Adams and Victor's Principles of Neurology, 12th Edition (True PDF) [12 ed.] 9781264264537, 1264264534, 9781264264520, 1264264526, 2022046842, 2022046843, 9781265435998, 1265435995

Table of contents :
Cover
Title Page
Copyright Page
Contents
Foreword
Preface
PART 1: THE CLINICAL METHOD OF NEUROLOGY
1 Approach to the Patient With Neurologic Disease
2 Diagnostic Testing in Neurologic Disease
PART 2: CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
SECTION 1 Disorders of Motility
3 Paralysis and Weakness
4 Disorders of Movement and Posture
5 Ataxia and Disorders of Cerebellar Function
6 Disorders of Stance and Gait
SECTION 2 Pain and Disorders of Somatic Sensation
7 Pain
8 Disorders of Non-Painful Somatic Sensation
9 Headache and Other Craniofacial Pains
10 Pain in the Back, Neck, and Extremities
SECTION 3 Disorders of the Special Senses
11 Disorders of Smell and Taste
12 Disturbances of Vision
13 Disorders of Ocular Movement and Pupillary Function
14 Deafness, Dizziness, and Disorders of Equilibrium
SECTION 4 Epilepsy and Disorders of Consciousness
15 Epilepsy and Other Seizure Disorders
16 Coma and Related Disorders of Consciousness
17 Faintness and Syncope
18 Sleep and Its Abnormalities
SECTION 5 Derangements of Intellect, Behavior, and Language Caused by Diffuse and Focal Cerebral Disease
19 Acute Confusional States
20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
21 Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum
22 Disorders of Speech and Language
SECTION 6 Disorders of Energy, Mood, and Autonomic and Endocrine Functions
23 Fatigue, Asthenia, Anxiety, and Depression
24 The Limbic Lobes and the Neurology of Emotion
25 Disorders of the Autonomic Nervous System, Respiration, and Swallowing
26 The Hypothalamus and Neuroendocrine Disorders
PART 3: GROWTH AND DEVELOPMENT OF THE NERVOUS SYSTEM AND THE NEUROLOGY OF AGING
27 Normal Development and Deviations in Development of the Nervous System
28 The Neurology of Aging
PART 4: MAJOR CATEGORIES OF NEUROLOGIC DISEASE
29 Disturbances of Cerebrospinal Fluid, Including Hydrocephalus, Pseudotumor Cerebri, and Low-Pressure Syndromes
30 Intracranial Neoplasms and Paraneoplastic Disorders
31 Bacterial, Fungal, Spirochetal, and Parasitic Infections of the Nervous System
32 Viral Infections of the Nervous System and Prion Diseases
33 Stroke and Cerebrovascular Diseases
34 Craniocerebral Trauma
35 Multiple Sclerosis and Other Neuroimmunologic Disorders
36 Inherited Metabolic Diseases of the Nervous System
37 Developmental Diseases of the Nervous System
38 Degenerative Diseases of the Nervous System
39 The Acquired Metabolic Disorders of the Nervous System
40 Diseases of the Nervous System Caused by Nutritional Deficiency
41 Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents
PART 5: DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
42 Diseases of the Spinal Cord
43 Diseases of the Peripheral Nerves
44 Diseases of the Cranial Nerves
45 Diseases of Muscle
46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity
PART 6: PSYCHIATRIC DISORDERS
47 Anxiety, “Functional” and Personality Disorders
48 Depression and Bipolar Disorder
49 Psychosis, Schizophrenia, Delusional, and Paranoid States
Index

Citation preview

Adams and Victor’s

PRINCIPLES OF

NEUROLOGY TWELFTH EDITION

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NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The author 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 sciences, neither the author nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information 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 confirm 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 administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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 Adams and Victor’s

PRINCIPLES OF

NEUROLOGY   TWELFTH EDITION

Allan H. Ropper, MD Professor of Neurology Harvard Medical School Associate Neurologist Brigham and Women’s Hospital Deputy Editor New England Journal of Medicine Boston, Massachusetts

Martin A. Samuels, MD, MACP, FAAN, FANA, FRCP, DSci (Hon) Miriam Sydney Joseph Distinguished Professor of Neurology Harvard Medical School Founding Chair, Department of Neurology Brigham and Women’s Hospital Massachusetts General Brigham Health Care System Boston, Massachusetts

Joshua P. Klein, MD, PhD Associate Professor of Neurology and Radiology Harvard Medical School Vice Chair, Clinical Affairs, Department of Neurology Chief, Division of Hospital Neurology Brigham and Women’s Hospital Boston, Massachusetts

Sashank Prasad, MD Associate Professor of Neurology Harvard Medical School Vice Chair for Education, Department of Neurology Brigham and Women’s Hospital Program Director Massachusetts General Brigham Neurology Residency Boston, Massachusetts

New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

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Copyright © 2023 by McGraw Hill LLC. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-1-26-426453-7 MHID: 1-26-426453-4 The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-426452-0, MHID: 1-26-426452-6. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw Hill eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com. Library of Congress Cataloging-in-Publication Data Names: Ropper, Allan H, author. | Samuels, Martin A, author. | Klein, Joshua, author. | Prasad, Sashank, author. Title: Adams and Victor’s principles of neurology / Allan H. Ropper, Martin A. Samuels, Joshua P. Klein, Sashank Prasad. Other titles: Principles of neurology Description: Twelfth edition. | New York : McGraw Hill, [2023] | Includes bibliographical references and index. | Summary: “This edition focuses on the wise application of science, evidence from trials, and is closely coupled to the traditional value of the neurological history and examination-essentially the craft of neurology”—Provided by publisher. Identifiers: LCCN 2022046842 (print) | LCCN 2022046843 (ebook) | ISBN 9781264264520 (hardcover) | ISBN 1264264526 (hardcover) | ISBN 9781264264537 (ebook) | ISBN 1264264534 (ebook) Subjects: MESH: Nervous System Diseases | Neurologic Manifestations Classification: LCC RC346 (print) | LCC RC346 (ebook) | NLM WL 140 | DDC 616.8–dc23/eng/20230120 LC record available at https://lccn.loc.gov/2022046842 LC ebook record available at https://lccn.loc.gov/2022046843 TERMS OF USE This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/ or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

Contents Foreword, vii Preface, ix

PART 1:  THE CLINICAL METHOD OF NEUROLOGY, 1 1  Approach to the Patient With Neurologic Disease, 3 2  Diagnostic Testing in Neurologic Disease,13

PART 2:  CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE, 51 SECTION 1  Disorders of Motility, 53 3 Paralysis and Weakness, 54 4  Disorders of Movement and Posture, 70 5 Ataxia and Disorders of Cerebellar Function, 109 6 Disorders of Stance and Gait, 121

Pain and Disorders of Somatic Sensation, 133 SECTION 2 

7  Pain, 134 8 Disorders of Non-Painful Somatic Sensation, 155 9 Headache and Other Craniofacial Pains, 173 10 Pain in the Back, Neck, and Extremities, 203

Disorders of the Special Senses, 229 SECTION 3 

11 Disorders of Smell and Taste, 230 12  Disturbances of Vision, 239 13  Disorders of Ocular Movement and Pupillary Function, 263 14  Deafness, Dizziness, and Disorders of Equilibrium, 292

Epilepsy and Disorders of Consciousness, 319 SECTION 4 

15 Epilepsy and Other Seizure Disorders, 320 16 Coma and Related Disorders of Consciousness, 361 17  Faintness and Syncope, 387 18 Sleep and Its Abnormalities, 399

Derangements of Intellect, Behavior, and Language Caused by Diffuse and Focal Cerebral Disease, 423 SECTION 5 

19 Acute Confusional States, 428 20  Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory, 436 21  Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum, 458 22 Disorders of Speech and Language, 489

Disorders of Energy, Mood, and Autonomic and Endocrine Functions, 509 SECTION 6 

23 Fatigue, Asthenia, Anxiety, and Depression, 510 24  The Limbic Lobes and the Neurology of Emotion, 520 25  Disorders of the Autonomic Nervous System, Respiration, and Swallowing, 531 26  The Hypothalamus and Neuroendocrine Disorders, 565

PART 3:  GROWTH AND DEVELOPMENT OF THE NERVOUS SYSTEM AND THE NEUROLOGY OF AGING, 579 27  Normal Development and Deviations in Development of the Nervous System, 581 28 The Neurology of Aging, 607

PART 4:  MAJOR CATEGORIES OF NEUROLOGIC DISEASE, 615 29  Disturbances of Cerebrospinal Fluid, Including Hydrocephalus, Pseudotumor Cerebri, and Low-Pressure Syndromes, 617 30  Intracranial Neoplasms and Paraneoplastic Disorders, 640 31 Bacterial, Fungal, Spirochetal, and Parasitic Infections of the Nervous System, 696 32  Viral Infections of the Nervous System and Prion Diseases, 739 33 Stroke and Cerebrovascular Diseases, 772 34  Craniocerebral Trauma, 879

v

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vi

Contents

35  Multiple Sclerosis and Other Neuroimmunologic Disorders, 908 36  Inherited Metabolic Diseases of the Nervous System, 940 37  Developmental Diseases of the Nervous System, 996 38  Degenerative Diseases of the Nervous System, 1052 39  The Acquired Metabolic Disorders of the Nervous System, 1125 40  Diseases of the Nervous System Caused by Nutritional Deficiency, 1153 41  Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents, 1177

44 Diseases of the Cranial Nerves, 1355 45 Diseases of Muscle, 1370 46  Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity, 1432

PART 6:  PSYCHIATRIC DISORDERS, 1467 47  Anxiety, “Functional” and Personality Disorders, 1469 48 Depression and Bipolar Disorder, 1488 49  Psychosis, Schizophrenia, Delusional, and Paranoid States, 1503 Index, 1519

PART 5:  DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE, 1223 42 Diseases of the Spinal Cord, 1225 43 Diseases of the Peripheral Nerves, 1276

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Foreword After an initial disastrous introduction to neurology as a medical student, my lifelong affair with the specialty began in 1977 as a medical resident followed by my first year of neurology residency in 1978. From the start, the first edition of Principles of Neurology became my bible, which I and my co-trainees read from cover to cover. The field has changed immensely since that time, and widely distributed neurology textbooks are multiauthored by experts in the large number of neurology subspecialties that now dominate the field. This results in chapters providing considerable detail but often in a very patchy, inconsistent, and sometimes inaccurate fashion. The publication of the twelfth edition of Adams and Victor’s celebrated text reaffirms that there is still an important place on the shelves of neurology trainees and practitioners for a volume that originated from the two remarkable neurological authorities, Raymond Adams and Maurice Victor, and is now written by four experienced authors sharing their clinical experience with a uniform approach to the presentation of the field that is typically lost in the world of multiauthored texts. As in the original, the current edition starts by emphasizing the classical approach to neurological patients. The authors highlight the importance of a solid understanding of neuroanatomy and the possible symptomatology caused by dysfunction of the nervous system that is critical to the combined deductive and inductive (Holmesian) approach to neurological diagnosis that makes the specialty of neurology so interesting and stimulating to those who practice it. Patient-based learning became a defined teaching approach long after Adams and Victor first wrote their text. However, the recognition of the importance of the patient in the acquisition of knowledge about a field, especially as it

applies to neurology, was clearly acknowledged and is paramount in subsequent editions, including this one. With the remarkable advances in neuroscience and medicine in general, it is impossible for a single textbook to cover all aspects of neurology in detail. This emphasizes the importance of lifelong learning in medicine that and clearly requires an initial strong clinical basis upon which to build and learn, as provided in this book. Although technology and understanding of the biological basis of disease and therapeutics are ever-changing, the way the patient presents to the clinician has changed little since the origins of medicine. This further highlights the importance of the consistent, patient-based approach provided here as well as the historical perspectives included. Finally, although the old portrayal of neurology as a “diagnose and adios” specialty is largely accepted as outmoded, the clinical knowledge-base and the coverage of research and therapeutic advances in Adams and Victor’s Principles of Neurology proactively encourage the clinician seeing patients suffering from neurological diseases to diagnose and administer, ameliorate, and advocate. This fitting 50th anniversary edition of the major textbook in neurology affirms the appeal and durability of an iconic vehicle for the transmission of knowledge and wisdom acquired through experience. Anthony E. Lang, OC, MD, FRCPC, FAAN, FCAHS, FRSC Director, Edmond J. Safra Program in Parkinson’s Disease and the Rossy PSP Centre Toronto Western Hospital Toronto, Ontario, Canada

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Preface We are very pleased to bring you the twelfth edition of Adams and Victor’s Principles of Neurology. The originators of this book, Raymond D. Adams and Maurice Victor, insisted that the basis of the practice of neurology as a medical discipline must always be related back to the patient. This guides the format and approach that we continue to adhere in the current edition. In the past few decades, there has been an explosion in understanding of the fundamental causes of neurological diseases. Just a few examples are the reclassification of brain tumors based on genetic changes and the novel autoantibody disorders that proliferate with each edition of major medical journals. In the present edition, there is hardly a category of disease that has not begun to yield to the tools of molecular biology and genetics The well-educated neurologist must be familiar with these advances and develop a foundation upon which to absorb ongoing discoveries, particularly as they pertain to modern treatment. But these do not always provide the basis for excellence in clinical practice. There is not so much a gap between science and practice as there is a tenuous equilibrium. Finding the sweet spot between them is a goal of the book. This project begins with a firm grounding in the principles of anatomy, physiology, biochemistry, and genetics that are essential to understanding neurological symptoms and signs that are artfully extracted, processed, and abstracted by the clinician in proximity to the patient. The first parts of the book attach these principles to clinical symptoms and signs. In subsequent parts, diseases are grouped by their clinical manifestations: dementia, ataxia, visual loss, muscular weakness, headache, depression, convulsion, and so on. This is after all, how patients present to physicians, as patients are not in a position to express the fundamental underlying biological cause of their aliments. The final sections tackle the diseases themselves, decidedly from the perspective of how each affects the nervous system rather than as isolated entities. This affords the reader an opportunity to comprehend what can, and as importantly what cannot, happen to the nervous system, a powerful tool that sharpens diagnostic skills and avoids overly broad differential diagnoses. More than laboratory science, clinical trials have continued to build the background of information that applies to large groups of patients with neurological disease, namely clinical trials that now guide practice. Clinicians are aware, however, that the results of a trial have less certain meaning for an individual patient. Our teacher C.M. Fisher was fond of the quip “There ain’t no more than one average Englishman.” Knowledge of trial design and statistical methods is helpful in gauging the certainty with which to apply information from trials and we try to point out the strengths and weaknesses of the results from major trials to provide a

context for implementing their results. It is the skillful use of this information that this book aims to inform. Will the single patient be helped or harmed? Because medicine deals with the realities and complexities of illness in the individual, the clinician makes a best approximation of the correct course. The wise application of science, evidence from trials, closely coupled to the traditional value of the neurological history and examination—essentially the craft of neurology—are the main purpose of this edition of Principles of Neurology. Furthermore, there is a vast territory that can only be explored in the human representations of disease. Aphasia, confusional states, headache, amnesia, developmental delay, in fact most of human behavior, have no animal models or only crude approximations. Examples of what makes us who we are fall in the purview of neurologists every day by demonstrating what is lost when the nervous system is damaged. Neurologists are inevitably clinical investigators and they depend on astute observation in the clinic and at the bedside. They have something to say on development, education, aging, the boundaries of what is normal and abnormal, and many other appended issues, if they choose to look at these subjects through the lens of daily practice. We also believe that teaching the skills of neurological observation is a trust that must not be broken and hope that a firm grounding in the way diseases affect patients will assist students, residents and early career neurologists in internalizing their experiences of each patient and the subsequent transgenerational transmission of knowledge about diseases of the nervous system. As has been our tradition, the book is written in a conversational style and we do not eschew stating our personal preferences when they are based on experience. We continue to find that readers value the uniformity of voice and approach of a few individual authors, rather than a discursive list of topics and writers. We thank Dr. Tim Lachman and the many others who read portions of this and previous editions for invaluable assistance in pointing out errors and the readers who have written to us with corrections and suggestions for improving the book. We hope this edition allows the physician to use the material as a basis for continued professional growth and enjoyment at all stages of professional life that will profit general and specialist clinicians. Welcome again to our world in this twelfth edition of Adams and Victor’s Principles of Neurology on its 50th anniversary. Allan H. Ropper, MD Martin A. Samuels, MD Joshua P. Klein, MD, PhD Sashank Prasad, MD

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PA R T

1

THE CLINICAL METHOD OF NEUROLOGY

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1 Approach to the Patient With Neurologic Disease

INTRODUCTION Neurology is the practice and study of diseases of the nervous system. It is among the most complex and exacting medical specialties and yet it is perhaps the most rewarding, encompassing as it does all aspects of human behavior, cognition, memory, movement, pain, sensory experience, and the homeostatic functions of the body that are under nervous control. Among the provocative aspects of neurology is the manner in which diseases disrupt the functions of the mind, but the field also encompasses the study of the diseases of nerves, muscles, spinal cord, and cerebral hemispheres. The neurologist occupies a special role by using extensive synthetic and analytical skill to explain neurologic symptoms and findings. Neurology is distinctive in allowing a type of detailed interpretation of signs and symptoms that, as a result of the fixed structure of the nervous system, provides certainty in diagnosis that is not possible in other fields. This is the method of localization that is almost unique to neurology. Part of the excitement of modern neurology is the incorporation of advances in imaging, and in the neurosciences including neurogenetics, neurochemistry, neuroepidemiology, and neuropathology, which now offer deep insights into the fundamental nature of disease. The close connections among neurology and the fields of internal medicine, psychiatry, neuropathology, developmental medicine and pediatrics, critical care, neurorehabilitation, and neurosurgery extend the purview of clinical neurology. As has occurred in other branches of medicine, increased understanding of disease and therapeutic options has led to the emergence of numerous subspecialties of neurology (Table 1-1). Neurologic symptoms, of course, do not present themselves as immediately referable to a part of the nervous system, and the neurologist must therefore be knowledgeable in all aspects of nervous system function and disease. The authors believe that a successful application of medical knowledge is attained by adhering to the principles of the clinical method, which has been retained to a greater degree in neurology than in other fields of medicine. Even the experienced neurologist faced with a complex clinical problem uses this basic approach.

THE CLINICAL METHOD In most cases, the clinical method consists of an orderly series of steps: 1. The symptoms and signs are secured with as much confidence as possible by history and physical examination. 2. The symptoms and physical signs considered relevant to the problem at hand are interpreted in terms of physiology and anatomy—that is, one identifies the disorder of function and the anatomic structures that are implicated. 3. These analyses permit the physician to localize the disease process, that is, to name the parts of the nervous system affected. This is the anatomic, or topographic diagnosis, which often allows the recognition of a characteristic clustering of symptoms and signs, constituting a syndrome. 4. From the anatomic diagnosis and other specific medical data—particularly the mode of onset and speed of evolution of the illness, the involvement of nonneurologic organ systems, the relevant past and family medical histories, and the imaging and laboratory findings—one deduces the etiologic diagnosis and its pathogenesis. 5. Finally, the physician should assess the degree of disability and determine whether it is temporary or permanent (functional diagnosis); this is important in managing the patient’s illness and judging the potential for restoration of function (prognosis). The likely causes of a neurologic disease are judged in the context of a patient’s personal and demographic characteristics, including their age, sex, race, ethnicity, and geographic circumstances. Knowledge of the incidence and prevalence of diseases among populations defined by these factors (base rates) is a valuable component of the diagnostic process. These change over time as, for example, during epidemics and may differ even within neighborhoods or regions of one country. In recent decades, some of these steps have been eclipsed by imaging methods that allow precise localization of a lesion and, furthermore, often characterize the category of disease. Parts of the elaborate examination that were intended to localize lesions are no longer as necessary

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4

Part 1 THE CLINICAL METHOD OF NEUROLOGY

Table 1-1

Table 1-2

NEUROLOGICAL SUBSPECIALTY SUBSPECIALTY

Stroke and cerebrovascular disease Neurological intensive care Cognitive, behavioral neurology, and neuropsychiatry Epilepsy Neuro-oncology Neuro-ophthalmology Neuromuscular Movement disorders Headache Multiple sclerosis and neuroimmunology Autonomic neurology Neuroimaging Hospital neurology Interventional neurology Oto- and vestibular neurology Pediatric and developmental neurology Neurological infections Sleep Pain Neuroendocrinology

THE MAJOR CATEGORIES OF NEUROLOGIC DISEASE CHAPTER

33 29, 33, 34 19–22, 38 15 30 12–13 43–46 4, 5, 6, 38 9 35 25 2 15,19, 20, 30–35 2, 33 14 27, 36, 37 31, 32 18 7–10 26

in every patient. Nonetheless, insufficient appreciation of the history and examination and the resulting overdependence on imaging lead to diagnostic errors and have other detrimental consequences. A clinical approach is usually more efficient and far more economical than reflexively resorting to imaging. Images are also replete with spurious or unrelated findings, which elicit unnecessary further testing and needless worry on the part of the patient. All of these steps are undertaken in the service of effective treatment, an ever-increasing aspect in neurology. As is emphasized repeatedly in later chapters, there is always a premium in the diagnostic process on the discovery of treatable diseases. Even when specific treatment is not available, accurate diagnosis may in its own right function as a therapy, as uncertainty about the cause of a neurologic illness may be as troubling to the patient than the disease itself. Of course, the solution to a clinical problem need not always be schematized in this way. The clinical method offers several alternatives in the order and manner by which information is collected and interpreted. In fact, in some cases, adherence to a formal scheme is not necessary at all. In relation to syndromic diagnosis, the clinical picture of Parkinson disease, for example, is usually so characteristic that the nature of the illness is at once apparent. In other cases, it is not necessary to carry the clinical analysis beyond the stage of the anatomic diagnosis, which, in itself, may virtually indicate the cause of a disease. For example, when vertigo, cerebellar ataxia, unilateral Horner syndrome, paralysis of a vocal cord, and analgesia of the face occur with acute onset, the cause is an occlusion of the vertebral artery, because all the involved structures lie in the lateral medulla, within the territory of this artery. Thus, the anatomic diagnosis determines and limits the etiologic possibilities. Some signs themselves are almost specific for

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Genetic–congenital or acquired variants Traumatic Degenerative Vascular Toxic Metabolic  Inherited  Acquired Neoplastic Inflammatory–immune Psychogenic Iatrogenic

a particular disease. Nonetheless, one must be cautious in calling any single sign pathognomonic as exceptions are found regularly. Ascertaining the cause of a clinical syndrome (etiologic diagnosis) requires knowledge of an entirely different order. Here one must be conversant with the clinical details, including the speed of onset, course, laboratory and imaging characteristics, and natural history of a multiplicity of diseases. When confronted with a constellation of clinical features that do not lend themselves to a simple or sequential analysis, one resorts to considering the broad division of diseases in all branches of medicine, as summarized in Table 1-2. Irrespective of the intellectual process that one utilizes in solving a particular clinical problem, the fundamental steps in diagnosis always involve the accurate elicitation of symptoms and signs and their correct interpretation in terms of disordered function of the nervous system. Most often when there is uncertainty or disagreement as to diagnosis, it is found later that the symptoms or signs were incorrectly interpreted in the first place. Repeated examinations may be necessary to establish the fundamental clinical findings beyond doubt. Hence the aphorism: In a difficult neurologic case, a second examination is the most helpful diagnostic test. It is advantageous to focus the clinical analysis on the principal symptom and signs and avoid being distracted by minor signs and uncertain clinical data. Of course, as mentioned, if the main sign has been misinterpreted—if a tremor has been mistaken for ataxia or fatigue for weakness— the clinical method is derailed from the start. Expert diagnosticians make successively more accurate estimates of the likely diagnosis, utilizing pieces of the history and findings on the examination to either affirm or exclude specific diseases. It is perhaps not surprising that the method of successive estimations works well; evidence from psychology reveals that this is the mechanism that the nervous system uses to process information. As the lessons of cognitive psychology have been applied to medical diagnosis, several heuristics (cognitive shortcuts) have been identified as both necessary to the diagnostic process and as pitfalls for the unwary clinician (see Tversky and Kahneman). Awareness of these heuristics offers the opportunity to incorporate corrective strategies. We openly discuss these heuristics and their pitfalls with our colleagues and

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Chapter 1 Approach to the Patient With Neurologic Disease

trainees to make them part of clinical reasoning. Investigators such as Redelmeier have identified the following categories of cognitive mistakes that are common in arriving at a diagnosis: 1. The framing effect reflects excessive weighting of specific initial data in the presentation of the problem. 2. Anchoring heuristic, in which an initial impression cannot be subsequently adjusted to incorporate new data. 3. Availability heuristic, in which experience with recent cases has an undue impact on the diagnosis of the case at hand. 4. Representative heuristic refers to the lack of appreciation of the frequency of disease in the population under consideration, a restatement of the Bayes theorem. 5. Blind obedience, in which there is undue deference to authority or to the results of a laboratory test. With our colleague Vickery, we have reviewed the workings of these heuristics in neurologic diagnosis. Any of these shortcuts produce a tendency to come to early closure in diagnosis. Often this is the result of premature fixation on some item in the history or examination, closing the mind to alternative diagnostic considerations. The first diagnostic formulation should be regarded as only a testable hypothesis, subject to modification when new items of information are secured. When several of the main features of a disease in its typical form are lacking, an alternative diagnosis should always be entertained. In general, however, one is more likely to encounter rare manifestations of common diseases than the typical manifestations of rare diseases (a paraphrasing of the Bayes theorem). Should the disease be in a stage of transition, time will allow the full picture to emerge and the diagnosis to be clarified. As pointed out by Chimowitz, students tend to err in failing to recognize a disease they have not seen, and experienced clinicians may fail to appreciate a rare variant of a common disease. There is no doubt that some clinicians are more adept than others at solving difficult clinical problems. Their talent is not intuitive, as sometimes is presumed, but is attributable to having paid close attention to the details of their experience with many diseases and having cataloged them for future reference. The unusual case is recorded in memory and can be resurrected when another one like it is encountered. To achieve expert performance in any area, whether cognitive, musical, or athletic, a prolonged period of personal experience and focused attention to the subject is required.

PREVALENCE AND INCIDENCE OF NEUROLOGIC DISEASE To offer the physician the broadest perspective on the relative frequency of neurologic diseases, estimates of their approximate impact in the world, taken from the Global Burden of Disease Study, commissioned by the World Health Organization and World Bank, published in Lancet in 2010 are summarized in Fig. 1-1. The main analysis was

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1% 3% 1% 1%

5

Hemorrhagic stroke Ischemic stroke

5%

Meningitis

8% 29%

8%

Migraine Other neurologic disorders Epilepsy

11%

Dementia Encephalitis 14%

18%

Parkinson Tension headache MS

Figure 1-1.  Contribution of neurologic conditions to the global burden of neurologic disease. The analysis, from WHO, includes communicable and noncommunicable diseases, but does not include traumatic brain injury or spine disease. (Reproduced with permission from Chin JH, Vora N. The global burden of neurologic diseases. Neurology, 2014; 83(4):349-351.)

of disability-adjusted life years (DALYs), which represent the years of life lost from premature death summed with the years of life lived with disability. Neurologic disease accounts for 8.6 percent of the total global DALY (including infections such as meningitis and encephalitis, and noncommunicable diseases such as stroke, epilepsy, dementia, and headache, but excluding traumatic brain injury). In summary, hemorrhagic stroke, ischemic stroke, and meningitis together account for approximately two-thirds of the total global burden caused by neurologic conditions. In relative terms, conditions such as Parkinson disease and multiple sclerosis were smaller contributors to the total global burden. Of course, these statistics differ markedly between developing and developed areas of the world. In addition, many neurologic conditions encountered in daily practice are not accounted for in these surveys and these frequencies of disease throughout the world were ascertained by various methods and must be considered approximations. Donaghy and colleagues provided a more detailed listing of the incidence of various neurologic diseases that are likely to be seen in the outpatient setting by a physician practicing in the United Kingdom. They noted stroke as far and away the most commonly encountered condition. More focused surveys, such as the one conducted by Hirtz and colleagues, give similar rates of prevalence, with migraine, epilepsy, and multiple sclerosis being the most common neurologic diseases in the general population, with 121, 7.1, and 0.9 per 1,000 persons in a year; stroke, traumatic brain injury, and spinal injury occurring in 183, 101, and 4.5 per 100,000 per year; and Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (ALS) among older individuals at rates of 67, 9.5, and 1.6 per 100,000 yearly. Data such as these assist in allocating societal resources, and they may be helpful in leading the physician to the correct diagnosis insofar as they emphasize the oft-stated dictum that “common conditions occur commonly” and therefore should be considered a priori to be more likely diagnoses (Table 1-3).

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Table 1-3 PREVALENCE OF THE MAJOR NEUROLOGIC DISORDERS IN THE UNITED STATES  

Degenerative diseases   Amyotrophic lateral sclerosis   Huntington disease   Parkinson disease   Alzheimer disease   Macular degeneration Autoimmune neurologic diseases   Multiple sclerosis Stroke, all types Central nervous system trauma  Head   Spinal cord Metabolic   Diabetic retinopathy Headache Epilepsy Back pain Peripheral neuropathy  Total  Inherited   Diabetic neuropathy Mental retardation  Severe  Moderate Schizophrenia Manic depressive illness

INDIVIDUALS AFFECTED

5 × 104 5 × 104 5 × 106 5 × 106 5 × 107 4 × 105 5 × 106 2 × 106 2.5 × 105 2 × 106 3 × 107 3 × 106 5 × 107 2.5 × 107 1 × 104 2 × 106 1 × 106 1 × 107 3 × 106 3 × 106

TAKING THE HISTORY In neurology, the physician is highly dependent on the cooperation of the patient for a reliable history, especially for a description of those symptoms that are unaccompanied by observable signs of disease. If the symptoms are in the sensory sphere, only the patient can tell what he sees, hears, or feels. The first step in the clinical encounter is to enlist the patient’s trust and cooperation and make him realize the importance of the history and examination procedure. Of course, no matter how reliable the history appears to be, verification of the patient’s account by a knowledgeable and objective informant is always desirable. When the patient’s cooperation is not possible, as for example in a comatose or confused individual or in a young child, an attempt should be made to acquire the necessary information from other sources. The following points about taking the neurologic history deserve further comment: 1. Special care must be taken to avoid suggesting to the patient the symptoms that one seeks. The patient should be discouraged from framing his symptom(s) in terms of a diagnosis that he may have heard; rather, he should be urged to give a simple description—being asked, for example, to choose a word that best describes his pain and to report precisely what he means by a particular term such as dizziness, imbalance, or vertigo. Otherwise there is a disposition on the part of the patient to emphasize aspects of the history that support a superficially plausible diagnosis. This problem

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is now amplified by the wide array of medical information available to patients through various sources such as the Internet. The patient who is given to highly circumstantial and rambling accounts can be kept on the subject of his illness by directive questions that draw out essential points. One should avoid suggesting terms to the patient, particularly those that prematurely confirm the physician’s preconceived diagnoses (“leading the witness”). 2. The setting in which the illness occurred, its mode of onset and evolution, and its course are of major importance. One must attempt to learn precisely how each symptom began and progressed. Often the nature of the disease process can be decided from these data alone, such as the typical sudden onset of stroke. If such information cannot be supplied by the patient or his family, it may be necessary to judge the course of the illness by what the patient was able to do at different times (e.g., how far he could walk, when he could no longer negotiate stairs or carry on his usual work) or by changes in the clinical findings between successive examinations. 3. In general, one tends to be careless in estimating the mental capacities of patients. Attempts are sometimes made to take histories from patients who are cognitively impaired or so confused that they have no idea why they are in a doctor’s office or a hospital. Young physicians and students have a natural tendency to “normalize” the patient’s cognitive performance, often collaborating with a hopeful family in the misperception that no real problem exists. This attempt at sympathy does not serve the patient and may delay the diagnosis of a potentially treatable disease. A common error is to pass lightly over inconsistencies in history and inaccuracies about dates and symptoms, only to discover later that these flaws in memory were the essential features of the illness. 4. Asking the patient to give his own interpretation of the possible meaning of symptoms sometimes exposes concern, depression, anxiety, suspiciousness, or even delusional thinking. This also may allow the patient to articulate fears about certain diseases such as brain tumor, dementia, motor neuron disease, or multiple sclerosis. Exposing these fears allows the physician to allay these concerns forthrightly.

THE NEUROLOGIC EXAMINATION The neurologic examination begins with observations in the waiting room, and continues as the patient proceeds to the examination room and while the history is being obtained. The manner in which the patient tells the story of his illness may betray confusion or incoherence in thinking, impairment of memory or judgment, or difficulty in comprehending or expressing ideas. A more extensive examination of attention, memory, cognitive ability, and language is undertaken if the history or the manner in which it is given indicates the problem lies in those spheres. Otherwise, asking the date and place, repeating and recalling words, and simple arithmetic are adequate screening procedures.

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One then proceeds from an examination of the cranial nerves to the testing of motor, reflex, and sensory functions of the upper and lower limbs. This is followed by an assessment of gait and station (standing position) observed before or after the rest of the examination. The thoroughness and focus of the neurologic examination must be governed by the type of clinical problem presented by the patient. To spend a half hour or more testing cerebral, cerebellar, cranial nerve, and sensorimotor function in a patient seeking treatment for a simple compression palsy of an ulnar nerve is pointless and uneconomical. Conversely, if the main problem relates to hand function, a detailed examination of the motor, sensory, and higher-order functions of the hand is undertaken. The examination must also be modified according to the condition of the patient. Obviously, many parts of the examination cannot be carried out in a comatose patient; also, infants and small children, as well as patients with psychiatric disease, must be examined in special ways. Similarly, the examination in acute situations that require urgent resolution must be necessarily compressed to an essential minimum that allows intelligent initial steps. When an abnormal finding is detected, whether cognitive, motor, or sensory, it becomes necessary to analyze the problem in a more elaborate fashion. Details of these sensitive examinations are addressed in appropriate chapters of the book and, cursorily, below. The neurologic examination is ideally performed and recorded in a relatively uniform manner to avoid omissions and facilitate the subsequent analysis of records. Some variation in the order of examination from physician to physician is understandable, but each examiner over time establishes a consistent pattern. If certain portions are intentionally not performed, these omissions should be stated so that those reading the description at a later time are not left wondering whether an abnormality was not previously detected. Portions of the general physical examination that may be particularly informative in the patient with neurologic disease should be included. For example, examination of the heart rate and blood pressure, as well as carotid and cardiac auscultation, may be essential in a patient with stroke. Likewise, the skin and eyes can reveal a number of conditions that pertain to congenital, metabolic, and infectious causes of neurologic disease. Aspects of general appearance, such as obesity or cachexia, may offer guidance to the likelihood of certain systemic illnesses.

The Detailed Examination of Patients With Neurologic Symptoms An inordinately large number of tests of neurologic function have been devised, and it is not proposed to review all of them here. Many tests are of doubtful value or are repetitions of simpler ones and to perform all of them on one patient would be unproductive. The danger with all clinical tests is to regard them as indicators of a particular disease rather than as ways of uncovering disordered functioning of the nervous system. The following approaches are relatively simple and provide the most useful information.

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Numerous guides to the examination of the nervous system are available (see the references at the end of this chapter). For a full account of these methods, the reader is referred to monographs on the subject, including those of Biller and colleagues (DeMyer’s), Spillane (Bickerstaff’s) Campbell (DeJong’s The Neurological Examination), and of the staff members of the Mayo Clinic, each of which approaches the subject from a different point of view.

Testing of Higher Cortical Functions Broadly speaking, the mental status examination has two main components, although the separation is somewhat artificial: the psychiatric aspects, which incorporate affect, mood, and normality of thought processes and content; and the cognitive aspects, which include the level of consciousness, awareness (attention), language, memory, visuospatial, and other executive abilities. These functions are tested in detail if the patient’s history or behavior has provided a reason to suspect some defect. Questions are first directed toward determining the patient’s orientation in time and place and insight into his current medical problem. Attention, speed of response, ability to give relevant answers to simple questions, and the capacity for sustained and coherent mental effort all lend themselves to straightforward observation. The patient’s account of his recent illness, dates of hospitalization, and day-to-day recollection of recent incidents are excellent tests of memory; the narration of the illness and the patient’s choice of words (vocabulary) and syntax provide information about language ability and coherence of thinking. There are many useful bedside tests of attention, concentration, memory, and cognition, for example, repetition of a series of digits in forward and reverse order, serial subtraction of 3s or 7s from 100, and recall of three items of information or a short story after an interval of 3 min. More detailed examination procedures appear in Chaps. 19 to 21. If there is any suggestion of a speech or language disorder, the nature of the patient’s spontaneous speech should be noted. In addition, the accuracy of reading, writing, and spelling, executing spoken commands, repeating words and phrases spoken by the examiner, naming objects, and parts of objects should be assessed. The ability to carry out commanded tasks (praxis) is pertinent to the evaluation of several aspects of cortical function. For example, commonly used tests are carrying out commanded and imitated gestures such as hammering a nail, blowing out a candle, throwing dice, and copying sequential hand positions. Visuospatial abilities may be tested by asking the patient to bisect a line, draw the numbers and hands of a clock face or the floor plan of one’s home or a map of one’s country, and copying figures. Recognition (gnosis) is tested by naming objects or pictures and describing their use.

Testing of Cranial Nerves The function of the cranial nerves is tested as a component of most examinations, in part because defects in their function are so easily recognizable and because certain

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abnormalities allow precise localization of a lesion. If one suspects a lesion in the anterior cranial fossa, the sense of smell should be tested and it should be determined whether odors can be discriminated. Visual fields can be outlined by having the patient indicate when the examiner’s finger moves or by counting fingers at the periphery of vision (confrontation testing), ideally by testing each eye separately. If an abnormality is suspected, perimetry provides a more sensitive method of confirming and mapping the defect. Pupil size and reactivity to light, direct, consensual, and during convergence, the position of the eyelids, and the range of ocular movements should next be observed. Details of these tests and their interpretations are given in Chaps. 11 to 13. Sensation over the face is tested with a pin and wisp of cotton. Also, the presence or absence of the corneal reflexes, direct and consensually, may be determined. Care must be taken to avoid eliciting blinking by a visual stimulus. Facial movements should be observed in repose and as the patient speaks and smiles, for a slight weakness may be more evident in these circumstances than on movements to command. Direct testing of facial power can be accomplished by asking the patient to forcefully close the eyes, purse the lips, and raise the brow. The auditory meatus and tympanic membranes should be inspected with an otoscope if there is a problem with hearing. A high-frequency (512 Hz) tuning fork held next to the ear and compared to applying it to the mastoid discloses hearing loss and distinguishes middleear (conductive) from neural deafness. An additional test of impaired bone or air conduction is performed by placing a high-frequency tuning fork in the center of the forehead and having the patient report any asymmetry in the sound. Audiograms and other special tests of auditory and vestibular function are needed if there is any suspicion of disease of the vestibulocochlear nerve or of the cochlea or labyrinths (see Chap. 14). The vocal cords may be inspected with special instruments in cases of suspected medullary or vagus nerve disease, especially when there is hoarseness. Voluntary pharyngeal elevation and elicited reflexes are meaningful if there is an asymmetrical response; bilateral absence of the gag reflex is seldom significant. Inspection of the tongue, both protruded and at rest, is helpful; atrophy and fasciculations may be seen and weakness detected. A slight deviation of the protruded tongue as a solitary finding can usually be disregarded, but a major deviation represents under action of the hypoglossal nerve and muscle on that side. The pronunciation of words should be noted. The jaw jerk (masseter tendon reflex) should be evaluated to localize the source of dysphagia, dysarthria, or dysphonia. In adults, abnormal reactions to tactile contact (reflexes) of the mouth and lips (such as sucking, snouting, rooting) reflect the reemergence of developmental reflexes and usually indicate the disease of frontal lobes. Failure to inhibit blinking in response to repetitive tapping of the brow (glabella) may indicate extrapyramidal or frontal disorders. The abnormal quality of speech and articulation, dysarthria, may give indications of weakness or other disorders

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of the lips, tongue, larynx, and pharynx. Certain patterns also conform to disorders of the cerebellum and parts of the brain stem and cerebrum. The abnormal speech patterns of spastic, ataxic, extrapyramidal, and neuromuscular disorders are elaborated mainly in Chap. 22.

Testing of Motor Function In the assessment of motor function, the most informative aspects are observations of the speed, power, muscle bulk, tone, and coordination. The maintenance of the supinated arms against gravity is a useful test; the weak arm, tiring first, soon begins to sag, or, in the case of a corticospinal lesion, to resume the more natural pronated position (“pronator drift”). An additional sign of subtle weakness of one side is the asymmetric “orbiting” of one forearm around the other when the patient is asked to rotate the fists or index fingers around the other. The strength of the legs can be tested with the patient prone and the knees flexed and observing downward drift of the weakened leg. In the supine position at rest, weakness due to an upper motor neuron lesion causes external rotation of the hip. In testing the power of the legs, it should be kept in mind that the hip flexors and quadriceps of most adults are stronger than the arm of the examiner. It is useful to have the limbs exposed and to inspect them for atrophy and fasciculations. Abnormalities of movement and posture as well as tremors may be revealed by observing the limbs at rest and in motion (see Chaps. 4 and 5). This is accomplished by watching the patient maintain the arms and move them from the prone to the supine positions; perform simple tasks, such as alternately touching his nose and the examiner’s finger; make rapid alternating movements that necessitate sudden acceleration and deceleration and changes in direction, such as tapping one hand on the other while alternating pronation and supination of the forearm; rapidly touch the thumb to each fingertip; and accomplish simple tasks such as buttoning clothes, opening a safety pin, or handling common tools. Estimates of the strength of leg muscles with the patient in bed may be unreliable; there may seem to be little or no weakness even though the patient cannot arise from a chair or from a kneeling position without help. Running the heel down the front of the shin, alternately touching the examiner’s finger with the toe and the opposite knee with the heel, and rhythmically tapping the heel on the shin are the only tests of coordination that need to be carried out in bed. The limbs are observed to determine if during natural activities, there is excessive or reduced quantity, speed or excursion of movement, tremor, and normal postural adjustments. The resistance of muscles during passive movement by the examiner (tone) gives information about spasticity and extrapyramidal rigidity.

Testing of Reflexes Testing of the tendon reflexes at the biceps, triceps, supinator-brachioradialis, patellar, and Achilles tendon are an adequate sampling of reflex activity. Underactive or barely elicitable reflexes can be facilitated by voluntary

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contraction of other muscles, such as pulling the grasped hands against each other (Jendrassik maneuver). The plantar reflexes, particularly the elicitation of the Babinski sign by stroking the lateral sole of the foot from heel to toe, are an essential part of most examinations. The sign is a dependable marker of damage to the corticospinal system as described in Chap. 3. The main features of the Babinski sign are dorsiflexion of the large toe and fanning of the other toes. Interpretation of the plantar response poses some difficulty because reactions besides the Babinski sign can be evoked. These include a quick withdrawal response of the foot and leg that does not signify disease; and a pathologic slower, spinal flexor reflex (flexion of knee and hip and dorsiflexion of toes and foot, “triple flexion”) that has similar significance to the Babinski sign. Avoidance and withdrawal responses interfere with the interpretation of the Babinski sign and can sometimes be overcome by utilizing alternative stimuli (e.g., squeezing the calf or Achilles tendon, flicking the fourth toe, downward scraping of the shin, lifting the straight leg, and others) or by having the patient scrape his own sole. Absence of the superficial cutaneous reflexes of the abdominal, cremasteric, and other muscles are useful ancillary tests for detecting corticospinal lesions, particularly when unilateral.

Testing of Sensory Function Because this part of the examination is attainable only through the subjective responses of the patient, it requires considerable cooperation. At the same time, it is subject to overinterpretation and suggestibility. Usually, sensory testing is reserved for the end of the examination and, if the findings are to be reliable, should not be prolonged. Each test should be explained briefly; too much discussion with a meticulous, introspective patient encourages the reporting of meaningless minor variations of stimulus intensity. It is not necessary to examine all areas of the skin surface. A quick survey of the face, neck, arms, trunk, and legs with a pin takes only a few seconds. Usually one is seeking differences between the two sides of the body (it is better to ask whether stimuli on opposite sides of the body feel the same than to ask if they feel different), a level below which sensation is lost, or a zone of relative or absolute analgesia (loss of pain sensibility) or anesthesia (loss of touch sensibility). Regions of sensory deficit can then be tested more carefully and mapped. Moving the stimulus from an area of diminished sensation into a normal area is recommended because it enhances the perception of a difference. The finding of a zone of heightened sensation (“hyperesthesia”) also calls attention to a disturbance of superficial sensation. The ability to perceive vibration may be tested by comparing the thresholds at which the patient and examiner lose perception at comparable bony prominences. We suggest recording the number of seconds for which the examiner appreciates vibration at the malleolus, toe, or finger after the patient reports that the fork has stopped buzzing. Joint position and the perception of movement of a digit

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can be tested by holding the body part at the sides and making small excursion at the adjacent joint. Variations in sensory findings from one examination to another reflect differences in the technique of examination as well as inconsistencies in the responses of the patient. Sensory testing is considered in greater detail in Chaps. 7 and 8.

Testing of Gait and Stance The examination is completed by observing the patient arise from a chair, stand and walk. An abnormality of stance or gait may be the most prominent or only neurologic abnormality, as in certain cerebellar or frontal lobe syndromes; and an impairment of posture and highly automatic adaptive movements in walking may provide diagnostic clues in the early stages of diseases such as Parkinson disease. Having the patient walk in tandem on a straight line may bring out a lack of balance and walking on the sides of the soles may elicit dystonic postures in the hands and trunk. Hopping or standing on one foot may also betray a lack of balance or weakness. Standing with feet together and eyes closed will bring out disequilibrium due to sensory loss (Romberg test) that is usually attributable to a disorder of the large diameter sensory fibers in the nerves and posterior columns of the spinal cord. Disorders of gait are discussed in Chap. 6.

The Screening Neurological Examination In the situation of a patient without neurologic symptoms, brevity is desirable but any test that is undertaken should be done carefully and recorded. Accurate recording of negative data may be useful in relation to some future illness that requires examination. As indicated in Table 1-4, the patient’s orientation, insight, judgment, and the integrity of language function are readily assessed in the course of taking the history. With respect to the cranial nerves, the size of the pupils and their reaction to light, ocular movements, visual and auditory acuity, and movements of the face, palate, and tongue should be tested. Observing the bare outstretched arms for atrophy, weakness (pronator drift), tremor, or abnormal movements; checking the strength Table 1-4 BRIEF NEUROLOGIC EXAMINATION IN THE GENERAL MEDICAL OR SURGICAL PATIENT 1. Orientation, insight into illness, and language assessed during taking of the history 2. Size of pupils, reaction to light, and visual and auditory acuity 3. Movement of eyes, face, tongue 4. Examination of the outstretched hands for atrophy, pronating or downward drift, tremor, power of grip, and wrist dorsiflexion 5. Biceps, supinator, and triceps tendon reflexes 6. Inspection of the legs during active flexion and extension of the hips, knees, and feet 7. Patellar, Achilles, and plantar responses 8. Vibration sensibility in the fingers and toes 9. Finger-to-nose and heel-to-shin testing of coordination 10. Gait

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of the extended and outstretched fingers; inquiring about sensory disturbances; and eliciting the biceps, brachioradialis, and triceps reflexes are usually sufficient for the upper limbs. Inspection and resistance of the muscles of the legs while the feet, toes, knees, and hips are actively flexed and extended; elicitation of the patellar, Achilles, and plantar responses testing of vibration and position sense in the fingers and toes; and assessment of coordination by having the patient alternately touch his nose and the examiner’s finger and run his heel up and down the front of the opposite leg, and observation of walking complete the essential parts of the neurologic examination. This entire procedure adds only a few minutes to the physical examination but the routine performance of these simple tests provides clues to the presence of a disease of which the patient is not aware. For example, the finding of absent Achilles reflexes and diminished vibratory sense in the feet and legs alerts the physician to the possibility of diabetic or nutritional neuropathy, even when the patient does not report symptoms.

THE COMATOSE PATIENT Although subject to obvious limitations, careful examination of the stuporous or comatose patient yields considerable information concerning the function of the nervous system. It is remarkable that, with the exception of cognitive function, almost all parts of the nervous system, including the cranial nerves, can be evaluated in the comatose patient. The demonstration of signs of focal cerebral or brain stem disease or of meningeal irritation is useful in the differential diagnosis of diseases that cause stupor and coma. The adaptation of the neurologic examination to the comatose patient is described in Chap. 16.

THE ANXIOUS, DEPRESSED, PSYCHOTIC, OR HYSTERICAL PATIENT One is compelled in the examination of psychiatric patients to be unusually critical of their statements and reports or symptoms. Many people, even those without psychiatric conditions, are highly suggestible and may display changes in sensory and motor function. The depressed patient, for example, may perceive impaired memory or weakness when actually there is neither amnesia nor reduced power, or the sociopath or hysteric may feign paralysis. The opposite is as often true: Psychotic patients may make accurate observations of their symptoms, only to have them ignored because of their mental state. It is well to keep in mind that patients with even the most extreme psychiatric disease are subject to all of the neurologic conditions typical of others of their age. By the manner in which the patient expresses ideas and responds to spoken or written requests, it is possible to determine whether there are hallucinations or delusions, defective memory, or other recognizable symptoms of brain disease merely by watching and listening to the

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patient. On occasion, mute and resistive patients judged to be psychotic prove to have some widespread cerebral disease.

INFANTS AND SMALL CHILDREN The reader is referred to the special methods of examination described by Volpe and the staff members of the Mayo Clinic, which are listed in the references and described in Chap. 27. Many of these tests address the developmental aspects of the child’s nervous system, and although some signs may be difficult to obtain because of the age of the patient, they still stand as the best reflections of the child’s neurologic state.

THE GENERAL MEDICAL EXAMINATION The general medical examination often reveals evidence of an underlying systemic disease that has secondarily affected the nervous system. In fact, many of the most serious neurologic problems are of this type. Two common examples will suffice: adenopathy or a lung infiltrate implicates neoplasia or sarcoidosis as the cause of multiple cranial nerve palsies, and the presence of low-grade fever, anemia, a heart murmur, and splenomegaly in a patient with unexplained stroke points to a diagnosis of bacterial endocarditis with embolic occlusion of cerebral arteries. The examination of a patient with stroke includes a determination of blood pressure, auscultation for carotid bruits, heart murmurs, and palpation of the pulse for heart rhythm.

INTEGRATION OF NEUROANATOMY, NEUROPHYSIOLOGY, MOLECULAR GENETICS, NEUROIMAGING, AND NEUROPATHOLOGY WITH THE CLINICAL METHOD Once the technique of obtaining reliable clinical data is attained, knowledge of the basic sciences of neurology is necessary to determine the cause of disease and its treatment. For this reason, each of the later chapters dealing with the motor system, sensation, special senses, consciousness, memory, and language is introduced by a review of the anatomic and physiologic facts that are necessary for understanding the associated clinical disorders. Physicians wishing to master neurology should be familiar with the anatomy of the corticospinal tract; motor unit (anterior horn cell, nerve, and muscle); basal ganglionic and cerebellar motor connections; main sensory pathways; cranial nerves; hypothalamus and pituitary; reticular formation of brain stem and thalamus; limbic system; areas of cerebral cortex and their major connections; visual, auditory, and autonomic systems; and cerebrospinal fluid pathways. A working knowledge of neurophysiology should include an understanding of neural excitability

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and nerve impulse propagation, neuromuscular transmission, and contractile process of muscle; spinal reflex activity; central neurotransmission; processes of neuronal excitation, inhibition, and release; and cortical activation and seizure production. The genetics and molecular biology of neurologic disease have assumed increasing importance in the past few decades. The practitioner should be familiar with the terminology of mendelian and mitochondrial genetics and the main aberrations in the genetic code that give rise to neurologic disease. The physician must be familiar with the imaging characteristics of the multitude of clinical diseases encountered in practice, and the risk and pitfalls of each technique, including computed tomography (CT), magnetic resonance imaging (MRI), radiographs, including those incorporating contrast agents, and ultrasound as discussed in Chap. 2. We believe the neurologist is greatly aided by knowledge of the neuropathologic changes that are produced by processes such as infarction, hemorrhage, demyelination, physical trauma, inflammation, neoplasm, and infection, to name the more common ones. Experience with the gross and microscopic appearances of these disease processes greatly enhances one’s ability to explain their clinical effects. The ability to mentally visualize the abnormalities of disease in nerve and muscle, brain and spinal cord, meninges, and blood vessels gives one a strong sense of which clinical features to expect of a particular process and which features are untenable or inconsistent with a particular diagnosis. An additional advantage of being exposed to neuropathology is, of course, that the clinician is able to intelligently evaluate pathologic changes and reports of material obtained by biopsy. For many conditions, there is a parallel representation of neuropathology through various imaging techniques. This allows the clinician to deduce the pathology from the imaging appearance and vice versa. From the foregoing description of the clinical method, it is evident that the use of laboratory aids, including imaging in the diagnosis of diseases of the nervous system, is ideally preceded by rigorous clinical examination. As in all of medicine, laboratory study can be planned intelligently only based on clinical information. To reverse this process is wasteful of medical resources and prone to the discovery of irrelevant information, and in some cases exposes a patient to unnecessary risk. In the prevention of neurologic disease, however, one resorts to two other approaches, namely, the use of genetic information and laboratory screening tests. Biochemical screening tests are applicable to an entire population and permit the identification of neurologic diseases in individuals, mainly infants and children, who have yet to show their first symptom; in some diseases, treatment can be instituted before the nervous system has suffered damage. Similarly in adults, screening for atherosclerosis and its underlying metabolic causes is profitable in certain populations as a way of preventing stroke. Genetic information enables the neurologist to arrive at the diagnosis of certain illnesses and to identify patients and relatives at risk of developing certain diseases. The laboratory methods that are available for neurologic diagnosis are discussed in Chap. 2. The relevant principles of genetic and laboratory screening methods for the

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prediction of disease are presented in the discussion of the disease to which they are applicable.

THERAPEUTICS IN NEUROLOGY There are a growing number of neurologic diseases for which specific therapy is available. Through advances in neuroscience, their number is steadily increasing. Among the most sweeping changes, now that many infectious diseases of the nervous system are being addressed, have been novel medications for stroke, multiple sclerosis, Parkinson disease, migraine, neuropathy, brain tumor, and epilepsy as summarized in a review of 200 years of neurology by Ropper. These therapies and the dosages, timing, and manner of administration of particular drugs are considered in later chapters in relation to the description of individual diseases and detailed in Samuels’s Manual of Neurologic Therapeutics, cited in the references. The neurologist should also be familiar with the proper application of surgical treatment when it is an integral part of the amelioration or cure of disease, as it is for brain tumor, degenerative and neoplastic diseases of the spine, cerebral aneurysm, extracranial arterial stenosis, and some congenital disease of the brain and spinal cord. There are, in addition, many diseases in which neurologic function can be restored to a varying degree by appropriate rehabilitation measures or by the judicious use of therapeutic agents. Randomized controlled trials play an ever-increasing role in therapeutic decisions. Claims for the effectiveness of a particular therapy based on statistical analysis of largescale clinical studies must be treated circumspectly. Was the study well conceived as reflected in a clearly stated hypothesis and outcome criteria; was there adherence to the plan for randomization and admission of cases into the study; were the statistical methods appropriate; and were the controls truly comparable? It has been our experience that the results of early stage trials must be accepted with caution and it is prudent to wait until further studies confirm the benefits that have been claimed. There are, of course, many instances in which evidence is not available or is not applicable to difficult individual therapeutic decisions. This is in part true because small albeit statistically significant effects in large groups may be of little consequence when applied to an individual patient. It goes without saying that data derived from trials must be used in the context of a patient’s overall physical and mental condition and age. Furthermore, for many neurologic conditions there is, at the moment, inadequate evidence on which to base treatment. Here, the physician makes judgments based on partial or insufficient data. Even deciding purposefully to wait before committing to an intervention displays wisdom. Even when no effective treatment is possible, neurologic diagnosis is more than an intellectual pastime. The first step in the scientific study of any disease process is the identification or all its manifestations in the living patient. In closing this introductory chapter, a comment regarding the extraordinary burden of diseases of the

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nervous system is appropriate. Conditions such as brain and spinal cord trauma, stroke, epilepsy, developmental delay, psychiatric diseases, and dementia are not just ubiquitous, but are highly disabling and often chronic in nature, altering in a fundamental way the lives of affected

individuals. Furthermore, the promise of cure or amelioration by new techniques such as molecular biology, genetic therapy, and brain–computer interfaces has excited vast interest, for which reason aspects of the current scientific insights are included in appropriate sections of the book.

