unrelated primary central nervous system tumor nant astrocytomas, for example, the presence of
such as craniopharyngioma has been reported on a necrosis differentiates tumors with the worst progno-
number of occasions. Although much of the evidence sis (glioblastoma multiforme) from those associated
is anecdotal, a role for ionizing radiation as an etio- with a longer but limited survival time (anaplastic as-
logic factor in a small number of primary central ner- trocytoma) (Nelson et al., 1983; Burger et al., 1985).
vous system tumors appears likely (Inskip et al., 1995; Morphologically based prognostic markers have also
Davis and Preston-Martin, 1998). been described for other types of central nervous sys-
The increased incidence of primary central nervous tem tumors (Kleihues and Cavenee, 2000).
system Iymphoma in patients with congenital or ac- The application of gene expression profiling to CNS
quired immunodeficiency syndromes, including AIDS, tumors may become an important means of assessing the
and in immunosuppressed transplant recipients points prognosis of primary CNS tumors. The profiling tech-
to the role of disturbed immunologic mechanisms in nique involves determining the pattern of expression of
the development of some tumors of this type (Hochberg hundreds or thousands of individual genes in tumor tis-
and Miller, 1988). sue samples. Messenger RNA (mRNA) sequences re-
A small number of primary brain tumors occur in flecting the active genes in a tissue sample are extracted
association with familial or hereditary cancer syn- from the sample and used to generate corresponding com-
dromes. Disorders of this type associated with primary plementary DNA (cDNA) sequences. These sequences are
brain tumors include neurofibromatoses 1 and 2, tuber- then labeled with a fluorescent dye and hybridized with
ous sclerosis, von Hippel-Lindau syndrome, Turcot’s DNA sequences representing genes of interest arranged
familial polyposis syndrome, and the nevoid basal cell in rows on a glass slide or nylon membrane (microar-
carcinoma syndrome (Inskip et al., 1995; Davis and ray). Hybridization of a cDNA sequence from the tissue
Preston-Martin, 1998). sample with a DNA sequence on the array is indicated
by the localization of the fluorescent label at the site of
hybridization and reflects activity or expression in the
PROGNOSTIC CONSIDERATIONS original tissue sample of the gene represented by that
DNA sequence on the array. A scanning microscope is
Prognostic factors are variable conditions or charac- used to measure the intensity of each fluorescent focus
teristics associated with a tumor or disease that predict to determine the degree to which gene is expressed. Cor-
relapse or survival. They are useful in selecting treat- relation of patterns of gene expression with the biologic
ment, analyzing the results of therapy, and advising pa- behavior and histologic features of particular tumors may
tients and their families (Mahaley et al., 1989). Prog- lead to more accurate prognostic estimates (Stephenson,
nostic factors associated with central nervous system 1999; Ladanyi et al., 2001).
tumors include both patient characteristics and certain
morphologic features of the neoplasm (Nelson et al.,
1983; Burger et al., 1985; Nelson et al., 1985). The re- EFFECTS OF ADJUVANT THERAPY
lationship and relative importance of these factors can
be assessed using multivariate analysis (Lew et al., The usual initial treatment of primary CNS tumors is
1983). surgical excision of as much of the tumor as possible.
FIGURE 14.3 Confluent foci of radiation necrosis involving white mat-

ter with minimal cellular reaction in adjacent parenchyma. H&E,
100.
FIGURE 14.1 Circumscribed, granular focus of radiation necrosis with mation, is reversible, and is treated with steroids. The
multiple small cavities involving the subcortical white matter. The early delayed lesions develop within weeks or months
overlying cortex appears intact.
following completion of the radiation therapy. They in-
volve the white matter and are reported to resemble the
In cases involving malignant tumors or incompletely demyelinative plaques in multiple sclerosis. The late de-
excised tumors the surgery is followed by adjuvant ther- layed lesion develops 6 months to 2 years after com-
apy with ionizing radiation or chemotherapy alone or pletion of radiation therapy. If the lesion is extensive
in combination to manage the disease. Unfortunately, it may present as an expanding, contrast-enhancing
both forms of adjuvant therapy may cause damage to mass and be mistaken for recurring tumor. The white
normal CNS tissue (Burger and Boyko, 1991; Bruner matter is selectively affected. Macroscopically, the ex-
et al., 1998). tensive lesion is evident as a yellow or granular white
Radiation injury is the most common therapeutic focus of necrosis with small cavities and petechiae (Fig.
complication, causing significant damage to brain pa- 14.1). Microscopically, multiple microscopic foci of
renchyma, and is most likely to develop when the to- white matter necrosis constitute the less extensive type
tal radiation dose exceeds 50 Gy (5000 rads). Three of lesion (Figs. 14.2, 14.3). Widespread areas of coag-
types are recognized: acute, early delayed, and late de- ulation necrosis, fibrinoid angionecrosis, angiofibrosis,
layed. The acute type appears to involve edema for- and clusters of telangiectatic blood vessels form the
FIGURE14.2 Microscopic focus of radiation necrosis involving cere-

bral white matter. Adjacent reactive cellular changes are minimal. FIGURE 14.4 Radiation necrosis of white matter with fibrinoid an-
H&E, 100. gionecrosis and angiofinrosis. H&E, 100.
14: INTRODUCTION TO NEUROONCOLOGY 271
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mation of macrophages, are limited in comparison to Lew R.A., Day C.L. Jr., Harrist T.J., Wood W.C., and Mihm M.C.
the reactive changes associated with infarction. The Jr. (1983). Multivariate analysis. Some guidelines for physicians.
pathogenesis of the late delayed lesion is unresolved. JAMA 249:641–643.
Occlusive vascular lesions, autoimmune reaction, and Mahaley M.S. Jr., Mettlin C., Natarajan N., Laws E.R., and Peace
disturbed nucleic acid metabolism of glial cells have B.B. (1989). National survey of patterns of care for brain-tumor
patients. J Neurosurg 71:826–836.
been suggested mechanisms. Nelson D.F., Nelson J.S., Davis D.R., Chang C.H., Griffin T.W., and
Pajak T.F. (1985). Survival and prognosis of patients with as-
trocytoma with atypical or anaplastic features. J Neurooncol
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changes produced by intrcranial tumors and by various forms of Peress N. (1983). Necrosis as a prognostic criterion in malignant
antineop[astic therapy. In: Russell and Rubinstein’s Pathology of supratentorial astrocytic gliomas. Cancer 52:550–554.
Tumors of the Nervous System, 6th ed. (D.D. Bigner, R.E. Nelson J.S., von Deimling A., Petersen I., and Janzer R.-C. (2000).
McLendon, and J.M. Bruner, eds.). Arnold, London, pp. Metastatic tumours of the CNS. In: Pathology and Genetics. Tu-
451–491. mours of the Nervous System, 2nd ed. (P. Kleihues and W.K.
Burger P.C., Vogel F.S., Green S.B., and Strike T.A. (1985). Glioblas- Cavenee, eds.). Oxford University Press, Oxford, pp. 250–253.
toma multiforme and anaplastic astrocytoma. Pathologic criteria Stephenson J. (1999). Human genome studies expected to revolu-
and prognostic implications. Cancer 56:1106–1111. tionize cancer classification. JAMA 282:927–928.
Burger P.C. and Boyko O.B. (1991). The pathology of central ner- Yung A., Sawaya R., Curran W., and Fuller G. (1996). Intracranial
vous system radiation injury In: Radiation Injury to the Nervous metastatic central nervous system tumors. In: Cancer in the
System (P.H. Gutin, S.A. Leibel, and G.E. Sheline, eds.). Raven Nervous System (V.A. Levin) Churchill Livingstone, New York,
Press, New York, pp. 191–208. p. 243.
15 Laboratory methods of brain
tumor analysis
PAUL E. MCKEEVER
This chapter is divided into four categories: specimen ing or desiccating it. This touch preparation usually
procurement, cell-type-specific markers, measures of shows cells and is especially valuable for soft specimens
proliferative capacity, and genetic markers (Nelson et suspected to be gliomas, lymphomas, or primitive neu-
al., 1983; Russell and Rubinstein, 1989; Burger et al., roectodermal tumors (PNETs). If necessary, a separate
1991; Burger and Scheithauer, 1994). Only methods 0.1 mm3 portion of firmer specimens refractory to
applicable to a cell or tissue specimen are within the touch preparations can be compressed between two
scope of this review. The tables summarize information slides without lateral smearing. Without drying, either
and cite references that document methods. specimen should be immediately fixed in ethanol and
stained with hematoxylin and eosin (H&E) to com-
plement the frozen section.
SPECIMEN PROCUREMENT Sampling large biopsies and resections should follow
these general principles: Sample each region that looks
The appropriate time to realize that more tissue is or feels different than the others. Whenever possible,
needed is during the biopsy procedure rather than af- include the edge of the lesion with macroscopically nor-
ter surgery. Intraoperative monitoring of biopsy tissue mal brain (and meninges). This cannot be overempha-
is recommended to optimize sampling and preparation sized, both to evaluate the margin of the lesion and as
of tissue for further procedures (Fig. 15.1A,B; see Color an internal control if immunohistochemistry is needed.
Fig. 15.1B in separate color insert). This allows the Save all unblocked tissue at least until the case is com-
pathologist to gauge the adequacy of the specimen. pleted.
Specimens which reveal only hemorrhage, necrosis, and Margins of neurosurgical specimens rarely require
normal or gliotic brain tissue require further sampling. ink. Exceptions include attempts to totally resect a tu-
Brain with a few glia (gliosis vs. glioma) is a particu- mor having a discrete margin with CNS (meningioma,
lar problem and should be sampled further. carcinoma, and skull-based tumor). Ink may also be
Intraoperative monitoring of the biopsy specimen al- used to preserve orientation of a large, whole specimen,
lows determination of the best region from which to such as is encountered in temporal lobe resections.
take another specimen for permanent section. Micro- Three major innovations contributed to the realization
scopic features may indicate the need for microbiologic of the dream of sampling nearly any region in the brain
culture or for special fixation for immunohistochem- with relatively low risk. These were improvements in ra-
istry. Unless the intraoperative microscopic diagnosis is diographic procedures delineating tumors, improvements
unequivocal, a small piece should be put in glutaralde- in stereotactic frames to correlate needle position with
hyde for possible electron microscopy. Such samples these radiographs, and improvements in needle design to
can be discarded if not needed but the need for rebiopsy minimize cutting dangerous vessels. Intraoperative feed-
can be avoided if they are needed. back on neurophysiologically sensitive regions decreases
During surgery, nuclear and cytoplasmic details are risk in awake adult patients (Hood and McKeever, 1989).
revealed best on cytologic preparations, while histo- Stereotactic procedures have been improved by intraop-
logic relationships are preserved on frozen sections erative neuropathologic monitoring of stereotactic spec-
(McKeever et al., 1997; Takekawa et al., 1998; Firlik imens. Immunohistochemistry (Table 15.1) and electron
et al., 1999). With care, a single microscopic slide can microscopy have been particularly valuable for subse-
be moved over and lightly touched to the specimen as quent confirmation of the diagnosis of these small spec-
it sits on its original moist gauze pad without smear- imens (Hood and McKeever, 1989).
272
15: LABORATORY METHODS OF BRAIN TUMOR ANALYSIS 273
A droglioma (WHO classification) to grade IV glioblas-

toma in two samples of the same tumor. Some samples
missed the tumor entirely. The practical implication of
this study for stereotactic biopsy interpretation is that
a stereotactic specimen may not adequately represent
the histologic heterogeneity of a glioma (Fig. 15.1 and
Color Fig. 15.1B in separate color insert). A diagnosis
other than glioblastoma (grade IV) on a stereotactic bi-
opsy of glioma carries a risk of inaccuracy on the ba-
sis of sampling alone.
These sampling problems should be compared with
the regional diagnostic alternative. For example, the
brain stem is a hazardous region to biopsy. Empiri-
cal therapy without biopsy invites inappropriate
B treatment. Open biopsy risks morbidity if the central
diagnostic portion of an intrinsic mass is sought, and
risks nondiagnostic specimens if only the periphery
is sampled. Thus, a needle stereotactically directed
around dangerous structures into the central region
of a deep brainstem mass may be the best alternative
(Hood and McKeever, 1989). Similar neuroanatomic
arguments for stereotactic biopsies have been ad-
vanced for the thalamic, pineal, and most sensitive
cerebral regions.
The specimen selected for permanent section should
be immediately fixed in formalin without extra han-
dling to avoid desiccation and crush artifacts. For im-
munohistochemistry, blanks with no more than two or
FIGURE 15.1 Stereotactic biopsies of a left temporoparietal mass in three sections per slide can be cut at initial sectioning
an elderly woman with aphasia for 6 weeks. (A) Her first specimen to conserve precious tissue (Tables 15.1, 15.2).
showed gliosis and rare neoplastic glia; classification and grade un-
certain. (B) Her last specimen showed the very pleomorphic fibrillar
cells, malignant nuclei, tumor necrosis, and vascular proliferation
of a glioblastoma, grade IV by World Health Organization criteria CELL-TYPE-SPECIFIC MARKERS
(Kleihues and Cavenee, 2000). See also Color Figure 15.1B. From
McKeever (2000b). New methods of brain tumor analysis. In: Mena
H, Morrison AL. Thirty-eighth Annual Dr. Kenneth M. Earle Memo- Cell-type-specific (phenotypic) markers allow classi-
rial Neuropathology Review, Washington, D.C., Armed Forces In- fication of brain tumors into specific diagnostic cat-
stitute of Pathology. egories which reflect common opinions about the pre-
sumed lineages of the neoplasm and the grade of
malignancy (Daumas-Duport et al., 1988; Shi et al.,
Sampling is the major impediment to accurate stereo- 1997; McKeever, 1999; Kleihues and Cavenee, 2000;
tactic diagnosis. The surgeon has no direct view in situ McKeever, 2000a). Classic and highly regarded phe-
of the region of tissue being sampled and is operating notypic analyses are based upon structural features
in a “black box.” A region of tissue with a higher grade which correlate with a known type of normal cell or
of malignancy may be millimeters away from the tis- with prognosis. Such analyses and correlations most
sue sampled but useless for diagnosis if missed. The commonly begin with frozen and then permanent
sampling problem is illustrated in a study of 1000 sam- (paraffin) sections stained with a general stain for
ples taken from 50 supratentorial gliomas: each sam- nuclei and cytoplasm like hematoxylin and eosin,
ple was interpreted independently of the others (Paulus followed by additional analytic methods when nec-
and Peiffer, 1989). Different specimens of the same tu- essary (Hart and Earle, 1973; McKeever and Spicer,
mor varied depending upon the heterogeneity of that 1987; Perentes and Rubinstein, 1987; Mrak, 1997).
particular tumor. Variations in different samples of the This chapter focuses on the additional analytic
same tumor diverged as widely as grade II oligoden- methods.
TABLE 15.1 Selected Immunohistochemical Stains to Identify CNS Tumors
Antigen/Antibody/Lectin Principal Tumors (Tissue) References
A6 (CD45RO) T lymphoma (T lymphocytes) Davey et al., 1990

Alpha fetoprotein (AFP) Embryonal carcinoma; endodermal Kurman and Scardino, 1981;
sinus tumor Bjornesson et al., 1985
Chromogranin Pituitary adenoma; paraganglioma Lloyd et al., 1988
(neuroendocrine cells)
Common leukocyte Lymphoma; germinoma (leukocytes) McKeever and Balentine, 1987;
antigen (CLA) Neuwelt et al., 1986
Cytokeratin (LMW Carcinoma; craniopharyngioma; chordoma; McKeever and Spicer, 1987;
CAM5.2; HMW 903, K576) epithelial cysts (epithelium) Thomas and Battifora, 1987
Desmin [Muscle-specific actin] Rhabdosarcoma; medullomyoblastoma; Biggs and Powers, 1984;
teratoma (muscle) Chowdhury et al., 1985
Epithelial membrane Carcinoma; meningioma; epithelial Meis et al., 1986;
antigen (EMA) cysts (epithelium) Andrew and Gradwell, 1986
Glial fibrillary acidic Glioma; (gliosis, astrocytes) Jessen et al., 1984;
protein (GFAP) Cáccamo and Rubinstein, 1997;
McKeever, 2000b
HMB 45 (Melen A) Melanoma; melanocytic tumors Thomson and Mackie, 1989
(melanocytes)
Human chorionic Choriocarcinoma; (placenta) Kurman and Scardino, 1981;
gonadotropin (HCG) Bjornsson et al., 1985
KP-1 (CD68) [Ham 56] Histiocytosis; myeloid/monocytic Ruco et al., 1989;
leukemia (macrophages) Warnke et al., 1989
L-26 B lymphoma (B lymphocytes) Davey et al., 1990
Leu-7 (HNK-1) (better Glioma; Schwannoma (gliosis, myelin) Perentes and Rubinstein, 1985, 1986
fixed w/ethanol)
Neurofilament Ganglion-cell tumors; neurofibroma; Gould et al., 1990;
pineocytoma; PNET (CNS parenchyma) Trojanowski et al., 1984
Pituitary peptides Pituitary adenoma (adenohypophysis) McKeever and Lloyd, 1997
Placental alkaline phosphatase Germ-cell tumors (placenta) McKeever, 1999
Prostate-specific antigen Prostatic carcinoma (prostate) Lynes et al., 1986;
Aumuller et al., 1990
S-100 protein Glioma; PNET; melanoma; Schwannoma; Nakamura et al., 1983;
neurofibroma; renal-cell carcinoma; histiocytosis; Abenoza and Sibley, 1986;
chondroma; chordoma (CNS parenchyma) Cochran and Wen, 1985
Synaptophysin Neuroendocrine tumors; PNET Gould et al., 1990;
(CNS parenchyma) Miller et al., 1993
Transthyretin Choroid plexus tumors Herbert et al., 1990
Ulex europaeus (UEA) Hemangioblastoma; angiogenic tumors McComb et al., 1982;
lectin [Factor VIII] (endothelium) Ordonez and Batsakis, 1984;
Feldenzer and McKeever, 1987
Vimentin Many tumors; excessive Ag in some Perentes and Rubinstein, 1997
meningiomas
These immunoperoxidase, immunofluorescent, and lectin stains assist the morphologist in classifying diagnostic categories of tumors found in the central ner-
vous system. Diagnostic categories are in large part based upon presumed lineages of neoplastic cells.
Source: Table adapted from McKeever PE, Blaivas M. The Brain, Spinal Cord and Meninges. Chapter 10 in: Sternberg SS, Antonioli DA, Carter D, Mills SE,
Oberman HA, eds. Diagnostic Surgical Pathology, 2nd Edition. New York: Raven Press, 1994:409–492.
274
TABLE 15.2 Patterns of CNS and Meningeal Neoplasia

Pattern Differential Diagnosis*
Cells infiltrating CNS parenchyma Margin of gliomas, lymphoma

Cells with distinct cytoplasm; fibrillar† cells Gliomas; Schwannoma; ganglioglioma; gliosarcoma; fibrous meningioma;
hemangioblastoma‡; melanoma; pineocytoma; sarcoma
Syncytial cells; hemangiopericytoma; choriocarcinoma Meningioma
Epithelioid§ cells Carcinoma; melanoma; craniopharyngioma; hemangioblastoma; chordoma;
paraganglioma; choroid plexus papilloma/carcinoma; ependymoma;
oligodendroglioma; pituitary adenoma; germ-cell tumor; medulloepithelioma
Fat Lipoma/liposarcoma
Cartilage Chondroma/chondrosarcoma
Crowded malignant nuclei and little cytoplasm Medulloblastoma/pineoblastoma/PNET; small-cell carcinoma; lymphoma;
rhabdosarcoma/medullomyoblastoma; leukemia
More than one of the above cell types Ependymomas; oligoastrocytoma; transitional meningioma; desmoplastic
medulloblastoma; germinoma; choriocarcinoma; teratoma
*Differential diagnosis of neoplasms that produce the pattern of CNS abnormality indicated on the left.
†The term “fibrillar cells” indicates cells that extend cytoplasmic processes bound by plasma membranes. Fibrillar cells may be unipolar, bipolar, or multipolar.
‡While not composed of fibrillary cells, hemangioblastomas appear fibrillary on frozen sectioning when lipid in stromal cells is released.
§The term “epithelioid” indicates cells with distinct cytoplasm and nonfibrillar cell margins which resemble epithelial cells.
Source: Table adapted from McKeever PE, Blaivas M. The Brain, Spinal Cord and Meninges. Chapter 9 in: Sternberg SS, Antonioli DA, Carter D, Eggleston
JC, Mills SE, Oberman HA, eds. Diagnostic Surgical Pathology. New York: Raven Press, 1989:320–321.
Most Common Methods of Cell-Type Identification 1997; McKeever, 1999). Electron microscopy has pro-
vided integral features defining new variants of these,
The three most commonly used methods of identifying like clear cell ependymoma and central neurocytoma.
cells are histochemistry, electron microscopy, and Many neuronal tumors are not stained by antineuro-
immunohistochemistry. Immunohistochemistry is the filament antibodies. This plus variable specificity of an-
newest of these modalities and in most need of review. tisynaptophysin in different laboratories recommends
Immunohistochemistry will be examined in detail, af- electron microscopy as an attractive alternative for
ter we briefly look at histochemistry and electron mi- proving neuronal features.
croscopy. Electron microscopy is challenged by newer immuno-
histochemical methods. The challenge is epitomized by
Histochemistry the intermediate filament. Ultrastructural differences
between these 8–10-nm-diameter filaments are some-
Histochemistry is less costly than immunohistochem- times too subtle to distinguish tumor cell phenotypes.
istry. Most interpretations of brain tumors begin with However, immunochemical differences in glial, muscu-
the hematoxylin stain for nuclei plus the eosin stain for lar, and epithelial filaments are readily detected by im-
tissue (H&E stain). Standard additional histochemical munohistochemistry with monoclonal antibodies spe-
stains are adequate for certain differentials. These in- cific for subtypes of these intermediate filaments
clude distinguishing tumors with collagen and reticulin (Perentes and Rubinstein, 1987; Caccamo and Rubin-
and identifying mucin and melanin (McKeever and stein, 1997; McKeever, 1999).
Balentine, 1987; McKeever, 1999). As additional epitopes are specifically localized im-
munohistochemically, the role of electron microscopic
analyses of CNS tumors will be further challenged.
Electron microscopy
However, the present perspective does not exclude elec-
The differential diagnosis may warrant ultrastructural tron microscopy from tumor analyses, because it has
analysis if brain tumors with distinct ultrastructural specific capabilities, which surpass those of known al-
features are favored. Such features include ependy- ternatives. One is the additional information it pro-
moma (Fig. 15.6C), meningioma, schwannoma, and vides. In contrast to immunohistochemistry, electron
neuronal tumors (Russell and Rubinstein, 1989; Burger microscopy provides additional structural information
et al., 1991; Burger and Scheithauer, 1994; Mrak, beyond the presence or absence of the requested
marker. For example, while an antidesmin immuno-

histochemical stain shows the presence or absence of
desmin, electron microscopy demonstrates numerous
other cellular constituents not necessarily considered
when the procedure was ordered. Thus, if initial in-
spection of a neoplasm raises the question of muscular
origin, an immunoperoxidase stain negative for desmin
would give little additional information other than “no
evidence of desmin.” The same neoplasm examined by
electron microscopy might reveal whorls and con-
densed masses of intermediate filaments suggesting
rhabdoid tumor (Biggs et al., 1987). Another neoplasm
negative for desmin by immunohistochemistry might
show a basal lamina around each spindle cell and long-
spaced collagen suggesting a schwannoma, yet another FIGURE 15.2 The avidin–biotin conjugate (ABC) immunoperoxidase
tumor might display the interdigitating cellular mem- method of localizing antigens. This star-shaped cell with three neo-
branes and desmosomes of a meningioma (Burger et plastic nuclei contains glial fibrils composed of strings of GFAP mol-
al., 1991; Mrak, 1997; McKeever, 1999). Unlike the ecules (g). To localize this GFAP, reagents are applied sequentially
with rinsing of the tissue section between applications of antibodies
“yes–no” answer from immunohistochemistry, electron (McKeever and Balentine, 1987). The primary anti-GFAP antibody
microscopy provides this complementary view of the binds a GFAP epitope. The secondary anti-immunoglobin (anti-Ig)
“subcellular forest” even to the diagnostician barking antibody has been biotinylated (i.e., biotin has been chemically linked
up the wrong tree. to it). If the primary antibody is mouse monoclonal anti-GFAP, then
the biotinylated (B) secondary antibody could be horse anti-mouse
Ig. Avidin (A), an egg-white protein that binds the vitamin biotin
very strongly, links the biotinylated secondary antibody to biotinyl-
Immunohistochemistry ated horseradish peroxidase (pxase). After rinsing again, the pxase can
Methods. Glial fibrillary acidic protein (GFAP) is the be colored brown by its enzymatic oxidation of diaminobenzidine
most specific marker of gliomas, especially astrocy- (DAB). From McKeever (2000b).
tomas and ependymomas, available today. Figure 15.2
depicts the sensitive and reliable avidin–biotin conju-
gate (ABC) method of localizing GFAP. The ABC binding strengths to different epitopes on an antigen.
method can be used to localize any tissue antigen for Thus, some of these are “bound” to detect the target
which a primary antibody is available. The primary an- antigen in an immunohistochemical procedure; how-
tibody is the first antibody applied to the tissue section. ever, some may also cross-react with other antigens.
It binds an epitope on the antigen itself, in this case Thus, polyclonal antibodies tend to be quite sensitive—
GFAP. A molecular bridge then links this bound anti- useful in detecting low levels of labile antigens but not
body with a label that can be seen, in this case a sub- as specific as monoclonal antibodies. Monoclonal an-
strate of the horseradish peroxidase (HRP) enzyme. tibodies are selected by a process that provides identi-
One of the best substrates is diaminobenzidine (DAB). cal antibodies with a single binding strength to one epi-
When oxidized by HRP, DAB produces a brown, highly tope. Ideally, this epitope and binding strength would
insoluble reaction product at the site of localization of be the best possible to localize the target antigen and
the antigen. The ABC method can achieve maximal sen- survive the numerous rinses inherent in the immuno-
sitivity and minimal background because the relatively histochemical method (McKeever and Balentine, 1987;
small avidin (68,000 M.W.) and biotin (244 M.W.) McKeever, 2000a). This, in fact, is rarely the case. The
molecules bind extremely tightly in a 4:1 ratio (Shi et result is usually high specificity for an epitope and less
al., 1997). The high affinity of avidin for biotin allows cross reaction with other antigens but relatively low
extensive rinsing between steps in the procedure to de- sensitivity for the target antigen. The clever diagnosti-
crease background without compromising sensitivity, cian can thus choose which is most important to de-
and avidin’s ability to bind four biotin molecules protect a given antigen.
vides amplification. A contemporary strategy to increase sensitivity while
The availability of both polyclonal antisera raised in retaining the specificity of monoclonal antibodies has
domesticated animals and monoclonal antibodies from been to produce a “cocktail” of monoclonal antibod-
rodents provides different tools for identifying cell types ies. Careful testing on antigen-negative control tissues
in tumors. As the name implies, polyclonal antisera are is needed to ensure that specificity has not been com-
a mixture of numerous antibodies with a variety of promised by such an oligoclonal mix. For example,
addition of AE1/3 to an anticytokeratin cocktail risks A

staining of astrocytes by cross reaction with GFAP
(Color Fig. 15.3A in separate color insert, and Fig.
15.3A–C).
Special immunoreactivity and pitfalls to interpreta-

tion. Table 15.1 alphabetically lists more than 20 im-
munohistochemical stains important in evaluating neu-
rosurgical tumors (plus alternatives in brackets). The
majority use monoclonal antibodies, but GFAP and
S-100 are detected with polyclonal antibodies. This sec-
tion includes comments about application and inter-
pretation of individual markers and specific exceptions
to these tabulated data.
The original source of many immunohistochemical B
antigens was a differentiated cell of specific lineage.
While the neoplastic counterparts of these non-
neoplastic cell lineages often express the expected anti-
gens, this marker fidelity is not universal. Neoplasms
may express unusual antigens (McKeever et al., 1984;
Stanton et al., 1987; Mork et al., 1988). For example,
primitive neuroectodermal tumors (PNETs) of the CNS
may express intermediate filaments commonly found
in carcinoma, muscle tumors, gliomas, and neuronal
neoplasms (Gould et al., 1990). Thus, the isolated ap-
plication of one or two of these markers without con-
sideration of clinical and morphologic features could
result in misinterpretation of a PNET. Individual glio-
blastomas and gliosarcomas produce focal cellular C
clusters positive for cytokeratin (Mork et al., 1988).
Some schwannomas and neurofibromas contain GFAP-
positive regions (Stanton et al., 1987). These examples
underscore the importance of viewing immunohisto-
chemical results in a morphologic context and as part
of a panel of suitable markers rather than in isolation.
In contrast to the aforementioned true neoplastic and
biologic variation, AE1/3 anticytokeratin antibodies
cross-react with GFAP in many systems. This can make
gliomas appear to be cytokeratin positive when they
are not (Color Fig. 15.3A in separate color insert, and
Fig. 15.3A–C). Cross-reacting epitopes, from a diag-
nostic viewpoint, are a hindrance. To choose the deci-
FIGURE 15.3 Three sections of a GFAP-positive high-grade astrocy-
sive diagnostic marker, seek immunohistochemical
toma. (A) is stained for GFAP. See also Color Figure 15.3A. (B) is
reagents with phenotypic purity of reactivity. In con- stained with a monoclonal antibody “cocktail” for cytokeratin that
trast to AE1/3, CAM5.2 is nonreactive with the inter- contains AE1/3, demonstrating cross-reactivity of AE1/3 for GFAP.
mediate filaments in astrocytomas. Thus, it is a pre- (C) is stained with CAM 5.2 monoclonal antibody, showing that this
ferred immunohistochemical stain for distinguishing glioma is actually cytokeratin negative. From McKeever (2000b).
nonglial epithelial neoplasms from gliomas (Table 15.1).
Monoclonal antibodies can be produced that avoid While all of the immunohistochemical reagents in
cross reactivity, which is more common in polyclonal Table 15.1 react with deparaffinized tissue, certain epi-
antibodies. A systematic study of glioma reactivities topes are affected by combined formalin fixation and
with 35 monoclonal antibodies to intermediate fila- paraffin embedding (Holund et al., 1981). Antigen res-
ments (Franke et al., 1991) assists the choice of opti- cue with individualized buffers, heat, and detergent aids
mal reagents for specific diagnostic problems. visualization of some of these epitopes (Shi et al., 1997).
In specific diagnostic situations, phenotypic markers treatable embryonal counterpart, medulloblastoma.

aid prediction of prognosis by specifying a subtype While one study found better prognosis among patients
within a phenotypically variable group of tumors. Al- with undifferentiated medulloblastomas (Packer et al.,
pha fetoprotein (AFP) (Fig. 15.4A), ectodermal mark- 1984), another found better prognosis among patients
ers, and human chorionic gonadotrophin (HCG) iden- with medulloblastomas having glial differentiation
tify elements of mixed germ cell tumor (endodermal (Goldberg-Stern et al., 1991).
sinus, teratomatous, embryonal, and choriocarcinoma-
tous) (Table 15.1) in germinomas (Color Fig. 15.4B in Combining analyses to interpret a neoplasm. A va-
separate color insert; Fig. 15.4B). These elements indi- riety of highly specific immunohistochemical markers
cate a poorer prognosis compared to pure germinoma. can be combined with standard approaches to interpret
Some secrete markers like AFP and HCG that can be a difficult CNS tumor. The recommended approach is
monitored in body fluids for tumor recurrence. to formulate a differential diagnosis based upon its neu-
GFAP highlights astrocytic elements that warn of tu- roanatomic location and cell type (Table 15.2), which
mor progression in oligodendroglial and neuronal tu- should indicate an appropriate combination of mark-
mors (Burger and Scheithauer, 1994; McKeever, 1999). ers to dissect the differential. Brain parenchyma, ven-
Positive mesenchymal and epithelial markers distinguish tricles, meninges, pineal, sellar, and central pontine
the malignant teratoid/rhabdoid tumor from its more angle regions harbor different groups of tumors. De-
termining whether the neoplastic cells extend fibrillar
cytoplasmic processes (Fig. 15.1B), resemble a syn-
A cytium, or form cohesive aggregates of epithelioid cells
(Fig. 15.5A; Color Fig. 15.5A in separate color insert)
can narrow the possibilities significantly (McKeever,
1999). The size of the neoplastic cells is also impor-
tant, particularly since a number of different malignant
tumors are primarily composed of small, crowded,
anaplastic cells. Finally, neoplasms composed of mixed
cell types comprise a general category (Table 15.2). Ad-
ditional distinguishing histologic features including de-
gree of anaplasia, mitoses, necrosis, cellular inclusions,
extracellular material and rosettes may significantly
narrow the differential (Burger et al., 1991; McKeever
et al., 1997; McKeever, 1999). This differential diag-
nosis suggests the most appropriate panel of immuno-
B histochemical stains to distinguish the diagnosis. Many
algorithms (Fig. 15.5B) can be generated to work up
to the diagnosis of different types of tumors (Figs.
15.5C, [color] 15.5D, 15.5E, 15.6A–C, 15.7A–C,
[color] 15.7D, 15.7E, and 15.8A,B,; also see color figs.
in separate color insert).
Immunohistochemistry (IHC) sometimes gives an un-
expected result. Staining panels should allow correct
interpretation despite such results. Here are general
guidelines for constructing immunohistochemical pan-
els, which facilitate correct interpretation: (1) Choose
the most decisive marker in the context of alternative
possibilities. GFAP is decisive in a differential between
glioma and meningioma (Table 15.1, Figs. 15.6B,
FIGURE 15.4 Immunoreactivity for alpha-fetoprotein (A) identified an 15.7B). It is not as valuable in distinguishing between
endodermal sinus tumor component mixed with germinoma (B, H&E astrocytoma and ependymoma, since both tumors ex-
stain; see also Color Figure 15.4B) in this biopsy of the pineal region press GFAP (Figs. 15.3A, 15.6B; Color Fig. 15.3A in
in an adolescent male. This subtype of germ cell tumor is more ag-
gressive than pure germinoma, and its discovery means that appro-
separate color insert). Neurofilament (NF) protein dis-
priate therapy and monitoring for recurrence can be initiated. From tinguishes well-differentiated neuronal tumors from
McKeever (2000b). oligodendroglioma and ependymoma, but NF is not
A C
B Oligodendroglioma
+ Glioma
Ependymoma
EM
Medulloepithelioma
FIGURE 15.5 Epithelioid cells in this tumor from the

+/− Transthyretin + CPP parietal lobe of an elderly woman show distinct bor-
ders between one cell and the next. These particular
epithelioid cells are pleomorphic and contain malig-
GFAP + Chordoma, Craniopharyngioma nant nuclear features (A, H&E; see also Color Fig-
ure 15.5A). The algorithm shown in (B) prescribes a
+ S100 way to dissect the differential of a brain tumor com-
posed of epithelioid cells. Nearby sections of the tu-
− CA mor shown in (A) are negative for GFAP (C), abun-
dantly positive for CAM 5.2 cytokeratin (D; see also
+ Adenoma Color Figure 15.5D), and negative for S-100 protein
(E). The algorithm leads to carcinoma (CA). From
+ PitH McKeever (2000b).
− Paraganglioma
− CK +/− CgA
− EMA + Meningioma
+ Melanoma
− HMB45
− Hemangioblastoma
D E
A neurofilament protein (Figs. 15.8A and 15.8B), and

these two neuronal markers can be supplemented by
saving 1–2 mm3 of tissue in glutaraldehyde in case elec-
tron microscopy is needed. (3) Aim for a positive iden-
tification whenever possible. In a differential of neu-
ronal versus ependymal tumor, a positive NF stain is
good evidence of neuronal differentiation (Fig. 15.8A),
but negative NF provides little evidence of ependymal
differentiation even though ependymomas are NF neg-
ative. (So are most other tumors.) For such a differen-
tial, it would be appropriate to include GFAP, since
ependymoma cells are GFAP positive (Fig. 15.6B), or
to identify ependymal features by electron microscopy
(Fig. 15.6C). (4) Confirm that the IHC-positive cells
B are neoplastic, using nuclear and cytologic features
(Color Fig. 15.9A&B). (5) Include positive and nega-
tive tissue controls for each immunostain. This is best
accomplished by sampling a portion of surrounding
normal tissue with the neoplasm in the same block
(Figs. 15.10A,B). This internal tissue control eliminates
variations in fixation and subsequent processing. How-
ever, such sampling is not always possible, so a section
of a standard control tissue of known reactivity is of-
ten substituted. The aforementioned five guidelines fa-
cilitate interpretation and are recommended even when
immunohistochemical staining is used to confirm a sin-
gle, strongly-suspected diagnosis.
C
Analyses demonstrating neoplasia

Markers that highlight neoplastic features in tissue.
Some phenotypic markers have uses other than to iden-
tify a cell. Some markers highlight normal and neo-
plastic tissue patterns to aid diagnosis.
Lectins plus DNA/RNA fluorochromes have been
used to identify specific topographic alterations pro-
duced by pituitary adenomas (McKeever et al., 1985).
Ricinus communis agglutinin (RCA) lectin helps dis-
tinguish normal pituitary from adenoma by accentuat-
ing the fibrovascular stroma. The stroma of normal pi-
tuitary is connected around individual acini in a pattern
FIGURE 15.6 This epithelioid neoplasm is from the spinal cord of a resembling chicken wire (Color Fig. 15.11A in separate
middle-aged man (A). Following the previous algorithm (Figure color insert). The adenoma has less fibrovascular
15.5B), it is GFAP positive (B), making electron microscopy (EM) a
deciding factor in its analysis. EM showed cilia, basal bodies, and
stroma. This stroma is unconnected and does not com-
microvilli that indicate ependymoma (C). Note how the GFAP ac- pletely partition the adenoma cells growing around the
centuates the few cellular processes in this clear cell ependymoma stroma (Color Fig. 15.11B in separate color insert). Un-
(B). From McKeever (2000b). connected stroma of adenoma looks different than con-
nected normal stroma with labeled RCA lectin or other
positive in all neuronal tumors. (2) Provide supple- markers of extracellular matrix (Weiss et al., 1990).
mental markers to corroborate staining. For gliomas, The normal topography of brain is striking when
S-100 protein and Leu-7 supplement GFAP, since most viewed with the neurofilament stain which highlights
GFAP-positive neoplasms will express these other anti- axons: it appears as a complex conduit of straight lines,
gens. For neuronal tumors, synaptophysin supplements parallel in white matter. A counterstain for nuclei like
A B
C D
FIGURE 15.7 This epithelioid neoplasm is a large lumbosacral mass

in a middle-aged woman. Its nuclei are regularly round to oval and
heavily speckled with chromatin (A, H&E). Following the previous
algorithm (Figure 15.5B), it is negative for GFAP (B), for cytokera-
tin (CK; C), for HMB45 (not illustrated), and for chromogranin A
(CgA; D). See also Color Figure 15.7D. Its positive epithelial mem-
brane antigen expression (E) led to the diagnosis of meningioma. It
was also positive for vimentin (not illustrated). This epithelioid vari-
ant of meningothelial meningioma demonstrates that not all samples
of meningiomas appear syncytial. From McKeever (2000b).
hematoxylin is extremely valuable in identifying histo- Demonstrating a monoclonal proliferation of neo-

logic relationships and in distinguishing neoplastic nu- plastic cells. Most of the markers listed in Table 15.1
clei. Viewed together, neurofilament-stained axons and are not effective in distinguishing neoplasm from nor-
hematoxylin-stained nuclei reveal neoplastic cells infil- mal. However, there are exceptions to this general-
trating brain tissue (McKeever, 2000). Diffuse gliomas ization. Certain groups of immunohistochemical
are readily apparent with this stain combination (Fig. markers distinguish a monoclonal neoplastic prolif-
15.12A). It is important to distinguish these from non- eration from a normally heterogeneous cell popula-
infiltrating gliomas that usually have a better progno- tion. Such is the case with the pituitary peptide hor-
sis (Fig. 15.12B). mone markers. Most pituitary adenomas express a
A lambda B cells) (Fig. 15.14A). To confirm malignant

B cells, a good hematoxylin nuclear counterstain on the
immunostained slide is recommended (Fig. 15.14B).
Cells with cytologic anaplasia including clumped and
marginated nuclear chromatin, mitoses, and karyor-
rhexis will share a single immunophenotype, distin-
guishing them from polyclonal reactive lymphocytes
with smaller nuclei, even when reactive lymphocytes
accompany the lymphoma.
In most cases immunohistochemical stains are suffi-
cient to demonstrate and subclassify pituitary adeno-
mas and brain lymphomas. For rare cases refractory to
immunohistochemical analysis, assays of messenger
RNA are available. For lymphomas, gene rearrange-
B ment can be assayed. These possibilities are addressed
in the next two sections.
FIGURE 15.8 This fibrillar and highly cellular tumor from the cere-
bellum of an elementary school age girl was positive for both neu-
rofilament (NF) protein (A) and synaptophysin (not illustrated). An-
other tumor from the cerebellum of an elementary school age boy
was only synaptophysin positive (B), and lacked NF protein (not il- B
lustrated). Neoplastic cells in both tumors were negative for GFAP,
common leukocyte antigen (CLA), and cytokeratin (CK) (not illus-
trated). By the algorithm in (C), both tumors are medulloblastomas.
From McKeever (2000b).
single hormone detectable by immunohistochemistry

(Fig. 15.13A–C). Less common than these, mixed
adenomas express a discrete oligoclonal subset (i.e.,
prolactin and growth hormone) of hormone products
(McKeever and Spicer, 1987; McKeever and Lloyd,
1997). Thus, the monoclonality (or oligoclonality) of
their hormone product distinguishes adenomas from
normal adenohypophysis and its variety of different
FIGURE 15.10 The first time this tumor in the left parietal lobe of a
secretory cells. young woman was stained for S-100 protein (A), it appeared nega-
Monoclonal proliferations of myelomas and lymph- tive. However, a tiny fragment of brain tissue (arrow) was present
omas have been demonstrated with immunoglobulin, in the corner serving as an internal control. Brain is highly S-100
light-chain, and lymphocyte-subset markers (Garvin et protein positive, but this piece did not stain, implicating a problem
with this staining batch. When the stain was repeated on another
al., 1976; Mason and Biberfield, 1980; Warnke and
section of this tumor, the brain fragment was positive (B). This re-
Rouse, 1985). The majority of primary CNS lymph- peat also stained the tumor, leading to the diagnosis of melanoma
omas are B lymphomas, which may be distinguished (with the subsequent help of a positive HMB45 stain, and ultimate
by their monoclonal nature (i.e., L-26, kappa, or discovery of a cutaneous melanoma). From McKeever (2000b).
A Markers of Ig chains do not always work well on

lymphomas. For Ig-subset identification, in situ hy-
bridization has been recommended to localize specific
messenger RNAs (mRNAs) for kappa and lambda im-
munoglobulin light chains in sections of paraffin-
embedded tissue (Weiss et al., 1990). This allows as-
FIGURE 15.12 The neurofilament immunohistochemical stain high-

lights axons in brain, facilitating evaluation of glioma infiltration
into brain tissue. Crowded round nuclei of an oligoastrocytoma dif-
fusely infiltrate between long axonal constituents of the underlying
brain tissue (A). In contrast, this pleomorphic xanthoastrocytoma
does not infiltrate between axons, and its margin with brain is dis-
tinct (B). From McKeever (2000b).
C
In situ mRNA hybridization. The detection of mes-
senger RNA codes for phenotypic markers is theoreti-
cally attractive for the diagnosis of neoplasms with lit-
tle or no expression of the suspected protein antigen.
Applied to pituitary adenomas, appropriate mRNA mes-
sages detected by in situ hybridization correspond with
their encoded peptide hormones, which are localized
immunohistochemically (Lloyd et al., 1989, 1990).
However, in situ hybridization showed increased sensi-
tivity compared to immunohistochemistry in detecting
the potential for growth hormone production by an ad-
enoma from a patient with acromegaly (Lloyd et al.,
1989). This case suggests that phenotypic analyses of pi-
tuitary adenoma mRNAs may reveal a capacity for hor- FIGURE 15.13 This pituitary adenoma produces prolactin (A), but not
growth hormone (B) nor adrenocorticotrophic hormone (ACTH;
mone production missed by immunohistochemistry in
[C]). Its monoclonal hormone product contrasts with the rim of mul-
certain cases in which the adenoma may either secrete tihormonal adenohypophysis below the adenoma compressed at its
immunoreactive hormone immediately upon production margin. Semi-serial sections from the same block of tissue. From Mc-
or produce hormone with low immunoreactivity. Keever (2000b).
A with Southern blot hybridization (Bayliss et al., 1990).

While it is good that these molecular techniques are
available if needed, L26 and A6 immunohistochemistry
plus H&E slides are sufficient for most primary brain
lymphomas.
The advent of immunohistochemical and oligonu-
cleotide reagents of much higher specificity than stan-
dard histochemical stains affords a bright future as in-
vestigators find ways to increase their sensitivity. Such
reagents may be combined with morphologic expertise
to solve critical diagnostic problems in neuropathology.
Contributions of cell-type identification to

diagnosis, treatment, and prognosis
B
Ultrastructural and immunohistochemical (IHC) meth-
ods have identified specific pathologic entities. The pri-
mary brain lymphoma and the giant cell glioblastoma
are such entities, redefined from among a diverse group
of “sarcomas.”
The primary brain lymphoma was originally classi-
fied as a reticulum cell sarcoma or microglioma. Elec-
tron microscopy and IHC for immunoglobulins re-
vealed their true phenotype (Garvin et al., 1976).
Today, there are specific B-lymphocyte cell-surface IHC
markers like L26 (CD20) that are more reliable for di-
agnosis on paraffin sections (Fig. 15.14B) than IHC
with anti-immunoglobulin antibodies. Malignant cells
FIGURE 15.14 The diagram (A) depicts L-26 and kappa light that express L26 and lack T-cell markers indicate the
chain lymphoma cells growing among lymphocytes. Cells with ma- tumor is a B-cell lymphoma (McKeever, 1999).
lignant nuclei stained with hematoxylin are B-lymphoma cells posi- For decades a brain tumor with remarkably large ma-
tive on their surfaces for the L-26 B-cell marker (B). These cells were lignant cells was considered to be a “monstrocellular
kappa positive (not illustrated). They were negative for T-cell and
macrophage markers (not illustrated). From a right temporal-
sarcoma.” However, the IHC stain for glial fibrillary
parietal tumor in a middle-aged man. From McKeever (2000b). acidic protein (GFAP) clarified its true nature (Color
Fig. 15.15 in separate color insert). Its large malignant
cells are GFAP positive, indicating the diagnosis of
giant cell glioblastoma (McKeever, 1998). GFAP is the
sessment of clonality in tissues, which are refractory to most specific marker of gliomas, especially of astrocy-
immunohistochemical analyses. tomas and ependymomas, available today.
For many decades, central neurocytomas were inter-
Analysis of gene rearrangements. This method is preted to be gliomas (Fig. 15.16A, B; see Color Fig.
applied to lymphocytes, which undergo genotypic re- 15.16B in separate color insert). The benign nature of
arrangements in the process of their normal phenotypic these neuronal tumors was not recognized, and some
diversification. Normal and reactive lymphocyte pop- were seriously overtreated with radiation when surgi-
ulations are polyclonal, producing numerous different cal excision would have sufficed. Today, these neuronal
rearrangements. A lymphoma produces a monoclonal tumors (Fig. 15.16A, C; Table 15.1) can be recognized
proliferation of a single rearrangement. A monoclonal with IHC for molecules expressed by neurons like
proliferation of one of these rearranged cells will am- synaptophysin, which distinguish them from gliomas
plify a specific DNA pattern above the heterogeneous (Figs. 15.16B, D; see Color Fig. 15.16B in separate
background of numerous other rearrangement pat- color insert) (Table 15.1).
terns. This pattern is detectable after digestion with re- Oligodendrogliomas have a better prognosis than as-
striction endonucleases, which cleave DNA at specific trocytomas, and many oligodendrogliomas are sensi-
nucleotide sequences; with agarose electrophoresis; and tive to treatment with procarbazine, lomustine, and vin-
A B
C D
FIGURE 15.16 Central neurocytomas and oligodendrogliomas are virtually indistinguishable on H&E
stains (A and B). See also Color Figure 15.16B. However, the central neurocytoma cells are synapto-
physin positive (C) and GFAP negative (not illustrated). In contrast, this oligodendroglioma has GFAP-
positive microgemistocytes (D) and is synaptophysin negative (not illustrated). Reproduced, with per-
mission, from McKeever (1998). Insights about brain tumors gained through immunohistochemistry and
in situ hybridization of nuclear and phenotypic markers. J Histochem Cytochem 46:585–594.
cristine (PCV) chemotherapy. This places a premium cific diagnostic categories of brain tumors with the
on recognition of oligodendrogliomas. GFAP stain dis- most variable range of prognoses. These proliferation
tinguishes microgemistocytes of oligodendrogliomas markers are discussed in the next section.
with their cytoplasmic round globules of GFAP im-
munoreactivity (Fig. 15.16D) from the elongated GFAP-
Measures of Proliferative Capacity
positive cellular processes of astrocytomas. GFAP-neg-
ative and Leu 7–positive cells with round nuclei are The standard histologic method for estimating prolifera-
common in oligodendrogliomas. tive capacity of a neoplasm has been its mitotic index.
A few gliomas are resectable (McKeever, 2000b). Histological assessment of mitoses is one of multiple cri-
Newer antineurofilament stains coupled with ABC im- teria used to grade malignancy of gliomas (Figs. 15.1B
munoperoxidase identify axons in gray and white mat- and 15.3C) (Daumas-Duport et al., 1988; Kleihues and
ter well enough to assess glioma margins for their sur- Cavenee, 2000). However, many primary brain tumors
gical resectability (Figs. 15.12A, B). In gray matter, contain so few mitoses that obtaining an accurate mitotic
synaptophysin staining of the neuropil can also be used index is an arduous process in large samples of tissue,
to assess glioma margins (McKeever, 2000c). and an impossible one in stereotactic biopsies. This
Assessment of cellular proliferation with immuno- dilemma is ameliorated by new methods which provide
histochemical methods more sensitive than mitotic in- a more complete assessment of proliferative phases of the
dices holds promise in assessing prognosis of the spe- cell cycle (Color Fig. 15.17 in separate color insert).
Proliferative phases of the cell cycle are composed of

G1-phase cells preparing to make DNA, S-phase cells
making DNA, and G2-phase cells preparing to mitose,
plus cells actually undergoing mitoses (M phase). Mi-
tosing cells represent only a small fraction of the cells
in proliferative phases of the cell cycle. This fraction
may not be a reliable indicator of the whole pool of
proliferating cells due to individual variations in length
of the various cell-cycle phases (Germano et al., 1989).
Assays other than the mitotic index quantitate a
larger and more representative portion of proliferating
FIGURE 15.19 Survival plots of glioblastoma patients with high
cells than mitoses (Figs. 15.18, 15.19, 15.21–24; also
(15%) and low (15%) S-phase cells assessed from flow cytome-
see Color Figs. 15.17 and 15.20 in separate color in- try of their tumors. Plot of data from McKeever et al. (1998); figure
sert). Flow cytometry and cytophotometry are com- from McKeever (2000b).
puterized optical measuring systems useful to measure
either DNA or the other markers described here. The
proliferation antigens have major clinical relevance,
and MIB-1 is the best available to date. The MIB-1 an- its cell-cycle phase (Color Fig. 15.17 in separate color
tibody is highly regarded and being intensively studied insert, and Fig. 15.18) after stoichiometric staining with
as a predictor of patient survival, being easier to em- a fluorescent dye such as propidium iodide (PI) or 4,
ploy than thymidine analogues and other markers. Pro- 6-diaminidino-2-phenylindole (DAPI). DAPI stains
liferating cell nuclear antigen (PCNA) and nucleolar or- DNA. Since PI stains DNA and RNA, it must be used
ganizers are still being studied. These methods of in combination with RNAase enzyme to eliminate in-
assessing proliferation are compared below. terference from RNA.
Since cells which have not entered the proliferative
phase of the cell cycle (G0 phase) contain the same
Flow cytometry
amount of DNA as G1-phase cells, clinical flow cy-
The flow cytometer passes tiny droplets containing in- tometers cannot distinguish these cells. Together they
dividual cells through a laser beam. Light emanating produce a single peak on the left side of the cytofluo-
from these individual cells at angles diverging from the rogram (Fig. 15.18). Another single peak composed of
laser beam are electronically collected and analyzed. G2 phase and mitosing cells accumulates on the right
Since the amount of DNA in a cell doubles between its side of the cytofluorogram. S-phase cells do not pro-
G1 and G2 phase of the cell cycle, its DNA will reflect duce a peak but rather a signal activity above baseline
between the left and right peaks of a diploid cytofluo-
rogram. Computer programs are available to distin-
guish three groups of cells: cells in G0/G1, cells in S,
and cells in G2/M phases of the cell cycle (McKeever
et al., 1990).
In addition to cell-cycle phases, flow cytometry mea-
sures ploidy. Ploidy is determined by the number of
chromosomes per tumor cell. Diploid human cells have
7 pg DNA in 46 chromosomes. Aneuploid cells have
either more or less than 7 pg DNA. This shifts their
peaks either to the right or left on the cytofluorogram.
Aneuploidy confounds signals of cell-cycle phases to a
greater or lesser degree (Frederiksen et al., 1979).
Flow cytometry has revealed that histologically be-
nign brain tumors and good prognosis are associated
FIGURE 15.18 Standard cytofluorogram to measure ploidy with sto-
with diploid cytofluorograms and low percentages of
ichiometric staining of DNA using a fluorescent dye that binds DNA.
Mitosing (M) and G2 phase cells have twice the DNA of G0 and G1 S-phase cells (Frederiksen et al., 1979; Zaprianov and
phase cells. S-phase cells making DNA are spread between the peaks. Christov, 1988). Applied to histologically indistin-
From McKeever (2000b). guishable glioblastomas, less than 15% of S-phase cells
in fresh glioblastoma tissue predicted better than averages of cells above diploid are therefore more difficult
age patient survival (McKeever et al., 1990; Fig. 15.19). with cytophotometry. Some studies do not attempt to
In another study, better prognosis with aggressive sur- distinguish S phase and G2/M phase and combine them
gery is predicted in patients with aneuploid than with as a single parameter of proliferation (Davenport and
diploid medulloblastoma (Tomita et al., 1988). These McKeever, 1987).
studies augment standard histopathologic criteria to
reach a new level of prognostic ability.
Thymidine analogs
Advantages of flow cytometry over other methods
of quantitating cellular proliferation are its ability Bromodeoxyuridine (BUDR) and iododeoxyuridine
to interrogate thousands of cells and thereby increase (IUDR) are halopyrimidine analogue of thymidine that
the statistical level of confidence, and its view of are incorporated into DNA during its synthesis in the
all phases of the cell cycle (Fig. 15.18). Disadvan- S phase of the cell cycle (Color Fig. 15.20 in separate
tages include its absolute requirement for prepara- color insert). Cells that have incorporated one of these
tions of individual cells. The requirement for indi- can be detected with specific monoclonal antibodies af-
vidual cells encumbers preparation of collagenous ter ethanol fixation and treatment of tissue sections to
tumors like meningiomas and schwannomas. Special expose the halopyrimidine epitopes (Wolfgang et al.,
enzyme digestions partially compensate for this dis- 1987) (Fig. 15.21). Since a fraction of all cells of a tu-
advantage. mor will have been in S phase incorporating BUDR dur-
ing the interval of drug exposure, these can be counted
and expressed as a percentage of total cells. This rela-
Cytophotometry
tionship is called the “proliferation index” or “label-
Cytophotometric quantitation of DNA depends upon ing index” (LI). The LI of a halopyrimidine or any of
measuring differences in the attenuation of transmitted the proliferation antigens is the number of antigen-
light. Darkness of stained cells or of sections of tissue positive nuclei divided by the total number of nuclei in
is measured through a microscope on a clean glass slide sampled microscopic areas of the tumor (Fig. 15.21).
and recorded in units of optical density. For determi- Simple microscopic methods facilitate random sam-
nation of amounts of DNA per nucleus, the Feulgen pling (Mukhopadhyay et al., 1990), while sampling
stain is most commonly used (De Reuck et al., 1979; “hot spots” of proliferation is done with a trained eye.
Giangaspero et al., 1987; Davenport and McKeever, In 38 patients with various brain tumors resected af-
1987), which stoichiometrically deposits Schiff’s stain ter a 1 hour pulse of in situ BUDR, increased grades
in place of DNA.
Many aspects of cytophotometry are similar to flow
cytometry. However, cytophotometry has major ad-
vantages. One is its ability to analyze small subpopu-
lations of less than a thousand cells. Individual nuclei
can be quantitated on a standard histologic section, so
it is not necessary to isolate individual cells prior to in-
terrogation.
The topographical capabilities of cytophotometry al-
low separate assessment of histologic subpopulations
of CNS tumors. The most aggressive population in
glioblastomas—the small anaplastic cells—has been
found to be diploid or near-diploid in DNA content
(Giangaspero et al., 1987). The vast majority of cells
in what are commonly called endothelial proliferations FIGURE 15.21 BUDR was administered while this tumor was viable.
of high-grade astrocytic gliomas are diploid, even when The dark nuclei are BUDR positive. The BUDR labeling index (LI) is
the astrocytic parenchyma is aneuploid (Davenport and the total number of dark nuclei divided by the total number of nuclei
McKeever, 1987). (labeled and unlabeled). Immunoperoxidase anti-BUDR with hema-
While computer-assisted image analysis allows quan- toxylin counterstain. Reproduced, with permission, from McKeever
and Blaivas (1994). The brain, spinal cord and meninges. In Sternberg
titation of the amount of DNA in 100–200 nuclei, the SS, Antonioli DA, Carter D, Mills SE, Oberman HA (eds). Diagnos-
sample size of cytophotometry does not approach that tic Surgical Pathology, Second edition, Figure 23, p. 427, vol. 1. Raven
of flow cytometry. Critical determinations of percent- Press, New York.
of malignancy were associated with increased LI

(Hoshino et al., 1986). Studies show increased LI as-
sociated with increased grade of malignancy in gliomas,
and these were associated with decreased survival rate
(McKeever et al., 1997; Nishizaki et al., 1990). In-
creased LI over 1% was associated with higher rates of
recurrence in meningiomas (Nishizaki et al., 1990).
The value of S phase in assessing the proliferative po-
tential of individual gliomas within a single histopath-
ologic category has been recognized. Applied to histo-
logically indistinguishable low-grade astrocytomas,
BUDR LI distinguished two groups with different prog-
nosis independent of other variables (Hoshino et al.,
1993). Patients with astrocytomas having an LI of less
than 1% had better survival than the group with an LI FIGURE 15.22 Astrocytoma immunohistochemically (IHC) stained
greater than 1% (Hoshino et al., 1988). with the ABC procedure for proliferating cell nuclear antigen (PCNA)
Since BUDR and IUDR are different thymidine ana- shows a spectrum of shades of dark nuclei. PCNA-negative nuclei
are counterstained blue with hematoxylin. Paraffin section.
logues, cells can be labeled with sequential pulses of
each analogue. With an anti-BUDR antibody that does
not cross-react with IUDR, the length of S phase and
potential doubling times of tumors can be measured 1994). Other studies have shown PCNA predictive by
from a single biopsy specimen. Potential doubling times univariate analysis only (Theunissen and Blaauw, 1993;
vary from 1 to more than 60 days (Shibuya et al., Ang et al., 1994). PCNA LI may reflect more than cel-
1993a). lular proliferation, since it may be involved in the re-
pair of damaged nonreplicating DNA (Coltrera and
Gown, 1991; Jackson et al., 1994; Aboussekhra and
Proliferation antigens
Wood, 1995; Hoyt et al., 1995).
These are antigens that increase during phases of cel-
lular proliferation (Gerdes et al., 1983; Burger et al., Ki-67 and MIB-1 antibodies. The Ki-67 monoclonal
1986; Prelich et al., 1987; Schroder et al., 1991; Parkins antibody (Gerdes et al., 1983) recognizes a nuclear pro-
et al., 1991; McCormick et al., 1993). Most prolifera- tein present in some G1, S, G2, and M phases of the cell
tion antigens are nuclear antigens. Since a fraction of cycle (Color Fig. 15.17 in separate color insert). The func-
nuclei show the proliferation antigen, these can be tion of this protein is not yet known, and its name refers
counted and related to the remaining cells by an LI sim- to only the city, Kiel, where it was found and its clone
ilar to that described for halopyrimidines (Burger et al., number. There is a nonlinear relationship between the
1986). Unlike halopyrimidines, proliferation antigens Ki-67 LI and mitotic index (Schroder et al., 1991). In a
occur naturally in tissue (Prelich et al., 1987; Garcia et study of Ki-67 expression among 40 brain tumors, higher
al., 1989; McCormick et al., 1993) and do not require LIs were associated with histologically malignant neo-
injecting patients or incubating living tissue in vitro plasms including metastatic carcinomas, anaplastic
with a drug. This facilitates their use in hospital labo- mixed glioma, and some glioblastomas (Burger et al.,
ratories. While proliferation antigens potentially ap- 1986). Ki-67 may help to define tumor cell proliferation
plicable to brain tumors are still being discovered, stud- in serial stereotactic biopsies (Parkins et al., 1991).
ies have concentrated on PCNA/cyclin and Ki-67. Low Ki-67 labeling indices predict longer survival in
groups of patients with various grades of glioma (Jaros
Proliferating cell nuclear antigen. PCNA/cyclin is an et al., 1992; Montine et al., 1994). One study of 36
auxiliary protein to DNA polymerase (Prelich et al., adult patients determined that the Ki-67 LI was more
1987) (Fig. 15.22). It is synthesized in late G1 and S significantly related to survival than the modified
phases of the cell cycle (Color Fig. 15.17 in separate Ringertz histopathologic grading system of astrocytic
color insert). PCNA LI increases with tumor grade gliomas (Montine et al., 1994). The mean Ki-67 LI of
(Revesz et al., 1993). Multivariate analysis of clinico- low-grade astrocytoma differed significantly from both
pathologic indices and PCNA LI of 45 gliomas showed anaplastic astrocytoma and glioblastoma (Montine et
that only PCNA and histopathologic diagnosis inde- al., 1994).
pendently predicted survival (Korkolopoulou et al., Recently, an improved antibody has been developed
FIGURE15.23 Astrocytoma IHC stained with the ABC procedure for B

MIB-1 antibody. MIB-1-negative nuclei are counterstained blue with
hematoxylin. Paraffin section.
that detects Ki-67 epitopes in paraffin sections (Mc-

Cormick et al., 1993) (Fig. 15.23). One study of World
Health Organization grade II–IV gliomas found MIB-
1 more predictive of survival than other proliferation
markers (McKeever et al., 1997). In another study, mul-
tivariate analysis showed MIB-LI to be the only inde-
pendent predictor of survival (Sallinen et al., 1994).
MIB-1 has been found useful in distinguishing long- vs.
C
short-surviving grade II astrocytoma patients (Mc- 1.0
Keever et al., 1998) (Figs. 15.24A–C). It helps distin-
guish grade II from grade III gliomas (Hsu et al., 1997).
0.8
It is better than histology in predicting outcome of
pediatric malignant gliomas (Pollack et al., 1997). It is
important in predicting outcome of oligodendro- 0.6
Probability
gliomas (Kros et al., 1996). In ependymomas, MIB-1

proliferation indices correlate with expression of telo-
merase, the enzyme that maintains chromosome length 0.4
and may immortalize cells (Rushing et al., 1997).
Logrank P-value<.0001
0.2
<=2
Nucleolar organizer regions >2
Nucleolar organizer regions (NORs) are intranuclear sites 0.0
of production of ribosomal RNA. They can be stained 0 2 4 6 8 10 12 14
with silver nitrate–gelatin–formic acid. Stained NORs per Years
nuclear profile can be counted and assessed structurally
FIGURE 15.24 MIB-1 antibody distinguishes grade II astrocytoma
(Kajiwara et al., 1990; Onda et al., 1994b; Louis et al., patients with long and short survival. The first patient with few
1991; Ross et al., 1993). These may provide new possi- brown MIB-1-positive nuclei survived more than 8 years (A). The
bilities for useful ancillary data in distinguishing and second patient with many MIB-1 positive nuclei survived less than
grading gliomas, but more studies are needed to deter- 6 months (B). Hematoxylin counterstains MIB-1-negative nuclei
purple. (C) Survival of grade II astrocytoma patients whose tumors
mine their diagnostic utility. The number of NORs in
had MIB-1 labeling indices of less than or equal to 2% and greater
other brain tumors does not always reflect their growth than 2%. From McKeever et al. (1998); reproduced with permis-
potential as assessed by the proliferative antigens dis- sion from the Journal of Neuropathology and Experimental
cussed previously (Shibuya et al., 1993b). Neurology.
Comparisons of proliferation markers tions conducive to DNA synthesis (Color Fig. 15.25 in
separate color insert). It detects small amounts of DNA,
The sudden abundance of histologic methods for as-
such as those present in a sample of cerebrospinal fluid
sessing proliferating cells raises questions about how
or a small biopsy (Hanson et al., 1990; Louis et al.,
they correlate with one another. Studies show that the
1992; Rhodes et al., 1994). DNA is uncoiled by pre-
LIs obtained with Ki-67 or MIB-1 vary from 1.5 to 2.5
cise heating. It is then cooled in the presence of two
times that of BUDR (Sasaki et al., 1988; Davis et al.,
oligonucleotide primers which flank the DNA segment
1995). This relationship is of course highly dependent
to be amplified, the four deoxynucleotide triphos-
upon the length of the labeling interval with BUDR.
phates, and heat-stable DNA polymerase. The oligo-
MIB-1 labeling indices correlated closely with BUDR
nucleotide primers are very short strands of DNA of
LI in 90 cerebral gliomas in one study (McKeever et
specific sequences which bind their natural counter-
al., 1997) and in 20 glioblastomas in another (Onda
parts and start amplification of the desired DNA seg-
et al., 1994a), except in regions of pseudopalisading
ment. Heating and cooling is repeated for many cycles,
with necrosis. Anti-PCNA showed a lower level of cor-
doubling the desired DNA segment with each cycle. The
relation with flow cytometric or BUDR criteria of pro-
strength of the PCR method is its incredible amplifica-
liferation than MIB-1 did (Sasaki et al., 1992; Hoyt et
tion, which facilitates subsequent recognition of ab-
al., 1995). Nucleolar organizer regions do not corre-
normal DNA sequences. It detects specific DNA se-
late closely with BUDR or Ki-67 (Shibuya et al.,
quence abnormalities in tumors (Roberts and Storch,
1993b).
1997) including loss of heterozygosity of chromosomal
Studies have attempted to determine the one prolif-
DNA (Muhammad et al., 1997) and translocations of
eration marker most predictive of survival. A study of
chromosomal DNA (Sorensen et al., 1993).
astrocytomas of all grades showed that MIB-1 had gen-
Fluorescence in situ hybridization (FISH) stains spe-
erally better prognostic sensitivity and specificity than
cific DNA sequences including repetitive sequences spe-
PCNA or DNA flow cytometry, but all three methods
cific for individual chromosomes (Van Oostenbrugge
had strong prognostic potential (Sallinen et al., 1994).
et al., 1997), whole chromosomes (McKeever et al.,
A study of grade II–IV gliomas found MIB-1 superior
1996), and specific genes. FISH (Color Fig. 15.26 in
to PCNA or BUDR in predicting survival (McKeever
separate color insert) and its immunocytochemical
et al., 1997).
counterpart localized with diaminobenzidine (DISH)
are potential diagnostic markers of brain tumors (Mc-
GENETIC MARKERS Keever and Wang, 1995; Rosso et al., 1997). They de-
tect chromosomal abnormalities in nonmitosing (inter-
Methods Applied to Tissue
phase) nuclei. Glioma progression is associated with
Polymerase chain reaction (PCR) is multiplication of increased aneuploid variation in signals for chromo-
DNA by repetitive heating and cooling under condi- somes 7 and 17 (McKeever and Wang, 1994) (Color
Chromosomal Oncogene Abnormal Stimulation Decreased
Alteration Activation Quantity/Quality of Patient

(Suppressor of Cellular Survival
Gene Gene Proliferation
Deactivation) Product
ANALYTIC METHODS:
Southern Southern Sequencing, Flow Cytometry, Survival

Blot, Karyotype, and Immunostaining Cytophotometry, Statistics
PCR, FISH Northern Blots, Proliferation Ag,
PCR BUDR
FIGURE 15.29 Paradigm of the mechanism by which a chromosomal alteration like the Burkitt’s lym-
phoma translocation (or loss of the RB1 tumor suppressor gene) may produce a neoplasm. From Mc-
Keever (2000b).
(Schröck et al., 1994; Schlegel et al., 1996). Further in-

vestigations with this powerful method are likely to fol-
low. The molecular basis of many CGH observations
remain to be understood.
Common Genetic Abnormalities and

Clinical Significance
Genetic abnormalities induce tumors and drive tumor
proliferation. The assessment of these mechanisms is a
rapidly evolving field. The process is well defined in
Burkitt’s lymphoma (Dalla-Favera et al., 1982). Its
chromosomal alteration is an 8–14 translocation,
FIGURE 15.30 Karyotype of a human glioblastoma. Amid other non- which brings the c-myc oncogene on a piece of chro-
random abnormalities, trisomy 7 and monosomy 10 are particularly mosome 8 near an immunoglobulin gene heavy-chain
characteristic. Reproduced from McKeever et al. (1996), with per-
locus on chromosome 14. This translocation changes
mission from Elsevier Science.
the sequence of the c-myc transcript. Oncogene acti-
vation results, perhaps due to increased stability of the
abnormal c-myc transcript. The increased quality of ab-
Fig. 15.27 in separate color insert). FISH has shown normal c-myc gene product results in stimulation of
malignant cells in CSF (Van Oostenbrugge et al., 1997). proliferation of the Burkitt’s lymphoma cells (Fig.
Comparative genomic hybridization (CGH) employs 15.29). Like a weed in a garden, proliferation produces
FISH in reverse to compare brain tumor DNA with growth of these abnormally proliferating cells, and de-
normal DNA (Color Fig. 15.28 in separate color insert). creased patient survival. Through this chain of events,
Tumor DNA is tagged with one molecule—biotin, for one translocation can influence cellular proliferation.
example. Normal DNA is labeled with another, like Translocations can be detected by PCR once the se-
digoxigenin. Their binding to metaphase spreads of nor- quences around it are known. Although most chromo-
mal human chromosomes is then compared. Many somal translocations of diagnostic significance occur
losses and gains of chromosomal DNA occur in gliomas outside the nervous system at the writing of this chap-
TABLE 15.3 Frequently Abnormal Chromosomes in Human Brain Tumors

Diagnosis Chromosome Abnormality Reference
Ependymoma 22 Monosomy Griffin et al., 1988; Stratton et al., 1989

10,12,17,X* Structural
Glioblastoma 7,19 Trisomy
10,13,14,17,22,Y Monosomy Bigner et al., 1988a; Ransom et al., 1992; Jenkins et al., 1989
1,5,9,17p* Double minute† Structural
Oligodendroglioma 1p,19q Deletion Rosso et al., 1997; Reifenberger et al., 1994; Fortin et al., 1999;
Smith et al., 1999
Medulloblastoma 1,17q* Structural Latimer et al., 1987; Bigner et al., 1988b; Vagner et al., 1994;
Giordana et al., 1997
Peripheral PNET 11q,22q Structural Sorensen et al., 1993
Meningioma 22 Monosomy Maltby et al., 1988
Schwannoma 22 Monosomy NF2‡ Couturier et al., 1990; Honda et al., 1995
*Translocations, rearrangements, partial deletions, or total loss occur in many other chromosomes, and this list is not intended to represent all of them. The
references provide more examples. Especially well-recognized abnormalities are in boldface type.
†Abnormal chromosomal fragments.
‡Loss of chromosome 22 occurs both in neurofibromatosis 2 (bilateral acoustic Schwannomas and propensity to develop other CNS tumors) and in sporadic
Schwannomas (Korf, 1997; Shen et al., 1996). In contrast, the neurofibromatosis 1 (von Recklinghausen’s disease, peripheral neurofibromatosis) gene is in chro-
mosome 17q (Korf, 1997).
Source: Table 3 is from McKeever PE. New methods of brain tumor analysis. In: Mena H, Morrison AL. Thirty-eighth Annual Kenneth M. Earle Memorial
Neuropathology Review, Washington, D.C. Armed Forces Institute of Pathology, 2000.
ter, the 11;22 translocation of peripheral primitive neu- pected by chance alone. Some of these are listed in
roectodermal tumors (pPNET) is a notable exception Table 15.3.
(Sorensen et al., 1993).
The flip side of this neoplastic coin is exemplified by
the retinoblastoma. By comparing incidences of famil- ACKNOWLEDGMENTS
ial and sporadic cases, Alfred Knudson proposed that Drs. Curtis A. Hanson, Ricardo V. Lloyd, Paul S. Meltzer, Susan
familial retinoblastoma is due to hereditary transmis- Sheldon, and Jeffrey M. Trent contributed valuable advice and slides.
Dianna Banka, Laura Hessler, Lisa Collom, and Kimberly Casto skill-
sion of one inactive allele of an autosomal gene (Knud-
fully edited and typed the manuscript. Supported in part by US Pub-
son, 1971). With only one active allele, a single loss of lic Health Services grant R01 CA68545 from the National Cancer
this allele results in the growth of a tumor much more Institute, NIH.
often in familial than sporadic retinoblastoma (Fig.
15.29). Decades after Knudson’s hypothesis, this tumor
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16 CNS tumors (excluding pituitary,
PNET, and embryonal tumors)
JOSEPH E. PARISI, HERNANDO MENA, AND
BERND W. SCHEITHAUER
Gliomas, principally astrocytomas, account for the ma- entiation and dedifferentiation are reflected in the con-
jority of brain tumors. These intrinsic tumors are tent of mature and immature cell forms, respectively,
derived from neuroectoderm and are classified on the that may be present. Neoplasia along more than one
basis of the predominant cell type (astrocyte, oligo- cell line not uncommonly occurs and results in tumors
dendrocyte, or ependymal cell). Although the term with mixed cell populations (mixed gliomas) of almost
glioma applies to all tumors of this group, in practice, every variety imaginable (Hart et al., 1974).
glioma usually refers to an infiltrative glial tumor, gen-
erally a diffuse astrocytoma or oligodendroglioma. Less
commonly, the term glioma has been applied to all tu- DIFFERENTIATION OF A GLIAL
mors of neuroepithelial origin, including those com- FROM A NONGLIAL NEOPLASM
posed of undifferentiated cells, of neuronal elements,
and of mixed cell populations. When presented with a brain tumor, especially in the
Incidence figures vary widely depending upon the pa- frozen section setting, it is useful for the pathologist to
tients studied. Most neurosurgical and neuropatholog- first distinguish a glial tumor from a nonglial tumor,
ical series report an incidence of gliomas as 40%–45% since this will aid the formulation of a differential diag-
of all intracranial tumors (Zulch, 1986; Burger and nosis significantly. In normal brain, the complex inter-
Scheithauer, 1994). Glial tumors are somewhat more mingling of glial and neuronal cell processes results in a
common in men (male:female ratio of 3:2), although delicate fibrillary feltwork background referred to as
as a group these are the most common intracranial neo- neuropil (Fig. 16.1). Although a characteristic of normal
plasms in both sexes. The incidence of gliomas is higher brain, it also is present in tumors of glial origin. Exam-
in children than in adults, accounting for about three- ination of “smear” or “squash” preparations of the bi-
quarters of all primary intracranial neoplasms in sub- opsy usually permits easy identification of the abundant
jects under the age of 15. Childhood gliomas are more cell processes that characterize gliomas (Fig. 16.2).
likely to be infratentorial in location, primarily involv-
ing cerebellum and brain stem, whereas adult examples
are more likely to be supratentorial. Although some re- TUMORS OF ASTROCYTIC ORIGIN
ports have suggested an increasing incidence of primary
brain tumors in recent years, particularly malignant Neoplasms originating from astrocytes constitute the
gliomas, careful population-based studies have indi- largest, most diverse, and most complex group of glial
cated that this “apparent” increase actually is a reflec- tumors. For any individual case, clinical behavior is
tion of improvements in diagnosis (Radharkrishnan et dependent upon several parameters, which include
al., 1995). not only histologic characteristics, but also relative
Most systems for classifying gliomas (as is the case circumscription (“diffuse” vs. “circumscribed” growth
for other tumors in general) are based upon the pur- pattern), topographical location and geometry, surgi-
ported cell of origin (histogenic hypothesis) and rest cal accessibility, and intrinsic biological features of the
upon the recognition of similarities between neoplastic tumor (see below).
cells and their “normal” glial counterparts in the de- Two major types of astrocytes are present in the nor-
veloping or mature nervous system. Degrees of differ- mal brain: fibrillary and protoplasmic. Most numerous
298
16: CNS TUMORS (EXCLUDING PITUITARY/PNET/EMBRYONAL) 299
FIGURE 16.1 White matter with reactive astrocytes. Note the rich fib- FIGURE 16.3 Reactive gliosis. The astrocytes show marked im-
rillary background (neuropil) that characterizes normal brain and munoreactivity to GFAP. Note also the relatively “even” distribu-
primary glial tumors. H&E. tion of the reactive cells in this field, as contrasted to the irregular
arrangement of the cells in a neoplasm. GFAP.
are the fibrillary astrocytes that reside mainly in the

white matter. With conventional staining methods, drocytes may be positive (Kepes, 1987; Perentes and
these cells are characterized by ovoid nuclei with mod- Rubinstein, 1987). Former histochemical techniques
erate chromatin content that occasionally forms promi- that were once used to demonstrate astrocytes include
nent clumps, and by very delicate cytoplasmic pro- phosphotungstic acid–hematoxylin (PTAH), Holzer,
cesses. A variety of special staining techniques may be and the gold and silver impregnation techniques of Ca-
utilized to demonstrate the fibrillary nature of these jal and Hortega. Protoplasmic astrocytes reside pri-
cells. Most often employed today is the immunocyto- marily in gray matter and are characterized by slightly
chemical demonstration of glial fibrillary acid protein larger and more irregular nuclei and by indistinct cy-
(GFAP) (Fig. 16.3). Ultrastructurally, the fibrillary as- toplasmic processes. Ultrastructurally, the protoplas-
trocyte contains large numbers of 8–9 nm intermediate mic astrocyte also contains glial fibrils, but fewer than
filaments, and it is to these filaments that GFAP is di- its fibrillary counterpart.
rected. GFAP immunoreactivity, although a highly re- In response to injury of any sort (inflammation, neo-
liable marker for astrocytes, does not distinguish neoplasia, vascular insult, or toxin), an astrocyte forms in-
plastic from reactive cells and is not restricted solely to creased numbers of glial fibers, with a consequent ex-
astrocytes since ependymal cells and some oligoden- pansion of its cytoplasmic profile. This usually results in
a cell with a stellate configuration, which is most evident
on smears and GFAP preparations, but in some instances
the injury response gives rise to a swollen or bloated pro-
file that is referred to as a gemistocyte or a gemistocytic
astrocyte. The stellate configuration usually is indicative
of a reactive process (Fig. 16.3). The presence of gemis-
tocytic astrocytes, however, must be viewed in the ap-
propriate context and does not always indicate a reactive
process. The gemistocytic astrocytoma is an uncommon
variant of astrocytoma that is comprised primarily of
gemistocytic astrocytes (see below). An often-minor com-
ponent of gemistocytic astrocytes is commonly found in
diffuse astrocytomas of high grade (Hoshino et al., 1975).
CLASSIFICATION OF ASTROCYTOMAS
FIGURE 16.2 Squash preparation of an astrocytoma. The abundant
glial processes characteristic of gliomas, particularly astrocytomas, Several systems have been used to classify gliomas.
are readily identifiable in squash or smear preparations. Giemsa. Most rely strictly upon the histopathological features
of the neoplasm without regard for its topography or TABLE 16.2 Classification of Astrocytomas
biologic characteristics, features often of clinical sig-
Diffuse Astrocytoma
nificance (Svien et al., 1949; Fields, 1989). While no (Fibrillary, Gemistocytic,
single classification scheme is entirely satisfactory, an Protoplasmic, Mixed) Circumscribed Astrocytomas
admittedly simplified, but clinically and pathologically
useful, approach separates astrocytomas into one of Grade 1–2 astrocytoma Pilocytic astrocytoma
(well-differentiated Pleomorphic xanthoastrocytoma
two groups: diffuse and circumscribed. Although both astrocytoma) (PXA)
are comprised of neoplastic astrocytes, there are im-
Grade 3 astrocytoma Subependymal giant cell
portant differences between them (Table 16.1). The dif- (anaplastic astrocytoma) astrocytoma (SEGA)
fuse astrocytomas, which are much more numerous, are Grade 4 astrocytoma
characterized by an infiltrative pattern of growth and (glioblastoma multiforme)
a distinct tendency to progress from low to high grade. Gliosarcoma (Feigin tumor)
Such lesions rarely are surgically resectable and post- Giant cell glioblastoma
operative survival correlates statistically with histologic
Small cell glioblastoma
grade. As such, the diffuse astrocytomas carry a rela-
tively unfavorable prognosis. In contrast, the circum-
scribed astrocytomas are characterized by relative cir-
cumscription and rarely or only infrequently undergo Also, progression to higher grade is more likely to oc-
anaplastic transformation. As a group, the circum- cur in older subjects, often precipitously, while neo-
scribed astrocytomas are histologically heterogeneous plasms in younger patients may remain stable in grade
but associated with a relatively favorable prognosis. for years.
Most occur early in life in characteristic geographical
locations, are often are cystic, and usually are amenable
to surgical excision. Since the histological grade of dif- DIFFUSE ASTROCYTOMAS
fuse astrocytomas predicts their biological behavior,
Diffuse astrocytomas are histologically diverse and may
such tumors are graded. In contrast, the circumscribed
be divided into fibrillary, protoplasmic, and gemisto-
astrocytomas biologically are almost always low grade
cytic types based upon the resemblance of the pre-
and for this reason are not, as a rule, assigned a his-
dominant cell to normal or reactive astrocytes. Al-
tological grade. Pleomorphic xanthoastrocytoma is the
though descriptive, separation on the basis of cytologic
exception (see below).
characteristics alone does not carry clinical significance
except in the case of the rare gemistocytic astrocytoma,
PROGNOSIS IN ASTROCYTOMAS which often progresses rapidly to a higher-grade lesion
(see below). The vast majority of diffuse astrocytomas
The prognosis of any given astrocytoma is dependent are fibrillary in nature. Since the histological grade of
upon several features that are often not mutually ex- diffuse astrocytomas is predictive of their biological be-
clusive. These include architectural features (diffuse or havior, these tumors are graded. As noted previously,
circumscribed), histological features (histologic type the circumscribed astrocytomas biologically almost al-
and grade), and clinical features (patient age, tumor lo- ways are low grade, and for this reason they are not
cation and geometry, and accessibility to surgery). Age assigned a histological grade. The simple designation
is a powerful prognostic indicator in diffuse astrocy- low-grade astrocytoma lacks precision and should be
tomas. Young individuals have a much better progno- avoided since it has been applied to both diffuse low-
sis than older patients (McCormack et al., 1992). grade and circumscribed pilocytic variants: the distinc-
tion between these two is essential.
Table 16.2 illustrates a practical working formula-
TABLE16.1 Features of Diffuse and tion for the classification of astrocytomas that is simi-
Circumscribed Astrocytomas lar to that recently adopted by WHO (Kleihues and
Diffuse Astrocytoma Circumscribed Astrocytoma Cavenee, 2000).
Infiltrative margin Relatively circumscribed margin

Histologic grades 1–4 Low grade Histologic Grading
Tendency to anaplasia Low tendency to anaplasia
The goal of any histologic grading system is to draw
Unfavorable prognosis Favorable prognosis
meaningful associations between the microscopic fea-
tures of a lesion and its biologic behavior. To be use-

ful, however, this presupposes that different grades
predict different biologic behaviors and that criteria for
the identification of each grade are clearly defined.
There are many systems for grading diffuse astrocy-
tomas. Four-grade (Daumas-Duport et al., 1988) and
three-grade (Ringertz, 1950) histological classifications
have been used by most pathologists. These rely on the
recognition of a spectrum of increasing degrees of
anaplasia: increased cellularity, nuclear pleomorphism,
mitoses, endothelial proliferation, and necrosis with or
without peripheral palisading of nuclei (pseudopal-
isading). Several theoretical and practical objections
have been levied against the use of histological grading
in astrocytomas. Workers generally agree upon what FIGURE 16.4 Glioblastoma multiforme. The tumor is heterogeneous
constitutes the highest- and the lowest-grade lesions, and accurate grading requires an adequate sampling of representa-
tive tissue.
but they often differ in their definition of intermediate-
grade lesions. The lack of firm pathologic criteria for
the separation of different grades has confused the terion present, a score of 1 is applied, and final grad-
problem and resulted in histologic grading that has not ing is based on a sum of criteria present (i.e., 0 crite-
been uniformly applied. Although grading has proven ria grade 1, 1 criterion grade 2, 2 criteria grade
useful for the diffuse astrocytomas, grading of other 3, and 3 or 4 criteria grade 4). Use of this grading
neuroglial neoplasms (oligodendrogliomas, ependymo- system distinguishes distinct patient groups with me-
mas, etc., see below) has not proven as reliable. dian survivals that correlate strongly with grade: me-
Most modern attempts to grade diffuse astrocytic tu- dian survival for patients with grades 2, 3, and 4 was
mors are three-tiered schemes that identify astrocy- 4 years, 1.6 years, and 0.7 years, respectively (Daumas-
toma, anaplastic astrocytoma, and glioblastoma multi- Duport and Scheithauer, 1987; Kim et al., 1991). This
forme—that is, grade 2, 3, and 4 tumors, respectively. scheme in modified form is the basis of the recently
In general, these categories bear a relationship to pa- adopted WHO grading scheme (Kleihues and Cavenee,
tient age at diagnosis: astrocytoma usually is diagnosed 2000).
a decade before anaplastic astrocytoma, and glioblas- Since diffuse astrocytomas are not histologically uni-
toma a decade later. form, an important practical problem in grading is
The widely utilized St. Anne-Mayo schema for grad- sampling error. Sampling issues must be considered in
ing diffuse astrocytomas (Daumas-Duport et al., 1988) the interpretation of small biopsies that may include a
is based upon the presence or absence of four mor- margin or periphery of the mass and not be represen-
phologic criteria: nuclear atypia, mitoses, endothelial tative of the main lesion. As a result, small and super-
proliferation, and necrosis (Table 16.3). For each cri- ficial biopsies of large gliomas may be inappropriately
graded as lower-grade lesions (Fig. 16.4). Thus, it is
important for the pathologist to be familiar with the
TABLE 16.3 St. Anne-Mayo Grading of Diffuse patient’s clinical history and radiographic findings. A
Fibrillary Astrocytomas close working relationship between the pathologist, ra-
diologist, and clinician is essential to ensure that a
MICROSCOPIC FEATURE meaningful biopsy interpretation is made.
Vascular Recently several specialized techniques have been ap-
Endothelial plied to gliomas to assess proliferative activity and
Proliferation St. Anne-Mayo growth potential. Although the infiltrative cells of as-
Nuclear atypia Mitosis and/or Necrosis Grade trocytoma typically show some proliferative activity, it
0 0 0 1 is best determined not on the basis of mitotic activity,
0 0 2
but rather on proliferation marker stains. The most
commonly applied technique is MIB-1 (Ki-67), a cell-
0 3
cycle-associated nuclear protein expressed during G1,
4
S, G2, and M phases, but not in G0 (Gerdes et al., 1991).
Source: Daumas-Duport et al. (1988). Immunoreactivity to Ki-67 correlates positively with
histologic grade, although it does not reliably distin- hancement. More commonly, the presence of enhance-
guish tumors of grades 3 and 4 (Giangaspero et al., ment, in fact, should prompt consideration of an
1987; Louis et al., 1991a). Some astrocytomas exhibit anaplastic variant, or a low-grade circumscribed tumor,
mutations in the p53 tumor suppressor gene (Reifen- as pilocytic astrocytoma, ganglioglioma, pleomorphic
berger et al., 1996a) and may represent a primary event xanthoastrocytoma, or subependymal giant cell astro-
in the “secondary” evolution of a tumor to glioblas- cytomas (see below).
toma multiforme (Biernat et al., 1997b). Grossly, the well-differentiated astrocytoma is an ill-
Astrocytomas also have been classified on the basis defined, white-gray, usually homogeneous mass with
of location, particularly brainstem and spinal examples, indistinct borders (Fig. 16.5). The diffuse infiltrative
regardless of histological type. Most are of the diffuse growth pattern results in distortion and enlargement
variety, often infiltrating widely and spanning the full rather than destruction of involved structures. Occa-
spectrum of histologic grades, although circumscribed, sionally, single or multiple cysts may be present.
usually pilocytic, astrocytomas may occur at any site. Microscopically, slightly enlarged and loosely
Brainstem gliomas, generally of the diffuse type, typi- arranged mildly atypical neoplastic cells expand the
cally arise in the pons; childhood examples (particu- white matter as a patternless diffusion of astrocytes,
larly in the second decade) are most common, but they gradually infiltrating preexisting structures (Fig. 16.6).
also may occur in adults. Such tumors rarely are re- The neoplastic nuclei are enlarged, irregular or cigar
sectable and generally carry a poor prognosis. Pilocytic shaped, and hyperchromatic. When isolated in intact
astrocytomas of the brain stem are often are exophytic parenchyma, the neoplastic cells have little cytoplasm,
and thus more resectable. Spinal cord astrocytomas are and their nuclei often appear naked. In more cellular
more often circumscribed and of the pilocytic type. Re- lesions, cytoplasm becomes apparent and the cells pos-
spective survivals are similar to those associated with sess scant, asymmetric, and often short processes. There
supratentorial examples. are no mitoses and vascular endothelial proliferation
and necrosis are lacking. Microcysts may appear as
round, fluid-filled cavities of variable size and contour
and may contain stainable mucoid or proteinaceous
Grade 1-2 Diffuse Fibrillary Astrocytoma
fluid. Calcification is present in about 15% of cases.
(Well-Differentiated Astrocytoma)
Particularly at the periphery of the tumor, only occa-
The grade 1-2 diffuse or well-differentiated fibrillary sional isolated tumor cells are identified in otherwise-
astrocytoma is the most benign of the fibrillary as- intact parenchyma (Fig. 16.7). As a rule, no solid tu-
trocytomas and accounts for about 20% of all mor center is found. The MIB-1 labeling index appears
gliomas. It most often is a tumor of the hemispheric to correlate with behavior (McKeever et al., 1998).
white matter of young adults (typically involving the
frontal lobe of young adult males, usually in the fourth
decade), but it can occur at any location and in a
broad range of ages. Despite the characteristic diffuse
infiltrative pattern of growth and potential to progress
from low to high grade, the well-differentiated astro-
cytoma generally is a slowly growing neoplasm, as re-
flected in a median survival of 8.2 years (Vertosick et
al., 1991) and in 5-year postoperative survivals rang-
ing from 38% with subtotal resection and radiother-
apy to 70% with gross total resection and radiother-
apy (Laws et al., 1984). Not infrequently, the tumor
undergoes dedifferentiation to a higher grade and ac-
quires the less favorable prognosis of the higher-grade
lesion.
On magnetic resonance imaging (MRI), the low-grade
astrocytoma shows decreased signal on T1-weighted im-
FIGURE 16.5 Low-grade (well-differentiated) diffuse astrocytoma.
ages, and increased signal on the T2-weighted and
The diffuse pattern of growth of this temporal example results in dis-
FLAIR (fluid-attenuated inversion recovery) images. Al- tortion and enlargement, rather than destruction, of invaded struc-
though the low-grade astrocytoma characteristically tures. The tumor appears as a homogeneous mass, with indistinct
does not enhance, a rare example may show focal en- borders.
TABLE 16.4 Gliosis vs. Glioma

Feature Gliosis (Reactive) Glioma (Neoplastic)
Cytology Stellate, uniform Variable

Cellularity Increased Increased
Distribution Even Irregular
Gray–white junction Preserved Lost
Mitoses Lacking Variable
Microcysts Rare Common
Microcalcifications Rare Occasional
Secondary structures Lacking Frequent
FIGURE 16.6 Low-grade (well-differentiated) diffuse astrocytoma.

Note irregular, pattern-less infiltration and relative uniformity of in-
filtrating cells. H&E.
the presence of microcysts and microcalcifications
(Figs. 16.8–16.11). None of these features, however,
is absolute, and correlation of clinical, radiographic,
A potential pitfall and not uncommon problem for and pathologic features is essential if a meaningful
the pathologist the need to make a distinction be- interpretation is to be made. In high-grade lesions,
tween low-grade diffuse astrocytoma and reactive the degree of cellularity and atypia usually becomes
gliosis. The recognition of a well-differentiated dif- sufficient to exclude a reactive process.
fuse astrocytoma is based upon the radiographic find- As neoplastic astrocytes expand and incorporate pre-
ings of a mass and the histologic demonstration of existing structures, several characteristic patterns of in-
increased cellularity and nuclear atypia. (The label filtration emerge. In gray matter, the infiltrating cells
chronic gliosis is somewhat of a misnomer since by tend to cluster about neurons (perineuronal satellito-
definition gliosis represents a reactive process that oc- sis) and collect in subpial and subventricular zones,
curs over a period of time.) Several histologic pa- forming perineuronal satellites (Fig. 16.12) and subpial
rameters assist in distinguishing of a low-grade neo- (Fig. 16.13) and subventricular accumulations. These
plastic process from a reactive process (Table 16.4). infiltrative patterns, known as the secondary structures
Features more indicative of a neoplastic process in- of Scherer (Scherer, 1938), are particularly common in
clude: a patternless and uneven distribution of the in- low- and intermediate-grade tumors but may be seen
creased cells, violation of the gray–white junction in any grade or type of infiltrative glioma and are re-
with secondary structure formation (see below), and liable features of neoplasia.
FIGURE 16.7 Low-grade (well-differentiated) diffuse astrocytoma. Iso- FIGURE 16.8 Low-grade (well-differentiated) diffuse astrocytoma.
lated tumor cells are present in otherwise intact parenchyma from Note the uneven patternless arrangement of the neoplastic cells.
the margin of an astrocytoma. H&E. H&E.
FIGURE 16.9 Low-grade (well-differentiated) diffuse astrocytoma. FIGURE 16.11 Low-grade (well-differentiated) diffuse astrocytoma.
The irregular distribution results from the tendency of the neoplas- The presence of microcalcifications should suggest the diagnosis of
tic cells to clump together. Compare with Fig. 16.1. H&E. low-grade astrocytoma. H&E.
Grade 3 Fibrillary Astrocytoma (Intermediate-Grade glioblastoma. Radiologic features of the anaplastic as-
Astrocytoma; Anaplastic Astrocytoma; Astrocytoma trocytoma, as with its histologic features, bridge the
with Atypical or Anaplastic Foci) spectrum between the low-grade lesion and the
glioblastoma. It generally shows a patchy or irregular
The anaplastic astrocytoma lies intermediate in the pattern of enhancement, although mitotically active le-
spectra of histologic features and clinical behavior be- sions may not enhance.
tween the well-differentiated diffuse fibrillary astrocy- Histologically, the anaplastic astrocytoma demon-
toma and glioblastoma multiforme. Although anaplas- strates focal or diffuse anaplastic features, including in-
tic astrocytomas may arise de novo, most follow creased cellularity, pleomorphism, and nuclear atypia,
malignant transformation of a well-differentiated as- as well as mitotic figures, the key feature of this tumor
trocytoma, with transition seen in the majority of re- (Fig. 16.14). As in well-differentiated examples, the
current tumors. Compared to the well-differentiated as- neoplastic astrocytes expand and incorporate preexist-
trocytoma, the anaplastic astrocytoma occurs at a ing structures. In gray matter, the infiltrating cells tend
somewhat older age (usually fifth and sixth decades) to cluster about neurons and collect in subpial and sub-
and is associated with a less favorable prognosis ventricular zones, forming perineuronal satellites and
(months after diagnosis) with rapid progression to subpial and subventricular accumulations. As noted
FIGURE 16.10 Low-grade (well-differentiated) diffuse astrocytoma. FIGURE 16.12 Anaplastic (grade 3) astrocytoma. Neuronal satellito-
Microcysts are more common in low-grade astrocytomas than in re- sis, a secondary structures of Scherer, is a characteristic feature of
active processes. H&E. cortical invasion. H&E.
of 45 and 60. Most occur in the deep white matter of

the cerebral hemisphere, usually frontotemporal lobes,
but no site is immune. Brainstem, cerebellar, and spinal
cord examples are well recognized, the former particu-
larly in childhood. The tumor may arise de novo (pri-
mary glioblastoma), or from a preexisting lower-grade
astrocytoma (secondary glioblastoma). The two variants
have differing genetic underpinnings (Biernat et al.,
1997a,b). True multifocality is uncommon. More often,
apparently multiple lesions represent foci of dedifferenti-
ation in a more diffuse lesion. Dissemination of glioblas-
toma multiforme (GBM) may occur via the cerebral
spinal fluid (Onda et al., 1989; Onda et al., 1990; Grabb
et al., 1992). Systemic metastases are rare (Barnard and
FIGURE16.13 Anaplastic (grade 3) astrocytoma. Subpial aggregation of
neoplastic cells, also a secondary structure of Scherer, commonly ac- Geddes, 1987). Tumor growth is very rapid and the prog-
companies neuronal satellitosis and indicates cortical invasion. H&E. nosis is dismal. Average survival is 18 months. Although
modern multimodality therapy has extended the life ex-
pectancy of patients with glioblastoma, survivals of
previously, these infiltrative patterns, known as the sec- greater than 2 years are exceptional.
ondary structures of Scherer (Scherer, 1938), are par- The name glioblastoma multiforme derives from the
ticularly common in intermediate-grade tumors but highly variable multiforme gross and microscopic ap-
may be seen in any grade or type of infiltrative glioma, pearances it can display. Most glioblastomas are highly
oligodendroglioma included. infiltrative, although on gross inspection, they often
Previously, most classification systems required the give the impression of demarcation. This apparent cir-
presence of vascular endothelial proliferation for the cumscription is due to the marked contrast of the usu-
designation of anaplastic astrocytoma. In more recent ally heterogeneous central portion, replete with cystic
schemes, however, the presence of mitoses alone places and degenerative changes, hemorrhage, and necrosis,
a tumor into the anaplastic or intermediate-grade cat- compared to the less grossly apparent permeative mar-
egory, while the appearance of endothelial prolifera- gin (Fig. 16.15). Infiltration often follows white mat-
tion and/or necrosis advances the tumor to grade 4.
Grade 4 Astrocytoma (Glioblastoma Multiforme)

The grade 4 astrocytoma is the most malignant and un-
fortunately the most frequent type of glioma, accounting
for the majority of brain tumors in men between the ages
FIGURE 16.15 Glioblastoma multiforme (grade 4 astrocytoma). This

FIGURE 16.14 Anaplastic (grade 3) astrocytoma. Increased cellularity large hemispheric mass is heterogeneous both grossly and micro-
and atypia, along with mitoses, are sufficient for the diagnosis. H&E. scopically. Note the “apparent circumscription” of the tumor.
FIGURE 16.18 Glioblastoma multiforme (grade 4 astrocytoma). Pe-

FIGURE 16.16 Glioblastoma multiforme (grade 4 astrocytoma). In- ripheral palisading of tumor nuclei about areas of necrosis
volvement of both cerebral hemispheres and the corpus callosum re- (pseudopalisading) results in a characteristic “geographic” appear-
sults in this characteristic “butterfly glioma” appearance of the tumor. ance at low power. H&E.
ter tracts. The particular tendency of GBM to cross the atypia, and mitotic figures; the number of mitoses is
midline via the corpus callosum results in the classic highly variable and in some cases is surprisingly low.
gross appearance of the butterfly glioma (Fig. 16.16). Areas of more differentiated astrocytoma may be pres-
Radiologically, the glioblastoma appears as a bright ent, typically dominating the periphery of the lesion;
usually somewhat irregular ring-enhancing mass thus, the biopsies from the edge of the mass may result
around a central zone of low signal or density on MR in undergrading (Glantz et al., 1991). Necrosis, with
images or CT scans. The periphery of the mass typi- or without palisading, is the most ominous prognostic
cally shows a broad zone of increased T2 signal, a re- feature (Nelson et al., 1983). Vascular proliferation in-
flection of tissue infiltration and edema. cludes both glomeruloid structures, so-named because
Utilizing current classification schemes, the histolog- of their resemblance to renal glomeruli, and multilay-
ical diagnosis of grade 4 astrocytoma rests upon the ering of endothelium (endothelial proliferation). The
presence of vascular endothelial proliferation that may latter is the prognostically significant vessel change.
be exuberant (Fig. 16.17) and/or upon foci of necrosis Angiogenesis likely represents an alteration in normal
with or without peripheral palisading of nuclei astrocyte–endothelial cell interaction modulated by sev-
(pseudopalisading) (Figs. 16.18, 16.9). Most GBMs eral growth factors (Betsholtz et al., 1989). Histologi-
also show prominent cellular pleomorphism, nuclear cally, a broad spectrum of astrocytic features may be
FIGURE 16.17 Glioblastoma multiforme (grade 4 astrocytoma). Note FIGURE 16.19 Glioblastoma multiforme (grade 4 astrocytoma). Note
increased cellularity and prominent glomeruloid formations due to extreme cellularity, atypia, vascular endothelial proliferation (top),
exuberant vascular endothelial proliferation. H&E. and large area of necrosis (bottom). H&E.
FIGURE16.20 Glioblastoma multiforme (grade 4 astrocytoma) with FIGURE 16.22 Glioblastoma multiforme (grade 4 astrocytoma) with
prominent lipidization of neoplastic cells. H&E. granular cell change. H&E.
present. GBMs may also show lipidization (Fig. 16.20) on chromosome 7 (Bigner et al., 1987; Biernat, 1997a,
(Kepes and Rubinstein, 1981). Since there is some cross b). Such tumors typically are primary glioblastomas
reactivity of the glial intermediate filaments for GFAP (see above).
and cytokeratin, the neoplastic cells may demonstrate The giant cell glioblastoma is regarded as a distinct
immunoreactivity for both markers. On occasion, ep- subtype. As the name implies, it is comprised primarily
ithelial (Fig. 16.21) (Mork et al., 1988), chondroid or of bizarre, multinucleated giant tumor cells. Areas of ne-
osseous metaplasia, granular cell change (Fig. 16.22) crosis with pseudopalisading and perivascular
may be conspicuous. pseudorosettes are common (Fig. 16.23). In some series,
Glioblastomas may invade the leptomeninges and giant cell glioblastomas are associated with a slightly bet-
dura to induce a marked fibrous (desmoplastic) reac- ter prognosis than the usual glioblastoma multiforme
tion. The resultant tumor is of firm consistency that (Margetts and Kalyan-Raman, 1989). This may be due
grossly mimics a meningioma. Biopsy of such a tumor to their often-marked circumscription, which permits a
discloses anaplastic astrocytes in a dense, fibrous gross total removal, as well as their composition of mul-
stroma, adjacent to and interspersed with areas of more tinucleated cells, which represent end-stage cells inca-
typical high-grade astrocytoma. pable of further mitotic activity. Prominent reticulin-rich
Amplified oncogenes have been reported in about stromal elements may be present, imparting a firm, well-
40% of GBMs. Most commonly amplified is the ep- circumscribed quality to the tumor—hence its prior des-
ithelial growth factor receptor (EGFr), which is located ignation, monstrocellular sarcoma (Fig. 16.24).
FIGURE 16.21 Glioblastoma multiforme (grade 4 astrocytoma) with FIGURE 16.23 Giant cell glioblastoma (grade 4 astrocytoma). Note
epithelioid features. H&E. the presence of prominent bizarre multinucleated giant cells. H&E.
FIGURE 16.24 Giant cell glioblastoma (grade 4 giant cell astrocy- FIGURE 16.26 Gliosarcoma. Surgical resection of a temporal lobe
toma). Abundant reticulin-rich stromal elements result in an often gliosarcoma. Note the superficial location, circumscription, and var-
sharply circumscribed lesion grossly. Reticulin. iegated cut section.
The small cell glioblastoma is a variant of the Nonetheless, gliosarcoma has been associated with an
glioblastoma and is comprised mainly of small, poorly increased likelihood of dissemination and extracranial
differentiated cells (Fig. 16.25). There is extensive mi- metastases. Gliosarcomas preferentially involve the
totic activity in addition to the usual features of the temporal lobe (Feigin and Gross, 1955; Morantz et al.,
glioblastoma. This variant more often is primary than 1976; Slowik et al., 1985; Ng and Poon, 1990).
secondary, usually is associated with EGFr amplifica- Macroscopically, the gliosarcoma displays a firm, cir-
tion, and carries a somewhat more sinister prognosis cumscribed, lobulated appearance reminiscent of menin-
than the conventional glioblastoma multiforme (Burger gioma or sarcoma. A cut section occasionally reveals a
et al., 2001). variegated, gritty, firm surface interspersed with softened
yellow zones of necrosis (Fig. 16.26). The histologic fea-
tures include variably organized fascicles of sarcomalike
Gliosarcoma (Feigin Tumor)
tissue, usually resembling fibrosarcoma or malignant fi-
Gliosarcoma is a well-recognized variant of GBM that brous histiocytoma, interspersed with areas of typical
accounts for 5%–10% of all high-grade gliomas in glioblastoma (Fig. 16.27). This biphasic arrangement is
large series. The clinical behavior of gliosarcomas is not best demonstrated with silver preparations for reticulin
significantly different from that of glioblastoma. Both fibers that highlight the reticulin-rich sarcoma compo-
share similar presenting and radiological features, age nent (Fig. 16.28) and immunohistochemistry for glial
and male predilections, and overall poor survival rates.
FIGURE 16.27 Gliosarcoma. Fascicles of well-organized fibrosarcoma

FIGURE 16.25 Small cell glioblastoma (grade 4 small cell astrocy- thought to originate from malignant transformation of vascular ele-
toma). The prominent cell is small and less well differentiated. H&E. ments are interspersed with areas of glioblastoma. H&E.
by a malignant mesenchymal tumor—the vigorous re-

action of glial cells transforming to glial malignancy. Al-
though ultrastructural and immunohistochemical (Grant
et al., 1989) studies have suggested that the sarcoma-
tous component of gliosarcomas may derive from un-
differentiated mesenchymal elements or transformed en-
dothelial cells (McComb et al., 1982), genetic studies
suggest the metaplasia mechanism because identical al-
terations are present in both gliomatous and sarcoma-
tous components (Biernat et al., 1995).
Unusual Forms of Diffuse Astrocytoma
FIGURE 16.28 Gliosarcoma. The reticulin-rich sarcoma component In its pure form, the protoplasmic astrocytoma is a rare
contrasts with the relatively reticulin-poor glioblastoma component
variant that arises in gray matter where protoplasmic
of this gliosarcoma. Reticulin.
astrocytes predominate. Grossly, compared to the well-
differentiated fibrillary astrocytoma, it is softer and has
fibrillary acidic protein (GFAP), which demonstrates the more discrete margins and tends to be more superfi-
glial component (Fig. 16.29). Gliosarcomas with ade- cially located. Microscopically, the tumor tends to be
noid formations resembling metastatic carcinoma (Kepes microcystic and is comprised of small, intersecting,
et al., 1982), chondroid and/or osseous metaplasia poorly fibrillated stellate cells (Fig. 16.30). Although
(Banerjee et al., 1989), and smooth muscle or rhab- there are few series of protoplasmic astrocytomas, the
domyosarcoma elements (Barnard et al., 1986; Haddad prognosis appears to be similar to that for low-grade
et al., 1991) have been described. The gliosarcoma is of fibrillary astrocytomas (Prayson, 1995).
considerable theoretical interest since it appears to rep- A rare form of diffuse astrocytoma carries the un-
resent a metaplasia of a glioma to a histologically unre- fortunate designation of adult pilocytic astrocytoma.
lated neoplasm (Meis et al., 1991). Alternatively, a less This tumor bears mentioning since it may be confused
likely mechanism suggests that the sarcomatous element with the ordinary juvenile pilocytic astrocytoma. Al-
arises from malignant transformation of vascular and though comprised of intersecting bundles of elongate
leptomeningeal fibroblasts within the preexisting high- (piloid) astrocytes, it is not well circumscribed and lacks
grade astrocytoma. The possibility of independently aris- both the biphasic histology and the relatively favorable
ing glioblastoma and sarcoma (i.e., a collision tumor) prognosis of the usual pilocytic astrocytoma. As such,
also has been suggested. Another less well-recognized it is considered to be a variant of the diffuse astrocy-
variant with composite glial and sarcomatous elements, toma. Foci of gemistocytes and cytologic atypia may
the sarcoglioma, is thought to result from brain invasion be present.
FIGURE 16.29 Gliosarcoma. GFAP highlights the glial component in FIGURE 16.30 Protoplasmic astrocytoma. The tumor is comprised of
contrast to the GFAP-negative sarcoma component. small stellate cells in a prominent microcystic background. H&E.
Although gemistocytes may be a component of any

diffuse astrocytoma, when they comprise the major cell
type, the term gemistocytic astrocytoma is applied.
Such tumors are very likely to transform anaplastically,
and they have a poor prognosis. Individual neoplastic
cells demonstrate abundant cytoplasm, often eccentric
nuclei, and polar rather than circumferential short,
stout processes (Fig. 16.31). Small numbers of perivas-
cular lymphocytes are common (Takeuchi and Barnard,
1976). Gemistocytic astrocytomas often evolve into a
high-grade astrocytoma (Fig. 16.32) within a relatively
short period of time, usually on the order of 5 years
(Krouwer et al., 1991). Even when astrocytomas fea-
ture a less prominent gemistocytic component (20%),
the tumor may be associated with a less favorable FIGURE16.32 Gemistocytic astrocytoma. This gemistocytic astrocy-
toma shows evolution into a small cell glioblastoma. H&E.
prognosis.
Gliomatosis cerebri also is of considerable theoreti-
cal interest since it represents the occurrence of a widely
grade process characterized by a diffuse infiltration of
infiltrative glioma, usually fibrillary astrocytoma, that
monomorphous, usually elongated, tumor cells that re-
simultaneously involves multiple regions of brain
semble microglia. Secondary structures are commonly
and/or spinal cord, without an obvious epicenter. Af-
present. In some cases, the cellularity is so low and the
fected tissue is expanded by permeation of otherwise-
nuclei are so bland that the diagnosis is difficult to
intact architecture involving multiple cerebral lobes or
make, even in large specimens (Ross et al., 1991). Al-
CNS compartments without the formation of a discrete
though gliomatosis cerebri is usually considered an “as-
mass (Dunn and Kernohan, 1957; Couch and Weiss,
trocytic” neoplasm, GFAP immunoreactivity is usually
1974; Kandler et al., 1991). Gliomatosis cerebri may
lacking or sparse. Oligodendroglial neoplasms fulfill-
occur at any age and induce a variety of neurological
ing the radiographic criteria of gliomatosis also have
abnormalities. The diagnosis rests upon both radio-
been reported (Balko et al., 1993).
graphic and histological criteria. Radiographically,
widespread increased T2 signal is present, often in both
hemispheres or in two or more cerebral lobes, basal
CIRCUMSCRIBED ASTROCYTOMAS
ganglia and/or thalami, and in some cases, in both in-
tracranial and spinal areas (Yanaka et al., 1992). His-
Pilocytic Astrocytoma
tologically, gliomatosis often is a low- to intermediate-
The pilocytic astrocytoma (or juvenile pilocytic astro-
cytoma), the prototype of the circumscribed astrocy-
toma, is very different from the diffuse astrocytoma
(Brat and Burger, 1998). It typically is well circum-
scribed, biologically low grade, and often demonstrates
distinctive histologic patterns that permit the patholo-
gist to make the diagnosis without equivocation (Gar-
cia et al., 1989; Gilles et al., 1983). Pilocytic astrocy-
tomas occur most often in the cerebellum (cystic
astrocytoma or cerebellar astrocytoma) of children,
usually in the first two decades of life. They are said
to follow the rule of the C’s (i.e., cerebellar, cystic,
childhood, circumscribed). Other common sites of
occurrence include the optic nerve (optic nerve glioma),
third ventricle/hypothalamus (infundibuloma), thala-
mus, and basal ganglia, and spinal cord. Occasional ex-
FIGURE 16.31 Gemistocytic astrocytoma. The neoplasm is comprised
amples occur in the cerebral hemispheres (Clark et al.,
of enlarged astrocytes with prominent eosinophilic cytoplasm, short 1985; Brat and Burger, 1998; Forsyth et al., 1993). The
stout processes, and usually eccentric nuclei. H&E. prognosis is excellent provided their location permits
resection. In cerebellar examples, surgery alone is usu-

ally curative. Childhood cerebellar pilocytic astrocy-
tomas are associated with 5, 10, and 25 year disease-
free survival rates of 92%, 88%, and 88%, respectively
(Hayostek et al., 1993). The same is true of supraten-
torial and spinal examples (Minehan et al., 1995). Ma-
lignant transformation is rare (Kleinman et al., 1978;
Kocks et al., 1989; Obana et al., 1991; Tomlinson et
al., 1994) and firm diagnostic criteria for anaplasia
have not been established. A pilocytic astrocytoma typ-
ically is very slow growing and relatively sharply de-
marcated. Roughly 60% are cystic, and often expan-
sion of the cyst accounts for increasing mass effect or
symptomatic recurrences. The tumor usually is re- FIGURE 16.34 Pilocytic astrocytoma. Typical biphasic histology with
stricted to the mural nodule, and in such cases, biopsy loose microcystic components, alternating with dense components
from the wall of the cyst may show only gliosis. comprised of elongated astrocytes punctuated by Rosenthal fibers
On imaging studies the pilocytic astrocytoma appears and granular bodies. H&E.
as a sharply demarcated, contrast-enhancing round or
oval smoothly marginated mass. Most are hypo- or
isodense/intense on CT and T1-weighted MR, and impactions of amorphous nonfibrillar, electron-dense
bright on T2-weighted MR. Some enhance uniformly material surrounded by intermediate (glial) filaments
while others have an enhancing mural nodule within a and lie within astrocytic processes. They stain red with
cyst. Surrounding cerebral edema typically is absent or Masson trichrome and blue with Luxol fast blue (LFB)
minimal. and show peripheral rimlike immunoreactivity for
Microscopically, the pilocytic astrocytoma is com- GFAP. Rosenthal fibers are not specific for pilocytic as-
prised of piloid astrocytes with fine bipolar tapering trocytoma, although they often are a conspicuous ele-
processes (Fig. 16.33) in a characteristic biphasic pat- ment (Fig. 16.35), particularly in compact areas. They
tern. Loose areas comprised of cells with a tendency to occur in a variety of reactive/destructive processes and
form microcysts and granular eosinophilic bodies al- should be regarded as a nonspecific marker of damage
ternate with more compact areas of elongated astro- to astrocytic processes.
cytes, which are punctuated by Rosenthal fibers (Fig. Additional diagnostically helpful features of pilocytic
16.34). Rosenthal fibers are brightly eosinophilic astrocytoma, particularly in microcystic areas, are
sausage- or corkscrew-shaped bodies of variable shape cellular or interstitial accumulations of periodic acid–
and size with a distinct hyaline quality. They represent Schiff (PAS)-positive protein droplets and eosinophilic
FIGURE 16.33 Pilocytic astrocytoma. The fine, delicate, hairlike pro- FIGURE 16.35 Pilocytic astrocytoma. Rosenthal fibers, although non-
cesses of the piloid astrocytes are shown to advantage on smear specific, often are conspicuous elements, particularly in dense areas
preparations. H&E. of a pilocytic astrocytoma. H&E.
FIGURE 16.36 Pilocytic astrocytoma. Note eosinophilic granular bod- FIGURE 16.38 Pilocytic astrocytoma. Leptomeningeal invasion com-
ies that are particularly prominent in loose areas of pilocytic astro- monly occurs but is of no known prognostic importance. H&E.
cytoma. H&E.
tracranial hemorrhage, perhaps as a result of vascular

alterations. About one-third of pilocytic astrocytomas,
granular bodies (EGBs) (Fig. 16.36) (Murayama et al.,
particularly those in very young patients, will show a
1992). Protein droplets are large, clustered, intracellu-
rare mitotic figure. Leptomeningeal invasion is fre-
lar eosinophilic globules, while EGBs are more finely
quent, does not indicate malignancy (Fig. 16.38), and
granular and often less brightly eosinophilic. The cores
often is characterized by small lobules of neoplastic
of EGBs show immunoreactivity for alpha-1-antit-
cells, the result of a desmoplastic reaction.
rypsin and alpha-1-antichymotrypsin (Friedberg et al.,
Some pilocytic astrocytomas, particularly cerebellar
1991). Neither EGBs nor protein droplets are specific
examples, may demonstrate areas superficially resem-
for pilocytic astrocytoma since both are commonly en-
bling oligodendroglioma (Fig. 16.39). The significance
countered in other low-grade tumors as pleomorphic
of this pattern, which usually is accompanied by more
xanthoastrocytoma and ganglion cell tumors.
obvious features of pilocytic astrocytoma, is unclear.
Degenerative changes, including cellular and nuclear
atypia, multinucleated giant cells with peripheral nu- Macroscopically discrete pilocytic astrocytomas show
variable degrees of parenchymal infiltration, ranging
clei (pennies on a plate), and glomeruloid as well as
from several millimeters in most cases, to several cen-
thick-walled vessels are common and sometimes promi-
timeters in some cerebellar examples. As a result, ax-
nent but do not indicate anaplasia (Fig. 16.37). Rarely
ons and even scattered neurons may be found in some
a pilocytic astrocytoma may present as a primary in-
cases. Nonetheless, infiltration is limited compared to
that of fibrillary tumors, and occurs more readily in
FIGURE 16.37 Pilocytic astrocytoma. Marked endothelial prolifera-

tion with glomeruloid formation or thick-walled vessels may be pres- FIGURE 16.39 Pilocytic astrocytoma. An oligodendrogliomalike com-
ent, but does not indicate malignancy. H&E. ponent sometimes is prominent in pilocytic astrocytoma. H&E.
white matter than in gray matter, as illustrated by re-

markably circumscribed thalamic tumors and more of-
ten ill-defined cerebellar lesions.
The significance of histologic malignancy or what
appears to be anaplastic transformation in pilocytic as-
trocytomas has yet to be resolved (Hayostek et al.,
1993; Tomlinson et al., 1994), since tumors with such
features are rare and may remain radiologically stable
for decades. Uncommonly, a pilocytic astrocytoma re-
curs rapidly and, in rare instances, disseminates widely
in the subarachnoid space (Civitello et al., 1988). Some
are bland and show only an increase in cellularity and
mitotic activity, while others display considerable nu-
clear pleomorphism, high cellularity, brisk mitotic ac-
FIGURE 16.41 Pleomorphic xanthoastrocytoma. The tumor is com-
tivity, significant endothelial proliferation, and occa-
posed of markedly atypical and pleomorphic astrocytes with bizarre
sional necrosis replete with palisading. Such tumors giant forms and xanthomatous cells. H&E.
also are generally solid, lacking or losing the obvious
cystic component of the classic pilocytic pattern. When
a tumor with obvious histologic features of malignancy
also exhibits underlying features of pilocytic astrocy- (ages 7 to 25 years; average 12.4 years in the original
toma, the designation malignant pilocytic astrocytoma series), often with a long history of seizures. The tu-
is appropriate. Nonetheless, prognostication is difficult. mor typically is supratentorial, superficial (involving
The recently described pilomyxoid astrocytoma, a le- the overlying meninges and cortex, but not the dura),
sion typically arising in the hypothalamic region, shows and in most cases is grossly cystic with a mural nod-
some pilocytic features but lacks Rosenthal fibers and ule (Fig. 16.40). Although the temporal lobe seems to
granular bodies; such tumors often undergo cran- be preferentially involved (Pasquier et al., 1985;
iospinal dissemination (Tihan and Burger, 1999). Kawano, 1991), other lobes and occasionally cerebel-
lum or spinal cord my be affected. Imaging features of
the PXA, similar to those of other circumscribed
Pleomorphic Xanthoastrocytoma
gliomas, include a sharply delimited superficial partially
The pleomorphic xanthoastrocytoma (PXA) is a rela- cystic hemispheric mass with an enhancing mural
tively uncommon but well-recognized variant of cere- nodule.
bral astrocytoma first described by Kepes et al. (1979). Microscopically the neoplasm is characterized by
Clinically it is a tumor of children and young adults compactness and cellular pleomorphism. PXAs are rel-
atively discrete and noninfiltrative but highly cellular,
consisting of markedly atypical astrocytes with bizarre
giant forms (Fig. 16.41), varying numbers of xan-
thomatous cells (Fig. 16.42), and a reticulin-rich net-
work that often surrounds individual cells or clusters
of tumor cells (Fig. 16.43). The latter initially suggested
PXA had a mesenchymal origin. The neoplastic cells,
however, show strong immunoreactivity to GFAP, con-
firming their glial origin (Fig. 16.44). As a rule, mitoses
are scant or absent, as is endothelial proliferation and
necrosis. Commonly present are eosinophilic granular
bodies (EGBs) comprised of small, eosinophilic, PAS-
positive droplets lying within astrocytic cytoplasm.
EGBs are common in low-grade tumors, including pi-
locytic astrocytomas, and ganglion cell tumors (Mu-
rayama et al., 1992). Collections of perivascular lym-
FIGURE 16.40 Pleomorphic xanthoastrocytoma. The tumor typically
is superficially located, intimately related to overlying meninges,
phocytes also are common in PXA. Uncommonly, a
sharply circumscribed, and usually associated with an underlying PXA contains large neoplastic ganglion cells (Kordek
cyst. H&E. et al., 1995) that must be distinguished from entrapped
FIGURE16.42 Pleomorphic xanthoastrocytoma. In some areas, xan- FIGURE16.44 Pleomorphic xanthoastrocytoma. The neoplastic cells
thomatous cells are prominent. H&E. show immunoreactivity to GFAP. GFAP.
non-neoplastic neurons by their arrangement and/or al., 1989). Although “anaplastic” examples with brisk
binucleation. Such examples are considered a form of mitotic activity, high MIB-1 labeling indices, vascular
ganglioglioma, since in some instances neurons are proliferation, and necrosis are prognostically less fa-
present in the recurrence but not the original specimen vorable (Macaulay et al.,1993), other important fac-
(Perry et al., 1997). At least one ganglioglioma is re- tors include the extent of resection and the degree of
ported to have recurred as PXA (Powell et al., 1996). mitotic activity (with 5 mitoses per 10 high-power
Despite its pleomorphic appearance, PXA is a WHO field [hpf] significant) (Giannini et al., 1999; Giannini
grade II tumor that has a relatively favorable progno- et al., 2000). The presence of necrosis, although con-
sis with long survivals; most patients are alive and well troversial (Pahapill et al., 1996), should be viewed with
at 15 years (Kros et al., 1991). Because of the pleo- concern. Since the prognosis of patients with the
morphic appearance of this tumor, it not uncommonly anaplastic variant is not grade-dependent, the 2000
is misdiagnosed: PXA has been judged to be a gigan- WHO classification of CNS tumors no longer provides
tocellular glioblastoma, an unclassified glioma, an atyp- a grade III designation; instead the term PXA with
ical fibroxanthoma, a monstrocellular sarcoma, and a anaplastic features is preferred.
glioblastoma.
In approximately 15% of cases, anaplastic trans-
formation takes place (Strom and Skullerud, 1983; Subependymal Giant Cell Astrocytoma
Weldon-Linne et al., 1983; Iwaki et al., 1987; Kepes et
The pathology of tuberous sclerosis includes hamar-
tomas of the cerebral cortex (cortical tubers), kidney
(angiomyolipoma), heart (rhabdomyoma), lymph
nodes, and retina, and the cerebral subependymal le-
sions, known as candle gutterings or, when large, as
subependymal giant cell astrocytomas (SEGAs). The
SEGA appears radiographically as a discrete partially
cystic and calcified irregularly enhancing mass at the
foramen of Monro. Microscopically, it is sharply de-
marcated from brain and displays a “solid” pattern of
growth. Characteristically present are unusual enlarged
cells with abundant glassy cytoplasm resembling that
of gemistocytic astrocytoma, and large nuclei with
prominent nucleoli resembling nuclei of neurons. Mi-
croscopically, it is sharply demarcated from brain and
displays a “solid” pattern of growth. Characteristically
FIGURE 16.43 Pleomorphic xanthoastrocytoma. A reticulin-rich net- present are unusual enlarged cells with abundant glassy
work is present, often with individual cells surrounded by a collar eosinophilic cytoplasm resembling that of gemistocytic
of reticulin. Reticulin. astrocytes, and large nuclei with prominent central nu-
Chordoid Glioma of the Third Ventricle

