Beruflich Dokumente
Kultur Dokumente
HARRISONS
TM
NEUROLOGY
IN CLINICAL
MEDICINE
Derived from Harrisons Principles of Internal Medicine, 18th Edition
Editors
DAN L. LONGO, MD ANTHONY S. FAUCI, MD
Professor of Medicine, Harvard Medical School; Chief, Laboratory of Immunoregulation;
Senior Physician, Brigham and Womens Hospital; Director, National Institute of Allergy and Infectious Diseases,
Deputy Editor, New England Journal of Medicine, National Institutes of Health,
Boston, Massachusetts Bethesda, Maryland
HARRISONS
TM
NEUROLOGY
IN CLINICAL
MEDICINE
EDITOR
Stephen L. Hauser, MD
Robert A. Fishman Distinguished
Professor and Chairman, Department of Neurology,
University of California, San Francisco, San Francisco, California
ASSOCIATE EDITOR
S. Andrew Josephson, MD
Associate Professor of Clinical Neurology
C. Castro-Franceschi and G. Mitchell Endowed Neurohospitalist Chair
Vice-Chairman, Parnassus Programs
University of California, San Francisco, San Francisco, California
New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto
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CONTENTS
29 Alzheimers Disease and Other Dementias . . . . 310 46 Guillain-Barr Syndrome and Other
William W. Seeley, Bruce L. Miller Immune-Mediated Neuropathies . . . . . . . . . . . 599
Stephen L. Hauser, Anthony A. Amato
30 Parkinsons Disease and Other Extrapyramidal
Movement Disorders . . . . . . . . . . . . . . . . . . . . 333 47 Myasthenia Gravis and Other Diseases of
C. Warren Olanow, Anthony H. V. Schapira the Neuromuscular Junction . . . . . . . . . . . . . . 609
Daniel B. Drachman
31 Ataxic Disorders . . . . . . . . . . . . . . . . . . . . . . . 357
Roger N. Rosenberg 48 Muscular Dystrophies and Other
Muscle Diseases . . . . . . . . . . . . . . . . . . . . . . . . 618
32 Amyotrophic Lateral Sclerosis and Other Motor Anthony A. Amato, Robert H. Brown, Jr.
Neuron Diseases . . . . . . . . . . . . . . . . . . . . . . . 370
Robert H. Brown, Jr. 49 Polymyositis, Dermatomyositis, and Inclusion
Body Myositis . . . . . . . . . . . . . . . . . . . . . . . . . 648
33 Disorders of the Autonomic Nervous System . . . . 380 Marinos C. Dalakas
Phillip A. Low, John W. Engstrom
50 Special Issues in Inpatient Neurologic
34 Trigeminal Neuralgia, Bells Palsy, and Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . 660
Other Cranial Nerve Disorders . . . . . . . . . . . . 392 S. Andrew Josephson, Martin A. Samuels
M. Flint Beal, Stephen L. Hauser
51 Atlas of Neuroimaging . . . . . . . . . . . . . . . . . . . 668
35 Diseases of the Spinal Cord . . . . . . . . . . . . . . . 400 Andre Furtado, William P. Dillon
Stephen L. Hauser, Allan H. Ropper
SECTION IV
36 Concussion and Other Head Injuries . . . . . . . . 415
CHRONIC FATIGUE SYNDROME
Allan H. Ropper
52 Chronic Fatigue Syndrome . . . . . . . . . . . . . . . 704
37 Primary and Metastatic Tumors of the Nervous
Gijs Bleijenberg, Jos W. M. van der Meer
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Lisa M. DeAngelis, Patrick Y. Wen
SECTION V
38 Neurologic Disorders of the Pituitary and PSYCHIATRIC DISORDERS
Hypothalamus . . . . . . . . . . . . . . . . . . . . . . . . . 439
Shlomo Melmed, J. Larry Jameson 53 Biology of Psychiatric Disorders . . . . . . . . . . . . 710
Robert O. Messing, John H. Rubenstein, Eric J. Nestler
39 Multiple Sclerosis and Other Demyelinating
Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474 54 Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . 720
Stephen L. Hauser, Douglas S. Goodin Victor I. Reus
Eric J. Nestler, MD, PhD Martin A. Samuels, MD, DSc(hon), FAAN, MACP, FRCP
Nash Family Professor and Chair, Department of Neuroscience; Di- Professor of Neurology, Harvard Medical School; Chairman, De-
rector, Friedman Brain Institute, Mount Sinai School of Medicine, partment of Neurology, Brigham and Womens Hospital, Boston,
New York, New York [53] Massachusetts [3, 50]
Jennifer Ogar, MS Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci
Speech Pathologist, Memory and Aging Center, University of University Department of Clinical Neurosciences, University
California, San Francisco, San Francisco, California; Acting Chief of College London; National Hospital for Neurology and Neurosur-
Speech Pathology at the Department of Veterans Affairs, Martinez, gery, Queens Square, London, United Kingdom [30]
California [19]
Marc A. Schuckit, MD
C. Warren Olanow, MD, FRCPC Distinguished Professor of Psychiatry, University of California, San
Department of Neurology and Neuroscience, Mount Sinai School Diego School of Medicine, La Jolla, California [56]
of Medicine, New York, New York [30]
William W. Seeley, MD
Michael A. Pesce, PhD Associate Professor of Neurology, Memory and Aging Center,
Professor Emeritus of Pathology and Cell Biology, Columbia Uni- University of California, San Francisco, San Francisco, California [29]
versity College of Physicians and Surgeons; Columbia University
Medical Center, New York, New York [Appendix] Wade S. Smith, MD, PhD
Professor of Neurology, Daryl R. Gress Endowed Chair of Neu-
Stanley B. Prusiner, MD rocritical Care and Stroke; Director, University of California, San
Director, Institute for Neurodegenerative Diseases; Professor, De- Francisco Neurovascular Service, San Francisco, San Francisco,
partment of Neurology, University of California, San Francisco, San California [27, 28]
Francisco, California [43]
Lewis Sudarsky, MD
Gil Rabinovici, MD
Associate Professor of Neurology, Harvard Medical School; Director
Attending Neurologist, Memory and Aging Center, University of
of Movement Disorders, Brigham and Womens Hospital, Boston,
California, San Francisco, San Francisco, California [19]
Massachusetts [13]
Neil H. Raskin, MD Morton N. Swartz, MD
Department of Neurology, University of California, San Francisco, Professor of Medicine, Harvard Medical School; Chief, Jackson
San Francisco, San Francisco, California [8] Firm Medical Service and Infectious Disease Unit, Massachusetts
James P. Rathmell, MD General Hospital, Boston, Massachusetts [41]
Associate Professor of Anesthesia, Harvard Medical School; Chief, Maria Carmela Tartaglia, MD, FRCPC
Division of Pain Medicine, Massachusetts General Hospital, Boston, Clinical Instructor of Neurology, Memory and Aging Center, Uni-
Massachusetts [7] versity of California, San Francisco, San Francisco, California [19]
Victor I. Reus, MD, DFAPA, FACP Kenneth L. Tyler, MD
Department of Psychiatry, University of California, San Francisco Reuler-Lewin Family Professor and Chair, Department of Neurol-
School of Medicine; Langley Porter Neuropsychiatric Institute, San ogy; Professor of Medicine and Microbiology, University of Colo-
Francisco, San Francisco, California [54] rado School of Medicine, Denver, Colorado; Chief of Neurology,
Gary S. Richardson, MD University of Colorado Hospital, Aurora, Colorado [40]
Senior Research Scientist and Staff Physician, Henry Ford Hospital, Jos W. M. van der Meer, MD, PhD
Detroit, Michigan [20] Professor of Medicine; Head, Department of General Internal Medi-
cine, Radboud University, Nijmegen Medical Centre, Nijmegen,
Elizabeth Robbins, MD
Netherlands [52]
Clinical Professor of Pediatrics, University of California,
San Francisco, San Francisco, California [6] Mark F. Walker, MD
Associate Professor, Department of Neurology, Case Western
Karen L. Roos, MD Reserve University School of Medicine; Daroff-Dell Osso Ocular
John and Nancy Nelson Professor of Neurology and Professor of Motility Laboratory, Louis Stokes Cleveland Department of Veter-
Neurological Surgery, Indiana University School of Medicine, ans Affairs Medical Center, Cleveland, Ohio [11]
Indianapolis, Indiana [40]
Patrick Y. Wen, MD
Allan H. Ropper, MD Professor of Neurology, Harvard Medical School; Dana-Farber Can-
Professor of Neurology, Harvard Medical School; Executive Vice cer Institute, Boston, Massachusetts [37]
Chair of Neurology, Raymond D. Adams Distinguished Clinician,
Brigham and Womens Hospital, Boston, Massachusetts [17, 35, 36] Charles M. Wiener, MD
Dean/CEO Perdana University Graduate School of Medicine,
Roger N. Rosenberg, MD Selangor, Malaysia; Professor of Medicine and Physiology,
Zale Distinguished Chair and Professor of Neurology, Department Johns Hopkins University School of Medicine, Baltimore, Maryland
of Neurology, University of Texas Southwestern Medical Center, [Review and Self-Assessment]
Dallas, Texas [31]
John W. Winkelman, MD, PhD
Myrna R. Rosenfeld, MD, PhD Associate Professor of Psychiatry, Harvard Medical School; Medical
Professor of Neurology and Chief, Division of Neuro-oncology, Director, Sleep Health Centers, Brigham and Womens Hospital,
University of Pennsylvania, Philadelphia, Pennsylvania [44] Boston, Massachusetts [20]
John H. Rubenstein, MD, PhD Shirley H. Wray, MB, ChB, PhD, FRCP
Nina Ireland Distinguished Professor in Child Psychiatry, Center for Professor of Neurology, Harvard Medical School; Department of
Neurobiology and Psychiatry, Department of Psychiatry, University Neurology, Massachusetts General Hospital, Boston, Massachusetts
of California, San Francisco, San Francisco, California [53] [22]
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PREFACE
The rst two editions of Harrisons Neurology in Clinical development of independent neurology services, depart-
Medicine were unqualied successes. Readers responded ments, and training programs at many medical centers,
enthusiastically to the convenient, attractive, expanded, reducing the exposure of trainees in internal medicine to
and updated stand-alone volume, which was based neurologic problems. All of these forces, acting within
upon the neurology and psychiatry sections from Harri- the fast paced environment of modern medical practice,
sons Principles of Internal Medicine. Our original goal was can lead to an overreliance on unfocused neuroimaging
to provide, in an easy-to-use format, full coverage of tests, suboptimal patient care, and unfortunate outcomes.
the most authoritative information available anywhere Because neurologists represent less than 1% of all physi-
of clinically important topics in neurology and psychia- cians, the vast majority of neurologic care must be de-
try, while retaining the focus on pathophysiology and livered by nonspecialists who are often generalists and
therapy that has always been characteristic of Harrisons. usually internists.
This new third edition of Harrisons Neurology in Clinical The old adage that neurologists know everything but
Medicine has been extensively updated to highlight recent do nothing has been rendered obsolete by advances in
advances in the understanding, diagnosis, treatment, and molecular medicine, imaging, bioengineering, and clinical
prevention of neurologic and psychiatric diseases. New research. Examples of new therapies include: thrombolytic
chapters discuss the pathogenesis and treatment of syn- therapy for acute ischemic stroke; endovascular recanaliza-
cope, dizziness and vertigo, smell and taste disorders, Par- tion for cerebrovascular disorders; intensive monitoring of
kinsons disease, tumors of the nervous system, peripheral brain pressure and cerebral blood ow for brain injury;
neuropathy, and neuropsychiatric problems among war effective therapies for immune-mediated neurologic dis-
veterans, among other topics. Extensively updated cover- orders; new designer drugs for migraine; the rst genera-
age of the dementias highlights new ndings from genet- tion of rational therapies for neurodegenerative diseases;
ics, molecular imaging, cell biology, and clinical research neural stimulators for Parkinsons disease; drugs for narco-
that are transforming our understanding of these common lepsy and other sleep disorders; and control of epilepsy by
problems. Neuroimmunology is another dynamic and surgical resection of small seizure foci precisely localized
rapidly changing eld of neurology, and the new edition by functional imaging and electrophysiology. The pipeline
of Harrisons provides extensive coverage of progress in continues to grow, stimulated by a quickening tempo of
this area, including a practical guide to navigating the large discoveries generating opportunities for rational design of
number of treatment options now available for multiple new diagnostics, interventions, and drugs.
sclerosis. Another new chapter reviews advances in deci- The founding editors of Harrisons Principles of Inter-
phering the pathogenesis of common psychiatric disorders nal Medicine acknowledged the importance of neurology
and discusses challenges to the development of more ef- but were uncertain as to its proper role in a textbook of
fective treatments. Many illustrative neuroimaging gures internal medicine. An initial plan to exclude neurology
appear throughout the section, and an updated and ex- from the rst edition (1950) was reversed at the eleventh
panded atlas of neuroimaging ndings is also included. We hour, and a neurology section was hastily prepared by
are extremely pleased that readers of the new edition of Houston Merritt. By the second edition, the section was
Harrisons will for the rst time be able to access a remark- considerably enlarged by Raymond D. Adams, whose
able series of high-denition video presentations including inuence on the textbook was profound. The third
wonderful guides to screening and detailed neurological neurology editor, Joseph B. Martin, brilliantly led the
examinations, as well as video libraries illustrating gait dis- book during the 1980s and 1990s as neurology was trans-
orders, focal cerebral disorders, and neuro-ophthalmologic formed from a largely descriptive discipline to one of the
disturbances. most dynamic and rapidly evolving areas of medicine.
For many physicians, neurologic diseases represent With these changes, the growth of neurology coverage
particularly challenging problems. Acquisition of the req- in Harrisons became so pronounced that Harrison sug-
uisite clinical skills is often viewed as time-consuming, gested the book be retitled, The Details of Neurology and
difcult to master, and requiring a working knowledge Some Principles of Internal Medicine. His humorous com-
of obscure anatomic facts and laundry lists of diagnostic ment, now legendary, underscores the depth of coverage
possibilities. The patients themselves may be difcult, as of neurologic medicine in Harrisons betting its critical
neurologic disorders often alter an individuals capacity role in the practice of internal medicine.
to recount the history of an illness or to even recognize The Editors are indebted to our authors, a group
that something is wrong. An additional obstacle is the of internationally recognized authorities who have
xiii
xiv Preface
magnicently distilled a daunting body of information the Internet to nd facts, but that he reads Harrisons
into the essential principles required to understand and to learn medicine. Our aim has always been to pro-
manage commonly encountered neurologic problems. vide the reader with an integrated, organic summary
Thanks also to Dr. Elizabeth Robbins who has served for of the science and the practice of medicine rather than
more than 15 years as managing editor of the neurology a mere compendium of chapters, and we are delighted
section of Harrisons; she has overseen the complex logis- and humbled by the continuing and quite remarkable
tics required to produce a multiauthored textbook, and growth in popularity of Harrisons at a time when many
has promoted exceptional standards for clarity, language, classics in medicine seem less relevant than in years
and style. Finally, we wish to acknowledge and express past. We are of course cognizant of the exibility in in-
our great appreciation to our colleagues at McGraw-Hill. formation delivery that todays readers seek, and so we
This new volume was championed by James Shanahan have also made the third edition of Harrisons Neurology
and impeccably managed by Kim Davis. in Clinical Medicine available in a number of eBook for-
We live in an electronic, wireless age. Information mats for all major devices, including the iPad (available
is downloaded rather than pulled from the shelf. Some via the iBookstore).
have questioned the value of traditional books in this It is our sincere hope that you will enjoy using Har-
new era. We believe that as the volume of information, risons Neurology in Clinical Medicine, Third Edition, as an
and the ways to access this information, continues to authoritative source for the most up-to-date information
grow, the need to grasp the essential concepts of medi- in clinical neurology.
cal practice becomes even more challenging. One of
our young colleagues recently remarked that he uses Stephen L. Hauser, MD
NOTICE
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in treatment and drug therapy are re-
quired. The authors and the publisher of this work have checked with sources
believed to be reliable in their efforts to provide information that is complete
and generally in accord with the standards accepted at the time of publication.
However, in view of the possibility of human error or changes in medical sci-
ences, neither the authors nor the publisher nor any other party who has been
involved in the preparation or publication of this work warrants that the in-
formation contained herein is in every respect accurate or complete, and they
disclaim all responsibility for any errors or omissions or for the results obtained
from use of the information contained in this work. Readers are encouraged
to conrm the information contained herein with other sources. For example
and in particular, readers are advised to check the product information sheet
included in the package of each drug they plan to administer to be certain that
the information contained in this work is accurate and that changes have not
been made in the recommended dose or in the contraindications for adminis-
tration. This recommendation is of particular importance in connection with
new or infrequently used drugs.
Review and self-assessment questions and answers were taken from Wiener CM,
Brown CD, Hemnes AR (eds). Harrisons Self-Assessment and Board Review, 18th ed.
New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5.
The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine
throughout the world.
The genetic icons identify a clinical issue with an explicit genetic relationship.
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SECTION I
INTRODUCTION TO
NEUROLOGY
CHAPTER 1
2
diplopia, and nystagmus should not trigger multiple features? Does the patient have difculty with brushing 3
sclerosis as an answer (etiology) but brainstem or hair or reaching upward (proximal) or buttoning but-
pons (location); then a diagnosis of brainstem arte- tons or opening a twist-top bottle (distal)? Negative
CHAPTER 1
riovenous malformation will not be missed for lack of associations may also be crucial. A patient with a right
consideration. Similarly, the combination of optic neu- hemiparesis without a language decit likely has a lesion
ritis and spastic ataxic paraparesis should initially suggest (internal capsule, brainstem, or spinal cord) different
optic nerve and spinal cord disease; multiple sclerosis from that of a patient with a right hemiparesis and apha-
(MS), CNS syphilis, and vitamin B12 deciency are treat- sia (left hemisphere). Other pertinent features of the
able disorders that can produce this syndrome. Once the history include the following:
helpful to obtain additional information from family, neoplastic drugs can cause peripheral neuropathy, and
friends, or other observers to corroborate or expand immunosuppressive agents such as cyclosporine can
the patients description. Memory loss, aphasia, loss produce encephalopathy. Excessive vitamin inges-
of insight, intoxication, and other factors may impair tion can lead to disease; for example vitamin A and
the patients capacity to communicate normally with pseudotumor cerebri, or pyridoxine and peripheral
the examiner or prevent openness about factors that neuropathy. Many patients are unaware that over-
Introduction to Neurology
have contributed to the illness. Episodes of loss of the-counter sleeping pills, cold preparations, and
consciousness necessitate that details be sought from diet pills are actually drugs. Alcohol, the most prev-
observers to ascertain precisely what has happened alent neurotoxin, is often not recognized as such by
during the event. patients, and other drugs of abuse such as cocaine
4. Family history. Many neurologic disorders have an and heroin can cause a wide range of neurologic
underlying genetic component. The presence of a abnormalities. A history of environmental or industrial
Mendelian disorder, such as Huntingtons disease or exposure to neurotoxins may provide an essential
Charcot-Marie-Tooth neuropathy, is often obvious clue; consultation with the patients coworkers or
if family data are available. More detailed questions employer may be required.
about family history are often necessary in polygenic 7. Formulating an impression of the patient. Use the
disorders such as MS, migraine, and many types of opportunity while taking the history to form an
epilepsy. It is important to elicit family history about impression of the patient. Is the information forth-
all illnesses, in addition to neurologic and psychiatric coming, or does it take a circuitous course? Is there
disorders. A familial propensity to hypertension or evidence of anxiety, depression, or hypochondriasis?
heart disease is relevant in a patient who presents Are there any clues to defects in language, memory,
with a stroke. There are numerous inherited neu- insight, or inappropriate behavior? The neurologic
rologic diseases that are associated with multisystem assessment begins as soon as the patient comes into
manifestations that may provide clues to the correct the room and the rst introduction is made.
diagnosis (e.g., neurobromatosis, Wilsons disease,
neuro-ophthalmic syndromes).
5. Medical illnesses. Many neurologic diseases occur in
the context of systemic disorders. Diabetes mellitus, THE NEUROLOGIC EXAMINATION
hypertension, and abnormalities of blood lipids pre-
dispose to cerebrovascular disease. A solitary mass The neurologic examination is challenging and complex;
lesion in the brain may be an abscess in a patient it has many components and includes a number of skills
with valvular heart disease, a primary hemorrhage in that can be mastered only through repeated use of the
a patient with a coagulopathy, a lymphoma or toxo- same techniques on a large number of individuals with
plasmosis in a patient with AIDS, or a metastasis in a and without neurologic disease. Mastery of the com-
patient with underlying cancer. Patients with malig- plete neurologic examination is usually important only
nancy may also present with a neurologic paraneo- for physicians in neurology and associated specialties.
plastic syndrome (Chap. 44) or complications from However, knowledge of the basics of the examina-
chemotherapy or radiotherapy. Marfans syndrome tion, especially those components that are effective in
and related collagen disorders predispose to dissection screening for neurologic dysfunction, is essential for all
of the cranial arteries and aneurysmal subarachnoid clinicians, especially generalists.
hemorrhage; the latter may also occur with polycystic There is no single, universally accepted sequence of
kidney disease. Various neurologic disorders occur the examination that must be followed, but most clini-
with dysthyroid states or other endocrinopathies. It is cians begin with assessment of mental status followed by
especially important to look for the presence of sys- the cranial nerves, motor system, sensory system, coor-
temic diseases in patients with peripheral neuropathy. dination, and gait. Whether the examination is basic or
Most patients with coma in a hospital setting have a comprehensive, it is essential that it be performed in
metabolic, toxic, or infectious cause. an orderly and systematic fashion to avoid errors and
6. Drug use and abuse and toxin exposure. It is essential to serious omissions. Thus, the best way to learn and gain
inquire about the history of drug use, both prescribed expertise in the examination is to choose ones own
and illicit. Sedatives, antidepressants, and other psy- approach and practice it frequently and do it in the
choactive medications are frequently associated with same exact sequence each time.
acute confusional states in the elderly. Aminoglycoside The detailed description of the neurologic examina-
antibiotics may exacerbate symptoms of weakness in tion that follows describes the more commonly used
parts of the examination, with a particular emphasis on values for dening normal performance, the test is 5
the components that are considered most helpful for 85% sensitive and 85% specic for making the diag-
the assessment of common neurologic problems. Each nosis of dementia that is moderate or severe, espe-
CHAPTER 1
section also includes a brief description of the minimal cially in educated patients. When there is sufcient
examination necessary for adequate screening for abnor- time available, the MMSE is one of the best meth-
malities in a patient who has no symptoms suggesting ods for documenting the current mental status of the
neurologic dysfunction. A screening examination done patient, and this is especially useful as a baseline assess-
in this way can be completed in 35 min. ment to which future scores of the MMSE can be
Several additional points about the examination are compared.
describe how he or she would respond to situations malities. Optic fundi should be examined with an oph-
having a variety of potential outcomes (e.g., What thalmoscope, and the color, size, and degree of swelling
would you do if you found a wallet on the sidewalk?). or elevation of the optic disc noted, as well as the color
Abstract thought can be tested by asking the patient and texture of the retina. The retinal vessels should be
to describe similarities between various objects or con- checked for size, regularity, arterial-venous nicking at
cepts (e.g., apple and orange, desk and chair, poetry crossing points, hemorrhage, exudates, etc.
Introduction to Neurology
CHAPTER 1
mastoid bone conduction (Rinne) and lateralization of a Tone
512-Hz tuning fork placed at the center of the forehead Muscle tone is tested by measuring the resistance to
(Weber) should be done if an abnormality is detected by passive movement of a relaxed limb. Patients often
history or examination. Any suspected problem should have difculty relaxing during this procedure, so it is
be followed up with formal audiometry. For further dis- useful to distract the patient to minimize active move-
cussion of assessing vestibular nerve function in the set- ments. In the upper limbs, tone is assessed by rapid
CN XII (hypoglossal)
Inspect the tongue for atrophy or fasciculations, position Strength
with protrusion, and strength when extended against Testing for pronator drift is an extremely useful method
the inner surface of the cheeks on each side. for screening upper limb weakness. The patient is asked
to hold both arms fully extended and parallel to the
ground with eyes closed. This position should be main-
MOTOR EXAMINATION tained for 10 s; any exion at the elbow or ngers or
The bare minimum: Look for muscle atrophy and check pronation of the forearm, especially if asymmetric, is a
extremity tone. Assess upper extremity strength by check- sign of potential weakness. Muscle strength is further
ing for pronator drift and strength of wrist or nger exten- assessed by having the patient exert maximal effort for
sors. Tap the biceps, patellar, and Achilles reexes. Test the particular muscle or muscle group being tested. It
for lower extremity strength by having the patient walk is important to isolate the muscles as much as possible,
normally and on heels and toes. i.e., hold the limb so that only the muscles of interest
are active. It is also helpful to palpate accessible muscles
The motor examination includes observations of mus- as they contract. Grading muscle strength and evaluat-
cle appearance, tone, strength, and reexes. Although gait ing the patients effort is an art that takes time and prac-
is in part a test of motor function, it is usually evaluated tice. Muscle strength is traditionally graded using the
separately at the end of the examination. following scale:
0 = no movement
1 = icker or trace of contraction but no associated
Appearance
movement at a joint
Inspect and palpate muscle groups under good light and 2 = movement with gravity eliminated
with the patient in a comfortable and symmetric position. 3 = movement against gravity but not against resistance
Check for muscle fasciculations, tenderness, and atrophy 4 = movement against a mild degree of resistance
or hypertrophy. Involuntary movements may be present at 4 = movement against moderate resistance
rest (e.g., tics, myoclonus, choreoathetosis), during main- 4+ = movement against strong resistance
tained posture (pill-rolling tremor of Parkinsons disease), 5 = full power
8 However, in many cases it is more practical to use coordination. Supercial abdominal reexes are elicited
the following terms: by gently stroking the abdominal surface near the umbi-
licus in a diagonal fashion with a sharp object (e.g., the
Paralysis = no movement
SECTION I
CHAPTER 1
lating the skin with single, very gentle touches of the the index nger on the distal thumb as quickly as pos-
examiners nger or a wisp of cotton. Pain is tested sible. In the lower limb, the patient rapidly taps the foot
using a new pin, and temperature is assessed using a against the oor or the examiners hand. Finger-to-nose
metal object (e.g., tuning fork) that has been immersed testing is primarily a test of cerebellar function; the
in cold and warm water. Vibration is tested using a patient is asked to touch his or her index nger repeti-
128-Hz tuning fork applied to the distal phalanx of the tively to the nose and then to the examiners out-
COORDINATION EXAMINATION
The bare minimum: Test rapid alternating movements of the NEUROLOGIC DIAGNOSIS
hands and the nger-to-nose and heel-knee-shin maneuvers.
The clinical data obtained from the history and exami-
Coordination refers to the orchestration and uid- nation are interpreted to arrive at an anatomic localiza-
ity of movements. Even simple acts require coopera- tion that best explains the clinical ndings (Table 1-2),
tion of agonist and antagonist muscles, maintenance of to narrow the list of diagnostic possibilities, and to select
posture, and complex servomechanisms to control the the laboratory tests most likely to be informative. The
rate and range of movements. Part of this integration laboratory assessment may include (1) serum electrolytes;
relies on normal function of the cerebellar and basal complete blood count; and renal, hepatic, endocrine,
ganglia systems. However, coordination also requires and immune studies; (2) cerebrospinal uid examination;
intact muscle strength and kinesthetic and proprio- (3) focused neuroimaging studies (Chap. 4); or (4) elec-
ceptive information. Thus, if the examination has dis- trophysiologic studies (Chap. 5). The anatomic localiza-
closed abnormalities of the motor or sensory systems, tion, mode of onset and course of illness, other medical
the patients coordination should be assessed with these data, and laboratory ndings are then integrated to estab-
limitations in mind. lish an etiologic diagnosis.
10 TABLE 1-2 The neurologic examination may be normal even in
FINDINGS HELPFUL FOR LOCALIZATION WITHIN THE patients with a serious neurologic disease, such as sei-
NERVOUS SYSTEM zures, chronic meningitis, or a TIA. A comatose patient
SECTION I
SIGNS
may arrive with no available history, and in such cases
the approach is as described in Chap. 17. In other
Cerebrum Abnormal mental status or cognitive
patients, an inadequate history may be overcome by a
impairment
Seizures
succession of examinations from which the course of
Unilateral weaknessa and sensory the illness can be inferred. In perplexing cases it is useful
abnormalities including head and limbs to remember that uncommon presentations of com-
Introduction to Neurology
Visual eld abnormalities mon diseases are more likely than rare etiologies. Thus,
Movement abnormalities (e.g., diffuse even in tertiary care settings, multiple strokes are usu-
incoordination, tremor, chorea) ally due to emboli and not vasculitis, and dementia with
Brainstem Isolated cranial nerve abnormalities myoclonus is usually Alzheimers disease and not due to
(single or multiple) a prion disorder or a paraneoplastic cause. Finally, the
Crossed weaknessa and sensory most important task of a primary care physician faced
abnormalities of head and limbs, e.g.,
with a patient who has a new neurologic complaint is
weakness of right face and left arm
and leg
to assess the urgency of referral to a specialist. Here, the
imperative is to rapidly identify patients likely to have
Spinal cord Back pain or tenderness
nervous system infections, acute strokes, and spinal cord
Weaknessa and sensory abnormalities
sparing the head
compression or other treatable mass lesions and arrange
Mixed upper and lower motor neuron for immediate care.
ndings
Sensory level
Sphincter dysfunction
Spinal roots Radiating limb pain
Weaknessb or sensory abnormalities fol-
lowing root distribution (see Figs. 15-2
and 15-3)
Loss of reexes
Peripheral nerve Mid or distal limb pain
Weaknessb or sensory abnormalities
following nerve distribution (see
Figs. 15-2 and 15-3)
Stocking or glove distribution of
sensory loss
Loss of reexes
Neuromuscular Bilateral weakness including face
junction (ptosis, diplopia, dysphagia) and
proximal limbs
Increasing weakness with exertion
Sparing of sensation
Muscle Bilateral proximal or distal weakness
Sparing of sensation
a
Weakness along with other abnormalities having an upper motor
neuron pattern, i.e., spasticity, weakness of extensors > exors in
the upper extremity and exors > extensors in the lower extremity,
hyperreexia.
b
Weakness along with other abnormalities having a lower motor
neuron pattern, i.e., accidity and hyporeexia.
CHAPTER 2
Daniel H. Lowenstein
Knowledge of the basic neurologic examination is appear daunting at rst, skills usually improve rapidly
an essential clinical skill. A simple neurologic screen- with repetition and practice. In this video, the tech-
ing examinationassessment of mental status, cranial nique of performing a simple and efcient screen-
nerves, motor system, sensory system, coordination, ing examination is presented. Videos for this chapter
and gaitcan be reliably performed in 35 min. can be accessed at the following link: http://www
Although the components of the examination may .mhprofessional.com/mediacenter/.
11
CHAPTER 3
Martin A. Samuels
The comprehensive neurologic examination is an irreplace- also becomes a thing of beautythe pinnacle of the art of
able tool for the efcient diagnosis of neurologic disorders. medicine. In this video, the most commonly used compo-
Mastery of its details requires knowledge of normal nervous nents of the examination are presented in detail, with a par-
system anatomy and physiology combined with personal ticular emphasis on those elements that are most helpful for
experience performing orderly and systematic examinations assessment of common neurologic problems. Videos for this
on large numbers of patients and healthy individuals. In chapter can be accessed at the following link: http://www
the hands of a great clinician, the neurologic examination .mhprofessional.com/mediacenter/.
12
CHAPTER 4
William P. Dillon
The clinician caring for patients with neurologic symptoms diagnostic information regarding bone marrow inltra-
is faced with myriad imaging options, including com- tive processes that are difcult to detect on CT.
puted tomography (CT), CT angiography (CTA), per-
fusion CT (pCT), magnetic resonance imaging (MRI),
MR angiography (MRA), functional MRI (fMRI), COMPUTED TOMOGRAPHY
MR spectroscopy (MRS), MR neurography (MRN),
TECHNIQUE
diffusion and diffusion track imaging (DTI), susceptibil-
ity weighted MR imaging (SWI), and perfusion MRI The CT image is a cross-sectional representation of
(pMRI). In addition, an increasing number of interven- anatomy created by a computer-generated analysis of
tional neuroradiologic techniques are available, includ- the attenuation of x-ray beams passed through a sec-
ing angiography catheter embolization, coiling, and tion of the body. As the x-ray beam, collimated to the
stenting of vascular structures; and spine diagnostic and desired slice width, rotates around the patient, it passes
interventional techniques such as diskography, transfo- through selected regions in the body. X-rays that are
raminal and translaminar epidural and nerve root injec- not attenuated by body structures are detected by sensi-
tions and blood patches. Recent developments such tive x-ray detectors aligned 180 from the x-ray tube.
as multidetector CTA (MDCTA) and gadolinium- A computer calculates a back projection image from
enhanced MRA, have narrowed the indications for the 360 x-ray attenuation prole. Greater x-ray attenu-
conventional angiography, which is now reserved for ation (e.g., as caused by bone) results in areas of high
patients in whom small-vessel detail is essential for diag- density, while soft tissue structures that have poor
nosis or for whom concurrent interventional therapy is attenuation of x-rays such as organs and air-lled cavi-
planned (Table 4-1). ties are lower in density. The resolution of an image
In general, MRI is more sensitive than CT for the depends on the radiation dose, the detector size, colli-
detection of lesions affecting the central nervous sys- mation (slice thickness), the eld of view, and the matrix
tem (CNS), particularly those of the spinal cord, size of the display. A modern CT scanner is capable of
cranial nerves, and posterior fossa structures. Diffusion obtaining sections as thin as 0.51 mm with submillime-
MR, a sequence sensitive to the microscopic motion ter resolution at a speed of 0.31 s per rotation; complete
of water, is the most sensitive technique for detect- studies of the brain can be completed in 210 s.
ing acute ischemic stroke of the brain or spinal cord, Multidetector CT (MDCT) is now standard in most
and it is also useful in the detection of encephalitis, radiology departments. Single or multiple (from 4 to
abscesses, and prion diseases. CT, however, is quickly 256) detectors positioned 180 to the x-ray source result
acquired and is widely available, making it a pragmatic in multiple slices per revolution of the beam around
choice for the initial evaluation of patients with acute the patient. The table moves continuously through the
changes in mental status, suspected acute stroke, hem- rotating x-ray beam, generating a continuous helix of
orrhage, and intracranial or spinal trauma. CT is also information that can be reformatted into various slice
more sensitive than MRI for visualizing ne osseous thicknesses and planes. Advantages of MDCT include
detail and is indicated in the initial evaluation of con- shorter scan times, reduced patient and organ motion,
ductive hearing loss as well as lesions affecting the skull and the ability to acquire images dynamically during
base and calvarium. MR may, however, add important the infusion of intravenous contrast that can be used to
13
14 TABLE 4-1 construct CT angiograms of vascular structures and CT
GUIDELINES FOR THE USE OF CT, ULTRASOUND, perfusion images (Fig. 4-1B and C). CTA images are
AND MRI postprocessed for display in three dimensions to yield
SECTION I
RECOMMENDED
angiogram-like images (Fig. 4-1C, 4-2 E and F, and
CONDITION TECHNIQUE see Fig. 27-4). CTA has proved useful in assessing the
cervical and intracranial arterial and venous anatomy.
Hemorrhage
Acute parenchymal CT, MR
Intravenous iodinated contrast is often administered
Subacute/chronic MRI
prior to or during a CT study to identify vascular struc-
Subarachnoid CT, CTA, lumbar puncture tures and to detect defects in the blood-brain barrier
Introduction to Neurology
hemorrhage angiography (BBB) that are associated with disorders such as tumors,
Aneurysm Angiography > CTA, MRA infarcts, and infections. In the normal CNS, only vessels
Ischemic infarction and structures lacking a BBB (e.g., the pituitary gland,
Hemorrhagic infarction CT or MRI choroid plexus, and dura) enhance after contrast admin-
Bland infarction MRI > CT, CTA, angiography istration. The use of iodinated contrast agents car-
Carotid or vertebral MRI/MRA ries a small risk of allergic reaction and adds additional
dissection
expense. While helpful in characterizing mass lesions as
Vertebral basilar CTA, MRI/MRA
insufciency well as essential for the acquisition of CTA studies, the
Carotid stenosis CTA > Doppler ultrasound, decision to use contrast material should always be con-
MRA sidered carefully.
Suspected mass lesion
Neoplasm, primary or MRI + contrast
metastatic INDICATIONS
Infection/abscess MRI + contrast
Immunosuppressed with MRI + contrast CT is the primary study of choice in the evaluation
focal ndings of an acute change in mental status, focal neurologic
Vascular malformation MRI angiography ndings, acute trauma to the brain and spine, sus-
White matter disorders MRI
pected subarachnoid hemorrhage, and conductive hear-
Demyelinating disease MRI contrast
Dementia MRI > CT
ing loss (Table 4-1). CT is complementary to MR in
Trauma the evaluation of the skull base, orbit, and osseous
Acute trauma CT (noncontrast) structures of the spine. In the spine, CT is useful in
Shear injury/chronic MRI + gradient echo imaging evaluating patients with osseous spinal stenosis and
hemorrhage spondylosis, but MRI is often preferred in those with
Headache/migraine CT (noncontrast)/MRI neurologic decits. CT can also be obtained following
Seizure intrathecal contrast injection to evaluate the intracra-
First time, no focal ?CT as screen contrast
nial cisterns (CT cisternography) for cerebrospinal uid
neurologic decits
Partial complex/refrac- MRI with coronal T2W imag-
(CSF) stula, as well as the spinal subarachnoid space
tory ing (CT myelography).
Cranial neuropathy MRI with contrast
Meningeal disease MRI with contrast
Spine COMPLICATIONS
Low back pain CT is safe, fast, and reliable. Radiation exposure
No neurologic decits MRI or CT after 4 weeks depends on the dose used but is normally between
With focal decits MRI > CT 2 and 5 mSv (millisievert) for a routine brain CT study.
Spinal stenosis MRI or CT Care must be taken to reduce exposure when imaging
Cervical spondylosis MRI or CT myelography children. With the advent of MDCT, CTA, and CT
Infection MRI + contrast, CT
perfusion, care must be taken to appropriately mini-
Myelopathy MRI + contrast
mize radiation dose whenever possible. Advanced soft-
Arteriovenous malforma- MRI, angiography
tion
ware that permits noise reduction may permit lower
radiation doses. The most frequent complications are
Abbreviations: CT, computed tomography; CTA, CT angiography;
associated with use of intravenous contrast agents. Two
MRA, MR angiography; MRI, magnetic resonance imaging; T2W,
T2-weighted. broad categories of contrast media, ionic and non-
ionic, are in use. Although ionic agents are relatively
safe and inexpensive, they are associated with a higher
incidence of reactions and side effects. As a result, ionic
agents have been largely replaced by safer nonionic
compounds.
Contrast nephropathy may result from hemodynamic 15
changes, renal tubular obstruction and cell damage,
or immunologic reactions to contrast agents. A rise in
CHAPTER 4
serum creatinine of at least 85 mol/L (1 mg/dL) within
48 h of contrast administration is often used as a de-
nition of contrast nephropathy, although other causes
of acute renal failure must be excluded. The prognosis
is usually favorable, with serum creatinine levels return-
ing to baseline within 12 weeks. Risk factors for
FIGURE 4-2
Acute left hemiparesis due to middle cerebral artery abrupt occlusion of the proximal right middle cerebral artery
occlusion. A. Axial noncontrast CT scan demonstrates high (arrow). E. Sagittal reformation through the right internal
density within the right middle cerebral artery (arrow) asso- carotid artery demonstrates a low-density lipid-laden plaque
ciated with subtle low density involving the right putamen (arrowheads) narrowing the lumen (black arrow) F. 3D surface-
(arrowheads). B. Mean transit time CT perfusion paramet- rendered CTA image demonstrates calcication and narrowing
ric map indicating prolonged mean transit time involving the of the right internal carotid artery (arrow), consistent with ath-
right middle cerebral territory (arrows). C. Cerebral blood erosclerotic disease. G. Coronal maximum-intensity projection
volume map shows reduced CBV involving an area within from MRA shows right middle cerebral artery (MCA) occlusion
the defect shown in B, indicating a high likelihood of infarc- (arrow). H and I. Axial diffusion-weighted image (H) and appar-
tion (arrows). D. Axial maximum-intensity projection from ent diffusion coefcient image (I) document the presence of a
a CTA study through the circle of Willis demonstrates an right middle cerebral artery infarction.
TABLE 4-2 of Rf energy (the echo), which is detected by the coils 17
GUIDELINES FOR PREMEDICATION OF PATIENTS that delivered the Rf pulses. The echo is transformed
WITH PRIOR CONTRAST ALLERGY by Fourier analysis into the information used to form
CHAPTER 4
12 h prior to examination:
an MR image. The MR image thus consists of a map of
Prednisone, 50 mg PO or methylprednisolone, 32 mg PO the distribution of hydrogen protons, with signal inten-
sity imparted by both density of hydrogen protons as
2 h prior to examination:
Prednisone, 50 mg PO or methylprednisolone, 32 mg PO
well as differences in the relaxation times (see below) of
and Cimetidine, 300 mg PO or ranitidine, 150 mg PO hydrogen protons on different molecules. While clini-
cal MRI currently makes use of the ubiquitous hydro-
Immediately prior to examination:
understood but is thought to include the release of medi- The rate of return to equilibrium of perturbed protons is
ators such as histamine, antibody-antigen reactions, and called the relaxation rate. The relaxation rate varies among
complement activation. Severe allergic reactions occur normal and pathologic tissues. The relaxation rate of a
in 0.04% of patients receiving nonionic media, sixfold hydrogen proton in a tissue is inuenced by local inter-
lower than with ionic media. Risk factors include a his- actions with surrounding molecules and atomic neigh-
tory of prior contrast reaction, food allergies to shellsh, bors. Two relaxation rates, T1 and T2, inuence the
and atopy (asthma and hay fever). In such patients, a signal intensity of the image. The T1 relaxation time
noncontrast CT or MRI procedure should be considered is the time, measured in milliseconds, for 63% of the
as an alternative to contrast administration. If iodinated hydrogen protons to return to their normal equilib-
contrast is absolutely required, a nonionic agent should rium state, while the T2 relaxation is the time for 63%
be used in conjunction with pretreatment with gluco- of the protons to become dephased owing to interac-
corticoids and antihistamines (Table 4-2). Patients with tions among nearby protons. The intensity of the signal
allergic reactions to iodinated contrast material do not within various tissues and image contrast can be mod-
usually react to gadolinium-based MR contrast material, ulated by altering acquisition parameters such as the
although such reactions can occur. It would be wise to interval between Rf pulses (TR) and the time between
pretreat patients with a prior allergic history to MR con- the Rf pulse and the signal reception (TE). So-called
trast administration in a similar fashion. T1-weighted (T1W) images are produced by keeping
the TR and TE relatively short. T2-weighted (T2W)
images are produced by using longer TR and TE times.
Fat and subacute hemorrhage have relatively shorter
MAGNETIC RESONANCE IMAGING T1 relaxation rates and thus higher signal intensity than
TECHNIQUE brain on T1W images. Structures containing more water
such as CSF and edema, have long T1 and T2 relax-
MRI is a complex interaction between hydrogen pro- ation rates, resulting in relatively lower signal intensity
tons in biologic tissues, a static magnetic eld (the on T1W images and a higher signal intensity on T2W
magnet), and energy in the form of radiofrequency (Rf) images (Table 4-3). Gray matter contains 1015%
waves of a specic frequency introduced by coils placed
next to the body part of interest. Images are made by
computerized processing of resonance information TABLE 4-3
received from protons in the body. Field strength of the
SOME COMMON INTENSITIES ON T1- AND
magnet is directly related to signal-to-noise ratio. While T2-WEIGHTED MRI SEQUENCES
1.5-Telsa magnets have become the standard high-
eld MRI units, 3T8T magnets are now available and SIGNAL INTENSITY
have distinct advantages in the brain and musculoskel- IMAGE TR TE CSF FAT BRAIN EDEMA
etal systems. Spatial localization is achieved by magnetic T1W Short Short Low High Low Low
gradients surrounding the main magnet, which impart T2W Long Long High Low High High
slight changes in magnetic eld throughout the imaging
FLAIR Long Long Low Medium High High
volume. Rf pulses transiently excite the energy state of
(T2)
the hydrogen protons in the body. Rf is administered
at a frequency specic for the eld strength of the mag- Abbreviations: CSF, cerebrospinal uid; TE, interval between Rf
net. The subsequent return to equilibrium energy state pulse and signal reception; TR, interval between radiofrequency (Rf)
(relaxation) of the hydrogen protons results in a release pulses; T1W and T2W, T1- and T2-weighted.
18 more water than white matter, which accounts for MR contrast material
much of the intrinsic contrast between the two on MRI
(Fig. 4-6B). T2W images are more sensitive than T1W The heavy-metal element gadolinium forms the
basis of all currently approved intravenous MR con-
SECTION I
FIGURE 4-3
Cerebral abscess in a patient with fever and a right B. Axial diffusion-weighted image demonstrates restricted
hemiparesis. A. Coronal postcontrast T1-weighted image diffusion (high signal intensity) within the lesion, which in this
demonstrates a ring enhancing mass in the left frontal lobe. setting is highly suggestive of cerebral abscess.
19
CHAPTER 4
Neuroimaging in Neurologic Disorders
A B
increases to 6.3% in those patients with a prior history contrast agents. The onset of NSF has been reported
of unspecied allergic reaction to iodinated contrast between 5 and 75 days following exposure; histologic
agents. Gadolinium contrast material can be adminis- features include thickened collagen bundles with sur-
tered safely to children as well as adults, although these rounding clefts, mucin deposition, and increased num-
agents are generally avoided in those under 6 months bers of brocytes and elastic bers in skin. In addition
of age. Renal failure does not occur. to dermatologic symptoms, other manifestations include
A rare complication, nephrogenic systemic brosis widespread brosis of the skeletal muscle, bone, lungs,
(NSF), has recently been reported in patients with renal pleura, pericardium, myocardium, kidney, muscle,
insufciency who have been exposed to gadolinium bone, testes, and dura. For this reason, the American
20
SECTION I
Introduction to Neurology
A B
FIGURE 4-5
Susceptibility weighted imaging in a patient with familial lesions (arrows). C. Susceptibility weighted image shows
cavernous malformations. A. Noncontrast CT scan shows numerous low-intensity lesions consistent with hemosiderin-
one hyperdense lesion in the right hemisphere (arrow). B. laden cavernous malformations (arrow).
T2-weighted fast spin echo image shows subtle low-intensity
College of Radiology recommends that prior to elec- 5. History of severe hepatic disease/liver transplant/
tive gadolinium-based MR contrast agent (GBMCA) pending liver transplant: for these patients it is rec-
administration, a recent (e.g., past 6 weeks) glomerular ommended that the patients GFR assessment be
ltration rate (GFR) assessment be obtained in patients nearly contemporaneous with the MR examination.
with a history of:
The incidence of NSF in patients with severe renal
1. Renal disease (including solitary kidney, renal trans- dysfunction (GFR <30) varies from 0.19 to 4%. A
plant, renal tumor) recent meta-analysis reported an odds ratio of 26.7 (95%
2. Age >60 years CI = 10.369.4) for development of NSF after gado-
3. History of hypertension linium administration in patients with impaired renal
4. History of diabetes function (GFR <30 mL/min/1.72 m). Thus, it is not
21
CHAPTER 4
Neuroimaging in Neurologic Disorders
A B
FIGURE 4-6
Diffusion tractography in cerebral glioma. A. An axial high signal glioma in left temporal lobe. C. Axial diffusion
postcontrast T1-weighted image shows a nonenhancing gli- fractional anisotropy image shows the position of the deep
oma (T) of the left temporal lobe cortex lateral to the bers of white matter bers (arrow) relative to the enhancing tumor (T).
the internal capsule. B. Coronal T2 FLAIR image demonstrates
recommended to administer gadolinium to any patient that is moved into a long, narrow gap within the mag-
with a GFR below 30. Caution is advised for patients net. Approximately 5% of the population experiences
with a GFR below 45. severe claustrophobia in the MR environment. This can
be reduced by mild sedation but remains a problem for
some. Unlike CT, movement of the patient during an
COMPLICATIONS AND CONTRAINDICATIONS
MR sequence distorts all the images; therefore, unco-
From the patients perspective, an MRI examination operative patients should either be sedated for the MR
can be intimidating, and a higher level of cooperation study or scanned with CT. Generally, children under
is required than with CT. The patient lies on a table the age of 10 years usually require conscious sedation
22 TABLE 4-4 spin echo MR images. Slower-owing blood, as occurs
COMMON CONTRAINDICATIONS TO MR IMAGING in veins or distal to arterial stenosis, may appear high in
Cardiac pacemaker or permanent pacemaker leads signal. However, using special pulse sequences called
SECTION I
Internal debrillatory device gradient echo sequences, it is possible to increase the signal
Cochlear prostheses intensity of moving protons in contrast to the low sig-
Bone growth stimulators nal background intensity of stationary tissue. This cre-
Spinal cord stimulators ates angiography-like images, which can be manipulated
Electronic infusion devices in three dimensions to highlight vascular anatomy and
Intracranial aneurysm clips (some but not all)
relationships.
Ocular implants (some) or ocular metallic foreign body
Introduction to Neurology
McGee stapedectomy piston prosthesis Time-of-ight (TOF) imaging, currently the tech-
Duraphase penile implant nique used most frequently, relies on the suppression
Swan-Ganz catheter of nonmoving tissue to provide a low-intensity back-
Magnetic stoma plugs ground for the high signal intensity of owing blood
Magnetic dental implants entering the section; arterial or venous structures may
Magnetic sphincters be highlighted. A typical TOF angiography sequence
Ferromagnetic IVC lters, coils, stentssafe 6 weeks after
results in a series of contiguous, thin MR sections
implantation
Tattooed eyeliner (contains ferromagnetic material and
(0.60.9 mm thick), which can be viewed as a stack
may irritate eyes) and manipulated to create an angiographic image data
set that can be reformatted and viewed in various planes
Note: See also http://www.mrisafety.com. and angles, much like that seen with conventional
angiography (Fig. 4-2G).
Phase-contrast MRA has a longer acquisition time
than TOF MRA, but in addition to providing anatomic
in order to complete the MR examination without information similar to that of TOF imaging, it can be
motion degradation. used to reveal the velocity and direction of blood ow
MRI is considered safe for patients, even at very high in a given vessel. Through the selection of different
eld strengths (>34 T). Serious injuries have been imaging parameters, differing blood velocities can be
caused, however, by attraction of ferromagnetic objects highlighted; selective venous and arterial MRA images
into the magnet, which act as missiles if brought too can thus be obtained. One advantage of phase-contrast
close to the magnet. Likewise, ferromagnetic implants MRA is the excellent suppression of high-signal-
such as aneurysm clips, may torque within the mag- intensity background structures.
net, causing damage to vessels and even death. Metallic MRA can also be acquired during infusion of
foreign bodies in the eye have moved and caused intra- contrast material. Advantages include faster imaging
ocular hemorrhage; screening for ocular metallic frag- times (12 min vs. 10 min), fewer ow-related arti-
ments is indicated in those with a history of metal work facts, and higher-resolution images. Recently, con-
or ocular metallic foreign bodies. Implanted cardiac trast-enhanced MRA has become the standard for
pacemakers are generally a contraindication to MRI extracranial vascular MRA. This technique entails
owing to the risk of induced arrhythmias; however, rapid imaging using coronal three-dimensional TOF
some newer pacemakers have been shown to be safe. sequences during a bolus infusion of 1520 mL of
All health care personnel and patients must be screened gadolinium-DTPA. Proper technique and timing
and educated thoroughly to prevent such disasters as the of acquisition relative to bolus arrival are critical for
magnet is always on. Table 4-4 lists common contra- success.
indications for MRI. MRA has lower spatial resolution compared with
conventional lm-based angiography, and therefore the
detection of small-vessel abnormalities, such as vasculitis
MAGNETIC RESONANCE ANGIOGRAPHY and distal vasospasm, is problematic. MRA is also less
sensitive to slowly owing blood and thus may not reli-
MR angiography is a general term describing several MR ably differentiate complete from near-complete occlu-
techniques that result in vascular-weighted images. sions. Motion, either by the patient or by anatomic
These provide a vascular ow map rather than the ana- structures, may distort the MRA images, creating arti-
tomic map shown by conventional angiography. On facts. These limitations notwithstanding, MRA has
routine spin echo MR sequences, moving protons proved useful in evaluation of the extracranial carotid
(e.g., owing blood, CSF) exhibit complex MR sig- and vertebral circulation as well as of larger-caliber
nals that range from high- to low-signal intensity rela- intracranial arteries and dural sinuses. It has also proved
tive to background stationary tissue. Fast-owing blood useful in the noninvasive detection of intracranial aneu-
returns no signal (ow void) on routine T1W or T2W rysms and vascular malformations.
ECHO-PLANAR MR IMAGING
task activation. Neuronal activity elicits a slight increase 23
in the delivery of oxygenated blood ow to a specic
Recent improvements in gradients, software, and region of activated brain. This results in an alteration in
CHAPTER 4
high-speed computer processors now permit extremely the balance of oxyhemoglobin and deoxyhemoglobin,
rapid MRI of the brain. With echo-planar MRI (EPI), which yields a 23% increase in signal intensity within
fast gradients are switched on and off at high speeds to veins and local capillaries. Further studies will determine
create the information used to form an image. In rou- whether these techniques are cost-effective or clinically
tine spin echo imaging, images of the brain can be useful, but currently preoperative somatosensory and
obtained in 510 min. With EPI, all of the informa- auditory cortex localization is possible. This technique
ed subarachnoid space. Low-dose CT myelography, in placement of an epidural blood patch should be con-
which CT is performed after the subarachnoid injec- sidered. Hearing loss is a rare complication of myelog-
tion of a small amount of relatively dilute contrast mate- raphy. It may result from a direct toxic effect of the
rial, has replaced conventional myelography for many contrast medium or from an alteration of the pressure
indications, thereby reducing exposure to radiation equilibrium between CSF and perilymph in the inner
and contrast media. Newer multidetector scanners now ear. Puncture of the spinal cord is a rare but serious
Introduction to Neurology
obtain CT studies quickly so that reformations in sagit- complication of cervical (C12) or high lumbar punc-
tal and coronal planes, equivalent to traditional myelog- ture. The risk of cord puncture is greatest in patients
raphy projections, are now routine. with spinal stenosis, Chiari malformations, or conditions
that reduce CSF volume. In these settings, a low-dose
lumbar injection followed by thin-section CT or MRI
INDICATIONS is a safer alternative to cervical puncture. Intrathecal
Myelography has been largely replaced by CT myelog- contrast reactions are rare, but aseptic meningitis and
raphy and MRI for diagnosis of diseases of the spinal encephalopathy may occur. The latter is usually dose
canal and cord (Table 4-1). Remaining indications for related and associated with contrast entering the intra-
conventional plain-lm myelography include the evalu- cranial subarachnoid space. Seizures occur follow-
ation of suspected meningeal or arachnoid cysts and the ing myelography in 0.10.3% of patients. Risk factors
localization of spinal dural arteriovenous or CSF stulas. include a preexisting seizure disorder and the use of a
Conventional myelography and CT myelography pro- total iodine dose of >4500 mg. Other reported compli-
vide the most precise information in patients with prior cations include hyperthermia, hallucinations, depression,
spinal fusion and spinal xation hardware. and anxiety states. These side effects have been reduced
by the development of nonionic, water-soluble contrast
agents as well as by head elevation and generous hydra-
CONTRAINDICATIONS tion following myelography.
Myelography is relatively safe; however, it should be
performed with caution in any patient with elevated
intracranial pressure, evidence of a spinal block, or a SPINE INTERVENTIONS
history of allergic reaction to intrathecal contrast media.
In patients with a suspected spinal block, MR is the DISKOGRAPHY
preferred technique. If myelography is necessary, only The evaluation of back pain and radiculopathy may
a small amount of contrast medium should be instilled require diagnostic procedures that attempt either to
below the lesion in order to minimize the risk of neu- reproduce the patients pain or relieve it, indicating
rologic deterioration. Lumbar puncture is to be avoided its correct source prior to lumbar fusion. Diskography
in patients with bleeding disorders, including patients is performed by uoroscopic placement of a 22- to
receiving anticoagulant therapy, as well as in those with 25-gauge needle into the intervertebral disk and sub-
infections of the overlying soft tissues. sequent injection of 13 mL of contrast media. The
intradiskal pressure is recorded, as is an assessment of the
patients response to the injection of contrast material.
COMPLICATIONS Typically little or no pain is felt during injection of a
Headache, nausea, and vomiting are the most fre- normal disk, which does not accept much more than
quent complications of myelography and are reported 1 mL of contrast material, even at pressures as high as
to occur in up to 38% of patients. These symptoms 415690 kPa (60100 lb/in2). CT and plain lms are
result from either neurotoxic effects of the contrast obtained following the procedure. Concerns have been
agent, persistent leakage of CSF at the puncture site, raised that diskography may contribute to an accelerated
or psychological reactions to the procedure. Vasova- rate of disk degeneration.
gal syncope may occur during lumbar puncture; it is
accentuated by the upright position used during lum-
SELECTIVE NERVE ROOT AND EPIDURAL
bar myelography. Adequate hydration before and
SPINAL INJECTIONS
after myelography will reduce the incidence of this
complication. Postural headache (postlumbar punc- Percutaneous selective nerve root and epidural blocks
ture headache) is generally due to leakage of CSF with glucocorticoid and anesthetic mixtures may be
from the puncture site, resulting in CSF hypotension. both therapeutic as well as diagnostic, especially if
a patients pain is relieved. Typically, 12 mL of an either by an underlying disease or by the injection of 25
equal mixture of a long-acting glucocorticoid such as hyperosmolar contrast agent. Ionic contrast media
betamethasone and a long-acting anesthetic such as are less well tolerated than nonionic media, probably
CHAPTER 4
bupivacaine 0.75% is instilled under CT or uoroscopic because they can induce changes in cell membrane
guidance in the intraspinal epidural space or adjacent to electrical potentials. Patients with dolichoectasia of the
an existing nerve root. basilar artery can suffer reversible brainstem dysfunction
and acute short-term memory loss during angiography,
owing to the slow percolation of the contrast material
and the consequent prolonged exposure of the brain.
ANGIOGRAPHY
Michael J. Aminoff
CHAPTER 5
C3-P3 P3-O1
P3-O1 F4-C4
Fp2-F4 C4-P4
F4-C4 P4-O2
C4-P4 T3-CZ
P4-O2 CZ-T4
Electrodiagnostic Studies of Nervous System Disorders: EEG, E voked Potentials, and EMG
A B
F3-A1
Fp1-F3
C3-A1 F3-C3
P3-A1 C3-P3
O1-A1 P3-O1
Fp2-F4
F4-A2
F4-C4
C4-A2
C4-P4
P4-A2 P4-O2
O2-A2
C D
FIGURE 5-1
A. Normal EEG showing a posteriorly situated 9-Hz alpha in other panels. (From MJ Aminoff, ed: Electrodiagnosis in Clini-
rhythm that attenuates with eye opening. B. Abnormal EEG cal Neurology, 5th ed. New York, Churchill Livingstone, 2005.) In
showing irregular diffuse slow activity in an obtunded patient this and the following gure, electrode placements are indicated
with encephalitis. C. Irregular slow activity in the right cen- at the left of each panel and accord with the international 10:20
tral region, on a diffusely slowed background, in a patient with system. A, earlobe; C, central; F, frontal; Fp, frontal polar; P, pari-
a right parietal glioma. D. Periodic complexes occurring once etal; T, temporal; O, occipital. Right-sided placements are indi-
every second in a patient with Creutzfeldt-Jakob disease. Hori- cated by even numbers, left-sided placements by odd numbers,
zontal calibration: 1 s; vertical calibration: 200 V in A, 300 V and midline placements by Z.
medication for individual patients (Fig. 5-2). The epi- to develop seizures, because in such circumstances epi-
sodic generalized spike-wave activity that occurs during leptiform activity is commonly encountered regardless
and between seizures in patients with typical absence of whether seizures occur. The EEG ndings are some-
epilepsy contrasts with focal interictal epileptiform dis- times used to determine whether anticonvulsant medi-
charges or ictal patterns found in patients with focal cation can be discontinued in epileptic patients who
seizures. These latter seizures may have no correlates have been seizure-free for several years, but the nd-
in the scalp-recorded EEG or may be associated with ings provide only a general guide to prognosis. Further
abnormal rhythmic activity of variable frequency, a seizures may occur after withdrawal of anticonvulsant
localized or generalized distribution, and a stereotyped medication despite a normal EEG or, conversely, may
pattern that varies with the patient. Focal or lateral- not occur despite a continuing EEG abnormality. The
ized epileptogenic lesions are important to recognize, decision to discontinue anticonvulsant medication is
especially if surgical treatment is contemplated. Inten- made on clinical grounds, and the EEG does not have a
sive long-term monitoring of clinical behavior and the useful role in this context except for providing guidance
EEG is required for operative candidates, however, and when there is clinical ambiguity or the patient requires
this generally also involves recording from intracranially reassurance about a particular course of action.
placed electrodes (which may be subdural, extradural, The EEG has no role in the management of tonic-
or intracerebral in location). clonic status epilepticus except when there is clinical
The ndings in the routine scalp-recorded EEG may uncertainty whether seizures are continuing in a coma-
indicate the prognosis of seizure disorders: In general, tose patient. In patients treated by pentobarbital-induced
a normal EEG implies a better prognosis than other- coma for refractory status epilepticus, the EEG nd-
wise, whereas an abnormal background or profuse epi- ings are useful in indicating the level of anesthesia and
leptiform activity suggests a poor outlook. The EEG whether seizures are occurring. During status epilepticus,
ndings are not helpful in determining which patients the EEG shows repeated electrographic seizures or con-
with head injuries, stroke, or brain tumors will go on tinuous spike-wave discharges. In nonconvulsive status
28 A THE EEG AND COMA
F3-C3
C3-P3
In patients with an altered mental state or some degree
of obtundation, the EEG tends to become slower as
SECTION I
P3-O1
consciousness is depressed, regardless of the underlying
F4-C4 cause (Fig. 5-1). Other ndings may also be present and
C4-P4 may suggest diagnostic possibilities, as when electro-
P4-O2 graphic seizures are found or there is a focal abnormality
T3-CZ indicating a structural lesion. The EEG generally slows
CZ-T4 in metabolic encephalopathies, and triphasic waves may
Introduction to Neurology
CHAPTER 5
cerebral disturbances are common ndings but provide also been used for mapping brain tumors, identifying
no reliable indication about the nature of the underly- the central ssure preoperatively, and localizing func-
ing pathology. tionally eloquent cortical areas such as those concerned
In patients with an acute encephalopathy, focal or with language.
lateralized periodic slow-wave complexes, sometimes
with a sharpened outline, suggest a diagnosis of her-
Electrodiagnostic Studies of Nervous System Disorders: EEG, E voked Potentials, and EMG
pes simplex encephalitis, and periodic lateralizing epi-
leptiform discharges (PLEDs) are commonly found EVOKED POTENTIALS
with acute hemispheric pathology such as a hematoma, SENSORY EVOKED POTENTIALS
abscess, or rapidly expanding tumor. The EEG ndings
in dementia are usually nonspecic and do not distin- The noninvasive recording of spinal or cerebral poten-
guish between the different causes of cognitive decline tials elicited by stimulation of specic afferent pathways
except in rare instances when, for example, the pres- is an important means of monitoring the functional
ence of complexes occurring with a regular repetition integrity of these pathways but does not indicate the
rate (so-called periodic complexes) supports a diagnosis pathologic basis of lesions involving them. Such evoked
of Creutzfeldt-Jakob disease (Fig. 5-1) or subacute scle- potentials (EPs) are so small compared to the back-
rosing panencephalitis. In most patients with demen- ground EEG activity that the responses to a number of
tias, the EEG is normal or diffusely slowed, and the stimuli have to be recorded and averaged with a com-
EEG ndings alone cannot indicate whether a patient puter in order to permit their recognition and deni-
is demented or distinguish between dementia and tion. The background EEG activity, which has no xed
pseudodementia. temporal relationship to the stimulus, is averaged out by
this procedure.
Visual evoked potentials (VEPs) are elicited by mon-
CONTINUOUS EEG MONITORING ocular stimulation with a reversing checkerboard pat-
The brief EEG obtained routinely in the laboratory tern and are recorded from the occipital region in the
often fails to reveal abnormalities that are transient and midline and on either side of the scalp. The compo-
infrequent. Continuous monitoring over 12 or 24 h nent of major clinical importance is the so-called P100
or longer may detect abnormalities or capture clini- response, a positive peak having a latency of approxi-
cal events that would otherwise be missed. The EEG is mately 100 ms. Its presence, latency, and symmetry
often recorded continuously in critically ill patients to over the two sides of the scalp are noted. Amplitude
detect early changes in neurologic status, which is par- may also be measured, but changes in size are much
ticularly useful when the clinical examination is limited. less helpful for the recognition of pathology. VEPs are
Continuous EEG recording in this context has been most useful in detecting dysfunction of the visual path-
used to detect acute events such as nonconvulsive sei- ways anterior to the optic chiasm. In patients with
zures or developing cerebral ischemia, to monitor cere- acute severe optic neuritis, the P100 is frequently lost
bral function in patients with metabolic disorders such or grossly attenuated; as clinical recovery occurs and
as liver failure, and to manage the level of anesthesia in visual acuity improves, the P100 is restored but with
pharmacologically induced coma. an increased latency that generally remains abnormally
prolonged indenitely. The VEP ndings are therefore
helpful in indicating previous or subclinical optic neuri-
tis. They may also be abnormal with ocular abnormali-
MAGNETOENCEPHALOGRAPHY AND ties and with other causes of optic nerve disease, such
MAGNETIC SOURCE IMAGING as ischemia or compression by a tumor. Normal VEPs
may be elicited by ash stimuli in patients with cortical
Recording the magnetic eld of the electrical activity of blindness. Routine VEPs record a mass response over
the brain (magnetoencephalography [MEG]) provides a a relatively large cortical area and thus may be insen-
means of examining cerebral activity that is less subject sitive to localized waveform abnormalities. A newer
to distortion by other biologic tissues than the EEG. technique, multifocal VEP, measures responses from 120
MEG is used in only a few specialized centers because individual sectors within each affected eye, and thus is
of the complexity and expense of the necessary equip- likely to be more sensitive than routine VEP.
ment. It permits the source of activity to be localized Brainstem auditory evoked potentials (BAEPs) are elic-
and coregistered with the MRI in a technique that is ited by monaural stimulation with repetitive clicks and
known as magnetic source imaging. In patients with focal are recorded between the vertex of the scalp and the
30 mastoid process or earlobe. A series of potentials, desig- SSEPs have been used to indicate the completeness of
nated by roman numerals, occurs in the rst 10 ms after the lesion. The presence or early return of a cortically
the stimulus and represents in part the sequential acti- generated response to stimulation of a nerve below
SECTION I
vation of different structures in the pathway between the injured segment of the cord indicates an incom-
the auditory nerve (wave I) and the inferior colliculus plete lesion and thus a better prognosis for functional
(wave V) in the midbrain. The presence, latency, and recovery than otherwise. In surgery, intraoperative EP
interpeak latency of the rst ve positive potentials monitoring of neural structures placed at risk by the
recorded at the vertex are evaluated. The ndings are procedure may permit the early recognition of dys-
helpful in screening for acoustic neuromas, detecting function and thereby permit a neurologic complication
Introduction to Neurology
CHAPTER 5
tion after stroke) and provides a means of monitoring
intraoperatively the functional integrity of central motor B 100 V
tracts. Nevertheless, it is not used widely for clinical
purposes. 100 ms
100 V
Electrodiagnostic Studies of Nervous System Disorders: EEG, E voked Potentials, and EMG
C D E
ELECTROPHYSIOLOGIC STUDIES OF
MUSCLE AND NERVE
10 ms
The motor unit is the basic element subserving motor
function. It is dened as an anterior horn cell, its axon FIGURE 5-3
and neuromuscular junctions, and all the muscle bers Activity recorded during EMG. A. Spontaneous brillation
innervated by the axon. The number of motor units in potentials and positive sharp waves. B. Complex repetitive
a muscle ranges from approximately 10 in the extraocu- discharges recorded in partially denervated muscle at rest.
lar muscles to several thousand in the large muscles of C. Normal triphasic motor unit action potential. D. Small,
the legs. There is considerable variation in the average short-duration, polyphasic motor unit action potential such
number of muscle bers within the motor units of an as is commonly encountered in myopathic disorders. E.
individual muscle, i.e., in the innervation ratio of dif- Long-duration polyphasic motor unit action potential such as
ferent muscles. Thus the innervation ratio is <25 in the may be seen in neuropathic disorders.
human external rectus or platysma muscle and between
1600 and 1700 in the medial head of the gastrocnemius the spontaneous activity of individual motor units) are
muscle. The muscle bers of individual motor units are characteristic of slowly progressive neuropathic disor-
divided into two general types by distinctive contrac- ders, especially those with degeneration of anterior horn
tile properties, histochemical stains, and characteristic cells (such as amyotrophic lateral sclerosis). Myotonic
responses to fatigue. Within each motor unit, all of the dischargeshigh-frequency discharges of potentials
muscle bers are of the same type. derived from single muscle bers that wax and wane
in amplitude and frequencyare the signature of myo-
tonic disorders such as myotonic dystrophy or myoto-
ELECTROMYOGRAPHY
nia congenita but occur occasionally in polymyositis or
The pattern of electrical activity in muscle (i.e., the other, rarer, disorders.
electromyogram [EMG]), both at rest and during activ- Slight voluntary contraction of a muscle leads to acti-
ity, may be recorded from a needle electrode inserted vation of a small number of motor units. The potentials
into the muscle. The nature and pattern of abnormali- generated by any muscle bers of these units that are
ties relate to disorders at different levels of the motor within the pickup range of the needle electrode will be
unit. recorded (Fig. 5-3). The parameters of normal motor
Relaxed muscle normally is electrically silent except unit action potentials depend on the muscle under study
in the end plate region, but abnormal spontaneous and age of the patient, but their duration is normally
activity (Fig. 5-3) occurs in various neuromuscular dis- between 5 and 15 ms, amplitude is between 200 V
orders, especially those associated with denervation or and 2 mV, and most are bi- or triphasic. The number
inammatory changes in affected muscle. Fibrillation of units activated depends on the degree of voluntary
potentials and positive sharp waves (which reect mus- activity. An increase in muscle contraction is associated
cle ber irritability) and complex repetitive discharges with an increase in the number of motor units that are
are most oftenbut not alwaysfound in denervated activated (recruited) and in the frequency with which
muscle and may also occur after muscle injury and in they discharge. With a full contraction, so many motor
certain myopathic disorders, especially inammatory units are normally activated that individual motor unit
disorders such as polymyositis. After an acute neuro- action potentials can no longer be distinguished, and
pathic lesion, they are found earlier in proximal rather a complete interference pattern is said to have been
than distal muscles and sometimes do not develop dis- produced.
tally in the extremities for 46 weeks; once present, The incidence of small, short-duration, polyphasic
they may persist indenitely unless reinnervation occurs motor unit action potentials (i.e., having more than four
or the muscle degenerates so completely that no viable phases) is usually increased in myopathic muscle, and an
tissue remains. Fasciculation potentials (which reect excessive number of units is activated for a specied degree
32 of voluntary activity. By contrast, the loss of motor units Recording
electrodes
that occurs in neuropathic disorders leads to a reduction
in number of units activated during a maximal contrac- Reference Ground
SECTION I
CHAPTER 5
severity of the underlying pathology, providing a guide
to prognosis, and detecting subclinical involvement of orthodromically (to the nerve terminals). Such anti-
other peripheral nerves. They enable a polyneuropathy dromic impulses cause a few of the anterior horn cells
to be distinguished from a mononeuropathy multiplex to discharge, producing a small motor response that
when this is not possible clinically, an important distinc- occurs considerably later than the direct response elic-
tion because of the etiologic implications. Nerve conduc- ited by nerve stimulation. The F wave so elicited is
sometimes abnormal (absent or delayed) with proximal
Electrodiagnostic Studies of Nervous System Disorders: EEG, E voked Potentials, and EMG
tion studies provide a means of following the progression
and therapeutic response of peripheral nerve disorders pathology of the peripheral nervous system, such as a
and are being used increasingly for this purpose in clinical radiculopathy, and may therefore be helpful in detect-
trials. They may suggest the underlying pathologic basis ing abnormalities when conventional nerve conduc-
in individual cases. Conduction velocity is often mark- tion studies are normal. In general, however, the clinical
edly slowed, terminal motor latencies are prolonged, utility of F-wave studies has been disappointing, except
and compound motor and sensory nerve action poten- perhaps in Guillain-Barr syndrome, where they are
tials may be dispersed in the demyelinative neuropathies often absent or delayed.
(such as in Guillain-Barr syndrome, chronic inamma-
tory polyneuropathy, metachromatic leukodystrophy,
or certain hereditary neuropathies); conduction block H-REFLEX STUDIES
is frequent in acquired varieties of these neuropathies. The H reex is easily recorded only from the soleus
By contrast, conduction velocity is normal or slowed muscle (S1) in normal adults. It is elicited by low-
only mildly, sensory nerve action potentials are small or intensity stimulation of the tibial nerve and represents a
absent, and there is EMG evidence of denervation in monosynaptic reex in which spindle (Ia) afferent bers
axonal neuropathies such as occur in association with constitute the afferent arc and alpha motor axons the
metabolic or toxic disorders. efferent pathway. The H reexes are often absent bilat-
The utility and complementary role of EMG and erally in elderly patients or with polyneuropathies and
nerve conduction studies are best illustrated by refer- may be lost unilaterally in S1 radiculopathies.
ence to a common clinical problem. Numbness and
paresthesias of the little nger and associated wasting
of the intrinsic muscles of the hand may result from
MUSCLE RESPONSE TO REPETITIVE
a spinal cord lesion, C8/T1 radiculopathy, brachial
NERVE STIMULATION
plexopathy (lower trunk or medial cord), or a lesion
of the ulnar nerve. If sensory nerve action poten- The size of the electrical response of a muscle to supra-
tials can be recorded normally at the wrist following maximal electrical stimulation of its motor nerve relates
stimulation of the digital bers in the affected n- to the number of muscle bers that are activated. Neu-
ger, the pathology is probably proximal to the dor- romuscular transmission can be tested by several dif-
sal root ganglia (i.e., there is a radiculopathy or more ferent protocols, but the most helpful is to record with
central lesion); absence of the sensory potentials, by surface electrodes the electrical response of a muscle to
contrast, suggests distal pathology. EMG examination supramaximal stimulation of its motor nerve by repeti-
will indicate whether the pattern of affected muscles tive (23 Hz) shocks delivered before and at selected
conforms to radicular or ulnar nerve territory, or is intervals after a maximal voluntary contraction.
more extensive (thereby favoring a plexopathy). There is normally little or no change in size of the
Ulnar motor conduction studies will generally also compound muscle action potential following repetitive
distinguish between a radiculopathy (normal ndings) stimulation of a motor nerve at 23 Hz with stimuli
and ulnar neuropathy (abnormal ndings) and will delivered at intervals after voluntary contraction of the
often identify the site of an ulnar nerve lesion. The muscle for about 2030 s, even though preceding activ-
nerve is stimulated at several points along its course ity in the junctional region inuences the release of ace-
to determine whether the compound action potential tylcholine and thus the size of the end-plate potentials
recorded from a distal muscle that it supplies shows a elicited by a test stimulus. This is because more acetyl-
marked alteration in size or area or a disproportion- choline is normally released than is required to bring the
ate change in latency, with stimulation at a particu- motor end-plate potentials to the threshold for generat-
lar site. The electrophysiologic ndings thus permit ing muscle ber action potentials. In disorders of neu-
a denitive diagnosis to be made and specic treat- romuscular transmission this safety factor is reduced.
ment instituted in circumstances where there is clini- Thus in myasthenia gravis, repetitive stimulation, par-
cal ambiguity. ticularly at a rate of between 2 and 5 Hz, may lead to a
34 depression of neuromuscular transmission, with a dec- record action potentials from two muscle bers belong-
rement in size of the response recorded from affected ing to the same motor unit. The time interval between
muscles. Similarly, immediately after a period of maxi- the two potentials will vary in consecutive discharges;
SECTION I
mal voluntary activity, single or repetitive stimuli of this is called the neuromuscular jitter. The jitter can be
the motor nerve may elicit larger muscle responses than quantied as the mean difference between consecutive
before, indicating that more muscle bers are respond- interpotential intervals and is normally between 10 and
ing. This postactivation facilitation of neuromuscu- 50 s. This value is increased when neuromuscular
lar transmission is followed by a longer-lasting period transmission is disturbed for any reason, and in some
of depression, maximal between 2 and 4 min after the instances impulses in individual muscle bers may fail
Introduction to Neurology
conditioning period and lasting for as long as 10 min or to occur because of impulse blocking at the neuromus-
so, during which responses are reduced in size. cular junction. Single-ber EMG is more sensitive than
Decrementing responses to repetitive stimulation repetitive nerve stimulation or determination of acetyl-
at 25 Hz are common in myasthenia gravis but may choline receptor antibody levels in diagnosing myasthe-
also occur in the congenital myasthenic syndromes. In nia gravis.
Lambert-Eaton myasthenic syndrome, in which there is Single-ber EMG can also be used to determine the
defective release of acetylcholine at the neuromuscular mean ber density of motor units (i.e., mean number of
junction, the compound muscle action potential elicited muscle bers per motor unit within the recording area)
by a single stimulus is generally very small. With repeti- and to estimate the number of motor units in a muscle,
tive stimulation at rates of up to 10 Hz, the rst few but this is of less immediate clinical relevance.
responses may decline in size, but subsequent responses
increase. If faster rates of stimulation are used (2050
Hz), the increment may be dramatic so that the ampli-
tude of compound muscle action potentials eventually BLINK REFLEXES
reaches a size that is several times larger than the ini- Electrical or mechanical stimulation of the supraorbital
tial response. In patients with botulism, the response to nerve on one side leads to two separate reex responses
repetitive stimulation is similar to that in Lambert-Eaton of the orbicularis oculian ipsilateral R1 response hav-
myasthenic syndrome, although the ndings are some- ing a latency of approximately 10 ms and a bilateral
what more variable and not all muscles are affected. R2 response with a latency in the order of 30 ms. The
trigeminal and facial nerves constitute the afferent and
efferent arcs of the reex, respectively. Abnormalities of
SINGLE-FIBER ELECTROMYOGRAPHY either nerve or intrinsic lesions of the medulla or pons
This technique is particularly helpful in detecting dis- may lead to uni- or bilateral loss of the response, and
orders of neuromuscular transmission. A special needle the ndings may therefore be helpful in identifying or
electrode is placed within a muscle and positioned to localizing such pathology.
CHAPTER 6
In experienced hands, lumbar puncture (LP) is usually low-molecular-weight heparin are at increased risk of
a safe procedure. Major complications are extremely post-LP spinal or epidural hematoma, and doses should
uncommon but can include cerebral herniation, injury be held for 24 h before the procedure.
to the spinal cord or nerve roots, hemorrhage, or infec- LP should not be performed through infected skin
tion. Minor complications occur with greater frequency as organisms can be introduced into the subarachnoid
and can include backache, post-LP headache, and radic- space (SAS).
ular pain or numbness.
ANALGESIA
IMAGING AND LABORATORY STUDIES
Anxiety and pain can be minimized prior to begin-
PRIOR TO LP
ning the procedure. Anxiety can be allayed by the use
Patients with an altered level of consciousness, a focal of lorazepam, 12 mg given PO 30 min prior to the
neurologic decit, new-onset seizure, papilledema, or procedure or IV 5 min prior to the procedure. Topi-
an immunocompromised state are at increased risk for cal anesthesia can be achieved by the application of a
potentially fatal cerebellar or tentorial herniation fol- lidocaine-based cream. Lidocaine 4% is effective when
lowing LP. Neuroimaging should be obtained in these applied 30 min prior to the procedure; lidocaine/pri-
patients prior to LP to exclude a focal mass lesion or locaine requires 60120 min. The cream should be
diffuse swelling. Imaging studies should include the applied in a thick layer so that it completely covers the
spine in patients with symptoms suggesting spinal cord skin; an occlusive dressing is used to keep the cream in
compression, such as back pain, leg weakness, urinary place.
retention, or incontinence. In patients with suspected
meningitis who require neuroimaging prior to diag-
nostic LP, administration of antibiotics, preferably fol- POSITIONING
lowing blood culture, should precede the neuroimaging
study. Proper positioning of the patient is essential. The pro-
Patients receiving therapeutic anticoagulation or cedure should be performed on a rm surface; if the
those with coagulation defects including thrombocy- procedure is to be performed at the bedside, the patient
topenia are at increased risk of post-LP spinal subdural should be positioned at the edge of the bed and not
or epidural hematomas, either of which can produce in the middle. The patient is asked to lie on his or
permanent nerve injury and/or paralysis. If a bleeding her side, facing away from the examiner, and to roll
disorder is suspected, the platelet count, international up into a ball. The neck is gently ante-exed and the
normalized ratio (INR), and partial thromboplastin time thighs pulled up toward the abdomen; the shoulders and
should be checked prior to lumbar puncture. There are pelvis should be vertically aligned without forward or
no data available to assess the safety of LP in patients backward tilt (Fig. 6-1). The spinal cord terminates
with low platelet counts; a count of <20,000/L is con- at approximately the L1 vertebral level in 94% of indi-
sidered to be a contraindication to LP. Bleeding com- viduals. In the remaining 6%, the conus extends to the
plications rarely occur in patients with platelet counts L2-L3 interspace. LP is therefore performed at or below
50,000/L and an INR 1.5. Patients receiving the L3-L4 interspace. A useful anatomic guide is a line
35
36 Level of the iliac crests 510 mini-boluses are injected, using a total of 5 mL
of lidocaine.
L3L4 interspace If possible, the LP should be delayed for 1015 min
SECTION I
position. Note that the shoulders and hips are in a vertical and slowly advanced. The bevel of the needle should be
plane; the torso is perpendicular to the bed. (From RP Simon maintained in a horizontal position, parallel to the direc-
et al [eds]: Clinical Neurology, 7th ed. New York, McGraw- tion of the dural bers and with the at portion of the
Hill, 2009.) bevel pointed upward; this minimizes injury to the bers
as the dura is penetrated. When lumbar puncture is per-
drawn between the posterior superior iliac crests, which formed in patients who are sitting, the bevel should be
corresponds closely to the level of the L3-L4 interspace. maintained in the vertical position. In most adults, the
The interspace is chosen following gentle palpation to needle is advanced 45 cm (12 in.) before the SAS is
identify the spinous processes at each lumbar level. reached; the examiner usually recognizes entry as a sud-
An alternative to the lateral recumbent position is the den release of resistance, a pop. If no uid appears
seated position. The patient sits at the side of the bed, despite apparently correct needle placement, then the
with feet supported on a chair. The patient is instructed needle may be rotated 90180. If there is still no uid,
to curl forward, trying to touch the nose to the umbi- the stylet is reinserted and the needle is advanced slightly.
licus. It is important that the patient not simply lean Some examiners halt needle advancement periodically
forward onto a bedside tabletop, as this is not an opti- to remove the stylet and check for ow of cerebrospinal
mal position for opening up the spinous processes. LP uid (CSF). If the needle cannot be advanced because it
is sometimes more easily performed in obese patients if hits bone, if the patient experiences sharp radiating pain
they are sitting. A disadvantage of the seated position is down one leg, or if no uid appears (dry tap), the
that measurement of opening pressure may not be accu- needle is partially withdrawn and reinserted at a differ-
rate. In situations in which LP is difcult using palpable ent angle. If on the second attempt the needle still hits
spinal landmarks, bedside ultrasound to guide needle bone (indicating lack of success in introducing it between
placement may be employed. the spinous processes), then the needle should be com-
pletely withdrawn and the patient should be repositioned.
The second attempt is sometimes more successful if the
TECHNIQUE patient straightens the spine completely prior to reposi-
tioning. The needle can then be reinserted at the same
Once the desired target for needle insertion has been level or at an adjacent one.
identied, the examiner should put on sterile gloves. Once the SAS is reached, a manometer is attached
After cleansing the skin with povidone-iodine or simi- to the needle and the opening pressure measured. The
lar disinfectant, the area is draped with a sterile cloth; examiner should look for normal oscillations in CSF
the needle insertion site is blotted dry using a sterile pressure associated with pulse and respirations. The
gauze pad. Proper local disinfection reduces the risk of upper limit of normal opening pressure with the patient
introducing skin bacteria into the SAS or other sites. supine is 180 mmH2O in adults but may be as high as
Local anesthetic, typically 1% lidocaine, 35 mL total, is 200250 mmH2O in obese adults.
injected into the subcutaneous tissue; in nonemergency CSF is allowed to drip into collection tubes; it should
situations a topical anesthetic cream can be applied (see not be withdrawn with a syringe. Depending on the
above). When time permits, pain associated with the clinical indication, uid is then obtained for studies
injection of lidocaine can be minimized by slow, serial including: (1) cell count with differential; (2) protein
injections, each one progressively deeper than the last, and glucose concentrations; (3) culture (bacterial, fun-
over a period of 5 min. Approximately 0.51 mL of gal, mycobacterial, viral); (4) smears (e.g., Grams and
lidocaine is injected at a time; the needle is not usu- acid-fast stained smears); (5) antigen tests (e.g., latex
ally withdrawn between injections. A pause of 15 s agglutination); (6) polymerase chain reaction (PCR)
between injections helps to minimize the pain of the amplication of DNA or RNA of microorganisms (e.g.,
subsequent injection. The goal is to inject each mini- herpes simplex virus, enteroviruses); (7) antibody lev-
bolus of anesthetic into an area of skin that has become els against microorganisms; (8) immunoelectrophoresis
numb from the preceding injection. Approximately for determination of -globulin level and oligoclonal
banding; and (9) cytology. Although 15 mL of CSF is when a patient is upright there is probably dilation and 37
sufcient to obtain all of the listed studies, the yield of tension placed on the brains anchoring structures, the
fungal and mycobacterial cultures and cytology increases pain-sensitive dural sinuses, resulting in pain. Although
CHAPTER 6
when larger volumes are sampled. In general 2030 mL intracranial hypotension is the usual explanation for
may be safely removed from adults. severe LP headache, the syndrome can occur in patients
A bloody tap due to penetration of a meningeal ves- with normal CSF pressure.
sel (a traumatic tap) may result in confusion with Because post-LP headache usually resolves without
subarachnoid hemorrhage (SAH). In these situations specic treatment, care is largely supportive with oral
a specimen of CSF should be centrifuged immediately analgesics (acetaminophen, nonsteroidal anti-inamma-
CONVENTIONAL
CONSTITUENT SI UNITS UNITS
Glucose 2.223.89 mmol/L 4070 mg/dL
a
Because cerebrospinal uid concentrations are equilibrium values,
NORMAL VALUES measurements of the same parameters in blood plasma obtained
at the same time are recommended. However, there is a time lag in
(See Table 6-2) In uninfected CSF, the normal white attainment of equilibrium, and cerebrospinal levels of plasma con-
stituents that can uctuate rapidly (such as plasma glucose) may not
blood cell count is fewer than ve mononuclear cells
achieve stable values until after a signicant lag phase.
(lymphocytes and monocytes) per L. Polymorpho- b
IgG index = CSF IgG (mg/dL) serum albumin (g/dL)/serum IgG (g/
nuclear leukocytes (PMNs) are not found in normal dL) CSF albumin (mg/dL).
unconcentrated CSF; however, rare PMNs can be
found in centrifuged or concentrated CSF specimens
such as those utilized for cytologic examination. Red
blood cells (RBCs) are not normally present in CSF;
if RBCs are present from a traumatic tap, their num-
ber decreases as additional CSF is collected. CSF glu-
cose concentrations <2.2 mmol/L (<40 mg/dL) are
abnormal.
SECTION II
CLINICAL
MANIFESTATIONS OF
NEUROLOGIC DISEASE
CHAPTER 7
The task of medicine is to preserve and restore health neurons, and sympathetic postganglionic neurons
and to relieve suffering. Understanding pain is essen- (Fig. 7-1). The cell bodies of primary sensory afferents
tial to both of these goals. Because pain is universally are located in the dorsal root ganglia in the vertebral
understood as a signal of disease, it is the most com- foramina. The primary afferent axon has two branches:
mon symptom that brings a patient to a physicians one projects centrally into the spinal cord and the other
attention. The function of the pain sensory system is projects peripherally to innervate tissues. Primary affer-
to protect the body and maintain homeostasis. It does ents are classied by their diameter, degree of myelina-
this by detecting, localizing, and identifying potential or tion, and conduction velocity. The largest-diameter
actual tissue-damaging processes. Because different dis- afferent bers, A-beta (A), respond maximally to light
eases produce characteristic patterns of tissue damage, touch and/or moving stimuli; they are present primarily
the quality, time course, and location of a patients pain in nerves that innervate the skin. In normal individuals,
complaint provide important diagnostic clues. It is the the activity of these bers does not produce pain. There
physicians responsibility to provide rapid and effective are two other classes of primary afferents: the small-
pain relief. diameter myelinated A-delta (A) and the unmyelin-
ated (C ber) axons (Fig. 7-1). These bers are present
in nerves to the skin and to deep somatic and visceral
structures. Some tissues, such as the cornea, are inner-
THE PAIN SENSORY SYSTEM
vated only by A and C ber afferents. Most A and C
Pain is an unpleasant sensation localized to a part of the ber afferents respond maximally only to intense (pain-
body. It is often described in terms of a penetrating or ful) stimuli and produce the subjective experience of
tissue-destructive process (e.g., stabbing, burning, twist- pain when they are electrically stimulated; this denes
ing, tearing, squeezing) and/or of a bodily or emotional them as primary afferent nociceptors (pain receptors). The
reaction (e.g., terrifying, nauseating, sickening). Further- ability to detect painful stimuli is completely abolished
more, any pain of moderate or higher intensity is accom- when conduction in A and C ber axons is blocked.
panied by anxiety and the urge to escape or terminate the Individual primary afferent nociceptors can respond
feeling. These properties illustrate the duality of pain: it to several different types of noxious stimuli. For exam-
is both sensation and emotion. When it is acute, pain is ple, most nociceptors respond to heat; intense cold;
characteristically associated with behavioral arousal and intense mechanical stimuli, such as a pinch; changes in
a stress response consisting of increased blood pressure, pH, particularly an acidic environment; and application
heart rate, pupil diameter, and plasma cortisol levels. In of chemical irritants including adenosine triphosphate
addition, local muscle contraction (e.g., limb exion, (ATP), serotonin, bradykinin, and histamine.
abdominal wall rigidity) is often present.
Sensitization
PERIPHERAL MECHANISMS When intense, repeated, or prolonged stimuli are
applied to damaged or inamed tissues, the threshold
The primary afferent nociceptor
for activating primary afferent nociceptors is lowered,
A peripheral nerve consists of the axons of three differ- and the frequency of ring is higher for all stimulus
ent types of neurons: primary sensory afferents, motor intensities. Inammatory mediators such as bradykinin,
40
Dorsal root 41
ganglion
Peripheral nerve
Spinal
cord
CHAPTER 7
A
C
Sympathetic
Sympathetic preganglionic
postganglionic
nerve-growth factor, some prostaglandins, and leukotri- A large proportion of A and C ber afferents inner-
enes contribute to this process, which is called sensitiza- vating viscera are completely insensitive in normal non-
tion. Sensitization occurs at the level of the peripheral injured, noninamed tissue. That is, they cannot be
nerve terminal (peripheral sensitization) as well as at the activated by known mechanical or thermal stimuli and
level of the dorsal horn of the spinal cord (central sensi- are not spontaneously active. However, in the presence
tization). Peripheral sensitization occurs in damaged or of inammatory mediators, these afferents become sen-
inamed tissues, when inammatory mediators activate sitive to mechanical stimuli. Such afferents have been
intracellular signal transduction in nociceptors, prompt- termed silent nociceptors, and their characteristic proper-
ing an increase in the production, transport, and mem- ties may explain how, under pathologic conditions, the
brane insertion of chemically gated and voltage-gated relatively insensitive deep structures can become the
ion channels. These changes increase the excitability of source of severe and debilitating pain and tenderness.
nociceptor terminals and lower their threshold for acti- Low pH, prostaglandins, leukotrienes, and other inam-
vation by mechanical, thermal, and chemical stimuli. matory mediators such as bradykinin play a signicant
Central sensitization occurs when activity, generated by role in sensitization.
nociceptors during inammation, enhances the excit-
ability of nerve cells in the dorsal horn of the spinal
cord. Following injury and resultant sensitization, nor-
Nociceptor-induced inammation
mally innocuous stimuli can produce pain. Sensitiza-
tion is a clinically important process that contributes to Primary afferent nociceptors also have a neuroeffec-
tenderness, soreness, and hyperalgesia (increased pain tor function. Most nociceptors contain polypeptide
intensity in response to the same noxious stimulus; e.g., mediators that are released from their peripheral termi-
moderate pressure causes severe pain). A striking exam- nals when they are activated (Fig. 7-2). An example
ple of sensitization is sunburned skin, in which severe is substance P, an 11-amino-acid peptide. Substance P
pain can be produced by a gentle slap on the back or a is released from primary afferent nociceptors and has
warm shower. multiple biologic activities. It is a potent vasodilator,
Sensitization is of particular importance for pain and degranulates mast cells, is a chemoattractant for leu-
tenderness in deep tissues. Viscera are normally relatively kocytes, and increases the production and release of
insensitive to noxious mechanical and thermal stimuli, inammatory mediators. Interestingly, depletion of sub-
although hollow viscera do generate signicant discomfort stance P from joints reduces the severity of experimen-
when distended. In contrast, when affected by a disease tal arthritis. Primary afferent nociceptors are not simply
process with an inammatory component, deep structures passive messengers of threats to tissue injury but also
such as joints or hollow viscera characteristically become play an active role in tissue protection through these
exquisitely sensitive to mechanical stimulation. neuroeffector functions.
42 A Primary activation Skin
K+
PG
BK
H+
SECTION II
Viscus Anterolateral
tract axon
FIGURE 7-3
The convergence-projection hypothesis of referred pain.
Clinical Manifestations of Neurologic Disease
Mast cell
terminals of primary afferent axons contact spinal neu-
SP H
SP rons that transmit the pain signal to brain sites involved
in pain perception. When primary afferents are acti-
vated by noxious stimuli, they release neurotransmit-
5HT BK ters from their terminals that excite the spinal cord
Platelet neurons. The major neurotransmitter released is gluta-
mate, which rapidly excites dorsal horn neurons. Pri-
mary afferent nociceptor terminals also release peptides,
including substance P and calcitonin gene-related pep-
FIGURE 7-2 tide, which produce a slower and longer-lasting excita-
Events leading to activation, sensitization, and spread tion of the dorsal horn neurons. The axon of each pri-
of sensitization of primary afferent nociceptor terminals. mary afferent contacts many spinal neurons, and each
A. Direct activation by intense pressure and consequent cell spinal neuron receives convergent inputs from many
damage. Cell damage induces lower pH (H+) and leads to primary afferents.
release of potassium (K+) and to synthesis of prostaglandins The convergence of sensory inputs to a single spinal
(PG) and bradykinin (BK). Prostaglandins increase the sensi- pain-transmission neuron is of great importance because
tivity of the terminal to bradykinin and other pain-producing it underlies the phenomenon of referred pain. All spi-
substances. B. Secondary activation. Impulses generated in
nal neurons that receive input from the viscera and deep
the stimulated terminal propagate not only to the spinal cord
musculoskeletal structures also receive input from the
but also into other terminal branches where they induce the
skin. The convergence patterns are determined by the
release of peptides, including substance P (SP). Substance
spinal segment of the dorsal root ganglion that supplies
P causes vasodilation and neurogenic edema with further
accumulation of bradykinin (BK). Substance P also causes
the afferent innervation of a structure. For example, the
the release of histamine (H) from mast cells and serotonin
afferents that supply the central diaphragm are derived
(5HT) from platelets. from the third and fourth cervical dorsal root ganglia.
Primary afferents with cell bodies in these same ganglia
supply the skin of the shoulder and lower neck. Thus,
CENTRAL MECHANISMS sensory inputs from both the shoulder skin and the cen-
tral diaphragm converge on pain-transmission neurons
The spinal cord and referred pain
in the third and fourth cervical spinal segments. Because
The axons of primary afferent nociceptors enter the of this convergence and the fact that the spinal neurons are most
spinal cord via the dorsal root. They terminate in the often activated by inputs from the skin, activity evoked in spi-
dorsal horn of the spinal gray matter (Fig. 7-3). The nal neurons by input from deep structures is mislocalized by
the patient to a place that roughly corresponds with the region 43
of skin innervated by the same spinal segment. Thus, inam- A F B
mation near the central diaphragm is usually reported as C
shoulder discomfort. This spatial displacement of pain
sensation from the site of the injury that produces it is SS
known as referred pain.
Thalamus
Hypothalamus
Ascending pathways for pain
CHAPTER 7
A majority of spinal neurons contacted by primary affer-
ent nociceptors send their axons to the contralateral Midbrain
thalamus. These axons form the contralateral spinotha- Spinothalamic
lamic tract, which lies in the anterolateral white matter tract
of the spinal cord, the lateral edge of the medulla, and Medulla
the lateral pons and midbrain. The spinothalamic path-
way is crucial for pain sensation in humans. Interruption Injury
NEUROPATHIC PAIN
Lesions of the peripheral or central nociceptive path-
ways typically result in a loss or impairment of pain sen-
sation. Paradoxically, damage to or dysfunction of these
pathways can also produce pain. For example, damage
to peripheral nerves, as occurs in diabetic neuropathy,
or to primary afferents, as in herpes zoster, can result
in pain that is referred to the body region innervated
by the damaged nerves. Pain may also be produced by
damage to the central nervous system (CNS), for exam-
ple, in some patients following trauma or cerebrovas-
cular injury to spinal cord, brainstem, or thalamic areas
that contain central nociceptive pathways. Such neuro-
pathic pains are often severe and are typically resistant to
standard treatments for pain.
Neuropathic pain typically has an unusual burning,
tingling, or electric shocklike quality and may be trig-
FIGURE 7-5
gered by very light touch. These features are rare in
Functional magnetic resonance imaging (fMRI) dem-
other types of pain. On examination, a sensory decit
onstrates placebo-enhanced brain activity in anatomic
is characteristically present in the area of the patients
regions correlating with the opioidergic descending
pain. Hyperpathia, a greatly exaggerated pain sensation
pain control system. Top panel, Frontal fMRI image shows
placebo-enhanced brain activity in the dorsal lateral prefron-
to innocuous or mild nociceptive stimuli, is also char-
tal cortex (DLPFC). Bottom panel, Sagittal fMRI images show
acteristic of neuropathic pain; patients often complain
placebo-enhanced responses in the rostral anterior cingu- that the very lightest moving stimulus evokes exquisite
late cortex (rACC), the rostral ventral medullae (RVM), the pain (allodynia). In this regard, it is of clinical interest
periaqueductal gray (PAG) area, and the hypothalamus. The that a topical preparation of 5% lidocaine in patch form
placebo-enhanced activity in all areas was reduced by nalox- is effective for patients with postherpetic neuralgia who
one, demonstrating the link between the descending opioi- have prominent allodynia.
dergic system and the placebo analgesic response. (Adapted A variety of mechanisms contribute to neuropathic
with permission from F Eippert et al: Neuron 63:533, 2009.) pain. As with sensitized primary afferent nociceptors, dam-
aged primary afferents, including nociceptors, become
circuit contain endogenous opioid peptides such as the highly sensitive to mechanical stimulation and may gen-
enkephalins and -endorphin. erate impulses in the absence of stimulation. Increased
The most reliable way to activate this endogenous sensitivity and spontaneous activity are due, in part, to an
opioid-mediated modulating system is by suggestion of increased concentration of sodium channels. Damaged pri-
pain relief or by intense emotion directed away from mary afferents may also develop sensitivity to norepineph-
the pain-causing injury (e.g., during severe threat or rine. Interestingly, spinal cord pain-transmission neurons
an athletic competition). In fact, pain-relieving endog- cut off from their normal input may also become sponta-
enous opioids are released following surgical procedures neously active. Thus, both CNS and peripheral nervous
and in patients given a placebo for pain relief. system hyperactivity contribute to neuropathic pain.
Sympathetically maintained pain these compounds inhibit cyclooxygenase (COX), and, 45
Patients with peripheral nerve injury occasionally develop except for acetaminophen, all have anti-inflammatory
spontaneous pain in the region innervated by the nerve. actions, especially at higher dosages. They are particu-
This pain is often described as having a burning quality. larly effective for mild to moderate headache and for
The pain typically begins after a delay of hours to days pain of musculoskeletal origin.
or even weeks and is accompanied by swelling of the Because they are effective for these common types
extremity, periarticular bone loss, and arthritic changes of pain and are available without prescription, COX
in the distal joints. The pain may be relieved by a local inhibitors are by far the most commonly used analge-
anesthetic block of the sympathetic innervation to the sics. They are absorbed well from the gastrointestinal
CHAPTER 7
affected extremity. Damaged primary afferent nocicep- tract and, with occasional use, have only minimal side
tors acquire adrenergic sensitivity and can be activated effects. With chronic use, gastric irritation is a common
by stimulation of the sympathetic outow. This con- side effect of aspirin and NSAIDs and is the problem
stellation of spontaneous pain and signs of sympathetic that most frequently limits the dose that can be given.
dysfunction following injury has been termed complex Gastric irritation is most severe with aspirin, which may
regional pain syndrome (CRPS). When this occurs after an cause erosion and ulceration of the gastric mucosa lead-
a
Antidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the
treatment of pain.
b
Gabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia.
Note: 5-HT, serotonin; NE, norepinephrine.
of NSAIDs, excluding aspirin. These drugs are contraindi- determining whether the drug has adequately relieved 47
cated in patients in the immediate period after coronary the pain and frequent reassessment to determine the
artery bypass surgery and should be used with caution optimal interval for dosing. The most common error made
in patients with a history of or significant risk factors for by physicians in managing severe pain with opioids is to pre-
cardiovascular disease. scribe an inadequate dose. Because many patients are reluc-
tant to complain, this practice leads to needless suffering.
OPIOID ANALGESICS Opioids are the most potent In the absence of sedation at the expected time of peak
pain-relieving drugs currently available. Of all analgesics, effect, a physician should not hesitate to repeat the initial
they have the broadest range of efficacy and provide the dose to achieve satisfactory pain relief.
CHAPTER 7
most reliable and effective method for rapid pain relief. An innovative approach to the problem of achiev-
Although side effects are common, most are reversible: ing adequate pain relief is the use of patient-controlled
nausea, vomiting, pruritus, and constipation are the most analgesia (PCA). PCA uses a microprocessor-controlled
frequent and bothersome side effects. Respiratory depres- infusion device that can deliver a baseline continuous
sion is uncommon at standard analgesic doses, but can dose of an opioid drug as well as preprogrammed addi-
be life-threatening. Opioid-related side effects can be tional doses whenever the patient pushes a button. The
cannot be given oral medication. The fentanyl transder- ical evaluation and behaviorally based treatment para-
mal patch has the advantage of providing fairly steady digms are frequently helpful, particularly in the setting
plasma levels, which maximizes patient comfort. of a multidisciplinary pain-management center. Unfor-
Recent additions to the armamentarium for treating tunately, this approach, while effective, remains largely
opioid-induced side effects are the peripherally acting underused in current medical practice.
opioid antagonists alvimopan (Entereg) and methyl- There are several factors that can cause, perpetuate,
Clinical Manifestations of Neurologic Disease
naltrexone (Rellistor). Alvimopan is available as an orally or exacerbate chronic pain. First, of course, the patient
administered agent that is restricted to the intestinal may simply have a disease that is characteristically pain-
lumen by limited absorption; methylnaltrexone is avail- ful for which there is presently no cure. Arthritis, can-
able in a subcutaneously administered form that has vir- cer, chronic daily headaches, bromyalgia, and diabetic
tually no penetration into the CNS. Both agents act by neuropathy are examples of this. Second, there may be
binding to peripheral -receptors, thereby inhibiting or secondary perpetuating factors that are initiated by dis-
reversing the effects of opioids at these peripheral sites. ease and persist after that disease has resolved. Examples
The action of both agents is restricted to receptor sites include damaged sensory nerves, sympathetic efferent
outside of the CNS; thus, these drugs can reverse the activity, and painful reex muscle contraction. Finally,
adverse effects of opioid analgesics that are mediated a variety of psychological conditions can exacerbate or
through their peripheral receptors without reversing even cause pain.
their analgesic effects. Both agents are effective for per- There are certain areas to which special attention
sistent ileus following abdominal surgery to the extent should be paid in a patients medical history. Because
that opioid analgesics used for postoperative pain control depression is the most common emotional disturbance
contribute to this serious problem. Likewise, both agents in patients with chronic pain, patients should be ques-
have been tested for their effectiveness in treating opi- tioned about their mood, appetite, sleep patterns, and
oid-induced bowel dysfunction (constipation) in patients daily activity. A simple standardized questionnaire,
taking opioid analgesics on a chronic basis. Although such as the Beck Depression Inventory, can be a use-
contradictory, the weight of evidence indicates that alvi- ful screening device. It is important to remember that
mopan can reduce the incidence and duration of ileus major depression is a common, treatable, and potentially
following major abdominal surgery and methylnaltrex- fatal illness.
one can produce rapid reversal of constipation in many Other clues that a signicant emotional disturbance
patients receiving opioids on a chronic basis. is contributing to a patients chronic pain complaint
include pain that occurs in multiple, unrelated sites; a
Opioid and COX Inhibitor Combinations
pattern of recurrent, but separate, pain problems begin-
When used in combination, opioids and COX inhibitors ning in childhood or adolescence; pain beginning at a
have additive effects. Because a lower dose of each can be time of emotional trauma, such as the loss of a parent or
used to achieve the same degree of pain relief and their spouse; a history of physical or sexual abuse; and past or
side effects are nonadditive, such combinations are used present substance abuse.
to lower the severity of dose-related side effects. However, On examination, special attention should be paid
fixed-ratio combinations of an opioid with acetaminophen to whether the patient guards the painful area and
carry a special risk. Dose escalation as a result of increased whether certain movements or postures are avoided
severity of pain or decreased opioid effect as a result of tol- because of pain. Discovering a mechanical component
erance may lead to levels of acetaminophen that are toxic to the pain can be useful both diagnostically and ther-
to the liver. Although acetaminophen-related hepatotoxicity apeutically. Painful areas should be examined for deep
is uncommon, it remains a leading cause for liver failure. tenderness, noting whether this is localized to muscle,
Thus, many practitioners have moved away from the use ligamentous structures, or joints. Chronic myofascial
of opioid-acetaminophen combination analgesics to avoid pain is very common, and, in these patients, deep pal-
the risk of excessive acetaminophen exposure as the dose pation may reveal highly localized trigger points that
of the analgesic is escalated. are rm bands or knots in muscle. Relief of the pain
following injection of local anesthetic into these trigger TABLE 7-2 49
points supports the diagnosis. A neuropathic component PAINFUL CONDITIONS THAT RESPOND TO
to the pain is indicated by evidence of nerve damage, TRICYCLIC ANTIDEPRESSANTS
such as sensory impairment, exquisitely sensitive skin, Postherpetic neuralgiaa
weakness, and muscle atrophy, or loss of deep tendon Diabetic neuropathya
reexes. Evidence suggesting sympathetic nervous sys- Tension headachea
tem involvement includes the presence of diffuse swell- Migraine headachea
ing, changes in skin color and temperature, and hyper- Rheumatoid arthritisa,b
sensitive skin and joint tenderness compared with the Chronic low back painb
CHAPTER 7
normal side. Relief of the pain with a sympathetic block Cancer
Central post-stroke pain
is diagnostic.
A guiding principle in evaluating patients with a
Controlled trials demonstrate analgesia.
b
chronic pain is to assess both emotional and organic fac- Controlled studies indicate benet but not analgesia.
tors before initiating therapy. Addressing these issues
together, rather than waiting to address emotional
issues after organic causes of pain have been ruled out,
CHRONIC OPIOID MEDICATION The long- pregabalin, see above) or antidepressants (nortripty-
term use of opioids is accepted for patients with pain line, desipramine, duloxetine, or venlafaxine) can be
due to malignant disease. Although opioid use for used as first-line drugs for patients with neuropathic
chronic pain of nonmalignant origin is controversial, pain. Systemically administered antiarrhythmic drugs
it is clear that for many such patients, opioid analge- such as lidocaine and mexiletene are less likely to be
sics are the best available option. This is understand- effective; although intravenous infusion of lidocaine
able because opioids are the most potent and have predictably provides analgesia in those with many
the broadest range of efficacy of any analgesic medica- forms of neuropathic pain, the relief is usually tran-
tions. Although addiction is rare in patients who first sient, typically lasting just hours after the cessation of
use opioids for pain relief, some degree of tolerance the infusion. The oral lidocaine congener mexiletene is
and physical dependence is likely with long-term use. poorly tolerated, producing frequent gastrointestinal
Therefore, before embarking on opioid therapy, other adverse effects. There is no consensus on which class
options should be explored, and the limitations and of drug should be used as a first-line treatment for any
risks of opioids should be explained to the patient. It is chronically painful condition. However, because rela-
also important to point out that some opioid analgesic tively high doses of anticonvulsants are required for
medications have mixed agonist-antagonist properties pain relief, sedation is very common. Sedation is also a
(e.g., pentazocine and butorphanol). From a practical problem with TCAs but is much less of a problem with
standpoint, this means that they may worsen pain by serotonin/norepinephrine reuptake inhibitors (SNRIs,
inducing an abstinence syndrome in patients who are e.g., venlafaxine and duloxetine). Thus, in the elderly
physically dependent on other opioid analgesics. or in those patients whose daily activities require high-
With long-term outpatient use of orally administered level mental activity, these drugs should be considered
opioids, it is desirable to use long-acting compounds the first line. In contrast, opioid medications should
such as levorphanol, methadone, or sustained-release be used as a second- or third-line drug class. While
morphine (Table 7-1). Transdermal fentanyl is another highly effective for many painful conditions, opioids
excellent option. The pharmacokinetic profile of these are sedating, and their effect tends to lessen over time,
drug preparations enables prolonged pain relief, mini- leading to dose escalation and, occasionally, a worsen-
mizes side effects such as sedation that are associated ing of pain due to physical dependence. Drugs of dif-
with high peak plasma levels, and reduces the likelihood ferent classes can be used in combination to optimize
of rebound pain associated with a rapid fall in plasma pain control.
opioid concentration. While long-acting opioid prepara- It is worth emphasizing that many patients, espe-
tions may provide superior pain relief in patients with a cially those with chronic pain, seek medical attention
continuous pattern of ongoing pain, others suffer from primarily because they are suffering and because only
intermittent severe episodic pain and experience supe- physicians can provide the medications required for
rior pain control and fewer side effects with the periodic pain relief. A primary responsibility of all physicians is to
use of short-acting opioid analgesics. Constipation is a minimize the physical and emotional discomfort of their
virtually universal side effect of opioid use and should patients. Familiarity with pain mechanisms and analgesic
be treated expectantly. A recent advance for patients medications is an important step toward accomplishing
with chronic debilitating conditions is the development this aim.
CHAPTER 8
HEADACHE
Headache is among the most common reasons patients ANATOMY AND PHYSIOLOGY
seek medical attention. Diagnosis and management are OF HEADACHE
based on a careful clinical approach augmented by an
understanding of the anatomy, physiology, and pharma- Pain usually occurs when peripheral nociceptors are
cology of the nervous system pathways that mediate the stimulated in response to tissue injury, visceral disten-
various headache syndromes. sion, or other factors (Chap. 7). In such situations, pain
perception is a normal physiologic response mediated
by a healthy nervous system. Pain can also result when
pain-producing pathways of the peripheral or central
GENERAL PRINCIPLES nervous system (CNS) are damaged or activated inap-
propriately. Headache may originate from either or
A classication system developed by the International
both mechanisms. Relatively few cranial structures are
Headache Society characterizes headache as primary
pain-producing; these include the scalp, middle menin-
or secondary (Table 8-1). Primary headaches are those
geal artery, dural sinuses, falx cerebri, and proximal seg-
in which headache and its associated features are the
ments of the large pial arteries. The ventricular epen-
disorder in itself, whereas secondary headaches are those
dyma, choroid plexus, pial veins, and much of the brain
caused by exogenous disorders. Primary headache often
parenchyma are not pain-producing.
results in considerable disability and a decrease in the
The key structures involved in primary headache
patients quality of life. Mild secondary headache, such
appear to be
as that seen in association with upper respiratory tract
infections, is common but rarely worrisome. Life- the large intracranial vessels and dura mater and the
threatening headache is relatively uncommon, but vigi- peripheral terminals of the trigeminal nerve that
lance is required in order to recognize and appropriately innervate these structures
treat such patients. the caudal portion of the trigeminal nucleus, which
extends into the dorsal horns of the upper cervical
spinal cord and receives input from the rst and sec-
TABLE 8-1
ond cervical nerve roots (the trigeminocervical com-
COMMON CAUSES OF HEADACHE plex)
PRIMARY HEADACHE SECONDARY HEADACHE rostral pain-processing regions, such as the ventro-
posteromedial thalamus and the cortex
TYPE % TYPE %
the pain-modulatory systems in the brain that modu-
Tension-type 69 Systemic infection 63 late input from trigeminal nociceptors at all levels of
Migraine 16 Head injury 4 the pain-processing pathways
Idiopathic stabbing 2 Vascular disorders 1 The innervation of the large intracranial vessels and
Exertional 1 Subarachnoid hemorrhage <1 dura mater by the trigeminal nerve is known as the
Cluster 0.1 Brain tumor 0.1 trigeminovascular system. Cranial autonomic symptoms,
such as lacrimation and nasal congestion, are prominent
Source: After J Olesen et al: The Headaches. Philadelphia, Lippin- in the trigeminal autonomic cephalalgias, including
cott, Williams & Wilkins, 2005. cluster headache and paroxysmal hemicrania, and may
51
52 also be seen in migraine. These autonomic symptoms puncture (LP) is also required, unless a benign etiology
reect activation of cranial parasympathetic pathways, can be otherwise established. A general evaluation of
and functional imaging studies indicate that vascu- acute headache might include the investigation of car-
lar changes in migraine and cluster headache, when diovascular and renal status by blood pressure monitor-
present, are similarly driven by these cranial auto- ing and urine examination; eyes by funduscopy, intra-
nomic systems. Migraine and other primary headache ocular pressure measurement, and refraction; cranial
types are not vascular headaches; these disorders arteries by palpation; and cervical spine by the effect of
do not reliably manifest vascular changes, and treat- passive movement of the head and by imaging.
ment outcomes cannot be predicted by vascular effects. The psychological state of the patient should also be
SECTION II
Migraine is a brain disorder, and best understood and evaluated since a relationship exists between head pain
managed as such. and depression. Many patients in chronic daily pain
cycles become depressed, although depression itself is
rarely a cause of headache. Drugs with antidepressant
CLINICAL EVALUATION OF ACUTE, NEW- actions are also effective in the prophylactic treatment
ONSET HEADACHE of both tension-type headache and migraine.
Underlying recurrent headache disorders may be
Clinical Manifestations of Neurologic Disease
The patient who presents with a new, severe headache activated by pain that follows otologic or endodontic
has a differential diagnosis that is quite different from the surgical procedures. Thus, pain about the head as the
patient with recurrent headaches over many years. In result of diseased tissue or trauma may reawaken an oth-
new-onset and severe headache, the probability of nd- erwise quiescent migrainous syndrome. Treatment of
ing a potentially serious cause is considerably greater than the headache is largely ineffective until the cause of the
in recurrent headache. Patients with recent onset of pain primary problem is addressed.
require prompt evaluation and appropriate treatment. Serious underlying conditions that are associated with
Serious causes to be considered include meningitis, sub- headache are described next. Brain tumor is a rare cause
arachnoid hemorrhage, epidural or subdural hematoma, of headache and even less commonly a cause of severe
glaucoma, tumor, and purulent sinusitis. When worri- pain. The vast majority of patients presenting with
some symptoms and signs are present (Table 8-2), rapid severe headache have a benign cause.
diagnosis and management are critical.
A complete neurologic examination is an essen-
tial rst step in the evaluation. In most cases, patients
with an abnormal examination or a history of recent- SECONDARY HEADACHE
onset headache should be evaluated by a CT or MRI
study. As an initial screening procedure for intracranial The management of secondary headache focuses on
pathology in this setting, CT and MRI methods appear diagnosis and treatment of the underlying condition.
to be equally sensitive. In some circumstances, a lumbar
MENINGITIS
TABLE 8-2 Acute, severe headache with stiff neck and fever sug-
HEADACHE SYMPTOMS THAT SUGGEST A SERIOUS gests meningitis. Lumbar puncture is mandatory. Often
UNDERLYING DISORDER there is striking accentuation of pain with eye move-
Worst headache ever ment. Meningitis can be easily mistaken for migraine
First severe headache in that the cardinal symptoms of pounding headache,
Subacute worsening over days or weeks
photophobia, nausea, and vomiting are frequently pres-
ent, perhaps reecting the underlying biology of some
Abnormal neurologic examination
of the patients.
Fever or unexplained systemic signs Meningitis is discussed in Chaps. 40 and 41.
Vomiting that precedes headache
Pain induced by bending, lifting, cough
Pain that disturbs sleep or presents immediately upon INTRACRANIAL HEMORRHAGE
awakening
Acute, severe headache with stiff neck but without
Known systemic illness fever suggests subarachnoid hemorrhage. A ruptured
Onset after age 55 aneurysm, arteriovenous malformation, or intraparen-
Pain associated with local tenderness, e.g., region of tem- chymal hemorrhage may also present with headache
poral artery alone. Rarely, if the hemorrhage is small or below the
foramen magnum, the head CT scan can be normal.
Therefore, lumbar puncture may be required to diag- appear in migraine. Most patients can recognize that 53
nose denitively subarachnoid hemorrhage. the origin of their head pain is supercial, external to
Intracranial hemorrhage is discussed in Chap. 28. the skull, rather than originating deep within the cra-
nium (the pain site for migraineurs). Scalp tenderness is
present, often to a marked degree; brushing the hair or
BRAIN TUMOR resting the head on a pillow may be impossible because
Approximately 30% of patients with brain tumors con- of pain. Headache is usually worse at night and often
sider headache to be their chief complaint. The head aggravated by exposure to cold. Additional ndings may
pain is usually nondescriptan intermittent deep, dull include reddened, tender nodules or red streaking of the
CHAPTER 8
aching of moderate intensity, which may worsen with skin overlying the temporal arteries, and tenderness of
exertion or change in position and may be associated the temporal or, less commonly, the occipital arteries.
with nausea and vomiting. This pattern of symptoms The erythrocyte sedimentation rate (ESR) is often,
results from migraine far more often than from brain though not always, elevated; a normal ESR does not
tumor. The headache of brain tumor disturbs sleep in exclude giant cell arteritis. A temporal artery biopsy fol-
about 10% of patients. Vomiting that precedes the lowed by immediate treatment with prednisone 80 mg
daily for the rst 46 weeks should be initiated when clini-
Headache
appearance of headache by weeks is highly characteristic
of posterior fossa brain tumors. A history of amenorrhea cal suspicion is high. The prevalence of migraine among
or galactorrhea should lead one to question whether a the elderly is substantial, considerably higher than that of
prolactin-secreting pituitary adenoma (or the polycystic giant cell arteritis. Migraineurs often report amelioration
ovary syndrome) is the source of headache. Headache of their headaches with prednisone; thus, caution must be
arising de novo in a patient with known malignancy used when interpreting the therapeutic response.
suggests either cerebral metastases or carcinomatous
meningitis, or both. Head pain appearing abruptly after GLAUCOMA
bending, lifting, or coughing can be due to a posterior
fossa mass, a Chiari malformation, or low CSF volume. Glaucoma may present with a prostrating headache
Brain tumors are discussed in Chap. 37. associated with nausea and vomiting. The headache
often starts with severe eye pain. On physical exami-
nation, the eye is often red with a xed, moderately
TEMPORAL ARTERITIS dilated pupil.
Glaucoma is discussed in Chap. 21.
(See also Chap. 21) Temporal (giant cell) arteritis is
an inammatory disorder of arteries that frequently
involves the extracranial carotid circulation. It is a com-
mon disorder of the elderly; its annual incidence is 77 PRIMARY HEADACHE SYNDROMES
per 100,000 individuals age 50 and older. The average
age of onset is 70 years, and women account for 65% Primary headaches are disorders in which headache
of cases. About half of patients with untreated tempo- and associated features occur in the absence of any
ral arteritis develop blindness due to involvement of the exogenous cause (Table 8-1). The most common are
ophthalmic artery and its branches; indeed, the isch- migraine, tension-type headache, and cluster headache.
emic optic neuropathy induced by giant cell arteritis is
the major cause of rapidly developing bilateral blindness
MIGRAINE
in patients >60 years. Because treatment with gluco-
corticoids is effective in preventing this complication, Migraine, the second most common cause of head-
prompt recognition of the disorder is important. ache, aficts approximately 15% of women and 6% of
Typical presenting symptoms include headache, men over a 1-year period. It is usually an episodic head-
polymyalgia rheumatica, jaw claudication, fever, and ache associated with certain features such as sensitiv-
weight loss. Headache is the dominant symptom and ity to light, sound, or movement; nausea and vomiting
often appears in association with malaise and muscle often accompany the headache. A useful description of
aches. Head pain may be unilateral or bilateral and is migraine is a benign and recurring syndrome of head-
located temporally in 50% of patients but may involve ache associated with other symptoms of neurologic dys-
any and all aspects of the cranium. Pain usually appears function in varying admixtures (Table 8-3). Migraine
gradually over a few hours before peak intensity is can often be recognized by its activators, referred to as
reached; occasionally, it is explosive in onset. The qual- triggers.
ity of pain is only seldom throbbing; it is almost invari- The brain of the migraineur is particularly sensi-
ably described as dull and boring, with superimposed tive to environmental and sensory stimuli; migraine-
episodic stabbing pains similar to the sharp pains that prone patients do not habituate easily to sensory stimuli.
54 TABLE 8-3 effects. Other brainstem regions likely to be involved in
SYMPTOMS ACCOMPANYING SEVERE MIGRAINE descending modulation of trigeminal pain include the
ATTACKS IN 500 PATIENTS nucleus locus coeruleus in the pons and the rostroven-
SYMPTOM PATIENTS AFFECTED, %
tromedial medulla.
Pharmacologic and other data point to the involve-
Nausea 87 ment of the neurotransmitter 5-hydroxytryptamine
Photophobia 82 (5-HT; also known as serotonin) in migraine. Approxi-
Lightheadedness 72 mately 60 years ago, methysergide was found to antago-
Scalp tenderness 65
nize certain peripheral actions of 5-HT and was intro-
SECTION II
Locus
CHAPTER 8
Dura coeruleus
Superior
salivatory nucleus
Magnus raphe
nucleus
Headache
TCC
Trigeminal
ganglion
Pterygopalatine
ganglion
FIGURE 8-1
Brainstem pathways that modulate sensory input. The turn project in the quintothalamic tract and, after decussat-
key pathway for pain in migraine is the trigeminovascular ing in the brainstem, synapse on neurons in the thalamus.
input from the meningeal vessels, which passes through the Important modulation of the trigeminovascular nociceptive
trigeminal ganglion and synapses on second-order neurons input comes from the dorsal raphe nucleus, locus coeruleus,
in the trigeminocervical complex (TCC). These neurons in and nucleus raphe magnus.
FIGURE 8-2
Positron emission tomography (PET) activation in lateralization of changes in this region of the brainstem cor-
migraine. In spontaneous attacks of episodic migraine there relates with lateralization of the head pain in hemicranial
is activation of the region of the dorsolateral pons; an iden- migraine; the scans shown in panels A and B are of patients
tical pattern is found in chronic migraine (not shown). This with acute migraine headache on the right and left side,
area, which includes the noradrenergic locus coeruleus, respectively. (From S Afridi et al: Brain 128:932, 2005.)
is fundamental to the expression of migraine. Moreover,
56
SECTION II
A B
Clinical Manifestations of Neurologic Disease
FIGURE 8-3
Posterior hypothalamic gray matter activation on positron morphometry demonstrates increased gray matter activity,
emission tomography (PET) in a patient with acute clus- lateralized to the side of pain in a patient with cluster head-
ter headache (A). (From A May et al: Lancet 352:275, 1998.) ache (B). (From A May et al: Nat Med 5:836, 1999.)
High-resolution T1-weighted MRI obtained using voxel-based
moving across the visual eld or of other neurologic but with little or no headache. Vertigo can be promi-
symptoms, is reported in only 2025% of patients. A nent; it has been estimated that one-third of patients
headache diary can often be helpful in making the diag- referred for vertigo or dizziness have a primary diagnosis
nosis; this is also helpful in assessing disability and the of migraine.
frequency of treatment for acute attacks. Patients with
episodes of migraine that occur daily or near-daily are
considered to have chronic migraine (see Chronic
TREATMENT Migraine Headaches
Daily Headache, later in this chapter). Migraine must
be differentiated from tension-type headache (discussed Once a diagnosis of migraine has been established, it
later), the most common primary headache syndrome is important to assess the extent of a patients disease
seen in clinical practice. Migraine at its most basic level is and disability. The Migraine Disability Assessment Score
headache with associated features, and tension-type headache is (MIDAS) is a well-validated, easy-to-use tool (Fig. 8-4).
headache that is featureless. Most patients with disabling head- Patient education is an important aspect of migraine
ache probably have migraine. management. Information for patients is available at
Patients with acephalgic migraine experience recurrent www.achenet.org, the website of the American Council
neurologic symptoms, often with nausea or vomiting, for Headache Education (ACHE). It is helpful for patients
to understand that migraine is an inherited tendency to
TABLE 8-4 headache; that migraine can be modified and controlled
SIMPLIFIED DIAGNOSTIC CRITERIA FOR MIGRAINE by lifestyle adjustments and medications, but it cannot
Repeated attacks of headache lasting 472 h in patients with a
be eradicated; and that, except in some occasions in
normal physical examination, no other reasonable cause for the women on oral estrogens or contraceptives, migraine is
headache, and: not associated with serious or life-threatening illnesses.
AT LEAST 2 OF THE PLUS AT LEAST 1 OF THE
FOLLOWING FEATURES: FOLLOWING FEATURES: NONPHARMACOLOGIC MANAGEMENT Mi-
graine can often be managed to some degree by a vari-
Unilateral pain Nausea/vomiting
ety of nonpharmacologic approaches. Most patients
Throbbing pain Photophobia and phonophobia benefit by the identification and avoidance of spe-
Aggravation by movement cific headache triggers. A regulated lifestyle is helpful,
Moderate or severe including a healthful diet, regular exercise, regular sleep
intensity patterns, avoidance of excess caffeine and alcohol, and
avoidance of acute changes in stress levels.
Source: Adapted from the International Headache Society Clas- The measures that benefit a given individual
sication (Headache Classication Committee of the International should be used routinely since they provide a simple,
Headache Society, 2004).
*MIDAS Questionnaire 57
INSTRUCTIONS: Please answer the following questions about ALL headaches you have had
over the last 3 months. Write zero if you did not do the activity in the last 3 months.
1. On how many days in the last 3 months did you miss work or school because
of your headaches? ............................................................................................... days
2. How many days in the last 3 months was your productivity at work or school
reduced by half or more because of your headaches (do not include days
you counted in question 1 where you missed work or school)? ............................ days
3. On how many days in the last 3 months did you not do household work
CHAPTER 8
because of your headaches? ................................................................................ days
4. How many days in the last 3 months was your productivity in household work
reduced by half or more because of your headaches (do not include days
you counted in question 3 where you did not do household work)? ..................... days
5. On how many days in the last 3 months did you miss family, social, or leisure
activities because of your headaches? ................................................................. days
Headache
A. On how many days in the last 3 months did you have a headache? (If a
headache lasted more than one day, count each day.) ......................................... days
B. On a scale of 010, on average how painful were these headaches? (Where
0 = no pain at all, and 10 = pain as bad as it can be.) ..........................................
*Migraine Disability Assessment Score
(Questions 15 are used to calculate the MIDAS score.)
Grade IMinimal or Infrequent Disability: 05
Grade IIMild or Infrequent Disability: 610
Grade IIIModerate Disability: 1120
Grade IVSevere Disability: > 20
Innovative Medical Research 1997
FIGURE 8-4
MIDAS Questionnaire.
Simple Analgesics
Acetaminophen, aspirin, caffeine Excedrin Two tablets or caplets q6h (max 8 per day)
Migraine
NSAIDs
Naproxen Aleve, Anaprox, generic 220550 mg PO bid
SECTION II
caffeine 100 mg
Naratriptan Amerge 2.5 mg tablet at onset; may repeat once after 4 h
Rizatriptan Maxalt 510 mg tablet at onset; may repeat after 2 h (max 30 mg/d)
Maxalt-MLT
Sumatriptan Imitrex 50100 mg tablet at onset; may repeat after 2 h (max 200 mg/d)
Frovatriptan Frova 2.5 mg tablet at onset, may repeat after 2 h (max 5 mg/d)
Almotriptan Axert 12.5 mg tablet at onset, may repeat after 2 h (max 25 mg/d)
Eletriptan Relpax 40 or 80 mg
Zolmitriptan Zomig 2.5 mg tablet at onset; may repeat after 2 h (max 10 mg/d)
Zomig Rapimelt
Nasal
Dihydroergotamine Migranal Nasal Spray Prior to nasal spray, the pump must be primed 4 times; 1 spray (0.5 mg) is
administered, followed in 15 min by a second spray
Sumatriptan Imitrex Nasal Spray 520 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg spray
(may repeat once after 2 h, not to exceed a dose of 40 mg/d)
Zolmitriptan Zomig 5 mg intranasal spray as one spray (may repeat once after 2 h, not to
exceed a dose of 10 mg/d)
Parenteral
Dihydroergotamine DHE-45 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week)
Sumatriptan Imitrex Injection 6 mg SC at onset (may repeat once after 1 h for max of 2 doses in 24 h)
Dopamine Antagonists
Oral
Metoclopramide Reglan,a generica 510 mg/d
Prochlorperazine Compazine,a generica 125 mg/d
Parenteral
Chlorpromazine Generica 0.1 mg/kg IV at 2 mg/min; max 35 mg/d
Metoclopramide Reglan,a generic 10 mg IV
Prochlorperazine Compazine,a generica 10 mg IV
Other
Oral
Acetaminophen, 325 mg, plus Midrin, Duradrin, generic Two capsules at onset followed by 1 capsule q1h (max 5 capsules)
dichloralphenazone, 100 mg,
plus isometheptene, 65 mg
Nasal
Butorphanol Stadola 1 mg (1 spray in 1 nostril), may repeat if necessary in 12 h
Parenteral
Narcotics Generica Multiple preparations and dosages; see Table 7-1
a
Not all drugs are specically indicated by the FDA for migraine. Local regulations and guidelines should be consulted.
Note: Antiemetics (e.g., domperidone 10 mg or ondansetron 4 or 8 mg) or prokinetics (e.g., metoclopramide 10 mg) are sometimes useful adjuncts.
Abbreviations: NSAIDs, nonsteroidal anti-inammatory drugs; 5-HT, 5-hydroxytryptamine.
TABLE 8-6
tans are selective 5-HT1B/1D receptor agonists. A variety 59
CLINICAL STRATIFICATION OF ACUTE SPECIFIC of triptans, 5-HT1B/1D receptor agonistsnaratriptan,
MIGRAINE TREATMENTS
rizatriptan, eletriptan, sumatriptan, zolmitriptan, almo-
CLINICAL SITUATION TREATMENT OPTIONS triptan, and frovatriptanare now available for the
Failed NSAIDs/anal- First tier treatment of migraine.
gesics Sumatriptan 50 mg or 100 mg PO Each drug in the triptan class has similar pharmaco-
Almotriptan 12.5 mg PO logic properties but varies slightly in terms of clinical
Rizatriptan 10 mg PO efficacy. Rizatriptan and eletriptan are the most effica-
cious of the triptans currently available in the United
CHAPTER 8
Eletriptan 40 mg PO
Zolmitriptan 2.5 mg PO States. Sumatriptan and zolmitriptan have similar rates
Slower effect/better tolerability
of efficacy as well as time to onset, with an advantage
Naratriptan 2.5 mg PO of having multiple formulations, whereas almotriptan,
Frovatriptan 2.5 mg PO frovatriptan, and naratriptan are somewhat slower in
Infrequent headache onset and are better tolerated. Clinical efficacy appears
Ergotamine 12 mg PO to be related more to the tmax (time to peak plasma
Headache
Dihydroergotamine nasal level) than to the potency, half-life, or bioavailability.
spray 2 mg This observation is consistent with a large body of data
Early nausea or dif- Zolmitriptan 5 mg nasal spray indicating that faster-acting analgesics are more effec-
culties taking tablets Sumatriptan 20 mg nasal spray tive than slower-acting agents.
Unfortunately, monotherapy with a selective oral
Rizatriptan 10 mg MLT wafer 5-HT1B/1D agonist does not result in rapid, consistent,
Headache recurrence Ergotamine 2 mg (most effective and complete relief of migraine in all patients. Triptans
PR/usually with caffeine) are not effective in migraine with aura unless given
Naratriptan 2.5 mg PO after the aura is completed and the headache initiated.
Almotriptan 12.5 mg PO Side effects are common though often mild and tran-
sient. Moreover, 5-HT1B/1D agonists are contraindicated
Eletriptan 40 mg
in individuals with a history of cardiovascular and cere-
Tolerating acute treat- Naratriptan 2.5 mg brovascular disease. Recurrence of headache is another
ments poorly
Almotriptan 12.5 mg important limitation of triptan use and occurs at least
Early vomiting Zolmitriptan 5 mg nasal spray occasionally in most patients. Evidence from random-
ized controlled trials show that coadministration of a
Sumatriptan 25 mg PR
longer-acting NSAID, naproxen 500 mg, with sumatrip-
Sumatriptan 6 mg SC
tan will augment the initial effect of sumatriptan and,
Menses-related Prevention importantly, reduce rates of headache recurrence.
headache Ergotamine PO at night Ergotamine preparations offer a nonselective means
Estrogen patches of stimulating 5-HT1 receptors. A nonnauseating dose
Treatment of ergotamine should be sought since a dose that pro-
Triptans vokes nausea is too high and may intensify head pain.
Dihydroergotamine nasal spray Except for a sublingual formulation of ergotamine, oral
formulations of ergotamine also contain 100 mg caf-
Very rapidly develop- Zolmitriptan 5 mg nasal spray
ing symptoms feine (theoretically to enhance ergotamine absorption
Sumatriptan 6 mg SC
and possibly to add additional analgesic activity). The
Dihydroergotamine 1 mg IM average oral ergotamine dose for a migraine attack is
2 mg. Since the clinical studies demonstrating the effi-
cacy of ergotamine in migraine predated the clinical
Administration (FDA) for the treatment of mild to mod- trial methodologies used with the triptans, it is difficult
erate migraine. The combination of aspirin and metoclo- to assess the clinical efficacy of ergotamine versus the
pramide has been shown to be comparable to a single triptans. In general, ergotamine appears to have a much
dose of sumatriptan. Important side effects of NSAIDs higher incidence of nausea than triptans, but less head-
include dyspepsia and gastrointestinal irritation. ache recurrence.
5-HT1 RECEPTOR AGONISTS
Nasal The fastest-acting nonparenteral antimigraine
Oral Stimulation of 5-HT1B/1D receptors can stop an therapies that can be self-administered include nasal
acute migraine attack. Ergotamine and dihydroergota- formulations of dihydroergotamine (Migranal), zolmi-
mine are nonselective receptor agonists, while the trip- triptan (Zomig nasal), or sumatriptan. The nasal sprays
60 result in substantial blood levels within 3060 min. Parenteral Narcotics are effective in the acute treat-
Although in theory nasal sprays might provide faster ment of migraine. For example, IV meperidine (50100
and more effective relief of a migraine attack than oral mg) is given frequently in the emergency room. This
formulations, their reported efficacy is only approxi- regimen works in the sense that the pain of migraine is
mately 5060%. Studies with an inhalational formula- eliminated. However, this regimen is clearly suboptimal
tion of dihydroergotamine indicate that its absorption for patients with recurrent headache. Narcotics do not
problems can be overcome to produce rapid onset of treat the underlying headache mechanism; rather, they
action with good tolerability. act to alter the pain sensation. Moreover, in patients tak-
ing oral narcotics such as oxycodone or hydrocodone,
SECTION II
CHAPTER 8
Postural symptoms
Contraindicated in asthma
Tricyclics
Amitriptyline 1075 mg at night Drowsiness
Dothiepin 2575 mg at night
Headache
Nortriptyline 2575 mg at night Note: Some patients may only need a total dose of 10 mg,
although generally 11.5 mg/kg body weight is required
Anticonvulsants
Topiramate 25200 mg/d Paresthesias
Cognitive symptoms
Weight loss
Glaucoma
Caution with nephrolithiasis
Valproate 400600 mg bid Drowsiness
Weight gain
Tremor
Hair loss
Fetal abnormalities
Hematologic or liver abnormalities
Gabapentin 9003600 mg qd Dizziness
Sedation
Serotonergic drugs
Methysergide 14 mg qd Drowsiness
Leg cramps
Hair loss
Retroperitoneal brosis (1-month drug holiday is required
every 6 months)
Flunarizineb 515 mg qd Drowsiness
Weight gain
Depression
Parkinsonism
No convincing evidence from controlled trials
Verapamil
Controlled trials demonstrate no effect
Nimodipine
Clonidine
SSRIs: uoxetine
a
Commonly used preventives are listed with typical doses and common side effects. Not all listed medicines are approved by the FDA; local
regulations and guidelines should be consulted.
b
Not available in the United States.
62 overall, placebo-controlled trials in chronic migraine Pathophysiology
were positive. Phenelzine and methysergide are usually The pathophysiology of TTH is incompletely under-
reserved for recalcitrant cases because of their serious stood. It seems likely that TTH is due to a primary dis-
potential side effects. Phenelzine is a monoamine oxi- order of CNS pain modulation alone, unlike migraine,
dase inhibitor (MAOI); therefore, tyramine-containing which involves a more generalized disturbance of sen-
foods, decongestants, and meperidine are contraindi- sory modulation. Data suggest a genetic contribution
cated. Methysergide may cause retroperitoneal or car- to TTH, but this may not be a valid nding: given
diac valvular fibrosis when it is used for >6 months, and the current diagnostic criteria, the studies undoubtedly
thus monitoring is required for patients using this drug; included many migraine patients. The name tension-type
SECTION II
the risk of fibrosis is about 1:1500 and is likely to reverse headache implies that pain is a product of nervous tension,
after the drug is stopped. but there is no clear evidence for tension as an etiology.
The probability of success with any one of the anti- Muscle contraction has been considered to be a feature
migraine drugs is 5075%. Many patients are managed that distinguishes TTH from migraine, but there appear
adequately with low-dose amitriptyline, propranolol, to be no differences in contraction between the two
topiramate, gabapentin, or valproate. If these agents fail headache types.
Clinical Manifestations of Neurologic Disease
CHAPTER 8
Attack frequency 1/alternate day8/d 140/d (>5/d for more than 3200/d
half the time)
Duration of attack 15180 min 230 min 5240 s
Autonomic features Yes Yes Yes (prominent conjunctival
injection and lacrimation)a
Headache
Migrainous featuresb Yes Yes Yes
Alcohol trigger Yes No No
Cutaneous triggers No No Yes
Indomethacin effect Yesc
Abortive treatment Sumatriptan injection No effective treatment Lidocaine (IV)
or nasal spray
Oxygen
Prophylactic treatment Verapamil Indomethacin Lamotrigine
Methysergide Topiramate
Lithium Gabapentin
a
If conjunctival injection and tearing not present, consider SUNA.
b
Nausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the side of the pain.
c
Indicates complete response to indomethacin.
Abbreviation: SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
pattern and length, frequency, and timing of attacks are Onset is nocturnal in about 50% of patients, and men
useful in classifying patients. Patients with TACs should are affected three times more often than women.
undergo pituitary imaging and pituitary function tests as Patients with cluster headache tend to move about dur-
there is an excess of TAC presentations in patients with ing attacks, pacing, rocking, or rubbing their head for
pituitary tumorrelated headache. relief; some may even become aggressive during attacks.
This is in sharp contrast to patients with migraine, who
prefer to remain motionless during attacks.
Cluster headache
Cluster headache is associated with ipsilateral symp-
Cluster headache is a rare form of primary headache toms of cranial parasympathetic autonomic activa-
with a population frequency of approximately 0.1%. tion: conjunctival injection or lacrimation, rhinorrhea
The pain is deep, usually retroorbital, often excruciat- or nasal congestion, or cranial sympathetic dysfunc-
ing in intensity, nonuctuating, and explosive in qual- tion such as ptosis. The sympathetic decit is periph-
ity. A core feature of cluster headache is periodicity. At eral and likely to be due to parasympathetic activation
least one of the daily attacks of pain recurs at about the with injury to ascending sympathetic bers surrounding
same hour each day for the duration of a cluster bout. a dilated carotid artery as it passes into the cranial cavity.
The typical cluster headache patient has daily bouts of When present, photophobia and phonophobia are far
one to two attacks of relatively short-duration unilateral more likely to be unilateral and on the same side of the
pain for 8 to 10 weeks a year; this is usually followed pain, rather than bilateral, as is seen in migraine. This
by a pain-free interval that averages a little less than 1 phenomenon of unilateral photophobia/phonophobia is
year. Cluster headache is characterized as chronic when characteristic of TACs. Cluster headache is likely to be
there is no signicant period of sustained remission. a disorder involving central pacemaker neurons in the
Patients are generally perfectly well between episodes. region of the posterior hypothalamus (Fig. 8-3).
64 regarding the early symptoms of ergotism, which may
TREATMENT Cluster Headache
include vomiting, numbness, tingling, pain, and cyanosis
The most satisfactory treatment is the administration of of the limbs; a weekly limit of 14 mg should be adhered to.
drugs to prevent cluster attacks until the bout is over. Lithium (600900 mg qd) appears to be particularly useful
However, treatment of acute attacks is required for all for the chronic form of the disorder.
cluster headache patients at some time. Many experts favor verapamil as the first-line pre-
ventive treatment for patients with chronic cluster
ACUTE ATTACK TREATMENT Cluster head-
headache or prolonged bouts. While verapamil com-
ache attacks peak rapidly, and thus a treatment with
pares favorably with lithium in practice, some patients
SECTION II
CHAPTER 8
PH can coexist with trigeminal neuralgia (PH-tic syn-
ABORTIVE THERAPY Therapy of acute attacks is
drome); similar to cluster-tic syndrome, each compo-
nent may require separate treatment. not a useful concept in SUNCT/SUNA since the attacks are
Secondary PH has been reported with lesions in the of such short duration. However, IV lidocaine, which arrests
region of the sella turcica, including arteriovenous mal- the symptoms, can be used in hospitalized patients.
formation, cavernous sinus meningioma, and epider- PREVENTIVE THERAPY Long-term prevention
moid tumors. Secondary PH is more likely if the patient
Headache
to minimize disability and hospitalization is the goal of
requires high doses (>200 mg/d) of indomethacin. In treatment. The most effective treatment for prevention is
patients with apparent bilateral PH, raised CSF pressure lamotrigine, 200400 mg/d. Topiramate and gabapentin
should be suspected. It is important to note that indo- may also be effective. Carbamazepine, 400500 mg/d,
methacin reduces CSF pressure. When a diagnosis of has been reported by patients to offer modest benefit.
PH is considered, MRI is indicated to exclude a pitu- Surgical approaches such as microvascular decom-
itary lesion. pression or destructive trigeminal procedures are sel-
dom useful and often produce long-term complications.
Greater occipital nerve injection has produced limited
SUNCT/SUNA
benefit in some patients. Occipital nerve stimulation
SUNCT (short-lasting unilateral neuralgiform headache is probably helpful in an important subgroup of these
attacks with conjunctival injection and tearing) is a rare patients. Complete control with deep-brain stimulation
primary headache syndrome characterized by severe, uni- of the posterior hypothalamic region was reported in a
lateral orbital or temporal pain that is stabbing or throb- single patient. For intractable cases, short-term preven-
bing in quality. Diagnosis requires at least 20 attacks, tion with IV lidocaine can be effective, as can occipital
lasting for 5240 s; ipsilateral conjunctival injection and nerve stimulation.
lacrimation should be present. In some patients conjunc-
tival injection or lacrimation is missing, and the diagnosis
of SUNA (short-lasting unilateral neuralgiform headache CHRONIC DAILY HEADACHE
attacks with cranial autonomic symptoms) can be made. The broad diagnosis of chronic daily headache (CDH)
can be applied when a patient experiences headache
Diagnosis
on 15 days or more per month. CDH is not a single
The pain of SUNCT/SUNA is unilateral and may be
entity; it encompasses a number of different headache
located anywhere in the head. Three basic patterns
syndromes, including chronic TTH as well as headache
can be seen: single stabs, which are usually short-lived;
secondary to trauma, inammation, infection, medica-
groups of stabs; or a longer attack comprising many
tion overuse, and other causes (Table 8-10). Popula-
stabs between which the pain does not completely
tion-based estimates suggest that about 4% of adults
resolve, thus giving a saw-tooth phenomenon with
have daily or near-daily headache. Daily headache may
attacks lasting many minutes. Each pattern may be seen
be primary or secondary, an important consideration in
in the context of an underlying continuous head pain.
guiding management of this complaint.
Characteristics that lead to a suspected diagnosis of
SUNCT are the cutaneous (or other) triggerability of
attacks, a lack of refractory period to triggering between APPROACH TO THE
attacks, and the lack of a response to indomethacin. PATIENT Chronic Daily Headache
Apart from trigeminal sensory disturbance, the neuro-
The first step in the management of patients with CDH
logic examination is normal in primary SUNCT.
is to diagnose any underlying condition (Table 810).
The diagnosis of SUNCT is often confused with tri-
For patients with primary headaches, diagnosis of the
geminal neuralgia (TN) particularly in rst-division TN
headache type will guide therapy. Preventive treat-
(Chap. 34). Minimal or no cranial autonomic symptoms
ments such as tricyclics, either amitriptyline or nortrip-
and a clear refractory period to triggering indicate a
tyline at doses up to 1 mg/kg, are very useful in patients
diagnosis of TN.
66 TABLE 8-10
Management of Medication Overuse: Out-
CLASSIFICATION OF CHRONIC DAILY HEADACHE patients For patients who overuse medications, it is
PRIMARY essential that analgesic use be reduced and eliminated.
One approach is to reduce the medication dose by 10%
>4 h DAILY <4 h DAILY SECONDARY
every 12 weeks. Immediate cessation of analgesic use
a
Chronic migraine Chronic cluster Posttraumatic is possible for some patients, provided there is no con-
headacheb Head injury traindication. Both approaches are facilitated by the use
Iatrogenic of a medication diary maintained during the month or
Postinfectious two before cessation; this helps to identify the scope of
SECTION II
Chronic tension- Chronic Inammatory, such as the problem. A small dose of an NSAID such as naproxen,
type headachea paroxysmal Giant cell arteritis 500 mg bid, if tolerated, will help relieve residual pain as
hemicrania Sarcoidosis analgesic use is reduced. NSAID overuse is not usually a
Behets syndrome problem for patients with daily headache when the dose
Hemicrania SUNCT/SUNA Chronic CNS is taken once or twice daily; however, overuse problems
continuaa infection may develop with more frequent dosing schedules. Once
Clinical Manifestations of Neurologic Disease
New daily persis- Hypnic Medication-overuse the patient has substantially reduced analgesic use, a
tent headachea headache headachea preventive medication should be introduced. It must be
emphasized that preventives generally do not work in the
a
May be complicated by analgesic overuse. presence of analgesic overuse. The most common cause
b
Some patients may have headache >4 h/d.
of unresponsiveness to treatment is the use of a preven-
Abbreviations: SUNA, short-lasting unilateral neuralgiform head-
ache attacks with cranial autonomic symptoms; SUNCT, short- tive when analgesics continue to be used regularly. For
lasting unilateral neuralgiform headache attacks with conjunctival some patients, discontinuing analgesics is very difficult;
injection and tearing. often the best approach is to directly inform the patient
that some degree of pain is inevitable during this initial
period.
with CDH arising from migraine or tension-type head-
ache. Tricyclics are started in low doses (1025 mg) Management of Medication Overuse: Inpa-
daily and may be given 12 h before the expected time tients Some patients will require hospitalization for
of awakening in order to avoid excess morning sleepi- detoxification. Such patients have typically failed efforts
ness. Anticonvulsants, such as topiramate, valproate, at outpatient withdrawal or have a significant medical
and gabapentin, are also useful in migraineurs. Flunari- condition, such as diabetes mellitus, which would com-
zine can also be very effective for some patients, as can plicate withdrawal as an outpatient. Following admission
methysergide or phenelzine. to the hospital, acute medications are withdrawn com-
pletely on the first day, in the absence of a contraindica-
MANAGEMENT OF MEDICALLY INTRAC- tion. Antiemetics and fluids are administered as required;
TABLE DISABLING CHRONIC DAILY HEAD- clonidine is used for opiate withdrawal symptoms. For
ACHE The management of medically intractable acute intolerable pain during the waking hours aspirin,
headache is difficult. At this time, the only promising 1 g IV (not approved in United States), is useful. IM chlor-
approach is occipital nerve stimulation, which appears promazine can be helpful at night; patients must be ade-
to modulate thalamic processing in migraine and quately hydrated. Three to five days into the admission
has also shown promise in chronic cluster headache, as the effect of the withdrawn substance settles a course
SUNCT/SUNA, and hemicrania continua (see next). of IV dihydroergotamine (DHE) can be employed. DHE,
MEDICATION-OVERUSE HEADACHE Over- administered every 8 h for 5 consecutive days, can induce
useof analgesic medication for headache can aggravate a significant remission that allows a preventive treatment
headache frequency and induce a state of refractory to be established. 5-HT3 antagonists, such as ondansetron
daily or near-daily headache called medication-overuse or granisetron, are often required with DHE to prevent
headache. A proportion of patients who stop taking significant nausea, and domperidone (not approved in
analgesics will experience substantial improvement in the United States) orally or by suppository can be very
the severity and frequency of their headache. However, helpful.
even after cessation of analgesic use, many patients NEW DAILY PERSISTENT HEADACHE New
continue to have headache, although they may feel clin- daily persistent headache (NDPH) is a clinically distinct
ically improved in some way, especially if they have been syndrome; its causes are listed in Table 8-11.
using codeine or barbiturates regularly. The residual
symptoms probably represent the underlying headache CLINICAL PRESENTATION The patient with
disorder. NDPH presents with headache on most if not all days
TABLE 8-11
toms appear to result from low volume rather than low 67
DIFFERENTIAL DIAGNOSIS OF NEW DAILY pressure: although low CSF pressures, typically 050
PERSISTENT HEADACHE
mmH2O, are usually identified, a pressure as high as 140
PRIMARY SECONDARY mmH2O has been noted with a documented leak.
Migrainous-type Subarachnoid hemorrhage Postural orthostatic tachycardia syndrome (POTS
[Chap. 33]) can present with orthostatic headache simi-
Featureless (tension-type) Low CSF volume headache
lar to low CSF volume headache and is a diagnosis that
Raised CSF pressure headache needs consideration here.
Posttraumatic headachea When imaging is indicated to identify the source of
CHAPTER 8
Chronic meningitis a presumed leak, an MRI with gadolinium is the initial
study of choice (Fig. 8-5). A striking pattern of diffuse
a
Includes postinfectious forms. meningeal enhancement is so typical that in the appro-
priate clinical context the diagnosis is established. Chiari
malformations may sometimes be noted on MRI; in such
and the patient can clearly, and often vividly, recall cases, surgery to decompress the posterior fossa usu-
Headache
the moment of onset. The headache usually begins ally worsens the headache. Spinal MRI with T2 weight-
abruptly, but onset may be more gradual; evolution ing may reveal a leak and spinal MRI may demonstrate
over 3 days has been proposed as the upper limit for spinal meningeal cysts whose role in these syndromes
this syndrome. Patients typically recall the exact day is yet to be elucidated. The source of CSF leakage may
and circumstances of the onset of headache; the new, be identified by spinal MRI, by CT, or increasingly with
persistent head pain does not remit. The first priority MR myelography, or with 111In-DTPA CSF studies; in the
is to distinguish between a primary and a secondary absence of a directly identified site of leakage, early
cause of this syndrome. Subarachnoid hemorrhage is emptying of 111In-DTPA tracer into the bladder or slow
the most serious of the secondary causes and must be progress of tracer across the brain suggests a CSF leak.
excluded either by history or appropriate investigation Initial treatment for low CSF volume headache is
(Chap. 28). bed rest. For patients with persistent pain, IV caffeine
Secondary NDPH (500 mg in 500 mL saline administered over 2 h) can be
very effective. An ECG to screen for arrhythmia should
Low CSF Volume Headache In these syn- be performed before administration. It is reasonable
dromes, head pain is positional: it begins when the to administer at least two infusions of caffeine before
patient sits or stands upright and resolves upon reclin- embarking on additional tests to identify the source of
ing. The pain, which is occipitofrontal, is usually a dull the CSF leak. Since IV caffeine is safe and can be curative,
ache but may be throbbing. Patients with chronic low
CSF volume headache typically present with a history of
headache from one day to the next that is generally not
present on waking but worsens during the day. Recum-
bency usually improves the headache within minutes,
but it takes only minutes to an hour for the pain to
return when the patient resumes an upright position.
The most common cause of headache due to per-
sistent low CSF volume is CSF leak following lumbar
puncture (LP). Post-LP headache usually begins within
48 h but may be delayed for up to 12 days. Its inci-
dence is between 10 and 30%. Beverages with caffeine
may provide temporary relief. Besides LP, index events
may include epidural injection or a vigorous Valsalva
maneuver, such as from lifting, straining, coughing,
clearing the eustachian tubes in an airplane, or multiple
orgasms. Spontaneous CSF leaks are well recognized,
and the diagnosis should be considered whenever the
headache history is typical, even when there is no obvi-
ous index event. As time passes from the index event,
the postural nature may become less apparent; cases FIGURE 8-5
Magnetic resonance image showing diffuse meningeal
in which the index event occurred several years before
enhancement after gadolinium administration in a patient
the eventual diagnosis have been recognized. Symp-
with low CSF volume headache.
68 it spares many patients the need for further investiga- infectious episode, typically viral meningitis, a flulike ill-
tions. If unsuccessful, an abdominal binder may be help- ness, or a parasitic infection. Complaints of dizziness,
ful. If a leak can be identified, an autologous blood patch vertigo, and impaired memory can accompany the head-
is usually curative. A blood patch is also effective for ache. Symptoms may remit after several weeks or persist
post-LP headache; in this setting, the location is empiri- for months and even years after the injury. Typically the
cally determined to be the site of the LP. In patients with neurologic examination is normal and CT or MRI stud-
intractable pain, oral theophylline is a useful alternative; ies are unrevealing. Chronic subdural hematoma may on
however, its effect is less rapid than caffeine. occasion mimic this disorder. In one series, one-third of
patients with NDPH reported headache beginning after
SECTION II
Raised CSF Pressure Headache Raised CSF a transient flulike illness characterized by fever, neck
pressure is well recognized as a cause of headache. stiffness, photophobia, and marked malaise. Evaluation
Brain imaging can often reveal the cause, such as a reveals no apparent cause for the headache. There is no
space-occupying lesion. NDPH due to raised CSF pres- convincing evidence that persistent Epstein-Barr infec-
sure can be the presenting symptom for patients with tion plays a role in this syndrome. A complicating factor
idiopathic intracranial hypertension (pseudotumor is that many patients undergo LP during the acute ill-
Clinical Manifestations of Neurologic Disease
cerebri) without visual problems, particularly when the ness; iatrogenic low CSF volume headache must be con-
fundi are normal. Persistently raised intracranial pres- sidered in these cases. Posttraumatic headache may also
sure can trigger chronic migraine. These patients typi- be seen after carotid dissection and subarachnoid hem-
cally present with a history of generalized headache orrhage, and following intracranial surgery. The underly-
that is present on waking and improves as the day ing theme appears to be that a traumatic event involving
goes on. It is generally worse with recumbency. Visual the pain-producing meninges can trigger a headache
obscurations are frequent. The diagnosis is relatively process that lasts for many years.
straightforward when papilledema is present, but the Treatment is largely empirical. Tricyclic antidepres-
possibility must be considered even in patients without sants, notably amitriptyline, and anticonvulsants such as
funduscopic changes. Formal visual field testing should topiramate, valproate, and gabapentin, have been used
be performed even in the absence of overt ophthal- with reported benefit. The MAOI phenelzine may also be
mic involvement. Headache on rising in the morning or useful in carefully selected patients. The headache usually
nocturnal headache is also characteristic of obstructive resolves within 35 years, but it can be quite disabling.
sleep apnea or poorly controlled hypertension.
Primary NDPH Primary NDPH occurs in both males
Evaluation of patients suspected to have raised CSF
and females. It can be of the migrainous type, with fea-
pressure requires brain imaging. It is most efficient to
tures of migraine, or it can be featureless, appearing as
obtain an MRI, including an MR venogram, as the initial
new-onset TTH (Table 8-11). Migrainous features are
study. If there are no contraindications, the CSF pres-
common and include unilateral headache and throb-
sure should be measured by LP; this should be done
bing pain; each feature is present in about one-third of
when the patient is symptomatic so that both the pres-
patients. Nausea, photophobia, and/or phonophobia
sure and the response to removal of 2030 mL of CSF
occur in about half of patients. Some patients have a
can be determined. An elevated opening pressure and
previous history of migraine; however, the proportion of
improvement in headache following removal of CSF is
NDPH sufferers with preexisting migraine is no greater
diagnostic.
than the frequency of migraine in the general population.
Initial treatment is with acetazolamide (250500 mg
At 24 months, 86% of patients are headache-free. Treat-
bid); the headache may improve within weeks. If inef-
ment of migrainous-type primary NDPH consists of using
fective, topiramate is the next treatment of choice; it
the preventive therapies effective in migraine (Table 8-7).
has many actions that may be useful in this setting,
Featureless NDPH is one of the primary headache forms
including carbonic anhydrase inhibition, weight loss,
most refractory to treatment. Standard preventive thera-
and neuronal membrane stabilization, likely mediated
pies can be offered but are often ineffective.
via effects on phosphorylation pathways. Severely dis-
abled patients who do not respond to medical treat-
ment require intracranial pressure monitoring and may
require shunting. OTHER PRIMARY HEADACHES
Hemicrania continua
Posttraumatic Headache A traumatic event
can trigger a headache process that lasts for many The essential features of hemicrania continua are moder-
months or years after the event. The term trauma is used ate and continuous unilateral pain associated with uc-
in a very broad sense: headache can develop following tuations of severe pain; complete resolution of pain with
an injury to the head, but it can also develop after an indomethacin; and exacerbations that may be associated
with autonomic features, including conjunctival injec- lesion causing obstruction of CSF pathways or displac- 69
tion, lacrimation, and photophobia on the affected side. ing cerebral structures can be the cause of the head pain.
The age of onset ranges from 11 to 58 years; women are Other conditions that can present with cough or exer-
affected twice as often as men. The cause is unknown. tional headache as the initial symptom include cerebral
aneurysm, carotid stenosis, and vertebrobasilar disease.
Benign cough headache can resemble benign exertional
TREATMENT Hemicrania Continua headache (discussed next), but patients with the former
condition are typically older.
Treatment consists of indomethacin; other NSAIDs
CHAPTER 8
appear to be of little or no benefit. The IM injection of 100
mg indomethacin has been proposed as a diagnostic tool TREATMENT Primary Cough Headache
and administration with a placebo injection in a blinded
fashion can be very useful diagnostically. Alternatively, a Indomethacin 2550 mg two to three times daily is the
trial of oral indomethacin, starting with 25 mg tid, then treatment of choice. Some patients with cough head-
50 mg tid, and then 75 mg tid, can be given. Up to two ache obtain pain relief with LP; this is a simple option
when compared to prolonged use of indomethacin, and
Headache
weeks at the maximal dose may be necessary to assess
whether a dose has a useful effect. Topiramate can be it is effective in about one-third of patients. The mecha-
helpful in some patients. Occipital nerve stimulation may nism of this response is unclear.
have a role in patients with hemicrania continua who are
unable to tolerate indomethacin. Primary exertional headache
Primary exertional headache has features resembling
Primary stabbing headache both cough headache and migraine. It may be pre-
The essential features of primary stabbing headache are cipitated by any form of exercise; it often has the pul-
stabbing pain conned to the head or, rarely, the face, satile quality of migraine. The pain, which can last
lasting from 1 to many seconds or minutes and occur- from 5 min to 24 h, is bilateral and throbbing at onset;
ring as a single stab or a series of stabs; absence of asso- migrainous features may develop in patients susceptible
ciated cranial autonomic features; absence of cutane- to migraine. Primary exertional headache can be pre-
ous triggering of attacks; and a pattern of recurrence at vented by avoiding excessive exertion, particularly in
irregular intervals (hours to days). The pains have been hot weather or at high altitude.
variously described as ice-pick pains or jabs and The mechanism of primary exertional headache is
jolts. They are more common in patients with other unclear. Acute venous distension likely explains one
primary headaches, such as migraine, the TACs, and syndrome, the acute onset of headache with strain-
hemicrania continua. ing and breath holding, as in weightlifters headache.
As exertion can result in headache in a number of seri-
ous underlying conditions, these must be considered
in patients with exertional headache. Pain from angina
TREATMENT Primary Stabbing Headache
may be referred to the head, probably by central con-
The response of primary stabbing headache to indo- nections of vagal afferents, and may present as exertional
methacin (2550 mg two to three times daily) is usu- headache (cardiac cephalgia). The link to exercise is the
ally excellent. As a general rule, the symptoms wax and main clinical clue that headache is of cardiac origin.
wane, and after a period of control on indomethacin, it Pheochromocytoma may occasionally cause exertional
is appropriate to withdraw treatment and observe the headache. Intracranial lesions and stenosis of the carotid
outcome. arteries are other possible etiologies.
Primary cough headache is a generalized headache that Exercise regimens should begin modestly and progress
begins suddenly, lasts for several minutes, and is precipi- gradually to higher levels of intensity. Indomethacin at
tated by coughing; it is preventable by avoiding cough- daily doses from 25 to 150 mg is generally effective in
ing or other precipitating events, which can include benign exertional headache. Indomethacin (50 mg),
sneezing, straining, laughing, or stooping. In all patients ergotamine (1 mg orally), dihydroergotamine (2 mg
with this syndrome, serious etiologies must be excluded by nasal spray), or methysergide (12 mg orally given
before a diagnosis of benign primary cough head- 3045 min before exercise) are useful prophylactic mea-
ache can be established. A Chiari malformation or any sures.
70 Primary Sex Headache aneurysm is uncertain. When neuroimaging studies and
LP exclude subarachnoid hemorrhage, patients with
Sex headache is precipitated by sexual excitement. The thunderclap headache usually do very well over the
pain usually begins as a dull bilateral headache that sud- long term. In one study of patients whose CT scans and
denly becomes intense at orgasm. The headache can CSF ndings were negative, 15% had recurrent epi-
be prevented or eased by ceasing sexual activity before sodes of thunderclap headache, and nearly half subse-
orgasm. Three types of sex headache are reported: a quently developed migraine or tension-type headache.
dull ache in the head and neck that intensies as sex- The rst presentation of any sudden-onset severe
ual excitement increases; a sudden, severe, explosive headache should be vigorously investigated with neuro-
headache occurring at orgasm; and a postural head-
SECTION II
headache is reported by men more often than women an intracranial aneurysm. In the presence of posterior
and may occur at any time during the years of sexual leukoencephalopathy, the differential diagnosis includes
activity. It may develop on several occasions in succes- cerebral angiitis, drug toxicity (cyclosporine, intrathecal
sion and then not trouble the patient again, even with- methotrexate/cytarabine, pseudoephedrine, or cocaine),
out an obvious change in sexual activity. In patients posttransfusion effects, and postpartum angiopathy.
who stop sexual activity when headache is rst noticed, Treatment with nimodipine may be helpful, although
the pain may subside within a period of 5 min to 2 h. In by denition the vasoconstriction of primary thunder-
about half of patients, sex headache will subside within clap headache resolves spontaneously.
6 months. About half of patients with sex headache
have a history of exertional headaches, but there is no
excess of cough headache. Migraine is probably more Hypnic headache
common in patients with sex headache. This headache syndrome typically begins a few hours
after sleep onset. The headaches last from 15 to 30
min and are typically moderately severe and general-
TREATMENT Primary Sex Headache ized, although they may be unilateral and can be throb-
bing. Patients may report falling back to sleep only to
Benign sex headaches recur irregularly and infrequently. be awakened by a further attack a few hours later; up
Management can often be limited to reassurance and to three repetitions of this pattern occur through the
advice about ceasing sexual activity if a mild, warning night. Daytime naps can also precipitate head pain.
headache develops. Propranolol can be used to prevent Most patients are female, and the onset is usually after
headache that recurs regularly or frequently, but the age 60 years. Headaches are bilateral in most, but may
dosage required varies from 40 to 200 mg/d. An alter- be unilateral. Photophobia or phonophobia and nausea
native is the calcium channelblocking agent diltiazem, are usually absent. The major secondary consideration
60 mg tid. Ergotamine (1 mg) or indomethacin (2550 in this headache type is poorly controlled hypertension;
mg) taken about 3045 min prior to sexual activity can 24-h blood pressure monitoring is recommended to
also be helpful. detect this treatable condition.
The importance of back and neck pain in our society The apposition of a superior and inferior facet consti-
is underscored by the following: (1) the cost of back tutes a facet joint. The functions of the posterior spine
pain in the United States exceeds $100 billion annually; are to protect the spinal cord and nerves within the spi-
approximately one-third of these costs are direct health nal canal and to provide an anchor for the attachment
care expenses, and two-thirds are indirect costs resulting of muscles and ligaments. The contraction of muscles
from loss of wages and productivity; (2) back symptoms attached to the spinous and transverse processes and
are the most common cause of disability in those <45 laminae works like a system of pulleys and levers that
years; (3) low back pain is the second most common results in exion, extension, and lateral bending move-
reason for visiting a physician in the United States; and ments of the spine.
(4) 1% of the U.S. population is chronically disabled Nerve root injury (radiculopathy) is a common cause
because of back pain. of neck, arm, low back, buttock, and leg pain (Figs.
15-2 and 15-3). The nerve roots exit at a level above
their respective vertebral bodies in the cervical region
ANATOMY OF THE SPINE (e.g., the C7 nerve root exits at the C6-C7 level) and
below their respective vertebral bodies in the thoracic
The anterior portion of the spine consists of cylindri- and lumbar regions (e.g., the T1 nerve root exits at the
cal vertebral bodies separated by intervertebral disks and T1-T2 level). The cervical nerve roots follow a short
held together by the anterior and posterior longitudi- intraspinal course before exiting. By contrast, because
nal ligaments. The intervertebral disks are composed of the spinal cord ends at the vertebral L1 or L2 level, the
a central gelatinous nucleus pulposus surrounded by a lumbar nerve roots follow a long intraspinal course and
tough cartilaginous ring, the annulus brosis. Disks are can be injured anywhere from the upper lumbar spine
responsible for 25% of spinal column length and allow to their exit at the intervertebral foramen. For example,
the bony vertebrae to move easily upon each other disk herniation at the L4-L5 level can produce not only
(Figs. 9-1 and 9-2). Desiccation of the nucleus pulp- L5 root compression, but also compression of the tra-
osus and degeneration of the annulus brosus increase versing S1 nerve root (Fig. 9-3).
with age and results in loss of height. The disks are larg- Pain-sensitive structures of the spine include the
est in the cervical and lumbar regions where move- periosteum of the vertebrae, dura, facet joints, annulus
ments of the spine are greatest. The functions of the brosus of the intervertebral disk, epidural veins and
anterior spine are to absorb the shock of body move- arteries, and the posterior longitudinal ligament. Disease
ments such as walking and running, and to protect the of these diverse structures may explain many cases of
contents of the spinal canal. back pain without nerve root compression. The nucleus
The posterior portion of the spine consists of the ver- pulposus of the intervertebral disk is not pain-sensitive
tebral arches and processes. Each arch consists of paired under normal circumstances. Pain sensation from within
cylindrical pedicles anteriorly and paired laminae poste- the spinal canal is conveyed partially by the sinuverte-
riorly. The vertebral arch also gives rise to two trans- bral nerve that arises from the spinal nerve at each spine
verse processes laterally, one spinous process posteri- segment and reenters the spinal canal through the inter-
orly, plus two superior and two inferior articular facets. vertebral foramen at the same level.
71
72 Posterior Posterior Anterior
Spinous
process Intervertebral
SECTION II
disk
Pedicle
Transverse
process
Body
A Anterior B
FIGURE 9-1
Vertebral anatomy. (From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Posi-
tioning. New York, McGraw-Hill, 1998; with permission.)
1
2
Attention is also focused on identification of risk factors
3 Cervical for serious underlying diseases; the majority of these
4
Cervical (7) curvature are due to radiculopathy, fracture, tumor, infection, or
5
6
7
referred pain from visceral structures (Table 9-1).
1 Local pain is caused by injury to pain-sensitive struc-
2
3
tures that compress or irritate sensory nerve endings.
4 The site of the pain is near the affected part of the back.
5
Thoracic Pain referred to the back may arise from abdominal or
6
curvature pelvic viscera. The pain is usually described as primarily
7
Thoracic (12) 8 abdominal or pelvic but is accompanied by back pain
9
and usually unaffected by posture. The patient may
10
11
occasionally complain of back pain only.
12 Pain of spine origin may be located in the back or
1 referred to the buttocks or legs. Diseases affecting the
2
upper lumbar spine tend to refer pain to the lumbar
region, groin, or anterior thighs. Diseases affecting the
Lumbar
Lumbar (5)
3
curvature lower lumbar spine tend to produce pain referred to the
4 buttocks, posterior thighs, or rarely the calves or feet.
5 Referred or sclerotomal pain may explain instances
where the pain crosses multiple dermatomes without
Sacrum Sacral evidence of nerve root compression.
curvature Radicular back pain is typically sharp and radiates
Coccyx from the low back to a leg within the territory of a nerve
Anterior view Right lateral view root (see Lumbar Disk Disease, later in this chapter).
FIGURE 9-2
Coughing, sneezing, or voluntary contraction of abdomi-
Spinal column. (From A Gauthier Cornuelle, DH Gronefeld: nal muscles (lifting heavy objects or straining at stool)
Radiographic Anatomy Positioning. New York, McGraw-Hill, may elicit the radiating pain. The pain may increase in
1998; with permission.) postures that stretch the nerves and nerve roots. Sitting
with the leg outstretched places traction on the sciatic
APPROACH TO THE nerve and L5 and S1 roots because the nerve passes pos-
PATIENT Back Pain
terior to the hip. The femoral nerve (L2, L3, and L4 roots)
passes anterior to the hip and is not stretched by sitting.
TYPES OF BACK PAIN Understanding the types The description of the pain alone often fails to distin-
of pain reported by patients is the essential first step. guish between sclerotomal pain and radiculopathy.
73
4th Lumbar
pedicle 4th Lumbar
vertebral body
L4 root
CHAPTER 9
Protruded
L4-L5 disk
5th Lumbar
vertebral body
L5 Root
S1 Root
S2 Root
FIGURE 9-3
Compression of L5 and S1 roots by herniated disks. (From Adams and Victors
Principles of Neurology, 9th ed. New York, McGraw-Hill, 2009; with permission.)
extension of the spine (with the patient prone or stand- stretches the L2-L4 nerve roots, lumbosacral plexus,
ing) is limited when nerve root compression, facet joint and femoral nerve, is considered positive if the patients
pathology, or other bony spine disease is present. usual back or limb pain is reproduced.
Pain from hip disease may mimic the pain of lumbar The neurologic examination includes a search for
spine disease. Hip pain can be reproduced by internal and focal weakness or muscle atrophy, focal reflex changes,
external rotation at the hip with the knee and hip in flexion diminished sensation in the legs, or signs of spinal cord
Clinical Manifestations of Neurologic Disease
(Patricks sign) and by tapping the heel with the examiners injury. The examiner should be alert to the possibility of
palm while the leg is extended (heel percussion sign). breakaway weakness, defined as fluctuating strength
With the patient supine, passive flexion of the during muscle testing. Breakaway weakness may be due
extended leg at the hip stretches the L5 and S1 nerve to pain or a combination of pain and underlying true
roots and the sciatic nerve (straight legraising maneu- weakness. Breakaway weakness without pain is almost
ver). Passive dorsiflexion of the foot during the maneu- always due to a lack of effort. In uncertain cases, elec-
ver adds to the stretch. While flexion to at least 80 is tromyography (EMG) can determine whether or not true
normally possible without causing pain, many patients weakness due to nerve tissue injury is present. Findings
normally report a tight, stretching sensation in the ham- with specific nerve lumbosacral nerve root lesions are
string muscles unrelated to back pain. The straight leg shown in Table 9-2 and are discussed next.
raising (SLR) test is positive if the maneuver reproduces
the patients usual back or limb pain. Eliciting the SLR LABORATORY, IMAGING, AND EMG STUD-
sign in the sitting position can help determine if the IES Routine laboratory studies are rarely needed for
finding is reproducible. The patient may describe pain the initial evaluation of nonspecific acute (<3 months
in the low back, buttocks, posterior thigh, or lower leg, duration) low back pain (ALBP). If risk factors for a serious
TABLE 9-2
LUMBOSACRAL RADICULOPATHYNEUROLOGIC FEATURES
EXAMINATION FINDINGS
LUMBOSACRAL
NERVE ROOTS REFLEX SENSORY MOTOR PAIN DISTRIBUTION
a
L2 Upper anterior thigh Psoas (hip exion) Anterior thigh
a
L3 Lower anterior thigh Psoas (hip exion) Anterior thigh, knee
Anterior knee Quadriceps (knee extension)
Thigh adduction
L4a Quadriceps (knee) Medial calf Quadriceps (knee extension)b Knee, medial calf
Thigh adduction Anterolateral thigh
Tibialis anterior (foot dorsiexion)
L5c Dorsal surfacefoot Peroneii (foot eversion)b Lateral calf, dorsal foot,
Lateral calf Tibialis anterior (foot dorsiexion) posterolateral thigh, but-
Gluteus medius (hip abduction) tocks
Toe dorsiexors
S1c Gastrocnemius/ Plantar surfacefoot Gastrocnemius/soleus (foot plan- Bottom foot, posterior calf,
soleus (ankle) Lateral aspectfoot tar exion)b posterior thigh, buttocks
Abductor hallucis (toe exors)b
Gluteus maximus (hip extension)
a
Reverse straight legraising sign presentsee Examination of the Back.
b
These muscles receive the majority of innervation from this root.
c
Straight legraising sign presentsee Examination of the Back.
underlying cause are present (Table 9-1), then laboratory TABLE 9-3 75
studies (complete blood count [CBC], erythrocyte sedi- CAUSES OF BACK OR NECK PAIN
mentation rate [ESR], urinalysis) are indicated. Congenital/Developmental
CT scanning is superior to routine x-rays for the Spondylolysis and spondylolisthesis
detection of fractures involving posterior spine struc-
Kyphoscoliosis
tures, craniocervical and craniothoracic junctions, C1
and C2 vertebrae, bone fragments within the spinal Spina bida occulta
canal, or misalignment; CT scans are increasingly used Tethered spinal cord
as a primary screening modality for moderate to severe
CHAPTER 9
Minor Trauma
trauma. In the absence of risk factors, these imaging
studies are rarely helpful in nonspecific ALBP. MRI and Strain or sprain
CT-myelography are the radiologic tests of choice for Whiplash injury
evaluation of most serious diseases involving the spine.
Fractures
MRI is superior for the definition of soft tissue structures,
whereas CT-myelography provides optimal imaging of Traumafalls, motor vehicle accidents
A step may be present on deep palpation of the poste- is common), sudden deceleration in an automobile acci-
rior elements of the segment above the spondylolisthetic dent, or direct injury. Neurologic impairment is com-
joint. The trunk may be shortened and the abdomen pro- mon, and early surgical treatment is indicated. In vic-
tuberant as a result. Anterolisthesis or retrolisthesis can also tims of blunt trauma, CT scans of the chest, abdomen,
occur at other cervical or lumbar levels in adults and be or pelvis can be reformatted to detect associated verte-
the source of neck or low back pain. Plain x-rays with the bral fractures.
neck or low back in exion and extension will reveal the
movement at the abnormal spinal segment. Surgery is con-
sidered for pain symptoms that do not respond to conser- LUMBAR DISK DISEASE
vative measures (e.g., rest, physical therapy), and in cases This is a common cause of chronic or recurrent low
with progressive neurologic decit, postural deformity, back and leg pain (Figs. 9-3 and 9-4). Disk disease is
slippage >50%, or scoliosis. most likely to occur at the L4-L5 or L5-S1 levels, but
Spina bida occulta is a failure of closure of one or sev- upper lumbar levels are involved occasionally. The
eral vertebral arches posteriorly; the meninges and spinal cause is often unknown; the risk is increased in over-
cord are normal. A dimple or small lipoma may overlie weight individuals. Disk herniation is unusual prior
the defect. Most cases are asymptomatic and discovered to age 20 years and is rare in the brotic disks of the
incidentally during an evaluation for back pain. elderly. Genetic factors may play a role in predisposing
Tethered cord syndrome usually presents as a progressive some patients to disk disease. The pain may be located
cauda equina disorder (see later), although myelopa- in the low back only or referred to a leg, buttock, or
thy may also be the initial manifestation. The patient is hip. A sneeze, cough, or trivial movement may cause
often a young adult who complains of perineal or peri- the nucleus pulposus to prolapse, pushing the frayed and
anal pain, sometimes following minor trauma. MRI weakened annulus posteriorly. With severe disk disease,
studies reveal a low-lying conus (below L1-L2) and a the nucleus may protrude through the annulus (hernia-
short and thickened lum terminale. tion) or become extruded to lie as a free fragment in the
spinal canal.
The mechanism by which intervertebral disk injury
TRAUMA causes back pain is controversial. The inner annulus
A patient complaining of back pain and an inability to brosus and nucleus pulposus are normally devoid of
move the legs may have a spinal fracture or dislocation, innervation. Inammation and production of proin-
and, with fractures above L1, spinal cord compression. ammatory cytokines within the protruding or ruptured
Care must be taken to avoid further damage to the spi- disk may trigger or perpetuate back pain. Ingrowth of
nal cord or nerve roots by immobilizing the back pend- nociceptive (pain) nerve bers into inner portions of
ing the results of radiologic studies. a diseased disk may be responsible for chronic disk-
ogenic pain. Nerve root injury (radiculopathy) from
disk herniation may be due to compression, inamma-
Sprains and strains
tion, or both; pathologically, demyelination and axonal
The terms low back sprain, strain, and mechanically induced loss are usually present.
muscle spasm refer to minor, self-limited injuries asso- A ruptured disk may be asymptomatic or cause back
ciated with lifting a heavy object, a fall, or a sudden pain, abnormal posture, limitation of spine motion
77
Herniated L4 disc
Herniated L4 disc
Compressed
Compressed
CHAPTER 9
L5 root
Thecal Sac
A B
(particularly exion), a focal neurologic decit, or intervertebral foramen are optimally visualized by CT-
radicular pain. A dermatomal pattern of sensory loss or myelography. The correlation of neuroradiologic ndings
a reduced or absent deep tendon reex is more sugges- to symptoms, particularly pain, is not simple. Contrast-
tive of a specic root lesion than is the pattern of pain. enhancing tears in the annulus brosus or disk protru-
Motor ndings (focal weakness, muscle atrophy, or fas- sions are widely accepted as common sources of back
ciculations) occur less frequently than focal sensory or pain; however, studies have found that many asymp-
reex changes. Symptoms and signs are usually unilat- tomatic adults have similar ndings. Asymptomatic disk
eral, but bilateral involvement does occur with large protrusions are also common and may enhance with
central disk herniations that compress multiple roots contrast. Furthermore, in patients with known disk herniation
or cause inammation of nerve roots within the spi- treated either medically or surgically, persistence of the hernia-
nal canal. Clinical manifestations of specic nerve root tion 10 years later had no relationship to the clinical outcome.
lesions are summarized in Table 9-2. There is suggestive In summary, MRI ndings of disk protrusion, tears in the
evidence that lumbar disk herniation with a nonprogres- annulus brosus, or contrast enhancement are common
sive nerve root decit can be managed nonsurgically. incidental ndings that, by themselves, should not dictate
The differential diagnosis covers a variety of seri- management decisions for patients with back pain.
ous and treatable conditions, including epidural abscess, The diagnosis of nerve root injury is most secure
hematoma, fracture, or tumor. Fever, constant pain when the history, examination, results of imaging
uninuenced by position, sphincter abnormalities, or studies, and the EMG are concordant. The correla-
signs of spinal cord disease suggest an etiology other tion between CT and EMG for localization of nerve
than lumbar disk disease. Absence of ankle reexes can root injury is between 65 and 73%. Up to one-third
be a normal nding in persons older than age 60 years of asymptomatic adults have a lumbar disk protrusion
or a sign of bilateral S1 radiculopathy. An absent deep detected by CT or MRI scans.
tendon reex or focal sensory loss may indicate injury Management of lumbar disk disease is discussed later
to a nerve root, but other sites of injury along the nerve in the chapter.
must also be considered. For example, an absent knee Cauda equina syndrome (CES) signies an injury
reex may be due to a femoral neuropathy or an L4 of multiple lumbosacral nerve roots within the spi-
nerve root injury. A loss of sensation over the foot and nal canal distal to the termination of the spinal cord
lateral lower calf may result from a peroneal or lateral at L1-2. Low back pain, weakness and areexia in
sciatic neuropathy or an L5 nerve root injury. Focal the legs, saddle anesthesia, or loss of bladder func-
muscle atrophy may reect a nerve root, peripheral tion may occur. The problem must be distinguished-
nerve, anterior horn cell disease, or disuse. from disorders of the lower spinal cord (conus medul-
A lumbar spine MRI scan or CT-myelogram is neces- laris syndrome), acute transverse myelitis (Chap. 35),
sary to establish the location and type of pathology. Spine and Guillain-Barr syndrome (Chap. 46). Combi-
MRIs yield exquisite views of intraspinal and adjacent ned involvement of the conus medullaris and cauda
soft tissue anatomy. Bony lesions of the lateral recess or equina can occur. CES is commonly due to a ruptured
78 lumbosacral intervertebral disk, lumbosacral spine frac- stenosis. Acquired factors that contribute to spinal ste-
ture, hematoma within the spinal canal (e.g., follow- nosis include degenerative diseases (spondylosis, spondy-
ing lumbar puncture in patients with coagulopathy), lolisthesis, scoliosis), trauma, spine surgery, metabolic or
compressive tumor, or other mass lesion. Treatment endocrine disorders (epidural lipomatosis, osteoporosis,
options include surgical decompression, sometimes acromegaly, renal osteodystrophy, hypoparathyroidism),
urgently, in an attempt to restore or preserve motor and Pagets disease. MRI provides the best denition of
or sphincter function, or radiotherapy for metastatic the abnormal anatomy (Fig. 9-5).
tumors (Chap. 37). Conservative treatment of symptomatic LSS includes
nonsteroidal anti-inammatory drugs (NSAIDs), acet-
SECTION II
Normal
Thecal sac Normal
Nerve roots
Facet joints
A B
FIGURE 9-5
Axial T2-weighted images of the lumbar spine. A. The image in the posterior thecal sac with the patient supine. B. The thecal
shows a normal thecal sac within the lumbar spinal canal. The sac is not well visualized due to severe lumbar spinal canal ste-
thecal sac is bright. The lumbar roots are dark punctuate dots nosis, partially the result of hypertrophic facet joints.
Ankylosing spondylitis 79
Uncinate hypertophy
This distinctive arthritic spine disease typically pres-
ents with the insidious onset of low back and buttock
pain. Patients are often males below age 40. Associ-
ated features include morning back stiffness, nocturnal
pain, pain unrelieved by rest, an elevated ESR, and
Compressed C7 root the histocompatibility antigen HLA-B27. Onset at a
young age and back pain improving with exercise are
B characteristic. Loss of the normal lumbar lordosis and
CHAPTER 9
exaggeration of thoracic kyphosis develop as the dis-
ease progresses. Inammation and erosion of the outer
bers of the annulus brosus at the point of contact
with the vertebral body are followed by ossication
C6-C7 disc bulge and bony growth that bridges adjacent vertebral bodies
and reduces spine mobility in all planes. MRI has been
use is a well-recognized risk factor. Whenever pyogenic T4, or other conditions described above should increase
osteomyelitis is found, the possibility of bacterial endo- the suspicion for a cause other than senile osteoporosis.
carditis should be considered. Back pain unrelieved by If tumor is suspected, a bone biopsy or diagnostic search
rest, spine tenderness over the involved spine segment, for a primary tumor is indicated. The sole manifestation
and an elevated ESR are the most common ndings of a compression fracture may be localized back pain
in vertebral osteomyelitis. Fever or an elevated white or radicular pain exacerbated by movement and often
reproduced by palpation over the spinous process of the
Clinical Manifestations of Neurologic Disease
METABOLIC CAUSES
Osteoporosis and osteosclerosis REFERRED PAIN FROM VISCERAL DISEASE
Immobilization or underlying conditions such as osteo- Diseases of the thorax, abdomen, or pelvis may refer
malacia, the postmenopausal state, renal disease, mul- pain to the posterior portion of the spinal segment that
tiple myeloma, hyperparathyroidism, hyperthyroidism, innervates the diseased organ. Occasionally, back pain
may be the rst and only manifestation. Upper abdom- and prolapse) or produce sacral pain after prolonged 81
inal diseases generally refer pain to the lower thoracic standing.
or upper lumbar region (eighth thoracic to the rst Menstrual pain may be felt in the sacral region.
and second lumbar vertebrae), lower abdominal dis- Poorly localized, cramping pain can radiate down the
eases to the midlumbar region (second to fourth lum- legs. Pain due to neoplastic inltration of nerves is typi-
bar vertebrae), and pelvic diseases to the sacral region. cally continuous, progressive in severity, and unrelieved
Local signs (pain with spine palpation, paraspinal mus- by rest at night. Less commonly, radiation therapy of
cle spasm) are absent, and little or no pain accompanies pelvic tumors may produce sacral pain from late radia-
routine movements of the spine. tion necrosis of tissue. Low back pain that radiates into
CHAPTER 9
one or both thighs is common in the last weeks of
pregnancy.
Low thoracic or lumbar pain with abdominal Urologic sources of lumbosacral back pain include
disease chronic prostatitis, prostate cancer with spinal metas-
tasis, and diseases of the kidney or ureter. Lesions
Tumors of the posterior wall of the stomach or duo-
of the bladder and testes do not often produce back
denum typically produce epigastric pain, but midline
pain. Infectious, inammatory, or neoplastic renal dis-
spine pathology that require urgent intervention, phen or NSAIDs, or for those with severe refractory pain.
including infection, cancer, or trauma. Risk factors for a As with muscle relaxants, these drugs are often sedat-
serious cause of ALBP are shown in Table 9-1. Labora- ing, so it may be useful to prescribe them at nighttime
tory and imaging studies are unnecessary if risk factors only. Side effects of short-term opioid use include nau-
are absent. CT or plain spine films are rarely indicated in sea, constipation, and pruritis; risks of long-term opioid
the first month of symptoms unless a spine fracture is use include hypersensitivity to pain, hypogonadism,
suspected. and dependency.
The prognosis is generally excellent. Many patients There is no evidence to support use of oral or
do not seek medical care and apparently improve on injected glucocorticoids for acute low back pain without
their own. Even among those seen in primary care, two- radiculopathy. Antiepileptic drugs, such as gabapentin,
thirds report being substantially improved after seven are not FDA approved for treating low back pain, and
weeks. This spontaneous improvement can mislead there is insufficient evidence to support their use in this
clinicians and researchers about the efficacy of treat- setting.
ment interventions. Perhaps as a result, many ineffective Nonpharmacologic treatments for acute low back
treatments have become widespread in the past, such pain include spinal manipulation, physical therapy,
as bed rest, lumbar traction, sacroiliac fusion, and coc- massage, acupuncture, transcutaneous electrical nerve
cygectomy. stimulation, ultrasound, diathermy, and magnets. Spi-
Clinicians should reassure patients that improve- nal manipulation appears to be roughly equivalent to
ment is very likely, and instruct them in self-care. Edu- conventional medical treatments and may be a useful
cation is an important part of treatment. Satisfaction alternative for patients who wish to avoid or who can-
and the likelihood of follow-up increase when patients not tolerate drug therapy. There is little evidence to sup-
are educated about prognosis, treatment methods, port the use of physical therapy, massage, acupuncture,
activity modifications, and strategies to prevent future laser therapy, therapeutic ultrasound, magnets, corsets,
exacerbations. In one study, patients who felt they did or lumbar traction. Though important for chronic pain,
not receive an adequate explanation for their symp- back exercises for acute back pain are generally not sup-
toms wanted further diagnostic tests. In general, bed ported by clinical evidence. There is no useful evidence
rest should be avoided, or kept to a day or two at most, regarding the value of ice or heat applications for ALBP;
for relief of severe symptoms. Several randomized trials many patients report temporary symptomatic relief
suggest that bed rest does not accelerate the pace of from ice, and heat may produce a short-term reduction
recovery. In general, the best activity recommendation in pain after the first week.
is for walking and early resumption of normal physical
activity, avoiding only strenuous manual labor. Possible CHRONIC LOW BACK PAIN WITHOUT
advantages of early ambulation for acute back pain RADICULOPATHY Chronic low back pain is
include maintenance of cardiovascular conditioning, defined as pain lasting >12 weeks; it accounts for 50% of
improved disk and cartilage nutrition, improved bone total back pain costs. Risk factors include obesity, female
and muscle strength, and increased endorphin levels. gender, older age, prior history of back pain, restricted
Specific back exercises or early vigorous exercise have spinal mobility, pain radiating into a leg, high levels of
not shown benefits for acute back pain, but may be use- psychological distress, poor self-rated health, minimal
ful for chronic pain. Application of heat by heating pads physical activity, smoking, job dissatisfaction, and wide-
or heated blankets is sometimes helpful. spread pain. In general, the same treatments that are
recommended for acute low back pain can be useful for acupuncture, and massage. The role of complementary 83
patients with chronic low back pain. In this setting, how- and alternative medicine approaches, aside from spi-
ever, the benefit of opioid therapy or muscle relaxants is nal manipulation, remains unclear. Biofeedback has not
less clear. been studied rigorously. As with acute back pain, spinal
Evidence supports the use of exercise therapy, manipulation may on average offer benefits similar to
and this can be one of the mainstays of treatment for conventional care. Rigorous recent trials of acupunc-
chronic back pain. Effective regimens have generally ture suggest that true acupuncture is not superior to
included a combination of gradually increasing aerobic sham acupuncture, but that both may offer an advan-
exercise, strengthening exercises, and stretching exer- tage over routine care. Whether this is due entirely to
CHAPTER 9
cises. Motivating patients is sometimes challenging, and placebo effects or to stimulation provided even by sham
supervised exercise is best, for example, with a support- acupuncture is uncertain. Some trials of massage ther-
ive physical therapist. In general, activity tolerance is apy have been encouraging, but this has been less well
the primary goal, while pain relief is secondary. Exercise studied than manipulation or acupuncture.
programs can reverse atrophy in paraspinal muscles and Studies of transcutaneous electrical nerve stimula-
strengthen extensors of the trunk. Supervised inten- tion (TENS) have reached conflicting conclusions, but a
number of randomized trials, all conducted in Europe. common cause of back pain with radiculopathy is a her-
Each of these studies included patients with back pain niated disk with nerve root impingement, resulting in
and a degenerative disk, but no sciatica. Three of the back pain with radiation down the leg. The prognosis
four trials concluded that lumbar fusion surgery was no for acute low back pain with radiculopathy due to disk
more effective than highly structured, rigorous rehabili- herniation (sciatica) is generally favorable, with most
tation combined with cognitive-behavioral therapy. The patients demonstrating substantial improvement over a
Clinical Manifestations of Neurologic Disease
fourth trial found an advantage of fusion surgery over matter of months. Serial imaging studies suggest spon-
haphazard usual care, which appeared to be less effec- taneous regression of the herniated portion of the disk
tive than the structured rehabilitation in other trials. in two-thirds of patients over 6 months. Nonetheless,
Given conflicting evidence, indications for surgery for there are several important treatment options for pro-
chronic back pain alone have remained controversial. viding symptom relief while this natural healing process
Both U.S. and British guidelines suggest considering unfolds.
referral for an opinion on spinal fusion for people who Resumption of normal activity as much as possible
have completed an optimal nonsurgical treatment pro- is usually the best activity recommendation. Random-
gram (including combined physical and psychological ized trial evidence suggests that bed rest is ineffective
treatment) and who have persistent severe back pain for for treating sciatica as well as for back pain alone. Acet-
which they would consider surgery. aminophen and NSAIDs are appropriate for pain relief,
The newest surgical treatment for degenerated disks although severe pain may require short courses of opi-
with back pain is disk replacement with prosthetic disks. oid analgesics.
These are generally designed as metal plates with a Epidural glucocorticoid injections have a role in pro-
polyethylene cushion sandwiched in between. The tri- viding temporary symptom relief for sciatica due to a
als that led to approval of these devices compared them herniated disk. Although randomized trial evidence is
to spine fusion, and concluded that the artificial disks conflicting, there appears to be some overall short-term
were not inferior. Serious complications appeared to be benefit for pain relief of sciatica. However, there does
somewhat more likely with the artificial disk. This treat- not appear to be a benefit in terms of reducing sub-
ment remains controversial for low back pain. sequent surgical interventions. Diagnostic nerve root
Intensive multidisciplinary rehabilitation programs blocks have been advocated to determine if pain origi-
may involve daily or frequent care involving physical nates from a specific nerve root. However, improvement
therapy, exercise, cognitive-behavioral therapy, a work- may result even when the nerve root is not responsible
place evaluation, and other interventions. For patients for the pain; this may occur as a placebo effect, from
who have not responded to other interventions, such a pain-generating lesion located distally along the
programs appear to offer some benefit. Systematic peripheral nerve, or from anesthesia of the sinuverte-
reviews suggest that the evidence is limited and effects bral nerve. The utility of diagnostic nerve root blocks
are moderate. remains a subject of debate.