References Biller J, Greuner G, Brazis P: DeMyer’s: Technique of the Neurologic Examination: A Programmed Text, 6th ed. New York, McGraw-Hill, 2011. Campbell WW: DeJong’s The Neurological Examination, 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2012. Chimowitz MI, Logigian EL, Caplan LP: The accuracy of bedside neurological diagnoses. Ann Neurol 28:78, 1990. Chin JH, Vora N: The global burden of neurologic diseases. Neurol 83:349, 2014. Donaghy M, Compston A, Rossor M, Warlow C: Clinical diagnosis. In: Brain’s Diseases of the Nervous System, 11th ed. Oxford, Oxford University Press, 2001, pp. 11–60. Global Burden of Disease Study 2010. Lancet 380:2053, 2012. Hirtz D, Thurman DJ, Gwinn-Hardy K, et al: How common are the “common” neurologic disorders? Neurol 68:326, 2007. Mayo Clinic Examinations in Neurology, 7th ed. St. Louis, MosbyYear Book, 1998.

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Redelmeier DA: Improving patient care. The cognitive psychology of missed diagnoses. Ann Intern Med 142:115, 2005. Ropper AH: Two centuries of neurology and psychiatry in the Journal. N Engl J Med 367:58, 2012. Samuels MA, Ropper AH: Samuels’s Manual of Neurologic Therapeutics, 8th ed. Philadelphia, Lippincott Williams & Wilkins, 2010. Spillane JA: Bickerstaff ’s Neurological Examination in Clinical Practice, 6th ed. Oxford, Blackwell Scientific, 1996. Tversky A, Kahneman D: Judgment under uncertainty; heuristics and biases. Science 185:1124, 1974. Vickery B, Samuels MA, Ropper AH: How neurologists think: A cognitive psychology perspective on missed diagnoses. Ann Neurol 67:425, 2010. Volpe JJ: Neurology of the Newborn, 5th ed. Philadelphia, Saunders, 2008.

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2 Diagnostic Testing in Neurologic Disease

Neurologic diagnosis is frequently determined solely on the basis of careful history and examination. In that case, ancillary testing is unnecessary or simply corroborates the clinical impression. It also happens that the diagnoses can be reduced to a few possibilities, but that testing is necessary to arrive at the correct one. The aim of the neurologist is to arrive at a diagnosis by artful integration of clinical data with laboratory procedures. Commonly, the clinician already has at his disposal some laboratory information when the patient presents for a consultation. This may orient or distract from the correct course of action. Only a few decades ago, the only laboratory tests available to the neurologist were examination of a sample of cerebrospinal fluid (CSF), radiography of the skull and spinal column, contrast myelography, pneumoencephalography, and electrophysiologic tests. The physician’s armamentarium has since been expanded to include a multitude of neuroimaging modalities, biochemical and immunologic assays, and genetic analyses. Some of these new methods give the impression of such accuracy that there is a temptation to substitute them for a detailed history and physical examination. Moreover, it is common in practice for laboratory testing to reveal abnormalities that are of no significance to the problem at hand or for imaging studies to show incidental lesions that have no bearing on the patient’s presenting symptoms. Consequently, the physician should always judge the relevance and significance of laboratory data only in the context of clinical findings. Hence, the neurologist must be familiar with all laboratory procedures relevant to neurologic disease, their reliability, and their hazards. What follows is a description of laboratory tests that have application to a diversity of neurologic diseases. Certain procedures that are pertinent to a particular category of disease—for example, audiography to study deafness; electronystagmography (ENG) in cases of vertigo; as well as nerve and muscle biopsy, where there is neuromuscular disease— are presented in the chapters devoted to these disorders.

EXAMINATION OF CEREBROSPINAL FLUID The information yielded by examination of the CSF is crucial in the diagnosis of certain neurologic diseases, particularly infectious and inflammatory conditions,

subarachnoid hemorrhage, and processes that alter intracranial pressure. Patterns of findings, or “formulas,” in the CSF generally denote particular classes of disease; these are summarized in Table 2-1. The fluid is most often obtained by lumbar puncture (LP), the technique and indications for which are described below.

Lumbar Puncture The LP is performed to obtain pressure measurements and procure a sample of the CSF for cellular, cytologic, chemical, bacteriologic, and other examinations. It is also utilized in special circumstances for the instillation of anesthetics, antibiotics, antitumor agents, or for drainage in order to reduce CSF pressure. Another diagnostic use is the injection of radiopaque substances and in myelography, or radioactive agents and in radionuclide cisternography. It is advisable to determine that the patient’s coagulation function is adequate. In general, it is safe to perform LP on patients without history or overt signs of coagulopathy and those who are not taking anticoagulant medications. An international normalized ratio (INR) less than or equal to 1.4 and platelet count greater than 50,000/mm3 are generally acceptable, as is the use of aspirin in conventional doses. Individuals with impaired platelet function from diseases such as alcoholism or uremia may have bleeding complications. For patients receiving non-vitamin K antagonists, it is appropriate, when possible to wait for the anticoagulant effect to wear off but it is more practical to use a reversal agent if time is essential. For patients receiving heparin by continuous infusion, the LP is best performed after the infusion has been discontinued for a period of time, and if possible, the partial thromboplastin time is in a safe range. There are circumstances, however, where these provisions are not practical. LP carries some risks if the CSF pressure is very high (evidenced mainly by headache and papilledema), as it increases the possibility of cerebellar or transtentorial herniation. The risk is considerable when there is an intracranial mass that distorts and displaces brain tissue, particularly asymmetric mass lesions near the tentorium or foramen magnum. The risk is much lower in patients with subarachnoid hemorrhage, in hydrocephalus with communication among all the ventricles, or with pseudotumor cerebri. Indeed, these are conditions in which repeated LPs may be therapeutic measures. In patients with purulent

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Table 2-1 CHARACTERISTIC CSF FORMULAS CONDITION

CELLS

PROTEIN 3

Bacterial infection

WBC > 50/mm , often greatly increased

100–250 mg/dL

Viral, fungal, spirochetal infection Tuberculous infection

WBC 10–100/mm3

50–200 mg/dL

WBC > 25/mm3

100–1,000 mg/dL

Subarachnoid hemorrhage

RBC > 500/mm3; slight increase in WBC

Cerebral hemorrhage, trauma Ischemic stroke Multiple sclerosis

RBC 50–200/mm3; higher if ventricular rupture of blood Normal or few WBC Normal or few WBC

Meningeal neoplasm

WBC 10–100/mm3

GLUCOSE

OTHER FEATURES

20–50 mg/dl; usually lower than half of blood glucose level Normal or slightly reduced 100,000/mm3) will the supernatant fluid be faintly xanthochromic due to contamination with serum bilirubin and lipochromes. The fluid from a traumatic tap should contain approximately one or two WBCs per 1,000 RBCs assuming that the hematocrit and peripheral WBC count are normal, but in reality, this ratio varies. With subarachnoid hemorrhage, the proportion of WBCs rises as RBCs hemolyze, sometimes reaching a level of several hundred per cubic millimeter; but the vagaries of this reaction are such that it, too, cannot be relied upon to distinguish traumatic from preexistent bleeding. The same can be said for crenation of RBCs, which occurs in both types of bleeding. Why red corpuscles undergo rapid hemolysis in the CSF is not clear. It is surely not because of osmotic differences, as the osmolarity of plasma and CSF is essentially the same. Fishman suggested that the low protein content of CSF disequilibrates the red cell membrane in some way. The pigments that discolor the CSF following subarachnoid hemorrhage are oxyhemoglobin, bilirubin, and methemoglobin (Barrows and colleagues). In pure form, these pigments are colored red (orange to orange-yellow with dilution), canary yellow, and brown, respectively. Oxyhemoglobin appears within several hours of hemorrhage, becomes maximal in approximately 36 h, and diminishes over a 7- to 9-day period. Bilirubin begins to appear in 2 to 3 days and increases in amount as the oxyhemoglobin decreases. Methemoglobin appears when blood is loculated or encysted and isolated from the flow of CSF. Spectrophotometric techniques can be used to distinguish the various hemoglobin breakdown products and thus determine the approximate time of bleeding. Not all xanthochromia of the CSF is caused by hemolysis of RBCs. With severe jaundice, both conjugated and unconjugated bilirubin diffuse into the CSF. The quantity of bilirubin in the CSF ranges from one-tenth to one-hundredth that in the serum. Elevation of CSF protein from any cause results in a faint opacity and xanthochromia. Only at protein levels greater than 150 mg/100 mL does the coloration become visible to the naked eye. Hypercarotenemia and hemoglobinemia (through hemoglobin breakdown products, particularly oxyhemoglobin) also impart a yellow tint to the CSF, as do blood clots in the subdural or epidural space of the cranium or spinal column. Myoglobin does not appear in the CSF because a low renal threshold for this pigment permits rapid clearing from the blood.

Cellularity During the first month of life, the CSF contains a larger number of mononuclear cells than in adults. Beyond this period, the CSF is normally nearly acellular (i.e., fewer than 5 lymphocytes or other mononuclear cells per cubic millimeter). An elevation of WBCs in the CSF signifies a reactive process, either to infectious agents, blood, chemical substances, an immunologic inflammation, a neoplasm, or vasculitis. The WBCs can be counted in an ordinary counting chamber, but their identification requires centrifugation of the fluid and staining of the sediment. Identification of malignant cells by the cytology

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laboratory is usually done by cytocentrifugation or other semiautomated liquid-based method, followed by cell fixation and staining. One can recognize and differentially count neutrophilic and eosinophilic leukocytes (the latter being prominent in some parasitic infections, neurosyphilis, and cholesterol emboli), lymphocytes, plasma cells, mononuclear cells, macrophages, and tumor cells. Bacteria and fungi can be seen in routinely stained preparations. An India ink preparation helps to distinguish between lymphocytes and Cryptococcus organisms. Acidfast bacilli will be found in appropriately stained samples. The monograph by Ali and Cibas is an excellent reference on CSF cytology. Flow cytometry permits the distinction between polyclonal and monoclonal proliferations, thus aiding in the detection of leukemia and lymphoma, and immunostaining techniques help identify metastatic solid tumors. These and other methods for the examination of cells in the CSF are discussed in the appropriate chapters.

Proteins In contrast to the high-protein content of blood (5,500 to 8,000 mg/dL), that of the lumbar spinal fluid is 45 to 50 mg/dL or less in the adult. The protein content of CSF from the basal cisterns is 10 to 25 mg/dL and that from the ventricles is 5 to 15 mg/dL. Based on work by Fishman and colleagues, this gradient may reflect the fact that CSF proteins leak to a greater degree at the lumbar roots than at higher levels of the neuraxis. An alternative explanation derives from the manner in which the spinal fluid is an ultrafiltrate of blood made by the choroid plexus in the lateral and the fourth ventricles, analogous to the formation of urine by the glomerulus. The amount of protein in the CSF would then be proportional to the length of time the fluid is in contact with the blood–CSF barrier. Thus, shortly after it is formed in the ventricles, the protein is low. More caudally in the basal cisterns, the protein is higher and in the lumbar subarachnoid space it is highest of all. In children, the protein concentration is somewhat lower at each level (49 >49 >50 >42 >42 >41

6–8 5.5–7.5 10 6–11 10 6–8

15 degrees) are considered abnormal, even at birth. Most children with developmental esotropic strabismus present between ages 2 and 3 years, whereas those with exotropia show the condition in a broader range of preschool years. Esodeviations are initially intermittent and then become persistent; exodeviations are commonly intermittent. In both cases, eye movements are full and the child initially alternates fixation. One type of esotropia, called accommodative esotropia, is an acquired problem in children that relates to hypermetropia (farsightedness) with compensatory engagement of the near response that drives the eyes to cross. Refractive correction for the hypermetropia within 6 months of the onset of the strabismus restores vision and usually leads to realignment of the eyes. Large degrees of esotropia that are not the result of hypermetropia are best treated by eye muscle surgery to realign the eyes. In contrast, persistent exotropic strabismus in a child can be associated with a developmental delay (as detailed in Chap. 37) or with ocular pathology. It does, however, frequently occur in neurologically normal children. If mild, intermittent exotropia is initially treated by one of a number of nonsurgical means such as patching and visual exercises to stimulate convergence; surgical correction is reserved for unresponsive cases (Donahue).

Table 13-2 ACTIONS OF THE EXTRAOCULAR MUSCLES MUSCLE

Medial rectus Lateral rectus Superior rectus Inferior rectus Superior oblique Inferior oblique

PRIMARY ACTION

Adduction Abduction Elevation Depression Intorsion Extorsion

SECONDARY ACTION

— — Intorsion Extorsion Depression Elevation

OCULOMOTOR NERVE

III VI III III IV III

(See also Fig. 13-5.)

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Once binocular fusion is established, usually by 6 months of age, any type of ocular muscle imbalance will cause diplopia, as images then fall on disparate or noncorresponding parts of the two functionally active retinas. During the critical period for visual development, particularly the first 2 years of life, a child can eliminate diplopia by suppressing the image from one eye. After a variable period, the suppression becomes permanent, and the individual has permanently reduced visual acuity in that eye because its representation in the visual cortex is diminished (amblyopia ex anopsia, as described in Chap. 12). Nonparalytic strabismus may create misleading ocular findings in the neurologic examination. Sometimes a slight phoric misalignment of the eyes is first noticed after a head injury or a febrile infection, or it may be exposed by any other neurologic disorder or drug intoxication that impairs fusional mechanisms (vergence).

Clinical Effects of Lesions of the Third, Fourth, and Sixth Nerves Third (Oculomotor) Nerve A complete third nerve palsy may include significant ptosis, as the levator palpebrae is the major muscle that elevates the eyelid, accompanied by an inability to rotate the eye upward, downward, or inward that corresponds to the weakness of the medial, superior, and inferior recti and the inferior oblique muscles. The remaining actions of the fourth and sixth nerves give rise to a position of the eye described by the mnemonic “down and out,” meaning in the infraducted and abducted position. The patient experiences diplopia in which the image from the affected eye is projected upward and medially. In addition, one finds a dilated, nonreactive pupil (iridoplegia) and paralysis of accommodation (cycloplegia) because of interruption of the parasympathetic fibers in the third nerve. Of note, the extrinsic and intrinsic (pupillary) eye muscles may be affected separately in certain diseases. For example, a lesion affecting the central portion of the oculomotor nerve, as occurs in diabetic ophthalmoplegia, typically spares the pupil, as the parasympathetic preganglionic pupilloconstrictor fibers lie near the surface (Kerr). Very little pathological material exists to study the precise lesion that is responsible for a microvasculopathic cranial nerve palsy, but an instance in which a patient diagnosed with third nerve palsy then soon died of other causes allowed the rare opportunity to study the issue carefully. Asbury and colleagues studied over 10,000 serial sections of the third nerve in this case, and in its segment in the cavernous sinus found a region of myelin pallor which they attributed to focal ischemia in a borderzone of the vaso nervorum vascular supply (Asbury). Conversely, compressive lesions of the nerve usually dilate the pupil as an early manifestation. After injury, regeneration of the third nerve fibers may be aberrant, in which case some of the fibers that originally moved the eye in a particular direction now reach another muscle or the iris; in the latter instance the pupil, which is unreactive to light, may constrict when the eye is turned up and in.

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273

Fourth (Trochlear) Nerve A lesion of the fourth nerve, which innervates the superior oblique muscle, is the most common cause of isolated symptomatic vertical diplopia (Keane; Palla and Straumann). Paralysis of the superior oblique muscle results in weakness of downward movement of the affected eye in the adducted position (Fig. 13-7E), so that the patient complains of special difficulty in reading or going downstairs. Examination of the eye movements may disclose subtle upward deviation that occurs on attempted adduction of the eye with horizontal gaze. Double vision from an isolated fourth neve palsy is made worse with ipsilateral head tilt. Compensatory head tilting to the opposite shoulder (Bielschowsky sign) is thus characteristic of fourth-nerve lesions; this maneuver causes intorsion of the unaffected eye and ameliorates the double vision. Lesions affecting the trochlear nucleus (rather than the nerve itself ) will cause paresis of the contralateral superior oblique muscle; here, the patient will tilt their head toward the side of the lesion to ameliorate the diplopia. Bilateral trochlear palsies, as may occur after head trauma, give a characteristic alternating hyperdeviation depending on the direction of gaze (unilateral traumatic trochlear paresis is still the more common finding with head injury). In the presence of a third nerve palsy, one can assess the function of the fourth nerve by evaluating whether the eye intorts on attempted down gaze.

Sixth (Abducens) Nerve Lesions of the sixth nerve result in a paralysis of the abducens muscle and a resultant weakness of lateral or outward movement leading to a crossing of the visual axes. The affected eye deviates medially, that is, in the direction of the opposing muscle. Diplopia is experienced as horizontal separation that is greatest when viewing in the direction of the sixth nerve palsy and in the distance (Fig 13-7A). With incomplete sixth nerve palsies, turning the head toward the side of the paretic muscle overcomes the diplopia. Many causes of combined ocular motor palsies, which are discussed in a later section, are listed in Table 13-3 and are illustrated in Fig. 13-7 and in the following text.

The Analysis of Diplopia The signs of the oculomotor palsies, as described previously, can manifest in various degrees of completeness. With complete palsies, the affected muscle can often be surmised from the resting dysconjugate positions of the globes. With incomplete paresis, having the patient perform common versional movements will usually disclose the faulty muscle(s) as the eyes are turned into the field of action of the paretic muscle. The muscle weakness may be so slight, however, that no strabismus or defect in ocular movement is obvious, yet the patient experiences diplopia. It is then necessary to use the patient’s report of the relative positions of the images of the two eyes or use methods that assess the pattern of ocular misalignment to determine the localization of the problem. It is frequently the case that patients with significant ocular misalignment from do not report diplopia, ostensibly because the false image

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becomes easier to perceptually ignore when the visual axes are widely separated. Two rules are applied to identify the affected ocular muscle in the analysis of diplopia:

Left gaze

Right gaze

Upward gaze

Downward gaze Rt. lat. rectus

Rt. med. rectus

A

B

Rt. inf. rectus

Rt. sup. rectus

C

D

Rt. sup. obl.

Rt. inf. obl.

E

F

Figure 13-7.  Diplopia fields with individual muscle paralysis. The red Maddox rod is in front of the right eye and gives rise to the straight line image, and the fields are projected as the patient sees the images. A. Paralysis of right lateral rectus. The vertical red line is displaced to the right and the separation of images increases on looking to the right. B. Paralysis of right medial rectus. Horizontal crossed diplopia increasing on looking to the left. C. Paralysis of right inferior rectus. Right eye does not move downward when eyes are turned to the right. Vertical diplopia (with the red line displaced inferiorly) increasing on looking to the right and down. D. Paralysis of right superior rectus. Right eye does not move upward when eyes are turned to the right. Vertical diplopia (with red line displaced superiorly) increasing on looking to the right and up. E. Paralysis of right superior oblique. Right eye does not move downward when eyes are turned to the left. Vertical diplopia (with red line displaced inferiorly) increasing on looking to the left and down. F. Paralysis of right inferior oblique. Right eye does not move upward when eyes are turned to the left. Vertical diplopia (with red line displaced superiorly) increasing on looking to the left and up.

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1. The direction in which the images are maximally separated indicates the action of the muscles at fault. For example, if the greatest horizontal separation is in looking to the right, either the right abductor (lateral rectus) or the left adductor (medial rectus) muscle is weak; conversely, if maximal when gazing to the left, the left lateral rectus or the right medial rectus are implicated (see Fig. 13-6A and B). As a corollary, if the separation is mainly horizontal, the paresis will be found in one of the horizontally acting recti (a small vertical disparity should be disregarded); if the separation is mainly vertical, the paresis will be found in the vertically acting muscles, and a small horizontal deviation should be disregarded. 2. The image projected farther from the center is attributable to the eye with the paretic muscle. The following maneuver for the analysis of diplopia allows this determination to be made simply. The patient is asked to follow an object or light into the six cardinal positions of gaze. When the position of maximal separation of images is identified, one eye is covered and the patient is asked to identify which image disappears. The red-glass test is an enhancement of this technique. A red glass is placed in front of the patient’s right eye (the choice of the right eye is arbitrary, but if the test is always done in the same way, interpretation is simplified). The patient is then asked to look at a flashlight (held at a distance of 1 m), to turn the eyes sequentially to the six cardinal points in the visual fields, and to indicate the positions of the red and white images and the relative distances between them. The positions of the two images are plotted as the patient indicates them to the examiner (i.e., from the patient’s perspective; Fig. 13-7). This allows the identification of both the field of maximal separation and the eye responsible for the eccentric image. If the white image on right lateral gaze is to the right of the red (i.e., the image from the left eye is projected outward), then the left medial rectus muscle is weak. If the maximum vertical separation of images occurs on looking downward and to the left and the white image is projected farther down than the red, the paretic muscle is the left inferior rectus; if the red image (from the right eye) is lower than the white, the paretic muscle is the right superior oblique. As already mentioned, correction of vertical diplopia by a tilting of the head implicates the superior oblique muscle of the opposite side (or the ipsilateral trochlear nucleus). Separation of images on looking up and to the right or left will similarly distinguish paresis of the inferior oblique and superior rectus muscles. Most patients are attentive enough to open and close each eye and determine the source of the image thrown most outward in the field of maximal separation. There are several alternative methods for studying the relative positions of the images of the two eyes (Leigh and Zee; Glaser). One, refinement of the red-glass test, is the Maddox rod, in which the occluder consists of

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275

Table 13-3 MAIN CAUSES OF INDIVIDUAL AND COMBINED OCULOMOTOR PALSIES Lesions of the Third (Oculomotor) Nerve Nuclear and intramedullary (fascicular)   Infarction (midbrain stroke)  Demyelination  Tumor  Trauma   Wernicke disease Radicular (subarachnoid space and tentorial edge)   Aneurysm (posterior communicating or basilar)   Meningitis (infectious, neoplastic, granulomatous)   Diabetic infarction  Tumor Raised intracranial pressure (shift and herniation of medial temporal lobe, hydrocephalus, pseudotumor cerebri) Cavernous sinus and superior orbital fissure   Diabetic infarction of nerve   Aneurysm of internal carotid artery   Carotid-cavernous fistula   Cavernous thrombosis (septic and bland) Tumor (pituitary, meningioma, nasopharyngeal carcinoma, metastasis)   Pituitary apoplexy   Sphenoid sinusitis and mucocele   Herpes zoster   Tolosa-Hunt syndrome Orbit  Trauma   Fungal infection (mucormycosis, etc.)   Tumor and granuloma   Orbital pseudotumor Uncertain localization  Migraine   Postinfectious cranial mono- and polyneuropathy Lesions of the Fourth (Trochlear) Nerve Nuclear and intramedullary (fascicular)   Midbrain hemorrhage and infarction  Tumor   Arteriovenous malformation  Demyelination Radicular (subarachnoid space)  Traumatic   Tumor (pineal, meningioma, metastasis, etc.)  Hydrocephalus

Pseudotumor cerebri and other causes of increased intracranial pressure Meningitis (infectious, neoplastic, granulomatous) Cavernous sinus and superior orbital fissure  Tumor   Tolosa-Hunt syndrome   Internal carotid aneurysm   Herpes zoster   Diabetic infarction Orbit  Trauma   Tumor and granuloma Lesions of the Sixth (Abducens) Nerve Nuclear (characterized by gaze palsy) and intramedullary (fascicular)   Möbius syndrome   Wernicke syndrome   Infarction (pontine stroke)  Demyelination  Tumor  Lupus Radicular (subarachnoid)  Aneurysm  Trauma  Meningitis   Tumor (clivus, fifth- and eighth-nerve schwannoma, meningioma) Petrous   Infection of mastoid and petrous bone   Thrombosis of inferior petrosal vein  Trauma Cavernous sinus and superior orbital fissure   Carotid aneurysm   Cavernous sinus thrombosis   Tumor (pituitary, nasopharyngeal, meningioma)   Tolosa-Hunt syndrome   Diabetic or arteritic infarction   Herpes zoster Orbit   Tumor and granulomas Uncertain localization  Migraine   Viral and postviral   Transient in newborns

a transparent red lens with series of parallel cylindrical bars that transform a point source of light into a red line perpendicular to the cylinder axes. The position of the red line is easily compared by the patient with the position of a white point source of light seen with the other eye. Another technique, the alternate cover test, requires less cooperation than the red-glass test and is, therefore, a passive maneuver that is more useful in the examination of children and inattentive patients. It does, however, require sufficient visual function to permit central fixation with each eye. The test consists of rapidly alternating an occluder or the examiner’s hand from one eye to another and observing the deviations from and return to the point of fixation, as described earlier in the discussion of tropias and phorias. Measuring the prismatic correction needed to neutralize the ocular misalignment in each field of gaze with a prism bar allows the quantification of deviation and provides a method to follow diplopia

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over time. The more sophisticated Lancaster test uses red/green glasses and a red and green bar of laser light projected on a screen to accomplish essentially the same result but has the advantage of reflecting the actual position and torsion of each eye. In all these tests, the examiner is aided by knowledge of the cardinal actions of the ocular muscles shown in Fig. 13-6 and Table 13-2. Monocular diplopia occurs most commonly in relation to diseases of the cornea and lens and occasionally the retina; usually the images are overlapping or superimposed rather than discrete. In some cases, no abnormality can be found and the symptom has a nonorganic basis. Monocular diplopia has been reported in association with cerebral disease (Safran et al), but this is a rare occurrence. Occasionally, patients with homonymous scotomas caused by a lesion of the occipital lobe will see multiple images (polyopia) in the defective field of vision, particularly when the target is moving.

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Causes of Individual Third, Fourth, and Sixth Nerve Palsies (Table 13-3) Ocular palsies may have a central cause—that is, a lesion of the nucleus or the intramedullary (fascicular) portion of the cranial nerve—but more often they are peripheral. Weakness of ocular muscles because of a lesion in the brainstem is usually accompanied by involvement of other cranial nerves and by signs referable to the “crossed” brainstem syndromes of a cranial nerve palsy on one side and weakness or other deficits on the opposite side (see Table 33-3 and Chap. 44). Peripheral lesions, which may or may not be solitary, have a great variety of causes. In the series reported by Rucker (1958, 1966), who analyzed 2,000 cases of oculomotor nerve palsies, the most common sources of individual ocular motor palsies were tumors at the base of the brain or skull (primary, metastatic, meningeal carcinomatosis), head trauma, ischemic infarction of a nerve (generally associated with diabetes), and aneurysms of the circle of Willis, in that order. The sixth nerve was affected in about half of the cases; third-nerve palsies were about half as common; and the fourth nerve was involved in less than 10 percent of cases. In 1,000 unselected cases (Rush and Younge), trauma was a more frequent cause than neoplasm and the frequency of aneurysm-related cases was fewer. Lesscommon causes of paralysis of the oculomotor nerves include variants of Guillain Barré syndrome, herpes zoster, giant cell arteritis, carcinomatous or lymphomatous meningitis, sarcoidosis and Tolosa-Hunt syndrome, as well as fungal, tuberculous, syphilitic, and other forms of meningitis. Ophthalmoplegic migraine is a relatively rare entity characterized by recurrent episodes of headache with cranial nerve palsy that resolves in the span of weeks to months. Diagnostic evaluations in these patients are generally unremarkable, but detailed imaging may disclose in some patients a small expansion or enhancement of the cranial nerve. The exact pathophysiologic mechanisms of this condition remain obscure. This entity is diagnosed in children after several similar episodes occur. Some of those individuals may continue to have episodes in adulthood, but the entity of ophthalmoplegic migraine should generally not be diagnosed for presentations beginning in adulthood, where other diagnoses must be strongly considered. Myasthenia gravis, discussed in Chap. 46, must always be considered in cases of ocular muscle palsy, particularly if several muscles are involved and if fluctuating ptosis is a prominent feature. Thyroid ophthalmopathy, discussed further on, presents in a similar fashion but usually with proptosis and eyelid retraction.

Third Nerve Palsy The third nerve is commonly compressed by aneurysm, tumor, or temporal lobe herniation. In a series of 206 cases of third-nerve palsy (Wray and Taylor), neoplastic diseases accounted for 25 percent and aneurysms for 18 percent. Of the neoplasms, 25 percent were parasellar meningiomas and 4 percent were pituitary adenomas. The palsy is

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usually chronic, progressive, and painless. As emphasized earlier, enlargement of the pupil is a sign of extramedullary third nerve compression because of the peripheral location in the nerve of the pupilloconstrictor fibers. By contrast, infarction of the nerve in diabetics usually spares the pupil, as the damage is situated in the central portion of the nerve. The oculomotor palsy that complicates diabetes (the cause in 11 percent in the Wray and Taylor series) develops over a few hours and is accompanied by pain, which may be severe, in the forehead and around the eye. The prognosis for recovery (as in other nonprogressive lesions of the oculomotor nerves) is usually good. In chronic compressive lesions of the third nerve (distal carotid, basilar, or, most commonly, posterior communicating artery aneurysm; pituitary tumor, meningioma, cholesteatoma) the pupil is almost always affected by way of dilatation or reduced light response. However, the chronicity of the lesion may permit aberrant nerve regeneration. This is manifest by pupillary constriction on adduction of the eye or by retraction of the upper lid on downward gaze or adduction. Rarely, children or young adults have recurrent attacks of ocular palsy in conjunction with an otherwise typical migraine (ophthalmoplegic migraine). The muscles (both extrinsic and intrinsic) innervated by the oculomotor, or less commonly, by the abducens nerve, are affected. Possibly, spasm of the vessels supplying these nerves or compression by edematous arteries causes a transitory ischemic paralysis but these are speculations. Arteriograms done after the onset of the palsy usually disclose no abnormality. Although the oculomotor palsy of migraine tends to recover, after repeated attacks there may be permanent partial paresis.

Fourth Nerve Palsy A fair number of cases of fourth nerve palsies remain idiopathic even after careful investigation. The fourth nerve is particularly vulnerable to head trauma. The reason for this vulnerability has been speculated to be the long, crossed course of the nerves. The fourth and sixth nerves are practically never involved by aneurysm. Herpes zoster ophthalmicus may affect any of the ocular motor nerves but particularly the trochlear, which shares a common sheath with the ophthalmic division of the trigeminal nerve. Diabetic infarction of the fourth nerve occurs, but far less frequently than infarction of the third or sixth nerves. Trochlear-nerve palsy may also be a false localizing sign in cases of increased intracranial pressure, but again, not nearly as often as abducens palsy. Trochlearnerve palsies have been described in patients with lupus erythematosus and with Sjögren syndrome, but their basic pathology is not known. Some cases of fourth-nerve palsy are idiopathic. Superior oblique myokymia is an unusual but easily identifiable movement disorder, characterized by recurrent episodes of vertical diplopia, monocular blurring of vision with oscillopsia, and a tremulous sensation in the affected eye; in this way it simulates a palsy. If the episodes occur during the examination, the globe is observed to make small arrhythmic torsional movements. Compression of the fourth nerve by a small

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looped branch of the basilar artery has been suggested as the cause, analogous to several other better documented vascular compression syndromes affecting cranial nerves. This notion is supported by findings on MRI (Yousry). Rare instances presage pontine glioma or demyelinating disease. The condition can be responsive to topical beta-blockers commonly used to treat glaucoma, or oral anticonvulsant medications such as carbamazepine or gabapentin.

Sixth Nerve Palsy Microvascular disease is a common cause of sixth nerve palsy in diabetics, in which case there is usually pain near the lateral canthus of the eye at the onset. An idiopathic form that occurs in the absence of diabetes is also well known. Isolated unilateral or bilateral sixth nerve palsy with global headache can be the initial manifestation of raised intracranial pressure from any source—including brain tumor, meningitis, and pseudotumor cerebri; rarely, it may appear after lumbar puncture, epidural injections, or insertion of a ventricular shunt. As the abducens nerve passes near the apex of the petrous bone it is in close relation to the trigeminal nerve. Both may be implicated by inflammatory or infectious lesions of the petrous (apex petrositis), manifest by facial pain and diplopia (Gradenigo syndrome). Among the causes of this syndrome is osteomyelitis of the petrous bone. Fractures at the base of the skull and petroclival tumors may have a similar effect, and sometimes head injury alone is the only assignable cause. Occasionally, the sixth nerve is compressed by a congenitally persistent trigeminal artery. A congenital form of bilateral abducens palsy is associated with bilateral facial paralysis (Möbius syndrome) as discussed in Chap. 37. Patients with the Duane retraction syndrome type 1 (abnormal formation of the sixth nerve) have limited abduction, and on adduction show characteristic retraction of the globe because of co-contraction of the medial rectus and lateral rectus muscles.

Cavernous Sinus Syndrome, Tolosa-Hunt syndrome, and Orbital Pseudotumor Some of the diseases discussed previously are associated with a degree of pain, often over the site of an affected nerve or muscle or in the immediately surrounding area. But the development over days or longer of a painful unilateral ophthalmoplegia should raise suspicion for other conditions such as aneurysm, tumor, or inflammatory and granulomatous process in the anterior portion of the cavernous sinus or the adjacent superior orbital fissure (Table 13-4). In the cavernous sinus syndrome, involvement of the ocular motor nerves on one or both sides is accompanied by periorbital pain and chemosis (see Fig. 13-5B). In a series of 151 such cases, the third nerve (typically with pupillary abnormalities) and sixth nerve were affected in almost all and the fourth nerve in one-third; complete ophthalmoplegia, usually unilateral, was present in 28 percent (Keane). Sensory loss in the distribution of the ophthalmic division of the trigeminal nerve was often present, a finding that is helpful in the differentiation of cavernous sinus

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Table 13-4 CAUSES OF PAINFUL OPHTHALMOPLEGIA Vascular   Intracavernous carotid artery aneurysm   Posterior communicating or posterior cerebral artery aneurysm   Cavernous sinus thrombosis (septic and aseptic)   Carotid-cavernous fistula   Diabetic oculomotor mononeuropathy   Temporal arteritis   Ophthalmoplegic migraine Neoplastic   Pituitary adenoma   Pituitary apoplexy   Pericavernous meningioma   Metastatic nodules to dura of cavernous sinus   Giant-cell tumor of orbital bone   Nasopharyngeal tumor invading cavernous sinus or orbit Inflammatory and infectious   Tolosa-Hunt syndrome   Orbital pseudotumor  Sinusitis  Mucocele   Herpes zoster  Mucormycosis  Sarcoidosis

disease from other causes of orbital edema and ocular muscle weakness. Trauma and neoplastic invasion are the most frequent causes of the cavernous sinus syndrome. Thrombophlebitis, intracavernous carotid aneurysm or fistula, fungal infection, meningioma, and pituitary tumor or hemorrhage account for a smaller proportion (see “Septic Cavernous Sinus Thrombophlebitis” and “Cavernous Sinus Thrombosis” in Chap. 33). A dural arteriovenous fistula is another rare cause. The idiopathic granulomatous painful condition of the cavernous sinus has been termed Tolosa-Hunt syndrome; a similar process affecting structures of the orbit is known as orbital pseudotumor. Orbital pseudotumor causes an inflammatory enlargement of the extraocular muscles, which often also encompasses the globe and other orbital contents (Fig. 13-8). It is often accompanied by injection of the conjunctiva and lid and slight proptosis. One or more muscles may be involved and there is a tendency to relapse and later to involve the opposite globe. Visual loss from compression of the optic nerve is a rare complication. Associations with connective tissue disease have been reported and IgG4-related sclerosis has increasingly been identified as a cause. Ultrasonography examination or CT scans of the orbit show enlargement of the orbital muscles including the tendons, as opposed to thyroid ophthalmopathy in which the muscles are enlarged but the muscle tendons are typically spared. The inflammatory changes of Tolosa-Hunt syndrome are limited to the superior orbital fissure and can sometimes be detected by MRI; coronal views taken after gadolinium infusion show the lesion to best advantage. However, sarcoidosis, lymphomatous infiltration, and a small meningioma may produce similar radiographic findings and granulomatous (temporal) arteritis rarely causes ophthalmoplegia.

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Table 13-5 CAUSES OF COMPLETE OPHTHALMOPLEGIA

Figure 13-8.  MRI of orbital pseudotumor showing bilateral swelling of the extraocular muscles and adjacent orbital contents. A “streaming” appearance of the fat as shown in the right retro-orbital compartment is characteristic. The process in this patient responded to corticosteroids.

Treatment Both orbital pseudotumor and Tolosa-Hunt syndrome are treated with corticosteroids. A marked response with reduction in pain and improved ophthalmoplegia in 1 or 2 days is typical; however, (Kline and Hoyt) tumors of the parasellar region that cause ophthalmoplegia may also respond, albeit not to the same extent. In both diseases, we have generally given prednisone 60 mg and tapered the medication slowly; although there are no data to guide the proper treatment, corticosteroids should be continued for several weeks or longer. The absence of a response to steroids should cause reconsideration of the diagnosis of Tolosa-Hunt syndrome. In cases with relapsing disease on attempted withdrawal of corticosteroids, initiation of additional steroid-sparing immunosuppressive medications can be an effective strategy.

Acute Ophthalmoplegia (Table 13-5) Total or nearly complete loss of eye movements of both eyes that evolves within a few days raises a limited number of diagnostic possibilities. An analysis of 60 such cases, found the responsible lesion to lie within the brainstem in 18 (usually infarction and less often Wernicke disease), in the cranial nerves in 26 (Guillain-Barré syndrome or tuberculous meningitis), within the cavernous sinus in 8 (tumors or infection), and at the neuromuscular junction in 8 (myasthenia gravis and botulism) (Keane). Our experience has tended toward the Miller Fisher variant of Guillain-Barré syndrome, as did a later series (Keane 1986, 2007), and myasthenia. The ophthalmoplegic form of Guillain-Barré syndrome is frequently associated with circulating antibodies to GQ1b ganglioside (see Chap. 44). There may be an accompanying paralysis of the dilator and constrictor of the pupil (“internal ophthalmoplegia”) that is not seen in myasthenia.

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Brainstem lesions   Wernicke disease*   Pontine infarction*   Infiltrating glioma   Acute disseminated encephalomyelitis and multiple sclerosis Cranial nerve lesions   Guillain-Barré syndrome*   Neoplastic meningitis   Granulomatous meningitis (tuberculous, sarcoid)   Cavernous sinus thrombosis   Tolosa-Hunt syndrome   Orbital pseudotumor* Neuromuscular junction syndromes   Myasthenia gravis*   Thyroid ophthalmopathy   Lambert-Eaton syndrome  Botulism*   Congenital myasthenic syndromes (“slow-channel” disease) Muscle disease Progressive external ophthalmoplegia (mitochondrial and dystrophic types)   Oculopharyngeal dystrophy Congenital polymyopathies (myotubular, nemaline rod, central core) *Acute syndromes are noted by an asterisk.

Unilateral complete ophthalmoplegia has an even more limited list of causes, largely related to local disease in the orbit and cavernous sinus, mainly infectious, neoplastic, or thrombotic.

Chronic and Progressive Bilateral Ophthalmoplegia This is most often caused by the mitochondrial myopathy known as progressive external ophthalmoplegia (“external” refers to the extra-ocular muscles, in contrast to the internal ocular muscles that mediate pupillary constriction and accommodation of the lens). The mitochondrial defect may show a mendelian (autosomal) inheritance pattern, as occurs with POLG1 and twinkle gene mutations in nuclear DNA, or may be the result of a mutation in mitochondrial DNA and show maternal inheritance only (see Chap. 45). Other causes include myasthenia gravis or Lambert-Eaton syndrome. The congenital myopathies are typically named for the morphologic characteristic of the affected limb musculature, and may include the central core, myotubular, and nemaline types. Another cause is the slow channel congenital myasthenic syndrome (see Chap. 46). Among the degenerative conditions, progressive supranuclear palsy may ultimately produce complete ophthalmoplegia, after first affecting vertical gaze. Thyroid ophthalmopathy as a cause of chronic ophthalmoparesis is discussed below.

Mechanical-Restrictive Ophthalmoparesis Including Thyroid Ophthalmopathy Several causes of pseudoparalysis of ocular muscles that are due to mechanical restriction of the ocular muscles are distinguished from the neuromuscular and brainstem diseases discussed previously. The mechanical restriction of motion can be confirmed by forced duction tests, in which

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the eye is physically pulled or pushed using forceps or a cotton swab applied to the sclera after anesthetizing the eye. Processes that infiltrate the orbit, such as lymphoma, carcinoma, and granulomatosis may limit the range of motion of individual or all the ocular muscles. In thyroid orbitopathy (also referred to as thyroid eye disease), a swollen and tight inferior or superior rectus muscle may limit upward and downward gaze, and involvement of the medial rectus limits abduction. The inferior rectus is involved in approximately 60 percent of cases, the medical rectus in 50 percent, and the superior rectus in 40 percent (Wiersinga). In most instances of thyroid ophthalmopathy, the diagnosis is suggested by associated proptosis, but in the absence of the latter sign, and particularly if the ocular muscles are affected on one side predominantly, there may be difficulty. The extraocular muscle enlargement can be demonstrated by CT scans and ultrasonography. In up to 20 percent of cases, the patient may be euthyroid or hypothyroid (Bahn). Teprotumumab, a monoclonal antibody against the insulin-like growth factor 1 receptor (which has been shown to be overexpressed by orbital fibroblasts in thyroid eye disease), has emerged as an effective treatment strategy to reduce proptosis and diplopia (Smith et al, 2017). This disorder is discussed further in Chap. 45.

Mixed Conjugate Gaze and Ocular Muscle Paralysis We have already considered two types of neural paralysis of the extraocular muscles: paralysis of conjugate movements (gaze) and paralysis of individual ocular muscles. Here we discuss a third, more complex one—namely, mixed gaze and ocular muscle paralysis. The mixed type is a sign of an intrapontine or mesencephalic lesion that may have a variety of causes.

Internuclear Ophthalmoplegia and Other Pontine Gaze Palsies With a complete lesion of the left MLF, the left ipsilateral eye fails to adduct when the patient looks to the right; this condition is referred to as left internuclear ophthalmoplegia (INO; Fig. 13-1). Reciprocally, with a lesion of the right MLF, the right eye fails to adduct when the patient looks to the left and the patient has a right INO. Quite often, rather than a complete paralysis of adduction, there are only slowed adducting saccades in the affected eye while the other eye quickly arrives at its fully abducted position. This slowing is best observed by having the patient make quick, large amplitude side-to-side refixation movements between two targets. Because the two medial longitudinal fasciculi lie close together adjacent to the midline, they are frequently affected together, yielding a bilateral INO. A second component of INO is nystagmus that is limited to, or most prominent in, the opposite (abducting) eye. The intensity of nystagmus varies greatly from case to case. Several explanations have been offered to account for this dissociated nystagmus. The favored one invokes Hering’s law in which activated pairs of yoked muscles receive equal and simultaneous innervation; because of

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an adaptive increase in innervation of the weak adductor, there is a commensurate increase in innervation to the strong abductor. A mismatch in the generated pulse and step signals results in dissociated nystagmus manifesting in that eye. Zee and colleagues evaluated this concept by assessing whether short-term patching of one eye altered the central adaptive response and therefore modulated the extent of abducting nystagmus in patients with INO. In several cases, they found that patching the affected eye for several days caused the abducting nystagmus in the fellow eye to diminish. Conversely, patching the unaffected eye lead to increased abducting nystagmus in the fellow eye. The MLF also contains axons that originate in the vestibular nuclei and govern vertical eye position, for which reason an INO is also often accompanied by a skew deviation (supranuclear vertical misalignment of the eyes). Vertical nystagmus and impaired vertical pursuit are other common features, especially with bilateral INO. When the MLF is affected by a lesion in the pons, convergence is spared and the alignment of the eyes in primary gaze is normal. In some cases, both eyes take an abducted position, giving rise to the “wall-eyed bilateral INO,” or WEBINO syndrome. Lesions involving the MLF in the high midbrain impair convergence and also cause exotropia because of proximity to the medial rectus subnucleus. Abducting nystagmus tends to be slight in this mesencephalic type. Cogan categorized INO based on the ability of the patient to perform convergence. He referred to a posterior INO when convergence was spared, implying that the lesion was caudal and the medial rectus subdivision of the oculomotor nuclear complex was preserved. He referred to an anterior INO when convergence was impaired, although this finding does not always require a rostral lesion that includes the medial rectus subnucleus; some patients with INO may have difficulty voluntarily initiating convergence on a near target, particularly when there is an associated skew deviation causing vertical diplopia as well. In contrast, the term “posterior INO of Lutz” refers to the rare presentation of abduction (not adduction) paresis for pursuit and saccades that can be overcome by vestibular stimulation, as described by Lutz in 1923. The responsible lesion is proposed to be between the PPRF and the sixth nerve nucleus. Etiology  The main cause of unilateral INO is a small paramedian pontine infarction or a demyelinating plaque of multiple sclerosis (which also commonly causes bilateral INO, as noted below) (Keane, 2005). Other lesions to be considered, which may account for about one-quarter of cases in total, are trauma, infiltrative tumors, infections, or other lesions of the brainstem and fourth ventricular region. Occasionally, an INO occurs with subdural hematoma or hydrocephalus. In addition, adductor weakness from myasthenia gravis can simulate an INO, even to the point of showing nystagmus in the abducting eye. Bilateral INO is most often the result of a demyelinating lesion (multiple sclerosis) in the posterior part of the midpontine tegmentum. Pontine myelinolysis, pontine infarction from basilar artery occlusion, Wernicke disease,

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or infiltrating tumors are other causes. Brainstem damage following compression by a large cerebral mass has on occasion produced the syndrome. An ipsilateral gaze palsy is the simplest oculomotor disturbance that results from a lesion in the paramedian tegmentum. More complex is the one-and-a-half syndrome that involves the pontine center for gaze plus the adjacent ipsilateral MLF on one side, combining a horizontal gaze palsy and INO on the same side. It is usually the result of a vascular or, less often, demyelinating lesion. The gaze palsy is, of course, on the side of the lesion and the eyes are deviated in the opposite direction. As a result, one eye lies fixed in the midline for all horizontal movements; the other eye makes only abducting movements and may demonstrate horizontal abducting nystagmus (see Fisher; also Wall and Wray). Unlike the situation of an INO alone, the mobile eye rests abducted because of the gaze palsy, a sign that has been termed “paralytic pontine exotropia.” In some cases, the patient is able to adduct the eye (“nonparalytic exotropia,” a condition which has other causes). An incomplete version of the one-and-a-half syndrome displays only bilateral nystagmus on gaze in one direction (due to paresis of gaze) and nystagmus only in the abducting eye with gaze directed to the other side (due to the lesion in the MLF on the same side). Thrombotic occlusion of the upper part of the basilar artery (“top of the basilar” syndromes) causes a variety of important eye movement abnormalities. These include upgaze or complete vertical gaze palsy, skew deviation, and so-called pseudoabducens palsy, mentioned earlier (Caplan). Skew deviation  Skew deviation is a disorder in which there is vertical deviation of one eye above the other that is caused by an imbalance of the supranuclear vestibular inputs to the ocular motor system. Unlike fourth nerve palsy, where the separation of images is incomitant, most pronounced when the affected eye is adducted and turned down, skew deviation is typically comitant, meaning that the amount of ocular misalignment is relatively similar in all directions of gaze. Skew deviation is associated with a variety of lesions of the cerebellum and the brainstem, particularly those involving the MLF. In lesions involving the vestibular nuclei, as occurs in lateral medullary infarction, the eye is lower on the side of the lesion. With lesions of the MLF or INC, which can also cause skew and an ocular tilt reaction, the eye is higher on the side of the lesion. With skew deviation due to cerebellar disease, the eye on the side of the lesion usually rests lower (in two-thirds of cases in Keane’s series), but sometimes it is higher than the other eye. The ocular tilt reaction, in which skew deviation (supranuclear vertical misalignment of the eyes) is a more dramatic version of skew deviation, which also includes ocular torsion and head tilt. It is attributed to an imbalance of otolithic-ocular and otolithic-colic reflexes. In some cases, the hypertropic eye has been known to alternate with the direction of gaze (“alternating skew”), with the right eye higher in right gaze and the left eye higher in left gaze. A cerebellar or other posterior fossa lesion is the usual cause. A mechanism for this sign has been proposed based on otolithic influences on cerebellar centers.

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Among the most unusual of the complex ocular disturbances is a subjective tilting of the entire visual field that creates an illusion of environmental tilting that may be 45, 90, or even 180 degrees vision (tortopia, or in the latter case, upside-down vision). Objects normally on the floor, such as chairs and tables, are perceived to be on the wall or ceiling. Presumably the phenomenon arises from imbalanced inputs from the vestibular-otolithic nucleus or its connections in the MLF, which provide gravitational information that is essential for maintaining the normal subjective sense of the visual vertical. Lateral medullary infarction has been a common cause of this tilting of vision; other cases may be migrainous (Ropper, 1983). Ocular lateropulsion, in which the eyes are driven to one side and the patient feels pushed or pulled in the same direction, is another component in some cases of lateral medullary infarction as discussed in Chap. 33.

NYSTAGMUS Nystagmus refers to involuntary rhythmic movements of the eyes and is of two general types. In the more common jerk nystagmus, the movements alternate between a slow component and a fast corrective component, or jerk, in the opposite direction. In pendular nystagmus, the oscillations are roughly equal in rate in both directions, although on lateral gaze the pendular type may be converted to the jerk type with the fast component to the side of gaze. Nystagmus reflects an imbalance in one or more of the systems that maintain stability of gaze. The causes may therefore be viewed as originating in (1) structures that maintain steadiness of gaze in the primary position; (2) the system for holding eccentric gaze—the so-called neural integrator; or (3) the VOR system, which maintains foveal fixation of images as the head moves. For clinical purposes, certain types of nystagmus are identified as corresponding to lesions in specific structures within each of these systems, and it is this approach that we take in the following pages. One classification considers nystagmus as the result of a disturbance in the vestibular apparatus or its brainstem nuclei, the cerebellum, or a number of specific regions of the brainstem such as the MLF. In testing for nystagmus, the eyes should be examined first in the central position and then during upward, downward, and lateral movements. Jerk nystagmus may be horizontal or vertical and is elicited particularly on ocular movement in these planes, or it may be rotatory and, rarely, retractory or vergent. By custom the direction of the nystagmus is designated according to the direction of the fast component (referred to as “beating” to that side). Drug intoxication is the most frequent cause of jerk nystagmus. Alcohol, barbiturates, other sedative-hypnotic drugs, phenytoin, and other antiepileptic drugs are the common causes. This form of nystagmus is most prominent on deviation of the eyes in the horizontal plane, but it also may appear in the vertical plane. In many normal individuals, a few irregular jerks are observed when the eyes are moved far to one side (“nystagmoid” jerks), but the movements cease once lateral

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fixation is attained. A fine rhythmic nystagmus may also occur normally in extreme lateral gaze (physiologic endgaze nystagmus), beyond the range of binocular vision; but it is bilateral and disappears as the eyes move a few degrees toward the midline. These latter movements are probably analogous to the tremulousness of skeletal muscles when maximally contracted. Oscillopsia is the symptom of illusory movement of the environment in which stationary objects seem to move back and forth, up and down, or from side to side. It may be caused by ocular flutter (a cerebellar sign as discussed later) or coarse nystagmus of any type. With lesions of the labyrinths (as in aminoglycoside toxicity), the symptom of oscillopsia is only provoked by motion—for example, walking or riding in an automobile—and indicates an impaired ability of the vestibular system to stabilize ocular fixation during body movement (i.e., impaired VOR function). In these circumstances, cursory examination of the eyes may disclose no abnormalities; however, if the patient’s head is rotated slowly from side to side or moved rapidly in one direction while attempting to fixate a target, impairment of normal reflexive smooth eye movements and their replacement by saccadic or nystagmoid movements is evoked (see Chap. 14 for further discussion of these tests). If episodic and involving only one eye, oscillopsia is usually caused by myokymia of an ocular muscle (usually the superior oblique).

Nystagmus of Labyrinthine Origin (See Also Chap. 14) This is predominantly a horizontal or vertical unidirectional jerk nystagmus, often with a slight torsional component. It is more prominent when visual fixation is eliminated, which can be accomplished with the use of Frenzel lenses (conversely, it is suppressed by fixation). Vestibular nystagmus of peripheral (labyrinthine) origin beats in most cases away from the side of the lesion and increases as the eyes are turned in the direction of the quick phase (Alexander’s law). In contrast, as noted below, nystagmus of brainstem and cerebellar origin is most apparent when the patient tries to maintain eccentric fixation and the direction of nystagmus changes with the direction of gaze. Tinnitus and hearing loss are often associated with disease of the peripheral labyrinthine mechanism. Vertigo, nausea, vomiting, and staggering also may accompany disease of any part of the labyrinthine-vestibular apparatus or its central connections. As a characteristic example, the intense nystagmus of benign positional vertigo (see Chap. 14) is evoked by moving from the sitting to the supine position, with the head turned to one side. In this condition, nystagmus of vertical-torsional type and vertigo develop a few seconds after changing head position and persist for another 10 to 15 s. When the patient sits up, the nystagmus changes to beat in the opposite direction.

Optokinetic Nystagmus When one is watching a moving object (e.g., the passing landscape from a train window, a rotating drum with vertical stripes, or a strip of cloth with similar stripes),

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a rhythmic jerk nystagmus called optokinetic nystagmus (OKN) normally appears. This phenomenon is explained by a slow involuntary pursuit movement iteratively followed by a quick saccadic movement in the opposite direction to fixate the next new target that is entering the visual field. With unilateral lesions of the parietal region, the slow pursuit phase of the OKN may be lost or diminished when the stimulus—for example, the striped OKN drum—is moving toward the side of the lesion, whereas rotation of the drum to the opposite side elicits a normal response. In contrast, patients with hemianopia caused by an occipital lobe lesion show a normal optokinetic response bilaterally. The loss of the pursuit phase with a parietal lesion presumably results from interruption of efferent pathways from the parietal cortex to the brainstem centers for conjugate gaze. On the other hand, individuals with a frontal lobe lesion will track a moving target in either horizontal direction but show little or no fast-phase correction in the direction opposite the lesion. An important additional fact about OKN is that the ability to evoke it proves that the patient is not blind. Each eye can be tested separately to exclude monocular blindness. Thus the test is of particular value in the examination of hysterical patients and malingerers who claim that they cannot see, and of neonates and infants (a nascent OKN is established within hours after birth and becomes more easily elicitable over the first few months of life). Demonstration of an intact OKN, however, merely demonstrates that some vision is preserved, and does not prove that the visual function is actually normal.

Caloric-Induced Nystagmus Labyrinthine stimulation—for example, irrigation of the external auditory canal with warm or cold water, or “caloric testing”—produces a marked nystagmus. Cold water induces a slow tonic deviation of the eyes toward the irrigated ear and a compensatory nystagmus in the opposite direction in a conscious, awake patient; warm water does the reverse. Thus the acronym taught to generations of medical students: COWS, or “cold opposite, warm same,” to refer to the direction of the fast phase of the induced nystagmus. The slow tonic ipsiversive component with cold water caloric testing occurs because the semicircular canals on the side are transiently inhibited and the vestibulo-ocular reflex therefore sends both eyes conjugately in that direction (as would occur if the head were turning in the opposite direction). The fast component of the nystagmus represents the corrective movement superimposed on this slow tonic gaze deviation. Comatose patients with an intact VOR will demonstrate the slow-phase gaze deviation without the fast-phase nystagmus to which this mnemonic refers. Vertical eye movements can also be assessed with caloric stimulation of the labyrinths. When cold water is instilled in both ears, reflexive nystagmus occurs with a downward slow phase and upbeating fast phase (the acronym CUWD, or “cold upbeat, warm downbeat” could be remembered). In general cold caloric testing is preferred to warm caloric testing, to avoid risk of injury to the ear canal that may occur if the water were too hot. Chapter 14 discusses the production of

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nystagmus by labyrinthine stimulation and other features of vestibular nystagmus.