This recently described clinicopathologic entity is de-
fined by its characteristic location and histopathologic
features. Only a small number of cases have been re-
ported (Brat et al., 1988; Brat et al., 2000; Cenacchi et
al., 2001; Galloway et al., 2001). The tumor occurs in
adulthood (20–70 years) with symptoms related to the
third ventricular location, including headache from ob-
structive hydrocephalus, and visual/hypothalamic dys-
function from local compression. MR images reveal a
diffusely enhancing, well-circumscribed mass in the an-
terior third ventricle and suprasellar region (Tonami et
al., 2000; Pomper et al., 2001).
FIGURE 16.45 Subependymal giant cell astrocytoma. Note composi- The tumor demonstrates an epithelioid appearance,
tion by enlarged cells, with abundant eosinophilic cytoplasm and with individual cells with prominent eosinophilic cyto-
large nuclei, many with prominent central nucleoli. H&E. plasm and a paucity of processes arranged as cohesive
clusters and cords within a variably abundant, basophilic,
vacuolated, myxoid stroma (Fig. 16.47). In some areas,
the stroma may be fibrous, engulfing nests of cells in a
cleoli resembling nuclei of neurons (Fig. 16.45) network of reticulin fibers. Nuclei are relatively uniform
(Bender and Yunis, 1980). These cells show im- and round or oval. Mitoses are absent or scarce, MIB-1
munoreactivity to GFAP (Fig. 16.46); hence the le- labeling is low, and microvascular proliferation and ne-
sion is designated as a subependymal giant cell crosis are not observed. Stromal lymphoplasmacytic in-
astrocytoma although immunohistochemical and ul- filtrates with Russell body formation often are present.
trastructural features indicate elements of neuronal Infiltration into adjacent brain is negligible although per-
differentiation (Nakamura and Becker, 1983). SEGAs, itumoral gliosis with Rosenthal fiber formation may be
due to their high vascularity, enhance brightly with prominent. The neoplastic cells show strong immunore-
contrast. They protrude into the lateral ventricle activity for glial fibrillary acidic protein (GFAP) vimentin,
and when large enough may obstruct the foramen of and in some cases, CD34. Some tumors express epithe-
Monro. On rare occasions, a SEGA occurs in a pa- lial membrane antigen (EMA) and S100 protein focally
tient without other stigmata of tuberous sclerosis, (Brat et al., 1988; Reifenberger et al., 1999; Brat et al.,
perhaps representing a form fruste of this disorder. 2000; Ricoy et al., 2000; Cenacchi et al., 2001; Galloway
SEGAs are WHO grade I lesions despite the occa- et al., 2001).
sional findings of mitoses and necrosis (Shepherd
et al., 1991).
FIGURE 16.47 Chordoid glioma. The cells demonstrate prominent

eosinophilic cytoplasm and paucity of processes, arranged as cohe-
FIGURE 16.46 Subependymal giant cell astrocytoma. Many neoplas- sive clusters and cords within an abundant vacuolated, myxoid
tic cells show immunoreactivity to GFAP. GFAP. stroma. H&E.
Due to the small number of reported cases and lim-

ited follow-up, the biologic behavior, prognosis, and
optimal therapy of chordoid glioma are not fully char-
acterized. Although histologically benign, the apparent
low growth potential and circumscription are offset by
the third ventricular location and difficulty in resection.
Some subtotally resected examples have continued to
enlarge. For reasons that are not clear, several patients
have died from pulmonary thromboembolism in the
postoperative period (Reifenberger et al., 1999; Brat et
al., 2000; Cenacchi et al., 2001).
NEURONAL AND MIXED NEURONAL–

GLIAL TUMORS FIGURE 16.49 Ganglioglioma showing biphasic pattern that includes
elongated astrocytic cells and larger ganglion cells. Hematoxylin and
eosin stain.
The recently revised WHO classification of these CNS
tumors includes (Nelson et al., 2000):
clude brain stem, cerebellum, spinal cord, and pineal
• Ganglioglioma and gangliocytoma
gland. CT imaging shows a circumscribed solid mass
• Desmoplastic infantile astrocytoma and gangli-
or a cyst with a mural nodule. The tumor may be hy-
oglioma
podense or isodense. Calcium may be present. Contrast
• Dysembryoplastic neuroepithelial tumor
enhancement is typical but may be faint or absent.
• Central neurocytoma
MR imaging shows a T1-weighted hypointense, T2-
• Cerebellar liponeurocytoma
weighted hyperintense circumscribed tumor or tumor
• Paraganglioma
nodule. Contrast enhancement varies from none to in-
tense, and may be solid, rim, or nodular. Cerebral tu-
Ganglioglioma and Gangliocytoma mors are commonly found as well-circumscribed, often
cystic masses containing a mural nodule, with superfi-
The ganglioglioma is the prototype of a mature gan-
cial extension into the cortex and leptomeninges (Fig.
glion cell tumor of the central nervous system (CNS),
16.48). The nodule, if present, contains diagnostic,
corresponding to the ganglioneuroma, its peripheral
biphasic tissue that has a glial phase which resembles
analogue. Gangliogliomas are typically lesions of chil-
a pilocytic astrocytoma: with a dense, fibrillary gliopil;
dren and young adults associated with a long clinical
Rosenthal fibers; granular eosinophilic bodies; lym-
history of seizure disorder, frequently of the temporal
phocytes; calcifications; and connective tissue (Fig.
lobe type (Wolf et al., 1988; Lang et al., 1993; Hirose
16.49). Other variants of the astrocytic component that
et al., 1997; Nelson et al., 2000). Other locations in-
may predominate in some cases include a fibrillary or
gemistocytic astrocytoma and a pleomorphic xan-
thoastrocytoma. Some tumors also may exhibit foci
of cells with perinuclear halos resembling oligoden-
droglioma. A congery of neurons, representing the sec-
ond phase, is dispersed throughout the gliopil, and their
appearance resembles that of raisins in a loaf of bread.
The neurons vary in shape and size, ranging from small
to intermediate and larger variants, many of which are
bi- or multinucleated, with the characteristic vesicular
nuclei, nucleoli, and Nissl substance of ganglion cells.
Associated round cell infiltrates represent lymphocytes
in most instances, as confirmed by immunoreactivity
with leukocyte common antigen (LCA) (Fig. 16.50).
The glial stroma is strongly positive for glial fibrillary
FIGURE 16.48 Ganglioglioma obtained as surgical specimen exhibit- acidic protein (GFAP) while the neuronal markers in-
ing sharply demarcated mural nodule. cluding synaptophysin and neurofilament proteins
FIGURE 16.50 Ganglioglioma showing ganglion cells, thick-walled FIGURE 16.51 T2- and T1-weighted MRI of a desmoplastic infantile
blood vessels, and perivascular lymphocytes. Hematoxylin and eosin ganglioglioma showing large cystic component involving frontotem-
stain. poral region and superficial solid component.
(NFPs) confirm the neuronal origin of the larger cells. bral lobes (Fig. 16.51). The solid component is usually
The ganglioglioma is amenable to complete surgical ex- superficial and extracerebral in relationship to the lep-
tirpation and potential clinical cure, and it is therefore tomeninges and is attached to the dura. It may be of
important to establish the correct diagnosis. Gangli- large size (Fig. 16.52). Microscopically, the neuronal
ogliomas correspond to WHO grade I and II lesions and glial elements are admixed with a dense, fibrous
(Nelson et al., 2000). There are occasional reports of stroma comprised of fibroblastic cells with deposition
malignant transformation associated with gangli- of a variable amount of reticulin and collagen fibers
oglioma (anaplastic ganglioglioma), although this is the (Figs. 16.53, 16.54). Some tumors may exhibit foci of
exception rather than the rule (Kalyan and Olivero, small, poorly differentiated cells that suggests a primi-
1987; Wolf et al., 1988; Hirose et al., 1997). Gangli- tive neuroectodermal tumor, which previously desig-
ogliomas with a malignant glial component, high- nated as a desmoplastic neuroblastoma (Vandenberg et
proliferation indices, and P53 labeling may have an ag- al., 1987) (Fig. 16.55). However, the presence of these
gressive clinical course (Kalyan and Olivero, 1987; primitive elements is not associated with an aggressive
Prayson et al., 1995; Hirose et al., 1997). Proliferation clinical behavior. A tumor with similar clinicopatho-
indices, as indicated by Ki-67/MIB-1 labeling are low logical features and comprised only of astrocytic ele-
(Wolf et al., 1988; Prayson et al., 1995; Hirose et al., ments was initially designated superficial cerebral
1997). Abnormal karyotypes involving several differ-
ent chromosomes have been found (Neumann et al.,
1993; Kordek et al., 1996). Gangliocytomas are WHO
grade I lesions composed of ganglion cells only (Nel-
son et al., 2000). The glial phase is not present.
Desmoplastic Infantile Astrocytoma

and Ganglioglioma
This lesion usually occurs in children under the age of
2 years, has solid and cystic components, and pre-
dominates in the supratentorial location (Taratuto et
al., 2000). On CT scan, the cystic component is hypo-
dense and the solid component appears isodense and
superficial and shows contrast enhancement. There
may be evidence of midline shift to the contralateral
hemisphere. The presentation may be that of a large, FIGURE 16.52 Large, solid component of a desmoplastic infantile gan-
superficial, cystic tumor involving one or several cere- glioglioma.
FIGURE 16.53 Desmoplastic infantile ganglioglioma comprised of a FIGURE 16.55 Desmoplastic infantile ganglioglioma showing compo-
heterogeneous cellular population including large and small astro- nent of small cells with nuclear pleomorphism. Hematoxylin and
cytic elements, ganglion cells, fibroblasts, and abundant intercellular eosin stain.
substance. Hematoxylin and eosin stain.
Dysembryoplastic Neuroepithelial Tumor

astrocytoma of infancy (Taratuto et al., 1982; de The dysembryoplastic neuroepithelial tumor (DNET) is
Chadarevian et al., 1990). The two entities, desmo- a newcomer to the scene of neuropathology. This WHO
plastic infantile ganglioglioma and superficial cerebral grade I lesion occurs predominantly in children and
astrocytoma, most probably represent different mani- young adults with a history of drug-resistant seizures
festations of the same tumor (Taratuto et al., 2000). (Daumas-Duport et al., 1988b). MRI defines the lesion
The proliferation index is low (Taratuto et al., 1994; better than CT scan, showing a cortical contrast en-
Tenreiro et al., 1995). Some studies suggest that the ge- hancing nodule. The lesion is characterized by an in-
netic abnormalities of these tumors are different than tracortical location, multinodularity, and adjacent ar-
those of other supratentorial astrocytomas. An origin eas of cortical dysplasia (Daumas-Duport et al., 2000)
from ectopic neuronal/glial rests or from subpial as- (Fig. 16.56). It has a preference for the temporal lobe,
trocytes has been postulated (Choi et al., 1987; Louis but other lobes may be involved. It has also been de-
et al., 1992; Aydin et al., 1993). The clinical behavior scribed in the basal ganglia, pons, and cerebellum
corresponds to a slow-growing neoplasm (WHO grade (Leung et al., 1994; Kuchelmeister et al., 1995). The
I) with survival longer than 8 years (Vandenberg et al., nodules expand the cerebral cortex and may extend
1993). into the subcortical white matter. The gross examina-
FIGURE 16.54 Desmoplastic infantile ganglioglioma showing abun- FIGURE 16.56 Dysembryoplastic neuroepithelial tumor showing cor-
dant intercellular collagen. Trichrome stain. tical location and nodularity. Hematoxylin and eosin stain.
tion shows that the cortical nodularity is usually

associated with a mucoid appearance. The microscopic
examination reveals a lesion comprised of a heteroge-
neous cellular population including small, oligoden-
drocytelike cells with round, uniform nuclei and GFAP-
positive astrocytes closely related to columns of axons
(Fig. 16.57). These columns delineate cystic spaces
where normal appearing neurons are present floating
in an acellular matrix (Fig. 16.58). This component has
been designated as the glioneuronal element. Recent
studies suggest that the small cells are of oligoden-
droglial origin (Wong et al., 1999). Tumors associated
with glial nodules in the cortex are being proposed to
be designated as complex variants. Areas of cortical
dysplasia with abnormal neurons and disorganized lay- FIGURE 16.58 Dysembryoplastic neuroepithelial tumor with neurons
ers are often present. Distinction of DNET from other present in cystic areas. Hematoxylin and eosin.
gliomas is extremely important since DNET is
amenable to surgical extirpation and prognosis is fa-
with involvement of the septum pellucidum, and that
vorable, even after incomplete excision. DNETs behave
often results in obstructive hydrocephalus (Figarella-
as low-grade lesions without progression to aggressive
Branger et al., 2000). Neuroimaging studies show an
forms. The proliferative indices vary from 0% to 8%
intraventricular mass that enhances after contrast ad-
(Daumas-Duport, 1993; Taratuto et al., 1995).
ministration. In addition, CT scans may show calcifi-
cation and cystic change. The III ventricle or more than
Central Neurocytoma one ventricle are less frequently involved (Morrison et
al., 1998). The tumor tends to remain within the ven-
The central neurocytoma was interpreted to be an
tricular lumen without CNS seeding or extraneural me-
intraventricular ependymoma or oligodendroglioma
tastasis. Eighty-one percent of the patients survive 5
prior to its identification and segregation as a separate
years or longer after complete or partial surgical exci-
entity, based on ultrastructural demonstration of in-
sion. The histologic pattern consists of abundant, rel-
tracytoplasmic neurosecretory granules (Hassoun et al.,
atively monotonous small cells with round nuclei, reg-
1982). This is an intraventricular lesion that usually
ular chromatin, and rare mitotic figures (Fig. 16.59).
strikes young to middle-aged adults, that is located
The perikaryon may show a perinuclear, optically
most frequently in the region of the foramen of Monro
empty clearing or halo artifact of oligodendroglioma.
The cells are associated with formation of a delicate,
FIGURE 16.57 Dysembryoplastic neuroepithelial tumor showing

glioneuronal element comprised of cystic spaces delimited by groups FIGURE 16.59 Central neurocytoma comprised of cells with round
of oligodendroglial and astrocytic cells associated with axons. Hema- nuclei and perinuclear halos. A network of delicate blood vessels is
toxylin and eosin stain. present. Hematoxylin and eosin stain.
finely fibrillar stroma. Perivascular rosettes suggestive of

ependymoma or large, relatively open rosettes similar to
those seen in pineocytomas may be present. In keeping
with the presence of intracytoplasmic neurosecretory
granules at the ultrastructural level (Fig. 16.60), the cells
show immunoreactivity for neuronal markers, including
synaptophysin, chromogranin, neuron-specific enolase
(NSE), class III beta tubulin, MAP-2, tau protein, and
NFP (von Deimling et al., 1991; Figarella et al., 1992;
Hessler et al., 1992). Occasional GFAP-positive cells are
present. Cells may show photoreceptor differentiation
with expression of retinal S antigen (Morrison et al.,
1998). A tumor with similar histological features has
been described in extraventricular locations including the
cerebral hemispheres and spinal cord. Due to the rela- FIGURE 16.61 Paraganglioma with cells organized in an organoid pat-
tern and perivascular rosettes. Hematoxylin and eosin stain.
tively favorable prognosis of this grade I lesion, it must
be accurately differentiated from grade II gliomas with
a similar histologic appearance, with particular differ-
ential emphasis on oligodendroglioma and ependy- al., 1996; Moran et al., 1997). The tumors are more fre-
moma. The proliferation index using the Ki-67 antibody quent in adult patients and the clinical presentation usu-
is low (Robbins et al., 1995). Cytogenetic studies de- ally reflects a mass lesion. Functional paragangliomas of
scribe abnormalities involving chromosomes 7 and 17 the CNS are extremely rare. The features of neu-
(Cerda-Nicolas et al., 1993; Taruscio et al., 1997). Tu- roimaging studies are nonspecific and the differential
mors with atypical histological features including mi- diagnosis of a spinal paraganglioma includes myxo-
toses, necrosis, and vascular proliferation had been de- papillary ependymoma, meningioma, schwannoma, and
scribed; however, their biological behavior remains hemangioblastoma. The lesion presents as an extra-
undetermined (von Deimling et al., 1990; Hassoun et al., medullary, intradural, well-demarcated tumor of the
1993). filum amenable to complete surgical excision. The tu-
mor is well vascularized and on the cut surface may ex-
hibit areas of hemorrhage and fibrosis. Less than 1% of
Paraganglioma
spinal paragangliomas are locally aggressive with infil-
Paragangliomas of the CNS are located predominantly tration of the adjacent bone (Moran et al., 1997). Dis-
within the spinal canal, mainly in the region of the cauda semination throughout the CSF pathways has occasion-
equina and filum terminale (Soffer et al., 2000). Other ally been reported (Blades et al., 1991; Roche et al.,
uncommon locations include the thoracic and cervical 1996). Histologically, central paragangliomas are simi-
regions, temporal bone, and sella turcica (Scheithauer et lar to their peripheral counterparts, with chief and sus-
tentacular cells arranged in alveolar (Zellballen),
organoid, and glandular patterns and in perivascular
rosettes (Fig. 16.61). Other features may include gan-
glionic differentiation and the presence of cytoplasmic
melanin (Moran et al., 1997). The chief cells im-
munoreact not only to conventional neuroendocrine
markers but also to neuropeptides, including somato-
statin and ACTH, as well as to keratin (Fig. 16.62). The
chief cells contain abundant cytoplasmic neurosecretory
granules (Fig. 16.63). The sustentacular cells, which con-
stitute a minority, are positive for S-100 protein.
OLIGODENDROGLIOMA AND
MIXED OLIGOASTROCYTOMA
FIGURE 16.60 Central neurocytoma with cells that contain small, The oligodendroglioma is a glial neoplasm comprised
electron-dense secretory granules in their cytoplasm and processes. of round, uniform cells with scant cytoplasmic pro-
droglioma typically appears as a heterogeneous par-

tially calcified hemispheric mass that often involves cor-
tex. Scalloped pressure erosion may occur in the over-
lying skull. Cystic components are common and most
examples show mild to moderate inhomogeneous con-
trast enhancement.
Macroscopically, the oligodendroglioma demon-
strates relative gross circumscription that may be ap-
parent at surgery. The tendency for cortical involve-
ment results in gyral expansion, and, on cut section,
obliteration of the usually distinct interface between
gray and white matter. The tumor often displays a soft
mucoid consistency. Unlike fibrillary astrocytomas,
oligodendrogliomas tend to be demarcated from un-
FIGURE 16.62 Paraganglioma with chief cells showing immunoreac- derlying white matter. This may be sharp, especially in
tivity for synaptophysin. Peroxidase–antiperoxidase method. more cellular examples. Calcification, when present,
varies from barely discernible to coarse.
The essential microscopic feature of the oligoden-
cesses that resemble the presumed cell of origin, the droglioma is cellular monotony. The tumor is com-
oligodendrocyte (Burger et al., 1987; Burger and Schei- prised of a relatively even distribution of monomor-
thauer, 1994; Reifenberger et al., 2000). Nonetheless, phous cells characterized by nuclei that are more often
there never has been substantial evidence to support a uniformly round than they are oval, with open or del-
definite origin of such tumors from mature oligoden- icate chromatin (Fig. 16.64). Nuclei are surrounded
drocytes. Indeed, the neoplastic cells do not express either by a rim of clear cytoplasm resulting in the clas-
markers of mature oligodendrocytes, produce myelin, sic “fried-egg” appearance (Fig. 16.65) or by a scant,
or demonstrate convincing oligodendroglial features at slightly eccentric rim of pink cytoplasm and few pro-
the ultrastructural level. Oligodendrogliomas likely cesses. Cell density generally is rather uniform, al-
arise from a glial precursor cell capable of both oligo- though distinct nodular zones of hypercellularity may
dendroglial and astrocytic differentiation (Shoshan et be seen (Fig. 16.66); such circumscribed nodules are
al., 1999). analogous to similar hypercellular foci in ependy-
In its classic form, the oligodendroglioma is clini- moma but are uncommon in fibrillary astrocytoma.
cally, radiologically, and pathologically distinctive. Al- Uniformity of nuclear size and shape are key diag-
though commonly quoted figures suggest oligoden- nostic features. Even in the presence of scattered large
drogliomas comprise 5%–15% of all gliomas, in recent hyperchromatic cells, the tendency to roundness re-
years it has become apparent that they are far more mains. With increased tumor grade, cellularity in-
common than previously thought. In our experience, creases and the tendency to nuclear pleomorphism
oligodendrogliomas occur at least as frequently as well- emerges.
differentiated astrocytomas of the diffuse (fibrillary)
type (Giannini et al., 2001).
Oligodendrogliomas occur throughout the CNS.
Most are supratentorial in location, arising within
white matter of the cerebral hemispheres, particularly
the frontal lobes, and occur primarily in adulthood
(peak 35–40 years), but they may occur at any age.
Males seem to be affected slightly more often. Oligo-
dendrogliomas often undergo slow clinical evolution
and frequently are associated with a long history of
seizures, the result of their tendency toward cortical in-
filtration. Calcification is common, and on occasion it
is gyriform in pattern. Neuroimaging suggests the di-
agnosis when calcification, cortical involvement, and
relative demarcation of deep aspects of the tumor are
present (Burger et al., 1987; Burger and Scheithauer, FIGURE 16.63 Paraganglioma showing chief cells with abundant cy-
1994; Reifenberger et al., 2000). The oligoden- toplasmic electron-dense neurosecretory granules.
FIGURE 16.64 Oligodendroglioma. Smear preparations best show the

FIGURE 16.66 Oligodendroglioma. Vague nodules of cells may arise
regular, somewhat hyperchromatic nuclei, small skirt of cytoplasm,
and relative lack of cell processes. within a less cellular neoplastic infiltrate. H&E.
Although nuclear uniformity and roundness charac- In addition to the distinctive rounded cells, oligo-
terize the oligodendroglioma, cytologic features, par- dendrogliomas may contain “transitional cells” in-
ticularly in tissue sections, vary considerably. The fried- cluding the gliofibrillary oligodendrocyte and the
egg appearance of the cell (i.e., with a prominent minigemistocyte (Herpers and Budka, 1984; Kros et al.,
perinuclear halo) is an artifact of delayed formalin fix- 1990; Kros et al., 1992; Sarkar et al., 1999). Due to
ation and due to influx of water; when present, how- their variable content of intracytoplasmic glial fila-
ever, it is diagnostically helpful. In tissues frozen or ments, these cells previously were thought indicative of
fixed promptly, the halo is lacking and the diagnosis astrocytic differentiation but now are accepted as part
must be predicated on nuclear features alone (Fig. of the oligodendroglial spectrum. The gliofibrillary
16.67). Freezing also induces hyperchromasia and nu- oligodendrocyte histologically is identical to the classic
clear irregularity, which results in the oligodendroglial oligodendroglioma cell but demonstrates a flame-
nuclei mimicking those of infiltrative astrocytoma on shaped perinuclear rim of GFAP-positive cytoplasm.
frozen section (Figs. 16.68, 16.69). For this reason, The minigemistocyte (Fig. 16.70) is smaller than the or-
some well-fixed, nonfrozen tissue always should be dinary astrocytic gemistocyte, lacks cytoplasmic pro-
saved (Fig. 16.69), particularly with small stereotactic cesses, and shows a globular paranuclear (skirtlike)
biopsies where sampling biases already may hinder ac- cytoplasmic immunoreactivity to GFAP. Both gliofib-
curate assessment. rillary oligodendrocytes and minigemistocytes possess
FIGURE 16.67 Oligodendroglioma. Although perinuclear halo for-

FIGURE 16.65 Oligodendroglioma. Note cellular uniformity and mation is a feature of delayed fixation, it is lacking in this promptly
prominent perinuclear “halos.” H&E. fixed specimen. H&E.
FIGURE 16.68 Oligodendroglioma. Short of showing regularity of the FIGURE 16.70 Oligodendroglioma with microgemistocytes. Such
cells, frozen sections often obscure helpful diagnostic features. Fur- plump cells with excentric cytoplasm (left) showing GFAP positivity
thermore, the process of freezing affects the cytologic features evi- (right) are seen in a minority of tumors.
dent on permanent sections. H&E.
eosinophilic cytoplasm that ultrastructurally corre-

round uniform nuclei, and not the elongated pleomor- sponds to degenerated mitochondria and glycogen
phic nuclei of neoplastic astrocytes. Their presence ap- storage. In contrast to the minigemistocyte, signet-ring
pears to be of no prognostic significance in oligoden- cells are filament poor and GFAP-negative. Occa-
drogliomas, and since they resemble the myelination sionally an oligodendroglioma may assume an epi-
glia of perinatal brains, they may in fact represent ear- thelioid or carcinomalike appearance with round-to-
lier stages of oligodendroglial differentiation, in which polygonal cells containing vesicular nuclei, sometimes
GFAP-positive cytoplasm is normal. with prominent nucleoli. Most of these are high-grade
Some oligodendrogliomas contain other variant cell examples and demonstrate more classic cytology and
types including cells with granular eosinophilic bod- infiltrative growth elsewhere. These cytologic varia-
ies, signet rings, and epithelioid cells. Eosinophilic tions in oligodendrocytes have been well described
granular cells (Takei et al., 1976), although reminis- (Daumas-Duport et al., 1997a). The characteristic dis-
cent of the eosinophilic granular bodies (EGBs) of pi- tribution of its vasculature is another reliable feature
locytic astrocytoma, PXA, and ganglioglioma, are in- in the diagnosis of oligodendroglioma. Blood vessels
tracellular and correspond to autophagic lysosomes in well-differentiated examples consist of short ar-
ultrastructurally. The signet-ring cell (Kros et al., borizing capillary segments arranged geometrically
1997) shows an eccentric, finely vacuolated, clear-to- and resembling chicken wire (Fig. 16.71). With ana-
plastic transformation, these become thickened and
FIGURE 16.69 Oligodendroglioma. Same specimen as in Figure 16.68,

but not frozen. Note the preservation of round, uniform nuclear fea- FIGURE 16.71 Oligodendroglioma. Note cellular uniformity and a
tures. H&E. geometric “chicken-wire” arrangement of vessels. H&E.
hypertrophied and may demonstrate frank endothe-

lial proliferation.
Oligodendrogliomas have a tendency for cortical in-
filtration, as evidenced by striking perineuronal satelli-
tosis (Fig. 16.72) and subpial and perivascular accu-
mulations of cells. Microcystic change is a frequent
occurrence in oligodendroglioma (Fig. 16.73), and in
some studies (Mork et al., 1986), one of prognostic sig-
nificance. Unusual patterns in oligodendroglioma in-
clude regimented palisading nuclei resembling primitive
polar spongioblastoma, as well as the formation of is-
lands or lobules of discrete or clustered cells surrounded
by a delicate fibrovascular stroma.
Like any process that infiltrates brain parenchyma,
oligodendrogliomas incite reactive astrocytosis. The re- FIGURE16.73 Oligodendroglioma. Intercellar mucin accumulation is
a common feature that may lead to cyst formation. H&E.
active cells appear as evenly distributed, stellate cells
with delicate nuclei, moderate quantities of eosinophilic
cytoplasm, and circumferential, tapering processes.
These cells, best demonstrated on GFAP preparations, to study (Smith et al., 1983; Mork et al., 1986; Kros
should not prompt a diagnosis of oligoastrocytoma et al., 1988; Daumas-Duport et al., 1997b), and as
(mixed oligodendroglioma–astrocytoma). such, there is no consensus of the features most im-
Although spontaneous and occasionally fatal hem- portant in grading. Microcysts and low cellularity are
orrhage is a rare complication of gliomas, a dispro- regarded as favorable prognostic factors, while the oth-
portionate number occur in oligodendrogliomas, a ten- ers generally are unfavorable.
dency that may be related to dystrophic changes within Smith et al. (1983), in a review of 323 cases from
vessels. the Armed Forces Institute of Pathology (AFIP) divided
oligodendrogliomas into four categories (A–D) in or-
der of increasing biologic aggressiveness based on nu-
Grading
clear pleomorphism, cellular density, endothelial pro-
Many studies have confirmed the prognostic signifi- liferation, and necrosis, but did not include mitoses as
cance of histologic grading in oligodendrogliomas. In a parameter. Although there were differences in sur-
general, the parameters used for grading include some vival between the least and most aggressive tumors,
combination of increased cellularity, microcyst forma- midgrade tumors constituted the majority and had sim-
tion, atypia, mitotic activity, vascular hypertrophy or ilar prognoses. Mork et al. (1986), in a study of 208
endothelial proliferation, and necrosis. The features cases, concluded that cellularity, necrosis, and micro-
most predictive of outcome, however, differ from study cyst formation were significantly associated with out-
come. Burger et al. (1987) studied 15 variables in 71
tumors and found necrosis and mitoses to be the only
histologic parameters independently associated with
survival. They recommended a two-tiered grading
scheme—oligodendroglioma and anaplastic oligoden-
droglioma—based on the absence or presence of ne-
crosis and mitoses. Daumas-Duport et al. (1997a,b), in
an analysis of 79 cases, found endothelial hyperplasia
and radiographic contrast enhancement to be the most
objective and powerful negative prognostic variables;
they proposed a radiologic–pathologic grading scheme
in which the presence of either feature qualified for the
designation of anaplastic oligodendroglioma.
The recent WHO schema (Reifenberger et al., 2000)
divides oligodendrogliomas into two categories: oligo-
FIGURE 16.72 Oligodendroglioma. Neuronal “satellitosis” is a char- dendroglioma (well-differentiated oligodendroglioma,
acteristic feature of the tumor when involving cortex. H&E. WHO grade II), and anaplastic oligodendroglioma
(WHO grade III), based on cellularity, nuclear pleo- of comparable grade. Median survivals for well-differ-
morphism, and mitoses, with vascular proliferation and entiated and anaplastic oligodendrogliomas range from
necrosis features of the anaplastic variant. This two- 9.8–11 years to 3.5–3.9 years, respectively (Shaw et al.,
tiered approach is also supported in the study of Gi- 1992; Daumas-Duport et al., 1997a). In some series,
aninni et al. (2001). The well-differentiated oligoden- shorter survivals have been reported in older patients,
droglioma includes a spectrum of lesions ranging from a not unexpected finding (Burger et al., 1987).
relatively hypocellular examples lacking cytologic In contrast to astrocytomas, a relatively large num-
atypia and mitoses to more cellular tumors with some ber of oligodendrogliomas are both radiosensitive and
atypia and absent to infrequent mitoses (grade II oligo- chemosensitive, particularly to the PCV (procarbazine,
dendroglioma). Tumors in the anaplastic category in- CCNU or lomustine, vincristine) regimen (Cairncross
clude those with brisk mitotic activity and endothelial et al., 1992; Cairncross et al., 1994; Kim et al., 1996).
hypertrophy (grade 3 oligodendroglioma) (Fig. 16.74), Recent advances in molecular genetics have identified
to those with obvious endothelial proliferation and specific genetic markers associated with the oligoden-
often-palisading necrosis (grade 4 oligodendroglioma). droglial phenotype and predictive of behavior. Several
Although a high-grade oligodendroglioma may exhibit groups (Cairncross et al., 1998; Perry et al., 1999; Bau-
all the hallmarks of a glioblastoma, it is important that man et al., 2000; Smith et al., 2000) have found 1p
it not be designated as glioblastoma, since therapeutic loss or combined 1p and 19q loss to be powerful prog-
approaches are different and overall prognosis im- nostic variables. It appears that a combined lp/19q dele-
proves (Shaw et al., 1992). Systemic metastasis is rare tion provides a relatively specific molecular signature
(Jellinger et al., 1969) and, as in the case of glioblas- for oligodendroglial tumors—in most oligoden-
toma, usually follows surgery. drogliomas both 1p and 19q chromosomal arms are
Although MIB-1 indices vary considerably from deleted, while a minority of cases show loss of either
study to study, there is a correlation between increased 1p or 19q (Bigner et al., 1999). Combined 1p/19q losses
labeling index and shorter survival. Oligoden- have associated strongly with oligodendroglial histol-
drogliomas with MIB-1 labeling indices of 5% or less ogy (Ritland et al., 1995). The pathogenic role of 1p
have been associated with median survival of 1718 and 19q deletions in oligodendrogliomas remains
days, while those with indices of >5% had a median enigmatic. Usually, inactivation of tumor suppressor
survival of 452 days (Coons et al., 1997). genes is associated with more aggressive clinical be-
havior. The opposite seems to occur in oligoden-
drogliomas, where losses of 1p/19q confer enhanced
Treatment and Prognostic Variables
susceptibility to therapy and improved survival. An-
Oligodendrogliomas, due to their infiltrative nature, are other curiosity is why losses of both chromosomes al-
not totally resectable. Five-year survivals of patients most always occur together in oligodendrogliomas.
with oligodendrogliomas, however, are better than
those of patients with diffuse (fibrillary) astrocytomas
Oligoastrocytoma
Oligoastrocytomas are mixed tumors, composed of
both neoplastic oligodendroglioma and fibrillary as-
trocytoma. Although the individual components may
be separate and distinct, in most cases they are inti-
mately admixed (Fig. 16.75). Recognition of the
neoplastic and reactive astrocytes, as well as the
GFAP-positive variants of oligodendrocytes, poses a
formidable challenge to pathologists. To qualify as an
oligoastrocytoma, a substantial proportion of neoplas-
tic astrocytes is required. Nonetheless, there is no con-
sensus regarding the proportion of cells required. Some
authors require at least 25% astrocytic cells for an
oligoastrocytoma diagnosis (Mork et al., 1986; Burger
et al., 1987), although the distinction of such tumors
FIGURE 16.74 Anaplastic (grade 3) oligodendroglioma. Note in-
from pure oligodendrogliomas, as well as from diffuse
creased cellularity, thickening of the vasculature due to endothelial astrocytomas, remains controversial, even among ex-
hypertrophy, and hyperplasia and mitotic figures. H&E. perienced neuropathologists. When a diagnosis of
matter, as well as neurons, and especially in thick sec-

tions, they may appear numerous. Attention to cyto-
logic detail aids in their distinction from tumor since
nuclei of neoplastic cells are larger, rounder, and have
coarser chromatin than normal perineural satellite cells.
Correlations with neuroimaging are important since the
diagnosis of tumor should not be seriously considered
if MR images show no abnormality. A nonspecific in-
crease in oligodendroglial cells commonly occurs in the
white matter of patients with longstanding seizures,
presumably on the basis of tissue contraction that ac-
companies chronic processes. Lack of significant cyto-
logic atypia and of proliferative activity all attest to the
benign nature of the process. A reactive influx of his-
FIGURE 16.75 Oligoastrocytoma. An intimate admixture of both
tiocytes within the setting of demyelinating disease or
oligodendroglia and astrocytes characterizes this mixed tumor. H&E.
infarct should not be mistaken for oligodendroglioma.
Histiocytes are delicately PAS-positive, lack staining for
S-100 protein, and are immunoreactive for macrophage
oligoastrocytoma is rendered, the relative composition markers, such as CD68 (KP-1 or PGM-1) and Ham 56.
should be specified (i.e., oligodendroglioma–predomi- The distinction of oligodendroglioma from infiltra-
nant, or astrocytoma–predominant, or equally repre- tive fibrillary astrocytoma may be difficult, particularly
sented). It is important to distinguish oligoastrocytoma when the specimen has been previously frozen and
from ordinary diffuse astrocytoma, since even a minor pleomorphism and hyperchromasia are artefactually in-
oligodendroglial component seems to confer a positive duced. In well-fixed specimens, the tendency to nuclear
influence on prognosis. This is especially true for elongation, coupled with the lack of perinuclear halos,
anaplastic variants that have shown some response to and chicken-wire vasculature, suggests the diagnosis of
chemotherapy (Glass et al., 1992; Kim et al., 1996). astrocytoma. Distinguishing gemistocytic astrocytoma
Although few prognostic studies have focused specifi- from oligodendrogliomas rich in minigemistocytes is
cally on oligoastrocytomas, in a study by Shaw et al. predicated upon the cell size (large in gemistocytic as-
(1994), median survival times were 6.3 years and 2.8 trocytoma) and the presence or absence of cytoplasmic
years for well-differentiated and anaplastic variants, processes (present in astrocytoma, absent in oligoden-
respectively. droglioma). Nonetheless, this is an important distinc-
tion to make since oligodendrogliomas and oligoastro-
cytomas typically progress slower, have prolonged
Immunohistochemical Features
survival, and are more responsive to therapy, compared
Oligodendrogliomas show S-100 immunoreactivity and to their astrocytic counterparts. Ependymomas on oc-
frequently (but not always) some degree of membrane casion demonstrate remarkable clear cell change, but
staining with Leu-7 (Nakagawa et al., 1986). Stains for
myelin-associated antigens, in general, are of little di-
agnostic use. As previously noted, oligodendrogliomas TABLE 16.5 Potential Oligodendroglioma Mimickers
may show several patterns of GFAP immunoreactivity,
Well-differentiated fibrillary astrocytoma
including flamelike reactivity in the cell body of the
Clear cell ependymoma
gliofibrillary oligodendrocyte and globular paranuclear
staining in the minigemistocyte. Neoplasms with “neurocytic” differentiation (central neurocytoma,
ganglioneurocytoma, glioneurocytoma, nodular
medulloblastoma)
Differential Diagnosis Dysembryoplastic neuroepithelial tumor (DNT)
Pilocytic astrocytoma with oligodendrogliomalike component
The differential diagnosis of oligodendrogliomas is
Clear cell meningioma
broad (Table 16.5). For practical purposes, it requires
the distinction of oligodendroglioma from normal an- Metastatic clear cell carcinoma
atomic variants, from reactive processes, and from Non-neoplastic macrophage-rich lesions (demyelinating disease,
progressive multifocal leukoencephalopathy (PML), subacute
other neoplasms. Oligodendrocytes in normal brain
infarct)
may congregate about vessels, particularly in white
unlike oligodendrogliomas they are sharply demarcated ithelial appearance of most ependymal cells, they are
(with pushing noninfiltrative borders), show marked closely related to glial cells and under reactive condi-
contrast enhancement and deep periventricular locations may undergo prominent glial fibrillogenesis.
tion, and exhibit at least some perivascular pseudo- Ependymomas arise throughout the neuroaxis, most
rosette formation, and ependymal features ultrastruc- often in a periventricular location. Rare ectopic exam-
turally. Central neurocytomas also are characterized by ples, arising in pre- or postsacral soft tissue, medi-
nuclear uniformity and frequent perinuclear halo astinum, lung, ovary, or broad ligament, have been de-
formations, but typically they involve the septum pel- scribed (Nobles and Lee, 1991).
lucidum, show contrast enhancement, exaggerated Most ependymomas occur in childhood (peak inci-
Homer Wright rosettes, and strongly synaptophysin im- dence 10–15 years), but all age groups are affected
munoreactivity. Extraventricular examples more regu- (Ernestus et al., 1991; Lyons and Kelly, 1991; Burger
larly show ganglionic and/or astrocytic differentiation. and Scheithauer, 1994; Schiffer and Wiestier, 2000).
The dysembryoplastic neuroepithelial tumor (DNT) Males and females are equally represented. Overall,
also enters into the differential since oligodendroglia- 60% of intracranial ependymomas are supratentorial
like cells are a large component of such tumors. The and 40% infratentorial; supratentorial examples pre-
diagnosis of DNT is facilitated by the recognition of dominate in childhood while infratentorial tumors are
architectural features, including patterned intracortical more common in adults. Supratentorial ependymomas
nodules of oligodendrocytelike cells, cortical neurons often are cystic and generally produce increased in-
within mucus-containing spaces (floating neurons), and tracranial pressure or mass effect. Posterior fossa tu-
the frequent association of cortical dysplasia in sur- mors obstruct CSF flow with resultant hydrocephalus.
rounding cortex. Occasionally a pilocytic astrocytoma Ependymomas represent 60% of gliomas of the spinal
will have a prominent oligodendroglial-like component cord (Fig. 16.76). Most spinal examples arise in the
and must be distinguished from oligodendroglioma. filum terminale as myxopapillary variants and occur pri-
Helpful features favoring pilocytic astrocytoma include marily in adults (Schweitzer and Batzdorf, 1992). Mul-
lesion location (cerebellum, hypothalamus, optic path- tifocal spinal cord examples often are associated with
way, brain stem, spinal cord), gross and radiographic neurofibromatosis type 2. Tumors of the spinal cord of-
demarcation, an often-cyst-enhancing mural nodule ar- ten are accompanied by a proximal and/or distal syrinx
chitecture, and biphasic histology with frequent (Fig. 16.77). The neuroimaging of ependymomas is sim-
eosinophilic granular bodies and Rosenthal fibers. ilar to that of other gliomas. On CT scans, most are
An occasional oligodendroglioma may mimic a
meningioma, particularly if it extends to the lep-
tomeningeal surface and histologically demonstrates
clear cell histology; in the absence of collagenous
stroma, thick-walled vessels and whorls the diagnosis
of glioma should be favored. Metastatic clear cell car-
cinoma typically has pushing (i.e., noninfiltrative) bor-
ders, epithelial regimented cytology, significant nuclear
atypia/pleomorphism with nucleolar prominence, and
cytokeratin and epithelial membrane antigen (EMA)
immunoreactivity.
EPENDYMOMA
The normal ependyma consists of a single layer of

cuboidal-to-columnar cells that lines the entire ventric-
ular system and extends throughout the spinal cord into
the filum terminale. In neonates but not adults, the cil-
iated cells rest upon a fibrillated layer of glial cells
(subependymal glia). Specialized elongate, distinctly
glial-appearing ependymal cells termed tanycytes are
best seen in the floor of the third ventricle as they tra- FIGURE 16.76 Ependymoma. The circumscription of ependymomas
verse the wall form pia to ependyma. Despite the ep- is illustrated by this spinal example.
FIGURE 16.79 Cellular ependymoma. Cell regularity, round to oval,

somewhat hyperchromatic nuclei with distinct nucleoli and promi-
nent perivascular pseudorosettes are typical features. Perivascular
pseudorosette formation is a very helpful diagnostic feature, one more
common than true rosettes. H&E.
shaped; despite lack of a capsule, they are demarcated

FIGURE 16.77 Ependymoma. On section this spinal ependymoma
shows irregular cystic components and syrinx formation both above and amenable to gross total removal (Figs. 16.78,
and below the mass. 16.79). The myxopapillary ependymoma often presents
as a sausage-shaped lesion that distends and attenuates
the filum, forming a delicate capsule the rupture of
isodense to brain, about one-half exhibit calcification. which may result in seeding the subarachnoid space at
Similarly, on MR images, the ependymoma is hypo- or the time of initial surgery.
isodense to brain on T1-weighted images and hyperin- Microscopically, the cellularity and architectural fea-
tense on T2-weighted images. Most show variable, mild tures of ependymomas are highly varied, a reflection of
to moderate inhomogeneous enhancement. their dual epithelial and glial nature (Fig. 16.78). Cel-
Macroscopically, ependymomas are lobulated and lular (Fig. 16.79), papillary (Fig. 16.80), and myx-
well circumscribed and present as fleshy, discrete opapillary (Fig. 16.81) variants are recognized (Table
masses. They generally displace rather than infiltrate 16.6). Cellular ependymomas demonstrate sheetlike
brain, and tend to fill ventricles and extend through growth of monomorphous cells; the cells have round-
ventricular foramina. Spinal examples typically are sit- to-oval, often hyperchromatic nuclei with distinct nu-
uated entirely within the cord and tend to be pencil- cleoli and, frequently, prominent cell processes that in
FIGURE 16.78 Ependymoma. The ependymoma exhibits either/or FIGURE 16.80 Papillary ependymoma. This uncommon variant ex-
both glial (left) or an epithelial phenotype (right). H&E. hibits a remarkably epithelial phenotype. H&E.
FIGURE 16.82 Ependymoma. True rosettes with a lumen may be in-

FIGURE 16.81 Myxopapillary ependymoma. Note the cohesive apparent at first glance. Unlike pseudorosettes (see Fig. 16.81), true
ependymal cells, the processes of which terminate around mucin-rich rosettes center upon a lumen, rather than a vessel. H&E.
perivascular spaces. H&E.
ymomas are noted for their pseudopapillary architec-

perivascular zones form pseudorosettes (Fig. 16.79). ture with perivascular accumulations of PAS- and Al-
Nearly all ependymomas show perivascular pseudo- cian blue–positive mucin. Mucin also may form ex-
rosettes, and it is uncommon to make this diagnosis in panses not associated with vessels. In some instances,
their absence. In contrast, only a minority show ep- mucin is so extensive as to simulate chordoma, myx-
ithelial features in the form of true ependymal rosettes oid chondrosarcoma, or mucinous carcinoma. Only an
canals or strips of ependymal epithelium. True rosettes occasional ependymoma shows prominent clear cell
(Fig. 16.82), although considered the sine qua none of change that mimics oligodendroglioma. Such clear cell
ependymoma, are infrequent. Under oil immersion, ble- ependymomas (Fig. 16.83) typically present as large
pharoplasts (ciliary basal bodies), a feature of ependy- cystic supratentorial masses in childhood. The rare
mal cells best seen in association with true rosettes, are tanycytic ependymoma (Fig. 16.84) is composed of
minute phosphotungstic acid hematoxylin (PTAH)- elongate cells that mimic pilocytic astrocytoma and
positive bodies in the apical cytoplasm. Their visual- show only vague pseudorosette formation; in such
ization in glial and in densely cellular epithelial-like re- cases, electron microscopic demonstration of ependy-
gions is aided by immmunohistochemisty (see below). mal features may be required to confirm the diagnosis.
The myxopapillary ependymoma (Fig. 16.81) is a Even more unusual is the finding of an ependymoma
morphologically unique tumor that occurs almost ex-
clusively in the region of the conus–cauda–filum
terminale, and rarely within the spinal cord or in-
tracranially (Sonneland et al., 1985; Specht et al., 1986;
Schweitzer and Batzdorf, 1992). Myxopapillary epend-
TABLE 16.6 Ependymoma Variants

Variant Histologic Features
Cellular High cellularity with few pseudorosettes;

infrequent rosettes
Papillary Pseudoepithelial growth pattern mimics
choroid plexus papilloma
Clear cell Oligolike appearance with perinuclear halos
Tanycytic Very long processes with vague
pseudorosettes; GFAP-positive FIGURE 16.83 “Clear cell” ependymoma. Though grossly circum-
Myxopapillary Conus/filum location; pseudopapillary with scribed, this tumor closely resembles an oligodendroglioma, both in
perivascular mucin microsections and on smear. Electron microscopy may be required
to confirm the diagnosis.
FIGURE 16.84 Tanycytic ependymoma. This tumor shows only vague FIGURE 16.85 Anaplastic (grade 3) ependymoma. Note marked nu-
pseudorosette formation and is composed of elongated cells mimic- clear atypia and mitotic activity. H&E.
king pilocytic astrocytoma. H&E.
with cartilage and/or bone (Mathews and Moossy, toma. All ependymomas, including myxopapillary,
1974), or melanin (Rosenblum et al., 1990). Well- clear cell, and tanycytic variants, exhibit some degree
known ultrastructural features of ependymomas in- of immunoreactivity for GFAP (Specht et al., 1986;
clude closely apposed cells demonstrating intercellular Cruz-Sanchez et al., 1988; Kaneko et al., 1990;
microrosettes, surface microvilli, and occasional cilia. Figarella-Branger et al., 1991). Whereas perivascular
Intercellular junctions usually take the form of zonu- pseudorosettes are immunoreactive, true rosettes lack
lae adherents or ribbon junctions. Cytoplasmic inter- GFAP staining. Immunostaining for S-100 protein also
mediate filaments, present in varying number and dis- is a uniform feature of ependymoma. Limited staining
tribution, are immunohistochemically identical to the for EMA and cytokeratin also may be seen, particu-
glial filaments of astrocytes. larly in well-differentiated papillary examples (Cruz-
Histologic grading of ependymomas is controversial Sanchez et al., 1988; Uematsu et al., 1989; Kaneko et
(Afra et al., 1983; Ilgren et al., 1984; Rawlings et al., al., 1990; Figarella-Branger et al., 1991). Cellular tu-
1988; Figarella-Branger et al., 1991; Lyons and Kelly, mors often feature paranuclear intercellular dot-like
1991; Schiffer et al., 1991; Schiffer and Wiestler, 2000). EMA staining, corresponding to microlumen forma-
In our experience, cytologic atypia and necrosis, par- tion. The designation ependymoblastoma should be
ticularly if unassociated with palisading, are of no clin- restricted to a highly characteristic, malignant ependy-
ical significance. Brisk mitotic activity and endothelial mal tumor of childhood, a part of the spectrum of em-
proliferation are unfavorable features (Fig. 16.85) (Afra
et al., 1983; Shaw et al., 1986; Nazar et al., 1990;
Figarella-Branger et al., 1991; Ernestus et al., 1991;
Schiffer et al., 1991; Schiffer and Wiestler, 2000). Prog-
nostic features of ependymoma that correlate best with
prognosis are largely clinical and include patient age
(unfavorable when less than 4 years), extent of tumor
resection, and tumor location (supratentorial being
more favorable than infratentorial). Seeding the sub-
arachnoid space may occur in some cases (Fig. 16.86).
The significance of proliferation markers is unsettled,
some studies finding a relationship (Nagashima et al.,
1988) and others none. Only an occasional ependy-
moma acquires features of glioblastoma (anaplasia, mi-
toses, endothelial proliferation, and necrosis with pal-
isading) and loss of ependymal features (perivascular
pseudorosettes); such tumors are considered highly FIGURE 16.86 Anaplastic (grade 3) ependymoma with subarachnoid
anaplastic (grade 4) ependymomas and not glioblas- (left) and ventricular (right) seeding. H&E.
bryonal tumors which include medulloepithelioma, glioma lacks GFAP reactivity but shows argyrophilia
cerebral neuroblastoma, medulloblastoma, PNET, pi- and immunoreactivity for synaptophysin, chromo-
neoblastoma, retinoblastoma, etc. granin, and neurotransmitter substances and S-100
protein–positive sustentacular cells surrounding the
Zellballen (Sonneland et al., 1986).
Differential Diagnosis
Due to their distinctive architecture, most ependymomas
Treatment and Prognosis
are not confused with other lesions. Difficulties may
arise, however, in examples with extensive glial differ- The prognosis of patients with ependymoma is variable
entiation. Nonetheless, an ependymoma with extensive and, as noted previously, depends in large part upon
fibrillary process formation that superficially resembles patient age tumor location, and extent of resection.
either ordinary fibrillary astrocytoma or pilocytic astro- Subtotally resected tumors tend to recur and ultimately
cytoma is solid in nature, displaces surrounding paren- may be fatal without adjuvant therapy. Only a small
chyma, and shows at least focal increased cellularity with proportion of ependymomas (5%) undergo cere-
perivascular pseudorosette formation. A high degree of brospinal dissemination and form symptomatic im-
suspicion is required in order not to miss tanycytic plants. These typically occur in association with local
ependymomas. Although their demarcation may suggest tumor recurrence (Ilgren et al., 1984), and as a rule,
the diagnosis, in instances where obvious perivascular they are high-grade lesions. Spinal ependymomas are
pseudorosettes are lacking, only electron microscopy associated with a more favorable prognosis, since gross
provides the diagnosis. Ependymomas with widespread total removal is frequently possible (Sonneland et al.,
epithelial features must not be mistaken for choroid 1985; Shaw et al., 1986; Schweitzer and Batzdorf,
plexus neoplasms or metastatic carcinoma. Unlike most 1992); this is particularly true of myxopapillary
ependymomas, choroid plexus papillomas and carcino- ependymomas, which, when encountered intact and re-
mas show obvious epithelial cytology with distinct sected totally, may be cured. More often, however, the
subepithelial basement membrane formation and uni- tumor capsule is only partially intact and already has
form cytokeratin reactivity. Although ependymomas of- seeded the lumbar sac (Davis and Barnard, 1985; Son-
ten show cytoplasmic EMA reactivity (see below), cho- neland et al., 1985; Schweitzer and Batzdorf, 1992).
roid plexus tumors are generally nonreactive. Metastatic Rarely, a tumor that occurs primarily in the region of
carcinomas generally lack S-100 and GFAP immunore- the filum terminale spreads to the brain. Myxopapil-
activity, and their EMA staining far exceeds that of lary ependymomas producing systemic metastases are
ependymoma. Lastly, ependymomas lack carcinoembry- typically those arising in pre- or postsacral soft tissues
onic antigen (CEA) immunoreactivity and do not express (Wolff et al., 1972; Kramer et al., 1988; Miralbell et
other tissue-specific markers of breast, prostate, or germ al., 1990).
cell derivation.
In the posterior fossa, highly cellular, rather pat-
ternless ependymomas may mimic medulloblastoma. SUBEPENDYMOMA
The latter, with only rare exception, are synaptophysin
immunoreactive despite occasional patchy staining for Grossly and microscopically, subependymomas are
GFAP. Unlike ependymomas, medulloblastomas gen- unique intraventricular tumors arising from subependy-
erally do not show microscopic demarcations from sur- mal glia. Since transitional tumors composed both of
rounding cerebellum and tend to displace the fourth ependymoma and subependymoma components do oc-
ventricle downward. Instead of perivascular or true cur, the subependymoma is generally considered a vari-
rosettes, medulloblastomas frequently possess Homer- ant of ependymoma. Most are small, asymptomatic,
Wright rosettes. Ultrastructurally, medulloblastomas fourth ventricular tumors found incidentally at au-
show primarily differentiation along neuronal lines, topsy; often they are multiple and occur in the elderly.
with microtubule-containing processes and small num- Uncommonly, subependymomas reach sufficient size to
bers of secretory granules. obstruct the flow of CSF and produce syptoms (Gan-
Myxopapillary ependymoma of the cauda equina en- dolfi et al., 1981; Lombardi et al., 1991).
genders a number of differential diagnostic possibili- Of these, most occur in males at a mean age of 40
ties, including schwannoma (which may show im- years, although examples have been reported in chil-
munoreactivity for GFAP but also may demonstrate a dren and as late as the ninth decade; nearly 75% are
dense intercellular pattern of reticulin staining) and infratentorial in location; spinal examples are rare
paraganglioma of the filum terminale. The paragan- (Scheithauer, 1978). Sites of predilection include the
lateral ventricle near the foramen of Monro (Schei-

thauer, 1978; Lombardi et al., 1991; Maiuri et al.,
1997), and the fourth ventricle (Fu et al., 1974; Az-
zarelli et al., 1977; Scheithauer, 1978; Gandolfi et al.,
1981; Lombardi et al., 1991). Familial cases have been
reported (Rea et al., 1983; Cheng et al., 1993). Radi-
ographically, the subependymoma, shows little if any
contrast enhancement—in supratentorial examples,
this allows distinction from other tumors that typically
enhance that also tend to occur near the foramen of
Monro (i.e., subependymal giant cell astrocytoma,
central neurocytoma, choroid plexus tumors) (Chieehi
et al., 1995). Typically it appears as a circumscribed
nonenhancing mass that is hypo- or isodense on CT FIGURE 16.88 Subependymoma. Note clustering of uniform cells at
scans, and hypo- to isointense on T1-weighted and mildly high power magnification. H&E.
hyperintense on T2-weighted MR images.
Grossly, subependymomas are sharply circum-
scribed, dome-shaped neoplasms that protrude into the mitoses, focal necrosis, and, on occasion, DNA aneu-
ventricle (Fig. 16.87). Their bases are flush with the un- ploidy are of no prognostic significance (Scheithauer,
derlying brain, a feature that facilitates gross total re- 1978). Prognosis is closely related to tumor site, mor-
section. Complete removal may not be possible in tu- tality being greatest in patients with tumors of the floor
mors arising on the floor of the fourth ventricle where of the fourth ventricle. Lesions situated in the lateral
the risk of secondary brainstem infarcts is substantial. ventricles and on the septum pellucidum are often to-
The basic histologic features of pure subependymomas tally resected. Unlike ependymomas, subependymomas
include low-power nodularity, relative hypocellularity, show no tendency to dedifferentiation or cerebrospinal
and tumor cells distributed in small nests separated by seeding. Rare reported features include sarcomatous
broad zones of cell processes rich in glial fibrils (Fig. vascular proliferation (Louis, 1989), a rhabdomyosar-
16.88). Lateral ventricular tumors often display promi- comatous component (Tomlinson et al., 1991), and
nent microcyst formation. The nuclei are regular with melanosis (Rosenblum et al., 1990).
delicate chromatin and inconspicuous nucleoli. Degen-
erative changes such as nuclear hyperchromasia, calci-
fication, vascular hyalinization, and hemosiderin de- CHOROID PLEXUS PAPILLOMA
position are common, particularly in large tumors (Fig.
16.89). Histologic features such as atypia, occasional The normal choroid plexus is formed from the tela
choroidea, a linear zone of ependymal–pial apposition
FIGURE 16.87 Subependymoma, floor of fourth ventricle. Note close FIGURE 16.89 Subependymoma. Large examples in particular dem-
apposition of the tumor to the ventricular surface. Luxolfust blue onstrate degenerative changes including nuclear hyperchromasia, cal-
(LFB)/H&E. cification, vascular hyalinization, and hemosiderin deposition. H&E.
associated with fibrovascular stroma that occurs on the

floor of the lateral ventricles, the roof of the third ven-
tricle, and in the lateral recesses of the fourth ventri-
cle. Glomerular vascular tufts covered by choroid
plexus epithelium, a derivative of the ependyma, form
the basic components of the choroid plexus. Papillo-
mas of the choroid plexus are rare (1% of brain tu-
mors) and are confined to areas where choroid plexus
is normally found, including, in decreasing order of fre-
quency, the fourth, lateral, and third ventricles and the
cerebellopontine angle.
Papillomas most often are encountered in the first
decade of life. Rare congenital examples may be diag-
nosed in utero (Anderson et al., 1995; Body et al., 1990)
FIGURE 16.91 Choroid plexus papilloma. Some cytologic atypia, an
or at birth (Tomita and Naidich et al., 1987; Buetow occasional mitotic figure, and even crowding or architectural com-
et al., 1990). Sites of predilection differ in children and plexity with disordered papillae are not indicative of malignancy.
adults, with the lateral ventricle favored in children and H&E.
the and fourth ventricle in adults. Inexplicably, lateral
ventricular tumors more often are left-sided (the same
is true of intraventricular meningiomas). Choroid like the epithelium of normal choroid plexus, that of
plexus papillomas may be bilateral (Gudeman et al., papillomas shows loss of the apical “hobnail” config-
1979) and characteristically are associated with sec- uration of normal cells, a tendency to cellular elonga-
ondary hydrocephalus, presumably the result of over- tion and crowding, and variation in the configuration
production of cerebrospinal fluid (Eisenberg et al., 1974; and location of nuclei within the cell (Fig. 16.90). Cy-
Ghatak and McWhorter, 1976). On neuroimaging, the tologic preparations demonstrate best the epithelial fea-
choroid plexus papilloma appears on noncontrast images tures of the papilloma. Scalloped calcified bodies are
as a mottled mass that is isodense/intense to brain and common within the stroma of papillomas. Cytologic
enhances intensely with contrast. atypia may be seen but mitoses are absent or infrequent
Choroid plexus papillomas are well-demarcated, pe- (Fig. 16.91). In rare cases, oncocytic change (Bonnin et
dunculated, cauliflowerlike masses composed of deli- al., 1987), acinar architecture with mucin production
cate papillary fronds that closely resemble the structure (Davis and Fox, 1970), osseous (Cardozo et al., 1985;
of normal choroid plexus. The cells are columnar, non- Duckett et al., 1991; Doran et al., 1995) or cartilagi-
ciliated, and arranged in an orderly but often crowded- nous metaplasia, or melanin pigmentation (Reimund et
to-pseudostratified fashion on fibrovascular stalks. Un- al., 1990; Watanabe et al., 1995) may occur.
Choroid plexus papillomas are immunoreactive for
S-100 protein, vimentin, transthyretin (pre-albumin)
and cytokeratins, but reactivity for EMA is focal at best
(Coffin et al., 1986; Kouno et al., 1988; Mannoji and
Becker, 1988). Focal ependymal differentiation, as ev-
idenced by GFAP positivity, is not uncommon and re-
flects the common histogenesis of ependyma and cho-
roid plexus epithelium (Kouno et al., 1988). Although
synaptophysin staining has been reported in choroid
plexus epithelium (Kepes and Collins, 1999), some
workers have not found this useful (Paulus and Brand-
ner, 1999). Ultrastructurally, choroid plexus epithelium
shows structural polarity, basement membrane at the
abluminal pole, complex interdigitation of cell mem-
branes on the lateral aspects, and apical microvilli as
well as occasional cilia (Navas and Battifora, 1978;
FIGURE 16.90 Choroid plexus papilloma. This tumor shows a cauli-
Matsushima, 1983).
flowerlike appearance grossly with somewhat disordered columnar Although the overall prognosis is favorable, subto-
cells resting upon a delicate fibrovascular stroma. H&E. tally resected choroid plexus papillomas may recur
(McGirr et al., 1988; Paulus and Janiseh, 1990). Cere- cinomas but usually is lacking in primary plexus tu-
brospinal fluid seeding, presumably due to fragmenta- mors (Kepes and Collins, 1999). Lack of CEA and sig-
tion of delicate papillae at the time of surgery, is rarely nificant EMA reactivity should prompt the diagnosis
of clinical significance (Leblame et al., 1998). of choroid plexus carcinoma. Electron microscopy may
demonstrate apical microvilli, clustered cilia, and zonu-
lae adherents, but it often is inconclusive since similar
CHOROID PLEXUS CARCINOMA features may be seen in metastatic carcinoma. Although
the carcinama is prone to brain invasion and cere-
Although some choroid plexus papillomas may show brospinal spread, some patients do remarkably well
atypical features, as crowding, disordered papillae, nu- (Berger et al., 1998; Geerts et al., 1996; Pencalet et al.,
clear atypia, occasional mitoses and focal necrosis, 1998). Systemic metastases are uncommon (Valladares
most of these, which are called atypical papillomas, do et al., 1980).
not behave in an aggressive manner. True carcinomas,
however, are frankly malignant and tend to aggressive
invasion of surrounding parenchyma. Neuroimaging is COLLOID CYST OF THE THIRD VENTRICLE
not specific and similar to that of the choroid plexus
papilloma. The carcinomas are far less well organized, The classification of unilocular cysts of the central ner-
often having lost much of their papillary architecture vous system is complex and confusing, but the distinc-
(Lewis, 1967; Dohrmann and Collias, 1975; Carpen- tive location and morphology of colloid cyst of the third
ter et al., 1982; McComb and Burger, 1983), and fea- ventricle make it a clear-cut pathologic entity (Little
ture necrosis, piling up of epithelium, and obvious cy- and MacCarty, 1974; Hall and Lunsford, 1987). Due
tologic anaplasia (Fig. 16.92). Mitotic indices are high, in part to their proximity and frequent attachment to
often exceeding 10 per 10 high-power (400) micro- the fibrous stroma of the choroid plexus, they origi-
scopic fields. Their immunohistochemical and ultra- nally were misinterpreted as choroid plexus cysts. Al-
structural features, nonetheless, are similar to those of ternatively, their characteristic location prompted some
papillomas (McComb and Burger, 1983). to suggest origin from the embryonic paraphysis, a
The vast majority of choroid plexus carcinomas oc- racemose, glandular structure derived from a telen-
cur in children under age 10. This diagnosis must be cephalic pouch. Many immunohistochemical (Lach et
made with great caution in adults, where most plexus al., 1993) and ultrastructural studies (Ghatak et al.,
carcinomas are metastases from a distant adenocarci- 1977; Lach and Scheithauer, 1992) have confirmed the
noma. The distinction can be facilitated by immunos- endodermal nature of colloid cysts. The rare concur-
tains. Primary plexus tumors show immunoreactivity rence of papillary craniopharyngioma (a tumor related
to S-100 protein, vimentin, and synaptophysin, while to Rathke pouch epithelium) and colloid cyst of the
EMA immunoreactivity occurs in most metastatic car- third ventricle supports this view (Oka et al., 1997).
Colloid cysts are characteristically located in the an-
terior roof of the third ventricle between the columns
of the fornices. Secondary attachment to surrounding
structures, particularly to the choroid plexus, is often
observed. They vary in size from small, incidentally en-
countered examples, to symptomatic lesions, most of
which are 1 cm or greater in size. Obstruction of the
foramen of Monro and secondary hydrocephalus result
in symptoms. Since the cysts may be pendulous, their
obstructive ball-valve effect can be intermittent and
may be fatal. Rare cysts attain massive size and com-
pletely fill the third ventricle. The content of colloid
cysts varies from a viscous mucus (that exhibits
increased density/signal on neuroimaging) to a firm
gelatin consistency. Neuroimaging is variable with
about two-thirds appearing as homogeneously hyper-
FIGURE 16.92 Choroid plexus carcinoma. Note lack of papillation,
dense/hyperintense and the remainder isodense/isoin-
high cellularity, and necrosis (upper right). The tumor showed brisk tense noncalcified masses. The cyst wall is composed
mitotic activity. H&E. of a delicate fibrous capsule lined by a single, pseu-
dostratified layer of columnar cells, some of which are cluding somatostatin (Reubi et al., 1986), cholecys-
ciliated. Goblet cells also are a typical feature. The tokinin (Mailleux and Vanderhaegen, 1990), and neu-
mucin content of the cyst is strongly PAS-positive, con- rotensin (Mailleux et al., 1990) have been reported.
tains scattered histiocytes, and occasionally features Their effect(s) on meningiomas is largely unknown. A
phospholipid crystals that may mimic fungal hyphae. variety of growth factor receptors are expressed, in-
Xanthogranulomatous degeneration also may be cluding epidermal growth factor (EGF) (Shiurba et al.,
seen. The cyst content has an irritative effect if spilled 1989), insulinlike growth factor (IGF) (Kurihara et al.,
into the ventricular system. Most colloid cysts occur in 1989), and platelet-derived growth factor (PDGF)
early adult life and demonstrate no sex predilection. (Maxwell et al., 1990; Wang et al., 1990)—these have
Resection is curative (Hall and Lunsford, 1987). been found to stimulate meningioma proliferation in
tissue culture. The expression in the same cell of both
PDGF receptor mRNA and PDGF polypeptide mRNA
NON-GLIAL NEOPLASMS may provide a clue about uncontrolled tumor growth
in meningiomas (Adams et al., 1991). An aminergic re-
Meningiomas
ceptor, the dopamine D1 receptor, also has been iden-
Meningiomas are relatively common neoplasms, ac- tified in cerebral meningiomas (Schrell et al., 1990).
counting for about 15% of all primary intracranial tu- Trauma has been suggested as a cause of menin-
mors. Most occur in middle life, usually after the third giomas (Barnett et al., 1986), but the relationship is not
decade, and show a marked female preference (Kepes, convincingly supported. A more compelling association
1982; Burger and Scheithauer, 1994; Louis et al., 2000). has emerged between meningiomas and previous irra-
The overall male to female ratio is approximately 1:2, diation, usually following its administration for in-
but 2:3 for intracranial meningiomas and 1:10 for intracranial neoplasia, a local (scalp) infection, or a cu-
traspinal meningiomas. This gender association is espe- taneous nevus (Soffer et al., 1983; Rubinstein et al.,
cially strong for meningiomas at certain sites, particu- 1984; Harrison et al., 1991). Cytogenetic studies in
larly sphenoid ridge, en plaque, and spinal examples. An meningiomas have most consistently demonstrated a
overall crude annual incidence rate of 1.85 per 100,000 loss of one homologue of chromosome 22 (monosomy
population has been reported with 1.16 for males and 22) localized to the distal part of the long arm of chro-
2.44 for women (Staneczek and Jänisch, 1992). At the mosome 22, the site, perhaps, of a putative tumor sup-
extremes of life, the male-to-female ratio levels and ap- presser gene (Seizinger et al., 1987; Louis et al., 2000).
proximate 1:1. Meningeal tumors are rare in children, The recent demonstration of loss of the Y chromosome
likely to be aggressive, and include papillary meningioma in about 40% of meningiomas in males suggests this
(Dreen et al., 1982; Davidson and Hope, 1989; Hope et alteration is associated with tumor progression (Logan
al., 1992) (see below). et al., 1990).
Growth of a meningioma appears to be hormonally Meningiomas originate from meningothelial cells
related. A meningioma may become clinically evident (arachnoidal cap cells) of the arachnoid membrane
during pregnancy or during the luteal phase of the men- (Kepes, 1982, 1986). Due to the intimate relationship
strual cycle (Bickerstaff et al., 1958). Hormonal assays of the arachnoid membrane and dura, meningiomas
indicate that most meningiomas express receptors to typically attach to the dura. Meningothelial cells are
progesterone, less to estrogen, or both (Cahill et al., most abundant in the arachnoid granulations, but are
1984). The role of hormones in the treatment of menin- found in small clusters in the intracranial and in-
giomas, however, has met with limited success. An as- traspinal arachnoidal membranes (Fig. 16.93), as well
sociation with extracranial malignancies, particularly as in the tela choroidea (Fig. 16.94), the source of in-
breast carcinoma, has emerged from several reports traventricular meningiomas (Fig. 16.95) (Guidetti et al.,
(Schoenberg et al., 1975; Jacobs et al., 1987; Knuckey 1985; Hanieh, 1989). These cells have a tendency to
et al., 1989), although some data do not support this form whorls and psammoma bodies, features common
relationship (Jacobs et al., 1992). in meningiomas.
The presence of a variety of receptor types (steroid, Approximately 90% of meningiomas are intracra-
peptidergic, growth factor, and aminergic) in menin- nial, 9% are intraspinal, and the remainder occur at
giomas suggests that these tumors may be targets for rare “ectopic” sites, such as diploe of the skull (in-
various hormones, neuropeptides, and neurotransmit- traosseous), orbit, middle ear, parotid gland, paranasal
ters. Binding sites for progesterone and estrogen (Mark- region, neck, and scalp (Kepes, 1982; Burger and
walder et al., 1983), androgens and glucocorticoids Scheithauer, 1994). Roughly in order of incidence,
(Lesch and Gross, 1987) and peptidergic receptors in- intracranial meningiomas occur in the following:
FIGURE 16.93 Clusters of arachnoidal cap cells, from which meningiomas originate, frequently are found
incidentally in the meninges of normals at autopsy. H&E.
parasagittal free convexity (50%), sphenoid ridge Radiologically, the meningioma is dural-based and
(Fig. 16.96), tuberculum sella, olfactory groove, fora- densely contrast enhancing. A wedge of neoplastic tis-
men magnum, optic sheath, tentorium, and choroid sue or of small vessels often lies within the angle be-
plexus. The thoracic region is favored at spinal lev- tween tumor and dura, producing the common but
els. Intraventricular meningiomas are rare and usu- nonspecific dural tail sign (Aoki et al., 1990). Grossly,
ally involve the left lateral ventricle (Fig. 16.95). meningiomas are sharply demarcated and rubbery-
Meningiomas usually occur singly. Multiple menin- firm. Most are highly vascular and derive their blood
giomas may be associated with neurofibromatosis supply from the external carotid supply. Some menin-
type 1 (NF-1, von Recklinghausen disease). Some- giomas, particularly large examples, may be associated
times, especially at the sphenoid ridge, the neoplasm with significant peritumoral edema (Bradac et al., 1986;
grows as a flattened plate or sheet referred to as Go et al., 1988; Atkinson and Lane, 1994).
meningioma en plaque.
FIGURE 16.95 A large meningioma originating from the right sphe-

FIGURE 16.94 Clustes of meingothelial cap cells also may be present noid wing. Note the extreme distortion of the underlying com-
in the tela choroidia. H&E. pressed brain.
FIGURE 16.97 Histologically typical meningioma. Degenerative nu-
FIGURE 16.96 A large intraventricular meningioma occupies the bulk clear atypia sometimes is quite prominent, H&E.
of the left lateral ventricle.
least one dominant type, neoplasms with mixed patterns

are not uncommon (Kepes, 1982). Characteristic light
Sharply demarcated, they tend not to infiltrate brain. microscopic features of meningiomas include a syncy-
They may, however, invade dura, penetrate adjacent tial arrangement of the cells (due to complex interdigi-
bone, and extend into surrounding muscle and soft tis- tations of adjacent cell processes that are “blurred” at
sues. The overlying bone often becomes reactively thick- light microscopic levels) (Fig. 16.98), intranuclear “vac-
ened (hyperostotic), but on occasion it may be lytic. A uoles” and “pseudoinclusions,” a tendency to form
lytic change indicates bone invasion, whereas in hyper- whorls, and the presence of psammoma bodies. The
ostosis, this is not always the case. The mere proximity meningothelial or syncytial variant (Fig. 16.99) is char-
of tumor to bone may result in hyperostosis. Menin- acterized by lobules of neoplastic cells with indistinct
giomas rarely metastasize but have a significant ten- borders and prominent intranuclear inclusions. The
dency to recur (Earle and Richany, 1969; Borovich and transitional form (Fig. 16.100), so termed because of
Doron, 1986; de la Monte et al., 1986). In some cases, features transitional between syncytial and fibrous
multiple recurrences may be associated with malignant types, demonstrates characteristic whorls, intranuclear
transformation (Cushing and Eisenhardt, 1938). pseudoinclusions, and psammoma bodies. The relatively
Microscopically, the diversity of histological appear- rare fibrous meningioma (Fig. 16.101), as the name sug-
ances initially led to complex methods of classification. gests, is composed of abundant spindled or elongated
For example, the classic monograph by Cushing and cells, sometimes in a prominent storiform or fascicular
Eisenhardt (Cushing and Eisenhardt, 1938) details 9 arrangement. The psammomatous meningioma (Fig.
major types and 20 subtypes of meningiomas. Adding 16.102), so termed because of the presence of excessive
to the confusion are tumors classically regarded as numbers of psammoma bodies, tends to predominate in
meningiomas, that actually derive from cells other than
meningothelial. Meningiomas undergo a variety of
metaplastic and degenerative changes that present a TABLE 16.7 Histological Variants of Meningiomas
bewildering array of histologic patterns. Degenerative
Benign variants
nuclear atypia (Fig. 16.97), for example, is common
and must not be mistaken for a feature of anaplasia. Meningothelial (syncytial)
Infarctlike necrosis may be seen in the occasional Fibroblastic
meningioma that undergoes a vascular accident, but Transitional
does not indicate a more aggressive behavior. Aggressive variants
Well-recognized histologic variants included in the Psammomatous
2000 WHO classification of CNS tumors are summa- Chordoid
rized in Table 16.7 (Louis et al., 2000). Little prognos- Papillary
tic significance is attached to the meningothelial (syn-
Rhabdoid
cytial), fibroblastic, transitional, and psammomatous
variants, and although most meningiomas display at Source: From Kleihues and Cavenee (2000).
FIGURE 16.98 Ultrastructurally, meningiomas are characterized by ir- FIGURE 16.100 The transitional meningioma (transitional between
regular nuclear contours and complex interdigitating cell processes meningothelial and fibroblastic variants) is characterized by promi-
with occasional desmosomes. nent, well-formed whorls. H&E.
spinal and olfactory groove locations; the psammoma lined glandular spaces filled with membranous debris.
body, a large extracellular basophilic laminated struc- The prominent, cobweblike, microcystic appearance of
ture, originates in the center of a whorl. microcystic meningiomas (Fig. 16.104) results from
Histological and immunohistochemical features of fluid-filled intercellular spaces enclosed by elongate cell
both mesenchymal and epithelial cells are exhibited by processes (Kleinman et al., 1980; Sobel and Michaud,
meningiomas. For example, nearly all meningiomas 1985). Such tumors also display prominent degenera-
express immunoreactivity for vimentin and epithelial tive nuclear atypia and may be accompanied by a cyst
membrane antigen (EMA), less often for cytokeratin, either within the tumor or in adjacent brain (Parisi et
and uncommonly for S-100 protein (Schnitt and Vo- al., 1986; Kulah et al., 1991; Odake, 1992). When an
gel, 1986; Theaker et al., 1986; Artlich and Schmidt, otherwise typical meningioma is accompanied by a par-
1990). The presence of distinct, often multiple, intra- ticularly vigorous inflammatory reaction—generally a
cytoplasmic eosinophilic hyaline inclusions (pseudop- host response composed of lymphocytes and plasma
sammoma bodies) is characteristic of the secretory cells—it is termed a lymphoplasmacytic meningioma
meningioma (Fig. 16.103) (Kepes, 1975; Alguacil- (Horten et al., 1979). Although chronic inflammation
Garcia et al., 1986; Louis et al., 1991). These inclu- may be seen in any type of meningioma, it occurs most
sions are strongly PAS-positive and diastase-resistant; often in chordoid examples (Couce et al., 2000). Oc-
ultrastructurally, they are composed of microvillous- casional meningiomas, termed angiomatous menini-
giomas (Fig. 16.105), are highly vascular.
FIGURE 16.99 There is a prominent syncytial arrangement (me-

ningothelial or syncytial meningioma) as well as many intranuclear FIGURE 16.101 The fibrous meningioma has a prominent, spindled
vacuoles. H&E. appearance. H&E.
FIGURE16.102 The psammatous meningioma contains abundant FIGURE 16.104 The microcystic meningioma shows prominent inter-
psammoma bodies. H&E. cellular cysts. H&E.
Metaplastic changes are common and give rise to dysgammaglobulinemia. More importantly, chordoid
xanthomatous, lipoblastic (Fig. 16.106) (Lattes and meningiomas are highly prone to recurrence when
Bigotti, 1991; Leroux et al., 1989), myxoid (Dahmen, subtotally resected (Kepes et al., 1988; Couce et al.,
1979; Harrison and Rose, 1985), chondroid, os- 2000).
teoblastic, or chordoid variants (Burger and Schei-
thauer, 1994). Evidence of epithelial differentiation in-
Biological behavior of meningiomas
cludes such ultrastructural features as desmosomal
attachments (Cervos-Navarro and Vasquez, 1969) and Although generally considered “benign,” meningiomas
the occasional presence of glandular structures (Kepes may be associated with significant morbidity, and
et al., 1983). Rarely the diagnosis of meningioma may sometimes death. Many clinical prognosticators have
be complicated by the presence of a metastatic carci- been reported, including patient age and sex. The ex-
noma within the meningioma (Lodrini et al., 1981). tent of surgical resection is dependent upon a variety
The uncommon chordoid meningioma (Fig. 16.107) of anatomic features: adverse site of disease (e.g., skull
is characterized histologically by distinctive cords of base, anterior visual pathway) and patterns of growth
epithelial-like cells mimicking those of chordoma. An (en plaque, invasion of dura, bone, soft tissue, dural si-
accompanying, occasionally prominent, lymphoplas- nus, or brain). Although histologic grading provides ad-
macytic inflammatory cell component may be seen ditional prognostic data and in some cases guides
and can be associated with microcytic anemia and/or further therapy, the diagnostic criteria for atypia and
FIGURE 16.103 The secretory meningioma contains abundant FIGURE 16.105 The angiomatous meningioma is characterized by a
eosinophilic glycogen-rich pseudopsammoma bodies. H&E. very prominent vascular component. H&E.
FIGURE16.106 Note lipoblastic change, a common metaplastic in B

meningiomas. H&E.
malignancy in meningiomas have been subjectively and

inconsistently applied (Kepes, 1982; Burger and Schei-
thauer, 1994; Louis et al., 2000). Historically, the des-
ignation “malignant meningioma” has been applied to
tumors with variable atypia, mitotic activity, and focal
necrosis, as well as to examples showing frank brain
invasion or extracranial metastasis. Recently studies
correlating operative, clinical follow-up and morpho-
logical data have defined three subgroups of menin-
gioma: typical meningioma, atypical (recurrence-prone) C
meningioma, and anaplastic (malignant) meningiomas.
Histological features of the atypical meningioma cate-
gory include hypercellularity, frequent mitoses (4
mitoses/10 hpf), uninterrupted patternless growth
(“sheeting”), macronucleoli (Fig. 16.108A) small cell
formation (Fig. 16.108B), and focal necrosis (Fig
FIGURE 16.108 Features of the atypical meningioma include hyper-

cellularity, frequent mitoses, macronucleoli (A), small cells (B), and
foci of necrosis (C). H&E.
16.108C) (Perry et al., 1997). Despite some variability

in histologic criteria, several studies have confirmed the
intermediate clinical behavior of so-called “atypical”
FIGURE 16.107 The chordoid meningioma is characterized by a mu- meningiomas (Jääskeläinen et al., 1985; Jääskeläinen et
cous-rich matrix containing “cords” of neoplastic cells. H&E. al., 1986). These categories of meningioma have been
assigned grades I, II, and III by WHO (Louis et al.,

2000).
Meningioma (histologically “typical” meningioma,

WHO grade I). Typical meningiomas include the well-
known meningothelial, fibroblastic, transitional, psam-
momatous variants. Their recurrence rate is low, the 5-
year recurrence rate approaching 12%, and metastases
are exquisitely rare (0.1%). A major factor influenc-
ing the postoperative prognosis is extent of excision
(Mirimanoff et al., 1985; Jaaskelainen, 1986; Kallio et
al., 1992; McCarthy et al., 1998). Completeness of re-
section is dependent upon site of disease and surgical
accessibility, pattern of growth, and presence of tumor
FIGURE 16.109 Anaplastic (malignant) meningioma. A feature of ma-
within dura, bone, soft tissue, or dural sinus. Recur- lignancy is excessive mitotic activity. H&E.
rences might arise from incomplete removal, especially
if the often-infiltrative dural attachment is left behind,
or from regional small satellite lesions (regional multi- do not fall into one of the malignant categories de-
centricity) (Borovich and Doron, 1986). scribed below (Table 16.8). Based on several grading
Occasionally, a typical meningioma will evolve into schemes (Jääskeläinen et al., 1985; de la Monte et al.,
a frankly malignant variant on subsequent resections 1986; Jääskeläinen, 1986; Jääskeläinen et al., 1986;
(Cushing and Eisenhardt, 1938; Burger and Schei- Maier et al., 1992; Perry et al., 1997), a meningioma
thauer, 1994). It is difficult to predict, on the basis of is identified as atypical if it displays four or more mi-
microscopic features alone, which tumors will recur toses per 10 high power fields (2.5 mitoses/mm2), or
and the interval to recurrence. Clearly, additional in- (in the absence of sufficient mitotic activity) at least
dicators of biologic aggressiveness need to be incor- three of the following: (1) sheeting (patternless) archi-
porated into a meaningful definition of malignancy. tecture; (2) marked cellularity (hypercellularity); (3)
Quantitative studies of DNA content by flow cytome- macronucleoli; (4) small cell formation.
try have provided disparate data (Crone et al., 1988), Although brain invasion formerly was considered a
while MIB-1 labeling and p53 staining (Grunewald et criterion of malignancy, more recent studies (Perry et
al., 1998; Karamitopoulou et al., 1998; Perry et al., al., 1997), suggest that it is not, especially in the ab-
1998) show some correlation between labeling index sence of significant anaplasia. Accordingly, the work-
and aggressive behavior. ing definition of atypical meningioma has been ex-
panded to include cases with cortical invasion.
Atypical meningioma (WHO grade II). Atypical Otherwise-typical meningiomas may exhibit nuclear
meningiomas display atypical histological features and atypia or an occasional mitotic figure. In contrast, atyp-
show an increased likelihood of recurrence, but they ical meningiomas display frequent, often atypical mi-
toses. The significance of focal necrosis is controversial
(McClean et al., 1993). Although in some series ne-
TABLE16.8 Atypical Meningioma Criteria (One or crosis has not proven to be a statistically significant
More Required) prognostic factor, its presence should prompt a careful
search for other atypical features.
High mitotic index (4 mitoses/10 hpf or 2.5/mm2) The 5 year recurrence and mortality rates for atypi-
or cal meningiomas are approximately 40% and 20%,
respectively.
At least three of the following:
Sheeting (patternless) architecture Anaplastic (malignant) meningioma (WHO grade
Hypercellularity III). The term malignant (or anaplastic) meningioma
Macronucleoli
(Fig. 16.109, Table 16.9) is applied to any meningioma
variant that demonstrates one of the following features:
Small cell formation
(1) excessive mitotic activity (20 mitoses/10 hpf or
Source: From Perry et al. (1997c). 12.5 mitoses/mm2) or (2) focal or diffuse loss of
TABLE 16.9 Malignant Meningioma Criteria

Excessive mitotic activity (20 mitoses/10 hpf or 12.5
mitoses/mm2)
or
Focal or diffuse loss of meningothelial differentiation with
sarcoma; carcinoma; or melanomalike appearance
Source: From Perry et al. (1997c).
meningothelial differentiation with sarcoma, carci-

noma, or melanomalike appearance. Such tumors are
rare.
Extracranial metastasis of meningioma is very rare.
FIGURE 16.111 The papillary meningioma. Note prominent
Although symptomatic spread is classically cited as a
pseudopapillae. H&E.
criterion for malignancy, this view has been challenged.
Most metastatic meningiomas are atypical, but some
are anaplastic or exhibit typical (benign) histology. about 30% and death by disease of 50% (Ludwin et
Also, previously included in the malignant category al., 1975; Pasquier et al., 1986; Fukushima et al.,
were the sarcomatous meningioma and the heman- 1989). Architecturally, the tumor is composed of rela-
giopericytic or angioblastic meningioma (heman- tively uniform cells similar to those of the typical
giopericytoma). These now are classified as malignant meningioma that are arranged in sheets prone to de-
mesenchymal, nonmeningeal tumors, similar to their hisce artifactually during processing into perivascular
soft tissue counterparts in the revised WHO classifica- cuffs and pseudopapillae. The neoplastic cells typically
tion (Louis et al., 2000). The no-longer-used term sar- maintain a close relationship with blood vessels, re-
comatous meningioma referred to a metaplastic menin- sembling the perivascular pseudorosettes of ependy-
gioma with features of a soft tissue sarcoma (Fig. momas. Mitoses are variable, but usually present.
16.110). True soft tissue sarcomas (usually malignant Papillary meningiomas consistently express membrane
fibrous histiocytoma or fibrosarcoma) are rare. immunoreactivity for EMA, and also show cytokeratin
Rare variants of meningioma associated with more and/or S-100 protein staining.
aggressive behavior include papillary, clear cell, and The recently recognized rhabdoid meningioma (Fig.
rhabdoid types, and possibly the chordoid variant. 16.112) (Perry et al.; 1998) shares this aggressive be-
The papillary meningioma (Fig. 16.111) most often havior and tends to arise in transition, often within re-
occurs in young subjects and is characterized by a recurrences of meningiomas with otherwise more typical
currence rate of about 70% and a rate of metastasis of histology.
FIGURE 16.110 The malignant mesenchymal nonmeningeal tumor,

formerly classified as a meningeal sarcoma, shows marked atypia and FIGURE 16.112 The rhadboid meningioma contains many rhabdoid
malignant fibrous histiocytoma pattern. H&E. cells. H&E.
Although clear cell meningiomas (Fig. 16.113) (Zor-

ludemir et al., 1995) typically exhibit benign histolog-
ical features, they are associated with aggressive be-
havior. Greater experience with these rare variants is
needed to determine whether histologic grading crite-
ria can be meaningfully applied.
Hemangiopericytoma
Intracranial hemangiopericytoma (HPC) was previ-
ously classified as a variant of meningioma (termed he-
mangiopericytic or angioblastic meningioma). Given its
histological similarity to soft tissue hemangiopericy-
toma, it now is classified under the malignant mes- FIGURE 16.114 Hemangiopericytoma. Like its soft tissue counterpart,
enchymal, nonmeningeal tumor category (Jääskeläinen the hemangiopericytoma of the meninges is densely cellular, com-
et al., 2000). This uncommon vascular neoplasm ac- prised of small carrot-shaped cells with variable mitotic activity, in-
counts for about 1%–5% of all meningeal-based tersected by numerous sinusoidal (“staghorn”) vascular channels.
H&E.
growths. HPC is an aggressive tumor with a high
propensity for local recurrences (26%–80% of cases)
and late extraneural metastases (10%–30% of cases),
particularly to bone, liver, and lung (Pitkethly et al., a distinctive mesenchymal neoplasm, unrelated to the
1970; Horten et al., 1977; Goellner et al., 1978; Iwaki meningioma.
et al., 1985; Jääskeläinen et al., 1985; Nakamura et Dural HPC may present at any age, although most
al., 1987; Guthrie et al., 1989; Mena et al., 1991). In occur during the fourth through sixth decades. Males
a series of 44 Mayo Clinic cases, the 5, 10, and 15 year are somewhat more frequently affected. Most in-
survival rates were 63%, 37%, and 21%, respectively tracranial examples originate in the meninges and at
(Guthrie et al., 1989). locations common to meningiomas. Spinal examples
The cell of origin of this neoplasm has been the sub- are rare; mot occur at cervical or thoracic levels (Har-
ject of considerable debate. The literature is replete with ris et al., 1978; Cappabianca et al., 1981). Radiologi-
observations favoring either a pericytic or meningothe- cally, the HPCs are discrete, meningeal-based masses
lial derivation (Horten et al., 1977). The behavioral, that may mimic meningioma, although extreme vascu-
histological, and immunohistochemical (Iwaki et al., larity results in a prolonged, dense tumor stain on an-
1985; Nakamura et al., 1987; Mena et al., 1991) sim- giography (Osborne et al., 1981). At surgery, the tu-
ilarities to soft tissue HPC (Enzinger and Smith, 1976) mor appears as a demarcated, rubbery, and highly
are compelling in that the CNS hemangiopericytoma is vascular mass usually attached to dura. Microscopically
densely cellular, the HPC is comprised of lobules of
closely packed, generally small, rounded to carrot-
shaped cells with scant cytoplasm, intersected by
prominent branching vessels with a characteristic
“staghorn” configuration (Fig. 16.114). Mitoses vary
in number. Reticulin stains typically show investment
of individual cells. Psammoma bodies and tight cell
whorls are not seen. Ultrastructural features include the
presence of intercellular basement-membrane-like ma-
terial and the absence of desmosomes (Battifora, 1973;
Horten et al., 1977; Peña, 1977; Nakamura et al.,
1987). HPCs show immunoreactivity to vimentin, but
unlike meningiomas, they do not stain with the ep-
ithelial markers EMA or keratin (Iwaki et al., 1985;
Nakamura et al., 1987; Wink et al., 1989; Nappi et al.,
1995). Dural hemangiopericytomas are regarded as
FIGURE 16.113 The clear cell meningioma is characterized by nu- “malignant” neoplasms, there is some correlation of
merous cells with watery-clear cytoplasm. H&E. histologic features and prognosis. In a series of 94 AFIP
cases, HPCs were divided into “differentiated” and

“anaplastic” groups by using criteria for the classifica-
tion of soft tissue HPC: they showed median survivals
of 144 and 62 months, respectively (Mena et al., 1991).
Capillary Hemangioblastoma (Hemangioblastoma)

The capillary hemangioblastoma is a benign, vascular
neoplasm of unknown origin that occurs in a relatively
restricted area of the nervous system. It accounts for
approximately 1%–2% of all intracranial neoplasms
and about 10% of tumors within the posterior fossa
(Jeffreys, 1975; Burger and Scheithauer, 1994; Bohling
et al., 2000). Most occur in the third through the fifth
decades of life and they are more common in males FIGURE 16.116 Histologic features of the capillary hemangioblastoma
include abundant thin-walled vascular channels intersected by en-
than females (2:1). Most originate in the cerebellum,
larged vacuolated stromal cells. H&E.
either vermis or hemisphere, followed by occurrence in
the cervical spinal cord, medulla, or pons. The tumor
presents as a variably cystic and solid intramedullary
mass (Fig. 16.115). Some spinal examples are associ- cerebellar neoplasm is referred to as a Lindau tumor;
ated with a syrinx (Enomoto et al., 1984; Fox et al., when associated with lesions outside of the CNS, the
1985) or origin at extramedullary sites (Wisoff et al., combination is known as Lindau syndrome. When a
1978; Ismail and Cole, 1984). Rare supratentorial ex- Lindau tumor is associated with a retinal capillary he-
amples, formerly regarded as a variant of meningioma mangioblastoma (retinal angioma or von Hippel tu-
because of their dural attachment, usually are associ- mor), the constellation is designated von Hippel-Lin-
ated with von Hippel-Lindau disease (Ishwar et al., dau disease or syndrome (Neumann et al., 1989).
1971). The capillary hemangioblastoma is slowly growing
The capillary hemangioblastoma may occur singly or and often presents as a cystic mass with a mural mod-
at multiple sites. It may be associated with retinal he- ule. The neuroimaging appearance is distinctive due
mangioblastoma and/or a variety of extra-CNS lesions, to the cystic nature of the lesion and the associated
including cysts of the liver, kidney, or pancreas, renal contrast-enhancing nodule. Symptoms may be related
cell adenomas, renal cell carcinomas, epididymal pap- to progressive enlargement of the cystic portion of the
illary cystadenomas, and pheochromocytomas. Al- tumor. Some patients may have an associated poly-
though most cases arise sporadically, a significant num- cythemia since the cystic fluid contains an erythropoi-
ber are familial (Bonebrake and Siqueina, 1964). The etinlike substance (Ward et al., 1958; Waldman et al.,
1961; Horton et al., 1991). The prognosis in heman-
gioblastomas following resection is excellent. Although
surgery is usually considered curative, recurrences have
been reported in incompletely excised cases (Penny-
backer, 1954).
Grossly, the tumors usually display a bright yellow
appearance due to the presence of abundant neutral
lipid. Microscopically, the histologic features of the tu-
mor are highly characteristic: there is a rich network
of capillaries lined by hyperplastic endothelial cells, per-
icytes. Surrounding the capillaries are large “stromal”
cells with abundant vacuolated, lipid-rich, poorly stain-
ing cytoplasm and a variably lobulated or pleomorphic
nucleus (Fig. 16.116). A rich reticulin network is pres-
ent and individual cells are often surrounded by a col-
lar of reticulin. Mitotic activity is not present, although
FIGURE16.115 Hemangioblastoma. This highly vascular cerebellar in some cases, nuclear pleomorphism may be consid-
tumor usually has both solid and cystic components. erable.
The origin of the “stromal” cell remains unresolved (Schwartz and Balentine, 1978). The cysts are smooth,
(Kawamura et al., 1973; Spence and Rubinstein, 1975; discrete, encapsulated structures with a characteristic
Ismail et al., 1985; Hufnagel et al., 1989). The litera- glistening, pearl-like sheen; because of the latter, epi-
ture is replete with reports supporting both glial and dermoid and dermoid cysts have been termed pearly
vascular origins. Ultrastructural and tissue culture stud- tumors. Typically the epidermoid contains white, flaky,
ies have not resolved the controversy (Cancilla and keratinous debris, while the dermoid contents include
Zimmerman, 1965; Spence and Rubinstein, 1975). The cheesy, granular material.
contention that the neoplasm is derived of undifferen- Imaging features of epidermoid and dermoid cysts are
tiated mesenchymal origin is based upon the absence determined by their contents. For the epidermoid, these
of staining with markers for endothelial, epithelial, include low (CSF-like) density/hypointensity without cal-
chromaffin, and smooth muscle (Frank et al., 1989). cifications on noncontrast CT scans and T1-weighted
Although classically regarded as tumors of vascular ori- MR images, and occasional peripheral enhancement.
gin, immunohistochemical studies have failed to show The dermoid typically demonstrates very low (fat-like)
staining for factor VIII/von Willebrand’s factor, and density/hypointensity and calcifications on noncontrast
some have suggested a possible neuronal/neuroen- CT scans and usually no enhancement.
docrine origin (Ismail, 1985; Frank et al., 1989). The histologic features are characteristic. The epi-
A practical problem in differential diagnosis arises dermoid cyst consists of a layer of stratified squamous
because of the often striking resemblance between a epithelium surrounded by a thin layer of connective tis-
capillary hemangioblastoma and a metastatic renal cell sue and filled with keratinous debris (Fig. 16.117). The
carcinoma. The problem is compounded by the fact dermoid cyst, in addition, contains pilosebaceous units
that patients with von Hippel-Lindau syndrome have with hair shafts and sebaceous glands (Fig. 16.118).
an increased incidence of renal cell carcinoma that may Malignant degeneration of epidermoid (Davidson and
metastasize to the central nervous system. Although Small, 1960; Fox and South, 1965; Wong et al., 1976;
both typically contain glycogen (usually more promi- Lewis et al., 1983; Goldman and Gandy, 1987) and
nent in the renal cell carcinoma), they can be separated dermoid (Gluszcz, 1961) cysts is exceptional.
reliably on the basis of immunohistochemistry. The ma-
jority of stromal cells show immunoreactivity to vi-
Lipoma
mentin and occasional cells to GFAP and S-100 pro-
tein, but none reacts to EMA; the latter cells are positive Lipomatous masses within the CNS are uncommon and
in renal cell carcinoma (Frank et al., 1989; Hufnagel thought to arise from remnants of ectopic tissue. Lipo-
et al., 1989; Mills et al., 1990). mas are comprised of mature fatty tissue with variable
vascular and fibroblastic elements. Their frequent as-
sociation with developmental malformations (e.g., age-
Epidermoid and Dermoid Cysts
nesis of the corpus callosum in intracranial locations,
Epidermoid and dermoid cysts are thought to arise and spina bifida, meningocele, etc., at spinal levels) sug-
from misplaced epithelial elements that become trapped
in the meninges, ventricles, or brain parenchyma.
Rarely, an epidermal cyst follows the introduction of
epithelial cells by percutaneous puncture for CSF aspi-
ration (Gutin et al., 1980). Most epidermoids develop
eccentrically in the region of the cerebellopontine an-
gle (Guidetti and Gagliardi, 1977; Berger and Wilson,
1985), although occurrence in a variety of locations,
including suprasellar (Eliash et al., 1983), intraventric-
ular (Giannotta et al., 1976; Eekhof et al., 1985; Fi-
ume et al., 1988), thalamus (Chandler et al., 1975), and
brain stem (Leal and Miles, 1978), have been reported.
Most dermoid cysts, by contrast, occur as posterior
fossa midline masses within the fourth ventricle or
between the cerebellar hemispheres (Guidetti and
Gagliardi, 1977). Presenting symptoms typically are FIGURE 16.117 Epidermoid cyst. The cyst contains thin, flaky, “dry”
those of a very slowly enlarging mass. Leakage of the keratinaceous debris, different from that of the craniopharyngioma
cyst contents may result in a chemical meningitis (compare with Fig. 16.125). H&E.
in adulthood. Most cases strike in the third through the

seventh decades. Children rarely are affected (Becker et
al., 1975; Wold and Laws, 1983; Coffin et al., 1993).
Males are affected more commonly than females
(2M:1F). The histologic features and typical sites of oc-
currence suggest origin from notochordal elements, and
accordingly, most arise at the extremes of the axial
skeleton. Approximately 40% occur at the base of the
skull, typically in the midline clivus. The remainder may
arise anywhere along the spinal axis, most commonly
at lumbosacral levels (78%), followed by cervical
(18%) and thoracic (4%) examples. Experimental
chordomalike lesions have been produced in rabbits by
FIGURE 16.118 Dermoid cyst. In addition to epidermal elements, der-
puncturing the nucleus pulposus (Congdon, 1952).
mal elements are present. H&E. Invariably the chordoma is accompanied by exten-
sive destruction of the surrounding bone. In addition
to local pain, common presenting signs and symptoms
gests that they are malformative in nature (Budka, are referable to pressure on adjacent neural elements
1974; Pierre-Kahn et al., 1986). Most intracranial ex- (e.g., pituitary gland, optic chiasm, or hypothalamus in
amples are midline in location. Typical locations in- clival examples; sphincter dysfunction in lumbosacral
clude above the corpus callosum (Budka, 1974; Wal- lesions, and root and/or cord compression in spinal ex-
lace, 1976; Gastaut et al., 1980; Gerber et al., 1982; amples) (Dahlin and MacCarty, 1952; Ariel and Verdu,
Kudoh et al., 1984), on the surface of the quadrigem- 1955; Higinbotham et al., 1967; Sundaresan et al.,
inal plate (Halmagyi and Evans, 1978), the cerebello- 1979; Murali et al., 1981; Volpe and Mazabraud,
pontine angle (Fukui et al., 1977; Rosenbloom et al., 1983; O’Neill et al., 1985; Rich et al., 1985). Exten-
1985; Steimle et al., 1985; Christensen et al., 1986; sion of a skull base chordoma antero-inferiorly may re-
Pensak et al., 1986), the cerebellum (Schmid, 1973), sult in a nasal–pharyngeal mass (Wright, 1967; Perzin
the area around the third ventricle (Esposito and Nardi, and Pushparaj, 1986).
1987), or in the Sylvian fissure (Hatashita et al., 1983; Chordomas generally are regarded as tumors of low
Dyck, 1985). At spinal levels, cervical, upper thoracic, malignant potential. Although they typically follow a
and lumbar levels are favored sites (Caram et al., 1957; relatively indolent but prolonged course, chordomas
Giuffre, 1966; Drapkin, 1974; Ammerman et al., 1976; are locally aggressive, subject to repeated local recur-
Walsh and Markesbery, 1980; White and Fraser, 1983; rences, and “malignant” by virtue of their location,
Knierim et al., 1987). Most intracranial lipomas are which often is not surgically accessible. Metastases have
found incidentally, although some may be associated been reported in approximately 25%–40% of cases
with seizures, especially when located in the corpus cal- (Wang and James, 1968; Stough et al., 1971; Aleksic
losum (Gastaut et al., 1980). Their distinctive hypo-
density on CT scans and low signal on MR images may
identify lipomas. Calcification often is present at the
periphery of these lesions.
Microscopically, the tumors are composed of mature
adipose tissue with variable degrees of fibroblastic and
vascular elements (Fig. 16.119) (Takeuchi et al., 1981;
Von Hanwehr et al., 1985; Wilkins et al., 1987;
Palkovic et al., 1988). Osseous (Friede, 1977) and
rarely cartilaginous (Budka, 1974) elements have been
reported in some intracranial lesions and muscle (Walsh
and Markesbery, 1980) in some spinal examples. Sur-
gical resection when complete is considered curative.
Chordoma
FIGURE 16.119 Lipoma. This lipoma, composed of mature fat, was
The chordoma is a slowly growing, locally destructive, located above the corpus callosum in this asymptomatic patient.
and potentially metastatic neoplasm that usually occurs H&E.
A B
FIGURE 16.120 Clivus chordoma. Note lobules of tumor cells (A) arranged in intersecting cords within
a mucoid-rich matrix (B). H&E.
et al., 1979; Chambers et al., 1980). Rarely, a true sar- mitoses, but these are not associated with increased bi-
coma has been reported in conjunction with a chor- ologic aggressiveness.
doma (Meis et al., 1987; Miettinen et al., 1987); the Considerable controversy surrounds the existence of
term dedifferentiated chordoma has been suggested for the chondroid chordoma (Fig. 16.122) (Brooks et al.,
this rare but aggressive variant (Meis et al., 1987). 1997). This lesion, originally described as a biphasic
On noncontrast CT scans, the chordoma appears as neoplasm with components of both chordoma and car-
a lytic destructive mass, often with calcification and tilaginous tissues, was associated with occurrence in
mixed cystic and solid components, and an associated younger patients (35 vs. 42 years) and a more favor-
soft tissue mass. Irregular hypointensity on T1-weighted able prognosis (16 vs. 4 years) (Heffelfinger et al.,
MR images may become hyperintense on proton density 1973). Much of the difficulty with this entity stems
and T2-weighted sequences. from the fact that histologically some low-grade chon-
Grossly, the chordoma is lobulated and usually drosarcomas are indistinguishable from chondroid
translucent gray with a friable firm or soft and muci-
nous consistency. Microscopically, a lobular arrange-
ment of the neoplastic cells (Fig. 16.120A) is charac-
teristic. The cells may be disposed in solid sheets or
irregular intersecting cords (Fig. 16.120B). Individual
cells are surrounded by and contain variable amounts
of mucin and demonstrate a vacuolated eosinophilic cy-
toplasm with fairly distinct cytoplasmic margins. Some
cells are distinctively large and vacuolated and are des-
ignated physaliphorous (bubble-bearing) cells (Fig.
16.121). Ultrastructurally, the small intracellular vac-
uoles correspond to dilated cisterns of coarse endo-
plasmic reticulum; epithelial attributes (desmosomes,
pinocytotic vesicles) also have been demonstrated (Mu-
rad and Murthy, 1970; Pèna et al., 1970; Kay and
Schatzki, 1972; Valderrama et al., 1983). Individual FIGURE 16.121 Clivus chordoma. Many large “physaliphorous” cells
cells may display considerable atypia and occasional are present. H&E.
Adamantinomatous craniopharyngioma
The more common adamantinomatous craniopharyn-
gioma occurs primarily during the first and second
decades of life, with a second peak occurrence in the
fifth decade. Most arise in the suprasellar area, where
symptoms result from compression of the optic chiasm,
extension into the sella and/or the third ventricle with
damage to the hypothalamus, and/or obstruction of
CSF flow. About 5% are confined to the sella, while
rare examples have been reported in the cerebellopon-
tine angle (Altinörs et al., 1984), pineal gland (Solarski
et al., 1978), nasopharynx (Majlessi et al., 1978),
paranasal area (Akimura et al., 1989) or sphenoid
FIGURE 16.122 The chondroid chordoma, in addition to typical chor- (Cooper and Ransohoff, 1972), or following presumed
doma components, contains cartilaginous features. H&E. implantation along a needle tract (Barloon et al., 1989).
Although the craniopharyngioma is a slow-growing,
benign neoplasm, it is situated in a relatively inacces-
chordomas. The chordoma, similar to the notochord sible area, making complete removal difficult. As a re-
from which it derives, shows immunohistochemical fea- sult, cyst drainage, partial resection, and postoperative
tures of both epithelial and mesenchymal cells, evi- radiation have been employed therapeutically. Recur-
denced by immunoreactivity both to cytokeratin and rences, although slow to develop, seem to be accom-
epithelial membrane antigen (EMA/epithelial markers), panied by increased adherence to local structures
as well as reactivity to S-100 protein (mesenchymal (Bartlett, 1971; Kahn et al., 1973; McMurry et al.,
marker) (Miettinen et al., 1983; Miettinen, 1984; Meis 1977; Sorva et al., 1987). Malignant transformation is
and Giraldo, 1988). In contrast, chondrosarcoma lacks extremely rare (Nelson et al., 1988).
reactivity to epithelial markers (cytokeratins and EMA) The cell of origin of the craniopharyngioma is con-
and stains only for S-100 protein. The immunohisto- troversial. It has been suggested that nests of squamous
chemical demonstration of chordomas with chondroid cells (epithelial nests of Erdheim), found incidentally on
features that expressed immunoreactivity only for mes- the anterior surface of the infundibulum or in the pars
enchymal markers led to questioning the existence of tuberalis of the pituitary, may give rise to this neoplasm
the chondroid chordomas and suggesting that it be re- (Luse and Kernohan, 1955; Goldberg and Eshbaught,
garded as a low-grade chondrosarcoma (Brooks et al., 1960). These nests, now known to result from meta-
1987). The controversy is yet not completely settled. plasia of the adenohypopheal cells of the pituitary stalk
Recent studies suggest that distinction of histologically (Asa et al., 1983), however, become more prominent
similar base-of-skull cartilaginous tumors be based with increasing age while craniopharyngioma is a tu-
upon immunohistochemical staining profiles. Lesions mor predominantly of childhood. Origin from Rathke’s
that stain with epithelial markers only, or with both cleft is supported by the occasional cleft cyst with ex-
epithelial and mesenchymal elements, may be regarded tensive squamous metaplasia of its lining. Resemblance
as chondroid chordomas, while others that show im- to the adamantinoma of the jaw is striking and cases
munoreactivity only for mesenchymal elements may be with tooth formation (Kalnis and Rossi, 1965;
considered chondrosarcomas (Wojno et al., 1992; Seemeyer et al., 1972) suggest a common embyronic
Mitchell et al., 1993; Rosenberg et al., 1994; Jeffrey et cell of origin with enamel organ potential.
al., 1995). Grossly, the tumors present as bulging suprasellar
mass (Fig. 16.123). Almost all have some degree of cal-
cification, especially childhood examples that may per-
Craniopharyngioma
mit visualization on plain X-rays (Sorva et al., 1987).
The craniopharyngioma is an epithelial tumor that con- CT or MR imaging reveals variably cystic–solid, par-
stitutes 2%–5% of all primary intracranial neoplasms. tially calcified, enhancing masses (Pusey et al., 1987).
Almost all occcur in the sellar regon. On the basis of The cut surface is variable, ranging from a mostly solid,
clinicopathologic studies, two distinct variants exist: firm nodular tumor to one with multiple cysts, filled
the classic adamantinomatous craniopharyngioma and with a “machine oil”–like liquid in which cholesterol
the less common papillary craniopharyngioma. crystals are present. This liquid can elicit a granulo-
FIGURE 16.123 Adamantinomatous craniopharyngioma. The tumor FIGURE 16.125 Adamantinomatous craniopharyngioma. The kera-
presents as a large globoid suprasellar mass that compresses and dis- tinizing nodules contain “wet” keratin that differs from the flaky
places cranial nerves and major cerebral vessels at the base of the “dry” keratin of the epidermoid cyst (compare with Fig. 16.117).
brain. The upward displacement and compression of the hypothala- H&E.
mus and third ventricle also contribute to the clinical presentation
of the mass.
into a peripheral zone of dense reactive gliosis that may
be easily mistaken for a glioma if biopsied (Fig. 16.126).
matous reaction if spilled into the subarachnoid space
(Patrick et al., 1974).
Papillary craniopharyngioma
The microscopic appearance is characteristic. The tu-
mor is composed of nests of epithelial cells that form A rather distinctive suprasellar neoplasm has been rec-
compact masses or surround cysts. The nests are sur- ognized relatively recently. It is papillary and its cellu-
rounded by a layer of columnar “basal” cells separated lar structure resembles more the oral–pharyngeal mu-
by a myxoid stroma, composed of loosely arranged stel- cosa than the adamantinomatous epithelium of the
late cells (Fig. 16.124), with whorls of cells and kera- classic craniopharyngioma. This lesion occurs predom-
tinized nodules containing “wet” keratin (Fig. 16.125). inately in adulthood, most frequently arises in the third
The distinctive”wet” keratin appears billowed and thick- ventricle, tends to be solid and not calcified, and has
ened, unlike the “dry,” thin, flaky variety characteristic been associated with a more favorable prognosis (Do-
of epidermoid cysts (Fig. 16.125, contast with Fig. bos et al., 1953; Cashion and Young, 1971; Gian-
16.117). The margins are sharp but irregular and merge gaspero et al., 1984; Kunishio et al., 1987; Linden et
FIGURE 16.124 Adamantinomatous craniopharyngioma. Microscop- FIGURE 16.126 Adamantinomatous craniopharyngioma. The margin
ically, nests of loosely textured stellate reticulum are enclosed by pal- of the craniopharyngioma often displays an exuberant reactive glio-
isading columnar cells that impart a “picket fence”–like appearance sis complete with Rosenthal fibers that may mimic pilocytic astro-
to the tumor. H&E. cytoma.
al., 1989; Crotty et al., 1992). Microscopically the skull. Epidural metastases, however, are relatively
tumor is comprised of prominent papillae of well- common in the vertebral column, where an actual
differentiated squamous epithelium (Fig. 16.127). epidural space exists.
Characteristic features of the adamantinomatous
craniopharyngioma are absent, so the term suprasellar
Epidural metastases
papillary squamous epithelioma, rather than papillary
craniopharyngioma is preferred for this lesion. Patients with spinal epidural metastases commonly
present with symptoms of cord compression. Epidural
Metastatic Neoplasms neoplasms almost never derive from the CNS and usu-
ally represent blood-borne metastases or direct exten-
The nervous system is a frequent target for malignant sion from an adjacent primary. Approximately half
neoplasms. No area is exempt, so many potential arise from breast, lung, or prostate primaries, followed
intra- and extra-axial sites for metastatic disease exist by lymphoma, melanoma, renal cell, sarcoma and mul-
(Takakura et al., 1982). Metastases may occur in skull, tiple myeloma (Byrne, 1992). Thoracic levels are most
vertebral body, dura, leptomeninges, nervous system commonly involved.
parenchyma, spinal nerve roots, and pituitary gland.
Unusual sites for metastases include choroid plexus
(Kohno et la., 1996), pineal gland (Weber et al., 1989), Leptomeningeal metastases
and subependymal–periventricular region (Vannier et This less common form of metastatic spread occurs in
al., 1986). Rarely, metastases to meningiomas and about 3% of patients with carcinoma or sarcoma, usu-
glioblastoma5 have been reported. More often than not, ally from breast or lung carcinoma, melanoma, or gas-
many sites are affected, so the incidence of multiple tric carcinoma (meningeal carcinomatosis) (Herman
metastases is higher than that of a solitary one. Exten- and Courville, 1965; Bramlet et al., 1976; Gonzalez-
sive edema usually develops in tissue adjacent to a me- Vitalel and Garcia-Bunuel, 1976; Theodore and Gen-
tastasis and frequently complicates the neurological delman, 1981; Kokkoris, 1983). Leukemia, especially
deficit. Most metastases are blood-borne, reaching in younger patients, affects the meninges more fre-
the nervous system via arteries or vertebral venous quently (22%) than lymphoma (11%) (Takakura et al.,
plexuses. Dissemination along peripheral nerves may 1982). Leptomeningeal involvement results from seed-
be involved in the genesis of meningeal carcinomatosis ing of the subarachnoid space, followed by widespread
(Herman and Courville, 1965; Gonzalez-Vitalel and dissemination, usually as a diffuse leptomeningeal pro-
Garcia-Bunuel, 1976; Kokkoris, 1983). cess, or less commonly as discrete nodules. The infil-
trate involves the subarachnoid and Virchow-Robin
Leptomeningeal and epidural metastases spaces. Infiltration of cranial and spinal nerve roots is
common. When a diffuse process results, the only gross
Symptomatic epidural metastases in the cranium are
evidence of involvement may be a barely perceptible
rare because of the firm adherence of the dura to the
clouding of the meninges, or, if more extensive, thick-
ening and opaqueness. Presenting symptoms may be re-
lated to involvement of nerve roots or complications of
hydrocephalus that may follow interference in CSF ab-
sorption. The CSF typically demonstrates elevated pro-
tein, low glucose, and the presence of malignant cells,
but no inflammatory cells on cytologic examination.
Microscopically, tumor cells typically are attached to
the inner surface of the arachnoid. The pia and glial
membrane seems to form a barrier that, to some ex-
tent, prevents infiltration into underlying parenchyma,
although invasion may follow disease progression.
Dural metastases
FIGURE 16.127 Papillary craniopharyngioma. The tumor is comprised