Some observers have raised concern that chronic Surgical intervention is indicated for patients who
back pain may often be overtreated. The use of opioids, have progressive motor weakness, demonstrated on
epidural glucocorticoid injections, facet joint injections, clinical examination or EMG, as a result of nerve root
and surgical intervention has increased rapidly in the injury. Urgent surgery is recommended for patients who
past decade, without corresponding population-level have evidence of the cauda equina syndrome or spinal
improvements in pain or functioning among patients cord compression, generally suggested by bowel or
with back pain. In each case, randomized trials provide bladder dysfunction, diminished sensation in a saddle
only minimal support for these treatments in the set- distribution, a sensory level, bilateral leg weakness, or
ting of chronic back pain without radiculopathy. For low bilateral leg spasticity.
back pain without radiculopathy, new British guidelines Surgery is also an important option for patients who
explicitly recommend against use of selective sero- have disabling radicular pain despite optimal conserva-
tonin reuptake inhibitors (SSRIs), any type of injection, tive treatment. Sciatica is perhaps the most common rea-
son for recommending spine surgery. Because patients TRAUMA TO THE CERVICAL SPINE 85
with a herniated disk and sciatica generally experience Trauma to the cervical spine (fractures, subluxation)
rapid improvement over a matter of weeks, most experts places the spinal cord at risk for compression. Motor
do not recommend considering surgery unless the vehicle accidents, violent crimes, or falls account for
patient has failed to respond to 68 weeks of appropri- 87% of cervical spinal cord injuries (Chap. 35). Immedi-
ate nonsurgical management. For patients who have not ate immobilization of the neck is essential to minimize
improved, randomized trials indicate that, compared to further spinal cord injury from movement of unstable
nonsurgical treatment, surgery results in more rapid pain cervical spine segments. The decision to obtain imag-
relief. However, after the first year or two of follow-up, ing should be based upon the nature of the injury. The
CHAPTER 9
patients with sciatica appear to have much the same level NEXUS low-risk criteria established that normally alert
of pain relief and functional improvement with or with- patients without palpation tenderness in the midline;
out surgery. Thus, both treatment approaches are reason- intoxication; neurologic decits; and painful distracting
able, and patient preferences should play a major role injuries had a very low likelihood of a clinically signi-
in decision making. Some patients will want the fastest cant traumatic injury to the cervical spine. The Cana-
possible relief and find surgical risks acceptable. Others dian C-spine rule recommends that imaging should be
C6 Biceps Thumb, index ngers Biceps (arm exion) Lateral forearm, thumb,
Radial hand/forearm Pronator teres (internal forearm rotation) index nger
C7 Triceps Middle ngers Tricepsa (arm extension) Posterior arm, dorsal
Dorsum forearm Wrist extensorsa forearm, lateral hand
Extensor digitoruma (nger extension)
C8 Finger exors Little nger Abductor pollicis brevis (abduction D1) 4th and 5th ngers,
Clinical Manifestations of Neurologic Disease
Medial hand and fore- First dorsal interosseous (abduction D2) medial forearm
arm Abductor digiti minimi (abduction D5)
T1 Finger exors Axilla and medial arm Abductor pollicis brevis (abduction D1) Medial arm, axilla
First dorsal interosseous (abduction D2)
Abductor digiti minimi (abduction D5)
a
These muscles receive the majority of innervation from this root.
that accompany specic cervical nerve root lesions are with symptoms or signs in the legs only. MRI is the
summarized in Table 9-4. While the classic patterns study of choice to dene the anatomic abnormalities,
are clinically helpful, there are numerous exceptions but plain CT is adequate to assess bony spurs, forami-
because (1) there is overlap in function between adja- nal narrowing, lateral recess stenosis, or OPLL. EMG
cent nerve roots, (2) symptoms and signs may be evi- and nerve conduction studies can localize and assess
dent in only part of the injured nerve root territory, and the severity of the nerve root injury.
(3) the location of pain is the most variable of the clini-
cal features.
OTHER CAUSES OF NECK PAIN
CERVICAL SPONDYLOSIS Rheumatoid arthritis (RA) of the cervical apophyseal
Osteoarthritis of the cervical spine may produce neck joints produces neck pain, stiffness, and limitation of
pain that radiates into the back of the head, shoul- motion. In advanced RA, synovitis of the atlantoaxial
ders, or arms, or may be the source of headaches in joint (C1-C2; Fig. 9-2) may damage the transverse liga-
the posterior occipital region (supplied by the C2-C4 ment of the atlas, producing forward displacement of
nerve roots). Osteophytes, disk protrusions, or hyper- the atlas on the axis (atlantoaxial subluxation). Radio-
trophic facet or uncovertebral joints may alone or in logic evidence of atlantoaxial subluxation occurs in 30%
combination compress one or several nerve roots at of patients with RA. Not surprisingly, the degree of
the intervertebral foramina (Fig. 9-6); this compres- subluxation correlates with the severity of erosive dis-
sion accounts for 75% of cervical radiculopathies. The ease. When subluxation is present, careful assessment is
roots most commonly affected are C7 and C6. Nar- important to identify early signs of myelopathy. Occa-
rowing of the spinal canal by osteophytes, ossica- sional patients develop high spinal cord compression
tion of the posterior longitudinal ligament (OPLL), or leading to quadriparesis, respiratory insufciency, and
a large central disk may compress the cervical spinal death. Surgery should be considered when myelopa-
cord. Combinations of radiculopathy and myelopathy thy or spinal instability is present. MRI is the imaging
may be present. When little or no neck pain accompa- modality of choice.
nies cord compression, the diagnosis may be confused Ankylosing spondylitis can cause neck pain and less
with amyotrophic lateral sclerosis (Chap. 32), multiple commonly atlantoaxial subluxation; surgery may be
sclerosis (Chap. 39), spinal cord tumors, or syringomy- required to prevent spinal cord compression. Acute
elia (Chap. 35). The possibility of cervical spondylosis herpes zoster presents as acute posterior occipital or
should be considered even when the patient presents neck pain prior to the outbreak of vesicles. Neoplasms
metastatic to the cervical spine, infections (osteomyelitis supraclavicular pain radiating down the arm, numb- 87
and epidural abscess), and metabolic bone diseases may be ness of the fourth and fth ngers or medial forearm,
the cause of neck pain. Neck pain may also be referred and weakness of intrinsic hand muscles innervated by
from the heart with coronary artery ischemia (cervical the ulnar and median nerves. Delayed radiation injury
angina syndrome). may produce similar ndings, although pain is less often
present and almost always less severe. A Pancoast tumor
of the lung is another cause and should be considered,
THORACIC OUTLET especially when a Horners syndrome is present. Supra-
The thoracic outlet contains the rst rib, the subclavian scapular neuropathy may produce severe shoulder pain,
CHAPTER 9
artery and vein, the brachial plexus, the clavicle, and the weakness, and wasting of the supraspinatus and infra-
lung apex. Injury to these structures may result in pos- spinatus muscles. Acute brachial neuritis is often confused
tural or movement-induced pain around the shoulder with radiculopathy; the acute onset of severe shoulder
and supraclavicular region. True neurogenic thoracic outlet or scapular pain is followed typically over days by weak-
syndrome (TOS) is an uncommon disorder resulting from ness of the proximal arm and shoulder girdle muscles
compression of the lower trunk of the brachial plexus innervated by the upper brachial plexus. The onset is
often preceded by an infection. The long thoracic nerve
BRACHIAL PLEXUS AND NERVES The evidence regarding treatment for neck pain is less
complete than that for low back pain. As with low back
Pain from injury to the brachial plexus or peripheral
pain, spontaneous improvement is the norm for acute
nerves of the arm can occasionally mimic pain of cer-
neck pain, and the usual goal of therapy is to provide
vical spine origin. Neoplastic inltration of the lower
symptom relief while natural healing processes proceed.
trunk of the brachial plexus may produce shoulder or
88 The evidence in support of nonsurgical treatments TREATMENT Neck Pain with Radiculopathy
for whiplash-associated disorders is generally of poor
quality and neither supports nor refutes the effective- The natural history of neck pain even with radiculopa-
ness of common treatments used for symptom relief. thy is favorable, and many patients will improve with-
Gentle mobilization of the cervical spine combined out specific therapy. Although there are no randomized
with exercise programs may be more beneficial than trials of NSAIDs for neck pain, a course of NSAIDs, with
usual care. Evidence is insufficient to recommend for or or without muscle relaxants, may be appropriate initial
against the use of cervical traction, neck collars, TENS, therapy. Other nonsurgical treatments are commonly
ultrasound, diathermy, or massage. The role of acupunc- used, including opioid analgesics, oral glucocorticoids,
SECTION II
ture for neck pain also remains ambiguous, with poor- cervical traction, and immobilization with a hard or soft
quality studies and conflicting results. cervical collar. However, there are no randomized tri-
For patients with neck pain unassociated with als to establish the effectiveness of these treatments in
trauma, supervised exercise, with or without mobiliza- comparison to natural history alone. Soft cervical collars
tion, appears to be effective. Exercises often include can be modestly helpful by limiting spontaneous and
shoulder rolls and neck stretches. Although there is rela- reflex neck movements that exacerbate pain.
Clinical Manifestations of Neurologic Disease
tively little evidence about the use of muscle relaxants, As for lumbar radiculopathy, epidural glucocorti-
analgesics, and NSAIDs in neck pain, many clinicians coids may provide short-term symptom relief in cervical
use these medications in much the same way as for low radiculopathy. If cervical radiculopathy is due to bony
back pain. compression from cervical spondylosis with foraminal
Low-level laser therapy directed at areas of tender- narrowing, then surgical decompression is generally
ness, local acupuncture points, or a grid of predeter- indicated to forestall progression of neurologic signs.
mined points is a controversial approach to the treat- Surgical treatment can produce rapid and substan-
ment of neck pain. The putative benefits might be tial symptom relief, although it is unclear whether long-
mediated by anti-inflammatory effects, reduction of term outcomes are improved over nonsurgical therapy.
skeletal muscle fatigue, or inhibition of transmission at Reasonable indications for cervical disk surgery include
neuromuscular junctions. A 2009 meta-analysis sug- a progressive radicular motor deficit, functionally limit-
gested that this treatment may provide greater pain ing pain that fails to respond to conservative manage-
relief than sham therapy for both acute and chronic ment, or spinal cord compression.
neck pain. Comparison to other conservative treatment Surgical treatments include anterior cervical diskec-
measures is needed. tomy alone, laminectomy with diskectomy, diskectomy
Although some surgical studies have proposed a with fusion, and disk arthroplasty (implanting an artifi-
role for anterior diskectomy and fusion in patients with cial cervical disk). Fusions can be performed with a vari-
neck pain, these studies generally have not been rigor- ety of techniques. The risk of subsequent radiculopathy
ously conducted. A systematic review suggested that or myelopathy at cervical segments adjacent to a fusion
there was no valid clinical evidence to support either is 3% per year and 26% per decade. Although this risk
cervical fusion or cervical disk arthroplasty in patients is sometimes portrayed as a late complication of sur-
with neck pain without radiculopathy. Similarly, there is gery, it may also reflect the natural history of degenera-
no evidence to support radiofrequency neurotomy or tive cervical disk disease. The durability of disk prosthe-
cervical facet injections for neck pain without radicu- ses is uncertain. Available data do not strongly support
lopathy. one surgical technique over another.
CHAPTER 10
SYNCOPE
Roy Freeman
Syncope is a transient, self-limited loss of consciousness for syncope-related hospitalization in the United States
due to acute global impairment of cerebral blood ow. is $2 billion. Syncope has a lifetime cumulative inci-
The onset is rapid, duration brief, and recovery spon- dence of up to 35% in the general population. The peak
taneous and complete. Other causes of transient loss of incidence in the young occurs between ages 10 and 30
consciousness need to be distinguished from syncope; years, with a median peak around 15 years. Neurally
these include seizures, vertebrobasilar ischemia, hypox- mediated syncope is the etiology in the vast majority of
emia, and hypoglycemia. A syncopal prodrome (presyn- these cases. In elderly adults, there is a sharp rise in the
cope) is common, although loss of consciousness may incidence of syncope after 70 years.
occur without any warning symptoms. Typical pre- In population-based studies, neurally mediated syn-
syncopal symptoms include dizziness, lightheadedness cope is the most common cause of syncope. The inci-
or faintness, weakness, fatigue, and visual and auditory dence is slightly higher in females than males. In young
disturbances. The causes of syncope can be divided into subjects there is often a family history in rst-degree
three general categories: (1) neurally mediated syncope relatives. Cardiovascular disease due to structural disease
(also called reex syncope), (2) orthostatic hypotension, or arrhythmias is the next most common cause in most
and (3) cardiac syncope. series, particularly in emergency room settings and in
Neurally mediated syncope comprises a heteroge- older patients. Orthostatic hypotension also increases in
neous group of functional disorders that are character- prevalence with age because of the reduced baroreex
ized by a transient change in the reexes responsible for responsiveness, decreased cardiac compliance, and atten-
maintaining cardiovascular homeostasis. Episodic vaso- uation of the vestibulosympathetic reex associated with
dilation and bradycardia occur in varying combinations, aging. In the elderly, orthostatic hypotension is substan-
resulting in temporary failure of blood pressure control. tially more common in institutionalized (5468%) than
In contrast, in patients with orthostatic hypotension due community dwelling (6%) individuals, an observation
to autonomic failure, these cardiovascular homeostatic most likely explained by the greater prevalence of pre-
reexes are chronically impaired. Cardiac syncope may disposing neurologic disorders, physiologic impairment,
be due to arrhythmias or structural cardiac diseases that and vasoactive medication use among institutionalized
cause a decrease in cardiac output. The clinical features, patients.
underlying pathophysiologic mechanisms, therapeu- The prognosis after a single syncopal event for all
tic interventions, and prognoses differ markedly among age groups is generally benign. In particular, syncope
these three causes. of noncardiac and unexplained origin in younger indi-
viduals has an excellent prognosis; life expectancy is
unaffected. By contrast, syncope due to a cardiac cause,
either structural heart disease or primary arrhythmic dis-
EPIDEMIOLOGY AND NATURAL
ease, is associated with an increased risk of sudden car-
HISTORY
diac death and mortality from other causes. Similarly,
Syncope is a common presenting problem, account- mortality rate is increased in individuals with syncope
ing for approximately 3% of all emergency room vis- due to orthostatic hypotension related to age and the
its and 1% of all hospital admissions. The annual cost associated comorbid conditions (Table 10-1).
89
90 TABLE 10-1 From the clinical standpoint, a fall in systemic systolic
blood pressure to 50 mmHg or lower will result in
HIGH-RISK FEATURES INDICATING
syncope. A decrease in cardiac output and/or systemic
HOSPITALIZATION OR INTENSIVE EVALUATION
OF SYNCOPE vascular resistancethe determinants of blood pres-
surethus underlies the pathophysiology of syncope.
Chest pain suggesting coronary ischemia
Common causes of impaired cardiac output include
Features of congestive heart failure decreased effective circulating blood volume; increased
Moderate or severe valvular disease thoracic pressure; massive pulmonary embolus; cardiac
Moderate or severe structural cardiac disease brady- and tachyarrhythmias; valvular heart disease; and
SECTION II
Trifascicular block
The sequence of changes on the electroencephalo-
Atrial brillation
gram of syncopal subjects during syncope comprises
Nonsustained ventricular tachycardia background slowing (often of high amplitude), followed
Family history of sudden death by attenuation or cessation of cortical activity prior to
Preexcitation syndromes return of slow waves, and then normal activity. Despite
the presence of myoclonic movements and other motor
Brugada pattern on ECG
activity, electroencephalographic seizure discharges are
not present in syncopal subjects.
PATHOPHYSIOLOGY
The upright posture imposes a unique physiologic stress CLASSIFICATION
upon humans; most, although not all, syncopal episodes
occur from a standing position. Standing results in pool- NEURALLY MEDIATED SYNCOPE
ing of 5001000 mL of blood in the lower extremi- Neurally mediated syncope is the nal pathway of a
ties and splanchnic circulation. There is a decrease complex central and peripheral nervous system reex arc.
in venous return to the heart and reduced ventricu- There is a sudden, transient change in autonomic efferent
lar lling that result in diminished cardiac output and activity characterized by increased parasympathetic out-
blood pressure. These hemodynamic changes provoke ow causing bradycardia and sympathoinhibition causing
a compensatory reex response, initiated by the baro- vasodilation. The change in autonomic efferent activity
receptors in the carotid sinus and aortic arch, resulting leads to a decrease in blood pressure and a subsequent fall
in increased sympathetic outow and decreased vagal in cerebral blood ow to below the limits of autoregula-
nerve activity (Fig. 10-1). The reex increases periph- tion (Fig. 10-2). In order to elicit this reex, a normal
eral resistance, venous return to the heart, and cardiac or functioning autonomic nervous system is necessary;
output and thus limits the fall in blood pressure. If this this is in contrast to the situation in autonomic failure.
response fails, as is the case chronically in orthostatic The triggers of the afferent limb of the reex arc vary and
hypotension and transiently in neurally mediated syn- may be clearly dened, e.g., the carotid sinus, the gastro-
cope, cerebral hypoperfusion occurs. intestinal tract, or the bladder. In many cases, however,
Syncope is a consequence of global cerebral hypo- the afferent arc is less easily recognized and, under many
perfusion and thus represents a failure of cerebral blood circumstances, the cause is multifactorial. Under these
ow autoregulatory mechanisms. Myogenic factors, circumstances it is likely that multiple afferent pathways
local metabolites, and to a lesser extent autonomic neu- converge on the central autonomic network within the
rovascular control are responsible for the autoregulation medulla that integrates the neural impulses and mediates
of cerebral blood ow (Chap. 28). Typically cerebral the vasodepressor-bradycardic response.
blood ow ranges from 50 to 60 mL/min per 100 g
brain tissue and remains relatively constant over perfu-
Classication of neurally mediated syncope
sion pressures ranging from 50 to 150 mmHg. Cessation
of blood ow for 68 s will result in loss of conscious- Neurally mediated syncope may be subdivided based on
ness, while impairment of consciousness ensues when the afferent pathway and provocative trigger. Vasova-
blood ow decreases to 25 mL/min per 100 g brain gal syncope (the common faint) is provoked by intense
tissue. emotion, pain, and/or orthostatic stress, whereas the
91
CHAPTER 10
Syncope
FIGURE 10-1
The Baroreex. A decrease in arterial pressure unloads the excitatory pathway) and from there to the rostral ventrolat-
baroreceptorsthe terminals of afferent bers of the glos- eral medulla (RVLM) (an inhibitory pathway). The activation of
sopharyngeal and vagus nervesthat are situated in the RVLM presympathetic neurons in response to hypotension
carotid sinus and aortic arch. This leads to a reduction in is thus predominantly due to disinhibition. In response to a
the afferent impulses that are relayed from these mechano- sustained fall in blood pressure, vasopressin release is medi-
receptors through the glossopharyngeal and vagus nerves ated by projections from the A1 noradrenergic cell group in
to the nucleus of the tractus solitarius (NTS) in the dorso- the ventrolateral medulla. This projection activates vasopres-
medial medulla. The reduced baroreceptor afferent activity sin-synthesizing neurons in the magnocellular portion of the
produces a decrease in vagal nerve input to the sinus node paraventricular nucleus (PVN) and the supraoptic nucleus
that is mediated by the neuroanatomical connections of the (SON) of the hypothalamus. Blue denotes sympathetic neu-
NTS to the nucleus ambiguus (NA). There is an increase in rons and green parasympathetic neurons. (From R Freeman:
sympathetic efferent activity that is mediated by the NTS N Engl J Med 358:615, 2008.)
projections to the caudal ventrolateral medulla (CVLM) (an
situational reex syncopes have specic localized stim- Alternately, neurally mediated syncope may be sub-
uli that provoke the reex vasodilation and bradycardia divided based on the predominant efferent pathway.
that leads to syncope. The underlying mechanisms have Vasodepressor syncope describes syncope predominantly
been identied and pathophysiology delineated for most due to efferent, sympathetic, vasoconstrictor failure; car-
of these situational reex syncopes. The afferent trigger dioinhibitory syncope describes syncope predominantly
may originate in the pulmonary system, gastrointesti- associated with bradycardia or asystole due to increased
nal system, urogenital system, heart, and carotid artery vagal outow; while mixed syncope describes syncope
(Table 10-2). Hyperventilation leading to hypocarbia in which there are both vagal and sympathetic reex
and cerebral vasoconstriction, and raised intrathoracic changes.
pressure that impairs venous return to the heart, play a
central role in many of the situational reex syncopes.
Features of neurally mediated syncope
The afferent pathway of the reex arc differs among
these disorders, but the efferent response via the vagus In addition to symptoms of orthostatic intolerance such
and sympathetic pathways is similar. as dizziness, lightheadedness, and fatigue, premonitory
92 125
120
100
100
HR (bpm)
HR (bpm)
80
75 60
50 40
20
25
120
150
SECTION II
125 100
BP (mm Hg)
BP (mm Hg)
100 80
75 60
50
40
25
20
Clinical Manifestations of Neurologic Disease
60 120 180 240 300 360 120 140 160 180 200
A Time (sec) B Time (sec)
FIGURE 10-2
A. The paroxysmal hypotensive-bradycardic response tilt table. B. The same tracing expanded to show 80 s of the
that is characteristic of neurally mediated syncope. Non- episode (from 80 to 200 s). BP, blood pressure; bpm, beats
invasive beat-to-beat blood pressure and heart rate are per minute; HR, heart rate.
shown over 5 min (from 60 to 360 s) of an upright tilt on a
features of autonomic activation may be present in syncope. Isometric counterpressure maneuvers of the
patients with neurally mediated syncope. These include limbs (leg crossing or handgrip and arm tensing) may
diaphoresis, pallor, palpitations, nausea, hyperventila- raise blood pressure and, by maintaining pressure in the
tion, and yawning. During the syncopal event, proximal autoregulatory zone, avoid or delay the onset of syn-
and distal myoclonus (typically arrhythmic and multifo- cope. Randomized controlled trials support this inter-
cal) may occur, raising the possibility of epilepsy. The vention.
eyes typically remain open and usually deviate upward. Fludrocortisone, vasoconstricting agents, and beta-
Urinary but not fecal incontinence may occur. Postictal adrenoreceptor antagonists are widely used by experts
confusion is rare, although visual and auditory halluci- to treat refractory patients, although there is no consis-
nations are sometimes reported. tent evidence from randomized, controlled trials for any
While some predisposing factors and provocative stim- pharmacotherapy to treat neurally mediated syncope.
uli are well established (for example, motionless upright Because vasodilation is the dominant pathophysiologic
posture, warm ambient temperature, intravascular vol- syncopal mechanism in most patients, use of a cardiac
ume depletion, alcohol ingestion, hypoxemia, anemia, pacemaker is rarely beneficial. Possible exceptions are
pain, the sight of blood, venipuncture, and intense emo- older patients in whom syncope is associated with asys-
tion), the underlying basis for the widely different thresh- tole or severe bradycardia, and patients with prominent
olds for syncope among individuals exposed to the same cardioinhibition due to carotid sinus syndrome. In these
provocative stimulus is not known. A genetic basis for patients, dual-chamber pacing may be helpful.
neurally mediated syncope may exist; several studies have
reported an increased incidence of syncope in rst-degree
relatives of fainters, but no gene or genetic marker has
been identied, and environmental, social, and cultural
ORTHOSTATIC HYPOTENSION
factors have not been excluded by these studies.
Orthostatic hypotension, dened as a reduction in
systolic blood pressure of at least 20 mmHg or dia-
stolic blood pressure of at least 10 mmHg within
TREATMENT Neurally Mediated Syncope 3 min of standing or head-up tilt on a tilt table, is a
manifestation of sympathetic vasoconstrictor (auto-
Reassurance, avoidance of provocative stimuli, and
nomic) failure (Fig. 10-3). In many (but not all)
plasma volume expansion with fluid and salt are the
cases, there is no compensatory increase in heart rate
cornerstones of the management of neurally mediated
despite hypotension; with partial autonomic failure,
TABLE 10-2 93
CAUSES OF SYNCOPE
A. Neurally Mediated Syncope
Vasovagal syncope
Provoked fear, pain, anxiety, intense emotion, sight of blood, unpleasant sights and odors, orthostatic
stress
Situational reex syncope
Pulmonary
Cough syncope, wind instrument players syncope, weightlifters syncope, mess tricka and faint-
CHAPTER 10
ing lark,b sneeze syncope, airway instrumentation
Urogenital
Postmicturition syncope, urogenital tract instrumentation, prostatic massage
Gastrointestinal
Swallow syncope, glossopharyngeal neuralgia, esophageal stimulation, gastrointestinal tract instru-
mentation, rectal examination, defecation syncope
Cardiac
Syncope
Swallow syncope, glossopharyngeal neuralgia, esophageal stimulation, gastrointestinal tract instru-
mentation, rectal examination, defecation syncope
Carotid sinus
Carotid sinus sensitivity, carotid sinus massage
Ocular
Ocular pressure, ocular examination, ocular surgery
B. Orthostatic Hypotension
Primary autonomic failure due to idiopathic central and peripheral neurodegenerative diseasesthe
synucleinopathies
Lewy body diseases
Parkinsons disease
Lewy body dementia
Pure autonomic failure
Multiple system atrophy (the Shy-Drager syndrome)
Secondary autonomic failure due to autonomic peripheral neuropathies
Diabetes
Hereditary amyloidosis (familial amyloid polyneuropathy)
Primary amyloidosis (AL amyloidosis; immunoglobulin light chain associated)
Hereditary sensory and autonomic neuropathies (HSAN) (especially type IIIfamilial dysautonomia)
Idiopathic immune-mediated autonomic neuropathy
Autoimmune autonomic ganglionopathy
Sjgrens syndrome
Paraneoplastic autonomic neuropathy
HIV neuropathy
Postprandial hypotension
Iatrogenic (drug-induced)
Volume depletion
C. Cardiac Syncope
Arrhythmias
Sinus node dysfunction
Atrioventricular dysfunction
Supraventricular tachycardias
Ventricular tachycardias
Inherited channelopathies
Cardiac structural disease
Valvular disease
Myocardial ischemia
Obstructive and other cardiomyopathies
Atrial myxoma
Pericardial effusions and tamponade
a
Hyperventilation for 1 min, followed by sudden chest compression.
b
Hyperventilation (20 breaths) in a squatting position, rapid rise to standing, then Valsalva.
94 75 74
72
HR (bpm)
HR (bpm)
70
70
65 68
200 180
SECTION II
150 150
BP (mm Hg)
BP (mm Hg)
100 120
50 90
Clinical Manifestations of Neurologic Disease
0 60
60 120 180 240 300 360 180 190 200 210 220
A Time (sec) Time (sec)
B
FIGURE 10-3
A. The gradual fall in blood pressure without a compen- upright tilt on a tilt table. B. The same tracing expanded to
satory heart rate increase that is characteristic of ortho- show 40 s of the episode (from 180 to 220 s). BP, blood pres-
static hypotension due to autonomic failure. Blood pressure sure; bpm, beats per minute; HR, heart rate.
and heart rate are shown over 5 min (from 60 to 360 s) of an
heart rate may increase to some degree but is insuf- occur suddenly, suggesting the possibility of a seizure or
cient to maintain cardiac output. A variant of ortho- cardiac cause.
static hypotension is delayed orthostatic hypoten- Supine hypertension is common in patients with
sion which occurs beyond 3 min of standing; this may orthostatic hypotension due to autonomic failure,
reect a mild or early form of sympathetic adrener- affecting over 50% of patients in some series. Ortho-
gic dysfunction. In some cases, orthostatic hypoten- static hypotension may present after initiation of ther-
sion occurs within 15 s of standing (so-called initial apy for hypertension, and supine hypertension may fol-
orthostatic hypotension), a nding that may repre- low treatment of orthostatic hypotension. However,
sent a transient mismatch between cardiac output and in other cases, the association of the two conditions
peripheral vascular resistance and does not represent is unrelated to therapy; it may in part be explained by
autonomic failure. baroreex dysfunction in the presence of residual sym-
Characteristic symptoms of orthostatic hypotension pathetic outow, particularly in patients with central
include light-headedness, dizziness, and presyncope autonomic degeneration.
(near-faintness) occurring in response to sudden pos-
tural change. However, symptoms may be absent or
Causes of neurogenic orthostatic hypotension
nonspecic, such as generalized weakness, fatigue, cog-
nitive slowing, leg buckling, or headache. Visual blur- Causes of neurogenic orthostatic hypotension include
ring may occur, likely due to retinal or occipital lobe central and peripheral autonomic nervous system dys-
ischemia. Neck paintypically in the suboccipital, pos- function (Chap. 33). Autonomic dysfunction of other
terior cervical, and shoulder region (the coat-hanger organ systems (including the bladder, bowels, sexual
headache)most likely due to neck muscle ischemia, organs, and sudomotor system) of varying severity fre-
may be the only symptom. Patients may report ortho- quently accompanies orthostatic hypotension in these
static dyspnea (thought to reect ventilation-perfusion disorders (Table 10-2).
mismatch due to inadequate perfusion of ventilated The primary autonomic degenerative disorders are
lung apices) or angina (attributed to impaired myo- multiple system atrophy (the Shy-Drager syndrome;
cardial perfusion even with normal coronary arteries). Chap. 33), Parkinsons disease (Chap. 30), demen-
Symptoms may be exacerbated by exertion, prolonged tia with Lewy bodies (Chap. 29), and pure auto-
standing, increased ambient temperature, or meals. Syn- nomic failure (Chap. 33). These are often grouped
cope is usually preceded by warning symptoms, but may together as synucleinopathies due to the presence of
alpha-synuclein, a small protein that precipitates pre- CARDIAC SYNCOPE 95
dominantly in the cytoplasm of neurons in the Lewy
body disorders (Parkinsons disease, dementia with Cardiac (or cardiovascular) syncope is caused by
Lewy bodies, and pure autonomic failure) and in the arrhythmias and structural heart disease. These may
glia in multiple system atrophy. occur in combination because structural disease ren-
Peripheral autonomic dysfunction may also accom- ders the heart more vulnerable to abnormal electrical
pany small ber peripheral neuropathies such as those activity.
seen in diabetes, amyloid, immune-mediated neuropa-
thies, hereditary sensory and autonomic neuropathies Arrhythmias
CHAPTER 10
(HSAN; particularly HSAN type III; familial dysauto-
nomia), and inammatory neuropathies (Chaps. 46 and Bradyarrhythmias that cause syncope include those due to
47). Less frequently, orthostatic hypotension is associ- severe sinus node dysfunction (e.g., sinus arrest or sino-
ated with the peripheral neuropathies that accompany atrial block) and atrioventricular block (e.g., Mobitz type
vitamin B12 deciency, neurotoxic exposure, HIV and II, high-grade, and complete AV block). The bradyar-
other infections, and porphyria. rhythmias due to sinus node dysfunction are often asso-
ciated with an atrial tachyarrhythmia, a disorder known
Syncope
Patients with autonomic failure and the elderly are
susceptible to falls in blood pressure associated with as the tachycardia-bradycardia syndrome. A prolonged
meals. The magnitude of the blood pressure fall is exac- pause following the termination of a tachycardic epi-
erbated by large meals, meals high in carbohydrate, and sode is a frequent cause of syncope in patients with the
alcohol intake. The mechanism of postprandial syncope tachycardia-bradycardia syndrome. Medications of sev-
is not fully elucidated. eral classes may also cause bradyarrhythmias of sufcient
Orthostatic hypotension is often iatrogenic. Drugs severity to cause syncope. Syncope due to bradycardia or
from several classes may lower peripheral resistance asystole is referred to as a Stokes-Adams attack.
(e.g., alpha-adrenoreceptor antagonists used to treat Ventricular tachyarrhythmias frequently cause syn-
hypertension and prostatic hypertrophy; antihyperten- cope. The likelihood of syncope with ventricular tachy-
sive agents of several classes; nitrates and other vasodi- cardia is in part dependent on the ventricular rate; rates
lators; tricyclic agents and phenothiazines). Iatrogenic below 200 beats per min are less likely to cause syn-
volume depletion due to diuresis and volume depletion cope. The compromised hemodynamic function during
due to medical causes (hemorrhage, vomiting, diarrhea, ventricular tachycardia is caused by ineffective ventricu-
or decreased uid intake) may also result in decreased lar contraction, reduced diastolic lling due to abbrevi-
effective circulatory volume, orthostatic hypotension, ated lling periods, loss of atrioventricular synchrony,
and syncope. and concurrent myocardial ischemia.
Several disorders associated with cardiac electro-
physiologic instability and arrhythmogenesis are due to
mutations in ion channel subunit genes. These include
TREATMENT Orthostatic Hypotension the long QT syndrome, Brugada syndrome, and cat-
echolaminergic polymorphic ventricular tachycardia.
The first step is to remove reversible causesusually The long QT syndrome is a genetically heterogeneous
vasoactive medications (Table 33-6). Next, nonphar- disorder associated with prolonged cardiac repolariza-
macologic interventions should be introduced. These tion and a predisposition to ventricular arrhythmias.
interventions include patient education regarding Syncope and sudden death in patients with long QT
staged moves from supine to upright; warnings about syndrome result from a unique polymorphic ventricular
the hypotensive effects of meal ingestion; instructions tachycardia called torsades des pointes that degenerates
about the isometric counterpressure maneuvers that into ventricular brillation. The long QT syndrome has
increase intravascular pressure (see earlier in this chap- been linked to genes encoding K+ channel -subunits,
ter); and raising the head of the bed to reduce supine K+ channel -subunits, voltage-gated Na+ channel, and
hypertension. Intravascular volume should be expanded a scaffolding protein, ankyrin B (ANK2). Brugada syn-
by increasing dietary fluid and salt. If these nonpharma- drome is characterized by idiopathic ventricular bril-
cologic measures fail, pharmacologic intervention with lation in association with right ventricular electrocar-
fludrocortisone acetate and vasoconstricting agents diogram (ECG) abnormalities without structural heart
such as midodrine and pseudoephedrine should be disease. This disorder is also genetically heterogeneous,
introduced. Some patients with intractable symptoms although it is most frequently linked to mutations in
require additional therapy with supplementary agents the Na+ channel -subunit, SCN5A. Catecholamin-
that include pyridostigmine, yohimbine, desmopressin ergic polymorphic tachycardia is an inherited, geneti-
acetate (DDAVP), and erythropoietin (Chap. 33). cally heterogeneous disorder associated with exercise-
or stress-induced ventricular arrhythmias, syncope, or
96 sudden death. Acquired QT interval prolongation, most intestinal, pulmonary, urogenital, pupillary, and cutane-
commonly due to drugs, may also result in ventricular ous manifestations that are similar to the premonitory
arrhythmias and syncope. features of syncope. Furthermore, the cardiovascular
manifestations of autonomic epilepsy include clinically
Structural disease significant tachycardias and bradycardias that may be of
Structural heart disease, (e.g., valvular disease, myocar- sufficient magnitude to cause loss of consciousness. The
dial ischemia, hypertrophic and other cardiomyopathies, presence of accompanying nonautonomic auras may
cardiac masses such as atrial myxoma, and pericardial help differentiate these episodes from syncope.
effusions) may lead to syncope by compromising cardiac Loss of consciousness associated with a seizure usu-
SECTION II
output. Structural disease may also contribute to other ally lasts longer than 5 min and is associated with pro-
pathophysiologic mechanisms of syncope. For example, longed postictal drowsiness and disorientation, whereas
cardiac structural disease may predispose to arrhyth- reorientation occurs almost immediately after a synco-
mogenesis; aggressive treatment of cardiac failure with pal event. Muscle aches may occur after both syncope
diuretics and/or vasodilators may lead to orthostatic and seizures, although they tend to last longer follow-
hypotension; and inappropriate reex vasodilation may ing a seizure. Seizures, unlike syncope, are rarely pro-
Clinical Manifestations of Neurologic Disease
occur with structural disorders such as aortic stenosis voked by emotions or pain. Incontinence of urine may
and hypertrophic cardiomyopathy, possibly provoked occur with both seizures and syncope; however, fecal
by increased ventricular contractility. incontinence does not occur with syncope.
Hypoglycemia may cause transient loss of conscious-
ness, typically in individuals with type 1 or type 2 diabe-
tes treated with insulin. The clinical features associated
TREATMENT Cardiac Syncope
with impending or actual hypoglycemia include tremor,
Treatment of cardiac disease depends upon the under- palpitations, anxiety, diaphoresis, hunger, and paresthe-
lying disorder. Therapies for arrhythmias include cardiac sias. These symptoms are due to autonomic activation
pacing for sinus node disease and AV block, and abla- to counter the falling blood glucose. Hunger, in par-
tion, anti-arrhythmic drugs, and cardioverter-defibril- ticular, is not a typical premonitory feature of syncope.
lators for atrial and ventricular tachyarrhythmias. These Hypoglycemia also impairs neuronal function, lead-
disorders are best managed by physicians with special- ing to fatigue, weakness, dizziness, and cognitive and
ized skills in this area. behavioral symptoms. Diagnostic difficulties may occur
in individuals in strict glycemic control; repeated hypo-
glycemia impairs the counterregulatory response and
leads to a loss of the characteristic warning symptoms
APPROACH TO THE
Syncope that are the hallmark of hypoglycemia.
PATIENT
Patients with cataplexy experience an abrupt partial
DIFFERENTIAL DIAGNOSIS Syncope is easily or complete loss of muscular tone triggered by strong
diagnosed when the characteristic features are present; emotions, typically anger or laughter. Unlike syncope,
however, several disorders with transient real or apparent consciousness is maintained throughout the attacks,
loss of consciousness may create diagnostic confusion. which typically last between 30 s and 2 min. There are
Generalized and partial seizures may be confused no premonitory symptoms. Cataplexy occurs in 6075%
with syncope; however, there are a number of differenti- of patients with narcolepsy.
ating features. Whereas tonic-clonic movements are the The clinical interview and interrogation of eyewit-
hallmark of a generalized seizure, myoclonic and other nesses usually allow differentiation of syncope from
movements also may occur in up to 90% of syncopal falls due to vestibular dysfunction, cerebellar disease,
episodes. Myoclonic jerks associated with syncope may extrapyramidal system dysfunction, and other gait dis-
be multifocal or generalized. They are typically arrhyth- orders. If the fall is accompanied by head trauma, a
mic and of short duration (<30 s). Mild flexor and exten- postconcussive syndrome, amnesia for the precipitat-
sor posturing also may occur. Partial- or partial-complex ing events, and/or the presence of loss of consciousness
seizures with secondary generalization are usually pre- may contribute to diagnostic difficulty.
ceded by an aura, commonly an unpleasant smell; fear Apparent loss of consciousness can be a manifesta-
anxiety; abdominal discomfort or other visceral sensa- tion of psychiatric disorders such as generalized anxiety,
tions. These phenomena should be differentiated from panic disorders, major depression, and somatization dis-
the premonitory features of syncope. order. These possibilities should be considered in indi-
Autonomic manifestations of seizures (autonomic viduals who faint frequently without prodromal symp-
epilepsy) may provide a more difficult diagnostic chal- toms. Such patients are rarely injured despite numerous
lenge. Autonomic seizures have cardiovascular, gastro- falls. There are no clinically significant hemodynamic
changes concurrent with these episodes. In contrast, syncope and in patients over age 50 years with recur- 97
transient loss of consciousness due to vasovagal syn- rent syncope of unknown etiology. This test should only
cope precipitated by fear, stress, anxiety, and emotional be carried out under continuous ECG and blood pres-
distress is accompanied by hypotension, bradycardia, or sure monitoring and should be avoided in patients with
both. carotid bruits, plaques, or stenosis.
INITIAL EVALUATION The goals of the initial Cardiac Evaluation ECG monitoring is indicated
evaluation are to determine whether the transient loss for patients with a high pretest probability of arrhyth-
of consciousness was due to syncope; to identify the mia causing syncope. Patients should be monitored in
CHAPTER 10
cause; and to assess risk for future episodes and serious hospital if the likelihood of a life-threatening arrhythmia
harm (Table 10-1). The initial evaluation should include a is high, e.g., patients with severe structural or coronary
detailed history, thorough questioning of eyewitnesses, artery disease, nonsustained ventricular tachycardia, tri-
and a complete physical and neurologic examination. fascicular heart block, prolonged QT interval, Brugadas
Blood pressure and heart rate should be measured in syndrome ECG pattern, and family history of sudden
the supine position and after 3 min of standing to deter- cardiac death. Outpatient Holter monitoring is recom-
Syncope
mine whether orthostatic hypotension is present. An ECG mended for patients who experience frequent syncopal
should be performed if there is suspicion of syncope due episodes (one or more per week), whereas loop record-
to an arrhythmia or underlying cardiac disease. Relevant ers, which continually record and erase cardiac rhythm,
electrocardiographic abnormalities include bradyarrhyth- are indicated for patients with suspected arrhythmias
mias or tachyarrhythmias, atrioventricular block, isch- with low risk of sudden cardiac death. Loop record-
emia, old myocardial infarction, long QT syndrome, and ers may be external (recommended for evaluation of
bundle branch block. This initial assessment will lead to episodes that occur at a frequency of greater than one
the identification of a cause of syncope in approximately per month) or implantable (if syncope occurs less fre-
50% of patients and also allows stratification of patients quently).
at risk for cardiac mortality. Echocardiography should be performed in patients
with a history of cardiac disease or if abnormalities
Laboratory Tests Baseline laboratory blood tests are found on physical examination or the electrocar-
are rarely helpful in identifying the cause of syncope. diogram. Echocardiographic diagnoses that may be
Blood tests should be performed when specific disor- responsible for syncope include aortic stenosis, hyper-
ders, e.g., myocardial infarction, anemia, and secondary trophic cardiomyopathy, cardiac tumors, aortic dissec-
autonomic failure, are suspected (Table 10-2). tion, and pericardial tamponade. Echocardiography also
has a role in risk stratification based on the left ventricu-
Autonomic Nervous System Testing (Chap. lar ejection fraction.
33) Autonomic testing including tilt table testing can be Treadmill exercise testing with ECG and blood pres-
performed in specialized centers. Autonomic testing is sure monitoring should be performed in patients who
helpful to uncover objective evidence of autonomic fail- have experienced syncope during or shortly after
ure and also to demonstrate a predisposition to neurally exercise. Treadmill testing may help identify exercise-
mediated syncope. Autonomic testing includes assess- induced arrhythmias (e.g., tachycardia-related AV block)
ments of parasympathetic autonomic nervous system and exercise-induced exaggerated vasodilation.
function (e.g., heart rate variability to deep respiration Electrophysiologic studies are indicated in patients
and a Valsalva maneuver), sympathetic cholinergic func- with structural heart disease and ECG abnormali-
tion (e.g., thermoregulatory sweat response and quan- ties in whom noninvasive investigations have failed
titative sudomotor axon reflex test), and sympathetic to yield a diagnosis. Electrophysiologic studies have
adrenergic function (e.g., blood pressure response to low sensitivity and specificity and should only be
a Valsalva maneuver and a tilt table test with beat-to- performed when a high pretest probability exists.
beat blood pressure measurement). The hemodynamic Currently, this test is rarely performed to evaluate
abnormalities demonstrated on tilt table test (Figs. patients with syncope.
10-2 and 10-3) may be useful in distinguishing ortho-
static hypotension due to autonomic failure from the Psychiatric Evaluation Screening for psychiat-
hypotensive bradycardic response of neurally mediated ric disorders may be appropriate in patients with recur-
syncope. Similarly, the tilt table test may help identify rent unexplained syncope episodes. Tilt table testing,
patients with syncope due to delayed or initial ortho- with demonstration of symptoms in the absence of
static hypotension. hemodynamic change, may be useful in reproduc-
Carotid sinus massage should be considered in ing syncope in patients with suspected psychogenic
patients with symptoms suggestive of carotid sinus syncope.
CHAPTER 11
Dizziness is a common, vexing symptom, and epidemi- (e.g., arrhythmia, transient ischemic attack/stroke)? (2)
ologic data indicate that more than 20% of adults expe- is it vestibular? and (3) if vestibular, is it peripheral or
rience dizziness within a given year. The diagnosis is central? A careful history and examination often pro-
frequently challenging, in part because patients use the vide enough information to answer these questions and
term to refer to a variety of different sensations, includ- determine whether additional studies or referral to a
ing feelings of faintness, spinning, and other illusions specialist is necessary.
of motion, imbalance, and anxiety. Other descriptive
words, such as light-headedness, are equally ambiguous,
referring in some cases to a presyncopal sensation due APPROACH TO THE
to hypoperfusion of the brain and in others to disequi- PATIENT Dizziness
librium and imbalance. Patients often have difculty
HISTORY When a patient presents with dizziness,
distinguishing among these various symptoms, and the
words they choose do not describe the underlying etiol- the first step is to delineate more precisely the nature
ogy reliably. of the symptom. In the case of vestibular disorders, the
Vascular disorders cause presyncopal dizziness as a physical symptoms depend on whether the lesion is
result of cardiac dysrhythmia, orthostatic hypotension, unilateral or bilateral and whether it is acute or chronic
medication effects, or another cause. Such presynco- and progressive. Vertigo, an illusion of self or environ-
pal sensations vary in duration; they may increase in mental motion, implies asymmetry of vestibular inputs
severity until loss of consciousness occurs, or they may from the two labyrinths or in their central pathways and
resolve before loss of consciousness if the cerebral isch- is usually acute. Symmetric bilateral vestibular hypo-
emia is corrected. Faintness and syncope, which are function causes imbalance but no vertigo. Because of
discussed in detail in Chap. 10, should always be con- the ambiguity in patients descriptions of their symp-
sidered when one is evaluating patients with brief epi- toms, diagnosis based simply on symptom character is
sodes of dizziness or dizziness that occurs with upright typically unreliable. The history should focus closely on
posture. other features, including whether dizziness is parox-
Vestibular causes of dizziness may be due to periph- ysmal or has occurred only once, the duration of each
eral lesions that affect the labyrinths or vestibular nerves episode, any provoking factors, and the symptoms that
or to involvement of the central vestibular pathways. accompany the dizziness.
They may be paroxysmal or due to a xed unilateral or Causes of dizziness can be divided into episodes
bilateral vestibular decit. Acute unilateral lesions cause that last for seconds, minutes, hours, or days. Com-
vertigo due to a sudden imbalance in vestibular inputs mon causes of brief dizziness (seconds) include benign
from the two labyrinths. Bilateral lesions cause imbal- paroxysmal positional vertigo (BPPV) and orthostatic
ance and instability of vision when the head moves hypotension, both of which typically are provoked by
(oscillopsia). Other causes of dizziness include nonvestib- changes in position. Attacks of migrainous vertigo and
ular imbalance and gait disorders (e.g., loss of proprio- Mnires disease often last hours. When episodes are
ception from sensory neuropathy, parkinsonism) and of intermediate duration (minutes), transient ischemic
anxiety. attacks of the posterior circulation should be consid-
In evaluating patients with dizziness, questions to ered, although these episodes also could be due to
consider include the following: (1) is it dangerous migraine or a number of other causes.
98
TABLE 11-1 99
FEATURES OF PERIPHERAL AND CENTRAL VERTIGO
PERIPHERAL (LABYRINTH OR
SIGN OR SYMPTOM VESTIBULAR NERVE) CENTRAL (BRAINSTEM OR CEREBELLUM)
Direction of associated nystagmus Unidirectional; fast phase opposite Bidirectional (direction-changing) or uni-
lesiona directional
Purely horizontal nystagmus without Uncommon May be present
torsional component
CHAPTER 11
Purely vertical or purely torsional Never presentb May be present
nystagmus
Visual xation Inhibits nystagmus No inhibition
Tinnitus and/or deafness Often present Usually absent
Associated central nervous system None Extremely common (e.g., diplopia, hic-
abnormalities cups, cranial neuropathies, dysarthria)
a
In Mnires disease, the direction of the fast phase is variable.
b
Combined vertical-torsional nystagmus suggests BPPV.
Symptoms that accompany vertigo may be help- opposite direction that resets the position of the eyes in
ful in distinguishing peripheral vestibular lesions from the orbits. Table 11-1 lists features that help distinguish
central causes. Unilateral hearing loss and other aural peripheral vestibular nystagmus from central nystagmus.
symptoms (ear pain, pressure, fullness) typically point Except in the case of acute vestibulopathy (e.g., vestibular
to a peripheral cause. Because the auditory pathways neuritis), if primary position nystagmus is easily seen in
quickly become bilateral upon entering the brainstem, the light, it is probably due to a central cause. Two forms
central lesions are unlikely to cause unilateral hearing of nystagmus that are characteristic of lesions of the cer-
loss (unless the lesion lies near the root entry zone of ebellar pathways are vertical nystagmus with downward
the auditory nerve). Symptoms such as double vision, fast phases (downbeat nystagmus) and horizontal nys-
numbness, and limb ataxia suggest a brainstem or cer- tagmus that changes direction with gaze (gaze-evoked
ebellar lesion. nystagmus).
Specialists find that the most useful bedside test of
EXAMINATION Because dizziness and imbalance peripheral vestibular function is the head impulse test, in
can be a manifestation of a variety of neurologic disor- which the vestibuloocular reflex (VOR) is assessed with
ders, the neurologic examination is important in the eval- small-amplitude (approximately 20 degrees) rapid head
uation of these patients. Particular focus should be given rotations; beginning in the primary position, the head is
to assessment of eye movements, vestibular function, rotated to the left or right while the patient is instructed
and hearing. The range of eye movements and whether to fixate on the examiners face. If the VOR is deficient, a
they are equal in each eye should be observed. Peripheral catch-up saccade is seen at the end of the rotation. This
eye movement disorders (e.g., cranial neuropathies, eye test can identify both unilateral (deficient VOR when the
muscle weakness) are usually disconjugate (different in head is rotated toward the weak side) and bilateral ves-
the two eyes). One should check pursuit (the ability to fol- tibular hypofunction.
low a smoothly moving target) and saccades (the ability All patients with episodic dizziness, especially if it is
to look back and forth accurately between two targets). provoked by positional change, should be tested with
Poor pursuit or inaccurate (dysmetric) saccades usually the Dix-Hallpike maneuver. The patient begins in a sit-
indicates central pathology, often involving the cerebel- ting position with the head turned 45 degrees; holding
lum. Finally, one should look for spontaneous nystagmus, the back of the head, the examiner then gently low-
an involuntary back-and-forth movement of the eyes. ers the patient into a supine position with the head
Most often nystagmus is of the jerk type, in which a slow extended backward by about 20 degrees, and observes
drift (slow phase) in one direction alternates with a rapid for nystagmus; after 30 s the patient is raised to the sit-
saccadic movement (quick phase or fast phase) in the ting position and after a 1-min rest the procedure is
100 repeated with the head turned to the other side. Use
hemorrhage), which may be life-threatening, or periph-
of Frenzel eyeglasses (self-illuminated goggles with
eral, affecting the vestibular nerve or labyrinth. Attention
convex lenses that blur the patients vision but allow
should be given to any symptoms or signs that point to
the examiner to see the eyes greatly magnified) can
central dysfunction (diplopia, weakness or numbness, dys-
improve the sensitivity of the test. If transient upbeating
arthria). The pattern of spontaneous nystagmus, if pres-
and torsional nystagmus are elicited in the supine posi-
ent, may be helpful (Table 11-1). If the head impulse test
tion, posterior canal BPPV can be diagnosed confidently
is normal, an acute peripheral vestibular lesion is unlikely.
and treated with a repositioning maneuver, and addi-
However, a central lesion cannot always be excluded with
tional testing can be avoided.
certainly on the basis of symptoms and examination alone;
SECTION II
CHAPTER 11
relieve symptoms at the time of an attack. ingeal-based infection or tumor, and other toxins. It
also may occur in patients with peripheral polyneuropa-
Mnires disease thy; in these patients, both vestibular loss and impaired
proprioception may contribute to poor balance. Finally,
Attacks of Mnires disease consist of vertigo, hearing unilateral processes such as vestibular neuritis and
loss, and pain, pressure, or fullness in the affected ear. Mnires disease may involve both ears sequentially,
The hearing loss and aural symptoms are key features resulting in bilateral vestibulopathy.
and IM)
Table 11-2 provides a list of commonly used medica- Benzodiazepines
tions for suppression of vertigo. As noted, these medi- Diazepam 2.5 mg 13 times daily
cations should be reserved for short-term control of Clonazepam 0.25 mg 13 times daily
active vertigo, such as during the first few days of acute Anticholinergic
vestibular neuritis, or for acute attacks of Mnires dis-
Scopolamine transdermalc Patch
Clinical Manifestations of Neurologic Disease
a
All listed drugs are approved by the U.S. Food and Drug Adminis-
tration, but most are not approved for the treatment of vertigo.
b
Usual oral (unless otherwise stated) starting dose in adults; a
higher maintenance dose can be reached by a gradual increase.
c
For motion sickness only.
d
For benign paroxysmal positional vertigo.
e
For Mnires disease.
f
For vestibular migraine.
g
For acute vestibular neuritis (started within three days of onset).
h
For psychosomatic vertigo.
CHAPTER 12
Michael J. Aminoff
Normal motor function involves integrated muscle Myopathic weakness is generally most marked in proxi-
activity that is modulated by the activity of the cere- mal muscles, whereas weakness from impaired neu-
bral cortex, basal ganglia, cerebellum, and spinal cord. romuscular transmission has no specic pattern of
Motor system dysfunction leads to weakness or paral- involvement. Weakness often is accompanied by other
ysis, which is discussed in this chapter, or to ataxia neurologic abnormalities that help indicate the site of
(Chap. 31) or abnormal movements (Chap. 30). The the responsible lesion. These abnormalities include
mode of onset, distribution, and accompaniments of changes in tone, muscle bulk, muscle stretch reexes,
weakness help suggest its cause. and cutaneous reexes (Table 12-1).
Weakness is a reduction in the power that can be Tone is the resistance of a muscle to passive stretch.
exerted by one or more muscles. Increased fatigabil- Central nervous system (CNS) abnormalities that cause
ity or limitation in function due to pain or articular weakness generally produce spasticity, an increase in
stiffness often is confused with weakness by patients. tone associated with disease of upper motor neurons.
Increased fatigability is the inability to sustain the perfor- Spasticity is velocity-dependent, has a sudden release
mance of an activity that should be normal for a person after reaching a maximum (the clasp-knife phenom-
of the same age, sex, and size. Increased time is required enon), and predominantly affects the antigravity mus-
sometimes for full power to be exerted, and this brady- cles (i.e., upper-limb exors and lower-limb exten-
kinesia may be misinterpreted as weakness. Severe pro- sors). Spasticity is distinct from rigidity and paratonia,
prioceptive sensory loss also may lead to complaints two other types of hypertonia. Rigidity is increased
of weakness because adequate feedback information tone that is present throughout the range of motion
about the direction and power of movements is lacking. (a lead pipe or plastic stiffness) and affects ex-
Finally, apraxia, a disorder of planning and initiating a ors and extensors equally; it sometimes has a cogwheel
skilled or learned movement unrelated to a signicant quality that is enhanced by voluntary movement of the
motor or sensory decit (Chap. 18), sometimes is mis- contralateral limb (reinforcement). Rigidity occurs with
taken for weakness. certain extrapyramidal disorders, such as Parkinsons
Paralysis indicates weakness that is so severe that disease. Paratonia (or gegenhalten) is increased tone that
a muscle cannot be contracted at all, whereas paresis varies irregularly in a manner that may seem related to
refers to weakness that is mild or moderate. The pre- the degree of relaxation, is present throughout the range
x hemi- refers to one-half of the body, para- to of motion, and affects exors and extensors equally; it
both legs, and quadri- to all four limbs. The sufx usually results from disease of the frontal lobes. Weak-
-plegia signies severe weakness or paralysis. ness with decreased tone (accidity) or normal tone occurs
The distribution of weakness helps to indicate the with disorders of motor units. A motor unit consists of a
site of the underlying lesion. Weakness from involve- single lower motor neuron and all the muscle bers that
ment of upper motor neurons occurs particularly in the it innervates.
extensors and abductors of the upper limb and the ex- Muscle bulk generally is not affected in patients with
ors of the lower limb. Lower motor neuron weakness upper motor neuron lesions, although mild disuse
does not have this selectivity but depends on whether atrophy eventually may occur. By contrast, atrophy is
involvement is at the level of the anterior horn cells, often conspicuous when a lower motor neuron lesion
nerve root, limb plexus, or peripheral nerveonly is responsible for weakness and also may occur with
muscles supplied by the affected structure are weak. advanced muscle disease.
103
104 TABLE 12-1
SIGNS THAT DISTINGUISH THE ORIGIN OF WEAKNESS
SIGN UPPER MOTOR NEURON LOWER MOTOR NEURON MYOPATHIC
Muscle stretch (tendon) reexes are usually increased and jaw muscles almost always are spared. With bilateral
with upper motor neuron lesions, although they may corticobulbar lesions, pseudobulbar palsy often develops:
Clinical Manifestations of Neurologic Disease
be decreased or absent for a variable period immediately dysarthria, dysphagia, dysphonia, and emotional labil-
after onset of an acute lesion. This is usuallybut not ity accompany bilateral facial weakness and a brisk jaw
invariablyaccompanied by abnormalities of cutaneous jerk. Spasticity accompanies upper motor neuron weak-
reexes (such as supercial abdominals; Chap. 1) and, in ness but may not be present in the acute phase. Upper
particular, by an extensor plantar (Babinski) response. motor neuron lesions also affect the ability to perform
The muscle stretch reexes are depressed in patients rapid repetitive movements. Such movements are slow
with lower motor neuron lesions when there is direct and coarse, but normal rhythmicity is maintained.
involvement of specic reex arcs. The stretch reexes Finger-nose-nger and heel-knee-shin maneuvers are
generally are preserved in patients with myopathic performed slowly but adequately.
weakness except in advanced stages, when they some-
times are attenuated. In disorders of the neuromuscu-
lar junction, the intensity of the reex responses may Lower motor neuron weakness
be affected by preceding voluntary activity of affected This pattern results from disorders of cell bodies of
muscles; that activity may lead to enhancement of ini- lower motor neurons in the brainstem motor nuclei and
tially depressed reexes in Lambert-Eaton myasthenic the anterior horn of the spinal cord or from dysfunc-
syndrome and, conversely, to depression of initially nor- tion of the axons of these neurons as they pass to skel-
mal reexes in myasthenia gravis (Chap. 47). etal muscle (Fig. 12-2). Weakness is due to a decrease
The distinction of neuropathic (lower motor neuron) in the number of muscle bers that can be activated
from myopathic weakness is sometimes difcult clinically, through a loss of motor neurons or disruption of their
although distal weakness is likely to be neuropathic, and connections to muscle. Loss of motor neurons does
symmetric proximal weakness myopathic. Fasciculations not cause weakness but decreases tension on the muscle
(visible or palpable twitch within a muscle due to the spindles, which decreases muscle tone and attenuates
spontaneous discharge of a motor unit) and early atro- the stretch reexes elicited on examination. An absent
phy indicate that weakness is neuropathic. stretch reex suggests involvement of spindle afferent
bers.
When a motor unit becomes diseased, especially in
PATHOGENESIS anterior horn cell diseases, it may discharge spontane-
ously, producing fasciculations that may be seen or felt
Upper motor neuron weakness
clinically or recorded by electromyography (EMG).
This pattern of weakness results from disorders that When motor neurons or their axons degenerate, the
affect the upper motor neurons or their axons in the denervated muscle bers also may discharge spontane-
cerebral cortex, subcortical white matter, internal cap- ously. These single muscle ber discharges, or brilla-
sule, brainstem, or spinal cord (Fig. 12-1). These tion potentials, cannot be seen or felt but can be recorded
lesions produce weakness through decreased activation with EMG. If lower motor neuron weakness is pres-
of the lower motor neurons. In general, distal muscle ent, recruitment of motor units is delayed or reduced,
groups are affected more severely than are proximal with fewer than normal activated at a particular dis-
ones, and axial movements are spared unless the lesion charge frequency. This contrasts with weakness of the
is severe and bilateral. With corticobulbar involve- upper motor neuron type, in which a normal number
ment, weakness usually is observed only in the lower of motor units is activated at a given frequency but with
face and tongue; extraocular, upper facial, pharyngeal, a diminished maximal discharge frequency.
Corticospinal 105
Sh Trunk
Hip
der
Wr ow
tract
oul
Fin ist
El b
um s
Th ger
Knee
b
ck
Ankle Ne
Brow
Toes
Eyelid
Nares
Lips
Tongue
Larynx
CHAPTER 12
Red nucleus
Reticular nuclei
Vestibular nuclei
Lateral corticospinal
Reticulospinal tract tract
Lateral
corticospinal tract
Rubrospinal
(ventrolateral)
tract
Ventromedial
bulbospinal
tracts
FIGURE 12-1
The corticospinal and bulbospinal upper motor neuron involved in the execution of learned, ne movements. Cor-
pathways. Upper motor neurons have their cell bodies in ticobulbar neurons are similar to corticospinal neurons but
layer V of the primary motor cortex (the precentral gyrus, or innervate brainstem motor nuclei.
Brodmanns area 4) and in the premotor and supplemental Bulbospinal upper motor neurons inuence strength and
motor cortex (area 6). The upper motor neurons in the pri- tone but are not part of the pyramidal system. The descend-
mary motor cortex are somatotopically organized, as illus- ing ventromedial bulbospinal pathways originate in the tec-
trated on the right side of the gure. tum of the midbrain (tectospinal pathway), the vestibular
Axons of the upper motor neurons descend through the nuclei (vestibulospinal pathway), and the reticular formation
subcortical white matter and the posterior limb of the inter- (reticulospinal pathway). These pathways inuence axial and
nal capsule. Axons of the pyramidal or corticospinal system proximal muscles and are involved in the maintenance of
descend through the brainstem in the cerebral peduncle of posture and integrated movements of the limbs and trunk.
the midbrain, the basis pontis, and the medullary pyramids. The descending ventrolateral bulbospinal pathways, which
At the cervicomedullary junction, most pyramidal axons originate predominantly in the red nucleus (rubrospinal path-
decussate into the contralateral corticospinal tract of the lat- way), facilitate distal limb muscles. The bulbospinal system
eral spinal cord, but 1030% remain ipsilateral in the anterior sometimes is referred to as the extrapyramidal upper motor
spinal cord. Pyramidal neurons make direct monosynaptic neuron system. In all gures, nerve cell bodies and axon ter-
connections with lower motor neurons. They innervate most minals are shown, respectively, as closed circles and forks.
densely the lower motor neurons of hand muscles and are
Alpha and gamma ner, but the loss of muscle bers is functional (due to
motor neurons inability to activate them) rather than related to muscle
ber loss. The number of muscle bers that are acti-
vated varies over time, depending on the state of rest of
Motor end plates on the neuromuscular junctions. Thus, fatigable weakness
voluntary muscle is suggestive of myasthenia gravis or other disorders of
(extrafusal fibers) the neuromuscular junction.
Clinical Manifestations of Neurologic Disease
Muscle spindle
(intrafusal fibers)
Hemiparesis
FIGURE 12-2 Hemiparesis results from an upper motor neuron lesion
Lower motor neurons are divided into a and g types. above the midcervical spinal cord; most such lesions
The larger motor neurons are more numerous and inner- are above the foramen magnum. The presence of other
vate the extrafusal muscle bers of the motor unit. Loss of neurologic decits helps localize the lesion. Thus, lan-
motor neurons or disruption of their axons produces lower guage disorders, cortical sensory disturbances, cogni-
motor neuron weakness. The smaller, less numerous motor tive abnormalities, disorders of visual-spatial integration,
neurons innervate the intrafusal muscle bers of the muscle apraxia, or seizures point to a cortical lesion. Homon-
spindle and contribute to normal tone and stretch reexes. ymous visual eld defects reect either a cortical or a
The motor neuron receives direct excitatory input from cor-
subcortical hemispheric lesion. A pure motor hemi-
ticomotoneurons and primary muscle spindle afferents. The
paresis of the face, arm, and leg often is due to a small,
and motor neurons also receive excitatory input from other
discrete lesion in the posterior limb of the internal cap-
descending upper motor neuron pathways, segmental sen-
sule, cerebral peduncle, or upper pons. Some brainstem
sory inputs, and interneurons. The motor neurons receive
direct inhibition from Renshaw cell interneurons, and other
lesions produce crossed paralyses, consisting of ipsi-
interneurons indirectly inhibit the and motor neurons.
lateral cranial nerve signs and contralateral hemiparesis
A tendon reex requires the function of all the illustrated (Chap. 27). The absence of cranial nerve signs or facial
structures. A tap on a tendon stretches muscle spindles weakness suggests that a hemiparesis is due to a lesion in
(which are tonically activated by motor neurons) and acti- the high cervical spinal cord, especially if it is associated
vates the primary spindle afferent neurons. These neurons with ipsilateral loss of proprioception and contralateral
stimulate the motor neurons in the spinal cord, producing a loss of pain and temperature sense (the Brown-Squard
brief muscle contraction, which is the familiar tendon reex. syndrome).
Acute or episodic hemiparesis usually results from isch-
emic or hemorrhagic stroke but also may relate to
acetylcholine receptors are opened, the end plate reaches hemorrhage occurring into brain tumors or may be a
threshold and thereby generates an action potential that result of trauma; other causes include a focal structural
spreads across the muscle ber membrane and into the lesion or an inammatory process as in multiple scle-
transverse tubular system. This electrical excitation activates rosis, abscess, or sarcoidosis. Evaluation (Fig. 12-3)
intracellular events that produce an energy-dependent begins immediately with a CT scan of the brain and
contraction of the muscle ber (excitation-contraction laboratory studies. If the CT is normal and an ischemic
coupling). stroke is unlikely, MRI of the brain or cervical spine is
Myopathic weakness is produced by a decrease in the performed.
number or contractile force of muscle bers activated Subacute hemiparesis that evolves over days or weeks
within motor units. With muscular dystrophies, inam- has an extensive differential diagnosis. A common cause
matory myopathies, or myopathies with muscle ber is subdural hematoma, especially in elderly or anticoag-
necrosis, the number of muscle bers is reduced within ulated patients, even when there is no history of trauma.
many motor units. On EMG, the size of each motor Infectious possibilities include cerebral abscess, fungal
unit action potential is decreased, and motor units must granuloma or meningitis, and parasitic infection. Weak-
be recruited more rapidly than normal to produce the ness from primary and metastatic neoplasms may evolve
107
DISTRIBUTION OF WEAKNESS
Alert
CHAPTER 12
Cerebral signs
Yes No
UMN signs LMN signs*
* or signs of myopathy
If no abnormality detected, consider spinal MRI.
If no abnormality detected, consider myelogram or brain MRI.
FIGURE 12-3
An algorithm for the initial workup of a patient with weak- LMN, lower motor neuron; MRI, magnetic resonance imaging;
ness. CT, computed tomography; EMG, electromyography; NCS, nerve conduction studies; UMN, upper motor neuron.
over days to weeks. AIDS may present with subacute Acute paraparesis may not be recognized as due to spi-
hemiparesis due to toxoplasmosis or primary CNS lym- nal cord disease at an early stage if the legs are accid
phoma. Noninfectious inammatory processes such as and areexic. Usually, however, there is sensory loss
multiple sclerosis or, less commonly, sarcoidosis merit in the legs with an upper level on the trunk, a dissoci-
consideration. If the brain MRI is normal and there are ated sensory loss suggestive of a central cord syndrome,
no cortical and hemispheric signs, MRI of the cervical or exaggerated stretch reexes in the legs with normal
spine should be undertaken. reexes in the arms. It is important to image the spinal
Chronic hemiparesis that evolves over months usually is cord (Fig. 12-3). Compressive lesions (particularly epi-
due to a neoplasm or vascular malformation, a chronic dural tumor, abscess, and hematoma but also a prolapsed
subdural hematoma, or a degenerative disease. If an intervertebral disk and vertebral involvement by malig-
MRI of the brain is normal, the possibility of a foramen nancy or infection), spinal cord infarction (propriocep-
magnum or high cervical spinal cord lesion should be tion usually is spared), an arteriovenous stula or other
considered. vascular anomaly, and transverse myelitis are among the
possible causes (Chap. 35).
Diseases of the cerebral hemispheres that produce
Paraparesis
acute paraparesis include anterior cerebral artery isch-
An intraspinal lesion at or below the upper thoracic emia (shoulder shrug also is affected), superior sagittal
spinal cord level is most commonly responsible, but a sinus or cortical venous thrombosis, and acute hydro-
paraparesis also may result from lesions at other loca- cephalus. If upper motor neuron signs are associated
tions that disturb upper motor neurons (especially with drowsiness, confusion, seizures, or other hemi-
parasagittal intracranial lesions) and lower motor neu- spheric signs, MRI of the brain should be undertaken.
rons (anterior horn cell disorders, cauda equina syn- Paraparesis may result from a cauda equina syndrome,
dromes due to involvement of nerve roots derived for example, after trauma to the low back, a mid-
from the lower spinal cord [Chap. 35], and peripheral line disk herniation, or an intraspinal tumor; although
neuropathies). sphincters are affected, hip exion often is spared, as is
108 sensation over the anterolateral thighs. Rarely, parapa- TABLE 12-2
resis is caused by a rapidly evolving anterior horn cell CAUSES OF EPISODIC GENERALIZED WEAKNESS
disease (such as poliovirus or West Nile virus infec- 1. Electrolyte disturbances, e.g., hypokalemia, hyperka-
tion), peripheral neuropathy (such as Guillain-Barr lemia, hypercalcemia, hypernatremia, hyponatremia,
syndrome; Chap. 46), or myopathy (Chap. 48). In such hypophosphatemia, hypermagnesemia
cases, electrophysiologic studies are diagnostically help- 2. Muscle disorders
ful and refocus the subsequent evaluation.
a. Channelopathies (periodic paralyses)
Subacute or chronic paraparesis with spasticity is caused
by upper motor neuron disease. When there is associ- b. Metabolic defects of muscle (impaired carbohydrate
or fatty acid utilization; abnormal mitochondrial
SECTION II
Quadriparesis or generalized weakness MRI of the cervical cord. If weakness is lower motor
neuron, myopathic, or uncertain in origin, the clinical
Generalized weakness may be due to disorders of the approach begins with blood studies to determine the
CNS or the motor unit. Although the terms quadri- level of muscle enzymes and electrolytes and an EMG
paresis and generalized weakness often are used inter- and nerve conduction study.
changeably, quadriparesis is commonly used when
an upper motor neuron cause is suspected, and gen- Subacute or chronic quadriparesis
eralized weakness when a disease of the motor unit is When quadriparesis due to upper motor neuron disease
likely. Weakness from CNS disorders usually is associ- develops over weeks, months, or years, the distinction
ated with changes in consciousness or cognition, with between disorders of the cerebral hemispheres, brain-
spasticity and brisk stretch reexes, and with alterations stem, and cervical spinal cord is usually possible clini-
of sensation. Most neuromuscular causes of general- cally. An MRI is obtained of the clinically suspected site
ized weakness are associated with normal mental func- of pathology. EMG and nerve conduction studies help
tion, hypotonia, and hypoactive muscle stretch reexes. distinguish lower motor neuron disease (which usually
The major causes of intermittent weakness are listed presents with weakness that is most profound distally)
in Table 12-2. A patient with generalized fatigabil- from myopathic weakness, which is typically proximal.
ity without objective weakness may have the chronic
fatigue syndrome (Chap. 52).
Monoparesis
Acute quadriparesis
Acute quadriparesis with onset over minutes may result Monoparesis usually is due to lower motor neuron dis-
from disorders of upper motor neurons (e.g., anoxia, ease, with or without associated sensory involvement.
hypotension, brainstem or cervical cord ischemia, trauma, Upper motor neuron weakness occasionally presents
and systemic metabolic abnormalities) or muscle (electro- as a monoparesis of distal and nonantigravity muscles.
lyte disturbances, certain inborn errors of muscle energy Myopathic weakness rarely is limited to one limb.
metabolism, toxins, and periodic paralyses). Onset over
hours to weeks may, in addition to these disorders, be Acute monoparesis
due to lower motor neuron disorders. Guillain-Barr If the weakness is predominantly in distal and nonan-
syndrome (Chap. 46) is the most common lower motor tigravity muscles and is not associated with sensory
neuron weakness that progresses over days to 4 weeks; impairment or pain, focal cortical ischemia is likely
the nding of an elevated protein level in the cerebrospi- (Chap. 27); diagnostic possibilities are similar to those
nal uid is helpful but may be absent early in the course. for acute hemiparesis. Sensory loss and pain usually
In obtunded patients, evaluation begins with a CT accompany acute lower motor neuron weakness; the
scan of the brain. If upper motor neuron signs are pres- weakness commonly is localized to a single nerve root
ent but the patient is alert, the initial test is usually an or peripheral nerve within the limb but occasionally
reects plexus involvement. If lower motor neuron of the neuromuscular junction (such as myasthenia 109
weakness is suspected or the pattern of weakness is gravis [Chap. 47]), may present with symmetric proxi-
uncertain, the clinical approach begins with an EMG mal weakness often associated with ptosis, diplopia, or
and a nerve conduction study. bulbar weakness and uctuating in severity during the
day. The extreme fatigability present in some cases of
Subacute or chronic monoparesis myasthenia gravis may even suggest episodic weak-
Weakness and atrophy that develop over weeks or ness, but strength rarely returns fully to normal. In
months are usually of lower motor neuron origin. If anterior horn cell disease, proximal weakness is usu-
they are associated with sensory symptoms, a peripheral ally asymmetric, but it may be symmetric if familial.
CHAPTER 12
cause (nerve, root, or plexus) is likely; in the absence Numbness does not occur with any of these diseases.
of such symptoms, anterior horn cell disease should be The evaluation usually begins with determination of
considered. In either case, an electrodiagnostic study the serum creatine kinase level and electrophysiologic
is indicated. If weakness is of the upper motor neuron studies.
type, a discrete cortical (precentral gyrus) or cord lesion
may be responsible, and an imaging study of the appro-
Weakness in a restricted distribution
Lewis Sudarsky
CHAPTER 13
history of falls. Older patients with decits in execu- a higher level gait disturbance. Physical therapy often
tive function may have particular difculty in managing improves walking to the degree that follow-up observa-
the attentional resources needed for dynamic balance tion may reveal a more specic underlying disorder.
when distracted.
Stiff-legged gait
DISORDERS OF GAIT Spastic gait is characterized by stiffness in the legs, an
Parkinsons patients within 2 years of onset and 26% by Cerebellar gait ataxia
the end of 5 years. Freezing of gait is even more com- Disorders of the cerebellum have a dramatic impact on
mon in some of the Parkinsons-related neurodegen- gait and balance. Cerebellar gait ataxia is characterized
erative disorders, such as progressive supranuclear palsy, by a wide base of support, lateral instability of the trunk,
multiple-system atrophy, and corticobasal degeneration. erratic foot placement, and decompensation of balance
These patients frequently present with axial stiffness, when attempting to walk tandem. Difculty main-
Clinical Manifestations of Neurologic Disease
postural instability, and a shufing gait while lacking the taining balance when turning is often an early feature.
characteristic pill-rolling tremor of Parkinsons disease. Patients are unable to walk tandem heel to toe, and dis-
Falls within the rst year suggest the possibility of pro- play truncal sway in narrow-based or tandem stance.
gressive supranuclear palsy. They show considerable variation in their tendency to
Hyperkinetic movement disorders also produce char- fall in daily life.
acteristic and recognizable disturbances in gait. In Hun- Causes of cerebellar ataxia in older patients include
tingtons disease (Chap. 29), the unpredictable occur- stroke, trauma, tumor, and neurodegenerative disease,
rence of choreic movements gives the gait a dancing including multiple-system atrophy (Chaps. 30 and 33)
quality. Tardive dyskinesia is the cause of many odd, and various forms of hereditary cerebellar degenera-
stereotypic gait disorders seen in patients chronically tion (Chap. 31). A short expansion at the site of the
exposed to antipsychotics and other drugs that block the fragile X mutation (fragile X pre-mutation) has been
D2 dopamine receptor. associated with gait ataxia in older men. Alcoholic cer-
ebellar degeneration can be screened by history and
often conrmed by MRI. In patients with ataxia, MRI
Frontal gait disorder
demonstrates the extent and topography of cerebellar
Frontal gait disorder, sometimes known as gait apraxia, atrophy.
is common in the elderly and has a variety of causes.
The term is used to describe a shufing, freezing gait
Sensory ataxia
with imbalance and other signs of higher cerebral dys-
function. Typical features include a wide base of sup- As reviewed earlier, balance depends on high-quality
port, short stride, shufing along the oor, and dif- afferent information from the visual and the vestibular
culty with starts and turns. Many patients exhibit systems and proprioception. When this information is
difculty with gait initiation, descriptively character- lost or degraded, balance during locomotion is impaired
ized as the slipping clutch syndrome. The term lower and instability results. The sensory ataxia of tabetic
body parkinsonism is also used to describe such patients. neurosyphilis is a classic example. The contemporary
Strength is generally preserved, and patients are able equivalent is the patient with neuropathy affecting
to make stepping movements when not standing and large bers. Vitamin B12 deciency is a treatable cause
maintaining balance at the same time. This disorder is of large-ber sensory loss in the spinal cord and periph-
best considered a higher level motor control disorder, as eral nervous system. Joint position and vibration sense
opposed to an apraxia (Chap. 18). are diminished in the lower limbs. The stance in such
The most common cause of frontal gait disorder is patients is destabilized by eye closure; they often look
vascular disease, particularly subcortical small-vessel down at their feet when walking and do poorly in the
disease. Lesions are frequently found in the deep fron- dark. Patients have been described with imbalance from
tal white matter and centrum ovale. Gait disorder may bilateral vestibular loss, caused by disease or by expo-
be the salient feature in hypertensive patients with sure to ototoxic drugs. Table 13-2 compares sensory
ischemic lesions of the deep hemisphere white matter ataxia with cerebellar ataxia and frontal gait disorder.
(Binswangers disease). The clinical syndrome includes Some frail older patients exhibit a syndrome of imbal-
mental change (variable in degree), dysarthria, pseudo- ance from the combined effect of multiple sensory de-
bulbar affect (emotional disinhibition), increased tone, cits. Such patients have disturbances in proprioception,
and hyperreexia in the lower limbs. vision, and vestibular sense that impair postural support.
TABLE 13-2 long-acting benzodiazepines, affect postural control and 113
increase the risk for falls. These disorders are important
FEATURES OF CEREBELLAR ATAXIA, SENSORY
to recognize because they are often treatable.
ATAXIA, AND FRONTAL GAIT DISORDERS
CEREBELLAR SENSORY
ATAXIA ATAXIA FRONTAL GAIT Psychogenic gait disorder
Base of Wide-based Narrow Wide-based Psychogenic disorders are common in neurologic prac-
support base, looks tice, and the presentation often involves gait. Some
down patients with extreme anxiety or phobia walk with
CHAPTER 13
Velocity Variable Slow Very slow exaggerated caution with abduction of the arms, as
Stride Irregular, Regular Short, shufing if walking on ice. This inappropriately overcautious
lurching with path gait differs in degree from the gait of the patient who
deviation is insecure and making adjustments for imbalance.
Romberg +/ Unsteady, +/ Depressed patients exhibit primarily slowness, a mani-
falls festation of psychomotor retardation, and lack of pur-
Heel shin Abnormal pose in their stride. Hysterical gait disorders are among
CHAPTER 13
Weakness and frailty Falls related to sensory decit
Patients who lack strength in antigravity muscles have Patients with somatosensory, visual, or vestibular de-
difculty rising from a chair, fatigue easily when walk- cits are prone to falls. These patients have particular dif-
ing, and have difculty maintaining their balance after a culty dealing with poor illumination or walking on
perturbation. These patients are often unable to get up uneven ground. These patients often express subjective
Problems with gait and balance are major causes of falls, ameliorate the underlying cause. In this video, examples
accidents, and resulting disability, especially in later life, of gait disorders due to Parkinsons disease, other extra-
and are often harbingers of neurologic disease. Early pyramidal disorders, and ataxias, as well as other common
diagnosis is essential, especially for treatable conditions, gait disorders, are presented. Videos for this chap-
as it may permit the institution of prophylactic mea- ter can be accessed at the following link: http://www
sures to prevent dangerous falls, and also to reverse or .mhprofessional.com/mediacenter/.
116
CHAPTER 15
Normal somatic sensation reects a continuous monitor- lost in sensory nerve bers. If the rate of loss is slow,
ing process, little of which reaches consciousness under lack of cutaneous feeling may be unnoticed by the
ordinary conditions. By contrast, disordered sensation, patient and difcult to demonstrate on examination,
particularly when experienced as painful, is alarming and even though few sensory bers are functioning; if it is
dominates the patients attention. Physicians should be rapid, both positive and negative phenomena are usually
able to recognize abnormal sensations by how they are conspicuous. Subclinical degrees of sensory dysfunction
described, know their type and likely site of origin, and may be revealed by sensory nerve conduction studies or
understand their implications. Pain is considered sepa- somatosensory evoked potentials (Chap. 5).
rately in Chap. 7. Whereas sensory symptoms may be either positive
or negative, sensory signs on examination are always a
measure of negative phenomena.
POSITIVE AND NEGATIVE SYMPTOMS
Abnormal sensory symptoms can be divided into two
TERMINOLOGY
categories: positive and negative. The prototypical posi-
tive symptom is tingling (pins and needles); other posi- Words used to characterize sensory disturbance are
tive sensory phenomena include altered sensations that descriptive and based on convention. Paresthesias and
are described as pricking, bandlike, lightning-like shoot- dysesthesias are general terms used to denote posi-
ing feelings (lancinations), aching, knifelike, twisting, tive sensory symptoms. The term paresthesias typically
drawing, pulling, tightening, burning, searing, electrical, refers to tingling or pins-and-needles sensations but may
or raw feelings. Such symptoms are often painful. include a wide variety of other abnormal sensations,
Positive phenomena usually result from trains of im- except pain; it sometimes implies that the abnormal
pulses generated at sites of lowered threshold or height- sensations are perceived spontaneously. The more gen-
ened excitability along a peripheral or central sensory eral term dysesthesias denotes all types of abnormal sen-
pathway. The nature and severity of the abnormal sen- sations, including painful ones, regardless of whether a
sation depend on the number, rate, timing, and distri- stimulus is evident.
bution of ectopic impulses and the type and function Another set of terms refers to sensory abnormalities
of nervous tissue in which they arise. Because positive found on examination. Hypesthesia or hypoesthesia refers
phenomena represent excessive activity in sensory path- to a reduction of cutaneous sensation to a specic type
ways, they are not necessarily associated with a sensory of testing such as pressure, light touch, and warm or
decit (loss) on examination. cold stimuli; anesthesia, to a complete absence of skin
Negative phenomena represent loss of sensory func- sensation to the same stimuli plus pinprick; and hypal-
tion and are characterized by diminished or absent gesia or analgesia, to reduced or absent pain perception
feeling that often is experienced as numbness and by (nociception), such as perception of the pricking quality
abnormal ndings on sensory examination. In disor- elicited by a pin. Hyperesthesia means pain or increased
ders affecting peripheral sensation, it is estimated that at sensitivity in response to touch. Similarly, allodynia
least one-half the afferent axons innervating a particular describes the situation in which a nonpainful stimulus,
site are lost or functionless before a sensory decit can once perceived, is experienced as painful, even excru-
be demonstrated by clinical examination. This thresh- ciating. An example is elicitation of a painful sensation
old varies in accordance with how rapidly function is by application of a vibrating tuning fork. Hyperalgesia
117
118 denotes severe pain in response to a mildly noxious spinal cord and make their rst synapse in the gracile or
stimulus, and hyperpathia, a broad term, encompasses all cuneate nucleus of the lower medulla. Axons of second-
the phenomena described by hyperesthesia, allodynia, order neurons decussate and ascend in the medial lemnis-
and hyperalgesia. With hyperpathia, the threshold for a cus located medially in the medulla and in the tegmen-
sensory stimulus is increased and perception is delayed, tum of the pons and midbrain and synapse in the VPL
but once felt, it is unduly painful. nucleus; third-order neurons project to parietal cortex.
Disorders of deep sensation arising from muscle spin- This large-ber system is referred to as the posterior col-
dles, tendons, and joints affect proprioception (position umnmedial lemniscal pathway (lemniscal, for short). Note
sense). Manifestations include imbalance (particularly that although the lemniscal and the anterolateral pathways
SECTION II
with eyes closed or in the dark), clumsiness of precision both project up the spinal cord to the thalamus, it is the
movements, and unsteadiness of gait, which are referred (crossed) anterolateral pathway that is referred to as the
to collectively as sensory ataxia. Other ndings on exam- spinothalamic tract by convention.
ination usually, but not invariably, include reduced or Although the ber types and functions that make up
absent joint position and vibratory sensibility and absent the spinothalamic and lemniscal systems are relatively
deep tendon reexes in the affected limbs. The Rom- well known, many other bers, particularly those asso-
berg sign is positive, which means that the patient sways ciated with touch, pressure, and position sense, ascend
Clinical Manifestations of Neurologic Disease
markedly or topples when asked to stand with feet close in a diffusely distributed pattern both ipsilaterally and
together and eyes closed. In severe states of deafferenta- contralaterally in the anterolateral quadrants of the spi-
tion involving deep sensation, the patient cannot walk nal cord. This explains why a complete lesion of the
or stand unaided or even sit unsupported. Continuous posterior columns of the spinal cord may be associated
involuntary movements (pseudoathetosis) of the out- with little sensory decit on examination.
stretched hands and ngers occur, particularly with eyes
closed.
EXAMINATION OF SENSATION
ANATOMY OF SENSATION
The main components of the sensory examination are
Cutaneous afferent innervation is conveyed by a rich tests of primary sensation (pain, touch, vibration, joint
variety of receptors, both naked nerve endings (noci- position, and thermal sensation [Table 15-1]).
ceptors and thermoreceptors) and encapsulated terminals Some general principles pertain. The examiner must
(mechanoreceptors). Each type of receptor has its own depend on patient responses, particularly when testing
set of sensitivities to specic stimuli, size and distinctness cutaneous sensation (pin, touch, warm, or cold), and
of receptive elds, and adaptational qualities. Much of this complicates interpretation. Further, examination
the knowledge about these receptors has come from the may be limited in some patients. In a stuporous patient,
development of techniques to study single intact nerve for example, sensory examination is reduced to observ-
bers intraneurally in awake, unanesthetized human ing the briskness of withdrawal in response to a pinch
subjects. It is possible not only to record from but also or another noxious stimulus. Comparison of response
to stimulate single bers in isolation. A single impulse, on one side of the body to that on the other is essential.
whether elicited by a natural stimulus or evoked by In an alert but uncooperative patient, it may not be
electrical microstimulation in a large myelinated afferent possible to examine cutaneous sensation, but some idea
ber, may be both perceived and localized. of proprioceptive function may be gained by noting the
Afferent bers of all sizes in peripheral nerve trunks patients best performance of movements requiring bal-
traverse the dorsal roots and enter the dorsal horn of ance and precision. Frequently, patients present with
the spinal cord (Fig. 15-1). From there the smaller sensory symptoms that do not t an anatomic localiza-
bers take a route to the parietal cortex different from tion and that are accompanied by either no abnormali-
that of the larger bers. The polysynaptic projections of ties or gross inconsistencies on examination. The exam-
the smaller bers (unmyelinated and small myelinated), iner should consider whether the sensory symptoms
which subserve mainly nociception, temperature sensibil- are a disguised request for help with psychological or
ity, and touch, cross and ascend in the opposite anterior situational problems. Discretion must be used in pur-
and lateral columns of the spinal cord, through the brain- suing this possibility. Finally, sensory examination of a
stem, to the ventral posterolateral (VPL) nucleus of the patient who has no neurologic complaints can be brief
thalamus and ultimately project to the postcentral gyrus and consist of pinprick, touch, and vibration testing in
of the parietal cortex (Chap. 7). This is the spinothalamic the hands and feet plus evaluation of stance and gait,
pathway or anterolateral system. The larger bers, which including the Romberg maneuver. Evaluation of stance
subserve tactile and position sense and kinesthesia, project and gait also tests the integrity of motor and cerebellar
rostrally in the posterior column on the same side of the systems.
119
Leg
Trunk Postcentral
cortex
Arm
Internal
capsule
Face
CHAPTER 15
Thalamus
Ventral
posterolateral
nucleus of
MIDBRAIN
Reticulothalamic pathway
Principal sensory
nucleus of V
PONS
Medial lemniscus
Nucleus
gracilis
Nucleus
cuneatus
MEDULLA
Nucleus
Spinothalamic tract
of spinal
tract V
SPINAL CORD
Spinothalamic tract
FIGURE 15-1
The main somatosensory pathways. The spinothalamic tract) to nuclei in the medulla, pons, and mesencephalon
tract (pain, thermal sense) and the posterior columnlemniscal and nuclear terminations of the tract are indicated. (From AH
system (touch, pressure, joint position) are shown. Offshoots Ropper, RH Brown, in Adams and Victors Principles of Neu-
from the ascending anterolateral fasciculus (spinothalamic rology, 9th ed. New York, McGraw-Hill, 2009.)
Touch Cotton wisp, ne brush Cutaneous mechanorecep- Large and small Lem, also D and SpTh
tors, also naked endings
Vibration Tuning fork, 128 Hz Mechanoreceptors, espe- Large Lem, also D
cially pacinian corpuscles
Joint position Passive movement of Joint capsule and tendon Large Lem, also D
specic joints endings, muscle spindles
Clinical Manifestations of Neurologic Disease
Abbreviations: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; SpTh, spinothalamic projection, contralat-
eral; Lem, posterior column and lemniscal projection, ipsilateral.
Greater
Lesser n. } occipital nerves
I
Great auricular n.
II
Great auricular n.
Ant. cut. n. of neck
III C5
Ant. cut. n. of neck T1 Supraclavicular ns.
C6
T2
Post.
Supraclavicular ns. Axillary n. 3
cut.
(circumflex) 4
Axillary n. rami Lat. Med. cut. n. of arm
T2 5
(circumflex) Ant. of cut. & intercostobrachial n.
3 6
4 Med. cut. n. of arm Post cut. n. of arm thor.rami
7
cut. & intercostobrachial n. (from radial n.) ns.
Lower lat.cut. n. of arm Lat. 5 8
9 Post. cut. n. of forearm
(from radial n.) rami 6
Lower 10 (from radial n.)
7 L1
of Lat. cut. of arm 11
cut. 8 Lat. cut. n. of forearm
(from radial n.) 12 Med.
thor. 9 cut. n. (from musculocut n.)
Med. cut. n. S1
Lat. cut. of forearm of forearm Post. rami of
ns. 10 of
(from musculocut. n.) Iliohypo- lumbar sacral Radial n.
rami 11 forearm
gastric n. & coccygeal ns.
12
Iliohypo- Radial n. Ulnar n.
Ilio-
gastric n. Inf. med.
inguinal n.
cluneal n. Inf. lat.
Femoral Genital Median n.
cluneal ns.
branch branch of
of genito- genitofem. Inf. med. n. of thigh Median n.
femoral n. n.
Ulnar n.
(lumbo-inguinal n.) Obturator n.
Dorsal n. of penis Post cut. n. of thigh
Lat. cut. n. of thigh
Intermed. & med. cut. ns. Scrotal branch of perineal n. Med. cut. n. of thigh
of thigh (from femoral n.) (from femoral n.)
Lat. cut. n.of calf
Obturator n. (from common femoral n.)
Saphenous n. Lat. plantar n.
(from femoral n.) Lat.cut. n. of calf Med.
(from common peroneal n.) Saphenous n.
plantar n. Lat.
(from femoral n.) plantar n.
Superficial
peroneal
Superficial peroneal n. n.
(from common peroneal n.)
Deep peroneal n. Supercial peroneal n.
(from common peroneal n.) (from common peroneal n.) Saphenous n.
Sural n. (from tibial n.) Calcanean branches
of tibial & sural ns. Sural n.
FIGURE 15-2
The cutaneous elds of peripheral nerves. (Reproduced by permission from W Haymaker, B Woodhall: Peripheral Nerve Inju-
ries, 2nd ed. Philadelphia, Saunders, 1953.)
121
C3
C5 C4
C3
C6
C
T1
6
C5 C7 C5
C3
C6 C8
C4 T1
T2 C4
T2 T3
T4
C5 T3 T5
T4 T6
CHAPTER 15
T5 T7 C5 C3
T6 T8 C4
T7 T9 T2 C5 C
T8 T10 6
T9 T11 C7
T1 T10 T12 C8
C6 L1 T1 C6
T11 L C6
L3 2 C7
T12
S1 C8 C8
L1 S2
L2 L1
S2 L1
L3 L2
L3 L34
L
L3 L4 L5 L5
S S3
2 S1 S
2 S4
L4 S2 S5
L2 L1
L3
L5 L4 L4 L5 S1 S2 L2 L5 S1 S2
L5 L4 L3
L3
S1
L4
L5 S1 S2
S1 L5 S2 L4
S1
L5
FIGURE 15-3 L5 S
S1 S2 L4
L5 2
Distribution of the sensory spinal roots on the surface of
the body (dermatomes). (From D Sinclair: Mechanisms of L L5 S1 L5
4 L
Cutaneous Sensation. Oxford, UK, Oxford University Press, 4
1981; with permission from Dr. David Sinclair.)
FIGURE 15-4
Dermatomes of the upper and lower extremities, outlined
appreciation of both cold and warmth should be tested by the pattern of sensory loss following lesions of single
because different receptors respond to each. nerve roots. (From JJ Keegan, FD Garrett: Anat Rec 102:409,
Touch usually is tested with a wisp of cotton or a 1948.)
ne camel hair brush. In general, it is better to avoid
testing touch on hairy skin because of the profusion of extended and eyes closed. Normal individuals can do
the sensory endings that surround each hair follicle. this accurately, with errors of 1 cm or less.
Joint position testing is a measure of proprioception, The sense of vibration is tested with a tuning fork
one of the most important functions of the sensory sys- that vibrates at 128 Hz. Vibration usually is tested over
tem. With the patients eyes closed, joint position is bony points, beginning distally; in the feet it is tested
tested in the distal interphalangeal joint of the great toe over the dorsal surface of the distal phalanx of the big
and ngers. If errors are made in recognizing the direc- toes and at the malleoli of the ankles, and in the hands
tion of passive movements, more proximal joints are dorsally at the distal phalanx of the ngers. If abnormal-
tested. A test of proximal joint position sense, primar- ities are found, more proximal sites can be examined.
ily at the shoulder, is performed by asking the patient Vibratory thresholds at the same site in the patient and
to bring the two index ngers together with arms the examiner may be compared for control purposes.
122 Quantitative sensory testing
Effective sensory testing devices are now available com- objects and coins in one hand but can do so in the other
mercially. Quantitative sensory testing is particularly are said to have astereognosis of the abnormal hand.
useful for serial evaluation of cutaneous sensation in
clinical trials. Threshold testing for touch and vibra-
tory and thermal sensation is the most widely used
application. LOCALIZATION OF SENSORY
ABNORMALITIES
SECTION II
tests, in the presence of normal primary sensation in an Dysesthesias without sensory ndings by examination
alert cooperative patient, signify a lesion of the pari- may be difcult to interpret. To illustrate, tingling dys-
etal cortex or thalamocortical projections to the pari- esthesias in an acral distribution (hands and feet) can be
etal lobe. If primary sensation is altered, these cortical systemic in origin, e.g., secondary to hyperventilation,
discriminative functions usually will be abnormal also. or induced by a medication such as acetazolamide. Dis-
Comparisons should always be made between analo- tal dysesthesias also can be an early event in an evolv-
gous sites on the two sides of the body because the ing polyneuropathy or may herald a myelopathy, such
decit with a specic parietal lesion is likely to be uni- as from vitamin B12 deciency. Sometimes distal dyses-
lateral. Interside comparisons are important for all cor- thesias have no denable basis. In contrast, dysesthesias
tical sensory testing. that correspond in distribution to a particular periph-
Two-point discrimination is tested with special calipers, eral nerve territory denote a lesion of that nerve trunk.
the points of which may be set from 2 mm to several For instance, dysesthesias restricted to the fth digit and
centimeters apart and then applied simultaneously to the the adjacent one-half of the fourth nger on one hand
site to be tested. The pulp of the ngertips is a common reliably point to disorder of the ulnar nerve, most com-
site to test; a normal individual can distinguish about monly at the elbow.
3-mm separation of points there.
Touch localization is performed by light pressure for an
Nerve and root
instant with the examiners ngertip or a wisp of cot-
ton wool; the patient, whose eyes are closed, is required In focal nerve trunk lesions severe enough to cause a
to identify the site of touch with the ngertip. Bilateral decit, sensory abnormalities are readily mapped and
simultaneous stimulation at analogous sites (e.g., the dor- generally have discrete boundaries (Figs. 15-2, 15-3 and
sum of both hands) can be carried out to determine 15-4). Root (radicular) lesions frequently are accom-
whether the perception of touch is extinguished con- panied by deep, aching pain along the course of the
sistently on one side or the other. The phenomenon related nerve trunk. With compression of a fth lumbar
is referred to as extinction or neglect. Graphesthesia refers (L5) or rst sacral (S1) root, as from a ruptured inter-
to the capacity to recognize with eyes closed letters vertebral disk, sciatica (radicular pain relating to the sci-
or numbers drawn by the examiners ngertip on the atic nerve trunk) is a common manifestation (Chap. 9).
palm of the hand. Once again, interside comparison is With a lesion affecting a single root, sensory decits
of prime importance. Inability to recognize numbers or may be minimal or absent because adjacent root territo-
letters is termed agraphesthesia. ries overlap extensively.
Stereognosis refers to the ability to identify common Isolated mononeuropathies may cause symptoms
objects by palpation, recognizing their shape, texture, beyond the territory supplied by the affected nerve, but
and size. Common standard objects such as keys, paper abnormalities on examination typically are conned to
clips, and coins are best used. Patients with normal ste- appropriate anatomic boundaries. In multiple mono-
reognosis should be able to distinguish a dime from a neuropathies, symptoms and signs occur in discrete ter-
penny and a nickel from a quarter without looking. ritories supplied by different individual nerves andas
Patients should be allowed to feel the object with only more nerves are affectedmay simulate a polyneu-
one hand at a time. If they are unable to identify it in ropathy if decits become conuent. With polyneu-
one hand, it should be placed in the other for compari- ropathies, sensory decits are generally graded, distal,
son. Individuals who are unable to identify common and symmetric in distribution (Chap. 45). Dysesthesias,
followed by numbness, begin in the toes and ascend Bilateral spinothalamic tract involvement occurs with 123
symmetrically. When dysesthesias reach the knees, they lesions affecting the center of the spinal cord, such as in
usually also have appeared in the ngertips. The process syringomyelia. There is a dissociated sensory loss with
appears to be nerve lengthdependent, and the decit impairment of pinprick and temperature appreciation
is often described as stocking-glove in type. Involve- but relative preservation of light touch, position sense,
ment of both hands and feet also occurs with lesions of and vibration appreciation.
the upper cervical cord or the brainstem, but an upper Dysfunction of the posterior columns in the spinal
level of the sensory disturbance may then be found on cord or of the posterior root entry zone may lead to
the trunk and other evidence of a central lesion may be a bandlike sensation around the trunk or a feeling of
CHAPTER 15
present, such as sphincter involvement or signs of an tight pressure in one or more limbs. Flexion of the
upper motor neuron lesion (Chap. 12). Although most neck sometimes leads to an electric shocklike sen-
polyneuropathies are pansensory and affect all modali- sation that radiates down the back and into the legs
ties of sensation, selective sensory dysfunction according (Lhermittes sign) in patients with a cervical lesion
to nerve ber size may occur. Small-ber polyneuropa- affecting the posterior columns, such as from multiple
thies are characterized by burning, painful dysesthesias sclerosis, cervical spondylosis, or recent irradiation to
with reduced pinprick and thermal sensation but with the cervical region.
Confusion, a mental and behavioral state of reduced which patients are withdrawn and quiet, with promi-
comprehension, coherence, and capacity to reason, nent apathy and psychomotor slowing.
is one of the most common problems encountered in This dichotomy between subtypes of delirium is a
medicine, accounting for a large number of emergency useful construct, but patients often fall somewhere along
department visits, hospital admissions, and inpatient a spectrum between the hyperactive and hypoactive
consultations. Delirium, a term used to describe an acute extremes, sometimes uctuating from one to the other
confusional state, remains a major cause of morbidity within minutes. Therefore, clinicians must recognize
and mortality rates, costing billions of dollars yearly in the broad range of presentations of delirium to identify
health care costs in the United States alone. Delirium all patients with this potentially reversible cognitive dis-
often goes unrecognized despite clear evidence that it is turbance. Hyperactive patients, such as those with delir-
usually the cognitive manifestation of serious underlying ium tremens, are easily recognized by their characteristic
medical or neurologic illness. severe agitation, tremor, hallucinations, and autonomic
instability. Patients who are quietly disturbed are over-
looked more often on the medical wards and in the ICU,
CLINICAL FEATURES OF DELIRIUM yet multiple studies suggest that this underrecognized
A multitude of terms are used to describe delirium, hypoactive subtype is associated with worse outcomes.
including encephalopathy, acute brain failure, acute confu- The reversibility of delirium is emphasized because
sional state, and postoperative or intensive care unit (ICU) many etiologies, such as systemic infection and medi-
psychosis. Delirium has many clinical manifestations, cation effects, can be treated easily. However, the
but essentially it is dened as a relatively acute decline long-term cognitive effects of delirium remain largely
in cognition that uctuates over hours or days. The unknown and understudied. Some episodes of delirium
hallmark of delirium is a decit of attention, although continue for weeks, months, or even years. The persis-
all cognitive domainsincluding memory, executive tence of delirium in some patients and its high recur-
function, visuospatial tasks, and languageare variably rence rate may be due to inadequate treatment of the
involved. Associated symptoms may include altered underlying etiology of the syndrome. In some instances,
sleep-wake cycles, perceptual disturbances such as hal- delirium does not disappear because there is underlying
lucinations or delusions, affect changes, and autonomic permanent neuronal damage. Even after an episode of
ndings that include heart rate and blood pressure delirium resolves, there may be lingering effects of the
instability. disorder. A patients recall of events after delirium var-
Delirium is a clinical diagnosis that can be made only ies widely, ranging from complete amnesia to repeated
at the bedside. Two broad clinical categories have been reexperiencing of the frightening period of confusion in
describedthe hyperactive and hypoactive subtypes a disturbing manner, similar to what is seen in patients
that are based on differential psychomotor features. The with posttraumatic stress disorder.
cognitive syndrome associated with severe alcohol with-
drawal remains the classic example of the hyperactive
RISK FACTORS
subtype, featuring prominent hallucinations, agitation,
and hyperarousal, often accompanied by life-threatening An effective primary prevention strategy for delirium
autonomic instability. In striking contrast is the hypo- begins with identication of patients at highest risk,
active subtype, exemplied by opiate intoxication, in including those preparing for elective surgery or being
125
126 admitted to the hospital. Although no single validated often difcult to appreciate in the setting of serious sys-
scoring system has been widely accepted as a screen temic illness and sedation. Delirium in the ICU should
for asymptomatic patients, there are multiple well- be viewed as an important manifestation of organ dys-
established risk factors for delirium. function not unlike liver, kidney, or heart failure.
The two most consistently identied risks are older Outside the acute hospital setting, delirium occurs in
age and baseline cognitive dysfunction. Individuals nearly two-thirds of patients in nursing homes and in
who are over age 65 or exhibit low scores on stan- over 80% of those at the end of life. These estimates
dardized tests of cognition develop delirium upon hos- emphasize the remarkably high frequency of this cogni-
pitalization at a rate approaching 50%. Whether age tive syndrome in older patients, a population expected
SECTION II
and baseline cognitive dysfunction are truly indepen- to grow in the upcoming decade with the aging of the
dent risk factors is uncertain. Other predisposing fac- baby boom generation.
tors include sensory deprivation, such as preexisting In previous decades an episode of delirium was
hearing and visual impairment, as well as indices for viewed as a transient condition that carried a benign
poor overall health, including baseline immobility, prognosis. Delirium now has been clearly associated
malnutrition, and underlying medical or neurologic with substantial morbidity rate and increased mortality
illness. rate and increasingly is recognized as a sign of serious
Clinical Manifestations of Neurologic Disease
In-hospital risks for delirium include the use of blad- underlying illness. Recent estimates of in-hospital mor-
der catheterization, physical restraints, sleep and sen- tality rates among delirious patients have ranged from
sory deprivation, and the addition of three or more new 25 to 33%, a rate similar to that of patients with sepsis.
medications. Avoiding such risks remains a key compo- Patients with an in-hospital episode of delirium have a
nent of delirium prevention as well as treatment. Sur- higher mortality rate in the months and years after their
gical and anesthetic risk factors for the development of illness compared with age-matched nondelirious hos-
postoperative delirium include specic procedures such pitalized patients. Delirious hospitalized patients have a
as those involving cardiopulmonary bypass and inad- longer length of stay, are more likely to be discharged
equate or excessive treatment of pain in the immediate to a nursing home, and are more likely to experience
postoperative period. subsequent episodes of delirium; as a result, this condi-
The relationship between delirium and demen- tion has enormous economic implications.
tia (Chap. 29) is complicated by signicant overlap
between the two conditions, and it is not always sim-
ple to distinguish between them. Dementia and preex- PATHOGENESIS
isting cognitive dysfunction serve as major risk factors
for delirium, and at least two-thirds of cases of delirium The pathogenesis and anatomy of delirium are incom-
occur in patients with coexisting underlying dementia. pletely understood. The attentional decit that serves
A form of dementia with parkinsonism, termed dementia as the neuropsychological hallmark of delirium appears
with Lewy bodies, is characterized by a uctuating course, to have a diffuse localization with the brainstem, thala-
prominent visual hallucinations, parkinsonism, and an mus, prefrontal cortex, and parietal lobes. Rarely, focal
attentional decit that clinically resembles hyperactive lesions such as ischemic strokes have led to delirium
delirium. Delirium in the elderly often reects an insult in otherwise healthy persons; right parietal and medial
to the brain that is vulnerable due to an underlying neu- dorsal thalamic lesions have been reported most com-
rodegenerative condition. Therefore, the development monly, pointing to the relevance of these areas to delir-
of delirium sometimes heralds the onset of a previously ium pathogenesis. In most cases, delirium results from
unrecognized brain disorder. widespread disturbances in cortical and subcortical
regions rather than a focal neuroanatomic cause. Elec-
troencephalogram (EEG) data in persons with delirium
usually show symmetric slowing, a nonspecic nding
EPIDEMIOLOGY
that supports diffuse cerebral dysfunction.
Delirium is a common disease, but its reported inci- Deciency of acetylcholine often plays a key role in
dence has varied widely with the criteria used to delirium pathogenesis. Medications with anticholin-
dene the disorder. Estimates of delirium in hospital- ergic properties can precipitate delirium in susceptible
ized patients range from 14 to 56%, with higher rates individuals, and therapies designed to boost choliner-
reported for elderly patients and patients undergoing hip gic tone such as cholinesterase inhibitors have, in small
surgery. Older patients in the ICU have especially high trials, been shown to relieve symptoms of delirium.
rates of delirium that range from 70 to 87%. The con- Dementia patients are susceptible to episodes of delir-
dition is not recognized in up to one-third of delirious ium, and those with Alzheimers pathology are known
inpatients, and the diagnosis is especially problematic in to have a chronic cholinergic deciency state due to
the ICU environment, where cognitive dysfunction is degeneration of acetylcholine-producing neurons in
the basal forebrain. Another common dementia asso-
Health Organizations International Classification of Dis-
127
ciated with decreased acetylcholine levels, dementia
eases (ICD). Unfortunately, these scales do not identify
with Lewy bodies, clinically mimics delirium in some
the full spectrum of patients with delirium. All patients
patients. Other neurotransmitters are also likely to be
who are acutely confused should be presumed deliri-
involved in this diffuse cerebral disorder. For example,
ous regardless of their presentation due to the wide
increases in dopamine can also lead to delirium. Patients
variety of possible clinical features. A course that fluc-
with Parkinsons disease treated with dopaminergic
tuates over hours or days and may worsen at night
medications can develop a delirium-like state that fea-
(termed sundowning) is typical but not essential for the
tures visual hallucinations, uctuations, and confusion.
CHAPTER 16
diagnosis. Observation of the patient usually will reveal
In contrast, reducing dopaminergic tone with dopamine
an altered level of consciousness or a deficit of atten-
antagonists such as typical and atypical antipsychotic
tion. Other hallmark features that may be present in a
medications has long been recognized as effective symp-
delirious patient include alteration of sleep-wake cycles,
tomatic treatment in patients with delirium.
thought disturbances such as hallucinations or delu-
Not all individuals exposed to the same insult will
sions, autonomic instability, and changes in affect.
develop signs of delirium. A low dose of an anticho-
linergic medication may have no cognitive effects on a
other symptoms that may accompany delirium, such as rarely the cause of delirium, but patients with underly-
depression and hallucinations, may help identify poten- ing extensive cerebrovascular disease or neurodegener-
tial therapeutic targets. ative conditions may not be able to cognitively tolerate
even relatively small new insults. Patients also should be
PHYSICAL EXAMINATION The general physical
screened for additional signs of neurodegenerative con-
examination in a delirious patient should include a care-
ditions such as parkinsonism, which is seen not only in
Clinical Manifestations of Neurologic Disease
CHAPTER 16
pesticides disorders.
Metabolic conditions Systemic infections often cause delirium, especially
Electrolyte disturbances: hypoglycemia, hyperglycemia, in the elderly. A common scenario involves the devel-
hyponatremia, hypernatremia, hypercalcemia, hypocal- opment of an acute cognitive decline in the setting
cemia, hypomagnesemia of a urinary tract infection in a patient with baseline
Hypothermia and hyperthermia dementia. Pneumonia, skin infections such as cellulitis,
CHAPTER 16
time patients remain in the confused state and may confusion through their sedative properties. Although
mask important diagnostic information. Recent trials of many clinicians still use benzodiazepines to treat acute
medications used to boost cholinergic tone in delirious confusion, their use should be limited to cases in which
patients have led to mixed results, and this strategy is delirium is caused by alcohol or benzodiazepine with-
not currently recommended. drawal.
Relatively simple methods of supportive care can
COMA
Allan H. Ropper
Coma is among the most common and striking prob- state, the patient has rudimentary vocal or motor behav-
lems in general medicine. It accounts for a substantial iors, often spontaneous, but some in response to touch,
portion of admissions to emergency wards and occurs visual stimuli, or command. Cardiac arrest with cerebral
on all hospital services. Coma demands immediate hypoperfusion and head injuries are the most common
attention and requires an organized approach. causes of the vegetative and minimally conscious states
There is a continuum of states of reduced alert- (Chap. 28). The prognosis for regaining mental facul-
ness, the most severe form being coma, dened as a ties once the vegetative state has supervened for several
deep sleeplike state from which the patient cannot be months is very poor, and after a year, almost nil, hence
aroused. Stupor refers to a higher degree of arousability the term persistent vegetative state. Most reports of dra-
in which the patient can be transiently awakened only matic recovery, when investigated carefully, are found
by vigorous stimuli, accompanied by motor behavior to yield to the usual rules for prognosis but there have
that leads to avoidance of uncomfortable or aggravating been rare instances in which recovery has occurred to a
stimuli. Drowsiness, which is familiar to all persons, sim- severely disabled condition and, in rare childhood cases,
ulates light sleep and is characterized by easy arousal and to an even better state. The possibility of incorrectly
the persistence of alertness for brief periods. Drowsiness attributing meaningful behavior to patients in the veg-
and stupor are usually accompanied by some degree of etative and minimally conscious states has created inor-
confusion (Chap. 16). A precise narrative description of dinate problems and anguish for families. On the other
the level of arousal and of the type of responses evoked hand, the question of whether these patients lack any
by various stimuli as observed at the bedside is prefer- capability for cognition has been reopened by functional
able to ambiguous terms such as lethargy, semicoma, or imaging studies demonstrating, in a small proportion of
obtundation. posttraumatic cases, cerebral activation in response to
Several other conditions that render patients unre- external stimuli.
sponsive and thereby simulate coma are considered Apart from the above conditions, several syndromes
separately because of their special signicance. The veg- that affect alertness are prone to be misinterpreted
etative state signies an awake but nonresponsive state in as stupor or coma. Akinetic mutism refers to a partially
a patient who has emerged from coma. In the vegeta- or fully awake state in which the patient is able to
tive state, the eyelids may open, giving the appearance form impressions and think, as demonstrated by later
of wakefulness. Respiratory and autonomic functions recounting of events, but remains virtually immobile
are retained. Yawning, coughing, swallowing, as well as and mute. The condition results from damage in the
limb and head movements persist and the patient may regions of the medial thalamic nuclei or the frontal
follow visually presented objects, but there are few, if lobes (particularly lesions situated deeply or on the orbi-
any, meaningful responses to the external and inter- tofrontal surfaces) or from extreme hydrocephalus. The
nal environmentin essence, an awake coma. The term abulia describes a milder form of akinetic mut-
term vegetative is unfortunate as it is subject to mis- ism characterized by mental and physical slowness and
interpretation. There are always accompanying signs diminished ability to initiate activity. It is also usually
that indicate extensive damage in both cerebral hemi- the result of damage to the frontal lobes and its connec-
spheres, e.g., decerebrate or decorticate limb postur- tions (Chap. 18). Catatonia is a curious hypomobile and
ing and absent responses to visual stimuli (see later). mute syndrome that occurs as part of a major psycho-
In the closely related but less severe minimally conscious sis, usually schizophrenia or major depression. Catatonic
132
patients make few voluntary or responsive movements, and loss of vertical and adduction movements of the 133
although they blink, swallow, and may not appear dis- eyes suggests that the lesion is in the upper brainstem.
tressed. There are nonetheless signs that the patient is Conversely, preservation of pupillary light reactivity and
responsive, although it may take ingenuity on the part of eye movements absolves the upper brainstem and
of the examiner to demonstrate them. For example, indicates that widespread structural lesions or metabolic
eyelid elevation is actively resisted, blinking occurs in suppression of the cerebral hemispheres is responsible
response to a visual threat, and the eyes move concomi- for coma.
tantly with head rotation, all of which are inconsistent
with the presence of a brain lesion causing unrespon- Coma due to cerebral mass lesions
CHAPTER 17
siveness. It is characteristic but not invariable in catato- and herniations
nia for the limbs to retain the postures in which they
have been placed by the examiner (waxy exibility, The cranial cavity is separated into compartments by
or catalepsy). With recovery, patients often have some infoldings of the dura. The two cerebral hemispheres
memory of events that occurred during their catatonic are separated by the falx, and the anterior and posterior
stupor. Catatonia is supercially similar to akinetic mut- fossae by the tentorium. Herniation refers to displace-
ism, but clinical evidence of cerebral damage such as ment of brain tissue into a compartment that it normally
Coma
Babinski signs and hypertonicity of the limbs is lacking. does not occupy. Coma and many of its associated
The special problem of coma in brain death is discussed signs can be attributed to these tissue shifts, and certain
later in this chapter. clinical features are characteristic of specic herniations
The locked-in state describes yet another type of pseu- (Fig. 17-1). They are in essence false localizing signs
docoma in which an awake patient has no means of since they derive from compression of brain structures
producing speech or volitional movement but retains at a distance from the mass.
voluntary vertical eye movements and lid elevation, The most common herniations are those in which
thus allowing the patient to signal with a clear mind. a part of the brain is displaced from the supratentorial
The pupils are normally reactive. Such individuals have to the infratentorial compartment through the tento-
written entire treatises using Morse code. The usual rial opening; this is referred to as transtentorial hernia-
cause is an infarction or hemorrhage of the ventral tion. Uncal transtentorial herniation refers to impaction
pons that transects all descending motor (corticospinal of the anterior medial temporal gyrus (the uncus) into
and corticobulbar) pathways. A similar awake but de- the tentorial opening just anterior to and adjacent to the
efferented state occurs as a result of total paralysis of the midbrain (Fig. 17-1A). The uncus compresses the third
musculature in severe cases of Guillain-Barr syndrome nerve as it traverses the subarachnoid space, causing
(Chap. 46), critical illness neuropathy (Chap. 28), and enlargement of the ipsilateral pupil (putatively because
pharmacologic neuromuscular blockade.
CHAPTER 17
acids and an increase in brain calcium and cerebrospinal ders, results from widespread structural cerebral damage,
uid (CSF) phosphate content. thereby simulating a metabolic disorder of the cortex.
Coma and seizures are common accompaniments of Hypoxia-ischemia is perhaps the best known and one in
large shifts in sodium and water balance in the brain. which it is not possible initially to distinguish the acute
These changes in osmolarity arise from systemic medi- reversible effects of hypoperfusion and oxygen depriva-
cal disorders, including diabetic ketoacidosis, the non- tion of the brain from the subsequent effects of neuro-
ketotic hyperosmolar state, and hyponatremia from nal damage. Similar bihemispheral damage is produced
Coma
any cause (e.g., water intoxication, excessive secretion by disorders that occlude small blood vessels throughout
of antidiuretic hormone, or atrial natriuretic peptides). the brain; examples include cerebral malaria, thrombotic
Sodium levels <125 mmol/L induce confusion, and thrombocytopenic purpura, and hyperviscosity. Diffuse
levels <115 mmol/L are associated with coma and con- white matter damage from cranial trauma or inamma-
vulsions. In hyperosmolar coma, the serum osmolarity tory demyelinating diseases causes a similar syndrome of
is generally >350 mosmol/L. Hypercapnia depresses coma.
the level of consciousness in proportion to the rise in
carbon dioxide (co2) tension in the blood. In all of these
metabolic encephalopathies, the degree of neurologic change APPROACH TO THE
Coma
PATIENT
depends to a large extent on the rapidity with which the serum
changes occur. The pathophysiology of other metabolic Acute respiratory and cardiovascular problems should
encephalopathies such as hypercalcemia, hypothy- be attended to prior to neurologic assessment. In most
roidism, vitamin B12 deciency, and hypothermia are instances, a complete medical evaluation, except for
incompletely understood but must also reect derange- vital signs, funduscopy, and examination for nuchal
ments of CNS biochemistry, membrane function, and rigidity, may be deferred until the neurologic evaluation
neurotransmitters. has established the severity and nature of coma. The
approach to the patient with coma from cranial trauma
Epileptic coma is discussed in Chap. 36.
Generalized electrical discharges of the cortex (seizures) HISTORY In many cases, the cause of coma is imme-
are associated with coma, even in the absence of epi- diately evident (e.g., trauma, cardiac arrest, or reported
leptic motor activity (convulsions). The self-limited coma drug ingestion). In the remainder, certain points are
that follows a seizure, the postictal state, may be due to especially useful: (1) the circumstances and rapidity
exhaustion of energy reserves or effects of locally toxic with which neurologic symptoms developed; (2) the
molecules that are the by-product of seizures. The post- antecedent symptoms (confusion, weakness, headache,
ictal state produces a pattern of continuous, generalized fever, seizures, dizziness, double vision, or vomiting);
slowing of the background EEG activity similar to that (3) the use of medications, illicit drugs, or alcohol; and
of other metabolic encephalopathies. (4) chronic liver, kidney, lung, heart, or other medical
disease. Direct interrogation of family, observers, and
ambulance technicians on the scene, in person or by
Toxic (including druginduced) coma telephone, is an important part of the evaluation.
This common class of encephalopathy is in large mea- GENERAL PHYSICAL EXAMINATION Fever
sure reversible and leaves no residual damage provided suggests a systemic infection, bacterial meningitis,
there has not been cardiorespiratory failure. Many encephalitis, heat stroke, neuroleptic malignant syn-
drugs and toxins are capable of depressing nervous sys- drome, malignant hyperthermia due to anesthetics
tem function. Some produce coma by affecting both or anticholinergic drug intoxication; only rarely is it
the brainstem nuclei, including the RAS, and the cere- attributable to a lesion that has disturbed hypotha-
bral cortex. The combination of cortical and brainstem lamic temperature-regulating centers (central fever).
signs, which occurs in certain drug overdoses, may lead A slight elevation in temperature may follow vigorous
to an incorrect diagnosis of structural brainstem disease.
136 convulsions. Hypothermia is observed with exposure; disorders of any type, regardless of location, frequently
alcoholic, barbiturate, sedative, or phenothiazine intoxi- cause limb extension, and almost all extensor posturing
cation; hypoglycemia; peripheral circulatory failure; or becomes predominantly flexor as time passes.
extreme hypothyroidism. Hypothermia itself causes
LEVEL OF AROUSAL A sequence of increasingly
coma only when the temperature is <31C (87.8F).
intense stimuli is used to determine the threshold for
Tachypnea may indicate systemic acidosis or pneumo-
arousal and the motor response of each side of the
nia or rarely infiltration of the brain with lymphoma.
body. The results of testing may vary from minute to
Aberrant respiratory patterns that reflect brainstem
minute, and serial examinations are most useful. Tick-
disorders are discussed later. Marked hypertension sug-
SECTION II
CHAPTER 17
unresponsiveness progresses. Horizontal divergence of
III III the eyes at rest is normal in drowsiness. As coma deep-
M ens, the ocular axes may become parallel again.
V L Pons Spontaneous eye movements in coma often take
F
Vl the form of conjugate horizontal roving. This finding
Vll
Vlll alone exonerates damage in the midbrain and pons and
Coma
has the same significance as normal reflex eye move-
Medulla ments (see next). Conjugate horizontal ocular devia-
Corneal-blink Reflex conjugate
reflex eye movements tion to one side indicates damage to the pons on the
opposite side or alternatively, to the frontal lobe on the
Respiratory
same side. This phenomenon is summarized by the fol-
neurons lowing maxim: The eyes look toward a hemispheral lesion
and away from a brainstem lesion. Seizures also drive the
eyes to one side but usually with superimposed clonic
movements of the globes. The eyes may occasionally
turn paradoxically away from the side of a deep hemi-
spheral lesion (wrong-way eyes). The eyes turn down
FIGURE 17-3 and inward with thalamic and upper midbrain lesions,
Examination of brainstem reexes in coma. Midbrain and typically thalamic hemorrhage. Ocular bobbing des-
third nerve function are tested by pupillary reaction to light, cribes brisk downward and slow upward movements
pontine function by spontaneous and reex eye movements of the eyes associated with loss of horizontal eye move-
and corneal responses, and medullary function by respira- ments and is diagnostic of bilateral pontine damage,
tory and pharyngeal responses. Reex conjugate, horizontal usually from thrombosis of the basilar artery. Ocular
eye movements are dependent on the medial longitudinal dipping is a slower, arrhythmic downward movement
fasciculus (MLF) interconnecting the sixth and contralateral followed by a faster upward movement in patients with
third nerve nuclei. Head rotation (oculocephalic reex) or normal reflex horizontal gaze; it indicates diffuse cortical
caloric stimulation of the labyrinths (oculovestibular reex) anoxic damage.
elicits contraversive eye movements (for details, see text). The oculocephalic reflexes, elicited by moving the
head from side to side or vertically and observing eye
severe midbrain damage, usually from compression by a movements in the direction opposite to the head move-
supratentorial mass. Ingestion of drugs with anticholin- ment, depend on the integrity of the ocular motor
ergic activity, the use of mydriatic eye drops, and direct nuclei and their interconnecting tracts that extend from
ocular trauma are among the causes of misleading the midbrain to the pons and medulla (Fig. 17-3). The
pupillary enlargement. movements, called somewhat inappropriately dolls
Unilateral miosis in coma has been attributed to dys- eyes (which refers more accurately to the reflex eleva-
function of sympathetic efferents originating in the pos- tion of the eyelids with flexion of the neck), are nor-
terior hypothalamus and descending in the tegmentum mally suppressed in the awake patient. The ability to
of the brainstem to the cervical cord. It is therefore of elicit them therefore indicates both reduced cortical
limited localizing value but is an occasional finding in influence on the brainstem and intact brainstem path-
patients with a large cerebral hemorrhage that affects ways, indicating that coma is caused by a lesion or dys-
the thalamus. Reactive and bilaterally small (12.5 mm) function in the cerebral hemispheres. The opposite, an
but not pinpoint pupils are seen in metabolic encepha- absence of reflex eye movements, usually signifies dam-
lopathies or in deep bilateral hemispheral lesions such age within the brainstem but can result infrequently
as hydrocephalus or thalamic hemorrhage. Even smaller from overdoses of certain drugs. Normal pupillary size
reactive pupils (<1 mm) characterize narcotic or barbi- and light reaction distinguishes most drug-induced
turate overdoses but also occur with extensive pontine comas from structural brainstem damage.
138 Thermal, or caloric, stimulation of the vestibular
calcium, osmolarity, and renal (blood urea nitrogen)
and hepatic (NH3) function. Toxicologic analysis is
apparatus (oculovestibular response) provides a more
necessary in any case of acute coma where the diag-
intense stimulus for the oculocephalic reflex but pro-
nosis is not immediately clear. However, the presence
vides essentially the same information. The test is per-
of exogenous drugs or toxins, especially alcohol, does
formed by irrigating the external auditory canal with
not exclude the possibility that other factors, particu-
cool water in order to induce convection currents in the
larly head trauma, are also contributing to the clini-
labyrinths. After a brief latency, the result is tonic devia-
cal state. An ethanol level of 43 mmol/L (0.2 g/dL) in
tion of both eyes to the side of cool-water irrigation
nonhabituated patients generally causes impaired men-
and nystagmus in the opposite direction. (The acronym
SECTION II
CHAPTER 17
cemia, uremia, hepatic coma, hypercarbia, addiso-
nian crisis, hypo- and hyperthyroid states, profound
(Table 17-1) The causes of coma can be divided into
nutritional deciency
three broad categories: those without focal neurologic c. Severe systemic infections: pneumonia, septicemia,
signs (e.g., metabolic and toxic encephalopathies); men- typhoid fever, malaria, Waterhouse-Friderichsen
ingitis syndromes, characterized by fever or stiff neck syndrome
and an excess of cells in the spinal uid (e.g., bacte- d. Shock from any cause
rial meningitis, subarachnoid hemorrhage); and condi- e. Postseizure states, status epilepticus, subclinical
Coma
tions associated with prominent focal signs (e.g., stroke, epilepsy
f. Hypertensive encephalopathy, eclampsia
cerebral hemorrhage). In most instances, coma is part
g. Severe hyperthermia, hypothermia
of an obvious medical problem, such as drug ingestion, h. Concussion
hypoxia, stroke, trauma, or liver or kidney failure. Con- i. Acute hydrocephalus
ditions that cause sudden coma include drug ingestion,
2. Diseases that cause meningeal irritation with or with-
cerebral hemorrhage, trauma, cardiac arrest, epilepsy, or
out fever, and with an excess of WBCs or RBCs in the
basilar artery embolism. Coma that appears subacutely CSF, usually without focal or lateralizing cerebral or
is usually related to a preexisting medical or neurologic brainstem signs; CT or MRI shows no mass lesion
problem or, less often, to secondary brain swelling of a a. Subarachnoid hemorrhage from ruptured aneurysm,
mass such as tumor or cerebral infarction. arteriovenous malformation, trauma
When cerebrovascular disease is the cause of coma, b. Acute bacterial meningitis
diagnosis can be difcult (Chap. 27). The most common c. Viral encephalitis
diseases are (1) basal ganglia and thalamic hemorrhage d. Miscellaneous: fat embolism, cholesterol embolism,
carcinomatous and lymphomatous meningitis, etc.
(acute but not instantaneous onset, vomiting, head-
ache, hemiplegia, and characteristic eye signs); (2) pon- 3. Diseases that cause focal brainstem or lateralizing
tine hemorrhage (sudden onset, pinpoint pupils, loss cerebral signs, with or without changes in the CSF; CT
of reex eye movements and corneal responses, ocu- and MRI are abnormal
a. Hemispheral hemorrhage (basal ganglionic,
lar bobbing, posturing, hyperventilation, and excessive thalamic) or infarction (large middle cerebral artery
sweating); (3) cerebellar hemorrhage (occipital headache, territory) with secondary brainstem compression
vomiting, gaze paresis, and inability to stand); (4) basi- b. Brainstem infarction due to basilar artery
lar artery thrombosis (neurologic prodrome or warning thrombosis or embolism
spells, diplopia, dysarthria, vomiting, eye movement and c. Brain abscess, subdural empyema
corneal response abnormalities, and asymmetric limb d. Epidural and subdural hemorrhage, brain contusion
paresis); and (5) subarachnoid hemorrhage (precipitous e. Brain tumor with surrounding edema
f. Cerebellar and pontine hemorrhage and infarction
coma after headache and vomiting). The most common
g. Widespread traumatic brain injury
stroke, infarction in the territory of the middle cerebral h. Metabolic coma (see earlier) with preexisting focal
artery, does not generally cause coma, but edema sur- damage
rounding large infarctions may expand during the rst i. Miscellaneous: cortical vein thrombosis, herpes
few days and act as a mass. simplex encephalitis, multiple cerebral emboli due
The syndrome of acute hydrocephalus accompanies to bacterial endocarditis, acute hemorrhagic leuko-
many intracranial diseases, particularly subarachnoid encephalitis, acute disseminated (postinfectious)
encephalomyelitis, thrombotic thrombocytopenic
hemorrhage. It is characterized by headache and some-
purpura, cerebral vasculitis, gliomatosis cerebri,
times vomiting that may progress quickly to coma with pituitary apoplexy, intravascular lymphoma, etc.
extensor posturing of the limbs, bilateral Babinski signs,
small unreactive pupils, and impaired oculocephalic Abbreviations: CSF, cerebrospinal uid; RBCs, red blood cells;
movements in the vertical direction. WBCs, white blood cells.
If the history and examination do not indicate the
cause of coma, then information obtained from CT Sometimes imaging results can be misleading such as
or MRI is needed. The majority of medical causes of when small subdural hematomas or old strokes are
coma can be established without a neuroimaging study. found, but the patients coma is due to intoxication.
140 BRAIN DEATH testing for at least 24 h if a cardiac arrest has caused
brain death or if the inciting disease is not known.
This is a state of cessation of cerebral function with Although it is largely accepted in Western society
preservation of cardiac activity and maintenance of that the respirator can be disconnected from a brain-
somatic function by articial means. It is the only type dead patient, problems frequently arise because of poor
of brain damage recognized as equivalent to death. communication and inadequate preparation of the
Several sets of criteria have been advanced for the family by the physician. Reasonable medical practice,
diagnosis of brain death and it is essential to adhere to ideally with the agreement of the family, allows the
those standards endorsed by the local medical com- removal of support or transfer out of an intensive care
munity. Ideal criteria are simple, can be assessed at
SECTION II
unit of patients who are not brain dead but whose neu-
the bedside, and allow no chance of diagnostic error. rologic conditions are nonetheless hopeless.
They contain three essential elements: (1) widespread
cortical destruction that is reected by deep coma and
unresponsiveness to all forms of stimulation; (2) global
brainstem damage demonstrated by absent pupillary TREATMENT Coma
light reaction and by the loss of oculovestibular and
Clinical Manifestations of Neurologic Disease
CHAPTER 17
is wise. Metabolic comas have a far better prognosis tive abilities of vegetative and minimally conscious
than traumatic ones. All systems for estimating prog- patients. In one series, about 10% of such patients
nosis in adults should be taken as approximations, could be trained to activate the frontal or temporal
and medical judgments must be tempered by factors lobes in response to requests by an examiner to imag-
such as age, underlying systemic disease, and general ine certain visuospatial tasks. In one case, a rudimen-
medical condition. In an attempt to collect prognostic tary form of one-way communication could be estab-
lished. There are also reports in a limited number of
Coma
information from large numbers of patients with head
injury, the Glasgow Coma Scale was devised; empiri- patients of improvement in cognitive function with
cally, it has predictive value in cases of brain trauma the implantation of thalamic-stimulating electrodes.
(Table 36-2). For anoxic and metabolic coma, clinical It is prudent to avoid generalizations from these
signs such as the pupillary and motor responses after experiments.
CHAPTER 18
M.-Marsel Mesulam
The cerebral cortex of the human brain contains occipitotemporal network for face and object recogni-
approximately 20 billion neurons spread over an area of tion, (4) a limbic network for retentive memory, and
2.5 m2. The primary sensory areas provide an obligatory (5) a prefrontal network for cognitive and behavioral
portal for the entry of sensory information into corti- control.
cal circuitry, and the primary motor areas provide a nal
common pathway for coordinating complex motor acts.
The primary sensory and motor areas constitute 10% of THE LEFT PERISYLVIAN NETWORK FOR
the cerebral cortex. The rest is subsumed by modality- LANGUAGE: APHASIAS AND RELATED
selective, heteromodal, paralimbic, and limbic areas col- CONDITIONS
lectively known as the association cortex (Fig. 18-1). The
association cortex mediates the integrative processes that Language allows the communication and elaboration of
subserve cognition, emotion, and behavior. A system- thoughts and experiences by linking them to arbitrary
atic testing of these mental functions is necessary for the symbols known as words. The neural substrate of lan-
effective clinical assessment of the association cortex and guage is composed of a distributed network centered in
its diseases. the perisylvian region of the left hemisphere. The poste-
According to current thinking, there are no cen- rior pole of this network is located at the temporopari-
ters for hearing words, perceiving space, or stor- etal junction and includes a region known as Wernickes
ing memories. Cognitive and behavioral functions area. An essential function of Wernickes area is to trans-
(domains) are coordinated by intersecting large-scale form sensory inputs into their neural word representa-
neural networks that contain interconnected cortical and tions so that they can establish the distributed associa-
subcortical components. The network approach to tions that give a word its meaning. The anterior pole
higher cerebral function has at least four implications of the language network is located in the inferior fron-
of clinical relevance: (1) A single domain such as lan- tal gyrus and includes a region known as Brocas area.
guage or memory can be disrupted by damage to any An essential function of this area is to transform neural
one of several areas as long as those areas belong to the word representations into their articulatory sequences
same network, (2) damage conned to a single area can so that the words can be uttered in the form of spo-
give rise to multiple decits involving the functions of ken language. The sequencing function of Brocas area
all the networks that intersect in that region, (3) dam- also appears to involve the ordering of words into sen-
age to a network component may give rise to mini- tences that contain a meaning-appropriate syntax (gram-
mal or transient decits if other parts of the network mar). Wernickes and Brocas areas are interconnected
undergo compensatory reorganization, and (4) indi- with each other and with additional perisylvian, tempo-
vidual anatomic sites within a network display a rela- ral, prefrontal, and posterior parietal regions, making up
tive (but not absolute) specialization for different behav- a neural network that subserves the various aspects of
ioral aspects of the relevant function. Five anatomically language function. Damage to any one of these com-
dened large-scale networks are most relevant to clini- ponents or to their interconnections can give rise to
cal practice: (1) a perisylvian network for language, (2) language disturbances (aphasia). Aphasia should be diag-
a parietofrontal network for spatial cognition, (3) an nosed only when there are decits in the formal aspects
142
language can be discerned, and in some others (includ- 143
ing a small minority of right handers) there is a right
hemisphere dominance for language. A language dis-
turbance that occurs after a right hemisphere lesion in a
right hander is called crossed aphasia.
CLINICAL EXAMINATION
CHAPTER 18
The clinical examination of language should include the
assessment of naming, spontaneous speech, comprehen-
sion, repetition, reading, and writing. A decit of nam-
ing (anomia) is the single most common nding in apha-
sic patients. When asked to name a common object
(pencil or wristwatch), the patient may fail to come up
with the appropriate word, may provide a circumlocu-
does not exceed the patients attention span. Other- cutious. The tendency for paraphasic errors may be so
wise, the failure of repetition becomes a reection of pronounced that it leads to strings of neologisms, which
the narrowed attention span rather than an indication of form the basis of what is known as jargon aphasia.
an aphasic decit. Reading should be assessed for de- Speech contains large numbers of function words (e.g.,
cits in reading aloud as well as comprehension. Writing prepositions, conjunctions) but few substantive nouns
is assessed for spelling errors, word order, and gram- or verbs that refer to specic actions. The output is
mar. Alexia describes an inability to either read aloud or therefore voluminous but uninformative. For example,
Clinical Manifestations of Neurologic Disease
comprehend single words and simple sentences; agraphia a patient attempts to describe how his wife acciden-
(or dysgraphia) is used to describe an acquired decit in tally threw away something important, perhaps his den-
the spelling or grammar of written language. tures: We dont need it anymore, she says. And with
The correspondence between individual decits of it when that was downstairs was my teeth-ticka
language function and lesion location does not display dendentithmy dentist. And they happened to be
a rigid one-to-one relationship and should be concep- in that bagsee? How could this have happened? How
tualized within the context of the distributed network could a thing like this happenSo she says we wont
model. Nonetheless, the classication of aphasias into need it anymoreI didnt think wed use it. And now
specic clinical syndromes helps determine the most if I have any problems anybody coming a month from
likely anatomic distribution of the underlying neuro- now, 4 months from now, or 6 months from now, I
logic disease and has implications for etiology and prog- have a new dentist. Where my twotwo little pieces
nosis (Table 18-1). The syndromes listed in Table 18-1 of dentist that I usethat Iall gone. If she throws the
are most applicable to aphasias caused by cerebrovascu- whole thing awayvisit some friends of hers and she
lar accidents (CVAs). They can be divided into central cant throw them away.
syndromes, which result from damage to the two epi- Gestures and pantomime do not improve communi-
centers of the language network (Brocas and Wernickes cation. The patient does not seem to realize that his or
areas), and disconnection syndromes, which arise from her language is incomprehensible and may appear angry
lesions that interrupt the functional connectivity of those and impatient when the examiner fails to decipher the
TABLE 18-1
CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS
REPETITION OF
COMPREHENSION SPOKEN LANGUAGE NAMING FLUENCY
CHAPTER 18
differentiate it from deafness, psychiatric disease, or hension decit for function words and syntax. Patients
malingering. Patients with Wernickes aphasia cannot with Brocas aphasia can be tearful, easily frustrated, and
express their thoughts in meaning-appropriate words profoundly depressed. Insight into their condition is pre-
and cannot decode the meaning of words in any modal- served, in contrast to Wernickes aphasia. Even when
ity of input. This aphasia therefore has expressive as well spontaneous speech is severely dysarthric, the patient
as receptive components. Repetition, naming, reading, may be able to display a relatively normal articulation of
and writing also are impaired. words when singing. This dissociation has been used to
aphasia that rapidly resolves into a conduction aphasia. are impaired. Speech is enriched in function words but
The paraphasic output in conduction aphasia interferes impoverished in substantive nouns and verbs denoting
with the ability to express meaning, but this decit is specic actions. Language output is uent but parapha-
not nearly as severe as the one displayed by patients sic, circumlocutious, and uninformative. Fluency may
with Wernickes aphasia. Associated neurologic signs be interrupted by word-nding hesitations. The lesion
in conduction aphasia vary according to the primary sites can be anywhere within the left hemisphere lan-
lesion site. guage network, including the middle and inferior
Clinical Manifestations of Neurologic Disease
CHAPTER 18
as a color anomia. The most common etiology of pure with language comprehension decits. The ability to
alexia is a vascular lesion in the territory of the poste- follow commands aimed at axial musculature (close the
rior cerebral artery or an inltrating neoplasm in the left eyes, stand up) is subserved by different pathways
occipital cortex that involves the optic radiations as well and may be intact in otherwise severely aphasic and
as the crossing bers of the splenium. Since the poste- apraxic patients. Since the handling of real objects is not
rior cerebral artery also supplies medial temporal com- impaired, ideomotor apraxia by itself causes no major
ponents of the limbic system, a patient with pure alexia limitation of daily living activities. Patients with lesions
CHAPTER 18
dromic specicity as the disease progresses.
Neuropathology
In the majority of PPA cases, the neuropathology falls
within the family of frontotemporal lobar degenera-
tions (FTLDs) and displays various combinations of
focal neuronal loss, gliosis, tau-positive inclusions
left half of sentences. When the examiner draws a large environment for additional information. A patient with
circle (12 to 15 cm [5 to 6 in.] in diameter) and asks simultanagnosia misses the forest for the trees. Com-
the patient to place the numbers 1 to 12 as if the circle plex visual scenes cannot be grasped in their entirety,
represented the face of a clock, there is a tendency to leading to severe limitations in the visual identication
crowd the numbers on the right side and leave the left of objects and scenes. For example, a patient who is
side empty. When asked to copy a simple line drawing, shown a table lamp and asked to name the object may
the patient fails to copy detail on the left, and when the look at its circular base and call it an ashtray. Some
patient is asked to write, there is a tendency to leave an patients with simultanagnosia report that objects they
unusually wide margin on the left. look at may vanish suddenly, probably indicating an
Two bedside tests that are useful in assessing neglect inability to look back at the original point of gaze after
are simultaneous bilateral stimulation and visual target cancel- brief saccadic displacements. Movement and distracting
lation. In the former, the examiner provides either uni- stimuli greatly exacerbate the difculties of visual per-
lateral or simultaneous bilateral stimulation in the visual, ception. Simultanagnosia sometimes can occur without
auditory, and tactile modalities. After right hemisphere the other two components of Blints syndrome.
injury, patients who have no difculty detecting uni- A modication of the letter cancellation task
lateral stimuli on either side experience the bilaterally described earlier can be used for the bedside diagnosis
presented stimulus as coming only from the right. This of simultanagnosia. In this modication, some of the
phenomenon is known as extinction and is a manifesta- targets (e.g., As) are made to be much larger than the
tion of the sensory-representational aspect of hemispa- others (7.5 to 10 cm vs. 2.5 cm [3 to 4 in. vs. 1 in.]
tial neglect. In the target detection task, targets (e.g., in height), and all targets are embedded among foils.
As) are interspersed with foils (e.g., other letters of the Patients with simultanagnosia display a counterintui-
alphabet) on a 21.5- to 28.0-cm (8.5 to 11 in.) sheet tive but characteristic tendency to miss the larger tar-
of paper, and the patient is asked to circle all the tar- gets (Fig. 18-3B). This occurs because the informa-
gets. A failure to detect targets on the left is a manifes- tion needed for the identication of the larger targets
tation of the exploratory decit in hemispatial neglect cannot be conned to the immediate line of gaze and
(Fig. 18-3A). Hemianopia is not by itself sufcient to requires the integration of visual information across
cause the target detection failure since the patient is free a more extensive eld of view. The greater difculty
to turn the head and eyes to the left. Target detection in the detection of the larger targets also indicates that
failures therefore reect a distortion of spatial atten- poor acuity is not responsible for the impairment of
tion, not just of sensory input. The normal tendency visual function and that the problem is central rather
in target detection tasks is to start from the left upper than peripheral.
quadrant and move systematically in horizontal or verti- Another manifestation of bilateral (or right-sided)
cal sweeps. Some patients show a tendency to start the dorsal parietal lobe lesions is dressing apraxia. A patient
process from the right and proceed in a haphazard fash- with this condition is unable to align the body axis with
ion. This represents a subtle manifestation of left neglect the axis of the garment and can be seen struggling as
even if the patient eventually manages to detect all the he or she holds a coat from its bottom or extends his
appropriate targets. Some patients with neglect also may or her arm into a fold of the garment rather than into
deny the existence of hemiparesis and may even deny its sleeve. Lesions that involve the posterior parietal
ownership of the paralyzed limb, a condition known as cortex also lead to severe difculties in copying simple
anosognosia. line drawings. This is known as a construction apraxia and
151
CHAPTER 18
Aphasia, Memory Loss, and Other Focal Cerebral Disorders
A
FIGURE 18-3
A. A 47-year-old man with a
large frontoparietal lesion in the
right hemisphere was asked to
circle all the As. Only targets
on the right are circled. This is
a manifestation of left hemis-
patial neglect. B. A 70-year-old
woman with a 2-year history of
degenerative dementia was able
to circle most of the small tar-
gets but ignored the larger ones.
This is a manifestation of simul-
tanagnosia. B
is much more severe if the lesion is in the right hemi- with neglect also may have hemiparesis, hemihypesthe-
sphere. In some patients with right hemisphere lesions, sia, and hemianopia on the left, but these are not invari-
the drawing difculties are conned to the left side of ant ndings. The majority of these patients display con-
the gure and represent a manifestation of hemispatial siderable improvement of hemispatial neglect, usually
neglect; in others, there is a more universal decit in within the rst several weeks. Blints syndrome results
reproducing contours and three-dimensional perspec- from bilateral dorsal parietal lesions; common settings
tive. Dressing apraxia and construction apraxia represent include watershed infarction between the middle and
special instances of a more general disturbance in spatial posterior cerebral artery territories, hypoglycemia, and
orientation. sagittal sinus thrombosis.
A progressive form of spatial disorientation known
as the posterior cortical atrophy syndrome most commonly
Causes of spatial disorientation represents a variant of Alzheimers disease with unusual
Cerebrovascular lesions and neoplasms in the right concentrations of neurobrillary degeneration in the
hemisphere are the most common causes of hemispatial parieto-occipital cortex and the superior colliculus. The
neglect. Depending on the site of the lesion, a patient patient displays a progressive Blints syndrome, usually
152 accompanied by dressing and construction apraxia. Cor- the object but can describe its use. In contrast, a patient
ticobasal degeneration, a type of FTLD with abnormal with visual agnosia is unable either to name a visually
tau inclusions, can have an asymmetric distribution. presented object or to describe its use. Face and object
When the atrophy shows a predilection for the right recognition disorders also can result from the simul-
cerebral hemisphere, a progressive left hemineglect syn- tanagnosia of Blints syndrome, in which case they are
drome emerges on a background of left-sided extrapyra- known as apperceptive agnosias as opposed to the asso-
midal dysfunction. ciative agnosias that result from inferior temporal lobe
lesions.
SECTION II
CHAPTER 18
scious knowledge of the experiences that led to the instances, usually associated with temporal lobe epilepsy
acquisition of these skills. or benzodiazepine intake, the retrograde component
The memory disturbance in the amnestic state is may dominate.
multimodal and includes retrograde and anterograde The assessment of memory can be quite challenging.
components. The retrograde amnesia involves an inabil- Bedside evaluations may detect only the most severe
ity to recall experiences that occurred before the onset impairments. Less severe memory impairments, as in the
of the amnestic state. Relatively recent events are more case of patients with temporal lobe epilepsy, mild head
and a retrograde amnesia for relatively recent events that the patient becomes socially disinhibited and shows
occurred before the onset. The syndrome usually resolves severe impairments of judgment, insight, and foresight.
within 24 to 48 h and is followed by the lling in of the The dissociation between intact intellectual function
period affected by the retrograde amnesia, although there and a total lack of even rudimentary common sense is
is persistent loss of memory for the events that occurred striking. Despite the preservation of all essential mem-
during the ictus. Recurrences are noted in approximately ory functions, the patient cannot learn from experience
20% of patients. Migraine, temporal lobe seizures, and and continues to display inappropriate behaviors with-
Clinical Manifestations of Neurologic Disease
perfusion abnormalities in the posterior cerebral territory out appearing to feel emotional pain, guilt, or regret
have been postulated as causes of transient global amnesia. when those behaviors repeatedly lead to disastrous con-
The absence of associated neurologic ndings occasion- sequences. The impairments may emerge only in real-
ally may lead to the incorrect diagnosis of a psychiatric life situations when behavior is under minimal external
disorder. control and may not be apparent within the structured
environment of the medical ofce. Testing judgment by
asking patients what they would do if they detected a
re in a theater or found a stamped and addressed enve-
THE PREFRONTAL NETWORK FOR lope on the road is not very informative since patients
ATTENTION AND BEHAVIOR who answer these questions wisely in the ofce may still
act very foolishly in the more complex real-life setting.
Approximately one-third of all the cerebral cortex in The physician must therefore be prepared to make a
the human brain is situated in the frontal lobes. The diagnosis of frontal lobe disease on the basis of historic
frontal lobes can be subdivided into motor-premotor, information alone even when the mental state is quite
dorsolateral prefrontal, medial prefrontal, and orbi- intact in the ofce examination.
tofrontal components. The terms frontal lobe syndrome
and prefrontal cortex refer only to the last three of these
four components. These are the parts of the cerebral
CLINICAL EXAMINATION
cortex that show the greatest phylogenetic expan-
sion in primates, especially in humans. The dorsolat- The emergence of developmentally primitive reexes,
eral prefrontal, medial prefrontal, and orbitofrontal also known as frontal release signs, such as grasping
areas, along with the subcortical structures with which (elicited by stroking the palm) and sucking (elicited by
they are interconnected (i.e., the head of the caudate stroking the lips) are seen primarily in patients with
and the dorsomedial nucleus of the thalamus), collec- large structural lesions that extend into the premo-
tively make up a large-scale network that coordinates tor components of the frontal lobes or in the context
exceedingly complex aspects of human cognition and of metabolic encephalopathies. The vast majority of
behavior. patients with prefrontal lesions and frontal lobe behav-
The prefrontal network plays an important role in ioral syndromes do not display these reexes.
behaviors that require multitasking and the integration Damage to the frontal lobe disrupts a variety of
of thought with emotion. Its integrity appears impor- attention-related functions, including working memory
tant for the simultaneous awareness of context, options, (the transient online holding of information), concen-
consequences, relevance, and emotional impact that tration span, the scanning and retrieval of stored infor-
allows the formulation of adaptive inferences, decisions, mation, the inhibition of immediate but inappropri-
and actions. Damage to this part of the brain impairs ate responses, and mental exibility. The capacity for
mental exibility, reasoning, hypothesis formation, focusing on a trend of thought and the ability to shift
abstract thinking, foresight, judgment, the online (atten- the focus of attention voluntarily from one thought
tive) holding of information, and the ability to inhibit or stimulus to another can become impaired. Digit
inappropriate responses. Cognitive operations impaired span (which should be seven forward and ve reverse)
by prefrontal cortex lesions often are referred to as is decreased; the recitation of the months of the year
executive functions. in reverse order (which should take less than 15 s) is
slowed; and the uency in producing words starting shoplifting, compulsive gambling, sexual indiscretions, 155
with the letter a, f, or s that can be generated in 1 min and obsessive-compulsive preoccupations, arising on
(normally v 12 per letter) is diminished even in nona- a background of indifference. In many patients with
phasic patients. Characteristically, there is a progres- Alzheimers disease, neurobrillary degeneration even-
sive slowing of performance as the task proceeds; e.g., tually spreads to prefrontal cortex and gives rise to com-
a patient asked to count backward by threes may say ponents of the frontal lobe syndrome, but almost always
100, 97, 94,91,88, etc., and may not complete on a background of severe memory impairment.
the task. In gono go tasks (where the instruction is Lesions in the caudate nucleus or in the dorsomedial
to raise the nger upon hearing one tap but keep it still nucleus of the thalamus (subcortical components of the
CHAPTER 18
upon hearing two taps), the patient shows a character- prefrontal network) also can produce a frontal lobe syn-
istic inability to keep still in response to the no go drome. This is one reason why the changes in mental
stimulus. Mental exibility (tested by the ability to shift state associated with degenerative basal ganglia diseases
from one criterion to another in sorting or matching such as Parkinsons disease and Huntingtons disease may
tasks) is impoverished; distractibility by irrelevant stim- take the form of a frontal lobe syndrome. Because of its
uli is increased; and there is a pronounced tendency for widespread connections with other regions of association
impersistence and perseveration. cortex, one essential computational role of the prefron-
the immediate eld of gaze. Some patients with frontal For example, patients with CVA and nonuent apha-
lobe disease can be extremely irritable and abusive to sias are more likely to benet from speech therapy than
spouses yet display all the appropriate social graces dur- are patients with uent aphasias and comprehension
ing a visit to the medical ofce. In such cases, the history decits. In general, lesions that lead to a denial of illness
may be more important than the bedside examination in (e.g., anosognosia) are associated with cognitive decits
charting a course of treatment. that are more resistant to rehabilitation. Periodic neuro-
Reactive depression is common in patients with psychological assessment is necessary for quantifying the
Clinical Manifestations of Neurologic Disease
higher cerebral dysfunction and should be treated. These pace of the improvement (or of the progression in the
patients may be overly sensitive to the usual doses of anti- case of dementias) and for generating specic recom-
depressants or anxiolytics and require a careful titration of mendations for cognitive rehabilitation, modications
dosage. Brain damage may cause a dissociation between in the home environment, the timetable for return-
feeling states and their expression so that a patient who ing to work in patients recovering from acute lesions,
may supercially appear jocular could still be suffering and the scheduling of retirement or disability status in
from an underlying depression that needs to be treated. patients with degenerative diseases. Determining driving
In many cases, agitation may be controlled with reas- competence is challenging, especially in the early stages
surance. In other cases, treatment with benzodiazepines, of dementing diseases. The diagnosis of a neurodegen-
antiepilectics, or sedating antidepressants may become erative disease is not by itself sufcient for asking the
necessary. If neuroleptics become absolutely necessary for patient to stop driving. An on-the-road driving test and
the control of agitation, atypical neuroleptics are prefer- reports from family members may help time decisions
able because of their lower extrapyramidal side effects. related to this very important activity.
Treatment with neuroleptics in elderly patients with There is a mistaken belief that dementias are ana-
dementia requires weighing the potential benets against tomically diffuse and that they cause global cogni-
the potentially serious side effects. tive impairments. This is true only at the terminal
Spontaneous improvement of cognitive decits due stages. During most of the clinical course, dementias
to acute neurologic lesions is common. It is most rapid are exquisitely selective with respect to anatomy and
in the rst few weeks but may continue for up to cognitive pattern. Alzheimers disease, for example,
2 years, especially in young individuals with single brain causes the greatest destruction in medial temporal areas
lesions. The mechanisms for this recovery are incom- belonging to the memory network and is clinically
pletely understood. Some of the initial decits appear characterized by a correspondingly severe amnesia.
to arise from remote dysfunction (diaschisis) in parts of There are other dementias in which memory is intact.
the brain that are interconnected with the site of ini- Selective degeneration of the frontal lobes in FTLD
tial injury. Improvement in these patients may reect, leads to a gradual dissolution of behavior and execu-
at least in part, a normalization of the remote dysfunc- tive functions. Primary progressive aphasia is charac-
tion. Other mechanisms may involve functional reor- terized by a gradual atrophy of the left perisylvian lan-
ganization in surviving neurons adjacent to the injury guage network and a selective dissolution of language
or the compensatory use of homologous structures, that can remain isolated for up to 10 years. An enlight-
e.g., the right superior temporal gyrus with recovery ened approach to the differential diagnosis and to the
from Wernickes aphasia. In some patients with large individualized care of patients with acute and progres-
lesions involving Brocas and Wernickes areas, only sive damage to the cerebral cortex requires an under-
Wernickes area may show contralateral compensatory standing of the principles that link neural networks to
reorganization (or bilateral functionality), giving rise to higher cerebral functions.
CHAPTER 19
Language and memory are essential human functions. disorders of language and speech (including the aphasias),
For the experienced clinician, the recognition of different memory (the amnesias), and other disorders of cognition
types of language and memory disturbances often pro- that are commonly encountered in clinical practice. Vid-
vides essential clues to the anatomic localization and diag- eos for this chapter can be accessed at the following link:
nosis of neurologic disorders. This video illustrates classic http://www.mhprofessional.com/mediacenter/.
157
CHAPTER 20
SLEEP DISORDERS
Disturbed sleep is among the most frequent health STATES AND STAGES OF SLEEP
complaints physicians encounter. More than one-half
of adults in the United States experience at least inter- States and stages of human sleep are dened on the
mittent sleep disturbance. For most, it is an occasional basis of characteristic patterns in the electroencephalo-
night of poor sleep or daytime sleepiness. However, the gram (EEG), the electrooculogram (EOGa measure
Institute of Medicine has estimated that 5070 million of eye-movement activity), and the surface electro-
Americans suffer from a chronic disorder of sleep and myogram (EMG) measured on the chin and neck. The
wakefulness, which can lead to serious impairment of continuous recording of this array of electrophysiologic
daytime functioning. In addition, such problems may parameters to dene sleep and wakefulness is termed
contribute to or exacerbate medical or psychiatric con- polysomnography.
ditions. Thirty years ago, many such complaints were Polysomnographic proles dene two states of sleep:
treated with hypnotic medications without further diag- (1) rapid-eye-movement (REM) sleep and (2) non-
nostic evaluation. Since then, a distinct class of sleep and rapid-eye-movement (NREM) sleep. NREM sleep is
arousal disorders has been identied. further subdivided into three stages, characterized by
increasing arousal threshold and slowing of the cortical
EEG. REM sleep is characterized by a low-amplitude,
mixed-frequency EEG similar to that of NREM stage
PHYSIOLOGY OF SLEEP AND N1 sleep. The EOG shows bursts of REM similar to
WAKEFULNESS those seen during eyes-open wakefulness. Chin EMG
activity is absent, reecting the brainstem-mediated
Given the opportunity, most adults will sleep 78 h per muscle atonia that is characteristic of that state.
night, although the timing, duration, and internal struc-
ture of sleep vary among healthy individuals and as a
ORGANIZATION OF HUMAN SLEEP
function of age. At the extremes, infants and the elderly
have frequent interruptions of sleep. In the United Normal nocturnal sleep in adults displays a consistent
States, adults tend to have one consolidated sleep epi- organization from night to night (Fig. 20-1). After
sode per day, although in some cultures sleep may be sleep onset, sleep usually progresses through NREM
divided into a mid-afternoon nap and a shortened night stages N1N3 sleep within 4560 min. Slow-wave
sleep. Two principal neural systems govern the expres- sleep (NREM stage N3 sleep) predominates in the rst
sion of the sleep and wakefulness states within the daily third of the night and comprises 1525% of total noc-
cycle. The rst potentiates sleep in proportion to the turnal sleep time in young adults. The percentage of
duration of wakefulness (the sleep homeostat), while slow-wave sleep is inuenced by several factors, most
the second rhythmically modulates sleep and wakeful- notably age (see later). Prior sleep deprivation increases
ness tendencies at appropriate phases of the 24-h day the rapidity of sleep onset and both the intensity and
(the circadian clock). Intrinsic abnormalities in the func- amount of slow-wave sleep.
tion of either of these systems, or extrinsic disturbances The rst REM sleep episode usually occurs in
(environmental, drug- or illness-related) that supersede the second hour of sleep. More rapid onset of REM
their normal expression, can lead to clinically recogniz- sleep in an adult (particularly if <30 min) may suggest
able sleep disorders. pathology such as endogenous depression, narcolepsy,
158
159
Awake
REM
N1 Age
23
N2
Sleep stage
N3
Awake
REM
Age
N1 68
N2
CHAPTER 20
N3
FIGURE 20-1
Stages of REM sleep (solid bars), the three stages of NREM wave sleep, frequent spontaneous awakenings, early sleep
sleep, and wakefulness over the course of the entire night onset, and early morning awakening. (From the Division of
Sleep Disorders
for representative young and older adult men. Characteristic Sleep Medicine, Brigham and Womens Hospital.)
features of sleep in older people include reduction of slow-
circadian rhythm disorders, or drug withdrawal. NREM the brainstem reticular formation, the midbrain, the
and REM alternate through the night with an aver- subthalamus, the thalamus, and the basal forebrain have
age period of 90110 min (the ultradian sleep cycle). all been suggested to play a role in the generation of
Overall, REM sleep constitutes 2025% of total sleep, wakefulness or EEG arousal.
and NREM stages N1 and N2 are 5060%. Current models suggest that the capacity for sleep
Age has a profound impact on sleep state organi- and wakefulness generation is distributed along an axial
zation (Fig. 20-1). Slow-wave sleep is most intense core of neurons extending from the brainstem ros-
and prominent during childhood, decreasing sharply trally to the basal forebrain. A cluster of -aminobutyric
coincident with puberty and across the second and acid (GABA) and galaninergic neurons in the ventro-
third decades of life. After age 30, there is a contin- lateral preoptic (VLPO) hypothalamus is selectively
ued decline in the amount of slow-wave sleep, and the activated coincident with sleep onset. These neurons
amplitude of delta EEG activity comprising slow-wave project to and inhibit the multiple neural wakefulness
sleep is profoundly reduced. The depth of slow-wave centers that comprise the ascending arousal system,
sleep, as measured by the arousal threshold to auditory and selective cell-specic lesions of VLPO substantially
stimulation, also decreases with age. In the otherwise reduce sleep time, indicating that the hypothalamic
healthy older person, slow-wave sleep may be com- VLPO neurons play an executive role in sleep regula-
pletely absent, particularly in males. Paradoxically, older tion. More recent data have identied another sleep
people are better able to tolerate acute sleep deprivation center, the median preoptic nucleus (MnPOn) of the
than young adults, maintaining reaction time and sus- hypothalamus with similar activation patterns and pro-
taining vigilance with fewer lapses of attention. jections, suggesting that, like that of wakefulness, exec-
A different age prole exists for REM sleep than for utive control of sleep may also be multicentric.
slow-wave sleep. In infancy, REM sleep may comprise Specic regions in the pons are associated with the
50% of total sleep time, and the percentage is inversely neurophysiologic correlates of REM sleep. Small lesions
proportional to developmental age. The amount of in the dorsal pons result in the loss of the descend-
REM sleep falls off sharply over the rst postnatal year ing muscle inhibition normally associated with REM
as a mature REM-NREM cycle develops; thereafter, sleep; microinjections of the cholinergic agonist car-
REM sleep occupies a relatively constant percentage of bachol into the pontine reticular formation produce
total sleep time. a state with all of the features of REM sleep. These
experimental manipulations are mimicked by patho-
logic conditions in humans and animals. A prominent
NEUROANATOMY OF SLEEP
feature of narcolepsy, for example, is abrupt, complete,
Experimental studies in animals have variously impli- or partial paralysis (cataplexy) in response to a variety of
cated the medullary reticular formation, the thalamus, stimuli, a pathologic activation of neural systems medi-
and the basal forebrain in the generation of sleep, while ating the atonia of normal REM sleep. In narcoleptic
160 dogs, physostigmine, a central cholinesterase inhibitor, translational feedback loops (Fig. 20-2). In evaluating a
increases the frequency of cataplexy episodes, while daily variation in humans, it is important to distinguish
atropine decreases their frequency. Conversely, in REM between those rhythmic components passively evoked
sleep behavior disorder (see later), patients suffer from a by periodic environmental or behavioral changes (e.g.,
failure of normal motor inhibition during REM sleep, the increase in blood pressure and heart rate that occurs
resulting in involuntary, occasionally violent, movement upon assumption of the upright posture) and those
arising out of dream episodes. actively driven by an endogenous oscillatory process
(e.g., the circadian variation in plasma cortisol that per-
sists under a variety of environmental and behavioral
NEUROCHEMISTRY OF SLEEP
SECTION II
conditions).
Early experimental studies that focused on the raphe While it is now recognized that many peripheral
nuclei of the brainstem appeared to implicate serotonin tissues in mammals have circadian clocks that regulate
as the primary sleep-promoting neurotransmitter, while diverse physiologic processes, these independent tissue-
catecholamines were considered to be responsible for specic oscillations are coordinated by a central neural
wakefulness. Simple neurochemical models have given pacemaker located in the suprachiasmatic nuclei (SCN)
Clinical Manifestations of Neurologic Disease
CLOCK
BMAL1
In the basal forebrain (BF), adenosine receptors on
cholinergic neurons are thought to play a role in assess- +
ing homeostatic sleep need by providing an index of E-Box Per1 gene
cellular energy status. Projections from these BF neu-
rons to executive sleep centers such as VLPO thus allow FIGURE 20-2
incorporation of homeostatic sleep need into the con- Model of the molecular feedback loop at the core of the
trol of sleep state expression. At a practical level, this mammalian circadian clock. The positive element of the
model suggests that the alerting effects of caffeine, an feedback loop (+) is the transcriptional activation of the Per1
adenosine receptor antagonist, reect the attenuation of gene (and probably other clock genes) by a heterodimer of
the transcription factors CLOCK and BMAL1 (also called
the homeostatic signal from the basal forebrain.
MOP3) bound to an E-box DNA regulatory element. The Per1
The prominent hypnotic effects of benzodiazepine
transcript and its product, the clock component PER1 pro-
receptor agonists suggest that endogenous ligands of this
tein, accumulate in the cell cytoplasm. As it accumulates,
receptor may be involved in normal sleep physiology.
the PER1 protein is recruited into a multiprotein complex
While neurosteroids with activity at this receptor have thought to contain other circadian clock component proteins
been identied, their role in normal sleep-wake control such as cryptochromes (CRYs), Period proteins (PERs), and
remains unclear. In addition, a broad array of endogenous others. This complex is then transported into the cell nucleus
sleep- and wake-promoting substances have been iden- (across the dotted line), where it functions as the negative
tied, the role of which in normal sleep-wake control element in the feedback loop () by inhibiting the activity of
remains unclear. These include corticotropin-releasing the CLOCK-BMAL1 transcription factor heterodimer. As a
hormone (CRH), prostaglandin D2, delta sleepinducing consequence of this action, the concentration of PER1 and
peptide, muramyl dipeptide, interleukin 1, fatty acid pri- other clock proteins in the inhibitory complex falls, allowing
mary amides, and melatonin. CLOCK-BMAL1 to activate transcription of Per1 and other
genes and begin another cycle. The dynamics of the 24-h
molecular cycle are controlled at several levels, including
PHYSIOLOGY OF CIRCADIAN RHYTHMICITY regulation of the rate of PER protein degradation by casein
kinase-1 epsilon (CK1E). Additional limbs of this genetic reg-
The sleep-wake cycle is the most evident of the many ulatory network, omitted for the sake of clarity, are thought
24-h rhythms in humans. Prominent daily variations to contribute stability. Question marks denote putative clock
also occur in endocrine, thermoregulatory, cardiac, pul- proteins, such as Timeless (TIM), as yet lacking genetic proof
monary, renal, gastrointestinal, and neurobehavioral of a role in the mammalian clock mechanism. (Copyright
functions. At the molecular level, endogenous circadian Charles J. Weitz, PhD, Department of Neurobiology, Harvard
rhythmicity is driven by self-sustaining transcriptional/ Medical School.)
of the hypothalamus. Bilateral destruction of these typically lack the detail and vividness of REM sleep 161
nuclei results in a loss of the endogenous circadian dreams. The incidence of NREM sleep dream recall
rhythm of locomotor activity, which can be restored can be increased by selective REM sleep deprivation,
only by transplantation of the same structure from a suggesting that REM sleep and dreaming per se are not
donor animal. The genetically determined period of this inexorably linked.
endogenous neural oscillator, which averages ~24.2 h
in humans, is normally synchronized to the 24-h period
of the environmental light-dark cycle. Small differences PHYSIOLOGIC CORRELATES OF SLEEP
in circadian period underlie variations in diurnal pref- STATES AND STAGES
CHAPTER 20
erence, with the circadian period shorter in individuals
who typically rise early compared to those who typi- All major physiologic systems are inuenced by sleep.
cally go to bed late. Entrainment of mammalian circa- Changes in cardiovascular function include a decrease in
dian rhythms by the light-dark cycle is mediated via the blood pressure and heart rate during NREM and partic-
retinohypothalamic tract, a monosynaptic pathway that ularly during slow-wave sleep. During REM sleep, pha-
links specialized, photoreceptive retinal ganglion cells sic activity (bursts of eye movements) is associated with
directly to the SCN. Humans are exquisitely sensitive variability in both blood pressure and heart rate medi-
Sleep Disorders
to the resetting effects of light, particularly the shorter ated principally by the vagus nerve. Cardiac dysrhyth-
wavelengths (~460500 nm) of the visible spectrum. mias may occur selectively during REM sleep. Respi-
The timing and internal architecture of sleep are ratory function also changes. In comparison to relaxed
directly coupled to the output of the endogenous cir- wakefulness, respiratory rate becomes more regular dur-
cadian pacemaker. Paradoxically, the endogenous cir- ing NREM sleep (especially slow-wave sleep) and tonic
cadian rhythms of sleep tendency, sleepiness, and REM REM sleep and becomes very irregular during phasic
sleep propensity all peak near the habitual wake time, REM sleep. Minute ventilation decreases in NREM
just after the nadir of the endogenous circadian tem- sleep out of proportion to the decrease in metabolic rate
perature cycle, whereas the circadian wake propensity at sleep onset, resulting in a higher PCO2.
rhythm peaks 13 h before the habitual bedtime. These Endocrine function also varies with sleep. Slow-wave
rhythms are thus timed to oppose the homeostatic sleep is associated with secretion of growth hormone
decline of sleep tendency during the habitual sleep epi- in men, while sleep in general is associated with aug-
sode and the rise of sleep tendency throughout the usual mented secretion of prolactin in both men and women.
waking day, respectively. Misalignment of the output of Sleep has a complex effect on the secretion of lutein-
the endogenous circadian pacemaker with the desired izing hormone (LH): during puberty, sleep is associated
sleep-wake cycle can, therefore, induce insomnia, with increased LH secretion, whereas sleep in the post-
decreased alertness, and impaired performance evident pubertal female inhibits LH secretion in the early fol-
in night-shift workers and airline travelers. licular phase of the menstrual cycle. Sleep onset (and
probably slow-wave sleep) is associated with inhibition
of thyroid-stimulating hormone and of the adrenocor-
ticotropic hormonecortisol axis, an effect that is super-
BEHAVIORAL CORRELATES OF SLEEP
imposed on the prominent circadian rhythms in the two
STATES AND STAGES
systems.
Polysomnographic staging of sleep correlates with The pineal hormone melatonin is secreted pre-
behavioral changes during specic states and stages. dominantly at night in both day- and night-active spe-
During the transitional state between wakefulness and cies, reecting the direct modulation of pineal activity
sleep (stage N1 sleep), subjects may respond to faint by the circadian pacemaker through a circuitous neu-
auditory or visual signals without awakening. Short- ral pathway from the SCN to the pineal gland. Mela-
term memory incorporation is inhibited at the onset of tonin secretion is not dependent upon the occurrence
NREM stage N1 sleep, which may explain why indi- of sleep, persisting in individuals kept awake at night.
viduals aroused from that transitional sleep stage fre- Secretion is inhibited by ambient light, an effect medi-
quently deny having been asleep. Such transitions may ated by a neural connection from the retina via the
intrude upon behavioral wakefulness after sleep depri- SCN. The role of endogenous melatonin in normal
vation, notwithstanding attempts to remain continuously sleep-wake regulation is unclear, but administration of
awake (see Shift-Work Disorder, later in this chapter). exogenous melatonin can potentiate sleepiness and facil-
Awakenings from REM sleep are associated with itate sleep onset when administered in the afternoon or
recall of vivid dream imagery >80% of the time. The evening, at a time when endogenous melatonin levels
reliability of dream recall increases with REM sleep epi- are low. The efcacy of melatonin as a sleep-promot-
sodes occurring later in the night. Imagery may also be ing therapy for patients with insomnia is currently not
reported after NREM sleep interruptions, though these known.
162 Sleep is also accompanied by alterations of thermo- Patients with excessive sleepiness should be advised
regulatory function. NREM sleep is associated with to avoid all driving until effective therapy has been
an attenuation of thermoregulatory responses to either achieved.
heat or cold stress, and animal studies of thermosensitive Completion by the patient of a day-by-day sleep-
neurons in the hypothalamus document an NREM- work-drug log for at least 2 weeks can help the physi-
sleep-dependent reduction of the thermoregulatory set- cian better understand the nature of the complaint.
point. REM sleep is associated with complete absence Work times and sleep times (including daytime naps
of thermoregulatory responsiveness, resulting in func- and nocturnal awakenings) as well as drug and alcohol
tional poikilothermy. However, the potential adverse use, including caffeine and hypnotics, should be noted
SECTION II
Obesity, snoring, hypertension Polysomnography with Obstructive Continuous positive airway pressure; ENT
respiratory monitoring sleep apnea surgery (e.g., uvulopalatopharyngoplasty);
dental appliance; pharmacologic therapy
(e.g., protriptyline); weight loss
CHAPTER 20
Cataplexy, hypnogogic hal- Polysomnography with Narcolepsy- Stimulants (e.g., modanil, methylpheni-
lucinations, sleep paralysis, multiple sleep latency cataplexy date); REM-suppressant antidepressants
family history testing syndrome (e.g., protriptyline); genetic counseling
Restless legs, disturbed sleep, Assessment for predispos- Restless legs Treatment of predisposing condition, if pos-
predisposing medical condi- ing medical conditions syndrome sible; dopamine agonists (e.g., pramipex-
tion (e.g., iron deciency or ole, ropinirole)
renal failure)
Sleep Disorders
Disturbed sleep, predispos- Sleep-wake diary Insomnias (see Treatment of predisposing condition and/
ing medical conditions (e.g., recording text) or change in therapy, if possible; behav-
asthma), and/or predisposing ioral therapy; short-acting benzodiazepine
medical therapies (e.g., the- receptor agonist (e.g., zolpidem)
ophylline)
Abbreviations: EMG, electromyogram; ENT, ears, nose, throat; REM, rapid eye movement.
environment that is not conducive to sleep, or irregu- (psychophysiologic insomnia, see next), amplication
larity in the timing or duration of the nightly sleep epi- of the time spent awake (paradoxical insomnia), physi-
sode. Noise, light, or technology (e.g., television, radio, ologic hyperarousal, and poor sleep hygiene (see ear-
cell phone, mobile email device or computer) in the lier) may all be present. As these processes may be both
bedroom can interfere with sleep, as can a bed partner causes and consequences of chronic insomnia, many
with periodic limb movements during sleep or one who individuals will have a progressive course to their symp-
snores loudly. Clocks can heighten the anxiety about toms in which the severity is proportional to the chro-
the time it has taken to fall asleep. Drugs that act on nicity, and much of the complaint may persist even after
the central nervous system, large meals, vigorous exer- effective treatment of the initial inciting etiology. Treat-
cise, or hot showers just before sleep may all interfere ment of insomnia is often directed to each of the puta-
with sleep onset. Many individuals participate in stress- tive contributing factors: behavior therapies for anxiety
ful work-related activities in the evening, producing a and negative conditioning (see later), pharmacotherapy
state incompatible with sleep onset. In preference to and/or psychotherapy for mood/anxiety disorders, and
hypnotic medications, patients should be counseled to an emphasis on maintenance of good sleep hygiene.
avoid stressful activities before bed, develop a soporic If insomnia persists after treatment of these contrib-
bedtime ritual, and prepare and reserve the bedroom uting factors, empirical pharmacotherapy is often used
environment for sleeping. Consistent, regular bedtimes on a nightly or intermittent basis. A variety of sedative
and rising times should be maintained daily, including compounds are used for this purpose. Alcohol and anti-
weekends. histamines are the most commonly used nonprescrip-
tion sleep aids. The former may help with sleep onset
but is associated with sleep disruption during the night
PRIMARY INSOMNIA
and can escalate into abuse, dependence, and with-
Many patients with chronic insomnia have no clear, drawal in the predisposed individual. Antihistamines,
single identiable underlying cause for their difcul- which are the primary active ingredient in most over-
ties with sleep. Rather, such patients often have mul- the-counter sleep aids, may be of benet when used
tiple etiologies for their insomnia, which may evolve intermittently but often produce rapid tolerance and
over the years. In addition, the chief sleep complaint may have multiple side effects (especially anticholiner-
may change over time, with initial insomnia predomi- gic), which limit their use, particularly in the elderly.
nating at one point, and multiple awakenings or non- Benzodiazepine-receptor agonists are the most effec-
restorative sleep occurring at other times. Subsyndromal tive and well-tolerated class of medications for insom-
psychiatric disorders (e.g., anxiety and mood com- nia. The broad range of half-lives allows exibility in
plaints), negative conditioning to the sleep environment the duration of sedative action. The most commonly
164 prescribed agents in this family are zaleplon (520 mg), Rigorous attention should be paid to improving sleep
with a half-life of 12 h; zolpidem (510 mg) and tri- hygiene, correction of counterproductive, arousing
azolam (0.1250.25 mg), with half-lives of 23 h; behaviors before bedtime, and minimizing exaggerated
eszopiclone (13 mg), with a half-life of 5.58 h; and beliefs regarding the negative consequences of insom-
temazepam (1530 mg) and lorazepam (0.52 mg), nia. Behavioral therapies are the treatment modality of
with half-lives of 612 h. Generally, side effects are choice, with intermittent use of medications. When
minimal when the dose is kept low and the serum con- patients are awake for >20 min, they should read or
centration is minimized during the waking hours (by perform other relaxing activities to distract themselves
using the shortest-acting effective agent). At least one from insomnia-related anxiety. In addition, bedtime and
SECTION II
benzodiazepine receptor agonist (eszopiclone) contin- wake time should be scheduled to restrict time in bed
ues to be effective for 6 months of nightly use. How- to be equal to their perceived total sleep time. This will
ever, longer durations of use have not been evaluated, generally produce sleep deprivation, greater sleep drive,
and it is unclear whether this is true of other agents in and, eventually, better sleep. Time in bed can then be
this class. Moreover, with even brief continuous use gradually expanded. In addition, methods directed
of benzodiazepine receptor agonists, rebound insom- toward producing relaxation in the sleep setting (e.g.,
nia can occur upon discontinuation. The likelihood of meditation, muscle relaxation) are encouraged.
Clinical Manifestations of Neurologic Disease
CHAPTER 20
continuity. disorders
In mania and hypomania, sleep latency is increased
and total sleep time can be reduced. Patients with anxi- A number of medical conditions are associated with
ety disorders tend not to show the changes in REM sleep disruptions of sleep. The association is frequently non-
and slow-wave sleep seen in endogenously depressed specic, e.g., sleep disruption due to chronic pain from
patients. Chronic alcoholics lack slow-wave sleep, have rheumatologic disorders. Attention to this association is
decreased amounts of REM sleep (as an acute response important in that sleep-associated symptoms are often
Sleep Disorders
to alcohol), and have frequent arousals throughout the the presenting or most bothersome complaint. Treat-
night. This is associated with impaired daytime alert- ment of the underlying medical problem is the most
ness. The sleep of chronic alcoholics may remain dis- useful approach. Sleep disruption can also result from
turbed for years after discontinuance of alcohol usage. the use of medications such as glucocorticoids (see
Sleep architecture and physiology are disturbed in later).
schizophrenia, with a decreased amount of slow-wave One prominent association is between sleep disrup-
sleep (NREM stage N3 sleep) and a lack of augmenta- tion and asthma. In many asthmatics there is a promi-
tion of REM sleep following REM sleep deprivation; nent daily variation in airway resistance that results in
chronic schizophrenics often show day-night reversal, marked increases in asthmatic symptoms at night, espe-
sleep fragmentation, and insomnia. cially during sleep. In addition, treatment of asthma
with theophylline-based compounds, adrenergic ago-
nists, or glucocorticoids can independently disrupt
sleep. When sleep disruption is a side effect of asthma
Insomnia associated with neurologic disorders treatment, inhaled glucocorticoids (e.g., beclometha-
A variety of neurologic diseases result in sleep disrup- sone) that do not disrupt sleep may provide a useful
tion through both indirect, nonspecic mechanisms alternative.
(e.g., pain in cervical spondylosis or low back pain) or Cardiac ischemia may also be associated with sleep dis-
by impairment of central neural structures involved in ruption. The ischemia itself may result from increases in
the generation and control of sleep itself. For exam- sympathetic tone as a result of sleep apnea. Patients may
ple, dementia from any cause has long been associ- present with complaints of nightmares or vivid, dis-
ated with disturbances in the timing of the sleep-wake turbing dreams, with or without awareness of the more
cycle, often characterized by nocturnal wandering and classic symptoms of angina or of the sleep-disordered
an exacerbation of symptomatology at night (so-called breathing. Treatment of the sleep apnea may substan-
sundowning). tially improve the angina and the nocturnal sleep qual-
Epilepsy may rarely present as a sleep complaint ity. Paroxysmal nocturnal dyspnea can also occur as a con-
(Chap. 26). Often the history is of abnormal behavior, sequence of sleep-associated cardiac ischemia that causes
at times with convulsive movements during sleep. The pulmonary congestion exacerbated by the recumbent
differential diagnosis includes REM sleep behavior dis- posture.
order, sleep apnea syndrome, and periodic movements Chronic obstructive pulmonary disease is also associated
of sleep (see earlier in this chapter). Diagnosis requires with sleep disruption, as are cystic brosis, menopause,
nocturnal polysomnography with a full EEG montage. hyperthyroidism, gastroesophageal reux, chronic renal failure,
Other neurologic diseases associated with abnormal and liver failure.
movements, such as Parkinsons disease, hemiballismus,
Huntingtons chorea, and Tourettes syndrome (Chap. 30),
are also associated with disrupted sleep, presumably
MEDICATION-, DRUG-, OR ALCOHOL-
through secondary mechanisms. However, the abnor-
DEPENDENT INSOMNIA
mal movements themselves are greatly reduced during
sleep. Headache syndromes (migraine or cluster headache) Disturbed sleep can result from ingestion of a wide
may show sleep-associated exacerbations (Chap. 8) by variety of agents. Caffeine is perhaps the most com-
unknown mechanisms. mon pharmacologic cause of insomnia. It produces
166 increased latency to sleep onset, more frequent arousals q8PM), which are the treatments of choice. Opioids,
during sleep, and a reduction in total sleep time for up benzodiazepines, and gabapentin may also be of thera-
to 814 h after ingestion. Even small amounts of coffee peutic value. Most patients with restless legs also expe-
can signicantly disturb sleep in some patients; there- rience periodic limb movements of sleep, although the
fore, a 1- to 2-month trial without caffeine should be reverse is not the case.
attempted in patients with these symptoms. Similarly,
alcohol and nicotine can interfere with sleep, despite
the fact that many patients use them to relax and pro- PERIODIC LIMB MOVEMENT DISORDER
mote sleep. Although alcohol can increase drowsiness (PLMD)
SECTION II
and shorten sleep latency, even moderate amounts of Periodic limb movements of sleep (PLMS), previously
alcohol increase awakenings in the second half of the known as nocturnal myoclonus, consists of stereotyped,
night. In addition, alcohol ingestion prior to sleep is 0.5- to 5.0-s extensions of the great toe and dorsi-
contraindicated in patients with sleep apnea because of exion of the foot, which recur every 2040 s dur-
the inhibitory effects of alcohol on upper airway mus- ing NREM sleep, in episodes lasting from minutes
cle tone. Acutely, amphetamines and cocaine suppress to hours, as documented by bilateral surface EMG
both REM sleep and total sleep time, which return to
Clinical Manifestations of Neurologic Disease
Respiratory effort
98 97 97 98 97 97 98 98 98
Arterial O2 saturation 94 93 95 96 95 95 94 95 93
93 92 92
90 89 91 90 92 90 88 90
86
A 30 s
CHAPTER 20
EEG
Chin EMG
Heart Rate
RAT EMG
Sleep Disorders
LAT EMG
B 30 s
FIGURE 20-3
Polysomnographic recordings of (A) obstructive sleep with a relatively constant intermovement interval and are
apnea and (B) periodic limb movement of sleep. Note the associated with changes in the EEG and heart rate accelera-
snoring and reduction in air ow in the presence of continued tion (lower panel). RAT, right anterior tibialis; LAT, left anterior
respiratory effort, associated with the subsequent oxygen tibialis. (From the Division of Sleep Medicine, Brigham and
desaturation (upper panel). Periodic limb movements occur Womens Hospital.)
viewed pejoratively, ascribed more often to a decit in several other states. Screening for sleep disorders, pro-
in motivation than to an inadequately addressed physi- vision of an adequate number of safe highway rest areas,
ologic sleep need. maintenance of unobstructed shoulder rumble strips, and
Specic questioning about the occurrence of sleep strict enforcement and compliance monitoring of hours-
episodes during normal waking hours, both intentional of-service policies are needed to reduce the risk of sleep-
and unintentional, is necessary to determine the extent related transportation crashes. Evidence for signicant
of the adverse effects of sleepiness on a patients day- daytime impairment in association either with the diag-
time function. Specic areas to be addressed include the nosis of a primary sleep disorder, such as narcolepsy or
occurrence of inadvertent sleep episodes while driving or sleep apnea, or with imposed or self-selected sleep-wake
in other safety-related settings, sleepiness while at work schedules (see Shift-Work Disorder) raises the issue
or school (and the relationship of sleepiness to work of the physicians responsibility to notify motor vehicle
and school performance), and the effect of sleepiness on licensing authorities of the increased risk of sleepiness-
social and family life. Standardized questionnaires, e.g., related motor vehicle crashes. As with epilepsy, legal
the Epworth Sleepiness Scale, are now commonly used requirements vary from state to state, and existing legal
in clinical and research settings to quantify daytime sleep precedents do not provide a consistent interpretation of
tendency and screen for excessive sleepiness. the balance between the physicians responsibility and
Driving is particularly hazardous for patients with the patients right to privacy. At a minimum, physicians
increased sleepiness. Reaction time is equally impaired should inform patients who report a history of nodding
by 24 h of sleep loss as by a blood alcohol level of off or falling asleep at the wheel or who have excessive
0.10 g/dL. More than half of Americans admit to having daytime sleepiness about the increased risk of operat-
fallen asleep while driving. An estimated 250,000 motor ing a motor vehicle, advise such patients not to drive a
vehicle crashes per year are due to drowsy drivers, caus- motor vehicle until the cause of the excessive sleepiness
ing about 20% of all serious crash injuries and deaths. has been diagnosed and successful treatment has been
Drowsy driving legislation, aimed at improving educa- implemented, and reevaluate the patient to determine
tion of all drivers about the hazards of driving drowsy when it is safe for the patient to resume driving. Each of
and establishing sanctions comparable to those for drunk those steps should be documented in the patients medi-
driving, has been enacted in New Jersey and is pending cal record.
168 The distinction between fatigue and sleepiness can be between wakefulness and sleep: (1) sudden weakness or
useful in the differentiation of patients with complaints loss of muscle tone without loss of consciousness, often
of fatigue or tiredness in the setting of disorders such as elicited by emotion (cataplexy); (2) hallucinations at
bromyalgia, chronic fatigue syndrome (Chap. 52), or sleep onset (hypnagogic hallucinations) or upon awak-
endocrine deciencies such as hypothyroidism or Addi- ening (hypnopompic hallucinations); and (3) muscle
sons disease. While patients with these disorders can paralysis upon awakening (sleep paralysis). The sever-
typically distinguish their daytime symptoms from the ity of cataplexy varies, as patients may have two to
sleepiness that occurs with sleep deprivation, substan- three attacks per day or per decade. Some patients with
tial overlap can occur. This is particularly true when the objectively conrmed narcolepsy (see later) may show
SECTION II
primary disorder also results in chronic sleep disruption no evidence of cataplexy. In those with cataplexy, the
(e.g., sleep apnea in hypothyroidism) or in abnormal extent and duration of an attack may also vary, from
sleep (e.g., bromyalgia). a transient sagging of the jaw lasting a few seconds to
While clinical evaluation of the complaint of exces- rare cases of accid paralysis of the entire voluntary
sive sleepiness is usually adequate, objective quanti- musculature for up to 2030 min. Symptoms of narco-
cation is sometimes necessary. Assessment of daytime lepsy typically begin in the second decade, although the
functioning as an index of the adequacy of sleep can onset ranges from ages 550 years. Once established,
Clinical Manifestations of Neurologic Disease
be made with the multiple sleep latency test (MSLT), the disease is chronic without remissions. Secondary
which utilizes repeated measurement of sleep latency forms of narcolepsy have been described (e.g., after
(time to onset of sleep) under standardized conditions head trauma).
during a day following quantied nocturnal sleep. The Narcolepsy affects about 1 in 4000 people in the
average latency across four to six tests (administered United States and appears to have a genetic basis.
every 2 h across the waking day) provides an objec- Recently, several convergent lines of evidence sug-
tive measure of daytime sleep tendency. Disorders of gest that the hypothalamic neuropeptide hypocretin
sleep that result in pathologic daytime somnolence can (orexin) is involved in the pathogenesis of narcolepsy:
be reliably distinguished with the MSLT. In addition, (1) a mutation in the hypocretin receptor 2 gene has
the multiple measurements of sleep onset may identify been associated with canine narcolepsy; (2) hypocretin
direct transitions from wakefulness to REM sleep that knockout mice that are genetically unable to produce
are suggestive of specic pathologic conditions (e.g., this neuropeptide exhibit behavioral and electrophysi-
narcolepsy). ologic features resembling human narcolepsy; and (3)
cerebrospinal uid levels of hypocretin are reduced in
most patients who have narcolepsy with cataplexy. The
NARCOLEPSY inheritance pattern of narcolepsy in humans is more
complex than in the canine model. However, almost
Narcolepsy is both a disorder of the ability to sus- all narcoleptics with cataplexy are positive for HLA
tain wakefulness voluntarily and a disorder of REM DQB1*0602, suggesting that an autoimmune process
sleep regulation (Table 20-2). The classic nar- may be responsible.
colepsy tetrad consists of excessive daytime som-
nolence plus three specic symptoms related to an
intrusion of REM sleep characteristics (e.g., mus-
cle atonia, vivid dream imagery) into the transition Diagnosis
The diagnostic criteria continue to be a matter of
debate. Certainly, objective verication of exces-
TABLE 20-2
sive daytime somnolence, typically with MSLT mean
PREVALENCE OF SYMPTOMS IN NARCOLEPSY sleep latencies <8 min, is an essential if nonspecic
SYMPTOM PREVALENCE, % diagnostic feature. Other conditions that cause exces-
Excessive daytime somnolence 100
sive sleepiness, such as sleep apnea or chronic sleep
deprivation, must be rigorously excluded. The other
Disturbed sleep 87
objective diagnostic feature of narcolepsy is the pres-
Cataplexy 76 ence of REM sleep in at least two of the naps during
Hypnagogic hallucinations 68 the MSLT. Abnormal regulation of REM sleep is also
Sleep paralysis 64 manifested by the appearance of REM sleep imme-
diately or within minutes after sleep onset in 50% of
Memory problems 50
narcoleptic patients, a rarity in unaffected individuals
Source: Modied from TA Roth, L Merlotti, in SA Burton et al (eds):
maintaining a conventional sleep-wake schedule. The
Narcolepsy 3rd International Symposium: Selected Symposium Pro- REM-related symptoms of the classic narcolepsy tetrad
ceedings. Chicago, Matrix Communications, 1989. are variably present. There is increasing evidence that
narcoleptics with cataplexy (one-half to two-thirds of episodes may be due to either an occlusion of the air- 169
patients) may represent a more homogeneous group way (obstructive sleep apnea), absence of respiratory effort
than those without this symptom. However, a history (central sleep apnea), or a combination of these factors
of cataplexy can be difcult to establish reliably. Hyp- (mixed sleep apnea) (Fig. 20-3). Failure to recognize and
nagogic and hypnopompic hallucinations and sleep treat these conditions appropriately may lead to impair-
paralysis are often found in nonnarcoleptic individuals ment of daytime alertness, increased risk of sleep-
and may be present in only one-half of narcoleptics. related motor vehicle accidents, hypertension and other
Nocturnal sleep disruption is commonly observed in serious cardiovascular complications, and increased
narcolepsy but is also a nonspecic symptom. Simi- mortality. Sleep apnea is particularly prevalent in over-
CHAPTER 20
larly, a history of automatic behavior during wake- weight men and in the elderly, yet it is estimated to
fulness (a trancelike state during which simple motor remain undiagnosed in 8090% of affected individu-
behaviors persist) is not specic for narcolepsy and als. This is unfortunate since effective treatments are
serves principally to corroborate the presence of day- available.
time somnolence.
Sleep Disorders
PARASOMNIAS
TREATMENT Narcolepsy
The term parasomnia refers to abnormal behaviors or
The treatment of narcolepsy is symptomatic. Somno- experiences that arise from or occur during sleep. A
lence is treated with wake-promoting therapeutics. continuum of parasomnias arise from NREM sleep,
Modafinil is now the drug of choice, principally because from brief confusional arousals to sleepwalking and
it is associated with fewer side effects than older stimu- night terrors. The presenting complaint is usually
lants and has a long half-life; 200400 mg is given as a related to the behavior itself, but the parasomnias can
single daily dose. Older drugs such as methylphenidate disturb sleep continuity or lead to mild impairments
(10 mg bid to 20 mg qid) or dextroamphetamine (10 mg in daytime alertness. Two main parasomnias occur in
bid) are still used as alternatives, particularly in refrac- REM sleep: REM sleep behavior disorder (RBD),
tory patients. which will be described later in this chapter, and
These latter medications are now available in slow- nightmare disorder.
release formulations, extending their duration of action
and allowing once-daily dosing.
Treatment of the REM-related phenomena of cata- Sleepwalking (somnambulism)
plexy, hypnagogic hallucinations, and sleep paralysis Patients affected by this disorder carry out automatic
requires the potent REM sleep suppression produced motor activities that range from simple to complex.
by antidepressant medications. The tricyclic antide- Individuals may walk, urinate inappropriately, eat,
pressants (e.g., protriptyline [1040 mg/d] and clomip- or exit from the house while remaining only partially
ramine [2550 mg/d]) and the selective serotonin reup- aware. Full arousal may be difcult, and individuals may
take inhibitors (SSRIs) (e.g., fluoxetine [1020 mg/d]) are rarely respond to attempted awakening with agitation
commonly used for this purpose. Efficacy of the anti- or even violence. Sleepwalking arises from slow-wave
depressants is limited largely by anticholinergic side sleep (NREM stage N3 sleep), usually in the rst 2 h of
effects (tricyclics) and by sleep disturbance and sexual the night, and is most common in children and adoles-
dysfunction (SSRIs). Alternately, gamma hydroxybutyr- cents, when these sleep stages are most robust. Episodes
ate (GHB), given at bedtime, and 4 h later, is effective in are usually isolated but may be recurrent in 16% of
reducing daytime cataplectic episodes. Adequate noc- patients. The cause is unknown, though it has a familial
turnal sleep time and planned daytime naps (when pos- basis in roughly one-third of cases.
sible) are important preventive measures.