Nystagmus Caused by Brainstem and Cerebellar Disease Brainstem lesions often cause a coarse, unidirectional, gaze-evoked nystagmus, which may be horizontal or vertical, meaning that the nystagmus is exaggerated when the eyes sustain an eccentric position of gaze. Unlike the vestibular nystagmus discussed above, the central type usually changes direction depending on the direction of gaze. Vertigo is typically less common or less intense than with labyrinthine nystagmus, and signs of disease of other nuclear structures and tracts in the brainstem are frequent. Downbeat nystagmus, which is always of central origin, is characteristic of lesions in the medullary–cervical region such as syringobulbia, Chiari malformation, basilar invagination, and demyelinating plaques. It has also been seen with Wernicke disease and may be an initial sign of either paraneoplastic brainstem encephalitis or cerebellar degeneration with opsoclonus. Downbeat nystagmus can occur in patients with lithium intoxication or with profound magnesium depletion (Saul and Selhorst). A study of 62 patients with downbeat nystagmus, found that half were associated with Chiari malformation and various forms of cerebellar degeneration; in most of the remainder, the cause could not be determined (Halmagyi and coworkers). Some cases are associated with antibodies against glutamic acid decarboxylase (GAD), which are also associated with the stiff person syndrome (Antonini). Spontaneous upbeat nystagmus can be observed in patients with demyelinating or vascular disease, tumors, or Wernicke disease. It has been associated with lesions of the midbrain and cerebellum (particularly the anterior cerebellar vermis). Also cited have been cases with a lesion at the pontomedullary junction involving the nucleus prepositus hypoglossi, which receives vestibular connections and projects to all brainstem and cerebellar regions concerned with ocular motor functions (Kato and associates). Smoking tobacco in significant quantities is another recognized cause. Nystagmus of several types—including gaze-evoked nystagmus, downbeat nystagmus, and “rebound nystagmus” (gaze-evoked nystagmus that changes direction with refixation to the primary position)—occurs with cerebellar disease, particularly with lesions of the vestibulocerebellum or with brainstem lesions that involve the nucleus prepositus hypoglossi and the medial vestibular nucleus. Also, characteristic of cerebellar disease are several closely related disorders of saccadic movement that appear as nystagmus (opsoclonus, flutter, dysmetria) described in the following text. Tumors situated in the cerebellopontine angle may cause a coarse, low-frequency horizontal nystagmus when looking toward the lesion with a fine, high-frequency nystagmus when looking in the opposite direction (Brun’s nystagmus). Nystagmus that occurs only in the abducting eye is referred to as dissociated nystagmus and is a common sign of INO, as discussed earlier.

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Infantile (Congenital, Pendular) Nystagmus This nystagmus can occur either in association with profound visual loss or as an isolated abnormality with relatively preserved visual function. When accompanied by visual loss, it may be associated with conditions such as ocular albinism, Leber’s congenital amaurosis, and various other diseases of the retina and refractive media. The defect in infantile nystagmus is postulated to be instability of smooth pursuit or gaze-holding mechanisms. A cardinal feature of this type of nystagmus is that it remains horizontal even during vertical movement. It is mainly pendular (sinusoidal) except in extremes of gaze, when it comes to resemble jerk nystagmus. Eye movement recordings demonstrate that the slow-phase eye movement has an exponentially increasing velocity phase that is unique among nystagmus; in other forms of nystagmus the velocity of the eye movements is either constant or decays. Infantile nystagmus is often suppressed during convergence. Many affected children have a “null position,” where the nystagmus is dampened in a particular direction of gaze. These patients, therefore, adopt a compensatory head turn to utilize the null position, where the retinal image is most stable, to its maximum effect. Also characteristic is a paradoxical response to optokinetic testing (see later), in which the quick phase is in the same direction as the drum rotation. The related condition of latent nystagmus refers to nystagmus that occurs when one eye is covered. The nystagmus that occurs is conjugate, present in both eyes, with the fast phase in the direction of the covered eye. The finding may occur when either is covered, or it may be asymmetric and occur only with covering one of the eyes but not the other. Latent nystagmus is considered to be a result of impaired development of binocular stereoscopic vision. It often co-exists with some degree of amblyopia, again reflecting the disruption of visual development early in life. Patients usually do not describe the experience of oscillopsia when the nystagmus occurs (i.e., the conscious perception of the visual environment shaking) because the congenital mechanisms associated with this nystagmus allow for suppression of that aspect of the visual experience. In some individuals with this condition who then lose vision in one eye later in life, the latent nystagmus becomes unmasked constantly and is termed manifest latent nystagmus. Even in adulthood, severe acquired blindness can produce nystagmus of pendular or jerk variety. Both horizontal and vertical components are evident and the characteristic feature is a fluctuation over several seconds of observation in the dominant direction of beating. The oscillations of the eyes are usually very rapid, increase on upward gaze, and may be associated with compensatory oscillations of the head. The formerly common syndrome of “miner’s nystagmus” is an associated condition that occurs in patients who have worked for many years in comparative darkness. Spasmus nutans, a specific type of pendular nystagmus of infancy, is accompanied by head nodding, and occasionally by wry positions of the neck. Most cases begin between the 4th and 12th months of life, never after the 3rd year. The nystagmus may be horizontal, vertical, or rotatory; it is usually more pronounced in one eye than the other (or

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Chapter 13 Disorders of Ocular Movement and Pupillary Function

limited to one eye) and can be intensified by immobilizing or straightening the head. Most infants recover within a few months or years. Most cases are idiopathic, but the clinical manifestations of spasmus nutans may be mimicked by lesions such as a perichiasmal or third ventricular tumor and rare cases accompany childhood retinal diseases. Although there is no direct connection to the rare childhood condition of bobble-head syndrome, which is caused by lesions in or adjacent to the third ventricle, they are similar in the rhythmic head movements as described in Chap. 29. Acquired forms of pendular nystagmus may occur with leukodystrophies, including Pelizaeus-Merzbacher syndrome (see Chap. 36), multiple sclerosis (see Chap. 35), and toluene intoxication. In the oculomasticatory myorhythmia of Whipple disease, the nystagmus is conjoined to rhythmic jaw movements (see Chap. 31).

Other Types of Nystagmus Convergence nystagmus refers to a rhythmic oscillation in which a slow abduction of both eyes is followed by a quick movement of adduction, usually accompanied by quick rhythmic retraction movements of the eyes (retraction nystagmus) and by one or more features of the Parinaud–dorsal midbrain syndrome discussed earlier in the chapter. There may also be rhythmic movements of the eyelids or a maintained spasm of convergence, best brought out on attempted elevation of the eyes on command or downward rotation of an OKN drum. These phenomena all point to a lesion of the upper midbrain tegmentum and are usually manifestations of vascular disease, traumatic damage, or a tumor such as a pinealoma that compresses this region. Seesaw nystagmus is a torsional-vertical oscillation in which the intorting eye moves up and the opposite (extorting) eye moves down, then both move in the reverse direction. It is occasionally observed in conjunction with chiasmatic bitemporal hemianopia caused by sellar or parasellar masses and after pituitary surgery. Periodic alternating nystagmus (PAN) is a remarkable horizontal jerking that periodically (every 90 s, or so) changes direction, interposed with a brief neutral period during which the eyes show no nystagmus, or jerk downward. PAN is seen with lesions in the lower brainstem but has also been reported with Creutzfeldt-Jakob disease, hepatic encephalopathy, lesions of the cerebellar nodulus, carcinomatous meningitis, anti-GAD antibodies, and varied other processes. A congenital form is associated with albinism. It differs from ping-pong gaze, which is a saccadic variant with a more rapid alternating of gaze from side to side and usually the result of severe bilateral hemispheric disease. So-called oculopalatal tremor is characterized by an irregular pendular nystagmus that is accompanied by involuntary movements of the palatal and pharyngeal muscles occurring at the same frequency, as discussed in Chap. 4. This syndrome often follows a lesion in the dorsal pons that disrupts the central tegmental tract, which is a component of the anatomical triangle of Guillain-Mollaret, connecting the red nucleus, inferior olive, and contralateral

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dentate nucleus of the cerebellum. Months after the acute injury, denervation of the inferior olive leads to hypertrophic degeneration, with the increased volume and signal intensity of the inferior olive often visible on MRI.

Other Spontaneous Ocular Movements Roving conjugate eye movements are characteristic of coma. Horizontal ocular deviations that shift every few seconds from side to side (ping-pong gaze) is a form of roving eye movement that occurs with bihemispheric infarctions or sometimes with posterior fossa lesions. Fisher has noted a similar slower, side-to-side pendular oscillation of the eyes (“windshield-wiper eyes”). This phenomenon has been associated with bilateral hemispheric lesions that have presumably released a brainstem oscillatory pacemaker. Ocular bobbing is a term coined by Fisher to describe a distinctive spontaneous fast downward jerk of the eyes followed by a slow upward drift to the midposition. It is observed in comatose patients in whom horizontal eye movements have been obliterated by large destructive lesions of the pons, less often of the cerebellum. The movements may be dysconjugate in the vertical plane, especially if there is an associated third-nerve palsy on one side. Other spontaneous vertical eye movements have been given a variety of confusing names: atypical bobbing, inverse bobbing, reverse bobbing, and ocular dipping. For the most part, they are observed in coma of metabolic or anoxic origin in which reflexive horizontal eye movements may be preserved (in distinction to ocular bobbing). Ocular dipping describes an arrhythmic slow conjugate downward movement followed in several seconds by a more rapid upward movement; it occurs spontaneously but may at times be elicited by moving the limbs or neck. Anoxic encephalopathy has been the most common cause, but a few cases have followed drug overdose (Ropper, 1981). Oculogyric crisis, formerly associated with postencephalitic parkinsonism, is now most often caused by phenothiazine and related drugs, as discussed earlier.

Saccadic Intrusions (Opsoclonus, Ocular Flutter, and Square Wave Jerks) This group of phasic or repetitive eye movements is distinguished from nystagmus in that each is composed of abnormal saccades without intervening slow-phase eye movements. Opsoclonus is the term applied to rapid, conjugate movements of the eyes in horizontal, rotatory, and vertical directions, often made worse by voluntary movement or the need to fixate the eyes. These bursts of saccadic movements are continuous and chaotic, without an intersaccadic pause (hence the colorful term saccadomania). They can be observed even when the eyes are closed, and often persist in sleep. As indicated in Chap. 4, they are usually part of a widespread myoclonus associated with paraneoplastic or parainfectious disease. In adults, lung, breast, and testicular cancer are important considerations, while in children an evaluation for neuroblastoma is essential (see “Paraneoplastic Cerebellar Degeneration” discussed in Chap. 30). Other less frequent causes include HIV, poststreptococcal infection, West Nile virus encephalitis, and rickettsial infections. Opsoclonus may also be observed in

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patients who are intoxicated with antidepressants, anticonvulsants, organophosphates, cocaine, lithium, thallium, and haloperidol; in the nonketotic hyperosmolar state; and in cerebral Whipple disease, where the eye movements are coupled with rhythmic jaw movements (oculomasticatory myorhythmia). A benign childhood form can persist for years without explanation and is responsive to adrenocorticotropic hormone (ACTH), as in the “dancing eyes” syndrome of Kinsbourne. In addition, a self-limited benign form exists in neonates. Ocular flutter refers to intermittent bursts of very rapid oscillations around the point of fixation limited to the horizontal plane; this abnormality is also associated with cerebellar disease. Flutter at the end of a saccade, called flutter dysmetria (“fish-tail nystagmus”) has the appearance of dysmetria, but careful analysis indicates that it is probably a different phenomenon. Whereas the inaccurate saccades of ocular saccadic dysmetria (an ataxic phenomenon) are separated by a brief pause (intersaccadic interval), flutter consists of consecutive saccades without an intersaccadic interval; that is, back-to-back saccades (Zee and Robinson). All those movements have the same implication of cerebellar cortical disease. One hypothesis relates opsoclonus and ocular flutter to a disorder of the saccadic “pause neurons,” but their exact anatomic basis has not been elucidated. Similar movements have been produced in monkeys by creating bilateral lesions in the pretectum. Some normal individuals can voluntarily induce flutter for brief periods, but the movement cannot be sustained (voluntary “nystagmus”). Square wave jerks refer to another type of involuntary saccades that disrupt fixation. The eyes are seen to horizontally move off target by several degrees, pause for approximately 200 ms, and then move back. The term square wave jerks comes from a description of the recording of these eye movements. Square wave jerks can be a normal finding in the elderly, but their frequency becomes increased in many conditions, particularly neurodegenerative disorders such as progressive supranuclear palsy. Ocular neuromyotonia describes an intermittent diplopia owing to paroxysmal contraction of one or more ocular muscles after their activation. The episodes may last approximately 30 to 60 s until there is cessation of the involuntary sustained contraction of the affected eye muscles. This condition most commonly occurs months to years after radiation that includes the field of the ocular motor nerves (and less characteristically occurs with vascular or tumor compression in the absence of a history of radiation therapy). Like superior oblique myokymia (discussed earlier), ocular neuromyotonia may respond to anticonvulsant medications such as carbamazepine.

Disorders of the Eyelids and Blinking A consideration of oculomotor disorders would be incomplete without reference to the eyelids and blinking. In the normal individual, the eyelids on both sides are at the same level with respect to the limbus of the cornea and there is a variable prominence of the eyes, depending on the width of the palpebral fissure. The function of the lids is to protect the delicate corneal surfaces against injury and

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the retinae against glare; this is done by blinking and lacrimation. Eyelid movement is normally coordinated with ocular movement—the upper lids elevate when looking up and descend when looking down. Turning the eyes quickly to the side is sometimes attended by a single blink, which is necessarily brief so as not to interfere with vision. When the blink duration is prolonged, it is indicative of an abnormally intense effort required to initiate the saccade; usually this is because of frontal lobe or basal ganglionic disease. Closure and opening of the eyelids is accomplished through the reciprocal actions of the levator palpebrae and orbicularis oculi muscles. The eyelids are kept open by the tonic contraction of the levator muscles, which overcomes the elastic properties of the periorbital muscles. Complete opening of the lids is aided by the superior tarsal (Müller) muscle, which is tonically innervated by sympathetic fibers. The eyelids close as a result of relaxation of the levator muscles and contraction of the orbicularis oculi muscles. The levator is innervated by the oculomotor nerve, and the orbicularis by the facial nerve. The trigeminal nerves provide sensation to the eyelids and are also the afferent limbs of corneal and palpebral reflexes. Central mechanisms for the control of blinking, in addition to the reflexive brainstem connections between the third, fifth, and seventh nerve nuclei, include polysynaptic circuits of the cerebrum, basal ganglia, and hypothalamus. Voluntary lid closure is initiated through frontobasal ganglionic connections. Normal blinking is bilateral and occurs irregularly at a rate of 12 to 20 times a minute, the frequency varying with the state of concentration and with emotion. The natural stimuli for the blink reflex are corneal contact, a tap on the brow or around the eye, visual threat, an unexpected loud sound, and, as indicated above, turning of the eyes to one side. There is normally a rapid adaptation of blinking in response to visual and auditory stimuli but not to corneal stimulation. Electromyography of the orbicularis oculi reveals two components of the blink response, an early and late one; these features are difficult to appreciate by clinical observation alone. The early monosynaptic response consists of only a slight movement of the upper lids; the immediately following polysynaptic response is more forceful and approximates the upper and lower lids. Whereas the early part of the blink reflex is beyond volitional control, the second part may be inhibited voluntarily. Blepharospasm, an excessive and forceful closure of the lids with increased frequency, is a common disorder that is seen in isolation or as part of a number of dyskinesias and drug-induced movement disorders. Extremes of this condition may result in functional blindness. Treatment for dry eye syndrome is often attempted but is ineffective; periodic injections with botulinum toxin can alleviate symptoms. The combination of blepharospasm with dystonic grimacing movements of the lower face is termed Meige syndrome. The opposite problem, reduced frequency of blinking (65

clear that the syndrome is the result of a loss of function mutation in a sodium channel gene (SCN1A in most cases). The initial seizures in these cases have been brought forward by a febrile episode or other neonatal event but they are subsequently characterized by unprovoked and treatment-resistant episodes. Febrile seizures represent a challenging problem in this age period. When febrile seizures are prolonged, focal, or accompanied by a neurologic deficit, they are referred to as complicated febrile seizures. These are distinguished from the benign familial febrile seizure syndrome discussed earlier in the chapter. While myoclonic activity with seizures in this age group raises concern of a serious condition, there is a common benign form with a heritable component and does not lead to developmental delay.

Seizures Presenting in Early Childhood A number of focal epilepsies may appear for the first time during this age period and carry a good prognosis, that is, the neurologic and intellectual capacities remain relatively unimpaired and seizures may cease in adolescence. These disorders begin between 3 and 13 years of age and there is often a familial predisposition. Most are marked by distinctive focal spike activity that is accentuated by sleep (see earlier, in reference to benign childhood epilepsy with centrotemporal or occipital spikes). Several of these have been discussed earlier under the “Other Epileptic Syndromes.” In one form, benign childhood epilepsy with centrotemporal spikes, unilateral tonic or clonic contractions of the face and limbs recur repeatedly with or without paresthesia; anarthria may follow the seizure. There are central and temporal spikes in the EEG interictally. Less commonly, the focus originates in an occipital lobe with EEG spiking on eye closure. An acquired aphasia characterizes the onset of another disorder in which there are partial or generalized motor seizures and multifocal spike or spike-andwave discharges in the EEG and deterioration of language function (Landau and Kleffner). As in any age group, there are structural causes of seizures that include medial temporal sclerosis, described in several places in this chapter, tumor, and arteriovenous malformation. Rasmussen encephalitis and intractable seizures have already been discussed under the “Other Epileptic Syndromes.” Among the generalized idiopathic epilepsies, the typical absence disorder, with its regularly recurring 3-per-second spike-and-wave EEG abnormality, begins

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in this age period (rarely before age 4 years) and carries a good prognosis. This seizure disorder responds well to medications, as indicated further on. Its features are fully described in “Absence Variants.” Convulsions in this age group may present around the age of 4 years as focal myoclonus with or without astatic seizures, atypical absence, or generalized tonic-clonic seizures. The EEG, repeated if initially normal, is most helpful in diagnosis; it reveals a paroxysmal 2- to 2.5-per-second spike-and-wave pattern on a background of predominant 4- to 7-Hz slow waves. Many of these cases qualify as the Lennox-Gastaut syndrome, are difficult to treat, and are likely to be associated with developmental delay. At this age, perhaps more than any other, the first burst of seizures may take the form of status epilepticus and, if not successfully controlled, may end fatally.

Seizures in Later Childhood and Adolescence These represent a common problem in practice but present a difficulty because this is the age at which syncope and psychogenic seizures begin to occur and alcohol and drug abuse may too begin. In this age period in particular, as the adolescent strives for independence, the social disruption caused by seizures are likely to take a toll on the relationships and educational progress of the emerging adult. Here, we also face the frequent issue relating to the nature and management of the first seizure in an otherwise normal young person. As in other age groups, the history often discloses the likely provocation of seizures, as for example, a young person has been sleep deprived or imbibing alcohol or a recreational drug and has a first seizure. A search for a cause of the first seizure in this age group is necessary by MRI, ECG, and EEG but these tests less frequently disclose an underlying lesion than in other age groups. Often, there has only been a single event and no clinical or EEG features to define the nature of the seizure disorder. However, the type of seizure that first brings the child or adolescent to medical attention is most likely to be a generalized tonic-clonic convulsion and may mark the beginning of idiopathic generalized epilepsy or juvenile myoclonic epilepsy, as described in earlier sections. A few patients have had a history of absence in which the EEG shows a characteristic polyspike pattern, about one-third with a photomyoclonic response. When the seizures are an expression of a congenital epileptic focus that is associated with developmental delay or scholastic failure, the diagnostic and therapeutic problem becomes demanding. In the group of younger individuals with longstanding seizures, nearly half have temporal lobe epilepsy. A study that followed 145 infants and children with intractable epilepsy found that the majority had developmental delay (Huttenlocher and Hapke). Opinion is divided on whether treatment is required for the older child or adolescent who comes to medical attention because of a first seizure that appears to be idiopathic. Age, sex, and the circumstances of the seizure (withdrawal from drugs or alcohol, myoclonic episodes, family history) all figure into the risk of subsequent seizures. What is apparent is that the early use of antiepileptic drugs has little effect on the occurrence of later seizures, though may reduce seizure frequency in the short term

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(Krumholz and colleagues; Marson and colleagues). When such cases have been observed without treatment, the risk of another seizure over 10 years was 13 percent unless the first episode was status epilepticus, in which case the risk was 41 percent (Hesdorfer and colleagues). Attention is given to regularizing sleep and minimizing alcohol and stimulants.

Seizures in Late Adult Life There is an increase in the incidence of seizures as the population ages—from 11.9 per 100,000 in the 40- to 60-yearold age group to 82 per 100,000 in those 60 years of age or older (Hauser and Kurland). Older individuals may live alone so there is no witness to the event, they often have multiple medical problems, they may have cognitive difficulty that impedes an accurate history, they likely take multiple medications, and cerebral imaging is likely to show abnormalities that may not be referable to the problem at hand. An older person who begins to have seizures of either focal or generalized type may harbor a primary or secondary tumor, a past cerebral infarct, or a traumatic cortical scar that had not declared itself clinically. For example, previous infarcts are by far the most common lesions underlying status epilepticus in late adult life (Sung and Chu). Probably the nature of the population in a given clinic determines the relative frequency of underlying causes. In any case, cerebral imaging usually settles the issue. However, many seizure-like events in this age group are the result of a cardiac arrhythmia, particularly ventricular tachycardia but also cardiac disorders not related to rhythm such as aortic stenosis. Therefore, ECG and longterm monitoring of heart rhythm are useful ancillary tests if the episode remains unexplained. Cortical and subcortical lesions, the result of previous traumatic contusions, are a particularly important cause of seizures; the lesions are revealed by brain imaging and are typically located in the anterior frontal and temporal lobes. Brain abscess and other inflammatory and infectious illnesses remain common causes of adult seizures in tropical regions. In the elderly, seizures as a result of advanced Alzheimer and other degenerative diseases occur in up to 10 percent of cases; moreover, these patients are subject to falls, subdural hematoma, and all other illnesses of old age, such as cancer, that secondarily affect the brain. In individuals with cancer, cerebral metastasis is certainly a common cause of a first seizure. In the common case of an adult with a first unexplained seizure, it has been our practice not to administer an antiepileptic medication unless there is an underlying structural lesion or an abnormality on a single EEG or with prolonged monitoring and to reevaluate the situation in 6 to 12 months. The decision regarding starting treatment in an older adult is informed by a number of factors including occupation, need for driving, safety of home environment, use of alcohol and other sedatives, anticipated compliance, and drug interactions. Usually, a second MRI and EEG are performed to exclude focal abnormalities that were not appreciated during the initial evaluation, but often these studies are again unrevealing. This approach has been prompted by data showing that about one-third of patients

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Chapter 15 Epilepsy and Other Seizure Disorders

with a single unprovoked seizure will have another seizure within 5 years; the risk is even greater if there is a history of seizures in a sibling, a complex febrile convulsion in childhood, or a spike-and-wave abnormality in the EEG. Moreover, the risk of recurrence is greatest in the first 24 months. In patients with two or three unexplained seizures, a far higher proportion, about 75 percent, have further seizures in the subsequent 4 years.

Seizures due to Underlying Medical Disease Several diseases announce themselves by an acute convulsion. Here we focus on generalized medical disorders as causes of single and episodic seizures, in contrast to structural lesions of the brain that cause focal or generalized epilepsy.

Withdrawal Seizures The possibility of withdrawal seizures in patients who abuse alcohol or use benzodiazepine and related sedative drugs, must be considered when seizures occur for the first time in adult life or in adolescence. Suspicion is raised by the stigmata of alcohol abuse or a history of prolonged anxiety requiring sedative drugs. Also, sleep disturbance, tremulousness, disorientation, illusions, and hallucinations can be associated with the convulsive phase of the withdrawal syndrome. Seizures in this setting may occur singly, but as often, in a brief flurry, the entire convulsive period lasting for several hours and rarely for a day or longer, during which time the patient may display twitchiness or myoclonus and be unduly sensitive to photic stimulation. Chapter 41 discusses alcohol and other drug-related seizures in detail.

Infections and Inflammatory-Immune Conditions An outburst of seizures is also a prominent feature of all varieties of bacterial meningitis, more so in children than in adults. Fever, headache, and stiff neck provide the clues to diagnosis, and lumbar puncture yields the salient data. In endemic areas and in individuals who have traveled from these areas, cysticercosis and tuberculous granulomas of the brain are very common causes of epilepsy. Myoclonic jerking and seizures may appear early in acute herpes simplex encephalitis and other forms of viral, treponemal, and parasitic encephalitis, including those derived from HIV infection, toxoplasmosis, and in subacute sclerosing panencephalitis. Seizures without fever or stiff neck may be the initial manifestation of syphilitic meningitis, a fact worth noting as this process has reemerged in immunocompromised individuals. A variety of autoimmune encephalitides, particularly those affecting limbic structures, may cause seizures as, for example, with the anti-NMDA receptor antibody that is associated with ovarian and other teratomas and other paraneoplastic conditions such as the antibody syndrome directed at the voltage-gated potassium channel complex (see Chap. 30).

Seizures in Metabolic Encephalopathy Uremia has a strong tendency to produce convulsions. Of interest is the relation of seizures to the development

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of acute anuric renal failure, generally from acute tubular necrosis but occasionally due to glomerular disease. Total anuria may be tolerated for several days without the appearance of neurologic signs, and then there is an abrupt onset of twitching, trembling, myoclonic jerks, and brief generalized motor seizures; acute hypertension probably plays a role. The entire motor constellation, one of the most dramatic in medicine, lasts several days until the patient sinks into terminal coma or recovers by dialysis. When this twitch-convulsive syndrome accompanies lupus erythematosus, seizures of undetermined cause, or generalized neoplasia, one should suspect its basis in renal failure. Other acute metabolic illnesses and electrolytic disorders complicated by generalized and multifocal motor seizures are hyponatremia and its opposite, the hypernatremic, hyperglycemic and other hyperosmolar states, hypoglycemia, thyrotoxicity, porphyria, hypomagnesemia, and hypocalcemia. In all these cases, rapidly evolving electrolyte abnormalities are more likely to cause seizures than those occurring gradually. For this reason it is not possible to assign absolute levels of sodium, blood urea nitrogen (BUN), osmolarity, or glucose concentrations above or below which seizures are likely to occur. Lead (in children) and mercury (in children and adults) are the most frequent of the metallic poisons, still rare as a group, that cause convulsions. The presence of these heavy metals in homeopathic treatments should not be overlooked. Generalized seizures, with or without twitching, occur in the advanced stages of many other illnesses, such as hypertensive encephalopathy, the posterior reversible encephalopathy syndrome from various drugs (PRES, as discussed in Chap. 33), sepsis—especially gram-negative septicemia with shock—and hepatic coma. Usually, seizures in these circumstances can be traced to an associated metabolic abnormality and are revealed by appropriate studies of the blood. Seizures are a central feature of the eclamptic syndrome as discussed in a separate section below. In most cases of seizures caused by metabolic and withdrawal states, treatment with antiepileptic drugs is not necessary as long as the underlying disturbance is rectified. Indeed, antiepileptic drugs are usually ineffective in halting the seizures if the metabolic disorder persists.

Medications and Other Drugs as Causes of Seizures In addition to the withdrawal states, a large number of medications are themselves capable of causing seizures, usually when toxic blood levels are attained. The antibiotic imipenem and excessive doses of other penicillin congeners as well as linezolid may be responsible, particularly if renal failure leads to drug accumulation. Cefepime, a fourth-generation cephalosporin, widely used for the treatment of gram-negative sepsis, can result in status epilepticus, if given in excessive dosage (Dixit and colleagues). Renal dysfunction, preexisting brain lesions and previous epilepsy have been emphasized as features associated with antibiotic-induced seizures (Sutter and colleagues, 2015), and they emphasize that the associations between seizures and specific antibiotics are often based on limited evidence.

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The tricyclic antidepressants, bupropion, and lithium may cause seizures, particularly in the presence of a structural brain lesion. Lidocaine and aminophylline are known to induce an unheralded single convulsion if administered too quickly or in excessive doses. The use of the analgesic tramadol has also been associated with seizures. Curiously, the anesthetic propofol, which is discussed further on as a potent anticonvulsant in the treatment of status epilepticus, has caused marked myoclonic phenomena in some patients and, rarely, seizures. These may occur during induction or emergence from anesthesia or as a delayed effect (Walder and colleagues). The list of medications that at one time or another have been associated with a convulsion is long and, if no other explanation for a single seizure is evident, the physician is advised to look up in standard references the side effects of the drugs being administered to the patient. In a few of our otherwise healthy adult patients, extreme sleep deprivation coupled with ingestion of large doses of antibiotics or adrenergic medications or other remedies that are used indiscriminately for the symptomatic relief of colds has been the only plausible explanation for a single or doublet seizure. Furthermore, many illicit drugs of several varieties may cause seizures. Among the most prominent are cocaine, high-potency synthetic cannabinoids, amphetamines, phencyclidine, psilocybin, and lysergic acid. Some of these cause convulsions through an intermediate of extreme hypertension of vasculopathy but others seem to have a direct neurotoxic effect.

Circulatory or Respiratory Arrest Cardiac arrest, suffocation or respiratory failure, carbon monoxide poisoning, or other causes of hypoxemic or hypoxemic-ischemic encephalopathy tend to induce diffuse myoclonic jerking and generalized seizures as cardiac function resumes. The myoclonic-convulsive phase of this condition may last only a few hours or days, in association with coma, stupor, and confusion; or it may persist indefinitely as an intention myoclonus state (Lance-Adams syndrome). These movements are to be distinguished from the convulsive movements of syncope discussed earlier in the chapter and in Chap. 17.

Cerebrovascular Diseases Convulsive seizures are quite uncommon in the acute or evolving phases of an arterial stroke. The ischemic convulsive phenomena of a limb-shaking TIA and a burst of generalized clonic motor activity during basilar artery occlusion have been mentioned earlier but are uncommon and are not truly epileptic phenomena. Embolic infarcts involving the cortex become epileptogenic in fewer than 10 percent of cases and only after an interval of several months or longer. Thrombotic infarcts involving the cortex are almost never convulsive at their onset. Lacunar infarctions, being deep and not involving the cortical surface, do not produce convulsions. In contrast, cortical venous thrombosis with underlying edema, ischemia, and infarction acts as a highly epileptogenic lesion (see Chap. 33). The same is true for hypertensive

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encephalopathy (including the above mentioned posterior reversible encephalopathy [PRES] and eclampsia) and thrombotic thrombocytopenic purpura (TTP), which has a strong tendency to cause nonconvulsive status epilepticus. The rupture of a saccular aneurysm is sometimes marked by one or two generalized convulsions that are not epileptic in nature and are probably predicated on the arrest of cerebral circulation. Cerebral hemorrhages, spontaneous or traumatic, that extend near the cortex, also may present with seizures acutely or become sources of recurrent focal seizures as a delayed consequence. The use of anticonvulsants as prophylaxis for seizures after a typical cortical stroke of embolic or thrombotic type or nontraumatic cerebral hemorrhage is not necessary. The rate of such seizures has been estimated to be 3 percent or less in the first year. This subject is addressed further in Chap. 33.

Seizures With Acute Head Injury It is not uncommon for severe concussion to be attended by brief convulsive movements (see Chap. 34). The appearance is in most cases of clonic twitching but may include a momentary tonic phase. Rarely, a prolonged clonic convulsion occurs. The nature of this event, whether originating in the reticular formation as a component of concussion, or from some disruption of cortical activity, is not clear. Almost invariably in our experience, the EEG recorded hours or a day later is normal, and imaging studies are likewise normal or show a small contusion. There is little to guide one in treatment of these patients; we tend to give a course of antiepileptic medications for several weeks, but it is not established if this is the correct approach. Aside from penetrating brain trauma, the risk of delayed seizures is low. Further details on this subject, particularly seizures that occur as a late effect of traumatic brain injury can be found in Chap. 34.

Seizures During Pregnancy Here one contends with two scenarios: the woman with epilepsy who becomes pregnant and the woman who has her first seizure during pregnancy. In the EURAP study, about two-thirds of women with epilepsy who become pregnant were found to have no change in seizure frequency or severity; the majority remained seizure free and the remainder were evenly split between those in whom the frequency either increased or decreased. A more recent multicenter prospective study examined the frequency of seizures in women with epilepsy through pregnancy and the post-partum period compared to age-matched nonpregnant women with epilepsy (Pennell and colleagues). No differences in seizure frequency during any trimester of pregnancy or in the post-partum period were found compared to the non-pregnant cohort, though there was a higher frequency of antiseizure medication dose increases in the pregnant group. Many antiepileptic medications also seem to be safe for the baby during breast-feeding in that only small amounts are excreted in lactated milk (Birnbaum and colleagues). The degree of penetration into breast milk is dependent on the extent of protein binding. Highly bound drugs do not

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appear in substantial concentrations and the converse is true. Relatively safe agents include carbamazepine, which is found to be 40 percent of the mother’s serum concentration, resulting in a neonatal blood level that is below the conventionally detectable amount. Phenytoin is excreted at 15 percent of maternal serum concentration, and valproate, being highly protein bound, is virtually absent in breast milk. No adverse effects have been attributed to these small amounts of these drugs. Those that appear in intermediate concentrations include levetiracetam, oxcarbazepine, tiagabine, vigabatrin, gabapentin, and topiramate. Drugs considered risky for the infant because of high concentrations in breast milk include phenobarbital, primidone, ethosuximide, zonisamide, and benzodiazepines. The risks of using this last group of drugs in the postpartum period must be weighed against the sedating effects of the medication on the neonate. In the past, issues regarding coagulopathy in the fetus exposed to phenobarbital (now infrequently used for adult seizure disorders) and certain other drugs are well known to obstetricians and pediatric specialists and are treated with the oral administration of vitamin K during the eighth month or intravenously before birth and then intramuscularly to the neonate.

Teratogenic Effects of Antiepileptic Medications Because it is important to prevent major convulsions in the pregnant epileptic woman, antiepileptic medication should not be discontinued or arbitrarily reduced, particularly if there have been recent convulsions. The conventional drugs (phenytoin, carbamazepine, levetiracetam, lamotrigine) are all tolerated in pregnancy comparably to their use before pregnancy. Plasma levels of most of these drugs, both the free and protein-bound fractions, fall slightly in pregnancy in part because they are cleared more rapidly from the blood but there is considerable inter-individual variability. It is important to monitor the drug levels so that adjustments can be made. The main issue, however, pertains to the potential teratogenicity of most of the drugs with valproate having more risk than the others, and a slight reduction in verbal IQ in children born of mothers who had been exposed to valproate during pregnancy. The most common teratogenic effects have been cleft lip and cleft palate, but infrequently also a subtle facial dysmorphism (“fetal anticonvulsant syndrome”), similar to the fetal alcohol syndrome. In general, the risk of major congenital defects is low; it increases to 4 to 5 percent in women taking antiepileptic drugs during pregnancy, in comparison to 2 to 3 percent in the overall population of pregnant women. These statistics have been essentially confirmed in a large study conducted among several Boston hospitals (Holmes and colleagues). When all types of malformations were included, both major and minor, 20 percent of infants born to mothers who took antiepileptics during pregnancy showed abnormalities, compared to 9 percent of mothers who had not taken medications. These authors identified “midface hypoplasia” (shortened nose, philtrum, or inner canthal distance) and finger hypoplasia as characteristic of anticonvulsant exposure; these changes were found in 13 and 8 percent of exposed

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infants, respectively. However, it should be emphasized that in large surveys, major malformations have occurred in only 5 percent of infants exposed to antiepileptic drugs. The infants born of a group of women with epilepsy who had not taken anticonvulsants during pregnancy showed an overall rate of dysmorphic features comparable to that in control infants, but there was still a 2 to 3 percent rate of facial and finger hypoplasia. This risk is shared more or less equally by all the major antiepileptics again, with valproate associated with a higher rate. Aggregating eight databases, a number of malformations of the nervous and somatic systems were found to be increased in comparison to other antiepileptic drugs (Jetnik and colleagues). Of equal or greater concern has been the finding that in utero exposure to valproate was associated with lower IQs (by 9 points) compared to lamotrigine in children at the age of 4 (Meador and colleagues). It is not clear if the effect persists after this age. Children who had been exposed to phenytoin or to carbamazepine also had slightly lower IQs, but this difference was ostensibly accounted for by lower maternal IQ. Some studies suggest that folate may have an ameliorating effect on this detrimental effect at age 3, whereas there is an uncertain benefit of folate in preventing fetal malformations due to the drugs. The risk of neural tube defects is also slightly increased by anticonvulsants during pregnancy, and greatest for the use of valproate. It had been considered to be reduced by giving folate before pregnancy has begun (it is not clear if this is true for valproate), but epilepsy experts avoid the use of valproate during pregnancy altogether. These risks are greater in women taking more than one anticonvulsant, so that monotherapy is a desirable goal. Furthermore, the risk is disproportionately increased in families with a history of these defects. Some of the newer anticonvulsants should probably be used cautiously until greater experience has been obtained. As each new drug has been introduced over the years, there has usually been a tentative claim of reduced teratogenic effects, often proven later to be incorrect. Claims have been made of safety in this regard for lamotrigine, causing many specialists to change from the more conventional drugs to this one in women who anticipate becoming pregnant, but lamotrigine levels tend to fall precipitously during pregnancy. A report by Cunnington and colleagues using registry information suggests that the incidence of major birth defects in the fetuses exposed to lamotrigine during the first trimester is just under 3 percent, similar to risk estimates for the general population but also close to the 3 to 4 percent risk derived from most registries of women on anticonvulsants. Polytherapy with lamotrigine and valproate raised the estimate of risk to 12 percent. For all the drugs, polytherapy has the highest risk and there is a significant dose effect for an individual drug on the likelihood of fetal malformation. If a woman with epilepsy has not required medications for a time before getting pregnant and has a seizure during pregnancy, the best choice of medication may be phenytoin for its advantage in rapid seizure control, or levetiracetam. Exposure of the fetus late in gestation poses few teratogenic risks. If a woman discovers she is pregnant while on an antiepileptic drug, changing medications is

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unlikely to reduce the chances of birth defects, even for valproate, but this drug retains the risk of lower IQ in the child. The special case of eclamptic seizures is managed by infusion of magnesium as noted below. Epileptic women of childbearing age who are on an antiepileptic medication, particularly those which induce cytochrome P450, should be advised that higher doses of the estradiol component of birth control agents are required or they may be exposed to the issues of becoming pregnant while antiepileptic medications. Phenytoin, carbamazepine, and topiramate induce hepatic enzymes and most other medications do not have this effect.

Seizures in Eclampsia (See Also Chap. 33) This syndrome appears during the last trimester of pregnancy or soon after delivery and may announce itself by hypertension and convulsions; the latter are generalized and tend to occur in clusters. The standard practice is to induce labor or perform a cesarean section and manage the seizures as one would manage those of hypertensive encephalopathy (of which this is one type). The administration of magnesium sulfate continues to be the favored treatment by obstetricians for the prevention of eclamptic seizures; two randomized trials have reestablished its value in preventing seizures in preeclamptic women (Lucas and colleagues) and in avoiding a second convulsion once one had occurred (Eclampsia Trial Collaborative Group). Magnesium sulfate, 10 g IM, followed by 5 g every 4 h, proved comparable to standard doses of phenytoin as prophylaxis for seizures. Our colleagues use a regimen of 4 g IV given over 5 to 10 min followed by a maintenance dose of 5 g every 4 h IM or 1 to 2 g/h IV. In nontoxic gestational epilepsy, approximately 25 percent of patients are found to have some disease (neoplastic, vascular, or traumatic) that will persist.

TREATMENT OF EPILEPSY The treatment of epilepsy of all types can be divided into four parts: the use of antiepileptic drugs, the surgical excision of epileptic foci and other surgical measures, the removal of causative and precipitating factors, and the regulation of physical and mental activity.

Antiepileptic Drugs—General Principles The goal of drug treatment is to create a seizure-free state if possible and with the fewest side effects. In the past, a few seizures a year had been considered adequate control but with numerous newer medications it is reasonable to try to eliminate seizures. On the other hand, it is equivalently deleterious to render a patient so impaired by the sedating or cognitive dulling effects of the medications as to interfere with function at work or school. The choice and dose of medication depends on many factors including sex, age, other medications, and renal or hepatic dysfunction or other medical conditions and psychiatric conditions that might be favorably influenced by a particular agent. As a general rule, starting in the lower dose range and

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attempting to provide twice daily or daily administration are favored. In approximately 70 percent of all patients with epilepsy, the seizures are controlled completely or almost completely by medications; in an additional 20 to 25 percent, the attacks are significantly reduced in number and severity. Almost half of the patients with a new seizure disorder can be controlled with a first medication, another approximately 15 percent respond to a second as monotherapy, and a third medication choice controls very few additional instances—the remaining cases are considered treatment-resistant (Kwan and Brodie). In more modern series, the response to a first agent of a newer class was similar, but subsequent agent cumulatively was somewhat more successful, achieving 75 percent control (Bonnett and colleagues). More importantly, the simultaneous use of medications presents special problems and the rates of suppression of seizures with each additional drug are low and generally not additive. This approach, however, may not apply to combinations of some of the newer drugs. An additional question regards whether to start treatment immediately in an adult with a first unprovoked seizure. The Multicentre trial for Early Epilepsy and Single Seizures (MESS) trial, which randomized large groups of patients after a first unprovoked seizure to either immediate treatment or none, concluded that the treated group had fewer subsequent seizures at 6 months (18 vs 26 percent), 2 years (32 vs 39 percent), and 5 years (42 vs 51 percent) and the differences were larger for those who had multiple seizures before randomization and the time to the next seizure was delayed (Marson and colleagues). However, the differences became less significant over time and the side effects of the medications, as judged by practical factors such as keeping a job, were no different between groups. The death rates were comparable as well. A 30-year longitudinal analysis of patients with newly diagnosed and treated epilepsy showed, perhaps surprisingly, that the tolerability of the newer AEDs was no better than the older AEDs (Alsfouk and colleagues). Factors such as tolerance of the medications, patient preferences, and nature of work must be taken into account when making decisions regarding antiepileptic medicines. Guidelines from the American Academy of Neurology generally accord with these views (Krumholz and colleagues). Table 15-5 lists the most commonly used drugs along with their mechanisms of action, their principal indications, and their major limitations. Table 15-6 lists the drugs along with their dosages, effective blood levels, and serum half-lives. Because of the long half-lives of phenytoin, phenobarbital, and ethosuximide, these drugs need to be taken only once daily, preferably at bedtime. Valproate and carbamazepine have shorter half-lives, and their administration should be spaced during the day. It is useful to be familiar with the serum protein-binding characteristics of antiepileptic drugs and the interactions among these drugs, and between antiepileptic and other drugs. Certain drugs are somewhat more effective in one type of seizure than in another, and it is necessary to use the proper drugs in optimum dosages for different circumstances. Initially, only one drug should be used, and the

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Table 15-5 MECHANISMS AND USES OF THE MAIN ANTIEPILEPTIC DRUGS GENERIC NAME

MECHANISM OF ACTION

Major Antiepileptic Used as Monotherapy Valproic acid Multiple, including GABA potentiation, NMDA inhibition, sodium channel inhibition, T-type calcium channel inhibition Phenytoin Sodium channel inhibitor

PRINCIPAL INDICATIONS

Focal and generalized seizures, absence seizures

Hepatic enzyme inhibitor, teratogenicity, weight gain

Focal and generalized seizures

Hepatic enzyme inducer, nonlinear pharmacokinetics, skin hypersensitivity Hepatic enzyme inducer, skin hypersensitivity, hyponatremia Hepatic enzyme inducer, hyponatremia Hepatic enzyme inducer, hyponatremia Hepatic enzyme inducer, skin sensitivity Hepatic enzyme inducer, skin hypersensitivity Mood disturbance, psychosis Less mood disturbance and psychosis than levetiracetam Nephrolithiasis, cognitive impairment, weight loss

Carbamazepine

Sodium channel inhibitor

Focal and generalized seizures

Oxcarbazepine Eslicarbazepine Phenobarbital Lamotrigine

Sodium channel inhibitor Sodium channel inhibitor GABA potentiation Sodium channel inhibitor

Focal seizures Focal seizures, adjunctive use only Focal and generalized seizures Focal and generalized seizures

Levetiracetam Brivaracetam

SV2A modulation SV2A modulation

Focal and generalized seizures Focal and generalized seizures

Topiramate

Focal and generalized seizures

Lacosamide Zonisamide

Multiple, including GABA potentiation, AMPA inhibition, sodium channel inhibition, calcium channel inhibition Sodium channel inhibition Sodium channel inhibition

Ethosuximide Clobazam

T-type calcium channel inhibition GABA potentiation

Gabapentin

Calcium channel inhibition

Pregabalin

Calcium channel inhibition

Perampanel

Glutamate (AMPA) inhibition

Vigabatrin

GABA potentiation

Clonazepam Diazepam Lorazepam Fosphenytoin Propofol

GABA potentiation GABA potentiation GABA potentiation Sodium channel inhibitor Multiple, including GABA potentiation and NMDA inhibition

Absence seizures Focal and generalized seizures, adjunctive use only Focal and generalized, adjunctive use only Focal and generalized, adjunctive use only Focal and generalized seizures, adjunctive use only Infantile spasms, focal and generalized seizures Adjunctive use only Adjunctive use only Adjunctive use only Focal and generalized seizures Adjunctive use only (for refractory status epilepticus)

Focal and generalized seizures Focal and generalized seizures

dosage increased until sustained therapeutic levels have been attained. If the first drug does not control seizures, a different one should be tried, but frequent shifting of drugs is not advisable; each should be given an adequate trial before another is substituted. A general approach to the choice of drug in certain common forms of epilepsy is given in Table 15-5 for adults and Table 15-7 for children, but it must be noted that there are a number of drugs that may be appropriate in each circumstance. Furthermore, the antiepileptic drugs have approved purposes as assigned by the Federal Drug Administration (FDA) and the European Medicines Agency (EMA). These are more restrictive than are found in general use but it is worthwhile being familiar with the standing of various medications. A tabular summary of these approvals, main uses, and their dates of inception that divide the agents into three generations can be found in a review that is current as of 2016 (Schmidt).

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MAJOR LIMITATIONS

Nephrolithiasis, cognitive impairment, weight loss Insomnia Tolerance, sedation

Weight gain

Retinal toxicity Tolerance, sedation Tolerance, sedation Tolerance, sedation Skin hypersensitivity Sedation, hypertriglyceridemia, hypotension

It is difficult to give definitive guidance on combining medications for refractory seizures. Several general principles are worth noting. First, it may seem sensible to avoid drug combinations with similar putative mechanisms because their side effects may be additive, for example, the addition of lamotrigine to carbamazepine or of phenytoin to carbamazepine may not be ideal but at the same time, it should be mentioned that the mechanism of action has little influence on clinical effectiveness and drugs of a similar class are often combined. Second, the clinician should be aware of known interactions through metabolic pathways such as valproate combined with either lamotrigine or phenobarbital as they share the cytochrome P450 degradation pathway. Third, although it is appropriate to use drugs that are known to be effective for the class of seizures under treatment, it is often necessary to extend the choices beyond these restrictions.

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Table 15-6 PHARMACOLOGIC ASPECTS OF ANTIEPILEPTIC DRUGS USUAL DOSAGE GENERIC NAME

TRADE NAME

Valproic acid Phenytoin Carbamazepine Oxcarbazepine Eslicarbazepine Phenobarbital Lamotrigine Levetiracetam Brivaracetam Topiramate Lacosamide Zonisamide Ethosuximide Clobazam Gabapentin Pregabalin Perampanel Vigabatrin Clonazepam Diazepam Lorazepam Fosphenytoin Propofol

Depakote Dilantin Tegretol Trileptal Aptiom Luminal Lamictal Keppra Briviact Topamax Vimpat Zonegran Zarontin Onfi Neurontin Lyrica Fycompa Sabril Klonopin Valium Ativan Cerebyx Diprivan

CHILDREN, mg/kg

30–60 4–7 20–30 10–40   3–5 (8 for infants) 0.5 20–60     6–8 mg/kg 100–600 mg/d 20–40         100–300 0.01–0.2   0.15–2 5–20 1.2–12 mg/kg/h

The therapeutic dose for any given patient must be determined, to some extent by clinical effect, guided by measurement of serum levels, as described below. Inquiry regarding seizure control and drug side effects is more valuable than adjustment of medication based solely on drug concentrations. Blood for serum levels is ideally drawn in the morning before the first dose of antiepileptic medication (“trough levels”), a practice that introduces consistency in measurement. A drug should not be discarded as being ineffective, even at the upper limits of therapeutic blood levels, when a slight increase in dosage would have led to suppression of attacks. On the other hand, drug levels can be helpful in detecting noncompliance or poor absorption in instances of inadequate seizure control. The management of seizures is facilitated by having patients chart their daily medication and the number, time, and circumstances of each episode. Furthermore, in some

ADULTS, mg/d

1,000–3,000 300–400 600–1,200 900–2,400 400–1200 90–200 300–500 500–3,000 50–200 400 300–400 mg/d   750–1,500 5–40 900–3,600 150–600 2–12 1,000–3,000 2–10 2–40 2–20 10–20 mg/kg 1.2–12 mg/kg/h

SERUM HALF-LIFE, h

6–15 12–36 14–25 1–5 13–20 40–120 15–60 6–8 9 20–30 13 hours 63 hours 20–60 16–42 5–7 6 105 5–11 18–50 60–72 12 8–30 min 40 minutes

EFFECTIVE BLOOD LEVEL, mg/mL

50–100 10–20 4–12     15–40 2–7           50–100           0.01–0.07        

instances, asking the patients about seizure frequency may be unreliable. Some patients find it helpful to use a dispenser that is filled with medications with sufficient pills to last the week. This indicates to the patient whether a dose had been missed and whether the supply of medications is running low. In general, higher serum concentrations of drugs are necessary for the control of focal seizures than for generalized ones. The usual blood level assay is of the total concentration of the drug (see Table 15-6); this is not a precise reflection of the amount of drug entering the brain, because—in the case of the most widely used antiepileptics— the large proportion of drug is bound to albumin and does not penetrate nervous tissue. Also, in patients who are malnourished or chronically ill or who have a constitutional reduction in proteins, there may be intoxication at low total serum levels. Certain antiepileptic drugs also

Table 15-7 CHOICES OF ANTIEPILEPTIC DRUGS IN CHILDHOOD SEIZURE DISORDERS SEIZURE TYPE

INITIAL CHOICE

Generalized tonic-clonic Myoclonic Absence

Valproate, carbamazepine Valproate, levetiracetam Valproate

Focal

Carbamazepine, phenytoin

Infantile spasms Lennox-Gastaut

ACTH, vigabatrin, Valproate

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SECOND

Lamotrigine, oxcarbazepine Lamotrigine Topiramate, levetiracetam, ethosuximide Valproate, levetiracetam, oxcarbazepine Valproate Topiramate, lamotrigine

THIRD

Phenytoin Phenobarbital, clobazam Lamotrigine Lamotrigine, vigabatrin, topiramate Lamotrigine Levetiracetam

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have active metabolites that are not measured by methods ordinarily used to determine serum concentrations but nonetheless produce toxicity. This is particularly true for the epoxide of carbamazepine. The situation may be further complicated by interactions between one drug and the metabolites of another, as, for example, the inhibition of epoxide hydrolase by valproic acid, leading to toxicity through the buildup of carbamazepine epoxide. In circumstances of unexplained toxicity in the face of conventionally obtained serum levels that are normal, measurement may be undertaken of the levels of free drug and the concentration of active metabolites. The use of saliva for measurement of free drug levels has merit but has not been adopted frequently in practice. The measurements correlate with free drug levels. It has the advantage of allowing the patient to collect a sample before breakfast and avoid venipuncture. Finally, the pharmacokinetics of each drug plays a role in toxicity and the serum level that is achieved with each alteration in the dose. This is particularly true of phenytoin, which, as the result of saturation of liver enzymatic capacity, has nonlinear kinetics once serum concentration exceeds 10 mg/mL. For this reason, a typical increase in dose from 300 to 400 mg daily results in a disproportionate elevation of the serum level and toxic side effects. Elevations in drug concentrations are also accompanied by prolongation of the serum half-life, which increases the time to reach a steady-state concentration of phenytoin after dosage adjustments. Contrariwise, carbamazepine is known to induce its own metabolism, so that doses adequate to control seizures at the outset of therapy are no longer effective several weeks later.

Antiepileptic Drug Interactions Antiepileptic drugs have manifold interactions with each other and with a wide variety of other drugs. Although many such interactions are known, only a few are of clinical significance and most pertain to older generations of medications, requiring adjustment of drug dosages (Kutt). Among the interactions, valproate often leads to accumulation of active phenytoin and phenobarbital by displacing them from serum proteins, as well as slightly elevating serum total levels. Some of the agents that alter the concentrations of antiepileptic medications are chloramphenicol, which causes the accumulation of phenytoin and phenobarbital, and erythromycin, which causes the accumulation of carbamazepine. Antacids reduce the blood phenytoin concentration, whereas histamine blockers used to reduce gastric acid output do the opposite. Salicylates reduce the total plasma levels of antiepileptic drugs but elevate the free fraction by displacing the drug from its protein carrier. More importantly, warfarin levels are decreased by the addition of phenobarbital or carbamazepine and may be increased by phenytoin although, with this last drug there may be unexpected alterations of the international normalized ratio (INR) in either direction. Enzyme-inducing drugs such as phenytoin, carbamazepine, and barbiturates can greatly increase the chance of breakthrough menstrual bleeding in women taking oral contraceptives and may lead to failure of contraceptive

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medications, and adjustments in the amount of estradiol must be made. These interactions are emphasized further below under the discussions of each agent. Hepatic function greatly affects antiepileptic drug concentrations, since most of these drugs are metabolized in the liver. Serum levels must be checked more frequently than usual if there is liver failure, and with hypoalbuminemia it is advisable to obtain free drug levels for reasons just mentioned. Renal function has an indirect effect on the concentrations of the commonly used antiepileptics, but some agents, such as levetiracetam, gabapentin, and pregabalin, are excreted through the kidneys and require dosage adjustment in cases of renal failure. The main renal effects of the drugs in general are alterations in protein binding induced by uremia. In end-stage renal failure, serum levels are not an accurate guide to therapy and the goal should be to attain adequate free concentrations, typically, 1 to 2 μg/mL. In addition, uremia causes the accumulation of phenytoin metabolites, which are measured with the parent drug by enzyme-multiplied immunoassay techniques. In patients who are being dialyzed, total blood levels of phenytoin tend to be low because of decreased protein binding; in this situation it is also necessary to track free (unbound) levels as it is for other highly protein bound drugs. Because dialysis removes many drugs, particularly levetiracetam, phenobarbital, topiramate, ethosuximide, and gabapentin, dosage of these drugs may have to be increased or doses may have to be administered after dialysis.

Skin Eruptions From Antiepileptic Drugs Rashes are the most frequent idiosyncratic reactions to the drugs used to treat epilepsy. The aromatic compounds (phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine) are the ones most often responsible. Furthermore, there is a high degree of cross-reactivity within this group, particularly between phenytoin, carbamazepine, and phenobarbital, and possibly, lamotrigine. The problem arises most often in the first month of use. The typical eruption is maculopapular, mainly on the trunk; it usually resolves within days of discontinuing the medication. More severe rashes may develop, sometimes taking the form of erythema multiforme and Stevens-Johnson syndrome, or even toxic epidermal necrolysis, especially with lamotrigine, discussed further below. Certain polymorphisms in HLA genes (HLA-B*1502) have been associated with an increased risk of these types of severe skin reactions in those of Asian ancestry. A polymorphism in HLA-A*3101 may be associated with skin eruptions in Caucasians (McCormack and colleagues). Another rare systemic hypersensitivity syndrome associated with the use of antiepileptic medications is one of high fever, rash, lymphadenopathy, and pharyngitis. Eosinophilia and hepatitis (or nephritis) may follow. If any of these reactions require that one of the aromatic drugs be replaced, valproate, gabapentin, topiramate, or levetiracetam are reasonable substitutes, depending, of course, on the nature of the seizures and other factors.