Dural metastases occur in about 10% of autopsied pa-
of well-differentiated squamous epithelium and intersecteding fi- tients with carcinoma or sarcoma. About half originate
brovascular stroma that impart a vague pseudopappilary appearance. from breast carcinoma, followed by lung carcinoma,
lymphoma and leukemia, melanoma, and GI carcinoma

(Takakura et al., 1982). Most dural metastases are mul-
tiple (Fig. 16.128).
Parenchymal metastases
The incidence of CNS parenchymal metastases varies
considerably, from 4.2% to 37% of all brain neo-
plasms, depending upon the case selection (Takakura
et al., 1982). The incidence is highest in autopsy series
of brain tumors in adults and lowest in series from neu-
rosurgical centers and young patients (Aronson et al.,
1964; Takakura et al., 1982). The surgical pathologist
often encounters specimens from patients with no
known primary metastases and thought to have a FIGURE 16.129 Parenchymal metastases. Multiplicity is the rule in
glioma, or patients with known metastases thought to metastatic disease of the brain. Note sharp circumscription of and
have a primary intracranial process. Survival following propensity for metastatic deposits to be located at gray–white junc-
tion and in deep gray matter structures.
surgery for metastatic carcinoma is highly variable, on
the order of months to 1 year (Perese, 1970). There are
data, however, documenting that patients with known
primaries who present with a solitary CNS metastasis prostate (Castaldo et al., 1983; Fervenza et al., 2000),
may derive significant palliation by the surgical removal ovary (Stein et al., 1986; Dauplat et al., 1987), esoph-
of the lesion (Galicich et al., 1980; Chan and Steinbok, agus (Gabrielsen et al., 1995), pancreas (Sabo and
1982). Kalynan-Raman, ?) or bladder (Davis et al., 1986; Vin-
The most common primary sources of cerebral chon et al., 1994). Although choriocarcinoma is rare,
parenchymal metastases are lung (approx. 35%) (Gal- it frequently involves the brain (Athanassiou et al.,
luzzi and Payne, 1956; Hirsch et al., 1982, 1983; 1983; Ishizuka et al., 1983). Metastatic sarcoma is un-
Tsukada et al., 1983; Nussbaum et al., 1996), breast common (Lu and Lee, 1961; Dal Canto and Valsamis,
(approx. 20%) (Tsukada et al., 1983; Boogerd et al., 1973; Nirmel et al., 1978; Saris et al., 1987) but seems
1993; Nussbaum et al., 1996), skin (malignant mela- to increase with prolonged survival time with chemo-
noma, approx. 10%) (Bullard et al., 1981; Choi et al., therapy (Espaiia et al., 1980; Gercovich et al., 1975).
1985; Retsas and Gershuny, 1988; Sampson et al., Most metastases lodge in the more vascular gray mat-
1998), kidney (approx. 10%) (Postler and Meyermann, ter of the brain, particularly at the junction between
1999), and gastrointestinal tract (approx. 5%) cortex and white matter (Fig. 16.126). They occur more
(Takakura et al., 1982). Rarely, metastases arise from commonly in the cerebrum than the cerebellum, prob-
ably because of the greater mass of the former, and are
rare in the brain stem (Weiss and Richardson, 1978).
The territory supplied by the middle cerebral artery is
involved most frequently (Delattre et al., 1988; Kindt,
1964), although metastases in arterial border zones also
are common. On CT or MR, metastatic lesions typically
are round, solid or ring-like contrast-enhancing mass of-
ten with a central low density/intensity region that cor-
related with a necrotic center. Surrounding edema is of-
ten prominent.
The metastasis usually has a characteristic gross ap-
pearance; it tends to be rounded, often with a central
zone of necrosis, and to display sharp margins (Fig.
16.129). An extensive zone of edema commonly de-
velops at the periphery and greatly increases the mass
effect of the tumor. The peripheral zone shows a reac-
FIGURE 16.128 Dural metastases. Knobby, irregular deposits on sub- tive gliosis, and if biopsied, may be misinterpreted as
dural surface represent metastases of adenocarcinoma of the breast. a low-grade or well-differentiated astrocytoma. The
edema surrounding a metastatic neoplasm (vasogenic

edema) responds dramatically to corticosteroid ther-
apy. Hemorrhage may be especially common in mela-
noma, choriocarcinoma, renal cell carcinoma, and lung
carcinoma (Mandybur, 1977).
Microscopic features of a metastatic lesion usually
mimic the primary lesion (Fig. 16.130). Carcinomas,
in contrast to glial tumors, display epithelial cells with
sharply defined cell margins without delicate pro-
cesses. Mitoses are numerous and large zones of ne-
crosis may be prominent. Sometimes a ring of viable
cells is preserved around blood vessels in a back-
ground of extensive necrosis. The margins of the tu-
mor are sharp but infiltrative. Neovascularity may
FIGURE 16.131 Differential immunostaining often is helpful in deter-
precede the growing margins of the neoplasm. Car- mining the primary site of a metastasis. In this case, immunoreac-
cinomas, although highly anaplastic, often display tivity of the neoplastic cells for both thyroid transcription factor
immunoreactivity for cytokeratins and EMA. Occa- (TTF) (left) and CK7 (right) are most consistent with a pulmonary
sionally, microscopic features of the metastasis do not primary.
identify the primary source, and in some cases, it may
be difficult to definitely distinguish between an
anaplastic metastasis and a glioblastoma with ep-
PROLIFERATIVE HEMATOPOIETIC DISORDERS
ithelial features. The availability of PAP immunos-
tains for a variety of cell lines, however, has greatly
Non-Hodgkin’s Malignant Lymphomas
improved our diagnostic accuracy in such instances
(Fig. 16.131) (Perry et al., 1997). Malignant lymphomas are divided between non-Hodg-
In contrast to intracranial parenchymal masses, kin’s lymphoma (NHML) and Hodgkin’s disease (Co-
spinal intramedullary metastases are very rare tran et al., 1999). Involvement of the central nervous
(Hashizume and Hirano, 1983; Grem et al., 1985; system (CNS) by NHML may occur as a primary le-
Schwechheimer and Lemminger, 1985; Dunne et al., sion with no evidence of nodal or visceral manifesta-
1986). Most commonly involved are thoracic levels. tions or as a secondary infiltration from a systemic lym-
Primary sites include lung in nearly half of cases, fol- phoma involving several organs (Traweek, 1998).
lowed by breast, kidney and melanoma (Schwech- Since the introduction of the term perithelial sarcoma
heimer and Lemminger, 1985). by Bailey to designate central nervous system lym-
phomas, other authors have used such diverse terms as
microglioma, reticulum cell sarcoma, and immuno-
blastic sarcoma and have proposed the origin of the
neoplastic cells to be transformed resident cells of the
CNS, such as microglial cells, or extraneural elements
of the reticuloendothelial system (Hochberg and Miller,
1988; Russell et al., 1989b). On the basis of morpho-
logic, electron microscopic, and immunohistochemical
studies, modern classifications recognize lymphocytic
elements as the neoplastic cells in the great majority of
nodal, visceral, and CNS NHML (Burger et al., 1991;
Cotran et al., 1999; Henry et al., 1974; Hochberg and
Miller, 1988; O’Neill and Illig, 1989; Traweek, 1998).
CNS-NHMLs recapitulate the spectrum of nodal lym-
phomas.
In the past, primary CNS-NHMLs were rare neo-
plasms that constituted less than 2% of all intracranial
FIGURE 16.130 Parenchymal metastasis. The histological features of
the metastatic lesion mimic the patient’s pulmonary primary. Note
tumors. Currently the incidence is estimated at
circumscription and extensive reactive gliosis in adjacent compressed 6.6%.(Miller et al., 1994). This increased incidence
brain. H&E. could be related to several risk factors, including con-
genital (Wiskott-Aldrich syndrome) and acquired (car- common lesions in primary CNS NHML are
diac and renal transplant recipients, AIDS) immuno- parenchymal; more than 75% are subependymal or in
deficiencies, collagen vascular diseases, and a family contact with the meninges, 60% are lobar, and 25%
history of cancer (Hochberg and Illig, 1988; Nakhleh are deeply located in midline structures such as the sep-
et al., 1989; O’Neill et al., 1989; Remick et al., 1990; tum pellucidum, basal ganglia, and corpus callosum
De Angelis, 1991; Hamilton-Dutoit et al., 1991; (O’Neill et al., 1989). In the cerebrum the frontopari-
Traweek, 1998; Paulus et al., 2000). Epstein-Barr virus etal region is the most common site. Other locations
(EBV) has been implicated in the development of cen- include the brain stem, cerebellum, and spinal cord.
tral nervous system lymphomas in immunocompetent Multiple lesions are found in all patients dying of AIDS,
and immunocompromised patients, and EBV sequences in contrast to 44% of non-AIDS patients (O’Neill et
have been found in a significant number of cases al., 1989). Meningeal infiltration is the most common
(Rouah et al., 1990; Bignon et al., 1991; Hamilton- lesion in the secondary tumors. Primary leptomeningeal
Dutoit et al., 1991; Nakhleh et al., 1991; Chang et al., involvement is rare and constitutes 7.6% of all primary
1993; Cinque et al., 1993; Morgello, 1995; Camilleri- central nervous system lymphomas (Lachance et al.,
Broet et al., 1997). NHMLs are slightly more common 1991).
in male than female patients. They are found in indi- Neuroimaging studies of the CNS usually show sin-
viduals of all ages but reach a peak incidence at 55 gle or multiple solid lesions that enhance after contrast
years in immunocompetent individuals (Henry et al., administration and without evidence of significant va-
1974). In patients with AIDS, CNS NHML presents at sogenic edema. Similar to glioblastoma multiforme, me-
a younger age and during childhood in those with con- tastasis and brain abscess, lymphomas may also exhibit
genital immunodeficiencies (Traweek, 1998; Paulus et ring enhancement.
al., 2000). The gross appearance of central nervous system
The clinical manifestations are nonspecific and could NHML is variable, mimicking infectious processes, vas-
be related to generalized or focal symptoms and signs cular lesions, or primary and metastatic neoplasms
or both (Henry et al., 1974; Hochberg et al., 1988; (Figs. 16.132–16.134). It can be a diffuse microscopic
Nakhleh et al., 1989; O’Neill et al., 1989; Remick et infiltrate that to the unassisted eye leaves the areas in-
al., 1990). Several neurologic syndromes, includ- volved intact. It can be identified as an area of tissue
ing uveocyclitis, subacute encephalitis, and multiple expansion in which the architecture is well preserved
sclerosis–like illness, may be the initial manifestation and may be associated with narrowing of cortical gyri
(O’Neill et al., 1989). Cerebrospinal fluid abnormali- and ventricles. Discrete nodules with a granular cut sur-
ties include increased protein content and mononuclear face or cystic change may be seen. The differential di-
cell pleocytosis (Henry et al., 1974; Hochberg et al., agnosis with a glioblastoma multiforme should be en-
1988; Nakhleh, 1989; O’Neill et al., 1989; Remick et tertained when the lymphoma diffusely infiltrates the
al., 1990; Lachance et al., 1991). Both contrast- parenchyma and reveals a variegated cut surface with
enhanced CT and magnetic resonance imaging demon-
strate the presence of homogeneous enhancing lesions
involving cerebrum, cerebellum, or brain stem (Hoch-
berg et al., 1988; O’Neill et al., 1989; Burger et al.,
1991). Multiple lesions are present in approximately
30% of patients. Ring-enhancing masses and peritu-
moral edema are exceptional. In most cases the diag-
nosis is confirmed by stereotactic needle biopsy
(Nakamine et al., 1989; DeAngelis, 1991a; Sherman et
al., 1991). Total or subtotal surgical excision should
be avoided (O’Neill et al., 1989; DeAngelis 1991a). The
prognosis for untreated patients is dismal; most die
within a year after diagnosis (Hochberg et al., 1988).
The tumor is radiosensitive; the combination of che-
motherapy followed by irradiation improved the me-
dian survival time to 42 months in a series of 31 pa-
tients (DeAngelis, 1991a).
Central nervous system NHML lesions may be FIGURE 16.132 Non-Hodgkin’s malignant lymphoma associated with
meningeal, parenchymal, or intravascular. The most discrete lesions in the basal ganglia.
FIGURE 16.135 Diffuse large B-cell lymphoma showing marked nu-

clear atypia and mitoses. Hematoxylin and eosin stain.
Most CNS NHMLs are high-grade lesions corre-

sponding to large B cells. At the periphery, the neo-
plastic infiltrate tends to be perivascular and is associ-
FIGURE 16.133 Non-Hodgkin’s malignant lymphoma with hemor-
ated with deposition of reticulin fibers arranged in
rhagic lesion in the white–gray-matter junction mimicking metasta- concentric layers that separate individual cells and cel-
tic carcinoma. lular groups (Figs. 16.136, 16.137). Non-neoplastic ad-
ventitial cells have been proposed as the source of these
reticulin fibers (Russell et al., 1989b). Collagen types
hemorrhage and necrosis; the latter is a feature of AIDS- I, II, IV, and V, laminin, and fibronectin are demon-
associated lymphoma. strated by immunohistochemistry within perivascular
On microscopic examination, CNS NHMLs exhibit spaces (Kalimo et al., 1985). The wide use of im-
a diffuse histologic pattern; nodular lymphomas are munohistochemical markers, such as CD45RB (leuko-
rare (Hochberg et al., 1988; O’Neill et al., 1989; Rus- cyte common antigen, LCA), CD20 (B-cell marker),
sell et al., 1989; Burger et al., 1991). The infiltrate is CD3 and CD45RO (UCHL-1) (T-cell markers), and
polymorphous and includes histiocytes, plasma cells, kappa and lambda light chains, has established that the
reactive and neoplastic lymphoid elements, microglial majority of central nervous system NHMLs are of
cells, and a variable number of reactive astrocytes; B-cell origin; T-cell and histiocytic lymphomas are ex-
mitoses and nuclear atypia are common (Fig. 16.135). tremely rare (Daniel et al., 1985; Teschima et al., 1990;
FIGURE 16.134 Non-Hodgkin’s malignant lymphoma with ill-de- FIGURE 16.136 Non-Hodgkin’s malignant lymphoma with infiltra-
marcated homogeneous pontine mass. tion of perivascular spaces. Hematoxylin and eosin stain.
lar infiltration (Fig. 16.138) (Hochberg et al., 1988;

Russell et al., 1989; Clark et al., 1991; Smadja et al.,
1991; Digiuseppe et al., 1994). In most cases it is a
manifestation of a generalized B-cell lymphoma in
which luminal infiltration is present in other organs,
commonly the skin and adrenal glands (Ferry et al.,
1988; Hochberg et al., 1988; Stroup et al., 1990; Glass
et al., 1993). The clinical manifestations are protean
and include dementia. Pathologic study shows multiple
small hemorrhagic and ischemic infarcts related to
plugging of the blood vessels involved by neoplastic
cells.
Hodgkin’s Disease
FIGURE 16.137 Non-Hodgkin’s malignant lymphoma exhibiting de-
position of reticulin fibers in perivascular spaces. Reticulin stain. Hodgkin’s disease is often localized to a single group
or groups of lymph nodes, and extranodal involvement
is rare. It is characterized histologically by the presence
Bednar et al., 1991; Ferracini et al., 1995). There is un- of neoplastic Reed-Sternberg cells or their variants in-
certainty regarding the applicability of the various clas- termixed with an inflammatory infiltrate variably com-
sifications of nodal lymphomas to CNS NHMLs includ- posed of lymphocytes, neutrophils, histiocytes, plasma
ing the Working Formulation of non-Hodgkin’s cells, and eosinophils (Cotran et al., 1999). The classic
Lymphomas for Clinical Usage, Revised Kiel Classi- Reed-Sternberg cell is binucleated, and each nucleus ex-
fication, Revised European-American Lymphoma hibits a single eosinophilic nucleolus surrounded by a
(REAL) Classification, and the WHO Classification. (Na- clear halo and has abundant amphophilic cytoplasm.
tional Cancer Institute, 1982; Lennart and Feller, 1992; They exhibit immuno-affinity for CD15 (Leu-M1) and
Kleihues et al., 1993; Harris et al., 1994). Currently, two CD30 (Ki-1). The Rye classification identifies four sub-
major categories are recognized: B- and T-cell lym- groups: lymphocyte predominance, mixed cellularity,
phomas. The value of subclassifying CNS NHMLs re- lymphocyte depletion, and nodular sclerosis (Lukes et
mains to be elucidated (Paulus and Janiseh, 2000). al., 1966). Neurologic complications may be found
Intravascular lymphoma is characterized by the pres- in about 20% of patients and could be related to
ence of neoplastic lymphocytic elements confined to the bone, parenchymal, and meningeal neoplastic infiltra-
lumen of small parenchymal and meningeal blood ves- tion or to several different nonneoplastic disorders
sels by the endothelium with no vascular or perivascu- (Fig. 16.139) (Sanchez et al., 1977; Scheithauer, 1979;
FIGURE 16.138 Intravascular lymphoma showing malignant cells con- FIGURE 16.139 Hodgkin’s disease with hemorrhagic lesions involv-
fined to the vascular lumen of a white matter blood vessel. Hema- ing periventricular regions and choroid plexi (courtesy of Julio H.
toxylin and eosin stain. Garcia, M.D.).
Dujovny et al., 1980; Sapozink et al., 1983; Ashby et

al., 1988). The meninges and structures at the skull
base are the sites most commonly involved.
Plasma Cell Neoplasms

Plasma cell neoplasms correspond to a group of ter-
minally differentiated B cells that have in common the
expansion of a single clone of plasma cells that secrete
a single complete immunoglobulin or its fragments
(Cotran et al., 1999). In the blood the immunoglob-
ulin is identified as the M (myeloma) component, and
it can be IgA, IgD, IgE, or IgM. Fractions of im-
munoglobulins are usually of a single type and include
either one of the light chains kappa and lambda or
the heavy chains alpha, gamma, and mu. If present in
the urine the light chains are known as Bence-Jones
proteins.
Solitary Plasmacytoma and Multiple Myeloma

The neoplastic proliferation of plasma cells is confined FIGURE 16.141 Multiple myeloma with formation of hemorrhagic
to a single or multiple bones. The vertebral column, epidural mass.
ribs, and skull are the most commonly affected (Co-
tran et al., 1999). The infiltrate, which starts within the
bone marrow, is characterized by mature and imma-
ture plasma cells with nuclear atypia, multiple nuclei, diologic appearance of punched-out defects. In both
and mitotic activity (Fig. 16.140). Russell bodies, iden- vertebral and calvarial myeloma the neoplastic process
tified as homogeneous eosinophilic cytoplasmic inclu- may extend into the epidural space and it infiltrates the
sions that correspond to packed immunoglobulins, are dura (DuPreez and Branca, 1991; Benli and Inci, 1995)
usually found. Destruction of cancellous and cortical (Fig. 16.141). Fifteen cases of primary intracranial soli-
bone is present. In the vertebral column these lytic le- tary plasmacytoma involving the meninges or cerebrum
sions may be associated with pathologic fractures and and 10 localized to the bones of the base of the skull
compressive paraplegia. In the skull they are usually were collected from the literature (Mancardi and
confined to the inner table, giving the characteristic ra- Mandybur, 1983). The bone lesions were accompanied
by cranial nerve palsies.
Histiocytoses
The histiocytoses are a group of heterogeneous dis-
orders characterized by proliferation of histiocytic
cells that belong either to the monocyte–macrophage
system (free and tissue macrophages) or to the den-
dritic cell system (Langerhans cell, interdigitating
dendritic cell, and dendritic reticulum cell) (Favara et
al., 1983; Malone 1991; Cotran et al., 1999). Mono-
cyte–macrophage cells are antigen-processing cells,
and dendritic cells present antigens to B or T cells.
Three main groups are recognized, including Langer-
hans-cell histiocytosis, histiocytosis related to mac-
rophages, and malignant histiocytic disorders (Writ-
FIGURE 16.140 Multiple myeloma comprised of plasma cells, some ing Group of the Histiocyte Society, 1987; Malone,
with atypical nuclei. Hematoxylin and eosin stain. 1991; Favara et al., 1997).
Langerhans-Cell Histiocytosis
Langerhans-cell histiocytosis, known also as histiocy-
tosis X, groups together Letterer-Siwe disease, Hand-
Schuller-Christian disease, and eosinophilic granuloma
(Favara et al., 1983; Malone 1991; Cotran et al., 1999).
These three entities represent different expressions of
the same disorder.
Acute disseminated Langerhans-cell histiocytosis
(Letterer-Siwe disease) shows a predilection for chil-
dren between 2 and 4 years of age (Favara et al., 1983;
Wattanabe et al., 1983; Malone 1991, Cotran et al.,
1999). Infiltration by histiocytic cells is found in many
organs and tissues, including the CNS. The clinical
course is variable and depends on the age at onset and
FIGURE 16.143 Langerhans cell with cytoplasmic Birbick granules (ar-
extent of organ involvement. If untreated, the disease row).
is usually fatal. Fifty percent of patients survive 5 years
with intensive chemotherapy.
Unifocal Langerhans-cell histiocytosis (eosinophilic
granuloma) is a benign disorder that affects children cellular infiltrate is composed of a variable number of
and young adults. Solitary lesions are usually present Langerhans cells, macrophages, eosinophils, lympho-
in bones (Cotran et al., 1999). Occasionally the dura, cytes, and multinucleated giant cells (Fig. 16.142).
brain, and spinal cord are involved (Favara et al., Mild-to-marked fibrosis and phagocytosis may be pres-
1983). The lesions may heal spontaneously or be cured ent. The Langerhans cells are identified by their abun-
by local excision or radiation therapy. dant homogeneous eosinophilic cytoplasm and lobu-
The onset of multifocal Langerhans-cell histiocytosis lated nuclei, which have a coffee bean appearance.
occurs before 5 years of age. Respiratory infections are Electron microscopy demonstrates diagnostic cytoplas-
common manifestations. Histiocytic infiltrates are mic Birbeck bodies with a pentalaminar rodlike tubu-
found in lymph nodes, liver, and spleen. Within the cra- lar structure and a dilated terminal end similar to a ten-
nial cavity the lesions tend to be present in multiple nis racquet (Fig. 16.143). (Favara et al., 1983; Malone,
bones, orbit, pituitary gland, and the hypothalamic re- 1991; Callihan 1995). Langerhans cells express CD1a
gion. This presentation is associated with the classical and HLA-DR.
triad of Hand-Schuller-Christian disease of lytic bone
lesions, exophthalmos, and diabetes insipidus (Malone,
Histiocytosis of Mononuclear Phagocytes
1991; Cotran et al., 1999). On microscopic study the
Sinus histiocytosis associated with massive
lymphadenopathy (Rosai-Dorfman disease)
In 1969 Rosai and Dorfman described a non-neoplas-
tic proliferation of histiocytes designated sinus histio-
cytosis associated with massive lymphoadenopathy. It
is found more frequently in children and adolescents,
who may develop cervical lymphadenopathy, fever,
anemia, polyclonal hypergammaglobulinemia, and an
elevated sedimentation rate (Foucar et al., 1990). In-
volvement of extranodal organs including the CNS is
rare (Kressler et al., 1976). In cases with CNS in-
volvement, most of the patients are adults with extra-
axial lesions related to cranial and spinal dura (Foucar
et al., 1982; Jones et al., 1997). Nodal lesions may be
absent. Microscopically, the lesions show a polymor-
FIGURE 16.142 Langerhans-cell histiocytosis comprised of mononu-
phous cellular infiltrate comprised of lymphocytes,
clear cells and abundant Langerhans cells with vacuolated cytoplasm. plasma cells, and variable numbers of histiocytes
Hematoxylin and eosin stain. with phagocytosed lymphocytes (emperipolesis) (Fig.
leukemia in blast crisis may also involve the CNS

(Schwartz et al., 1975; Barcos et al., 1987).
Leukemic infiltrates can be found in the dura, lep-
tomeninges, brain, and spinal cord (Fig. 16.146). Lep-
tomeningeal infiltration is the most commonly observed
lesion and can be associated with extension into cra-
nial nerves and spinal nerve roots. In leukemic patients
dural infiltration varies from 20% to 93%, lep-
tomeningeal from 20% to 71%, and parenchymal from
16% to 25% (Azzarelli et al., 1977; Russell et al.,
1989). Within the central nervous system the leukemic
cells are protected by the blood–brain barrier from the
effects of cytotoxic drugs and may survive to initiate a
relapse. The development of prophylactic CNS therapy
FIGURE 16.144 Rosai-Dorfman disease of the CNS showing lym- has reduced the incidence of this complication and con-
phocytes, plasma cells, and histiocytes with emperipolesis. Hema- tributed to an increase in the survival time of children
toxylin and eosin stain.
with leukemia (Pochedly, 1990). The leukemic infiltra-
tion of the brain parenchyma is possibly metastatic and
follows a pathway of perivenular connective tissue that
16.144). The histiocytes express CD68 and S-100 pro- starts in the bone marrow and extends through the dura
tein and are negative for CD1a (Fig. 16.145). The prog- and leptomeninges into the parenchyma (Azzarelli et
nosis is excellent after surgical excision (Resnick et al., al., 1984). It has been proposed that leukemic cells pro-
1996; Jones et al., 1997). liferate within vascular lumens and may migrate into
the parenchyma through a system of specialized endo-
Leukemias thelial cells that, in the guinea pig, are present in sev-
eral organs, including the brain (Azzarelli et al., 1989).
Craniospinal complications of leukemias include dif- Granulocytic sarcoma (chloroma) is the formation of
fuse or focal infiltrates, solid neoplastic masses (gran- solid tumoral masses by leukemic infiltrates in bones,
ulocytic sarcoma), and intraparenchymal and extra- different organs, and soft tissues (Rappaport, 1966).
parenchymal hemorrhages (Nieri et al., 1960; Russell The characteristic green color of the lesion is attributed
et al., 1989). Central nervous system manifestations are to the myeloperoxidase content of the neoplastic cells.
more common in acute lymphoblastic and myeloblas- This neoplasm may be found in the dura and brain pa-
tic leukemias (Stewart et al., 1981; Russell et al., 1989). renchyma and could antedate the systemic manifesta-
Chronic lymphocytic leukemia and chronic myeloid tions of the disease (Llena et al., 1978; Doshi et al.,
1991).
FIGURE 16.145 Rosai-Dorfman disease of the CNS showing histio-

cytes with immunoreactivity for S-100 protein. Peroxidase-antiper- FIGURE 16.146 Leukemic infiltrate of the optic nerve composed of
oxidase method. cells with atypical nuclei. Hematoxylin and eosin stain.
Parenchymal, subarachnoid, and dural hemorrhages tures of photoreceptors and neuroendocrine cells and
are complications of different types of leukemias. In- stain positively for retinal S-antigen and neuronal
tracerebral hemorrhages are usually multiple, terminal, markers (Editorial, Lancet, 1974; Wurtmann and
and associated with fulminating blastic crisis (Fig. Moskowitz, 1977; Erlich and Apuzzo, 1985; Perentes
16.147) (Freireich et al., 1960). It is related to in- et al., 1986).
travascular clumping of leukemic blasts in small per- The pineal interstitial cells are believed to be astro-
forating blood vessels (Nieri et al., 1968; Russell et al., cytic in origin (Cooper, 1932). They are spindle-shaped
1989). Subarachnoid and dural hemorrhages are prob- cells with elongated hyperchromatic nuclei, scant cyto-
ably related to other factors including thrombocytope- plasm, and delicate processes that extend for various
nia. Recently, the incidence of intracranial hemorrhage distances through the gland. They are present in
in leukemia has been decreased with the use of leuko- perivascular spaces and between parenchymal cells. In-
pheresis and improvements in platelet and blood fac- terstitial cells stain positively for GFAP, S-100 protein,
tor transfusion therapy (Traweek, 1998). and vimentin (Papasozomenos, 1983; Erlich and
Apuzzo, 1985; Zang et al., 1985). Other cells include
fibroblasts, skeletal muscle fibers, lymphocytes, plasma
TUMORS OF THE PINEAL REGION cells, macrophages, and endothelial cells (Quay, 1965).
The normal lobular pattern of the pineal gland
The pineal gland is present in almost all vertebrate emerges during the first decade of life. The gland is cov-
species. The predominant cell types within the adult ered by pia mater and divided into lobules separated
mammalian pineal gland are parenchymal (95%) and by connective tissue septa (Cooper, 1932; Quay, 1965).
interstitial (5%) cells (Lewis, 1990). The pineal Mineralized deposits are constantly present in humans
parenchymal cells, or pinealocytes, are polygonal with by the age of 16 years, containing hydroxyapatite, cal-
vesicular nuclei, usually a single nucleolus, and homo- cium and other trace elements (Michotte et al., 1977).
geneous eosinophilic cytoplasm. The silver carbonate Tumors of the pineal region are rare, constituting
impregnation technique for pineal parenchymal cells 0.4%–1% of all intracranial neoplasms (Russell et al.,
demonstrates cellular processes that end in club-shaped 1989a). The incidence is higher in children (Hoffman
enlargements and form a radiating marginal zone in et al., 1983). For unknown reasons pineal neoplasms
close relationship to blood vessels (DeGirolami and are more common in Japan, where they have been re-
Schmidek, 1973). Ultrastructural studies of the human ported to range from 4.5% to 8.4% of all intracranial
pineal gland have demonstrated dense-core vesicles, tumors (Araki et al., 1969).
5–8 nm intermediate filaments, microtubules, cilia with As the histogenesis of pineal region neoplasms has
a 9+0 microtubular pattern, junctional complexes re- become better understood, the classification and
sembling synapses, and other cytoplasmic organelles nomenclature have changed greatly in the last decades.
within the pinealocytes (Kurumado and Mori, 1976; Most of these tumors can be classified as either germi-
Kurumado and Mori, 1977). Pinealocytes share fea- nal or pineal parenchymal in origin.
Tumors of Pineal Parenchymal Cells

The recently revised WHO classification of the central
nervous system tumors divides neoplasms of pineal
parenchymal cells into pineocytoma, pineoblastoma, and
pineal parenchymal tumors (PPTs) of intermediate dif-
ferentiation (Mena et al., 2000). These neoplasms con-
stitute almost 20% of all pineal tumors (Herrick, 1984).
Both pineocytoma and pineoblastoma may show
neuronal, retinoblastomatous (Flexner-Wintersteiner
rosettes and fleurettes), ganglionic (ganglion cells), and
astrocytic differentiation (Herrick et al., 1979).
Pineocytoma
FIGURE 16.147 Leukemia associated with multiple parenchymal hem- Pineocytomas account for approximately 45% of all
orrhages. PPTs and tend to affect young adults (Herrick et al.,
1979; Schild et al., 1993; Mena et al., 1995; Regis et Electron microscopy demonstrates well-differenti-
al., 1996). The lesion is a slow-growing neoplasm with ated cells with cytoplasmic organelles including neu-
a long clinical course. Neuroimaging studies usually rosecretory granules. The cells exhibit cellular processes
disclose a well demarcated round pineal mass that en- that contain microtubules and have terminal expan-
hances after contrast administration and is associated sions with synaptic vesicles (Herrick et al., 1979; Jou-
with hydrocephalus. Calcification is frequently present. vet et al., 1994; Min et al., 1994). If present, ganglion
On gross examination, the tumor is a well-circum- cells are characterized by prominent rough endoplas-
scribed pale-gray mass confined to the pineal gland mic reticulum and many secretory granules (Min et al.,
without infiltration of adjacent structures or cere- 1994). Photoreceptor cells show cytoplasmic annulate
brospinal fluid dissemination (Schild et al., 1996). Ex- lamellae, formation of intercellular lumens, cilia with
tracranial metastases seldom occur (D’Andrea et al., 90 microtubule configuration, and synaptic ribbons
1987; Mena et al., 1995). On histologic study the pi- (Herrick et al., 1979; Jouvet et al., 1994; Min et al.,
neocytoma shows mild-to-moderate cellularity and is 1994).
composed of uniform cells with round-to-ovoid nuclei Pineocytomas correspond to WHO grade II lesions
and homogeneous cytoplasm arranged in a solid pat- (Mena et al., 2000). The 5 year patient survival rate is
tern or ill-defined lobules. The presence of large pi- 86% (Schild et al., 1996). Survival is not affected by
neocytomatous rosettes composed of mature cells and the presence of divergent differentiation (Rubinstein,
a central area filled with cytoplasmic processes is char- 1981; Mena et al., 1995).
acteristic (Fig. 16.148) (Borit et al., 1980; Mena et al.,
2000). The stroma consists of delicate blood vessels
Pineoblastoma
lined by a single layer of endothelial cells supported by
scant reticulin fibers. Calcification may be present. The Pineoblastomas are malignant, poorly differentiated
cellular processes, which end in clublike expansions, neoplasms histologically similar to other primitive neu-
are better demonstrated with silver stains or methods roectodermal tumors of the central nervous system (De-
for pineal parenchymal cells (DeGirolami et al., 1973). Girolami et al., 1973; Herrick et al., 1979; Borit et al.,
The neoplastic cells express a variety of neuronal 1980). They may occur at any age but have a predilec-
markers including synaptophysin, neuron-specific eno- tion for children and adolescents prior to 20 years of
lase (NSE), NFP, and class III beta-tubulin (Numoto, age (Herrick et al., 1979; Hoffman et al., 1983; Schild
1994; Mena et al., 1995). Photosensory differentiation et al., 1993; Chang et al., 1995; Mena et al., 1995).
is evident by immunoreactivity to retinal S antigen (Per- Neuroimaging studies show a lobulated, poorly de-
entes et al., 1986; Mena et al., 1995). Astrocytic dif- marcated mass lesion with homogenous enhancement
ferentiation with positive cells for GFAP has been re- after contrast administration. The neoplasm tends to
ported (Herrick et al., 1979; Coca et al., 1992; Mena replace the pineal gland, infiltrates adjacent structures,
et al., 1995). and disseminates throughout the cerebrospinal fluid
pathways (DeGirolami et al., 1973; Hoffman et al.,
1983; Vaquero et al., 1992; Chang et al., 1995; Jakacki
et al., 1995; Mena et al., 1995). Metastases to bones,
lungs, and lymph nodes are reported (Herrick et al.,
1979; Rushing et al., 1991). Histologic examination re-
veals high cellularity. The growth is composed of small
cells with a high nuclear/cytoplasmic ratio; irregular,
hyperchromatic nuclei with an occasional small single
nucleolus; scant cytoplasm; and indistinct cellular bor-
ders. Mitoses, necrosis, and Homer-Wright rosettes are
common (Fig. 16.149).
The immunoreactivity of pineoblastomas is similar to
pineocytomas and may include positivity for neuronal
(synaptophysin, NSE, NFP, class III beta-tubulin), glial
(GFAP), and photoreceptor (retinal S antigen) markers
(Perentes et al., 1986; Numoto 1994; Mena et al., 1995).
FIGURE 16.148 Pineocytoma composed of cells with uniform nuclei
Electron microscopy shows poorly differentiated
and formations of large pineocytomatous rosettes. Hematoxylin and cells that contain a scant number of cytoplasmic or-
eosin stain. ganelles including a few neurosecretory granules and
that include well-differentiated astrocytoma, anaplastic

astrocytoma, and glioblastoma multiforme (DeGiro-
lami et al., 1973; Edwards et al., 1988). True pineal
astrocytomas are extremely rare (Papasozomenos and
Shapiro, 1981; DeGirolami et al., 1983). In our expe-
rience with seven tumors that occurred in children,
there were five well-differentiated tumors and two
anaplastic variants (Rushing et al., 1991).
Germ Cell Neoplasms

The WHO classification of brain tumors includes the
following variants of germ cell neoplasms: germinoma,
embryonal carcinoma, yolk sac tumor, choriocarci-
FIGURE 16.149 Pineoblastoma comprised of cells with irregular nu- noma, teratoma, and mixed (Rosenblum et al., 2000).
clei and scant cytoplasm arranged in Homer-Wright rosettes. Hema-
Teratomas are further subdivided into immature and
toxylin and eosin stain.
mature variants and those with malignant transforma-
tion.
microtubules that are also present in short cytoplasmic Intracranial germ cell tumors constitute less than 1%
processes (Markesbery et al., 1981; Min et al., 1994). of all intracranial tumors. They tend to be more fre-
Zonula adherens and zonula occludens junctional com- quent in some Asian countries (Matsutani et al., 1997).
plexes may be present between cells (Markesbery et al., The incidence is higher in children during the second
1981; Jouvet et al., 1994; Min et al., 1994). decade of life, which coincides with the onset of pu-
Pineoblastomas are classified as WHO grade 4 tu- berty (Bjornsson et al., 1985; Rueda-Pedraza et al.,
mors (Mena et al., 2000). Patient survival depends on 1987; Perez et al., 1990; Hoffman et al., 1991). Al-
the extent of the disease at the time of diagnosis. Sur- though a predominance in male patients is character-
vival beyond 2 years after diagnosis is rare (Herrick, istic, suprasellar and congenital neoplasms predomi-
1984; Mena et al., 1995). Pineoblastomas may be pres- nate in females (Rueda-Pedraza et al., 1987; Legido et
ent in patients with familial(bilateral) retinoblastoma, al., 1989; Hoffman et al., 1991). An increased inci-
a condition known as trilateral retinoblastoma which dence has been observed in patients with Klinefelter’s
is usually associated with a poor outcome (Lueder et syndrome, Down syndrome, and neurofibromatosis
al., 1991; DePotter et al., 1994; Marcus et al., 1998). type 1 (Fujita et al., 1992; Hasle et al., 1995).
Metastases to the CNS and the vertebral column are In the neuroaxis, germ cell tumors are found more
the most common cause of death (Marcus et al., 1998). frequently in the suprasellar and pineal regions, third
Projected 1, 3, and 5 year survival rates for patients
with pineoblastoma are 88%, 78%, and 58%, respec-
tively (Schild, 1993).
Pineal parenchymal tumors of

intermediate differentiation
Pineal parenchymal tumors (PPTs) of intermediate dif-
ferentiation are characterized by moderate cellularity,
mild nuclear atypia, occasional mitosis, and absence of
pineocytomatous rosettes (Fig. 16.150) (Schild et al.,
1993; Jouvet et al., 1994; Mena et al., 1995). Survival
beyond 4 years after surgical excision has been en-
countered (Jouvet et al., 1994).
Tumors of Pineal Interstitial Cells

FIGURE 16.150 Pineal parenchymal tumor of intermediate differenti-
Tumors of the pineal interstitial cells are classified as ation comprised of cells arranged in a diffuse solid pattern. Hema-
astrocytomas and are divided into several categories toxylin and eosin stains.
ventricle, posterior fossa, and pancranial region (Ru-

binstein 1981; Rueda-Pedraza et al., 1987; Hoffman et
al., 1991). As a result of their location, all intracranial
germ cell tumors, regardless of histologic type, mani-
fest similar neurologic, ophthalmologic, and endo-
crinologic signs and symptoms, including increased in-
tracranial pressure, visual deficits, diabetes insipidus,
hydrocephalus, precocious puberty, and panhypopitu-
itarism (Rueda-Pedraza et al., 1987; Edwards et al.,
1988; Legido et al., 1989; Hoffman et al., 1991).
In recent years many substances have been used
as markers for gonadal and extragonadal germ cell
tumors. These markers are present in serum, cere-
brospinal fluid, and tissues and are routinely used in
clinical and pathologic diagnosis and follow-up (Hoff- FIGURE 16.152 Germinoma showing biphasic pattern comprised of
man et al., 1991). They are grouped into two main cat- large epithelial-like cells and small lymphocytes. Hematoxylin and
eosin stain.
egories: oncofetal substances and cellular enzymes
(Mostofi et al., 1987). Oncofetal substances include al-
pha-fetoprotein (AFP) and three placental glyco-
proteins: human chorionic gonadotropin (HCG, beta the hormone. PLAP is a surface glycoprotein elaborated
fraction), human placental lactogen (HPL), and preg- by primordial germ cells and syncytiotrophoblastic
nancy-specific antigen (SP1). Cellular enzymes are pla- cells. High levels of PLAP are present with several types
cental alkaline phosphatase (PLAP) and lactic dehy- of germ cell tumors, mainly germinomas.
drogenase. Of these markers the most frequently The histogenesis of intracranial germ cell tumors is
employed are AFP, HCG, and PLAP. AFP is produced unknown. Several hypotheses had been proposed in-
by the yolk sac, liver, and mucous glands of the gas- cluding an origin from misplaced totipotential germ
trointestinal tract. High levels of AFP are associated cells (Teilum, 1965; Dehner, 1983; Van Meir et al.,
with yolk sac tumors, liver, neoplasms, non-neoplastic 1998). This is supported by similar chromosomal ab-
hepatic lesions, and some tumors of the upper gas- normalities involving chromosome 12 (chromosome
trointestinal tract. HCG is synthesized by the placenta, 12p duplication or “isochromosome 12p”) that have
as well as trophoblastic and nontrophoblastic tumors. been found in testicular, mediastinal, and intracranial
In germ cell tumors high levels of HCG are explained germ cell tumors (De Bruin et al., 1994; Dal Cin et al.,
by the presence of pure choriocarcinoma, by mixed tu- 1998; Losi et al., 1998). Others favor displaced em-
mors with a choriocarcinoma component, or by the bryonic tissues in the developing neural tube (Sano,
presence of syncytiotrophoblastic cells, which produce 1999).
Germinoma
The germinoma is by far the most common of the cen-
tral nervous system germ cell tumors and is the most
common pineal neoplasm (DeGirolami et al., 1973;
Hoffman et al., 1991). On gross examination the neo-
plasm exhibits a homogeneous, soft, granular cut sur-
face without hemorrhage or necrosis (Fig. 16.151). It
is histologically analogous to the seminoma of the testis
and the dysgerminoma of the ovary by both light and
electron microscopic criteria. The tumor is composed
of large polygonal cells having fairly abundant cyto-
plasmic glycogen and nuclei with a prominent nucleo-
lus and is separated into lobules by a delicate fi-
brovascular stroma (Fig. 16.152). The cells are similar
FIGURE 16.151 Multicentric germinoma involving pineal and to primordial germinal cells. The immunochemical re-
suprasellar regions. action for PLAP is usually positive (Mostofi et al.,
1987; Shinoda et al., 1988). A few germinomas may

show positive cells for cytokeratins (Felix et al., 1990;
Ho et al., 1992). Invariably there is an associated in-
filtrate of lymphocytes (T cells), sometimes forming fol-
licles with germinal centers. Some germinomas exhibit
a foreign body granulomatous reaction, which is
thought to represent an immune response to antigens
produced by the neoplastic cells (Kraichoke et al., 1988;
Mostofi et al., 1988). Syncytiotrophoblastic cells in a
germinoma may account for an elevation in the levels
of serum HCG, but the presence of these cells does not
represent choriocarcinoma per se, with its adverse prog-
nosis (Mostofi et al., 1988). Germinomas with syncy-
tiotrophoblastic cells may show an increase in recur-
rence and a decrease in survival (Uematsu et al., 1992; FIGURE 16.154 Embryonal carcinoma with cells arranged in tubular
Matsutani et al., 1998). Germinomas are highly ra- and glandular structures. Hematoxylin and eosin stain.
diosensitive, and radiation therapy is the primary mo-
dality of treatment, with 5 year survival rates of
65%–95% (Rosenblum et al., 2000). areas of necrosis and hemorrhage. Seeding throughout
the CSF may be present (Fig. 16.153). Light microscopy
shows primitive cells with a high nuclear/cytoplasmic
Embryonal carcinoma
ratio, vesicular nuclei with a single nucleolus, scant
Pure intracranial embryonal carcinoma is seldom cytoplasm, and indistinct cellular borders arranged in
found. Two cases were identified in the study from the tubular, glandular, papillary, and solid patterns (Fig.
Mayo Clinic on 70 intracranial germ cell tumors and 16.154). Additional features include frequent mitoses,
none in the AFIP series on 54 cases (Bjornsson et al., necrosis, and hemorrhage. Elevated AFP in embryonal
1985; Rueda-Pedraza et al., 1987). When present, em- carcinoma may be due to associated yolk sac or ter-
bryonal carcinoma is usually a component of a mixed atoma elements (Mostofi et al., 1987). The cells are
germ cell tumor. Like the other nongerminomatous tu- strongly positive for cytokeratins and PLAP (Felix et
mors, embryonal carcinoma on gross inspection shows al., 1990; Ho et al., 1992).
Yolk sac tumor

Yolk sac tumor is also known as endodermal sinus tu-
mor and infantile embryonal carcinoma. The yok sac
tumor has been reported to constitute up to 5.6% of
all intracranial germ cell tumors (Rueda-Pedraza et al.,
1987). It is composed of small cuboidal to low colum-
nar cells with vacuolated or eosinophilic cytoplasm and
vesicular nuclei arranged in several histologic patterns
that include pseudopapillary, reticular, polyvesicular,
and solid. The pseudopapillary pattern is associated
with the formation of Schiller-Duval bodies, which con-
sist of glomeruloid structures lined by a single layer of
cuboidal cells projecting into a cavity covered by ep-
ithelial cells (Fig. 16.155). Eosinophilic, periodic
acid–Schiff–positive, hyaline globules may be present
intracellularly or extracellularly; these globules may
contain AFP (Mostofi et al., 1987; Stachura et al.,
1980).
The neoplastic cells are positive for AFP, a feature
FIGURE 16.153 Embryonal carcinoma of pineal region with lep- useful for the identification of yolk sac tumor elements
tomeningeal dissemination and formation of hemorrhagic lesions. in mixed germ cell tumors and for its differentiation
FIGURE 16.155 Endodermal sinus tumor with cells arranged in a FIGURE 16.157 Choriocarcinoma showing multinucleated syntiotro-
pseudopapillary pattern and formation of Schiller-Duval bodies. phoblastic cells positive for HCG. Peroxidase antiperoxidase method.
Hematoxylin and eosin stain.
from germinoma and embryonal carcinoma (Bjornsson are small cells with vacuolated cytoplasm and round
et al., 1985; Rueda-Pedraza et al., 1987; Felix et al., vesicular nuclei. The syncytiotrophoblastic cells are
1990; Ho et al., 1992). positive for beta HCG, HPL, and SP1 (Fig. 16.157).
High levels of HCG have been reported in cerebrospinal
fluid, urine, and primary tumor and its metastases
Choriocarcinoma
(Mostofi et al., 1987; Hoffman et al., 1991). The neo-
The choriocarcinoma is a highly malignant neoplasm plasm has a tendency to bleed spontaneously because
with a poor prognosis that shows differentiation along it contains numerous, thin-walled, poorly supported
trophoblastic lines (Teilum, 1965). Intracranial chori- blood vessels.
ocarcinoma may occur as a pure tumor, as an admix-
ture with other germ cell components, or as a meta-
Teratoma
static deposit. Until 1984, only 35 cases of pure
intracranial choriocarcinoma had been reported in the In the AFIP series, 36 (67%) of 54 intracranial germ
literature (Chan et al., 1984). The tumor is composed cell tumors contained teratomatous elements as either
of cytotrophoblastic and syncytiotrophoblastic, multi- pure or mixed neoplasms (Rueda-Pedraza et al., 1987).
nucleated giant cells (Fig. 16.156). Cytotrophoblasts The teratoma is a germ cell neoplasm that contains dif-
ferentiated elements derived from all three germinal lay-
FIGURE 16.156 Choriocarcinoma composed of cytotrophoblastic cells

with single nucleus and multinucleated syntiotrophoblastic cells. FIGURE 16.158 Mature teratoma showing a focus of keratinized squa-
Hematoxylin and eosin stain. mous epithelium.
FIGURE 16.159 Mature teratoma showing cartilage. FIGURE 16.161 Immature teratoma showing immature neuroepithe-
lial and mesenchymal elements. Hematoxylin and eosin stain.
ers. Teratomas are classified as mature, immature, or

malignant. Mature teratomas are composed of well- The presence of small areas of immature tissues in an
differentiated tissues, similar to adult tissues. Ectoderm otherwise mature teratoma qualifies the tumor as an
frequently is represented by skin and skin adnexae and immature teratoma. A malignant teratoma is charac-
by neural tissue (Fig. 16.158). Mature brain, including terized by the presence of areas containing an adeno-
proliferation of oligodendroglial and choroid plexus, carcinoma, a squamous cell carcinoma or a sarcoma
has been reported. Mesodermal derivatives such as car- such as a rhabdomyosarcoma (Preissig et al., 1979;
tilage, bone, fat, fibrous tissue, and muscle may be pres- Bjornsson et al., 1985; Rueda-Pedraza et al., 1987).
ent (Fig. 16.159). Endodermal elements may consist of The immunoreactivity of teratomas corresponds to
respiratory and gastrointestinal tract epithelium (Fig. the various tissues present. High levels of AFP may be
16.160). Liver, pancreas, and salivary gland tissue also related to the presence of gastrointestinal tract mucous
may be present. glands. Mature teratomas tend to be noninvasive and
Immature teratomas are composed of elements re- susceptible to complete excision. Adjuvant chemother-
sembling fetal tissues, including primitive neuroecto- apy may improve the outcome (Balmaceda et al., 1996;
derm composed of small cells arranged in rosettes or Schild et al., 1996; Matsutami et al., 1998).
as sheets and canals of cells that recapitulate the neural
tube in addition to immature mesodermal elements
such as loose mesenchyme and cartilage (Fig. 16.161). Nonneoplastic Cysts
Small single or multiloculated cysts filled with pro-
teinaceous material are frequently found at postmortem
examination. These probably arise as a result of de-
generative changes in the pineal gland. In our experi-
ence with 16 pineal cysts, 12 became symptomatic and
the patients, all adults, required surgical excision
(Rushing et al., 1991). On microscopic study the cav-
ity is lined by dense gliotic tissue with Rosenthal fibers
and focal old hemorrhage; remnants of the pineal gland
are usually present at the periphery of the mass.
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17 Embryonal tumors of the central
nervous system
LUCY B. RORKE
Central nervous system (CNS) tumors composed of em- that protrude into the lumen. Use of the periodic
bryonic neuroepithelial cells occur, not surprisingly, pri- acid–Schiff (PAS) stain is helpful in identifying the mem-
marily in infants and children. Amongst the three major branes. The cells may be columnar or cuboidal and are
histological types, medulloepitheliomas are the least fre- oriented at right angles to the membranes or pseudos-
quent, whereas primitive neuroectodermal tumors tratified. Nuclei contain coarse chromatin and often ex-
(PNETs) are the most common malignant CNS tumors hibit one or more nucleoli. Mitotic figures are abundant
of children. The atypical teratoid/rhabdoid tumor and tend to be most prominent near the luminal border
(AT/RT) is being diagnosed with increasing frequency (Color Fig. 17.1C in separate color insert).
now that it has been defined as a unique neoplasm, sep- Although the tubular arrangement may predominate
arate from PNETs with which it was typically confused it is more common to find intervening fields of cells re-
(Rorke et al., 1996). Pathological and cytogenetic fea- sembling neuropil within which glial cells, neurons, or
tures of each tumor type will be described. mesenchymal elements may be found (Auer and Becker,
1983; Caccamo et al., 1989). Whereas some glial cells
may be recognizable as fully differentiated astrocytes,
MEDULLOEPITHELIOMA oligodendroglia, or ependymal cells, a considerable
proportion of the astrocytes, as least, can only be iden-
Medulloepitheliomas are biologically malignant CNS tified by use of immunohistochemistry or at the ultra-
tumors that basically occur only in infants and young structural level. Similarly, whereas mature neurons may
children; some are already quite large at birth. This tu- also be seen, differentiation along this line is more ac-
mor type was proposed as a unique entity by Bailey curately established by identification of neuronal cy-
and Cushing (1926). Although such tumors may arise toskeletal protein or by examination with the electron
anywhere in the CNS, they are most common within microscope (Color Fig. 17.1D in separate color insert).
the cerebral hemispheres. While much less frequent In rare instances, the tumor cells may contain melanin
than gliomas in the pons, a few have developed in that pigment (Sharma et al., 1998).
site and have been misdiagnosed on clinical and radi- Application of various antibodies utilizing immuno-
ological grounds (Molloy et al., 1996) (Color Fig. histochemical techniques (IHCs) has established that
17.1A in separate color insert). Boys and girls are the cells forming the tubular structures typically express
equally affected. vimentin and microtubule-associated protein type 5
Tumors with the histological features of medulloep- (MAP-5). Less consistent is expression of neurofilament
ithelioma occur in the orbit or on a peripheral nerve, protein (NFP), cytokeratin (CK) and epithelial mem-
but in these sites, they are not necessarily confined to brane antigen (EMA) (Caccamo et al., 1989; Troost et
children, and many follow a different clinical course al., 1990; Khoddami and Becker, 1997). There is strong
(Nakamura et al., 1982). expression of nestin, however, primarily in the basal
The tumors arising in the cerebrum are typically area of the epithelium (Tohyama et al., 1992; Khad-
large, well-circumscribed growths that often contain dami and Becker, 1997). Glial fibrillary acidic protein
cysts and calcium deposits. These tumors are prone to (GFAP) is only expressed in the nontubular portions of
disseminate throughout the ventricular and subarach- the tumor, if at all, the extent varying with the degree
noid space. of differentiation. Like other embryonal neuroepithe-
Histopathological features are distinctive and once lial tumors, utilization of IHC methods may uncover
seen are usually recognized a second time without diffi- differentiation along other lines, such as muscle. Of
culty. The tumor cells form tubular structures resembling course, melanocytic differentiation can be identified
the primitive neural tube (Color Fig. 17.1B in separate with only H&E and confirmed with use of the Fontana
color insert). Tubular structures formed by the cells stain.
which are pseudostratified have an external limiting Ultrastructural features of medulloepitheliomas have
membrane, and sometimes an internal limiting mem- been defined by Pollak and Friede (1977) and Troost
brane. Cells at the luminal surface often have fine blebs et al. (1990). Cells forming the tubular structures have
383
primitive lateral cell junctions (zonulae adherentes) and all neoplasms formed by poorly differentiated cells. The
a basal lamina which is continuous but often folded. A tumors that he studied all arose in the adrenal gland,
true membrane on the luminal surface was not identi- with the exception of one which had been removed from
fied, although an amorphous surface coating was seen. the cerebellum by Harvey Cushing, his contemporary at
The component cells were poorly differentiated and had the Peter Bent Brigham Hospital in Boston. He thought
only sparse cytoplasmic organelles. these tumors were composed of more or less undiffer-
As noted, it has been suggested that the canalicular entiated nerve cells and named them neurocytoma or
structures in medulloepitheliomas recapitulate the em- neuroblastoma, depending on the degree of differentia-
bryonic neural tube, and as such, the tumor cells are tion. A few years later, Vanzetti (1915) renamed the cere-
thought to carry the potential to develop along the same bellar tumor neuroblastoma malignum, but Ribbert
lines found in the CNS, namely, neuronal and glial (in- (1918) changed the name to spongioblastoma 3 years
cluding ependymal) (Rubinstein, 1970; Tohyama et al., thereafter, apparently because he decided that this tu-
1992; Khoddami and Becker, 1997). Certainly study of mor was glial and not neuronal. In 1925, Masson and
tumors in this category demonstrates that this indeed Dreyfus (1925) applied the compromise name neu-
occurs to a greater or lesser degree. In those tumors rogliocytoma embryonaire, reflecting their view that the
containing a mesenchymal component, it has been sug- tumor contained both neuronal and glial cells.
gested that the distinction between this tumor and Also in 1925, Bailey and Cushing (1925) published
teratomas is somewhat blurred, particularly since their now-famous paper describing 29 tumors located
teratomas often contain a considerable primitive neu- in the cerebellar vermis of children and young adults,
roectodermal component (Auer and Becker, 1983; Cac- which they thought were composed of spongioblasts
camo et al., 1989). (immature glial cells). They called such tumors spon-
Aside from distinguishing between medulloepithe- gioblastoma cerebelli but were forced to find another
lioma and teratoma, the other tumor type that may name for them after Globus and Strauss (1925) de-
raise some diagnostic problem is the PNET which dis- scribed a cerebral tumor of adults with totally differ-
plays ependymal differentiation—that is, the so-called ent histologic features, which they named spongioblas-
“ependymoblastoma” (Rubinstein, 1970). The canals toma multiforme.
or rosettes found in PNETs with ependymal differenti- On review, Bailey and Cushing proposed that the
ation may consist of multilayered cells but are more cells composing the tumor were not spongioblasts af-
typically formed by a single layer. Moreover, they do ter all, but similar to the germinal or “indifferent” cells
not rest on a basal lamina but merge into the sur- that had been described by Schaper (1894, 1897) and
rounding cells. In contrast to the medulloepithelioma- that were said to have the capacity to differentiate into
tous canal, the cells forming the ependymal canals con- either neurons or glial cells. Initially Schaper’s studies
tain cilia and basal bodies, and there is often a of cerebellar development led him to believe that the
condensation of the luminal border of the ependymal external granular cells were still undifferentiated bipo-
cells that suggests a lamina. tential cells, and hence he called them indifferent cells.
To date, no cytogenetic study of medulloepitheliomas In his later studies of central nervous system develop-
has been reported. These are biologically malignant tu- ment he expanded his concept of indifferent cells and
mors which tend to disseminate through cerebrospinal noted that they also played a role in development of
pathways. Although most infants and children die the cerebrum and spinal cord. Bailey and Cushing ap-
within a year of diagnosis, gross total resection may propriated Schaper’s notion of an undifferentiated cell,
improve survival (Molloy et al., 1996). renamed it a medulloblast, and called tumors derived
from this embyronic cell medulloblastomas.
Within the following 10 years, other investigators
PRIMITIVE NEUROECTODERMAL TUMORS proferred different names for this tumor: sphaeroblas-
toma polymorphon (Marburg, 1931), neurospongioma
Historical Background
(Roussy et al., 1931), and granuloblastoma (Stevenson
Recognition of a class of CNS tumors composed pri- and Echlin, 1934). The last name was applied by
marily of poorly differentiated neuroepithelial cells oc- Stevenson and Echlin, who though that the neoplasm
curred early in the twentieth century when James Homer was derived from the external granular layer of the
Wright (1910) called attention to a group of tumors that cerebellum.
he thought were different from those in the general cat- In their original 1925 paper, Bailey and Cushing
egory of sarcoma, a term used by pathologists to include (1925) considered the medulloblastoma a uniquely
17: EMBRYONAL TUMORS OF THE CNS 385
cerebellar tumor, probably arising from dysplastic cell Millen et al., 1999). While it is important to define the
rests in the roof of the fourth ventricle, although a foot- specific genes and interactions governing control of neu-
note reports that five similar tumors had also been iden- rodevelopment, as there may indeed be parallels between
tified in the cerebrum of adults. A few years later they normal developmental pathways and tumors composed
reclassified three of these, but two fulfilling the crite- of primitive neuroepithelial cells (Trojanowski et al.,
ria for diagnosis of medulloblastomas remained (Cush- 1992), it must also be remembered that the growth and
ing, 1930). They neither resolved the question of differentiation potential of transformed cells is governed
extracerebellar medulloblastoma nor attempted to ex- by genetic events within the neoplastic cells which do
plain why this indifferent cell or medulloblast should not necessarily follow normal pathways.
be restricted to the cerebellum. Supporters of the suggestion that the medulloblas-
In the process of studies of the developing cerebellum, toma is a sarcoma have not been lacking. A few years
Kershman (1938) concluded that the external granular after Bailey and Cushing published their paper, Nishii
cell was the medulloblast and hence was not found else- (1929) cited a number of cases in support of this view.
where in the central nervous system. He, like Bailey and Tissue culture studies by Kersting (1961) and Gullotta
Cushing, chose to ignore Schaper’s 1897 paper (Schaper, (1967) also suggested that the medulloblastoma was
1897). Through a process of circular reasoning, he made primarily a mesenchymal tumor, although Gullotta
the following claim: “That the medulloblast is a cell pe- conceded that some medulloblastomas might contain a
culiar to the developing cerebellar cortex is substanti- neuroepithelial component.
ated by the fact that the medulloblastoma is almost ex- Polak (1967), however, challenged the claim that the
clusively a tumor of the cerebellum.” medulloblastoma is a distinct tumor entity. He asserted
Tuthill’s suggestion (Tuthill, 1938) that medul- that careful histologic evaluation allows placement into
loblasts (Schaper’s indifferent cells) could be found in the categories of neuroblastoma, isomorphous glio-
the infant cerebrum was largely ignored. Raaf and Ker- blastoma, oligodendroglioma, and microglioma (lym-
nohan (1944) revived the opinion of Bailey and Cush- phoma, by current diagnostic criteria). He concluded
ing that the medulloblastoma was derived from dys- his paper on the subject with the strong statement,
plastic cell rests in the posterior medullary velum, and “Bailey and Cushing’s concept of the medulloblastoma
Ringertz and Tola (1950) further postulated that some is re-examined and found to be without scientific
of these tumors arose in the anterior medullary velum. foundation.”
In a review of the origin and histogenesis of medul- Neither Polak’s view nor the opinion that the medul-
loblastoma, Rubinstein (1981) also held that this was loblastoma is really a sarcoma has enjoyed wide sup-
a uniquely cerebellar tumor, reiterating Stevenson and port. It is conceded, however, that sarcomas may rarely
Echlin’s suggestion that the germinative cell giving rise occur as primary central nervous system tumors (Rus-
to the medulloblastoma is the cerebellar external gran- sell and Rubinstein, 1989).
ular cell and that this cell, found only in the cerebel- Associated with the question of histogenesis of the
lum, is capable of bipotential differentiation. cerebellar medulloblastoma is the problem of origin
Investigators subsequently attempted to confirm or and nosology of histologically similar tumors occurring
refute that assertion and some studies did indeed sup- elsewhere in the central nervous system and pineal
port it (Fujita et al., 1966; Fujita, 1967; Hanaway, gland. By convention, a tumor in the cerebrum histo-
1967; Das, 1976), whereas others indicated that the ex- logically similar to the medulloblastoma is most com-
ternal granular cell can develop only into a neuron (Alt- monly called a central or cerebral neuroblastoma
man, 1972; Del Cerro and Snider, 1972; Swarz and Del (Horten and Rubinstein, 1976) and one located in the
Cerro, 1977; Koppel et al., 1978; Ghandour et al., pineal gland a pineoblastoma (Rubinstein, 1981). A
1981; Bell et al., 1989). host of other names has been added to the list for his-
Progress in the molecular genetics of CNS develop- tologic variations of these tumors (Table 17.1).
ment in general, and the cerebellum in particular, has Although no other class of central nervous system
made it clear that this is an exceptionally complex pro- tumors is separated into unique nosologic entities
cess which involves an enormous number of genes. An based on location, the practice of applying different
historical review of the bipotential or CNS stem cell may names to tumors resembling the medulloblastoma but
be found in Jacobson (1991) and specific details of cere- arising outside the cerebellum has been justified by
bellar cell specification and differentiation are well sum- Rubinstein (1989), who asserted that the cell of ori-
marized by Hatten and coworkers (Hatten and Heintz, gin differs depending on the site from which the tu-
1995; Alder et al., 1996, 1999; Hatten et al., 1997; mor springs.
TABLE17.1 Diagnostic Terms Used for tumors that were histologically similar but located in
Medulloblastoma the cerebellum were by convention called medulloblas-
toma and excluded from analysis. With the exception
Term Reference
of polar spongioblastoma, Hart and Earle’s definition
Sarcoma Gullotta, 1967 of the histologic features of this group as tumors com-
Kersting, 1961 posed largely of undifferentiated cells that occasionally
Nishii, 1929 demonstrated differentiation along glial or neuronal
Neuroblastoma Pearl and Takei, 1981 lines with or without a mesenchymal component dif-
Polak, 1967 fered in no substantial way from histologic featuress of
Wright, 1910
medulloblastoma or cerebral neuroblastoma. In many
respects it was also similar to the pineoblastoma, al-
Yagashita et al., 1980
though tumors in this location infrequently contain fi-
Yagashita et al., 1982
brocollagenous tissue.
Neuroblastoma malignum Vanzetti, 1915
The practicing pathologist attempting to apply diag-
Spongioblastoma Ribbert, 1897 nostic criteria to a specific tumor thus faces a nosologic
Neurogliocytome embryonnaire Masson and Dreyfus, 1925 nightmare. Which among the smörgasbord of diagnos-
Sphaeroblastoma polymorphon Marburg, 1931 tic terms should be chosen (Table 17.1)? This issue
Neurospongioma Rubinstein, 1981 will be addressed in greater detail at the end of the
Granuloblastoma Stevenson and Echlin, 1934 chapter.
Isomorphous glioblastoma Polak, 1967
Oligodendroglioma Polak, 1967 Pathologic Features of Poorly Differentiated
Microglioma (lymphoma) Polak, 1967 Neuroepithelial Tumors
Small cell type medulloblastoma Palmer et al., 1981
Before consideration of the nosologic problem, a de-
Astrocytic medulloblastoma Palmer et al., 1981
scription of the gross and microscopic features of the
Ependymal medulloblastoma Palmer et al., 1981
poorly differentiated neuroepithelial tumors (PNETs) is
Ependymoblastoma Rubinstein, 1981
in order.
Neuronal medulloblastoma Palmer et al., 1981 Typically, PNETs are soft and pink, although color
Matrix cell tumor Sato et al., 1980 may vary from tan to red. Tumors that have a promi-
“Blue” tumor Leestma and Earle, 1973 nent connective tissue component may be tan-white and
firm. The tumors most frequently arise in the cerebel-
lar vermis but may be located more laterally in a hemi-
sphere (Color Fig. 17.3A in separate color insert). They
also occur in the pineal gland, cerebrum, spinal cord,
This approach incorporates the “defective embryo- and brain stem (in decreasing order of frequency). The
genetic” theory introduced by Cohnheim (1882), elab- tumors are occasionally hemorrhagic (especially those
orated by Ribbert (1897), and then adopted by Bailey in the pineal gland) and in fact may announce their
and Cushing (1926), when they published their schema presence by a spontaneous hemorrhage. Rarely, they
for classification of gliomas (Fig. 17.2). This theory as- contain a cyst or cysts. Some tumors, especially in the
serted that tumors are caused by overgrowth of cells cerebrum, have sharply demarcated borders.
arrested at a specific stage of embryologic development. The neoplasms frequently disseminate throughout
Currently this idea enjoys minimal support, since over- the central nervous system via the cerebrospinal fluid
whelming evidence supports the view that tumors arise and hence coat the leptomeninges and ependymal sur-
from neoplastic transformation of normal cells, an idea face, forming nodules of varying sizes in these regions
that already had adherents in the late 1920s (Roussy or on nerve roots (Color Fig. 17.3B in separate color
and Cornil, 1928). insert). Less often, they spread directly through the
In 1973, Hart and Earle (1973) published a paper ti- parenchyma.
tled “Primitive Neuroectodermal Tumors of the Brain Although PNETs share certain characteristic micro-
in Children.” This paper analyzed 23 poorly differen- scopic features, they may vary widely in other respects.
tiated cerebral neuroepithelial tumors that did not ful- Classically, PNETs are densely cellular, consisting of a
fill diagnostic criteria for medulloepithelioma, cen- cell population with small, round, deeply basophilic nu-
tral (cerebral) neuroblastoma, polar spongioblastoma, clei with a minimal surrounding perikaryon. Nuclei of-
ependymoblastoma, or pineal parenchymal tumors. All ten appear to be embedded within a granulofibrillar
Medullary epithelium
(medulloepithelioma)
Apolar neuroblast
Pineal proparenchyma Primitive spongioblast Medulloblast
(pineoblastoma) (neuroepithelioma) (medulloblastoma)
Bipolar spongioblast Bipolar neuroblast

(spongioblastoma
multiforme)
Ependymal Unipolar spongioblast Unipolar neuroblast

spongioblast (spongioblastome (neuroblastoma)
(ependymoblastoma) unipolare)
Astroblast
(astroblastoma) Multipolar neuroblast
Ependyma Oligodendroglia
(ependymoma) (oligodendroglioma)
Choroidal Pineal Pineal Fibrillary Protoplasmic

epithelium neuroglia parenchyma astrocytes astrocytes
(papilloma (astrocytoma (astrocytoma Neurones
choroideum) (Pinealoma) fibrillare) protoplasmaticum) (ganglioneuroma)
FIGURE 17.2 The Bailey-Cushing histogenetic classification of central neuroepithelial tumors. From Rorke (1983).
neuropil-like background (Color Fig. 17.3C in separate in what has been described as an “Indian file” pattern.
color insert). Many tumors, however, are composed of This combination of features is called desmoplastic
cells with larger, somewhat more pleomorphic nuclei medulloblastoma and is said to occur more commonly
with or without identifiable cytoplasm. Chromatin is in the cerebellar hemispheric tumors (Color Fig. 17.4A
often coarse, and nucleoli are sometimes apparent in separate color insert).
(Color Fig. 17.3D in separate color insert). Mitotic ac- Occasionally, astrocytes are recognizable with hema-
tivity is variable, with some tumors containing no mi- toxylin and eosin stains, but identification of neuronal
toses recognizable by routine cell stains. Almost every features requires use of special staining techniques be-
tumor contains necrotic (apoptotic) cells, mostly rec- cause neoplastic ganglion cells are rarely present. A va-
ognizable with the high-magnification lens, although riety of these applied by earlier investigators for recog-
field necrosis is occasionally present. nition of both glial and neuronal differentiation include
Usually, the cells grow diffusely, but they may ex- silver carbonate methods, phosphotungstic acid–hema-
hibit certain characteristic patterns, most commonly the toxylin (PTAH), Bielschowsky, and Bodian, among
circular arrangement into rosettes. These rosettes are others. Currently, immunoperoxidase methods are used
typically the small Homer Wright variety (Color Fig. (Color Fig. 17.4C–F in separate color insert). Rarely,
17.3E in separate color insert). The large Homer mature neoplastic neurons, smooth or striated muscle,
Wright type of rosette, described by Borit and col- or melanocytes are also found (Color Fig. 17.4B in sep-
leagues (1980) in pineal tumors, is also occasionally arate color insert).
found in cerebellar neoplasms. Pseudorosettes, ependy- Giangaspero and associates (1992) described a
mal canals, and Flexner-Wintersteiner rosettes may also highly aggressive cerebellar tumor in infants that they
be present, but the last most commonly in pineal named large-cell medulloblastoma. Whether this is
tumors. similar to the unusual embryonal tumor that contains
Another pattern consists of round islands of cells, of- a prominent rhabdoid cell population, described by
ten with a lighter neuropil-type background, or linear Lefkowitz and coworkers (1987), who called it atyp-
arrays of primitive tumor cells streaming along a neu- ical teratoid tumor of infancy remains an unresolved
ropil that together strongly resembles embryonic brain issue.
(Color Fig. 17.3F in separate color insert). This pattern The literature contains a number of reports of a tu-
has also been called cerebellar neuroblastoma. The is- mor that was originally called lipomatous medul-
lands may be seen in tumors in which cells are arrayed loblastoma, the first of which appeared in 1978 (Bech-
in linear fashion along delicate connective tissue fibers tel et al., 1978). This histological subtype apparently
occurs only in adults, the age range extending from 36 scription marker of granule cells, has also been found
to 67 years. Since the original report, a variety of other (Yakota et al., 1996).
diagnostic terms have been suggested, including neu- Cytogenetic studies of CNS PNETs arising in sites
rolipoma (Ellison et al., 1993), medullocytoma (Gian- outside of the cerebellum are scanty, largely reflecting
gaspero et al., 1996), lipomatous glioneurocytoma rarity of this tumor type elsewhere in the CNS. In con-
(Alleyne et al., 1998), and lipidized mature neuroecto- trast to PNET-MB only one cerebral PNET has dem-
dermal tumor of the cerebellum (Gonzalez-Campora onstrated an i(17)q abnormality (Pruchon et al., 1994).
and Weller, 1998). Most recently, it has been suggested Studies by a number of investigators have uncovered a
that this tumor is not a PNET-medulloblastoma (MB) variety of nonrandom cytogenetic gains and losses (Bur-
at all and should be called cerebellar neurolipocytoma nett et al., 1997; Biegel, 1999), expression of N-myc
(Kleihues et al., 2000). (Moriuchi et al., 1996), germline mutation of TP53
The ultrastructural features of the primitive neu- (Reifenberger et al., 1998), the Neuro D family of ba-
roectodermal tumors with and without evidence of sic helix-loop-helix transcription factors, and achaete-
differentiation are outlined in detail elsewhere scute, another neurogenic transcription factor with ho-
(Rorke, 1983). Routine use of this diagnostic tool is mology to Neuro D genes (Rostomily et al., 1997); this
limited by cost, availability, and problems of sam- particular gene was expressed in three of five cerebral
pling. PNETs.
To date there is relatively little known of the cyto-
genetic abnormalities of PNETs arising in the pineal,
Cytogenetics of Primitive Neuroectodermal Tumors
the so-called pineoblastoma. Although the pineal is
A considerable number of cytogenetic abnormalities phylogenetically related to the retina, indeed, it has
have been identified in primtive neuroectodermal tu- been called the “third eye” by some, and it also occa-
mors arising in the cerebellum—that is, medulloblas- sionally harbors tumors similar to retinoblastoma, so-
tomas (PNET-MBs). called “trilateral retinoblastoma,” the Rb gene associ-
An abnormality of chromosome 17 is generally ated with that tumor, has not been identified in pineal
touted as the most characteristic chromosomal abnor- neoplasms (Bader et al., 1982).
mality of PNET-MB, as it has been found in about 50%
of these tumors (Bigner et al., 1988; Griffin et al., 1988;
The Nosologic Problem
Biegel et al., 1995). However, almost as many display
losses on chromosome 10q and 11 (41% each), gain of Of the many diagnostic terms applied to CNS tumors
chromosome 7 (44%) (Reardon et al., 1997), or loss composed of primitive neuroepithelial cells, the most
of genetic material of chromosome 1q (20%–40%) enduring has been medulloblastoma, even though the
(Blaeker et al., 1996; Kraus et al., 1996). Moreover, embryonal cerebellar cell from which this tumor was
Schofield et al. have demonstrated a high rate of loss said to be derived, namely the medulloblast, is gener-
of heterozygosity of chromosome 9q in the desmo- ally conceded to be a scientific myth.
plastic variant of PNET-MB (Schofield et al., 1995; Efforts to reexamine the nosologic problem objec-
Giangaspero et al., 2000). tively continue to meet considerable resistance, con-
Involvement of chromosome 9q is particularly inter- firming Maerterlinck’s observation, “At every crossing
esting as this chromosome contains a putative tumor on the road that leads to the future, each progressive
suppressor locus related to the Drosophila segment po- spirit is opposed by a thousand men appointed to guard
larity gene patched (PTCH). This, in turn, is related to the past.”
sonic hedgehog, a major mitogen for cerebellar granu- Retention of the diagnostic term medulloblastoma,
lar cell progenitors which carry its receptor PTCH along with its counterparts cerebral (central) neuro-
(Wechsler-Reya and Scott, 1999). blastoma, pineoblastoma, and ependymoblastoma, has
Adding to the complexity of the molecular genet- merit because of familiarity and the enormous litera-
ics of PNET-MB has been identification of neural ture in which those diagnoses have been used. How-
transcription markers most common of which are ever, the major objection to continued use of these
genes in the PAX (paired-box containing) family. terms is that many of the premises upon which they are
Messenger RNA of two of the nine members of this based have not been validated.
family, namely PAX 5 and PAX 6, has been identi- Thus, two pediatric neuropathologists independently
fied by in situ hybridization in 70% and 78% of reexamined these issues and offered a solution (Becker
PNET-MB, respectively (Koznik et al., 1995; Vincent and Hinton, 1983; Rorke, 1983). They looked at all
et al., 1996). In addition, ZIC, another neural tran- CNS tumors having in common a predominant popu-
lation of apparently primitive or undifferentiated neu- would expect to find a disproportionately large num-
roepithelial cells. Although recognizing that site of ori- ber of CNS PNETs in the cerebellum. At the same time,
gin may govern biologic behavior or be important in it has been established that primitive neuroepithelial
other ways, they gave the site secondary status, focus- cells also remain in much smaller numbers in the
ing instead on the histologic features of the tumor. The subependymal germinal zone of the cerebrum and other
following facts emerged: sites (Goldman, 1995; Gage, 2000). Under the cir-
cumstances it was proposed that a classification scheme
1. Central nervous system tumors composed largely
be based upon the nature of the cells of which the tu-
of undifferentiated neuroepithelial cells arise most com-
mors were composed, leaving behind hypotheses re-
monly in the cerebellar vermis of children.
garding cell of origin (Rorke, 1983).
2. These cerebellar vermian tumors exhibit consid-
Studies by a number of investigators have established
erable histologic variation, including neuronal and glial
that tumors composed of poorly differentiated cells
differentiation (primarily astrocytic and ependymal),
may remain undifferentiated or contain clones or indi-
a variable connective tissue component, and rarely,
vidual cells that differentiate along neuronal, astrocytic,
smooth or striated muscle or melanocytic differentia-
ependymal, muscle, melanocytic or photoreceptor lines,
tion.
singly or in combination (Molenaar et al., 1989; Gould
3. If site of origin is unknown, the conventional di-
et al., 1990). Particularly interesting are the observa-
agnosis based on these features cannot be applied.
tions of Molenaar et al. (1989) and Gould et al. (1990),
4. Tumors with some or all of these histologic fea-
who established that individual tumor cells may si-
tures arise less frequently in cerebral hemispheres,
multaneously express two or even three different anti-
pineal gland, spinal cord, and brain stem.
gens, such as NFP and GFAP, vimentin-GFAP-NFP, vi-
Because these tumors arising in various sites in the CNS mentin-GFAP-desmin, etc. The classification scheme
are difficult to separate histologically, it became ap- proposed by Rorke and associates takes these obser-
parent that relevance of the hypothetical concepts of vations into consideration (Rorke et al., 1985) (Table
cell of origin, such as medulloblast or external granule 17.2).
cell (of the PNET-MB) required reappraisal. If the ba- These nosologic issues were discussed in detail by an
sic tenet is that neoplasia results from genetic trans- international group of neuropathologists in Houston in
formation of a normal cell that then follows aberrant 1988 (see pp. 5–113 in Fields, 1989) and 2 years later
pathways of expression governed by factors other than by a World Health Organization (WHO) committee
those that normally regulate growth and development, dealing with the revision of the 1979 WHO histologic
arguments relative to the specific cell of origin of a given classification of brain tumors (Zülch, 1979; Kleihues
tumor are not so important except in a general sense. et al., 1993).
Clearly, the cell of origin of tumors arising in the CNS This second WHO committee meeting in 1990 de-
must be a cell that is located in that portion of the cided to retain the familiar diagnostic terms of medul-
body, just as a tumor intrinsic to the liver must be de- loblastoma (MB), neuroblastoma, ependymoblastoma,
rived from a cell in that organ. With regard to the group and pineoblastoma, but added the category primitive
of central primitive neuroectodermal tumors it is gen- neuroectodermal tumor (PNET) under the general
erally agreed that they most likely originate from trans- heading embryonal tumors. The MB and three variants
formation of a poorly differentiated, primitive or mi-
totically active neuroepithelial cell. Since the immature
CNS contains the largest number of such cells which TABLE 17.2 Rorke Classification of Central Nervous
are potential targets for transformation, it is no sur- System Primitive Neuroectodermal Tumors*
prise that tumors of this histological type are most com- Primitive neuroectodermal tumor, not otherwise specified
mon in infants and children. Furthermore, the mitoti-
Primitive neuroectodermal tumor with astrocytic differentiation
cally active cerebellar granular cells comprise a major
Primitive neuroectodermal tumor with ependymal differentiation
pool that could be attacked. In addition, the cerebel-
Primitive neuroectodermal tumor with neuronal differentiation
lum harbors more dysplastic cell rests than occur else-
where in the CNS (Rorke et al., 1968). A number of Primitive neuroectodermal tumor with mesenchymal differentiation
(striated and smooth muscle)
investigators have suggested that these dysplastic cells
Primitive neuroectodermal tumor with melanocytic differentiation
are vulnerable to transformation (Raaf and Kernohan,
1944); these rests also contain mitotically active cells Primitive neuroectodermal tumor with multipotential or bipotential
differentiation
at birth and shortly thereafter (Yachnis et al., 1994).
Hence, if the arguments put forward are correct one *Added site designations as recommented by Rorke and associates (1985).
were included in the PNET category, but separation be- TABLE17.4 World Health Organization Classification
tween those and PNETs with or without differentiation of Embryonal Tumors
along various cell lines—or neuroblastoma, ependy-
Medulloepithelioma
moblastomas, and pineoblastoma—remained problem-
Ependymoblastoma
atic (Kleihues et al., 1993) (Table 17.3).
Medulloblastoma
Yet another WHO committee met in 1999 and
changed the classification again. The old diagnostic Medullomyoblastoma
terms, medulloblastoma, ependymoblastoma, medul- Melanotic medulloblastoma
lomyoblastoma, melanotic medulloblastoma, and pi- Supratentorial primitive neuroectodermal tumor (PNET)
neoblastoma were retained, and a new subtype of Atypical teratoid/rhabdoid tumor
medulloblastoma, large cell medulloblastoma, was
Source: Kleihues and Cavenee (2000).
added. Cerebral neuroblastoma and ganglioneuroblas-
toma were folded into a category called supratentorial
primitive neuroectodermal tumor (S-PNET), implying
that neuroblastomatous tumors only occur in the supra- of chromosomal abnormalities, whereas there is a
tentorial space (Kleihues and Cavenee, 2000) (Table paucity of information regarding cytogenetic abnor-
17.4). Such a concept clearly does not correspond to malities in PNETs in other sites because they are much
reality. Many cerebellar PNETs—that is, medulloblas- less common than those arising in the posterior fossa.
tomas—display evidence of neuronal differentiation Furthermore, a review of cytogenetic findings amongst
that may range from identification of the undifferenti- the major diagnostic categories of CNS tumors reveals
ated tumor cells by use of monoclonal antibodies for both similarities and considerable variation within a
NFP, to recognizable ganglion cells by routine H&E given category (Kleihues and Cavenee, 2000). The as-
staining. Another major objection to this term is that sumption that a specific cytogenetic profile exists for
it creates a diagnostic category based upon location in each histological type of tumor may be unrealistic,
the nervous system, although the WHO classification given the nature of the neoplastic process. Therefore,
scheme purports to be based upon histology. prudence dictates caution in drawing premature con-
It has been suggested that medulloblastoma is clusions regarding histogenesis and nosology based
uniquely different from other PNETs because the cy- upon cytogenetics.
togenetics of the former are different from the latter Critics of the umbrella term PNET have considered
(Giangaspero et al., 2000). As already noted, the many it an oversimplification of a complex nosologic prob-
medulloblastomas that have been studied exhibit a host lem (Rubinstein, 1985), and have further objected on
the grounds that it is all too easy to cast any difficult-
to-diagnose tumor into this category. Unwillingness to
TABLE17.3 World Health Organization Classification use available diagnostic tools is a failing of the pathol-
of Embryonal and Pineal Tumors ogist, not the classification system.
As noted, pathologists currently have at least nine(!)
Embryonal tumors
classification schemes from which to choose when con-
Medulloepithelioma fronted with the problem of diagnosing an embryonal
Neuroblastoma (Variant: ganglioneuroblastoma) neuroepithelial tumor (Tables 17.3–17.11). This is akin
Ependymoblastoma to a neuropathological tower of Babel. It is regrettable
Retinoblastoma that consensus cannot be reached, for it makes com-
Primitive neuroectodermal tumors (PNETs) with multipotential munication with clinicians caring for patients with
differentiation these tumors problematic indeed.
Neuronal, astrocytic, ependymal, muscle, melanotic, etc.
Medulloblastoma (Variants: desmoplastic medulloblastoma,
medullomyoblastoma, melanocytic medulloblastoma) ATYPICAL TERATOID/RHABDOID TUMOR
Pineal tumors Atypical teratoid/rhabdoid tumor (AT/RT) was defined

Pineocytoma
as a unique entity in 1996 and separated from PNET-
MBs, with which it was typically grouped (Rorke et al.,
Pineoblastoma
1996). In some respects that might have been an ap-
Mixed pineocytoma/pineoblastoma
propriate diagnosis in view of the fact that two-thirds
Source: Kleihues et al. (1993). of these tumors contain fields composed of primitive
17.5 Becker Classification of Embryonal

TABLE TABLE 17.7 Burger, Scheithauer, and Vogel
Tumors (1989) Classification of Embryonal Neoplasms (1991)
Primitive neuroectodermal tumor Primitive neuroectodermal tumor
Primitive neuroectodermal tumor with astrocytes Medulloepithelioma
Primitive neuroectodermal tumor with neuronal cells Medulloblastoma
Primitive neuroectodermal tumor with oligodendroglia Medullomyoblastoma and melanotic medulloblastoma
Primitive neuroectodermal tumor with ependymal cells Neuroblastoma
Primitive neuroectodermal tumor with melanin pigment Ependymoblastoma
Primitive neuroectodermal tumor with muscle elements Primitive polar spongioblastoma
Primitive neuroectodermal tumor with fleurettes and/or Flexner-
Wintersteiner rosettes
Primitive neuroectodermal tumor with neural tube–like structures
doid component, and, in fact, 15% of a group of 52

such tumors consisted only of rhabdoid cells. Two-
thirds have a major PNET component, one-third a mes-
neuroepithelial cells. However, they also contain areas enchymal component with or without PNET areas, and
consisting of rhabdoid cells, an unusual neoplastic cell one-quarter contain neoplastic epithelium, which may
originally described in renal tumors in infants (Weeks be adenomatous, squamous, or simply be arranged in
et al., 1989), and in some cases a neoplastic epithelial nests (Rorke et al., 1996) (Color Fig. 17.5B–D in sep-
and/or mesenchymal component. arate color insert).
To date, 188 cases have been observed, 184 of which The typical rhabdoid cell is round to oval, medium
have been in infants or children, 94% of whom were in size, and has an eccentric nucleus with a prominent
5 years of age or less at diagnosis. Average age of the nucleolus. Cytoplasm is finely granular or homoge-
four adults is 32 years (Rorke and Biegel, 2000). These neous, and sometimes has a dense, pink character sug-
tumors are biologically aggressive and most patients die gesting an inclusion body. The cell borders tend to be
within a year following diagnosis. distinct (Color Fig. 17.5E in separate color insert).
About one-half occur in the poserior fossa, and al- Some rhabdoid cells are small and may have a cyto-
most 45% are supratentorial (Color Fig. 17.5A in sep- plasmic tail; in contrast, some are huge, bizarre cells
arate color section). They exhibit an unusual tendency with more than one nucleus. At the ultrastructrual level,
to arise in the cerebellopontine angle, and about one- whorled bundles of intermediate filaments fill the cy-
third have already spread through CSF pathways at toplasm (Biggs et al., 1987) (Fig. 17.6).
presentation. The PNET component basically exhibits the expected
The neuroimaging and gross features of the AT/RT features of that tumor—namely, sheets of primitive
are similar to those of PNETs (Rorke and Biegel, 2000), neuroepithelial cells with or without rosettes of the
but the histological features are different. They may be Homer Wright or Flexner-Wintersteiner variety. Nei-
straightforward or complex, depending upon the num- ther the desmoblastic nor the nodular variant of PNET
ber of different tissue types that are present (Burger et
al., 1988; Rorke et al., 1996). All tumors have a rhab-
TABLE17.8 Burger and Scheithauer Classification of
Embryonal Tumors (1994)
17.6 Cytogenetic Classification of Embryonal
TABLE Primitive neuroectodermal tumor
Tumors of the Neuroepithelium Medulloepithelioma
Medulloepithelioma Neuroblastoma and ganglioneuroblastoma
Cerebral neuroblastoma Olfactory neuroblastoma (esthesioneuroblastoma)
Polar spongioblastoma Retinoblastoma
Ependymoblastoma Melanotic neuroectodemal tumor of infancy
Cerebellar medulloblastoma Ependymoblastoma
Pineoblastoma Medulloblastoma
Retinoblastoma Medullomyoblastoma and melanotic medulloblastoma
Other embryonal tumors
Source: Russell and Rubinstein (1989).
TABLE 17.9 Lantos, Vandenberg, and Kleihues 17.11 Rorke Classification of Embryonal
TABLE
Classification of Embryonal Tumors (1998) Tumors of the CNS
Medulloblastoma Medulloepithelioma
Ependymoblastoma Primitive neuroectodermal tumor, NOS
Neuroblastoma PNET with glial differentiation
Ganglioneuroblastoma PNET with ependymal differentiation
Central neuroblastoma PNET with neuronal differentiation
Olfactory neuroblastoma PNET with multipotential or bipotential differentiation
Primitive neuroectodermal tumour (including muscle or melanocytic)
Medulloblastoma Atypical teratoid/rhabdoid tumor
Atypical teratoid/rhabdoid tumour
actin (SMA) as well (Color Figs. 17.5F, 17.7A in sep-

has been observed in the AT/RT. Rarely, ependymal arte color insert). These rhabdoid cells may also
canals or neural tube–like structures are identified. strongly express GFAP, NFP, and/or keratin, but never
The mesenchymal component may display a tight express desmin or any markers for germ cell tumors
fascicular pattern, suggestive of a sarcoma (Gonzalez- (Color Fig. 17.7B–D in separate color insert). The
Crussi et al., 1982; Manhoff et al., 1995), or the spin- PNET portions variably express vimentin, GFAP, NFP,
dle cells may be loosely arranged. SMA, and/or desmin; the mesenchymal tissue expresses
An adenomatous pattern resembling an adenocarci- vimentin and sometimes SMA and/or desmin; and the
noma or choroid plexus carcinoma, squamous epithe- epithelial portions express keratin, and less commonly,
lium or nests of cells expressing keratin antigens, but vimentin and/or EMA.
otherwise with no particular distinguishing features, In contrast to the majority of other primary CNS tu-
comprise the histologic manifestations of the epithelial mors, the cytogenetic abnormality associated with
component. AT/RT appears to be unique. It is present in 90% of
Field necrosis and hemorrhages are quite common, the tumors and consists of monosomy or a deletion of
but the vasculature does not appear to be unique in any chromosome 22, as determined by fluorescence in situ
way. hybridization or loss of heterozygosity studies (Biegel,
Pattern of antigen expression is complex and varies 1999). The involved gene is hSNF5/INI 1, which maps
according to the cell types comprising the tumor. There to chromosome band 22q 11.2 (Versteege et al., 1998;
is consistent expression of EMA and vimentin by the Biegel, 1999).
rhabdoid cells and often expression of smooth-muscle
TABLE17.10 McLendon et al. Classification of

Tumors of Neuronal Cells and of Primitive
Biopotential Precursors (1998)
Medulloepithelioma
Medulloblastoma (including cerebellar neuroblastoma)
Neuroblastoma
Central neurocytoma
Ganglioneuroma (gangliocytoma) and ganglioglioma
Special variants of gangliocytoma and ganglioglioma
Intrasellar, endocrinologically active gangliocytoma
Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos
disease)
Desmoplastic infantile ganglioglioma FIGURE 17.6 Electron micrograph of cell in AT/RT demonstrating
Dysembryoplastic neuroepithelial tumor abundant, sweeping mass of intermediate filaments. Magnification

10,000.
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18 Pituitary tumors and related lesions
BERND W. SCHEITHAUER
With rare exception (Colohan et al., 1986) the nohypophyseal cells have become apparent as a result
pituitary, a compound epithelial and neuroectodermal of the application of immunocytology, in situ hy-
gland, resides in the sella turcica, a specialized portion bridization, and ultrastructural techniques to both nor-
of the sphenoid bone. Despite its uniform appearance mal and neoplastic pituitaries. The morphological and
at the hematoxylin and eosin (H&E) level, the anterior immunochemical features of normal pituitary cells are
lobe consists of three zones, including a central mucoid summarized in Table 18.1.
wedge and lateral components termed acidophilic Ultrastructurally, adenohypophyseal cells show the
wings. The term mucoid refers to the abundance of ba- characteristics of epithelial cells. They contain the full
sophilic, periodic acid–Schiff (PAS)-positive cells en- complement of organelles required for hormone pro-
gaged in adrenocorticotropin (ACTH) and thyrotropin duction and export. Secretory granules vary in num-
(TSH)-producing cells. Gonadotropic follicle cells en- ber, size, electron density, and shape; their character-
gaged in stimulating and luteinizing hormone (FSH- istics alone are insufficient for the accurate functional
LH) production are also basophilic but are widely dis- identification of pituitary cell types. Intermediate fila-
tributed. The posterior lobe also contains ACTH cells ments, particularly keratin, are a regular feature of GH
scattered or clustered among the axons. The finding is and ACTH cells (Halliday et al., 1990). The process of
termed basophil invasion and increases with age. The hormone production, packaging, and release involves
lateral wings contain mainly growth hormone (GH) their synthesis within the rough endoplasmic reticulum,
and, to a lesser extent, prolactin (PRL)-producing cells. selective glycosylation and condensation into progran-
When sufficiently granulated, both GH and PRL cells ules within the Golgi apparatus, and granule matura-
stain positively with such acidic dyes as eosin, phlox- tion during transit to the cell membrane. The process
ine, and Orange-G. The cystic intermediate lobe rem- of hormone release normally occurs at the vascular pole
nants of Rathke’s cleft are lined by cuboidal-to- of the cell. In one mechanism of hormone release, gran-
columnar, ciliated, mucin-producing, or granulated ules traverse the cell membrane, come to lie in the ex-
adenohypophyseal cells. A posteriorly incomplete tracellular space, and diffuse into the vascular com-
sleeve of anterior pituitary tissue, the pars tuberalis, ex- partment. Not all adenohypophyseal cells secrete their
tends upward along the pituitary stalk; the majority of products by this process of exocytosis; indeed, it is ob-
cells at this location are ACTH- or gonadotropin- served normally only in lactotrophs and gonadotrophs.
producing. In this location, squamous metaplasia of se- An alternative mechanism of hormone release, trans-
cretory cells is commonly seen (Asa et al., 1983). membrane effusion, involves passage of the granule
Cells of the anterior pituitary are arranged in cords content through the cell membrane with resultant re-
surrounded by a delicate investment of connective tis- duction in granule electron density. Recent studies have
sue and capillaries (Figs. 18.1, 18.2). Loosely classified demonstrated the presence of growth factors in specific
according to their tinctorial characteristics, acidophilic, secretory cells of the anterior pituitary (Halper et al.,
basophilic, and chromophobic cells comprise 40%, 1992) and in secretory granules also containing pitu-
10%, and 50% of cells, respectively. The hormone itary hormones (Vidal et al., 1999).
products of normal pituitary cells are easily visualized The posterior lobe (neurohypophysis) of the pituitary
by immunohistochemistry (Table 18.1). Both GH and consists almost entirely of the terminations of axons of
PRL cells are histogenetically related and represent hypothalamic neurons as well as specialized glial cells
members of the “acidophil line.” The gonadotropins (pituicytes) in a delicate capillary stroma. Their princi-
FSH and LH are produced by the same cell; in con- ple hormones include vasopressin and oxytocin. A de-
junction with TSH cells, they comprise the glycopro- tailed discussion of the anatomy and physiology and
tein-hormone-producing cells. The histogenetic and pathology of the posterior pituitary and hypothalamus
often spatially intimate relationships of the various ade- is beyond the scope of this chapter. The reader is thus
396
18: PITUITARY TUMORS AND RELATED LESIONS 397
18.2). Literature regarding clinical and pathologic as-

pects of these tumors is voluminous (Randall et al.,
1984; Kovacs and Horvath, 1986; Scheithauer et al.,
1987; Kay and Laws, 1995; Horvath et al., 1997; Asa,
1998; Scheithauer et al., 2000; Thapar et al., 2000).
Their incidence approaches 15% of intracranial neo-
plasms. This relatively high figure is attributable to the
ready detection of often-hypersecreting microadenomas
by improved radioimmunoassay and neuroimaging
techniques. At present, given the tendency to treat pro-
lactinomas medically, the relative proportion of non-
functioning adenomas is increasing. Although adeno-
mas mainly affect females and tend to occur in the third
to sixth decades, no age group is exempt, not even chil-
FIGURE 18.1 Normal pituitary gland. Variably staining cells are
dren (Kane et al., 1992; Partington et al., 1994; Lein-
arranged in cords. Hematoxylin and eosin.
ung et al., 1995). An association with MEN-1 has been
documented (Asa et al., 1984b; Scheithauer et al.,
1987).
referred to more comprehensive texts (Horvath and Ko-
Symptomatic adenomas vary in size from microade-
vacs, 1980; Randall et al., 1984; Kovacs and Horvath,
nomas, which are often hyperfunctional and conve-
1986; Pernicone et al., 1992; Scheithauer et al., 1992;
niently defined as tumors less than 1 cm in diameter,
Horvath and Kovacs, 1997; Scheithauer et al., 1997a,b;
to often nonfunctioning macroadenomas, which often
Asa, 1998; Reeves et al., 1998; Scheithauer, 1998,
“diffusely” enlarge the sella and exhibit suprasellar
1999; Thorner et al., 1998; Stefaneanu et al., 2000;
extension. Mass effects of the latter typically cause en-
Thapar et al., 2000)
docrine hypofunction. Nonfunctioning macroadeno-
mas may be relatively asymptomatic and are occasion-
ally an incidental radiographic finding (Ebersold et al.,
PITUITARY NEOPLASIA
1986). Multiple adenomas are very uncommon in sur-
gical series (Kontogeorgos et al., 1992). A preoperative
Adenomas
diagnosis of multiple adenoma based on endocrine data
General comments may not be possible (Kontogeorgos et al., 1992; Wynne
et al., 1992b).
Pituitary adenomas are not rare. Incidental examples
The development of an adenoma is thought to pro-
are found in nearly 25% of subjects coming to autopsy
ceed through a stage indistinguishable from adenoma-
(Costello, 1936) and are occasionally multiple (Konto-
tous hyperplasia. With continued growth, the lesion ex-
georgos et al., 1991a). An immunocytochemical study
of 100 subclinical adenomas found at autopsy showed
no correlation between their functional type and the
patients’ clinical history (McComb et al., 1983). The
majority were null cell adenomas (50%) and pro-
lactinomas (45%); the remaining tumors showed vari-
able immunocytologic evidence of functional differen-
tiation. Pituitary adenomas, particularly prolactin cell
adenomas, are also common in animals (Kovacs et al.,
1977; Kovacs and Horvath, 1986). Recent evidence has
confirmed their clonal origin (Jacoby et al., 1990), and
the presence of cytogenetic (Rock et al., 1993) as well
as molecular genetic abnormalities (Karga et al., 1992;
Cyrns et al., 1993; Herman et al., 1993; Lloyd, 1993;
Boggild et al., 1994; Irofumi et al., 1995).
Pituitary adenomas are the principle lesion in the new
2000 World Health Organization classification of pi- FIGURE 18.2 Normal pituitary gland. Uniform cord architecture is
tuitary adenomas (Scheithauer et al., 2000) (Table readily seen on reticulin stain.
TABLE 18.1 Morphology of the Normal Pituitary Gland*
Percent of Immunoperoxidase
Cell Product Cells Location Characteristics Histochemical Staining Staining
GH Growth hormone 50 Concentrated in lateral Polypeptide; 191 aa, A–C (densely and sparsely granulated): GH†
wings anterolaterally MW 22,000 eosin, phloxine, Orange G
PRL Prolactin 10–30 Concentrated in lateral Polypeptide; 198 aa, A–C (densely and sparsely granulated): PRL†
wings posteriorly MW 23,500 eosin, phloxine, Brooke’s
carmoisine, Herlant’s erythrosin
ACTH Adrenocorticotropic 10–20 Concentrated in Polypeptide; 39 aa, B: periodic acid–Schiff, lead ACTH, -lipotropin,
and related mucoid wedge; often MW 4507 hematoxylin -endorphin,
hormones clustered (minor melanocyte-stimulating
population in hormone
posterior lobe)
LH, FSH Luteinizing and 10 Generalized LH‡; glycoprotein; B: periodic acid–Schiff, aldehyde LH, FSH, subunit
follicle-stimulating 115 aa, MW 28,260 fuchsin, aldehyde thionine
hormones
TSH Thyrotropic 5 Concentrated in Glycoprotein; 125 aa, B: periodic acid-Schiff, aldehyde TSH, subunit
hormone anterior mucoid MW 28,000; fuchsin, aldehyde thionine
wedge subunit consists of 110
aa with 1 carbohydrate
moiety
Source: Modified from Scheithauer (1999).