Sleep terrors
This disorder, also called pavor nocturnus, occurs pri-
SLEEP APNEA SYNDROMES
marily in young children during the rst several hours
Respiratory dysfunction during sleep is a common, after sleep onset, in slow-wave sleep (NREM stage N3
serious cause of excessive daytime somnolence as well sleep). The child suddenly screams, exhibiting auto-
as of disturbed nocturnal sleep. An estimated 25 nomic arousal with sweating, tachycardia, and hyper-
million individuals in the United States have a reduc- ventilation. The individual may be difcult to arouse
tion or cessation of breathing for 10150 s from 30 to and rarely recalls the episode on awakening in the
several hundred times every night during sleep. These morning. Parents are usually reassured to learn that the
170 condition is self-limited and benign and that no specic REM sleep behavior disorder (RBD)
therapy is indicated. Both sleep terrors and sleepwalking
represent abnormalities of arousal. In contrast, nightmares RBD is a rare condition that is distinct from other para-
occur during REM sleep and cause full arousal, with somnias in that it occurs during REM sleep. It primarily
intact memory for the unpleasant episode. aficts men of middle age or older, many of whom have
an existing, or developing, neurologic disease. Approxi-
mately one-half of patients with RBD will develop
Sleep bruxism Parkinsons disease (Chap. 30) within 1020 years. Pre-
Bruxism is an involuntary, forceful grinding of teeth senting symptoms consist of agitated or violent behav-
during sleep that affects 1020% of the population. The ior during sleep, as reported by a bed partner. In con-
SECTION II
patient is usually unaware of the problem. The typical trast to typical somnambulism, injury to the patient or
age of onset is 1720 years, and spontaneous remission bed partner is not uncommon, and, upon awakening,
usually occurs by age 40. Sex distribution appears to be the patient reports vivid, often unpleasant, dream imag-
equal. In many cases, the diagnosis is made during den- ery. The principal differential diagnosis is nocturnal sei-
tal examination, damage is minor, and no treatment is zures, which can be excluded with polysomnography.
indicated. In more severe cases, treatment with a rub- In RBD, seizure activity is absent on the EEG, and dis-
Clinical Manifestations of Neurologic Disease
ber tooth guard is necessary to prevent disguring tooth inhibition of the usual motor atonia is observed in the
injury. Stress management or, in some cases, biofeed- EMG during REM sleep, at times associated with com-
back can be useful when bruxism is a manifestation of plex motor behaviors. The pathogenesis is unclear, but
psychological stress. There are anecdotal reports of ben- damage to brainstem areas mediating descending motor
et using benzodiazepines. inhibition during REM sleep may be responsible. In
support of this hypothesis are the remarkable similarities
between RBD and the sleep of animals with bilateral
Sleep enuresis lesions of the pontine tegmentum in areas controlling
Bedwetting, like sleepwalking and night terrors, is REM sleep motor inhibition. Treatment with clonaz-
another parasomnia that occurs during sleep in the epam (0.51.0 mg qhs) provides sustained improvement
young. Before age 5 or 6 years, nocturnal enure- in almost all reported cases.
sis should probably be considered a normal feature of
development. The condition usually improves sponta-
neously by puberty, has a prevalence in late adolescence
CIRCADIAN RHYTHM SLEEP
of 13%, and is rare in adulthood. In older patients with
enuresis, a distinction must be made between primary
DISORDERS
and secondary enuresis, the latter being dened as bed- A subset of patients presenting with either insomnia or
wetting in patients who have previously been fully con- hypersomnia may have a disorder of sleep timing rather
tinent for 612 months. Treatment of primary enuresis than sleep generation. Disorders of sleep timing can be
is reserved for patients of appropriate age (>5 or 6 years) either organic (i.e., due to an abnormality of circadian
and consists of bladder training exercises and behav- pacemaker[s] or its input from entraining stimuli) or
ioral therapy. Urologic abnormalities are more common environmental (i.e., due to a disruption of exposure to
in primary enuresis and must be assessed by urologic entraining stimuli from the environment). Regardless
examination. Important causes of secondary enuresis of etiology, the symptoms reect the inuence of the
include emotional disturbances, urinary tract infections underlying circadian pacemaker on sleep-wake func-
or malformations, cauda equina lesions, epilepsy, sleep tion. Thus, effective therapeutic approaches should aim
apnea, and certain medications. Symptomatic pharma- to entrain the oscillator at an appropriate phase.
cotherapy is usually accomplished with desmopressin
(0.2 mg qhs), oxybutynin chloride (510 mg qhs), or
imipramine (1050 mg qhs). Jet lag disorder
More than 60 million persons experience transmeridian
air travel annually, which is often associated with exces-
Miscellaneous parasomnias
sive daytime sleepiness, sleep onset insomnia, and fre-
Other clinical entities may be characterized as a para- quent arousals from sleep, particularly in the latter half of
somnia or a sleep-related movement disorder in that the night. Gastrointestinal discomfort is common. The
they occur selectively during sleep and are associated syndrome is transient, typically lasting 214 d depend-
with some degree of sleep disruption. Examples include ing on the number of time zones crossed, the direction
jactatio capitis nocturna (nocturnal headbanging, rhythmic of travel, and the travelers age and phase-shifting capac-
movement disorder), confusional arousals, sleep-related ity. Travelers who spend more time outdoors report-
eating disorder, and nocturnal leg cramps. edly adapt more quickly than those who remain in hotel
rooms, presumably due to brighter (outdoor) light expo- lapses of consciousness. The sleepy individual may thus 171
sure. Avoidance of antecedent sleep loss and obtain- attempt to perform routine and familiar motor tasks
ing nap sleep on the afternoon prior to overnight travel during the transition state between wakefulness and
greatly reduce the difculty of extended wakefulness. sleep (stage N1 sleep) in the absence of adequate pro-
Laboratory studies suggest that sub milligram doses of the cessing of sensory input from the environment. Motor
pineal hormone melatonin can enhance sleep efciency, vehicle operators are especially vulnerable to sleep-
but only if taken when endogenous melatonin concen- related accidents since the sleep-deprived driver or
trations are low (i.e., during biologic daytime), and that operator often fails to heed the warning signs of fatigue.
melatonin may induce phase shifts in human rhythms. A Such attempts to override the powerful biologic drive
CHAPTER 20
large-scale clinical trial evaluating the safety and efcacy for sleep by the sheer force of will can yield a cata-
of melatonin as a treatment for jet lag disorder and other strophic outcome when sleep processes intrude involun-
circadian sleep disorders is needed. tarily upon the waking brain. Such sleep-related atten-
In addition to jet lag associated with travel across tional failures typically last only seconds but are known
time zones, many patients report a behavioral pattern on occasion to persist for longer durations. These fre-
that has been termed social jet lag, in which their bed- quent brief intrusions of stage N1 sleep into behavioral
times and wake times on weekends or days off occur wakefulness are a major component of the impaired
Sleep Disorders
48 h later than they do during the week. This recur- psychomotor performance seen with sleepiness. There is
rent displacement of the timing of the sleep-wake cycle a signicant increase in the risk of sleep-related, fatal-
is common in adolescents and young adults and is asso- to-the-driver highway crashes in the early morning and
ciated with sleep onset insomnia, poorer academic per- late afternoon hours, coincident with bimodal peaks in
formance, increased risk of depressive symptoms, and the daily rhythm of sleep tendency.
excessive daytime sleepiness. Resident physicians constitute another group of
workers at risk for accidents and other adverse conse-
quences of lack of sleep and misalignment of the circa-
Shift-work disorder
dian rhythm. Recurrent scheduling of resident physi-
More than 7 million workers in the United States regu- cians to work shifts of 24 h or more consecutive hours
larly work at night, either on a permanent or rotating impairs psychomotor performance to a degree that is
schedule. Many more begin work between 4 A.M. and comparable to alcohol intoxication, doubles the risk of
7 A.M., requiring them to commute and then work dur- attentional failures among intensive care unit interns
ing the time of day that they would otherwise be asleep. working at night, and signicantly increases the risk of
In addition, each week millions more elect to remain serious medical errors in intensive care units, includ-
awake at night to meet deadlines, drive long distances, ing a vefold increase in the risk of serious diagnostic
or participate in recreational activities. This results mistakes. Some 20% of hospital interns report making
in both sleep loss and misalignment of the circadian a fatigue-related mistake that injured a patient, and 5%
rhythm with respect to the sleep-wake cycle. admit making a fatigue-related mistake that results in
Studies of regular night-shift workers indicate that the death of a patient. Moreover, working for >24 h
the circadian timing system usually fails to adapt suc- consecutively increases the risk of percutaneous inju-
cessfully to such inverted schedules. This leads to a mis- ries and more than doubles the risk of motor vehicle
alignment between the desired work-rest schedule and crashes on the commute home. For these reasons, in
the output of the pacemaker and in disturbed daytime 2008 the Institute of Medicine concluded that the
sleep in most individuals. Sleep deprivation, increased practice of scheduling resident physicians to work for
length of time awake prior to work, and misalignment more than 16 consecutive hours without sleep is haz-
of circadian phase produce decreased alertness and per- ardous for both resident physicians and their patients.
formance, increased reaction time, and increased risk of From 5 to 10% of individuals scheduled to work at
performance lapses, thereby resulting in greater safety night or in the early morning hours have much greater
hazards among night workers and other sleep-deprived than average difculties remaining awake during night
individuals. Sleep disturbance nearly doubles the risk work and sleeping during the day; these individuals are
of a fatal work accident. Additional problems include diagnosed with chronic and severe shift-work disor-
higher rates of breast, colorectal, and prostate cancer der (SWD). Patients with this disorder have a level of
and of cardiac, gastrointestinal, and reproductive dis- excessive sleepiness during night work and insomnia
orders in long-term night-shift workers. Recently, the during day sleep that the physician judges to be clini-
World Health Organization has added night-shift work cally signicant; the condition is associated with an
to its list of probable carcinogens. increased risk of sleep-related accidents and with some
Sleep onset is associated with marked attenuation of the illnesses associated with night-shift work. Patients
in perception of both auditory and visual stimuli and with chronic and severe SWD are profoundly sleepy at
172 night. In fact, their sleep latencies during night work circadian phase, with the temperature minimum dur-
average just 2 min, comparable to mean sleep latency ing the constant routine occurring later than normal.
durations of patients with narcolepsy or severe daytime This delayed phase could be due to (1) an abnormally
sleep apnea. long, genetically determined intrinsic period of the
endogenous circadian pacemaker; (2) an abnormally
reduced phase-advancing capacity of the pacemaker;
TREATMENT Shift-Work Disorder (3) a slower rate of buildup of homeostatic sleep drive
during wakefulness; or (4) an irregular prior sleep-wake
Caffeine is frequently used to promote wakefulness. schedule, characterized by frequent nights when the
SECTION II
However, it cannot forestall sleep indefinitely, and it patient chooses to remain awake well past midnight (for
does not shield users from sleep-related performance social, school, or work reasons). In most cases, it is dif-
lapses. Postural changes, exercise, and strategic place- cult to distinguish among these factors, since patients
ment of nap opportunities can sometimes temporarily with an abnormally long intrinsic period are more likely
reduce the risk of fatigue-related performance lapses. to choose such late-night activities because they are
Properly timed exposure to bright light can facilitate unable to sleep at that time. Patients tend to be young
adults. This self-perpetuating condition can persist for
Clinical Manifestations of Neurologic Disease
CHAPTER 20
the endogenous circadian rhythms are in phase with improve the understanding of its pathophysiology.
the local environment, symptoms remit. The inter- Diagnostic and therapeutic procedures may also be
vals between symptomatic periods may last several affected by the time of day at which data are collected.
weeks to several months. Blind individuals unable to Examples include blood pressure, body temperature,
perceive light are particularly susceptible to this disor- the dexamethasone suppression test, and plasma corti-
der, although it can occur in sighted patients. Nightly sol levels. The timing of chemotherapy administration
low-dose (0.5 mg) melatonin administration has been has been reported to have an effect on the outcome of
Sleep Disorders
reported to improve sleep and, in some cases, to induce treatment. In addition, both the toxicity and effective-
synchronization of the circadian pacemaker. ness of drugs can vary during the day. For example,
more than a vefold difference has been observed in
mortality rates following administration of toxic agents
MEDICAL IMPLICATIONS OF CIRCADIAN
to experimental animals at different times of day. Anes-
RHYTHMICITY
thetic agents are particularly sensitive to time-of-day
Prominent circadian variations have been reported in effects. Finally, the physician must be increasingly aware
the incidence of acute myocardial infarction, sudden of the public health risks associated with the ever-
cardiac death, and stroke, the leading causes of death increasing demands made by the duty-rest-recreation
in the United States. Platelet aggregability is increased schedules in our round-the-clock society.
CHAPTER 21
DISORDERS OF VISION
Jonathan C. Horton
THE HUMAN VISUAL SYSTEM optic chiasm, and optic tract to reach targets in the
brain. The majority of bers synapse on cells in the
The visual system provides a supremely efcient means lateral geniculate body, a thalamic relay station. Cells
for the rapid assimilation of information from the in the lateral geniculate body project in turn to the
environment to aid in the guidance of behavior. The primary visual cortex. This massive afferent retino-
act of seeing begins with the capture of images focused geniculocortical sensory pathway provides the neural
by the cornea and lens on a light-sensitive membrane substrate for visual perception. Although the lat-
in the back of the eye called the retina. The retina is eral geniculate body is the main target of the retina,
actually part of the brain, banished to the periphery to separate classes of ganglion cells project to other sub-
serve as a transducer for the conversion of patterns of cortical visual nuclei involved in different functions.
light energy into neuronal signals. Light is absorbed Ganglion cells that mediate pupillary constriction and
by photopigment in two types of receptors: rods and circadian rhythms are light sensitive owing to a novel
cones. In the human retina there are 100 million rods visual pigment, melanopsin. Pupil responses are medi-
and 5 million cones. The rods operate in dim (scoto- ated by input to the pretectal olivary nuclei in the
pic) illumination. The cones function under daylight midbrain. The pretectal nuclei send their output to
(photopic) conditions. The cone system is specialized the Edinger-Westphal nuclei, which in turn provide
for color perception and high spatial resolution. The parasympathetic innervation to the iris sphincter via an
majority of cones are within the macula, the portion interneuron in the ciliary ganglion. Circadian rhythms
of the retina that serves the central 10 of vision. In are timed by a retinal projection to the suprachiasmatic
the middle of the macula a small pit termed the fovea, nucleus. Visual orientation and eye movements are
packed exclusively with cones, provides the best visual served by retinal input to the superior colliculus. Gaze
acuity. stabilization and optokinetic reexes are governed by a
Photoreceptors hyperpolarize in response to light, group of small retinal targets known collectively as the
activating bipolar, amacrine, and horizontal cells in the brainstem accessory optic system.
inner nuclear layer. After processing of photorecep- The eyes must be rotated constantly within their
tor responses by this complex retinal circuit, the ow orbits to place and maintain targets of visual interest on
of sensory information ultimately converges on a nal the fovea. This activity, called foveation, or looking, is
common pathway: the ganglion cells. These cells trans- governed by an elaborate efferent motor system. Each
late the visual image impinging on the retina into a eye is moved by six extraocular muscles that are sup-
continuously varying barrage of action potentials that plied by cranial nerves from the oculomotor (III),
propagates along the primary optic pathway to visual trochlear (IV), and abducens (VI) nuclei. Activity in
centers within the brain. There are a million ganglion these ocular motor nuclei is coordinated by pontine and
cells in each retina and hence a million bers in each midbrain mechanisms for smooth pursuit, saccades, and
optic nerve. gaze stabilization during head and body movements.
Ganglion cell axons sweep along the inner surface Large regions of the frontal and parietooccipital cortex
of the retina in the nerve ber layer, exit the eye at control these brainstem eye movement centers by pro-
the optic disc, and travel through the optic nerve, viding descending supranuclear input.
174
CLINICAL ASSESSMENT OF VISUAL 175
FUNCTION
REFRACTIVE STATE
In approaching a patient with reduced vision, the rst
step is to decide whether refractive error is responsible.
In emmetropia, parallel rays from innity are focused per-
fectly on the retina. Sadly, this condition is enjoyed by
CHAPTER 21
only a minority of the population. In myopia, the globe
is too long, and light rays come to a focal point in front
of the retina. Near objects can be seen clearly, but dis-
tant objects require a diverging lens in front of the eye.
In hyperopia, the globe is too short, and hence a con-
verging lens is used to supplement the refractive power
of the eye. In astigmatism, the corneal surface is not per-
Disorders of Vision
fectly spherical, necessitating a cylindrical corrective
lens. In recent years it has become possible to correct
refractive error with the excimer laser by performing
LASIK (laser in situ keratomileusis) to alter the curva-
ture of the cornea.
With the onset of middle age, presbyopia develops as
the lens within the eye becomes unable to increase its
refractive power to accommodate on near objects. To
compensate for presbyopia, an emmetropic patient must
use reading glasses. A patient already wearing glasses
for distance correction usually switches to bifocals. The
only exception is a myopic patient, who may achieve
clear vision at near simply by removing glasses contain-
ing the distance prescription.
Refractive errors usually develop slowly and remain
stable after adolescence, except in unusual circum-
stances. For example, the acute onset of diabetes mel-
litus can produce sudden myopia because of lens edema
induced by hyperglycemia. Testing vision through a
pinhole aperture is a useful way to screen quickly for
refractive error. If visual acuity is better through a pin-
hole than it is with the unaided eye, the patient needs FIGURE 21-1
refraction to obtain best corrected visual acuity. The Rosenbaum card is a miniature, scale version of the
Snellen chart for testing visual acuity at near. When the
visual acuity is recorded, the Snellen distance equivalent
should bear a notation indicating that vision was tested at
VISUAL ACUITY near, not at 6 m (20 ft), or else the Jaeger number system
The Snellen chart is used to test acuity at a distance of should be used to report the acuity.
6 m (20 ft). For convenience, a scale version of the Snel-
len chart called the Rosenbaum card is held at 36 cm best corrected acuity of 6/60 (20/200) or less in the bet-
(14 in.) from the patient (Fig. 21-1). All subjects should ter eye or a binocular visual eld subtending 20 or less.
be able to read the 6/6 m (20/20 ft) line with each eye For driving the laws vary by state, but most states require
using their refractive correction, if any. Patients who need a corrected acuity of 6/12 (20/40) in at least one eye for
reading glasses because of presbyopia must wear them for unrestricted privileges. Patients with a homonymous hemi-
accurate testing with the Rosenbaum card. If 6/6 (20/20) anopia should not drive.
acuity is not present in each eye, the deciency in vision
must be explained. If it is worse than 6/240 (20/800), acu-
PUPILS
ity should be recorded in terms of counting ngers, hand
motions, light perception, or no light perception. Legal The pupils should be tested individually in dim light
blindness is dened by the Internal Revenue Service as a with the patient xating on a distant target. If the pupils
176 respond briskly to light, there is no need to check the
near response, because isolated loss of constriction
(miosis) to accommodation does not occur. For this
reason, the ubiquitous abbreviation PERRLA (pupils
equal, round, and reactive to light and accommodation)
implies a wasted effort with the last step. However, it is
important to test the near response if the light response
is poor or absent. Light-near dissociation occurs with
neurosyphilis (Argyll Robertson pupil), with lesions of
SECTION II
CHAPTER 21
angle-closure glaucoma, and iris sphincter rupture from ments cause congenital X-linked color blindness in
blunt trauma. 8% of males. Affected individuals are not truly color
blind; rather, they differ from normal subjects in the
way they perceive color and the way they combine
EYE MOVEMENTS AND ALIGNMENT primary monochromatic lights to match a particular
color. Anomalous trichromats have three cone types,
Eye movements are tested by asking the patient, with
but a mutation in one cone pigment (usually red or
Disorders of Vision
both eyes open, to pursue a small target such as a penlight
green) causes a shift in peak spectral sensitivity, altering
into the cardinal elds of gaze. Normal ocular versions
the proportion of primary colors required to achieve a
are smooth, symmetric, full, and maintained in all direc-
color match. Dichromats have only two cone types and
tions without nystagmus. Saccades, or quick rexation
therefore will accept a color match based on only two
eye movements, are assessed by having the patient look
primary colors. Anomalous trichromats and dichromats
back and forth between two stationary targets. The eyes
have 6/6 (20/20) visual acuity, but their hue discrimi-
should move rapidly and accurately in a single jump to
nation is impaired. Ishihara color plates can be used to
their target. Ocular alignment can be judged by holding
detect red-green color blindness. The test plates con-
a penlight directly in front of the patient at about 1 m.
tain a hidden number that is visible only to subjects
If the eyes are straight, the corneal light reex will be
with color confusion from red-green color blindness.
centered in the middle of each pupil. To test eye align-
Because color blindness is almost exclusively X-linked,
ment more precisely, the cover test is useful. The patient
it is worth screening only male children.
is instructed to gaze upon a small xation target in the
The Ishihara plates often are used to detect acquired
distance. One eye is covered suddenly while the second
defects in color vision, although they are intended as a
eye is observed. If the second eye shifts to xate on the
screening test for congenital color blindness. Acquired
target, it was misaligned. If it does not move, the rst eye
defects in color vision frequently result from disease
is uncovered and the test is repeated on the second eye.
of the macula or optic nerve. For example, patients
If neither eye moves, the eyes are aligned orthotropically.
with a history of optic neuritis often complain of color
If the eyes are orthotropic in primary gaze but the patient
desaturation long after their visual acuity has returned
complains of diplopia, the cover test should be performed
to normal. Color blindness also can result from bilat-
with the head tilted or turned in whatever direction elic-
eral strokes involving the ventral portion of the occipital
its diplopia. With practice the examiner can detect an
lobe (cerebral achromatopsia). Such patients can per-
ocular deviation (heterotropia) as small as 12 with the
ceive only shades of gray and also may have difculty
cover test. Deviations can be measured by placing prisms
recognizing faces (prosopagnosia). Infarcts of the domi-
in front of the misaligned eye to determine the power
nant occipital lobe sometimes give rise to color anomia.
required to neutralize the xation shift evoked by cover-
Affected patients can discriminate colors but cannot
ing the other eye.
name them.
FIGURE 21-3
Ventral view of the brain, correlating patterns of visual 30 by using a gray scale format. Areas of visual eld loss
eld loss with the sites of lesions in the visual pathway. are shown in black. The examples of common monocular,
The visual elds overlap partially, creating 120 of central bin- prechiasmal eld defects are all shown for the right eye. By
ocular eld anked by a 40 monocular crescent on either convention, the visual elds are always recorded with the left
side. The visual eld maps in this gure were done with a eyes eld on the left and the right eyes eld on the right, just
computer-driven perimeter (Humphrey Instruments, Carl as the patient sees the world.
Zeiss, Inc.). It plots the retinal sensitivity to light in the central
light thresholds, these static perimeters provide a sen- in an inferior-temporal eld cut. Damage to the macula
sitive means of detecting scotomas in the visual eld. causes a central scotoma (Fig. 21-3B).
They are exceedingly useful for serial assessment of Optic nerve disease produces characteristic patterns
visual function in chronic diseases such as glaucoma and of visual eld loss. Glaucoma selectively destroys axons
pseudotumor cerebri. that enter the superotemporal or inferotemporal poles
The crux of visual eld analysis is to decide whether of the optic disc, resulting in arcuate scotomas shaped
a lesion is before, at, or behind the optic chiasm. If a like a Turkish scimitar, which emanate from the blind
scotoma is conned to one eye, it must be due to a spot and curve around xation to end at against the
lesion anterior to the chiasm, involving either the optic horizontal meridian (Fig. 21-3C). This type of eld
nerve or the retina. Retinal lesions produce scotomas defect mirrors the arrangement of the nerve ber layer
that correspond optically to their location in the fundus. in the temporal retina. Arcuate or nerve ber layer sco-
For example, a superior-nasal retinal detachment results tomas also result from optic neuritis, ischemic optic
neuropathy, optic disc drusen, and branch retinal artery inferior quadrantic homonymous hemianopia (Fig. 179
or vein occlusion. 21-3K). Lesions of the primary visual cortex give rise to
Damage to the entire upper or lower pole of the dense, congruous hemianopic eld defects. Occlusion
optic disc causes an altitudinal eld cut that follows the of the posterior cerebral artery supplying the occipital
horizontal meridian (Fig. 21-3D). This pattern of visual lobe is a common cause of total homonymous hemi-
eld loss is typical of ischemic optic neuropathy but also anopia. Some patients with hemianopia after occipital
results from retinal vascular occlusion, advanced glau- stroke have macular sparing, because the macular rep-
coma, and optic neuritis. resentation at the tip of the occipital lobe is supplied by
About half the bers in the optic nerve originate collaterals from the middle cerebral artery (Fig. 21-3L).
CHAPTER 21
from ganglion cells serving the macula. Damage to Destruction of both occipital lobes produces corti-
papillomacular bers causes a cecocentral scotoma that cal blindness. This condition can be distinguished from
encompasses the blind spot and macula (Fig. 21-3E). If bilateral prechiasmal visual loss by noting that the pupil
the damage is irreversible, pallor eventually appears in responses and optic fundi remain normal.
the temporal portion of the optic disc. Temporal pallor
from a cecocentral scotoma may develop in optic neu-
ritis, nutritional optic neuropathy, toxic optic neuropa- DISORDERS
Disorders of Vision
thy, Lebers hereditary optic neuropathy, and compres-
RED OR PAINFUL EYE
sive optic neuropathy. It is worth mentioning that the
temporal side of the optic disc is slightly more pale than Corneal abrasions
the nasal side in most normal individuals. Therefore, it Corneal abrasions are seen best by placing a drop of uo-
sometimes can be difcult to decide whether the tem- rescein in the eye and looking with the slit lamp, using a
poral pallor visible on fundus examination represents a cobalt-blue light. A penlight with a blue lter will suf-
pathologic change. Pallor of the nasal rim of the optic ce if a slit lamp is not available. Damage to the corneal
disc is a less equivocal sign of optic atrophy. epithelium is revealed by yellow uorescence of the
At the optic chiasm, bers from nasal ganglion cells exposed basement membrane underlying the epithelium.
decussate into the contralateral optic tract. Crossed It is important to check for foreign bodies. To search
bers are damaged more by compression than are the conjunctival fornices, the lower lid should be pulled
uncrossed bers. As a result, mass lesions of the sel- down and the upper lid everted. A foreign body can be
lar region cause a temporal hemianopia in each eye. removed with a moistened cotton-tipped applicator after
Tumors anterior to the optic chiasm, such as meningio- a drop of a topical anesthetic such as proparacaine has
mas of the tuberculum sella, produce a junctional sco- been placed in the eye. Alternatively, it may be possible
toma characterized by an optic neuropathy in one eye to ush the foreign body from the eye by irrigating copi-
and a superior-temporal eld cut in the other eye (Fig. ously with saline or articial tears. If the corneal epithe-
21-3G). More symmetric compression of the optic chi- lium has been abraded, antibiotic ointment and a patch
asm by a pituitary adenoma (Fig. 38-4), meningioma, should be applied to the eye. A drop of an intermediate-
craniopharyngioma, glioma, or aneurysm results in a acting cycloplegic such as cyclopentolate hydrochloride
bitemporal hemianopia (Fig. 21-3H). The insidious 1% helps reduce pain by relaxing the ciliary body. The
development of a bitemporal hemianopia often goes eye should be reexamined the next day. Minor abrasions
unnoticed by the patient and will escape detection by may not require patching and cycloplegia.
the physician unless each eye is tested separately.
It is difcult to localize a postchiasmal lesion accu-
rately, because injury anywhere in the optic tract, lat- Subconjunctival hemorrhage
eral geniculate body, optic radiations, or visual cortex This results from rupture of small vessels bridging the
can produce a homonymous hemianopia (i.e., a tem- potential space between the episclera and the con-
poral hemield defect in the contralateral eye and a junctiva. Blood dissecting into this space can produce
matching nasal hemield defect in the ipsilateral eye) a spectacular red eye, but vision is not affected and the
(Fig. 21-3I). A unilateral postchiasmal lesion leaves hemorrhage resolves without treatment. Subconjunctival
the visual acuity in each eye unaffected, although the hemorrhage is usually spontaneous but can result from
patient may read the letters on only the left or right half blunt trauma, eye rubbing, or vigorous coughing. Occa-
of the eye chart. Lesions of the optic radiations tend to sionally it is a clue to an underlying bleeding disorder.
cause poorly matched or incongruous eld defects in
each eye. Damage to the optic radiations in the tempo-
Pinguecula
ral lobe (Meyers loop) produces a superior quadrantic
homonymous hemianopia (Fig. 21-3J), whereas injury Pinguecula is a small, raised conjunctival nodule at
to the optic radiations in the parietal lobe results in an the temporal or nasal limbus. In adults such lesions are
180 extremely common and have little signicance unless antibiotics such as sulfacetamide 10%, polymyxin-
they become inamed (pingueculitis). A pterygium resem- bacitracin, or a trimethoprim-polymyxin combination.
bles a pinguecula but has crossed the limbus to encroach Smears and cultures usually are reserved for severe,
on the corneal surface. Removal is justied when symp- resistant, or recurrent cases of conjunctivitis. To prevent
toms of irritation or blurring develop, but recurrence is a contagion, patients should be admonished to wash their
common problem. hands frequently, not to touch their eyes, and to avoid
direct contact with others.
Blepharitis
Allergic conjunctivitis
SECTION II
topical antibiotics such as bacitracin/polymyxin B oph- cobblestone papillae. Atopic conjunctivitis occurs in sub-
thalmic ointment. An external hordeolum (sty) is caused jects with atopic dermatitis or asthma. Symptoms caused
by staphylococcal infection of the supercial accessory by allergic conjunctivitis can be alleviated with cold
glands of Zeis or Moll located in the eyelid margins. An compresses, topical vasoconstrictors, antihistamines, and
internal hordeolum occurs after suppurative infection mast cell stabilizers such as cromolyn sodium. Topi-
of the oil-secreting meibomian glands within the tarsal cal glucocorticoid solutions provide dramatic relief of
plate of the eyelid. Systemic antibiotics, usually tetra- immune-mediated forms of conjunctivitis, but their
cyclines or azithromycin, sometimes are necessary for long-term use is ill advised because of the complications
treatment of meibomian gland inammation (meibomi- of glaucoma, cataract, and secondary infection. Topical
tis) or chronic, severe blepharitis. A chalazion is a pain- nonsteroidal anti-inammatory drugs (NSAIDs) (e.g.,
less, granulomatous inammation of a meibomian gland ketorolac tromethamine) are better alternatives.
that produces a pealike nodule within the eyelid. It can
be incised and drained or injected with glucocorticoids. Keratoconjunctivitis sicca
Basal cell, squamous cell, or meibomian gland carci-
noma should be suspected with any nonhealing ulcer- Also known as dry eye, this produces a burning foreign-
ative lesion of the eyelids. body sensation, injection, and photophobia. In mild
cases the eye appears surprisingly normal, but tear pro-
duction measured by wetting of a lter paper (Schirmer
Dacryocystitis
strip) is decient. A variety of systemic drugs, including
An inammation of the lacrimal drainage system, dac- antihistaminic, anticholinergic, and psychotropic medi-
ryocystitis can produce epiphora (tearing) and ocular cations, result in dry eye by reducing lacrimal secre-
injection. Gentle pressure over the lacrimal sac evokes tion. Disorders that involve the lacrimal gland directly,
pain and reux of mucus or pus from the tear puncta. such as sarcoidosis and Sjgrens syndrome, also cause
Dacryocystitis usually occurs after obstruction of the dry eye. Patients may develop dry eye after radiation
lacrimal system. It is treated with topical and systemic therapy if the treatment eld includes the orbits. Prob-
antibiotics, followed by probing or surgery to reestab- lems with ocular drying are also common after lesions
lish patency. Entropion (inversion of the eyelid) or ectro- affecting cranial nerve V or VII. Corneal anesthesia is
pion (sagging or eversion of the eyelid) can also lead to particularly dangerous, because the absence of a normal
epiphora and ocular irritation. blink reex exposes the cornea to injury without pain
to warn the patient. Dry eye is managed by frequent
and liberal application of articial tears and ocular lubri-
Conjunctivitis
cants. In severe cases the tear puncta can be plugged or
Conjunctivitis is the most common cause of a red, irri- cauterized to reduce lacrimal outow.
tated eye. Pain is minimal, and visual acuity is reduced
only slightly. The most common viral etiology is ade-
Keratitis
novirus infection. It causes a watery discharge, a mild
foreign-body sensation, and photophobia. Bacterial Keratitis is a threat to vision because of the risk of cor-
infection tends to produce a more mucopurulent exu- neal clouding, scarring, and perforation. Worldwide,
date. Mild cases of infectious conjunctivitis usually are the two leading causes of blindness from keratitis are
treated empirically with broad-spectrum topical ocular trachoma from chlamydial infection and vitamin A
deciency related to malnutrition. In the United States, involvement (Hutchinsons sign). Herpes zoster oph- 181
contact lenses play a major role in corneal infection and thalmicus produces corneal dendrites, which can be
ulceration. They should not be worn by anyone with difcult to distinguish from those seen in herpes sim-
an active eye infection. In evaluating the cornea, it is plex. Stromal keratitis, anterior uveitis, raised intraocu-
important to differentiate between a supercial infection lar pressure, ocular motor nerve palsies, acute retinal
(keratoconjunctivitis) and a deeper, more serious ulcerative necrosis, and postherpetic scarring and neuralgia are
process. The latter is accompanied by greater visual loss, other common sequelae. Herpes zoster ophthalmicus is
pain, photophobia, redness, and discharge. Slit-lamp treated with antiviral agents and cycloplegics. In severe
examination shows disruption of the corneal epithe- cases, glucocorticoids may be added to prevent perma-
CHAPTER 21
lium, a cloudy inltrate or abscess in the stroma, and an nent visual loss from corneal scarring.
inammatory cellular reaction in the anterior chamber.
In severe cases, pus settles at the bottom of the anterior Episcleritis
chamber, giving rise to a hypopyon. Immediate empiri-
cal antibiotic therapy should be initiated after corneal This is an inammation of the episclera, a thin layer
scrapings are obtained for Grams stain, Giemsa stain, of connective tissue between the conjunctiva and the
and cultures. Fortied topical antibiotics are most effec- sclera. Episcleritis resembles conjunctivitis, but it is a
Disorders of Vision
tive, supplemented with subconjunctival antibiotics as more localized process and discharge is absent. Most
required. A fungal etiology should always be considered cases of episcleritis are idiopathic, but some occur in
in a patient with keratitis. Fungal infection is common the setting of an autoimmune disease. Scleritis refers
in warm humid climates, especially after penetration of to a deeper, more severe inammatory process that
the cornea by plant or vegetable material. frequently is associated with a connective tissue dis-
ease such as rheumatoid arthritis, lupus erythematosus,
polyarteritis nodosa, granulomatosis with polyangiitis
Herpes simplex
(Wegeners) or relapsing polychondritis. The inam-
The herpesviruses are a major cause of blindness from mation and thickening of the sclera can be diffuse or
keratitis. Most adults in the United States have serum nodular. In anterior forms of scleritis, the globe assumes
antibodies to herpes simplex, indicating prior viral a violet hue and the patient complains of severe ocu-
infection. Primary ocular infection generally is caused lar tenderness and pain. With posterior scleritis the pain
by herpes simplex type 1 rather than type 2. It mani- and redness may be less marked, but there is often pro-
fests as a unilateral follicular blepharoconjunctivitis that ptosis, choroidal effusion, reduced motility, and visual
is easily confused with adenoviral conjunctivitis unless loss. Episcleritis and scleritis should be treated with
telltale vesicles appear on the periocular skin or con- NSAIDs. If these agents fail, topical or even systemic
junctiva. A dendritic pattern of corneal epithelial ulcer- glucocorticoid therapy may be necessary, especially if an
ation revealed by uorescein staining is pathognomonic underlying autoimmune process is active.
for herpes infection but is seen in only a minority of
primary infections. Recurrent ocular infection arises Uveitis
from reactivation of the latent herpesvirus. Viral erup-
tion in the corneal epithelium may result in the char- Involving the anterior structures of the eye, uveitis also
acteristic herpes dendrite. Involvement of the corneal is called iritis or iridocyclitis. The diagnosis requires slit-
stroma produces edema, vascularization, and iridocy- lamp examination to identify inammatory cells oat-
clitis. Herpes keratitis is treated with topical antiviral ing in the aqueous humor or deposited on the corneal
agents, cycloplegics, and oral acyclovir. Topical gluco- endothelium (keratic precipitates). Anterior uveitis
corticoids are effective in mitigating corneal scarring but develops in sarcoidosis, ankylosing spondylitis, juve-
must be used with extreme caution because of the dan- nile rheumatoid arthritis, inammatory bowel disease,
ger of corneal melting and perforation. Topical gluco- psoriasis, reactive arthritis (formerly known as Reiters
corticoids also carry the risk of prolonging infection and syndrome), and Behets disease. It also is associated
inducing glaucoma. with herpes infections, syphilis, Lyme disease, oncho-
cerciasis, tuberculosis, and leprosy. Although anterior
uveitis can occur in conjunction with many diseases,
Herpes zoster
no cause is found to explain the majority of cases. For
Herpes zoster from reactivation of latent varicella this reason, laboratory evaluation usually is reserved for
(chickenpox) virus causes a dermatomal pattern of pain- patients with recurrent or severe anterior uveitis. Treat-
ful vesicular dermatitis. Ocular symptoms can occur ment is aimed at reducing inammation and scarring
after zoster eruption in any branch of the trigemi- by judicious use of topical glucocorticoids. Dilatation
nal nerve but are particularly common when vesicles of the pupil reduces pain and prevents the formation of
form on the nose, reecting nasociliary (V1) nerve synechiae.
182 Posterior uveitis or neurologic disease. The diagnosis is made by mea-
suring the intraocular pressure during an acute attack
This is diagnosed by observing inammation of the or by observing a narrow chamber angle by means of
vitreous, retina, or choroid on fundus examination. a specially mirrored contact lens. Acute angle closure
It is more likely than anterior uveitis to be associated is treated with acetazolamide (PO or IV), topical beta
with an identiable systemic disease. Some patients blockers, prostaglandin analogues, 2-adrenergic ago-
have panuveitis, or inammation of both the anterior nists, and pilocarpine to induce miosis. If these measures
and posterior segments of the eye. Posterior uveitis fail, a laser can be used to create a hole in the periph-
is a manifestation of autoimmune diseases such as sar- eral iris to relieve pupillary block. Many physicians are
coidosis, Behets disease, Vogt-Koyanagi-Harada syn-
SECTION II
syphilis, Lyme disease, tuberculosis, cat-scratch disease, permanent damage to the eye and serves as an inad-
Whipples disease, and brucellosis. In multiple sclero- vertent provocative test to identify patients with nar-
sis, chronic inammatory changes can develop in the row angles who would benet from prophylactic laser
extreme periphery of the retina (pars planitis or inter- iridectomy.
mediate uveitis).
Endophthalmitis
Acute angle-closure glaucoma
This results from bacterial, viral, fungal, or parasitic
This is a rare and frequently misdiagnosed cause of a infection of the internal structures of the eye. It usu-
red, painful eye. Susceptible eyes have a shallow ante- ally is acquired by hematogenous seeding from a remote
rior chamber because the eye has either a short axial site. Chronically ill, diabetic, or immunosuppressed
length (hyperopia) or a lens enlarged by the gradual patients, especially those with a history of indwelling
development of cataract. When the pupil becomes mid- IV catheters or positive blood cultures, are at great-
dilated, the peripheral iris blocks aqueous outow via est risk for endogenous endophthalmitis. Although
the anterior chamber angle and the intraocular pressure most patients have ocular pain and injection, visual loss
rises abruptly, producing pain, injection, corneal edema, is sometimes the only symptom. Septic emboli from
obscurations, and blurred vision. In some patients, ocu- a diseased heart valve or a dental abscess that lodge in
lar symptoms are overshadowed by nausea, vomiting, or the retinal circulation can give rise to endophthalmitis.
headache, prompting a fruitless workup for abdominal White-centered retinal hemorrhages (Roths spots) are
considered pathognomonic for subacute bacterial endo-
carditis, but they also appear in leukemia, diabetes, and
many other conditions. Endophthalmitis also occurs as
a complication of ocular surgery, occasionally months
or even years after the operation. An occult penetrat-
ing foreign body or unrecognized trauma to the globe
should be considered in any patient with unexplained
intraocular infection or inammation.
CHAPTER 21
FIGURE 21-5 FIGURE 21-7
Hollenhorst plaque lodged at the bifurcation of a retinal Hypertensive retinopathy with scattered ame (splinter)
Disorders of Vision
arteriole proves that a patient is shedding emboli from the hemorrhages and cotton-wool spots (nerve ber layer
carotid artery, great vessels, or heart. infarcts) in a patient with headache and a blood pressure of
234/120.
an embolus that becomes stuck within a retinal arte- patients with diseased valves, atrial brillation, or wall
riole (Fig. 21-5). If the embolus breaks up or passes, motion abnormalities.
ow is restored and vision returns quickly to normal In rare instances, amaurosis fugax results from low
without permanent damage. With prolonged interrup- central retinal artery perfusion pressure in a patient
tion of blood ow, the inner retina suffers infarction. with a critical stenosis of the ipsilateral carotid artery
Ophthalmoscopy reveals zones of whitened, edematous and poor collateral ow via the circle of Willis. In this
retina following the distribution of branch retinal arte- situation, amaurosis fugax develops when there is a dip
rioles. Complete occlusion of the central retinal artery in systemic blood pressure or a slight worsening of the
produces arrest of blood ow and a milky retina with carotid stenosis. Sometimes there is contralateral motor
a cherry-red fovea (Fig. 21-6). Emboli are composed or sensory loss, indicating concomitant hemispheric
of cholesterol (Hollenhorst plaque), calcium, or platelet- cerebral ischemia.
brin debris. The most common source is an athero- Retinal arterial occlusion also occurs rarely in
sclerotic plaque in the carotid artery or aorta, although association with retinal migraine, lupus erythemato-
emboli also can arise from the heart, especially in sus, anticardiolipin antibodies (Fig. 21-6), anticoagulant
deciency states (protein S, protein C, and antithrom-
bin deciency), pregnancy, IV drug abuse, blood dys-
crasias, dysproteinemias, and temporal arteritis.
Marked systemic hypertension causes sclerosis of reti-
nal arterioles, splinter hemorrhages, focal infarcts of
the nerve ber layer (cotton-wool spots), and leak-
age of lipid and uid (hard exudate) into the macula
(Fig. 21-7). In hypertensive crisis, sudden visual loss
can result from vasospasm of retinal arterioles and reti-
nal ischemia. In addition, acute hypertension may pro-
duce visual loss from ischemic swelling of the optic disc.
Patients with acute hypertensive retinopathy should be
treated by lowering the blood pressure. However, the
blood pressure should not be reduced precipitously,
because there is a danger of optic disc infarction from
sudden hypoperfusion.
FIGURE 21-6 Impending branch or central retinal vein occlusion can
Central retinal artery occlusion combined with ischemic produce prolonged visual obscurations that resemble
optic neuropathy in a 19-year-old woman with an elevated those described by patients with amaurosis fugax. The
titer of anticardiolipin antibodies. Note the orange dot (rather veins appear engorged and phlebitic, with numer-
than cherry red) corresponding to the fovea and the spared ous retinal hemorrhages (Fig. 21-8). In some patients
patch of retina just temporal to the optic disc. venous blood ow recovers spontaneously, whereas
184 AION is divided into two forms: arteritic and nonar-
teritic. The nonarteritic form is most common. No
specic cause can be identied, although diabetes and
hypertension are common risk factors. No treatment is
available. About 5% of patients, especially those >age
60, develop the arteritic form of AION in conjunction
with giant cell (temporal) arteritis. It is urgent to rec-
ognize arteritic AION so that high doses of glucocorti-
coids can be instituted immediately to prevent blindness
SECTION II
CHAPTER 21
FIGURE 21-10
Retrobulbar optic neuritis is characterized by a normal fun-
Disorders of Vision
dus examination initially, hence the rubric the doctor sees FIGURE 21-11
nothing, and the patient sees nothing. Optic atrophy devel- Optic atrophy is not a specic diagnosis but refers to the
ops after severe or repeated attacks. combination of optic disc pallor, arteriolar narrowing, and
nerve ber layer destruction produced by a host of eye dis-
multiple sclerosis after optic neuritis is 50%. In patients eases, especially optic neuropathies.
with two or more demyelinating plaques on brain mag-
netic resonance (MR) imaging, treatment with inter- neuropathy, visual loss also can develop gradually and
feron -1a can retard the development of more lesions. produce optic atrophy (Fig. 21-11) without a phase of
In summary, an MR scan is recommended in every acute optic disc edema. Many agents have been impli-
patient with a rst attack of optic neuritis. When visual cated as a cause of toxic optic neuropathy, but the evi-
loss is severe (worse than 20/100), treatment with IV dence supporting the association for many is weak. The
followed by oral glucocorticoids hastens recovery. If following is a partial list of potential offending drugs
multiple lesions are present on the MR scan, treatment or toxins: disulram, ethchlorvynol, chloramphenicol,
with interferon -1a should be considered. amiodarone, monoclonal anti-CD3 antibody, cipro-
oxacin, digitalis, streptomycin, lead, arsenic, thallium,
d-penicillamine, isoniazid, emetine, and sulfonamides.
Lebers hereditary optic neuropathy
Deciency states induced by starvation, malabsorption,
This disease usually affects young men, causing grad- or alcoholism can lead to insidious visual loss. Thia-
ual, painless, severe central visual loss in one eye, fol- mine, vitamin B12, and folate levels should be checked
lowed weeks or months later by the same process in the in any patient with unexplained bilateral central scoto-
other eye. Acutely, the optic disc appears mildly ple- mas and optic pallor.
thoric with surface capillary telangiectases but no vas-
cular leakage on uorescein angiography. Eventually Papilledema
optic atrophy ensues. Lebers optic neuropathy is caused
by a point mutation at codon 11778 in the mitochon- This connotes bilateral optic disc swelling from raised
drial gene encoding nicotinamide adenine dinucleotide intracranial pressure (Fig. 21-12). Headache is a com-
dehydrogenase (NADH) subunit 4. Additional muta- mon but not invariable accompaniment. All other
tions responsible for the disease have been identi- forms of optic disc swelling (e.g., from optic neuritis
ed, most in mitochondrial genes that encode proteins or ischemic optic neuropathy) should be called optic
involved in electron transport. Mitochondrial muta- disc edema. This convention is arbitrary but serves to
tions that cause Lebers neuropathy are inherited from avoid confusion. Often it is difcult to differentiate pap-
the mother by all her children, but usually only sons illedema from other forms of optic disc edema by fun-
develop symptoms. dus examination alone. Transient visual obscurations
are a classic symptom of papilledema. They can occur
in only one eye or simultaneously in both eyes. They
Toxic optic neuropathy
usually last seconds but can persist longer. Obscurations
This can result in acute visual loss with bilateral optic follow abrupt shifts in posture or happen spontaneously.
disc swelling and central or cecocentral scotomas. Such When obscurations are prolonged or spontaneous, the
cases have been reported to result from exposure to eth- papilledema is more threatening. Visual acuity is not
ambutol, methyl alcohol (moonshine), ethylene gly- affected by papilledema unless the papilledema is severe,
col (antifreeze), or carbon monoxide. In toxic optic long-standing, or accompanied by macular edema and
186
SECTION II
cranial pressure. This obese young woman with pseudotu- ogy within the optic disc. They sometimes are confused with
mor cerebri was misdiagnosed as a migraineur until fundus papilledema.
examination was performed, showing optic disc elevation,
hemorrhages, and cotton-wool spots.
hemorrhage. Visual eld testing shows enlarged blind avoid an unnecessary evaluation for papilledema. Ultra-
spots and peripheral constriction (Fig. 21-3F). With sound or CT scanning is sensitive for detection of bur-
unremitting papilledema, peripheral visual eld loss ied optic disc drusen because they contain calcium. In
progresses in an insidious fashion while the optic nerve most patients, optic disc drusen are an incidental, innoc-
develops atrophy. In this setting, reduction of optic disc uous nding, but they can produce visual obscurations.
swelling is an ominous sign of a dying nerve rather than On perimetry they give rise to enlarged blind spots and
an encouraging indication of resolving papilledema. arcuate scotomas from damage to the optic disc. With
Evaluation of papilledema requires neuroimaging to increasing age, drusen tend to become more exposed on
exclude an intracranial lesion. MR angiography is appro- the disc surface as optic atrophy develops. Hemorrhage,
priate in selected cases to search for a dural venous sinus choroidal neovascular membrane, and AION are more
occlusion or an arteriovenous shunt. If neuroradiologic likely to occur in patients with optic disc drusen. No
studies are negative, the subarachnoid opening pressure treatment is available.
should be measured by lumbar puncture. An elevated
pressure, with normal cerebrospinal uid, points by exclu- Vitreous degeneration
sion to the diagnosis of pseudotumor cerebri (idiopathic intra-
cranial hypertension). The majority of patients are young, This occurs in all individuals with advancing age, lead-
female, and obese. Treatment with a carbonic anhydrase ing to visual symptoms. Opacities develop in the vitre-
inhibitor such as acetazolamide lowers intracranial pressure ous, casting annoying shadows on the retina. As the eye
by reducing the production of cerebrospinal uid. Weight moves, these distracting oaters move synchronously,
reduction is vital but often unsuccessful. If acetazolamide with a slight lag caused by inertia of the vitreous gel. Vit-
and weight loss fail and visual eld loss is progressive, a reous traction on the retina causes mechanical stimula-
shunt should be performed without delay to prevent blind- tion, resulting in perception of ashing lights. This pho-
ness. Occasionally, emergency surgery is required for sud- topsia is brief and is conned to one eye, in contrast to
den blindness caused by fulminant papilledema. the bilateral, prolonged scintillations of cortical migraine.
Contraction of the vitreous can result in sudden separa-
tion from the retina, heralded by an alarming shower of
Optic disc drusen
oaters and photopsia. This process, known as vitreous
These are refractile deposits within the substance of the detachment, is a common involutional event in the elderly.
optic nerve head (Fig. 21-13). They are unrelated to It is not harmful unless it damages the retina. A careful
drusen of the retina, which occur in age-related macu- examination of the dilated fundus is important in any
lar degeneration. Optic disc drusen are most common in patient complaining of oaters or photopsia to search for
people of northern European descent. Their diagnosis is peripheral tears or holes. If such a lesion is found, laser
obvious when they are visible as glittering particles on the application can forestall a retinal detachment. Occasion-
surface of the optic disc. However, in many patients they ally a tear ruptures a retinal blood vessel, causing vitre-
are hidden beneath the surface, producing pseudopapill- ous hemorrhage and sudden loss of vision. On attempted
edema. It is important to recognize optic disc drusen to ophthalmoscopy the fundus is hidden by a dark red
haze of blood. Ultrasound is required to examine the a fortied city, hence the term fortication spectra. Patients 187
interior of the eye for a retinal tear or detachment. If the descriptions of fortication spectra vary widely and can
hemorrhage does not resolve spontaneously, the vitre- be confused with amaurosis fugax. Migraine patterns usu-
ous can be removed surgically. Vitreous hemorrhage also ally last longer and are perceived in both eyes, whereas
results from the fragile neovascular vessels that proliferate amaurosis fugax is briefer and occurs in only one eye.
on the surface of the retina in diabetes, sickle cell anemia, Migraine phenomena also remain visible in the dark
and other ischemic ocular diseases. or with the eyes closed. Generally they are conned to
either the right or the left visual hemield, but sometimes
Retinal detachment both elds are involved simultaneously. Patients often
CHAPTER 21
have a long history of stereotypic attacks. After the visual
This produces symptoms of oaters, ashing lights, and symptoms recede, headache develops in most patients.
a scotoma in the peripheral visual eld corresponding to
the detachment (Fig. 21-14). If the detachment includes
the fovea, there is an afferent pupil defect and the visual Transient ischemic attacks
acuity is reduced. In most eyes, retinal detachment starts Vertebrobasilar insufciency may result in acute hom-
with a hole, ap, or tear in the peripheral retina (rheg- onymous visual symptoms. Many patients mistakenly
Disorders of Vision
matogenous retinal detachment). Patients with peripheral describe symptoms in the left or right eye when in fact
retinal thinning (lattice degeneration) are particularly vul- the symptoms are occurring in the left or right hemi-
nerable to this process. Once a break has developed in eld of both eyes. Interruption of blood supply to the
the retina, liqueed vitreous is free to enter the subretinal visual cortex causes a sudden fogging or graying of
space, separating the retina from the pigment epithelium. vision, occasionally with ashing lights or other posi-
The combination of vitreous traction on the retinal sur- tive phenomena that mimic migraine. Cortical ischemic
face and passage of uid behind the retina leads inexo- attacks are briefer in duration than migraine, occur in
rably to detachment. Patients with a history of myopia, older patients, and are not followed by headache. There
trauma, or prior cataract extraction are at greatest risk for may be associated signs of brainstem ischemia, such as
retinal detachment. The diagnosis is conrmed by oph- diplopia, vertigo, numbness, weakness, and dysarthria.
thalmoscopic examination of the dilated eye.
Stroke
Classic migraine Stroke occurs when interruption of blood supply from
(See also Chap. 8) This usually occurs with a visual aura the posterior cerebral artery to the visual cortex is pro-
lasting about 20 min. In a typical attack, a small central longed. The only nding on examination is a hom-
disturbance in the eld of vision marches toward the onymous visual eld defect that stops abruptly at the
periphery, leaving a transient scotoma in its wake. The vertical meridian. Occipital lobe stroke usually is due
expanding border of migraine scotoma has a scintillat- to thrombotic occlusion of the vertebrobasilar system,
ing, dancing, or zigzag edge, resembling the bastions of embolus, or dissection. Lobar hemorrhage, tumor,
abscess, and arteriovenous malformation are other com-
mon causes of hemianopic cortical visual loss.
CHAPTER 21
appear as small discrete yellow lesions clustered in the visual acuity.
macula (Fig. 21-16). With time they become larger,
more numerous, and conuent. The retinal pigment
epithelium becomes focally detached and atrophic, Central serous chorioretinopathy
causing visual loss by interfering with photoreceptor This primarily affects males between the ages of 20 and
function. Treatment with vitamins C and E, beta-caro- 50. Leakage of serous uid from the choroid causes
tene, and zinc may retard dry macular degeneration.
Disorders of Vision
small, localized detachment of the retinal pigment epi-
Exudative macular degeneration, which develops thelium and the neurosensory retina. These detach-
in only a minority of patients, occurs when neovascu- ments produce acute or chronic symptoms of metamor-
lar vessels from the choroid grow through defects in phopsia and blurred vision when the macula is involved.
Bruchs membrane and proliferate underneath the reti- They are difcult to visualize with a direct ophthalmo-
nal pigment epithelium or the retina. Leakage from scope because the detached retina is transparent and
these vessels produces elevation of the retina, with only slightly elevated. Diagnosis of central serous cho-
distortion (metamorphopsia) and blurring of vision. rioretinopathy is made easily by uorescein angiogra-
Although the onset of these symptoms is usually grad- phy, which shows dye streaming into the subretinal
ual, bleeding from a subretinal choroidal neovascular space. The cause of central serous chorioretinopathy is
membrane sometimes causes acute visual loss. Neo- unknown. Symptoms may resolve spontaneously if the
vascular membranes can be difcult to see on fun- retina reattaches, but recurrent detachment is common.
dus examination because they are located beneath the Laser photocoagulation has beneted some patients
retina. Fluorescein angiography and optical coherence with this condition.
tomography, a new technique for acquiring images of
the retina in cross-section, are extremely useful for their
detection. Major or repeated hemorrhage under the Diabetic retinopathy
retina from neovascular membranes results in brosis,
development of a round (disciform) macular scar, and A rare disease until 1921, when the discovery of insulin
permanent loss of central vision. resulted in a dramatic improvement in life expectancy
for patients with diabetes mellitus, diabetic retinopathy
is now a leading cause of blindness in the United States.
The retinopathy takes years to develop but eventually
appears in nearly all cases. Regular surveillance of the
dilated fundus is crucial for any patient with diabetes.
In advanced diabetic retinopathy, the proliferation of
neovascular vessels leads to blindness from vitreous
hemorrhage, retinal detachment, and glaucoma. These
complications can be avoided in most patients by
administration of panretinal laser photocoagulation at
the appropriate point in the evolution of the disease.
Retinitis pigmentosa
This is a general term for a disparate group of rod-cone
dystrophies characterized by progressive night blind-
ness, visual eld constriction with a ring scotoma, loss
FIGURE 21-16 of acuity, and an abnormal electroretinogram (ERG). It
Age-related macular degeneration begins with the accu- occurs sporadically or in an autosomal recessive, domi-
mulation of drusen within the macula. They appear as scat- nant, or X-linked pattern. Irregular black deposits of
tered yellow subretinal deposits. clumped pigment in the peripheral retina, called bone
190
SECTION II
retinal periphery known as bone spicules. There is also mass in the inferior temporal fundus, just encroaching upon
atrophy of the retinal pigment epithelium, making the vascu- the fovea.
lature of the choroid easily visible.
spicules because of their vague resemblance to the spic- macular holes, however, are caused by local vitreous
ules of cancellous bone, give the disease its name (Fig. traction within the fovea. Vitrectomy can improve acu-
21-17). The name is actually a misnomer because reti- ity in selected cases.
nitis pigmentosa is not an inammatory process. Most
cases are due to a mutation in the gene for rhodopsin, Melanoma and other tumors
the rod photopigment, or in the gene for peripherin, a
glycoprotein located in photoreceptor outer segments. Melanoma is the most common primary tumor of the
Vitamin A (15,000 IU/d) slightly retards the deteriora- eye (Fig. 21-18). It causes photopsia, an enlarging sco-
tion of the ERG in patients with retinitis pigmentosa toma, and loss of vision. A small melanoma is often dif-
but has no benecial effect on visual acuity or elds. cult to differentiate from a benign choroidal nevus. Serial
Lebers congenital amaurosis, a rare cone dystrophy, examinations are required to document a malignant pat-
has been treated by replacement of the missing RPE65 tern of growth. Treatment of melanoma is controversial.
protein through gene therapy, resulting in modest Options include enucleation, local resection, and irra-
improvement in visual function. Some forms of retini- diation. Metastatic tumors to the eye outnumber primary
tis pigmentosa occur in association with rare, hereditary tumors. Breast and lung carcinomas have a special pro-
systemic diseases (olivopontocerebellar degeneration, pensity to spread to the choroid or iris. Leukemia and
Bassen-Kornzweig disease, Kearns-Sayre syndrome, lymphoma also commonly invade ocular tissues. Some-
Refsums disease). Chronic treatment with chloroquine, times their only sign on eye examination is cellular debris
hydroxychloroquine, and phenothiazines (especially thi- in the vitreous, which can masquerade as a chronic pos-
oridazine) can produce visual loss from a toxic retinopa- terior uveitis. Retrobulbar tumor of the optic nerve (menin-
thy that resembles retinitis pigmentosa. gioma, glioma) or chiasmal tumor (pituitary adenoma,
meningioma) produces gradual visual loss with few
objective ndings except for optic disc pallor. Rarely,
Epiretinal membrane sudden expansion of a pituitary adenoma from infarction
This is a brocellular tissue that grows across the inner and bleeding (pituitary apoplexy) causes acute retrobul-
surface of the retina, causing metamorphopsia and bar visual loss, with headache, nausea, and ocular motor
reduced visual acuity from distortion of the macula. A nerve palsies. In any patient with visual eld loss or optic
crinkled, cellophane-like membrane is visible on the atrophy, CT or MR scanning should be considered if the
retinal examination. Epiretinal membrane is most com- cause remains unknown after careful review of the his-
mon in patients over 50 years of age and is usually uni- tory and thorough examination of the eye.
lateral. Most cases are idiopathic, but some occur as a
result of hypertensive retinopathy, diabetes, retinal
PROPTOSIS
detachment, or trauma. When visual acuity is reduced
to the level of about 6/24 (20/80), vitrectomy and sur- When the globes appear asymmetric, the clinician must
gical peeling of the membrane to relieve macular puck- rst decide which eye is abnormal. Is one eye recessed
ering are recommended. Contraction of an epiretinal within the orbit (enophthalmos), or is the other eye pro-
membrane sometimes gives rise to a macular hole. Most tuberant (exophthalmos, or proptosis)? A small globe or a
Horners syndrome can give the appearance of enoph- paranasal sinuses, especially by contiguous spread of infec- 191
thalmos. True enophthalmos occurs commonly after tion from the ethmoid sinus through the lamina papyracea
trauma, from atrophy of retrobulbar fat, or from fracture of the medial orbit. A history of recent upper respiratory
of the orbital oor. The position of the eyes within the tract infection, chronic sinusitis, thick mucus secretions, or
orbits is measured by using a Hertel exophthalmometer, dental disease is signicant in any patient with suspected
a handheld instrument that records the position of the orbital cellulitis. Blood cultures should be obtained, but
anterior corneal surface relative to the lateral orbital rim. they are usually negative. Most patients respond to empiri-
If this instrument is not available, relative eye position cal therapy with broad-spectrum IV antibiotics. Occasion-
can be judged by bending the patients head forward and ally, orbital cellulitis follows an overwhelming course, with
CHAPTER 21
looking down upon the orbits. A proptosis of only 2 mm massive proptosis, blindness, septic cavernous sinus throm-
in one eye is detectable from this perspective. The devel- bosis, and meningitis. To avert this disaster, orbital celluli-
opment of proptosis implies a space-occupying lesion in tis should be managed aggressively in the early stages, with
the orbit and usually warrants CT or MR imaging. immediate imaging of the orbits and antibiotic therapy
that includes coverage of methicillin-resistant Staphylococ-
cus aureus (MRSA). Prompt surgical drainage of an orbital
Graves ophthalmopathy
abscess or paranasal sinusitis is indicated if optic nerve func-
Disorders of Vision
This is the leading cause of proptosis in adults. The pro- tion deteriorates despite antibiotics.
ptosis is often asymmetric and can even appear to be
unilateral. Orbital inammation and engorgement of
the extraocular muscles, particularly the medial rectus Tumors
and the inferior rectus, account for the protrusion of Tumors of the orbit cause painless, progressive proptosis.
the globe. Corneal exposure, lid retraction, conjuncti- The most common primary tumors are hemangioma,
val injection, restriction of gaze, diplopia, and visual loss lymphangioma, neurobroma, dermoid cyst, adenoid
from optic nerve compression are cardinal symptoms. cystic carcinoma, optic nerve glioma, optic nerve menin-
Graves ophthalmopathy is treated with oral prednisone gioma, and benign mixed tumor of the lacrimal gland.
(60 mg/d) for 1 month, followed by a taper over several Metastatic tumor to the orbit occurs frequently in breast
months, topical lubricants, eyelid surgery, eye muscle carcinoma, lung carcinoma, and lymphoma. Diagnosis by
surgery, or orbital decompression. Radiation therapy is ne-needle aspiration followed by urgent radiation ther-
not effective. apy sometimes can preserve vision.
CHAPTER 21
Orbital pseudotumor, myositis, infection, tumor, thy- additional signs that suggest brainstem damage from
roid disease, and muscle entrapment (e.g., from a blow- infarction, hemorrhage, tumor, or infection.
out fracture) cause restrictive diplopia. The diagnosis of Injury to structures surrounding fascicles of the ocu-
restriction is usually made by recognizing other associ- lomotor nerve descending through the midbrain has
ated signs and symptoms of local orbital disease in con- given rise to a number of classic eponymic designations.
junction with imaging. In Nothnagels syndrome, injury to the superior cerebellar
peduncle causes ipsilateral oculomotor palsy and con-
Disorders of Vision
tralateral cerebellar ataxia. In Benedikts syndrome, injury
Myasthenia gravis
to the red nucleus results in ipsilateral oculomotor palsy
(See also Chap. 47) This is a major cause of diplopia. and contralateral tremor, chorea, and athetosis. Claudes
The diplopia is often intermittent, variable, and not syndrome incorporates features of both of these syn-
conned to any single ocular motor nerve distribution. dromes, by injury to both the red nucleus and the supe-
The pupils are always normal. Fluctuating ptosis may be rior cerebellar peduncle. Finally, in Webers syndrome,
present. Many patients have a purely ocular form of the injury to the cerebral peduncle causes ipsilateral oculo-
disease, with no evidence of systemic muscular weak- motor palsy with contralateral hemiparesis.
ness. The diagnosis can be conrmed by an IV edro- In the subarachnoid space the oculomotor nerve
phonium injection or by an assay for antiacetylcholine is vulnerable to aneurysm, meningitis, tumor, infarc-
receptor antibodies. Negative results from these tests do tion, and compression. In cerebral herniation the nerve
not exclude the diagnosis. Botulism from food or wound becomes trapped between the edge of the tentorium
poisoning can mimic ocular myasthenia. and the uncus of the temporal lobe. Oculomotor palsy
After restrictive orbital disease and myasthenia gra- also can result from midbrain torsion and hemorrhages
vis are excluded, a lesion of a cranial nerve supplying during herniation. In the cavernous sinus, oculomo-
innervation to the extraocular muscles is the most likely tor palsy arises from carotid aneurysm, carotid cavern-
cause of binocular diplopia. ous stula, cavernous sinus thrombosis, tumor (pituitary
adenoma, meningioma, metastasis), herpes zoster infec-
tion, and the Tolosa-Hunt syndrome.
Oculomotor nerve
The etiology of an isolated, pupil-sparing oculomo-
The third cranial nerve innervates the medial, inferior, tor palsy often remains an enigma even after neuroim-
and superior recti; inferior oblique; levator palpebrae aging and extensive laboratory testing. Most cases are
superioris; and the iris sphincter. Total palsy of the ocu- thought to result from microvascular infarction of the
lomotor nerve causes ptosis, results in a dilated pupil, and nerve somewhere along its course from the brainstem
leaves the eye down and out because of the unop- to the orbit. Usually the patient complains of pain.
posed action of the lateral rectus and superior oblique. Diabetes, hypertension, and vascular disease are major
This combination of ndings is obvious. More challeng- risk factors. Spontaneous recovery over a period of
ing is the diagnosis of early or partial oculomotor nerve months is the rule. If this fails to occur or if new nd-
palsy. In this setting, any combination of ptosis, pupil ings develop, the diagnosis of microvascular oculomotor
dilation, and weakness of the eye muscles supplied by the nerve palsy should be reconsidered. Aberrant regenera-
oculomotor nerve may be encountered. Frequent serial tion is common when the oculomotor nerve is injured
examinations during the evolving phase of the palsy help by trauma or compression (tumor, aneurysm). Miswir-
ensure that the diagnosis is not missed. The advent of an ing of sprouting bers to the levator muscle and the
oculomotor nerve palsy with a pupil involvement, espe- rectus muscles results in elevation of the eyelid upon
cially when accompanied by pain, suggests a compressive downgaze or adduction. The pupil also constricts upon
lesion, such as a tumor or circle of Willis aneurysm. Neu- attempted adduction, elevation, or depression of the
roimaging should be obtained, along with a CT or MR globe. Aberrant regeneration is not seen after oculomo-
angiogram. Occasionally, a catheter arteriogram must be tor palsy from microvascular infarct and hence vitiates
done to exclude an aneurysm. that diagnosis.
194 Trochlear nerve meningitis), subarachnoid hemorrhage, trauma, and
compression by aneurysm or dolichoectatic vessels. At
The fourth cranial nerve originates in the midbrain, the petrous apex, mastoiditis can produce deafness, pain,
just caudal to the oculomotor nerve complex. Fibers and ipsilateral abducens palsy (Gradenigos syndrome). In
exit the brainstem dorsally and cross to innervate the the cavernous sinus, the nerve can be affected by carotid
contralateral superior oblique. The principal actions of aneurysm, carotid cavernous stula, tumor (pituitary
this muscle are to depress and intort the globe. A palsy adenoma, meningioma, nasopharyngeal carcinoma), herpes
therefore results in hypertropia and excyclotorsion. The infection, and Tolosa-Hunt syndrome.
cyclotorsion seldom is noticed by patients. Instead, they Unilateral or bilateral abducens palsy is a classic sign
complain of vertical diplopia, especially upon reading
SECTION II
aneurysm. The trochlear nerve is particularly apt to suf- nal uid leak).
fer injury after closed head trauma. The free edge of the Treatment of abducens palsy is aimed at prompt cor-
tentorium is thought to impinge on the nerve during rection of the underlying cause. However, the cause
a concussive blow. Most isolated trochlear nerve pal- remains obscure in many instances despite diligent eval-
sies are idiopathic and hence are diagnosed by exclusion uation. As was mentioned earlier for isolated trochlear
as microvascular. Spontaneous improvement occurs or oculomotor palsy, most cases are assumed to repre-
over a period of months in most patients. A base-down sent microvascular infarcts because they often occur
prism (conveniently applied to the patients glasses as a in the setting of diabetes or other vascular risk factors.
stick-on Fresnel lens) may serve as a temporary measure Some cases may develop as a postinfectious mononeu-
to alleviate diplopia. If the palsy does not resolve, the ritis (e.g., after a viral u). Patching one eye or applying
eyes can be realigned by weakening the inferior oblique a temporary prism will provide relief of diplopia until
muscle. the palsy resolves. If recovery is incomplete, eye mus-
cle surgery nearly always can realign the eyes, at least
Abducens nerve in primary position. A patient with an abducens palsy
that fails to improve should be reevaluated for an occult
The sixth cranial nerve innervates the lateral rectus etiology (e.g., chordoma, carcinomatous meningitis,
muscle. A palsy produces horizontal diplopia, worse carotid cavernous stula, myasthenia gravis). Skull base
on gaze to the side of the lesion. A nuclear lesion has tumors are easily missed even on contrast-enhanced
different consequences, because the abducens nucleus neuroimaging studies.
contains interneurons that project via the medial lon-
gitudinal fasciculus to the medial rectus subnucleus of
Multiple ocular motor nerve palsies
the contralateral oculomotor complex. Therefore, an
abducens nuclear lesion produces a complete lateral These should not be attributed to spontaneous micro-
gaze palsy from weakness of both the ipsilateral lateral vascular events affecting more than one cranial nerve at
rectus and the contralateral medial rectus. Fovilles syn- a time. This remarkable coincidence does occur, espe-
drome after dorsal pontine injury includes lateral gaze cially in diabetic patients, but the diagnosis is made
palsy, ipsilateral facial palsy, and contralateral hemi- only in retrospect after all other diagnostic alternatives
paresis incurred by damage to descending corticospi- have been exhausted. Neuroimaging should focus on
nal bers. Millard-Gubler syndrome from ventral pontine the cavernous sinus, superior orbital ssure, and orbital
injury is similar except for the eye ndings. There is lat- apex, where all three ocular motor nerves are in close
eral rectus weakness only, instead of gaze palsy, because proximity. In a diabetic or immunocompromised host,
the abducens fascicle is injured rather than the nucleus. fungal infection (Aspergillus, Mucorales, Cryptococcus) is
Infarct, tumor, hemorrhage, vascular malformation, and a common cause of multiple nerve palsies. In a patient
multiple sclerosis are the most common etiologies of with systemic malignancy, carcinomatous meningitis is
brainstem abducens palsy. a likely diagnosis. Cytologic examination may be nega-
After leaving the ventral pons, the abducens nerve tive despite repeated sampling of the cerebrospinal uid.
runs forward along the clivus to pierce the dura at The cancer-associated Lambert-Eaton myasthenic syn-
the petrous apex, where it enters the cavernous sinus. drome also can produce ophthalmoplegia. Giant cell
Along its subarachnoid course it is susceptible to men- (temporal) arteritis occasionally manifests as diplopia
ingitis, tumor (meningioma, chordoma, carcinomatous from ischemic palsies of extraocular muscles. Fishers
syndrome, an ocular variant of Guillain-Barr, produces Internuclear ophthalmoplegia 195
ophthalmoplegia with areexia and ataxia. Often the This results from damage to the medial longitudinal
ataxia is mild, and the reexes are normal. Antiganglio- fasciculus ascending from the abducens nucleus in the
side antibodies (GQ1b) can be detected in about 50% of pons to the oculomotor nucleus in the midbrain (hence,
cases. internuclear). Damage to bers carrying the conju-
gate signal from abducens interneurons to the contra-
lateral medial rectus motoneurons results in a failure
Supranuclear disorders of gaze of adduction on attempted lateral gaze. For example, a
These are often mistaken for multiple ocular motor patient with a left internuclear ophthalmoplegia (INO)
CHAPTER 21
nerve palsies. For example, Wernickes encephalopathy will have slowed or absent adducting movements of the
can produce nystagmus and a partial decit of horizon- left eye (Fig. 21-19). A patient with bilateral injury
tal and vertical gaze that mimics a combined abducens to the medial longitudinal fasciculus will have bilateral
and oculomotor nerve palsy. The disorder occurs in INO. Multiple sclerosis is the most common cause,
malnourished or alcoholic patients and can be reversed although tumor, stroke, trauma, or any brainstem pro-
by thiamine. Infarct, hemorrhage, tumor, multiple scle- cess may be responsible. One-and-a-half syndrome is due
Disorders of Vision
rosis, encephalitis, vasculitis, and Whipples disease are to a combined lesion of the medial longitudinal fascic-
other important causes of supranuclear gaze palsy. Dis- ulus and the abducens nucleus on the same side. The
orders of vertical gaze, especially downward saccades, patients only horizontal eye movement is abduction of
are an early feature of progressive supranuclear palsy. the eye on the other side.
Smooth pursuit is affected later in the course of the
disease. Parkinsons disease, Huntingtons disease, and
olivopontocerebellar degeneration also can affect verti- Vertical gaze
cal gaze. This is controlled at the level of the midbrain. The neu-
The frontal eye eld of the cerebral cortex is involved ronal circuits affected in disorders of vertical gaze are
in generation of saccades to the contralateral side. After not fully elucidated, but lesions of the rostral intersti-
hemispheric stroke, the eyes usually deviate toward the tial nucleus of the medial longitudinal fasciculus and the
lesioned side because of the unopposed action of the interstitial nucleus of Cajal cause supranuclear paresis of
frontal eye eld in the normal hemisphere. With time, upgaze, downgaze, or all vertical eye movements. Dis-
this decit resolves. Seizures generally have the oppo- tal basilar artery ischemia is the most common etiology.
site effect: the eyes deviate conjugately away from the Skew deviation refers to a vertical misalignment of the
irritative focus. Parietal lesions disrupt smooth pursuit eyes, usually constant in all positions of gaze. The nd-
of targets moving toward the side of the lesion. Bilat- ing has poor localizing value because skew deviation has
eral parietal lesions produce Blints syndrome, which been reported after lesions in widespread regions of the
is characterized by impaired eye-hand coordination brainstem and cerebellum.
(optic ataxia), difculty initiating voluntary eye move-
ments (ocular apraxia), and visuospatial disorientation Parinauds syndrome
(simultanagnosia). Also known as dorsal midbrain syndrome, this is a dis-
tinct supranuclear vertical gaze disorder caused by dam-
age to the posterior commissure. It is a classic sign of
Horizontal gaze hydrocephalus from aqueductal stenosis. Pineal region
tumors, cysticercosis, and stroke also cause Parinauds
Descending cortical inputs mediating horizontal gaze syndrome. Features include loss of upgaze (and some-
ultimately converge at the level of the pons. Neu- times downgaze), convergence-retraction nystagmus on
rons in the paramedian pontine reticular formation are attempted upgaze, downward ocular deviation (setting
responsible for controlling conjugate gaze toward the sun sign), lid retraction (Colliers sign), skew deviation,
same side. They project directly to the ipsilateral abdu- pseudoabducens palsy, and light-near dissociation of the
cens nucleus. A lesion of either the paramedian pon- pupils.
tine reticular formation or the abducens nucleus causes
an ipsilateral conjugate gaze palsy. Lesions at either
Nystagmus
locus produce nearly identical clinical syndromes, with
the following exception: vestibular stimulation (ocu- This is a rhythmic oscillation of the eyes, occurring
locephalic maneuver or caloric irrigation) will succeed physiologically from vestibular and optokinetic stimu-
in driving the eyes conjugately to the side in a patient lation or pathologically in a wide variety of diseases
with a lesion of the paramedian pontine reticular forma- (Chap. 11). Abnormalities of the eyes or optic nerves,
tion but not in a patient with a lesion of the abducens present at birth or acquired in childhood, can produce
nucleus. a complex, searching nystagmus with irregular pendular
196 (sinusoidal) and jerk features. This nystagmus is com-
monly referred to as congenital sensory nystagmus. This
is a poor term because even in children with congeni-
tal lesions, the nystagmus does not appear until several
months of age. Congenital motor nystagmus, which looks
similar to congenital sensory nystagmus, develops in the
absence of any abnormality of the sensory visual system.
Visual acuity also is reduced in congenital motor nys-
tagmus, probably by the nystagmus itself, but seldom
SECTION II
Jerk nystagmus
This is characterized by a slow drift off the target, fol-
lowed by a fast corrective saccade. By convention, the
nystagmus is named after the quick phase. Jerk nystag-
Clinical Manifestations of Neurologic Disease
Gaze-evoked nystagmus
This is the most common form of jerk nystagmus.
When the eyes are held eccentrically in the orbits,
they have a natural tendency to drift back to primary
position. The subject compensates by making a cor-
rective saccade to maintain the deviated eye position.
Many normal patients have mild gaze-evoked nys-
tagmus. Exaggerated gaze-evoked nystagmus can be
induced by drugs (sedatives, anticonvulsants, alcohol);
muscle paresis; myasthenia gravis; demyelinating dis-
ease; and cerebellopontine angle, brainstem, and cer-
ebellar lesions.
Vestibular nystagmus
Vestibular nystagmus results from dysfunction of the laby-
rinth (Mnires disease), vestibular nerve, or vestibular
nucleus in the brainstem. Peripheral vestibular nystag-
mus often occurs in discrete attacks, with symptoms
of nausea and vertigo. There may be associated tinni-
tus and hearing loss. Sudden shifts in head position may
FIGURE 21-19 provoke or exacerbate symptoms.
Left internuclear ophthalmoplegia (INO). A. In primary posi-
tion of gaze the eyes appear normal. B. Horizontal gaze to Downbeat nystagmus
the left is intact. C. On attempted horizontal gaze to the right, Downbeat nystagmus results from lesions near the
the left eye fails to adduct. In mildly affected patients the eye craniocervical junction (Chiari malformation, basilar
may adduct partially or more slowly than normal. Nystagmus invagination). It also has been reported in brainstem or
is usually present in the abducted eye. D. T2-weighted axial cerebellar stroke, lithium or anticonvulsant intoxication,
MRI image through the pons showing a demyelinating plaque alcoholism, and multiple sclerosis. Upbeat nystagmus is
in the left medial longitudinal fasciculus (arrow).
associated with damage to the pontine tegmentum from the saccades are conned to the horizontal plane, the 197
stroke, demyelination, or tumor. term ocular utter is preferred. It can result from viral
encephalitis, trauma, or a paraneoplastic effect of neu-
Opsoclonus roblastoma, breast carcinoma, and other malignancies. It
This rare, dramatic disorder of eye movements consists has also been reported as a benign, transient phenom-
of bursts of consecutive saccades (saccadomania). When enon in otherwise healthy patients.
CHAPTER 21
Disorders of Vision
CHAPTER 22
Shirley H. Wray
The proper control of eye movements requires the an introduction to distinctive eye movement disorders
coordinated activity of many different anatomic struc- encountered in the context of neuromuscular, para-
tures in the peripheral and central nervous system, and neoplastic, demyelinating, neurovascular, and neurode-
in turn manifestations of a diverse array of neurologi- generative disorders is presented. Videos for this chap-
cal and medical disorders are revealed as disorders of ter can be accessed at the following link: http://www
eye movement. In this remarkable video collection, .mhprofessional.com/mediacenter/.
198
CHAPTER 23
All environmental chemicals necessary for life enter After coalescing into bundles surrounded by glia-like
the body by the nose and mouth. The senses of smell ensheathing cells (termed la), the receptor cell axons
(olfaction) and taste (gustation) monitor those chemi- pass through the cribriform plate to the olfactory bulbs,
cals, determine the avor and palatability of foods and where they synapse with dendrites of other cell types
beverages, and warn of dangerous environmental condi- within the glomeruli (Fig. 23-2). These spherical struc-
tions, including re, air pollution, leaking natural gas, tures, which make up a distinct layer of the olfactory
and bacteria-laden foodstuffs. These senses contribute bulb, are a site of convergence of information, since
signicantly to quality of life and, when dysfunctional, many more bers enter than leave them. Receptor
can have untoward physical and psychological conse- cells that express the same type of receptor project to
quences. A basic understanding of these senses in health the same glomeruli, effectively making each glomerulus
and disease is critical for the physician, since thousands a functional unit. The major projection neurons of the
of patients present to doctors ofces each year with olfactory systemthe mitral and tufted cellssend pri-
complaints of chemosensory dysfunction. Among the mary dendrites into the glomeruli, connecting not only
more important developments in neurology has been with the incoming receptor cell axons but with den-
the discovery that decreased smell function is per- drites of periglomerular cells. The activity of the mitral/
haps the rst sign of neurodegenerative diseases such as tufted cells is modulated by the periglomerular cells,
Alzheimers disease (AD) and Parkinsons disease (PD), secondary dendrites from other mitral/tufted cells, and
signifying their presymptomatic phase. granule cells, the most numerous cells of the bulb. The
latter cells, which are largely GABAergic, receive inputs
from central brain structures and modulate the output
ANATOMY AND PHYSIOLOGY of the mitral/tufted cells. Interestingly, like the olfac-
tory receptor cells, some cells within the bulb undergo
Olfactory system
replacement. Thus, neuroblasts formed within the ante-
Odorous chemicals enter the nose during inhalation and rior subventricular zone of the brain migrate along the
active snifng as well as during deglutition. After reach- rostral migratory stream, ultimately becoming granule
ing the highest recesses of the nasal cavity, they dis- and periglomerular cells.
solve in the olfactory mucus and diffuse or are actively The axons of the mitral and tufted cells synapse
transported to receptors on the cilia of olfactory recep- within the primary olfactory cortex (POC) (Fig. 23-3).
tor cells. The cilia, dendrites, cell bodies, and proximal The POC is dened as the cortical structures that
axonal segments of these bipolar cells are situated within receive direct projections from the olfactory bulb, most
a specialized neuroepithelium that covers the cribriform notably the piriform and entorhinal cortices. Although
plate, the superior nasal septum, the superior turbinate, olfaction is unique in that its initial afferent projec-
and sectors of the middle turbinate (Fig. 23-1). Each of tions bypass the thalamus, persons with damage to the
the 6 million bipolar receptor cells expresses only one thalamus can exhibit olfactory decits, particularly ones
of 450 receptor protein types, most of which respond of odor identication. Those decits probably reect
to more than a single chemical. When damaged, the the involvement of thalamic connections between the
receptor cells can be replaced by stem cells near the primary olfactory cortex and the orbitofrontal cortex
basement membrane. Unfortunately, such replacement (OFC), where odor identication occurs. The close
is often incomplete. anatomic ties between the olfactory system and the
199
200
SECTION II
Clinical Manifestations of Neurologic Disease
FIGURE 23-1
Anatomy of the olfactory neural pathways, showing the port [FACS], Georgetown University Medical Center; used
distribution of olfactory receptors in the roof of the nasal with permission.)
cavity. (Copyright David Klemm, Faculty and Curriculum Sup-
Circumvallate
CHAPTER 23
Taste
bud
TRC
Foliate
Taste
Fungiform
FIGURE 23-4
Schematic of the taste bud and its opening (pore), as well as the location of buds on the three major
types of papillae: fungiform (anterior), foliate (lateral), and circumvallate (posterior). TRC, taste receptor
cell.
in a liquid, tastants enter the opening of the taste bud greater petrosal and chorda tympani nerves); CN IX
the taste poreand bind to receptors on microvilli, (the glossopharyngeal nerve); and CN X (the vagus nerve)
small extensions of receptor cells within each taste bud. (Fig. 23-5). CN VII innervates the anterior tongue and
Such binding changes the electrical potential across the
taste cell, resulting in neurotransmitter release onto the
rst-order taste neurons. Although humans have 7500
taste buds, not all harbor taste-sensitive cells; some con-
tain only one class of receptor (e.g., cells responsive
only to sugars), whereas others contain cells sensitive
to more than one class. The number of taste receptor
cells per taste bud ranges from zero to well over 100.
A small family of three G-protein-coupled receptors
(GPCRs)T1R1, T1R2, and T1R3mediate sweet
and umami taste sensations. Umami (savory) refers to
the avors of meat, cheese, and broth due to glutamate
and related compounds. Bitter sensations, in contrast,
depend on T2R receptors, a family of 30 GPCRs
expressed on cells different from those which express
the sweet and umami receptors. T2Rs sense a wide
range of bitter substances but do not distinguish among
them. Sour tastants are sensed by the PKD2L1 recep-
tor, a member of the transient receptor potential protein
(TRP) family. Perception of salty sensations, such as FIGURE 23-5
those induced by sodium chloride, arises from the entry Schematic of the cranial nerves that mediate taste func-
of Na+ ions into the cells via specialized membrane tion, including the chorda tympani nerve (CN VII), the glos-
channels such as the amiloride-sensitive Na+ channel. sopharyngeal nerve (CN IX), and the vagus nerve (CN X).
Taste information is sent to the brain via three cra- (Copyright David Klemm, Faculty and Curriculum Support
nial nerves (CNs): CN VII (the facial nerve, which [FACS], Georgetown University Medical Center; used with
involves the intermediate nerve with its branches, the permission.)
202 all of the soft palate, CN IX innervates the posterior 40
sublingual glands, whereas the greater petrosal nerve Scores on the University of Pennsylvania Smell Identi-
supplies the palatine glands, thereby inuencing saliva cation Test (UPSIT) as a function of subject age and sex.
production. Numbers by each data point indicate sample sizes. Note that
The axons of the projection cells that synapse with women identify odorants better than men at all ages. (From
taste buds enter the rostral portion of the nucleus of the Doty et al: Science 226:1421, 1984. Copyright 1984 Ameri-
solitary tract (NTS) within the medulla of the brainstem can Association for the Advancement of Science.)
(Fig. 23-5). From the NTS, neurons then project to a
division of the ventroposteromedial thalamic nucleus
(VPM) via the medial lemniscus. From there projec- infections, head trauma, and chronic rhinosinusitis. The
tions are made to the rostral part of the frontal opercu- physiologic basis for most head traumarelated losses
lum and adjoining insula, a brain region considered the is the shearing and subsequent scarring of the olfactory
primary taste cortex (PTC). Projections from the primary la as they pass from the nasal cavity into the brain cav-
taste cortex then go to the secondary taste cortex, namely, ity. The cribriform plate does not have to be fractured
the caudolateral OFC. This brain region is involved in or show pathology for smell loss to be present. Severity
the conscious recognition of taste qualities. Moreover, of trauma, as indexed by a poor Glasgow Coma Rating
since it contains cells that are activated by several sen- on presentation and the length of posttraumatic amne-
sory modalities, it is probably a center for establishing sia, is associated with higher risk of olfactory impair-
avor. ment. Fewer than 10% of posttraumatic anosmic patients
recover age-related normal function over time. Upper
respiratory infections, such as those associated with the
common cold, inuenza, pneumonia, or HIV, can
DISORDERS OF OLFACTION
directly and permanently harm the olfactory epithelium
The ability to smell is inuenced by factors such as age, by decreasing receptor cell numbers, damaging cilia on
sex, general health, nutrition, smoking, and reproduc- remaining receptor cells, and inducing the replacement
tive state. Women typically outperform men on tests of of sensory epithelium with respiratory epithelium. The
olfactory function and retain normal smell function to a smell loss associated with chronic rhinosinusitis is related
later age. Signicant decrements in the ability to smell to disease severity, with most loss occurring in cases in
are present in over 50% of the population between 65 which rhinosinusitis and polyposis are both present.
and 80 years of age and in 75% of those 80 years and Although systemic glucocorticoid therapy usually can
older (Fig. 23-6). Such presbyosmia helps explain why induce short-term functional improvement, it does not,
many elderly persons report that food has little avor, on average, return smell test scores to normal, implying
a problem that can result in nutritional disturbances. It that chronic permanent neural loss is present and/or that
also helps explain why a disproportionate number of short-term administration of systemic glucocorticoids
the elderly die in accidental gas poisonings. A relatively does not mitigate the inammation completely. It is well
complete listing of conditions and disorders that have established that microinammation in an otherwise seem-
been associated with olfactory dysfunction is presented ingly normal epithelium can inuence smell function.
in Table 23-1. A number of neurodegenerative diseases are accom-
Aside from aging, the three most common identiable panied by olfactory impairment, including AD, PD,
causes of long-lasting or permanent smell loss seen in the Huntingtons disease, Down syndrome, parkinsonism-
clinic are, in order of frequency, severe upper respiratory dementia complex of Guam, dementia with Lewy bodies
TABLE 23-1 203
DISORDERS AND CONDITIONS ASSOCIATED WITH COMPROMISED OLFACTORY FUNCTION
AS MEASURED BY OLFACTORY TESTING
22q11 deletion syndrome Liver disease
AIDS/HIV infection Lubag disease
Adenoid hypertrophy Medications
Adrenal cortical insufciency Migraine
Age Multiple sclerosis
CHAPTER 23
Alcoholism Multi-infarct dementia
Allergies Narcolepsy with cataplexy
Alzheimers disease Neoplasms, cranial/nasal
Amyotrophic lateral sclerosis Nutritional deciencies
Anorexia nervosa Obstructive pulmonary disease
(DLB), multiple system atrophy, vascular parkinsonism, associated with higher levels of AD-related pathology
corticobasal syndrome, frontotemporal dementia, mul- even after controlling for apolipoprotein E4 alleles and
tiple sclerosis (MS), and idiopathic rapid eye movement the level of episodic memory function present at the time
(REM) behavioral sleep disorder (iRBD). The olfac- of olfactory testing. Olfactory impairment in PD often
tory disturbance of MS varies as a function of the plaque predates the clinical diagnosis by at least 4 years. Studies
activity within the frontal and temporal lobes. In post- of the sequence of Lewy body and abnormal -synuclein
mortem studies of patients with very mild presymp- development in staged PD cases, along with evidence
tomatic signs of AD, poorer smell function has been that the smell loss presents early, is stable over time, and is
204 not affected by PD medications, suggest that the olfactory inammatory conditions), (3) damage to the taste buds
bulbs may be, along with the dorsomotor nucleus of the themselves (e.g., local trauma, invasive carcinomas), (4)
vagus, the site of rst neural damage in PD. Smell loss is damage to the neural pathways innervating the taste
more marked in patients with early clinical manifestations buds (e.g., middle ear infections), (5) damage to cen-
of DLB than in those with mild AD. Interestingly, smell tral structures (e.g., multiple sclerosis, tumor, epilepsy,
loss is minimal or nonexistent in progressive supranuclear stroke), and (6) systemic disturbances of metabolism
palsy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (e.g., diabetes, thyroid disease, medications). Bells palsy
(MPTP)-induced parkinsonism. is among the most common causes of CN VII injury
The smell loss seen in iRBD is of the same magni- that results in taste disturbance. Unlike CN VII, CN
SECTION II
tude as that found in PD. This is of particular inter- IX is relatively protected along its path, although iat-
est to clinicians since patients with iRBD frequently rogenic interventions such as tonsillectomy, bronchos-
develop PD and hyposmia. iRBD may actually repre- copy, laryngoscopy, and radiation therapy can result in
sent an early associated condition of PD. REM behavior selective injury. Migraine is associated on rare occasions
disorder not only is seen in its idiopathic form but also with a gustatory prodrome or aura, and certain tastes
can be associated with narcolepsy. This led to a study may trigger a migraine. Although a number of disorders
of narcoleptic patients with and without REM behav- can affect CN IX, including tumors, trauma, vascular
Clinical Manifestations of Neurologic Disease
ior disorder that demonstrated that narcolepsy, inde- lesions, and infection, it remains unclear if noticeable
pendent of REM behavior disorder, was associated with taste disturbance can result from such factors.
signicant impairments in olfactory function. Orexin A, Although both taste and smell can be adversely inu-
also known as hypocretin-1, is dramatically diminished enced by pharmacologic agents, drug-related taste alter-
or undetectable in the cerebrospinal uid of patients ations are more common. Indeed, over 250 medications
with narcolepsy and cataplexy. The orexin-containing have been reported to alter the ability to taste. Major
neurons in the hypothalamus project throughout the offenders include antineoplastic agents, antirheumatic
olfactory system (from the olfactory epithelium to the drugs, antibiotics, and blood pressure medications. Ter-
olfactory cortex), and damage to these orexin-contain- binane, a commonly used antifungal, has been linked
ing projections may be one underlying mechanism for to taste disturbance lasting up to 3 years. In a controlled
impaired olfactory performance in narcoleptic patients. trial, nearly two-thirds of individuals taking eszopiclone
The administration of intranasal orexin A (hypocre- (Lunesta) experienced a bitter dysgeusia which was
tin-1) appears to result in improved olfactory function stronger in women, systematically related to the time
relative to a placebo, supporting the notion that mild since drug administration, and positively correlated with
olfactory impairment is not only a primary feature of both blood and saliva levels of the drug. Intranasal use
narcolepsy with cataplexies but that CNS orexin de- of nasal gels and sprays containing zinccommon over-
ciency may be a fundamental part of the mechanism for the-counter prophylactics for upper respiratory viral
this loss. infectionshas been implicated in loss of smell func-
tion. Whether their efcacy in preventing such infec-
tions, which are the most common cause of anosmia
and hyposmia, outweighs their potential detriment to
DISORDERS OF TASTE smell function requires study.
As with olfaction, a number of systemic disorders
The majority of patients who present with complaints can affect taste. They include chronic renal failure, end-
of taste dysfunction exhibit olfactory, not taste, loss. stage liver disease, vitamin and mineral deciencies,
This is the case because most avors attributed to taste diabetes, and hypothyroidism, to name a few. Psychi-
actually depend on retronasal stimulation of the olfac- atric conditions can be associated with chemosensory
tory receptors during deglutition. As noted earlier, alterations (e.g., depression, schizophrenia, bulimia). A
taste buds only mediate basic tastes such as sweet, sour, review of tactile, gustatory, and olfactory hallucinations
bitter, salty, and umami. Signicant impairment of demonstrated that no one type of hallucinatory experi-
whole-mouth gustatory function is rare outside of gen- ence is pathognomonic to any specic diagnosis.
eralized metabolic disturbances or systemic use of some
medications, since taste bud regeneration occurs and
peripheral damage alone would require the involve-
ment of multiple cranial nerve pathways. Nonetheless, CLINICAL EVALUATION
taste can be inuenced by (1) the release of foul-tasting In most cases, a careful clinical history will establish the
materials from the oral cavity from oral medical con- probable etiology of a chemosensory problem, includ-
ditions and appliances (e.g., gingivitis, purulent sial- ing questions about its nature, onset, duration, and pattern
adenitis), (2) transport problems of tastants to the taste of uctuations. Sudden loss suggests the possibility of head
buds (e.g., drying of the orolingual mucosa, infections, trauma, ischemia, infection, or a psychiatric condition.
Gradual loss can reect the development of a progressive accurately. A number of standardized olfactory and taste 205
obstructive lesion. Intermittent loss suggests the likelihood tests are commercially available. Most evaluate the abil-
of an inammatory process. The patient should be asked ity of patients to detect and identify odors or tastes. For
about potential precipitating events, such as cold or u example, the most widely used of these tests, the 40-item
infections before symptom onset, as they often are under- University of Pennsylvania Smell Identication Test
appreciated. Information regarding head trauma, smok- (UPSIT), employs norms based on nearly 4000 normal
ing habits, drug and alcohol abuse (e.g., intranasal cocaine, subjects. A determination is made of both absolute dys-
chronic alcoholism in the context of Wernickes and Kor- function (i.e., mild loss, moderate loss, severe loss, total
sakoffs syndromes), exposures to pesticides and other toxic loss, probable malingering) and relative dysfunction (per-
CHAPTER 23
agents, and medical interventions are also informative. A centile rank for age and sex). Although electrophysiologic
determination of all the medications the patient was tak- testing is available at some smell and taste centers (e.g.,
ing before and at the time of symptom onset is important, odor event-related potentials), such tests require com-
since many can cause chemosensory disturbances. Comor- plex stimulus presentation and recording equipment and
bid medical conditions associated with smell impairment, rarely provide additional diagnostic information. In addi-
such as renal failure, liver disease, hypothyroidism, diabe- tion to electrogustometers, commercial chemical taste
tes, and dementia, should be assessed. Delayed puberty in tests are now available. Most employ lter paper strips
helpful. One common approach is a short course of oral occasionally inuence B12 absorption. This can result
prednisone, typically 60 mg daily for 4 days and then in a relative deciency of B12, theoretically contribut-
tapered by 10 mg daily. The utility of restoring olfac- ing to olfactory nerve disturbance. B2 (riboavin) and
tion with either topical or systemic glucocorticoids has magnesium supplements are reported in the alterna-
been studied. Topical intranasal glucocorticoids were tive medicine literature to aid in the management of
less effective in general than systemic glucocorticoids; migraine headaches that may be associated with smell
however, nasal steroid administration techniques were dysfunction.
Clinical Manifestations of Neurologic Disease
not analyzed. Intranasal glucocorticoids are more effec- A number of medicines have been reported to ame-
tive if administered in Moffetts position (head in the liorate olfactory symptoms, although strong scientic
inverted position such as over the edge of the bed with evidence for efcacy is generally lacking. A report that
the bridge of the nose perpendicular to the oor). After theophylline improved smell function was not double-
head trauma, an initial trial of glucocorticoids may help blinded and lacked a control group, failing to take into
reduce local edema and the potential deleterious deposi- account that some meaningful improvement occurs
tion of scar tissue around olfactory la at the level of the without treatment. Indeed, the percentage of patients
cribriform plate. reported to be responsive to the treatment was about
Treatments are limited for patients with chemosen- the same as that noted by others to show spontaneous
sory loss or primary injury to neural pathways. None- improvement over a similar time period (50%). Anti-
theless, spontaneous recovery can occur. In a follow-up epileptics and some antidepressants (e.g., amitriptyline)
study of 542 patients presenting with smell loss from a have been used to treat dysosmias and smell distor-
variety of causes, modest improvement occurred over tions, particularly after head trauma. Ironically, amitrip-
an average period of 4 years in about half the partici- tyline is also frequently on the list of medications that
pants. However, only 11% of the anosmic and 23% can ultimately distort smell and taste function, possibly
of the hyposmic patients regained normal age-related from its anticholinergic effects. The use of donepezil
function. Interestingly, the amount of dysfunction pres- (an acetylcholinesterase inhibitor) in AD may result in
ent at the time of presentation, not etiology, was the improvements in smell identication measures that cor-
best predictor of prognosis. Other predictors were the relate with overall clinician-based impressions of change
patients age and the time between the onset of dys- scales (Clinician Interview Based Impression of Sever-
function and initial testing. ity [CIBIC]-plus). Smell identication function could
A nonblinded study reported that patients with become a useful measure to assess overall treatment
hyposmia may benet from smelling strong odors (e.g., response with this medication.
eucalyptol, citronella, eugenol, and phenyl ethyl alco- A major and often overlooked element of therapy
hol) before going to bed and immediately upon awak- comes from chemosensory testing itself. Conrmation
ing each day over the course of several months. The or lack of conrmation of loss is benecial to patients
rationale for this approach comes from animal stud- who come to believe, in light of unsupportive fam-
ies demonstrating that prolonged exposure to odorants ily members and medical providers, that they may be
can induce increased neural activity within the olfactory crazy. In cases in which the loss is minor, patients
bulb. -Lipoic acid (200 mg two or three times daily), can be informed of the likelihood of a more posi-
an essential cofactor for many enzyme complexes with tive prognosis. Importantly, quantitative testing places
possible antioxidant effects, has been reported to be the patients problem into overall perspective. Thus, it
benecial in mitigating smell loss after viral infection of is often therapeutic for an older person to know that
the upper respiratory tract, although double-blind stud- although his or her smell function is not what it used
ies are needed to conrm this observation. This agent to be, it still falls above the average of his or her peer
has also been suggested to be useful in some cases of group. Without testing, many such patients are simply
hypogeusia and burning mouth syndrome. told they are getting old and nothing can be done for
The use of zinc and vitamin A in treating olfac- them, leading in some cases to depression and decreased
tory disturbances is controversial; not much benet self-esteem.
CHAPTER 24
DISORDERS OF HEARING
Anil K. Lalwani
Hearing loss is one of the most common sensory disor- chain in the middle ear serve as an impedance-matching
ders in humans and can present at any age. Nearly 10% mechanism, improving the efciency of energy transfer
of the adult population has some hearing loss, and one- from air to the uid-lled inner ear.
third of individuals age >65 years have a hearing loss of Stereocilia of the hair cells of the organ of Corti,
sufcient magnitude to require a hearing aid. which rests on the basilar membrane, are in con-
tact with the tectorial membrane and are deformed by
the traveling wave. A point of maximal displacement of
PHYSIOLOGY OF HEARING
the basilar membrane is determined by the frequency of
The function of the external and middle ear is to the stimulating tone. High-frequency tones cause maxi-
amplify sound to facilitate conversion of the mechanical mal displacement of the basilar membrane near the base
energy of the sound wave into an electrical signal by the of the cochlea, whereas for low-frequency sounds, the
inner ear hair cells, a process called mechanotransduc- point of maximal displacement is toward the apex of the
tion (Fig. 24-1). Sound waves enter the external audi- cochlea.
tory canal and set the tympanic membrane in motion, The inner and outer hair cells of the organ of Corti
which in turn moves the malleus, incus, and stapes of have different innervation patterns, but both are mecha-
the middle ear. Movement of the footplate of the sta- noreceptors. The afferent innervation relates princi-
pes causes pressure changes in the uid-lled inner ear, pally to the inner hair cells, and the efferent innervation
eliciting a traveling wave in the basilar membrane of relates principally to outer hair cells. The motility of the
the cochlea. The tympanic membrane and the ossicular outer hair cells alters the micromechanics of the inner
External Tympanic
acoustic membrane Vestibule Oval
canal window
Eustachian tube
Round
Lobe window Cochlear
duct
A External ear B
FIGURE 24-1
Ear anatomy. A. Drawing of modied coronal section the middle and inner ear demonstrated. B. High-resolution
through external ear and temporal bone, with structures of view of inner ear.
207
208 hair cells, creating a cochlear amplier, which explains auditory pathways (Fig. 24-2). In general, lesions in the
the exquisite sensitivity and frequency selectivity of the auricle, external auditory canal, or middle ear that impede the
cochlea. transmission of sound from the external environment to the
Beginning in the cochlea, the frequency specicity is inner ear cause conductive hearing loss, whereas lesions that
maintained at each point of the central auditory path- impair mechanotransduction in the inner ear or transmission of
way: dorsal and ventral cochlear nuclei, trapezoid body, the electrical signal along the eighth nerve to the brain cause
superior olivary complex, lateral lemniscus, inferior col- sensorineural hearing loss.
liculus, medial geniculate body, and auditory cortex. At
low frequencies, individual auditory nerve bers can
Conductive hearing loss
SECTION II
Hearing Loss
Cerumen impaction
TM perforation
Cholesteatoma History
SOM abnormal normal
AOM
External auditory Otologic examination Pure tone and
canal atresia/ speech audiometry
stenosis
Eustachian tube
dysfunction
Tympanosclerosis
FIGURE 24-2
An algorithm for the approach to hearing loss. HL, hear- media; BAER, brainstem auditory evoked response; *CT
ing loss; SNHL, sensorineural hearing loss; TM, tympanic scan of temporal bone; MRI scan.
membrane; SOM, serous otitis media; AOM, acute otitis
occurs with necrosis of the long process of the incus in Disorders that lead to the formation of a pathologic 209
trauma or infection; otosclerosis; or uid, scarring, or third window in the inner ear can be associated with
neoplasms in the middle ear. Rarely, inner ear malfor- conductive hearing loss. There are normally two major
mations or pathologies may also be associated with con- openings, or windows, that connect the inner ear with
ductive hearing loss. the middle ear and serve as conduits for transmission of
Eustachian tube dysfunction is extremely common sound; these are, respectively, the oval and round win-
in adults and may predispose to acute otitis media dows. A third window is formed where the normally
(AOM) or serous otitis media (SOM). Trauma, AOM, hard otic bone surrounding the inner ear is eroded; dis-
or chronic otitis media are the usual factors responsi- sipation of the acoustic energy at the third window is
CHAPTER 24
ble for tympanic membrane perforation. While small responsible for the inner ear conductive hearing loss.
perforations often heal spontaneously, larger defects The superior semicircular canal dehiscence syndrome
usually require surgical intervention. Tympanoplasty resulting from erosion of the otic bone over the supe-
is highly effective (>90%) in the repair of tympanic rior circular canal can present with conductive hearing
membrane perforations. Otoscopy is usually suf- loss that mimics otosclerosis. A common symptom is
cient to diagnose AOM, SOM, chronic otitis media, vertigo evoked by loud sounds (Tullio phenomenon),
cerumen impaction, tympanic membrane perfora- by Valsalva maneuvers that change middle ear pressure,
Disorders of Hearing
tion, and eustachian tube dysfunction; tympanometry or by applying positive pressure on the tragus (the car-
can be useful to conrm the clinical suspicion of these tilage anterior to the external opening of the ear canal).
conditions. Patients with this syndrome also complain of being able
Cholesteatoma, a benign tumor composed of strati- to hear the movement of their eyes and neck. A large
ed squamous epithelium in the middle ear or mastoid, jugular bulb or jugular bulb diverticulum can create a
occurs frequently in adults. This is a slowly growing third window by eroding into the vestibular aqueduct
lesion that destroys bone and normal ear tissue. Theo- or posterior semicircular canal; the symptoms are simi-
ries of pathogenesis include traumatic immigration and lar to those of the superior semicircular canal dehiscence
invasion of squamous epithelium through a retraction syndrome.
pocket, implantation of squamous epithelia in the mid-
dle ear through a perforation or surgery, and metaplasia
following chronic infection and irritation. On exami- Sensorineural hearing loss
nation, there is often a perforation of the tympanic Sensorineural hearing loss results from either damage to
membrane lled with cheesy white squamous debris. A the mechanotransduction apparatus of the cochlea or
chronically draining ear that fails to respond to appro- disruption of the electrical conduction pathway from
priate antibiotic therapy should raise suspicion of a cho- the inner ear to the brain. Thus, injury to hair cells,
lesteatoma. Conductive hearing loss secondary to ossic- supporting cells, auditory neurons, or the central audi-
ular erosion is common. Surgery is required to remove tory pathway can cause sensorineural hearing loss. Dam-
this destructive process. age to the hair cells of the organ of Corti may be caused
Conductive hearing loss with a normal ear canal by intense noise, viral infections, ototoxic drugs (e.g.,
and intact tympanic membrane suggests either ossicular salicylates, quinine and its synthetic analogues, amino-
pathology or the presence of third window in the glycoside antibiotics, loop diuretics such as furosemide
inner ear (see later). Fixation of the stapes from oto- and ethacrynic acid, and cancer chemotherapeutic
sclerosis is a common cause of low-frequency conduc- agents such as cisplatin), fractures of the temporal bone,
tive hearing loss. It occurs equally in men and women meningitis, cochlear otosclerosis (see earlier), Mnires
and is inherited as an autosomal dominant trait with disease, and aging. Congenital malformations of the
incomplete penetrance; in some cases, it may be a inner ear may be the cause of hearing loss in some
manifestation of osteogenesis imperfecta. Hearing adults. Genetic predisposition alone or in concert with
impairment usually presents between the late teens environmental exposures may also be responsible (see
and the forties. In women, the otosclerotic process is later).
accelerated during pregnancy, and the hearing loss is Presbycusis (age-associated hearing loss) is the most
often rst noticeable at this time. A hearing aid or a common cause of sensorineural hearing loss in adults. In
simple outpatient surgical procedure (stapedectomy) the early stages, it is characterized by symmetric, gentle
can provide adequate auditory rehabilitation. Exten- to sharply sloping high-frequency hearing loss. With
sion of otosclerosis beyond the stapes footplate to progression, the hearing loss involves all frequencies.
involve the cochlea (cochlear otosclerosis) can lead to More importantly, the hearing impairment is associated
mixed or sensorineural hearing loss. Fluoride therapy with signicant loss in clarity. There is a loss of discrim-
to prevent hearing loss from cochlear otosclerosis is of ination for phonemes, recruitment (abnormal growth
uncertain value. of loudness), and particular difculty in understanding
210 speech in noisy environments such as at restaurants (see later). Hearing loss can accompany hereditary senso-
and social events. Hearing aids are helpful in enhanc- rimotor neuropathies and inherited disorders of myelin.
ing the signal-to-noise ratio by amplifying sounds that Tumors of the cerebellopontine angle such as vestibular
are close to the listener. Although hearing aids are able schwannoma and meningioma usually present with asym-
to amplify sounds, they cannot restore the clarity of hearing. metric sensorineural hearing loss with greater deterioration
Thus, amplication with hearing aids may provide only of speech understanding than pure tone hearing. Multi-
limited rehabilitation once the word recognition score ple sclerosis may present with acute unilateral or bilateral
deteriorates below 50%. Cochlear implants are the treat- hearing loss; typically, pure tone testing remains relatively
ment of choice when hearing aids prove inadequate, stable while speech understanding uctuates. Isolated laby-
SECTION II
even when hearing loss is incomplete (see later). rinthine infarction can present with acute hearing loss and
Mnires disease is characterized by episodic vertigo, vertigo due to a cerebrovascular accident involving the
uctuating sensorineural hearing loss, tinnitus, and aural posterior circulation, usually the anterior inferior cerebellar
fullness. Tinnitus and/or deafness may be absent during artery; it may also be the heralding sign of impending cata-
the initial attacks of vertigo, but it invariably appears as strophic basilar artery infarction (Chap. 27).
the disease progresses and increases in severity during A nding of conductive and sensory hearing loss in
acute attacks. The annual incidence of Mnires dis- combination is termed mixed hearing loss. Mixed hear-
Clinical Manifestations of Neurologic Disease
ease is 0.57.5 per 1000; onset is most frequently in the ing losses are due to pathology of both the middle and
fth decade of life but may also occur in young adults inner ear, as can occur in otosclerosis involving the ossi-
or the elderly. Histologically, there is distention of the cles and the cochlea, head trauma, chronic otitis media,
endolymphatic system (endolymphatic hydrops) lead- cholesteatoma, middle ear tumors, and some inner ear
ing to degeneration of vestibular and cochlear hair cells. malformations.
This may result from endolymphatic sac dysfunction Trauma resulting in temporal bone fractures may be
secondary to infection, trauma, autoimmune disease, associated with conductive, sensorineural, or mixed
inammatory causes, or tumor; an idiopathic etiology hearing loss. If the fracture spares the inner ear, there
constitutes the largest category and is most accurately may simply be conductive hearing loss due to rupture
referred to as Mnires disease. Although any pattern of of the tympanic membrane or disruption of the ossicular
hearing loss can be observed, typically, low-frequency, chain. These abnormalities can be surgically corrected.
unilateral sensorineural hearing impairment is pres- Profound hearing loss and severe vertigo are associated
ent. MRI should be obtained to exclude retrocochlear with temporal bone fractures involving the inner ear.
pathology such as a cerebellopontine angle tumor or A perilymphatic stula associated with leakage of inner
demyelinating disorder. Therapy is directed toward the ear uid into the middle ear can occur and may require
control of vertigo. A 2-g/d low-salt diet is the mainstay surgical repair. An associated facial nerve injury is not
of treatment for control of rotatory vertigo. Diuretics, a uncommon. CT is best suited to assess fracture of the
short course of glucocorticoids, and intratympanic gen- traumatized temporal bone, evaluate the ear canal, and
tamicin may also be useful adjuncts in recalcitrant cases. determine the integrity of the ossicular chain and the
Surgical therapy of vertigo is reserved for unresponsive involvement of the inner ear. CSF leaks that accompany
cases and includes endolymphatic sac decompression, temporal bone fractures are usually self-limited; the
labyrinthectomy, and vestibular nerve section. Both lab- value of prophylactic antibiotics is uncertain.
yrinthectomy and vestibular nerve section abolish rota- Tinnitus is dened as the perception of a sound when
tory vertigo in >90% of cases. Unfortunately, there is there is no sound in the environment. It may have a
no effective therapy for hearing loss, tinnitus, or aural buzzing, roaring, or ringing quality and may be pulsa-
fullness from Mnires disease. tile (synchronous with the heartbeat). Tinnitus is often
Sensorineural hearing loss may also result from any associated with either a conductive or sensorineural
neoplastic, vascular, demyelinating, infectious, or degen- hearing loss. The pathophysiology of tinnitus is not well
erative disease or trauma affecting the central auditory understood. The cause of the tinnitus can usually be
pathways. HIV leads to both peripheral and central audi- determined by nding the cause of the associated hear-
tory system pathology and is associated with sensorineural ing loss. Tinnitus may be the rst symptom of a serious
hearing impairment. condition such as a vestibular schwannoma. Pulsatile
Primary diseases of the central nervous system can tinnitus requires evaluation of the vascular system of the
also present with hearing impairment. Characteristically, head to exclude vascular tumors such as glomus jugu-
a reduction in clarity of hearing and speech comprehen- lare tumors, aneurysms, dural arteriovenous stulas, and
sion is much greater than the loss of the ability to hear stenotic arterial lesions; it may also occur with SOM. It
pure tone. Auditory testing is consistent with an auditory is most commonly associated with some abnormality of
neuropathy; normal otoacoustic emissions (OAE) and an the jugular bulb such as a large jugular bulb or jugular
abnormal auditory brainstem response (ABR) are typical bulb diverticulum.
GENETIC CAUSES OF HEARING LOSS nant (DFNA). Less than 5% is X-linked or maternally 211
inherited via the mitochondria.
More than half of childhood hearing impairment Nearly 100 loci harboring genes for nonsyndromic
is thought to be hereditary; hereditary hearing HHI have been mapped, with equal numbers of domi-
impairment (HHI) can also manifest later in life. nant and recessive modes of inheritance; numerous
HHI may be classied as either nonsyndromic, when genes have now been cloned (Table 24-1). The hear-
hearing loss is the only clinical abnormality, or syn- ing genes fall into the categories of structural proteins
dromic, when hearing loss is associated with anomalies (MYH9, MYO7A, MYO15, TECTA, DIAPH1), tran-
in other organ systems. Nearly two-thirds of HHIs are scription factors (POU3F4, POU4F3), ion channels
CHAPTER 24
nonsyndromic, and the remaining one-third are syn- (KCNQ4, SLC26A4), and gap junction proteins (GJB2,
dromic. Between 70 and 80% of nonsyndromic HHI GJB3, GJB6). Several of these genes, including GJB2,
is inherited in an autosomal recessive manner and des- TECTA, and TMC1, cause both autosomal dominant
ignated DFNB; another 1520% is autosomal domi- and recessive forms of nonsyndromic HHI. In general,
Disorders of Hearing
TABLE 24-1
HEREDITARY HEARING IMPAIRMENT GENES
DESIGNATION GENE FUNCTION DESIGNATION GENE FUNCTION
because it is responsible for nearly 20% of all cases of Alport syndrome COL4A3-5 Cytoskeletal protein
childhood deafness; half of genetic deafness in children BOR syndrome EYA1 Developmental gene
is GJB2-related. Two frameshift mutations, 35delG
SIX5 Developmental gene
and 167delT, account for >50% of the cases; however,
SIX1 Developmental gene
SECTION II
CHAPTER 24
larger tumors. In addition to hearing loss, Mnires dis-
ease may be associated with episodic vertigo, tinnitus, The minimum audiologic assessment for hearing loss
and aural fullness. Hearing loss with otorrhea is most should include the measurement of pure tone air-
likely due to chronic otitis media or cholesteatoma. conduction and bone-conduction thresholds, speech
Examination should include the auricle, external ear reception threshold, word recognition score, tympa-
canal, and tympanic membrane. The external ear canal nometry, acoustic reexes, and acoustic-reex decay.
of the elderly is often dry and fragile; it is preferable This test battery provides a screening evaluation of the
Disorders of Hearing
to clean cerumen with wall-mounted suction or ceru- entire auditory system and allows one to determine
men loops and to avoid irrigation. In examining the whether further differentiation of a sensory (cochlear)
eardrum, the topography of the tympanic membrane from a neural (retrocochlear) hearing loss is indicated.
is more important than the presence or absence of Pure tone audiometry assesses hearing acuity for pure
the light reflex. In addition to the pars tensa (the lower tones. The test is administered by an audiologist and is
two-thirds of the eardrum), the pars flaccida above the performed in a sound-attenuated chamber. The pure
short process of the malleus should also be examined tone stimulus is delivered with an audiometer, an elec-
for retraction pockets that may be evidence of chronic tronic device that allows the presentation of specic fre-
eustachian tube dysfunction or cholesteatoma. Insuf- quencies (generally between 250 and 8000 Hz) at spe-
flation of the ear canal is necessary to assess tympanic cic intensities. Air- and bone-conduction thresholds
membrane mobility and compliance. Careful inspection are established for each ear. Air-conduction thresholds
of the nose, nasopharynx, and upper respiratory tract are determined by presenting the stimulus in air with
is indicated. Unilateral serous effusion should prompt a the use of headphones. Bone-conduction thresholds are
fiberoptic examination of the nasopharynx to exclude determined by placing the stem of a vibrating tuning
neoplasms. Cranial nerves should be evaluated with fork or an oscillator of an audiometer in contact with
special attention to facial and trigeminal nerves, which the head. In the presence of a hearing loss, broad-spec-
are commonly affected with tumors involving the cer- trum noise is presented to the nontest ear for masking
ebellopontine angle. purposes so that responses are based on perception from
The Rinne and Weber tuning fork tests, with a 512-Hz the ear under test.
tuning fork, are used to screen for hearing loss, differ- The responses are measured in decibels. An audiogram
entiate conductive from sensorineural hearing losses, is a plot of intensity in decibels of hearing threshold
and to confirm the findings of audiologic evaluation. versus frequency. A decibel (dB) is equal to 20 times the
Rinnes test compares the ability to hear by air conduc- logarithm of the ratio of the sound pressure required to
tion with the ability to hear by bone conduction. The achieve threshold in the patient to the sound pressure
tines of a vibrating tuning fork are held near the open- required to achieve threshold in a normal hearing per-
ing of the external auditory canal, and then the stem is son. Therefore, a change of 6 dB represents doubling
placed on the mastoid process; for direct contact, it may of sound pressure, and a change of 20 dB represents a
be placed on teeth or dentures. The patient is asked to tenfold change in sound pressure. Loudness, which
indicate whether the tone is louder by air conduction depends on the frequency, intensity, and duration of a
or bone conduction. Normally, and in the presence of sound, doubles with approximately each 10-dB increase
sensorineural hearing loss, a tone is heard louder by air in sound pressure level. Pitch, on the other hand, does
conduction than by bone conduction; however, with not directly correlate with frequency. The percep-
conductive hearing loss of 30 dB (see Audiologic tion of pitch changes slowly in the low and high fre-
Assessment), the bone-conduction stimulus is per- quencies. In the middle tones, which are important for
ceived as louder than the air-conduction stimulus. For human speech, pitch varies more rapidly with changes
the Weber test, the stem of a vibrating tuning fork is in frequency.
placed on the head in the midline and the patient asked Pure tone audiometry establishes the presence and
whether the tone is heard in both ears or better in one severity of hearing impairment, unilateral vs. bilateral
ear than in the other. With a unilateral conductive hear- involvement, and the type of hearing loss. Conduc-
tive hearing losses with a large mass component, as is
214 often seen in middle ear effusions, produce elevation of negative pressure in the middle ear, as with eustachian
thresholds that predominate in the higher frequencies. tube obstruction, the point of maximal compliance
Conductive hearing losses with a large stiffness compo- occurs with negative pressure in the ear canal (type C).
nent, as in xation of the footplate of the stapes in early A tympanogram in which no point of maximal compli-
otosclerosis, produce threshold elevations in the lower ance can be obtained is most commonly seen with dis-
frequencies. Often, the conductive hearing loss involves continuity of the ossicular chain (type Ad). A reduction
all frequencies, suggesting involvement of both stiffness in the maximal compliance peak can be seen in otoscle-
and mass. In general, sensorineural hearing losses such rosis (type As).
as presbycusis affect higher frequencies more than lower During tympanometry, an intense tone elicits con-
SECTION II
frequencies. An exception is Mnires disease, which traction of the stapedius muscle. The change in compli-
is characteristically associated with low-frequency sen- ance of the middle ear with contraction of the stapedius
sorineural hearing loss. Noise-induced hearing loss has muscle can be detected. The presence or absence of this
an unusual pattern of hearing impairment in which acoustic reex is important in determining the etiology
the loss at 4000 Hz is greater than at higher frequen- of hearing loss as well as in the anatomic localization
cies. Vestibular schwannomas characteristically affect the of facial nerve paralysis. The acoustic reex can help
higher frequencies, but any pattern of hearing loss can differentiate between conductive hearing loss due to
Clinical Manifestations of Neurologic Disease
CHAPTER 24
nals conducted via the inferior vestibular nerve. VEMP any stigma associated with their use. In general, the more
is a biphasic, short-latency response recorded from the severe the hearing impairment, the larger the hearing aid
tonically contracted sternocleidomastoid muscle in required for auditory rehabilitation. Digital hearing aids
response to loud auditory clicks or tones. VEMPs may lend themselves to individual programming, and mul-
be diminished or absent in patients with early and late tiple and directional microphones at the ear level may
Mnires disease, vestibular neuritis, benign paroxysmal be helpful in noisy surroundings. Since all hearing aids
positional vertigo, and vestibular schwannoma. On the amplify noise as well as speech, the only absolute solu-
Disorders of Hearing
other hand, the threshold for VEMPs may be lower in tion to the problem of noise is to place the microphone
cases of superior canal dehiscence, other inner ear dehis- closer to the speaker than the noise source. This arrange-
cence, and perilymphatic stula. ment is not possible with a self-contained, cosmetically
acceptable device. A significant limitation of rehabilita-
tion with a hearing aid is that while it is able to enhance
Imaging studies
detection of sound with amplification, it cannot restore
The choice of radiologic tests is largely determined clarity of hearing that is lost with presbycusis.
by whether the goal is to evaluate the bony anatomy Patients with unilateral deafness have difficulty
of the external, middle, and inner ear or to image the with sound localization and reduced clarity of hearing
auditory nerve and brain. Axial and coronal CT of the in background noise. They may benefit from a CROS
temporal bone with ne 0.3- to 0.6-mm cuts is ideal (contralateral routing of signal) hearing aid in which
for determining the caliber of the external auditory a microphone is placed on the hearing-impaired side
canal, integrity of the ossicular chain, and presence of and the sound is transmitted to the receiver placed on
middle-ear or mastoid disease; it can also detect inner the contralateral ear. The same result may be obtained
ear malformations. CT is also ideal for the detection with a bone-anchored hearing aid (BAHA), in which a
of bone erosion with chronic otitis media and choles- hearing aid clamps to a screw osseointegrated into the
teatoma. MRI is superior to CT for imaging of ret- skull on the hearing-impaired side. Like the CROS hear-
rocochlear pathology such as vestibular schwannoma, ing aid, the BAHA transfers the acoustic signal to the
meningioma, other lesions of the cerebellopontine contralateral hearing ear, but it does so by vibrating the
angle, demyelinating lesions of the brainstem, and skull. Patients with profound deafness on one side and
brain tumors. Both CT and MRI are equally capa- some hearing loss in the better ear are candidates for a
ble of identifying inner ear malformations and assess- BICROS hearing aid; it differs from the CROS hearing aid
ing cochlear patency for preoperative evaluation of in that the patient wears a hearing aid, and not simply
patients for cochlear implantation. a receiver, in the better ear. Unfortunately, CROS and
BAHA devices are often judged by patients to be unsat-
isfactory.
TREATMENT Disorders of the Sense of Hearing In many situations, including lectures and the the-
ater, hearing-impaired persons benefit from assistive
In general, conductive hearing losses are amenable to devices that are based on the principle of having the
surgical correction, while sensorineural hearing losses speaker closer to the microphone than any source of
are more difficult to manage. Atresia of the ear canal can noise. Assistive devices include infrared and frequency-
be surgically repaired, often with significant improve- modulated (FM) transmission as well as an electromag-
ment in hearing. Tympanic membrane perforations due netic loop around the room for transmission to the indi-
to chronic otitis media or trauma can be repaired with viduals hearing aid. Hearing aids with telecoils can also
an outpatient tympanoplasty. Likewise, conductive be used with properly equipped telephones in the same
hearing loss associated with otosclerosis can be treated way.
by stapedectomy, which is successful in 9095% of In the event that the hearing aid provides inadequate
cases. Tympanostomy tubes allow the prompt return of rehabilitation, cochlear implants may be appropriate.
normal hearing in individuals with middle ear effusions. Criteria for implantation include severe to profound
216
hearing loss with open-set sentence cognition of 40% Although speech should be in a loud, clear voice, one
under best aided conditions. Worldwide, nearly 200,000 should be aware that in sensorineural hearing losses
hearing impaired children and adults have received in general and in hard-of-hearing elderly in particular,
cochlear implants. Cochlear implants are neural pros- recruitment (abnormal perception of loud sounds) may
theses that convert sound energy to electrical energy be troublesome. Above all, optimal communication can-
and can be used to stimulate the auditory division of not take place without both parties giving it their full
the eighth nerve directly. In most cases of profound and undivided attention.
hearing impairment, the auditory hair cells are lost
but the ganglionic cells of the auditory division of the
SECTION II
rience sound that helps with speech reading, allows tubes in middle-ear effusions lasting v12 weeks. Loss of
open-set word recognition, and helps in modulating vestibular function and deafness due to aminoglycoside
the persons own voice. Usually, within the first 36 antibiotics can largely be prevented by careful monitor-
months after implantation, adult patients can under- ing of serum peak and trough levels.
stand speech without visual cues. With the current gen- Some 10 million Americans have noise-induced
eration of multichannel cochlear implants, nearly 75% hearing loss, and 20 million are exposed to hazard-
of patients are able to converse on the telephone. For ous noise in their employment. Noise-induced hear-
individuals who have had both eighth nerves destroyed ing loss can be prevented by avoidance of exposure to
by trauma or bilateral vestibular schwannomas (e.g., loud noise or by regular use of ear plugs or uid-lled
neurofibromatosis type 2), brainstem auditory implants ear muffs to attenuate intense sound. High-risk activi-
placed near the cochlear nucleus may provide auditory ties for noise-induced hearing loss include wood and
rehabilitation. metal working with electrical equipment and target
Tinnitus often accompanies hearing loss. As for back- practice and hunting with small rearms. All internal-
ground noise, tinnitus can degrade speech comprehen- combustion and electric engines, including snow and
sion in individuals with hearing impairment. Therapy leaf blowers, snowmobiles, outboard motors, and chain
for tinnitus is usually directed toward minimizing the saws, require protection of the user with hearing pro-
appreciation of tinnitus. Relief of the tinnitus may be tectors. Virtually all noise-induced hearing loss is pre-
obtained by masking it with background music. Hear- ventable through education, which should begin before
ing aids are also helpful in tinnitus suppression, as are the teenage years. Programs of industrial conservation of
tinnitus maskers, devices that present a sound to the hearing are required by Occupational Safety and Health
affected ear that is more pleasant to listen to than the Administration (OSHA) when the exposure over an
tinnitus. The use of a tinnitus masker is often followed 8-h period averages 85 dB. OSHA mandates that work-
by several hours of inhibition of the tinnitus. Antide- ers in such noisy environments have hearing monitor-
pressants have been shown to be beneficial in helping ing and protection programs that include a pre-employ-
patients cope with tinnitus. ment screen, annual audiologic assessment, as well as
Hard-of-hearing individuals often benefit from a the mandatory use of hearing protectors. Exposure to
reduction in unnecessary noise in the environment (e.g., loud sounds above 85 dB in the work environment is
radio or television) to enhance the signal-to-noise ratio. restricted by OSHA, with halving of allowed exposure
Speech comprehension is aided by lip reading; there- time for each increment of 5 dB above this threshold:
fore, the impaired listener should be seated so that the for example 90 dB exposure is permitted for 8 h; 95 dB
face of the speaker is well illuminated and easily seen. for 4 h, and 100 dB for 2 h.
SECTION III
DISEASES OF THE
NERVOUS SYSTEM
CHAPTER 25
The human nervous system is the organ of conscious- disordered processing and, ultimately, aggregation of the
ness, cognition, ethics, and behavior; as such, it is the protein, leading to cell death (see Protein Aggregation
most intricate structure known to exist. More than and Neurodegeneration).
one-third of the 23,000 genes encoded in the human There is great optimism that complex genetic dis-
genome are expressed in the nervous system. Each orders that are caused by combinations of genetic and
mature brain is composed of 100 billion neurons, sev- environmental factors have become tractable prob-
eral million miles of axons and dendrites, and >1015 lems. Genome-wide association studies (GWAS) have
synapses. Neurons exist within a dense parenchyma of been carried out in many complex neurologic disor-
multifunctional glial cells that synthesize myelin, pre- ders, with many hundreds of variants identied, nearly
serve homeostasis, and regulate immune responses. all of which confer only a small increment in disease
Measured against this background of complexity, the risk (1.151.5 fold). GWAS are rooted in the com-
achievements of molecular neuroscience have been mon disease, common variant hypothesis, as they
extraordinary. This chapter reviews selected themes in examine potential risk alleles that are relatively com-
neuroscience that provide a context for understand- mon (e.g., >5%) in the general population. More
ing fundamental mechanisms that underlie neurologic than 1000 GWAS have been carried out to date, with
disorders. notable successes such as the identication of >50 risk
alleles for multiple sclerosis. Furthermore, when bioin-
formatics tools are used, risk variants can be aligned in
NEUROGENETICS functional biologic pathways to identify novel patho-
genic mechanisms as well as to reveal heterogene-
The landscape of neurology has been transformed by ity (e.g., different pathways in different individuals).
modern molecular genetics. More than 350 different Despite these successes, many experienced geneticists
disease-causing genes have been identied, and >1000 question the value of common disease-associated vari-
neurologic disorders have been genetically mapped to ants, particularly whether they are actually causative
various chromosomal locations. Several hundred neu- or merely mark the approximate locations of more
rologic and psychiatric disorders now can be diagnosed importanttruly causativerare mutations.
through genetic testing (http://www.ncbi.nlm.nih.gov/sites/ This debate has set the stage for the next revolu-
GeneTests/?db=GeneTests). The vast majority of these tion in human genetics, made possible by the devel-
disorders represent highly penetrant mutations that cause opment of increasingly efcient and cost-effective
rare neurologic disorders; alternatively, they represent rare high-throughput sequencing methodologies. It is cur-
monogenic causes of common phenotypes. Examples of rently possible to sequence an entire human genome in
the latter include mutations of the amyloid precursor pro- approximately an hour, at a cost of only $4000 for the
tein in familial Alzheimers disease, the microtubule-asso- entire coding sequence (whole-exome) or $10,000
ciated protein tau (MAPT) in frontotemporal dementia, for the entire genome; it is certain that these costs will
and -synuclein in Parkinsons disease. These discoveries continue to decline. This makes it feasible to look
have been profoundly important because the mutated gene for disease-causing sequence variations in individual
in a familial disorder often encodes a protein that is also patients with the possibility of identifying rare variants
pathogenetically involved (although not mutated) in the that cause disease. The utility of this approach was dem-
typical, sporadic form. The common mechanism involves onstrated by whole-genome sequencing in a patient
218
with Charcot-Marie-Tooth neuropathy in which com- of exon 10containing transcripts of MAPT can cause 219
pound heterozygous mutations were identied in the frontotemporal dementia. Aberrant splicing also con-
SH3TC2 gene that then were shown to co-segregate tributes to the pathogenesis of Duchennes, myotonic,
with the disease in other members of the family. and fascioscapulohumeral muscular dystrophies; ataxia-
It is also increasingly recognized that not all genetic telangiectasia; neurobromatosis; some inherited atax-
diseases or predispositions are caused by simple changes ias; and fragile X syndrome, among other disorders. It
in the linear nucleotide sequence of genes. As the com- is also likely that subtle variations of splicing will inu-
plex architecture of the human genome becomes better ence many genetically complex disorders. For example,
dened, many disorders that result from alterations in a splicing variant of the interleukin 7 receptor chain,
copy numbers of genes (gene-dosage effects) resulting resulting in production of more soluble and less mem-
from unequal crossing-over are likely to be identied. As brane-bound receptor, was found to be associated with
much as 510% of the human genome consists of nonho- susceptibility to multiple sclerosis (MS) in multiple dif-
mologous duplications and deletions, and these appear to ferent populations.
occur with a much higher mutational rate than is the case Epigenetics refers to the mechanisms by which lev-
for single base pair mutations. The rst copy-number els of gene expression can be exquisitely modulated
disorders to be recognized were Charcot-Marie-Tooth not by variations in the primary genetic sequence of
disease type 1A (CMT1A), caused by a duplication in DNA but rather by postgenomic alterations in DNA
CHAPTER 25
the gene encoding the myelin protein PMP22, and the and chromatin structure, which inuence how, when,
reciprocal deletion of the gene causing hereditary liabil- and where genes are expressed. DNA methylation and
ity to pressure palsies (HNPP) (Chap. 45). Gene-dosage the methylation and acetylation of histone proteins that
effects are causative in some cases of Parkinsons disease interact with nuclear DNA to form chromatin are key
(-synuclein), Alzheimers disease (amyloid precursor mediators of these events. Epigenetic processes appear
protein), spinal muscular atrophy (survival motor neu- to be dynamically active even in postmitotic neurons.
are responsible for a growing list of human neurologic mutations in channel genes. As the full repertoire of
diseases (Table 25-1). Most are caused by mutations human ion channels and related proteins is identied,
in ion channel genes or by autoantibodies against ion it is likely that additional channelopathies will be dis-
channel proteins. One example is epilepsy, a syndrome covered. In addition to rare disorders that result from
of diverse causes characterized by repetitive, synchro- obvious mutations, it is likely that less penetrant allelic
nous ring of neuronal action potentials. Action poten- variations in channel genes or their pattern of expres-
Diseases of the Nervous System
tials normally are generated by the opening of sodium sion might underlie susceptibility to some apparently
channels and the inward movement of sodium ions sporadic forms of epilepsy, migraine, or other disorders.
down the intracellular concentration gradient. Depo- For example, mutations in the potassium channel gene
larization of the neuronal membrane opens potassium Kir2.6 have been found in many individuals with thyro-
channels, resulting in outward movement of potassium toxic hypokalemic periodic paralysis, a disorder similar
TABLE 25-1
EXAMPLES OF NEUROLOGIC CHANNELOPATHIES
CATEGORY DISORDER CHANNEL TYPE MUTATED GENE CHAP. REF.
Genetic
Ataxias Episodic ataxia-1 K KCNA1 31
Episodic ataxia-2 Ca CACNL1A
Spinocerebellar ataxia-6 Ca CACNL1A
Migraine Familial hemiplegic migraine 1 Ca CACNL1A 8
Familial hemiplegic migraine 3 Na SCN1A
Epilepsy Benign neonatal familial convulsions K KCNQ2, KCNQ3 26
Generalized epilepsy with febrile convulsions Na SCN1B
plus
Periodic paralysis Hyperkalemic periodic paralysis Na SCN4A 48
Hypokalemic periodic paralysis Ca CACNL1A3
Myotonia Myotonia congenita Cl CLCN1 48
Paramyotonia congenita Na SCN4A
Deafness Jervell and Lange-Nielsen syndrome (deafness, K KCNQ1, KCNE1 24
prolonged QT interval, and arrhythmia)
Autosomal dominant progressive deafness K KCNQ4
Autoimmune
Paraneoplastic Limbic encephalitis Kv1 44
Acquired neuromyotonia Kv1 44
Cerebellar ataxia Ca (P/Q type) 44
Lambert-Eaton syndrome Ca (P/Q type) 44
to hypokalemic periodic paralysis but precipitated by substantia nigra of the midbrain and projecting to the 221
stress from thyrotoxicosis or carbohydrate loading. striatum (nigrostriatal pathway) in Parkinsons disease
and in heroin addicts after the ingestion of the toxin
MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine).
A second important dopaminergic system arising in
NEUROTRANSMITTERS AND the midbrain is the mediocorticolimbic pathway, which
NEUROTRANSMITTER RECEPTORS is implicated in the pathogenesis of addictive behaviors
including drug reward. Its key components include the
Synaptic neurotransmission is the predominant means midbrain ventral tegmental area (VTA), median fore-
by which neurons communicate with each other. Classic brain bundle, and nucleus accumbens (see Fig. 53-1).
neurotransmitters are synthesized in the presynaptic region The cholinergic pathway originating in the nucleus
of the nerve terminal; stored in vesicles; and released into basalis of Meynert plays a role in memory function in
the synaptic cleft, where they bind to receptors on the Alzheimers disease.
postsynaptic cell. Secreted neurotransmitters are eliminated Addictive drugs share the property of increasing dopamine
by reuptake into the presynaptic neuron (or glia), diffu- release in the nucleus accumbens. Amphetamine increases
sion away from the synaptic cleft, and/or specic inacti- intracellular release of dopamine from vesicles and
vation. In addition to the classic neurotransmitters, many reverses transport of dopamine through the dopamine
CHAPTER 25
neuropeptides have been identied as denite or probable transporters. Patients prone to addiction show increased
neurotransmitters; they include substance P, neurotensin, activation of the nucleus accumbens after administra-
enkephalins, -endorphin, histamine, vasoactive intes- tion of amphetamine. Cocaine binds to dopamine trans-
tinal polypeptide, cholecystokinin, neuropeptide Y, and porters and inhibits dopamine reuptake. Ethanol inhib-
somatostatin. Peptide neurotransmitters are synthesized its inhibitory neurons in the VTA, leading to increased
in the cell body rather than the nerve terminal and may dopamine release in the nucleus accumbens. Opioids
Acetylcholine (ACh) Motor neurons in spinal cord neuro- Acetylcholinesterases (nerve gases)
O muscular junction Myasthenia gravis (antibodies to ACh
receptor)
CH3COCH2N(CH3)3 Congenital myasthenic syndromes
(mutations in ACh receptor subunits)
Lambert-Eaton syndrome (antibodies to
Ca channels impair ACh release)
Botulism (toxin disrupts ACh release by
exocytosis)
Basal forebrain widespread cortex Alzheimers disease (selective cell death)
Autosomal dominant frontal lobe epi-
lepsy (mutations in CNS ACh receptor)
Interneurons in striatum Parkinsons disease (tremor)
SECTION III
Abbreviations: CNS, central nervous system; MAOA, monoamine oxidase A; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SSRI, selec-
tive serotonin reuptake inhibitor.
different stimuli and is characterized by a circumferen- typically myelinates a single axon. Myelin is a lipid-rich 223
tially expanding negative potential that propagates at a material formed by a spiraling process of the membrane
characteristic speed of 20 m/s and is associated with an of the myelinating cell around the axon, creating mul-
increase in extracellular potassium. tiple membrane bilayers that are tightly apposed (com-
pact myelin) by charged protein interactions. Several
inhibitors of axon growth are expressed on the innermost
(periaxonal) lamellae of the myelin membrane (see Stem
SIGNALING PATHWAYS AND GENE Cells and Transplantation). A number of clinically
TRANSCRIPTION important neurologic disorders are caused by inherited
mutations in myelin proteins of the CNS or PNS (Fig.
The fundamental issue of how memory, learning, and 25-1). Constituents of myelin also have a propensity to
thinking are encoded in the nervous system is likely to be targeted as autoantigens in autoimmune demyelinating
be claried by identication of the signaling pathways disorders (Fig. 25-2). Specication to oligodendrocyte
involved in neuronal differentiation, axon guidance,
and synapse formation and by an understanding of how
these pathways are modulated by experience. Many MOG PMP22
CHAPTER 25
tiple individual components, are expressed in the ner-
vous system. Elucidation of these signaling pathways has PLP Po
begun to provide insights into the causes of a variety
of neurologic disorders, including inherited disorders Myelin basic protein
Myelin basic protein
of cognition such as X-linked mental retardation. This
problem affects 1 in 500 males, and linkage studies
Po PLP
in different families suggest that as many as 60 different
Flow B cell
Activated
lymphocyte
Gelatinases
CD 31 LFA-1
4 Integrin
ICAM
VCAM
Basal lamina
Blood-brain Chemokines
barrier Microglia/macrophages
and cytokines
endothelium
Astrocytes
Activated Heat-shock T cell
proteins?
SECTION III
Microglia/ activation
macrophages IFN-
IL-2
Fc receptor
Chemokines
IL-1, IL-12 Antibody
Brain tissue Complement
TNF, IFN, free radicals, vasoactive amines,
Diseases of the Nervous System
Myelin damage
FIGURE 25-2
A model for experimental allergic encephalomyelitis (EAE). recruitment of a secondary inammatory wave; and immune-
Crucial steps for disease initiation and progression include mediated myelin destruction. ICAM, intercellular adhesion
peripheral activation of preexisting autoreactive T cells; hom- molecule; LFA-1, lymphocyte function-associated antigen-1;
ing to the CNS and extravasation across the blood-brain bar- VCAM, vascular cell adhesion molecule; IFN, interferon; IL,
rier; reactivation of T cells by exposed autoantigens; secre- interleukin; TNF, tumor necrosis factor.
tion of cytokines; activation of microglia and astrocytes and
precursor cells (OPCs) is transcriptionally regulated by including roles in neurotransmission and in the synaptic
the Olig 2 and Yin Yang 1 genes, whereas myelination reorganization involved in learning and memory. The
mediated by postmitotic oligodendrocytes depends on a neurotrophin (NT) family contains nerve growth fac-
different transcription factor, myelin gene regulatory factor tor (NGF), brain-derived neurotrophic factor (BDNF),
(MRF). It is noteworthy that in the normal adult brain NT3, and NT4/5. The neurotrophins act at TrK and
large numbers of OPCs (expressing platelet-derived p75 receptors to promote survival of neurons. Because
growth factor receptor alpha [PDGFR-] and NG2) are
widely distributed but do not myelinate axons, even in TABLE 25-3
demyelinating environments such as lesions of MS. The NEUROTROPHIC FACTORS
characterization of these cells, including an understand-
Neurotrophin family Transforming growth factor family
ing of their transcriptional regulation and functional roles, Nerve growth factor Glial-derived neurotrophic family
could result in novel approaches to remyelination and Brain-derived Neurturin
brain repair. neurotrophic factor Persephin
Neurotrophin-3 Fibroblast growth factor family
Neurotrophin-4 Hepatocyte growth factor
Neurotrophin-6 Insulin-like growth factor (IGF) family
Cytokine family IGF-1
NEUROTROPHIC FACTORS Ciliary neurotrophic factor IGF-2
Leukemia inhibitory factor
Neurotrophic factors (Table 25-3) are secreted pro- Interleukin 6
teins that modulate neuronal growth, differentiation, Cardiotrophin-1
repair, and survival; some have additional functions,
of their survival-promoting and antiapoptotic effects, with four pluripotency factors (SOX2, KLF4, cMYC, 225
neurotrophic factors are in theory outstanding candi- and Oct4), and this generates induced pluripotent stem
dates for therapy for disorders characterized by prema- cells (iPSCs). These adult-derived stem cells sidestep the
ture death of neurons as occurs in amyotrophic lateral ethical issues of utilizing stem cells derived from human
sclerosis (ALS) and other degenerative motor neuron embryos. The development of these cells has tremen-
disorders. Knockout mice lacking receptors for ciliary dous promise for both studying disease mechanisms and
neurotrophic factor (CNTF) or BDNF show loss of testing therapeutics. There is no consensus on the best
motor neurons, and experimental motor neuron death way to generate and differentiate iPSCs; however, tech-
can be rescued by treatment with various neurotrophic niques to avoid using viral vectors and the use of Cre-
factors, including CNTF, BDNF, and vascular endothe- lox systems to remove reprogramming factors result in
lial growth factor (VEGF). However, in phase 3 clini- a better match of gene expression proles with those of
cal trials, growth factors were ineffective in human ALS. embryonic stem cells. Thus far, iPSC cells have been
The growth factor glial-derived neurotrophic factor made from patients with all the major human neurode-
(GDNF) is important for survival of dopaminergic neu- generative diseases, and studies utilizing them are under
rons. Direct infusions of GDNF showed initial promise way.
in Parkinsons disease (PD), but the benets were not Although stem cells hold tremendous promise
replicated in a larger clinical trial. for the treatment of debilitating neurologic diseases
CHAPTER 25
such as Parkinsons disease and spinal cord injury, it
should be emphasized that medical application is in
STEM CELLS AND TRANSPLANTATION its infancy. Major obstacles are the generation of posi-
tion- and neurotransmitter-dened subtypes of neu-
The nervous system is traditionally considered to be a rons and their isolation as pure populations of the
nonmitotic organ, particularly with respect to neu- desired cells. This is crucial to avoid persistence of
Compelling evidence for a role of excitotoxicity, espe- injury. These channels offer a potential new therapeutic
cially in ischemic neuronal injury, is derived from experi- target for stroke.
ments in animal models. Experimental models of stroke Apoptosis, or programmed cell death, plays an impor-
are associated with increased extracellular concentrations tant role in both physiologic and pathologic conditions.
of the excitatory amino acid neurotransmitter gluta- During embryogenesis, apoptotic pathways operate to
mate, and neuronal damage is attenuated by denervation destroy neurons that fail to differentiate appropriately or
of glutamate-containing neurons or the administration reach their intended targets. There is mounting evidence
of glutamate receptor antagonists. The distribution of for an increased rate of apoptotic cell death in a variety of
cells sensitive to ischemia corresponds closely with that acute and chronic neurologic diseases. Apoptosis is char-
of N-methyl-D-aspartate (NMDA) receptors (except for acterized by neuronal shrinkage, chromatin condensation,
cerebellar Purkinje cells, which are vulnerable to hypox- and DNA fragmentation, whereas necrotic cell death is
emia-ischemia but lack NMDA receptors), and competi- associated with cytoplasmic and mitochondrial swelling
tive and noncompetitive NMDA antagonists are effective followed by dissolution of the cell membrane. Apoptotic
in preventing focal ischemia. In global cerebral ischemia, death and necrotic cell death can coexist or be sequential
non-NMDA receptors (kainic acid and -amino-3- events, depending on the severity of the initiating insult.
hydroxyl-5-methyl-4-isoxazole-propionate [AMPA]) are Cellular energy reserves appear to have an important role
activated, and antagonists to these receptors are protec- in these two forms of cell death, with apoptosis favored
tive. Experimental brain damage induced by hypoglyce- under conditions in which ATP levels are preserved.
mia also is attenuated by NMDA antagonists. Evidence of DNA fragmentation has been found in a
Excitotoxicity is not a single event but rather a cas- number of degenerative neurologic disorders, including
cade of cell injury. Excitotoxicity causes inux of cal- Alzheimers disease, Huntingtons disease, and ALS. The
cium into cells, and much of the calcium is sequestered best characterized genetic neurologic disorder related to
in mitochondria rather than in the cytoplasm. Increased apoptosis is infantile spinal muscular atrophy (Werdnig-
cytoplasmic calcium causes metabolic dysfunction and Hoffmann disease), in which two genes thought to be
free radical generation; activates protein kinases, phos- involved in the apoptosis pathways are causative.
pholipases, nitric oxide synthase, proteases, and endo- Mitochondria are essential in controlling specic
nucleases; and inhibits protein synthesis. Activation apoptosis pathways. The redistribution of cytochrome c,
of nitric oxide synthase generates nitric oxide (NO), as well as apoptosis-inducing factor (AIF), from mito-
which can react with superoxide (O2 ) to generate per- chondria during apoptosis leads to the activation of a
oxynitrite (ONOO), which may play a direct role in cascade of intracellular proteases known as caspases. Cas-
neuronal injury. Another critical pathway is activa- pase-independent apoptosis occurs after DNA dam-
tion of poly-ADP-ribose polymerase, which occurs in age, activation of poly-ADP-ribose polymerase, and
Mg2+ Mg2+ 227
Glutamate NMDA receptor Glutamate NMDA receptor
Glycine-(D-series) Glycine-(D-series)
Preserved
Impaired ATP generation
ATP generation
[Ca2+]
[Ca2+]
Mitochondrial swelling,
NOS rupture of outer membrane
NOS NO + O2 ONOO
PTP activation
NO + O2 Oxidative
stress
[Ca2+]
O2 O2
[Ca2+]
Caspase 9
Aif Cytc
SOD Catalase
O2 H2O2 H2O
CHAPTER 25
ONOO Hydrogen peroxide
Peroxynitrite
OH Aif Apaf1 + dATP
Hydrogen ion
A B
FIGURE 25-3
Involvement of mitochondria in cell death. A severe exci- occur due either to an abnormality in an excitotoxicity amino
totoxic insult (A) results in cell death by necrosis, whereas a acid receptor, allowing more Ca2+ ux, or to impaired func-
mild excitotoxic insult (B) results in apoptosis. After a severe tioning of other ionic channels or of energy production, which
insult (such as ischemia), there is a large increase in glutamate may allow the voltage-dependent NMDA receptor to be acti-
activation of NMDA receptors, an increase in intracellular Ca2+ vated by ambient concentrations of glutamate. This event
concentrations, activation of nitric oxide synthase (NOS), and can then lead to increased mitochondrial Ca2+ and free radi-
increased mitochondrial Ca2+ and superoxide generation fol- cal production, yet relatively preserved ATP generation. The
lowed by the formation of ONOO. This sequence results in mitochondria may then release cytochrome c (Cytc), caspase
damage to cellular macromolecules including DNA, leading to 9, apoptosis-inducing factor (Aif), and perhaps other media-
activation of poly-ADP-ribose polymerase (PARS). Both mito- tors that lead to apoptosis. The precise role of the PTP in
chondrial accumulation of Ca2+ and oxidative damage lead this mode of cell death is still being claried, but there does
to activation of the permeability transition pore (PTP) that is appear to be involvement of the adenine nucleotide trans-
linked to excitotoxic cell death. A mild excitotoxic insult can porter that is a key component of the PTP.
translocation of AIF into the nucleus. Redistribution involved in opening the permeability transition pore, are
of cytochrome c is prevented by overproduction of the resistant to necrosis produced by focal cerebral ischemia.
apoptotic protein BCL2 and is promoted by the pro-
apoptotic protein BAX. These pathways may be trig-
gered by activation of a large pore in the mitochondrial PROTEIN AGGREGATION AND
inner membrane known as the permeability transition pore, NEURODEGENERATION
although in other circumstances they occur indepen-
dently. Recent studies suggest that blocking the mito- The possibility that protein aggregation plays a role
chondrial pore reduces both hypoglycemic and ischemic in the pathogenesis of neurodegenerative diseases is a
cell death. Mice decient in cyclophilin D, a key protein major focus of current research. Protein aggregation is
228 a major histopathologic hallmark of neurodegenerative mutations in Opa1 cause autosomal dominant optic
diseases. Deposition of -amyloid is strongly implicated atrophy. Both -amyloid and mutant huntingtin pro-
in the pathogenesis of Alzheimers disease. Genetic tein induce mitochondrial fragmentation and neuronal
mutations in familial Alzheimers disease cause increased cell death associated with increased activity of Drp1. In
production of -amyloid with 42 amino acids, which addition, mutations in genes causing autosomal recessive
has an increased propensity to aggregate, compared with Parkinsons disease, parkin and PINK1, cause abnormal
-amyloid with 40 amino acids. Mutations in genes mitochondrial morphology and result in impairment of
encoding the MAPT lead to altered splicing of tau and the ability of the cell to remove damaged mitochondria
the production of neurobrillary tangles in fronto- by autophagy.
temporal dementia and progressive supranuclear palsy. The current major scientic question is whether pro-
Familial Parkinsons disease is associated with mutations tein aggregates contribute to neuronal death or whether
in leucine-rich repeat kinase 2 (LRRK2), -synuclein, par- they are merely secondary bystanders. A major focus in
kin, PINK1, and DJ-1. PINK1 is a mitochondrial kinase all the neurodegenerative diseases is now on small pro-
(see later), and DJ-1 is a protein involved in protection tein aggregates termed oligomers. These aggregates may
from oxidative stress. Parkin, which causes autosomal be the toxic species of -amyloid, -synuclein, and
recessive early-onset Parkinsons disease, is a ubiqui- proteins with expanded polyglutamines such as those
tin ligase. The characteristic histopathologic feature of that are associated with Huntingtons disease. Protein
SECTION III
Parkinsons disease is the Lewy body, an eosinophilic aggregates are usually ubiquinated, which targets them
cytoplasmic inclusion that contains both neurolaments for degradation by the 26S component of the protea-
and -synuclein. Huntingtons disease and cerebellar some. An inability to degrade protein aggregates could
degenerations are associated with expansions of polyglu- lead to cellular dysfunction, impaired axonal transport,
tamine repeats in proteins, which aggregate to produce and cell death by apoptotic mechanisms.
neuronal intranuclear inclusions. Familial ALS is asso- Autophagy is the degradation of cystolic components
Diseases of the Nervous System
ciated with superoxide dismutase mutations and cyto- in lysosomes. There is increasing evidence that autoph-
plasmic inclusions that contain superoxide dismutase. agy plays an important role in degradation of protein
An important nding was the discovery that the ubi- aggregates in the neurodegenerative diseases, and it is
quinated inclusions observed in most cases of ALS and impaired in Alzheimers disease (AD), Parkinsons dis-
the most common form of frontotemporal dementia are ease, and Huntingtons disease (HD). Autophagy is par-
composed of TAR DNA binding protein 43 (TDP-43). ticularly important to the health of neurons, and failure
Subsequently, mutations in the TDP-43 gene and in of autophagy contributes to cell death. In Huntingtons
the fused in sarcoma gene (FUS) were found in familial disease, a failure of cargo recognition occurs, contrib-
ALS. These two proteins are involved in transcription uting to protein aggregates and cell death. Rapamycin,
regulation as well as RNA metabolism. In autosomal which induces autophagy, exerts benecial therapeutic
dominant neurohypophyseal diabetes insipidus, muta- effects in transgenic mouse models of AD, PD, and HD.
tions in vasopressin result in abnormal protein process- In experimental models of Huntingtons disease and
ing, accumulation in the endoplasmic reticulum, and cerebellar degeneration, protein aggregates are not well
cell death. correlated with neuronal death and may be protective.
Another key mechanism linked to cell death is A substantial body of evidence suggests that the mutant
mitochondrial dynamics, which refer to the processes proteins with polyglutamine expansions in these dis-
involved in movement of mitochondria, as well as in eases bind to transcription factors and that this contrib-
mitochondrial ssion and fusion, which play a critical utes to disease pathogenesis. In Huntingtons disease
role in mitochondrial turnover and in replenishment there is dysfunction of the transcriptional co-regulator
of damaged mitochondria. Mitochondrial dysfunction PGC-1, a key regulator of mitochondrial biogenesis.
is strongly linked to the pathogenesis of a number of There is evidence that impaired function of PGC-1 is
neurodegenerative diseases, such as Friedreichs ataxia, also important in both Parkinsons disease and Alzheim-
which is caused by mutations in an iron-binding pro- ers disease, making it an attractive target for treatments.
tein that plays an important role in transferring iron to Agents that upregulate gene transcription are neuropro-
iron-sulfur clusters in aconitase and complex I and II tective in animal models of these diseases. A number of
of the electron transport chain. Mitochondrial ssion compounds have been developed to block -amyloid
is dependent on the dynamin-related proteins (Drp1), production and/or aggregation, and these agents are
which bind to its receptor Fis, whereas mitofuscins 1 being studied in early clinical trials in humans. Another
and 2 (MF 1/2) and optic atrophy protein 1 (Opa1) approach under investigation is immunotherapy with
are responsible for fusion of the outer and inner mito- antibodies that bind -amyloid, tau, or -synuclein.
chondrial membrane, respectively. Mutations in Mfn2 Another emerging theme is the role of chronic
cause Charcot-Marie-Tooth neuropathy type 2A, and inammation, and in particular of activated microglia
and innate immunity, in the pathogenesis of many neu- of neural circuits and how they operate and how this 229
rodegenerative diseases. Activation of Toll-like recep- can be modeled to produce improved understanding
tors (TLR) in response to pattern-recognition signals of physiologic processes. fMRI uses contrast mecha-
from damaged or aging cells, including those mediated nisms related to physiologic changes in tissue, and brain
by heat shock proteins or aggregated proteins, can trig- perfusion can be studied by observing the time course
ger or amplify pro-inammatory responses. Familial of changes in brain water signal as a bolus of injected
frontotemporal degeneration (Chap. 29) is caused by paramagnetic gadolinium contrast moves through the
mutations in the gene encoding progranulin, a growth brain. More recently, to study intrinsic contrast-related
factor that regulates inammation via binding to tumor local changes in blood oxygenation with brain activ-
necrosis factor (TNF) receptors. ity, blood-oxygen-level-dependent (BOLD) contrast
has been used to provide a rapid noninvasive approach
for functional assessment. These techniques have been
used reliably in both behavioral and cognitive sciences.
SYSTEMS NEUROSCIENCE
One example is the use of fMRI to demonstrate mir-
Systems neuroscience refers to study of the functions of ror neuron systems, imitative pathways activated when
neurocircuits and the way they relate to brain function, observing actions of others (Fig. 25-4). Mirror neu-
behavior, motor activity, and cognition. Brain imag- rons are thought to be important for social condition-
CHAPTER 25
ing techniques, primarily functional MRI (fMRI) and ing and for many forms of learning, and abnormalities
positron emission tomography (PET), have made it pos- in mirror neurons may underlie some autism disorders.
sible to investigate cognitive processes such as percep- Data also suggest that enhancement of mirror neuron
tion, making judgments, paying attention, and thinking. pathways might have potential for rehabilitation after
This has allowed insights into how networks of neu- stroke. Other examples of the use of fMRI include the
rons operate to produce behavior. Many of these stud- study of memory. Recent studies have shown that not
FIGURE 25-4
Mirror neuron systems are bilaterally activated during imi- primary visual cortex for imitated actions presented to the right
tation. A. Bilateral activations (circled in yellow) in inferior fron- visual eld (in red, left visual cortex) and to the left visual eld (in
tal mirror neuron areas during imitation, as measured by BOLD blue, right visual cortex). C. Lateralized primary motor activation
fMRI signal changes. In red, activation during right hand imita- for hand actions imitated with the right hand (in red, left motor
tion. In blue, activation during left hand imitation. B. In contrast, cortex) and with the left hand (in blue, right motor cortex). (From
there is lateralized (contralateral) primary visual activation of the L Aziz-Zadeh et al: J Neurosci 26:2964, 2006.)
230 memory consolidation, it also involves activation in myelin and axonal injuries as well as brain development.
the ventral medial prefrontal cortex. Consolidation Advances in understanding neural processing have led
of memory over time results in decreased activity of to the development of the ability to demonstrate that
the hippocampus and progressively stronger activa- humans have on-line voluntary control of human tem-
tion in the ventral medial prefrontal region associated poral lobe neurons.
with retrieval of consolidated memories. fMRI also A further advance that has far-reaching implica-
has been utilized to identify sequences of brain activa- tions for the development of novel interventions for
tion involved in normal movements and alterations in neurologic, including behavioral, conditions has been
their activation associated with both injury and recov- the development of deep-brain stimulation as a highly
ery and to plan neurosurgical operations. Diffusion ten- effective therapeutic intervention for treating exces-
sor imaging is a recently developed MRI technique that sively ring neurons in the subthalamic nucleus of
can measure macroscopic axonal organization in ner- patients with Parkinsons disease and the precingulate
vous system tissues; it appears to be useful in assessing cortex in patients with depression.
SECTION III
Diseases of the Nervous System
CHAPTER 26
Daniel H. Lowenstein
A seizure (from the Latin sacire, to take possession of) (ILAE) Commission on Classication and Terminol-
is a paroxysmal event due to abnormal excessive or syn- ogy, 20052009 has provided an updated approach
chronous neuronal activity in the brain. Depending on to classication of seizures (Table 26-1). This system
the distribution of discharges, this abnormal brain activ- is based on the clinical features of seizures and associ-
ity can have various manifestations, ranging from dra- ated electroencephalographic ndings. Other potentially
matic convulsive activity to experiential phenomena not distinctive features such as etiology or cellular substrate
readily discernible by an observer. Although a variety are not considered in this classication system, although
of factors inuence the incidence and prevalence of sei- this will undoubtedly change in the future as more is
zures, 510% of the population will have at least one learned about the pathophysiologic mechanisms that
seizure, with the highest incidence occurring in early underlie specic seizure types.
childhood and late adulthood. A fundamental principle is that seizures may be either
The meaning of the term seizure needs to be carefully focal or generalized. Focal seizures originate within net-
distinguished from that of epilepsy. Epilepsy describes a works limited to one cerebral hemisphere (note that the
condition in which a person has recurrent seizures due to term partial seizures is no longer used). Generalized sei-
a chronic, underlying process. This denition implies zures arise within and rapidly engage networks distrib-
that a person with a single seizure, or recurrent seizures uted across both cerebral hemispheres. Focal seizures are
due to correctable or avoidable circumstances, does not usually associated with structural abnormalities of the
necessarily have epilepsy. Epilepsy refers to a clinical brain. In contrast, generalized seizures may result from
phenomenon rather than a single disease entity, since cellular, biochemical, or structural abnormalities that
there are many forms and causes of epilepsy. How- have a more widespread distribution. There are clear
ever, among the many causes of epilepsy there are vari- exceptions in both cases, however.
ous epilepsy syndromes in which the clinical and patho-
logic characteristics are distinctive and suggest a specic TABLE 26-1
underlying etiology. CLASSIFICATION OF SEIZURES
Using the denition of epilepsy as two or more
1. Focal seizures
unprovoked seizures, the incidence of epilepsy is 0.3 (Can be further described as having motor, sensory,
0.5% in different populations throughout the world, and autonomic, cognitive, or other features)
the prevalence of epilepsy has been estimated at 510 2. Generalized seizures
persons per 1000. a. Absence
Typical
Atypical
b. Tonic clonic
CLASSIFICATION OF SEIZURES c. Clonic
d. Tonic
Determining the type of seizure that has occurred is e. Atonic
essential for focusing the diagnostic approach on par- f. Myoclonic
ticular etiologies, selecting the appropriate therapy, 3. May be focal, generalized, or unclear
and providing potentially vital information regarding Epileptic spasms
prognosis. The International League against Epilepsy
231
232 FOCAL SEIZURES known as a Jacksonian march, represents the spread
of seizure activity over a progressively larger region of
Focal seizures arise from a neuronal network either motor cortex. Second, patients may experience a local-
discretely localized within one cerebral hemisphere ized paresis (Todds paralysis) for minutes to many hours
or more broadly distributed but still within the in the involved region following the seizure. Third, in
hemisphere. With the new classication system, the rare instances the seizure may continue for hours or
subcategories of simple focal seizures and complex days. This condition, termed epilepsia partialis continua, is
focal seizures have been eliminated. Instead, depending often refractory to medical therapy.
on the presence of cognitive impairment, they can be Focal seizures may also manifest as changes in somatic
described as focal seizures with or without dyscognitive sensation (e.g., paresthesias), vision (ashing lights or
features. Focal seizures can also evolve into generalized formed hallucinations), equilibrium (sensation of falling
seizures. In the past this was referred to as focal seizures or vertigo), or autonomic function (ushing, sweating,
with secondary generalization, but the new system relies on piloerection). Focal seizures arising from the temporal
specic descriptions of the type of generalized seizures or frontal cortex may also cause alterations in hearing,
that evolve from the focal seizure. olfaction, or higher cortical function (psychic symp-
The routine interictal (i.e., between seizures) elec- toms). This includes the sensation of unusual, intense
troencephalogram (EEG) in patients with focal seizures odors (e.g., burning rubber or kerosene) or sounds
SECTION III
is often normal or may show brief discharges termed (crude or highly complex sounds), or an epigastric sen-
epileptiform spikes, or sharp waves. Since focal seizures sation that rises from the stomach or chest to the head.
can arise from the medial temporal lobe or inferior Some patients describe odd, internal feelings such as
frontal lobe (i.e., regions distant from the scalp), the fear, a sense of impending change, detachment, deper-
EEG recorded during the seizure may be nonlocaliz- sonalization, dj vu, or illusions that objects are grow-
ing. However, the seizure focus is often detected using ing smaller (micropsia) or larger (macropsia). These sub-
sphenoidal or surgically placed intracranial electrodes.
Diseases of the Nervous System
CHAPTER 26
ers tend to emphasize the more dramatic, general-
ized convulsive phase of the seizure and overlook the the EEG.
more subtle, focal symptoms present at onset. In some
cases, the focal onset of the seizure becomes apparent Atypical absence seizures
only when a careful history identies a preceding aura. Atypical absence seizures have features that deviate both
Often, however, the focal onset is not clinically evident clinically and electrophysiologically from typical absence
and may be established only through careful EEG analy-
extremely long (i.e., many hours) in patients with pro- CURRENTLY UNCLASSIFIABLE SEIZURES
longed seizures or underlying central nervous system Not all seizure types can be designated as focal or
(CNS) diseases such as alcoholic cerebral atrophy. generalized, and they should therefore be labeled as
The EEG during the tonic phase of the seizure shows unclassiable until additional evidence allows a valid
a progressive increase in generalized low-voltage fast classication. Epileptic spasms are such an example.
activity, followed by generalized high-amplitude, poly- These are characterized by a briey sustained exion or
Diseases of the Nervous System
spike discharges. In the clonic phase, the high-ampli- extension of predominantly proximal muscles, includ-
tude activity is typically interrupted by slow waves to ing truncal muscles. The EEG in these patients usually
create a spike-and-wave pattern. The postictal EEG shows hypsarrhythmias, which consist of diffuse, giant
shows diffuse slowing that gradually recovers as the slow waves with a chaotic background of irregular,
patient awakens. multifocal spikes and sharp waves. During the clini-
There are a number of variants of the generalized cal spasm, there is a marked suppression of the EEG
tonic-clonic seizure, including pure tonic and pure background (the electrodecremental response). The
clonic seizures. Brief tonic seizures lasting only a few electromyogram (EMG) also reveals a characteristic
seconds are especially noteworthy since they are usu- rhomboid pattern that may help distinguish spasms from
ally associated with specic epileptic syndromes having brief tonic and myoclonic seizures. Epileptic spasms
mixed seizure phenotypes, such as the Lennox-Gastaut occur predominantly in infants and likely result from
syndrome (discussed later). differences in neuronal function and connectivity in the
immature versus mature CNS.
Atonic seizures
Atonic seizures are characterized by sudden loss of pos-
EPILEPSY SYNDROMES
tural muscle tone lasting 12 s. Consciousness is briey
impaired, but there is usually no postictal confusion. A Epilepsy syndromes are disorders in which epilepsy is
very brief seizure may cause only a quick head drop or a predominant feature, and there is sufcient evidence
nodding movement, while a longer seizure will cause (e.g., through clinical, EEG, radiologic, or genetic
the patient to collapse. This can be extremely danger- observations) to suggest a common underlying mecha-
ous, since there is a substantial risk of direct head injury nism. Three important epilepsy syndromes are listed
with the fall. The EEG shows brief, generalized spike- next; additional examples with a known genetic basis
and-wave discharges followed immediately by diffuse are shown in Table 26-2.
slow waves that correlate with the loss of muscle tone.
Similar to pure tonic seizures, atonic seizures are usually
seen in association with known epilepsy syndromes. JUVENILE MYOCLONIC EPILEPSY
Juvenile myoclonic epilepsy (JME) is a generalized seizure
disorder of unknown cause that appears in early adoles-
Myoclonic seizures
cence and is usually characterized by bilateral myoclonic
Myoclonus is a sudden and brief muscle contraction that jerks that may be single or repetitive. The myoclonic sei-
may involve one part of the body or the entire body. zures are most frequent in the morning after awakening
TABLE 26-2 235
EXAMPLES OF GENES ASSOCIATED WITH EPILEPSY SYNDROMESa
GENE (LOCUS) FUNCTION OF GENE CLINICAL SYNDROME COMMENTS
CHRNA4 (20q13.2) Nicotinic acetylcholine recep- Autosomal dominant nocturnal Rare; rst identied in a large
tor subunit; mutations cause frontal lobe epilepsy (ADNFLE); Australian family; other fami-
alterations in Ca2+ ux through childhood onset; brief, nighttime lies found to have mutations
the receptor; this may reduce seizures with prominent motor in CHRNA2 or CHRNB2, and
amount of GABA release in pre- movements; often misdiag- some families appear to have
synaptic terminals nosed as primary sleep disorder mutations at other loci
KCNQ2 (20q13.3) Voltage-gated potassium chan- Benign familial neonatal con- Rare; other families found to
nel subunits; mutation in pore vulsions (BFNC); autosomal have mutations in KCNQ3;
regions may cause a 2040% dominant inheritance; onset in sequence and functional
reduction of potassium currents, 1st week of life in infants who homology to KCNQ1, muta-
which will lead to impaired repo- are otherwise normal; remission tions of which cause long QT
larization usually within weeks to months; syndrome and a cardiac-audi-
long-term epilepsy in 1015% tory syndrome
SCN1B (19q12.1) -Subunit of a voltage-gated Generalized epilepsy with febrile Incidence uncertain; GEFS+
CHAPTER 26
sodium channel; mutation dis- seizures plus (GEFS+); auto- identied in other families with
rupts disulde bridge that is somal dominant inheritance; mutations in other sodium
crucial for structure of extracel- presents with febrile seizures channel subunits (SCN1A
lular domain; mutated -subunit at median 1 year, which may and SCN2A) and GABAA
leads to slower sodium channel persist >6 years, then variable receptor subunit (GABRG2 and
inactivation seizure types not associated GABRA1); signicant pheno-
with fever typic heterogeneity within same
family, including members with
a
The rst four syndromes listed in the table (ADNFLE, BFNC, GEFS+, and ADPEAF) are examples of idiopathic epilepsies associated with identied
gene mutations. The last three syndromes are examples of the numerous Mendelian disorders in which seizures are one part of the phenotype.
Abbreviations: GABA, -aminobutyric acid; PME, progressive myoclonus epilepsy.
236 and can be provoked by sleep deprivation. Conscious- TABLE 26-3
ness is preserved unless the myoclonus is especially severe.
CHARACTERISTICS OF THE MESIAL TEMPORAL
Many patients also experience generalized tonic-clonic sei- LOBE EPILEPSY SYNDROME
zures, and up to one-third have absence seizures. Although
History
complete remission is relatively uncommon, the seizures
respond well to appropriate anticonvulsant medication. History of febrile seizures Rare generalized seizures
There is often a family history of epilepsy, and genetic Family history of epilepsy Seizures may remit and
Early onset reappear
linkage studies suggest a polygenic cause. Seizures often intractable
Clinical Observations
LENNOX-GASTAUT SYNDROME Aura common Postictal disorientation
Behavioral arrest/stare Memory loss
Lennox-Gastaut syndrome occurs in children and Complex automatisms Dysphasia (with focus in
is dened by the following triad: (1) multiple sei- Unilateral posturing dominant hemisphere)
zure types (usually including generalized tonic-clonic,
Laboratory Studies
atonic, and atypical absence seizures); (2) an EEG
showing slow (<3 Hz) spike-and-wave discharges Unilateral or bilateral anterior temporal spikes on EEG
and a variety of other abnormalities; and (3) impaired Hypometabolism on interictal PET
SECTION III
cognitive function in most but not all cases. Lennox- Hypoperfusion on interictal SPECT
Gastaut syndrome is associated with CNS disease or Material-specic memory decits on intracranial amobarbi-
dysfunction from a variety of causes, including devel- tal (Wada) test
opmental abnormalities, perinatal hypoxia/ischemia, MRI Findings
trauma, infection, and other acquired lesions. The
multifactorial nature of this syndrome suggests that it Small hippocampus with increased signal on T2-weighted
sequences
Diseases of the Nervous System
FIGURE 26-1
Mesial temporal lobe epilepsy. The EEG suggested a right
THE CAUSES OF SEIZURES AND temporal lobe focus. Coronal high-resolution T2-weighted
EPILEPSY fast spin echo magnetic resonance image obtained through
the body of the hippocampus demonstrates abnormal high-
Seizures are a result of a shift in the normal balance of signal intensity in the right hippocampus (white arrows; com-
excitation and inhibition within the CNS. Given the pare with the normal hippocampus on the left, black arrows)
numerous properties that control neuronal excitability, consistent with mesial temporal sclerosis.
it is not surprising that there are many different ways to These observations emphasize the concept that 237
perturb this normal balance, and therefore many differ- the many causes of seizures and epilepsy result from a
ent causes of both seizures and epilepsy. Three clinical dynamic interplay between endogenous factors, epilep-
observations emphasize how a variety of factors deter- togenic factors, and precipitating factors. The poten-
mine why certain conditions may cause seizures or epi- tial role of each needs to be carefully considered when
lepsy in a given patient. determining the appropriate management of a patient
with seizures. For example, the identication of pre-
1. The normal brain is capable of having a seizure under the disposing factors (e.g., family history of epilepsy) in a
appropriate circumstances, and there are differences between patient with febrile seizures may increase the necessity
individuals in the susceptibility or threshold for seizures. for closer follow-up and a more aggressive diagnostic
For example, seizures may be induced by high fevers evaluation. Finding an epileptogenic lesion may help
in children who are otherwise normal and who in the estimation of seizure recurrence and duration of
never develop other neurologic problems, including therapy. Finally, removal or modication of a precipi-
epilepsy. However, febrile seizures occur only in a tating factor may be an effective and safer method for
relatively small proportion of children. This implies preventing further seizures than the prophylactic use of
there are various underlying endogenous factors that anticonvulsant drugs.
inuence the threshold for having a seizure. Some of
CHAPTER 26
these factors are clearly genetic, as it has been shown
that a family history of epilepsy will inuence the
likelihood of seizures occurring in otherwise nor-
CAUSES ACCORDING TO AGE
mal individuals. Normal development also plays an
important role, since the brain appears to have dif- In practice, it is useful to consider the etiologies of sei-
ferent seizure thresholds at different maturational zures based on the age of the patient, as age is one of
CHAPTER 26
Tramadol
Local anesthetics Cocaine of the N-methyl-D-aspartate (NMDA) subtype of the
Dietary supplements Phencyclidine excitatory amino acid receptor, which causes additional
Methylphenidate
Ephedra (ma huang) Ca2+ inux and neuronal activation; and (4) ephaptic
Gingko Flumazenila
interactions related to changes in tissue osmolarity and
Immunomodulatory drugs cell swelling. The recruitment of a sufcient number of
Cyclosporine neurons leads to the propagation of seizure activity into
absence seizures, and there is good evidence that the These syndromes are therefore part of the larger group
genetic forms of absence epilepsy may be associated of channelopathies causing paroxysmal disorders such as
with mutations of components of this system. cardiac arrhythmias, episodic ataxia, periodic weakness,
and familial hemiplegic migraine. In contrast, gene muta-
tions observed in symptomatic epilepsies (i.e., disorders in
which other neurologic abnormalities such as cognitive
MECHANISMS OF EPILEPTOGENESIS impairment, coexist with seizures) are proving to be asso-
Diseases of the Nervous System
Epileptogenesis refers to the transformation of a normal ciated with pathways inuencing CNS development or
neuronal network into one that is chronically hyper- neuronal homeostasis. A current challenge is to identify
excitable. There is often a delay of months to years the multiple susceptibility genes that underlie the more
between an initial CNS injury such as trauma, stroke, common forms of idiopathic epilepsies. Recent stud-
or infection and the rst seizure. The injury appears ies suggest that ion channel mutations and chromosomal
to initiate a process that gradually lowers the seizure microdeletions may be the cause of epilepsy in a subset of
threshold in the affected region until a spontaneous sei- these patients.
zure occurs. In many genetic and idiopathic forms of
epilepsy, epileptogenesis is presumably determined by
developmentally regulated events.
MECHANISMS OF ACTION OF
Pathologic studies of the hippocampus from patients
ANTIEPILEPTIC DRUGS
with temporal lobe epilepsy have led to the suggestion
that some forms of epileptogenesis are related to struc- Antiepileptic drugs appear to act primarily by blocking
tural changes in neuronal networks. For example, many the initiation or spread of seizures. This occurs through
patients with MTLE have a highly selective loss of a variety of mechanisms that modify the activity of ion
neurons that may contribute to inhibition of the main channels or neurotransmitters, and in most cases the
excitatory neurons within the dentate gyrus. There is drugs have pleiotropic effects. The mechanisms include
also evidence that, in response to the loss of neurons, inhibition of Na+-dependent action potentials in a fre-
there is reorganization or sprouting of surviving neu- quency-dependent manner (e.g., phenytoin, carbamaze-
rons in a way that affects the excitability of the net- pine, lamotrigine, topiramate, zonisamide, lacosamide,
work. Some of these changes can be seen in experimen- runamide), inhibition of voltage-gated Ca2+ chan-
tal models of prolonged electrical seizures or traumatic nels (phenytoin, gabapentin, pregabalin), attenuation of
brain injury. Thus, an initial injury such as head injury glutamate activity (lamotrigine, topiramate, felbamate),
may lead to a very focal, conned region of structural potentiation of GABA receptor function (benzodiaz-
change that causes local hyperexcitability. The local epines and barbiturates), increase in the availability of
hyperexcitability leads to further structural changes that GABA (valproic acid, gabapentin, tiagabine), and mod-
evolve over time until the focal lesion produces clini- ulation of release of synaptic vesicles (levetiracetam).
cally evident seizures. Similar models have provided The two most effective drugs for absence seizures, etho-
strong evidence for long-term alterations in intrinsic, suximide and valproic acid, probably act by inhibiting
biochemical properties of cells within the network such as T-type Ca2+ channels in thalamic neurons.
chronic changes in glutamate or GABA receptor func- In contrast to the relatively large number of anti-
tion. Recent work has suggested that induction of epileptic drugs that can attenuate seizure activity, there
are currently no drugs known to prevent the formation such as sleep deprivation, systemic diseases, electrolyte 241
of a seizure focus following CNS injury. The even- or metabolic derangements, acute infection, drugs that
tual development of such antiepileptogenic drugs lower the seizure threshold (Table 26-5), or alcohol or
will provide an important means of preventing the illicit drug use should also be identied.
emergence of epilepsy following injuries such as head The general physical examination includes a search
trauma, stroke, and CNS infection. for signs of infection or systemic illness. Careful exami-
nation of the skin may reveal signs of neurocutane-
ous disorders such as tuberous sclerosis or neurobro-
APPROACH TO THE matosis, or chronic liver or renal disease. A nding of
PATIENT Seizure
organomegaly may indicate a metabolic storage disease,
When a patient presents shortly after a seizure, the first and limb asymmetry may provide a clue to brain injury
priorities are attention to vital signs, respiratory and car- early in development. Signs of head trauma and use of
diovascular support, and treatment of seizures if they alcohol or illicit drugs should be sought. Auscultation of
resume (see Treatment: Seizures and Epilepsy). Life- the heart and carotid arteries may identify an abnormal-
threatening conditions such as CNS infection, metabolic ity that predisposes to cerebrovascular disease.
derangement, or drug toxicity must be recognized and All patients require a complete neurologic examina-
tion, with particular emphasis on eliciting signs of cere-
CHAPTER 26
managed appropriately.
When the patient is not acutely ill, the evaluation bral hemispheric disease (Chap. 1). Careful assessment
will initially focus on whether there is a history of earlier of mental status (including memory, language function,
seizures (Fig. 26-2). If this is the first seizure, then the and abstract thinking) may suggest lesions in the ante-
emphasis will be to: (1) establish whether the reported rior frontal, parietal, or temporal lobes. Testing of visual
episode was a seizure rather than another paroxysmal elds will help screen for lesions in the optic pathways
event, (2) determine the cause of the seizure by identify- and occipital lobes. Screening tests of motor func-
History
Physical examination
Exclude
Syncope
Transient ischemic attack
Migraine
Acute psychosis
Other causes of episodic cerebral dysfunction
Laboratory studies
Assess: adequacy of antiepileptic therapy CBC
Side effects Electrolytes, calcium, magnesium
Serum levels Serum glucose
SECTION III
suggesting a metabolic
or infectious disorder
MRI scan
Normal Abnormal or change in and EEG
neurologic exam
Further workup
Lumbar puncture
Cultures Focal features of
Subtherapeutic Therapeutic Treat identifiable Endocrine studies seizures
antiepileptic antiepileptic metabolic abnormalities CT Focal abnormalities
levels levels Assess cause of MRI if focal on clinical or lab
neurologic change features present examination
Other evidence of
neurologic
Appropriate Increase antiepileptic dysfunction
Treat underlying
increase or therapy to maximum
metabolic abnormality
resumption tolerated dose;
of dose consider alternative
antiepileptic drugs
Consider: Antiepileptic therapy
Yes No
FIGURE 26-2
Evaluation of the adult patient with a seizure. CBC, complete blood count; CNS, central nervous system; CT, computed
tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging.
disorder, however, because focal seizures may originate not possible to obtain the EEG during a clinical event.
from a region of the cortex that cannot be detected by Continuous monitoring for prolonged periods in video-
standard scalp electrodes. The EEG is always abnormal EEG telemetry units for hospitalized patients or the use
during generalized tonic-clonic seizures. Since seizures of portable equipment to record the EEG continuously
are typically infrequent and unpredictable, it is often on cassettes for v24 h in ambulatory patients has made it
easier to capture the electrophysiologic accompaniments suggestive of a benign, generalized seizure disorder such 243
of clinical events. In particular, video-EEG telemetry as absence epilepsy. MRI has been shown to be supe-
is now a routine approach for the accurate diagnosis of rior to CT for the detection of cerebral lesions asso-
epilepsy in patients with poorly characterized events or ciated with epilepsy. In some cases MRI will identify
seizures that are difcult to control. lesions such as tumors, vascular malformations, or other
The EEG may also be helpful in the interictal period pathologies that need immediate therapy. The use of
by showing certain abnormalities that are highly sup- newer MRI methods such as 3-Tesla scanners, multi-
portive of the diagnosis of epilepsy. Such epileptiform channel head coils, three-dimensional structural imaging
activity consists of bursts of abnormal discharges contain- at submillimeter resolution, and new pulse sequences
ing spikes or sharp waves. The presence of epileptiform including uid-attenuated inversion recovery (FLAIR),
activity is not specic for epilepsy, but it has a much has increased the sensitivity for detection of abnormali-
greater prevalence in patients with epilepsy than in nor- ties of cortical architecture, including hippocampal atro-
mal individuals. However, even in an individual who phy associated with mesial temporal sclerosis, as well as
is known to have epilepsy, the initial routine interictal abnormalities of cortical neuronal migration. In such
EEG may be normal up to 60% of the time. Thus, the cases the ndings may not lead to immediate therapy,
EEG cannot establish the diagnosis of epilepsy in many but they do provide an explanation for the patients sei-
cases. zures and point to the need for chronic anticonvulsant
CHAPTER 26
The EEG is also used for classifying seizure disorders therapy or possible surgical resection.
and aiding in the selection of anticonvulsant medica- In the patient with a suspected CNS infection or
tions. For example, episodic generalized spike-wave mass lesion, CT scanning should be performed emer-
activity is usually seen in patients with typical absence gently when MRI is not immediately available. Other-
epilepsy and may be seen with other generalized epi- wise, it is usually appropriate to obtain an MRI study
lepsy syndromes. Focal interictal epileptiform discharges within a few days of the initial evaluation. Functional
vomiting
hallucinogens) unconsciousness
Benign paroxysmal vertigo
Migraine Apnea Duration of tonic 3060 s Never more than
Confusional migraine Night terrors or clonic move- 15 s
Basilar migraine Sleepwalking ments
Facial appearance Cyanosis, Pallor
during event frothing at
Diseases of the Nervous System
mouth
from the lying or sitting position. Patients with syncope
Disorientation and Many minutes to <5 min
often describe a stereotyped transition from conscious- sleepiness after hours
ness to unconsciousness that includes tiredness, sweating, event
nausea, and tunneling of vision, and they experience a Aching of muscles Often Sometimes
relatively brief loss of consciousness. Headache or incon- after event
tinence usually suggests a seizure but may on occasion
Biting of tongue Sometimes Rarely
also occur with syncope. A brief period (i.e., 110 s) of
convulsive motor activity is frequently seen immediately Incontinence Sometimes Sometimes
at the onset of a syncopal episode, especially if the patient Headache Sometimes Rarely
remains in an upright posture after fainting (e.g., in a
a
dentists chair) and therefore has a sustained decrease in May be sudden with certain cardiac arrhythmias.
cerebral perfusion. Rarely, a syncopal episode can induce
a full tonic-clonic seizure. In such cases the evaluation
must focus on both the cause of the syncopal event as experienced epileptologists. This is especially true for
well as the possibility that the patient has a propensity for psychogenic seizures that resemble focal seizures with
recurrent seizures. dyscognitive features, since the behavioral manifesta-
tions of focal seizures (especially of frontal lobe origin)
can be extremely unusual, and in both cases the rou-
PSYCHOGENIC SEIZURES
tine surface EEG may be normal. Video-EEG monitor-
Psychogenic seizures are nonepileptic behaviors that ing is very useful when historic features are nondiagnos-
resemble seizures. They are often part of a conver- tic. Generalized tonic-clonic seizures always produce
sion reaction precipitated by underlying psychological marked EEG abnormalities during and after the seizure.
distress. Certain behaviors such as side-to-side turning For suspected focal seizures of temporal lobe origin, the
of the head, asymmetric and large-amplitude shaking use of additional electrodes beyond the standard scalp
movements of the limbs, twitching of all four extremi- locations (e.g., sphenoidal electrodes) may be required
ties without loss of consciousness, and pelvic thrust- to localize a seizure focus. Measurement of serum
ing are more commonly associated with psychogenic prolactin levels may also help to distinguish between
rather than epileptic seizures. Psychogenic seizures organic and psychogenic seizures, since most gener-
often last longer than epileptic seizures and may wax alized seizures and some focal seizures are accompa-
and wane over minutes to hours. However, the distinc- nied by rises in serum prolactin (during the immediate
tion is sometimes difcult on clinical grounds alone, and 30-min postictal period), whereas psychogenic seizures
there are many examples of diagnostic errors made by are not. The diagnosis of psychogenic seizures does not
exclude a concurrent diagnosis of epilepsy, since the
For example, a patient who has seizures in the setting
245
two often coexist.
of sleep deprivation should obviously be advised to
maintain a normal sleep schedule. Many patients note
TREATMENT Seizures and Epilepsy an association between alcohol intake and seizures, and
they should be encouraged to modify their drinking
Therapy for a patient with a seizure disorder is almost habits accordingly. There are also relatively rare cases of
always multimodal and includes treatment of underly- patients with seizures that are induced by highly spe-
ing conditions that cause or contribute to the seizures, cific stimuli such as a video game monitor, music, or an
avoidance of precipitating factors, suppression of recur- individuals voice (reflex epilepsy). If there is an associ-
rent seizures by prophylactic therapy with antiepilep- ation between stress and seizures, stress reduction tech-
tic medications or surgery, and addressing a variety niques such as physical exercise, meditation, or counsel-
of psychological and social issues. Treatment plans ing may be helpful.
must be individualized, given the many different types
and causes of seizures as well as the differences in effi- ANTIEPILEPTIC DRUG THERAPY Antiepilep-
cacy and toxicity of antiepileptic medications for each tic drug therapy is the mainstay of treatment for most
patient. In almost all cases a neurologist with experi- patients with epilepsy. The overall goal is to completely
CHAPTER 26
ence in the treatment of epilepsy should design and prevent seizures without causing any untoward side
oversee implementation of the treatment strategy. effects, preferably with a single medication and a dosing
Furthermore, patients with refractory epilepsy or those schedule that is easy for the patient to follow. Seizure
who require polypharmacy with antiepileptic drugs classification is an important element in designing the
should remain under the regular care of a neurologist. treatment plan, since some antiepileptic drugs have dif-
ferent activities against various seizure types. However,
TREATMENT OF UNDERLYING CONDI-
there is considerable overlap between many antiepilep-
the commonly used antiepileptic drugs can cause simi- Phenobarbital Gabapentina
lar, dose-related side effects such as sedation, ataxia, Primidone Lacosamidea
and diplopia. Long-term use of some agents in adults, Felbamate Phenobarbital
especially the elderly, can lead to osteoporosis. Close Primidone
follow-up is required to ensure these side effects are Felbamate
promptly recognized and reversed. Most of the older
a
As adjunctive therapy.
drugs and some of the newer ones can also cause
Diseases of the Nervous System
Phenytoin Dilantin Tonic-clonic 300400 24 h (wide 1020 g/mL Dizziness Gum hyperplasia Level increased by isoniazid, sul-
(diphenyl- Focal-onset mg/d (36 variation, Diplopia Lymphadenopathy fonamides, uoxetine
hydantoin mg/kg, dose- Ataxia Hirsutism Level decreased by enzyme-
adult; 48 depen- Incoordination Osteomalacia inducing drugsa
mg/kg, dent) Confusion Facial coarsening Altered folate metabolism
child); qd- Skin rash
bid
Carbam- Tegretolb Tonic-clonic 6001800 1017 h 612 g/mL Ataxia Aplastic anemia Level decreased by enzyme-
azepine Carbatrol Focal-onset mg/d (15 Dizziness Leukopenia inducing drugsa
35 mg/kg, Diplopia Gastrointestinal Level increased by erythromycin,
child); bid- Vertigo irritation propoxyphene, isoniazid, cimeti-
qid Hepatotoxicity dine, uoxetine
Hyponatremia
Valproic Depakene Tonic-clonic 7502000 15 h 50125 g/mL Ataxia Hepatotoxicity Level decreased by enzyme-
acid Depakoteb Absence mg/d (20 Sedation Thrombocytopenia inducing drugsa
Atypical 60 mg/kg); Tremor Gastrointestinal
absence bid-qid irritation
Myoclonic Weight gain
Focal-onset Transient alopecia
Atonic Hyperammonemia
Lamotrigine Lamictalb Focal-onset 150500 25 h Not established Dizziness Skin rash Level decreased by enzyme-
Tonic-clonic mg/d; bid 14 h (with Diplopia Stevens-Johnson inducing drugsa and oral contra-
Atypical enzyme- Sedation syndrome ceptives
absence inducers) Ataxia Level increased by valproic acid
Myoclonic 59 h (with Headache
Lennox- valproic
Gastaut acid)
syndrome
Ethosuxi- Zarontin Absence 7501250 60 h, adult 40100 g/mL Ataxia Gastrointestinal Level decreased by enzyme-
mide mg/d (20 30 h, child Lethargy irritation inducing drugsa
40 mg/kg); Headache Skin rash Level increased by valproic acid
qd-bid Bone marrow sup-
pression
(continued)
247
248
Diseases of the Nervous System SECTION III
TABLE 26-9
DOSAGE AND ADVERSE EFFECTS OF COMMONLY USED ANTIEPILEPTIC DRUGS (CONTINUED)
Gabapentin Neurontin Focal-onset 9002400 59 h Not established Sedation Gastrointestinal No known signicant interactions
mg/d; tid- Dizziness irritation
qid Ataxia Weight gain
Fatigue Edema
Topiramate Topamax Focal-onset 200400 2030 h Not established Psychomotor Renal stones (avoid Level decreased by enzyme-
Tonic-clonic mg/d; bid slowing use with other inducing drugsa
Lennox- Sedation carbonic anhy-
Gastaut Speech or lan- drase inhibitors)
syndrome guage problems Glaucoma
Fatigue Weight loss
Paresthesias Hypohidrosis
Tiagabine Gabitril Focal-onset 3256 79 h Not established Confusion Gastrointestinal Level decreased by enzyme-
mg/d; Sedation irritation inducing drugsa
bid-qid Depression
Dizziness
Speech or lan-
guage problems
Paresthesias
Psychosis
Phenobar- Luminol Tonic-clonic 60180 90 h 1040 g/mL Sedation Skin rash Level increased by valproic acid,
bital Focal-onset mg/d; qd Ataxia phenytoin
Confusion
Dizziness
Decreased libido
Depression
Primidone Mysoline Tonic-clonic 7501000 Primidone, Primidone, 412 Same as pheno- Level increased by valproic acid,
Focal-onset mg/d; bid- 815 h g/mL barbital phenytoin
tid Phenobar- Phenobarbital,
bital, 90 h 1040 g/mL
Clonaz- Klonopin Absence 112 mg/d; 2448 h 1070 ng/mL Ataxia Anorexia Level decreased by enzyme-
epam Atypical qd-tid Sedation inducing drugsa
absence Lethargy
Myoclonic
Felbamate Felbatol Focal-onset 24003600 1622 h Not established Insomnia Aplastic anemia Increases phenytoin, valproic acid,
Lennox- mg/d, tid- Dizziness Hepatic failure active carbamazepine metabolite
Gastaut qid Sedation Weight loss
syndrome Headache Gastrointestinal
Tonic-clonic irritation
Levetirace- Kepprab Focal-onset 10003000 68 h Not established Sedation Anemia No known signicant interactions
tam mg/d; qd- Fatigue Leukopenia
bid Incoordination
Mood changes
Zonisamide Zonegran Focal-onset 200400 5068 h Not established Sedation Anorexia Level decreased by enzyme-
Tonic-clonic mg/d; qd- Dizziness Renal stones inducing drugsa
bid Confusion Hypohidrosis
Headache
Psychosis
Oxcarbaze- Trileptal Focal-onset 9002400 1017 h Not established Fatigue See carbamazepine Level decreased by enzyme-
pine Tonic-clonic mg/d (30 (for active Ataxia inducing drugsa
45 mg/kg, metabolite) Dizziness May increase phenytoin
child); bid Diplopia
Vertigo
Headache
Lacosamide Vimpat Focal-onset 200400 13 h Not established Dizziness GI irritation Level decreased by enzyme-
mg/d; bid Ataxia Cardiac conduction inducing drugsa
Diplopia (PR interval pro-
Vertigo longation)
Runamide Banzel Lennox- 3200 mg/d 610 h Not established Sedation GI irritation Level decreased by enzyme-
Gastaut (45 mg/kg, Fatigue Leukopenia inducing drugsa
syndrome child); bid Dizziness Cardiac conduction Level increased by valproic acid
Ataxia (QT interval pro- May increase phenytoin
Headache longation)
Diplopia
a
Phenytoin, carbamazepine, phenobarbital.
b
Extended-release product available.
249
250 problems, and it should not be used in patients at risk This process may take months or longer if the baseline
for the development of glaucoma or renal stones. seizure frequency is low. Most anticonvulsant drugs
Valproic acid is an effective alternative for some need to be introduced relatively slowly to minimize
patients with focal seizures, especially when the seizures side effects, and patients should expect that minor side
generalize. Gastrointestinal side effects are fewer when effects such as mild sedation, slight changes in cogni-
using the valproate semisodium formulation (Depakote). tion, or imbalance will typically resolve within a few
Valproic acid also rarely causes reversible bone marrow days. Starting doses are usually the lowest value listed
suppression and hepatotoxicity, and laboratory testing under the dosage column in Table 26-9. Subsequent
is required to monitor toxicity. This drug should generally increases should be made only after achieving a steady
be avoided in patients with preexisting bone marrow or state with the previous dose (i.e., after an interval of five
liver disease. Irreversible, fatal hepatic failure appearing or more half-lives).
as an idiosyncratic rather than dose-related side effect is Monitoring of serum antiepileptic drug levels can be
a relatively rare complication; its risk is highest in children very useful for establishing the initial dosing schedule.