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Discontinuation of Antiepileptic Drugs

Specific Drugs in the Treatment of Seizures

Withdrawal of medications may be undertaken in patients who have been free of seizures for a prolonged period. There are few firm rules to guide the physician in this decision. One plan, applicable to most forms of epilepsy, is to obtain an EEG whenever withdrawal of medication is contemplated. We have taken the approach that if the tracing is abnormal by way of showing paroxysmal activity, it is generally better to continue treatment. However, a normal EEG may not be helpful in making the decision to discontinue medications. A prospective study showed that in patients who had been seizure-free during 2 years of treatment with a single drug, one-third relapsed after discontinuation of the drug, and this relapse rate was much the same in adults and children, and whether the drug was tapered over a period of weeks versus months (Callaghan and colleagues). The relapse rate was lower in patients with absence and generalized-onset seizures than in patients with focal seizures. Another study gave results similar to those of the large Medical Research Council Antiepileptic Drug Withdrawal Study— namely, that after 2 years on a single anticonvulsant during which no seizures had occurred, the rate of relapse was 40 percent 2.5 years later and 50 percent at 5 years after discontinuation; this compared to a seizure recurrence rate of 20 percent for patients remaining on medication (Specchio and colleagues). Some have suggested that a longer seizure-free period is associated with a lesser rate of relapse. Often in practice, the suggestion to stop medications after a lengthy seizure-free period comes from the patient, for example if pregnancy is planned or there are untoward side effects but otherwise, the change is never risk-free and therefore is infrequently impelled by the physician. Decisions regarding the cessation of medication are also tempered by patient’s desire to continue driving and their concern that another seizure may prevent or delay a return to driving. Patients with juvenile myoclonic epilepsy, even those with long seizure-free periods, should probably continue medication life-long, but there have been no thorough studies to support this dictum. In young women with this disorder who plan to become pregnant, changing from valproate to levetiracetam may be sensible. The appropriate duration of treatment for postinfarction epilepsy has not been studied, and most neurologists continue to use one drug indefinitely. Interestingly, epilepsy caused by military brain wounds tends to wane in frequency or to disappear in 20 to 30 years, thereafter, no longer requiring treatment (Caveness). Childhood uncomplicated absence seizures do not require lifelong treatment either. As discussed earlier, a curious and unexplained lesion in the splenium of the corpus callosum has been detected in patients who have had their antiepileptic drug(s) withdrawn in the previous few days. In a review of 16 patients, there was no clinical correlate for this change (Gürtler and colleagues). A broad range of drugs was implicated, and the lesion was most prominent on T2-weighted MRI sequences. Various metabolic derangements cause similar lesions; the mechanism in all these instances has not been established and the lesion is very often reversible (Doherty and colleagues, Garcia-Monco and colleagues).

General Comments

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The putative mechanisms of action of the most commonly used drugs are reasonably well known, but gaps remain. A schematic depiction of putative drug actions at excitatory and inhibitory synapses is adopted in Fig. 15-4 (Bialer and White) and summarized in Table 15-5. There it is apparent that for each of these two physiologic classes of neurons (excitatory and inhibitory), some medications have their main effect on voltage-gated ion channels and others, on membrane receptors or intracellular vesicular activity. Phenytoin, carbamazepine, levetiracetam, and valproate are representative antiepileptic drugs that may be considered “broad spectrum” and are more or less equally effective in the treatment of both generalized and focal seizures (see Table 15-6 for typical initial dosages). The first two of these drugs act by blocking voltage-gated sodium channels, thus preventing abnormal neuronal firing and seizure spread. Lamotrigine has become an alternative for treating focal seizures with a different side effect profile from the other three (Schmidt). Because carbamazepine (or the related oxcarbazepine) and levetiracetam have somewhat fewer side effects, one or the other is preferred as the initial drug by many neurologists, though phenytoin and valproate have very similar therapeutic and side-effect profiles. In many cases, levetiracetam, phenytoin, or carbamazepine alone will control seizures. If not, the use of valproate (which facilitates GABA activity) alone, or the combined use of two medications, produces better control. Levetiracetam has attained popularity largely because of its lack of interactions with other antiepileptic and other medications including chemotherapeutic agents and anticoagulant medications. Carbamazepine, levetiracetam, and valproate are probably preferable to phenytoin for children because they do not coarsen facial features and do not produce gingival hypertrophy or gynecomastia. Because of the high incidence of myoclonic epilepsy in adolescence, it has been the practice of many neurologists to use valproate as the first drug in this age group. Weight gain, menstrual irregularities (see later) during the period of initiation of valproate, and its teratogenic effects also must be accounted for in the choice of initial drug for otherwise uncomplicated seizures in young women. Most of the commonly used antiepileptic drugs cause, to varying degrees, a decrease in bone density and an increased risk of fracture from osteoporosis in older patients, particularly in women. Several mechanisms are probably active, among them, induction of the cytochrome P450 system, which enzymatically degrades vitamin D. No specific recommendations have been offered to counteract this effect of bone loss, but many practitioners have advised patients to take calcium supplements, vitamin D, or one of the bisphosphonates if there is no contraindication, and to periodically check bone density. Finally, several reports and meta-analyses over the past decades have suggested that antiepileptic drugs taken together as a class, increase the incidence of depression and suicide, both in individuals with epilepsy and psychiatric patients. The issue may never be entirely resolved

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Excitatory Synapse Phenytoin, carbamazepine, valproic acid, felbamate, rufinamide, lamotrigine, lacosamide, topiramate, zonisamide, oxcarbazepine

Propagated action potential

Excitatory presynaptic terminal

Na+

Voltage-gated Na+ channel

Depolarization

Gabapentin, Pregabalin

Vesicular release

Glutamate

K+

Felbamate

Postsynaptic neuron

Levetiracetam

SV2A

K+

Topiramate

AMPA and kainate receptors

NMDA receptor Ca2+, Na+

Na+ (Ca2+)

A Inhibitory Synapse Glutamate GAD

Glial cell

GABA

Inhibitory presynaptic terminal

Vigabatrin GABA-T GABA-T Succinic GABA semialdehyde

Succinic semialdehyde Tiagabine GATI

Felbamate, topiramate, zonisamide

GABA

Benzodiazepines

Postsynaptic neuron

GABAA receptor

B

because of confounding factors but a patient level-analysis showed no such relationship in epilepsy once underlying depression was accounted for (Arana and colleagues). However, this assessment was contrary to an earlier FDA meta-analysis and it may not hold for certain drugs, for example, levetiracetam.

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Barbiturates

Cl–

Figure 15-4. Schematic depiction of sites and mechanisms of action of antiepileptic drugs on excitatory and inhibitory synapses. GABA, gamma amino butyric acid; GAD: glutamic acid decarboxylase; GATI: GABA transporter (also known as SLC6A1). (Reproduced with permission from Bialer M, White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov. 2010;9(1):68–82.)

Phenytoin  This sodium channel blocker has been used for decades for focal and generalized seizures. Its advantages are low cost, wide availability, ease of monitoring of blood levels and ability to rapidly achieve therapeutic levels with, oral, intravenous, and intramuscular preparations. Rash, fever, lymphadenopathy, eosinophilia

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and other blood dyscrasias, and polyarteritis are manifestations of idiosyncratic phenytoin hypersensitivity; their occurrence calls for discontinuation of the medication. Overdose with phenytoin causes ataxia, diplopia, and stupor. The prolonged use of phenytoin leads to hirsutism, enlargement of gums from hyperplasia of connective tissue and epithelium with subsequent periodontal disease, and coarsening of facial features in children. A clinical trial suggested that folate supplementation may prevent gingival hyperplasia in children (Arya and colleagues). Chronic phenytoin use over several decades may occasionally be associated with peripheral neuropathy and probably with a form of cerebellar degeneration (Lindvall and Nilsson); it is not clear if these are strictly dose-related effects or idiosyncratic reactions. An antifolate effect on blood and interference with vitamin K metabolism have also been reported, for which reason pregnant women taking phenytoin (and in fact most other antiepileptic drugs) should be given folate supplementation and vitamin K before delivery and the newborn infant also should receive vitamin K to prevent bleeding. Phenytoin should not be used together with disulfiram, chloramphenicol, sulfamethizole, or cyclophosphamide, and the use of either phenobarbital or phenytoin is not advisable in patients receiving warfarin because of the undesirable interactions already described. Choreoathetosis is a rare idiosyncratic side effect. Fosphenytoin for intramuscular and intravenous administration allows somewhat faster attainment of serum levels and may have minor advantages in special circumstances, especially the availability of the IM route. Intravenous phenytoin and fosphenytoin, including their risks, are discussed further in the section on status epilepticus. Carbamazepine  This drug, also a blocker of sodium channels like phenytoin, causes many of the same side effects as phenytoin, but to a slightly lesser degree. There is induction of hepatic enzymes and “autoinduction,” leading to declining drug levels after a few weeks of administration. Mild leukopenia is common, and there have been rare instances of pancytopenia, hepatic enzyme abnormalities, pancreatitis, hyponatremia (resulting from inappropriate antidiuretic hormone [ADH] secretion), and, rarely, diabetes insipidus as idiosyncratic reactions. It is advisable therefore, that a CBC and liver function tests (some practitioners omit the latter because of the infrequency of hepatic problems) be done before or soon after treatment is instituted and that counts are rechecked regularly. Idiosyncratic rashes, some as severe as Stevens-Johnson syndrome and toxic epidermal necrolysis may occur, particularly in Asian individuals carrying the HLA-B*1502 haplotype as mentioned above. It has not been considered useful to check all patients for this haplotype, but screening for the haplotype is recommended in genetically at-risk populations. Oxcarbazepine, an analogue of carbamazepine, has fewer of these side effects than the parent drug, especially marrow toxicity, but its long-term therapeutic value is not as well established. It has the advantage of being titrated upward at a more rapid rate than carbamazepine. Doserelated side effects are similar to carbamazepine but it has less hepatic enzyme induction. Some patients report weight gain after continued use. Hyponatremia has been reported in 3 percent of patients taking oxcarbazepine.

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Should drowsiness or increased seizure frequency occur, this complication should be suspected. Rashes occur at the same or slightly lower rate than with carbamazepine and there is considerable cross-reactivity for this side effect. Elevated cholesterol and osteoporosis are lesser effects, shared also with carbamazepine. Valproate  This drug in all its related forms is considered to be GABA-ergic, acting through glutamic acid decarboxylase, but also displaying some sodium channel blocking features. All preparations of this drug are occasionally hepatotoxic, an adverse effect that is usually (but not invariably) limited to children 2 years of age and younger. The use of valproate with hepatic enzyme-inducing drugs increases the risk of liver toxicity. However, mild elevations of serum ammonia and mild impairments of liver function tests in an adult do not require discontinuation of the drug. An increasingly emphasized problem with valproate has been weight gain during the first months of therapy. In one study there was an average addition of 5.8 kg, and even more in those disposed to obesity. In addition, menstrual irregularities and polycystic ovarian syndrome may appear in young women taking the drug, perhaps as a consequence of the aforementioned weight gain. Pancreatitis is a rare but important complication of valproate. Tremor and slight bradykinesias have been seen and they vaguely simulate parkinsonism. The major issues, however, pertain to its use in pregnancy as discussed earlier. An intravenous form of valproate is available and may be useful in status epilepticus. The maximum recommended rate of administration is 3 mg/kg per min. Phenobarbital  Introduced as an antiepileptic drug in 1912, it is as effective as phenytoin and carbamazepine, but because of its dose-related toxic effects—drowsiness and mental dullness, nystagmus, and staggering, as well as the availability of better alternatives—it is now infrequently used in adults. It inhibits sodium currents through the sodium channel and has been found to have some additional GABAergic effect. The drug strongly induces cytochrome P450 and therefore has interactions with many medications. There are infrequent disorders of connective tissue, such as frozen shoulder and Dupuytren contractures that have been attributed to long-term use. The adverse effects of primidone are much the same. Both drugs may provoke behavioral problems in developmentally delayed children, and they are still used to advantage as an adjunctive anticonvulsant and as primary therapy in infantile seizures. The rate of teratogenicity is increased (stated to be approximately 5.5 percent) and comparable to other main-line drugs. Lamotrigine  This drug closely resembles phenytoin in having a broad spectrum of antiseizure activity but has different features relating to toxicity. It functions by selectively blocking the slow sodium channel, thereby preventing the release of the excitatory transmitters glutamate and aspartate. It is effective as a first-line and adjunctive drug for generalized and focal seizures and may be an alternative to valproate in young women because it does not provoke weight gain and ovarian problems. The main limitation to its use has been a serious rash in approximately 1 percent of patients, requiring discontinuation of the drug, and lesser dermatologic eruptions in 12 percent. It should be pointed out that some registries have reported considerably lower

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rates of these complications and the slow introduction of the medication may reduce the incidence of drug eruptions (see Skin Eruptions From Antiepileptic Drugs). Rare cases of reversible chorea have been reported, especially with the concurrent use of phenytoin. Combined use with valproate greatly increases the serum level of lamotrigine. It has been said to have a more favorable teratogenic profile than most other drugs. Dosing depends greatly on the concurrent use of other drugs, reducing its dose and rapidity of escalation if used with other enzyme-inducing AEDs such as phenytoin or carbamazepine and particularly with valproate. Levetiracetam  This novel drug with uncertain mechanism has been useful in the treatment of both partial and generalized seizures. The agent interacts with the SV2A synaptic vesicle protein, but how this relates to its antiepileptic properties is still being investigated. It is well tolerated if initiated slowly but may produce considerable sleepiness and dizziness if used at high doses. It also may produce irritability and depression or exaggerate underlying depression, even to the point of suicidality. A major advantage is that there are no important interactions with other antiepileptic drugs and it is renally excreted for which reason it is often chosen as a first-line agent in patients who have organ failure and require numerous medications, as well as those receiving hepatically metabolized chemotherapeutics. There are some data showing a favorable teratogenic profile. Other antiepileptic drugs  Two other drugs, gabapentin and vigabatrin, were synthesized specifically to enhance the intrinsic inhibitory system of GABA in the brain. Gabapentin is chemically similar to GABA, but its anticonvulsant mechanism is not known; it has an apparent effect on calcium channels. It is moderately effective in partial and secondary generalized seizures and has the advantage of not being metabolized by the liver. Vigabatrin inhibits GABA transaminase. Vigabatrin is no longer used in adults because of the side effect of photoreceptor retinal damage. Tiagabine is considered to be an inhibitor of GABA reuptake. Topiramate has much the same mode of action and probably a broader effectiveness as tiagabine. It will rarely cause serious dermatologic side effects, especially if used with valproate, and appears to induce renal stones in 1.5 percent of patients, lower in women. Angle-closure glaucoma has also been reported as a complication. A minor problem has been the development of hyperchloremic metabolic acidosis. It has high teratogenicity in most studies. Lacosamide, a potent drug for seizures that have a focal onset and generalize or remain focal, is currently used mainly as an adjunctive therapy. Like levetiracetam, its mechanism of action is not entirely known but it has been shown to modulate voltage-gated sodium channel activity. It may be titrated upward rapidly and has limited pharmacokinetic interactions, but its effective range of blood levels is narrow; also, like levetiracetam, it is renally excreted. The availability of an intravenous preparation is also notable. The main but infrequent side effects are headache and diplopia. The drug may prolong the P-R interval and worsen heart failure for which reason an ECG is often checked. Ethosuximide and valproate are equally effective for the treatment of absence seizures, the former having fewer

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cognitive side effects (Glauser and colleagues). The use of ethosuximide is virtually limited to this indication. It is good practice, to avoid excessive sleepiness, to begin with a single dose of 250 mg of ethosuximide per day and to increase it every week until the optimum therapeutic effect is achieved. Methsuximide is useful in individual cases where ethosuximide and valproate have failed. In patients with benign absence attacks that are associated with photosensitivity, myoclonus, and clonic or tonic-clonic seizures (including juvenile myoclonic epilepsy), valproate is the drug of choice. Valproate is particularly useful in children who have both absence and grand mal attacks, as the use of this drug alone often permits the control of both types of seizures. The concurrent use of valproate and clonazepam has been known to produce absence status. Zonisamide, similar to topiramate, seems to be useful for myoclonic epilepsy but its main use is currently as an adjuvant. It is not predominantly a sodium channel blocker and can be taken with carbamazepine. Some clinicians have found it to produce fewer cognitive side effects than topiramate. New antiepileptic medications are being introduced regularly, among the newer ones is brivaracetam that is likely to display broad activity against seizure types and lack of interaction with other medications seen with levetiracetam. Perampanel, retigabine, rufinamide, pregabalin, felbamate, eslicarbazepine, and several in the benzodiazepine class including clobazam find special use, mostly in epilepsy clinics that treat recalcitrant seizures. The medications used in the neonatal and infant population are discussed below.

Treatment of Seizures in the Neonate and Young Child This specialized area of neonatal seizures is discussed by Volpe, and in children, by Guerrini. In general, phenobarbital has been preferred for seizure control in infancy. Probably the form of epilepsy that is most difficult to treat is the childhood Lennox-Gastaut syndrome. Some of these patients have as many as 50 or more seizures per day, and there may be no effective combination of anticonvulsant medications. Valproic acid (900 to 2,400 mg/d) will reduce the frequency of spells in approximately half the cases. Some of the relatively newer drugs—lamotrigine, topiramate, vigabatrin—are each effective in approximately 25 percent of cases. Clonazepam also has had limited success. In the case of Dravet syndrome, a disorder of the sodium channel, antiepileptic drugs that block that channel are avoided (see Cannabinoids, below). In the treatment of infantile spasms, ACTH or adrenal corticosteroids had been used, but vigabatrin is now found to be as effective, including in patients with underlying tuberous sclerosis (Elterman and colleagues).

Status Epilepticus Recurrent generalized convulsions at a frequency that precludes regaining of consciousness in the interval between seizures (convulsive status) constitutes the most serious problem in epilepsy, with an overall mortality previously reported at 20 to 30 percent (Towne and colleagues), but has been lower in more recent years. Some patients who

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die of epilepsy do so because of uncontrolled seizures of this type, complicated by the effects of the underlying illness or an injury sustained as a result of a convulsion. Rising temperature, acidosis, hypotension, and renal failure from myoglobinuria are a sequence of life-threatening events that may be encountered in cases of convulsive status epilepticus. Prolonged convulsive status (for longer than 30 min) also carries a risk of serious neurologic sequelae (epileptic encephalopathy). The MRI during and for days after a bout of status epilepticus may show signal abnormalities in the region of a focal seizure or in the hippocampi, most often reversible, but we have had several such patients who awakened and were left in a permanent amnesic state. The MRI changes are most evident on T2 and diffusion-weighted sequences. With regard to acute medical complications, from time to time a case of neurogenic pulmonary edema is encountered during or just after the convulsions, and some patients may become extremely hypertensive, making it difficult to distinguish the syndrome from hypertensive encephalopathy. The etiologies of status epilepticus vary among age groups, but all the fundamental causes of seizures are able to produce the syndrome. The most recalcitrant cases we have encountered in adults have been associated with viral or paraneoplastic encephalitis, old traumatic injury, and epilepsy with severe mental retardation. Stroke and brain tumor have, in contrast, been infrequent causes. Several groups have emphasized autoimmune forms of encephalitis including the paraneoplastic variety as the most common explanations for new-onset refractory status epilepticus but add that over half of cases remain cryptogenic (Gaspard and coworkers).

Treatment of Convulsive Status Epilepticus (Table 15-8) The many regimens that have been proposed for the treatment of status epilepticus attest to the fact that no one of them is altogether satisfactory and none is clearly superior (Treiman and colleagues). We have had the success with the following program, which reflects several published approaches (Bleck). When the patient is first seen, an initial assessment of cardiorespiratory function is made and an oral airway established. A large-bore intravenous line is inserted; blood is drawn for glucose, BUN, electrolytes, and a metabolic and drug screen. A normal saline infusion is begun and a bolus of glucose is given (with thiamine if malnutrition and alcoholism are potential factors). To rapidly suppress the seizures, we generally use diazepam intravenously at a rate of about 2 mg/min until the seizures cease or a total of 20 mg has been given; alternatively, lorazepam, 0.1 mg/kg given by intravenous push at a rate not to exceed 2 mg/min, is now favored, being marginally more effective than diazepam because of its clinically longer duration of action (see Table 15-8). Immediately thereafter, a loading dose (20 mg/kg) of phenytoin is administered by vein at a rate of less than 50 mg/min. More rapid administration risks hypotension and heart block; consequently, it is recommended that the blood pressure and electrocardiogram be monitored during the infusion. Phenytoin must be given through a freely running line with normal saline (it precipitates in

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Table 15-8 APPROACH TO THE TREATMENT OF STATUS EPILEPTICUS IN ADULTS Initial assessment   Ensure adequate ventilation, oxygenation, blood pressure   Intubate if necessary, based on low oxygen saturation and   labored breathing   Insert intravenous line   Administer glucose and thiamine in appropriate circumstances   Send toxic screen   Assess quickly for cranial and cervical injury if onset of seizures   is unwitnessed Immediate suppression of convulsions   Lorazepam or diazepam, 2 to 4 mg/min IV to a total dose of 10 to  15 mg with blood pressure monitoring when higher rates or doses are used Initiation or reloading with anticonvulsants   Phenytoin 15–20 mg/kg IV at 25–50 mg/min in normal saline or   fosphenytoin at 50 to 75 mg/min General anesthetic doses of medication for persistent status epilepticus   Midazolam 0.2 mg/kg loading dose followed by infusion at   0.1 to 0.4 mg/kg/h or propofol 2 mg/kg/h Further treatment if convulsions or electrographic seizures persist after several hours   May add valproate or phenobarbital 10 mg/min to total dose of  20 mg/kg as additional anticonvulsants intravenously, or carbamazepine or levetiracetam by nasogastric tube if there is gastric and bowel activity   Consider neuromuscular paralysis with EEG monitoring if   convulsions persist   Pentobarbital 10 mg/kg/h   Inhalational anesthetics (isoflurane)

other fluids) and should not be injected intramuscularly. A study has demonstrated the superiority of using lorazepam instead of phenytoin as the first drug to control status, but this is not surprising considering the longer latency of onset of phenytoin (Treiman and colleagues). Recently intravenous valproate 40 mg/kg or levetiracetam 60 mg/kg have been used as alternatives to phenytoin. In the field, emergency medical technicians can administer lorazepam or midazolam. Attesting to the benefit of rapidly treating seizures, it has been shown that intramuscular administration is slightly superior to the intravenous route simply because of the delay in inserting an intravenous line (Silbergleit and colleagues). It has also been shown that diazepines can be administered by paramedical workers in nursing homes with good effect in status epilepticus, terminating the seizures in about half of cases (Alldredge and colleagues). Nonetheless, a long-acting antiseizure medication such as phenytoin must be given immediately after a diazepine has controlled the initial seizures. An alternative is the water-soluble drug fosphenytoin, which is administered in the same dose equivalents as phenytoin but can be injected at twice the maximum rate. Moreover, it can be given intramuscularly in cases where venous access is difficult. However, the delay in hepatic conversion of fosphenytoin to active phenytoin makes the latency of clinical effect approximately the same for both drugs.

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In an epileptic patient known to be taking seizure medications chronically but in whom the serum level of drug is unknown, it is probably best to administer the full recommended dose of phenytoin. If it can be established that the serum phenytoin is above 10 mg/mL, a lower loading dose may be advisable. If seizures continue, an additional 5 mg/kg is indicated. If this fails to suppress the seizures and status has persisted for 20 to 30 min, an endotracheal tube should be inserted and O2 administered. Having emphasized the dangers of this syndrome, at each stage of treatment it is worthwhile considering if a refractory convulsive episode is of psychogenic, nonepileptic nature. The reader is referred to the previous section on this subject. Several approaches have been suggested to control status epilepticus that persists after these efforts. At this stage we have resorted to the approach of giving high doses of midazolam (0.2 mg/kg loading dose followed by an infusion of 0.1 to 0.4 mg/kg/h as determined by clinical and EEG monitoring) (Kumar and Bleck). If seizures continue, the dose can be raised as blood pressure permits. We have used in excess of 20 mg/h because of a diminishing effect over days. This regimen of midazolam and phenytoin may be maintained for several days without major ill effect in previously healthy patients. Propofol given in a bolus of 2 mg/kg and then as an intravenous drip of 2 to 8 mg/kg/h is an effective alternative to midazolam, but after 24 h the drug behaves like a high dose of barbiturate and there may be hypotension. Prolonged use of propofol may precipitate hypertriglyceridemia-associated pancreatitis or a fatal shock and acidosis (propofol syndrome). Valproate, phenytoin, and levetiracetam are available as intravenous preparations, making them suitable for administration in status epilepticus. Metanalyses have variously shown that one of these medications is superior to another (i.e., levetiracetam versus phenytoin), either in terms of treating benzodiazepine-refractory status epilepticus or its safety profile. Another dependable approach is an infusion of either pentobarbital, starting with 5 mg/kg, or phenobarbital, at a rate of 100 mg/min until the seizures stop or a total dose of 20 mg/kg is reached; a long period of stupor must be anticipated after. Hypotension often limits the continued use of the barbiturates, but this problem can be managed by fluid infusions, dopamine, and neosynephrine (Parviainen and colleagues). If none of these measures controls the seizures, a more aggressive approach is taken to temporarily subdue all brain electrical activity using general anesthesia. The preferred medications for this purpose have been pentobarbital or propofol, which, despite their moderate efficacy as primary anticonvulsants, are easier to manage than the alternative inhalational anesthetic agents. An initial intravenous dose of 5 mg/kg pentobarbital or 2 mg/kg propofol is given slowly to induce an EEG burst-suppression pattern, which is then maintained by the administration of pentobarbital, 0.5 to 2 mg/kg/h, or propofol, up to 10 mg/kg/h. Every 12 to 24 h, the rate of infusion is slowed to determine whether the seizures have stopped. Most instances of status epilepticus that cannot be controlled with the combination of standard anticonvulsants and midazolam will respond

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to high doses of barbiturates or to propofol, but these infusions cause hypotension and cannot be carried out for long periods (Lowenstein and Aldredge). More recent work has shown that prolonged infusions of neurosteroid medications such as allopregnanolone, a modulator of synaptic and extrasynaptic GABAA receptors, may be effective as an adjunctive agent in treating highly refractory status epilepticus (Vaitkevicius and colleagues). Even a ketogenic diet, more commonly employed in childhood epilepsy as discussed further on, has been suggested as an ancillary treatment in these difficult cases of truly refractory status epilepticus (Thakur and colleagues). Should the seizures continue, either clinically or electrographically, despite all these medications, one is justified in the assumption that the convulsive tendency is so strong that it cannot be checked by reasonable quantities of medications. However, a few patients in this predicament have survived and awakened, even at times with minimal neurologic damage depending on the underlying cause. The volatile anesthetic agent isoflurane has also been used in these circumstances with good effect, as we have reported (Ropper and colleagues), but the continuous administration of inhalational anesthetic agents is impractical in most critical care units. Halothane has been relatively ineffective as an anticonvulsant, but ether, although impractical, has in the past been effective in some. In the end, in patients with truly intractable status, one usually depends on phenytoin, phenobarbital (smaller doses in infants and children than are shown in Table 15-8), and on measures that safeguard the patient’s vital functions. Ketamine infusions have been a last resort, in combination with a midazolam infusion. A few times over the years, we have also resorted to inducing ketosis in adults by manipulating the nutrition given through a nasogastric tube. As a cautionary note, a series suggested that adverse events such as infection as well as mortality are higher in patients receiving intravenous anesthetic drugs compared to those who did not receive them but the possibility of confounding by the severity of illness must be taken into account before accepting a causal relationship (Sutter and colleagues, 2014). A word is added here concerning neuromuscular paralysis and continuous EEG monitoring in status epilepticus. With failure of aggressive anticonvulsant and anesthetic treatment, there may be a temptation to paralyze all muscular activity, an effect easily attained with drugs such as pancuronium, while neglecting the underlying seizures. The use of neuromuscular blocking drugs without a concomitant attempt to suppress seizure activity is inadvisable. If such measures are undertaken, continuous or frequent intermittent EEG monitoring is essential; this may also be also helpful in the early stages of status epilepticus in that it guides the dosages of anticonvulsants required to suppress the seizures. In the related but less-serious condition of acute repetitive seizures, in which the patient awakens between convulsions, a diazepam gel, which is well absorbed if given rectally, is available and has been found useful in institutional and home care of epileptic patients. A similar effect has been attained by the nasal or buccal (transmucosal)

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administration of midazolam, which is absorbed from these sites (5 mg/mL, 0.2 mg/kg nasally; 2 mL to 10 mg buccally). Midazolam may be preferred among the diazepines for transmucosal use because it produces somewhat less respiratory depression than the others in the class and has been more effective at controlling seizures (McIntyre and colleagues). Still, only half were controlled. These approaches have found their main use in children with frequent seizures who live in supervised environments, where a nurse or parent is available to administer the medication. Absence status should be managed by intravenous lorazepam, valproic acid, or both, followed by ethosuximide. Nonconvulsive generalized status is treated along the lines of convulsive status, usually stopping short of using anesthetic agents (Meierkord and Holtkamp). In the case of epilepsia partialis continua, typically a difficult condition to fully control, a balance must be found between stopping the phenomenon and the risk of overuse of medications that can produce stupor. The patient must be involved by way of determining how troubling the movements are.

Surgical Treatment of Epilepsy The surgical excision of epileptic foci that have not responded to intensive and prolonged medical therapy is being used with increasing effectiveness. At these centers, it has been estimated that approximately 25 percent of all patients with epilepsy are candidates for surgical therapy and more than half of these may benefit from extirpation of the epileptic cortical focus. With increasing experience and standardized approaches, especially in patients with temporal lobe epilepsy, it has been suggested that many patients are waiting too long before the surgical option is employed. A perspective that may promote surgery even further is the observation that approximately 60 percent of patients with focal seizures will respond to a conventional anticonvulsant, but that among the remainder, few will respond to the addition of a second or third drug. However, considerable effort, time, and technology are required to determine the site of epileptic discharge and the method of safe removal of the cortical tissue. To locate the discharging focus requires a careful analysis of clinical, imaging, and EEG findings, often including those obtained by long-term video/EEG monitoring and, sometimes, intracranial EEG recording by means of intraparenchymal depth electrodes and subdural strip and grid electrodes. Functional imaging, magnetoencephalography, and EEG power spectrum analysis have been introduced to supplement these methods. The most favorable candidates for surgery are those with focal seizures that induce altered consciousness and a unilateral temporal lobe focus. In this group, rates of cure and significant improvement approach 90 percent in some series but overall, are probably closer to 50 percent after 5 years. A randomized trial gave representative results after temporal lobectomy of 58 percent of 40 carefully studied patients remaining seizure-free after 1 year, in contrast to 8 percent on medication alone (Wiebe and colleagues). Furthermore, among those patients who remain free of

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seizures for 1 year after surgery, more than half are still free of seizures after 10 years and most of the remainder had one or fewer episodes per year (Yoon and colleagues). It should be emphasized that most of the patients who underwent surgery in these studies still required anticonvulsant medication. Even in the group of patients with temporal lobe foci who have no lesion on MRI but have subtle signal changes in the hippocampus, 60 percent of patients can be made free of disabling seizures with surgery (Bell and colleagues). Of course, as discussed earlier, advances in MRI, especially the use of higher field strength magnets, have permitted the detection of subtle lesions that may have been missed in earlier studies. Excision of cortical tissue that contains a structural lesion outside of the temporal lobe accomplishes complete seizure-free states in approximately 50 percent. Taking all seizure types together, only approximately 10 percent of patients obtain no improvement at all and less than 5 percent are worse. The matter of resection of areas of focal cortical dysplasias in children is a highly specialized area. The histologic features of the dysplasia (Blümcke and Spreafico), including their association with other lesions such as tumors and vascular malformations are important determinants of the success of surgery (Fauser and colleagues). A single-center study of 116 children with drug-resistant epilepsy has showed greater freedom from seizures and improved quality of life in those who underwent epilepsy surgery compared to those who received only medical therapy (Dwivedi and colleagues). Other surgical procedures of value in highly selected cases are sectioning of the corpus callosum, which is for the most part palliative, and hemispherectomy, which may be curative in special circumstances. The most encouraging results with callosotomy have been obtained in the control of intractable partial and secondarily generalized seizures, particularly when atonic drop attacks are the most disabling seizure type. Removal of the entire cortex of one hemisphere, in addition to the amygdala and hippocampus, has been of value in children, as well as in some adults with severe and extensive unilateral cerebral disease and intractable contralateral motor seizures and hemiplegia. Rasmussen encephalitis, Sturge-Weber disease, and large porencephalic cysts at times fall into this category. Surgical, focused radiation, or endovascular reduction of arteriovenous malformations may reduce the frequency of seizures, but the results in this regard are somewhat unpredictable (see Chap. 34).

Vagal Nerve Stimulation This technique has found some favor in cases of intractable partial and secondarily generalizing seizures. A pacemaker-like device is implanted in the anterior chest wall and stimulating electrodes are connected to the vagus nerve at the left carotid bifurcation. The procedure is well tolerated except for hoarseness in some cases. Several trials have demonstrated an average of 25 percent reduction in seizure frequency among patients who were resistant to all manner of anticonvulsant drugs (Vagus Nerve Stimulation Study Group; and Chadwick). The mechanism by which vagal stimulation produces its effects is unclear,

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Chapter 15 Epilepsy and Other Seizure Disorders

and its role in the management of seizures continues to be studied. Stimulation of the cerebellum and of other sites in the brain has also been used in the control of seizures, with no clear evidence of success.

Ketogenic Diet Since the 1920s, interest in this form of seizure control has varied, being revived periodically in centers caring for many children with intractable epilepsy. Despite the absence of controlled studies showing its efficacy or an agreed-on hypothesis for its mechanism, several trials in the first half of the twentieth century, and again more recently, demonstrated a reduction in seizures in half of the patients, including handicapped children with severe and sometimes intractable episodes. The diet is used mainly in children between the ages of 1 and 10 years. The regimen is initiated during hospitalization by starvation for a day or two to induce ketosis, followed by a diet in which 80 to 90 percent of the calories are derived from fat (Vining). The difficulties in making such a diet palatable leads to its abandonment by about one-third of children and their families. A summary of experience from the numerous trials of the ketogenic diet has been reviewed (Lefevre and Aronson) and its use in a study of 58 children has been reported (Kinsman and colleagues). The diet was found to be effective in refractory cases of epilepsy in childhood, reducing seizure frequency in two-thirds of children and allowing a reduction in the amount of anticonvulsant medication in many. It has also been commented that some benefit persists even after the diet has been stopped. Nephrolithiasis is a complication in somewhat less than 10 percent of children, and this risk is particularly high if topiramate is being used. The ketogenic diet is the main treatment for children with GLUT1 deficiency syndrome.

Cannabinoids For lack of a better place to comment, we note that cannabinoids are being introduced for the treatment of epilepsy, most prominently to date in cases of Dravet syndrome. A double-blind placebo-controlled trial in children and young adults with Dravet syndrome and drug-resistant seizures showed a reduction in frequency of convulsive seizures as well as an improvement in overall condition as reported by caregivers in those treated with cannabidiol compared to placebo, but also a higher rate of adverse events in the cannabidiol group (Devinsky and colleagues, 2017).

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Safety and Regulation of Physical and Mental Activity Driving and Epilepsy A person with incompletely controlled epilepsy should not be allowed to drive an automobile. Only a few states in the United States and most provinces of Canada mandate that physicians report patients with seizures under their care to the state motor vehicle bureau. Nonetheless, physicians should counsel such a patient regarding the obvious danger to himself and others if a seizure should occur while driving (the same holds for the risks of swimming, bathing, climbing, or operating machinery unattended). What few data are available suggest that accidents caused directly by a seizure are rare and, in any case, 15 percent have been the result of a first episode of seizure that could not have been anticipated. In some states where a driver’s license has been suspended on the occurrence of a seizure, there is usually some provision for its reinstatement—such as a physician’s declaration that the patient is under medical care and has been seizure-free for some period of time (usually 6 months or 1 to 2 years). The Epilepsy Foundation website can be consulted for updated information regarding restrictions on driving, and this serves as an excellent general resource for patients and their families (http://www.efa.org).

General Health Measures The most important factors in seizure breakthrough, next to the abandonment of medication or a natural reduction of serum levels of medication, are loss of sleep and abuse of alcohol or other drugs. The need for moderation in the use of alcohol must be stressed, as well as the need to maintain regular hours of sleep. With proper safeguards, even potentially more dangerous sports, such as swimming, may be permitted. However, operating unguarded machinery, climbing ladders, or taking baths behind locked doors are not advisable; such a person should swim only in the company of a good swimmer. There is concern about mothers with epilepsy bathing their infants without additional safety guards. Psychosocial difficulties are common and must be identified and addressed early. The stigma of epilepsy remains an issue in society. Advice and reassurance to attempt to pursue a normal life will aid in preventing or overcoming any feelings of inferiority and self-consciousness of many younger patients with epilepsy. However, the situation is rarely so simple, and patients and their families may benefit from more extensive counseling.

References Afawi Z, Oliver KL, Kivity S, et al: Multiplex families with epilepsy. Neurol 86:718, 2016. Alldredge BK, Gelb AM, Isaacs SM, et al: A comparison of lorazepam, diazepam, and placebo for the treatment of out-ofhospital status epilepticus. N Engl J Med 345:631, 2001. Alsfouk BAA, Brodie MJ, Walters M, et al: Tolerability of antiseizure medications in individuals with newly diagnosed epilepsy. JAMA Neurol 77:574, 2020.

Ropper_Ch15_p0319-p0360.indd 357

Annegers JF, Hauser WA, Shirts SB, Kurland LT: Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 316:493, 1987. Antel JP, Rasmussen T: Rasmussen’s encephalitis and the new hat. Neurol 46:9, 1996. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM: Suicide related events in patients treated with antiepileptic drugs. N Engl J Med 363:542, 2010.

10/02/23 6:10 PM

358

Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE

Arya R, Gulati S, Kabra M, et al: Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurol 76:1338, 2011. Baykan B, Altindag EA, Bebek N, et al: Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy. Neurol 70:2123, 2008. Bear DM, Fedio P: Quantitative analysis of interictal behavior in temporal lobe epilepsy. Arch Neurol 34:454, 1977. Bell ML, Rao So EL, et al: Epilepsy surgery outcomes in temporal lobe epilepsy with a normal MRI. Epilepsia 50:2053, 2009. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51:676, 2010. Bialer N, White HS: Key factors in the discovery and development of new antiepileptic drugs. Nature Rev Drug Discov 9:68, 2010. Bien CG, Benninger FO, Urbach H, et al: Localizing value of epileptic visual auras. Brain 123:244, 2000. Bien CG, Granata T, Antozzi C, et al: Pathogenesis, diagnosis and treatment of Rasmussen encephalitis. Brain 128:454, 2005. Birnbaum AK, Meador KJ, Karanam A, et al: Antiepileptic drug exposure in infants of breastfeeding mothers with epilepsy. JAMA Neurol 77:441, 2020. Bleck TP: Intensive care unit management of patients with status epilepticus. Epilepsia 48 (Suppl 8):59, 2007. Blümcke I, Spreafico R: An international consensus classification for focal cortical dysplasias. Lancet Neurol 10:26, 2011. Bonnett LJ, Smith CT, Donegan S, Marson AG: Treatment outcome after failure of a first antiepileptic drug. Neurol 83:552, 2014. Callaghan N, Garrett A, Goggin T: Withdrawal of anticonvulsant drugs in patients free of seizures for two years. N Engl J Med 318:942, 1988. Cascino GD: Intractable partial epilepsy: Evaluation and treatment. Mayo Clin Proc 65:1578, 1990. Caveness WF: Onset and cessation of fits following craniocerebral trauma. J Neurosurg 20:570, 1963. Chadwick D: Vagal nerve stimulation for epilepsy. Lancet 357:1726, 2001. Chinchilla D, Dulac O, Roban O, et al: Reappraisal of Rasmussen syndrome with special emphasis on treatment with high dose steroids. J Neurol Neurosurg Psychiatry 57:1325, 1994. Cunningham M, Tennis P: Lamotrigine and the risk of malformations in pregnancy. Neurol 64:955, 2005. Currie S, Heathfield KWG, Henson RA, Scott DF: Clinical course and prognosis of temporal lobe epilepsy. Brain 94:173, 1971. Devinsky O, Kelley K, Yacubian EM, et al: Postictal behavior: A clinical and subdural electroencephalographic study. Arch Neurol 51:254, 1994. Devinsky O: Sudden unexpected death in epilepsy. N Engl J Med 365:1801, 2011. Devinsky O, Hesdorffer DC, Thurman DJ, et al: Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol 15:1075, 2016. Devinsky O, Cross JH, Laux L, et al: Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 376:2011, 2017. Dixit S, Kurle P, Buyan-Dent L, Sheth RD: Status epilepticus associated with cefepime. Neurol 54:2153, 2000. Doherty MJ, Jayadev S, Watson NF, et al: Clinical implications of splenium magnetic resonance imaging changes. Arch Neurol 62:433, 2005. Dwivedi R, Ramanujam B, Chandra PS, et al: Surgery for drugresistant epilepsy in children. N Engl J Med 377:1639, 2017. Ebner A, Dinner DS, Noachtar S, Luders H: Automatisms with preserved responsiveness: A lateralizing sign in psychomotor seizures. Neurol 45:61, 1995.

Ropper_Ch15_p0319-p0360.indd 358

Eclampsia Trial Collaborative Group: Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 345:1455, 1995. Englot DJ, Yang L, Hamid H, et al: Impaired consciousness in temporal lobe seizures: role of cortical slow activity. Brain 133:3764, 2010. Elterman RD, Shields WD, Mansfield KA, et al: Randomized trial of vigabatrin in patients with infantile spasms. Neurol 57:1416, 2001. Engel J Jr, Pedley TA: Epilepsy: A Comprehensive Textbook. Philadelphia, Davis, 1998. EURAP Study Group. Seizure control and treatment in pregnancy. Neurol 66:354, 2006. Falconer MA: Genetic and related aetiological factors in temporal lobe epilepsy: A review. Epilepsia 12:13, 1971. Fauser S, Bast T, Altenmüller DM, et al: Factors influencing surgical outcome in patients with focal cortical dysplasia. J Neurol Neurosurg Psychiatry 79:103, 2008. Fisher RS, Chan DW, Bare M, et al: Capillary prolactin measurements for diagnosis of seizures. Ann Neurol 29:187, 1991. Fisher RS, Cross JH, French JA, et al: Operational classification of seizure types by the International League Against Epilepsy: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:522, 2017. Forster FM: Reflex Epilepsy, Behavioral Therapy, and Conditional Reflexes. Springfield, IL, Charles C Thomas, 1977. French JA, Williamson PD, Thadani VM, et al: Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 34:774, 1993. Friedman D, Devinsky O: Cannabinoids in the treatment of epilepsy. N Engl J Med 373:1048, 2015. Galovic M, van Dooren VQH, Postma TS, et al: Progressive cortical thinning in patients with focal epilepsy. JAMA Neurol 76:1230, 2019. Garcia-Monco JC, Cortina IE, Ferreira E, et al: Reversible splenial lesion syndrome (RESLES): what’s in a name? J Neuroimaging 21:1, 2011. Gaspard N, Foreman BP, Alvarez V, et al: New-onset refractory status epilepticus. Neurol 85:1604, 2015. Gastaut H, Aguglia U, Tinuper P: Benign versive or circling epilepsy with bilateral 3-cps spike and wave discharges in late childhood. Ann Neurol 9:301, 1986. Geschwind N: Interictal behavioral changes in epilepsy. Epilepsia 24(Suppl):523, 1983. Glauser TA, Craan A, Shinnar S, et al: Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362:790, 2010. Gloor P: Experiential phenomena of temporal lobe epilepsy: Facts and hypothesis. Brain 113:1673, 1990. Goldensohn E: The relevance of secondary epileptogenesis to the treatment of epilepsy: Kindling and the mirror focus. Epilepsia 25(Suppl 2):156, 1984. Gowers WR: Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms and Treatment. New York, Dover, 1964 (originally published in 1885; reprinted as volume 1 in The American Academy of Neurology reprint series). Guerrini R: Epilepsy in children. Lancet 367:499, 2006. Guo JN, Kim R, Chen Y, et al: Impaired consciousness in patients with absence seizures investigated by functional MRI, EEG, and behavioural measures: a cross-sectional study. Lancet Neurol 15:1336, 2016. Gürtler S, Ebner A, Tuxhorn I, et al: Transient lesion in the splenium of the corpus callosum and antiepileptic drug withdrawal. Neurol 11;65(7):1032, 2005. Hauser WA, Annegers JF: Epidemiology of epilepsy. In: Laidlaw JP, Richens A, Chadwick D (eds): Textbook of Epilepsy, 4th ed. New York, Churchill Livingstone, 1992, pp 23–45.

10/02/23 6:10 PM

Chapter 15 Epilepsy and Other Seizure Disorders Hauser WA, Annegers JF: Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota, 1935–1984. Epilepsia 34:453, 1993. Hauser WA, Kurland LT: The epidemiology of epilepsy in Rochester, Minnesota, 1935–1967. Epilepsia 16:1, 1975. Hauser WA, Rich SS, Lee JR, et al: Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 338:429, 1998. Hesdorfer DC, Logroscina G, Cascino G, et al: Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann Neurol 44:908, 1998. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvulsants. N Engl J Med 344:1132, 2001. Huttenlocher PR, Hapke RJ: A follow-up study of intractable seizures in childhood. Ann Neurol 28:699, 1990. Jellinger K: Neuropathologic aspects of infantile spasms. Brain Dev 9:349, 1987. Jetnik J, Loane MA, Dolk H, et al: Valproic acid monotherapy in pregnancy and major congenital malformations. N Eng J Med 362:285, 2010. Kinsman SL, Vining EP, Quaskey SA, et al: Efficacy of the ketogenic diet for intractable seizure disorders. Epilepsia 33:1132, 1992. Krumholz A, Wiebe S, Gronseth GS, et al: Evidence-based guideline: Management of an unprovoked first seizure in adults. Neurol 84:1705, 2015. Kumar A, Bleck TP: Intravenous midazolam for the treatment of status epilepticus. Crit Care Med 20:438, 1992. Kutt H: Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 25(Suppl 2):188, 1984. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314, 2000. Landau WM, Kleffner FR: Syndrome of acquired aphasia with convulsive disorder in children. Neurology 7:523, 1957. Leestma JE, Walczak T, Hughes JR, et al: A prospective study on sudden unexpected death in epilepsy. Ann Neurol 26:195, 1989. Lefevre F, Aronson N: Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics 105:46, 2000. Lempert T, Bauer M, Schmidt D: Syncope: A videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 36:233, 1994. Lennox MA: Febrile convulsions in childhood. Am J Dis Child 78:868, 1949. Lennox W, Lennox MA: Epilepsy and Related Disorders. Boston, Little, Brown, 1960. Leutzmezer F, Serles W, Lehner J, et al: Postictal nose wiping: A lateralizing sign in temporal lobe complex partial seizures. Neurol 51:1175, 1998. Le Van Quyen M, Martinerie J, Navarro V, et al: Anticipation of epileptic seizures from standard EEG recordings. Lancet 357:189, 2001. Lindvall O, Nilsson B: Cerebellar atrophy following phenytoin intoxication. Ann Neurol 16:258, 1984. Litt B, Esteller R, Echauz J, et al: Epileptic seizures may begin hours in advance of clinical onset: A report of five patients. Neuron 30:51, 2001. Lowenstein DH, Aldredge BK: Status epilepticus. N Engl J Med 338:970, 1998. Lowerison MW, Josephson CB, Jetté N, et al: Association of levels of specialized care with risk of premature mortality in patients with epilepsy. JAMA Neurol 76:1352, 2019. Lucas MJ, Leveno KJ, Cunningham FG: A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 333:201, 1995. Marson A, Jacoby A, Johnson A, et al: Medical Research Council MESS Study Group: Immediate versus deferred antiepileptic

Ropper_Ch15_p0319-p0360.indd 359

359

drug treatment for early epilepsy and single seizures: A randomised controlled trial. Lancet 365:2007, 2005. McCormack M, Alfirevic A, Bourgeois S, et al: HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 354:12, 2011. McIntyre J, Robertson S, Norris E, et al: Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: A randomised controlled trial. Lancet 366:205, 2005. Meador KJ, Baker GA, Browning N, et al: Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Eng J Med 360:1597, 2009. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 337:1175, 1991. Meierkord H, Holtkamp M. Non-convulsive status epilepticus in adults: Clinical forms and treatment. Lancet Neurology 6:329, 2007. Messouak O, Yayaoui M, Benabdeljalil M, et al: La maladie de Lafora a revelation tardive. Rev Neurol 158:74, 2002. Nabbout R, Prud’homme J, Herman A, et al: A locus for simple pure febrile seizures maps to chromosome 6q22-24. Brain 125:2668, 2002. Ohtahara S: Seizure disorders in infancy and childhood. Brain Dev 6:509, 1984. Olsen H, Shen Y, Avallone J, et al: Copy number variation plays and important role in clinical epilepsy. Ann Neurol 75:943, 2014. Palmini AL, Gloor P, Jones-Gotman M: Pure amnestic seizures in temporal lobe epilepsy. Brain 115:749, 1992. Panayiotopoulos CP: Early-onset benign childhood occipital seizure susceptibility syndrome: A syndrome to recognize. Epilepsia 40:621, 1999. Parviainen I, Usaro A, Kalviainen R, et al: High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurol 59:1249, 2002. Pedley TA (ed): Epilepsy: A Comprehensive Textbook. Philadelphia, Li’pincott-Raven, 1998. Penfield W, Jasper HH: Epilepsy and Functional Anatomy of the Human Brain. Boston, Little, Brown, 1954. Pennell PB, French JA, May RC, et al: Changes in seizure frequency and antiepileptic therapy during pregnancy. N Engl J Med 383:2547, 2020. Penry JK, Porter RJ, Dreifuss FE: Simultaneous recording of absence seizures with video tape and electroencephalography. Brain 98:427, 1975. Plouin P: Benign neonatal convulsions (familial and nonfamilial). In: Roger J, Drevet C, Bureau M, et al (eds): Epileptic Syndromes in Infancy, Childhood, and Adolescence. London, John Libbey Eurotext, 1985, pp 2–9. Plum F, Howse DC, Duffy TE: Metabolic effects of seizures. Res Publ Assoc Res Nerv Ment Dis 53:141, 1974. Rasmussen T, Olszewski J, Lloyd-Smith D: Focal seizures due to chronic localized encephalitis. Neurol 8:435, 1958. Rocca WA, Sharbrough FW, Hauser WA, et al: Risk factors for complex partial seizures: A population-based case-control study. Ann Neurol 21:22, 1987. Rodin E, Schmaltz S: The Bear-Fedio personality inventory and temporal lobe epilepsy. Neurol 34:591, 1984. Ropper AH: “Convulsions” in basilar artery disease. Neurol 38:1500, 1988. Ropper AH, Kofke A, Bromfield E, Kennedy S: Comparison of isoflurane, halothane and nitrous oxide in status epilepticus. Ann Neurol 19:98, 1986. Salanova V, Andermann F, Rasmussen T, et al: Parietal lobe epilepsy. Clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988. Brain 118:607, 1995.

10/02/23 6:10 PM

360

Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE

Schmidt D: Starting, choosing, changing and discontinuing drug treatment for epilepsy patients. Neurol Clin 34:363, 2016. Silbergleit R, Durkalski V, Lowenstein D, et al: Intramuscular therapy for prehospital status epilepticus. N Engl J Med 366:591, 2012. Sillanpää M, Shinnar S: Long-term mortality in childhood-onset epilepsy. N Engl J Med 363:252, 2010. Specchio LM, Tramacere L, LaNeve A, Beghi E: Discontinuing anti-epileptic drugs in patients who are seizure-free on monotherapy. J Neurol Neurosurg Psychiatry 72:22, 2002. Sung C, Chu N: Status epilepticus in the elderly: Aetiology, seizure type and outcome. Acta Neurol Scand 80:51, 1989. Sutter R, Marsch S, Fuhr P, et al: Anesthetic drugs in status epilepticus: Risk or rescue. Neurology 82:656, 2014. Sutter R, Rüegg S, Tschudin-Sutter S: Seizures as adverse events of antibiotic drugs. Neurol 85:1332, 2015. Sutula TP, Pitkänen A: More evidence for seizure-induced neuron loss. Is hippocampal sclerosis both cause and effect of epilepsy? Neurol 57:169, 2001. Taylor I, Scheffer IE, Berkovic SF: Occipital epilepsies: Identification of specific and newly recognized syndromes. Brain 126:753, 2003. Thakur KT, Probasco JC, Hocker SE, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurol 82:665, 2014. Thomas JE, Regan TJ, Klass DW: Epilepsia partialis continua: A review of 32 cases. Arch Neurol 34:266, 1977. Towne AR, McGee FE, Mercer EL, et al: Mortality in a community based status epilepticus study. Neurology 40(Suppl 1):229, 1990. Treiman DM, Meyers PD, Walton NY, et al: A comparison of four treatments for generalized status epilepticus. N Engl J Med 339:792, 1998. Trimble MR: Personality disturbance in epilepsy. Neurol 33:1332, 1983. Tumani H, Jobs C, Brettschneider I: Effect of epileptic seizures on the cerebrospinal fluid: A systematic retrospective analysis. Epilepsy Res 114:23, 2015. Twyman RE, Gahring LC, Spiess J, Rogers SW: Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site. Neuron 14:755, 1995.

Ropper_Ch15_p0319-p0360.indd 360

Vadlamudi L, Milne RL, Lawrence K, et al: Genetics of epilepsy. The testimony of twins in the molecular era. Neurol 83:1042, 2014. Vaitkevicius H, Husain AM, Rosenthal ES, et al: First-in-man allopregnanolone use in super-refractory status epilepticus. Ann Clin Transl Neurol 4:411, 2017. Vagus Nerve Stimulation Study Group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurol. 45:224, 1995. Varadkar S, Bien CG, Kruse CA, et al: Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 13:195, 2014. Villani F, Pincherle A, Antozzi C, et al: Adult-onset Rasmussen’s encephalitis: Anatomical-electrographic-clinical features. Epilepsia 47:41, 2006. Vining EP: The ketogenic diet. Adv Exp Med Biol 497:225, 2002. Volpe JJ: Neurology of the Newborn, 4th ed. Philadelphia, Saunders, 2001. Walder B, Tramer MR, Seeck M: Seizure-like phenomena and propofol. A systematic review. Neurol 58:1327, 2002. Waxman SG, Geschwind N: The interictal behavior syndrome of temporal lobe epilepsy. Arch Gen Psychiatry 32:1580, 1975. Wendl H, Bien CG, Bernasconi P, et al: GluR3 antibodies: Prevalence in focal epilepsy but not specific for Rasmussen’s encephalitis. Neurol 57:1511, 2001. West, WJ (1841): On a peculiar form of infantile convulsions. Lancet 35:724, 1841. Wiebe S, Blume WT, Girvin JP, et al: A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345:311, 2001. Wylie E, Luders H, Morris HH, et al: The lateralizing significance of versive head and eye movements during epileptic seizures. Neurol 36:606, 1212, 1986. Yoon HH, Kwon HL, Mattson RH: Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery. Neurol 61:445, 2003. Zeman AZ, Boniface SJ, Hodges JR: Transient epileptic amnesia: A description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry 64:435, 1998.