*aa, amino acid; MW, molecular weight; A, acidophilic; B, basophilic; C, chromophobic.
†Rare acidophilic stem cells, presumed to be precursor cells producing both GH and PRL, are present in the normal pituitary gland.
‡FSH, LH, and TSH have a common 92-amino acid 14,000 MW glycoprotein subunit and are produced in the same cell.
TABLE 18.2 Histologic Classification of

Adenohypophysial Tumors—2000 WHO
Classification
Diagnosis Code*
1. Adenoma
2. 1.1. Typical 8140/0
2. 1.2. Atypical 8140/1
2. Carcinoma 8010/3
3. Soft tissue tumors
2. 3.1. Postirradiation sarcoma
2. 3.2. Benign soft tissue tumors
4. Secondary tumors
5. Tumorlike lesions FIGURE 18.4 Pituitary adenoma. This well-formed adenoma shows
2. 5.1. Pituitary hyperplasia paucity of reticulin and compression of pituitary adonoma. Reticulin
stain.
2. 5.2. Rathke cleft cyst
2. 5.3. Lymphocytic hypophysitis
2. 5.4. Giant cell granuloma symptoms and endocrinopathy related to hypothalamic
Source: Corenblum et al. (1976).
compression. Parasellar extension to involve the cav-
*Morphology code for the International Classification of Diseases for On- ernous sinuses is also common. Although inferior ex-
cology (ICD-0) and the Systematized Nomenclature of Medicine (SNOMED). tension into sinuses is frequently seen, presentation of
an adenoma as a nasal mass is rare. Secondary degen-
erative changes, such as necrosis, cyst formation, or
pands and compresses surrounding normal pituitary
frank “apoplexy” within large adenomas, reflect their
parenchyma, condensing its delicate connective tissue
compressive effects upon the local vascular supply. A
scaffolding to form a tenuous line of demarcation sur-
variety of adenoma types, more often nonfunctional
gically suggesting a “capsule” (Figs. 18.3, 18.4). An in-
than hormonally active, may undergo apoplexy (see
termediate stage wherein acinar architecture, albeit ex-
below).
panded, is still discernible and monomorphism is not
Ectopic adenomas are rare (Lloyd et al., 1986a;
fully developed has been termed a tumorlette. With
Takahata et al., 1995; Hori et al., 1999). Some arise
continued growth, adenomas compress surrounding pi-
in the sphenoid sinus or beneath the oral mucoperios-
tuitary, expand the sella, thin the dura, demineralize or
teum, a location at which they represent neoplastic
erode the sellar floor, and undergo extrasellar exten-
transformation of the pharyngeal pituitary (Kay et al.,
sion. Pituitary adenomas may exit the sella in several
1950; Lloyd et al., 1986a; Hori et al., 1999). Rare ex-
directions. When suprasellar, the latter results in visual
amples also occur in the nasal cavity (Kay et al., 1950),
third ventricle (Kleinschmidt-DeMasters et al., 1990),
or the suprasellar region (Takahata et al, 1995). Pitu-
itary adenoma may even be a component of an ovar-
ian teratoma (Palmer et al., 1990).
The common histogenetic relationship between
Rathke’s cleft cyst (see below) and pituitary adenoma
has been used to explain the occurrence of occasional
cystic, intrasellar masses with combined features of
both (Kepes, 1978; Nishio et al.,1987; Nakasu et al.,
1989).
Surgical pathology
When small in size, the location of adenomas within
the gland reflects the distribution of their normal cel-
FIGURE 18.3 Incidental pituitary adenoma. This minute, circum- lular counterpart. Few human tumors possess the va-
scribed tumor shows cytologic uniformity and paucity of stroma. riety of growth patterns exhibited by the pituitary ade-
nomas (Fig. 18.5). Although the histologic patterns en-

countered may be characteristic of some adenoma
types—for example, perivascular pseudorosettes or
papillae in gonadotrophic adenomas—they are of no
prognostic significance. Their recognition is more im-
portant because they mimic lesions that enter into the
differential diagnosis of pituitary adenoma. Because tu-
mor identification depends in part on pattern recogni-
tion, large intact fragments should be obtained with
minimal mechanical injury. Minute specimens may
even preclude the distinction of adenoma from normal
tissue or from foci of micronodular hyperplasia. Frozen
tissues are of limited value for critical light microscopy
or immunochemistry, and are useless for electron mi-
FIGURE 18.6 Pituitary adenoma, smear. Note some pleomorphism,
croscopy. Optimally the latter requires prompt fixation nucleolar prominence, and uniform tinctorial characteristics of the
in glutaraldehyde, but formalin fixation is perfectly ad- cytoplasm. A mitotic figure is also seen. Hematoxylin and eosin.
equate for diagnostic purposes.
The role of the pathologist in the assessment of pa-
tients with pituitary adenomas begins at the time of
A common “crush” artifact produced by the mis-
surgery. Although frozen sections may be obtained to
handling of either normal or neoplastic pituitary tissue
positively identify adenoma tissue and to assess resec-
consists of hyperchromatic cells mimicking metastatic
tion margins, total excision of adenomas is complicated
small cell carcinoma. The distinction is simple, since
by a variety of factors, including their soft consistency,
normal pituitary tissue lacks mitoses and adenomas ex-
irregular tumor shape, lack of precise cleavage planes,
hibit them only rarely and have low MIB-1 labeling in-
and microfoci of dural invasion. As a result, most sur-
dices (Thapar et al., 1996a). Unsightly “empty acini”
geons are content with “gross total” resections. Close
are produced by a suction effect upon the normal gland
cooperation between the surgeon and the surgical
and geometric, often triangular tissue defects are caused
pathologist is necessary to optimize tissue evaluation.
by sponge compression artifact. Neither should pose a
Due to artifacts induced by freezing, we use frozen sec-
diagnostic problem.
tions sparingly, reserving virtually all tissue for high-
quality permanent sections and immunohistochemistry.
Instead, we rely upon cytologic smears or touch prepa-
rations. These result in a high-quality preparation that
readily permits the distinction of adenoma from nor-
mal pituitary tissue (Figs. 18.6, 18.7).
A B
FIGURE 18.5 Pituitary adenoma. Pattern variation, here illustrated as FIGURE 18.7 Normal pituitary gland, smear. Note nuclear uniformity,
the diffuse (A) and papillary (B), is typical of pituitary adenomas. small nucleoli, and variation cytoplasmic staining ranging from chro-
Hematoxylin and eosin. mophobic to acidophilic and basophilic. Hematoxylin and eosin.
TABLE 18.3 Ultrastructural Classification of Adenohypophysial Tumors—2000 WHO Classification

Tumor Type Ultrastructural Variant Frequency (%)
Growth hormone cell adenoma Densely granulated 3.0

Sparsely granulated 2.0
Prolactin cell adenoma Sparsely granulated 29.0
Densely granulated 1.0
Adenomas with growth hormone and Mixed GH-PRL cell adenoma 5.0
prolactin cell differentiation Mammosomatotroph cell adenoma 1.0
Acidophil stem cell adenoma 2.0
ACTH cell adenoma Densely granulated 10.0
Sparsely granulated 1.0
Crooke cell variant 1.0
TSH cell adenoma 1.0
FSH-LH cell adenoma Male type 10–15
Female type
Null cell adenoma Non-oncocytic 10–15
Oncocytic 10.0
Other adenomas Silent “corticotroph” subtype 1 1.5
Silent “corticotroph” subtype 2 0.5
Silent adenoma subtype 3 0.5
Plurimorphous adenomas—e.g., GH-PRL-TSH, 5.0
PRL-ACTH, FSH-LH–ACTH, etc.
Unclassified
Source: Scheithauer et al. (2000), WHO.
Classification TABLE 18.4 Pituitary Adenomas

Only in recent years have advances in the clinical and Tinctorial Functional/Immunohistochemical
biochemical evaluation of patients with pituitary ade-
Acidophilic Somatotropic, densely granulated
nomas been accompanied by progress in surgical
Lactotropic, densely granulated
pathology. The classification of adenomas, based upon
their tinctorial characteristics, into eosinophilic, ba- Mixed somatotropic–lactotropic with
prominent, densely granulated component
sophilic, and chromophobic types is of little value. The
Null cell, oncocytic type
same is true of complex histochemical stains—for ex-
ample, PAS–Orange-G—intended to differentiate types Basophilic Corticotropic, densely granulated
of secretory cells in normal tissue or adenoma cells, Thyrotropic, densely granulated (rare)
since results are often unreliable or nonspecific, even Gonadotropic, densely granulated (rare)
in experienced laboratories. The “functional classifica- Chromophobic Somatotropic, sparsely granulated
tion” of adenomas developed by Kovacs and Horvath Lactotropic, sparsely granulated
(Table 18.3) is predicated upon their ultrastructural Mixed somatotropic–lactotropic with
features correlating with immunohistochemistry (Hor- prominent, sparsely granulated component
vath and Kovacs, 1976; Horvath and Kovacs, 1980; Acidophil stem cell
Kovacs and Horvath, 1986; Horvath et al., 1997). Corticotropic, sparsely granulated
Thus, a comparison between the tinctorial and func- Thyrotropic, sparsely granulated
tional classifications of pituitary adenomas shows lit- Gonadotropic, sparsely granulated
tle correlation (Table 18.4). For example, eosinophilic Null cell, non-oncocytic type
adenomas, previously thought to be solely GH-
producing, may be engaged in the production of GH, PRL haps with time, improved antisera specificity and a
or both, or may lack hormone production. Basophilic ade- heightened understanding of the clinical and prognos-
nomas, particularly those strongly PAS-positive, are al- tic importance of our observations will result in a
most always associated with Cushing’s disease, but classification of pituitary adenomas firmly based on im-
weakly PAS-reactive tumors may produce ACTH, FSH, munohistochemistry alone. For the present, tissue cul-
LH, or TSH. The greatest disparity between the tinctor- ture, immunoelectron microscopy, in situ hybridiza-
ial and functional classifications is seen in “chromopho- tion, and dynamic tests such as the hemolytic plaque
bic” adenomas. Such tumors were thought to be non- assay remain experimental methods.
functional but in actuality may produce a spectrum of
hormones. The clinicopathologic features of the various
adenoma subtypes are summarized in Table 18.5. PEPTIDE HORMONE–PRODUCING ADENOMAS
Immunohistochemistry GH Cell Adenoma

Standard immunoperoxidase techniques, as well as the Approximately 30% of pituitary adenomas are associ-
more sensitive avidin-biotin peroxidase complex (ABC) ated with clinical or immunohistochemical evidence of
method, have been applied to pituitary adenomas with GH production. Our understanding of their complex
great success. Their degree of immunopositivity is pathology has evolved steadily (Kovacs and Horvath,
roughly proportional to their hormone content. Al- 1973; Corenblum et al., 1976; Horvath et al., 1981;
though these techniques provide information regarding Horvath et al., 1985; Laws et al., 1985; Scheithauer et
products being synthesized, they are static, yielding no al., 1986c). Only a minority are engaged solely in GH
information regarding the presence or rate of hormone production, the remainder being either plurihormonal
secretion. (see below) or variants of GH- and PRL-producing ade-
Reference to the hormonal immunotype of pituitary nomas (see below) (Corenblum et al., 1976; Horvath
adenomas is made throughout this chapter. Their genet al., 1981; Horvath et al., 1985; Laws et al., 1985;
eral immunophenotype, however, has been less fully Scheithauer et al., 1986a,c; Thapar et al., 1997). Un-
studied (Lloyd et al., 1985; Ironside et al., 1987; Lloyd like prolactinomas, the majority of GH cell adenomas
et al., 1996) and varies somewhat with adenoma type. are variably acidophilic, reflecting at least moderate
granule content (Figs. 18.8, 18.9). Sparsely granulated
adenomas comprise the remainder, which appear chro-
Electron microscopy
mophobic (Fig. 18.10). Although nonspecific, the his-
Ultrastructurally, the cells of pituitary adenomas often tologic pattern of GH adenomas is often diffuse. Nu-
resemble their normal counterparts (Horvath and Ko- clear pleomorphism and multinucleation may be seen
vacs, 1976; Horvath and Kovacs, 1980; Kovacs and in occasional examples, but they are of no clinical
Horvath, 1986b; Robert and Hardy, 1986; Horvath et significance.
al., 1997; Scheithauer, 1999). Their principal cyto- Tumors associated with acromegaly or gigantism
plasmic feature is the presence of secretory granules. may be adenomas making GH alone, GH, and PRL, or
Although their morphology may be distinctive, it alone more often plurihormonal adenomas (Kovacs and Hor-
cannot serve as the basis for cell identification. Instead, vath, 1973; Corenblum et al., 1976; Horvath et al.,
typing of normal and neoplastic cells depends upon sev- 1981, 1985; Laws et al., 1985; Scheithauer et al.,
eral parameters, including cell and nuclear shape, or- 1986a,c; Thapar et al., 1997). Immunostains show vari-
ganelle content, nature and disposition of cytoplasmic able positivity. In sparsely granulated adenomas the re-
microfilaments, granule morphology, and the type of action is weak, but most apparent in the Golgi region
granule excretion. Although the ultrastructural studies of the cells. In contrast, densely granulated tumors
of Horvath and Kovacs (1976, 1980, 1986) are the ba- show strong, generalized cytoplasmic reactivity. Ultra-
sis of the 2000 WHO classification of adenohypophy- structurally, sparsely granulated tumors contain small
seal tumors (Scheithauer et al., 2000), electron mi- numbers of granules measuring 100–250 nm, and pos-
croscopy is critical for precise subclassification in only sess a characteristic cytoplasmic feature, the paranu-
a minority of cases. For example, ultrastructural study clear “fibrous body” composed of intermediate fila-
is useful for distinguishing (1) mixed GH cell/PRL cell ments (cytokeratin) (Halliday, 1990) (Fig. 18.11). Such
as well as mammosomatotropic adenoma from the filament whorls may entrap organelles and secretory
more aggressive acidophilic stem cell adenoma, and (2) granules but are not themselves composed of GH. Fi-
the identification of silent subtype III adenomas. Per- brous bodies are virtually diagnostic of GH-producing
TABLE 18.5 Clinicopathologic Features of Pituitary Adenomas
Gross Features
Tumor Type Incidence Clinical Staininga Hormone Blood Immuno Sizeb Invasion
Lactotrophic adenomas 25% Amenorrhea/ C PRL 52% overall

35% micro/
sparsely granulated galactorrhea,
65% macro
impotence
densely granulated 1% Amenorrhea/ A PRL
somatotrophic Impotence
Somatotrophic adenoma 5% Acromegaly/ C-A GH 50% overall
sparsely granulated gigantism 15% micro/
85% macro
densely granulated 5% A GH
Mixed GH cell/PRL cell 5% Acromegaly or A/C GH/PRL / / 25% micro/ 31% overall
gigantism 75% macro
hyperprolactinemia
Mammosomatotroph 3% Acromegaly A GH/PRL / / Features similar
PRL symptoms to mixed GH
cell/PRL cell adenoma
Acidophil stem cell 1% Hyperprolactinemia C GH/PRL / / Usually invasive

or “nonfunctional,” macroadenomas
occasional
acromegaly
Corticotrophic adenomas 10% Hypercortisolism B ACTH 85% micro/ 8%
Cushing’s ( endorphin)- 15% macro
-LPH, MSH
Crooke’s cell 0.5% Hypercortisolism B Usually macro Frequent
nonfunctioning
Silent corticotrophic 3% Mass symptoms B-C Endorphins, and 100% 82%
hypopituitarism related compounds
Nelson’s 2% Pigmentation, B-C ACTH 30% micro/ 17%
mass symptoms ( endorphin)- 70% macro 64%
-LPH, MSH
TABLE 18.5 Clinicopathologic Features of Pituitary Adenomas (continued)
Gross Features
Tumor Type Incidence Clinical Staininga Hormone Blood Immuno Sizeb Invasion
Gonadotrophic 7–15% Setting of C-B FSH/LH ( 100% 21%

hypogonadism, subunit) macro
functionally silent
mass effects
Thyrotrophic 1% Setting of hypo- or C-B TSH ( Usually
hyperthyroidism subunit) invasive
macroadenoma
Plurihormonal 10% Usually acromegaly C-A Usually //- Usually 25% micro/ 31%
hyperprolactinemia GH/PRL/TSH, // 75% macro 59%
Glycoprotein hormone subunit, 52% overall
production is includes
rarely expressed unusual
combinations
Null cell 20%
non-oncocytic 14% Visual symptoms, C None mild PRL (glycoprotein 95% macro
hypopituitarism, increase due to hormone or
headaches pituitary stalk other reactivities
compression in occasional cells) 42% overall
oncocytic 6% Visual symptoms, A None mild PRL (glycoprotein
hypopituitarism, increase due to hormone or
headaches pituitary stalk other reactivities
compression in occasional cells)
Silent subtype III 3% Mass effects; mimics C to Variable Low-level Usually invasive
prolactinoma in mild A reactivities for macroadenoma
females various hormones
aA,acidophilic; B, basophilic; C, chromophobic.
bMicro, microadenoma (1 cm diameter); macro, macroadenoma (1 cm diameter).
Source: Modified from Colohan et al. (1986).
A B A
FIGURE 18.8 Densely granulated growth hormone cell adenoma. B

Granular eosinophilia (A) and strong growth hormone (GH) im-
munoreactivity (B) are the result of high granule content. (A) Hema-
toxylin and eosin; (B) GH immunostain.
adenoma cells. They also are seen in both mixed GH

cell/PRL cell adenomas and acidophil stem cell adeno-
mas (see below). Similar structures have been identified
in a variety of nonpituitary, neuroendocrine, and
peptide-secreting neoplasms. In contrast, the cells of
densely granulated tumors resemble normal soma-
totrophs in showing prominent rough endoplasmic
reticulum, well-developed Golgi complexes, and large FIGURE 18.10 Sparsely granulated growth hormone cell adenoma.
numbers of 300–600 nm granules, but lacking filament Cells show little or no eosinophilia, but feature spherical parameter
whorls. “fibrous bodies” composed of cytokeratin (A). Stains for growth hor-
Although the notion that an inverse relationship ex- mone show scant reactivity (B). Note lack of staining in the fibrous
ists between cytoplasmic granularity and secretory ac- bodies within the immunoreactive cell. (A) Hematoxylin and eosin;
(B) GH immunoperoxidase method.
tivity has not borne out, the morphology of GH-

producing adenomas does correlate with tumor behav-
ior. Light and electron microscopic studies have shown
that sparsely granulated adenomas are more aggressive
than densely granulated adenomas, particularly when
they occur in young women. In a correlative study of
the macroscopic and ultrastructural features of 95 GH-
secreting pituitary adenomas, sparsely granulated tu-
mors were not found among microadenomas but were
three times more likely to show invasive behavior than
were densely granulated lesions. In contrast, of densely
granulated adenomas, nearly 40% were microadeno-
mas and only 10% showed invasion, more often focal
rather than diffuse (Robert, 1979). The aggressiveness
of sparsely granulated tumors may be explained in part
FIGURE 18.9 Densely granulated growth hormone cell adenoma. Siz-
able (350–500 nm) secretory granules are numerous and synthetic by their frequent production of growth hormone–
organelles are well developed. Courtesy Dr. E. Horvath, St. Michael’s releasing hormone (GHRH), an example of autocrine
Hospital, Toronto, Ontario, Canada. stimulation (Thapar et al., 1997).
(Thorner et al., 1982; Scheithauer et al., 1983b, 1984;

Kovacs et al., 1984).
Prolactin Cell Adenoma (Prolactinoma)

Prolactinomas are the most recent of the major ade-
noma types to be recognized (Kovacs et al., 1975). They
are as often micro- as macroadenomas and show a dis-
tinct tendency to form microcalcifications (Lipper et al.,
1984) (Fig. 18.13). Although normal PRL cells are ei-
ther densely or sparsely granulated, hence either aci-
dophilic or chromophobic, the majority of prolactino-
mas are chromophobic due to paucity of secretory
FIGURE 18.11 Sparsely granulated growth hormone cell adenoma. granules (Kovacs et al., 1975; Horvath and Kovacs,
Note well-differentiated cytoplasm and prominent “fibrous bodies” 1986). Because the PRL molecule, like growth hor-
composed of intermediate filaments in electron micrograph. Cour- mone, is devoid of a carbohydrate component, PAS
tesy of Dr. E. Horvath, St. Michael’s Hospital, Toronto, Ontario, stains are uniformly negative. Immunoperoxidase
Canada.
stains for PRL are positive in both the rare, densely
granulated PRL cell adenoma that shows diffuse cyto-
plasmic staining and in the common, sparsely granu-
The vast majority of adenomas associated with lated variant. Reactivity in the latter is paranuclear due
acromegaly belong to the plurihormonal group—that to staining of the Golgi region (Fig. 18.14), a helpful
is, tumors engaged not only in the production of GH, diagnostic feature in view of the sparsity of secretory
but of prolactin and one or more glycoprotein hor- granules (Fig. 18.15). As a rule of thumb, serum pro-
mones, most often TSH and/or the common, biologi- lactin levels are roughly proportionate to tumor size
cally nonfunctional glycoprotein subunit (Scheithauer (Randall et al., 1985).
et al., 1986a,c; Berg et al., 1988; Kontogeorgos et al., Studies of prolactinomas have shown sparsely gran-
1991b). Acromegaly is rarely due to processes other ulated PRL cell adenoma to exhibit characteristic ul-
than pituitary adenoma (Laws et al., 1985; Scheithauer trastructural features, including abundant rough endo-
et al., 1986c). Examples include GHRH production by plasmic reticulum often disposed in concentric whorls
hypothalamic hamartoma (Scheithauer et al., 1983b; (nebenkern formation) and small (150–550 nm) secre-
Asa et al., 1984b) (Fig. 18.12) and GH cell hyperpla- tory granules subject to “misplaced exocytosis,” a form
sia due to ectopic GHRH production, often by a neu- of granule extrusion into the intercellular space remote
roendocrine tumor of the lung or gastrointestinal tract from the capillary interface (Kovacs et al., 1975; Robert
A B
FIGURE 18.12 Hypothalamic neuronal hamartoma. This was a large FIGURE 18.13 Prolactin cell adenoma. As seen on this T1-weighted
lesion in hypothalamus of an elderly man produced growth-hormone- MRI scan (A), the tumor is a laterally situated microadenoma. On
releasing hormone (GHRH) which induced a growth hormone ade- routine stain (B) the lesion is chromophobic and exhibits microcal-
noma and longstanding acromegaly. Hematoxylin and eosin. cifications. (B) Hematoxylin and eosin.
long term, dopaminergic agents may produce tumor fi-

brosis. The clinicopathologic features of prolactinomas
are summarized in Table 18.5.
Compression of the pituitary stalk or its interruption
by any lesion results in loss of dopamine-mediated hy-
pothalamic suppression of prolactin secretion. Termed
the “stalk section effect,” it permits a variety of sellar
region masses to mimic prolactinoma (pseudopro-
lactinomas) (Randall et al., 1983). Increased intrasel-
lar pressure may also contribute to this effect (Lees et
al., 1987).
Mixed GH Cell/PRL Cell Adenoma

FIGURE 18.14 Prolactin cell adenoma. Note strong paranuclear im-
munoreactivity for prolactin in a distribution corresponding to the It is well known that the majority of GH-producing
Golgi complex. GH immunostain. adenomas also secrete prolactin. Indeed, approximately
40% of patients with acromegaly have evidence of hy-
perprolactinemia. The clinical diagnosis of a mixed GH
and Hardy, 1975) (Fig. 18.15). Cells with features sim- cell/PRL cell adenoma cannot be made with certainty
ilar to those of sparsely granulated prolactin cell ade- in that any sellar region tumor of sufficient size may
noma occur in the pituitary of late pregnancy (“preg- interfere with the release of dopamine, the normal pro-
nancy cells”) and in the pituitaries of subjects receiving lactin-inhibiting factor, thus resulting in nontumoral
estrogen therapy. prolactin elevation. Furthermore, since the predomi-
Less than one-half of operated, endocrinologically nant clinical feature of mixed GH cell/PRL cell adeno-
functional pituitary tumors are prolactinomas. Many, mas is acromegaly, the effects of PRL secretion may go
particularly in young reproductive-age females, are mi- unnoticed. Mixed GH cell/PRL cell adenomas have
croadenomas. In males virtually all are macroadeno- been well characterized (Corenblum et al., 1976) and
mas and many are invasive (Randall et al., 1985). Due are of interest in that they represent an adenoma com-
to the popularity of dopamine-agonist therapy, the fre- posed of two distinct, albeit related, cell lines (Fig.
quency of prolactinomas in surgical series has de- 18.16). They comprise but a few percent of pituitary
creased. These agents produce involution and atrophy adenomas and their behavior is somewhat more indo-
(Tindall et al., 1982; Barrow et al., 1984; Mori et al., lent than that of the far more common GH-plurihor-
1985; Niwa et al., 1987) rather than cell death; they monal adenoma. Immunostains generally show mixed
arrest tumor growth but are not curative. Administered
FIGURE 18.16 Mixed growth hormone cell–prolactin cell adenoma.

FIGURE 18.15 Misplaced exocytosis (arrow) and abundance of rough Note the presence of two distinct cell types, densely granulated
endoplasmic reticulum are typical features of prolactin cell adenoma. growth hormone cells and sparsely granulated prolactin cells with
Courtesy of Dr. E. Horvath, St. Michael’s Hospital, Toronto, On- granule exocytoses (arrowhead). Courtesy of Dr. E. Horvath, St.
tario, Canada. Michael’s Hospital, Toronto, Ontario, Canada.
GH cell/PRL cell adenomas to be quite reactive for both A

hormones. Ultrastructural studies serve to distinguish
this form of mixed adenoma from ordinary GH cell ad-
enoma as well as from mammosomatotroph and aci-
dophil stem cell adenomas (see below). Electron mi-
croscopy usually reveals the presence of both densely
granulated somatotrophs and lactotrophs of an either
densely or sparsely granulated type.
Mammosomatotroph Cell Adenomas

These unusual GH- and PRL-producing tumors repre-
sent approximately 1% of pituitary adenomas. Staining
for GH and PRL is generally abundant. Ultrastructurally B
it is monomorphous, being composed of cells exhibiting
both somatotropic and lactotropic differentiation. Large,
often mottled, secretory granules as well as intercellular
electron dense deposits of secretory material are hall-
marks. Like the bicellular mixed GH cell/PRL cell ade-
noma, this is not an aggressive lesion. Mammosoma-
totroph cell adenoma must be distinguished from the
more aggressive acidophil stem cell adenoma.
Acidophil Stem Cell Adenoma

This unique variant of pituitary adenoma is relatively
rare, representing about 1% of all such tumors. In view
FIGURE 18.18 Acidophil stem cell adenoma. These large, aggressive
of its aggressive nature, it represents an important noso-
tumors exhibit far less prolactin immunoreactivity (A) than do pro-
logic entity (Horvath et al., 1981). Acidophil stem cell lactomas. Electron microscopy shows the giant “blown out” mito-
adenomas are thought to represent a proliferation of chondria to be devoid of cristae. (B) PRL immunostain.
immature or “stem” cells of the acidophil line. Similar
cells are rarely found in the normal pituitary. Most aci-
dophil stem cell adenomas are either clinically non- By light microscopy the acidophil stem cell adenoma
functioning or simulate prolactinoma. Serum GH lev- is often chromophobic; oncocytic change is less com-
els usually not elevated, and acromegaly is uncommon. mon. On occasion, H&E-stained sections show the
presence of a cytoplasmic vacuole (Fig. 18.17). Im-
munoperoxidase preparations on consecutive micro-
sections show the presence of both GH and PRL within
the same tumor cell (Fig. 18.18). Ultrastructural stud-
ies are nonetheless needed to confirm the diagnosis. Un-
like mixed GH cell/PRL cell adenoma, a bicellular le-
sion is composed of a single cell type with features
intermediate between GH and PRL cells. These include
the presence of both cytoplasmic “fibrous bodies” and
misplaced exocytoses. Giant mitochondria are also
common, the basis of the occasional light microscopi-
cally evident vacuoles.
PLURIHORMONAL ADENOMAS
FIGURE 18.17 Acidophil stem cell adenoma. Although not a regular
feature at the light microscopic level, giant mitochondria in some ex- Tumors elaborating unexpected combinations of hor-
amples are evident as cytoplasmic vacuoles. Hematoxylin and eosin. mones, most often GH, PRL, and one or more glyco-
protein hormones (usually TSH and subunit) are not Corticotroph Cell (ACTH-Producing) Adenomas
uncommon (Horvath et al., 1983; Scheithauer, 1986a).
In an ultrastructural and immunohistologic study of 22
They account for the majority of adenomas in acro-
surgically resected ACTH adenomas associated with ei-
megaly. The glycoprotein hormones are neither clini-
ther Cushing’s disease or Nelson’s syndrome (Robert
cally expressed nor evident as serum elevations. Pluri-
et al., 1978; Robert and Hardy, 1986), 16 were mi-
hormonal adenomas are of particular interest in that
croadenomas showing little change on sellar tomogra-
they may consist of one or more ultrastructurally dis-
phy, 3 were large but not invasive adenomas, 1 showed
tinct cell types. Thus an ultrastructurally monomor-
local invasion, and only 2 were diffusely invasive. This
phous tumor composed of GH cells alone may produce
gross spectrum is typical of ACTH adenomas that pres-
multiple biochemically dissimilar hormones. The very
ent with hyperfunction. Symptoms of mass effect or in-
existence of such tumors refutes the “one cell–one hor-
vasiveness are uncommon. Most ACTH adenomas arise
mone” theory and has influenced our concepts of pi-
within the central pituitary or “mucoid wedge.” Sellar
tuitary cytogenesis (Fig. 18.19).
enlargement and capsular invasion by corticotropic
adenomas are directly related to tumor size and asso-
ciated with a significant decrease in the likelihood of a
ACTH-PRODUCING ADENOMAS
surgical cure. Corticotrophic adenomas, situated pos-
teriorly, either partly or entirely within the neurohy-
A spectrum of lesions underlies ACTH excess (Lloyd
pophysis, may arise from intermediate lobe corti-
et al., 1986b). The most frequent combination of le-
cotrophs, functionally distinct cells less prone to
sions underlying Cushing’s syndrome is a basophilic
undergo Crooke’s hyalinization. Such tumors are often
pituitary adenoma associated with adrenal cortical
functionally “silent” (see below).
hyperplasia. Far less common is corticotroph cell hy-
perplasia due to a hypothalamic disturbance or to an
ectopic corticotropin-releasing hormone (CRH)-
Cushing’s disease
producing tumor. Among pituitary adenomas, the in-
cidence of corticotropin tumors is approximately 20%. The majority, approximately 85% of ACTH-produc-
Patients range widely in age and females are most of- ing tumors, are microadenomas, some no more than 2
ten affected. Although end-organ insufficiency (Addi- mm in diameter. Of microadenomas, only about 10%
son’s disease) is associated with nodular corticotropic are invasive. Macroadenomas, however, are often in-
hyperplasia, tumorlette formation, and a small increase vasive. By light microscopy the majority of ACTH ade-
in ACTH cell adenomas, it plays no clinically signifi- nomas are amphophilic and PAS-positive (Fig. 18.20).
cant role in the genesis of ACTH-cell adenomas (Schei- Chromophobic tumors are uncommon and usually
thauer et al., 1983a). macroadenomas. Immunohistologic studies show
ACTH within adenoma cells, as well as other pro-
opiomelanocortic (POMC) derivatives, such as -
lipotropin hormone (-LPH) and related products of
the endorphins, encephalins, and melanocyte stimulat-
ing hormone. Two ultrastructural features characterize
ACTH adenomas, secretory granules of which often are
“teardrop shaped” and of variable electron density, and
perinuclear intermediate filaments (cytokeratin) (Hall-
iday, 1990) (Fig. 18.21). Massive accumulation of the
latter is the basis of Crooke’s hyaline change in non-
tumoral corticotrophs, the result of cortisol excess due
to pituitary/adrenal disease or iatrogenic causes (Fig.
18.22). It has been suggested that such fibril accumu-
lation acts as a “physiologic brake” on the mechanism
of granule secretion. On occasion, ACTH adenomas
show Crooke’s hyalinization. Such tumors are typically
Cushing’s disease-associated, invasive macroadenomas.
FIGURE 18.19 Plurihormonal adenoma. This acromegaly-associated
Their occurrence suggests the presence of cortisol re-
tumor produced not only growth hormone and prolactin but, as seen ceptors and of ongoing hormone feedback (Felix et al.,
in this figure, abundant -subunit as well. -SU Immunostain. 1981; Gaffey submitted b).
B FIGURE 18.21 Corticotroph cell adenoma. This Cushing’s disease–

associated lesion shows variation in shape and electron density of se-
cretory granules, as well as perinuclear intermediate filaments. Cour-
tesy of Dr. E. Horvath, St. Michael’s Hospital, Toronto, Ontario,
Canada.
cotroph adenomas, they are basophilic to chromophobic

and immunoreactive for ACTH and/or other POMC de-
rivatives. By definition, they are unassociated with clini-
cal signs of glucocorticoid excess or ACTH elevation. Per-
haps such tumors elaborate biochemically abnormal,
endocrinologically inactive products. Silent corticotroph
adenomas show morphologic variation and occur in two
FIGURE 18.20 Corticotroph cell adenoma. On H&E stain (A) such
forms, subtypes I and II (Horvath et al., 1980; Schei-
tumors are usually amphophilic. The periodic acid–Schiff stain (B) thauer, in press). The former are indistinguishable from
may be strongly reactive. ordinary ACTH adenomas of Cushing’s disease. Both tu-
mors show a significant incidence of infarction and fre-
quently recur (Scheithauer, in press). The “silent subtype
Nelson’s syndrome III adenoma,” a poorly understood form once considered
a silent corticotropic adenoma, remains a nosologic
In contrast to the adenomas of Cushing’s disease, the ma- enigma (Horvath et al., 1988).
jority of which are microadenomas, approximately 70%
of the tumors of Nelson’s syndrome are macroadenomas.
Fully 65% are invasive. Most are amphophilic or weakly
so, and neither their histochemical nor immunocytologic
features differ significantly from those of Cushing’s dis-
ease. Perinuclear cytokeratin filaments are sparse or ab-
sent due to lack of glucocorticoid feedback. One clini-
copathologic study of 19 cases of Nelson’s syndrome
reported an interval of 7 months to 18 years from adrena-
lectomy to transsphenoidal exploration; three patients
died of their tumor, and only four were considered cured
on the basis of postoperative ACTH levels (Wilson,
1979). Malignant transformations with associated ex-
tracranial metastases may occur (Mountcastle et al.,
1989; Pernicone et al., 1997; Gaffey, submitted b).
FIGURE 18.22 Crooke’s hyaline change in nontumoral pituitary. Scat-
Silent Corticotroph Adenomas tered cells show a prominent, hyalin, fibrillar ring at the periphery
of the cell. This change, which results from both endogenous and ex-
Endocrinologically nonfunctioning variants of ACTH- ogenous glucocorticoid excess, may rarely be seen in corticotroph
producing tumor are uncommon. Termed silent corti- cell adenoma as well. Hematoxylin and eosin.
GLYCOPROTEIN HORMONE– pogonadism (Kovacs et al., 1980a). Males and females

PRODUCING ADENOMAS are almost equally affected. The tumors usually are
compressive, have the lowest rate of invasion of any
FSH and/or LH Cell Adenomas macroadenoma (20%), and feature a very low recur-
rence rate. In a small proportion of cases (15%), blood
Gonadotrophs comprise approximately 10% of normal levels of LH and FSH are mildly elevated. No symp-
anterior pituitary cells and are fairly uniformly dis- toms of hypersecretion are seen.
tributed throughout its substance. Like corticotrophs
they are basophilic and PAS-positive. Immunostains
show them to be spherical and to contain both FSH Thyrotroph Cell (TSH-Producing) Adenomas
and LH as well as subunit. Thyrotroph cells are present in only small numbers in
Gonadotrophic adenomas represent approximately the normal adenohypophysis. Most are situated in the
10% of pituitary adenomas. Sizable numbers have only anterior “mucoid wedge.” Polygonal to elongate, their
recently been studied by ultrastructural and immuno- basophilic cytoplasm contains PAS-positive, TSH- and
histochemical methods (Young et al., 1978; Horvath -subunit-immunoreactive secretory granules.
and Kovacs, 1984; Trouillas et al., 1986; Kontogeor- Thyrotropic cell adenomas are rare and occur in the
gos et al., 1993). Unlike normal LH/FSH-producing setting of either hyper- (Gharib et al., 1982; Girod et
cells, those of gonadotrophic adenomas are usually al., 1986; Wynne et al., 1992) or hypothyroidism (Fa-
chromophobic and contain few peripherally situated, tourechi et al., 1984). The majority are chromophobic
PAS-positive granules. Immunostains show quite vari- tumors with only slight PAS-positivity. All are TSH and
able reactivity for FSH and/or LH (Fig. 18.23). The most are also -subunit immunoreactive. Electron mi-
same is true of -subunit staining. Occasional tumors croscopy of the relatively few thyrotroph cell adeno-
are entirely immunonegative, thus simulating null cell mas that have been studied shows sparse, often pe-
adenoma. Ultrastructurally, the neoplastic cells contain ripherally situated secretory granules as well as
only small numbers of 50–150 nm granules, many sub- cytoplasmic microtubules, particularly within cell pro-
plasmalemmal in location. The electron microscopic cesses. These ultrastructural features are unlike those
features of gonadotropic adenomas, particularly those of thyroid deficiency cells. The majority of TSH cell
of males, are variable; some are well differentiated, and adenomas are invasive macroadenomas.
others resemble null cell adenomas. In contrast, tumors
in females are recognized by a highly characteristic fea-
ture, vesiculation of the Golgi complex (Horvath and ADENOMAS UNASSOCIATED
Kovacs, 1984). WITH HORMONE PRODUCTION
The clinical features of gonadotrophic adenomas
have been well studied (Young et al., 1996). Most be- Null Cell Adenomas
come evident only when large enough to produce mass
effects on surrounding structures. The majority occur Approximately 20% of adenomas show no clinical ev-
in elderly persons or in the setting of longstanding hy- idence of hormone production (Ebersold et al., 1986),
A B
FIGURE18.23 Gonadotroph cell adenoma. Many such tumors show perivascular rosette formation and (A)
immunoreactivity for not only follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) but for
-subunit as well. (A) Hematoxylin and eosin; (B) LH immunostains.
A B
FIGURE 18.24 Null cell adenoma, nononcocytic type. This endocrinologically nonfunctional, chromo-
phobic tumor (A) usually lacks immunoreactivity for all but scant glycoprotein hormones, often -sub-
unit. (A) Hematoxylin and eosin; (B) -subunit immunostain.
scant if any hormone immunoreactivity, and an ultra- eosinophilic, strikingly granular cytoplasm (Fig. 18.25).
structural lack of specific differentiation. By definition Basic dyes and PAS stains are essentially negative in
such tumors are designated null cell adenomas. Their cy- both null cell adenoma variants. In most cases im-
togenesis remains the object of lively discussion (Kovacs munostains show minor glycoprotein reactivity; only
et al., 1990; Kontogeorgos et al., 1993). The formerly occasionally are rare GH- or PRL-reactive cell may be
used term undifferentiated cell adenomas should be dis-
carded because it implies anaplasia and aggressive be-
havior, neither of which is the case. Although most null
cell adenomas are metabolically inactive and show little
or no immunoreactivity for pituitary hormones (LH,
FSH, or subunit), it is unlikely that they represent a
homogenous tumor group (Kontogeorgos et al., 1993).
It is of interest that, in vitro, LH and FSH secretion may
be seen in response to gonadotropin-releasing hormone
(GnRH) have administration (Asa et al., 1986).
Depending upon their content of mitochondria, null
cell adenomas occur in either non-oncocytic or onco-
cytic form (Kovacs and Horvath, 1986). No prognos-
tic significance is attached to the degree of oncocytic
change. By light microscopy, non-oncocytic null cell
adenomas fall into the chromophobe group and can-
FIGURE 18.25 Null cell adenoma, oncocytic type. Aside from their
not be distinguished from other forms of sparsely gran- abundance of mitochondria, these tumors resemble nononcocytic null
ulated adenomas without immunohistochemical stud- cell adenomas in both clinical and pathologic terms. Hematoxylin
ies (Fig. 18.24). Oncocytic null cell adenomas have and eosin.
with suprasellar extension. Invasion is evident in ap-

proximately 40% of cases.
PITUITARY APOPLEXY
Abrupt hemorrhagic necrosis of a pituitary adenoma,

most often a nonfunctioning macroadenoma (Wakai et
al., 1981; Mohr and Hardy, 1982; Ebersold et al.,
1983), constitutes a surgical emergency. Although it oc-
curs in approximately 1% of pituitary adenoma cases,
a careful histologic review of routine adenomectomy
specimens shows some element of necrosis, degenera-
FIGURE 18.26 Null cell adenoma, nononcocytic type. Note paucity
tion, or cyst formation in nearly 10% (Horvath and
of organelles and of secretory granules. Kovacs, 1980; Mohr and Hardy, 1982). On occasion,
destruction of an adenoma causes resolution of en-
docrinopathy. Rarely, infarction follows endocrine test-
seen. Electron microscopy demonstrates sparse, often ing (Okuda et al., 1994).
peripherally situated secretory granules of very small Specimens derived from apoplexy cases often consist
size. Both rough endoplasmic reticulum and Golgi are of necrotic and/or hemorrhagic tissue in which only
poorly developed (Fig. 18.26). ghosts of neoplastic cells and the typical delicate vas-
Due to their lack of significant hormone production, culature of an adenoma are seen. Reticulin stains high-
null cell adenomas become clinically manifest due to light the latter and serve to confirm the presence of a
their mass effects. Virtually all are macroadenomas tumor (Fig. 18.27). Unless necrosis is subtotal, im-
A B
FIGURE 18.27 Pituitary apoplexy. This macroadenoma underwent hemorrhagic infarction. On hema-
toxylin and eosin stain (A), only the “ghosts” of adenoma cells remain. The basic architectural pattern
becomes evident on reticulin stain (B).
munostaining of apoplexy specimens is of no value tural studies have shown the transition of adenoma to
since nonspecific staining often results. ganglion cells (Scheithauer et al., 1991; Horvath et al.,
1994). With the exception of one pituitary carcinoma
in which the primary tumor was neuron-containing
NEURONAL DIFFERENTIATION IN (Scheithauer et al., 1991), the behavior of adenomas
PITUITARY ADENOMAS with neuronal metaplasia is that of ordinary adenomas.
This was even true of an example in which the neurons
Pituitary Adenomas with Neuronal Metaplasia appeared immature or neuroblastic (Lach et al., 1996).
Rarely, ganglion cells occur in pituitary adenomas.
Most, but not all (Asa et al., 1984b; Li et al., 1989;
Geddes et al., 2000), are GH-producing and functional. BEHAVIOR OF ADENOHYPOPHYSIAL TUMORS
Recent evidence indicates that they are not develop-
mental malformations (Asa et al., 1984b; Scheithauer Adenoma—Noninvasive and Invasive
et al., 1983b), but a manifestation of neuronal meta-
Pituitary adenomas with invasion of dura, bone, and
plasia of adenoma cells (Horvath et al., 1994). In sup-
sinus mucosa or cavernous sinus(s) are clinically and
port of this concept are: (1) the lack of the pituitary
pathologically distinct from ones showing only expan-
hyperplasia that should accompany excess growth hor-
sile or compressive growth. Certainly they grow more
mone–releasing hormone (GHRH) production, (2) im-
quickly (Landolt et al., 1987). Local or even extensive
munohistochemical and ultrastructural studies demon-
invasion, although a reflection of aggressive potential,
strating cells with transitional features, and (3) the
is not indicative of malignancy. The difficulty in iden-
recent demonstration of GHRH in pituitary adenomas
tifying tumors with aggressive potential is due to the
(Thapar et al., 1997).
rather benign microscopic appearance of even widely
Morphologically, ganglion cells may be few or nu-
infiltrative tumors. There are no reliable light micro-
merous; neuropil also varies (Fig. 18.28). In most cases,
scopic or ultrastructural features that distinguish inva-
adenoma cells lie clustered among the neurons. Tran-
sive from less aggressive adenomas. As presently de-
sitional cells feature ample cytoplasm, vesicular nuclei,
fined (Schaithauer et al., 2000), the same is true of
and sizable central nucleoli. Binucleation may be seen.
pituitary carcinoma (Scheithauer et al., submitted).
Fully developed neurons exhibit Nissl substance and
The incidence of invasion varies greatly depending
sizable processes. Neurons show both the hormone im-
upon whether gross (35%), radiographic (10%), or mi-
munoprofile of the adenoma cells, including epithelial
croscopic (80%) criteria are applied (Selman, 1986).
markers, and neuronal markers (class III tubulin and
It has become the practice to consider “invasive”
occasionally neurofilament protein) (Scheithauer et al.,
only those tumors found to be so on the basis of
1991). Nerve growth factor receptor may be seen in
radiographic or operative findings (Scheithauer et al.,
both cell types (Scheithauer et al., 1991). Ultrastruc-
1986b). In that invasion serves to decompress the sella,
hypopituitarism due to compressive effects and supra-
sellar extension occur less frequently than with expan-
sile, noninvasive adenomas. Among the presenting signs
of cavernous sinus invasion, cranial neuropathies result
from compression more often than invasion of cranial
nerves. Lastly, tumor extension along dural planes is
often seen. In addition to ensheathment nerves, inva-
sion of vascular adventitia and dural sinuses may also
be seen. As a rule, apposition of tumor to brain results
in compression rather than invasion. The frequency of
gross operative invasion as it relates to functional tu-
mor type is summarized in Table 18.4.
Modern methods are somewhat simplifying the iden-
tification of aggressive tumors. Although morphology
is a poor discriminator between noninvasive and inva-
sive adenomas, mitotic activity does differ (Thapar et
FIGURE 18.28 Neuronal metaplasia in pituitary adenoma. Note neu-
rons within substance of this prolactin (PRL) cell adenoma. Most al., 1996c). The same is true of MIB-1 labeling indices
such tumors are actually GH-producing and acromegaly-associated. (37% vs. 73%) and the frequency of p53 protein im-
Hematoxylin and eosin. munoreactivity in the two groups (0.7% vs 15%) (Na-
gashima et al., 1986; Thapar et al., 1996a,b; Gaffey et al., 1995). Most carcinomas are well differentiated but,
al., submitted a). The expression of cytokine inter- like meningiomas, their spectrum ranges from lesions
leukin-6 (Gandour-Edwards et al., 1996), heat-shock with little cellular atypia to occasional examples with
protein-27 (Gandour-Edwards et al., 1996), and type frank cytologic malignancy. Proliferative activity is not
IV collagenase (Kawamoto et al., 1996b) has also been closely linked to atypia. To further the analogy with
associated with invasiveness. The same is true of re- meningiomas, some adenomas are cytologically benign
duced expression of the metastasizing suppressor gene but widely infiltrative, a situation previously discussed.
NM-23 (Irofumi et al., 1995). Preliminary studies sug- Therefore, as with meningiomas and various other en-
gest that neither metalloproteinase (Kawamoto et al., docrine neoplasms, the definition of malignancy and its
1996a) nor cadherin expression significantly contrib- application are problematic (Kovacs et al., 1996; Per-
utes to invasiveness (Kawamoto et al., 1997). nicone et al., 1997; Scheithauer at al, 2000). The 2000
World Health Organization (WHO) classification
(Scheithauer et al., 2000) restricts the designation pi-
Atypical Adenoma
tuitary carcinoma to those rare lesions demonstrating
In order to identify tumors likely to be aggressive, a either or both craniospinal spread and metastasis to ex-
category intermediate between ordinary or “typical” tracranial sites—usually lymph nodes, liver, or bone
adenomas and pituitary carcinoma has been created (Kovacs et al., 1996; Pernicone et al., 1997; Scheithauer
(Kovacs et al., 1996; Pernicone et al., 1997; Scheithauer at al, 2000). Most carcinomas do feature increased mi-
at al, 2000). As a rule, such tumors are more often in- totic activity but not over malignancy in the histologic
vasive macroadenomas. By definition atypical adeno- or cytologic sense. Cellular pleomorphism and nuclear
mas exhibit increased proliferative activity (more than atypia can be seen but are of little or no prognostic sig-
occasional mitoses), an MIB-1 labeling index over 3%, nificance.
and often p53 immunoreactivity despite lack of a mu- Although ultrastructural studies have shown pitu-
tation (Kovacs et al., 1996; Pernicone et al., 1997; itary carcinomas to be less well differentiated than their
Scheithauer at al, 2000). Since these findings are asso- adenoma counterparts (Scheithauer et al., 1985b), the
ciated with invasion and/or recurrence, the designation prognostic significance of this finding remains to be de-
“atypical” earmarks even more potentially aggressive termined. Even though the presence of brisk mitotic ac-
tumors. The clinical usefulness of this category in iden- tivity suggests a higher likelihood of invasion and per-
tifying aggressive tumors and perhaps ones that might haps future metastatic spread, it is not an indicator of
metastasize remains to be seen. malignancy. Not all mitotically active adenomas pur-
sue an aggressive course. Conversely, tumors with few
mitoses have been known to metastasize. At present,
Other prognostic parameters
identifying pituitary carcinomas prior to metastasis re-
A number of studies have tried to correlate DNA con- mains an elusive goal. Only time will tell whether ear-
tent with tumor behavior (Anniko et al., 1984; Fitzgib- marking atypical adenomas (see above) will facilitate
bons et al., 1988; Gaffey et al., submitted ab). Although the early identification of carcinomas. Once metastases
some adenomas are aneuploid, this common abnor- become apparent, life expectancy is often less than 1
mality appears to be of little prognostic significance year (Pernicone et al., 1997), which underscores the
(Gaffey et al., submitted b). need for timely detection.
Cytogenetic studies have also sought to identify kary-
otypic patterns associated with aggressive behavior. In
one series, abnormalities were more frequent in hor- DIFFERENTIAL DIAGNOSIS
monally functioning tumors. These often involved chro-
mosomes 1, 4, 7, and 19 (Rock et al., 1993). No signif- First and foremost, the differential diagnosis of pitu-
icant differences were observed between invasive and itary adenoma must include normal or simply com-
noninvasive tumors, despite the fact that functioning tu- pressed anterior pituitary tissue. The distinction is of
mors are more often invasive (Scheithauer et al., 1986b). obvious importance but may be difficult with the small
specimens obtained at transsphenoidal resection. Since
the nuclear/cytoplasmic ratio of adenoma cells is often
Pituitary Carcinoma
higher than that of the normal gland, tissue sections
As a rule, pituitary carcinomas are endocrinologically tend to look “bluer.” Although adenomas are charac-
functioning tumors that produce prolactin, ACTH, or terized by cellular monotony, normal gland may also
growth hormone (Fitzgibbons et al., 1988). Nonfunc- appear monomorphous. This is particularly true of
tioning carcinomas are very uncommon (Beauchesne et specimens from the lateral wings wherein eosinophilic
GH cells abound are found in large number. In other tochemical and immunostains suffice in the process of
portions of the gland, one more readily sees a mix of differential diagnosis.
acidophilic, basophilic, and chromophobic cells. This
helpful variation in cytology is often obscured by
Pituitary Hyperplasia
frozen sections, but a good-quality permanent section
with hematoxylin and eosin usually reveals the nor- By definition, hyperplasia is a non-neoplastic increase
mal architectural pattern in which distinct acini are in cell number. Despite the once commonly held belief
encompassed by delicate sinusoidal vasculature. The that hyperplasia does not exist in the pituitary, there is
normal, often somewhat nodular, disposition of no doubt that it occurs and can be the cause of clini-
ACTH cells within the mucoid wedge also should cally and biochemically manifest disease (Saeger and
not be mistaken for adenoma. In contrast, adenoma Lüdecke, 1983). Hyperplasia can be focal, nodular, or
tissue is histologically monotonous and lacks the aci- diffuse and may involve any one and, in some instances,
nar pattern. The difference between normal pituitary several adenohypophyseal cell types. The condition is
and adenoma is most obvious on reticulin stain. difficult to diagnose, especially in small fragments of
Whether performed on frozen (Velasco et al., 1977) surgically removed tissues. Another complicating fac-
or permanent sections, it shows effacement of acinar tor in diagnosis is the fact that in the normal gland,
architecture. adenohypophyseal cells are unevenly distributed. Fur-
Smear or touch preparations are very useful in dis- thermore, corticotrophs may be somewhat nodular in
tinguishing pituitary adenomas from other lesions. Ad- disposition.
enoma cells are cytologically benign and possess an Growth hormone cell hyperplasia is usually diffuse
“endocrine” chromatin pattern. Mitoses are uncom- and occurs in association with hypothalamic hamar-
mon, but cellular pleomorphism, binucleation, and nu- toma (Asa et al., 1984b; Scheithauer et al., 1983b), ex-
cleolar enlargement are occasionally seen. Cytoplasmic trapituitary tumors (Thorner et al., 1982; Scheithauer
granulation varies among the different adenoma sub- et al., 1983b; Kovacs et al., 1984), producing growth
types but tends to be uniform in any one tumor. They hormone-releasing hormone (GHRH). Hypothalamic
detach individually rather than maintaining cohesion, dysregulation may also be a cause (Zimmerman et al.,
as characterizes metastatic carcinoma. Their nuclei also 1993). Accumulation of GH-producing cells is not seen
differ significantly from the anaplastic nuclei of meta- in pituitary tissue surrounding growth hormone cell
static carcinomas (Branch and Laws, 1987; Marin et adenomas of acromegaly. However, mammosoma-
al., 1992) and those of other sellar region and skull totroph cell hyperplasia may be seen in the setting of
base tumors, such as meningioma (Grisoli et al., 1983; gigantism (Zimmerman et al., 1993).
Solero et al., 1983) and plasmacytoma (Bilbao et al., Prolactin cell hyperplasia is most often diffuse, but
1978; Urbanski et al., 1980). may be focal or nodular. It occurs in pregnancy (Schei-
Also to be excluded are other monomorphous or thauer et al., 1990; Stefaneanu et al., 1992), lactation,
small cell tumors occurring in the sellar region, in- estrogen treatment (Mountcastle et al., 1989), long-
cluding lymphoma, germinoma (Ghatak et al., 1969; standing primary hypothyroidism (Pioro et al., 1988),
Poon et al., 1988), paraganglioma (Zambaziotis et al., and rarely in the nontumorous adenohypophysis har-
1999) and glomangioma (Asa et al., 1984a). Although boring a prolactin cell adenoma. Prolactin cell hyper-
rare salivary gland tumors primary in the sellar region plasia may also be present in patients with GRH-
must be considered (Hampton et al., 1997). Carcinoma producing extrapituitary tumors. Prolactinomas in as-
metastatic to a pituitary adenoma has been reported on sociation with lactotroph hyperplasia have been re-
more than one occasion (Molinatti et al., 1985; Post et ported to occur in the rat (Kovacs et al., 1977).
al., 1988; Ramsey et al., 1988). Even less frequent is Corticotroph cell hyperplasia, either nodular or dif-
the occurrence of ectopic suprasellar adenohypophy- fuse, may be the basis of Cushing’s disease (Figs. 18.29,
seal tissue clinically mimicking an adenoma (Colohan 18.30). It has been reported in patients with corti-
et al., 1986). Pituitary adenomas may closely mimic cotropin-releasing hormone (CRH) producing extrapi-
oligodendroglioma and ependymoma but, with the ex- tuitary tumors (Carey et al., 1984; Wakabayashi et al.,
ception of rare astrocytic tumors, gliomas do not enter 1985; O’Brien et al., 1992) and is occasionally seen in
into the differential diagnosis of adenoma. the nontumorous adenohypophysis harboring a corti-
The distinctive immunohistochemical features of var- cotrophic adenoma (Saeger and Lüdecke, 1983). Un-
ious of these neoplasms are summarized in Table 18.6. derstandably, it is a regular feature in Addison’s dis-
Although electron microscopy plays a role in the clas- ease (Scheithauer et al., 1983a). In rare instances,
sification of some adenomas, in most cases routine his- corticotropic hyperplasia has no apparent etiology
TABLE 18.6 Immunostaining in the Differential Diagnosis of Sellar and Perisellar Lesions
Astrocytoma
(Pituicytoma),
Oligodendro- Granular
Pituitary Olfactory glioma, Cell
Staininga Adenomab Carcinoma Melanoma Germinoma Meningioma Chordoma Neuroblastoma Lymphoma Myeloma Ependymoma Tumor Paraganglioma Schwannoma
Pituitary //
hormones
Keratin (10%) 5% //
EMA e //g
S-100 10%c 20% // i
protein
CEA 5% / /
Vimentin 10%d f // h ?
Neuro- // ?
filament
GFAP // +j
Leuk C Ag //
Ig light //
chains
aEMA, epithelial membrane antigen; CEA, carcinoembryonic antigen; Leuk C Ag, leukocyte common antigen.
bSee Lloyd et al. (94).
cBreast and müllerian carcinomas.
dCarcinomas of thyroid, kidney, and adrenal, and germ cell tumors.
eLymphocytoplasmacytoid and pleomorphic large cell (Ki-1) lymphomas.
fApproximately 50% of large cell lymphomas.
gParanuclear and occasional membranous staining may be observed in the ependymoma.
hCytoplasmic lysosomes may produce artifactual positivity.
iSustentacular and often chief cells react.
jSustentacular cells may react.
plastic transformation than normal cells, (3) hyper-

plastic cells can transform to tumor cells, and (4) what
the underlying mechanism of hyperplasia is.
Inflammatory Lesions
Lymphocytic hypophysitis
In addition to Sheehan’s syndrome, which results from
intrapartum shock with accompanying ischemic necro-
sis of the anterior pituitary, pituitary insufficiency of
pregnancy or the postpartum period may also result
from an autoimmune process termed lymphocytic hy-
pophysitis (Asa et al.,1981; Baskin et al., 1982; Cos-
FIGURE 18.29 Corticotroph cell hyperplasia. Note aggregation of man et al., 1989). Although originally described in the
adrenocorticotropin (ACTH) immunoreactive cells into a large clus- autopsy literature, cases are increasingly coming to light
ter. ACTH immunostain.
during life (Thodou et la., 1995). The vast majority
occur in females and are pregnancy-associated. The
mechanism of immune injury appears to be both hu-
(Young et al., 1988). Such primary hyperplasia may re-
moral—the result of the development of antipituitary
sult from an undisclosed hypothalamic stimulus.
antibodies—and cellular. The lymphoplasmacytic infil-
Thyrotroph cell hyperplasia is a distinct finding in
trate contains B as well as T cells. Microscopically, sim-
the pituitaries of patients with longstanding primary
ilar lesions may be present in other organs including
hypothyroidism (Scheithauer et al., 1985a; Pioro et al.,
the thyroid adrenals and ovaries. Although panhy-
1988). It can be nodular or diffuse and is readily iden-
popituitarism is the rule, on rare occasions, isolated pi-
tified in immunostained sections. Prolactin cell hyper-
tuitary hormone deficiencies result (Jensen et al., 1986).
plasia is a common accompaniment, the stimulatory
In that prolactin elevations commonly accompany
result of thyrotropin-releasing hormone (TRH) pro-
(“stalk section effect”) sellar lesions, one must be cau-
duction by the hypothalamus.
tious not to reflexly interpret a sellar mass associated
Gonadotroph cell hyperplasia is not well defined, but
with hyperprolactinemia as a prolactinoma, especially
it can be seen in the pituitaries of patients in whom pri-
in pregnancy. Treatment of lymphocytic hypophysitis
mary hypogonadism commenced at a young age. Fur-
consists of a decompressive biopsy and hormone re-
ther work is required to establish the morphologic cri-
placement. The specimen is characteristically yellow
teria for its diagnosis. It remains to be determined
and firm to rubbery. Microscopically, it consists of a
whether (1) hyperplasia is a predecessor of adenoma,
lymphoplasmacytic and, to a lesser extent, a histiocytic
(2) hyperplastic cells are more prone to undergo neo-
infiltrate within the interstitium and in pituitary cords
(Fig. 18.31). Germinal centers may be noted. In chronic
phases, destruction of pituitary parenchyma results in
fibrosis. Lymphocytic hypophysitis should not be con-
fused with the small lymphocytic infiltrates occasion-
ally observed in the intermediate zone of normal pitu-
itary glands.
Giant cell granuloma of the pituitary

Giant cell granuloma of the pituitary is a rare condi-
tion that affects the anterior pituitary of adults. Unlike
lymphocytic hypophysitis, it shows neither a sex pre-
dilection nor an association with pregnancy (Doniach
and Wright, 1951; Del Pozo et al. 1980; Taylon and
FIGURE 18.30 Corticotroph cell hyperplasia (same patient as in pre- Duff, 1980; Siqueira et al., 1989). The infiltrate con-
vious figure). The marked expansion of this same acinus by the hy- sists of noncaseating granulomas with accompanying
perplastic ACTH cells is evident on reticulin stain. destruction of pituitary parenchyma, as well as fibro-
the syndrome results from spontaneous infarction of

the normal gland or of an adenoma.
Rathke’s Cleft Cyst

Cysts derived from Rathke’s cleft, a remnant of the an-
lage of the anterior pituitary, are a common autopsy
finding. Symptomatic examples are uncommon, usually
measure greater than 1 cm in diameter, and produce
visual disturbance as well as hyperprolactinemia
(Yoshida et al., 1977; Steinberg et al., 1982). Resection
is curative.
Uniloculate and thin-walled, Rathke’s cleft cysts con-
tain watery-to-mucinous fluid. Microscopically, their
FIGURE 18.31 Lymphocytic hypophysitis. This lesion was pregnancy-
lining consists of goblet, ciliated, and to a lesser extent,
associated and consists of a lymphoplasmocytic infiltrate in the an-
terior pituitary. Hematoxylin and eosin. secretory cells of anterior pituitary type. Unusual fea-
tures of Rathke’s cleft cyst include squamous metapla-
sia, xanthogranulomatous inflammation, and amyloid
deposition (Concha et al., 1975). Rathke’s cleft cysts
sis (Fig. 18.32). Schaumann bodies of the type seen in are occasionally seen in association with pituitary ad-
sarcoidosis may be seen, but lymphocytic hypophysi- enoma—no surprise given the high (nearly 25%) fre-
tis is unassociated with posterior pituitary or hypo- quency of incidental adenomas (Concha et al., 1975).
thalamic involvement, or with systemic evidence of The relationship of such concurrent lesions to the so-
sarcoidosis. Understandably, microbiologic studies called “transitional tumor,” a unique lesion exhibiting
and stains for organisms are necessary to exclude an features of both Rathke’s cleft cyst and adenoma
infectious process, particularly tuberculosis or fungal (Kepes, 1978; Nishio et al., 1987; Nakasu et al., 1989),
infection. remains unclear.
Empty Sella Syndrome Miscellaneous Lesions

Although a misnomer, empty sella syndrome refers to The scope of this chapter precludes a discussion of a
an anatomic state in which the sella appears rather variety of medical disorders; reviews and miscellaneous
empty (Spaziante et al., 1981). Two major types are references abound (Horvath and Kovacs, 1980; Whitaker
known: et al., 1985; Scheithauer et al., 1988, 1997a,b; Sano et
Primary empty sella syndrome is probably develop- al., 1989; Horvath et al., 1997).
mental in origin and results from incomplete develop-
ment of the sellar diaphragm, which permits the arach-
noid membrane to descend through the defect. Not
surprisingly, the abnormality may be seen in children
(Nass et al., 1986). Invagination of the arachnoid mem-
brane into the pituitary fossa results in compression of
the pituitary. In that the sella may be enlarged, radio-
graphic studies often suggest the presence of a tumor.
The lesion is usually asymptomatic, but occasional pro-
lapse of the optic chiasm results in visual field defects.
In addition, traction on the pituitary stalk may produce
hyperprolactinemia (“stalk section effect”). On occa-
sion, empty sella and pituitary adenoma coexist
(Gharib et al., 1983).
Secondary empty sella syndrome refers to a situation
in which the sellar contents are reduced in volume due FIGURE 18.32 Giant cell hypophysitis. This lesion occurred in a mid-
dle-aged woman with hypopituitarism and was limited to the ante-
to tissue loss. It is most commonly seen after resection
rior pituitary gland. It was unassociated with systemic disease and
or irradiation of an intrasellar tumor. Less frequently, contained no microorganisms. Hematoxyin and eosin.
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19 Tumors of the peripheral nervous
system (including the craniospinal
nerve roots)
CATERINA GIANNINI AND BERND W. SCHEITHAUER
The pathologic spectrum of tumors of the peripheral ner- saying that careful correlation of morphologic data
vous system (PNS) is broad, despite their derivation from with clinical and surgical descriptions is essential to ar-
a rather limited repertoire of nerve sheath cells. Putative riving at a correct diagnosis.
precursor cells subject to neoplastic transformation re-
side in all three nerve compartments (endo-, peri-, and
epineurium). These include: (1) Schwann cells, which en- BENIGN TUMORS OF PERIPHERAL NERVE
sheath myelinated and unmyelinated axons, (2) per-
ineurial cells that comprise the perineurium and are an The two principal tumors of peripheral nerve are
integral part of the blood–nerve barrier, and (3) fibro- schwannoma and neurofibroma. Their comparative
blasts, endothelial cells, and pericytes, as well as adipose features are summarized in Table 19.2.
cells. Tumors of peripheral nerves occur in benign and
malignant form and show a variable association with
Schwannoma and Its Variants
neurofibromatosis of types 1 (von Recklinghausen’s dis-
ease, peripheral NF, NF1) and 2 (central NF, NF2). A By definition, schwannomas are benign, generally en-
discussion of the genetic basis and clinical spectrum of capsulated tumors composed of cells with advanced
these disorders appears in Chapter 20. schwannian differentiation. This is evident at the light
The currently accepted classification of peripheral microscopic, immunohistochemical, and ultrastructural
nerve tumors includes: (1) neoplasms showing differ- level. As the most common tumors of peripheral nerve,
entiation along neurogenic lines, these being the most they occur in several histologic forms, at all ages but
numerous, (2) tumors with mesenchymal or other lines peaking in incidence between the fourth and six
of differentiation, but primary in nerve, and (3) tumors decades, and show no sex predilection (with the ex-
secondarily involving the PNS. The classification of ception of intracranial lesions, which favor females at
principal peripheral nerve tumors is summarized in a ratio of 2:1).
Table 19.1. It follows the general guidelines of the The vast majority of conventional schwannomas are
World Health Organization (Kleihues et al., 1993), and solitary, sporadically occurring tumors. Only very small
of the recently published AFIP fascicle, Tumors of the subsets are typically multiple, those occurring in the
Peripheral Nervous System (Scheithauer et al., 1999). setting of neurofibromatosis type 2 (NF2) and in
The PNS also gives rise to a variety of non neoplastic schwannomatosis, an only recently defined condition
lesions that clinically mimic peripheral nerve neo- (Izumi et al., 1971; MacCollin et al., 1996). As a whole,
plasms. These include reactive, inflammatory, hyper- schwannomas most frequently affect sensory nerves,
plastic, and malformative processes (see Table 19.4). A such as the vestibular nerve(s) and dorsal spinal nerve
working knowledge of normal PNS anatomy, as well roots. Located on chromosome 22q12, the NF2 gene
as of the basic responses to injury exhibited by this encodes for merlin, a protein closely related to the pro-
highly specialized tissue, provides insight into the broad tein 4.1 family of cytoskeleton-associated proteins
spectrum of lesions discussed herein. For a more ex- (MacCollin et al., 1994; Louis et al., 1995; Kleihues
haustive overview, the reader is directed to recent re- and Cavanee, 2000). The latter are primarily involved
view (Scheithauer et al., 1999). Lastly, it goes without in linking integral membrane proteins with the cy-
425
TABLE 19.1 Peripheral Nerve Tumors

Benign Malignant
Schwannoma MPNST
Conventional Epithelioid
Cellular With divergent differentiation
Plexiform Melanotic (malignant melanotic
Melanotic (psammomatous) schwannoma)
Arising in schwannoma
Neurofibroma Arising in ganglioneuroma/
ganglioneuroblastoma
Diffuse
Arising in paraganglioma
Localized
Perineurial
Plexiform
Massive soft tissue
Primitive neuroectodermal tumor
(PNET) neuroepithelioma
Perineurioma
Malignant granular cell tumor
Intraneural
Lymphoma
Soft tissue
Secondary/metastatic tumors
Dermal nerve sheath myxoma Carcinoma

Melanoma
Neurothekeoma
Sarcoma
Granular cell tumor
Lymphoma
Ganglioneuroma
Others
Paraganglioma
Lipoma
Hemangioma
“Angiomatosis”
Hemangioblastoma
toskeleton. Mutations of the NF2 gene are also found origin is identified in less than 50% of cases. Rare tu-
in a large proportion of sporadic schwannomas (Jacoby mors are “intraosseous” (Emory et al., 1993). Of these,
et al., 1994). The occurrence of multiple, histologically most affect the mandible, wherein they arise at the level
proven schwannomas without associated vestibular tu- of the dental foramen (Spjut et al., 1971). Less frequent
mors or other manifestations of NF2 is recognized as a are examples arising in a vertebral body (Polkey, 1975).
clinically and genetically distinct condition. Termed Schwannomas arising from nerve roots, more often
schwannomatosis, it appears to represent a distinct vari- sensory than motor, may be located in the paraspinal
ant of neurofibromatosis (MacCollin et al., 1996; Ja- region, posterior mediastinum, retroperitoneum, and
coby et al., 1997; Jacoby et al., 1999). Solitary schwan- sacrum. Of these, some show central extension through
nomas are only rarely encountered in NF1. Radiation- an intervertebral foramen. It is in the cervicothoracic
induced schwannomas have also been reported (Shore- region that lesions often exhibit sizable intra- and ex-
Freedman et al., 1983; Salvati et al., 1992; Sznajder et traspinal components (“dumbbell” tumors) (Fig. 19.1).
al., 1996) but, as a rule, are solitary lesions histologi- As a rule, schwannomas occurring in the cauda equina
cally indistinguishable from conventional schwannomas. are entirely intradural, lie distal to the conus medullaris,
Outside the craniospinal axis, the most common sites are sausage shaped, and displace surrounding nerve
of occurrence of conventional schwannomas are the roots. Intracranial schwannomas most often arise in the
head and neck region and the flexor surfaces of the ex- vestibular portion of the 8th cranial nerve (Kleihues
tremities. Their location is generally deep. A nerve of and Cavanee, 2000). The 9th and 10th cranial nerves
19: TUMORS OF THE PERIPHERAL NERVOUS SYSTEM 427
TABLE 19.2 Clinicopathologic Distinction of Schwannoma and Neurofibroma

Schwannoma Neurofibroma*
Non-NF1 associated/occasional NF2 associated NF1 associated/non-NF2 associated

Frequently affects extremities Frequently involves the trunk
Usually solitary Frequently solitary
Nerve often identified Nerve infrequently identified
Eccentric to nerve Incorporates nerve
Globular Globular, fusiform, or diffuse
Encapsulated Delicately surrounded by perineurium and epineurium (solitary and plexiform
neurofibroma); no capsule (diffuse neurofibroma)
Nonmucoid, soft to firm Mucoid and firm
Tan to yellow, opaque Gray-tan, opalescent
Occasionally cystic Noncystic
High cellularity Low-to-moderate cellularity
Biphasic Antoni A and B patterns Uniphasic pattern with gradual changes in cellularity
Scant or no stromal mucin Mucin-rich matrix
Axons often absent Axons often present
Palisading and Verocay bodies Wagner-Meissner or rarely Pacinian-like corpuscles; no palisading
Composed of Schwann cells Composed of Schwann cells, perineurial-like cells, fibroblasts, and transitional cells
Mast cells infrequent Mast cells frequent
Malignant transformation extremely rare Malignant transformation rare (2% of patients with NF1)
*Exclusive of plexiform neurofibroma.
are less often affected. Visceral schwannomas most af- et al., 1976), and kidney (Scheithauer et al., 1999) has
fect the gastrointestinal tract, particularly the stomach also been reported. Rarely, schwannomas arise in the
(Daimaru et al., 1988; Melvin and Wilkinson, 1993; sella, cavernous sinus, brain, or spinal cord parenchyma
Sarlomo-Rikala and Mieltinen, 1995). Whereas most (Goebel et al., 1979; Inoue et al., 1990), or within a
are incidental findings, some present with pain or hem- lateral cerebral ventricle (Casadei et al., 1993). The lat-
orrhage due to overlying mucosal ulceration. Involve- ter presumably originate in the tela choroidea, either
ment of the heart (Factor et al., 1976), lung (Silverman from nerve twigs innervating the meninges or from ec-
topic Schwann cells.
On CT or MRI, schwannomas appear as sharply cir-
cumscribed masses showing either uniform or hetero-
geneous enhancement, a reflection of their cellular com-
position and the presence of degenerative changes such
as cyst formation, hemorrhage, or necrosis. At the
macroscopic level, most schwannomas are globular,
smooth surfaced tumors measuring less than 10 cm in
greatest diameter (Fig. 19.2). Occasional tumors, espe-
cially in skin or subcutaneous tissue, are multinodular
or plexiform. Peripheral tumors are surrounded by a
distinct, often thick collagenous capsule. A parent nerve
is identifiable in less than half of cases, usually in in-
stances wherein the nerve is sizable (Fig. 19.2). On cut
surface, they vary from solid to cystic and in color from
tan to bright yellow. The latter is a reflection of lipid
FIGURE 19.1 Schwannoma. This drawing illustrates the characteristic
“dumbbell” appearance often seen in spinal examples with an intra- accumulation within tumor cells. Large tumors often
and paraspinal component. Note spinal cord compression and ex- show poorly formed bands of fibrosis, as well as de-
pansion of the nerve foramen. Cystic degeneration is also apparent. generative changes including hemorrhage related to
these areas as are thick-walled, hyalinized and thin-

walled, ectatic vessels (Fig. 19.6). Thrombosis with or
without necrosis, as well as perivascular hemosiderin
deposits, is also common. Since schwannomas are solid,
noninfiltrative tumors that come to lie eccentric to their
parent nerve (Fig. 19.7), residual nerve fibers are not
dispersed throughout the substance of the lesion. In-
stead, they lie bundled in its capsule or, on occasion,
in subcapsular portions of the tumor.
Advanced degenerative nuclear changes, including
marked pleomorphism, hyperchromasia, and cytoplas-
mic pseudoinclusion formation, are commonly seen in
longstanding schwannomas (Fig. 19.8). Such features
of “ancient schwannomas” are of no prognostic sig-
FIGURE 19.2 Sacral schwannoma. Note the parent nerve embedded nificance. As in conventional schwannomas, mitoses
in the capsule of this solid, globular tumor. are absent or scant and MIB-1 labeling indices are low.
While bona fide cartilaginous, osseous, and even adi-
pose metaplasia is occasionally seen in schwannomas,
vascular sclerosis, cystic changes, and calcification reports of “glandular” differentiation in cutaneous
(Fig. 19.3). schwannomas probably represent entrapped cutaneous
Microscopically, schwannomas consist entirely of adnexae rather than divergent epithelial differentiation
neoplastic Schwann cells arranged in two basic tissue (Scheithauer et al., 1999). Pseudoepithelial change in
patterns termed Antoni A and B (Fig. 19.4). Their rel- the lining of degenerative cysts is, however, a common
ative proportions and the transition between them vary, finding.
giving rise to an ample morphological spectrum. An- By immunohistochemistry and at the ultrastructural
toni A tissue consists of compact, spindled cells with level, the neoplastic cells comprising schwannomas of
large, elongate, blunt-ended nuclei, often with ample all types exhibit highly distinctive features and closely
pink cytoplasm and no discernible cell borders (Fig. resemble normal Schwann cells. Immunoreactivity for
19.4A). Collagen is rather abundant as is evident on S100 protein is uniform and strong (Johnson et al.,
reticulin or trichrome stains. It is in Antoni A tissue 1988; Jacoby et al., 1994). Glial fibrillary acidic pro-
that one sees Verocay bodies, alternating arrangements tein (GFAP) immunoreactivity is present in fully half
of palisaded nuclei and cell processes (Fig. 19.5). An- of schwannomas (Jacoby et al., 1994; Johnson et al.,
toni B tissue consists of loosely arranged cells with mul- 1988, Kawahara et al., 1988). In addition, collagen IV
tipolar processes set in a pale mucopolysaccharide-rich and laminin stains highlight the presence of a pericel-
matrix (Fig. 19.4B). Microcyst formation is frequent in lular basement membrane (McComb and Bigner, 1985;
A B
FIGURE 19.3 Schwannoma. Degenerative phenomena, including hemorrhage (A) and cystic change (B)
are frequent findings, especially in sizable tumors.
A stromal long-spacing collagen (“Luse bodies”) (Er-

landson, 1994; Scheithauer et al., 1999).
Cellular schwannoma
Originally described by Woodruff et al., this variant of
schwannoma is characterized by high cellularity, a pre-
dominant Antoni A pattern, and absence of well-
formed Verocay bodies (Woodruff et al., 1981). Cel-
lular schwannoma occurs at any age, its maximal
incidence being in the fourth decade. Females are twice
as often affected. Generally solitary, this tumor has no
significant association with neurofibromatosis (Jacoby
B et al., 1994; Scheithauer et al., 1999). Cellular schwan-
noma is unrelated to and should not be confused with
a well-differentiated malignant peripheral nerve sheath
tumor (MPNST). As a benign tumor, it permits nerve-
sparing surgery and does not require adjuvant therapy.
Common sites of occurrence of cellular schwannoma
include the paravertebral region of the mediastinum,
the retroperitoneum, and the pelvis (Casadei et al.,
1995). Cranial nerves may also be affected, most often
the fifth and the eighth. Like conventional schwanno-
FIGURE 19.4 Schwannoma. Two principal histologic patterns typify

these tumors. Antoni A tissue (A) consists of spindle cells with elon-
gated nuclei arranged in fascicles, an obviously schwannian feature,
whereas Antoni B pattern (B) is loose textured and composed of
Schwann cells with round nuclei and delicate, cobweblike processes.
Scheithauer et al., 1999). Ultrastructural features in-

clude cytoplasmic intermediate filaments, intertwining
cytoplasmic processes occasionally surrounding colla-
gen bundles (“mesaxon formation”), pericellular base-
ment membranes which are often reduplicated, and
FIGURE 19.5 Schwannoma. In Antoni A tissue, nuclei and cell processes FIGURE 19.6 Schwannoma. Common degenerative changes include
are often aligned and staggered to form distinctive Verocay bodies. the presence of thick, hyalinized vessels (A) and cyst formation (B).
high-power fields (HPF) are commonly seen; excep-

tional examples may show 10 or even more. Their ul-
trastructural features are also uniformly those of well-
differentiated Schwann cells. Cellular schwannomas
show strong diffuse immunoreactivity for S-100 pro-
tein and collagen IV/laminin, as well as frequent GFAP
staining (Fletcher et al., 1987; White et al., 1990;
Deruaz et al., 1993; Casadei et al., 1995). Given their
morphologic features, particularly high cellularity and
mitotic activity, cellular schwannomas are often mis-
taken for MPNST. This is particularly true in biopsy
specimens. Obviously, the differential diagnosis is crit-
ical (Table 19.3).
FIGURE 19.7 Schwannoma. These smooth-surfaced, encapsulated tu- Plexiform schwannoma

mors begin as a microscopic nodule within a nerve fascicle. With
continued growth, they become eccentric to the parent nerve, thus Defined as growing in a plexiform or multinodular pat-
permitting a nerve-sparing resection. tern, this variant of schwannoma is generally superfi-
cial in location. It affects dermal and subcutaneous tis-
sue most often and occurs in the extremities, followed
mas, they grossly appear well circumscribed and en- by the head and neck region, and trunk (Scheithauer et
capsulated (Fig. 19.9). Their average size is 5 cm, but al., 1999) (Fig. 19.10). Only rare examples arise in mu-
examples up to 20 cm in diameter have been reported. cosae or at visceral sites (Woodruff et al., 1983b; Bar-
On cut surface, cellular schwannomas are more fleshy bosa and Hansen, 1984; Hirose et al., 1997a). Plexi-
and homogeneous than conventional examples. Cystic form schwannomas preferentially affect young adults
degeneration and/or hemorrhage is infrequent. Micro- and show no sex predilection. Although they are not
scopically, the relatively high cellularity and predomi- specifically associated with NF1 or NF2, some occur
nance of Antoni A tissue in cellular schwannomas is in patients with multiple schwannomas (schwanno-
unaccompanied by Verocay body formation. Subcap- matosis). The prognosis is excellent following local ex-
sular or perivascular lymphocytic infiltrates are cision. Recurrence is infrequent.
commonly seen. The cytologic features are those of
schwannomas, with uniform, elongate, often sinuous
Melanotic schwannoma
and tapered nuclei as well as eosinophilic cytoplasm
(Fig. 19.9). Mitoses vary in number. Indices of 1–4/10 This unique tumor is defined by its composition of well-
differentiated Schwann cells featuring melanosomes.
Melanin production is variable. Since Hodson’s first de-
scription of a somatic nerve example and its correct
identification as a schwannoma (Hodson, 1961), more
than 70 cases have been described (Scheithauer et al.,
1999). Melanotic schwannomas are rare, occur at all
ages with a peak in the third decade, and show a slight
female predominance (1.4:1). Many, but not all, in-
volve identifiable nerves, either somatic or autonomic.
Spinal nerves are most often affected (46%), followed
by cranial nerves, sympathetic ganglia, and autonomic
nerves of the gastrointestinal tract. Unlike conventional
schwannomas, melanotic tumors are relatively demar-
cated but not well encapsulated. Typical examples are
composed of spindle cells with some tendency to whorl
formation and occasional palisading of nuclei. Epithe-
FIGURE 19.8 Schwannoma. Degenerative nuclear changes include
marked pleomorphism, hyperchromasia, and cytoplasmic pseudoin- lioid cells are also a common feature. Stromal histio-
clusion formation. These features typify so called “ancient schwan- cytes, a frequent finding, are often more heavily pig-
nomas.” mented than the neoplastic cells. In some cases overall
C D
FIGURE 19.9 Cellular schwannoma. These well-circumscribed, encapsulated tumors are more fleshy than
conventional schwannomas (A). The Antoni A pattern predominates (B). Individual cells are enmeshed
in reticulin (C). Proliferative activity is evidenced by low to moderate mitotic activity (D) and MIB-1
labeling (D).
pigmentation is so great as to obscure cytologic detail 1986; Carney, 1990). The last includes primarily Cush-
and to require hydrogen peroxide “bleaching.” Uni- ing’s syndrome due to bilateral multinodular adrenal
form immunoreactivity for S-100 protein is the rule, cortical hyperplasia, and acromegaly due to pituitary
but collagen IV or laminin staining varies somewhat adenoma.
from dense and intercellular to partly lobular. Ultra- Approximately 10% of melanotic schwannomas fol-
structural features are those of well-differentiated low a malignant clinical course characterized by re-
Schwann cells which vary in shape and in intermediate currence, aggressive behavior, and/or metastasis. His-
filament content. Long-spacing collagen may also be tologic findings common to clinically malignant tumors
seen. Variably pigmented melanosomes vary in num- include large vesicular nuclei, violaceous macronucle-
ber but are present by definition. oli, frequent and occasionally abnormal mitoses, as well
Approximately half of melanotic schwannomas con- as ample necrosis.
tain psammoma bodies. The distinction of “psammo-
matous” from conventional melanotic schwannomas is
Neurofibroma
of importance, since approximately 50% of psammo-
matous tumors are associated with the Carney’s Neurofibroma is a benign peripheral nerve sheath tu-
complex, a dominantly inherited autosomal disorder mor composed of an admixture of Schwann, perineur-
characterized by spotty, often facial, lentiginous pig- ial, and fibroblastic cells, as well as of cells with inter-
mentation, myxomas of heart, skin, or breast, and en- mediate features. Unlike schwannomas, they permeate
docrine overactivity (Carney et al., 1985; Carney et al., their parent nerve, overrunning residual myelinated and
TABLE 19.3 Conventional Schwannoma, Cellular Schwannoma, and MPNST: Differential Diagnosis
Findings Classical Schwannoma Cellular Schwannoma MPNST
Gross Usually globoid encapsulated tumor that has Usually globoid encapsulated tumor, firmer Fusiform or globoid, pseudocapsulated
abundant homogenous light tan tissue, than classical schwannoma, and (infiltrative of surrounding tissues),
and may be cystic or hemorrhagic and homogeneously tan. Occasionally firm, cream-tan, usually grossly
show yellow patches. No gross necrosis patches of yellow, but no gross necrotic tumor
necrosis
Microscopic Antoni A and B areas with Verocay bodies; Mainly hypercellular Antoni A tissue. Cells Markedly hypercellular, fasciculated, spindle
commonly find hyalinized thick-walled are arranged in fascicles or whorls and cell tumor generally consisting of cells
blood vessels and lipid-laden may show marked hyperchromasia and of a uniform size and pronounced
histiocytes. Mitotic figures infrequently nuclear pleomorphism. Notable are hyperchromasia. Geographic necrosis
present. Extremely rare see malignant lymphoid deposits in capsule or and mitotic counts in excess of 4/10
transformation perivascular area. Commonly find HPF are common. Epithelioid cells
thick-walled blood vessels and predominate in about 5% of
collections of lipid-laden histiocytes. tumors and 15% show
Rare foci of necrosis. Mitoses not heterologous glandular or sarcomatous
uncommon but usually number no elements
more than 4/10 HPF
Immunohistochemical Diffuse and strong expression of S-100 Diffuse and strong expression of S-100 S-100 protein expression in scattered cells of
protein protein 50–70% of cases
Electron microscopy Well-differentiated cells with long, often Similar to classical schwannoma. Increased Poorly differentiated cells with more
interlacing cytoplasmic processes coated cellularity. More nuclear atypia and pleomorphic nuclei, thick cytoplasmic
by basement membrane on their free occasionally residual arrays of long, processes, and sometimes patchy
surfaces. Intercellular long-spacing basement membrane-coated basement membrane. Long spacing
collagen common cytoplasmic processes. Long-spacing collagen rarely seen
collagen less common
Clinical behavior May cause bone erosion and can recur if May cause bone erosion and recur if Has a proclivity to invade and destroy
incompletely excised. Thus far 5 incompletely excised. Thus far no nearby soft tissues, recur locally, and
reported examples with malignant clinically malignant examples metastasize distantly (usually to lung).
transformation that followed a malignant About 90% are high-grade
clinical course lesions
A fuse cutaneous neurofibromas form large, ill-defined

plaques in dermis and subcutaneous tissue, but their
texture is similar to that of the localized form. These
tumors and ones with a mixed growth pattern are of-
ten seen in NF1. Localized intraneural neurofibromas,
such as those involving nerve trunks, are characterized
by fusiform enlargement of the nerve that may be mi-
nor or massive. They come to clinical attention either
as a visible or palpable lesion of superficial soft tissues.
When deeply situated, they may cause neurologic, of-
ten sensory symptoms in a nerve distribution. Lesions
associated with NF1 are often proximal where they in-
volve spinal nerve roots, frequently at the cervical level
(Harkin and Reed, 1969; Woodruff et al., 1983a; Hal-
B liday et al., 1991). Unlike schwannomas, they lack a
thick capsule and are white and translucent in appear-
ance (Fig. 19.13). In favorably oriented sections, either
transverse or midlongitudinal, residual nerve fibers may
be visible at their centers. These are particularly evi-
dent on myelin or axon stains. The plexiform neurofi-
broma, a highly distinctive lesion, tends to affect siz-
able nerves (Fig. 19.14A). By definition, such tumors
involve separate nerve fascicles (Fig. 19.14B). When oc-
curring in nonbranching nerve, they result in a ropy le-
sion in which the strands remain apposed. In contrast,
a complex tangle results when a branching nerve is af-
fected. When massive, such tumors produce marked de-
formity of the affected regions. Plexiform neurofibroma
FIGURE 19.10 Plexiform schwannoma. This longstanding tumor,
present for over 50 years, involves skin and subcutaneous tissue. Note may also involve viscera (Fig. 19.15). A diagnosis of
gross nodularity (A) and obvious schwannian differentiation with plexiform neurofibroma, particularly of a major nerve,
Verocay body formation (B). (A) was reproduced with permission is pathognomonic of NF1. Approximately 5% of plex-
from Hirose et al. (1997). iform neurofibromas undergo malignant transforma-
unmyelinated nerve fibers (Fig. 19.11). The essential

differences between these two most common types of
PNS tumors are summarized in Table 19.2.
Neurofibromas are common. Most are solitary le-
sions unassociated with an inheritable syndrome. The
minority occur in patients with NF1 and are more of-
ten multiple. Neurofibromas occur at all ages and show
no sex predilection. Most form superficial, dermal,
and/or subcutaneous nodules (Fig. 19.12). Less fre-
quent are examples arising in a major nerve trunk.
Based on their pattern of growth and site of occurrence,
several distinct forms of neurofibroma have been de-
scribed: localized and diffuse cutaneous neurofibromas,
localized intraneural tumors, plexiform neurofibromas,
and, lastly, a massive soft tissue variant. Localized cu-
taneous neurofibromas appear as soft nodular or poly-
FIGURE 19.11 Localized intraneural neurofibroma. This drawing il-
poid lesions often less than 2 cm in diameter. Clini- lustrates the typical permeative, intraneural, growth of such neu-
cally, they are painless and freely movable (Fig. 19.12). rofibromas, which results in localized, fusiform enlargement of the
Fully 90% are solitary and sporadic in occurrence. Dif- nerve. Residual entrapped axons are present throughout the lesion.
tion, an event very uncommon in localized intraneural negative. Whereas CD34 preparations are generally
neurofibromas and particularly in cutaneous lesions. positive, the nature of the immunoreactive cells,
Also indicative of NF1 are massive soft tissue neurofi- whether of nerve sheath, fibroblastic, or mono-
bromas, very diffuse tumors that frequently feature a cyte/macrophage lineage, remains unsettled. Ultra-
plexiform component. By causing massive soft tissue structurally, it is the presence of perineurial-like cells
enlargement, they result in “localized gigantism” or the that typifies neurofibromas (Erlandson, 1994; Schei-
formation of pendulous masses of neurofibromatous thauer et al., 1999). The terms atypical and cellular
tissue, particularly around limb girdles. The now anti- neurofibroma refer to two microscopic features dis-
quated term elephantiasis neuromatosa has been ap- played by neurofibromas consisting, respectively, of
plied to these lesions. the presence of atypical cells and of diffuse hypercel-
A number of microscopic features are common to lularity (Woodruff et al., 1983a; Scheithauer et al.,
the various forms of neurofibroma noted above (Fig. 1999). These are illustrated in Figures 19.17 and
19.16). Typical tumors are rather hypocellular and 19.18. Such tumors should not be mistaken for ma-
feature an abundant mucoid matrix. Cells are widely lignancy. The presence of atypical cells, often a focal
distributed and possess ovoid-to-spindle, often finding, is considered the morphologic equivalent of
curved, nuclei. Without the use of immunocyto- degenerative atypia in so-called “ancient schwan-
chemistry, their long, thin cytoplasmic processes are noma.” To distinguish low-grade MPNST from cel-
hardly discernible. As previously noted, the cellular lular neurofibroma a triad of findings has been pro-
composition of neurofibromas is complex and in- posed: (1) the presence of definite cell crowding; (2)
cludes Schwann and perineurial-like cells, as well as nuclear enlargement, at least three times the size of
fibroblasts and cells with transitional features. This ordinary neurofibroma nuclei; and (3) hyperchroma-
mixed population is most evident at the immunohis- sia. Low-level mitotic activity can be seen in cellular
tochemical and ultrastructural level. All neurofibro- neurofibromas, and as a sole finding it is not suffi-
mas stain for S-100 protein, but the number of im- cient for a diagnosis of MPNST.
munopositive cells varies and is often considerably
lower than in schwannomas (Hirose et al., 1986;
Perineurioma
Scheithauer et al., 1999). Despite the presence of cells
with ultrastructural features of perineurial cells, ep- The designation perineurioma is applied to two benign
ithelial membrane antigen (EMA) stains are generally nerve sheath tumors, both of which are composed ex-
FIGURE 19.12 Localized cutaneous neurofibroma. These two examples occupy the dermis and show rel-
ative circumscription. Often, but not always, such tumors are separated from the epidermis by a free
zone.
FIGURE 19.13 Localized intraneural neurofibroma. The tumor is FIGURE 19.15 Plexiform neurofibroma, small bowel. Both grossly (A)
ovoid, has a delicate capsule, and is a gray-white and translucent on and on whole-mount section (B) this plexiform neurofibroma in-
cut surface. volves the entire bowel wall.
clusively of well-differentiated perineurial cells. One is mosome 22 abnormality in both supports their histo-
a soft tissue neoplasm, the other an intraneural tumor genetic relationship (Emory et al., 1995; Giannini et
with distinctive clinicopathologic features (Emory et al., al., 1997).
1995; Giannini et al., 1997; Scheithauer et al., 1999). Intraneural perineurioma is characterized by in-
The recent cytogenetic demonstration of a clonal chro- trafascicular proliferation of perineurial cells. Their
A B
FIGURE 19.14 Plexiform neurofibroma, sciatic nerve. At the gross (A) and microscopic (B) level, the mul-
tiple enlarged fascicles of this lesion are replaced by neurofibromatous tissue.
A B
C D
FIGURE 19.16 Localized intraneural neurofibroma. Such tumors are relatively hypocellular and composed
of widely spaced, ovoid-to-spindle nuclei in a mucoid matrix. Cytoplasmic processes are long, thin, and
hardly discernable (A). Collagen bundles often follow the course of preexisting nerve fibers and may be
either long and narrow or wide and blocky, an appearance likened to “shredded carrots” (B). Entrapped
axons are often identified, as are ganglion cells in cases wherein a dorsal root ganglion is overrun (C).
Also distinctive is the finding of tactilelike structures, ones more often resembling Meissnerian corpus-
cles than pacinian bodies (D).
pattern of growth is distinctive and results in a micro- and MRI scans demonstrate segmental, fusiform en-
scopic picture superficially resembling hypertrophic largement of the affected nerve trunk.
neuropathy of the inherited and acquired type. It is due Grossly, the nerve shows uniform enlargement that
to this resemblance that intraneural perineurioma was spans several and rarely many centimeters of its length.
once termed localized hypertrophic neuropathy. That Upon opening the epineurium, individual nerve fasci-
designation should be reserved for a rare form of lo- cles appear enlarged and pale. The characteristic his-
calized Schwann cell proliferation with onion-bulb for- tologic appearance of the lesion is best seen in cross
mation (Scheithauer et al., 1999). sections wherein whorls of perineurial cells surround
Intraneural perineuriomas typically occur in adoles- single nerve fibers and even capillaries (Fig. 19.19). This
cents and young adults and affect both sexes with equal spinning of cells sometimes extends to adjacent whorls.
frequency. Nerves most commonly involved include the It is this peculiar wrapping arrangement of cells that
radial, tibial, and sciatic. Cranial nerve examples are has been referred to as “pseudo-onion bulb” forma-
rare. Patients generally present with muscle weakness tion. Longitudinal sections show ill-defined parallel
which has evolved over a period of months to years. bundles of perineurial cells, a pattern characteristic but
Sensory symptoms are uncommon. On physical exam- more difficult to recognize. In longstanding lesions,
ination, muscle atrophy may be apparent. Electromyo- both myelin and axons are often lost. Occasional tu-
graphy generally shows chronic denervation. Both CT mors may become remarkably sclerotic. Perineurial
they exhibit only partial function. Resection, although

curative, should be avoided.
The soft tissue perineurioma is composed of well-dif-
ferentiated perineurial cells. Originally termed storiform
perineurial fibroma, its perineurial nature was only re-
cently confirmed by electron microscopy and immuno-
histochemistry (Lazarus and Trombetta, 1978; Reed and
Harkin, 1983). Such tumors generally present as a mass
in subcutaneous tissue and less commonly in deep soft
tissue of the extremities or trunk. Rare maxillary sinus,
visceral and even intracranial examples have been re-
ported (Giannini et al., 1997; Giannini et al., 1998b, Val-
Boceed 1997). Most occur in middle-age, females being
more often affected than males (4:1). Soft tissue per-
FIGURE 19.17 Atypical neurofibroma. These tumors are characterized
by the presence of cells with degenerative atypia, mainly large, pleo- ineuriomas are well demarcated, but not encapsulated.
morphic, and hyperchromatic nuclei. These are usually a focal find- Round or ovoid and ranging in size from 1 to 20 cm,
ing and resemble those of so-called “ancient schwannomas.” No mi- they are unassociated with an identifiable nerve. Histo-
totic activity or appreciable MIB-1 labeling is seen in such cells. logically, soft tissue perineuriomas are composed of elon-
gate tumor cells aligned in bundles, interweaving fasci-
cles, loose whorls, and vague storiform patterns. Cell
cells show immunoreactivity for EMA, while residual nuclei are elongate with tapered ends. EMA immunore-
axons and their Schwann sheath are highlighted by neu- activity in their long, thin cell processes may be difficult
rofilament and S-100 protein stains, respectively. Al- to demonstrate. The ultrastructural features are those of
though their number and spatial distribution are strik- well-differentiated perineurial cells. Complete resection is
ingly abnormal, the ultrastructural features of the curative. No recurrence has been reported following gross
neoplastic cells are those of normal perineurium. Re- total removal.
sidual nerve fibers are easily recognized.
Intraneural perineurioma is a benign tumor that
grows slowly and progressively impairs nerve function. Miscellaneous Benign Peripheral Nerve Tumors
Simple biopsy of a nerve fascicle is sufficient for diag-
Nerve sheath myxoma and neurothekeoma
nosis. Affected nerves should be preserved, even though
These two multinodular cutaneous tumors have long
been considered myxoid and cellular variants of the
FIGURE 19.18 Cellular neurofibromas. Such tumors are often worri- FIGURE 19.19 Intraneural perineurioma. Cross sections demonstrate
somely cellular and may feature low level mitotic activity. The dis- hypercellular fascicles containing distinctive “pseudo-onion bulbs.”
tinction from malignant peripheral nerve sheath tumor (MPNST) is The latter consist of perineurial cells surrounding axons and their ac-
based upon degree of cellularity, hyperchromasia, and nuclear size, companying Schwann cell sheaths. Even endoneurial microvessels can
those of MPNST being about three times the size of normal Schwann be ensheathed. Perineurial cells of some onion bulbs sweep to invest
cells. adjacent axons as well.
same lesion (Gallager and Helwig, 1980; Pulitzer and amples, underscores the neurogenic nature of granular
Reed, 1985). Ultrastructural and immunohistochemi- cell tumor.
cal studies support the notion that each is a distinct en- Granular cell tumors occur at any age, with a peak
tity (Alvira et al., 1976; Alessi et al., 1988; Argenyi et incidence between the fourth and sixth decades and
al., 1993, 1995, Anyervall et al., 1984). The nerve more often affect females and blacks (Strong et al.,
sheath myxoma is a spindle cell neoplasm showing 1970). Most arise in skin and subcutaneous tissue, pri-
Schwann cell differentiation at both the light and elec- marily of the head and neck (Peterson, 1974; Alessi et
tron microscopic level. Thus, it could be considered a al., 1988). Their single most frequent site of occurrence
myxoid variant of schwannoma. Unlike nerve sheath is the tongue (Miller et al., 1977; Lack et al., 1980).
myxoma, neurothekeomas do not stain for S-100 pro- Others include the larynx, gastrointestinal tract, and
tein and show ultrastructural features more closely re- breast (Scheithauer et al., 1999).
sembling fibroblasts. Nerve sheath myxomas mainly af- The majority of granular cell tumors present as soli-
fect adults in the third to the fifth decade; like tary, relatively well-circumscribed lesions measuring less
schwannomas, they show a female predilection (2:1). than 3 cm in greatest dimension. Approximately 10%
Most occur in the skin of the hands, back, arm, head, are multifocal. Nearly all, certainly more than 90% are
and neck. Only rare examples involve the oral mucosa. benign and are cured by local excision. Negative surgi-
In contrast, neurothekeomas affect mainly children and cal margins are of importance since, after incomplete re-
young adults, particularly female (2:1) and often in- section, local recurrence is seen in up to 50%.
volve the face, especially the nasomalar, nasolabial, and Less than 10% of granular cell tumors are aggres-
lower forehead regions. sive lesions that promptly recur and spread to re-
Both nerve sheath myxoma and neurothekeoma gional lymph nodes or other sites. The lungs are
present as solitary, firm, well-demarcated, variably the most common site of distant metastasis. Although
mucoid, and often multinodular lesions ranging in clinically malignant examples may be impossible to
size from 0.5 to 3 cm. Neither affects nerves. Nerve distinguish from benign granular cell tumors on
sheath myxoma is generally hypocellular, and is com- the basis of histological criteria, high cellularity as
posed of spindle and stellate cells with long processes well as cellular pleomorphism, prominent nucleoli,
immersed in an abundant, myxoid matrix strongly re- readily identifiable mitoses, and foci of necrosis are
active for Alcian blue. In contrast, neurothekeoma is generally seen in malignant examples (Usui et al.,
a moderately to markedly cellular lesion composed of 1977).
both spindle and epithelioid cells. Cytoplasm is gen-
erally abundant. Multinucleated cells are frequent.
Ganglioneuroma
The cells tend to cluster and in some areas show a
loose whorl formation. Mitoses may be frequent (up The benign tumors called ganglioneuromas are com-
10 10 HPF). Myxoid stroma is less abundant than posed of mature ganglion cells associated with abun-
in nerve sheath myxoma. A cellular variant of neu- dant nerve fibers, predominantly of unmyelinated type,
rothekeoma, one with little or no myxoid stroma, has and accompanying Schwann cells (Scheithauer et al.,
also been described (Barnhill and Mihm, 1990). As 1999). Most occur in children and young adults and
mentioned above, nerve sheath myxoma and neu- show a distinct female predilection. An association with
rothekeoma can be distinguished based on these im- NF1, although uncommon, is well established (Kleihues
munohistochemical and EM characterizations. Both and Cavanee, 1997). Endocrine or functional symp-
are benign and are adequately treated by complete toms due to tumoral production of hormones or
excision. neurotransmitters—for example, vasoactive intestinal
polypeptide or cathecolamines—have been reported
(Scheithauer et al., 1999).
Granular cell tumor
Ganglioneuromas most often arise at sites wherein
This distinctive tumor is composed of sheets of granu- sympathetic ganglia are found, including the posterior
lar cells with abundant eosinophilic, PAS-positive cy- mediastinum, paraspinous region, retroperitoneum,
toplasm containing large numbers of what on ultra- adrenal medulla, and pelvis. Most present as large,
structure are secondary lysosomes. Immunoreactivity solid, well-circumscribed masses surrounded by a thin
for S-100 protein and CD68 are characteristic (Schei- pseudocapsule. Only infrequent examples show gross
thauer et al., 1999). An occasional association with cra- calcifications or prominent cystic change. The ganglion
nial and spinal nerves, as well as rare plexiform ex- cells comprising these tumors, along with their variable
accompaniment of satellite cells, are fully mature. Neu- MALIGNANT TUMORS OF PERIPHERAL NERVE
ronal processes often appear out of proportion to the
number of ganglion cells present. Although Schwann Malignant Peripheral Nerve Sheath
cells faithfully surround them, myelin is generally lim- Tumor (MPNST) and Its Variants
ited to entrapped normal nerve fibers. Ganglion cells
Conventional MPNST
may be concentrated in some areas and sparse in oth-
ers. Thorough sampling of ganglion cell–containing tu- By definition, the designation MPNST includes only
mors is necessary to exclude the presence of immature, malignant tumors exhibiting nerve sheath differentia-
neuroblastic components as are seen in immature gan- tion (Scheithauer et al., 1999). Thus, mesenchymal neo-
glioneuroma and ganglioneuroblastoma. Although dif- plasms composed of fibroblasts, endothelial cells, and
ferences in patient age and tumor distribution support pericytes are not included. Many, but not all, MPNSTs
the view that these are separate, distinct entities, the arise in identifiable nerves. Although in concept any
precise relationship between ganglioneuroma and neu- nerve sheath cell may give rise to an MPNST, the vast
roblastic tumors remains to be settled. The known oc- majority show some schwannian features. It is for this
currence of maturation of ganglioneuroblastoma to reason that all MPNSTs were historically “lumped” un-
ganglioneuroma, either spontaneously or after adjuvant der the misleading term malignant schwannomas. This
therapy, and at either primary or metastatic sites, sug- designation is to be avoided in that it invites confusion
gests that some ganglioneuromas represent fully differ- with cellular schwannoma and promotes the notion
entiated neuroblastic tumors. that MPNSTs arise in transition from these or even con-
In the adrenal medulla, ganglioneuroma may occur ventional schwannomas. Given the spindle cell mor-
in association with pheochromocytoma. In such “com- phology of MPNSTs and their capacity for collagen
posite tumors,” the two components are often distinct production, the terms neurogenic sarcoma and neu-
(Moore and Biggs, 1995). A well-differentiated gan- rofibrosarcoma crept into use. Both are incorrect since
glion cell component may also occur in paragangliomas Schwann cells are neuroectodermal rather than mes-
of the cauda equina and duodenum (Schmitt et al., enchymal in nature. Thus, sarcoma is an obvious mis-
1982; Scheithauer et al., 1986; Sonneland et al., 1986). nomer. The term MPNST, however, is very appropri-
At visceral sites, such as the gastrointestinal tract in ate and encompasses the entire spectrum of malignant
multiple endocrine neoplasia type IIB, the ganglioneu- tumors derived from nerve sheath.
romatous proliferation is diffuse and involves all bowel Comprising approximately 5% of malignant soft tis-
layers. sue tumors, MPNSTs are relatively rare (Lewis and
Ganglioneuromas are benign. Resection is curative. Brennan, 1996). Although a significant proportion arise
Only on very rare occasion does an MPNST arise in a de novo, as many as one-half occur in the setting of
ganglioneuroma (Kodet et al., 1986; Scheithauer et al., NF1 (Sordillo et al., 1981; Ducatman et al., 1986;
1999). Hruban et al., 1990; Kourea et al., 1998). As many as
two-thirds arise in transition from neurofibroma, usu-
ally of the plexiform type. Only very rare examples of
Miscellaneous non-neurogenic tumors
MPNST arise in transition from other neuroectodermal
Various benign non-neurogenic tumors occasionally tumors, such as schwannoma (Woodruff et al., 1994),
arise in peripheral nerve roots and trunks; these include ganglioneuroma/ganglioneuroblastoma (Ricci et al.,
meningioma (Harkin and Reed, 1969; Coons and John- 1984), or pheochromocytoma (Miettinen and Saari,
son, 1988), paraganglioma (Sonneland et al., 1986; 1988; Min et al., 1988; Sakaguchi et al., 1996). The
Singh et al., 1993; Walansky et al., 1996), hemangioma clinical and pathologic features of these exquisitely rare
(Vigna et al., 1994; Ergin et al., 1988; Roncaroli et al., tumors differ significantly from those of conventional
2000), hemangioblastoma (Giannini et al., 1998a), and MPNSTs.
lipoma (Terzis et al., 1978; Rusko and Larsen, 1981). The vast majority of MPNSTs occur in adults 20–50
Even adrenal cortical adenomas, presumably arising in years of age, in females slightly more often than males.
heterotopic adrenal tissue, rarely occur in nerve roots Tumors occurring in association with NF1 present a
(Kepes et al., 1990; Mitchell et al., 1993). Amyloidoma full decade earlier (Ducatman et al., 1986; Hruban et
of peripheral nerve is a rarity (Gabet et al., 1989; al., 1990). Approximately 10% of MPNSTs arise in
O’Brien et al., 1994; Laeng et al., 1998); as in CNS a field of prior irradiation (Foley et al., 1980; Ducat-
amyloidomas, no association with systemic amyloido- man et al., 1983; Yakulis et al., 1996; Kourea et al.,
sis has been observed. 1998).
On balance, MPNSTs affects medium size and large

nerves. Sites of predilection include brachial and lum-
bosacral plexus as well as the buttocks and thighs. The
sciatic is the single nerve most often affected. MPNSTs
only rarely involve cranial or visceral nerves.
The macroscopic appearance of an MPNST is that
of a firm, globular or fusiform mass, one well circum-
scribed but not encapsulated. Most are larger than 5
cm and many, but certainly not all, are centered upon
an identifiable nerve trunk (Fig. 19.20). Their cut sur-
faces are typically cream or gray in color and show foci
of necrosis and/or hemorrhage (Fig. 19.20). Although
histologic pattern variation is marked, the majority of
MPNSTs are composed of tightly packed spindle cells
with hyperchromatic nuclei three times the size of those
of neurofibroma (Fig. 19.21). The cells vary in config-
uration from wavy or schwannian to straight or fi-
brosarcomalike. Their corresponding disposition in in-
terweaving sinuous bundles or stiff herringbone
arrangements also suggests these lines of differentia-
FIGURE 19.21 MPNST. Typical examples are highly cellular and com-
posed of spindle cells disposed in sweeping fascicles or a herringbone
pattern. Most such tumors are obviously high grade, featuring nu-
merous mitotic figures as well as necrosis.
tion. Other patterns include diffuse and patternless,

alternating low and dense cellularity, concentrated
perivascular cellularity, and even hemangiopericytoma-
B like. The majority of the tumors, particularly in NF1,
are of high grade and exhibit brisk mitotic activity as
well as zones of necrosis with or without palisading
(Fig. 19.21). Immunoreactivity for S-100 protein, Leu-
7, and/or myelin basic protein is reportedly seen in
50%–70% of the cases, most often in scattered tumor
cells (Scheithauer et al., 1999; Wein et al., 1983). Typ-
ically, Leu-7 reactivity is less than that of S-100 pro-
tein. Stains for myelin basic protein are least helpful
(Scheithauer et al., 1999). Staining for p53 protein is a
common feature of MPNST and has been associated
with an unfavorable prognosis (Halling et al., 1996;
Kindblom et al., 1995).
Ultrastructurally, the cells of MPNST often show
little or no differentiation. As a result, electron mi-
FIGURE 19.20 MPNST. Of these two examples, one lies eccentric to
an identifiable nerve trunk (A), while the other does not (B). Both croscopy is of limited utility in establishing the diag-
tumors are large, fleshy, and show zones of necrosis. Note lack of a nosis in obviously high-grade lesions. Low-grade
capsule. Instead, infiltrated muscle surrounds the lesions. tumors, however, usually show more obvious differen-
tiation along schwannian lines, including the presence lesions and larger, deeply seated tumors. A nerve of ori-
of cytoplasmic intermediate filaments, cell processes, gin is demonstrated in about 50% of cases. The diag-
rudimentary junctions, and the presence of often dis- nosis of epithelioid MPNST is based upon (1) evidence
continuous basement membrane (Hirose et al., 1992). of origin from nerve trunk, (2) the frequent presence
Only a minority of tumors exhibit distinctly fibroblas- of a significant spindle cell component identical to con-
tic or perineurial features (Hirose et al., 1997b). ventional MPNST, and (3) the finding of immunohis-
One feature of MPNSTs is their high frequency of tochemical and ultrastructural features of schwannian
local recurrence following surgical excision. Rates of differentiation. Most tumors show strong, diffuse cy-
recurrence have ranged from 40% for tumors of the toplasmic immunoreactivity for S-100 protein. In ad-
extremities to 68% for paraspinous lesions (Hruban et dition, they lack staining for the melanoma-associated
al., 1990; Koura et al., 1998). In these same studies, marker HMB-45. Only occasional lesions are positive
overall rate of metastasis were high, 65% and 68%, for cytokeratin and/or EMA. Despite lack of processes
respectively, with no significant differences relative to in the epithelioid component, the ultrastructural fea-
tumor location. Most common sites of metastasis in- tures are those of Schwann cells and include often well-
clude lung, bone, pleura, soft tissue, liver, and brain. formed basal lamina, the basis of collagen IV, or
Although rates of metastasis were slightly higher in pa- laminin immunoreactivity (Alvira et al., 1976; Taxy
tients without NF1, the difference was not statistically and Battifora, 1981; DiCarolo et al., 1986; Lodding et
significant. The prognosis is poor; overall 5 and 10 year al., 1986).
survival rates vary from 34% to 52% and from 23% Although epithelioid MPNSTs carry a better prog-
to 34%, respectively (Hruban et al., 1990; Koura et al., nosis than the conventional variant (Laskin et al.,
1998; Wong et al., 1998). 1991), deep-seated tumors undergo distant metastasis
more often than superficial lesions (Laskin et al., 1991).
Epithelioid MPNST
MPNST with divergent differentiation
The designation epithelial MPNST is applied to tumors
with a predominantly epithelial-like cytology, featuring Approximately 15% of MPNSTs show divergent mes-
polygonal cells with abundant cytoplasm (Fig. 19.22). enchymal and/or epithelial differentiation (Ducatman
Such tumors are rare and represent less than 5% of all and Scheithauer, 1984). Heterologous mesenchymal ele-
MPNSTs. They occur over a wide age range (first to ments are obviously malignant and include rhab-
ninth decades) and show no sex predilection or asso- domyosarcoma, chondrosarcoma, osteosarcoma, and,
ciation with NF1 (DiCarolo et al., 1986; Lodding et rarely, angiosarcoma. Tumors showing myoid differen-
al., 1986; Axiotis et al., 1990; Laskin et al., 1991). tiation are most frequent and have been termed malig-
They preferentially affect the limbs and are prognosti- nant triton tumor (Fig. 19.23), (Woodruff et al., 1973).
cally divided into superficially situated, generally small Epithelial elements often have a relatively benign histo-
logic appearance and include mucin-producing intestinal-
type glands, squamous nests, and hormone-producing
neuroendocrine cells (Woodruff et al., 1993) (Fig. 19.23).
So-called “multidirectional” MPNSTs show both epithe-
lial and mesenchymal elements, usually glandular and
rhabdomyosarcomatous components. MPNSTs with di-
vergent differentiation are more often associated with
NF1 than the conventional variant; the frequency varies
from approximately 60% in malignant triton tumors to
75% in glandular MPNSTs (Scheithauer et al., 1999).
On balance, the prognosis is also poorer than that of pa-
tients with conventional tumors, their 5 year survival
rates being 12% and 21%, respectively.
MPNST in transformation from tumors other