<2 years old, especially those taking other antiepileptic However, the published therapeutic ranges of serum
drugs or with inborn errors of metabolism. drug concentrations are only an approximate guide for
Levetiracetam, zonisamide, tiagabine, gabapentin, determining the proper dose for a given patient. The
SECTION III
and lacosamide are additional drugs currently used for key determinants are the clinical measures of seizure
the treatment of focal seizures with or without evolu- frequency and presence of side effects, not the labo-
tion into generalized seizures. Phenobarbital and other ratory values. Conventional assays of serum drug lev-
barbiturate compounds were commonly used in the els measure the total drug (i.e., both free and protein
past as first-line therapy for many forms of epilepsy. bound). However, it is the concentration of free drug
However, the barbiturates frequently cause sedation in that reflects extracellular levels in the brain and corre-
adults, hyperactivity in children, and other more subtle lates best with efficacy. Thus, patients with decreased
Diseases of the Nervous System
cognitive changes; thus, their use should be limited to levels of serum proteins (e.g., decreased serum albumin
situations in which no other suitable treatment alterna- due to impaired liver or renal function) may have an
tives exist. increased ratio of free to bound drug, yet the concen-
tration of free drug may be adequate for seizure con-
Antiepileptic Drug Selection for General-
trol. These patients may have a subtherapeutic drug
ized Seizures Valproic acid and lamotrigine are cur-
level, but the dose should be changed only if seizures
rently considered the best initial choice for the treatment
remain uncontrolled, not just to achieve a therapeutic
of primary generalized, tonic-clonic seizures. Topiramate,
level. It is also useful to monitor free drug levels in such
zonisamide, phenytoin, and carbamazepine are suitable
patients. In practice, other than during the initiation or
alternatives. Valproic acid is also particularly effective in
modification of therapy, monitoring of antiepileptic
absence, myoclonic, and atonic seizures and is therefore
drug levels is most useful for documenting compliance.
the drug of choice in patients with generalized epilepsy
If seizures continue despite gradual increases to the
syndromes having mixed seizure types. Importantly, car-
maximum tolerated dose and documented compli-
bamazepine, oxcarbazepine, and phenytoin can worsen
ance, then it becomes necessary to switch to another
certain types of generalized seizures, including absence,
antiepileptic drug. This is usually done by maintain-
myoclonic, tonic, and atonic seizures. Ethosuximide is a
ing the patient on the first drug while a second drug is
particularly effective drug for the treatment of uncompli-
added. The dose of the second drug should be adjusted
cated absence seizures, but it is not useful for tonic-clonic
to decrease seizure frequency without causing toxicity.
or focal seizures. Ethosuximide rarely causes bone mar-
Once this is achieved, the first drug can be gradually
row suppression, so that periodic monitoring of blood
withdrawn (usually over weeks unless there is significant
cell counts is required. Lamotrigine appears to be particu-
toxicity). The dose of the second drug is then further opti-
larly effective in epilepsy syndromes with mixed, general-
mized based on seizure response and side effects. Mono-
ized seizure types such as JME and Lennox-Gastaut syn-
therapy should be the goal whenever possible.
drome. Topiramate, zonisamide, and felbamate may have
similar broad efficacy.
When to Discontinue Therapy Overall, about
Initiation and Monitoring of Therapy Because 70% of children and 60% of adults who have their sei-
the response to any antiepileptic drug is unpredict- zures completely controlled with antiepileptic drugs can
able, patients should be carefully educated about the eventually discontinue therapy. The following patient
approach to therapy. The goal is to prevent seizures profile yields the greatest chance of remaining seizure
and minimize the side effects of therapy; determination free after drug withdrawal: (1) complete medical control
of the optimal dose is often a matter of trial and error. of seizures for 15 years; (2) single seizure type, either
focal or generalized; (3) normal neurologic examination, trauma and increased mortality associated with ongo- 251
including intelligence; and (4) normal EEG. The appropri- ing seizures, the patient should have an efficient but
ate seizure-free interval is unknown and undoubtedly relatively brief attempt at medical therapy and then be
varies for different forms of epilepsy. However, it seems referred for surgical evaluation.
reasonable to attempt withdrawal of therapy after 2 years The most common surgical procedure for patients
in a patient who meets all of the above criteria, is moti- with temporal lobe epilepsy involves resection of the
vated to discontinue the medication, and clearly under- anteromedial temporal lobe (temporal lobectomy) or a
stands the potential risks and benefits. In most cases it is more limited removal of the underlying hippocampus
preferable to reduce the dose of the drug gradually over and amygdala (amygdalohippocampectomy). Focal
23 months. Most recurrences occur in the first 3 months seizures arising from extratemporal regions may be
after discontinuing therapy, and patients should be abolished by a focal neocortical resection with pre-
advised to avoid potentially dangerous situations such as cise removal of an identified lesion (lesionectomy).
driving or swimming during this period. When the cortical region cannot be removed, multiple
subpial transection, which disrupts intracortical con-
Treatment of Refractory Epilepsy Approxi-
nections, is sometimes used to prevent seizure spread.
mately one-third of patients with epilepsy do not
Hemispherectomy or multilobar resection is useful for
respond to treatment with a single antiepileptic drug,
CHAPTER 26
some patients with severe seizures due to hemispheric
and it becomes necessary to try a combination of drugs
abnormalities such as hemimegalencephaly or other
to control seizures. Patients who have focal epilepsy
dysplastic abnormalities, and corpus callosotomy has
related to an underlying structural lesion or those with
been shown to be effective for disabling tonic or atonic
multiple seizure types and developmental delay are
seizures, usually when they are part of a mixed-seizure
particularly likely to require multiple drugs. There are
syndrome (e.g., Lennox-Gastaut syndrome).
currently no clear guidelines for rational polypharmacy,
Presurgical evaluation is designed to identify the
of seizures following resective surgery can have a very neuronal injury. Furthermore, CNS injury can occur
beneficial effect on quality of life. even when the patient is paralyzed with neuromuscular
Not all medically refractory patients are suitable blockade but continues to have electrographic seizures.
candidates for resective surgery. For example, some The most common causes of GCSE are anticonvulsant
patients have seizures arising from more than one site, withdrawal or noncompliance, metabolic disturbances,
making the risk of ongoing seizures or potential harm drug toxicity, CNS infection, CNS tumors, refractory
from the surgery unacceptably high. Vagus nerve stim-
Diseases of the Nervous System
Seizures continuing
Consider valproate
25 mg/kg IV in pts. Fosphenytoin 710 mg/kg PE IV 150 mg/min
normally taking or phenytoin 710 mg/kg IV 50 mg/min
valproate and who may
be subtherapeutic Seizures continuing
Consider valproate
25 mg/kg IV
No immediate access to ICU
CHAPTER 26
Admit Seizures continuing
to ICU
Phenobarbital 10 mg/kg IV 60 mg/min
FIGURE 26-3
be carefully addressed by educating the patient about progestins or intramuscular medroxyprogesterone may
epilepsy and by ensuring that family members, teachers, be of benet to a subset of women.
fellow employees, and other associates are equally well
informed. The Epilepsy Foundation of America (www
.epilepsyfoundation.org) is a patient advocacy organiza- PREGNANCY
tion and a useful source of educational material, as is the Most women with epilepsy who become pregnant will
Diseases of the Nervous System
CHAPTER 26
primidone cause a transient and reversible deciency of acid) to 300% (levetiracetam). Given the overall bene-
vitamin Kdependent clotting factors in 50% of new- ts of breast-feeding and the lack of evidence for long-
born infants. Although neonatal hemorrhage is uncom- term harm to the infant by being exposed to antiepi-
mon, the mother should be treated with oral vitamin K leptic drugs, mothers with epilepsy can be encouraged
(20 mg/d, phylloquinone) in the last 2 weeks of preg- to breast-feed. This should be reconsidered, however, if
nancy, and the infant should receive intramuscular vita- there is any evidence of drug effects on the infant such
CEREBROVASCULAR DISEASES
Cerebrovascular diseases include some of the most com- ow persists for a longer duration, then infarction in the
mon and devastating disorders: ischemic stroke, hem- border zones between the major cerebral artery distri-
orrhagic stroke, and cerebrovascular anomalies such as butions may develop. In more severe instances, global
intracranial aneurysms and arteriovenous malformations hypoxia-ischemia causes widespread brain injury; the
(AVMs). They cause 200,000 deaths each year in the constellation of cognitive sequelae that ensues is called
United States and are a major cause of disability. The hypoxic-ischemic encephalopathy (Chap. 28). Focal ischemia
incidence of cerebrovascular diseases increases with age, or infarction, conversely, is usually caused by thrombo-
and the number of strokes is projected to increase as sis of the cerebral vessels themselves or by emboli from
the elderly population grows, with a doubling in stroke a proximal arterial source or the heart. Intracranial hemor-
deaths in the United States by 2030. Most cerebrovas- rhage is caused by bleeding directly into or around the
cular diseases are manifest by the abrupt onset of a focal brain; it produces neurologic symptoms by producing a
neurologic decit, as if the patient was struck by the mass effect on neural structures, from the toxic effects of
hand of God. A stroke, or cerebrovascular accident, blood itself, or by increasing intracranial pressure.
is dened by this abrupt onset of a neurologic decit
that is attributable to a focal vascular cause. Thus, the APPROACH TO THE
denition of stroke is clinical, and laboratory studies PATIENT Cerebrovascular Disease
including brain imaging are used to support the diag-
nosis. The clinical manifestations of stroke are highly Rapid evaluation is essential for use of time-sensitive
variable because of the complex anatomy of the brain treatments such as thrombolysis. However, patients
and its vasculature. Cerebral ischemia is caused by a with acute stroke often do not seek medical assistance
reduction in blood ow that lasts longer than several on their own, both because they are rarely in pain, as
seconds. Neurologic symptoms are manifest within well as because they may lose the appreciation that
seconds because neurons lack glycogen, so energy fail- something is wrong (anosognosia); it is often a family
ure is rapid. If the cessation of ow lasts for more than member or a bystander who calls for help. Therefore,
a few minutes, infarction or death of brain tissue results. patients and their family members should be counseled
When blood ow is quickly restored, brain tissue can to call emergency medical services immediately if they
recover fully and the patients symptoms are only tran- experience or witness the sudden onset of any of the
sient: This is called a transient ischemic attack (TIA). The following: loss of sensory and/or motor function on one
standard denition of TIA requires that all neurologic side of the body (nearly 85% of ischemic stroke patients
signs and symptoms resolve within 24 h regardless of have hemiparesis); change in vision, gait, or ability to
whether there is imaging evidence of new permanent speak or understand; or if they experience a sudden,
brain injury; stroke has occurred if the neurologic signs severe headache.
and symptoms last for >24 h. However, a newly pro- There are several common causes of sudden-onset
posed denition classies those with new brain infarc- neurologic symptoms that may mimic stroke, includ-
tion as ischemic strokes regardless of whether symptoms ing seizure, intracranial tumor, migraine, and metabolic
persist. A generalized reduction in cerebral blood ow encephalopathy. An adequate history from an observer
due to systemic hypotension (e.g., cardiac arrhythmia, that no convulsive activity occurred at the onset rea-
myocardial infarction, or hemorrhagic shock) usually sonably excludes seizure; however, ongoing com-
produces syncope (Chap. 10). If low cerebral blood plex partial seizures without tonic-clonic activity may
256
mimic stroke. Tumors may present with acute neuro- ALGORITHM FOR STROKE AND TIA MANAGEMENT 257
logic symptoms due to hemorrhage, seizure, or hydro- Stroke or TIA
CHAPTER 27
warfarin (Chap. 28) surgery
behind no residual symptoms and with a normal MRI stent cause cause
study of the brain. Classically, metabolic encephalopa-
thies produce fluctuating mental status without focal
Deep venous thrombosis prophylaxis
neurologic findings. However, in the setting of prior Physical, occupational, speech therapy
stroke or brain injury, a patient with fever or sepsis may Evaluate for rehab, discharge planning
Secondary prevention based on disease
manifest hemiparesis, which clears rapidly when the
infection is remedied. The metabolic process serves to
Cerebrovascular Diseases
FIGURE 27-1
unmask a prior deficit. Medical management of stroke and TIA. Rounded boxes
Once the diagnosis of stroke is made, a brain imag- are diagnoses; rectangles are interventions. Numbers are
ing study is necessary to determine if the cause of percentages of stroke overall. ABCs, airway, breathing, cir-
stroke is ischemia or hemorrhage (Fig. 27-1). CT imag- culation; BP, blood pressure; CEA, carotid endarterectomy;
ing of the brain is the standard imaging modality to ICH, intracerebral hemorrhage; SAH, subarachnoid hemor-
detect the presence or absence of intracranial hemor- rhage; TIA, transient ischemic attack.
rhage (see Imaging Studies). If the stroke is ischemic,
administration of recombinant tissue plasminogen anatomy, the site of occlusion, and likely systemic
activator (rtPA) or endovascular mechanical thrombec- blood pressure. A decrease in cerebral blood ow to
tomy may be beneficial in restoring cerebral perfusion zero causes death of brain tissue within 410 min; val-
(see Treatment: Acute Ischemic Stroke). Medical man- ues <1618 mL/100 g tissue per minute cause infarc-
agement to reduce the risk of complications becomes tion within an hour; and values <20 mL/100 g tissue
the next priority, followed by plans for secondary pre- per minute cause ischemia without infarction unless
vention. For ischemic stroke, several strategies can prolonged for several hours or days. If blood ow
reduce the risk of subsequent stroke in all patients, is restored prior to a signicant amount of cell death,
while other strategies are effective for patients with the patient may experience only transient symptoms,
specific causes of stroke such as cardiac embolus and and the clinical syndrome is called a TIA. Tissue sur-
carotid atherosclerosis. For hemorrhagic stroke, aneu- rounding the core region of infarction is ischemic but
rysmal subarachnoid hemorrhage (SAH) and hyperten- reversibly dysfunctional and is referred to as the isch-
sive intracranial hemorrhage are two important causes. emic penumbra. The penumbra may be imaged by using
The treatment and prevention of hypertensive intra- perfusion-diffusion imaging with MRI or CT (see later
cranial hemorrhage are discussed later in this chapter. and Figs. 27-15 and 27-16). The ischemic penum-
SAH is discussed in Chap. 28. bra will eventually infarct if no change in ow occurs,
and hence saving the ischemic penumbra is the goal of
revascularization therapies.
ISCHEMIC STROKE Focal cerebral infarction occurs via two distinct path-
ways (Fig. 27-2): (1) a necrotic pathway in which cel-
PATHOPHYSIOLOGY OF ISCHEMIC STROKE lular cytoskeletal breakdown is rapid, due principally to
Acute occlusion of an intracranial vessel causes reduc- energy failure of the cell; and (2) an apoptotic pathway
tion in blood ow to the brain region it supplies. The in which cells become programmed to die. Ischemia
magnitude of ow reduction is a function of collat- produces necrosis by starving neurons of glucose and
eral blood ow and this depends on individual vascular oxygen, which in turn results in failure of mitochondria
258 CASCADE OF CEREBRAL ISCHEMIA
Arterial Occlusion
Thrombolysis
Ischemia Reperfusion
Thrombectomy
Inflammatory
Energy failure PARP response
Glutamate
release
Mitochondrial
Leukocyte
damage
adhesion
Glutamate
Ca2+/Na+ influx Apoptosis Arachidonic acid
receptors
production
Lipolysis
Proteolysis
iNOS Free radical
formation
Membrane and
SECTION III
Cell Death
FIGURE 27-2
Major steps in the cascade of cerebral ischemia. See text for details. iNOS, inducible nitric oxide synthase; PARP, poly-A
Diseases of the Nervous System
ribose polymerase.
to produce ATP. Without ATP, membrane ion pumps scan to differentiate between ischemic stroke and hem-
stop functioning and neurons depolarize, allowing intra- orrhagic stroke; there are no reliable clinical findings
cellular calcium to rise. Cellular depolarization also that conclusively separate ischemia from hemorrhage,
causes glutamate release from synaptic terminals; excess although a more depressed level of consciousness,
extracellular glutamate produces neurotoxicity by acti- higher initial blood pressure, or worsening of symptoms
vating postsynaptic glutamate receptors that increase after onset favor hemorrhage, and a deficit that is maxi-
neuronal calcium inux. Free radicals are produced by mal at onset, or remits, suggests ischemia. Treatments
membrane lipid degradation and mitochondrial dys- designed to reverse or lessen the amount of tissue
function. Free radicals cause catalytic destruction of infarction and improve clinical outcome fall within six
membranes and likely damage other vital functions of categories: (1) medical support, (2) IV thrombolysis, (3)
cells. Lesser degrees of ischemia, as are seen within the endovascular techniques, (4) antithrombotic treatment,
ischemic penumbra, favor apoptotic cellular death caus- (5) neuroprotection, and (6) stroke centers and rehabili-
ing cells to die days to weeks later. Fever dramatically tation.
worsens brain injury during ischemia, as does hypergly-
cemia (glucose >11.1 mmol/L [200 mg/dL]), so it is MEDICAL SUPPORT When ischemic stroke occurs,
reasonable to suppress fever and prevent hyperglycemia the immediate goal is to optimize cerebral perfusion in
as much as possible. Induced moderate hypothermia the surrounding ischemic penumbra. Attention is also
to mitigate stroke is the subject of continuing clinical directed toward preventing the common complications
research. of bedridden patientsinfections (pneumonia, urinary,
and skin) and deep venous thrombosis (DVT) with pul-
monary embolism. Many physicians use pneumatic com-
TREATMENT Acute Ischemic Stroke pression stockings to prevent DVT; subcutaneous heparin
(unfractionated and low-molecular weight) is safe and
After the clinical diagnosis of stroke is made, an orderly more effective and can be used concomitantly.
process of evaluation and treatment should follow (Fig. Because collateral blood flow within the ischemic
27-1). The first goal is to prevent or reverse brain injury. brain is blood pressure dependent, there is contro-
Attend to the patients airway, breathing, and circula- versy about whether blood pressure should be low-
tion (ABCs), and treat hypoglycemia or hyperglycemia if ered acutely. Blood pressure should be lowered if there
identified. Perform an emergency noncontrast head CT is malignant hypertension or concomitant myocardial
ischemia or if blood pressure is >185/110 mmHg and orrhage, treatment with IV rtPA within 3 h of the onset 259
thrombolytic therapy is anticipated. When faced with of ischemic stroke improved clinical outcome.
the competing demands of myocardium and brain, low- Three subsequent trials of IV rtPA did not confirm
ering the heart rate with a 1-adrenergic blocker (such this benefit, perhaps because of the dose of rtPA
as esmolol) can be a first step to decrease cardiac work used, the timing of its delivery, and small sample size.
and maintain blood pressure. Fever is detrimental and When data from all randomized IV rtPA trails were
should be treated with antipyretics and surface cooling. combined, however, efficacy was confirmed in the
Serum glucose should be monitored and kept at <6.1 <3-h time window, and efficacy likely extended to
mmol/L (110 mg/dL) using an insulin infusion if neces- 4.5 h if not 6 h. Based on these combined results, the
sary. European Cooperative Acute Stroke Study (ECASS) III
Between 5 and 10% of patients develop enough study explored the safety and efficacy of rtPA in the
cerebral edema to cause obtundation or brain hernia- 3- to 4.5-h time window. Unlike the NINDS study,
tion. Edema peaks on the second or third day but can patients older than 85 years of age and diabetic
cause mass effect for 10 days. The larger the infarct, the patients were excluded. In this 821-patient, random-
greater the likelihood that clinically significant edema will ized study efficacy was again confirmed, although
develop. Water restriction and IV mannitol may be used less robust than in the 03 h time window. In the
CHAPTER 27
to raise the serum osmolarity, but hypovolemia should be rtPA group, 52.4% achieved a good outcome while
avoided as this may contribute to hypotension and wors- 45.2% of the placebo group had a good outcome at
ening infarction. Combined analysis of three randomized 90 days (OR 1.34, p = 0.04). The symptomatic intracra-
European trials of hemicraniectomy (craniotomy and nial hemorrhage rate was 2.4% in the rtPA group and
temporary removal of part of the skull) shows that hemi- 0.2% in the placebo group (p = 0.008).
craniectomy markedly reduces mortality, and the clinical Based on these data, rtPA is being reviewed for
outcomes of survivors are acceptable. approval in the 34.5-h window in Europe, but is only
Cerebrovascular Diseases
Special vigilance is warranted for patients with cer- approved for 03 h in the United States and Canada.
ebellar infarction. Such strokes may mimic labyrinthitis Use of IV tPA is now considered a central component of
because of prominent vertigo and vomiting; the pres- primary stroke centers (see later) as the first treatment
ence of head or neck pain should alert the physician proven to improve clinical outcomes in ischemic stroke
to consider cerebellar stroke from vertebral artery dis- and is cost-effective and cost-saving. One may be able
section. Even small amounts of cerebellar edema can to select patients beyond the 4.5-h window, who will
acutely increase intracranial pressure (ICP) or directly benefit from thrombolysis using advanced neuroim-
compress the brainstem. The resulting brainstem com- aging (see neuroimaging section), but this is currently
pression can result in coma and respiratory arrest and investigational. The time of stroke onset is defined as
require emergency surgical decompression. Prophy- the time the patients symptoms began or the time the
lactic suboccipital decompression of large cerebellar patient was last seen as normal. Patients who awaken
infarcts before brainstem compression, although not with stroke have the onset defined as when they went
tested rigorously in a clinical trial, is practiced at most to bed. Table 27-1 summarizes eligibility criteria and
stroke centers. instructions for administration of IV rtPA.
intracranial hemorrhage
Major surgery in preceding cular devices in combination with rtPA appears safe,
14 days primary stroke centers may administer rtPA to eli-
Minor stroke symptoms gible patients, and then rapidly refer such patients to
Gastrointestinal bleeding
comprehensive stroke centers that have endovascu-
in preceding 21 days
Recent myocardial infarc- lar capability for further intervention. Such a design
allows centralization of resource-intensive endo-
Diseases of the Nervous System
tion
Coma or stupor vascular centers in order to serve larger populations
of patients. Use of mechanical techniques to restore
Administration of rtPA
blood flow have not as yet been studied in a random-
Intravenous access with two peripheral IV lines (avoid arte- ized trial so the clinical efficacy of these treatments
rial or central line placement)
remain unproven and the focus of active investiga-
Review eligibility for rtPA tion.
Administer 0.9 mg/kg IV (maximum 90 mg) IV as 10% of
total dose by bolus, followed by remainder of total dose
over 1 h ANTITHROMBOTIC TREATMENT
Frequent cuff blood pressure monitoring Platelet Inhibition Aspirin is the only antiplatelet
agent that has been proven effective for the acute treat-
No other antithrombotic treatment for 24 h
ment of ischemic stroke; there are several antiplatelet
For decline in neurologic status or uncontrolled blood agents proven for the secondary prevention of stroke
pressure, stop infusion, give cryoprecipitate, and reimage (see later). Two large trials, the International Stroke
brain emergently
Trial (IST) and the Chinese Acute Stroke Trial (CAST),
Avoid urethral catheterization for v2 h found that the use of aspirin within 48 h of stroke onset
a
reduced both stroke recurrence risk and mortality mini-
See Activase (tissue plasminogen activator) package insert for
complete list of contraindications and dosing.
mally. Among 19,435 patients in IST, those allocated
Abbreviations: BP, blood pressure; HCT, hematocrit; INR, interna- to aspirin, 300 mg/d, had slightly fewer deaths within
tional normalized ratio; MCA, middle cerebral artery; PTT, partial 14 days (9.0 versus 9.4%), significantly fewer recurrent
thromboplastin time. ischemic strokes (2.8 versus 3.9%), no excess of hem-
orrhagic strokes (0.9 versus 0.8%), and a trend toward
a reduction in death or dependence at 6 months (61.2
(FDA); however, many stroke centers offer this treatment versus 63.5%). In CAST, 21,106 patients with ischemic
based on these data. stroke received 160 mg/d of aspirin or a placebo for
Endovascular mechanical thrombectomy has rec- up to 4 weeks. There were very small reductions in the
ently shown promise as an alternative or adjunc- aspirin group in early mortality (3.3 versus 3.9%), recur-
tive treatment of acute stroke in patients who are rent ischemic strokes (1.6 versus 2.1%), and dependency
ineligible for, or have contraindications to, throm- at discharge or death (30.5 versus 31.6%). These trials
bolytics or in those who have failed to have vas- demonstrate that the use of aspirin in the treatment of
cular recanalization with IV thrombolytics (see Fig. AIS is safe and produces a small net benefit. For every
27-15). The Mechanical Embolus Removal in Cere- 1000 acute strokes treated with aspirin, about 9 deaths
or nonfatal stroke recurrences will be prevented in the and instruction in overcoming the deficit. The goal of 261
first few weeks and 13 fewer patients will be dead or rehabilitation is to return the patient to home and to
dependent at 6 months. maximize recovery by providing a safe, progressive regi-
The glycoprotein IIb/IIIa receptor inhibitor abciximab men suited to the individual patient. Additionally, the
was found to cause excess intracranial hemorrhage and use of restraint therapy (immobilizing the unaffected
should be avoided in acute stroke. Clopidogrel is being side) has been shown to improve hemiparesis following
tested as a way to prevent stroke following TIA and stroke, even years following the stroke, suggesting that
minor ischemic stroke. physical therapy can recruit unused neural pathways.
This finding suggests that the human nervous system is
Anticoagulation Numerous clinical trials have
more adaptable than originally thought and has stimu-
failed to demonstrate any benefit of anticoagulation lated active research into physical and pharmacologic
in the primary treatment of atherothrombotic cere-
strategies that can enhance long-term neural recovery.
bral ischemia. Several trials have investigated anti-
platelet versus anticoagulant medications given within
1224 h of the initial event. The U.S. Trial of Organon
10172 in Acute Stroke Treatment (TOAST), an investi-
gational low-molecular-weight heparin (LMWH), failed
CHAPTER 27
to show any benefit over aspirin. Use of SC unfraction-
ated heparin versus aspirin was tested in IST. Heparin ETIOLOGY OF ISCHEMIC STROKE
given SC afforded no additional benefit over aspirin (Figs. 27-1 and 27-3 and Table 27-2) Although the
and increased bleeding rates. Several trials of LMWHs initial management of AIS often does not depend on
have also shown no consistent benefit in AIS. Further- the etiology, establishing a cause is essential in reduc-
more, trials generally have shown an excess risk of brain ing the risk of recurrence. Particular focus should be
Cerebrovascular Diseases
and systemic hemorrhage with acute anticoagulation. on atrial brillation and carotid atherosclerosis, as these
Therefore, trials do not support the routine use of hep- etiologies have proven secondary prevention strategies.
arin or other anticoagulants for patients with athero- The clinical presentation and examination ndings often
thrombotic stroke. establish the cause of stroke or narrow the possibilities
to a few. Judicious use of laboratory testing and imag-
NEUROPROTECTION Neuroprotection is the con-
ing studies completes the initial evaluation. Neverthe-
cept of providing a treatment that prolongs the brains less, nearly 30% of strokes remain unexplained despite
tolerance to ischemia. Drugs that block the excitatory extensive evaluation.
amino acid pathways have been shown to protect neu- Clinical examination should focus on the periph-
rons and glia in animals, but despite multiple human eral and cervical vascular system (carotid auscultation for
trials, they have not yet been proven to be beneficial. bruits, blood pressure, and pressure comparison between
Hypothermia is a powerful neuroprotective treatment in arms), the heart (dysrhythmia, murmurs), extremities
patients with cardiac arrest (Chap. 28) and is neuroprotec- (peripheral emboli), and retina (effects of hypertension
tive in animal models of stroke, but it has not been ade- and cholesterol emboli [Hollenhorst plaques]). A com-
quately studied in patients with ischemic stroke. plete neurologic examination is performed to localize
STROKE CENTERS AND REHABILITA- the site of stroke. An imaging study of the brain is nearly
TION Patient care in comprehensive stroke units always indicated and is required for patients being con-
followed by rehabilitation services improves neuro- sidered for thrombolysis; it may be combined with CT-
logic outcomes and reduces mortality. Use of clinical or MRI-based angiography to interrogate the neck and
pathways and staff dedicated to the stroke patient can intracranial vessels (see Imaging Studies). A chest x-ray,
improve care. Stroke teams that provide emergency electrocardiogram (ECG), urinalysis, complete blood
24-h evaluation of acute stroke patients for acute medi- count, erythrocyte sedimentation rate (ESR), serum elec-
cal management and consideration of thrombolysis or trolytes, blood urea nitrogen (BUN), creatinine, blood
endovascular treatments are essential components of sugar, serologic test for syphilis, serum lipid prole, pro-
primary and comprehensive stroke centers, respectively. thrombin time (PT), and partial thromboplastin time
Proper rehabilitation of the stroke patient includes (PTT) are often useful and should be considered in all
early physical, occupational, and speech therapy. It patients. An ECG may demonstrate arrhythmias or reveal
is directed toward educating the patient and family evidence of recent myocardial infarction (MI).
about the patients neurologic deficit, preventing the
complications of immobility (e.g., pneumonia, DVT and Cardioembolic stroke
pulmonary embolism, pressure sores of the skin, and
Cardioembolism is responsible for 20% of all ischemic
muscle contractures), and providing encouragement
strokes. Stroke caused by heart disease is primarily due
262 Intracranial Penetrating
atherosclerosis artery disease
Carotid Flow
plaque with reducing
arteriogenic carotid
emboli stenosis Internal
carotid
External
carotid
Common
Atrial fibrillation carotid
Cardiogenic
emboli
Valve disease
SECTION III
A B C
Left ventricular
thrombi
FIGURE 27-3
Pathophysiology of ischemic stroke. A. Diagram illus- the major intracranial arteries; and (3) hypoperfusion caused
Diseases of the Nervous System
trating the three major mechanisms that underlie ischemic by ow-limiting stenosis of a major extracranial (e.g., internal
stroke: (1) occlusion of an intracranial vessel by an embolus carotid) or intracranial vessel, often producing watershed
that arises at a distant site (e.g., cardiogenic sources such ischemia. B and C. Diagram and reformatted CT angiogram
as atrial brillation or artery-to-artery emboli from carotid of the common, internal, and external carotid arteries. High-
atherosclerotic plaque), often affecting the large intracranial grade stenosis of the internal carotid artery, which may be
vessels; (2) in situ thrombosis of an intracranial vessel, typi- associated with either cerebral emboli or ow-limiting isch-
cally affecting the small penetrating arteries that arise from emia, was identied in this patient.
to embolism of thrombotic material forming on the location and size of an infarct within a vascular territory
atrial or ventricular wall or the left heart valves. These depend on the extent of the collateral circulation.
thrombi then detach and embolize into the arterial cir- The most signicant causes of cardioembolic stroke
culation. The thrombus may fragment or lyse quickly, in most of the world are nonrheumatic (often called
producing only a TIA. Alternatively, the arterial occlu- nonvalvular) atrial brillation, MI, prosthetic valves,
sion may last longer, producing stroke. Embolic strokes rheumatic heart disease, and ischemic cardiomyopathy
tend to be sudden in onset, with maximum neuro- (Table 27-2). Cardiac disorders causing brain embolism
logic decit at once. With reperfusion following more are discussed in the respective chapters on heart diseases.
prolonged ischemia, petechial hemorrhage can occur A few pertinent aspects are highlighted here.
within the ischemic territory. This is usually of no clini- Nonrheumatic atrial brillation is the most com-
cal signicance and should be distinguished from frank mon cause of cerebral embolism overall. The presumed
intracranial hemorrhage into a region of ischemic stroke stroke mechanism is thrombus formation in the brillat-
where the mass effect from the hemorrhage can cause a ing atrium or atrial appendage, with subsequent embo-
decline in neurologic function. lization. Patients with atrial brillation have an average
Emboli from the heart most often lodge in the annual risk of stroke of 5%. The risk of stroke can be
MCA, the posterior cerebral artery (PCA), or one of estimated by calculating the CHADS2 score (see Table
their branches; infrequently, the anterior cerebral artery 27-3). Left atrial enlargement is an additional risk factor
(ACA) territory is involved. Emboli large enough to for formation of atrial thrombi. Rheumatic heart dis-
occlude the stem of the MCA (34 mm) lead to large ease usually causes ischemic stroke when there is promi-
infarcts that involve both deep gray and white matter nent mitral stenosis or atrial brillation. Recent MI may
and some portions of the cortical surface and its under- be a source of emboli, especially when transmural and
lying white matter. A smaller embolus may occlude involving the anteroapical ventricular wall, and prophy-
a small cortical or penetrating arterial branch. The lactic anticoagulation following MI has been shown to
TABLE 27-2 foramen ovale or atrial septal defect. Bubble-contrast echo- 263
CAUSES OF ISCHEMIC STROKE cardiography (IV injection of agitated saline coupled with
either transthoracic or transesophageal echocardiography)
COMMON CAUSES UNCOMMON CAUSES
can demonstrate a right-to-left cardiac shunt, revealing
Thrombosis Hypercoagulable disorders the conduit for paradoxical embolization. Alternatively,
Lacunar stroke (small Protein C deciency a right-to-left shunt is implied if immediately following
vessel) Protein S deciency IV injection of agitated saline, the ultrasound signature of
Large vessel thrombosis Antithrombin III deciency
bubbles is observed during transcranial Doppler insonation
Dehydration Antiphospholipid syndrome
Factor V Leiden mutationa
of the MCA; pulmonary AVMs should be considered if
Embolic occlusion
Prothrombin G20210 this test is positive yet an echocardiogram fails to reveal
Artery-to-artery
Carotid bifurcation mutationa an intracardiac shunt. Both techniques are highly sensitive
Aortic arch Systemic malignancy for detection of right-to-left shunts. Besides venous clot,
Arterial dissection Sickle cell anemia fat and tumor emboli, bacterial endocarditis, IV air, and
Cardioembolic -Thalassemia amniotic uid emboli at childbirth may occasionally be
Atrial brillation Polycythemia vera responsible for paradoxical embolization. The importance
Mural thrombus Systemic lupus erythema-
tosus
of right-to-left shunt as a cause of stroke is debated, partic-
Myocardial infarction ularly because such shunts are present in 15% of the gen-
CHAPTER 27
Dilated cardiomyopathy Homocysteinemia
Valvular lesions Thrombotic thrombocyto- eral population. Some studies have suggested that the risk
Mitral stenosis penic purpura is only elevated in the presence of a coexisting atrial septal
Mechanical valve Disseminated intravascu- aneurysm. The presence of a venous source of embolus,
Bacterial endocarditis lar coagulation most commonly a deep venous thrombus, may provide
Paradoxical embolus Dysproteinemias conrmation of the importance of a right-to-left shunt in
Atrial septal defect Nephrotic syndrome
a particular case.
Inammatory bowel dis-
Cerebrovascular Diseases
Patent foramen ovale Bacterial endocarditis can cause valvular vegetations
Atrial septal aneurysm ease
Oral contraceptives that can give rise to septic emboli. The appearance of
Spontaneous echo
contrast Venous sinus thrombosisb multifocal symptoms and signs in a patient with stroke
Fibromuscular dysplasia makes bacterial endocarditis more likely. Infarcts of
Vasculitis microscopic size occur, and large septic infarcts may
Systemic vasculitis (PAN, evolve into brain abscesses or cause hemorrhage into
granulomatosis with the infarct, which generally precludes use of antico-
polyangiitis [Wegeners],
Takayasus, giant cell
agulation or thrombolytics. Mycotic aneurysms caused
arteritis) by septic emboli give rise to SAH or intracerebral
Primary CNS vasculitis hemorrhage.
Meningitis (syphilis, tuber-
culosis, fungal, bacte-
rial, zoster)
Cardiogenic Artery-to-artery embolic stroke
Mitral valve calcication
Thrombus formation on atherosclerotic plaques may
Atrial myxoma
Intracardiac tumor
embolize to intracranial arteries producing an artery-to-
Marantic endocarditis artery embolic stroke. Less commonly, a diseased vessel
Libman-Sacks endocarditis may acutely thrombose. Unlike the myocardial vessels,
Subarachnoid hemorrhage artery-to-artery embolism, rather than local thrombosis,
vasospasm appears to be the dominant vascular mechanism causing
Drugs: cocaine, amphet- brain ischemia. Any diseased vessel may be an embolic
amine source, including the aortic arch, common carotid,
Moyamoya disease
Eclampsia
internal carotid, vertebral, and basilar arteries. Carotid
bifurcation atherosclerosis is the most common source
a
Chiey cause venous sinus thrombosis.
of artery-to-artery embolus, and specic treatments
b
May be associated with any hypercoagulable disorder. have proven efcacy in reducing risk.
Abbreviations: CNS, central nervous system; PAN, polyarteritis
nodosa.
Carotid atherosclerosis
reduce stroke risk. Mitral valve prolapse is not usually a Atherosclerosis within the carotid artery occurs most
source of emboli unless the prolapse is severe. frequently within the common carotid bifurcation
Paradoxical embolization occurs when venous thrombi and proximal internal carotid artery. Additionally, the
migrate to the arterial circulation, usually via a patent carotid siphon (portion within the cavernous sinus) is
264 TABLE 27-3
RECOMMENDATIONS ON CHRONIC USE OF ANTITHROMBOTICS FOR VARIOUS CARDIAC CONDITIONS
CONDITION RECOMMENDATION
a
CHADS2 score calculated as follows: 1 point for age >75 years, 1 point for hypertension, 1 point for congestive heart failure, 1 point for diabe-
tes, and 2 points for stroke or TIA; sum of points is the total CHADS2 score.
Abbreviations: Dose of aspirin is 50325 mg/d; target INR for VKA is 2.5 unless otherwise specied. INR, international normalized ratio; LMWH,
low-molecular-weight heparin; TIA, transient ischemic attack; VKA, vitamin K antagonist.
Sources: Modied from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest 133:593S, 2008.
also vulnerable to atherosclerosis. Male gender, older form, requiring urgent treatment to prevent rerupture. 265
age, smoking, hypertension, diabetes, and hypercholes- Treating asymptomatic pseudoaneurysms following dis-
terolemia are risk factors for carotid disease, as they are section is controversial. The cause of dissection is usu-
for stroke in general (Table 27-4). Carotid atheroscle- ally unknown and recurrence is rare. Ehlers-Danlos
rosis produces an estimated 10% of ischemic stroke. type IV, Marfans disease, cystic medial necrosis, and
Carotid disease can be classied by whether the ste- bromuscular dysplasia are associated with dissections.
nosis is symptomatic or asymptomatic and by the degree Trauma (usually a motor vehicle accident or a sports
of stenosis (percent narrowing of the narrowest segment injury) can cause carotid and vertebral artery dissections.
compared to a more distal internal carotid segment). Spinal manipulative therapy is independently associated
Symptomatic carotid disease implies that the patient has with vertebral artery dissection and stroke. Most dissec-
experienced a stroke or TIA within the vascular distri- tions heal spontaneously, and stroke or TIA is uncom-
bution of the artery, and it is associated with a greater mon beyond 2 weeks. Although there are no trials
risk of subsequent stroke than asymptomatic stenosis, comparing anticoagulation to antiplatelet agents, many
in which the patient is symptom free and the stenosis is physicians treat acutely with anticoagulants then convert
detected through screening. Greater degrees of arterial to antiplatelet therapy after demonstration of satisfactory
narrowing are generally associated with a greater risk vascular recanalization.
of stroke, except that those with near occlusions are at
CHAPTER 27
lower risk of stroke.
SMALL-VESSEL STROKE
Other causes of artery-to-artery embolic stroke
Intracranial atherosclerosis produces stroke either by an The term lacunar infarction refers to infarction follow-
embolic mechanism or by in situ thrombosis of a dis- ing atherothrombotic or lipohyalinotic occlusion of a
eased vessel. It is more common in patients of Asian small artery (30300 m) in the brain. The term small-
and African-American descent. Recurrent stroke risk vessel stroke denotes occlusion of such a small penetrat-
Cerebrovascular Diseases
is 15% per year, similar to symptomatic untreated ing artery and is now the preferred term. Small-vessel
carotid atherosclerosis. strokes account for 20% of all strokes.
Dissection of the internal carotid or vertebral arter- Pathophysiology
ies or even vessels beyond the circle of Willis is a com- The MCA stem, the arteries comprising the circle of
mon source of embolic stroke in young (age <60 years) Willis (A1 segment, anterior and posterior communicat-
patients. The dissection is usually painful and precedes ing arteries, and P1 segment), and the basilar and ver-
the stroke by several hours or days. Extracranial dissec- tebral arteries all give rise to 30- to 300-m branches
tions do not cause hemorrhage because of the tough that penetrate the deep gray and white matter of the
adventitia of these vessels. Intracranial dissections, con- cerebrum or brainstem (Fig. 27-4). Each of these
versely, may produce SAH because the adventitia of small branches can occlude either by atherothrom-
intracranial vessels is thin and pseudoaneurysms may botic disease at its origin or by the development of
TABLE 27-4
RISK FACTORS FOR STROKE
NUMBER NEEDED TO TREATa
a
Number needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here.
Abbreviation: N/A, not applicable.
266 Deep branches of the
Anterior cerebral a. middle cerebral a.
Anterior cerebral a.
Internal
carotid a.
Middle cerebral a.
Internal carotid a. Middle cerebral a.
SECTION III
Diseases of the Nervous System
Basilar a.
Vertebral a.
Basilar a.
Deep branches
Vertebral a. of the basilar a.
FIGURE 27-4
Diagrams and reformatted CT angiograms in the coronal posterior circulation, similar arteries arise directly from the
section illustrating the deep penetrating arteries involved in vertebral and basilar arteries to supply the brainstem (lower
small-vessel strokes. In the anterior circulation, small pen- panels). Occlusion of a single penetrating artery gives rise to
etrating arteries called lenticulostriates arise from the proxi- a discrete area of infarct (pathologically termed a lacune, or
mal portion of the anterior and middle cerebral arteries and lake). Note that these vessels are too small to be visualized
supply deep subcortical structures (upper panels). In the on CT angiography.
lipohyalinotic thickening. Thrombosis of these vessels Transient symptoms (small-vessel TIAs) may herald
causes small infarcts that are referred to as lacunes (Latin a small-vessel infarct; they may occur several times a
for lake of uid noted at autopsy). These infarcts day and last only a few minutes. Recovery from small-
range in size from 3 mm to 2 cm in diameter. Hyper- vessel strokes tends to be more rapid and complete than
tension and age are the principal risk factors. recovery from large-vessel strokes; in some cases, how-
ever, there is severe permanent disability. Often, insti-
Clinical manifestations tution of combined antithrombotic treatments does not
The most common lacunar syndromes are the following: (1) prevent eventual stroke in stuttering lacunes.
pure motor hemiparesis from an infarct in the posterior limb A large-vessel source (either thrombosis or embo-
of the internal capsule or basis pontis; the face, arm, and lism) may manifest initially as a lacunar syndrome
leg are almost always involved; (2) pure sensory stroke from with small-vessel infarction. Therefore, the search for
an infarct in the ventral thalamus; (3) ataxic hemiparesis from embolic sources (carotid and heart) should not be com-
an infarct in the ventral pons or internal capsule; and (4) pletely abandoned in the evaluation of these patients.
dysarthria and a clumsy hand or arm due to infarction in the Secondary prevention of lacunar stroke involves risk
ventral pons or in the genu of the internal capsule. factor modication, specically reduction in blood
pressure (see Primary and Secondary Prevention of and if exchange transfusion is ceased, their stroke rate 267
Stroke and TIA). increases again along with MCA velocities.
Fibromuscular dysplasia affects the cervical arteries
and occurs mainly in women. The carotid or vertebral
LESS COMMON CAUSES OF STROKE arteries show multiple rings of segmental narrowing
(Table 27-2) Hypercoagulable disorders primarily cause alternating with dilatation. Occlusion is usually incom-
increased risk of venous thrombosis and therefore may plete. The process is often asymptomatic but occasion-
cause venous sinus thrombosis. Protein S deciency and ally is associated with an audible bruit, TIAs, or stroke.
homocysteinemia may cause arterial thromboses as well. Involvement of the renal arteries is common and may
Systemic lupus erythematosus with Libman-Sacks endo- cause hypertension. The cause and natural history of
carditis can be a cause of embolic stroke. These con- bromuscular dysplasia are unknown. TIA or stroke
ditions overlap with the antiphospholipid syndrome, generally occurs only when the artery is severely nar-
which probably requires long-term anticoagulation to rowed or dissects. Anticoagulation or antiplatelet ther-
prevent further stroke. apy may be helpful.
Venous sinus thrombosis of the lateral or sagittal sinus Temporal (giant cell) arteritis is a relatively com-
or of small cortical veins (cortical vein thrombosis) mon afiction of elderly persons in which the exter-
occurs as a complication of oral contraceptive use, nal carotid system, particularly the temporal arteries,
CHAPTER 27
pregnancy and the postpartum period, inammatory undergo subacute granulomatous inammation with
bowel disease, intracranial infections (meningitis), and giant cells. Occlusion of posterior ciliary arteries derived
dehydration. It is also seen with increased incidence from the ophthalmic artery results in blindness in one or
in patients with laboratory-conrmed thrombophilia both eyes and can be prevented with glucocorticoids. It
(Table 27-2) including polycythemia, sickle cell ane- rarely causes stroke as the internal carotid artery is usu-
mia, deciencies of proteins C and S, factor V Leiden ally not inamed. Idiopathic giant cell arteritis involving
Cerebrovascular Diseases
mutation (resistance to activated protein C), anti- the great vessels arising from the aortic arch (Takayasus
thrombin III deciency, homocysteinemia, and the arteritis) may cause carotid or vertebral thrombosis; it is
prothrombin G20210 mutation. Women who take rare in the Western hemisphere.
oral contraceptives and have the prothrombin G20210 Necrotizing (or granulomatous) arteritis, occurring alone
mutation may be at particularly high risk for sinus or in association with generalized polyarteritis nodosa or
thrombosis. Patients present with headache and may granulomatosis with polyangiitis (Wegeners), involves
also have focal neurologic signs (especially parapare- the distal small branches (<2 mm diameter) of the main
sis) and seizures. Often, CT imaging is normal unless intracranial arteries and produces small ischemic infarcts
an intracranial venous hemorrhage has occurred, but in the brain, optic nerve, and spinal cord. The cerebro-
the venous sinus occlusion is readily visualized using spinal uid (CSF) often shows pleocytosis, and the pro-
MR- or CT-venography or conventional x-ray angi- tein level is elevated. Primary central nervous system vas-
ography. With greater degrees of sinus thrombosis, culitis is rare; small or medium-sized vessels are usually
the patient may develop signs of increased ICP and affected, without apparent systemic vasculitis. The dif-
coma. Intravenous heparin, regardless of the presence ferential diagnosis includes other inammatory causes of
of intracranial hemorrhage, has been shown to reduce vascular caliber change including infection (tubercular,
morbidity and mortality, and the long-term outcome fungal), sarcoidosis, angiocentric lymphoma, carcinoma-
is generally good. Heparin prevents further thrombosis tous meningitis, as well as noninammatory causes such
and reduces venous hypertension and ischemia. If an as atherosclerosis, emboli, connective tissue disease,
underlying hypercoagulable state is not found, many vasospasm, migraine-associated vasculopathy, and drug-
physicians treat with vitamin K antagonists (VKAs) associated causes. Some cases follow the postpartum
for 36 months then convert to aspirin, depending on period and are self-limited.
the degree of resolution of the venous sinus throm- Patients with any form of vasculopathy may present
bus. Anticoagulation is often continued indenitely if with insidious progression of combined white and gray
thrombophilia is diagnosed. matter infarctions, prominent headache, and cognitive
Sickle cell anemia (SS disease) is a common cause of decline. Brain biopsy or high-resolution conventional
stroke in children. A subset of homozygous carriers of x-ray angiography is usually required to make the diag-
this hemoglobin mutation develop stroke in child- nosis (Fig. 27-5). An inammatory prole found on
hood, and this may be predicted by documenting high- lumbar puncture favors an inammatory cause. In cases
velocity blood ow within the MCAs using transcranial where inammation is conrmed, aggressive immu-
Doppler ultrasonography. In children who are identi- nosuppression with glucocorticoids, and often cyclo-
ed to have high velocities, treatment with aggressive phosphamide, is usually necessary to prevent progres-
exchange transfusion dramatically reduces risk of stroke, sion; a diligent investigation for infectious causes such
268 Patients complain of headache and manifest uctuat-
ing neurologic symptoms and signs, especially visual
symptoms. Sometimes cerebral infarction ensues, but
typically the clinical and imaging ndings suggest that
ischemia reverses completely. MRI ndings are charac-
teristic, and conventional x-ray angiography may also be
helpful in establishing the diagnosis.
Leukoaraiosis, or periventricular white matter disease, is
the result of multiple small-vessel infarcts within the
subcortical white matter. It is readily seen on CT or
MRI scans as areas of white matter injury surrounding
the ventricles and within the corona radiata. Areas of
lacunar infarction are often seen also. The pathophysi-
ologic basis of the disease is lipohyalinosis of small pene-
trating arteries within the white matter, likely produced
FIGURE 27-5 by chronic hypertension. Patients with periventricular
Cerebral angiogram from a 32-year-old male with central white matter disease may develop a subcortical demen-
SECTION III
nervous system vasculopathy. Dramatic beading (arrows) tia syndrome, depending on the amount of white mat-
typical of vasculopathy is seen. ter infarction, and it is likely that this common form of
dementia may be delayed or prevented with antihyper-
as tuberculosis is essential prior to immunosuppression. tensive medications (Chap. 29).
With prompt recognition and treatment, many patients CADASIL (cerebral autosomal dominant arteriopa-
can make an excellent recovery. thy with subcortical infarcts and leukoencephalopa-
Drugs, in particular amphetamines and perhaps
Diseases of the Nervous System
CHAPTER 27
minimal risk; others are expensive and carry substantial
is a contraindication to thrombolysis. However, since
risk but may be valuable for selected high-risk patients.
Identification and control of modifiable risk factors is
TABLE 27-5 the best strategy to reduce the burden of stroke, and
RISK OF STROKE FOLLOWING TIA: THE ABCD2
the total number of strokes could be reduced substan-
SCORE tially by these means (Table 27-4).
Cerebrovascular Diseases
CLINICAL FACTOR SCORE ATHEROSCLEROSIS RISK FACTORS Older
A: Age v60 years 1 age, family history of thrombotic stroke, diabetes mel-
litus, hypertension, tobacco smoking, abnormal blood
B: SBP >140 mmHg or DBP 1
>90 mmHg cholesterol (particularly, low high-density lipoprotein
[HDL] and/or high low-density lipoprotein [LDL]), and
C: Clinical symptoms
other factors are either proven or probable risk factors
Unilateral weakness 2 for ischemic stroke, largely by their link to atherosclerosis.
Speech disturbance with- 1 Risk of stroke is much greater in those with prior stroke
out weakness or TIA. Many cardiac conditions predispose to stroke,
D: Duration including atrial fibrillation and recent MI. Oral contracep-
>60 min 2 tives and hormone replacement therapy increase stroke
risk, and certain inherited and acquired hypercoagulable
1059 min 1
states predispose to stroke. Hypertension is the most
D: Diabetes (oral medica- 1 significant of the risk factors; in general, all hypertension
tions or insulin)
should be treated. The presence of known cerebrovascu-
Total Score Sum Each Category lar disease is not a contraindication to treatment aimed
2
ABCD Score Total 3-Month Rate of Stroke (%)a at achieving normotension. Also, the value of treating
0 0 systolic hypertension in older patients has been clearly
1 2
established. Lowering blood pressure to levels below
those traditionally defining hypertension appears to
2 3
reduce the risk of stroke even further. Data are particu-
3 3 larly strong in support of thiazide diuretics and angioten-
4 8 sin-converting enzyme inhibitors.
5 12 Several trials have confirmed that statin drugs reduce
the risk of stroke even in patients without elevated
6 17
LDL or low HDL. The Stroke Prevention by Aggressive
7 22
Reduction in Cholesterol Levels (SPARCL) trial showed
a
benefit in secondary stroke reduction for patients with
Data ranges are from 5 cohorts.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood
recent stroke or TIA, who were prescribed atorvastatin,
pressure. 80 mg/d. The primary prevention trial, Justification for
Source: SC Johnston et al: Validation and renement of score to the Use of Statins in Prevention: An Intervention Trial
predict very early stroke risk after transient ischaemic attack. Lancet Evaluating Rosuvastatin (JUPITER), found that patients
369: 283, 2007.
270 with low LDL (<130 mg/dL) caused by elevated C-reac- trial, which led to FDA approval, found that it was only
tive protein benefitted by daily use of this statin. Pri- marginally more effective than aspirin in reducing risk
mary stroke occurrence was reduced by 51% (hazard of stroke. The Management of Atherothrombosis with
ratio 0.49, p = 0.004) and there was no increase in the Clopidogrel in High-Risk Patients (MATCH) trial was a
rates of intracranial hemorrhage. Therefore, a statin large multicenter, randomized double-blind study that
should be considered in all patients with prior ischemic compared clopidogrel in combination with aspirin to
stroke. Tobacco smoking should be discouraged in all clopidogrel alone in the secondary prevention of TIA
patients. Tight control of blood sugar in patients with or stroke. The MATCH trial found no difference in TIA or
type 2 diabetes lowers stroke risk MI and death of any stroke prevention with this combination, but did show
cause, but no trial sufficiently powered to detect a sig- a small but significant increase in major bleeding com-
nificant reduction in stroke has yet been performed. plications (3% versus 1%). In the Clopidogrel for High
Statins, more aggressive blood pressure control, and Atherothrombotic Risk and Ischemic Stabilization,
pioglitazone (an agonist of peroxisome proliferator-acti- Management, and Avoidance (CHARISMA) trial, which
vated receptor gamma) are effective. included a subgroup of patients with prior stroke or TIA
along with other groups at high risk of cardiovascular
ANTIPLATELET AGENTS Platelet antiaggre- events, there was no benefit of clopidogrel combined
gation agents can prevent atherothrombotic events, with aspirin compared to aspirin alone. Thus, the use of
SECTION III
including TIA and stroke, by inhibiting the formation of clopidogrel in combination with aspirin is not recom-
intraarterial platelet aggregates. These can form on dis- mended for stroke prevention. However, these trials did
eased arteries, induce thrombus formation, and occlude not enroll patients immediately after the stroke or TIA,
the artery or embolize into the distal circulation. Aspi- and the benefits of combination therapy were greater
rin, clopidogrel, and the combination of aspirin plus among those treated earlier, so it is possible that clopi-
extended-release dipyridamole are the antiplatelet dogrel combined with aspirin may be beneficial in this
Diseases of the Nervous System
agents most commonly used for this purpose. Ticlopi- acute period. Ongoing studies are currently addressing
dine has been largely abandoned because of its adverse this question.
effects but may be used as an alternative to clopidogrel. Dipyridamole is an antiplatelet agent that inhibits
Aspirin is the most widely studied antiplatelet the uptake of adenosine by a variety of cells, includ-
agent. Aspirin acetylates platelet cyclooxygenase, ing those of the vascular endothelium. The accumu-
which irreversibly inhibits the formation in platelets of lated adenosine is an inhibitor of aggregation. At least
thromboxane A2, a platelet aggregating and vasocon- in part through its effects on platelet and vessel wall
stricting prostaglandin. This effect is permanent and phosphodiesterases, dipyridamole also potentiates the
lasts for the usual 8-day life of the platelet. Paradoxi- antiaggregatory effects of prostacyclin and nitric oxide
cally, aspirin also inhibits the formation in endothelial produced by the endothelium and acts by inhibiting
cells of prostacyclin, an antiaggregating and vasodi- platelet phosphodiesterase, which is responsible for
lating prostaglandin. This effect is transient. As soon the breakdown of cyclic AMP. The resulting elevation
as aspirin is cleared from the blood, the nucleated in cyclic AMP inhibits aggregation of platelets. Dipyri-
endothelial cells again produce prostacyclin. Aspirin damole is erratically absorbed depending on stomach
in low doses given once daily inhibits the production pH, but a newer formulation combines timed-release
of thromboxane A2 in platelets without substantially dipyridamole, 200 mg, with aspirin, 25 mg, and has
inhibiting prostacyclin formation. Higher doses of aspi- better oral bioavailability. This combination drug was
rin have not been proven to be more effective than studied in three trials. The European Stroke Prevention
lower doses, and 50325 mg/d of aspirin is generally Study (ESPS) II showed efficacy of both 50 mg/d of aspi-
recommended for stroke prevention. rin and extended-release dipyridamole in preventing
Ticlopidine and clopidogrel block the adenosine stroke, and a significantly better risk reduction when
diphosphate (ADP) receptor on platelets and thus pre- the two agents were combined. The ESPRIT (European/
vent the cascade resulting in activation of the glyco- Australasian Stroke Prevention in Reversible Ischaemia
protein IIb/IIIa receptor that leads to fibrinogen binding Trial) trial confirmed the ESPS-II results. This was an
to the platelet and consequent platelet aggregation. open-label, academic trial in which 2739 patients with
Ticlopidine is more effective than aspirin; however, it stroke or TIA treated with aspirin were randomized to
has the disadvantage of causing diarrhea, skin rash, and, dipyridamole, 200 mg twice daily, or no dipyridamole.
in rare instances, neutropenia and thrombotic thrombo- Primary outcome was the composite of death from all
cytopenic purpura (TTP). Clopidogrel rarely causes TTP vascular causes, nonfatal stroke, nonfatal MI, or major
but does not cause neutropenia. The Clopidogrel versus bleeding complication. After 3.5 years of follow-up, 13%
Aspirin in Patients at Risk of Ischemic Events (CAPRIE) of patients on aspirin and dipyridamole and 16% on
aspirin alone (hazard ratio 0.80, 95% confidence index Most physicians in North America recommend 81325 271
[CI] 0.660.98) met the primary outcome. In the Preven- mg/d, while most Europeans recommend 50100 mg.
tion Regimen for Effectively Avoiding Second Strokes Clopidogrel or extended-release dipyridamole plus aspi-
(PRoFESS) trial, the combination of extended-release rin are being increasingly recommended as first-line
dipyridamole and aspirin was compared directly with drugs for secondary prevention. Similarly, the choice of
clopidogrel with and without the angiotensin receptor aspirin, clopidogrel, or dipyridamole plus aspirin must
blocker telmisartan in a study of 20,332 patients. There balance the fact that the latter are more effective than
were no differences in the rates of second stroke (9% aspirin but the cost is higher, and this is likely to affect
each) or degree of disability in patients with median long-term patient adherence. The use of platelet aggre-
follow-up of 2.4 years. Telmisartan also had no effect gation studies in individual patients taking aspirin is
on these outcomes. This suggests that these antiplate- controversial because of limited data.
let regimens are similar, and also raises questions about ANTICOAGULATION THERAPY AND EMBO-
default prescription of agents to block the angiotensin LIC STROKE Several trials have shown that anti-
pathway in all stroke patients. The principal side effect coagulation (INR range, 23) in patients with chronic
of dipyridamole is headache. The combination cap- nonvalvular (nonrheumatic) atrial fibrillation prevents
sule of extended-release dipyridamole and aspirin is cerebral embolism and is safe. For primary prevention
CHAPTER 27
approved for prevention of stroke. and for patients who have experienced stroke or TIA,
Many large clinical trials have demonstrated clearly anticoagulation with a VKA reduces the risk by about
that most antiplatelet agents reduce the risk of all 67%, which clearly outweighs the 13% risk per year of
important vascular atherothrombotic events (i.e., isch- a major bleeding complication. A recent randomized
emic stroke, MI, and death due to all vascular causes) trial compared the new oral thrombin inhibitor dabi-
in patients at risk for these events. The overall relative gatran to VKAs in a noninferiority trial to prevent stroke
reduction in risk of nonfatal stroke is about 2530% and
Cerebrovascular Diseases
or systemic embolization in nonvalvular atrial fibrilla-
of all vascular events is about 25%. The absolute reduc- tion. Two doses of dabigatran were used: 110 mg/d and
tion varies considerably, depending on the particular 150 mg/d. Both dose tiers of dabigatran were noninfe-
patients risk. Individuals at very low risk for stroke seem rior to VKAs in preventing second stroke and systemic
to experience the same relative reduction, but their risks embolization, and the higher dose tier was superior
may be so low that the benefit is meaningless. Con- (relative risk 0.66; 95% CI, 0.53 to 0.82; P < 0.001) and the
versely, individuals with a 1015% risk of vascular events rate of major bleeding was lower in the lower dose tier
per year experience a reduction to about 7.511%. of dabigatran compared to VKAs. This drug is likely more
Aspirin is inexpensive, can be given in low doses, convenient to take as no blood monitoring is required
and could be recommended for all adults to prevent to titrate the dose and its effect is independent of oral
both stroke and MI. However, it causes epigastric dis- intake of vitamin K. For patients who cannot take anti-
comfort, gastric ulceration, and gastrointestinal hem- coagulant medications, clopidogrel plus aspirin was
orrhage, which may be asymptomatic or life threaten- compared to aspirin alone in the Atrial Fibrillation Clopi-
ing. Consequently, not every 40- or 50-year-old should dogrel Trial with Irbesartan for Prevention of Vascular
be advised to take aspirin regularly because the risk of Events (ACTIVE-A). Clopidogrel combined with aspirin
atherothrombotic stroke is extremely low and is out- was more effective than aspirin alone in preventing vas-
weighed by the risk of adverse side effects. Conversely, cular events, principally stroke, but increases the risk of
every patient who has experienced an atherothrom- major bleeding (relative risk 1.57, P < 0.001).
botic stroke or TIA and has no contraindication should The decision to use anticoagulation for primary pre-
be taking an antiplatelet agent regularly because the vention is based primarily on risk factors (Table 27-3).
average annual risk of another stroke is 810%; another The history of a TIA or stroke tips the balance in favor
few percent will experience an MI or vascular death. of anticoagulation regardless of other risk factors. Since
Clearly, the likelihood of benefit far outweighs the risks this risk factor is so important, many clinicians are per-
of treatment. forming extended ambulatory monitoring to detect
The choice of antiplatelet agent and dose must bal- intermittent atrial fibrillation in otherwise cryptogenic
ance the risk of stroke, the expected benefit, and the risk stroke since its detection would shift toward prescrip-
and cost of treatment. However, there are no definitive tion of oral anticoagulation long term.
data, and opinions vary. Many authorities believe low- Because of the high annual stroke risk in untreated
dose (3075 mg/d) and high-dose (6501300 mg/d) rheumatic heart disease with atrial fibrillation, primary
aspirin are about equally effective. Some advocate very prophylaxis against stroke has not been studied in a
low doses to avoid adverse effects, and still others advo- double-blind fashion. These patients generally should
cate very high doses to be sure the benefit is maximal. receive long-term anticoagulation.
272 Anticoagulation also reduces the risk of embolism in A patients risk of stroke and possible benefit from
acute MI. Most clinicians recommend a 3-month course surgery are related to the presence of retinal ver-
of anticoagulation when there is anterior Q-wave infarc- sus hemispheric symptoms, degree of arterial steno-
tion, substantial left ventricular dysfunction, congestive sis, extent of associated medical conditions (of note,
heart failure, mural thrombosis, or atrial fibrillation. VKAs NASCET and ECST excluded high-risk patients with
are recommended long-term if atrial fibrillation persists. significant cardiac, pulmonary, or renal disease), insti-
Stroke secondary to thromboembolism is one of the tutional surgical morbidity and mortality, timing of sur-
most serious complications of prosthetic heart valve gery relative to symptoms, and other factors. A recent
implantation. The intensity of anticoagulation and/or meta-analysis of the NASCET and ECST trials demon-
antiplatelet therapy is dictated by the type of prosthetic strated that endarterectomy is most beneficial when
valve and its location. performed within 2 weeks of symptom onset. In addi-
If the embolic source cannot be eliminated, anticoag- tion, benefit is more pronounced in patients >75 years,
ulation should in most cases be continued indefinitely. and men appear to benefit more than women.
Many neurologists recommend combining antiplatelet In summary, a patient with recent symptomatic
agents with anticoagulants for patients who fail anti- hemispheric ischemia, high-grade stenosis in the appro-
coagulation (i.e., have another stroke or TIA). priate internal carotid artery, and an institutional peri-
operative morbidity and mortality rate of 6% generally
SECTION III
CHAPTER 27
other than stroke. The trial was terminated early because
(SAPPHIRE) trial randomized high-risk patients (defined as
of an increased risk of adverse events related to warfarin
patients with clinically significant coronary or pulmonary
anticoagulation. With a mean follow-up of 1.8 years, the
disease, contralateral carotid occlusion, restenosis after
primary endpoint was seen in 22.1% in the aspirin group
endarterectomy, contralateral laryngeal-nerve palsy, prior
and 21.8% of the warfarin group. Death from any cause
radical neck surgery or radiation, or age >80) with symp-
was seen in 4.3% of the aspirin group and 9.7% of the
tomatic carotid stenosis >50% or asymptomatic stenosis
warfarin group; 3.2% of patients on aspirin experienced
Cerebrovascular Diseases
>80% to either stenting combined with a distal emboli-
major hemorrhage, compared to 8.3% of patients taking
protection device or endarterectomy. The risk of death,
warfarin.
stroke, or MI within 30 days and ipsilateral stroke or death
Given the worrisome natural history of symptomatic
within 1 year was 12.2% in the stenting group and 20.1%
intracranial atherosclerosis (in the aspirin arm of the
in the endarterectomy group (p = .055), suggesting that
WASID trial, 15% of patients experienced a stroke within
stenting is at the very least comparable to endarterectomy
the first year, despite current standard aggressive medi-
as a treatment option for this patient group at high risk of
cal therapy), some centers treat symptomatic lesions
surgery. However, the outcomes with both interventions
with intracranial angioplasty and stenting. This inter-
may not have been better than leaving the carotid stenoses
vention is currently being compared to aspirin therapy
untreated, particularly for the asymptomatic patients, and
in a prospective, randomized trial. It is unclear whether
much of the benefit seen in the stenting group was due to
EC-IC bypass, or other grafting procedures of extracra-
a reduction in periprocedure MI. In 2010, the results of two
nial blood supply to the pial arteries, are of value in such
randomized trials comparing stents to endarterectomy in
patients.
low-risk patients were published. The Carotid Revasculariza-
tion Endarterectomy versus Stenting Trial (CREST) enrolled Dural Sinus Thrombosis Limited evidence exists
2502 patients with either asymptomatic or symptomatic to support short-term usage of anticoagulants, regard-
stenosis. The 30-day risk of stroke was 4.1% in the stent less of the presence of intracranial hemorrhage, for venous
group and 2.3% in the surgical group, but the 30-day risk infarction following sinus thrombosis.
of MI was 1.1% in the stent group and 2.3% in the surgery
group, suggesting relative equivalence of risk between the
procedures. At median follow-up of 2.5 years, the combined
endpoint of stroke, MI, and death was the same (7.2% stent
versus 6.8% surgery). The International Carotid Stenting
(ICSS) trial randomized 1713 symptomatic patients to stents
STROKE SYNDROMES
versus endarterectomy and found a different result: At 120
days, the incidence of stroke, MI, or death was 8.5% in the A careful history and neurologic examination can often
stenting group versus 5.2% in the endarterectomy group localize the region of brain dysfunction; if this region
(p = 0.006), and longer term follow-up is currently under corresponds to a particular arterial distribution, the pos-
way. Differences between trial designs, selection of stent, sible causes responsible for the syndrome can be nar-
and operator experience may explain these important dif- rowed. This is of particular importance when the
ferences. Until more data are available on both trials, there patient presents with a TIA and a normal examination.
remains controversy as to who should receive a stent or For example, if a patient develops language loss and a
right homonymous hemianopia, a search for causes
274 of left middle cerebral emboli should be performed.
A nding of an isolated stenosis of the right internal
carotid artery in that patient, for example, suggests an
asymptomatic carotid stenosis, and the search for other
causes of stroke should continue. The following sections
Internal
describe the clinical ndings of cerebral ischemia associ- capsule
ated with cerebral vascular territories depicted in Figs.
27-4, and 27-6 through 27-14. Stroke syndromes are
divided into: (1) large-vessel stroke within the anterior Claustrum
Caudate
circulation, (2) large-vessel stroke within the posterior
circulation, and (3) small-vessel disease of either vascular
bed. Anterior Putamen
cerebral a.
Anterior cerebral a.
be occluded by intrinsic disease of the vessel (e.g., ath-
erosclerosis or dissection) or by embolic occlusion Middle cerebral a.
from a proximal source as discussed earlier. Occlusion Deep branches of middle cerebral a.
of each major intracranial vessel has distinct clinical Postcerebral a.
manifestations.
Deep branches of ant. cerebral a.
Diseases of the Nervous System
Post. parietal a.
Prerolandic a.
Angular a.
Lateral
orbitofrontal a.
Sup. division
middle cerebral a.
Post. temporal a.
Temporopolar a.
Visual radiation
Inf. division
middle cerebral a.
CHAPTER 27
Ant. temporal a.
KEY
Cerebrovascular Diseases
FIGURE 27-7
Diagram of a cerebral hemisphere, lateral aspect, show- Central, suprasylvian speech area and parietooccipital cortex
ing the branches and distribution of the middle cerebral of the dominant hemisphere
artery and the principal regions of cerebral localization. Note Conduction aphasia: Central speech area (parietal operculum)
the bifurcation of the middle cerebral artery into a superior Apractagnosia of the nondominant hemisphere, anosog-
and inferior division. nosia, hemiasomatognosia, unilateral neglect, agnosia for
Signs and symptoms: Structures involved the left half of external space, dressing apraxia, con-
Paralysis of the contralateral face, arm, and leg; sensory structional apraxia, distortion of visual coordinates, inac-
impairment over the same area (pinprick, cotton touch, vibra- curate localization in the half eld, impaired ability to judge
tion, position, two-point discrimination, stereognosis, tactile distance, upside-down reading, visual illusions (e.g., it may
localization, barognosis, cutaneographia): Somatic motor appear that another person walks through a table): Non-
area for face and arm and the bers descending from the leg dominant parietal lobe (area corresponding to speech area in
area to enter the corona radiata and corresponding somatic dominant hemisphere); loss of topographic memory is usually
sensory system due to a nondominant lesion, occasionally to a dominant one
Motor aphasia: Motor speech area of the dominant hemi- Homonymous hemianopia (often homonymous inferior
sphere quadrantanopia): Optic radiation deep to second temporal
Central aphasia, word deafness, anomia, jargon speech, convolution
sensory agraphia, acalculia, alexia, nger agnosia, right-left Paralysis of conjugate gaze to the opposite side: Frontal
confusion (the last four comprise the Gerstmann syndrome): contraversive eye eld or projecting bers
division of the MCA in the nondominant hemisphere is and dysarthria will be prominent (clumsy hand, dysar-
involved. thria lacunar syndrome). Lacunar infarction affecting
Occlusion of a lenticulostriate vessel produces small- the globus pallidus and putamen often has few clinical
vessel (lacunar) stroke within the internal capsule signs, but parkinsonism and hemiballismus have been
(Fig. 27-6). This produces pure motor stroke or sen- reported.
sory-motor stroke contralateral to the lesion. Ischemia
within the genu of the internal capsule causes primar- Anterior cerebral artery
ily facial weakness followed by arm then leg weakness The ACA is divided into two segments: the precom-
as the ischemia moves posterior within the capsule. munal (A1) circle of Willis, or stem, which connects the
Alternatively, the contralateral hand may become ataxic internal carotid artery to the anterior communicating
276 Motor
Medial
rolandic a.
cortex
Post.
Secondary Pericallosal a. Sensory parietal a.
motor area cortex
Medial Splenial a.
prerolandic a.
Lateral posterior
Callosomarginal a. choroidal a.
Post. thalamic a.
Frontopolar a. Parietooccipital a.
Visual
cortex
Ant. cerebral a.
Striate area
along calcarine
sulcus
Medial orbitofrontal a. Calcarine a.
Post. communicating a. Post. temporal a.
SECTION III
FIGURE 27-8
Diagram of a cerebral hemisphere, medial aspect, show- Contralateral grasp reex, sucking reex, gegenhalten
Diseases of the Nervous System
ing the branches and distribution of the anterior cerebral (paratonic rigidity): Medial surface of the posterior frontal
artery and the principal regions of cerebral localization. lobe; likely supplemental motor area
Signs and symptoms: Structures involved Abulia (akinetic mutism), slowness, delay, intermittent
Paralysis of opposite foot and leg: Motor leg area interruption, lack of spontaneity, whispering, reex distrac-
A lesser degree of paresis of opposite arm: Arm area of tion to sights and sounds: Uncertain localizationprobably
cortex or bers descending to corona radiata cingulate gyrus and medial inferior portion of frontal, parietal,
Cortical sensory loss over toes, foot, and leg: Sensory area and temporal lobes
for foot and leg Impairment of gait and stance (gait apraxia): Frontal cortex
Urinary incontinence: Sensorimotor area in paracentral near leg motor area
lobule Dyspraxia of left limbs, tactile aphasia in left limbs: Corpus
callosum
artery, and the postcommunal (A2) segment distal to the white matter posterolateral to it, through which pass
the anterior communicating artery (Figs. 27-4, 27-6, some of the geniculocalcarine bers (Fig. 27-9). The
and 27-8). The A1 segment gives rise to several deep complete syndrome of anterior choroidal artery occlu-
penetrating branches that supply the anterior limb of the sion consists of contralateral hemiplegia, hemianesthesia
internal capsule, the anterior perforate substance, amyg- (hypesthesia), and homonymous hemianopia. However,
dala, anterior hypothalamus, and the inferior part of the because this territory is also supplied by penetrating ves-
head of the caudate nucleus (Fig. 27-6). sels of the proximal MCA and the posterior communi-
Occlusion of the proximal ACA is usually well toler- cating and posterior choroidal arteries, minimal decits
ated because of collateral ow through the anterior com- may occur, and patients frequently recover substantially.
municating artery and collaterals through the MCA and Anterior choroidal strokes are usually the result of in
PCA. Occlusion of a single A2 segment results in the situ thrombosis of the vessel, and the vessel is particu-
contralateral symptoms noted in Fig. 27-8. If both A2 larly vulnerable to iatrogenic occlusion during surgical
segments arise from a single anterior cerebral stem (con- clipping of aneurysms arising from the internal carotid
tralateral A1 segment atresia), the occlusion may affect artery.
both hemispheres. Profound abulia (a delay in verbal and
Internal carotid artery
motor response) and bilateral pyramidal signs with para-
paresis or quadriparesis and urinary incontinence result. The clinical picture of internal carotid occlusion varies
depending on whether the cause of ischemia is propa-
Anterior choroidal artery gated thrombus, embolism, or low ow. The cortex
This artery arises from the internal carotid artery and supplied by the MCA territory is affected most often.
supplies the posterior limb of the internal capsule and With a competent circle of Willis, occlusion may go
Ant. cerebral a. unnoticed. If the thrombus propagates up the internal 277
Internal carotid artery into the MCA or embolizes it, symptoms
carotid a. Post.
communicating a. are identical to proximal MCA occlusion (see earlier).
Sometimes there is massive infarction of the entire deep
Post. cerebral a. white matter and cortical surface. When the origins of
both the ACA and MCA are occluded at the top of the
Ant. carotid artery, abulia or stupor occurs with hemiplegia,
choroidal a. Medial posterior
choroidal a.
hemianesthesia, and aphasia or anosognosia. When the
PCA arises from the internal carotid artery (a congu-
Mesencephalic ration called a fetal posterior cerebral artery), it may also
paramedian As. become occluded and give rise to symptoms referable to
Ant. temporal a.
its peripheral territory (Figs. 27-8 and 27-9).
Splenial a. In addition to supplying the ipsilateral brain, the inter-
nal carotid artery perfuses the optic nerve and retina via
Parietooccipital a. Hippocampal a.
the ophthalmic artery. In 25% of symptomatic internal
Calcarine a. carotid disease, recurrent transient monocular blindness
Post. temporal a.
(amaurosis fugax) warns of the lesion. Patients typically
CHAPTER 27
describe a horizontal shade that sweeps down or up across
Post. thalamic a. the eld of vision. They may also complain that their
Visual vision was blurred in that eye or that the upper or lower
cortex Lateral posterior
choroidal a. half of vision disappeared. In most cases, these symptoms
last only a few minutes. Rarely, ischemia or infarction of
FIGURE 27-9 the ophthalmic artery or central retinal arteries occurs at
Cerebrovascular Diseases
Inferior aspect of the brain with the branches and distribution the time of cerebral TIA or infarction.
of the posterior cerebral artery and the principal anatomic struc-
A high-pitched prolonged carotid bruit fading into
tures shown.
Signs and symptoms: Structures involved diastole is often associated with tightly stenotic lesions.
Peripheral territory (see also Fig. 27-12). Homonymous hemi- As the stenosis grows tighter and ow distal to the ste-
anopia (often upper quadrantic): Calcarine cortex or optic radia- nosis becomes reduced, the bruit becomes fainter and
tion nearby. Bilateral homonymous hemianopia, cortical blindness, may disappear when occlusion is imminent.
awareness or denial of blindness; tactile naming, achromatopia
(color blindness), failure to see to-and-fro movements, inability Common carotid artery
to perceive objects not centrally located, apraxia of ocular move- All symptoms and signs of internal carotid occlusion
ments, inability to count or enumerate objects, tendency to run into
may also be present with occlusion of the common
things that the patient sees and tries to avoid: Bilateral occipital
lobe with possibly the parietal lobe involved. Verbal dyslexia with- carotid artery. Jaw claudication may result from low
out agraphia, color anomia: Dominant calcarine lesion and poste- ow in the external carotid branches. Bilateral common
rior part of corpus callosum. Memory defect: Hippocampal lesion carotid artery occlusions at their origin may occur in
bilaterally or on the dominant side only. Topographic disorientation Takayasus arteritis.
and prosopagnosia: Usually with lesions of nondominant, calcarine,
and lingual gyrus. Simultanagnosia, hemivisual neglect: Dominant
visual cortex, contralateral hemisphere. Unformed visual hallucina-
tions, peduncular hallucinosis, metamorphopsia, teleopsia, illusory Stroke within the posterior circulation
visual spread, palinopsia, distortion of outlines, central photopho-
bia: Calcarine cortex. Complex hallucinations: Usually nondominant The posterior circulation is composed of the paired ver-
hemisphere. tebral arteries, the basilar artery, and the paired poste-
Central territory. Thalamic syndrome: sensory loss (all modali- rior cerebral arteries. The vertebral arteries join to form
ties), spontaneous pain and dysesthesias, choreoathetosis, inten- the basilar artery at the pontomedullary junction. The
tion tremor, spasms of hand, mild hemiparesis: Posteroventral
nucleus of thalamus; involvement of the adjacent subthalamus
basilar artery divides into two posterior cerebral arter-
body or its afferent tracts. Thalamoperforate syndrome: crossed ies in the interpeduncular fossa (Figs. 27-4, 27-8, and
cerebellar ataxia with ipsilateral third nerve palsy (Claudes syn- 27-9). These major arteries give rise to long and short
drome): Dentatothalamic tract and issuing third nerve. Webers circumferential branches and to smaller deep penetrat-
syndrome: third nerve palsy and contralateral hemiplegia: Third ing branches that supply the cerebellum, medulla, pons,
nerve and cerebral peduncle. Contralateral hemiplegia: Cerebral
midbrain, subthalamus, thalamus, hippocampus, and
peduncle. Paralysis or paresis of vertical eye movement, skew
deviation, sluggish pupillary responses to light, slight miosis and medial temporal and occipital lobes. Occlusion of each
ptosis (retraction nystagmus and tucking of the eyelids may be vessel produces its own distinctive syndrome.
associated): Supranuclear bers to third nerve, interstitial nucleus
of Cajal, nucleus of Darkschewitsch, and posterior commissure. Posterior cerebral artery
Contralateral rhythmic, ataxic action tremor; rhythmic postural or In 75% of cases, both PCAs arise from the bifurcation
holding tremor (rubral tremor): Dentatothalamic tract. of the basilar artery; in 20%, one has its origin from
278 the ipsilateral internal carotid artery via the posterior in memory, particularly if it occurs in the dominant
communicating artery; in 5%, both originate from the hemisphere. The defect usually clears because memory
respective ipsilateral internal carotid arteries (Figs. 27-8 has bilateral representation. If the dominant hemisphere
and 27-9). The precommunal, or P1, segment of the is affected and the infarct extends to involve the sple-
true posterior cerebral artery is atretic in such cases. nium of the corpus callosum, the patient may demon-
PCA syndromes usually result from atheroma forma- strate alexia without agraphia. Visual agnosia for faces,
tion or emboli that lodge at the top of the basilar artery; objects, mathematical symbols, and colors and ano-
posterior circulation disease may also be caused by dis- mia with paraphasic errors (amnestic aphasia) may also
section of either vertebral artery and bromuscular occur in this setting, even without callosal involvement.
dysplasia. Occlusion of the posterior cerebral artery can produce
Two clinical syndromes are commonly observed peduncular hallucinosis (visual hallucinations of brightly
with occlusion of the PCA: (1) P1 syndrome: midbrain, colored scenes and objects).
subthalamic, and thalamic signs, which are due to dis- Bilateral infarction in the distal PCAs produces cor-
ease of the proximal P1 segment of the PCA or its pen- tical blindness (blindness with preserved pupillary light
etrating branches (thalamogeniculate, Percheron, and reaction). The patient is often unaware of the blindness
posterior choroidal arteries); and (2) P2 syndrome: corti- or may even deny it (Antons syndrome). Tiny islands
cal temporal and occipital lobe signs, due to occlusion of vision may persist, and the patient may report that
SECTION III
of the P2 segment distal to the junction of the PCA vision uctuates as images are captured in the preserved
with the posterior communicating artery. portions. Rarely, only peripheral vision is lost and cen-
tral vision is spared, resulting in gun-barrel vision.
P1 syndromes Bilateral visual association area lesions may result in
Infarction usually occurs in the ipsilateral subthala- Balints syndrome, a disorder of the orderly visual scan-
mus and medial thalamus and in the ipsilateral cerebral ning of the environment (Chap. 18), usually resulting
Diseases of the Nervous System
peduncle and midbrain (Figs. 27-9 and 27-14). A third from infarctions secondary to low ow in the water-
nerve palsy with contralateral ataxia (Claudes syn- shed between the distal PCA and MCA territories, as
drome) or with contralateral hemiplegia (Webers syn- occurs after cardiac arrest. Patients may experience per-
drome) may result. The ataxia indicates involvement sistence of a visual image for several minutes despite
of the red nucleus or dentatorubrothalamic tract; the gazing at another scene (palinopsia) or an inability to
hemiplegia is localized to the cerebral peduncle (Fig. synthesize the whole of an image (asimultanagnosia).
2 7-14). If the subthalamic nucleus is involved, con- Embolic occlusion of the top of the basilar artery can
tralateral hemiballismus may occur. Occlusion of the produce any or all of the central or peripheral territory
artery of Percheron produces paresis of upward gaze symptoms. The hallmark is the sudden onset of bilateral
and drowsiness, and often abulia. Extensive infarction in signs, including ptosis, pupillary asymmetry or lack of
the midbrain and subthalamus occurring with bilateral reaction to light, and somnolence.
proximal PCA occlusion presents as coma, unreactive
pupils, bilateral pyramidal signs, and decerebrate rigidity. Vertebral and posterior inferior cerebellar
Occlusion of the penetrating branches of thalamic arteries
and thalamogeniculate arteries produces less extensive The vertebral artery, which arises from the innominate
thalamic and thalamocapsular lacunar syndromes. The artery on the right and the subclavian artery on the left,
thalamic Djrine-Roussy syndrome consists of contralateral consists of four segments. The rst (V1) extends from
hemisensory loss followed later by an agonizing, searing its origin to its entrance into the sixth or fth transverse
or burning pain in the affected areas. It is persistent and vertebral foramen. The second segment (V2) traverses
responds poorly to analgesics. Anticonvulsants (carbam- the vertebral foramina from C6 to C2. The third (V3)
azepine or gabapentin) or tricyclic antidepressants may passes through the transverse foramen and circles around
be benecial. the arch of the atlas to pierce the dura at the foramen
magnum. The fourth (V4) segment courses upward to
P2 syndromes join the other vertebral artery to form the basilar artery;
(See also Figs. 27-8 and 27-9.) Occlusion of the dis- only the fourth segment gives rise to branches that sup-
tal PCA causes infarction of the medial temporal and ply the brainstem and cerebellum. The posterior inferior
occipital lobes. Contralateral homonymous hemiano- cerebellar artery (PICA) in its proximal segment sup-
pia with macula sparing is the usual manifestation. plies the lateral medulla and, in its distal branches, the
Occasionally, only the upper quadrant of visual eld is inferior surface of the cerebellum.
involved. If the visual association areas are spared and Atherothrombotic lesions have a predilection for
only the calcarine cortex is involved, the patient may be V1 and V4 segments of the vertebral artery. The rst
aware of visual defects. Medial temporal lobe and hip- segment may become diseased at the origin of the ves-
pocampal involvement may cause an acute disturbance sel and may produce posterior circulation emboli;
collateral ow from the contralateral vertebral artery or Separating these symptoms from those of viral labyrin- 279
the ascending cervical, thyrocervical, or occipital arter- thitis can be a challenge, but headache, neck stiffness,
ies is usually sufcient to prevent low-ow TIAs or and unilateral dysmetria favor stroke.
stroke. When one vertebral artery is atretic and an ath-
erothrombotic lesion threatens the origin of the other, Basilar artery
the collateral circulation, which may also include retro- Branches of the basilar artery supply the base of the pons
grade ow down the basilar artery, is often insufcient and superior cerebellum and fall into three groups: (1)
(Figs. 27-4 and 27-9). In this setting, low-ow TIAs paramedian, 710 in number, which supply a wedge of
may occur, consisting of syncope, vertigo, and alternat- pons on either side of the midline; (2) short circumfer-
ing hemiplegia; this state also sets the stage for throm- ential, 57 in number, that supply the lateral two-thirds
bosis. Disease of the distal fourth segment of the verte- of the pons and middle and superior cerebellar peduncles;
bral artery can promote thrombus formation manifest as and (3) bilateral long circumferential (superior cerebel-
embolism or with propagation as basilar artery throm- lar and anterior inferior cerebellar arteries), which course
bosis. Stenosis proximal to the origin of the PICA can around the pons to supply the cerebellar hemispheres.
threaten the lateral medulla and posterior inferior sur- Atheromatous lesions can occur anywhere along
face of the cerebellum. the basilar trunk but are most frequent in the proximal
If the subclavian artery is occluded proximal to the basilar and distal vertebral segments. Typically, lesions
CHAPTER 27
origin of the vertebral artery, there is a reversal in the occlude either the proximal basilar and one or both
direction of blood ow in the ipsilateral vertebral artery. vertebral arteries. The clinical picture varies depend-
Exercise of the ipsilateral arm may increase demand on ing on the availability of retrograde collateral ow from
vertebral ow, producing posterior circulation TIAs, or the posterior communicating arteries. Rarely, dissection
subclavian steal. of a vertebral artery may involve the basilar artery and,
Although atheromatous disease rarely narrows the depending on the location of true and false lumen, may
Cerebrovascular Diseases
second and third segments of the vertebral artery, this produce multiple penetrating artery strokes.
region is subject to dissection, bromuscular dysplasia, Although atherothrombosis occasionally occludes the
and, rarely, encroachment by osteophytic spurs within distal portion of the basilar artery, emboli from the heart
the vertebral foramina. or proximal vertebral or basilar segments are more com-
Embolic occlusion or thrombosis of a V4 segment monly responsible for top of the basilar syndromes.
causes ischemia of the lateral medulla. The constellation Because the brainstem contains many structures in
of vertigo, numbness of the ipsilateral face and contra- close apposition, a diversity of clinical syndromes may
lateral limbs, diplopia, hoarseness, dysarthria, dysphagia, emerge with ischemia, reecting involvement of the
and ipsilateral Horners syndrome is called the lateral corticospinal and corticobulbar tracts, ascending sensory
medullary (or Wallenbergs) syndrome (Fig. 27-10). Most tracts, and cranial nerve nuclei (Figs. 27-11, 27-12,
cases result from ipsilateral vertebral artery occlusion; in 27-13, and 27-14).
the remainder, PICA occlusion is responsible. Occlu- The symptoms of transient ischemia or infarction in
sion of the medullary penetrating branches of the ver- the territory of the basilar artery often do not indicate
tebral artery or PICA results in partial syndromes. Hemi- whether the basilar artery itself or one of its branches
paresis is not a feature of vertebral artery occlusion; however, is diseased, yet this distinction has important implica-
quadriparesis may result from occlusion of the anterior spinal tions for therapy. The picture of complete basilar occlusion,
artery. however, is easy to recognize as a constellation of bilateral long
Rarely, a medial medullary syndrome occurs with infarc- tract signs (sensory and motor) with signs of cranial nerve and
tion of the pyramid and contralateral hemiparesis of the cerebellar dysfunction. A locked-in state of preserved
arm and leg, sparing the face. If the medial lemniscus and consciousness with quadriplegia and cranial nerve signs
emerging hypoglossal nerve bers are involved, contra- suggests complete pontine and lower midbrain infarc-
lateral loss of joint position sense and ipsilateral tongue tion. The therapeutic goal is to identify impending basilar
weakness occur. occlusion before devastating infarction occurs. A series
Cerebellar infarction with edema can lead to sud- of TIAs and a slowly progressive, uctuating stroke are
den respiratory arrest due to raised ICP in the posterior extremely signicant, as they often herald an athero-
fossa. Drowsiness, Babinski signs, dysarthria, and bifacial thrombotic occlusion of the distal vertebral or proximal
weakness may be absent, or present only briey, before basilar artery.
respiratory arrest ensues. Gait unsteadiness, headache, TIAs in the proximal basilar distribution may pro-
dizziness, nausea, and vomiting may be the only early duce vertigo (often described by patients as swimming,
symptoms and signs and should arouse suspicion of this swaying, moving, unsteadiness, or light-headed-
impending complication, which may require neurosur- ness). Other symptoms that warn of basilar thrombosis
gical decompression, often with an excellent outcome. include diplopia, dysarthria, facial or circumoral numbness,
280 Medial lemniscus
Pyramid
12th n.
Spinothalamic tract
Inferior olive
Ventral
spinocerebellar tract
10th n. Medulla
Dorsal
spinocerebellar tract Descending
sympathetic
Nucleus ambiguus tract
motor 9 +10
Restiform
Descending nucleus body
and tract - 5th n.
Olivocerebellar
Tractus solitarius fibers
with nucleus Cerebellum
Vestibular
nucleus 12th n.
Medial longitudinal fasciculus
nucleus
Medullary syndrome:
SECTION III
Lateral Medial
FIGURE 27-10
Axial section at the level of the medulla, depicted sche- Horners syndrome (miosis, ptosis, decreased
matically on the left, with a corresponding MR image on the sweating): Descending sympathetic tract
right. Note that in Figs. 27-10 through 27-14, all drawings Dysphagia, hoarseness, paralysis of palate, paraly-
Diseases of the Nervous System
are oriented with the dorsal surface at the bottom, matching sis of vocal cord, diminished gag reex: Issuing
the orientation of the brainstem that is commonly seen in all bers ninth and tenth nerves
modern neuroimaging studies. Approximate regions involved Loss of taste: Nucleus and tractus solitarius
in medial and lateral medullary stroke syndromes are shown. Numbness of ipsilateral arm, trunk, or leg: Cuneate
Signs and symptoms: Structures involved and gracile nuclei
1. Medial medullary syndrome (occlusion of vertebral Weakness of lower face: Genuected upper motor
artery or of branch of vertebral or lower basilar artery) neuron bers to ipsilateral facial nucleus
On side of lesion On side opposite lesion
Paralysis with atrophy of one-half half the tongue: Impaired pain and thermal sense over half the body,
Ipsilateral twelfth nerve sometimes face: Spinothalamic tract
On side opposite lesion 3. Total unilateral medullary syndrome (occlusion of vertebral
Paralysis of arm and leg, sparing face; impaired artery): Combination of medial and lateral syndromes
tactile and proprioceptive sense over one-half the 4. Lateral pontomedullary syndrome (occlusion of vertebral
body: Contralateral pyramidal tract and medial artery): Combination of lateral medullary and lateral infe-
lemniscus rior pontine syndrome
2. Lateral medullary syndrome (occlusion of any of ve 5. Basilar artery syndrome (the syndrome of the lone ver-
vessels may be responsiblevertebral, posterior infe- tebral artery is equivalent): A combination of the various
rior cerebellar, superior, middle, or inferior lateral medul- brainstem syndromes plus those arising in the posterior
lary arteries) cerebral artery distribution.
On side of lesion Bilateral long tract signs (sensory and motor; cerebellar
Pain, numbness, impaired sensation over one-half and peripheral cranial nerve abnormalities): Bilateral long
the face: Descending tract and nucleus fth nerve tract; cerebellar and peripheral cranial nerves
Ataxia of limbs, falling to side of lesion: Uncertain Paralysis or weakness of all extremities, plus all bulbar
restiform body, cerebellar hemisphere, cerebellar musculature: Corticobulbar and corticospinal tracts bilat-
bers, spinocerebellar tract (?) erally
Nystagmus, diplopia, oscillopsia, vertigo, nausea,
vomiting: Vestibular nucleus
and hemisensory symptoms. In general, symptoms of basi- an initial symptom of basilar occlusion. Most often TIAs,
lar branch TIAs affect one side of the brainstem, whereas whether due to impending occlusion of the basilar artery
symptoms of basilar artery TIAs usually affect both sides, or a basilar branch, are short lived (530 min) and repeti-
although a herald hemiparesis has been emphasized as tive, occurring several times a day. The pattern suggests
Corticospinal and
corticobulbar tract
281
Spinothalamic
tract Medial lemniscus
Dorsal
cochlear
nucleus
7th n. nucleus
Restiform body Medial longitudinal Cerebellum
fasciculus
Vestibular nucleus
6th n. nucleus
CHAPTER 27
complex
Inferior pontine syndrome:
Lateral Medial
FIGURE 27-11
Axial section at the level of the inferior pons, depicted 2. Lateral inferior pontine syndrome (occlusion of anterior
Cerebrovascular Diseases
schematically on the left, with a corresponding MR image on inferior cerebellar artery)
the right. Approximate regions involved in medial and lateral On side of lesion
inferior pontine stroke syndromes are shown. Horizontal and vertical nystagmus, vertigo, nausea,
Signs and symptoms: Structures involved vomiting, oscillopsia: Vestibular nerve or nucleus
1. Medial inferior pontine syndrome (occlusion of parame- Facial paralysis: Seventh nerve
dian branch of basilar artery) Paralysis of conjugate gaze to side of lesion: Center
On side of lesion for conjugate lateral gaze
Paralysis of conjugate gaze to side of lesion (preser- Deafness, tinnitus: Auditory nerve or cochlear
vation of convergence): Center for conjugate lateral nucleus
gaze Ataxia: Middle cerebellar peduncle and cerebellar
Nystagmus: Vestibular nucleus hemisphere
Ataxia of limbs and gait: Likely middle cerebellar Impaired sensation over face: Descending tract and
peduncle nucleus fth nerve
Diplopia on lateral gaze: Abducens nerve On side opposite lesion
On side opposite lesion Impaired pain and thermal sense over one-half the
Paralysis of face, arm, and leg: Corticobulbar and body (may include face): Spinothalamic tract
corticospinal tract in lower pons
Impaired tactile and proprioceptive sense over one-
half of the body: Medial lemniscus
intermittent reduction of ow. Many neurologists treat Occlusion of a branch of the basilar artery usually causes
with heparin to prevent clot propagation. unilateral symptoms and signs involving motor, sensory, and
Atherothrombotic occlusion of the basilar artery with cranial nerves. As long as symptoms remain unilateral, con-
infarction usually causes bilateral brainstem signs. A gaze cern over pending basilar occlusion should be reduced.
paresis or internuclear ophthalmoplegia associated with Occlusion of the superior cerebellar artery results in
ipsilateral hemiparesis may be the only manifestation of severe ipsilateral cerebellar ataxia, nausea and vomiting,
bilateral brainstem ischemia. More often, unequivocal dysarthria, and contralateral loss of pain and temperature
signs of bilateral pontine disease are present. Complete sensation over the extremities, body, and face (spino-
basilar thrombosis carries a high mortality. and trigeminothalamic tracts). Partial deafness, ataxic
282 Corticospinal and
corticopontine tracts
Medial
lemniscus
Temporal lobe
5th n.
Mid-pons
Lateral
lemniscus 5th cranial
nerve
Middle
cerebellar
peduncle
Spinothalamic
tract
Superior cerebellar
SECTION III
Midpontine syndrome:
Lateral Medial
FIGURE 27-12
Diseases of the Nervous System
Axial section at the level of the midpons, depicted sche- Variable impaired touch and proprioception when
matically on the left, with a corresponding MR image on the lesion extends posteriorly: Medial lemniscus
right. Approximate regions involved in medial and lateral 2. Lateral midpontine syndrome (short circumferential artery)
midpontine stroke syndromes are shown. On side of lesion
Signs and symptoms: Structures involved Ataxia of limbs: Middle cerebellar peduncle
1. Medial midpontine syndrome (paramedian branch of Paralysis of muscles of mastication: Motor bers or
midbasilar artery) nucleus of fth nerve
On side of lesion Impaired sensation over side of face: Sensory bers
Ataxia of limbs and gait (more prominent in bilateral or nucleus of fth nerve
involvement): Pontine nuclei On side opposite lesion
On side opposite lesion Impaired pain and thermal sense on limbs and
Paralysis of face, arm, and leg: Corticobulbar and trunk: Spinothalamic tract
corticospinal tract
tremor of the ipsilateral upper extremity, Horners syn- Occlusion of one of the short circumferential
drome, and palatal myoclonus may occur rarely. Partial branches of the basilar artery affects the lateral two-
syndromes occur frequently (Fig. 27-13). With large thirds of the pons and middle or superior cerebellar
strokes, swelling and mass effects may compress the peduncle, whereas occlusion of one of the paramedian
midbrain or produce hydrocephalus; these symptoms branches affects a wedge-shaped area on either side of
may evolve rapidly. Neurosurgical intervention may be the medial pons (Figs. 27-11 through 27-13).
lifesaving in such cases.
Occlusion of the anterior inferior cerebellar artery
produces variable degrees of infarction because the size IMAGING STUDIES
of this artery and the territory it supplies vary inversely See also Chap. 4.
with those of the PICA. The principal symptoms
include: (1) ipsilateral deafness, facial weakness, vertigo,
CT scans
nausea and vomiting, nystagmus, tinnitus, cerebellar
ataxia, Horners syndrome, and paresis of conjugate lat- CT radiographic images identify or exclude hemorrhage
eral gaze; and (2) contralateral loss of pain and tempera- as the cause of stroke, and they identify extraparenchy-
ture sensation. An occlusion close to the origin of the mal hemorrhages, neoplasms, abscesses, and other con-
artery may cause corticospinal tract signs (Fig. 27-11). ditions masquerading as stroke. Brain CT scans obtained
Pontine nuclei and
Corticospinal tract
283
pontocerebellar fibers
Temporal lobe
Medial
lemniscus
Basilar artery
Central
tegmental
bundle
Lateral
lemniscus
Spinothalamic Superior
tract pons
Medial longitudinal Superior cerebellar
fasciculus peduncle
CHAPTER 27
Lateral Medial
FIGURE 27-13
Axial section at the level of the superior pons, depicted 2. Lateral superior pontine syndrome (syndrome of supe-
schematically on the left, with a corresponding MR image on rior cerebellar artery)
the right. Approximate regions involved in medial and lateral On side of lesion
Cerebrovascular Diseases
superior pontine stroke syndromes are shown. Ataxia of limbs and gait, falling to side of lesion:
Signs and symptoms: Structures involved Middle and superior cerebellar peduncles, superior
1. Medial superior pontine syndrome (paramedian branches surface of cerebellum, dentate nucleus
of upper basilar artery) Dizziness, nausea, vomiting; horizontal nystagmus:
On side of lesion Vestibular nucleus
Cerebellar ataxia (probably): Superior and/or middle Paresis of conjugate gaze (ipsilateral): Pontine con-
cerebellar peduncle tralateral gaze
Internuclear ophthalmoplegia: Medial longitudinal Skew deviation: Uncertain
fasciculus Miosis, ptosis, decreased sweating over face (Horn-
Myoclonic syndrome, palate, pharynx, vocal cords, ers syndrome): Descending sympathetic bers
respiratory apparatus, face, oculomotor apparatus, Tremor: Localization unclearDentate nucleus,
etc.: Localization uncertaincentral tegmental bun- superior cerebellar peduncle
dle, dentate projection, inferior olivary nucleus On side opposite lesion
On side opposite lesion Impaired pain and thermal sense on face, limbs,
Paralysis of face, arm, and leg: Corticobulbar and and trunk: Spinothalamic tract
corticospinal tract Impaired touch, vibration, and position sense, more in
Rarely touch, vibration, and position are affected: leg than arm (there is a tendency to incongruity of pain
Medial lemniscus and touch decits): Medial lemniscus (lateral portion)
in the rst several hours after an infarction generally and intracranial arteries, intracranial veins, aortic arch,
show no abnormality, and the infarct may not be seen and even the coronary arteries in one imaging session.
reliably for 2448 h. CT may fail to show small isch- Carotid disease and intracranial vascular occlusions are
emic strokes in the posterior fossa because of bone arti- readily identied with this method (Fig. 27-3). After
fact; small infarcts on the cortical surface may also be an IV bolus of contrast, decits in brain perfusion pro-
missed. duced by vascular occlusion can also be demonstrated
Contrast-enhanced CT scans add specicity by (Fig. 27-15) and used to predict the region of infarcted
showing contrast enhancement of subacute infarcts and brain and the brain at risk of further infarction (i.e., the
allow visualization of venous structures. Coupled with ischemic penumbra, see Pathophysiology of Ischemic
newer generation multidetector scanners, CT angiogra- Stroke). CT imaging is also sensitive for detecting
phy (CTA) can be performed with administration of IV SAH (though by itself does not rule it out), and CTA
iodinated contrast allowing visualization of the cervical can readily identify intracranial aneurysms (Chap. 28).
284 3rd n.
Internal
Red nucleus Basilar artery carotid
Crus cerebri
artery
Substantia
nigra
Medial
lemniscus
Spinothalamic
tract
3rd nerve Midbrain
nucleus Periaqueductal
gray matter
Cerebral aqueduct
Superior colliculus
Midbrain syndrome:
SECTION III
Lateral Medial
FIGURE 27-14
Axial section at the level of the midbrain, depicted sche- Paralysis of face, arm, and leg: Corticobulbar and
matically on the left, with a corresponding MR image on the corticospinal tract descending in crus cerebri
right. Approximate regions involved in medial and lateral 2. Lateral midbrain syndrome (syndrome of small pene-
Diseases of the Nervous System
midbrain stroke syndromes are shown. trating arteries arising from posterior cerebral artery)
Signs and symptoms: Structures involved On side of lesion
1. Medial midbrain syndrome (paramedian branches of Eye down and out secondary to unopposed
upper basilar and proximal posterior cerebral arteries) action of fourth and sixth cranial nerves, with dilated
On side of lesion and unresponsive pupil: Third nerve bers and/or
Eye down and out secondary to unopposed third nerve nucleus
action of fourth and sixth cranial nerves, with dilated On side opposite lesion
and unresponsive pupil: Third nerve bers Hemiataxia, hyperkinesias, tremor: Red nucleus,
On side opposite lesion dentatorubrothalamic pathway
Because of its speed and wide availability, noncontrast diffusion are equivalent measure of the ischemic pen-
head CT is the imaging modality of choice in patients umbra (see Pathophysiology of Ischemic Stroke and
with acute stroke (Fig. 27-1), and CTA and CT per- Fig. 27-16), and patients showing large regions of mis-
fusion imaging may also be useful and convenient match may be better candidates for acute revasculariza-
adjuncts. tion. MR angiography is highly sensitive for stenosis of
extracranial internal carotid arteries and of large intra-
MRI cranial vessels. With higher degrees of stenosis, MR
angiography tends to overestimate the degree of steno-
MRI reliably documents the extent and location of sis when compared to conventional x-ray angiography.
infarction in all areas of the brain, including the pos- MRI with fat saturation is an imaging sequence used
terior fossa and cortical surface. It also identies intra- to visualize extra or intracranial arterial dissection. This
cranial hemorrhage and other abnormalities but is less sensitive technique images clotted blood within the
sensitive than CT for detecting acute blood. MRI dissected vessel wall.
scanners with magnets of higher eld strength produce MRI is less sensitive for acute blood products than CT
more reliable and precise images. Diffusion-weighted and is more expensive and time consuming and less read-
imaging is more sensitive for early brain infarction ily available. Claustrophobia also limits its application.
than standard MR sequences or CT (Fig. 27-16), as Most acute stroke protocols use CT because of these
is uid-attenuated inversion recovery (FLAIR) imaging limitations. However, MRI is useful outside the acute
(Chap. 4). Using IV administration of gadolinium con- period by more clearly dening the extent of tissue injury
trast, MR perfusion studies can be performed. Brain and discriminating new from old regions of brain infarc-
regions showing poor perfusion but no abnormality on tion. MRI may have particular utility in patients with
285
CHAPTER 27
Cerebrovascular Diseases
FIGURE 27-15
Acute left middle cerebral artery (MCA) stroke with right of the vessels following successful thrombectomy 8 h after
hemiplegia but preserved language. A. CT perfusion stroke symptom onset (right panel). D. The clot removed with
mean-transit time map showing delayed perfusion of the left a thrombectomy device (L5, Concentric Medical, Inc.). E. CT
MCA distribution (blue). B. Predicted region of infarct (red) scan of the brain 2 days later; note infarction in the region
and penumbra (green) based on CT perfusion data. C. Con- predicted in B but preservation of the penumbral region by
ventional angiogram showing occlusion of the left internal successful revascularization.
carotidMCA bifurcation (left panel), and revascularization
TIA. It is also more likely to identify new infarction, stroke with mechanical thrombectomy devices. Ran-
which is a strong predictor of subsequent stroke. domized trials support use of thrombolytic agents deliv-
ered intraarterially in patients with acute MCA stroke
Cerebral angiography by showing that vessels are effectively recanalized and
clinical outcomes are improved at 90 days. Cerebral
Conventional x-ray cerebral angiography is the gold angiography coupled with endovascular techniques for
standard for identifying and quantifying atherosclerotic cerebral revascularization are becoming routine in the
stenoses of the cerebral arteries and for identifying and United States and Europe and likely soon in Japan.
characterizing other pathologies, including aneurysms, Centers capable of these techniques are termed compre-
vasospasm, intraluminal thrombi, bromuscular dyspla- hensive stroke centers to distinguish them from primary
sia, arteriovenous stula, vasculitis, and collateral chan- stroke centers that can administer IV rtPA but not per-
nels of blood ow. Endovascular techniques, which are form endovascular therapy. Conventional angiogra-
evolving rapidly, can be used to deploy stents within phy carries risks of arterial damage, groin hemorrhage,
delicate intracranial vessels, to perform balloon angio- embolic stroke, and renal failure from contrast nephrop-
plasty of stenotic lesions, to treat intracranial aneurysms athy, so it should be reserved for situations where less
by embolization, and to open occluded vessels in acute invasive means are inadequate.
286 Ultrasound techniques
Stenosis at the origin of the internal carotid artery can
be identied and quantied reliably by ultrasonography
that combines a B-mode ultrasound image with a Dop-
pler ultrasound assessment of ow velocity (duplex
ultrasound). Transcranial Doppler (TCD) assessment of
MCA, ACA, and PCA ow and of vertebrobasilar ow
is also useful. This latter technique can detect stenotic
lesions in the large intracranial arteries because such
lesions increase systolic ow velocity. Furthermore,
TCD can assist thrombolysis and improve large artery
recanalization following rtPA administration; the poten-
tial clinical benet of this treatment is the subject of
ongoing study. In many cases, MR angiography com-
bined with carotid and transcranial ultrasound studies
eliminates the need for conventional x-ray angiography
SECTION III
Head trauma Intraparenchymal: frontal lobes, anterior Coup and contrecoup injury during brain
temporal lobes; subarachnoid deceleration
Hypertensive hemorrhage Putamen, globus pallidus, thalamus, Chronic hypertension produces hemor-
cerebellar hemisphere, pons rhage from small (100 m) vessels in
these regions
Transformation of prior ischemic infarc- Basal ganglion, subcortical regions, Occurs in 16% of ischemic strokes
tion lobar with predilection for large hemispheric
infarctions
Metastatic brain tumor Lobar Lung, choriocarcinoma, melanoma, renal
cell carcinoma, thyroid, atrial myxoma
Coagulopathy Any Uncommon cause; often associated
with prior stroke or underlying vascular
anomaly
CHAPTER 27
Drug Lobar, subarachnoid Cocaine, amphetamine, phenylpropa-
nolamine
Arteriovenous malformation Lobar, intraventricular, subarachnoid Risk is 24% per year for bleeding
Aneurysm Subarachnoid, intraparenchymal, rarely Mycotic and nonmycotic forms of aneu-
subdural rysms
Amyloid angiopathy Lobar Degenerative disease of intracranial ves-
Cerebrovascular Diseases
sels; linkage to Alzheimers disease,
rare in patients <60 years
Cavernous angioma Intraparenchymal Multiple cavernous angiomas linked
to mutations in KRIT1, CCM2, and
PDCD10 genes
Dural arteriovenous stula Lobar, subarachnoid Produces bleeding by venous hyperten-
sion
Capillary telangiectasias Usually brainstem Rare cause of hemorrhage
small penetrating artery deep in the brain. The most FIGURE 27-17
common sites are the basal ganglia (especially the puta- Hypertensive hemorrhage. Transaxial noncontrast CT scan
men), thalamus, cerebellum, and pons. When hemor- through the region of the basal ganglia reveals a hematoma
rhages occur in other brain areas or in nonhypertensive involving the left putamen in a patient with rapidly progres-
patients, greater consideration should be given to hem- sive onset of right hemiparesis.
orrhagic disorders, neoplasms, vascular malformations,
Diseases of the Nervous System
and other causes. The small arteries in these areas seem paralysis may worsen until the affected limbs become
most prone to hypertension-induced vascular injury. accid or extend rigidly. When hemorrhages are large,
The hemorrhage may be small or a large clot may form drowsiness gives way to stupor as signs of upper brain-
and compress adjacent tissue, causing herniation and stem compression appear. Coma ensues, accompanied
death. Blood may dissect into the ventricular space, by deep, irregular, or intermittent respiration, a dilated
which substantially increases morbidity and may cause and xed ipsilateral pupil, and decerebrate rigidity. In
hydrocephalus. milder cases, edema in adjacent brain tissue may cause
Most hypertensive intraparenchymal hemorrhages progressive deterioration over 1272 h.
develop over 3090 min, whereas those associated Thalamic hemorrhages also produce a contralateral
with anticoagulant therapy may evolve for as long as hemiplegia or hemiparesis from pressure on, or dissec-
2448 h. Within 48 h macrophages begin to phago- tion into, the adjacent internal capsule. A prominent
cytize the hemorrhage at its outer surface. After 16 sensory decit involving all modalities is usually present.
months, the hemorrhage is generally resolved to a slit- Aphasia, often with preserved verbal repetition, may
like orange cavity lined with glial scar and hemosiderin- occur after hemorrhage into the dominant thalamus,
laden macrophages. and constructional apraxia or mutism occurs in some
cases of nondominant hemorrhage. There may also be
Clinical manifestations a homonymous visual eld defect. Thalamic hemor-
Although not particularly associated with exertion, rhages cause several typical ocular disturbances by virtue
ICHs almost always occur while the patient is awake of extension inferiorly into the upper midbrain. These
and sometimes when stressed. The hemorrhage gen- include deviation of the eyes downward and inward
erally presents as the abrupt onset of focal neurologic so that they appear to be looking at the nose, unequal
decit. Seizures are uncommon. The focal decit typi- pupils with absence of light reaction, skew devia-
cally worsens steadily over 3090 min and is associated tion with the eye opposite the hemorrhage displaced
with a diminishing level of consciousness and signs of downward and medially, ipsilateral Horners syndrome,
increased ICP such as headache and vomiting. absence of convergence, paralysis of vertical gaze, and
The putamen is the most common site for hyper- retraction nystagmus. Patients may later develop a
tensive hemorrhage, and the adjacent internal capsule chronic, contralateral pain syndrome (Djrine-Roussy
is usually damaged (Fig. 27-17). Contralateral hemi- syndrome).
paresis is therefore the sentinel sign. When mild, the In pontine hemorrhages, deep coma with quadriple-
face sags on one side over 530 min, speech becomes gia usually occurs over a few minutes. There is often
slurred, the arm and leg gradually weaken, and the eyes prominent decerebrate rigidity and pinpoint (1 mm)
deviate away from the side of the hemiparesis. The pupils that react to light. There is impairment of reex
horizontal eye movements evoked by head turning by pathologic demonstration of Congo red staining of 289
(dolls-head or oculocephalic maneuver) or by irriga- amyloid in cerebral vessels. The 2 and 4 allelic varia-
tion of the ears with ice water (Chap. 17). Hyperpnea, tions of the apolipoprotein E gene are associated with
severe hypertension, and hyperhidrosis are common. increased risk of recurrent lobar hemorrhage and may
Death often occurs within a few hours, but small hem- therefore be markers of amyloid angiopathy. Currently,
orrhages are compatible with survival. there is no specic therapy, although antiplatelet and
Cerebellar hemorrhages usually develop over sev- anticoagulating agents are typically avoided.
eral hours and are characterized by occipital headache, Cocaine and methamphetamine are frequent causes of
repeated vomiting, and ataxia of gait. In mild cases there stroke in young (age <45 years) patients. ICH, ischemic
may be no other neurologic signs other than gait ataxia. stroke, and SAH are all associated with stimulant use.
Dizziness or vertigo may be prominent. There is often Angiographic ndings vary from completely normal
paresis of conjugate lateral gaze toward the side of the arteries to large-vessel occlusion or stenosis, vasospasm,
hemorrhage, forced deviation of the eyes to the oppo- or changes consistent with vasculopathy. The mecha-
site side, or an ipsilateral sixth nerve palsy. Less frequent nism of sympathomimetic-related stroke is not known,
ocular signs include blepharospasm, involuntary closure but cocaine enhances sympathetic activity causing acute,
of one eye, ocular bobbing, and skew deviation. Dys- sometimes severe, hypertension, and this may lead to
arthria and dysphagia may occur. As the hours pass, the hemorrhage. Slightly more than one-half of stimulant-
CHAPTER 27
patient often becomes stuporous and then comatose related intracranial hemorrhages are intracerebral, and
from brainstem compression or obstructive hydroceph- the rest are subarachnoid. In cases of SAH, a saccular
alus; immediate surgical evacuation before brainstem aneurysm is usually identied. Presumably, acute hyper-
compression occurs may be lifesaving. Hydrocephalus tension causes aneurysmal rupture.
from fourth ventricle compression can be relieved by Head injury often causes intracranial bleeding. The
external ventricular drainage, but denitive hematoma common sites are intracerebral (especially temporal and
Cerebrovascular Diseases
evacuation is essential for survival. If the deep cerebellar inferior frontal lobes) and into the subarachnoid, subdu-
nuclei are spared, full recovery is common. ral, and epidural spaces. Trauma must be considered in
any patient with an unexplained acute neurologic de-
Lobar hemorrhage cit (hemiparesis, stupor, or confusion), particularly if the
decit occurred in the context of a fall (Chap. 36).
Symptoms and signs appear over several minutes. Most Intracranial hemorrhages associated with anticoagulant
lobar hemorrhages are small and cause a restricted clini- therapy can occur at any location; they are often lobar
cal syndrome that simulates an embolus to an artery or subdural. Anticoagulant-related ICHs may evolve
supplying one lobe. For example, the major neuro- slowly, over 2448 h. Coagulopathy and thrombocyto-
logic decit with an occipital hemorrhage is hemiano- penia should be reversed rapidly, as discussed later. ICH
pia; with a left temporal hemorrhage, aphasia and delir- associated with hematologic disorders (leukemia, aplastic
ium; with a parietal hemorrhage, hemisensory loss; and anemia, thrombocytopenic purpura) can occur at any
with frontal hemorrhage, arm weakness. Large hemor- site and may present as multiple ICHs. Skin and mucous
rhages may be associated with stupor or coma if they membrane bleeding is usually evident and offers a diag-
compress the thalamus or midbrain. Most patients with nostic clue.
lobar hemorrhages have focal headaches, and more than Hemorrhage into a brain tumor may be the rst mani-
one-half vomit or are drowsy. Stiff neck and seizures are festation of neoplasm. Choriocarcinoma, malignant
uncommon. melanoma, renal cell carcinoma, and bronchogenic car-
cinoma are among the most common metastatic tumors
Other causes of intracerebral hemorrhage
associated with ICH. Glioblastoma multiforme in adults
Cerebral amyloid angiopathy is a disease of the elderly in and medulloblastoma in children may also have areas of
which arteriolar degeneration occurs and amyloid is ICH.
deposited in the walls of the cerebral arteries. Amyloid Hypertensive encephalopathy is a complication of malig-
angiopathy causes both single and recurrent lobar hem- nant hypertension. In this acute syndrome, severe
orrhages and is probably the most common cause of hypertension is associated with headache, nausea, vom-
lobar hemorrhage in the elderly. It accounts for some iting, convulsions, confusion, stupor, and coma. Focal
intracranial hemorrhages associated with IV throm- or lateralizing neurologic signs, either transitory or per-
bolysis given for MI. This disorder can be suspected in manent, may occur but are infrequent and therefore
patients who present with multiple hemorrhages (and suggest some other vascular disease (hemorrhage, embo-
infarcts) over several months or years, or in patients lism, or atherosclerotic thrombosis). There are reti-
with micro-bleeds seen on brain MRI sequences sen- nal hemorrhages, exudates, papilledema (hypertensive
sitive for hemosiderin, but it is denitively diagnosed retinopathy), and evidence of renal and cardiac disease.
290 In most cases ICP and CSF protein levels are elevated. may persist for months. MRI, although more sensitive
MRI brain imaging shows a pattern of typically poste- for delineating posterior fossa lesions, is generally not
rior (occipital > frontal) brain edema that is reversible necessary in most instances. Images of owing blood
and termed reversible posterior leukoencephalopathy. The on MRI scan may identify AVMs as the cause of the
hypertension may be essential or due to chronic renal hemorrhage. MRI, CT angiography, and conventional
disease, acute glomerulonephritis, acute toxemia of x-ray angiography are used when the cause of intracra-
pregnancy, pheochromocytoma, or other causes. Low- nial hemorrhage is uncertain, particularly if the patient
ering the blood pressure reverses the process, but stroke is young or not hypertensive and the hematoma is not
can occur, especially if blood pressure is lowered too in one of the four usual sites for hypertensive hemor-
rapidly. Neuropathologic examination reveals multifo- rhage. Postcontrast CT imaging may reveal acute hema-
cal to diffuse cerebral edema and hemorrhages of vari- toma enhancement signifying bleeding at the time of
ous sizes from petechial to massive. Microscopically, imaging; this dot-sign portends increased mortality.
there are necrosis of arterioles, minute cerebral infarcts, Some centers routinely perform CT and CT angiogra-
and hemorrhages. The term hypertensive encephalopa- phy with postcontrast CT imaging in one sitting to rap-
thy should be reserved for this syndrome and not for idly identify any macrovascular etiology of the hemor-
chronic recurrent headaches, dizziness, recurrent TIAs, rhage and provide prognostic information at the same
or small strokes that often occur in association with high time. Since patients typically have focal neurologic signs
SECTION III
CHAPTER 27
Infratentorial Origin of Hemorrhage Surprisingly, ICP is often normal even with large
No 0 intraparenchymal hemorrhages. However, if the hema-
toma causes marked midline shift of structures with
Yes 1
consequent obtundation, coma, or hydrocephalus,
Glasgow Coma Scale Score osmotic agents coupled with induced hyperventilation
1315 0 can be instituted to lower ICP (Chap. 28). These maneu-
vers will provide enough time to place a ventricu-
Cerebrovascular Diseases
512 1
34 2 lostomy or ICP monitor. Once ICP is recorded, further
hyperventilation and osmotic therapy can be tailored
Total Score Sum of each category
to the individual patient to keep cerebral perfusion
above
pressure (MAP-ICP) above 60 mmHg. For example, if
OBSERVED WALK ICP is found to be high, CSF can be drained from the
ICH SCORE MORTALITY AT 30 INDEPENDENTLY AT
TOTAL DAYS (%) 12 MONTHS (%) ventricular space and osmotic therapy continued; per-
sistent or progressive elevation in ICP may prompt sur-
0 0 70
gical evacuation of the clot or withdrawal of support.
1 13 60 Alternately, if ICP is normal or only mildly elevated,
2 26 33 induced hyperventilation can be reversed and osmotic
3 72 3 therapy tapered. Since hyperventilation may actu-
4 97 8
ally produce ischemia by cerebral vasoconstriction,
induced hyperventilation should be limited to acute
5 100 None
resuscitation of the patient with presumptive high ICP
and eliminated once other treatments (osmotic ther-
Although a score of 6 is possible with the scale, no patient was
observed to present with this combination of ndings, and it is con-
apy or surgical treatments) have been instituted. Glu-
sidered highly likely to be fatal. cocorticoids are not helpful for the edema from intra-
Abbreviation: ICH, intracerebral hemorrhage. cerebral hematoma.
Sources: JC Hemphill et al: Stroke 32:891, 2001; JC Hemphill et al:
Neurology 73:1088, 2009. PREVENTION Hypertension is the leading cause
of primary ICH. Prevention is aimed at reducing hyper-
tension, eliminating excessive alcohol use, and discon-
tinuing use of illicit drugs such as cocaine and amphet-
amines. Patients with amyloid angiopathy should avoid
patients in the initial medical management group ulti- antithrombotic agents.
mately had surgery for neurologic deterioration. Overall,
these data do not support routine surgical evacuation
of supratentorial hemorrhages; however, many centers
operate on patients with progressive neurologic dete-
rioration. Surgical techniques continue to evolve, and VASCULAR ANOMALIES
minimally invasive endoscopic hematoma evacuation
Vascular anomalies can be divided into congenital vas-
may prove beneficial in future trials.
cular malformations and acquired vascular lesions.
292 CONGENITAL VASCULAR MALFORMATIONS the AVM and contrast may demonstrate the abnormal
blood vessels. Once identied, conventional x-ray angi-
True arteriovenous malformations (AVMs), venous anoma- ography is the gold standard for evaluating the precise
lies, and capillary telangiectasias are lesions that usually anatomy of the AVM.
remain clinically silent through life. AVMs are prob- Surgical treatment of symptomatic AVMs, often with
ably congenital but cases of acquired lesions have been preoperative embolization to reduce operative bleeding,
reported. is usually indicated for accessible lesions. Stereotaxic
True AVMs are congenital shunts between the arte- radiation, an alternative to surgery, can produce a slow
rial and venous systems that may present as headache, sclerosis of the AVM over 23 years.
seizures, and intracranial hemorrhage. AVMs consist of Patients with asymptomatic AVMs have about an
a tangle of abnormal vessels across the cortical surface 24% per year risk for hemorrhage. Several angio-
or deep within the brain substance. AVMs vary in size graphic features can be used to help predict future
from a small blemish a few millimeters in diameter to bleeding risk. Paradoxically, smaller lesions seem to
a large mass of tortuous channels composing an arte- have a higher hemorrhage rate. The impact of recur-
riovenous shunt of sufcient magnitude to raise cardiac rent hemorrhage on disability is relatively modest, so
output and precipitate heart failure. Blood vessels form- the indication for surgery in asymptomatic AVMs is
ing the tangle interposed between arteries and veins are debated. A large-scale randomized trial is currently
SECTION III
usually abnormally thin and histologically resemble both addressing this question.
arteries and veins. AVMs occur in all parts of the cere- Venous anomalies are the result of development of
bral hemispheres, brainstem, and spinal cord, but the anomalous cerebral, cerebellar, or brainstem venous
largest ones are most frequently in the posterior half of drainage. These structures, unlike AVMs, are functional
the hemispheres, commonly forming a wedge-shaped venous channels. They are of little clinical signicance
lesion extending from the cortex to the ventricle. and should be ignored if found incidentally on brain
Bleeding, headache, or seizures are most common
Diseases of the Nervous System
CHAPTER 27
Cerebrovascular Diseases
CHAPTER 28
Life-threatening neurologic illness may be caused by a Edema can lead to increased ICP as well as tissue shifts
primary disorder affecting any region of the neuraxis or and brain displacement from focal processes (Chap. 17).
may occur as a consequence of a systemic disorder such These tissue shifts can cause injury by mechanical dis-
as hepatic failure, multisystem organ failure, or cardiac tention and compression in addition to the ischemia of
arrest (Table 28-1). Neurologic critical care focuses on impaired perfusion consequent to the elevated ICP.
preservation of neurologic tissue and prevention of sec-
ondary brain injury caused by ischemia, edema, and ele- Ischemic cascade and cellular injury
vated intracranial pressure (ICP). Management of other
organ systems proceeds concurrently and may need to When delivery of substrates, principally oxygen and
be modied in order to maintain the overall focus on glucose, is inadequate to sustain cellular function, a
neurologic issues. series of interrelated biochemical reactions known
as the ischemic cascade is initiated (see Fig. 27-2). The
release of excitatory amino acids, especially glutamate,
PATHOPHYSIOLOGY leads to inux of calcium and sodium ions, which dis-
rupt cellular homeostasis. An increased intracellular cal-
Brain edema cium concentration may activate proteases and lipases,
Swelling, or edema, of brain tissue occurs with many which then lead to lipid peroxidation and free radi-
types of brain injury. The two principal types of edema calmediated cell membrane injury. Cytotoxic edema
are vasogenic and cytotoxic. Vasogenic edema refers to ensues, and ultimately necrotic cell death and tissue
the inux of uid and solutes into the brain through an infarction occur. This pathway to irreversible cell death
incompetent blood-brain barrier (BBB). In the normal is common to ischemic stroke, global cerebral isch-
cerebral vasculature, endothelial tight junctions associ- emia, and traumatic brain injury. Penumbra refers to
ated with astrocytes create an impermeable barrier (the areas of ischemic brain tissue that have not yet under-
BBB), through which access into the brain interstitium gone irreversible infarction, implying that these regions
is dependent upon specic transport mechanisms. The are potentially salvageable if ischemia can be reversed.
BBB may be compromised in ischemia, trauma, infec- Factors that may exacerbate ischemic brain injury
tion, and metabolic derangements. Typically, vasogenic include systemic hypotension and hypoxia, which fur-
edema develops rapidly following injury. Cytotoxic ther reduce substrate delivery to vulnerable brain tis-
edema refers to cellular swelling and occurs in a vari- sue, and fever, seizures, and hyperglycemia, which can
ety of settings, including brain ischemia and trauma. increase cellular metabolism, outstripping compensatory
Early astrocytic swelling is a hallmark of ischemia. Brain processes. Clinically, these events are known as second-
edema that is clinically signicant usually represents ary brain insults because they lead to exacerbation of the
a combination of vasogenic and cellular components. primary brain injury. Prevention, identication, and
294
TABLE 28-1 treatment of secondary brain insults are fundamental 295
goals of management.
NEUROLOGIC DISORDERS IN CRITICAL ILLNESS
An alternative pathway of cellular injury is apoptosis.
LOCALIZATION This process implies programmed cell death, which may
ALONG
NEUROAXIS SYNDROME occur in the setting of ischemic stroke, global cerebral
ischemia, traumatic brain injury, and possibly intra-
Central Nervous System cerebral hemorrhage. Apoptotic cell death can be dis-
Brain: Cerebral Global encephalopathy tinguished histologically from the necrotic cell death
hemispheres Delirium
Sepsis
of ischemia and is mediated through a different set of
Organ failurehepatic, renal biochemical pathways. At present, interventions for pre-
Medication relatedsedatives, hypnot- vention and treatment of apoptotic cell death remain
ics, analgesics, H2 blockers, antihyper- less well dened than those for ischemia. Excitotoxic-
tensives
Drug overdose
ity and mechanisms of cell death are discussed in more
Electrolyte disturbancehyponatremia, detail in Chap. 25.
hypoglycemia
Hypotension/hypoperfusion
Hypoxia Cerebral perfusion and autoregulation
CHAPTER 28
Meningitis
Subarachnoid hemorrhage
Brain tissue requires constant perfusion in order to
Wernickes disease ensure adequate delivery of substrate. The hemody-
Seizurepostictal or nonconvulsive namic response of the brain has the capacity to preserve
status perfusion across a wide range of systemic blood pres-
Hypertensive encephalopathy
Hypothyroidismmyxedema
sures. Cerebral perfusion pressure (CPP), dened as
Focal decits the mean systemic arterial pressure (MAP) minus the
75
CMR-O2/Metabolism
Edema Viscosity
ICP Vasodilation O2 delivery
CSF
Hypercapnia
Pharmacologic
25 CBV
FIGURE 28-2
Ischemia and vasodilatation. Reduced cerebral perfusion
25 75 125 175
pressure (CPP) leads to increased ischemia, vasodilation,
BP, mmHg
increased intracranial pressure (ICP), and further reductions
FIGURE 28-1 in CPP, a cycle leading to further neurologic injury. CBV,
Autoregulation of cerebral blood ow (solid line). Cerebral cerebral blood volume; CMR, cerebral metabolic rate; CSF,
perfusion is constant over a wide range of systemic blood
SECTION III
CHAPTER 28
convulsive status epilepticus. Untreated continuous or
of CSF, intravascular blood, edema, or a mass lesion may
frequently recurrent seizures may cause neuronal injury,
result in a significant increase in ICP and a decrease in
making the diagnosis and treatment of seizures crucial
cerebral perfusion. This is a fundamental mechanism
in this patient group. Lumbar puncture (LP) may be nec-
of secondary ischemic brain injury and constitutes an
essary to exclude infectious processes, and an elevated
emergency that requires immediate attention. In gen-
opening pressure may be an important clue to cere-
eral, ICP should be maintained at <20 mmHg and CPP
bral venous sinus thrombosis. In patients with coma or
CHAPTER 28
outcome
(03)
HYPOXIC-ISCHEMIC ENCEPHALOPATHY or
Day 3
This occurs from lack of delivery of oxygen to the brain Absent pupil or corneal Yes FPR
Poor
reflexes; extensor or absent 0%
because of hypotension or respiratory failure. Causes motor response
outcome
(03)
include myocardial infarction, cardiac arrest, shock, no
asphyxiation, paralysis of respiration, and carbon monox-
Indeterminate outcome
CHAPTER 28
as lorazepam or midazolam. The presence of family tremor, or asterixis can occur. Sepsis-associated enceph-
members in the ICU may also help to calm and ori- alopathy is quite common, occurring in the majority of
ent agitated patients, and in severe cases, low doses of patients with sepsis and multisystem organ failure. Diag-
neuroleptics (e.g., haloperidol 0.51 mg) can be useful. nosis is often difcult because of the multiple potential
Current strategies focus on limiting the use of sedative causes of neurologic dysfunction in critically ill patients
medications when this can be done safely. and requires exclusion of structural, metabolic, toxic, and
FIGURE 28-7
FIGURE 28-6 Wernickes disease. Coronal T1-weighted postcontrast MRI
Central pontine myelinolysis. Axial T2-weighted MR scan reveals abnormal enhancement of the mammillary bodies
through the pons reveals a symmetric area of abnormal high (arrows), typical of acute Wernickes encephalopathy.
signal intensity within the basis pontis (arrows).
Diseases of the Nervous System
CHAPTER 28
CRITICAL CARE DISORDERS OF THE tion. The precise mechanism of critical illness polyneu-
PERIPHERAL NERVOUS SYSTEM ropathy remains unclear, but circulating factors such as
cytokines, which are associated with sepsis and SIRS,
Critical illness with disorders of the peripheral ner- are thought to play a role. It has been reported that up
vous system (PNS) arises in two contexts: (1) primary to 70% of patients with the sepsis syndrome have some
neurologic diseases that require critical care interven- degree of neuropathy, although far fewer have a clinical
tions such as intubation and mechanical ventilation, syndrome profound enough to cause severe respiratory
MYOPATHY
Critically ill patients, especially those with sepsis, fre- SUBARACHNOID HEMORRHAGE
quently develop muscle wasting, often in the face of
seemingly adequate nutritional support. The assump- Subarachnoid hemorrhage (SAH) renders the brain crit-
SECTION III
tion has been that this represents a catabolic myopathy ically ill from both primary and secondary brain insults.
brought about as a result of multiple factors, including Excluding head trauma, the most common cause of
elevated cortisol and catecholamine release and other SAH is rupture of a saccular aneurysm. Other causes
circulating factors induced by the SIRS. In this syn- include bleeding from a vascular malformation (arte-
drome, known as cachectic myopathy, serum creatine riovenous malformation or dural arterial-venous stula)
kinase levels and electromyography (EMG) are normal. and extension into the subarachnoid space from a pri-
Diseases of the Nervous System
Muscle biopsy shows type II ber atrophy. Panfascicular mary intracerebral hemorrhage. Some idiopathic SAHs
muscle ber necrosis may also occur in the setting of are localized to the perimesencephalic cisterns and are
profound sepsis. This so-called septic myopathy is charac- benign; they probably have a venous or capillary source,
terized clinically by weakness progressing to a profound and angiography is unrevealing.
level over just a few days. There may be associated ele-
vations in serum creatine kinase and urine myoglobin.
Saccular (berry) aneurysm
Both EMG and muscle biopsy may be normal initially
but eventually show abnormal spontaneous activity and Autopsy and angiography studies have found that about
panfascicular necrosis with an accompanying inamma- 2% of adults harbor intracranial aneurysms, for a prev-
tory reaction. Both of these myopathic syndromes may alence of 4 million persons in the United States; the
be considered under the broader heading of critical illness aneurysm will rupture, producing SAH, in 25,000
myopathy. 30,000 cases per year. For patients who arrive alive at
Acute quadriplegic myopathy describes a clinical syn- hospital, the mortality rate over the next month is about
drome of severe weakness seen in the setting of glu- 45%. Of those who survive, more than half are left with
cocorticoid and nd-NMBA use. The most frequent major neurologic decits as a result of the initial hem-
scenario in which this is encountered is the asthmatic orrhage, cerebral vasospasm with infarction, or hydro-
patient who requires high-dose glucocorticoids and cephalus. If the patient survives but the aneurysm is not
nd-NMBA to facilitate mechanical ventilation. This obliterated, the rate of rebleeding is about 20% in the
muscle disorder is not due to prolonged action of nd- rst 2 weeks, 30% in the rst month, and about 3% per
NMBAs at the neuromuscular junction but, rather, is an year afterwards. Given these alarming gures, the major
actual myopathy with muscle damage; it has occasion- therapeutic emphasis is on preventing the predictable
ally been described with high-dose glucocorticoid use early complications of the SAH.
alone. Clinically this syndrome is most often recognized Unruptured, asymptomatic aneurysms are much
when a patient fails to wean from mechanical ventila- less dangerous than a recently ruptured aneurysm. The
tion despite resolution of the primary pulmonary pro- annual risk of rupture for aneurysms <10 mm in size is
cess. Pathologically, there may be vacuolar changes in 0.1%, and for aneurysms v10 mm in size is 0.51%;
both type I and type II muscle bers with evidence of the surgical morbidity rate far exceeds these percent-
regeneration. Acute quadriplegic myopathy has a good ages. Because of the longer length of exposure to risk of
prognosis. If patients survive their underlying criti- rupture, younger patients with aneurysms >10 mm in
cal illness, the myopathy invariably improves and most size may benet from prophylactic treatment. As with
patients return to normal. However, because this syn- the treatment of asymptomatic carotid stenosis, this risk-
drome is a result of true muscle damage, not just pro- benet strongly depends on the complication rate of
longed blockade at the neuromuscular junction, this treatment.
Giant aneurysms, those >2.5 cm in diameter, occur important characteristic is sudden onset. Occasionally, 305
at the same sites (see later) as small aneurysms and these ruptures may present as headache of only moder-
account for 5% of cases. The three most common loca- ate intensity or as a change in the patients usual head-
tions are the terminal internal carotid artery, middle ache pattern. The headache is usually generalized, often
cerebral artery (MCA) bifurcation, and top of the basi- with neck stiffness, and vomiting is common.
lar artery. Their risk of rupture is 6% in the rst year Although sudden headache in the absence of focal
after identication and may remain high indenitely. neurologic symptoms is the hallmark of aneurysmal rup-
They often cause symptoms by compressing the adja- ture, focal neurologic decits may occur. Anterior com-
cent brain or cranial nerves. municating artery or MCA bifurcation aneurysms may
Mycotic aneurysms are usually located distal to the rupture into the adjacent brain or subdural space and
rst bifurcation of major arteries of the circle of Willis. form a hematoma large enough to produce mass effect.
Most result from infected emboli due to bacterial endo- The decits that result can include hemiparesis, aphasia,
carditis causing septic degeneration of arteries and sub- and abulia.
sequent dilation and rupture. Whether these lesions Occasionally, prodromal symptoms suggest the loca-
should be sought and repaired prior to rupture or left to tion of a progressively enlarging unruptured aneurysm.
heal spontaneously is controversial. A third cranial nerve palsy, particularly when associated
with pupillary dilation, loss of ipsilateral (but retained
CHAPTER 28
Pathophysiology contralateral) light reex, and focal pain above or
Saccular aneurysms occur at the bifurcations of the large- behind the eye, may occur with an expanding aneurysm
to medium-sized intracranial arteries; rupture is into the at the junction of the posterior communicating artery
subarachnoid space in the basal cisterns and often into the and the internal carotid artery. A sixth nerve palsy may
parenchyma of the adjacent brain. Approximately 85% indicate an aneurysm in the cavernous sinus, and visual
of aneurysms occur in the anterior circulation, mostly on eld defects can occur with an expanding supraclinoid
motor decit, may have with or without Severe cerebral edema in patients with infarction
intermittent reex motor decits from vasospasm may increase the ICP enough to
posturing reduce cerebral perfusion pressure. Treatment may
5 Coma, reex posturing or GCS score 36, include mannitol, hyperventilation, and hemicrani-
accid with or without ectomy; moderate hypothermia may have a role as
motor decits well.
Diseases of the Nervous System
CHAPTER 28
abnormalities that follow the distribution of sympathetic
nerves rather than the major coronary arteries, with rel-
ative sparing of the ventricular wall apex. The sympa-
thetic nerves themselves appear to be injured by direct
toxicity from the excessive catecholamine release. An
asymptomatic troponin elevation is common. Serious
ventricular dysrhythmias are unusual.
undergo emergent ventriculostomy to measure ICP and ment with induced hypertension and hypervolemia
to treat high ICP in order to prevent cerebral ischemia. generally requires monitoring of arterial and central
Medical therapies designed to combat raised ICP (e.g., venous pressures; it is best to infuse pressors through
mild hyperventilation, mannitol, and sedation) can also a central venous line as well. Volume expansion helps
be used as needed. High ICP refractory to treatment is a prevent hypotension, augments cardiac output, and
poor prognostic sign. reduces blood viscosity by reducing the hematocrit.
Prior to definitive treatment of the ruptured aneu- This method is called triple-H (hypertension, hemodi-
Diseases of the Nervous System
rysm, care is required to maintain adequate cerebral lution, and hypervolemic) therapy.
perfusion pressure while avoiding excessive elevation If symptomatic vasospasm persists despite optimal
of arterial pressure. If the patient is alert, it is reasonable medical therapy, intraarterial vasodilators and percuta-
to lower the blood pressure to normal using nicardip- neous transluminal angioplasty are considered. Vasodi-
ine, labetolol, or esmolol. If the patient has a depressed latation by direct angioplasty appears to be permanent,
level of consciousness, ICP should be measured and the allowing triple-H therapy to be tapered sooner. The
cerebral perfusion pressure targeted to 6070 mmHg. pharmacologic vasodilators (verapamil and nicardipine)
If headache or neck pain is severe, mild sedation and do not last more than about 24 h, and therefore multi-
analgesia are prescribed. Extreme sedation is avoided ple treatments may be required until the subarachnoid
because it can obscure changes in neurologic status. blood is reabsorbed. Although intraarterial papaverine
Adequate hydration is necessary to avoid a decrease in is an effective vasodilator, there is evidence that papav-
blood volume predisposing to brain ischemia. erine may be neurotoxic, so its use should generally be
Seizures are uncommon at the onset of aneurysmal avoided.
rupture. The quivering, jerking, and extensor posturing Acute hydrocephalus can cause stupor or coma. It
that often accompany loss of consciousness with SAH may clear spontaneously or require temporary ventric-
are probably related to the sharp rise in ICP rather than ular drainage. When chronic hydrocephalus develops,
seizure. However, anticonvulsants are sometimes given ventricular shunting is the treatment of choice.
as prophylactic therapy since a seizure could theoreti- Free-water restriction is contraindicated in patients
cally promote rebleeding. with SAH at risk for vasospasm because hypovole-
Glucocorticoids may help reduce the head and neck mia and hypotension may occur and precipitate cere-
ache caused by the irritative effect of the subarach- bral ischemia. Many patients continue to experience a
noid blood. There is no good evidence that they reduce decline in serum sodium despite receiving parenteral
cerebral edema, are neuroprotective, or reduce vascu- fluids containing normal saline. Frequently, supplemen-
lar injury, and their routine use therefore is not recom- tal oral salt coupled with normal saline will mitigate
mended. hyponatremia, but often patients also require hyper-
Antifibrinolytic agents are not routinely prescribed tonic saline. Care must be taken not to correct serum
but may be considered in patients in whom aneurysm sodium too quickly in patients with marked hyponatre-
treatment cannot proceed immediately. They are associ- mia of several days duration, as central pontine myelin-
ated with a reduced incidence of aneurysmal rerupture olysis may occur.
but may also increase the risk of delayed cerebral infarc- All patients should have pneumatic compression
tion and deep-vein thrombosis (DVT). stockings applied to prevent pulmonary embolism.
Unfractionated heparin administered subcutaneously heparin is contraindicated in patients with ruptured and 309
for DVT prophylaxis can be initiated immediately fol- untreated aneurysms. It is a relative contraindication
lowing endovascular treatment and within days fol- following craniotomy for several days, and it may delay
lowing craniotomy and surgical clipping and is a useful thrombosis of a coiled aneurysm. Following craniotomy,
adjunct to pneumatic compression stockings. Treatment use of inferior vena cava filters is preferred to prevent
of pulmonary embolus depends on whether the aneu- further pulmonary emboli, while systemic anticoagula-
rysm has been treated and whether or not the patient tion with heparin is preferred following successful endo-
has had a craniotomy. Systemic anticoagulation with vascular treatment.
CHAPTER 28
Neurologic Critical Care
CHAPTER 29
Dementia, a syndrome with many causes, affects >4 proles; accordingly, accurate diagnosis guides effective
million Americans and results in a total health care cost pharmacotherapy.
of >$100 billion annually. It is dened as an acquired AD begins in the transentorhinal region, spreads to
deterioration in cognitive abilities that impairs the suc- the hippocampus, and then moves to lateral and poste-
cessful performance of activities of daily living. Mem- rior temporal and parietal neocortex, eventually caus-
ory is the most common cognitive ability lost with ing a more widespread degeneration. Vascular dementia is
dementia; 10% of persons >70 and 2040% of indi- associated with focal damage in a random patchwork of
viduals >85 have clinically identiable memory loss. cortical and subcortical regions or white matter tracts that
In addition to memory, other mental faculties may be disconnect nodes within distributed networks. In keeping
affected; these include language, visuospatial ability, with the anatomy, AD typically presents with memory
calculation, judgment, and problem solving. Neuropsy- loss accompanied later by aphasia or navigational prob-
chiatric and social decits also arise in many dementia lems. In contrast, patients with dementias that begin in
syndromes, resulting in depression, apathy, hallucina- frontal or subcortical regions such as frontotemporal demen-
tions, delusions, agitation, insomnia, and disinhibition. tia (FTD) or Huntingtons disease (HD) are less likely to
The most common forms of dementia are progressive, begin with memory problems and more likely to have
but some are static and unchanging or uctuate from difculties with judgment, mood, and behavior.
day to day or even minute to minute. Most patients Lesions of cortical-striatal pathways produce specic
with Alzheimers disease (AD), the most prevalent form effects on behavior. The dorsolateral prefrontal cortex
of dementia, begin with memory impairment, although bears connections with a central band of the caudate.
in other dementias, such as frontotemporal dementia, Lesions of either node or connecting white matter path-
memory loss is not a presenting feature. Focal cerebral ways result in poor organization and planning, decreased
disorders are discussed in Chap. 18 and illustrated in a cognitive exibility, and impaired working memory. The
video library in Chap. 19. lateral orbital frontal cortex connects with the ventrome-
dial caudate. Lesions of this system cause impulsiveness,
distractibility, and disinhibition. The anterior cingulate
cortex projects to the nucleus accumbens, and interrup-
tion of these connections produces apathy, poverty of
FUNCTIONAL ANATOMY OF THE speech, or even akinetic mutism. All corticostriatal sys-
DEMENTIAS tems also include topographically organized projections
Dementia syndromes result from the disruption of spe- through the pallidum and thalamus, and damage to these
cic large-scale neuronal networks; the location and nodes can likewise reproduce the clinical syndrome of
severity of synaptic and neuronal loss combine to pro- corticostriatal damage.
duce the clinical features (Chap. 18). Behavior and
mood are modulated by noradrenergic, serotonergic,
THE CAUSES OF DEMENTIA
and dopaminergic pathways, whereas cholinergic signal-
ing is critical for attention and memory functions. The The single strongest risk factor for dementia is increasing
dementias differ in the relative neurotransmitter decit age. The prevalence of disabling memory loss increases
310
with each decade over age 50 and is usually associated TABLE 29-1 311
with the microscopic changes of AD at autopsy. Yet DIFFERENTIAL DIAGNOSIS OF DEMENTIA
some centenarians have intact memory function and no
Most Common Causes of Dementia
evidence of clinically signicant dementia. Whether
dementia is an inevitable consequence of normal human Alzheimers disease Alcoholisma
aging remains controversial. Vascular dementia Parkinsons disease
The many causes of dementia are listed in Table 29-1. Multi-infarct Drug/medication intoxicationa
Diffuse white matter
The frequency of each condition depends on the age disease (Binswangers)
group under study, the access of the group to medical
care, the country of origin, and perhaps racial or ethnic Less Common Causes of Dementia
background. AD is the most common cause of demen-
tia in Western countries, accounting for more than half Vitamin deciencies Toxic disorders
Thiamine (B1): Wernickes Drug, medication, and nar-
of all patients. Vascular disease is considered the second encephalopathya cotic poisoninga
most frequent cause for dementia and is particularly com- B12 (subacute combined Heavy metal intoxicationa
mon in elderly patients or populations with limited access degeneration)a Dialysis dementia (aluminum)
to medical care, where vascular risk factors are under- Nicotinic acid (pellagra)a Organic toxins
treated. Often, vascular disease is mixed with other neu- Endocrine and other organ Psychiatric
CHAPTER 29
failure Depression (pseudodementia)a
rodegenerative disorders, making it difcult, even for the Hypothyroidisma Schizophreniaa
neuropathologist, to estimate the contribution of cere- Adrenal insufciency and Conversion reactiona
brovascular disease to the cognitive disorder in an indi- Cushings syndromea Degenerative disorders
vidual patient. Dementias related to Parkinsons disease Hypo- and hyperparathy- Huntingtons disease
roidisma Dementia with Lewy bodies
(PD) are extremely common, and temporally can follow Renal failurea Progressive supranuclear
a parkinsonian disorder as seen with PD-related demen- Liver failurea palsy
carry these dominant mutations) gosity for methionine form changes, gliosis
or valine
Abbreviations: AD, Alzheimers disease; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia.
Diseases of the Nervous System
MCI to AD include a prominent memory decit, fam- HISTORY The history should concentrate on the
ily history of dementia, presence of an apolipoprotein 4 onset, duration, and tempo of progression. An acute or
(Apo 4) allele, small hippocampal volumes, and AD-like subacute onset of confusion may represent delirium and
signature of cortical atrophy, low cerebrospinal uid A should trigger the search for intoxication, infection, or
and elevated tau or positive amyloid imaging with Pitts- metabolic derangement. An elderly person with slowly
burgh Compound-B (PiB), although the latter remains progressive memory loss over several years is likely to suf-
an experimental approach not yet available for routine fer from AD. Nearly 75% of patients with AD begin with
clinical use. memory symptoms, but other early symptoms include
The major degenerative dementias include AD, DLB, difficulty with managing money, driving, shopping, fol-
FTD and related disorders, HD, and prion diseases, includ- lowing instructions, finding words, or navigating. A per-
ing Creutzfeldt-Jakob disease (CJD). These disorders are all sonality change, disinhibition, and weight gain or com-
associated with the abnormal aggregation of a specic pro- pulsive eating suggest FTD, not AD. FTD is also suggested
tein: A42 and tau in AD; -synuclein in DLB; tau, TAR by prominent apathy, compulsivity, or progressive loss of
DNA-binding protein of 43kDa (TDP-43), or fused in speech fluency or word comprehension, and by a relative
sarcoma (FUS) in FTD; huntingtin in HD; and misfolded sparing of memory or visuospatial abilities. The diagnosis
prion protein (PrPsc) in CJD (Table 29-2). of DLB is suggested by early visual hallucinations; par-
kinsonism; brittle proneness to delirium or sensitivity to
psychoactive medications; REM behavior disorder (RBD,
the loss of skeletal muscle paralysis during dreaming); or
APPROACH TO THE
Dementias Capgras syndrome, the delusion that a familiar person
PATIENT
has been replaced by an impostor.
Three major issues should be kept at the forefront: (1) A history of stroke with irregular stepwise progres-
What is the most accurate diagnosis? (2) Is there a treat- sion suggests vascular dementia. Vascular dementia
able or reversible component to the dementia? (3) Can is also commonly seen in the setting of hypertension,
the physician help to alleviate the burden on caregivers? atrial fibrillation, peripheral vascular disease, and diabe-
A broad overview of the approach to dementia is shown tes. In patients suffering from cerebrovascular disease,
in Table 29-3. The major degenerative dementias can it can be difficult to determine whether the dementia is
usually be distinguished by the initial symptoms; neuro- due to AD, vascular disease, or a mixture of the two as
psychological, neuropsychiatric, and neurologic findings; many of the risk factors for vascular dementia, includ-
and neuroimaging features (Table 29-4). ing diabetes, high cholesterol, elevated homocysteine,
TABLE 29-3 313
EVALUATION OF THE PATIENT WITH DEMENTIA
ROUTINE EVALUATION OPTIONAL FOCUSED TESTS OCCASIONALLY HELPFUL TESTS
CHAPTER 29
REVERSIBLE CAUSES IRREVERSIBLE/DEGENERATIVE DEMENTIAS PSYCHIATRIC DISORDERS
Abbreviations: PET, positron emission tomography; RPR, rapid plasma reagin (test); SPECT, single-photon emission CT; VDRL, Venereal
Disease Research Laboratory (test for syphilis).
and low exercise, are also risk factors for AD. Rapid pro- irradiation, an autoimmune diathesis, or a remote his-
gression with motor rigidity and myoclonus suggests tory of gastric surgery can result in B12 deficiency. Certain
CJD. Seizures may indicate strokes or neoplasm but also occupations, such as working in a battery or chemical
occur in AD, particularly early age of onset AD. Gait dis- factory, might indicate heavy metal intoxication. Careful
turbance is common in vascular dementia, PD/DLB, or review of medication intake, especially for sedatives and
normal-pressure hydrocephalus (NPH). A prior history of analgesics, may raise the issue of chronic drug intoxica-
high-risk sexual behaviors or intravenous drug use should tion. An autosomal dominant family history is found in
trigger a search for central nervous system (CNS) infec- HD and in familial forms of AD, FTD, DLB, or prion disor-
tion, especially for HIV or syphilis. A history of recurrent ders. The recent death of a loved one, or depressive signs
head trauma could indicate chronic subdural hematoma, such as insomnia or weight loss, raises the possibility of
dementia pugilistica, or NPH. Subacute onset of severe depression-related cognitive impairments.
amnesia and psychosis with mesial temporal T2 hyperin-
tensities on MRI should raise concern for paraneoplastic PHYSICAL AND NEUROLOGIC EXAMINA-
limbic encephalitis, especially in a long-term smoker or TION A thorough general and neurologic examination
other patients at risk for cancer. Related nonparaneo- is essential to document dementia, to look for other signs
plastic autoimmune conditions can present with a similar of nervous system involvement, and to search for clues
tempo and imaging signature. Alcoholism creates risk for suggesting a systemic disease that might be responsi-
malnutrition and thiamine deficiency. Veganism, bowel ble for the cognitive disorder. Typical AD does not affect
314 TABLE 29-4
CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS
DISEASE FIRST SYMPTOM MENTAL STATUS NEUROPSYCHIATRY NEUROLOGY IMAGING
AD Memory loss Episodic memory Initially normal Initially normal Entorhinal cortex
loss and hippocampal
atrophy
FTD Apathy; poor judgment/ Frontal/executive, Apathy, disinhibi- May have vertical Frontal, insular,
insight, speech/lan- language; spares tion, hyperorality, gaze palsy, axial and/or temporal
guage; hyperorality drawing euphoria, depres- rigidity, dystonia, atrophy; spares
sion alien hand, or MND posterior parietal
lobe
DLB Visual hallucinations, Drawing and fron- Visual hallucina- Parkinsonism Posterior parietal
REM sleep disorder, tal/executive; tions, depression, atrophy; hippo-
delirium, Capgras syn- spares memory; sleep disorder, campi larger than
drome, parkinsonism delirium prone delusions in AD
CJD Dementia, mood, anxi- Variable, frontal/ Depression, anxiety Myoclonus, rigidity, Cortical ribboning
SECTION III
Abbreviations: AD, Alzheimers disease; CBD, cortical basal degeneration; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies;
FTD, frontotemporal dementia; MND, motor neuron disease; PSP, progressive supranuclear palsy.
motor systems until later in the course. In contrast, FTD thyroid dysfunction, Lyme disease, or vasculitis. Dry, cool
patients often develop axial rigidity, supranuclear gaze skin, hair loss, and bradycardia suggest hypothyroidism.
palsy, or a motor neuron disease reminiscent of amyo- Fluctuating confusion associated with repetitive stereo-
trophic lateral sclerosis (ALS). In DLB, the initial symptoms typed movements may indicate ongoing limbic, tem-
may include the new onset of a parkinsonian syndrome poral, or frontal seizures. Hearing impairment or visual
(resting tremor, cogwheel rigidity, bradykinesia, festi- loss may produce confusion and disorientation misinter-
nating gait) but often starts with visual hallucinations or preted as dementia. Such sensory deficits are common in
dementia. Symptoms referable to the lower brainstem the elderly but can be a manifestation of mitochondrial
(RBD, gastrointestinal or autonomic problems) may arise disorders.
years before parkinsonism or dementia. Corticobasal syn-
drome (CBS) features asymmetric akinesia and rigidity, COGNITIVE AND NEUROPSYCHIATRIC EXA-
dystonia, myoclonus, alien limb phenomena, and pyra- MINATION Brief screening tools such as the mini-
midal or cortical sensory deficits. Associated cognitive mental status examination (MMSE) help to confirm the
features include nonfluent aphasia with or without motor presence of cognitive impairment and to follow the pro-
speech impairment, executive dysfunction, apraxia, or a gression of dementia (Table 29-5). The MMSE, a simple
behavioral disorder. Progressive supranuclear palsy (PSP) 30-point test of cognitive function, contains tests of ori-
is associated with unexplained falls, axial rigidity, dyspha- entation, working memory (e.g., spell world backwards),
gia, and vertical gaze deficits. CJD is suggested by the episodic memory (orientation and 3-word recall), lan-
presence of diffuse rigidity, an akinetic-mute state, and guage comprehension, naming, and figure copying. In
prominent, often startle-sensitive myoclonus. most patients with MCI and some with clinically apparent
Hemiparesis or other focal neurologic deficits sug- AD, the MMSE may be normal and a more rigorous set
gest vascular dementia or brain tumor. Dementia with a of neuropsychological tests will be required. When the
myelopathy and peripheral neuropathy suggests vitamin etiology for the dementia syndrome remains in doubt,
B12 deficiency. Peripheral neuropathy could also indicate a specially tailored evaluation should be performed
another vitamin deficiency, heavy metal intoxication, that includes tasks of working and episodic memory,
TABLE 29-5 315
A functional assessment should also be performed.
THE MINI-MENTAL STATUS EXAMINATION The physician should determine the day-to-day impact of
POINTS the disorder on the patients memory, community affairs,
hobbies, judgment, dressing, and eating. Knowledge of
Orientation
the patients day-to-day function will help the clinician
Name: season/date/day/month/ 5 (1 for each name) and the family to organize a therapeutic approach.
year Neuropsychiatric assessment is important for diag-
Name: hospital/oor/town/state/ 5 (1 for each name) nosis, prognosis, and treatment. In the early stages of
country AD, mild depressive features, social withdrawal, and irri-
Registration tability or anxiety are the most prominent psychiatric
Identify three objects by name 3 (1 for each object) changes, but patients often maintain core social skills into
and ask patient to repeat the middle or late stages, when delusions, agitation, and
Attention and calculation sleep disturbance may emerge. In FTD, dramatic person-
ality change featuring apathy, overeating, compulsions,
Serial 7s; subtract from 100 5 (1 for each subtrac-
(e.g., 9386797265) tion) disinhibition, euphoria, and loss of empathy are early
and common. DLB is associated with visual hallucina-
Recall
CHAPTER 29
tions, delusions related to person or place identity, RBD,
Recall the three objects pre- 3 (1 for each object) and excessive daytime sleepiness. Dramatic fluctuations
sented earlier
occur not only in cognition but also in primary arousal,
Language such that caregivers may seek emergency room evalua-
Name pencil and watch 2 (1 for each object) tion for suspected stroke. Vascular dementia can present
Repeat No ifs, ands, or buts 1 with psychiatric symptoms such as depression, anxiety,
delusions, disinhibition, or apathy.
before irreversible brain injury has occurred. In the mean- cause is AD. It is estimated that the annual total cost of
time, however, the significance of detecting brain amy- caring for a single AD patient in an advanced stage of
loid in an asymptomatic elder remains a topic of vigorous the disease is >$50,000. The disease also exacts a heavy
investigation. Similarly, MRI perfusion and functional con- emotional toll on family members and caregivers. AD
nectivity methods are being explored as potential treat- can occur in any decade of adulthood, but it is the most
ment-monitoring strategies. common cause of dementia in the elderly. AD most
Diseases of the Nervous System
Lumbar puncture need not be done routinely in the often presents with an insidious onset of memory loss
evaluation of dementia, but it is indicated when CNS followed by a slowly progressive dementia over several
infection or inflammation are credible diagnostic possi- years. Pathologically, atrophy is distributed throughout
bilities. Cerebrospinal fluid (CSF) levels of tau protein and the medial temporal lobes, as well as lateral and medial
A42 show differing patterns with the various dementias; parietal lobes and lateral frontal cortex. Microscopically,
however, the sensitivity and specificity of these mea- there are neuritic plaques containing A, neurobrillary
sures are not yet sufficiently high to warrant routine use. tangles (NFTs) composed of hyperphosphorylated tau
Formal psychometric testing, although not necessary laments, and accumulation of amyloid in blood vessel
in every patient with dementia, helps to document the walls in cortex and leptomeninges (see Pathology).
severity of cognitive disturbance, suggest psychogenic The identication of four different susceptibility genes
causes, and provide a more formal method for follow- for AD has provided a foundation for rapid progress in
ing the disease course. Electroencephalogram (EEG) is understanding the biologic basis of the disorder.
rarely helpful except to suggest CJD (repetitive bursts of
FIGURE 29-1
PET images obtained with the amyloid-imaging agent have control-like levels of amyloid, some have AD-like levels
Pittsburgh Compound-B ([11C]PIB) in a normal control (left); of amyloid, and some have intermediate levels. AD, Alzheim-
three different patients with mild cognitive impairment (MCI, ers disease; MCI, mild cognitive impairment; PET, positron
center); and a mild AD patient (right). Some MCI patients emission tomography.
CLINICAL MANIFESTATIONS dressing, and toileting. Hyperactive tendon reexes and 317
myoclonic jerks (sudden brief contractions of various
The cognitive changes of AD tend to follow a charac- muscles or the whole body) may occur spontaneously or
teristic pattern, beginning with memory impairment in response to physical or auditory stimulation. Gener-
and spreading to language and visuospatial decits. Yet, alized seizures may also occur. Often death results from
approximately 20% of patients with AD present with malnutrition, secondary infections, pulmonary emboli,
nonmemory complaints such as word-nding, organi- heart disease, or, most commonly, aspiration. The typical
zational, or navigational difculty. In the early stages of duration of AD is 810 years, but the course can range
the disease, the memory loss may go unrecognized or be from 1 to 25 years. For unknown reasons, some AD
ascribed to benign forgetfulness. Once the memory loss patients show a steady decline in function, while others
becomes noticeable to the patient and spouse and falls have prolonged plateaus without major deterioration.
1.5 standard deviations below normal on standardized
memory tests, the term MCI is applied. This construct
provides useful prognostic information, because approxi-
mately 50% of patients with MCI (roughly 12% per year)
DIFFERENTIAL DIAGNOSIS
will progress to AD over 4 years. Slowly the cognitive Early in the disease course, other etiologies of dementia
problems begin to interfere with daily activities, such as should be excluded (Table 29-1). Neuroimaging studies
CHAPTER 29
keeping track of nances, following instructions on the (CT and MRI) do not show a single specic pattern with
job, driving, shopping, and housekeeping. Some patients AD and may be normal early in the course of the disease.
are unaware of these difculties (anosognosia), while oth- As AD progresses, more distributed but usually posterior-
ers remain acutely attuned to their decits. Changes in predominant cortical atrophy becomes apparent, along
environment (such as vacations or hospital stays) may be with atrophy of the medial temporal memory structures
disorienting, and the patient may become lost on walks (Fig. 29-2A, B). The main purpose of imaging is to
or while driving. In the middle stages of AD, the patient exclude other disorders, such as primary and second-
EPIDEMIOLOGY
The most important risk factors for AD are old age and
a positive family history. The frequency of AD increases
with each decade of adult life, reaching 2040% of the
population over the age of 85. A positive family history of
dementia suggests a genetic cause of AD, although auto-
somal dominant inheritance occurs in only 2% of patients
with AD. Female sex may also be a risk factor indepen-
dent of the greater longevity of women. Some AD patients
have a past history of head trauma with concussion. AD is
more common in groups with low educational attainment,
but education inuences test-taking ability, and it is clear
SECTION III
A42 A40 P3
Toxic Nontoxic Nontoxic
Amyloidogenic
FIGURE 29-4
Amyloid precursor protein (APP) is catabolized by , ,
FIGURE 29-3 and secretases. A key initial step is the digestion by either
CHAPTER 29
Mature neuritic plaque with a dense central amyloid core secretase (BASE) or secretase (ADAM10 or ADAM17
surrounded by dystrophic neurites (thioavin S stain). (Image [TACE]), producing smaller nontoxic products. Cleavage
courtesy of S. DeArmond, University of California; with per- of the secretase product by secretase (Step 2) results
mission.) in either the toxic A42 or the nontoxic A40 peptide; cleav-
age of the secretase product by secretase produces the
is cleaved by and secretases. The normal function of nontoxic P3 peptide. Excess production of A42 is a key ini-
A is unknown. APP has neurotrophic and neuroprotec- tiator of cellular damage in Alzheimers disease. Current AD
rare syndrome. Mutations in PS-1 tend to produce AD search for reversible causes of their cognitive impairment.
with an earlier age of onset (mean onset 45 years) and a Nevertheless, Apo 4 remains the single most important
shorter, more rapidly progressive course (mean duration biologic marker associated with AD risk, and studies of
67 years) than the disease caused by mutations in PS- 4s functional role and diagnostic utility are progressing
2 (mean onset 53 years; duration 11 years). Although rapidly. The 4 allele is not associated with risk for FTD,
some carriers of uncommon PS-2 mutations have had DLB, or CJD, although some evidence suggests that 4
Diseases of the Nervous System
onset of dementia after the age of 70, mutations in the may exacerbate the phenotype of non-AD degenerative
presenilins are rarely involved in the more common disorders. Additional genes are also likely to be involved
sporadic cases of late-onset AD occurring in the gen- in AD, especially as minor risk alleles for sporadic forms of
eral population. Genetic testing for these uncommon the disease. Recent genome-wide association studies have
mutations is now commercially available. This diagnos- implicated the clusterin (CLU), phosphatidylinositol-bind-
tic avenue is likely to be revealing only in early-age-of- ing clathrin assembly protein (PICALM), and complement
onset familial AD and should be performed in the con- component (3b/4b) receptor 1 (CR1) genes, and research-
text of formal genetic counseling, especially when there ers are now working to understand the potential role of
are asymptomatic persons at risk. these genes in AD pathogenesis. CLU may play a role in
A discovery of great importance has been that the Apo synapse turnover, PICALM participates in clathrin-medi-
gene on chromosome 19 is involved in the pathogen- ated endocytosis, and CR1 may be involved in amyloid
esis of late-onset familial and sporadic forms of AD. Apo clearance through the complement pathway.
participates in cholesterol transport and has three alleles:
2, 3, and 4. The Apo 4 allele confers increased risk of
AD in the general population, including sporadic and late-
age-of-onset familial forms. Approximately 2430% of the TREATMENT Alzheimers Disease
nondemented white population has at least one 4 allele
(1215% allele frequency), and about 2% are 4/4 homo- The management of AD is challenging and gratifying,
zygotes. Among patients with AD, 4065% have at least despite the absence of a cure or a robust pharmacologic
one 4 allele, a highly signicant difference compared with treatment. The primary focus is on long-term ameliora-
controls. Conversely, many AD patients have no 4 allele, tion of associated behavioral and neurologic problems, as
and 4 carriers may never develop AD. Therefore, 4 is well as providing caregiver support.
neither necessary nor sufcient to cause AD. Neverthe- Building rapport with the patient, family members,
less, the Apo 4 allele, especially in the homozygous state, and other caregivers is essential to successful manage-
represents the most important genetic risk factor for AD ment. In the early stages of AD, memory aids such as
and acts as a dose-dependent disease modier, with the notebooks and posted daily reminders can be helpful.
earliest age of onset associated with the 4 homozygosity. Family members should emphasize activities that are
Precise mechanisms through which Apo 4 confers AD pleasant and curtail those that are unpleasant. In other
risk or hastens onset remain unclear, but 4 may produce words, practicing skills that have become difficult, such
less efcient amyloid clearance. Apo can be identied in as through memory games and puzzles, will often frus-
neuritic plaques and may also be involved in neurobril- trate and depress the patient without proven benefits.
lary tangle formation, because it binds to tau protein. Apo
Kitchens, bathrooms, stairways, and bedrooms need to markedly dampened enthusiasm for hormonal treat- 321
be made safe, and eventually patients must stop driving. ments to prevent dementia. Additionally, no benefit has
Loss of independence and change of environment may been found in the treatment of AD with estrogen alone.
worsen confusion, agitation, and anger. Communication A randomized, double-blind, placebo-controlled trial
and repeated calm reassurance are necessary. Caregiver of an extract of Ginkgo biloba found modest improve-
burnout is common, often resulting in nursing home ment in cognitive function in subjects with AD and vascu-
placement of the patient or new health problems for lar dementia. Unfortunately, a comprehensive 6-year mul-
the caregiver, and respite breaks for the caregiver help ticenter prevention study using Ginkgo biloba found no
to maintain a successful long-term therapeutic milieu. slowing of progression to dementia in the treated group.
Use of adult day care centers can be helpful. Local and Vaccination against A42 has proved highly effica-
national support groups, such as the Alzheimers Asso- cious in mouse models of AD, helping clear brain amyloid
ciation and the Family Caregiver Alliance, are valuable and preventing further amyloid accumulation. In human
resources. Internet access to these resources has become trials, this approach led to life-threatening complica-
available to clinicians and families in recent years. tions, including meningoencephalitis, but modifications
Donepezil (target dose, 10 mg daily), rivastigmine of the vaccine approach using passive immunization
(target dose, 6 mg twice daily or 9.5-mg patch daily), with monoclonal antibodies are currently being evalu-
CHAPTER 29
galantamine (target dose 24 mg daily, extended-release), ated in phase 3 trials. Another experimental approach
memantine (target dose, 10 mg twice daily), and tacrine to AD treatment has been the use of and secretase
are the drugs presently approved by the Food and Drug inhibitors that diminish the production of A42, but the
Administration (FDA) for treatment of AD. Due to hepa- first two placebo-controlled trials of secretase inhibi-
totoxicity, tacrine is no longer used. Dose escalations for tors, tarenflurbil and semagacestat, were negative, and
each of these medications must be carried out over 46 semagacestat may have accelerated cognitive decline
weeks to minimize side effects. The pharmacologic action compared to placebo. Medications that modify tau phos-
VASCULAR DEMENTIA
Dementia associated with cerebrovascular disease can be
divided into two general categories: multi-infarct demen-
SECTION III
FIGURE 29-5
called multi-infarct dementia. The strokes may be large or
Diffuse white matter disease. Axial uid-attenuated inver-
small (sometimes lacunar) and usually involve several dif-
sion recovery (FLAIR) MR image through the lateral ventricles
ferent brain regions. The occurrence of dementia depends reveals multiple areas of hyperintensity involving the peri-
partly on the total volume of damaged cortex, but it is ventricular white matter as well as the corona radiata and
also more common in individuals with left-hemisphere striatum (arrows). While seen in some individuals with normal
lesions, independent of any language disturbance. Patients cognition, this appearance is more pronounced in patients
typically report previous discrete episodes of sudden neu- with dementia of a vascular etiology.
rologic deterioration. Many patients with multi-infarct
dementia have a history of hypertension, diabetes, coro- of multi-infarct dementia. Early symptoms are mild con-
nary artery disease, or other manifestations of widespread fusion, apathy, anxiety, psychosis, and memory, spatial,
atherosclerosis. Physical examination usually shows focal or executive decits. Marked difculties in judgment and
neurologic decits such as hemiparesis, a unilateral Babin- orientation and dependence on others for daily activities
ski sign, a visual eld defect, or pseudobulbar palsy. Recur- develop later. Euphoria, elation, depression, or aggres-
rent strokes result in a stepwise disease progression. Neu- sive behaviors are common as the disease progresses. Both
roimaging reveals multiple areas of infarction. Thus, the pyramidal and cerebellar signs may be present. A gait
history and neuroimaging ndings differentiate this condi- disorder is present in at least half of these patients. With
tion from AD; however, both AD and multiple infarctions advanced disease, urinary incontinence and dysarthria with
are common and sometimes co-occur. With normal aging, or without other pseudobulbar features (e.g., dysphagia,
there is also an accumulation of amyloid in cerebral blood emotional lability) are frequent. Seizures and myoclonic
vessels, leading to a condition called cerebral amyloid angiopa- jerks appear in a minority of patients. This disorder appears
thy (without dementia), which predisposes older persons to result from chronic ischemia due to occlusive disease of
to lobar hemorrhage and brain microhemorrhages. AD small, penetrating cerebral arteries and arterioles (micro-
patients appear to be at increased risk for amyloid angiopa- angiopathy). Any disease-causing stenosis of small cere-
thy, and this may explain some of the observed association bral vessels may be the critical underlying factor, although
between AD and stroke. hypertension is the major cause. The term Binswangers
Some individuals with dementia are discovered on disease should be used with caution, because it does not
MRI to have bilateral abnormalities of subcortical white clearly identify a single entity.
matter, termed diffuse white matter disease, often occurring Other rare causes of white matter disease also pres-
in association with lacunar infarctions (Fig. 29-5). The ent with dementia, such as adult metachromatic leuko-
dementia may be insidious in onset and progress slowly, dystrophy (arylsulfatase A deciency) and progressive
features that distinguish it from multi-infarct dementia, but multifocal leukoencephalopathy (JC virus infection).
other patients show a stepwise deterioration more typical A dominantly inherited form of diffuse white matter
disease is known as cerebral autosomal dominant arteriopathy tumor necrosis factor (TNF) receptors. How progranu- 323
with subcortical infarcts and leukoencephalopathy (CADA- lin mutations lead to FTD is unknown. Both MAPT and
SIL). Clinically, there is a progressive dementia devel- GRN mutations are associated with parkinsonian fea-
oping in the fth to seventh decades in multiple fam- tures, while ALS is rare with these mutations. In contrast,
ily members who may also have a history of migraine familial FTD with ALS has been linked to chromosome
and recurrent lacunar stroke without hypertension. Skin 9. Mutations in the valosin-containing protein (chro-
biopsy may show pathognomonic osmophilic gran- mosome 9) and the charged multivesicular body protein
ules in the media of arterioles. The disease is caused by 2b (CHMP2b) genes (chromosome 3) also lead to rare
mutations in the Notch 3 gene, and genetic testing is autosomal dominant forms of familial FTD. Mutations
commercially available. The frequency of this disorder is in the TDP-43 and FUS genes (see later) cause familial
unknown, and there are no effective treatments. ALS, sometimes in association with an FTD syndrome,
Mitochondrial disorders can present with stroke-like although a few patients presenting with FTD alone have
episodes and can selectively injure basal ganglia or cortex. been reported.
Many such patients show other ndings suggestive of a In FTD, early symptoms are divided among behavioral,
neurologic or systemic disorder such as ophthalmoplegia, language, and sometimes motor abnormalities, reecting
retinal degeneration, deafness, myopathy, neuropathy, or degeneration of the anterior insular, frontal, and temporal
diabetes. Diagnosis is difcult, but serum or (especially) regions, basal ganglia, and motor neurons. Cognitive test-
CHAPTER 29
CSF levels of lactate and pyruvate may be abnormal, ing typically reveals spared memory but impaired planning,
and biopsy of affected tissue, preferably muscle, may be judgment, or language. Poor business decisions and dif-
diagnostic. culty organizing work tasks are common, and speech and
Treatment of vascular dementia must be focused on language decits often emerge. Patients with FTD often
preventing new ischemic injury by stabilizing or remov- show an absence of insight into their condition. Common
ing the underlying causes, such as hypertension, diabetes, behavioral features include apathy, disinhibition, weight
FIGURE 29-6
Frontotemporal dementia (FTD). Coronal MRI sections
FTLD-tau FTLD-TDP FTLD-FUS
from representative patients with behavioral variant FTD
(left), semantic dementia (center), and progressive nonu-
ent aphasia (right). Areas of early and severe atrophy in each Picks CBD PSP
Type 1 Type 2 aFTLD-U NIFID
3R tau 4R tau 4R tau
syndrome are highlighted (white arrowheads). The behavioral
FTDP-17 Tau NOS Type 3 Type 4
variant features anterior cingulate and frontoinsular atro- (MAPT ) 3R/4R tau (PGRN ) (VCP )
BIBD
phy, spreading to orbital and dorsolateral prefrontal cortex.
Semantic dementia shows prominent temporopolar atro- FIGURE 29-8
phy, more often on the left. Progressive nonuent aphasia is
SECTION III
CHAPTER 29
tively for hyperphosphorylated tau. Classical Picks disease is In addition to its overlap with FTD and CBD (see
seen in only 1020% of patients with frontotemporal dementia. later), PSP is often confused with idiopathic Parkinsons
Scale bar represents 50 microns. (CP-13 antibody courtesy of P. disease (PD). Although elderly patients with PD may have
Davies.) restricted upgaze, they do not develop downgaze pare-
of the behaviors that accompany FTD, such as depres- sis or other abnormalities of voluntary eye movements
sion, hyperorality, compulsions, and irritability, can be typical of PSP. Dementia occurs in 20% of patients
nitive impairment, who slowly develop a dementia that cant benet, reducing hallucinosis, stabilizing delusional
is associated with visual hallucinations and uctuating symptoms, and even helping with RBD in some patients.
alertness. When this occurs after an established diagno- Exercise programs maximize motor function and protect
sis of PD, many use the term Parkinsons disease demen- against fall-related injury. Antidepressants are often nec-
tia (PDD). In others, the dementia and neuropsychiatric essary. Atypical antipsychotics may be required for psy-
syndrome precede the parkinsonism, and this constel- chosis but can worsen extrapyramidal syndromes, even
lation is referred to as DLB. Both PDD and DLB may
Diseases of the Nervous System
CHAPTER 29
dementias, particularly AD, vascular dementia, DLB, and Numerous attempts to improve NPH diagnosis with
PSP. For NPH, the clinical triad includes an abnormal various special studies and predict the success of ventricu-
gait (ataxic or apractic), dementia (usually mild to mod- lar shunting have been undertaken. These tests include
erate, with an emphasis on executive impairment), and radionuclide cisternography (showing a delay in CSF
urinary urgency or incontinence. Neuroimaging reveals absorption over the convexity) and various efforts to
enlarged lateral ventricles (hydrocephalus) with little or monitor and alter CSF ow dynamics, including a con-
FIGURE 29-10
Normal-pressure hydrocephalus. A. Sagittal T1-weighted dilation of the lateral, third, and fourth ventricles with a pat-
MR image demonstrates dilation of the lateral ventricle and ent aqueduct, typical of communicating hydrocephalus. B.
stretching of the corpus callosum (arrows), depression of the Axial T2-weighted MR images demonstrate dilation of the
oor of the third ventricle (single arrowhead), and enlarge- lateral ventricles. This patient underwent successful ventricu-
ment of the aqueduct (double arrowheads). Note the diffuse loperitoneal shunting.
328 during, and after lumbar CSF drainage. Occasionally, There is no specic treatment because the previous thia-
when a patient with AD presents with gait impairment mine deciency has produced irreversible damage to the
(at times due to comorbid subfrontal vascular injury) and medial thalamic nuclei and mammillary bodies. Mammil-
absent or only mild cortical atrophy on CT or MRI, dis- lary body atrophy may be visible on MRI in the chronic
tinguishing NPH from AD can be challenging. Hippo- phase (Fig. 28-7).
campal atrophy on MRI favors AD, whereas a character- Vitamin B12 deciency, as can occur in pernicious ane-
istic magnetic gait with external hip rotation, low foot mia, causes a megaloblastic anemia and may also damage
clearance and short strides, along with prominent truncal the nervous system (Chap. 35). Neurologically, it most
sway or instability, favors NPH. The diagnosis of NPH commonly produces a spinal cord syndrome (myelopa-
should be avoided when hydrocephalus is not detected thy) affecting the posterior columns (loss of vibration
on imaging studies, even if the symptoms otherwise t. and position sense) and corticospinal tracts (hyperac-
Thirty to fty percent of patients identied by careful tive tendon reexes with Babinski signs); it also damages
diagnosis as having NPH will improve with ventricular peripheral nerves (neuropathy), resulting in sensory loss
shunting. Gait may improve more than cognition, but with depressed tendon reexes. Damage to myelinated
many reported failures to improve cognitively may have axons may also cause dementia. The mechanism of neu-
resulted from comorbid AD. Short-lasting improve- rologic damage is unclear but may be related to a de-
ment is common. Patients should be carefully selected ciency of S-adenosyl methionine (required for methyla-
SECTION III
for shunting, because subdural hematoma, infection, and tion of myelin phospholipids) due to reduced methionine
shunt failure are known complications and can be a cause synthase activity or accumulation of methylmalonate,
for early nursing home placement in an elderly patient homocysteine, and propionate, providing abnormal sub-
with previously mild dementia. strates for fatty acid synthesis in myelin. The neurologic
Dementia can accompany chronic alcoholism (Chap. 56) sequelae of vitamin B12 deciency may occur in the
and may result from associated malnutrition, especially of absence of hematologic manifestations, making it criti-
Diseases of the Nervous System
B vitamins, particularly thiamine. Other poorly dened cal to avoid using the CBC and blood smear as a substi-
aspects of chronic alcoholism may, however, also pro- tute for measuring B12 blood levels. Treatment with par-
duce cerebral damage. A rare idiopathic syndrome of enteral vitamin B12 (1000 g intramuscularly daily for a
dementia and seizures with degeneration of the corpus week, weekly for a month, and monthly for life for per-
callosum has been reported primarily in male Italian red nicious anemia) stops progression of the disease if insti-
wine drinkers (Marchiafava-Bignami disease). tuted promptly, but complete reversal of advanced ner-
Thiamine (vitamin B1) deciency causes Wernickes vous system damage will not occur.
encephalopathy (Chap. 28). The clinical presentation Deciency of nicotinic acid (pellagra) is associated
features a malnourished patient (frequently but not nec- with skin rash over sun-exposed areas, glossitis, and
essarily alcoholic) with confusion, ataxia, and diplopia angular stomatitis. Severe dietary deciency of nico-
resulting from inammation and necrosis of periventric- tinic acid along with other B vitamins such as pyridox-
ular midline structures, including dorsomedial thalamus, ine may result in spastic paraparesis, peripheral neuropa-
mammillary bodies, midline cerebellum, periaqueductal thy, fatigue, irritability, and dementia. This syndrome has
gray matter, and trochlear and abducens nuclei. Dam- been seen in prisoners of war and in concentration camps
age to the dorsomedial thalamus correlates most closely but should be considered in any malnourished individual.
with the memory loss. Prompt administration of paren- Low serum folate levels appear to be a rough index of
teral thiamine (100 mg intravenously for 3 days followed malnutrition, but isolated folate deciency has not been
by daily oral dosage) may reverse the disease if given in proved as a specic cause of dementia.
the rst days of symptom onset. However, prolonged CNS infections usually cause delirium and other acute
untreated thiamine deciency can result in an irreversible neurologic syndromes. However, some chronic CNS
dementia/amnestic syndrome (Korsakoffs syndrome) or infections, particularly those associated with chronic
even death. meningitis (Chap. 41), may produce a dementing illness.
In Korsakoffs syndrome, the patient is unable to recall The possibility of chronic infectious meningitis should
new information despite normal immediate memory, be suspected in patients presenting with a dementia or
attention span, and level of consciousness. Memory for behavioral syndrome, who also have headache, meningis-
new events is seriously impaired, whereas knowledge mus, cranial neuropathy, and/or radiculopathy. Between
acquired prior to the illness remains relatively intact. 20 and 30% of patients in the advanced stages of HIV
Patients are easily confused, disoriented, and cannot infection become demented (Chap. 42). Cardinal features
store information for more than a few minutes. Super- include psychomotor retardation, apathy, and impaired
cially, they may be conversant, engaging, and able to memory. This syndrome may result from secondary
perform simple tasks and follow immediate commands. opportunistic infections but can also be caused by direct
Confabulation is common, although not always present. infection of CNS neurons with HIV. Neurosyphilis was
a common cause of dementia in the preantibiotic era; it is at work or home. Chronic lead poisoning from inad- 329
now uncommon but can still be encountered in patients equately re-glazed pottery has been reported. Fatigue,
with multiple sex partners, particularly among patients depression, and confusion may be associated with epi-
with HIV. Characteristic CSF changes consist of pleocy- sodic abdominal pain and peripheral neuropathy. Gray
tosis, increased protein, and a positive Venereal Disease lead lines appear in the gums, usually accompanied by an
Research Laboratory (VDRL) test. anemia with basophilic stippling of red blood cells. The
Primary and metastatic neoplasms of the CNS (Chap. clinical presentation can resemble that of acute intermit-
37) usually produce focal neurologic ndings and sei- tent porphyria, including elevated levels of urine por-
zures rather than dementia, but if tumor growth begins phyrins as a result of the inhibition of -aminolevulinic
in the frontal or temporal lobes, the initial manifes- acid dehydrase. The treatment is chelation therapy with
tations may be memory loss or behavioral changes. A agents such as ethylenediamine tetraacetic acid (EDTA).
paraneoplastic syndrome of dementia associated with Chronic mercury poisoning produces dementia, periph-
occult carcinoma (often small cell lung cancer) is termed eral neuropathy, ataxia, and tremulousness that may
limbic encephalitis. In this syndrome, confusion, agitation, progress to a cerebellar intention tremor or choreoath-
seizures, poor memory, emotional changes, and frank etosis. The confusion and memory loss of chronic arsenic
dementia may occur. Paraneoplastic encephalitis associ- intoxication is also associated with nausea, weight loss,
ated with NMDA receptor antibodies presents as a progres- peripheral neuropathy, pigmentation and scaling of the
CHAPTER 29
sive psychiatric disorder with memory loss and seizures; skin, and transverse white lines of the ngernails (Mees
affected patients are often young women with ovarian lines). Treatment is chelation therapy with dimercaprol
teratoma (Chap. 44). (BAL). Aluminum poisoning is rare but was documented
A nonconvulsive seizure disorder may underlie a syn- with the dialysis dementia syndrome, in which water
drome of confusion, clouding of consciousness, and gar- used during renal dialysis was contaminated with exces-
bled speech. Often, psychiatric disease is suspected, but sive amounts of aluminum. This poisoning resulted in a
hippocampus or medial thalamic nucleus bilaterally. ciated with the personal past. At the same time, memory
The ALS/parkinsonian/dementia complex of Guam is a for other recent events and the ability to learn and use
rare degenerative disease that has occurred in the Cham- new information are preserved. The episodes usually last
orro natives on the island of Guam. Individuals may have hours or days and occasionally weeks or months while
any combination of parkinsonian features, dementia, and the patient takes on a new identity. On recovery, there
motor neuron disease. The most characteristic pathologic is a residual amnesia gap for the period of the fugue.
Diseases of the Nervous System
features are the presence of NFTs in degenerating neu- Very rarely does selective loss of autobiographic informa-
rons of the cortex and substantia nigra and loss of motor tion reect a focal injury to the brain areas involved with
neurons in the spinal cord, although recent reanalysis these functions.
has shown that some patients with this illness also show Psychiatric diseases may mimic dementia. Severely
coexisting TDP-43 pathology. Epidemiologic evidence depressed or anxious individuals may appear demented,
supports a possible environmental cause, such as exposure a phenomenon sometimes called pseudodementia. Mem-
to a neurotoxin or an infectious agent with a long latency ory and language are usually intact when carefully tested,
period. One interesting but unproven candidate neu- and a signicant memory disturbance usually suggests
rotoxin occurs in the seed of the false palm tree, which an underlying dementia, even if the patient is depressed.
Guamanians traditionally used to make our. The ALS Patients in this condition may feel confused and unable
syndrome is no longer present in Guam, but a dementing to accomplish routine tasks. Vegetative symptoms, such
illness with rigidity continues to be seen. as insomnia, lack of energy, poor appetite, and concern
Rarely, adult-onset leukodystrophies, lysosomal stor- with bowel function, are common. Onset is often more
age diseases, and other genetic disorders can present as a abrupt, and the psychosocial milieu may suggest promi-
dementia in middle to late life. Metachromatic leukodys- nent reasons for depression. Such patients respond to
trophy (MLD) causes a progressive psychiatric or demen- treatment of the underlying psychiatric illness. Schizo-
tia syndrome associated with extensive, conuent frontal phrenia is usually not difcult to distinguish from demen-
white matter abnormality. MLD is diagnosed by measur- tia, but occasionally the distinction can be problematic.
ing arylsulfatase A enzyme activity in white blood cells. Schizophrenia generally has a much earlier age of onset
Adult-onset presentations of adrenoleukodystrophy have (second and third decades) than most dementing illnesses,
been reported in female carriers, and these patients often and is associated with intact memory. The delusions and
feature spinal cord and posterior white matter involve- hallucinations of schizophrenia are usually more complex
ment. Adrenoleukodystrophy is diagnosed with measure- and bizarre than those of dementia. Some chronic schizo-
ment of plasma very long chain fatty acids. CADASIL phrenics develop an unexplained progressive dementia
is another genetic syndrome associated with white mat- late in life that is not related to AD. Conversely, FTD,
ter disease, often frontally and temporally predominant. HD, vascular dementia, DLB, AD, or leukoencephalopa-
Diagnosis is made with skin biopsy, which shows osmo- thy can begin with schizophrenia-like features, leading to
philic granules in arterioles, or, increasingly, through the misdiagnosis of a psychiatric condition. Later age of
genetic testing for mutations in Notch 3 (see earlier). The onset, signicant decits on cognitive testing, or the pres-
neuronal ceroid lipofuscinoses are a genetically hetero- ence of abnormal neuroimaging point toward a degen-
geneous group of disorders associated with myoclonus, erative condition. Memory loss may also be part of a
seizures, and progressive dementia. Diagnosis is made by conversion disorder. In this situation, patients commonly
complain bitterly of memory loss, but careful cognitive 331
testing either does not conrm the decits or demon- able side-effect profile, second-generation antipsychotics
strates inconsistent or unusual patterns of cognitive prob- such as quetiapine (starting dose, 12.525 mg daily) can
lems. The patients behavior and wrong answers to be used for patients with agitation, aggression, and psy-
questions often indicate that he or she understands the chosis, although the risk profile for these compounds is sig-
question and knows the correct answer. nificant. When patients do not respond to treatment, it is
Clouding of cognition by chronic drug or medication use, usually a mistake to advance to higher doses or to use anti-
often prescribed by physicians, is an important cause of cholinergics or sedatives (such as barbiturates or benzodi-
dementia. Sedatives, tranquilizers, and analgesics used azepines). It is important to recognize and treat depression;
to treat insomnia, pain, anxiety, or agitation may cause treatment can begin with a low dose of an SSRI (e.g., esci-
confusion, memory loss, and lethargy, especially in the talopram 510 mg daily) while monitoring for efficacy and
elderly. Discontinuation of the offending medication toxicity. Sometimes apathy, visual hallucinations, depres-
often improves mentation. sion, and other psychiatric symptoms respond to the cho-
linesterase inhibitors, especially in DLB, obviating the need
for other more toxic therapies.
Cholinesterase inhibitors are being used to treat AD
(donepezil, rivastigmine, galantamine) and PDD (riv-
CHAPTER 29
astigmine). Other compounds, such as anti-inflamma-
TREATMENT Dementia tory agents, are being investigated in the treatment or
prevention of AD. These approaches are reviewed in the
The major goals of dementia management are to treat treatment sections for individual disorders earlier in this
correctable causes and to provide comfort and support chapter. Memantine proves useful when treating some
to the patient and caregivers. Treatment of underlying patients with moderate to severe AD; its major benefit
relates to decreasing caregiver burden, most likely by
PARKINSONS DISEASE AND RELATED likely responsible for the nondopaminergic clinical fea-
DISORDERS tures listed in Table 30-1. Indeed, there is evidence
that pathology begins in the peripheral autonomic ner-
Parkinsons disease (PD) is the second commonest neu- vous system, olfactory system, and dorsal motor nucleus
rodegenerative disease, exceeded only by Alzheimers of the vagus nerve in the lower brainstem, and then
disease (AD). It is estimated that approximately 1 mil- spreads in a sequential manner to affect the upper brain-
lion persons in the United States and 5 million persons stem and cerebral hemispheres. These studies suggest
in the world suffer from this disorder. PD affects men that dopamine neurons are affected in midstage disease.
and women of all races, all occupations, and all coun- Indeed, several studies suggest that symptoms reect-
tries. The mean age of onset is about 60 years, but cases ing nondopaminergic degeneration such as constipation,
can be seen in patients in their 20s, and even younger. anosmia, rapid eye movement (REM) behavior sleep
The frequency of PD increases with aging, and based disorder, and cardiac denervation precede the onset of
on projected population demographics, it is estimated the classic motor features of the illness.
that the prevalence will dramatically increase in future
decades.
Clinically, PD is characterized by rest tremor, rigid- DIFFERENTIAL DIAGNOSIS
ity, bradykinesia, and gait impairment, known as the Parkinsonism is a general term that is used to dene a
cardinal features of the disease. Additional features symptom complex manifest by bradykinesia with rigidity
can include freezing of gait, postural instability, speech and/or tremor. It has a wide differential diagnosis (Table
difculty, autonomic disturbances, sensory alterations, 30-2) and can reect damage to different components
mood disorders, sleep dysfunction, cognitive impair- of the basal ganglia. The basal ganglia comprise a group
ment, and dementia (Table 30-1), all known as non- of subcortical nuclei that include the striatum (putamen
dopaminergic features because they do not fully respond and caudate nucleus), subthalamic nucleus (STN), globus
to dopaminergic therapy. pallidus pars externa (GPe), globus pallidus pars interna
Pathologically, the hallmark features of PD are (GPi), and the SNc (Fig. 30-2). The basal ganglia play
degeneration of dopaminergic neurons in the substantia an important role in regulating normal motor behavior.
nigra pars compacta (SNc), reduced striatal dopamine, It is now appreciated that basal ganglia also play a role in
and intracytoplasmic proteinaceous inclusions known modulating emotional and cognitive functions. Among
as Lewy bodies (Fig. 30-1). While interest has primar- the different forms of parkinsonism, PD is the most com-
ily focused on the dopamine system, neuronal degen- mon (approximately 75% of cases). Historically, PD was
eration with inclusion body formation can also affect diagnosed based on the presence of two of three parkin-
cholinergic neurons of the nucleus basalis of Meynert sonian features (tremor, rigidity, bradykinesia). However,
(NBM), norepinephrine neurons of the locus coeru- postmortem studies found a 24% error rate when these
leus (LC), serotonin neurons in the raphe nuclei of the criteria were used. Clinicopathologic correlation stud-
brainstem, and neurons of the olfactory system, cere- ies subsequently determined that parkinsonism associ-
bral hemispheres, spinal cord, and peripheral autonomic ated with rest tremor, asymmetry, and a good response
nervous system. This nondopaminergic pathology is to levodopa was more likely to predict the correct
333
334 TABLE 30-1
CLINICAL FEATURES OF PARKINSONS DISEASE
CARDINAL FEATURES OTHER MOTOR FEATURES NONMOTOR FEATURES
pathologic diagnosis. With these revised criteria (known and it is important to make the diagnosis at as early a
as the U.K. brain bank criteria), the clinical diagnosis of time point as possible. Genetic testing is not generally
SECTION III
PD is conrmed pathologically in 99% of cases. employed at present, but it can be helpful for identify-
Imaging of the brain dopamine system in PD with ing at-risk individuals in a research setting. Mutations
positron emission tomography (PET) or single-photon of the LRRK2 gene (see later) have attracted particu-
emission computed tomography (SPECT) shows reduced lar interest as they are the commonest cause of familial
uptake of striatal dopaminergic markers, particularly in PD and are responsible for approximately 1% of typi-
the posterior putamen (Fig. 30-3). Imaging can be use- cal sporadic cases of the disease. Mutations in LRRK2
Diseases of the Nervous System
ful in difcult cases or research studies but is rarely nec- are particularly common causes of PD in Ashkenazi
essary in routine practice, as the diagnosis can usually be Jews and North African Berber Arabs. The penetrance
established on clinical criteria alone. This may change of the most common LRRK2 mutation ranges from 28
in the future when there is a disease-modifying therapy to 74%, depending on age. Mutations in the parkin gene
B C
FIGURE 30-1
Pathologic specimens from a patient with Parkinsons dis- reduced numbers of cells in SNc in PD (right) compared to con-
ease (PD) compared to a normal control demonstrating (A) trol (left), and (C) Lewy bodies (arrows) within melanized dopa-
reduction of pigment in SNc in PD (right) vs control (left), (B) mine neurons in PD. SNc, substantia nigra pars compacta.