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16 Coma and Related Disorders of Consciousness

In hospital and emergency neurology, the clinical analysis of unresponsive and comatose patients is an urgent practical necessity. The underlying disease and the direction in which it is evolving must be determined rapidly in order to protect the brain against irreversible damage. When called upon, the physician must therefore be prepared to implement prompt action that allows little time for deliberate, leisurely investigation. Some idea of the dimensions of the problem of coma, and how little it has changed over time, can be obtained from published statistics. Almost ninety years ago, in two large municipal hospitals, it was estimated that 3 percent of all emergency admissions were for diseases that had caused coma. Alcoholism, cerebral trauma, and cerebrovascular diseases were the most common, accounting for 82 percent of the comatose patients admitted to the Boston City Hospital (Solomon and Aring). Epilepsy, drug intoxication, diabetes, and severe infections were the other major causes. It is perhaps surprising to learn that contemporary figures from large city hospitals differ only slightly, with intoxication, stroke, and cranial trauma still standing as the “big three” of coma-producing conditions. For example, in a series described in the 1980s (Plum and Posner) (Table 16-1), a majority was the result of exogenous (drug overdose) and endogenous (metabolic) intoxications and hypoxia, 25 percent of cases proved to have cerebrovascular disease, and intracranial masses—such as tumors, abscesses, and hemorrhages—made up about one-third of cases. Subarachnoid hemorrhage, meningitis, and encephalitis accounted for another 5 percent. Perhaps the proportions of the main causes have changed but in a more contemporary review of 14 studies of coma etiology, excluding trauma, the main causes were stroke (including intracerebral and subarachnoid hemorrhage), postanoxic coma, poisoning (including intoxication), and metabolic encephalopathy (Horsting et al). Common in many series, although obvious and often transient, is coma that follows seizures or resuscitation from cardiac arrest. The terms consciousness, confusion, stupor, unconsciousness, and coma have been endowed with so many different meanings that it is almost impossible to avoid ambiguity in their usage. They are not strictly medical terms but are also literary, philosophic, and psychologic ones. The word consciousness is the most ambiguous of all. William James remarked that everyone knows what consciousness is until they attempt to define it. To the

psychologist, consciousness denotes a state of continuous awareness of one’s self and environment, essentially selfconsciousness. Knowledge of self includes all “feelings, attitudes and emotions, impulses, volitions, and the active or striving aspects of conduct”; in short, a near continuous self-awareness of a person’s mental functioning, particularly of cognitive processes. These can be judged only by the individual’s verbal account of his introspections and indirectly, by his actions. Physicians, aspiring to be practical, give greater credence to the patient’s behavior and reactions to stimuli than to what the patient reports. In this way the term consciousness is used in its broadest operational meaning— namely, the state of awareness of self and environment, and normal responsiveness to external stimulation and inner need. This narrow definition has an advantage in that unconsciousness has the opposite meaning: A state of unawareness of self and environment or a suspension of those mental activities by which people are made aware of themselves and their environment, coupled with an observable diminished responsiveness to environmental stimuli. The last of these qualities, arousal, or alertness, or the level of consciousness, refers to the appearance of being awake as displayed by the facial muscles, eye opening, fixity of gaze, and body posture, that is, wakefulness. A distinction is made in medicine between the level of consciousness reflected in the degree of alertness, and the content of consciousness, reflecting the quality and coherence of thought and behavior. For neurological purposes, the loss of normal arousal is the more important aspect of disordered consciousness and the one identified by laypersons and physicians as being the central feature of coma. For psychiatry, the bizarre and illogical qualities of psychosis are a component of the study of psychiatric disease. However, there many situations in which a reduced level of alertness and altered content of consciousness coincide. These are characterized as states of confusion, or delirium and are among the most ubiquitous syndromes in medicine as discussed in Chap. 19. Much more could be said about the history of our ideas concerning consciousness, and the theoretical problems with its definition. There has been a polemic among philosophers of mind as to whether it will ever be possible to understand mind and consciousness in terms of reductionist physical entities, such as neural networks that can be extracted from functional imaging data, and cellular

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Table 16-1 FINAL DIAGNOSIS IN 500 PATIENTS ADMITTED TO HOSPITAL WITH “COMA OF UNKNOWN ETIOLOGY” Metabolic and other diffuse disorders Drug poisoning Anoxia or ischemia Hepatic encephalopathy Encephalomyelitis and encephalitis Subarachnoid hemorrhage Endocrine disorders (including diabetes) Acid–base disorders Temperature regulation Uremic encephalopathy Pulmonary disease Nutritional disorders Nonspecific metabolic coma Supratentorial mass lesions Intracerebral hematoma Subdural hematoma Cerebral infarct Brain tumor Brain abscess Epidural hematoma Thalamic infarct Pituitary apoplexy Closed head injury Subtentorial lesions Brainstem infarct Pontine hemorrhage Cerebellar hemorrhage Cerebellar tumor Cerebellar infarct Brainstem demyelination Cerebellar abscess Posterior fossa subdural hemorrhage Basilar migraine Psychiatric disorders

326 (65%) 149 87 17 14 13 12 12 9 8 3 1 1 101 (20%) 44 26 9 7 6 4 2 2 1 65 (13%) 40 11 5 3 2 1 1 1 1 8 (2%)

Note: Listed here are only those patients in whom the initial diagnosis was uncertain, and a final diagnosis was established. Thus, obvious poisonings and closed head injuries are underrepresented. Source: Adapted from Plum and Posner.

and molecular systems. Although it serves little practical purpose to review these subjects here, one constructive approach is to define the neurobiologic correlates of those elements of clinical consciousness that are subject to observation by behavioral, electrical, and particularly imaging methods. These controversies are informed in neurology by analyses of those neurologic disorders that disturb perception and consciousness of perception (e.g., phantom limb and “blindsight”).

STATES OF NORMAL AND IMPAIRED CONSCIOUSNESS The states of drowsiness, stupor, and coma as described below, exist in a continuum and with gradations and fluctuations between these summary descriptions. The following

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characteristics provide a convenient terminology for describing the states of awareness and responsiveness of patients.

Normal Alertness This is the condition of a normal person when awake. The individual is fully responsive to a thought or perception and indicates by behavior and speech the same awareness of self and environment as that of the examiner. There is attention to, and interaction with, the immediate surroundings. This normal state may fluctuate during the day from one of keen alertness or deep concentration with a marked constriction of the field of attention to one of mild general inattentiveness, but even in the latter circumstance, the normal individual can be brought immediately to a state of full alertness and mental function.

Confusion The term confusion admittedly lacks precision, but in operational terms, it denotes an inability to think with customary speed, clarity, and coherence. Almost all states of confusion are marked by some degree of inattentiveness and disorientation and for some investigators, these last two qualities have come to define confusion or are considered obligate findings. In this condition, the patient does not consider all elements of the immediate environment. This state also implies a degree of imperceptiveness and distractibility, referred to in the past as “clouding of the sensorium.” Sidestepping for the moment the difficulty in defining thinking, a term that refers variably to problemsolving or to the coherence of ideas, confusional states incorporate a disorder of thinking. Confusion results most often from a process that influences the brain globally, such as a toxic or metabolic disturbance or a dementia. In addition, any condition that causes drowsiness or stupor, including the natural state that comes from sleep deprivation, results in some degradation of mental performance and the emergence of inattentiveness, which qualifies as a state of confusion. In this way, confusion, as mentioned, exists along the axis of content of consciousness but is most closely linked to alertness and the level of consciousness. Special forms of confusional state can also accompany focal cerebral disease, particularly in the right hemisphere, or result from focal disorders that disturb language, memory, or visuospatial orientation, but a distinction is made between these limited disruptions in mental function and the more common global confusional state. The focal disorders of mental function represent special states that are analyzed differently, matters discussed further in Chaps. 19 and 21. The mildest degree of confusion may be so slight that it can be overlooked unless the examiner searches for deviations from the patient’s normal behavior and ability to carry on a coherent conversation. The patient may even be roughly oriented as to time and place, with only occasional irrelevant remarks betraying a lack of clarity and slowness of thinking. Their responses are inconsistent, attention span is reduced, and they are unable to stay on one topic, together suggesting a fundamental flaw in attention. This is usually accompanied by disorientation and distractibility, leaving the patient at the mercy of every stimulus.

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In parallel, sequences of movement reveal poor planning and impersistence. Severely confused and inattentive persons are unable to do more than carry out the simplest commands, and these only inconsistently and in brief sequence. Speech may be limited to a few words or phrases; or the opposite pertains— namely, some confused individuals are voluble. They give the appearance of being unaware of much that goes on around them, are disoriented in time and place, do not grasp their immediate situation or the predicament of their own confusion, and may misidentify people or objects. These illusions may lead to fear or agitation. Occasionally, hallucinatory, illusionary, or delusional experiences impart a psychotic cast to the clinical picture, obscuring the deficit in attention. Most events that involve the confused patient leave no trace in memory; in fact, the capacity to recall events of the past hours or days is one of the most delicate tests of mental clarity. Another is the use of working memory, which requires the temporary storage of the solution of one task for use in the next. A deficit in working memory can be demonstrated by tests of serial subtraction or the spelling of words or repeating a phone number forward and then backward. All of these defects are tied to impaired registration of information rather than to a fault in memory and again betray inattention as a central feature of most confusional states. The observed behavior of a confused person transcends inattention. It may incorporate clouded interpretation of internal and external experience, and an inability to integrate and attach symbolic meaning to experience (apperception). The degree of confusion often varies from hour to hour. It tends to be least pronounced in the morning and increases as the day wears on, peaking in the early evening hours (“sundowning”) when the patient is fatigued, and environmental cues are not as clear. In current medical writings, the terms delirium and confusion are used interchangeably. However, in the syndrome of delirium tremens, observed mostly in withdrawal from alcohol, the vivid hallucinations; extreme agitation; trembling, startling easily, and signs of overactivity of the autonomic nervous system have suggested to us that the term delirium should be retained for this type of distinctive confusional syndrome as elaborated in Chap. 19. An agitated, hypersympathetic, hallucinatory state occurs in other circumstances besides alcohol withdrawal. As a result, trials in the ICU have had to create the terms “quiet delirium” and “agitated delirium”, which simply are throwbacks to the original terms. However, the widespread adoption of the term delirium as representative of all nondescript confusional states makes it difficult to persevere in the polemic of separating a calm confusional state from the agitated form.

Drowsiness and Stupor Drowsiness denotes an inability to sustain a wakeful state without the application of external stimuli. Mental, speech, and physical activity are reduced. The state is indistinguishable from light sleep, sometimes including slow arousal elicited by speaking to the patient or applying a tactile stimulus. Furthermore, in distinction to stupor discussed later, drowsy individuals sustain alertness for at least some brief period, without the further necessity

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of external stimuli. As a rule, some degree of inattentiveness and mild confusion are coupled with drowsiness, both improving with arousal. The patient shifts positions somewhat naturally and without prompting. The lids droop; there may be snoring, the jaw and limb muscles are slack, and the limbs are relaxed. Stupor describes a state deeper than drowsiness, in which the patient can be roused only by vigorous and repeated stimuli and usually repeated stimulation to sustain arousal. Responses to spoken commands are either absent, curtailed, or slow and inadequate. Restless or stereotyped motor activity is common, and there is a reduction or elimination of the natural shifting of body positions. When left unstimulated, these patients quickly drift back into a deep sleep-like state. The eyes are usually found to be displaced slightly outward and upward, a feature that is shared with sleep. The breathing pattern may or may not be altered, depending on how the underlying disease has affected the nervous system. In psychiatry, the term stupor had been used in a second sense—to denote an uncommon condition in which the perception of sensory stimuli is presumably normal but activity is suspended and motor activity is profoundly diminished (catatonia, or catatonic stupor). A practical method of making distinctions between drowsiness and stupor was given by Fisher, who suggested that a verbal command is required to overcome drowsiness whereas a noxious stimulus is required to overcome stupor.

Coma The patient who is incapable of being aroused by external stimuli or inner need, is comatose. There are variations in the degree of coma, and the findings and signs depend in part on the underlying cause of the disorder. In its deepest stages, no meaningful or purposeful reaction of any kind is obtainable and corneal, pupillary, and pharyngeal responses are diminished. In lighter stages, sometimes referred to by the ambiguous terms semicoma or obtundation, most of the above reflexes can be elicited, and the plantar reflexes may be either flexor or extensor (Babinski sign). The depth of coma and stupor may be gauged by the response to externally applied stimuli and is most useful in assessing the direction in which the disease is evolving, particularly when compared in serial examinations.

Relationship of Sleep to Coma Persons in sleep give little evidence of being aware of themselves or their environment; in this respect, they are unconscious. Sleep shares a number of other several features with the pathologic states of drowsiness, stupor, and coma. These include yawning, closure of the eyelids, cessation of blinking and reduction in swallowing, upward deviation or divergence or roving movements of the eyes, loss of muscular tone, decrease or loss of tendon reflexes, and even the presence of Babinski signs and irregular respirations, sometimes Cheyne-Stokes in type. Upon being awakened from deep sleep, a normal person may be confused for a few moments, as every physician knows from personal experience. Nevertheless, sleeping persons may still respond to unaccustomed stimuli and are capable of some mental activity in the form of dreams that leave

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traces of memory, thus differing from stupor or coma. The most important difference, of course, is that persons in sleep, when stimulated, can be roused to normal and persistent consciousness. There are important physiologic differences as well. Cerebral oxygen uptake does not decrease during sleep, as it usually does in coma. Recordable electrical activity—electroencephalographic (EEG) and cerebral evoked responses—and spontaneous motor activity differ in the two states, as indicated later in this chapter and in Chap. 18. The anatomic and physiologic bases for these differences are only partly known.

VEGETATIVE AND MINIMALLY CONSCIOUS STATES, LOCKED-IN SYNDROME, AND AKINETIC MUTISM Several conditions are juxtaposed to the continuum of drowsiness, stupor, and coma. They stand apart as a result of special characteristics or by their underlying cause but, with the exception of the locked-in state, they are each form of diminished consciousness.

Vegetative State (Unresponsive Wakefulness) With increasing refinements in the treatment of severe systemic diseases and cerebral injury, larger numbers of patients, who formerly would have died, have survived for indefinite periods without regaining meaningful mental function, regrettably termed the “vegetative state,” and recently renamed unresponsive wakefulness. For the first week or two after severe cerebral injury, these patients are in a state of deep coma. Then they begin to open their eyes, at first in response to painful stimuli, and later spontaneously and for increasingly prolonged periods. The patient may blink in response to threat or to light and intermittently, the eyes move from side to side, seemingly following objects or fixating momentarily on the physician or a family member and giving the erroneous impression of recognition. Respiration may quicken in response to stimulation, and certain automatisms—such as swallowing, bruxism, grimacing, grunting, and moaning—may be observed (Zeman). However, the patient remains unresponsive and for the most part, unconscious, does not speak, and shows no signs of awareness of the environment or inner need; motor activity is limited to primitive postural and reflex movements of the limbs. There is loss of sphincter control. There may be arousal or wakefulness in alternating cycles as reflected in partial eye opening, but the patient regains neither awareness nor purposeful behavior as gauged by an examiner at the bedside. It is, in effect, an awake unconscious state. One sign of the vegetative state is a lack of consistent visual following of objects; because brief observation of ocular movements is subject to misinterpretation, repeated examinations are required. Perspectives on the completeness of unresponsivity that is established by bedside examination in the vegetative state have been altered by the findings of what would be considered by most investigators as conscious activity that can be detected by functional imaging in response to

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certain commands and verbal cues such as the individual’s name as detailed below. If the vegetative syndrome of unconscious awakening persists for 3 months after nontraumatic brain injury or 12 months after traumatic injury, the syndrome has been termed the persistent vegetative state (PVS; Jennett and Plum). These terms had gained acceptance and apply to the clinical appearance whatever the underlying cause. Additional terms, besides unresponsive wakefulness, that have been used to describe this syndrome of preserved autonomic and respiratory function without cognition include apallic syndrome (also called awake unawareness) and neocortical death. A position paper has codified the features of the PVS and suggests dropping a number of related ambiguous terms, although some, such as akinetic mutism, discussed further on, have a more specific neurologic meaning and are still useful (Multi-Society Task Force on PVS). The most common pathologic bases of the vegetative state are diffuse cerebral injury as a result of closed head trauma, widespread neuronal loss in the cortex after cardiac arrest or other form of hypoxemia, and thalamic necrosis from a number of causes. The vegetative state or the minimally conscious state described further on, may also be the terminal phase of progressive cortical degenerative processes such as Alzheimer and Creutzfeldt-Jakob disease, where the pathologic changes are mainly cortical but may include the thalamus. It is worth noting that the prominent pathologic changes in the vegetative state can be in the thalamic and subthalamic nuclei, as in the widely known Quinlan case (Kinney et al) rather than solely in the cortex as often stated; this holds for postanoxic as well as traumatic cases. A review of the pathology of the vegetative state found these thalamic changes but attributed them to secondary degeneration from white matter and cortical lesions (J.H. Adams and colleagues). In several of our cases, the thalamic damage stood almost alone as the cause of persistent “awake coma.” In traumatic cases, the pathologic findings are often of diffuse subcortical white matter degeneration (described as diffuse axonal injury), thalamic degeneration, and ischemic damage in the cortex. Further insight is found in a study of brain morphometry by MRI, which determined that in patients with early vegetative or minimally conscious states, there was global brain atrophy but the thalamic and basal ganglionic structures were disproportionately affected (Lutkenhoff and colleagues). Taken together, these anatomic findings indicate that in the PVS, the cortex is either diffusely injured or effectively disconnected and isolated from the thalamus, or the thalamic nuclei required for the maintenance of alertness are destroyed (see further on under Anatomy and Physiology of Alertness and Coma). In either the traumatic or anoxic types of PVS, atrophy of the cerebral white matter leads to secondary ventricular enlargement and thinning of the corpus callosum. These observations notwithstanding, there is little doubt that the nature of the vegetative state is complex and may be separable into categories defined by the locus of brain damage. For example, an observation in a 23-yearold woman who had been vegetative for 5 months after a

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head injury, there was cortical activity in the middle and superior temporal gyri in response to the presentation of spoken sentences that was similar to the brain activity elicited by the same stimuli in normal individuals (Owen and colleagues). Several similar demonstrations of vegetative patients have shown that there can be brain activation to the patient’s own name and not to other names (Di et al). Further compelling demonstrations of cognitive processing in vegetative and minimally conscious patients have been reported by functional MRI. Five of 54 patients, all with traumatic brain injury, but none after anoxic ischemic damage, could willfully modulate focal brain activity by imagining playing tennis (frontal lobe activation) or mentally navigating a familiar place such as their home (temporal lobe activation) (Monti and colleagues). In one patient, this activity was used as a means of communication. Using highly processed EEG, patients with acute coma who were unresponsive but not in a vegetative state, 16 of 104 had patterns of activation in response to commands or stimuli and a larger proportion of those recovered than those without this activation (Claassen et al) These data suggest that some forms of mental processing can go on during a vegetative state (more persuasively during the minimally conscious state), but it is not clear if this situation is representative of the state and does it provide information about selfawareness, a requisite for consciousness. At a minimum, these demonstrations emphasize the care that must be taken in establishing diagnoses of PVS and minimally conscious states and in assuming the patient is truly unresponsive. Whether these findings with functional imaging simply reflect preserved islands of function in severe brain injury that cannot be examined clinically or whether they require an entire rethinking of the neurologic examination that determines the state of consciousness cannot yet be stated (Ropper, 2010). An additional observation of some consequence is the finding of axonal growth over time in a patient with traumatic brain injury who had been in a minimally conscious state (further on) for 19 years and then began to speak and comprehend, while remaining virtually quadriplegic. Voss and colleagues, using MRI diffusion tensor imaging, have shown axonal sprouting in the posterior parietal and midline cerebellar regions. They compared the results of tensor imaging to a patient who had been in a minimally conscious state for 6 years without improvement and to 20 normal individuals. Their findings are subject to several interpretations, but axonal growth in the parietal lobes offers a potential explanation for the few instances in which recovery from severe injury does occur. When combining these with findings of other groups, a case can be made for the posterior parietal regions as necessary for integrated consciousness and also raise the possibility that certain islands of limited awareness may be dissociated from global brain function (Laureys and colleagues, 1999). It is difficult to predict which comatose patients will later fall permanently into the vegetative or minimally conscious categories. Of 45 patients with signs of the vegetative state at 1 week after onset, 13 had awakened and 5 of these had satisfactory outcomes. After being vegetative for close to 2 weeks, only 1 recovered to a level of moderate disability; after 2 weeks, the prognosis was uniformly

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poor (Plum and Posner, 1980). Larger studies have given similar results (Higashi and colleagues, 1977). As a rough guide to prognosis specifically in head injury, Braakman and colleagues found that among a large group of comatose patients, 59 percent regained consciousness within 6 h, but of those in a vegetative state at 3 months, none became independent. At no time before 3 or 6 months was it possible to distinguish patients who would remain in a vegetative state from those who would die. Further comments regarding recovery are made in the next section on the minimally conscious state. A study by the Multi-Society Task Force on PVS concluded that the outcome from a vegetative state is better in traumatic as compared to nontraumatic cases. J.H. Adams and coworkers have proposed that this reflects differences in the state of thalamic neurons in the two situations. They suggested that after acute hypoxia, neurons subjected to ischemic necrosis are liable to be permanently lost; by contrast, in trauma, the loss of thalamic neurons is more frequently secondary to transsynaptic degeneration following diffuse axonal injury, allowing a greater potential for recovery. Many of these ideas are speculative. Laboratory features  The vegetative state is associated with a grossly abnormal EEG and is characterized by one of a number of abnormal patterns. There may be predominantly low-amplitude delta-frequency background activity, burst suppression, widespread alpha and theta activity, an alpha coma pattern, and sleep spindles, all of which have been described in this syndrome, as summarized by Hansotia (see Chap. 2). One important feature is a lack of the normal change in the background EEG activity during and immediately after stimulating the patient. In all these clinical states, the profound and widespread dysfunction of the cerebrum is also reflected by extreme reductions in cerebral blood flow (CBF) and metabolism, measured with positron emission tomography (PET) and other techniques. On the basis of PET studies in a patient with carbon monoxide poisoning, Laureys and colleagues observed that the main difference between the vegetative state and the later state in which the patient has recovered was the degree of hypometabolism in the parietal lobe association area. Anatomic changes in this same cortical region have been implicated in the transition from minimally conscious to a more awake state. The finding in PET studies that noxious somatosensory stimulation fails to activate the association cortices is consistent with the concept that large regions of cortex are isolated from thalamic input or that the critical parietal interpretive areas are isolated from the rest of the cortex. Of practical value is the observation that the CT and MRI may show progressive and profound cerebral atrophy in cases of vegetative state. In the absence of this atrophy after several months or more, it may be unwise to offer a pessimistic prognosis.

Minimally Conscious State The vegetative state blends into a less severe but still profound disorder of consciousness that has been termed

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“minimally conscious state,” wherein the patient is capable of some rudimentary behavior such as following a simple command, gesturing, or producing single words or brief phrases, always in an inconsistent way from one examination to another (Giacino et al). There is preservation of the ability to carry out basic motor behaviors that demonstrate a degree of awareness. The minimally conscious state is found as a transitional or permanent condition and is sometimes difficult to separate from akinetic mutism discussed further on. Any notion of such a patient’s selfawareness is conjectural, but there may be an impressive array of behaviors and activation of associative regions of the cerebral cortex that suggest that processing of external information is taking place beyond a rudimentary level (see discussion by Bernat). The causes and pathologic changes underlying the minimally conscious state are identical to those of the vegetative state, including the frequent finding of thalamic and multiple cerebral lesions. Viewed from on perspective, the distinction between them is one of degree. It is useful to maintain a critical view of reports of remarkable recovery after months or years of prolonged coma or the vegetative state. When the details of such cases become known, it is sometimes evident that recovery might reasonably have been expected. There are, however, instances of partial recovery in patients—particularly children and young adults—who display vegetative features for several weeks or, even several months after injury (Andrews and Childs and Mercer). Such observations cast doubt on unqualified claims of success with certain therapies, such as specialized sensory stimulation. Nevertheless, the rare occurrence of late recovery in adults must be acknowledged (see Andrews; Higashi et al; and Rosenberg et al, 1977) and a relation of awakening to the recovery of connections to the parietal lobes has already been mentioned. Cases of improvement from the “minimally conscious state” are more plausible than those from the vegetative state. Contrasting the notion that late recovery is exceptional, a case series (Estraneo and colleagues) of 50 consecutive patients in PVS for a year, 10 showed improvement at an average of 2 years but all were severely impaired. In anohter series (Luaté and coworkers), none of 12 vegetative patients improved at 5 years but 13 of 39 minimally conscious cases emerged to consciousness with severe disability. Of course, the application of these terms to a patient often leads to the withdrawal of care, and a self-fulfilling poor prognosis. This is a much-discussed problem that has not been satisfactorily addressed but it emphasizes that simply labeling patients with PVS or MCS has implications for accurately assessing the natural history of some diseases. A provocative therapeutic observation has been improved function by stimulating the medial (intralaminar) thalamic nuclei through implanted electrodes in a patient who had been initially vegetative and had made a natural transition to a minimally conscious state after traumatic brain injury (Schiff and colleagues). Longer periods of eye opening and increased responses to execute commands, such as bringing a cup to his mouth, were observed, including, for the first time since his injury, intelligible verbalization. The authors point out that this individual had preserved language cortex and connections between

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thalamus and cortex. Whether this remarkable result is generalizable is not known. It must be remarked that the degree of disability that families find acceptable varies greatly and leads to difficult decisions regarding the continuation of medical care. The knowledgeable, sympathetic, and flexible physician is in the best position to offer perspective and guide these matters over the long periods of time required, as discussed at the end of this chapter.

Locked-in Syndrome The states of coma described above, and the vegetative state must be distinguished from a syndrome in which there is little or no disturbance of consciousness, but only an inability of the patient to respond adequately with motor activity and speech. This condition is referred to as the locked-in syndrome or the deefferented state. The term pseudocoma as a synonym for this state is best avoided because it is used by some physicians to connote the unconsciousness of the hysteric or malingerer, the dissociative state, or catatonia. The locked-in syndrome is most often caused by a large lesion of the ventral pons (basis pontis), usually as a result of occlusion of the basilar artery. Such infarctions spare both the somatosensory pathways, and the ascending neuronal systems responsible for arousal and wakefulness, as well as certain midbrain elements that allow the eyelids to be raised in wakefulness. The damage essentially completely interrupts the descending corticobulbar and corticospinal tracts, depriving the patient of speech and the capacity to respond in any way except by voluntary vertical gaze and by blinking. Severe motor neuropathy (e.g., Guillain-Barré syndrome), pontine myelinolysis, or periodic paralysis may produce a similar effect.

Akinetic Mutism One could logically refer to the locked-in state as akinetic mutism insofar as the patient is akinetic (motionless) and mute, but this is not the sense in which the term was originally used by Cairns and colleagues, who described a patient who gave the appearance of being awake but was unresponsive (actually, their patient was able to answer in whispered monosyllables). Following each of several drainings of a third ventricular cyst, the patient again became responsive but had no memory of events that had taken place when she was in the akinetic mute state. This state of apparent vigilance in an imperceptive and unresponsive patient has been referred to by French authors as coma vigile, but this is also confusing because the same term has been applied to the vegetative state. The term akinetic mutism has been applied to yet another group of patients who are silent and inert as a result of bilateral lesions of the anterior parts of the frontal lobes or in the thalamus, leaving intact the motor and sensory pathways. The patient is profoundly apathetic, lacking to an extreme degree the psychic drive or impulse to action. There is a marked delay in verbal and motor responses (abulia), however, the abulic patient, unlike Cairns’ patient, registers most of what is happening about him and if intensely stimulated, may speak normally, relating events observed in the recent and distant past.

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Catatonia The is a state in which the individual appears unresponsive, in a way that simulates stupor, light coma, or akinetic mutism. It is most often associated with psychosis. There are no signs of structural brain disease, such as pupillary or reflex abnormalities. As in the normal awake state, oculocephalic responses are muted—that is, the eyes move concurrently with the head as it is turned. There is usually resistance to eye opening, and some patients display a waxy flexibility of passive limb movement that gives the examiner a feeling of bending a wax rod (flexibilitas cerea); there may also the retention for a long period of seemingly uncomfortable limb postures (catalepsy). Peculiar motor mannerisms or repetitive motions, seen in a number of these patients, may give the impression of seizures; choreiform jerking has also been reported, but the latter sign should also suggest the possibility of seizure activity. The EEG shows normal posterior alpha activity that is attenuated by stimulation. Catatonia is discussed further in Chaps. 19 and 49. Because there is considerable imprecision in the use of terms by which the states of reduced consciousness are designated, the physician is better advised to supplement designations such as coma and akinetic mutism by simple descriptions indicating whether the patient appears awake or asleep, drowsy or alert, aware or unaware of his surroundings, and responsive or unresponsive to a variety of stimuli. This requires that the patient be observed more for a longer period and more frequently than the several minutes usually devoted to this portion of the neurologic examination.

BRAIN DEATH In the 1950s, European neurologists called attention to a state of coma in which the brain was irreversibly damaged and had ceased to function, but pulmonary and cardiac function could still be maintained by artificial means. Mollaret and Goulon referred to this condition as coma dépassé (a state beyond coma). A Harvard Medical School committee in 1968 called it brain death and established a set of clinical criteria by which it could be recognized (see Beecher et al; the report is often said to be from the “Beecher Committee”). R.D. Adams, who was a member of the committee, defined the state as one of complete unresponsiveness to all modes of stimulation, arrest of respiration, and absence of all EEG activity for 24 h. The concept that a person is dead if the brain is dead and that death of the brain may precede the cessation of cardiac function has over the years posed a number of important ethical, legal, and social problems, as well as medical ones. All aspects of brain death have since been the subject of close study by several professional and governmental committees, which for the most part have followed the 1968 guidelines for determining that the brain is dead and equating this state with the traditional version of death as the inevitable dissolution of the body after cardiac and respiratory function have permanently ceased. The American Academy of Neurology published guidelines on this subject in 1995 and affirmed them with some refinements in 2010.

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The monograph by Wijdicks is a comprehensive modern source on the subject of brain death and also addresses the subject from an international perspective. The philosophical underpinnings of the equating of brain death to death, giving it the same status as cessation of cardiorespiratory death, are more complex. In particular, the ethical and moral dimensions of brain death are subject to differing interpretations in various societies, religions, and cultures. Some of these are reviewed in a perspective article by prominent writers (Magnus, Wilford, and Caplan), who suggest that the wide medical and societal acceptance of brain death makes it an important construct, not to be abandoned because of philosophical objections. One justification for equating brain death with somatic death is the general inevitability of cardiorespiratory failure in patients who fulfill the standard criteria. This tenet has exceptions, among the most striking of which is a well-studied case of 20-year survival in a boy who had meningitis (Reptinger and colleagues), and other cases of long that have been described with varying degrees of documentation. These have been collected (Shewmon) making the point that arguments equating brain death with death on the basis of the brain’s role in creating “somatic unity” are weakened by the existence of such long surviving cases as well as by delivery of live babies from braindead mothers. Further clouding the issue of validity of brain death is the proposal by British and Scandinavian neurologists that death of the brain stem alone is adequate to fulfill the precepts of brain death. In the end, these philosophical concerns truly matter but the operational state called brain death at the moment serves both patients and society well and is compatible with most of the world’s religions. The central considerations in the clinical diagnosis of brain death are (1) absence of all cerebral functions; (2) absence of all brain stem functions, including spontaneous respiration; and (3) irreversibility of the state. Following from the last of these criteria, it is necessary to demonstrate an irrefutable cause of the underlying catastrophic brain damage (e.g., trauma, cardiac arrest, cerebral hemorrhage) and to exclude reversible causes such as drug overdose and extreme hypothermia. In the diagnosis of brain death, the absence of cerebral function is demonstrated by the presence of deep coma and total lack of spontaneous movement and of motor and vocal responses to all visual, auditory, and cutaneous stimulation. Spinal reflexes (deep tendons reflexes) may persist, and the toes often flex slowly in response to plantar stimulation; but a well-developed Babinski sign is unusual (although its presence does not exclude brain death). Extensor or flexor posturing is seen from time to time as a transitional phenomenon just before or after brain death becomes evident, and the status of these movements in the diagnosis is ambiguous, but most criteria consider these movements to be incompatible with brain death, as they reflect functioning of brain stem centers. The physician should therefore proceed cautiously in declaring a patient dead in the presence of posturing and should consider conducting the examination again at a later time. The complete absence of brain stem function is judged by the loss of spontaneous eye movements, the resting

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position of both globes at the meridian of the palpebral fissures, and lack of response to oculocephalic and caloric (vestibulo-ocular) testing; the presence of dilated or midposition fixed pupils (not smaller than 3 mm); paralysis of bulbar musculature (no facial movement or gag, cough, corneal, or sucking reflexes); absence of motor and autonomic responses to noxious stimuli; and absence of respiratory movements. The clinical findings should show complete absence of brain function, not an approximation that might be reflected, for example, by small or poorly reactive pupils, slight eye deviation with oculovestibular stimulation, or posturing of the limbs, as mentioned earlier. As a demonstration of destruction of the medulla, it has become customary to perform an apnea test to demonstrate unresponsiveness of the medullary centers to a high carbon dioxide tension. This test is conducted by first employing preoxygenation of the lungs for several minutes with high-inspired oxygen tension, the purpose of which is to displace nitrogen from the alveoli and create a reservoir of oxygen that will diffuse into the pulmonary circulation. The patient can then be disconnected from the respirator for several minutes, during which time 100 percent oxygen is being delivered by cannula or ventilator that has its pumping mechanism turned off; this allows the arterial PCO2 to rise to above 50 or 60 mm Hg (typically, CO2 rises approximately 2.5 mm Hg/min at normal body temperature—slower if the patient is hypothermic). The induced hypercarbia serves both as a stimulus to breathing and confirms that spontaneous ventilation mediated by medullary centers has failed. (Of course, peripheral causes of ventilatory failure such as paralytic drugs and GuillainBarre syndrome should not be present.) If no breathing is observed and blood gases show that an adequate level of PCO2 has been attained, this component of brain death is corroborated. Several sets of formal criteria have incorporated a CO2 concentration of 60 mm Hg (7.98 kPa [kilopascals]) as adequate to stimulate the medulla, even under circumstances in which it has been badly damaged. In our experience, patients who have severely brain stem damage but nonetheless breathe and therefore are not brain dead, have shown this activity at a PCO2 well below 50 mm Hg, but there are exceptions in which higher levels are required as a stimulus. The risks of apnea testing are minimal, as discussed in the American Academy of Neurology’s 2010 document, but hypotension, hypoxemia, cardiac arrhythmias, and lung barotrauma may occasionally occur. In patients who cannot tolerate the test for more than a brief period because it produces hypotension, raising the arterial CO2 by insufflation of this gas has been suggested, but this approach has not been studied extensively. Delivering oxygen during the test with a low tidal volume and a ventilator rate of 1 to 2 breaths per minute or by continuous positive airway pressure may ameliorate hypoxia and resultant hypotension, but this technique has also not been adequately studied. Many, but not all, brain-dead patients have diabetes insipidus. The absence of this syndrome in some cases reflects the imprecision of the clinical examination in detecting a total loss of brain function. Other ancillary

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bedside tests may be conducted to corroborate brain death. Among the ones used in special circumstances is the absence of tachycardia in response to the injection of atropine; this reflects the loss of cardiac innervation by damaged medullary vagal neurons. The authors have observed dramatic spontaneous movements when severe hypoxia is attained following terminal disconnection from the ventilator. These include opisthotonos with chest expansion that simulates a breath, elevation of the arms and crossing them in front of the chest or neck (given the name Lazarus sign by Ropper in 1984), head-turning, shoulder shrugging, and variants of posturing-like movements. For this reason, it may be advisable for the family not to be in attendance immediately after mechanical ventilation has been discontinued. The EEG provides confirmation of cerebral death, and some institutions prefer to include corroboration by the demonstration of electrocerebral silence (“flat” or, more accurately, isoelectric EEG, shown first by Schwab). However, most U.S. institutions do not require an EEG for the confirmation of death. Electrocerebral silence is considered to be present if there is no electrical potential of more than 2 mV during a 30-min recording except for artifacts created by the ventilator, electrocardiograph, and surrounding electrical devices; as importantly, the absence of these artifacts suggests a technical problem with the recording. There are cases on record in which a patient with an isoelectric EEG has had preserved brain stem reflexes so that cerebral unresponsiveness and a flat EEG do not alone, in most criteria and guidelines, signify brain death; isoelectric EEG may also be reversible in states of profound hypothermia or intoxication with sedative-hypnotic drugs and immediately following cardiac arrest. Therefore, it has been recommended that the diagnosis of brain death not be entertained until several hours have passed from the time of initial observation. If the examination is performed at least approximately 6 h after the precipitating event, and there is prima facie evidence of overwhelming brain injury from trauma, or massive cerebral hemorrhage (the most common conditions causing brain death), there is probably no need for serial testing. If cardiac arrest was the antecedent event, or the cause of neurologic damage is unclear, or drug or alcohol intoxication could reasonably have played a role in suppressing the brain stem reflexes, it is advisable to wait for about 24 h before repeating the testing and pronouncing the patient dead. Toxicologic screening of the serum or urine is requisite in these circumstances. The impact of any requirement to perform a second brain death examination at some interval such as 6 h has been studied (Lustbader and coworkers). This extensive survey in New York State, where a second examination had been recommended by a panel, was instructive; of 1,311 adult and pediatric cases, none who were found to be brain dead regained brain stem function on a second test that was performed about 18 h later. However, 12 percent had cardiac arrest and in others, consent for organ donation was withheld during the time between examinations. Several authoritative authors have argued on this basis against the need for a second brain death test.

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Because evoked potentials show variable abnormalities in brain-dead patients, they are probably not of primary value in the diagnosis but if performed, all cerebral activity should be absent. Some centers use nuclide brain scanning or cerebral angiography to demonstrate an absence of blood flow to the brain, equating this with brain death. This approach is acceptable and may be necessary if facial trauma, burns, or other injury prevent evaluation of pupillary and ocular reflexes but there are technical pitfalls in the use of these methods. The specificity of radionuclide scanning is close to 100 percent but there is a selfreferential aspect to this statement as the clinical diagnosis has been used as a gold standard. An additional problem arises in the observation that the sensitivity may be only about 75 percent (Joffe et al). False-negative tests are possible if a small amount of filling of the intracranial vertebral arteries with angiography or nuclide uptake in the inferior cerebellum is demonstrated. The same can be said for a degree of imprecision in transcranial Doppler sonography, which in brain death shows a to-and-fro, pendelfluss blood-flow pattern in the basal vessels. The main difficulties that arise in relation to brain death are perhaps not the technical ones discussed above, but those involving the sensitive conversations with the family of the patient and, to some extent, with other medical professionals. These tasks often fall to the neurologist. It is best not to embark on clinical or EEG testing for brain death unless there is a clear intention on the part of the physician to remove the ventilator or follow through with organ donation at the end of the process. The nature of testing for brain death and its potential outcome should be explained to the family in plain language. The family’s desires regarding organ transplantation should be sought after adequate time has passed for them to absorb the shock of the circumstances. Neurologists must, of course, resist pressures from diverse sources that might lead them to the premature designation of a declaration of brain death. To avoid the appearance of conflict of motivations, most centers have a separate team, often from an organ bank, to address the issues of organ transplantation after brain death has been established. The complex matter of a family’s desire to maintain ventilation and other medical support in a braindead relative is best addressed with consideration and counseling by the physician and clergy, ethics (“optimal care”) committees, and hospital staff, so as to avoid confrontation. Time often allows such situations to be defused. At the same time, it should be clarified that brain death is an operational state that allows transplantation to proceed or typically mandates withdrawal of ventilation and blood pressure support. Patients with overwhelming brain injuries need not fulfill these absolute criteria in order for medical support to be withdrawn. If the case for recovery is futile and the family and physician agree, of if the patient’s wishes are unequivocally known from preceding documents or discussions, support can be withdrawn in most jurisdictions and the obligate quest for brain death becomes a trap. A task force for the determination of brain death in children (updated by Nakagawa et al) has recommended the adoption of essentially the same criteria as for adults.

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However, the difficulty in evaluating the status of nervous function in relation to perinatal insults, has led this group to suggest that the determination not be made before the seventh postnatal day and that the period of observation should be extended to 48 h. As with adults, the possibility of reversible brain dysfunction from toxins, drugs, hypothermia, and hypotension must always be considered.

RECURRING STUPOR AND COMA Aside from repeated drug overdose, recurring episodes of stupor are usually a result of the recurrence of an underlying endogenous biochemical derangement such as the hyperammonemia of hepatic failure. A similar periodic hyperammonemic coma in children and adults can come about from urea cycle enzyme defects, such as ornithine transcarbamylase deficiency. These are discussed in Chap. 36. Under the title of idiopathic recurring stupor, a rare condition has been described in adult men who displayed a prolonged state of deep sleepiness lasting from hours to days intermittently over a period of many years. Despite the impression of a sleep disorder related to narcolepsy, the EEG showed widespread fast (beta) activity, and both the stupor and EEG changes were reversed by flumazenil, a benzodiazepine receptor antagonist. During the bouts, a many-fold increase of circulating endozepine-4, an ostensibly naturally occurring diazepine agonist, was present in the serum and spinal fluid. Subsequently, the authors of the original reports (Lugaresi et al) found, by the use of more advanced techniques, that intoxication with lorazepam may have accounted for at least some of the cases. Although such cases in which diazepine antagonists reverse episodes of recurrent coma continue to be reported (Huberfeld et al), the status of this entity remains ambiguous because of the difficulty in excluding exogenous ingestion of drugs. The vigilance-producing drug, modafinil, has also been effective in one report (Scott and Ahmed). A peculiar form of transient unresponsiveness in elderly individuals has been described (Haimovic and Beresford). It accounted for 2 percent of hospitalized patients referred to them for coma. The EEG and other evaluations gave no explanation, but their 5 patients had various systemic illnesses. It may recur but appears to be benign. We have experience with three such patients over the years, all men in their seventh or eighth decades, who had no systemic illness and who showed no Babinski signs, pupillary abnormalities and, for the most part, eye movement limitations (one had disproportionately better horizontal than vertical gaze with oculocephalic testing). Their eyes were closed and they could be aroused briefly and inconsistently to a drowsy state. EEG showed mild diffuse slowing but without organized sleep-like activity. Patients with advanced Parkinson disease will occasionally and intermittently display a similar episodic unresponsiveness but with eyes open. It is unclear to us whether migraine can cause a similar syndrome of unresponsiveness, as suggested in a study

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of familial hemiplegic migraine (Fitzsimmons and Wolfenden). Basilar migraine may exceptionally cause transient stupor and coma. Catatonic stupor and Kleine– Levin syndrome of periodic hypersomnolence (Chap. 18) and the behavioral change of catatonia also need to be considered.

THE ELECTROENCEPHALOGRAM AND DISTURBANCES OF CONSCIOUSNESS The EEG provides confirmations of the fact that states of impaired consciousness are expressions of neurophysiologic changes in the cerebrum. Some form of alteration of brain electrical activity occurs in almost all disturbances of consciousness except for milder degrees of confusion, delirium tremens, and in catatonia, where the preservation of normal background EEG activity can aid in diagnosis. These alterations usually consist of disorganization of the EEG background pattern, including disappearance of the normal alpha rhythm and replacement by random slow waves of low to moderate voltage in the initial stages of confusion and drowsiness; a more regular pattern of slow, 2- to 3-per second waves of high voltage in stupor; slow low-voltage waves or intermittent suppression of organized electrical activity in deep coma of cerebral hypoxia and ischemia; and, ultimately, complete absence of electrical activity in brain death. The EEG broadly reflects the depth of certain metabolic comas, particularly those caused by hepatic or renal failure. In these conditions, the slow waves become higher in amplitude as coma deepens, ultimately assuming a high-voltage rhythmic delta pattern and a triphasic configuration. Not all cerebral disorders that cause confusion, stupor, and coma have the same effects on the EEG. In cases of intoxication with sedatives, fast (beta) activity initially replaces normal rhythms. Coma in which myoclonus or twitching is a major clinical feature may show frequent sharp waves or a sharpness of the background slowing of the EEG. A relatively normal EEG is characteristic of delirium tremens as already commented. The differences in EEG changes among metabolic derangements probably represent biologic distinctions at the neuronal level that have not yet been elucidated (see also Chap. 2). In some deeply comatose patients, the EEG may transiently show diffuse and variable alpha frequency (8- to 12-Hz) activity, which may be mistaken for the normal physiologic alpha rhythm. In addition to these aberrant features, the activity displays no reactivity to sensory stimuli. Alpha coma is associated with pontine or diffuse cortical lesions and has a poor prognosis (Iragui and McCutchen). An even less common EEG abnormality is “spindle coma,” in which sleep spindles dominate the record (see “Disorders of Sleep Related to Neurologic Disease” in Chap. 18). The EEG may also demonstrate continuous seizure activity (nonconvulsive status), making it valuable in the diagnosis of unresponsive states of obscure cause.

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ANATOMY AND NEUROPHYSIOLOGY OF ALERTNESS AND COMA Our current understanding of the anatomy and physiology of alertness comes largely from the experiments of Bremer and of Moruzzi and Magoun in the 1930s and 1940s. Observing cats in which the brain stem had sectioned between the pons and midbrain and at the level of the lower medulla, Bremer found that the rostral section caused a sleep-like state and “synchronized” EEG rhythms that were characteristic of sleep; animals with the lower section remained awake with appropriate “desynchronized” EEG rhythms. He interpreted this to mean, in large part correctly, that a constant stream of sensory stimuli, provided by trigeminal and spinal sources, funneled through the upper brain stem was required to maintain the awake state. Subsequently, a system of “nonspecific” projections from the thalamus to all cortical regions, independent of any specific sensory nucleus, has been demonstrated. A critical refinement of this concept resulted from the observation by Moruzzi and Magoun that electrical stimulation of the medial midbrain tegmentum and adjacent areas just above this level caused a lightly anesthetized animal to become suddenly alert and its EEG to change correspondingly, that is, to become “desynchronized,” in a manner identical to normal arousal by sensory stimuli. The sites at which stimulation led to arousal consisted of a series of points extending from the nonspecific medial thalamic nuclei down through the caudal midbrain. These loci were situated along a loosely organized core of neurons that anatomists refer to as the reticular system or reticular formation. The anatomic studies of the Scheibels have described widespread innervation of the reticular formation by multiple bifurcating and collateral axons of the ascending sensory systems, implying that this area is maintained in a tonically active state by ascending sensory stimulation. Because this region, especially the medial thalamus, projects widely to the cerebral hemispheres, the concept arose of a reticular activating system (RAS or ARAS, ascending reticular activating system) that maintains the alert state and the inactivation or destruction of which led to an unarousable state. In this way, despite a number of experimental inconsistencies (see Steriade), the paramedian upper brain stem tegmentum and lower diencephalon have come to be conceived as the locus of the arousal system of the brain. The anatomic boundaries of the RAS are somewhat indistinct. The neurons of this system are interspersed throughout the paramedian regions of the upper (rostral) pontine and midbrain tegmentum; at the thalamic level, the RAS includes the functionally related posterior paramedian, parafascicular, and medial portions of the centromedian and adjacent intralaminar nuclei. What is salient for clinical work is that the nuclei of the reticular formation receive collaterals from the spinothalamic and trigeminal–thalamic pathways and project not just to the sensory cortex of the parietal lobe, as do the thalamic relay nuclei for somatic sensation, but to the whole of the cerebral cortex. Thus, it would seem that sensory

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stimulation has a double effect—it conveys information to the brain from somatic structures and the environment and also activates those parts of the nervous system on which the maintenance of consciousness depends. The cerebral cortex not only receives impulses from the RAS but reciprocally modulates this incoming information via corticofugal projections to the reticular formation. Although the physiology of the RAS is far more complicated than this simple formulation would suggest, it nevertheless, as a working idea, retains a great deal of clinical credibility, and makes comprehensible some of the neuropathologic observations noted further on, as well as the effects of deep brain stimulation to improve function in minimally conscious patients (see further on). The presence of normal alpha rhythm with the eyes closed is a marker for wakefulness, but its representation at the cortical surface is not required for wakefulness as it is obliterated in cases of bilateral occipital infarction. It is, of course, possible that deep nuclei are still projecting the rhythm to other parts of the cerebrum and it was assumed that this maintains wakefulness but even this precept is not clear. Although for many years it has been stated that arousal causes a desynchronization of brainwave activity (in distinction to the synchronized activity of sleep), it has become apparent that during wakefulness, there also is a widespread low-voltage fast rhythm (gamma rhythm of frequency of 30 to 60 Hz). This activity, coordinated by the thalamus, has been theorized to synchronize cortical activity and to account perhaps for the unification of modular aspects of experience (color, shape, motion) that are processed in different cortical regions. In this way, the rhythm is said to “bind” various aspects of a sensory experience or memory. This fast and widespread electrographic activity is not appreciated with the usual EEG surface recordings but it can be extracted by sophisticated mathematical transformations. Using such electrophysiologic methods that the gamma rhythm can be detected over the primary somatosensory cortex after an electrical stimulus on the contralateral hand is perceived, but not if the patient fails to perceive it (Meador et al). The clinical relevance of the rhythm is uncertain, but it has elicited interest because it may give insight into several intriguing questions about conscious experience. In the last decade, a novel perspective on the anatomical basis of consciousness has been derived from the study of functional and anatomical connectivity of brain regions as reflected by functional MRI studies and diffusion tensor imaging, respectively. At least three such interconnected networks have been detected, a salience network that has been theorized to underlie conscious perception of stimuli, a default mode network for internal thought, and an executive control network for externally guided awareness. Of these, the salience network was most closely correlated with behavioral signs of awareness but that changes in the default network corresponded to regaining consciousness after coma (Qin and colleagues, 2015). These studies are interesting but only correlative and their meaning and place in clinical concepts will certainly evolve in the next decades.

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METABOLIC AND TOXIC ENCEPHALOPATHIES Many diseases and exogenous agents interfere with the metabolic activities of the nerve cells in the cerebral cortex and the central nuclei of the brain. The better-known examples are hypoxemia, global ischemia, hypoglycemia, hyper- and hypo-osmolar states, acidosis, alkalosis, hypokalemia, hyperammonemia, hypercalcemia, hypercarbia, drug intoxication, and severe vitamin deficiencies (see Chap. 39). In general, the loss of consciousness in these conditions parallels a reduction in cerebral metabolism. For example, in the case of global ischemia, in which oxygen and glucose are removed from the brain, an acute drop in CBF to 25 mL/min/100 g brain tissue from its normal 55 mL/min/100 g causes slowing of the EEG and syncope or impaired consciousness; a drop in CBF below 12 to 15 mL/min/100 g causes electrocerebral silence, coma, and cessation of most neuronal metabolic and synaptic functions. Even lower levels of ischemia are tolerated if they arise more slowly, but neurons cannot survive when flow is reduced below 8 to 10 mL/min/100 g. Oxygen consumption of 2 mg/min/100 g (approximately half of normal) is incompatible with an alert state. In other types of metabolic encephalopathy, CBF may stay near normal while metabolism is greatly reduced. An exception is the coma that arises from seizures, in which metabolism and blood flow are greatly increased. Extremes of body temperature (above 41°C [105.8°F] or below 30°C [86°F]) also induce coma through a nonspecific effect on the metabolic activity of neurons. Some of these metabolic changes are probably epiphenomena, reflecting in each encephalopathy a specific type of dysfunction in neurons and their supporting cells. Again, in reference to reducing the level of consciousness, for most metabolic alterations, the rate of change of the underlying derangement is as important as its absolute level. The endogenous metabolic toxins that are responsible for coma in many common medical conditions cannot always be identified. In diabetes, for example, acetone bodies (acetoacetic acid, β-hydroxybutyric acid, and acetone) are present in high concentration but which causes coma is not entirely clear; similarly in uremia, there is probably an accumulation of dialyzable small molecular toxins, notably phenolic derivatives of the aromatic amino acids but these are not clearly the proximate cause of coma. In hepatic coma, elevation of blood NH3 (ammonia) to five to six times normal levels corresponds roughly to the level of coma but the direct effect of ammonia on neurons is not fully characterized. Lactic acidosis may affect the brain by lowering arterial blood pH to less than 7.0 and this alone may suffice to alter neuronal metabolism globally. The impairment of consciousness that accompanies pulmonary insufficiency is related mainly to hypercapnia. Restated, the toxic effects of these molecules have not been confirmed or well understood, as further on. In acute hyponatremia (Na < 120 mEq/L) of whatever cause, neuronal dysfunction is probably a result of the intracellular movement of water, leading to neuronal swelling and loss of potassium chloride from the cells. The mode of action of

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bacterial toxins and cytokines released during the systemic inflammatory response of sepsis is likewise incompletely understood. Drugs such as general anesthetics, which are addressed more fully in a later section, alcohol, opiates, barbiturates, antiepileptic drugs, antidepressants, and benzodiazepines induce coma by their direct effects on neuronal membranes in the cerebrum and RAS or on neurotransmitters and their receptors. Others, such as methyl alcohol and ethylene glycol, both acts directly and by producing a metabolic acidosis. Although the coma of toxic and metabolic diseases usually evolves through stages of drowsiness, confusion, and stupor (and the reverse sequence occurs during emergence from coma), each disease imparts its own characteristic clinical features. The sudden and excessive neuronal discharge that characterizes an epileptic seizure is another common mechanism of coma. Focal seizure activity has little effect on consciousness until it spreads from one side of the brain (and the body if there is a convulsion) to the other. Coma then ensues, presumably because the extension of the seizure discharge to deep central neuronal structures paralyzes their function. In other types of seizures, in which consciousness is interrupted from the very beginning, a diencephalic origin has been postulated (centrencephalic seizures of Penfield, as discussed in Chap. 15), but this idea has been contentious for decades. Concussion exemplifies yet another pathophysiologic mechanism of coma. In closed head injury, it has been shown that at the moment of the concussive injury, there is a transient but large increase in intracranial pressure, on the order of 200 to 700 lb/in2, lasting a few thousandths of a second. The vibration set up in the skull and transmitted to the brain was for many years thought to be the basis of the abrupt paralysis of nervous function that characterizes concussive head injury (commotio cerebri). While not excluding this mechanism, it is as likely that the sudden swirling motion of the brain induced by acceleration or deceleration from a blow to the head produces a rotation (torque) of the cerebral hemispheres around the axis of the upper brain stem. Disruption of the function of neurons in this region due to mechanical deformation is probably the proximate cause of loss of consciousness. These same physical forces, when extreme, cause multiple shearing lesions or hemorrhages in the diencephalon and upper brain stem. Chap. 34 fully discusses the subject of concussion. Yet another form of coma is the artificial produced by inhalation anesthetics. The effects of general anesthesia had for many years been attributed to changes in the physical chemistry of neuronal membranes. More recently, it has been recognized that interactions with ligand-gated ion channels, particularly gamma-aminobutyric acid (GABA)-A receptors and alterations in neurotransmitter function, are a more likely mechanism of anesthesiainduced unconsciousness. Summaries of what is known about the metabolic neurochemistry of anesthetics are available (Campagna and colleagues and Brown and coworkers); they emphasize changes in neurotransmitter function rather than alterations in membrane fluidity but still do not give a unified theory of the effects of these agents, partly because different classes of drug act at

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different sites. Inhalation anesthetics are unusual among coma-producing drugs with respect to the sequence of inhibitory and excitatory effects that they produce at different concentrations. With anesthesia, sufficient inhibition of brain stem activity can be attained to eliminate the pupillary responses and the corneal reflexes. Both return to normal by the time the patient is able to speak. Sustained clonus, exaggerated tendon reflexes, and Babinski signs are common during the process of arousal. Rosenberg and associates systematically studied these findings. Preexisting focal cerebral deficits from strokes often worsen transiently with the administration of anesthetics, as is true to a lesser extent with other sedatives, metabolic encephalopathies, and hyperthermia.