FIGURE 19.22 Epithelioid MPNST. Such tumors are composed of than neurofibroma
plump epithelioid cells with large, round, vesicular nuclei and promi-
nent nucleoli. Abundant eosinophilic cytoplasm lends a somewhat Rare MPNSTs arise in transformation from schwan-
rhabdoid appearance. noma, ganglioneuroma/ganglioneuroblastoma, or pheo-
A B
FIGURE 19.23 MPNST with divergent differentiation. These rare tumors most often exhibit mesenchy-
mal elements, particularly rhabdomyoblasts (“malignant triton tumor”) (A). (B) An example of glan-
dular MPNST in which epithelial differentiation takes the form of relatively benign-appearing glands,
including goblet and neuroendocrine cells.
chromocytoma. Well-documented examples of each have Secondary involvement of peripheral nerves by other
been reported (Ricci et al., 1984; Miettinen and Saari, tumors occurs both by direct extension and metastasis.
1988; Min et al., 1988; Woodruff et al., 1994; Sakaguchi Examples include carcinoma, sarcoma, melanoma, and
et al., 1996). We limit our discussion to MPNSTs aris- leukemia/lymphoma. The pattern of involvement de-
ing in schwannoma, the others being exceedingly rare. pends in large part upon tumor type (Scheithauer et al.,
Less than 10 bona fide cases of MPNST–ex-schwannoma 1999). Carcinoma and melanoma typically spread
have been reported (Scheithauer et al., 1999). All arose along the perineurium, occasionally for long distances,
in adults at a mean age of 56 years and without gender and can eventually enter the endoneurium. Metastatic
predilection. None showed an NF1 association and, with involvement of ganglia is also a well-known occurrence.
the exception of a single case, there was no history of In the head and neck, squamous carcinoma may spread
prior irradiation to the site. The tumors generally ex- proximally by way of cranial nerve branches, especially
ceeded 5 cm and all exhibited an underlying classic the fifth nerve, to gain access to the central nervous
schwannoma with Antoni A and B areas. In most cases, system. With respect to sarcomas, nerve involvement is
the MPNST component was purely epithelioid with generally limited to epineurium. Lymphoma/leukemia
round to polygonal cells, oval nuclei, prominent nucle- typically involves the subperineurial space, endoneur-
oli, and ample eosinophilic cytoplasm. In two instances, ial septae, and endoneurium.
the malignant component resembles a round cell, “prim-
itive-appearing neuroectodermal tumor.” Necrosis was a
frequent feature. The outcome of the patients was very TUMORLIKE CONDITIONS AFFECTING
poor with distant metastases in 50% as well as locally PERIPHERAL NERVE
aggressive behavior leading to patient demise. Of MPN-
STs arising in ganglioneuroma/ganglioneuroblastoma, As already mentioned, a variety of non-neoplastic le-
some have occurred de novo, others as a complication of sions affect the PNS. These are summarized in Table
prior radiation therapy. 19.4 as illustrated in the recent third series AFIP fasci-
cle Tumors of the Peripheral Nervous System (Schei-
thauer et al., 1999). Only principal, frequently en-
Other Malignant Peripheral Nerve Tumors
countered lesions are discussed.
Primitive neuroectodermal tumor arising in peripheral
nerve, including so-called peripheral neuroepithe-
Traumatic Neuroma
liomas, are very rare when compared to examples oc-
curring in soft tissue (Scheithauer et al., 1999). Involved This non-neoplastic, masslike lesion often develops at
nerves have included the sciatic, median, ulnar, radial, the site of partial or complete nerve transection and is
intercostal, lateral popliteal, and sacral roots. Malig- the consequence of a disorderly and functionally un-
nant granular cell tumor has already been mentioned successful attempt at nerve fiber regeneration (Lund-
(see page 438). borg, 1987; Dyck et al., 1993). Also termed amputa-
TABLE 19.4 Tumorlike Conditions Affecting ing, an attempt to regenerate and achieve reinnervation
Peripheral Nerve of the original target. The terminal ends of the axons
at the nodes of Ranvier immediately proximal to the
Reactive lesions
site of interruption may each give rise to as many as
Traumatic neuroma 25 sprouts. Only those new fibers successfully con-
Localized interdigital neuritis necting with the original or a new, but meaningful tar-
Pacinian neuroma get go on to mature and remain functional. The re-
Nerve cysts mainder undergo progressive atrophy and ultimately
Endometriosis of sciatic nerve disappear. The probability of a regenerating axon en-
Heterotopic ossification of nerve tering the Büngner bands of the distal stump and be-
ing guided to the original or to an alternate target is
Inflammatory and infectious lesions influenced by a variety of factors. Among these, the
type of injury appears to be of paramount importance.
Inflammatory pseudotumor of nerve
Maintainance of continuity of the nerve sheaths has a
Sarcoidosis of nerve
major influence upon minimizing mismatch of nerve
Leprous neuropathy
fibers and Büngner bands. Therefore, it is no surprise
that nerve regeneration following experimental crush
Hyperplastic lesions injury resulting only in axonal transection is followed
Palisaded encapsulated neuroma by almost complete restoration of nerve structure and
Mucosal neuroma, neuromatosis, and ganglioneuromatosis of function (Thomas and Haftek, 1968). When nerve con-
with multiple endocrine syndrome type IIB MEN IIB tinuity is partly or completely lost, with damage to
Mucosal neuroma, ganglioneuroma/ganglioneuromatosis, and epineurium, perineurium, and vascular structures,
neuronal intestinal dysplasia unassociated MEN IIB nerve fiber outgrowth proceeds haphazardly as is ac-
Localized hypertrophic neuropathy companied by proliferation of Schwann and perineur-
ial cells. The resulting structure, composed of disor-
Hamartoma and choristoma dered nerve fibers partially surrounded by a perineurial
Lipofibromatous hamartoma of nerve investment, forms the traumatic neuroma.
Neuromuscular choristoma Clinically, traumatic neuromas often arise in post-
surgical settings, either at somatic or visceral sites of
injury. Some follow seemingly insignificant injuries.
tion neuroma, the lesion typically develops following They generally present as a firm, tender, and often
nerve injury. While the distal stump of a transected painful nodule. Grossly traumatic neuromas appear as
nerve fiber undergoes wallerian degeneration with a localized bulbous expansion at the end of a transected
complete degeneration and removal of axons and proximal stump (Fig. 19.24A). Microscopically, it con-
myelin, the proximal stump is the site of axon sprout- sists of a disorderly tangle of regenerating axons ar-
A B
FIGURE 19.24 Traumatic neuroma. The gross bulbous expansion at the proximal end of this transected
sciatic nerve is shown, representing the neuroma (A). In yet another example, disordered tangles of re-
generating axons are present at the site of injury (B). Note that fewer axons exit the lesion (on the left
side of the picture).
rayed in microfascicles of varying size. Both fiber size croscopic and ultrastructural observations of a metastasizing ma-
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20 Inherited tumor syndromes involving
the nervous system
JAMES S. NELSON
The inherited tumor syndromes involving the nervous cisely as well as information concerning the molecular
system are a group of genetically determined disorders pathogenesis of the lesions.
with neoplastic or dysplastic lesions in the nervous sys-
tem and in extraneural tissues. The group includes the
conditions discussed in this chapter: neurofibromatosis NEUROFIBROMATOSIS
1 (NF1), neurofibromatosis 2 (NF2), von Hippel-
Lindau disease (VHL), tuberous sclerosis complex There are two principal forms of this disorder: neu-
(TSC), and Cowden/Lhermitte-Duclos disease (CLDD). rofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2)
Other syndromes of this type include the Li-Fraumeni (Gutmann et al., 1997). Prior to the the 1980s and the
syndrome, Turcot’s syndrome, and the nevoid basal cell “NIH Consensus Conference Statement on Neurofi-
carcinoma syndrome (Kleihues and Cavenee, 2000). bromatosis” (1988), NF1 and NF2 were not generally
NF1, NF2, VHL, and TSC have also been classified recognized as different diseases. NF1 was commonly
as neurocutaneous diseases (NCDs), or phakomatoses. referred to as von Recklinghausen’s disease, multiple
The two terms are sometimes used synonymously. The neurofibromatosis, peripheral neurofibromatosis, or
NCDs are a collection of familial and spontaneously von Recklinghausen’s neurofibromatosis; NF2 was
occurring disorders with lesions involving both the ner- referred to as central neurofibromatosis, bilateral
vous system and the skin that are not necessarily neo- acoustic neurofibromatosis, or hereditary vestibular
plastic or dysplastic. The criteria defining this collec- schwannoma syndrome (Huson, 1994a).
tion are arbitrary, because some of the conditions NF1 and NF2 are genetically distinct autosomal
classified as NCDs do not include skin lesions—for ex- dominant disorders. The genes for both forms have
ample, VHL (Gomez, 1987, 1991). been cloned (Viskochil, 1998; MacCollin and Gusella,
Phakomatosis is a term suggested by Van der Hoeve 1999). NF1 and NF2 also occur in mosaic forms (Rug-
(1923) as a generic designation originally for two of gieri and Huson, 2001). NF1 is significantly more com-
the more common NCDs, NF1 and TSC. It is derived mon than NF2. In addition to NF1 and NF2, the oc-
from the Greek word phakos, meaning “motherspot.” currence of other forms of neurofibromatosis has been
The motherspots referred to by Van der Hoeve were proposed on the basis of clinical findings (Riccardi,
the malformative and dysplastic lesions often found in 1992). Information concerning the association of these
the brain, skin, and viscera of patients with the two conditions with unique genetic profiles, however, is
diseases. The motherspots were considered similar, ex- lacking.
cept for the absence of neval cells, to cutaneous nevi
or birthmarks. The masses or tumors developing from
the motherspots were called phakomas. They repre- NEUROFIBROMATOSIS 1
sented a spectrum of proliferative activity including be-
nign and malignant neoplasms. Later, Van der Hoeve NF1 corresponds to the classic disorder described by
added VHL (1932) and Sturge-Weber disease (1936) von Recklinghausen and is the most common form of
to the list of phakomatoses. neurofibromatosis. The characteristic features are pe-
Molecular genetic studies have increased the under- ripheral neurofibromas, café-au-lait spots, Lisch nod-
standing of the disorders previously classfied as NCD ules, and axillary freckling. Approximately one-third of
or phakomatoses. The studies provide a genetic basis patients with NF1 will have some form of intellectual
for identifying or classifying these disorders more pre- handicap or learning difficulty; seizure disorders occur
448
20: INHERITED TUMOR SYNDROMES INVOLVING THE NERVOUS SYSTEM 449
in 7% of patients. NF1 is an autosomal dominant dis-

ease with a birth incidence of 1/2500 to 1/3300, and a
prevalence between 1/4000 and 1/5000 (Huson,
1994a,b). Between 30% and 50% of cases represent
new mutations. The penetrance is essentially 100%;
however, expressivity is variable. The defective gene is
located on the long arm of chromosome 17. Neurofi-
bromin, the NF1 gene product, appears to function as
a tumor suppressor protein (Marchuk and Collins,
1994).
The most prominent neuropathologic lesions involve
the peripheral nervous system. Virtually all NF1 pa-
tients eventually develop some type of cutaneous neu-
rofibroma. Plexiform neurofibromas occur in approx- FIGURE 20.2 NF1. Plexiform neurofibroma. Expansion of three ad-
imately 30% of NF1 patients (Figs. 20.1, 20.2). jacent fascicles by tumor cells. Residual clusters of axons and myelin
Neurofibromas involving the spinal nerve roots are sheaths are present in the central areas of two of the fascicles. H&E,
found in 1.5% of cases (Huson, 1994b). Malignant pe- 100.
ripheral nerve sheath tumors develop from neurofibro-
mas in approximately 5% of patients with NF1, usu- One of the tumors was an anaplastic astrocytoma and
ally after 10 years of age (Meis et al., 1992; Huson, the other, a glioblastoma. Studies reporting the oc-
1994b). However, younger children may be affected currence of other types or sites of intracranial tumors
(Meis et al., 1992). The incidence of vestibular schwan- in NF1 are difficult to assess because they may in-
noma is not increased in NF1 patients (Hughes, 1994). clude unrecognized cases of NF2. The series reported
Reports from the NF1 studies that specifically ex- by Ilgren et al. (1985) includes cases of hypothalamic
clude cases of NF2 indicate that symptomatic in- astrocytoma, cerebellar astrocytoma, cerebellar
tracranial tumors occur in 1.5–3.8% of NF1 patients. ependymoma, and intramedullary spinal cord glioma.
Optic gliomas are the most common intracranial tu- Most of these cases were probably NF1 because none
mor associated with NF1; however, these studies also of the patients studied had vestibular schwannomas.
include cases of brain stem or temporal lobe glioma Rubinstein (1986) in a study of central and periph-
and meningioma (Figs. 20.3, 20.4). There were no eral neurofibromatosis found microscopic CNS pro-
cases of vestibular schwannoma in the two studies
(Huson, 1994b; Créange et al., 1999). The occurrence
of two NF1 patients with intramedullary spinal cord
glioma has been documented by Yagi et al. (1997).
FIGURE 20.1 NF1. Plexiform neurofibroma, bisected surgical speci-

men. A remnant of the normal nerve is in continuity with the cylin- FIGURE 20.3 NF1. Bilateral optic glioma. The tumor expands both
drical tumor. optic nerves and the chiasm.
NEUROFIBROMATOSIS 2
NF2 is also an autosomal dominant disorder with a

birth incidence of 1 per 33,000–40,000 persons and a
symptomatic prevalence of 1 per 210,000 persons. Ap-
proximately 50% of cases are new mutations. Pene-
trance is close to 100% by 60 years of age. The sever-
ity of the disease varies (Evans et al., 1992a). The
genetic and phenotypic characteristics of NF2 are dis-
tinct from those of NF1. The NF2 gene is located on
the long arm of chromosome 22 and encodes a puta-
tive tumor suppressor protein referred to as merlin or
schwannomin (Rouleau et al., 1993; Trofatter et al.,
FIGURE 20.4 NF1. Optic glioma (pilocytic astrocytoma). Bundles of 1993; Louis et al., 1995). The characteristic feature of
spindle-shaped tumor astrocytes partially separated by remnants of NF2 is bilateral vestibular schwannoma. Although
optic nerve septa. H&E, 120. schwannomas may occasionally occur in NF1, they sel-
dom, if ever, involve the vestibular nerve, and bilateral
vestibular schwannomas are never found in patients
liferative foci involving the subependymal glia, with NF1. Café-au-lait spots and cutaneous neurofi-
meningoencephalic glia in the pons and cerebellum, bromas are less common in NF2 than in NF1. Plexi-
and the mural cells of blood vessels in five cases iden- form neurofibromas and Lisch nodules are rare occur-
tified as peripheral neurofibromatosis. rences in NF2 (Martuza and Ojemann, 1982; Garreto
Other lesions or complications associated with NF1 et al., 1989; Michels et al., 1989; Sadeh et al., 1989).
are aqueductal stenosis, gastrointestinal neurofibro- The clinical and pathologic features of NF2 vestibu-
mas, endocrine tumors (including pheochromocy- lar schwannomas and sporadic vestibular schwanno-
toma), myelodysplastic disorders, renal artery steno- mas differ in some respects. The average age for onset
sis, rhabdomyosarcoma, and skeletal abnormalities, of symptoms in NF2 cases is in the third decade and
such as scoliosis, sphenoid wing dysplasia, pseu- after the fourth decade for sporadic cases (Evans et al.,
doarthrosis, and macrocephaly (Hughes, 1994; Hu- 1992a–c). A comparison of the histologic features of
son, 1994b). NF2 and sporadic vestibular schwannomas showed
Although laboratory studies are helpful in identify- that a lobular growth arrangement of the tumor cells
ing complications of neurofibromatosis, there are no occurred much more frequently in the NF2 tumors than
specific laboratory tests for the disorder. According to in the sporadic tumors (Fig. 20.5). In other respects
the NIH Consensus Conference on Neurofibromatosis NF2 and sporadic vestibular schwannomas were simi-
(1988), the diagnosis of NF1 is made when two or more lar (Sobel, 1993).
of the following conditions are present:
1. Six or more cáfe-au-lait macules whose greatest
diameters are greater than 5 mm in prepubescent pa-
tients and greater than 15 mm in postpubescent pa-
tients
2. Two or more neurofibromas of any type or one
plexiform neurofibroma
3. Freckling in the axillary or inguinal region
4. A distinctive osseous lesion, such as spheroid thin-
ning of long-bone cortex with or without pseudoar-
throsis
5. Optic glioma
6. Two or more Lisch nodules (melanocytic hamar-
tomas of the iris)
7. A parent, sibling, or offspring with NF1 on the FIGURE 20.5 NF2. Lobular or plexiform arrangement of tumor cells
basis of the above criteria characteristic of NF2 vestibular schwannomas. H&E, 120.
Central nervous system tumors such as schwanno-

mas of other cranial and spinal nerve roots, multiple
meningiomas, and gliomas, usually pilocytic astrocy-
toma or ependymoma involving the brain stem or
spinal cord, occur with increased frequency in patients
with NF2. The incidence of optic glioma, however, is
not increased in NF2 patients. Other characteristic neu-
ropathologic lesions include schwannosis, meningioan-
giomatosis, microhamartoma, and intracranial calcifi-
cations (Figs. 20.6, 20.7). Presenile cataracts or lens
opacities develop in approximately 60% of NF2 pa-
tients (Rubinstein, 1986; Wiestler et al., 1989; Evans
et al., 1992a–c; Short et al., 1994; Louis et al., 1995).
According to the criteria developed by the NIH Con-
sensus Conference on Neurofibromatosis (1988), the
diagnosis of NF2 is made on patients with either: (1)
bilateral 8th cranial nerve masses seen with appropri-
ate imaging techniques—for example, computed to- FIGURE 20.7 NF2. Meningioangiomatosis. Surgical specimen. Islands
mography or magnetic resonance imaging, or (2) a par- of cerebral cortex are separated by perivascular bundles of spindle-
shaped meningeal and fibroblastic cells. H&E, 10.
ent, sibling, or offspring with NF2 and either a
unilateral 8th nerve mass or any two of these lesions:
neurofibroma, meningioma, glioma, schwannoma, or
posterior capsular cataract or lens opacity at a young a family history of NF2, Evans et al. (1992b) have sug-
age. Subsequently, the NIH Consensus Conference on gested expanding the NF2 criteria to include persons
Acoustic Neuroma (Eldridge and Parry, 1992) modi- without a family history of NF2 who have any of the
fied these criteria so that NF2 is diagnosed when pa- following conditions: (1) unilateral vestibular schwan-
tients have either: (1) bilateral 8th nerve masses seen noma and one or more of these lesions: neurofibroma,
by magnetic resonance imaging with gadolinium, or (2) meningioma, glioma, schwannoma, posterior capsular
a parent, sibling, or offspring with NF2 and either a cataract or lens opacity at a young age, or cerebral cal-
unilateral 8th nerve mass or one of these lesions: neu- cification; (2) multiple meningiomas (two or more) and
rofibroma, meningioma, glioma, schwannoma, or pos- unilateral vestibular schwannoma; or (3) multiple
terior capsular cataract or lens opacity at a young age. meningiomas (two or more) and one or more of these
Because 50% of NF2 cases are new mutations without lesions: neurofibroma, meningioma, glioma, schwan-
noma, posterior capsular cataract or lens opacity at a
young age, or cerebral calcification.
VON HIPPEL-LINDAU DISEASE
Von Hippel-Lindau disease is an autosomal dominant

disease caused by mutations in a tumor suppressor gene
on the short arm of chromosome 3 (Latif et al., 1993;
Friedrich, 2001). The birth incidence ranges from
1/36,000 to 1/45,500 live births; the prevalence of het-
erozygotes is between 1/38,900 and 1/85,000 persons
(Maher et al., 1991; Neumann et al., 1995; Maddock
et al., 1996). Penetrance is estimated to exceed 90%
by 60 years of age. Expressivity varies even within fam-
ilies. The mutation rate is uncertain, but the ratio of
familial to sporadic cases in the literature is 12 to 15:1
FIGURE 20.6 NF2. Schwannosis. Perivascular collections of Schwann (Maher et al., 1990a). The disease is characterized by
cells. Trichrome, 400. hemangioblastomas of the cerebellum, spinal cord, and
retina, renal cell carcinoma, pheochromocytoma, and

cysts of the kidney, pancreas, and epididymis (Figs.
20.8, 20.9). Recently, the association of endolymphatic
sac tumors causing tinnitus or deafness with VHL has
been reported (Friedrich, 1999).
In a comprehensive study of 152 patients with von
Hippel-Lindau disease reported by Maher et al.
(1990a), the age of onset of the disease varied from 4
to 68 years, with a mean of 26 years. The most com-
mon presenting lesion was retinal angiomatosis fol-
lowed by cerebellar hemangioblastoma, renal cell
carcinoma, pheochromocytoma, and spinal heman-
gioblastoma. The most common severe complications
were retinal angiomatosis and cerebellar heman-
FIGURE 20.9 von Hippel-Lindau disease. Cerebellar hemangioblas-
gioblastoma (both 60%), renal cell carcinoma (28%), toma. Groups of stromal cells with foamy cytoplasm separated by
spinal cord hemangioblastoma (13%), and pheochro- branching vascular channels. H&E, 240.
mocytoma (7%). Less serious complications included
renal, epididymal, and pancreatic cysts. The actuarial
median survival was 49 years. The two most frequent
causes of death were renal cell carcinoma (24/51) and mangioblastomas are not available. The mean age of
cerebellar hemangioblastoma (21/51). VHL is some- diagnosis of cerebellar hemangioblastoma in von
times classified as type 1 if there is no family history Hippel-Lindau disease is 29 years, which is significantly
of pheochromocytoma; type 2A if there is a family his- younger than the mean age of 48 years for sporadic
tory of pheochromocytoma without renal cell carci- cases of cerebellar hemangioblastoma (Neumann et al.,
noma or pancreatic cysts; and type 2B if there is a fam- 1989; Maher et al., 1990a,b).
ily history of pheochromocytoma with renal cell The criteria suggested by Melmon and Rosen (1964)
carcinoma and pancreatic cysts (Michels, 1997). Cen- are commonly used for the diagnosis of von Hippel-
tral nervous system hemangioblastomas may occur spo- Lindau disease: two or more central nervous system
radically or in association with von Hippel-Lindau dis- hemangioblastomas, or a single central nervous system
ease. In both instances, similar anatomic sites are hemangioblastoma associated with a visceral manifes-
involved—that is, cerebellum, spinal cord, brain stem, tation of the disease. In cases with a family history of
and cerebrum. However, in von Hippel-Lindau disease retinal or central nervous system hemangioblastoma
the two most common locations are the cerebellum and only one hemangioblastoma or visceral lesion is re-
the spinal cord. Approximately 30% of all cerebellar quired. Neumann (1987) has proposed modifying these
hemangioblastomas are associated with von Hippel- criteria to include patients with either retinal angioma
Lindau disease; comparable data for spinal cord he- or CNS hemangioblastoma who have an immediate
family member with at least one typical VHL lesion.
TUBEROUS SCLEROSIS COMPLEX
Tuberous sclerosis complex (TSC) is an autosomal

dominant disorder characterized by tumors and hamar-
tomas involving a variety of organ systems and tissues
including the brain, heart, skin, lung, and kidney. It is
caused by mutations involving either the TSC1 gene lo-
cated on the long arm of chromosome 9 or the TSC2
gene located on the long arm of chromosome 16. Both
genes have been cloned (The European Consortium,
1993; van Slegtenhorst et al., 1997). The TSC1 gene
FIGURE 20.8 Von Hippel-Lindau disease. Cerebellar hemangioblas- product is a protein called hamartin; the TSC2 gene
toma. Hemorrhagic cyst with a mural nodule involving cerebellar product is a protein called tuberin. The available evi-
cortex. dence indicates both hamartin and tuberin are tumor
or growth suppressor proteins (Carbonara et al., 1994;

Green et al., 1994a,b). The TSC1 and TSC2 pheno-
types appear to be indistinguishable (Povey et al.,
1994). The penetrance is high, but expressivity is vari-
able (Webb and Osborne, 1991; Smalley et al., 1994).
Up to 60% of TSC cases may represent new mutations
(Sampson et al., 1989). Estimates of the prevalence of
this disease at all ages up to the seventh decade vary
from approximately 1 in 15,000 to 1 in 30,000 per-
sons. In populations under 20 years of age estimate of
prevalence range from 1 in 12,000 to 1 in 13,400 per-
sons (Hunt and Lindenbaum, 1984; Sampson et al.,
1989; Shepherd et al., 1991; Ahlsen et al., 1994). The
birth incidence has been estimated at 6 per 100,000
live births (Shepherd et al., 1991a).
The characteristic central nervous system lesions of
TSC are hamartomas involving the cerebral cortex and
ventricular surfaces. and astrocytic tumors arising
FIGURE 20.11 Tuberous sclerosis. Surface of lateral ventricle with ven-
along the borders of the cerebral ventricles. The corti- tricular hamartoma (candle guttering, subependymal nodule).
cal hamartomas, called tubers, are composed of mal-
formed astrocytes and neurons, dysplastic cells with as-
trocytic and neuronal features, and astrocytic fibers
(Fig. 20.10). Lesions resembling tubers may also de- The ventricular hamartomas are thought to be the
velop in the cerebellum. The ventricular hamartomas, origin of subependymal giant cell astrocytomas associ-
also called subependymal nodules or candle gutterings, ated with TSC (Fig. 20.15). These tumors are usually
are usually located in the thalamostriate sulcus (Fig. located near the foremen of Monro. They develop in
20.11). They are composed of cells resembling large 5%–6% of TSC patients, but, possibly, may occur in
bodied astrocytes, the processes of these cells, and foci the absence of any evidence of TSC (Bonnin et al., 1984;
of calcification (Figs. 20.12, 20.13). Dysplastic foci of Shepherd et al., 1991b). The tumors are well circum-
neurons and astrocytes can be found in the subcortical scribed, slowly growing, and composed of large,
white matter (Fig. 20.14). Ultrastructural and im- fusiform, piriform, and strap-shaped astrocytes that
munohistochemical studies have shown that the cells in stain variably for glial fibrillary acid protein, neuron-
the ventricular masses and some dysplastic cells in the specific enolase, and other glial or neuronal antigens
cortical tubers have features of astrocytic differentia- (Bonnin et al., 1984; Lopes et al., 1996). These tumors
tion and stain variably for glial fibrillary acid protein rarely undergo malignant change but may obstruct ven-
(Bender and Yunis, 1980; Short et al., 1995). tricular pathways, causing increased intracranial pres-
FIGURE 20.10 Tuberous sclerosis. Lateral cerebral convexity with FIGURE 20.12 Tuberous sclerosis. Sharply demarcated subependymal
frontal and temporal tubers. nodule (ventricular hamartoma). H&E, 10.
FIGURE 20.13 Tuberous sclerosis. Subependymal nodule (ventricular

hamartoma) composed of cells resembling gemistocytic astrocytes.
H&E, 240. FIGURE 20.15 Tuberous sclerosis. Subependymal giant cell astrocy-
toma composed of cells resembling gemistocytic astrocytes. Compare
with Figure 20.13. H&E, 240.
sure. Occasionally, they are the site of massive hemor-
rhage (Shepherd et al., 1991b).
Outside the nervous system, other important lesions ules protruding into the ventricles, and multiple retinal
associated with TSC are facial angiofibromas, ungual astrocytomas. The calcified subependymal nodules may
fibromas, cysts and angiomyolipomas of the kidney, be diagnosed by imaging studies. The cortical tuber,
and cardiac rhabdomyomas. Pulmonary lymphan- subependymal nodules, and giant-cell astrocytoma must
giomyomatosis occurs in less than 1% of TSC cases but be confirmed histologically. Histological confirmation
is an important cause of death in this condition (Shep- for the facial, lingual, and retinal lesions is not neces-
herd et al., 1991c). sary if the lesion is clinically obvious. Each of the pri-
The Diagnostic Criteria Committee of the National mary criteria is considered diagnostic of definite TSC. In
Tuberous Sclerosis Association has identified primary, the absence of primary features, the diagnosis of definite
secondary, and tertiary features of TSC for use alone or TSC may also be made on the basis of specified combi-
in various combinations as reliable criteria for the clin- nations of secondary and tertiary features. Other com-
ical diagnosis of definite, probable, or suspect TSC. The binations of these features form criteria for the diagno-
primary features identified by the committee are: facial sis of probable or suspect TSC (Roach et al., 1992).
angiofibromas (adenoma sebaccum), multiple ungual fi-
bromas, cortical tuber, subependymal nodule or giant-
cell astrocytoma, multiple calcified subependymal nod- COWDEN/LHERMITTE-DUCLOS DISEASE
Cowden disease is an autosomal dominant disorder in-

volving the skin and other tissues or organs. The dis-
order is characterized by multiple cutaneous tricho-
lemmomas; oral papillomas, fibromas, and keratoses;
hyperkeratoses involving the hands and feet; gastroin-
testinal polyps; carcinoma and fibrocystic disease of the
breast; tumors of the ovary and uterus; thyroid abnor-
malities including adenoma and goiter; and macro-
cephaly (increased head circumference) (Starink, 1984;
Starink et al., 1986; Hanssen et al., 1993). Cowden dis-
ease appears to be regularly associated with mutations
of PTEN/MMAC1, an apparent tumor suppressor gene
located on the long arm of chromosome 10 (Liaw et
al., 1997; Nelen et al., 1997).
FIGURE 20.14 Tuberous sclerosis. Focal collection of dysplastic neu- Lhermitte-Duclos disease refers to a CNS disorder in
rons and astrocytes in the subcortical white matter. H&E, 400. which a dysplastic mass of neurons, glia, and myeli-
nated axons occupies all or part of one cerebellar hemi-

sphere, and it is associated clinically with progressive
headache, ataxia, visual disturbances, and, occasion-
ally, sudden death from cerebellar herniation. Familial
cases have been reported (Ambler et al., 1969; Eng et
al., 1994). One or more features of Cowden disease are
present in approximately 35% of reported cases of
Lhermitte-Duclos disease (Nelson et al., 1994; Vinchon
et al., 1994). At least 16 cases of Cowden disease and
associated Lhermitte-Duclos disease have been docu-
mented (Koch et al., 1999). Some of these occurred
in families with demonstrated mutations of the PTEN/
MMAC1 gene (Liaw et al., 1997; Nelen et al., 1997).
A few cases of medulloblastoma and meningioma a FIGURE 20.17 Lhermitte-Duclos disease. Junction of normal and mal-
have been reported in connection with Cowden disease formed cerebellar cortex. H&E, 240.
(Bagan et al., 1989; Lyons et al., 1993). Nevertheless,
Lhermitte-Duclos disease is regarded as the principal
CNS lesion associated with Cowden disease. border of the lesion with normal cerebellar cortex,
The pathologic features of Lhermitte-Duclos disease the outer layer of myelinated axons is contiguous with
include grossly evident enlargement of the folia within the molecular layer of normal cerebellar cortex, and
the affected portion of the cerebellum (Fig. 20.16). In the inner layer of dysmorphic neurons is contiguous
most cases only one hemisphere is involved. The change with the Purkinje and internal granular cell layers of
in the size of the folia is readily apparent with both T1- normal cerebellar cortex (Fig. 20.17). The neuronal
and T2-weighted magnetic resonance imaging (Reeder component of thje lesion comprises both small and
et al., 1988). Microscopically, the normal cerebellar large cells (Fig. 20.18). Foci of calcification may also
cortex is replaced with an outer layer of myelinated ax- be present. Proliferative activity within the lesion ap-
ons and an inner layer of dysmorphic neurons. At the pears to be very low (Hair et al., 1992; Nelson et al.,
1994). The classification of the lesion as a malforma-
tion or hamartoma with some potential proliferative
capacity is debated. Cases of recurrence following re-
section have been reported. The recurrences usually
have occured many years after the initial resection
(Marano et al., 1988; Stapleton et al., 1992; Williams
et al., 1992). Increased production of neurofilament
proteins by abnormal granule cells within the lesion
leading to hypertrophy of the neurons and their axons
FIGURE 20.16 Lhermitte-Duclos disease. Cerebellar hemisphere with

enlarged folia that extend across the midline. Transaxial T1-weighted FIGURE 20.18 Lhermitte-Duclos disease. Dysplastic neurons replac-
MRI. ing normal cerebellar cortex. H&E, 240.
rather than cell proliferation has been suggested as a Gomez M.R. (1991). Neurocutaneous diseases. In: Neurology in
possible mechanism for development of an enlarging Clinical Practice, (W.G. Bradley, R.B. Daroff, and G.M. Fenichel,
eds.). Butterworth-Heinemann, Boston, pp. 1323–1342.
mass (Yachnis et al., 1988). Green A.J., Smith M., and Yates J.R. (1994a). Loss of heterozygos-
ity on chromosome 16p13.3 in hamartomas from tuberous scle-
rosis patients. Nat Genet 6:193–196.
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21 Pathology of non-neoplastic,
regional disorders of the spinal cord
RONALD C. KIM
This brief overview will deal with disorders that affect findings based on postmortem injection studies. The
the spinal cord primarily or in a particularly distinctive conclusions drawn by Lazorthes and his colleagues on
manner. The more generalized pathological processes the basis of their studies (Lazorthes et al., 1966a,b; La-
in which there is secondary or incidental spinal cord zorthes, 1972) seem to be in close accordance with
involvement will not be addressed, as they are discussed what is known clinically and pathologically of spinal
elsewhere in this volume. vascular insufficiency. According to these authors,
blood is delivered to the spinal cord through 3 major,
functionally isolated territories of supply (Fig. 21.1):
SPINAL VASCULAR DISEASE 1. The upper (cervicothoracic) region, which consists
of the cervical and upper 2–3 thoracic segments of the
Anatomical Considerations spinal cord, receives blood from several sources. The
upper 3 or 4 cervical segments are supplied by the an-
Before entering into a discussion of spinal vascular dis-
terior spinal artery as it descends from the intracranial
ease, it is useful to review briefly what is known
vertebral arteries; the midcervical spinal cord is sup-
anatomically of the patterns of arterial supply and ve-
plied by branches of the ascending vertebral arteries;
nous drainage of the spinal cord. The discussion that
and the lower cervical and upper thoracic segments are
follows is based on the observations of many investi-
supplied mainly by a branch arising from one of the
gators (Adamkiewicz, 1882; Kadyi, 1889; Tureen,
costocervical trunks.
1938; Suh and Alexander, 1939; Gillilan, 1958, 1970,
2. The rather poorly collateralized intermediate
1978; Corbin, 1960; Lazorthes, 1972; Rodríguez-Baeza
(midthoracic) region, which extends approximately
et al., 1989, 1991; Sliwa and Maclean, 1992; Alleyne
from T4 to T8, is usually supplied by a single thoracic
et al., 1998; Fehlings and Skaf, 1998).
radicular artery that enters the spinal canal near the
The anterior spinal artery is formed rostrally from
7th thoracic vertebral body.
solitary branches of the intracranial portions of the ver-
3. The lower (thoracolumbar) region, which consists
tebral arteries, and, as it descends in the midline along
of the lower 3 or 4 thoracic segments and the lumbar
the ventral surface of the medulla and spinal cord, it
enlargement, is supplied mainly by a single, usually left-
receives major contributions from seven to eight
sided caudal thoracic or rostral lumbar arterial branch,
penetrating radiculomedullary (radiculospinal) arteries.
the great radicular artery of Adamkiewicz or lumbar
Since the anterior spinal arterial network, which is not
enlargement artery. In approximately 75% of instances
necessarily continuous throughout its extent, is the ma-
this vessel accompanies the 10th, 11th, or 12th tho-
jor source of blood supply to the spinal cord, it is im-
racic nerve root into the spinal canal.
portant to be aware of the limited number of vessels
that contribute to its formation. Although radicular ar- This formulation, which is based on postmortem in-
teries accompany each of the ventral spinal roots, most jection studies performed under relatively high pres-
of them provide blood to the nerve roots or the lep- sure, implies that the ability of the spinal arterial sys-
tomeninges rather than to the spinal cord itself. The tem to provide collaterals in the event of localized
range of anatomical variations within this system is circulatory impairment is rather limited, with the ex-
considerable and, in any given instance, may be clini- ception of the leptomeningeal perimedullary anasto-
cally relevant. There is, in addition, some disagreement motic network (see below). Furthermore, there is gen-
with regard to both the nature and the significance of eral agreement that the middle thoracic segments
459
As seen in transverse section, arterial blood flows

centripetally through radially oriented penetrating pe-
ripheral branches (derived from the leptomeningeal
perimedullary anastomotic network) to supply the pe-
ripheral white matter and posterior horns, and cen-
trifugally through arterial sulcal branches to supply
most of the spinal gray (except for the posterior horns)
and the deep white matter (Fig. 21.2). Although the an-
terior spinal arterial network provides blood to the an-
terior two-thirds of the spinal cord and the posterior
network supplies the posterior third, infarction of the
entire territory of supply of either the anterior or the
posterior arterial system is encountered relatively
rarely. This is attributable to the effectiveness of col-
lateral supply through leptomeningeal perimedullary
arterial anastomoses, which tend to spare the periph-
eral white matter, in contrast to the end-arterial nature
of the central sulcal arterial system, which renders the
FIGURE 21.1 Diagrammatic representation of the arterial blood sup-

ply of the spinal cord according to Lazorthes. (From Vinken and
Bruyn, 1972, with permission.)
(T4–T7), which are not as richly vascularized as the

rest of the spinal cord, are particularly vulnerable to
the effects of reduced blood flow.
The posterior spinal arterial network is derived from
the smaller but more numerous and rostrocaudally
more evenly distributed posterior divisions of the radic-
ular arteries (Gillilan, 1958; Fazio, 1971). At cervical
and lumbar levels it is often visible as a pair of plexi-
form longitudinal channels placed just medial to the
dorsal spinal roots. In the thoracic region the network
is more variable and not infrequently discontinuous.
The posterior spinal arterial system forms a part of the
leptomeningeal perimedullary network that anasto-
moses with the anterior spinal arterial system. These
connections are particularly prominent at the level of FIGURE 21.2 Diagrammatic representation of the intramedullary ar-
the conus medullaris, where they form an anastomotic terial blood supply of the spinal cord according to Lazorthes. (From
loop (224). Vinken and Bruyn, 1972, with permission.)
21: NON-NEOPLASTIC DISORDERS OF THE SPINAL CORD 461
spinal gray more vulnerable to the effects of impaired eral anterior, lateral, and dorsal white matter drains ra-
blood flow. Probably for these same reasons, infarction dially toward the surface to enter the coronal plexus of
is seldom if ever recognized as being limited to the the- veins within the leptomeninges. Except for the anterior
oretical border (“watershed”) zones of supply between spinal vein, which is fairly constant, the surface venous
the anterior and posterior spinal arterial systems or be- pattern shows considerable variability and tortuosity,
tween the central sulcal and leptomeningeal peri- especially posteriorly. A particularly large vein, the
medullary networks. great anterior radicular vein, emerges from the lower
The pattern of venous drainage of the spinal cord is thoracic or upper lumbar spinal cord, usually on the
separate and distinct from that of the arterial supply left side. The leptomeningeal veins drain via 8–12
(Kadyi, 1889; Tureen, 1938; Herren and Alexander, radiculomedullary veins into the epidural venous
1939; Suh and Alexander, 1939; Lazorthes, 1962; plexus, which, in turn, is connected to the azygos/hemi-
Gillilan, 1970, 1978) (Fig. 21.3). Intramedullary spinal azygos/caval system through a perivertebral venous
veins drain along one of two pathways. Blood from the plexus.
gray and anterior white commissures, anterior horns, Although the dynamics of flow through the spinal ve-
and ventromedial white matter flows through central nous system has not been well studied with the aid of
sulcal tributaries into the anterior median spinal vein, contrast media, Di Chiro and Doppman (Di Chiro and
whereas that arising from the posterior horns and lat- Doppman, 1970) have shown angiographically that ar-
FIGURE 21.3 Diagrammatic representation of the intramedullary pattern of venous drainage of the spinal
cord. (From Gillilan, 1970, with permission.)
teriovenous malformations, even those positioned cau- Arterial Infarction of the Spinal Cord
dally within the spinal canal, are often drained by dis-
tended veins upward past the foramen magnum into the Arterial infarction of the spinal cord more frequently
cranial cavity. The same appears to be true for thora- results from impairment of blood flow originating out-
columbar dural arteriovenous fistulas (Rosenblum et al., side rather than within the spinal canal. Extraspinal
1987). In addition, these authors have observed that the causes include systemic circulatory insufficiency (e.g.,
cervical spinal veins of rhesus monkeys appear normally hypotension or cardiac arrest) and operative manipu-
to drain in the same direction (Di Chiro and Doppman, lation or disease of the aorta or its primary branches,
1970). Taylor and Byrnes (Taylor and Byrnes, 1974) and juxtamedullary or intramedullary causes include
produced experimental obstruction within the upper cer- infection (e.g., lues), embolism (e.g., fibrocartilaginous
vical spinal canal and found downward distension of the or atheromatous), and delayed radiation effect.
spinal veins below this level. These findings suggest that
the normal drainage of venous blood from the spinal
Sudden systemic circulatory impairment
cord is directed rostrally and may be of importance in
understanding the pathogenesis of myelopathies associ- Sudden systemic circulatory impairment, such as that
ated with nonocclusive impairment of venous outflow encountered during severe hypotension or cardiac ar-
(see below). rest, may lead to spinal cord infarction even in the ab-
A C
FIGURE 21.4 Ischemic spinal cord necrosis in a 59-year-old man who became paraplegic after an episode
of cardiac arrest and died 9 weeks later without intracranial evidence of hypoxic damage. (A) Trans-
verse sections of spinal cord at lower thoracic (upper row), lumbar (middle row), and sacral (lower row)
levels, showing central tissue breakdown and cavitation. (B) Low-power photomicrograph of the sacral
spinal cord showing damage that is limited largely to the spinal gray. Masson trichrome stain. (C) Di-
agrammatic representation of the distribution of necrosis, illustrating a progressive rostrocaudal increase
in the extent of the damage.
sence of morphologically demonstrable cerebral isch- lus (Fig. 21.5), a pattern of necrosis that was attributed
emia (Blumbergs and Byrne, 1980; Kim et al., 1988b). to infarction at the border zone of supply between the
The pattern of damage is rather characteristic (Fig. anterior and posterior spinal arteries. In our experience,
21.4). Beginning at midthoracic levels there are sym- sudden impairment of spinal cord perfusion not un-
metrical, dorsoventrally oriented columns of tissue ne- commonly results in the development, at midthoracic
crosis affecting the ventral portions of the posterior levels, of symmetrical lesions within the ventral por-
horns and the dorsolateral portions of the anterior tions of the posterior horns and dorsolateral portions
horns. At lower thoracic and lumbar levels these lesions of the anterior horns, as we have already described.
widen progressively to involve most of the posterior and Such damage, we believe, may possibly represent
virtually all of the anterior horns, with sparing of the central/peripheral border zone infarction. It would ap-
commissural gray. Below this, the commissural gray is pear, therefore, that several types of watershed infarc-
usually also affected. The size of the damaged area as tion may be encountered, particularly at thoracic spinal
seen in cross section shows some variability, so ischemic levels, although the specific pathogenetic factors that
necrosis may, on the one hand, affect only a small pro- determine which type of lesion will result are presently
portion of the spinal gray or, on the other, extend con- unknown.
siderably into the adjoining white matter (Madow and
Alpers, 1949). The predominance of damage within the
Injury to the aorta or its primary branches
spinal gray from T4 downward is probably attributable
both to the relatively poorer vascularization of the Ischemic myelopathy may be a consequence of either
spinal cord at and below upper thoracic levels and to operative manipulation, traumatic rupture, dissecting
the effectiveness of the collateral circulation within the aneurysms, or acute thrombosis of the aorta, and is
perimedullary arterial network, from which penetrating more likely to occur in association with thoracic than
branches arise to supply mainly white matter. with abdominal aortic injury sites (Szilagyi et al., 1978;
One might anticipate finding, in cases of sudden sys- Keye et al., 1980; Ross, 1985). The limits of tolerance
temic circulatory impairment, ischemic tissue necrosis to aortic cross-clamping have been variously estimated
at the border zones of arterial supply (i.e., “watershed” to range between 18 and 30 minutes (Adams and van
infarction), similar to that observed within the brain. Geertruyden, 1956; Katz et al., 1981; Cunningham et
Theoretically, along the longitudinal axis of the spinal al., 1982). The likelihood of spinal cord infarction is
cord, there are cervicothoracic/middle thoracic and considerably greater during emergency aortic surgery
middle thoracic/thoracolumbar arterial border zones than during elective procedures, and the risk of para-
and, as seen in transverse section, there are anterior plegia is higher when the operative site is above the re-
spinal/posterior spinal and central/peripheral arterial nal arteries (Bacher et al., 1999; Mauney et al., 1995).
border zones (Hassler, 1966; Zülch and Kurth-Schu- There may be a delay in the onset of paraplegia until
macher, 1970; Turnbull, 1971; Lazorthes, 1972; Zülch, 24–48 hours after operative occlusion of the aorta, clin-
1976). According to Zülch (Zülch and Kurth-Schu- ically and in experimental animals (Hollier et al., 1988;
macher, 1970; Zülch, 1976), watershed infarction of Moore and Hollier, 1991). The basis for this is poorly
the spinal cord is most likely to develop at T4 as a
biconical, “pencil-shaped” zone of softening situated
along the border zone of supply between the anterior
and posterior spinal arteries, either within the ventral
white matter and adjoining dorsocentral spinal gray
or within the base of the posterior horn. However,
Hashizume et al. (1983), who studied 12 spinal cords
with lesions of this type, concluded that mechanical
compression (e.g., by extradural metastatic disease) was
of greater importance than ischemia in its development.
Wolf et al. (1990) described an arcuate zone of coag-
ulative necrosis within the lower thoracic spinal cord
in a patient with aortic dissection from the aortic valve
to the renal arteries who suffered a cardiac arrest from
which he was successfully resuscitated. This lesion,
which was accompanied by cerebral watershed infarcts,
affected the dorsomedial portions of the lateral funi- FIGURE21.5 Arterial border zone infarction within the spinal cord.
culi and most of the ventral half of the dorsal funicu- (From Wolf et al., 1990, with permission.)
understood, although Sakurai and his colleagues (Saku- Wolf et al., 1990), it is difficult to be certain, in any
rai et al., 1998), in a rabbit model of delayed-onset given instance, of its relative importance in the pro-
paraplegia, observed overexpression of apoptosis- duction of ischemic spinal cord damage. Acute aortic
promoting Fas antigen 8–24 hours after reperfusion, thrombosis, arising either spontaneously or as a result
followed by evidence of apoptosis and subsequent loss of blunt abdominal trauma, may lead to the develop-
of motor neurons. The pattern of damage associated ment of paraplegia (Kochar et al., 1987; Sumpio and
with acute aortic injury is often quite similar to that Gusberg, 1987). It may be difficult in such circum-
seen following sudden systemic circulatory impairment, stances to distinguish, on clinical grounds alone, be-
with preferential involvement of the spinal gray and tween spinal cord and peripheral nerve ischemia (Killen
relative sparing of the white matter (Fig. 21.6) (Thomp- and Foster, 1960). Although there is a sparsity of de-
son, 1956; Hogan and Romanul, 1966; Kepes and tailed descriptions of the neuropathological findings,
Reynard, 1973; Moossy, 1979; Kim et al., 1988b) alone report (Kochar et al., 1987) does provide a gross
though, in some instances, almost the entire cross-sec- illustration of transversely sectioned segments of spinal
tional extent of the spinal cord may be affected (Scott cord that appears to show hemorrhagic infarction
and Sancetta, 1949; Schwarz et al., 1950; Hughes, within the territory of supply of the anterior spinal
1964b; Leramo et al., 1986). In a minority of instances artery.
of aortic aneurysm dissection (Weisman and Adams,
1944; Hashizume et al., 1997) infarction was confined
Intercostal arterial infarction
to the territory of supply of the anterior spinal artery.
Theoretically, dissection may lead to spinal cord in- The literature contains several reports of ischemic
farction either by lowering systemic blood pressure or myelopathy after rib resection for sympathectomy
by obstructing or shearing one or more intercostal or (Mosberg et al., 1954; Nathan, 1956; Hughes and Mac-
lumbar feeding arteries. Despite the fact that arterial Intyre, 1963) or after thoracotomy (Thomas and
obstruction or interruption has been observed repeat- Dwyer, 1950; Rouquès and Passelecq, 1957; Garland
edly (Scott and Sancetta, 1949; Schwarz et al., 1950; et al., 1966), presumably on the basis of damage to an
A B
FIGURE 21.6 Spinal cord necrosis in a man who died 13 months af-
ter repair of a dissecting thoracic aortic aneurysm (and in whom
paraplegia developed prior to operative intervention). (A) Gross pho-
tograph of the heart and aorta, showing the Dacron graft and the
true and false lumens. The arterial feeders to the spinal cord appeared
to have been preserved. (B) Transverse sections of the spinal cord at
lower thoracic (upper row), lumbar (middle row), and sacral (lower
row) levels, showing central necrosis and cavitation. (C) Low-power
photomicrograph at L3, showing cavitary necrosis that is limited
largely to the gray matter. Hematoxylin-eosin stain. (From Kim SW,
et al., 1988b, with permission.)
intercostal artery. The case described by Hughes and of the spinal cord (Lazorthes et al., 1971; Sliwa and
MacIntyre (1963) was characterized pathologically by Maclean, 1992).
ischemic atrophy, without cavitation, of the ventral and Doppman (1993), however, has expressed skepticism
lateral portions of the middle to lower thoracic spinal as to whether or not ligation of the segmental artery
cord that was attributed to reduction in blood flow from which the artery of Adamkiewicz arises necessar-
through the anterior spinal artery. We have seen a sim- ily leads to spinal cord infarction. He and his colleagues
ilar pattern of damage in a man who, for purposes of were unable to produce infarction after ligating the
resection and graft replacement of a thoracoabdominal artery in monkeys (the only animal with a spinal cord
aortic aneurysm, underwent resection of the left sixth blood supply similar to that of humans) because of col-
rib and reimplantation of the left 9th and 10th inter- lateral supply to the lumbar enlargement through tho-
costal arteries, and who developed postoperative para- racic feeding vessels (Fried et al., 1969). In addition he
plegia and a T11–T12 pain and temperature sensory cited the failure of others (Savader et al., 1993) to show
level. At his death 4 years later there was ischemic at- that preoperative angiographic identification and in-
rophy, without frank cavitation, of the ventral and lat- traoperative sparing of the artery of Adamkiewicz did
eral portions of the thoracic and lumbar spinal cord not completely protect the spinal cord.
(Fig. 21.7).
The above observations suggest that regional inter-
Vertebral arterial infarction
ruption of blood flow through segmental arteries (in-
cluding, presumably, the artery of Adamkiewicz) may Acute vertebral artery insufficiency could theoretically
be partially compensated for by flow from collateral lead to ischemic damage to the cervical spinal cord since
channels which, though sufficient to prevent spinal cord this vessel is a major source of blood supply to this
cavitation, is not sufficient to prevent ventral ischemic area. Rarely, distal obstruction of the artery, which typ-
atrophy. The relative sparing of the posterior spinal ically results in lateral medullary infarction, may, if the
artery territory of supply may in turn be due to the thrombosis is extensive, produce damage to the up-
richer anastomotic network over the posterior surface permost cervical spinal cord (Dhamoon et al., 1984).
A B
FIGURE 21.7 Ischemic atrophy of the anterior portion of the spinal

cord 41/2 years after rib resection and reimplantation of the left 9th
and 10th intercostal arteries for repair of a thoracoabdominal aor-
tic aneurysm. (A) Consecutive transverse sections of the spinal cord
from T10 through S1, showing ventral shrinkage and darkening,
without cavitation. (B) Low-power photomicrograph at L3, show-
ing reduction in volume and pallor of myelin staining within the ven-
tral half of the spinal cord. Luxol fast blue–cresyl violet stain. (C)
Diagrammatic recapitulation of the pattern of spinal cord damage.
Obstruction more proximally is usually the result of

traumatic neck injury (Carpenter, 1961; Hughes,
1964a). Pathologically, in one of the cases described by
Hughes (1964a), there was a large central area of ne-
crosis at C6 that was presumed to have resulted from
kinking of the vertebral arteries (which were patent at
autopsy) in the neck, although, in our view, the possi-
bility of central spinal cord damage due to the direct
effects of traumatic hyperflexion or hyperextension (see
below) was not completely ruled out.
Spinal arterial territorial infarction

Infarction in the territory of supply of the anterior
spinal artery need not, as we have already indicated,
be accompanied by obstruction of that vessel. The num-
ber of cases in which occlusion of the arterial trunk has
been documented pathologically is, in fact, quite small. FIGURE 21.8 Infarction within the territory of supply of the anterior
Earlier reports implicated neurosyphilis as the most spinal artery. Note the presence of coagulative necrosis within the
common causative factor (Spiller, 1909; Margulis, ventral white matter and medial portions of the anterior horns. Luxol
1930) but, more recently, the importance of athero- fast blue–cresyl violet stain.
sclerosis (Zeitlin and Lichtenstein, 1936), atheroma-
tous or fibrocartilaginous embolism (Naiman et al.,
1961; Reich, 1968; Laguna and Cravioto, 1973; Slavin The term anterior spinal artery syndrome, which is
et al., 1975; Moossy, 1979; Srigley et al., 1981; Moor- used to denote a clinical state characterized by paraly-
house et al., 1992), cervical spondylosis (Hughes, sis and loss of lateral spinothalamic tract–mediated
1964b; Hughes and Brownell, 1964), or other factors pain and temperature perception with relative sparing
has been emphasized. The extent of infarction, as seen of posterior column–mediated prioprioception and vi-
in transverse section, may vary considerably, depend- bratory sensation (Steegmann, 1952; Lazorthes, 1972;
ing upon the longitudinal extent of arterial occlusion Fosburg and Brewer, 1976; Sliwa and Maclean, 1992;
and the degree of involvement of secondary branches Cheshire et al., 1996), is often misleading, and its use
(Fig. 21.8). Thus, for example, in the patient described should be discouraged, since it implies a pattern of
by Naiman et al. (1961) and again by Moossy (1979), damage corresponding to the territory of supply of the
coagulative necrosis affecting virtually all of the classi- anterior spinal artery. In our experience, the syndrome
cal territory of supply of the anterior spinal artery (in- is characterized by a pathological picture that may vary
cluding the ventromedial portions of the lateral corti- considerably but that often affects gray matter much
cospinal tracts) was associated with occlusion of the more severely (Fig. 21.9). The pain and temperature
main arterial trunk as well as its anterior sulcal and pathway traverses the entire spinal cord and, in doing
smaller branches by fibrocartilaginous emboli. Moor- so, courses through both gray and white matter; for
house, et al. (1992) described localized territorial in- this reason, functional interruption may occur at a
farction at T10–L1 in a woman with fibrocartilaginous number of anatomical sites. Occlusion of the anterior
embolism to the anterior spinal arterial trunk at that spinal artery is rare and, when it occurs, is usually em-
level. In the cases reported by Laguna and Cravioto bolic. Only in a small minority of instances have we
(1973) and by Slavin et al. (1975), in which obstruc- observed classical territorial infarction in association
tion by atheromatous embolism apparently was limited with the syndrome. For this reason, we prefer the term
to the main trunk of the artery, there was relative spar- anterior spinal cord syndrome, as is used in referring
ing of the lateral and ventral white matter. In the pa- to traumatic myelopathies.
tient described by Hughes and Brownell (1964), in Pathologically documented examples of posterior
whom thrombosis of the anterior spinal artery was pre- spinal artery occlusion with infarction are even rarer
sumed to be related to cervical spondylosis, the cross- in the postneurosyphilitic era. Périer et al. (1960) de-
sectional extent of the infarct was greatest at those lev- scribed two examples, one of which was the result of
els at which the thrombus had propagated into sulcal atheromatous embolism, and Hughes (1970) described
and intraspinal branches. a patient who was given phenol intrathecally. In each
this may be misleading, since the diagnosis is almost al-

ways made at autopsy, and since cervical lesions are
more frequently associated with a fatal outcome. Ante-
mortem diagnosis is extremely difficult, and it is likely
that many with involvement lower in the neuraxis are
identified as patients with myelopathy of unknown
cause. The pathogenesis of this condition is not under-
stood, but may possibly be related either to pressurized
intravascular injection of disc material during axial stress
(Naiman et al., 1961) or to herniation of disc tissue into
the vertebral body sinusoids (Schmorl’s node formation)
(Feigin et al., 1965; Srigley et al., 1981; Toro et al., 1994;
McLean et al., 1995; Tosi et al., 1996; Fahey et al.,
1998). Atheromatous embolism, of course, occurs
strictly on the arterial side of the spinal intramedullary
circulation. Despite the rarity with which vascular oc-
clusion has been documented pathologically (Périer et
FIGURE 21.9 Diagram of the distribution of spinal cord damage in al., 1960; Herrick and Mills, 1971; Laguna and
three patients with the “anterior spinal artery” syndrome: (A) from
Cravioto, 1973; Slavin et al., 1975; Rodriguez-Baeza,
a patient who suffered ischemic myelopathy after cardiac arrest, (B)
from a patient who developed atheromatous embolism to the ante- 1991) the condition referred to as atherosclerotic
rior spinal artery, and (C) from a patient who had undergone de- myelopathy, which is more popular in Europe than it is
layed operative evacuation of a dorsal spinal epidural hematoma in this country, has been presumed to develop on this
many years earlier. The anterior spinal artery was patent in patients basis (Hughes and Brownell, 1966; Jellinger, 1967;
A and C. The broken line indicates the neuroanatomical pathway for
Wolman and Bradshaw, 1968; Fieschi et al., 1970). Clin-
pain and temperature.
ically, this disorder is said to affect elderly subjects with
a history of heart disease and to be characterized by the
protracted development of upper and lower motor neu-
instance, the brunt of the damage was borne by the ron signs in the relative absence of sensory dysfunction.
posterior portions of the dorsal and lateral funiculi and Pathologically, emboli that are arrested within the
by the intervening posterior horns. Examples docu- anterior or posterior spinal arterial trunks tend to pro-
mented by MRI include one that developed in associ- duce territorial spinal cord infarction, although the size
ation with vertebral artery dissection (Bergquist et al., of the damaged area may vary from case to case de-
1997) and another that resulted from inadvertent ad- pending on the longitudinal extent of obstruction and
ministration of glue into a posterior radiculomedullary on the integrity of the perimedullary collateral arterial
artery (Mascalchi et al., 1998). supply. Those that obstruct only the smaller in-
tramedullary branches are more likely to produce mul-
tiple small infarcts within the gray and white matter
Embolic spinal arterial infarction
(Fig. 21.10); at times, however, there may be little or
In those few instances in which intramedullary arterial no evidence of damage to the spinal cord parenchyma
obstruction has been demonstrated pathologically, it has (Soloway and Aronson, 1964). Finding emboli micro-
usually been due to fibrocartilaginous or atheromatous scopically, particularly atheromatous emboli, may re-
emboli (Périer et al., 1960; Naiman et al., 1961; Reich, quire an exhaustive search through many sections. It is
1968; Herrick and Mills, 1971; Kepes and Reynard, our experience as well as that of others (Hashizume et
1973; Laguna and Cravioto, 1973; Slavin et al., 1975; al., 1997) that one may find thrombosed vessels in only
Moossy, 1979; Ho et al., 1980; Bots et al., 1981; Srigley a few of which cholesterol cleft formation is evident.
et al., 1981; Kestle et al., 1989; Bockenek and Bach,
1990; Mikulis et al., 1992). In roughly half of the
Venous Infarction of the Spinal Cord
recorded examples of fibrocartilaginous embolism,
which may also affect the intramedullary veins, there is The potential effects of impaired spinal venous outflow
a history of minor head or neck trauma or of lifting have not received much attention in the literature. This
(Bockenek and Bach, 1990; Kestle et al., 1989; Moor- is probably best accounted for in part by the relative
house et al., 1992). The literature suggests that the cer- rarity with which obstruction is demonstrated anatom-
vical spinal cord is affected most commonly, although ically within the spinal intraparenchymal or lep-
A Venous thrombosis or embolism

The most dramatic effects of impaired venous drainage
are those of venous infarction due to thrombus for-
mation within the spinal leptomeningeal or epidural
veins. Infarction that occurs in this setting may be ei-
ther hemorrhagic or largely nonhemorrhagic in nature.
Hemorrhagic infarction is characterized clinically by
sudden onset, rapid progression, back pain, and rela-
tively short survival (average, 26 days) (Gruner and
Lapresle, 1962; Hughes, 1971; Nagashima et al., 1974;
Rao et al., 1982); pathologically, damage tends to pre-
dominate centrally within the gray matter, with promi-
nent hemorrhagic perivenous extravasation of blood
B that may evolve into frank intramedullary hemorrhage.
Nonhemorrhagic infarction, by contrast, is character-
ized by protracted onset (over a period of weeks), slow
progression, absence of back pain, and a long survival
period (average, 44 weeks) (Garland et al., 1966;
Neumayer, 1966; Urquhart-Hay and Teague, 1974;
Kawashima et al., 1977; Kim et al., 1984); morpho-
logically, there is extensive, largely nonhemorrhagic co-
agulative necrosis beginning within the peripheral white
matter, with variable but sometimes considerable in-
volvement of the spinal gray (Fig. 21.11). The basis for
the development of one or the other type of infarction
C is unclear but is likely related both to the rate and to
the extent of venous thrombosis.
Identification of fibrocartilaginous emboli, to which
we have already alluded, may at times be limited to the
intramedullary venous circulation, in which case it typ-
ically produces smaller, more discrete, and more widely
distributed infarcts that may be either hemorrhagic
or nonhemorrhagic in character (Feigin et al., 1965;
Bodechtel, 1968; Jurkovic and Eiben, 1970).
Decompression sickness (Caisson disease)

Decompression sickness, in which symptoms of spinal
cord dysfunction seem to predominate, occurs more fre-
FIGURE 21.10 Multiple thoracic spinal cord infarcts due to athero- quently among those with a patent foramen ovale
matous embolism in a 75-year-old man who died 10 weeks after the (Wilmshurst et al., 1989), and is thought to represent
sudden onset of left leg weakness and loss of pain and temperature
perception that was worse on the left. (The right side of the spinal
the effects of accumulation of free gas (nitrogen) that
cord is on the left side of the photograph.) Low-power photomicro- is liberated when tissue gas tension rises rapidly above
graphs at T5 (A) and T6 (B) show the presence of several small foci the ambient pressure (e.g., when a diver ascends too
of coagulative necrosis. Luxol fast blue–cresyl violet stain. (C) Pho- rapidly to the surface), thereby activating the clotting
tomicrograph of atheromatous embolism within small intra- cascade (Melamed et al., 1992). When there is struc-
parenchymal spinal arterial branches. Hematoxylin-eosin stain.
tural damage it typically becomes evident as multiple
small foci of perivascular necrosis, sometimes hemor-
tomeningeal venous system, in part by the failure to rhagic, particularly within the white matter (Haymaker
recognize that impairment of venous outflow may orig- and Davison, 1950; Haymaker and Johnson, 1955;
inate outside of this system, and in part by the fact that Palmer et al., 1987, 1981; Calder et al., 1989). The
such impairment need not be accompanied by occlu- pathogenesis of these lesions is debated. The contention
sive venous obstruction. that impairment of epidural venous drainage is of
A B
C D
FIGURE 21.11 Nonhemorrhagic venous infarction of the spinal cord in a 71-year-old man who devel-
oped paraplegia and sensory loss over a period of 5–6 weeks and who died after 16 weeks of illness.
(A) Transverse sections of spinal cord from cervical to sacral levels, showing liquefactive necrosis (mid-
dle and lower rows). (B) Low-power photomicrograph at L5, showing tissue breakdown within the ven-
tral two-thirds of the spinal cord. Hematoxylin-eosin stain. (C) Photomicrograph of the anterior me-
dian sulcus at T12, showing thrombosis, organization, and recanalization within the anterior median
spinal vein (lower right) and its sulcal tributary (above), with preservation of the anterior spinal artery
(lower left). Hematoxylin-eosin stain. (D) Diagrammatic representation of the distribution of spinal cord
damage. (A and D from Kim et al., 1984, with permission.)
major importance (Haymaker and Johnson, 1955) is compressed as a result of extravascular (autochtonous)
supported by experimental cinevenographic studies gas bubble formation (Pearson, 1997).
demonstrating the presence of obstruction within this
system (Hallenbeck et al., 1975). Others, using trans-
Nonocclusive impairment of spinal venous outflow
cranial Doppler sonography, have demonstrated the ap-
pearance of arterial gas bubbles during decompression, Impairment of venous drainage with ischemic damage
noting that the bubbles correlate with the size of the to the parenchyma of the spinal cord may also occur
right-to-left shunt through a patent foramen ovale, and in the absence of thrombo-occlusive disease. In cases
say that paradoxical embolism and arterial obstruction of brain death with sufficiently prolonged somatic sur-
are of greater pathogenetic importance (Ries et al., vival, for example, the presence, within the rostral cer-
1999). Still another view is that arteries and veins are vical spinal cord, of circumferentially distributed zones
of coagulative necrosis, with relative sparing ventro-

medially, is well documented (Lindenberg, 1971; Parisi
et al., 1982; Schneider and Matakas, 1971), and is fre-
quently associated with radially oriented peripheral
perivenous hemorrhages at more caudal spinal levels
(Figs. 21.12, 21.13). Despite the absence of venous
thrombosis, we believe that the most logical explana-
tion for these changes is the obstruction of the upward
flow of spinal venous blood (Di Chiro and Doppman,
1970) by impacted cerebellar tonsils at the level of the
foramen magnum. The morphological alterations ob-
served at rostral cervical spinal levels are distributed
within the territory drained by the radial group of
parenchymal veins draining into the leptomeningeal
coronal plexus (Gillilan, 1970), and therefore represent FIGURE 21.13 Thoracic spinal cord in brain death, showing periph-
venous infarction. erally distributed, radially oriented perivenous extravasation of
Aboulker and his colleagues (Aboulker et al., 1975, blood. Hematoxylin-eosin stain.
1977) have argued, largely on clinical grounds, that
spinal venous hypertension and myelopathy may also
occur as a consequence of abnormalities within the effecting a rise in spinal venous pressure which, even
caval system of veins (such as stenosis, compression, in the absence of venous thrombosis, may cause the
and thrombosis). According to these authors, the spinal spinal cord to undergo slowly progressive ischemic at-
epidural venous engorgement that prevails radiograph- rophy.
ically is indicative of chronic stasis and inadequate The role played by interference with venous drainage
drainage, which form the basis for symptomatic spinal in cases of subacute or chronic spinal cord “compres-
cord dysfunction. Recently, Heller et al. (1996) de- sion” (e.g., by epidural metastases) has been empha-
scribed the clinical and radiological findings in a sized by a number of investigators (Barron et al., 1959;
woman who, after undergoing endoscopic sclerother- Auld and Buerman, 1966; Ikeda et al., 1980; Kato,
apy for esophageal varices, developed what was pre- 1985; Arguello et al., 1990; Lada et al., 1997). As seen
sumed to be venous infarction of the spinal cord. in transverse section, even when the configuration of
Chronic myelopathy may also develop in the pres- the spinal cord is preserved, the typical appearance of
ence of an arteriovenous fistula (usually dural) that the spinal cord is one of multiple wedge-shaped foci,
drains into the spinal leptomeningeal venous system. with their apices directed inward, of microcystic rar-
This vascular abnormality, which is discussed in more efaction or coagulative necrosis within the peripheral
detail in the section entitled “Spinal Vascular Malfor- white matter (Fig. 21.14) (McAlhany and Netsky,
mations,” appears to interfere with venous drainage by 1955; Shibasaki et al., 1983). When advanced, damage
may extend more deeply, even into the spinal gray.
Smaller lesions, when favorably sectioned, are fre-
quently seen to be perivenous, and may be associated
with hemorrhagic extravasation (Manabe et al., 1989).
Microangiographic and histological studies of animal
models of spinal epidural neoplastic disease seem to
provide strong support for the idea that these lesions
are the result of epidural venous obstruction and, there-
fore, represent venous infarcts (Ikeda et al., 1980; Kato
et al., 1985; Arguello et al., 1990). The morphological
effects described above should be distinguished from
the cylindrical necrotic cores that may also be encoun-
tered occasionally (and that are more frequently seen
following traumatic injury) within the ventral portions
FIGURE 21.12 Midcervical spinal cord in brain death, showing pe-
of the posterior columns. These lesions seem to evolve
ripherally distributed dorsal and lateral ischemic necrosis. Masson more acutely, and their appearance is probably more
trichrome stain. closely related to mechanical compression than to im-
were observed at all spinal levels (but especially in the

vicinity of the cervical and lumbar enlargements), usu-
ally presented with an episode of hemorrhage, were
characterized angiographically by the presence of ve-
nous or arterial aneurysms and by bidirectional venous
drainage, and were associated with a good postopera-
tive outcome only 49% of the time. Low-flow dural
AVFs, however, appeared to be acquired later in life
(average age of onset, 49 years), were seldom if ever
observed above midthoracic spinal cord levels, pre-
sented most frequently with gradually progressive para-
paresis, were characterized angiographically by the ab-
sence of vascular aneurysms and by rostrally directed
venous drainage, and were associated with a good ther-
apeutic outcome 88% of the time.
FIGURE 21.14 Myelopathy in a man with prostatic carcinoma that
metastasized to the thoracic vertebral column, for which radiation
With respect to intramedullary AVMs, the patho-
therapy was initiated a few days prior to death. Although no mass logical findings are similar to those observed within the
lesion was identified within the spinal canal at autopsy, the spinal cranial cavity (Jellinger, 1986). Within the lep-
cord at the level in question contained multiple, peripherally accen- tomeninges overlying the affected region there are en-
tuated foci of coagulative necrosis. Luxol fast blue–cresyl violet stain. larged, tortuous blood vessels, including one or more
abnormal arteries and several veins, some of which may
run the length of the spinal cord (Wyburn-Mason,
paired venous drainage (Hashizume et al., 1983, 1997; 1943). These surface channels are directly continuous
Shibasak et al., 1983). with a dense conglomeration of intramedullary blood
vessels that may replace the spinal cord parenchyma ei-
ther entirely or in part (Fig. 21.15). The malformation
Spinal Vascular Malformations
may be fed by one or more radiculomedullary arteries.
A detailed description of central nervous system vas- Aneurysmal dilatation of adjoining veins or arteries
cular malformations (telangiectases, cavernous an- may be observed. Histologically, the vascular nidus is
giomas, arteriovenous malformations, and venous composed of abnormal, closely packed blood vessels
angiomas) and proliferative vascular lesions (heman- that cannot readily be identified as either arteries or
gioblastomas and hemangiopericytomas) is presented veins. Their walls are heavily collagenized and are de-
elsewhere. The focus of this discussion will, therefore, void of smooth muscle or elastic tissue. Highly char-
be on spinal arteriovenous malformations (AVMs) and acteristic is the presence of remarkable, often abrupt
arteriovenous fistulas (AVFs). variations in the thickness of the walls of individual
It is only relatively recently that several groups of in- vessels. Mural calcification and intraluminal thrombus
vestigators have been able, with the aid of spinal an- formation are occasionally encountered. The walls of
giography and angiotomography, to define the distin- feeding arteries and, especially, of draining veins may
guishing clinical and hemodynamic features of spinal show considerable hypertrophy and hyalinization.
AVMs and AVFs (Kendall and Logue, 1977; Logue, What remains of the intervening spinal cord paren-
1979; Merland et al., 1980; Oldfield et al., 1983; chyma typically shows pallor of myelin staining, glio-
Symon et al., 1984; Gueguen et al., 1987; Rosenblum sis, hemosiderin deposition, and other histological ev-
et al., 1987; Wrobel et al., 1988; Criscuolo et al., 1989; idence of chronic injury.
Hall et al., 1989; Alleyne et al., 1998). Rosenblum et In most cases of spinal dural AVF, the vascular nidus
al. (1987) subdivided intradural AVMs into juvenile is either embedded within or situated adjacent to the
AVMs (which affect the entire cross-sectional extent of dura ensheathing a nerve root (Merland et al., 1980;
the spinal cord), glomus AVMs (which are more lo- Benhaiem et al., 1983; Rosenblum et al., 1987). Ben-
calized), and direct (intramedullary or paramedullary) haiem, et al. (1983), who described the histological ap-
AVFs. In their series of patients, there were some in- pearance of the vascular lesion in surgically obtained
teresting contrasts between intradural AVMs and dural material, found the feeding arterial channel to be of
AVFs. High-flow intradural AVMs, which they pre- normal appearance and the draining vein to be char-
sume to be of vascular embryological origin, tended to acterized by fibrous mural thickening and a variable
become symptomatic earlier in life (average, 27 years), degree of luminal narrowing. The fistula itself was rep-
A ings, including subacute necrotic myelitis, Foix-

Alajouanine syndrome (Criscuolo et al., 1989), an-
gioma racemosum venosum (Wyburn-Mason, 1943),
angiodysgenetic necrotizing myelopathy (Scholz and
Manuelidis, 1951), and type I spinal arteriovenous
malformation (Ommaya, 1985). Pathologically, the
leptomeningeal veins, especially dorsally, are dilated
and tortuous and may, in advanced cases, form an
elaborate coiled plexus of vessels extending over the
length of the spinal cord (Wyburn-Mason, 1943;
Aminoff et al., 1974). The spinal cord typically is con-
siderably reduced in cross-sectional area and is char-
acterized by ill-defined softening and brownish dis-
coloration, particularly within the gray matter (Fig.
21.16). Microscopically, the leptomeningeal veins in
the affected regions show marked collagenization of
their walls. The intima is often eccentrically thickened,
and there may be evidence, on occasion, of thrombo-
B sis, organization, or recanalization. At more rostral
levels the veins, though dilated, show lesser degrees
of mural thickening. The appearance of the arteries is
usually entirely normal. Within the parenchyma of the
spinal cord there is widespread hyaline thickening of
the venocapillary network, with perivascular extrava-
sation of erythrocytes and hemosiderin deposition.
Typically these abnormalities are associated with ill-
defined areas of tissue pallor and rarefaction that may
progress, in more severely affected regions, to frank
cavitation.
The mechanism of neurological deterioration in
cases of spinal dural AVF is believed to be different
from that in cases of spinal intramedullary AVM. In
FIGURE 21.15 Spinal intramedullary arteriovenous malformation
the latter instance, spinal cord damage is thought to
(AVM). (A) Replacement of the upper thoracic spinal cord by a mas-
sive conglomeration of abnormal blood vessels. (B) Low-power pho-
be due either to hemorrhage (i.e., into the subarach-
tomicrograph of a cervical spinal AVM, showing the presence of nu- noid compartment or into the parenchyma) or to ar-
merous collagenized vascular channels within both the leptomeninges terial “steal” (Rosenblum et al., 1987). With spinal
and the parenchyma of the spinal cord. Masson trichrome stain. dural AVFs, however, both angiographic and histo-
Courtesy of Dr. Joseph E. Parisi. logic evidence would seem to indicate that the shunt-
ing of arterial blood into leptomeningeal veins leads
to spinal venous hypertension, thereby interfering
resented by an irregular, thin-walled channel embed- with venous drainage and producing venocongestive
ded in the dura. Because precise postmortem localiza- myelopathy (Aminoff et al., 1974; Williamson, 1975;
tion of the fistulous communication, which typically Rosenblum et al., 1987). Parenthetically, it might be
occurs at or below T4, is very difficult in the absence added that spinal venous hypertension and myelopa-
of spinal angiography, and because the lesion is highly thy may also be produced by AVFs situated outside
amenable to surgical therapy (Oldfield et al., 1983), the spinal canal, including the pelvis (Weingrad et al.,
there are as yet no detailed postmortem descriptions of 1979), retroperitoneal region (Merland et al., 1980),
the pathological findings within the spinal cord of an- and cranial cavity (Wrobel, 1988; Partington et al.,
giographically confirmed cases, although biopsy find- 1992; Hähnel et al., 1998). Interestingly, similar
ings have been described (Hurst et al., 1995). Never- changes have been described in the brain in associa-
theless, the general belief is that the morphological tion with intracranial dural AVFs (Friede and Roess-
changes are similar to those described by Foix and Ala- mann, 1969; Friede and Schubiger, 1981; Nakada et
jouanine (1926) and by others under a variety of head- al., 1985; Hinokuma et al., 1990).
A B
FIGURE 21.16 Spinal dural arteriovenous fistula (AVF). (A) A cluster of

distended draining veins over the dorsal surface of the lower thoracic
spinal cord. (B) Transverse sections of lower thoracic and lumbar spinal
cord, showing central hemorrhagic discoloration. (C) Low-power pho-
tomicrograph of lower thoracic spinal cord, showing marked thicken-
ing of the walls of veins due to elevated venous pressure. Masson
trichrome stain. (D) Photomicrograph of spinal cord parenchyma,
showing thickening and hyalinization of the walls of small venules, as
well as hemorrhagic extravasation. Masson trichrome stain.
TRAUMATIC SPINAL CORD INJURY damage produced. Immediately fatal spinal cord injuries
are seen preferentially in the upper cervical region, at
A detailed account of the epidemiology of traumatic and below the craniospinal junction, in part because of
spinal cord injury is beyond the scope of this discus- the relatively high mobility of the skull upon the spine
sion, and the reader is referred to several reviews on and in part because of damage to the respiratory path-
the subject (Kurtzke, 1975; Guttmann, 1976a; Ander- ways. Davis, et al. (1971), in a coroner’s office–based
son et al., 1980; Young et al., 1982; Balentine, 1988). autopsy study, found that 61% of those with high cer-
In peacetime, such injuries are most commonly caused vical spinal cord injury also suffered associated brain in-
by motor vehicle accidents, followed by falls and by jury. Half of those with injuries in this region sustained
sports injuries (especially diving accidents) (Kurtzke, damage to the interspinous or anterior or posterior lon-
1975; Tator and Edmonds, 1979). Particularly if one gitudinal ligaments or to the ligamentum flavum, usu-
includes fatal injuries, the actual frequency with which ally in close proximity to the vertebral body of C1; torn
traumatic spinal cord injury occurs in the general pop- or ruptured intervertebral discs, when observed, oc-
ulation is difficult to estimate (Ergas, 1985). curred most frequently at the C5–C6 interspace.
Certain regional anatomical features seem to play a The mid- and lower cervical region (i.e., spinal
role in determining both the nature and severity of the C4–C8) is the most common site of immediate, nonfa-
tal traumatic injury (Balentine, 1988). Damage to the of destruction) and by spastic weakness that is greater
spinal cord may be the result of hyperflexion, hyperin the arms than in the legs. Preferential upper ex-
extension (deflexion), hyperrotation, compression, or tremity weakness was for many years believed to be
any combination thereof. Vertebral fracture may or based on the more medial positioning of the lateral cor-
may not be present, but there is virtually always dam- ticospinal tract fibers carrying impulses to the arms as
age to the ligaments. opposed to those carrying impulses to the legs, but it
The spinal cord from vertebral levels T1–T10 ap- has recently been emphasized that there is little or no
pears to be less susceptible to nonpenetrating injury be- direct anatomical or physiological evidence to support
cause of the protection afforded by the rib cage, be- such somatotopical organization (Levi et al., 1996). In-
cause of the more limited mobility of the spine in this deed, those few detailed studies that are available sug-
region, and because of the higher canal-to-cord diam- gest that fibers carrying impulses to the arms and legs
eter ratio. are diffusely distributed within the corticospinal tract
Nonpenetrating injuries at and below lower thoracic (Barnard and Woolsey, 1956; Bucy et al., 1964; Liu
spinal levels appear frequently to have been sustained and Chambers, 1964; Nathan et al., 1990). The ap-
in the sitting position (usually in motor vehicle acci- pearance of a Brown-Séquard syndrome, with con-
dents), although some are the result of falls from a tralateral loss of pain and temperature perception and
height. They are often associated with vertebral body ipsilateral spastic weakness and loss of proprioception,
fractures of “bursting” or comminuted type. The mech- most frequently is the result of a penetrating (stab)
anism of bone damage is presumed to be axial load- wound and is often incomplete.
ing, frequently with flexion or rotational components There are many ways to classify traumatic injuries
that enhance the likelihood of damage to the spinal to the spinal cord but, for purposes of this discussion,
cord by rendering the fracture less stable (Bedbrook, we will subdivide them into penetrating (open) injuries,
1976; Willen et al., 1989). Pathological studies in parain which the dura is breached, and blunt (closed) in-
plegic subjects have shown that these lesions are usu- juries, in which the integrity of the dura is preserved.
ally accompanied by disc injuries, loosening or avul- The spinal cord lesions that are produced may be re-
sion (but not rupture) of the anterior longitudinal garded as being either primary or secondary in nature.
ligament, and partial or total rupture of the posterior Primary lesions (e.g., contusion, laceration, and com-
longitudinal ligament (Willen et al., 1989). Damage to pression) are those that develop at the moment of im-
the spinal cord itself is somewhat variable, but compact, whereas secondary lesions evolve subsequent to
plete necrosis is not infrequently observed. the time of injury. Early secondary lesions, most of
Only a few brief comments will be made regarding which are circulatory in origin, include necrosis, hem-
the neurological deficit associated with traumatic spinal orrhage, edema, thromboembolic infarction, and in-
cord injury. For a more detailed discussion, the reader fection. Late secondary lesions, which are more ap-
is referred elsewhere (Tator, 1996). With severe in- parent months to years after injury, include wallerian
juries, the initial period of spinal shock, which may last degeneration, syringomyelia, arachnoidopathy, and re-
for up to 6 weeks (Guttmann, 1976b; Atkinson and generative phenomena.
Atkinson, 1996; Nacimiento and Noth, 1999), is char-
acterized by areflexic flaccid weakness and complete
Penetrating Injuries
sensory loss below the level of the lesion. In cases of
complete destruction of the spinal cord—for example, Penetrating injuries, in which the dura is breached and
crush injury or transection—the deficit will persist, al- the continuity of the spinal cord is disrupted directly
though spastic paralysis and hyperactive reflexes will by the injuring agent, may be induced by a wide vari-
eventually develop. Hyperflexion injuries not infre- ety of objects. In civilian life most of these injuries in
quently result in the appearance of an anterior spinal the United States are caused by missiles (gunshot
cord syndrome in which there is hypesthesia (due to in- wounds) or sharp objects (stab wounds). Their neuro-
volvement of the anterior spinothalamic tracts), hypal- logical effects will depend on the segmental level at
gesia (due to involvement of the lateral spinothalamic which they occur and on the completeness with which
tracts), and spastic hyperreflexic weakness (due to in- the spinal cord is destroyed. Missiles more commonly
volvement of the lateral corticospinal tracts). The cen- penetrate the spinal canal from the back, as the verte-
tral spinal cord syndrome typically follows hyperex- bral column confers considerable protection against all
tension injuries and, with damage at cervical spinal but those of high-velocity type (Bailey, 1971). Since
cord levels, is characterized by a variable degree of loss missiles may produce injury either directly or by driv-
of posterior column sensation (depending on the extent ing bone fragments through the dura, the extent of
damage to the spinal cord may vary considerably, rang- pletely crushed, to determine its contribution to the vic-
ing from relatively mild focal necrosis to transection or tim’s death, especially when there is extensive injury to
complete crush injury. other organ systems. In addition, the continuity of the
In the case of stab wounds, the instrument of injury vertebral column is usually restored immediately after
is usually a knife, although screwdrivers, ice picks, and the injury, particularly in cases of severe hyperexten-
other tools have also been used. The majority of in- sion, thereby making it more difficult to detect the pres-
juries of this type occur in the thoracic region. The ence of spinal cord injury (Kakulas, 1984). Finally, tis-
blade typically enters obliquely between adjoining lam- sue necrosis, even if extensive, requires a survival period
inae, through a lamina (thus driving bone fragments in- of 6–24 hours or more for histological recognition.
ward), or through an intervertebral foramen. Damage Grossly evident vascular disruption of any significant
to the spinal cord may occur either directly, through degree, such as vertebral artery injury, epidural or sub-
interruption of its vascular supply, or by pushing it dural hemorrhage, anterior spinal artery thrombosis,
against the opposite face of the bony wall (i.e., “con- or frank hematomyelia, is seldom encountered. In the
trecoup” injury) (Lipschitz and Block, 1962; Lipschitz, absence of transection or severe crush injury, surpris-
1976). Blunt instruments usually lead to bruising, ingly little may be seen (Tator and Koyanagi, 1997).
whereas sharp instruments commonly cause associated With closed injuries, even if one or more of the verte-
bleeding. For the foregoing reasons, the nature of the bral bodies is fractured, bone does not penetrate the
resulting neurological deficit will vary. Most often there dura. Preservation of the continuity of the vertebral col-
is a partial or complete Brown-Séquard syndrome (Bai- umn does not necessarily imply the absence of severe,
ley, 1971; Jellinger, 1976; Lipschitz, 1976). The cen- irreversible damage to the spinal cord. Thorough anal-
tral portions of the posterior columns are usually pro- ysis requires complete examination of the surrounding
tected by the overlying spinous processes. bone and soft tissue. As seen in cross section, the only
gross or histological evidence of injury to the spinal
cord proper may be the presence of petechial hemor-
rhages.
NONPENETRATING INJURIES
Acutely Fatal Spinal Cord Lesions Primary Nonlethal Spinal Cord Lesions
It is convenient to subdivide nonpenetrating traumatic In those instances in which the victim survives more
spinal cord injuries into those that are acutely fatal and than a few hours after injury, morphological alterations
those that are not. Substantially less has been written are easier to recognize. Although primary nonpene-
of injuries with an immediately lethal outcome. There trating spinal cord injuries are traditionally sub-
are several reasons for this. In most countries injuries classified in a manner similar to those affecting the
of this type usually fall under the purview of coroners’ brain—namely, concussion, contusion, laceration, and
offices and forensic pathologists, amongst whom the compression (Bailey, 1971)—some of these terms are
level of interest in fatal spinal cord injury generally is seldom actually used when referring to the spinal cord.
not high, particularly if death can be attributed to other The standard definition of concussion is the imme-
causes. Access to forensic material on the part of those diate and temporary loss of spinal cord function with-
with a deep level of academic interest in the subject is out demonstrable anatomical changes (Bailey, 1971;
quite limited in this country. Virtually all of those in- Jellinger, 1976; Atkinson and Atkinson, 1996). Such a
juries that are immediately fatal occur in the high cer- definition implies that the opportunity seldom if ever
vical region, and the overwhelming majority of those arises to examine human or experimental material sub-
sustained during peacetime are attributable to motor jected to this type of injury and that, even if it did,
vehicle accidents, in which case sites of severe bodily nothing of significance would be found. Particularly
injury are usually multiple. The postmortem diagnosis confusing are literature references to descriptions of
of acutely fatal spinal cord injury requires a high index morphological alterations within “concussed” spinal
of suspicion and meticulous examination, with the aid cords that often are not of minor degree (Bailey, 1971;
of radiographs, of the cervical spine and surrounding Jellinger, 1976). The term is probably better suited to
soft tissues. There is no history of quadriplegia or other clinical usage only, to denote injury that is followed by
neurological deficit to direct the prosector’s attention the rapid and complete resolution of neurological
to this region. Even when the presence of spinal cord deficits (Zwimpfer, 1990).
damage is documented it may be difficult, except in The opportunity to examine spinal cord contusions,
cases in which the spinal cord is transected or com- which presumably result from impaction against the
bony wall of the spinal canal, seldom arises except in nantly pericapillary extravasates of blood and serum
experimental model systems, unless they are severe, in constituents within the spinal gray (Allen, 1914;
which case the term crush injury is preferred. These le- Ducker et al., 1971; Ducker, 1976; Kakulas, 1984;
sions are almost always associated with bony fracture Iizuka, 1987; Balentine, 1988; Tator and Fehlings,
or dislocation or both, and the severity of the damage 1991). Over a period of several hours these hemor-
is accounted for by the relatively close proximity of the rhages may coalesce or become more numerous. Evi-
opposing walls of the spinal canal as compared to those dence of injury to axons (in the form of axonal
of the skull. swellings or spheroids) and nerve cell bodies becomes
Laceration of the spinal cord is a rare event in the apparent shortly thereafter. In patients who survive for
absence of a penetrating injury, and is most frequently at least 3 hours or so, injured axons can be readily de-
associated with vertebral fracture and introduction of tected immunocytochemically using antibodies to the
spicules of bone into the spinal cord parenchyma. Hem- -amyloid component of amyloid precursor protein,
orrhages of varying degree may also be observed. The which accumulates within axonal varicosities owing to
resulting neurological deficit depends on the severity impairment of axoplasmic flow (Kakulas, 1999; Cor-
and location of the damage. nish et al., 2000). From 8 to 24 hours progressive
Acute traumatic spinal cord compression, also a rel- edema of the white matter, as evidenced by pallor of
atively rare occurrence (Wolman, 1964; Bedbrook, myelin staining and by tissue rarefaction, begins at the
1966; Jellinger, 1972), is seen most frequently in asso- level of injury and spreads into adjoining segments.
ciation with fracture/dislocations and subluxations. As Macrophages first become recognizable at about 8
already indicated, vertebral body continuity is often re- hours, increasing in numbers rapidly thereafter. As-
stored immediately after the injury, even if there has troglial cells that are immunoreactive for glial fibrillary
been bony compression (Jellinger, 1972; Kakulas, acidic protein start to become prominent at 48–72
1984). Spinal cord compression is believed by some to hours. After 24–48 hours have elapsed, there is exten-
be an important factor in patients with cervical spondy- sive coagulative necrosis at the site of hemorrhage, fol-
losis who are subjected to sudden, severe hyperexten- lowed by tissue breakdown progressing to cavitation.
sion (Wilkinson, 1960, 1971; Pathak et al., 2000). With Although the pathophysiological basis for the histo-
less severe compression there may be hemorrhages logical sequence of events described above is not fully
within the spinal gray or hemorrhagic necrosis, espe- understood, work in experimental animals seems to
cially dorsally within the spinal cord (Jellinger, 1972). suggest that vascular (particularly venous) integrity is
Particularly characteristic is the appearance of a cylin- disrupted by the injury (Dohrmann et al., 1971),
drical core of necrosis, tapering in conical fashion thereby accounting for the development of the hemor-
above and below the site of maximal compression, rhages. Axonal injury also appears to be primary, and
within the ventral portions of the posterior columns may be due either to interruptions in continuity or to
(Davison, 1945; Jellinger, 1972, 1976; Balentine, alterations in axoplasmic flow (Bailey, 1960; Bresna-
1988). The genesis of this lesion has been likened to han, 1978; Balentine, 1988). Impairment of microcir-
squeezing a tube of toothpaste (McVeigh, 1923). culatory perfusion, particularly of the white matter, has
Necrotic cores of this type are generally seen only with been demonstrated in colloidal carbon studies, and may
acute spinal cord compression. Compression that extend for a considerable distance from the site of in-
evolves more slowly, such as that due to neoplasm, is jury (Wallace et al., 1986). In addition, there is a con-
believed to produce spinal cord damage on the basis of siderable reduction in regional spinal blood flow, as
impairment of venous outflow, as discussed in the sec- shown by a variety of techniques (Tator and Fehlings,
tion entitled “Nonocclusive Impairment of Spinal Ve- 1991), as well as impairment of autoregulation (Guha
nous Outflow.” Exceptionally severe compression is et al., 1986). Reduced arterial perfusion at the site of
synonymous with complete spinal cord crush injury and injury, in combination with a frequently observed post-
is characterized by total parenchymal necrosis at the traumatic decline in systemic blood pressure and car-
level of injury. diac output (Guha and Tator, 1988), is believed to be
of importance in the development of post-traumatic
ischemic spinal cord necrosis.
Secondary Spinal Cord Lesions
Other early consequences of traumatic spinal cord
Based largely on experimental studies, in the absence injury that may greatly increase the extent of tissue
of spinal cord transection or complete crush, the earli- damage within minutes or hours of impact include the
est alteration that is visible by light microscopy is the release of vasoactive substances and excitotoxic neu-
appearance, within minutes of the injury, of predomi- rotransmitters (Choi, 1988; Panter et al., 1990; Liu et
al., 1991), Ca2 and K ion shifts (Balentine and Spec-

tor, 1977; Young, 1992), generation of oxygen free rad-
icals and lipid membrane peroxidation (Braughler and
Hall, 1989, 1992; Barut et al., 1993), loss of energy
metabolism (Clendenon et al., 1978), and activation of
the arachidonic acid cascade (Demediuk et al., 1985;
Hsu et al., 1985). A detailed account of these factors
is beyond the scope of this discussion, but they are of
great theoretical importance because of current re-
search efforts to limit their effects (Tator, 1995).
Traumatic demyelination, in which there is relative
sparing of axons, has not been studied in human ma-
terial to the degree that it has in animal models of spinal
cord injury (Blight, 1985; Bunge et al., 1997). It is most
readily observed around the epicenter of the primary FIGURE 21.18 Spinal intramedullary traumatic neuromata. Hema-
impact site, and its development is probably related at toxylin-eosin stain.
least in part to oligodendroglial apoptosis (pro-
grammed cell death), which has been described in both
human and experimental material (Li et al., 1996, that enhances conduction through demyelinated axons
1999; Liu et al., 1997; Emery et al., 1998). Its clinical (Blight, 1989; Hansebout et al., 1993). Focal remyeli-
relevance lies in the potential for treatment with agents nation of central axons, when seen, appears to be ac-
such as 4-aminopyridine, a potassium channel blocker complished by Schwann cells rather than by oligoden-
drocytes (Kakulas, 1999).
At later stages—that is, after months or years have
A
elapsed—the dura is densely adherent to and often in-
separable from the underlying spinal cord. This is due
to proliferation of collagen that is presumably of arach-
noidal cell origin. With severe injuries it may be im-
possible to delineate the spinal cord parenchyma. His-
tologically there may be very little residual spinal cord
tissue, and what remains is typically encased in an ir-
regular mass of collagen that is adherent to but usually
B separated from the overlying dura by small nests of
arachnoidal cells (Fig. 21.17). Variable degrees of
parenchymal cavitation may be seen but, particularly
where damage is maximal, an abundance of traumatic
neuromata (Fig. 21.18) is frequently observed and is
presumed to represent mainly regenerative sprouts from
disrupted perivascular nerve twigs from spinal nerve
roots, especially the centrally directed neurites of dor-
sal root ganglion cells (Hughes and Brownell, 1963b;
Wolman, 1967; Sung et al., 1981; Kamiya and
Hashizume, 1989). Wallerian degeneration of ascend-
ing fibers above and descending fibers below the level
of injury is not readily identified until 11/2 to 2 months
have elapsed.
FIGURE 21.17 Traumatic myelopathy. (A) Low-power photomicro- Of particular interest is the development of delayed
graph of midcervical spinal cord from a quadriplegic. There has been post-traumatic syringomyelia. This phenomenon is
a considerable loss of parenchymal tissue, and the little that remains characterized by the appearance, often after a latent pe-
is densely adherent to the overlying dura. Hematoxylin-eosin stain.
riod averaging 5–10 years or more, of syringomyelic
(B) Higher-power view of the ventral cervical spinal cord at an ad-
joining level, showing the collagen-filled subarachnoid compartment cavitation extending for a considerable distance above
to be separated from the dura (lower left) by a layer of arachnoidal or below the level of the injury (Barnett et al., 1973;
cells. Hematoxylin-eosin stain. Barnett and Jousse, 1976; Rossier et al., 1985). The ac-
FIGURE 21.19 Post-traumatic syringomyelia. The spinal cord was se-

verely injured at C5 (center left) and, at autopsy many years later, a
syringomyelic cavity was seen to extend downward to midthoracic
levels (upper right).
tual frequency with which this complication occurs is

not known but, with the advent of techniques such as
magnetic resonance imaging (MRI), it is much more
widely recognized than it was in years past. A recent
estimate has placed the incidence at over 20% (Nielsen
et al., 1999). Cavitation may progress either rostrally FIGURE 21.21 Low-power photomicrograph of syringomyelic cavita-
tion within the lower cervical spinal cord, four segments below the
or caudally and may extend over a few segments or
site of maximal injury. Note the dense collagen deposition within the
along the whole length of the spinal cord (Figs. subarachnoid compartment, with entrapment of nerve roots. Bodian
21.19–21.21). The clinical manifestations typically stain.
evolve over a period of weeks or months or years al-
though occasionally it progresses much more rapidly,
over a period of several hours. Evidence of increasing
upward into the brain stem, there may be evidence of
neurological deficit tends to be more dramatic in para-
trigeminal or other cranial nerve dysfunction. Patho-
plegics who develop cavitation that progresses upward
logically, the cavity often originates at the level of in-
than in quadriplegics who develop cavitation that pro-
jury, although at times it may begin some distance
gresses downward, for obvious reasons. Sensory deficits
away. It usually extends to one side of the spinal cord,
predominate during the early stages, but eventually mo-
and may be multiple. Detailed examination ordinarily
tor weakness becomes apparent. If cavitation extends
fails to reveal any direct connection with the central
canal, fourth ventricle, or subarachnoid compartment.
The cavity itself contains no epithelial lining and is typ-
ically bordered by a dense layer of glial tissue. There
is some debate as to the mechanisms by which post-
traumatic syringomyelia develops. One explanation is
that it results from progressive tearing, during episodes
of elevated venous back pressure (e.g., associated with
coughing, sneezing, or Valsalva maneuvers) causing a
spinal cord that has been rendered less mobile by the
presence of adhesive arachnoidopathy (Barnett et al.,
1973; Barnett and Jousse, 1976). The studies of Heiss
and his colleagues (1999) may also be of relevance. Us-
FIGURE 21.20 Post-traumatic syringomyelia. (A) In this instance the
cavity extended upward from the site of injury at C5 (upper center) ing cine MR imaging in patients with Chiari I malfor-
into the rostral cervical spinal cord (upper left). (B) The cavity ended mation, these investigators showed that, during systole,
within the medulla. the cerebellar tonsils, which occluded the subarachnoid
compartment at the foramen magnum, acted in pis- present in the vast majority of individuals over the age
tonlike fashion to produce subarachnoid pressure of 50 (Collins, 1950). In most instances, however, it is
waves that compressed the spinal cord and propagated asymptomatic (Fig. 21.22). The development of neu-
syrinx fluid downward, whereas, during diastole, sy- rological dysfunction depends on a number of factors,
rinx fluid flowed upward, thus suggesting that the pro- including the degree of narrowing of the spinal canal,
gression of syringomyelia was directly related to ob- the superadded effects of trauma, and the severity of
struction of the subarachnoid flow of CSF; it is possible associated root-sleeve fibrosis (Wilkinson, 1971). Us-
that a similar mechanism may be operative in post- ing a variety of techniques, several groups of investi-
traumatic syringomyelia, in which there is also ob- gators (Wolf et al., 1956; Burrows, 1963; Hughes and
struction of CSF flow at the injury site. The role played Brownell, 1965; Pathak et al., 2000) have measured the
by vascular factors is unknown. minimum midsagittal diameter of the spinal canal and
have found it to be reduced by an average of approx-
imately 3 mm below normal in cases of cervical spondy-
MYELOPATHY DUE TO DISEASES OF THE losis, an effect that would be magnified in a congeni-
SPINAL COLUMN tally narrow canal. Since this diameter is still some 2–3
mm greater than the midsagittal diameter of the spinal
Intervertebral Disc Disease cord at this level (Burrows, 1963; Wilkinson, 1971),
subjects with this degree of narrowing would not nec-
Intervertebral disc disease is a major cause of spinal essarily be symptomatic, but they would be consider-
disability. In the cervical region, neurological dysfunc- ably more susceptible to the effects of hyperextension
tion is most commonly associated with cervical spondy- or hyperflexion such as might occur with superimposed
losis, whereas, in the lumbar region, disability is more traumatic injury. Indeed, it is not uncommon for a pa-
often attributable to acute disc prolapse. tient to develop quadriparesis acutely after a fall, a dive,
Intervertebral discs, which are situated between the a blow to the head, a “whiplash” injury, or manipula-
surfaces of adjoining vertebral bodies, undergo pro-
gressive alterations with increasing age. The internal
portion of the disc consists of a notochordal remnant,
the nucleus pulposus, that is under considerable
pressure (Petter, 1933). The denser peripheral portion,
the annulus fibrosus, is composed of concentrically
arranged lamellae of fibrocartilage, and, in the cervical
region, is thicker between the anterior margins of the
vertebral bodies than it is posteriorly. Particularly af-
ter the age of 50, there is a progressive decrease in the
water content and in the elasticity of the disc (Püschel,
1930; Saunders and Inman, 1939), thus rendering it
more susceptible to injury. The resulting narrowing of
the disc space presumably leads to the formation of os-
teophytes or bony spurs at those sites where the mar-
gins of the vertebral bodies come into contact (Wilkin-
son, 1960, 1971). From a clinical standpoint, the most
important vertebral osteophytes are those that project
posteriorly into the spinal canal or laterally into the in-
tervertebral foramina. This is most likely to occur
where mobility is greatest—namely, at the C5–C6 and
C6–C7 interspaces (Bowden, 1971).
Cervical Spondylosis (Spondylosis Deformans)

Cervical spondylosis represents the bony alterations in
FIGURE 21.22 MRI of cervical spondylosis in a relatively asympto-
adjacent vertebral bodies consequent to the degenera- matic man who died of massive pulmonary embolism on the day be-
tive intervertebral disc changes that have been described fore he was scheduled to have surgery. Autopsy disclosed no histo-
above. A significant degree of cervical spondylosis is logical evidence of spinal cord damage.
tion of the neck (Wilkinson, 1971). Among sympto- A

matic patients, the midsagittal diameter may not nec-
essarily be the most reliable indicator of spinal canal
encroachment. Axial radiographs may disclose the pres-
ence of narrowing that is more severe parasagittally.
Yu et al. (1986), in a computer-assisted myelographic
study showed that although concavity of the anterior
surface of the spinal canal was the commonest type of
deformity (thereby resulting in narrowing that was
maximal in the midline), many, particularly those with
radiculopathy, showed lateral deformity on one or both
sides.
Symptomatic cervical spondylosis most often appears
after the age of 50. Clinically, there may be evidence
of radiculopathy or myelopathy or both (Ferguson and
Caplan, 1985). The root syndrome is characterized by
upper-extremity radicular pain and paresthesias that
are often aggravated by neck movement, coughing,
sneezing, or straining. Radicular weakness may be ac-
companied by atrophy or muscle fasciculations, hy-
poactive tendon reflexes, and impairment of pain and
temperature perception. Myelopathy is typically char-
acterized by spastic lower-extremity weakness with hy-
perreflexia and Babinski signs, impairment of posterior
B
column sensation with gait ataxia and paresthesias,
upper-extremity sensorimotor abnormalities, and, in
the later stages, sphincter dysfunction. Occasionally,
the clinical picture may be one of a partial Brown-
Séquard syndrome (Bedford et al., 1952; Kohno et al.,
1999). If precipitated by trauma, the initial deficit may
be acute quadriparesis.
There have been a number of carefully executed
pathological studies of cervical spondylotic myelopa-
thy (Bedford et al., 1952; Brain et al., 1952; Mair and
FIGURE 21.24 Cervical spondylosis with myelopathy in a man with

hemiparesis who became quadriplegic immediately after myelogra-
phy and who died 1 week later. (A) Transverse sections of the spinal
cord at C3 and C4, showing necrosis within both gray and white
matter. (B) Low-power photomicrograph at C3, showing early cav-
itary necrosis. Note the ovoid contour of the spinal cord. Luxol fast
blue–cresyl violet stain.
Druckman, 1953; Wilkinson, 1960, 1971; Hughes and

Brownell, 1963a; Ono et al., 1977; Ogino et al., 1983).
Grossly, the ventral surface of the spinal dura is in-
dented by the spondylotic bar(s) and the underlying
FIGURE 21.23 Cervical spondylosis with myelopathy in a man who, spinal cord is softened and ovoid in contour. Micro-
7 years prior to death, became quadriplegic after having struck the scopically, there is usually a somewhat symmetrical
back of his neck against a chair. In this low-power photomicrograph “butterfly” zone of partial necrosis affecting the lateral
of cervical spinal cord, there is pallor of staining, particularly within
the lateral and posterior columns and intervening spinal gray. Note
columns, the lateral portions of the spinal gray, and the
the relative preservation of the subpial white matter. Luxol fast ventral portions of the posterior columns (Figs. 21.23,
blue–cresyl violet stain. 21.24). The pattern of damage may vary, however,
from one of marked asymmetry (Bedford et al., 1952) sure may rise to 100 pounds per square inch or more
to one of near-total necrosis (Hughes and Brownell, (Wilkinson, 1971). Such pressure is considerably aug-
1963a). Hughes and Brownell (1964) described a pa- mented by axially directed compressive forces in the
tient whose cervical spondylosis was complicated by hyperflexed position, in which case posterior disc pro-
thromboembolism within the anterior spinal artery and lapse is more likely to occur (Adams and Hutton,
who developed infarction in the territory of supply of 1982). This is the situation that prevails, for example,
that vessel. when heavy lifting is attempted in the stooped position,
The pathogenetic basis for the pattern of spinal cord which is a relatively common clinical setting for disc
damage just described is unclear. The general belief is prolapse. Disc prolapse or traumatic disruption may
that it is due either to impaired vascular perfusion or to also occur during falls and rear-end collisions. Most in-
mechanical compression. Those who have argued for a juries occur in the lower lumbar region, although the
vascular etiology have alluded to the relatively infrequent lower cervical and thoracic regions may also be affected
finding of compression intraoperatively and the lack of (Crock, 1976). Since lumbar injuries tend to be situ-
correspondence, in most instances, between the level of ated below the conus medullaris, the compressive ef-
neurological dysfunction and the level of bony disease fects are exerted on the nerve roots of the cauda equina.
(Taylor, 1964; Gooding, 1974). Turnbull (1971), in ad- Usually there is some degree of disruption of the pos-
dition, felt that sparing of the anterior and posterior terior longitudinal ligament with loss of integrity of the
columns was difficult to explain if mechanical compres- annulus fibrosus. Disc material may be extruded into
sion was an important factor. He suggested that antero- the subdural compartment (Kataoka, 1989). In surgi-
posterior spinal cord flattening would elongate lateral cally obtained material, the most reliable histological
penetrating blood vessels, thus producing ischemia. Oth- indicator of prolapsed (as opposed to nonprolapsed)
ers (Taylor, 1964) suggested that impairment of flow disc material appears to be neovascularization within
through radicular vessels might be of importance; the re- the fragments of fibrocartilage (Weidner and Rice,
sults of several radicular arterial ligation studies in ex- 1968; Chitkara, 1991; Pai et al., 1999).
perimental animals (Shimomura et al., 1968; Hukuda
and Wilson, 1972; Gooding et al., 1975; Wingerchuk et
Myelopathy in Rheumatoid Disease
al., 1999), however, still leave this formulation open to
question. Those who have argued against a vascular eti- Direct involvement of structures within the spinal canal
ology have emphasized that the damaged area does not is infrequently observed and may occur either in the
ordinarily correspond to a clearly defined territory of ar- form of a necrotizing parenchymal vasculitis (Watson
terial supply (Hughes and Brownell, 1963a), and that et al., 1977) or in the form of dural or leptomeningeal
vascular obstruction is rarely demonstrated (Nuvick, rheumatoid nodule formation (Fig. 21.25) (Steiner and
1972). Yu et al. (1986), in their computer-assisted myel- Gelbloom, 1959; Hauge, 1961; Gutmann and Hable,
ographic study, found an excellent correlation between
the pattern of spinal canal deformity and the nature of
the neurological deficit and, noting the reexpansion of
the spinal cord and the clinical improvement that fol-
lowed after operative intervention, concluded that me-
chanical compression was of great importance in their
development. It is likely that a combination of factors,
including some that have yet to be considered, are oper-
ative (Fehlings and Skaf, 1998). In a correlative MRI
pathological study involving mostly patients with cervi-
cal spondylosis who had suffered traumatic injury, buck-
ling of the ligamenta flava into an already narrowed
spinal canal appeared to have resulted in diffuse disrup-
tion of axons, particularly within the lateral columns
(Quencer et al., 1992).
Traumatic Disc Injury FIGURE 21.25 Rheumatoid nodule formation within the cervical
spinal leptomeninges and dura mater. Secondary necrosis is also ev-
As stated previously, the nucleus pulposus is under con- ident within the underlying spinal cord parenchyma (lower left).
siderable tension. In the standing position, disc pres- Hematoxylin-eosin stain.
1963). Ordinarily there is active systemic disease with

evidence of intracranial involvement as well (Kim,
1980).
Myelopathy may also be associated with rheumatoid
disease of the cervical spine, which is seen with sur-
prisingly high frequency (Kim and Collins, 1981; Fuji-
wara et al., 1998). Vertebral subluxation, usually at-
lantoaxial but sometimes subaxial, may be observed at
several levels, and tends to occur in patients with more
advanced disease. Perhaps because of the large width
of the spinal canal relative to that of the spinal cord at
this level, clinical evidence of progressive myelopathy
is uncommon (Smith et al., 1972; Williams, 1974). At-
lantoaxial subluxation in a forward direction, which is
due mainly to disease of the transverse ligament of the
atlas and of the odontoid process, allows the atlas to
slide forward on the axis, causing compression of the
upper cervical spinal cord (Fig. 21.26) (Bland, 1974;
Nakano et al., 1978). When this happens, the spinal
cord, as seen in cross section, assumes a triangular con-
figuration, mainly because of flattening of its ventral FIGURE 21.27 Diagram comparing the effects of rheumatoid sublux-
ation (A) and cervical spondylosis (B) upon the spinal cord. Note the
surface against the anterior wall of the spinal canal differences in spinal cord contour and in the distribution of tissue
(Kim and Collins, 1981). Characteristically, there may necrosis (as shown by the stippled areas). (From Kim and Collins,
be necrosis within the anterior horns, ventral posterior 1981, with permission.)
horns, and commissural gray, with extension into the
adjoining ventral portions of the posterior columns and
medial portions of the lateral columns (Hughes, 1977;
magnum, with resultant damage to the lower brain
Nakano et al., 1978). This pattern of necrosis offers an
stem, sometimes in association with vertebral artery
interesting contrast to that associated with cervical
thrombosis (Webb et al., 1968; Ball and Sharp, 1971;
spondylosis (Fig. 21.27), although the manner in which
Jones and Kaufmann, 1976).
it evolves is not known. Atlantoaxial subluxation in a
vertical direction may lead to upward and backward
displacement of the odontoid process into the foramen
MISCELLANEOUS MYELOPATHIES
Postangiography Myelopathy
The development of spinal cord necrosis after the in-
travascular administration of contrast material for di-
agnostic purposes is well recognized. This complication
has been reported most frequently following abdomi-
nal aortography (Abeshouse et al., 1956; McCormack,
1956; Hare, 1957; Killen and Foster, 1960; Hughes and
Brownell, 1965; Andrianakos et al., 1975), although a
very few have followed vertebral angiography (Ederli
et al., 1962; Bejjani et al., 1998; Pathak et al., 2000).
Aortography-associated myelopathy appears to have
been the result of unintentional spinal angiography af-
ter entry of contrast through radiculomedullary feed-
ing arteries (Di Chiro, 1974; Margolis, 1970). The con-
trast agent that, in the past, was most often responsible
FIGURE 21.26 Rheumatoid disease with atlantoaxial subluxation,
showing posterior displacement of the odontoid process (straight ar- for the development of irreversible spinal cord damage
rows) and compression of the lower medulla and upper cervical spinal was sodium acetrizoate (Urokon), which is no longer
cord (curved arrow). (From Kim and Collins, 1981, with permission.) available on the market. Clinically severe myelopathy
usually becomes manifest within a few hours after the phenol (Berry and Olszewski, 1963; Hughes, 1970),
procedure, as lower-extremity weakness or paralysis, ethanol (Hughes, 1966), distilled water (Kelly et al.,
sensory loss, and sphincter dysfunction. The few pub- 1975), hypertonic saline (Kim RC et al., 1988b),
lished reports of pathological findings in the spinal cord steroids (Bernat et al., 1976), methylene blue (Sharr et
have described changes that vary somewhat according al., 1978; Wolman, 1966), chemotherapeutic agents
to the length of survival (Antoni and Lindgren, 1949; (particularly cytosine arabinoside) (Breuer et al., 1977;
Abeshouse et al., 1956; McCormack, 1956; Hare, Mena et al., 1981; Clark et al., 1982; Hahn et al., 1983;
1957; Ederli et al., 1962; Hughes and Brownell, 1965), Bates et al., 1985), ammonium sulfate (Guttman and
but advanced disease has been characterized typically Pardee, 1944), and magnesium sulfate (Guttman and
by either centrally predominant or near-total gray and Wolf, 1944). The most frequently described lesion is a
white matter destruction from lower thoracic levels circumferential zone of loss of myelinated axons situ-
downward, with a marked reduction in overall cross- ated largely within (but not always limited to) the pe-
sectional area in the affected regions. The histological ripheral white matter (Fig. 21.28). Nerve roots may
preservation of the arterial supply and venous drainage also be affected. Occasionally there is evidence of mural
has been emphasized repeatedly. Margolis and his col- necrosis within or thrombosis of leptomeningeal blood
leagues (1956, 1970) studied the effects of administra- vessels (Brain and Russell, 1937; Greenfield et al.,
tion of sodium acetrizoate into the aortas of dogs and 1955; Hughes, 1970). With more prolonged survival,
were consistently able to produce spinal cord lesions marked fibrous thickening of the leptomeninges, espe-
that were characterized initially by hemorrhagic ne- cially dorsally, has been described (Winkelman, 1952;
crosis or edema, and subsequently by cavitation, within Hughes, 1966; Tsukagoshi et al., 1970; Bates et al.,
the central gray and immediately adjoining white mat- 1985; Kim et al., 1988).
ter. They concluded, on the basis of their work, that The suggestion has been made that cerebrospinal
damage to the spinal cord was most likely to result with fluid (CSF) manipulation alone may also result in struc-
higher volumes or concentrations of contrast medium, tural spinal cord damage. This idea is based, in part,
with injection sites near the origins of major segmen- on a series of carefully designed experiments performed
tal (radiculomedullary) feeder arteries, and with the an- by Bunge et al. in cats in which, following repeated
imal placed in the supine position (presumably because withdrawal and reinjection of small quantities of CSF
of the high specific gravity of the agent). Once again, through an intracisternal catheter, a narrow, circum-
there was no evidence of vascular obstruction. For this ferentially distributed zone of demyelination was pro-
reason, and because of the demonstration by Broman duced (Bunge and Settlage, 1957; Bunge et al., 1960).
and Olsson (1956) that the intravascular administra- A similar type of lesion has also been reported in hu-
tion of contrast media disrupts the blood–brain bar- mans (Friede and Roessmann, 1969).
rier, it is widely believed that spinal cord necrosis is a
consequence of direct toxicity on the part of the agent
rather than of impaired vascular perfusion (Margolis,
1956; Killen and Foster, 1960; Di Chiro, 1974).
Myelopathy after Intrathecal Injections

A large variety of agents have been administered in-
trathecally for purposes of anesthesia, pain relief, di-
agnosis, or treatment. In a very few instances this has
resulted in the rapid onset of neurological dysfunction,
usually paraplegia. On some occasions it has not been
possible to determine with certainty whether this ad-
verse outcome was attributable to the agent itself, to a
contaminant, or to something contained in the vehicle
(such as a preservative). Morphological alterations
within the spinal cord have been described following
FIGURE 21.28 Spinal cord at L2 in a patient who received intrathe-
the intrathecal administration of spinal anesthetics
cal hypertonic saline for pain relief 16 months prior to death, show-
(particularly the “caine” derivatives) (Brain and Rus- ing loss of myelinated axons circumferentially within the white mat-
sell, 1937; Guttman and Pardee, 1944; Greenfield et ter. There is also damage centrally within the anterior horns. Luxol
al., 1955; Wolman, 1966; Tsukagoshi et al., 1970), fast blue–cresyl violet stain.
Chronic Adhesive Spinal Arachnoidopathy lying spinal cord for a distance of one or two spinal
segments or more beyond the level of injury. In trans-
Although clinically significant spinal leptomeningeal inverse section, the damaged spinal cord remnants may
flammation and fibrous thickening (arachnoiditis) have be embedded in a thick collar of connective tissue that
been recognized for nearly a century, the frequency is adherent to the dura (Fig. 21.29). A similar picture
with which they occur in relation to chronic disabling has occasionally been described following such non-
back disease has come to be appreciated only in recent traumatic conditions as chronic tuberculous meningitis
years. Many relatively large series of clinical cases that (Brooks et al., 1954; Dastur and Wadia, 1969), in-
have appeared in the literature attest to the diversity of trathecal injection (Bernat et al., 1976), or massive
mechanisms that may lead to its development, includ- spinal subarachnoid hemorrhage (Feigin et al., 1971;
ing pyogenic infection, the intrathecal administration Kim et al., 1989), in which case the collar of connec-
of a variety of agents for diagnosis or for therapy, sub- tive tissue may extend for a considerable distance
arachnoid or subdural hemorrhage, back surgery, trau- within the spinal canal (Fig. 21.30). Less severe arach-
matic spinal injury, and degenerative (e.g., interverte- noidopathy may be evident as focal or diffuse lep-
bral disc) disease of the spinal canal (Lombardi et al., tomeningeal opacification with little or no adherence
1962; Jørgensen et al., 1975; Benner and Ehni, 1978; to the overlying dura. Microscopically, there is a vari-
Burton, 1978; Hansen et al., 1978; Quiles et al., 1978; able degree of fibrous leptomeningeal thickening (Fig.
Shaw et al., 1978). Whereas, in the early part of this 21.31a) that is particularly easily appreciated with the
century, infectious diseases such as syphilis and tuber- aid of connective tissue stains. With massive thicken-
culosis were held to be accountable for the majority of ing the zone of collagen deposition tends to adhere to
cases (Elkington, 1936, 1951; Mackay, 1939; Brooks both the dura and the spinal cord and may be seen, in
et al., 1954; Dastur and Wadia, 1969; Wadia and Das- places, to be separated from the adjoining dura by scat-
tur, 1969; Williams, 1974), clinical evidence suggests tered small aggregates of arachnoidal cells (Fig.
that, at the present time, the use of myelographic con- 21.31b). This would seem to imply that the formation
trast media, either alone or in combination with surgi- of collagen has taken place largely within the sub-
cal intervention, is the most frequently identified con- arachnoid compartment, entrapping nerve roots and
tributing factor in the developed nations of the world blood vessels. Some degree of neovascularization may
(Elkington, 1936; Halaburt and Lester, 1973; Jør- be seen, but residual infiltration by inflammatory cells
gensen et al., 1975; Benner and Ehni, 1978; Burton, is usually sparse unless the pathological process that
1978, 1985; Hansen et al., 1978; Quiles et al., 1978; led to its development is still active. Osseous metapla-
Shaw et al., 1978; Burton et al., 1981; Hoffman, 1983). sia may also be observed (Fig. 21.32) (Smith et al.,
Nonetheless, in a sizable proportion (one-third to two- 1983; Slavin et al., 1999).
thirds) of patients the etiology is unclear (Elkington,
1936; Lombardi et al., 1962; Whisler, 1978).
Although it has been stated that chronic adhesive
spinal arachnoidopathy is manifested clinically by back
pain, multisegmental root pain, paresthesias or other
sensory disturbances, and (in a few) lower extremity
weakness (French, 1946; Whisler, 1978; Esses and
Morley, 1983), the signs and symptoms are somewhat
lacking in specificity, making diagnosis difficult in the
absence of a high index of suspicion (Hoffman, 1983;
Fahey et al., 1998). The recent development of strict
myelographic criteria (Jørgensen et al., 1975; Haughton
et al., 1977; Shaw et al., 1978) and the advent of tech-
niques such as MRI (Ross et al., 1987) have facilitated
clinical identification of the condition and have pro-
vided a better appreciation of its prevalence.
The pathological appearance of the spinal cord will
FIGURE 21.29 Chronic adhesive spinal arachnoidopathy in a patient
vary to some extent according to the mode of devel-
who had undergone back surgery in the lumbar region on numerous
opment. Grossly, in cases of old traumatic injury in occasions. The subarachnoid and subdural compartments are oblit-
which the integrity of the bony canal has been dis- erated by a dense mass of fibrous tissue. Note also the darkening
rupted, the dura is often inseparable from the under- and softening of the posterior columns.
symptoms of which may not appear until many months

or years after the initial injury. Cavitation appears al-
ways to arise beneath the thickened leptomeninges and
is, therefore, felt to be related pathogenetically to the
development of chronic adhesive spinal arachnoidopa-
thy (Davison and Keschner, 1933; Mackay, 1939; Lu-
bin, 1940; Nelson, 1943; Feigin et al., 1971; Barnett et
al., 1973; Barnett and Jousse, 1976; Macdonald et al.,
1988). Although some (Davison and Keschner, 1933;
Lubin, 1940; Macdonald et al., 1988; Caplan, 1990)
FIGURE 21.30 Chronic adhesive spinal arachnoidopathy in a man

who developed persistent postoperative oozing through the ventric-
ular system into the spinal subarachnoid compartment after needle
biopsy of the left frontal lobe. Massive fibrosis is observed between
the dura and spinal cord.
B
Morphologically, the most important secondary
complications of chronic adhesive spinal arachnoido-
pathy are focal myelomalacia and intramedullary cav-
itation (syringomyelia). It is difficult to estimate from
the literature the frequency with which these compli-
cations occur. At least two patterns of focal myeloma-
lacia have been described. The first is the formation of
a cylindrical myelomalacic “core” that is situated with
the ventral posterior columns, with extension into the
contiguous portions of the dorsomedial dorsal horns.
Lesions of this type have been described both clinically
(Holmes, 1915; Barnett et al., 1973; Barnett and Jousse,
1976) and experimentally (McVeigh, 1923) in the acute
phase of injury, and it has been suggested (Barnett and
Jousse, 1976; Barnett et al., 1973), though never
proven, that they may subsequently give rise to sy-
ringomyelic cavities. A second pattern of focal myelo-
malacia is exemplified in a reported case of localized,
dorsally accentuated adhesive arachnoidopathy fol-
lowing intrathecal hypertonic saline administration FIGURE 21.31 Photomicrographs of spinal cord from the patient de-
(Kim et al., 1988). This consisted of tissue breakdown scribed in Figure 21.30. (A) Low-power photomicrograph showing
within the dorsal portion of the spinal cord that ap- massive collagen deposition that is particularly evident dorsally, em-
peared to have resulted from mechanical constriction bedding spinal nerve roots. Masson trichrome stain. (B) Higher-
power view of the dorsal surface, showing dura (above), spinal cord
by fibrotically thickened leptomeninges (Fig. 21.33). (below), and intervening collagen deposition. Note the presence of a
Intramedullary cavitation may be associated with the layer of arachnoidal cells separating the mass of collagen from the
development of a progressive myelopathy, the signs and overlying dura. Hematoxylin-eosin stain.
A syndrome), lupus myelopathy, paraneoplastic disease,

and idiopathic acute (progressive) necrotic myelopathy
(Kim, 1991).
Neuromyelitis optica, which is characterized clini-
cally by blindness and paraplegia (Mandler et al., 1993;
Neumayer, 1966), has been described either alone (Bau-
doin et al., 1998) or in association with a variety of
disorders, including neoplasia (Kuroda et al., 1993),
multiple sclerosis (Stansbury, 1949; Cloys and Netsky,
1970), acute disseminated encephalomyelitis (Cloys
and Netsky, 1970), varicella-zoster (McAlpine et al.,
1959; Chusid et al., 1979), mumps (Chusid et
B al., 1979), rubeola (Chusid et al., 1979), infectious
mononucleosis (Williamson, 1975), systemic lupus ery-
thematosus (SLE) (April and Vansonnenberg, 1976;
Kinney et al., 1979), pulmonary tuberculosis (Hughes
and Mair, 1977; Barbizet et al., 1980; Slavin et al.,
1999), clioquinol intoxication (Tateishi et al., 1973;
Pallis, 1984; Rose and Gawel, 1984), and after tetanus
toxoid booster administration (Topaloglu et al., 1992).
FIGURE 21.32 Spinal cord of a man who was rendered paraplegic in In all of these conditions, spinal cord involvement may
a motor vehicle accident 14 years prior to death. (A) Transverse sec- occur without optic neuropathy. Additionally, clini-
tions showing maximal spinal cord damage in the mid- to lower-
cally silent lesions at other sites within the nervous sys-
thoracic region (lower left and upper right) and, in the lumbar re-
gion (lower right), adhesive arachnoidopathy with ventral ossifica- tem may subsequently be documented at autopsy. Neu-
tion. (B) Low-power photomicrograph of lumbar spinal cord, show- romyelitis optica is, therefore, a clinical syndrome the
ing bone formation within the ventral spinal leptomeninges. pathogenesis and morphological basis of which will
Hematoxylin-eosin stain. vary according to the etiology.
Clinically, lupus myelopathy ordinarily becomes ap-
parent within a few years of the onset of SLE, although
have expressed the view that syringomyelia is the re- occasionally it is the presenting manifestation (Kewal-
sult of circulatory impairment imposed by lep- ramani et al., 1978; Al-Husaini and Jamal, 1985; Prop-
tomeningeal thickening, others (Barnett et al., 1973; per and Bucknall, 1989; Tola et al., 1992). It may ei-
Barnett and Jousse, 1976) feel that it is more likely a ther progress rapidly or follow a course of relapses and
consequence of acute myelomalacic core formation at remissions. Any part of the spinal cord may be affected
the time of the initial injury. Cavitation may also ex-
tend for a considerable distance above or below the
original site of injury, resulting in the appearance of a
delayed-onset myelopathy (Barnett et al., 1973; Barnett
and Jousse, 1976). Such extension is thought to be at-
tributable to the loss of mobility of a tethered spinal
cord, rendering it less able to adapt to movement and
to alterations of venous back pressure that may occur
during such acts as coughing, straining, and sneezing.
Necrotizing Myelopathy
Progressive spinal cord necrosis may, on occasion, de-
velop in the absence of a clearly demonstrable circula-
tory disturbance, traumatic injury, infection, primary
FIGURE 21.33 Low-power photomicrograph of lower thoracic spinal
inflammatory process, toxin exposure, nutritional de-
cord from the patient described in Figure 21.32, showing dorsally
ficiency, or compression by neoplasm. Necrotizing accentuated fibrous thickening of the leptomeninges and secondary
myelopathy of this type can be conveniently subdivided tissue breakdown within the underlying spinal cord. Masson
into four main categories: neuromyelitis optica (Devic’s trichrome stain. (From Kim et al., 1988a, with permission.)
but, in most instances, the brunt of the damage is seen sparse inflammatory response. It is a diagnosis that, at
at or below thoracic levels. The foci of softening that the present time, can only be made postmortem, and
are observed grossly in the acute phase are due to co- then only by exclusion. As our knowledge of the patho-
agulative or liquefactive necrosis (Penn and Rowan, genesis of the necrotizing myelopathies advances, it is
1968; Andrianakos et al., 1975; Allen et al., 1979; likely that this disorder will prove to be a syndrome of
Nakano et al., 1989). Circumferential pallor with bal- diverse etiology.
looning degeneration of myelin sheaths and axonal
damage has also been described (Johnson and Richard-
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22 Non-neoplastic diseases of the
peripheral nervous system
ROBERT E. SCHMIDT
The most frequently sampled peripheral nerve in clin- panded the range of studies that can be performed on
ical settings is the sural nerve, a predominantly sensory peripheral nerve. Immunohistochemical studies con-
nerve distributed to the lateral aspect of the foot. This tribute to the analysis of: the presence and localization
entire nerve is typically sampled over the course of a of discrete molecules, such as myelin-associated pro-
few centimeters; however, in some cases fascicular bi- teins, immunoglobulins, and amyloid components; the
opsy is performed. nature of inflammatory processes including identifica-
The sural nerve biopsy specimen is studied using tion of various T-cell subtypes, cytokines, and cell ad-
hematoxylin and eosin, trichrome (for connective tis- hesion molecules; the identification of the nature of
sue), and silver stains (for axons), as well as with spe- proliferating endoneurial elements in neoplastic infil-
cialized stains as needed (e.g., Congo red for amyloid trates or primary neoplasms; alterations of growth fac-
or Hirsch-Peiffer acidified cresyl violet stain for tors and their receptors after nerve injury; and iden-
metachromatic materials). tification of accumulated intra-axonal cytoskeletal
A biopsy of the entire cross section of the sural nerve materials (e.g., neurofilaments, peripherin).
contains approximately 6 to 12 individual fascicles of Individual or small groups of lightly fixed, osmicated
nerve (Fig. 22.1) embedded in the epineurium, which myelinated axons can be dissected or “teased” out of
consists of collagenous connective tissue, scattered fat a fascicle to provide detailed information about the
cells, and blood vessels. Each fascicle is delimited from state of individual myelinated axons (Fig. 22.3). Each
the epineurium by the perineurium (arrows, Fig. 22.1). myelin internode, maintained by a single Schwann cell,
The perineurium consists of several laminae of flattened ranges in length from 0.2 to 1.8 mm, a value which is
perineurial cells (arrowheads, Fig. 22.2) with numbers dependent on axon size (larger axons tend to have
of laminae decreasing proximodistally in parallel with longer myelin internodes) and is consistent over the
diminishing fascicular size. Perineurial cells, the inner- sampled course of an individual normal axon. Active
most layers of which are joined together by tight junc- demyelination, remyelination, axonal degeneration,
tions, restrict entry of foreign materials into the en- and axonal regeneration produce characteristic teased
doneurium and may show minute calcifications as a fiber alterations. Also, teased fibers may provide in-
nonspecific finding in various neuropathies. Several formation on the prior history of nerve injury, since
septae of perineurial cells may subdivide individual fas- previous cycles of axonal degeneration and regenera-
cicles, in some cases in anticipation of branching. The tion are distinguishable from demyelination and re-
endoneurial space—technically, the space inside the myelination by teased fiber analysis.
perineurial cell sheath and outside the axon–Schwann One-micron-thick plastic embedded sections of pe-
cell unit (arrows, Fig. 22.2)—contains collagen, a mu- ripheral nerve (Figs. 22.4, 22.5) provide a wealth of in-
copolysaccharide ground substance, and small volumes formation. Myelinated axons range in diameter from 2
of fluid, which can be sampled by micropuncture us- to 18 m (coarsely separated into small and large
ing specialized techniques. Other cellular elements myelinated axon populations, Fig. 22.5) with myelin
within the endoneurium are small capillaries and thickness related directly to axonal size. Characteristic
venules, scattered fibroblasts (approximately 10 times patterns of nerve injury in plastic sections (e.g., patchy
fewer fibroblasts than Schwann cell nuclei), occasional interfascicular or intrafascicular axon loss, preferential
macrophage/monocytes, which are frequently perivas- loss of small or large myelinated axons, presence of
cular, and scattered mast cells. neurofilamentous axonal swellings) may suggest dis-
The development of sophisticated methods for light crete pathogenetic mechanisms and disease entities.
and ultrastructural immunolocalization has greatly ex- Qualitative information is also provided on the degree
497
FIGURE 22.1 Sural nerve. Individual fascicles of nerve, delimited by FIGURE22.3 Sural nerve, teased fiber preparation. Multiple nodes of
the perineurium (arrows), are surrounded by epineurium, which con- Ranvier (arrows) separate internodes of myelin (osmium).
sists of connective tissue, the vasa nervorum, and scattered fat cells.
H&E.
axonopathy may produce a deceptively unimpressive
appearance with collagen pockets mimicking the ap-
of myelinated axon loss, presence of active axonal de- pearance of axons, although collagen pockets do not
generation or demyelination, identification of regener- show densities comparable to intra-axonal subcellular
ative axonal clusters, onion-bulb formation, the nature organelles. Occasional collagen pockets may also be
of endoneurial cellular infiltrates, and amyloid deposi- seen in normal nerves, in which they anchor the
tion. Unmyelinated axons can be seen in plastic sec- Schwann cells of unmyelinated axons to endoneurial
tions; however, their accurate characterization requires connective tissue.
ultrastructural investigation. Morphometry provides quantitative data con-
Ultrastructural study provides a detailed look at the cerning numbers of myelinated and unmyelinated ax-
subcellular composition of individual myelinated axons ons, relative axon and myelin dimensions, and fre-
(Peters et al., 1991) as well as characterization of 0.2–2 quency distribution of axons by size, which may
m unmyelinated axons (Fig. 22.6), which outnumber identify a population of fibers at risk for a specific
myelinated axons in sural nerve. Loss of unmyelinated pathologic process. Certain pathologic processes tar-
axons may result in the formation of numerous “col- get discrete subpopulations of axons (Table 22.1);
lagen pockets” in which longitudinal bundles of colla- for example, amyloid neuropathy (Fig. 22.8) may re-
gen are held by Schwann cells in lieu of axons (Fig. sult in marked and selective loss of small myelinated
22.7). By light microscopy this pattern of unmyelinated axons.
FIGURE 22.2 Sural nerve. Myelinated axons (arrows), Schwann cells, FIGURE 22.4 Sural nerve. A large fascicle and its constituent axons
fibroblasts, and the endoneurial microvasculature are enclosed within are seen well in plastic sections (1-m-thick toluidine blue–stained
the perineurial sheath (arrowheads). plastic section).
22: NON-NEOPLASTIC DISEASES OF THE PNS 499
FIGURE 22.5 Sural nerve. A well-preserved complement of large and

small myelinated axons and endoneurial vessels is shown. Unmyeli- FIGURE 22.7 Sural nerve. Although collagen pockets (arrows) are
nated axons are also noted, although they are not seen well with common in small numbers in normal nerves, significantly increased
light microscopy. Plastic section, toluidine blue. numbers may develop following loss of unmyelinated axons (elec-
tron micrograph).
Tissue culture techniques are increasingly important

in the analysis of human and experimental neu- (distal axonopathy or dying-back neuropathy). Initial
ropathies, allowing selected processes to be investigated destruction and early catabolism of degenerating
under precisely controlled conditions. myelin and axons occur within a few days in the
Schwann cell (Fig. 22.10) and subsequently continue in
hematogenously derived macrophages, which begin to
BASIC PATHOLOGIC MECHANISMS substantively invade the endoneurium after 3–4 days
(Fig. 22.11), accompanied by activation of macro-
Axonal Degeneration phages resident in the endoneurium. Axonal regenera-
tion is partially dependent on the reutilization of cho-
A multitude of neuropathic processes results in degen-
lesterol within the endoneurium (Goodrum et al.,
eration of the axon and subsequent degeneration of
2000). Simultaneously, early regenerative events begin
myelin (shown schematically in Fig. 22.9). Often the
with the proliferation of Schwann cells and their pro-
distal portion of the axon is preferentially involved and
cesses, which accumulate within the original basal lam-
degeneration appears to spread toward the cell body
ina of the axon–Schwann cell unit as bands of Büngner
(Fig. 22.12). Concomitantly, axonal regeneration be-
gins, consisting of sprouting of the proximal viable por-
tion of the axon and the proximodistal growth of
TABLE22.1 Neuropathies Which Selectively Target

Subpopulations of Axons
Preferential Loss of Preferential Loss of
Small Axons Large Axons
Amyloid Uremia
Fabry’s disease Abetalipoproteinemia
Tangier disease Thallium, arsenic
Leprosy Vincristine
Riley-Day syndrome Friedreich’s ataxia
FIGURE 22.6 Sural nerve. A single myelinated axon with a Schwann HSANs (hereditary sensory and Cisplatin
cell nucleus is surrounded by unmyelinated axons enclosed in dense autonomic neuropathies)
Schwann cell cytoplasm. The punctate material in the endoneurial Diabetes (some forms) Acute intermittent porphyria
space is collagen cut in cross section (electron micrograph).
regenerative sprouts within the bands of Büngner.