TABLE 30-2 335
DIFFERENTIAL DIAGNOSIS OF PARKINSONISM
Parkinsons Disease Atypical Parkinsonisms Secondary Parkinsonism Other Neurodegenerative
Genetic Multiple-system atrophy Drug-induced Disorders
Sporadic Cerebellar type (MSA-c) Tumor Wilsons disease
Dementia with Lewy bodies Parkinson type (MSA-p) Infection Huntingtons disease
Progressive supranuclear Vascular Neurodegeneration with
palsy Normal-pressure brain iron accumulation
Corticobasal ganglionic hydrocephalus SCA 3 (spinocerebellar
degeneration Trauma ataxia)
Frontotemporal dementia Liver failure Fragile Xassociated
Toxins (e.g., carbon mon- ataxia-tremor-parkinsonism
oxide, manganese, MPTP, Prion disease
cyanide, hexane, methanol, Dystonia-parkinsonism
carbon disulde) (DYT3)
Alzheimers disease with
parkinsonism
CHAPTER 30
should be considered in patients with disease onset prior also have degeneration of dopamine neurons. Patholog-
to 40 years. ically, neurodegeneration occurs without Lewy bodies
(see later for individual conditions). Metabolic imaging
of the basal ganglia/thalamus network may be helpful,
Atypical and secondary parkinsonism
reecting a pattern of decreased activity in the GPi with
Striatum
(Putamen and
Caudate)
STN Striatum
Globus Pallidus
SNc
Globus Pallidus
SNc
FIGURE 30-2
Basal ganglia nuclei. Schematic (A) and postmortem (B) basal ganglia. SNc, substantia nigra pars compacta; STN,
coronal sections illustrating the various components of the subthalamic nucleus.
336
A B
FIGURE 30-3
SECTION III
[11C]dihydrotetrabenazine PET (a marker of VMAT2) in posterior putamen and tends to be asymmetric. (Courtesy of
healthy control (A) and PD (B) patient. Note the reduced Dr. Jon Stoessl.)
striatal uptake of tracer which is most pronounced in the
scans, high signal change in the region of the external are primarily used to treat gastrointestinal problems, are
surface of the putamen (putaminal rim) in MSA-p, or also neuroleptic agents and common causes of secondary
cerebellar and brainstem atrophy (the pontine hot cross parkinsonism and tardive dyskinesia. Other drugs that
Diseases of the Nervous System
buns sign [Fig. 33-2]) in MSA-c. can cause secondary parkinsonism include tetrabenazine,
Progressive supranuclear palsy (PSP) is a form of amiodarone, and lithium.
atypical parkinsonism that is characterized by slow ocu- Finally, parkinsonism can be seen as a feature of
lar saccades, eyelid apraxia, and restricted eye move- other degenerative disorders such as Wilsons dis-
ments with particular impairment of downward gaze. ease, Huntingtons disease (especially the juvenile form
Patients frequently experience hyperextension of the known as Westphal variant), dopa-responsive dystonia,
neck with early gait disturbance and falls. In later stages, and neurodegenerative disorders with brain iron accu-
speech and swallowing difculty and dementia become mulation such as pantothenate kinase (PANK)associated
evident. MRI may reveal a characteristic atrophy of the neurodegeneration (formerly known as Hallervorden-
midbrain with relative preservation of the pons (the Spatz disease).
hummingbird sign on midsagittal images). Pathologi- Some features that suggest parkinsonism might
cally, PSP is characterized by degeneration of the SNc be due to a condition other than PD are shown in
and pallidum along with neurobrillary tangles and Table 30-3.
GCIs that stain for tau.
Corticobasal ganglionic degeneration is less common
and is usually manifest by asymmetric dystonic contrac- ETIOLOGY AND PATHOGENESIS
tions and clumsiness of one hand coupled with cortical Most PD cases occur sporadically (8590%) and are of
sensory disturbances manifest as apraxia, agnosia, focal unknown cause. Twin studies suggest that environmen-
myoclonus, or alien limb phenomenon (where the tal factors likely play the more important role in patients
limb assumes a position in space without the patient older than 50 years, with genetic factors being more
being aware of it). Dementia may occur at any stage of important in younger patients. Epidemiologic studies
the disease. MRI frequently shows asymmetric cortical suggest increased risk with exposure to pesticides, rural
atrophy. Pathologic ndings include achromatic neu- living, and drinking well water and reduced risk with
ronal degeneration with tau deposits similar to those cigarette smoking and caffeine. However, no environ-
found in PSP. mental factor has yet been determined to cause PD. The
Secondary parkinsonism can be associated with drugs, environmental hypothesis received a boost with the
stroke, tumor, infection, or exposure to toxins such as demonstration in the 1980s that MPTP (1-methyl-4-
carbon monoxide or manganese. Dopamine-blocking phenyl-1,2,5,6-tetrahydropyridine), a byproduct of the
agents such as the neuroleptics are the commonest cause illicit manufacture of a heroin-like drug, caused a PD-
of secondary parkinsonism. These drugs are most widely like syndrome in addicts in northern California. MPTP
used in psychiatry, but physicians should be aware that is transported to the central nervous system, where it is
drugs such as metoclopramide and chlorperazine, which metabolized to form MPP+, a mitochondrial toxin that
TABLE 30-3 TABLE 30-4 337
FEATURES SUGGESTING ALTERNATE DIAGNOSIS GENETIC CAUSES OF PD
THAN PD
NAME CHROMOSOME LOCUS GENE INHERITANCE
ALTERNATE DIAGNOSIS TO
SYMPTOMS/SIGNS CONSIDER Park 1 Chr 4 q21-23 -Synuclein AD
Early speech and gait Atypical parkinsonism Park 3 Chr 2 p13 Unknown AD
impairment Park 4 Chr 4 q21-23 -Synuclein AD
Exposure to neuroleptics Drug-induced parkinsonism Park 5 Chr 4 p14 UCHL-1 AD
Onset prior to age 40 Genetic form of PD Park 6 Chr 1 p35-36 PINK-1 AR
Liver disease Wilsons disease, non- Park 7 Chr 1 p36 DJ-1 AR
Wilsonian hepatolenticular
degeneration Park 8 Chr 12 p11-q13 LRRK2 AR/Sp
Early hallucinations Dementia with Lewy bodies Park 9 Chr 1 p36 ATP13A2 AR
CHAPTER 30
Poor or no response to an Atypical or secondary par- Park 11 Chr 2 q36-37 GIGYF2 AD
adequate trial of levodopa kinsonism Park 12 Chr X q21-25 Unknown Sp
Physical Exam Park 13 Chr 2 p13 Omi/HtrA2 AD
Dementia as rst symptom Dementia with Lewy bodies Park 14 Chr 22 q13 PLA2G6 AR
Prominent orthostatic MSA-p Park 15 Chr 22 q12-13 FBX07 AR
hypotension Park 16 Chr 1 q32 Unknown SP
els of unwanted proteins could also result from impaired corresponding cortical motor regions in a somatotopic
clearance. Proteins are normally cleared by the ubiquitin manner to help regulate motor function. The striatum is
proteasome system or the autophagy/lysosome pathway. the major input region of the basal ganglia, while the GPi
These pathways are defective in patients with sporadic and SNr are the major output regions. The input and
PD, and interestingly -synuclein is a prominent com- output regions are connected via direct and indirect path-
ponent of Lewy bodies in these cases. Further, mutations ways that have reciprocal effects on the output pathway.
Diseases of the Nervous System
in parkin (a ubiquitin ligase that attaches ubiquitin to The output of the basal ganglia provides inhibitory tone
misfolded proteins to promote their transport to the pro- to thalamic and brainstem neurons that in turn connect
teasome for degradation) and UCH-L1 (which cleaves to motor systems in the cerebral cortex and spinal cord to
ubiquitin from misfolded proteins to permit their entry regulate motor function. Dopaminergic projections from
into the proteasome) are causative in other cases of famil- SNc neurons serve to modulate neuronal ring and to
ial PD. Collectively, these ndings implicate abnormal stabilize the basal ganglia network.
protein accumulation in the etiology of PD. Indeed, in In PD, dopamine denervation leads to increased r-
laboratory models both overexpression of -synuclein or ing of neurons in the STN and GPi, resulting in exces-
impairment of proteasomal clearance mechanisms leads to sive inhibition of the thalamus, reduced activation of
degeneration of dopamine neurons with inclusion body cortical motor systems, and the development of parkin-
formation. sonian features (Fig. 30-5). The current role of surgery
Mitochondrial dysfunction has also been implicated in the treatment of PD is based upon this model, which
in familial PD. Several causative genes (parkin, PINK1, predicted that lesions or high-frequency stimulation of
and DJ1) either localize to mitochondria and/or cause the STN or GPi might reduce this neuronal overactiv-
mitochondrial dysfunction in transgenic animals. Post- ity and improve PD features.
mortem studies have also shown a defect in complex I
of the respiratory chain in the SNc of patients with spo-
radic PD.
TREATMENT Parkinsons Disease
Six different LRRK2 mutations have been linked to
PD, with the Gly2019Ser being the commonest. The
mechanism responsible for cell death with this mutation LEVODOPA Since its introduction in the late 1960s,
is not known but is thought to involve altered kinase levodopa has been the mainstay of therapy for PD.
activity. Experiments in the late 1950s by Carlsson demonstrated
Mutations in the glucocerebrosidase (GBA) gene that blocking dopamine uptake with reserpine caused
associated with Gauchers disease are also associated rabbits to become parkinsonian; this could be reversed
with an increased risk of idiopathic PD. Again the with the dopamine precursor, levodopa. Subsequently,
mechanism is not precisely known, but it is notewor- Hornykiewicz demonstrated a dopamine deficiency in
thy that it is associated with altered autophagy and lyso- the striatum of PD patients and suggested the potential
somal function, suggesting that mutations in this gene benefit of dopaminergic replacement therapy. Dopa-
might also impair protein clearance leading to PD. mine does not cross the blood-brain barrier (BBB), so
Whole-genome association studies have provided clinical trials were initiated with levodopa, a precursor of
conicting results. Most recently, linkage to mutations
Normal PD Dyskinesia 339
Cortex Cortex Cortex
DA DA
SNc SNc SNc
CHAPTER 30
A PPN B PPN C PPN
FIGURE 30-5
Basal ganglia organization. Classic model of the organiza- kinesia results from decreased ring of the output regions,
tion of the basal ganglia in the normal, PD, and levodopa- resulting in excessive cortical activation by the thalamus.
induced dyskinesia state. Inhibitory connections are shown This component of the model is not completely correct as
dopamine. Studies over the course of the next decade motor features of PD, prolongs independence and
confirmed the value of levodopa and revolutionized the employability, improves quality of life, and increases life
treatment of PD. span. Almost all PD patients experience improvement,
Levodopa is routinely administered in combination and failure to respond to an adequate trial should cause
with a peripheral decarboxylase inhibitor to prevent the diagnosis to be questioned.
its peripheral metabolism to dopamine and the devel- There are, however, important limitations of levo-
opment of nausea and vomiting due to activation of dopa therapy. Acute dopaminergic side effects include
dopamine receptors in the area postrema that are not nausea, vomiting, and orthostatic hypotension. These
protected by the BBB. In the United States, levodopa is are usually transient and can generally be avoided by
combined with the decarboxylase inhibitor carbidopa gradual titration. If they persist, they can be treated with
(Sinemet), while in many other countries it is combined additional doses of a peripheral decarboxylase inhibi-
with benserazide (Madopar). Levodopa is also available tor (e.g., carbidopa) or a peripheral dopamine-blocking
in controlled-release formulations as well as in combina- agent such as domperidone (not available in the United
tion with a COMT inhibitor (see later). Levodopa remains States). More important are motor complications (see
the most effective symptomatic treatment for PD and later) that develop in the majority of patients treated
the gold standard against which new therapies are com- long-term with levodopa therapy. In addition, fea-
pared. No current medical or surgical treatment pro- tures such as falling, freezing, autonomic dysfunction,
vides antiparkinsonian benefits superior to what can be sleep disorders, and dementia may emerge that are
achieved with levodopa. Levodopa benefits the classic not adequately controlled by levodopa. Indeed, these
340
nondopaminergic features are the primary source of dis- doses of levodopa. The classic model of the basal ganglia
ability and main reason for nursing home placement for has been useful for understanding the origin of motor
patients with advanced PD. features in PD, but has proved less valuable for under-
Levodopa-induced motor complications consist of standing levodopa-induced dyskinesias (Fig. 30-5). The
fluctuations in motor response and involuntary move- model predicts that dopamine replacement might exces-
ments known as dyskinesias (Fig. 30-6). When patients sively inhibit the pallidal output system, thereby leading
initially take levodopa, benefits are long-lasting (many to increased thalamocortical activity, enhanced stimula-
hours) even though the drug has a relatively short half- tion of cortical motor regions, and the development of
life (6090 min). With continued treatment, however, dyskinesia. However, lesions of the pallidum that com-
the duration of benefit following an individual dose pletely destroy its output are associated with ameliora-
becomes progressively shorter until it approaches the tion rather than induction of dyskinesia as suggested
half-life of the drug. This loss of benefit is known as by the classic model. It is now thought that dyskinesia
the wearing-off effect. At the same time, many patients results from levodopa-induced alterations in the GPi neu-
develop dyskinesias. These tend to occur at the time of ronal firing pattern (pauses, bursts, synchrony, etc.) and
maximal clinical benefit and peak plasma concentra- not simply the firing frequency alone. This in turn leads to
tion (peak-dose dyskinesia). They are usually choreiform the transmission of misinformation from pallidum to thal-
SECTION III
in nature but can manifest as dystonia, myoclonus, or amus/cortex, resulting in dyskinesia. Pallidotomy might
other movement disorders. They are not troublesome thus ameliorate dyskinesia by blocking this abnormal fir-
when mild, but can be disabling when severe and can ing pattern and preventing the transfer of misinformation
limit the ability to fully utilize levodopa to control PD to motor systems.
features. In more advanced states, patients may cycle Current information suggests that altered neuronal
between on periods complicated by disabling dyskine- firing patterns and motor complications relate to non-
sias and off periods in which they suffer severe parkin- physiologic levodopa replacement. Striatal dopamine
Diseases of the Nervous System
sonism. Patients may also experience diphasic dyskine- levels are normally maintained at a relatively constant
sias, which occur as the levodopa dose begins to take level. In the PD state, dopamine neurons degenerate
effect and again as it wears off. These dyskinesias typi- and striatal dopamine is dependent on peripheral avail-
cally consist of transient, stereotypic, rhythmic move- ability of levodopa. Intermittent doses of short-acting
ments that predominantly involve the lower extremi- levodopa do not restore dopamine in a physiologic
ties and are frequently associated with parkinsonism manner and cause dopamine receptors to be exposed
in other body regions. They can be relieved by increas- to alternating high and low concentrations of dopa-
ing the dose of levodopa, although higher doses may mine. This intermittent or pulsatile stimulation of dopa-
induce more severe peak-dose dyskinesia. mine receptors induces molecular changes in striatal
The cause of levodopa-induced motor complications neurons and neurophysiologic changes in pallidal neu-
is not precisely known. They are more likely to occur in rons, leading to the development of motor complica-
young individuals with severe disease and with higher tions. It has been hypothesized that more continuous
Clinical effect
Clinical effect
threshold
Response
Response threshold Response
threshold
threshold
FIGURE 30-6
Changes in motor response associated with chronic duration of a benecial motor response to levodopa (wear-
levodopa treatment. Levodopa-induced motor complica- ing off) and the appearance of dyskinesias complicating on
tions. Schematic illustration of the gradual shortening of the time.
delivery of levodopa might prevent the development Acute side effects of dopamine agonists include 341
of motor complications. Indeed, continuous levodopa nausea, vomiting, and orthostatic hypotension. As
infusion is associated with improvement in both off with levodopa, these can usually be avoided by slow
time and dyskinesia in advanced PD patients, but this titration. Hallucinations and cognitive impairment
approach has not yet been proved to prevent dyskinesia are more common with dopamine agonists than with
in clinical trials. levodopa. Sedation with sudden unintended episodes
Behavioral alterations can be encountered in levodopa- of falling asleep while driving a motor vehicle have been
treated patients. A dopamine dysregulation syndrome reported. Patients should be informed about this poten-
has been described where patients have a craving for tial problem and should not drive when tired. Injections
levodopa and take frequent and unnecessary doses of the of apomorphine and patch delivery of rotigotine can be
drug in an addictive manner. PD patients taking high doses complicated by development of skin lesions at sites of
of levodopa can also have purposeless, stereotyped behav- administration. Recently, it has become appreciated that
iors such as the meaningless assembly and disassembly or dopamine agonists are associated with impulse-control
collection and sorting of objects. This is known as punding, disorders, including pathologic gambling, hypersexu-
a term taken from the Swedish description of the mean- ality, and compulsive eating and shopping. The pre-
ingless behaviors seen in chronic amphetamine users. cise cause of these problems, and why they appear to
CHAPTER 30
Hypersexuality and other impulse-control disorders are occur more frequently with dopamine agonists than
occasionally encountered with levodopa, although these levodopa, remains to be resolved, but reward systems
are more commonly seen with dopamine agonists. associated with dopamine and alterations in the ventral
striatum have been implicated.
MAO-B INHIBITORS Inhibitors of monoamine
DOPAMINE AGONISTS Dopamine agonists are oxidase type B (MAO-B) block central dopamine metab-
a diverse group of drugs that act directly on dopamine
levodopa with a COMT inhibitor reduces off time and livido reticularis, weight gain, and impaired cognitive
prolongs on time in fluctuating patients while enhanc- function. Amantadine should always be discontinued
ing motor scores. Two COMT inhibitors have been gradually as patients can experience withdrawal symp-
approved, tolcapone and entacapone. There is also a toms.
combination tablet of levodopa, carbidopa, and enta- A list of the major drugs and available dosage
capone (Stalevo). strengths is provided in Table 30-5.
Diseases of the Nervous System
CHAPTER 30
Dopamine agonists
Pramipexole 0.125, 0.25, 0.251.0 mg tid
0.5, 1.0, 1.5 mg
Pramipexole ER 0.375, 0.75, 13 mg/d
1.5. 3.0, 4.5 mg
Ropinirole 0.25, 0.5, 1.0, 3.0 mg 624 mg/d
a
Treatment should be individualized. Generally, drugs should be started in low doses and titrated to optimal dose.
Note: Drugs should not be withdrawn abruptly but should be gradually lowered or removed as appropriate.
Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase type B.
(see earlier). However, this procedure is not optimal for suitable for performing bilateral procedures with rela-
patients with bilateral disease, as bilateral lesions are tive safety.
associated with side effects such as dysphagia, dysar- DBS for PD primarily targets the STN or the GPi. It
thria, and impaired cognition. provides dramatic results, particularly with respect to
Most surgical procedures for PD performed today off time and dyskinesias, but does not improve fea-
utilize deep brain stimulation (DBS). Here, an electrode tures that fail to respond to levodopa and does not pre-
is placed into the target area and connected to a stim- vent the development or progression of nondopami-
ulator inserted SC over the chest wall. DBS simulates nergic features such as freezing, falling, and dementia.
the effects of a lesion without necessitating a brain The procedure is thus primarily indicated for patients
lesion. The stimulation variables can be adjusted with who suffer disability resulting from levodopa-induced
respect to electrode configuration, voltage, frequency, motor complications that cannot be satisfactorily con-
and pulse duration in order to maximize benefit and trolled with drug manipulation. Side effects can be seen
minimize adverse side effects. In cases with intolerable with respect to the surgical procedure (hemorrhage,
side effects, stimulation can be stopped and the sys- infarction, infection), the DBS system (infection, lead
tem removed. The procedure has the advantage that it break, lead displacement, skin ulceration), or stimula-
does not require making a lesion in the brain and is thus tion (ocular and speech abnormalities, muscle twitches,
344 paresthesias, depression, and rarely suicide). Recent into the host genome, and is associated with long-last-
studies indicate that benefits following DBS of the STN ing transgene expression. Studies performed to date in
and GPi are comparable, but that GPi stimulation may PD have delivered aromatic amino acid decarboxylase
be associated with a reduced frequency of depression. with or without tyrosine hydroxylase to the striatum to
While not all PD patients are candidates, the procedure facilitate dopamine production; glutamic acid decar-
is profoundly beneficial for many. Research studies are boxylase to the STN to inhibit overactive neuronal firing
currently examining additional targets that might ben- in this nucleus; and trophic factors such as GDNF (glial-
efit gait dysfunction, depression, and cognitive impair- derived neurotrophic factor) and neurturin to the stria-
ment in PD patients. tum to enhance and protect residual dopamine neurons
in the SNc by way of retrograde transmission. Positive
EXPERIMENTAL SURGICAL THERAPIES FOR
results have been reported with open-label studies, but
PD There has been considerable scientific and pub-
these have not yet been confirmed in double-blind tri-
lic interest in a number of novel therapies as possible
als. While gene delivery technology has great potential,
treatments for PD. These include cell-based therapies
this approach also carries the risk of possible unantici-
(such as transplantation of fetal nigral dopamine cells
pated side effects, and current approaches also do not
or dopamine neurons derived from stem cells), gene
address the nondopaminergic features of the illness.
therapies, and trophic factors. Transplant strategies are
SECTION III
based on implanting dopaminergic cells into the stria- MANAGEMENT OF THE NONMOTOR AND
tum to replace degenerating SNc dopamine neurons. NONDOPAMINERGIC FEATURES OF PD
Fetal nigral mesencephalic cells have been demon- While most attention has focused on the dopaminergic
strated to survive implantation, reinnervate the stria- features of PD, management of the nondopaminergic
tum in an organotypic manner, and restore motor func- features of the illness should not be ignored. Some
tion in PD models. Several open-label studies reported nonmotor features, while not thought to reflect dopa-
Diseases of the Nervous System
positive results. However, two double-blind, sham minergic pathology, nonetheless benefit from dopami-
surgerycontrolled studies failed to show significant nergic drugs. For example, problems such as anxiety,
benefit of fetal nigral transplantation in comparison to panic attacks, depression, sweating, sensory problems,
a sham operation with respect to their primary end- freezing, and constipation all tend to be worse during
points. Post hoc analyses showed possible benefits in off periods, and they improve with better dopaminer-
patients aged <60 years and in those with milder dis- gic control of the underlying PD state. Approximately
ease. It is now appreciated that grafting of fetal nigral 50% of PD patients suffer depression during the course
cells is associated with a previously unrecognized form of the disease that is frequently underdiagnosed and
of dyskinesia that persists even after lowering or stop- undertreated. Antiparkinsonian agents can help, but
ping levodopa. In addition, there is evidence that after antidepressants should not be withheld, particularly
many years, transplanted healthy embryonic dopamine for patients with major depression. Serotonin syn-
neurons from unrelated donors can develop PD pathol- dromes have been a theoretical concern with the com-
ogy, suggesting that they somehow became affected bined use of selective serotonin reuptake inhibitors
by the disease process. Most importantly, it is not clear (SSRIs) and MAO-B inhibitors, but are rarely encoun-
how replacing dopamine cells alone will improve non- tered. Anxiety can be treated with short-acting benzo-
dopaminergic features such as falling and dementia, diazepines.
which are the major sources of disability for patients Psychosis can be a major problem in PD. In contrast
with advanced disease. These same concerns apply to to AD, hallucinations are typically visual, formed, and
dopamine neurons derived from stem cells, which have nonthreatening and can limit the use of dopaminergic
not yet been tested in PD patients, and bear the addi- agents to adequately control PD features. Psychosis in
tional theoretical concern of unanticipated side effects PD often responds to low doses of atypical neurolep-
such as tumors. The short-term future for this technol- tics. Clozapine is the most effective, but it can be asso-
ogy as a treatment for PD, at least in its current state, is ciated with agranulocytosis, and regular monitoring
therefore not promising. is required. For this reason, many physicians start with
Gene therapy involves viral vector delivery of the quetiapine even though it is not as effective as clozap-
DNA of a therapeutic protein to specific target regions. ine in controlled trials. Hallucinations in PD patients are
The DNA of the therapeutic protein can then be incor- often a harbinger of a developing dementia.
porated into the genome of host cells and thereby, in Dementia in PD (PDD) is common, affecting as many
principle, provide continuous and long-lasting delivery as 80% of patients. Its frequency increases with aging
of the therapeutic molecule. The AAV2 virus has been and, in contrast to AD, primarily affects executive func-
most often used as the viral vector because it does not tions and attention, with relative sparing of language,
promote an inflammatory response, is not incorporated memory, and calculations. PDD is the commonest cause
of nursing home placement for PD patients. When of the normal inhibition of motor movements that typi- 345
dementia precedes, or develops within 1 year after, the cally accompanies REM sleep. Low doses of clonazepam
onset of motor dysfunction, it is by convention referred are usually effective in controlling this problem. Consul-
to as dementia with Lewy bodies (DLB; Chap. 29). These tation with a sleep specialist and polysomnography may
patients are particularly prone to have hallucinations be necessary to identify and optimally treat sleep prob-
and diurnal fluctuations. Pathologically, DLB is char- lems.
acterized by Lewy bodies distributed throughout the NONPHARMACOLOGIC THERAPY Gait dys-
cerebral cortex (especially the hippocampus and amyg- function with falling is an important cause of disability
dala). It is likely that DLB and PDD represent a PD spec- in PD. Dopaminergic therapies can help patients whose
trum rather than separate disease entities. Levodopa gait is worse in off time, but there are currently no spe-
and other dopaminergic drugs can aggravate cognitive cific therapies available. Canes and walkers may become
function in demented patients and should be stopped necessary.
or reduced to try and provide a compromise between Freezing episodes, where patients freeze in place for
antiparkinsonian benefit and preserved cognitive func- seconds to minutes, are another cause of falling. Freez-
tion. Drugs are usually discontinued in the following ing during off periods may respond to dopaminergic
sequence: anticholinergics, amantadine, dopamine ago- therapies, but there are no specific treatments for on
CHAPTER 30
nists, COMT inhibitors, and MAO-B inhibitors. Eventually, period freezing. Some patients will respond to sensory
patients with cognitive impairment should be managed cues such as marching in place, singing a song, or step-
with the lowest dose of standard levodopa that pro- ping over an imaginary line.
vides meaningful antiparkinsonian effects and does not Exercise, with a full range of active and passive move-
aggravate mental function. Anticholinesterase agents ments, has been shown to improve and maintain func-
such as rivastigmine and donepezil reduce the rate of tion for PD patients. It is less clear that formal physical
deterioration of measures of cognitive function in con-
CHAPTER 30
Tic Brief, repeated, stereotyped muscle con- may develop a rest tremor. These typically begin after a
tractions that are often suppressible. Can
be simple and involve a single muscle
latency of a few seconds (emergent tremor). The exam-
group or complex and affect a range of iner must take care to differentiate the effect of tremor
motor activities on measurement of tone in ET from the cog-wheel
rigidity found in PD.
CHAPTER 30
are often brought out by task-specic activities such as
handwriting (writers cramp), playing a musical instru-
TREATMENT Dystonia
ment (musicians cramp), or putting (the yips). Focal
dystonias can extend to involve other body regions Treatment of dystonia is for the most part symptom-
(about 30% of cases), and are frequently misdiagnosed atic except in rare cases where treatment of a primary
as psychiatric or orthopedic in origin. Their cause is not underlying condition is available. Wilsons disease
ETIOLOGY
HD is caused by an increase in the number of polyglu-
CHOREAS tamine (CAG) repeats (>40) in the coding sequence of
the huntingtin gene located on the short arm of chro-
HUNTINGTONS DISEASE (HD)
mosome 4. The larger the number of repeats, the ear-
HD is a progressive, fatal, highly penetrant autosomal lier the disease is manifest. Acceleration of the process
dominant disorder characterized by motor, behavioral, tends to occur, particularly in males, with subsequent
and cognitive dysfunction. The disease is named for generations having larger numbers of repeats and ear-
George Huntington, a family physician who described lier age of disease onset, a phenomenon referred to as
cases on Long Island, New York, in the nineteenth anticipation. The gene encodes the highly conserved
century. Onset is typically between the ages of 25 cytoplasmic protein huntingtin, which is widely distrib-
and 45 years (range, 370 years) with a prevalence of uted clean in neurons throughout the CNS, but whose
28 cases per 100,000 and an average age at death of function is not known. Models of HD with striatal
351
CHAPTER 30
FIGURE 30-8
Huntingtons disease. A. Coronal FLAIR MRI shows (arrows). B. Axial FLAIR image demonstrates abnormal high
enlargement of the lateral ventricles reecting typical atrophy signal in the caudate and putamen (arrows).
HUNTINGTONS DISEASELIKE 1
(HDL1), HUNTINGTONS DISEASELIKE
TREATMENT Huntingtons Disease 2 (HDL2)
Treatment involves a multidisciplinary approach, with HDL1 is a rare inherited disorder due to mutations of
medical, neuropsychiatric, social, and genetic counsel- the protein located at 20p12. Patients exhibit onset of
ing for patients and their families. Dopamine-block- personality change in the third or fourth decade, fol-
ing agents may control the chorea. Tetrabenazine has lowed by chorea, rigidity, myoclonus, ataxia, and epi-
recently been approved for the treatment of chorea in lepsy. HDL2 is an autosomal dominantly inherited dis-
the United States, but it may cause secondary parkin- order manifesting in the third or fourth decade with a
sonism. Neuroleptics are generally not recommended variety of movement disorders, including chorea, dysto-
because of their potential to induce other more trou- nia, or parkinsonism and dementia. Most patients are of
bling movement disorders and because HD chorea African descent. Acanthocytosis can sometimes be seen
tends to be self-limited and is usually not disabling. in these patients, and they must be differentiated from
Depression and anxiety can be greater problems, and neuroacanthocytosis. HDL2 is caused by an abnormally
patients should be treated with appropriate antidepres- expanded CTG/CAG trinucleotide repeat expansion in
sant and antianxiety drugs and monitored for mania the junctophilin-3 (JPH3) gene on chromosome 16q24.3.
and suicidal ideations. Psychosis can be treated with The pathology of HDL2 also demonstrates intranuclear
atypical neuroleptics such as clozapine (50600 mg/d), inclusions immunoreactive for ubiquitin and expanded
quetiapine (50600 mg/d), and risperidone (28 mg/d). polyglutamine repeats.
352 OTHER CHOREAS can also be seen in paraneoplastic syndromes associated
with anti-CRMP-5 or anti-Hu antibodies.
Chorea can be seen in a number of disorders. Syden- Paroxysmal dyskinesias are a group of rare disorders
hams chorea (originally called St. Vitus dance) is more characterized by episodic, brief involuntary movements
common in females and is typically seen in childhood that can include chorea, dystonia, and ballismus. Paroxys-
(515 years). It often develops in association with prior mal kinesigenic dyskinesia (PKD) is a familial childhood-
exposure to group A streptococcal infection and is onset disorder in which chorea or chorea-dystonia is pre-
thought to be autoimmune in nature. With the reduc- cipitated by sudden movement or running. Attacks may
tion in the incidence of rheumatic fever, the inci- affect one side of the body, last seconds to minutes at a
dence of Sydenhams chorea has fallen, but it can still time, and recur several times a day. Prognosis is usually
be seen in developing countries. It is characterized by good, with spontaneous remission in later life. Low-dose
the acute onset of choreiform movements, behavioral anticonvulsant therapy (e.g., carbamazepine) is usually
disturbances, and occasionally other motor dysfunc- effective if required. Paroxysmal nonkinesigenic dyskine-
tions. Chorea generally responds to dopamine-blocking sia (PNKD) involves attacks of dyskinesia precipitated by
agents, valproic acid, and carbamazepine, but is self-lim- alcohol, caffeine, stress, or fatigue. Like PKD, it is familial
ited and treatment is generally restricted to those with and childhood in onset and the episodes are often choreic
severe chorea. Chorea may recur in later life, particu- or dystonic, but have longer duration (minutes to hours)
SECTION III
larly in association with pregnancy (chorea gravidarum) and are less frequent (13/d).
or treatment with sex hormones.
Chorea-acanthocytosis (neuroacanthocytosis) is a pro-
gressive and typically fatal autosomal recessive disorder that
is characterized by chorea coupled with red cell abnormali- TREATMENT Paroxysmal Nonkinesigenic Dyskinesia
ties on peripheral blood smear (acanthocytes). The cho-
Diagnosis and treatment of the underlying condition,
rea can be severe and associated with self-mutilating
Diseases of the Nervous System
CHAPTER 30
currently being explored.
ible urge to express them. Tics vary in intensity and may
be absent for days or weeks only to recur, occasionally in a
different pattern. Tics tend to present between ages 2 and
15 years (mean 7 years) and often lessen or even disappear MYOCLONUS
in adulthood. Associated behavioral disturbances include
anxiety, depression, attention decit hyperactivity disorder, Myoclonus is a brief, rapid (<100 ms) shock-like, jerky
in adults (e.g., blepharospasm, torticollis, or oromandib- withdrawal can induce worsening. TD can persist after
ular dystonia). The reaction can develop within min- withdrawal of antipsychotics and can be difcult to
utes of exposure, and can be successfully treated in most treat. Benets may be achieved with valproic acid, anti-
cases with parenteral administration of anticholinergics cholinergics, or botulinum toxin injections. In refrac-
(benztropine or diphenhydramine) or benzodiazepines tory cases, catecholamine depleters such as tetrabenazine
(lorazepam or diazepam). Choreas, stereotypic behav- may be helpful. Tetrabenazine can be associated with
iors, and tics may also be seen, particularly following dose-dependent sedation and orthostatic hypotension.
acute exposure to CNS stimulants such as methylpheni- Other approaches include baclofen (4080 mg/d), clon-
date, cocaine, or amphetamines. azepam (18 mg/d), or valproic acid (7503000 mg/d).
Chronic neuroleptic exposure can also be associated
with tardive dystonia with preferential involvement of
SUBACUTE axial muscles and characteristic rocking movements of
Akathisia is the commonest reaction in this category. It the trunk and pelvis. Tardive dystonia frequently per-
consists of motor restlessness with a need to move that sists despite stopping medication and patients are often
is alleviated by movement. Therapy consists of remov- refractory to medical therapy. Valproic acid, anticholin-
ing the offending agent. When this is not possible, ergics, and botulinum toxin may occasionally be ben-
symptoms may be ameliorated with benzodiazepines, ecial. Tardive akathisia, tardive Tourette, and tardive
anticholinergics, blockers, or dopamine agonists. tremor syndromes are rare but may also occur after
chronic neuroleptic exposure.
Neuroleptic medications can also be associated with
TARDIVE SYNDROMES a neuroleptic malignant syndrome (NMS). NMS is
These disorders develop months to years after initia- characterized by muscle rigidity, elevated temperature,
tion of neuroleptic treatment. Tardive dyskinesia (TD) altered mental status, hyperthermia, tachycardia, labile
is the commonest and is typically composed of cho- blood pressure, renal failure, and markedly elevated cre-
reiform movements involving the mouth, lips, and atine kinase levels. Symptoms typically evolve within
tongue. In severe cases, the trunk, limbs, and respira- days or weeks after initiating the drug. NMS can also
tory muscles may also be affected. In approximately be precipitated by the abrupt withdrawal of antiparkin-
one-third of patients, TD remits within 3 months of sonian medications in PD patients. Treatment involves
stopping the drug, and most patients gradually improve immediate cessation of the offending antipsychotic drug
over the course of several years. In contrast, abnormal and the introduction of a dopaminergic agent (e.g., a
movements may develop after stopping the offend- dopamine agonist or levodopa), dantrolene, or a benzo-
ing agent. The movements are often mild and more diazepine. Treatment may need to be undertaken in an
intensive care setting and includes supportive measures genetic forms is 27 years, although pediatric cases are 355
such as control of body temperature (antipyretics and recognized. The severity of symptoms is variable. Sec-
cooling blankets), hydration, electrolyte replacement, ondary RLS may be associated with pregnancy or a
and control of renal function and blood pressure. range of underlying disorders, including anemia, ferri-
Drugs that have serotonin-like activity (tryptophan, tin deciency, renal failure, and peripheral neuropathy.
MDMA or ecstasy, meperidine) or that block sero- The pathogenesis probably involves disordered dopa-
tonin reuptake can induce a rare, but potentially fatal, mine function, which may be peripheral or central, in
serotonin syndrome that is characterized by confusion, association with an abnormality of iron metabolism.
hyperthermia, tachycardia, and coma as well as rigidity, Diagnosis is made on clinical grounds but can be sup-
ataxia, and tremor. Myoclonus is often a prominent fea- ported by polysomnography and the demonstration of
ture, in contrast to NMS, which it resembles. Patients PLMs. The neurologic examination is normal. Second-
can be managed with propranolol, diazepam, diphen- ary RLS should be excluded and ferritin levels, glucose,
hydramine, chlorpromazine, or cyproheptadine as well and renal function should be measured.
as supportive measures. Most RLS sufferers have mild symptoms that do not
A variety of drugs can also be associated with parkin- require specic treatment. General measures to improve
sonism (see earlier) and hyperkinetic movement disor- sleep hygiene and quality should be attempted rst. If
ders. Some examples include phenytoin (chorea, dystonia, symptoms remain intrusive, low doses of dopamine
CHAPTER 30
tremor, myoclonus), carbamazepine (tics and dystonia), agonists, e.g., pramipexole (0.250.5 mg) and ropinirole
tricyclic antidepressants (dyskinesias, tremor, myoclonus), (12 mg), are given 12 h before bedtime. Levodopa
uoxetine (myoclonus, chorea, dystonia), oral contracep- can be effective but is frequently associated with aug-
tives (dyskinesia), adrenergics (tremor), buspirone (akathi- mentation (spread and worsening of restlessness and its
sia, dyskinesias, myoclonus), and digoxin, cimetidine, appearance earlier in the day) or rebound (reappearance
diazoxide, lithium, methadone, and fentanyl (dyskinesias). sometimes with worsening of symptoms at a time com-
terized by neurodegeneration and astrogliosis, particu- disorders are common (estimated 23% of patients in a
larly in the basal ganglia. movement disorder clinic), more frequent in women,
WD should always be considered in the differential disabling for the patient and family, and expensive for
diagnosis of a movement disorder in a child. Low levels society (estimated $20 billion annually). Clinical features
of blood copper and ceruloplasmin and high levels of suggesting a psychogenic movement disorder include an
urinary copper may be present, but normal levels do acute onset and a pattern of abnormal movement that
Diseases of the Nervous System
not exclude the diagnosis. CT brain scan usually reveals is inconsistent with a known movement disorder. Diag-
generalized atrophy in established cases and 50% have nosis is based on the nonorganic quality of the move-
hypointensity in the caudate head, globus pallidum, ment, the absence of ndings of an organic disease pro-
substantia nigra, and red nucleus. MRI shows symmet- cess, and positive features that specically point to a
ric hyperintensity on T2-weighted images in the puta- psychogenic illness such as variability and distractibility.
men, caudate, and pallidum. However, correlation of For example, the magnitude of a psychogenic tremor is
imaging changes with clinical features is not good. It is increased with attention and diminishes or even disap-
very rare for WD patients with neurologic features not pears when the patient is distracted by being asked to
to have KF rings. Nevertheless, liver biopsy with dem- perform a different task or is unaware that he or she is
onstration of high copper levels remains the gold stan- being observed. Other positive features suggesting a
dard for the diagnosis. psychogenic problem include a tremor frequency that is
In the absence of treatment, the course is progres- variable or that entrains with the frequency of move-
sive and leads to severe neurologic dysfunction and ment in the contralateral limb, and a positive response
early death. Treatment is directed at reducing tis- to placebo medication. Associated features can include
sue copper levels and maintenance therapy to prevent nonanatomic sensory ndings, give-way weakness, and
reaccumulation. There is no clear consensus on treat- astasia-abasia (an odd, gyrating gait; Chap. 13). Comor-
ment and all patients should be managed in a unit with bid psychiatric problems such as anxiety, depression,
expertise in WD. Penicillamine is frequently used to and emotional trauma may be present, but are not nec-
increase copper excretion, but it may lead to a wors- essary for the diagnosis of a psychogenic movement
ening of symptoms in the initial stages of therapy. disorder to be made. Psychogenic movement disorders
Side effects are common and can to some degree be can occur as an isolated entity or in association with an
attenuated by coadministration of pyridoxine. Tetra- underlying organic problem. The diagnosis can often be
thiomolybdate blocks the absorption of copper and is made based on clinical features alone and unnecessary
used instead of penicillamine in many centers. Trien- tests or medications avoided. Underlying psychiatric
tine and zinc are useful drugs for maintenance therapy. problems may be present and should be identied and
Effective treatment can reverse the neurologic features treated, but many patients with psychogenic movement
in most patients, particularly when started early. Some disorders have no obvious psychiatric pathology. Psy-
patients stabilize and a few may still progress, espe- chotherapy and hypnosis may be of value for patients
cially those with hepatocerebral disease. KF rings tend with conversion reaction, and cognitive behavioral
to decrease after 36 months and disappear by 2 years. therapy may be helpful for patients with somatoform
Adherence to maintenance therapy is a major chal- disorders. Patients with hypochondriasis, factitious dis-
lenge in long-term care. orders, and malingering have a poor prognosis.
CHAPTER 31
ATAXIC DISORDERS
Roger N. Rosenberg
357
358 TABLE 31-1
ETIOLOGY OF CEREBELLAR ATAXIA
SYMMETRIC AND PROGRESSIVE SIGNS FOCAL AND IPSILATERAL CEREBELLAR SIGNS
Intoxication: Intoxication: mer- Paraneoplastic Vascular: cerebellar Neoplastic: cer- Stable gliosis
alcohol, lithium, cury, solvents, syndrome infarction, hemor- ebellar glioma or secondary to
phenytoin, barbi- gasoline, glue; Anti-gliadin rhage, or subdural metastatic tumor vascular lesion
turates (positive cytotoxic che- antibody hematoma (positive for neo- or demyelinating
history and toxi- motherapeutic, syndrome Infectious: cerebel- plasm on MRI/CT) plaque (stable
cology screen) hemotherapeutic Hypothyroidism lar abscess (mass Demyelinating: mul- lesion on MRI/CT
drugs lesion on MRI/CT, tiple sclerosis (his- older than several
history in support tory, CSF, and MRI months)
of lesion) are consistent)
Acute viral cereb- Alcoholic- Inherited diseases AIDS-related Congenital lesion:
ellitis (CSF sup- nutritional Tabes dorsalis (ter- multifocal leuko- Chiari or Dandy-
SECTION III
Abbreviations: CSF, cerebrospinal uid; CT, computed tomography; MRI, magnetic resonance imaging.
Diseases of the Nervous System
chronic infection. Hypothyroidism must always be con- as a Chiari malformation (Chap. 35) or a congenital cyst
sidered as a readily treatable and reversible form of gait of the posterior fossa (Dandy-Walker syndrome).
ataxia. Infectious diseases that can present with ataxia
are meningovascular syphilis and tabes dorsalis due to
degeneration of the posterior columns and spinocer- THE INHERITED ATAXIAS
ebellar pathways in the spinal cord.
These may show autosomal dominant, autosomal reces-
FOCAL ATAXIA Acute focal ataxia commonly sive, or maternal (mitochondrial) modes of inheritance.
results from cerebrovascular disease, usually ischemic A genomic classication (Table 31-2) has now largely
infarction or cerebellar hemorrhage. These lesions typi- superseded previous ones based on clinical expression
cally produce cerebellar symptoms ipsilateral to the alone.
injured cerebellum and may be associated with an Although the clinical manifestations and neuropatho-
impaired level of consciousness due to brainstem com- logic ndings of cerebellar disease dominate the clinical
pression and increased intracranial pressure; ipsilateral picture, there may also be characteristic changes in the
pontine signs, including sixth and seventh nerve pal- basal ganglia, brainstem, spinal cord, optic nerves, ret-
sies, may be present. Focal and worsening signs of acute ina, and peripheral nerves. In large families with domi-
ataxia should also prompt consideration of a posterior nantly inherited ataxias, many gradations are observed
fossa subdural hematoma, bacterial abscess, or primary from purely cerebellar manifestations to mixed cerebel-
or metastatic cerebellar tumor. CT or MRI studies will lar and brainstem disorders, cerebellar and basal ganglia
reveal clinically significant processes of this type. Many syndromes, and spinal cord or peripheral nerve disease.
of these lesions represent true neurologic emergencies, Rarely, dementia is present as well. The clinical picture
as sudden herniation, either rostrally through the tento- may be homogeneous within a family with dominantly
rium or caudal herniation of cerebellar tonsils through inherited ataxia, but sometimes most affected family
the foramen magnum, can occur and is usually devas- members show one characteristic syndrome, while one or
tating. Acute surgical decompression may be required several members have an entirely different phenotype.
(Chap. 28). Lymphoma or progressive multifocal leu-
koencephalopathy (PML) in a patient with AIDS may
present with an acute or subacute focal cerebellar syn-
AUTOSOMAL DOMINANT ATAXIAS
drome. Chronic etiologies of progressive ataxia include The autosomal spinocerebellar ataxias (SCAs) include
multiple sclerosis (Chap. 39) and congenital lesions such SCA types 1 through 28, dentatorubropallidoluysian
TABLE 31-2 359
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS
NAME LOCUS PHENOTYPE
SCA1 (autosomal dominant type 1) 6p22-p23 with CAG repeats (exonic); Ataxia with ophthalmoparesis, pyramidal
leucine-rich acidic nuclear protein and extrapyramidal ndings; genetic
(LANP), region-specic interaction pro- testing is available; 6% of all autosomal
tein dominant (AD) cerebellar ataxia
Ataxin-1
SCA2 (autosomal dominant type 2) 12q23-q24.1 with CAG repeats (exonic) Ataxia with slow saccades and minimal
Ataxin-2 pyramidal and extrapyramidal ndings;
genetic testing available; 13% of all AD
cerebellar ataxia
Machado-Joseph disease/SCA3 14q24.3-q32 with CAG repeats (exonic); Ataxia with ophthalmoparesis and vari-
(autosomal dominant type 3) codes for ubiquitin protease (inactive able pyramidal, extrapyramidal, and
with polyglutamine expansion); altered amyotrophic signs; dementia (mild);
turnover of cellular proteins due to pro- 23% of all AD cerebellar ataxia; genetic
teosome dysfunction testing available
CHAPTER 31
MJDataxin-3
SCA4 (autosomal dominant type 4) 16q22.1-ter; pleckstrin homology Ataxia with normal eye movements, sen-
domain-containing protein, family G, sory axonal neuropathy, and pyramidal
member 4 (PLEKHG4; puratrophin-1: signs; genetic testing available
Purkinje cell atrophy associated
protein-1, including spectrin repeat and
the guanine-nucleotide exchange
Ataxic Disorders
factor, GEF for Rho GTPases)
SCA5 (autosomal dominant type 5) 11p12-q12; -III spectrin mutations Ataxia and dysarthria; genetic testing
(SPTBN2); stabilizes glutamate trans- available
porter EAAT4; descendants of Presi-
dent Abraham Lincoln
SCA6 (autosomal dominant type 6) 19p13.2 with CAG repeats in 1A- Ataxia and dysarthria, nystagmus, mild
voltagedependent calcium channel proprioceptive sensory loss; genetic
gene (exonic); CACNA1A protein, P/Q testing available
type calcium channel subunit
SCA7 (autosomal dominant type 7) 3p14.1-p21.1 with CAG repeats (exonic); Ophthalmoparesis, visual loss, ataxia,
ataxin-7; subunit of GCN5, histone dysarthria, extensor plantar response,
acetyltransferase-containing com- pigmentary retinal degeneration;
plexes; ataxin-7 binding protein; Cbl- genetic testing available
associated protein (CAP; SH3D5)
SCA8 (autosomal dominant type 8) 13q21 with CTG repeats; noncoding; 3 Gait ataxia, dysarthria, nystagmus, leg
untranslated region of transcribed RNA; spasticity, and reduced vibratory sen-
KLHL1AS sation; genetic testing available
SCA10 (autosomal dominant type 10) 22q13; pentanucleotide repeat ATTCT Gait ataxia, dysarthria, nystagmus; par-
repeat; noncoding, intron 9 tial complex and generalized motor sei-
zures; polyneuropathy; genetic testing
available
SCA11 (autosomal dominant type 11) 15q14-q21.3 by linkage Slowly progressive gait and extremity
ataxia, dysarthria, vertical nystagmus,
hyperreexia
SCA12 (autosomal dominant type 12) 5q31-q33 by linkage; CAG repeat; Tremor, decreased movement, increased
protein phosphatase 2A, regulatory reexes, dystonia, ataxia, dysautono-
subunit B (PPP2R2B); protein PP2A, mia, dementia, dysarthria; genetic test-
serine/threonine phosphatase ing available
(continued)
360 TABLE 31-2
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS (CONTINUED)
NAME LOCUS PHENOTYPE
SCA13 (autosomal dominant type 13) 19q13.3-q14.4 Ataxia, legs>arms; dysarthria, horizontal
nystagmus; delayed motor develop-
ment; mental developmental delay;
tendon reexes increased; MRI:
cerebellar and pontine atrophy; genetic
testing available
SCA14 (autosomal dominant type 14) 19q-13.4; protein kinase C (PRKCG), Gait ataxia; leg>arm ataxia; dysarthria;
missense mutations including in-frame pure ataxia with later onset; myoclo-
deletion and a splice site mutation nus; tremor of head and extremities;
among others; serine/threonine kinase increased deep tendon reexes at
ankles; occasional dystonia and sensory
neuropathy; genetic testing available
SCA15 (autosomal dominant type 15) 3p24.2-3pter Gait and extremity ataxia, dysarthria;
nystagmus; MRI: superior vermis
SECTION III
SCA17 (autosomal dominant type 17) 6q27; CAG expansion in the TATA- Gait ataxia, dementia, parkinsonism,
binding protein (TBP) gene dystonia, chorea, seizures; hyperre-
exia; dysarthria and dysphagia; MRI
shows cerebral and cerebellar atrophy;
genetic testing available
SCA18 (autosomal dominant type 18) 7q22-q32 Ataxia; motor/sensory neuropathy; head
tremor; dysarthria; extensor plantar
responses in some patients; sensory
axonal neuropathy; EMG denervation;
MRI: cerebellar atrophy
SCA19 (autosomal dominant type 19) 1p21-q21 Ataxia, tremor, cognitive impairment,
myoclonus; MRI: atrophy of cerebellum
SCA20 (autosomal dominant) 11p13-q11 Dysarthria; gait ataxia; ocular gaze
evoked saccades; palatal tremor; den-
tate calcication on CT; MRI: cerebral
atrophy
SCA21 (autosomal dominant) 7p21.3-p15.1 Ataxia, dysarthria, extrapyramidal
features of akinesia, rigidity, tremor,
cognitive defect; reduced deep tendon
reexes; MRI: cerebellar atrophy,
normal basal ganglia and brainstem
SCA22 (autosomal dominant) 1p21-q23 Pure cerebellar ataxia; dysarthria; dys-
phagia; nystagmus; MRI: cerebellar
atrophy
SCA23 (autosomal dominant) 20p13-12.3 Gait ataxia; dysarthria; extremity ataxia;
ocular nystagmus, dysmetria; leg vibra-
tion loss; extensor plantar responses;
MRI: cerebellar atrophy
(continued)
TABLE 31-2 361
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS (CONTINUED)
NAME LOCUS PHENOTYPE
CHAPTER 31
MRI: cerebellar atrophy; genetic testing
available
SCA28 (autosomal dominant) 18p11.22-q11.2 Extremity and gait ataxia; dysarthria;
nystagmus; ophthalmoparesis; leg
hyperreexia and extensor plantar
responses; MRI: cerebellar atrophy
SCA30 (autosomal dominant) 4q34.3-q35.1 Candidate gene ODZ3; gait ataxia, dys-
Ataxic Disorders
arthria, saccades; nystagmus, brisk
tendon reexes in legs; MRI: cerebellar
atrophy
SCA31 (autosomal dominant) 16q22.1 Pentanucleotide (TGGAA)N repeat inser-
tions; previously called SCA4; gait
ataxia; limb dysmetria; MRI: cerebellar
atrophy
Dentatorubropallidoluysian atrophy 12p13.31 with CAG repeats (exonic) Ataxia, choreoathetosis, dystonia, sei-
(autosomal dominant) Atrophin 1 zures, myoclonus, dementia; genetic
testing available
Friedreichs ataxia (autosomal recessive) 9q13-q21.1 with intronic GAA repeats, Ataxia, areexia, extensor plantar
in intron at end of exon 1 responses, position sense decits, car-
Frataxin defective; abnormal regulation diomyopathy, diabetes mellitus, sco-
of mitochondrial iron metabolism; iron liosis, foot deformities; optic atrophy;
accumulates in mitochondria in yeast late-onset form, as late as 50 years
mutants with preserved deep tendon reexes,
slower progression, reduced skeletal
deformities, associated with an inter-
mediate number of GAA repeats and
missense mutations in one allele of
frataxin; genetic testing available
Friedreichs ataxia (autosomal recessive) 8q13.1-q13.3 (-TTP deciency) Same as phenotype that maps to 9q but
associated with vitamin E deciency;
genetic testing available
Sensory ataxic neuropathy and oph- 15q25; mutations in DNA polymerase- Young adultonset ataxia, sensory neu-
thalmoparesis (SANDO) with dysarthria gamma (POLG) gene that leads to ropathy, ophthalmoparesis, hearing
(autosomal recessive) mtDNA deletions loss, gastric symptoms; a variant of
progressive external ophthalmoplegia;
MRI: cerebellar and thalamic abnor-
malities; mildly increased lactate and
creatine kinase
(continued)
362 TABLE 31-2
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS (CONTINUED)
NAME LOCUS PHENOTYPE
syndrome (MERRF) (maternal inheri- 8344; also mutation at 8356 myopathy, ataxia
tance)
Mitochondrial encephalopathy, tRNAleu mutation at 3243; also at 3271 Headache, stroke, lactic acidosis, ataxia
lactic acidosis, and stroke syndrome and 3252
(MELAS) (maternal inheritance)
Neuropathy; ataxia; retinitis pigmentosa ATPase6 (Complex 5); mtDNA point Neuropathy; ataxia; retinitis pigmentosa;
(NARP) mutation at 8993 dementia; seizures
Episodic ataxia, type 1 (EA-1) 12p13; potassium voltage-gated chan- Episodic ataxia for minutes; provoked by
(autosomal dominant) nel gene, KCNA1; Phe249Leu muta- startle or exercise; with facial and hand
tion; variable syndrome myokymia; cerebellar signs are not pro-
gressive; choreoathetotic movements;
responds to phenytoin; genetic testing
available
Episodic ataxia, type 2 (EA-2) 19p-13(CACNA1A) (allelic with SCA6) Episodic ataxia for days; provoked by
(autosomal dominant) (1A-voltagedependent calcium chan- stress, fatigue; with down-gaze nys-
nel subunit); point mutations or small tagmus; vertigo; vomiting; headache;
deletions; allelic with SCA6 and familial cerebellar atrophy results; progressive
hemiplegic migraine cerebellar signs; responds to acetazol-
amide; genetic testing available
Episodic ataxia, type 3 (autosomal 1q42 Episodic ataxia; 1 min to over 6 h;
dominant) induced by movement; vertigo and
tinnitus; headache; responds to acet-
azolamide
Episodic ataxia, type 4 (autosomal Not mapped Episodic ataxia; vertigo; diplopia; ocular
dominant) slow pursuit defect; no response to
acetazolamide
Episodic ataxia, type 5 (autosomal 2q22-q23; CACNB44 protein Episodic ataxia; hours to weeks; sei-
dominant) zures
Episodic ataxia, type 6 5p13; SLC1A3; glutamate transporter in Episodic ataxia; seizures; cognitive
astrocytes impairment; under 24 h
(continued)
TABLE 31-2 363
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS (CONTINUED)
NAME LOCUS PHENOTYPE
Episodic ataxia, type 7 (autosomal 19q13 Episodic ataxia; vertigo, weakness; less
dominant) than 24 h
Episodic ataxia with seizures, migraine, SLC1A3; 5p13; EAAT1 protein; missense Ataxia, duration 24 days; episodic
and alternating hemiplegia (autosomal mutations; glial glutamate transporter hypotonia; delayed motor milestones;
dominant) (GLAST); 1047 C to G; proline to argi- seizures; migraine; alternating hemiple-
nine gia; mild truncal ataxia; coma; febrile
illness as a trigger; MRI: cerebellar
atrophy
Fragile X tremor/ataxia syndrome Xq27.3; CGG premutation expansion Late-onset ataxia with tremor, cognitive
(FXTAS) X-linked dominant in FMR1 gene; expansions of 55200 impairment, occasional parkinson-
repeats in 5 UTR of the FMR-1 mRNA; ism; males typically affected, although
presumed dominant toxic RNA effect affected females also reported; syn-
drome is of high concern if affected
CHAPTER 31
male has grandson with mental retar-
dation (fragile X syndrome); MRI shows
increased T2 signal in middle cerebellar
peduncles, cerebellar atrophy, and
occasional widespread brain atrophy;
genetic testing available
Ataxia telangiectasia (autosomal reces- 11q22-23; ATM gene for regulation of Telangiectasia, ataxia, dysarthria, pulmo-
Ataxic Disorders
sive) cell cycle; mitogenic signal transduc- nary infections, neoplasms of lymphatic
tion and meiotic recombination system; IgA and IgG deciencies; dia-
betes mellitus, breast cancer; genetic
testing available
Early-onset cerebellar ataxia with 13q11-12 Ataxia; neuropathy; preserved deep
retained deep tendon reexes (autoso- tendon reexes; impaired cognitive and
mal recessive) visuospatial functions; MRI, cerebellar
atrophy
Ataxia with oculomotor apraxia (AOA1) 9p13; protein is member of histidine Ataxia; dysarthria; limb dysmetria; dys-
(autosomal recessive) triad superfamily, role in DNA repair tonia; oculomotor apraxia; optic atro-
phy; motor neuropathy; late sensory
loss (vibration); genetic testing avail-
able
Ataxia with oculomotor apraxia 2 (AOA2) 9q34; senataxin protein, involved in RNA Gait ataxia; choreoathetosis; dysto-
(autosomal recessive) maturation and termination; helicase nia; oculomotor apraxia; neuropathy,
superfamily 1 vibration loss, position sense loss,
and mild light touch loss; absent leg
deep tendon reexes; extensor plantar
response; genetic testing available
Cerebellar ataxia with muscle coenzyme 9p13 Ataxia; hypotonia; seizures; mental retar-
Q10 deciency (autosomal recessive) dation; increased deep tendon reexes;
extensor plantar responses; coenzyme
Q10 levels reduced with about 25%
of patients with a block in transfer of
electrons to complex 3; may respond
to coenzyme 10
Joubert syndrome (autosomal recessive) 9q34.3 Ataxia; ptosis; mental retardation; oculo-
motor apraxia; nystagmus; retinopathy;
rhythmic tongue protrusion; episodic
hyperpnea or apnea; dimples at wrists
and elbows; telecanthus; micrognathia
(continued)
364 TABLE 31-2
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS (CONTINUED)
NAME LOCUS PHENOTYPE
Sideroblastic anemia and spinocerebel- Xq13; ATP-binding cassette 7 (ABCB7; Ataxia; elevated free erythrocyte proto-
lar ataxia (X-linked recessive) ABC7) transporter; mitochondrial inner porphyrin levels; ring sideroblasts in
membrane; iron homeostasis; export bone marrow; heterozygous females
from matrix to the intermembrane may have mild anemia but not ataxia
space
Infantile-onset spinocerebellar ataxia of 10q23.3-q24.1; twinkle protein (gene); Infantile ataxia, sensory neuropathy;
Nikali et al (autosomal recessive) homozygous for Tyr508Cys missense athetosis, hearing decit, reduced deep
mutations tendon reexes; ophthalmoplegia, optic
atrophy; seizures; primary hypogonad-
ism in females
Hypoceruloplasminemia with ataxia and Ceruloplasmin gene; 3q23-q25 Gait ataxia and dysarthria; hyperreexia;
dysarthria (autosomal recessive) (trp 858 ter) cerebellar atrophy by MRI; iron deposi-
tion in cerebellum, basal ganglia, thala-
mus, and liver; onset in the 4th decade
SECTION III
Spinocerebellar ataxia with neuropathy Tyrosyl-DNA phosphodiesterase-1 Onset in 2nd decade; gait ataxia, dysar-
(SCAN1) (autosomal recessive) (TDP-1) 14q31-q32 thria, seizures, cerebellar vermis atro-
phy on MRI, dysmetria
Abbreviations: CSF, cerebrospinal uid; EMG, electromyogram; MRI, magnetic resonance imaging.
Diseases of the Nervous System
atrophy (DRPLA), and episodic ataxia (EA) types 1 and 2 and inducing neuronal apoptosis. An earlier age of onset
(Table 31-2). SCA1, SCA2, SCA3 (Machado-Joseph dis- (anticipation) and more aggressive disease in subsequent
ease [MJD]), SCA6, SCA7, and SCA17 are caused by generations are due to further expansion of the CAG
CAG triplet repeat expansions in different genes. SCA8 triplet repeat and increased polyglutamine number in the
is due to an untranslated CTG repeat expansion, SCA12 mutant ataxin. The most common disorders are discussed
is linked to an untranslated CAG repeat, and SCA10 is later.
caused by an untranslated pentanucleotide repeat. The
clinical phenotypes of these SCAs overlap. The geno-
type has become the gold standard for diagnosis and clas- SCA1
sication. CAG encodes glutamine, and these expanded SCA1 was previously referred to as olivopontocerebellar
CAG triplet repeat expansions result in expanded poly- atrophy, but genomic data have shown that that entity
glutamine proteins, termed ataxins, that produce a toxic represents several different genotypes with overlapping
gain of function with autosomal dominant inheritance. clinical features.
Although the phenotype is variable for any given dis-
ease gene, a pattern of neuronal loss with gliosis is pro-
Symptoms and signs
duced that is relatively unique for each ataxia. Immu-
nohistochemical and biochemical studies have shown SCA1 is characterized by the development in early or
cytoplasmic (SCA2), neuronal (SCA1, MJD, SCA7), and middle adult life of progressive cerebellar ataxia of the
nucleolar (SCA7) accumulation of the specic mutant trunk and limbs, impairment of equilibrium and gait,
polyglutamine-containing ataxin proteins. Expanded slowness of voluntary movements, scanning speech,
polyglutamine ataxins with more than 40 glutamines nystagmoid eye movements, and oscillatory tremor of
are potentially toxic to neurons for a variety of reasons the head and trunk. Dysarthria, dysphagia, and oculo-
including the following: high levels of gene expres- motor and facial palsies may also occur. Extrapyramidal
sion for the mutant polyglutamine ataxin in affected symptoms include rigidity, an immobile face, and par-
neurons; conformational change of the aggregated pro- kinsonian tremor. The reexes are usually normal, but
tein to a -pleated structure; abnormal transport of the knee and ankle jerks may be lost, and extensor plantar
ataxin into the nucleus (SCA1, MJD, SCA7); binding responses may occur. Dementia may be noted but is
to other polyglutamine proteins, including the TATA- usually mild. Impairment of sphincter function is com-
binding transcription protein and the CREB-binding mon, with urinary and sometimes fecal incontinence.
protein, impairing their functions; altering the efciency Cerebellar and brainstem atrophy are evident on MRI
of the ubiquitin-proteosome system of protein turnover; (Fig. 31-1).
Nuclear localization, but not aggregation, of ataxin-1 365
appears to be required for cell death initiated by the
mutant protein.
SCA2
Symptoms and signs
Another clinical phenotype, SCA2, has been described in
patients from Cuba and India. Cuban patients probably
are descendants of a common ancestor, and the popula-
tion may be the largest homogeneous group of patients
with ataxia yet described. The age of onset ranges from
265 years, and there is considerable clinical variability
within families. Although neuropathologic and clini-
cal ndings are compatible with a diagnosis of SCA1,
including slow saccadic eye movements, ataxia, dysar-
CHAPTER 31
thria, parkinsonian rigidity, optic disc pallor, mild spastic-
ity, and retinal degeneration, SCA2 is a unique form of
cerebellar degenerative disease.
FIGURE 31-1
Sagittal MRI of the brain of a 60-year-old man with gait
ataxia and dysarthria due to SCA1, illustrating cerebellar GENETIC CONSIDERATIONS
atrophy (arrows). MRI, magnetic resonance imaging; SCA1,
Ataxic Disorders
spinocerebellar ataxia type 1. The gene in SCA2 families also contains CAG
repeat expansions coding for a polyglutamine-
Marked shrinkage of the ventral half of the pons, dis- containing protein, ataxin-2. Normal alleles con-
appearance of the olivary eminence on the ventral sur- tain 1532 repeats; mutant alleles have 3577 repeats.
face of the medulla, and atrophy of the cerebellum are
evident on gross postmortem inspection of the brain. MACHADO-JOSEPH DISEASE/SCA3
Variable loss of Purkinje cells, reduced numbers of cells
in the molecular and granular layer, demyelination of MJD was rst described among the Portuguese and
the middle cerebellar peduncle and the cerebellar hemi- their descendants in New England and California. Sub-
spheres, and severe loss of cells in the pontine nuclei sequently, MJD has been found in families from Portu-
and olives are found on histologic examination. Degen- gal, Australia, Brazil, Canada, China, England, France,
erative changes in the striatum, especially the putamen, India, Israel, Italy, Japan, Spain, Taiwan, and the United
and loss of the pigmented cells of the substantia nigra States. In most populations, it is the most common
may be found in cases with extrapyramidal features. autosomal dominant ataxia.
More widespread degeneration in the central nervous
system (CNS), including involvement of the posterior Symptoms and signs
columns and the spinocerebellar bers, is often present. MJD has been classied into three clinical types. In type
I MJD (amyotrophic lateral sclerosisparkinsonism
dystonia type), neurologic decits appear in the rst
GENETIC CONSIDERATIONS two decades and involve weakness and spasticity of
extremities, especially the legs, often with dystonia of
SCA1 encodes a gene product, called ataxin-1, the face, neck, trunk, and extremities. Patellar and ankle
which is a novel protein of unknown function. clonus are common, as are extensor plantar responses.
The mutant allele has 40 CAG repeats located The gait is slow and stiff, with a slightly broadened base
within the coding region, whereas alleles from unaf- and lurching from side to side; this gait results from
fected individuals have f36 repeats. A few patients with spasticity, not true ataxia. There is no truncal titubation.
3840 CAG repeats have been described. There is a Pharyngeal weakness and spasticity cause difculty with
direct correlation between a larger number of repeats speech and swallowing. Of note is the prominence of
and a younger age of onset for SCA1. Juvenile patients horizontal and vertical nystagmus, loss of fast saccadic
have higher numbers of repeats, and anticipation is pres- eye movements, hypermetric and hypometric saccades,
ent in subsequent generations. Transgenic mice carry- and impairment of upward vertical gaze. Facial fascicu-
ing SCA1 developed ataxia and Purkinje cell pathology. lations, facial myokymia, lingual fasciculations without
366 atrophy, ophthalmoparesis, and ocular prominence are proprioceptive sensory loss have yielded another locus. Of
common early manifestations. interest is that different mutations in the same gene for the
In type II MJD (ataxic type), true cerebellar decits of 1A voltage-dependent calcium channel subunit (CACN-
dysarthria and gait and extremity ataxia begin in the sec- LIA4; also referred to as the CACNA1A gene) at 19p13
ond to fourth decades along with corticospinal and extra- result in different clinical disorders. CAG repeat expan-
pyramidal decits of spasticity, rigidity, and dystonia. Type sions (2127 in patients; 416 triplets in normal individu-
II is the most common form of MJD. Ophthalmoparesis, als) result in late-onset progressive ataxia with cerebellar
upward vertical gaze decits, and facial and lingual fascicu- degeneration. Missense mutations in this gene result in
lations are also present. Type II MJD can be distinguished familial hemiplegic migraine. Nonsense mutations result-
from the clinically similar disorders SCA1 and SCA2. ing in termination of protein synthesis of the gene product
Type III MJD (ataxic-amyotrophic type) presents yield hereditary paroxysmal cerebellar ataxia or EA. Some
in the fth to the seventh decades with a pancerebellar patients with familial hemiplegic migraine develop pro-
disorder that includes dysarthria and gait and extremity gressive ataxia and also have cerebellar atrophy.
ataxia. Distal sensory loss involving pain, touch, vibra-
tion, and position senses and distal atrophy are promi-
nent, indicating the presence of peripheral neuropathy. SCA7
The deep tendon reexes are depressed to absent, and This disorder is distinguished from all other SCAs by the
SECTION III
there are no corticospinal or extrapyramidal ndings. presence of retinal pigmentary degeneration. The visual
The mean age of onset of symptoms in MJD is abnormalities rst appear as blue-yellow color blindness
25 years. Neurologic decits invariably progress and and proceed to frank visual loss with macular degeneration.
lead to death from debilitation within 15 years of onset, In almost all other respects, SCA7 resembles several other
especially in patients with types I and II disease. Usually, SCAs in which ataxia is accompanied by various noncer-
patients retain full intellectual function. ebellar ndings, including ophthalmoparesis and extensor
Diseases of the Nervous System
The major pathologic ndings are variable loss of plantar responses. The genetic defect is an expanded CAG
neurons and glial replacement in the corpus striatum repeat in the SCA7 gene at 3p14-p21.1. The expanded
and severe loss of neurons in the pars compacta of the repeat size in SCA7 is highly variable. Consistent with
substantia nigra. A moderate loss of neurons occurs in this, the severity of clinical ndings varies from essentially
the dentate nucleus of the cerebellum and in the red asymptomatic to mild late-onset symptoms to severe,
nucleus. Purkinje cell loss and granule cell loss occur in aggressive disease in childhood with rapid progression.
the cerebellar cortex. Cell loss also occurs in the den- Marked anticipation has been recorded, especially with
tate nucleus and in the cranial nerve motor nuclei. Spar- paternal transmission. The disease protein, ataxin-7, forms
ing of the inferior olives distinguishes MJD from other aggregates in nuclei of affected neurons, as has also been
dominantly inherited ataxias. described for SCA1 and SCA3/MJD.
SCA8
GENETIC CONSIDERATIONS This form of ataxia is caused by a CTG repeat expan-
The gene for MJD maps to 14q24.3-q32. Unstable sion in an untranslated region of a gene on chromosome
CAG repeat expansions are present in the MJD 13q21. There is marked maternal bias in transmission,
gene coding for a polyglutamine-containing protein perhaps reecting contractions of the repeat during sper-
named ataxin-3, or MJD-ataxin. An earlier age of onset matogenesis. The mutation is not fully penetrant. Symp-
is associated with longer repeats. Alleles from normal toms include slowly progressive dysarthria and gait ataxia
individuals have between 12 and 37 CAG repeats, while beginning at 40 years of age with a range between 20
MJD alleles have 6084 CAG repeats. Polyglutamine- and 65 years. Other features include nystagmus, leg spas-
containing aggregates of ataxin-3 (MJD-ataxin) have ticity, and reduced vibratory sensation. Severely affected
been described in neuronal nuclei undergoing degenera- individuals are nonambulatory by the fourth to sixth
tion. MJD-ataxin codes for a ubiquitin protease, which decades. MRI shows cerebellar atrophy. The mechanism
is inactive due to expanded polyglutamines. Proteosome of disease may involve a dominant toxic effect occur-
function is impaired, resulting in altered clearance of pro- ring at the RNA level, as occurs in myotonic dystrophy.
teins and cerebellar neuronal loss.
DENTATORUBROPALLIDOLUYSIAN
SCA6 ATROPHY
Genomic screening for CAG repeats in other fami- DRPLA has a variable presentation that may include
lies with autosomal dominant ataxia and vibratory and progressive ataxia, choreoathetosis, dystonia, seizures,
myoclonus, and dementia. DRPLA is due to unstable trunk and extremities), absence of deep tendon reexes, 367
CAG triplet repeats in the open reading frame of a and weakness (greater distally than proximally) are usu-
gene named atrophin located on chromosome 12p12- ally found. Loss of vibratory and proprioceptive sen-
ter. Larger expansions are found in patients with ear- sation occurs. The median age of death is 35 years.
lier onset. The number of repeats is 49 in patients with Women have a signicantly better prognosis than men.
DRPLA and f26 in normal individuals. Anticipation Cardiac involvement occurs in 90% of patients. Car-
occurs in successive generations, with earlier onset of diomegaly, symmetric hypertrophy, murmurs, and con-
disease in association with an increasing CAG repeat duction defects are reported. Moderate mental retar-
number in children who inherit the disease from their dation or psychiatric syndromes are present in a small
father. One well-characterized family in North Caro- percentage of patients. A high incidence of diabetes
lina has a phenotypic variant known as the Haw River mellitus (20%) is found and is associated with insulin
syndrome, now recognized to be due to the DRPLA resistance and pancreatic -cell dysfunction. Musculo-
mutation. skeletal deformities are common and include pes cavus,
pes equinovarus, and scoliosis. MRI of the spinal cord
shows atrophy (Fig. 31-2).
EPISODIC ATAXIA The primary sites of pathology are the spinal cord,
dorsal root ganglion cells, and the peripheral nerves.
CHAPTER 31
EA types 1 and 2 are two rare dominantly inherited dis- Slight atrophy of the cerebellum and cerebral gyri may
orders that have been mapped to chromosomes 12p (a occur. Sclerosis and degeneration occur predominantly
potassium channel gene) for type 1 and 19p for type 2. in the spinocerebellar tracts, lateral corticospinal tracts,
Patients with EA-1 have brief episodes of ataxia with and posterior columns. Degeneration of the glossopha-
myokymia and nystagmus that last only minutes. Startle, ryngeal, vagus, hypoglossal, and deep cerebellar nuclei
sudden change in posture, and exercise can induce epi- is described. The cerebral cortex is histologically normal
sodes. Acetazolamide or anticonvulsants may be thera-
Ataxic Disorders
except for loss of Betz cells in the precentral gyri. The
peutic. Patients with EA-2 have episodes of ataxia with peripheral nerves are extensively involved, with a loss
nystagmus that can last for hours or days. Stress, exer- of large myelinated bers. Cardiac pathology consists of
cise, or excessive fatigue may be precipitants. Acetazol- myocytic hypertrophy and brosis, focal vascular bro-
amide may be therapeutic and can reverse the relative muscular dysplasia with subintimal or medial deposition
intracellular alkalosis detected by magnetic resonance of periodic acidSchiff (PAS)-positive material, myo-
spectroscopy. Stop codon, nonsense mutations causing cytopathy with unusual pleomorphic nuclei, and focal
EA-2 have been found in the CACNA1A gene, encod- degeneration of nerves and cardiac ganglia.
ing the 1A voltage-dependent calcium channel subunit
(see SCA6).
extremely low levels of frataxin mRNA, as compared nuclei. The inferior olives of the medulla may also have
with carriers and unrelated individuals; thus, disease neuronal loss. There is a loss of anterior horn neurons in
appears to be caused by a loss of expression of the frataxin the spinal cord and of dorsal root ganglion cells associ-
protein. Frataxin is a mitochondrial protein involved ated with posterior column spinal cord demyelination.
in iron homeostasis. Mitochondrial iron accumulation A poorly developed or absent thymus gland is the most
due to loss of the iron transporter coded by the mutant consistent defect of the lymphoid system.
Diseases of the Nervous System
CHAPTER 31
appropriate antibiotic therapy should be instituted in tion of symptoms of episodic ataxia. At present, identi-
antibody-positive patients. Aminoacidopathies, leuko- fication of an at-risk persons genotype, together with
dystrophies, urea-cycle abnormalities, and mitochon- appropriate family and genetic counseling, can reduce
drial encephalomyopathies may produce ataxia, and the incidence of these cerebellar syndromes in future
some dietary or metabolic therapies are available for generations.
Ataxic Disorders
CHAPTER 32
370
TABLE 32-1 371
ETIOLOGY OF MOTOR NEURON DISORDERS
DIAGNOSTIC CATEGORY INVESTIGATION
Structural lesions MRI scan of head (including foramen magnum and cervi-
Parasagittal or foramen magnum tumors cal spine)
Cervical spondylosis
Chiari malformation of syrinx
Spinal cord arteriovenous malformation
Infections CSF exam, culture
Bacterialtetanus, Lyme Lyme titer
Viralpoliomyelitis, herpes zoster Anti-viral antibody
Retroviralmyelopathy HTLV-1 titers
Intoxications, physical agents 24-h urine for heavy metals
Toxinslead, aluminum, others Serum lead level
Drugsstrychnine, phenytoin
Electric shock, x-irradiation
CHAPTER 32
Immunologic mechanisms Complete blood counta
Plasma cell dyscrasias Sedimentation ratea
Autoimmune polyradiculopathy Total proteina
Motor neuropathy with conduction block Anti-GM1 antibodiesa
Paraneoplastic Anti-Hu antibody
Paracarcinomatous MRI scan, bone marrow biopsy
Metabolic Fasting blood sugara
a
Denotes studies that should be obtained in all cases.
Abbreviations: CSF, cerebrospinal uid; FUS/TLS, fused in sarcoma/translocated in liposarcoma; HTLV-1, human T cell lymphotropic virus;
PTH, parathyroid; WBC, white blood cell.
do the parasympathetic neurons in the sacral spinal cord evidence of the disease is insidiously developing asym-
(the nucleus of Onufrowicz, or Onuf) that innervate the metric weakness, usually rst evident distally in one of
sphincters of the bowel and bladder. the limbs. A detailed history often discloses recent devel-
opment of cramping with volitional movements, typically
in the early hours of the morning (e.g., while stretching
CLINICAL MANIFESTATIONS
in bed). Weakness caused by denervation is associated
The manifestations of ALS are somewhat variable with progressive wasting and atrophy of muscles and,
depending on whether corticospinal neurons or lower particularly early in the illness, spontaneous twitching of
motor neurons in the brainstem and spinal cord are motor units, or fasciculations. In the hands, a preponder-
more prominently involved. With lower motor neu- ance of extensor over exor weakness is common. When
ron dysfunction and early denervation, typically the rst the initial denervation involves bulbar rather than limb
372 TABLE 32-2 muscles, the problem at onset is difculty with chew-
ing, swallowing, and movements of the face and tongue.
SPORADIC MOTOR NEURON DISEASES
Early involvement of the muscles of respiration may lead
Chronic Entity to death before the disease is far advanced elsewhere.
Upper and lower motor neuron Amyotrophic lateral With prominent corticospinal involvement, there is
Predominantly upper motor sclerosis hyperactivity of the muscle-stretch reexes (tendon jerks)
neuron Primary lateral sclerosis
and, often, spastic resistance to passive movements of the
Predominantly lower motor Multifocal motor neu-
neuron ropathy with conduction affected limbs. Patients with signicant reex hyperactiv-
block ity complain of muscle stiffness often out of proportion to
Motor neuropathy with weakness. Degeneration of the corticobulbar projections
paraproteinemia or innervating the brainstem results in dysarthria and exag-
cancer geration of the motor expressions of emotion. The latter
Motor predominant leads to involuntary excess in weeping or laughing (pseu-
peripheral neuropathies
dobulbar affect).
Other Virtually any muscle group may be the rst to show
Associated with other neurodegenerative disorders signs of disease, but, as time passes, more and more mus-
Secondary motor neuron disorders (see Table 32-1) cles become involved until ultimately the disorder takes
SECTION III
EPIDEMIOLOGY
FIGURE 32-1
Amyotrophic lateral sclerosis. Axial T2-weighted MRI scan The illness is relentlessly progressive, leading to death
through the lateral ventricles of the brain reveals abnormal from respiratory paralysis; the median survival is from
high signal intensity within the corticospinal tracts (arrows). 35 years. There are very rare reports of stabilization
This MRI feature represents an increase in water content in or even regression of ALS. In most societies there is an
myelin tracts undergoing Wallerian degeneration second- incidence of 13 per 100,000 and a prevalence of 35
ary to cortical motor neuronal loss. This nding is com- per 100,000. Several endemic foci of higher prevalence
monly present in ALS, but can also be seen in AIDS-related exist in the western Pacic (e.g., in specic regions of
encephalopathy, infarction, or other disease processes that Guam or Papua New Guinea). In the United States and
produce corticospinal neuronal loss in a symmetric fashion. Europe, males are somewhat more frequently affected
than females. Epidemiologic studies have incriminated cervical spondylosis with osteophytes projecting into 373
risk factors for this disease including exposure to pes- the vertebral canal can produce weakness, wasting, and
ticides and insecticides, smoking, and, in one report, fasciculations in the upper limbs and spasticity in the
service in the military. While ALS is overwhelmingly a legs, closely resembling ALS. The absence of cranial
sporadic disorder, some 510% of cases are inherited as nerve involvement may be helpful in differentiation,
an autosomal dominant trait. although some foramen magnum lesions may compress
the twelfth cranial (hypoglossal) nerve, with resulting
paralysis of the tongue. Absence of pain or of sensory
FAMILIAL ALS changes, normal bowel and bladder function, normal
roentgenographic studies of the spine, and normal cere-
Several forms of selective motor neuron disease are
brospinal uid (CSF) all favor ALS. Where doubt exists,
inheritable (Table 32-3). Familial ALS (FALS) involves
MRI scans and contrast myelography should be per-
both corticospinal and lower motor neurons. Apart
formed to visualize the cervical spinal cord.
from its inheritance as an autosomal dominant trait, it is
Another important entity in the differential diagnosis
clinically indistinguishable from sporadic ALS. Genetic
of ALS is multifocal motor neuropathy with conduction block
studies have identied mutations in the genes encod-
(MMCB), discussed later. A diffuse, lower motor axonal
ing the cytosolic enzyme SOD1 (superoxide dismutase),
neuropathy mimicking ALS sometimes evolves in asso-
CHAPTER 32
and the RNA binding proteins TDP43 (encoded by
ciation with hematopoietic disorders such as lymphoma
the TAR DNA binding protein gene), and FUS/TLS
or multiple myeloma. In this clinical setting, the pres-
(fused in sarcoma/translocated in liposarcoma), as the
ence of an M-component in serum should prompt con-
most common causes of FALS. Mutations in SOD1
sideration of a bone marrow biopsy. Lyme disease may
account for about 20% of cases of FALS, while TDP43
also cause an axonal, lower motor neuropathy, although
and FUS/TLS each represent about 5% of familial cases.
typically with intense proximal limb pain and a CSF
Rare mutations in other genes are also clearly impli-
(continued)
TABLE 32-3 375
GENETIC MOTOR NEURON DISEASES (CONTINUED)
UNUSUAL
DISEASE LOCUS GENE INHERITANCE ONSET GENE FUNCTION FEATURES
CHAPTER 32
SPG31 2p REEP1 AD Early Mitochondrial Rarely, amyo-
protein trophy
SPG33 10q ZFYVE27 AD Adult Interacts with Pes equinus
spastin
SPG42 3q Acetyl-CoA- AD Variable Solute carrier
transporter
(continued)
376 TABLE 32-3
GENETIC MOTOR NEURON DISEASES (CONTINUED)
UNUSUAL
DISEASE LOCUS GENE INHERITANCE ONSET GENE FUNCTION FEATURES
Abbreviations: ALS, amyotrophic lateral sclerosis; BSCL2, Bernadelli-Seip congenital lipodystrophy 2B; FSP, familial spastic paraplegia; FUS/
TLS, fused in sarcoma/translocated in liposarcoma; TDP43, Tar DNA binding protein 43 kd.
in individuals with bizarre behavior and a move- protein, impairment of axonal transport, reduced pro-
duction of ATP and other perturbations of mitochon-
Diseases of the Nervous System
CHAPTER 32
and pramipexole and tamoxifen, which are neuroprotec- onset of the disease.
tive. Interventions such as antisense oligonucleotides
(ASO) that diminish expression of mutant SOD1 protein
prolong survival in transgenic ALS mice and rats and are
Adult Tay-Sachs disease
also now in trial for SOD1-mediated ALS. Several reports have described adult-onset, predomi-
In the absence of a primary therapy for ALS, a vari- nantly lower motor neuropathies arising from de-
ety of rehabilitative aids may substantially assist ALS ciency of the enzyme -hexosaminidase (hex A). These
titers of mono- and polyclonal antibodies to ganglioside In its pure form, FSP is usually transmitted as an auto-
GM1; it is hypothesized that the antibodies produce somal trait; most adult-onset cases are dominantly
selective, focal, paranodal demyelination of motor neu- inherited. Symptoms usually begin in the third or
rons. MMCB is not typically associated with corticospi- fourth decade, presenting as progressive spastic weak-
nal signs. In contrast with ALS, MMCB may respond ness beginning in the distal lower extremities; however,
dramatically to therapy such as IV immunoglobulin or there are variants with onset so early that the differen-
chemotherapy; it is thus imperative that MMCB be
Diseases of the Nervous System
CHAPTER 32
Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases
CHAPTER 33
The autonomic nervous system (ANS) innervates the than could be achieved by the modulation of a single
entire neuraxis and permeates all organ systems. It regu- system.
lates blood pressure (BP), heart rate, sleep, and bladder Acetylcholine (ACh) is the preganglionic neurotrans-
and bowel function. It operates automatically; its full mitter for both divisions of the ANS as well as the post-
importance becomes recognized only when ANS func- ganglionic neurotransmitter of the parasympathetic neu-
tion is compromised, resulting in dysautonomia. Hypo- rons; the preganglionic receptors are nicotinic, and the
thalamic disorders that cause disturbances in homeostasis postganglionic are muscarinic in type. Norepinephrine
are discussed in Chap. 38. (NE) is the neurotransmitter of the postganglionic sym-
pathetic neurons, except for cholinergic neurons inner-
vating the eccrine sweat glands.
ANATOMIC ORGANIZATION
The activity of the ANS is regulated by central neurons
responsive to diverse afferent inputs. After central inte- CLINICAL EVALUATION
gration of afferent information, autonomic outow is
CLASSIFICATION
adjusted to permit the functioning of the major organ
systems in accordance with the needs of the organism Disorders of the ANS may result from pathology of
as a whole. Connections between the cerebral cortex either the CNS or the peripheral nervous system (PNS)
and the autonomic centers in the brainstem coordinate (Table 33-2). Signs and symptoms may result from
autonomic outow with higher mental functions. interruption of the afferent limb, CNS processing cen-
The preganglionic neurons of the parasympathetic ters, or efferent limb of reex arcs controlling auto-
nervous system leave the central nervous system (CNS) nomic responses. For example, a lesion of the medulla
in the third, seventh, ninth, and tenth cranial nerves produced by a posterior fossa tumor can impair BP
as well as the second and third sacral nerves, while the responses to postural changes and result in orthostatic
preganglionic neurons of the sympathetic nervous sys- hypotension (OH). OH can also be caused by lesions
tem exit the spinal cord between the rst thoracic and of the spinal cord or peripheral vasomotor nerve bers
the second lumbar segments (Fig. 33-1). These are (e.g., diabetic autonomic neuropathy). Lesions of the
thinly myelinated. The postganglionic neurons, located efferent limb cause the most consistent and severe OH.
in ganglia outside the CNS, give rise to the postgan- The site of reex interruption is usually established by
glionic unmyelinated autonomic nerves that innervate the clinical context in which the dysautonomia arises,
organs and tissues throughout the body. Responses to combined with judicious use of ANS testing and neuro-
sympathetic and parasympathetic stimulation are fre- imaging studies. The presence or absence of CNS signs,
quently antagonistic (Table 33-1), reecting highly association with sensory or motor polyneuropathy,
coordinated interactions within the CNS; the resultant medical illnesses, medication use, and family history are
changes in parasympathetic and sympathetic activity often important considerations. Some syndromes do not
provide more precise control of autonomic responses t easily into any classication scheme.
380
Parasympathetic Sympathetic
TABLE 33-1 381
FUNCTIONAL CONSEQUENCES OF NORMAL ANS
A
ACTIVATION
III
SYMPATHETIC PARASYMPATHETIC
VII
IX
B X
Heart rate Increased Decreased
Blood pressure Increased Mildly decreased
C
Bladder Increased sphinc- Voiding (decreased
D H ter tone tone)
Bowel motility Decreased motility Increased
J Lung Bronchodilation Bronchoconstric-
E
T1 tion
2
3 Sweat glands Sweating
4 Arm
F
Heart 5 Pupils Dilation Constriction
Heart
6
7
Adrenal glands Catecholamine
release
CHAPTER 33
8 Viscera
9
10 Sexual function Ejaculation, Erection
11 K orgasm
12
L1 Lacrimal glands Tearing
Adrenal medulla
2
(preganglionic Parotid glands Salivation
Bowel supply)
Abbreviations: BP, blood pressure; HR, heart rate; POTS, postural orthostatic tachycardia syndrome.
urinary frequency and small bladder volumes and even- Gastrointestinal autonomic dysfunction typically pres-
tually in incontinence (upper motor neuron or spas- ents as severe constipation. Diarrhea occurs occasionally
tic bladder). By contrast, PNS disease of autonomic (as in diabetes mellitus) due to rapid transit of contents
nerve bers results in large bladder volumes, urinary or uncoordinated small-bowel motor activity, or on an
frequency, and overow incontinence (lower motor osmotic basis from bacterial overgrowth associated with
neuron accid bladder). Measurement of bladder vol- small-bowel stasis. Impaired glandular secretory function
ume (postvoid residual) is a useful bedside test for dis- may cause difculty with food intake due to decreased
tinguishing between upper and lower motor neuron salivation or eye irritation due to decreased lacrimation.
bladder dysfunction in the early stages of dysautonomia. Occasionally, temperature elevation and vasodilation
TABLE 33-3 TABLE 33-4 383
SYMPTOMS OF ORTHOSTATIC INTOLERANCE PREVALENCE OF ORTHOSTATIC HYPOTENSION IN
Lightheadedness (dizziness) 88% DIFFERENT DISORDERS
CHAPTER 33
Source: From PA Low et al: Mayo Clin Proc 70:617, 1995. of OH by medications may also be the first sign of an
underlying autonomic disorder. The history may reveal
can result from anhidrosis because sweating is normally an underlying cause for symptoms (e.g., diabetes, Par-
important for heat dissipation. Lack of sweating after a kinsons disease) or specific underlying mechanisms (e.g.,
hot bath, during exercise, or on a hot day can suggest cardiac pump failure, reduced intravascular volume). The
sudomotor failure. relationship of symptoms to meals (splanchnic pooling),
OH (also called orthostatic or postural hypotension) is standing on awakening in the morning (intravascular
Abbreviations: CCBs, calcium channel blockers; HCTZ, hydrochlo- ger a reduction in heart rate (increased vagal tone), and
rothiazide; SSRIs, selective serotonin reuptake inhibitors. decreases in BP trigger an increase in heart rate (reduced
vagal tone). The Valsalva response is tested in the supine
position. The subject exhales against a closed glottis (or
sought. Standing time to first symptom and presyncope into a manometer maintaining a constant expiratory
should be followed for management. pressure of 40 mmHg) for 15 s while measuring changes
Physical examination includes measurement of supine in heart rate and beat-to-beat BP. There are four phases
and standing pulse and BP. OH is defined as a sustained of BP and heart rate response to the Valsalva maneuver.
drop in systolic (20 mmHg) or diastolic (10 mmHg) BP Phases I and III are mechanical and related to changes in
within 3 min of standing. In nonneurogenic causes of OH intrathoracic and intraabdominal pressure. In early phase
(such as hypovolemia), the BP drop is accompanied by a II, reduced venous return results in a fall in stroke volume
compensatory increase in heart rate of >15 beats/min. A and BP, counteracted by a combination of reflex tachycar-
clue that the patient has neurogenic OH is the aggravation dia and increased total peripheral resistance. Increased
or precipitation of OH by autonomic stressors (such as a total peripheral resistance arrests the BP drop 58 s
meal, hot tub/hot bath, and exercise). Neurologic examina- after the onset of the maneuver. Late phase II begins with
tion should include mental status (neurodegenerative dis- a progressive rise in BP toward or above baseline. Venous
orders), cranial nerves (impaired downgaze with progres- return and cardiac output return to normal in phase IV.
sive supranuclear palsy; abnormal pupils with Horners or Persistent peripheral arteriolar vasoconstriction and
Adies syndrome), motor tone (Parkinsons disease and par- increased cardiac adrenergic tone result in a temporary
kinsonian syndromes), and reflexes and sensation (poly- BP overshoot and phase IV bradycardia (mediated by the
neuropathies). In patients without a clear diagnosis initially, baroreceptor reflex).
follow-up evaluations may reveal the underlying cause. Autonomic function during the Valsalva maneuver
Disorders of autonomic function should be consid- can be measured using beat-to-beat blood pressure or
ered in patients with symptoms of altered sweating heart rate changes. The Valsalva ratio is defined as the
(hyperhidrosis or hypohidrosis), gastroparesis (bloating, maximum phase II tachycardia divided by the minimum
nausea, vomiting of old food), constipation, impotence, phase IV bradycardia (Table 33-8). The ratio reflects the
or bladder dysfunction (urinary frequency, hesitancy, or integrity of the entire baroreceptor reflex arc and of
incontinence). sympathetic efferents to blood vessels.
CHAPTER 33
ACh-induced sweating. A reduced or absent response surface of the body changes color with sweat produc-
indicates a lesion of the postganglionic sudomotor tion during temperature elevation. The pattern of color
axon. For example, sweating may be reduced in the changes is a measure of regional sweat secretion. A
feet as a result of distal polyneuropathy (e.g., diabe- postganglionic lesion is present if both QSART and TST
SPINAL CORD
Spinal cord lesions from any cause may result in focal
autonomic decits or autonomic hyperreexia (e.g.,
spinal cord transection or hemisection) affecting bowel,
bladder, sexual, temperature-regulation, or cardiovascu-
lar functions. Quadriparetic patients exhibit both supine
hypertension and OH after upward tilting. Autonomic
dysreexia describes a dramatic increase in blood pressure
in patients with traumatic spinal cord lesions above the
FIGURE 33-2
SECTION III
CHAPTER 33
liver transplantation can be successful. The response of of autonomic disturbances with OH, enteric neuropa-
primary amyloidosis to melphalan and stem cell trans- thy (gastroparesis, ileus, constipation/diarrhea), and
plantation has been mixed. Death is usually due to car- cholinergic failure; the latter consists of loss of sweating,
diac or renal involvement. Postmortem studies reveal sicca complex, and a tonic pupil. Autoantibodies against
amyloid deposition in many organs, including two sites the ganglionic ACh receptor (A3 AChR) are present in
that contribute to autonomic failure: intraneural blood the serum of many patients and are now considered to
vessels and autonomic ganglia. Pathologic examination be diagnostic of this syndrome. In general, the antibody
that results in low supine plasma NE levels and norad- absent fungiform papillae on the tongue, and labile BP
renergic supersensitivity. Some studies have questioned may be present. Episodic abdominal crises and fever are
the specicity of PAF as a distinct clinical entity. Some common. Pathologic examination of nerves reveals a
cases are ganglionic antibodypositive and thus rep- loss of small myelinated and unmyelinated nerve bers.
resent a type of AAN. Between 10 and 15% of cases The defective gene, named IKBKAP, is also located on
evolve into MSA. the long arm of chromosome 9. Pathogenic mutations
may prevent normal transcription of important mol-
Diseases of the Nervous System
CHAPTER 33
bral infarction, rapidly expanding tumors, subarach-
AND CAUSALGIA
noid hemorrhage, hydrocephalus, or (less commonly)
an acute spinal cord lesion. Lesions involving the dien- The failure to identify a primary role of the ANS in
cephalon may be more prone to present with dysauto- the pathogenesis of these disorders has resulted in a
nomia, but the most consistent setting is that of an acute change of nomenclature. Complex regional pain syn-
intracranial catastrophe of sufcient size and rapidity to drome (CRPS) types I and II are now used in place
produce a massive catecholaminergic surge. The surge of reex sympathetic dystrophy (RSD) and causalgia,
CHAPTER 33
Disorders of the Autonomic Nervous System
CHAPTER 34
2)
nerves; these distinctive disorders are reviewed in this
(V
C2
ry
chapter. Disorders of ocular movement are discussed in
illa
3)
ax
Chap. 21, disorders of hearing in Chap. 24, and vertigo
r (V
M
ula
and disorders of vestibular function in Chap. 11.
n dib
Ma
C3
ANATOMIC CONSIDERATIONS
The trigeminal (fth cranial) nerve supplies sensation
to the skin of the face and anterior half of the head FIGURE 34-1
(Fig. 34-1). Its motor part innervates the masseter and The three major sensory divisions of the trigeminal nerve
pterygoid masticatory muscles. consist of the ophthalmic, maxillary, and mandibular nerves.
392
Pathophysiology 393
TREATMENT Trigeminal Neuralgia
Symptoms result from ectopic generation of action
potentials in pain-sensitive afferent bers of the fth Drug therapy with carbamazepine is effective in 50
cranial nerve root just before it enters the lateral sur- 75% of patients. Carbamazepine should be started
face of the pons. Compression or other pathology in as a single daily dose of 100 mg taken with food and
the nerve leads to demyelination of large myelinated increased gradually (by 100 mg daily in divided doses
bers that do not themselves carry pain sensation but every 12 days) until substantial (>50%) pain relief is
become hyperexcitable and electrically coupled with achieved. Most patients require a maintenance dose of
smaller unmyelinated or poorly myelinated pain bers 200 mg qid. Doses >1200 mg daily provide no additional
in close proximity; this may explain why tactile stimuli, benefit. Dizziness, imbalance, sedation, and rare cases of
conveyed via the large myelinated bers, can stimu- agranulocytosis are the most important side effects of
late paroxysms of pain. Compression of the trigeminal carbamazepine. If treatment is effective, it is usually con-
nerve root by a blood vessel, most often the superior tinued for 1 month and then tapered as tolerated. Oxcar-
cerebellar artery or on occasion a tortuous vein, is the bazepine (3001200 mg bid) is an alternative to carbam-
source of trigeminal neuralgia in a substantial proportion azepine, has less bone marrow toxicity, and probably is
of patients. In cases of vascular compression, age-related equally efficacious. If these agents are not well tolerated
CHAPTER 34
brain sagging and increased vascular thickness and tortu- or are ineffective, lamotrigine 400 mg daily or phenytoin,
osity may explain the prevalence of trigeminal neuralgia 300400 mg daily, are other options. Baclofen may also
in later life. be administered, either alone or in combination with an
anticonvulsant. The initial dose is 510 mg tid, gradually
increasing as needed to 20 mg qid.
Differential diagnosis If drug treatment fails, surgical therapy should be
offered. The most widely used method currently is micro-
can affect the rst (ophthalmic) division; the accompa- facial muscles.
nying corneal anesthesia increases the risk of ulceration A complete interruption of the facial nerve at the sty-
(neuro keratitis). lomastoid foramen paralyzes all muscles of facial expres-
Loss of sensation over the chin (mental neuropathy) sion. The corner of the mouth droops, the creases and
can be the only manifestation of systemic malignancy. skinfolds are effaced, the forehead is unfurrowed, and
Rarely, an idiopathic form of trigeminal neuropathy is the eyelids will not close. Upon attempted closure of the
observed. It is characterized by numbness and paresthe- lids, the eye on the paralyzed side rolls upward (Bells
Diseases of the Nervous System
sias, sometimes bilaterally, with loss of sensation in the phenomenon). The lower lid sags and falls away from the
territory of the trigeminal nerve but without weakness conjunctiva, permitting tears to spill over the cheek.
of the jaw. Gradual recovery is the rule. Tonic spasm Food collects between the teeth and lips, and saliva may
of the masticatory muscles, known as trismus, is symp- dribble from the corner of the mouth. The patient com-
tomatic of tetanus or may occur in patients treated with plains of a heaviness or numbness in the face, but sensory
phenothiazine drugs. loss is rarely demonstrable and taste is intact.
If the lesion is in the middle-ear portion, taste is lost
over the anterior two-thirds of the tongue on the same
side. If the nerve to the stapedius is interrupted, there is
hyperacusis (sensitivity to loud sounds). Lesions in the
TABLE 34-1 internal auditory meatus may affect the adjacent audi-
TRIGEMINAL NERVE DISORDERS tory and vestibular nerves, causing deafness, tinnitus, or
Nuclear (brainstem) Peripheral nerve lesions dizziness. Intrapontine lesions that paralyze the face usu-
lesions Nasopharyngeal carcinoma ally affect the abducens nucleus as well, and often the
Multiple sclerosis Trauma corticospinal and sensory tracts.
Stroke Guillain-Barr syndrome If the peripheral facial paralysis has existed for some
Syringobulbia Sjgrens syndrome time and recovery of motor function is incomplete, a
Glioma Collagen-vascular diseases continuous diffuse contraction of facial muscles may
Lymphoma Sarcoidosis
appear. The palpebral ssure becomes narrowed, and
Preganglionic lesions Leprosy
Acoustic neuroma Drugs (stilbamidine, the nasolabial fold deepens. Attempts to move one
Meningioma trichloroethylene) group of facial muscles may result in contraction of all
Metastasis Idiopathic trigeminal (associated movements, or synkinesis). Facial spasms, ini-
Chronic meningitis neuropathy tiated by movements of the face, may develop (hemifacial
Cavernous carotid spasm). Anomalous regeneration of seventh nerve bers
aneurysm may result in other troublesome phenomena. If bers
Gasserian ganglion
originally connected with the orbicularis oculi come
lesions
Trigeminal neuroma
to innervate the orbicularis oris, closure of the lids may
Herpes zoster cause a retraction of the mouth, or if bers originally
Infection (spread from otitis connected with muscles of the face later innervate the
media or mastoiditis) lacrimal gland, anomalous tearing (crocodile tears)
may occur with any activity of the facial muscles, such
395
Superior
salivatory
nucleus Geniculate Major superficial
Motor nucleus ganglion petrosal nerve Lacrimal gland
VI n. Trigeminal
V n. ganglion
Motor nucleus
VII n. 1
2
Nucleus 3
C
fasciculus Pterygopalatine
solitarius VII n. B ganglion
To nasal and
A palatine glands
Fasciculus Chorda
solitarius tympani
CHAPTER 34
Lingual
nerve
Sublingual gland
Submandibular
ganglion Submandibular gland
as eating. Another facial synkinesia is triggered by jaw and that it may be incomplete. The presence of incom-
opening, causing closure of the eyelids on the side of plete paralysis in the rst week is the most favorable
the facial palsy (jaw-winking). prognostic sign.
Pathophysiology
BELLS PALSY
In acute Bells palsy there is inammation of the facial
The most common form of facial paralysis is Bells palsy. nerve with mononuclear cells, consistent with an infec-
The annual incidence of this idiopathic disorder is 25 per tious or immune cause. Herpes simplex virus (HSV) type
100,000 annually, or about 1 in 60 persons in a lifetime. 1 DNA was frequently detected in endoneurial uid and
posterior auricular muscle, suggesting that a reactivation
Clinical manifestations of this virus in the geniculate ganglion may be respon-
sible for most cases. Reactivation of varicella zoster virus
The onset of Bells palsy is fairly abrupt, maximal weak-
is associated with Bells palsy in up to one-third of cases,
ness being attained by 48 h as a general rule. Pain
and may represent the second most frequent cause. A
behind the ear may precede the paralysis for a day or
variety of other viruses have also been implicated less
two. Taste sensation may be lost unilaterally, and hyper-
commonly. An increased incidence of Bells palsy was
acusis may be present. In some cases there is mild cere-
also reported among recipients of inactivated intranasal
brospinal uid lymphocytosis. MRI may reveal swelling
inuenza vaccine, and it was hypothesized that this could
and uniform enhancement of the geniculate ganglion
have resulted from the Escherichia coli enterotoxin used as
and facial nerve and, in some cases, entrapment of the
adjuvant or to reactivation of latent virus.
swollen nerve in the temporal bone. Approximately
80% of patients recover within a few weeks or months.
Differential diagnosis
Electromyography may be of some prognostic value;
evidence of denervation after 10 days indicates there There are many other causes of acute facial palsy that
has been axonal degeneration, that there will be a long must be considered in the differential diagnosis of Bells
delay (3 months as a rule) before regeneration occurs, palsy. Lyme disease can cause unilateral or bilateral facial
396 palsies; in endemic areas, 10% or more of cases of facial
palsy are likely due to infection with Borrelia burgdorferi.
The Ramsay Hunt syndrome, caused by reactivation of
herpes zoster in the geniculate ganglion, consists of a
severe facial palsy associated with a vesicular eruption in
the external auditory canal and sometimes in the phar-
ynx and other parts of the cranial integument; often the
eighth cranial nerve is affected as well. Facial palsy that
is often bilateral occurs in sarcoidosis and in Guillain-
Barr syndrome (Chap. 46). Leprosy frequently involves
the facial nerve, and facial neuropathy may also occur
in diabetes mellitus, connective tissue diseases includ-
ing Sjgrens syndrome, and amyloidosis. The rare
Melkersson-Rosenthal syndrome consists of recurrent facial
paralysis; recurrentand eventually permanentfacial
(particularly labial) edema; and, less constantly, plication
of the tongue. Its cause is unknown. Acoustic neuromas
SECTION III
CHAPTER 34
enon or with varying degrees of spasm of other facial the trapezius and sternocleidomastoid muscles make up
muscles. Severe, persistent cases of blepharospasm can the jugular foramen syndrome (Table 34-2).
be treated by local injection of botulinum toxin into
the orbicularis oculi. Facial myokymia refers to a ne
rippling activity of the facial muscles; it may be caused
DYSPHAGIA AND DYSPHONIA
by multiple sclerosis or follow Guillain-Barr syndrome
(Chap. 46). When the intracranial portion of one vagus (tenth cra-
Sphenoid ssure (superior orbital) III, IV, rst division V, VI Invasive tumors of sphenoid bone; aneurysms
Lateral wall of cavernous sinus III, IV, rst division V, VI, often with Infection, thrombosis, aneurysm, or stula
proptosis of cavernous sinus; invasive tumors from
sinuses and sella turcica; benign granuloma
responsive to glucocorticoids
Retrosphenoid space II, III, IV, V, VI Large tumors of middle cranial fossa
Apex of petrous bone V, VI Petrositis; tumors of petrous bone
Internal auditory meatus VII, VIII Tumors of petrous bone (dermoids, etc.);
infectious processes; acoustic neuroma
Pontocerebellar angle V, VII, VIII, and sometimes IX Acoustic neuroma; meningioma
Jugular foramen IX, X, XI Tumors and aneurysms
SECTION III
Posterior laterocondylar space IX, X, XI, XII Tumors of parotid gland and carotid body
and metastatic tumors
Posterior retroparotid space IX, X, XI, XII, and Horner syndrome Tumors of parotid gland, carotid body, lymph
nodes; metastatic tumor; tuberculous adenitis
Diseases of the Nervous System
CHAPTER 34
some cases of multiple cranial neuropathy, and chronic Anatomy of the cavernous sinus in coronal section, illus-
glandular tuberculosis the cause of a few others. Platyba- trating the location of the cranial nerves in relation to the vas-
sia, basilar invagination of the skull, and the Chiari mal- cular sinus, internal carotid artery (which loops anteriorly to
formation are additional causes. A purely motor disorder the section), and surrounding structures.
without atrophy always raises the question of myasthenia
gravis (Chap. 47). As noted earlier, Guillain-Barr syn-
400
mately the first lumbar vertebral body. The lower spinal ened deep tendon reflexes, Babinski signs, and eventual
401
nerves take an increasingly downward course to exit spasticity (the upper motor neuron syndrome). Trans-
via intervertebral foramens. The first seven pairs of cer- verse damage to the cord also produces autonomic
vical spinal nerves exit above the same-numbered ver- disturbances consisting of absent sweating below the
tebral bodies, whereas all the subsequent nerves exit implicated cord level and bladder, bowel, and sexual
below the same-numbered vertebral bodies because dysfunction.
of the presence of eight cervical spinal cord segments The uppermost level of a spinal cord lesion can also
but only seven cervical vertebrae. The relationship be localized by attention to the segmental signs corre-
between spinal cord segments and the corresponding sponding to disturbed motor or sensory innervation by
vertebral bodies is shown in Table 35-2. These relation- an individual cord segment. A band of altered sensation
ships assume particular importance for localization of (hyperalgesia or hyperpathia) at the upper end of the
lesions that cause spinal cord compression. Sensory sensory disturbance, fasciculations or atrophy in mus-
loss below the circumferential level of the umbilicus, for cles innervated by one or several segments, or a muted
example, corresponds to the T10 cord segment but indi- or absent deep tendon reflex may be noted at this level.
cates involvement of the cord adjacent to the seventh These signs also can occur with focal root or peripheral
or eighth thoracic vertebral body (Figs. 15-2 and 15-3). nerve disorders; thus, they are most useful when they
CHAPTER 35
In addition, at every level the main ascending and occur together with signs of long tract damage. With
descending tracts are somatotopically organized with a severe and acute transverse lesions, the limbs initially
laminated distribution that reflects the origin or destina- may be flaccid rather than spastic. This state of spinal
tion of nerve fibers. shock lasts for several days, rarely for weeks, and should
not be mistaken for extensive damage to the anterior
Determining the Level of the Lesion The
horn cells over many segments of the cord or for an
presence of a horizontally defined level below which
acute polyneuropathy.
ing pathways of the spinal cord are shown in Fig. 35-1. drome produces arm weakness out of proportion to leg
Most fiber tractsincluding the posterior columns and weakness and a dissociated sensory loss, meaning loss
the spinocerebellar and pyramidal tractsare situated of pain and temperature sensations over the shoulders,
on the side of the body they innervate. However, affer- lower neck, and upper trunk (cape distribution), in con-
ent fibers mediating pain and temperature sensation trast to preservation of light touch, joint position, and
ascend in the spinothalamic tract contralateral to the vibration sense in these regions. Spinal trauma, syringo-
Diseases of the Nervous System
side they supply. The anatomic configurations of these myelia, and intrinsic cord tumors are the main causes.
Posterior Columns
(Joint Position, Vibration, Pressure)
Fasciculus Fasciculus
cuneatus gracilis Anterior horn
Dorsal root
Dorsal (motor neurons)
spinocerebellar S
T L
tract C
Lateral
corticospinal
Ventral L/ Distal limb
(pyramidal) tract
spinocerebellar S
movements
tract S
L Rubrospinal
T
C tract
L/
S T C
L
S Lateral
F
P reticulospinal
D
Lateral E tract
spinothalamic
tract
S L T C Vestibulospinal
Pain, tract Axial and
temperature Ventral proximal
reticulospinal limb
Ventral tract movements
root Ventral Tectospinal
spinothalamic Ventral tract
tract (uncrossed)
corticospinal
Pressure, touch tract
(minor role)
Distal limb
movements
(minor role)
FIGURE 35-1
Transverse section through the spinal cord, compos- spinothalamic tracts ascend contralateral to the side of the
ite representation, illustrating the principal ascending (left) body that is innervated. C, cervical; D, distal; E, extensors; F,
and descending (right) pathways. The lateral and ventral exors; L, lumbar; P, proximal; S, sacral; T, thoracic.
Anterior Spinal Artery Syndrome Infarction
symptoms initially simulate Guillain-Barr syndrome, 403
of the cord is generally the result of occlusion or dimin-
but involvement of the trunk with a sharply demarcated
ished flow in this artery. The result is extensive bilateral
spinal cord level indicates the myelopathic nature of the
tissue destruction that spares the posterior columns. All
process. In severe and abrupt cases, areexia reecting
spinal cord functionsmotor, sensory, and autonomic
spinal shock may be present, but hyperreexia super-
are lost below the level of the lesion, with the striking
venes over days or weeks; persistent areexic paralysis
exception of retained vibration and position sensation.
with a sensory level indicates necrosis over multiple seg-
ments of the spinal cord.
Foramen Magnum Syndrome Lesions in this
area interrupt decussating pyramidal tract fibers des-
tined for the legs, which cross caudal to those of the APPROACH TO THE Compressive and Noncompressive
arms, resulting in weakness of the legs (crural paresis). PATIENT Myelopathy
Compressive lesions near the foramen magnum may
produce weakness of the ipsilateral shoulder and arm DISTINGUISHING COMPRESSIVE FROM
followed by weakness of the ipsilateral leg, then the NONCOMPRESSIVE MYELOPATHY The first
contralateral leg, and finally the contralateral arm, an priority is to exclude a treatable compression of the
around-the-clock pattern that may begin in any of the cord by a mass. The common causes are tumor, epidu-
CHAPTER 35
four limbs. There is typically suboccipital pain spreading ral abscess or hematoma, herniated disk, or vertebral
to the neck and shoulders. pathology. Epidural compression due to malignancy
Intramedullary and Extramedullary Syn- or abscess often causes warning signs of neck or back
dromes It is useful to differentiate intramedullary pain, bladder disturbances, and sensory symptoms
processes, arising within the substance of the cord, from that precede the development of paralysis. Spinal sub-
extramedullary ones that compress the spinal cord or luxation, hemorrhage, and noncompressive etiologies
CHAPTER 35
FIGURE 35-4
MRI of an intramedullary astrocytoma. Sagittal T1-weighted
postcontrast image through the cervical spine demonstrates
expansion of the upper cervical spine by a mass lesion ema-
nating from within the spinal cord at the cervicomedullary
FIGURE 35-3
of polymorphonuclear cells, an elevated protein level, MRI of a spinal epidural abscess due to tuberculosis.
and a reduced glucose level, but the responsible organism A. Sagittal T2-weighted free spin-echo MR sequence. A
is not cultured unless there is associated meningitis. Blood hypointense mass replaces the posterior elements of C3
cultures are positive in <25% of cases. and extends epidurally to compress the spinal cord (arrows).
B. Sagittal T1-weighted image after contrast administra-
tion reveals a diffuse enhancement of the epidural process
(arrows) with extension into the epidural space.
Diseases of the Nervous System
Treatment is by decompressive laminectomy with Treatment consists of prompt reversal of any underly-
debridement combined with long-term antibiotic treat- ing clotting disorder and surgical decompression. Surgery
ment. Surgical evacuation prevents development of paral- may be followed by substantial recovery, especially in
ysis and may improve or reverse paralysis in evolution, but patients with some preservation of motor function preop-
it is unlikely to improve deficits of more than several days eratively. Because of the risk of hemorrhage, lumbar punc-
duration. Broad-spectrum antibiotics should be started ture should be avoided whenever possible in patients with
empirically before surgery and then modified on the basis severe thrombocytopenia or other coagulopathies.
of culture results; medication is continued for at least
4 weeks. If surgery is contraindicated or if there is a fixed
Hematomyelia
paraplegia or quadriplegia that is unlikely to improve fol-
lowing surgery, long-term administration of systemic and Hemorrhage into the substance of the spinal cord is a rare
oral antibiotics can be used; in such cases, the choice of result of trauma, intraparenchymal vascular malforma-
antibiotics may be guided by results of blood cultures. tion (see later in the chapter), vasculitis due to polyarteri-
However, paralysis may develop or progress during anti- tis nodosa or systemic lupus erythematosus (SLE), bleeding
biotic therapy; thus, initial surgical management remains disorders, or a spinal cord neoplasm. Hematomyelia pres-
the treatment of choice unless the abscess is limited in ents as an acute painful transverse myelopathy. With large
size and causes few or no neurologic signs. lesions, extension into the subarachnoid space results in
With prompt diagnosis and treatment of spinal epi- subarachnoid hemorrhage (Chap. 28). Diagnosis is by MRI
dural abscess, up to two-thirds of patients experience or CT. Therapy is supportive, and surgical intervention is
significant recovery. generally not useful. An exception is hematomyelia due to
an underlying vascular malformation, for which selective
spinal angiography may be indicated, followed by surgery
Spinal epidural hematoma to evacuate the clot and remove the underlying vascular
Hemorrhage into the epidural (or subdural) space causes lesion.
acute focal or radicular pain followed by variable signs of a
spinal cord or conus medullaris disorder. Therapeutic anti-
NONCOMPRESSIVE MYELOPATHIES
coagulation, trauma, tumor, or blood dyscrasias are predis-
posing conditions. Rare cases complicate lumbar puncture The most frequent causes of noncompressive acute
or epidural anesthesia. MRI and CT conrm the clinical transverse myelopathy (ATM) are spinal cord infarc-
suspicion and can delineate the extent of the bleeding. tion; systemic inammatory disorders, including SLE and
TABLE 35-3 two-thirds of the spinal cord; the posterior spinal arter- 407
EVALUATION OF ACUTE TRANSVERSE MYELOPATHY ies, which often become less distinct below the midtho-
1. MRI of spinal cord with and without contrast (exclude racic level, supply the posterior columns.
compressive causes). Spinal cord ischemia can occur at any level; however,
2. CSF studies: Cell count, protein, glucose, IgG index/ the presence of the artery of Adamkiewicz creates a water-
synthesis rate, oligoclonal bands, VDRL; Grams stain, shed of marginal blood ow in the upper thoracic seg-
acid-fast bacilli, and India ink stains; PCR for VZV, ments. With systemic hypotension or cross-clamping of
HSV-2, HSV-1, EBV, CMV, HHV-6, enteroviruses, HIV; the aorta, cord infarction occurs at the level of greatest
antibody for HTLV-I, Borrelia burgdorferi, Mycoplasma
ischemic risk, usually T3-T4, and also at boundary zones
pneumoniae, and Chlamydia pneumoniae; viral, bacte-
rial, mycobacterial, and fungal cultures. between the anterior and posterior spinal artery territories
3. Blood studies for infection: HIV; RPR; IgG and IgM which may result in a rapidly progressive syndrome (over
enterovirus antibody; IgM mumps, measles, rubella, hours) of weakness and spasticity with little sensory change.
group B arbovirus, Brucella melitensis, Chlamydia psittaci, Acute infarction in the territory of the anterior spinal
Bartonella henselae, schistosomal antibody; cultures for artery produces paraplegia or quadriplegia, dissociated
B. melitensis. Also consider nasal/pharyngeal/anal cul- sensory loss affecting pain and temperature sense but
tures for enteroviruses; stool O&P for Schistosoma ova.
sparing vibration and position sense, and loss of sphinc-
4. Immune-mediated disorders: ESR; ANA; ENA; dsDNA;
ter control (anterior cord syndrome). Onset may be
CHAPTER 35
rheumatoid factor; anti-SSA; anti-SSB, complement
levels; antiphospholipid and anticardiolipin antibodies; sudden and dramatic but more typically is progressive
p-ANCA; antimicrosomal and antithyroglobulin antibodies; over minutes or a few hours, quite unlike stroke in the
if Sjgren syndrome suspected, Schirmer test, salivary cerebral hemispheres. Sharp midline or radiating back
gland scintography, and salivary/lacrimal gland biopsy. pain localized to the area of ischemia is frequent. Are-
5. Sarcoidosis: Serum angiotensin-converting enzyme; exia due to spinal shock is often present initially; with
serum Ca; 24-h urine Ca; chest x-ray; chest CT; total time, hyperreexia and spasticity appear. Less common
body gallium scan; lymph node biopsy.
barrier associated with inammation, is present in many mixed connective tissue disease, Behets syndrome, vascu-
acute cases. A brain MRI is most helpful in gauging the litis with perinuclear antineutrophilic cytoplasmic antibod-
likelihood that a case of myelitis represents an initial ies (p-ANCA), and primary CNS vasculitis.
attack of MS. A normal scan indicates that the risk of Another important consideration in this group is sar-
evolution to MS is low, 1015% over 5 years; in con- coid mye-lopathy that may present as a slowly progressive
trast, the nding of multiple periventricular T2-bright or relapsing disorder. MRI reveals an edematous swelling
lesions indicates a much higher risk, >50% over 5 years of the spinal cord that may mimic tumor; there is almost
Diseases of the Nervous System
and >90% by 14 years. The CSF may be normal, but always gadolinium enhancement of active lesions and
more often there is a mild mononuclear cell pleocytosis, in some cases of the adjacent surface of the cord; lesions
with normal or mildly elevated CSF protein levels; oli- may be single or multiple, and on axial images, enhance-
goclonal bands are variable, but when bands are present, ment of the central cord is usually present. The typical
a diagnosis of MS is more likely. CSF prole consists of a variable lymphocytic pleocytosis
There are no adequate trials of therapy for MS- and mildly elevated protein level; in a minority of cases
associated transverse myelitis. Intravenous methyl- reduced glucose and oligoclonal bands are found. The
prednisolone (500 mg qd for 3 days) followed by oral diagnosis is particularly difcult when systemic mani-
prednisone (1 mg/kg per day for several weeks, then festations of sarcoid are minor or absent (nearly 50% of
gradual taper) has been used as initial treatment. A cases) or when other typical neurologic manifestations of
course of plasma exchange is indicated for severe cases the diseasesuch as cranial neuropathy, hypothalamic
if glucocorticoids are ineffective. involvement, or meningeal enhancement visualized by
MRIare lacking. A slit-lamp examination of the eye to
Neuromyelitis optica
search for uveitis; chest x-ray and CT to assess pulmonary
NMO is an immune-mediated demyelinating disor- involvement; and mediastinal lymphadenopathy, serum
der consisting of a severe myelopathy that is typically or CSF angiotensin-converting enzyme (ACE; present in
longitudinally extensive, meaning that the lesion spans only a minority of cases), serum calcium, and a gallium
three or more vertebral segments. NMO is associated scan may assist in the diagnosis. The usefulness of spinal
with optic neuritis that is often bilateral and may pre- uid ACE is uncertain. Initial treatment is with oral glu-
cede or follow myelitis by weeks or months, and also by cocorticoids; immunosuppressant drugs are used for resis-
brainstem and in some cases hypothalamic involvement. tant cases.
However, isolated recurrent myelitis without optic
nerve involvemement can occur in NMO; affected indi- Postinfectious myelitis
viduals are usually female, and often of Asian ancestry. Many cases of myelitis, termed postinfectious or postvac-
CSF studies reveal a variable mononuclear pleocytosis cinal, follow an infection or vaccination. Numerous
of up to several hundred cells per microliter; unlike MS, organisms have been implicated, including Epstein-Barr
oligoclonal bands are generally absent. Diagnostic serum virus (EBV), cytomegalovirus (CMV), mycoplasma,
autoantibodies against the water channel protein aqua- inuenza, measles, varicella, rubeola, and mumps. As
porin-4 are present in 6070% of patients with NMO. in the related disorder acute disseminated encephalo-
NMO has also been associated with SLE and antiphos- myelitis (Chap. 39), postinfectious myelitis often begins
pholipid antibodies (see later) as well as with other con- as the patient appears to be recovering from an acute
nective tissue diseases; rare cases are paraneoplastic in febrile infection, or in the subsequent days or weeks,
but an infectious agent cannot be isolated from the ner- tissue overgrowth on nerve roots results in radicular arm 409
vous system or spinal uid. The presumption is that the pain, most often in a C5 or C6 distribution. Compres-
myelitis represents an autoimmune disorder triggered by sion of the cervical cord, which occurs in fewer than
infection and is not due to direct infection of the spinal one-third of cases, produces a slowly progressive spastic
cord. No randomized controlled trials of therapy exist; paraparesis, at times asymmetric and often accompanied
treatment is usually with glucocorticoids or, in fulmi- by paresthesias in the feet and hands. Vibratory sense
nant cases, plasma exchange. is diminished in the legs, there is a Romberg sign, and
occasionally there is a sensory level for vibration on the
Acute infectious myelitis upper thorax. In some cases, coughing or straining pro-
Many viruses have been associated with an acute myeli- duces leg weakness or radiating arm or shoulder pain.
tis that is infectious in nature rather than postinfectious. Dermatomal sensory loss in the arms, atrophy of intrin-
Nonetheless, the two processes are often difcult to sic hand muscles, increased deep-tendon reexes in the
distinguish. Herpes zoster is the best characterized viral legs, and extensor plantar responses are common. Uri-
myelitis, but herpes simplex virus (HSV) types 1 and 2, nary urgency or incontinence occurs in advanced cases,
EBV, CMV, and rabies virus are other well-described but there are many alternative causes of these prob-
causes. HSV-2 (and less commonly HSV-1) produces a lems in older individuals. A tendon reex in the arms is
distinctive syndrome of recurrent sacral myelitis in asso- often diminished at some level, most often at the biceps
CHAPTER 35
ciation with outbreaks of genital herpes mimicking MS. (C5-C6). In individual cases, radicular, myelopathic, or
Poliomyelitis is the prototypic viral myelitis, but it is combined signs may predominate. The diagnosis should
more or less restricted to the gray matter of the cord. be considered in cases of progressive cervical myelopa-
Chronic viral myelitic infections, such as that due to thy, paresthesias of the feet and hands, or wasting of the
HIV, are discussed later. hands.
Bacterial and mycobacterial myelitis (most are essen- Diagnosis is usually made by MRI and may be sus-
detects many but not all AVMs (Fig. 35-6). An uncer- made by demonstration of HTLV-Ispecic antibody in
tain proportion not detected by MRI may be visualized serum by enzyme-linked immunosorbent assay (ELISA),
by CT myelography as enlarged vessels along the surface conrmed by radioimmunoprecipitation or Western
of the cord. Denitive diagnosis requires selective spinal blot analysis. There is no effective treatment, but symp-
angiography, which denes the feeding vessels and the tomatic therapy for spasticity and bladder symptoms may
extent of the malformation. Endovascular embolization be helpful.
Diseases of the Nervous System
SYRINGOMYELIA
Syringomyelia is a developmental cavity of the cervical
cord that is prone to enlarge and produce progressive
myelopathy. Symptoms begin insidiously in adoles-
cence or early adulthood, progress irregularly, and may
undergo spontaneous arrest for several years. Many
young patients acquire a cervical-thoracic scoliosis.
More than half of all cases are associated with Chiari
type 1 malformations in which the cerebellar tonsils
protrude through the foramen magnum and into the
cervical spinal canal. The pathophysiology of syrinx
expansion is controversial, but some interference with
FIGURE 35-6
the normal ow of CSF seems likely, perhaps by the
Arteriovenous malformation. Sagittal MR scans of the
Chiari malformation. Acquired cavitations of the cord
thoracic spinal cord: T2 fast spin-echo technique (left) and
T1 postcontrast image (right). On the T2-weighted image
in areas of necrosis are also termed syrinx cavities; these
(left), abnormally high signal intensity is noted in the central
follow trauma, myelitis, necrotic spinal cord tumors,
aspect of the spinal cord (arrowheads). Numerous punctate and chronic arachnoiditis due to tuberculosis and other
ow voids indent the dorsal and ventral spinal cord (arrow). etiologies.
These represent the abnormally dilated venous plexus The presentation is a central cord syndrome consisting
supplied by a dural arteriovenous stula. After contrast of dissociated sensory loss (loss of pain and temperature
administration (right), multiple, serpentine, enhancing veins sensation with sparing of touch and vibration) and are-
(arrows) on the ventral and dorsal aspect of the thoracic exic weakness in the upper limbs. The sensory decit
spinal cord are visualized, diagnostic of arteriovenous mal- has a distribution that is suspended over the nape of
formation. This patient was a 54-year-old man with a 4-year the neck, shoulders, and upper arms (cape distribution)
history of progressive paraparesis. or in the hands. Most cases begin asymmetrically with
unilateral sensory loss in the hands that leads to injuries 411
and burns that are not appreciated by the patient. Muscle TREATMENT Syringomyelia
wasting in the lower neck, shoulders, arms, and hands
Treatment of syringomyelia is generally unsatisfactory. The
with asymmetric or absent reexes in the arms reects
Chiari tonsillar herniation is usually decompressed, gener-
expansion of the cavity into the gray matter of the cord.
ally by suboccipital craniectomy, upper cervical laminec-
As the cavity enlarges and further compresses the long
tomy, and placement of a dural graft. Obstruction of fourth
tracts, spasticity and weakness of the legs, bladder and
ventricular outflow is reestablished by this procedure. If the
bowel dysfunction, and a Horners syndrome appear.
syrinx cavity is large, some surgeons recommend direct
Some patients develop facial numbness and sensory loss
decompression or drainage by one of a number of meth-
from damage to the descending tract of the trigeminal
ods, but the added benefit of this procedure is uncertain,
nerve (C2 level or above). In cases with Chiari mal-
and morbidity is common. With Chiari malformations,
formations, cough-induced headache and neck, arm,
shunting of hydrocephalus should generally precede any
or facial pain are reported. Extension of the syrinx into
attempt to correct the syrinx. Surgery may stabilize the
the medulla, syringobulbia, causes palatal or vocal cord
neurologic deficit, and some patients improve.
paralysis, dysarthria, horizontal or vertical nystagmus,
Syringomyelia secondary to trauma or infection is
episodic dizziness or vertigo, and tongue weakness with
treated with a decompression and drainage procedure in
atrophy.
CHAPTER 35
which a small shunt is inserted between the syrinx cavity
MRI scans accurately identify developmental and
and the subarachnoid space; alternatively, the cavity can
acquired syrinx cavities and their associated spinal cord
be fenestrated. Cases due to intramedullary spinal cord
enlargement (Fig. 35-7). MRI scans of the brain and the
tumor are generally managed by resection of the tumor.
entire spinal cord should be obtained to delineate the
full longitudinal extent of the syrinx, assess posterior
fossa structures for the Chiari malformation, and deter-
loplasmin. Some cases follow gastrointestinal procedures beginning later in adulthood and without adrenal insuf-
that result in impaired copper absorption; others have ciency. Diagnosis is usually made by demonstration of
been associated with excess zinc from health food supple- elevated levels of very long chain fatty acids in plasma
ments or, until recently, use of zinc-containing denture and in cultured broblasts. The responsible gene
creams, which impair copper absorption via induction of encodes ADLP, a peroxisomal membrane transporter
metallothionein, a copper-binding protein. Many cases that is a member of the ATP-binding cassette (ABC)
Diseases of the Nervous System
are idiopathic. Improvement or at least stabilization may family. Steroid replacement is indicated if hypoadrenal-
be expected with reconstitution of copper stores by oral ism is present, and bone marrow transplantation and
supplementation. The pathophysiology and pathology of nutritional supplements have been attempted for this
the idiopathic form are not known. condition without clear evidence of efcacy.
CHAPTER 35
ed only through periodic reassessment. tent catheterization, or, if that is not feasible, by use
of a condom catheter in men or a permanent indwell-
ing catheter. Surgical options include the creation of an
REHABILITATION OF articial bladder by isolating a segment of intestine that
SPINAL CORD DISORDERS can be catheterized intermittently (enterocystoplasty) or
can drain continuously to an external appliance (urinary
TABLE 35-4
EXPECTED NEUROLOGIC FUNCTION FOLLOWING COMPLETE CORD LESIONS
LEVEL SELF-CARE TRANSFERS MAXIMUM MOBILITY
Source: Adapted from JF Ditunno, CS Formal: N Engl J Med 330:550, 1994; with permission.
414 Spasticity is aided by stretching exercises to main- to diminish their quality of life. Randomized controlled
tain mobility of joints. Drug treatment is effective studies indicate that gabapentin or pregabalin is useful in
but may result in reduced function, as some patients this setting. Management of chronic pain is discussed in
depend upon spasticity as an aid to stand, transfer, Chap. 7.
or walk. Baclofen (15240 mg/d in divided doses) is A paroxysmal autonomic hyperreexia may occur
effective; it acts by facilitating -aminobutyric acid following lesions above the major splanchnic sympa-
(GABA)-mediated inhibition of motor reex arcs. thetic outow at T6. Headache, ushing, and diapho-
Diazepam acts by a similar mechanism and is useful for resis above the level of the lesion, as well as transient
leg spasms that interrupt sleep (24 mg at bedtime). severe hypertension with bradycardia or tachycardia, are
Tizanidine (28 mg tid), an 2-adrenergic agonist that the major symptoms. The trigger is typically a noxious
increases presynaptic inhibition of motor neurons, is stimulusfor example, bladder or bowel distention, a
another option. For nonambulatory patients, the direct urinary tract infection, or a decubitus ulcer. Treatment
muscle inhibitor dantrolene (25100 mg qid) may consists of removal of offending stimuli; ganglionic
be used, but it is potentially hepatotoxic. In refrac- blocking agents (mecamylamine, 2.55 mg) or other
tory cases, intrathecal baclofen administered via an short-acting antihypertensive drugs are useful in some
implanted pump, botulinum toxin injections, or dorsal patients.
rhizotomy may be required to control spasticity. Attention to these details allows longevity and a
SECTION III
Despite the loss of sensory function, many patients productive life for patients with complete transverse
with spinal cord injury experience chronic pain sufcient myelopathies.
Diseases of the Nervous System
CHAPTER 36
Allan H. Ropper
Almost 10 million head injuries occur annually in the brain within the skull due to inertia and rotation
United States, about 20% of which are serious enough of the cerebral hemispheres on the relatively xed
to cause brain damage. Among men <35 years, accidents, upper brainstem. Loss of consciousness in concussion
usually motor vehicle collisions, are the chief cause of is believed to result from a transient electrophysi-
death and >70% of these involve head injury. Further- ologic dysfunction of the reticular activating system
more, minor head injuries are so common that almost in the upper midbrain that is at the site of rotation
all physicians will be called upon to provide immediate (Chap. 17).
care or to see patients who are suffering from various Gross and light-microscopic changes in the brain
sequelae. are usually absent following concussion but biochemical
Medical personnel caring for head injury patients should and ultrastructural changes, such as mitochondrial ATP
be aware that (1) spinal injury often accompanies head depletion and local disruption of the blood-brain barrier,
injury, and care must be taken in handling the patient to are transient abnormalities. CT and MRI scans are usually
prevent compression of the spinal cord due to instability of normal; however, a small number of patients will be
the spinal column; (2) intoxication is a common accom- found to have a skull fracture, an intracranial hemor-
paniment of traumatic brain injury and, when appropriate, rhage, or brain contusion.
testing should be carried out for drugs and alcohol; and (3) A brief period of both retrograde and anterograde
additional injuries, including rupture of abdominal organs, amnesia is characteristic of concussion and it recedes
may produce vascular collapse or respiratory distress that rapidly in alert patients. Memory loss spans the moments
requires immediate attention. before impact but may encompass the previous days or
weeks (rarely months). With severe injuries, the extent
of retrograde amnesia roughly correlates with the severity
of injury. Memory is regained from the most distant to
TYPES OF HEAD INJURIES more recent memories, with islands of amnesia occa-
sionally remaining. The mechanism of amnesia is not
CONCUSSION
known. Hysterical posttraumatic amnesia is not uncommon
This form of minor head injury refers to an immediate after head injury and should be suspected when inex-
and transient loss of consciousness that is associated plicable behavioral abnormalities occur, such as recounting
with a short period of amnesia. Many patients do not events that cannot be recalled on later testing, a bizarre
lose consciousness after a minor head injury but instead affect, forgetting ones own name, or a persistent
are dazed or confused, or feel stunned or star struck. anterograde decit that is excessive in comparison with the
Severe concussion may precipitate a brief convulsion degree of injury. Amnesia is discussed in Chap. 18.
or autonomic signs such as facial pallor, bradycardia, A single, uncomplicated concussion only infre-
faintness with mild hypotension, or sluggish pupillary quently produces permanent neurobehavioral changes
reaction, but most patients are quickly neurologically in patients who are free of preexisting psychiatric and
normal. neurologic problems. Nonetheless, residual problems
The mechanics of a typical concussion involve sudden in memory and concentration may have an anatomic
deceleration of the head when hitting a blunt object. correlate in microscopic cerebral lesions (later in the
This creates an anterior-posterior movement of the chapter).
415
416 CONTUSION, BRAIN HEMORRHAGE, AND some subarachnoid bleeding. Blood in the cerebrospinal
AXONAL SHEARING LESIONS uid (CSF) due to trauma may provoke a mild inam-
matory reaction. Over a few days, contusions acquire a
A surface bruise of the brain, or contusion, consists of surrounding contrast enhancement and edema that may
varying degrees of petechial hemorrhage, edema, and be mistaken for tumor or abscess. Glial and macrophage
tissue destruction. Contusions and deeper hemorrhages reactions result in chronic, scarred, hemosiderin-stained
result from mechanical forces that displace and compress depressions on the cortex (plaques jaunes) that are the
the hemispheres forcefully and by deceleration of the main source of posttraumatic epilepsy.
brain against the inner skull, either under a point of Torsional or shearing forces within the brain cause
impact (coup lesion) or, as the brain swings back, in the hemorrhages of the basal ganglia and other deep regions.
antipolar area (contrecoup lesion). Trauma sufcient Large hemorrhages after minor trauma suggest that there
to cause prolonged unconsciousness usually produces is a bleeding diathesis or cerebrovascular amyloidosis. For
some degree of contusion. Blunt deceleration impact, as unexplained reasons, deep cerebral hemorrhages may not
occurs against an automobile dashboard or from falling develop until several days after injury. Sudden neuro-
forward onto a hard surface, causes contusions on the logic deterioration in a comatose patient or a sudden rise
orbital surfaces of the frontal lobes and the anterior and in intracranial pressure (ICP) suggests this complication
basal portions of the temporal lobes. With lateral forces, and should therefore prompt investigation with a CT
SECTION III
FIGURE 36-2
FIGURE 36-1 Multiple small areas of hemorrhage and tissue disruption
Traumatic cerebral contusion. Noncontrast CT scan dem- in the white matter of the frontal lobes on noncontrast CT
onstrating a hyperdense hemorrhagic region in the anterior scan. These appear to reect an extreme type of the diffuse
temporal lobe. axonal shearing lesions that occur with closed head injury.
SKULL FRACTURES orbits. Depressed skull fractures are typically compound, 417
but they are often asymptomatic because the impact
A blow to the skull that exceeds the elastic tolerance of energy is dissipated in breaking the bone; some have
the bone causes a fracture. Intracranial lesions accompany underlying brain contusions. Debridement and explo-
roughly two-thirds of skull fractures and the presence of ration of compound fractures are required in order to
a fracture increases many-fold the chances of an under- avoid infection; simple fractures do not require surgery.
lying subdural or epidural hematoma. Consequently,
fractures are primarily markers of the site and severity of
CRANIAL NERVE INJURIES
injury. They also provide potential pathways for entry
of bacteria to the CSF with a risk of meningitis and The cranial nerves most often injured with head trauma
for leakage of CSF outward through the dura. Severe are the olfactory, optic, oculomotor, and trochlear; the
orthostatic headache results from lowered pressure in rst and second branches of the trigeminal nerve; and
the spinal uid compartment. the facial and auditory nerves. Anosmia and an apparent
Most fractures are linear and extend from the point loss of taste (actually a loss of perception of aromatic
of impact toward the base of the skull. Basilar skull frac- avors, with retained elementary taste perception) occur
tures are often extensions of adjacent linear fractures in 10% of persons with serious head injuries, particularly
over the convexity of the skull but may occur indepen- from falls on the back of the head. This is the result of
CHAPTER 36
dently owing to stresses on the oor of the middle cranial displacement of the brain and shearing of the ne olfac-
fossa or occiput. Basilar fractures are usually parallel to tory nerve laments that course through the cribriform
the petrous bone or along the sphenoid bone and directed bone. At least partial recovery of olfactory and gustatory
toward the sella turcica and ethmoidal groove. Although function is expected, but if bilateral anosmia persists for
most basilar fractures are uncomplicated, they can cause several months, the prognosis is poor. Partial optic
CSF leakage, pneumocephalus, and cavernous-carotid nerve injuries from closed trauma result in blurring of
stulas. Hemotympanum (blood behind the tympanic vision, central or paracentral scotomas, or sector defects.
by these hematomas can be life threatening, making it from damage in each region can usually be detected.
imperative to identify them rapidly by CT or MRI scan The bleeding that causes larger hematomas is primarily
and to remove them when appropriate. venous in origin, although additional arterial bleeding
sites are sometimes found at operation, and a few large
Acute subdural hematoma (Fig. 36-3) hematomas have a purely arterial origin.
Direct cranial trauma may be minor and is not required
Diseases of the Nervous System
FIGURE 36-3
Acute subdural hematoma. Noncontrast CT scan reveals a FIGURE 36-4
hyperdense clot which has an irregular border with the brain Acute epidural hematoma. The tightly attached dura is
and causes more horizontal displacement (mass effect) than stripped from the inner table of the skull, producing a charac-
might be expected from its thickness. The disproportionate teristic lenticular-shaped hemorrhage on noncontrast CT scan.
mass effect is the result of the large rostral-caudal extent of Epidural hematomas are usually caused by tearing of the middle
these hematomas. Compare to Fig. 36-4. meningeal artery following fracture of the temporal bone.
sequence. Rapid surgical evacuation and ligation or and intermixed serous uid. Bilateral chronic hemato- 419
cautery of the damaged vessel is indicated, usually the mas may fail to be detected because of the absence of
middle meningeal artery that has been lacerated by an lateral tissue shifts; this circumstance in an older patient
overlying skull fracture. is suggested by a hypernormal CT scan with fullness
of the cortical sulci and small ventricles. Infusion of
Chronic subdural hematoma (Fig. 36-5) contrast material demonstrates enhancement of the vas-
cular brous capsule surrounding the collection. MRI
A history of trauma may or may not be elicited in relation reliably identies subacute and chronic hematomas.
to chronic subdural hematoma; the injury may have Clinical observation coupled with serial imaging is a
been trivial and forgotten, particularly in the elderly and reasonable approach to patients with few symptoms, such
those with clotting disorders. Headache is common but as headache alone, and small chronic subdural collections.
not invariable. Additional features may include slowed Treatment of minimally symptomatic chronic subdural
thinking, vague change in personality, seizure, or a mild hematoma with glucocorticoids is favored by some clini-
hemiparesis. The headache uctuates in severity, some- cians, but surgical evacuation is more often successful. The
times with changes in head position. Bilateral chronic brous membranes that grow from the dura and encapsu-
subdural hematomas produce perplexing clinical syndromes late the collection require removal to prevent recurrent uid
and the initial clinical impression may be of a stroke, brain accumulation. Small hematomas are resorbed, leaving only
CHAPTER 36
tumor, drug intoxication, depression, or a dementing the organizing membranes. On imaging studies very
illness. Drowsiness, inattentiveness, and incoherence of chronic subdural hematomas are difcult to distinguish
thought are more generally prominent than focal signs from hygromas, which are collections of CSF from a
such as hemiparesis. Rarely, chronic hematomas cause rent in the arachnoid membrane.
brief episodes of hemiparesis or aphasia that are indistin-
guishable from transient ischemic attacks. Patients with
individual then undertakes a graduated program of terested, slowed mental state (abulia) alternating with
activity until there are no further symptoms with exercise irascibility (inferior frontal and frontopolar contusions);
(Table 36-1). These guidelines are designed in part (3) a focal decit such as aphasia or mild hemiparesis
TABLE 36-1
GUIDELINES FOR MANAGEMENT OF CONCUSSION IN SPORTS
Diseases of the Nervous System
Severity of Concussion
Grade 1: Transient confusion, no loss of consciousness (LOC), all symptoms resolve within 15 min.
Grade 2: Transient confusion, no LOC, but concussive symptoms or mental status abnormalities persist longer than 15 min.
Grade 3: Any LOC, either brief (seconds) or prolonged (minutes).
On-Site Evaluation
1. Mental status testing
a. Orientationtime, place, person, circumstances of injury
b. Concentrationdigits backward, months of year in reverse order
c. Memorynames of teams, details of contest, recent events, recall of three words and objects at 0 and 5 min
2. Finger-to-nose with eyes open and closed
3. Pupillary symmetry and reaction
4. Romberg and tandem gait
5. Provocative testing40-yard sprint, 5 push ups, 5 sit ups, 5 knee bends (development of dizziness, headaches, or other
symptoms is abnormal)
Management Guidelines
Grade 1: Remove from contest. Examine immediately and at 5-min intervals. May return to contest if exam clears within 15 min.
A second grade 1 concussion eliminates player for 1 week, with return contingent upon normal neurologic assessment at rest
and with exertion.
Grade 2: Remove from contest, cannot return for at least 1 week. Examine at frequent intervals on sideline. Formal neurologic
exam the next day. If headache or other symptoms persist for 1 week or longer, CT or MRI scan is indicated. After 1 full
asymptomatic week, repeat neurologic assessment at rest and with exercise before cleared to resume play. A second grade 2
concussion eliminates player for at least 2 weeks following complete resolution of symptoms at rest or with exertion. If imaging
shows abnormality, player is removed from play for the season.
Grade 3: Transport by ambulance to emergency department if still unconscious or worrisome signs are present; cervical spine
stabilization may be indicated. Neurologic exam and, when indicated, CT or MRI scan will guide subsequent management.
Hospital admission indicated when signs of pathology are present or if mental status remains abnormal. If ndings are normal
at the time of the initial medical evaluation, the athlete may be sent home, but daily exams as an outpatient are indicated. A
brief (LOC for seconds) grade 3 concussion eliminates player for 1 week, and a prolonged (LOC for minutes) grade 3 concussion
for 2 weeks, following complete resolution of symptoms. A second grade 3 concussion should eliminate player from sports
for at least 1 month following resolution of symptoms. Any abnormality on CT or MRI scans should result in termination of the
season for the athlete, and return to play at any future time should be discouraged.
Source: Modied from Quality Standards Subcommittee of the American Academy of Neurology: The American Academy of Neurology Practice
Handbook. The American Academy of Neurology, St. Paul, MN, 1997.
(due to subdural hematoma or convexity contusion, or, TABLE 36-2 421
less often, carotid artery dissection); (4) confusion and GLASGOW COMA SCALE FOR HEAD INJURY
inattention, poor performance on simple mental tasks,
EYE OPENING (E) VERBAL RESPONSE (V)
and uctuating orientation (associated with several types
of injuries, including those described earlier and with Spontaneous 4 Oriented 5
medial frontal contusions and interhemispheric subdural To loud voice 3 Confused, 4
hematoma); (5) repetitive vomiting, nystagmus, drowsi- disoriented
ness, and unsteadiness (labyrinthine concussion, but To pain 2 Inappropriate 3
words
occasionally due to a posterior fossa subdural hematoma
Nil 1 Incomprehensible 2
or vertebral artery dissection); and (6) diabetes insipidus sounds
(damage to the median eminence or pituitary stalk). Nil 1
Injuries of this degree are often complicated by drug or alcohol
BEST MOTOR RESPONSE (M)
intoxication, and clinically inapparent cervical spine injury may
be present. Obeys 6
After surgical removal of hematomas, most patients Localizes 5
in this category improve over weeks. During the rst Withdraws (exion) 4
week, the state of alertness, memory, and other cogni- Abnormal exion 3
CHAPTER 36
posturing
tive functions often uctuate, and agitation is common.
Extension posturing 2
Behavioral changes tend to be worse at night, as with Nil 1
many other encephalopathies, and may be treated with
small doses of antipsychotic medications. Subtle abnor- Note: Coma score = E + M + V. Patients scoring 3 or 4 have an
malities of attention, intellect, spontaneity, and memory 85% chance of dying or remaining vegetative, while scores >11
return toward normal weeks or months after the injury, indicate only a 510% likelihood of death or vegetative state and
85% chance of moderate disability or good recovery. Intermediate
TABLE 37-1
INTRODUCTION
SYMPTOMS AND SIGNS AT PRESENTATION OF
Primary brain tumors are diagnosed in approximately BRAIN TUMORS
52,000 people each year in the United States. At least HIGH- LOW-
one-half of these tumors are malignant and associated GRADE GRADE
GLIOMA GLIOMA MENINGIOMA METASTASES
with a high mortality rate. Glial tumors account for about (%) (%) (%) (%)
60% of all primary brain tumors, and 80% of those are
malignant neoplasms. Meningiomas account for 25%, Generalized
vestibular schwannomas 10%, and central nervous sys- Impaired 50 10 30 60
tem (CNS) lymphomas about 2%. Brain metastases are cognitive
function
three times more common than all primary brain tumors
combined and are diagnosed in approximately 150,000 Hemiparesis 40 10 36 60
people each year. Metastases to the leptomeninges and Headache 50 40 37 50
epidural space of the spinal cord each occur in approxi- Lateralizing
mately 35% of patients with systemic cancer and are also
Seizures 20 70+ 17 18
a major cause of neurologic disability in this population.
Aphasia 20 <5 18
Visual eld 7
decit
APPROACH TO THE Primary and Metastatic Tumors of the
PATIENT Nervous System
CLINICAL FEATURES Brain tumors of any type to the side of a tumor. Occasionally, headaches have
can present with a variety of symptoms and signs that features of a typical migraine with unilateral throb-
fall into two categories: general and focal; patients often bing pain associated with visual scotoma. Personality
have a combination of the two (Table 37-1). General changes may include apathy and withdrawal from social
or nonspecific symptoms include headache, cogni- circumstances, mimicking depression. Focal or lateral-
tive difficulties, personality change, and gait disorder. izing findings include hemiparesis, aphasia, or visual
Generalized symptoms arise when the enlarging tumor field defect. Lateralizing symptoms such as hemipare-
and its surrounding edema cause an increase in intra- sis are typically subacute and progressive. A visual field
cranial pressure or direct compression of cerebrospinal defect is often not noticed by the patient; its presence
fluid (CSF) circulation leading to hydrocephalus. The may only be revealed after it leads to an injury such as
classic headache associated with a brain tumor is most an automobile accident occurring in the blind visual
evident in the morning and improves during the day, field. Language difficulties may be mistaken for con-
but this particular pattern is actually seen in a minor- fusion. Seizures are a common presentation of brain
ity of patients. Headache may be accompanied by nau- tumors, occurring in about 25% of patients with brain
sea or vomiting when intracranial pressure is elevated. metastases or malignant gliomas but can be the pre-
Headaches are often holocephalic but can be ipsilateral senting symptom in up to 90% of patients with low-
423
424 grade gliomas. Most seizures have a focal signature that surgery, radiotherapy (RT), and chemotherapy. However,
reflects their location in the brain and many proceed to symptomatic treatments apply to brain tumors of any
secondary generalization. All generalized seizures that type. Most high-grade malignancies are accompanied
arise from a brain tumor will have a focal onset whether by substantial surrounding edema, which contributes
or not it is apparent clinically. to neurologic disability and raised intracranial pres-
NEUROIMAGING Cranial MRI is the preferred diag-
sure. Glucocorticoids are highly effective at reducing
nostic test for any patient suspected of having a brain perilesional edema and improving neurologic function,
tumor, and should be performed with gadolinium con- often within hours of administration. Dexamethasone
trast administration. CT scan should be reserved for has been the glucocorticoid of choice because of its
those patients unable to undergo MRI (e.g., pacemaker). relatively low mineralocorticoid activity. Initial doses are
Malignant brain tumorswhether primary or meta- typically 12 mg to 16 mg a day in divided doses given
statictypically enhance with gadolinium and may orally or IV (both are equivalent). While glucocorticoids
have central areas of necrosis; they are characteristically rapidly ameliorate symptoms and signs, their long-
surrounded by edema of the neighboring white matter. term use causes substantial toxicity including insomnia,
Low-grade gliomas typically do not enhance with gad- weight gain, diabetes mellitus, steroid myopathy, and
olinium and are best appreciated on fluid-attenuated personality changes. Consequently, a taper is indicated
as definitive treatment is administered and the patient
SECTION III
TABLE 37-2
GENETIC SYNDROMES ASSOCIATED WITH PRIMARY BRAIN TUMORS
CHAPTER 37
SYNDROME INHERITANCE GENE/PROTEIN ASSOCIATED TUMORS
a
Various DNA mismatch repair gene mutations may cause a similar clinical phenotype, also referred to as Turcots syndrome, in which there is a
predisposition to nonpolyposis colon cancer and brain tumors.
Abbreviations: AD, autosomal dominant; APC, adenomatous polyposis coli; AR, autosomal recessive; ch, chromosome; PTEN, phosphatase
and tensin homologue; TSC, tuberous sclerosis complex.
426 Cell-of-Origin: Stem/Progenitor Cells
Secondary Glioblastoma (WHO Grade IV)* Primary Glioblastoma (WHO Grade IV)*
FIGURE 37-1
Diseases of the Nervous System
Genetic and chromosomal alterations involved in the heterozygosity; MDM2, murine double minute 2; PDGF,
development of primary and secondary glioblastomas. platelet-derived growth factor; PDGFR, platelet-derived growth
A slash indicates one or the other or both. DCC, deleted factor receptor; PIK3CA, phosphatidylinositol 3-kinase, cata-
in colorectal carcinoma; EGFR, epidermal growth fac- lytic; PTEN, phosphatase and tensin homologue; RB, retino-
tor receptor; IDH, isocitrate dehydrogenase; LOH, loss of blastoma; WHO, World Health Organization.
novo and are characterized by EGFR amplication and in eradicating these tumors. There is intense interest in
mutations, and deletion or mutation of PTEN. Second- developing therapeutic strategies that effectively target
ary glioblastomas arise in younger patients as lower- tumor stem cells.
grade tumors and transform over a period of several
years into glioblastomas. These tumors have inactivation
of the p53 tumor suppressor gene, overexpression of INTRINSIC MALIGNANT TUMORS
PDGFR, and mutations of the isocitrate dehydrogenase
1 and 2 genes. Despite their genetic differences, primary ASTROCYTOMAS
and secondary glioblastomas are morphologically indis-
These are inltrative tumors with a presumptive glial
tinguishable, although they are likely to respond differ-
cell of origin. The World Health Organization (WHO)
ently to molecular therapies. The molecular subtypes of
classies astrocytomas into four prognostic grades based
medulloblastomas are also being elucidated. Approxi-
on histologic features: grade I (pilocytic astrocytoma,
mately 25% of medulloblastomas have activating muta-
subependymal giant cell astrocytoma); grade II (dif-
tions of the sonic hedgehog signaling pathway, raising
fuse astrocytoma); grade III (anaplastic astrocytoma);
the possibility that inhibitors of this pathway may have
and grade IV (glioblastoma). Grades I and II are con-
therapeutic potential.
sidered low-grade, and grades III and IV high-grade,
The adult nervous system contains neural stem cells
astrocytomas.
that are capable of self-renewal, proliferation, and dif-
ferentiation into distinctive mature cell types. There Low-grade astrocytoma
is increasing evidence that neural stem cells, or related These tumors occur predominantly in children and
progenitor cells, can be transformed into tumor stem young adults.
cells and give rise to primary brain tumors, including
gliomas and medulloblastomas. These stem cells appear Grade I astrocytomas
to be more resistant to standard therapies than the Pilocytic astrocytomas (WHO grade I) are the most
tumor cells themselves and contribute to the difculty common tumor of childhood. They occur typically in
the cerebellum but may also be found elsewhere in the maximal safe surgical resection followed by radiotherapy 427
neuraxis, including the optic nerves and brainstem. Fre- with concurrent and adjuvant temozolomide, or with
quently they appear as cystic lesions with an enhanc- radiotherapy and adjuvant temozolomide alone.
ing mural nodule. They are potentially curable if they
can be completely resected. Giant cell subependymal Grade IV astrocytoma (glioblastoma)
astrocytomas are usually found in the ventricular wall Glioblastoma accounts for the majority of high-grade
of patients with tuberous sclerosis. They often do not astrocytomas. They are the most common cause of
require intervention but can be treated surgically or malignant primary brain tumors, with over 10,000 cases
with inhibitors of the mammalian target of rapamycin diagnosed each year in the United States. Patients usu-
(mTOR). ally present in the sixth and seventh decades of life with
headache, seizures, or focal neurologic decits. The
Grade II astrocytomas
tumors appear as ring-enhancing masses with central
These are inltrative tumors that usually present with
necrosis and surrounding edema (Fig. 37-3). These are
seizures in young adults. They appear as nonenhancing
highly inltrative tumors, and the areas of increased T2/
tumors with increased T2/FLAIR signal (Fig. 37-2).
FLAIR signal surrounding the main tumor mass con-
If feasible, patients should undergo maximal surgical
tain invading tumor cells. Treatment involves maxi-
resection, although complete resection is rarely possible
mal surgical resection followed by partial-eld external
CHAPTER 37
because of the invasive nature of the tumor. Radiother-
beam radiotherapy (6000 cGy in thirty 200-cGy frac-
apy is helpful, but there is no difference in overall sur-
tions) with concomitant temozolomide, followed by
vival between radiotherapy administered postoperatively
612 months of adjuvant temozolomide. With this regi-
or delayed until the time of tumor progression. There is
men, median survival is increased to 14.6 months com-
increasing evidence that chemotherapeutic agents such
pared to only 12 months with radiotherapy alone, and
as temozolomide, an oral alkylating agent, can be help-
2-year survival is increased to 27%, compared to 10%
ful in some patients.
Gliomatosis cerebri
Rarely, patients may present with a highly inltrating,
nonenhancing tumor involving more than two lobes.
These tumors do not qualify for the histologic diagnosis
of glioblastoma but behave aggressively and have a simi-
larly poor outcome. Treatment involves radiotherapy
and temozolomide chemotherapy.
Oligodendroglioma
A
Oligodendrogliomas account for approximately 1520%
of gliomas. They are classied by the WHO into well-
differentiated oligodendrogliomas (grade II) or anaplas-
tic oligodendrogliomas (AOs) (grade III). Tumors with
oligodendroglial components have distinctive features
such as perinuclear clearinggiving rise to a fried-
egg appearanceand a reticular pattern of blood vessel
growth. Some tumors have both an oligodendroglial as
well as an astrocytic component. These mixed tumors,
or oligoastrocytomas (OAs), are also classied into well-
differentiated OA (grade II) or anaplastic oligoastrocyto-
mas (AOAs) (grade III).
Grade II oligodendrogliomas and OAs are generally
more responsive to therapy and have a better progno-
sis than pure astrocytic tumors. These tumors present
similarly to grade II astrocytomas in young adults. The
tumors are nonenhancing and often partially calcied.
They should be treated with surgery and, if necessary,
B radiotherapy and chemotherapy. Patients with oligoden-
FIGURE 37-4 drogliomas have a median survival in excess of 10 years.
Postgadolinium T1 MRI of a recurrent glioblastoma Anaplastic oligodendrogliomas and AOAs present in the
before (A) and after (B) administration of bevacizumab. Note fourth and fth decades as variably enhancing tumors. They
the decreased enhancement and mass effect. are more responsive to therapy than grade III astrocytomas.
Co-deletion of chromosomes 1p and 19q, mediated by an 429
unbalanced translocation of 19p to 1q, occurs in 61 to 89%
of patients with AO and 14 to 20% of patients with AOA.
Tumors with the 1p and 19q co-deletion are particularly
sensitive to chemotherapy with procarbazine, lomustine
(cyclohexylchloroethylnitrosourea [CCNU]), and vincris-
tine (PCV) or temozolomide, as well as to radiotherapy.
Median survival of patients with AO or AOA is approxi-
mately 36 years.
Ependymomas
Ependymomas are tumors derived from ependymal
cells that line the ventricular surface. They account for
approximately 5% of childhood tumors and frequently
arise from the wall of the fourth ventricle in the poste-
rior fossa. Although adults can have intracranial epen-
CHAPTER 37
dymomas, they occur more commonly in the spine,
especially in the lum terminale of the spinal cord
where they have a myxopapillary histology. Ependy- FIGURE 37-5
momas that can be completely resected are potentially Postgadolinium T1 MRI demonstrating a large bifrontal
curable. Partially resected ependymomas will recur and primary central nervous system lymphoma (PCNSL). The
require irradiation. The less common anaplastic epen- periventricular location and diffuse enhancement pattern are
CHAPTER 37
If the meningioma is small and asymptomatic, no nal nerve roots.
intervention is necessary and the lesion can be observed Vestibular schwannomas may be found incidentally
with serial MRI studies. Larger, symptomatic lesions on neuroimaging or present with progressive unilat-
should be resected surgically. If complete resection is eral hearing loss, dizziness, tinnitus, or less commonly,
achieved, the patient is cured. Incompletely resected symptoms resulting from compression of the brain-
tumors tend to recur, although the rate of recurrence stem and cerebellum. On MRI they appear as densely
(>1 cm) that produce symptoms by mass effect, giving rise Colloid cysts
to headaches, visual impairment (such as bitemporal hemi-
anopia), and hypopituitarism. Prolactin-secreting tumors These usually arise in the anterior third ventricle and
respond well to dopamine agonists such as bromocriptine may present with headaches, hydrocephalus, and very
and cabergoline. Other pituitary tumors usually require rarely sudden death. Surgical resection is curative or
treatment with surgery and sometimes radiotherapy or a third ventriculostomy may relieve the obstructive
Diseases of the Nervous System
CRANIOPHARYNGIOMAS
NEUROCUTANEOUS SYNDROMES
Craniopharyngiomas are rare, usually suprasellar, par- (PHAKOMATOSES)
tially calcied, solid, or mixed solid-cystic benign
tumors that arise from remnants of Rathkes pouch. A number of genetic disorders are characterized by
They have a bimodal distribution, occurring predomi- cutaneous lesions and an increased risk of brain tumors.
nantly in children but also between the ages of 55 and Most of these disorders have an autosomal dominance
65 years. They present with headaches, visual impair- inheritance with variable penetrance.
ment, and impaired growth in children and hypopitu-
itarism in adults. Treatment involves surgery, radiother-
apy, or the combination of the two. NEUROFIBROMATOSIS TYPE 1 (NF1)
(VON RECKLINGHAUSENS DISEASE)
NF1 is an autosomal dominant disorder with an inci-
OTHER BENIGN TUMORS dence of approximately 1 in 26003000. Approximately
half the cases are familial; the remainder are new muta-
Dysembryoplastic neuroepithelial tions arising in patients with unaffected parents. The
tumors (DNTs) NF1 gene on chromosome 17q11.2 encodes a protein,
These are benign, supratentorial tumors, usually in the neurobromin, a guanosine triphosphatase (GTPase)-acti-
temporal lobes. They typically occur in children and vating protein (GAP) that modulates signaling through
young adults with a long-standing history of seizures. If the ras pathway. Mutations of the NF1 gene result in
the seizures are refractory, surgical resection is curative. a large number of nervous system tumors including
neurobromas, plexiform neurobromas, optic nerve
gliomas, astrocytomas, and meningiomas. In addition
Epidermoid cysts
to neurobromas, which appear as multiple, soft, rub-
These consist of squamous epithelium surrounding a bery cutaneous tumors, other cutaneous manifestations
keratin-lled cyst. They are usually found in the cer- of NF1 include caf au lait spots and axillary freck-
ebellopontine angle and the intrasellar and suprasel- ling. NF1 is also associated with hamartomas of the
lar regions. They may present with headaches, cra- iris termed Lisch nodules, pheochromocytomas, pseu-
nial nerve abnormalities, seizures, or hydrocephalus. doarthrosis of the tibia, scoliosis, epilepsy, and mental
Imaging studies demonstrate extraaxial lesions with retardation.
NEUROFIBROMATOSIS TYPE 2 (NF2) TABLE 37-3 433
FREQUENCY OF NERVOUS SYSTEM METASTASES
NF2 is less common than NF1, with an incidence of BY COMMON PRIMARY TUMORS
1 in 25,00040,000. It is an autosomal dominant dis-
order with full penetrance. As with NF1, approxi- BRAIN % LM % ESCC %
mately half the cases arise from new mutations. The Lung 41 17 15
NF2 gene on 22q encodes a cytoskeletal protein Breast 19 57 22
merlin (moesin, ezrin, radixin-like protein) that
Melanoma 10 12 4
functions as a tumor suppressor. NF2 is characterized
by bilateral vestibular schwannomas in over 90% of Prostate 1 1 10
patients, multiple meningiomas, and spinal ependymo- GIT 7 5
mas and astrocytomas. Treatment of bilateral vestibular Renal 3 2 7
schwannomas can be challenging because the goal is to Lymphoma <1 10 10
preserve hearing for as long as possible. These patients
Sarcoma 7 1 9
may also have posterior subcapsular lens opacities and
retinal hamartomas. Other 11 18
CHAPTER 37
Abbreviations: ESCC, epidural spinal cord compression; GIT, gas-
TUBEROUS SCLEROSIS (BOURNEVILLES trointestinal tract; LM, leptomeningeal metastases.
DISEASE)
This is an autosomal dominant disorder with an inci-
dence of approximately 1 in 5000 to 10,000 live births. greatest propensity to metastasize to the brain, being
It is caused by mutations in either the TSC1 gene, found in 80% of patients at autopsy (Table 37-3).
which maps to chromosome 9q34, and encodes a pro- Other tumor types such as ovarian and esophageal car-
CHAPTER 37
almost 40% of patients who have a metastasis resected
from the cerebellum.
A
CLINICAL FEATURES
Leptomeningeal metastases are characterized clinically
CHAPTER 37
brain barrier, resulting in increased edema and elevated questionable.
intracranial pressure. This is usually manifest as head- Leukoencephalopathy is seen most commonly after
ache, lethargy, nausea and vomiting, and can be both WBRT as opposed to focal RT. On T2 or FLAIR
prevented and treated with the administration of gluco- MR sequences there is diffuse increased signal seen
corticoids. There is no acute RT toxicity that affects the throughout the hemispheric white matter, often bilat-
spinal cord. erally and symmetrically. There tends to be a periven-
Thiotepa
a severe encephalopathy, which is reversible with dis- Chronic encephalopathy
continuation of the drug and the use of methylene blue (dementia) Peripheral neuropathy
for severely affected patients. Fludarabine also causes a Methotrexate Vinca alkaloids
severe global encephalopathy that may be permanent. Carmustine Cisplatin
Procarbazine
Bevacizumab and other anti-VEGF agents can cause Cytarabine
Fludarabine Etoposide
posterior reversible encephalopathy syndrome. Cispla- Teniposide
Diseases of the Nervous System
tin can cause hearing loss and less frequently vestibular Visual loss Cytarabine
dysfunction. Tamoxifen Taxanes
Gallium nitrate Suramin
Cisplatin Bortezomib
Fludarabine
Cerebellar dysfunction/ataxia
5-Fluorouracil
( levamisole)
Cytarabine
Procarbazine
The anterior pituitary often is referred to as the mas- growth hormone (GH), (3) adrenocorticotropic hormone
ter gland because, together with the hypothalamus, it (ACTH), (4) luteinizing hormone (LH), (5) follicle-
orchestrates the complex regulatory functions of many stimulating hormone (FSH), and (6) thyroid-stimulating
other endocrine glands. The anterior pituitary gland hormone (TSH) (Table 38-1). Pituitary hormones are
produces six major hormones: (1) prolactin (PRL), (2) secreted in a pulsatile manner, reecting stimulation by
TABLE 38-1
ANTERIOR PITUITARY HORMONE EXPRESSION AND REGULATION
Tissue-specic T-Pit Prop-1, Pit-1 Prop-1, Pit-1 Prop-1, Pit-1, TEF SF-1, DAX-1
transcription
factor
Fetal 6 weeks 8 weeks 12 weeks 12 weeks 12 weeks
appearance
Hormone POMC GH PRL TSH FSH LH
Protein Polypeptide Polypeptide Polypeptide Glycoprotein Glycoprotein
, subunits , subunits
Amino acids 266 (ACTH 139) 191 199 211 210 204
Stimulators CRH, AVP, gp-130 GHRH, ghrelin Estrogen, TRH, TRH GnRH, activins,
cytokines VIP estrogen
Inhibitors Glucocorticoids Somatostatin, IGF-I Dopamine T3, T4, dopamine, Sex steroids, inhibin
somatostatin,
glucocorticoids
Target gland Adrenal Liver, other tissues Breast, other Thyroid Ovary, testis
tissues
Trophic effect Steroid production IGF-I production, Milk production T4 synthesis and Sex steroid produc-
growth induction, secretion tion, follicle growth,
insulin antago- germ cell maturation
nism
Normal range ACTH, 422 pg/L <0.5 g/La M <15; F <20 g/L 0.15 mU/L M, 520 IU/L, F
(basal), 520 IU/L
a
Hormone secretion integrated over 24 h.
Abbreviations: M, male; F, female. For other abbreviations, see text.
Source: Adapted from I Shimon, S Melmed, in S Melmed, P Conn (eds): Endocrinology: Basic and Clinical Principles. Totowa, NJ, Humana,
2005.
439
440 an array of specic hypothalamic releasing factors. Each importance of recognizing subtle clinical manifestations
of these pituitary hormones elicits specic responses in and performing the correct laboratory diagnostic tests.
peripheral target tissues. The hormonal products of those
peripheral glands, in turn, exert feedback control at the
level of the hypothalamus and pituitary to modulate
pituitary function (Fig. 38-1). Pituitary tumors cause ANATOMY AND DEVELOPMENT
characteristic hormone-excess syndromes. Hormone
deciency may be inherited or acquired. Fortunately, ANATOMY
there are efcacious treatments for the various pituitary The pituitary gland weighs 600 mg and is located
hormone-excess and -deciency syndromes. Nonethe- within the sella turcica ventral to the diaphragma sella;
less, these diagnoses are often elusive; this emphasizes the it consists of anatomically and functionally distinct ante-
rior and posterior lobes. The bony sella is contiguous to
vascular and neurologic structures, including the cav-
ernous sinuses, cranial nerves, and optic chiasm. Thus,
TRH SRIF GHRH
expanding intrasellar pathologic processes may have sig-
CRH GnRH nicant central mass effects in addition to their endocri-
Dopamine nologic impact.
SECTION III
+ + + +
Pituitary
T4/T3 Superior
hypophyseal Stalk
Thermogenesis
metabolism Thyroid artery
glands + Liver Inferior
Long portal hypophyseal
Testosterone vessels artery
Lactation
Inhibin
Spermatogenesis Trophic
Secondary sex Testes hormone
+
characteristics secreting
cells
Estradiol Chondrocytes Posterior
Progesterone Anterior pituitary
Inhibin Ovaries Linear and
organ growth
pituitary
Ovulation
Short portal
Secondary sex
vessel
characteristics Hormone
IGF-1 secretion
CHAPTER 38
Development/structural
The posterior pituitary is supplied by the inferior Transcription factor defect
hypophyseal arteries. In contrast to the anterior pituitary, Pituitary dysplasia/aplasia
the posterior lobe is directly innervated by hypothalamic Congenital CNS mass, encephalocele
neurons (supraopticohypophyseal and tuberohypophyseal Primary empty sella
nerve tracts) via the pituitary stalk. Thus, posterior pitu- Congenital hypothalamic disorders (septo-optic
itary production of vasopressin (antidiuretic hormone dysplasia, Prader-Willi syndrome, Laurence-
Moon-Biedl syndrome, Kallmann syndrome)
HESX1 gene, which is involved in early development rhea and failure of secondary sexual development.
of the ventral prosencephalon. These children exhibit Kallmann syndrome and other causes of congeni-
variable combinations of cleft palate, syndactyly, ear tal GnRH deciency are characterized by low LH
deformities, hypertelorism, optic atrophy, micropenis, and FSH levels and low concentrations of sex steroids
and anosmia. Pituitary dysfunction leads to diabetes (testosterone or estradiol). In sporadic cases of isolated
insipidus, GH deciency and short stature, and, occa- gonadotropin deciency, the diagnosis is often one of
Diseases of the Nervous System
CHAPTER 38
surgical trauma; vascular events such as apoplexy; pitu- when appropriate (discussed later).
itary or hypothalamic neoplasms, craniopharyngioma,
lymphoma, or metastatic tumors; inammatory disease Lymphocytic hypophysitis
such as lymphocytic hypophysitis; inltrative disorders This occurs most often in postpartum women; it usu-
such as sarcoidosis, hemochromatosis, and tuberculosis; ally presents with hyperprolactinemia and MRI evi-
or irradiation. dence of a prominent pituitary mass that often resembles
masses also may undergo clinically silent infarction and cemia is contraindicated in patients with active coronary
involution with development of a partial or totally artery disease or seizure disorders.
empty sella by cerebrospinal uid (CSF) lling the dural
herniation. Rarely, small but functional pituitary ade-
nomas may arise within the rim of pituitary tissue, and TREATMENT Hypopituitarism
they are not always visible on MRI.
Hormone replacement therapy, including glucocorti-
coids, thyroid hormone, sex steroids, growth hormone,
PRESENTATION AND DIAGNOSIS and vasopressin, is usually safe and free of complica-
The clinical manifestations of hypopituitarism depend tions. Treatment regimens that mimic physiologic hor-
on which hormones are lost and the extent of the mone production allow for maintenance of satisfactory
hormone deciency. GH deciency causes growth clinical homeostasis. Effective dosage schedules are out-
disorders in children and leads to abnormal body lined in Table 38-4. Patients in need of glucocorticoid
composition in adults (discussed later). Gonadotro- replacement require careful dose adjustments during
pin deciency causes menstrual disorders and infertil- stressful events such as acute illness, dental procedures,
ity in women and decreased sexual function, infertil- trauma, and acute hospitalization.
ity, and loss of secondary sexual characteristics in men.
TSH and ACTH deciency usually develop later in
the course of pituitary failure. TSH deciency causes
growth retardation in children and features of hypothy- HYPOTHALAMIC, PITUITARY, AND
roidism in children and adults. The secondary form of OTHER SELLAR MASSES
adrenal insufciency caused by ACTH deciency leads
PITUITARY TUMORS
to hypocortisolism with relative preservation of miner-
alocorticoid production. PRL deciency causes failure Pituitary adenomas are the most common cause of pitu-
of lactation. When lesions involve the posterior pitu- itary hormone hypersecretion and hyposecretion syn-
itary, polyuria and polydipsia reect loss of vasopressin dromes in adults. They account for 15% of all intra-
secretion. Epidemiologic studies have documented an cranial neoplasms and have been identied with a
increased mortality rate in patients with long-standing population prevalence of 80/100,000. At autopsy, up
pituitary damage, primarily from increased cardiovascu- to one-quarter of all pituitary glands harbor an unsus-
lar and cerebrovascular disease. Previous head or neck pected microadenoma (<10 mm diameter). Similarly,
irradiation is also a determinant of increased mortality pituitary imaging detects small clinically inapparent
rates in patients with hypopituitarism. pituitary lesions in at least 10% of individuals.
TABLE 38-3 445
TESTS OF PITUITARY SUFFICIENCY
Growth Insulin tolerance test: regular insulin 30, 0, 30, 60, 120 min for Glucose <40 mg/dL; GH should be >3
hormone (0.050.15 U/kg IV) glucose and GH g/L
GHRH test: 1 g/kg IV 0, 15, 30, 45, 60, 120 min Normal response is GH >3 g/L
for GH
L-Arginine test: 30 g IV over 30 min 0, 30, 60, 120 min for GH Normal response is GH >3 g/L
L-Dopa test: 500 mg PO 0, 30, 60, 120 min for GH Normal response is GH >3 g/L
Prolactin TRH test: 200500 g IV 0, 20, and 60 min for TSH Normal prolactin is >2 g/L and
and PRL increase >200% of baseline
ACTH Insulin tolerance test: regular insulin 30, 0, 30, 60, 90 min for Glucose <40 mg/dL
(0.050.15 U/kg IV) glucose and cortisol Cortisol should increase by >7 g/dL
or to >20 g/dL
CRH test: 1 g/kg ovine CRH IV at 0, 15, 30, 60, 90, 120 min for Basal ACTH increases 2- to 4-fold and
CHAPTER 38
8 A.M. ACTH and cortisol peaks at 20100 pg/mL
Cortisol levels >2025 g/dL
Metyrapone test: metyrapone Plasma 11-deoxycortisol and Plasma cortisol should be <4 g/dL to
(30 mg/kg) at midnight cortisol at 8 A.M.; ACTH can assure an adequate response
also be measured Normal response is 11-deoxycortisol
>7.5 g/dL or ACTH >75 pg/mL
Standard ACTH stimulation test: ACTH 0, 30, 60 min for cortisol and Normal response is cortisol >21 g/dL
a
Evoked PRL response indicates lactotrope integrity.
Note: For abbreviations, see text.
446 TABLE 38-4 TABLE 38-5
HORMONE REPLACEMENT THERAPY FOR ADULT CLASSIFICATION OF PITUITARY ADENOMASa
HYPOPITUITARISMa
ADENOMA CELL HORMONE CLINICAL
TROPHIC HORMONE ORIGIN PRODUCT SYNDROME
DEFICIT HORMONE REPLACEMENT
Lactotrope PRL Hypogonadism,
ACTH Hydrocortisone galactorrhea
(1020 mg A.M.; 510 mg P.M.) Gonadotrope FSH, LH, Silent or
Cortisone acetate (25 mg A.M.; subunits hypogonadism
12.5 mg P.M.)
Prednisone (5 mg A.M.) Somatotrope GH Acromegaly/
gigantism
TSH L-Thyroxine (0.0750.15 mg daily)
Corticotrope ACTH Cushings
FSH/LH Males disease
Testosterone enanthate
(200 mg IM every 2 weeks) Mixed growth GH, PRL Acromegaly,
Testosterone skin patch (5 mg/d) hormone and hypogonadism,
Females prolactin cell galactorrhea
Conjugated estrogen Other plurihormonal Any Mixed
SECTION III
otropins acromegaly
GH Adults: Somatotropin Thyrotrope TSH Thyrotoxicosis
(0.11.25 mg SC qd) Null cell None Pituitary failure
Children: Somatotropin
(0.020.05 [mg/kg per day]) Oncocytoma None Pituitary failure
CHAPTER 38
binding protein (CREB), thereby promoting somato- 17q23-24 hyperplasia and
trope cell proliferation and GH secretion. adenomas (10%)
Characteristic loss of heterozygosity (LOH) in various Atrial myxomas
Schwannomas
chromosomes has been documented in large or inva- Adrenal hyperplasia
sive macroadenomas, suggesting the presence of putative Lentigines
tumor suppressor genes at these loci. LOH of chromo-
Familial pituitary AIP (11q13.3) Acromegaly/
niopharyngiomas. CT is useful to dene calcications half of pituitary metastases originate from breast cancer;
and evaluate invasion into surrounding bony structures about 25% of patients with metastatic breast cancer have
and sinuses. such deposits. Rarely, pituitary stalk involvement results
Treatment usually involves transcranial or trans- in anterior pituitary insufciency. The MRI diagno-
sphenoidal surgical resection followed by postop- sis of a metastatic lesion may be difcult to distinguish
erative radiation of residual tumor. Surgery alone is from an aggressive pituitary adenoma; the diagnosis may
Diseases of the Nervous System
curative in less than half of patients because of recur- require histologic examination of excised tumor tissue.
rences due to adherence to vital structures or because Primary or metastatic lymphoma, leukemias, and plas-
of small tumor deposits in the hypothalamus or brain macytomas also occur within the sella.
parenchyma. The goal of surgery is to remove as much Hypothalamic hamartomas and gangliocytomas may arise
tumor as possible without risking complications associ- from astrocytes, oligodendrocytes, and neurons with
ated with efforts to remove rmly adherent or inacces- varying degrees of differentiation. These tumors may
sible tissue. In the absence of radiotherapy, about 75% overexpress hypothalamic neuropeptides, including
of craniopharyngiomas recur, and 10-year survival is GnRH, GHRH, and CRH. With GnRH-producing
less than 50%. In patients with incomplete resection, tumors, children present with precocious puberty,
radiotherapy improves 10-year survival to 7090% but psychomotor delay, and laughing-associated seizures.
is associated with increased risk of secondary malignan- Medical treatment of GnRH-producing hamartomas
cies. Most patients require lifelong pituitary hormone with long-acting GnRH analogues effectively sup-
replacement. presses gonadotropin secretion and controls premature
Developmental failure of Rathkes pouch oblit- pubertal development. Rarely, hamartomas also are
eration may lead to Rathkes cysts, which are small (<5 associated with craniofacial abnormalities; imperfo-
mm) cysts entrapped by squamous epithelium and are rate anus; cardiac, renal, and lung disorders; and pitu-
found in about 20% of individuals at autopsy. Although itary failure as features of Pallister-Hall syndrome, which
Rathkes cleft cysts do not usually grow and are often is caused by mutations in the carboxy terminus of the
diagnosed incidentally, about a third present in adult- GLI3 gene. Hypothalamic hamartomas are often con-
hood with compressive symptoms, diabetes insipi- tiguous with the pituitary, and preoperative MRI
dus, and hyperprolactinemia due to stalk compression. diagnosis may not be possible. Histologic evidence of
Rarely, hydrocephalus develops. The diagnosis is sug- hypothalamic neurons in tissue resected at transsphe-
gested preoperatively by visualizing the cyst wall on noidal surgery may be the rst indication of a primary
MRI, which distinguishes these lesions from craniopha- hypothalamic lesion.
ryngiomas. Cyst contents range from CSF-like uid to Hypothalamic gliomas and optic gliomas occur mainly in
mucoid material. Arachnoid cysts are rare and generate an childhood and usually present with visual loss. Adults
MRI image that is isointense with cerebrospinal uid. have more aggressive tumors; about a third are associ-
Sella chordomas usually present with bony clival ero- ated with neurobromatosis.
sion, local invasiveness, and, on occasion, calcication. Brain germ cell tumors may arise within the sellar
Normal pituitary tissue may be visible on MRI, distin- region. They include dysgerminomas, which frequently
guishing chordomas from aggressive pituitary adeno- are associated with diabetes insipidus and visual loss.
mas. Mucinous material may be obtained by ne-needle They rarely metastasize. Germinomas, embryonal carci-
aspiration. nomas, teratomas, and choriocarcinomas may arise in the
parasellar region and produce hCG. These germ cell TABLE 38-7 449
tumors present with precocious puberty, diabetes insipi- FEATURES OF SELLAR MASS LESIONSa
dus, visual eld defects, and thirst disorders. Many
IMPACTED STRUCTURE CLINICAL IMPACT
patients are GH-decient with short stature.
Pituitary Hypogonadism
Hypothyroidism
METABOLIC EFFECTS OF HYPOTHALAMIC Growth failure and adult
hyposomatotropism
LESIONS
Hypoadrenalism
Lesions involving the anterior and preoptic hypotha- Optic chiasm Loss of red perception
lamic regions cause paradoxical vasoconstriction, tachy- Bitemporal hemianopia
cardia, and hyperthermia. Acute hyperthermia usually Superior or bitemporal eld
is due to a hemorrhagic insult, but poikilothermia may defect
also occur. Central disorders of thermoregulation result Scotoma
from posterior hypothalamic damage. The periodic hypo- Blindness
thermia syndrome is characterized by episodic attacks of Hypothalamus Temperature dysregulation
rectal temperatures <30C (86F), sweating, vasodila- Appetite and thirst disor-
ders
CHAPTER 38
tion, vomiting, and bradycardia. Damage to the ven-
Obesity
tromedial hypothalamic nuclei by craniopharyngiomas, Diabetes insipidus
hypothalamic trauma, or inammatory disorders may Sleep disorders
be associated with hyperphagia and obesity. This region Behavioral dysfunction
appears to contain an energy-satiety center where mel- Autonomic dysfunction
anocortin receptors are inuenced by leptin, insulin, Cavernous sinus Opthalmoplegia with or
POMC products, and gastrointestinal peptides. Polydip- without ptosis or diplopia
pregnancy and puberty, the height may reach 1012 mm. on T2-weighted images.
The upper aspect of the adult pituitary is at or slightly
concave, but in adolescent and pregnant individuals, this
Ophthalmologic evaluation
surface may be convex, reecting physiologic pituitary
enlargement. The stalk should be midline and vertical. Because optic tracts may be contiguous to an expand-
CT scan is reserved to dene the extent of bony erosion ing pituitary mass, reproducible visual eld assessment
Diseases of the Nervous System
Laboratory investigation
The presenting clinical features of functional pituitary
adenomas (e.g., acromegaly, prolactinomas, or Cush-
ings syndrome) should guide the laboratory stud-
ies (Table 38-8). However, for a sellar mass with no
obvious clinical features of hormone excess, laboratory
studies are geared toward determining the nature of the
tumor and assessing the possible presence of hypopitu-
itarism. When a pituitary adenoma is suspected based
on MRI, initial hormonal evaluation usually includes
(1) basal PRL; (2) insulin-like growth factor (IGF) I; (3)
24-h urinary free cortisol (UFC) and/or overnight oral
dexamethasone (1 mg) suppression test; (4) subunit,
FSH, and LH; and (5) thyroid function tests. Additional
hormonal evaluation may be indicated based on the
FIGURE 38-4 results of these tests. Pending more detailed assessment
Pituitary adenoma. Coronal T1-weighted postcontrast MR of hypopituitarism, a menstrual history, measurement of
image shows a homogeneously enhancing mass (arrow- testosterone and 8 A.M. cortisol levels, and thyroid func-
heads) in the sella turcica and suprasellar region compatible tion tests usually identify patients with pituitary hor-
with a pituitary adenoma; the small arrows outline the carotid mone deciencies that require hormone replacement
arteries. before further testing or surgery.
TABLE 38-8 451
management and follow-up are necessary for these
SCREENING TESTS FOR FUNCTIONAL PITUITARY
ADENOMAS patients.
MRI with gadolinium enhancement for pituitary
TEST COMMENTS visualization, new advances in transsphenoidal surgery
Acromegaly Serum IGF-I Interpret IGF-I relative and in stereotactic radiotherapy (including gamma-
to age- and sex- knife radiotherapy), and novel therapeutic agents have
matched controls improved pituitary tumor management. The goals of
Oral glucose tol- Normal subjects pituitary tumor treatment include normalization of
erance test with should suppress excess pituitary secretion, amelioration of symptoms
GH obtained at growth hormone to and signs of hormonal hypersecretion syndromes, and
0, 30, and 60 <1 g/L shrinkage or ablation of large tumor masses with relief
min of adjacent structure compression. Residual anterior
Prolacti- Serum PRL Exclude medications pituitary function should be preserved during treat-
noma ment and sometimes can be restored by removing the
MRI of the sella tumor mass. Ideally, adenoma recurrence should be pre-
should be ordered if vented.
CHAPTER 38
prolactin is elevated
TRANSSPHENOIDAL SURGERY Transsphenoidal
Cushings 24-h urinary free Ensure urine collection
rather than transfrontal resection is the desired surgical
disease cortisol is total and accurate
approach for pituitary tumors, except for the rare inva-
Dexamethasone Normal subjects sive suprasellar mass surrounding the frontal or middle
(1 mg) at suppress to
fossa or the optic nerves or invading posteriorly behind
11 P.M. and <5 g/dL
fasting plasma the clivus. Intraoperative microscopy facilitates visual
CHAPTER 38
mass of 21,500 kDa; it is weakly homologous to GH ACTION
and human placental lactogen (hPL), reecting the
duplication and divergence of a common GH-PRL- The PRL receptor is a member of the type I cytokine
hPL precursor gene. PRL is synthesized in lactotropes, receptor family that also includes GH and interleu-
which constitute about 20% of anterior pituitary cells. kin (IL) 6 receptors. Ligand binding induces receptor
Lactotropes and somatotropes are derived from a com- dimerization and intracellular signaling by Janus kinase
Granulomas
inltrative disorders, and radiation-induced dam-
Rathkes cyst
age cause elevated PRL levels, usually in the range of Irradiation
30100 g/L. Plurihormonal adenomas (including GH Trauma
and ACTH tumors) may hypersecrete PRL directly. Pituitary stalk section
Pituitary masses, including clinically nonfunctioning Suprasellar surgery
pituitary tumors, may compress the pituitary stalk to III. Pituitary hypersecretion
Diseases of the Nervous System
CHAPTER 38
dopamine tone. Granulomatous infiltrates occasionally
amenorrhea is a self-limiting disorder usually associated with
respond to glucocorticoid administration. In patients
moderately elevated PRL levels. Galactorrhea may occur
with irreversible hypothalamic damage, no treatment
spontaneously, or it may be elicited by nipple pressure.
may be warranted. In up to 30% of patients with hyper-
In both men and women, galactorrhea may vary in color
prolactinemiausually without a visible pituitary micro-
and consistency (transparent, milky, or bloody) and arise
adenomathe condition may resolve spontaneously.
either unilaterally or bilaterally. Mammography or ultra-
MANAGEMENT OF PROLACTINOMA
ELEVATED PROLACTIN LEVELS
Symptomatic Prolactinoma
Test visual
fields
Microadenoma Macroadenoma
Test pituitary
reserve function
Titrate Titrate
Drug intolerance
dopamine agonist dopamine agonist
FIGURE 38-6
Management of prolactinoma. MRI, magnetic resonance imaging; PRL, prolactin.
457
decreased D2 dopamine receptor numbers or a postre- and mood swings have been reported in up to 5% of
ceptor defect. D2 receptor gene mutations in the pituitary patients and may be due to the dopamine agonist prop-
have not been reported. erties or to the lysergic acid derivative of the compounds.
Rare reports of leukopenia, thrombocytopenia, pleural
Cabergoline An ergoline derivative, cabergoline is
fibrosis, cardiac arrhythmias, and hepatitis have been
a long-acting dopamine agonist with high D2 receptor
described. Patients with Parkinsons disease who receive
affinity. The drug effectively suppresses PRL for >14 days
at least 3 mg of cabergoline daily have been reported to
after a single oral dose and induces prolactinoma shrink-
be at risk for development of cardiac valve regurgitation.
age in most patients. Cabergoline (0.5 to 1.0 mg twice
Studies analyzing over 500 prolactinoma patients receiv-
weekly) achieves normoprolactinemia and resumption
ing recommended doses of cabergoline (up to 2 mg
of normal gonadal function in 80% of patients with
weekly) have shown no evidence for an increased inci-
microadenomas; galactorrhea improves or resolves
dence of valvular disorders. Nevertheless, as no controlled
in 90% of patients. Cabergoline normalizes PRL and
prospective studies are available, it is prudent to perform
shrinks 70% of macroprolactinomas. Mass effect symp-
echocardiograms before initiating standard-dose caber-
toms, including headaches and visual disorders, usually
goline therapy.
improve dramatically within days after cabergoline ini-
tiation; improvement of sexual function requires several
CHAPTER 38
Surgery Indications for surgical adenoma debulk-
weeks of treatment but may occur before complete nor- ing include dopamine resistance or intolerance and the
malization of prolactin levels. After initial control of PRL presence of an invasive macroadenoma with compro-
levels has been achieved, cabergoline should be reduced mised vision that fails to improve after drug treatment.
to the lowest effective maintenance dose. In 5% of Initial PRL normalization is achieved in about 70% of
treated patients harboring a microadenoma, hyperpro- microprolactinomas after surgical resection, but only
lactinemia may resolve and not recur when dopamine 30% of macroadenomas can be resected successfully.
GH, can be identied by using double immunostain- Integrated 24-h GH secretion is higher in women and
ing techniques. Somatotrope development and GH is also enhanced by estrogen replacement. Using stan-
transcription are determined by expression of the cell- dard assays, random GH measurements are undetectable
specic Pit-1 nuclear transcription factor. Five distinct in 50% of daytime samples obtained from healthy sub-
genes encode GH and related proteins. The pituitary jects and are also undetectable in most obese and elderly
GH gene (hGH-N) produces two alternatively spliced subjects. Thus, single random GH measurements do not
Diseases of the Nervous System
products that give rise to 22-kDa GH (191 amino distinguish patients with adult GH deciency from nor-
acids) and a less abundant 20-kDa GH molecule with mal persons.
similar biologic activity. Placental syncytiotrophoblast GH secretion is profoundly inuenced by nutritional
cells express a GH variant (hGH-V) gene; the related factors. Using newer ultrasensitive GH assays with a
hormone human chorionic somatotropin (HCS) is sensitivity of 0.002 g/L, a glucose load suppresses GH
expressed by distinct members of the gene cluster. to <0.7 g/L in women and to <0.07 g/L in men.
Increased GH pulse frequency and peak amplitudes
occur with chronic malnutrition or prolonged fasting.
SECRETION GH is stimulated by intravenous L-arginine, dopamine,
and apomorphine (a dopamine receptor agonist), as well
GH secretion is controlled by complex hypothalamic as by -adrenergic pathways. -Adrenergic blockage
and peripheral factors. GHRH is a 44-amino-acid induces basal GH and enhances GHRH- and insulin-
hypothalamic peptide that stimulates GH synthesis and evoked GH release.
release. Ghrelin, an octanoylated gastric-derived peptide,
and synthetic agonists of the GHS-R induce GHRH
and also directly stimulate GH release. Somatostatin
ACTION
(somatotropin-release inhibiting factor [SRIF]) is syn-
thesized in the medial preoptic area of the hypothala- The pattern of GH secretion may affect tissue responses.
mus and inhibits GH secretion. GHRH is secreted in The higher GH pulsatility observed in men compared
discrete spikes that elicit GH pulses, whereas SRIF sets with the relatively continuous GH secretion in women
basal GH secretory tone. SRIF also is expressed in many may be an important biologic determinant of linear
extrahypothalamic tissues, including the CNS, gastroin- growth patterns and liver enzyme induction.
testinal tract, and pancreas, where it also acts to inhibit The 70-kDa peripheral GH receptor protein has
islet hormone secretion. IGF-I, the peripheral target structural homology with the cytokine/hematopoi-
hormone for GH, feeds back to inhibit GH; estrogen etic superfamily. A fragment of the receptor extracel-
induces GH, whereas chronic glucocorticoid excess lular domain generates a soluble GH binding protein
suppresses GH release. (GHBP) that interacts with GH in the circulation. The
Surface receptors on the somatotrope regulate GH liver and cartilage contain the greatest number of GH
synthesis and secretion. The GHRH receptor is a G receptors. GH binding to preformed receptor dimers is
proteincoupled receptor (GPCR) that signals through followed by internal rotation and subsequent signaling
the intracellular cyclic AMP pathway to stimulate through the JAK/STAT pathway. Activated STAT pro-
somatotrope cell proliferation as well as GH production. teins translocate to the nucleus, where they modulate
Inactivating mutations of the GHRH receptor cause expression of GH-regulated target genes. GH analogues
that bind to the receptor but are incapable of mediating sensitivity in patients with severe insulin resistance and 459
receptor signaling are potent antagonists of GH action. diabetes. In cachectic subjects, IGF-I infusion (12 g/kg per
A GH receptor antagonist (pegvisomant) is approved for hour) enhances nitrogen retention and lowers choles-
treatment of acromegaly. terol levels. Longer-term subcutaneous IGF-I injections
GH induces protein synthesis and nitrogen retention enhance protein synthesis and are anabolic. Although
and impairs glucose tolerance by antagonizing insulin bone formation markers are induced, bone turnover also
action. GH also stimulates lipolysis, leading to increased may be stimulated by IGF-I.
circulating fatty acid levels, reduced omental fat mass, IGF-I side effects are dose-dependent, and overdose
and enhanced lean body mass. GH promotes sodium, may result in hypoglycemia, hypotension, uid reten-
potassium, and water retention and elevates serum levels tion, temporomandibular jaw pain, and increased intra-
of inorganic phosphate. Linear bone growth occurs as a cranial pressure, all of which are reversible. Avascular
result of complex hormonal and growth factor actions, femoral head necrosis has been reported. Chronic excess
including those of IGF-I. GH stimulates epiphyseal IGF-I administration presumably would result in features
prechondrocyte differentiation. These precursor cells of acromegaly.
produce IGF-I locally, and their proliferation is also
responsive to the growth factor.