PATHOLOGIC ANATOMY OF COMA AND HERNIATION SYNDROMES Coma due to damage to the brain is produced by one of two broad types of processes: The first is clearly structural, or morphologic, consisting either of a discrete structural lesion in the upper brain stem and lower diencephalon (which may be primary or secondary to compression) or of widespread destructive changes throughout the hemispheres. The second type is metabolic or submicroscopic of the type discussed above under the topic or metabolic encephalopathy, resulting in suppression of neuronal activity in the cerebrum and RAS. The clinical examination in coma is designed to separate these mechanisms and to gauge the depth or seriousness of underlying dysfunction. With regard to visible structural lesions, the study of a large number of coma cases has disclosed 3 types of lesions, each of which directly or indirectly damage the function of the RAS or its projections to the cerebral hemispheres. In the first type, a large mass in one cerebral hemisphere is demonstrable—chiefly a tumor; abscess; massive infarct; or intracerebral, subdural, or epidural hemorrhage. These mass lesions cause coma by secondary compression of the midbrain and central thalamic region of the RAS. Either lateral displacement or direct compression of these structures by the advancing medical temporal lobe which is forced into the tentorial opening may be the proximate cause of compression (see below and also Chap. 30). Likewise, a cerebellar lesion may compress the adjacent upper brain stem reticular region by displacing it forward and upward. A detailed clinical record will show the coma to have coincided with these displacements and herniations as discussed further on. In the second structural configuration, which occurs less frequently, a destructive lesion is located immediately within the thalamus or midbrain, in which case the neurons of the RAS are damaged directly. This pattern characterizes upper brain stem stroke from basilar artery occlusion, thalamic and upper brain stem hemorrhages, and some forms of traumatic damage. In the third type of structural damage, there is widespread bilateral damage to the cortex and cerebral white matter, the result of traumatic damage (contusions, diffuse

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axonal injury), bilateral ischemic strokes or hemorrhages, encephalitis, meningitis, hypoxia, or global ischemia. The coma in these cases results from interruption of thalamocortical impulses or from generalized destruction of cortical neurons. It is only if the cerebral lesions are bilateral and extensive that consciousness is impaired. Many of the diseases in this category also cause severe thalamic damage of the type mentioned earlier. Thus, the pathologic changes found in cases of coma are compatible with physiologic deductions—namely that the state of coma correlates with lesions of the diencephalic cortical-activating systems. Small and discrete lesions restricted to the upper dorsal brain stem and lower midline thalami are the smallest ones sufficient to produce coma. A study by Parvizi and Damasio, on the basis of 9 cases of restricted dorsal bilateral pontine lesions, suggested that damage at a site caudal to the midbrain RAS may also cause coma. This view expands our concepts of the areas of the reticular system that are necessary for (Bodien et al), but further study is justified. One conceptual explanation for this configuration implicating the pons in coma would be the disruption of noradrenergic input from the locus coeruleus to the reticular system. However, in the largest group of cases of coma, no structural lesion is revealed by any technique of conventional pathology. Instead, a metabolic or toxic abnormality or generalized electrical discharge (seizure) causes neuronal failure at a subcellular or molecular level. As pointed out above, large, destructive, or spaceconsuming lesions of the cerebrum, such as hemorrhage, tumor, abscess, or infarction with brain swelling, usually impair consciousness indirectly by lateral and downward displacement of the subthalamic–upper brain stem structures and herniation of the medial part of the temporal lobe (uncus, hippocampus) into the opening in the tentorium. One consequence of purely lateral displacement of the midbrain, perhaps in contrast to the conventional notion of compression by herniation, is that the upper midbrain is pushed against the opposite edge of the tentorium (the Kernohan notch or, more properly, the Kernohan-Woltman phenomenon). This configuration causes weakness and a Babinski sign ipsilateral to the hemispheral lesion and later, extensor posturing on that side. The posterior cerebral artery and rarely the cisternal segment of the ipsilateral oculomotor nerve may also be compressed at the edge of the tentorium, leading to infarction of the occipital lobe in the former, and ophthalmoparesis with pupillary enlargement in the latter. It follows from the foregoing discussion that unilateral destructive lesions of the hemispheres, such as infarcts or hemorrhages, do not usually cause coma unless they create some degree of mass effect, which secondarily compresses the upper brain stem. There are exceptions in which patients with massive strokes affecting the territory of the internal carotid artery are drowsy and inattentive from the onset, even before brain swelling occurs. More often, they are simply apathetic with a tendency to keep their eyes closed, a state that may be misinterpreted as stupor. The term herniation refers to the translocation of a portion of the cerebral or cerebellar hemisphere from

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its normal position to an adjacent compartment that is bounded by dural folds, a phenomenon that is evident both at the autopsy table and by imaging of the brain. Thus, herniations are termed transfalcine (across the falx) or transtentorial (through the tentorial aperture) or are named by the structure that is displaced—cerebellar, uncal, etc. Figure 16-1 and Table 16-2 describe these displacements of brain tissue between dural compartments. Plum and Posner, following from observations by McNealy and Plum, divided the transtentorial brain stem displacements into two groups: one a central herniation syndrome with downward displacement and midline compression of the upper brain stem, and the other a unilateral insertion of the medial temporal lobe, including the uncal gyrus, into the tentorial opening and subsequent compression of the midbrain from the sides. According to these authors, the central syndrome takes the form of a rostral–caudal deterioration of brain stem function: There is first apathy and drowsiness and, often, periodic Cheyne-Stokes pattern of respiration; following this, the pupils become small and react very little to light; “doll’s-head” (“doll’s-eyes,” oculocephalic) eye movements are still elicitable, as are deviations of the eyes in response to cold-water caloric testing. Bilateral Babinski signs can be detected early; later, grasp reflexes and decorticate postures appear. These signs give way to a downward gradient of brain stem signs: coma; medium-sized fixed pupils that are referable to midbrain damage; bilateral decerebrate postures; loss of vestibulo-ocular (caloric, oculovestibular) responses all of which are the result of pontine damage; irregular breathing patterns that implicate medullary destruction; and death.

1 M

4

2

3

Figure 16-1.  Schematic depiction of brain herniations between dural compartments. Transfalcial (1), transtentorial uncal-parahippocampal (2), cerebellar tonsillar (3), and horizontal (4), causing Kernohan– Woltman notch phenomenon. Herniations are shown in pink. M = mass.

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Table 16-2 CLINICOPATHOLOGIC FEATURES OF TEMPORAL LOBE–TRANSTENTORIAL HERNIATION PATHOLOGIC CHANGE

Injury to outer fibers of ipsilateral oculomotor nerve

Creasing of contralateral cerebral peduncle (Kernohan notch)

MECHANISM

Strangulation of nerve between herniating tissue and medial petroclinoid ligament; stretching of nerve over clivus from lateral displacement of midbrain; entrapment of nerve between posterior cerebral and superior cerebellar arteries from downward displacement of midbrain Pressure of laterally displaced midbrain against sharp edge of tentorium

Lateral flattening of midbrain, and zones of necrosis and secondary hemorrhages in tegmentum and base of subthalamus, midbrain, and upper pons (Duret hemorrhages)

Crushing of midbrain between herniating temporal lobe and opposite leaf of tentorium and vascular occlusion (hemorrhages around arterioles and veins)

Unilateral or bilateral infarction (hemorrhagic) of occipital lobes

Compression of posterior cerebral artery against the tentorium by herniating temporal lobe

Raised intracranial pressure and hydrocephalus

Lateral flattening of aqueduct and third ventricle and blockage of perimesencephalic subarachnoid space

The uncal syndrome, the result of herniation of the medial temporal lobe into the tentorial opening, differs in that drowsiness in the early stages is accompanied or preceded by unilateral pupillary dilatation, most often on the side of the mass, as a result of compression of the third nerve by the advancing uncal gyrus. Our own experience does not consistently accord with this distinction between the two herniation syndromes. We have not consistently been able to detect an orderly sequence of neural dysfunction from the diencephalic to the medullary level but this is not necessarily a contrary view to the herniation model. With lateral shift and uncal herniation, one sometimes observes smallness of the pupils, rather than ipsilateral pupillary dilatation, just as drowsiness develops. Or, infrequently, the contralateral pupil may dilate before the ipsilateral one. Nor is it clear that the dilatation of one pupil is always due to compression of the oculomotor nerve by the herniated uncus. As often in pathologic material, the third nerve is stretched and angulated over the clivus or compressed under the descended posterior cerebral artery. Involvement of the third nerve nucleus or its fibers of exit within the midbrain may be responsible for the dilatation of the opposite pupil, the usual occurrence after the pupil on the side of the mass has become fixed (Ropper, 1990). In our serial study of 12 patients with brain swelling and lateral diencephalic–mesencephalic shifts caused by hemispheral infarcts, 4 initially had no ipsilateral pupillary enlargement; in 1 patient, the pupillary enlargement was contralateral; in 3 patients, the pupils were symmetrical when drowsiness gave way to stupor or coma (Ropper and Shafran, 1984). Cyclic Cheyne-Stokes breathing was an early sign of deterioration. In one patient, the first motor sign was an ipsilateral decerebrate rigidity rather than decorticate posturing; most of the patients had bilateral Babinski signs by the time they became stuporous. The appearance of a Babinski sign on the nonhemiparetic side

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CLINICAL DISORDERS

Pupillary dilatation (Hutchinson pupil), ophthalmoplegia later

Hemiplegia ipsilateral to herniation (false localizing sign) and bilateral corticospinal tract signs Cheyne-Stokes respirations; stupor; coma; bipyramidal signs; decerebration; dilated, fixed pupils and alterations of gaze (facilitated oculocephalic reflex movement giving way to loss of all response to head movement and labyrinthine stimulation) Usually none detectable during coma; hemianopia (unilateral or bilateral) with recovery Increasing depth of coma, rising blood pressure, bradycardia (Cushing response)

has been a relatively dependable but not invariant sentinel of secondary brain tissue shift at the tentorial opening. The important elements of secondary compression of the upper brain stem may occur in some cases entirely above the plane of the tentorium and be due to horizontal shift of structures rather than to herniation. With acute masses, a 3- to 5-mm horizontal displacement of the pineal calcification is associated with drowsiness; 5 to 8 mm, with stupor; and greater than 8 or 9 mm, with coma (Ropper, 1986). Shift of the septum pellucidum less dependably predicts the level of consciousness. The degree of vertical tissue distortion differs between cases. Pleasure and colleagues described a syndrome of low cerebrospinal fluid (CSF) pressure causing a purely downward herniation and stupor that was corrected by the infusion of fluid into the spinal canal. Others, notably Reich and colleagues, have found evidence for vertical shift to be more compelling than for horizontal displacement. In any case, the location in reference to the tentorial opening, the size of a mass, and the rapidity of its expansion all determine the degree of brain distortion and displacement of crucial structures in the diencephalon and upper midbrain. Frontal and occipital hemorrhages are less likely to displace deep structures and to cause coma than are clots of equivalent size in the parietal or temporal lobes (Andrews and colleagues, 1988). Nor is it surprising that slowly enlarging masses, such as brain tumors, can cause massive displacements of brain tissue, yet result in few clinical changes. In other words, all of the above comments must take into consideration the rate of evolution of a mass and its location and relationship to vital structures that maintain arousal. The neural dysfunction of deep structures, particularly of the RAS, resulting from compression is probably due to ischemia but this issue has not been well studied and it is possible that mechanical distortion of neurons or glia may contribute.

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Chapter 16 Coma and Related Disorders of Consciousness

CLINICAL APPROACH TO THE COMATOSE PATIENT Many times, the primary disorder underlying coma is perfectly obvious, as with severe cranial trauma or a known drug overdose. All too often, however, the comatose patient is brought to the hospital with little pertinent medical information. The need for efficiency in reaching a diagnosis and providing acute care demands that the physician has a methodical approach that first addresses the common and treatable causes of coma. When the comatose patient is first seen, the patient’s airway is cleared and blood pressure is restored; if trauma has occurred, one must check for bleeding from a wound or ruptured organ (e.g., spleen or liver). With hypotension, placement of a central venous line and administration of fluids and pressor agents, oxygen, blood, or glucose solutions (preferably after blood is drawn for glucose determinations and thiamine is administered) take precedence over diagnostic procedures. If respirations are shallow or labored, or if there is emesis with a threat of aspiration, tracheal intubation and mechanical ventilation are instituted. An oropharyngeal airway is otherwise adequate in a comatose patient who is breathing normally. Deeply comatose patients with shallow respirations require endotracheal intubation. The patient with a head injury may also have suffered a fracture of the cervical vertebrae, in which case caution must be exercised in moving the head and neck as well as in intubation lest the spinal cord be inadvertently damaged. These matters are discussed in detail further on, under “Management of the Acutely Comatose Patient.” An inquiry is then made as to the circumstances in which the person was found and their previous health, whether there was a history of diabetes, a head injury, a convulsion, alcohol or drug use, or a prior episode of coma or attempted suicide. Persons who accompany the comatose patient to the hospital should be encouraged to remain until they have been questioned. In addition to the basic laboratory tests that apply to coma, a toxicology screen is usually appropriate. In assessing confusion, stupor, or coma in an already hospitalized patient, it is usually instructive to review the patient’s medications carefully. A number of compounds may reduce alertness to the point of profound somnolence or stupor, particularly if there are underlying medical problems (e.g., a liver failure). Prominent in lists of iatrogenic drug intoxications are sedatives, antiepileptic drugs, opiates, certain antibiotics, antidepressants, and antipsychosis compounds. From an initial survey, many of the common causes of coma, such as severe head injury, alcoholism or other forms of drug intoxication, and hypertensive brain hemorrhage, are readily recognized. Following this, the basic electrolyte, glucose, and renal function tests are established as a derangement of any of these may lead to stupor or coma. In certain circumstances, a toxicology screen may be added, as if the patient is being seen the first time in an emergency setting.

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General Examination Alterations in vital signs (temperature, heart rate, respiratory rate, and blood pressure) are important aids in diagnosis. Fever is most often the result of a systemic infection such as pneumonia or bacterial meningitis or viral encephalitis. An excessively high body temperature (42°C [107.6°F] or 43°C [109.4°F]) associated with dry skin should arouse suspicion of heat stroke or intoxication by a drug with anticholinergic activity. Fever should not be too easily ascribed to a brain lesion that has disturbed the temperature-regulating center, so-called central fever, which is a rare occurrence. Hypothermia is observed in patients with alcohol or barbiturate intoxication, drowning, exposure to cold, peripheral circulatory failure, advanced tuberculous meningitis, and myxedema. Slow breathing points to opiate or barbiturate intoxication and occasionally to hypothyroidism, whereas deep, rapid breathing (Kussmaul respiration) should suggest the presence of pneumonia, diabetic or uremic acidosis, pulmonary edema, or the less-common occurrence of an intracranial disease that causes central neurogenic hyperventilation (CNH). Diseases that elevate intracranial pressure or damage the brain often cause slow, irregular, or cyclic Cheyne-Stokes respiration. The various disordered patterns of breathing and their clinical significance are described further on. Vomiting at the outset of sudden coma, particularly if combined with pronounced hypertension, is characteristic of cerebral hemorrhage within the hemispheres, brain stem, cerebellum, or subarachnoid spaces. Marked hypertension is observed in patients with cerebral hemorrhage and in hypertensive encephalopathy and in children with markedly elevated intracranial pressure. Hypotension is the usual finding in states of depressed consciousness because of diabetes, alcohol or barbiturate intoxication, internal hemorrhage, myocardial infarction, dissecting aortic aneurysm, septicemia, Addison disease, or massive brain trauma. The heart rate, if exceptionally slow, suggests heart block from medications such as tricyclic antidepressants or anticonvulsants, or if combined with periodic breathing and hypertension, an increase in intracranial pressure. Inspection of the skin may yield valuable information. Cyanosis of the lips and nail beds signifies inadequate oxygenation. Cherry-red coloration is typical of carbon monoxide poisoning. Multiple bruises (particularly a bruise or boggy area in the scalp), bleeding, CSF leakage from an ear or the nose, or periorbital hemorrhage greatly raises the likelihood of cranial fracture and intracranial trauma or of a severe coagulopathy causing intracranial bleeding. Telangiectases and hyperemia of the face and conjunctivae are the common stigmata of alcoholism; myxedema imparts a characteristic puffiness of the face, and hypopituitarism an equally characteristic sallow complexion. Marked pallor suggests internal hemorrhage. A macular-hemorrhagic rash indicates the possibility of meningococcal infection, staphylococcal endocarditis, typhus, or Rocky Mountain spotted fever. Excessive sweating suggests hypoglycemia or shock, and excessively dry skin, diabetic acidosis, or uremia. Large blisters, sometimes bloody, may form over pressure points such as the buttocks if the patient has been

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motionless for a time; this sign is particularly characteristic of the deeply unresponsive and prolonged motionless state of acute sedation, alcohol, and opiate intoxication. Thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation, and diffuse fat embolism after bone injury may cause diffuse petechiae or purpura; the last of these are often aggregated in the anterior axillary folds. The odor of the breath may provide a clue to the etiology of coma. Alcohol is easily recognized. The spoiled-fruit odor of diabetic ketoacidotic coma, the uriniferous odor of uremia, the musky and slightly fecal fetor of hepatic coma, and the burnt almond odor of cyanide poisoning are distinctive enough to be identified by physicians who possess a keen sense of smell. The distinctive odor of melena, experienced in the former open wards of large hospitals, is a sign of rapid gastrointestinal bleeding.

Neurologic Examination of the Stuporous or Comatose Patient Although limited in some ways in comparison to the examination of the alert patient, the neurologic examination of the comatose patient offers considerable information and is relatively simple. Watching the patient without interference for a few moments yields useful information. The predominant postures of the limbs and body; the presence or absence of spontaneous movements on one side; the position of the head and eyes; and the rate, depth, and rhythm of respiration each give substantial information. The state of responsiveness is then estimated by noting the patient’s reaction to sequentially more vigorous stimuli starting with calling his name, to simple commands, and then to noxious stimuli such as tickling the nares, supraorbital or sternal pressure, pinching the side of the neck or inner parts of the arms or thighs, or applying pressure to the knuckles. By this method, one can roughly estimate both the degree of unresponsiveness and changes from hour to hour. Vocalization may persist in stupor and will be the first response to be lost as coma appears. Grimacing and deft avoidance movements of stimulated parts of the body are preserved in stupor; their presence substantiates the integrity of corticobulbar and corticospinal tracts. Yawning and spontaneous shifting of body positions indicate a minimal degree of unresponsiveness. These signs have been elegantly summarized by Fisher in an iconic paper based on his own observations. The widely adopted Glasgow Coma Scale, constructed originally as a quick and simple means of quantitating the responsiveness of patients with cerebral trauma, can be used in the grading of other acute comaproducing diseases as mentioned earlier in this chapter (see also Chap. 34). Meningismus is a fairly specific but somewhat insensitive sign of meningeal irritation as commented in Chap. 1. In all but the deepest stages of coma, meningeal irritation from either bacterial meningitis or subarachnoid hemorrhage will cause some resistance to the initial excursion of passive flexion of the neck but not to extension, turning, or tilting of the head. Resistance to movement of the neck in all directions may be part of generalized muscular rigidity

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or dystonia or indicate disease of the cervical spine. In the infant, bulging of the anterior fontanel is at times a more reliable sign of meningitis than is a stiff neck. A cerebellar herniation or decerebrate rigidity may also create resistance to passive flexion of the neck and be confused with meningeal irritation. Hemiplegia is exposed by a lack of restless movements of the limbs on one side and by inadequate protective movements in response to painful stimuli. The weakened limbs are usually slack and, if lifted from the bed, they “fall flail.” The hemiplegic leg lies in a position of external rotation (this may also be caused by a fractured femur), and the affected thigh appears wider and flatter than the nonhemiplegic one. In expiration, the cheek and lips puff out on the paralyzed side of the face. In most cases, hemiplegia and an accompanying Babinski sign are indicative of a contralateral hemispheral lesion; but with lateral mass effect and compression of the opposite cerebral peduncle against the tentorium, extensor posturing, a Babinski sign, and weakness of arm and leg may appear ipsilateral to the lesion (the earlier-mentioned Kernohan-Woltman sign). A moan or grimace may be provoked by painful stimuli applied to one side but not to the other, reflecting hemianesthesia. During grimacing in response to stimuli, facial weakness may be noted. Restless movements of both arms and both legs and grasping and picking movements signify that the corticospinal tracts are more or less intact. Oppositional resistance to passive movement (paratonic rigidity), complex avoidance movements, and discrete protective movements have the same meaning; especially if they are bilateral and they suggest the coma is not deep. Abduction movements (away from the midline) to escape a noxious stimulus have the same significance and differentiate a motor response from posturing, described below. Focal motor epilepsy indicates that the corticospinal pathway to the convulsing side is intact. With massive destruction of a cerebral hemisphere, as occurs in hypertensive hemorrhage or internal carotid–middle cerebral artery occlusion, seizure activity may be manifest solely in the ipsilateral limbs, the contralateral limbs being prevented from participating by the hemiplegia. Elaborate forms of semivoluntary movement may be manifest on the nonhemiparetic side in patients with extensive disease in one hemisphere; they probably represent some type of disinhibition of cortical and subcortical movement patterns. Choreic, athetotic, or hemiballistic movements indicate a disorder of the basal ganglionic and subthalamic structures, just as they do in the alert patient, but are not helpful in localizing the cause of coma. Of the various indicators of brain stem function, the most useful are pupillary size and reactivity, ocular movements, vestibulo-ocular reflexes and, to a lesser extent, the pattern of breathing. These functions, like consciousness itself, are dependent on the integrity of structures in the midbrain and rostral pons.

Pupillary Reactions A unilaterally enlarged (“Hutchinson”) pupil is an early indicator of stretching or compression of the third nerve

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Chapter 16 Coma and Related Disorders of Consciousness

and reflects the presence of an ipsilateral overlying hemispheral mass as described earlier in the section on herniations. A loss of light reaction usually precedes enlargement of the pupil. As a transitional phenomenon, the pupil may become oval or pear-shaped or appear to be off center (corectopia) because of a differential loss of innervation of a portion of the pupillary sphincter. The light-unreactive pupil continues to enlarge to a size of 6 to 9 mm diameter and is soon joined by a slight outward deviation of the eye. In unusual instances, the pupil contralateral to the mass may enlarge first; this has reportedly been the case in 10 percent of subdural hematomas but has been far less frequent in our experience. As midbrain displacement continues, both pupils dilate and become unreactive to light, probably as a result of compression of the oculomotor nuclei in the rostral midbrain (Ropper, 1990). The last step in the evolution of brain stem compression tends to be a slight reduction in pupillary size on both sides, to 5 mm or smaller. Normal pupillary size, shape, and light reflexes indicate integrity of midbrain structures and direct attention to a cause of coma other than a mass. Pontine tegmental lesions cause extremely miotic pupils ( 210/110 mm Hg (lower in eclampsia and in children), headache, seizures, hypertensive retinal changes Petechiae, seizures shifting focal signs

Slow or cyclic respiration, rising blood pressure, hemiparesis, unilateral enlarged pupil Signs of cranial and facial injury

Hemiplegia, unilateral unresponsive, or enlarged pupil

Hemiplegia, hypertension, cyclic breathing, specific ocular signs (see Chap. 13) Extensor posturing and bilateral Babinski signs; early loss of oculocephalic responses; ocular bobbing

IMPORTANT CLINICAL FINDINGS

USEFUL POINTS IN THE DIFFERENTIAL DIAGNOSIS OF THE COMMON CAUSES OF COMA

Table 16-3 IMPORTANT LABORATORY FINDINGS

CT and MRI show contusions, hemorrhages, and other injuries; CSF may be bloody Rim-enhancing mass with surrounding edema Posterior predominant hypodensity on CT and T2 hyperintensity on MRI affecting gray matter and subcortical white matter; CSF pressure elevated Multiple small cortical infarctions and/or microhemorrhages; thrombocytopenia Possible cerebral edema; meningeal enhancement; pleocytosis, increased protein, low glucose in CSF Cisternal and sulcal blood; bloody or xanthochromic CSF under increased pressure

Hyperdense basilar artery (acute thrombosis) on CT; reduced diffusivity and T2 hyperintensity (on MRI) in brainstem and PCA territory; normal cerebrospinal fluid (CSF) Extensive edema, loss of gray-white matter differentiation, sulcal and ventricular effacement, subfalcine and uncal herniation Hyperdense blood on CT; CSF xanthochromic with relatively low protein

Hyperdense blood on CT

REMARKS

(Continued)

Sudden onset with severe headache

Similar to fat embolism; multifocal microvasculopathy Subacute or acute onset

Unstable blood pressure, associated systemic injuries Systemic infection or neurosurgical procedure, fever Acute or subacute evolution, use of aminophylline or catecholamine medications

Signs or history of trauma, headache, confusion, progressive drowsiness

Coma preceded by drowsiness for several days after stroke

Sudden onset, often with headache, vomiting; history of chronic hypertension; late pupillary enlargement Onset subacute (thrombosis); or sudden (rostral basilar embolism)

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Carbon monoxide intoxication Global ischemia–anoxia

Hypoglycemia

Diabetic coma Uremia Hepatic coma

Hypercapnia Severe infections (septic shock); heat stroke Seizures

 

 

 

 

 

 

 

 

 

Opioid intoxication

 

Extreme hyperthermia, rapid respiration Episodic disturbance of behavior or convulsive movements

Papilledema, diffuse myoclonus, asterixis

Signs of extracellular fluid deficit, hyper ventilation with Kussmaul respiration, “fruity” breath Hypertension; sallow, dry skin, uriniferous breath, twitch-convulsive syndrome Jaundice, ascites, and other signs of portal hypertension; asterixis

Same as in anoxia

Rigidity, decerebrate postures, fever, seizures, myoclonus

Slow respiration, cyanosis, constricted pupils Cherry-red skin

Hypothermia, hypotension

Sedative intoxication

IMPORTANT CLINICAL FINDINGS

Hypothermia, hypotension, flushed skin, alcohol breath

SPECIFIC DISORDER

Alcohol intoxication

Coma without focal neu rologic signs or menin geal irritation; CT scan and CSF normal  

GENERAL GROUP

In status epilepticus, reduced diffusivity on MRI in the involved cortex; characteristic EEG changes

Vary according to cause

Glycosuria, hyperglycemia, acidosis; reduced serum bicarbonate; ketonemia and ketonuria, or hyperosmolarity Protein and casts in urine; elevated blood urea nitrogen and serum creatinine; anemia, acidosis, hypocalcemia T1 hyperintensity from manganese deposition in globus pallidi and other structures; Elevated blood NH3 levels; CSF yellow (bilirubin) with normal or slightly elevated protein Increased CSF pressure; PCO2 may exceed 75 mm Hg; EEG theta and delta activity

Reduced diffusivity in globuspallidi; Carboxyhemoglobin Reduced diffusivity and edema in cerebral and cerebellar cortex and deep nuclei; CSF normal; EEG may be iso electric or show high-voltage delta Low blood and CSF glucose

Drug in urine and blood; electroencephalogram (EEG) often shows fast activity  

Elevated blood alcohol

IMPORTANT LABORATORY FINDINGS

USEFUL POINTS IN THE DIFFERENTIAL DIAGNOSIS OF THE COMMON CAUSES OF COMA (CONTINUED)

Table 16-3 REMARKS

Onset over a few days or after paracentesis or hemorrhage from varices; confusion, stupor, asterixis, and characteristic EEG changes precede coma Advanced pulmonary disease; profound coma and brain damage uncommon Evidence of a specific infection or expo sure to extreme heat History of previous attacks

Progressive apathy, confusion, and asterixis precede coma

Characteristic slow evolution through stages of nervousness, hunger, sweating, flushed face; then pallor, shallow respirations, and seizures History of polyuria, polydipsia, weight loss, or diabetes

Abrupt onset following cardiopulmonary arrest; damage permanent if anoxia exceeds 3–5 min

History of intake of drug; suicide attempt Administration of naloxone causes awakening and pupil enlargement Pallidal necrosis

May be combined with head injury, infection, or hepatic failure

Chapter 16 Coma and Related Disorders of Consciousness

diabetic acidosis, or following a seizure. In hypertensive encephalopathy, focal signs may also be present. Occasionally, for no understandable reason, one leg may seem to move less, one plantar reflex may be extensor, or seizures may be predominantly or entirely unilateral in a metabolic coma, particularly in the hyperglycemic–hyperosmolar states. Babinski signs and extensor rigidity, conventionally considered to be indicators of structural disease, do sometimes occur in profound intoxications with a number of agents or with hepatic encephalopathy. The diagnosis of concussion or of postictal coma depends on observation of the precipitating event or indirect evidence, as discussed in Chap. 34. Usually, a convulsive seizure is marked by a bitten tongue, urinary incontinence, and an elevated creatine kinase–skeletal muscle fraction; it may be followed by another seizure or burst of seizures. The presence of small clonic or myoclonic convulsive movements of a hand or foot or fluttering of the eyelids or eyes makes an EEG useful to determine whether underlying status epilepticus is the cause of coma. This state, nonconvulsive status epilepticus, described in Chap. 15, must be considered in the diagnosis of unexplained coma, especially in known epileptics (see Table 16-3). With respect to the second group with signs primarily of meningeal irritation (head retraction, stiffness of neck on forward bending, Kernig and Brudzinski signs), bacterial meningitis and subarachnoid hemorrhage are the usual causes. However, if the coma is profound, stiff neck may be absent in both infants and adults. In such cases, the spinal fluid must be examined in order to establish the diagnosis. In most cases of bacterial meningitis, the CSF pressure is elevated but is not exceptionally high (usually 10 BPM and 159 cm 3.  Grip strength (lb) BMI ≤ 24 ≤29 BMI ≤ 23 BMI 24.1–26 ≤30 BMI 23.1–26 BMI 26.1–28 ≤30 BMI 26.1–29 BMI > 28 ≤32 BMI > 29 4.  Physical activity 2,000 >10,000

Subacute blood, contusions, CSF disorders Infarcts, inflammation, tumors   Edema, inflammation

“Most pathology” Edema, inflammation, gliosis

Fat, water, acute blood CSF; otherwise like T2

 

 

Acute infarction

Acute ischemic stroke

   

   

Hemorrhages, calcification Spine and orbit studies (eliminates fat signals)

   

Blood after several days Blood  

T1-weighted

2,000

Proton (spin) density Fluid-attenuated inversion recovery (FLAIR) Diffusion-weighted image (DWI) Susceptibility sequence Short tau inversion recovery (STIR)

80

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DARK

Solids, calcium

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malformations, and other blood vessel diseases such as arthritis and vasospasm. Conventional contrast angiography has largely been supplanted by CT angiography, magnetic resonance angiography (MRA), and venography (MRV) for the visualization of large intracranial arteries and veins (see Fig. 2-2J and K). These techniques have the advantage of relative safety (intravenous injection of contrast media is required for CT angiography, but arterial catheterization is not required) but do not give refined images of the smaller blood vessels. The MRI-based technique of “time of flight” imaging does not require contrast injection and can provide highly detailed views of the vasculature, though strictly speaking, this technique uses the flow of blood as a surrogate for luminal patency, and so stenoses can occasionally appear worse than on contrastbased angiography techniques. Partly as a result of the increased use and availability of endovascular thrombectomy, it has become useful to determine if there is ischemic, but not yet infarcted, brain tissue. The main techniques to detect salvageable ischemic brain tissue are CT and MR perfusion. Both involve the rapid acquisition of images during the passage of a contrast agent through brain tissue. A time-intensity curve is derived, and from this curve, measurements of CBF, blood

volume, and transit time can be displayed (Fig. 33-4). A penumbral-ischemic region is identified by increased transit time (or reduced flow) with relatively maintained blood volume. In comparison, infarcted tissue is identified by reduced blood volume that is beyond the threshold for reversible tissue damage; this region should correspond to the findings on diffusion weighted imaging. Other procedures for the investigation of cerebrovascular disease include Doppler ultrasound flow studies, which demonstrate atheromatous plaques and stenoses of large vessels, particularly of the internal and common carotid arteries in the neck but also of the vertebrobasilar arteries. The aortic arch can be examined for atheromata by echocardiography. The transcranial Doppler technique has reached a degree of precision whereby occlusion or spasm of the proximal arterial branches arising from the circle of Willis can be detected and roughly quantitated, but the test requires considerable skill to perform effectively. Various methods of measuring regional blood flow with positron emission tomography (PET) and radionuclide imaging find use in special instances discussed in appropriate sections of the chapter. The EEG and lumbar puncture have lost favor in stroke diagnosis, but they were used as a readily available means

Slope of curve = cerebral blood flow

Signal

Area under curve = cerebral blood volume

Time to peak

A

B

Time

C

D

Figure 33-4.  In perfusion imaging, a time-intensity curve (A) is generated by measurement of the passage of contrast material through brain tissue. The slope of the curve represents blood flow and the area under the curve represents blood volume. Voxel measurements of these parameters are converted to color maps showing blood flow, volume, and contrast transit time throughout the brain. Arterial occlusions alter the timeintensity curve by either flattening the slope of the curve or reducing the area under the curve. As an example, an acute occlusion of the proximal segment of the right middle cerebral artery produces a region of signal abnormality on diffusion-weighted imaging (B) that is matched in size by an area of reduced blood volume (C). This area represents infarcted tissue. The area of prolonged transit time (D) affects a larger territory, particularly posteriorly. The difference between this territory and the infarcted zone represents the ischemic penumbra and is often referred to as the diffusion-perfusion mismatch.

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Chapter 33 Stroke and Cerebrovascular Diseases

of detecting cortical infarction in the wake of ischemia of a region of one hemisphere. It may allow the distinction to be made between the occlusion of a small vessel (lacunar) and a large (embolic) vessel because focal EEG abnormalities are sparse or absent with a deep lacunar stroke. The technique finds more use in distinguishing between transient alterations in the nervous function that are a result of seizures and episodes caused by focal ischemia.

Neurovascular Physical Examination Whereas cerebral arteries can be evaluated only indirectly, more direct clinical means of physical examination are available for the evaluation of the common and internal carotid arteries in the neck. With severe atherosclerotic stenosis at the level of the carotid sinus, auscultation discloses a bruit, best heard with the bell of the stethoscope held against the skin just tightly enough to create a seal (excessive pressure creates a diaphragm of the skin and filters the low-pitched frequencies that are typical of the bruit of carotid stenosis). The presence of a bruit in the neck is an indication of cerebrovascular disease, but its detection is not highly correlated with the presence of severely stenotic lesions as assessed by ultrasonography or angiography. Occasionally, a bruit at the angle of the jaw is caused by stenosis at the origin of the external carotid artery or is a radiated murmur from the aortic valve and can then be misleading. If the bruit is loudest at the angle of the jaw, the stenosis usually lies at the proximal internal carotid; if heard lower in the neck, it is in the common carotid or subclavian artery and may be radiated from the aortic valve. Rarely, stenosis in vertebral arteries or vascular malformations at the base of the brain produces bruits that are heard posteriorly in the neck. An additional though infrequent sign of carotid occlusion is the presence of a bruit over the opposite carotid artery, heard by placing the bell of the stethoscope over the eyeball (ocular bruit). This murmur is often caused by augmented circulation through the patent vessel, but there have been as many instances in our experience when a bruit over the eye instead reflects a stenosis in the intracranial portion of the carotid artery on that side Pessin and colleagues (1983). These and other tests for indirectly assessing carotid flow have been supplanted by ultrasound and imaging of the carotid artery. Retinal examination remains valuable in that it may demonstrate emboli within retinal arteries, either shiny white or reddish in appearance; this is another important sign of carotid disease (crystalline cholesterol, termed Hollenhorst plaque, is sloughed from an atheromatous ulcer). This examination may be useful if there has been transient or persistent visual loss. Despite this exegesis on the neurovascular examination, the modern view is that it provides little assistance in diagnosis and may be misleading, especially regarding a carotid bruit, which may or may not indicate important stenosis, especially in asymptomatic patients. At best, these examinations can reasonably lead to ultrasound or CT or MRI of the involved vessels to establish the presence of disease and follow its course.

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Neurological Scales Used in Ischemic Stroke Trials and Clinical Evaluation (Table 33-4) It has become necessary, as a shorthand, to devise numerical scales for evaluating the severity and outcome of strokes. This trend began with the canonical NIH sponsored trial of intravenous tPA (Marler et al), as discussed in a later section on treatment, but various scales have since expanded to fill many roles, particularly in clinical trials. The inception of thrombolysis and endovascular thrombectomy for acute stroke treatment has intensified the need to make rapid evaluations of stroke severity and offer an efficient way to summarize the patient’s clinical deficits and ultimate outcome. Some scales are intended mainly as predictive tools. The deficiencies of the scales and their pitfalls have been discussed in the literature and we can only add to a lament that the scales are a surrogate for a careful examination and something essential to neurology is lost by employing them blindly. All are approximations to neurological deficits or imaging features of stroke. Nevertheless, the field of stroke has been greatly advanced by well-planned and well-implemented clinical trials of new treatments that use these scales among the criteria by which patients are enrolled and outcome is assessed. If a scale score is used for this purpose in a trial, it seems logical that only patients similarly defined can be expected to benefit from a treatment when it is translated to clinical practice. Herewith, we summarize some of the main current scales used in ischemic trials with the items in the scales given in Table 33-4; they are again brought up in applicable sections on treatment. There are other such scales that are not as widely used as the ones outlined here, and undoubtedly, new ones will be devised as the need arises. Some of the main ones are described here. National Institute of Health Stroke Scale (NIHSS) (Table 33-4)  There are 13 essential elements, each scored 0 to 3 or 0 to 2, and some having scores for each of the left and right sides. The range of the total score is 0 to 42 with higher scores denoting worse function. It may be considered a categorical scale as it has neither ordinal, cardinal, or continuous characteristics; i.e., a one or two point difference in parts of the scale is not similar to a one or two point difference in other parts. There are inherent limitations to the scale because, for example, in coma the level of consciousness is scored as 3, and then several items, such as ataxia, will necessarily have no evaluable score and the upper range becomes 39. A score can be obtained in most patients in less than 10 minutes, but training is required for the score to be consistent with scores obtained by other examiners. The score emphasizes motor deficits over others, underemphasizes non-dominant deficits such as apraxia and agnosia and has low sensitivity for deficits in the vertebrobasilar circulation than the anterior circulation. In broad terms, with some variation between publications, scores of over 25 have been used to denote very severe stroke; 15 to 24, severe stroke; 5 to 14, mild to moderately severe stroke; and less than 5, mild stroke. There have been modified versions of the NIHSS, including one with patient assessed values for each item, that are not as widely used.

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Table 33-4 SELECTED SCORING SYSTEMS IN ISCHEMIC STROKE TRIALS AND CLINICAL ASSESSMENT NIH Stroke Scale (NIHSS); Range 0 to 42, higher scores denote more severe deficit; numbers represent possible scores for each item, higher indicating better function) Points 1A.  Level of consciousness 0 to 3 1B.  Response to month and age 0 to 3 1C.  Response to blink eyes and squeeze hand 0 to 2 2.  Horizontal eye movements 0 to 2 3.  Visual fields 0 to 3 4.  Facial palsy 0 to 3 5A.  Left arm drift 0 to 4 5B.  Right arm drift 0 to 4 6A.  Left leg drift 0 to 4 6B.  Limb leg drift 0 to 4 7.  Limb ataxia 0 to 2 8.  Sensation 0 to 2 9.  Aphasia 0 to 3 10.  Dysarthria 0 to 2 11.  Extinction/inattention 0 to 2 Modified Rankin Outcome Scale (mRS); Range 0 to 6, higher scores indicating more disability 0   No symptoms 1    No significant disability despite symptoms; able to perform usual activities 2    Slight disability; unable to perform all previous activities but able to look after own affairs without assistance 3    Moderate disability; requires some help but able to walk without assistance 4    Moderately severe disability; unable to walk without assistance and unable to attend own bodily needs without assistance 5    Severe disability; bedridden, incontinent, and requires constant nursing care and attention 6   Death Barthel Index of Activities of Daily Living; Range 0 to 100; lower scores indicating greater difficulty with daily function Each category scored as 0, 5, 10, or 15 Total score of 0 to 20 indicates total dependency on others and 100 reflects normal functioning Feeding Bathing Grooming Dressing Bowel control Bladder control Toilet use Transfers Mobility on level surfaces Stairs ABCD2 stroke prediction tool after TIA Range 0 to 8; higher score predicting greater likelihood of subsequent stroke Total score of 0 to 3 indicates low risk of stroke; 1% at 2 days after TIA to 3% at 90 days Points Age >60 1 BP > 140 systolic or >90 diastolic 1 TIA features   Unilateral weakness 2   Dysarthria without weakness 1 Duration of TIA   10–59 minutes 1   >60 minutes 2 Diabetes 1 Alberta Stroke Program Early CT Score (ASPECTS); Range 0 to 10; lower score signifying more ischemic territories (1 point subtracted from 10 for each territory involved Caudate Internal capsule Lentiform nucleus Insular ribbon Anterior middle cerebral cortical territory Middle cerebral cortex lateral to insula Posterior middle cerebral cortex Anterior cortex immediately rostral to M1 Lateral cortex immediately rostral to M3 Posterior cortex immediately rostral to M3 Thrombolysis in Cerebral Infarction Score (TICI); higher scores indicate better recanalization/perfusion after revascularization Grade 0   no perfusion Grade 1    penetration of contrast with minimal perfusion Grade 2b     partial filling (less than two-thirds) of the vascular territory (generally considered successful recanalization) Grade 2c     complete filling of vascular territory but slower than normal (usually considered successful perfusion) Grade 3    complete (successful) recanalization (Continued)

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Table 33-4 SELECTED SCORING SYSTEMS IN ISCHEMIC STROKE TRIALS AND CLINICAL ASSESSMENT (CONTINUED) CHA2DS2-VASC Stroke Prediction in Atrial Fibrillation Points Assigned for Each Item Heart failure or ejection fraction < 35% 1 Hypertension 1 Age   75 years 2 Previous stroke or TIA 2 Diabetes 1 Coronary or peripheral vascular disease 1 Female 1

Summed Score Likelihood of Stroke Per Year 1… 1.3% 2… 2.2%

Modified Rankin Outcome Scale (mRS) (Table 33-4)  This is a scale of neurologic disability, ranging from 0 to 6 (seven categories) and may be considered categorical in nature. Zero represents no symptoms and 6 represents death. A single point change represents a clinically meaningful difference but there is latitude in determining which category to assign to an individual patient. A point of uncertainty in the literature is how to define “good” outcome, and many stroke trials 0 to 3 for this category, although three indicates moderate disability; requiring some help but able to walk without assistance; other trials have used 0 to 2 for a good outcome. Less training is required than for NIHSS and the scores are often obtained by nonphysicians or can be obtained from patient report. The scales have been expanded to use in head injury and other neurologic conditions. Barthel Index (Table 33-4)  This is a functional scale of the activities of daily living that is often used to gauge outcomes. It has fairly explicit categories such as feeding, bathing, dressing, and mobility that are easy to determine but have very variable point scoring that emphasizes transfers, mobility on level surfaces, and toileting. The range is 0 to 100 with higher scores indicating better function (100 indicates totally independent and scores of 0 to 20 indicate total dependency). As with mRS, the scale has been used to gauge the degree of independence for disorders other than stroke. ABCD2 Score (Table 33-4)  This scale was devised as a prediction tool for triaging patients with a TIA based on the likelihood of the stroke soon after the TIA. It has eight categories that combine age and current physiologic factors such as blood pressure, with diabetes and the clinical characteristics of the TIA. The range is 0 to 8 with higher scores corresponding to a greater risk of stroke in the short term. Although useful, it may not accurately determine which patients require immediate evaluation as atrial fibrillation and carotid artery stenosis are found in a proportion of patients with low scores. Alberta Stroke Program Early CT Score (ASPECTS) (Table 33-4)  This scale was designed to determine the extent of early ischemic change in the territory of the MCA on a

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3… 3.2% 4… 4.0% 5… 6.7% 6… 9.8% 7… 6.9% 8… 6.7%   9... 15.2%

cranial CT. The range is 0 to 10 in one point and is deducted from 10 for each cortical or subcortical structure that demonstrates subtle or overt alterations that suggest infarction. It is found its main utility in identifying patients who have twothirds or more of the MCA territory infarcted as an exclusionary criterion for certain clinical trials and practices. Thrombolysis in Cerebral Infarction Score (TICI) (Table 33-4)  This tool was devised to determine the adequacy of revascularization after thrombolysis or thrombectomy. As originally conceived, it scored from grade 0, no perfusion; grade 2, partial perfusion; to grade 3, complete perfusion of the vascular territory. The second category has been further subdivided into 2b and 2c depending on the rate at which contrast passes an obstruction. The scales have been applied variously to the middle cerebral stem, branches of the MCA, and other vessels. CHA2DS2VASC-c (CHADS-VASC) Stroke Predictive Scale for Atrial Fibrillation (Table 33-4)  This risk-factorbased scoring system was developed to stratify future likelihood of stroke in patients with atrial fibrillation and as an aid to clinical decision-making regarding anticoagulation. It incorporates patient age, sex, history of congestive heart failure, hypertension, prior stroke/TIA/thromboembolism, vascular disease (including myocardial infarction, peripheral arterial disease, or aortic plaque), and diabetes. Scores range from 0 to 9 and higher scores indicate an increased annual risk of stroke due to atrial fibrillation. (Risk scores in table are approximate). In general terms, a score of zero suggests low risk (may not require anticoagulation), a score of 1 suggests low-moderate risk (should consider anticoagulation), and a score of 2 or greater suggests moderatehigh risk (should be anticoagulated).

THE NEUROLOGICAL SYNDROMES OF ISCHEMIC STROKE The clinical picture that results from an occlusion of any one artery differs in minor ways from one patient to another, but there is sufficient uniformity to justify the

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assignment of a typical syndrome to each of the major cerebral and cervical arteries. The identification of these syndromes by examination has been one of the cardinal skills of the clinical neurologist. The following descriptions apply particularly to the clinical effects of ischemia and infarction caused by embolism and thrombosis. Although intracerebral hemorrhage within a specific vascular territory may give rise to many of the same effects, the total clinical picture is different because hemorrhage usually involves regions supplied by more than one artery and, by its deep extension and pressure effects, causes secondary features of headache, vomiting, and hypertension, as well as a series of falsely localizing signs, as described in Chaps. 16 and 30.

Carotid Artery Syndromes The carotid system on each side consists of three major arteries: the common carotid, internal carotid, and external carotid. As indicated in Fig. 33-1, the right common carotid artery arises at the level of the sternoclavicular notch from the innominate (brachiocephalic) artery, and the left common carotid comes directly from the aortic arch. The common carotid arteries ascend in the neck to approximately the C4 level, just below the angle of the jaw, where each divides into external and internal branches (the bifurcation may be above or below this point). The carotid vessels are subject to atherosclerotic narrowing, atherothrombotic occlusion, arterial dissection, and rarely, other processes such as vasculitis. There are two ways in which carotid stenosis causes ischemic symptoms; the main one is by embolization from atherosclerosis, platelet-fibrin material, or superimposed clot originating in the artery and the less common one is hypoperfusion as a result of occlusion of a vessel and inadequate collateral flow to the ipsilateral cerebral hemisphere. Disease of the common carotid artery accounts for less than 1 percent of cases of carotid artery syndrome, the remainder being from disease of the internal carotid artery. Nevertheless, the common carotid can be affected by an atheromatous plaque at its origin in the thorax, more often on the left side. Atherosclerotic stenosis or occlusion of the midportion of the common carotid may also occur years after radiation therapy for laryngeal, thyroid, or other head and neck cancer. If the bifurcation is patent, few, if any, symptoms may result because retrograde flow from the external carotid maintains internal carotid flow and perfusion of the brain. The remainder of this discussion is concerned with disease of the internal carotid artery. The territory supplied by this vessel and its main branches are shown in Figs. 3-1 and 33-2. The territory affected by diminished blood flow in the brain in cases of carotid occlusion is dependent on the configuration of the circle of Willis. In extreme instances where the circle of Willis provides no communication to the side of an occluded carotid artery because of insufficient anterior and posterior communicating arteries on that side, thus isolating the hemisphere from blood flow, infarction involving the anterior two-thirds of the cerebral hemisphere may result. If the two anterior cerebral arteries

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arise from a common stem on one side and the ipsilateral carotid artery is the sole blood supply to that side of the brain, infarction may occur in the territories of both vessels. The territory supplied by the posterior cerebral artery will also be included if this vessel is supplied by the internal carotid rather than the basilar artery (a configuration that reflects a residual fetal origin of the posterior cerebral artery). However, occlusion in the first part of the internal carotid artery immediately beyond the carotid bifurcation is usually silent because of adequate supply from these other vessels. If one internal carotid artery had been occluded at an earlier time, occlusion of the opposite one may rarely cause bilateral cerebral infarction, again in the circumstances of inadequacy of the posterior communicating arteries of both sides thus isolating the hemispheres from flow through the vertebrobasilar arterial system. The clinical effects in such cases may include coma with quadriplegia and continuous horizontal “metronomic” conjugate eye movements. Occlusion of the distal intracranial portion of the internal carotid artery (the “T”; Fig. 33-2), usually by an embolus, usually produces a clinical picture like that of MCA occlusion: contralateral hemiplegia, hemihypesthesia, and aphasia (with involvement of the dominant hemisphere). When the anterior cerebral territory is included, there are additional features of leg paralysis, as described further on. Patients with such large infarctions are usually immediately drowsy or stuporous because of an ill-defined effect on cerebral function. Headache, located as a rule above the eyebrow, on the side of the infarction, may occur with thrombosis or embolism of the carotid artery, but cranial pain is not invariable or is mild. The headache associated with occlusion of the MCA tends to be more lateral at the temple; that of posterior cerebral occlusion is located in or behind the eye. When the circulation of one carotid artery has been incompletely compromised by arterial stenosis or dissection (the latter is discussed in a later section), reducing blood flow in both the middle and anterior cerebral territories on that side, the zone of maximal ischemia often lies in a region over the cerebral convexities between the two vascular territories (“cortical watershed” or “borderzone”) or, alternatively, in the deep portions of the hemisphere between the territories of the lenticulostriate branches and the penetrating vessels from the convexity (“internal” or “deep watershed”). The infarction in the first instance occupies a region in the high parietal and frontal cortex and the adjacent subcortical white matter. Its size depends upon the adequacy of collateral vessels. Weakness tends to involve the shoulder and hip more than the hand and face, corresponding to the location of these functions in the motor cortex. With long-standing carotid stenosis, the cortical watershed zone shifts downward toward the perisylvian portions of the MCA territory, even to the extent that a stroke may weaken facial movement or cause a nonfluent aphasia and with impaired perfusion of the deep watershed with chronic carotid occlusion, infarctions of varying size are situated in the subfrontal and subparietal portions of the centrum semiovale.

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The situation can be somewhat different in cases of total circulatory collapse from cardiac arrest, in which perfusion fails not only in the watershed areas between the middle and anterior cerebral arteries but also between the middle and posterior cerebral arteries. Bilateral infarctions are then situated within a zone that extends in an approximately sickle-shaped strip of variable width from the cortical convexity of the frontal lobe through the high parietal lobe to the occipitoparietal junction. Deeper infarctions also occur, but they more often take the form of contiguous extensions of the just described cortical infarction into the subjacent white matter. There may appear to be several separate infarctions after hypoperfusion states, but these often turn out to be only the visible portions of a larger border-zone lesion. The internal carotid artery also supplies the optic nerve and retina (Fig. 33-1). For this reason, transient monocular blindness occurs prior to the onset of stroke in 10 to 25 percent of cases of symptomatic carotid occlusion. Yet central retinal artery ischemia is a relatively rare manifestation of carotid artery occlusion, presumably because of efficient collateral supply to the globe. Ocular signs of carotid occlusion, therefore, include transient monocular blindness or visual loss or dimness of vision with exercise, after exposure to bright light, or on assuming an upright position; retinal atrophy and pigmentation; atrophy of the iris; peripapillary arteriovenous anastomoses in the retinae; and claudication of jaw muscles. However, the cardinal clinical signs of internal carotid stenoses, ulcerations, and dissections are TIAs corresponding mainly to parts AREA FOR CONTRAVERSION OF EYES AND HEAD Rolandic A BROCA AREA (MOTOR APHASIA) Prerolandic A Sup. division of middle cerebral A

of the territory supplied by the MCA (transient unilateral weakness, numbness, aphasia as described below). It is a subject of debate whether these are the result of fibrin platelet emboli or a reduction in blood flow. TIAs were discussed earlier, but here it can be stated again that they represent an important risk factor for stroke.

Middle Cerebral Artery Stroke Syndromes The MCA has a main trunk (stem, also termed M1) that is the segment from the top of the internal carotid artery to the division of the MCA into its main branches and has superficial and deep hemispheral branches that together supply the largest portion of the cerebral hemisphere. Its two main branches (bifurcation) are the superior division (supplying the rolandic and prerolandic areas) or the inferior division (supplying the lateral temporal and inferior parietal lobes), each designated as M2 segments; see Figs. 33-2 and 33-5. Some patients have a trifurcation into two main branches and one subsidiary branch. Through these cortical branches, it supplies the lateral (convexity) part of the cerebral hemisphere (see Figs. 33-2 and 33-6) encompassing (1) the cortex and white matter of the lateral and inferior parts of the frontal lobe—including motor areas 4 and 6, contraversive centers for lateral gaze and the motor speech area of Broca (dominant hemisphere); (2) the cortex and white matter of the parietal lobe, including the primary and secondary sensory cortices and the angular and supramarginal gyri; and (3) the superior parts of the temporal lobe and insula, including the receptive language PO = PARIETAL OPERCULUM (CONDUCTION APHASIA)

MOTOR SENSORY

PPR = POST. PARIETAL REGION (ALEXIA WITH AGRAPHIA)

HIP TRUNK ARM HANDS FINGERS THUMB FACE LIPS TONGUE MOUTH PO

Ant. parietal A

Post. parietal A

Angular A PPR

Lateral orbito-frontal A

793

VISU A

L RADIATION

VISUAL CORTEX WERNICKE AREA (SENSORY APHASIA)

Inf. division of middle cerebral A

Post. temporal A

Middle cerebral stem Temporal polar A Ant. temporal A

AUDITORY AREA

Lateral geniculate body

Figure 33-5.  Diagram of the left cerebral hemisphere, lateral aspect, showing the courses of the middle cerebral artery and its branches and the principal regions of cerebral localization. Below is a list of the clinical manifestations of infarction in the territory of this artery and the corresponding regions of cerebral damage.

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Figure 33-6.  Diagram of one cerebral hemisphere, coronal section, showing the regions of blood supply of the major cerebral vessels.

area of Wernicke. Through its deep penetrating or lenticulostriate branches it supplies the putamen, a large part of the head and body of the caudate nucleus (shared with the Heubner artery, see further on), the outer globus pallidus, the posterior limb of the internal capsule, and most of the deep white matter of the corona radiata (see Fig. 33-6).

MCA Stem (M1) Occlusion Syndrome The MCA may be occluded in its stem or one of its branches. An occlusion at the stem blocks the flow in the small deep penetrating vessels as well as in superficial cortical branches. An occlusion at the distal end of the stem blocks only the orifices of the divisions of the artery in the Sylvian sulcus but leaves unaffected the deep penetrating vessels. The idealized picture of total occlusion of the stem is one of contralateral hemiplegia (involving the face, arm, and leg as a result of infarction of the posterior limb of the internal capsule), hemianesthesia, and can include homonymous visual field deficit (because of infarction of the lateral geniculate body), with a deviation of the head and eyes toward the side of the lesion. In addition, there is a variable but usually global aphasia with left hemispheric lesions and anosognosia and amorphosynthesis with rightsided lesions (see Chap. 21). Partial syndromes encompassing several parts of this ensemble are common. At the onset of the stroke, the patient may be drowsy because of an ill-defined effect of widespread paralysis of neurologic function, as commented in the section on internal carotid artery occlusion. If there are adequate collateral vessels

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over the surface of the hemisphere, only those components of the stroke referable to the deep structures may be evident (mainly hemiplegia and facial weakness); as discussed below, the cortical elements of aphasia, agnosia, and apraxia then being absent or mild. Occlusion of the stem of the MCA is usually caused by embolus and less often by a thrombus superimposed on a local atherosclerotic plaque, as mentioned in earlier sections, but studies over the years have shown that most middle cerebral occlusions are embolic (Fisher, 1975; Caplan, 1989). The embolus may lodge in the stem or, more often, drift into one of the main divisions. Small emboli infrequently enter solely one or more of the penetrating branches of the stem and cause a small deep infarction (lacune), but the frequency of this occurrence has not been well studied. In the circumstance of stenosis of the MCA with occlusion of the vessel by a superimposed thrombus, the stroke is often preceded by TIAs, producing a picture resembling that of carotid stenosis or occlusion (see Caplan, 1989). Transient monocular blindness does not occur as a direct result of MCA thrombosis (or embolism) because the occlusion is distal to the ophthalmic artery. In epidemiologic studies, Asian populations are disproportionally affected by this form of intracranial atherosclerosis, and diabetes and hypertension are risk factors for all ethnicities. MCA Syndromes Resulting in Deep Hemispheral Infarctions (Striatocapsular infarction)  A number of interesting syndromes occur with deep lesions in the territory of the penetrating vessels of the MCA, collectively known

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as lenticulostriate, or penetrating vessels (see Figs. 33-8 and 33-9). Most, as mentioned, are attributable to emboli that lodge in the stem of the main vessel, although imaging studies may show a patent MCA, implying that the embolus has moved on or possibly entered these vessels primarily. Other strokes in this territory are undoubtedly atherothrombotic, as mentioned earlier. The resultant lesions in the corona radiata are larger than typical lacunar infarctions (see further on) but have a similar pathoanatomy. Although the infarction is centered in the deep white matter, most of the syndromes include a fragment of one of the cortical stroke patterns described further on. The most common type is a large striatocapsular infarction (Weiller and colleagues). There is usually a degree of hemiparesis and some have aphasia or hemineglect. Aphasia, when it occurs, tends to be a limited form of the Broca type and is often short-lived. With smaller deep strokes, incomplete motor syndromes affecting only the arm and hand, without language disturbance or neglect, are common; these are difficult to differentiate from small embolic cortical strokes. Homonymous hemianopia is an even less frequent occurrence with deep strokes from MCA stem occlusion, but it may occur with posterior capsular lesions, probably as a result of damage to the region of the lateral geniculate nucleus and optic radiations.