Schwann cells composing regenerative bands are in-
duced by macrophage-derived interleukin 1 to produce
nerve growth factor (NGF) and its p75 receptor as well
as other neurotrophic substances. It has been specu-
lated that NGF may be bound to NGF receptors on the
surface of Schwann cell processes in order to present
NGF to the sprouting and regenerating axons as a
trophic and tropic stimulus (Taniuchi et al., 1986). Sub-
sequently, several axons begin to mature within a sin-
gle Schwann cell tube, giving rise to small groups of
thinly myelinated axons—that is, regenerative clusters
(Fig. 22.13)—which ultrastructurally consist of several
myelinated axons held within the basal lamina of the
FIGURE 22.8 Sural nerve. This section of amyloid neuropathy dem-
onstrates preferential loss of small myelinated axons. Plastic section,
original Schwann cell (Fig. 22.14), although with time
toluidine blue. the original basal lamina may disappear. Over time one
FIGURE 22.9 Main stages of Wallerian degeneration and regeneration of myelinated peripheral nerve
axon. (From Poirier et al., 1990, with permission.)
FIGURE22.12 Band of Büngner composed of Schwann cell processes

which are surrounded by the original basal lamina (arrows), pre-
FIGURE 22.10 Sural nerve, axonal degeneration. Degeneration of the sumably derived from a large myelinated axon (electron micrograph).
axon and myelin sheath begins in Schwann cells (arrows). Plastic sec-
tion, toluidine blue.
Teased fiber preparations may contribute to the de-
tailed understanding of the pathologic history of in-
dominant axon emerges and the others regress, which dividual axons in which axonal degeneration has pre-
results in a myelinated axon whose myelin sheath is rel- viously occurred. Specifically, morphometric plots of
atively thin for its axon caliber (arrow, Fig. 22.15). internodal length vs. axonal diameter in normal nerves
Functional recovery eventually may occur, although re- show a linear relationship; however, axons which
constitution of the original complement of axons is un- have previously degenerated and regenerated demon-
common. Alternatively, in the end stages of a chronic strate a uniform internodal length in axons of differ-
severe neuropathic process the nerve may consist of rare ent diameters.
preserved axons accompanied by scattered fibroblasts Often the terms axonal degeneration and Wallerian
and Schwann cells. Such an end-stage nerve provides degeneration are used interchangeably; however, dif-
little information concerning the process which preferences exist. Wallerian degeneration, strictly defined,
ceded it. Loss of unmyelinated axons may result in the is the microscopic reaction of the cellular elements of
formation of numerous collagen pockets in which lon- a nerve segment distal to a site of mechanical damage
gitudinal bundles of collagen are held by Schwann cells or transection. Processes similar to axonal degenera-
in lieu of axons, a process which may be deceptively tion occur in Wallerian degeneration, but in Wallerian
unimpressive by light microscopy.
FIGURE 22.13 Significant loss of small and large myelinated axons is

FIGURE 22.11 Sural nerve, axonal degeneration. Slightly later stage accompanied by prominent regenerative axonal clusters (arrows)—
than in Fig. 22.10 shows Schwann cells with debris as well as a few that is, collections of small, thinly myelinated regenerating axons.
lipid-laden endoneurial macrophages (arrows) (plastic section). Plastic section, toluidine blue.
FIGURE 22.14 Ultrastructural appearance of a regenerative axonal

cluster consists of several thinly myelinated axons held within a com-
munal basal lamina (arrows) of the original, since degenerated, axon
(electron micrograph). FIGURE 22.16 Rat pineal axon. Certain processes, as illustrated by
the acrylamide-intoxicated axons shown, exhibit a pathologic “sig-
nature” during axonal degeneration (electron micrograph).
degeneration histologic changes appear synchronized—
that is, most axons and Schwann cells in any given fas-
cicle are at the same stage of reaction, whereas in with relative preservation of axonal integrity (Fig.
chronic neuropathies axonal degeneration and regen- 22.17). The focus of the pathologic process is the
eration often occur simultaneously. In addition, the his- Schwann cell or the myelin sheath itself, which results
tologic appearance of wallerian degeneration is stereo- in the degeneration of the myelin sheath and, if the
typed in contrast to axonal degenerations, in which original Schwann cell survives the insult, initial myelin
distinctive pathologic signatures (e.g., swollen axons degradation within its cytoplasm. As in axonal degen-
containing collections of neurofilaments or tubulovesic- eration, hematogenous and intrinsic macrophages en-
ular elements, Fig. 22.16, or the distinctive appearance gulf the debris provided by the Schwann cell. Schwann
of neuroaxonal dystrophy) may occur. cell proliferation with eventual remyelination of indi-
vidual internodes is typical, often beginning within a
Segmental Demyelination few days, and frequently results in the replacement of
each lost myelin internode by several shorter interca-
Segmental demyelination represents preferential dam- lated internodes.
age to one or several internodes of the myelin sheath Morphometric plots of axonal diameter vs. internodal
length in teased fiber preparations may provide evidence
of previous episodes of demyelination and remyelina-
tion. Typically, in demyelinative neuropathies, measure-
ment of internodal length along the course of individual
axons shows marked variation from node to node in pre-
viously demyelinated and remyelinated nerves compared
with normal nerves (Fig. 22.18). This pattern corre-
sponds to the replacement of myelin originally lost from
the domain of a single Schwann cell by several prolifer-
ated Schwann cells with smaller territories.
Secondary Demyelination
The concept of secondary demyelination integrates ax-
onopathy and demyelination. Demyelinated segments
FIGURE 22.15 Regenerated axons (arrows) exhibit myelin sheaths
are preferentially located along the course of selected
which are too thin for their axonal calibers. Plastic section, toluidine axons, which may show atrophic or other degenerative
blue. changes while entirely sparing other axons. This con-
FIGURE 22.17 Main stages of segmental demyelination and remyelination of a myelinated peripheral
axon (From Poirier et al., 1990, with permission.)
trasts with the typical situation in segmental demyeli- eases (e.g., acute intermittent porphyria, diabetes,
nation, in which demyelinative segments are randomly Friedreich’s ataxia, giant axonal neuropathy).
located on individual axons. The mechanism appears
to involve an abnormality in the relationship of the
Schwann cell to its ensheathed axon, resulting in myelin TOXIN-INDUCED NEUROPATHIES
wrinkling and secondary myelin loss. The best-studied
example is uremic neuropathy (Dyck et al., 1971), al- Axonopathies
though the process may occur in a number of other dis-
A large number of substances (only a few are listed in
Table 22.2), ranging from environmental substances
and industrial chemicals to drugs and cancer
chemotherapeutic agents, may induce neuropathies
(Spencer and Schaumburg, 1980) characterized by ax-
onal degeneration.
In many cases the mechanisms remain unknown;
however, one group of toxins (Fig. 22.19) are known
to selectively target the process of axonal transport
(Ochs and Brimijoin, 1993). Axonal transport com-
prises several phases, including fast and slow or-
thograde transport, fast retrograde transport, and turn-
around transport, in which the polarity of transport is
reversed, usually at the synapse but also at a site of in-
jury. A variety of toxins target particular phases of
transport or, even more selectively, the transport of dis-
FIGURE 22.18 Sural nerve, teased fiber preparation. This axon, whose crete substances. Iminodipropionitrile (IDPN), methyl-
nodes of Ranvier are designated by arrows, shows adjacent intern-
N-butyl-ketone (MnBK), 2,5-hexane-dione (2,5-HD),
odes of markedly different lengths, which probably reflects interca-
lation of two internodes in the space initially occupied by a single aluminum, and carbon disulfide are experimental or en-
internode as part of the repair of segmental demyelination, with sub- vironmental toxins that target neurofilament transport
sequent loss of myelin from one of the intercalated nodes (osmium). and metabolism and, as a result, cause the accumula-
TABLE 22.2 Toxin-mediated Neuropathies Myelinopathy

Related to Axonal Transport Drugs Lead, diphtheria toxin, perhexilene, lysolecithin, and
hexachlorophene are prominent toxins directed at the
Iminodipropionitrile (IDPN) Isoniazid
Schwann cell, its myelin sheath, or both, although the
Methyl N-butyl ketone (MnBK) Hydralazine
precise targeted element differs between toxins. Other
N-Hexane Disulfiram
myelinopathic agents are listed in Table 22.2.
Aluminum Amiodarone
Carbon disulfide Dapsone
Vinblastine, vincristine Misonidazole ISCHEMIC NEUROPATHY
Taxol Amitriptyline
Colchicine Nitrofurantoin The vascular supply of the peripheral nerve (the vasa
Zinc pyridinethione (ZPT) Thalidomide nervorum) is typically rich and anastomotic (Fig.
Bromophenylacetylurea (BPAU) Chloramphenicol 22.20), and substantial decrease in nerve blood flow is
Cisplatin needed to interrupt function. A variety of clinical neu-
Primarily Myelinopathic Almitrine
ropathies is thought to develop as the result of dimin-
ished blood flow (Table 22.3). This list of ischemic neu-
Lead Perhexilene
ropathies includes vasculopathic neuropathies such as
Diphtheria Toxin
diabetic symmetrical sensorimotor neuropathy as well
Lysolecithin Other
as neuropathies with vasculitis (i.e., vasculopathies with
Triethyltin Acrylamide angionecrosis) (Asbury and Johnson, 1978; Hawke et
Trichloroethylene Dimethylaminopropionitrile al., 1991; Moore, 2000). Vasculitic neuropathy in dif-
Hexachlorophene (DMAPN) ferent clinical conditions may preferentially involve ves-
Buckthorn toxin Chlordecone (Kepone) sels of differing sizes ranging from small to medium-
6-Aminonicotinamide Diisopropylfluorophosphate
(DFP)
Triorthocresyl phosphate
Metals
(TOCP)
Arsenic Mipafox
Mercury Ethanol (?)
Thallium
Gold
tion of neurofilaments as marked swellings along the

axon. Vinblastine, vincristine, and taxol, potent
cancer chemotherapeutic agents, interrupt micro-
tubule function (which is critical for the process of
axonal transport) and produce clinical neuropathies.
Acrylamide, used in a variety of manufacturing pro-
cesses and in laboratories, can produce distinc-
tive paranodal neurofilamentous accumulations or
tubulovesicular aggregates involving the distal por-
tions of axons. Zinc pyridinethione (ZPT) and bro-
mophenylacetylurea (BPAU) preferentially target the
turnaround process, resulting in axonal swellings at
nerve terminals. Similarly, diabetes in experimental
animals appears to influence the turnaround process FIGURE 22.19 Schematic diagram of sites of damage of various tox-
but involves other phases of orthograde and retro- ins and pathogenetic processes on the axonal transport apparatus
grade transport as well. (From Ochs and Brimijoin, 1993, with permission.)
to cycles of endoneurial edema, vascular collapse, and

increased endoneurial pressure without the presence of
frank vasculitis. The involvement of the vasa nervorum
by vasculitis is commonly focal with major occlusions
only a few hundred microns from apparently unin-
volved vessels, which underscores the need for light mi-
croscopic sampling of multiple levels of nerves in pre-
sumed vasculitic neuropathy. Recent studies have
suggested a favorable effect of vascular endothelial
growth factor (VEGF) gene transfer on ischemic neu-
ropathies (Schratzberger et al., 2000).
Polyarteritis Nodosa
FIGURE 22.20 Sural nerve. Numerous epineurial and endoneurial
blood vessels (arrows) compose the microcirculation of peripheral Polyarteritis nodosa is the prototypic vasculitic neu-
nerves—in this case, involved by intravascular lymphoma. Ulex eu-
ropathy. Involvement of peripheral nerve may ap-
ropeus stain.
proach 100% of cases at autopsy. The wall of epineur-
ial arteries may be entirely destroyed by an infiltrate
sized epineurial arterioles (e.g., polyarteritis nodosa and containing polymorphonuclear leukocytes, macro-
isolated PNS vasculitis) to a predilection for small en- phages, monocytes, and fibrin (Fig. 22.21) as well as
doneurial vessels (e.g., systemic lupus erythematosus immunoglobulin and complement. There may be focal
[SLE], paraneoplastic or hypersensitivity vasculitis), or loss of vascular integrity in polyarteritis nodosa as il-
may involve several vascular populations (e.g., rheu- lustrated by a longitudinal section of a small epineur-
matoid arthritis). The microvasculature of the nerve ial artery immunostained for smooth muscle actin (Fig.
may cross the perineurial border tangentially, which 22.22), which also illustrates the focal nature of the
has been thought to favor collapse of the vasculature inflammatory process. Axons in fascicles adjacent to
in response to increased endoneurial pressure, leading arteritis may be minimally involved or, much less fre-
quently, completely infarcted. Significant fascicle-
to-fascicle or intrafascicular (Fig. 22.23) variability of
TABLE 22.3 Ischemic (Vasculopathic) Neuropathies
axon loss is common in, but not pathognomonic of,
Isolated PNS vasculitis ischemic neuropathies. The clinical pattern of mono-
Polyarteritis nodosa neuritis multiplex reflects the distribution of significant
Collagen vascular diseases (systemic lupus erythematosus, vasculitic “hits” on the vasa nervorum; however, isch-
rheumatoid arthritis, Sjögren’s syndrome, progressive systemic emic foci may summate to result in a pattern of distal
sclerosis) symmetrical neuropathy. Following recovery, damaged
Paraneoplastic microvasculitis
Cranial arteritis
Köhlmeier-Degos arteritis
Hypersensitivity angiitis (serum sickness)
Allergic granulomatosis of Churg-Strauss
Thromboangiitis obliterans (Buerger’s disease)
Diabetes
Infectious (Lyme disease, AIDS)
Amyloid
Hyperviscosity syndromes (macroglobulinemia and
cryoglobulinemia, polycythemia, sickle cell disease,
thrombocytopenia)
Wegener’s granulomatosis
Adulterated rapeseed oil
FIGURE 22.21 Sural nerve, polyarteritis nodosa. A large epineurial
Miscellaneous (cold exposure, entrapment with compression,
injections) artery shows fibrinoid necrosis with a prominent inflammatory in-
filtrate rich in polymorphonuclear leukocytes. H&E.
FIGURE 22.22 Sural nerve, polyarteritis nodosa. Damage to an arte- FIGURE 22.24 Sural nerve, chronic vasculitis. Damaged vessels may
rial wall may be focal as illustrated in a longitudinal section stained show residual inflammatory infiltrate, as well as focal fibrosis and
for smooth muscle actin (SMA). SMA immunohistochemical local- recanalization (arrows). H&E.
ization.
the pathologic appearance of blood vessel damage is

vasculature may heal with fibrosis, frequently asym- deceptively benign and consists of a mononuclear cell
metrical; luminal obliteration; and recanalization (Fig. infiltrate surrounding small arteries and veins in the
22.24), which provides lasting evidence for the process. epineurium with little evidence of loss of vascular con-
tinuity or significant angionecrosis. This histologic ap-
pearance may represent an early or mild vascular in-
Collagen Vascular Diseases
jury or represent an area adjacent to more substantial
A variety of histopathologic findings have been de- vascular damage. This pattern is to be distinguished
scribed in the nerves of patients with collagen vascular from the collection of small numbers of lymphocytes,
diseases (SLE, rheumatoid arthritis, progressive sys- which are not uncommon in the epineurial vasculature
temic sclerosis, Sjögren’s syndrome [Johnson and and thought to be of little diagnostic significance
Richardson, 1968; Hughes et al., 1982]), and more (Midroni and Bilbao, 1995). Immunohistologic meth-
than one type of injury may occur in any given patient. ods may demonstrate prominent deposition of im-
Rheumatoid arthritis may result in a pattern of munoglobulins and complement within the vascular
mononeuritis multiplex histologically comparable to wall in SLE; however, this finding is not specific for
that illustrated in polyarteritis nodosa. Alternatively, it SLE neuropathy and may simply reflect the presence of
may exhibit only microvasculitis (Fig. 22.25) in which underlying circulating immune complexes, which are
known components of the disease.
FIGURE 22.23 Sural nerve, vasculitic neuropathy. Focal intrafascicu-

lar loss of myelinated axons (delimited by arrows) in a single fasci- FIGURE 22.25 Sural nerve, rheumatoid arthritis. An epineurial vessel
cle suggests, but does not establish, an ischemic pathogenesis. Plas- (arrow) shows microvasculitis with a prominent mononuclear cell in-
tic section, toluidine blue. filtrate without significant angionecrosis. H&E.
NEUROPATHIES WITH AN
IMMUNE-MEDIATED MECHANISM
Guillain-Barré Syndrome
Immune-mediated neuropathies have typically been
classified as cell-mediated or antibody-mediated. Neu-
ropathies thought to have primarily a cell-mediated au-
toimmune pathogenesis include Guillain-Barré syn-
drome (GBS, acute idiopathic polyneuritis), which
includes a classical demyelinative pattern (acute in-
flammatory demyelinating polyneuropathy, AIDP), as
well as newly described acute motor (sensory) axonal
neuropathy (AM[S]AN), chronic inflammatory de-
myelinating polyradiculoneuropathy (CIDP), and, in FIGURE 22.27 Sural nerve, Guillain-Barré syndrome, AIDP pattern.
Demyelinated axon (arrow) with adjacent myelin debris in macro-
experimental animals, experimental allergic neuritis
phages is surrounded by myelinated axons. Plastic section, toluidine
(EAN). Antibody-mediated neuropathies include anti- blue.
MAG (myelin-associated glycoprotein), anti-Hu, and
other neuropathies. However, the designation of neu-
ropathies as either cell- or antibody-mediated is some- accompany patchy loss of myelin (Fig. 22.26). Im-
what artificial and may ultimately confuse the issue, munohistochemical studies may be used to demonstrate
since even in EAN in which the disease may be pas- subpopulations of lymphocytes and macrophages inti-
sively transferred to naïve animals with T cells alone, mately associated with demyelinated axons. One-
the process soon becomes exceedingly complex (Ho et micron-thick plastic sections demonstrate axons in var-
al., 1998) and involves recruited cellular elements, hu- ious stages of demyelination (arrow, Fig. 22.27) and
moral antibodies (locally synthesized or hematoge- remyelination with intimately associated macrophages
nously derived), and an admixture of cytokines in a containing myelin debris (Honaver et al., 1991). A
heterogenous milieu. characteristic and distinctive ultrastructural picture of
the active demyelinative process involves macrophage-
Acute inflammatory demyelinating mediated (M, Figs. 22.28, 22.29) stripping of other-
polyneuropathy (classical demyelinative wise normal-appearing myelin sheaths. Macrophages
form of Guillain-Barré syndrome) (M, Fig. 22.29) and their processes (arrow, Fig. 22.29)
can be found within the Schwann cell basal lamina be-
A prominent perivascular epineurial and endoneurial
lymphocytic infiltrate, consisting mostly of T cells, may
FIGURE 22.26 Sural nerve, Guillain-Barré syndrome, acute inflam- FIGURE 22.28 Sural nerve, Guillain-Barré syndrome, AIDP pattern.
matory demyelinating polyneuropathy (AIDP) pattern. Scattered A macrophage M, located within the basal lamina and Schwann cell
perivascular and endoneurial inflammatory infiltrate (white arrows) cytoplasm, is in the process of stripping off and engulfing segments
is accompanied by patchy loss of myelin (black arrows). LFB-PAS. of the myelin sheath. Electron micrograph.
tivated T cells may instruct B cells to proliferate and

secrete myelin-directed antibodies or release a variety
of cytokines, some of which have vascular effects, di-
minishing the integrity of the blood nerve barrier or
inducing macrophage activation. The loss of the
blood–nerve barrier is thought to increase the number
of recruited monocytes and macrophages in the en-
doneurium and to make the endoneurial space more
accessible to circulating cytokines and antibodies.
Cytokines (including but not limited to IFN and
TNF) stimulate the expression of MHC class II ele-
ments on antigen-presenting cells (perhaps perivascu-
lar hematogenously derived cells, macrophages, or
FIGURE 22.29 Sural nerve, Guillain-Barré syndrome, AIDP pattern. Schwann cells), resulting in the stimulation of the clonal
Higher magnification view of electron micrograph of Figure 22.28 proliferation of T cells and further activating macro-
shows small macrophage-derived pseudopodium (arrow) intimately
associated with a segment of stripped myelin. Electron micrograph.
phages to proliferate and release additional cytokines,
proteases, and reactive oxygen species into the milieu,
producing myelinopathy. It is thought that antibodies
neath a rim of Schwann cell cytoplasm (arrowheads, bound to myelin may secondarily bind to macrophages
Fig. 22.29). Completion of the demyelinative process through their Fc receptors. Circulating antibodies di-
(Fig. 22.30) is usually followed by Schwann cell pro- rected against targets within the endoneurium may sec-
liferation and remyelination of the denuded internode, ondarily gain access through a damaged blood–nerve
even in the presence of ongoing demyelination in ad- barrier, which may explain the salutary effect of
jacent fibers and a persistent inflammatory infiltrate. A plasmapheresis.
degree of axonal loss or axonopathy is typically seen,
probably because of the altered endoneurial environ-
Acute motor (sensory) axonal neuropathy
ment, which may contain a variety of toxic cytokines.
(axonal form of Guillain-Barré syndrome)
Alternatively, some axons may be lost following loss
of their parent neurons. Recently an “axonal form” of GBS has been described
Although many details remain to be determined, it in which the axon, rather than the myelin sheath, ap-
is thought (Hartung et al., 1995) that antigenic epitopes pears to be the primary target (reviewed in Chowdhury
of infectious agents, such as the bacterium Campy- and Arora, 2001). Pathologically, macrophages may be
lobacter jejuni, which causes some forms of gastroen- found immediately adjacent to nodes of Ranvier or ex-
teritis, are shared with peripheral nerve antigen(s). Ac- tending their processes through the Schwann cell base-
ment membrane at the level of the node of Ranvier,
which culminates in their entry into the periaxonal
space (Fig. 22.31, Griffin et al., 1995). Substantial num-
bers of degenerating axons may be demonstrated in
FIGURE 22.30 Sural nerve, Guillain-Barré syndrome, AIDP pattern. FIGURE 22.31 Peripheral nerve, acute motor axonal neuropathy.
Several macrophages (white arrows) containing phagocytosed myelin Macrophages (M) and their processes are intercalated between the
debris are shown within the Schwann cell basal lamina adjacent to axon (A) and its myelin sheath (From Griffin et al., 1995, with per-
completely demyelinated axon (black arrow). Electron micrograph. mission.)
some cases; in others, denervated neuromuscular junc-

tions and loss of intramuscular axons have been re-
ported, which may explain the rapid clinical reversal
which occurs in some cases. It has been proposed that
initially an antibody may target a constituent of the
node of Ranvier to which it binds, fixes complement,
and secondarily recruits macrophages, eventually re-
sulting in axonal dysfunction or, in some cases, axonal
degeneration. Clinical axonal GBS may be associated
with a more aggressive course and poorer outcome,
electrophysiologic and pathologic evidence of promi-
nent axonopathy, and an increased incidence of enteric
C. jejuni infection (which results in seasonal variation
in incidence in epidemic cases in northern China). A FIGURE 22.33 Sural nerve, CIDP. Onion bulbs (arrows) and axons
role for antibody directed against GM1 ganglioside (the with thinned myelin sheaths may be prominent in some cases of
possible antibody target at the node of Ranvier) has CIDP. Plastic section, toluidine blue.
been proposed in its pathogenesis. The role of C. jejuni
in the pathogenesis of the various related syndromes
underlying GBS is being actively investigated at this
time; it appears that C. jejuni enteric infections are fre- in which ataxia, areflexia, and ophthalmoplegia are
quent in both the classical demyelinative and axonal prominent. These patients frequently exhibit antibod-
forms of Guillain-Barré syndrome, although they are ies against the ganglioside GQ1b (Koga et al., 1998),
relatively more frequent in axonal forms. Recent work which appears to be concentrated at the nodes of Ran-
suggests that different serotypes of C. jejuni may result vier, particularly those of the oculomotor nerves.
in the synthesis of antibodies against different bacterial
components, which may contribute to clinical and
Chronic Inflammatory Demyelinating
pathologic variations in its presentation (Ho et al.,
Polyradiculoneuropathy
1998). There is also a suggestion that AMAN and AIDP
may differ in the degree of association with certain The pathologic findings in CIDP reflect the chronicity
HLA alleles (Monos et al., 1997). of a pathologic process of ongoing cycles of demyeli-
nation and remyelination in which pathologic findings
differ from fascicle to fascicle (Fig. 22.32). As in AIDP,
Miller-Fischer variant of Guillain-Barré syndrome
macrophage-mediated demyelination represents a patho-
The Miller-Fisher variant of GBS is distinguished from logic hallmark; additional findings include onion bulbs
AIDP and AMAN by a distinctive clinical syndrome in a minority of cases (Fig. 22.33), edema, and an in-
flammatory infiltrate consisting of mononuclear cells,
macrophages, and lymphocytes. Some investigators
have proposed that CIDP is a chronic form of Guillain-
Barré syndrome. Human leukocyte antigen (HLA) sub-
types are differentially distributed in patients with GBS
in comparison with CIDP. Specifically, GBS typically
involves patients of all HLA subtypes, reflecting their
frequency in the studied population, whereas in the re-
lapsing form of CIDP certain HLA subtypes are over-
represented. Failure to suppress and terminate the typ-
ically monophasic attack of GBS, possibly due to an
abnormality of immune regulation, could result in the
remitting and relapsing course of CIDP.
Less is known about the role of antibodies in the
pathogenesis of the various forms of GBS; however, cir-
FIGURE 22.32 Peripheral nerve, chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP). Fascicle-to-fascicle variability in culating antibodies may gain access to the endoneurium
myelinated axon density may be significant in CIDP (From Midroni through an abnormally permeable blood–nerve barrier,
and Bilbao, 1995, with permission.) which may explain the often salutary clinical effects of
plasmapheresis in some cases of Guillain-Barré syn-

drome and CIDP.
Experimental Allergic Neuritis

The experimental disorder experimental allergic neuri-
tis (EAN) is produced by injection of experimental an-
imals with homogenized peripheral nerve admixed with
Freund’s reagent or may be passively induced by in-
jection of T-cell lines directed against peripheral myelin
proteins (e.g., Po and P2 proteins). The characteristic
ultrastructural pathology includes distinctive macro-
phage-mediated myelin stripping as in clinical AIDP.
Studies of passively transmitted experimental T-cell- FIGURE 22.35 Sural nerve, anti-MAG neuropathy. The myelin sheath
mediated inflammatory peripheral neuropathy in rats shows expansion of the periodicity of external laminae producing a
have demonstrated that differences in the extent of de- biphasic appearance. Electron micrograph.
myelination vs. Wallerian degeneration may reflect the
number of injected T cells. The adoptive transfer of
pure P2 protein-specific CD4 T cells derived from rats (MAG), a molecule which is located in noncompacted
with EAN into recipient naïve rats results in axonal de- myelin and inner adaxonal membrane (Scherer and Ar-
generation with mild demyelination; however, the same royo, 2002). Immunohistolocalization studies demon-
T cells administered with antimyelin antibodies induce strate the deposition of anti-MAG IgM antibody in the
a more demyelinative pattern of injury which may re- myelin sheaths of peripheral nerve axons (Fig. 22.34).
flect opening the blood–nerve barrier to circulating an- Ultrastructural immunolocalization studies have dem-
tibodies (Taylor et al., 2001). onstrated the deposition of anti-MAG antibody in ar-
eas of altered myelin periodicity, resulting in wide-
spaced myelin (Figs. 22.35, 22.36) and eventually in
Anti-Myelin-Associated Glycoprotein Neuropathy
demyelination. Wide-spaced myelin, representing ex-
A number of patients with a slowly progressive de- pansion of myelin lamellae at the intraperiod line, how-
myelinating neuropathy have been found to have an as- ever, is not specific for anti-MAG neuropathy. Axonal
sociated IgM monoclonal gammopathy (monoclonal degeneration may also occur prominently in this syn-
gammopathy of unknown significance, MGUS syndrome. Immunosuppression and plasmapheresis have
drome, reviewed in Vital, 2001) in which the M pro- resulted in transient improvement in some cases. Injec-
tein is directed against myelin-associated glycoprotein tion of serum antibodies from MGUS patients into
FIGURE 22.34 Sural nerve, anti-MAG (myelin-associated glycopro-

tein) neuropathy. Fluorescent antibody to IgM antibody is deposited FIGURE 22.36 Sural nerve, anti-MAG neuropathy. Higher magnifi-
on myelin sheaths of large and small scattered axons (arrows), rep- cation of Figure 22.35 illustrating compact myelin and an outer rim
resenting sites of antibody bound to MAG. IgM immunofluorescence. of widely-spaced myelin. Electron micrograph.
tion rather than prominent demyelination in many of

these neuropathies. High serum titers of anti-GM1 gan-
glioside antibody have been identified in some patients
with sensorimotor neuropathy in which demyelinative
and axonal degenerative components probably coexist.
The autoimmune nature of these neuropathies suggests
that immunolytic therapy may be beneficial.
Anti-Hu Antibody (Paraneoplastic

Neuropathy and Ganglioradiculitis)
One form of paraneoplastic neuropathy is thought to
result from the cross reaction of an antibody (Anti-Hu,
FIGURE 22.37 Sural nerve, paraneoplastic neuropathy. Microvascu- type I antineuronal nuclear antibody, ANNA-1) which
lar, endoneurial, and epineurial mononuclear cell infiltrates may be is frequently produced in response to small cell carci-
prominent in paraneoplastic neuropathy. H&E.
noma of the lung. Reaction of the antibody with dor-
sal root ganglia (DRG) neurons and sensory axons re-
sults in microvascular collections of mononuclear
the endoneurium of experimental animals has been re- inflammatory cells in peripheral nerve (Fig. 22.37) with
ported to produce an abnormality of conduction little evidence of angionecrosis, suggesting that the pro-
velocity. cess is more autoimmune than ischemic. Inflammatory
changes that occur in dorsal root ganglia in paraneo-
plastic sensory ganglioradiculitis are parenchymal and
Antiglycolipid, Antisulfatide, and
less vasocentric than inflammatory changes in parane-
Antiganglioside Neuropathies
oplastic involvement of peripheral nerve. Prominent
Recent studies have identified a number of patients with loss of dorsal root ganglion neurons may reflect an au-
peripheral neuropathies whose sera contain other (non- toimmune pathogenesis.
MAG) antibodies against various biochemical con-
stituents (Pestronk, 1991). Increased IgM antibodies
against GM1 have been identified in patients with a dis- METABOLIC NEUROPATHIES
tinctive motor neuropathy with focal areas of conduc-
tion block in which demyelination is associated with The neuropathies which may accompany a variety of
superimposed axonal degeneration. A group of patients metabolic diseases are a pathogenetically heteroge-
has been identified in whom an idiopathic, predomi- neous group (Table 22.4), some of which represent ge-
nantly sensory neuropathy with high serum titers of an- netic diseases with identified metabolic abnormalities;
tisulfatide antibodies is present. Similar findings have others are acquired. Nerve injury may be primary in
been reported for some patients with sensorimotor neu- the disease or represent a variety of superimposed pro-
ropathies. Nerve conduction studies have provided ev- cesses such as vasculopathy resulting in an ischemic
idence for the presence of significant axonal degenera- pathogenesis.
TABLE 22.4 Metabolic and Endocrine Neuropathies

Diabetes Acute intermittent porphyria Galactosemia
Uremia Selected leukodystrophies Hypothyroidism
Tangier disease Krabbe’s disease Fabry’s disease
Vitamin deficiencies Metachromatic leukodystrophy Acromegaly
Thiamine Adrenomyeloneuropathy Hyperoxaluria
Pyridoxine (B5)
Folate
Cobalamin (B12)
Vitamin E
Diabetes
Diabetes is associated with a complex spectrum of neu-
ropathies (symmetric sensorimotor, asymmetric—
including proximal syndromes involving cranial and so-
matic nerves—or autonomic, see review by Dyck and
Giannini, 1996), the pathogenesis of which is being un-
raveled in human and experimental animal studies
(Sugimoto et al., 2000). Multiple pathogenetic mecha-
nisms have been proposed and are summarized at the
end of this section.
Symmetric Sensorimotor Polyneuropathy

Symmetric sensorimotor polyneuropathy is the best
known of the neuropathies of diabetes. The distal sen-
sory problems range from trivial electrophysiologic al- FIGURE 22.39 Sural nerve, diabetic symmetrical sensorimotor neu-
terations to stocking-glove anesthesia. Neuropathy may ropathy. Reduplication of the vascular basal lamina is characteristic,
develop after years of diabetes, or neuropathic symp- but not pathognomonic of, diabetic neuropathy. Electron micro-
toms may be the presenting sign of diabetes. Pathologic graph.
findings are dominated by variable degrees of myeli-
nated and unmyelinated axon loss (Fig. 22.38), result-
(Dyck et al., 1986a,b) provide evidence for involvement
ing in residual bands of Büngner and numerous re-
of the vasculature and multifocal axon loss in the de-
generative clusters. Thickened basement membranes,
velopment of the neuropathy. Multiple ischemic foci
which may reflect failure in the turnover of biochemi-
involving the proximal portions of the peripheral nerves
cally altered basal laminae, are typically seen in the en-
extending from the nerve root to distal limb nerves are
doneurial microvasculature, in Schwann cells, and par-
thought to summate and produce a more symmetric
ticularly in perineurial cells. Although thickening of the
and uniform axon loss distally. Some patients, includ-
microvasculature (arrows, Fig. 22.38) by reduplicated
ing a number with chronic involvement or mild symp-
basal laminae (Fig. 22.39) is characteristic of diabetic
toms of neuropathy, show demyelination, remyelina-
neuropathy, it is not specific for that disorder. Patho-
tion, and occasional onion bulbs. Occasional patients
logic findings are accentuated in the distalmost por-
with painful diabetic neuropathy may have preferential
tions of the peripheral nerves as described in dying-
loss of small myelinated and unmyelinated axons, al-
back neuropathies. Detailed morphometric studies
though this issue is not resolved.
Asymmetric Diabetic Neuropathies

The category of asymmetric diabetic neuropathies
includes lumbosacral radiculoplexus neuropathy (dia-
betic amyotrophy), sometimes referred to as proximal
neuropathy, truncal radiculopathy, upper limb
mononeuropathy, and cranial nerve palsies. Occasional
diabetic patients experience sudden or subacute onset
of motor dysfunction, involving large nerves to the
lower limb or cranial nerves (chiefly oculomotor nerves,
but others may be involved). The pathologic charac-
terization of this group of neuropathies may involve an
autoimmune component resulting in an inflammatory
microvasculitis involving the vasa nervorum and/or per-
ineuritis (Figs. 22.40, 22.41) and an axonopathy which
FIGURE 22.38 Sural nerve, diabetic symmetrical sensorimotor neu-
ropathy. Marked loss of small and large myelinated axons is ac- ranges from scattered degenerating axons to the for-
companied by prominent thickening of the microvasculature (ar- mation of an “injury neuroma.” (Dyck and Winde-
rows). Plastic section, toluidine blue. bank, 2002)
system have been reported, although significant loss of

axons from the abdominal vagus nerve has been de-
scribed in diabetic gastroparesis (Guy et al., 1984). Re-
cent studies demonstrate the development of markedly
swollen neurofilament-laden axons and synapses in the
relative absence of neuron loss in the prevertebral sym-
pathetic autonomic ganglia of autopsied diabetic hu-
man subjects (Fig. 22.42; Schmidt et al., 1993) prema-
turely and in greater numbers than aged subjects.
Studies of autonomic neuropathy in diabetic rat mod-
els (Schmidt and Plurad, 1986) have identified the sim-
ilar development of neuroaxonal dystrophy involving
preterminal axons and synapses of prevertebral (celiac,
FIGURE 22.40 Sural nerve, diabetic asymmetric neuropathy. This pro- superior mesenteric) sympathetic ganglia. Significant
cess results in loss of axons that varies considerably from fascicle to loss of myelinated axons in the greater splanchnic
fascicle. Plastic section, toluidine blue. nerves (i.e., the preganglionic axons to prevertebral
sympathetic ganglia) has also been described (Low et
al., 1975). In diabetic animal models, subpopulations
Diabetic Autonomic Neuropathy of autonomic fibers within the gut, bladder, penis, and
Although dysfunction of the autonomic nervous system other end organs may show preferential damage.
manifesting as orthostatic hypotension, loss of cardiac
reflexes, esophageal dysmotility, gastroparesis, chronic Pathogenetic Mechanisms of Diabetic Neuropathy
diarrhea or constipation, bladder distention with sec-
ondary infectious complications, impotence, or sweat- Investigation of several rodent models of diabetic neu-
ing abnormalities may complicate and shorten the life ropathy has suggested a variety of pathogenetic mech-
of patients with diabetes, relatively little is known of anisms (Greene et al., 1985; Sugimoto et al., 2000). In-
the pathologic abnormalities underlying the develop- vestigators have favored the development of distal
ment of these complications. The pathogenesis of au- symmetrical sensorimotor neuropathy as the result of
tonomic neuropathy with the myriad symptoms and epineurial and endoneurial vasculopathy with altered
sites of involvement may not reflect the same patho- nerve blood flow as the cause of endoneurial hypoxia
genetic mechanisms or may be differently distributed (Low et al., 1987) and a variety of secondary bio-
in portions of the sympathetic, parasympathetic, en- chemical and electrophysiologic alterations, although
teric, and visceral sensory nervous systems. Few sys- this issue remains contentious. Peripheral nerves do not
tematic studies of the diabetic parasympathetic nervous
FIGURE 22.42 Human superior mesenteric sympathetic ganglion, di-

FIGURE 22.41 Sural nerve, diabetic asymmetric neuropathy. Higher abetic autonomic neuropathy. Prevertebral sympathetic autonomic
magnification view of Figure 22.40 demonstrates perineurial in- neurons in a diabetic subject are intimately related to markedly en-
flammation and proliferation as well as perivascular inflammation larged axonal termini (arrows), typically containing large amounts
involving epineural blood vessels. Plastic section, toluidine blue. of neurofilaments. Bielschowsky silver stain.
require insulin for glucose entry and, therefore, sig- Fabry’s Disease
nificantly elevated intra-axonal glucose concentration
results in its metabolism along minor pathways, In this rare X-linked recessive condition, in which a de-
chiefly the polyol pathway, producing increased ficiency of -galactosidase A has been identified, loss
amounts of the impermeable sugar alcohol sorbitol of small myelinated and unmyelinated axons is ac-
and resulting in abnormal phosphoinositide metabo- companied by distinctive inclusions in perineurial cells
lism (Greene et al., 1985). Inhibition of the polyol and the endothelium.
pathway in experimental diabetic animals has re-
sulted in marked improvement of various neuropathic Vitamin Deficiencies
parameters (Tomlinson et al., 1984, 1985); however,
results in diabetic human subjects generally have been Deficiencies of pyridoxine, thiamine, vitamin E (found
disappointing. In animal studies and subsequently in in abetalipoproteinemia, cystic fibrosis, and biliary
humans, an unusual alteration of the perinodal junc- atresia), niacin, cobalamin, and multiple nutritional de-
tional apparatus (axoglial dysjunction; Sima et al., ficiencies in a recent Cuban “epidemic” are associated
1986) of myelinated axons has been described which with several forms of neuropathy.
may result in myelinopathy at those sites and even-
tually cause nerve conduction deficits, although re- Others
cent studies concerning the existence of the entity
conflict (Dyck and Giannini, 1996). Diabetes also re- Hypothyroidism, acute intermittent porphyria, galac-
sults in diminished axonal transport of a variety of tosemia, “hepatic” neuropathy, acromegaly, chronic
materials (Schmidt et al., 1975; Jakobsen et al., 1981; respiratory insufficiency, and critical illness neuropa-
Tomlinson et al., 1984, 1985) including structural thy have been described.
proteins (particularly neurofilaments), neurotrans-
mitters, or organelles. Exaggerated nonenzymatic gly-
cosylation of a variety of intracellular and extracel- HYPERTROPHIC (“ONION-BULB”) NEUROPATHIES
lular structural proteins may contribute to the
dysfunction of peripheral somatic nerves (Brownlee The proliferation and concentric layering of Schwann
et al., 1988). Deficiencies in the amount or regula- cells and their processes in response to multiple
tion of neurotrophic substances (e.g., nerve growth episodes of demyelination and subsequent remyelina-
factor [NGF], NT-3, and insulinlike growth factors) tion results in “onion bulbs,” distinctive structures
are thought to contribute to the development of both which are the hallmark of hypertrophic neuropathy.
symmetrical sensorimotor neuropathy as well as au- Onion bulbs can be identified in H&E stained sections
tonomic neuropathy (Hellweg and Hartung, 1990; of peripheral nerve (Fig. 22.43), in trichrome stains for
Ishii, 1993; Fernyhough et al., 1995). Recent clinical collagen (Fig. 22.44), in immunhistochemical detection
trials of NGF have, unfortunately, not produced a of basal lamina using collagen type IV (Fig. 22.45), and
significant salutary effect. Defects in axonal regener- in semithin plastic sections (Fig. 22.46). The imbricated
ation and synaptic turnover (synaptic dysplasia;
Schmidt, 1996) have also been proposed to result in
the development of neuroaxonal dystrophy in selected
sympathetic ganglia. These pathogenetic mechanisms
are not mutually exclusive and may interact in the
production of the variety of diabetic neuropathies in
clinical settings.
Uremia
The neuropathy accompanying chronic uremia is char-
acterized by demyelination; however, analysis of teased
fibers shows concentration of demyelinated segments
on some axons and complete sparing of others. At-
rophic axons are identified, even during the active FIGURE 22.43 Sural nerve, hypertrophic neuropathy. Large aggregates
phases of demyelination, suggesting that the demyeli- of concentric Schwann cell processes and collagen produce distinc-
native process is secondary. tive “onion bulbs” as seen with H&E.
FIGURE 22.44 Sural nerve, hypertrophic neuropathy. Onion bulbs are FIGURE 22.46 Sural nerve, hypertrophic neuropathy. The relationship
well visualized by a trichrome stain for collagen. Trichrome stain. of concentric Schwann cell processes to axons with diminished to ab-
sent myelin sheaths is shown. Plastic section, toluidine blue.
layers of Schwann cell processes (Fig. 22.47) and col-

lagen usually surround a central axon which demon- in hypertrophic neuropathies in human subjects (Mar-
strates thinned or absent myelin. Small numbers of tini, 1997; Werner et al., 1998).
onion bulbs may be seen in almost any chronic de-
myelinative condition; however, in onion-bulb or hy-
Hypertrophic Charcot-Marie-Tooth Disease
pertrophic neuropathies they dominate the pathologic
(Hereditary Motor Sensory Neuropathy–1 A,B, X)
picture. Nerves may be palpably enlarged and conduc-
tion velocities markedly decreased. Many hypertrophic Inherited typically as an autosomal dominant condition
neuropathies are transmitted genetically. and initially thought to represent a primary axonopa-
Significant progress has been made in understanding thy with secondary demyelination, recent studies of
the pathogenetic mechanisms underlying certain human some forms of Charcot-Marie-Tooth (CMT) have iden-
peripheral nerve diseases, particularly the hypertrophic tified a duplication or point mutation in the gene for
neuropathies involving alterations in peripheral myelin PMP-22 (CMT1A, chromosome 17), an integral myelin
protein-22 (PMP-22), Po, EGR2 and connexin-32 glycoprotein enriched in compact myelin, a defect in
(Werner et al., 1998; D’Urso et al., 1999). Spontaneous the early growth response 2 gene (EGR2) or a point
and genetically engineered animal models have been de-
veloped by targeting several genes known to be altered
FIGURE 22.47 Sural nerve, hypertrophic neuropathy. Ultrastructural

FIGURE 22.45 Sural nerve, hypertrophic neuropathy. Immunolocal- appearance of onion bulbs demonstrates concentric imbricated
ization of type IV collagen, which stains basal laminae, strongly stains Schwann cell processes and collagen surrounding a demyelinated
Schwann cell processes. Type IV collagen immunolocalization. axon. Electron micrograph.
mutation in Po myelin protein (CMT1B, chromosome Hereditary Neuropathy with Pressure Palsies
1), which is also needed for proper myelin structure.
Cases of X-linked CMT may demonstrate a defect in Teased fiber preparations of hereditary neuropathy
the gene for connexin 32. with pressure palsies (HNPP) a dominantly inherited
Overexpression of PMP-22 in transgenic rodents neuropathy, demonstrate marked focal hypermyelina-
results in a pathologic picture of hypomyelination tion (tomaculi) characterized by redundant myelin folds
and onion-bulb formation. Mice heterozygous for a (which show apparent marked thickening of the myelin
null mutation in Po also develop progressive de- sheath in plastic sections, Fig. 22.48), demyelination,
myelination and onion-bulb formation (Werner et al., and remyelination. Tomaculi are not confined to HNPP
1998). and may be demonstrated in a variety of neuropathies.
New molecular genetic evidence suggests deletion of a
region including the PMP-22 gene underlies this neu-
Dejerine-Sottas Disease ropathy (Gabriel et al., 1997); patients are thus mono-
somic for the region of chromosome number 17 in-
This entity, beginning in early life, may underlie some
cluding the PMP-22 gene. Mice with diminished or
cases of congenital hypomyelinating syndrome, which
absent PMP-22 gene product are reported to develop
may vary in histopathology from cases with classic
hypermyelinative tomaculi, demyelination, and func-
onion bulbs to those composed of concentric turns of
tional impairment as well as structures resembling
basal lamina without Schwann cell processes, and, in
onion bulbs.
some cases, to frank amyelination. A demonstrable ge-
netic defect in the PMP-22, EGR2, or myelin protein
Po has been identified. Po-deficient mice develop pe- Hereditary Giant Axonal Neuropathy
ripheral neuropathy characterized by hypomyelination,
Axons are typically distended by aggregates of abnor-
demyelination, onion-bulb formation, and impaired
mal neurofilaments and exhibit markedly thinned
nerve conduction (Martini, 1997; Werner et al., 1998).
myelin sheaths (Fig. 22.49). These abnormalities are ac-
companied by a variety of central nervous system symp-
Refsum’s Disease toms. Schwann and perineurial cells, endoneurial fi-
broblasts, and endothelial cells may have aggregates of
Caused by phytanic acid oxidase deficiency, this entity
filaments, suggesting a generalized abnormality of in-
also results in an onion-bulb neuropathy.
termediate filament metabolism. The gene responsible
for giant axonal neuropathy codes for the synthesis of
Chronic inflammatory demyelinating gigaxonin, presumably a cytoskeletal protein (Bomont
polyradiculoneuropathy et al., 2000).
Significant numbers of onion bulbs occur in a minor-
ity of patients with CIDP.
Other neuropathies with hypertrophic changes

Conditions with lesser degrees of onion-bulb forma-
tion include experimental manipulations (i.e., multi-
ple cycles of tourniquet application, lead intoxication,
experimental allergic neuritis) and several leuko-
dystrophies (e.g., Krabbe’s disease, metachromatic
leukodystrophy, and, less frequently, adrenoleukody-
strophy).
GENETIC NEUROPATHIES
Many examples of hereditary neuropathy are included FIGURE 22.48 Sural nerve, tomaculous neuropathy. An axon shows
in the previous sections related to major known or marked myelin thickening (arrow) in tomaculous neuropathy. Plas-
speculative pathogenetic mechanisms. tic section, toluidine blue.
opathies, hereditary ataxias, Fabry’s disease, and the

leukodystrophies are inherited disorders in which pe-
ripheral neuropathy develops.
AMYLOID NEUROPATHY
Amyloid is not a single biochemically defined sub-

stance; rather, it represents an extracellular deposit of
proteins arranged in a -pleated sheet configuration.
Amyloid may arise from fragments of immunoglobulin
light chains, transthyretin, or other proteins. Peripheral
nerve disease does not always accompany systemic
FIGURE 22.49 Peripheral nerve, giant axonal neuropathy. Many
myelinated axons show marked enlargement by neurofilaments and amyloidoses. Deposition of immunoglobulin light
attenuation of the thickness of myelin sheaths (arrows). Plastic sec- chain–derived amyloid in nerve is particularly signifi-
tion, toluidine blue. Illustration courtesy of Dr. Juan Bilbao. cant in primary amyloidosis and in amyloidosis asso-
ciated with dysglobulinemias. Amyloid deposition also
occurs in hereditary amyloidoses, such as Andrade’s
Hereditary Sensory and Autonomic Neuropathies
disease (Andrade, 1952) and an Indiana form, in which
Several forms of hereditary sensory and autonomic neu- the deposited amyloid is derived from transthyretin, as
ropathy (HSAN) have been described: well as Iowa (mutated apolipoprotein A) and Finnish
(gelsolin) forms.
1. HSAN I, acral sensory neuropathy, has an auto-
Amyloid deposition in nerve may show a variety of
somal dominant mode of transmission.
patterns, with prominent deposits within the en-
2. HSAN II, acral sensory neuropathy, is transmit-
doneurium (Fig. 22.50), often in association with the
ted as a recessive trait. This is a congenital neuropathy
endoneurial and epineurial vasculature or in epineurial
with prominent loss of myelinated axons and relative
connective tissue. In addition, compression neu-
sparing of unmyelinated axons.
ropathies may develop in response to amyloid deposits,
3. HSAN III, familial dysautonomia (Riley-Day syn-
particularly those in a perispinal distribution in which
drome), is characterized by neuronal loss in sensory and
root compression may occur. Amyloid can be stained
sympathetic ganglia with variable involvement of
with Congo red and made to develop a characteristic
parasympathetic ganglia. Although the loss of selected
apple green birefringence with polarization (Fig.
sympathetic and sensory ganglia in Riley-Day syndrome
22.51). Immunohistochemistry can also be used to
resembles the reported neuronal loss in neonatal guinea
identify the source material of the amyloid, as illus-
pigs which had been deprived of NGF by an autoim-
trated in a patient with a plasma cell dyscrasia with
mune paradigm during gestation and after birth, differ-
ences exist in the involvement of parasympathetic gan-
glia (Pearson et al., 1983). Subsequent molecular genetic
studies also have failed to identify a defective structural
-NGF gene or NGF receptor genes in familial dysau-
tonomia (Breakefield et al., 1984, 1986); however, re-
cent studies (Anderson et al., 2001; Slaugenhaupt et al.,
2001) have described a defect in the gene encoding the
IB kinase complex–associated protein (IKAP).
4. HSAN IV is congenital autosomal recessive sen-
sory neuropathy with anhidrosis. Mutations in trkA,
the high affinity NGF receptor, have been described
(Indo et al., 1996).
Other Genetic Neuropathies

FIGURE 22.50 Sural nerve, amyloid neuropathy. Amyloid (arrows) is
Ataxia-telangiectasia, multisystem atrophy, poly- distributed within the wall of an endoneurial blood vessel and ex-
glucosan body disease, mitochondrial encephalomy- tends into the adjacent endoneurium. H&E.
FIGURE22.51 Sural nerve, amyloid neuropathy. A Congo red stain

for amyloid (A) shows birefringence with polarized light (B).
Courtesy of Dr. A. Pestronk.
endoneurial vascular amyloid composed of -im- FIGURE 22.53 Sural nerve, amyloid neuropathy. Amyloid is deposited
in asymmetric aggregates (arrow) adjacent to an endoneurial vessel
munoglobulin light chains (Fig. 22.52). One-micron in the presence of a preferential loss of small myelinated axons. Plas-
thick sections of peripheral nerve show preferential loss tic section, toluidine blue.
of small myelinated axons and an asymmetric aggre-
gate of perivascular amyloid (Fig. 22.53). Ultrastruc-
tural examination demonstrates asymmetrical deposi- vulnerable part of the nerve in such cases may be the
tion of amyloid around an endoneurial vessel (Fig. superficial vasculature extrinsic to the nerve. Several
22.54), which shows its characteristic ultrastructural specialized types of infectious neuropathies occur.
filamentous composition (Fig. 22.55).
One mechanism resulting in axonal dysfunction pro-
Herpes Zoster
posed in familial amyloid polyneuropathy involves
transthyretin-derived amyloid fibril interaction with Herpes zoster is characterized by the painful develop-
advanced glycosylation end-product receptors (RAGEs) ment of a vesicular cutaneous rash corresponding to
with resultant upregulation of increased TNF, IL-1, the dermatomal distribution of an involved (typically
and nitric oxide synthase levels (Sousa et al., 2001). thoracic) dorsal root ganglion or trigeminal ganglion.
At the time of initial varicella (chickenpox) infection in
childhood, virus in cutaneous lesions gains access to
INFECTIOUS NEUROPATHIES terminal portions of peripheral sensory nerves, para-
sitizes the retrograde axonal transport apparatus, and
The perineurium provides a protective sheath to axons is transported to the cell body. At that time the virus,
traversing an area of infection and can usually with-
stand a significant inflammatory infiltrate. The most
FIGURE22.52 Sural nerve, amyloid neuropathy. Endoneurial vascu- FIGURE 22.54 Sural nerve, amyloid neuropathy. Ultrastructural ex-
lar amyloid is demonstrated by immunolocalization for -im- amination of shows asymmetric perivascular amyloid deposits. Elec-
munoglobulin light chains. Immunofluorescence. tron micrograph.
more frequently, within the nuclei of satellite cells (Fig.

22.57). Spread of virus along dorsal roots to the spinal
cord with subsequent significant myelitis is a recorded
(Hogan and Krigman, 1973), but relatively rare,
complication.
Leprosy
Leprosy is an infectious disorder resulting in the loss
of cutaneous sensation and motor function. Nerves rou-
tinely become infected with Mycobacterium leprae dur-
ing the initial phases of the disease. Nerves serving the
distal part of the extremities are particularly affected,
FIGURE 22.55 Sural nerve, hypertrophic neuropathy. Increased mag- a phenomenon which may reflect temperature sensitiv-
nification of the amyloid deposits shown in Figure 22.54 demon- ity of the bacterium. Two major histopathologic pat-
strates its fibrillar quality. Electron micrograph. terns of involvement are seen, lepromatous and tuber-
culoid, reflecting the host’s immune status. In patients
with a compromised immune response the resultant lep-
using mechanisms that are only now being investigated, romatous form of leprosy consists of epineurial and en-
becomes latent in dorsal root and trigeminal ganglia. doneurial inflammation (Fig. 22.58) and fibrosis (Job,
Latent virus in neurons is not visible ultrastructurally, 1987). The inflammatory reaction is accompanied by
although the viral genome is present and detectable numerous organisms that can be demonstrated within
with molecular techniques. At intervals, frequently Schwann cells (particularly those of unmyelinated ax-
times of acutely or chronically altered immune status, ons), endoneurial macrophages (lepra cells, arrows, Fig.
the virus may emerge from latency in the DRG and un- 22.59), endothelial or perineurial cells, and possibly the
dergo orthograde axonal transport to sensory nerve ter- axon itself. Demyelination and axonal degeneration
mini in the skin. The area of the skin served by the in- (particularly of small unmyelinated and myelinated ax-
fected dorsal root ganglion develops an eruption of ons) have been described. Patients with intact immune
herpes zoster, or shingles. At the time of the cutaneous function react by producing granulomas that involve
eruption the dorsal root ganglion typically shows he- skin and adjacent nerves (tuberculoid leprosy), which
morrhagic ganglioradiculitis (Fig. 22.56). Necrotic neu- may result in nearly complete loss of nerve tissue as
rons and satellite cells in dorsal root and trigeminal part of a bystander effect. As expected in a form char-
ganglia are admixed with angionecrosis, hemorrhage, acterized by prominent reaction, organisms are diffi-
and an inflammatory mononuclear cell infiltrate. cult to find. In both types of leprous neuropathy nerves
Cowdry type A inclusions are seen in neurons and, are often enlarged and may be palpated through the
FIGURE 22.56 Thoracic dorsal root ganglion, herpes zoster. This dor- FIGURE 22.57 Thoracic dorsal root ganglion, herpes zoster. A de-
sal root ganglion shows hemorrhagic ganglioradiculitis in a patient generating neuron is surrounded by several satellite cells with promi-
with active herpes zoster. H&E. nent intranuclear viral inclusions (arrows). H&E.
FIGURE 22.59 Sural nerve, lepromatous leprosy. A large number of

FIGURE 22.58 Sural nerve, lepromatous leprosy. Epineurial, per- organisms are found in endoneurial macrophages (lepra cells, ar-
ineurial, and endoneurial inflammation is prominent in lepromatous rows). Courtesy of Dr. Juan Bilbao.
leprosy; however, granulomas are not identified. H&E.
are matters of current investigation. In early stages of

skin. Borderline (dimorphous) cases, with features of seroconversion patients may develop an inflammatory
both forms, are also described. demyelinating polyneuropathy closely resembling Guil-
lain-Barré syndrome or CIDP, which may be accom-
panied by antinerve antibodies. Also during an early
Human Immunodeficiency Virus–Related Neuropathies
stage of the illness, some patients develop a vasculitic
A number of types of peripheral neuropathy are asso- pattern in which HIV antigens may be demonstrated in
ciated with human immunodeficiency virus (HIV) in- vessel walls and circulating antigen/antibody complexes
fection (Lipkin et al., 1985; Eidelberg et al., 1986; El- are present. Mononeuropathy multiplex involving cra-
der et al., 1986; Bailey et al., 1988; Cornblath and nial or spinal nerves often exhibits an inflammatory in-
McArthur, 1988; Parry, 1988; Kolson and Gonzalez- filtrate within the endoneurium and perivascular re-
Scarano, 2001; reviewed recently in Pardo et al., 2001; gions, occasionally progressing to frank vasculitis.
shown in Table 22.5). The precise pathogenetic mech- Distal symmetrical neuropathy, which can produce
anisms underlying the different presentations and the pain and paresthesias in later stages of the disease, is
question of direct involvement of the HIV virus itself characterized by acute and chronic axonal degenera-
TABLE 22.5 HIV-Associated Neuropathies

Subtype of Neuropathy (NP) Clinical Stage Mechanism
1. Distal sensory NP AIDS(CDC C) Macrophage-mediated axonopathy

2. Toxic antiretroviral drug NP Any (CDC A–C) Mitochondrial DNA synthesis
3. Mononeuritis multiplex vasculitic form CDC B Immune complex deposition
3. CMV multiple MonoNP AIDS (CDC C) CMV infection of Schwann cells, vessels
4. Inflammatory demyelinating NP
3. GBS (demyelinating or axonal) Pre-AIDS or AIDS Immune dysfunction
3. CIDP Pre-AIDS or AIDS Immune dysfunction
5. Opportunistic infectious NP
3. CMV polyradiculopathy AIDS CMV necrotizing NP
3. Herpes zoster radiculopathy AIDS VZV: Schwann cells and endothelium
6. Neoplastic (lymphoma) AIDS Endoneurial infiltration
7. Other
3. Sensory NP/dorsal radiculopathy Pre-AIDS or AIDS Immune dysfunction
3. Diffuse infiltrative lymphocytosis AIDS CD8 hyperlymphocytosis/ vasculopathy
Source: Pardo et al. (2001).

CDC A–C, Centers for Disease Control stages A, B, and C.
FIGURE 22.60 Cytomegalovirus-associated neuropathy, AIDS. Late in FIGURE 22.62 Traumatic neuroma. A small peripheral nerve ends in
the course of HIV infection, patients may develop CMV infection a disorganized swollen mass. H&E stain.
(arrows) of peripheral nerve, typically involving roots adjacent to the
spinal cord.
tribute to the neuropathic environment and are thought
to reflect an effect on mitochondrial DNA.
tion, segmental demyelination, macrophage infiltra-
tion, and, in some cases, microvascular necrosis of
capillary walls. Dorsal root ganglia may also show neu- Lyme Disease
ron loss and inflammation with infiltration of Cranial and peripheral nerve involvement in Lyme dis-
macrophages as part of distal symmetrical polyneu- ease, usually during its secondary phase, may show an
ropathy. Autonomic neuropathy and lumbosacral epineurial or perineurial perivascular lymphocytic/
radiculopathy are late events in the course of the dis- plasmacytic infiltrate (i.e., “perivasculitis” or poly-
ease. Lumbosacral radiculopathy is characterized radiculoneuritis) and axonal degeneration. Organisms
by cytomegalovirus infection of Schwann cells (Fig. typically are not present in involved nerves and the re-
22.60) which may also involve endoneurial and action may reflect molecular mimicry between an ax-
epineurial vessels resulting in a necrotizing vasculitis. onal antigen and Borrelia burgdorferi.
Various therapeutic agents (e.g., ddI, ddC) may con-
TRAUMATIC NEUROPATHY
Several forms of traumatic injury to nerve result in

histopathologic findings. Acute compression of nerve,
FIGURE 22.61 Traumatic neuroma. A peripheral nerve ends in a sur- FIGURE 22.63 Traumatic neuroma. The neuroma consists of numer-
gically induced neuroma in a patient subjected to neck dissection for ous minifascicles of axons enveloped in connective tissue. Trichrome
carcinoma. stain.
FIGURE 22.64 Traumatic neuroma. Minifascicles are surrounded by FIGURE 22.66 Traumatic neuroma. Minifascicles contain a comple-
perineurium (arrows). Type IV collagen immunolocalization. ment of large and small myelinated and unmyelinated axons sur-
rounded by a delicate perineurium. Plastic section, toluidine blue
stain.
as might occur in “Saturday night palsy” of the radial
nerve, is characterized by focal loss of myelin and is re-
paired by remyelination. Chronic nerve compression, the basal laminae of the microvasculature and Schwann
as might accompany the carpal tunnel syndrome, may cells. Groups of thinly myelinated axons and unmyeli-
result in demyelination and axonal degeneration nated axons compose a minifascicle as illustrated by
(Ochoa et al., 1972; Neary and Eames, 1975; Neary et the proliferation of large numbers of delicate neurofil-
al., 1975; Ochoa and Marotte, 1980). Traumatic dam- ament immunoreactive axons (Fig. 22.65) that vary in
age to peripheral nerve with loss of continuity may size and myelination status (Fig. 22.66). As treatment
cause the development of a traumatic neuroma (Fig. for the painful condition, resection of the neuroma and
22.61), which is a combination of degenerative and apposition of separated proximal and distal nerve
regenerative processes. Axons proximal to the injury stumps or placement of a nerve graft across the site of
form numerous regenerative sprouts that may become injury may facilitate regeneration. Morton’s neuroma,
disoriented and disorganized at the injury site and sub- a traumatic lesion that frequently develops on one of
sequently form a mass (Fig. 22.62) composed of large the plantar interdigital nerves, causes significant pain.
numbers of minifascicles (Fig. 22.63) admixed in a col- The lesion, thought to develop in response to repeated
lagenous matrix and surrounded by a few layers of per- compression and trauma, consists of an admixture of
ineurium (arrows, Fig. 22.64). The perineurial cells proliferated connective tissue elements involving
stain strongly for collagen type IV (Fig. 22.64), as do epineurium and perineurium, which may be accompa-
nied by evidence of axonal interruption and minifasci-
cle formation. Surgical resection is generally followed
by resolution of the symptoms.
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23 Neuromuscular diseases
REID R. HEFFNER, JR.
From an organizational standpoint, it is useful to begin upon the referring physician, who has familiarity with
with a classification of neuromuscular diseases. The clas- the patient undergoing biopsy, to make certain that a
sification presented here is not meant to be comprehen- representative muscle is sampled. The biopsy site
sive, but to enumerate disorders which are commonly en- should reflect the disease process. Thus, if symptoms
countered. This is a standard classification modified from indicate disease involving the legs and sparing the arms,
Walton et al. (1994), generally accepted by the majority a biopsy that is not obtained from the lower extremity
of U.S. and British physicians, which does not attempt is unlikely to accurately portray the disease process.
to reconcile every nosology and all diverse viewpoints Moreover, the biopsy should be obtained from a mus-
into a single system (Table 23.1). Many of the diseases cle in which the disease process is in a more active
appear in the table as a reminder to the reader and will phase, yet not from muscle in which there is severe
not be discussed in the text. For further explanation and weakness or wasting. Because of marked atrophy and
greater detail concerning the subject of neuromuscular loss of muscle fibers often accompanied by interstitial
diseases, a list of general references is provided at the con- fibrosis, disease in its terminal stages is extremely dif-
clusion of the chapter (Layzer, 1985; Engel and Franzini- ficult to interpret. It should also be emphasized that the
Armstrong, 1994; Heffner and Schochet, 1994; Walton muscle biopsy is likely to be free of significant patho-
et al., 1994; Heffner, 1997, 1999). logic change if the patient does not have weakness the
origins of which are muscular. Patients with anemias,
electrolyte disturbances, and certain systemic metabolic
CLINICAL INFORMATION disorders frequently experience weakness, but a mus-
cle biopsy is not indicated as a diagnostic procedure.
In order to save time in the pathological evaluation of Biopsies at sites of previous trauma or prior unrelated
the muscle biopsy and to avoid diagnostic errors, it is focal disease are contraindicated. The most common
highly desirable that the tissue specimen be accompanied types of traumatic injury are needle tracts resulting
by adequate clinical data. The muscle biopsy is often the from electromyography (EMG) or intramuscular injec-
culmination of the diagnostic work-up of the patient, tions of therapeutic medications. The pathologist may
which begins with a thorough clinical history, physical be mislead by the pathologic reaction in traumatized
examination, and clinical laboratory tests. In order to re- muscle in which there is necrosis, fiber regeneration,
mind the clinician, who may be unaware of precisely inflammation, and scar formation. At the tendinous in-
what information is important in a particular case, to sertions, and to some extent at fascial junctions, the
provide adequate clinical data, in our institution we sup- normal histology is characterized by variable fiber size
ply a form that the requesting physician is expected to and increased numbers of internal nuclei. Dense colla-
complete and return with the biopsy specimen (Fig. 23.1). gen trabeculae extend from the tendon, separating the
After the biopsy is reviewed by the pathologist, frequently fibers and simulating endomysial fibrosis (Fig. 23.2).
the referring clinician is contacted for additional infor- Therefore, the muscle biopsy should be taken from the
mation and is given a preliminary diagnosis if additional deep, central, or belly portion of the muscle to avoid
studies are necessary for a definitive interpretation. these areas unless a biopsy of the fascia is specified for
diagnostic purposes.
Proper preparation of the muscle specimen is a
COLLECTION AND PREPARATION prerequisite for accurate pathological interpretation
OF THE MUSCLE SAMPLE (Bossen, 1984). Because of special handling and pro-
cessing requirements, muscle biopsies should not be
Muscle biopsies should be performed by individuals submitted to the laboratory at the end of the work day
with proficiency in biopsy technique. It is incumbent or on weekends. Prior notification of the muscle biopsy
525
TABLE 23.1 Classification of Neuromuscular Disease
Congenital myopathies Myotonic disorders (continued)
Central core disease Other myotonic diseases
Multicore myopathy Chondrodystophic myotonia (Schwartz-Jampel)
Nemaline myopathy Hyperkalemic periodic paralysis (Anderson)
Myotubular (centronuclear) myopathy Drug-induced
Fiber type disproportion Paraneoplastic
Fingerprint body myopathy
Desmin myopathy Carbohydrate storage disease
Rigid spine syndrome Acid maltase deficiency (Pompe)
Reducing body myopathy Debrancher deficiency (Forbes)
Cytoplasmic body myopathy Brancher deficiency (Anderson)
Zebra body myopathy Phosphorylase deficiency (McArdle)
Phosphorylase b kinase deficiency
Muscular dystrophies Phosphofructokinase deficiency (Tarui)
Congenital Phosphogycerate kinase deficiency
Fukuyama type Phosphoglycerate mutase deficiency
Walker-Warburg type Lactic dehydrogenase deficiency
Merosin deficiency Polyglucosan body disease
X-linked recessive
Duchenne type Lipid storage disease
Becker type Carnitine deficiency
Emery-Dreifuss type Carnitine palmitoyltransferse deficiency
Facioscapulohumeral Acyl-CoA dehydrogenase deficiencies
Limb girdle Chanarin disease
Sarcoglycanopathies Batten’s disease
Calpain 3 defect Fabry’s disease
Distal myopathy
Dominant inheritance Mitochondrial myopathies
Welander type Defective energy conservation
NonWelander type Luft’s disease
Recessive inheritance Impaired substrate utilization
Miyoshi type (limb girdle dystrophy type 2B) Pyruvate decarboxylase deficiency
Limb girdle type 2G Pyruvate dehydrogenase deficiency
Ocular Respiratory chain defects
Oculopharyngeal Leigh’s disease
Oculopharyngeal distal type MELAS
MERRF
Myotonic disorders Kearns-Sayre syndrome
Protein kinase abnormality MNGIE
Myotonic dystrophy Alper’s disease
Chloride channel disease Lowe’s disease
Dominant myotonia congenita (Thomson) Miscellaneous
Recessive myotonia congenita (Becker) Drugs such as ziduvodine
Sodium channel disease Ischemia
Hyperkalemic periodic paralysis Aging
Paramyotonia Canavan’s disease
Myotonia fluctuans Zellweger’s disease
Menkes’ disease
526
TABLE 23.1 Classification of Neuromuscular Disease (continued)
Endocrine myopathies Inflammatory myopathies (continued)
Thyroid disorders Immune-mediated
Acromegaly Granulomastous
Cushing’s disease Sarcoidosis
Addison’s disease Idiopathic
Hyperparathyroidism Systemic connective tissue diseases
Vasculitis
Other metabolic myopathies Polymyositis
Malnutrition Dermatomyositis
Malignant hyperthermia Inclusion body myositis
Myoadenylate deaminase deficiency Drug-induced myositis
Renal disease Focal myositis
Amyloidosis Myositis ossificans
Periodic paralyses Disorders of neuromuscular transmission
Hypokalemic Immune-mediated
Thyrotoxic hypokalemic Myasthenia gravis
Hyperkalemic with myotonia Eaton-Lambert syndrome
Hyperkalemic without myotonia Congenital myasthenic syndromes
Hyperkalemic with dysthythmias Impaired acetylcholine release or synthesis
Paramyotonia congenita Congenital paucity of secondary synaptic clefts
End-plate acetylcholinesterase deficiency
Toxic myopathies Deficiency of acetylcholine receptor
Steroid myopathy Slow channel syndromes
Critical care myopathy Fast channel syndromes
Alcohol related myopathies Toxic
Drug-induced myopathies
Chloroquine Denervating diseases
Cimetidine Diseases of motor neuron

Colchicine Infections
D-penicillamine Paraneoplastic
Emetine Metabolic
Ipecac Toxic
Pentazocine Immune-mediated
Vincristine Inherited
Spinal muscular atrophies
Paraneolastic myopathies Kennedy’s syndrome
Dermatomyositis Charcot-Marie-Tooth disease
Intramuscular nerve twig disease Spinocerebellar atrophies
Myasthenic syndrome Familial amyotrophic lateral sclerosis
Radiculopathy/neuropathy Idiopathic amyotrophic lateral sclerosis
Motor neuron disease Peripheral neuropathies
Inflammatory myopathies
Infections
Bacterial
Fungal
Viral
Parasitic
527
MUSCLE/NERVE BIOPSY EXAMINATION REQUEST
SUNY Regional Neuromuscular Diagnostic Laboratory
GENERAL INFORMATION
Patient
Name:
Age and Sex:
Hospital:
Pathology Number:
Referring Physician:
Physician’s Telephone Number:
Date Obtained:
Muscle Biopsied:
CLINICAL DIAGNOSIS AND MEDICAL HISTORY
WORKING DIAGNOSIS:
Clinical Findings
Weakness:
Pain, Cramps:
Atrophy:
Myotonia:
Fasciculations:
Sensory Symptoms:
Associated Diseases
Alcoholism:
Cancer:
Collagen Vascular:
Diabetes or Other Endocrine:
Toxin or Drug Exposure:
Current Medications:
Lab Data
Nerve Conduction and EMG Findings:
FBS: ANA Titer

BUN: Anti-DNA Titer
CPK: Rheum. factor
SPEP: SRP antibody:
Myoglobinuria: Mi-2 antibody:
ESR: Jo-1 antibody:
Other antibodies:
FIGURE 23.1 Sample request form for muscle biopsy consultation. Courtesy of SUNY Regional Neuromuscular Diagnostic Laboratory.
procedure which prepares the laboratory for receipt of the necessary surgical instruments. The muscle biopsy
the specimen is recommended. If possible, it is desir- is routinely obtained in two stages. Prior to dissection
able for the laboratory technician to assist during the and excision, the initial specimen is immobilized in an
biopsy procedure to collect the specimen properly. isometric position by clamping the proximal and dis-
Some institutions recommend that a muscle biopsy tray tal ends in a muscle forceps. The muscle forceps or
or kit be available. The tray is comprised of sterile mus- clamp prevents contraction artifact which is caused by
cle biopsy clamps (Fig. 23.3) and containers with transecting the muscle and immersing it in fixative. Be-
fixative, particularly for electron microscopy where cause the muscle is introduced into the instrument
standard fixatives routinely accessible to physicians lengthwise, the specimen is properly oriented for pro-
performing biopsies may not be adequate, as well as cessing. The biopsy is stretched entirely across the
23: NEUROMUSCULAR DISEASES 529
(Engel and Franzini-Armstrong, 1994; Heffner, 1997).

Most striated muscles are divided into numerous bun-
dles of fibers. Each of these fascicles is surrounded by
a sleeve composed of connective tissue, the perimysium.
Within the perimysium are the arteriolar and venous
blood vessels, intramuscular nerves, and muscle spin-
dles. The intramuscular nerves and their branches
(twigs) are particularly evident at the innervation zone
of the muscle belly. The study of intramuscular twigs
and motor end plates is a specialized endeavor which
is beyond the scope of this chapter. Identification of
the end-plate region is possible by motor point biopsy
in which the end-plate region is identified by electrical
stimulation. Hence motor point biopsies must be
FIGURE 23.2 Interface of tendon (right) and muscle. Fibers in this lo- planned in advance. Many of the techniques used to
cation normally vary in size and internal nuclei are prevalent. H&E. study end plates require processing which is different
from the routine biopsy procedure. Typically, the ter-
minal axons and end plates are demonstrated using
clamp so that its dimensions, measuring 0.5 cm in di-
methylene blue staining, heavy metal impregnations, or
ameter and 1 cm in length, are always predictable. The
histochemical stains such as cholinesterase reactions.
biopsy should be large enough to be representative of
Muscle spindles are present in all muscles and are more
the lesion which has been sampled. The fixed specimen
easily identified in the muscle belly region. The outer
can be subdivided into samples for routine paraffin sec-
capsular portion of the spindle, which is composed of
tions, 1 m resin-embedded sections, and electron mi-
fibrous connective tissue, encloses the contractile por-
croscopic studies. Material destined for electron mi-
tion of the organ, the small intrafusal fibers. Within
croscopy is generally fixed in properly buffered (pH
each fascicle, the individual fibers are invested by the
7.4) glutaraldehyde. After approximately 15 minutes of
endomysium, a delicate network of mesenchymal tis-
fixation, thin strips of muscle are removed from the
sue which supports the elaborate capillary bed that sup-
clamped specimen and cut, using a dissecting micro-
plies the metabolically active muscle cells. The muscle
scope, into smaller pieces for further fixation in glu-
fiber is a multinucleated, pseudosyncytial cell which is
taraldehyde. A second specimen for the preparation of
cylindroid in shape. Most muscle fibers are several cen-
frozen sections remains unfixed and need not be
timeters in length, typically extending the length of a
clamped. It should measure about 1.0 0.2 0.5 cm
fascicle without interruption or branching. The cross-
and is transported to the laboratory on saline-
sectional anatomy of a fascicle is that of multiple,
moistened gauze to prevent drying. A number of freez-
closely approximated myocytes which are polygonal or
ing techniques have been used, although a proven
multifaceted in configuration (Color Fig. 23.4 in sepa-
method employs liquid nitrogen with a quenching time
rate color insert). The sarcolemmal nuclei in transverse
of 5–10 seconds. Whatever technique is preferred, it is
mandatory that the freezing process proceed extremely
rapidly. Serial cryostat sections in our laboratory are
routinely stained with H&E, rapid Gomori trichrome
(RTC), and three standard histochemical reactions—
ATPase (pH 9.4 and 4.6), NADH-TR (tetrazolium re-
ductase), and phosphorylase. Depending on the case
and when indicated, other stains for glycogen (PAS)
and for fat as well as additional histochemical reactions
are performed. Frozen tissue may also be utilized for
immunohistochemical or biochemical studies.
NORMAL MUSCLE
FIGURE 23.3 Muscle clamps (open at lower left and closed in upper
The evaluation of the muscle biopsy requires an un- right). Jaws of clamp close on muscle specimen, preventing contrac-
derstanding of the normal structure of skeletal muscle tion.
sections are ordinarily peripherally marginated, num-

bering up to five or six per fiber. The diameter of mus-
cle fibers is dependent upon several determinants. Age
is a factor in that muscle fibers are smaller in children
and in the elderly than in healthy young adults. Fiber
size is greater in men than in women, possibly because
of genetic and hormonal influences and probably be-
cause of more strenuous physical activity in males. It
is recognized that, regardless of gender, certain kinds
of exercise induce muscle hypertrophy. In normal in-
dividuals of all ages, proximal muscles are composed
of fibers having a greater average diameter (85–90 m)
than do acral or ocular muscles (20 m). It appears
that the muscles devoted to precision, finely integrated
movement have fibers of smaller diameter than mus- FIGURE 23.6 Normal muscle. Three fiber populations are seen. Type
cles designed for postural, less-refined activities. 1 fibers are dark. Type 2a fibers are light, and type 2b are interme-
diate in staining intensity (reverse ATPase, pH 4.5).
For many decades the physical and biochemical dif-
ferences between types of skeletal muscles and muscle
fibers have been under study (Table 23.2). In lower ver-
tebrates, exemplified by certain species of birds, the dis- the technique of enzyme histochemistry. Most labora-
tinction between red (weight bearing) and white (alar) tories rely upon at least two complementary histo-
muscles is very obvious. The color of red muscle is due chemical reactions performed on fresh-frozen sections
to the greater myoglobin content. Red muscle, endowed for the purposes of fiber typing. The myofibrillary AT-
with more mitochondria and having a higher capillary Pase reaction is considered to be the most accurate and
density and greater blood flow, depends upon aerobic reliable histochemical reaction to distinguish between
respiration and has more facility for postural or sus- fiber types. During the reaction, the last of a series of
tained activity. White muscle, rich in glycogen but with steps results in the precipitation of insoluble black
a smaller mitochondrial population, can be more effi- cobaltous sulfide at the original site of enzyme activity
cient under conditions of anaerobic respiration and has within the fiber. The reaction is pH dependent so that
been adapted to sudden or intermittent activity. In con- a continuum of staining reactivities can be achieved as
trast to animal muscle, which may be composed en- the incubating medium is brought from basic to acidic.
tirely of red or white fibers, all human muscles are com- At a pH of 9.4, which is the standard or alkaline AT-
posed of red (type 1) and white (type 2) fibers arranged Pase reaction, type 1 fibers appear pale and type 2 fibers
in a mosaic, checkerboardlike pattern. Anatomic loca- appear intensely stained (Color Fig. 23.5 in separate
tion of the muscle and its function has considerable in- color insert). In the alkaline reaction, intermediately
fluence on the proportion of type 1 and type 2 fibers stained fibers are not observed. By lowering the pH of
present, although the average muscle has about twice the incubating solution into the acidic range, the AT-
the number of type 2 fibers as type 1 fibers. The types Pase reaction is reversed such that type 1 fibers are very
of fibers and their distribution within a muscle are not dark, and type 2 fibers are either very light (type 2a)
discernible in paraffin sections and are revealed through or intermediate (type 2b) (Fig. 23.6). In normal human
muscle, type 2a and 2b fibers are found in approxi-
mately equal numbers. The oxidative enzyme content
TABLE 23.2 Histochemical Fiber Types in of the myofiber is indicative of the utilization of the tri-
Skeletal Muscle carboxylic acid cycle, the cytochrome system, and other
metabolic pathways for aerobic metabolism. The stain-
Type 1 Type 2
ing of fibers in the commonly used oxidative enzyme
Color Red White reactions such as the NADH-TR and the succinic de-
ATPase activity (pH 9.4) Low High hydrogenase reactions is the obverse of the alkaline AT-
Oxidative enzyme staining High Low–moderate Pase reaction. When muscle tissue containing enzyme
Glycogen content Low High is incubated with substrate and a colorless soluble tetra-
Phosphorylase activity Low High
zolium salt like nitroblue tetrazolium, the tetrazolium
salt accepts an electron during the oxidation reduction
Lipid content High Low–moderate
reaction and is reduced to a colored, insoluble formazin
compound that is deposited at the site of the reduction. cells comprise 5%–10% of parasarcolemmal nuclei.
Darkly stained fibers are oxidative or type 1 and less Satellite cells are considered to be resting myogenic el-
intensely stained fibers are type 2 (Color Fig. 23.7 in ements which serve as a source of regeneration after
separate color insert). The staining properties of type muscle fiber injury. Each muscle fiber is composed of
2 fibers permit subdivision of the nonoxidative fibers numerous parallel myofibrils, which are tiny stave-
into two subpopulations. Type 2b fibers appear virtu- shaped structures measuring 1–3 m in diameter. The
ally unstained whereas type 2a fibers stained with in- myofibril is longitudinally divided into a copular series
termediate intensity between type 1 and 2b. Since ox- of identical sarcomeres (Fig. 23.8). These contractile
idative enzyme reactions are essentially mitochondrial subunits are all of equal length and are in register with
stains, the sarcoplasmic intermyofibrillary network is other myofibrils within the muscle fiber. The regimen-
outlined and has a somewhat stippled appearance. tation of the sarcomeres results in a periodicity which
Myophosphorylase is a sarcoplasmic enzyme in all mus- gives the muscle fiber its cross-striated appearance. The
cle fibers, the abundance of which is relatively parallel length of the rectangular sarcomeres, 2.5–3 m, is the
to that of glycogen. Phosphorylase catalyzes the cleav- distance between consecutive Z lines which represent
age of 1,4-glucosidic linkages in glycogen and is more the lateral borders of a sarcomere. The Z line (Zwis-
plentiful in glycolytic (type 2) fibers. In theory, type 2 chenscheibe), or intermediate disc, is a highly electron-
fibers will stain more intensely than type 1 fibers, but dense plate perpendicular to the longitudinal axis of
in our experience the staining reaction is unpredictable the myofibril. The Z band bisects the I (isotropic un-
for fiber typing. Moreover, the color reaction fades der polarized light) bands shared by adjacent sarcom-
rapidly with exposure to light, necessitating review of eres. The I bands are less osmiophilic and more nar-
the stained slides as soon as possible. From a practical row than the centrally positioned A (anisotropic under
standpoint, the phosphorylase reaction is useful in polarized light) band. The alternating bands are ex-
screening for possible cases of McArdle’s disease. While plained in terms of the orderly arrangement of con-
stains for glycogen such as PAS are not reliable histo- tractile filaments inside the myofibril. The thick fila-
chemical markers for fiber typing, they are utilized to ments, which are largely composed of myosin, are 15
identify glycogen storage disease. The number of sar- nm in diameter. The thin filaments, containing chiefly
coplasmic lipid vacuoles is greater in type 1 fibers since actin but also troponin and tropomyosin, measure 8
they are a fuel for mitochondrial metabolism. Like nm in diameter. The thick filaments are restricted to
glycogen stains, fat stains are not dependable for the the A band and determine its length. Extending from
differentiation of fiber types, but they are useful in the their sites of attachment on the Z band, the thin fila-
diagnosis of lipid storage disease. ments traverse the entire I band in which only thin fil-
Longitudinal sections where the architecture is stri-
ated, rather than transverse sections, are optimal for
the ultrastructural examination of muscle (Heffner,
1975). The muscle cell membrane separating the sar-
coplasm from the extracellular space measures about 8
nm in width and may be difficult to appreciate except
at higher magnifications, in which the membrane is
noted to consist of three layers—a central electron-
lucent zone between two electron-dense lines measur-
ing 2.5 nm. Coating the plasmalemma and continuous
with the basement membrane is the glycocalyx. Exter-
nal to the glycocalyx, the basement membrane, with a
mean width of 20–30 nm, is more easily identified. Un-
der high-resolution electron microscopy, the basal lam-
ina is divided into a thicker (15 nm) lamina densa and
an inner relatively electron lucent layer, the lamina rara,
measuring 5 nm in thickness. The satellite cells, with
little visible cytoplasm and devoid of sarcomeres, are FIGURE 23.8 Normal muscle. Electron micrograph illustrates the it-
lodged between the basement membrane and the plas- erative arrangement of the sarcomeres. The narrow Z bands which
are most osmiophilic bisect the I bands which have the lightest-stain-
malemma of the myocyte. Their nuclei cannot be dis- ing intensity. Broader A bands are intermediately stained. Mito-
tinguished from those of mature muscle fibers in rou- chondria are oriented longitudinally and are frequently situated be-
tine microscopic sections. In fact, the nuclei of satellite tween the myofibrils.
aments are present, and enter the A band, interdigitat- comeres. At the A–I band junctions, terminal cisterns
ing with the myosin-containing filaments. The Z line, or sacs of the sarcoplasmic reticulum are frequently en-
a major component of which is actinin, is gridlike in countered. Pairs of terminal cisterns of the SR, between
structure. The Z lines move toward the center of the which is a centrally lucent transverse tubule, form the
sarcomere at the time of muscular contraction. As the triads. While the T tubules are seen as hollow profiles,
thick and thin filaments glide past each other, the I the terminal cisternae contain a moderately electron-
bands become greatly narrowed, reducing the length of dense granular material.
the sarcomere. The organelles within the muscle cell
tend to locate adjacent to the sarcolemmal nuclei and/or
between the myofibrils. Intracellular glycogen in elec- COMMON ARTIFACTS
tron micrographs appears as spherical particles which
are 20–30 nm in diameter ( glycogen). These granules Contraction artifact occurs when muscle fibers are not
are found in greater numbers in the I-band region and maintained in an isometric condition during surgical
are not prevalent in the subsarcolemmal portion of the excision or fixation. Due to vigorous and unopposed
muscle fiber, unless the fiber is injured. Subsarcolem- contraction, the muscle fibers begin to shred themselves
mal collections of glycogen granules are commonly ob- apart (Color Fig. 23.9 in separate color insert). This
served in a variety of neuromuscular diseases as a non- commonly encountered artifact is more obvious in lon-
specific finding. Glycolytic muscle fibers contain greater gitudinal sections, in which dark perpendicular con-
amounts of glycogen than oxidative fibers. Lipid vac- traction bands and lucent tears occur within the sar-
uoles containing triglycerides are darkly stained in elec- coplasm. In transverse sections, these tears appear as
tron micrographs when the specimen is primarily fixed irregular cracks within the fibers. Contraction artifact
in osmium tetroxide. Vacuoles are more lightly stained particularly jeopardizes tissue submitted for electron
or even lucent after glutaraldehyde fixation. Lipid microscopic study, since the normally striated archi-
droplets are generally found close to mitochondria and tecture is destroyed by disruption and disorientation of
are more numerous in type 1 fibers, inasmuch as fatty the myofibrils. Crush artifact can be as damaging to
acid oxidative metabolism occurs within the mito- the muscle as contraction. During the biopsy proce-
chondria. Mitochondria seem to be concentrated within dure, the portion of the sample to be later examined
the I bands and often lie adjacent to the Z lines with should not be squeezed with a forceps or clamp and
their long axes parallel to the longitudinally dispersed the ends of the specimen within the teeth of the biopsy
myofibrils. Most of the mitochondria are oval or el- clamp should not be submitted for histologic exami-
liptical in configuration and seldom exceed 1.0 m in nation. Crush artifact typically fragments the myofib-
greatest dimension. They are exceptionally sensitive to rils and disrupts the mitochondria and other organelles.
inadequate fixation, often swelling and becoming vac- Incorrect freezing of the freshly removed muscle spec-
uolated under such circumstances. The sarcotubular imen or improper storage of the frozen sample com-
system (SRT) is composed of the sarcoplasmic reticu- monly leads to vacuolization of the muscle fibers (Color
lum (SR) and the transverse (T) tubules. As the name Fig. 23.10 in separate color insert). The most common
implies, the transverse tubules generally run trans- causes of this type of artifact are initial freezing in a
versely and are situated primarily at the junctions of cryostat or storage in a conventional as opposed as an
the A and I bands. They form a tubular network which ultra-low (70°C) freezer. Vacuolar artifact closely im-
surrounds the longitudinally oriented myofibrils. The itates the pathologic appearance of some vacuolar my-
transverse tubules originate as invaginations of the opathies. This artifact also distorts other types of
plasma membrane and are accessible to extracellular pathological change within fibers, making proper in-
tracer molecules. The T tubules vary in diameter from terpretation more difficult.
80 to 100 nm when perpendicular to the fiber axis and Unlike pathologic vacuoles, vacuoles due to freezing
20–30 nm with a flattened contour at the triads. In con- artifact are more often in the center of the specimen but
trast to the transverse tubules with extracellular com- may be limited to the periphery of the tissue block. With
munications, the sarcoplasmic reticulum, which is a minimal artifact, small vacuoles are numerous in each
specialized smooth endoplasmic reticulum, is a closed, fiber, uniform in size, and most apparent between the
internalized array of tubules and cisterns that branches myofibrils. Vacuoles in the region of more pronounced
in both longitudinal and transverse directions between artifact are arranged in a gradient according to size.
the myofibrils. In routine electron microscopic studies, Smaller vacuoles are seen near the properly frozen inter-
longitudinal portions of the SR form cisterns which ap- face with progressively larger vacuoles forming toward
pear as tubular dilatations in the center of the sar- the areas of greatest artifact. Where there is severe arti-
fact, large, clear sarcoplasmic vacuoles form rectangular TABLE 23.3 Fiber Atrophy Is Present in Muscle Tissue
and other noncircular geometric shapes.
Pathologic Findings Associated Diseases
Type 1 atrophy MyD, congenital myopathies*

GENERAL REACTIONS OF MUSCLE TO INJURY Type 2 atrophy MG, disuse, steroid myopathy, early
denervation, cachexia, malignancy
Atrophy and Hypertrophy Grouped atrophy Neurogenic disease
Panfascicular atrophy Infantile spinal muscular atrophy
Pathologically small and enlarged muscle fibers are com-
mon manifestations of a number of neuromuscular dis- Perifascicular atrophy Dermatomyositis
eases. The evaluation of these changes is greatly facili- *Includes rod myopathy, myotubular myopathy, and fiber type dispropor-
tated by examining transverse sections of muscle. tion.
Frequently paraffin sections are less informative than his- MG, myasthenia gravis; MyD, myotonic dystrophy.
tochemical preparations. Because the muscle cell depends

upon neural and other trophic influences for its integrity,
analysis may be indispensable when changes in fiber di-
interruption of these trophic factors can result in fiber
ameters are minor and subtle (Bennington and Krupp,
atrophy. Hence, a common pathogenesis of fiber atro-
1984). Morphometry can be done as a manual exercise
phy in neuromuscular disease involves denervation. To
by obtaining measurements directly from a microscopic
maintain normal size, the muscle fiber must continue to
slide using an eyepiece micrometer, although this pro-
undergo contraction on a regular basis. Clinically, dis-
cedure is somewhat time consuming. Morphometric
use resulting in muscle atrophy is frequently found after
analysis can also be performed electronically with the
prolonged bed rest or immobilization by orthopedic de-
assistance of a computerized image analysis system.
vices such as casts, splints, or braces. A reduction in fiber
Computerized system analyzers can make quantitative
volume may also be a consequence of aging, poor nu-
determinations on photographs of a biopsy or directly
trition, or ischemia. Finally, for reasons which are poorly
on microscopic sections. Because of the speed of com-
understood, atrophy of muscle fibers is a common find-
puterized systems, it is not difficult to generate statisti-
ing in primary muscle (myopathic) disorders. Hypertro-
cally significant morphometric data in a relatively brief
phy is most often ascribable to greater muscular work,
period of time. From a diagnostic standpoint, it is for-
either as a result of exercise or as a compensatory reac-
tunate that the atrophic or hypertrophic process may be
tion of normal muscle fibers to atrophy of neighboring
selective, affecting principally a single fiber type, or non-
myocytes (Fig. 23.11). Under certain circumstances,
selective, indiscriminatingly affecting all types equally
muscle fibers on a constant stretch will also undergo hy-
(Engel, 1970). Type 2 fiber atrophy (Color Fig. 23.12 in
pertrophy. Although a detailed discussion is beyond the
separate color insert), the most frequently encountered
scope of this chapter, the technique of morphometric
example of selective fiber atrophy, is associated with
myasthenia gravis, denervation in the early stages, dis-
use, and as a paraneoplastic complication of systemic
malignancy (Barron and Heffner, 1978). The most com-
mon cause of selective type 2 fiber atrophy is drug-in-
duced after long-term corticosteroid therapy. Selective
type 1 fiber atrophy commonly occurs in myotonic dy-
strophy but can also be seen in several congenital my-
opathies such as nemaline myopathy and congenital fiber
type disproportion (Table. 23.3). Hypertrophy involv-
ing predominantly type 1 fibers may develop in normal
athletes who participate in endurance training programs
and within muscles under constant, excessive stretch. As
a pathologic finding, selective type 1 fiber hypertrophy
is highly suggestive of Werdnig-Hoffmann disease. Run-
ners, particularly sprinters, develop hypertrophy of type
2 fibers as a compensatory physiologic condition. Patho-
FIGURE 23.11 Fiber atrophy and hypertrophy. Many fibers are ab-
normally small in diameter. Some are filled with pyknotic nuclear
logic type 2 hypertrophy is described in patients with
clusters. One fiber is excessively enlarged, with rounded contour. congenital fiber type disproportion. Nonselective fiber
H&E. atrophy and hypertrophy are more common, but less
specific than selective variations in fiber size. Nonse- TABLE23.4 Internal Nuclei Are Present in
lective fiber atrophy is a very frequent finding in den- Muscle Tissue
ervation. Nonselective fiber hypertrophy has been de-
Location or Condition Nuclear Characteristics
scribed in limb–girdle dystrophy, myotonia congenita,
and acromegaly. Fiber shape and the pattern of atro- Tendinous insertion Normal size and shape
phy may be clues to the diagnosis in certain atrophic Fiber regeneration Large, vesicular, with nucleoli
conditions. Neurogenic atrophy should be suspected Myotonic dystrophy Small, pyknotic, numerous
whenever small, angulated muscle fibers are encoun- Limb–girdle syndrome Variable from pyknotic to normal
tered (Fig. 23.13). Such fibers tend to appear Myotubular myopathy Large, central, sometimes lobulated
fusiform—longer in one direction, where the dimension Chronic denervation Small, pyknotic in clusters
is comparable to the normal fiber diameter, and flat-
tened or narrow in the other direction, with dimensions
considerably smaller than normal fiber diameters. The
ends of angular fibers are typically tapered or pointed.
With the exception of Werdnig-Hoffmann disease, tervals along the length of the myocyte. Based on mor-
small fibers which are rounded are encountered in my- phometric studies in transverse sections of normal mus-
opathic diseases. When five or more small angular cle, the nuclei are peripheral or subsarcolemmal in
fibers are located in close proximity, grouped atrophy 97%–99% of fibers. The exceptions to this statement,
has taken place and is a sign of chronic neurogenic dis- as already mentioned above, are fascial and tendinous
ease. In part because the growth of muscle is still pro- interfaces where internal nuclei are normally present
gressing, the pattern of neurogenic atrophy is different (Table 23.4). Since one of the most frequent abnor-
in infants. In Werdnig-Hoffmann disease, for example, malities involving the muscle fiber is a variance in nu-
grouped atrophy is more extensive, so the majority of clear position, in patients with a variety of neuromus-
fibers within each fascicle are severely atrophic, pro- cular diseases, the numbers of internal nuclei are
ducing the picture of panfascicular atrophy. A distinc- nonspecifically increased, generally in less than 10% of
tive pattern of atrophy also occurs in dermatomyositis. fibers. While the surrounding sarcoplasm appears un-
Probably as a result of intramuscular vascular disease affected, fibers with internal nuclei are often at least
and ischemia, the atrophy of fibers is perifascicular mildly atrophic (Fig. 23.14). If the majority of fibers
and restricted almost entirely to the periphery of the contain eccentric internal nuclei, the diagnosis of my-
fascicles. otonic dystrophy should be entertained. In longitudi-
nal sections, these nuclei occur in rows or chains within
the sarcoplasm. Unlike myotonic dystrophy, where nu-
Nuclear Internalization
clear position is variable and, as the name suggests, in
A hallmark of the normal muscle fiber is multinucle- centronuclear myopathy, a single, central or paracen-
ation, with sarcolemmal nuclei located at regular in- tral nucleus is seen within virtually every fiber. These
FIGURE 23.13 Fiber atrophy. Many of the fibers are small and an- FIGURE 23.14 Internal nuclei. Several fibers contain nuclei that have
gular in shape. The pattern is typical of neurogenic atrophy. migrated inward from the normal peripheral position. H&E.
nuclei appear active, exceeding the normal size with a

dispersion of the chromatin. As a result of fiber ne-
crosis, the nuclei do not remain stationary in a pe-
ripheral location. Sarcolemmal nuclei commonly mi-
grate internally in degenerating and regenerating fibers,
irrespective of the cause. Markedly atrophic fibers also
contain internal nuclei. They seem to remain viable in
spite of a process which is reducing fiber volume, and
they tend to be multiple and pyknotic.
Fiber Necrosis
Fiber necrosis may occur as a minor change in many
muscle diseases, usually myopathies, but is prevalent in
the muscle dystrophies, particularly Duchenne type, FIGURE 23.15 Fiber necrosis. The sarcoplasmic structure of the fiber
and in the inflammatory myopathies, such as poly- at the center is disrupted. The sarcoplasm is granular and fragmented.
myositis (Table 23.5). The earliest sign of necrosis in H&E.
light microscopic sections is a loss of cross striations
and a change in the color of the muscle fiber which is
best appreciated in H&E stains. The acutely necrotic in a biopsy, with or without identifiable fiber necrosis,
cell first turns brightly eosinophilic before losing its suggests that necrosis has occurred or is occurring
staining qualities, becoming dusky pink in color. Dur- nearby in muscle tissue that has not been part of the
ing the interim, the sarcoplasm assumes a coarsely gran- biopsy sample. Two mechanisms appear to be respon-
ular appearance (Fig. 23.15). The nuclei become se- sible for regeneration of muscle fibers. The mature my-
quentially pyknotic, fragmented, and finally no longer ofiber has a limited regenerative capacity which in-
visible. When the necrotic process reaches its final cludes ribosome formation and the elaboration of
stage, the sarcoplasm is vacuolated or disintegrated as contractile and membrane proteins. This mechanism
phagocytosis of the necrotic debris supervenes. Inci- becomes important when necrosis of a muscle cell is
dental to the highly efficient phagocytic process, the segmental. The focus of regenerative activity originates
sarcoplasmic contents are evacuated by scavenger mac- from buds of sarcoplasm within the viable sarcomeres
rophages that fill the vacant spaces. Frequently prior surrounding the damaged sarcoplasm. A major mech-
to the removal of the necrotic sarcoplasm, regeneration anism for muscle fiber regeneration involves the satel-
occurs so that both regenerative and phagocytic activ- lite cells which, in response to injury, undergo my-
ity are visualized in the same fiber. oblastic transformation (Chou and Nonaka, 1977).
These cells become activated, proceed through all
phases of the cell cycle, undergo mitosis, and fuse with
Fiber Regeneration
adjacent myoblasts to form multinucleated myotubes.
Fiber necrosis seems to be a powerful inducement for The myotubes eventually mature, synthesizing the con-
regeneration. Thus, the presence of regenerating fibers tractile proteins and various organelles, restoring the
previously necrotic cell to a fully differentiated muscle
fiber. When the activated satellite cell undergoes my-
TABLE23.5 Fiber Necrosis Is Present in
oblastic transformation and multiple myoblasts are
Muscle Tissue
formed, the basement membrane is utilized as a frame-
Pathologic Findings Associated Diseases work for organization and migration. Myoblast fusion
is generally associated with cytoplasmic basophilia, al-
Small groups of necrotic fibers Duchenne dystrophy
lowing regenerating fibers to be rapidly recognized in
Perifascicular necrosis Dermatomyositis
H&E-stained sections. Ultrastructurally, regenerating
Random fiber necrosis PM, IBM, infections
fibers at this stage contain numerous ribosomes, and
Infarcts with large areas PAN the results of thin and thick myofilament synthesis can
of necrosis
be seen. The nuclei in regenerating fibers are typically
Extensive, diffuse Rhabdomyolysis (especially
internalized and increased in number. These nuclei are
alcoholics, military recruits)
enlarged, have prominent nucleoli, and exhibit a stip-
PM, polymyositis; IBM, inclusion body myositis; PAN, polyarteritis nodosa. pled chromatin pattern (Fig. 23.16).
an incidental finding in a number of disorders, such as

thyroid disease. In periodic paralysis, particularly im-
mediately following an attack, vacuolar change may be
striking. These vacuoles are clear and devoid of either
glycogen or lipid. Rimmed vacuoles which represent
foci of autophagic activity in the sarcoplasm, which will
be described below, are an important feature in inclu-
sion body myositis and certain types of muscular
dystrophy.
Inflammation
Acute inflammation characterized by the presence of
neutrophils is generally associated with infection,
FIGURE 23.16 Fiber regeneration. The sarcoplasm is basophilic and trauma, or ischemia. Chronic inflammation is most of-
internal nuclei are vesicular with prominent nucleoli. H&E. ten encountered in the immune-mediated inflammatory
myopathies, such as polymyositis. Based on a review
of our case material, the inflammatory myopathies
comprise approximately 29% of the cases in our files.
Vacuolar Changes
In polymyositis and dermatomyositis the inflammatory
The vacuolar myopathies, including storage diseases cells, chiefly mature lymphocytes, extend throughout
and the periodic paralyses, are characterized by the the endomysium, surrounding necrotic fibers or intra-
presence of vacant spaces within many muscle fibers muscular blood vessels without significant infiltration
(Table 23.6). The presence of vacuoles may indicate ab- of vascular walls. Mural invasion of vascular structures
normal accumulations of glycogen or lipid. Conse- by inflammatory cells is the common parameter which
quently, unexplained vacuolar change in routine mi- unites all types of vasculitis. The systemic connective
croscopic sections should prompt the pathologist to tissue diseases may all, sometime during the course of
perform stains for glycogen (PAS) and fat on frozen the illness, have some form of vasculitis which involves
sections. Glycogen deposits are often solubilized dur- skeletal muscle as well as other organs (Table 23.7).
ing the processing of paraffin sections, leaving empty
spaces in the fibers. Lipid is also very labile in tissue
Fibrosis and Fatty Infiltration
processed for paraffin embedding as a result of the de-
hydration process through alcohols. Increased amounts In normal adult muscle, the connective tissue sur-
of lipid in muscle cells usually indicates the presence of rounding each fascicle (perimysium), and particularly
a lipid storage disease or mitochondrial myopathy. within the fascicles (endomysium), is not conspicuous
Glycogen-containing vacuoles must be investigated to and is consistent in appearance from fascicle to fasci-
exclude glycogen storage disease, particularly when nucle. The perifascicular connective tissue in children is
merous, but deposits of glycogen are not uncommonly normally more prominent and should not be misinter-
preted as fibrosis by the pathologist unfamiliar with the
TABLE23.6 Sarcoplasmic Vacuoles Are Present in

Muscle Tissue TABLE 23.7 Inflammation Is Present in Muscle Tissue
Pathologic Findings Associated Diseases
Pathologic Findings Associated Disease
Center of specimen, often Freezing artifact
Perivascular, angiocentric DM, connective tissue disease,
arranged in size gradient
FSHD
Typically subsarcolemmal, Glycogen storage disease
Endomysial, around fibers PM, IBM, viral
PAS positive
Nodular infiltrates Rheumatoid arthritis,
Scattered fibers, small, round, Lipid storage disease,
granulomatous disease
osmiophilic, ORO positive mitochondrial myopathies
Polymorphous with eosinophils PAN, drug induced, trichinosis,
Rimmed, ubiquitin positive IBM, distal myopathy, OPD
eosinophilic fasciitis
Clear vacuoles Periodic paralysis
DM, dermatomyositis; FSHD, facioscapulohumeral dystrophy; PM,
IBM, inclusion body myositis, OPD, oculopharyngeal dystrophy. polymyositis; IBM, inclusion body myositis; PAN, polyarteritis nodosa.
normal anatomical structure of immature muscle. In- without the benefit of modern techniques, was reported
terfascicular collections of adipose tissue may occur in to be normal. While the diagnosis of benign congeni-
excessively obese people and should not be confused tal hypotonia became very fashionable, it was severely
with pathological fatty infiltration. In chronic neuro- flawed because of the lack of adequate pathologic study
muscular disease of either neurogenic or myogenic ori- and uniform natural history. In fact, follow-up indi-
gin, interstitial fibrosis and fatty infiltration are com- cated that the clinical course in such patients ranged
mon, although the pathogenesis of this process is poorly from complete recovery to moderately severe disabil-
understood. Even small amounts of intrafascicular con- ity. It is not surprising then that, like its predecessor,
nective tissue and fat are assumed to be pathologic the term benign congenital hypotonia is no longer con-
changes and signify previous damage to muscle fibers. sidered to represent a diagnosis and is misleading in
More severe fibrosis and fatty replacement develop in many ways.
end-stage disease (Fig. 23.17). Biopsies of such muscles The congenital myopathies are a heterogeneous
should be avoided, since all end-stage muscle disease, group of presumably primary muscle disorders, which
whatever the original cause, tends to look similar and probably includes most of the cases formerly placed un-
defies accurate diagnosis. der the rubric of benign congenital hypotonia. Despite
the name, not all cases are congenital and symptoms
are not invariably present at birth. However, the con-
CONGENITAL MYOPATHIES genital myopathies do share several features in com-
mon. The patient is frequently afflicted in early child-
Historically, when faced with a young patient who had hood with symptoms of the floppy infant syndrome.
muscle weakness, the pediatrician or other clinician Among the characteristic findings are muscular weak-
frequently resorted to the designation, Oppenheim’s ness, more severe proximally; poor muscle tone; lack
(1900) amyotonia congenita. We now realize that amy- of spontaneous movement; and relative preservation of
otonia congenita was not a diagnosis but rather a term deep tendon reflexes. As inherited diseases, the various
which indicated that the disease did not progress, a de- congenital myopathies often exhibit a familial inci-
termination requiring a follow-up period measured in dence. In contrast to the muscular dystrophies and in-
years. In a study of 109 cases of amyotonia congenita, fantile spinal muscular atrophies, the clinical course is
Walton (1956) introduced the concept of benign con- relatively benign and not infrequently reversible. Since
genital hypotonia and suggested that amyotonia con- the congenital myopathies are not easily distinguishable
genita be abandoned as a meaningful diagnosis. Based from a clinical standpoint, the muscle biopsy becomes
upon a subset of 17 cases, benign congenital hypoto- an indispensable part of the diagnostic evaluation. With
nia was defined as nonprogressive, like Oppenheim’s the advent of techniques which were quite new at the
amyotonia congenita, manifesting symptoms of hypo- time, particularly enzyme histochemistry and electron
tonia and delayed motor milestones. Muscle biopsy, microscopy, in the late 1950s many previously unrec-
ognized neuromuscular diseases were discovered. Thus
a new era in diagnostic pathology began.
The problem of the floppy infant who cannot be
properly interrogated or examined because of age is
compounded by the variety of diseases which can sim-
ulate a primary myopathy. Suprasegmental disorders,
caused by abnormalities of the brain and higher cen-
ters associated with motor function, account for a large
proportion of patients who present as floppy infants.
Perinatal hypoxia is a frequent cause of suprasegmen-
tal illness. As they mature, the mental disability in these
infants becomes more apparent. Despite the fact that
they appear weak during manipulation, spontaneous
movements of the extremities occur against gravity, and
the deep tendon reflexes are often brisk. Muscle biop-
sies in such infants typically reveal selective atrophy of
FIGURE 23.17 End-stage muscle disease. There is a loss of fibers,
type 2 fibers or nonselective fiber atrophy. Other
which have been replaced by interstitial fibrosis and adipose tissue. suprasegmental causes of hypotonia are Down syn-
H&E. drome, certain forms of cerebral palsy, and a variety
of malformations and metabolic disorders. Diseases of if not most patients are susceptible to the malignant hy-
the anterior horn cell, especially infantile spinal mus- perthermia syndrome (see the section titled Metabolic
cular atrophy, must be excluded in the work-up of in- Myopathies). Most families have followed an autoso-
fants with hypotonia. Peripheral neuropathies, which mal dominant inheritance pattern of low penetrance,
are rare in the neonatal age group, occasionally mani- although some sporadic cases have been reported. The
fest as hypotonia. Disturbances of the neuromuscular abnormal gene has recently been localized to the q13.1
junction, notably babies born to mothers with myas- band of chromosome 19. At least 17 missense muta-
thenia gravis, should be considered in the differential tions have been reported (Manning et al. 1998) in the
diagnosis. Myasthenia in such children is transient and RYR 1 gene, which codes for ryanodine receptor pro-
neuromuscular function returns to normal within sev- tein. Serum enzyme determinations such as creatine
eral weeks. Myasthenia gravis may also infrequently kinase (CK) are not usually elevated and electromyo-
occur in newborn infants without a family history of graphic (EMG) studies reveal mild myopathic abnor-
disease. Under these circumstances, the myasthenic dis- malities.
order persists and may be rapidly progressive. In the muscle biopsy, a single, centrally located de-
Primary muscle diseases, other than the congenital fect or core is present in the majority of muscle fibers
myopathies, affecting the infant and young child in- (Fig. 23.18). The percentage of core-containing fibers
clude congenital muscular dystrophy and myotonic dy- varies from case to case and more than one core per
strophy. The latter, when presenting in an infant, is fiber may be seen in some myocytes. Oxidative enzyme
characterized by a clinical picture that differs from reactions are the preferred technique for the identifi-
adult-onset myotonic dystrophy. The infant’s face is cation of cores, which appear as foci of depleted or ab-
long and thin with tenting of the upper lip. Moderate sent enzyme activity. Cores are sometimes also deficient
mental retardation is often seen. Although the child is in PAS and phosphorylase staining. From an ultra-
floppy, myotonia is seldom detectable clinically or elec- structural standpoint, cores may be structured or un-
trically for some time after birth. Important clues to structured. In the structured core, the cross striations
the diagnosis come from a careful examination of the are maintained with preservation of the A, I, and Z
mother, who is likely to have signs of myotonic dys- bands (Neville and Brooke, 1973). Conversely, the
trophy. A number of metabolic disorders are associated cross banding pattern is absent or markedly disrupted
with weakness and hypotonia in the infant or child. in the unstructured core, which may represent a later
Most important in this category are the lipid and glyco- stage in the progression of core formation (Fig. 23.19).
gen storage diseases, particularly Pompe’s disease. Electron microscopy also reveals a reduction or absence
in mitochondria and other organelles within the core
zone. A predominance of type 1 fibers is common in
Central Core Disease
central core disease. Particularly in more severely af-
Central core disease was one of the first of the con- fected muscles, virtually 100% of fibers are oxidative
genital myopathies to be described. The original report
by Shy and Magee (1957) was of a “congenital non-
progressive myopathy” affecting four males and one fe-
male over three generations. On the basis of the char-
acteristic changes seen microscopically in muscle,
Greenfield et al. (1958) proposed the term central core
disease. From the large number of cases that have been
studied since that time, a more complete clinical and
pathological picture has emerged (Bethlem and Mey-
jes, 1960). Central core disease generally begins at or
shortly after birth with hypotonia as a major symptom.
These children usually walk late and motor milestones
are delayed. Tight heel cords and muscle contractures
may be found. Skeletal abnormalities such as congeni-
tal hip dislocation, pes cavus or pes planus, and
kyphoscoliosis are not infrequent. The child tends to
remain slender and is unable to run, jump, or climb as
well as his or her peers. Many patients accept their con- FIGURE23.18 Central core disease. Many fibers contain a single core
dition and do not consider themselves disabled. Some which is poorly stained. NADH-TR.
of organelles, particularly mitochondria and glycogen.