DISORDERS OF GROWTH AND
CHAPTER 38
DEVELOPMENT
Skeletal maturation and somatic growth
INSULIN-LIKE GROWTH FACTORS
The growth plate is dependent on a variety of hormonal
Although GH exerts direct effects in target tissues, stimuli, including GH, IGF-I, sex steroids, thyroid hor-
many of its physiologic effects are mediated indirectly mones, paracrine growth factors, and cytokines. The
through IGF-I, a potent growth and differentiation fac- growth-promoting process also requires caloric energy,
Growth hormone insensitivity testing. Age- and sex-matched IGF-I levels are not suf-
This is caused by defects of GH receptor structure or ciently sensitive or specic to make the diagnosis but
signaling. Homozygous or heterozygous mutations of can be useful to conrm GH deciency. Pituitary MRI
the GH receptor are associated with partial or complete may reveal pituitary mass lesions or structural defects.
GH insensitivity and growth failure (Laron syndrome). Molecular analyses for known mutations should be
The diagnosis is based on normal or high GH levels, undertaken when the cause of short stature remains
Diseases of the Nervous System
with decreased circulating GHBP, and low IGF-I levels. cryptic, or when additional clinical features suggest a
Very rarely, defective IGF-I, IGF-I receptor, or IGF-I gentic cause.
signaling defects are also encountered. STAT5B muta-
tions result in immunodeciency with abrogated GH
signaling, leading to short stature with normal or ele-
vated GH levels and low IGF-I levels. TREATMENT Disorders of Growth and Development
CHAPTER 38
Cardiovascular risk factors
useful index of therapeutic responses but are not suf-
Impaired cardiac structure and function
Abnormal lipid prole
ciently sensitive for diagnostic purposes. The most
Decreased brinolytic activity validated test to distinguish pituitary-sufcient patients
Atherosclerosis from those with AGHD is insulin-induced (0.050.1
Omental obesity U/kg) hypoglycemia. After glucose reduction to
Imaging 40 mg/dL, most individuals experience neurogly-
density increases, but this response is gradual (>1 year). Central <1
Many patients note significant improvement in quality Hypothalamic hamartoma, choristoma, <1
of life when evaluated by standardized questionnaires. ganglioneuroma
The effect of GH replacement on mortality rates in GH- Peripheral <1
deficient patients is currently the subject of long-term
Bronchial carcinoid, pancreatic islet cell
prospective investigation.
tumor, small cell lung cancer, adrenal
About 30% of patients exhibit reversible dose- adenoma, medullary thyroid carcinoma,
related fluid retention, joint pain, and carpal tunnel syn- pheochromocytoma
drome, and up to 40% exhibit myalgias and paresthesia.
Patients receiving insulin require careful monitoring for Source: Adapted from S Melmed: N Engl J Med 322:966, 1990.
dosing adjustments, as GH is a potent counterregula- Abbreviations: GH, growth hormone; PRL, prolactin.
tory hormone for insulin action. Patients with type 2
diabetes mellitus initially develop further insulin resis-
tance. However, glycemic control improves with the sus- stem-cell adenomas, features of hyperprolactinemia
tained loss of abdominal fat associated with long-term (hypogonadism and galactorrhea) predominate over
GH replacement. Headache, increased intracranial pres- the less clinically evident signs of acromegaly. Occa-
sure, hypertension, and tinnitus occur rarely. Pituitary sionally, mixed plurihormonal tumors are encountered
tumor regrowth and progression of skin lesions or other that also secrete ACTH, the glycoprotein hormone
tumors are being assessed in long-term surveillance subunit, or TSH in addition to GH. Patients with par-
programs. To date, development of these potential side tially empty sellas may present with GH hypersecretion
effects does not appear significant. due to a small GH-secreting adenoma within the com-
pressed rim of pituitary tissue; some of these may reect
the spontaneous necrosis of tumors that were previously
ACROMEGALY larger. GH-secreting tumors rarely arise from ectopic
pituitary tissue remnants in the nasopharynx or midline
Etiology sinuses.
GH hypersecretion is usually the result of a somatotrope There are case reports of ectopic GH secretion by
adenoma but may rarely be caused by extrapituitary tumors of pancreatic, ovarian, lung, or hematopoietic
lesions (Table 38-11). In addition to more common origin. Rarely, excess GHRH production may cause
GH-secreting somatotrope adenomas, mixed mammo- acromegaly because of chronic stimulation of somato-
somatotrope tumors and acidophilic stem-cell adenomas tropes. These patients present with classic features of
secrete both GH and PRL. In patients with acidophilic acromegaly, elevated GH levels, pituitary enlargement
on MRI, and pathologic characteristics of pituitary Generalized visceromegaly occurs, including cardio- 463
hyperplasia. The most common cause of GHRH- megaly, macroglossia, and thyroid gland enlargement.
mediated acromegaly is a chest or abdominal carcinoid The most signicant clinical impact of GH excess
tumor. Although these tumors usually express positive occurs with respect to the cardiovascular system. Cor-
GHRH immunoreactivity, clinical features of acro- onary heart disease, cardiomyopathy with arrhythmias,
megaly are evident in only a minority of patients with left ventricular hypertrophy, decreased diastolic func-
carcinoid disease. Excessive GHRH also may be elabo- tion, and hypertension ultimately occur in most patients
rated by hypothalamic tumors, usually choristomas or if untreated. Upper airway obstruction with sleep apnea
neuromas. occurs in more than 60% of patients and is associated
with both soft tissue laryngeal airway obstruction and
Presentation and diagnosis central sleep dysfunction. Diabetes mellitus develops
in 25% of patients with acromegaly, and most patients
Protean manifestations of GH and IGF-I hypersecre- are intolerant of a glucose load (as GH counteracts
tion are indolent and often are not clinically diagnosed the action of insulin). Acromegaly is associated with
for 10 years or more. Acral bony overgrowth results in an increased risk of colon polyps and mortality from
frontal bossing, increased hand and foot size, mandibu- colonic malignancy; polyps are diagnosed in up to one-
lar enlargement with prognathism, and widened space third of patients. Overall mortality is increased about
CHAPTER 38
between the lower incisor teeth. In children and ado- threefold and is due primarily to cardiovascular and
lescents, initiation of GH hypersecretion before epiphy- cerebrovascular disorders and respiratory disease. Unless
seal long bone closure is associated with development GH levels are controlled, survival is reduced by an aver-
of pituitary gigantism (Fig. 38-8). Soft tissue swell- age of 10 years compared with an age-matched control
ing results in increased heel pad thickness, increased population.
shoe or glove size, ring tightening, characteristic coarse
FIGURE 38-8
Features of acromegaly/gigantism. A 22-year-old man affected twin are apparent. Their clinical features began to
with gigantism due to excess growth hormone is shown diverge at the age of approximately 13 years. (Reproduced
to the left of his identical twin. The increased height and from R Gagel, IE McCutcheon: N Engl J Med 340:524, 1999;
prognathism (A) and enlarged hand (B) and foot (C) of the with permission.)
464 features raise the possibility of acromegaly. Due to normalized within 34 days. In 10% of patients, acro-
the pulsatility of GH secretion, measurement of a sin- megaly may recur several years after apparently suc-
gle random GH level is not useful for the diagnosis or cessful surgery; hypopituitarism develops in up to 15%
exclusion of acromegaly and does not correlate with of patients after surgery.
disease severity. The diagnosis of acromegaly is con-
SOMATOSTATIN ANALOGUES Somatosta-
rmed by demonstrating the failure of GH suppres-
tin analogues exert their therapeutic effects through
sion to <0.4 g/L within 12 h of an oral glucose load
SSTR2 and SSTR5 receptors, both of which invariably are
(75 g). When newer ultrasensitive GH assays are used,
expressed by GH-secreting tumors. Octreotide acetate is
normal nadir GH levels are even lower (<0.05 g/L).
an eight-amino-acid synthetic somatostatin analogue. In
About 20% of patients exhibit a paradoxical GH rise
contrast to native somatostatin, the analogue is relatively
after glucose. PRL should be measured, as it is elevated
resistant to plasma degradation. It has a 2-h serum half-
in 25% of patients with acromegaly. Thyroid func-
life and possesses 40-fold greater potency than native
tion, gonadotropins, and sex steroids may be attenuated
somatostatin to suppress GH. Octreotide is administered
because of tumor mass effects. Because most patients
by subcutaneous injection, beginning with 50 g tid; the
will undergo surgery with glucocorticoid coverage, tests
dose can be increased gradually up to 1500 g/d. Fewer
of ACTH reserve in asymptomatic patients are more
than 10% of patients do not respond to the analogue.
efciently deferred until after surgery.
SECTION III
preserve pituitary function. drug levels for several weeks after intramuscular injec-
Surgical resection of GH-secreting adenomas is the tion. GH suppression occurs for as long as 6 weeks after
initial treatment for most patients (Fig. 38-9). Soma- a 30-mg intramuscular injection; long-term monthly
tostatin analogues are used as adjuvant treatment treatment sustains GH and IGF-I suppression and
for preoperative shrinkage of large invasive macroad- also reduces pituitary tumor size in 50% of patients.
enomas, immediate relief of debilitating symptoms, Lanreotide autogel, a slow-release depot somatosta-
and reduction of GH hypersecretion; in frail patients tin preparation, is a cyclic somatostatin octapeptide
experiencing morbidity; and in patients who decline analogue that suppresses GH and IGF-I hypersecre-
surgery or, when surgery fails, to achieve biochemical tion after a 60-mg subcutaneous injection. Long-term
control. Irradiation or repeat surgery may be required monthly administration controls GH hypersecretion
for patients who cannot tolerate or do not respond in two-thirds of treated patients and improves patient
to adjunctive medical therapy. The high rate of late compliance because of the long interval required
hypopituitarism and the slow rate (515 years) of bio- between drug injections. Rapid relief of headache and
chemical response are the main disadvantages of soft tissue swelling occurs in 75% of patients within
radiotherapy. Irradiation is also relatively ineffective in days to weeks of somatostatin analogue initiation. Most
normalizing IGF-I levels. Stereotactic ablation of GH- patients report symptomatic improvement, including
secreting adenomas by gamma-knife radiotherapy is amelioration of headache, perspiration, obstructive
promising, but initial reports suggest that long-term apnea, and cardiac failure.
results and side effects are similar to those observed
Side Effects Somatostatin analogues are well toler-
with conventional radiation. Somatostatin analogues
ated in most patients. Adverse effects are short-lived and
may be required while awaiting the full benefits of
mostly relate to drug-induced suppression of gastrointes-
radiotherapy. Systemic sequelae of acromegaly, includ-
tinal motility and secretion. Nausea, abdominal discom-
ing cardiovascular disease, diabetes, and arthritis,
fort, fat malabsorption, diarrhea, and flatulence occur in
should be managed aggressively. Mandibular surgical
one-third of patients, and these symptoms usually remit
repair may be indicated.
within 2 weeks. Octreotide suppresses postprandial gall-
SURGERY Transsphenoidal surgical resection by bladder contractility and delays gallbladder emptying; up
an experienced surgeon is the preferred primary treat- to 30% of patients develop long-term echogenic sludge
ment for both microadenomas (cure rate 70%) and or asymptomatic cholesterol gallstones. Other side
macroadenomas (<50% cured). Soft tissue swelling effects include mild glucose intolerance due to transient
improves immediately after tumor resection. GH levels insulin suppression, asymptomatic bradycardia, hypothy-
return to normal within an hour, and IGF-I levels are roxinemia, and local injection site discomfort.
MANAGEMENT OF ACROMEGALY 465
GH-Secreting
Adenoma
Debulking required
Surgery
for CNS pressure effects
controlled Measure
GH/IGF-I
CHAPTER 38
or add dopamine agonist
GH receptor
controlled Measure uncontrolled antagonist
Monitor
GH/IGF-I Radiation therapy
Reoperation
FIGURE 38-9
GH RECEPTOR ANTAGONIST Pegvisomant attenuated over time. However, 50% of patients require
antagonizes endogenous GH action by blocking periph- at least 8 years for GH levels to be suppressed to <5 g/L;
eral GH binding to its receptor. Consequently, serum this level of GH reduction is achieved in about 90% of
IGF-I levels are suppressed, reducing the deleteri- patients after 18 years but represents suboptimal GH
ous effects of excess endogenous GH. Pegvisomant is suppression. Patients may require interim medical ther-
administered by daily subcutaneous injection (1020 apy for several years before attaining maximal radiation
mg) and normalizes IGF-I in >90% of patients. GH lev- benefits. Most patients also experience hypothalamic-
els, however, remain elevated as the drug does not have pituitary damage, leading to gonadotropin, ACTH, and/
antitumor actions. Side effects include reversible liver or TSH deficiency within 10 years of therapy.
enzyme elevation, lipodystrophy, and injection site pain. In summary, surgery is the preferred primary treat-
Tumor size should be monitored by MRI. ment for GH-secreting microadenomas (Fig. 38-9). The
Combined treatment with monthly somatostatin high frequency of GH hypersecretion after macroade-
analogues and weekly or biweekly pegvisomant injec- noma resection usually necessitates adjuvant or primary
tions has been used effectively in resistant patients. medical therapy for these larger tumors. Patients unable
to receive or respond to unimodal medical treatment
DOPAMINE AGONISTS Bromocriptine and cab-
may benefit from combined treatments or can be offered
ergoline may modestly suppress GH secretion in some
radiation.
patients. High doses of bromocriptine (20 mg/d) or
cabergoline (0.5 mg/d) are usually required to achieve
modest GH therapeutic efficacy. Combined treatment
with octreotide and cabergoline may induce additive
biochemical control compared with either drug alone. ADRENOCORTICOTROPIC HORMONE
RADIATION External radiation therapy or high- SYNTHESIS
energy stereotactic techniques are used as adjuvant
therapy for acromegaly. An advantage of radiation is ACTH-secreting corticotrope cells constitute about
that patient compliance with long-term treatment is 20% of the pituitary cell population. ACTH (39 amino
not required. Tumor mass is reduced, and GH levels are acids) is derived from the POMC precursor protein (266
amino acids) that also generates several other peptides,
466 including -lipotropin, -endorphin, met-enkephalin, stress response. ACTH induces adrenocortical ste-
-melanocyte-stimulating hormone (-MSH), and cor- roidogenesis by sustaining adrenal cell proliferation and
ticotropin-like intermediate lobe protein (CLIP). The function. The receptor for ACTH, designated melano-
POMC gene is potently suppressed by glucocorticoids cortin-2 receptor, is a GPCR that induces steroidogenesis
and induced by CRH, arginine vasopressin (AVP), and by stimulating a cascade of steroidogenic enzymes.
proinammatory cytokines, including IL-6, as well as
leukemia inhibitory factor.
CRH, a 41-amino-acid hypothalamic peptide syn-
thesized in the paraventricular nucleus as well as in ACTH DEFICIENCY
higher brain centers, is the predominant stimulator of Presentation and diagnosis
ACTH synthesis and release. The CRH receptor is a
Secondary adrenal insufciency occurs as a result of
GPCR that is expressed on the corticotrope and signals
pituitary ACTH deciency. It is characterized by
to induce POMC transcription.
fatigue, weakness, anorexia, nausea, vomiting, and,
occasionally, hypoglycemia. In contrast to primary adre-
nal failure, hypocortisolism associated with pituitary fail-
SECRETION ure usually is not accompanied by hyperpigmentation or
mineralocorticoid deciency.
SECTION III
endogenous rhythm, ACTH levels are increased by mass effects of other pituitary adenomas or sellar lesions
physical and psychological stress, exercise, acute illness, may lead to ACTH deciency, but usually in combina-
and insulin-induced hypoglycemia. tion with other pituitary hormone deciencies. Partial
Loss of cortisol feedback inhibition, as occurs in pri- ACTH deciency may be unmasked in the presence
mary adrenal failure, results in extremely high ACTH of an acute medical or surgical illness, when clinically
levels. Glucocorticoid-mediated negative regulation of signicant hypocortisolism reects diminished ACTH
the hypothalamic-pituitary-adrenal (HPA) axis occurs as reserve. Rarely, TPIT or POMC mutations result in
a consequence of both hypothalamic CRH suppression primary ACTH deciency.
and direct attenuation of pituitary POMC gene expres-
sion and ACTH release. Laboratory diagnosis
Acute inammatory or septic insults activate the
HPA axis through the integrated actions of proinam- Inappropriately low ACTH levels in the setting of low
matory cytokines, bacterial toxins, and neural signals. cortisol levels are characteristic of diminished ACTH
The overlapping cascade of ACTH-inducing cytokines reserve. Low basal serum cortisol levels are associated
(tumor necrosis factor [TNF]; IL-1, -2, and -6; and leu- with blunted cortisol responses to ACTH stimula-
kemia inhibitory factor) activates hypothalamic CRH tion and impaired cortisol response to insulin-induced
and AVP secretion, pituitary POMC gene expression, hypoglycemia, or testing with metyrapone or CRH.
and local pituitary paracrine cytokine networks. The
resulting cortisol elevation restrains the inammatory
response and enables host protection. Concomitantly, TREATMENT ACTH Deciency
cytokine-mediated central glucocorticoid receptor resis-
tance impairs glucocorticoid suppression of the HPA. Glucocorticoid replacement therapy improves most fea-
Thus, the neuroendocrine stress response reects the net tures of ACTH deficiency. The total daily dose of hydrocor-
result of highly integrated hypothalamic, intrapituitary, tisone replacement preferably should not exceed 25 mg
and peripheral hormone and cytokine signals. daily, divided into two or three doses. Prednisone (5 mg
each morning) is longer-acting and has fewer mineralo-
corticoid effects than hydrocortisone. Some authorities
ACTION advocate lower maintenance doses in an effort to avoid
cushingoid side effects. Doses should be increased sever-
The major function of the HPA axis is to maintain
alfold during periods of acute illness or stress.
metabolic homeostasis and mediate the neuroendocrine
CUSHINGS SYNDROME TABLE 38-12 467
(ACTH-PRODUCING ADENOMA) CLINICAL FEATURES OF CUSHINGS SYNDROME
(ALL AGES)
Etiology and prevalence
SYMPTOMS/SIGNS FREQUENCY, %
Pituitary corticotrope adenomas account for 70% of patients
with endogenous causes of Cushings syndrome. However, Obesity or weight gain (>115% 80
it should be emphasized that iatrogenic hypercortisolism is ideal body weight)
the most common cause of cushingoid features. Ectopic Thin skin 80
tumor ACTH production, cortisol-producing adrenal ade- Moon facies 75
nomas, adrenal carcinoma, and adrenal hyperplasia account
Hypertension 75
for the other causes; rarely, ectopic tumor CRH production
is encountered. Purple skin striae 65
ACTH-producing adenomas account for about Hirsutism 65
1015% of all pituitary tumors. Because the clinical fea- Menstrual disorders (usually 60
tures of Cushings syndrome often lead to early diagno- amenorrhea)
sis, most ACTH-producing pituitary tumors are rela- Plethora 60
tively small microadenomas. However, macroadenomas
CHAPTER 38
Abnormal glucose tolerance 55
also are seen while some ACTH-expressing adenomas
Impotence 55
are clinically silent. Cushings disease is 510 times
more common in women than in men. These pitu- Proximal muscle weakness 50
itary adenomas exhibit unrestrained ACTH secretion, Truncal obesity 50
with resultant hypercortisolemia. However, they retain Acne 45
partial suppressibility in the presence of high doses of Bruising 45
TABLE 38-13
DIFFERENTIAL DIAGNOSIS OF ACTH-DEPENDENT CUSHINGS SYNDROMEa
a
ACTH-independent causes of Cushings syndrome are diagnosed by suppressed ACTH levels and an adrenal mass in the setting of hypercor-
tisolism. Iatrogenic Cushings syndrome is excluded by history.
Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; F, female; M, male.
in patients with hypertension or in the presence of a 469
well-visualized pituitary adenoma on MRI. tion with pituitary irradiation to block adrenal effects of
persistently high ACTH levels.
Ketoconazole, an imidazole derivative antimycotic
agent, inhibits several P450 enzymes and effectively
TREATMENT Cushings Syndrome lowers cortisol in most patients with Cushings disease
when administered twice daily (6001200 mg/d). Ele-
Selective transsphenoidal resection is the treatment of
vated hepatic transaminases, gynecomastia, impotence,
choice for Cushings disease (Fig. 38-10). The remission
gastrointestinal upset, and edema are common side
rate for this procedure is 80% for microadenomas but
effects. Metyrapone (24 g/d) inhibits 11-hydroxylase
<50% for macroadenomas. After successful tumor resec-
activity and normalizes plasma cortisol in up to 75% of
tion, most patients experience a postoperative period
patients. Side effects include nausea and vomiting, rash,
of symptomatic ACTH deficiency that may last up to
and exacerbation of acne or hirsutism. Mitotane (o,p-
12 months. This usually requires low-dose cortisol
DDD; 36 g/d orally in four divided doses) suppresses
replacement, as patients experience both steroid with-
cortisol hypersecretion by inhibiting 11-hydroxylase
drawal symptoms and have a suppressed HPA axis.
and cholesterol side-chain cleavage enzymes and by
Biochemical recurrence occurs in approximately 5% of
destroying adrenocortical cells. Side effects of mitotane
patients in whom surgery was initially successful.
CHAPTER 38
include gastrointestinal symptoms, dizziness, gyneco-
When initial surgery is unsuccessful, repeat surgery
mastia, hyperlipidemia, skin rash, and hepatic enzyme
is sometimes indicated, particularly when a pituitary
elevation. It also may lead to hypoaldosteronism. Other
source for ACTH is well documented. In older patients,
agents include aminoglutethimide (250 mg tid), trilo-
in whom issues of growth and fertility are less impor-
stane (2001000 mg/d), cyproheptadine (24 mg/d), and
tant, hemi- or total hypophysectomy may be necessary
IV etomidate (0.3 mg/kg per hour). Glucocorticoid insuf-
if a discrete pituitary adenoma is not recognized. Pitu-
ficiency is a potential side effect of agents used to block
and pituitary levels and is mediated in part by its con- decreased muscle mass with weakness, reduced beard
version to estrogens. and body hair growth, soft testes, and characteristic ne
Although GnRH is the main regulator of LH and FSH facial wrinkles. Osteoporosis occurs in both untreated
secretion, FSH synthesis is also under separate control by hypogonadal women and men.
the gonadal peptides inhibin and activin, which are mem-
bers of the transforming growth factor (TGF-) family. Laboratory investigation
Diseases of the Nervous System
CHAPTER 38
therapy is used for ovulation induction. Follicular growth derived FSH elevation. Premenopausal women have
and maturation are initiated using hMG or recombinant cycling FSH levels, also preventing clear-cut diagnostic
FSH; hCG or human luteinizing hormone (hLH) is subse- distinction from tumor-derived FSH. In men, gonad-
quently injected to induce ovulation. As in men, pulsatile otropin-secreting tumors may be diagnosed because of
GnRH therapy can be used to treat hypothalamic causes of slightly increased gonadotropins (FSH > LH) in the set-
gonadotropin deficiency. ting of a pituitary mass. Testosterone levels are usually
Low risk of
visual loss Surgery
Histologic diagnosis
Observe Surgery
SECTION III
Follow-up: MRI MRI Trophic hormone MRI May require Trophic hormone
testing and disease-specific testing and
replacement therapy replacement
FIGURE 38-11
Diseases of the Nervous System
CHAPTER 38
most of these adenomas are large and locally invasive.
Normal circulating thyroid hormone levels are achieved
TSH-SECRETING ADENOMAS in about two-thirds of patients after surgery. Thyroid
ablation or antithyroid drugs (methimazole and pro-
TSH-producing macroadenomas are rare but are often pylthiouracil) can be used to reduce thyroid hormone
large and locally invasive when they occur. Patients levels. Somatostatin analogue treatment effectively
usually present with thyroid goiter and hyperthyroid- normalizes TSH and subunit hypersecretion, shrinks
Demyelinating disorders are immune-mediated condi- astrocytic proliferation (gliosis). Surviving oligodendro-
tions characterized by preferential destruction of central cytes or those that differentiate from precursor cells can
nervous system (CNS) myelin. The peripheral nervous partially remyelinate the surviving naked axons, pro-
system (PNS) is spared, and most patients have no evi- ducing so-called shadow plaques. In many lesions, oli-
dence of an associated systemic illness. Multiple sclerosis godendrocyte precursor cells are present in large num-
(MS), the most common disease in this category, is sec- bers but fail to differentiate and remyelinate. Over time,
ond only to trauma as a cause of neurologic disability ectopic lymphocyte follicles appear in perivascular and
beginning in early to middle adulthood. perimeningeal regions, consisting of aggregates of T and
B cells and resembling secondary lymphoid structures.
Although relative sparing of axons is typical of MS,
MULTIPLE SCLEROSIS partial or total axonal destruction can also occur, espe-
cially within highly inammatory lesions. Thus, MS is
Multiple sclerosis (MS) is a chronic disease characterized not solely a disease of myelin, and neuronal pathology
by inammation, demyelination, gliosis (scarring), and is increasingly recognized as a major contributor to irre-
neuronal loss; the course can be relapsing-remitting or versible neurologic disability. Inammation and plaque
progressive. Lesions of MS typically occur at different formation are present in the cerebral cortex, and sig-
times and in different CNS locations (i.e., disseminated nicant axon loss indicating death of neurons is wide-
in time and space). MS affects 350,000 individuals in spread, specially in advanced cases (see Neurodegen-
the United States and 2.5 million individuals world- eration, later in this chapter).
wide. Manifestations of MS vary from a benign illness
to a rapidly evolving and incapacitating disease requir- Physiology
ing profound lifestyle adjustments.
Nerve conduction in myelinated axons occurs in a sal-
tatory manner, with the nerve impulse jumping from
PATHOGENESIS one node of Ranvier to the next without depolariza-
tion of the axonal membrane underlying the myelin
Anatomy sheath between nodes (Fig. 39-1). This produces con-
New MS lesions begin with perivenular cufng by siderably faster conduction velocities (70 m/s) than
inammatory mononuclear cells, predominantly T cells the slow velocities (1 m/s) produced by continuous
and macrophages, which also inltrate the surround- propagation in unmyelinated nerves. Conduction block
ing white matter. At sites of inammation, the blood- occurs when the nerve impulse is unable to traverse
brain barrier (BBB) is disrupted, but unlike vasculitis, the demyelinated segment. This can happen when the
the vessel wall is preserved. Involvement of the humoral resting axon membrane becomes hyperpolarized due
immune system is also evident; small numbers of B lym- to the exposure of voltage-dependent potassium chan-
phocytes also inltrate the nervous system, and myelin- nels that are normally buried underneath the myelin
specic autoantibodies are present on degenerating sheath. A temporary conduction block often follows a
myelin sheaths. As lesions evolve, there is prominent demyelinating event before sodium channels (originally
474
Saltatory nerve impulse One proposed explanation for the latitude effect on 475
MS is that there is a protective effect of sun exposure.
Myelin sheath
Exposure of the skin to ultraviolet-B (UVB) radiation
Axon
from the sun is essential for the biosynthesis of vitamin
D, and this endogenous production is the most impor-
tant source of vitamin D in most individuals. At high
Na+ channels Node of Ranvier
A latitudes, the amount of UVB radiation reaching the
earths surface is often insufcient, particularly during
winter months, and, consequently, low serum levels of
Continuous nerve impulse
Myelin sheath Myelin sheath vitamin D are common in temperate zones. Prospec-
Axon tive studies have conrmed that vitamin D deciency
is associated with an increase in MS risk and prelimi-
nary data also suggest that ongoing deciency may
Na+ channels
B
increase the relapse rate in established MS. Immunoreg-
ulatory effects of vitamin D could explain this apparent
FIGURE 39-1 relationship.
Nerve conduction in myelinated and demyelinated axons. At least three sequential (population-wide) envi-
CHAPTER 39
A. Saltatory nerve conduction in myelinated axons occurs ronmental events are implicated in the causal pathway
with the nerve impulse jumping from one node of Ran- leading to MS. The rst factor seems to occur either in
vier to the next. Sodium channels (shown as breaks in the utero or in the early postnatal period and is supported,
solid black line) are concentrated at the nodes where axonal in part, by the almost twofold increase in MS risk for
depolarization occurs. B. Following demyelination, additional dizygotic twins of MS probands (5.4%) compared to
sodium channels are redistributed along the axon itself, siblings (2.9%). It is also supported by the month-of-
thereby allowing continuous propagation of the nerve action
Epstein-Barr virus (EBV) infection playing some role in other autoimmune diseases in addition to MS. The vari-
MS is supported by a number of epidemiologic and lab- ants identied thus far all lack specicity and sensitivity
oratory studies. A higher risk of infectious mononucle- for MS; thus they are not useful for diagnosis or to pre-
osis (associated with relatively late EBV infection) and dict the future course of the disease.
higher antibody titers to latency-associated EBV nuclear
antigen are associated with MS. At this time, however, Immunology
Diseases of the Nervous System
CHAPTER 39
reveal that bursts of focal inammatory disease activity lated reason may show evidence of asymptomatic MS.
occur far more frequently than would have been pre- Symptoms of MS are extremely varied and depend on
dicted by the frequency of relapses. Thus, early in MS the location and severity of lesions within the CNS
most disease activity is clinically silent. The triggers (Table 39-2). Examination often reveals evidence of
causing these bursts are unknown, although the fact neurologic dysfunction, often in asymptomatic locations.
that patients may experience relapses after nonspecic For example, a patient may present with symptoms in
Visual blurring in MS may result from ON or diplo- of MS but is actually uncommon, occurring in <20% of
pia (double vision); if the symptom resolves when either patients. Cognitive dysfunction sufcient to impair activ-
eye is covered, the cause is diplopia. ities of daily living is rare.
Diplopia may result from internuclear ophthalmople- Depression, experienced by approximately half of patients,
gia (INO) or from palsy of the sixth cranial nerve (rarely can be reactive, endogenous, or part of the illness itself,
the third or fourth). An INO consists of impaired and can contribute to fatigue. Fatigue is experienced by
adduction of one eye due to a lesion in the ipsilateral 90% of patients; this symptom is the most common rea-
medial longitudinal fasciculus (Chap. 21). Prominent son for work-related disability in MS. Fatigue can be
nystagmus is often observed in the abducting eye, along exacerbated by elevated temperatures, by depression, by
with a small skew deviation. A bilateral INO is partic- expending exceptional effort to accomplish basic activities
ularly suggestive of MS. Other common gaze distur- of daily living, or by sleep disturbances (e.g., from frequent
bances in MS include (1) a horizontal gaze palsy, (2) a nocturnal awakenings to urinate).
one and a half syndrome (horizontal gaze palsy plus Sexual dysfunction may manifest as decreased libido,
an INO), and (3) acquired pendular nystagmus. impaired genital sensation, impotence in men, and dimin-
Sensory symptoms are varied and include both pares- ished vaginal lubrication or adductor spasms in women.
thesias (e.g., tingling, prickling sensations, formications, Facial weakness due to a lesion in the pons may resem-
pins and needles, or painful burning) and hypesthesia ble idiopathic Bells palsy (Chap. 34). Unlike Bells palsy,
(e.g., reduced sensation, numbness, or a dead feeling). facial weakness in MS is usually not associated with ipsi-
Unpleasant sensations (e.g., feelings that body parts are lateral loss of taste sensation or retroauricular pain.
swollen, wet, raw, or tightly wrapped) are also common. Vertigo may appear suddenly from a brainstem lesion,
Sensory impairment of the trunk and legs below a hori- supercially resembling acute labyrinthitis (Chap. 11).
zontal line on the torso (a sensory level) indicates that Hearing loss may also occur in MS but is uncommon.
the spinal cord is the origin of the sensory disturbance. It
is often accompanied by a bandlike sensation of tightness
Ancillary symptoms
around the torso. Pain is a common symptom of MS,
experienced by >50% of patients. Pain can occur any- Heat sensitivity refers to neurologic symptoms produced
where on the body and can change locations over time. by an elevation of the bodys core temperature. For
Ataxia usually manifests as cerebellar tremors (Chap. 31). example, unilateral visual blurring may occur during a
Ataxia may also involve the head and trunk or the voice, hot shower or with physical exercise (Uhthoffs symptom).
producing a characteristic cerebellar dysarthria (scanning It is also common for MS symptoms to worsen tran-
speech). siently, sometimes dramatically, during febrile illnesses
(see Acute Attacks or Initial Demyelinating Episodes, RRMS PPMS 479
later). Such heat-related symptoms probably result from
transient conduction block (discussed earlier).
Disability
Disability
Lhermittes symptom is an electric shocklike sensation
(typically induced by exion or other movements of the
neck) that radiates down the back into the legs. Rarely,
it radiates into the arms. It is generally self-limited but
Time Time
may persist for years. Lhermittes symptom can also
A C
occur with other disorders of the cervical spinal cord
(e.g., cervical spondylosis). SPMS PRMS
Paroxysmal symptoms are distinguished by their brief
duration (10 s to 2 min), high frequency (540 epi-
Disability
Disability
sodes per day), lack of any alteration of consciousness
or change in background electroencephalogram dur-
ing episodes, and a self-limited course (generally last-
ing weeks to months). They may be precipitated by
Time Time
hyperventilation or movement. These syndromes may
CHAPTER 39
B D
include Lhermittes symptom; tonic contractions of a
limb, face, or trunk (tonic seizures); paroxysmal dysar- FIGURE 39-2
thria and ataxia; paroxysmal sensory disturbances; and Clinical course of multiple sclerosis (MS). A. Relapsing/
several other less well characterized syndromes. Parox- remitting MS. B. Secondary progressive MS. C. Primary pro-
ysmal symptoms probably result from spontaneous dis- gressive MS. D. Progressive/relapsing MS.
charges, arising at the edges of demyelinated plaques
TABLE 39-3
DIAGNOSTIC CRITERIA FOR MS
clinical evidence of 1 lesion 1 T2 lesion on MRI in at least two out of four MS-typical regions of the CNS
(periventricular, juxtacortical, infratentorial, or spinal cord)
OR
Await a further clinical attack implicating a different CNS site
1 attack; objective clinical Dissemination in time, demonstrated by
evidence of 2 or more lesions Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing
lesions at any time
OR
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its
timing with reference to a baseline scan
OR
Await a second clinical attack
1 attack; objective clinical Dissemination in space and time, demonstrated by:
evidence of 1 lesion (clinically For dissemination in space
isolated syndrome) 1 T2 lesion in at least two out of four MS-typical regions of the CNS (periventricular,
juxtacortical, infratentorial, or spinal cord)
OR
Await a second clinical attack implicating a different CNS site
AND
For dissemination in time
Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing
lesions at any time
OR
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing
with reference to a baseline scan
OR
Await a second clinical attack
Insidious neurologic progression One year of disease progression (retrospectively or prospectively determined)
suggestive of MS (PPMS) PLUS
Two out of the three following criteria
Evidence for dissemination in space in the brain based on 1 T2+ lesions in the MS-
characteristic periventricular, juxtacortical, or infratentorial regions
Evidence for dissemination in space in the spinal cord based on 2 T2+ lesions in the cord
Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)
CHAPTER 39
Multiple Sclerosis and Other Demyelinating Diseases
A B
C D
FIGURE 39- 3
MRI ndings in MS. A. Axial rst-echo image from are frequent in MS and rare in vascular disease. C. Sagittal
T2-weighted sequence demonstrates multiple bright sig- T2-weighted fast spin echo image of the thoracic spine dem-
nal abnormalities in white matter, typical for MS. B. Sagit- onstrates a fusiform high-signal-intensity lesion in the mid-
tal T2-weighted FLAIR (uid attenuated inversion recovery) thoracic spinal cord. D. Sagittal T1-weighted image obtained
image in which the high signal of CSF has been suppressed. after the intravenous administration of gadolinium DTPA
CSF appears dark, while areas of brain edema or demy- reveals focal areas of blood-brain barrier disruption, identi-
elination appear high in signal as shown here in the corpus ed as high-signal-intensity regions (arrows).
callosum (arrows). Lesions in the anterior corpus callosum
482 located in the corpus callosum, periventricular white The measurement of oligoclonal banding (OCB) in the
matter, brainstem, cerebellum, or spinal cord are par- CSF also assesses intrathecal production of IgG. OCBs
ticularly helpful diagnostically. Different criteria for the are detected by agarose gel electrophoresis. Two or more
use of MRI in the diagnosis of MS have been proposed OCBs are found in 7590% of patients with MS. OCBs
(Table 39-3). may be absent at the onset of MS, and in individual
The total volume of T2-weighted signal abnormal- patients the number of bands may increase with time.
ity (the burden of disease) shows a signicant (albeit It is important that paired serum samples be studied to
weak) correlation with clinical disability, as do mea- exclude a peripheral (i.e., non-CNS) origin of any OCBs
sures of brain atrophy. Approximately one-third of detected in the CSF.
T2-weighted lesions appear as hypointense lesions A mild CSF pleocytosis (>5 cells/L) is present in
(black holes) on T1-weighted imaging. Black holes may 25% of cases, usually in young patients with RRMS.
be a marker of irreversible demyelination and axonal A pleocytosis of >75 cells/L, the presence of polymor-
loss, although even this measure depends on the timing phonuclear leukocytes, or a protein concentration >1
of the image acquisition (e.g., most acute Gd-enhancing g/L (>100 mg/dL) in CSF should raise concern that the
T2 lesions are T1 dark). patient may not have MS.
Newer MRI measures such as magnetization transfer
ratio (MTR) imaging, and proton magnetic resonance
SECTION III
Evoked potentials
TABLE 39-4
EP testing assesses function in afferent (visual, auditory,
DISORDERS THAT CAN MIMIC MS
and somatosensory) or efferent (motor) CNS pathways.
EPs use computer averaging to measure CNS electric Acute disseminated encephalomyelitis (ADEM)
potentials evoked by repetitive stimulation of selected Antiphospholipid antibody syndrome
peripheral nerves or of the brain. These tests provide Behets disease
the most information when the pathways studied are
Cerebral autosomal dominant arteriopathy, subcortical
clinically uninvolved. For example, in a patient with a
infarcts, and leukoencephalopathy (CADASIL)
remitting and relapsing spinal cord syndrome with sen-
sory decits in the legs, an abnormal somatosensory EP Congenital leukodystrophies (e.g., adrenoleukodystrophy,
metachromatic leukodystrophy)
following posterior tibial nerve stimulation provides lit-
tle new information. By contrast, an abnormal visual EP Human immunodeciency virus (HIV) infection
in this circumstance would permit a diagnosis of clini- Ischemic optic neuropathy (arteritic and nonarteritic)
cally denite MS (Table 39-3). Abnormalities on one or Lyme disease
more EP modalities occur in 8090% of MS patients. Mitochondrial encephalopathy with lactic acidosis and
EP abnormalities are not specic to MS, although a stroke (MELAS)
marked delay in the latency of a specic EP component
Neoplasms (e.g., lymphoma, glioma, meningioma)
(as opposed to a reduced amplitude or distorted wave-
shape) is suggestive of demyelination. Sarcoid
Sjgrens syndrome
CHAPTER 39
alternative diagnoses will vary with each clinical situa- expected during gestation (especially in the last trimes-
tion; however, an erythrocyte sedimentation rate, serum ter), but more attacks than expected in the rst 3 months
B12 level, ANA, and treponemal antibody should prob- postpartum. When considering the pregnancy year as a
ably be obtained in all patients with suspected MS. whole (i.e., 9 months pregnancy plus 3 months postpar-
tum), the overall disease course is unaffected. Decisions
about childbearing should thus be made based on (1)
CHAPTER 39
Side effects of short-term glucocorticoid therapy
rate and improves disease severity measures such as
include fluid retention, potassium loss, weight gain, gas-
EDSS progression and MRI-documented disease burden.
tric disturbances, acne, and emotional lability. Concur-
IFN- should be considered in patients with either
rent use of a low-salt, potassium-rich diet and avoidance
RRMS or SPMS with superimposed relapses. In patients
of potassium-wasting diuretics is advisable. Lithium
with SPMS but without relapses, efficacy has not been
carbonate (300 mg orally bid) may help to manage
established. Head-to-head trials suggest that higher
emotional lability and insomnia associated with gluco-
a
Percentage reductions (or increases) have been calculated by dividing the reported rates in the treated group by the comparable rates in the
placebo group, except for MRI disease burden, which was calculated as the difference in the median percentage change between the treated
and placebo groups.
b
Severity = 1 point EDSS progression, sustained for 3 months (in the IFN--1a 30 g qw trial, this change was sustained for 6 months; in the
IFN--1b trial, this was over 3 years).
c
Different studies measured these MRI measures differently, making comparisons difcult (numbers for new T2 represent the best case scenario
for each trial).
Diseases of the Nervous System
d
New lesions seen on T2-weighted MRI.
e
p = .001.
p = .01.
f
g
p = .05.
h
Not FDA-approved at time of publication.
Abbreviations: IFN-, interferon ; GA, glatiramer acetate; MTX, mitoxantrone; NTZ, natalizumab; FGM, ngolimod; CLD, cladribine; IM, intra-
muscular; SC, subcutaneous; IV, intravenous; PO, oral; qod, every other day; qw, once per week; tiw, three times per week; qd, daily; q3mo,
once every 3 months; qmo, once per month; qyr, once per year; ns, not signicant; nr, not reported.
outcomes of disability and relapse rate. The reason for IFN- doses. Glatiramer acetate, 20 mg, is administered by
this clinical-radiologic dissociation is unresolved. For- subcutaneous injection every day. Injection-site reactions
tunately, however, there are few situations where mea- also occur with glatiramer acetate. Initially, these were
surement of antibodies is necessary. Thus, for a patient thought to be less severe than with IFN--1b, although
doing well on therapy, the presence of antibodies two recent head-to-head comparisons of high-dose IFN-
should not affect treatment. Conversely, for a patient to glatiramer acetate did not bear out this impression. In
doing poorly on therapy, alternative treatment should be addition, approximately 15% of patients experience one
considered, even if there are no detectable antibodies. or more episodes of flushing, chest tightness, dyspnea,
palpitations, and anxiety after injection. This systemic
Glatiramer Acetate Glatiramer acetate is a syn-
reaction is unpredictable, brief (duration <1 h), and tends
thetic, random polypeptide composed of four amino
not to recur. Finally, some patients experience lipoatro-
acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine).
phy, which, on occasion, can be disfiguring and require
Its mechanism of action may include (1) induction of anti-
cessation of treatment.
gen-specific suppressor T cells; (2) binding to MHC mol-
ecules, thereby displacing bound MBP; or (3) altering the Natalizumab Natalizumab (Tysabri) is a humanized
balance between proinflammatory and regulatory cyto- monoclonal antibody directed against the 4 subunit of
kines. Glatiramer acetate reduces the attack rate (whether 41 integrin, a cellular adhesion molecule expressed on
measured clinically or by MRI) in RRMS. Glatiramer the surface of lymphocytes. It prevents lymphocytes from
acetate may also benefit disease severity measures, binding to endothelial cells, thereby preventing lympho-
although this is less well established than for the relapse cytes from penetrating the BBB and entering the CNS.
rate. Therefore, glatiramer acetate should be considered Natalizumab greatly reduces the attack rate and significantly
in RRMS patients. Its usefulness in progressive disease is improves all measures of disease severity in MS. Moreover,
entirely unknown. Head-to-head clinical trials suggest it is well tolerated and the dosing schedule of monthly
that glatiramer acetate has about equal efficacy to high intravenous infusions make it very convenient for patients.
However, because of the development of progressive mul- ation of the medication is necessary. First-degree heart
487
tifocal leukoencephalopathy (PML) in approximately 0.2% block and bradycardia can also occur, the latter necessi-
of patients treated with natalizumab for more than 2 years, tating the prolonged (6-h) observation of patients receiv-
natalizumab is currently recommended only for patients ing their first dose.
who have failed other therapies or who have particularly
Teriunomide Teriflunomide (Aubagio) is an oral
aggressive disease presentations. Its usefulness in the treat-
inhibitor of the enzyme dihydroorotate dehydroge-
ment of progressive disease has not been studied. Head-to-
nase involved in pyramiding synthesis. Clinical trials
head data for natalizumab against low-dose (weekly) IFN-
using once daily dosages of 7 or 14 mg revealed modest
showed a clear superiority of natalizumab in RRMS; the trial
effects on relapse rate (approximately 30% compared
design, however, was biased against IFN- (i.e., patients
to placebo), and an effect on disability at the higher
recruited could already be considered IFN- treatment fail-
dose. Possible side effects include hepatic toxicity, nau-
ures). Natalizumab, 300 g, is administered by IV infusion
sea, and hair thinning. Teriflunomide can remain in the
each month. Treatment with natalizumab is, in general, well
blood for many months following administration and is
tolerated. A small percentage (<10%) of patients experience
considered teratogenic.
hypersensitivity reactions (including anaphylaxis) and 6%
develop neutralizing antibodies to the molecule. Mitoxantrone Hydrochloride Mitoxantrone
CHAPTER 39
The major concern with long-term treatment is the (Novantrone), an anthracenedione, exerts its antineoplas-
risk of PML. Because the risk is extremely low during the tic action by (1) intercalating into DNA and producing
first year of treatment with natalizumab, we currently both strand breaks and interstrand cross-links, (2) interfer-
recommend treatment for periods of 1218 months ing with RNA synthesis, and (3) inhibiting topoisomerase II
only for most patients; after this time, a change to (involved in DNA repair). The FDA approved mitoxantrone
another disease-modifying therapy should be consid- on the basis of a single (relatively small) phase III clinical
ered. Recently, a blood test to detect antibodies against trial in Europe, in addition to an even smaller phase II study
GRESSIVE MS
these agents can improve the long-term outcome of MS,
especially when administered early in the RRMS stage of SPMS High-dose IFN- probably has a beneficial
the illness. Beneficial effects seen in early MS include a effect in patients with SPMS who are still experiencing
reduction in the relapse rate, a reduction in CNS inflam- acute relapses. IFN- is probably ineffective in patients
mation as measured by MRI, and a prolongation in the with SPMS who are not having acute attacks. Glatiramer
time to reach certain disability outcomes such as SPMS acetate and natalizumab have not been studied in this
Diseases of the Nervous System
Relapsing-Remitting MS Progressive MS
Secondary Primary
Acute neurologic change Stable progressive MS progressive MS
Functional No functional
impairment impairment
No Yes 1. IFN-1a, or No proven treatment
2. IFN-1b
Methylprednisolone/ Symptomatic Prophylaxis
prednisone therapy Repeat clinical exam
1. IFN-1a, or Consider
and MRI in 6 months
2. IFN-1b, or Intolerant or
3. Glatiramer acetate or poor response
4. Fingolimod
Identify and treat any
underlying infection or trauma
Clinical or No
MRI change change Consider Rx with one of the following:
Good Intolerant or 1. Mitoxantrone 4. Pulse cyclophosphamide
response poor response 2. Azathioprine 5. IVIg
Continue periodic 3. Methotrexate 6. Pulse methylprednisolone
clinical/ MRI
Continue Successive trials assessments
therapy of alternatives B
Natalizumab
A
FIGURE 39-4
Therapeutic decision-making for MS.
patient population. Although mitoxantrone has been example, no reliable case of mercury poisoning resem-
489
approved for patients with progressive MS, this is not bling typical MS has ever been described.
the population studied in the pivotal trial. Therefore, Although potential roles for EBV, HHV-6, or chlamydia
no evidence-based recommendation can be made with have been suggested for MS, these reports are uncon-
regard to its use in this setting. firmed, and treatment with antiviral agents or antibiot-
ics is not currently appropriate.
PPMS No therapies have been convincingly shown
Most recently, chronic cerebrospinal insufficiency
to modify the course of PPMS. A phase III clinical trial
(CCSVI) has been proposed as a cause of multiple scle-
of glatiramer acetate in PPMS was stopped because of
rosis and vascular-surgical intervention recommended.
lack of efficacy. A phase II/III trial of rituximab in PPMS
However, the failure of independent investigators to
was also negative, but in a preplanned secondary analy-
even approximate the initial claims of 100% sensitivity
sis treatment appeared to slow disability progression in
and 100% specificity for the diagnostic procedure raised
patients with gadolinium-enhancing lesions at entry; a
considerable doubt that CCSVI is a real entity. Certainly,
follow-up trial with the humanized anti-CD20 therapy
any potentially dangerous surgery should be avoided
ocrelizumab will soon begin. A trial of mitoxantrone in
until more rigorous science is available.
PPMS is ongoing.
CHAPTER 39
OFF-LABEL TREATMENT OPTIONS FOR SYMPTOMATIC THERAPY For all patients, it
RRMS AND SPMS Azathioprine (23 mg/kg per is useful to encourage attention to a healthy lifestyle,
day) has been used primarily in SPMS. Meta-analysis of including maintaining an optimistic outlook, a healthy
published trials suggests that azathioprine is marginally diet, and regular exercise as tolerated (swimming is
effective at lowering relapse rates, although a benefit on often well tolerated because of the cooling effect of
disability progression has not been demonstrated. cold water). It is reasonable also to correct vitamin
Methotrexate (7.520 mg/week) was shown in one
bacteria. Prophylactic administration of antibiotics is cally of attacks of acute ON and myelitis. Attacks of
sometimes necessary but may lead to colonization by ON can be bilateral (rare in MS) or unilateral; myelitis
resistant organisms. Intermittent catheterization may can be severe and transverse (rare in MS) and is typi-
help to prevent recurrent infections. cally longitudinally extensive, involving three or more
Treatment of constipation includes high-fiber diets contiguous vertebral segments. Attacks of ON may be
and fluids. Natural or other laxatives may help. Fecal precede or follow an attack of myelitis by days, months,
incontinence may respond to a reduction in dietary fiber. or years, or vice versa. In contrast to MS, progressive
Depression should be treated. Useful drugs include symptoms do not occur in NMO. The brain MRI was
the selective serotonin reuptake inhibitors (fluoxetine, classically thought to be normal at the onset of NMO,
2080 mg/d; or sertraline, 50200 mg/d), the tricyclic but recent studies now indicate that asymptomatic
antidepressants (amitriptyline, 25150 mg/d; nortripty- lesions sometimes resembling typical MS are common.
line, 25150 mg/d; or desipramine, 100300 mg/d), and Lesions involving the hypothalamus, periaqueductal
the non-tricyclic antidepressants (venlafaxine, 75225 region of the brainstem, or cloud-like white mat-
mg/d). ter lesions in the cerebral hemispheres are suggestive of
Fatigue may improve with assistive devices, help NMO. Brainstem disease can present with nausea and
in the home, or successful management of spasticity. vertigo, and large hemispheral lesions can present as
Patients with frequent nocturia may benefit from anti- encephalopathy or seizures. Spinal cord MRI typically
cholinergic medication at bedtime. Primary MS fatigue reveals a focal enhancing region of swelling and cavita-
may respond to amantadine (200 mg/d), methylpheni- tion, extending over three or more spinal cord segments
date (525 mg/d), or modafinil (100400 mg/d). and often located in central gray matter structures. His-
Cognitive problems may respond to the cholinester- topathology of these lesions may reveal thickening of
ase inhibitor donepezil hydrochloride (10 mg/d). blood-vessel walls, demyelination, deposition of anti-
Paroxysmal symptoms respond dramatically to low- body and complement, a characteristic loss of astrocytes,
dose anticonvulsants (acetazolamide, 200600 mg/d; and aquaporin-4 staining not seen in MS.
carbamazepine, 50400 mg/d; phenytoin, 50300 mg/d; NMO, which is uncommon in whites compared
or gabapentin, 6001800 mg/d). with Asians and Africans, is best understood as a syn-
Heat sensitivity may respond to heat avoidance, air- drome with diverse causes. Up to 40% of patients have
conditioning, or cooling garments. a systemic autoimmune disorder, often systemic lupus
Sexual dysfunction may be helped by lubricants to aid erythematosus, Sjgrens syndrome, p-ANCA (peri-
in genital stimulation and sexual arousal. Management nuclear antineutrophil cytoplasmic antibody)associated
vasculitis, myasthenia gravis, Hashimotos thyroiditis,
or mixed connective tissue disease. In others, onset
patients with one of the following regimens: mycophe-
491
may be associated with acute infection with varicella-
nolate mofetil (250 mg bid gradually increasing to 1000
zoster virus, EBV, HIV, or tuberculosis. Rare cases
mg bid); B cell depletion with anti-CD20 monoclonal
appear to be paraneoplastic and associated with breast,
antibody (Rituxan); or a combination of glucocorti-
lung, or other cancers. NMO is often idiopathic, how-
coids (500 mg IV methylprednisolone daily for 5 days;
ever. NMO is usually disabling over time; in one series,
then oral prednisone 1 mg/kg per day 2 months, fol-
respiratory failure from cervical myelitis was present in
lowed by slow taper) plus azathioprine (2 mg/kg per day
one-third of patients, and 8 years after onset 60% of
started on week 3). By contrast, available evidence sug-
patients were blind and more than half had permanent
gests that use of IFN- is ineffective and paradoxically
paralysis of one or more limbs.
may increase the risk of NMO relapses.
A highly specic autoantibody directed against the
water channel protein aquaporin-4 is present in the
sera of 6070% of patients who have a clinical diag-
nosis of NMO. Seropositive patients have a very high
ACUTE DISSEMINATED
risk for future relapses. Aquaporin-4 is localized to the
foot processes of astrocytes in close apposition to endo-
ENCEPHALOMYELITIS (ADEM)
thelial surfaces. It is likely that aquaporin-4 antibodies ADEM has a monophasic course and is most frequently
CHAPTER 39
are directly pathogenic in NMO, as passive transfer of associated with an antecedent infection (postinfectious
antibodies from NMO patients into laboratory animals encephalomyelitis); approximately 5% of ADEM cases
reproduced histologic features of the disease. follow immunization (postvaccinal encephalomyelitis).
When MS affects individuals of African or Asian ADEM is more common in children than adults. The
ancestry, there is a propensity for demyelinating lesions hallmark of ADEM is the presence of widely scattered
to involve predominantly the optic nerve and spinal small foci of perivenular inammation and demyelination
the initial days of the illness. Transient CSF oligoclonal atypical MS.
banding has been reported. MRI usually reveals extensive
changes in the brain and spinal cord, consisting of white
matter hyperintensities on T2 and FLAIR sequences with
gadolinium enhancement on T1-weighted sequences. TREATMENT Acute Disseminated Encephalomyelitis
493
494
Headache, Fever, Nuchal Rigidity
Yes No
and/or surgical
interventions Immediate blood culture
Encephalitis and lumbar puncture
FIGURE 40-1
The management of patients with suspected CNS infection. LCMV, lymphocytic choriomeningitis virus; MNCs, mononuclear
ADEM, acute disseminated encephalomyelitis; AFB, acid-fast cells; MRI, magnetic resonance imaging; PCR, polymerase
bacillus; Ag, antigen; CSF, cerebrospinal uid; CT, computed chain reaction; PMNs, polymorphonuclear leukocytes; PPD,
tomography; CTFV, Colorado tick fever virus; CXR, chest puried protein derivative; TB, tuberculosis; VDRL, Venereal
x-ray; DFA, direct uorescent antibody; EBV, Epstein-Barr Disease Research Laboratory; VZV, varicella-zoster virus; WNV,
virus; HHV, human herpesvirus; HSV, herpes simplex virus; West Nile virus.
Tier 3 Evaluation
(based on epidemiology)
CHAPTER 40
Raccoon Wild rodent Cat Swimming in
exposure or or hamster exposure lakes or ponds
Hx of pica exposure or nonchlorinated
water
Bartonella spp.
individuals with chronic and debilitating diseases such cells, and gain access to the CSF. Some bacteria, such as
as diabetes, cirrhosis, or alcoholism and in those with S. pneumoniae, can adhere to cerebral capillary endothe-
chronic urinary tract infections. Gram-negative meningitis lial cells and subsequently migrate through or between
can also complicate neurosurgical procedures, particu- these cells to reach the CSF. Bacteria are able to multiply
larly craniotomy. rapidly within CSF because of the absence of effective
Otitis, mastoiditis, and sinusitis are predisposing and host immune defenses. Normal CSF contains few white
Diseases of the Nervous System
associated conditions for meningitis due to Streptococci blood cells (WBCs) and relatively small amounts of
sp., gram-negative anaerobes, S. aureus, Haemophilus sp., complement proteins and immunoglobulins. The pau-
and Enterobacteriaceae. Meningitis complicating endo- city of the latter two prevents effective opsonization of
carditis may be due to viridans streptococci, S. aureus, S. bacteria, an essential prerequisite for bacterial phagocy-
bovis, the HACEK group (Haemophilus sp., Actinobacillus tosis by neutrophils. Phagocytosis of bacteria is further
actinomycetemcomitans, Cardiobacterium hominis, Eikenella impaired by the uid nature of CSF, which is less con-
corrodens, Kingella kingae), or enterococci. ducive to phagocytosis than a solid tissue substrate.
Group B streptococcus, or S. agalactiae, was previously A critical event in the pathogenesis of bacterial men-
responsible for meningitis predominantly in neonates, ingitis is the inammatory reaction induced by the
but it has been reported with increasing frequency in invading bacteria. Many of the neurologic manifestations
individuals >50 years of age, particularly those with and complications of bacterial meningitis result from the
underlying diseases. immune response to the invading pathogen rather than
L. monocytogenes is an increasingly important cause from direct bacteria-induced tissue injury. As a result,
of meningitis in neonates (<1 month of age), pregnant neurologic injury can progress even after the CSF has
women, individuals >60 years, and immunocompro- been sterilized by antibiotic therapy.
mised individuals of all ages. Infection is acquired by The lysis of bacteria with the subsequent release of
ingesting foods contaminated by Listeria. Foodborne cell-wall components into the subarachnoid space is
human listerial infection has been reported from con- the initial step in the induction of the inammatory
taminated coleslaw, milk, soft cheeses, and several types response and the formation of a purulent exudate in
of ready-to-eat foods, including delicatessen meat and the subarachnoid space (Fig. 40-2). Bacterial cell-wall
uncooked hotdogs. components, such as the lipopolysaccharide (LPS) mol-
The frequency of H. inuenzae type b meningitis in ecules of gram-negative bacteria and teichoic acid
children has declined dramatically since the introduc- and peptidoglycans of S. pneumoniae, induce menin-
tion of the Hib conjugate vaccine, although rare cases geal inammation by stimulating the production of
of Hib meningitis in vaccinated children have been inammatory cytokines and chemokines by microg-
reported. More frequently, H. inuenzae causes meningitis lia, astrocytes, monocytes, microvascular endothelial
in unvaccinated children and older adults, and non-b cells, and CSF leukocytes. In experimental models of
H. influenzae is an emerging pathogen. meningitis, cytokines including tumor necrosis factor
Staphylococcus aureus and coagulase-negative staph- alpha (TNF-) and interleukin 1 (IL-1) are pres-
ylococci are important causes of meningitis that ent in CSF within 12 h of intracisternal inoculation of
occurs following invasive neurosurgical procedures, LPS. This cytokine response is quickly followed by an
particularly shunting procedures for hydrocephalus, or increase in CSF protein concentration and leukocytosis.
497
Invasion of SAS by meningeal pathogens
CHAPTER 40
Exudate in SAS obstructs
outflow and resorption of
CSF and surrounds
and infiltrates
Cerebral
cerebral vasculature blood flow blood flow
ischemia
Intracranial pressure
Coma
FIGURE 40-2
The pathophysiology of the neurologic complications of bacterial meningitis. CSF, cerebrospinal uid; SAS, subarachnoid
space.
Chemokines (cytokines that induce chemotactic migra- CSF through the ventricular system and diminishes the
tion in leukocytes) and a variety of other proinammatory resorptive capacity of the arachnoid granulations in the
cytokines are also produced and secreted by leukocytes dural sinuses, leading to obstructive and communicating
and tissue cells that are stimulated by IL-1 and TNF-. hydrocephalus and concomitant interstitial edema.
In addition, bacteremia and the inammatory cytokines Inammatory cytokines upregulate the expression of
induce the production of excitatory amino acids, reactive selectins on cerebral capillary endothelial cells and leuko-
oxygen and nitrogen species (free oxygen radicals, nitric cytes, promoting leukocyte adherence to vascular endo-
oxide, and peroxynitrite), and other mediators that can thelial cells and subsequent migration into the CSF. The
induce death of brain cells, especially in the dentate adherence of leukocytes to capillary endothelial cells
gyrus of the hippocampus. increases the permeability of blood vessels, allowing for
Much of the pathophysiology of bacterial meningi- the leakage of plasma proteins into the CSF, which adds
tis is a direct consequence of elevated levels of CSF to the inammatory exudate. Neutrophil degranulation
cytokines and chemokines. TNF- and IL-1 act syn- results in the release of toxic metabolites that contribute
ergistically to increase the permeability of the blood- to cytotoxic edema, cell injury, and death. Contrary to
brain barrier, resulting in induction of vasogenic edema previous beliefs, CSF leukocytes probably do little to
and the leakage of serum proteins into the subarachnoid contribute to the clearance of CSF bacterial infection.
space (Fig. 40-2). The subarachnoid exudate of pro- During the very early stages of meningitis, there is
teinaceous material and leukocytes obstructs the ow of an increase in cerebral blood ow, soon followed by a
498 decrease in cerebral blood ow and a loss of cerebro- most important of these clues is the rash of menin-
vascular autoregulation (Chap. 28). Narrowing of the gococcemia, which begins as a diffuse erythematous
large arteries at the base of the brain due to encroachment maculopapular rash resembling a viral exanthem; how-
by the purulent exudate in the subarachnoid space ever, the skin lesions of meningococcemia rapidly
and inltration of the arterial wall by inammatory become petechial. Petechiae are found on the trunk
cells with intimal thickening (vasculitis) also occur and and lower extremities, in the mucous membranes and
may result in ischemia and infarction, obstruction of conjunctiva, and occasionally on the palms and soles.
branches of the middle cerebral artery by thrombosis,
thrombosis of the major cerebral venous sinuses, and
thrombophlebitis of the cerebral cortical veins. The DIAGNOSIS
combination of interstitial, vasogenic, and cytotoxic
edema leads to raised ICP and coma. Cerebral herniation When bacterial meningitis is suspected, blood cultures
usually results from the effects of cerebral edema, either should be immediately obtained and empirical antimi-
focal or generalized; hydrocephalus and dural sinus or crobial and adjunctive dexamethasone therapy initiated
cortical vein thrombosis may also play a role. without delay (Table 40-1). The diagnosis of bacte-
rial meningitis is made by examination of the CSF
(Table 40-2). The need to obtain neuroimaging stud-
SECTION III
and nuchal rigidity, but the classic triad may not be in order to obtain neuroimaging studies, empirical anti-
present. A decreased level of consciousness occurs in biotic therapy should be initiated after blood cultures are
>75% of patients and can vary from lethargy to coma. obtained. Antibiotic therapy initiated a few hours prior to
Fever and either headache, stiff neck, or an altered level LP will not signicantly alter the CSF WBC count or
of consciousness will be present in nearly every patient glucose concentration, nor is it likely to prevent visu-
with bacterial meningitis. Nausea, vomiting, and photo- alization of organisms by Grams stain or detection of
phobia are also common complaints. bacterial nucleic acid by polymerase chain reaction
Seizures occur as part of the initial presentation of (PCR) assay.
bacterial meningitis or during the course of the illness The classic CSF abnormalities in bacterial meningitis
in 2040% of patients. Focal seizures are usually due (Table 40-2) are (1) polymorphonuclear (PMN) leukocy-
to focal arterial ischemia or infarction, cortical venous tosis (>100 cells/L in 90%), (2) decreased glucose con-
thrombosis with hemorrhage, or focal edema. General- centration (<2.2 mmol/L [<40 mg/dL] and/or CSF/
ized seizure activity and status epilepticus may be due to serum glucose ratio of <0.4 in 60%), (3) increased pro-
hyponatremia, cerebral anoxia, or, less commonly, the tein concentration (>0.45 g/L [>45 mg/dL] in 90%),
toxic effects of antimicrobial agents such as high-dose and (4) increased opening pressure (>180 mmH2O in
penicillin. 90%). CSF bacterial cultures are positive in >80% of
Raised ICP is an expected complication of bacterial patients, and CSF Grams stain demonstrates organisms
meningitis and the major cause of obtundation and in >60%.
coma in this disease. More than 90% of patients will CSF glucose concentrations <2.2 mmol/L (<40 mg/dL)
have a CSF opening pressure >180 mmH2O, and are abnormal, and a CSF glucose concentration of zero
20% have opening pressures >400 mmH2O. Signs of can be seen in bacterial meningitis. Use of the CSF/
increased ICP include a deteriorating or reduced level serum glucose ratio corrects for hyperglycemia that may
of consciousness, papilledema, dilated poorly reactive mask a relative decrease in the CSF glucose concentra-
pupils, sixth nerve palsies, decerebrate posturing, and tion. The CSF glucose concentration is low when the
the Cushing reex (bradycardia, hypertension, and CSF/serum glucose ratio is <0.6. A CSF/serum glucose
irregular respirations). The most disastrous complication ratio <0.4 is highly suggestive of bacterial meningitis
of increased ICP is cerebral herniation. The incidence but may also be seen in other conditions, including fungal,
of herniation in patients with bacterial meningitis has tuberculous, and carcinomatous meningitis. It takes
been reported to occur in as few as 1% to as many as 8% from 30 min to several hours for the concentration of
of cases. CSF glucose to reach equilibrium with blood glucose
Attention to clinical features that are hallmarks of levels; therefore, administration of 50 mL of 50% glucose
infection with certain pathogens may provide invalu- (D50) prior to LP, as commonly occurs in emer-
able clues to the diagnosis of individual organisms. The gency room settings, is unlikely to alter CSF glucose
TABLE 40-1 TABLE 40-2 499
ANTIBIOTICS USED IN EMPIRICAL THERAPY CEREBROSPINAL FLUID (CSF) ABNORMALITIES IN
OF BACTERIAL MENINGITIS AND FOCAL CNS BACTERIAL MENINGITIS
INFECTIONSa
Opening pressure >180 mmH2O
INDICATION ANTIBIOTIC White blood cells 10/L to 10,000/L;
neutrophils predominate
Preterm infants to infants Ampicillin + Red blood cells Absent in nontraumatic tap
<1 mon cefotaxime Glucose <2.2 mmol/L (<40 mg/dL)
Infants 13 mo Ampicillin + cefotaxime CSF/serum glucose <0.4
or ceftriaxone Protein >0.45 g/L (>45 mg/dL)
Immunocompetent children >3 Cefotaxime, ceftriax- Grams stain Positive in >60%
mo and adults <55 one or cefepime + Culture Positive in >80%
vancomycin Latex agglutination May be positive in patients with
Adults >55 and adults of any Ampicillin + cefotax- meningitis due to S. pneumoniae,
age with alcoholism or other ime, ceftriaxone N. meningitidis, H. inuenzae type
debilitating illnesses or cefepime + b, E. coli, group B streptococci
vancomycin Limulus lysate Positive in cases of
Hospital-acquired meningitis, post- Ampicillin + ceftazi- gram-negative meningitis
CHAPTER 40
traumatic or postneurosurgery dime or meropenem + PCR Detects bacterial DNA
meningitis, neutropenic patients, vancomycin
or patients with impaired
Abbreviation: PCR, polymerase chain reaction.
cell-mediated immunity
TOTAL DAILY DOSE AND DOSING INTERVAL
headache, fever, altered consciousness, focal neurologic def- promptly in all patients with suspected meningitis who
icits (e.g., dysphasia, hemiparesis), and focal or generalized have focal features, both to detect the intracranial infection
seizures. The ndings on CSF studies, neuroimag- and to search for associated areas of infection in the sinuses
ing, and electroencephalogram (EEG) distinguish or mastoid bones.
HSV encephalitis from bacterial meningitis. The typi- A number of noninfectious CNS disorders can mimic
cal CSF prole with viral CNS infections is a lympho- bacterial meningitis. Subarachnoid hemorrhage (SAH;
Diseases of the Nervous System
cytic pleocytosis with a normal glucose concentration, Chap. 28) is generally the major consideration. Other
in contrast to PMN pleocytosis and hypoglycorrhachia possibilities include chemical meningitis due to rupture
characteristic of bacterial meningitis. MRI abnormali- of tumor contents into the CSF (e.g., from a cystic
ties (other than meningeal enhancement) are not seen glioma or craniopharyngioma epidermoid or dermoid
in uncomplicated bacterial meningitis. By contrast, in cyst); drug-induced hypersensitivity meningitis; carcino-
HSV encephalitis, on T2-weighted and uid-attenuated matous or lymphomatous meningitis; meningitis associ-
inversion recovery (FLAIR) MRI images, high signal ated with inammatory disorders such as sarcoid, systemic
intensity lesions are seen in the orbitofrontal, anterior, lupus erythematosus (SLE), and Behets syndrome; pituitary
and medial temporal lobes in the majority of patients apoplexy; and uveomeningitic syndromes (Vogt-Koyanagi-
within 48 h of symptom onset. Some patients with HSV Harada syndrome).
encephalitis have a distinctive periodic pattern on EEG On occasion, subacutely evolving meningitis (Chap. 41)
(discussed later). may be considered in the differential diagnosis of acute
Rickettsial disease can resemble bacterial meningi- meningitis. The principal causes include Mycobacterium
tis. Rocky Mountain spotted fever (RMSF) is trans- tuberculosis, Cryptococcus neoformans, Histoplasma capsulatum,
mitted by a tick bite and caused by the bacteria Rick- Coccidioides immitis, and Treponema pallidum.
ettsia rickettsii. The disease may present acutely with
high fever, prostration, myalgia, headache, nausea,
and vomiting. Most patients develop a characteristic rash
within 96 h of the onset of symptoms. The rash is ini- TREATMENT Acute Bacterial Meningitis
tially a diffuse erythematous maculopapular rash that
may be difcult to distinguish from that of meningo- EM P I R I C A L A N T I M I C R O B I A L T H E R A P Y
coccemia. It progresses to a petechial rash, then to a (Table 40-1) Bacterial meningitis is a medical emergency.
purpuric rash and, if untreated, to skin necrosis or gan- The goal is to begin antibiotic therapy within 60 min
grene. The color of the lesions changes from bright of a patients arrival in the emergency room. Empirical
red to very dark red, then yellowish-green to black. antimicrobial therapy is initiated in patients with sus-
The rash typically begins in the wrist and ankles and pected bacterial meningitis before the results of CSF
then spreads distally and proximally within a matter Grams stain and culture are known. S. pneumoniae and
of a few hours, involving the palms and soles. Diag- N. meningitidis are the most common etiologic organ-
nosis is made by immunouorescent staining of skin isms of community-acquired bacterial meningitis. Due to
biopsy specimens. Ehrlichioses are also transmitted by the emergence of penicillin- and cephalosporin-resistant
a tick bite. These are small gram-negative coccobacilli S. pneumoniae, empirical therapy of community-acquired
of which two species cause human disease. Anaplasma suspected bacterial meningitis in children and adults
phagocytophilum causes human granulocytic ehrlichiosis should include a combination of dexamethasone, a
third- or fourth-generation cephalosporin (e.g., cef-
TABLE 40-3 501
ANTIMICROBIAL THERAPY OF CNS BACTERIAL
triaxone, cefotaxime, or cefepime), and vancomycin,
INFECTIONS BASED ON PATHOGENa
plus acyclovir, as HSV encephalitis is the leading dis-
ease in the differential diagnosis, and doxycycline dur- ORGANISM ANTIBIOTIC
ing tick season to treat tick-borne bacterial infections.
Neisseria meningitides
Ceftriaxone or cefotaxime provide good coverage for Penicillin-sensitive Penicillin G or ampicillin
susceptible S. pneumoniae, group B streptococci, and Penicillin-resistant Ceftriaxone or cefotaxime
H. influenzae and adequate coverage for N. meningiti- Streptococcus pneumoniae
dis. Cefepime is a broad-spectrum fourth-generation Penicillin-sensitive Penicillin G
cephalosporin with in vitro activity similar to that of Penicillin-intermediate Ceftriaxone or cefotaxime
cefotaxime or ceftriaxone against S. pneumoniae and N. or cefepime
meningitidis and greater activity against Enterobacter spe- Penicillin-resistant (Ceftriaxone or cefotaxime
or cefepime) + vancomycin
cies and Pseudomonas aeruginosa. In clinical trials,
Gram-negative bacilli Ceftriaxone or cefotaxime
cefepime has been demonstrated to be equivalent to (except Pseudomonas
cefotaxime in the treatment of penicillin-sensitive pneu- spp.)
mococcal and meningococcal meningitis, and it has Pseudomonas aeruginosa Ceftazidime or cefepime or
CHAPTER 40
been used successfully in some patients with meningi- meropenem
tis due to Enterobacter species and P. aeruginosa. Ampicillin Staphylococci spp.
should be added to the empirical regimen for coverage Methicillin-sensitive Nafcillin
Methicillin-resistant Vancomycin
of L. monocytogenes in individuals <3 months of age,
Listeria monocytogenes Ampicillin + gentamicin
those >55, or those with suspected impaired cell-mediated
Haemophilus inuenzae Ceftriaxone or cefotaxime
immunity because of chronic illness, organ transplan- or cefepime
tation, pregnancy, malignancy, or immunosuppres- Streptococcus agalactiae Penicillin G or ampicillin
is recommended for pneumococcal meningitis. by endotoxin. Dexamethasone does not alter TNF-
Patients with S. pneumoniae meningitis should have a production once it has been induced. The results of
repeat LP performed 2436 h after the initiation of anti- clinical trials of dexamethasone therapy in children,
microbial therapy to document sterilization of the CSF. predominantly with meningitis due to H. influenzae
Failure to sterilize the CSF after 2436 h of antibiotic and S. pneumoniae, have demonstrated its efficacy in
therapy should be considered presumptive evidence of decreasing meningeal inflammation and neurologic
Diseases of the Nervous System
antibiotic resistance. Patients with penicillin- and ceph- sequelae such as the incidence of sensorineural hearing
alosporin-resistant strains of S. pneumoniae who do not loss.
respond to intravenous vancomycin alone may benefit A prospective European trial of adjunctive therapy
from the addition of intraventricular vancomycin. The for acute bacterial meningitis in 301 adults found that
intraventricular route of administration is preferred over dexamethasone reduced the number of unfavorable
the intrathecal route because adequate concentrations outcomes (15 vs. 25%, p = .03) including death (7 vs.
of vancomycin in the cerebral ventricles are not always 15%, p = .04). The benefits were most striking in patients
achieved with intrathecal administration. with pneumococcal meningitis. Dexamethasone (10 mg
intravenously) was administered 1520 min before the
Listeria Meningitis Meningitis due to L. mono- first dose of an antimicrobial agent, and the same dose was
cytogenes is treated with ampicillin for at least 3 weeks repeated every 6 h for 4 days. These results were con-
(Table 40-3). Gentamicin is added in critically ill patients firmed in a second trial of dexamethasone in adults with
(2 mg/kg loading dose, then 7.5 mg/kg per day given pneumococcal meningitis. Therapy with dexametha-
every 8 h and adjusted for serum levels and renal func- sone should ideally be started 20 min before, or not
tion). The combination of trimethoprim (1020 mg/kg later than concurrent with, the first dose of antibiotics. It
per day) and sulfamethoxazole (50100 mg/kg per day) is unlikely to be of significant benefit if started >6 h after
given every 6 h may provide an alternative in penicillin- antimicrobial therapy has been initiated. Dexametha-
allergic patients. sone may decrease the penetration of vancomycin into
CSF, and it delays the sterilization of CSF in experimen-
Staphylococcal Meningitis Meningitis due to
tal models of S. pneumoniae meningitis. As a result, its
susceptible strains of S. aureus or coagulase-negative
potential benefit should be carefully weighed when
staphylococci is treated with nafcillin (Table 40-3). Van-
vancomycin is the antibiotic of choice. Alternatively,
comycin is the drug of choice for methicillin-resistant
vancomycin can be administered by the intraventricular
staphylococci and for patients allergic to penicillin. In
route.
these patients, the CSF should be monitored during
One of the concerns for using dexamethasone in
therapy. If the CSF is not sterilized after 48 h of intravenous
adults with bacterial meningitis is that in experimental
vancomycin therapy, then either intraventricular or
models of meningitis, dexamethasone therapy increased
intrathecal vancomycin, 20 mg once daily, can be added.
hippocampal cell injury and reduced learning capacity.
Gram-Negative Bacillary Meningitis The This has not been the case in clinical series. The efficacy
third-generation cephalosporinscefotaxime, ceftri- of dexamethasone therapy in preventing neurologic
axone, and ceftazidimeare equally efficacious for sequelae is different between high- and low-income
the treatment of gram-negative bacillary meningitis, countries. Three large randomized trials in low-income
countries (sub-Saharan Africa, Southeast Asia) failed to
on moving the eyes. Nuchal rigidity is present in most 503
cases but may be mild and present only near the limit of
show benefit in subgroups of patients. The lack of efficacy
neck anteexion. Constitutional signs can include malaise,
of dexamethasone in these trials has been attributed to
myalgia, anorexia, nausea and vomiting, abdominal pain,
late presentation to the hospital with more advanced
and/or diarrhea. Patients often have mild lethargy or
disease, antibiotic pretreatment, malnutrition, infection
drowsiness; however, profound alterations in conscious-
with HIV, and treatment of patients with probable, but
ness, such as stupor, coma, or marked confusion do not
not microbiologically proven, bacterial meningitis. The
occur in viral meningitis and suggest the presence of
results of these clinical trials suggest that patients in
encephalitis or other alternative diagnoses. Similarly,
sub-Saharan Africa and those in low-income countries
seizures or focal neurologic signs or symptoms or neu-
with negative CSF Grams stain and culture should not
roimaging abnormalities indicative of brain parenchymal
be treated with dexamethasone.
involvement are not typical of viral meningitis and suggest
INCREASED INTRACRANIAL PRESSURE the presence of encephalitis or another CNS infectious or
Emergency treatment of increased ICP includes elevation inammatory process.
of the patients head to 3045, intubation and hyper-
ventilation (Paco2 2530 mmHg), and mannitol. Patients ETIOLOGY
with increased ICP should be managed in an intensive
CHAPTER 40
care unit; accurate ICP measurements are best obtained Using a variety of diagnostic techniques, including CSF
with an ICP monitoring device. PCR, culture, and serology, a specic viral cause can
Treatment of increased intracranial pressure is discussed be found in 7590% of cases of viral meningitis. The
in detail in Chap. 28. most important agents are enteroviruses (including
echoviruses and coxsackieviruses in addition to num-
bered enteroviruses), HSV type 2 (HSV-2), HIV, and
PROGNOSIS arboviruses (Table 40-4). CSF cultures are positive in
CHAPTER 40
with coxsackievirus B5 and echovirus strains 6, 9, and
Other laboratory studies
30. Coxsackievirus strains A9, B3, and B4 are more
All patients with suspected viral meningitis should have commonly associated with individual cases. EV71 has
a complete blood count and differential, liver and renal produced large epidemics of neurologic disease out-
function tests, erythrocyte sedimentation rate (ESR), side the United States, especially in Southeast Asia, but
and C-reactive protein, electrolytes, glucose, creatine most recently reported cases in the United States have
philia, which can persist for a week or more. The rarity bodies, or by positive CSF cultures.
of hypoglycorrhachia in WNV infection as well as EBV infections may also produce aseptic meningitis,
the absence of positive Grams stains and the negative with or without associated infectious mononucleosis.
cultures helps distinguish these patients from those with The presence of atypical lymphocytes in the CSF or
bacterial meningitis. The presence of increased numbers peripheral blood is suggestive of EBV infection but may
of plasmacytoid cells or Mollaret-like large mononuclear occasionally be seen with other viral infections. EBV is
Diseases of the Nervous System
cells in the CSF may be a clue to the diagnosis of WNV almost never cultured from CSF. Serum and CSF serology
infection. Denitive diagnosis of arboviral meningo- can help establish the presence of acute infection, which
encephalitis is based on demonstration of viral-specic is characterized by IgM viral capsid antibodies (VCAs),
IgM in CSF or seroconversion. CSF PCR tests are antibodies to early antigens (EAs), and the absence of
available for some viruses in selected diagnostic labora- antibodies to EBV-associated nuclear antigen (EBNA).
tories and at the Centers for Disease Control and Pre- CSF PCR is another important diagnostic test, although
vention (CDC), but in the case of WNV, sensitivity positive results may reect viral reactivation associated
(70%) of CSF PCR is less than that of CSF serology. with other infectious or inammatory processes.
HSV-2 meningitis has been increasingly recognized HIV meningitis should be suspected in any patient
as a major cause of viral meningitis in adults, and over- presenting with a viral meningitis with known or sus-
all it is probably second in importance to enterovi- pected risk factors for HIV infection. Meningitis may
ruses as a cause of viral meningitis, accounting for 5% occur following primary infection with HIV in 510%
of total cases overall and undoubtedly a higher fre- of cases and less commonly at later stages of illness.
quency of those cases occurring in adults and/or out- Cranial nerve palsies, most commonly involving cranial
side of the summer-fall period when enterovirus infec- nerves V, VII, or VIII, are more common in HIV men-
tions are increasingly common. HSV meningitis occurs ingitis than in other viral infections. Diagnosis can be
in 25-35% of women and 10-15% of men at the conrmed by detection of HIV genome in blood or
time of an initial (primary) episode of genital herpes. CSF. Seroconversion may be delayed, and patients with
Of these patients, 20% go on to have recurrent attacks negative HIV serologies who are suspected of having
of meningitis. Diagnosis of HSV meningitis is usually HIV meningitis should be monitored for delayed sero-
by HSV CSF PCR as cultures may be negative, espe- conversion. For further discussion of HIV infection, see
cially in patients with recurrent meningitis. Demonstra- Chap. 42.
tion of intrathecal synthesis of HSV-specic antibody Mumps should be considered when meningitis
may also be useful in diagnosis, although antibody tests occurs in the late winter or early spring, especially in
are less sensitive and less specic than PCR and may males (male/female ratio 3:1). With the widespread
not become positive until after the rst week of infec- use of the live attenuated mumps vaccine in the United
tion. In contrast to HSV encephalitis in adults in which States since 1967, the incidence of mumps meningitis
>90% of cases are due to HSV-1, the overwhelming has fallen by >95%; however, mumps remains a poten-
majority of HSV meningitis is due to HSV-2. Although tial source of infection in nonimmunized individuals and
a history of or the presence of HSV genital lesions is an populations. Rare cases (10100:100,000 vaccinated
important diagnostic clue, many patients with HSV individuals) of vaccine-associated mumps meningitis
meningitis give no history and have no evidence of have been described, with onset typically 24 weeks
after vaccination. The presence of parotitis, orchitis,
possibility of encephalitis or parenchymal brain involve- 507
oophoritis, pancreatitis, or elevations in serum lipase
ment; and those patients who have an atypical CSF pro-
and amylase is suggestive of mumps meningitis; how-
file should be hospitalized. Oral or intravenous acyclovir
ever, their absence does not exclude the diagnosis.
may be of benefit in patients with meningitis caused by
Clinical meningitis was previously estimated to occur in
HSV-1 or -2 and in cases of severe EBV or VZV infection.
1030% of patients with mumps parotitis; however, in
Data concerning treatment of HSV, EBV, and VZV menin-
a recent U.S. outbreak of nearly 2600 cases of mumps,
gitis are extremely limited. Seriously ill patients should
only 11 cases of meningitis were identied, suggesting
probably receive intravenous acyclovir (1530 mg/kg
the incidence may be lower than previously suspected.
per day in three divided doses), which can be followed
Mumps infection confers lifelong immunity, so a doc-
by an oral drug such as acyclovir (800 mg, five times
umented history of previous infection excludes this
daily), famciclovir (500 mg tid), or valacyclovir (1000 mg
diagnosis. Patients with meningitis have a CSF pleocy-
tid) for a total course of 714 days. Patients who are less
tosis that can exceed 1000 cells/L in 25%. Lympho-
ill can be treated with oral drugs alone. Patients with HIV
cytes predominate in 75%, although CSF neutrophilia
meningitis should receive highly active antiretroviral ther-
occurs in 25%. Hypoglycorrhachia occurs in 1030% of
apy (Chap. 42).
patients and may be a clue to the diagnosis when present.
Patients with viral meningitis who are known to have
Diagnosis is typically made by culture of virus from
CHAPTER 40
deficient humoral immunity (e.g., X-linked agamma-
CSF or by detecting IgM antibodies or seroconversion.
globulinemia) and who are not already receiving either
CSF PCR is available in some diagnostic and research
intramuscular gamma globulin or intravenous immu-
laboratories.
noglobulin (IVIg) should be treated with these agents.
LCMV infection should be considered when asep-
Intraventricular administration of immunoglobulin
tic meningitis occurs in the late fall or winter and in
through an Ommaya reservoir has been tried in some
individuals with a history of exposure to house mice
patients with chronic enteroviral meningitis who have
of consciousness (confusion, behavioral abnormalities), 1459 conrmed cases of neuroinvasive disease per year
or a depressed level of consciousness ranging from mild in the United States and 100177 deaths. In 2008 and
lethargy to coma, and evidence of either focal or diffuse 2009 there was an unexpected and dramatic decline in
neurologic signs and symptoms. Patients with encephali- both the number of WNV neuroinvasive cases (2008
tis may have hallucinations, agitation, personality change, = 687, 2009 = 335) and the number of deaths (2008 =
behavioral disorders, and, at times, a frankly psychotic 44, 2009 = 30). New causes of viral CNS infections are
Diseases of the Nervous System
state. Focal or generalized seizures occur in many patients constantly appearing, as evidenced by the recent out-
with encephalitis. Virtually every possible type of focal break of cases of encephalitis in Southeast Asia caused
neurologic disturbance has been reported in viral enceph- by Nipah virus, a newly identied member of the Para-
alitis; the signs and symptoms reect the sites of infection myxoviridae family; of meningitis in Europe caused by
and inammation. The most commonly encountered Toscana virus, an arbovirus belonging to the Bunyavi-
focal ndings are aphasia, ataxia, upper or lower motor rus family; and of neurologic disorders associated with
neuron patterns of weakness, involuntary movements major epidemics of Chikungunya virus, a togavirus, in
(e.g., myoclonic jerks, tremor), and cranial nerve de- Africa, India, and Southeast Asia.
cits (e.g., ocular palsies, facial weakness). Involvement of
the hypothalamic-pituitary axis may result in temperature
dysregulation, diabetes insipidus, or the development of LABORATORY DIAGNOSIS
the syndrome of inappropriate secretion of antidiuretic CSF examination
hormone (SIADH). Even though neurotropic viruses
CSF examination should be performed in all patients
typically cause pathologic injury in distinct regions of the
with suspected viral encephalitis unless contraindicated
CNS, variations in clinical presentations make it impos-
by the presence of severely increased ICP. The char-
sible to reliably establish the etiology of a specic case of
acteristic CSF prole is indistinguishable from that of
encephalitis on clinical grounds alone (see Differential
viral meningitis and typically consists of a lymphocytic
Diagnosis, later in the chapter).
pleocytosis, a mildly elevated protein concentration,
and a normal glucose concentration. A CSF pleocyto-
sis (>5 cells/L) occurs in >95% of immunocompetent
ETIOLOGY patients with documented viral encephalitis. In rare
In the United States, there are 20,000 reported cases cases, a pleocytosis may be absent on the initial LP but
of encephalitis per year, although the actual number present on subsequent LPs. Patients who are severely
of cases is likely to be signicantly larger. Despite com- immunocompromised by HIV infection, glucocorti-
prehensive diagnostic efforts, the majority of cases of coid or other immunosuppressant drugs, chemother-
acute encephalitis of suspected viral etiology remain apy, or lymphoreticular malignancies may fail to mount
of unknown cause. Hundreds of viruses are capable of a CSF inammatory response. CSF cell counts exceed
causing encephalitis, although only a limited subset is 500/L in only about 10% of patients with encephali-
responsible for most cases in which a specic cause is tis. Infections with certain arboviruses (e.g., EEE virus
identied (Table 40-4). The most commonly identi- or California encephalitis virus), mumps, and LCMV
ed viruses causing sporadic cases of acute encephalitis may occasionally result in cell counts >1000/L, but
in immunocompetent adults are herpesviruses (HSV, this degree of pleocytosis should suggest the possibility
of nonviral infections or other inammatory processes. situations a positive test makes the diagnosis almost cer- 509
Atypical lymphocytes in the CSF may be seen in EBV tain (9899%). There have been several recent reports of
infection and less commonly with other viruses, includ- initially negative HSV CSF PCR tests that were obtained
ing CMV, HSV, and enteroviruses. Increased numbers early (72 h) following symptom onset and that became
of plasmacytoid or Mollaret-like large mononuclear positive when repeated 13 days later. The frequency of
cells have been reported in WNV encephalitis. Poly- positive HSV CSF PCRs in patients with herpes enceph-
morphonuclear pleocytosis occurs in 45% of patients alitis also decreases as a function of the duration of illness,
with WNV encephalitis and is also a common feature in with only 20% of cases remaining positive after 14
CMV myeloradiculitis in immunocompromised patients. days. PCR results are generally not affected by 1 week
Large numbers of CSF PMNs may be present in patients of antiviral therapy. In one study, 98% of CSF specimens
with encephalitis due to EEE virus, echovirus 9, and, remained PCR-positive during the rst week of initia-
more rarely, other enteroviruses. However, persist- tion of antiviral therapy, but the numbers fell to 50%
ing CSF neutrophilia should prompt consideration by 814 days and to 21% by >15 days after initiation of
of bacterial infection, leptospirosis, amebic infection, antiviral therapy.
and noninfectious processes such as acute hemorrhagic The sensitivity and specicity of CSF PCR tests for
leukoencephalitis. About 20% of patients with enceph- viruses other than herpes simplex have not been deni-
alitis will have a signicant number of red blood cells tively characterized. Enteroviral CSF PCR appears to
CHAPTER 40
(>500/L) in the CSF in a nontraumatic tap. The patho- have a sensitivity and specicity of >95%. The specicity
logic correlate of this nding may be a hemorrhagic of EBV CSF PCR has not been established. Positive
encephalitis of the type seen with HSV; however, CSF EBV CSF PCRs associated with positive tests for other
red blood cells occur with similar frequency and in simi- pathogens have been reported and may reect reactiva-
lar numbers in patients with nonherpetic focal encepha- tion of EBV latent in lymphocytes that enter the CNS
litides. A decreased CSF glucose concentration is distinctly as a result of an unrelated infectious or inammatory
assist in the differentiation between a focal, as opposed and-slow complexes originating in one or both temporal
to a diffuse, encephalitic process. Focal ndings in a lobes and repeating at regular intervals of 23 s. The
patient with encephalitis should always raise the pos- periodic complexes are typically noted between days
sibility of HSV encephalitis. Examples of focal nd- 2 and 15 of the illness and are present in two-thirds of
ings include: (1) areas of increased signal intensity in pathologically proven cases of HSV encephalitis.
the frontotemporal, cingulate, or insular regions of the Signicant MRI abnormalities are found in only
brain on T2-weighted, FLAIR, or diffusion-weighted two-thirds of patients with WNV encephalitis, a fre-
Diseases of the Nervous System
MRI (Fig. 40-3); (2) focal areas of low absorption, quency less than that with HSV encephalitis. When
mass effect, and contrast enhancement on CT; or (3) present, abnormalities often involve deep brain structures,
periodic focal temporal lobe spikes on a background of including the thalamus, basal ganglia, and brainstem,
rather than the cortex and may only be apparent on
FLAIR images. EEGs in patients with WNV encepha-
litis typically show generalized slowing that may be
more anteriorly prominent rather than the temporally
predominant pattern of sharp or periodic discharges
more characteristic of HSV encephalitis. Patients with
VZV encephalitis may show multifocal areas of hemor-
rhagic and ischemic infarction, reecting the tendency
of this virus to produce a CNS vasculopathy rather than
a true encephalitis. Immunocompromised adult patients
with CMV often have enlarged ventricles with areas of
increased T2 signal on MRI outlining the ventricles and
subependymal enhancement on T1-weighted post-con-
trast images. Table 40-5 highlights specic diagnostic
test results in encephalitis that can be useful in clinical
decision-making.
Brain biopsy
Brain biopsy is now generally reserved for patients in
whom CSF PCR studies fail to lead to a specic diag-
nosis, who have focal abnormalities on MRI, and who
FIGURE 40-3
continue to show progressive clinical deterioration
Coronal FLAIR magnetic resonance image from a
despite treatment with acyclovir and supportive therapy.
patient with herpes simplex encephalitis. Note the area of
increased signal in the right temporal lobe (left side of image)
DIFFERENTIAL DIAGNOSIS
conned predominantly to the gray matter. This patient had
predominantly unilateral disease; bilateral lesions are more Infection by a variety of other organisms can mimic
common but may be quite asymmetric in their intensity. viral encephalitis. In studies of biopsy-proven HSV
TABLE 40-5 or chronic granulomatous amebic meningoencephalitis. 511
USE OF DIAGNOSTIC TESTS IN ENCEPHALITIS Naegleria thrive in warm, iron-rich pools of water,
including those found in drains, canals, and both natural
The best test for WNV encephalitis is the CSF IgM antibody
test. The prevalence of positive CSF IgM tests increases
and human-made outdoor pools. Infection has typically
by about 10% per day after illness onset and reaches occurred in immunocompetent children with a history
7080% by the end of the rst week. Serum WNV IgM of swimming in potentially infected water. The CSF,
can provide evidence for recent WNV infection, but in the in contrast to the typical prole seen in viral encepha-
absence of other ndings does not establish the diagnosis litis, often resembles that of bacterial meningitis with a
of neuroinvasive disease (meningitis, encephalitis, acute neutrophilic pleocytosis and hypoglycorrhachia. Motile
accid paralysis). trophozoites can be seen in a wet mount of warm, fresh
Approximately 80% of patients with proven HSV encephalitis
CSF. There have been an increasing number of cases of
have MRI abnormalities involving the temporal lobes. This
percentage likely increases to >90% when FLAIR and DWI Balamuthia mandrillaris amebic encephalitis mimicking
MR sequences are also utilized. The absence of temporal acute viral encephalitis in children and immunocompe-
lobe lesions on MR reduces the likelihood of HSV encepha- tent adults. This organism has also been associated with
litis and should prompt consideration of other diagnostic encephalitis in recipients of transplanted organs from a
possibilities. donor with unrecognized infection. No effective treat-
The CSF HSV PCR test may be negative in the rst 72 h ment has been identied, and mortality approaches
CHAPTER 40
of symptoms of HSV encephalitis. A repeat study should
100%.
be considered in patients with an initial early negative
PCR in whom diagnostic suspicion of HSV encephalitis
Encephalitis can be caused by the raccoon pinworm
remains high and no alternative diagnosis has yet been Baylisascaris procyonis. Clues to the diagnosis include a
established. history of raccoon exposure, especially of playing in or
Detection of intrathecal synthesis (increased CSF/serum HSV eating dirt potentially contaminated with raccoon feces.
antibody ratio corrected for breakdown of the blood-brain Most patients are children, and many have an associated
CHAPTER 40
slowly over 1 h, rather than by rapid or bolus infusion, indefinite period. Induction therapy should be contin-
to minimize the risk of renal dysfunction. Care should ued until patients show a decline in CSF pleocytosis and
be taken to avoid extravasation or intramuscular or sub- a reduction in CSF CMV DNA copy number on quanti-
cutaneous administration. The alkaline pH of acyclovir tative PCR testing (where available). Doses should be
can cause local inflammation and phlebitis (9%). Dose adjusted in patients with renal insufficiency. Treatment is
adjustment is required in patients with impaired renal often limited by the development of granulocytopenia
glomerular filtration. Penetration into CSF is excellent, and thrombocytopenia (2025%), which may require
CHAPTER 40
present with fever, cough, sputum production, and highly sensitive and specic test for cryptococcal menin-
chest pain. The pulmonary infection is often self-limited. gitis. A reactive CSF cryptococcal antigen test establishes
A localized pulmonary fungal infection can then remain the diagnosis. The detection of the histoplasma poly-
dormant in the lungs until there is an abnormality in saccharide antigen in CSF establishes the diagnosis of a
cell-mediated immunity that allows the fungus to reacti- fungal meningitis but is not specic for meningitis due
vate and disseminate to the CNS. The most common to H. capsulatum. It may be falsely positive in coccidioidal
CHAPTER 40
in immunocompromised individuals, any therapeutic
hancing white matter lesions. interventions designed to enhance or restore immuno-
The CSF is typically normal, although mild elevation competence should be considered. Perhaps the most
in protein and/or IgG may be found. Pleocytosis occurs dramatic demonstration of this is disease stabiliza-
in <25% of cases, is predominantly mononuclear, and tion and, in rare cases, improvement associated with
rarely exceeds 25 cells/L. PCR amplication of JCV the improvement in the immune status of HIV-positive
DNA from CSF has become an important diagnostic patients with AIDS following institution of HAART. In
sion, patients develop a characteristic periodic pattern mon intracranial infection, with an incidence of
with bursts of high-voltage, sharp, slow waves every 0.31.3:100,000 persons per year. Predisposing
38 s, followed by periods of attenuated (at) back- conditions include otitis media and mastoiditis, paranasal
ground. The CSF is acellular with a normal or mildly sinusitis, pyogenic infections in the chest or other body
elevated protein concentration and a markedly elevated sites, penetrating head trauma or neurosurgical procedures,
gamma globulin level (>20% of total CSF protein). CSF and dental infections. In immunocompetent individuals
the most important pathogens are Streptococcus spp.
Diseases of the Nervous System
CHAPTER 40
and multiple abscesses often (50%) have a hematogenous developed on the cortical than on the ventricular side of
origin. These abscesses show a predilection for the ter- the lesion. This stage correlates with the appearance of
ritory of the middle cerebral artery (i.e., posterior frontal a ring-enhancing capsule on neuroimaging studies. The
or parietal lobes). Hematogenous abscesses are often nal stage, late capsule formation (day 14 and beyond),
located at the junction of the gray and white matter is dened by a well-formed necrotic center surrounded
and are often poorly encapsulated. The microbiology by a dense collagenous capsule. The surrounding area
on T1-weighted images with irregular postgadolinium leukocytosis, 60% an elevated ESR, and 80% an ele-
enhancement and as an area of increased signal inten- vated C-reactive protein. Blood cultures are positive in
sity on T2-weighted images. Cerebritis is often not 10% of cases overall but may be positive in >85% of
visualized by CT scan but, when present, appears as patients with abscesses due to Listeria.
an area of hypodensity. On a contrast-enhanced CT
scan, a mature brain abscess appears as a focal area of
hypodensity surrounded by ring enhancement with sur-
Diseases of the Nervous System
FIGURE 40-4
Pneumococcal brain abscess. Note that the abscess wall gadolinium administration on the coronal T1-weighted image
has hyperintense signal on the axial T1-weighted MRI (A, (C). The abscess is surrounded by a large amount of vaso-
black arrow), hypointense signal on the axial proton density genic edema and has a small daughter abscess (C, white
images (B, black arrow), and enhances prominently after arrow). (Courtesy of Joseph Lurito, MD; with permission.)
receiving antibiotic therapy alone. A small amount of 521
TREATMENT Brain Abscess
enhancement may remain for months after the abscess
Optimal therapy of brain abscesses involves a combina- has been successfully treated.
tion of high-dose parenteral antibiotics and neurosurgical
drainage. Empirical therapy of community-acquired
PROGNOSIS
brain abscess in an immunocompetent patient typically
includes a third- or fourth-generation cephalosporin The mortality rate of brain abscess has declined in parallel
(e.g., cefotaxime, ceftriaxone, or cefepime) and metroni- with the development of enhanced neuroimaging tech-
dazole (see Table 40-1 for antibiotic dosages). In patients niques, improved neurosurgical procedures for stereotactic
with penetrating head trauma or recent neurosurgical aspiration, and improved antibiotics. In modern series,
procedures, treatment should include ceftazidime as the mortality rate is typically <15%. Signicant sequelae,
the third-generation cephalosporin to enhance cover- including seizures, persisting weakness, aphasia, or mental
age of Pseudomonas spp. and vancomycin for coverage of impairment, occur in 20% of survivors.
staphylococci. Meropenem plus vancomycin also provides
good coverage in this setting.
Aspiration and drainage of the abscess under stereo- NONBACTERIAL CAUSES OF
CHAPTER 40
tactic guidance are beneficial for both diagnosis and INFECTIOUS FOCAL CNS LESIONS
therapy. Empirical antibiotic coverage should be modi-
fied based on the results of Grams stain and culture of the ETIOLOGY
abscess contents. Complete excision of a bacterial abscess Neurocysticercosis is the most common parasitic disease
via craniotomy or craniectomy is generally reserved for of the CNS worldwide. Humans acquire cysticercosis
multiloculated abscesses or those in which stereotactic by the ingestion of food contaminated with the eggs of
aspiration is unsuccessful. the parasite T. solium. Toxoplasmosis is a parasitic disease
CHAPTER 40
myelitis in the posterior wall of the frontal or other
sinuses. SDE may also develop from direct introduction untreated SDE, the increasing mass effect and increase
of bacteria into the subdural space as a complication of in ICP cause progressive deterioration in consciousness,
a neurosurgical procedure. The evolution of SDE can leading ultimately to coma.
be extremely rapid because the subdural space is a large
compartment that offers few mechanical barriers to the
spread of infection. In patients with sinusitis-associated DIAGNOSIS
FIGURE 40-6
Subdural empyema. There is marked enhancement of the images (A, B) but markedly hyperintense on the proton
dura and leptomeninges (A, B, straight arrows) along the left densityweighted (C, curved arrow) image. (Courtesy of
medial hemisphere. The pus is hypointense on T1-weighted Joseph Lurito, MD; with permission.)
524 CSF examination should be avoided in patients with Epidural abscess
known or suspected SDE as it adds no useful informa-
tion and is associated with the risk of cerebral herniation.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of the combination of headache,
fever, focal neurologic signs, and seizure activity that
progresses rapidly to an altered level of consciousness
includes subdural hematoma, bacterial meningitis, viral
encephalitis, brain abscess, superior sagittal sinus throm-
bosis, and acute disseminated encephalomyelitis. The
presence of nuchal rigidity is unusual with brain abscess FIGURE 40-7
or epidural empyema and should suggest the possibility Cranial epidural abscess is a collection of pus between the
of SDE when associated with signicant focal neuro- dura and the inner table of the skull.
logic signs and fever. Patients with bacterial meningitis
also have nuchal rigidity but do not typically have focal
SECTION III
evacuation of the empyema, either through craniotomy, frontal sinuses, middle ear, mastoid, or orbit. An epidural
craniectomy, or burr-hole drainage, is the definitive step abscess may develop contiguous to an area of osteomy-
in the management of this infection. Empirical antimicro- elitis, when craniotomy is complicated by infection of
bial therapy for community-acquired SDE should include the wound or bone ap, or as a result of direct infec-
a combination of a third-generation cephalosporin (e.g., tion of the epidural space. Infection in the frontal sinus,
cefotaxime or ceftriaxone), vancomycin, and metronida- middle ear, mastoid, or orbit can reach the epidural
zole (see Table 40-1 for dosages). Patients with hospital- space through retrograde spread of infection from septic
acquired SDE may have infections due to Pseudomonas thrombophlebitis in the emissary veins that drain these
spp. or MRSA and should receive coverage with a carba- areas or by way of direct spread of infection through
penem (e.g., meropenem) and vancomycin. Metronidazole areas of osteomyelitis. Unlike the subdural space, the
is not necessary for anti-anaerobic therapy when merope- epidural space is really a potential rather than an actual
nem is being used. Parenteral antibiotic therapy should be compartment. The dura is normally tightly adherent to
continued for a minimum of 34 weeks after SDE drainage. the inner skull table, and infection must dissect the dura
Patients with associated cranial osteomyelitis may require away from the skull table as it spreads. As a result, epi-
longer therapy. Specific diagnosis of the etiologic organ- dural abscesses are often smaller than SDEs. Cranial epi-
isms is made based on Grams stain and culture of fluid dural abscesses, unlike brain abscesses, only rarely result
obtained via either burr holes or craniotomy; the initial from hematogenous spread of infection from extracra-
empirical antibiotic coverage can be modified accordingly. nial primary sites. The bacteriology of a cranial epidural
abscess is similar to that of SDE (discussed earlier). The
etiologic organisms of an epidural abscess that arises from
PROGNOSIS frontal sinusitis, middle-ear infections, or mastoiditis are
Prognosis is inuenced by the level of consciousness of the usually streptococci or anaerobic organisms. Staphy-
patient at the time of hospital presentation, the size of the lococci or gram-negative organisms are the usual cause
empyema, and the speed with which therapy is instituted. of an epidural abscess that develops as a complication of
Long-term neurologic sequelae, which include seizures craniotomy or compound skull fracture.
and hemiparesis, occur in up to 50% of cases.
CLINICAL PRESENTATION
CRANIAL EPIDURAL ABSCESS Patients present with fever (60%), headache (40%),
nuchal rigidity (35%), seizures (10%), and focal decits
Cranial epidural abscess is a suppurative infection occurring (5%). Development of symptoms may be insidious, as
in the potential space between the inner skull table and the empyema usually enlarges slowly in the conned
dura (Fig. 40-7). anatomic space between the dura and the inner table
of the skull. Periorbital edema and Potts puffy tumor, SDE; epidural abscess; or infection in the skin of the 525
reecting underlying associated frontal bone osteomyelitis, face, paranasal sinuses, middle ear, or mastoid.
are present in 40%. In patients with a recent neuro-
surgical procedure, wound infection is invariably present,
but other symptoms may be subtle and can include ANATOMY AND PATHOPHYSIOLOGY
altered mental status (45%), fever (35%), and headache The cerebral veins and venous sinuses have no valves;
(20%). The diagnosis should be considered when fever therefore, blood within them can ow in either
and headache follow recent head trauma or occur in the direction. The superior sagittal sinus is the largest of
setting of frontal sinusitis, mastoiditis, or otitis media. the venous sinuses (Fig. 40-8). It receives blood from
the frontal, parietal, and occipital superior cerebral
DIAGNOSIS veins and the diploic veins, which communicate with
the meningeal veins. Bacterial meningitis is a common
Cranial MRI with gadolinium enhancement is the predisposing condition for septic thrombosis of the
procedure of choice to demonstrate a cranial epidural superior sagittal sinus. The diploic veins, which drain
abscess. The sensitivity of CT is limited by the pres- into the superior sagittal sinus, provide a route for the
ence of signal artifacts arising from the bone of the inner spread of infection from the meninges, especially in
skull table. The CT appearance of an epidural empyema cases where there is purulent exudate near areas of the
CHAPTER 40
is that of a lens or crescent-shaped hypodense extraaxial superior sagittal sinus. Infection can also spread to the
lesion. On MRI, an epidural empyema appears as a lenti- superior sagittal sinus from nearby SDE or epidural
form or crescent-shaped uid collection that is hyper- abscess. Dehydration from vomiting, hypercoagulable
intense compared to CSF on T2-weighted images. On states, and immunologic abnormalities, including the
T1-weighted images, the uid collection may be either presence of circulating antiphospholipid antibodies, also
isointense or hypointense compared to brain. Follow- contribute to cerebral venous sinus thrombosis. Throm-
CHAPTER 41
early infection (commonly CSF (sputum, urine, gastric suppressed or AIDS; young
<500 WBC/L); low CSF contents if indicated); tuber- children; fever, meningismus,
glucose, high protein culostearic acid detection in night sweats, miliary TB on
CSF; identify tubercle bacil- x-ray or liver biopsy; stroke
lus on acid-fast stain of CSF due to arteritis
or protein pellicle; PCR
Lyme disease (Bannwarths Mononuclear cells; elevated Serum Lyme antibody titer; History of tick bite or
(continued)
530 TABLE 41-2
INFECTIOUS CAUSES OF CHRONIC MENINGITIS (CONTINUED)
Fungal Causes
Cryptococcus neoformans Mononuclear cells; count not India ink or fungal wet mount AIDS and immune suppres-
elevated in some patients of CSF (budding yeast); sion; pigeon exposure; skin
with AIDS blood and urine cultures; and other organ involvement
antigen detection in CSF due to disseminated infection
Coccidioides immitis Mononuclear cells (some- Antibody detection in CSF Exposure historysouth-
times 1020% eosinophils); and serum western US; increased viru-
often low glucose lence in dark-skinned races
Candida sp. Polymorphonuclear or Fungal stain and culture of IV drug abuse; post surgery;
mononuclear CSF prolonged intravenous ther-
apy; disseminated candidiasis
Histoplasma capsulatum Mononuclear cells; low Fungal stain and culture Exposure historyOhio and
SECTION III
CHAPTER 41
for 34 weeks
Lymphocytic Mononuclear cells Antibody in serum Contact with rodents or their
choriomeningitis excreta; may persist for
34 weeks
Echovirus Mononuclear cells; may have Virus isolation from CSF Congenital hypogammaglob-
low glucose ulinemia; history of recurrent
meningitis
Abbreviations: AFB, acid-fast bacillus; CMV, cytomegalovirus; CSF, cerebrospinal fluid; CT, computed tomography; EBV, Epstein-
Barr virus; ELISA, enzyme-linked immunosorbent assay; EM, electron microscopy; FTA, fluorescent treponemal antibody absorption
test; HSV, herpes simplex virus; MHA-TP, microhemagglutination assayT. pallidum; MRI, magnetic resonance imaging; PAS, peri-
odic acidSchiff; PCR, polymerase chain reaction; RPR, rapid plasma reagin test; TB, tuberculosis; VDRL, Venereal Disease Research
Laboratory test.
In some cases, diagnosis may be established by recogni- (Sjgrens syndrome), or iridocyclitis (Behets syndrome)
tion and biopsy of unusual skin lesions (Behets syn- and is essential to assess visual loss from papilledema.
drome, cryptococcosis, blastomycosis, SLE, Lyme disease, Aphthous oral lesions, genital ulcers, and hypopyon sug-
IV drug use, sporotrichosis, trypanosomiasis) or enlarged gest Behets syndrome. Hepatosplenomegaly suggests
lymph nodes (lymphoma, tuberculosis, sarcoid, infec- lymphoma, sarcoid, tuberculosis, or brucellosis. Herpetic
tion with HIV, secondary syphilis, or Whipples disease). A lesions in the genital area or on the thighs suggest HSV-2
careful ophthalmologic examination may reveal uveitis infection. A breast nodule, a suspicious pigmented skin
[Vogt-Koyanagi-Harada syndrome, sarcoid, or central ner- lesion, focal bone pain, or an abdominal mass directs
vous system (CNS) lymphoma], keratoconjunctivitis sicca attention to possible carcinomatous meningitis.
532 TABLE 41-3
NONINFECTIOUS CAUSES OF CHRONIC MENINGITIS
Malignancy Mononuclear cells, elevated Repeated cytologic exami- Metastatic cancer of breast,
protein, low glucose nation of large volumes of lung, stomach, or pancreas;
CSF; CSF exam by polariz- melanoma, lymphoma, leu-
ing microscopy; clonal lym- kemia; meningeal glioma-
phocyte markers; deposits tosis; meningeal sarcoma;
on nerve roots or meninges cerebral dysgerminoma;
seen on myelogram or meningeal melanoma or B
contrast-enhanced MRI; cell lymphoma
meningeal biopsy
Chemical compounds (may Mononuclear or PMNs, low Contrast-enhanced CT scan History of recent injection into
cause recurrent meningitis) glucose, elevated protein; or MRI the subarachnoid space;
xanthochromia from sub- Cerebral angiogram to detect history of sudden onset of
arachnoid hemorrhage in aneurysm headache; recent resection
week prior to presentation of acoustic neuroma or cra-
SECTION III
Abbreviations: ANCA, anti-neutrophil cytoplasmic antibodies; CN, cranial nerve; CSF, cerebrospinal uid; CT, computed tomography; HSV, her-
pes simplex virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PMNs, polymorphonuclear cells.
CHAPTER 41
as a potential manifestation of chronic meningitis,
proper analysis of the CSF is essential. However, if the
possibility of raised ICP exists, a brain imaging study
should be performed before lumbar puncture. If ICP
is elevated because of a mass lesion, brain swelling, or
a block in ventricular CSF outflow (obstructive hydro-
cephalus), then lumbar puncture carries the potential
CHAPTER 41
Chronic and Recurrent Meningitis
CHAPTER 42
HIV NEUROLOGY
>500/L A1 B1 C1
200499/L A2 B2 C2
<200/L A3 B3 C3
TABLE 42-3
CLINICAL CATEGORIES OF HIV INFECTION
Category A: Consists of one or more of the conditions listed below in an adolescent or adult (>13 years) with documented HIV infection. Con-
CHAPTER 42
ditions listed in categories B and C must not have occurred.
Asymptomatic HIV infection
Persistent generalized lymphadenopathy
Acute (primary) HIV infection with accompanying illness or history of acute HIV infection
Category B: Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical
category C and that meet at least one of the following criteria: (1) The conditions are attributed to HIV infection or are indicative of a defect in
cell-mediated immunity; or (2) the conditions are considered by physicians to have a clinical course or to require management that is compli-
cated by HIV infection. Examples include, but are not limited to, the following:
HIV Neurology
Bacillary angiomatosis
Candidiasis, oropharyngeal (thrush)
Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 month
Hairy leukoplakia, oral
Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome
Idiopathic thrombocytopenic purpura
Listeriosis
Pelvic inammatory disease, particularly if complicated by tuboovarian abscess
Peripheral neuropathy
Category C: Conditions listed in the AIDS surveillance case denition.
Candidiasis of bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical cancer, invasivea
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 months duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV-related
Herpes simplex: chronic ulcer(s) (>1 months duration); or bronchitis, pneumonia, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 months duration)
Kaposis sarcoma
Lymphoma, Burkitts (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site (pulmonarya or extrapulmonary)
Mycobacterium, other species or unidentied species, disseminated or extrapulmonary
Pneumocystis jiroveci pneumonia
Pneumonia, recurrenta
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome due to HIV
a
Added in the 1993 expansion of the AIDS surveillance case denition.
Source: MMWR 42(No. RR-17), December 18, 1992.
538 cause cytopathic effects either directly or indirectly. begins with the high-afnity binding of the gp120 pro-
The most common cause of HIV disease throughout tein via a portion of its V1 region near the N terminus
the world, and certainly in the United States, is HIV- to its receptor on the host cell surface, the CD4 mol-
1, which comprises several subtypes with different geo- ecule (Fig. 42-2). The CD4 molecule is a 55-kDa pro-
graphic distributions. HIV-2 was rst identied in 1986 tein found predominantly on a subset of T lymphocytes
in West African patients and was originally conned to that are responsible for helper function in the immune
West Africa. However, a number of cases that can be system. It is also expressed on the surface of monocytes/
traced to West Africa or to sexual contacts with West macrophages and dendritic/Langerhans cells. Once
Africans have been identied throughout the world. gp120 binds to CD4, the gp120 undergoes a conforma-
tional change that facilitates binding to one of a group
of co-receptors. The two major co-receptors for HIV-1
MORPHOLOGY OF HIV are CCR5 and CXCR4. Both receptors belong to the
family of seven-transmembrane-domain G protein
Electron microscopy shows that the HIV virion is an coupled cellular receptors, and the use of one or the
icosahedral structure (Fig. 42-1A) containing numerous other or both receptors by the virus for entry into the
external spikes formed by the two major envelope pro- cell is an important determinant of the cellular tropism
teins, the external gp120 and the transmembrane gp41. of the virus. Certain dendritic cells express a diversity of
SECTION III
The virion buds from the surface of the infected cell C-type lectin receptors on their surface, one of which
and incorporates a variety of host proteins, including is called DC-SIGN, that also bind with high afnity to
major histocompatibility complex (MHC) class I and II the HIV gp120 envelope protein, allowing the den-
antigens, into its lipid bilayer. The structure of HIV-1 is dritic cell to facilitate the binding of virus to the CD4+
schematically diagrammed in Fig. 42-1B. T cell upon engagement of dendritic cells with CD4+
T cells. Following binding of the envelope protein
Diseases of the Nervous System
gp41
Matrix
Capsid Lipid
membrane
RNA
gp120 Reverse
transcriptase
A B
FIGURE 42-1
A. Electron micrograph of HIV. Figure illustrates a typical transmembrane components of the envelope, genomic
virion following budding from the surface of a CD4+ T lym- RNA, enzyme reverse transcriptase, p18(17) inner mem-
phocyte, together with two additional incomplete virions in brane (matrix), and p24 core protein (capsid). (Copyright by
the process of budding from the cell membrane. B. Struc- George V. Kelvin. Adapted from RC Gallo: Sci Am 256:46,
ture of HIV-1, including the gp120 outer membrane, gp41 1987.)
Cellular DNA 539
Unintegrated
linear DNA
Integrase
Reverse gp120
transcriptase
Integrated
proviral DNA CD4
Genomic
mRNA
RNA
Genomic RNA
HIV
Co-receptor
CHAPTER 42
Fusion
Budding Protein synthesis,
processing, and assembly
Mature HIV virion
HIV Neurology
FIGURE 42-2
The replication cycle of HIV. See text for description. (Adapted from AS Fauci: Nature 384:529, 1996.)
upon itself to bring the virion and target cell together. The viral protein Vif targets APOBEC for proteasomal
Following fusion, the preintegration complex, com- degradation.
posed of viral RNA and viral enzymes and surrounded With activation of the cell, the viral DNA accesses
by a capsid protein coat, is released into the cytoplasm the nuclear pore and is exported from the cytoplasm
of the target cell. As the preintegration complex tra- to the nucleus, where it is integrated into the host cell
verses the cytoplasm to reach the nucleus, the viral chromosomes through the action of another virally
reverse transcriptase enzyme catalyzes the reverse tran- encoded enzyme, integrase. HIV provirus (DNA) selec-
scription of the genomic RNA into DNA, and the pro- tively integrates into the nuclear DNA preferentially
tein coat opens to release the resulting double-stranded within introns of active genes and regional hotspots.
HIV-DNA. At this point in the replication cycle, the This provirus may remain transcriptionally inactive
viral genome is vulnerable to cellular factors that can (latent) or it may manifest varying levels of gene expres-
block the progression of infection. In particular, the sion, up to active production of virus.
cytoplasmic TRIM5- protein in rhesus macaque Cellular activation plays an important role in the rep-
cells blocks SIV replication at a point shortly after lication cycle of HIV and is critical to the pathogene-
the virus fuses with the host cell. Although the exact sis of HIV disease. Following initial binding and inter-
mechanisms of action of TRIM5- remain unclear, nalization of virions into the target cell, incompletely
the human form is inhibited by cyclophilin A and is reverse-transcribed DNA intermediates are labile in
not effective in restricting HIV replication in human quiescent cells and do not integrate efciently into the
cells. The recently described APOBEC family of cel- host cell genome unless cellular activation occurs shortly
lular proteins also inhibits progression of virus infec- after infection. Furthermore, some degree of activation
tion after virus has entered the cell. APOBEC proteins of the host cell is required for the initiation of transcrip-
bind to nascent reverse transcripts and deaminate viral tion of the integrated proviral DNA into either genomic
cytidine, causing hypermutation of HIV genomes. It is RNA or mRNA. This latter process may not necessarily
still not clear whether (1) viral replication is inhibited be associated with the detectable expression of the clas-
by the binding of APOBEC to the virus genome with sic cell surface markers of activation. In this regard, acti-
subsequent accumulation of reverse transcripts, or (2) vation of HIV expression from the latent state depends
by the hypermutations caused by the enzymatic deami- on the interaction of a number of cellular and viral fac-
nase activity of APOBEC proteins. HIV has evolved tors. Following transcription, HIV mRNA is trans-
a powerful strategy to protect itself from APOBEC. lated into proteins that undergo modication through
540 glycosylation, myristylation, phosphorylation, and cleav- reside as macrophages, or macrophages can be directly
age. The viral particle is formed by the assembly of HIV infected within the brain. The precise mechanisms
proteins, enzymes, and genomic RNA at the plasma whereby HIV enters the brain are unclear; however,
membrane of the cells. Budding of the progeny virion they are thought to relate, at least in part, to the ability
occurs through specialized regions in the lipid bilayer of of virus-infected and immune-activated macrophages to
the host cell membrane known as lipid rafts, where the induce adhesion molecules such as E-selectin and vascu-
core acquires its external envelope. The virally encoded lar cell adhesion molecule-1 (VCAM-1) on brain endo-
protease then catalyzes the cleavage of the gag-pol pre- thelium. Other studies have demonstrated that HIV
cursor to yield the mature virion. Progression through gp120 enhances the expression of intercellular adhe-
the virus replication cycle is profoundly inuenced by a sion molecule-1 (ICAM-1) in glial cells; this effect may
variety of viral regulatory gene products. Likewise, each facilitate entry of HIV-infected cells into the CNS and
point in the replication cycle of HIV is a real or potential may promote syncytia formation. Virus isolates from
target for therapeutic intervention. Thus far, the reverse the brain are preferentially R5 strains as opposed to X4
transcriptase, protease, and integrase enzymes as well as strains; in this regard, HIV-infected individuals who are
the process of virustarget cell binding and fusion have heterozygous for CCR5-32 appear to be relatively
proven clinically to be susceptible to pharmacologic protected against the development of HIV encepha-
disruption. lopathy compared to wild-type individuals. Distinct
SECTION III
CHAPTER 42
initiation of combination antiretroviral therapy (cART). rologic function of an HIV-infected individual should
It has also been suggested that the CNS may serve be considered normal unless clinical signs and symptoms
as a relatively sequestered site for a reservoir of latently suggest otherwise.
infected cells that might be a barrier for the eradication HIV-associated dementia (also known as HIV encepha-
of the virus by cART. lopathy) consists of a constellation of signs and symp-
toms of CNS disease. While this is generally a late com-
HIV Neurology
plication of HIV infection that progresses slowly over
months, it can be seen in patients with CD4+ T cell
CLINICAL MANIFESTATIONS counts >350 cells/L. A major feature of this entity is
Clinical disease of the nervous systems accounts for a the development of dementia, dened as a decline in
signicant degree of morbidity in a high percentage cognitive ability from a previous level. It may present
of patients with HIV infection (Table 42-1). The neu- as impaired ability to concentrate, increased forgetful-
rologic problems that occur in HIV-infected individu- ness, difculty reading, or increased difculty perform-
als may be either primary to the pathogenic processes of ing complex tasks. Initially these symptoms may be
HIV infection or secondary to opportunistic infections or indistinguishable from ndings of situational depression
neoplasms. Among the more frequent opportunistic dis- or fatigue. In contrast to cortical dementia (such as
eases that involve the CNS are toxoplasmosis, cryptococ- Alzheimers disease), aphasia, apraxia, and agnosia are
cosis, progressive multifocal leukoencephalopathy, and uncommon, leading some investigators to classify HIV-
primary CNS lymphoma. Other less common problems associated dementia as a subcortical dementia charac-
include mycobacterial infections; syphilis; and infection terized by defects in short-term memory and executive
with CMV, HTLV-I, T. cruzi, or Acanthamoeba. Over- function. In addition to dementia, patients with HIV-
all, secondary diseases of the CNS occur in approximately associated dementia may also have motor and behav-
one-third of patients with AIDS. These data antedate the ioral abnormalities. Among the motor problems are
widespread use of cART, and this frequency is consid- unsteady gait, poor balance, tremor, and difculty with
erably less in patients receiving effective antiretroviral rapid alternating movements. Increased tone and deep
drugs. Primary processes related to HIV infection of the tendon reexes may be found in patients with spinal
nervous system are reminiscent of those seen with other cord involvement. Late stages may be complicated by
lentiviruses, such as the Visna-Maedi virus of sheep. bowel and/or bladder incontinence. Behavioral prob-
lems include apathy and lack of initiative, with pro-
gression to a vegetative state in some instances. Some
NEUROLOGIC DISEASES CAUSED BY HIV patients develop a state of agitation or mild mania.
These changes usually occur without signicant changes
HIV-associated cognitive impairment
in level of alertness. This is in contrast to the nding
The term HIV-associated neurocognitive disorders (HAND) of somnolence in patients with dementia due to toxic/
is used to describe a spectrum of disorders that range metabolic encephalopathies.
from asymptomatic neurocognitive impairment (ANI) HIV-associated dementia is the initial AIDS-dening
to minor neurocognitive disorder (MND) to clinically illness in ~3% of patients with HIV infection and thus
severe dementia. The most severe form, HIV-associated only rarely precedes clinical evidence of immunode-
dementia (HAD), also referred to as the AIDS dementia ciency. Clinically signicant encephalopathy eventually
542 TABLE 42-4
CLINICAL STAGING OF HIV ENCEPHALOPATHY (AIDS DEMENTIA COMPLEX)
STAGE DEFINITION
Nearly or absolutely mute. Paraparetic or paraplegic with urinary and fecal incontinence.
develops in ~25% of untreated patients with AIDS. As a baseline MMSE. However, changes in MMSE scores
Diseases of the Nervous System
immunologic function declines, the risk and severity of may be absent in patients with mild HIV-associated
HIV encephalopathy increase. Autopsy series suggest dementia. Imaging studies of the CNS, by either MRI
that 8090% of patients with HIV infection have his- or CT, often demonstrate evidence of cerebral atro-
tologic evidence of CNS involvement. Several classi- phy (Fig. 42-3). MRI may also reveal small areas of
cation schemes have been developed for grading HIV- increased density on T2-weighted images. Lumbar
associated dementia; a commonly used clinical staging puncture is an important element of the evaluation
system is outlined in Table 42-4. of patients with HIV infection and neurologic abnor-
The precise cause of HIV-associated dementia malities. It is generally most helpful in ruling out or
remains unclear, although the condition is thought to
be a result of a combination of direct effects of HIV on
the CNS and associated immune activation. HIV has
been found in the brains of patients with HIV-associ-
ated dementia by Southern blot, in situ hybridization,
PCR, and electron microscopy. Multinucleated giant
cells, macrophages, and microglial cells appear to be the
main cell types harboring virus in the CNS. Histologi-
cally, the major changes are seen in the subcortical areas
of the brain and include pallor and gliosis, multinucle-
ated giant cell encephalitis, and vacuolar myelopathy.
Less commonly, diffuse or focal spongiform changes
occur in the white matter. Areas of the brain involved
in motor, language, and judgment are most severely
affected.
There are no specic criteria for a diagnosis of
HIV-associated dementia, and this syndrome must
be differentiated from a number of other diseases
that affect the CNS of HIV-infected patients. The FIGURE 42-3
diagnosis of dementia depends upon demonstrating AIDS dementia complex. Postcontrast CT scan through
a decline in cognitive function. This can be accom- the lateral ventricles of a 47-year-old man with AIDS, altered
plished objectively with the use of a Mini-Mental Sta- mental status, and dementia. The lateral and third ventricles
tus Examination (MMSE) in patients for whom prior and the cerebral sulci are abnormally prominent. Mild white
scores are available. For this reason, it is advisable for matter hypodensity is also seen adjacent to the frontal horns
all patients with a diagnosis of HIV infection to have of the lateral ventricles.
making a diagnosis of opportunistic infections. In HIV myelopathy 543
HIV-associated dementia, patients may have the non-
specic ndings of an increase in CSF cells and protein Spinal cord disease, or myelopathy, is present in ~20%
level. While HIV RNA can often be detected in the of patients with AIDS, often as part of HIV-associated
spinal uid and HIV can be cultured from the CSF, neurocognitive disorder. In fact, 90% of the patients
this nding is not specic for HIV-associated demen- with HIV-associated myelopathy have some evidence
tia. There appears to be no correlation between the of dementia, suggesting that similar pathologic processes
presence of HIV in the CSF and the presence of HIV- may be responsible for both conditions. Three main
associated dementia. Elevated levels of macrophage types of spinal cord disease are seen in patients with
chemoattractant protein (MCP-1), 2-microglobulin, AIDS. The rst of these is a vacuolar myelopathy. This
neopterin, and quinolinic acid (a metabolite of trypto- condition is pathologically similar to subacute com-
phan reported to cause CNS injury) have been noted bined degeneration of the cord such as occurs with per-
in the CSF of patients with HIV-associated demen- nicious anemia. Although vitamin B12 deciency can be
tia. These ndings suggest that these factors as well as seen in patients with AIDS as a primary complication of
inammatory cytokines may be involved in the patho- HIV infection, it does not appear to be responsible for
genesis of this syndrome. the myelopathy seen in the majority of patients. Vacuo-
Combination antiretroviral therapy is of benet in lar myelopathy is characterized by a subacute onset and
CHAPTER 42
patients with HIV-associated dementia. Improvement often presents with gait disturbances, predominantly
in neuropsychiatric test scores has been noted for both ataxia and spasticity; it may progress to include blad-
adult and pediatric patients treated with antiretrovirals. der and bowel dysfunction. Physical ndings include
The rapid improvement in cognitive function noted evidence of increased deep tendon reexes and exten-
with the initiation of cART suggests that at least some sor plantar responses. The second form of spinal cord
component of this problem is quickly reversible, again disease involves the dorsal columns and presents as a
pure sensory ataxia. The third form is also sensory in
HIV Neurology
supporting at least a partial role of soluble mediators
in the pathogenesis. It should also be noted that these nature and presents with paresthesias and dysesthesias
patients have an increased sensitivity to the side effects of the lower extremities. In contrast to the cognitive
of neuroleptic drugs. The use of these drugs for symp- problems, these spinal cord syndromes do not respond
tomatic treatment is associated with an increased risk well to antiretroviral drugs, and therapy is mainly
of extrapyramidal side effects; therefore, patients with supportive.
HIV-associated dementia who receive these agents must One important disease of the spinal cord that also
be monitored carefully. It is felt by many physicians involves the peripheral nerves is a myelopathy and poly-
that the decrease in the prevalence of severe cases of radiculopathy seen in association with CMV infec-
HIV-associated dementia brought about by cART has tion. This entity is generally seen late in the course of
resulted in an increase in the prevalence of milder forms HIV infection and is fulminant in onset, with lower
of this disorder. extremity and sacral paresthesias, difculty in walking,
areexia, ascending sensory loss, and urinary reten-
tion. The clinical course is rapidly progressive over a
period of weeks. CSF examination reveals a predomi-
Aseptic meningitis nantly neutrophilic pleocytosis, and CMV DNA can
Aseptic meningitis may be seen in any but the very late be detected by CSF PCR. Therapy with ganciclovir or
stages of HIV infection. In the setting of acute primary foscarnet can lead to rapid improvement, and prompt
infection patients may experience a syndrome of head- initiation of foscarnet or ganciclovir therapy is impor-
ache, photophobia, and meningismus. Rarely, an acute tant in minimizing the degree of permanent neuro-
encephalopathy due to encephalitis may occur. Cranial logic damage. Combination therapy with both drugs
nerve involvement may be seen, predominantly cranial should be considered in patients who have been previ-
nerve VII but occasionally V and/or VIII. CSF nd- ously treated for CMV disease. Other diseases involving
ings include a lymphocytic pleocytosis, elevated protein the spinal cord in patients with HIV infection include
level, and normal glucose level. This syndrome, which HTLV-I-associated myelopathy (HAM), neurosyphilis,
cannot be clinically differentiated from other viral men- infection with herpes simplex or varicella-zoster, TB,
ingitides (Chap. 41), usually resolves spontaneously and lymphoma.
within 24 weeks; however, in some patients, signs and
symptoms may become chronic. Aseptic meningitis may
HIV neuropathy
occur any time in the course of HIV infection; how-
ever, it is rare following the development of AIDS. This Peripheral neuropathies are common in patients with
fact suggests that clinical aseptic meningitis in the con- HIV infection. They occur at all stages of illness and
text of HIV infection is an immune-mediated disease. take a variety of forms. Early in the course of HIV
544 infection, an acute inammatory demyelinating poly- syndrome characterized by proximal muscle weakness
neuropathy resembling Guillain-Barr syndrome may and myalgias. Quite pronounced elevations in cre-
occur (Chap. 46). In other patients, a progressive or atine kinase may occur in asymptomatic patients, par-
relapsing-remitting inammatory neuropathy resem- ticularly after exercise. The clinical signicance of this
bling chronic inammatory demyelinating polyneu- as an isolated laboratory nding is unclear. A variety
ropathy (CIDP) has been noted. Patients commonly of both inammatory and noninammatory pathologic
present with progressive weakness, areexia, and mini- processes have been noted in patients with more severe
mal sensory changes. CSF examination often reveals a myopathy, including myober necrosis with inamma-
mononuclear pleocytosis, and peripheral nerve biopsy tory cells, nemaline rod bodies, cytoplasmic bodies, and
demonstrates a perivascular inltrate suggesting an mitochondrial abnormalities. Profound muscle wasting,
autoimmune etiology. Plasma exchange or IVIg has often with muscle pain, may be seen after prolonged
been tried with variable success. Because of the immu- zidovudine therapy. This toxic side effect of the drug
nosuppressive effects of glucocorticoids, they should is dose-dependent and is related to its ability to inter-
be reserved for severe cases of CIDP refractory to fere with the function of mitochondrial polymerases. It
other measures. Another autoimmune peripheral neu- is reversible following discontinuation of the drug. Red
ropathy seen in patients with AIDS is mononeuritis ragged bers are a histologic hallmark of zidovudine-
multiplex (due to a necrotizing arteritis of peripheral induced myopathy.
SECTION III
oxynucleoside therapy. It is more common in taller patients with congenital or acquired T cell immu-
individuals, older individuals, and those with lower nodeciencies. AIDS is no exception; at least 6% of
CD4 counts. Two-thirds of patients with AIDS may all patients with AIDS develop lymphoma at some
be shown by electrophysiologic studies to have some time during the course of their illness. This is a 120-
evidence of peripheral nerve disease. Presenting symp- fold increase in incidence compared to the general
toms are usually painful burning sensations in the feet population. In contrast to the situation with Kaposis
and lower extremities. Findings on examination include sarcoma, primary CNS lymphoma, and most oppor-
a stocking-type sensory loss to pinprick, temperature, tunistic infections, the incidence of AIDS-associated
and touch sensation and a loss of ankle reexes. Motor systemic lymphomas has not experienced as dramatic
changes are mild and are usually limited to weakness a decrease as a consequence of the widespread use of
of the intrinsic foot muscles. Response of this condi- effective cART. Lymphoma occurs in all risk groups,
tion to antiretrovirals has been variable, perhaps because with the highest incidence in patients with hemophilia
antiretrovirals are responsible for the problem in some and the lowest incidence in patients from the Carib-
instances. When due to dideoxynucleoside therapy, bean or Africa with heterosexually acquired infec-
patients with lower extremity peripheral neuropa- tion. Lymphoma is a late manifestation of HIV infec-
thy may complain of a sensation that they are walking tion, generally occurring in patients with CD4+ T
on ice. Other entities in the differential diagnosis of cell counts <200/L. As HIV disease progresses, the
peripheral neuropathy include diabetes mellitus, vita- risk of lymphoma increases. The attack rate for lym-
min B12 deciency, and side effects from metronidazole phoma increases exponentially with increasing dura-
or dapsone. For distal symmetric polyneuropathy that tion of HIV infection and decreasing level of immuno-
fails to resolve following the discontinuation of dide- logic function. At 3 years following a diagnosis of HIV
oxynucleosides, therapy is symptomatic; gabapentin, infection, the risk of lymphoma is 0.8% per year; by
carbamazepine, tricyclics, or analgesics may be effective 8 years after infection, it is 2.6% per year. As individu-
for dysesthesias. Treatment-naive patients may respond als with HIV infection live longer as a consequence of
to cART. improved cART and better treatment and prophylaxis
of opportunistic infections, it is anticipated that the
incidence of lymphomas may increase.
HIV myopathy
The clinical presentation of lymphoma in patients
Myopathy may complicate the course of HIV infec- with HIV infection is quite varied, ranging from focal
tion; causes include HIV infection itself, zidovudine, seizures to rapidly growing mass lesions in the oral
and the generalized wasting syndrome. HIV-associated mucosa to persistent unexplained fever. At least 80%
myopathy may range in severity from an asymptom- of patients present with extranodal disease, and a simi-
atic elevation in creatine kinase levels to a subacute lar percentage have B-type symptoms of fever, night
sweats, or weight loss. Virtually any site in the body that are primary CNS lymphomas, CNS disease is also 545
may be involved. The most common extranodal site is seen in HIV-infected patients with systemic lymphoma.
the CNS, which is involved in approximately one-third Approximately 20% of patients with systemic lym-
of all patients with lymphoma. Approximately 60% of phoma have CNS disease in the form of leptomenin-
these cases are primary CNS lymphoma. geal involvement. This fact underscores the importance
of lumbar puncture in the staging evaluation of patients
CNS lymphoma with systemic lymphoma.
Primary CNS lymphoma accounts for ~20% of the cases Both conventional and unconventional approaches
of lymphoma in patients with HIV infection. In contrast have been employed in an attempt to treat HIV-related
to HIV-associated Burkitts lymphoma, primary CNS lymphomas. Systemic lymphoma is generally treated by
lymphomas are usually positive for EBV. In one study, the oncologist with combination chemotherapy. Earlier
the incidence of Epstein-Barr positivity was 100%. This disappointing gures are being replaced with more opti-
malignancy does not have a predilection for any par- mistic results for the treatment of systemic lymphoma
ticular age group. The median CD4+ T cell count at following the availability of more effective cART and
the time of diagnosis is ~50/L. Thus, CNS lymphoma the use of rituximab in CD20+ tumors. While there is
generally presents at a later stage of HIV infection controversy regarding the use of antiretrovirals during
than systemic lymphoma. This fact may at least in part chemotherapy, there is no question that their use overall
CHAPTER 42
explain the poorer prognosis for this subset of patients. in patients with HIV lymphoma has improved survival.
Primary CNS lymphoma generally presents with As in most situations in patients with HIV disease, those
focal neurologic decits, including cranial nerve nd- with the higher CD4+ T cell counts tend to do better.
ings, headaches, and/or seizures. MRI or CT gener- Response rates as high as 72% with a median survival of
ally reveals a limited number (one to three) of 3- to 33 months and disease-free intervals up to 9 years have
5-cm lesions (Fig. 42-4). The lesions often show been reported. Treatment of primary CNS lymphoma
HIV Neurology
ring enhancement on contrast administration and may remains a signicant challenge. Treatment is complicated
occur in any location. Locations that are most com- by the fact that this illness usually occurs in patients with
monly involved with CNS lymphoma are deep in the advanced HIV disease. Palliative measures such as radia-
white matter. Contrast enhancement is usually less pro- tion therapy provide some relief. The prognosis remains
nounced than that seen with toxoplasmosis. The main poor in this group, with a 2-year survival of 29%.
diseases in the differential diagnosis are cerebral toxo-
plasmosis and cerebral Chagas disease. In addition to
the 20% of lymphomas in HIV-infected individuals HIV-related opportunistic infections
The most common HIV-related neurologic opportunis-
tic infections are toxoplasmosis, cryptococcal infections,
and progressive multifocal leukoencephalopathy. The
risk of many such infections correlates well with the
CD4+ T cell count (Fig. 42-5). A selected group of
common and important opportunistic infections of the
nervous system in patients with HIV is discussed next.
Cryptococcosis
C. neoformans is the leading infectious cause of men-
ingitis in patients with AIDS. It is the initial AIDS-
dening illness in ~2% of patients and generally occurs
in patients with CD4+ T cell counts <100/L. Cryp-
tococcal meningitis is particularly common in patients
with AIDS in Africa, occurring in ~5% of patients. Most
patients present with a picture of subacute meningoen-
cephalitis with fever, nausea, vomiting, altered mental
FIGURE 42-4 status, headache, and meningeal signs. The incidence of
Central nervous system lymphoma. Postcontrast T1- seizures and focal neurologic decits is low. The CSF
weighted MR scan in a patient with AIDS, an altered mental prole may be normal or may show only modest eleva-
status, and hemiparesis. Multiple enhancing lesions, some tions in WBC or protein levels and decreases in glucose.
ring-enhancing, are present. The left Sylvian lesion shows In addition to meningitis, patients may develop crypto-
gyral and subcortical enhancement, and the lesions in the coccomas and cranial nerve involvement. Approximately
caudate and splenium (arrowheads) show enhancement of one-third of patients also have pulmonary disease.
adjacent ependymal surfaces. Uncommon manifestations of cryptococcal infection
546
300
CD4 (cells/L3)
200
*
*
100
* *
* * * * * *
* * * * *
0
HSV HZos Crp KS Cry Can PCP NHL DEM PML WS Tox CMV PCP2 MAC
Opportunistic illness
FIGURE 42-5
Relationship between CD4+ T cell counts and the devel- virus infection; HZos, herpes zoster; KS, Kaposis sarcoma;
SECTION III
opment of opportunistic diseases. Boxplot of the median MAC, Mycobacterium avium complex bacteremia; NHL, non-
(line inside the box), rst quartile (bottom of the box), third Hodgkins lymphoma; PCP, primary Pneumocystis jiroveci
quartile (top of the box), and mean (asterisk) CD4+ lympho- pneumonia; PCP2, secondary P. jiroveci pneumonia; PML,
cyte count at the time of the development of opportunistic progressive multifocal leukoencephalopathy; Tox, Toxo-
disease. Can, candidal esophagitis; CMV, cytomegalovirus plasma gondii encephalitis; WS, wasting syndrome. (From
infection; Crp, cryptosporidiosis; Cry, cryptococcal menin- RD Moore, RE Chaisson: Ann Intern Med 124:633, 1996.)
gitis; DEM, AIDS dementia complex; HSV, herpes simplex
Diseases of the Nervous System
include skin lesions that resemble molluscum contagiosum, most common in patients from the Caribbean and from
lymphadenopathy, palatal and glossal ulcers, arthritis, France, where the seroprevalence of T. gondii is around
gastroenteritis, myocarditis, and prostatitis. The prostate 50%. Toxoplasmosis is generally a late complication
gland may serve as a reservoir for smoldering cryptococ- of HIV infection and usually occurs in patients with
cal infection. The diagnosis of cryptococcal meningitis is CD4+ T cell counts <200/L. Cerebral toxoplasmo-
made by identication of organisms in spinal uid with sis is thought to represent a reactivation of latent tissue
India ink examination or by the detection of cryptococ- cysts. It is 10 times more common in patients with anti-
cal antigen. A biopsy may be needed to make a diag- bodies to the organism than in patients who are serone-
nosis of CNS cryptococcoma. Treatment is with IV gative. Patients diagnosed with HIV infection should be
amphotericin B, at a dose of 0.7 mg/kg daily, or lipo- screened for IgG antibodies to T. gondii during the time
somal amphotericin 4-6 mg/kg daily, with ucytosine, of their initial workup. Those who are seronegative
25 mg/kg qid for at least 2 weeks, and, if possible, until should be counseled about ways to minimize the risk of
the CSF culture turns negative. This is followed by primary infection including avoiding the consumption of
uconazole, 400 mg/d PO for 8 weeks, and then u- undercooked meat and careful hand washing after contact
conazole, 200 mg/d until the CD4+ T cell count has with soil or changing the cat litter box. The most com-
increased to >200 cells/L for 6 months in response to mon clinical presentation of cerebral toxoplasmosis in
cART. Repeated lumbar puncture may be required to patients with HIV infection is fever, headache, and focal
manage increased intracranial pressure. Symptoms may neurologic decits. Patients may present with seizure,
recur with initiation of cART as an immune reconstitu- hemiparesis, or aphasia as a manifestation of these focal
tion syndrome. Other fungi that may cause meningitis in decits or with a picture more inuenced by the accom-
patients with HIV infection are C. immitis and H. capsu- panying cerebral edema and characterized by confusion,
latum. Meningoencephalitis has also been reported due dementia, and lethargy, which can progress to coma. The
to Acanthamoeba or Naegleria. diagnosis is usually suspected on the basis of MRI nd-
ings of multiple lesions in multiple locations, although
Toxoplasmosis in some cases only a single lesion is seen. Pathologically,
Toxoplasmosis has been one of the most common causes these lesions generally exhibit inammation and central
of secondary CNS infections in patients with AIDS, necrosis and, as a result, demonstrate ring enhancement
but its incidence is decreasing in the era of cART. It is on contrast MRI (Fig. 42-6) or, if MRI is unavailable
Progressive multifocal leukoencephalopathy 547
(PML)
JC virus, a human polyomavirus that is the etiologic
agent of progressive multifocal leukoencephalopathy (PML),
is an important opportunistic pathogen in patients
with AIDS. While ~80% of the general adult popula-
tion have antibodies to JC virus, indicative of prior
infection, <10% of healthy adults show any evidence
of ongoing viral replication. PML is the only known
clinical manifestation of JC virus infection. It is a late
manifestation of AIDS and is seen in ~4% of patients
with AIDS. The lesions of PML begin as small foci of
demyelination in subcortical white matter that eventu-
ally coalesce. The cerebral hemispheres, cerebellum, and
brainstem may all be involved. Patients typically have
a protracted course with multifocal neurologic decits,
FIGURE 42-6 with or without changes in mental status. Approxi-
CHAPTER 42
Central nervous system toxoplasmosis. A coronal post- mately 20% of patients experience seizures. Ataxia,
contrast T1-weighted MR scan demonstrates a peripheral hemiparesis, visual eld defects, aphasia, and sensory
enhancing lesion in the left frontal lobe, associated with an defects may occur. MRI typically reveals multiple, non-
eccentric nodular area of enhancement (arrow); this so-called enhancing white matter lesions that may coalesce and
eccentric target sign is typical of toxoplasmosis.
have a predilection for the occipital and parietal lobes.
The lesions show signal hyperintensity on T2-weighted
HIV Neurology
images and diminished signal on T1-weighted images.
or contraindicated, on double-dose contrast CT. There The measurement of JC virus DNA levels in CSF has a
is usually evidence of surrounding edema. In addition to diagnostic sensitivity of 76% and a specicity of close to
toxoplasmosis, the differential diagnosis of single or mul- 100%. Prior to the availability of cART, the majority of
tiple enhancing mass lesions in the HIV-infected patient patients with PML died within 36 months of the onset
includes primary CNS lymphoma and, less commonly, of symptoms. Paradoxical worsening of PML has been
TB or fungal or bacterial abscesses. The denitive diag- seen with initiation of cART as an immune reconstitu-
nostic procedure is brain biopsy. However, given the tion syndrome. There is no specic treatment for PML;
morbidity than can accompany this procedure, it is usu- however, a minimal median survival of 2 years and sur-
ally reserved for the patient who has failed 24 weeks vival of >15 years have been reported in patients with
of empiric therapy. If the patient is seronegative for T. PML treated with cART for their HIV disease. Unfor-
gondii, the likelihood that a mass lesion is due to toxo- tunately only ~50% of patients with HIV infection and
plasmosis is <10%. In that setting, one may choose to PML show neurologic improvement with cART. Stud-
be more aggressive and perform a brain biopsy sooner. ies with other antiviral agents such as cidofovir have
Standard treatment is sulfadiazine and pyrimethamine failed to show clear benet. Factors inuencing a favor-
with leucovorin as needed for a minimum of 46 weeks. able prognosis for PML in the setting of HIV infection
Alternative therapeutic regimens include clindamycin in include a CD4+ T cell count >100/L at baseline and
combination with pyrimethamine; atovaquone plus pyri- the ability to maintain an HIV viral load of <500 copies
methamine; and azithromycin plus pyrimethamine plus per milliliter. Baseline HIV-1 viral load does not have
rifabutin. Relapses are common, and it is recommended independent predictive value of survival. PML is one
that patients with a history of prior toxoplasmic encepha- of the few opportunistic infections that continues to
litis receive maintenance therapy with sulfadiazine, pyri- occur with some frequency despite the widespread use
methamine, and leucovorin as long as their CD4+ T cell of cART.
counts remain <200 cells/L. Patients with CD4+ T cell
counts <100/L and IgG antibody to Toxoplasma should Chagas disease
receive primary prophylaxis for toxoplasmosis. Fortu- Reactivation American trypanosomiasis may present as acute
nately, the same daily regimen of a single double-strength meningoencephalitis with focal neurologic signs, fever,
tablet of TMP/SMX used for P. jiroveci prophylaxis pro- headache, vomiting, and seizures. Accompanying car-
vides adequate primary protection against toxoplasmosis. diac disease in the form of arrhythmias or heart failure
Secondary prophylaxis/maintenance therapy for toxo- should increase the index of suspicion. The presence of
plasmosis may be discontinued in the setting of effective antibodies to Trypanosoma cruzi supports the diagnosis.
cART and increases in CD4+ T cell counts to >200/L In South America, reactivation of Chagas disease is con-
for 6 months. sidered to be an AIDS-dening condition and may be
548 the initial AIDS-dening condition. The majority of cerebral vascular disease, thrombotic thrombocytopenic
cases occur in patients with CD4+ T cell counts <200 purpura, and cocaine or amphetamine use.
cells/L. Lesions appear radiographically as single or
multiple hypodense areas, typically with ring enhance- Seizures
ment and edema. They are found predominantly in the Seizures may be a consequence of opportunistic infec-
subcortical areas, a feature that differentiates them from tions, neoplasms, or HIV-associated dementia. The sei-
the deeper lesions of toxoplasmosis. T. cruzi amasti- zure threshold is often lower than normal in patients with
gotes, or trypanosomes, can be identied from biopsy advanced HIV infection due to the frequent presence of
specimens or CSF. Other CSF ndings include ele- electrolyte abnormalities. Seizures are seen in 1540% of
vated protein and a mild (<100 cells/L) lymphocytic patients with cerebral toxoplasmosis, 1535% of patients
pleocytosis. Organisms can also be identied by direct with primary CNS lymphoma, 8% of patients with cryp-
examination of the blood. Treatment consists of benz- tococcal meningitis, and 750% of patients with HIV-
imidazole (2.5 mg/kg bid) or nifurtimox (2 mg/kg qid) associated dementia. Seizures may also be seen in patients
for at least 60 days, followed by maintenance therapy with CNS tuberculosis, aseptic meningitis, and progres-
for the duration of immunodeciency with either drug sive multifocal leukoencephalopathy. Seizures may be the
at a dose of 5 mg/kg three times a week. As is the case presenting clinical symptom of HIV disease. In one study
with cerebral toxoplasmosis, successful therapy with of 100 patients with HIV infection presenting with a rst
SECTION III
antiretrovirals may allow discontinuation of therapy for seizure, cerebral mass lesions were the most common
Chagas disease. cause, responsible for 32 of the 100 new-onset seizures.
Of these 32 cases, 28 were due to toxoplasmosis and 4
to lymphoma. HIV-associated dementia accounted for
Specic neurologic presentations an additional 24 new-onset seizures. Cryptococcal men-
Stroke ingitis was the third most common diagnosis, responsible
Diseases of the Nervous System
Stroke may occur in patients with HIV infection. In for 13 of the 100 seizures. In 23 cases, no cause could be
contrast to the other causes of focal neurologic de- found, and it is possible that these cases represent a sub-
cits in patients with HIV infection, the symptoms of category of HIV-associated dementia. Of these 23 cases,
a stroke are sudden in onset. Patients with HIV infec- 16 (70%) had two or more seizures, suggesting that anti-
tion have an increased prevalence of many classic risk convulsant therapy is indicated in all patients with HIV
factors associated with stroke, including smoking and infection and seizures unless a rapidly correctable cause is
diabetes. It also appears that HIV infection itself can found. While phenytoin remains the initial treatment of
lead to an increase in carotid artery stiffness. Among choice, hypersensitivity reactions to this drug have been
the secondary infectious diseases in patients with HIV reported in >10% of patients with AIDS, and therefore
infection that may be associated with stroke are vascu- the use of phenobarbital, valproic acid, or levetiracetam
litis due to cerebral varicella zoster or neurosyphilis and must be considered as an alternative. Due to a variety of
septic embolism in association with fungal infection. drug-drug interactions between antiseizure medications
Other elements of the differential diagnosis of stroke in and antiretrovirals, drug levels need to be monitored
the patient with HIV infection include atherosclerotic carefully.
CHAPTER 43
PRION DISEASES
Prions are infectious proteins that cause degeneration in the prion protein (PrP) is the fundamental event under-
of the central nervous system (CNS). Prion diseases are lying prion diseases (Table 43-1).
disorders of protein conformation, the most common Four new concepts have emerged from studies of pri-
of which in humans is called Creutzfeldt-Jakob disease ons: (1) Prions are the only known infectious pathogens
(CJD). CJD typically presents with dementia and myoc- that are devoid of nucleic acid; all other infectious agents
lonus, is relentlessly progressive, and generally causes possess genomes composed of either RNA or DNA
death within a year of onset. Most CJD patients are that direct the synthesis of their progeny. (2) Prion dis-
between 50 and 75 years of age; however, patients as eases may be manifest as infectious, genetic, and sporadic
young as 17 and as old as 83 have been recorded.
In mammals, prions reproduce by binding to the nor-
mal, cellular isoform of the prion protein (PrPC) and stimu- TABLE 43-1
lating conversion of PrPC into the disease-causing isoform GLOSSARY OF PRION TERMINOLOGY
(PrPSc). PrPC is rich in -helix and has little -structure,
Prion Proteinaceous infectious particle that lacks
while PrPSc has less -helix and a high amount of
nucleic acid. Prions are composed entirely
-structure (Fig. 43-1). This -to- structural transition of PrPSc molecules. They can cause
scrapie in sheep and goats, and related
neurodegenerative diseases of humans
Helix A
such as Creutzfeldt-Jakob disease (CJD).
PrPSc Disease-causing isoform of the prion
Helix B protein. This protein is the only identiable
macromolecule in puried preparations of
Helix B Helix C scrapie prions.
PrPC Cellular isoform of the prion protein. PrPC is
Helix C
the precursor of PrPSc.
PrP 27-30 A fragment of PrPSc, generated by
truncation of the NH2-terminus by limited
digestion with proteinase K. PrP 27-30
A Recombinant PrP B PrPSc model
retains prion infectivity and polymerizes
FIGURE 43-1 into amyloid.
Structures of prion proteins. A. NMR structure of Syrian ham- PRNP PrP gene located on human chromosome 20.
ster recombinant (rec) PrP(90231). Presumably, the structure Prion rod An aggregate of prions composed
of the -helical form of recPrP(90231) resembles that of PrPC. largely of PrP 27-30 molecules. Created
recPrP(90231) is viewed from the interface where PrPSc is by detergent extraction and limited
thought to bind to PrPC. Shown are: -helices A (residues 144 proteolysis of PrPSc. Morphologically and
157), B (172193), and C (200227). Flat ribbons depict -strands histochemically indistinguishable from
S1 (129131) and S2 (161163). ( A , from SB Prusiner: N Engl J many amyloids.
Med 344:1516, 2001; with permission.) B. Structural model of PrP amyloid Amyloid containing PrP in the brains of
PrPSc. The 90160 region has been modeled onto a -helical animals or humans with prion disease;
architecture while the COOH terminal helices B and C are pre- often accumulates as plaques.
served as in PrPC. (Image prepared by C. Govaerts.)
549
550 disorders; no other group of illnesses with a single etiol- of brains from dead relatives during ritualistic cannibalism.
ogy presents with such a wide spectrum of clinical mani- With the cessation of ritualistic cannibalism in the late
festations. (3) Prion diseases result from the accumulation 1950s, kuru has nearly disappeared, with the exception
of PrPSc, the conformation of which differs substantially of a few recent patients exhibiting incubation periods of
from that of its precursor, PrPC. (4) PrPSc can exist in a >40 years. Iatrogenic CJD (iCJD) seems to be the result
variety of different conformations, each of which seems of the accidental inoculation of patients with prions. Vari-
to specify a particular disease phenotype. How a specic ant CJD (vCJD) in teenagers and young adults in Europe
conformation of a PrPSc molecule is imparted to PrPC is the result of exposure to tainted beef from cattle with
during prion replication to produce nascent PrPSc with bovine spongiform encephalopathy (BSE).
the same conformation is unknown. Additionally, it is Six diseases of animals are caused by prions (Table
unclear what factors determine where in the CNS a par- 43-2). Scrapie of sheep and goats is the prototypic prion
ticular PrPSc molecule will be deposited. disease. Mink encephalopathy, BSE, feline spongiform
encephalopathy, and exotic ungulate encephalopathy are
all thought to occur after the consumption of prion-
infected foodstuffs. The BSE epidemic emerged in
SPECTRUM OF PRION DISEASES
Britain in the late 1980s and was shown to be due to
The sporadic form of CJD is the most common prion dis- industrial cannibalism. Whether BSE began as a spo-
SECTION III
order in humans. Sporadic CJD (sCJD) accounts for 85% radic case of BSE in a cow or started with scrapie in
of all cases of human prion disease, while inherited prion sheep is unknown. The origin of chronic wasting dis-
diseases account for 1015% of all cases (Table 43-2). ease (CWD), a prion disease endemic in deer and elk
Familial CJD (fCJD), Gerstmann-Strussler-Scheinker in regions of North America, is uncertain. In contrast
(GSS) disease, and fatal familial insomnia (FFI) are all dom- to other prion diseases, CWD is highly communicable.
inantly inherited prion diseases that are caused by muta- Feces from asymptomatic, infected cervids contain prions
Diseases of the Nervous System
tions in the PrP gene. that are likely to be responsible for the spread of CWD.
Although infectious prion diseases account for
<1% of all cases and infection does not seem to
EPIDEMIOLOGY
play an important role in the natural history of
these illnesses, the transmissibility of prions is an impor- CJD is found throughout the world. The incidence of
tant biologic feature. Kuru of the Fore people of New sCJD is approximately one case per million population,
Guinea is thought to have resulted from the consumption and thus it accounts for about 1 in every 10,000 deaths.
TABLE 43-2
THE PRION DISEASES
DISEASE HOST MECHANISM OF PATHOGENESIS
Human
Kuru Fore people Infection through ritualistic cannibalism
iCJD Humans Infection from prion-contaminated hGH, duramater grafts, etc.
vCJD Humans Infection from bovine prions
fCJD Humans Germ-line mutations in PRNP
GSS Humans Germ-line mutations in PRNP
FFI Humans Germ-line mutation in PRNP (D178N, M129)
sCJD Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc?
sFI Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc?
Animal
Scrapie Sheep, goats Infection in genetically susceptible sheep
BSE Cattle Infection with prion-contaminated MBM
TME Mink Infection with prions from sheep or cattle
CWD Mule deer, elk Unknown
FSE Cats Infection with prion-contaminated beef
Exotic ungulate Greater kudu, nyala,or oryx Infection with prion-contaminated MBM
encephalopathy
Abbreviations: BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease; CWD, chronic wasting disease; fCJD, familial
Creutzfeldt-Jakob disease; FFI, fatal familial insomnia; FSE, feline spongiform encephalopathy; GSS, Gerstmann-Strussler-Scheinker dis-
ease; hGH, human growth hormone; iCJD, iatrogenic Creutzfeldt-Jakob disease; MBM, meat and bone meal; sCJD, sporadic Creutzfeldt-Jakob
disease; sFI, sporadic fatal insomnia; TME, transmissible mink encephalopathy; vCJD, variant Creutzfeldt-Jakob disease.
Because sCJD is an age-dependent neurodegenerative PrP Polypeptide CHO CHO GPI 551
disease, its incidence is expected to increase steadily as
older segments of populations in developed and devel- S S
oping countries continue to expand. Although many
geographic clusters of CJD have been reported, each PrPC 209 amino acids
CHAPTER 43
with rodents demonstrate that oral infection with pri-
ons can occur, but the process is inefcient compared to
intracerebral inoculation. Prion strains
The existence of prion strains raised the question of how
PATHOGENESIS
heritable biologic information can be enciphered in a mol-
Prion Diseases
The human prion diseases were initially classied as ecule other than nucleic acid. Various strains of prions
neurodegenerative disorders of unknown etiology on have been dened by incubation times and the distribu-
the basis of pathologic changes being conned to the tion of neuronal vacuolation. Subsequently, the patterns of
CNS. With the transmission of kuru and CJD to apes, PrPSc deposition were found to correlate with vacuolation
investigators began to view these diseases as infectious proles, and these patterns were also used to characterize
CNS illnesses caused by slow viruses. Even though prion strains.
the familial nature of a subset of CJD cases was well Persuasive evidence that strain-specic information is
described, the signicance of this observation became enciphered in the tertiary structure of PrPSc comes from
more obscure with the transmission of CJD to animals. transmission of two different inherited human prion dis-
Eventually the meaning of heritable CJD became clear eases to mice expressing a chimeric human-mouse PrP
with the discovery of mutations in the PRNP gene of transgene. In FFI, the protease-resistant fragment of PrPSc
these patients. The prion concept explains how a dis- after deglycosylation has a molecular mass of 19 kDa,
ease can manifest as a heritable as well as an infectious whereas in fCJD and most sporadic prion diseases, it is
illness. Moreover, the hallmark of all prion diseases, 21 kDa (Table 43-3). This difference in molecular mass
whether sporadic, dominantly inherited, or acquired by was shown to be due to different sites of proteolytic
infection, is that they involve the aberrant metabolism cleavage at the NH2 termini of the two human PrPSc
of PrP. molecules, reecting different tertiary structures. These
A major feature that distinguishes prions from viruses distinct conformations were not unexpected because the
is the nding that both PrP isoforms are encoded by a amino acid sequences of the PrPs differ.
chromosomal gene. In humans, the PrP gene is desig- Extracts from the brains of patients with FFI trans-
nated PRNP and is located on the short arm of chro- mitted disease into mice expressing a chimeric human-
mosome 20. Limited proteolysis of PrPSc produces a mouse PrP transgene and induced formation of the
smaller, protease-resistant molecule of 142 amino acids 19-kDa PrPSc, whereas brain extracts from fCJD and
designated PrP 27-30; PrPC is completely hydrolyzed sCJD patients produced the 21-kDa PrPSc in mice
under the same conditions (Fig. 43-2). In the pres- expressing the same transgene. On second passage, these
ence of detergent, PrP 27-30 polymerizes into amyloid. differences were maintained, demonstrating that chime-
Prion rods formed by limited proteolysis and detergent ric PrPSc can exist in two different conformations based
extraction are indistinguishable from the laments that on the sizes of the protease-resistant fragments, even
aggregate to form PrP amyloid plaques in the CNS. though the amino acid sequence of PrPSc is invariant.
Both the rods and the PrP amyloid laments found in This analysis was extended when patients with spo-
brain tissue exhibit similar ultrastructural morphology radic fatal insomnia (sFI) were identied. Although
and green-gold birefringence after staining with Congo they did not carry a PRNP gene mutation, the patients
red dye. demonstrated a clinical and pathologic phenotype that
552 TABLE 43-3
DISTINCT PRION STRAINS GENERATED IN HUMANS WITH INHERITED PRION DISEASES AND TRANSMITTED TO
TRANSGENIC MICEa
INCUBATION TIME
INOCULUM HOST SPECIES HOST PrP GENOTYPE [DAYS SEM] (n/n0) PrPSc(kDa)
a
Tg(MHu2M) mice express a chimeric mouse-human PrP gene.
Notes: Clinicopathologic phenotype is determined by the conformation of PrPSc in accord with the results of the transmission of human prions
from patients with FFI to transgenic mice. fCJD, familial Creutzfeldt-Jakob disease; FFI, fatal familial insomnia.
SECTION III
was indistinguishable from that of patients with FFI. important or even sole determinant of the tertiary struc-
Furthermore, 19-kDa PrPSc was found in their brains, ture of PrPC, PrPSc seems to function as a template in
and on passage of prion disease to mice expressing a determining the tertiary structure of nascent PrPSc mol-
chimeric human-mouse PrP transgene, 19-kDa PrPSc ecules as they are formed from PrPC. In turn, prion
was also found. These ndings indicate that the disease diversity appears to be enciphered in the conformation
Diseases of the Nervous System
phenotype is dictated by the conformation of PrPSc and of PrPSc, and thus prion strains seem to represent differ-
not the amino acid sequence. PrPSc acts as a template ent conformers of PrPSc.
for the conversion of PrPC into nascent PrPSc. On the In general, transmission of prion disease from one
passage of prions into mice expressing a chimeric ham- species to another is inefcient, in that not all intracere-
ster-mouse PrP transgene, a change in the conformation brally inoculated animals develop disease, and those that
of PrPSc was accompanied by the emergence of a new fall ill do so only after long incubation times that can
strain of prions. approach the natural life span of the animal. This spe-
Many new strains of prions were generated using cies barrier to transmission is correlated with the degree
recombinant (rec) PrP produced in bacteria; recPrP of similarity between the amino acid sequences of PrPC
was polymerized into amyloid brils and inoculated in the inoculated host and of PrPSc in the prion inocu-
into transgenic mice expressing high levels of wild-type lum. The importance of sequence similarity between the
mouse PrPC; about 500 days later, the mice died of prion host and donor PrP argues that PrPC directly interacts
disease. The incubation times of the synthetic prions in with PrPSc in the prion conversion process.
mice were dependent on the conditions used for polym-
erization of the amyloid brils. Highly stable amyloids
gave rise to stable prions with long incubation times; SPORADIC AND INHERITED PRION
low-stability amyloids led to prions with short incubation DISEASES
times. Amyloids of intermediate stability gave rise to pri-
ons with intermediate stabilities and intermediate incuba- Several different scenarios might explain the initiation
tion times. Such ndings are consistent with earlier stud- of sporadic prion disease: (1) A somatic mutation may
ies showing that the incubation times of synthetic and be the cause and thus follow a path similar to that for
naturally occurring prions are directly proportional to the germ-line mutations in inherited disease. In this situ-
stability of the prion. ation, the mutant PrPSc must be capable of target-
ing wild-type PrPC, a process known to be possible
for some mutations but less likely for others. (2) The
Species barrier
activation energy barrier separating wild-type PrPC
Studies on the role of the primary and tertiary structures from PrPSc could be crossed on rare occasions when
of PrP in the transmission of prion disease have given viewed in the context of a population. Most individu-
new insights into the pathogenesis of these maladies. als would be spared while presentations in the elderly
The amino acid sequence of PrP encodes the species with an incidence of 1 per million would be seen. (3)
of the prion, and the prion derives its PrPSc sequence PrPSc may be present at low levels in some normal cells,
from the last mammal in which it was passaged. While where it performs some important, as yet unknown,
the primary structure of PrP is likely to be the most function. The level of PrPSc in such cells is hypothesized
to be sufciently low as to be not detected by routine of the Japanese population, and this group appears to be 553
bioassay. In some altered metabolic states, the cellular resistant to prion disease. Dominant-negative inhibition
mechanisms for clearing PrPSc might become compro- of prion replication was also found with substitution of
mised and the rate of PrPSc formation would then begin the basic residue arginine at position 171; sheep with
to exceed the capacity of the cell to clear it. The third arginine are resistant to scrapie prions but are susceptible
possible mechanism is attractive since it suggests PrPSc to BSE prions that were inoculated intracerebrally.
is not simply a misfolded protein, as proposed for the
rst and second mechanisms, but that it is an alterna-
tively folded molecule with a function. Moreover, the
multitude of conformational states that PrPSc can adopt,
as described earlier, raises the possibility that PrPSc or INFECTIOUS PRION DISEASES
another prion-like protein might function in a process IATROGENIC CJD
like short-term memory where information storage
occurs in the absence of new protein synthesis. Accidental transmission of CJD to humans appears to
More than 40 different mutations resulting in non- have occurred with corneal transplantation, contaminated
conservative substitutions in the human PRNP gene electroencephalogram (EEG) electrode implantation, and
have been found to segregate with inherited human surgical procedures. Corneas from donors with inappar-
CHAPTER 43
prion diseases. Missense mutations and expansions in the ent CJD have been transplanted to apparently healthy
octapeptide repeat region of the gene are responsible for recipients who developed CJD after prolonged incu-
familial forms of prion disease. Five different mutations bation periods. The same improperly decontaminated
of the PRNP gene have been linked genetically to heri- EEG electrodes that caused CJD in two young patients
table prion disease. with intractable epilepsy caused CJD in a chimpanzee 18
Although phenotypes may vary dramatically within months after their experimental implantation.
Surgical procedures may have resulted in accidental
Prion Diseases
families, specic phenotypes tend to be observed with
certain mutations. A clinical phenotype indistinguish- inoculation of patients with prions, presumably because
able from typical sCJD is usually seen with substitutions some instrument or apparatus in the operating theater
at codons 180, 183, 200, 208, 210, and 232. Substitutions became contaminated when a CJD patient underwent
at codons 102, 105, 117, 198, and 217 are associated with surgery. Although the epidemiology of these studies is
the GSS variant of prion disease. The normal human PrP highly suggestive, no proof for such episodes exists.
sequence contains ve repeats of an eight-amino-acid
sequence. Insertions from two to nine extra octarepeats Dura mater grafts
frequently cause variable phenotypes ranging from a
condition indistinguishable from sCJD to a slowly pro- More than 160 cases of CJD after implantation of dura
gressive dementing illness of many years duration to an mater grafts have been recorded. All of the grafts were
early-age-of-onset disorder that is similar to Alzheimers thought to have been acquired from a single manufac-
disease. A mutation at codon 178 resulting in substitution turer whose preparative procedures were inadequate
of asparagine for aspartic acid produces FFI if a methio- to inactivate human prions. One case of CJD occurred
nine is encoded at the polymorphic 129 residue on the after repair of an eardrum perforation with a pericar-
same allele. Typical CJD is seen if the D178N mutation dium graft.
occurs with a valine encoded at position 129 of the same
allele. Human growth hormone and pituitary
gonadotropin therapy
HUMAN PRNP GENE POLYMORPHISMS The transmission of CJD prions from contaminated
Polymorphisms inuence the susceptibility to sporadic, human growth hormone (hGH) preparations derived
inherited, and infectious forms of prion disease. The from human pituitaries has been responsible for fatal cer-
methionine/valine polymorphism at position 129 not ebellar disorders with dementia in >180 patients rang-
only modulates the age of onset of some inherited prion ing in age from 10 to 41 years. These patients received
diseases but can also determine the clinical phenotype. injections of hGH every 24 days for 412 years. If it is
The nding that homozygosity at codon 129 predis- thought that these patients developed CJD from injec-
poses to sCJD supports a model of prion production that tions of prion-contaminated hGH preparations, the pos-
favors PrP interactions between homologous proteins. sible incubation periods range from 4 to 30 years. Only
Substitution of the basic residue lysine at position 218 recombinant hGH is now used therapeutically so that
in mouse PrP produced dominant-negative inhibition possible contamination with prions is no longer an issue.
of prion replication in transgenic mice. This same lysine Four cases of CJD have occurred in women receiving
at position 219 in human PrP has been found in 12% human pituitary gonadotropin.
554 VARIANT CJD gray matter of brains infected with CJD prions. Astro-
cytic processes lled with glial laments form extensive
The restricted geographic occurrence and chronol- networks.
ogy of vCJD raised the possibility that BSE prions had Amyloid plaques have been found in 10% of CJD
been transmitted to humans through the consump- cases. Puried CJD prions from humans and animals
tion of tainted beef. More than 190 cases of vCJD have exhibit the ultrastructural and histochemical character-
occurred, with >90% of these in Britain. vCJD has also istics of amyloid when treated with detergents during
been reported in people either living in or originat- limited proteolysis. In rst passage from some human
ing from France, Ireland, Italy, Netherlands, Portugal, Japanese CJD cases, amyloid plaques have been found in
Spain, Saudi Arabia, United States, Canada, and Japan. mouse brains. These plaques stain with antibodies raised
The steady decline in the number of vCJD cases over against PrP.
the past decade argues that there will not be a prion dis- The amyloid plaques of GSS disease are morphologi-
ease epidemic in Europe, similar to those seen for BSE cally distinct from those seen in kuru or scrapie. GSS
and kuru. What is certain is that prion-tainted meat plaques consist of a central dense core of amyloid sur-
should be prevented from entering the human food rounded by smaller globules of amyloid. Ultrastruc-
supply. turally, they consist of a radiating brillar network of
The most compelling evidence that vCJD is caused amyloid brils, with scant or no neuritic degeneration.
SECTION III
by BSE prions was obtained from experiments in mice The plaques can be distributed throughout the brain
expressing the bovine PrP transgene. Both BSE and but are most frequently found in the cerebellum. They
vCJD prions were efciently transmitted to these trans- are often located adjacent to blood vessels. Congophilic
genic mice and with similar incubation periods. In angiopathy has been noted in some cases of GSS disease.
contrast to sCJD prions, vCJD prions did not transmit In vCJD, a characteristic feature is the presence of
disease efciently to mice expressing a chimeric human- orid plaques. These are composed of a central core
mouse PrP transgene. Earlier studies with nontransgenic
Diseases of the Nervous System
CHAPTER 43
after the onset of clinical signs and symptoms, whereas
some live for up to 5 years. CSF, and focal white matter changes on MRI or angio-
graphic abnormalities all favor vasculitis.
Paraneoplastic conditions, particularly limbic enceph-
DIAGNOSIS alitis and cortical encephalitis, can also mimic CJD. In
The constellation of dementia, myoclonus, and peri- many of these patients, dementia appears prior to the
odic electrical bursts in an afebrile 60-year-old patient diagnosis of a tumor, and in some, no tumor is ever
Prion Diseases
generally indicates CJD. Clinical abnormalities in CJD found. Detection of the paraneoplastic antibodies is
are conned to the CNS. Fever, elevated sedimentation often the only way to distinguish these cases from CJD.
rate, leukocytosis in blood, or a pleocytosis in cerebro- Other diseases that can simulate CJD include neurosyphi-
spinal uid (CSF) should alert the physician to another lis, AIDS dementia complex (Chap. 42), progressive multi-
etiology to explain the patients CNS dysfunction. focal leukoencephalopathy (Chap. 40), subacute sclerosing
Variations in the typical course appear in inherited panencephalitis, progressive rubella panencephalitis, herpes
and transmitted forms of the disease. fCJD has an earlier simplex encephalitis (Chap. 40), diffuse intracranial tumor
mean age of onset than sCJD. In GSS disease, ataxia is (gliomatosis cerebri; Chap. 37), anoxic encephalopathy,
usually a prominent and presenting feature, with demen- dialysis dementia, uremia, hepatic encephalopathy, voltage-
tia occurring late in the disease course. GSS disease typi- gated potassium channel (VGkC) autoimmune encephalop-
cally presents earlier than CJD (mean age 43 years) and athy, and lithium or bismuth intoxication.
is typically more slowly progressive than CJD; death
usually occurs within 5 years of onset. FFI is character-
ized by insomnia and dysautonomia; dementia occurs LABORATORY TESTS
only in the terminal phase of the illness. Rare sporadic
The only specic diagnostic tests for CJD and other
cases have been identied. vCJD has an unusual clinical
human prion diseases measure PrPSc. The most widely
course, with a prominent psychiatric prodrome that may
used method involves limited proteolysis that gener-
include visual hallucinations and early ataxia, while frank
ates PrP 27-30, which is detected by immunoassay after
dementia is usually a late sign of vCJD.
denaturation. The conformation-dependent immunoas-
say (CDI) is based on immunoreactive epitopes that are
exposed in PrPC but buried in PrPSc. In humans, the
DIFFERENTIAL DIAGNOSIS diagnosis of CJD can be established by brain biopsy if
Many conditions may mimic CJD supercially. Demen- PrPSc is detected. If no attempt is made to measure PrPSc,
tia with Lewy bodies (Chap. 29) is the most common but the constellation of pathologic changes frequently
disorder to be mistaken for CJD. It can present in a sub- found in CJD is seen in a brain biopsy, then the diagnosis
acute fashion with delirium, myoclonus, and extrapyra- is reasonably secure (see Neuropathology, earlier in the
midal features. Other neurodegenerative disorders (Chap. chapter). The high sensitivity and specicity of cortical
29) to consider include AD, frontotemporal dementia, ribboning and basal ganglia hyperintensity on FLAIR and
corticobasal degeneration, progressive supranuclear palsy, diffusion-weighted MRI for the diagnosis of CJD have
ceroid lipofuscinosis, and myoclonic epilepsy with Lafora greatly diminished the need for brain biopsy in patients
bodies (Chap. 26). The absence of abnormalities on dif- with suspected CJD. Because PrPSc is not uniformly dis-
fusion-weighted and uid-attenuated inversion recovery tributed throughout the CNS, the apparent absence of
556 PrPSc in a limited sample such as a biopsy does not rule neuron-specic enolase and tau occur in CJD but lack
out prion disease. At autopsy, sufcient brain samples specicity for diagnosis.
should be taken for both PrPSc immunoassay, preferably The EEG is often useful in the diagnosis of CJD,
by CDI, and immunohistochemistry of tissue sections. although only about 60% of individuals show the typi-
To establish the diagnosis of either sCJD or familial cal pattern. During the early phase of CJD, the EEG is
prion disease, sequencing the PRNP gene must be per- usually normal or shows only scattered theta activity.
formed. Finding the wild-type PRNP gene sequence In most advanced cases, repetitive, high-voltage, tri-
permits the diagnosis of sCJD if there is no history to phasic, and polyphasic sharp discharges are seen, but in
suggest infection from an exogenous source of prions. many cases their presence is transient. The presence of
The identication of a mutation in the PRNP gene these stereotyped periodic bursts of <200 ms duration,
sequence that encodes a nonconservative amino acid occurring every 12 s, makes the diagnosis of CJD very
substitution argues for familial prion disease. likely. These discharges are frequently but not always
CT may be normal or show cortical atrophy. MRI is symmetric; there may be a one-sided predominance
valuable for distinguishing sCJD from most other condi- in amplitude. As CJD progresses, normal background
tions. On FLAIR sequences and diffusion-weighted imag- rhythms become fragmentary and slower.
ing, 90% of patients show increased intensity in the basal
ganglia and cortical ribboning (Fig. 43-3). This pattern is
CARE OF CJD PATIENTS
SECTION III
CHAPTER 43
tion or produced from a transgene, have been shown ing into grafted neurons, where it initiates aggregation
to prevent prion disease when prions are introduced by of nascent -synuclein into brils that coalesce to form
a peripheral route, such as intraperitoneal inoculation. Lewy bodies.
Unfortunately, the antibodies were ineffective in mice Taken together, a wealth of data argues that all neu-
inoculated intracerebrally with prions. Several drugs, rodegenerative diseases are caused by proteins that
including pentosan polysulfate as well as porphyrin and undergo aberrant processing, which results in their
phenylhydrazine derivatives, delay the onset of disease in
Prion Diseases
assembly into amyloid brils. In each degenerative brain
animals inoculated intracerebrally with prions if the drugs disease, prion-like protein processing is responsible for
are given intracerebrally beginning soon after inoculation. the accumulation of a particular protein in an altered
state that leads to neurodegeneration. Interestingly,
once these aberrant, prion-like proteins have polym-
PRION-LIKE PROTEINS CAUSING erized into amyloid brils, they are probably inert.
OTHER NEURODEGENERATIVE Amyloid plaques containing PrPSc are a nonobligatory
DISEASES feature of prion disease in humans and animals. Further-
more, amyloid plaques in AD do not correlate with the
There is mounting evidence that prion-like changes level of dementia; however, the level of soluble (oligo-
in protein conformation underlie Alzheimers (AD), meric) A peptide does correlate with memory loss and
Parkinsons (PD), and Huntingtons (HD) diseases as other intellectual decits.
CHAPTER 44
PARANEOPLASTIC NEUROLOGIC
SYNDROMES
CHAPTER 44
a
A variety of target antigens have been identied.
Abbreviations: CRMP, collapsing response-mediator protein; SCLC, small cell lung cancer.
dyscrasias or lymphoma without evidence of inam- there is evidence that prompt tumor control improves the
matory inltrates or deposits of immunoglobulin, cryo- neurologic outcome. Therefore, the major concern of the
TABLE 44-3
ANTIBODIES TO CELL SURFACE OR SYNAPTIC ANTIGENS, SYNDROMES, AND ASSOCIATED TUMORS
ANTIBODY NEUROLOGIC SYNDROME TUMOR TYPE WHEN ASSOCIATED
a
A direct pathogenic role of these antibodies has been demonstrated.
b
Anti-VGKC-related proteins are pathogenic for some types of neuromyotonia.
c
Anti-VGCC antibodies are pathogenic for LEMS.
d
These antibodies are strongly suspected to be pathogenic.
Abbreviations: AChR, acetylcholine receptor; AMPAR, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; GABABR, gamma-
aminobutyric acid B receptor; GAD, glutamic acid decarboxylase; LEMS, Lambert-Eaton myasthenic syndrome; NMDAR, N-methyl-D-aspartate
receptor; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel.
560
A B
SECTION III
FIGURE 44-1
Antibodies to NR1/NR2 subunits of the NMDA receptor which is highly enriched in dendritic processes. Panel B
in a patient with paraneoplastic encephalitis and ovarian shows the antibody reactivity with cultures of rat hippocampal
teratoma. Panel A is a section of dentate gyrus of rat hip- neurons; the intense green immunolabeling is due to the anti-
pocampus immunolabeled (brown staining) with the patients bodies against the NR1 subunits of NMDA receptors.
antibodies. The reactivity predominates in the molecular layer,
Diseases of the Nervous System
(e.g., metastasis, infection), neuropathologic findings are onstrate a neoplasm. For example, the frequent asso-
not specific for PND. Furthermore, there are no specific ciation of Lambert-Eaton myasthenic syndrome (LEMS)
radiologic or electrophysiologic tests that are diagnostic of with SCLC should lead to a chest and abdomen CT or
PND. The presence of antineuronal antibodies (Tables 44-2 body positron emission tomography (PET) scan and, if
and 44-3) may help in the diagnosis, but only 6070% of negative, periodic tumor screening for at least 3 years
PNDs of the CNS and less than 20% of those involving the
peripheral nervous system have neuronal or neuromus-
cular antibodies that can be used as diagnostic tests.
MRI and CSF studies are important to rule out neuro-
logic complications due to the direct spread of cancer,
particularly metastatic and leptomeningeal disease. In
most PNDs the MRI findings are nonspecific. Paraneo-
plastic limbic encephalitis is usually associated with
characteristic MRI abnormalities in the mesial tempo-
ral lobes (discussed later), but similar findings can occur
with other disorders (e.g., nonparaneoplastic autoim-
mune limbic encephalitis, and human herpesvirus type
6 [HHV-6] encephalitis) (Fig. 44-2). The CSF profile of
patients with PND of the CNS or dorsal root ganglia
typically consists of mild to moderate pleocytosis (<200
mononuclear cells, predominantly lymphocytes), an
increase in the protein concentration, intrathecal synthe-
sis of IgG, and a variable presence of oligoclonal bands.
PND OF NERVE AND MUSCLE If symptoms
involve peripheral nerve, neuromuscular junction, or
muscle, the diagnosis of a specific PND is usually estab-
lished on clinical, electrophysiologic, and pathologic FIGURE 44-2
Fluid-attenuated inversion recovery sequence MRI of a
grounds. The clinical history, accompanying symptoms
patient with limbic encephalitis and LGI1 antibodies. Note
(e.g., anorexia, weight loss), and type of syndrome dic-
the abnormal hyperintensity involving the medial aspect of
tate the studies and degree of effort needed to dem-
the temporal lobes.
in combination: (1) cortical encephalitis, which may pres- 561
after the neurologic diagnosis. In contrast, the weak ent as epilepsia partialis continua; (2) limbic encephalitis,
association of polymyositis with cancer calls into ques- characterized by confusion, depression, agitation, anxi-
tion the need for repeated cancer screenings in this situ- ety, severe short-term memory decits, partial complex
ation. Serum and urine immunofixation studies should seizures, and sometimes dementia (the MRI usually
be considered in patients with peripheral neuropathy of shows unilateral or bilateral medial temporal lobe abnor-
unknown cause; detection of a monoclonal gammopa- malities, best seen with T2 and uid-attenuated inver-
thy suggests the need for additional studies to uncover sion recovery sequences, and occasionally enhancing
a B cell or plasma cell malignancy. In paraneoplastic with gadolinium); (3) brainstem encephalitis, resulting in
neuropathies, diagnostically useful antineuronal anti- eye movement disorders (nystagmus, opsoclonus, supra-
bodies are limited to anti-CV2/CRMP5 and anti-Hu. nuclear or nuclear paresis), cranial nerve paresis, dysar-
For any type of PND, if antineuronal antibodies are thria, dysphagia, and central autonomic dysfunction;
negative, the diagnosis relies on the demonstration (4) cerebellar gait and limb ataxia; (5) myelitis, which may
of cancer and the exclusion of other cancer-related or cause lower or upper motor neuron symptoms, myoc-
independent neurologic disorders. Combined CT and lonus, muscle rigidity, and spasms; and (6) autonomic
PET scans often uncover tumors undetected by other dysfunction as a result of involvement of the neuraxis at
tests. For germ-cell tumors of the testis and teratomas multiple levels, including hypothalamus, brainstem, and
CHAPTER 44
of the ovary ultrasound and MRI may reveal tumors autonomic nerves (see autonomic neuropathy). Cardiac
undetectable by PET. arrhythmias, postural hypotension, or central hypoven-
tilation are frequent causes of death in patients with
encephalomyelitis.
Paraneoplastic encephalomyelitis and focal encepha-
SPECIFIC PARANEOPLASTIC litis are usually associated with SCLC, but many other
NEUROLOGIC SYNDROMES
A B C
FIGURE 44-3
MRI and tumor of a patient with anti-Ma2-associated brainstem. Panel C corresponds to a section of the patients
encephalitis. Panels A and B are uid-attenuated inversion orchiectomy incubated with a specic marker (Oct4) of germ-
recovery MRI sequences showing abnormal hyperintensi- cell tumors. The positive (brown) cells correspond to an intra-
ties in the medial temporal lobes, hypothalamus, and upper tubular germ-cell neoplasm.
562 women, who develop acute limbic dysfunction or less
TREATMENT Encephalomyelitis and Focal Encephalitis frequently prominent psychiatric symptoms; 70% of the
patients have an underlying tumor in the lung, breast, or
Most types of paraneoplastic encephalitis and encepha-
thymus. The neurologic disorder responds to treatment
lomyelitis respond poorly to treatment. Stabilization
of the tumor and immunotherapy. Neurologic relapses
of symptoms or partial neurologic improvement may
may occur; these also respond to immunotherapy and are
occasionally occur, particularly if there is a satisfac-
not necessarily associated with tumor recurrence.
tory response of the tumor to treatment. The roles of
Encephalitis with -aminobutyric acid type B (GABAB)
plasma exchange, intravenous immunoglobulin (IVIg),
receptor antibodies usually presents with limbic encepha-
and immunosuppression have not been established.
litis and seizures; 50% of the patients have SCLC or a
Approximately 30% of patients with anti-Ma2-associated
neuroendocrine tumor of the lung. Neurologic symp-
encephalitis respond to treatment of the tumor (usually
toms often respond to immunotherapy and treatment
a germ-cell neoplasm of the testis) and immunotherapy.
of the tumor if found. Patients may have additional
antibodies to glutamic acid decarboxylase (GAD), of
ENCEPHALITIDES WITH ANTIBODIES TO unclear signicance. Other antibodies to nonneuronal
CELL-SURFACE OR SYNAPTIC PROTEINS proteins are often found in these patients as well as in
(TABLE 44-3) patients with AMPA receptor antibodies, indicating a
SECTION III
CHAPTER 44
and dementia also occur. The tumors most frequently lower trunk and legs, but it can affect the upper extremi-
involved in anti-Ri-associated syndromes are breast and ties and neck. Symptoms improve with sleep and general
ovarian cancer. If the tumor is not successfully treated, anesthetics. Electrophysiologic studies demonstrate con-
the neurologic syndrome in adults often progresses to tinuous motor unit activity. Antibodies associated with the
encephalopathy, coma, and death. In addition to treating stiff-person syndrome target proteins (GAD, amphiphysin)
the tumor, symptoms may respond to immunotherapy involved in the function of inhibitory synapses utilizing
(glucocorticoids, plasma exchange, and/or IVIg). -aminobutyric acid (GABA) or glycine as neurotransmit-
plasma exchange is not proved. metric or asymmetric distal axonal sensorimotor neurop-
athy with variable proximal weakness. It predominantly
affects elderly men and is associated with an elevated
erythrocyte sedimentation rate and increased CSF pro-
PARANEOPLASTIC PERIPHERAL tein concentration. SCLC and lymphoma are the pri-
NEUROPATHIES mary tumors involved. Glucocorticoids and cyclophos-
Diseases of the Nervous System
CHAPTER 44
POLYMYOSITIS-DERMATOMYOSITIS Patients develop acute onset of night blindness and
shimmering, ickering, or pulsating photopsias that often
Polymyositis and dermatomyositis are discussed in detail progress to visual loss. The ERG shows reduced b waves
in Chap. 49. with normal dark adapted a waves. Paraneoplastic optic
neuritis and uveitis are very uncommon and can develop
in association with encephalomyelitis. Some patients
ACUTE NECROTIZING MYOPATHY
PERIPHERAL NEUROPATHY
Peripheral nerves are composed of sensory, motor, and usually identify the category of pathology that is pres-
autonomic elements. Diseases can affect the cell body of ent (Table 45-2). Despite an extensive evaluation,
a neuron or its peripheral processes, namely the axons in approximately half of patients no etiology is ever
or the encasing myelin sheaths. Most peripheral nerves found; these patients typically have a predominately
are mixed and contain sensory and motor as well as sensory polyneuropathy and have been labeled as hav-
autonomic bers. Nerves can be subdivided into three ing idiopathic or cryptogenic sensory polyneuropathy
major classes: large myelinated, small myelinated, and (CSPN).
small unmyelinated. Motor axons are usually large
myelinated bers that conduct rapidly (approximately
50 m/s). Sensory bers may be any of the three types. INFORMATION FROM THE HISTORY AND
Large-diameter sensory bers conduct proprioception PHYSICAL EXAMINATION: SEVEN KEY
and vibratory sensat ion to the brain, while the smaller- QUESTIONS (TABLE 45-1)
diameter myelinated and unmyelinated bers transmit 1. What systems are involved?
pain and temperature sensation. Autonomic nerves are
also small in diameter. Thus, peripheral neuropathies It is important to determine if the patients symptoms
can impair sensory, motor, or autonomic function, and signs are motor, sensory, autonomic, or a combina-
either singly or in combination. Peripheral neuropa- tion of these. If the patient has only weakness without
thies are further classied into those that primarily affect any evidence of sensory or autonomic dysfunction, a
the cell body (e.g., neuronopathy or ganglionopathy), motor neuropathy, neuromuscular junction abnormal-
myelin (myelinopathy), and the axon (axonopathy). ity, or myopathy should be considered. Some peripheral
These different classes of peripheral neuropathies have neuropathies are associated with signicant autonomic
distinct clinical and electrophysiologic features. This nervous system dysfunction. Symptoms of autonomic
chapter discusses the clinical approach to a patient sus- involvement include fainting spells or orthostatic light-
pected of having a peripheral neuropathy, as well as headedness; heat intolerance; or any bowel, bladder, or
specic neuropathies, including hereditary and acquired sexual dysfunction (Chap. 33). There will typically be
neuropathies. The inammatory neuropathies are dis- an orthostatic fall in blood pressure without an appro-
cussed in Chap. 46. priate increase in heart rate. Autonomic dysfunction
in the absence of diabetes should alert the clinician to
the possibility of amyloid polyneuropathy. Rarely, a
pandysautonomic syndrome can be the only manifesta-
GENERAL APPROACH tion of a peripheral neuropathy without other motor or
sensory ndings. The majority of neuropathies are pre-
In approaching a patient with a neuropathy, the clini- dominantly sensory in nature.
cian has three main goals: (1) identify where the lesion
is, (2) identify the cause, and (3) determine the proper
2. What is the distribution of weakness?
treatment. The rst goal is accomplished by obtaining
a thorough history, neurologic examination, and elec- Delineating the pattern of weakness, if present, is
trodiagnostic and other laboratory studies (Fig. 45-1). essential for diagnosis, and in this regard two additional
While gathering this information, seven key questions questions should be answered: (1) Does the weakness
are asked (Table 45-1), the answers to which can only involve the distal extremity or is it both proximal
566
567
Patient Complaint: ? Neuropathy
Yes No
Evaluation of other
Mononeuropathy Mononeuropathy multiplex Polyneuropathy disorder or
reassurance and
follow-up
EDx EDx EDx
CHAPTER 45
form of
Decision on need CIDP
for surgery (nerve repair, Possible
transposition, or release Review history for toxins; Test for paraprotein,
nerve If chronic or If acute: GBS
procedure) test for associated if negative
biopsy Test for paraprotein, subacute: CIDP
systemic disease or
HIV, Lyme disease intoxication
Review family IVIg or
Treatment appropriate history; examine Treatment plasmapheresis;
for specific diagnosis If tests are family members; for CIDP; supportive
negative, consider Treatment appropriate genetic testing see Ch. 46 care including
for specific diagnosis
Peripheral Neuropathy
treatment for respiratory assistance
CIDP
Genetic counseling if appropriate
FIGURE 45-1
Approach to the evaluation of peripheral neuropathies. CIDP, chronic inammatory demyelinating polyradiculoneuropathy;
GBS, Guillain-Barr syndrome.
and distal? and (2) Is the weakness focal and asymmet- mononeuropathies, or multiple mononeuropathies (e.g.,
ric or is it symmetric? Symmetric proximal and distal mononeuropathy multiplex) must be considered.
weakness is the hallmark of acquired immune demy-
elinating polyneuropathies, both the acute form (acute
inammatory demyelinating polyneuropathy [AIDP] 3. What is the nature of the sensory
involvement?
also known as Guillain-Barr syndrome [GBS]) and
the chronic form (chronic inammatory demyelinat- The patient may have loss of sensation (numbness),
ing polyneuropathy [CIDP]). The importance of nd- altered sensation to touch (hyperpathia or allodynia), or
ing symmetric proximal and distal weakness in a patient uncomfortable spontaneous sensations (tingling, burn-
who presents with both motor and sensory symptoms ing, or aching) (Chap. 15). Neuropathic pain can be
cannot be overemphasized because this identies the burning, dull, and poorly localized (protopathic pain),
important subset of patients who may have a treat- presumably transmitted by polymodal C nociceptor
able acquired demyelinating neuropathic disorder (i.e., bers, or sharp and lancinating (epicritic pain), relayed
AIDP or CIDP). by A-delta bers. If pain and temperature perception
Findings of an asymmetric or multifocal pattern of are lost, while vibratory and position sense are preserved
weakness narrows the differential diagnosis. Some neu- along with muscle strength, deep tendon reexes, and
ropathic disorders may present with unilateral extremity normal nerve conduction studies, a small-ber neuropa-
weakness. In the absence of sensory symptoms and signs, thy is likely. This is important, as the most likely cause
such weakness evolving over weeks or months would of small-ber neuropathies, when one is identied, is
be worrisome for motor neuron disease (e.g., amyo- diabetes mellitus or glucose intolerance. Amyloid neu-
trophic lateral sclerosis [ALS]), but it would be impor- ropathy should be considered as well in such cases, but
tant to exclude multifocal motor neuropathy that may be most of these small-ber neuropathies remain idiopathic
treatable (Chap. 32). In a patient presenting with asym- in nature despite extensive evaluation.
metric subacute or acute sensory and motor symptoms Severe proprioceptive loss also narrows the differ-
and signs, radiculopathies, plexopathies, compressive ential diagnosis. Affected patients will note imbalance,
568 TABLE 45-1 5. What is the temporal evolution?
APPROACH TO NEUROPATHIC DISORDERS: SEVEN
KEY QUESTIONS
It is important to determine the onset, duration, and evo-
lution of symptoms and signs. Does the disease have an
1. What systems are involved?
acute (days to 4 weeks), subacute (48 weeks), or chronic
Motor, sensory, autonomic, or combinations (>8 weeks) course? Is the course monophasic, progres-
2. What is the distribution of weakness? sive, or relapsing? Most neuropathies are insidious and
Only distal versus proximal and distal slowly progressive in nature. Neuropathies with acute
Focal/asymmetric versus symmetric and subacute presentations include GBS, vasculitis, and
3. What is the nature of the sensory involvement? radiculopathies related to diabetes or Lyme disease. A
relapsing course can be present in CIDP and porphyria.