MCA Branch Syndromes Superior Division An embolus passing through the MCA most often lodges in one of its two main branches. Atherothrombotic occlusion within these vessels also occurs but is infrequent. Complete infarction in the territory of the superior division causes a dense sensorimotor deficit in the contralateral face and arm, but, to a lesser extent, the leg, as well as ipsilateral deviation of the head and eyes; it, therefore, differs from the MCA stem occlusion syndrome in partly sparing the leg and foot with prominent weakness in the arm and face (“brachiofacial,” or “chierobrachial” paralysis); there is no impairment of alertness. Less extensive strokes in the superior division territory are more common than this archetype and the deficits are correspondingly milder. If the occlusion is long lasting (not merely transient ischemia with disintegration of the embolus), there is often slow improvement; after a few months, the patient is able to walk with a slightly spastic leg if the leg had been affected, while the motor deficits of the arm and face may remain. The sensory cortex is involved in most such infarcts, but sensory symptoms may be mild. The deficits on examination follow the topographic pattern of the motor deficits and may be less apparent compared to the motor loss or it may be profound, resembling that of a thalamic infarct (as described in Chap. 8). The loss takes the form of stereoanesthesia, agraphesthesia, impaired position sense, tactile localization, and two-point discrimination, as well as variable changes in touch, pain, and temperature sense (see Chap. 21). With left-sided lesions, there is initially a variable degree of aphasia, occasionally to the point of mutism, or there is a predominantly nonfluent (Broca’s) aphasia, reflected by effortful, hesitant, grammatically simplified, and dysmelodic speech (see Chap. 22).

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Embolic occlusion limited to one of the distal branches of the superior division, perhaps the most common stroke seen in clinical practice, produces a more circumscribed infarct that further fractionates the above-described syndromes. With occlusion of the ascending frontal branch, the motor deficit is limited to the face and arm with little or no weakness of the leg, and the latter, if weakened at all, soon improves. With left-sided lesions, there is dysfluent and agrammatic speech and normal comprehension (Broca aphasia). Embolic occlusion of the left rolandic branch alone results in sensorimotor paresis with severe dysarthria but little evidence of aphasia. A small branch occlusion may give rise solely to a brachial monoplegia or hand and wrist weakness, mainly in extension, that simulates a problem in the peripheral nervous system. Embolic occlusion of ascending parietal and other posterior branches of the superior division may cause no sensorimotor deficit but only a conduction aphasia (see Chap. 22) and ideomotor apraxia. There are many other limited stroke syndromes or combinations of deficits relating to small regions of damage in the frontal, parietal, or temporal lobes. Among these are the Gerstmann syndrome and various forms of agnosia (in some patients, these may be in the territory of the inferior division of the MCA discussed below). Most of these are discussed in Chap. 21, which details the result of lesions in particular parts of the cerebrum. As indicated earlier, the distal territory of the MCA may also be rendered ischemic by failure of the systemic circulation, especially if the carotid artery is stenotic; this situation may simulate embolic branch occlusions. Inferior Division Occlusion of the inferior division of the MCA is slightly less frequent than occlusion of the superior one but, again, nearly always the result of embolism. The usual result in left-sided lesions is Wernicke aphasia, which generally remains static for days or weeks after which some improvement can be expected. In lessextensive infarcts that are the result of selective distal branch occlusions (superior parietal, angular, or posterior temporal branches), the deficit in comprehension of spoken and written language may be especially severe. As with superior division stroke, there may be mutism at the outset, but the two are differentiated by a severe receptive language deficit with inferior division infarction. After a few months, the deficits usually improve, often to the point where they are evident only in self-generated efforts to read and copy visually presented words or phrases. With either right- or left-hemispheric lesions, there is usually superior quadrantanopia or homonymous hemianopia and, with right-sided ones, a left visual neglect and other signs of amorphosynthesis may be apparent (Chap. 21). Rarely, an agitated confusional state may be a prominent feature of nondominant hemispheral lesions and sometimes of dominant ones. Some of the syndromes applicable to the angular gyrus and the supramarginal gyrus may occur in strokes within this division, depending on the distributions of the vessels in an individual. Bilateral cerebral infarctions involving mainly the insular–perisylvian (anterior opercular) regions manifest themselves by a diplegia of the face, tongue, and masseters that results in anarthria without aphasia (Bakar et al).

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Anterior Cerebral Artery Stroke Syndromes Most anterior cerebral artery strokes are of the embolic variety, far less often atherosclerotic, and occasionally due to other processes such as vasospasm or vasculitis. The cortical branches of the artery supply the anterior threequarters of the medial surface of the frontal lobe, including its medial-orbital surface, the frontal pole, a strip of the

lateral surface of the cerebral hemisphere along its superior border, and the anterior four-fifths of the corpus callosum. Deep branches, arising near the circle of Willis (proximal and distal to the anterior communicating artery) supply the anterior limb of the internal capsule, the inferior part of the head of the caudate nucleus, and the anterior part of the globus pallidus (Figs. 33-6 and 33-7).

B Figure 33-7.  A. Diagram of the right cerebral hemisphere, medial aspect, showing the branches and distribution of the anterior cerebral artery and the principal regions of cerebral localization. Below is a list of the clinical manifestations of infarction in the territory of this artery and the corresponding regions of cerebral damage. Also shown is the course of the main branch of the posterior cerebral artery on the medial side of the hemisphere. Note: Hemianopia does not occur; transcortical aphasia occurs rarely (isolation of the language areas) (see Chap. 22). B. Axial diffusion-weighted MRI showing an acute ischemic infarction in the anterior cerebral artery territory.

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Lateral lenticulostriate A

Medial lenticulostriate A

Superior division MCA

Anterior cerebral A Huebner A

Inferior division MCA

Middle cerebral A

Internal carotid A

The largest of these deep branches is the artery of Heubner (“recurrent artery of Heubner”; Fig. 33-8). This artery, which may, in fact, be up to four small vessels, shares its territory of supply with anteriorly placed lenticulostriate arteries that emanate from the MCA. Strokes in this territory cause infarction of the head of the caudate and adjacent white matter. In the past, this was a common stroke syndrome from meningovascular syphilis. The clinical picture of anterior cerebral artery stroke depends on the location and size of the infarct, which, in turn, relates to the site of the occlusion (proximal or distal to the anterior communicating artery), the pattern of the circle of Willis, and the other ischemia-modifying factors mentioned earlier. Well-studied cases of infarction in the territory of the anterior cerebral artery are not numerous; hence the syndromes have not been completely elucidated (see Brust for a review of the literature and a description of developmental abnormalities of the artery). Occlusion of the stem of the anterior cerebral artery, proximal to its connection with the anterior communicating artery (A1 segment), is usually well tolerated because adequate collateral flow is provided by the anterior cerebral artery of the opposite side through the communicating vessel. Maximal disturbance occurs when both arteries arise from one anterior cerebral stem, in which case there is infarction of the anterior and medial parts of both cerebral hemispheres resulting in paraplegia, incontinence, abulia and nonfluent aphasic symptoms, and frontal lobe personality changes (see Chap. 21). Complete infarction as a result of occlusion of one anterior cerebral artery distal to the anterior communicating artery (A2 segment) results in a sensorimotor deficit

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Figure 33-8.  Corrosion preparations with plastics demonstrating penetrating branches of the anterior and middle cerebral arteries. The medial and lateral lenticulostriate arterioles are labeled, along with the recurrent artery of Heubner. (Reproduced by permission from Krayenbühl H, Yasargil MG: Radiological anatomy and topography of the cerebral arteries, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 11. Vascular Diseases of the Nervous System. Part 1. Amsterdam, NorthHolland, 1972.)

of the opposite foot and leg and, to a lesser degree, of the shoulder and arm, with sparing of the hand and face, the complementary pattern to superior division, MCA strokes (the distribution of which is shown in the MRI of Fig. 33-7). The motor disorder is more pronounced in the foot and leg than in the hip and thigh. Sensory loss, when it occurs, is mainly of the discriminative modalities, but it may be mild or absent. The head and eyes may initially deviate to the side of the lesion. Urinary incontinence, a contralateral grasp reflex, and paratonic rigidity (gegenhalten) of the opposite limbs may be evident. With a left-sided occlusion, there may be a “sympathetic apraxia” of the left arm and leg or involuntary misdirected movements of the left arm (alien arm or hand), as described in Chaps. 3 and 21. Language disturbances, particularly transcortical motor aphasia (see Chap. 22), may occur with left anterior cerebral artery territory stroke but are not the rule. Disorders of behavior that may be overlooked in cases of anterior cerebral artery occlusion are abulia, or a slowness and lack of spontaneity in all reactions, muteness or a tendency to speak in whispers, and distractibility. Distal branch occlusions of the anterior cerebral artery produce only fragments of the total syndrome, usually a spastic weakness or associative sensory loss in the opposite foot and leg. With occlusion of penetrating branches of the ACA, typified by occlusion of Heubner’s artery, the anterior limb of the internal capsule and caudate is usually involved. In a series of 18 cases of unilateral caudate region infarcts, transient hemiparesis was present in 13 (Caplan and associates). Dysarthria and either abulia or agitation and hyperactivity also may occur. Stuttering and language difficulty occurred with two of the left-sided lesions and visuospatial

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neglect with three of the right-sided ones. There have been cases in which occlusions of the proximal artery (ACA), which included the Heubner artery, resulted in right hemiplegia (predominant in the leg) with grasping and groping responses of the right hand and buccofacial apraxia that were accompanied by a diminution or absence of spontaneous speech, agraphia, and a limited ability to name objects and compose word lists but with a striking preservation of the ability to repeat spoken and written sentences (i.e., transcortical motor aphasia) (Alexander and Schmitt). With bilateral caudate infarctions, a syndrome of inattentiveness, abulia, forgetfulness, and sometimes agitation and psychosis has been observed. Transitory choreoathetosis and other dyskinesias (we have seen cases of ballismus) have also been attributed to ischemia of the caudate and anterior basal ganglia, occurring sometimes under conditions of prolonged standing and exercise (Caplan and Sergay; Margolin and Marsden).

Anterior Choroidal Artery Stroke Syndrome The anterior choroidal artery is a long, narrow vessel that springs from the internal carotid, just distal to the origin of the posterior communicating artery. It supplies the internal segment of the globus pallidus and posterior limb of the internal capsule and several contiguous structures including (in most patients) the optic tract (Fig. 33-9). It then penetrates the temporal horn of the lateral ventricle, where it supplies the choroid plexus and anastomoses with the posterior choroidal artery. This being a small caliber artery, strokes in its territory may be due to in situ atherosclerosis at its origin in the internal carotid, usually in diabetics, but occlusion of the orifice of the vessel by an embolus may be more common (Leys and colleagues). Infarction is a known complication of clipping of an aneurysm at the upper reaches of the carotid artery that entraps the anterior choroidal artery.

Only a few complete clinicopathologic studies have been made of a distinctive syndrome caused by occlusion of this artery. The core features consisted of contralateral hemiplegia, hemihypesthesia, and homonymous sectorial hemianopia as a result of involvement of the posterior limb of the internal capsule and white matter posterolateral to it, through which the geniculocalcarine tract also passes, and the lateral geniculate nucleus (Foix and colleagues). There has been discussion regarding the vascular supply of the lateral geniculate nucleus; several authors have suggested that the anterior choroidal artery supplies the lateral and medial portions of the nucleus and a lesion there causes a homonymous quandrantopias in the upper and lower fields but sparing a sector that lies along the equator (cleverly called “quadruple quadrantanopia”). The complimentary stroke in the lateral geniculate is from occlusion of the posterior (lateral) choroidal artery, which supplies the middle segment of the nucleus and gives rise to a sectorial defect lying along the equatorial visual field (Frisen et al; Osborne et al). The combination of extensive unilateral motor, sensory, and visual impairment in an individual with well-preserved language and cognition distinguishes this anterior choroidal syndrome from more common ones involving the major cerebral arteries. However, in cases identified by CT in which the lesion appeared to lie in the vascular territory of this artery, the clinical syndrome fell short of what was expected on anatomic grounds (Decroix and colleagues). With right-sided lesions, there may be left spatial neglect and constructional apraxia; slight disorders of speech and language may accompany left-sided lesions. The variability of the stroke syndrome is probably the result of corresponding variability of its supply to the posterior paraventricular area of the corona radiata and adjacent regions by overlapping small surrounding vessels (Hupperts and colleagues), and there may not be a uniform syndrome attributable. It may be remembered that in the past, in order to abolish the tremor and rigidity of unilateral Parkinson disease, the anterior choroidal artery was surgically ligated without these other effects having been produced.

Posterior Cerebral Artery Stroke Syndromes

Figure 33-9. Diagram of the regions of blood supply of the diencephalon. Distribution of the (1) anterior cerebral artery, (2) posterior cerebral artery, (3) anterior and posterior choroidal arteries, (4) posterior communicating artery, and (5) internal carotid artery. (Reproduced by permission from Krayenbühl H, Yasargil MG: Radiological anatomy and topography of the cerebral arteries. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 11. Vascular Diseases of the Nervous System. Part 1. Amsterdam: North-Holland; 1972.)

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In approximately 70 percent of individuals, both posterior cerebral arteries are formed by the bifurcation of the basilar artery. Thin posterior communicating arteries join this system to the ipsilateral internal carotid arteries. In up to 20 to 25 percent, one posterior cerebral artery arises from the basilar in the usual way, but the other arises from the internal carotid, representing a persistent fetal pattern of circulation (“fetal PCA”); fewer than 5 percent have an unusual configuration in which both posterior cerebral arteries arise from the corresponding carotid arteries (“bilateral fetal PCA”). Most strokes in the posterior cerebral artery territories are embolic in origin, either cardioembolic or less often from a thrombus in a more proximal vessel and, least commonly, to atherosclerosis in the proximal posterior cerebral artery. The complex configuration and branches of the proximal segment of the posterior cerebral artery (P1 segment from the terminus of the basilar artery to the ostium of the posterior communicating artery) are illustrated in Figs. 33-10, and 33-11. The interpeduncular branches,

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B Figure 33-10.  A. Inferior aspect of the left hemisphere showing the branches and distribution of the posterior cerebral artery and the principal anatomic structures supplied. The vessel is considered from the perspective of its proximal and distal territories. Listed below are the clinical manifestations produced by infarction in these territories and the corresponding regions of damage. Tremor in repose has been omitted because of the uncertainty of its occurrence in the posterior cerebral artery syndrome. Peduncular hallucinosis may occur in thalamic-subthalamic ischemic lesions, but the exact location of the lesion is unknown. B. Axial diffusion-weighted MRI showing an acute ischemic infarction in the posterior cerebral artery territory. (Reproduced by permission from Krayenbühl H, Yasargil MG: Radiological anatomy and topography of the cerebral arteries, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 11. Vascular Diseases of the Nervous System. Part 1. Amsterdam, North-Holland, 1972, pp 65–101 @ Elsevier.)

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Part 4 MAJOR CATEGORIES OF NEUROLOGIC DISEASE Medial posterior choroidal A (1 to 2 brs.)

Posterior comm. A Tuberothalamic A

Lateral posterior choroidal A (1 to 6 brs.)

Inferolateral A (5 to 10 brs.)

Paramedian A (superior ramus) Middle ramus Inferior ramus Superior cerebellar A

P2 P1

Posterior cerebral A

P3

Basilar A B

A

B

C Figure 33-11.  The posterior cerebral and basilar arteries. A. The terminus of the basilar artery and branches originating from the P1 through P3 segments. (Reproduced with permission from Schmahmann JD. Vascular syndromes of the thalamus. Stroke. 2003;34(9):2264-2278.) B. Lateral view of the brain showing the branches of the posterior cerebral artery. (From Krayenbühl H, Yasargil MG: Radiological anatomy and topography of the cerebral arteries, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 11. Vascular Diseases of the Nervous System. Part 1. Amsterdam, North-Holland, 1972. Courtesy of Dr. M Gazi Yasargil.) C. Axial diffusion-weighted MRI showing an acute ischemic infarction due to occlusion of an artery of Percheron, an anatomic variant, in which an azygos paramedian artery supplies both sides of the posterior-medial thalamus.

which arise just above the basilar bifurcation, supply the red nuclei, the substantia nigra bilaterally, medial parts of the cerebral peduncles, oculomotor and trochlear nuclei and nerves, reticular substance of the upper brainstem, decussation of the superior cerebellar peduncles, medial longitudinal fasciculi, and medial lemnisci. As pointed out

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by Percheron (whose name is applied to the largest of the interpeduncular vessels), the configuration of the paramedian mesencephalic arteries varies considerably: in some cases, two small vessels arise symmetrically, one from each side; in others, a single artery arises from one posterior cerebral stem (proximal P1), which then bifurcates.

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In the latter case, one posterior cerebral stem, through a small artery, supplies the medial thalamic territories on both sides, and an occlusion of this artery produces a bilateral butterfly shaped lesion in the medial parts of the diencephalon (Castaigne et al). The thalamoperforate branches (also called paramedian thalamic arteries) arise slightly more distally from the posterior cerebral artery stem, nearer the junction of the posterior cerebral and posterior communicating arteries (P2 segment of the artery) and supply the inferior, medial, and anterior parts of the thalamus. The thalamogeniculate branches arise still more distally, opposite the lateral geniculate body, and supply the geniculate body and the central and posterior parts of the thalamus. Medial branches emerging from the posterior cerebral artery as it encircles the midbrain, supply the lateral part of the cerebral peduncle, lateral tegmentum and corpora quadrigemina, and pineal gland. Posterior choroidal branches run to the posterosuperior thalamus, choroid plexus, posterior parts of the hippocampus, and psalterium (decussation of deep white matter fornices). Most importantly clinically, the terminal or cortical branches of the posterior cerebral artery supply the inferomedial part of the temporal lobe and the medial occipital lobe, including the lingula, cuneus, precuneus, and visual Brodmann areas 17, 18, and 19 (see Figs. 33-6 and 33-10). Occlusion of the posterior cerebral artery produces a profusion of clinical features because both the upper brainstem, which is replete with important structures and the inferomedial parts of the temporal and occipital lobes lie within its supply. The site of the occlusion and the arrangement of the circle of Willis, in large measure, determine the location and extent of the resulting infarct. For example, occlusion proximal to the posterior communicating artery may be asymptomatic or have only transitory effects if the collateral flow is adequate from the Circle of Willis). In older series of posterior cerebral artery strokes (Milandre and coworkers), the causes were mainly atherosclerotic. Our experience has differed in that the proportion of presumed embolic occlusions has been far greater than that of other causes. For the convenience of exposition, it is helpful to divide the posterior cerebral artery syndromes into three groups: (1) proximal (involving interpeduncular, thalamic perforant, and thalamogeniculate branches), (2) cortical (inferior temporal and medial occipital), and (3) bilateral.

Proximal PCA Syndromes (See Figs. 33-11 and 33-12) The thalamic syndrome of Dejerine and Roussy (see also Chap. 7) follows infarction of the sensory relay nuclei in the thalamus, the result of occlusion of thalamogeniculate branches. Occlusion of the small vessels supplying these territories from in situ atherothrombosis or embolic occlusion of the posterior cerebral artery is the most common cause. There is both a deep and cutaneous sensory loss, usually severe in degree, of the opposite side of the body, including the trunk and face, sometimes accompanied by a transitory hemiparesis. A homonymous hemianopia may be conjoined. In some instances, there is a dissociated

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Figure 33-12.  Regions supplied by the posterior segment of the circle of Willis, lateral view (A) and basal view (B). A. (1) Posterior cerebral artery; (2) superior cerebellar artery; (3) basilar artery and superior cerebellar artery; (4) posterior inferior cerebellar artery; (5) vertebral artery (posterior inferior cerebellar artery, anterior spinal artery, posterior spinal artery). B. (1) Posterior cerebral artery; (2) superior cerebellar artery; (3) paramedian branches of the basilar artery and spinal artery; (4) posterior inferior cerebellar artery; (5) vertebral artery; (6) anterior inferior cerebellar artery; (7) dorsal spinal artery. Reproduced by permission from Krayenbühl H, Yasargil MG: Radiological anatomy and topography of the cerebral arteries, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 11. Vascular Diseases of the Nervous System. Part 1. Amsterdam: North-Holland; 1972.)

sensory loss—pain and thermal sensation being more affected than touch, vibration, and position—or only one part of the body may be anesthetic. The characteristic feature is always sensory loss that includes the entire hemibody up to the midline. After an interval, sensation begins to return, and the patient may develop pain, paresthesia, and hyperpathia in the affected parts. The painful paresthetic syndrome may persist for years. There may also

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be a distortion of taste, athetotic posturing of the hand, and alteration of mood. Mania and depression have occasionally been observed with infarction of the diencephalon and adjacent structures, but the data are usually incomplete. Central midbrain and subthalamic syndromes are a result of occlusion of the interpeduncular branches (Percheron vessel) of the posterior cerebral artery. The clinical syndromes include palsies of vertical gaze, stupor, or coma. Syndromes of the paramedian arteries, including the proximal posterior cerebral artery, have as their main feature a third-nerve palsy on the side of the lesion combined with contralateral hemiplegia (Weber syndrome), contralateral ataxic tremor (Claude syndrome), or contralateral ataxia and hemiplegia (Benedikt syndrome), as summarized in Table 33-5. Anteromedial-inferior thalamic syndromes follow occlusion of the thalamoperforant branches. Here the most common effect is an extrapyramidal movement disorder (hemiballismus or hemichoreoathetosis or, less often, asterixis). Deep sensory loss, hemiataxia, or tremor may be added in various combinations. Hemiballismus is

usually a result of occlusion of a small branch to the subthalamic nucleus or its connections with the pallidum. Occlusion of the paramedian thalamic branches to the mediodorsal nucleus is a recognized cause of an amnesic (Korsakoff ) syndrome; this simulates but is less common than infarction of the hippocampi from occlusion of the medial temporal branch of the posterior cerebral artery as noted below.

Cortical Syndromes of the Posterior Cerebral Artery Occlusion of branches to the temporal and occipital lobes gives rise to a homonymous hemianopia as a result of involvement of the primary visual receptive areas (calcarine or striate cortex) or of the converging geniculocalcarine fibers. The hemianopia may be incomplete and involve the upper quadrants of the visual fields more than the lower ones (see Chap. 12). Macular, or central, vision is often spared (macular sparing) because of collateral blood supply of the occipital pole from distal branches of the middle

Table 33-5 INTRAMEDULLARY BRAINSTEM SYNDROMESa EPONYMb

SITE

CRANIAL NERVES INVOLVED

TRACTS INVOLVED

SIGNS

USUAL CAUSE

Weber syndrome

Base of midbrain

III

Corticospinal tract

Oculomotor palsy with crossed hemiplegia

Claude syndrome

Tegmentum of midbrain

III

Oculomotor palsy with contralateral cerebellar ataxia and tremor

Benedikt syndrome

Tegmentum of midbrain

III

Nothnagel syndrome Parinaud syndrome

Tectum of midbrain Dorsal midbrain

Unilateral or bilateral III  

Millard-Gubler syndrome and RaymondFoville syndrome Avellis syndrome

Base of pons

VII and often VI

Red nucleus, superior cerebellar peduncles after decussation Red nucleus, corticospinal tract, and superior cerebellar peduncles after decussation Superior cerebellar peduncles Supranuclear mechanism for upward gaze and other structures in periaqueductal gray matter Corticospinal tract

Tegmentum of medulla

X

Paralysis of soft palate and vocal cord and contralateral hemianesthesia

Infarct or tumor

Jackson syndrome Wallenberg syndrome

Tegmentum of medulla Lateral tegmentum of medulla

X, XII

Spinothalamic tract; sometimes descending pupillary fibers, with Bernard-Horner syndrome Corticospinal tract

Avellis syndrome plus ipsilateral tongue paralysis Ipsilateral V, IX, X, XI palsy, Horner syndrome, and cerebellar ataxia; contralateral loss of pain and temperature sense

Infarct or tumor

Spinal V, IX, X, XI

Lateral spinothalamic tract Descending pupillodilator fibers Spinocerebellar and olivocerebellar tracts

Oculomotor palsy with contralateral cerebellar ataxia, tremor, and corticospinal signs, may have choreoathetosis Ocular palsies (IIIrd n.), paralysis of gaze, nystagmus, and ataxia Paralysis of upward gaze and accommodation; fixed pupils

Facial and abducens palsy and contralateral hemiplegia; sometimes gaze palsy to side of lesion

Vascular occlusion, tumor, aneurysm Vascular occlusion, tumor, aneurysm Infarct, hemorrhage, tuberculoma, tumor Tumor Pinealoma and other lesions of dorsal midbrain, hydrocephalus Infarct or tumor

Occlusion of vertebral or posterior– inferior cerebellar artery

a

See also Table 44-1, which lists the brainstem syndromes due to extramedullary lesions. See Wolf JK: The Classical Brainstem Syndromes. Springfield, IL, Charles C Thomas, 1971, for translations of original reports.

b

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(or rarely anterior) cerebral arteries. Other features seen in a few instances are visual hallucinations in the blind parts of the visual fields (Cogan) or metamorphopsia and palinopsia (Brust and Behrens). Occipital infarcts of the dominant hemisphere may cause alexia without agraphia, anomia (amnesic aphasia), a variety of visual agnosias, and rarely some degree of impaired memory. The anomias, when they occur, are most severe for colors, but the naming of other visually presented material, such as pictures, mathematical symbols, and manipulable objects, may also be impaired. The patient may treat objects as familiar—that is, describe their functions and use them correctly—but be unable to name them. Color anomia (a form of “central achromatopsia”) and amnesic aphasia are more often present in this syndrome. The defect in retentive memory is of varying severity and may or may not improve with the passage of time. These syndromes are described in Chaps. 21 and 22. A complete proximal arterial occlusion leads to a syndrome that combines cortical and anterior-proximal syndromes in part or totally. As mentioned, the vascular lesion may be either an embolus or an atherosclerotic thrombus, but more often, the former.

Bilateral Posterior Cerebral Artery Stroke Syndromes These occur as a result of successive infarctions or from a single embolic or thrombotic occlusion of the upper basilar artery, especially if the posterior communicating arteries are small or absent or from the global failure of circulation. Bilateral lesions of the occipital lobes, if extensive, cause “cortical blindness” that is essentially bilateral homonymous hemianopia, sometimes accompanied by unformed visual hallucinations. The pupillary reflexes are preserved and the optic discs appear normal. Sometimes the patient is unaware of being blind and denies the problem even when it is pointed out to him (Anton syndrome). More frequently, the lesions are incomplete, and a sector of the vision, usually on one side, remains intact. When the visual remnant is small, vision may seemingly fluctuate from moment to moment as the patient attempts to capture the image in the island of intact vision, in which case hysteria may be incorrectly inferred. In bilateral lesions confined to the occipital poles, there may be a loss of central vision only (homonymous central scotomas). With more anteriorly placed lesions of the occipital pole, there may be homonymous paracentral scotomas or the occipital poles may be spared, leaving the patient with only central vision (bilateral central or macular sparing). Horizontal or altitudinal field homonymous defects are usually a result of similar restricted lesions affecting the upper or lower banks of the calcarine sulci (essentially, quadrantanopia). The Balint syndrome (see Chap. 21) is an effect of bilateral occipitoparietal border-zone lesions. With bilateral lesions that involve the inferomedial portions of the temporal lobes, including the hippocampi and their associated structures, the impairment of memory may be severe, causing the Korsakoff amnesic state. In several of our patients, a solely left-sided infarction of the inferomedial temporal lobe impaired retentive memory.

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Bilateral mesiotemporal-occipital lesions also cause a lack of recognition of faces (prosopagnosia). These and other effects of temporal and occipital lesions are discussed in Chaps. 12 and 22.

Vertebral Artery Stroke Syndromes The vertebral arteries are the chief arteries of the medulla, each supplying the lower three-fourths of the pyramid, the medial lemniscus, all or nearly all of the retroolivary (lateral medullary) region, the restiform body, and the posteroinferior part of the cerebellar hemisphere through the posterior inferior cerebellar arteries (Figs. 33-2 and 33-13). The relative sizes of the vertebral arteries vary considerably and in approximately 10 percent of cases, one vessel is so small that the other is essentially the only artery of supply to the brainstem. The dominant vertebral artery can usually be identified by the convexity of the basilar artery, which swings in a direction away from the dominant vertebral artery. This may be helpful to the clinician in identifying that the dominant vertebral artery is occluded. If there is no collateral flow from the carotid system via the circle of Willis, occlusion of one functional vertebral artery is equivalent to occlusion of the basilar artery (see below). The posteroinferior cerebellar artery (PICA) is usually a branch of the vertebral artery but can have a common origin and form a loop with the anteroinferior cerebellar artery (AICA) from the basilar artery. It is necessary to keep these anatomic variations in mind in considering the effects of vertebral artery occlusion. The vertebral artery is assigned four numerical segments for convenience of explication. They are V1, from the origin to the first entry into the cervical transverse foramen (usually C6 as noted); V2, from the transverse foramen to the uppermost foramen (at C1); V3 from this site to the dural penetration at the foramen magnum; and V4 from the dural entry to the junction with the opposite vertebral artery and the origin of the basilar artery. The vertebral arteries may be occluded by atherothrombosis in their intracranial portion or at their origin at the subclavian artery or the arch of the aorta. Because the vertebral arteries have a long extracranial course and pass through the transverse processes of the cervical vertebrae, entering at C6 to proceeding rostrally to the C1 vertebrae before entering the cranial cavity, they are subject to trauma, spondylotic compression, and a variety of other vertebral diseases. With the exception of arterial dissection, in our experience, the other causes of vascular occlusion in this list happen only infrequently. We rarely see convincing examples of spondylotic occlusion, but several cases have been reported. Extreme extension of the neck, as experienced by people who are having their hair washed in salons or during yoga positions, may give rise to transient symptoms in the territory of a vertebral artery. Dissection of the vertebral artery, discussed in more detail in a later section, declares itself by cervicooccipital pain ipsilateral to the dissection and deficits of brainstem function. One’s attention is drawn to the diagnosis of vertebral dissection where there have been vigorous and protracted bouts of coughing or trauma to the neck or head.

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Figure 33-13.  Transverse section through the upper medulla, reflecting regions supplied by the vertebral arteries and their branches.

Examples of posterior circulation stroke in children have been reported in association with odontoid hypoplasia and other atlantoaxial dislocations, causing the vertebral arteries to be stretched or kinked in their course through the transverse processes of C1-C2 (Phillips et al). The results of acute vertebral artery occlusion are variable, and there may be no symptoms if an artery is occluded extracranially and there is adequate flow from the opposite vertebral artery or other collateral supply. In a configuration in which one vertebral artery is occluded just proximal to the origin of its PICA branch, and the opposite vertebral artery is open and sufficient in size, there may be no symptoms because the PICA is still filled by retrograde flow through its vertebral artery. Occlusion of a vertebral artery low in the neck is usually also compensated by anastomotic flow to the upper part of the via the thyrocervical, deep cervical, and occipital arteries or by reflux from the circle of Willis. If the occlusion of the artery is so situated as to block the posterior inferior cerebellar artery supplying the lateral medulla and inferior cerebellum (PICA), a characteristic syndrome results with vertigo being a prominent symptom (see “Lateral Medullary Syndrome” described further on). If the subclavian artery is blocked proximal to the origin of the left vertebral artery, exercise of the arm on that side may draw blood from the right vertebral and basilar arteries, retrograde down the left vertebral and into the distal left subclavian artery—sometimes resulting in the symptoms of basilar insufficiency. This phenomenon, described in 1961 by Reivich and colleagues, was referred

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to by Fisher (1961) as the subclavian steal. Its most notable features are vertigo and other brainstem signs coupled with transient weakness on exercise of the left arm. There may also be headache and claudication or pain of the arm. Less often, occlusion of the vertebral artery or one of its medial branches produces an infarct that involves the medullary pyramid, the medial lemniscus, and the emergent hypoglossal fibers; the resultant syndrome consists of a contralateral paralysis of arm and leg (with sparing of the face), contralateral loss of position and vibration sense, and ipsilateral paralysis and later atrophy of the tongue. This is the medial medullary syndrome (Fig. 33-13). A more limited lesion, from occlusion of one spinal artery arising from the vertebral artery, gives rise to a contralateral hemiplegia (rarely a quadriplegia) that spares the face. When the vertebral branch to the anterior spinal artery is blocked, flow from the other (corresponding) branch is usually sufficient to prevent infarction of the cervical cord, but we and others have described solely pyramidal infarction with hemiplegia or quadriplegia that spares the face (Ropper et al).

Lateral Medullary Syndrome Known also as the Wallenberg syndrome (who described a case in 1895), this common stroke is produced by infarction of a wedge of lateral medulla lying posterior to the inferior olivary nucleus (see Fig. 33-13). The complete syndrome, as outlined by Fisher and colleagues (1961) comprises (a) symptoms derived from the vestibular nuclei

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(vertigo, nystagmus, oscillopsia, vomiting); (b) spinothalamic tract (contralateral or, less often, ipsilateral impairment of pain and thermal sense over half the body); (c) descending sympathetic tract (ipsilateral Horner syndrome—miosis, ptosis, decreased sweating); (d) issuing fibers of the ninth and tenth nerves (hoarseness, dysphagia, hiccough, ipsilateral paralysis of the palate and vocal cord, diminished gag reflex); (e) utricular nucleus (vertical diplopia and illusion of tilting of vision and rotation of the vertical meridian, rarely so severe as to produce upside down vision); (f ) olivocerebellar, spinocerebellar fibers, restiform body and inferior cerebellum (ipsilateral ataxia of limbs, falling or toppling to the ipsilateral side, and the sensation of lateropulsion); (g) descending tract and nucleus of the fifth nerve (pain, burning, and impaired sensation over ipsilateral half of the face); (h) nucleus and tractus solitarius (loss of taste); and rarely, (i) cuneate and gracile nuclei (numbness of ipsilateral limbs). Fragmentary syndromes are frequent, especially at the onset of the stroke. These subsyndromes consist mainly of vertigo but may include ptosis, toppling stance and gait, vertical diplopia, hoarseness and disequilibrium, or other combinations short of the entire syndrome. While vertigo is the most frequent feature, it alone is not usually an indication of lateral medullary infarction. The smallest infarctions we have encountered gave rise only to symptoms of lateropulsion and mild ipsilateral limb ataxia and, in one case, with a very small region of pontomedullary infarction on MRI, vertigo, and associated gait difficulty. The eye signs of lateral medullary infarction are also varied and quite interesting. Nystagmus is almost invariable. Direction-changing nystagmus (with different positions of gaze) is a useful feature that suggests brainstem forms of nystagmus (see Chap. 13). There may be a fragment of an internuclear ophthalmoplegia or a skew deviation (hypotropia on the side of the stroke). There may be hypometric saccades toward the side of the lesion and hypermetric saccades in the opposite direction. The entire lateral medullary syndrome, one of the most striking in neurology, is usually caused by infarction, with only a small number of cases being the result of hemorrhage, demyelination, or tumor. Although it has traditionally been attributed to occlusion of the PICA, as mentioned earlier, careful studies have shown that most cases are due to vertebral artery occlusion by atherothrombosis; in the remainder, either the posterior inferior cerebellar artery or one of the lateral medullary arteries is occluded by atherothrombosis. Embolism to the PICA is a less-frequent cause. The inferior cerebellum may be affected in isolation if the embolus travels distal to the medullary branches of the PICA, causing vomiting, vertigo, and ataxia with occipitonuchal headache but without Horner syndrome, hiccoughs, palatal paralysis, and other features of medullary infarction. We and others have had experience with patients who initially have considerable recovery from lateral medullary infarction in the first days and weeks but experience sudden death from respiratory or cardiac arrest, even in the absence of cerebellar swelling or basilar artery thrombosis (Norrving and Cronqvist). The related and important issue of cerebellar swelling after vertebral artery or PICA

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occlusion and the need for surgical decompression is discussed later in the chapter.

Basilar Artery Stroke Syndromes The branches of the basilar artery may be grouped as follows: (1) paramedian, emanating from the dorsal surface of the basilar artery and entering the ventral pons in 7 to 10 pairs, supplying a wedge of pons on either side of the midline; (2) short circumferential, emanating from the sides of the basilar artery in 5 to 7 pairs and, supplying the lateral two-thirds of the pons and the middle and superior cerebellar peduncles; (3) long circumferential, 2 on each side (the superior and anterior inferior cerebellar arteries), which run laterally around the pons to reach the cerebellar hemispheres (see Figs. 33-2, 33-15 and 33-16); and (4) several paramedian (interpeduncular) branches at the bifurcation of the basilar artery and origins of the posterior cerebral arteries supplying the high midbrain and medial subthalamic regions that are aligned with and intermingle with the proximal branches of the posterior cerebral artery described above. Basilar artery occlusion, typically because of local thrombosis that is superimposed on a preexisting atherosclerotic plaque, can arise in several ways: (1) the most common is occlusion of the basilar artery itself, usually in the lower or middle third at the site of an atherosclerotic plaque; (2) occlusion of both vertebral arteries, which produces the equivalent of basilar artery occlusion if the circle of Willis is inadequate; and (3) occlusion of a single vertebral artery when it is the only one of adequate size and the Circle of Willis is inadequate. Embolism does not usually occlude the basilar artery except in its most rostral portion when a clot usually lodges at the terminal bifurcation (“top-of-thebasilar syndrome” (Caplan 1980). This is putative because a clot small enough to pass through a vertebral artery should be able to traverse the length of the basilar artery, which is of greater diameter than either vertebral artery. Also, atherothrombosis may involve a branch of the basilar artery rather than the trunk (basilar branch occlusion). The syndrome of basilar artery occlusion, as delineated by Kubik and Adams, reflects the involvement of a large number of structures bilaterally: corticospinal and corticobulbar tracts; cerebellum, middle and superior cerebellar peduncles; medial and lateral lemnisci; spinothalamic tracts; medial longitudinal fasciculi; pontine nuclei; vestibular and cochlear nuclei; descending hypothalamospinal sympathetic fibers; and the third through eighth cranial nerves (the nuclei and their segments within the brainstem). Thus, the complete syndrome comprises bilateral long tract signs (sensory and motor) with variable cerebellar, cranial nerve, and other segmental abnormalities of the brainstem. An important clinical configuration alluded to above, the top of the basilar syndrome is the result of occlusion of the distal end of the basilar artery, usually from embolus, causing coma from infarction of the high midbrain reticular activating system with varying combinations of oculomotor disturbances (roving eye movements or eyes looking downward and inward with inability to reflexly

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elicit upward movements), hemianopia, bilateral ptosis, and pupillary enlargement with preserved reaction to light (Petit and coworkers and Castaigne and associates). Spontaneous recanalization of the vessel may occur, but in a delayed fashion, after the infarct has been established. MRI demonstrates one of several patterns of infarction in the central midbrain and in bilateral posterior thalamic region, typically in the shape of a butterfly, and more variably, uni- or bilateral posterior cerebral artery territory infarction. Yet another clinical constellation, the result of occlusion of the midbasilar artery, gives rise to the locked-in syndrome, in which the patient is mute and quadriplegic but conscious, reflecting interruption of descending motor pathways in the base of the pons but sparing of the reticular activating system (“locked-in” syndrome; see Chap. 16). Horizontal eye movements are obliterated, but vertical ones and some ability to elevate the eyelids are spared. The pupils become extremely small but retain some reaction to light. Midbasilar disease may also cause coma if the posterior communicating arteries are inadequate to perfuse the distal basilar artery territory. In the full syndrome of basilar occlusion with coma, quadriplegia, and ophthalmoplegia, it is usually not difficult to make the correct diagnosis. The aim should be, however, to recognize basilar insufficiency long before the stage of the total deficit has been reached. The early manifestations (in the form of TIAs) occur in many combinations, described in detail further on.

Basilar Artery Branch Occlusion Although the finding of bilateral neurologic signs strongly suggests brainstem involvement, the signs may also be limited to one side of the body. The most characteristic manifestation of basilar branch strokes is the “crossed” cranial nerve and long tract sensory or motor deficit reflecting a unilateral segmented infarction of the brainstem. These syndromes, which may involve any of cranial nerves III through XII, are listed in Table 33-5 and are discussed further in Chap. 44. These crossed syndromes were the basis of the start of neurology as a specialty of medicine in the mid- and late 19th century and are remembered largely by their eponymous designations. Limited, small infarctions on one side of the brainstem are usually due to occlusion of small penetrating vessels that originate in the basilar artery. These strokes clinically equate with lacunar infarctions discussed earlier (see Fig. 33–17). A principal finding may be pure motor hemiplegia from infarction of the descending corticospinal fibers in the base of the pons on one side, as discussed below under Distinguishing capsular from pontine hemiplegia. Emboli coursing through the basilar artery can also occlude the mouths of several small penetrating vessels and cause larger heterogeneous infractions. A larger infarction in the territory of one circumferential vessel may be due to an embolus or result from an atherosclerotic plaque in the parent basilar artery. The clinical distinction is made by the rapidity of onset and the presence of risk factors such as atrial fibrillation for embolus or diabetes and hypertension for small vessel occlusion.

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The main signs of occlusion of the superior cerebellar artery, the most rostral circumferential branch of the basilar, are ipsilateral cerebellar ataxia of the limbs (referable to middle and superior cerebellar peduncles); nausea and vomiting; slurred speech; and loss of pain and thermal sensation over the opposite side of the body (spinothalamic tract). Static tremor of the ipsilateral upper extremity, an ipsilateral Horner syndrome, and palatal myoclonus have also been reported. With occlusion of the anterior inferior cerebellar artery (AICA), the extent of the infarct is extremely variable, as the size of this artery and the territory it supplies vary inversely with the size and territory of supply of the PICA. The principal findings are vertigo, vomiting, nystagmus, tinnitus, and sometimes unilateral deafness; facial weakness; ipsilateral cerebellar ataxia (inferior or middle cerebellar peduncle); an ipsilateral Horner syndrome and paresis of conjugate lateral gaze; and contralateral loss of pain and temperature sense of the arm, trunk, and leg (lateral spinothalamic tract) as shown in Fig. 33-15. The tinnitus, if present at all, may be overwhelming, called “screaming” by some of our patients. If the occlusion is close to the origin of the artery, the corticospinal fibers may also be involved, producing a hemiplegia; if distal, there may be cochlear and labyrinthine infarction. Cerebellar swelling generally does not occur according to case series with AICA territory infarction (Amarenco and Hauw), but we have seen such instances. Distinguishing Capsular from Pontine Hemiplegia  It is often not possible to distinguish a hemiplegia of pontine origin from one of deep cerebral origin unless there is an associated cranial nerve palsy that allows triangulation of the lesion to a part of the brainstem. In both, the face, arm, hand, leg, and foot are affected because of the location of the descending motor fibers into a small segmental region in both structures. With brainstem lesions, as with cerebral ones, a flaccid paralysis gives way to spasticity after a few days or weeks, and there is no satisfactory explanation for the occurrence in some cases of spasticity from the onset of the stroke. A closely related syndrome from infarction in the base of the pons is hemiparesis and ataxia of the limbs on the same side (ataxic-hemiparesis). With a hemiplegia of pontine origin, however, the eyes may deviate to the side of the paralysis, that is, the opposite of what occurs with supratentorial lesions. If there are sensory features, the pattern may be helpful in that coextensive hemiplegia and sensory loss indicates that the lesion is in the cerebrum and not in the brainstem. Also, dissociated sensory deficit over the ipsilateral face and contralateral half of the body indicates a lesion in the lower brainstem, while a hemisensory loss including the face and involving all modalities indicates a lesion in the upper brainstem, in the thalamus, or deep in the white matter of the parietal lobe. When position sense, two-point discrimination, and tactile localization are affected relatively more than pain or thermal and tactile sense, a cerebral lesion is suggested; the converse indicates a brainstem localization. Bilateral motor and sensory signs are almost certain evidence that the lesion lies in the brainstem and these combined lesions are the basis of the locked in syndrome. Additional manifestations that strongly favor a brainstem site are vertigo, diplopia, cerebellar ataxia, a Horner

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Medial longitudinal fasciculus 6th N nucleus complex Vestibular nucleus Restiform body 7th N nucleus Cerebellum

Dorsal cochlear nucleus Descending tract and nucleus of 5th N Spinothalamic tract 8th N 7th N

Lateral inferior pontine syndrome

Middle cerebellar peduncle Medial lemniscus

Medial inferior pontine syndrome

6th N

Corticospinal and corticobular tract Pontine nuclei and ponto-cerebellar fibers Figure 33-14.  Transverse section through the lower pons, reflecting the regions supplied by the lower basilar artery including its anterior inferior cerebellar artery branch.

syndrome, and deafness. The numerous brainstem syndromes illustrate the important point that the cerebellar pathways, spinothalamic tract, trigeminal nucleus, and sympathetic fibers can be involved at different rostral-caudal levels so that “neighboring” phenomena are required to identify the exact site of the infarction. As mentioned, myriad of proper names has been applied to the brainstem syndromes, as shown in Tables 33-5 and 44-1. Many of them were originally described in relation to tumors, trauma, and other nonvascular diseases. The diagnosis of vascular disorders in this region of the brain is not greatly facilitated by knowledge of these

shorthand eponyms and it is profitable to be familiar with the anatomy of the brainstem. To recapitulate regarding occlusion of large cerebral arteries in the posterior circulation, the principal syndromes to be recognized are the full basilar, vertebral– PICA, posteroinferior cerebellar, anteroinferior cerebellar, superior cerebellar, pontomedullary, and medial medullary. These are depicted in Figures 33-14 through 33-16, supplied originally by C.M. Fisher and used in previous editions of this book. Other syndromes referable to the vertebrobasilar arterial system can usually be identified as fragments or combinations of the major ones.

Figure 33-15.  Transverse section through the midpons in the regions supplied by the midbasilar artery and its short circumferential and paramedian branches.

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Figure 33-16.  Transverse section through the upper pons and the regions supplied by the upper basilar artery and its superior cerebellar artery branch.

TREATMENT OF ISCHEMIC STROKE The main objectives in ischemic cerebrovascular disease are the amelioration of the acute deficit and the prevention of future stroke (secondary prevention). It is now also a major goal of general medicine to reduce the incidence of modifiable risk factors for stroke (primary prevention) by addressing hypertension, smoking, glucose control, and lipid lowering. These, and the use of anticoagulants to prevent stroke in patient with atrial fibrillation, are components of primary and secondary prevention. Although the risk of recurrent stroke is dependent on the underlying mechanism, insight has been gained by the study of patients with minor strokes or high-risk TIAs, in which the estimated recurrence rates are approximately 4 percent at 90 days, 5 percent at a year and another 6 percent between the end of the first year and the fifth year (Amarenco and colleagues, 2016, 2018). The treatment of acute stroke may therefore be divided into three broad parts: management in the acute phase by measures to restore the circulation and arrest the pathologic process, physical therapy and rehabilitation, and measures to prevent further strokes and progression of vascular disease.

Management in the Acute Phase With the introduction of thrombolytic agents and advances in endovascular procedures for thrombectomy, acute stroke treatment has evolved to emphasize rapid restoration of perfusion through occluded cerebral vessels. The steps in the process are now dominated by rapidly determining the patient’s eligibility for intravenous or intra-arterial revascularization and the timing of these steps has been derived from a series of randomized clinical trials. Current practice is to use intravenous thrombolysis within 4.5 h of stroke onset (Hacke et al, 2008) and, in some cases, longer.

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If vascular imaging performed during or after intravenous thrombolysis treatment shows large vessel occlusion (distal internal carotid or proximal middle cerebral arteries), the patient may be eligible for endovascular thrombectomy with or without preceding intravenous thrombolysis. If vascular imaging shows no proximal arterial occlusion, endovascular procedures are not undertaken. If there is a large vessel occlusion and the patient is seen between 4.5 and 6 h of stroke onset, endovascular treatment may be undertaken based on several randomized trials including SWIFT-PRIME (see Saver et al) with various imaging criteria for determining eligibility, most based on a discrepancy between perfusion and infarction of the affected region or a discrepancy between the clinical deficit and the extent of infarction. Beyond 6 h after stroke onset, and extending possibly to 18 h and even to 24 h, and there is large vessel occlusion, endovascular treatment is possible if advanced imaging demonstrates the former mismatch between the size of the infarction (diffusion volume) and a region of hypoperfused ischemic, but not yet infarcted tissue (perfusion defect). This has resulted in the concept that perfusion defects could be a better gauge than the time interval from the onset of symptoms for predicting response to treatment. Some of these issues are taken up below. A problem embedded in these approaches is that of determining the precise onset of the time of stroke. This is usually possible from the patient and observers history, but many strokes become apparent when the patient awakens from sleep, leaving the time of onset uncertain. Demonstration of a mismatch between perfusion and diffusion seemingly obviates this problem of the “time last seen well.” Whatever approach is implemented, there is a premium on delivering treatment as soon as is feasible. There are also clinical and laboratory features that preclude various of these steps, as noted below. Medical systems have had to adapt to the resource requirements to carry out these therapies.

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A

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B

Figure 33-17.  Axial diffusion-weighted MRI of acute lacunar infarctions. A. Left capsular infarction causing a right pure motor hemiplegia. B. Left pontine infarction causing a clumsy hand–dysarthria syndrome.

Intravenous Thrombolytic Agents Tissue plasminogen activators (recombinant tPA) convert plasminogen to plasmin. These drugs were shown to be effective in the treatment of stroke decades after the demonstration that they were effective for coronary artery occlusion. Alteplase and tenecteplase are the main genetically engineered forms of plasminogen activators. Tenecteplase has a higher fibrin specificity and longer duration of action compared to alteplase. In the following discussion, we use “tPA” to represent all tissue plasminogen activators. The benchmark study organized by the National Institute of Neurological and Communicative Disorders and Stroke (see the NINCDS and Stroke rtPA Stroke Study Group in the references) provided evidence of benefit from intravenous tPA. In that trial, the design of which is simple by modern standards, treatment within 3 h of the onset of symptoms led to a 30 percent increase in the number of patients who remained with little or no neurologic deficit3 months after the stroke; this benefit persisted when assessed 1 year later (Kwiatkowski and associates). Two aspects of most trials of thrombolytic agents are notable: the benefits extend to all types of ischemic strokes, including those caused by occlusion of small vessels (lacunes), and improvement is usually not apparent in the days immediately following treatment (spontaneous improvement from stroke is common) but can be discerned when patients were examined at 3 months. In the historically important, seminal NIH study, in which tPA was administered in a dose of 0.9 mg/kg, 10 percent of which was given as an initial bolus, followed by an infusion of the remainder over 1 h. A dose of 90 mg was not

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exceeded, this being lower than the dose used for myocardial infarction. The relative improvement in the neurologic state came at the expense of a 6 percent risk of symptomatic cerebral hemorrhage and 4 percent of insignificant hemorrhages seen on imaging, that is, a lower rate than in most previous studies but twice the expected rate without thrombolysis (some of the hemorrhages were into the area of infarction and did not cause symptomatic worsening). Patients were excluded from the study if they had massive cerebral infarctions (encompassing more than two-thirds of the territory of the MCA), had high scores on a clinical stroke scale that was devised for the National Institutes of Health (NIH) study (discussed earlier in the section on “Neurological Scales Used in Stroke Trials and Clinical Evaluation” (Table 33-4) and available at: http://www. ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf and from other sources) had uncontrolled hypertension, were more than 80 years of age or had recently received anticoagulants (except aspirin). Further analysis of the NINCDS trial demonstrated that patients who were treated earliest within the 3-h time frame had more benefit than those treated later; indeed, the administration of tPA in the time between 2.5 and 3 h after the stroke was of less value. One subsequent trial has suggested that a lower dose of tPA (0.6 mg/kg) is non-inferior to the standard dose in a population of predominantly Asian patients (Anderson et al 2016), but this has not been widely adopted. Almost all subsequent trials of intravenous thrombolysis have been derivative of this trial and have largely expanded the criteria for inclusion by time from the onset of stroke, size of stroke, and patient age or have adopted an approach to selecting patients based on imaging characteristics discussed earlier.

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Tenecteplase, doses of 0.25 mg/kg or 0.4 mg/kg have been used for thrombolysis and achieved similar results to alteplase (tPA) (Logallo et al; Parsons et al and Campbell et al) in some trials showing an improved rate of revascularization before thrombectomy compared to tPA. In some patients with basilar artery occlusion and coma of brief duration and those without extensive thrombosis, prompt tPA treatment has at times also resulted in an overall improvement in neurologic function, but there have been numerous exceptions and there have been no satisfactory trials specifically for thrombolysis in this type of stroke to demonstrate benefit. Generally agreed upon guidelines of the American Heart Association are used as inclusion and exclusion criteria for the use of intravenous thrombolysis, as shown in Table 33-6. Intracranial and systemic bleeding as an adverse event is, of course, a concern and a minor but interesting point is that some patients who had been receiving angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension can have angioneurotic edema as a side effect of tPA. Generally excluded from trials of thrombolysis are patients in whom the deficit is either slight (e.g., hand affected only, dysarthria alone, minor aphasia), rapidly improving, or, more importantly, is so large as to implicate almost the entire territory of the MCA. This generally corresponds to an NIHSS score of 3 or less. As a result, patients with these mild degrees of deficit or those who are improving rapidly (difficult to quantify) are also excluded from treatment in clinical practice. Also ambiguous is the treatment of patients with acute stroke in whom the referable cerebral vessels are entirely patent. Public health education is intended to increase the number of stroke patients who seek early attention and thus raise the proportion who may be eligible for tPA or endovascular treatment.

Endovascular (Intra-arterial) Thrombectomy Removal of an intravascular clot or thrombolytic substances injected intraarterially (intra-arterial thrombolysis) or mechanical lysis for disruption has been increasingly used to restore blood flow in occluded major cerebral vessels. The technique generally involves a device that retrieves clots from the intravascular lumen, but there are variations in technical approaches. It is not clear what proportion of patients with stroke are in a category appropriate for endovascular treatment and this probably varies by geographic region. The initial trials of endovascular treatment were conducted in patients up to 6 h after stroke (e.g., Berkhermer et al) but this time window has been extended to 8 hours (e.g., Jovin et al, 2015) and even to 16 to 24 h with appropriate patient selection (Goyal et al) (only a few of the many trials are cited here). The main criterion for the selection of patients for endovascular thrombectomy in most trials has been occlusion of the intracranial internal carotid, middle, or (less often) anterior cerebral arteries. The use of the ASPECTS scale (Table 33-4) to gauge the extent of infarction imaging features has been mentioned earlier

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Table 33-6 SUMMARY OF AMERICAN HEART ASSOCIATION (AHA)/ AMERICAN STROKE ASSOCIATION (ASA) 2018 INCLUSION/ EXCLUSION CRITERIA FOR IV ALTEPLASE IN ACUTE ISCHEMIC STROKE Inclusion Criteria   Onset of symptoms 3 or 4.5 hours  Acute intercranial hemorrhage or history of intracranial  hemorrhage  Symptoms and signs suggestive of subarachnoid hemorrhage  CT brain imaging that exhibits extensive regions of clear   hypoattenuation (obvious hypodensity)  Prior ischemic stroke or severe head trauma within 3 months  Acute posttraumatic brain infarction that occurs during acute   in-hospital phase  Intracranial/intraspinal surgery within 3 months  GI malignancy or GI bleeding within 21 days  Pretreatment systolic blood pressure >185 mm Hg or diastolic   blood pressure >110 mm Hg despite therapy (see Table 167-9)  Platelet count 1.7 or activated PTT >40 s, or prothrombin time >15 s   Use of low-molecular-weight heparin within preceding 48 h  Current use of direct thrombin inhibitors or direct factor Xa  inhibitors with elevated sensitive laboratory tests (such as activated PTT, INR, platelet count, and ecarin clotting time [ECT]; thrombin time; or appropriate factor Xa activity assays)   Current use of glycoprotein IIb/IIIa receptor inhibitors  Current infective endocarditis   Known or suspected aortic arch dissection  Intra-axial intracranial neoplasm   Blood glucose level 155 mEq/L) and dehydration are observed in diabetes insipidus, the neurologic causes of which include head trauma with damage to the pituitary stalk (see Chap. 26), and in nonketotic diabetic coma, protracted diarrhea in infants, and the deprivation of fluid intake in the stuporous patient. The last condition is usually

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associated with a brain lesion that impairs consciousness. Exceptionally, in patients with chronic hydrocephalus, the hypothalamic thirst center is rendered inactive and severe hypernatremia, stupor, and coma may follow a failure to drink. In hypernatremia from any cause, the brain volume is manifestly reduced. Retraction of the cerebral cortex from the dura has been known to rupture a bridging vein and cause a subdural hematoma. As is true for hyponatremia, the degree of CNS disturbance in hypernatremia is generally related to the rate at which the serum Na rises. Slowly rising values, to levels as high as 170 mEq/L, may be surprisingly well tolerated. Rapid elevations of sodium shrink the brain, especially in infants. Extremely high levels cause impairment of consciousness with asterixis, myoclonus, seizures, and choreiform movements. In addition, muscular weakness, rhabdomyolysis, and myoglobinuria have been reported. In hypernatremia with hyperosmolality, the brain retains its volume more effectively than do other organs by a compensatory mechanism that has been attributed to the presence of “idiogenic osmoles,” possibly glucose, glucose metabolites, and amino acids. The impairment of neuronal function in this state is not understood. Theoretically one would expect neuronal shrinkage and possibly alteration of the synaptic surface of the cell.