A closely related disease described in two patients has
been designated focal loss of cross-striations (van
Wijngaarden et al., 1977).
Nemaline (Rod) Myopathy

The two earliest descriptions of this disease were pub-
lished in the same year. In a report by Conen et al.
(1963) myogranules were described in a child with clin-
ical signs of congenital hypotonia. The same disorder
was described by Shy et al. (1963), who preferred the
term nemaline myopathy. The inheritance pattern in
nemaline myopathy is not firmly established, although
FIGURE 23.19 Central core disease. Ultrastructurally, in the unstruc- the mode of inheritance is considered to be autosomal
tured core the orderly arrangement of the sarcomeres is lost due to dominant in most cases. Due to the much higher inci-
disorganization and disruption of the myofilaments, accompanied by
Z band streaming.
dence in females and the apparent lack of male-to-male
transmission, it has been proposed that nemaline my-
opathy in some families may be transmitted as an
X-linked dominant trait. One gene locus in dominantly
in type. Cores are not a unique and specific pathologic inherited cases is in the 1q22 band of chromosome 1,
finding, since they may be present in small numbers in the site of the TPM3 gene, which codes for the slow
a variety of disease states. In our experience, corelike isoform of -tropomyosin. A missense mutation causes
regions, sometimes known as core/targetoids, are most a change in the N terminal of tropomyosin that en-
likely to be encountered in neurogenic atrophy. As a hances actin binding (Laing et al., 1995). Another al-
nonspecific finding, cores are almost never found in tered gene product in dominant disease is actin, which
more than 10% of fibers, where they are more apt to is coded by the gene ACTA 1 on chromosome 1q42
be eccentric. They are also more variable in size and while in recessive disease it is nebulin coded by the gene
less pale in oxidative reactions than in central core NEB on chromosome 2q13–q33 (Pelin et al., 1997). In
disease. early infancy, patients are frequently floppy and expe-
rience feeding difficulties. Most children are late walk-
ing, and there is a delay in acquiring other motor skills.
Multicore Disease
In addition to facial muscle weakness, there is facial dys-
Multicore disease, sometimes called minicore disease morphism with elongation of the face and prognathism
(Paljarvi et al., 1987), is a congenital, usually nonpro-
gressive myopathy characterized by hypotonia, diffuse
muscle weakness which is greater proximally, and
delayed early motor milestones (Heffner et al., 1976;
Shuaib et al., 1988). A family history is commonly pres-
ent and the disorder is more frequent in males. Addi-
tional clinical features include kyphosis, scoliosis, and
muscle contractures. The typical pathological findings
are type 1 fiber predominance, disproportionately small
type 1 fibers, and a multiplicity of minute, corelike
structures in the majority of muscle fibers. Multicores
resemble central cores in that they are pale in most
stains, such as PAS, trichrome and NADH-TR. They
are numerous within each fiber and are oriented with
their long axis perpendicular to the longitudinal di-
mension of the fiber, so they are disk shaped in fibers
that are sectioned lengthwise (Fig. 23.20). By electron FIGURE 23.20 Multicore myopathy. Numerous linear, disclike, poorly
microscopy, there is disorganization of the myofibrils reactive regions are seen along the lengths of the fibers sectioned lon-
within multicores which also contain reduced numbers gitudinally. NADH-TR.
of the jaw. Other skeletal abnormalities include disorder is due to a maturational arrest has been ques-
kyphoscoliosis, high arched palate, temporomandibular tioned and the more descriptive term, centronuclear
ankylosis, pes cavus or planus, and pectus excavatum. myopathy, is often used in place of the original name.
The axial musculature lacks bulk and the limbs are very From a clinical standpoint, patients with myotubular
slender, although muscle strength, while reduced, is myopathy seem to fall into one of two relatively dis-
greater than the muscle mass would indicate. tinct groups. The first group of patients, like those in
The name nemaline is based on the Greek root nema, the original report, typically have a myopathic facies,
which means “thread,” to emphasize the presence of ptosis, extraocular weakness as well as facial weakness,
threads or rodlike structures in this disease. In nemaline and limb weakness which is often greater distally than
myopathy, numerous rods are seen in clusters immedi- proximally. On examination, foot drop is a common
ately beneath the sarcolemma. Rods are best demon- clinical sign. This type of illness appears to be due to
strated in RTC stains on frozen sections where they ap- an autosomal recessive inherited trait. The onset of
pear as deep purple linear structures measuring 2–4 m symptoms is commonly at birth or in early infancy and
in length (Color Fig. 23.21 in separate color insert). In symptoms may be progressive. A second group of pa-
paraffin sections, rods are stained with phosphotungstic tients exhibits symptoms which are milder and later in
acid hematoxylin (PTAH) stains and are well visualized onset during childhood or adult life. Ptosis, external
in 1–2 m resin sections. Rods are not stained with any ophthalmoplegia, and facial weakness are uncommon
of the standard enzyme histochemical reactions and are in these patients. Weakness of neck muscles is a more
easily overlooked in H&E-stained sections. Ultrastruc- typical finding. There is weakness of the extremities
turally, rods are osmiophilic, elongated, rectangular which tends to be greater in the legs than in the arms.
structures having a dimension of up to 6–7 m (Color The primary pattern of inheritance in this group ap-
Fig. 23.22 in separate color insert). When sectioned pears to be autosomal dominant, in which the MYF6
transversely, they appear as tetragonal filamentous arrays gene on 12q21 is possibly affected. An X-linked dis-
and appear to originate from the Z disc. Their latticelike ease in which the abnormal gene MTM1 is located on
appearance, resembling the normal Z band, supports the chromosome Xq.27.3–q28 has also been reported.
concept that rods originate from and perhaps represent More than 140 mutations have been described in this
proliferations of Z bands (Price and Pearson, 1965). gene, which codes for myotubularin (Laporte et al.,
Their structural continuity with thin filaments does not 1997), a tyrosine phosphatase.
contradict this concept. Rods were initially recognized in Since the original report in the literature, more than
congenital nemaline myopathy, but since the original de- 70 cases have been described. The biopsies in almost
scription of this disorder, it has become increasingly ev- all patients conform to a certain stereotype character-
ident that rods are not specific or unique to a single dis- ized by the predominance of type 1 fibers and atrophy
ease entity. For example, rods have been seen in such of type 1 fibers which may vary from mild to severe.
diverse conditions as schizophrenia, Parkinson’s disease, Peripherally located nuclei are rarely seen and most
polymyositis, and muscular dystrophy. The diagnosis of fibers contain a single central or slightly eccentric nu-
nemaline myopathy rests upon the appropriate clinical cleus (Fig. 23.23). The central nuclei tend to be larger
picture and the pathologic demonstration of numerous
rods in the muscle biopsy in which a majority of fibers
contain many rodlike structures.
Myotubular Myopathy
In 1966 Spiro et al. described this entity with the des-
ignation myotubular myopathy to explain the presence
of central nuclei within most of the muscle fibers of af-
fected patients. In view of the fact that myotubes, which
precede the development of normal adult muscle fibers,
do not persist beyond the 20th week of fetal life, it was
proposed that this disease represents a possible matu-
rational arrest in the development of muscle tissue. Af-
ter denervation in neonatal rats, a picture similar to
myotubular myopathy can be produced. However, FIGURE 23.23 Myotubular myopathy. Many of the fibers have a sin-
there is no solid evidence for denervation as a patho- gle, internal, often central or paracentral nucleus which may be en-
genic factor in human disease. The concept that this larged and vesicular. H&E.
than normal with a vesicular chromatin pattern. Nu- are nonspecific but consistent with myopathy. Exami-
cleoli are not generally seen within such nuclei, how- nation of the muscle biopsy reveals atrophy of type 1
ever. Even light microscopic examination reveals per- fibers, sometimes in association with a predominance
inuclear rarefaction in the majority of fibers (Schochet of type 1 fibers. In H&E-stained microscopic sections,
et al., 1972). Ultrastructurally, muscle fibers resemble numerous subsarcolemmal, eosinophilic inclusions are
myotubes in which a chain of central nuclei is evident. encountered. Ultrastructurally, these inclusions resem-
The perinuclear zone resembles a core in which the sar- ble a fingerprint and are composed of concentrically
coplasm appears incompletely developed and the my- arranged lamellae (Fig. 23.25). Under high magnifica-
ofibrils are disorganized. Unlike cores, the internuclear tion, the lamellae are spaced approximately 35 nm
regions of sarcoplasm are darkly stained in oxidative apart and are sometimes arranged in curvilinear pat-
enzyme reactions (Sarnat et al., 1981). Some central terns. Lamellar profiles have a sawtooth appearance,
nuclei are lobulated with irregular margins, and the with each individual tooth being 3 nm in width and
chromatin is clumped. 12 nm in height. The sawtooth arrangement exhibits a
periodicity of 18 nm. The presence of fingerprint bod-
ies cannot be considered entirely specific for fingerprint
Fiber Type Disproportion
body myopathy. However, when they occur in other
The name that has been popularized for this congeni- conditions such as myotonic dystrophy, they are seen
tal myopathy, fiber type disproportion, is somewhat in only an occasional muscle fiber.
unsatisfying in that it fails to specify the essential patho-
logic features—uniform atrophy of type 1 fibers and
Desmin Myopathy
hypertrophy of type 2 fibers (Color Fig. 23.24 in sep-
arate color insert). Type 1 fiber predominance is com- This disease often follows a dominant pattern of in-
monly observed, so glycolytic fibers may be a small part heritance with onset usually in childhood or young
of the total fiber population. This disease was first dis- adulthood. Affected patients have distal weakness, dys-
covered as an outgrowth of Brooke and Engel’s (1969) phagia, and cardiomyopathy. Involvement of intestinal
analysis of muscle biopsies in children. Clinically, fiber and vascular smooth muscle has been described (Ariza
type disproportion is noted at birth or during early in- et al. 1995; Abraham et al. 1998). Frozen sections
fancy. In some families, the disease is presumably an stained with RTC show smudged areas in the periph-
inherited myopathy, but the inheritance mechanism has eral sarcoplasm of some fibers (Fig. 23.26). They are
never been clearly established. An autosomal recessive not stained in most enzymatic reactions but are highly
mode of inheritance has been proposed in many cases, reactive in immunostains for desmin (Color Fig. 23.27
while an autosomal dominant pattern has been sug- in separate color insert). Under the electron microscope
gested in others. Hypotonia and muscle contractures the abnormal regions contain electron-dense, granular,
are among the most common symptoms. Contractures and filamentous material which is often arranged in
frequently involve the hands and feet. Congenital dis- register with the Z bands. The desmin gene on chro-
location of the hip is either unilateral or bilateral in ap-
proximately 50% of cases. Other abnormalities include
short stature, high arched palate, valgus and varus foot
deformities, and scoliosis. Weakness affecting the trunk
and limb muscles is variable and often most severe in
the first 2–3 years of life. The clinical course is also
variable and ranges from a rapidly fatal form in infancy
to a slowly progressive disease with relatively good
prognosis (Clancy et al., 1980; Torres and Moxley,
1992).
Fingerprint Body Myopathy

This congenital myopathy is familial in some cases,
slowly progressive, and characterized by generalized
weakness and hypotonia (Payne and Curless 1977; Cur-
less et al., 1978). In addition to muscle disease, several FIGURE 23.25 Fingerprint body myopathy. An inclusion resembling
patients have been reported to be mentally retarded. a fingerprint composed of curved lamellae is located under the sar-
CK levels in serum are usually normal. EMG findings colemma.
THE MUSCULAR DYSTROPHIES
Our knowledge concerning the pathogenesis of the

muscular dystrophies continues to be incomplete, but
the tools of molecular biology are beginning to unlock
a number of the secrets surrounding the dystrophies.
In some ways, the muscular dystrophies are similar
both clinically and pathologically, although each type
of dystrophy is a discrete entity. In general, the initial
symptoms of dystrophy begin in childhood or early
adulthood. Muscular weakness, which is often more se-
vere proximally, is unremittingly progressive. Since the
various dystrophies are genetically inherited, a family
history of neuromuscular disease is common in many
FIGURE 23.26 Desmin myopathy. Several fibers can be seen with instances. Like the congenital myopathies, the patho-
eosinophilic, subsarcolemmal, ovoid bodies representing collections logic picture in each of the dystrophies is relatively
of desmin filaments. H&E.
characteristic.
Congenital Muscular Dystrophy

mosome 2q35 reportedly shows a missense mutation Congenital muscular dystrophy is actually a heteroge-
or deletion in some cases (Goldfarb et al., 1998). The neous category from which at least three distinct sub-
CRYAB gene, which codes for - crystalline on chro- types emerge. Fukuyama congenital muscular dystro-
mosome 11q21–23, is affected in other areas. phy (FCMD) is an autosomal recessive disease with the
defective gene coding for fukutin mapped to chromo-
some 9q31–q33 (Kobayashi et al., 1998). The disease
Rigid Spine Syndrome
is more common in Japan, but the disease is being rec-
The central clinical finding in this condition is the ognized with increasing frequency in other geographic
striking limitation of cervical and dorsolumbar spine locations (Takada et al., 1984). The major clinical find-
flexion, which leads to the development of contrac- ings include onset in the first months of life (Fukuyama
ture of the neck in extension and scoliosis (Poewe et et al., 1960), generalized muscular weakness, facial
al., 1985; Van Munster et al., 1986). The deformity muscle involvement, hypotonia, and joint contractures.
of the spine is said to be caused by a shortening of In approximately 50% of cases, seizures are reported.
the erector trunci muscles. Flexion contractures af- Mental retardation (IQ 30–50) and microcephaly are
fecting other joints including the elbows, knees, and part of the syndrome. Myopia is a common symptom
feet are common. Accompanying proximal weakness in the absence of structural ocular abnormalities. Mus-
of the extremities tends to be mild and nonprogres- cular weakness is progressive but the clinical course is
sive. Rigid spine syndrome is considerably more com- somewhat variable. Cerebral CT scans reveal decreased
mon in males. The clinical symptoms usually begin densities in the white matter which are usually bilat-
in childhood. Many cases occur sporadically, but eral and symmetrical. Pathologically, there is cortical
some forms of congenital muscular dystrophy pro- dysplasia and micropolygyria of the cerebrum and cere-
duce the syndrome. A recessive form with a disease bellum associated with hydrocephalus and fusion of the
locus at chromosome 1p35–36 (Moghadaszadeh et cerebral hemispheres. The histologic changes in muscle
al., 1998) and a form with normal merosin are ex- biopsies are relatively nonspecific. Variation in fiber
amples. It also occurs in facioscapuloperoneal dys- size, internal nuclei, interstitial fibrosis, and fatty infil-
trophy (Palmucci et al., 1991) and rod myopathy tration are frequently described. In some patients, type
(Topaloglu et al., 1994). The histologic findings in 1 fiber predominance and/or atrophy of type 1 fibers
muscle biopsies are nonspecific, but interstitial fibro- is reported.
sis and type 1 fiber predominance are observed in A second subtype, Walker-Warburg syndrome, or
many cases. Other pathologic features include a vari- cerebro-ocular dysplasia–muscular dystrophy (COD-
ation in fiber size, sometimes with selective type 1 MD), is associated with ocular and central nervous sys-
fiber atrophy, and increased numbers of internal tem abnormalities which include agyria, polymicro-
nuclei. gyria, heterotopias, and ocular abnormalities, the most
notable of which are cataracts, anterior chamber angle (Bonilla et al., 1988) and according to recent work is
abnormalities, retinal dysplasia, and hypoplasia of the attached to the sarcolemma by a transmembrane of the
optic nerves (Dambska et al., 1982). Skeletal muscle is glycoprotein complex composed of and dystrogly-
reported to be deficient in the 2 chain of laminin can. The N terminal of the dystrophin molecule is
(Wewer et al., 1995). In the muscle biopsy, which tends bound to F actin within the sarcoplasm and the C ter-
to resemble FCMD, fiber necrosis and regeneration minal is bound to dystroglycan (Worton, 1995). Dy-
may also be evident. The prognosis is poor in this sub- strophin is presumed to promote sarcolemmal stabil-
type, and patients usually die before the age of 2. ity, which may be most critical during muscular
A third group of patients is distinguishable from the contraction (Uchino et al., 1989). It is postulated that
previous two by the lack of focal signs and symptoms the absence of dystrophin causes membrane destabi-
referable to the brain and by normal intelligence. CT lization, allowing an influx of calcium ions into the sar-
scans in some patients have revealed hypodense areas coplasm (Cornelio and Dones, 1984). The shift in cal-
within the cerebral white matter (Morandi et al., 1999). cium activates cellular proteases, which initiate cell
Perhaps 50% of patients are reported to have an ab- necrosis (Fong et al., 1990). Rarely a DMD phenotype
normality of merosin (2 chain of laminin 2) (Brett et has normal muscle dystrophin and a single missense
al., 1998). The laminin 2 isoform found in the basal mutation in the dystrophin gene (Goldberg et al.,
lamina of skeletal muscle is connected to the subunit 1998).
of the dystroglycan complex. The defective gene LAMA Affected male infants are normal neurologically at
2, is located on chromosome 6q2. The muscle biopsy birth, but by the time the child begins to stand or walk
findings are dystrophic but otherwise nonspecific. At- the first clinical symptoms of dystrophy are apparent.
rophic fibers, variation in fiber size, nuclear internal- What seems to begin as a delayed mastery of motor
ization, and interstitial fibrosis which at times is strik- control or clumsiness soon becomes outright weakness
ing are the common pathologic features. involving the shoulder and pelvic girdles and the ex-
tremities. The loss of strength is greater in the proximal
axial muscles and tends to spare muscles innervated by
Duchenne Muscular Dystrophy
the cranial nerves except the sternocleidomastoids. By
Duchenne muscular dystrophy (DMD) is the most com- age 5 or 6 the gait is noted to be lordotic and wad-
mon form of muscular dystrophy with a prevalence rate dling. The phenomenon of pseudohypertrophy is char-
of 1 per 3500 live male births. DMD occurs almost ex- acteristic of Duchenne dystrophy. It has a predilection
clusively in young males, the peak age of onset being for certain muscles, such as the calf, lateral thigh, but-
between 2 and 5 years of age. Inherited as an X-linked tocks, infraspinatus, and deltoids. Pseudohypertrophic
recessive trait, Duchenne dystrophy is a disorder in muscles, which are partially replaced by fat and fibrous
which genetic mapping studies have located the DMD tissue, are flabby and weak despite their enlargement.
gene in the Xp21 region of the short arm of the X chro- After age 6–8 years, muscle mass and strength steadily
mosome (Hejtnancik et al., 1986). Recent studies have diminish, although distal muscles remain more func-
identified the gene as a 2500 kb sequence which ap- tional than those of the trunk and proximal limbs. The
pears to be the largest known human gene (Koenig et distribution of weakness is commonly associated with
al., 1987). The high mutation rate in this form of dy- the Gowers maneuver when the patient attempts to
strophy, accounting for about one-third of new cases, stand. As a disparity in weakness of agonist and an-
is presumably due to the excessive size of the DMD tagonist muscle groups develops, joint contractures be-
gene (Prior, 1991). According to investigations using come an increasingly severe problem. Kyphoscoliosis
cDNA probes, 65% of patients with Duchenne dys- occurs as a result of weakness in paraspinal muscles.
trophy have deletions in the DMD gene (Liechti- Involvement of respiratory muscles leads to diminished
Gallati et al., 1989). More accurate diagnosis of pre- pulmonary function, carbon dioxide retention and hy-
natal disease and of the carrier state is now possible poxia, and respiratory infections. Cardiomyopathy is
based upon the identification of DMD gene deletions. commonly manifested by EKG abnormalities such as
Molecular studies have demonstrated that patients with tall right precordial R waves and deep Q waves in limb
Duchenne dystrophy lack the DMD gene product dys- leads. Tachycardia (mean 100 per minute), which is la-
trophin, a 430 kd rod-shaped protein molecule which bile and sinus in origin, and abnormalities of cardiac
is abundant in skeletal muscle (Hoffman et al., 1988). conduction, particularly intraatrial defects, are detected
Dystrophin is also present in smaller concentrations in in at least one half of patients. Of interest is the fact
smooth and cardiac muscle and other cells. Dystrophin that, in contrast to the skeletal muscle disease, cardiac
is closely associated with the muscle cell membrane disease is very slowly progressive. Although 10% of pa-
tients develop congestive heart failure, it is usually a

late event. Early reports noted the presence of mental
retardation in DMD. The lack of mental acuity is ap-
parent at an early age and is not progressive. The re-
duced intelligence quotient (mean IQ 83) is unrelated
to the lack of motor development, extent of physical
incapacitation, or stage of the disease. Laboratory eval-
uation of the patient is particularly valuable as an early
indicator of dystrophy, since serum CK levels reach a
peak at approximately 3 years and may precede the ac-
tual pathologic changes in skeletal muscle. Elevated en-
zymes are highest in the early stages of disease and fall
as muscle mass decreases. Serum enzyme abnormalities
of pyruvate kinase, alanina aminotransfersae (ALT), as-
partate aminotransferase (AST), carbonic anhydrase III, FIGURE 23.30 Duchenne muscular dystrophy. Endomysial fibrosis has
and lactic dehydrogenase parallel those of creatine expanded the normally unobtrusive interstitial spaces around the
kinase. fibers. H&E.
In the muscle biopsy, one of the earliest signs of
disease is the presence of hyaline fibers (Fig. 23.28).
Abnormally rounded and either enlarged or con-
tracted, hyaline fibers are more darkly stained than countered and are most numerous in DMD. It is im-
normal fibers in both paraffin and frozen sections un- portant to exclude the possibility of contraction arti-
der most staining conditions, even histochemical fact in biopsies with hyaline fibers, since excessive
methods. The typical deep staining reaction is best contraction may produce hyaline fiber change.
appreciated in H&E and trichrome stains where the Necrotic and regenerating fibers are more abundant
sarcoplasm is smudged and homogeneous. Ultra- than in other forms of dystrophy. In the earlier stages
structurally, the myofibrillar architecture is disturbed of disease, for reasons which are obscure, necrotic
in hyaline fibers, which are considered to represent and regenerating fibers are frequently seen in clusters
an early stage of muscle fiber necrosis (Cullen and (Color Fig. 23.29 in separate color insert). Fibrosis of
Fulthorpe, 1975). It is sometimes possible in serial the endomysium, usually a reaction to injury in
sections of a fiber to visualize areas of necrosis and chronic longstanding muscle disease, occurs relatively
phagocytosis alternating with regions of sarcoplasmic early in DMD (Fig. 23.30). Endomysial fibrosis is
hyalinization. Hyaline fibers may be seen in other patchy, focal, and disproportionately greater than the
neuromuscular diseases but are most commonly en- apparent injury to muscle cells. This seemingly para-
doxical connective tissue response prompted ob-
servers in the past to speculate that a mesenchymal
disturbance was the primary event in the pathogene-
sis of Duchenne dystrophy. In many biopsies, there
is a failure of fiber typing in histochemical reactions,
particularly ATPase preparations. The fibers are un-
differentiated, and intermediate between type 1 and
type 2 in their staining properties. Some observers
have stressed the high proportion of type 2C fibers,
which are darkly stained in oxidative and standard
ATPase reactions. This finding may be explained by
the abundance of regenerating fibers which react as
type 2C fibers histochemically.
Immunostaining can be utilized to detect membrane
associated dystrophin protein (Ohlendieck et al.,
1993). In normal biopsies, essentially all fibers show
sarcolemmal immunoreactivity for dystrophin (Fig.
FIGURE 23.28Duchenne muscular dystrophy. Two hyaline fibers with 23.31). Very few, if any, fibers in DMD are positively
opaque sarcoplasm are somewhat rounded in configuration. H&E. stained.
Facioscapulohumeral (FSH) dystrophy tends to be a rel-

atively mild and slowly progressive myopathy which be-
gins in the second and third decades and does not sig-
nificantly shorten life span. Unlike Duchenne dystrophy,
pseudohypertrophy of muscle, mental retardation, and
cardiac dysfunction are not part of the clinical picture,
but sensorineural hearing loss is common (Brouwer et
al., 1991). As the name suggests, the muscles affected
to the maximum extent are those of the face, shoulder,
and upper arm. Wasting as well as weakness initially
occurs in the facial muscles and on physical examina-
tion, smiling and wrinkling of the brow are noted to be
compromised. Whistling is difficult due to involvement
of the orbicularis oris, and speech becomes indistinct.
FIGURE 23.31 Limb-girdle dystrophy. Normal staining pattern for While a typical myopathic facies is developing, weak-
dystrophin in a case of muscular dystrophy that is not of the ness and atrophy are descending to the muscles of the
Duchenne type. The sarcolemmal regions of the fibers are outlined.
Immunostain for dystrophin.
shoulder girdle and arm and eventually to the trunk and
legs. The muscle biopsy reveals numerous atrophic and
hypertrophic muscle fibers without significant fiber ne-
crosis or regeneration. A common observation is the
Becker Dystrophy
presence of moth-eaten fibers which are most easily de-
Becker dystrophy is a benign, X-linked muscular dys- tected in oxidative enzyme reactions (Color Fig. 23.32
trophy of low incidence (1/30,000) which has many sim- in separate color insert). The patchy, uneven staining
ilarities to Duchenne muscular dystrophy. In compari- reaction is seen as multiple tiny zones of absent enzyme
son to DMD, the age of onset is later, symptoms are less activity. The moth-eaten zones vary in size and num-
severe, and the rate of progression is more indolent. The ber, are randomly distributed in the sarcoplasm, and
pattern of muscle weakness recapitulates that of DMD have irregular, poorly defined edges. Ultrastructurally,
and pseudohypertrophy of muscle, especially the calves, the moth-eaten areas consist of mitochondrial loss and
is virtually always present. Cardiac involvement is mild, disruption of the myofilaments. Since those portions of
if present at all, and mental retardation affects only a the sarcoplasm adjacent to moth-eaten areas are intact,
minority of patients. Molecular techniques including it is assumed that the moth-eaten fiber is affected by a
linkage studies using restriction fragment length poly- reversible type of injury and is capable of complete re-
morphisms disclose that the gene loci of Duchenne dy- covery. Although moth-eaten fibers are prevalent in fa-
strophy and Becker dystrophy are allelic (Guttman and cioscapulohumeral and limb-girdle dystrophy, our own
Fishbeck, 1989). While muscle in DMD lacks dys- case material points out that such fibers are nonspecific
trophin, in Becker dystrophy the muscle contains ade- and may be associated with a variety of myopathies and
quate amounts of this protein, but it is abnormal in mo- denervating conditions, where they may be numerous.
lecular size (Angelini et al., 1990) or is deformed in The observation of inflammatory cells, the vast major-
structure (Hoffman et al., 1988). The muscle biopsy is ity of which are mature lymphocytes, distinguishes this
characterized by a disparity in fiber diameters due to the dystrophy from others where inflammation generally is
presence of many atrophic and hypertrophic fibers. Fiber not part of the pathologic picture. Inflammatory cells
necrosis and regeneration are not prevalent, but en- are more frequently seen during the early stages of FSH
domysial fibrosis is typically seen. Many internal nuclei dystrophy and are likely to be entirely absent in chronic
and splitting fibers are encountered. disease.
Facioscapulohumeral Dystrophy Limb-Girdle Syndrome

In most families this form of dystrophy appears to con- In 1954 Walton and Nattrass published a study of a
form to an autosomal dominant mode of inheritance large series of patients which they considered to have
with the gene locus residing on the q35 telomeric re- a benign form of muscular dystrophy, and the term
gion of chromosome 4 (Sarfarzi et al., 1992), where limb-girdle dystrophy was proposed for this condition.
11–100 D4Z4 repeat units occur. In disease, by a dele- With the passage of time, it has become clear that limb-
tion process, the repeats are reduced to fewer than 11. girdle dystrophy cannot be regarded as a single disease
entity. It is actually a syndrome with many subtypes al., 1977). Myocytes that have become hypertrophic
which share common features including proximal are likely to undergo the process of splitting, resulting
axial muscle weakness, pseudohypertrophy in about in the formation of smaller fibers which appear to be
one-third of patients, frequent cardiac involvement, and mature muscle fibers with intact sarcoplasm. Prior to
relatively slow disease progression. Most cases are char- the conclusion of the splitting process, the fiber be-
acterized by an onset in late adolescence or young comes lobular due to invaginations which form slitlike
adulthood and autosomal recessive inheritance (types spaces between the lobules. Within each space are ex-
2A–G), although dominant inheritance (types 1A–D) is tensions of the original sarcolemma, which remains
also recognized (Chutkow et al., 1986). These cases continuous around the dividing portions of the fiber.
have been associated with sarcoglycan deficiencies, Moth-eaten fibers may be conspicuous in some cases
most commonly a lack of adhalin or sarcoglycan of limb-girdle syndrome.
(Duggan et al., 1997). The sarcoglycans are a trans-
membrane unit adjacent to the dystroglycan complex
Distal Myopathy
to which dystrophin is attached. To date, four sarco-
glycans (-) have been described (Dubowitz, 1997). Distal myopathy, a rare disease, is not uniformly cate-
Sarcoglycanopathies (types 2C, 2D, 2E, and 2F) have gorized as a dystrophy because of its unusual clinical
been reported in connection with defects in genes for features. Some authorities now propose distal myopa-
, , , and sarcoglycan on chromosomes 13q12, thy as a hereditary form of inclusion body myositis.
17q12–q21, 4q 12, and 5q33, respectively. Type 2A, Like limb-girdle syndrome, distal myopathy appears to
in which sarcoglycans are normal, is caused by a mu- be a heterogeneous group of disorders that are unified
tation in the gene encoding calpain 3, a calcium- by distal weakness and atrophy. Aside from inclusion
activated protease located on chromosome 15q15.1– body myositis, at least four clinical forms of hereditary
q.21.1 (Anderson et al., 1998). Abnormal genes in types distal myopathy are recognized, the most common be-
2B and 2G appear to have been found in chromosomes ing Welander dystrophy, which is most prevalent in
2p13 and 7q11. These genes code for dysferlin and Scandinavia. This type of distal myopathy is domi-
telethonin. nantly inherited and more common in males with a
As might be imagined, in view of the heterogeneous peak age of onset at about 50 years of age. The dis-
clinical picture, the pathologic findings are variable ease is linked to chromosome 2p13 and may be allelic
and nonspecific in limb-girdle syndrome. Occasional with Miyoshi myopathy. Clinical symptoms may be de-
necrotic and regenerating muscle fibers may be dis- tected in the early 20s or remain inapparent until the
covered in the biopsy. Many internal nuclei tend to be mid-70s. This form of dystrophy is indolent in its pro-
seen, and there is a variation in fiber diameters due to gression and almost invariably begins in the hands.
both atrophy and hypertrophy. Hypertrophic fibers are Non-Scandinavian distal myopathy is also dominantly
usually abnormally rounded and some appear to be inherited and late in onset (mean age 40–50). Muscu-
splitting (Fig. 23.33) into two or more parts (Swash et lar involvement usually begins in the legs rather than
the hands, and the disease is slowly progressive. Early
adult onset distal myopathy is a recessively inherited
disease that has been well described in Persians and
Japanese, generally beginning in the 20s and 30s (Isaacs
et al., 1988). Japanese cases (Miyoshi variant) have
been mapped to chromosome 2p12–p14, site of the dys-
ferlin gene (Liu et al., 1998). Clinical symptoms may
first appear in either the hands or legs. Miyoshi my-
opathy, despite a common gene locus, is clinically dis-
tinct from type 2B limb girdle dystrophy.
A controversial myopathy with distal weakness and
rimmed vacuoles has been linked to an abnormal gene
on chromosome 17 which codes for telethonin, a reg-
ulator of sarcomere assembly. Its locus on 17q11–q12
near the locus for adhalin deficiency (limb-girdle dys-
trophy type 2D at 17q12–q21) has convinced some that
FIGURE 23.33 Limb-girdle dystrophy. Fiber splitting is seen in which this disorder should be classified as limb-girdle dystro-
the fiber at the center has split into six segments. H&E. phy type 2G (Moreira et al., 1997).
Examination of the muscle biopsy tends to reveal in- ciency. As a result, the forehead becomes wrinkled and
creased numbers of internal nuclei as well as a varia- the head is tilted backward. The impairment of ocular
tion in fiber diameters. Selective atrophy of type 1 fibers movements may lead to diplopia, although total exter-
is particularly common in Welander dystrophy (Ed- nal ophthalmoplegia is rare. Difficulty swallowing solid
strom, 1975). Rimmed vacuoles have been described in foods is often the first sign of dysphagia. Progressive
the non-Scandinavian cases (Markesbery et al., 1977). dysphagia is associated with an intolerance of liquids
The rimmed vacuole is well demarcated from the sur- and eventually with malnutrition. Dysphonia in some
rounding sarcoplasm and is filled with granular mate- patients is a consequence of weakness of palatal and
rial which may be most evident at the vacuolar margin laryngeal muscles. Mild involvement of facial muscles
or rim. In RTC stains performed on frozen sections, occurs later in the course of disease. Weakness of dis-
the granular material is characteristically red in color. tal muscles appears in a variant of OPD, oculopha-
At the electron microscopic level, the rimmed vacuole ryngeal distal dystrophy, which is primarily restricted
does not always appear limited by a membrane. Within to Japan (Fukuhara et al., 1982). OPD is a slowly pro-
the vacuole are numerous tubular or filamentous struc- gressive disorder that may be complicated after many
tures with a diameter of 10–20 nm. The rimmed vac- years by starvation or aspiration pneumonia. Morpho-
uole is probably a variant of the autophagic vacuole, a logic studies indicate that most muscles are probably
membrane-bound structure in which autodigestion oc- affected in this disease, although the ocular, facial, and
curs as a normal process within many types of cells and pharyngeal muscles are most severely affected. Mild
which may be reflected histochemically by acid phos- nonspecific changes include some increase in the num-
phatase activity (Fig. 23.34). ber of internal nuclei, interstitial fibrosis, and rare fiber
necrosis. Histochemical preparations reveal many small
angular fibers which stain intensely in oxidative enzyme
Oculopharyngeal Muscular Dystrophy
reactions. Rimmed vacuoles have been described in
Typically transmitted by an autosomal dominant mode most cases (Neville and Brooke, 1973). Vacuoles are
of inheritance with complete penetrance, oculopharyn- similar to those seen in distal myopathy and are com-
geal muscular dystrophy (OPD) is a late-onset myopa- prised of irregular or round clear spaces at the rim of
thy beginning in the fifth and sixth decades. A signi- which is granular or linear material that is basophilic
ficant proportion of patients are of Hispanic or in H&E stains and red in RTC stains. According to
French-Canadian origin. A number of familial cases some reports, rimmed vacuoles are more likely to be
from Spain and France have been reported. In the ma- located in axial muscles than in ocular muscles. Ultra-
jority of cases, ptosis is the initial symptom. Ptosis may structural examination of muscle in OPD discloses the
begin asymmetrically but is always bilateral. With in- presence of tubular inclusions within sarcolemmal nu-
creasing severity of the ptosis, the patient cannot raise clei. The tubules, with a diameter of 8.5 nm, are un-
the upper eyelids and tries to compensate for the defi- branched and generally arranged in a haphazard man-
ner. Sometimes tubules are organized into palisades
(Coquet et al., 1983). Intranuclear inclusions tend to
occur in about 5% of sarcolemmal nuclei and thus may
be difficult to locate. The tubular inclusions contain in-
soluble PABPN1 with expanded polyalanine tracts.
OPD is due to short expansions of GCG repeats in the
polyCA binding protein nuclear 1 (PABPN1) gene on
chromosome 14q11–q13. The coding region normally
contains six triplet repeats. In OPD short (GCG)8–13
expansions occur in the first exon of the PABPN1 gene.
Myotonic Muscular Dystrophy

Myotonic muscular dystrophy (MyD) is the most fre-
quently encountered of the myotonic disorders, which
also include myotonia congenita, paramyotonia, chon-
FIGURE 23.34 Distal myopathy. A rimmed vacuole exhibiting abun- drodystrophic myotonia (Schwartz-Jampel syndrome),
dant enzyme activity is visualized as a focus of coarse red granules and acquired myotonia, which may be drug-induced or
indicative of acid phosphatase activity. Acid phosphatase. associated with malignancy. MyD is the most common
muscular dystrophy in adults, with an overall incidence quent of which are heart block and atrial flutter. De-
in the United States of approximately 5–6 per 100,000 spite the presence of cardiomyopathy in the majority
population. Depending on the geographic area, the of patients, severe congestive cardiac failure is rare. In
prevalence of myotonic dystrophy (1/10,000) may ex- addition to the involvement of striated muscle, smooth
ceed that of Duchenne dystrophy (Speer et al., 1990). muscle is also affected. Dysphagia may reflect
Linkage studies indicate that the MyD gene, a 200 kb esophageal disease. In the large bowel, reduced motil-
interval, is located on the long arm of chromosome 19 ity, signs of spastic colon, and megacolon have been
(19q13.3). The gene mutation is associated with an in- observed. Smooth muscle involvement in the urinary
sertion of additional CTG repeats (Caskey et al., 1992). bladder and uterus has also been reported. Mild
The normal gene has up to 40 repeats, whereas the changes in mental status including apathy and a gen-
MyD gene may contain from 50 to several hundred re- eral decline in social skills are observed in many pa-
peats. Larger numbers of trinucleotide repeats are pre- tients. Additional very common features are hyper-
dictors of more severe disease. The MyD gene codes somnia and a diminished intellect. The basis for the
for myotonin protein kinase, which has led to its des- central nervous system symptoms and signs is poorly
ignation as the DMPK gene. The function of this pro- understood, although cerebral cortical atrophy and
tein kinase is unclear, stimulating discussion about ventricular dilatation have been observed by CT. En-
the true significance of the trinucleotide repeats in docrine disturbances have received considerable atten-
myotonic dystrophy. The repeats may actually affect tion. Hyperinsulinism and insulin resistance in the
neighboring genes, perhaps reducing the expression of absence of overt diabetes mellitus, gonadal atrophy (es-
the DMAHP gene, which regulates cell ion homeosta- pecially in males), and pituitary dysfunction are com-
sis. While this type of dystrophy is dominantly inher- mon. Cataracts are reported in over 90% of patients.
ited, penetrance is variable, so the age of onset and con- These are best detected during slit-lamp examination,
stellation of clinical findings vary considerably. when they appear as multicolored, refractile subcapsu-
Typically MyD begins during the third or fourth decade lar opacities.
with weakness of facial muscles and ptosis. As muscle Before the disease enters a chronic phase wherein dy-
wasting progresses, the cheeks appear hollow and the strophic features are evident, the muscle biopsy is char-
face is without expression. Sternomastoid muscle atro- acterized by numerous internal sarcolemmal nuclei and
phy is noted in contrast to sparing of the posterior cer- atrophy of type 1 fibers. Most of the fibers contain in-
vical muscles. Involvement of the extremities begins dis- ternal nuclei, and multiple internal nuclei are com-
tally and affects the muscles of the hands and feet, as monly seen in a single fiber (Fig. 23.35). Internal nu-
well as the wrist extensors and dorsiflexors of the foot. clei are typically pyknotic and oval or even somewhat
Myotonia, a delay in muscle relaxation after normal elongated in shape. Fiber atrophy is random without
contraction, is an early sign of disease. The phenome- grouping of small fibers. Atrophic fibers vary from
non of myotonia may be elicited by vigorous muscle round to angular in shape. A large proportion of type
contraction or percussion with a reflex hammer. Pa-
tients frequently do not complain of myotonia, or they
describe their myotonia as a stiffness which may be pre-
cipitated by exposure to cold. It is easiest to detect my-
otonia in the hand clinically. Percussion of the thenar
eminence will often induce myotonia, as will having the
patient firmly seize an object, after which there will be
a delayed relaxation of the grip. EMG may be impor-
tant in the diagnosis, particularly when myotonia is
clinically silent. The principal electrical features are
excessive insertional activity and myotonic potentials
which are repetitive discharges that build and decline
in both amplitude and frequency. Myotonic potentials
are sometimes best demonstrated with movement of the
needle electrode. Myotonic dystrophy is a multisystem
disease which may be first encountered by a variety of
specialists other than neurologists. Cardiac manifesta- FIGURE23.35 Myotonic dystrophy. Commonly in this disease one or
tions are very common and can lead to sudden death. more, often pyknotic, internal nuclei are seen in many of the fibers.
Many patients have EKG abnormalities, the most fre- H&E.
1 fibers are involved in the atrophic process, which ex- 17 in the q21–q23 region. Infantile acid maltase defi-
clusively affects type 1 fibers in some cases. Ring fibers ciency or Pompe’s disease is classically a fatal systemic
are found without difficulty in most cases of myotonic disease with onset within the first few months of life.
dystrophy (Fig. 23.36). Such fibers are composed of Numerous mutations are reported but the most com-
two zones as seen in cross sections of muscle. The outer mon is a deletion at exon 18. These mutations often
zone or ring is composed of a peripheral bundle of my- result in an absence of enzyme in affected cells. Rapidly
ofibrils that encircles the inner portion of the fiber, progressive, this form of the disease usually results in
which appears normal in structure. The ring is oriented death by age 2, often from cardiorespiratory failure.
in the transverse plane while the normal inner portion Progressive weakness, hypotonia, macroglossia, and
of the sarcoplasm is oriented longitudinally. In paraf- organomegaly comprise the features of this generalized
fin sections the ring is easily visible in PAS stains. Resin disorder. Liver enlargement may be especially promi-
sections are probably best for the detection of ring nent. Specialized techniques such as echo- and angio-
fibers by light microscopy. Ultrastructurally, the ab- cardiography demonstrate narrowing of the left ven-
normally oriented myofibrils tend to exhibit a normal tricular outflow and thickening of the ventricular
architecture although hypercontraction of the sarcom- septum. EKG reveals left ventricular hypertrophy, a
eres may be present (Heffner, 1975). Biopsies of pa- short PR interval, and high QRS voltage. Massive ac-
tients with longstanding myotonic dystrophy are not cumulations of glycogen, which may reach 15% of wet
diagnostic. Dystrophic changes such as fiber necrosis weight of the affected tissue, are present in skeletal
and regeneration occur in association with interstitial muscle, cardiac muscle, and liver. Microscopic tissue
fibrosis and marked fiber atrophy. examination discloses glycogen deposits in smooth
muscle, renal glomeruli, lymphocytes, and central ner-
vous system. Within the brain and spinal cord, motor
METABOLIC MYOPATHIES neurons in the brain stem and spinal cord contain the
largest accumulations of glycogen. Adult-onset acid
Carbohydrate Storage Diseases maltase deficiency begins at an interval from early
adulthood to middle age. The late-onset form is slowly
Acid maltase deficiency
progressive and more highly focused within skeletal
Acid maltase ( glucosidase) is a lysosomal enzyme, the muscle (Engel et al., 1973; Karpati et al., 1977). A large
activity of which is maximal at pH 4–5. As a result of number of mutations have been described. Some are
enzyme cleavage, glucose is liberated from glycogen, complicated, such as a deletion of intron 1 that results
oligosaccharides, and maltose. Acid maltase deficiency, in splicing out of exon 2 and a reduction but not an
designated as type II glycogenosis, is an autosomal re- absence of enzyme (Huie et al., 1994). Patients gener-
cessive disease which is clinically manifest in two ma- ally present with proximal muscle weakness involving
jor forms. The defective gene is located on chromosome the chest, abdomen, and extremities. The clinical pic-
ture may be confused with limb-girdle dystrophy, late-
onset congenital myopathy, or polymyositis. Approxi-
mately 30%–40% of adult patients are first seen by the
physician because of respiratory failure. Symptoms typ-
ical of this complication are fatigue, dyspnea, and or-
thopnea. Involvement of respiratory muscles eventually
occurs in most patients during the later stages of dis-
ease. Respiratory failure frequently plays an important
role in the demise of such patients. Cardiomegaly and
hepatomegaly are not usually part of the disease pro-
cess in adults. The accumulation of glycogen in skele-
tal muscle is never greater than 5% of wet tissue weight.
Examination of the muscle biopsy reveals numerous
vacuoles which vary in size within the muscle fibers. In
infants, two vacuoles replace much of the sarcoplasm.
In paraffin sections, vacuoles are clear, while in frozen
FIGURE 23.36 Myotonic dystrophy. Two ring fibers are seen. The
sections stained with H&E they are filled with blue-
more peripheral ring is often distinguished from the normal internal brown granular material that is very distinctive of
portion of the fibers by the presence of cross striations. PTAH. glycogen deposits, even in the absence of special stains
(Fig. 23.37). Vacuoles are PAS positive, particularly in finitive diagnosis is seldom established before age 10 and
frozen sections, where tissue processing has not re- not uncommonly until age 20–30. McArdle’s disease is
moved much of the glycogen. Vacuoles react strongly characterized by exercise intolerance, myalgia, stiffness,
in acid phosphatase preparations, reflecting the fact and muscle cramps, the last being rare in children. Pa-
that they represent secondary lysosomes. In adults with tients most frequently complain of pain and stiffness dur-
indolent disease, interstitial fibrosis may be prominent. ing or after exertion or exercise. Symptoms are relieved
Ultrastructurally, glycogen accumulations are variable by rest. Commonly exertional intolerance is precipitated
in appearance. The typical vacuole is surrounded by by either high-intensity activity of brief duration such as
membrane-containing glycogen granules of normal size running up a flight of stairs or sustained but less intense
or of reduced diameter indicating partial degradation. effort such as walking uphill or bicycling. Many patients
Collections of freely dispersed glycogen which are not do not appreciate the significance of their symptoms and
membrane bound may also be seen. Autophagic vac- simply avoid activities which result in pain or cramps.
uoles containing heterogeneous contents representing During exercise patients frequently experience a second-
the breakdown of sarcoplasm as well as of glycogen wind phenomenon exemplified by increased endurance
granules also are encountered. Membrane-bound col- following a brief rest prompted by the onset of stiffness
lections of glycogen are important diagnostically since and myalgia. In most patients the disease is episodic and
they do not occur frequently in normal muscle. These only troublesome during periods of more strenuous ac-
membrane-bound vacuoles are presumptive evidence of tivity, but permanent weakness is reported in less than
acid maltase deficiency, although they may also occa- one-third of patients. Vigorous exercise tends to be fol-
sionally be encountered in other glycogen storage dis- lowed by myoglobinuria in about 50% of individuals.
eases. Inasmuch as acid maltase activity cannot be dem- Renal failure is a significant risk in patients with myo-
onstrated histochemically, definitive diagnosis requires globinuria. Serum CK is elevated in the vast majority at
biochemical analysis of muscle or other tissue. rest. A valuable ancillary procedure in the diagnosis of
McArdle’s disease is the ischemic exercise test. The test
is not specific for McArdle’s disease since defects in the
McArdle’s disease
glycolytic pathway can reduce lactate production under
Type V glycogenosis or myophosphorylase deficiency is ischemic conditions. Positive tests have also been re-
an inherited, often familial disease in which the mode of ported in patients with phosphofructokinase deficiency
transmission is considered to be autosomal recessive. The and debrancher deficiency. In McArdle’s disease, the ba-
muscle phosphorylase gene is located on chromosome sis for the tourniquet test is the fact that affected pa-
11q13. The disease is genetically heterogenous and due tients cannot generate adequate lactate since they are un-
to several recently described point mutations (Tsujino et able to properly break down 1,4-glucosidic linkages.
al., 1993). Although symptoms of long duration are ret- Following 1 minute of standardized exercise of ischemic
rospectively obtained during diagnostic evaluation, de- muscle, there is a three- to fivefold increase of venous
lactate in normal subjects. In patients with McArdle’s
disease, the change in lactate is minimal or absent in ap-
proximately 95% of tested individuals. Histologically,
numerous linear or crescent-shaped vacuoles are found
in the subsarcolemmal portions of the muscle fibers (Fig.
23.38). These vacuoles stain intensely with PAS. How-
ever, in mild cases, no vacuoles may be visible, even in
PAS stains. Necrotic and regenerating fibers may be ev-
ident, particularly in cases in which myoglobinuria has
occurred. Under the electron microscope, large numbers
of -glycogen particles are seen within the vacuoles and
between myofibrils to a lesser extent. Histochemical re-
actions are useful in confirming an absence of phos-
phorylase activity.
In normal muscle, the phosphorylase enzyme occurs
in an inactive and an active form. The inactive enzyme,
FIGURE 23.37 Acid maltase deficiency. In frozen sections, glycogen
phosphorylase b, a dimer, is converted to the active
deposits appear granular and are stained intensely blue in color. form, phosphorylase a, a tetramer, by the enzyme phos-
H&E. phorylase b kinase. Recent reports indicate that a dis-
ciency involving M subunit–containing isozymes. A sec-

ond form of PFK deficiency results from a lack of the
L subunits of the enzyme. The major problem in this
group of patients, who are free of muscular symptoms,
is hemolytic anemia. The microscopic examination of
the muscle biopsy in muscular or typical PFK deficiency
is indistinguishable from McArdle’s disease. Numerous
PAS-positive crescents are visualized under the sar-
colemma of muscle fibers. By electron microscopy,
these crescents are shown to contain glycogen particles.
It is possible, but often difficult, to demonstrate PFK
deficiency histochemically (Bonilla and Schotland,
1970). Since histochemical stains are relatively unreli-
able, the diagnosis of PFK deficiency should be con-
FIGURE 23.38 McArdle’s disease. Abnormal collections of glycogen firmed by biochemical analysis of muscle tissue.
typically form crescent-shaped foci beneath the sarcolemma. PAS.
Lafora’s disease and polyglucosan body disease

ease indistinguishable from McArdle’s disease is due to Lafora’s disease is a systemic disorder which is pro-
to an absence of phosphorylase b kinase, so active phos- gressive and fatal. The disease is familial and trans-
phorylase cannot be produced from inactive phospho- mitted as an autosomal recessive defect with genetic
rylase b. Immunostudies have demonstrated deficien- mapping to chromosome 6q23–q25 (Minassian et al.,
cies of one or more of the , , and enzyme subunits 1999). Onset is in school-age children between the ages
in affected patients (Wilkinson et al., 1994). The re- of 6 and 18. Epilepsy is a common presenting symp-
cessive form of disease is reported to have a gene lo- tom. Myoclonus or grand mal seizures may occur. Neu-
cus on chromosome 16. The locus for an X-linked form rologic findings also include deterioration of intel-
is on chromosome Xq12–q13. lectual function, dysarthria, ataxia, spasticity, and
muscular weakness. Although the major pathologic
changes are in the central nervous system, Lafora’s dis-
Phosphofructokinase (PFK) deficiency
ease is a generalized metabolic disturbance with in-
Type VII glycogenosis or Tarui’s disease is an inherited volvement of heart, liver, skin, peripheral nerves, and
glycogen storage disorder that resembles McArdle’s dis- voluntary muscle. Visualization of Lafora bodies within
ease clinically and pathologically (Layzer et al., 1967). affected cells is essential for the diagnosis. In H&E-
For unexplained reasons, PFK deficiency is more com- stained sections of the CNS, Lafora bodies are round
mon in males and is presumed to be recessively inher- and basophilic (Fig. 23.39). Typical Lafora bodies are
ited in most families. Clinical manifestations, usually
beginning in childhood, are marked by muscular aching
and stiffness brought on by exercise. Especially vigor-
ous or sustained exercise may result in nausea, vomit-
ing, severe weakness, and myoglobunia. Fixed weak-
ness is much less common than in McArdle’s disease.
Unlike McArdle’s disease, a normal elevation in venous
lactate may occur during the tourniquet test. PFK is a
tetrameric protein in which three different subunits—
L, M, and P—are found in varying combinations. The
muscle enzyme is a homotetramer composed of four
identical M subunits. Red cell isozymes contain L as
well as M subunits. Typical PFK deficiency is due to a
genetic absence of the M subunit, which causes my-
opathy. The abnormal gene is located on chromosome
12q13 (Howard et al., 1996) with at least 15 known FIGURE 23.39 Lafora’s disease. A characteristic Lafora body is seen
mutations in the PFK-M gene. Red blood cell hemoly- within an anterior horn cell in the spinal cord. The inclusions have
sis occurs as a consequence of erythrocyte PFK defi- a darker central region and may be laminated. H&E.
characterized by a dark central region from which fil-

amentous material radiates toward the periphery of the
inclusion. In the central nervous system Lafora bodies
are not membrane bound. Biopsies of muscle, as well
as other tissues such as liver, reveal inclusions which
may be somewhat different from classic Lafora bodies
(Neville et al., 1974). These accumulations of polysac-
charide are round, granular or opaque structures which
stain blue in H&E stains and red in PAS preparations
(Fig. 23.40). When viewed under the electron micro-
scope, these polysaccharide inclusions appear to be
composed of short branching filaments measuring 6 nm
in diameter. The filaments often are present within vesi-
cles which are surrounded by a membrane (Carpenter
et al., 1974). The filamentous material resembles amy- FIGURE 23.42 Lipid storage myopathy. Numerous lipid-containing
lopectin. Based upon biochemical studies, Lafora bod- vacuoles in the sarcoplasm characteristically appear pale green in
color. Toluidine blue.
ies are composed of glucose polymers known as
polyglucosans. Of late, Lafora’s disease is considered
to encompass several storage diseases including adult
Lipid Storage Diseases
polyglucosan body disease This late-onset, slowly pro-
gressive disorder affects the CNS and peripheral ner- The lipid storage diseases are characterized by patholog-
vous system while sparing muscle fibers. The muscle ical accumulations of fat within muscle fibers and other
biopsy is characterized by neurogenic atrophy and cellular elements within the muscle biopsy (DiMauro et
polyglucosan bodies within the intramuscular nerve al., 1980). In some disorders, lipid storage may also oc-
twigs. Polyglucosan bodies are also found in type IV cur in other organs. Like the glycogen storage diseases,
glycogen storage disease. Both polyglucosan body dis- the lipid storage diseases are often suspected in routine
ease with late onset and type IV glycogenosis have a microscopic sections because of vacuolar change within
deficiency of glycogen branching enzyme. In both dis- cells. Lipid-containing vacuoles are detected in frozen sec-
eases, a number of mutations involving the glycogen tions stained with oil red O or other suitable fat stains
branching enzyme gene on chromosome 3p12 have (Color Fig. 23.41 in separate color insert). In resin-em-
been reported, the most common being the Tyr 329 Ser bedded tissue, lipid vacuoles exhibit a light green color
mutation (Lossos et al., 1998). in toluidine blue–stained sections (Fig. 23.42).
Carnitine deficiency
Carnitine is required for the transport of long-chain
fatty acids into the mitochondria and for the control
of the coenzyme A (CoA)/acyl–Co A ratio. A deficiency
in carnitine renders long-chain fatty acids, the primary
substrate of oxidation, unavailable for mitochondr-
ial metabolism. Carnitine deficiency can occur as a my-
opathy in which the disease is confined to skeletal mus-
cle (Engel and Angelini, 1973) or as a systemic disorder
which may be primary or secondary. Muscle carnitine
deficiency is a slowly progressive disease with mild
muscle weakness, the onset of which may range from
infancy to middle age. Muscle pain on exertion has
been reported in some patients. Primary systemic car-
nitine deficiency is rare. There are many causes of sec-
FIGURE 23.40 Lafora’s disease. Numerous polyglucosan bodies,
which are often round and well-demarcated, are seen in the muscle ondary carnitine deficiency, but the most common un-
fibers. The inclusions are without internal structure, opaque, and derlying conditions are acyl–Co A dehydrogenase
sometimes slightly basophilic. H&E. deficiencies, of which there are several variants, and a
number of organic acidurias. Secondary carnitine defi- A molecules which must be transferred to carnitine
ciency has also been associated with Reye’s syndrome, by the enzyme CPT I. The acyl group is transferred
chronic renal failure, liver cirrhosis, malnutrition, and from Co A to carnitine by CPT I, which spans the
myxedema. Systemic carnitine deficiency is recognized outer mitochondrial membrane. While attached to
by the presence of acute encephalopathy with stupor carnitine, acyl groups are ferried within the mito-
or coma, cardiac failure, hepatic dysfunction, and chondrial membrane by a translocase, carnitine-acyl-
hypoglycemia in many patients. As a reflection of sys- carnitine carrier. A deficiency of this carrier has re-
temic disease, serum carnitine levels are reduced below cently been described (Huizing et al., 1998). Once
normal. In carnitine deficiency, the essential pathologic across the inner mitochondrial membrane, a second
change in the muscle biopsy is diffuse vacuolization of CPT (CPT II) which is bound to the inner face of the
muscle fibers. In a single fiber, vacuoles tend to be mul- membrane catalyzes the reformation of acyl–Co A
tiple and variable in size. In oil red O stains and in resin from acylcarnitine. Acyl–Co A compounds are then
sections they are readily identified as containing lipid available for oxidation, and free carnitine is recy-
(Color Fig. 23.41 in separate color insert). Ultrastruc- cled to the cytosol outside the mitochondrial com-
tural examination of muscle may reveal abnormal mi- partment. The enzyme CPT II is a homotetramer com-
tochondria with respect to size and shape. Changes may posed of 68 kd monomers. The CPT II gene, 20 Kb
be reminiscent of those seen in the mitochondrial my- in size, is located on chromosome 1p32. More than
opathies. None of the alterations seen pathologically is 15 mutations of the CPT II gene have been reported.
specific and the diagnosis of carnitine deficiency de- Approximately 60% of mutant alleles associated with
pends on biochemical analysis of tissue. adult myopathic disease involve a missense Ser 113
Leu mutation (Taroni et al., 1993). However, with
each new publication the considerable molecular het-
Carnitine palmitoyltransferase deficiency
erogeneity of CPT II mutations becomes increasingly
A major presenting symptom in adults is myoglobin- evident.
uria, often precipitated by exercise or fasting. Less com-
mon factors inducing myoglobinuria are infection,
Batten’s disease
stress, or sleep deprivation. Myoglobinuria is frequently
episodic and patients usually experience myoglobinuria Batten’s disease (juvenile ceroid–lipofuscinosis) is an in-
on several occasions before seeking medical attention. herited disorder affecting young children with an on-
Other clinical features are muscular weakness, tight- set between 3 and 10 years of age. Delayed mental de-
ness, cramps, and tenderness when the muscle is pal- velopment, deterioration of motor function, myoclonus
pated. Renal failure may develop as a result of myo- and generalized seizures, and ataxia are among the clin-
globinuria. A lethal neonatal phenotype and a severe ical findings. Visual disturbances with pigmentary re-
infantile form have also been described. Carnitine pa- generation of the retina as well as optic atrophy are
lymitoyltransferase (CPT) deficiency is usually inher- common. Muscular weakness and hypotonia are part
ited as an autosomal recessive trait and the predomi- of the clinical disease. Batten’s disease is a generalized
nance of male patients (85%) is unexplained. In lysosomal storage disorder involving neurons, Schwann
approximately 75% of patients, if the muscle biopsy is cells, endothelial cells, eccrine glands, and smooth mus-
evaluated between episodes of myoglobinuria, no sig- cle. Microscopic examination of the muscle biopsy re-
nifiant morphologic changes are observed whatsoever. veals numerous clear vacuoles in muscle fibers and less
Abnormal lipid accumulation is a variable finding and commonly within muscle spindles, satellite cells, and
is not required for diagnosis. Necrotic and regenerat- intramuscular nerve twigs (Carpenter et al., 1972). In
ing fibers have been described in occasional biopsies, H&E stains, the vacuoles may contain small basophilic
presumably in relation to recent myoglobinuria. A de- regions. Positive staining is also achieved with PAS, fat
ficiency of CPT must be established by biochemical stains, and acid phosphatase reactions. When viewed
means. under fluorescence microscopy, vacuoles are autofluo-
The function of CPT is to facilitate the movement rescent and silver-yellow in color. Ultrastructurally,
of long-chain fatty acids into the mitochondria. Af- membrane-bound cytosomes containing curvilinear
ter entry into the cell, long-chain fatty acids are es- bodies are observed (Carpenter and Karpati, 1986).
terified on the cytosolic side of the outer mitochon- These structures are composed of curved lamellae
drial membrane to acyl–coenzyme A. The inner which are in the form of semicircles or crescents (Fig.
mitochondrial membrane is impermeable to acyl–Co 23.43). The lamellae are made up of arrays of parallel
Mitochondrial Myopathies
From a historical perspective, Luft and colleagues

(1962) were the first to describe structural abnormali-
ties of mitochondria, thus originating the concept of
mitochondrial disease in muscle. Subsequently Shy et
al. (1966) began to recognize the diversity of the mi-
tochondrial myopathies based on ultrastructural ex-
amination. Terms such as pleoconial and megaconial
were introduced to indicate abnormalities of mito-
chondrial shape and size. By today’s standards, these
purely descriptive terms are clearly inadequate, failing
to consider the biochemical defects and the molecular
abnormalities which are currently emerging as the
FIGURE 23.43 Batten’s disease. Ultrastructurally, the sarcoplasmic cy- means of classifying the mitochondrial myopathies. As
tosomes contain curvilinear bodies composed of curved lamellae. was apparent almost from the beginning, the mito-
chondrial myopathies are a heterogeneous and bewil-
dering group clinically, pathologically, and biochemi-
cally (DiMauro et al., 1980; Tassin and Brucher, 1982;
lines, which are paired. Within each pair, the osmio- Bauserman and Heffner, 1984). A number of reported
philic lines are separated by electron lucent spaces mea- cases appear to be sporadic, while others are geneti-
suring 1.5 mn in width. Pairs of lines in turn are sep- cally inherited through either nuclear or mitochondrial
arated from one another by a wide lucent space DNA. The onset of disease ranges from infancy to
measuring 2.5 nm. It is known that the cytosomes in adulthood. The distribution of muscle weakness may
Batten’s disease contain polyisoprenols and dolichols, be generalized, although there is an unexplained high
but the metabolic defect in this disease is still under in- frequency of ptosis and ophthalmoplegia due to ex-
vestigation. traocular muscle dysfunction. Mitochondrial distur-
bances may be restricted to skeletal muscle or be more
widespread. In the past, when organs other than mus-
Fabry’s disease
cle were affected, the condition was sometimes referred
Fabry’s disease is a sex-linked metabolic disorder lo- to as ophthalmoplegia plus (Drachman, 1968) or ocu-
calized to chromosome Xq22. It is characterized by an- locraniosomatic neuromuscular disease (Olson et al.,
giokeratomas of the skin, corneal opacities, and renal 1972), indicating involvement of the retina, central ner-
insufficiency. A peripheral neuropathy is associated vous system, heart, endocrine glands, and other organs.
with intermittent pain and diminished sweating. In this diverse group of primary mitochondrial disor-
Fabry’s disease is a generalized deficiency of the en- ders, the initial and dominant pathologic changes af-
zyme galactosidase, resulting in the storage of ce- fect the mitochondria. Typically there is a biochemical
ramide trihexoside in a variety of organs including derangement, usually related to a defect in mitochon-
blood vessels, especially endothelial cells, glomeruli, pe- drial metabolism. Although the distinction is becoming
ripheral nerve, and myocardial cells. Abnormal lipid increasingly blurred, in some instances the morphologic
storage occurs primarily in intramuscular blood vessels, mitochondrial changes appear to be secondary rather
both in endothelial cells and pericytes, in muscle biopsy than primary. For example, mitochondrial abnormali-
specimens (Sima and Robertson, 1978). Cytosomal ties have been described in Canavan’s disease, Zell-
structures react positively in PAS and fat stains and in weger’s syndrome, myotonic dystrophy, acid maltase
acid phosphatase preparations. Occasional deposits of deficiency, hyperthyroidism (Norris and Panner, 1966),
granular material, usually subsarcolemmal in location, ischemia, and as a consequence of treatment with phar-
represent lipid storage in resin sections. Ultrastructural macologic agents such as steroids and zidovudine. In
examination reveals membrane-bound, concentric the secondary disorders, as a general rule a preexisting
lamellae which are predictably found in intramuscular clinical condition is present, and the mitochondrial
nerves and blood vessels (Color Fig. 23.44 in separate changes are only a minor part of the entire pathologic
color insert). Lamellar structures appear to be com- picture.
posed of parallel osmiophilic lines having a periodicity One explanation of the myopathies which do not re-
of 6.5–7.0 nm. sult from inborn genetic mutations is that they are as-
sociated with impaired mitochondrial protein synthe-

sis (DiMauro and Moraes, 1993). The subsequent
harmful effects on oxidative phosphorylation become
a stimulus for mitochondrial proliferation.
The structural abnormalities of mitochondria are
similar in all of these mitochondrial myopathies, dif-
fering only in the severity and the combination of mor-
phological abnormalities. For this reason, it is not
possible to classify or definitively diagnose specific mi-
tochondrial myopathies based solely upon morphologic
criteria. Most of these myopathies are characterized by
the presence of ragged-red fibers (Color Fig. 23.45 in
separate color insert) which are identified in RTC stains
on frozen sections as bright red, subsarcolemmal ir-
regular protrusions from the cell surface, so the mar- FIGURE 23.47 Mitochondrial myopathy. Abnormal mitochondria
gins of involved fibers have an undulating, ragged ap- contain cristae arranged in a whorl-like fashion.
pearance. Ragged-red fibers are also visible in oxidative
enzyme reactions, where abnormal collections of mito-
chondria are seen as intensely stained, coarsely granu- (Fig. 23.48). The appearance of some paracrystalline
lar deposits that are not only subsarcolemmal, but inclusions suggests that they arise from cristae within
sometimes diffuse throughout the fiber (Fig. 23.46). Ul- the mitochondrion. They are composed of parallel, in-
trastructurally, ragged-red fibers are noteworthy for tersecting dense lines separated by lucent spaces.
their accumulations of mitochondria which are en- A central function of mitochondria involves energy
larged, misshapen, and often crowded together in clus- metabolism. There are numerous points along the meta-
ters. The cristae within the mitochondria may be ex- bolic process where defects can occur, including trans-
cessive or reduced in number, leaving lucent regions port of substrates into the mitochondria, substrate
within the matrix. The cristae may be disorganized, or utilization, oxidation and phosphorylation coupling,
abnormally arranged, sometimes forming concentric respiratory chain function, and ATP synthesis. These
whorls (Fig. 23.47). Inclusions within the mitochondr- defects form one basis by which the mitochondrial my-
ial matrix are exemplified by glycogen aggregates, floc- opathies are classified from a metabolic standpoint. An-
cular densities, myelin figures, and paracrystalline other way to structure our thinking about mitochon-
structures which typically exhibit a square or rectan- drial diseases is based on mitochondrial genetics, which
gular conformation and resemble a grid or parking lot will be discussed momentarily.
FIGURE 23.46 Mitochondrial myopathy. A fiber containing increased FIGURE 23.48 Mitochondrial myopathy. Abnormal mitochondria
numbers of mitochondria is intensely stained for oxidative enzyme contain rectangular, paracrystalline inclusions with a gridlike struc-
activity, particularly in the subsarcolemmal regions. NADH-TR. ture.
Defective energy conservation well as in the synthesis of fatty acids and acetylcholine.
Defects in the PDH complex lead to a variety of clini-
The most familiar example of disordered oxidation–
cal syndromes (Old and DeVito, 1989). The diagnosis
phosphorylation coupling is Luft’s disease, the first mi-
should be suspected when there is lactic acidosis, with
tochondrial myopathy to be recorded (Luft et al.,
or without an elevation of blood pyruvate, failure to
1962). In this sporadic condition, symptoms begin in
thrive, hypotonia, respiratory difficulties, and seizures.
childhood or early adolescence with severe hyperme-
Among the well-defined syndromes associated with
tabolism manifested as fever, heat intolerance, contin-
pyruvate dehydrogenase deficiency is Leigh’s syndrome
uous sweating, dyspnea at rest, polyphagia without
(subacute necrotizing encephalomyelopathy). This dis-
weight gain, and polydipsia. The basal metabolic rate
order is inherited as an autosomal recessive trait with
is markedly increased, but thyroid function tests are
onset during infancy or early childhood. Central ner-
normal. Ragged-red fibers are seen in the muscle bi-
vous system symptoms such as somnolence, blindness,
opsy. Excessive numbers of mitochondria which are en-
deafness, and ataxia predominate, but peripheral neu-
larged and abnormally shaped are visualized ultra-
ropathy is frequently encountered as well. Hypotonia
structurally. Oxidative phosphorylation in muscle
and muscle weakness are at times components of the
mitochondria reveals a maximum respiratory rate in
clinical presentation (Crosby and Chou, 1974). The le-
the absence of ADP, suggesting a loss of respiratory
sions in the central nervous system resemble those of
control, so oxidation preceeds at an exceptionally rapid
Wernicke’s encephalopathy. In addition to PDH defi-
rate independent of phosphorylation. Excess energy is
ciency, Leigh’s disease has been reported in association
inefficiently converted to heat, leading to hypermetab-
with several other abnormalities, including a deficiency
olism and hyperthermia. Normally the rate of mito-
of cytochrome c oxidase, complex I deficiency (defec-
chondrial respiration is based on the metabolic re-
tive gene on chromosome 11q.13), mutations in the
quirement of the cell, and energy is conserved. The
tRNALys gene (Santorelli et al., 1998), and a T 씮 G
major control mechanism is the ratio of ATP to ADP.
mutation at nucleotide 8993 in the gene for ATPase
As ATP is converted to ADP during muscle contrac-
synthase (complex V). These observations expose the
tion, ADP becomes the stimulus for mitochondrial
flaw in classifying the mitochondrial disorders strictly
respiration.
on a metabolic basis.
Subsequent to the observation of Luft et al. (1962),
it has become evident that many cases of mitochondr-
ial myopathy are associated with a functional defect of Respiratory Chain Defects
oxidative phosphorylation which is loosely coupled
Many mitochondrial myopathies have defects in the
within the mitochondria. The uncoupling of mito-
respiratory chain, a series of five functional units or
chondrial phosphorylation in which appropriate sub-
complexes comprising 82 subunits located within the
strates are oxidized in the absence of phosphorylation
inner mitochondrial membrane (Schapira, 1998). Com-
of ADP to ATP is a common metabolic situation in a
plex I (NADH-coenzyme Q [ubiquinone] reductase)
number of the mitochondrial myopathies and is con-
contains 26 polypeptides and includes NADH dehy-
sidered to be an epiphenomenon and not a primary de-
drogenase. Complex II (succinate–coenzyme Q reduc-
fect of mitochondrial function.
tase) is composed of five polypeptides and includes
FAD-dependent succinate dehydrogenase. Complex III
(coenzyme Q–cytochrome c reductase) contain 10
Impaired substrate utilization
polypeptides as well as two species of cytochrome b
Those diseases within this category are carnitine defi- and cytochrome c1. Complex IV (cytochrome c oxi-
ciency and carnitine palmitoyltransferase deficiency, dase) contains two cytochromes, a and a3, and is com-
both of which are discussed above, pyruvate decar- posed of 13 subunits. Recent work confirms the notion
boxylase deficiency, and pyruvate dehydrogenase defi- that the mitochondria are the only source of extranu-
ciency. Of the defects involving pyruvate metabolism, clear DNA, each mitochondrion containing multiple
those affecting the pyruvate dehydrogenase (PDH) copies of an identical circular genome, 16,569 base
complex are the most important. The PDH complex is pairs in length, that encodes ND1–ND6 and ND4L in
a multienzyme system situated at the inner mitochon- complex I, one subunit in complex III (cytochrome b),
drial membrane and within the matrix compartment. three subunits (I–III) in cytochrome c oxidase, and two
The complex regulates the conversion of pyruvate, the subunits in ATPase synthase (complex V). Diseases in
product of glycolysis, to acetyl–Co A which plays a cen- which there is disordered function of the respiratory-
tral role in the metabolism of the citric acid cycle as chain components encoded by mitochondrial DNA
(mtDNA) may be the result of mutations in the mito- and calcification within the basal ganglia. These lesions
chondrial genome. Furthermore, since mtDNA is in- are more easily be detected using MRI (Clark et al.,
herited only from the mother, such diseases may ex- 1996). Muscle weakness is observed in most patients
hibit a maternal pattern of inheritance. Point muta- but is often overshadowed by the symptoms of en-
tions in mtDNA appear to be responsible for mito- cephalopathy. In addition to the presence of ragged-red
chondrial myopathy, encephalopathy, lactacidosis, fibers which stain positively for cytochrome c oxidase
stroke (MELAS), myoclonus epilepsy and ragged-red (COX) in the muscle biopsy, many intramuscular ar-
fiber disease (MERRF), and Leber’s hereditary optic teries contain granular deposits having high succinate
neuropathy. Large-scale deletions of varying size have dehydrogenase activity within the walls (Hasegawa et
been described in Kearns-Sayre syndrome and chronic al., 1991). Electron microscopic examination of blood
progressive external ophthalmoplegia (Yamamota et vessels reveals increased numbers of enlarged and
al., 1991). atypical appearing mitochondria in endothelial and
Another feature of the mitochondrial myopathies is smooth muscle cells (Prayson and Wang, 1998).
the presence of ragged red fibers, but in limited num- Another condition in which lactic acidosis is a no-
bers. The reason that not all fibers are affected involves table feature is MNGIE (myopathy, neuropathy, gas-
another rule of mitochondrial genetics–heteroplasmy. troenteropathy and encephalopathy), a recessively in-
In dividing cells, each daughter cell receives approxi- herited disease with a defect on chromosome 22q.13.
mately equal numbers of mitochondria. However, the Multiple deletions in the gene have been described.
cell doubling process does not regulate the appror- Principle findings are diarrhea, pseudo-obstruction due
tioning of mitochondria. Consequently, if a dividing to intestinal smooth muscle involvement, progressive
cell has a mutation in a fraction of its mitochondria, external ophthalmoplegia, neuropathy, deafness, and
one daughter cell may receive a larger share of mito- leukoencephalopathy.
chondria with a mutation than the other. If this idea is Deficiencies of complex II and complex III are un-
carried to its logical conclusion, in skeletal muscle some common. A review of the reported cases indicates that
fibers will be normal and the remainder will be ragged symptoms range from encephalopathy to myopathy,
red fibers. This phenotype is assumed to have a larger with or without ophthalmoplegia. Patients with my-
burden of mitochondria with the genetic defect. It is opathy typically complain of muscle stiffness, pain, and
believed that a threshold of at least 60% mutant mi- exercise intolerance.
tochondrial DNA must be present for functional defi- A deficiency of complex IV (cytochrome c oxidase)
ciency to occur. is expressed in a wide variety of clinical syndromes in-
A number of clinical syndromes have been described cluding Alper’s syndrome, Leigh’s syndrome, Menkes’
in association with complex I (NADH–coenzyme Q re- disease, and Lowe’s syndrome. Apart from these, in in-
ductase) deficiency. One such group of patients have a fants, two distinct forms of myopathy have been re-
myopathy beginning in childhood that is characterized ported. Most infants with the fatal form of myopathy
by exercise intolerance, myalgia, and muscular weak- die by age 1 year. Such children suffer from hypoto-
ness. A more common presentation is that of multi- nia, respiratory insufficiency, failure to thrive, and lac-
system disease which often fulfills the diagnostic crite- tic acidosis. Histochemical stains for COX are nonre-
ria for mitochondrial myopathy, encephalopathy, lactic active. Immunohistochemical studies reveal an absence
acidosis, and strokelike episodes (MELAS). MELAS of nuclear DNA-encoded subunit VII a,b of cytochrome
may be sporadic or familial with maternal inheritance. oxidase. In the benign form of infantile myopathy in
Molecular studies have shown that in MELAS there is which virtually complete recovery occurs by age 3,
a point mutation in the tRNALeu(UUR) gene, most com- there is an absence of subunit VII a,b and mtDNA-
monly in nucleotide 3243 (A 씮 G) (Ciafaloni et al., encoded subunit II.
1991). In most cases there is an abrupt onset of symp- MERRF is a hereditary encephalomyopathy that ap-
toms characterized by strokelike episodes before the age pears to be transmitted by non-Mendelian maternal in-
of 15 accompanied by lactic acidosis. Symptoms of en- heritance. The common clinical features are myoclonus,
cephalopathy include migrainelike headache, seizures, seizures, ataxia, dementia, muscular weakness, and
vomiting, aphasia, transient hemiplegia or hemianopia, short stature with onset before age 20 (Lombes et al.,
changes in mental status with psychiatric symptoms or 1989). The defect in the cytochrome c oxidase system
dementia, and hearing difficulties. Mental deterioration is due to a mutation (A8344G) in the tRNALys gene of
is progressive and neurologic deficits may increase sub- the mitochondrial genome (Yoneda et al., 1991) or
sequent to repeated strokelike episodes. CT scans re- much less commonly to the tRNASer (UCN) gene (Jaksch
veal multiple low density areas in the cerebral cortex et al., 1998). Another well-known syndrome associated
with a defect in complex IV is the Kearns-Sayre syn- Myoadenylate deaminase deficiency

drome (KSS) (Berenberg et al., 1977). KSS is an exam-
Adenylate (AMP) deaminase is an enzyme present in
ple of a mitochondrial disease in which mutations
skeletal muscle tissue which converts adenosine
affect many genes at once, either by deletions or by du-
monophosphate to ammonia and inosine monophos-
plications of large segments of genetic material
phate. An inherited deficiency of this enzyme leads to
(Zanssen et al., 1998). The most common mutation is
exercise intolerance with muscular pain and cramps in
a 4977 basepair deletion which has been termed the
many patients (Fishbein et al., 1978; Sabina et al.,
common deletion. A sporadic condition with onset be-
1992). Despite these symptoms, patients do not expe-
fore age 20, KSS is usually recognized by the combi-
rience significant muscle weakness. Myoadenylate
nation of progressive external ophthalmoplegia, pig-
deaminase or its absence can be detected using histo-
mentary degeneration of the retina, and cardiac
chemical stains on frozen sections or by biochemical
conduction defects including heart block. Additional
techniques. Except for a lack of enzyme, muscle biop-
features include ataxia, sensorineural neural hearing
sies in affected individuals are generally unremarkable.
loss, short stature, insulin-dependent diabetes mellitus,
AMP deaminase deficiency has also been reported in
and hypoparathyroidism.
asymptomatic patients in whom it apparently repre-
The importance of mitochondrial damage in the ag-
sents a clinically incidental (subclinical) finding (Kele-
ing process is now being recognized. Without an effec-
man et al., 1982). Finally, a secondary absence of en-
tive repair system, mitochondrial DNA is vulnerable to
zyme has been encountered in individuals with other
mutations which take a cumulative toll on mitochon-
neuromuscular diseases, such as dystrophy and infan-
drial functions as they multiply with time. Constant ex-
tile spinal muscular atrophy. Primary (inherited) AMP
posure to oxygen free radicals which stray from the
deaminase deficiency is associated with very low (2%
respiratory chain causes a decline in mitochondrial res-
normal) enzyme activity, compared to higher residual
piratory function in elderly individuals. As a result, cells
activity in secondary deficiency.
which have little or no ability to turn over, such as neu-
The gene which codes for muscular deaminase
rons and muscle, are most likely to be affected by di-
(AMPD1) has been localized to chromosome 1p21–p13
minishing mitochondrial reserve. Late-onset mitochon-
by in situ hybridization and somatic cell hybrid analy-
drial myopathy is an insidious and progressive disease
sis. In patients with primary AMP deaminase defi-
characterized by mild-to-severe proximal weakness that
ciency, a severely truncated deaminase peptide is found.
is more apparent in the legs. Some patients also have
This enzyme alteration is often due to a nonsense mu-
ptosis or dysphagia. Unlike normal older subjects,
tation (C 씮 T transition) at nucleotide 34 of the
ragged-red fibers are found in the muscle biopsies of
AMPD1 gene (Morisaki et al., 1992).
these patients. Abnormal fibers show succinate dehy-
drogenase hyperreactivity but are negative for COX
staining. The absence of COX activity is segmental
Malignant hyperthermia
within a single muscle fiber. A number of different dele-
tions in mitochondrial DNA are described in late-onset Malignant hyperthermia (MH) is a familial, often dom-
mitochondrial myopathy (Brierley et al., 1998). inantly inherited disorder which is episodic in nature
Patients with HIV infection who are treated with zi- (Nelson and Flewellen, 1983). The incidence of MH re-
dovudine (AZT) frequently develop a mitochondrial actions is about 1 in 15,000 anesthetics, but these sta-
myopathy in which there is a decline in respiratory tistics underestimate the true disease prevalence. At-
chain capacity involving succinate–cytochrome c re- tacks are precipitated during surgical procedures by
ductase, cytochrome c oxidase, and citrate synthase the administration of general anesthesia, particularly a
(Mhiri et al., 1991). Zidovudine is a DNA chain ter- combination of potent inhalational anesthetics like
minator that inhibits mitochondrial DNA polymerase, halothane and succinylcholine or other depolarizing
which is responsible for mtDNA synthesis, and is there- muscle relaxants. In the absence of a family history, the
fore toxic to muscle as well as cardiac mitochondria disease may be first recognized in the operating room
(Lamperth et al., 1991). Morphologically, numerous when the patient’s body temperature rapidly rises, typ-
ragged-red fibers are observed in the muscle biopsy ically at a rate of 1°C per every 5 minute period until
(Dalakas et al., 1990). Under the electron microscope, the attack is under control. By this time the tempera-
the mitochondria are usually numerous and have dis- ture may have reached 43°C (110°F). The rise in tem-
ordered structure with paracrystalline inclusions. Other perature is due to a marked increase in muscle metab-
drugs implicated in mitochondrial damage are corti- olism associated with generalized, sustained muscle
costeroids, lidocaine, emetine, and colchicine. rigidity. Physiologically, oxygen consumption increases,
as does lactate production, leading to acidosis. The un- muscle relaxants such as vecuronium or pancuronium
controlled metabolic activity generates excessive heat. are predisposed to this condition. Many cases of this
Increased permeability of muscle cell membranes, pos- disease exhibit selective loss of myosin filaments that
sible due in part to increased cellular lactate, results in may be best demonstrated by electron microscopic ex-
elevated serum potassium and myoglobinuria, often amination of the biopsy (Al-Lozi et al., 1994). The
complicated by renal failure. Published reports indicate myosin-deficient fibers, which are numerous in light
a 70% mortality in untreated patients. microscopic sections, are angular and unstained in
The diagnosis of MH cannot be made on morpho- ATPase reactions at any pH.
logic grounds. The muscle biopsy is usually unremark-
able or characterized by nonspecific findings. Some
cases of MH have been associated with other neuro- INFLAMMATORY MYOPATHIES
muscular diseases, particularly central core disease and
more recently CPT II deficiency. The diagnosis should Bacterial Myositis
be suspected when there is a family history of disease
or there is an unexplained elevation of serum CK. De- Bacterial infections of muscle are more common in
finitive diagnosis has been based on the contracture tropical and subtropical regions of the world than in
test, in which muscle contractility is evaluated in vitro the more temperate zones (Kallen et al., 1982). Bacte-
during exposure to caffeine and/or halothane. Patients rial myositis may be focal, typically producing an in-
are considered to be MH susceptible if muscle fibers tramuscular abscess (pyomyositis), or the infection may
develop contractures which exceed normal threshold be more generalized, with multiple lesions. Muscle in-
after exposure to caffeine or halothane. The future of fection may arise by a hematogenous route or may ex-
accurate diagnosis will depend on the molecular at- tend from a focus of infection adjacent to the muscle.
tributes of MH, which is really a syndrome caused by Closed trauma to muscle predisposes to bacterial in-
a lengthening list of genetic abnormalities. There are at fection. Pyogenic organisms are most frequently re-
least four established types of malignant hyperthermia sponsible for bacterial myositis, Staphylococcus aureus
(MHS 1–4). MH-central core disease (MHS 1) involves being the most important. Patients with bacterial
a defect in the Ca2 release channel (ryanodine recep- myositis are generally acutely ill with fever, septicemia,
tor) and inappropriate release of calcium from the sar- and leukocytosis. Marked muscle tenderness may be
coplasmic reticulum (SR), promoting sustained muscle found. Widespread necrosis is seen pathologically, in-
contraction (MacLennan and Phillips, 1992). Molecu- volving not only muscle fibers but interstitial compo-
lar studies have recently demonstrated at least 17 dif- nents and blood vessels as well. The inflammatory in-
ferent point mutations in the RYR1 gene, which en- filtrate is mixed, containing both lymphocytes and
codes the ryanodine receptor protein which is part of neurophils. Even with special stains, bacteria are diffi-
the Ca2 release channel of the muscle SR (Richter et cult to visualize within the tissue.
al., 1997). Some mutations cause only MH without
central core disease. Linkage between MH and RYR1,
Viral Myositis
which has been mapped to chromosome 19 (region
19q13.1–q13.2), has been shown in almost 50% of Many viral illnesses are accompanied by myalgia and
MH families. The gene locus in MHS 2 is on chromo- muscle weakness. Influenza and coxsackie viruses are
some 17q11.2–q24, involving the sodium channel 2/ well-known causes of myositis as part of a systemic vi-
subunit (Moslehi et al., 1998). In MHS 3, the gene cod- ral process. Viruses which have less commonly been
ing for the L-type voltage-dependent Ca2 channel sub- implicated in the pathogenesis of myositis are parain-
unit is affected. The defective gene in MHS 4 has been fluenza, hepatitis B, and Echoviruses. Influenza myosi-
localized to chromosome 3q13.1. tis occurs during epidemics, usually in children (Mejl-
szenkier et al., 1973). The disease is characterized by
severe muscle pain and swelling which is most evident
Critical care myopathy
in the lower extremities. The symptoms tend to last 1–2
This entity has recently been reported in acutely ill pa- weeks and resolve spontaneously. Viral infection of
tients who have been admitted to the intensive care muscle may result in rhabdomyolysis. Coxsackievirus,
unit. There is marked generalized weakness with res- Echovirus, and adenovirus are agents associated with
piratory muscle involvement. The course is rapidly pro- this type of infection. Patients with this potentially fa-
gressive, although reversible, if recognized early and ap- tal complication are gravely ill, with nausea, vomiting,
propriately treated. Patients receiving steroids and and profound muscular weakness. Myoglobinuria may
be complicated by acute tubular necrosis and renal muscle biopsy reveals hemorrhagic necrosis accompa-
failure. nied by acute inflammation. Fungi can be identified in
Neuromuscular disease in the acquired immunode- sections stained with appropriate silver methods.
ficiency syndrome is common but is most often at-
tributable to peripheral neuropathy (Lange et al.,
Parasitic Infections
1988). A small number of cases of myositis due to
HIV infection have been reported (Simpson and Ben- An important protozoal infection of muscle in North
der, 1988). Muscle involvement closely resembles America is caused by toxoplasma. Toxoplasmosis of
polymyositis and is characterized by generalized mus- skeletal muscle occurs in immunocompromised patients
cular weakness, elevated serum CK, and myopathic with dissementated disease who show signs of menin-
features on electromyography. Muscle fiber necrosis gitis, myocarditis, and pneumonia (Gherardi et al.,
and lymphocytic inflammation are seen pathologi- 1992). These patients are likely to have fever and lym-
cally. Multinucleated giant cells, reminiscent of those phadenopathy. Necrotic fibers surrounded and some-
described in the brains of AIDS patients, have occa- times invaded by neutrophils and lymphocytes are seen
sionally been reported in skeletal muscle (Bailey et al., in skeletal muscle. Organisms are difficult to identify
1987). The presence of nemaline rods in patients with in tissue sections, either as cysts measuring up to 50
HIV myopathy is of uncertain significance (Dwyer et m in diameter and containing numerous bradyzoites
al., 1992). Epidemiologic studies of human T-cell leu- or as tachyzoites within the endomysium. Toxoplasmas
kemia virus type I (HTLV-1) indicate an association are perhaps best visualized under fluorescence mi-
of this infection with polymyositis. In Jamaica, where croscopy utilizing fluorescein-labeled antitoxoplasma
the prevalence of HTLV-1 infection ranges from 7% antibodies.
to 18%, a number of patients with polymyositis were Another common parasitic disease of skeletal mus-
reportedly seropositive for HTLV-1 (Wiley et al., cle is trichinosis, most cases of which are traced to the
1989). ingestion of pork products which have been inade-
Chronic fatigue syndrome is of uncertain etiology, quately cooked or consumed raw. When the larval form
although it is presumed to be viral in origin. Epstein- of the nematode spreads via the bloodstream, the mus-
Barr (EB) virus and coxsackievirus have been most fre- culature is invaded. Myalgia, muscle tenderness, and
quently implicated in the pathogenesis (Dowsett et al., weakness, which is usually mild, follows. Concurrent
1990; Gold et al., 1990). The syndrome tends to affect involvement of the skin results in periorbital and con-
younger women, who complain of headache, sleep dis- junctival edema, subconjunctival hemorrhage, and a pe-
turbances, sore throat, lymphadenopathy, fever, and techial or urticarial dermatosis. Severe disease is com-
lassitude. Patients typically report diffuse myalgias and plicated by myocarditis and meningitis. In the vast
muscular weakness, although muscle strength is mini- majority of patients, there is eosinophilic leukocytosis,
mally diminished on physical examination. The patho- which may be the only marker of illness in subclinical
logic features of chronic fatigue syndrome have not disease. The presence of larvae in skeletal muscle causes
been extensively studied. In approximately 50 patients an inflammatory response and muscle fiber necrosis. A
evaluated at our institution, 10% had inflammatory in- pronounced interstitial inflammatory infiltrate devel-
filtrates within the muscle biopsy. These were perivas- ops in which eosinophils are prominent. The inflam-
cular, lymphocytic, and not abundant. Many patients matory cell population also includes lymphocytes and
exhibited a variation in fiber size due to atrophy of type other mononuclear cells (Gross and Ochoa, 1979). In
2 fibers. our experience, larvae often cannot be identified in the
muscle biopsy, although encapsulated cysts, focal fi-
brosis or calcification, and foci of granulomatous in-
Fungal Myositis
flammation remain long after the organisms are no
Fungal infection of muscle is uncommon and generally longer viable. When trichinella are seen, they are usu-
localized to one muscle or muscle group. Abscess for- ally found as single, coiled, encysted larvae.
mation has been reported in actinomycosis, sporotri- Cysticercosis is most common in the Indian subcon-
chosis, and histoplasmosis. Diffuse myositis is associ- tinent, but it is well known in eastern Europe, Central
ated with disseminated candidiasis, frequently in America, and Mexico. The infection results from in-
patients with systemic malignancy. A distinctive clini- gesting raw or inadequately cooked pork containing the
cal picture includes fever, papular rash, and diffuse encysted larvae of the tapeworm Taenia solium. Dur-
muscle weakness with severe muscle tenderness. The ing hematogenous dissemination, as in trichinosis, the
disease may begin with fever, muscle pain, muscular Systemic Connective Tissue Disease and Vasculitis
weakness, and peripheral eosinophilia. Many organs
may be affected, including the brain, giving rise to neu- A detailed discussion of these disorders is not possible,
rologic symptoms. A remarkable feature of muscle in- but a few essentials on the involvement of skeletal mus-
volvement is striking pseudohypertrophy which may in- cle in this diverse group may be appropriate. At our in-
volve the tongue or the limb muscles, especially the stitution, skeletal muscle is considered by many clini-
calves (Jacob and Mathew, 1968). The diagnosis is cians to be an accessible tissue that is frequently
made by visualizing encysted larval forms in muscle or biopsied as a means of establishing a diagnosis of sys-
other tissues. Larvae may be surrounded by a mixed temic connective tissue disease (SCTD) or vasculitis.
inflammatory infiltrate containing many eosinophils. Many of these biopsies are normal or minimally ab-
Cysts become surrounded by a fibrous capsule that normal with nonspecific findings. The muscle biopsy is
eventually calcifies along with the encysted parasite. more likely to yield valuable diagnostic information
when the patient has muscle weakness and/or an ele-
vated serum CK. In systemic lupus erythematosus (SLE)
Granulomatous Myositis
approximately 10% of patients have muscle involve-
Aside from myositis due to infectious diseases that are ment (Foote et al., 1982). The characteristic lesion is
characterized by granulomatous inflammation like tu- found in the small blood vessels in the endomysium and
berculosis, leprosy, brucellosis, tularemia, and parasitic perimysium. The vasculitis of SLE is recognized by the
infections, two additional granulomatous diseases of presence of fibrinoid necrosis of blood vessel walls
uncertain etiology are noteworthy. Sarcoid myopathy which are smudged and eosinophilic. Neutrophils and
may manifest as a slowly progressive proximal my- nuclear dust are visualized in and around the vascular
opathy affecting the extremities. Patients complain of walls. Immunofluorescence microscopy will demon-
muscle weakness and wasting that is evident on phys- strate deposits of immunoglobulins and complement
ical examination. In some individuals, there is nodu- within the walls of the blood vessels. These appear as
larity of the muscles which can be palpated. When my- dense, granular subendothelial deposits under the elec-
opathy develops in sarcoidosis, the disease has usually tron microscope. Polyarteriitis nodosa (PAN) affects
existed for a long time, and there are signs of pul- skeletal muscle somewhat more frequently than SLE.
monary or systemic disease. In our experience, muscle The characteristic lesion is seen in larger intramuscu-
biopsy in sarcoid myopathy is a relatively low-yield lar arteries in the perimysium and epimysium. The in-
procedure. From a total of 12 cases submitted for di- flammatory process extends to all layers of the vessel
agnosis, granulomatous inflammation was encountered wall, usually an artery, and is associated with necrosis
in only three of our cases. The granulomas in sar- of the muscularis. The inflammatory infiltrate is com-
coidosis are typically located near larger blood vessels posed of neutrophils, lymphocytes, histiocytes, and
or in the perimysium. They are sharply demarcated and eosinophils, which are often abundant. All stages of
composed of epithelioid cells, giant cells, and lympho- angiitis, ranging from acute to chronic, occur in PAN,
cytes. However, nonspecific pathologic findings are although this may be difficult to see in a muscle biopsy
more commonly observed in sarcoidosis. Among in which a small number of vessels is affected. Some-
these are nonselective fiber atrophy, type 2 atrophy, or times only the “healed” lesions are visualized. The di-
features of neurogenic atrophy secondary to peri- agnosis of PAN can only be suspected in older lesions
pheral neuropathy, a not-infrequent occurrence in this without inflammation, in which the arteries are nar-
disorder. rowed and their walls are asymmetrically thickened due
Idiopathic granulomatous myopathy with histologic to fibrosis. The muscle biopsy in rheumatoid arthritis
features similar to sarcoidosis occurs in middle-aged and generally reveals nonspecific changes, most often atro-
elderly patients, usually women (Lynch and Bansal, phy of type 2 fibers (Magyar et al., 1977). The diag-
1973). This type of myositis is slowly progressive over a nostic nodular lesions are only occasionally present.
period of 10 years or more, is resistant to corticosteroid These well-circumscribed inflammatory nodules are lo-
therapy, and has an affinity for the lower extremities. cated in the perimysium and are composed of lym-
Muscle weakness and wasting tends to be greatest in the phocytes and numerous plasma cells without germinal
thighs. Identifying this form of granulomatous myopa- centers. Polymyalgia rheumatica is associated with tem-
thy is a diagnosis of exclusion and requires that other poral (giant cell) arteritis, occurs commonly in women
granulomatous disease such as sarcoidosis be eliminated over 50 years of age, and is characterized by muscular
by appropriate medical investigations. stiffness and pain in the neck and shoulders. A marked
elevation in the erythrocyte sedimentation rate (ESR) which is fiber necrosis. While humoral mechanisms
is usually present. In many cases a dramatic reversal of may also be at work in PM, their role in the patho-
symptoms is obtained with corticosteroid therapy. A genesis of this disease is unclear. Although deposits of
common misconception among some clinicians is that immunoglobulins and complement visualized by im-
polymyalgia rheumatica is due to myositis. In fact, the munofluorescence microscopy have been reported in
muscle biopsy is free of inflammation. Fiber atrophy, some cases of polymyositis (Oxenhandler et al., 1977),
selectively involving type 2 fibers, is generally the only Studies in our laboratory and several others have shown
pathologic abnormality (Brooke and Kaplan, 1972). that these deposits are consistently absent in polymyosi-
tis (Heffner et al., 1979). However, not only in PM but
also in other diseases where fiber necrosis is seen, such
Polymyositis
as Duchenne dystrophy, the lytic C5b-9 complement of
Most investigators agree that polymyositis (PM) is the membrane attack complex (MAC) has been localized
most common inflammatory myopathy in adults. Based to necrotic fibers. The presence of MAC is indicative
on epidemiologic data, polymyositis reportedly has an of complement activation, which appears to play a non-
average annual incidence of 5–10 cases per million pop- specific and poorly understood role in fiber necrosis
ulation and is slightly more prevalent in black individ- under diverse disease conditions (Engel and Biesecker,
uals. In our experience PM has a somewhat higher in- 1982). The inflammatory cells in polymyositis invade
cidence than epidemiologic studies would suggest. The the endomysium, often surrounding necrotic fibers but
average age of onset of symptoms is 37 and the disease generally avoiding intramuscular blood vessels (Fig.
is more prevalent (2:1) in women between the ages of 23.49). The inflammatory elements are primarily ma-
20 and 40 years. Muscular weakness begins somewhat ture lymphocytes. The inflammatory response is virtu-
abruptly over a period of several weeks. Although prox- ally free of plasma cells, neutrophils, and eosinophils.
imal muscles are more severely involved, weakness is Engel and Arahata (1986) have demonstrated that ap-
generalized. While facial and extraocular muscles are proximately 30% of the mononuclear cells encircling
seldom affected, distal muscles are not spared in many muscle fibers are macrophages and 70% are T cells.
patients. Other symptoms commonly encountered are The majority of T cells are CD8 cytotoxic/suppressor
fever, malaise, dysphagia due to involvement of pha- cells, many of which are activated, expressing Ia mark-
ryngeal muscles, and myalgias. The clinical course is ers. Major histocompatibility complex class I (MHC-I)
often one of remissions and exacerations. Laboratory expression is required for antigen-specific T-cell-
studies can be very useful in the diagnosis. During the directed cytotoxicity. In immunocytochemical studies
acute phase there is an elevation of the ESR and a rise of PM, fibers invaded by CD8 cytotoxic lymphocytes
in plasma CK levels. EMG recordings disclose small, express MHC-I antigen, which is not normally present
short-duration, polyphasic motor units with increased in muscle cells. Increased MHC-I expression in muscle
insertional activity and spontaneous potentials in ap- fibers is presumed to be mediated by interferons which
proximately 90% of patients. are released by inflammatory cells (Emslie-Smith et al.,
Autoantibodies have been detected in patients with
polymyositis. Patients with antibody to signal recogni-
tion particle, composed of cytoplasmic RNA and six
protein subunits, have a particularly acute form of dis-
ease. They are often African Americans and their dis-
ease is resistent to treatment. Antibodies against the
Jo-1 antigen, a subunit of histidyl tRNA synthetase, are
often detected in patients with PM, particularly those
having interstitial lung disease (Wasicek et al., 1984).
Diffuse interstitial pulmonary disease is discovered in
up to 70% of patients with polymyositis as opposed to
30% of patients with dermatomyositis.
Polymyositis is an autoimmune disease in which the
evidence for a cell-mediated mechanism of tissue de-
struction is very compelling. A number of immunologic
studies suggest that lymphocytes, predominantly T
cells, become sensitized to muscle antigens, leading to FIGURE 23.49 Polymyositis. Endomysial lymphocytes typically sur-
a cell-mediated attack on muscle fibers, the result of round muscle fibers during active disease. H&E.
1989). In the acute phase of disease, many inflamma-

tory cells and necrotic fibers are observed. With the
passage of time, increased numbers of regenerating
fibers are evident. In chronic polymyositis, inflamma-
tory infiltrates may be sparse and fibrosis of the en-
domysium and perimysium is associated with striking
atrophy of fibers.
Dermatomyositis
Adult dermatomysitis (DM) is more prevalent in
women, although the female to male ratio (3:2) is lower
than in polymyositis (PM). The manifestations of mus-
cle involvement in dermatomyositis are very similar to
those in polymyositis, such that some authorities con- FIGURE 23.50 Dermatomyositis. Immunofluorescence microscopy
sider both to be part of a single disease process. In demonstrates vascular and sarcolemmal deposits of IgG.
90%–95% of patients, a cutaneous rash is the initial
symptom. The dermatologic disturbances are variable,
often heralded by a dusky erythematous eruption in a somewhat thickened but are typically free of acute in-
butterfly pattern on the face or by a violaceous rash on flammatory cells.
the eyelid accompanied by periorbital edema. Skin le- Lymphocytic inflammation tends to be located
sions are also frequently present on the neck, shoul- around blood vessels as opposed to PM, where infil-
ders, and extensor surfaces of the extremities, parti- trates surround muscle fibers. Most lymphocytes are T
cularly over the fingers and toes. Erythematous, cells, but larger numbers of CD4 lymphocytes and B
sometimes scaling lesions are seen on the knuckles in cells are present as compared to polymyositis. Particu-
association with telangiectasia and periungual hyper- larly in childhood DM, ultrastructural studies reveal
emia. In some cases of childhood DM, the disease is a more dramatic changes in the intramuscular blood ves-
systemic angiopathy involving, in addition to skin and sels than are evident under the light microscope. The
muscle, a variety of organs such as intestine, peripheral abnormalities are more prevalent in capillaries than in
nerve, and subcutaneous tissues (Banker, 1975). Calci- arterioles or venules. Marked swelling of endothelial
fications develop subcutaneously. Subcutaneous nod- cells is almost always present. Less commonly endo-
ules ulcerate in certain locations like knuckles, heels, thelial cell necrosis and fibrin thrombi are seen. Nu-
and elbows. Vasculitis of the gastrointestinal tract pro- merous virallike undulating tubules are identified in en-
duces mucosal ulcerations, with or without GI bleed- dothelial cells and pericytes (Banker and Victor, 1966).
ing. Ischemia of the intestine can rarely lead to perfo- As a result of vascular damage, a loss of capillaries is
ration. a constant feature in the muscle of children with der-
There is mounting evidence to show that, in contrast matomyositis (Carpenter et al., 1976). The loss of cap-
to polymyositis, the humoral rather than the cellular arm illaries appears to begin at the periphery of the fasci-
of the immune system is more important in the devel- cles. In adult type dermatomyositis, the extent of
opment of dermatomyositis. Observations utilizing im- vascular damage is more variable and the reduction in
munofluorescence microscopy suggest that the disease intramuscular capillaries occurs only in only some cases
results from an immune complex–mediated vasculopa- (Emslie-Smith and Engel, 1990). Perifascicular atrophy
thy. With direct immunofluorescence techniques, de- is more extensive in advanced cases and occurs more
posits of immunoglobulin (IgG, IgM) and complement, frequently in childhood dermatomyositis (Fig. 23.51).
particularly C3, can be demonstrated in intramuscular The limitation of atrophy to the periphery of the fas-
blood vessels in most children and in many adults with cicles has been explained on the basis of ischemia due
DM (Fig. 23.50), and the C5b-9 complement membrane to the aforementioned vascular damage. Logically, isch-
attack complex has been immunolocalized to vascular emia would be greatest in the distal vascular bed, which
structures (Kissel et al., 1986). The granular appearance is located at the fascicular edges.
of the deposits is also consistent with the presence of im- Dermatomyositis and less frequently polymyositis
mune complexes, although the antigenic portion of the are associated with malignant tumors. Patients who
complex is thus far unknown. Deposits are most often have antibody to Mi-2, which is present in some indi-
observed in perimysial veins and arteries, which may be viduals with typical DM, have a favorable prognosis.
rogenic pattern has been observed in some cases (Eisen

et al., 1983). Light microscopic examination of muscle
tissue may initially suggest polymyositis, in that lym-
phocytic inflammation, fiber necrosis, and regeneration
are present. However, necrosis and inflammation are
variable and fiber regeneration is often absent. An im-
portant initial clue to the diagnosis is the presence of
small angular fibers, often in groups, suggesting den-
ervation in a setting of inflammatory myopathy. Often
there is also fiber hypertrophy with splitting, an un-
usual finding in most inflammatory myopathies.
Cryostat sections are required to identify the char-
acteristic vacuoles containing small granules which are
basophilic in H&E and red in RTC stains (Color Fig.
FIGURE 23.51 Dermatomyositis. There is atrophy of the fibers at the 23.52 in separate color insert). Rimmed vacuoles are
periphery of the fascicles. ATPase, pH 9.4. recognized by a lining of granules at the margins of the
vacuoles. Vacuoles react for acid phosphatase and im-
munostain for ubiquitin. Ultrastructurally, the ba-
Thos who lack anti–Mi-2 antibody are more likely to sophilic granules are composed of whorls of membra-
have a malignancy or interstitial lung disease. Statisti- nous material (Fig. 23.53). Whorls are usually located
cal analysis of patients with inflammatory myopathies in aggregates beneath the sarcolemma. The vacuoles are
reveals that the incidence of malignancy in patients with assumed to be autophagic but they are not always com-
DM and PM is about 10%. In patients who are 55 pletely membranebound. Under the electron micro-
years or older, the incidence of malignancy is 25%. The scope, masses of viruslike filaments (inclusions) are de-
most commonly encountered malignancies are carci- tected within muscle fiber nuclei (Fig. 23.54) and in the
nomas of the lung, breast, and gastrointestinal tract. It sarcoplasm, often in association with rimmed vacuoles.
is important to remember that the malignancy may be These tubulofilamentous structures comprising the in-
occult and appear to be preceded by a paraneoplastic clusion bodies are arranged in bundles and measure
myositis. By the same token, a harbinger of recurrent 15–18 nm in overall diameter with an inner diameter
tumor may be the development of dermatomyositis or of 6.0 nm. Often filaments are present in a small num-
polymyositis. While corticosteroid therapy represents ber of fibers, making them difficult to locate. The na-
the mainstay of therapy in the treatment of PM and ture of the filaments which may form eosinophilic in-
DM, these anti-inflammatory agents are of less value clusions in routine sections (Fig. 23.55) is obscure, but
in perineoplastic myositis. the possibility of a viral origin has now been aban-
doned. Immunohistochemical investigations once sug-
Inclusion Body Myositis
Inclusion body myositis (IBM) was probably first de-
scribed by Chou (1967), who observed myxoviruslike
particles in the nuclei and sarcoplasm of muscle fibers
of a patient considered to have chronic polymyositis.
Since that time, IBM has emerged as an inflammatory
myopathy distinct from polymyositis and dermato-
myositis (Carpenter et al., 1978; Dalakas, 1991). Most
patients are males who are over the age of 50. The dis-
ease tends to be indolent in its course, but slowly
progressive and resistant to steroid therapy. Muscle in-
volvement is generalized, although sometimes asym-
metrical or greater distally. Dysphagia is present in
about one-third of patients. Serum CK is normal or
minimally elevated. Higher CK levels are reported in
younger patients, who are more apt to be women. EMG FIGURE 23.53 Inclusion body myositis. Collections of whorled mem-
is more often interpreted as myopathic. However a neu- branes are seen in a rimmed vacuole ultrastructurally.
Some patients with features of IBM are sufficiently