Temperature loss or burning or stabbing pain (e.g., small
ber)
Vibratory or proprioceptive loss (e.g., large ber) 6. Is there evidence for a hereditary
4. Is there evidence of upper motor neuron involvement? neuropathy?
Without sensory loss In patients with slowly progressive distal weakness
With sensory loss over many years with very little in the way of sensory
5. What is the temporal evolution? symptoms yet with signicant sensory decits on clini-
SECTION III
Acute (days to 4 weeks) cal examination, the clinician should consider a heredi-
Subacute (4 to 8 weeks) tary neuropathy (e.g., Charcot-Marie-Tooth disease or
Chronic (>8 weeks) CMT). On examination, the feet may show arch and toe
6. Is there evidence for a hereditary neuropathy? abnormalities (high or at arches, hammertoes); scoliosis
Family history of neuropathy
may be present. In suspected cases, it may be necessary
Lack of sensory symptoms despite sensory signs to perform both neurologic and electrophysiologic stud-
Diseases of the Nervous System
CHAPTER 45
tary plexopathy (HNPP, HNA), idiopathic
Pattern 5: Asymmetric distal weakness without sensory loss
With upper motor neuron ndings
Consider: motor neuron disease
Without upper motor neuron ndings
Consider: progressive muscular atrophy, juvenile monomelic amyotrophy (Hirayama disease), multifocal motor neuropa-
Peripheral Neuropathy
thy, multifocal acquired motor axonopathy
Pattern 6: Symmetric sensory loss and distal areexia with upper motor neuron ndings
Consider: Vitamin B12, vitamin E, and copper deciency with combined system degeneration with peripheral neuropathy,
hereditary leukodystrophies (e.g., adrenomyeloneuropathy)
Pattern 7: Symmetric weakness without sensory loss
With proximal and distal weakness
Consider: spinal muscular atrophy
With distal weakness
Consider: hereditary motor neuropathy (distal SMA) or atypical CMT
Pattern 8: Asymmetric proprioceptive sensory loss without weakness
Consider causes of a sensory neuronopathy (ganglionopathy):
Cancer (paraneoplastic)
Sjgrens syndrome
Idiopathic sensory neuronopathy (possible GBS variant)
Cisplatin and other chemotherapeutic agents
Vitamin B6 toxicity
HIV-related sensory neuronopathy
Pattern 9: Autonomic symptoms and signs
Consider neuropathies associated with prominent autonomic dysfunction:
Hereditary sensory and autonomic neuropathy
Amyloidosis (familial and acquired)
Diabetes mellitus
Idiopathic pandysautonomia (may be a variant of Guillain-Barr syndrome)
Porphyria
HIV-related autonomic neuropathy
Vincristine and other chemotherapeutic agents
Abbreviations: CIDP, chronic inammatory demyelinating polyneuropathy; CMT, Charcot-Marie-Tooth disease; CMV, cytomegalovirus; GBS,
Guillain-Barr syndrome; HIV, human immunodeciency virus; HNA, hereditary neuralgic amyotrophy; SMA, spinal muscular atrophy.
570 be valuable. The electrophysiologic data provides addi- further suggests an acquired demyelinating neuropathy
tional information about the distribution of the neu- (e.g., GBS or CIDP) as opposed to a hereditary demy-
ropathy that will support or refute the ndings from elinating neuropathy (e.g., CMT type 1).
the history and physical examination; it can conrm Autonomic studies are used to assess small myelinated
whether the neuropathic disorder is a mononeuropa- (A-delta) or unmyelinated (C) nerve ber involvement.
thy, multiple mononeuropathy (mononeuropathy mul- Such testing includes heart rate response to deep breath-
tiplex), radiculopathy, plexopathy, or generalized poly- ing, heart rate, and blood pressure response to both the
neuropathy. Similarly, EDx evaluation can ascertain Valsalva maneuver and tilt-table testing, and quantita-
whether the process involves only sensory bers, motor tive sudomotor axon reex testing (Chap. 33). These
bers, autonomic bers, or a combination of these. studies are particularly useful in patients who have pure
Finally, the electrophysiologic data can help distinguish small-ber neuropathy or autonomic neuropathy in
axonopathies from myelinopathies as well as axonal which routine NCS are normal.
degeneration secondary to ganglionopathies from the
more common length-dependent axonopathies.
OTHER IMPORTANT LABORATORY
NCS are most helpful in classifying a neuropathy as
INFORMATION
being due to axonal degeneration or segmental demy-
elination (Table 45-3). In general, low-amplitude In patients with generalized symmetric peripheral neu-
SECTION III
potentials with relatively preserved distal latencies, con- ropathy, a standard laboratory evaluation should include
duction velocities, and late potentials, along with bril- a complete blood count, basic chemistries including
lations on needle EMG, suggest an axonal neuropathy. serum electrolytes and tests of renal and hepatic func-
On the other hand, slow conduction velocities, pro- tion, fasting blood glucose (FBS), HbA1c, urinalysis,
longed distal latencies and late potentials, relatively pre- thyroid function tests, B12, folate, erythrocyte sedimen-
served amplitudes, and the absence of brillations on tation rate (ESR), rheumatoid factor, antinuclear anti-
Diseases of the Nervous System
needle EMG imply a primary demyelinating neuropa- bodies (ANA), serum protein electrophoresis (SPEP),
thy. The presence of nonuniform slowing of conduc- and urine for Bence Jones protein. An oral glucose
tion velocity, conduction block, or temporal dispersion tolerance test is indicated in patients with painful
TABLE 45-3
ELECTROPHYSIOLOGIC FEATURES: AXONAL DEGENERATION VS. SEGMENTAL DEMYELINATION
AXONAL DEGENERATION SEGMENTAL DEMYELINATION
Abbreviations: CB, conduction block; CMAP, compound motor action potential; EMG, electromyography; SNAP, sensory nerve action potential.
sensory neuropathies even if FBS and HbA1c are normal, (SSA) and single strand binding (SSB) in addition to the 571
as the test is abnormal in about one-third of such patients. routine ANA. To workup a possible paraneoplastic sensory
Serum and urine immunoxation electrophoresis (IFE) ganglionopathy, anti-neuronal nuclear antibodies (e.g.,
are necessary, rather than just an SPEP, in patients with a anti-Hu antibodies) should be obtained (Chap. 44). These
demyelinating neuropathy or if one suspects amyloidosis antibodies are most commonly seen in patients with small
(e.g., severe autonomic symptoms) as an IFE is more sen- cell carcinoma of the lung but are seen also in breast, ovar-
sitive at identifying a monoclonal gammopathy. A skel- ian, lymphoma, and other cancers. Importantly, the para-
etal survey should be performed in patients with acquired neoplastic neuropathy can precede the detection of the
demyelinating neuropathies and M-spikes to look for cancer, and detection of these autoantibodies should lead
osteosclerotic or lytic lesions. Patients with monoclonal to a search for malignancy.
gammopathy should also be referred to a hematologist for
consideration of a bone marrow biopsy. In addition to
the previously mentioned tests, patients with a mononeu- NERVE BIOPSIES
ropathy multiplex pattern of involvement should have a Nerve biopsies are now rarely indicated for evaluation of
vasculitis workup, including antineutrophil cytoplasmic neuropathies. The primary indication for nerve biopsy
antibodies (ANCA), cryoglobulins, hepatitis serology, is suspicion for amyloid neuropathy or vasculitis. In
Western blot for Lyme disease, HIV, and occasionally a most instances, the abnormalities present on biopsies do
CHAPTER 45
cytomegalovirus (CMV) titer. not help distinguish one form of peripheral neuropathy
There are many autoantibody panels (various anti- from another (beyond what is already apparent by clini-
ganglioside antibodies) marketed for screening routine cal examination and the NCS). Nerve biopsies should
neuropathy patients for a treatable condition. These only be done if the NCS studies are abnormal. The sural
autoantibodies have no proven clinical utility or added nerve is most commonly biopsied because it is a pure
benet beyond the information obtained from a com- sensory nerve and biopsy will not result in loss of motor
Peripheral Neuropathy
plete clinical examination and detailed EDx. A heavy function. In suspected vasculitis, a combination biopsy of
metal screen is also not necessary as a screening proce- a supercial peroneal nerve (pure sensory) and the under-
dure, unless there is a history of possible exposure or lying peroneus brevis muscle obtained from a single small
suggestive features on examination (e.g., severe painful incision increases the diagnostic yield. Tissue can be ana-
sensorimotor and autonomic neuropathy and alope- lyzed by frozen section and parafn section to assess the
ciathallium; severe painful sensorimotor neuropathy supporting structures for evidence of inammation, vas-
with or without GI disturbance and Mees linesarse- culitis, or amyloid deposition. Semithin plastic sections,
nic; wrist or nger extensor weakness and anemia with teased ber preparations, and electron microscopy are
basophilic stippling of red blood cellslead). used to assess the morphology of the nerve bers and to
In patients with suspected GBS or CIDP, a lumbar distinguish axonopathies from myelinopathies.
puncture is indicated to look for an elevated cerebral
spinal uid (CSF) protein. In idiopathic cases of GBS
and CIDP, there should not be pleocytosis in the CSF. SKIN BIOPSIES
If cells are present, one should consider HIV infection, Skin biopsies are sometimes used to diagnose a small-
Lyme disease, sarcoidosis, or lymphomatous or leuke- ber neuropathy. Following a punch biopsy of the skin
mic inltration of nerve roots. Some patients with GBS in the distal lower extremity, immunologic staining can
and CIDP have abnormal liver function tests. In these be used to measure the density of small unmyelinated
cases, it is important to also check for hepatitis B and C, bers. The density of these nerve bers is reduced in
HIV, CMV, and Epstein-Barr virus (EBV) infection. In patients with small-ber neuropathies in whom nerve
patients with an axonal GBS (by EMG/NCS) or those conduction studies and routine nerve biopsies are often
with a suspicious coinciding history (e.g., unexplained normal. This technique may allow for an objective
abdominal pain, psychiatric illness, signicant autonomic measurement in patients with mainly subjective symp-
dysfunction), it is reasonable to screen for porphyria. toms. However, it adds little to what one already knows
In patients with a severe sensory ataxia, a sensory gan- from the clinical examination and EDx.
glionopathy or neuronopathy should be considered. The
most common causes of sensory ganglionopathies are
Sjgrens syndrome and a paraneoplastic neuropathy. Neu-
ropathy can be the initial manifestation of Sjgrens syn- SPECIFIC DISORDERS
drome. Thus, one should always inquire about dry eyes
HEREDITARY NEUROPATHIES
and mouth in patients with sensory signs and symptoms.
Further, some patients can manifest sicca complex with- Charcot-Marie-Tooth (CMT) disease is the most com-
out full-blown Sjgrens syndrome. Thus, patients with mon type of hereditary neuropathy. Rather than one dis-
sensory ataxia should have an senile systemic amyloidosis ease, CMT is a syndrome of several genetically distinct
572 disorders (Table 45-4). The various subtypes of CMT CMTs, but physical and occupational therapy can be ben-
are classied according to the nerve conduction veloci- ecial as can bracing (e.g., ankle-foot orthotics for foot-
ties and predominant pathology (e.g., demyelination drop) and other orthotic devices.
or axonal degeneration), inheritance pattern (autoso-
mal dominant, recessive, or X-linked), and the specic
CMT1
mutated genes. Type 1 CMT (or CMT1) refers to inher-
ited demyelinating sensorimotor neuropathies, while CMT1 is the most common form of hereditary neu-
the axonal sensory neuropathies are classied as CMT2. ropathy, with the ratio of CMT1:CMT2 being approx-
By denition, motor conduction velocities in the arms imately 2:1. Affected individuals usually present in the
are slowed to less than 38 m/s in CMT1 and are greater rst to third decade of life with distal leg weakness (e.g.,
than 38 m/s in CMT2. However, most cases of CMT1 footdrop), although patients may remain asymptomatic
actually have motor nerve conduction velocities (NCVs) even late in life. People with CMT generally do not
between 20 and 25 m/s. CMT1 and CMT2 usually begin complain of numbness or tingling, which can be helpful
in childhood or early adult life; however, onset later in in distinguishing CMT from acquired forms of neurop-
life can occur, particularly in CMT2. Both are associated athy in which sensory symptoms usually predominate.
with autosomal dominant inheritance, with a few excep- Although usually asymptomatic in this regard, reduced
tions. CMT3 is an autosomal dominant neuropathy that sensation to all modalities is apparent on examination.
SECTION III
appears in infancy and is associated with severe demyelin- Muscle stretch reexes are unobtainable or reduced
ation or hypomyelination. CMT4 is an autosomal reces- throughout. There is often atrophy of the muscles
sive neuropathy that typically begins in childhood or early below the knee (particularly the anterior compartment),
adult life. There are no medical therapies for any of the leading to so-called inverted champagne bottle legs.
Diseases of the Nervous System
TABLE 45-4
CLASSIFICATION OF CHARCOT-MARIE-TOOTH DISEASE AND RELATED NEUROPATHIES
NAME INHERITANCE GENE LOCATION GENE PRODUCT
CMT1
CMT1A AD 17p11.2 PMP-22 (usually duplication
of gene)
CMT1B AD 1q21-23 MPZ
CMT1C AD 16p13.1-p12.3 LITAF
CMT1D AD 10q21.1-22.1 ERG2
CMT1E (with deafness) AD 17p11.2 Point mutations in
PMP 22 gene
CMT1F AD 8p13-21 Neurolament light chain
CMT1X X-linked dominant Xq13 Connexin-32
HNPP AD 17p11.2 PMP-22
1q21-23 MPZ
CMT2
CMT2A2 (allelic to HMSN VI with AD 1p36.2 MFN2
optic atrophy)
CMT2B AD 3q13-q22 RAB7
CMT2B1 (allelic to LGMD 1B) AR 1q21.2 Lamin A/C
CMT2B2 AR and AD 19q13 MED25 for AR
Unknown for AD
CMT2C (with vocal cord and AD 12q23-24 TRPV4
diaphragm paralysis)
CMT2D (allelic to distal SMA5) AD 7p14 Glycine tRNA synthetase
CMT2E (allelic to CMT 1F) AD 8p21 Neurolament light chain
CMT2F AD 7q11-q21 Heat-shock 27-kDa
protein-1
(continued)
TABLE 45-4 573
CLASSIFICATION OF CHARCOT-MARIE-TOOTH DISEASE AND RELATED NEUROPATHIES (CONTINUED)
NAME INHERITANCE GENE LOCATION GENE PRODUCT
CHAPTER 45
AR 19q13 Periaxon
CMT4
CMT4A AR 8q13-21.1 GDAP1
CMT4B1 AR AR 11q23 MTMR2
CMT4B2 11p15 MTMR13
Peripheral Neuropathy
CMT4C AR 5q23-33 SH3TC2
CMT4D AR 8q24 NDRG1
(HMSN-Lom)
CMT4E AR - Probably includes PMP22,
(Congenital hypomyelinating neuropathy) MPZ, and ERG-2
CMT4F AR 19q13.1-13.3 Periaxin
CMT4G AR 10q23.2 HKI
CMT4H AR 12q12-q13 Frabin
CMT4J AR 6q21 FIG4
HNA AD 17q24 SEPT9
HMSN-P AD 3q13-q14 ?
HSAN1 AD; 9q22 SPTLC1
Rare AR and
X-linked cases
also reported
HSAN2 AR 12p13.33 PRKWNK1
HSAN3 AR 9q21 IKAP
HSAN4 AR 3q trkA/NGF
receptor
HSAN5 AD or AR 1p11.2-p13.2 NGFb
Abbreviations: AARS, alanyl-tRNA synthetase; AD, autosomal dominant; AR, autosomal recessive; CMT, Charcot-Marie-Tooth; ERG2, early
growth response-2 protein; FIG4, FDG1-related F actinbinding protein; GDAP1, ganglioside-induced differentiation-associated protein-1; HK1,
hexokinase 1; HMSN-P, hereditary motor and sensory neuropathy-proximal; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropa-
thy with liability to pressure palsies; HSAN; hereditary sensory and autonomic neuropathy; IKAP, kB kinase complex-associated protein; LGMD,
limb girdle muscular dystrophy; LITAF, lipopolysaccharide-induced tumor necrosis factor factor; MED25, mediator 25; MFN2, mitochondrial
fusion protein mitofusin 2 gene; MPZ, myelin protein zero protein; MTMR2, myotubularin-related protein-2; NDRG1, N-myc downstream regu-
lated 1; PMP-22, peripheral myelin protein-22; PRKWNK1, protein kinase, lysine decient 1; PRPS1, phosphoribosylpyrophosphate synthetase
1; RAB7, Ras-related protein 7; SEPT9, Septin 9; SH3TC2, SH3 domain and tetratricopeptide repeats 2; SMA, spinal muscular atrophy; SPTLC1,
serine palmitoyltransferase long-chain base 1; TrkA/NGF, tyrosine kinase A/nerve growth factor; tRNA, transfer ribonucleic acid; TRPV4, transient
receptor potential cation channel, subfamily V, member 4.
Source: Modied from AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008.
574 Motor NCVs are usually in the 2025 m/s range. usually inherited in an autosomal recessive fashion.
Nerve biopsies usually are not performed on patients Electrophysiologic and histologic evaluations can show
suspected of having CMT1, as the diagnosis usually can demyelinating or axonal features. CMT4 is genetically
be made by less invasive testing (e.g., NCS and genetic heterogenic (Table 45-4).
studies). However, when done, the biopsies reveal reduc-
tion of myelinated nerve bers with a predilection for the CMT1X
loss of the large-diameter bers and Schwann cell prolif- CMT1X is an X-linked dominant disorder with clinical
eration around thinly or demyelinated bers, forming so- features similar to CMT1 and -2, except that the neu-
called onion bulbs. ropathy is much more severe in men than in women.
CMT1A is the most common subtype of CMT1, CMT1X accounts for approximately 1015% of CMT
representing 70% of cases, and is caused by a 1.5-mega- overall. Men usually present in the rst two decades of life
base (Mb) duplication within chromosome 17p11.2-12 with atrophy and weakness of the distal arms and legs, are-
wherein the gene for peripheral myelin protein-22 exia, pes cavus, and hammertoes. Obligate women carri-
(PMP-22) lies. This results in patients having three cop- ers are frequently asymptomatic, but can develop signs and
ies of the PMP-22 gene rather than two. This protein symptoms. Onset in women is usually after the second
accounts for 25% of myelin protein and is expressed decade of life, and the neuropathy is milder in severity.
in compact portions of the peripheral myelin sheath. NCS reveal features of both demyelination and axo-
SECTION III
Approximately 20% of patients with CMT1 have nal degeneration that are more severe in men compared
CMT1B, which is caused by mutations in the myelin to women. In men, motor NCVs in the arms and legs
protein zero (MPZ). CMT1B is for the most part clini- are moderately slowed (in the low to mid 30-m/s range).
cally, electrophysiologically, and histologically indis- About 50% of men with CMT1X have motor NCVs
tinguishable from CMT1A. MPZ is an integral myelin between 15 and 35 m/s with about 80% of these falling
protein and accounts for more than half of the myelin between 25 and 35 m/s (intermediate slowing). In con-
Diseases of the Nervous System
protein in peripheral nerves. Other forms of CMT1 are trast, about 80% of women with CMT1X have NCV in
much less common and again indistinguishable from the normal range and 20% had MNCV in the interme-
one another clinically and electrophysiologically. diate range. CMT1X is caused by mutations in the con-
nexin 32 gene. Connexins are gap junction structural
CMT2
proteins that are important in cell-to-cell communication.
CMT2 tends to present later in life compared to CMT1.
Affected individuals usually become symptomatic in the Hereditary neuropathy with liability to
second decade of life; some cases present earlier in child- pressure palsies (HNPP)
hood, while others remain asymptomatic into late adult HNPP is an autosomal dominant disorder related to
life. Clinically, CMT2 is for the most part indistinguish- CMT1A. While CMT1A is usually associated with a
able from CMT1. NCS are helpful in this regard; in con- 1.5-Mb duplication in chromosome 17p11.2 that results
trast to CMT1, the velocities are normal or only slightly in an extra copy of PMP-22 gene, HNPP is caused by
slowed. The most common cause of CMT2 is a mutation inheritance of the chromosome with the correspond-
in the gene for mitofusin 2 (MFN2), which accounts for ing 1.5-Mb deletion of this segment, and thus affected
one-third of CMT2 cases overall. MFN2 localizes to the individuals have only one copy of the PMP-22 gene.
outer mitochondrial membrane, where it regulates the Patients usually manifest in the second or third decade
mitochondrial network architecture by fusion of mito- of life with painless numbness and weakness in the dis-
chondria. The other genes associated with CMT2 are tribution of single peripheral nerves, although multiple
much less common. mononeuropathies can occur. Symptomatic mononeu-
ropathy or multiple mononeuropathies are often pre-
CMT3
cipitated by trivial compression of nerve(s) as can occur
CMT3 was originally described by Dejerine and Sottas as with wearing a backpack, leaning on the elbows, or
a hereditary demyelinating sensorimotor polyneuropathy crossing ones legs for even a short period of time. These
presenting in infancy or early childhood. Affected children pressure-related mononeuropathies may take weeks or
are severely weak. Motor NCVs are markedly slowed, months to resolve. In addition, some affected individu-
typically 510 m/s or less. Most cases of CMT3 are caused als manifest with a progressive or relapsing, generalized
by point mutations in the genes for PMP-22, MPZ, or and symmetric, sensorimotor peripheral neuropathy that
ERG-2, which are also the genes responsible for CMT1. resembles CMT.
CHAPTER 45
Abetalipoproteinemia (Bassen-Kornzweig disease)
thies in which sensory and autonomic dysfunction predom-
inates over muscle weakness, unlike CMT, in which motor Disorders of Defective DNA Repair
ndings are most prominent (Table 45-4). Nevertheless, Ataxia-telangiectasia
affected individuals can develop motor weakness and there Cockayne syndrome
can be overlap with CMT. There are no medical therapies Giant Axonal Neuropathy
available to treat these neuropathies, other than prevention
Peripheral Neuropathy
Porphyria
and treatment of mutilating skin and bone lesions.
Of the HSANs, only HSAN1 typically presents in Acute intermittent porphyria (AIP)
adults. The HSAN1 is the most common of the HSANs Hereditary coproporphyria (HCP)
and is inherited in an autosomal dominant fashion. Affected Variegate porphyria (VP)
individuals with HSAN1 usually manifest in the second Familial Amyloid Polyneuropathy (FAP)
through fourth decade of life. HSAN1 is associated with
Transthyretin-related
the degeneration of small myelinated and unmyelinated
nerve bers leading to severe loss of pain and temperature Gelsolin-related
sensation, deep dermal ulcerations, recurrent osteomyelitis, Apolipoprotein A1-related
Charcot joints, bone loss, gross foot and hand deformities,
and amputated digits. Although most people with HSAN1
do not complain of numbness, they often describe burning, overshadowed by complications arising from the asso-
aching, or lancinating pains. Autonomic neuropathy is not ciated premature atherosclerosis (e.g., hypertension,
a prominent feature, but bladder dysfunction and reduced renal failure, cardiac disease, and stroke) that often lead
sweating in the feet may occur. HSAN1A is caused by to death by the fth decade of life. Some patients also
mutations in the serine palmitoyltransferase long-chain base manifest primarily with a dilated cardiomyopathy.
1 (SPTLC1) gene. Fabry disease is caused by mutations in the -gala-
ctosidase gene that leads to the accumulation of
ceramide trihexoside in nerves and blood vessels. A
OTHER HEREDITARY NEUROPATHIES decrease in -galactosidase activity is evident in leuko-
(TABLE 45-5) cytes and cultured broblasts. Glycolipid granules may
be appreciated in ganglion cells of the peripheral and
FABRY DISEASE sympathetic nervous systems and in perineurial cells.
Fabry disease (angiokeratoma corporis diffusum) is an Enzyme replacement therapy with -galactosidase B
X-linked dominant disorder. While men are more can improve the neuropathy if patients are treated early,
commonly and severely affected, women can also show before irreversible nerve ber loss.
severe signs of the disease. Angiokeratomas are reddish-
purple maculopapular lesions that are usually found
ADRENOLEUKODYSTROPHY/
around the umbilicus, scrotum, inguinal region, and
ADRENOMYELONEUROPATHY
perineum. Burning or lancinating pain in the hands
and feet often develops in males in late childhood or Adrenoleukodystrophy (ALD) and adrenomyeloneu-
early adult life. However, the neuropathy is usually ropathy (AMN) are allelic X-linked dominant disorders
576 caused by mutations in the peroxisomal transmem- phytanic precursors (phytols: sh oils, dairy products,
brane adenosine triphosphate-binding cassette (ABC) and ruminant fats) from the diet.
transporter gene. Patients with ALD manifest with
CNS abnormalities. However, 30% with mutations in
this gene present with the AMN phenotype that typi- TANGIER DISEASE
cally manifests in the third to fth decade of life with Tangier disease is a rare autosomal recessive disorder
mild to moderate peripheral neuropathy combined with that can present as (1) asymmetric multiple mononeu-
progressive spastic paraplegia (Chap. 35). Rare patients ropathies, (2) a slowly progressive symmetric polyneu-
present with an adult-onset spinocerebellar ataxia or ropathy predominantly in the legs, or (3) a pseudo-
only with adrenal insufciency. syringomyelia pattern with dissociated sensory loss
EDx is suggestive of a primary axonopathy with sec- (i.e., abnormal pain/temperature perception but pre-
ondary demyelination. Nerve biopsies demonstrate a loss served position/vibration in the arms [Chap. 35]).
of myelinated and unmyelinated nerve bers with lamel- The tonsils may appear swollen and yellowish-orange
lar inclusions in the cytoplasm of Schwann cells. Very in color, while there may also be splenomegaly and
long chain fatty acid (VLCFA) levels (C24, C25, and lymphadenopathy.
C26) are increased in the urine. Laboratory evidence of Tangier disease is caused by mutations in the ATP-
adrenal insufciency is evident in approximately two- binding cassette transporter 1 (ABC1) gene, which leads
SECTION III
thirds of patients. The diagnosis can be conrmed by to markedly reduced levels of high-density lipoprotein
genetic testing. (HDL) cholesterol levels while triacylglycerol levels
Adrenal insufciency is managed by replacement are increased. Nerve biopsies reveal axonal degenera-
therapy; however, there is no proven effective therapy tion with demyelination and remyelination. Electron
for the neurologic manifestations of ALD/AMN. Diets microscopy demonstrates abnormal accumulation of
low in VLCFAs and supplemented with Lorenzos oil lipid in Schwann cells, particularly those encompassing
Diseases of the Nervous System
(erucic and oleic acids) reduce the levels of VLCFAs umyelinated and small myelinated nerves. There is no
and increase the levels of C22 in serum, broblasts, and specic treatment.
liver; however, several large, open-label trials of Loren-
zos oil failed to demonstrate efcacy.
PORPHYRIA
Porphyria is a group of inherited disorders caused by
defects in heme biosynthesis. Three forms of porphyria
REFSUM DISEASE
are associated with peripheral neuropathy: acute inter-
Refsum disease can manifest in infancy to early adult- mittent porphyria (AIP), hereditary coproporphyria
hood with the classic tetrad of (1) peripheral neuropathy, (HCP), and variegate porphyria (VP). The acute neuro-
(2) retinitis pigmentosa, (3) cerebellar ataxia, and (4) ele- logic manifestations are similar in each, with the excep-
vated CSF protein concentration. Most affected individu- tion that a photosensitive rash is seen with HCP and VP
als develop progressive distal sensory loss and weakness in but not in AIP. Attacks of porphyria can be precipitated
the legs leading to footdrop by their 20s. Subsequently, by certain drugs (usually those metabolized by the P450
the proximal leg and arm muscles may become weak. system), hormonal changes (e.g., pregnancy, menstrual
Patients may also develop sensorineural hearing loss, car- cycle), and dietary restrictions.
diac conduction abnormalities, ichthyosis, and anosmia. An acute attack of porphyria may begin with sharp
Serum phytanic acid levels are elevated. Sensory and abdominal pain. Subsequently, patients may develop
motor NCS reveal reduced amplitudes, prolonged laten- agitation, hallucinations, or seizures. Several days later,
cies, and slowed conduction velocities. Nerve biopsy back and extremity pain followed by weakness ensues,
demonstrates a loss of myelinated nerve bers, with mimicking GBS. Weakness can involve the arms or the
remaining axons often thinly myelinated and associated legs and can be asymmetric, proximal, or distal in distri-
with onion bulb formation. bution, as well as affecting the face and bulbar muscu-
Refsum disease is genetically heterogeneous but lature. Dysautonomia and signs of sympathetic overac-
autosomal recessive in nature. Classical Refsum dis- tivity are common (e.g., pupillary dilation, tachycardia,
ease with childhood or early adult onset is caused by and hypertension). Constipation, urinary retention, and
mutations in the gene that encodes for phytanoyl-CoA incontinence can also be seen.
-hydroxylase (PAHX). Less commonly, mutations in The CSF protein is typically normal or mildly elevated.
the gene encoding peroxin 7 receptor protein (PRX 7) Liver function tests and hematologic parameters are usu-
are responsible. These mutations lead to the accumula- ally normal. Some patients are hyponatremic due to inap-
tion of phytanic acid in the central and peripheral ner- propriate secretion of antidiuretic hormone. The urine
vous systems. Refsum disease is treated by removing may appear brownish in color secondary to the high
concentration of porphyrin metabolites. Accumulation of from systemic complications of amyloidosis (e.g., renal 577
intermediary precursors of heme (i.e., -aminolevulinic failure) 1215 years after the onset of the neuropathy.
acid, porphobilinogen, uroporphobilinogen, copropor- Gelsolin-related amyloidosis (Finnish type) is charac-
phyrinogen, and protoporphyrinogen) are found in urine. terized by the combination of lattice corneal dystrophy
Specic enzyme activities can also be measured in erythro- and multiple cranial neuropathies that usually begin in
cytes and leukocytes. The primary abnormalities on EDx the third decade of life. Over time, a mild generalized
are marked reductions in CMAP amplitudes and signs of sensorimotor polyneuropathy develops. Autonomic dys-
active axonal degeneration on needle EMG. function does not occur.
The porphyrias are inherited in an autosomal domi-
nant fashion. AIP is associated with porphobilinogen
deaminase deciency, HCP is caused by defects in cop-
roporphyrin oxidase, and VP is associated with proto- ACQUIRED NEUROPATHIES
porphyrinogen oxidase deciency. The pathogenesis of
the neuropathy is not completely understood. Treat- PRIMARY OR AL AMYLOIDOSIS
ment with glucose and hematin may reduce the accu- Besides FAP, amyloidosis can also be acquired. In pri-
mulation of heme precursors. Intravenous glucose is mary or AL amyloidosis, the abnormal protein deposition
started at a rate of 1020 g/h. If there is no improve-
CHAPTER 45
is composed of immunoglobulin light chains. AL amyloi-
ment within 24 h, intravenous hematin 25 mg/kg per dosis occurs in the setting of multiple myeloma, Walden-
day for 314 days should be given. strms macroglobulinemia, lymphoma, other plasmacy-
tomas, or lymphoproliferative disorders, or without any
other identiable disease.
FAMILIAL AMYLOID POLYNEUROPATHY Approximately 30% of patients with AL primary amy-
loidosis present with a polyneuropathy, most typically
Peripheral Neuropathy
Familial amyloid polyneuropathy (FAP) is phenotypically
painful dysesthesias and burning sensations in the feet.
and genetically heterogeneous and is caused by mutations
However, the trunk can be involved and some manifest
in the genes for transthyretin (TTR), apolipoprotein
with a mononeuropathy multiplex pattern. CTS occurs in
A1, or gelsolin. The majority of patients with FAP have
25% of patients and may be the initial manifestation. The
mutations in the TTR gene. Amyloid deposition may
neuropathy is slowly progressive, and eventually weakness
be evident in abdominal fat pad, rectal, or nerve biop-
develops along with large-ber sensory loss. Most patients
sies. The clinical features, histopathology, and EDx reveal
develop autonomic involvement with postural hyperten-
abnormalities consistent with a generalized or multifocal,
sion, syncope, bowel and bladder incontinence, constipa-
predominantly axonal but occasionally demyelinating,
tion, impotence, and impaired sweating. Patients generally
sensorimotor polyneuropathy.
die from their systemic illness (renal failure, cardiac disease).
Patients with TTR-related FAP usually develop
The monoclonal protein may be composed of IgG,
insidious onset of numbness and painful paresthesias in
IgA, IgM, or only free light chain. Lambda () is more
the distal lower limbs in the third to fourth decade of
common than light chain (>2:1) in AL amyloidosis. The
life, although some patients develop the disorder later
CSF protein is often increased (with normal cell count),
in life. Carpal tunnel syndrome (CTS) is common.
and thus the neuropathy may be mistaken for CIDP
Autonomic involvement can be severe, leading to pos-
(Chap. 46). Nerve biopsies reveal axonal degeneration
tural hypotension, constipation or persistent diarrhea,
and amyloid deposition in either a globular or diffuse pat-
erectile dysfunction, and impaired sweating. Amyloid
tern inltrating the perineurial, epineurial, and endoneurial
deposition also occurs in the heart, kidneys, liver, and
connected tissue and in blood vessel walls.
the corneas. Patients usually die 1015 years after the
The median survival of patients with primary amyloi-
onset of symptoms from cardiac failure or complications
dosis is less than 2 years, with death usually from progres-
from malnutrition. Because the liver produces much of
sive congestive heart failure or renal failure. Chemotherapy
the bodys TTR, liver transplantation has been used to
with melphalan, prednisone, and colchicine, to reduce the
treat FAP related to TTR mutations. Serum TTR lev-
concentration of monoclonal proteins, and autologous
els decrease after transplantation, and improvement in
stem cell transplantation may prolong survival, but whether
clinical and EDx features have been reported.
the neuropathy improves is controversial.
Patients with apolipoprotein A1related FAP (Van
Allen type) usually present in the fourth decade with
numbness and painful dysesthesias in the distal limbs.
DIABETIC NEUROPATHY
Gradually, the symptoms progress, leading to proximal
and distal weakness and atrophy. Although autonomic Diabetes mellitus (DM) is the most common cause of
neuropathy is not severe, some patients develop diar- peripheral neuropathy in developed countries. DM
rhea, constipation, or gastroparesis. Most patients die is associated with several types of polyneuropathy:
578 distal symmetric sensory or sensorimotor polyneuropathy, usually show reduced amplitudes and mild to moder-
autonomic neuropathy, diabetic neuropathic cachexia, ate slowing of conduction velocities (CVs). Nerve biopsy
polyradiculoneuropathies, cranial neuropathies, and other reveals axonal degeneration, endothelial hyperplasia, and,
mononeuropathies. Risk factors for the development of occasionally, perivascular inammation. Tight control of
neuropathy include long-standing, poorly controlled DM glucose can reduce the risk of developing neuropathy or
and the presence of retinopathy and nephropathy. improve the underlying neuropathy. A variety of medica-
tions have been used with variable success to treat painful
Diabetic distal symmetric sensory and symptoms associated with DSPN, including antiepileptic
sensorimotor polyneuropathy (DSPN) medications, antidepressants, sodium channel blockers, and
other analgesics (Table 45-6).
DSPN is the most common form of diabetic neuropathy
and manifests as sensory loss beginning in the toes that
Diabetic autonomic neuropathy
gradually progresses over time up the legs and into the n-
gers and arms. When severe, a patient may develop sen- Autonomic neuropathy is typically seen in combina-
sory loss in the trunk (chest and abdomen), initially in the tion with DSPN. The autonomic neuropathy can mani-
midline anteriorly and later extending laterally. Tingling, fest as abnormal sweating, dysfunctional thermoregula-
burning, deep aching pains may also be apparent. NCS tion, dry eyes and mouth, pupillary abnormalities, cardiac
SECTION III
TABLE 45-6
TREATMENT OF PAINFUL SENSORY NEUROPATHIES
THERAPY ROUTE DOSE SIDE EFFECTS
First-Line
Diseases of the Nervous System
Source: Modied from AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008.
arrhythmias, postural hypotension, gastrointestinal abnor- neuropathy, most typically carpal tunnel syndrome. 579
malities (e.g., gastroparesis, postprandial bloating, chronic Rarely, a generalized sensory polyneuropathy character-
diarrhea or constipation), and genitourinary dysfunc- ized by painful paresthesias and numbness in both the
tion (e.g., impotence, retrograde ejaculation, inconti- legs and hands can occur. Treatment is correction of the
nence). Tests of autonomic function are generally abnor- hypothyroidism.
mal, including sympathetic skin responses and quantitative
sudomotor axon reex testing. Sensory and motor NCS
generally demonstrate features described earlier with SJGRENS SYNDROME
DSPN. Sjgrens syndrome, characterized by the sicca complex of
xerophthalmia, xerostomia, and dryness of other mucous
Diabetic radiculoplexus neuropathy (diabetic membranes, can be complicated by neuropathy. Most
amyotrophy or Bruns-Garland syndrome) common is a length-dependent axonal sensorimotor neu-
Diabetic radiculoplexus neuropathy is the presenting mani- ropathy characterized mainly by sensory loss in the distal
festation of DM in approximately one-third of patients. extremities. A pure small-ber neuropathy or a cranial
Typically, patients present with severe pain in the low neuropathy, particularly involving the trigeminal nerve,
back, hip, and thigh in one leg. Rarely, the diabetic poly- can also be seen. Sjgrens syndrome is also associated
with sensory neuronopathy/ganglionopathy. Patients with
CHAPTER 45
radiculoneuropathy begins in both legs at the same time.
Atrophy and weakness of proximal and distal muscles in sensory ganglionopathies develop progressive numbness
the affected leg become apparent within a few days or and tingling of the limbs, trunk, and face in a non-length-
weeks. The neuropathy is often accompanied or heralded dependent manner such that symptoms can involve the
by severe weight loss. Weakness usually progresses over face or arms more than the legs. The onset can be acute or
several weeks or months, but can continue to progress for insidious. Sensory examination demonstrates severe vibra-
18 months or more. Subsequently, there is slow recovery tory and proprioceptive loss leading to sensory ataxia.
Peripheral Neuropathy
but many are left with residual weakness, sensory loss, and Patients with neuropathy due to Sjgrens syndrome
pain. In contrast to the more typical lumbosacral radiculo- may have antinuclear antibodies (ANA), SS-A/Ro, and
plexus neuropathy, some patients develop thoracic radicu- SS-B/La antibodies in the serum but most do not. NCS
lopathy or, even less commonly, a cervical polyradiculo- demonstrate reduced amplitudes of sensory studies in the
neuropathy. CSF protein is usually elevated, while the affected limbs. Nerve biopsy demonstrates axonal degen-
cell count is normal. ESR is often increased. EDx reveals eration. Nonspecic perivascular inammation may be
evidence of active denervation in affected proximal and present, but only rarely is there necrotizing vasculitis.
distal muscles in the affected limbs and in paraspinal mus- There is no specic treatment for neuropathies related to
cles. Nerve biopsies may demonstrate axonal degeneration Sjgrens syndrome. When vasculitis is suspected, immu-
along with perivascular inammation. Patients with severe nosuppressive agents may be benecial. Occasionally,
pain are sometimes treated in the acute period with gluco- the sensory neuronopathy/ganglionopathy stabilizes or
corticoids, although a randomized controlled trial has yet improves with immunotherapy, such as IVIg.
to be performed, and the natural history of this neuropathy
is gradual improvement. RHEUMATOID ARTHRITIS
Diabetic mononeuropathies or multiple Peripheral neuropathy occurs in at least 50% of patients
mononeuropathies with rheumatoid arthritis (RA) and may be vasculitic in
nature. Vasculitic neuropathy can present with a mono-
The most common mononeuropathies are median neu-
neuropathy multiplex, a generalized symmetric pattern of
ropathy at the wrist and ulnar neuropathy at the elbow,
involvement, or a combination of these patterns. Neuropa-
but peroneal neuropathy at the bular head, and sci-
thies may also be due to drugs used to treat the RA (e.g.,
atic, lateral femoral, cutaneous, or cranial neuropathies
tumor necrosis blockers, leunomide). Nerve biopsy often
also occur. In regard to cranial mononeuropathies, sev-
reveals thickening of the epineurial and endoneurial blood
enth nerve palsies are relatively common but may have
vessels as well as perivascular inammation or vasculitis,
other, nondiabetic etiologies. In diabetics, a third nerve
with transmural inammatory cell inltration and brinoid
palsy is most common, followed by sixth nerve, and,
necrosis of vessel walls. The neuropathy often is responsive
less frequently, fourth nerve palsies. Diabetic third nerve
to immunomodulating therapies.
palsies are characteristically pupil-sparing (Chap. 21).
CHAPTER 45
ness leading to admission to a medical intensive care unit Patients are generally treated with multiple drugs: dap-
(ICU) are GBS and myasthenia gravis (Chap. 47). How- sone, rifampin, and clofazimine. Other medications that
ever, weakness developing in critically ill patients while in are employed include thalidomide, peoxacin, ooxacin,
the ICU is usually caused by critical illness polyneuropa- sparoxacin, minocycline, and clarithromycin. Patients
thy (CIP) or critical illness myopathy (CIM), or much less are generally treated for 2 years. Treatment is some-
commonly, by prolonged neuromuscular blockade. From times complicated by the so-called reversal reaction, par-
Peripheral Neuropathy
a clinical and EDx standpoint, it can be quite difcult to ticularly in borderline leprosy. The reversal reaction can
distinguish these disorders. Most specialists suggest that occur at any time during treatment and develops because
CIM is more common. Both CIM and CIP develop as of a shift to the tuberculoid end of the spectrum, with an
a complication of sepsis and multiple organ failure. They increase in cellular immunity during treatment. The cel-
usually present as an inability to wean a patient from a lular response is upregulated as evidenced by an increased
ventilator. A coexisting encephalopathy may limit the release of tumor necrosis factor , interferon , and
neurologic exam, in particular the sensory examination. interleukin 2, with new granuloma formation. This can
Muscle stretch reexes are absent or reduced. result in an exacerbation of the rash and the neuropathy
Serum creatine kinase (CK) is usually normal; an as well as in appearance of new lesions. High-dose glu-
elevated serum CK would point to CIM as opposed to cocorticoids blunt this adverse reaction and may be used
CIP. NCS reveal absent or markedly reduced ampli- prophylactically at treatment onset in high-risk patients.
tudes of motor and sensory studies in CIP, while sen- Erythema nodosum leprosum (ENL) is also treated with
sory studies are relatively preserved in CIM. Needle glucocorticoids or thalidomide.
EMG usually reveals profuse positive sharp waves and
brillation potentials, and it is not unusual in patients
with severe weakness to be unable to recruit motor unit LYME DISEASE
action potentials. The pathogenic basis of CIP is not Lyme disease is caused by infection with Borrelia burg-
known. Perhaps circulating toxins and metabolic abnor- dorferi, a spirochete usually transmitted by the deer tick
malities associated with sepsis and multiorgan failure Ixodes dammini. Neurologic complications may develop
impair axonal transport or mitochondrial function, lead- during the second and third stages of infection. Facial
ing to axonal degeneration. neuropathy is most common and is bilateral in about
half of cases, which is rare for idiopathic Bells palsy.
LEPROSY (HANSEN DISEASE) Involvement of nerves is frequently asymmetric. Some
patients present with a polyradiculoneuropathy or mul-
Leprosy, caused by the acid-fast bacteria Mycobacterium tiple mononeuropathies. EDx is suggestive of a primary
leprae, is the most common cause of peripheral neu- axonopathy. Nerve biopsies can reveal axonal degenera-
ropathy in Southeast Asia, Africa, and South America. tion with perivascular inammation. Treatment is with
Clinical manifestations range from tuberculoid leprosy at antibiotics.
one end to lepromatous leprosy at the other end of the
spectrum, with borderline leprosy in between. Neu-
DIPHTHERITIC NEUROPATHY
ropathies are most common in patients with borderline
leprosy. Supercial cutaneous nerves of the ears and dis- Diphtheria is caused by the bacteria Corynebacterium diph-
tal limbs are commonly affected. Mononeuropathies, theriae. Infected individuals present with ulike symptoms
582 of generalized myalgias, headache, fatigue, low-grade HIV-related inammatory demyelinating
fever, and irritability within a week to 10 days of the polyradiculoneuropathy
exposure. About 2070% of patients develop a periph-
Both AIDP and CIDP can occur as a complication of
eral neuropathy caused by a toxin released by the bacte-
HIV infection. AIDP usually develops at the time of
ria. Three to 4 weeks after infection, patients may note
seroconversion, while CIDP can occur any time in the
decreased sensation in their throat and begin to develop
course of the infection. Clinical and EDx features are
dysphagia, dysarthria, hoarseness, and blurred vision due
indistinguishable from idiopathic AIDP or CIDP (dis-
to impaired accommodation. A generalized polyneu-
cussed in next chapter). In addition to elevated protein
ropathy may manifest 2 or 3 months following the initial
levels, lymphocytic pleocytosis is evident in the CSF, a
infection, characterized by numbness, paresthesias, and
nding that helps distinguish this HIV-associated poly-
weakness of the arms and legs and occasionally ventila-
radiculoneuropathy from idiopathic AIDP/CIDP.
tory failure. CSF protein can be elevated with or without
lymphocytic pleocytosis. EDx suggests a diffuse axonal
sensorimotor polyneuropathy. Antitoxin and antibiotics HIV-related progressive polyradiculopathy
should be given within 48 h of symptom onset. Although
An acute, progressive lumbosacral polyradiculoneuropa-
early treatment reduces the incidence and severity of
thy usually secondary to cytomegalovirus (CMV) infec-
some complications (i.e., cardiomyopathy), it does
tion can develop in patients with AIDS. Patients present
SECTION III
antiviral therapy.
HIV infection can result in a variety of neurologic com-
plications, including peripheral neuropathies. Approxi-
mately 20% of HIV-infected individuals develop a neu- HIV-related multiple mononeuropathies
ropathy either as a direct result of the virus itself, other Multiple mononeuropathies can also develop in patients
associated viral infections (e.g., cytomegalovirus), or with HIV infection, usually in the context of AIDS.
neurotoxicity secondary to antiviral medications (dis- Weakness, numbness, paresthesias, and pain occur in the
cussed later). The major presentations of peripheral distribution of affected nerves. Nerve biopsies can reveal
neuropathy associated with HIV infection include (1) axonal degeneration with necrotizing vasculitis or peri-
distal symmetric polyneuropathy (DSP), (2) inamma- vascular inammation. Glucocorticoid treatment is indi-
tory demyelinating polyneuropathy (including both cated for vasculitis directly due to HIV infection.
GBS and CIDP), (3) multiple mononeuropathies (e.g.,
vasculitis, CMV-related), (4) polyradiculopathy (usually
CMV-related), (5) autonomic neuropathy, and (6) sen- HIV-related sensory neuronopathy/
sory ganglionitis. ganglionopathy
Dorsal root ganglionitis is a very rare complication of
HIV infection, and neuronopathy can be the presenting
HIV-related distal symmetric manifestation. Patients develop sensory ataxia similar to
polyneuropathy (DSP) idiopathic sensory neuronopathy/ganglionopathy. NCS
DSP is the most common form of peripheral neuropa- reveal reduced amplitudes or absence of SNAPs.
thy associated with HIV infection and usually is seen in
patients with AIDS. It is characterized by numbness and
painful paresthesias involving the distal extremities. The HERPES VARICELLA-ZOSTER VIRUS
pathogenic basis for DSP is unknown but is not due to Peripheral neuropathy from herpes varicella-zoster
actual infection of the peripheral nerves. The neuropathy (HVZ) infection results from reactivation of latent virus
may be immune mediated, perhaps caused by the release or from a primary infection. Two-thirds of infections
of cytokines from surrounding inammatory cells. Vita- in adults are characterized by dermal zoster in which
min B12 deciency may contribute in some instances but severe pain and paresthesias develop in a dermatomal
is not a major cause of most cases of DSP. Some anti- region followed within a week or two by a vesicu-
retroviral agents (e.g., dideoxycytidine, dideoxyinosine, lar rash in the same distribution. Weakness in muscles
stavudine) are also neurotoxic and can cause a painful innervated by roots corresponding to the dermatomal
sensory neuropathy. distribution of skin lesions occurs in 530% of patients.
Approximately 25% of affected patients have continued hallucinations or seizures, or cerebellar ataxia. Polyclonal 583
pain (postherpetic neuralgia, or PHN). A large clini- antineuronal antibodies (IgG) directed against a 35- to
cal trial demonstrated that vaccination against zoster 40-kD protein or complex of proteins, the so-called Hu
reduces the incidence of HZ among vaccine recipients antigen, are found in the sera or CSF in the majority of
by 51% and reduces the incidence of PHN by 67%. patients with paraneoplastic PEM/SN. CSF may be nor-
Treatment of postherpetic neuralgia is symptomatic mal or may demonstrate mild lymphocytic pleocytosis
(Table 45-6). and elevated protein. PEM/SN is probably the result of
antigenic similarity between proteins expressed in the
tumor cells and neuronal cells, leading to an immune
CYTOMEGALOVIRUS response directed against both cell types. Treatment of
the underlying cancer generally does not affect the course
CMV can cause an acute lumbosacral polyradiculopathy
of PEM/SN. However, occasional patients may improve
and multiple mononeuropathies in patients with HIV
following treatment of the tumor. Unfortunately, plasma-
infection and in other immune deciency conditions.
pheresis, intravenous immunoglobulin, and immunosup-
pressive agents have not shown benet.
EPSTEIN-BARR VIRUS
CHAPTER 45
Epstein-Barr virus (EBV) infection has been associated NEUROPATHY SECONDARY TO TUMOR
with GBS, cranial neuropathies, mononeuropathy mul- INFILTRATION
tiplex, brachial plexopathy, lumbosacral radiculoplexop- Malignant cells, in particular leukemia and lymphoma,
athy, and sensory neuronopathies. can inltrate cranial and peripheral nerves, leading to
mononeuropathy, mononeuropathy multiplex, polyra-
diculopathy, plexopathy, or even a generalized symmetric
Peripheral Neuropathy
HEPATITIS VIRUSES distal or proximal and distal polyneuropathy. Neuropa-
Hepatitis B and C can cause multiple mononeuropa- thy related to tumor inltration is often painful; it can be
thies related to vasculitis, AIDP, or CIDP. the presenting manifestation of the cancer or the herald-
ing symptom of a relapse. The neuropathy may improve
with treatment of the underlying leukemia or lymphoma
or with glucocorticoids.
NEUROPATHIES ASSOCIATED WITH
MALIGNANCY
NEUROPATHY AS A COMPLICATION OF
Patients with malignancy can develop neuropathies
BONE MARROW TRANSPLANTATION
due to (1) a direct effect of the cancer by invasion or
compression of the nerves, (2) remote or paraneoplastic Neuropathies may develop in patients who undergo
effect, (3) a toxic effect of treatment, or (4) as a con- bone marrow transplantation (BMT) because of the
sequence of immune compromise caused by immuno- toxic effects of chemotherapy, radiation, infection, or
suppressive medications. The most common associated an autoimmune response directed against the peripheral
malignancy is lung cancer, but neuropathies also com- nerves. Peripheral neuropathy in BMT is often associ-
plicate carcinoma of the breast, ovaries, stomach, colon, ated with graft-versus-host disease (GVHD). Chronic
rectum, and other organs, including the lymphoprolif- GVHD shares many features with a variety of auto-
erative system. immune disorders, and it is possible that an immune-
mediated response directed against peripheral nerves is
responsible. Patients with chronic GVHD may develop
PARANEOPLASTIC SENSORY cranial neuropathies, sensorimotor polyneuropathies,
NEURONOPATHY/GANGLIONOPATHY multiple mononeuropathies, and severe generalized
Paraneoplastic encephalomyelitis/sensory neuronopathy peripheral neuropathies resembling AIDP or CIDP.
(PEM/SN) usually complicates small cell lung carcinoma The neuropathy may improve by increasing the inten-
(Chap. 44). Patients usually present with numbness and sity of immunosuppressive or immunomodulating ther-
paresthesias in the distal extremities that are often asym- apy and resolution of the GVHD.
metric. The onset can be acute or insidiously progres-
sive. Prominent loss of proprioception leads to sensory
LYMPHOMA
ataxia. Weakness can be present, usually secondary to an
associated myelitis, motor neuronopathy, or concurrent Lymphomas may cause neuropathy by inltration or
Lambert-Eaton myasthenic syndrome (LEMS). Many direct compression of nerves or by a paraneoplastic pro-
patients also develop confusion, memory loss, depression, cess. The neuropathy can be purely sensory or motor,
584 but most commonly is sensorimotor. The pattern of composed of or heavy chains or light chains, may
involvement may be symmetric, asymmetric, or multi- be identied in the serum or urine. EDx usually shows
focal, and the course may be acute, gradually progres- reduced amplitudes with normal or only mildly abnormal
sive, or relapsing and remitting. EDx can be compatible distal latencies and conduction velocities. A superimposed
with either an axonal or demyelinating process. CSF median neuropathy at the wrist is common. Abdominal
may reveal lymphocytic pleocytosis and an elevated fat pad, rectal, or sural nerve biopsy can be performed to
protein. Nerve biopsy may demonstrate endoneurial look for amyloid deposition. Unfortunately, the treat-
inammatory cells in both the inltrative and the para- ment of the underlying MM does not usually affect the
neoplastic etiologies. A monoclonal population of cells course of the neuropathy.
favors lymphomatous invasion. The neuropathy may
respond to treatment of the underlying lymphoma or
immunomodulating therapies. NEUROPATHIES ASSOCIATED WITH
MONOCLONAL GAMMOPATHY OF
MULTIPLE MYELOMA UNCERTAIN SIGNIFICANCE (SEE CHAP. 33)
Toxic neuropathies secondary to
Multiple myeloma (MM) usually presents in the fth to
chemotherapy
seventh decade of life with fatigue, bone pain, anemia,
SECTION III
and hypercalcemia. Clinical and EDx features of neu- Many of the commonly used chemotherapy agents can
ropathy occur in as many as 40% of patients. The most cause a toxic neuropathy (Table 45-7). The mechanisms
common pattern is that of a distal, axonal, sensory, or by which these agents cause toxic neuropathies vary as
sensorimotor polyneuropathy. Less frequently, a chronic can the specic type of neuropathy produced. The risk
demyelinating polyradiculoneuropathy may develop (see of developing a toxic neuropathy or more severe neurop-
POEMS, Chap. 46). MM can be complicated by amy- athy appears to be greater in patients with a preexisting
Diseases of the Nervous System
loid polyneuropathy and should be considered in patients neuropathy (e.g., Charcot-Marie-Tooth disease, diabetic
with painful paresthesias, loss of pinprick and temperature neuropathy) and those who also take other potentially
discrimination, and autonomic dysfunction (suggestive neurotoxic drugs (e.g., nitrofurantoin, isoniazid, disul-
of a small-ber neuropathy) and carpal tunnel syndrome. ram, pyridoxine). Chemotherapeutic agents usually cause
Expanding plasmacytomas can compress cranial nerves a sensory greater than motor length-dependent axonal
and spinal roots as well. A monoclonal protein, usually neuropathy or neuronopathy/ganglionopathy.
TABLE 45-7
TOXIC NEUROPATHIES SECONDARY TO CHEMOTHERAPY
MECHANISM OF NERVE
DRUG NEUROTOXICITY CLINICAL FEATURES HISTOPATHOLOGY EMG/NCS
Vinca alkaloids Interfere with axonal Symmetric, S-M, Axonal degeneration Axonal sensorimotor
(vincristine, vin- microtubule assembly; large-/small-ber of myelinated and PN; distal denervation
blastine, vindesine, impairs axonal trans- PN; autonomic unmyelinated bers; on EMG; abnormal
vinorelbine) port symptoms common; regenerating clusters, QST, particularly vibra-
infrequent cranial minimal segmental tory perception
neuropathies demyelination
Cisplatin Preferential damage to Predominant large- Loss of large > small Low-amplitude or unob-
dorsal root ganglia: ber sensory neu- myelinated and unmy- tainable SNAPs with
?binds to and cross- ronopathy; sensory elinated bers; axonal normal CMAPs and
links DNA ataxia degeneration with small EMG; abnormal QST,
?inhibits protein syn- clusters of regenerating particularly vibratory
thesis bers; secondary seg- perception
?impairs axonal transport mental demyelination
Taxanes (paclitaxel, Promotes axonal Symmetric, predomi- Loss of large > small Axonal sensorimotor
docetaxel) microtubule assembly; nantly sensory, PN; myelinated and PN; distal denervation
interferes with axonal large-ber modalities unmyelinated bers; on EMG; abnormal
transport affected more than axonal degeneration QST, particularly vibra-
small-ber with small clusters of tory perception
regenerating bers;
secondary segmental
demyelination
(continued)
TABLE 45-7 585
TOXIC NEUROPATHIES SECONDARY TO CHEMOTHERAPY (CONTINUED)
MECHANISM OF NERVE
DRUG NEUROTOXICITY CLINICAL FEATURES HISTOPATHOLOGY EMG/NCS
CHAPTER 45
cell inltrates poral dispersion)
Ara-C Unknown; GBS-like syndrome; Loss of myelinated Axonal, demyelinat-
?selective Schwann pure sensory neu- nerve bers; axonal ing, or mixed S-M PN;
cell toxicity; ropathy; brachial degeneration; segmen- denervation on EMG
?immunomodulating plexopathy tal demyelination; no
effects inammation
Etoposide (VP-16) Unknown; Length-dependent, None described Abnormalities consistent
Peripheral Neuropathy
?selective dorsal root sensory predominant with an axonal S-M PN
ganglia toxicity PN; autonomic neu-
ropathy
Bortezomib (Vel- Unknown Length-dependent, Not reported Abnormalities consistent
cade) sensory, predomi- with an axonal sensory
nantly small-ber, PN neuropathy with early
small-ber involvement
(abnormal autonomic
studies)
Abbreviations: CSF, cerebrospinal uid; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barr syndrome; NCS, nerve con-
duction studies; PN, polyneuropathy; QST, quantitative sensory testing; S-M, sensorimotor.
Source: From AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008.
OTHER TOXIC NEUROPATHIES to the superimposed myopathy. NCS reveal mild slow-
ing of motor and sensory nerve conduction velocities
Neuropathies can develop as complications of toxic with a mild to moderate reduction in the amplitudes,
effects of various drugs and other environmental expo- although NCS may be normal in patients with only
sures (Table 45-8). The more common neuropathies the myopathy. EMG demonstrates myopathic muscle
associated with these agents are discussed here. action potentials (MUAPs), increased insertional activity
in the form of positive sharp waves, brillation poten-
tials, and occasionally myotonic potentials, particu-
CHLOROQUINE AND
larly in the proximal muscles. Neurogenic MUAPs and
HYDROXYCHLOROQUINE
reduced recruitment are found in more distal muscles.
Chloroquine and hydroxychloroquine can cause a toxic Nerve biopsy demonstrates autophagic vacuoles within
myopathy characterized by slowly progressive, pain- Schwann cells. Vacuoles may also be evident in muscle
less, proximal weakness and atrophy, which is worse biopsies. The pathogenic basis of the neuropathy is not
in the legs than the arms. In addition, neuropathy can known but may be related to the amphiphilic proper-
also develop with or without the myopathy leading to ties of the drug. These agents contain both hydropho-
sensory loss and distal weakness. The neuromyopa- bic and hydrophilic regions that allow them to interact
thy usually appears in patients taking 500 mg daily for with the anionic phospholipids of cell membranes and
a year or more but has been reported with doses as low organelles. The drug-lipid complexes may be resis-
as 200 mg/d. Serum CK levels are usually elevated due tant to digestion by lysosomal enzymes, leading to the
586 TABLE 45-8
TOXIC NEUROPATHIES
MECHANISM OF NERVE
DRUG NEUROTOXICITY CLINICAL FEATURES HISTOPATHOLOGY EMG/NCS
Chloroquine and Amphiphilic properties Loss of large- and Axonal degeneration Low-amplitude or unobtain-
hydroxychloro- may lead to drug-lipid small-ber sensory with autophagic able SNAPs with normal
quine complexes that are modalities and distal vacuoles in nerves or reduced CMAPs ampli-
indigestible and result weakness in length- as well as muscle tudes; distal denervation on
in accumulation of dependent pattern; bers EMG; irritability and
autophagic vacuoles superimposed myopa- myopathic-appearing
Diseases of the Nervous System
CHAPTER 45
weakness that may reveal degenera- reduced CMAPs amplitudes
resemble GBS tion of dorsal root
ganglia and anterior
horn cells
Pyridoxine (vita- Unknown Dysesthesias and sen- Marked loss of sen- Reduced amplitudes or
min B6) sory ataxia; impaired sory axons and cell absent SNAPs
large-ber sensory bodies in dorsal root
Peripheral Neuropathy
modalities on exami- ganglia
nation
Isoniazid Inhibits pyridoxal Dysesthesias and sen- Marked loss of sen- Reduced amplitudes or
phosphokinase lead- sory ataxia; impaired sory axons and cell absent SNAPs and to lesser
ing to pyridoxine de- large-ber sensory bodies in dorsal root extent CMAPs
ciency modalities on ganglia and degen-
examination eration of the dorsal
columns
Ethambutol Unknown Numbness with loss of Axonal degeneration Reduced amplitudes or
large-ber modalities absent SNAPs
on examination
Antinucleosides Unknown Dysesthesia and sen- Axonal degeneration Reduced amplitudes or
sory ataxia; impaired absent SNAPs
large-ber sensory
modalities on exami-
nation
Phenytoin Unknown Numbness with loss of Axonal degenera- Low-amplitude or unobtain-
large-ber modalities tion and segmental able SNAPs with normal or
on examination demyelination reduced CMAPs amplitudes
Lithium Unknown Numbness with loss of Axonal degeneration Low-amplitude or unobtain-
large-ber modalities able SNAPs with normal or
on examination reduced CMAPs amplitudes
Acrylamide Unknown; may be Numbness with loss of Degeneration of sen- Low-amplitude or unobtain-
caused by impaired large-ber modalities sory axons in periph- able SNAPs with normal or
axonal transport on examination; sen- eral nerves and reduced CMAPs amplitudes
sory ataxia; mild distal posterior columns,
weakness spinocerebellar
tracts, mammillary
bodies, optic tracts,
and corticospinal
tracts in the CNS
588 TABLE 45-8
TOXIC NEUROPATHIES (CONTINUED)
MECHANISM OF NERVE
DRUG NEUROTOXICITY CLINICAL FEATURES HISTOPATHOLOGY EMG/NCS
PN ensues
Hexacarbons Unknown; may lead to Acute, severe senso- Axonal degenera- Features of a mixed axonal
covalent cross-linking rimotor PN that may tion and giant axons and/or demyelinating senso-
between neurola- resemble GBS swollen with neuro- rimotor axonal PNreduced
ments laments amplitudes, prolonged distal
latencies, conduction block,
and slowing of CVs
Diseases of the Nervous System
Lead Unknown; may inter- Encephalopathy; motor Axonal degeneration Reduction of CMAP ampli-
fere with mitochondria neuropathy (often of motor axons tudes with active denerva-
resembles radial neu- tion on EMG
ropathy with wrist and
nger drop); autonomic
neuropathy; bluish-
black discoloration of
gums
Mercury Unknown; may com- Abdominal pain and Axonal degenera- Low-amplitude or unobtain-
bine with sulfhydryl nephrotic syndrome; tion; degeneration of able SNAPs with normal or
groups encephalopathy; dorsal root ganglia, reduced CMAPs amplitudes
ataxia; paresthesias calcarine, and cer-
ebellar cortex
Thallium Unknown Encephalopathy; pain- Axonal degeneration Low-amplitude or unobtain-
ful sensory symptoms; able SNAPs with normal or
mild loss of vibration; reduced CMAPs amplitudes
distal or generalized
weakness may also
develop; autonomic
neuropathy; alopecia
Arsenic Unknown; may com- Abdominal discomfort, Axonal degeneration Low-amplitude or unobtain-
bine with sulfhydryl burning pain and par- able SNAPs with normal or
groups esthesias; generalized reduced CMAPs amplitudes;
weakness; autonomic may have demyelinating fea-
insufciency; can tures: prolonged distal laten-
resemble GBS cies and slowing of CVs
Gold Unknown Distal paresthesias and Axonal degeneration Low-amplitude or unobtain-
reduction of all sensory able SNAPs
modalities
Abbreviations: CMAP, compound motor action potential; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barr syndrome;
MUAP, muscle action potential; NCS, nerve conduction studies; PN, polyneuropathy; S-M, sensorimotor; SNAP, sensory nerve action potential.
Source: From AA Amato, J Russell: Neuromuscular Disease. New York, McGraw-Hill, 2008.
formation of autophagic vacuoles lled with myeloid at high doses (116 mg/d), patients can develop a severe 589
debris that may in turn cause degeneration of nerves sensory neuropathy with dysesthesias and sensory ataxia.
and muscle bers. The signs and symptoms of the neu- NCS reveal absent or markedly reduced SNAP ampli-
ropathy and myopathy are usually reversible following tudes with relatively preserved CMAPs. Nerve biopsy
discontinuation of medication. reveals axonal loss of ber at all diameters. Loss of dor-
sal root ganglion cells with subsequent degeneration of
both the peripheral and central sensory tracts have been
AMIODARONE reported in animal models.
Amiodarone can cause a neuromyopathy similar to
chloroquine and hydroxychloroquine. The neuromy-
opathy typically appears after patients have taken the ISONIAZID
medication for 23 years. Nerve biopsy demonstrates One of the most common side effects of isonia-
a combination of segmental demyelination and axo- zid (INH) is peripheral neuropathy. Standard doses of
nal loss. Electron microscopy reveals lamellar or dense INH (35 mg/kg per d) are associated with a 2% inci-
inclusions in Schwann cells, pericytes, and endothelial dence of neuropathy, while neuropathy develops in at
cells. The inclusions in muscle and nerve biopsies have least 17% of patients taking in excess of 6 mg/kg per
persisted as long as 2 years following discontinuation of d. The elderly, malnourished, and slow acetylators are
CHAPTER 45
the medication. at increased risk for developing the neuropathy. INH
inhibits pyridoxal phosphokinase, resulting in pyridox-
ine deciency and the neuropathy. Prophylactic admin-
COLCHICINE istration of pyridoxine 100 mg/d can prevent the neu-
Colchicine can also cause a neuromyopathy. Patients ropathy from developing.
usually present with proximal weakness and numb-
Peripheral Neuropathy
ness and tingling in the distal extremities. EDx reveals
features of an axonal polyneuropathy. Muscle biopsy ANTIRETROVIRAL AGENTS
reveals a vacuolar myopathy, while sensory nerves dem- The nucleoside analogues zalcitabine (dideoxycytidine
onstrate axonal degeneration. Colchicine inhibits the or ddC), didanosine (dideoxyinosine or ddI), stavudine
polymerization of tubulin into microtubules. The dis- (d4T), lamivudine (3TC), and antiretroviral nucleoside
ruption of the microtubules probably leads to defective reverse transcriptase inhibitor (NRTI) are used to treat
intracellular movement of important proteins, nutrients, HIV infection. One of the major dose-limiting side
and waste products in muscle and nerves. effects of these medications is a predominantly sensory,
length-dependent, symmetrically painful neuropathy.
Zalcitabine (ddC) is the most extensively studied of the
THALIDOMIDE
nucleoside analogues and at doses greater than 0.18 mg/
Thalidomide is an immunomodulating agent used to kg per d is associated with a subacute onset of severe
treat multiple myeloma, GVHD, leprosy, and other burning and lancinating pains in the feet and hands.
autoimmune disorders. Thalidomide is associated with NCS reveal decreased amplitudes of the SNAPs with
severe teratogenic effects as well as peripheral neu- normal motor studies. The nucleoside analogues inhibit
ropathy that can be dose-limiting. Patients develop mitochondrial DNA polymerase, which is the sus-
numbness, painful tingling, and burning discomfort in pected pathogenic basis for the neuropathy. Because
the feet and hands and less commonly muscle weak- of a coasting effect, patients can continue to worsen
ness and atrophy. Even after stopping the drug for 46 even 23 weeks after stopping the medication. Follow-
years, as many as 50% patients continue to have signi- ing dose reduction, improvement in the neuropathy is
cant symptoms. NCS demonstrate reduced amplitudes seen in most patients after several months (mean time
or complete absence of sensory nerve action potentials about 10 weeks).
(SNAPs), with preserved conduction velocities when
obtainable. Motor NCS are usually normal. Nerve
biopsy reveals a loss of large-diameter myelinated bers HEXACARBONS (n-HEXANE, METHYL
and axonal degeneration. Degeneration of dorsal root n-BUTYL KETONE)/GLUE SNIFFERS
ganglion cells has been reported at autopsy. NEUROPATHY
n-Hexane and methyl n-butyl ketone are water-insol-
uble industrial organic solvents that are also present in
PYRIDOXINE (VITAMIN B6) TOXICITY
some glues. Exposure through inhalation, accidentally
Pyridoxine is an essential vitamin that serves as a coen- or intentionally (glue snifng), or through skin absorp-
zyme for transamination and decarboxylation. However, tion can lead to a profound subacute sensory and motor
590 polyneuropathy. NCS demonstrate decreased ampli- feet, abdominal pain, and vomiting. Increased thirst,
tudes of the SNAPs and CMAPs with slightly slow sleep disturbances, and psychotic behavior may be
CVs. Nerve biopsy reveals a loss of myelinated bers noted. Within the rst week, patients develop pigmen-
and giant axons that are lled with 10-nm neurola- tation of the hair, an acne-like rash in the malar area
ments. Hexacarbon exposure leads to covalent cross- of the face, and hyperreexia. By the second and third
linking between axonal neurolaments that result in week, autonomic instability with labile heart rate and
their aggregation, impaired axonal transport, swelling of blood pressure may be seen. Hyporeexia and alope-
the axons, and eventual axonal degeneration. cia also occur but may not be evident until the third or
fourth week following exposure. With severe intoxica-
tion, proximal weakness and involvement of the cranial
LEAD nerves can occur. Some patients require mechani-
Lead neuropathy is uncommon, but it can be seen in cal ventilation due to respiratory muscle involvement.
children who accidentally ingest lead-based paints in The lethal dose of thallium is variable, ranging from 8
older buildings and in industrial workers exposed to to 15 mg/kg body weight. Death can result in less than
lead-containing products. The most common presenta- 48 h following a particularly large dose. NCS demon-
tion of lead poisoning is an encephalopathy; however, strate features of a primarily axonal sensorimotor poly-
symptoms and signs of a primarily motor neuropa- neuropathy. With acute intoxication, potassium ferric
SECTION III
thy can also occur. The neuropathy is characterized by ferrocyanide II may be effective in preventing absorp-
an insidious and progressive onset of weakness usu- tion of thallium from the gut. However, there may be
ally beginning in the arms, in particular involving the no benet once thallium has been absorbed. Unfortu-
wrist and nger extensors, resembling a radial neu- nately, chelating agents are not very efcacious. Ade-
ropathy. Sensation is generally preserved; however, the quate diuresis is essential to help eliminate thallium
autonomic nervous system can be affected. Laboratory from the body without increasing tissue availability
Diseases of the Nervous System
CHAPTER 45
This typically occurs in older individuals and results from ned cereal grains, wheat germ, yeast, soybean our, and
an inability to adequately absorb cobalamin in food pro- pork. Beriberi means I cant, I cant in Singhalese, the
tein. No apparent cause of deciency is identied in a language of natives of what was once part of the Dutch
signicant number of patients with cobalamin deciency. East Indies (now Sri Lanka). Dry beriberi refers to neuro-
The use of nitrous oxide as an anesthetic agent or from pathic symptoms. The term wet beriberi is used when car-
recreational use can produce acute cobalamin deciency diac manifestations predominate (in reference to edema).
Peripheral Neuropathy
neuropathy and subacute combined degeneration. Beriberi was relatively uncommon until the late 1800s
Complaints of numb hands typically appear before when it became widespread among people for whom
lower extremity paresthesias are noted. A preferential rice was a dietary mainstay. This epidemic was due to a
large-ber sensory loss affecting proprioception and new technique of processing rice that removed the germ
vibration with sparing of small-ber modalities is pres- from the rice shaft, rendering the so-called polished rice
ent; an unsteady gait reects sensory ataxia. These fea- decient in thiamine and other essential nutrients.
tures, coupled with diffuse hyperreexia and absent Symptoms of neuropathy follow prolonged de-
Achilles reexes, should always focus attention on the ciency. These begin with mild sensory loss and/or
possibility of cobalamin deciency. Optic atrophy and, burning dysesthesias in the toes and feet and aching and
in severe cases, behavioral changes ranging from mild cramping in the lower legs. Pain may be the predomi-
irritability and forgetfulness to severe dementia and nant symptom. With progression, patients develop fea-
frank psychosis may appear. The full clinical picture of tures of a nonspecic generalized polyneuropathy, with
subacute combined degeneration is uncommon. CNS distal sensory loss in the feet and hands.
manifestations, especially pyramidal tract signs, may Blood and urine assays for thiamine are not reli-
be missing, and in fact some patients may only exhibit able for diagnosis of deciency. Erythrocyte transketo-
symptoms of peripheral neuropathy. lase activity and the percentage increase in activity (in
EDx shows an axonal sensorimotor neuropathy. vitro) following the addition of thiamine pyrophosphate
CNS involvement produces abnormal somatosensory (TPP) may be more accurate and reliable. EDx shows
and visual evoked potential latencies. The diagnosis is nonspecic ndings of an axonal sensorimotor poly-
conrmed by nding reduced serum cobalamin levels. neuropathy. When a diagnosis of thiamine deciency
In up to 40% of patients, anemia and macrocytosis are is made or suspected, thiamine replacement should be
lacking. Serum methylmalonic acid and homocyste- provided until proper nutrition is restored. Thiamine is
ine, the metabolites that accumulate when cobalamin- usually given intravenously or intramuscularly at a dose
dependent reactions are blocked, are elevated. Antibod- of 100 mg/d. Although cardiac manifestations show a
ies to intrinsic factor are present in approximately 60%, striking response to thiamine replacement, neurologic
and antiparietal cell antibodies in about 90%, of individ- improvement is usually more variable and less dramatic.
uals with pernicious anemia.
Cobalamin deciency can be treated with various
regimens of cobalamin. One typical regimen consists of
1000 g cyanocobalamin IM weekly for 1 month and
VITAMIN E DEFICIENCY
monthly thereafter. Patients with food cobalamin mal- The term vitamin E is usually used for -tocopherol, the
absorption can absorb free cobalamin and therefore can most active of the four main types of vitamin E. Because
be treated with oral cobalamin supplementation. An oral vitamin E is present in animal fat, vegetable oils, and
592 various grains, deciency is usually due to factors other essentially been eradicated in most Western countries by
than insufcient intake. Vitamin E deciency usually means of enriching bread with niacin. Nevertheless, pel-
occurs secondary to lipid malabsorption or in uncommon lagra continues to be a problem in a number of under-
disorders of vitamin E transport. One hereditary disorder developed regions, particularly in Asia and Africa, where
is abetalipoproteinemia, a rare autosomal dominant disor- corn is the main source of carbohydrate. Neurologic
der characterized by steatorrhea, pigmentary retinopathy, manifestations are variable; abnormalities can develop
acanthocytosis, and progressive ataxia. Patients with cys- in the brain and spinal cord as well as peripheral nerves.
tic brosis may also have vitamin E deciency secondary When peripheral nerves are involved, the neuropathy is
to steatorrhea. There are genetic forms of isolated vita- usually mild and resembles beriberi. Treatment is with
min E deciency not associated with lipid malabsorption. niacin 40250 mg/d.
Vitamin E deciency may also occur as a consequence of
various cholestatic and hepatobiliary disorders as well as
short-bowel syndromes resulting from the surgical treat- COPPER DEFICIENCY
ment of intestinal disorders. A syndrome that has only recently been described is
Clinical features may not appear until many years after myeloneuropathy secondary to copper deciency. Most
the onset of deciency. The onset of symptoms tends to patients present with lower limb paresthesias, weakness,
be insidious, and progression is slow. The main clinical spasticity, and gait difculties. Large-ber sensory func-
SECTION III
features are spinocerebellar ataxia and polyneuropathy, tion is impaired, reexes are brisk, and plantar responses
thus resembling Friedreich ataxia or other spinocerebel- are extensor. In some cases, light touch and pinprick
lar ataxias. Patients manifest progressive ataxia and signs of sensation are affected, and nerve conduction studies
posterior column dysfunction, such as impaired joint posi- indicate sensorimotor axonal polyneuropathy in addi-
tion and vibratory sensation. Because of the polyneurop- tion to myelopathy.
athy, there is hyporeexia, but plantar responses may be Hematologic abnormalities are a known complication
Diseases of the Nervous System
extensor as a result of the spinal cord involvement. Other of copper deciency; these can include microcytic ane-
neurologic manifestations may include ophthalmoplegia, mia, neutropenia, and occasionally pancytopenia. Because
pigmented retinopathy, night blindness, dysarthria, pseu- copper is absorbed in the stomach and proximal jejunum,
doathetosis, dystonia, and tremor. Vitamin E deciency many cases of copper deciency are in the setting of prior
may present as an isolated polyneuropathy, but this is gastric surgery. Excess zinc is an established cause of cop-
very rare. The yield of checking serum vitamin E levels per deciency. Zinc upregulates enterocyte production
in patients with isolated polyneuropathy is extremely low, of metallothionine, which results in decreased absorption
and this test should not be part of routine practice. of copper. Excessive dietary zinc supplements or den-
Diagnosis is made by measuring -tocopherol levels ture cream containing zinc can produce this clinical pic-
in the serum. EDx shows features of an axonal neuropa- ture. Other potential causes of copper deciency include
thy. Treatment is replacement with oral vitamin E, but malnutrition, prematurity, total parenteral nutrition, and
high doses are not needed. For patients with isolated ingestion of copper chelating agents.
vitamin E deciency, treatment consists of 15006000 Following oral or IV copper replacement, some
IU/d in divided doses. patients show neurologic improvement, but this may
take many months or not occur at all. Replacement
VITAMIN B6 DEFICIENCY consists of oral copper sulfate or gluconate 2 mg one
to three times a day. If oral copper replacement is not
Vitamin B6, or pyridoxine, can produce neuropathic
effective, elemental copper in the copper sulfate or cop-
manifestations from both deciency and toxicity. Vita-
per chloride forms can be given as 2 mg IV daily for
min B6 toxicity was discussed earlier. Vitamin B6 de-
35 days, then weekly for 12 months until copper lev-
ciency is most commonly seen in patients treated with
els normalize. Thereafter, oral daily copper therapy can
isoniazid or hydralazine. The polyneuropathy of vitamin
be resumed. In contrast to the neurologic manifesta-
B6 is nonspecic, manifesting as a generalized axonal
tions, most of the hematologic indices completely nor-
sensorimotor polyneuropathy. Vitamin B6 deciency can
malize in response to copper replacement therapy.
be detected by direct assay. Vitamin B6 supplementation
with 50100 mg/d is suggested for patients being treated
with isoniazid or hydralazine. This same dose is appro- NEUROPATHY ASSOCIATED WITH
priate for replacement in cases of nutritional deciency. GASTRIC SURGERY
Polyneuropathy may occur following gastric surgery for
PELLAGRA (NIACIN DEFICIENCY)
ulcer, cancer, or weight reduction. This usually occurs
Pellagra is produced by deciency of niacin. Although in the context of rapid, signicant weight loss and recur-
pellagra may be seen in alcoholics, this disorder has rent, protracted vomiting. The clinical picture is one of
acute or subacute sensory loss and weakness. Neuropathy sensory symptoms and signs progressing proximally up to 593
following weight loss surgery usually occurs in the rst the knees and elbows. The disorder does not lead to sig-
several months after surgery. Weight reduction surgical nicant motor disability over time. The relatively benign
procedures include gastrojejunostomy, gastric stapling, course of this disorder should be explained to patients.
vertical banded gastroplasty, and gastrectomy with Roux-
en-Y anastomosis. The initial manifestations are usually
numbness and paresthesias in the feet. In many cases, no
specic nutritional deciency factor is identied. MONONEUROPATHIES/PLEXOPATHIES/
Management consists of parenteral vitamin supple- RADICULOPATHIES
mentation, especially including thiamine. Improvement
has been observed following supplementation, parenteral MEDIAN NEUROPATHY
nutritional support, and reversal of the surgical bypass. CTS is a compression of the median nerve in the carpal
The duration and severity of decits before identication tunnel at the wrist. The median nerve enters the hand
and treatment of neuropathy are important predictors of through the carpal tunnel by coursing under the trans-
nal outcome. verse carpal ligament. The symptoms of CTS consist of
numbness and paresthesias variably in the thumb, index,
middle, and half of the ring nger. At times, the pares-
CHAPTER 45
thesias can include the entire hand and extend into the
CRYPTOGENIC (IDIOPATHIC) forearm or upper arm or can be isolated to one or two
SENSORY AND SENSORIMOTOR ngers. Pain is another common symptom and can be
POLYNEUROPATHY located in the hand and forearm and, at times, in the
proximal arm. CTS is common and often misdiagnosed
CSPN is a diagnosis of exclusion, established after a as thoracic outlet syndrome. The signs of CTS are
Peripheral Neuropathy
careful medical, family, and social history; neurologic decreased sensation in the median nerve distribution;
examination; and directed laboratory testing. Despite reproduction of the sensation of tingling when a per-
extensive evaluation, the cause of polyneuropathy in as cussion hammer is tapped over the wrist (Tinels sign)
many as 50% of all patients is idiopathic. CSPN should or the wrist is exed for 3060 s (Phalens sign); and
be considered a distinct diagnostic subset of periph- weakness of thumb opposition and abduction. EDx is
eral neuropathy. The onset of CSPN is predominantly extremely sensitive and shows slowing of sensory and,
in the sixth and seventh decades. Patients complain of to a lesser extent, motor median potentials across the
distal numbness, tingling, and often burning pain that wrist. Treatment options consist of avoidance of pre-
invariably begins in the feet and may eventually involve cipitating activities; control of underlying systemic-asso-
the ngers and hands. Patients exhibit a distal sensory ciated conditions if present; nonsteroidal anti-inamma-
loss to pinprick, touch, and vibration in the toes and tory medications; neutral (volar) position wrist splints,
feet, and occasionally in the ngers. It is uncommon especially for night use; glucocorticoid/anesthetic injec-
to see signicant proprioception decits, even though tion into the carpal tunnel; and surgical decompression
patients may complain of gait unsteadiness. However, by dividing the transverse carpal ligament. The surgical
tandem gait may be abnormal in a minority of cases. option should be considered if there is a poor response
Neither subjective nor objective evidence of weakness to nonsurgical treatments; if there is thenar muscle atro-
is a prominent feature. Most patients have evidence of phy and/or weakness; and if there are signicant dener-
both large- and small-ber loss on neurologic exam and vation potentials on EMG.
EDx. Approximately 10% of patients have only evi- Other proximal median neuropathies are very uncom-
dence of small-ber involvement. The ankle muscle mon and include the pronator teres syndrome and ante-
stretch reex is frequently absent, but in cases with pre- rior interosseous neuropathy. These often occur as a par-
dominantly small-ber loss, this may be preserved. The tial form of brachial plexitis.
EDx ndings range from isolated sensory nerve action
potential abnormalities (usually with loss of amplitude),
to evidence for an axonal sensorimotor neuropathy, to
ULNAR NEUROPATHY AT THE ELBOW
a completely normal study (if primarily small bers are
CUBITAL TUNNEL SYNDROME
involved). Therapy primarily involves the control of
neuropathic pain (Table 45-6) if present. These drugs The ulnar nerve passes through the condylar groove
should not be used if the patient has only numbness and between the medial epicondyle and the olecranon.
tingling but no pain. Symptoms consist of paresthesias, tingling, and numb-
Although no treatment is available that can reverse an ness in the medial hand and half of the fourth and the
idiopathic distal peripheral neuropathy, the prognosis is entire fth ngers, pain at the elbow or forearm, and
good. Progression often does not occur or is minimal, with weakness. Signs consist of decreased sensation in an
594 ulnar distribution, Tinels sign at the elbow, and weak- occasionally medications for neuropathic pain, can be
ness and atrophy of ulnar-innervated hand muscles. The used (Table 45-6). Rarely, locally injecting the nerve
Froment sign indicates thumb adductor weakness and with an anesthetic can be tried. There is no role for
consists of exion of the thumb at the interphalangeal surgery.
joint when attempting to oppose the thumb against the
lateral border of the second digit. EDx may show slow-
ing of ulnar motor nerve conduction velocity across the FEMORAL NEUROPATHY
elbow with prolonged ulnar sensory latencies. Treat- Femoral neuropathies can arise as complications of ret-
ment consists of avoiding aggravating factors, using roperitoneal hematoma, lithotomy positioning, hip
elbow pads, and surgery to decompress the nerve in the arthroplasty or dislocation, iliac artery occlusion, femo-
cubital tunnel. Ulnar neuropathies can also rarely occur ral arterial procedures, inltration by hematogenous
at the wrist in the ulnar (Guyon) canal or in the hand, malignancy, penetrating groin trauma, pelvic surgery
usually after trauma. including hysterectomy and renal transplantation, and
diabetes (a partial form of lumbosacral diabetic plexop-
RADIAL NEUROPATHY athy); some cases are idiopathic. Patients with femoral
neuropathy have difculty extending their knee and
The radial nerve winds around the proximal humerus in exing the hip. Sensory symptoms occurring either on
SECTION III
the spiral groove and proceeds down the lateral arm and the anterior thigh and/or medial leg occur in only half
enters the forearm, dividing into the posterior interos- of reported cases. A prominent painful component is
seous nerve and supercial nerve. The symptoms and the exception rather than the rule, may be delayed, and
signs consist of wristdrop; nger extension weakness; is often self-limited in nature. The quadriceps (patellar)
thumb abduction weakness; and sensory loss in the dor- reex is diminished.
sal web between the thumb and index nger. Triceps
Diseases of the Nervous System
CHAPTER 45
Immune-mediated brachial plexus neuropathy
RADICULOPATHIES Immune-mediated brachial plexus neuropathy (IBPN)
goes by various terms, including acute brachial plexi-
Radiculopathies are most often due to compression tis, neuralgic amyotrophy, and Parsonage-Turner syndrome.
from degenerative joint disease and herniated disks, but IBPN usually presents with an acute onset of severe
there are a number of unusual etiologies (Table 45-9). pain in the shoulder region. The intense pain usually
Peripheral Neuropathy
Degenerative spine disease affects a number of differ- lasts several days to a few weeks, but a dull ache can
ent structures, which narrow the diameter of the neu- persist. Individuals who are affected may not appreci-
ral foramen or canal of the spinal column and compro- ate weakness of the arm early in the course because the
mise nerve root integrity; these are discussed in detail in pain limits movement. However, as the pain dissipates,
Chap. 9. weakness and often sensory loss are appreciated. Attacks
can occasionally recur.
Clinical ndings are dependent on the distribution
of involvement (e.g., specic trunk, divisions, cords, or
TABLE 45-9
terminal nerves). The most common pattern of IBPN
CAUSES OF RADICULOPATHY
involves the upper trunk or a single or multiple mono-
Herniated nucleus pulposus neuropathies primarily involving the suprascapular, long
Degenerative joint disease thoracic, or axillary nerves. Additionally, the phrenic
Rheumatoid arthritis and anterior interosseous nerves may be concomitantly
Trauma
affected. Any of these nerves may also be affected in iso-
lation. EDx is useful to conrm and localize the site(s)
Vertebral body compression fracture
of involvement. Empirical treatment of severe pain with
Potts disease glucocorticoids is often used in the acute period.
Compression by extradural mass (e.g., meningioma,
metastatic tumor, hematoma, abscess)
Primary nerve tumor (e.g., neurobroma, schwannoma, Brachial plexopathies associated with
neurinoma) neoplasms
Carcinomatous meningitis Neoplasms involving the brachial plexus may be pri-
Perineurial spread of tumor (e.g., prostate cancer) mary nerve tumors, local cancers expanding into the
Acute inammatory demyelinating polyradiculopathy plexus (e.g., Pancoast lung tumor or lymphoma), and
Chronic inammatory demyelinating polyradiculopathy
metastatic tumors. Primary brachial plexus tumors are
less common than the secondary tumors and include
Sarcoidosis
schwannomas, neurinomas, and neurobromas. Sec-
Amyloidoma ondary tumors affecting the brachial plexus are more
Diabetic radiculopathy common and are always malignant. These may arise
Infection (Lyme disease, herpes zoster, cytomegalovirus, from local tumors, expanding into the plexus. For
syphilis, schistosomiasis, strongyloides) example, a Pancoast tumor of the upper lobe of the
lung may invade or compress the lower trunk, while
596 Dorsal scapular
Lateral
Upper anterior
subscapular thoracic Suprascapular C5
L
Axillary
Musculocutaneous C6
Radial P Subclavius
C7
Median
C8
Ulnar
M
Medial Medial
antibrachial anterior
T1
cutaneous Thoracodorsal thoracic
Lower
Medial subscapular
Long thoracic
brachial
cutaneous
Anterior Posterior
FIGURE 45-2
Brachial plexus anatomy. L, lateral; M, medial; P, poste- Electromyography. Baltimore, Williams and Wilkins, 1974, p.
rior. (From J Goodgold: Anatomical Correlates of Clinical 126, with permission.)
Diseases of the Nervous System
L5 Psoas abscess
Malignant neoplasm
Benign neoplasm
S1 Radiation
Amyloid
Superior gluteal
Diabetic radiculoplexus neuropathy
S2 Idiopathic radiculoplexus neuropathy
Inferior gluteal Sarcoidosis
Aortic occlusion/surgery
S3 Lithotomy positioning
Hip arthroplasty
CHAPTER 45
Pelvic fracture
S4 Obstetric injury
Common
Sciatic peroneal
Tibial
To sphincter proximity. The differential diagnosis of plexopathy
Peripheral Neuropathy
Pudendal
ani externus
includes disorders of the conus medullaris and cauda
FIGURE 45-4 equina (polyradiculopathy). If there is a paucity of pain
Lumbosacral plexus. Posterior divisions are in orange, and sensory involvement, motor neuron disease should
anterior divisions are in yellow. (From J Goodgold: Anatomi- be considered as well.
cal Correlates of Clinical Electromyography. Baltimore, Wil- The causes of lumbosacral plexopathies are listed in
liams and Wilkins, 1974, p. 126, with permission.) Table 45-10. Diabetic radiculopathy (discussed ear-
lier) is a fairly common cause of painful leg weakness.
Lumbosacral plexopathies are a well-recognized compli-
The plexus lies on the posterior and posterolateral wall cation of retroperitoneal hemorrhage. Various primary
of the pelvis with its components converging toward and metastatic malignancies can affect the lumbosacral
the sciatic notch. The lateral trunk of the sciatic nerve plexus as well; these include carcinoma of the cervix,
(which forms the common peroneal nerve) arises from endometrium, and ovary; osteosarcoma; testicular can-
the union of the dorsal branches of the lumbosacral cer; multiple myeloma; lymphoma; acute myelogenous
trunk (L4, L5) and the dorsal branches of the S1 and leukemia; colon cancer; squamous cell carcinoma of the
S2 spinal nerve ventral rami. The medial trunk of the rectum; adenocarcinoma of unknown origin; and intra-
sciatic nerve (which forms the tibial nerve) derives from neural spread of prostate cancer.
the ventral branches of the same ventral rami (L4-S2).
RECURRENT NEOPLASTIC DISEASE OR
RADIATION-INDUCED PLEXOPATHY
LUMBOSACRAL PLEXOPATHIES The treatment for various malignancies is often radia-
Plexopathies are typically recognized when motor, tion therapy, the eld of which may include parts of the
sensory, and if applicable, reex decits occur in mul- brachial plexus. It can be difcult in such situations to
tiple nerve and segmental distributions conned to one determine if a new brachial or lumbosacral plexopathy
extremity. If localization within the lumbosacral plexus is related to tumor within the plexus or from radiation-
can be accomplished, designation as a lumbar plexopa- induced nerve damage. Radiation can be associated with
thy, a sacral plexopathy, a lumbosacral trunk lesion, or microvascular abnormalities and brosis of surrounding
a pan-plexopathy is the best localization that can be tissues, which can damage the axons and the Schwann
expected. Although lumbar plexopathies may be bilat- cells. Radiation-induced plexopathy can develop months
eral, usually occurring in a stepwise and chronologically or years following therapy and is dose dependent.
dissociated manner, sacral plexopathies are more likely Tumor invasion is usually painful and more com-
to behave in this manner due to their closer anatomic monly affects the lower trunk, while radiation injury
598 is often painless and affects the upper trunk. Imag- EVALUATION AND TREATMENT
ing studies such as MRI and CT scans are useful but OF PLEXOPATHIES
can be misleading with small microscopic invasion of
the plexus. EMG can be informative if myokymic dis- Most patients with plexopathies will undergo both
charges are appreciated, as this nding strongly suggests imaging with MRI and EDx evaluations. Severe pain
radiation-induced damage. from acute idiopathic lumbosacral plexopathy may
respond to a short course of glucocorticoids.
SECTION III
Diseases of the Nervous System
CHAPTER 46
GUILLAIN-BARR SYNDROME sensory decits (e.g., loss of pain and temperature sensa-
tion) are usually relatively mild, but functions subserved
Guillain-Barr syndrome (GBS) is an acute, frequently by large sensory bers, such as deep tendon reexes and
severe, and fulminant polyradiculoneuropathy that is proprioception, are more severely affected. Bladder dys-
autoimmune in nature. It occurs year-round at a rate function may occur in severe cases but is usually tran-
of between 1 and 4 cases per 100,000 annually; in the sient. If bladder dysfunction is a prominent feature and
United States, 50006000 cases occur per year. Males comes early in the course, diagnostic possibilities other
are at slightly higher risk for GBS than females, and in than GBS should be considered, particularly spinal cord
Western countries adults are more frequently affected disease. Once clinical worsening stops and the patient
than children. reaches a plateau (almost always within 4 weeks of
onset), further progression is unlikely.
Autonomic involvement is common and may occur
Clinical manifestations
even in patients whose GBS is otherwise mild. The
GBS manifests as a rapidly evolving areexic motor usual manifestations are loss of vasomotor control with
paralysis with or without sensory disturbance. The usual wide uctuation in blood pressure, postural hypoten-
pattern is an ascending paralysis that may be rst noticed sion, and cardiac dysrhythmias. These features require
as rubbery legs. Weakness typically evolves over hours close monitoring and management and can be fatal.
to a few days and is frequently accompanied by tin- Pain is another common feature of GBS; in addition
gling dysesthesias in the extremities. The legs are usu- to the acute pain described earlier, a deep aching pain
ally more affected than the arms, and facial diparesis is may be present in weakened muscles that patients liken
present in 50% of affected individuals. The lower cra- to having overexercised the previous day. Other pains
nial nerves are also frequently involved, causing bulbar in GBS include dysesthetic pain in the extremities as a
weakness with difculty handling secretions and main- manifestation of sensory nerve ber involvement. These
taining an airway; the diagnosis in these patients may pains are self-limited and often respond to standard
initially be mistaken for brainstem ischemia. Pain in the analgesics (Chap. 7).
neck, shoulder, back, or diffusely over the spine is also Several subtypes of GBS are recognized, as deter-
common in the early stages of GBS, occurring in 50% mined primarily by electrodiagnostic (Edx) and patho-
of patients. Most patients require hospitalization, and in logic distinctions (Table 46-1). The most common
different series up to 30% require ventilatory assistance variant is acute inammatory demyelinating polyneurop-
at some time during the illness. The need for mechani- athy (AIDP). Additionally, there are two axonal variants,
cal ventilation is associated with more severe weakness which are often clinically severethe acute motor axo-
on admission, a rapid tempo of progression, and the nal neuropathy (AMAN) and acute motor sensory axo-
presence of facial and/or bulbar weakness during the nal neuropathy (AMSAN) subtypes. In addition, a range
rst week of symptoms. Fever and constitutional symp- of limited or regional GBS syndromes are also encoun-
toms are absent at the onset and, if present, cast doubt tered. Notable among these is the Miller Fisher syndrome
on the diagnosis. Deep tendon reexes attenuate or (MFS), which presents as rapidly evolving ataxia and are-
disappear within the rst few days of onset. Cutaneous exia of limbs without weakness, and ophthalmoplegia,
599
600 TABLE 46-1
Acute inammatory Adults affected more than children; Demyelinating First attack on Schwann cell surface;
demyelinating 90% of cases in Western world; widespread myelin damage,
polyneuropathy (AIDP) recovery rapid; anti-GM1 antibodies macrophage activation, and
(<50%) lymphocytic inltration; variable
secondary axonal damage
Acute motor axonal Children and young adults; prevalent Axonal First attack at motor nodes of
neuropathy (AMAN) in China and Mexico; may be Ranvier; macrophage activation,
seasonal; recovery rapid; anti-GD1a few lymphocytes, frequent
antibodies periaxonal macrophages; extent of
axonal damage highly variable
Acute motor sensory Mostly adults; uncommon; recovery Axonal Same as AMAN, but also affects
axonal neuropathy slow, often incomplete; closely sensory nerves and roots; axonal
(AMSAN) related to AMAN damage usually severe
SECTION III
Miller Fisher syndrome Adults and children; uncommon; Demyelinating Few cases examined; resembles
(MFS) ophthalmoplegia, ataxia, and AIDP
areexia; anti-GQ1b antibodies (90%)
Diseases of the Nervous System
often with pupillary paralysis. The MFS variant accounts vaccine, prepared in nervous system tissue, is impli-
for 5% of all cases and is strongly associated with anti- cated as a trigger of GBS in developing countries where
bodies to the ganglioside GQ1b (see Immunopatho- it is still used; the mechanism is presumably immuni-
genesis). Other regional variants of GBS include (1) zation against neural antigens. GBS also occurs more
pure sensory forms; (2) ophthalmoplegia with anti-GQ1b frequently than can be attributed to chance alone in
antibodies as part of severe motor-sensory GBS; (3) GBS patients with lymphoma (including Hodgkins disease),
with severe bulbar and facial paralysis, sometimes associ- in HIV-seropositive individuals, and in patients with
ated with antecedent cytomegalovirus (CMV) infection systemic lupus erythematosus (SLE). C. jejuni has also
and anti-GM2 antibodies; and (4) acute pandysautonomia been implicated in summer outbreaks of AMAN among
(Chap. 33). children and young adults exposed to chickens in rural
China.
Antecedent events
Immunopathogenesis
Approximately 70% of cases of GBS occur 13 weeks
after an acute infectious process, usually respiratory or Several lines of evidence support an autoimmune basis
gastrointestinal. Culture and seroepidemiologic tech- for acute inammatory demyelinating polyneuropathy
niques show that 2030% of all cases occurring in (AIDP), the most common and best-studied type of
North America, Europe, and Australia are preceded GBS; the concept extends to all of the subtypes of GBS
by infection or reinfection with Campylobacter jejuni. (Table 46-1).
A similar proportion is preceded by a human her- It is likely that both cellular and humoral immune
pes virus infection, often CMV or Epstein-Barr virus. mechanisms contribute to tissue damage in AIDP. T
Other viruses and also Mycoplasma pneumoniae have cell activation is suggested by the nding that elevated
been identied as agents involved in antecedent infec- levels of cytokines and cytokine receptors are present
tions, as have recent immunizations. The swine inu- in serum (interleukin [IL] 2, soluble IL-2 receptor) and
enza vaccine, administered widely in the United States in cerebrospinal uid (CSF) (IL-6, tumor necrosis fac-
in 1976, is the most notable example. Inuenza vaccines tor , interferon-). AIDP is also closely analogous to
in use from 1992 to 1994, however, resulted in only an experimental T cellmediated immunopathy desig-
one additional case of GBS per million persons vacci- nated experimental allergic neuritis (EAN). EAN is induced
nated, and the more recent seasonal inuenza vaccines in laboratory animals by immune sensitization against
appear to confer a GBS risk of <1 per million. A recent protein fragments derived from peripheral nerve pro-
study demonstrated that there does not appear to be an teins, and in particular against the P2 protein. Based
increased risk of GBS with meningococcal vaccinations on analogy to EAN, it was initially thought that AIDP
(Menactra) contrary to early reports. Older-type rabies was likely to be primarily a T cellmediated disorder;
however, abundant data now suggest that autoantibod- infection. Furthermore, isolates of C. jejuni from stool 601
ies directed against nonprotein determinants may be cultures of patients with GBS have surface glycolipid
central to many cases. structures that antigenically cross react with gangliosides,
Circumstantial evidence suggests that all GBS results including GM1, concentrated in human nerves. Sialic
from immune responses to nonself antigens (infectious acid residues from pathogenic C. jejuni strains can also
agents, vaccines) that misdirect to host nerve tissue trigger activation of dendritic cells via signaling through
through a resemblance-of-epitope (molecular mimicry) a toll-like receptor (TLR4), promoting B-cell differen-
mechanism (Fig. 46-1). The neural targets are likely tiation and further amplifying humoral autoimmunity.
to be glycoconjugates, specically gangliosides (Table Another line of evidence is derived from experience
46-2; Fig. 46-2). Gangliosides are complex glycosphin- in Europe with parenteral use of puried bovine brain
golipids that contain one or more sialic acid residues; gangliosides for treatment of various neuropathic dis-
various gangliosides participate in cell-cell interactions orders. Between 5 and 15 days after injection, some
(including those between axons and glia), modulation recipients developed acute motor axonal GBS with high
of receptors, and regulation of growth. They are typi- titers of anti-GM1 antibodies that recognized epitopes at
cally exposed on the plasma membrane of cells, render- nodes of Ranvier and motor endplates. Experimentally,
ing them susceptible to an antibody-mediated attack. anti-GM1 antibodies can trigger complement-mediated
Gangliosides and other glycoconjugates are present in injury at paranodal axon-glial junctions, disrupting the
CHAPTER 46
large quantity in human nervous tissues and in key sites, clustering of sodium channels and likely contributing to
such as nodes of Ranvier. Antiganglioside antibodies, conduction block (see Pathophysiology).
most frequently to GM1, are common in GBS (2050% Anti-GQ1b IgG antibodies are found in >90% of
of cases), particularly in those preceded by C. jejuni patients with MFS (Table 46-2; Fig. 46-2), and titers
Ganglioside
(GM-1 and others)
CD4 B cell B cell
O
TCR
lgG
A
MHC II Cj
Cj
Cjj
C Myelin
Schwann cell sheath
Cj
Cj plasmalemma
CIDPa (MGUS associated) (25%) Neural binding sites IgG, IgA (monoclonal)
Chronic sensory > motor neuropathy SPGP, SGLPG (on MAG) (50%) IgM (monoclonal)
Uncertain (50%) IgM (monoclonal)
Multifocal motor neuropathy (MMN) GM1, GalNAcGD1a, others (2550%) IgM (polyclonal, monoclonal)
Chronic sensory ataxic neuropathy GD1b, GQ1b, and other b-series gangliosides IgM (monoclonal)
Diseases of the Nervous System
CHAPTER 46
estimated electrophysiologically. More secondary axo- (Table 46-3). Other disorders that may enter into the
nal degeneration correlates with a slower rate of recov- differential diagnosis include acute myelopathies (espe-
ery and a greater degree of residual disability. When a cially with prolonged back pain and sphincter distur-
severe primary axonal pattern is encountered electro- bances); diphtheria (early oropharyngeal disturbances);
physiologically, the implication is that axons have degen- Lyme polyradiculitis and other tick-borne paralyses;
erated and become disconnected from their targets, spe- porphyria (abdominal pain, seizures, psychosis); vascu-
or upper respiratory tract infection is common. treatment, or may be delayed for several weeks. The
2. Cerebrospinal Fluid Features Supporting Diagnosis lack of noticeable improvement following a course of
a. Elevated or serial elevation of CSF protein. IVIg or PE is not an indication to treat with the alternate
b. CSF cell counts are <10 mononuclear cell/mm3. treatment. However, there are occasional patients who
3. Electrodiagnostic Medicine Findings Supportive of
are treated early in the course of GBS and improve, who
Diagnosis
a. 80% of patients have evidence of NCV slowing/ then relapse within a month. Brief retreatment with
conduction block at some time during disease the original therapy is usually effective in such cases.
process. Glucocorticoids have not been found to be effective in
b. Patchy reduction in NCV attaining values less GBS. Occasional patients with very mild forms of GBS,
than 60% of normal. especially those who appear to have already reached a
c. Distal motor latency increase may reach 3 times plateau when initially seen, may be managed conserva-
normal values.
tively without IVIg or PE.
d. F-waves indicate proximal NCV slowing.
e. About 1520% of patients have normal NCV
In the worsening phase of GBS, most patients
ndings. require monitoring in a critical care setting, with par-
f. No abnormalities on nerve conduction studies ticular attention to vital capacity, heart rhythm, blood
may be seen for several weeks. pressure, nutrition, deep vein thrombosis prophy-
III. Findings Reducing Possibility of Diagnosis laxis, cardiovascular status, early consideration (after
1. Asymmetric weakness 2 weeks of intubation) of tracheotomy, and chest
2. Failure of bowel/bladder symptoms to resolve physiotherapy. As noted, 30% of patients with GBS
3. Severe bowel/bladder dysfunction at initiation of
require ventilatory assistance, sometimes for pro-
disease
4. Greater than 50 mononuclear cells/mm3 in CSF longed periods of time (several weeks or longer). Fre-
5. Well-demarcated sensory level quent turning and assiduous skin care are important,
IV. Exclusionary Criteria as are daily range-of-motion exercises to avoid joint
1. Diagnosis of other causes of acute neuromuscular contractures and daily reassurance as to the generally
weakness (e.g., myasthenia gravis, botulism, polio- good outlook for recovery.
myelitis, toxic neuropathy).
2. Abnormal CSF cytology suggesting carcinomatous
invasion of the nerve roots
Prognosis and recovery
Abbreviations: CSF, cerebrospinal uid; NCV, nerve conduction
velocity.
Approximately 85% of patients with GBS achieve
Source: AA Amato, D Dumitru, in D Dumitru et al (eds): Electrodiag- a full functional recovery within several months to a
nostic Medicine, 2nd ed. Philadelphia, Hanley & Belfus, 2002. year, although minor ndings on examination (such
as areexia) may persist and patients often complain of Diagnosis 605
continued symptoms, including fatigue. The mortal-
ity rate is <5% in optimal settings; death usually results The diagnosis rests on characteristic clinical, CSF, and
from secondary pulmonary complications. The out- electrophysiologic ndings. The CSF is usually acellular
look is worst in patients with severe proximal motor with an elevated protein level, sometimes several times
and sensory axonal damage. Such axonal damage may normal. As with GBS, a CSF pleocytosis should lead to
be either primary or secondary in nature (see Patho- the consideration of HIV infection, leukemia or lym-
physiology, earlier in the chapter), but in either case phoma, and neurosarcoidosis. Edx ndings reveal variable
successful regeneration cannot occur. Other factors degrees of conduction slowing, prolonged distal latencies,
that worsen the outlook for recovery are advanced distal and temporal dispersion of CMAPs, and conduc-
age, a fulminant or severe attack, and a delay in the tion block as the principal features. In particular, the pres-
onset of treatment. Between 5 and 10% of patients ence of conduction block is a certain sign of an acquired
with typical GBS have one or more late relapses; such demyelinating process. Evidence of axonal loss, presum-
cases are then classied as chronic inammatory demy- ably secondary to demyelination, is present in >50% of
elinating polyneuropathy (CIDP). patients. Serum protein electrophoresis with immunox-
ation is indicated to search for monoclonal gammopathy
and associated conditions (see Monoclonal Gammopa-
CHAPTER 46
thy of Undetermined Signicance, later in the chapter).
CHRONIC INFLAMMATORY In all patients with presumptive CIDP, it is also reason-
DEMYELINATING POLYNEUROPATHY able to exclude vasculitis, collagen vascular disease (espe-
cially SLE), chronic hepatitis, HIV infection, amyloidosis,
CIDP is distinguished from GBS by its chronic course. and diabetes mellitus. Other associated conditions include
In other respects, this neuropathy shares many features inammatory bowel disease and lymphoma.
with the common demyelinating form of GBS, includ-
CHAPTER 46
in the chapter), and their response to immunosuppres- techniques.
sive agents is also similar. An exception is the syndrome Approximately one-third of biopsy-proven cases of
of IgM kappa monoclonal gammopathy associated with vasculitic neuropathy are nonsystemic in that the vas-
an indolent, longstanding, sometimes static sensory culitis appears to affect only peripheral nerves. Consti-
neuropathy, frequently with tremor and sensory ataxia. tutional symptoms are absent, and the course is more
Most patients are male and older than age 50 years. In indolent than that of PAN. The erythrocyte sedimen-
the majority, the monoclonal IgM immunoglobulin
VASCULITIC NEUROPATHY
Peripheral nerve involvement is common in polyarteri- ANTI-HU PARANEOPLASTIC
tis nodosa (PAN), appearing in half of all cases clinically NEUROPATHY
and in 100% of cases at postmortem studies. The most
common pattern is multifocal (asymmetric) motor-sen- This uncommon immune-mediated disorder mani-
sory neuropathy (mononeuropathy multiplex) due to fests as a sensory neuronopathy (i.e., selective dam-
ischemic lesions of nerve trunks and roots; however, age to sensory nerve bodies in dorsal root ganglia).
608 The onset is often asymmetric with dysesthesias and only expressed by neurons. The same proteins are usu-
sensory loss in the limbs that soon progress to affect ally expressed by SCLC, triggering in some patients
all limbs, the torso, and face. Marked sensory ataxia, an immune response characterized by antibodies and
pseudoathetosis, and inability to walk, stand, or even cytotoxic T cells that cross-react with the Hu pro-
sit unsupported are frequent features and are second- teins of the dorsal root ganglion neurons, resulting in
ary to the extensive deafferentation. Subacute sen- immune-mediated neuronal destruction. An encepha-
sory neuronopathy may be idiopathic, but more lomyelitis may accompany the sensory neuronopathy
than half of cases are paraneoplastic, primarily related and presumably has the same pathogenesis. Neurologic
to lung cancer, and most of those are small cell lung symptoms usually precede, by 6 months, the identi-
cancer (SCLC). Diagnosis of the underlying SCLC cation of SCLC. The sensory neuronopathy runs its
requires awareness of the association, paraneoplastic course in a few weeks or months and stabilizes, leav-
testing, and often PET scanning for the tumor. The ing the patient disabled. Most cases are unresponsive
target antigens are a family of RNA-binding proteins to treatment with glucocorticoids, IVIg, PE, or immu-
(HuD, HuC, and Hel-N1) that in normal tissues are nosuppressant drugs.
SECTION III
Diseases of the Nervous System
CHAPTER 47
Daniel B. Drachman
Myasthenia gravis (MG) is a neuromuscular disorder the peaks of postsynaptic folds. The structure of the
characterized by weakness and fatigability of skeletal mus- AChR has been fully elucidated; it consists of ve sub-
cles. The underlying defect is a decrease in the number units (2, 1, 1, and 1 or ) arranged around a cen-
of available acetylcholine receptors (AChRs) at neuro- tral pore. When ACh combines with the binding sites
muscular junctions due to an antibody-mediated autoim- on the subunits of the AChR, the channel in the
mune attack. Treatment now available for MG is highly AChR opens, permitting the rapid entry of cations,
effective, although a specic cure has remained elusive. chiey sodium, which produces depolarization at the
end-plate region of the muscle ber. If the depolariza-
tion is sufciently large, it initiates an action potential
that is propagated along the muscle ber, triggering
PATHOPHYSIOLOGY muscle contraction. This process is rapidly terminated
At the neuromuscular junction (Fig. 47-1), acetylcho- by hydrolysis of ACh by acetylcholinesterase (AChE),
line (ACh) is synthesized in the motor nerve terminal which is present within the synaptic folds, and by diffu-
and stored in vesicles (quanta). When an action poten- sion of ACh away from the receptor.
tial travels down a motor nerve and reaches the nerve In MG, the fundamental defect is a decrease in the
terminal, ACh from 150 to 200 vesicles is released number of available AChRs at the postsynaptic muscle
and combines with AChRs that are densely packed at membrane. In addition, the postsynaptic folds are attened,
A Normal B MG
Axon
Mitochondria
Vesicle
Release site
Nerve
terminal
Muscle AChR
AChE
FIGURE 47-1
Diagrams of (A) normal and (B) myasthenic neuromus- reduced number of AChRs (stippling); attened, simplied
cular junctions. AChE, acetylcholinesterase. See text for postsynaptic folds; and a widened synaptic space. (Modi-
description of normal neuromuscular transmission. The ed from DB Drachman: N Engl J Med 330:1797, 1994;
MG junction demonstrates a normal nerve terminal; a with permission.)
609
610 or simplied. These changes result in decreased ef- of muscles. The weakness increases during repeated use
ciency of neuromuscular transmission. Therefore, although (fatigue) or late in the day, and may improve following
ACh is released normally, it produces small end-plate rest or sleep. The course of MG is often variable. Exac-
potentials that may fail to trigger muscle action potentials. erbations and remissions may occur, particularly during
Failure of transmission at many neuromuscular junctions the rst few years after the onset of the disease. Remis-
results in weakness of muscle contraction. sions are rarely complete or permanent. Unrelated
The amount of ACh released per impulse normally infections or systemic disorders can lead to increased
declines on repeated activity (termed presynaptic run- myasthenic weakness and may precipitate crisis (dis-
down). In the myasthenic patient, the decreased ef- cussed later).
ciency of neuromuscular transmission combined with The distribution of muscle weakness often has a
the normal rundown results in the activation of fewer characteristic pattern. The cranial muscles, particularly
and fewer muscle bers by successive nerve impulses the lids and extraocular muscles, are typically involved
and hence increasing weakness, or myasthenic fatigue. early in the course of MG; diplopia and ptosis are com-
This mechanism also accounts for the decremental mon initial complaints. Facial weakness produces a
response to repetitive nerve stimulation seen on electro- snarling expression when the patient attempts to
diagnostic testing. smile. Weakness in chewing is most noticeable after
The neuromuscular abnormalities in MG are brought prolonged effort, as in chewing meat. Speech may have
SECTION III
about by an autoimmune response mediated by spe- a nasal timbre caused by weakness of the palate, or a
cic anti-AChR antibodies. The anti-AChR antibodies dysarthric mushy quality due to tongue weakness.
reduce the number of available AChRs at neuromuscu- Difculty in swallowing may occur as a result of weak-
lar junctions by three distinct mechanisms: (1) accelerated ness of the palate, tongue, or pharynx, giving rise to
turnover of AChRs by a mechanism involving cross- nasal regurgitation or aspiration of liquids or food. Bul-
linking and rapid endocytosis of the receptors; (2) damage bar weakness is especially prominent in MuSK anti-
bodypositive MG. In 85% of patients, the weakness
Diseases of the Nervous System
CHAPTER 47
Anti-AChR radioimmunoassay: 85% positive in gen- interact repeatedly with the limited number of AChRs
eralized MG; 50% in ocular MG; denite diagnosis if in MG, producing improvement in muscle strength.
positive; negative result does not exclude MG. 40% Edrophonium is used most commonly for diagnos-
of AChR antibodynegative patients with generalized
tic testing because of the rapid onset (30 s) and short
MG have anti-MuSK antibodies.
duration (5 min) of its effect. An objective end-point
Repetitive nerve stimulation: decrement of >15% at
3 Hz: highly probable
must be selected to evaluate the effect of edrophonium,
such as weakness of extraocular muscles, impairment of
Slow channel Most common; weak Repetitive muscle Autosomal Excitotoxic end- Quinidine:
forearm extensors; response on nerve dominant; , , plate myopathy; decreases end-
onset 2nd to 3rd stimulation; prolonged AChR mutations decreased AChRs; plate damage;
decade; variable channel opening and postsynaptic made worse by
severity MEPP duration damage anti-AChE
Low-afnity Onset early; Brief and infrequent Autosomal reces- Normal end-plate 3,4-DAP; anti-
fast channel moderately severe; channel openings; sive; may be het- structure AChE
ptosis, EOM involve- opposite of slow eroallelic
ment; weakness and channel syndrome
fatigue
Severe AChR Early onset; variable Decremental response Autosomal reces- Increased length of Anti-AChE;
deciencies severity; fatigue; to repetitive sive; mutations end plates; variable ?3,4-DAP
typical MG features nerve stimulation; most common; synaptic folds
decreased MEPP many different
SECTION III
amplitudes mutations
AChE Early onset; variable Decremental response Mutant gene for Small nerve termi- Worse with anti-
deciency severity; scoliosis; to repetitive nerve AChEs collagen nals; degenerated AChE drugs
may have normal stimulation anchor junctional folds
EOM, absent
pupillary responses
Diseases of the Nervous System
Abbreviations: AChR, acetylcholine receptor; AChE, acetylcholinesterase; EOM, extraocular muscles; MEPP, miniature end-plate potentials;
3,4-DAP, 3,4-diaminopyridine.
These disorders share many of the clinical features of penicillamine (used for scleroderma or rheumatoid arthri-
autoimmune MG, including weakness and fatigability tis) may result in true autoimmune MG, but the weak-
of skeletal muscles, in some cases involving extraocular ness is usually mild, and recovery occurs within weeks or
muscles (EOMs), lids, and proximal muscles, similar to months after discontinuing its use. Aminoglycoside anti-
the distribution in autoimmune MG. CMS should be biotics or procainamide can cause exacerbation of weak-
suspected when symptoms of myasthenia have begun ness in myasthenic patients; very large doses can cause
in infancy or childhood and AChR antibody tests are neuromuscular weakness in normal individuals.
consistently negative. Features of four of the most com- LEMS is a presynaptic disorder of the neuromus-
mon forms of CMS are summarized in Table 47-2. cular junction that can cause weakness similar to that
Although clinical features and electrodiagnostic and of MG. The proximal muscles of the lower limbs
pharmacologic tests may suggest the correct diagno- are most commonly affected, but other muscles may
sis, molecular analysis is required for precise elucida- be involved as well. Cranial nerve ndings, includ-
tion of the defect; this may lead to helpful treatment as ing ptosis of the eyelids and diplopia, occur in up to
well as genetic counseling. In the forms that involve the 70% of patients and resemble features of MG. How-
AChR, a wide variety of mutations have been identi- ever, the two conditions are usually readily distin-
ed in each of the subunits, but the subunit is affected guished, since patients with LEMS have depressed
in 75% of these cases. In most of the recessively or absent reexes and experience autonomic changes
inherited forms of CMS, the mutations are heteroallelic; such as dry mouth and impotence. Nerve stimulation
that is, different mutations affecting each of the two produces an initial low-amplitude response and, at low
alleles are present. rates of repetitive stimulation (23 Hz), decremen-
tal responses like those of MG; however, at high rates
(50 Hz), or following exercise, incremental responses
Differential diagnosis
occur. LEMS is caused by autoantibodies directed
Other conditions that cause weakness of the cranial and/ against P/Q-type calcium channels at the motor nerve
or somatic musculature include the nonautoimmune terminals, which can be detected in 85% of LEMS
CMS discussed earlier, drug-induced myasthenia, Lam- patients by radioimmunoassay. These autoantibod-
bert-Eaton myasthenic syndrome (LEMS), neurasthenia, ies result in impaired release of ACh from nerve ter-
hyperthyroidism, botulism, intracranial mass lesions, and minals. Most patients with LEMS have an associated
progressive external ophthalmoplegia. Treatment with malignancy, most commonly small cell carcinoma of
the lung, which may express calcium channels that in MG may occasionally be due to an intracranial mass 613
stimulate the autoimmune response. The diagnosis of lesion that compresses nerves to the EOMs (e.g., sphe-
LEMS may signal the presence of a tumor long before noid ridge meningioma), but MRI of the head and orbits
it would otherwise be detected, permitting early usually reveals the lesion.
removal. Treatment of LEMS involves plasmapher- Progressive external ophthalmoplegia is a rare con-
esis and immunosuppression, as for MG. 3,4-Diami- dition resulting in weakness of the EOMs, which may
nopyridine (3,4-DAP) and pyridostigmine may also be accompanied by weakness of the proximal muscles
be symptomatically helpful. 3,4-DAP acts by block- of the limbs and other systemic features. Most patients
ing potassium channels, which results in prolonged with this condition have mitochondrial disorders that
depolarization of the motor nerve terminals and thus can be detected on muscle biopsy (Chap. 48).
enhances ACh release. Pyridostigmine prolongs the
action of ACh, allowing repeated interactions with Search for associated conditions
AChRs.
Botulism is due to potent bacterial toxins produced (Table 47-3) Myasthenic patients have an increased
by any of seven different strains of Clostridium botuli- incidence of several associated disorders. Thymic abnor-
num. The toxins enzymatically cleave specic proteins malities occur in 75% of patients, as noted earlier.
essential for the release of acetylcholine from the motor Neoplastic change (thymoma) may produce enlarge-
CHAPTER 47
nerve terminal, thereby interfering with neuromuscu- ment of the thymus, which is detected by CT scanning
lar transmission. Most commonly, botulism is caused of the anterior mediastinum. A thymic shadow on CT
by ingestion of improperly prepared food containing scan may normally be present through young adult-
toxin. Rarely, the nearly ubiquitous spores of C. botu- hood, but enlargement of the thymus in a patient aged
linum may germinate in wounds. In infants the spores >40 years is highly suspicious of thymoma. Hyperthy-
may germinate in the GI tract, and release toxin, caus- roidism occurs in 38% of patients and may aggravate
TREATMENT
The prognosis has improved strikingly as a result of Good risk Poor risk Plasmapheresis
(good FVC) (low FVC) or intravenous Ig
advances in treatment. Nearly all myasthenic patients
can be returned to full productive lives with proper then
therapy. The most useful treatments for MG include If unsatisfactory
anticholinesterase medications, immunosuppressive Thymectomy Improved If not
Diseases of the Nervous System
improved
agents, thymectomy, and plasmapheresis or intrave-
nous immunoglobulin (IVIg) (Fig. 47-2). Evaluate clinical status; if indicated,
go to immunosuppression
CHAPTER 47
example, if immediate improvement is essential either ment of side effects.
because of the severity of weakness or because of the
patients need to return to activity as soon as possible, Other Immunosuppressive Drugs Mycophe-
IVIg should be administered or plasmapheresis should nolate mofetil, azathioprine, cyclosporine, tacrolimus,
be undertaken. For the intermediate term, glucocorti- and occasionally cyclophosphamide are effective in many
coids and cyclosporine or tacrolimus generally produce patients, either alone or in various combinations.
clinical improvement within a period of 13 months. Mycophenolate mofetil has become one of the most
CHAPTER 47
unusual effort any effort at rest
Procaine, Xylocaine in large amounts
Examination
Procainamide (for arrhythmias)
BP Pulse Wt Arm abduction time R L
Botulinum toxin Edema Deltoids R L
Vital capacity Biceps R L
Botox exacerbates weakness Cataracts? R L Triceps R L
EOMS Grip R L
Quinine derivatives Ptosis time Iliopsoas R L
Skeletal muscle diseases, or myopathies, are disorders Most muscle disorders cause persistent weakness (Fig.
with structural changes or functional impairment of 48-2). In the majority of these, including most types
muscle. These conditions can be differentiated from of muscular dystrophy, polymyositis, and dermatomy-
other diseases of the motor unit (e.g., lower motor neu- ositis, the proximal muscles are weaker than the distal
ron or neuromuscular junction pathologies) by charac- and are symmetrically affected, and the facial muscles
teristic clinical and laboratory ndings. are spared, a pattern referred to as limb-girdle. The dif-
Myasthenia gravis and related disorders are discussed ferential diagnosis is more restricted for other patterns
in Chap. 47; dermatomyositis, polymyositis, and inclu- of weakness. Facial weakness (difculty with eye closure
sion body myositis are discussed in Chap. 49. and impaired smile) and scapular winging (Fig. 48-3)
are characteristic of facioscapulohumeral dystrophy
(FSHD). Facial and distal limb weakness associated with
hand grip myotonia is virtually diagnostic of myotonic
CLINICAL FEATURES dystrophy type 1. When other cranial nerve muscles are
Most myopathies present with proximal, symmetric weak, causing ptosis or extraocular muscle weakness,
limb weakness (arms or legs) with preserved reexes the most important disorders to consider include neu-
and sensation. However, asymmetric and predomi- romuscular junction disorders, oculopharyngeal mus-
nantly distal weakness can be seen in some myopathies. cular dystrophy, mitochondrial myopathies, or some of
An associated sensory loss suggests injury to peripheral the congenital myopathies (Table 48-1). A pathogno-
nerve or the central nervous system (CNS) rather than monic pattern characteristic of inclusion body myosi-
myopathy. On occasion, disorders affecting the motor tis is atrophy and weakness of the exor forearm (e.g.,
nerve cell bodies in the spinal cord (anterior horn cell wrist and nger exors) and quadriceps muscles that is
disease), the neuromuscular junction, or peripheral often asymmetric. Less frequently, but important diag-
nerves can mimic ndings of myopathy. nostically, is the presence of a dropped head syndrome
indicative of selective neck extensor muscle weakness.
The most important neuromuscular diseases associated
Muscle weakness
with this pattern of weakness include myasthenia gra-
Symptoms of muscle weakness can be either intermit- vis, amyotrophic lateral sclerosis, late-onset nemaline
tent or persistent. Disorders causing intermittent weakness myopathy, hyperparathyroidism, focal myositis, and
(Fig. 48-1) include myasthenia gravis, periodic paralyses some forms of inclusion body myopathy. A nal pat-
(hypokalemic, hyperkalemic, and paramyotonia congen- tern, recognized because of preferential distal extrem-
ita), and metabolic energy deciencies of glycolysis (espe- ity weakness, is typical of a unique category of muscular
cially myophosphorylase deciency), fatty acid utiliza- dystrophy, the distal myopathies.
tion (carnitine palmitoyltransferase deciency), and some It is important to examine functional capabilities
mitochondrial myopathies. The states of energy de- to help disclose certain patterns of weakness (Table
ciency cause activity-related muscle breakdown accom- 48-2). The Gowers sign (Fig. 48-4) is particularly
panied by myoglobinuria, appearing as light-brown- to useful. Observing the gait of an individual may dis-
dark-brown-colored urine. close a lordotic posture caused by combined trunk and
618
DIAGNOSTIC EVALUATION OF INTERMITTENT WEAKNESS 619
Intermittent weakness
Myoglobinuria
No Yes
Variable weakness includes Exam normal between attacks Exam usually normal between attacks
EOMs, ptosis, bulbar and limb muscles Proximal > distal weakness during attacks Proximal > distal weakness during attacks
No Yes Low potassium Normal or elevated Reduced lactic acid rise Normal lactic acid rise
level potassium level Consider glycolytic defect Consider CPT deficiency
or other fatty acid
Hyperkalemic PP metabolism disorders
AChR AB and MuSK Hypokalemic PP
AChR AB or MuSK Paramyotonia congenita
AB positive AB negative
CHAPTER 48
Acquired MG Congenital MG
Acquired MG Muscle biopsy
Lambert-Eaton DNA test confirms diagnosis defines specific defect
myasthenic syndrome
FIGURE 48-1
Diagnostic evaluation of intermittent weakness. AChR transferase; EOMs, extraocular muscles; MG, myasthenia gra-
AB, acetylcholine receptor antibody; CPT, carnitine palmitoyl- vis; PP, periodic paralysis.
Proximal > distal Ptosis, EOMs Facial and Facial, distal, Proximal & distal Distal Dropped head
PM; DM; muscular OPMD; scapular winging quadriceps; (hand grip), & Distal myopathy MG; PM; ALS;
dystrophies; mitochondrial (FSHD) handgrip myotonia quadriceps hyperpara-
mitochondrial myopathy; Myotonic muscular IBM thyroid
and metabolic myotubular dystrophy
myopathies; myopathy
toxic, endocrine
myopathies
FIGURE 48-2
Diagnostic evaluation of persistent weakness. Examina- lohumeral dystrophy; IBM, inclusion body myositis; DM,
tion reveals one of seven patterns of weakness. The pattern dermatomyositis; PM, polymyositis; MG, myasthenia gra-
of weakness in combination with the laboratory evaluation vis; ALS, amyotrophic lateral sclerosis; CK, creatine kinase;
leads to a diagnosis. EOMs, extraocular muscles; OPMD, EMG, electromyography.
oculopharyngeal muscular dystrophy; FSHD, facioscapu-
620 TABLE 48-2
OBSERVATIONS ON EXAMINATION THAT DISCLOSE
MUSCLE WEAKNESS
FUNCTIONAL IMPAIRMENT MUSCLE WEAKNESS
CHAPTER 48
Muscular Dystrophies and Other Muscle Diseases
FIGURE 48-5
Lordotic posture, exaggerated by standing on toes, associ-
ated with trunk and hip weakness.
A muscle contracture is different from a muscle cramp. In activity, paramyotonia congenita is named for a para-
both conditions, the muscle becomes hard, but a contrac- doxical phenomenon whereby the myotonia worsens
ture is associated with energy failure in glycolytic disorders. with repetitive activity.
The muscle is unable to relax after an active muscle con-
traction. The EMG shows electrical silence. Confusion Muscle enlargement and atrophy
is created because contracture also refers to a muscle that
Diseases of the Nervous System
cannot be passively stretched to its proper length (xed In most myopathies muscle tissue is replaced by fat and
contracture) because of brosis. In some muscle disor- connective tissue, but the size of the muscle is usually
ders, especially in Emery-Dreifuss muscular dystrophy and not affected. However, in many limb-girdle muscular
Bethlems myopathy, xed contractures occur early and dystrophies (and particularly the dystrophinopathies)
represent distinctive features of the disease. enlarged calf muscles are typical. The enlargement rep-
Muscle stiffness can refer to different phenomena. resents true muscle hypertrophy, thus the term pseudo-
Some patients with inammation of joints and periar- hypertrophy should be avoided when referring to these
ticular surfaces feel stiff. This condition is different from patients. The calf muscles remain very strong even late
the disorders of hyperexcitable motor nerves causing in the course of these disorders. Muscle enlargement
stiff or rigid muscles. In stiff-person syndrome, spontane- can also result from inltration by sarcoid granulomas,
ous discharges of the motor neurons of the spinal cord amyloid deposits, bacterial and parasitic infections, and
cause involuntary muscle contractions mainly involving focal myositis. In contrast, muscle atrophy is char-
the axial (trunk) and proximal lower extremity mus- acteristic of other myopathies. In dysferlinopathies
cles. The gait becomes stiff and labored, with hyper- (LGMD2B), there is a predilection for early atrophy
lordosis of the lumbar spine. Superimposed episodic of the gastrocnemius muscles, particularly the medial
muscle spasms are precipitated by sudden movements, aspect. Atrophy of the humeral muscles is characteristic
unexpected noises, and emotional upset. The muscles of facioscapulohumeral dystrophy (FSHD).
relax during sleep. Serum antibodies against glutamic
acid decarboxylase are present in approximately two-
thirds of cases. In neuromyotonia (Isaacs syndrome) there
is hyperexcitability of the peripheral nerves manifesting LABORATORY EVALUATION
as continuous muscle ber activity. Myokymia (groups A limited battery of tests can be used to evaluate a sus-
of fasciculations associated with continuous undula- pected myopathy. Nearly all patients require serum
tions of muscle) and impaired muscle relaxation are the enzyme level measurements and electrodiagnostic studies as
result. Muscles of the leg are stiff, and the constant con- screening tools to differentiate muscle disorders from other
tractions of the muscle cause increased sweating of the motor unit diseases. The other tests describedDNA
extremities. This peripheral nerve hyperexcitability is studies, the forearm exercise test, and muscle biopsyare
mediated by antibodies that target voltage-gated potas- used to diagnose specic types of myopathies.
sium channels. The site of origin of the spontaneous
nerve discharges is principally in the distal portion of
Serum enzymes
the motor nerves.
Myotonia is a condition of prolonged muscle con- CK is the preferred muscle enzyme to measure in the
traction followed by slow muscle relaxation. It always evaluation of myopathies. Damage to muscle causes
the CK to leak from the muscle ber to the serum. TABLE 48-4 623
The MM isoenzyme predominates in skeletal muscle, MYOTONIC DISORDERS
while creatine kinase-myocardial bound (CK-MB) is Myotonic dystrophy type 1
the marker for cardiac muscle. Serum CK can be ele-
Myotonic dystrophy type 2/proximal myotonic myopathy
vated in normal individuals without provocation, pre-
sumably on a genetic basis or after strenuous activity, Myotonia congenita
minor trauma (including the EMG needle), a prolonged Paramyotonia congenita
muscle cramp, or a generalized seizure. Aspartate ami- Hyperkalemic periodic paralysis
notransferase (AST), alanine aminotransferase (ALT), Chondrodystrophic myotonia (Schwartz-Jampel syndrome)
aldolase, and lactic dehydrogenase (LDH) are enzymes
sharing an origin in both muscle and liver. Problems Centronuclear/myotubular myopathya
arise when the levels of these enzymes are found to Drug-induced
be elevated in a routine screening battery, leading to Cholesterol-lowering agents (statin medications,
the erroneous assumption that liver disease is present brates)
when in fact muscle could be the cause. An elevated Cyclosporine
-glutamyl transferase (GGT) helps to establish a liver Chloroquine
origin since this enzyme is not found in muscle. Glycogen storage disordersa (Pompes disease, deb-
CHAPTER 48
rancher deciency, branching enzyme deciency)
Electrodiagnostic studies Myobrillar myopathiesa
trates associated with muscle bers containing rimmed pain. The chest deformity with scoliosis impairs pulmo-
vacuoles, amyloid deposits within bers, and TDP-43 nary function, which is already diminished by muscle
inclusions are characteristic of inclusion body myosi- weakness. By age 1618 years, patients are predisposed
tis; while perivascular, perimysial inammation asso- to serious, sometimes fatal pulmonary infections. Other
ciated with perifascicular atrophy are features of der- causes of death include aspiration of food and acute gas-
matomyositis. In addition, the congenital myopathies tric dilation.
Diseases of the Nervous System
have distinctive light and electron microscopy features A cardiac cause of death is uncommon despite the
essential for diagnosis. Mitochondrial and metabolic presence of a cardiomyopathy in almost all patients.
(e.g., glycogen and lipid storage diseases) myopathies Congestive heart failure seldom occurs except with
also demonstrate distinctive histochemical and electron- severe stress such as pneumonia. Cardiac arrhyth-
microscopic proles. Biopsied muscle tissue can be sent mias are rare. The typical electrocardiogram (ECG)
for metabolic enzyme or mitochondrial DNA analyses. shows an increased net RS in lead V1; deep, narrow Q
A battery of antibodies is available for the identication waves in the precordial leads; and tall right precordial
of missing components of the dystrophin-glycoprotein R waves in V1. Intellectual impairment in Duchennes
complex and related proteins to help diagnose specic dystrophy is common; the average intelligence quo-
types of muscular dystrophies. Western blot analysis tient (IQ) is 1 SD below the mean. Impairment of
on muscle specimens can be performed to determine intellectual function appears to be nonprogressive and
whether specic muscle proteins are reduced in quan- affects verbal ability more than performance.
tity or are of abnormal size.
Laboratory features
Serum CK levels are invariably elevated to between 20
HEREDITARY MYOPATHIES
and 100 times normal. The levels are abnormal at birth
Muscular dystrophy refers to a group of hereditary pro- but decline late in the disease because of inactivity and
gressive diseases each with unique phenotypic and loss of muscle mass. EMG demonstrates features typical
genetic features (Tables 48-5, 48-6, and 48-7). of myopathy. The muscle biopsy shows muscle bers
of varying size as well as small groups of necrotic and
regenerating bers. Connective tissue and fat replace
DUCHENNES MUSCULAR DYSTROPHY lost muscle bers. A denitive diagnosis of Duchennes
This X-linked recessive disorder, sometimes also called dystrophy can be established on the basis of dystrophin
pseudohypertrophic muscular dystrophy, has an incidence of deciency in a biopsy of muscle tissue or mutation anal-
30 per 100,000 live-born males. ysis on peripheral blood leukocytes, as discussed later.
Duchennes dystrophy is caused by a mutation of
the gene that encodes dystrophin, a 427-kDa protein
Clinical features
localized to the inner surface of the sarcolemma of the
Duchennes dystrophy is present at birth, but the dis- muscle ber. The dystrophin gene is >2000 kb in size
order usually becomes apparent between ages 3 and and thus is one of the largest identied human genes.
5 years. The boys fall frequently and have difculty It is localized to the short arm of the X chromosome at
TABLE 48-5 625
PROGRESSIVE MUSCULAR DYSTROPHIES
DEFECTIVE GENE/ OTHER ORGAN
TYPE INHERITANCE PROTEIN ONSET AGE CLINICAL FEATURES SYSTEMS INVOLVED
CHAPTER 48
Limb-girdle AD/AR Several (Tables Early childhood to Slow progressive weak- Cardiomyopathy
48-6, 48-7) early adult ness of shoulder and hip
girdle muscles
Emery-Dreifuss XR/AD Emerin/Lamins A/C Childhood to adult Elbow contractures, Cardiomyopathy
Nesprin-1, humeral and peroneal
Nesprin 2, weakness
TMEM43
Xp21. The most common gene mutation is a deletion. allows for an unequivocal diagnosis, makes possible
The size varies but does not correlate with disease accurate testing of potential carriers, and is useful for
severity. Deletions are not uniformly distributed over prenatal diagnosis.
the gene but rather are most common near the begin- A diagnosis of Duchennes dystrophy can also be
ning (5 end) and middle of the gene. Less often, Duch- made by Western blot analysis of muscle biopsy spec-
ennes dystrophy is caused by a gene duplication or imens, revealing abnormalities on the quantity and
point mutation. Identication of a specic mutation molecular weight of dystrophin protein. In addition,
626 TABLE 48-6
AUTOSOMAL DOMINANT LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMDS)
DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE
Abbreviations: CK, creatine kinase; EMG, electromyography; NCS, nerve conduction studies.
immunocytochemical staining of muscle with dystro- transmembrane protein complexes, the dystroglycans
phin antibodies can be used to demonstrate absence and the sarcoglycans. The dystroglycans bind to the
or deciency of dystrophin localizing to the sarco- extracellular matrix protein merosin, which is also com-
lemmal membrane. Carriers of the disease may dem- plexed with 1 and 7 integrins (Tables 48-5, 48-6,
onstrate a mosaic pattern, butdystrophin analysis of 48-7). Dysferlin complexes with caveolin-3 (which
muscle biopsy specimens for carrier detection is not binds to neuronal nitric oxide synthase, or nNOS)
reliable. but not with the dystrophin-associated proteins or the
integrins. In some of the congenital dystrophies and
limb-girdle muscular dystrophies (LGMDs), there is
loss of function of different enzymes that glycosylate
Pathogenesis
-dystroglycan, which thereby inhibits proper binding
Dystrophin is part of a large complex of sarcolemmal pro- to merosin: POMT1, POMT2, POMGnT1, Fukutin,
teins and glycoproteins (Fig. 48-6). Dystrophin binds Fukutin-related protein, and LARGE.
to F-actin at its amino terminus and to -dystroglycan The dystrophin-glycoprotein complex appears to
at the carboxyl terminus. -Dystroglycan complexes to confer stability to the sarcolemma, although the func-
-dystroglycan, which binds to laminin in the extracellu- tion of each individual component of the complex is
lar matrix (ECM). Laminin has a heterotrimeric molecular incompletely understood. Deciency of one member of
structure arranged in the shape of a cross with one heavy the complex may cause abnormalities in other compo-
chain and two light chains, 1 and 1. The laminin heavy nents. For example, a primary deciency of dystrophin
chain of skeletal muscle is designated laminin 2. Colla- (Duchennes dystrophy) may lead to secondary loss of
gen proteins IV and VI are also found in the ECM. Like the sarcoglycans and dystroglycan. The primary loss of a
-dystroglycan, the transmembrane sarcoglycan proteins single sarcoglycan (see Limb-Girdle Muscular Dystro-
also bind to dystrophin; these ve proteins (designated - phy, later in the chapter) results in a secondary loss of
through -sarcoglycan) complex tightly with each other. other sarcoglycans in the membrane without uniformly
More recently, other membrane proteins implicated in affecting dystrophin. In either instance, disruption of
muscular dystrophy have been found to be loosely afli- the dystrophin-glycoprotein complexes weakens the
ated with constituents of the dystrophin complex. These sarcolemma, causing membrane tears and a cascade of
include caveolin-3, 7 integrin, and collagen VI. events leading to muscle ber necrosis. This sequence
Dystrophin localizes to the cytoplasmic face of of events occurs repeatedly during the life of a patient
the muscle cell membrane. It complexes with two with muscular dystrophy.
TABLE 48-7 627
AUTOSOMAL RECESSIVE LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMDS)
DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE
CHAPTER 48
Cognitive function normal
LGMD2G Onset age 10 to 15 Serum CK 317 normal Telethonin
Proximal and distal muscle weakness NCS normal
EMG myopathic
LGMD2H Onset 1st to 3rd decade Serum CK 225 normal TRIM32 gene
Proximal muscle weakness NCS normal
a
Tibial muscular dystrophy is a form of titin deciency with only distal muscle weakness (see Table 48-9).
Abbreviations: CK, creatine kinase; EMG, electromyography; NCS, nerve conduction studies; POMT1, protein-O-mannosyl transferase 1;
POMT2, protein-O-mannosyltransferase 2; POMGnT1, O-linked mannose beta 1,2-N-acetylglucosaminyltransferase.
628 Extracellular weakness becomes more generalized. Signicant facial
Collagen VI
muscle weakness is not a feature. Hypertrophy of mus-
Merosin cles, particularly in the calves, is an early and prominent
Dystoglycan
nding.
complex Sarcoglycan Most patients with Beckers dystrophy rst experience
complex difculties between ages 5 and 15 years, although onset
in the third or fourth decade or even later can occur. By
1 7 denition, patients with Beckers dystrophy walk beyond
nNOS
age 15, while patients with Duchennes dystrophy are
Caveolin-3 Integrin
typically in a wheelchair by the age of 12. Patients with
Dystrophin Calpain Dysferlin complex Beckers dystrophy have a reduced life expectancy, but
F-Actin most survive into the fourth or fth decade.
Golgi
Mental retardation may occur in Beckers dystro-
phy, but it is not as common as in Duchennes. Car-
POMT1 diac involvement occurs in Beckers dystrophy and
Intracelluar may result in heart failure; some patients manifest with
POMGnT1 only heart failure. Other less common presentations are
SECTION III
FIGURE 48-6
Selected muscular dystrophyassociated proteins in the Laboratory features
cell membrane and Golgi complex.
Diseases of the Nervous System
CHAPTER 48
emerged as the most common disorders. accounts for overlapping phenotypes (Fig. 48-7).
referred to as arthrogryposis. Respiratory failure may be tinct molecular genetic defects: myotonic dystrophy
seen in some cases. type 1 (DM1), the classic disease originally described by
The CNS is affected in some forms of CMD. In Steinert, and myotonic dystrophy type 2 (DM2), also
merosin and FKRP deciency, cerebral hypomyelin- called proximal myotonic myopathy (PROMM).
ation may be seen by MRI, though only a small num-
ber of patients have mental retardation and seizures. Clinical features
Diseases of the Nervous System
Merosin deciency Onset at birth with hypotonia, joint con- Serum CK 535 normal Laminin 2 chain
tractures, delayed milestones, general- EMG myopathic
ized muscle weakness NCS abnormal in some cases
Cerebral hypomyelination, less often
cortical dysplasia
Normal intelligence usually, some with
MR (6%) and seizures (8%)
Partial deciency leads to milder
phenotype (LGMD picture)
Fukitin-related Onset at birth or shortly after Serum CK 1050 normal Fukutin-related protein
protein deciencyb Hypotonia and feeding problems EMG myopathic
Weakness of proximal muscles, espe- NCS normal
cially shoulder girdles
Hypertrophy of leg muscles
CHAPTER 48
Joint contractures
Cognition normal
Fukuyama congenital Onset at birth Serum CK 1050 normal Fukutin
muscular dystrophy b Hypotonia, joint contractures EMG myopathic
Generalized muscle weakness NCS normal
Hypertrophy of calf muscles MRI shows hydrocephalus and
Seizures, mental retardation periventricular and frontal
a
All are inherited as recessive traits.
b
There is phenotypic overlap between disorders related to defective glycosylation. In muscle, this is a consequence of altered glycosylation of
dystroglycans; in brain/eye, other glycosylated proteins are involved. Clinically, Walker-Warburg syndrome is more severe, with death by 1 year.
Abbreviations: CK, creatine kinase; EMG, electromyography; LGMD, limb-girdle muscular dystrophy; MR, mental retardation; NCS, nerve
conduction studies.
atrophy, insulin resistance, and decreased esophageal and hypersomnia, and cognitive defects. Cardiac conduction
colonic motility. defects occur but are less common, and the hatchet face
Congenital myotonic dystrophy is a more severe form of and frontal baldness are less consistent features. A very
DM1 and occurs in 25% of infants of affected moth- striking difference is the failure to clearly identify a con-
ers. It is characterized by severe facial and bulbar weak- genital form of DM2.
ness, transient neonatal respiratory insufciency, and
mental retardation.
Laboratory features
DM2, or PROMM, has a distinct pattern of muscle
weakness affecting mainly proximal muscles. Other fea- The diagnosis of myotonic dystrophy can usually be
tures of the disease overlap with DM1, including cata- made on the basis of clinical ndings. Serum CK lev-
racts, testicular atrophy, insulin resistance, constipation, els may be normal or mildly elevated. EMG evidence
632 of myotonia is present in most cases of DM1 but may
block, or trifascicular conduction disturbances with
be more patchy in DM2. Muscle biopsy shows mus-
marked prolongation of the PR interval. Molded ankle-
cle atrophy, which selectively involves type 1 bers
foot orthoses help stabilize gait in patients with foot
in 50% of cases, and ringed bers in DM1 but not in
drop. Excessive daytime somnolence with or without
DM2. Typically, numerous internalized nuclei can be
sleep apnea is not uncommon. Sleep studies, noninva-
seen in individual muscle bers as well as atrophic bers
sive respiratory support (biphasic positive airway pres-
with pyknotic nuclear clumps in both DM1 and DM2.
sure, BiPAP), and treatment with modafinil may be ben-
Necrosis of muscle bers and increased connective tis-
eficial.
sue, common in other muscular dystrophies, are less
apparent in myotonic dystrophy.
DM1 and DM2 are both autosomal dominant
disorders. New mutations do not appear to contribute FACIOSCAPULOHUMERAL (FSH)
to the pool of affected individuals. DM1 is transmit- MUSCULAR DYSTROPHY
ted by an intronic mutation consisting of an unstable This form of muscular dystrophy has a prevalence of
expansion of a CTG trinucleotide repeat in a serine- 1 in 20,000. There are two forms of FSHD that have
threonine protein kinase gene (named DMPK) on chro- similar pathogenesis, as will be discussed. Most patients
mosome 19q13.3. An increase in the severity of the have FSHD type 1 (95%), while approximately 5% have
SECTION III
disease phenotype in successive generations (genetic FSHD2. FSHD1 and FSHD2 are clinically and his-
anticipation) is accompanied by an increase in the num- topathologically identical. FSHD is not to be confused
ber of trinucleotide repeats. A similar type of mutation with the genetically distinct scapuloperoneal dystrophies.
has been identied in fragile X syndrome. The unsta-
ble triplet repeat in myotonic dystrophy can be used
Clinical features
for prenatal diagnosis. Congenital disease occurs almost
Diseases of the Nervous System
exclusively in infants born to affected mothers; it is pos- The condition typically has an onset in childhood or
sible that sperm with greatly expanded triplet repeats do young adulthood. In most cases, facial weakness is the
not function well. initial manifestation, appearing as an inability to smile,
DM2 is caused by a DNA expansion mutation con- whistle, or fully close the eyes. Weakness of the shoul-
sisting of a CCTG repeat in intron 1 of the ZNF9 gene der girdles, rather than the facial muscles, usually brings
located at chromosome 3q13.3-q24. The gene is believed the patient to medical attention. Loss of scapular stabi-
to encode an RNA-binding protein expressed in many lizer muscles makes arm elevation difcult. Scapular
different tissues, including skeletal and cardiac muscle. winging (Fig. 48-3) becomes apparent with attempts at
The DNA expansions in DM1 and DM2 almost cer- abduction and forward movement of the arms. Biceps
tainly impair muscle function by a toxic gain of func- and triceps muscles may be severely affected, with rela-
tion of the mutant mRNA. In both DM1 and DM2, tive sparing of the deltoid muscles. Weakness is invari-
the mutant RNA appears to form intranuclear inclu- ably worse for wrist extension than for wrist exion,
sions composed of aberrant RNA. These RNA inclu- and weakness of the anterior compartment muscles of
sions sequester RNA-binding proteins essential for the legs may lead to footdrop.
proper splicing of a variety of other mRNAs. This leads In most patients, the weakness remains restricted to
to abnormal transcription of multiple proteins in a vari- facial, upper extremity, and distal lower extremity mus-
ety of tissues/organ systems, in turn causing the systemic cles. In 20% of patients, weakness progresses to involve
manifestations of DM1 and DM2. the pelvic girdle muscles, and severe functional impair-
ment and possible wheelchair dependency result.
Characteristically, patients with FSHD do not have
involvement of other organ systems, although labile
TREATMENT Myotonic Dystrophy
hypertension is common, and there is an increased
The myotonia in DM1 rarely warrants treatment, though incidence of nerve deafness. Coats disease, a disor-
some patients with DM2 are significantly bothered der consisting of telangiectasia, exudation, and retinal
by the discomfort related to the associated muscle detachment, also occurs.
stiffness. Phenytoin and mexiletine are the preferred
agents for the occasional patient who requires an anti- Laboratory features
myotonia drug; other agents, particularly quinine and
The serum CK level may be normal or mildly elevated.
procainamide, may worsen cardiac conduction. A car-
EMG usually indicates a myopathic pattern. The mus-
diac pacemaker should be considered for patients with
cle biopsy shows nonspecic features of a myopathy.
unexplained syncope, advanced conduction system
A prominent inammatory inltrate, which is often
abnormalities with evidence of second-degree heart
multifocal in distribution, is present in some biopsy
samples. The cause or signicance of this nding is by electron microscopy are shown to contain membra- 633
unknown. nous whorls, accumulation of glycogen, and other non-
An autosomal dominant inheritance pattern with specic debris related to lysosomes. A distinct feature
almost complete penetrance has been established, but of oculopharyngeal dystrophy is the presence of tubular
each family member should be examined for the pres- laments, 8.5 nm in diameter, in muscle cell nuclei.
ence of the disease, since 30% of those affected are Oculopharyngeal dystrophy has an autosomal domi-
unaware of involvement. FSHD1 is associated with nant inheritance pattern with complete penetrance. The
deletions of tandem 3.3-kb repeats at 4q35. The dele- incidence is high in French-Canadians and in Spanish-
tion reduces the number of repeats to a fragment of American families of the southwestern United States.
<35 kb in most patients. Within these repeats lies the Large kindreds of Italian and of eastern European Jew-
DUX4 gene, which usually is not expressed. In patients ish descent have been reported. The molecular defect in
with FSHD1 these deletions in the setting of a specic oculopharyngeal muscular dystrophy is a subtle expan-
polymorphism leads to hypomethylation of the region sion of a modest polyalanine repeat tract in a poly-
and toxic expression of the DUX 4 gene. Interest- RNA-binding protein (PABP2) in muscle.
ingly, in patients with FSHD2, there is no deletion but
in the setting of the same polymorphism there again is
seen hypomethylation of the region and the permissive TREATMENT Oculopharyngeal Dystrophy
CHAPTER 48
expression of the DUX4 gene. In either instance, the
permissive polymorphism introduces a polyadenylation Dysphagia can lead to significant undernourishment
signal that results in an aberrant, toxic DUX4 transcript. and inanition, making oculopharyngeal muscular dys-
trophy a potentially life-threatening disease. Cricopha-
ryngeal myotomy may improve swallowing, although
it does not prevent aspiration. Eyelid crutches can
TREATMENT Facioscapulohumeral Muscular Dystrophy
(tibial distribution) with progres- EMG reveals irritative myopathy PDX motif-containing protein
sion to distal arms and proximal Muscle biopsies demonstrate (ZASP)
muscles rimmed vacuoles and features
of myobrillar myopathy
Laings distal Onset childhood to 3rd decade Serum CK is normal or slightly AD
myopathy Distal lower extremity weakness elevated Myosin heavy chain 7
Diseases of the Nervous System
CHAPTER 48
staining sometimes demonstrates accumulation of des- aligned sarcomeres associated with Z disk streaming.
min and other proteins in MFM, large deposits of myo- Autosomal dominant inheritance is characteristic;
sin heavy chain in the subsarcolemmal region of type sporadic cases also occur. The disease is caused by point
1 muscle bers in Laings myopathy, and reduced or mutations of the ryanodine receptor gene on chromo-
absent dysferlin in Miyoshis myopathy. some 19q, encoding the calcium-release channel of the
The affected genes and their gene products are listed sarcoplasmic reticulum of skeletal muscle; mutations of
CHAPTER 48
Pompes disease is inherited as an autosomal recessive kinase (severe). In phosphoglycerate kinase deciency,
disorder caused by mutations of the -glucosidase gene. the usual clinical presentation is a seizure disorder asso-
Enzyme replacement therapy (ERT) with IV recombi- ciated with mental retardation; exercise intolerance is an
nant human -glucosidase has been shown to be ben- infrequent manifestation.
ecial in infantile-onset Pompes disease. Clinical ben- In all of these conditions, the serum CK levels uc-
ets in the infantile disease include reduced heart size, tuate widely and may be elevated even during symp-
do not exhibit myoglobinuria, however. Strength is Oxidation of the major nutrients derived from car-
normal between attacks. In contrast to disorders caused bohydrate, fat, and protein leads to the generation of
by defects in glycolysis, in which muscle cramps follow reducing equivalents. The latter are transported through
short, intense bursts of exercise, the muscle pain in CPT the respiratory chain in the process known as oxidative
II deciency does not occur until the limits of utilization phosphorylation. The energy generated by the oxidation-
have been exceeded and muscle breakdown has already reduction reactions of the respiratory chain is stored in
Diseases of the Nervous System
begun. Episodes of rhabdomyolysis may produce severe an electrochemical gradient coupled to ATP synthesis.
weakness. In young children and newborns, CPT II A novel feature of mitochondria is their genetic com-
deciency can present with a very severe clinical picture position. Each mitochondrion possesses a DNA genome
including hypoketotic hypoglycemia, cardiomyopathy, that is distinct from that of the nuclear DNA. Human
liver failure, and sudden death. mitochondrial DNA (mtDNA) consists of a double-
Serum CK levels and EMG ndings are both usually strand, circular molecule comprising 16,569 base pairs.
normal between episodes. A normal rise of venous lac- It codes for 22 transfer RNAs, 2 ribosomal RNAs, and
tate during forearm exercise distinguishes this condition 13 polypeptides of the respiratory chain enzymes. The
from glycolytic defects, especially myophosphorylase genetics of mitochondrial diseases differ from the genet-
deciency. Muscle biopsy does not show lipid accumu- ics of chromosomal disorders. The DNA of mitochon-
lation and is usually normal between attacks. The diag- dria is directly inherited from the cytoplasm of the
nosis requires direct measurement of muscle CPT or gametes, mainly from the oocyte. The sperm contributes
genetic testing. very little of its mitochondria to the offspring at the time
CPT II deciency is much more common in men of fertilization. Thus, mitochondrial genes are derived
than women (5:1); nevertheless, all evidence indicates almost exclusively from the mother, accounting for
autosomal recessive inheritance. A mutation in the gene maternal inheritance of some mitochondrial disorders.
for CPT II (chromosome 1p36) causes the disease in Patients with mitochondrial myopathies have clini-
some individuals. Attempts to improve exercise tolerance cal manifestations that usually fall into three groups:
with frequent meals and a low-fat, high-carbohydrate chronic progressive external ophthalmoplegia (CPEO),
diet, or by substituting medium-chain triglycerides in the skeletal muscleCNS syndromes, and pure myopathy
diet, have not proven to be benecial. simulating muscular dystrophy or metabolic myopathy.
CHAPTER 48
mon, including gonadal dysfunction in both sexes with and 15q2226. In the chromosome 4q-related form of
delayed puberty, short stature, and infertility. Diabetes disease, mutations of the gene encoding the heart and
mellitus is a cardinal sign of mitochondrial disorders and skeletal musclespecic isoform of the adenine nucleo-
is estimated to occur in 13% of KSS patients. Other less tide translocator 1 (ANT1) gene are found. This highly
common endocrine disorders include thyroid disease, abundant mitochondrial protein forms a homodi-
hyperaldosteronism, Addisons disease, and hypopara- meric inner mitochondrial channel through which
thyroidism. Both mental retardation and dementia are
Mitochondrial myopathy, encephalopathy, myoglobinuria without xed weakness and thus resem-
lactic acidosis, and strokelike episodes ble a glycogen storage disorder or CPT deciency.
(MELAS)
MELAS is the most common mitochondrial encephalo- Mitochondrial DNA depletion syndromes
myopathy. The term strokelike is appropriate because the Mitochondrial DNA depletion syndrome (MDS) is a het-
Diseases of the Nervous System
cerebral lesions do not conform to a strictly vascular dis- erogeneous group of disorders that are inherited in an
tribution. The onset in the majority of patients is before autosomal recessive fashion and can present in infancy or
age 20. Seizures, usually partial motor or generalized, adults. MDS can be caused by mutations in genes (TK2,
are common and may represent the rst clearly recog- DGUOK, RRM2B, TYMP, SUCLA1, and SUCLA2)
nizable sign of disease. The cerebral insults that resem- that lead to depletion of pools of mitochondrial deoxyri-
ble strokes cause hemiparesis, hemianopia, and cortical bonucleotide (dNTP) pools necessary for mtDNA replica-
blindness. A presumptive stroke occurring before age tion The other major cause of MDS is a set of mutations in
40 should place this mitochondrial encephalomyopathy genes essential for mtDNA replication (e.g., POLG1 and
high in the differential diagnosis. Associated conditions C10orf2). The clinical phenotypes associated with MDS
include hearing loss, diabetes mellitus, hypothalamic vary. Patients may develop a severe encephalopathy (e.g.,
pituitary dysfunction causing growth hormone de- Leighs syndrome), PEO, an isolated myopathy, myo-
ciency, hypothyroidism, and absence of secondary sex- neuro-gastrointestinal-encephalopathy (MNGIE), and a
ual characteristics. In its full expression, MELAS leads to sensory neuropathy with ataxia.
dementia, a bedridden state, and a fatal outcome. Serum
lactic acid is typically elevated. The CSF protein is also
increased but is usually f1 g/L (100 mg/dL). Muscle
biopsies show ragged red bers. Neuroimaging dem- DISORDERS OF MUSCLE MEMBRANE
onstrates basal ganglia calcication in a high percentage EXCITABILITY
of cases. Focal lesions that mimic infarction are present
Muscle membrane excitability is affected in a group of
predominantly in the occipital and parietal lobes. Strict
disorders referred to as channelopathies. The heart may
vascular territories are not respected, and cerebral angi-
also be involved, resulting in life-threatening complica-
ography fails to demonstrate lesions of the major cere-
tions (Table 48-10).
bral blood vessels.
MELAS is caused by maternally inherited point
mutations of mitochondrial tRNA genes. Most of the CALCIUM CHANNEL DISORDERS OF
tRNA mutations are lethal, accounting for the paucity MUSCLE
of multigeneration families with this syndrome. The
Hypokalemic periodic paralysis (HypoKPP)
A3243G point mutation in tRNALeu(UUR) is the most
common, occurring in 80% of MELAS cases. About Onset occurs at adolescence. Men are more often
10% of MELAS patients have other mutations of the affected because of decreased penetrance in women. Epi-
tRNALeu(UUR) gene, including 3252G, 3256T, 3271C, sodic weakness with onset after age 25 is almost never
and 3291C. Other tRNA gene mutations have also due to periodic paralyses, with the exception of thyro-
been reported in MELAS, including G583A tRNAPhe, toxic periodic paralysis (discussed later). Attacks are often
TABLE 48-10 641
CLINICAL FEATURES OF PERIODIC PARALYSIS AND NONDYSTROPHIC MYOTONIAS
CALCIUM CHANNEL SODIUM CHANNEL POTASSIUM CHANNEL
Mode of inheritance AD AD AD AD
Age of onset Adolescence Early childhood Early childhood Early childhood
b
Myotonia No Yes Yes No
Episodic weakness Yes Yes Yes Yes
Frequency of attacks Daily to yearly May be 23/d With cold, usually rare Daily to yearly
of weakness
Duration of attacks of 212 h From 12 h to >1 d 224 h 224 h
weakness
Serum K+ level during Decreased Increased or Usually normal Variable
attacks of weakness normal
CHAPTER 48
Effect of K+ loading No change Increased Increased myotonia No change
myotonia, then
weakness
Effect of muscle No change Increased myo- Increased myotonia, then No change
cooling tonia weakness
Fixed weakness Yes Yes Yes Yes
provoked by meals high in carbohydrates or sodium studies are normal, with the exception that myopathic
and may accompany rest following prolonged exercise. MUAPs may be seen in patients with xed weakness.
Weakness usually affects proximal limb muscles more HypoKPP is caused by mutations in either of two
than distal. Ocular and bulbar muscles are less likely to be genes. HypoKPP type 1, the most common form,
affected. Respiratory muscles are usually spared but when is inherited as an autosomal dominant disorder with
they are involved, the condition may prove fatal. Weak- incomplete penetrance. These patients have mutations
ness may take as long as 24 h to resolve. Life-threatening in the voltage-sensitive, skeletal muscle calcium chan-
cardiac arrhythmias related to hypokalemia may occur nel gene, CALCL1A3 (Fig. 48-8). Approximately 10%
during attacks. As a late complication, patients com- of cases are HypoKPP type 2, arising from mutations in
monly develop severe, disabling proximal lower extrem- the voltage-sensitive sodium channel gene (SCN4A).
ity weakness. In either instance, the mutations lead to an abnormal
Attacks of thyrotoxic periodic paralysis resemble gating pore current that predisposes the muscle cell to
those of primary HypoKPP. Despite a higher incidence depolarize when potassium levels are low. It is also now
of thyrotoxicosis in women, men, particularly those of recognized that some cases of thyrotoxic HypoKPP are
Asian descent, are more likely to manifest this compli- caused by genetic variants in a potassium channel (Kir
cation. Attacks abate with treatment of the underlying 2.6), whose expression is regulated by thyroid hormone.
thyroid condition. The chloride channel is envisioned to have 10
A low serum potassium level during an attack, membrane-spanning domains. The positions of muta-
excluding secondary causes, establishes the diagnosis. tions causing dominantly and recessively inherited myo-
Interattack muscle biopsies show the presence of single tonia congenita are indicated, along with mutations that
or multiple centrally placed vacuoles or tubular aggre- cause this disease in mice and goats.
gates. Provocative tests with glucose and insulin to
establish a diagnosis are usually not necessary and are
potentially hazardous. TREATMENT Hypokalemic Periodic Paralysis
In the midst of an attack of weakness, motor conduc-
The acute paralysis improves after the administration of
tion studies may demonstrate reduced amplitudes, whereas
potassium. Muscle strength and ECG should be moni-
EMG may show electrical silence in severely weak mus-
tored. Oral KCl (0.20.4 mmol/kg) should be given every
cles. In between attacks, the EMG and nerve conduction
642 Sodium channel subunit
I II III IV
patients require treatment with triamterine (25100
mg/d) or spironolactone (25100 mg/d). However, in
Outside
patients with HypoKPP type 2, attacks of weakness can
1 234 5 6 be exacerbated with acetazolamide.
Inside
1
NH3 COO2
HyperKPP PC PAM
SODIUM CHANNEL DISORDERS OF
Calcium channel subunit
MUSCLE
I II III IV
H H G Hyperkalemic periodic paralysis (HyperKPP)
Outside
R R The term hyperkalemic is misleading since patients are
often normokalemic during attacks. The fact that attacks
Inside are precipitated by potassium administration best denes
1 the disease. The onset is in the rst decade; males and
NH3
COO2 females are affected equally. Attacks are brief and mild,
SECTION III
NH3 COO2 muscles stiff and painful. This disorder can be confused
with paramyotonia congenita, myotonia congenita, and
Myotonia Congenita Myotonia Congenita ADR (murine)
Dominant Recessive insertion proximal myotonic myopathy (DM2).
Myotonic goat adrmto (murine) Potassium may be slightly elevated but may also be
Ala Pro stop
normal during an attack. As in HypoKPP, nerve con-
FIGURE 48-8 duction studies in HyperKPP muscle may demonstrate
The sodium and calcium channels are depicted here reduced motor amplitudes and the EMG may be silent
as containing four homologous domains, each with six in very weak muscles. In between attacks of weakness,
membrane-spanning segments. The fourth segment of each the conduction studies are normal. The EMG will often
domain bears positive charges and acts as the voltage sen- demonstrate myotonic discharges during and between
sor for the channel. The association of the four domains attacks.
is thought to form a pore through which ions pass. Sodium The muscle biopsy shows vacuoles that are smaller,
channel mutations are shown along with the phenotype that less numerous, and more peripheral compared to the
they confer. HyperKPP, hyperkalemic periodic paralysis; PC, hypokalemic form or tubular aggregates. Provocative
paramyotonia congenita; PAM, potassium-aggravated myo- tests by administration of potassium can induce weak-
tonia. See text for details. ness but are usually not necessary to establish the diag-
nosis. HyperKPP and potassium-aggravated myotonia
30 min. Only rarely is IV therapy necessary (e.g., when
are inherited as autosomal dominant disorders. Muta-
swallowing problems or vomiting is present). Admin-
tions of the voltage-gated sodium channel SCN4A
istration of potassium in a glucose solution should be
gene (Fig. 48-8) cause these conditions. For patients
avoided because it may further reduce serum potas-
with frequent attacks, acetazolamide (1251000 mg/d)
sium levels. Mannitol is the preferred vehicle for admin-
is helpful. We have found mexiletine to be helpful in
istration of IV potassium. The long-term goal of therapy
patients with signicant myotonia.
is to avoid attacks. This may reduce late-onset, fixed
weakness. Patients should be made aware of the impor- Paramyotonia congenita
tance of a low-carbohydrate, low-sodium diet and con-
In paramyotonia congenita (PC), the attacks of weak-
sequences of intense exercise. Prophylactic administra-
ness are cold-induced or occur spontaneously and are
tion of acetazolamide (1251000 mg/d in divided doses)
mild. Myotonia is a prominent feature but worsens
reduces or may abolish attacks in HypoKPP type 1. Para-
with muscle activity (paradoxical myotonia). This is in
doxically the potassium is lowered, but this is offset by
contrast to classic myotonia in which exercise alleviates
the beneficial effect of metabolic acidosis. If attacks per-
the condition. Attacks of weakness are seldom severe
sist on acetazolamide, oral KCl should be added. Some
enough to require emergency room treatment. Over
time patients develop interattack weakness as they do in noted in infancy and early childhood. The severity less- 643
other forms of periodic paralysis. PC is usually associ- ens in the third to fourth decade. Myotonia is worsened
ated with normokalemia or hyperkalemia. by cold and improved by activity. The gait may appear
Serum CK is usually mildly elevated. Routine sen- slow and labored at rst but improves with walking.
sory and motor nerve conduction studies are normal. In Thomsens disease muscle strength is normal, but in
Cooling of the muscle often dramatically reduces the Beckers disease, which is usually more severe, there
amplitude of the compound muscle action potentials. may be muscle weakness. Muscle hypertrophy is usually
EMG reveals diffuse myotonic potentials in PC. Upon present. Myotonic discharges are prominently displayed
local cooling of the muscle, the myotonic discharges by EMG recordings.
disappear as the patient becomes unable to activate Serum CK is normal or mildly elevated. The muscle
MUAPs. biopsy shows hypertrophied bers. The disease is inher-
PC is inherited as an autosomal dominant condition; ited as dominant or recessive and is caused by mutations
voltage-gated sodium channel mutations (Fig. 48-8) are of the chloride channel gene (Fig. 48-8) that increase
responsible and thus this disorder is allelic with Hyper- muscle cell excitability. Many patients will not require
KPP and potassium-aggravated myotonia. Patients with treatment and learn that the symptoms improve with
PC seldom seek treatment during attacks. Oral adminis- activity. Medications that can be used to decrease myo-
tration of glucose or other carbohydrates hastens recovery. tonia include quinine, phenytoin, and mexiletine.
CHAPTER 48
Since interattack weakness may develop after repeated epi-
sodes, prophylactic treatment is usually indicated. Thiazide
diuretics (e.g., chlorothiazide, 2501000 mg/d) and mexi-
letine (slowly increase dose from 450 mg/d) are reported ENDOCRINE AND METABOLIC
to be helpful. Patients should be advised to increase carbo- MYOPATHIES
hydrates in their diet.
CHAPTER 48
but the weakness can occur
without their use. Chronic steroid
administration produces pre-
MYOPATHIES OF SYSTEMIC ILLNESS dominantly proximal weakness.
Nondepolarizing Acute quadriplegic myopathy can
Systemic illnesses such as chronic respiratory, cardiac, neuromuscular occur with or without concomi-
or hepatic failure are frequently associated with severe blocking agents tant glucocorticoids.
CHAPTER 48
induced by D-penicillamine, with a higher incidence and antimicrotubular drugs (colchicine) (Table 48-11).
estimated at 7%. These disorders resolve with drug Muscle biopsy can be useful in the identication of tox-
withdrawal, although immunosuppressive therapy may icity since autophagic vacuoles are prominent patho-
be warranted in severe cases. logic features of these toxins.
Marinos C. Dalakas
The inammatory myopathies represent the largest group associated with muscle wasting. Sensation remains
of acquired and potentially treatable causes of skeletal normal. The tendon reexes are preserved but may be
muscle weakness. They are classied into three major absent in severely weakened or atrophied muscles, espe-
groups: polymyositis (PM), dermatomyositis (DM), and cially in IBM, where atrophy of the quadriceps and the
inclusion body myositis (IBM). distal muscles is common. Myalgia and muscle tender-
ness may occur in a small number of patients, usually
early in the disease, and particularly in DM associated
CLINICAL FEATURES with connective tissue disorders. Weakness in PM and
The prevalence of the inammatory myopathies is esti- DM progresses subacutely over a period of weeks or
mated at 1 in 100,000. PM as a stand-alone entity is a months and rarely acutely; by contrast, IBM progresses
rare disease. DM affects both children and adults and very slowly, over years, simulating a late-life muscular
women more often than men. IBM is three times more dystrophy (Chap. 48) or slowly progressive motor neu-
frequent in men than in women, more common in ron disorder (Chap. 32).
whites than blacks, and is most likely to affect persons
aged >50 years.
These disorders present as progressive and symmet- SPECIFIC FEATURES
ric muscle weakness except for IBM, which can have (Table 49-1)
an asymmetric pattern. Patients usually report increas-
ing difculty with everyday tasks requiring the use of
Polymyositis
proximal muscles, such as getting up from a chair,
climbing steps, stepping onto a curb, lifting objects, or The actual onset of PM is often not easily determined,
combing hair. Fine-motor movements that depend on and patients typically delay seeking medical advice for
the strength of distal muscles, such as buttoning a shirt, several weeks or even months. This is in contrast to
sewing, knitting, or writing, are affected only late in the DM, in which the rash facilitates early recognition (dis-
course of PM and DM, but fairly early in IBM. Falling cussed later). PM mimics many other myopathies and is
is common in IBM because of early involvement of the a diagnosis of exclusion. It is a subacute inammatory
quadriceps muscle, with buckling of the knees. Ocular myopathy affecting adults, and rarely children, who do
muscles are spared, even in advanced, untreated cases; not have any of the following: rash, involvement of the
if these muscles are affected, the diagnosis of inam- extraocular and facial muscles, family history of a neuro-
matory myopathy should be questioned. Facial muscles muscular disease, history of exposure to myotoxic drugs
are unaffected in PM and DM, but mild facial muscle or toxins, endocrinopathy, neurogenic disease, muscular
weakness is common in patientswith IBM. In all forms dystrophy, biochemical muscle disorder (deciency of a
of inammatory myopathy, pharyngeal and neck-exor muscle enzyme), or IBM as excluded by muscle biopsy
muscles are often involved, causing dysphagia or dif- analysis (discussed later). As an isolated entity, PM is a
culty in holding up the head (head drop). In advanced rare (and overdiagnosed) disorder; more commonly,
and rarely in acute cases, respiratory muscles may also be PM occurs in association with a systemic autoimmune
affected. Severe weakness, if untreated, is almost always or connective tissue disease, or with a known viral or
648
TABLE 49-1 649
FEATURES ASSOCIATED WITH INFLAMMATORY MYOPATHIES
CHARACTERISTIC POLYMYOSITIS DERMATOMYOSITIS INCLUSION BODY MYOSITIS
CHAPTER 49
a
Systemic lupus erythematosus, rheumatoid arthritis, Sjgrens syndrome, systemic sclerosis, mixed connective tissue disease.
b
Crohns disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylos-
ing spondylitis, Behets syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimotos disease, granulomatous
diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasakis disease, autoimmune throm-
bocytopenia, hypergammaglobulinemic purpura, hereditary complement deciency, IgA deciency.
c
HIV (human immunodeciency virus) and HTLV-I (human T cell lymphotropic virus type I).
d
Drugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), and contaminated tryptophan (dermatomyositis-like
bacterial infection. Drugs, especially D-penicillamine, DM usually occurs alone but may overlap with
statins, or zidovudine (AZT), may also trigger an scleroderma and mixed connective tissue disease. Fasci-
inammatory myopathy similar to PM. itis and thickening of the skin, similar to that seen in
chronic cases of DM, have occurred in patients with the
eosinophilia-myalgia syndrome associated with the inges-
Dermatomyositis tion of contaminated L-tryptophan.
DM is a distinctive entity identied by a characteristic
rash accompanying, or more often preceding, muscle
Inclusion body myositis
weakness. The rash may consist of a blue-purple dis-
coloration on the upper eyelids with edema (helio- In patients 50 years of age, IBM is the most com-
trope rash), a at red rash on the face and upper trunk, mon of the inammatory myopathies. It is often mis-
and erythema of the knuckles with a raised violaceous diagnosed as PM and is suspected only later when a
scaly eruption (Gottrons sign). The erythematous rash patient with presumed PM does not respond to therapy.
can also occur on other body surfaces, including the Weakness and atrophy of the distal muscles, especially
knees, elbows, malleoli, neck and anterior chest (often foot extensors and deep nger exors, occur in almost
in a V sign), or back and shoulders (shawl sign), and may all cases of IBM and may be a clue to early diagnosis.
worsen after sun exposure. In some patients, the rash is Some patients present with falls because their knees col-
pruritic, especially on the scalp, chest, and back. Dilated lapse due to early quadriceps weakness. Others present
capillary loops at the base of the ngernails are also with weakness in the small muscles of the hands, espe-
characteristic. The cuticles may be irregular, thickened, cially nger exors, and complain of inability to hold
and distorted, and the lateral and palmar areas of the objects such as golf clubs or perform tasks such as turn-
ngers may become rough and cracked, with irregu- ing keys or tying knots. On occasion, the weakness and
lar, dirty horizontal lines, resembling mechanics hands. accompanying atrophy can be asymmetric and selec-
The weakness can be mild, moderate, or severe enough tively involve the quadriceps, iliopsoas, triceps, biceps,
to lead to quadriparesis. At times, the muscle strength and nger exors, resembling a lower motor neuron
appears normal, hence the term dermatomyositis sine myo- disease. Dysphagia is common, occurring in up to 60%
sitis. When muscle biopsy is performed in such cases, of IBM patients, and may lead to episodes of choking.
however, signicant perivascular and perimysial inam- Sensory examination is generally normal; some patients
mation is often seen. have mildly diminished vibratory sensation at the ankles
650 that presumably is age-related. The pattern of distal 7. Arthralgias, synovitis, or deforming arthropathy with
weakness, which supercially resembles motor neuron subluxation in the interphalangeal joints can occur
or peripheral nerve disease, results from the myopathic in some patients with DM and PM who have Jo-1
process affecting distal muscles selectively. Disease pro- antibodies (discussed later).
gression is slow but steady, and most patients require
an assistive device such as cane, walker, or wheelchair Association with malignancies
within several years of onset.
In at least 20% of cases, IBM is associated with sys- Although all the inammatory myopathies can have a
temic autoimmune or connective tissue diseases. Famil- chance association with malignant lesions, especially
ial aggregation of typical IBM may occur; such cases in older age groups, the incidence of malignant con-
have been designated as familial inammatory IBM. This ditions appears to be specically increased only in
disorder is distinct from hereditary inclusion body myopa- patients with DM and not in those with PM or IBM.
thy (h-IBM), which describes a heterogeneous group of The most common tumors associated with DM are
recessive, and less frequently dominant, inherited syn- ovarian cancer, breast cancer, melanoma, colon can-
dromes; the h-IBMs are noninammatory myopathies. cer, and non-Hodgkins lymphoma. The extent of the
A subset of h-IBM that spares the quadriceps muscles search that should be conducted for an occult neoplasm
has emerged as a distinct entity. This disorder, originally in adults with DM depends on the clinical circum-
SECTION III
described in Iranian Jews and now seen in many ethnic stances. Tumors in these patients are usually uncovered
groups, is linked to chromosome 9p1 and results from by abnormal ndings in the medical history and physi-
mutations in the UDP-N-acetylglucosamine 2-epimerase/ cal examination and not through an extensive blind
N-acetylmannosamine kinase (GNE) gene. search. The weight of evidence argues against per-
forming expensive, invasive, and nondirected tumor
searches. A complete annual physical examination with
Diseases of the Nervous System
CHAPTER 49
nomenon, nonerosive arthritis, and the MHC molecules kines and chemokines, induces expression of vascular cell
Molecular mimicry,
tumors, viruses?
C1 C3a
C4
C3bNEO
B cell
T cell
Cytokines
NO, TNF-
STAT-1, Chemokines,
Cathepsin, TGF-
FIGURE 49-1
Immunopathogenesis of dermatomyositis. Activation of plasmacytoid dendritic cells, CD4 T cells, and macrophages
complement, possibly by autoantibodies (Y), against endo- trafc from the circulation to the muscle. Endothelial expres-
thelial cells and formation of C3 via the classic or alternative sion of vascular cell adhesion molecule (VCAM) and inter-
pathway. Activated C3 leads to formation of C3b, C3bNEO, cellular adhesion molecule (ICAM) is induced by cytokines
and membrane attack complexes (MAC), which are depos- released by the mononuclear cells. Integrins, specically
ited in and around the endothelial cell wall of the endomysial very late activation antigen (VLA)-4 and lymphocyte function
capillaries. Deposition of MAC leads to destruction of cap- associated antigen (LFA)-1, bind VCAM and ICAM and pro-
illaries, ischemia, or microinfarcts, most prominent in the mote T cell and macrophage inltration of muscle through
periphery of the fascicles, and perifascicular atrophy. B cells, the endothelial cell wall.
652 adhesion molecule (VCAM) 1 and intercellular adhesion muscle bers, is probably induced by cytokines secreted
molecule (ICAM) 1 on endothelial cells, and facilitates by activated T cells and macrophages. The CD8/
migration of activated lymphoid cells to the perimysial MHC-I complex is characteristic of PM and IBM; its
and endomysial spaces. Necrosis of the endothelial cells, detection can aid in conrming the histologic diagnosis
reduced numbers of endomysial capillaries, ischemia, and of PM, as discussed later. The cytotoxic CD8 T cells
muscle-ber destruction resembling microinfarcts occur. contain perforin and granzyme granules directed toward
The remaining capillaries often have dilated lumens in the surface of the muscle bers and capable of induc-
response to the ischemic process. Larger intramuscular ing myonecrosis. Analysis of T cell receptor molecules
blood vessels may also be affected in the same pattern. expressed by the inltrating CD8 cells has revealed
Residual perifascicular atrophy reects the endofascicular clonal expansion and conserved sequences in the anti-
hypoperfusion that is prominent in the periphery of mus- gen-binding region, both suggesting an antigen-driven
cle fascicles. Increased expression of type I interferon- T cell response. Whether the putative antigens are
inducible proteins is also noted in these regions. endogenous (e.g., muscle) or exogenous (e.g., viral)
By contrast, in PM and IBM a mechanism of T sequences is unknown. Viruses have not been identied
cellmediated cytotoxicity is likely. CD8 T cells, along within the muscle bers. Co-stimulatory molecules and
with macrophages, initially surround and eventually their counterreceptors, which are fundamental for T cell
invade and destroy healthy, nonnecrotic muscle bers activation and antigen recognition, are strongly upreg-
SECTION III
that aberrantly express class I MHC molecules. MHC-I ulated in PM and IBM. Key molecules involved in
expression, absent from the sarcolemma of normal T cellmediated cytotoxicity are depicted in Fig. 49-2.
Antigen
Macrophage
Systemic immune compartment
Diseases of the Nervous System
Co-stimulation MHC
TCR Clonal expansion
CD8
Infection?
CD8
Integrins
Chemokines VCAM-1
LFA-4
(MCP-1, Mig, IP-10) MMPs
CD8 CD8
Cytokines
IFN- TNF-
MMP-9 IL-1, 2
CD28 CTLA-4 LFA-1
TCR IFN-
BB1 ICAM-1 MMP-9
MMP-2 TFN-
MHC-I Perforin IL-1, 2
Calnexin
MHC-I
Ag Necrosis
(virus, muscle
peptide) TAP 2m
Endoplasmic reticulum
FIGURE 49-2
Cell-mediated mechanisms of muscle damage in poly- cells and their attachment to the muscle surface. Muscle ber
myositis (PM) and inclusion body myositis (IBM). Antigen- necrosis occurs via perforin granules released by the autoag-
specic CD8 cells are expanded in the periphery, cross the gressive T cells. A direct myocytotoxic effect exerted by the
endothelial barrier, and bind directly to muscle bers via T cell cytokines interferon (IFN) , interleukin (IL) 1, or tumor necrosis
receptor (TCR) molecules that recognize aberrantly expressed factor (TNF) may also play a role. Death of the muscle ber
MHC-I. Engagement of co-stimulatory molecules (BB1 and is mediated by necrosis. MHC class I molecules consist of a
ICOSL) with their ligands (CD28, CTLA-4, and ICOS), along heavy chain and a light chain [2 microglobulin (2m)] com-
with ICAM-1/LFA-1, stabilize the CD8muscle ber interac- plexed with an antigenic peptide that is transported into the
tion. Metalloproteinases (MMPs) facilitate the migration of T endoplasmic reticulum by TAP proteins.
The role of nonimmune factors in IBM related to long-term therapy with AZT, character- 653
ized by fatigue, myalgia, mild muscle weakness, and
In IBM, the presence of Congo redpositive amy- mild elevation of creatine kinase (CK). AZT-induced
loid deposits within some vacuolated muscle bers and myopathy, which generally improves when the drug
abnormal mitochondria with cytochrome oxidase is discontinued, is a mitochondrial disorder character-
negative bers suggest that, in addition to the autoim- ized histologically by ragged-red bers. AZT inhib-
mune component, there is also a degenerative process. its -DNA polymerase, an enzyme found solely in the
Similar to Alzheimers disease, the intracellular amyloid mitochondrial matrix.
deposits in IBM are immunoreactive against amyloid
precursor protein (APP), -amyloid, chymotrypsin,
apolipoprotein E, presenilin, ubiquitin, and phosphor-
ylated tau, but it is unclear whether these deposits,
DIFFERENTIAL DIAGNOSIS
which are also seen in other vacuolar myopathies, are
directly pathogenic or represent secondary phenom- The clinical picture of the typical skin rash and proxi-
ena. The same is true for the mitochondrial abnormali- mal or diffuse muscle weakness has few causes other
ties, which may also be secondary to the effects of aging than DM. However, proximal muscle weakness with-
or a bystander effect of upregulated cytokines. Expres- out skin involvement can be due to many conditions
CHAPTER 49
sion of cytokines and upregulation of MHC class I by other than PM or IBM.
the muscle bers may cause an endoplasmic reticulum
stress response resulting in intracellular accumulation of
stressor molecules or misfolded glycoproteins and acti- Subacute or chronic progressive muscle
vation of nuclear factor B (NF-B), leading to further weakness
cytokine activation. This may be due to denervating conditions such as the
ferase deciency (Chap. 48). Several animal parasites, present. The disorder may develop after a viral infec-
including protozoa (Toxoplasma, Trypanosoma), cestodes tion or in association with cancer. Some patients have
(cysticerci), and nematodes (trichinae), may produce a antibodies against signal recognition particle (SRP). The
focal or diffuse inammatory myopathy known as para- muscle biopsy demonstrates necrotic bers inltrated
sitic polymyositis. Staphylococcus aureus, Yersinia, Streptococ- by macrophages but only rare, if any, T cell inltrates.
cus, or anaerobic bacteria may produce a suppurative Muscle MHC-I expression is only slightly and focally
Diseases of the Nervous System
myositis, known as tropical polymyositis, or pyomyositis. upregulated. The capillaries may be swollen with hya-
Pyomyositis, previously rare in the West, is now occa- linization, thickening of the capillary wall, and deposi-
sionally seen in AIDS patients. Other bacteria, such as tion of complement. Some patients respond to immu-
Borrelia burgdorferi (Lyme disease) and Legionella pneu- notherapy, but others are resistant.
mophila (Legionnaires disease), may infrequently cause
myositis.
Patients with periodic paralysis experience recur- Hyperacute necrotizing fasciitis/myositis
(esh-eating disease)
rent episodes of acute muscle weakness without pain,
always beginning in childhood. Chronic alcoholics may This a fulminant infectious disease, seen most often in
develop painful myopathy with myoglobinuria after a the tropics or in conditions with poor hygiene, char-
bout of heavy drinking. Acute painless muscle weakness acterized by widespread necrosis of the supercial fas-
with myoglobinuria may occur with prolonged hypoka- cia and muscle of a limb; if the scrotum, perineum, and
lemia, or hypophosphatemia and hypomagnesemia, usu- abdominal wall are affected, the condition is referred
ally in chronic alcoholics or in patients on nasogastric to as Fourniers gangrene. It may be caused by group
suction receiving parenteral hyperalimentation. A -hemolytic streptococcus, methicillin-sensitive S.
aureus, Pseudomonas aeruginosa, Vibrio vulnicus, clostridial
species (gas gangrene), or polymicrobial infection with
Myofasciitis
anaerobes and facultative bacteria; toxins from these
This distinctive inammatory disorder affecting muscle bacteria may act as superantigens. The port of bacte-
and fascia presents as diffuse myalgias, skin induration, rial entry is usually a trivial cut or skin abrasion and the
fatigue, and mild muscle weakness; mild elevations of source is contact with carriers of the organism. Indi-
serum CK are usually present. The most common form viduals with diabetes mellitus, immunodeciency states,
is eosinophilic myofasciitis characterized by periph- or systemic illnesses such as liver failure are most sus-
eral blood eosinophilia and eosinophilic inltrates in ceptible. Systemic varicella is a predisposing factor in
the endomysial tissue. In some patients, the eosino- children.
philic myositis/fasciitis occurs in the context of parasitic The disease presents with swelling, pain, and redness
infections, vasculitis, mixed connective tissue disease, in the involved area followed by a rapid tissue necrosis
hypereosinophilic syndrome, or toxic exposures (e.g., of fascia and muscle that progresses at an estimated rate
toxic oil syndrome, contaminated L-tryptophan) or of 3 cm/h. Emergency debridement, antibiotics, as well
with mutations in the calpain gene. A distinct subset as IVIg, or even hyperbaric oxygen have been recom-
of myofasciitis is characterized by pronounced inl- mended. In progressive or advanced cases, amputation
tration of the connective tissue around the muscle by of the affected limb may be necessary to avoid a fatal
sheets of periodic acidSchiff-positive macrophages outcome.
Drug-induced myopathies patients show some response to nonsteroidal anti- 655
inammatory agents or glucocorticoids, though most
D-Penicillamine, procainamide, and statins may produce
continue to have indolent complaints. An indolent fas-
a true myositis resembling PM, and a DM-like illness ciitis in the setting of an ill-dened connective tissue
had been associated with the contaminated prepara- disorder may be present, and these patients should not
tions of L-tryptophan. As noted earlier, AZT causes a be labeled as having a psychosomatic disorder. Chronic
mitochondrial myopathy. Other drugs may elicit a fatigue syndrome, which may follow a viral infection,
toxic noninammatory myopathy that is histologi- can present with debilitating fatigue, fever, sore throat,
cally different from DM, PM, or IBM. These include painful lymphadenopathy, myalgia, arthralgia, sleep
cholesterol-lowering agents such as clobrate, lovas- disorder, and headache (Chap. 52). These patients do
tatin, simvastatin, or provastatin, especially when com- not have muscle weakness, and the muscle biopsy is
bined with cyclosporine, amiodarone, or gembrozil. normal.
Statin-induced necrotizing myopathy or asymptomatic
elevations of CK usually improve after discontinuation
of the drug. In rare patients, however, muscle weakness DIAGNOSIS
continues to progress even after the statin is withdrawn; The clinically suspected diagnosis of PM, DM, or IBM
in these cases, a diagnostic muscle biopsy is indicated, is conrmed by analysis of serum muscle enzymes,
CHAPTER 49
and if evidence of inammation and MHC-I upregula- EMG ndings, and muscle biopsy (Table 49-2).
tion is present, immunotherapy for PM should be con- The most sensitive enzyme is CK, which in active
sidered. Rhabdomyolysis and myoglobinuria have been disease can be elevated as much as ftyfold. Although
rarely associated with amphotericin B, -aminocaproic the CK level usually parallels disease activity, it can be
acid, fenuramine, heroin, and phencyclidine. The use normal in some patients with active IBM or DM, espe-
of amiodarone, chloroquine, colchicine, carbimazole, cially when associated with a connective tissue disease.
emetine, etretinate, ipecac syrup, chronic laxative or
a
Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a sub-
acute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no
exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy ndings).
b
In some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new
Diseases of the Nervous System
onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness.
c
See text for details.
d
An adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive
to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis.
e
If the muscle biopsy does not contain vacuolated bers but shows chronic myopathy with hypertrophic bers, primary inammation with the
CD8/MHC-I complex and cytochrome oxygenasenegative bers, the diagnosis is probable inclusion body myositis.
f
If rash is absent but muscle biopsy ndings are characteristic of dermatomyositis, the diagnosis is probable dermatomyositis.
sarcolemma, even in bers not invaded by CD8+ cells. disorders with secondary, nonspecic, inammation,
The CD8/MHC-I lesion is characteristic and essen- such as in some muscular dystrophies. When the disease
tial to conrm or establish the diagnosis and to exclude is chronic, connective tissue is increased and may react
positively with alkaline phosphatase.
In DM the endomysial inammation is predomi-
nantly perivascular or in the interfascicular septae and
aroundrather than withinthe muscle fascicles (Fig.
49-4). The intramuscular blood vessels show endothelial
hyperplasia with tubuloreticular proles, brin thrombi,
and obliteration of capillaries. The muscle bers
undergo necrosis, degeneration, and phagocytosis, often
in groups involving a portion of a muscle fasciculus in a
wedgelike shape or at the periphery of the fascicle, due
to microinfarcts within the muscle. This results in peri-
fascicular atrophy, characterized by 210 layers of atro-
phic bers at the periphery of the fascicles. The pres-
ence of perifascicular atrophy is diagnostic of DM, even
in the absence of inammation.
In IBM (Fig. 49-5), there is endomysial inammation
FIGURE 49-3 with T cells invading MHC-I-expressing nonvacuolated
Cross-section of a muscle biopsy from a patient with muscle bers; basophilic granular deposits distributed
polymyositis demonstrates scattered inammatory foci with around the edge of slitlike vacuoles (rimmed vacuoles);
lymphocytes invading or surrounding muscle bers. Note loss of bers, replaced by fat and connective tissue,
lack of chronic myopathic features (increased connective hypertrophic bers, and angulated or round bers; rare
tissue, atrophic or hypertrophic bers) as seen in inclusion eosinophilic cytoplasmic inclusions; abnormal mito-
body myositis. chondria characterized by the presence of ragged-red
bers or cytochrome oxidasenegative bers; and amy- 657
loid deposits within or next to the vacuoles best visual-
ized with crystal violet or Congo-red staining viewed
with uorescent optics. Electron microscopy dem-
onstrates lamentous inclusions in the vicinity of the
rimmed vacuoles. In at least 15% of patients with the
typical clinical phenotype of IBM, no vacuoles or amy-
loid deposits can be identied in muscle biopsy, leading
to an erroneous diagnosis of PM. Close clinicopatho-
logic correlations are essential; if uncertain, a repeat
muscle biopsy from another site is often helpful.