different to justify the designation of hereditary IBM
(Darin et al., 1998). The distinguishing criteria include
hereditary disease that may be either dominant or re-
cessive, lack of inflammation, and sometimes sparing
of the quadriceps femoris. Some cases have been linked
to disease loci on chromosome 9p1–q1. Not all au-
thorities accept these cases as IBM since they call into
question the definition of IBM and run the risk of re-
ducing it to a vague entity with excessively flexible cri-
teria. Also unresolved, if one accepts the concept of
hereditary IBM, is where to classify diseases like We-
lander’s distal myopathy, Nonaka-type distal myopa-
thy, and Miyoshi-type distal muscular dystrophy, all of
FIGURE 23.54 Inclusion body myositis. The electron micrograph of which are difficult to differentiate from hereditary IBM.
an intranuclear inclusion illustrates bundles of abnormal filaments
measuring 15–18 nm in diameter.
Drug-Induced Inflammatory Myopathy
The use of certain therapeutic drugs may be compli-
gested that inclusion bodies may contain mumps virus cated by the development of myositis. Perhaps the best
(Chou, 1986). In situ hybridization studies have not known example of this phenomena is the use of D-
confirmed the presence of mumps virus infection. penicillamine, which is associated with an inflamma-
Subtle nuclear changes are present in many cases of tory myopathy similar to polymyositis. Other drugs
IBM. They may range from a condensation of the nu- representing a potential cause of myositis include
clear matrix to a loss of the nuclear membrane. Fila- methyldopa, cimetidine, penicillin, certain diuretics,
ments within the nucleus may be seen to extrude into procainamide, and hydralazine. Drug-induced myositis
the sarcoplasm under the electron microscope. A po- is typically characterized by mild muscular weakness
tentially pivotal role of the nucleus in this disease is with myalgias. Serum CK is usually normal or mildly
suggested by the discovery of a single-stranded DNA elevated. In the muscle biopsy, necrosis of muscle fibers
binding protein which accumulates in the muscle fiber is not widespread. Inflammatory infiltrates are often
nuclei. In many biopsies of IBM patients, ragged-red perivascular and contain a disproportionate number of
fibers are seen. Abnormal fibers stain COX negative eosinophils. The presence of eosinophils should alert
but are highly reactive for succinate dehydrogenase the observer to the possibility of drug-induced disease
(SDH). In situ hybridization studies show multiple mi- or tryptophan myopathy. The later disease has been re-
tochondrial DNA deletions in COX-deficient fibers ported in patients receiving large doses of the amino
(Santorelli et al., 1996). One frequent finding is the so-
called “common deletion,” which is also found in
Kearns-Sayre syndrome and aging muscle.
A series of recent publications has drawn attention
to several curious findings in IBM (Askansas et al.,
1998). Muscle fibers contain amyloid, which is best
demonstrated under fluorescence microscopy rather
than by Congo red staining, paired helical filaments
and protein, and abnormal accumulations of apolipo-
protein E (Apo E). These similarities to the neuronal
alterations in Alzheimer’s disease, to which may also
be added the detection of -amyloid and -amyloid pre-
cursor protein deposits in muscle fibers from IBM pa-
tients, seem almost contradicted by another observa-
tion. There are sarcoplasmic inclusions that are
immunoreactive for prion protein and an overexpres-
sion of prion protein mRNA in IBM. The significance FIGURE 23.55 Inclusion body myositis. Eosinophilic intranuclear in-
of these observations is still under investigation. clusions are seen in two muscle fibers. H&E.
acid L-tryptophan, which has been prescribed as a di- expected finding in lesions which have been present for
etary supplement and as a treatment for depression and a longer period of time. In some cases of focal myosi-
insomnia. The association between the eosinophilia tis, histologic signs of denervation including grouped
myalgia syndrome (EMS) and L-tryptophan ingestion atrophy, type grouping, and target fiber formation are
reached epidemic proportions in 1989 and the Food present (Heffner and Barron, 1980). Based on our ex-
and Drug Administration removed tryptophan prepa- perience in nearly 50 cases, focal myositis is a self-
rations from the market. It remains unclear whether limited inflammatory condition which does not recur
the syndrome represents an allergic reaction to trypto- following surgical removal of the mass. It must be dis-
phan or to a contaminant in the preparation, but it has tinguished from PM, which rarely begins as a focal pro-
been established that all cases were due to ingestion of cess (Heffner and Barron, 1981).
a product from one Japanese company. EMS is recog- As in the case in other pseudotumors of skeletal mus-
nized by the presence of diffuse muscle weakness, se- cle, the pathogenesis of focal myositis is unknown. The
vere myalgias, fatigue, edema, skin rash and indura- inflammatory nature of focal myositis suggests an in-
tion, and peripheral blood eosinophilia often in excess fectious etiology, but all attempts to identify an or-
of 1,000/mm3 (Kamb et al., 1992). Muscle biopsy re- ganism have been unsuccessful. In a few cases, trauma
veals a fascial and interstitial inflammatory infiltrate has preceded the process. External injury to the affected
composed of lymphocytes and some eosinophils (Lin et region is seldom reported by these patients, although
al. 1992). some individuals do remember twisting or stretching
the affected muscle group several weeks before the de-
velopment of a mass lesion. The role of denervation in
Focal Myositis
this disorder has not been adequately explained. It has
Focal myositis is an entity which may be considered been difficult to determine whether denervation repre-
under the heading of inflammatory pseudotumorlike sents the cause or the effect. One may assume that the
myositis ossificans, proliferative myositis, and nodular changes of denervation in focal myositis are more
fasciitis (Heffner et al., 1977). These are reactive or logically secondary, the result of an enlarging of the
reparative processes whose expansive features suggest pseudotumor, which then compresses nerves within the
neoplasia clinically. Most patients are adults, although affected muscle. The damage to distal intramuscular
the range of age varies from early childhood to the sev- nerves eventually leads to neurogenic atrophy of mus-
enth decade. The incidence of focal myosistis appears cle. The compensatory hypertrophy of intact muscle
to be approximately equal in males and females. Focal fibers may partly explain the expansile behavior of
myositis typically presents as a solitary, often painful, these lesions
intramuscular mass which reaches its maximum size in
a few weeks. Indolent lesions may enlarge for a year
or more prior to diagnosis. Focal myositis most com-
DISORDERS OF THE NEUROMUSCULAR JUNCTION
monly occurs in the lower extremity but lesions also
arise almost anywhere, including the trunk, arm, neck,
Myasthenia Gravis
and facial muscles. At surgery the lesion is discovered
deep within a single muscle or muscle group, but spar- Myasthenia gravis (MG) is an acquired, immune-
ing the fascia. It is often poorly circumscribed and the mediated disease of neuromuscular transmission
margins are defined better by palpation than inspec- (Johns, 1982). A relatively commonly encountered dis-
tion. Most lesions measure less than 5 cm in greatest order, MG has a prevalence of approximately 50 per
dimension. In microscopic sections varying numbers of 1,000,000 population. In young adults and children,
necrotic and regenerating fibers are seen in association MG is more frequent in females, whereas after the age
with lymphocytic inflammation, which is often promi- of 50 the disease is more likely to be seen in males. MG
nent. Many atrophic and some hypertrophic fibers are is characterized by the insidious onset of easy fatiga-
encountered. Fiber splitting is often apparent in hy- bility, worse after exertion but improving following
pertrophic fibers. It should be noted that both fiber hy- rest, which begins in extraocular muscles in more than
pertrophy and splitting are distinctly uncommon in PM half of patients. Muscles innervated by cranial nerves
and most other inflammatory myopathies, except IBM. are usually affected. The eventual development of gen-
While most of the inflammatory elements are lympho- eralized disease is more severe proximally than distally.
cytic, plasma cells and small numbers of eosinophils Early symptoms suggesting the diagnosis are ptosis, ex-
are also seen. Interstitial fibrosis, with expansion of pressionless face, open mouth, inability to smile (myas-
both the endomysium and the perimysial septa, is an thenic snarl), difficulty chewing, nasal speech, dyspho-
nia, and a tendency to choke on food. Untreated dis- edrophonium is the basis of the Tensilon test, which
ease may undergo spontaneous remission lasting sev- may be difficult to interpret when measurable im-
eral weeks or months. provement does not occur. In 95% of the cases, a decre-
Intensive research during the past decade has shown ment in motor action potentials during repetitive stim-
that patients with MG synthesize antibodies directed ulation is observed by EMG. More sophisticated
against the postsynaptic membrane of the motor end electrical examination relies on the use of single-fiber
plate which block neuromuscular transmission and EMG. The presence of serum antibodies to the acetyl-
damage the end-plate region (Lindstrom et al., 1976). choline receptor is detected by the clinical laboratory
Polyclonal IgG antibodies to the nicotinic acetylcholine in 80%–90% of patients. In our experience, the mus-
receptor (AChR), typically to the subunit, are pres- cle biopsy may be unremarkable. The finding of type
ent in nearly 90% of patients with MG. Antibody to 2 fiber atrophy is suggestive of MG, but is nonspecific
the ε subunit can change the properties of the AChR and is frequently associated with other disorders
channel, thereby reducing conductance and resulting in such as disuse, acute denervation, and therapy with cor-
a form of the slow channel syndrome (Wintzen et al., ticosteroids. Lymphocytic inflammation (lymphor-
1998). Antibody to acetylcholine receptor can be used rhages) is a distinctly rare event. An investigation of
to passively transfer disease to mice. In humans, there neuromuscular junctions is not practical in routine
is abundant evidence that the humoral arm of the im- muscle biopsies. End plates are localized within the in-
mune system is critical in the pathogenesis of MG. A nervation zone of the muscle and are usually only
number of reports have documented the presence of amenable to identification using electrical stimulation
IgG and complement at the postsynaptic membrane of during the muscle biopsy. Furthermore, processing of
the neuromuscular junction (Engel et al., 1977). As a the tissue to visualize neuromuscular junctions requires
consequence of antibody deposition, complement is ac- special apparatus and expertise.
tivated so that the lytic phase of the complement se-
quence is found at the end-plate region (Sahashi et al.,
Eaton-Lambert Syndrome
1980). Destruction of the junctional folds is associated
with the presence of the lytic C9 complement compo- This syndrome is an autoimmune presynaptic disorder
nent (Fazekas et al., 1986). The deposition of immune of neuromuscular transmission (Eaton and Lambert,
complexes at the neuromuscular junction is reflected in 1957). It is frequently associated with carcinoma of the
the abnormal ultrastructure of the motor end plates, lung. Patients typically complain of excessive fatigabil-
which become simplified (Santa et al., 1972). Injury to ity and weakness involving proximal limb muscles
the junctional folds leads to a reduction in their num- while ocular and bulbar muscles are relatively spared.
ber, widening of the synaptic clefts, and shortening of Neurologic examination reveals hyporeflexia and in-
the postsynaptic membrane. The role of the thymus creased strength during voluntary muscular contrac-
gland in the development of MG continues to be some- tion, at least initially. Dry mouth, constipation, and im-
what elusive. Thymic hyperplasia occurs in approxi- potence reflect involvement of the autonomic nervous
mately 65% of patients with MG. Such glands contain system in many patients. Neuromuscular transmission
increased numbers of B cells, which may form follicles. is defective at lower frequencies of stimulation, but im-
In about 15% of patients, a thymoma is discovered, proves at high frequency. The functional abnormality
usually signifying more severe disease. Patients with in Eaton-Lambert syndrome is due to a decrease in the
thymoma, as well as those with late-onset MG, have number of quanta of acetylcholine released from the
antibodies to titin (Aarli, 1999). Sensitization to the motor nerve terminal, resulting in impaired neuromus-
acetylcholine receptor probably arises in the thymus cular transmission. Presynaptic stores of acetylcholine
gland, at least in thymic hyperplasia. Thymocytes in are normal, as are postsynaptic responses to quanta of
the form of AChR-specific helper T cells are capable of acetylcholine. Quantitative freeze-fracture electron mi-
stimulating B lymphocytes to produce antibody. Such croscopy discloses a depletion of presynaptic membrane
thymocytes are not restricted to the thymus gland and active zones and active-zone particles. The latter rep-
travel to other antibody producing regions, since anti- resent the sites of voltage-sensitive calcium channels in
body is produced by blood lymphocytes and peripheral the presynaptic membrane. The diminution in quantal
lymphoid organs. release of acetylcholine appears to be related to reduced
The clinical diagnosis of MG depends upon several calcium entry into the nerve terminal. Both non-
tests which may be used in combination when the di- neoplastic and neoplastic-associated Eaton-Lambert
agnosis is more problematic. A positive response to syndrome, 60% of which is discovered in association
short-acting acetylcholinesterase inhibitors such as with oat cell carcinoma of the lung, are immune-
mediated. Symptoms improve after plasmapheresis and amplitude of miniature end-plate potentials (MEPPS).
after treatment with corticosteroids or immunosup- Pathologically the number of motor end plates per fiber
pressants. The physiological features of the syndrome is greater than normal, possibly a compensatory phe-
can be transferred to mice by intraperitoneal injections nomenon (Wokke et al., 1989). The secondary synap-
of IgG from patient’s serum. In the passive transfer tic clefts in the CPSC syndrome are poorly developed
model, freeze-fracture studies show changes in the ac- and resemble those of fetal muscle (Smit et al., 1988).
tive zones of the presynaptic membrane similar to those Secondary clefts are few in number, shallow, and rela-
described in human Eaton-Lambert syndrome. The tively unbranched.
membrane abnormalities in Eaton-Lambert syndrome End-plate AChE deficiency has been under renewed
are mediated by IgG, and the particles within the ac- investigation, based upon the application of these ad-
tive zones are the targets of the autoimmune reaction vanced techniques. In this recessive abnormality of the
(Nagel et al., 1988). In paraneoplastic Eaton-Lambert neuromuscular junction, the defective gene is on chro-
syndrome, it is of interest that oat cell carcinoma cells mosome 3p25, where mutations in the coding for the
have functional calcium channels. Experimental data collagenlike tail subunit (ColQ) of heteromeric asym-
support the idea that IgG autoantibodies, which bind metric enzyme have been described. In this disease,
to carcinoma cell antigenic determinants, are also re- normal asymmetric AChE, which is attached to the end-
sponsible for the Eaton-Lambert syndrome (Lang et al., plate basement membrane by its ColQ, is absent and
1989). A high incidence of autoantibodies to the P/Q replaced by AChE with truncated ColQ. Several reces-
type of calcium channel in patients with this syndrome sive mutations of the gene which codes for ColQ have
has recently been reported (Lennon et al., 1995). been reported. At the end plate, the motor nerve ter-
minals are small and the postsynaptic folds are simpli-
fied.
Congenital Myasthenic Syndromes
Severe deficiency of AChR results from a number of
The congenital myasthenic syndromes (CMSs) are a familial, recessive mutations which often affect the
heterogeneous group of genetic diseases which encom- (adult) subunit, resulting in a substitution of the (fe-
pass presynaptic defects of acetylcholine (ACh) release tal) for the subunit of the receptor. This would ex-
or synthesis and postsynaptic disorders ranging from plain single-channel recordings which show fetal AChR
deficiencies of end-plate acetylcholinesterase AChE and at the end plate (Ohno et al., 1998). Pathologically in-
acetylcholine receptors to kinetic abnormalities of the creased numbers of end-plate regions are spread over
acetylcholine receptor (AChR) Today the diagnosis of the muscle fiber. Although the junctional folds appear
CMS relies more on in vitro electrophysiology and so- undisturbed, some of the end plates are small and sim-
phisticated molecular testing than on pathological cri- plified. The density of AChR on the junctional folds is
teria. Therefore, they will only be considered briefly. reduced and it is found in a patchy distribution.
For a summary of the latest information on the CMSs, The kinetic abnormalities of the AChR include sev-
readers are referred to the review by Engel et al. (1999). eral congenital slow-channel myasthenic syndromes
Two presynaptic diseases are well described. The con- with increased responsiveness to ACh, causing a patho-
dition known as paucity of synaptic vesicles is associ- logic gain of function. Multiple point mutations in the
ated with reduced quantal release of neurotransmitter. AChR-subunit genes have been reported. Abnormali-
The onset of bulbar and limb weakness is usually at ties in the ion channel lead to delayed closure or re-
birth. In the presynaptic disorder, called impaired peated reopenings. Consequently in these syndromes
resynthesis of ACh, the defect is recessively inherited the slow acetylcholine-induced ion channels allow an
with the disease locus on chromosome 10q11. Onset is increased influx of calcium into the neuromuscular
at birth and ptosis and apnea are prominent features. junction. The slow channel syndromes are dominantly
Pathologically the synaptic vesicles are noted to be inherited, familial diseases, usually manifest in early
small in size. adult life (Engel, 1984). The pattern of weakness and
Among the postsynaptic disorders, the congenital fatigability is distinctive, being more severe in the neck,
paucity of secondary synaptic clefts (CPSC) syndrome shoulders, and especially the forearm (Engel et al.,
was one of the earliest to be recognized. CPSC syn- 1982). Histochemical analysis of muscle reveals a pre-
drome is a familial, recessively inherited disorder with dominance of type 1 fibers and nonselective fiber at-
onset in children or young adults. The disease is gen- rophy. Electron microscopic studies show degeneration
erally nonprogressive and characterized by ptosis and of the junctional folds and loss of acetylcholine recep-
extraocular muscular weakness. The number of acetyl- tor. MEPPS are biexponentially decaying and pro-
choline receptors is reduced, causing a reduction in the longed in duration.
The other kinetic abnormality of the AChR is the

fast-channel syndrome, with decreased responsiveness
to Ach and pathologic loss of function. This recessively
inherited syndrome is associated with mutations of the
- and -subunit genes, which have the opposite effects
to those seen in the slow-channel syndrome. No patho-
logic changes in the motor end plate have been
described.
DENERVATING DISEASES
Injury to the peripheral nervous system—to the motor

neuron or to its myelinated axon within the peripheral
nerve—is usually followed by neurogenic atrophy of FIGURE 23.57 Neurogenic atrophy. Chronic denervation is charac-
the muscle fibers innervated by the damaged motor terized by grouping of atrophic fibers. H&E.
units. Relying on information derived from examining
the muscle biopsy alone, the pathologist will not be
able to make a specific diagnosis, since the morpho- cess is not type selective and involves both type 1 and
logic changes in most denervating diseases are similar, type 2 fibers generally. As a result of chronic denerva-
although some distinction can be made between neu- tion, the normal checkerboard staining pattern seen in
rogenic atrophy in adults and infants. The hallmark of histoenzymatic reactions may be replaced by large
denervation in patients of all ages is muscle fiber atro- groups of fibers with similar histochemical staining
phy (Armbrustmacher, 1978). As discussed previously, properties (Karpati and Engel, 1968). The development
because the muscle fiber is dependent upon neu- of type grouping (Color Fig. 23.58 in separate color in-
rotrophic influences to maintain its integrity, any insert) is due to reinnervation of deefferented muscle
terference with these influences is likely to be followed fibers by neighboring intramuscular nerves which have
by atrophy. In neurogenic atrophy found in adults, as been stimulated to sprout and reestablish contact with
fibers become small they assume an angular or ensate atrophic fibers, thereby reinnervating them. Target
shape. Such fibers typically appear flattened or fusiform fibers are a highly reliable indicator of chronic neuro-
with tapering ends (Fig. 23.13). Even in fibers which genic atrophy (Engel, 1961). Despite their usefulness,
have undergone severe atrophy, the longer diameter target fibers are not a sine qua non of denervation, since
may approach that of a normal fiber while the shorter they are present in less than 25% of cases. A number
diameter is considerably reduced. During the early of investigators have commented upon the similarity
stages of denervation, the atrophic process seems to pri- between cores and targets. However, targets almost al-
marily affect type 2 fibers. The pattern of atrophy at ways occur singularly within the fiber, and their di-
this time is one of random distribution of smaller fibers. ameter is usually greater than that of a core. Whereas
In that the atrophic changes are somewhat nonspecific, cores are believed to extend the entire length of the
staining frozen sections for esterase may be valuable fiber, the target is frequently restricted in its longitudi-
(Color Fig. 23.56 in separate color insert). Denervated nal dimension. Although the central zone of the target
fibers may be distinguished from atrophic fibers in is similar to, if not identical to, the core, it is framed
other conditions by positive esterase staining. As the by a rather narrow zone between the center and the re-
process of denervation continues, the proportion of at- maining periphery of the myofiber, the sarcomeres of
rophic type 1 and type 2 fibers tends to equalize. More- which are normal in structure. This intermediate zone
over, the pattern of atrophy changes from one of ran- is intensely stained in oxidative enzyme reactions (Fig.
dom distribution to that of grouped atrophy in which 23.59). The staining reactions are otherwise variable,
collections of five or more atrophic angular fibers are but target fibers may be identified in virtually any stain-
located in close proximity (Fig. 23.57). Fiber hyper- ing procedure. Frozen sections are invariably superior
trophy may occur in neurogenic diseases, particularly to paraffin sections for the visualization of target fibers.
when the process is chronic and long standing. Hyper- Often in RTC and H&E stains, the central region of
trophic fibers are considered to represent a compen- the target is poorly stained while the intermediate zone
satory reaction to the reduced effectiveness of fibers is considerably darker than the normal sarcoplasm of
which have undergone atrophy. The hypertrophic pro- the affected fiber.
of viral disease in the anterior horn cells. A separate

and still unsettled question is whether some cases of
amyotrophic lateral sclerosis (ALS) represent infection
with polio virus. Several reports indicate an increased
incidence of cancer in patients with motor neuron dis-
ease. This association is controversial and has not been
confirmed in several subsequent studies. If paraneo-
plastic anterior horn cell disease does exist, it is prob-
ably rare (Mitsumoto et al., 1989). Patients with lym-
phoma may develop a motor neuronopathy that may
be difficult to distinguish from ALS although the dis-
ease process is more benign (Rowland et al., 1992). In
adults, as well as in children, hexosaminidase A defi-
ciency is a recognized cause of motor neuron disease
FIGURE 23.59 Neurogenic atrophy. Target fibers have central, poorly (Johnson et al., 1982). As a consequence of this reces-
stained, corelike regions surrounded by an intensely reactive rim. sively inherited enzyme deficiency, GM2 gangliosides
NADH-TR.
accumulate in neurons, producing the clinical picture
of spinal muscular atrophy. Other inherited, multisys-
tem disorders in which there is anterior horn cell de-
In contrast to the above changes, which characterize generation include the spinocerebellar degenerations
adult denervation, neurogenic atrophy in infants has a such as Friedreich’s ataxia and Kennedy’s disease, the
different pathologic appearance, particularly in spinal latter characterized by X-linked recessive inheritance,
muscular atrophy. Fiber atrophy tends to be severe and onset in early adulthood, loss of bulbar and spinal mo-
widespread, especially in young infants. The large num- tor neurons, gynecomastia, testicular atrophy, and im-
bers of atrophic fibers within many fascicles, a pattern potence. The disorder has been mapped to Xq11–q12,
known as panfascicular atrophy, conceptually repre- the site of the androgen receptor (AR) gene. The mo-
sents the infantile counterpart of grouped atrophy in lecular defect within the gene is a highly polymorphic
the adult (Color Fig. 23.60 in separate color insert). In- trinucleotide repeat involving CAG (Amato et al.,
stead of an angular configuration, atrophic fibers are 1993). A common finding is an expanded triple repeat
typically rounded, a paradoxical finding since abnor- to about double normal size in the first exon of the an-
mally round fibers are otherwise typical of myopathy. drogen receptor gene. Nuclear inclusions composed of
Hypertrophic fibers are more consistently observed in mutant AR protein have recently been discovered in
Werdnig-Hoffmann disease than in denervating dis- motor neurons (Li et al., 1998). Joseph’s disease, mul-
eases of adults. The hypertrophic process may be re- tiple system atrophy, and Guamanian ALS, all disor-
stricted to type 1 fibers. Unlike adult denervation, neu- ders with parkinsonian features, commonly manifest
rogenic disease in infants is not characterized by type symptoms of anterior horn cell disease. Many epi-
grouping or target fiber formation. demiologic studies have shown that environmental fac-
tors are important in the pathogenesis of Guamanian
ALS. Investigations of the Chamorros on Guam have
Diseases of the Motor Neuron
identified the cycad bean, used as a food and medicine
In the adult patient population, in addition to amyo- in the northern Mariana islands, as a possible cause of
trophic lateral sclerosis and its variants, many other this form of motor neuron disease (Spencer et al.,
conditions are associated with damage to the anterior 1987). -N-methylamino-L-alanine, a substance de-
horn cells (Rowland, 1991). Among the infectious dis- rived from the cycad bean, has proven to be a neuro-
eases, the most familiar are poliomyelitis and Jakob- toxin when administered to primates.
Creutzfeldt disease. The problem of post–polio syn- ALS is discussed in detail elsewhere and will only be
drome, in which progressive disease begins anew many reviewed briefly here. ALS is a progressive degenera-
years after recovery from acute poliomyelitis, has re- tive disease with onset in adults ranging in age from
ceived considerable attention in recent years (Dalakas 35 to 65 years. The clinical course is one of relentless
et al., 1986). It is assumed that in most of these cases deterioration with an average survival of 3 years. The
the delayed progression of disease after paralytic po- majority of cases are sporadic, although familial dis-
liomyelitis is due to decompensation of previously ease occurs in 5%–10% of cases. The latter is said to
damaged but surviving muscles rather than reactivation have an earlier onset, more rapid course, and a ten-
dency to involve ascending pathways such as the dor- (Werdnig-Hoffmann disease) is an acute illness, gener-
sal columns and spinocerebellar tracts of the spinal ally diagnosed at birth (1 out of 6000 newborns) or
cord. shortly thereafter by the presence of severe generalized
Juvenile-onset familial ALS (FALS) has been linked muscle weakness and hypotonia. Dysphagia, aspiration
to chromosome 2q and 9q in recessively and domi- of food and secretions, and respiratory distress culmi-
nantly inherited forms. The best-known dominant form nate in a fatal outcome by age 2. Type II SMA begins
is associated with mutations in the Cu–Zn superoxide more insidiously between 6 and 18 months of age.
dismutase (S0D1) gene located on chromosome 21. It Many of these children survive for several years, al-
is likely that mutant SOD1 proteins are in some way though they have severe motor disabilities. A chronic
toxic to motor neurons, perhaps by oxidative reactions form of disease (type III SMA) is manifest after age 1
catalyzed by mutant enzymes (Brown, 1997). ALS, by year to 18 months. In this group of patients, proximal
definition, is a disease of the upper and lower motor muscle weakness and fasciculations of the tongue are
neurons, but in some cases one group of neurons is pre- observed in the majority of patients. The prognosis in
dominantly affected. In addition to weakness, which type III SMA is considerably better than in the earlier
increases with severity as the disease progresses, mus- onset forms. It is not unusual for patients in this group
cle atrophy beginning distally, and fasciculations reflect to reach adulthood. Kugelberg-Welander disease is a
involvement of lower motor neurons. Bulbar disease is juvenile spinal muscular atrophy which has been con-
commonly associated with dysphagia and dysarthria. sidered to be a distinct entity in the past but is really
Spasticity, hyperreflexia, and pathologic reflexes rep- a form of type III SMA. A number of reports indicate
resent disordered corticospinal tract function. The a male predominance in this SMA variant. All three
pathogenesis of ALS has been under intense study types of SMA have been considered as autosomal re-
worldwide for two decades without resounding success. cessively inherited disorders in which mutations of the
The prevalence of ALS around the globe ranges from SMN genes (SMN1 and SMN2) have now been estab-
4 to 6 per 100,000 population. Several epidemiologic lished. Linkage analysis has shown that the gene most
studies have been provocative, such as those dealing responsible for SMA (SMN1) is located in the q11.2–
with disease on Guam, yet at the same time they have q13.3 region of chromosome 5 (Munsat et al., 1990).
been somewhat disappointing. Suggestions that heavy The genetic data suggests that more severe forms of
metals like aluminum, lead, and silicon are fundamen- spinal muscular atrophy are the result of larger dele-
tal in the development of motor neuron disease remain tions in the telomeric survival motor neuron (SMN1)
highly speculative (Pierce-Ruhland and Patten, 1980; gene, which is unstable. The majority of severe SMA
Mitchell et al. 1986). One of the most interesting re- patients have homozygous deletions of exons 7 and 8
cent discoveries is the link between lower motor neu- of the SMN1 gene (Gambardella et al., 1998). Muta-
ron disease and immune reactions to neuronal gan- tions of the centromeric gene SMN2 alone do not usu-
gliosides. Approximately 75% of patients with ALS ally lead to SMA. Another gene located nearby, the
have serum antibodies (IgM) to GM1 and GD1a gan- neuronal apotosis inhibitory protein (NAIP) gene, is of-
gliosides (Pestronk, 1991). IgM reactivity to GM1 gan- ten deleted in SMA. Deletions of NAIP are thought to
glioside appears to correlate with lower neuron motor add to the severity of disease.
disease. Of interest is the finding that patients with mo- Peripheral nerve disease is an extremely common
tor neuropathy may also have IgM anti-GM1 ganglio- cause of muscle weakness. A discussion of the pe-
side antibodies. Deposits of IgM have been demon- ripheral neuropathies is beyond the scope of this chap-
strated at the nodes of Ranvier and paranodal myelin ter and is presented separately. It is worth emphasiz-
of peripheral nerve. (Santoro et al., 1990). The signif- ing the fact that some knowledge of these diseases is
icance of anti-GM1 antibodies has not been completely important in the interpretation of muscle biopsies. In
elucidated, but epitopes of GM1 are located on the sur- our experience, denervating disease is especially wor-
face of spinal motor neurons and the nodes of Ranvier, thy of consideration in patients with alcoholism, dia-
both of which may represent binding sites for autoan- betes mellitus, cancer, and systemic connective tissue
tibodies. disease.
Spinal muscular atrophy is the most common exam-
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Index
Page numbers followed by cf, f, and t indicate color figures, figures, and tables, respectively.
ABC (avidin-biotin conjugate), 276–278, Pathology), oligodendroglioma Amyotonia congenita, 537. See also
276f, 277f, 15.3cf grading, 324–325 Congenital myopathies
Abrasions, to head, 140, 141f AFP (alpha-fetoprotein), 278, 278f, 362 Amyotrophic lateral sclerosis (ALS),
Abscesses, brain, 50–51, 50f Agyria, 32, 32f 234–235, 570–571
ABZs (arterial boundary zones), 113 Alcohol intoxication Amyotrophic lateral sclerosis/
Acid maltase deficiency, 549–550, 550f acute, 179 Parkinsonism dementia complex
Acidophil stem cell adenoma, 408, 408f central pontine myelinolysis, 180–182, of Guam (ALS/PDC), 235–236,
Acquired immunodeficiency syndrome 181f, 182f 570
(AIDS) cerebellar degeneration in, 179–180, Amyotrophy, diabetic, 512, 513f
autopsy evidence of, 97–98, 97t 180f Anaplastic oligodendroglioma, 324–325,
myopathies, 102, 102f, 103f fetal alcohol syndrome and, 182–183 325f
neuropathology, 96–98, 97t Marchiafava-Bignami disease, 180 Anaplastic transformation, of pilocytic
opportunistic infections ALD (adrenoleukodystrophy), 210–211, astrocytomas, 313
cytomegalovirus encephalomyelitis, 210f, 260–261, 261f Anencephaly, 29–30, 29f
104–105, 105f, 106f Alder-Reilly granules, 210 Aneurysm, aortic dissection, 464
herpes virus, 105 ALD protein, 210 Angiomas, venous, 133–134
progressive multifocal Alexander’s disease, 261, 262f Angiomatous meningioma, 338, 339f
leukoencephalopathy, 106 Alpha-fetoprotein (AFP), 278, 278f, 362 Angiopathies, traumatic, 136
toxoplasmosis, 102–104, 104f, 105f Alpha-synuclein, in Lewy bodies 223- Anterior spinal artery
varicella-zoster virus, 105–106, 224, 223f anatomy, 459, 460f
106f ALS (amyotrophic lateral sclerosis), syndrome, 466, 467f
peripheral neuropathies, 101–102 234–235, 570–571 territorial infarction, 466–467, 466f,
primary central nervous system ALS/PDC (amyotrophic lateral 467f
lymphomas in, 106–107, 107f sclerosis/Parkinsonism dementia Anterior spinal cord syndrome, 121,
spinal cord diseases, 100, 100t complex of Guam), 235–236 466, 467f
ACTH cells, 396 Aluminum intoxication, 192 Anticonvulsants
ACTH-producing adenomas, 409–410, Alzheimer’s disease (AD) phenytoin intoxication, 185–186,
409f, 410f age and, 238, 243–244 185f
Actinomycete infections, 57–58, 58f diagnosis, 238, 243–244 usage during pregnancy, 186
Activation, of microglia, 17 epidemiology, 238–239 Antiganglioside neuropathy, 511
Acute disseminated encephalomyelitis gender and, 238 Antiglycolipid neuropathy, 511
(ADE), 255–256 hereditary genetic factors, 239 Anti-Hu antibody neuropathy, 511,
Acute hemorrhagic leukoencephalitis, neuropathology, 239–243, 239f–243f 511f
256, 256f neurotransmitters in, 244 Anti-myelin-associated glycoprotein
Acute posterior multifocal placoid pathogenesis, 244–245 neuropathy, 510–511, 510f
pigment epitheliopathy preclinical, 244 Antisulfatide neuropathy, 511
(APMPPE), 137 risk factors, 239 Aorta
AD. See Alzheimer’s disease Amebic meningoencephalitis, 70–72, 71f cross-clamping, 463–464
Adamantinomatous craniopharyngioma, American trypanosomiasis, 72–73 injury, spinal cord arterial infarction
348–349, 349f Amputation neuroma, 443–444, 443f and, 463–464, 464f
ADE (acute disseminated Amyloid thrombosis, acute, 464
encephalomyelitis), 255–256 in cerebral amyloid angiopathy, 130, Aortic aneurysm dissection, 464
Adenoid formations, in gliosarcoma, 132t APMPPE (acute posterior multifocal
309, 309f senile plaques, in Alzheimer’s disease, placoid pigment epitheliopathy),
Adenomas, pituitary. See Pituitary 241, 241f, 242f 137
adenomas Amyloid neuropathy, 517–518, Apolipoprotein E
4 alleles, 229, 239
Adrenoleukodystrophy (ALD), 210–211, 517f–519f Apoptosis
210f, 260–261, 261f Amyloid precursor protein, in Alzheimer’s neuronal, 12–13, 12f
AFIP (Armed Forces Institute of disease, 241, 241f, 242f oligodendroglial, 18
579
580 INDEX
Aqueduct primary and secondary (reactive), Birbeck granules, in Langerhans-cell

forking, 33, 33f 15–16, 15f, 27 histiocytosis, 357, 357f
gliosis, 33, 34f Astrogliosis, 15 Blastomycosis, 59
septum formation, 33 Atheromatous embolism, 467 Bleeding diatheses, 136
stenosis, 33 Atherosclerosis, 126 Blood–brain barrier
Aquifuga, 84–85, 85f Atherosclerotic myelopathy, 467 computerized tomography of, 21, 22f
Arachnoidopathy, chronic adhesive Atrophy function of, 3
spinal, 484–486, 484f–486f muscle fiber, 533–534, 533t, 533f, in infant, 28
AraC intoxication (cytosine arabinoside 534f, 23.12cf Blood-cerebrospinal fluid barrier, 3
intoxication), 187 neurogenic, 569, 569f, 570f, 23.58cf Blood pressure
Arbovirus encephalitis, 80–81 Atypical teratoid/rhaboid tumor autoregulation, 113
Arhinencephaly, 31 (AT/RT), 390–392, 392f, 17.5cf, mean arterial, 113
Armed Forces Institute of Pathology 17.7cf Borrelia burgdorferi, 57
(AFIP), oligodendroglioma Atypical teratoid tumor of infancy, 387 Brain. See also specific brain structures
grading, 324–325 Autopsy examination, 2–4 and disorders
Arnold-Chiari malformation (Chiari type AVFs. See Arteriovenous fistulas abscesses, 50–51, 50f
II), 34, 34f Avidin-biotin conjugate (ABC), arterial boundary zones, 113
Arsenic intoxication, 189–190, 189f, 276–278, 276f, 277f, 15.3cf blood flow to, 176
190f AVMs. See Arteriovenous malformations edema, 4, 6–7, 7f
Arterial boundary zones (ABZs), 113 Axoglial dysjunction, 514 cytotoxic, 6, 7
Arteriovenous fistulas (AVFs) Axonopathies, toxin-induced, 503–504, definition of, 4
spinal, 472, 473f 504t, 504f deleterious effects of, 7
spinal venous infarction and, 470 Axons gross morphologic changes in, 6,
Arteriovenous malformations (AVMs), degeneration, 125, 499–502, 500f–502f 7f
131–134, 132f relative sparing, in multiple sclerosis, interstitial or hydrocephalic, 6, 7
spinal, 471–472, 472f 250 microscopic changes in, 6–7
Aseptic meningitis, 79–80 ultrastructure, 498, 499f vasogenic, 4, 7
Aspergillosis, 61–63, 63f AZT (zidovudine), 102 hemorrhage
Astrocytes cause of, 122
fibrillary, 15, 298–299 delayed intracerebral, 166
glial fibrillary protein in, 5–6t, 299, Bacterial infections epidural. See Epidural hemorrhage
299f brain abscesses, 50–51, 50f intracerebral, 165–166, 166f
morphologic reactions to injury, neonatal meningitis, 45–47 intracranial. See Intracranial
15–16, 15f purulent leptomeningitis, 45 hemorrhage
protoplasmic, 15, 298–299 Bacterial meningitis intradural, 37
tau-positive inclusions in, 16–17 diagnosis, 49 neuropathology of, 123–125, 123f,
Astrocytomas neonatal, 45–46 124f
circumscribed, 300, 300t pathogens, 46–47 subarachnoid. See Subarachnoid
chordoid glioma of third ventricle, pathology, 47–50, 46f, 47f hemorrhage
315–316, 315f Bacterial myositis, 559 subdural. See Subdural hemorrhage
pilocytic, 310–313, 311f, 312f Bailey-Cushing histogenetic classification herniation. See Brain herniation
pleomorphic xanthoastrocytoma, of central neuroepithelial tumors, of infants/children, 27–28, 168–169
313–314, 313f, 314f 387f swelling, 166–167, 167f
subependymal giant cell, 314–315, Balo’s concentric sclerosis, 253, 254f vesicles
315f Basilar skull fractures, 144–145, 145f primary, 24–25
classification of, 299–300, 300t Basophil invasion, 386 secondary, 25
desmoplastic infantile, 317–318, 317f Batten’s disease, 553–554, 554f weight, 27
diffuse, 300, 300t Batten-Vogt syndrome, 202–203 Brain biopsy
categories of, 300, 300t Battle sign, 141 for intraoperative monitoring, 272,
grade 1-2 fibrillary, 302–304, Becker classification of embryonal 15.1cf
302f–305f, 303t tumors, 390, 391t sampling problems, 273
grade 3 fibrillary, 304–305, 304f, Becker dystrophy, 545 specimens, immunohistochemical
305f Benign congenital hypotonia, 537. See stains for, 272, 274t
grade 4, 305–308, 305f–308f also Congenital myopathies Brain death, 114, 469–470, 470f
histologic grading method, Berry aneurysms, 128–130, 129f Brain herniation
300–302, 301t, 301f Bilirubin, in kernicterus, 41–42 central, 8
pliocytic, 309 Binswanger’s disease (subcortical cingulate, 9–10
unusual forms, 309–310, 309f, 310f arteriosclerotic encephalopathy), definition of, 8
gemistocytic, 310, 310f 115, 115f, 128 tonsillar, 9, 9f
prognosis, 300 Biopsy transtentorial, 8
protoplasmic, 309, 309f brain biopsy, 272–273, 274t uncal or medial temporal lobe, 8–9,
Astrocytosis muscle. See Muscle biopsy 8f, 9f
fibrillary, 15 sural nerve. See Sural nerve biopsy ventral cerebellar, 9, 9f
INDEX 581
Brain injuries Burger, Scheithauer, Vogel classification development

hypoxic, 167–168 of embryonal tumors, 390, 391t molecular genetics of, 384
perinatal, 37–43, 39f–42f. See also Burger and Scheithauer classification of normal, 24–28
specific perinatal brain injuries embryonal tumors, 390, 391t endothelial cells of, 3
secondary, from global ischemia, Burkitt’s lymphoma, genetic immune privilege of, 3
113–115, 113t, 114f, 115f abnormalities in, 291 injury, reactions to
traumatic Burnt-out plaque, 241, 242f brain edema, 4, 6–7, 7f
brainstem avulsion, 154–155, 155f Burst lobe, 148, 166 brain herniation, 8–10
contusions, 146–148, 147f Butterfly glioma, 306, 306f cellular, 11–18, 12f–18f
crush-type, 151 hydrocephalus, 10–11, 10f
diffuse axonal, 151–154, 152f intracranial pressure increase, 7–8
from falling, 151 CAA. See Cerebral amyloid angiopathy malformations, 28–29
immediate-impact, 146 CADASIL (cerebral autosomal dominant causes of, 28–29
from penetrating injuries, 155–157, arteriopathy with subcortical definition of, 28
156f, 157f infarcts and frequency of, 28
primary complications, 157–167, leukoencephalopathy), 135–136 myelin in, 246, 247f
159f, 160f, 162f–166f Cadmium intoxication, 192 regenerative capacity of, 2–3
secondary complications, 167–168, CAG repeats (cytosine-adenine-guanine Central neurocytoma, 319–320, 319f,
167f repeats), 230 320f
from stab wounds, 157, 158f Caisson disease, 468–469 Central pontine myelinolysis
Brainstem California group viruses, 81 in alcoholism, 180–182, 181f, 182f
avulsion, 154–155, 155f Campylobacter jejuni, Guillain-Barré histopathology, 262–263, 263f
hemorrhages, from brain herniation, syndrome and, 508, 509 Centrospinal ischemic injuries, 121
9, 9f Canavan’s disease, 262, 262f Cephalhematoma, 37
neurodegenerative diseases of, Candidiasis, 58–59, 59f CERAD criteria, 244
232–234, 232f–234f Capillary hemangioblastoma, 344–345, Cerebellar degeneration, in alcoholism,
Brain tumors. See also specific types of 344f 179–180, 180f
abnormal chromosomes in, 291t Capillary telangiectasias, 133, 133f Cerebellar neuroblastoma, 387
age-specific incidence of, 268 Capsid, 78 Cerebellar neurolipocytoma, 388
of astrocytic origin, 298–299, 299f. Caput succedaneum, 37 Cerebellum
See also Astrocytomas Carbohydrate storage diseases, 549–552, development of, 26
biopsy specimens 550f–552f neurodegenerative diseases of,
immunohistochemical stains for, Carbon monoxide intoxication, 232–234, 232f–234f
272, 274t 177–178, 178f Cerebral amyloid angiopathy (CAA)
procurement of, 272–273, 273f Carcinomas in Alzheimer’s disease, 242–243, 242f
sampling problems, 273 choroid plexus, 334, 334f macroscopic features, 131, 132f
cell type–specific markers, 272 pituitary, 415 microscopic features, 130–131, 131f
electron microscopy, 275–276 Cardiac embolism, to brain, 115–116, protein composition of amyloid in,
histochemistry methods for, 275 115t 130, 132t
immunohistochemistry methods for, Carnegie staging, 24 Cerebral aneurysms, 128–130, 129f,
276–278, 280–284, 276f–284f, Carnitine deficiency, 552–553 130f
15.11cf Carnitine palmitoyltransferase Cerebral autosomal dominant
differential diagnosis, 275t deficiency, 553 arteriopathy with subcortical
etiology, 269 Cat-scratch disease, 57 infarcts and leukoencephalopathy
genetic abnormalities in, 291–292, Cavernous hemangiomas, 133, 133f (CADASIL), 135–136
291f, 291t Cavitary encephalopathies, 42 Cerebral dysplasias, 32
genetic markers, 290–292, 290f, 291f, Cavitary infarct, 117–118, 117f Cerebral hyperemia, 167
291t CBD (corticobasal degeneration), Cerebral infarcts, sequential
of glial origin, 298, 299f. See also 227–228 organization of, 124–125, 124t,
Gliomas CBTRUS (Central Brain Tumor Registry 125f, 126f
histochemistry, 275 of US), 268 Cerebral malaria, 72, 72f
incidence of, 267–268 Cell-cycle phases, flow cytometry, 286, Cerebral vasculature, neonatal, 28
nonglial origin, 298 286f, 15.17cf Cerebral veins, thromboses of, 136
pineal region, 359–365, 360f–365f Celloidin embedding method, 4 Cerebritis, 51, 52f
prevalence of, 267–268 Cellular schwannomas, 429–430, 431f, Cerebro-ocular dysplasia-muscular
radiation therapy, 270–271, 270f, 432t dystrophy (COD-MD), 542–543
271f Central Brain Tumor Registry of US Cerebrospinal fluid, in tuberculous
Bromodeoxyuridine (BUDR), 287–288, (CBTRUS), 268 meningitis, 52
287f, 290 Central chromatolysis, 13, 13f Cerebrovascular disease
Bruises, to head, 140–141, 141f Central core disease, 538–539, 538f, 539f acute posterior multifocal placoid
BUDR (bromodeoxyuridine), 287–288, Central nervous system pigment epitheliopathy, 137
287f, 290 demyelinative diseases. See atherosclerosis, 126
Bunina bodies, 15 Demyelinative diseases bleeding diatheses, 136
582 INDEX
Cerebrovascular disease (Continued) Chronic fatigue syndrome, 560 spinal cord, 475–476
cerebral amyloid angiopathy, Chronic inflammatory demyelinating Corpora amylacea, 15
130–131, 131f, 132f, 132t polyradiculoneuropathy (CIDP), Corpus callosum
cerebral aneurysms, 128–130, 129f, 509–510, 509f, 516 agenesis, 32, 33f
130f Circle of Willis saccular aneurysms, defects of, 32, 33f
clinical disorders, 122–123 128–130, 129f Corticobasal degeneration (CBD),
crack cocaine abuse, 136–137 Circulation, systemic 227–228
Dego’s disease, 137 ischemic disorders, 112 Corticotroph cell adenomas, 409
genetic, 135–136 sudden impairment of, spinal cord Corticotroph cell hyperplasia, 416, 418,
hypertensive, 126–128, 127f, 128f arterial infarction and, 462–463, 418f
neoplastic, 135 462f, 463f Cowden/Lhermitte-Duclos disease,
Sneeden’s syndrome, 137 Cisplatin intoxication, 187 454–456, 455f
subarachnoid hemorrhage, 130, 130f CJD (Creutzfeldt-Jakob disease), 90–91, Coxsackievirus, 86
thromboses of dural sinuses and 91f CPSC (congenital paucity of secondary
central veins, 136 Clear cell meningiomas, 343, 343f synaptic clefts), 568
traumatic angiopathies, 136 c-myc gene product, 291 Crack cocaine abuse, 136–137
vascular malformations, 131–134, Coagulation necrosis, 116–117 Cranial arteritis, 134–135, 135f
132f, 133f Coccidioidomycosis, 60–61, 62f Cranial nerve palsies, diabetic, 512,
Cervical spondylosis, 479–481, 479f, 480f COD-MD (cerebro-ocular dysplasia- 513f
CGH (comparative genomic muscular dystrophy), 542–543 Craniopharyngioma, 348
hybridization), 291 Coenurosis, 68 adamantinomatous, 348–349, 349f
Chagas disease, 72–73 Collagen pockets, 501 papillary, 349–350, 350f
Charcot-Bouchard aneurysms, 127–128, Collagen vascular diseases, 506, 506f Craniorachischisis, 30
128f Colloid cyst of third ventricle, 334–335 Creutzfeldt-Jakob disease (CJD), 90–91,
Charcot-Marie-Tooth disease, Comminuted skull fractures, 145, 146f 91f
hypertrophic, 515–516 Comparative genomic hybridization Criblé lacunes, 127, 128f
Chemotherapeutic agents, intoxication (CGH), 291 Critical care myopathy, 559
from, 186–188, 188f Computerized tomography (CT), 21, 22f Crooke’s hyalinization, in Cushing’s
Chiari malformations Concussion, spinal cord, 475 disease, 409, 410f
type I, 34, 34f Congenital hydrocephalus, 32–33, 33f Cross-clamping, aortic, 463–464
type II, 34, 34f aqueductal obstruction and, 33, 33f, Cross-reacting epitopes, 277
Chicken-wire vasculature, in 34f Crushing head injuries, 151
oligodendroglioma, 323–324, Chiari malformations and, 34, 34f Cryptococcosis, 59–60, 61f
323f, 326 Dandy-Walker syndrome, 34, 35f CT (computerized tomography), 21, 22f
Chief cells, in paraganglioma, 320, 320f, Congenital muscular dystrophy, Cushing’s disease, 409–410, 410f
321f 542–543 Cyanide poisoning, 178–179
Childhood ataxia with diffuse Congenital myasthenic syndromes, Cysticercosis, 66–68, 66f, 67f, 560–561
hypomyelination, 262 568–569 Cysts, nonneoplastic pineal, 365
Children Congenital myopathies Cytochrome c oxidase deficiency, 195
brain contusions in, 149–150 central core disease, 538–539, 538f, Cytogenesis, neuronal and glial, 25
brain of, 168–169 539f Cytogenetics
skull of, 168–169 desmin, 541–542, 542f embryonal tumor classification, 390,
strokes in, 120 fiber type disproportion, 541, 541f 391t
traumatic head injuries in, 168–172, fingerprint body, 541, 541f of primitive neuroectodermal tumors,
171f historical aspects, 537–538 388
accidental vs. nonaccidental, 172 multicore disease, 539, 539f Cytokines, in multiple sclerosis, 251
from rotation or acceleration- myotubular, 540–541, 540f Cytomegalovirus infections
deceleration, 170–171 nemaline, 539–540 congenital, 83
from shearing force, 171, 171f rigid spine syndrome, 542 encephalomyelitis, in AIDS, 83,
Chondroid chordoma, 347–348, 348f Congenital paucity of secondary 104–105, 105f, 106f
Chordoid glioma of third ventricle, synaptic clefts (CPSC), 568 meningoencephalitis, 83, 84f
315–316, 315f Contrecoup contusions, 148–149, 149f, Cytophotometry, 287
Chordomas, 346–348, 347f, 348f 150f Cytosine-adenine-guanine repeats (CAG
Choriocarinoma, 364, 364f Contusions repeats), 230
Choroid meningioma, 339, 340f brain, 146–148, 147f Cytosine arabinoside intoxication
Choroid plexus contrecoup, 148–149, 149f, 150f (AraC), 187
carcinomas, 334, 334f coup, 148
papillomas, 332–334, 333f fracture, 150–151, 151f
Chromosomal abnormalities, in Down’s herniation, 151 DAI. See Diffuse axonal injury
syndrome, 35 in infants/children, 149–150 Dandy-Walker syndrome, 34, 35f
Chronic adhesive spinal at a distance, 157 Dawson’s fingers, 247
arachnoidopathy, 484–486, to head, 140–141, 141f DDN (delayed death of neurons), 114
484f–486f herniation, 157 Decompression sickness, 468–469
INDEX 583
Dego’s disease, 137 macroscopic features, 151–152, 152f Embolism, venous spinal cord infarction,
Dejerine-Sottas disease, 516 microscopic features, 152–154, 153f 468, 469f
Delayed death of neurons (DDN), 114 Diffuse cerebral swelling, 167 Embryonal carcinoma, 363, 363f
Delayed intracerebral hemorrhage, 166 Diffuse plaques, 242, 242f Embryonal tumors
Dementia Diplomyelia, 30 Becker classification, 390, 391t
of Alzheimer’s disease DISH (diaminobenzidine in situ Burger, Scheithauer, Vogel
genetic factors in, 239 hybridization), 290–291 classification, 390, 391t
preclinical, 244 Dissecting aneurysms, 129 Burger and Scheithauer classification,
frontotemporal, 227 Disseminated intravascular coagulation 390, 391t
with grains, 229–230 (DIC), in bacterial meningitis, cytogenetic classification, 390, 391t
HIV-associated, 96 49 Lantos, Vandenberg and Kleihus
with Lewy bodies, 222, 224–226, Distal axonopathy, 499 classification, 390, 392t
225f Distal myopathy, 546–547, 547f Rorke classification, 390, 392t
non-Alzheimer’s, non-Lewy body, DMD (Duchenne muscular dystrophy), WHO classification, 389–390, 390t
226–230, 228f, 229f 543–544, 544f Embryonic development, assessment
senile, with tangles, 229 DNET (dysembryoplastic neuroepithelial criteria for, 24
Demyelination tumor), 318–319, 318f, 319f Empty sella syndrome, 419
primary, 246 Down’s syndrome Empyemas, subdural, 51, 52f
secondary, 502–503 chromosomal abnormalities in, 35 Encephalitic rabies, 85
segmental, 246–247, 502, 503f incidence of, 35 Encephalitis
Demyelinative diseases morphology of, 36, 36f arbovirus, 80–81
iatrogenic, 262–263, 263f Drug-induced inflammatory myopathy, herpesvirus, 82–83, 83f
immune-mediated. See also Multiple 565–566 HIV-associated, 98–100, 98f–100f
sclerosis DSM IV (Diagnostic and Statistical measles inclusion-body, 87
acute disseminated Manual of Mental Disorders), viral, 80
encephalomyelitis, 255–256 Alzheimer’s disease diagnostic Encephalomyelitis
acute hemorrhagic criteria, 238 cytomegalovirus, in AIDS, 104–105,
leukoencephalitis, 256, 256f Duchenne muscular dystrophy (DMD), 105f, 106f
infectious, 256–258, 257f 543–544, 544f, 23.29cf viral, 80
metabolic, 258–262, 259f–262f Dural metastases, 350–351, 351f Encephalomyeloradiculitis, viral, 80
Denervating diseases, 569–571, 569f, Dural sinuses, thromboses of, 136 Encephalopathy, Wernicke-Korsakoff,
23.56cf Dural tail sign, 336 192–194, 192f, 193f
Dermatomyositis, 563–564, 563f, 564f Duret hemorrhages, 9, 9f Endocrine neuropathies, 511–514, 511t,
Dermoid cysts, 345, 346f Dying-back neuropathy, 499 512f, 513f
Desmin myopathy, 541–542, 542f, Dysembryoplastic neuroepithelial tumor End-plate AChE deficiency, 568
23.27cf (DNET), 318–319, 318f, 319f Entamoeba histolytica, 71–72
Desmoplastic infantile astrocytoma, Dysplasias Enteroviruses, aseptic meningitis and,
317–318, 317f cerebral, 32 79–80
Desmoplastic medulloblastoma, 387 cortical, 31 Environmental factors, in neural tube
Desmoplastic neuroblastoma, 317, 318f Dysraphias. See Neural tube, defects defects, 29
Developmental disorders. See specific Eosinophilic meningitis, 65
developmental disorders Eosinophilic neuronal necrosis, 12, 12f
Devic’s disease, 253 EAE (experimental allergic Ependymal cells, injury, reactions to,
Diabetic neuropathies, 512 encephalomyelitis), 254–255, 18
asymmetric, 512, 513f 254f Ependymoblastoma, 33–331, 384
autonomic, 513, 513f EAN (experimental allergic neuritis), Ependymoma
pathogenic mechanisms, 513–514 510 abnormal chromosomes in, 291t
systemic sensorimotor Eastern equine encephalitis (EEE), 81 cellular, 328–329, 328f
polyneuropathy, 512, 512f Eaton-Lambert syndrome, 567–568 circumscription, 327, 327f
Diagnosis, general considerations for, 2 Ecchymosis clear cell, 329, 329f
Diagnostic and Statistical Manual of mastoid, 141 differential diagnosis, 331
Mental Disorders (DSM IV), periorbital, 141, 141f histologic grading, 330–331, 330f
Alzheimer’s disease diagnostic Echinococcosis, 68 incidence of, 327
criteria, 238 Echovirus, 86 macroscopic features, 328
Diaminobenzidine in situ hybridization Ectopias, 31 microscopic features, 328–331,
(DISH), 290–291 EEE (Eastern equine encephalitis), 81 328f–330f
Diastatic skull fractures, 145–146, 146f Electron microscopy myxopapillary, 329, 329f
DIC (disseminated intravascular of brain tumors, 275–276 neuroimaging, 327–328
coagulation), in bacterial specimens, fixation methods for, 4 prognosis, 331
meningitis, 49 Elephantiasis neuromatosa, 434 tanycytic, 329–330, 330f
Diencephalon, development, 26 EMA (epithelial membrane antigen) treatment, 331
Diffuse axonal injury (DAI) Embolic spinal arterial infarction, 467, Epidermoid cysts, 345, 345f
in infants/children, 170–172, 171f 468f Epidural abscesses, 51
584 INDEX
Epidural hemorrhage, from traumatic Frontotemporal dementia, 227 in ependymoma differential diagnosis,
head injury, 157–161, 159f, 160f Frontotemporal dementia and 331
associated injuries, 159 parkinsonism linked to tissue controls, 280, 15.9cf
CT scan of, 160–161 chromosome 17 (FTDP-17), 227 Glial stars (nodules), 17
incidence of, 157–158 FSH cell adenomas, 411, 411f Glioblastoma
location of, 158–159, 159f FTDP-17 (frontotemporal dementia and abnormal chromosomes in, 291t
rate of evolution, 160 parkinsonism linked to flow cytometry, 286–287, 286f
volume of, 159–160 chromosome 17), 227 primary, 305, 307
Epidural metastases, 350 Fukuyama congenital muscular secondary, 305
Epithelial membrane antigen (EMA) dystrophy (FCMD), 542–543 Glioblastoma multiforme, 301, 301f,
Escherichia coli, neonatal meningitis Fungal myositis, 560 305–308, 305f–308f
and, 47 Fusiform aneurysms, 128 Gliofibrillary oligodendrocyte, in
État criblé, 127, 128f oligodendroglioma, 322
État lacunairé, 127, 128f Gliomas
Ethanol intoxication, 179–183, GAE (granulomatous amebic classification of, 298
180f–182f encephalitis), 70–73, 72f incidence of, 298
Ethylene glycol intoxication, 184, 184f Gangliocytoma, 317 mixed, 298
Exencephaly, 30 Ganglioglioma vs. gliosis, 303, 303t
Experimental allergic encephalomyelitis desmoplastic infantile, 317–318, 317f Gliomatosis cerebri, 310
(EAE), 254–255, 254f locations of, 316–317, 316f, 317f Gliosarcoma, 308–309, 308f, 309f
Experimental allergic neuritis (EAN), microscopic features, 316–317, 316f, Gliosis
510 317f aqueductal, 33, 34f
Extradural hemorrhage, 37 Ganglioneuroma, 439 vs. glioma, 303, 303t
Ganglioradiculitis, 511, 511f Globoid cell leukodystrophy (Krabbe’s
Gangliosidosis (neuronal storage disease), 258–259, 259f
Fabry’s disease, 199–200, 200f, 514, disorder), 13–14, 14f Globoid cells, 259, 259f
554, 23.44cf Gaucher’s disease, 198–199, 199f Glomeruloid structures, 306
Facioscapulohumeral dystrophy, 545, Gemistocytic astrocytoma, 310, 310f Glycoprotein-hormone producing
23.32cf Gene expression profiling, of CNS adenomas, 411, 411f
Failures of fusion. See Neural tube, tumors, 269 GM1 gangliosidoses, 202, 202f
defects Gene rearrangement analyses, 284 GM2 gangliosidoses, 200–202, 201f
Falls, brain injury from, 151 Genetic diseases, cerebrovascular, Gonadotrph cell hyperplasia, 418
Fatal familial insomnia, 91–92 135–136 Gracile tract degeneration (GTD), 101,
Fatty infiltration, in muscle injury, Genetic factors 101f
536–537, 537f in Alzheimer’s disease, 239 Granular bodies, in pilocytic
FCMD (Fukuyama congenital muscular markers for brain tumors, 290–292, astrocytoma, 311–312, 312f
dystrophy), 542–543 290f, 291f, 291t Granular cell tumor, 438–439
Feigin tumor (gliosarcoma), 308–309, in multiple sclerosis, 254 Granuloblastoma, 384
308f, 309f Genetic neuropathies, 516–517, 516f, Granulocytic sarcoma, 358
Fetal alcohol syndrome, 35, 182–183 517f Granulomatosis infantisepica, 47
Fiber necrosis, in muscle injury, 535, Germ cell neoplasms, pineal, 361–362, Granulomatous amebic encephalitis
535t, 535f 362f (GAE), 70–73, 72f
Fiber type disproportion, 541, 541f, Germinal matrix (ventricular zone), 25 Granulomatous myositis, 561
23.23cf Germinal matrix hemorrhage, neonatal, Granulovacular degeneration, in
Fibrocartilaginous embolism, 467 38–39, 39f Alzheimer’s disease, 243, 243f
Fibrosis, in muscle injury, 536–537, Germinoma, 362–363, 362f Granulovacuolar bodies, 14–15
537f Gerstmann-Sträussler-Scheinker disease Gray-matter necrosis, neonatal, 40–41
Fingerprint body myopathy, 541, 541f (GSS), 91 Group B Streptococcus, neonatal
“Finnish snowballs,” 203 GFAP. See Glial fibrillary acidic protein meningitis and, 45–46
FISH (fluorescence in situ hybridization), GH cell adenomas, 402, 405–406, 405f, Growth hormone cell hyperplasia, 416
290–291, 15.27cf 406f GSS (Gerstmann-Sträussler-Scheinker
Fixation methods, 3–4 Giant axonal neuropathy, hereditary, disease), 91
Flaviviruses, 81–82, 81t 516, 517f GTD (gracile tract degeneration), 101,
Floating neurons, 327 Giant cell glioblastoma, 307, 307f 101f
Florid plaques, 91 Giant cell granuloma of pituitary, Guillain-Barré syndrome, 507
Flow cytometry, 286–287, 286f, 287f, 418–419, 419f axonal form, 508–509, 508f
15.17cf Glial cells, development of, 25 classic demyelinative, 507–508, 507f,
Fluorescence in situ hybridization Glial fibrillary acidic protein (GFAP) 508f
(FISH), 290–291, 15.27cf ABC detection method for, 276–278, Miller-Fisher variant, 509
Focal myositis, 566 276f, 277f, 15.3cf Gunshot wounds
Fracture contusions, 150–151, 151f in astrocytes, 299, 299f to head, 142, 142f, 155–157, 156f,
Fragile X syndrome, 36 in astrocytic intermediate filaments, 157f
Friedreich’s ataxia, 233–234, 234f 15 to spinal cord, 474–475
INDEX 585
Haemophilus influenzae meningitis, 47, subaponeurotic, 37 Human T-cell lymphotropic virus type 1
48 subarachnoid. See Subarachnoid (HTLV-1), 95
Hallervorden-Spatz disease (HSD), hemorrhage Hunter’s syndrome, 206
231–232 subdural. See Subdural hemorrhage Huntington’s disease, 230, 230f
Haltia-Santavuori type neuronal ceroid- Hemorrhagic infarction, of spinal cord, Hurler-Scheie’s syndrome, 205
lipofuscinosis, 203 469 Hurler’s disease, 205, 205f
Harles-Scheie’s syndrome, 205 Hemorrhagic transformation, secondary, Hutchinson triad, 57
Head examination, external, 140 118, 118f Hydatid disease, 68
Head injuries Hereditary giant axonal neuropathy, Hydranencephaly, 42
from blunt trauma, 140–142, 141f, 516, 517f Hydrocephalus
142f, 168–170 Hereditary motor sensory neuropathy, causes of, 10
brainstem avulsion, 154–155, 155f 515–516 clinical features of, 10–11
crushing, 151 Hereditary sensory and autonomic congenital, 32–33, 33f
diffuse axonal, 151–154, 152f neuropathies, 517 definition of, 10
examination Herniation contusions, 151, 157 gross morphologic changes in, 10, 10f
internal of scalp, 143, 143f Herpes simplex virus-1 (HSV-1), 82 normal pressure, 11
of skull, 143–144, 143f Herpes simplex virus-2 (HSV-2), 83 obstructive, 10
from falling, 151 Herpes virus infections communicating, 10
incidence of, 140 in AIDS, 105 noncommunicating, 10
in infants/children, 168–172, 171f encephalitis, 82–83, 83f Hydromyelia, 30
from penetrating trauma, 142, 142f, Herpes zoster infection, neuropathy of, Hydrophobia, 84–85, 85f
155–157, 156f–158f 518–519, 519f Hyperplasia, pituitary gland, 416, 418,
Hemangioblastoma, 344–345, 344f Heteropias, 31 418f
Hemangiopericytoma (HPC), 343–344 Hexacarbon intoxication, 188–189, Hypertensive cerebrovascular disease,
incidence, 343 188f, 189f 126–128, 127f, 128f
staghorn configuration, 343, 343f Hexachlorophene intoxication, 185, Hypertensive encephalopathy, 123
types 185f Hypertrophic neuropathies, 514–516,
capillary hemangioblastoma, HHV-6 (human herpesvirus type 6), 83 514f, 515f
344–345, 344f Hippocampal sclerosis, 114 Hypertrophy
chordomas, 346–348, 347f, 348f Hippocampus, development of, 27 in denervating diseases, 569
craniopharyngioma, 348–350, 349f, Hirano bodies, 14–15, 243, 243f muscle fiber, 533–534, 533f
350f Histoplasmosis, 59, 60f Hypoxia, brain
dermoid cysts, 345, 346f Histiocytosis, 356–358, 357f, 358f cellular changes from, 176–177, 177f
epidermoid cysts, 345, 345f History of neuropathology, 1–2 damage from, 167–168
lipomas, 345–346, 346f HIV infection. See Human Hypoxic-ischemic lesions, neonatal,
Hematomas, scalp, 37 immunodeficiency virus (HIV) 39–40
Hematopoietic system diseases Hodgkin’s disease, 355–356, 355f
histiocytoses, 356–357, 357f Holoprosencephaly
Hodgkin’s disease, 355–356, 355f etiology of, 31 Idiopathic acute (progressive) necrotic
leukemias, 358–359, 358f morphology of, 30–31, 31f myelopathy, 487
multiple myeloma, 356, 356f HPC. See Hemangiopericytoma Immune factors, in multiple sclerosis,
non-Hodgkin’s malignant lymphoma, HSD (Hallervorden-Spatz disease), 254–255, 254f
352–355, 353f–355f 231–232 Immune-mediated neuropathies,
plasma cell neoplasms, 356 HSV-1 (herpes simplex virus-1), 82 507–511, 507f–510f
solitary plasmacytoma, 356 HSV-2 (herpes simplex virus-2), 83 Immune privilege, of central nervous
Hemorrhage HTLV-1 (human T-cell lymphotropic system, 3
brainstem, 9, 9f virus type 1), 95 Immunohistochemistry
delayed intracerebral, 166 Human herpesvirus type 6 (HHV-6), 83 medulloepithelioma, 383
Duret, 9, 9f Human immunodeficiency virus (HIV). methods, 276–278, 280–284,
epidural. See Epidural hemorrhage See also Acquired 276f–284f
extracranial peritoneal, 37 immunodeficiency syndrome avidin-biotin conjugate, 276–278,
extradural, 37 neuropathies, 520–521, 520t, 521f 276f, 277f, 15.3cf
germinal matrix, neonatal, 38–39, 39f Human immunodeficiency virus combining analyses, 278, 280,
intracerebral, 165–166, 166f infection (HIV) 279f–282f, 15.5cf, 15.7cf
intracranial. See Intracranial clinical manifestations, 95–96 gene rearrangement analyses, 284
hemorrhage encephalitis, 98–100, 98f–100f pitfalls to interpretation, 277–278,
intradural, 37 gracile tract degeneration, 101, 101f 278f, 15.4cf
intraventricular, 165 pathogenesis, 95 in situ mRNA hybridization,
parenchymal, 38, 359, 359f pathologic manifestations, 96–98, 97t 283–284
perinatal, 37–39, 39f seroconversion, 98 in pituitary adenoma differential
periventricular-intraventricular, spinal cord diseases, 100, 100t diagnosis, 415–416, 418–419,
38–39, 39f vacuolar myelopathy, 100–101, 100f, 417t, 419f
retinal, in infants/children, 170 101f, 101t Inclusion bodies, 14–15, 14f
586 INDEX
Inclusion body myositis, 564–565, 564f, toxic metal, 189–192, 189f, 190f Kufs type of neuronal ceroid-
565f, 23.52cf trichloroethylene, 189 lipofuscinosis, 204–205
Incomplete infarction, 118–119, 119f Intracerebral hemorrhage, 165–166, Kuru, 90, 90f
Indifferent cells, 384 166f
Infant Intracranial hemorrhage
myelination in, 27 peritoneal, 37–39, 39f Lacerations
Infantile spinal muscular atrophy, 571, from traumatic head injury head/scalp, 142, 142f
23.60cf burst lobe, 166 spinal cord, 476
Infants delayed intracerebral, 166 Lactic acidosis, in mitochondrial
brain, 168–169 epidural, 157–161, 159f, 160f myopathies, 557
contusions in, 149–150 subarachnoid, 164–165, 164f Lacunar infarcts
normal, 27–28 subdural, 161–164, 162f, 163f in hypertension, 127, 128f
skull of, 168–169 Intracranial pressure, increased, 7–8, microscopic features, 119–120, 119f
traumatic head injuries in, 168–172, 167, 167f neuropathology, 123–124, 123f
171f Intradural hemorrhage, 37 in subcortical leukoencephalopathy,
Infarction Intraneural perineuroma, 436–437, 437f 115
anemic or white, 116–118, 117f Intrathecal injections, myelopathy after, Lafora bodies, 14
cavitary, 117–118, 117f 483, 483f Lafora’s disease, 551–552, 551f, 552f
definition of, 116 Intraventricular hemorrhage, 165 Laminar necroses, 114, 114f
hemorrhagic or red, 118, 118f Ischemia Langerhans-cell histiocytosis, 357, 357f
incomplete, 118–119, 119f classification of, 112–113 Lantos, Vandenberg and Kleihus
lacunar, 119–120, 119f definition of, 112–113 classification of embryonal
neuropathology, 123–125, 123f, 124f disorders of, 112. See also specific tumors, 390, 392t
venous, 120, 120t ischemic disorders Large-cell medulloblastoma, 387
Infectious neuropathies, 518–521, focal or local, 113. See also Stroke LCA (leukocyte common antigen), 316
519f–521f, 520t brain injuries caused by, 115–120, LCM (lymphocytic choriomeningitis
Infectious vasculitis, 134 115t, 116t, 117f–119f virus), 79–80
Inflammation, in muscle injury, 536, global, 113 Lead intoxication, 190
536t neuropathology of, 123–124 Leigh’s disease, 195
Inflammatory demyelinative mass, secondary brain injuries, 113–115, Leprosy
presenting as neoplasm, 253 113t, 114f, 115f dimorphous or borderline form, 54
Inflammatory myopathies, 559–566, moderate, incomplete infarction and, lepromatous form, 54
562f–565f, 23.52cf 118–119, 119f neuropathy of, 519–520, 520f
Inherited tumor syndromes severity of, 112, 113 tuberculoid form, 54
Cowden/Lhermitte-Duclos disease, to spinal cord, 120–121 Leptomeningeal metastases, 350
454–456, 455f Ischemic neuropathy Leptomeningitis, purluent, 45
neurofibromatosis, 448–452, classification, 504–505, 505t Leukemias, craniospinal complications,
449f–451f collagen vascular diseases, 506, 506f 358–359, 358f
tuberous sclerosis complex, 452–454, polyarteritis nodosa, 505–506, 505f, Leukoaraiosis, 115
453f, 454f 506f Leukocyte common antigen (LCA), 316
Von Hippel-Lindau disease, 451–452, Ischemic white matter disease, 124 Leukodystrophies, 207–211, 207f–210f,
452f Isopropyl alcohol intoxication, 185 258–262, 259f–262f. See also
Intercostal arterial infarction, 464–465, specific leukodystrophies
465f Lewy bodies, 14, 14f, 223–224, 223f
Interdigital neuritis, localized, 444 Jansky-Bielschowsky type of neuronal Lewy body diseases
Interleukins, in multiple sclerosis, 251 ceroid-lipofuscinosis, 203–204, dementia with Lewy bodies, 222,
Intermediate filament, 275 203f, 204f 224–226, 225f
Intervertebral disc Juvenile ceroid-lipofuscinosis (Batten’s diagnosis of, 222–223
disease, 479 disease), 553–554, 554f differential diagnosis, 222
traumatic injury, 481 Juvenile-onset familial amyotrophic Parkinson’s disease, 222, 226
Intoxication lateral sclerosis, 571 Lewy neurites, 224
carbon monoxide, 177–178, 178f Juvenile pilocytic astrocytomas, LH cell adenomas, 411, 411f
from chemotherapeutic agents, 310–313, 311f, 312f Lichtheim plaques, 196
186–188, 188f Light microscopy, specimens, fixation
cyanide, 178–179 methods for, 4
ethanol, 179–183, 180f–182f Kearns-Sayre syndrome, 557, 558 Limb-girdle syndrome, 545–546, 545f,
ethylene glycol, 184, 184f Kernicterus, 41–42 546f
hexacarbon, 188–189, 188f, 189f Kernohan’s notch, 8–9, 9f Lipidized mature neuroectodermal
hexachlorophene, 185, 185f Ki-67 antibodies, 288–289 tumor of the cerebellum, 388
isopropyl alcohol, 185 Knudson hypothesis, 292 Lipid storage diseases, 552–554, 552f,
methanol, 183–184, 183f Korsakoff’s psychosis, 194 554f, 23.42cf
phenytoin, 185–186, 185f Krabbe’s disease, 207–208, 207f, 208f, Lipoblastic changes, in meningoma, 339,
toluene, 189 258–259, 259f 340f
INDEX 587
Lipofibromatous hamartoma, 444 Medulloblasts, 384, 385 208–210, 209f, 259–260, 259f,
Lipofuscin, 11 Medulloepithelioma, 383–384, 17.1cf 260f
Lipomas, 345–346, 346f Melanin, 11 Metastases, 350–351, 351f
Lipomatous glioneurocytoma, 388 Melanocytes, leptomeningeal, 11 parenchymal, 351–352, 351f, 352f
Lipomatous medulloblastoma, 387–388 Melanosomes, 11 Methanol intoxication, 183–184, 183f
Liquefactive necrosis, 117 Melanotic schwannomas, 430–431 Methotrexate intoxication, 186–187
Lissencephaly, 32 MELAS, 557 MGUS (monoclonal gammopathy of
Listeria monocytogenes, neonatal Meningeal neoplasia, differential unknown significance), 510–511,
meningitis and, 47 diagnosis, 275t 510f
Localized hypertrophic neuropathy, 436 Meningiomas MH (malignant hyperthermia), 558–559
Lou Gehrig’s disease, 234–235 abnormal chromosomes in, 291t MIB-1 antibodies, 288–289, 289f
Luft’s disease, 556 anaplastic malignant, grade III, Microcystic meningioma, 338, 339f
Lupus cerebritis, 134 341–343, 342t, 342f, 343f Microglia
Lupus myelopathy, 486–487 atypical, grade II, 341, 341t activation of, 17
Luse bodies, 429 biological behavior of, 339–340, 340f clustering. See Neuronophagia
Lyme borreliosis, 57 causes of, 335 injury, response to, 17, 17f, 18f
Lyme disease, 521 clear cell, 343, 343f perivascular, 17
Lymphocytic choriomeningitis virus dural tail sign, 336 Micropolygyria, 32, 32f
(LCM), 79–80 en plaque, 336 Microtubules, morphologic changes in,
Lymphocytic hypophysitis, 418, 419f gender and, 335 13
Lymphoplasmacytic meningioma, 338, grade I, 341 Microvasculitis, in collagen vascular
339f histologic variants, 337–339, 337t, disease, 506, 506f
Lyssa bodies, 85 337f–339f Migrational disorders, 31
hormones and, 335 Miller-Fisher variant of Guillain-Barré
incidence/prevalence, 335 syndrome, 509
Macrophages, with myelin debris, in location of, 335–336, 336f Minigemistocyte, in oligodendroglioma,
multiple sclerosis, 250, 250f macroscopic features, 337 322, 322f
Magnetic resonance imaging (MRI), microscopic features, 337–339, Mitochondrial myopathies, 554–559,
21–23, 22f, 23f 337f–339f 555f
Malignant hyperthermia (MH), 558–559 origin of, 335, 336f with defective energy conservation,
Malignant peripheral nerve sheath papillary, 342, 342f 556
tumor (MPNST) rhabdoid, 342, 342f with impaired substrate utilization,
conventional, 439–441, 440f Meningitis 556
with divergent differentiation, aseptic, 79–80 with respiratory chain defects,
441–442, 442f bacterial 556–558
epithelioid, 441, 441f childhood/ adult, 47–50, 46f, 47f Mixed GH cell/PRL adenomas,
in transformation, 442 pathology, 47–50, 46f, 47f 407–408, 407f
Malignant pilocytic astrocytomas, 313 coccidioidomycosis, 60–61, 62f MNGIE, 557
Malignant triton tumor, 442, 442f neonatal, 45–47 Monoclonal gammopathy of unknown
Mammosomatotroph cell adenomas, tuberculous, 52 significance (MGUS), 510–511,
408 Meningoencephalitis, viral, 80 510f
Manganese intoxication, 190–191 Meningomyelocele, 30, 30f Monoclonal neoplastic proliferation,
Marburg type multiple sclerosis, Meningovascular syphilis, 56 281–282, 283f, 284f
252–253, 253f Mercury intoxication, 191 Mononuclear cell infiltrate, prominent,
Marchiafava-Bignami disease, 180 MERRF, 557–558 in multiple sclerosis, 250–251,
Marinesco bodies, 15 Mesaxon formation, 429 251f
Maroteaux-Lamy disease, 206 Mesencephalic flexure, 25 Mononuclear phagocytes, histiocytosis
Mass effect, 116, 117f Mesencephalon of, 357–358, 358f, 357–358,
Mastoid ecchymosis, 141 development of, 24 358f
Maturation phenomenon, 114 histogenesis of, 26 Monstrocellular sarcoma, 307, 308f
McArdle’s disease, 550–551, 551f Metabolic diseases, 197–207, 198f–205f. Morquio’s syndrome, 206
McLendon classification of primitive See also specific metabolic Morton’s neuroma, 444, 522
biopotential precursors, 390, 392t diseases Motor neuron disease, 234–235,
Measles inclusion-body encephalitis, 87 Metabolic myopathies 570–571
Medulla, development of, 26 carbohydrate storage diseases, Motor sensory axonal neuropathy,
Medulloblastomas 549–552, 550f–552f 508–509, 508f
abnormal chromosomes in, 291t lipid storage diseases, 552–554, 552f, MPNST. See Malignant peripheral nerve
CBTRUS data, 268 554f, 23.42cf sheath tumor
desmoplastic, 387 mitochondrial myopathies, 554–559, MPS (mucopolysaccharidoses), 205–207,
diagnostic terms for, 384–386, 386t 555f 205f
histogenesis, 385 Metabolic neuropathies, 511–514, 511t, MRI (magnetic resonance imaging),
large-cell, 387 512f, 513f 21–23, 22f, 23f
lipomatous, 387–388 Metachromatic leukodystrophy, MS. See Multiple sclerosis
588 INDEX
MSA (multiple systems atrophy), 231, blastomycosis, 59 Myotubular myopathy, 540–541, 540f
231f candidiasis, 58–59, 59f
Mucoid wedge, 396 causes of, 58
Mucopolysaccharidoses (MPS), coccidioidomycosis, 60–61, 62f Naegleria fowleri, 70
205–207, 205f cryptococcosis, 59–60, 61f NCL (neuronal ceroid-lipofuscinosis),
Mucormycosis, 63, 64f histoplasmosis, 59, 60f 202–203
Multicore disease, 539, 539f mucormycosis, 63, 64f Nebenkern formation, 406
Multicystic encephalopathy, 42–43 paracoccidioidomycosis, 64 Neck examination, external, 140
Multi-infarct dementia, causes of, Myelin Necrotizing myelopathy, 486–487, 487f
122–123 in central nervous system, 246–247, Negri bodies, 84, 85, 85f
Multiple myeloma, 356, 356f 247f Neisseria meningitidis meningitis, 47, 49
Multiple sclerosis (MS) function of, 246 Nelson’s syndrome, 410
acute, 252–253, 253f loss, in multiple sclerosis, 249–250, Nemaline myopathy, 539–540, 23.21cf
forms of, 247 249f Nematodal diseases, 64–66
pathogenic mechanisms, 254–255, in peripheral nervous system, 246, Neonatal meningitis, 45–47
254f 13.3cf Nerve cell death
pathology widely-spaced, 510, 510f eosinophilic neuronal necrosis, 12, 12f
gross, 247–248, 247f–249f Myelination, in full-term infant, 27 neuronal apoptosis, 12–13, 12f
microscopic, 248–251, 249f–251f, Myelinolysis, central pontine in Nerve sheath myxoma, 438
249t alcoholism, 180–182, 181f, 182f Nervous system
plaques, inactive, 252, 252f, 253f Myelinopathy, toxin-induced, 504, 504t anatomy of, 2
remyelination, 251–252, 251f, 252f Myelocele, 30 divisions of. See Central nervous
variants, 252–254, 253f Myelopathy system; Peripheral nerves
Multiple systems atrophy (MSA), 231, after intrathecal injections, 483, 483f Neural tube
231f idiopathic acute necrotic, 487 defects, 29
Mumps, 86–87 necrotizing, 486–487, 487f anencephaly, 29–30, 29f
Muscle biopsy paraneoplastic necrotizing, 487, 487f etiology of, 29
artifacts, common, 532–533, 23.9cf, postangiography, 482–483 meningomyelocele, 30, 30f
23.29cf in rheumatoid disease, 481–482, 481f, myelocele, 30, 30f
normal muscle, 529–532, 530t, 530f, 482f development of, 25
531f, 23.4cf–23.6cf from spinal column diseases, formation of, 24–25
specimen processing, 525, 528 479–482, 479f–482f Neuroblastoma, 292, 384
technique, 525 transverse, 121 Neuroblastoma malignum, 384
tray, 528–529, 529f traumatic spinal cord, 476–477, 477f Neuroborreliosis, Lyme, 57
Muscle injury, general reactions Myeloradiculitis, acute, 86 Neurocutaneous diseases, 448
atrophy, 533–534, 533t, 533f, 534f Myoadenylate deaminase deficiency, 558 neurofibromatoses, 448–452,
fatty infiltration, 536–537, 537f Myogranules, 539 449f–451f
fiber necrosis, 535, 535t, 535f Myopathies tuberous sclerosis complex, 452–454,
fiber regeneration, 535, 536f AIDS-related, 102, 102f, 103f 453f, 454f
fibrosis, 536–537, 537f congenital, 537–542, 538f–542f, von Hippel-Lindau disease, 344,
hypertrophy, 533–534, 533f 23.21cf–23.27cf 451–452, 452f
inflammation, 536, 536t critical care, 559 Neurocytoma
nuclear internalization, 534–535, distal, 546–547, 547f central, 319–320, 319f, 320f
534t, 534f drug-induced inflammatory, 565–566 differential diagnosis, 284, 15.16Bcf
vacuolar changes, 536, 536t inflammatory, 559–566, 562f–565f, terminology, 384
Muscular dystrophy 23.52cf Neurodegenerative diseases
Becker, 545 metabolic, 549–559, 550f–552f, 554f, Alzheimer’s disease. See Alzheimer’s
congenital, 542–543 555f disease
distal myopathy, 546–547, 547f carbohydrate storage diseases, amyotrophic lateral
Duchenne, 543–544, 544f, 23.29cf 549–552, 550f–552f sclerosis/Parkinsonism dementia
facioscapulohumeral, 545, 23.32cf lipid storage diseases, 552–554, complex of Guam, 235–236
limb-girdle syndrome, 545–546, 545f, 552f, 554f, 23.42cf of basal ganglia
546f mitochondrial, 554–559, 555f Huntington’s disease, 230, 230f
myotonic, 547–549, 548f, 549f mitochondrial, 554–559, 555f Parkinson’s disease. See Parkinson’s
oculopharyngeal, 547 Myositis disease
Myasthenia gravis, 566–567 bacterial, 559 of brainstem and/or cerebellum,
Mycobacterial infections focal, 566 232–234, 232f–234f
leprosy, 54 fungal, 560 classification of, 220–222, 221f,
sarcoidosis, 54–55, 55f granulomatous, 561 222f
tuberculosis, 51–52, 54, 53f, 54f inclusion body, 564–565, 564f, 565f biochemical-based, 221, 222f
Whipple’s disease, 55, 56f polymyositis, 562–563, 562f genetic, 221–222, 222f
Mycotic infections viral, 559–560 inclusion-based, 220, 221f
aneurysms, 128 Myotonic muscular dystrophy, 547–549, neuroanatomic, 220, 221f
aspergillosis, 61–63, 63f 548f, 549f common features of, 220
INDEX 589
Lewy body-associated. See Lewy body Neurons Null cell adenomas, 411–413, 412f,
diseases development of, 25 413f
non-Alzheimer’s, non-Lewy body ferrugination of, 12
dementias, 226–230, 228f, 229f injuries of, progressive/reversible, 13
of spinal cord, 234–235, 234f injury of, 11 Occlusive arterial disease, hematologic
terminology, 238 inclusion bodies and, 14–15, 14f causes of, 115–116, 116t
Neurofibrillary tangle, in Alzheimer’s perikaryon of, 11 Oculocraniosomatic neuromuscular
disease, 240–241, 240f, 241f Neurooncology. See Tumors, CNS disease, 554. See also
Neurofibrils Neuropathies Mitochondrial myopathies
degeneration of, 13, 14f amyloid, 517–518, 517f–519f Oculopharyngeal muscular dystrophy, 547
ultrastructure of, 13 antiganglioside, 511 Oligoastrocytomas
Neurofibromas, 431, 433 antiglycolipid, 511 differential diagnosis, 326–327, 326t
atypical, 435–436, 437f anti-HU antibody, 511, 511f immunohistochemical features, 326
cellular, 435–436, 437f anti-Hu antibody, 511, 511f microscopic features, 325–326, 326f
clinicopathologic distinctions, 427t antisulfatide, 511 Oligodendrocytes
localized and diffuse cutaneous, 433, with axon targets, 499t cytological inclusions, 18
434f diabetic, 512–514, 512f, 513f injury, reactions to, 18, 18f
localized intraneural, 433, 434f– genetic, 516–517, 516f, 517f Oligodendroglia, 246, 247f
436f hypertrophic, 514–516, 514f, 515f Oligodendrogliomas
plexiform, 433–434, 435f immune-mediated, 507–511, abnormal chromosomes in, 291t
Neurofibromatoses, 448 507f–510f anaplastic, 324–325, 325f
type 1, 448–450, 449f, 450f infectious, 518–521, 519f–521f, 520t classic form, 320–321
type 2, 450–451, 450f, 451f ischemic. See Ischemic neuropathy differential diagnosis, 284, 15.16Bcf
Neurofilaments, morphologic changes metabolic/endocrine, 511–514, 511t, genetic abnormalities in, 292
in, 13 512f, 513f grading, 324–325
Neurogliocytoma embryonaire, 384 “onion-bulb,” 514–516, 514f, 515f macroscopic features, 321
Neurolipoma, 388 paraneoplastic, 511, 511f microscopic features, 321–324,
Neuromas toxin-induced, 503–504, 504t, 504f 322f–324f
palisaded encapsulated, 444 traumatic, 521–522, 522f prognosis, 284–285
traumatic, 443–444, 443f, 521–522, vasculopathic. See Ischemic prognostic variables, 325
522f neuropathy treatment, 325
Neuromuscular choristoma, 444 Neuropathology Olivopontocerebellar atrophies, 233,
Neuromuscular diseases anatomic principles of, 2–3 233f
classification, 525, 526t–527t history of, 1–2 “Onion-bulb” neuropathies, 514–516,
clinical evaluation, 525, 528f morphologic techniques, 3–4. See also 514f, 515f
congenital myopathies, 537–542, specific morphologic techniques Ophthalmolegia plus, 554. See also
538f–542f Neuropil threads, 242, 241f, 298, 299f Mitochondrial myopathies
denervating, 569–571, 569f Neurosarcoidosis, 54–55, 55f Oppenheim’s amyotonia congenita, 537.
inflammatory myopathies, 559–566, Neurosyphilis, 55–57, 56f, 57f See also Congenital myopathies
562f–565f Neurothekeoma, 438
metabolic myopathies, 549–559, Neurotransmitters, in Alzheimer’s
550f–552f, 554f, 555f disease, 244 Pachygyria, 32, 32f
muscle biopsy. See Muscle biopsy Neurulation Palisaded encapsulated neuroma, 444
muscular dystrophies, 542–549, primary, 24–25 Papillary craniopharyngioma, 349–350,
544f–549f secondary, 25 350f
of neuromuscular junction, 566–569 Niemann-Pick disease, 197–198, 198f Papillomas, choroid plexus, 332–334,
Neuromyelitis optica, 486 Nissl granules, 201 333f
Neuronal and mixed neuronal-glial Nissl substance, 11, 13, 13f Paracoccidioidomycosis, 64
tumors Nitrosourea compounds, intoxication Paraffin embedding method, 4
gangliocytoma, 317 from, 188 Paraganglioma, 320, 320f, 321f
ganglioglioma, 316–317, 316f, 317f Nocardiosis, 58 Paragonimiasis, 68–69
WHO classification, 316 Non-hemorrhagic infarction, of spinal Paralytic rabies, 85
Neuronal ceroid-lipofuscinosis, 202–203 cord, 469 Paraneoplastic necrotizing myelopathy,
Haltia-Santavuori type, 203 Non-Hodgkin’s malignant lymphoma, 487, 487f
Jansky-Bielschowsky type, 203–204, 352–355, 353f–355f Paraneoplastic neuropathy, 511, 511f
203f, 204f Noninfectious vasculitis, 134 Parasitic infections
Kufs type, 204–205 Normal pressure hydrocephalus, 11 myopathies of, 560–561
Spielmeyer-Sjögren type, 204, 204f NORs (nucleolar organizer regions), 289 nematodal, 64–66
Neuronal differentiation, in pituitary Notch 3 mutations, 135 platyhelminth infections, 66–69, 66f,
adenomas, 414, 414f Nuclear internalization, in muscle injury, 67f
Neuronal satellitosis, in 534–535, 534t, 534f protozoal, 69–73, 69f–72f
oligodendroglioma, 324, 324f Nucleocapsid, 78 Parenchymal hemorrhage
Neuronal storage disorders, 13–14, 14f Nucleolar organizer regions (NORs), multiple, in leukemia, 359, 359f
Neuronophagia, 17, 17f 289 neonatal, 38
590 INDEX
Parenchymal metastases, 351–352, 351f, Pineal region tumors PML. See Progressive multifocal
352f types of, 359–365, 360f–365f leukoencephalopathy
Parkinson’s disease, 222, 226 WHO classification, 389–390, 390t PNCA (proliferating cell nuclear
Pathoklysis, 113 Pineoblastoma, 360–361, 361f, 388 antigen), 288, 288f, 290
PCR (polymerase chain reaction), 290, Pineocytoma, 359–360, 360f PNETs. See Primitive neuroectodermal
15.25cf Pituitary adenomas tumors
Pearly tumors, 345 ACTH-producing, 409–410, 409f, Pneumococcal meningitis, 48
Pelizaeus-Merzbacher disease, 261–262 410f Poisonings. See Intoxication
Penetrating trauma, to head, 142, 142f, atypical, 415 Poliovirus infection, 86, 86f
155–157, 156f, 157f classification of, 401–402, 401f Polyarteritis nodosa, 505–506, 505f,
Perinatal period clinicopathologic features, 403t–404t 506f, 561
brain injury in, 37–43, 39f–42f. See crush artifact, 400 Polyglucosan body disease, 551–552,
also specific perinatal brain development of, 397, 399, 399f 551f, 552f
injuries differential diagnosis, 415–416, Polyhydramnios, with anencephaly, 30
Perineuromas 418–419, 417t, 419f Polymerase chain reaction (PCR), 290,
intraneural, 436–437, 437f ectopic, 399 15.25cf
soft tissue, 437–438 electron microscopy, 402 Polymicrogyria, 32, 32f
Peripheral nerves glycoprotein-hormone producing, 411, Polymyositis, 562–563, 562f
myelin in, 246, 13.3cf 411f Polyneuropathy, acute inflammatory
regenerative capacity, 2–3 hemorrhagic necrosis of, 413–414, 413f demyelinating, 507–508, 507f,
tumorlike conditions, 443–444, 443f histologic classification of, 397, 399, 508f
tumors. See Peripheral nerve tumors 399t Polyol pathway, 514
Peripheral nerve tumors, 425 immunohistochemistry, 402, 401t Polyoma virus JC, 88–89
benign invasive, 414–415 Pons, development of, 26
ganglioneuroma, 439 with neuronal metaplasia, 414, 414f Pontine flexure, 25
granular cell tumor, 438–439 noninvasive, 414 Poorly differentiated neuroepithelial
nerve sheath myxoma, 438 peptide hormone-producing tumors. See Primitive
neurofibroma, 431, 433–436, 433t, GH cell, 402, 405–406, 405f, 406f neuroectodermal tumors
434f–437f mixed GH cell/PRL, 407–408, 407f Porencephaly, 41, 41f
neurothekeoma, 438 prolactin cell, 406–407, 406f, 407f Postangiography myelopathy, 482–483
non-neurogenic, 439 plurihormonal, 408–409, 409f Posterior spinal arterial network, 460,
perineuroma, 436–438, 437f prognostic factors, 415 460f
schwannomas. See Schwannomas surgical pathology, 399–400, 400f Posterior spinal artery, occlusion,
classification, 425, 426t symptomatic, 397 466–467
malignant, 426t, 439–443, 440f–442f unassociated with hormone Post-polio syndrome, 570
secondary involvement, 442–443 production, 411–413, 412f, 413f Preclinical Alzheimer’s disease, 244
Peripheral neuropathies, AIDS-related, Pituitary apoplexy, 413–414, 413f Pregnancy, anticonvulsant usage during,
101–102 Pituitary gland 186
Peripheral palasading, 306, 306f adenomas. See Pituitary adenomas Premature infants, germinal matrix
Periventricular-intraventricular anterior, cells in, 396 hemorrhage in, 39
hemorrhage, 38–39, 39f carcinoma, 415 Prenatal period, length of, 24
Periventricular leukomalacia, 40, 40f giant cell granuloma of, 418–419, Pressure palsies, hereditary neuropathy
Periventricular white matter, in multiple 419f with, 516, 516f
sclerosis, 247, 248f hyperplasia, 416, 418, 418f Primary diseases, 2
Phakomatosis, 448 inflammatory lesions, 418–419, 419f Primitive neuroectodermal tumors
Phenotypic markers, 277–278, 278f, morphology, normal, 396–397, 397f, (PNETs)
15.4cf 398t chromosomal abnormalities, 291t
Phenytoin intoxication, 185–186, 185f mucoid wedge, 396 classification, 268
Phosphofructokinase deficiency, 551 posterior lobe, 396–397 nosologic problem, 388–390, 389t
Phycomycosis (mucormycosis), 63, 64f Placental alkaline phosphatase (PLAP), Rorke, 389, 389t
Physaliphorous cells, 347, 347f 362 WHO, 389–390, 390t
Pick’s bodies, 14, 229, 229f Plantar neuroma, 444 cytogenetics, 388
Pick’s disease, 228–229, 228f, 229f Plaques, demyelinative, in multiple differential diagnosis, 384
Pilocytic astrocytomas, circumscribed, sclerosis, 247, 248f, 250 historical background, 384–386
310–313, 311f, 312f Plasma cell neoplasms, 356 medulloblastomas. See
Pilomyxoid astrocytomas, 313 Platyhelminth infection, 66–69, 66f, 67f Medulloblastomas
Pineal gland Pleomorphic xanthoastrocytoma (PXA), microscopic features, 386, 17.3cf,
cell types in, 359 313–314, 313f, 314f 17.4cf
development of, 359 Plexiform schwannomas, 430, 433f pathologic features, 386–388, 387f
interstitial cell tumors, 361–365, Pilocytic astrocytoma, diffuse, 309 peripheral, 442
361f–365f Ploidy, flow cytometry, 286–287, 286f Prion diseases
parenchymal cell tumors, 359–361, Plurihormonal adenomas, 408–409, Creutzfeldt-Jakob disease, 90–91, 91f
360f, 361f 409f fatal familial insomnia, 91–92
INDEX 591
Gerstmann-Sträussler-Scheinker Retinal hemorrhage, in infants/children, SEGAs (subependymal giant cell

disease, 91 170 astrocytomas), 314–315, 315f
kuru, 90, 90f Retinoblastoma, genetic abnormalities Segmental demyelination, 502, 503f
pathogenesis of, 89–90 in, 292 Selective vulnerability, 3, 113, 176
variant Creutzfeldt-Jakob disease, 91 Retrovirus infection, of central nervous Senile dementia with tangles, 229
Probst’s bundles, 32 system, 95 Senile plaques, in Alzheimer’s disease,
Proencephalon, histogenesis of, 26–27 Reversible ischemic neurologic deficits 241–242, 241f, 242f
Programmed cell death, 477. See also (RINDs), 122 Shaken baby syndrome, 168–169
Apoptosis, 12–13, 13f, 18 Rheumatoid disease, myelopathy in, Sheenan’s syndrome, 418
Progressive disseminated histoplasmosis, 481–482, 481f, 482f Silent corticotroph adenomas, 410
59, 60f Rhombencephalon Sinus histiocytosis associated with
Progressive multifocal development of, 24 massive lymphadenopathy,
leukoencephalopathy (PML) histogenesis of, 26 357–358, 358f
in AIDS, 106 Ribbon junctures, 330 Skeletal muscle
histopathology, 256–258, 257f, 258f Ricin communis agglutin (RCA), 280 histochemistry, 530–5310t
macroscopic features, 87–88, 89f Rigid spine syndrome, 542 normal morphology, 529–532, 530f,
microscopic features, 87–89, 89f RINDs (reversible ischemic neurologic 531f
Progressive supranuclear palsy (PSP), deficits), 122 Skull
232–233, 232f Rorke classification examination of, 143–144, 143f
Prolactin cell adenomas (prolactinomas), of embryonal tumors, 390, 392t fractures, 144
406–407, 406f, 407f of primitive neuroectodermal tumors, basilar, 144–145, 145f
Prolactin cell hyperplasia, 416 389, 389t childhood, 146
Proliferating cell nuclear antigen Rosai-Dorfman disease, 357–358, 358f comminuted, 145, 146f
(PNCA), 288, 288f, 290 Rotational shear force theory, 147–148 depressed, 145, 145f
Proliferation antigens, 288–289, 288f, Rye classification, 355 diastatic, 145–146, 146f
289f linear, 144, 144f
Proliferation index, 287 with subdural hemorrhage, 162
Prosencephalon, development of, 24 Saccular (berry) aneurysms, 128–130, of infants/children, 168–169
Protoplasmic astrocytoma, 309, 309f 129f SLC (subcortical leukoencephalopathy),
Protozoal diseases, 69–73, 69f–72f Sandhoff’s disease, 201–202 115, 115f
Psammoma bodies, 343 Sanfilippo’s syndrome, 206 SLE (systemic lupus erythematosus), 561
Psammomatous meningiomas, 337–338, Sarcoidosis, 54–55, 55f Slow virus diseases. See Prion diseases
338f Sarcoma Sly’s syndrome, 206–207
Pseudallescheria boydii, 64 historical background, 384 SMA (spinal muscular atrophy), 235,
Pseudolaminar necroses, 114 neurogenic, 439 571, 23.60cf
Pseudoprolactinomas, 407 Saturday night palsy, 522 Small cell glioblastoma, 308, 308f
Pseudosammoma bodies, 338, 339f Scalp Sneeden’s syndrome, 137
PSP (progressive supranuclear palsy), internal examination, 143, 143f Soft tissue perineuromas, 437–438
232–233, 232f lacerations of, 142, 142f Solitary plasmacytoma, 356
PXA (pleomorphic xanthoastrocytoma), Scheie’s syndrome, 205 Solvent intoxications, 188–189, 188f,
313–314, 313f, 314f Scherer, secondary structures of, 303, 189f
Pyruvate dehydrogenase, 556 304f, 305f, 305 Sphaeroblastoma polymorphon, 384
Schilder’s disease, 253–254 Spheroids, 231
Schistosomiasis, 68 Spielmeyer-Sjögren type of neuronal
Rabies, 84–85, 85f Schwannomas, 425–429 ceroid-lipofuscinosis, 204, 204f
“Raccoon eyes,” 141, 141f abnormal chromosomes in, 291t Spina bifida
Radiation therapy, for brain tumors, cellular, 429–430, 431f, 432t cystica, 30
270–271, 270f, 271f clinicopathologic distinctions, 427t occult, 30
Rathke’s cleft cyst, 419 dumbbell shape, 426, 427f open, 30, 30f
RB1 tumor suppresser gene, 292 gender and, 425 Spinal column diseases, myelopathy
RCA (Ricin communis agglutinin), 280 immunohistochemistry, 428 from, 479–482, 479f–482f
REAL classification of non-Hodgkin’s locations of, 425–427 Spinal cord
malignant lymphoma, 355 macroscopic features, 427–428, abnormalities, in occult spina bifida,
Reed-Sternberg cells, 355 428f 30
Refsum’s disease, 516 malignant. See Malignant peripheral arterial infarction
Remyelination, in multiple sclerosis, nerve sheath tumor aortic and/or primary branch
251–252, 251f, 252f melanotic, 430–431 injuries, 463–464, 464f
Reperfusion, 118 microscopic features, 428–429, 429f, embolic, 467, 468f
Respiratory brain, 114 430f extraspinal causes of, 462
Respiratory chain defects, in plexiform, 430, 433f intercostal, 464–465, 465f
mitochondrial myopathies, Schwannomatosis, 25 sudden systemic circulatory
556–558 Secondary diseases, 2 impairment and, 462–463, 462f,
Retinal angina, 344 Secretory meningioma, 338, 339f 463f
592 INDEX
Spinal cord (Continued) Status spongiosis, 243 hypertrophic neuropathies, 514–516,

territorial, 466–467, 466f, 467f Storiform perineurial fibroma, 437–438 514f, 515f
vertebral, 465–466 Stroke ischemic neuropathy, 504, 504f
arterial supply, 459–461, 460f in children/young adults, 120 polyarteritis nodosa, 505–506, 505f,
compression, 470–471, 471f, 476 definition of, 122 506f
damage hemorrhagic, 112 segmental demyelination, 502, 503f
in chronic adhesive spinal histologic abnormalities, 117 specimen
arachnoidopathy, 484–486, initial diagnosis, 112 staining for, 497
484f–486f ischemic, 112, 116 ultrastructure of, 497–499, 498f,
in necrotizing myelopathy, spinal, 120–121 499f
486–487, 487f terminology, 112 Survival motor neuron gene, 235
in spondylosis deformans, 479–481, Stromal cells, in hemangioblastoma, Synaptic dysplasia, 514
479f, 480f 344–345 Syncytial meningiomas, 337, 338t
demyelination, traumatic, 476–477, Strongyloidiasis, 65–66 Syringobulbia, 35
477f Sturge-Weber disease, 36–37, 36f Syringomyelia
histogenesis of, 25–26 Subacute necrotizing encephalopathy delayed post-traumatic, 477–479,
HIV-associated diseases, 100, 100t (Leigh’s disease), 195 478f
ischemic injuries, 120–121 Subacute sclerosing panencephalitis secondary, 35
in multiple sclerosis, 248, 249f (SSPE), 87, 88f Systemic connective tissue disease and
neurodegenerative diseases of, Subaponeurotic hemorrhage, 37 vasculitis, 561–562
234–235, 234f Subarachnoid hemorrhage Systemic lupus erythematosus (SLE), 561
traumatic injuries complications of, 130, 130f Systemic sensorimotor polyneuropathy,
anatomic features and, 473–474 in infants/children, 170–171 in diabetes, 512, 512f
nonpenetrating, 474, 475–479, neonatal, 38
477f, 478f from traumatic head injury, 164–165,
penetrating, 474–475 164f Tabes dorsalis, 56–57, 57f
tumors, 268. See also specific tumors intracerebral, 165–166, 166f Tangles, senile dementia with, 229
venous drainage intraventricular, 165 Tanycytes, 327
abnormal, 470 Subcortical leukoencephalopathy Tauopathies, 226–230, 228f, 229f
normal, 461–462, 461f (Binswanger’s disease), 115, 115f, Tau protein, 226–227, 240–241
venous infarction, 467–468, 469f, 128 Tay-Sachs disease, 200–201, 201f
467–468 Subdural abscesses, 51 Telencephalic periventricular
in decompression sickness, 468–469 Subdural hemorrhage leukomalacia, 40
nonocclusive impairment of in infants/children, 170 Telencephalon, development of, 26–27
outflow, 469–471, 470f, 471f neonatal, causes of, 37–38 Temporal arteritis, 134–135, 135f
vascular malformations and, from traumatic head injury, 161–164, Teratoma, 364–365, 365f, 384
471–472, 472f, 473f 162f, 163f Thallium intoxication, 191–192
Spinal muscular atrophy (SMA), 571, acute, 161–162, 162f, 163f Thiamine deficiency, 192–194, 192f, 193f
23.60cf, 235 age of, 163–164 Third ventricle, colloid cyst of, 334–335
Spinal vascular disease chronic, 163 Thrombosis
anatomical considerations, 459–462, mortality rates, 161 acute aortic, 464
460f, 461f subacute, 161, 163 venous spinal cord infarction, 468,
arterial infarction of spinal cord. See unilateral vs. bilateral, 161–162, 469f
Spinal cord, arterial infarction 162f Thymidine analogs, 287–288, 287f
Spingolipidoses, 197 Subependymal giant cell astrocytomas Thyrotroph cell adenomas, 411
Spirochetal infections, 55–57, 56f, 57f (SEGAs), 314–315, 315f Thyrotroph cell hyperplasia, 418
Spondylosis deformans, 479–481, 479f, Subependymoma, 331–332, 332f TIAs (transient ischemic attacks), 122,
480f Sudanophilic droplets, in neonatal brain, 136
Spongiform vacuolization, in dementia 27–28 Toluene intoxication, 189
with Lewy bodies, 225, 225f Sudanophilic leukodystrophy, 262 Toxic metal intoxications, 189–192,
Spongioblastoma, 384 Sulci, 27 189f, 190f
Spongioblastoma cerebelli, 384 Sulfatase deficiencies, with Toxin-induced neuropathies, 503–504,
Spongioblastoma multiforme, 384 metachromatic leukodystrophy, 504t, 504f
Sporotrichosis, 64 209–210 Toxoplasma gondii, 102–104
SSPE (subacute sclerosing Sural nerve biopsy Toxoplasmosis
panencephalitis), 87, 88f amyloid neuropathy, 517–518, acquired, 69–70, 70f
St. Louis encephalitis, 81 517f–519f in AIDS, 102–104, 104f, 105f
Stab wounds axonal degeneration, 499–502, congenital, 69, 69f
to head, 142, 157, 158f 500f–502f of skeletal muscle, 560
to spinal cord, 474–475 diabetic neuropathies, 512, 512f, 513f Transient arterial occlusions, 116, 117
Stains, immunohistochemical Guillain-Barré syndrome, classic Transient ischemic attacks (TIAs), 122,
for brain biopsy specimens, 272, 274t demyelinative, 507–508, 507f, 508f 136
diagnostic, 4, 5t–6t hereditary neuropathy with pressure Transitional cells, in oligodendroglioma,
Status marmoratus, 41, 41f palsies, 516, 516f 322
INDEX 593
Transmissible spongiform etiology, 269 mumps, 86–87

encephalopathies. See Prion genetic markers, 290–292, 290f, 291f, myeloradiculitis, 86
diseases 291t poliovirus, 86, 86f
Transverse myelopathy, 121 incidence of, 267–268 rabies, 84–85, 85f
Trauma location of, 267 varicella-zoster, 83–84
blunt, to head, 140–142, 141f, 142f non-glial, meningiomas. See West nile virus, 81, 82
brain damage from. See Brain injuries, Meningiomas chronic and subacute, 87–89, 88f, 89f
traumatic pineal region, 359–365, 360f–365f classification of, 78–79
to head. See Head injuries prevalence of, 267–268 diagnosis, 78
intervertebral disc, 481 primary, 267 histologic landmarks of, 81t
neuropathies, 521–522, 522f incidence of, 268 transmission of, 79
penetrating, to head, 142, 142f location of, 267 Viral myositis, 559–560
to spinal cord prognostic factors, 269 Viruses, neurotrophic. See also Viral
anatomic features and, 473–474 proliferative capacity measures, infections
nonpenetrating, 474, 475–479, 285–290, 286f–289f California group, 81
477f, 478f secondary, 267 categories of, 78–79, 79t
penetrating, 474–475 incidence of, 267–268 flaviviruses, 81–82, 81t
Treponema pallidum, 55–56 measles, 87
Trichinella spiralis, 65 structure of, 78
Trichinosis, 65, 560 Ulegyria, 41, 41f tropism, 95
Trichloroethylene intoxications, 189 Upper limb mononeuropathy, diabetic, Visceral larva migrans, 65
Truncal radiculopathy, diabetic, 512, 512, 513f Vitamin deficiencies, 192–197,
513f Uremia, neuropathy of, 514 193f–197f. See also specific
Trypanosomiasis, 72–73 vitamin deficiencies
Tuberculomas, 53, 54 B12, 195–196
Tuberculosis Vacuolar changes, in muscle injury, 536, E, 196, 197f
histologic examination, 52 536t neuropathy of, 514
pathogens, 52 Vacuolar myelopathy, HIV-associated, VLCFA (very long-chain fatty acids), 261
pathology, gross, 52, 53f 100–101, 100f, 101f, 101t Von Hippel-Lindau disease, 344,
prevalence of, 51–52 Vanishing white matter disease, 262 451–452, 452f
vascular complications, 52, 54f Variant Creutzfeldt-Jakob disease
Tuberous sclerosis complex (TSC), (vCJD), 91
452–454, 453f, 454f Varicella-zoster virus infections, 83–84, Walker-Warburg syndrome, 542
Tubulin, in neurofibrils, 13 105–106, 106f Wallerian degeneration (axonal
Tumorlette, pituitary, 399 Vascular malformations, 131–134, 132f, degeneration), 125, 497–499,
Tumor necrosis factor, in multiple 133f 500f–502f
sclerosis, 251 Vasculitis Waterhouse-Friderichsen syndrome, 49
Tumors, CNS. See also Brain tumors; infectious, 134 Watersheds, 113
specific types of noninfectious, 134 Wernicke-Korsakoff syndrome,
adjuvant therapy, 269–271, 270f, Vasculopathic neuropathy. See Ischemic 192–194, 192f, 193f
271f neuropathy Western equine encephalitis, 81
cell-type-specific markers, 272 Vasospasm, from subarachnoid West Nile virus, 81, 82
decisive, 278 hemorrhage, 130 Weston-Hurst disease (acute
in diagnosis, 284–285 vCJD (variant Creutzfeldt-Jakob hemorrhagic leukoencephalitis),
electron microscopy, 275–276 disease), 91 256, 256f
histochemistry methods for, 275 Venezuelan equine encephalitis (VEE), Whipple’s disease, 55, 56f
immunohistochemistry methods for, 81 WHO classification
276–278, 280–284, 276f–284f, Venous angiomas, 133–134 of non-Hodgkin’s malignant
15.11cf Venous infarcts, 120, 120t, 124, 124f lymphoma, 355
monoclonal neoplastic proliferation, Vertebral arterial infarction, 465–466 oligodendroglioma grading, 324–325
281–282, 283f, 284f Very long-chain fatty acids (VLCFA), of pituitary adenomas, 401, 402, 401f
of neoplastic tissue features, 261 of primitive neuroectodermal tumors,
280–281, 283f, 15.11cf Vincristine intoxication, 187–188, 188f 389–390, 390t
prognosis and, 284–285, 285f Viral infections Wiskott-Aldrich syndrome, 353
supplemental, 280 acute, 79–87, 81t
in treatment, 284–285 arbovirus encephalitis, 80–81
characteristics, distinctive, 267 aseptic meningitis, 79–80 Yolk sac tumor, 363–364, 364f
differential diagnosis, 275t California group-related, 81
embryonal coxsackievirus, 86
atypical teratoid/rhaboid, 390–392, cytomegalovirus, 83, 84f Z bands, 531, 531f
392f echovirus, 86 Zebra bodies, in Hurler’s disease, 205,
medulloepithelioma, 383–384 encephalitis, 80 205f
primitive neuroectodermal. See flavivirus-related, 81–82, 81t Zidovudine (AZT), 102
Primitive neuroectodermal tumors herpesvirus encephalitis, 82–83, 83f Z lines, 531–532

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Principles and Practice

JAMES S.NELSON, M.D. et al.,

OXFORD UNIVERSITY PRESS

JAMES S. NELSON, M.D.

Copyright © 2003 by Oxford University Press, Inc.

Oxford is a registered trademark of Oxford University Press

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Library of Congress Cataloging-in-Publication Data

18. Pituitary Tumors and Related Lesions, 396

STEVEN C. BAUSERMAN, M.D. RONALD C. KIM, M.D.

CAROL K. PETITO, M.D.

SUZANNE Z. POWELL, M.D.

LUCY B. RORKE, M.D.

ELISABETH J. RUSHING, M.D.

BERND W. SCHEITHAUER, M.D.

ROBERT E. SCHMIDT, M.D., Ph.D.

SYDNEY S. SCHOCHET, JR., M.D.

EVOLUTION OF NEUROPATHOLOGY Riggs, were certified (Abell, 1988, personal communica-

A-beta amyloid Formalin Paraffin Immunostain Amyloid, senile plaque

TABLE 1.1 Common Neuropathology Stains (continued)

Source: Bancroft and Stevens (1996) and Carson (1997).

by successful treatment. These abnormalities, however,

cerebellar displacement is commonly referred to as ton-

FIGURE 1.6 Ventral cerebellar herniation (tonsils and biventral lob-

Nerve cell death ures should be viewed as approximations rather than

FIGURE 1.8 Eosinophilic neuronal necrosis. Slightly shrunken neurons

difficulty in distinguishing apoptosis from other simi-

ments belong to the family of intermediate filaments.

FIGURE 1.12 Neuronal storage disorder (gangliosidosis). The cell bod-

The microglia respond to a variety of neuro-

Oligodendroglial cytoplasmic inclusions have been

FIGURE 2.2 Same case as in Figure 2.1. Contrast-enhanced CT shows

less than 45 milliseconds are T1-weighted; scans with

the blood–brain barrier (Fig. 2.3). The contrast agent

FIGURE 2.4 Same case as in Figure 2.3. T2-weighted, nonenhanced REFERENCES

TERMINOLOGY, CONVENTIONS, AND DEFINITIONS length or biparietal diameter directly or by ultra-

terior horns. During the second and third months of Mesencephalon

absent or reduced fetal zone. Abnormalities of other

Heteropias and ectopias. Collections of neurons and

Lissencephaly, agyria/pachygyria, and polymicro-

sis, forking, and septum formation) were regarded as

FIGURE 3.7 Hydrocephalus. Marked dilatation of the lateral ventri-

hydromyelia (distension of the central canal of the

clude growth retardation, dysmorphic cranial or facial

Syringomyelia Down Syndrome

Fetal Alcohol Syndrome

FIGURE 3.15 Sturge-Weber disease. Cerebral cortical resection. Ex-

Cephalhematoma. This hemorrhage is beneath the

escape without lasting neurologic complications. Fur-

gional accentuation of the necrotic lesions are not

ability of the blood–brain barrier resulting from endo- Porencephaly

BACTERIAL INFECTIONS brospinal fluid (CSF) dynamics. When the meningitis

Purulent Leptomeningitis Neonatal Meningitis

mortality rate (Laavetter et al., 1971; Bell and Mc-

The gross features of meningitis in neonates are simi-

A rial infection are due to atypical mycobacteria (espe-

FIGURE 4.5 (A) Tuberculosis (MRI). T1-weighted coronal MR image

volvement usually starts in the ulnar nerve at the el-

A jacent neural parenchyma, particularly the hypothala-

frontal and temporal lobes (Fig. 4.9). Striatal atrophy

sought. Borrelia organisms have been recovered after

flora. A wide variety of conditions promote invasion Histoplasmosis

FIGURE 4.15 (A) Coccidioidomycosis meningitis (MRI). T1-weighted