CHAPTER 49
dermatomyositis demonstrates atrophy of the bers at the and ameliorate the extramuscular manifestations (rash,
periphery of the fascicle (perifascicular atrophy).
FIGURE 49-5
Cross-sections of a muscle biopsy from a patient with of amyloid visualized with crystal violet (B), cytochrome oxi-
inclusion body myositis demonstrate the typical features dasenegative bers, indicative of mitochondrial dysfunction
of vacuoles with lymphocytic inltrates surrounding non- (C), and ubiquitous MHC-I expression at the periphery of all
vacuolated or necrotic bers (A), tiny endomysial deposits bers (D).
658 dysphagia, dyspnea, fever). When strength improves, appear, attempts to lower the prednisone dose
the serum CK falls concurrently; however, the reverse is repeatedly result in a new relapse, or rapidly pro-
not always true. Unfortunately, there is a common ten- gressive disease with evolving severe weakness and
dency to chase or treat the CK level instead of the mus- respiratory failure develops.
cle weakness, a practice that has led to prolonged and The following drugs are commonly used but
unnecessary use of immunosuppressive drugs and erro- have never been tested in controlled studies: (1)
neous assessment of their efficacy. It is prudent to dis- Azathioprine is well tolerated, has few side effects,
continue these drugs if, after an adequate trial, there is and appears to be as effective for long-term therapy
no objective improvement in muscle strength whether as other drugs. The dose is up to 3 mg/kg daily. (2)
or not CK levels are reduced. Agents used in the treat- Methotrexate has a faster onset of action than aza-
ment of PM and DM include the following: thioprine. It is given orally starting at 7.5 mg weekly
for the first 3 weeks (2.5 mg every 12 h for 3 doses),
1. Glucocorticoids. Oral prednisone is the initial treat-
with gradual dose escalation by 2.5 mg per week to
ment of choice; the effectiveness and side effects of
a total of 25 mg weekly. A rare side effect is metho-
this therapy determine the future need for stronger
trexate pneumonitis, which can be difficult to distin-
immunosuppressive drugs. High-dose prednisone,
guish from the interstitial lung disease of the primary
at least 1 mg/kg per day, is initiated as early in the
myopathy associated with Jo-1 antibodies (described
SECTION III
CHAPTER 49
every-other-day prednisone along with mycophenolate maintenance therapy. Up to 30% may be left with some
in an effort to slow disease progression, even though residual muscle weakness. Relapses may occur at any
there is no objective evidence or controlled study to time.
support this practice. In two controlled studies of IVIg in IBM has the least favorable prognosis of the inflam-
IBM, minimal benefit in up to 30% of patients was found; matory myopathies. Most patients will require the use
the strength gains, however, were not of sufficient mag- of an assistive device such as a cane, walker, or wheel-
nitude to justify its routine use. Another trial of IVIg com- chair within 510 years of onset. In general, the older
Inpatient neurologic consultations usually involve ques- is kept steady at higher MAP, but a rapid lowering of
tions about specic disease processes or prognostica- pressure can more easily lead to ischemia on the lower
tion after various cerebral injuries. Common reasons end of the autoregulatory curve. This autoregulatory
for neurologic consultation include stroke (Chap. 27), phenomenon is achieved through both myogenic and
seizures (Chap. 26), altered mental status (Chap. 16), neurogenic inuences causing small arterioles to con-
headache (Chap. 8), and management of coma and tract and dilate. When the systemic blood pressure
other neurocritical care conditions (Chaps. 17 and 28). exceeds the limits of this mechanism, breakthrough of
This chapter focuses on additional common reasons autoregulation occurs, resulting in hyperperfusion via
for consultation that are not addressed elsewhere in the increased cerebral blood ow, capillary leakage into the
text. interstitium, and resulting edema. The predilection of
all of the hyperperfusion disorders to affect the posterior
rather than anterior portions of the brain may be due
to a lower threshold for autoregulatory breakthrough in
CONSULTATIONS REGARDING CENTRAL the posterior circulation.
NERVOUS SYSTEM DYSFUNCTION While elevated or relatively elevated blood pressure
is common in many of these disorders, some hyperper-
HYPERPERFUSION STATES
fusion states such as calcineurin-inhibitor toxicity occur
A group of neurologic disorders shares the common with no apparent pressure rise. In these cases, vaso-
feature of hyperperfusion playing a key role in patho- genic edema is likely due primarily to dysfunction of
genesis. These seemingly diverse syndromes include the capillary endothelium itself, leading to breakdown
hypertensive encephalopathy, eclampsia, postcarotid of the blood-brain barrier. It is useful to separate dis-
endarterectomy syndrome, and toxicity from calci- orders of hyperperfusion into those caused primarily by
neurin-inhibitor medications. Modern imaging tech- increased pressure and those due mostly to endothe-
niques and experimental models suggest that vasogenic lial dysfunction from a toxic or autoimmune etiology
edema is usually the primary process leading to neuro- (Table 50-1). In reality, both of these pathophysiologic
logic dysfunction; therefore, prompt recognition and processes are likely playing some role in each of these
management of this condition should allow for clinical disorders.
recovery if superimposed hemorrhage or infarction has The clinical presentation of the hyperperfusion syn-
not occurred. dromes is similar with prominent headaches, seizures, or
The brains autoregulatory capability successfully focal decits. Headaches have no specic characteristics,
maintains a fairly stable cerebral blood ow in adults range from mild to severe, and may be accompanied
despite alterations in systemic mean arterial pressure by alterations in consciousness ranging from confusion
(MAP) ranging from 50150 mmHg. In patients with to coma. Seizures may be present, and these can be of
chronic hypertension, this cerebral autoregulation curve multiple types depending on the severity and location of
is shifted, resulting in autoregulation working over a the edema. Nonconvulsive seizures have been described
much higher range of pressures (e.g., 70175 mmHg). in hyperperfusion states; therefore, a low threshold for
In these hypertensive patients, cerebral blood ow obtaining an electroencephalogram (EEG) in these
660
TABLE 50-1 661
SOME COMMON ETIOLOGIES OF HYPERPERFUSION
SYNDROME
Disorders in which increased capillary pressure dominates
the pathophysiology
Hypertensive encephalopathy, including secondary
causes such as renovascular hypertension, pheochro-
mocytoma, cocaine use, etc.
Postcarotid endarterectomy syndrome
Preeclampsia/eclampsia
High-altitude cerebral edema
Disorders in which endothelial dysfunction dominates the
pathophysiology
Calcineurin-inhibitor toxicity
Chemotherapeutic agent toxicity (e.g., cytarabine, aza-
thioprine, 5-uorouracil, cisplatin, methotrexate)
CHAPTER 50
Glucocorticoids
Erythropoietin
FIGURE 50-1
HELLP syndrome (hemolysis, elevated liver enzyme
Axial uid-attenuated inversion recovery (FLAIR) MRI of
levels, low platelet count)
the brain in a patient taking cyclosporine after liver trans-
Thrombotic thrombocytopenic purpura (TTP) plantation, who presented with seizures, headache, and
CHAPTER 50
erative period and for the months to years thereafter. pathogens include the usual bacterial organisms associ-
Neurologic consultants should view these patients as a ated with surgical procedures and indwelling catheters.
special population at risk for both unique neurologic Starting in the second month posttransplant, opportu-
complications as well as for the usual disorders found in nistic infections of the CNS become more common,
any critically ill inpatient. including Nocardia and Toxoplasma species as well as
Immunosuppressive medications are administered in fungal infections such as aspergillosis. Viral infections
age. Despite this corrective mechanism, when hyper- monly, other cerebral processes such as meningitis or
natremia is severe (serum sodium >160 mmol/L [>160 stroke. In these cases, the degree of renal sodium excre-
meq/L]) or occurs rapidly, cellular metabolic processes tion can be remarkable, and large amounts of saline,
fail and encephalopathy will result. There are many eti- hypertonic saline, or oral sodium may need to be given
ologies of hypernatremia including, most commonly, in a judicious fashion in order to avoid complications
renal and extrarenal losses of water. Causes of neuro- from cerebral edema.
Diseases of the Nervous System
CALCIUM DISTURBANCES
RADIAL NEUROPATHY
Hypercalcemia usually occurs in the setting of either
hyperparathyroidism or systemic malignancy. Neuro- Radial nerve injury classically presents with weakness
logic manifestations include encephalopathy as well as of extension of the wrist and ngers (wrist drop)
muscle weakness due to reduced neuromuscular excit- with or without more proximal weakness of exten-
ability. Seizures can occur but are more common in sor muscles of the upper extremity, depending on the
states of low calcium. site of injury. Sensory loss is in the distribution of the
Hypocalcemia in adults often follows surgical treatment radial nerve, which includes the dorsum of the hand
of the thyroid or parathyroid. Seizures and altered mental (Fig. 50-3A). Compression at the level of the axilla,
status dominate the neurologic picture and usually resolve e.g., resulting from use of crutches, includes weakness
with calcium repletion. Tetany is due to spontaneous, of the triceps, brachioradialis, and supinator muscles in
repetitive action potentials in peripheral nerves and remains addition to wrist drop. A more common site of com-
CHAPTER 50
the classic sign of symptomatic hypocalcemia. pression occurs in the spiral groove of the upper arm
in the setting of a humerus fracture or from sleeping
with the arm draped over a bench or chair (Saturday
MAGNESIUM DISTURBANCES night palsy). Sparing of the triceps is the rule when the
nerve is injured in this location. Because extensors of
Disorders of magnesium are difcult to correlate with the upper extremity are injured preferentially in radial
serum levels because a very small amount of total-body nerve injury, these lesions may be mistaken for the
Lateral cutaneous
nerve of arm
Posterior cutaneous
nerve of arm
Lateral cutaneous
Posterior cutaneous nerve of calf
nerve of forearm Sensory distribution of the ulnar nerve
Superficial peroneal nerve
Superficial branch
Deep peroneal
nerve
D E
Sensory distribution
Anterior femoral
SECTION III
Saphenous nerve
Diseases of the Nervous System
FIGURE 50-3
Sensory distribution of peripheral nerves commonly affected by entrapment neuropathies. A. Radial nerve. B. Ulnar nerve.
C. Peroneal nerve. D. Femoral nerve. E. Lateral femoral cutaneous nerve.
nerve transposition and release of the exor carpi ulnaris PROXIMAL FEMORAL NEUROPATHY
aponeurosis.
Lesions of the proximal femoral nerve are relatively
uncommon but may present dramatically with weak-
PERONEAL NEUROPATHY
ness of hip exion, quadriceps atrophy, weakness of knee
The peroneal nerve winds around the head of the b- extension (often manifesting with leg-buckling falls), and
ula in the leg below the lateral aspect of the knee, and an absent patellar reex. Adduction of the thigh is spared
its supercial location at this site makes it vulnerable to as these muscles are supplied by the obturator nerve,
trauma. Patients present with weakness of foot dorsi- thereby distinguishing a femoral neuropathy from a more
exion (foot drop) as well as with weakness in ever- proximal lumbosacral plexus lesion. The sensory loss
sion but not inversion at the ankle. Sparing of inversion, found is in the distribution of the femoral nerve sensory
which is a function of muscles innervated by the tibial branches on the anterior part of the thigh (Fig. 50-3D).
nerve, helps to distinguish peroneal neuropathies from Compressive lesions from retroperitoneal hematomas or
L5 radiculopathies. Sensory loss involves the lat- masses are common, and a CT of the pelvis should be
eral aspect of the leg as well as the dorsum of the foot obtained in all cases of femoral neuropathy to exclude
(Fig. 50-3C). Fractures of the bular head may be these conditions. Bleeding into the pelvis resulting in
responsible for peroneal neuropathies, but in the peri- hematoma can occur spontaneously, following trauma,
operative setting poorly applied braces exerting pressure or after intrapelvic surgeries such as renal transplantation.
on the nerve while the patient is unconscious are more In intoxicated or comatose patients, stretch injuries to the
often responsible. Tight-tting stockings or casts of the femoral nerve are seen following prolonged, extreme hip
upper leg can also cause a peroneal neuropathy, and exion or extension. Rarely, attempts at femoral vein
thin individuals and those with recent weight loss are at or arterial puncture can be complicated by injury to this
increased risk. nerve.
LATERAL FEMORAL CUTANEOUS NERVE a herniated lumbar disc is not common during preg- 667
nancy, but compressive injuries of the lumbosacral
The symptoms of lateral femoral cutaneous nerve entrap- plexus do occur secondary to either the fetal head
ment, commonly known as meralgia paresthetica, passing through the pelvis or the use of forceps dur-
include sensory loss, pain, and dysesthesia in part of the ing delivery. These plexus injuries are more frequent
area supplied by the nerve (Fig. 50-3E). There is no with cephalopelvic disproportion and often present
motor component to the nerve, and therefore weakness with a painless unilateral foot drop which must be dis-
is not a part of this syndrome. Symptoms often are wors- tinguished from a peroneal neuropathy caused by pres-
ened by standing or walking. Compression of the nerve sure on the nerve while in lithotomy position during
occurs where it enters the leg near the inguinal ligament, delivery. Other compressive mononeuropathies of
usually in the setting of tight-tting belts, pants, corsets, pregnancy include meralgia paresthetica, carpal tun-
or recent weight gain, including that of pregnancy. The nel syndrome, femoral neuropathy when the thigh
differential diagnosis of these symptoms includes hip is abducted severely in an effort to facilitate delivery
problems such as trochanteric bursitis. of the fetal shoulder, and obturator neuropathy dur-
ing lithotomy positioning. The latter presents with
medial thigh pain that may be accompanied by weak-
OBSTETRIC NEUROPATHIES ness of thigh adduction. There is also a clear association
CHAPTER 50
Pregnancy and delivery place women at special risk between pregnancy and an increased frequency of idio-
for a variety of nerve injuries. Radiculopathy due to pathic facial palsy (Bells palsy).
ATLAS OF NEUROIMAGING
FIGURE 51-1
Limbic encephalitis (Chap. 44) lobes (arrow-heads) including the hippocampi (left greater
Coronal (A, B), axial uid-attenuated inversion recovery (FLAIR) than right) without signicant mass effect (arrows). There was
(C, D), and axial T2-weighted (E) MR images demonstrate no enhancement on postgadolinium images (not shown).
abnormal high signal involving the bilateral mesial temporal
668
669
CHAPTER 51
FIGURE 51-1
(continued )
Atlas of Neuroimaging
FIGURE 51-2
CNS tuberculosis Sagittal T2-weighted MR image of the cervical spine (D)
Axial T2-weighted MRI (A) demonstrates multiple lesions demonstrates a hypointense lesion in the subarachnoid
(arrows) with peripheral high signal and central low signal, space at the level of T5 (arrow).
located predominantly in the cortex and subcortical white mat- Sagittal T1-weighted MR image postgadolinium of the cervi-
ter, as well as in the basal ganglia. cal spine (E) demonstrates enhancement of the lesion in the
Axial T1-weighted MR images postgadolinium (B, C) dem- subarachnoid space at the level of T5 (arrow).
onstrate ring enhancement of the lesions (arrows) and addi-
tional lesions in the subarachnoid space (arrowheads).
670
SECTION III
Diseases of the Nervous System
FIGURE 51-3
Neurosyphilis
FIGURE 51-2 Case I
(continued ) Axial T2-weighted MR images (A, B) demonstrate well-
dened areas of abnormal high signal in the basal ganglia
bilaterally and in a wedge-shaped distribution in the right
parietal lobe (arrows).
Axial (C, D) T1-weighted images postgadolinium.
Coronal (E, F) T1-weighted images postgadolinium demon-
strate irregular ring enhancement of the lesions (arrows).
671
FIGURE 51-3
(continued )
672
SECTION III
Diseases of the Nervous System
FIGURE 51-4
Neurosyphilis Axial (B) and coronal (C) T1-weighted MR images postgad-
Case II olinium demonstrate peripheral enhancement of the lesion
Axial T2-weighted MRI (A) demonstrates a dural-based, (arrows).
peripherally hyperintense and centrally hypointense lesion
located lateral to the left frontal lobe (arrow).
673
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-5
Histoplasmosis of the pons Axial T1-weighted MR image postgadolinium (C) demon-
Axial FLAIR (A) and T2-weighted (B) MR images demonstrate strates ring enhancement of the lesion in the right pons
a low signal mass in the right pons (arrows) with surrounding (arrow). Of note, there was no evidence of restricted diffusion
vasogenic edema. (not shown).
674
SECTION III
Diseases of the Nervous System
FIGURE 51-6
Coccidiomycosis meningitis of the perimesencephalic cisterns (arrows), as well as the sylvian
Axial postcontrast CT (A) and axial (B) and coronal (C) T1- and interhemispheric ssures.
weighted MR images postgadolinium demonstrate enhancement
675
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-7
Candidiasis in a newborn Axial T1-weighted MR images postgadolinium (B, C) demon-
Axial T2-weighted MR image (A) demonstrates multiple strate marked enhancement of the lesions (arrowheads).
punctate foci of low signal diffusely distributed in the brain ADC map (D, E) demonstrates restricted diffusion of water
parenchyma (arrowhead). molecules in the lesions (arrowheads).
676
SECTION III
Diseases of the Nervous System
FIGURE 51-8
CNS aspergillosis Axial T2-weighted MR images (C, D) demonstrate intrinsic
Axial FLAIR MR images (A, B) demonstrate multiple areas of low signal in the lesions (arrows), suggesting the presence
abnormal high signal in the basal ganglia as well as cortex of blood products. Some of the lesions also show vasogenic
and subcortical white matter (arrows). There is also abnormal edema. Coronal (E) and axial (F) T1-weighted MR images
high signal in the subarachnoid space adjacent to the lesions postgadolinium demonstrate peripheral enhancement of the
(arrowheads) that can correspond to blood or high protein lesions (arrows).
content.
677
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-9
Invasive sinonasal aspergillosis
Axial T2-weighted MR image (A) demonstrates an irregu-
larly shaped low signal lesion involving the left orbital apex
(arrow).
FIGURE 51-8 B. T1-weighted image pregadolinium demonstrates low sig-
(continued ) nal in left anterior clinoid process (arrow).
C. T1-weighted image postgadolinium demonstrates enhance-
ment of lesion (arrow).
678
SECTION III
FIGURE 51-9
(continued )
Diseases of the Nervous System
FIGURE 51-11
Neurosarcoid
Case I
Coronal (A) and axial (B) T1-weighted images postgado-
linium with fat suppression demonstrate a homogeneously
enhancing well-circumscribed mass centered in the left
Meckels cave (arrows).
FIGURE 51-10
Behets disease
Axial FLAIR MRI demonstrates abnormal high signal involv-
ing the anterior pons (arrow); following gadolinium adminis-
tration, the lesion was nonenhancing (not shown). Brainstem
lesions are typical of Behets disease, caused primarily by
vasculitis and in some cases demyelinating lesions.
679
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-13
Neurosarcoid
Case III
Axial FLAIR images (AE) demonstrate abnormal high signal
and slight expansion in the midbrain, dorsal pons, and pineal
region (arrows) without signicant mass effect.
Sagittal T1-weighted images postgadolinium (F) with fat sup-
pression demonstrate abnormal enhancement in the mid-
brain, dorsal pons, and pineal region (arrows).
FIGURE 51-12
Neurosarcoid
Case II
Axial (A, B) and sagittal (C) T1-weighted images postgado-
linium with fat suppression demonstrate a homogeneously
enhancing mass involving the hypothalamus and the pituitary
stalk (arrows).
FIGURE 51-13
(continued )
SECTION III Diseases of the Nervous System
680
681
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-14
Neurosarcoid cerebral peduncles, bilateral gyrus rectus, right frontal lobe
Case IV periventricular white matter, and patchy areas in bilateral
Axial T2-weighted images (AD) demonstrate numerous temporal lobes.
areas of abnormal hyperintensity involving the corpus cal- T1-weighted images postgadolinium (EH) demonstrate
losum, left internal capsule and globus pallidus, bilateral abnormal enhancement of those areas with high T2 signal.
FIGURE 51-14
(continued )
SECTION III Diseases of the Nervous System
682
683
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-16
Middle cerebral artery stenosis (Chap. 27)
Time-of-ight (TOF) MR angiography (MRA) (A, B) reveals
narrowing within the left M1 segment that is likely secondary
to atherosclerosis (arrows).
FIGURE 51-15
Histiocytosis
Sagittal T1-weighted image (A) demonstrates enlargement of
the pituitary stalk (arrow) and absence of the posterior pitu-
itary intrinsic T1 hyperintensity (arrowhead).
Sagittal and coronal T1-weighted images postgadolinium (B,
C) demonstrate enhancement of the pituitary stalk and infun-
dibulum (arrows).
684
SECTION III
Diseases of the Nervous System
FIGURE 51-17
Lacunar infarction (Chap. 27) frontal horn of the left lateral ventricle, suggestive of an old
Axial noncontrast CT (A) demonstrates abnormal hypoden- infarction (arrow). A small area of slight hyperintensity is also
sity involving the left anterior putamen and anterior limb of seen in the posterior limb of the right internal capsule that
internal capsule with ex-vacuo dilatation of the adjacent can correspond to an acute lacunar infarct (arrowhead).
frontal horn of the left lateral ventricle, suggestive of an old Diffusion-weighted image (C) and apparent diffusion coef-
infarction (arrow). A small area of slight hypodensity is also cient (ADC) map (D) demonstrate restricted water motion in
seen in the posterior limb of the right internal capsule that the lesion of the posterior limb of the right internal capsule,
can correspond to an acute infarct (arrowhead). strongly suggestive for an acute lacunar infarct (arrowhead).
Axial FLAIR MRI (B) demonstrates abnormal high sig- There is no evidence of restricted diffusion in the old infarct
nal involving the left anterior putamen and anterior limb of (arrow).
internal capsule with ex-vacuo dilatation of the adjacent
685
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-18
Cerebral autosomal dominant arteriopathy with subcor- white matter (arrows). Coronal FLAIR MRI (C, D) demon-
tical infarcts and leukoencephalopathy (CADASIL) (Chap. strates multiple patchy areas of abnormal high signal in the
27) periventricular white matter bilaterally, including the temporal
Axial T2-weighted MR images (A, B) demonstrate multiple lobes (arrows). In some of these areas, there are small areas
patchy areas of abnormal high signal in the periventricular of tissue loss (encephalomalacia) (arrowheads).
686
SECTION III
Diseases of the Nervous System
FIGURE 51-19
CNS vasculitis (Chap. 27) Conventional angiography (C) demonstrates multiple seg-
Axial noncontrast CT (A) demonstrates a large hyperdense ments of intracranial arterial narrowing, some of which have
intraparenchymal hematoma surrounded by hypodense vaso- associated adjacent areas of focal arterial dilatation. These
genic edema in the right parietal lobe. abnormalities are suggestive of vasculitis.
Axial T2-weighted MRI (B) demonstrates a large hypointense
intraparenchymal hematoma surrounded by hyperintense
vasogenic edema in the right parietal lobe.
687
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-20
Superior sagittal sinus thrombosis (Chap. 27) adjacent sulci. These ndings are suggestive of vasogenic
Noncontrast CT of the head (A) demonstrates increased den- edema with subarachnoid hemorrhage (arrowheads).
sity in the superior sagittal sinus, suggestive of thrombosis Diffusion-weighted images (E, F) and ADC maps (G, H) dem-
(arrow), and small linear hyperdensities in some temporal onstrate restricted diffusion of the abnormal areas on FLAIR,
lobe sulci, suggestive of subarachnoid hemorrhage (arrow- suggestive of infarct.
heads). Phase-contrast venography of the brain (I) demonstrates
Axial T1-weighted MRI (B) demonstrates absence of ow absence of signal in the superior sagittal sinus down to the
void in the superior sagittal sinus, suggestive of thrombosis. torcular herophili, and left transverse sinus and jugular vein.
Coronal FLAIR images (C, D) demonstrate areas of abnormal Axial (J) and coronal (K) T1-weighted images postgadolinium
high signal involving the gray and the subcortical white mat- demonstrate a lling defect in the superior sagittal sinus,
ter of the right frontal and left parietal lobes, as well as the suggestive of thrombosis.
FIGURE 51-20
(continued )
SECTION III Diseases of the Nervous System
688
689
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-21
Multiple system atrophy (Chap. 30)
Axial T2-weighted MR image (A) reveals symmetric poorly
circumscribed abnormal high signal in the middle cerebellar
peduncles bilaterally (arrowheads).
Sagittal T1-weighted MR image (B) demonstrates pontine
atrophy and enlarged cerebellar ssures as a result of cer-
ebellar atrophy (arrows).
FIGURE 51-20
(continued )
690
SECTION III
Diseases of the Nervous System
FIGURE 51-22
Huntingtons disease (Chap. 30) Axial (B) and coronal (C) FLAIR images demonstrate bilateral
Axial noncontrast CT (A) demonstrates symmetric bilateral symmetric abnormal high signal in the caudate and putamen.
severe atrophy involving the caudate nuclei, putamen, and Coronal T1-weighted image (D) demonstrates enlarged fron-
globus pallidi bilaterally with consequent enlargement of the tal horns with abnormal conguration. Also note diffusely
frontal horns of the lateral ventricles (arrows). There is also decreased marrow signal, which could represent anemia or
diffuse prominence of the sulci indicating generalized cortical myeloproliferative disease.
atrophy.
691
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-23
Bells palsy (Chap. 34) toid artery that enters the foramen and supplies the tympanic
Axial T1-weighted images postgadolinium with fat suppres- cavity, the tympanic antrum, mastoid cells, and the semicir-
sion (AC) demonstrate diffuse smooth linear enhancement cular canals.
along the left facial nerve, involving the second and third Coronal T1-weighted images postgadolinium with fat sup-
segments (genu, tympanic, and mastoid) within the tempo- pression (D, E) demonstrate the course of the enhancing
ral bone (arrows). Note that there is no evidence of a mass facial nerve (arrows). Although these ndings are highly sug-
lesion. A potential pitfall for facial nerve enhancement in the gestive of Bells palsy, the diagnosis is established on clinical
stylomastoid foramen is the enhancement of the stylomas- grounds.
692
SECTION III
FIGURE 51-24
Spinal cord infarction (Chap. 35) T1-weighted MR image of the lumbar spine postgadolinium
Diseases of the Nervous System
Sagittal T2-weighted MR image of the lumbar spine (A) dem- (B) demonstrates mild enhancement (arrow).
onstrates poorly dened areas of abnormal high signal in the Sagittal diffusion-weighted MR image of the lumbar spine
conus medullaris and mild cord expansion (arrow). (C) demonstrates restricted diffusion (arrow) in the areas of
abnormal high signal on the T2-weighted image (A).
FIGURE 51-25
Acute transverse myelitis (Chap. 35) Sagittal T1-weighted MR image postgadolinium (B) demon-
Sagittal T2-weighted MR image (A) demonstrates abnormal strates abnormal enhancement in the posterior half of the
high signal in the cervical cord extending from C1 to T1 with cord from C2 to T1 (arrows).
associated cord expansion (arrows).
693
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-26
Acute disseminated encephalomyelitis (ADEM) (Chap. 39) Following administration of gadolinium, corresponding axial
Axial T2-weighted (A) and coronal FLAIR (B) images demon- (C) and coronal (D) T1-weighted images demonstrate irregu-
strate abnormal areas of high signal involving predominantly lar enhancement consistent with blood-brain barrier break-
the subcortical white matter of the frontal lobe bilaterally, and down and inammation; some lesions show incomplete rim
left caudate head. enhancement, typical for demyelination.
694
SECTION III
Diseases of the Nervous System
FIGURE 51-27
Bals concentric sclerosis (a variant of multiple sclerosis) of the body and splenium of the corpus callosum and the
(Chap. 39) callosal-septal interface (arrowhead). Some of the lesions
Coronal FLAIR MRI (A) demonstrates multiple areas of reveal concentric layers, typical of Bals concentric sclero-
abnormal high signal in the supratentorial white matter bilat- sis (arrows).
erally. The lesions are ovoid in shape, perpendicular to the Sagittal (F) and axial (G, H) T1-weighted MR images post-
orientation of the lateral ventricles, and with little mass effect. gadolinium demonstrate abnormal enhancement of all lesions
Axial (B) and sagittal (CE) T2-weighted MR images dem- with some of the lesions demonstrating concentric ring enhance-
onstrate multiple areas of abnormal high signal in the supra- ment (arrows).
tentorial white matter bilaterally, as well as the involvement
695
FIGURE 51-28
Hashimotos encephalopathy (Chap. 40) Axial T1-weighted images (B, C) pre- and postgadolinium
Axial FLAIR (A) demonstrates focal area of abnormal high demonstrate cortical/pial enhancement in the region of high
signal involving the gray and white matter in the left frontal signal on FLAIR.
lobe. There is also a small area of abnormal high signal in the
precentral gyrus.
697
CHAPTER 51
Atlas of Neuroimaging
FIGURE 51-29
Brachial plexopathy (Chap. 45) Diffusion-weighted MR imaging (E) demonstrates abnormal
Axial (A), sagittal (B), and coronal (C, D) short tau inversion reduced diffusion within the right C6, C7, and C8 nerve roots
recovery (STIR) MR images demonstrate abnormal enlarge- and their corresponding trunks and divisions (arrow). These
ment and abnormal high signal involving the right C6, C7, ndings are compatible with radiation-induced brachial
and C8 nerve roots, and the trunks and divisions that origi- plexopathy.
nate from these roots (arrows).
698
SECTION III
FIGURE 51-31
CT facet fracture
FIGURE 51-29
Axial CT demonstrates fracture line along the C2 facet (arrow).
(continued )
Diseases of the Nervous System
FIGURE 51-30
Anterior dens dislocation
Sagittal CT demonstrates the tip of the dens below the ante-
rior arch of C2 (arrow), indicating anterior dislocation. FIGURE 51-32
Compression fracture
Sagittal T2-weighted MRI demonstrates compression frac-
ture of C7 (*) and high signal within the spinous processes
of C6-C7 (arrows) and to a lesser degree C5-C6. This is sug-
gestive of interspinous ligament injury. Note the pad under
the patients neck to maintain neck alignment during the
scanning time.
699
CHAPTER 51
A B
FIGURE 51-33
Epidural hematoma strates the extension of the acute epidural hematoma (*) and
Atlas of Neuroimaging
Axial noncontrast CT (A) demonstrates a high-density epidu- a disk bulge (arrowhead), which further contributes to spinal
ral collection in the cervical spine (*), which is consistent with canal narrowing. CT is the imaging procedure of choice to
acute hemorrhage. Also noted is mass effect on the spinal detect acute hematoma.
cord (arrowheads). Sagittal reformatted CT image (B) demon-
FIGURE 51-36
Ligament injury after trauma
Coronal CT reconstruction demonstrates abnormal asymme-
Diseases of the Nervous System
A B
FIGURE 51-39
Sacral insufciency fracture
Axial T2-weighted MRI (A) and T1-weighted MRI (B) dem-
onstrate symmetric high T2 and low T1 signal involving the
FIGURE 51-37 sacral alae longitudinally (arrows).
Odontoid fracture
Sagittal CT demonstrates disruption of the main reference
cervical lines. 1: Anterior vertebral body line; 2: Posterior ver-
tebral body line; 3: Spinolaminar line.
701
CHAPTER 51
A B
FIGURE 51-40
Subdural hematoma
Atlas of Neuroimaging
Sagittal T2-weighted MRI (A) and axial noncontrast T1-weighted MRI (B) demonstrate subdural collection in the lumbosacral
region (**). Note that the epidural fat is compressed but not involved (arrow).
A B
FIGURE 51-41
Teardrop fracture
Sagittal CT (A) demonstrates fracture line separating the antero-inferior corner of C6 (arrow). Sagittal T2-weighted MRI (B) dis-
plays cord injury (arrow).
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SECTION IV
CHRONIC FATIGUE
SYNDROME
CHAPTER 52
DEFINITION EPIDEMIOLOGY
Chronic fatigue syndrome (CFS) is a disorder characterized CFS is seen worldwide, with adult prevalence rates
by persistent and unexplained fatigue resulting in severe varying between 0.2 and 0.4%. In the United States, the
impairment in daily functioning. Besides intense fatigue, prevalence is higher in women, members of minority
most patients with CFS report concomitant symptoms groups (African and Native Americans), and individuals
such as pain, cognitive dysfunction, and unrefreshing sleep. with lower levels of education and occupational status.
Additional symptoms can include headache, sore throat, Approximately 75% of all CFS patients are women.
tender lymph nodes, muscle aches, joint aches, feverish- The mean age of onset is between 29 and 35 years. It is
ness, difculty sleeping, psychiatric problems, allergies, and probable that many patients go undiagnosed and/or do
abdominal cramps. Criteria for the diagnosis of CFS have not seek help.
been developed by the U.S. Centers for Disease Control
and Prevention (Table 52-1).
CHAPTER 52
Low physical activity pattern patients, nor do any correlate with the severity of CFS.
In theory, symptoms of CFS could result from exces-
sive production of a cytokine, such as interleukin 1, that
induces asthenia and other ulike symptoms; however,
compelling data in support of this hypothesis are lacking.
found in Epstein-Barr virus load and immunologic reac- There is some evidence that CFS patients have mild
potential fatigue-precipitating factors are sought. The found to be the only beneficial interventions in CFS.
severity of fatigue is difcult to assess quantitatively; a Some patient groups argue against these approaches
brief questionnaire is often helpful (Fig. 52-1). because of the implication that CFS is a purely mental
The patient should be informed of the current disorder. CBT is a psychotherapeutic approach directed
understanding of precipitating and perpetuating factors and at changing condition-related cognitions and behaviors.
effective treatments, and be offered general advice about CBT for CFS aims at changing a patients perpetuating fac-
Chronic Fatigue Syndrome
disease management. If CBT for CFS is not available tors by exploiting various techniques and components.
Scoring:
Yes, No,
1, 2 and 4: 7 6 5 4 3 2 1 3: Reversed
that is true that is not true
FIGURE 52-1
Shortened fatigue questionnaire (SFQ).
It includes educating the patient about the etiologic CBT is generally the more complex treatment, which 707
model, setting goals, restoring fixed bedtime and might explain why CBT studies tend to yield better
wake-up time, challenging and changing fatigue- and improvement rates than GET trials.
activity-related cognitions, reducing symptom focusing, Not all patients benefit from CBT or GET. Predictors of
spreading activities evenly throughout the day, gradu- poor outcome are somatic comorbidity, current disability
ally increasing physical activity, planning a return to claims, and severe pain. CBT offered in an early stage of the
work, and resuming other activities. The intervention, illness reduces the burden of CFS for the patient as well
which typically consists of 1214 sessions spread over as society in terms of decreased medical and disability-
6 months, helps CFS patients gain control over their related costs.
symptoms.
GET is based on the model of deconditioning and
exercise intolerance and usually involves a home exer-
cise program that continues for 35 months. Walking PROGNOSIS
or cycling is systematically increased, with set target
Full recovery from untreated CFS is rare: the median
heart rates. Evidence that deconditioning is the basis
annual recovery rate is 5% (range 031%) and the
for symptoms in CFS is lacking, however. The primary
improvement rate 39% (range 863%). Patients with an
component of CBT and GET that results in a reduction
underlying psychiatric disorder and those who continue
in fatigue is the change in the patients perception of
to attribute their symptoms to an undiagnosed medical
fatigue and focus on symptoms.
condition have poorer outcomes.
CHAPTER 52
Chronic Fatigue Syndrome
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SECTION V
PSYCHIATRIC
DISORDERS
CHAPTER 53
Psychiatric disorders are central nervous system diseases symptoms with relatively preserved cognitive function-
characterized by disturbances in emotion, cognition, ing and language skills are described as having Aspergers
motivation, and socialization. As a result of their high syndrome.
prevalence, early onset, and persistence, they contribute
substantially to the burden of illness worldwide. Most
EPIDEMIOLOGY
psychiatric disorders are heterogeneous syndromes that
currently lack well-dened neuropathology and bona There has been a dramatic increase in the diagnosis of
de biological markers. Therefore, diagnoses continue to ASDs, from 1/1000 (1950s1990s) to a current level
be made solely from clinical observations using criteria of 1/150. Whether this increase reects increased
in the Diagnostic and Statistical Manual of Mental Disor- disease prevalence remains uncertain; ongoing studies
ders of the American Psychiatric Association (2000), 4th are searching for genetic, environmental, and sociologic
edition, text revision (DSM-IVTR). Recent advances mechanisms that may have contributed to this change.
in neuroimaging are beginning to provide evidence of In the 1950s1960s, psychological factors were held to
brain pathology, which may one day be used for diag- underlie autism. This conception was largely debunked
nosis and for following treatment. Family, twin, and by the 1970s, with the demonstration that prenatal
adoption studies have shown that all common psychi- rubella and phenylketonuria can cause ASDs, and with
atric syndromes are highly heritable, with genetic risk evidence for the genetic etiology of ASDs from twin
comprising 2090% of disease vulnerability. The epi- studies. There is ongoing public concern that vaccines
demiology, genetics, and biology of four common psy- in general, or mercury-based preservatives in vaccines,
chiatric disordersautism, schizophrenia, mood disor- can cause ASDs; however, large epidemiologic analyses
ders, and drug addictionare presented in this chapter. have not supported this as an etiology. Whether envi-
A detailed discussion of the clinical manifestations and ronmental factors, such as perinatal infection and various
treatment of schizophrenia and mood disorders can be toxins, for example, ethanol, illicit drugs, medications,
found in Chap. 54. Further discussion of alcoholism can and mutagenic agents, play a role is unclear.
be found in Chap. 56, opiate addiction in Chap. 57, and
cocaine and other drugs of abuse in Chap. 58.
NEUROPATHOLOGY AND NEUROIMAGING
ASDs show no dening neuroanatomic phenotype
that would indicate neurodevelopmental abnormalities.
AUTISM SPECTRUM DISORDERS However, structural neuroimaging and histologic studies
of postmortem brain provide evidence for anatomic
The DSM-IVTR criteria for autism spectrum disorders defects. There is a modest increase in cerebrum growth
(ASDs) require delays or abnormal functioning in social (10%; affecting both the white and grey matter) during
interactions, language as used in social communication, early childhood (years 13), with the largest effect in the
and symbolic or imaginative play, with onset prior to frontal lobes; the growth rate then decreases with age.
age 3. In addition to abnormal social behavior, ASDs are Cerebellar size is increased by about 7% in children
frequently, but not always, associated with reduced IQ under age 5 years, but is decreased in older patients, and
and epilepsy. Individuals who exhibit some autism-like there are reduced (30%) numbers of cerebellar Purkinje
710
neurons. Finally, there is reduced cell size and increased for autism compared with prevalence in the general 711
cell density in the limbic areas of the brain. population. For unknown reasons, ASDs affect four
times as many boys as girls. ASDs are also geneti-
CHAPTER 53
cally heterogeneous. More than 20 known mutations,
GENETICS
including copy number variations, account for about
ASDs are highly heritable; concordance rates in 1020% of all cases, though none of these causes indi-
monozygotic twins (6090%) are roughly tenfold vidually accounts for more than 12% (Table 53-1).
higher than in dizygotic twins and siblings, and rst- Many of the genes linked to ASDs can also cause
degree relatives show about ftyfold increased risk other illnesses. For instance, mutations in MeCP2,
are associated with both ASDs and schizophrenia. antipsychotic drugs are efcacious for positive symptoms
It is likely that many cases of ASDs result from more only and generally lack efcacy for negative and cogni-
complex genetic mechanisms, including inheritance of tive symptoms.
multiple genetic variants or epigenetic modications.
EPIDEMIOLOGY
Psychiatric Disorders
PATHOGENESIS
Schizophrenia is common, affecting males and females
Despite the genetic heterogeneity of ASDs, there are roughly equally, with a worldwide prevalence of approx-
some common themes that may explain pathogenesis. imately 1%. Environmental risks are thought to include
These include mutations in proteins involved in the prenatal exposure to viral infection (inuenza), prenatal
formation and function of synapses, control over poor nutrition, perinatal hypoxia, psychotropic drug
the size and projections of neurons, production and use (in particular, cannabis), and psychological stress.
signaling of neurotransmitters and neuromodulators, Advanced paternal age, birth order, and season of birth
the function of ion channels, general cell metabolism, have also been implicated. However, none of these envi-
gene expression, and protein synthesis (see Table 53-1). ronmental inuences has a specic or strong association
Many of these mutations have a clear relationship to with most cases of schizophrenia.
activity-dependent neural responses and can affect the
development of neural systems that underlie cogni-
tion and social behaviors. They may be detrimental by NEUROPATHOLOGY AND NEUROIMAGING
altering the balance of excitatory vs. inhibitory synaptic
The best-established neuropathologic nding in schizo-
signaling in local and extended circuits, and by altering
phrenia is enlargement of the lateral ventricles of the
the mechanisms that control brain growth. Another
cerebral hemispheres. This is accompanied by a reduc-
class of mutations affects genes (e.g., PTEN and Tsc)
tion in cortical thickness. These abnormalities are not
that negatively regulate signaling from several types
specic to schizophrenia and are seen in many other
of extracellular stimuli, including those transduced by
conditions, including many neurodegenerative dis-
receptor tyrosine kinases. Their dysregulation can have
orders. However, there is a general consensus that
pleiotropic effects, including altering brain and neuronal
the reduction in cortical thickness in schizophrenia
growth as well as synaptic development and function.
is associated with increased cell packing density and
With further understanding of pathogenesis and the
reduced neuropil (dened as axons, dendrites, and
denition of specic ASD subtypes, there is reason to
glial cell processes) without an overt change in neu-
believe that effective therapies will be identied, as in
ronal cell number. Specic classes of interneurons in
the case of dietary treatments for phenylketonuria. In
prefrontal cortex consistently show reduced expression
addition, work in mouse models (e.g., with fragile X or
of the gene encoding the enzyme glutamic acid decar-
Rett syndrome mutations) has suggested that autism-
boxylase 1 (GAD1), which synthesizes -aminobutyric
like behavioral abnormalities can be reversed even in
acid (GABA), the principal inhibitory neurotransmitter
fully developed adult animals by reversing the underly-
in the brain. Functional imaging studies, by positron
ing pathology, which holds out hope for many affected
emission tomography (PET) or functional magnetic
individuals.
resonance imaging (MRI), show evidence of reduced
metabolic or neural activity in the dorsolateral pre-
frontal cortex at rest and when performing psycho-
SCHIZOPHRENIA logical tests of executive function, including working
memory. Alleles of two candidate risk genes (catechol-
Schizophrenia appears to be a heterogeneous collec- O-methyltransferase [COMT] and metabotropic glu-
tion of many distinct diseases, which remain poorly tamate receptor 3 [mGluR3]) are reported to affect
dened but linked by common clinical features. Three dorsolateral prefrontal cortex activity, but these ndings
major symptom clusters are seen in schizophrenia: posi- need to be replicated in larger samples. Similar patho-
tive, negative, and cognitive symptoms. Positive symp- logic and brain imaging abnormalities are seen in several
toms include hallucinations and delusions, experiences other brain regions, in particular, the hippocampus.
that are not characteristic of normal mental life. Nega- There are also numerous reports of abnormalities in
tive symptoms represent decits in normal functions such myelin and oligodendrocytes in the cerebral cortex of
as blunted affect, impoverished speech, asocial behavior, patients with schizophrenia.
GENETICS in the striatum elicited by an acute dose of amphetamine 713
has been demonstrated by PET imaging in some patients
Twins studies establish the heritability of schizophrenia, with schizophrenia. However, it is unclear whether this
with co-inheritance at 50% for monozygotic twins
CHAPTER 53
abnormality reects the underlying illness or a lasting
and 10% for dizygotic twins. Genomewide linkage effect of antipsychotic medications. In contrast, reduced
and association studies, and studies of copy number activity of dopamine at D1 dopamine receptors in the
variation, have identied many regions and alleles that prefrontal cortex has been implicated in working memory
confer increased disease risk, particularly near genes decits based on the cognitive effects of D1 receptor ago-
on chromosome 22 (disrupted in schizophrenia 1 nists and antagonists in the illness. Nevertheless, inferring
[DISC1], COMT, neuregulin 1, the neuregulin recep-
EPIDEMIOLOGY
Mood disorders are common, with a prevalence of GENETICS
12% for bipolar disorder, 5% for major depres- Although depression and bipolar disorder are highly heri-
sion, and 1520% for milder forms of depression. table, the specic genes that comprise this risk remain
Between 4050% of the risk for depression appears to unknown. As noted earlier, some of the genes impli-
be genetic. Nongenetic factors as diverse as stress and cated in autism or schizophrenia seem to cause bipolar
emotional trauma, viral infections, and even stochastic disorder in some families. Large genomewide association
(random) processes during brain development have studies have identied genes for diacylglycerol kinase
been implicated in the etiology. Depressive syndromes (DGKH), ankyrin G (ANK3), an L-type voltage-gated
can occur in the context of general medical condi- calcium channel (CACNA1C), and a gene-rich region
tions such as endocrine disturbances (hyper- or hypo- on chromosome 16p12 as being associated with bipolar
cortisolemia, hyper- or hypothyroidism), autoimmune disorder, but these ndings await conrmation by addi-
diseases, Parkinsons disease, traumatic brain injury, tional studies. Numerous susceptibility genes have also
certain cancers, asthma, diabetes, and stroke. Depres- been implicated in linkage and association studies, but
sion and obesity/metabolic syndrome are important none has yet been denitively established as a bona de
risk factors for each other. In predisposed individuals, depression gene. However, a few genes with variants that
stressful life events can lead to clear-cut depressive may modify depression risk are worthy of mention since
episodes, while severe stress can induce posttraumatic they may be linked to mechanisms of pathogenesis (dis-
stress disorder (PTSD), instead of depression. Bipolar cussed later). These include genes for the type 1 receptor
disorder is characterized by episodes of mania and for corticotrophin-releasing factor (CRHR1); the gluco-
depression and is one of the most heritable of psychi- corticoid receptor gene (GR); FKBP5, which encodes
atric illnesses, with genetic risk of 80%. Stress and a chaperone protein for the glucocorticoid receptor; the
disrupted circadian rhythms can promote the manic serotonin transporter gene (SLA6A4); the catechol-O-
episodes, during which patients exhibit extremely methyltransferase gene (COMT); and brain-derived neu-
elevated mood, abnormal thought patterns, and some- rotrophic factor (BDNF).
times psychosis. Several of these clinical signs can
resemble certain features of schizophrenia; indeed,
recent epidemiologic and genetic research has ques-
PATHOGENESIS
tioned the DSM-IVTR designations of bipolar disorder,
schizophrenia, and schizoaffective disorder as distinct Human and animal research in depression has focused
syndromes. on the long-term effects of chronic stress on the brain
715
CHAPTER 53
FC
DR
HP
LC
Amy
Glutamatergic
GABAergic
Dopaminergic
Peptidergic
FIGURE 53-1
Neural circuitry of depression and addiction. The gure The ventral tegmental area (VTA) provides dopaminergic
shows a simplied summary of a series of limbic circuits input to each of the limbic structures. Norepinephrine (from
in brain that regulate mood and motivation and are impli- the locus coeruleus or LC) and serotonin (from the dorsal
cated in depression and addiction. Shown in the gure are raphe [DR] and other raphe nuclei) innervate all of the regions
the hippocampus (HP) and amygdala (Amy), regions of pre- shown. In addition, there are strong connections between the
frontal cortex, nucleus accumbens (NAc), and hypothalamus hypothalamus and the VTA-NAc pathway. Important peptider-
(Hyp). Only a subset of the known interconnections among gic projections from the hypothalamus include those from the
these brain regions is shown. Also shown is the innervation arcuate nucleus that release -endorphin and melanocortin
of several of these brain regions by monoaminergic neurons. and from the lateral hypothalamus that release orexin.
and their reversal by antidepressant medications; promi- leads to a decrease in the birth of new neurons in the
nent examples are discussed here. A subset of depressed adult hippocampus. Interestingly, antidepressant treat-
patients show elevated levels of cortisol associated with ments reverse these effects of stress, and the antidepres-
increased production of corticotrophin-releasing factor sant effects of these medications seem to depend, in part,
from the hypothalamus and perhaps other brain regions on their ability to promote hippocampal neurogenesis in
(e.g., amygdala). In animals, sustained elevations in glu- animal models of depression. The clinical ramications of
cocorticoids impair hippocampal function, in part via such observations are unproven, although similar regula-
direct damage to hippocampal neurons, which is con- tion of adult hippocampal neurogenesis may be important
sistent with reduced hippocampal volumes seen in some for certain forms of learning and memory.
depressed humans. As the hippocampus exerts the major Another important target of stress in animals is
inhibitory inuence over the hypothalamic-pituitary- the nucleus accumbens, where stress regulation of
adrenal axis, impairment of hippocampal function would numerous signaling events (dopaminergic transmission
lead to still further increases in glucocorticoid secretion, and BDNF signaling are two examples) exert potent
establishing a pathologic feed-forward loop. effects on depression-like behavioral abnormalities.
Stress-induced damage to the hippocampus, and per- While a reduction in BDNF in the hippocampus pro-
haps other limbic regions (e.g., amygdala), in animals is motes depression-like behaviors, an induction of BDNF
also mediated in part by reduced levels of BDNF and in the nucleus accumbens promotes depression; similar
other growth factors and cytokines. Furthermore, stress changes in BDNF expression have been observed in
716 postmortem brains of depressed patients. Thus the role gene expression is methylation of cytosine residues in
of BDNF in regulating mood is highly brain-region DNA, which inhibits gene transcription. DNA meth-
specic. ylation has been shown to be important for inherited
SECTION V
In contrast to depression, animal models of mania as maternal effects on emotional behavior. Thus, rats born
well as bipolar disorder have proved much more elu- to mothers that exhibit low levels of nurturing behavior
sive. Mice with loss-of-function mutations in the Clock show increased anxiety and reduced expression of hippo-
or GluR6 glutamate receptor genes or transgenic mice campal glucocorticoid receptors due to increased meth-
that overexpress glycogen synthase kinase 3 (GSK3) ylation of the receptor gene. They pass these traits on to
show manic-like behavioral abnormalities, although the their offspring, but cross-fostering by mothers that dis-
Psychiatric Disorders
relevance of these observations to human mania remains play high levels of nurturing reverses them. As research
unknown. into epigenetic mechanisms progresses, there is hope
The observation that tricyclic antidepressants (e.g., that it may become possible to identify specic depres-
imipramine) inhibit serotonin and/or norepinephrine sion-associated alterations in human chromatin.
reuptake, and that monoamine oxidase inhibitors (e.g.,
tranylcypromine) are effective antidepressants, initially
led to the view that depression is caused by a deciency
of these monoamines. However, this hypothesis has not SUBSTANCE USE DISORDERS
been well substantiated, although variants in the sero-
tonin transporter, and in the COMT gene, have been The DSM-IVTR uses the terms substance dependence and
associated with altered mood states in some individuals. substance abuse to describe substance use disorders. It is
Nevertheless, these medications, particularly the tricy- unfortunate that the term substance dependence instead of
clics, have formed the basis of antidepressant discovery addiction is used, because dependence can develop with-
efforts, with virtually all of todays marketed antidepres- out addiction, and addiction involves much more than
sants being SSRIs (e.g., uoxetine, sertraline, citalo- dependence per se. Physical dependence develops through
pram), serotonin, and norepinephrine reuptake inhibitors resetting of homeostatic cellular mechanisms to permit
(SNRIs) (e.g., venlafaxine, duloxetine), or norepineph- normal function despite the continued presence of a
rine reuptake inhibitors (NRIs) (e.g., atomoxetine). drug; when drug intake is terminated abruptly, a with-
A cardinal feature of all antidepressant medications drawal syndrome emerges. Withdrawal from alcohol or
is that long-term administration is needed for their other sedative-hypnotics causes nervous system hyper-
mood-elevating effects. This means that their short- activity, whereas withdrawal from psychostimulants
term actions, namely promotion of serotonin or nor- produces fatigue and sedation. Tolerance is a reduction
epinephrine function, is not per se antidepressant but in response to a drug, which like dependence, develops
rather induces a cascade of adaptations in the brain that after repeated use. It results from a change in drug
underlie their clinical effects. The nature of these thera- metabolism (pharmacokinetic tolerance) or cell signaling
peutic drug-induced adaptations has not been identied (pharmacodynamic tolerance). It is important to recog-
with certainty. Presumably, the rich innervation of the nize that many nonaddictive medications induce tolerance
brains limbic circuitry by serotonin and norepinephrine and physical dependence, including -adrenergic antag-
(Fig. 53-1) provide the anatomic basis of their therapeu- onists (e.g., propranolol) and 2-adrenergic agonists
tic actions. (e.g., clonidine).
Lithium is a highly effective drug for bipolar disor- What sets drugs of abuse apart is their unique ability
der, and competes with magnesium to inhibit magne- to produce euphoria, a positive emotional state charac-
sium-dependent enzymes, including GSK3 and several terized by intensely pleasant feelings that are rewarding
enzymes involved in phosphoinositide signaling leading and reinforcing since they motivate users to take the drug
to activation of protein kinase C. These ndings have repeatedly. Tolerance develops to the rewarding proper-
led to discovery programs focused on developing GSK3 ties of most abused drugs during periods of heavy use,
and PKC inhibitors as potential novel treatments for which promotes the use of higher drug doses. In addi-
mood disorders. Another commonly prescribed drug tion, psychological (or motivational) dependence develops
for bipolar disorder is valproic acid, which has pleio- through the resetting of cellular mechanisms within
tropic effects, including inhibition of histone deacety- reward-related regions of the brain and leads to negative
lases (HDACs). Histone acetylation promotes transcrip- emotional symptoms resembling depression during drug
tional activation through posttranslational modication withdrawal. Addictive drugs can also cause sensitization,
of N-terminal lysine residues in histones and thereby an increased drug effect upon repeated use, as exempli-
causes chromatin decondensation. HDAC inhibitors ed by the paranoid psychosis induced by chronic use of
have shown some antidepressant effects in animal mod- cocaine or other psychostimulants (e.g., amphetamine).
els of depression. Another form of epigenetic control of Addiction, therefore, results from drug-induced changes
in reward-related regions of the brain that lead to a established susceptibility loci are regions on chromo- 717
complex mixture of tolerance, sensitization, and motiva- somes 4 and 5 containing GABAA receptor gene clusters
tional dependence, in addition to powerful conditioning linked to alcohol use disorders and the nicotinic acetyl-
CHAPTER 53
effects of these drugs mediated by the brains memory choline receptor gene cluster on chromosome 15 asso-
circuits. ciated with nicotine and alcohol dependence. There are
reports of numerous other addiction susceptibility genes
(e.g., variants in COMT, the -opioid receptor, and
EPIDEMIOLOGY
the serotonin transporter), but further work is needed
Substance use disorders, especially those involving alco- to validate these ndings. In addition, several genes
Repeated intake of abused drugs induces specic and specic behavioral abnormalities that characterize
changes in cellular signal transduction, synaptic strength the addicted state. For example, acute activation of
(long-term potentiation or depression), and neuronal -opioid receptors by morphine or other opiates acti-
structure (altered dendritic branching or cell soma size) vates Gi/o proteins leading to inhibition of adenylyl
within the brains reward circuitry. These modications cyclase, resulting in reduced cAMP production, pro-
are mediated in part by changes in gene expression, tein kinase A (PKA) activation, and activation of the
achieved by drug regulation of transcription factors transcription factor CREB. Repeated administration of
(e.g., CREB [cAMP response element binding protein] these drugs (Fig. 53-2) evokes a homeostatic response
and FosB) and their target genes. Together, these resulting in upregulation of adenylyl cyclases, increased
drug-induced adaptations underlie alterations in numerous production of cAMP, and increased activation of PKA
neurotransmitter systems (e.g., glutamate, GABA, dopa- and CREB. Such upregulation of cAMP signaling has
mine), growth factors (e.g., BDNF), neuropeptides (e.g. been identied in the locus coeruleus, periaqueductal
corticotrophin releasing factor), and intracellular signal- gray, VTA, and nucleus accumbens and contributes to
ing cascades. These adaptations provide opportunities opiate craving and signs of opiate withdrawal. The fact
for developing treatments targeted to drug-addicted that endogenous opioid peptides do not produce toler-
individuals. The fact that the spectrum of these adapta- ance and dependence while morphine and heroin do
tions partly differ depending on the particular addictive may relate to the recent observation that, unlike endog-
substance used creates opportunities for treatments that enous opioids, morphine and heroin are weak inducers
are specic for different classes of addictive drugs and of -opioid receptor desensitization and endocytosis.
that may, therefore, be less likely to disturb basic mech- Therefore, these drugs cause prolonged receptor activa-
anisms that govern motivation and reward. tion and inhibition of adenylyl cyclases, which provides
Increasingly, causal relationships are being estab- a powerful stimulus for the upregulation of cAMP sig-
lished between individual molecular-cellular adaptations naling that characterizes the opiate-dependent state.
-opioid 719
receptor
Ca2+
CHAPTER 53
AC
Gi/o
cAMP Increased
R R
Regulation of
C C C C proteins by PKA
phosphorylation
PKA
Nucleus
+
P
CREB
FIGURE 53-2
Opiate action in the locus coeruleus (LC). Binding of changes in neuronal function. Chronic administration of opi-
opiate agonists to -opioid receptors catalyzes nucleotide ates increases levels of AC isoforms, PKA catalytic (C) and
exchange on Gi and Go proteins, leading to inhibition of regulatory (R) subunits, and the phosphorylation of several
adenylyl cyclase, neuronal hyperpolarization via activation proteins, including CREB (indicated by red arrows). These
of K+ channels, and inhibition of neurotransmitter release via changes contribute to the altered phenotype of the drug-
inhibition of Ca2/+ channels. Activation of Gi/o also inhibits addicted state. For example, the excitability of LC neurons
adenylyl cyclase (AC), reducing protein kinase A (PKA) is increased by enhanced cAMP signaling, although the
activity and phosphorylation of several PKA substrate pro- ionic basis of this effect remains unknown. Activation of
teins, thereby altering their function. For example, opiates CREB causes upregulation of AC isoforms and tyrosine
reduce phosphorylation of the cAMP response element- hydroxylase, the rate-limiting enzyme in catecholamine
binding protein (CREB), which appears to initiate long-term biosynthesis.
CHAPTER 54
MENTAL DISORDERS
Victor I. Reus
Mental disorders are common in medical practice and care physicians should base referrals to a psychiatrist on
may present either as a primary disorder or as a comor- the presence of signs and symptoms of a mental disorder
bid condition. The prevalence of mental or substance and not simply on the absence of a physical explanation
use disorders in the United States is approximately 30%, for a patients complaint. The physician should discuss
only one-third of whom are currently receiving treat- with the patient the reasons for requesting the referral
ment. Global burden of disease statistics indicate that 4 or consultation and provide reassurance that he or she
of the 10 most important causes of disease worldwide will continue to provide medical care and work collabor-
are psychiatric in origin. atively with the mental health professional. Consultation
The revised fourth edition for use by primary care with a psychiatrist or transfer of care is appropriate when
physicians of the Diagnostic and Statistical Manual (DSM- physicians encounter evidence of psychotic symptoms,
IV-PC) provides a useful synopsis of mental disorders mania, severe depression, or anxiety; symptoms of post-
most likely to be seen in primary care practice. The traumatic stress disorder (PTSD); suicidal or homicidal
current system of classication is multiaxial and includes preoccupation; or a failure to respond to rst-order
the presence or absence of a major mental disorder (axis I), treatment. The biology of psychiatric and addictive dis-
any underlying personality disorder (axis II), general orders is discussed in Chap. 53.
medical condition (axis III), psychosocial and environ-
mental problems (axis IV), and overall rating of general
psychosocial functioning (axis V).
Changes in health care delivery underscore the need
for primary care physicians to assume responsibility for ANXIETY DISORDERS
the initial diagnosis and treatment of the most common
mental disorders. Prompt diagnosis is essential to ensure Anxiety disorders, the most prevalent psychiatric ill-
that patients have access to appropriate medical ser- nesses in the general community, are present in 1520%
vices and to maximize the clinical outcome. Validated of medical clinic patients. Anxiety, dened as a subjec-
patient-based questionnaires have been developed that tive sense of unease, dread, or foreboding, can indicate
systematically probe for signs and symptoms associated a primary psychiatric condition or can be a component
with the most prevalent psychiatric diagnoses and guide of, or reaction to, a primary medical disease. The pri-
the clinician into targeted assessment. Prime MD (and mary anxiety disorders are classied according to their
a self-report form, the PHQ) and the Symptom-Driven duration and course and the existence and nature of
Diagnostic System for Primary Care (SDDS-PC) are precipitants.
inventories that require only 10 min to complete and When evaluating the anxious patient, the clinician
link patient responses to the formal diagnostic criteria of must rst determine whether the anxiety antedates or
anxiety, mood, somatoform, and eating disorders and to postdates a medical illness or is due to a medication side
alcohol abuse or dependence. effect. Approximately one-third of patients presenting
A physician who refers patients to a psychiatrist with anxiety have a medical etiology for their psychi-
should know not only when doing so is appropriate but atric symptoms, but an anxiety disorder can also present
also how to refer, since societal misconceptions and the with somatic symptoms in the absence of a diagnosable
stigma of mental illness impede the process. Primary medical condition.
720
PANIC DISORDER TABLE 54-2 721
DIAGNOSTIC CRITERIA FOR AGORAPHOBIA
Clinical manifestations
1. Anxiety about being in places or situations from which
CHAPTER 54
Panic disorder is dened by the presence of recurrent and escape might be difcult (or embarrassing) or in which
unpredictable panic attacks, which are distinct episodes help may not be available in the event of having an
of intense fear and discomfort associated with a variety unexpected or situationally predisposed panic attack
of physical symptoms, including palpitations, sweating, or panic-like symptoms. Agoraphobic fears typically
trembling, shortness of breath, chest pain, dizziness, and involve characteristic clusters of situations that include
being outside the home alone; being in a crowd or
a fear of impending doom or death (Table 54-1). Par-
standing in a line; being on a bridge; and traveling in a
Mental Disorders
esthesias, gastrointestinal distress, and feelings of unreal- bus, train, or automobile.
ity are also common. Diagnostic criteria require at least 1 2. The situations are avoided (e.g., travel is restricted) or
month of concern or worry about the attacks or a change else are endured with marked distress or with anxiety
in behavior related to them. The lifetime prevalence of about having a panic attack or panic-like symptoms, or
panic disorder is 13%. Panic attacks have a sudden onset, require the presence of a companion.
developing within 10 min and usually resolving over the 3. The anxiety or phobic avoidance is not better
accounted for by another mental disorder such as
course of an hour, and they occur in an unexpected fash-
social phobia (e.g., avoidance limited to social situ-
ion. The frequency and severity of panic attacks vary, ations because of fear of embarrassment), specic
ranging from once a week to clusters of attacks separated phobia (e.g., avoidance limited to a single situation
by months of well-being. The rst attack is usually out- like elevators), obsessive-compulsive disorder (e.g.,
side the home, and onset is typically in late adolescence to avoidance of dirt in someone with an obsession about
early adulthood. In some individuals, anticipatory anxiety contamination), posttraumatic stress disorder (e.g.,
develops over time and results in a generalized fear and avoidance of stimuli associated with a severe stressor),
a progressive avoidance of places or situations in which or separation anxiety disorder (e.g., avoidance of leaving
home or relatives).
a panic attack might recur. Agoraphobia, which occurs
commonly in patients with panic disorder, is an acquired
Source: Reprinted with permission from the Diagnostic and Statistical
irrational fear of being in places where one might feel Manual of Mental Disorders, Fourth Edition, Text Revision. Copyright
trapped or unable to escape (Table 54-2). Typically, it 2000 American Psychiatric Association.
leads the patient into a progressive restriction in lifestyle
and, in a literal sense, in geography. Frequently, patients
are embarrassed that they are housebound and depen- will fail to recognize the syndrome if direct questioning is
dent on the company of others to go out into the world not pursued.
and do not volunteer this information; thus physicians
Differential diagnosis
TABLE 54-1 A diagnosis of panic disorder is made after a medical eti-
DIAGNOSTIC CRITERIA FOR PANIC ATTACK ology for the panic attacks has been ruled out. A variety
A discrete period of intense fear or discomfort, in which of cardiovascular, respiratory, endocrine, and neurologic
four or more of the following symptoms developed conditions can present with anxiety as the chief com-
abruptly and reached a peak within 10 min: plaint. Patients with true panic disorder will often focus
1. Palpitations, pounding heart, or accelerated heart rate on one specic feature to the exclusion of others. For
2. Sweating example, 20% of patients who present with syncope as
3. Trembling or shaking a primary medical complaint have a primary diagnosis
4. Sensations of shortness of breath or smothering
of a mood, anxiety, or substance-abuse disorder, the
5. Feeling of choking
6. Chest pain or discomfort
most common being panic disorder. The differential
7. Nausea or abdominal distress diagnosis of panic disorder is complicated by a high rate
8. Feeling dizzy, unsteady, lightheaded, or faint of comorbidity with other psychiatric conditions, espe-
9. Derealization (feelings of unreality) or depersonaliza- cially alcohol and benzodiazepine abuse, which patients
tion (being detached from oneself) initially use in an attempt at self-medication. Some 75%
10. Fear of losing control or going crazy of panic disorder patients will also satisfy criteria for
11. Fear of dying major depression at some point in their illness.
12. Paresthesias (numbness or tingling sensations)
13. Chills or hot ushes
When the history is nonspecic, physical examina-
tion and focused laboratory testing must be used to rule
Source: Reprinted with permission from the Diagnostic and Statistical
out anxiety states resulting from medical disorders such
Manual of Mental Disorders, Fourth Edition, Text Revision. Copyright as pheochromocytoma, thyrotoxicosis, or hypoglycemia.
2000 American Psychiatric Association. Electrocardiogram (ECG) and echocardiogram may
722 detect some cardiovascular conditions associated with
orthostatic hypotension, and the need to maintain
panic such as paroxysmal atrial tachycardia and mitral
a low-tyramine diet (avoidance of cheese and wine)
valve prolapse. In two studies, panic disorder was the
have limited their use, however. Antidepressants typi-
SECTION V
Achievable goals of treatment are to decrease the fre- Patients with generalized anxiety disorder (GAD) have
quency of panic attacks and to reduce their intensity. persistent, excessive, and/or unrealistic worry associated
The cornerstone of drug therapy is antidepressant med- with muscle tension, impaired concentration, autonomic
ication (Tables 54-3 through 54-5). Selective serotonin arousal, feeling on edge or restless, and insomnia
reuptake inhibitors (SSRIs) benefit the majority of panic (Table 54-7). Onset is usually before age 20 years, and
disorder patients and do not have the adverse effects of a history of childhood fears and social inhibition may
tricyclic antidepressants (TCAs). Fluoxetine, paroxetine, be present. The lifetime prevalence of GAD is 56%;
sertraline, and the selective serotonin-norepinephrine the risk is higher in rst-degree relatives of patients with
reuptake inhibitor (SNRI) venlafaxine have received the diagnosis. Interestingly, family studies indicate that
approval from the U.S. Food and Drug Administration GAD and panic disorder segregate independently. More
(FDA) for this indication. These drugs should be started than 80% of patients with GAD also suffer from major
at one-third to one-half of their usual antidepressant depression, dysthymia, or social phobia. Comorbid sub-
dose (e.g., 510 mg fluoxetine, 2550 mg sertraline, 10 mg stance abuse is common in these patients, particularly
paroxetine, 37.5 mg venlafaxine). Monoamine oxidase alcohol and/or sedative/hypnotic abuse. Patients with
inhibitors (MAOIs) are also effective and may specifically GAD worry excessively over minor matters, with life-
benefit patients who have comorbid features of atypical disrupting effects; unlike in panic disorder, complaints
depression (i.e., hypersomnia and weight gain). Insomnia, of shortness of breath, palpitations, and tachycardia are
relatively rare.
TABLE 54-3 723
ANTIDEPRESSANTS
CHAPTER 54
NAME USUAL DAILY DOSE, mg SIDE EFFECTS COMMENTS
SSRIs
Fluoxetine (Prozac) 1080 Headache; nausea and other Once-daily dosing, usually in
Sertraline (Zoloft) 50200 GI effects; jitteriness; insom- the morning; uoxetine has
Paroxetine (Paxil) 2060 nia; sexual dysfunction; can very long half-life; must not
Fluvoxamine (Luvox) 100300 affect plasma levels of other be combined with MAOIs
Citalopram (Celexa) 2060 medicines (except sertraline);
Mental Disorders
Escitalopram (Lexapro) 1030 akathisia rare
TCAs
Amitriptyline (Elavil) 150300 Anticholinergic (dry mouth, Once-daily dosing, usually
Nortriptyline (Pamelor) 50200 tachycardia, constipation, qhs; blood levels of most
Imipramine (Tofranil) 150300 urinary retention, blurred TCAs available; can be lethal
Desipramine (Norpramin) 150300 vision); sweating; tremor; in O.D. (lethal dose = 2 g);
Doxepin (Sinequan) 150300 postural hypotension; cardiac nortriptyline best tolerated,
Clomipramine (Anafranil) 150300 conduction delay; sedation; especially by elderly
weight gain
Mixed Norepinephrine/Serotonin Reuptake Inhibitors and Receptor Blockers
Venlafaxine (Effexor) 75375 Nausea; dizziness; dry mouth; Bid-tid dosing (extended
headaches; increased blood release available); lower
pressure; anxiety and potential for drug interac-
insomnia tions than SSRIs; contraindi-
cated with MAOIs
Desvenlafaxine, (Pristiq) 50400 Nausea, dizziness, insomnia Primary metabolite of
venlafaxine. No increased
efcacy with higher dosing
Duloxetine (Cymbalta) 4060 Nausea, dizziness, headache, May have utility in treatment
insomnia, constipation of neuropathic pain and
stress incontinence
Mirtazapine (Remeron) 1545 Somnolence; weight gain; Once daily dosing
neutropenia rare
Mixed-Action Drugs
Bupropion (Wellbutrin) 250450 Jitteriness; ushing; seizures Tid dosing, but sustained
in at-risk patients; anorexia; release also available; fewer
tachycardia; psychosis sexual side effects than
SSRIs or TCAs; may be
useful for adult ADD
Trazodone (Desyrel) 200600 Sedation; dry mouth; Useful in low doses for sleep
ventricular irritability; postural because of sedating effects
hypotension; priapism rare with no anticholinergic side
effects
Nefazodone (Serzone) 300600 Sedation; headache; dry Discontinued sale in United
mouth; nausea; constipation States and several other
countries due to risk of liver
failure
Amoxapine (Asendin) 200600 Sexual dysfunction Lethality in overdose; EPS
possible
MAOIs
Phenelzine (Nardil) 4590 Insomnia; hypotension; May be more effective in
Tranylcypromine (Parnate) 2050 anorgasmia; weight gain; patients with atypical
Isocarboxazid (Marplan) 2060 hypertensive crisis; toxic reac- features or treatment-
tions with SSRIs; narcotics refractory depression
Transdermal selegiline 612 Local skin reaction, No dietary restrictions with
(Emsam) hypertension 6 mg dose
Abbreviations: ADD, attention decit disorder; EPS, extrapyramidal symptoms; MAOIs, monoamine oxidase inhibitors; SSRIs, selective sero-
tonin reuptake inhibitors;TCAs, tricyclic antidepressants.
724 TABLE 54-4 TABLE 54-5
MANAGEMENT OF ANTIDEPRESSANT SIDE EFFECTS POSSIBLE DRUG INTERACTIONS WITH SELECTIVE
SEROTONIN REUPTAKE INHIBITORS
COMMENTS AND MANAGEMENT
SECTION V
CHAPTER 54
EQUIVALENT PO
NAME DOSE, mg ONSET OF ACTION HALF-LIFE, h COMMENTS
Benzodiazepines
Diazepam (Valium) 5 Fast 2070 Active metabolites; quite sedating
Flurazepam 15 Fast 30100 Flurazepam is a prodrug; metabolites
(Dalmane) are active; quite sedating
Mental Disorders
Triazolam (Halcion) 0.25 Intermediate 1.55 No active metabolites; can induce
confusion and delirium, especially in
elderly
Lorazepam (Ativan) 1 Intermediate 1020 No active metabolites; direct hepatic
glucuronide conjugation; quite sedating
Alprazolam (Xanax) 0.5 Intermediate 1215 Active metabolites; not too sedating;
may have specic antidepressant
and antipanic activity; tolerance and
dependence develop easily
Chlordiazepoxide 10 Intermediate 530 Active metabolites; moderately
(Librium) sedating
Oxazepam (Serax) 15 Slow 515 No active metabolites; direct glucuro-
nide conjugation; not too sedating
Temazepam 15 Slow 912 No active metabolites; moderately
(Restoril) sedating
Clonazepam 0.5 Slow 1850 No active metabolites; moderately
(Klonopin) sedating
Nonbenzodiazepines
Buspirone (BuSpar) 7.5 2 weeks 23 Active metabolites; tid dosingusual
daily dose 1020 mg tid; nonsedating;
no additive effects with alcohol; useful
for controlling agitation in demented or
brain-injured patients
TABLE 54-7
DIAGNOSTIC CRITERIA FOR GENERALIZED ANXIETY DISORDER
A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a
number of events or activities (such as work or school performance).
B. The person nds it difcult to control the worry.
C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms
present for more days than not for the past 6 months): (1) restlessness or feeling keyed up or on edge; (2) being easily
fatigued; (3) difculty concentrating or mind going blank; (4) irritability; (5) muscle tension; (6) sleep disturbance (difculty
falling or staying asleep, or restless unsatisfying sleep).
D. The focus of the anxiety and worry is not conned to features of an axis I disorder [e.g., the anxiety or worry is not about
having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as
in obsessive-compulsive disorder), being away from home or close relatives (as in separation anxiety disorder), gaining
weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having a serious
illness (as in hypochondriasis)], and the anxiety and worry do not occur exclusively during posttraumatic stress disorder.
E. The anxiety, worry, or physical symptoms cause clinically signicant distress or impairment in social, occupational, or other
important areas of functioning.
F. The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general
medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, a psychotic disorder, or a
pervasive developmental disorder.
Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Copyright
2000 American Psychiatric Association.
726 PHOBIC DISORDERS
the development of tolerance and the risk of abuse and
Clinical manifestations
dependence. Withdrawal must be closely monitored as
SECTION V
relapses can occur. It is important to warn patients that The cardinal feature of phobic disorders is a marked
concomitant use of alcohol or other sedating drugs and persistent fear of objects or situations, exposure to
may be neurotoxic and impair their ability to function. which results in an immediate anxiety reaction. The
An optimistic approach that encourages the patient to patient avoids the phobic stimulus, and this avoidance
clarify environmental precipitants, anticipate his or her usually impairs occupational or social functioning. Panic
reactions, and plan effective response strategies is an attacks may be triggered by the phobic stimulus or may
Psychiatric Disorders
essential element of therapy. occur spontaneously. Unlike patients with other anxiety
Adverse effects of benzodiazepines generally parallel disorders, individuals with phobias usually experience
their relative half-lives. Longer-acting agents, such as anxiety only in specic situations. Common phobias
diazepam, chlordiazepoxide, flurazepam, and clonazepam, include fear of closed spaces (claustrophobia), fear of
tend to accumulate active metabolites, with resultant blood, and fear of ying. Social phobia is distinguished
sedation, impairment of cognition, and poor psychomotor by a specic fear of social or performance situations in
performance. Shorter-acting compounds, such as alpra- which the individual is exposed to unfamiliar individu-
zolam and oxazepam, can produce daytime anxiety, early als or to possible examination and evaluation by others.
morning insomnia, and, with discontinuation, rebound Examples include having to converse at a party, use
anxiety and insomnia. Although patients develop toler- public restrooms, and meet strangers. In each case, the
ance to the sedative effects of benzodiazepines, they affected individual is aware that the experienced fear is
are less likely to habituate to the adverse psychomotor excessive and unreasonable given the circumstance. The
effects. Withdrawal from the longer half-life benzodi- specic content of a phobia may vary across gender,
azepines can be accomplished through gradual, step- ethnic, and cultural boundaries.
wise dose reduction (by 10% every 12 weeks) over Phobic disorders are common, affecting 10% of the
612 weeks. It is usually more difficult to taper patients population. Full criteria for diagnosis are usually satis-
off shorter-acting benzodiazepines. Physicians may ed rst in early adulthood, but behavioral avoidance
need to switch the patient to a benzodiazepine with a of unfamiliar people, situations, or objects dating from
longer half-life or use an adjunctive medication such as early childhood is common.
a beta blocker or carbamazepine, before attempting to In one study of female twins, concordance rates for
discontinue the benzodiazepine. Withdrawal reactions agoraphobia, social phobia, and animal phobia were
vary in severity and duration; they can include depres- found to be 23% for monozygotic twins and 15% for
sion, anxiety, lethargy, diaphoresis, autonomic arousal, dizygotic twins. A twin study of fear conditioning, a
and, rarely, seizures. model for the acquisition of phobias, demonstrated a
Buspirone is a nonbenzodiazepine anxiolytic agent. heritability of 3545%, and a genomewide linkage scan
It is nonsedating, does not produce tolerance or depen- identied a risk locus on chromosome 14 in a region
dence, does not interact with benzodiazepine receptors previously implicated in a mouse model of fear. Animal
or alcohol, and has no abuse or disinhibition potential. studies of fear conditioning have indicated that processing
However, it requires several weeks to take effect and of the fear stimulus occurs through the lateral nucleus of
requires thrice-daily dosing. Patients who were previ- the amygdala, extending through the central nucleus
ously responsive to a benzodiazepine are unlikely to and projecting to the periaqueductal gray region, lateral
rate buspirone as equally effective, but patients with hypothalamus, and paraventricular hypothalamus.
head injury or dementia who have symptoms of anxiety
and/or agitation may do well with this agent. Escitalo-
pram, paroxetine, and venlafaxine are FDA approved for
the treatment of GAD, usually at doses that are compara- TREATMENT Phobic Disorders
ble to their efficacy in major depression. Benzodiazepines
are contraindicated during pregnancy and breast-feeding. Beta blockers (e.g., propranolol, 2040 mg orally 2 h
Anticonvulsants with GABAergic properties may also before the event) are particularly effective in the treat-
be effective against anxiety. Gabapentin, oxcarbazepine, ment of performance anxiety (but not general social
tiagabine, pregabalin, and divalproex have all shown phobia) and appear to work by blocking the peripheral
some degree of benefit in a variety of anxiety-related manifestations of anxiety such as perspiration, tachycar-
syndromes. Agents that selectively target GABAA recep- dia, palpitations, and tremor. MAOIs alleviate social pho-
tor subtypes are currently under development, and it is bia independently of their antidepressant activity, and
hoped that these will lack the sedating, memory-impairing, paroxetine, sertraline, and venlafaxine have received FDA
and addicting properties of benzodiazepines. approval for treatment of social anxiety. Benzodiazepines
TABLE 54-8 727
can be helpful in reducing fearful avoidance, but the DIAGNOSTIC CRITERIA FOR POSTTRAUMATIC
chronic nature of phobic disorders limits their usefulness. STRESS DISORDER
CHAPTER 54
Behaviorally focused psychotherapy is an important A. The person has been exposed to a traumatic event in
component of treatment, as relapse rates are high when which both of the following were present:
medication is used as the sole treatment. Cognitive- 1. The person experienced, witnessed, or was con-
behavioral strategies are based upon the finding that dis- fronted with an event or events that involved actual
torted perceptions and interpretations of fear-producing or threatened death or serious injury, or a threat to
the physical integrity of self or others.
stimuli play a major role in perpetuation of phobias.
2. The persons response involved intense fear,
Mental Disorders
Individual and group therapy sessions teach the patient helplessness, or horror.
to identify specific negative thoughts associated with
B. The traumatic event is persistently reexperienced in
the anxiety-producing situation and help to reduce the
one (or more) of the following ways:
patients fear of loss of control. In desensitization therapy, 1. Recurrent and intrusive distressing recollections of
hierarchies of feared situations are constructed and the the event, including images, thoughts, or perceptions.
patient is encouraged to pursue and master gradual expo- 2. Recurrent distressing dreams of the event.
sure to the anxiety-producing stimuli. 3. Acting or feeling as if the traumatic event were
Patients with social phobia, in particular, have a high recurring (includes a sense of reliving the experi-
rate of comorbid alcohol abuse, as well as of other psy- ence, illusions, hallucinations, and dissociative
ashback episodes, including those that occur on
chiatric conditions (e.g., eating disorders), necessitating
awakening or when intoxicated).
the need for parallel management of each disorder if 4. Intense psychological distress at exposure to internal
anxiety reduction is to be achieved. or external cues that symbolize or resemble an aspect
of the traumatic event.
5. Physiologic reactivity on exposure to internal or
STRESS DISORDERS external cues that symbolize or resemble an aspect
Clinical manifestations of the traumatic event.
C. Persistent avoidance of stimuli associated with the
Patients may develop anxiety after exposure to extreme trauma and numbing of general responsiveness (not
traumatic events such as the threat of personal death or present before the trauma), as indicated by three or
injury or the death of a loved one. The reaction may more of the following:
occur shortly after the trauma (acute stress disorder) or be 1. Efforts to avoid thoughts, feelings, or conversations
delayed and subject to recurrence (PTSD) (Table 54-8). associated with the trauma
In both syndromes, individuals experience associated 2. Efforts to avoid activities, places, or people that
symptoms of detachment and loss of emotional respon- arouse recollections of the trauma
3. Inability to recall an important aspect of the trauma
sivity. The patient may feel depersonalized and unable to 4. Markedly diminished interest or participation in
recall specic aspects of the trauma, though typically it signicant activities
is reexperienced through intrusions in thought, dreams, 5. Feeling of detachment or estrangement from others
or ashbacks, particularly when cues of the original 6. Restricted range of affect (e.g., unable to have loving
event are present. Patients often actively avoid stimuli feelings)
that precipitate recollections of the trauma and demon- 7. Sense of a foreshortened future (e.g., does not expect
strate a resulting increase in vigilance, arousal, and star- to have a career, marriage, children, or a normal life
span)
tle response. Patients with stress disorders are at risk for
the development of other disorders related to anxiety, D. Persistent symptoms of increased arousal (not present
mood, and substance abuse (especially alcohol). Between before the trauma), as indicated by two (or more) of the
following:
5 and 10% of Americans will at some time in their life 1. Difculty falling or staying asleep
satisfy criteria for PTSD, with women more likely to be 2. Irritability or outbursts of anger
affected than men. 3. Difculty concentrating
Risk factors for the development of PTSD include a 4. Hypervigilance
past psychiatric history and personality characteristics of 5. Exaggerated startle response
high neuroticism and extroversion. Twin studies show E. Duration of the disturbance (symptoms in criteria B, C,
a substantial genetic inuence on all symptoms associ- and D) is more than 1 month
ated with PTSD, with less evidence for an environmen- F. The disturbance causes clinically signicant distress or
tal effect. impairment in social, occupational, or other important
areas of functioning.
Etiology and pathophysiology
Source: Reprinted with permission from the Diagnostic and Statistical
It is hypothesized that in PTSD there is excessive Manual of Mental Disorders, Fourth Edition, Text Revision. Copyright
release of norepinephrine from the locus coeruleus in 2000 American Psychiatric Association.
728 response to stress and increased noradrenergic activ- Comorbid conditions are common, the most frequent
ity at projection sites in the hippocampus and amyg- being depression, other anxiety disorders, eating disor-
dala. These changes theoretically facilitate the encoding ders, and tics. OCD has a lifetime prevalence of 23%
SECTION V
of fear-based memories. Greater sympathetic responses worldwide. Onset is usually gradual, beginning in early
to cues associated with the traumatic event occur in adulthood, but childhood onset is not rare. The disor-
PTSD, although pituitary adrenal responses are blunted. der usually has a waxing and waning course, but some
cases may show a steady deterioration in psychosocial
functioning.
TREATMENT Stress Disorders
Psychiatric Disorders
CHAPTER 54
regulation of mood, behavior, and affect. Mood disorders adverse cardiac events and thus are reasonable rst-line
are subdivided into (1) depressive disorders, (2) bipolar drugs for patients at risk for TCA-related complications.
disorders, and (3) depression in association with medical SSRIs may interfere with hepatic metabolism of antico-
illness or alcohol and substance abuse (Chaps. 56 through agulants, however, causing increased anticoagulation.
58). Major depressive disorder (MDD) is differenti- In patients with cancer, the mean prevalence of
ated from bipolar disorder by the absence of a manic depression is 25%, but depression occurs in 4050% of
Mental Disorders
or hypomanic episode. The relationship between pure patients with cancers of the pancreas or oropharynx.
depressive syndromes and bipolar disorders is not well This association is not due to the effect of cachexia
understood; MDD is more frequent in families of bipolar alone, as the higher prevalence of depression in patients
individuals, but the reverse is not true. In the Global with pancreatic cancer persists when compared to those
Burden of Disease Study conducted by the World Health with advanced gastric cancer. Initiation of antidepres-
Organization, unipolar major depression ranked fourth sant medication in cancer patients has been shown to
among all diseases in terms of disability-adjusted life-years improve quality of life as well as mood. Psychothera-
and was projected to rank second by the year 2020. In peutic approaches, particularly group therapy, may have
the United States, lost productivity directly related to some effect on short-term depression, anxiety, and pain
mood disorders has been estimated at $55.1 billion per symptoms.
year. Depression occurs frequently in patients with neurologic
disorders, particularly cerebrovascular disorders, Parkin-
sons disease, dementia, multiple sclerosis, and traumatic
DEPRESSION IN ASSOCIATION WITH brain injury. One in ve patients with left-hemisphere
MEDICAL ILLNESS stroke involving the dorsolateral frontal cortex experiences
Depression occurring in the context of medical illness major depression. Late-onset depression in otherwise
is difcult to evaluate. Depressive symptomatology may cognitively normal individuals increases the risk of a sub-
reect the psychological stress of coping with the dis- sequent diagnosis of Alzheimers disease. Both TCA and
ease, may be caused by the disease process itself or by SSRI agents are effective against these depressions, as are
the medications used to treat it, or may simply coexist stimulant compounds and, in some patients, MAOIs.
in time with the medical diagnosis. The reported prevalence of depression in patients
Virtually every class of medication includes some agent with diabetes mellitus varies from 8 to 27%, with the
that can induce depression. Antihypertensive drugs, severity of the mood state correlating with the level of
anticholesterolemic agents, and antiarrhythmic agents hyperglycemia and the presence of diabetic complica-
are common triggers of depressive symptoms. Iatrogenic tions. Treatment of depression may be complicated by
depression should also be considered in patients receiv- effects of antidepressive agents on glycemic control.
ing glucocorticoids, antimicrobials, systemic analge- MAOIs can induce hypoglycemia and weight gain,
sics, antiparkinsonian medications, and anticonvulsants. while TCAs can produce hyperglycemia and carbohy-
To decide whether a causal relationship exists between drate craving. SSRIs, like MAOIs, may reduce fasting
pharmacologic therapy and a patients change in mood, plasma glucose, but they are easier to use and may also
it may sometimes be necessary to undertake an empirical improve dietary and medication compliance.
trial of an alternative medication. Hypothyroidism is frequently associated with fea-
Between 20 and 30% of cardiac patients manifest a tures of depression, most commonly depressed mood and
depressive disorder; an even higher percentage experi- memory impairment. Hyperthyroid states may also present
ence depressive symptomatology when self-reporting in a similar fashion, usually in geriatric populations.
scales are used. Depressive symptoms following unstable Improvement in mood usually follows normalization of
angina, myocardial infarction, cardiac bypass surgery, or thyroid function, but adjunctive antidepressant medication
heart transplant impair rehabilitation and are associated is sometimes required. Patients with subclinical hypothy-
with higher rates of mortality and medical morbidity. roidism can also experience symptoms of depression and
Depressed patients often show decreased variability in cognitive difculty that respond to thyroid replacement.
heart rate (an index of reduced parasympathetic nervous The lifetime prevalence of depression in HIV-positive
system activity), which may predispose individuals to individuals has been estimated at 2245%. The rela-
ventricular arrhythmia and increased morbidity. Depres- tionship between depression and disease progression is
sion also appears to increase the risk of developing cor- multifactorial and likely to involve psychological and
onary heart disease, possibly through increased platelet social factors, alterations in immune function, and central
aggregation. TCAs are contraindicated in patients with nervous system (CNS) disease. Chronic hepatitis C
730 infection is also associated with depression, which may TABLE 54-9
worsen with interferon- treatment. CRITERIA FOR A MAJOR DEPRESSIVE EPISODE
Some chronic disorders of uncertain etiology, such A. Five (or more) of the following symptoms have been
SECTION V
as chronic fatigue syndrome (Chap. 52) and bromyal- present during the same 2-week period and represent
gia, are strongly associated with depression and anxiety; a change from previous functioning; at least one of the
patients may benet from antidepressant treatment or symptoms is either (1) depressed mood or (2) loss of
anticonvulsant agents such as pregabalin. interest or pleasure. Note: Do not include symptoms
that are clearly due to a general medical condition, or
mood-incongruent delusions or hallucinations.
1. Depressed mood most of the day, nearly every day,
DEPRESSIVE DISORDERS
Psychiatric Disorders
CHAPTER 54
disability and also responds to pharmacologic treatment. treatment.
Depression is approximately twice as common in Diurnal variations in symptom severity and alterations
women as in men, and the incidence increases with age in circadian rhythmicity of a number of neurochemical
in both sexes. Twin studies indicate that the liability and neurohumoral factors suggest that biologic differ-
to major depression of early onset (before age 25) is ences may be secondary to a primary defect in regulation
largely genetic in origin. Negative life events can pre- of biologic rhythms. Patients with major depression show
Mental Disorders
cipitate and contribute to depression, but genetic factors consistent ndings of a decrease in rapid eye movement
inuence the sensitivity of individuals to these stressful (REM) sleep onset (REM latency), an increase in REM
events. In most cases, both biologic and psychosocial density, and, in some subjects, a decrease in stage IV delta
factors are involved in the precipitation and unfolding slow-wave sleep.
of depressive episodes. The most potent stressors appear Although antidepressant drugs inhibit neurotransmit-
to involve death of a relative, assault, or severe marital ter uptake within hours, their therapeutic effects typically
or relationship problems. emerge over several weeks, implicating adaptive changes
Unipolar depressive disorders usually begin in early in second messenger systems and transcription factors as
adulthood and recur episodically over the course of a possible mechanisms of action.
lifetime. The best predictor of future risk is the number The pathogenesis of depression is discussed in detail
of past episodes; 5060% of patients who have a rst in Chap. 53.
episode have at least one or two recurrences. Some
patients experience multiple episodes that become
more severe and frequent over time. The duration of TREATMENT Depressive Disorders
an untreated episode varies greatly, ranging from a few
months to 1 year. The pattern of recurrence and clinical Treatment planning requires coordination of short-term
progression in a developing episode are also variable. strategies to induce remission combined with longer
Within an individual, the nature of episodes (e.g., spe- term maintenance designed to prevent recurrence. The
cic presenting symptoms, frequency and duration) most effective intervention for achieving remission and
may be similar over time. In a minority of patients, a preventing relapse is medication, but combined treat-
severe depressive episode may progress to a psychotic ment, incorporating psychotherapy to help the patient
state; in elderly patients, depressive symptoms may be cope with decreased self-esteem and demoralization,
associated with cognitive decits mimicking dementia improves outcome (Fig. 54-1). Approximately 40%
(pseudodementia). A seasonal pattern of depression, of primary care patients with depression drop out of
called seasonal affective disorder, may manifest with onset treatment and discontinue medication if symptomatic
and remission of episodes at predictable times of the improvement is not noted within a month, unless addi-
year. This disorder is more common in women, whose tional support is provided. Outcome improves with (1)
symptoms are anergy, fatigue, weight gain, hypersomnia, increased intensity and frequency of visits during the
and episodic carbohydrate craving. The prevalence first 46 weeks of treatment, (2) supplemental educa-
increases with distance from the equator, and improve- tional materials, and (3) psychiatric consultation as indi-
ment may occur by altering light exposure. cated. Despite the widespread use of SSRIs and other
second-generation antidepressant drugs, there is no
Etiology and pathophysiology convincing evidence that this class of antidepressant is
more efficacious than TCAs. Between 60 and 70% of all
Although evidence for genetic transmission of unipolar depressed patients respond to any drug chosen, if it is
depression is not as strong as in bipolar disorder, mono- given in a sufficient dose for 68 weeks. There is no ideal
zygotic twins have a higher concordance rate (46%) antidepressant; no current compound combines rapid
than dizygotic siblings (20%), with little support for any onset of action, moderate half-life, a meaningful rela-
effect of a shared family environment. tionship between dose and blood level, a low side effect
Neuroendocrine abnormalities that reect the neu- profile, minimal interaction with other drugs, and safety
rovegetative signs and symptoms of depression include: in overdose.
(1) increased cortisol and corticotropin-releasing hor- A rational approach to selecting which antidepres-
mone (CRH) secretion, (2) an increase in adrenal size, sant to use involves matching the patients preference
(3) a decreased inhibitory response of glucocorticoids to and medical history withthe metabolic and side effect
dexamethasone, and (4) a blunted response of thyroid- profile of the drug (Tables 54-4 and 54-5). A previous
stimulating hormone (TSH) level to infusion of thyroid- response, or a family history of a positive response, to
releasing hormone (TRH). Antidepressant treatment leads
732 MEDICAL MANAGEMENT OF MAJOR DEPRESSIVE DISORDER supply when suicide is a risk. Most patients require a
ALGORITHM daily dose of 150200 mg of imipramine or amitriptyline
Determine whether there is a history of good response to a medication or its equivalent to achieve a therapeutic blood level
SECTION V
Begin new medication at 1/3 to 1/2 target dose if drug is a TCA, rable blood level. P450 profiling using genetic chip tech-
bupropion, venlafaxine, or mirtazapine, or full dose as tolerated if drug nology may be clinically useful in predicting individual
is an SSRI.
sensitivity.
Second-generation antidepressants include amoxap-
If problem side effects occur, evaluate possibility of tolerance; consider
temporary decrease in dose or adjunctive treatment. ine, maprotiline, trazodone, and bupropion. Amoxapine
is a dibenzoxazepine derivative that blocks norepineph-
If unacceptable side effects continue, taper drug over 1 week and
rine and serotonin reuptake and has a metabolite that
initiate new trial; consider potential drug interactions in choice. shows a degree of dopamine blockade. Long-term use
of this drug carries a risk of tardive dyskinesia. Maproti-
Evaluate response after 6 weeks at target dose; if response is line is a potent noradrenergic reuptake blocker that has
inadequate, increase dose in stepwise fashion as tolerated. little anticholinergic effect but may produce seizures.
Bupropion is a novel antidepressant whose mechanism
If inadequate response after maximal dose, consider tapering and of action is thought to involve enhancement of norad-
switching to a new drug vs adjunctive treatment; if drug is a TCA,
obtain plasma level to guide further treatment.
renergic function. It has no anticholinergic, sedating, or
orthostatic side effects and has a low incidence of sexual
side effects. It may, however, be associated with stimu-
FIGURE 54-1 lant-like side effects, may lower seizure threshold, and
A guideline for the medical management of major has an exceptionally short half-life, requiring frequent
depressive disorder. SSRI, selective serotonin reuptake dosing. An extended-release preparation is available.
inhibitor; TCA, tricyclic antidepressant. SSRIs such as fluoxetine, sertraline, paroxetine, citalo-
pram, and escitalopram cause a lower frequency of anti-
cholinergic, sedating, and cardiovascular side effects
a specific antidepressant often suggests that that drug but a possibly greater incidence of gastrointestinal com-
be tried first. Before initiating antidepressant therapy, the plaints, sleep impairment, and sexual dysfunction than
physician should evaluate the possible contribution of do TCAs. Akathisia, involving an inner sense of restless-
comorbid illnesses and consider their specific treatment. ness and anxiety in addition to increased motor activ-
In individuals with suicidal ideation, particular attention ity, may also be more common, particularly during the
should be paid to choosing a drug with low toxicity if first week of treatment. One concern is the risk of sero-
taken in overdose. The SSRIs, and other newer antidepres- tonin syndrome, thought to result from hyperstimula-
sant drugs are distinctly safer in this regard; neverthe- tion of brainstem 5HT1A receptors and characterized by
less, the advantages of TCAs have not been completely myoclonus, agitation, abdominal cramping, hyperpy-
superseded. The existence of generic equivalents make rexia, hypertension, and potentially death. Serotoner-
TCAs relatively cheap, and for secondary tricyclics, par- gic agonists taken in combination should be monitored
ticularly nortriptyline and desipramine, well-defined closely for this reason. Considerations such as half-life,
relationships among dose, plasma level, and thera- compliance, toxicity, and drug-drug interactions may
peutic response exist. The steady-state plasma level guide the choice of a particular SSRI. Fluoxetine and its
achieved for a given drug dose can vary more than ten- principal active metabolite, norfluoxetine, for example,
fold between individuals and plasma levels may help have a combined half-life of almost 7 days, resulting in a
in interpreting apparent resistance to treatment and/ delay of 5 weeks before steady-state levels are achieved
or unexpected drug toxicity. The principal side effects and a similar delay for complete drug excretion once
of TCAs are antihistamine (sedation) and anticholiner- its use is discontinued. All the SSRIs may impair sexual
gic (constipation, dry mouth, urinary hesitancy, blurred function, resulting in diminished libido, impotence, or
vision). TCAs are contraindicated in patients with seri- difficulty in achieving orgasm. Sexual dysfunction fre-
ous cardiovascular risk factors and overdoses of tricy- quently results in noncompliance and should be asked
clic agents can be lethal, with desipramine carrying the about specifically. Sexual dysfunction can sometimes be
greatest risk. It is judicious to prescribe only a 10-day ameliorated by lowering the dose, by instituting weekend
drug holidays (two or three times a month), or by treat- Regardless of the treatment undertaken, the response 733
ment with amantadine (100 mg tid), bethanechol (25 should be evaluated after 2 months. Three-quarters of
CHAPTER 54
mg tid), buspirone (10 mg tid), or bupropion (100150 patients show improvement by this time, but if remission
mg/d). Paroxetine appears to be more anticholinergic is inadequate the patient should be questioned about
than either fluoxetine or sertraline, and sertraline carries compliance and an increase in medication dose should
a lower risk of producing an adverse drug interaction be considered if side effects are not troublesome. If this
than the other two. Rare side effects of SSRIs include approach is unsuccessful, referral to a mental health spe-
angina due to vasospasm and prolongation of the pro- cialist is advised. Strategies for treatment then include
thrombin time. Escitalopram is the most specific of cur- selection of an alternative drug, combinations of anti-
Mental Disorders
rently available SSRIs and appears to have no specific depressants, and/or adjunctive treatment with other
inhibitory effects on the P450 system. classes of drugs, including lithium, thyroid hormone,
Venlafaxine, desvenlafaxine, and duloxetine block atypical antipsychotic agents, and dopamine agonists.
the reuptake of both norepinephrine and serotonin A large randomized trial (STAR-D) was unable to show
but produce relatively little in the way of traditional tri- preferential efficacy, but the addition of atypical anti-
cyclic side effects. Unlike the SSRIs, venlafaxine has a psychotic drugs has received FDA approval. Patients
relatively linear dose-response curve. Patients should whose response to an SSRI wanes over time may benefit
be monitored for a possible increase in diastolic blood from the addition of buspirone (10 mg tid) or pindolol
pressure, and multiple daily dosing is required because (25 mg tid) or small amounts of a TCA such as desipra-
of the drugs short half-life. An extended-release form is mine (25 mg bid or tid). Most patients will show some
available and has a somewhat lower incidence of gas- degree of response but aggressive treatment should be
trointestinal side effects. Mirtazapine is a TCA that has a pursued until remission is achieved, and drug treatment
unique spectrum of activity. It increases noradrenergic should be continued for at least 69 more months to
and serotonergic neurotransmission through a block- prevent relapse. In patients who have had two or more
ade of central 2-adrenergic receptors and postsynaptic episodes of depression, indefinite maintenance treat-
5HT2 and 5HT3 receptors. It is also strongly antihista- ment should be considered.
minic and, as such, may produce sedation. It is essential to educate patients both about depres-
With the exception of citalopram and escitalopram, sion and the benefits and side effects of medications
each of the SSRIs may inhibit one or more cytochrome they are receiving. Advice about stress reduction and
P450 enzymes. Depending on the specific isoenzyme cautions that alcohol may exacerbate depressive symp-
involved, the metabolism of a number of concomitantly toms and impair drug response are helpful. Patients
administered medications can be dramatically affected. should be given time to describe their experience, their
Fluoxetine and paroxetine, for example, by inhibiting outlook, and the impact of the depression on them and
2D6, can cause dramatic increases in the blood level of their families. Occasional empathic silence may be as
type 1C antiarrhythmics, while sertraline, by acting on helpful for the treatment alliance as verbal reassurance.
3A4, may alter blood levels of carbamazepine, or digoxin. Controlled trials have shown that cognitive-behavioral
The MAOIs are highly effective, particularly in atypical and interpersonal therapies are effective in improving
depression, but the risk of hypertensive crisis following psychological and social adjustment and that a com-
intake of tyramine-containing food or sympathomimetic bined treatment approach is more successful than med-
drugs makes them inappropriate as first-line agents. ication alone for many patients.
Transdermal selegiline may avert this risk at low dose.
Common side effects include orthostatic hypotension,
weight gain, insomnia, and sexual dysfunction. MAOIs BIPOLAR DISORDER
should not be used concomitantly with SSRIs, because Clinical manifestations
of the risk of serotonin syndrome, or with TCAs, because
of possible hyperadrenergic effects.
Bipolar disorder is characterized by unpredictable
swings in mood from mania (or hypomania) to depres-
Electroconvulsive therapy is at least as effective as
sion. Some patients suffer only from recurrent attacks
medication, but its use is reserved for treatment-resistant
of mania, which in its pure form is associated with
cases and delusional depressions. Transcranial magnetic
increased psychomotor activity; excessive social extro-
stimulation (TMS) is approved for treatment-resistant
version; decreased need for sleep; impulsivity and
depression and has been shown to have efficacy in several
impairment in judgment; and expansive, grandiose, and
controlled trials. Vagus nerve stimulation (VNS) has also
sometimes irritable mood (Table 54-10). In severe
recently been approved for treatment-resistant depres-
mania, patients may experience delusions and paranoid
sion, but its degree of efficacy is controversial. Deep brain
thinking indistinguishable from schizophrenia. One-half
stimulation is another treatment that is being used experi-
of patients with bipolar disorder present with a mixture
mentally in treatment-resistant cases.
of psychomotor agitation and activation with dysphoria,
734 TABLE 54-10 for patients who have four or more episodes of either
CRITERIA FOR A MANIC EPISODE depression or mania in a given year. This pattern occurs
A. A distinct period of abnormally and persistently ele- in 15% of all patients, almost all of whom are women.
SECTION V
vated, expansive, or irritable mood, lasting at least 1 In some cases, rapid cycling is linked to an underlying
week (or any duration if hospitalization is necessary) thyroid dysfunction and, in others, it is iatrogenically trig-
B. During the period of mood disturbance, three (or more) of gered by prolonged antidepressant treatment. Approxi-
the following symptoms have persisted (four if the mood mately one-half of patients have sustained difculties in
is only irritable) and have been present to a signicant work performance and psychosocial functioning, with
degree: depressive phases being more responsible for impairment
1. Inated self-esteem or grandiosity
Psychiatric Disorders
than mania.
2. Decreased need for sleep (e.g., feels rested after Bipolar disorder is common, affecting 1.5% of
only 3 h of sleep)
3. More talkative than usual or pressure to keep talking
the population in the United States. Onset is typically
4. Flight of ideas or subjective experience that between 20 and 30 years of age, but many individuals
thoughts are racing report premorbid symptoms in late childhood or early
5. Distractibility (i.e., attention too easily drawn to adolescence. The prevalence is similar for men and
unimportant or irrelevant external stimuli) women; women are likely to have more depressive and
6. Increase in goal-directed activity (either socially, at men more manic episodes over a lifetime.
work or school, or sexually) or psychomotor agitation
7. Excessive involvement in pleasurable activities that
have a high potential for painful consequences (e.g., Differential diagnosis
engaging in unrestrained buying sprees, sexual The differential diagnosis of mania includes secondary
indiscretions, or foolish business investments)
mania induced by stimulant or sympathomimetic drugs,
C. The symptoms do not meet criteria for a mixed episode. hyperthyroidism, AIDS, neurologic disorders, such as
D. The mood disturbance is sufciently severe to cause Huntingtons or Wilsons disease, and cerebrovascu-
marked impairment in occupational functioning or in lar accidents. Comorbidity with alcohol and substance
usual social activities or relationships with others, or to abuse is common, either because of poor judgment and
necessitate hospitalization to prevent harm to self or
increased impulsivity or because of an attempt to self-treat
others, or there are psychotic features.
the underlying mood symptoms and sleep disturbances.
E. The symptoms are not due to the direct physiologic effects
of a substance (e.g., a drug of abuse, a medication, or
other treatment) or a general medical condition (e.g., Etiology and pathophysiology
hyperthyroidism). Genetic predisposition to bipolar disorder is evident from
family studies; the concordance rate for monozygotic
Note: Manic-like episodes that are clearly caused by somatic antide-
pressant treatment (e.g., medication, electroconvulsive therapy, light
twins approaches 80%. Patients with bipolar disorder also
therapy) should not count toward a diagnosis of bipolar I disorder. appear to have altered circadian rhythmicity, and lithium
Source: Reprinted with permission from the Diagnostic and Sta- may exert its therapeutic benet through a resynchroni-
tistical Manual of Mental Disorders, Fourth Edition, Text Revision. zation of intrinsic rhythms keyed to the light/dark cycle.
Copyright 2000 American Psychiatric Association.
A detailed discussion of the pathogenesis of bipolar disor-
der is presented in Chap. 53.
anxiety, and irritability. It may be difcult to distinguish
mixed mania from agitated depression. In some bipolar
patients (bipolar II disorder), the full criteria for mania are
lacking, and the requisite recurrent depressions are sepa- TREATMENT Bipolar Disorder
rated by periods of mild activation and increased energy
(Table 54-11) Lithium carbonate is the mainstay of
(hypomania). In cyclothymic disorder, there are numerous
treatment in bipolar disorder, although sodium valpro-
hypomanic periods, usually of relatively short duration,
ate and olanzapine are equally effective in acute mania,
alternating with clusters of depressive symptoms that
as is lamotrigine in the depressed phase. The response
fail, either in severity or duration, to meet the criteria
rate to lithium carbonate is 7080% in acute mania,
of major depression. The mood uctuations are chronic
with beneficial effects appearing in 12 weeks. Lithium
and should be present for at least 2 years before the
also has a prophylactic effect in prevention of recur-
diagnosis is made.
rent mania and, to a lesser extent, in the prevention of
Manic episodes typically emerge over a period of days
recurrent depression. A simple cation, lithium is rapidly
to weeks, but onset within hours is possible, usually in
absorbed from the gastrointestinal tract and remains
the early morning hours. An untreated episode of either
unbound to plasma or tissue proteins. Some 95% of a
depression or mania can be as short as several weeks or
given dose is excreted unchanged through the kidneys
last as long as 812 months, and rare patients have an
within 24 h.
unremitting chronic course. The term rapid cycling is used
TABLE 54-11
effect by interfering with the synthesis and release of 735
CLINICAL PHARMACOLOGY OF MOOD STABILIZERS thyroid hormones. More serious side effects include
tremor, poor concentration and memory, ataxia, dysar-
CHAPTER 54
SIDE EFFECTS AND OTHER
AGENT AND DOSING EFFECTS thria, and incoordination. There is suggestive, but not
Lithium Common Side Effects conclusive, evidence that lithium is teratogenic, induc-
ing cardiac malformations in the first trimester.
Starting dose: 300 mg Nausea/anorexia/diarrhea,
bid or tid ne tremor, thirst, polyuria, In the treatment of acute mania, lithium is initiated
Therapeutic blood level: fatigue, weight gain, acne, at 300 mg bid or tid, and the dose is then increased
0.81.2 meq/L folliculitis, neutrophilia, by 300 mg every 23 days to achieve blood levels of
Mental Disorders
hypothyroidism 0.81.2 meq/L. Because the therapeutic effect of lith-
Blood level is increased by ium may not appear until after 710 days of treatment,
thiazides, tetracyclines, adjunctive usage of lorazepam (12 mg every 4 h) or
and NSAIDs
clonazepam (0.51 mg every 4 h) may be beneficial
Blood level is decreased by
bronchodilators, verapamil, to control agitation. Antipsychotics are indicated in
and carbonic anhydrase patients with severe agitation who respond only par-
inhibitors tially to benzodiazepines. Patients using lithium should
Rare side effects: Neurotox- be monitored closely, since the blood levels required
icity, renal toxicity, hyper- to achieve a therapeutic benefit are close to those
calcemia, ECG changes associated with toxicity.
Valproic Acid Common Side Effects Valproic acid may be better than lithium for patients
Starting dose: 250 mg tid Nausea/anorexia, weight who experience rapid cycling (i.e., more than four epi-
Therapeutic blood level: gain, sedation, tremor, sodes a year) or who present with a mixed or dysphoric
50125 g/mL rash, alopecia mania. Tremor and weight gain are the most common
Inhibits hepatic metabolism side effects; hepatotoxicity and pancreatitis are rare
of other medications toxicities.
Rare side effects: Pancre-
Carbamazepine and oxcarbazepine, although not
atitis, hepatotoxicity, Ste-
vens-Johnson syndrome formally approved by the FDA for bipolar disorder, have
clinical efficacy in the treatment of acute mania. Second-
Carbamazepine/
generation antipsychotic drugs (olanzapine, quetiapine,
Oxcarbazepine Common Side Effects
risperidone, ziprasidone, aripiprazole, and asenapine)
Starting dose: 200 mg bid Nausea/anorexia, sedation,
have also been shown to be effective, either alone or in
for carbamazepine, 150 mg rash, dizziness/ataxia
bid for oxcarbazepine Carbamazepine, but not
combination with a mood stabilizer. An increased risk of
Therapeutic blood level: oxcarbazepine, induces weight gain and other metabolic abnormalities is a con-
412 g/mL for carbam- hepatic metabolism of cern with these agents.
azepine other medications The recurrent nature of bipolar mood disorder
Rare side effects: Hypona- necessitates maintenance treatment. A sustained
tremia, agranulocytosis, blood lithium level of at least 0.8 meq/L is impor-
Stevens-Johnson tant for optimal prophylaxis and has been shown to
syndrome
reduce risk of suicide, a finding not yet apparent for
Lamotrigine Common Side Effects other mood stabilizers. Compliance is frequently an
Starting dose: 25 mg/d Rash, dizziness, headache, issue and often requires enlistment and education
tremor, sedation, nausea of concerned family members. Efforts to identify and
Rare side effect: Stevens- modify psychosocial factors that may trigger epi-
Johnson syndrome
sodes are important, as is an emphasis on lifestyle
regularity. Antidepressant medications are some-
Abbreviations: NSAIDs, nonsteroidal anti-inammatory drugs; ECG,
electrocardiogram.
times required for the treatment of severe break-
through depressions, but their use should generally
be avoided during maintenance treatment because
of the risk of precipitating mania or accelerating
Serious side effects from lithium are rare, but minor the cycle frequency. Loss of efficacy over time may
complaints such as gastrointestinal discomfort, nausea, be observed with any of the mood-stabilizing agents.
diarrhea, polyuria, weight gain, skin eruptions, alopecia, In such situations, an alternative agent or combina-
and edema are common. Over time, urine-concentrating tion therapy is usually helpful.
ability may be decreased, but significant nephrotoxicity Consensus guidelines for the treatment of acute mania
does not usually occur. Lithium exerts an antithyroid and bipolar depression are described in Table 54-12.
736 TABLE 54-12 TABLE 54-13
CONSENSUS GUIDELINES ON THE DRUG DIAGNOSTIC CRITERIA FOR SOMATIZATION
TREATMENT OF ACUTE MANIA AND BIPOLAR DISORDER
SECTION V
aripiprazole, conventional
course of the disturbance:
antipsychotic, or risperidone
1. Four pain symptoms: a history of pain related to
Hypomania Lithium, lamotrigine, or at least four different sites or functions (e.g., head,
valproic acid alone abdomen, back, joints, extremities, chest, rectum,
Severe depression with Venlafaxine, bupropion, or during menstruation, during sexual intercourse, or
psychosis paroxetine plus lithium plus during urination)
olanzapine, or risperidone; 2. Two gastrointestinal symptoms: a history of at least
consider ECT two gastrointestinal symptoms other than pain (e.g.,
nausea, bloating, vomiting other than during preg-
Severe depression without Bupropion, paroxetine, nancy, diarrhea, or intolerance of several different
psychosis sertraline, venlafaxine, or foods)
citalopram plus lithium 3. One sexual symptom: a history of at least one sexual
Mild to moderate Lithium or lamotrigine or reproductive symptom other than pain (e.g., sexual
depression alone; add bupropion if indifference, erectile or ejaculatory dysfunction,
needed irregular menses, excessive menstrual bleeding,
vomiting throughout pregnancy)
Abbreviation: ECT, electroconvulsive therapy. 4. One pseudoneurologic symptom: a history of at least
Source: From GS Sachs et al: Postgrad Med April, 2000. one symptom or decit suggesting a neurologic con-
dition not limited to pain (conversion symptoms such
as impaired coordination or balance, paralysis or
localized weakness, difculty swallowing or lump in
SOMATOFORM DISORDERS throat, aphonia, urinary retention, hallucinations, loss
of touch or pain sensation, double vision, blindness,
CLINICAL MANIFESTATIONS deafness, seizures; dissociative symptoms such as
Patients with multiple somatic complaints that can- amnesia; or loss of consciousness other than fainting)
C. Either of the following:
not be explained by a known medical condition or by 1. After appropriate investigation, each of the symp-
the effects of alcohol or of recreational or prescription toms in criterion B cannot be fully explained by
drugs are commonly seen in primary care practice; one a known general medical condition or the direct
survey indicated a prevalence of such complaints of 5%. effects of a substance (e.g., a drug of abuse, a
In somatization disorder, the patient presents with multiple medication)
physical complaints referable to different organ systems 2. When there is a related general medical condition, the
(Table 54-13). Onset is usually before age 30 years, physical complaints or resulting social or occupational
impairment are in excess of what would be expected
and the disorder is persistent. Formal diagnostic criteria
from the history, physical examination, or laboratory
require the recording of at least four pain, two gastroin- ndings
testinal, one sexual, and one pseudoneurologic symptom. D. The symptoms are not intentionally produced or
Patients with somatization disorder often present with feigned (as in factitious disorder or malingering).
dramatic complaints, but the complaints are inconsistent.
Symptoms of comorbid anxiety and mood disorder are Source: Reprinted with permission from the Diagnostic and Statistical
common and may be the result of drug interactions due Manual of Mental Disorders, Fourth Edition, Text Revision. Copyright
2000 American Psychiatric Association.
to regimens initiated independently by different physi-
cians. Patients with somatization disorder may be impul-
sive and demanding and frequently qualify for a formal of serious medical illness that persists despite reassurance
comorbid psychiatric diagnosis. In conversion disorder, the and appropriate medical evaluation. As with somatiza-
symptoms focus on decits that involve motor or sen- tion disorder, patients with hypochondriasis have a his-
sory function and on psychological factors that initiate tory of poor relationships with physicians stemming from
or exacerbate the medical presentation. Like somatiza- their sense that they have been evaluated and treated
tion disorder, the decit is not intentionally produced inappropriately or inadequately. Hypochondriasis can be
or simulated, as is the case in factitious disorder (malin- disabling in intensity and is persistent, with waxing and
gering). In hypochondriasis, the essential feature is a belief waning symptomatology.
In factitious illnesses, the patient consciously and vol- personality change may be the rst sign of serious neu- 737
untarily produces physical symptoms of illness. The term rologic, endocrine, or other medical illness. Patients
Munchausens syndrome is reserved for individuals with with frontal lobe tumors, for example, can present with
CHAPTER 54
particularly dramatic, chronic, or severe factitious illness. changes in motivation and personality while the results
In true factitious illness, the sick role itself is gratifying. A of the neurologic examination remain within normal
variety of signs, symptoms, and diseases have been either limits. Individuals with personality disorders are often
simulated or caused by factitious behavior, the most com- regarded as difcult patients in clinical medical prac-
mon including chronic diarrhea, fever of unknown origin, tice because they are seen as excessively demanding
intestinal bleeding or hematuria, seizures, and hypoglyce- and/or unwilling to follow recommended treatment
Mental Disorders
mia. Factitious disorder is usually not diagnosed until 510 plans. Although DSM-IV portrays personality disorders
years after its onset, and it can produce signicant social as qualitatively distinct categories, there is an alternative
and medical costs. In malingering, the fabrication derives perspective that personality characteristics vary as a con-
from a desire for some external reward such as a narcotic tinuum between normal functioning and formal mental
medication or disability reimbursement. disorder.
Personality disorders have been grouped into three
overlapping clusters. Cluster A includes paranoid, schiz-
TREATMENT Somatoform Disorders oid, and schizotypal personality disorders. It includes
individuals who are odd and eccentric and who main-
Patients with somatization disorders are frequently sub- tain an emotional distance from others. Individuals have
jected to many diagnostic tests and exploratory surgeries a restricted emotional range and remain socially isolated.
in an attempt to find their real illness. Such an approach Patients with schizotypal personality disorder frequently
is doomed to failure and does not address the core issue. have unusual perceptual experiences and express magical
Successful treatment is best achieved through behavior beliefs about the external world. The essential feature of
modification, in which access to the physician is tightly paranoid personality disorder is a pervasive mistrust and
regulated and adjusted to provide a sustained and pre- suspiciousness of others to an extent that is unjustied by
dictable level of support that is less clearly contingent available evidence. Cluster B disorders include antisocial,
on the patients level of presenting distress. Visits can borderline, histrionic, and narcissistic types and describe
be brief and should not be associated with a need for a individuals whose behavior is impulsive, excessively
diagnostic or treatment action. Although the literature emotional, and erratic. Cluster C incorporates avoid-
is limited, some patients with somatization disorder may ant, dependent, and obsessive-compulsive personality
benefit from antidepressant treatment. types; enduring traits are anxiety and fear. The bound-
Any attempt to confront the patient usually creates aries between cluster types are to some extent articial,
a sense of humiliation and causes the patient to aban- and many patients who meet criteria for one personal-
don treatment from that caregiver. A better strategy is to ity disorder also meet criteria for aspects of another. The
introduce psychological causation as one of a number of risk of a comorbid major mental disorder is increased
possible explanations and to include factitious illness as an in patients who qualify for a diagnosis of personality
option in the differential diagnoses that are discussed. disorder.
Without directly linking psychotherapeutic intervention
to the diagnosis, the patient can be offered a face-saving
means by which the pathologic relationship with the
TREATMENT Personality Disorders
health care system can be examined and alternative
approaches to life stressors developed. Dialectical behavior therapy (DBT) is a cognitive-behavioral
approach that focuses on behavioral change while pro-
viding acceptance, compassion, and validation of the
PERSONALITY DISORDERS patient. Several randomized trials have demonstrated
the efficacy of DBT in the treatment of personality disorders.
Clinical manifestations Antidepressant medications and low-dose antipsychotic
Personality disorders are characteristic patterns of drugs have some efficacy in cluster A personality disor-
thinking, feeling, and interpersonal behavior that are ders, while anticonvulsant mood-stabilizing agents and
relatively inexible and cause signicant functional MAOIs may be considered for patients with cluster B
impairment or subjective distress for the individual. diagnoses who show marked mood reactivity, behavioral
The observed behaviors are not secondary to another dyscontrol, and/or rejection hypersensitivity. Anxious or
mental disorder, nor are they precipitated by substance fearful cluster C patients often respond to medications
abuse or a general medical condition. This distinc- used for axis I anxiety disorders (discussed earlier). It is
tion is often difcult to make in clinical practice, as important that the physician and the patient have rea-
738 sonable expectations vis--vis the possible benefit of
estimated 300,000 episodes of acute schizophrenia occur
annually in the United States, resulting in direct and
any medication used and its side effects. Improvement
indirect costs of $62.7 billion.
may be subtle and observable only over time.
SECTION V
Differential diagnosis
SCHIZOPHRENIA The diagnosis is principally one of exclusion, requiring
the absence of signicant associated mood symptoms,
Clinical manifestations any relevant medical condition, and substance abuse. Drug
Schizophrenia is a heterogeneous syndrome character- reactions that cause hallucinations, paranoia, confusion, or
Psychiatric Disorders
ized by perturbations of language, perception, thinking, bizarre behavior may be dose-related or idiosyncratic; par-
social activity, affect, and volition. There are no patho- kinsonian medications, clonidine, quinacrine, and procaine
gnomonic features. The syndrome commonly begins derivatives are the most common prescription medi-
in late adolescence, has an insidious (and less com- cations associated with these symptoms. Drug causes
monly acute) onset, and, often, a poor outcome, progress- should be ruled out in any case of newly emergent psy-
ing from social withdrawal and perceptual distortions chosis. The general neurologic examination in patients
to recurrent delusions and hallucinations. Patients may with schizophrenia is usually normal, but motor rigid-
present with positive symptoms (such as conceptual dis- ity, tremor, and dyskinesias are noted in one-quarter of
organization, delusions, or hallucinations) or negative untreated patients.
symptoms (loss of function, anhedonia, decreased emo-
tional expression, impaired concentration, and dimin- Epidemiology and pathophysiology
ished social engagement) and must have at least two of
these for a 1-month period and continuous signs for at Epidemiologic surveys identify several risk factors for
least 6 months to meet formal diagnostic criteria. As schizophrenia, including genetic susceptibility, early devel-
individuals age, positive psychotic symptoms tend to opmental insults, winter birth, and increasing parental age.
attenuate and some measure of social and occupational Genetic factors are involved in at least a subset of individu-
function may be regained. Negative symptoms pre- als who develop schizophrenia. Schizophrenia is observed
dominate in one-third of the schizophrenic population in 6.6% of all rst-degree relatives of an affected proband.
and are associated with a poor long-term outcome and If both parents are affected, the risk for offspring is 40%.
a poor response to drug treatment. However, marked The concordance rate for monozygotic twins is 50%,
variability in the course and individual character of compared to 10% for dizygotic twins. Schizophrenia-
symptoms is typical. prone families are also at risk for other psychiatric dis-
The four main subtypes of schizophrenia are catatonic, orders, including schizoaffective disorder and schizotypal
paranoid, disorganized, and residual. Many individu- and schizoid personality disorders, the latter terms designating
als have symptoms of more than one type. Catatonic-type individuals who show a lifetime pattern of social and
describes patients whose clinical presentation is dominated interpersonal decits characterized by an inability to form
by profound changes in motor activity, negativism, and close interpersonal relationships, eccentric behavior, and
echolalia or echopraxia. Paranoid-type describes patients mild perceptual distortions. The pathogenesis of schizo-
who have a prominent preoccupation with a specic phrenia is discussed in detail in Chap. 53.
delusional system and who otherwise do not qualify as
having disorganized-type disease, in which disorganized
speech and behavior are accompanied by a supercial
or silly affect. In residual-type disease, negative symptom- TREATMENT Schizophrenia
atology exists in the absence of delusions, hallucinations,
Antipsychotic agents (Table 54-14) are the cornerstone
or motor disturbance. The term schizophreniform disorder
of acute and maintenance treatment of schizophre-
describes patients who meet the symptom requirements
nia and are effective in the treatment of hallucinations,
but not the duration requirements for schizophrenia, and
delusions, and thought disorders, regardless of etiology.
schizoaffective disorder is used for those who manifest symp-
The mechanism of action involves, at least in part, bind-
toms of schizophrenia and independent periods of mood
ing to dopamine D2/D3 receptors in the ventral striatum;
disturbance. Prognosis depends not on symptom sever-
the clinical potencies of traditional antipsychotic drugs
ity but on the response to antipsychotic medication. A
parallel their affinities for the D2 receptor, and even the
permanent remission without recurrence does occasion-
newer atypical agents exert some degree of D2 receptor
ally occur. About 10% of schizophrenic patients commit
blockade. All neuroleptics induce expression of the
suicide.
immediate-early gene c-fos in the nucleus accumbens,
Schizophrenia is present in 0.85% of individuals
a dopaminergic site connecting prefrontal and limbic
worldwide, with a lifetime prevalence of 11.5%. An
TABLE 54-14 739
ANTIPSYCHOTIC AGENTS
CHAPTER 54
USUAL PO DAILY
NAME DOSE, mg SIDE EFFECTS SEDATION COMMENTS
First-Generation Antipsychotics
Low-potency
Chlorpromazine 1001000 Anticholinergic effects; ortho- +++ EPSEs usually not prominent;
(Thorazine) stasis; photosensitivity; cho- can cause anticholinergic
Thioridazine (Mellaril) 100600 lestasis; QT prolongation delirium in elderly patients
Mental Disorders
Midpotency
Triuoperazine (Stelazine) 250 Fewer anticholinergic side ++ Well tolerated by most
effects patients
Perphenazine (Trilafon) 464 Fewer EPSEs than with higher ++
potency agents.
Loxapine (Loxitane) 30100 Frequent EPSEs ++
Molindone (Moban) 30100 Frequent EPSEs 0 Little weight gain
High potency
Haloperidol (Haldol) 520 No anticholinergic side effects; 0/+ Often prescribed in doses
EPSEs often prominent that are too high; long-acting
Fluphenazine (Prolixin) 120 Frequent EPSEs 0/+ injectable forms of haloperidol
Thiothixene (Navane) 250 Frequent EPSEs 0/+ and uphenazine available
Second-Generation Antipsychotics
Clozapine (Clozaril) 150600 Agranulocytosis (1%); weight ++ Requires weekly WBC count
gain; seizures; drooling; for rst 6 months, then
hyperthermia biweekly if stable
Risperidone (Risperdal) 28 Orthostasis + Requires slow titration;
EPSEs observed with doses
>6 mg qd
Olanzapine (Zyprexa) 1030 Weight gain ++ Mild prolactin elevation
Quetiapine (Seroquel) 350800 Sedation; weight gain; anxiety +++ Bid dosing
Ziprasidone (Geodon) 120200 Orthostatic hypotension +/++ Minimal weight gain; increases
QT interval
Aripiprazole (Abilify) 1030 Nausea, anxiety, insomnia 0/+ Mixed agonist/antagonist
Paliperidone (Invega) 312 Restlessness, EPSEs + Active metabolite of
risperidone
Iloperidone (Fanapt) 1224 Dizziness, hypotension 0/+ Requires dose titration
Asenapine (Saphris) 1020 Dizziness, EPSEs, weight gain ++ Sublingual tablets; bid dosing
Lurasidone (Latuda) 4080 Nausea, EPSEs ++ Uses CYP3A4
cortices. The clinical efficacy of newer atypical neurolep- perphenazine, and thiothixene, are more likely to induce
tics, however, may involve N-methyl-D-aspartate (NMDA) extrapyramidal side effects. The model atypical anti-
receptor blockade, 1- and 2-noradrenergic activity, psychotic agent is clozapine, a dibenzodiazepine that
altering the relationship between 5HT2 and D2 receptor has a greater potency in blocking the 5HT2 than the D2
activity, as well as faster dissociation of D2 binding and receptor and a much higher affinity for the D4 than the
effects on neuroplasticity. D2 receptor. Its principal disadvantage is a risk of blood
Conventional neuroleptics differ in their potency dyscrasias. Paliperidone is a recently approved agent
and side-effect profile. Older agents such as chlorproma- that is a metabolite of risperidone and shares many of
zine and thioridazine, are more sedating and anticholin- its properties. Unlike other antipsychotics, clozapine
ergic and more likely to cause orthostatic hypotension, does not cause a rise in prolactin level. Approximately
while higher potency antipsychotics such as haloperidol, 30% of patients who do not benefit from conventional
740 antipsychotic agents will have a better response to this may contribute to poor adherence if not specifically
drug, which also has a demonstrated superiority to addressed. Anticholinergic and parkinsonian symptoms
other antipsychotic agents in preventing suicide; how- respond well to trihexyphenidyl, 2 mg bid, or benztro-
SECTION V
ever, its side-effect profile makes it most appropriate for pine mesylate, 12 mg bid. Akathisia may respond to
treatment-resistant cases. Risperidone, a benzisoxazole beta blockers. In rare cases, more serious and occasion-
derivative, is more potent at 5HT2 than D2 receptor sites, ally life-threatening side effects may emerge, including
like clozapine, but it also exerts significant 2 antago- hyperprolactinemia, ventricular arrhythmias, gastroin-
nism, a property that may contribute to its perceived testinal obstruction, retinal pigmentation, obstructive
ability to improve mood and increase motor activity. jaundice, and neuroleptic malignant syndrome (char-
Psychiatric Disorders
CHAPTER 54
antidepressant medications may sometimes be useful in
treating the acute symptoms, but only if independent
ASSESSMENT AND EVALUATION OF evidence for an appropriate psychiatric diagnosis exists.
VIOLENCE
Primary care physicians may encounter situations in
which family, domestic, or societal violence is discov- MENTAL HEALTH PROBLEMS IN THE
Mental Disorders
ered or suspected. Such an awareness can carry legal and HOMELESS
moral obligations; many state laws mandate reporting of
child, spousal, and elder abuse. Physicians are frequently There is a high prevalence of mental disorders and sub-
the rst point of contact for both victim and abuser. stance abuse among homeless and impoverished indi-
Approximately 2 million older Americans and 1.5 mil- viduals. Depending on the denition used, estimates of
lion U.S. children are thought to experience some the total number of homeless individuals in the United
form of physical maltreatment each year. Spousal abuse States range from 800,000 to 2 million, one-third of
is thought to be even more prevalent. An interview whom qualify as having a serious mental disorder. Poor
study of 24,000 women in 10 countries found a lifetime hygiene and nutrition, substance abuse, psychiatric ill-
prevalence of physical or sexual violence that ranged ness, physical trauma, and exposure to the elements
from 15 to 71%; these individuals are more likely to combine to make the provision of medical care chal-
suffer from depression, anxiety, somatization disorder, lenging. Only a minority of these individuals receive
and substance abuse and to have attempted suicide. In formal mental health care; the main points of contact
addition, abused individuals frequently express low self- are outpatient medical clinics and emergency depart-
esteem, vague somatic symptomatology, social isolation, ments. Primary care settings represent a critical site in
and a passive feeling of loss of control. Although it is which housing needs, treatment of substance depen-
essential to treat these elements in the victim, the rst dence, and evaluation and treatment of psychiatric illness
obligation is to ensure that the perpetrator has taken can most efciently take place. Successful intervention
responsibility for preventing any further violence. Sub- is dependent on breaking down traditional administra-
stance abuse and/or dependence and serious mental ill- tive barriers to health care and recognizing the physical
ness in the abuser may contribute to the risk of harm constraints and emotional costs imposed by homeless-
and require direct intervention. Depending on the situ- ness. Simplifying health care instructions and follow-up,
ation, law enforcement agencies, community resources allowing frequent visits, and dispensing medications in
such as support groups and shelters, and individual and limited amounts that require ongoing contact are pos-
family counseling can be appropriate components of a sible techniques for establishing a successful therapeutic
treatment plan. A safety plan should be formulated with relationship.
CHAPTER 55
NEUROPSYCHIATRIC ILLNESSES
IN WAR VETERANS
Charles W. Hoge
Neuropsychiatric sequelae are common in combat vet- negatively impacted marriages, parenting, educational
erans. Advances in personal protective body armor, goals, and civilian occupations. The stresses of service in
armored vehicles, battleeld resuscitation, and the speed these conicts have led to a signicant increase in the
of evacuation to tertiary care have considerably improved rate of suicide in personnel from the two branches of
the survivability of battleeld injuries, resulting in a service involved in the greatest level of ground combat
greater awareness of the silent wounds associated with (army, marines).
service in a combat zone. Although psychiatric and neu- Service in a war zone can involve extreme physical
rologic problems have been well documented in veterans stress in austere environments, prolonged sleep deprivation,
of prior wars, the conicts in Iraq and Afghanistan have physical injury, exposure to highly life-threatening events
been unique in terms of the level of commitment by the and hazards such as explosive devices, sniper re, ambushes,
U.S. Department of Defense (DoD) and Department of indirect re from rockets and mortars, and chemical
Veterans Affairs (VA), Veterans Health Administration pollutants. Certain events such as loss of a close friend in
(VHA) to support research as the wars have unfolded, combat, leave indelible scars. All of these experiences have
and to utilize that knowledge to guide population-level additive effects on health, likely mediated through physio-
screening, evaluation, and treatment initiatives. logic mechanisms involving dysregulation of neuroendocrine
These conicts, like previous ones, have produced hun- and autonomic nervous system (ANS) functions.
dreds of thousands of combat veterans, many of whom Veterans of virtually all wars have reported elevated
have received or will need care in government and civil- rates of generalized and multisystem physical, cognitive,
ian medical facilities. Studies have shown that service in the and psychological health concerns that often become the
Iraq and Afghanistan theaters is associated with signicantly focus of treatment months or years after returning home.
elevated rates of mental disorders. Two conditions in partic- These multisystem health concerns include sleep distur-
ular have been labeled the signature injuries related to these bance, memory and concentration problems, headaches,
wars: posttraumatic stress disorder (PTSD) and mild trau- musculoskeletal pain, gastrointestinal symptoms (including
matic brain injury (mTBI)also known as concussion. gastroesophageal reux), residual effects of war-time inju-
Although particular emphasis will be given in this chapter ries, fatigue, anger, hyperarousal symptoms, high blood
to PTSD and concussion/mTBI, it is important to under- pressure, rapid heart rate (sometimes associated with panic
stand that service in all wars is associated with a number of symptoms), sexual problems, and symptoms associated
health concerns that coexist and overlap, and a multidisci- with PTSD and depression. In order to provide optimal
plinary patient-centered approach to care is necessary. care to veterans with these symptoms, it is important to
understand how the symptoms interrelate, and to consider
the possibility that there may be underlying combat-related
EPIDEMIOLOGY OF WAR-RELATED physiologic effects.
PSYCHOLOGICAL AND NEUROLOGIC
CONDITIONS
POSTWAR SYMPTOMS
Service members from the current decade of war have
faced multiple deployments to two very different high- The overlapping and multisystem health symptoms
intensity combat theaters, and the cumulative strain has reported by warriors from every generation have been
742
given different labels, and have led to debates among Veterans understandably may become angry at the sug- 743
medical professionals as to whether these are medi- gestion that their postwar health concerns are stress-related
ated primarily by physical or psychological causes. For or psychological, and thus it is necessary for primary care
CHAPTER 55
example, World War I produced extensive debate about professionals to be sensitive to this concern.
whether shell shock, diagnosed in more than 80,000
British soldiers, was neurologic (commotional from
PTSD
the brain being shaken in the skull by concussive blasts)
or psychological (emotional or neurasthenia) in PTSD is the most common mental disorder docu-
origin. World War II veterans were said to suffer from mented following war-zone service. Studies from the
use disorders (SUDs), as well as risky behaviors (e.g., injury, there are stark clinical and epidemiologic dis-
aggression, accidents); it has been estimated that up to 80% tinctions between concussion/mTBI and moderate or
of patients with PTSD exhibit one or more comorbid severe TBI (Table 55-1). Concussion/mTBI is dened
conditions. Misuse of alcohol or substances is most preva- as a blow or jolt to the head that results in brief loss
lent, often reecting self-medication. PTSD is also associ- of consciousness (LOC) for <30 min (most commonly
ated with tolerance and withdrawal symptoms related to only a few seconds to minutes), posttraumatic amnesia
(PTA) of <24 h (most commonly <1 h), or tran-
Psychiatric Disorders
CHAPTER 55
MILD TBI (CONCUSSION) MOD/SEVERE TBI
concussion/mTBI, but highlight the complex interrela- Management is largely symptom-focused, and ideally
tionships of war-related health problems. carried out within primary-care based structures of care.
Studies of veterans who sustained concussions in Iraq Optimal care avoids unnecessary specialty referrals, use
or Afghanistan have suggested that blast mechanisms of nonevidence-based interventions, or poor communi-
produce similar clinical outcomes as nonblast mecha- cation that results in negative expectations. Concussion
nisms, in contrast to expectations based on animal research has shown that negative expectations are one of
models. An explosion can produce serious injury from the most important risk factors for persistent symptoms.
rapid atmospheric pressure changes (primary blast wave While many questions remain regarding the long-
mechanism), as well as from ying debris (secondary term health effects of concussions (particularly multiple
blast mechanism) or by being thrown into a hard object concussions) sustained during deployment, these are
(tertiary blast mechanism). Secondary and tertiary important battleeld injuries that require careful atten-
mechanisms are similar to other mechanical mechanisms tion. However, they need to be addressed within the
of concussions sustained during accidents. The possibil- context of all other war-related health concerns.
ity of a unique head injury from the primary blast wave
in otherwise uninjured soldiers appears to be low, but
cannot be discounted. STIGMA AND BARRIERS TO CARE
Multisystem health problems that lack clear case de-
nitions do not lend themselves well to uniform public Adding to the complexity of treating veterans is stigma
health strategies such as screening. Nevertheless, mass and other barriers to care. Despite extensive education
population screening for concussion/mTBI was man- efforts among military leaders and service members,
dated for all U.S. service members returning from Iraq perceptions of stigma have shown little change over the
or Afghanistan and all veterans presenting for care at VA many years of war; warriors are concerned that they will
health care facilities. These screening processes, which be perceived as weak by peers or leaders if they seek
attempt to apply the acute concussion case denition care. Studies showed that less than one-half of service
(lacking symptoms, time-course, or impairment) months members with serious mental health problems receive
or years after injury, led to sharp criticism that they needed care. Many factors contribute to this, including
were encouraging clinicians to misattribute common the pervasive nature of stigma in society in general (par-
postwar symptoms to concussion/mTBI. ticularly among men), the critical importance of group
746 cohesiveness of military teams, the nature of avoidance
self-medication with alcohol or substances, chronic use of
symptoms in PTSD, and sometimes skepticism that
nonsteroidal anti-inflammatory agents (which can contrib-
mental health professionals will be able to help.
ute to rebound headaches or pain), chronic use of sedative-
SECTION V
includes the number of years served, military occu- have been validated for use in primary care, and have
pation, deployment locations and dates, illnesses or been used frequently in veterans: the four-question
injuries resulting from service, and significant combat Primary Care PTSD Screen (PC-PTSD), the two-question
traumatic experiences that may be continuing to affect Patient Health Questionnaire (PHQ-2), and the three-
the individual (Table 55-2). The clinician should evalu- question Alcohol Use Disorders Identification Test-
ate the degree to which the patients current difficul- Consumption module (AUDIT-C) (Table 55-3).
ties reflect the normal course of readjusting after the Since the clinical definition of an acute concus-
intense occupational experience of combat. It is helpful sion/mTBI does not include symptoms, time-course,
to reinforce the many strengths associated with being or impairment, there is currently no clinically validated
a professional in the military: courage, honor, service to screening process for use months or years after injury.
country, resiliency in combat, leadership, ability to work However, it is important to gather information about
as cohesive workgroup with peers, and demonstrated all injuries sustained during deployment, including any
skills in handling extreme stress. that resulted in loss or alteration of consciousness or
One of the challenges with current medical practice is loss of memory around the time of the event. If concus-
that there may be multiple providers with different clinical sion injuries have occurred, the clinician should assess
perspectives. Care should be coordinated through the pri- the number of such injuries, the duration of time uncon-
mary care clinician, with the assistance of a care manager scious, and injury mechanisms. This should be followed
if needed. It is particularly important to continually evaluate by an assessment of any postconcussive symptoms
all medications prescribed by other practitioners and immediately following the injury event (e.g., headaches,
assess for possible long-term side effects, dependency, dizziness, tinnitus, nausea, irritability, insomnia, and
or drug-drug interactions. Particular attention should be concentration or memory problems), and the severity
given to the level of chronic pain and sleep disturbance, and duration of such symptoms.
TABLE 55-2
SPECIFIC CONSIDERATIONS IN THE MEDICAL EVALUATION OF VETERANS
Occupational context of Deployment locations and dates, combat experiences or other deployment stressors, frequent
health concerns moves, separations from family, impact of deployment on civilian occupation (for reservists)
Medical problems during History of deployment-related injuries (including concussions), environmental exposures, sleep
deployment pattern during deployment, use of caffeine/energy drinks, use of other substances
Current medical history Current symptoms, level of chronic pain, sleep problems, evidence of persistent physiologic hyper-
arousal (hypertension, tachycardia, panic symptoms, concentration/memory problems, irritability/
anger, sleep disturbance), chronic use of caffeine or energy drinks, chronic use of nonsteroidal
anti-inammatory medications, chronic use of narcotic pain medications, chronic use of nonben-
zodiazepine sedative-hypnotic medications, chronic use of benzodiazepines for sleep or anxiety
Mental health assessment Screen for PTSD, major depressive disorder. Ask about suicidal or homicidal ideation, intent, or
plans, as well as access to rearms
Alcohol/substance use Screen for alcohol and substance use disorders, quantity and frequency of use, and evidence of
tolerance. Inquire about self-medication (e.g., use of alcohol for sleep or to calm down or
forget war-zone experiences)
Functional impairment Impact of current symptoms on social and occupational functioning. High-risk behaviors
(e.g., drinking and driving, reckless driving, aggression)
Social support, impact Level of social support. Readjustment stress on spouse, children, or other family members
of military service on
marriage and family
TABLE 55-3 747
PRIMARY CARE MENTAL HEALTH SCREENING TOOLS
PC-PTSD Screen
CHAPTER 55
1. Have you ever had any experience that was so frightening, horrible, or upsetting that, in the past month, you:
Have had nightmares about it or thought about it when you did not want to? Yes No
Tried hard not to think about it or went out of your way to avoid situations Yes No
that remind you of it?
Were constantly on guard, watchful, or easily startled? Yes No
Felt numb or detached from others, activities, or your surroundings? Yes No
Note: If either (or both) questions are marked 2 or 3 (more than half the days or higher), this is considered a positive screen for depression.
Source: K Kroenke et al: The Patient Health Questionnaire-2: Validity of a two-item depression screener. Med Care 41:1284, 2003.
AUDIT-C Alcohol Screen
3a. How often do you have a drink containing alcohol?
Never (0) Monthly or less (1) Two or four times a month (2) Two to three times per week (3) Four or more times a week (4)
3b. How many drinks containing alcohol do you have on a typical day when you are drinking?
1 or 2 (0) 3 or 4 (1) 5 or 6 (2) 7 or 9 (3) 10 or more (4)
3c. How often do you have six or more drinks on one occasion?
Never (0) Less than Monthly (1) Monthly (2) Two to three times per week (3) Four or more times a week (4)
Note: A positive AUDIT-C screen is dened as a total score for men 4; for women 3. A report of drinking 6 or more drinks on one occasion
should prompt an in-depth assessment of drinking.
Source: K Bush et al: The AUDIT Alcohol Consumption Questions (AUDIT-C): An effective brief screening test for problem drinking. Arch Intern
Med 158:1789, 1998.
[PHQ-9] or National Center for PTSD Checklist), as well as lacking a specific FDA indication, there is increasing evi-
risk assessment for suicide or homicide. It is important to dence that serotonin norepinephrine reuptake inhibitors
assess the impact of depression or PTSD symptoms on (SNRIs) (e.g., venlafaxine and duloxetine) and mirtazapine
occupational functioning and interpersonal relationships. are also effective. (See Table 54-3 for recommended dos-
A positive screen for alcohol misuse should prompt ages.)
a brief motivational intervention that includes bringing CBT interventions include narrative therapy (often
Psychiatric Disorders
attention to the elevated level of drinking, informing called imaginal exposure), in vivo exposure focused
the veteran about the effects of alcohol on health, rec- on retraining the body not to react to stimuli related to
ommending limiting use or abstaining, exploring and traumatic reminders (e.g., a crowded mall), and tech-
setting goals related to drinking behavior, and follow-up niques to modulate physiologic hyperarousal (e.g., dia-
and referral to specialty care if needed. This type of brief phragmatic breathing, progressive muscle relaxation).
primary care intervention has been found to be effec- A number of complementary alternative medicine
tive, and should be incorporated into routine practice. approaches including acupuncture, mindfulness medi-
One way to facilitate dialogue about this topic with vet- tation, yoga, and massage are also being tested in PTSD.
erans is to point out how hyperarousal associated with Although not evidence-based treatments per se, if they
combat service can lead to increased craving for alcohol facilitate a relaxation response and alleviation of hyper-
as the body searches for ways to modulate this. Veter- arousal symptoms, they can be considered useful adjunctive
ans may consciously or unconsciously drink more to modalities.
help with sleep, reduce arousal, or avoid thinking about There have been no head-to-head comparisons of
events that happened downrange. A key educational medication compared with psychotherapy for treatment
strategy is to help the veteran to learn that drinking to of PTSD. It is reasonable for primary care clinicians to
get to sleep actually damages sleep architecture and consider initiating treatment for mild to moderate PTSD
makes sleep worse (e.g., reduces rapid eye movement symptoms with an SSRI, and refer patients to a mental
[REM] sleep initially followed by rebound REM activity health professional if there are more severe symptoms,
and early morning wakening). significant comorbidity, safety concerns, or limited
response to initial treatment. All PTSD treatments are
SPECIFIC TREATMENT STRATEGIES FOR associated with a sizable proportion of individuals who
PTSD AND COMORBID DEPRESSION PTSD fail to respond adequately, and it is often necessary to
and depression are highly comorbid in combat veter- add modalities or switch treatment. SNRIs may be use-
ans, and the evidence-based treatments are similar, ful alternatives to SSRIs if there has been nonresponse,
involving either antidepressant medications, cognitive side effects, or if there is comorbid pain (duloxetine, in
behavioral therapy (CBT), or both. Psychoeducation that particular, has indications for pain). Both SSRIs and SNRIs
assists veterans to understand that their symptoms of can increase anxiety initially; patients should be warned
PTSD have a basis in adaptive survival mechanisms and about this possibility and treatment should be initiated
skills they exhibited in combat can facilitate therapeutic with the lowest recommended dose (or even one-half of
rapport. Remaining hypervigilant to threat, being able the lowest dose for a few days) and gradually increased
to shut down emotions, being able to function on less thereafter. Mirtazapine use can cause drowsiness and
sleep, and using anger to help focus and control fear are weight gain. Antidepressants also are likely to be useful
all adaptive beneficial survival skills in a combat envi- in comorbid depression, which is common in veterans
ronment. Therefore, PTSD for warriors is both a medical with PTSD. All antidepressants have potential drug-drug
disorder and a set of reactions that have their roots in interactions that must be considered.
the physiologic adaptation and skills they successfully Many other medications have been used in PTSD,
applied in combat. including tricyclic antidepressants, benzodiazepines,
It is important to know that combat is not the only atypical antipsychotics, and anticonvulsants. In general,
important trauma in a war-zone environment. Rape, these should be prescribed in conjunction with psychiat-
assault, and accidents also occur. Rape or assault by a fel- ric consultation, because of their greater side effects and
low service member, which affects a greater number of risks. Benzodiazepines, in particular, should be avoided
women veterans, can be particularly devastating because in combat veterans. Studies have shown that they do
it destroys the vital feeling of safety that individuals not reduce core PTSD symptoms, are likely to exacer-
derive from their own unit peers in a war environment. bate substance use disorders that are common in veterans
The treatments for PTSD considered by most consen- with PTSD, and may produce significant rebound anxiety.
sus guideline committees to have an A level of evidence Veterans with PTSD often report symptomatic relief
upon initiation of a benzodiazepine, but this is generally generally not been shown to be effective for mTBI in ran- 749
short lived and associated with a high risk of tolerance domized clinical studies, though consensus groups have
CHAPTER 55
and dependence that can worsen recovery. Atypical supported its use.
antipsychotics, which have gained widespread popular- General recommendations for the clinical manage-
ity as adjunctive treatment for depression, anxiety, or ment of persistent, chronic postconcussive symptoms
sleep problems, have significant long-term side effects, include treating physical and cognitive health prob-
including metabolic effects (e.g., glucose dysregulation), lems based on symptom presentation, coexisting health
weight gain, and cardiovascular risks. problems, and individual preferences; and addressing
Sleep disturbance should be addressed initially with coexisting depression, PTSD, substance use disorders, or
ALCOHOLISM
AND DRUG
DEPENDENCY
CHAPTER 56
Marc A. Schuckit
752
20%
MEOS
Acetaldehyde in the ventral tegmentum and related brain regions, and 753
this effect plays an important role in continued alco-
Ethanol hol use, craving, and relapse. The changes in dopa-
Alcohol mine pathways are also linked to increases in stress
80% Acetaldehyde
dehydrogenase hormones, including cortisol and adrenocorticotropic
Aldehyde hormone (ACTH) during intoxication and decreases
dehydrogenase
in these hormones during withdrawal. Such alterations
Acetyl CoA are likely to contribute to both feelings of reward dur-
Acetate
ing intoxication and depression during falling blood
CHAPTER 56
Citric acid
cycle alcohol concentrations. Also closely linked to alterations
in dopamine (especially in the nucleus accumbens) are
Fatty acids alcohol-induced changes in opioid receptors, with acute
CO2 + Water
alcohol also causing release of beta endorphins.
FIGURE 56-1 Additional important neurochemical changes include
The metabolism of alcohol. MEOS, microsomal ethanol- increases in synaptic levels of serotonin during acute
oxidizing system. intoxication, and subsequent upregulation of serotonin
tolerance develops through neurochemical changes that Another common consequence of alcohol use is
maintain relatively normal physiologic functioning impaired judgment and coordination, increasing the risk
despite the presence of alcohol. Subsequent decreases in of accidents and injury. In the United States, 40% of
blood levels contribute to symptoms of withdrawal. (3) drinkers have at some time driven while intoxicated.
Individuals learn to adapt their behavior so that they can Heavy drinking can also be associated with headache,
function better than expected under inuence of the thirst, nausea, vomiting, and fatigue the following day, a
drug (learned or behavioral tolerance). hangover syndrome that is responsible for much missed
Alcoholism and Drug Dependency
The cellular changes caused by chronic ethanol expo- time and temporary cognitive decits at work and school.
sure may not resolve for several weeks or longer fol- The effect of alcohol on the nervous system is even
lowing cessation of drinking. Rapid decreases in blood more pronounced among alcohol-dependent individuals.
alcohol levels before that time can result in a withdrawal Chronic high doses cause peripheral neuropathy in 10%
syndrome, which is most intense during the rst 5 days, of alcoholics: similar to diabetes, patients experience
but some symptoms (e.g., disturbed sleep and anxiety) bilateral limb numbness, tingling, and paresthesias, all
can take up to 46 months to resolve. of which are more pronounced distally. Approximately
1% of alcoholics develop cerebellar degeneration or atrophy.
This is a syndrome of progressive unsteady stance and
gait often accompanied by mild nystagmus; neuroimag-
THE EFFECTS OF ETHANOL ON ORGAN ing studies reveal atrophy of the cerebellar vermis. Fortu-
SYSTEMS nately, very few alcoholics (perhaps as few as 1 in 500 for
the full syndrome) develop Wernickes (ophthalmoparesis,
Relatively low doses of alcohol (one or two drinks per
ataxia, and encephalopathy) and Korsakoffs (retrograde
day) have potential benecial effects of increasing high-
and anterograde amnesia) syndromes, although a higher
density lipoprotein cholesterol and decreasing aggregation
proportion have one or more neuropathologic ndings
of platelets, with a resulting decrease in risk for occlu-
related to these syndromes. These occur as the result of
sive coronary disease and embolic strokes. Red wine has
low levels of thiamine, especially in predisposed individu-
additional potential health-promoting qualities at rela-
als, e.g., those with transketolase deciency. Alcoholics
tively low doses due to avinols and related substances,
can manifest cognitive problems and temporary memory
which may work by inhibiting platelet activation. Modest
impairment lasting for weeks to months after drinking
drinking might also decrease the risk for vascular demen-
very heavily for days or weeks. Brain atrophy, evident
tia and, possibly, Alzheimers disease. However, any
as ventricular enlargement and widened cortical sulci on
potential healthful effects disappear with the regular con-
MRI and CT scans, occurs in 50% of chronic alcohol-
sumption of three or more drinks per day, and knowl-
ics; these changes are usually reversible if abstinence is
edge about the deleterious effects of alcohol can both
maintained. There is no single alcoholic dementia syn-
help the physician to identify patients with alcohol abuse
drome; rather, this label is used to describe patients who
and dependence, and to supply them with information
have apparently irreversible cognitive changes (possibly
that might help motivate a change in behavior.
from diverse causes) in the context of chronic alcoholism.
NERVOUS SYSTEM
Psychiatric comorbidity
Approximately 35% of drinkers (and a much higher
proportion of alcoholics) experience a blackout, an epi- As many as two-thirds of alcohol-dependent individu-
sode of temporary anterograde amnesia, in which the als meet the criteria for a psychiatric syndrome in the
person forgets all or part of what occurred during a fourth edition of the Diagnostic and Statistical Manual of
drinking evening. Another common problem, one seen Mental Disorders (DSM-IV) of the American Psychi-
after as few as one or two drinks shortly before bedtime, atric Association (Chap. 54). Half of these relate to a
is disturbed sleep. Although alcohol might initially help preexisting antisocial personality manifesting as impul-
a person to fall asleep, it disrupts sleep throughout the sivity and disinhibition that contribute to both alcohol
and drug dependence. The lifetime risk is 3% in males, general population, accounting for an estimated 10% or 755
and v80% of such individuals demonstrate alcohol and/ more of the total cases. Alcohol impairs gluconeogenesis
or drug dependence. Another common comorbid- in the liver, resulting in a fall in the amount of glucose
ity occurs with dependence on illicit substances. The produced from glycogen, increased lactate production,
remainder of alcoholics with psychiatric syndromes have and decreased oxidation of fatty acids. This contrib-
preexisting conditions such as schizophrenia or manic- utes to an increase in fat accumulation in liver cells. In
depressive disease and anxiety disorders such as panic healthy individuals these changes are reversible, but with
disorder. The comorbidities of alcoholism with inde- repeated exposure to ethanol, especially daily heavy
pendent psychiatric disorders might represent an overlap drinking, more severe changes in the liver occur, includ-
CHAPTER 56
in genetic vulnerabilities, impaired judgment in the use ing alcohol-induced hepatitis, perivenular sclerosis, and
of alcohol from the independent psychiatric condition, cirrhosis, with the latter observed in an estimated 15% of
or an attempt to use alcohol to alleviate some of the alcoholics. Perhaps through an enhanced vulnerability to
symptoms of the disorder or side effects of medications. infections, alcoholics have an elevated rate of hepatitis C,
Many psychiatric syndromes can be seen temporar- and drinking in the context of that disease is associated
ily during heavy drinking and subsequent withdrawal. with more severe liver deterioration.
These alcohol-induced conditions include an intense
mitral valve regurgitation. Atrial or ventricular arrhyth- est and reversible decrease in serum thyroxine (T4); and
mias, especially paroxysmal tachycardia, can also occur a more marked decrease in serum triiodothyronine (T3).
temporarily after heavy drinking in individuals showing Hormone irregularities should be reevaluated as they
no other evidence of heart diseasea syndrome known may disappear after a month of abstinence.
as the holiday heart.
CHAPTER 56
alcoholic is more often a blue- or white-collar worker lished, the course of alcoholism is likely to be one of
or homemaker. The lifetime risk for alcoholism among exacerbations and remissions, with little difculty in
physicians is similar to that of the general population. temporarily stopping or controlling alcohol use when
problems develop, but without help, desistance usually
gives way to escalations in alcohol intake and subse-
GENETICS quent problems. Following treatment, between half and
two-thirds of alcoholics maintain abstinence for years,
1. How often do you have a drink Never (0) to 4+ per not to destabilize vital signs or worsen confusion. An
containing alcohol? week (4) alternative approach is to use an antipsychotic medica-
2. How many drinks containing 1 or 2 (0) to 10+ (4) tion (e.g., 0.55 mg of haloperidol PO or IM every 48
alcohol do you have on a typical h as needed, or olanzapine 2.510 mg IM repeated at 2
day?
and 6 h, if needed).
3. How often do you have six or Never (0) to daily or
more drinks on one occasion? almost daily (4) Intervention There are two main elements to inter-
4. How often during the last year Never (0) to daily or vention in a person with alcoholism: motivational inter-
have you found that you were almost daily (4) viewing and brief interventions. During motivational
not able to stop drinking once interviewing, the clinician helps the patient to think
you had started? through the assets (e.g., comfort in social situations) and
5. How often during the last year Never (0) to daily or liabilities (e.g., health and interpersonal related prob-
have you failed to do what was almost daily (4) lems) of the current pattern of drinking. The patients
normally expected from you responses are key, and the clinician should listen empa-
because of drinking?
thetically, helping to weigh options and encouraging
6. How often during the last year Never (0) to daily or the patient to take responsibility for changes that need
have you needed a rst drink in almost daily (4)
to be made. Patients should be reminded that only they
the morning to get yourself going
after a heavy drinking session?
can decide to avoid the consequences that will occur
without changes in drinking. The process of motiva-
7. How often during the last year Never (0) to daily or
tional interviewing has been summarized by the acro-
have you had a feeling of guilt or almost daily (4)
remorse after drinking? nym FRAMES: Feedback to the patient; Responsibility to
be taken by the patient; Advice, rather than orders, on
8. How often during the last year Never (0) to daily or
what needs to be done; Menus of options that might be
have you been unable to remem- almost daily (4)
ber what happened the night considered; Empathy for understanding of the patients
before because you had been thoughts and feelings; and Self-efficacy, i.e., offering
drinking? support for the capacity of the patient to succeed in
9. Have you or someone else been No (0) to yes, during making changes.
injured as a result of your drink- the last year (4) Once the patient begins to consider change, the
ing? emphasis shifts to brief interventions designed to help
10. Has a relative, friend, doctor No (0) to yes, during the patient understand more about potential action.
or other health worker been the last year (4) Discussions focus on consequences of high alcohol con-
concerned about your drinking sumption, suggested approaches to stopping drinking,
or suggested that you should cut and help in recognizing and avoiding situations likely
down? to lead to heavy drinking. Both motivational interview-
ing and brief interventions can be carried out in 15-min
a
The AUDIT is scored by summing the 10 values. A score >8 may sessions, but because patients do not always change
indicate harmful alcohol use.
Source: Adapted from DF Reinert, GP Allen: Alcoholism: Clinical & behavior right away, multiple meetings are often
Experimental Research 26:272, 2002, and from MA Schuckit: Drug required to explain the problem, discuss optimal treat-
and Alcohol Abuse: A Clinical Guide to Diagnosis and Treatment, ments, and explain the benefits of abstinence.
6th ed. New York, Springer 2006.
Alcohol Withdrawal If the patient agrees to stop or 10 mg of diazepam given PO every 46 h on the first 759
drinking, sudden decreases in alcohol intake can pro- day, with doses then decreased to zero over the next 5
duce withdrawal symptoms, many of which are the days. While alcohol withdrawal can be treated in a hos-
opposite of those produced by intoxication. Features pital, patients in good physical condition who demon-
include tremor of the hands (shakes); agitation and strate mild signs of withdrawal despite low blood alco-
anxiety; autonomic nervous system overactivity includ- hol concentrations and who have no prior history of DTs
ing an increase in pulse, respiratory rate, and body tem- or withdrawal seizures can be considered for outpatient
perature; and insomnia. These symptoms usually begin detoxification. These patients should return daily for
within 510 h of decreasing ethanol intake, peak on day evaluation of vital signs and can be hospitalized if signs
CHAPTER 56
2 or 3, and improve by day 4 or 5, although mild levels and symptoms of withdrawal escalate.
of these problems may persist for 46 months as a pro- Treatment of the patient with DTs can be challeng-
tracted abstinence syndrome. ing, and the condition is likely to run a course of 35
About 25% of alcoholics experience a withdrawal days regardless of the therapy employed. The focus of
seizure, with the risk increasing in the context of con- care is to identify and correct medical problems and to
comitant medical problems, misuse of additional drugs, control behavior and prevent injuries. Many clinicians
in the absence of alcohol (i.e., why it is a good idea to oral doses, has similar modest effects; acamprosate
continue to abstain) and helping the patient to manage inhibits NMDA receptors, decreasing mild symptoms of
free time without alcohol, develop a nondrinking peer protracted withdrawal. Several trials of combined nal-
group, and handle stresses on the job. trexone and acamprosate using doses similar to those
The physician serves an important role in identify- noted earlier have reported that the combination may
ing the alcoholic, diagnosing and treating associated be superior to either drug alone, although not all stud-
Alcoholism and Drug Dependency
Thomas R. Kosten
761
762 primarily associated with the mu receptor. A fourth endogenous ligand beta endorphin. Epigenetic methyla-
type of opiate receptor, the orphanin receptor, also tion changes also occur on the DNA of the mu receptor
modulates pain but is not affected by opiate drugs. gene of opiate addicts. DNA methylation inhibits gene
These opiate receptors are all G proteinlinked and transcription.
coupled to the cyclic adenosine monophosphate (cyclic This molecular cascade links acute intoxication and
AMP) second messenger system and to potassium sedation to chronic opiate dependence and withdrawal
channels. Opiates are inhibitory and block the potas- within the specic neuroanatomic structure of the locus
sium channels from opening and depolarizing the neu- coeruleus. The locus coeruleus is the brains largest con-
ron, which would produce an action potential. Thus, centration of noradrenergic neurons and is responsible
SECTION VI
opiates acutely inhibit neuronal activity. Analgesia and for a large proportion of brain cortical activation. When
sedation are induced through this inhibition of specic large opiate doses saturate and activate all of its mu
brain pathways, while the high from opiates involves receptors, its steady rate of action potentials can cease
an indirect activation of a different brain pathwaythe due to the inactivation of potassium channels. When
mesolimbic dopamine pathway. this direct inhibitory effect is sustained over weeks and
The various effects of opiates are related to the spe- months of opiate use, a secondary set of regulatory
cic neuroanatomic locations of mu receptors. Rein- effects take place in the cyclic AMP system that leads to
Alcoholism and Drug Dependency
forcing and euphoric effects of opiates occur in the tolerance, dependence, and withdrawal symptoms.
dopaminegic pathway from the ventral tegmental Opiate withdrawal symptoms reect overactivity of
area (VTA) to the nucleus accumbens, where opiates adrenergic neurons that are located in the locus ceru-
increase synaptic levels of dopamine. This increase is leus. Opiates suppress the activity of these neurons,
due to inhibition of GABAergic neurons that inhibit and when this suppression continues chronically from
both the VTA and nucleus accumbens activity. How- daily opiate use, a secondary upregulation occurs in
ever, the high only occurs when the rate of change in adenyl cyclase enzyme capacity and the production of
dopamine is fast. Large, rapidly administered doses of cyclic AMP from ATP. This upregulation is a homeo-
opiates block GABA inhibition and produce a burst static response to the chronic opiate suppression, but
of nucleus accumbens activity that is associated with when that suppression is terminated by discontinuing
high in all abused drugs. Therefore, routes of admin- the opiate, this enhanced adenyl cyclase activity leads to
istration that slowly increase opiate blood and brain a marked increase in cyclic AMP. The now very high
levels, such as oral and transdermal routes, are effective levels of cyclic AMP activate the sodium-potassium
for analgesia and sedation but do not produce an opi- channels and produce a high level of action potentials
ate high that follows smoking and intravenous routes. in these adrenergic neurons. This adrenergic arousal
Other acute effects such as analgesia and respiratory is one basis for the symptoms of opiate withdrawal
depression leading to overdose are due to stimulation of and takes about 7 days to readjust to normal levels of
opiate receptors located in other areas such as the locus adenyl cyclase activity and the associated resolution of
coeruleus. opiate withdrawal symptoms. This molecular model
Opiate dependence and withdrawal are chronic of adrenergic neuronal activation during withdrawal has
effects related to the cyclic AMP system. This second had important treatment implications, such as the use of
messenger phosphorylates various intracellular pro- clonidine for opioid withdrawal.
teins and produces a cascade of changes reaching into
the nucleus and DNA. Immediate early gene products
such as c-fos and c-jun are activated followed by regula- PHARMACOLOGY
tion of other genes with more sustained protein tran-
scription such as delta c-fos. With these sustained gene Tolerance and withdrawal commonly occur with chronic
activations, several receptor-level changes occur, includ- daily use as quickly as 68 weeks depending on the dose
ing downregulation of receptor numbers, reduced neu- and frequency of dosing. Tolerance appears to be pri-
ronal cell-surface receptor trafcking, uncoupling of G marily a pharmacodynamic rather than pharmacokinetic
proteins from the mu opiate receptors, and upregula- effect, with relatively limited induction of the cytochrome
tion of cyclic AMP second messenger systems. These P450 or other liver enzymes. The metabolism of opi-
effects are also reective of genetic risk factors for ates occurs in the liver primarily through the cytochrome
drug dependence, with estimates of up to 50% of the P450 systems of 2D6 and 3A4. They then are conjugated
risk for dependence due to polygenic inheritance. Spe- to glucuronic acid and excreted in small amounts in feces.
cic functional genetic polymorphisms in the mu opi- The plasma half-lives generally range from 2.5 to 3 h for
ate receptor gene appear associated with this risk for morphine and more than 22 h for methadone. The short-
opiate abuse, including one producing a threefold est half-lives of several minutes are for fentanyl-related opi-
increase in this receptors afnity for opiates and the ates and the longest are for buprenorphine and its active
metabolites, which can block opiate withdrawal for up well below those typical of overdose can produce clini- 763
to 3 days after a single dose. Tolerance to the mental cally signicant complications. In overdoses, aspiration
effects of opioids leads to the need for ever-increasing pneumonia is a common complication due to loss of
amounts of drugs to sustain the desired euphoriant the choking reex. Opiates reduce gut motility, which
effectsas well as to avoid the discomfort of with- is helpful for diarrhea, but can lead to nausea, consti-
drawal. This combination has the expected consequence pation, and anorexia with weight loss. Deaths have
of strongly reinforcing dependence once it has started. occurred in early methadone maintenance programs
The role of endogenous opioid peptides in opioid due to severe constipation and toxic megacolon. Opi-
dependence is uncertain. ates may prolong QT intervals and lead to sudden death
CHAPTER 57
The clinical aspects of abuse are tied to route of in some patients. Two opiates particularly noted for this
administration and the rapidity of an opiate bolus in complication are methadone and a long-acting form
reaching the brain. Intravenous and smoked adminis- of methadone called LAAM that was withdrawn from
tration is routine not only because it is the most ef- the market. Orthostatic hypotension may occur due to
cient route but also because it rapidly produces a bolus histamine release and peripheral blood vessel dilation,
of high drug concentration in the brain. This bolus which is an opiate effect usefully applied to managing
produces a rush, followed by euphoria, a feeling of acute myocardial infarction.
maintenance and detoxification purposes. Alpha-2-ad- period is usually required since most benzodiazepines
renergic agonists are primarily used for detoxification. remain active for considerably longer than flumazenil.
Antagonists are used to accelerate detoxification and Support of vital functions may include oxygen and
then continued postdetoxification to prevent relapse. positive-pressure breathing, IV fluids, pressor agents for
Only the residential medication-free programs have had hypotension, and cardiac monitoring to detect QT prolon-
success that comes close to matching that of the med- gation, which might require treatment. Activated charcoal
Alcoholism and Drug Dependency
ication-based programs. Success of the various treat- and gastric lavage may be helpful for oral ingestions, but
ment approaches is assessed as retention in treatment, intubation will be needed if the patient is stuporous.
reduced opioid and other drug use, as well as secondary
Opiate Withdrawal Treatment The principles
outcomes such as HIV risk behaviors, crime, psychiatric
symptoms, and medical comorbidity. of detoxification are the same for all drugs: to substitute
Stopping opiates is like stopping most drugs of a longer-acting, orally active, pharmacologically equiva-
abuseit is much easier to stop than to prevent relapses. lent drug for the abused drug, stabilize the patient on
Long-term relapse prevention for opioid-dependent per- that drug, and then gradually withdraw the substituted
sons requires combined pharmacologic and psychosocial drug. Methadone is admirably suited for such use in
approaches. Chronic users tend to prefer pharmacologic opioid-dependent persons, and the partial mu agonist
approaches; those with shorter histories of drug abuse buprenorphine is another option. Clonidine, a centrally
are more amenable to detoxification and psychosocial acting sympatholytic agent, has also been used for
interventions. detoxification. By reducing central sympathetic outflow,
clonidine mitigates many of the signs of sympathetic
Opiate Overdose Treatment Managing over- overactivity. Clonidine has no narcotic action and is not
dose requires naloxone and support of vital functions, addictive. Lofexidine, a clonidine analogue with less
including intubation if needed. The opiate antagonist hypotensive effect, is being developed for use.
naloxone is given at 0.42 mg IV or IM, with an expected
response within 12 min. If the overdose is due to Methadone for Detoxication Methadone dose
buprenorphine, then naloxone might be required at tapering regimens for detoxification range from 2 to 3
total doses of 10 mg or greater, but primary buprenor- weeks to as long as 180 days, but this approach is con-
phine overdose is nearly impossible because this agent troversial given the relative effectiveness of methadone
is a partial opiate agonist. Partial agonism means that maintenance and the low success rates of detoxifica-
as the dose of buprenorphine is increased, it has greater tion. Unfortunately, the vast majority of patients tend
opiate antagonist than agonist activity. Thus, a 0.2-mg to relapse to heroin or other opiates during or after
buprenorphine dose leads to analgesia and sedation, the detoxification period, indicative of the chronic and
while a hundred times greater 20-mg dose produces relapsing nature of opioid dependence.
profound opiate antagonism, precipitating opiate with- Buprenorphine for Detoxication Because it is
drawal in a person who was opiate dependent on mor- a partial agonist, buprenorphine produces fewer with-
phine or methadone. When 10 mg of naloxone fails to drawal symptoms and may allow briefer detoxifications
produce arousal in the patient, another cause of toxic- compared with full agonists like methadone, but it does
ity must be found. Before reaching such large naloxone not appear to have better outcomes than methadone
doses, however, it is important to recognize that the tapering. Buprenorphine is superior to the alpha-2-
goal is to reverse the respiratory depression and not to adrenergic agonist clonidine in reducing symptoms of
administer so much naloxone that it precipitates opi- withdrawal, retaining patients in a withdrawal protocol,
ate withdrawal. Because naloxone only lasts a few hours and in treatment completion.
and most opiates last considerably longer, close moni-
toring and an IV naloxone drip is frequently employed Alpha-2-Adrenergic Agonists for Detoxi-
to provide a continuous level of antagonism for 2472 h cation Several alpha-2-adrenergic agonists have
depending on the opiate used in the overdose (e.g., relieved opioid withdrawal by suppressing central
noradrenergic hyperactivity. Alpha-2-adrenergic ago-
IV drug use, criminal activity, and HIV risk behaviors 765
and mortality. Methadone can prolong the QT inter-
nists moderate the symptoms of noradrenergic hyper-
val at rates as high as 16% above the rates in non-meth-
activity via actions in the central nervous system.
adone-maintained, drug-injecting patients, but it has
Clonidine relieves some signs and symptoms of opiate
been used safely in the treatment of opioid dependence
withdrawal such as lacrimation, rhinorrhea, muscle pain,
for 40 years.
joint pain, restlessness, and gastrointestinal symptoms,
but it is not a drug of abuse or dependence. Unfortu- Buprenorphine maintenance
nately, clonidine is associated with significant hypoten- While France and Australia have had sublingual buprenor-
sion, which has stimulated investigation of lofexidine,
CHAPTER 57
phine maintenance since 1996, the USFDA approved it as
guanfacine, and guanabenz acetate. Lofexidine can be a Schedule III drug in 2002 for managing opiate depen-
dosed up to 2 mg/d and appears to be associated dence. Unlike the full agonist methadone, buprenorphine
with fewer adverse effects, and it is therefore likely to is a partial agonist of mu-opioid receptors with a slow
replace clonidine as the leading opioid withdrawal onset and long duration of action, allowing for alternate-
treatment in this drug class. Clonidine or lofexidine are day dosing. Its partial agonism reduces the risk of uninten-
typically administered orally, in three or four doses per tional overdose but limits its efcacy to patients who need
Medication-free treatment
Most opiate addicts enter medication-free treatments PREVENTION
in inpatient, residential, or outpatient settings, but 1-
to 5-year outcomes are very poor compared to phar- Preventing opiate abuse represents a critically impor-
macotherapy except for residential settings lasting 6 tant challenge for physicians. Opiate prescriptions are
to 18 months. The residential programs require full the most common source of drugs accessed by adoles-
SECTION VI
immersion in a regimented system that has progres- cents who begin a pattern of illicit drug abuse; in the
sively increasing levels of independence and respon- United States, 9000 adolescents become opiate abusers
sibility within a controlled community of fellow drug every day. The major sources of these drugs are family
abusers. These medication-free programs, as well as the members, not drug dealers or the Internet. Pain man-
pharmacotherapy programs, also include counseling and agement involves giving sufcient opiates to relieve the
behavioral treatments designed to teach interpersonal pain over as short a period of time as the pain warrants.
Alcoholism and Drug Dependency
and cognitive skills for coping with stress and for avoid- The patient then needs to dispose of any remaining opi-
ing situations leading to easy access to drugs or to crav- ates, not save them in the medicine cabinet, because this
ing. Relapse is prevented by having the individual very behavior leads to diversion to adolescents. Finally, phy-
gradually reintroduced to greater responsibilities and to sicians should never prescribe opiates for themselves.
CHAPTER 58
The abuse of cocaine and other psychostimulant drugs produces physiologic and behavioral effects when admin-
reects a complex interaction between the pharmacologic istered orally, intranasally, intravenously, or via inhalation
properties of each drug, the personality and expectations following pyrolysis (smoking). The reinforcing effects of
of the user, and the environmental context in which the cocaine appear to be related to activation of dopaminer-
drug is used. Polydrug abuse involving the concurrent gic neurons in the mesolimbic system. Cocaine increases
use of several drugs with different pharmacologic effects synaptic concentrations of the monamine neurotransmit-
is increasingly common. Some forms of polydrug abuse, ters dopamine, norepinephrine, and serotonin by binding
such as the combined use of heroin and cocaine intrave- to transporter proteins in presynaptic neurons and block-
nously, are especially dangerous and are a major problem ing reuptake.
in hospital emergency rooms. Sometimes one drug is
used to enhance the effects of another, as with the com-
bined use of benzodiazepines and methadone, or cocaine Prevalence of cocaine use
and heroin in methadone-maintained patients.
Chronic cocaine and psychostimulant abuse may cause Cocaine is widely available throughout the United
a number of adverse health consequences, and preexist- States, and cocaine abuse occurs in virtually all social and
ing disorders such as hypertension and cardiac disease economic strata of society. The prevalence of cocaine
may be exacerbated by drug abuse. The combined use abuse in the general population has been accompanied
of two or more drugs may accentuate medical complica- by an increase in cocaine abuse by heroin-dependent
tions associated with abuse of one of them. Chronic drug persons, including those in methadone maintenance pro-
abuse is often associated with immune system dysfunction grams. Intravenous cocaine is often used concurrently
and increased vulnerability to infections, which in turn with IV heroin. This combination purportedly attenu-
contributes to the risk for HIV infection. In addition, ates the postcocaine crash and substitutes a cocaine
concurrent use of cocaine and opiates (the speedball) high for the heroin high blocked by methadone.
is frequently associated with needle sharing by IV drug
users. Intravenous drug abusers continue to represent the
largest single group of persons with HIV infection in sev- Acute and chronic intoxication
eral major metropolitan areas in the United States as well There has been an increase in both IV administration
as in many parts of Europe and Asia. and inhalation of pyrolyzed cocaine via smoking. Fol-
lowing intranasal administration, changes in mood
and sensation are perceived within 35 min, and peak
COCAINE effects occur at 1020 min. The effects rarely last more
than 1 h. Inhalation of pyrolyzed materials includes
Cocaine is a stimulant and a local anesthetic with potent inhaling crack/cocaine or smoking coca paste, a prod-
vasoconstrictor properties. The leaves of the coca plant uct made by extracting cocaine preparations with am-
(Erythroxylon coca) contain 0.51% cocaine. The drug mable solvents, and cocaine free-base smoking. Free-
base cocaine, including the freebase prepared with
a
Deceased. sodium bicarbonate (crack), has become increasingly
767
768 popular because of the relative high potency of the inhibition of prolactin secretion by the anterior pitu-
compound and its rapid onset of action (810 s follow- itary. Cocaine abuse by pregnant women, particu-
ing smoking). larly crack smoking, has been associated with both an
Cocaine produces a brief, dose-related stimulation and increased risk of congenital malformations in the fetus
enhancement of mood and an increase in cardiac rate and and perinatal cardiovascular and cerebrovascular dis-
blood pressure. Body temperature usually increases fol- ease in the mother. However, cocaine abuse per se is
lowing cocaine administration, and high doses of cocaine probably not the sole cause of these perinatal disorders,
may induce lethal pyrexia or hypertension. Because because maternal cocaine abuse is often associated with
cocaine inhibits reuptake of catecholamines at adrener- poor nutrition and prenatal health care as well as poly-
SECTION VI
gic nerve endings, the drug potentiates sympathetic ner- drug abuse that may contribute to the risk for perinatal
vous system activity. Cocaine has a short plasma half-life disease.
of approximately 4560 min. It is metabolized by plasma Psychological dependence on cocaine, indicated by
esterases, and cocaine metabolites are excreted in urine. inability to abstain from frequent compulsive use, has
The very short duration of the euphorigenic effects of also been reported. Although the occurrence of with-
cocaine observed in chronic abusers is probably due to drawal syndromes involving psychomotor agitation and
both acute and chronic tolerance. Frequent self-adminis- autonomic hyperactivity remains controversial, severe
Alcoholism and Drug Dependency
tration of the drug (two to three times per hour) is often depression (crashing) following cocaine intoxication
reported by chronic cocaine abusers. Alcohol is often may accompany drug withdrawal.
used to modulate both the cocaine high and the dyspho-
ria associated with the abrupt disappearance of cocaines
effects. A metabolite of cocaine, cocaethylene, has been
detected in the blood and urine of persons who concur- TREATMENT Cocaine Overdose and Chronic Abuse
rently abuse alcohol and cocaine. Cocaethylene induces
Treatment of cocaine overdose is a medical emergency
changes in cardiovascular function similar to those of
that is best managed in an intensive care unit. Cocaine
cocaine alone, and the pathophysiologic consequences of
toxicity produces a hyperadrenergic state character-
alcohol abuse plus cocaine abuse may be additive when
ized by hypertension, tachycardia, tonic-clonic seizures,
both are used together.
dyspnea, and ventricular arrhythmias. Intravenous diaz-
The prevalent assumption that cocaine inhalation
epam in doses up to 0.5 mg/kg administered over an
or IV administration is relatively safe is contradicted by
8-h period has been shown to be effective for control of
reports of death from respiratory depression, cardiac
seizures. Ventricular arrhythmias have been managed
arrhythmias, and convulsions associated with cocaine use.
successfully by administration of 0.51 mg of proprano-
In addition to generalized seizures, neurologic compli-
lol IV. Since many instances of cocaine-related mortal-
cations may include headache, ischemic or hemorrhagic
ity have been associated with concurrent use of other
stroke, or subarachnoid hemorrhage. Disorders of cere-
illicit drugs (particularly heroin), the physician must be
bral blood ow and perfusion in cocaine-dependent per-
prepared to institute effective emergency treatment for
sons have been detected with magnetic resonance spec-
multiple drug toxicities.
troscopy (MRS) studies. Severe pulmonary disease may
Treatment of chronic cocaine abuse requires the
develop in individuals who inhale crack cocaine; this
combined efforts of primary care physicians, psychia-
effect is attributed both to the direct effects of cocaine
trists, and psychosocial care providers. Early abstinence
and to residual contaminants in the smoked material.
from cocaine use is often complicated by symptoms
Hepatic necrosis may occur following chronic crack/
of depression and guilt, insomnia, and anorexia, which
cocaine use. Protracted cocaine abuse may also cause par-
may be as severe as those observed in major affective
anoid ideation and visual and auditory hallucinations, a
disorders. Individual and group psychotherapy, family
state that resembles alcoholic hallucinosis.
therapy, and peer group assistance programs are often
Although men and women who abuse cocaine may
useful for inducing prolonged remission from drug
report that the drug enhances libidinal drive, chronic
use. A number of medications used for the treatment
cocaine use causes signicant loss of libido and adversely
of various medical and psychiatric disorders have been
affects sexual function. Impotence and gynecomastia
administered to reduce the duration and severity of
have been observed in male cocaine abusers, and these
cocaine abuse and dependence. The search for a medi-
abnormalities often persist for long periods follow-
cation that is both safe and highly effective for cocaine
ing cessation of drug use. Women who abuse cocaine
detoxification or maintenance of abstinence is continu-
may have major derangements in menstrual cycle func-
ing. Although psychotherapy may be effective, no spe-
tion, including galactorrhea, amenorrhea, and infertility.
cific form of psychotherapy or behavioral modification is
Chronic cocaine abuse may cause persistent hyperpro-
uniquely beneficial.
lactinemia as a consequence of disordered dopaminergic
from marijuana smoking than from orally ingested can- 769
MARIJUANA AND CANNABIS nabis compounds. Acute marijuana intoxication may
COMPOUNDS produce a perception of relaxation and mild euphoria
Cannabis sativa contains >400 compounds in addition to resembling mild to moderate alcohol intoxication. This
the psychoactive substance, delta-9-tetrahydrocannabi- condition is usually accompanied by some impairment
nol (THC). Marijuana cigarettes are prepared from the in thinking, concentration, and perceptual and psycho-
leaves and owering tops of the plant, and a typical mar- motor function. Higher doses of cannabis may pro-
ijuana cigarette contains 0.51 g of plant material. The duce more pronounced impairment in concentration
usual THC concentration varies between 10 and 40 mg, and perception, as well as greater sedation. Although
CHAPTER 58
but concentrations >100 mg per cigarette have been the acute effects of marijuana intoxication are relatively
detected. Hashish is prepared from concentrated resin of benign in normal users, the drug can precipitate severe
C. sativa and contains a THC concentration of between emotional disorders in individuals who have anteced-
8 and 12% by weight. Hash oil, a lipid-soluble plant ent psychotic or neurotic problems. Like other psy-
extract, may contain THC between 25 and 60% and choactive compounds, both the users expectations
may be added to marijuana or hashish to enhance its and the environmental context are important determi-
nants of the type and severity of the effects of marijuana
and heavy marijuana use during pregnancy. Marijuana prevention programs, methamphetamine was consid-
has also been implicated in derangements of the immune ered second only to cocaine as a drug threat to society
system; in chromosomal abnormalities; and in inhibition by the U.S. Department of Justice in 2009. Hospital
of DNA, RNA, and protein synthesis; however, these admissions for methamphetamine treatment more than
ndings have not been conrmed or related to any spe- doubled between 1998 and 2007, and young adults
cic physiologic effect in humans. (aged 1825 years) have the highest use rates.
Alcoholism and Drug Dependency
CHAPTER 58
an epidemic of LSD abuse during the 1960s. Imposition and analgesia. Physical signs of intoxication may include
of stringent constraints on the manufacture and distribu- horizontal or vertical nystagmus, ushing, diaphoresis,
tion of LSD (classied as a Schedule I substance by the and hyperacusis. Behavioral changes include distortions of
U.S. Food and Drug Administration), as well as public body image, disorganization of thinking, and feelings of
recognition that psychedelic experiences induced by estrangement. Higher doses of PCP (510 mg) may pro-
LSD were a health hazard, have resulted in a reduction duce profuse salivation, vomiting, myoclonus, fever, stu-
por, or coma. PCP doses of v10 mg cause convulsions,
CHAPTER 58
Cocaine and Other Commonly Abused Drugs
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APPENDIX
This Appendix contains tables of reference values for units (SI, systme international dunits) is used in most
laboratory tests, special analytes, and special function countries and in some medical journals. However,
tests. A variety of factors can inuence reference values. clinical laboratories may continue to report values in
Such variables include the population studied, the dura- traditional or conventional units. Therefore, both
tion and means of specimen transport, laboratory meth- systems are provided in the Appendix. The dual system
ods and instrumentation, and even the type of container is also used in the text except for (1) those instances in
used for the collection of the specimen. The reference which the numbers remain the same but only the ter-
or normal ranges given in this appendix may there- minology is changed (mmol/L for meq/L or IU/L for
fore not be appropriate for all laboratories, and these mIU/mL), when only the SI units are given; and (2)
values should only be used as general guidelines. When- most pressure measurements (e.g., blood and cerebrospi-
ever possible, reference values provided by the labora- nal uid pressures), when the traditional units (mmHg,
tory performing the testing should be utilized in the mmH2O) are used. In all other instances in the text the
interpretation of laboratory data. Values supplied in SI unit is followed by the traditional unit in parentheses.
this Appendix reect typical reference ranges in adults.
Pediatric reference ranges may vary signicantly from
adult values.
REFERENCE VALUES FOR
In preparing the Appendix, the authors have taken
into account the fact that the system of international
LABORATORY TESTS
TABLE 1
HEMATOLOGY AND COAGULATION
ANALYTE SPECIMEN SI UNITS CONVENTIONAL UNITS
Antithrombin III P
Antigenic 220390 mg/L 2239 mg/dL
Functional 0.71.30 U/L 70130%
Anti-Xa assay (heparin assay) P
Unfractionated heparin 0.30.7 kIU/L 0.30.7 IU/mL
Low-molecular-weight heparin 0.51.0 kIU/L 0.51.0 IU/mL
Danaparoid (Orgaran) 0.50.8 kIU/L 0.50.8 IU/mL
Autohemolysis test WB 0.0040.045 0.44.50%
Autohemolysis test with glucose WB 0.0030.007 0.30.7%
Bleeding time (adult) <7.1 min <7.1 min
Bone marrow: See Table 7
Clot retraction WB 0.501.00/2 h 50100%/2 h
Cryobrinogen P Negative Negative
D-dimer P 220740 ng/mL FEU 220740 ng/mL FEU
APPENDIX
Hematocrit WB
Adult males 0.3880.464 38.846.4
Adult females 0.3540.444 35.444.4
Hemoglobin
Plasma P 650 mg/L 0.65.0 mg/dL
Whole blood: WB
Adult males 133162 g/L 13.316.2 g/dL
Adult females 120158 g/L 12.015.8 g/dL
Hemoglobin electrophoresis WB
Hemoglobin A 0.950.98 9598%
Hemoglobin A2 0.0150.031 1.53.1%
Hemoglobin F 00.02 02.0%
Hemoglobins other than A, A2, or F Absent Absent
Heparin-induced thrombocytopenia antibody P Negative Negative
APPENDIX
Immature platelet fraction (IPF) WB 0.0110.061 1.16.1%
Joint uid crystal JF Not applicable No crystals seen
Joint uid mucin JF Not applicable Only type I mucin present
Leukocytes
Alkaline phosphatase (LAP) WB 0.21.6 kat/L 13100 /L
Count (WBC) WB 3.549.06 109/L 3.549.06 103/mm3
Abbreviations: JF, joint uid; P, plasma; PRP, platelet-rich plasma; S, serum; WB, whole blood.
TABLE 2
CLINICAL CHEMISTRY AND IMMUNOLOGY
ANALYTE SPECIMEN SI UNITS CONVENTIONAL UNITS
(continued)
TABLE 2 779
CLINICAL CHEMISTRY AND IMMUNOLOGY (CONTINUED)
ANALYTE SPECIMEN SI UNITS CONVENTIONAL UNITS
Androstendione (adult) S
Males 0.813.1 nmol/L 2389 ng/dL
Females
Premenopausal 0.917.5 nmol/L 26214 ng/dL
Postmenopausal 0.462.9 nmol/L 1382 ng/dL
Angiotensin-converting enzyme (ACE) S 0.151.1 kat/L 967 U/L
Anion gap S 716 mmol/L 716 mmol/L
Apolipoprotein A-1 S
Male 0.941.78 g/L 94178 mg/dL
Female 1.011.99 g/L 101199 mg/dL
Apolipoprotein B S
Male 0.551.40 g/L 55140 mg/dL
Female 0.551.25 g/L 55125 mg/dL
APPENDIX
Arterial blood gases WB
[HCO3] 2230 mmol/L 2230 meq/L
PCO2 4.36.0 kPa 3245 mmHg
pH 7.357.45 7.357.45
PO2 9.613.8 kPa 72104 mmHg
Aspartate aminotransferase (AST, SGOT) S 0.200.65 kat/L 1238 U/L
APPENDIX
Supine (30 min) <273 pmol/L <50 pg/mL
Sitting <328 pmol/L <60 pg/mL
Standing (30 min) <491 pmol/L <90 pg/mL
Erythropoietin S 427 U/L 427 U/L
Estradiol S, P
Female
APPENDIX
Lipoprotein (a) S 0300 mg/L 030 mg/dL
Low-density lipoprotein (LDL) (see Table 5)
Luteinizing hormone (LH) S, P
Female
Menstruating:
Follicular phase 2.015.0 U/L 2.015.0 mIU/mL
APPENDIX
Thyroid-stimulating hormone S 0.344.25 mIU/L 0.344.25 IU/mL
Thyroxine, free (fT4) S 9.016 pmol/L 0.71.24 ng/dL
Thyroxine, total (T4) S 70151 nmol/L 5.411.7 g/dL
Thyroxine index (free) S 6.710.9 6.710.9
Transferrin S 2.04.0 g/L 200400 mg/dL
(continued)
TABLE 3 787
TOXICOLOGY AND THERAPEUTIC DRUG MONITORING (CONTINUED)
THERAPEUTIC RANGE TOXIC LEVEL
APPENDIX
Lamotrigine 11.754.7 mol/L 314 g/mL >58.7 mol/L >15 g/mL
Lidocaine 5.121.3 mol/L 1.25.0 g/mL >38.4 mol/L >9.0 g/mL
Lithium 0.51.3 mmol/L 0.51.3 meq/L >2 mmol/L >2 meq/L
Methadone 1.03.2 mol/L 0.31.0 g/mL >6.5 mol/L >2 g/mL
Methamphetamine 0.070.34 mol/L 0.010.05 g/mL >3.35 mol/L >0.5 g/mL
Methanol >6 mmol/L >20 mg/dL
TABLE 4
VITAMINS AND SELECTED TRACE MINERALS
REFERENCE RANGE
APPENDIX
CO2 content 2024 mmol/L 2024 meq/L
Abbreviations: LDL, low-density lipoprotein; HDL, high-density
lipoprotein. PCO2 67 kPa 4549 mmHg
Source: Executive summary of the third report of the National pH 7.317.34
Cholesterol Education Program (NCEP) expert panel on detec- Glucose 2.223.89 mmol/L 4070 mg/dL
tion, evaluation, and treatment of high blood cholesterol in adults Lactate 12 mmol/L 1020 mg/dL
(adult treatment panel III). JAMA 2001; 285:248697. Implications
of Recent Clinical Trials for the National Cholesterol Education Total protein:
a
Since cerebrospinal uid concentrations are equilibrium values,
measurements of the same parameters in blood plasma obtained
at the same time are recommended. However, there is a time lag in
attainment of equilibrium, and cerebrospinal levels of plasma con-
stituents that can uctuate rapidly (such as plasma glucose) may
not achieve stable values until after a signicant lag phase.
b
IgG index = CSF IgG (mg/dL) serum albumin (g/dL)/serum IgG
(g/dL) CSF albumin (mg/dL).
790 TABLE 7A TABLE 8
DIFFERENTIAL NUCLEATED CELL COUNTS OF STOOL ANALYSIS
BONE MARROW ASPIRATESa
REFERENCE RANGE
OBSERVED 95% RANGE
RANGE (%) (%) MEAN (%) CONVENTIONAL
SI UNITS UNITS
Blast cells 03.2 03.0 1.4
Promyelocytes 3.613.2 3.212.4 7.8 Alpha-1- 540 mg/L 54 mg/dL
Neutrophil 421.4 3.710.0 7.6 antitrypsin
myelocytes Amount 0.10.2 kg/d 100200 g/24 h
Eosinophil 05.0 02.8 1.3 Coproporphyrin 6111832 nmol/d 4001200 g/24 h
myelocytes Fat
Adult <7 g/d
Metamyelocytes 17.0 2.35.9 4.1 Adult on <4 g/d
Neutrophils fat-free diet
Males 21.045.6 21.942.3 32.1 Fatty acids 021 mmol/d 06 g/24 h
Females 29.646.6 28.845.9 37.4 Leukocytes None None
Eosinophils 0.44.2 0.34.2 2.2 Nitrogen <178 mmol/d <2.5 g/24 h
Eosinophils 0.97.4 0.76.3 3.5 pH 7.07.5
APPENDIX
a
Based on bone marrow aspirate from 50 healthy volunteers
(30 men, 20 women).
Abbreviation: M:E, myeloid to erythroid ratio.
Source: BJ Bain: Br J Haematol 94:206, 1996.
TABLE 7B
BONE MARROW CELLULARITY
OBSERVED
AGE RANGE 95% RANGE MEAN
APPENDIX
Bence Jones protein, urine, quantitative
Free Kappa 1.424.2 mg/L 0.142.42 mg/dL
Free Lambda 0.26.7 mg/L 0.020.67 mg/dL
K/L ratio 2.0410.37 2.0410.37
Calcium (10 meq/d or 200 mg/d dietary <7.5 mmol/d <300 mg/d
calcium)
(continued)
792 TABLE 9
URINE ANALYSIS AND RENAL FUNCTION TESTS (CONTINUED)
REFERENCE RANGE
Microalbumin
Normal 0.00.03 g/d 030 mg/d
Microalbuminuria 0.030.30 g/d 30300 mg/d
Clinical albuminuria >0.3 g/d >300 mg/d
Microalbumin/creatinine ratio
Normal 03.4 g/mol creatinine 030 g/mg creatinine
Microalbuminuria 3.434 g/mol creatinine 30300 g/mg creatinine
Clinical albuminuria >34 g/mol creatinine >300 g/mg creatinine
2-Microglobulin 0160 g/L 0160 g/L
Norepinephrine 89473 nmol/d 1580 g/d
N-telopeptide (cross-linked), NTx
Female, premenopausal 1794 nmol BCE/mmol creatinine 1794 nmol BCE/mmol creatinine
APPENDIX
Female, postmenopausal 26124 nmol BCE/mmol creatinine 26124 nmol BCE/mmol creatinine
Male 2183 nmol BCE/mmol creatinine 2183 nmol BCE/mmol creatinine
BCE = bone collagen equivalent
Osmolality 100800 mOsm/kg 100800 mOsm/kg
Oxalate
Male 80500 mol/d 744 mg/d
Laboratory Values of Clinical Importance