Hypo- and Hyperkalemia The main clinical effect of hypokalemia (≤ 2.0 mEq/L) is generalized muscular weakness (see Chap. 45). A mild confusional state had been alluded to in the literature but must be very infrequent. The electrolyte condition is readily corrected by adding K to intravenous fluid and infusing it at no more than 4 to 6 mEq/h. Hyperkalemia (> 7 mEq/L) also may manifest itself by generalized muscle weakness, although the main effects are changes in the electrocardiogram (ECG), possibly leading to cardiac arrest.

Other Metabolic Encephalopathies Limitation of space permits only brief reference to other metabolic disturbances that may present as episodic confusion, stupor, or coma. The most important members of this group are summarized below. Hypercalcemia  This is defined as an elevation of the serum calcium concentration greater than 10.5 mg/dL. If the serum protein content is normal, Ca levels greater than 12 mg/dL are required to produce neurologic symptoms. However, with low-serum albumin levels, an increased proportion of the serum Ca is in the unbound or ionized form (on which the clinical effects depend), and symptoms may occur with total serum Ca levels as low as 10 mg/dL. In young persons, the most common cause of hypercalcemia is hyperparathyroidism (either primary or secondary); in older persons, osteolytic bone tumors, particularly metastatic carcinoma and multiple myeloma, are often causative. Less common causes are vitamin D intoxication, prolonged immobilization, hyperthyroidism, sarcoidosis, and decreased calcium excretion (renal failure). Anorexia, nausea and vomiting, fatigue, and headache are usually the initial symptoms, followed by confusion (rarely a delirium) and drowsiness, progressing to stupor

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or coma in untreated patients. A history of recent constipation is common. Diffuse myoclonus and rigidity occur occasionally, as do elevations of spinal fluid protein (up to 175 mg/100 mL). Convulsions are uncommon. Hypocalcemia  The usual manifestations are paresthesias, tetany, and seizures. With severe and persistent hypocalcemia, altered mental status in the form of depression, confusion, dementia, or personality change can occur. Anxiety to the point of panic attack is also known. Even coma may result, in which case there may be papilledema as a result of increased intracranial pressure. Aside from the raised pressure, the CSF shows no consistent abnormality. This increase in intracranial pressure may be manifest by headache and papilledema without altered mentation or with visual obscurations. Hypoparathyroidism is discussed again further on, under “Acquired Metabolic Diseases Presenting as Progressive Extrapyramidal Syndromes.” Other electrolyte and acid–base disorders  Severe metabolic acidosis from any cause produces a syndrome of drowsiness, stupor, and coma, with dry skin and Kussmaul breathing. The CNS depression does not correlate with the concentration of ketones. Possibly, there are associated effects on neurotransmitters. It is often not possible to separate the effects of acidosis from those caused by an underlying condition or toxic ingestion. In infants and children, acidosis may occur in the course of hyperammonemia, isovaleric acidemia, maple syrup urine disease, lactic and glutaric acidemia, hyperglycinemia, and other disorders, which are described in detail in Chap. 36. High-voltage slow activity predominates in the EEG, and correction of the acidosis or elevated ammonia level restores CNS function to normal provided that coma was not prolonged or complicated by hypoxia or hypotension. In uncomplicated acidotic coma, no recognizable neuropathologic change has been observed by light microscopy. Encephalopathy as a consequence of Addison disease (adrenal insufficiency) may be attended by episodic confusion, stupor, or coma without special identifying features; it is usually precipitated in the addisonian patient by infection or surgical stress. Hemorrhagic destruction of the adrenals in meningococcal meningitis (WaterhouseFriderichsen syndrome) is another cause. Hypotension and diminished cerebral circulation and hypoglycemia are the most readily recognized metabolic abnormalities; measures that correct these conditions reverse the adrenal crisis in some instances.

Central Pontine Myelinolysis and Other Patterns of Osmotic Demyelination Adams and colleagues observed a rapidly evolving quadriplegia and pseudobulbar palsy in a young alcoholic man who had entered the hospital 10 days earlier with symptoms of alcohol withdrawal. Postmortem examination several weeks later disclosed a large, symmetrical, essentially demyelinative lesion occupying the greater part of the base of the pons. Over the next 5 years, 3 additional cases (2 alcoholic patients and 1 with scleroderma) were studied clinically and pathologically, and in 1959 these 4 cases were reported under the heading of central pontine

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myelinolysis (CPM) (Adams et al). This term was chosen because it reflects both the main anatomic localization of the disease and its essential pathologic attribute: the remarkable dissolution of the sheaths of myelinated fibers and the sparing of neurons. Once attention was focused on this distinctive lesion, many other reports appeared, and it became apparent that other areas of myelin in the brain could be similarly affected. The exact incidence of this disease is not known, but in a series of 3,548 consecutive autopsies in adults, the typical lesion was found in 9 cases, or 0.25 percent (Victor and Laureno).

Pathologic Features One is compelled to define this disease in terms of its pathologic anatomy because this stands as its most characteristic feature, but it has been appreciated that the pons is not the only structure that may be affected. Transverse sectioning of the fixed brainstem discloses a grayish discoloration and fine granularity in the center of the base of the pons. The lesion may be only a few millimeters in diameter, or it may occupy almost the entire ventral pons. There is always a rim of intact myelin between the lesion and the surface of the pons. Posteriorly, it may reach and involve the medial lemnisci and, in the most advanced cases, other tegmental structures as well. Rarely, the lesion encroaches on the midbrain but it does not extend as far as the medulla. Identical extrapontine myelinolytic foci in the internal capsule, deep cerebral white matter and corpus callosum may occur independently (extrapontine myelinolysis). Exceptionally, symmetrically distributed lesions are found in the thalamus, subthalamic nucleus, striatum, amygdaloid nuclei, lateral geniculate body, white matter of the cerebellar folia (Wright and colleagues). Microscopically, the fundamental abnormality consists of destruction of the myelinated sheaths throughout the lesion, with relative sparing of the axons and intactness of the nerve cells of the pontine nuclei. These changes begin and are most severe in the geometric center of the pons, where they may proceed to frank necrosis of tissue. Reactive phagocytes and glia cells are in evidence throughout the demyelinative focus, but oligodendrocytes are depleted. Signs of inflammation are conspicuously absent. This constellation of pathologic findings provides easy differentiation of the lesion from infarction and the inflammatory demyelination of multiple sclerosis and postinfectious encephalomyelitis. Microscopically, the lesion resembles that of Marchiafava-Bignami disease (see Chap. 40), with which CPM is rarely associated. In the chronic alcoholic, Wernicke disease is often associated with osmotic demyelination, but the lesions bear no resemblance to one another in terms of topography and histology.

Clinical Features More than half the cases have appeared in the late stages of chronic alcoholism, often in association with Wernicke disease and polyneuropathy. Most cases occur in the context of other serious medical conditions, and diseases with which osmotic demyelination has been conjoined are chronic renal failure being treated with dialysis, hepatic failure, advanced lymphoma, cancer, cachexia from a variety of other causes, severe bacterial infections, dehydration

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and electrolyte disturbances, acute hemorrhagic pancreatitis, and pellagra. The changes in serum sodium concentration, with which the process is closely aligned, are discussed below. The two sexes are affected equally, and the patients do not fall into any one age period. Whereas the cases first reported had occurred in adults, there are now many reports of the disease in children, particularly in those with severe burns (McKee and colleagues). In many patients there are no symptoms or signs that betray the pontine lesion, presumably because it is so small, extending only 2 to 3 mm on either side of the median raphe and involving only a small portion of the corticopontine or pontocerebellar fibers. In others, its presence is obscured by coma from a metabolic or other associated disease. Prior to the inception of MRI only a minority of cases, exemplified by the first patient observed by Adams and colleagues, were recognized during life. In this patient, a serious alcoholic with delirium tremens and pneumonia, there evolved, over a period of several days, a flaccid paralysis of all four limbs and an inability to chew, swallow, or speak (thus simulating occlusion of the basilar artery). Pupillary reflexes, movements of the eyes and lids, corneal reflexes, and facial sensation were spared. In some instances, however, conjugate eye movements are limited, and there may be nystagmus. With survival for several days, the tendon reflexes become more active, followed by spasticity and extensor posturing of the limbs on painful stimulation. Some patients are left in a state of mutism and paralysis with relative intactness of sensation and comprehension (pseudocoma, or locked-in syndrome). The capacity of CT and especially MRI to visualize the pontine lesion has greatly increased the frequency of premortem diagnoses. A characteristic MRI appearance of a trident shape in the pons is visualized only several days after the onset of symptoms but diffusion restriction in the lower pons may appear in a day or so after motor signs (Fig. 39-6). Brainstem auditory evoked responses also disclose the lesions that encroach on the pontine tegmentum.

Figure 39-6.  T2-weighted MRI showing the typical lesion of central pontine myelinolysis in an alcoholic patient.

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Variants of this syndrome are being encountered with increasing frequency. Two of our elderly patients, with confusion and stupor but without signs of corticospinal or pseudobulbar palsy, recovered; however, they were left with a severe dysarthria and cerebellar ataxia lasting many months. After 6 months, these patients’ nervous system function was essentially restored to normal. In reference to the pathogenesis of this lesion, originally both patients had serum Na levels of 99 mEq/L, but information about the rate of correction of serum Na was not available. Another of our patients developed a typical locked-in syndrome after the rapid correction of a serum sodium of 104 mEq/L; large symmetrical lesions of the frontal cortex and underlying white matter were found, but no pontine lesion. Brainstem infarction caused by basilar artery occlusion may be simulated by pontine myelinolysis. Sudden onset or step-like progression of the clinical state, asymmetry of long tract signs, and more extensive involvement of tegmental structures of the pons as well as the midbrain and thalamus are the distinguishing characteristics of vertebrobasilar thrombosis or embolism. On MRI, an evolving infarction shows signal changes on diffusion-weighted imaging, often extending to the ventral surface of the pons, while the primary finding in osmotic demyelination is abnormal hyperintensity on T2-weighted images without associated restricted diffusion, and sparing of the ventral surface of the pons. Massive pontine demyelination in acute or chronic relapsing multiple sclerosis rarely produces a pure pontine syndrome. The clinical features and context provide the clues to correct diagnosis.

Etiology and Pathogenesis As mentioned in the section on hyponatremia, a rapid rise in serum osmolality to normal or higher-than-normal levels is an almost obligate antecedent of this process. One encounters this most commonly in the rapid correction of hyponatremia. In cases related to the correction of hyponatremia, the initial serum sodium concentration is less than 130 mEq/L and usually much lower; this was the case in all the patients reported by Burcar and colleagues and by Karp and Laureno. Laureno (1983) demonstrated the importance of serum sodium in the pathogenesis of this disease experimentally. Dogs made severely hyponatremic (100 to 115 mEq/L) had the electrolyte disorder corrected rapidly by infusion of hypertonic (3 percent) saline; this led to spastic quadriparesis and pontine and extrapontine lesions were found at autopsy, indistinguishable in their distribution and histologic features from those of the human disease. Hyponatremia alone or slowly corrected hyponatremia (< 15 mEq/dL in the initial 24 h) did not produce the disease. In burn patients, extreme serum hyperosmolality has been the important factor in the pathogenesis of demyelination (McKee and colleagues). They found the characteristic pontine and extrapontine lesions in 10 of 139 severely burned patients who were examined after death. Each of their patients with CPM had suffered a prolonged, nonterminal episode of severe serum hyperosmolality, which coincided temporally with the onset of the lesion, as judged by its histologic features. Hyponatremia was

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not prominent and no other independent features could explain the changes. These observations suggest that rapidly rising osmolarity may be a cause of the osmotic demyelination syndromes. The pathogenesis is not known but all one can say is that specific myelinated regions of the brain, most often but not exclusively the center of the base of the pons, have a susceptibility to rapid increase in serum osmolality. Karp and Laureno, based on their experience and that of Sterns and colleagues, have suggested that to avoid CPM the hyponatremia be corrected by no more than 10 mEq/L in the initial 24 h and by no more than about 21 mEq/L in the initial 48 h. Current recommendations are even more conservative—that the rate of correction of hyponatremia should not exceed 6 to 8 mEq/L over any 24-hour period.

ACQUIRED METABOLIC DISEASES PRESENTING AS PROGRESSIVE EXTRAPYRAMIDAL SYNDROMES These syndromes are usually of mixed type; that is, they include a number of basal ganglionic and cerebellar symptoms in various combinations. They emerge as part of acquired chronic hepatocerebral degeneration or chronic hypoparathyroidism or as sequels to kernicterus, hypoxic, or hypoglycemic encephalopathy. The basal ganglionic– cerebellar symptoms that result from severe anoxia and hypoglycemia were described in the preceding section and in Chaps. 4 and 5. Kernicterus and calcification of the basal ganglia and cerebellum are considered in Chap. 36 and further on in this chapter. Acquired hypoparathyroidism may also lead to calcification of the basal ganglia and an extrapyramidal disorder. Choreiform movements are also observed in patients with hyperosmolar coma and with severe hyperthyroidism, ascribed by Weiner and Klawans to a disturbance of dopamine metabolism.

Chronic Acquired (Non-Wilsonian) Hepatocerebral Degeneration Patients who survive an episode or several episodes of hepatic coma are sometimes left with residual neurologic abnormalities such as tremor of the head or arms, asterixis, grimacing, choreic movements and twitching of the limbs, dysarthria, ataxia of gait, or impairment of intellectual function. These symptoms may worsen with repeated attacks of stupor and coma. In few patients with chronic liver disease, permanent neurologic abnormalities become manifest in the absence of discrete episodes of hepatic coma. Patients deteriorate neurologically over a period of months or years. Examination of their brains discloses foci of destruction of nerve cells and other parenchymal elements in addition to a widespread transformation of astrocytes, changes very much similar to those of Wilson disease. Probably the first to describe this acquired type of hepatocerebral degeneration was van Woerkom, whose report appeared only two years after Wilson’s original description of the familial form. A full account of the cases

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reported as well as the extensive experience of our colleagues with this disorder is contained in the article by Victor, Adams, and Cole.

Clinical Features The first symptom may be a tremor of the outstretched arms, fleeting arrhythmic twitches of the face and limbs (resembling either myoclonus or chorea), or a mild unsteadiness of gait with action tremor. As the condition evolves over months or years, a characteristic dysarthria, ataxia, wide-based, unsteady gait, and choreoathetosis, mainly of the face, neck, and shoulders, are joined in a syndrome. Mental function is slowly altered, taking the form of a dementia with a seeming lack of concern about the illness. A coarse, rhythmic tremor of the arms appearing with certain sustained postures, corticospinal tract signs (“hepatic paraplegia”), and diffuse EEG abnormalities complete the clinical picture. Other less-frequent signs are rigidity, grasp reflexes, tremor in repose, nystagmus, asterixis, and action or intention myoclonus. In essence, each of the neurologic abnormalities observed in patients with acute hepatic encephalopathy are also part of chronic hepatocerebral degeneration, the only difference being that the abnormalities are evanescent in the former and irreversible and progressive in the latter. As a rule, all measurable hepatic functions are altered but the chronic neurologic disorder correlates best with an elevation of serum ammonia (usually > 200 mg/dL). Unlike Wilson disease, where the cirrhosis usually remains occult for a long time, there is no question about its presence in the acquired syndrome; jaundice, ascites, and esophageal varices are manifest in most of the acquired cases. Wilson disease, which enters into the differential diagnosis, is usually not difficult to differentiate on clinical grounds, although the distinction in some cases requires the critical evidence of familial occurrence, Kayser-Fleischer rings (never found in the acquired type), and certain biochemical abnormalities (diminished serum ceruloplasmin, elevated serum copper, and elevated urinary copper excretion, discussed in this chapter).

Pathology The cerebral lesions are localized more regularly in the cortex than is the case in Wilson disease. In some specimens an irregular gray line of necrosis or gliosis can be observed throughout both hemispheres and the lenticular nuclei may be shrunken and discolored. These lesions resemble hypoxic ones and may be concentrated in the vascular border zones but they tend to spare the hippocampus, globus pallidus, and deep folia of the cerebellar cortex, the sites of predilection in anoxic encephalopathy. Microscopically, a widespread hyperplasia of protoplasmic astrocytes is visible in the deep layers of the cerebral cortex and in the cerebellar cortex as well as in thalamic and lenticular nuclei and other nuclear structures of the brainstem. In the necrotic zones, the myelinated fibers and nerve cells are destroyed, with marginal fibrous gliosis; at the corticomedullary junction, in the striatum (particularly in the superior pole of the putamen) and in the cerebellar white matter, microcavitation may be prominent. Protoplasmic astrocytic nuclei contain PAS-positive glycogen granules.

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Some nerve cells appear swollen and chromatolyzed, taking the form of the Opalski cells usually associated with Wilson disease. The similarity of the lesions in the familial and acquired forms of hepatocerebral disease is striking. Pathogenesis  It is evident that a close relationship exists between the acute, transient form of hepatic encephalopathy and the chronic, largely irreversible hepatocerebral syndrome; frequently one blends imperceptibly into the other. The feature that ties these entities is the existence of portal–systemic shunting of blood. As noted above, this relationship is reflected in the pathologic findings as well. It appears that the parenchymal damage in the chronic disease simply represents the most severe degree of a pathologic process that in its mildest form is reflected in an astrocytic hyperplasia alone. Reducing the serum ammonia by the measures that are effective in acute hepatic encephalopathy will cause a recession of many of the chronic neurologic abnormalities—not completely, but to an extent that permits the patient to function better.

stature, round face, short neck, stocky body build, shortening of metacarpal and metatarsal bones and phalanges from premature epiphyseal closure) are rarely seen in pure hypoparathyroidism. A similar deposition of iron and calcium in the walls of small blood vessels of the lenticular and dentate nuclei, and to a lesser extent in other parts of the brain, is a common finding in normal older individuals (Fahr disease). It also occurs in animals. Occasionally, it reaches a degree of severity that destroys striatal or dentate neurons. In such cases, CT will reveal the deposits (see Fig. 36-8), but the cause of the deposits is unknown. Apparently some protein in the capillary walls has an avidity for both calcium and iron.

Hypoparathyroidism

Cerebellar Ataxia With Myxedema

This condition and pseudohypoparathyroidism were mentioned in relation to the hereditary metabolic disorders in Chap. 36. In the past, the usual cause was surgical removal of the parathyroid glands during subtotal thyroidectomy, although there continue to be idiopathic cases. With refinements in surgical technique and the use of radiation and drug therapy for thyroid disease, the number of surgically created cases has declined in proportion to nonsurgical ones. The condition in children may occur in pure form, presumably as an agenesis of the parathyroid glands, with unmeasurable levels of parathyroid hormone in the blood, or as part of the DiGeorge syndrome of agenesis of the thymus and parathyroid glands, organs that are embryologically derived from the third and fourth branchial clefts. Hypoparathyroidism is also part of a familial disorder in which a deficiency of thyroid, ovarian, and adrenal function, pernicious anemia, and other defects are combined, based presumably on autoimmune mechanisms. Other causes are intestinal malabsorption, pancreatic insufficiency, and vitamin D deficiency. In all instances the low levels of parathormone and normal responses to injected hormone permit the recognition of a primary defect of the parathyroid glands and distinguish it from all other conditions in which there is hypocalcemia and hyperphosphatemia. The clinical manifestations, mainly attributable to the effects of hypocalcemia, are tetany, paresthesias, muscle cramps, laryngeal spasm, and convulsions. Children with this disease may be irritable and show behavioral changes. In adults with chronic hypocalcemia, calcium deposits occur in the basal ganglia, dentate nuclei, and cerebellar cortex. In such patients we have observed unilateral tremor, a restless choreoathetotic hand, bilateral rigidity, slowness of movement and flexed posture resembling Parkinson disease, and ataxia of the limbs and gait—in various combinations. Interestingly, the multiple skeletal and developmental abnormalities that characterize both pseudohypoparathyroidism (a failure of sensitivity to the hormone) and pseudopseudohypoparathyroidism (short

The association of myxedema and cerebellar ataxia has been mentioned sporadically in medical writings since the latter part of the nineteenth century. In a small series of six such cases, all showed gait ataxia; in addition, some degree of ataxia of the arms and dysarthria were present in four, and nystagmus in two (Jellinek and Kelly). A similar clinical experience was reported based on a study of 24 patients with either primary or secondary hypothyroidism (Cremer and colleagues). There are only a few reports of the pathologic changes. The myxedematous patient described by Price and Netsky had also been an abuser of alcohol, and the clinical signs (ataxia of gait and of the legs) and pathologic changes (loss of Purkinje cells and gliosis of the molecular layer, most pronounced in the vermis) could be distinguished from those caused by alcoholism and malnutrition. Scattered throughout the nervous system of their case were unusual glycogen-containing bodies, similar but not identical to corpora amylacea. These structures, designated myxedema bodies by Price and Netsky, were also observed in the cerebellar white matter of a second case of myxedema; there were no other neuropathologic changes, however, and this patient had shown no ataxia during life. It is difficult to know whether these peculiar bodies have anything to do with myxedema. If they do, it should be possible to demonstrate them in more than two cases. Our colleagues did not see them in one carefully studied case of myxedema, nor have they been described by others. Serum creatine kinase (CK) is also slightly elevated in hypothyroidism, presumably because of its slowed metabolism. Thyroid medication corrects the defect in motor coordination and normalizes the CK, raising the possibility that this is the result of a subcellular mechanism. Table 5-3 summarizes the various causes of cerebellar ataxia, including some of the metabolic ones. Notable metabolic disorders, some heritable, in which ataxia may be a leading manifestation include GM2 gangliosidosis, possibly sprue (discussed in the following text), and a large number of neonatal and infantile aminoacidopathies.

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Effects of Hyperthermia on the Cerebellum The damaging effects of hyperthermia, like those of anoxia, involve the brain diffusely. In the case of hyperthermia, however, the changes are disproportionately severe in the cerebellum. The acute manifestations of profound hyperthermia are coma and convulsions, frequently complicated by shock and renal failure. Patients who survive the initial stage of the illness frequently show signs of widespread cerebral affection, such as confusion and pseudobulbar and spastic paralysis. These abnormalities tend to resolve gradually, leaving the patient with a more or less pure disorder of cerebellar function. The most extensive account of the effects of hyperthermia is that of Malamud and colleagues. These authors studied 125 fatal cases of heat stroke but their observations are probably applicable to hyperthermia of other types. In patients who survived less than 24 h, the changes consisted mainly of a loss of some of the Purkinje cells and swelling, pyknosis, and disintegration of those that remained. In cases surviving beyond 24 h, there was almost complete degeneration of the Purkinje cells, with gliosis throughout the cerebellar cortex as well as degeneration of the dentate nuclei. The changes in the cerebellar cortex were equally pronounced in the hemispheres and vermis. The unanswered question is whether high temperature alone is an adequate cause or whether it must be combined with hypoxia and ischemia. It is of interest that this syndrome is not seen in patients with infective fevers, malignant hyperthermia, or the malignant neuroleptic syndrome—either the neuropathologic changes or the clinical cerebellar syndrome in survivors.

Cerebellar Syndromes Associated With Celiac Disease (Sprue, Gluten Sensitive Enteropathy) Most often, the neurologic association with this disease has been a peripheral neuropathy, as described in Chap. 43. In addition, a progressive cerebellar ataxia of gait and limbs, sometimes with polymyoclonus in association with a gluten-sensitive enteropathy, has been the subject of several reports. The underlying cause of the enteropathy is an intestinal allergy to gluten in wheat that produces a villous atrophy of the intestinal mucosa. Between 0.5 and 1 percent of the white population are affected with the intestinal disorder. The typical features are diarrhea and malabsorption but many individuals are asymptomatic (see also Chap. 40). The neurologic disorder may appear several years after onset of the enteropathy and, in addition to ataxia, usually includes signs of peripheral neuropathy and rarely, myelopathy or encephalopathy (dementia) or psychiatric symptoms (Hallert and Astrom; Hallert and Deerefeldt). A rare spinocerebellar syndrome was described (Cooke and Smith). According to Finelli and colleagues, neurologic abnormalities occur in approximately 10 percent of cases of adult celiac sprue. This subject was reviewed by Bhatia and colleagues and extensively by Hadjivassiliou and colleagues (1998, 2002). The latter authors emphasize the frequent occurrence of ataxia in patients with gluten sensitivity and, more specifically, antibodies to

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transglutaminase and endomysium, but, curiously, often without overt signs of bowel disease. There is also an association of sprue in more than 90 percent of patients with the HLA DQ2 and DQ8 genotypes. The few cases that have come to autopsy have shown severe cerebellar atrophy, a finding that may also be disclosed by MRI. Hadjivassiliou and colleagues (1998) observed lymphocytic infiltration and perivascular cuffing in the cerebellar cortex and peripheral nerves in one autopsied case but not in another, changes that they took to represent immunologic injury to these parts. Despite these associations, some authors have been skeptical of a “gluten ataxia” (see the editorial by Cross and Golumbek and the contrary case for a valid connection by Hadjivassiliou et al, 2002). Reports of improvement in the ataxia following the institution of a gluten-free diet are conflicting. The situation is further complicated by the finding that antigliadin antibodies (which are not autoantibodies but are directed against gluten, the offending agent), while not specific for celiac disease, do correspond to the presence of neurologic manifestations (ataxia and neuropathy); however, the more specific antiendomysium and antitransglutaminase autoantibody markers of sprue have little apparent relation to the presence of neurologic disease. Even more confusing is the claim that half of these patients will have one or another antibody but no clinical enteropathy, making it necessary to perform a small-bowel biopsy to detect villous atrophy. A gluten-free diet is necessary, not only to reduce the enteropathy, if present, but also to reduce the chances of the later development of a bowel lymphoma. The medical issues relating to celiac disease and the use of antibody tests and bowel biopsy are reviewed by Farrell and Kelly. We have sought evidence by antibody testing and bowel biopsy of sprue in numerous patients with an ataxia of obscure origin and have only rarely found it. Nevertheless, the evidence presented in the writings of several authors, particularly Hadjivassiliou, suggest that sprue may underlie some cases of subacute ataxia in adults. Paraneoplastic cerebellar degeneration and Creutzfeldt-Jakob disease should always be considered in the differential diagnosis of a case of subacute cerebellar ataxia. Vitamin E deficiency may induce a similar syndrome with features of spinocerebellar dysfunction. Jejunoileal bypass operations, in addition to causing a chronic arthropathy, neuropathy, and vasculitic skin lesions, may give rise to an episodic confusion and cerebellar ataxia associated with a lactic acidosis and abnormalities of pyruvate metabolism. Overfeeding and fasting are provocative factors (Dahlquist and colleagues).

ACQUIRED METABOLIC DISEASE PRESENTING AS PSYCHOSIS AND DEMENTIA Milder forms of metabolic diseases that cause episodic stupor and coma, if persistent, may have a protracted course and are then difficult to distinguish from the dementias (see Chap. 20). Examples are associated with chronic hepatic

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encephalopathy and the syndromes of episodic hypoglycemia, chronic hypercalcemia (in multiple myeloma, metastatic cancer, and sarcoidosis), hyponatremia, and hypernatremia. Unlike the common types of dementia described in Chap. 20, the acquired metabolic diseases are nearly always accompanied by a degree of drowsiness and inattentiveness—attributes that usually allow an encephalopathic confusional state to be distinguished from a dementia. The presence of asterixis is also an aid. If the onset of the illness is abrupt rather than gradual and of brief duration, and if therapy reverses the condition, restoring full mental clarity, the conclusion is justified that one is dealing with a confusional state, but at any one time in the active phase of the disease, the clinical state may resemble dementia. An episodic confusional state lasting days and weeks in the course of a medical illness or following an operation should always raise the suspicion of one of the aforementioned metabolic derangements (or an adverse effect of a drug). Usually, however, if these causes can be excluded, one falls back on a rather unsatisfactory interpretation— that a combination of drugs, fever, toxemia, and unspecifiable metabolic disorders is responsible. The “septic encephalopathy” described earlier in this chapter conforms to this ambiguous notion. In the endocrine encephalopathies described below, the clinical phenomena may take the form of a delirium. Confusional states may be combined with agitation, hallucinations, delusions, anxiety, and depression, and the time span of the illness may be in terms of weeks and months rather than days. Certain aspects of the endocrine psychoses are discussed further on.

Cushing Syndrome and Corticosteroid Psychoses Derangements of mental function that follow administration of adrenocorticotropic hormone (ACTH) and of corticosteroids have become the prototypes of iatrogenic psychoses. The same disturbances of mental function may accompany Cushing disease (see “Corticosteroid and Adrenocorticotropic Hormone Psychosis” in Chap. 49). Experience with this neuropsychiatric condition came originally from observations of patients receiving ACTH and later from those receiving prednisone for a variety of neurologic and medical diseases. With low doses there is usually no psychic effect other than a sense of well-being and decreased fatigability. At higher doses (equivalent to 60 to 100 mg/d of prednisone), approximately 10 to 15 percent of patients become overly active, emotionally labile, and unable to sleep. Unless the dose is promptly reduced, a progressive shift in mood follows, usually toward euphoria and hypomania, but sometimes toward depression and then inattentiveness, distractibility, and mild confusion. The EEG becomes less well modulated and slower frequencies appear. A minority of patients experience frank hallucinations and delusions, giving the illness a truly psychotic stamp and raising the suspicion of schizophrenia or bipolar disease. In nearly all instances, there is a mixture of confusion and mood change, distinguishing the state from other mundane metabolic encephalopathies. Withdrawal of medication relieves the symptoms but full recovery may

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take several days to a few weeks, at which time, as with all confusional states and deliria, the patient has only a fragmentary recollection of events that occurred during the illness. The neurologic basis of this condition is poorly understood. Its attribution to premorbid personality traits or a disposition to psychiatric illness is unconvincing. Critical studies of cellular or subcellular metabolism and morphologic changes are lacking. “Cerebral atrophy” (ventricular enlargement and sulcal widening) has been shown radiologically in patients with Cushing disease and after a prolonged period of corticosteroid therapy, but the basis of this change also is unclear (Momose and colleagues). In most cases of brain shrinkage, withdrawal of steroids has led to a reduction in ventricular size, as documented on sequential imaging studies. In patients with Cushing disease because of adrenal or basophilic pituitary tumors, mental changes suggestive of dementia and enlarged ventricles are unusual, especially by comparison to the incidence of these changes with exogenous corticosteroids. Here again, there is a peculiar combination of mood changes and impaired cognitive function. A frank psychosis may occur. This condition is described more completely in Chap. 49 and the attendant proximal myopathy, in Chap. 45.

Thyroid Encephalopathies Hyperthyroidism Allusions to psychosis in thyrotoxic patients are frequent in the medical literature. Mental confusion, seizures, manic or depressive attacks, and delusions occur singly or in combination. Action tremor is almost universal, and chorea occurs occasionally in various combinations with proximal muscular weakness. In descriptions of abnormal movements, it is often not clear whether it was chorea, tremor, myoclonus, or just fidgetiness that was observed. Treatment of the hyperthyroidism gradually restores the mental state to normal, leaving one with no explanation of what had happened to the CNS. The separate associations of hyperthyroidism with periodic paralysis and myasthenia are discussed in later chapters. Thyroid crisis or “storm” refers to a fulminant increase in the symptoms and signs of thyrotoxicosis—extreme restlessness, tachycardia, fever, vomiting, and diarrhea— leading to delirium or coma. In the past, this was a not uncommon postoperative event in patients poorly prepared for thyroid surgery. Now it is seen mainly in patients with inadequately treated or untreated thyrotoxicosis complicated by serious medical or surgical illness.

Hashimoto Encephalopathy (Steroid-Responsive Encephalopathy Syndrome) Brain and associates described an encephalopathy consisting of confusion, altered consciousness, and prominent myoclonus in patients with Hashimoto disease. The details have been elaborated by several authors (Shaw and colleagues and Chong and associates). Some cases have had a relapsing course over months or years. It is important to note that most have had normal thyroid function. There are

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in these cases, however, high titers of several antithyroid antibodies, particularly antibodies against thyroid peroxidase and thyroglobulin; some affected individuals have more than one such antibody. Ferracci and colleagues found evidence of the production of these antibodies in the nervous system and of their presence in spinal fluid. One must be cautious, however, in interpreting the presence of antithyroid antibodies in the blood, as they are detected in many people without an encephalopathy, particularly older women, and in two-thirds of patients with Graves disease. The most commonly observed syndrome is of confusion or stupor accompanied by multifocal myoclonus, but seizures—including myoclonic and rarely, nonconvulsive status epilepticus, may occur as well. Hemiparesis, ataxia, psychosis, and unusual tremors, including those of the palate, have been reported in individual cases as in the series reported by Castillo and colleagues; they found tremor, transient aphasia, myoclonus, ataxia, and seizures to be present in that order of frequency. Many had liver function abnormalities and one-fifth showed inflammatory changes in the CSF. Some of the reports included children. Often there are other members of the family with a different autoimmune disease. It has been the myoclonic aspect of the encephalopathy, a feature of all of the cases we have observed, which has usually led to consideration of this diagnosis. It is not uncommon for such cases to be mistaken for Creutzfeldt-Jakob disease (subacute spongiform encephalopathy). Early descriptions of the illness included a pleocytosis of the spinal fluid and white matter lesions, but we have not consistently noted these abnormalities. What limited pathology there is, in a case studied after 5 months of illness, has shown only nonspecific activation of microglia cells (Perrot and colleagues). Treatment  The encephalopathic symptoms and high titers of antithyroid antibodies respond well to steroid therapy (Chong and colleagues). In the case reported by Newcomer and associates, a rapid reversal of thyrotoxic coma (and corticospinal signs) was effected by plasma exchange, in parallel with a reduction in T4 and T3 levels, and similar results were reported by Boers and Colebatch. The circulating antibodies and the response to corticosteroids and plasma exchange implicate an immune pathogenesis, perhaps similar to paraneoplastic limbic encephalitis (see “Encephalomyelitis Associated with Carcinoma and Limbic Encephalitis” in Chap. 30) such as the encephalitis that may accompany ovarian teratoma, and to lupus.

Hypothyroidism As a rule, in the myxedematous patient, cognitive activity is slowed; in exceptional cases, there is a significant confusional state or stupor. When such changes have been observed, we have noted drowsiness, inattentiveness, and apathy as early features. In two cases observed by our colleagues, the somnolence was so extreme that the patients could not stay awake long enough to be fed or examined. They were in a state of hypothermic stupor but exhibited no other neurologic abnormality. In extreme form, the state progresses to “myxedema coma.” This state is often precipitated by stresses, particularly surgery and sepsis, mainly

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in the elderly. Hypothermia, hyponatremia and elevation of serum creatine kinase (CK) concentration, hypoventilation, and elevation of the CSF protein can be expected. The clinical state and laboratory abnormalities are reversed within a few days by thyroid medication. The treatment of myxedema coma has several refined aspects, including the need to administer thyroid hormone cautiously. Hypothyroidism is associated with a number of distinctive myopathic disturbances, which are discussed in Chap. 45. The ataxia and peripheral neuropathy that are sometimes observed in patients with myxedema were described earlier and in Chap. 43.

Neonatal Myxedema (Cretinism) This form of severe intrauterine hypothyroidism (in mother and fetus) or postnatally as a hereditary or acquired thyroid disease, is probably the most frequent and potentially preventable and correctable metabolic cause of encephalopathy in the world. Although the condition is most common in goitrous regions where there is a lack of iodine, it may also be the result of any of several genetically determined defects in thyroxin synthesis. In areas of endemic cretinism, additional factors may be operative, such as the widespread ingestion of cassava, which contains a toxic goitrogen that inhibits the uptake of iodine by the thyroid. The symptoms and signs of congenital thyroid deficiency are not usually recognizable at birth but become apparent only after a few weeks; more often the diagnosis is first made between the 6th and 12th months of life. Physiologic jaundice tends to have been severe and prolonged (up to 3 months), and this, along with widening of the posterior fontanelle and mottling of the skin, should raise suspicion of the disease. Two types of early life hypothyroidism are recognized— sporadic and endemic. The sporadic type occurs occasionally in developed countries (less than once in 4,000 live births) and is a consequence of a congenital metabolic or anatomic disorder of the thyroid gland. At birth, the gland is either absent or represented by cysts, indicating a failure of development or a destructive lesion. In the sporadic form, in the latter part of the first year, stunting of growth and delay in psychomotor development become evident. Untreated, the child is severely developmentally delayed but placid and good natured; such children sleep contentedly for longer periods than normal children. Sitting, standing, and walking are delayed. Movements are slow, and if tendon reflexes can be obtained, their relaxation time is clearly delayed. The body temperature is low, and the extremities are cold and cyanotic. Although the head is small, the fontanelles may not close until the sixth or seventh year, and there is delayed ossification. This type of hypothyroidism is preventable by treatment with thyroid hormone. Endemic cretinism is most common in developing countries, with an estimated incidence in some areas of 5 to 15 percent. DeLong and colleagues, based on epidemiologic surveys mainly in western China, have distinguished two forms of endemic cretinism: neurologic and myxedematous. The occurrence of the two different types

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is governed by the timing, duration, and severity of the iodine deficiency. The neurologic form of neonatal myxedema is characterized by varying degrees of deaf-mutism or lesser degrees of hearing loss, dysarthria, proximal limb and truncal rigid-spastic motor disorder involving mainly the lower extremities, and cognitive impairment of a characteristic type. In the most severely affected, there is also strabismus, kyphoscoliosis, underdevelopment of leg muscles, and frontal lobe release signs. Bone age, head size, and height are normal and there are none of the coarse facial features of the myxedematous form. In the myxedematous form of endemic cretinism, short stature, microcephaly, coarse facial features, and delayed psychomotor development are the main features. There is no deafness or spastic rigidity of the limbs. In typical instances, the face is pale and puffy; the skin dry; the hair coarse, scanty, and dry; the eyelids thickened; the thickened lips parted by the enlarged tongue; the forehead low; and the base of the nose broad. There are fat pads above the clavicles and in the axillae. The abdomen is protuberant, often with an umbilical hernia, and the head is small. DeLong and others attribute neurologic cretinism to a lack of available iodine in the mother and fetus during the second and third trimesters of pregnancy; neither mother nor fetus produces thyroxine. It is during the latter part of the second trimester, when the cochleas and the neuronal population of the cerebral cortex and basal ganglia are forming, that these structures suffer irreparable damage from lack of thyroid hormone. The effects of this mid-fetal hypothyroidism and iodine deficiency cannot be corrected by giving thyroid hormone at birth and thereafter. It can be prevented only by providing iodine therapy to the mother before and during the first trimester of pregnancy (Cao and colleagues). The myxedematous form of cretinism is more likely to occur from lack of thyroid hormone in the late second and the third trimesters. The congenital mental disorder ranges from apathy and absence of social interaction to an alert, cooperative state but slowness in higher-order thinking and verbal facility is always evident. The status of the thyroid gland varies; among patients with the neurologic features of cretinism, about half have goiters or have palpable glands; in the rest, the glands are atrophied; practically all patients with myxedematous cretinism are athyrotic. Although typical examples of neurologic and myxedematous hypothyroidism are readily distinguished, both types may exist in the same endemic area, and stigmata of both forms may be recognized in the same individual. The QRS complex of the ECG is of low voltage; the EEG is slower than normal, with less alpha activity; the CSF contains an excess of protein (50 to 150 mg/dL); and the serum T3 and T4, protein-bound iodine, and radioactive iodine uptake are all subnormal. Serum cholesterol is increased (300 to 600 mg/dL). At autopsy the brain of neurologic cretinism, although small, is normally formed, with all central and brainstem structures and cortical sulcation intact. A reduction in number of nerve cells was described by Marinesco, especially in the fifth cortical layer, but others have not confirmed this finding. The use of Golgi and other silver

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techniques has shown decreased interneuronal distances (packing density is increased, as in the immature cortex) where there is a deficiency of neuropil. The latter change is because of a poverty of dendritic branchings and crossings, and presumably there is a decrease of the synaptic surfaces of cells (Eayrs). Thyroid hormone appears to be essential, not for neuronal formation and migration but for dendritic–axonal development and organization. There is substantial evidence that the administration of iodized salt or iodinated vegetable oil or iodide tablets to populations of women who are at risk of iodine deficiency before and during the first trimester of pregnancy prevents sporadic and endemic cretinism. Treatment begun during the second trimester protects the fetal brain to a varying degree. Treatment that is started after the beginning of the third trimester does not improve the neurologic status, although head growth and statural development may improve slightly (Cao et al). In sporadic cretinism, if the condition is recognized at birth and treated consistently with thyroid hormones, height and mental development can be stimulated to normal or near-normal levels. The extent of recovery depends on the severity and duration of intrauterine hypothyroidism, that is, its duration before treatment was begun and the adequacy of therapy. In most patients, some degree of cognitive impairment persists throughout life.

“Pancreatic Encephalopathy” This term was introduced by Rothermich and von Haam in 1941 to describe what they considered to be a fairly uniform clinical state in patients with acute abdominal symptoms referable to pancreatic disease, mainly pancreatitis. The encephalopathy, as they described it, consisted of an agitated, confused state, sometimes with hallucinations and clouding of consciousness, dysarthria, and changing rigidity of the limbs—all of which fluctuated over a period of hours or days. Coma and quadriplegia have been reported. At autopsy, a variety of lesions have been described; two cases have had central pontine myelinolysis and others have had small foci of necrosis and edema, petechial hemorrhages, and “demyelination” scattered through the cerebrum, brainstem, and cerebellum. These have been uncritically attributed to the action of released lipases and proteases from the diseased pancreas. The term pancreatic encephalopathy is now more often applied to a depressive illness that seems to occur with disproportionate frequency before the symptoms of a pancreatic cancer become apparent. More common in our experience are numerous cases of pancreatic cancer and sequential cerebral emboli from nonbacterial thrombotic (marantic) endocarditis. The status of pancreatic encephalopathy, in the authors’ opinion, is uncertain. It has been suggested that before such a diagnosis can be entertained in a patient with acute pancreatitis, one must exclude delirium tremens, shock, renal failure, hypoglycemia, diabetic acidosis, hyperosmolality, and hypocalcemia or hypercalcemia— any one of which may complicate the underlying disease. Other cases conform to the encephalopathy of multiorgan failure, discussed earlier.

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References Adams RD, Foley JM: The neurological disorder associated with liver disease. Res Publ Assoc Res Nerv Ment Dis 32:198, 1953. Adams RD, Victor M, Mancall EL: Central pontine myelinolysis. Arch Neurol Psychiatry 81:154, 1959. Aikawa N, Shinozawa Y, Ishibiki K, et al: Clinical analysis of multiple organ failure in burned patients. Burns Incl Therm Inj 13:103, 1987. Alfrey AC, Legendre GR, Kaehny WD: The dialysis encephalopathy syndrome: Possible aluminum intoxication. N Engl J Med 294:184, 1976. Als-Nielsen B, Kjaergard LL, Gluud C: Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy. Cochrane Database Syst Rev 4:CD002798, 2001. Arieff AI: Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 314:1529, 1986. Arrich J, Holzer M, Havel C, et al: Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2:4128, 2016. Auer RN: Progress review: Hypoglycemic brain damage. Stroke 17:699, 1986. Austen FK, Carmichael MW, Adams RD: Neurologic manifestations of chronic pulmonary insufficiency. N Engl J Med 257:579, 1957. Basile AS, Hughes RD, Harrison PM, et al: Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med 325:473, 1991. Bass NM, Mullen KD, Sanyal A, et al: Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071, 2010. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557, 2002. Bhatia MP, Brown P, Gregory R, et al: Progressive myoclonic ataxia associated with coeliac disease. Brain 118:1087, 1995. Boers PM, Colebatch JG: Hashimoto’s encephalopathy responding to plasma-pheresis. J Neurol Neurosurg Psychiatr 70:132, 2001. Bolton C, Young GB, Zochodne DW: The neurological complications of sepsis. Ann Neurol 33:94, 1993. Booth CM, Boone RH, Tomlinson G, Detsky AS: Is this patient dead, vegetative, or severely impaired? JAMA 291:870, 2004. Brain L, Jellinek EH, Ball K: Hashimoto’s disease and encephalopathy. Lancet 2:512, 1966. Burcar PJ, Norenberg MD, Yarnell PR: Hyponatremia and central pontine myelinosis. Neurology 27:223, 1977. Burn DJ, Bates D: Neurology and the kidney. J Neurol Neurosurg Psychiatry 65:810, 1998. Butterworth RF, Giguiere JF, Michaud J, et al: Ammonia: Key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 6:1, 1987. Cao X-Y, Jian GX-M, Dou Z-H, et al: Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 331:1739, 1994. Castillo P, Woodruff B, Caselli R, et al: Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 63:197, 2006. Cavanagh JB: Liver bypass and the glia. Res Publ Assoc Res Nerv Ment Dis 53:13, 1974. Choi DW, Rothman SM: The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171, 1990. Choi IS: Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 40:433, 1983. Chong JY, Rowland LP, Utiger RD: Hashimoto encephalopathy: Syndrome or myth? Arch Neurol 60:164, 2003.

Ropper_Ch39_p1125-p1152.indd 1150

Cooke WT, Smith WT: Neurologic disorders associated with adult coeliac disease. Brain 89:683, 1966. Cremer GM, Goldstine NP, Paris J: Myxedema and ataxia. Neurology 19:37, 1969. Cross AH, Golumbek PT: Neurologic manifestations of celiac disease. Neurology 60:1566, 2003. Dahlquist NR, Perrault J, Callaway CW: D-Lactic acidosis and encephalopathy after jejunoileostomy: Response to overfeeding and to fasting in humans. Mayo Clin Proc 59:141, 1984. DeLong GR, Stanbury JB, Fierro-Benitez R: Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Dev Med Child Neurol 27:317, 1985. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, The Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 356:1842, 2007. Dooling EC, Richardson EP Jr: Delayed encephalopathy after strangling. Arch Neurol 33:196, 1976. Eayrs JT: Influence of the thyroid on the central nervous system. Br Med Bull 16:122, 1960. Farrell RJ, Kelly CP: Celiac sprue. N Engl J Med 346:180, 2002. Ferracci F, Morett OG, Candeago RM, et al: Antithyroid antibodies in the CSF. Their role in the pathogenesis of Hashimoto’s encephalopathy. Neurology 60:712, 2003. Finelli PF, McEntee WJ, Ambler M, Kestenbaum D: Adult celiac disease presenting as cerebellar syndrome. Neurology 30:245, 1980. Fischer JE, Baldessarini RJ: Pathogenesis and therapy of hepatic coma, in Popper H, Schaffner F (eds): Progress in Liver Disease. New York, Grune & Stratton, 1976, pp 363–397. Fishman RA: Cell volume, pumps and neurologic function: Brain’s adaptation to osmotic stress. Res Publ Assoc Res Nerv Ment Dis 53:159, 1974. Foley JM, Watson CW, Adams RD: Significance of the electroencephalographic changes in hepatic coma. Trans Am Neurol Assoc 51:161, 1950. Gomcelli YB, Kutku L, Cavdar L, et al: Different clinical manifestations of hyperammonemic encephalopathy. Epilepsy Behav 10:583, 2007. Hackett PH, Roach RC: High-altitude illness. N Engl J Med 345:107, 2001. Hadjivassiliou M, Grünewald RA, Chatopadhyay AK, et al: Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 352:1582, 1998. Hadjivassiliou M, Grünewald RA, Davies-Jones GA: Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 72:560, 2002. Hallert C, Astrom J: Psychic disturbances in adult celiac disease: II. Psychological findings. Scand J Gastroenterol 17:21, 1982. Hallert C, Deerefeldt T: Psychic disturbances in adult celiac disease: I. Clinical manifestations. Scand J Gastroenterol 17:17, 1982. Harrison TR, Mason MF, Resnick H: Observations on the mechanism of muscular twitchings in uremia. J Clin Invest 15:463, 1936. Herrera L, Kazemi H: CSF bicarbonate regulation in metabolic acidosis: Role of HCO3 formation in CSF. J Appl Physiol 49:778, 1980. Hornbein TF, Townes BD, Schoene RB, et al: The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med 321:1714, 1989. Huttenlocher P, Trauner D: Reye’s syndrome in infancy. Pediatrics 62:84, 1978.

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Chapter 39 The Acquired Metabolic Disorders of the Nervous System Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:549, 2002. Jellinek EH, Kelly RE: Cerebellar syndrome in myxedema. Lancet 2:225, 1960. Johnson GM, Scurletis TD, Carroll NB: A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 24:464, 1963. Jones EA, Basile AS: Does ammonia contribute to increased GABAergic neurotransmission in liver failure? Metab Brain Dis 13:351, 1998. Junker AE, Als-Nielsen B, Gluud C, et al: Dopamine agents for hepatic encephalopathy. Cochrane Database Syst Rev 2:CD003047, 2014. Karp BI, Laureno R: Pontine and extrapontine myelinolysis: A neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 72:359, 1993. Krane EJ, Rockoff MA, Wallman JK, Walsdorf HU: Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med 312:1147, 1985. Kreiger D, Kreiger S, Jansen O, et al: Manganese and chronic hepatic encephalopathy. Lancet 346:270, 1995. Lance JW, Adams RD: The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 87:111, 1963. Laureno R: Central pontine myelinolysis following rapid correction of hyponatremia. Ann Neurol 13:232, 1983. Lederman RS, Henry CE: Progressive dialysis encephalopathy. Ann Neurol 4:199, 1978. Levy DE, Caronna JJ, Singer BH, et al: Predicting outcome from hypoxic-ischemic coma. JAMA 253:1420, 1985. Lidofsky SD, Bass NM, Prager MC, et al: Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology 16:1, 1992. Lyon G, Dodge PR, Adams, RD: The acute encephalopathies of obscure origins in infants and children. Brain 84:680, 1961. Maddrey WC, Weber FL Jr, Coulter AW, et al: Effects of keto analogues of essential amino acids in portal-systemic encephalopathy. Gastroenterology 71:190, 1976. Malamud N, Haymaker W, Custer RP: Heat stroke: A clinic pathologic study of 125 fatal cases. Mil Surg 99:397, 1946. Malouf R, Brust JCM: Hypoglycemia: Causes, neurological manifestations, and outcome. Ann Neurol 17:421, 1985. Marinesco G: Lesions en myxoedeme congenitale avec idiotie. Encephale 19:265, 1924. Marshall JR: Neuropsychiatric aspects of renal failure. J Clin Psychiatry 40:181, 1979. McDermott W, Adams RD: Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia. J Clin Invest 33:1, 1954. McKee AC, Winkelman MD, Banker BQ: Central pontine myelinolysis in severely burned patients: Relationship to serum hyperosmolality. Neurology 38:1211, 1988. Momose KJ, Kjellberg RN, Kliman B: High incidence of cortical atrophy of the cerebral and cerebellar hemisphere in Cushing’s disease. Radiology 99:341, 1971. Morgan MY, Jakobovits AW, James IM, Sherlock S: Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy. Gastroenterology 78:663, 1980. Mullen KD: Benzodiazepine compounds and hepatic encephalopathy. N Engl J Med 325:509, 1991. Myers RAM, Snyder SK, Emhoff TA: Subacute sequelae of carbon monoxide poisoning. Ann Emerg Med 14:1163, 1985. Naylor CD, O’Rourke K, Detsky AS, Baker JP: Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy: A meta-analysis. Gastroenterology 97:1033, 1989.

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Nelson PB, Seif SM, Maroon JC, Robinson AG: Hyponatremia in intracranial disease: Perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg 55:938, 1981. Newcomer J, Haire W, Hartman CR: Coma and thyrotoxicosis. Ann Neurol 14:689, 1983. Nielsen N, Wetterslev J, Cronberg T, et al: Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 369:2197, 2013. Norenberg MD: Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis 13:319, 1998. Oppenheimer BS, Fishberg AM: Hypertensive encephalopathy. Arch Intern Med 41:264, 1928. Pant SS, Rebeiz J, Richardson EP: Spastic paraparesis following portacaval shunt. Neurology 18:134, 1968. Parkinson IS, Ward MK, Kerr DNS: Dialysis encephalopathy, bone disease and anemia: The aluminum intoxication syndrome during regular hemodialysis. J Clin Pathol 34:1285, 1981. Perrot X, Firaud P, Biacabe A-G, et al: Encephalopathie d’Hashimoto: Une observation anatomo-clinique. Rev Neurol 158:461, 2002. Plum F, Posner JB, Hain RF: Delayed neurological deterioration after anoxia. Arch Intern Med 110:18, 1962. Pomier-Layrargues G, Rose C, Spahr L, et al: Role of manganese in the pathogenesis of portal-systemic encephalopathy. Metab Brain Dis 13:311, 1998. Price TR, Netsky MG: Myxedema and ataxia: Cerebellar alterations and “neural myxedema bodies.” Neurology 16:957, 1966. Raskin NH, Fishman RA: Neurologic disorders in renal failure. N Engl J Med 294:143, 204, 1976. Reye RDK, Morgan G, Baral J: Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 2:749, 1963. Rothermich NO, von Haam E: Pancreatic encephalopathy. J Clin Endocrinol 1:872, 1941. Rothstein JD, Herlong HF: Neurologic manifestations of hepatic disease. Neurol Clin 7:563, 1989. Sahney A, Sharma BC, Jindal A, et al: A double-blind randomized controlled trial to assess efficacy of bromocriptine in cirrhotic patients with hepatic parkinsonism. Liver Int 39:684, 2019. Schenone AL, Cohen A, Patarroyo G, et al: Therapeutic hypothermia after cardiac arrest: A systematic review/meta-analysis exploring the impact of expanded criteria and targeted temperature. Resuscitation 108:102, 2016. Schoch HJ, Fischer S, Marti HH: Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 125:2549, 2002. Shaw PJ, Walls TJ, Neman MB, et al: Hashimoto’s encephalopathy: A steroid-responsive disorder associated with high anti-thyroid antibody titers—report of 5 cases. Neurology 41:228, 1991. Shaywitz BA, Rothstein P, Venes JL: Monitoring and management of increased intracranial pressure in Reye syndrome: Results in 29 children. Pediatrics 66:198, 1980. Sterns RH, Riggs JE, Schochet SS: Osmotic demyelination syndromes following correction of hyponatremia. N Engl J Med 314:1535, 1986. Summerskill WHJ, Davidson EA, Sherlock S, Steiner RE: The neuropsychiatric syndrome associated with hepatic cirrhosis and extensive portal collateral circulation. Q J Med 25:245, 1956. Thomas PK, King RH, Feng SF, et al: Neurological manifestations in chronic mountain sickness: The burning feet–burning hands syndrome. J Neurol Neurosurg Psychiatry 69:447, 2000. Trauner DA: Treatment of Reye syndrome. Ann Neurol 7:2, 1980. van Woerkom W: La cirrhose hepatique avec alterations dans les centres nerveux evoluant chez des sujets d’age moyen. Nouv Iconogr Salpétrière 27:41, 1914.

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Victor M, Adams RD, Cole M: The acquired (non-Wilsonian) type of chronic hepatocerebral degeneration. Medicine (Baltimore) 44:345, 1965. Victor M, Laureno R: Neurologic complications of alcohol abuse: Epidemiologic aspects, in Schoenberg BS (ed): Advances in Neurology. Vol 19. New York, Raven Press, 1978, pp 603–617. Volhard F: Clinical aspects of Bright’s disease, in Berglund H, Medes G, Huber CG, et al (eds): The Kidney in Health and Disease. Philadelphia, Lea & Febiger, 1935, pp 665–673. von Hosslin C, Alzheimer A: Ein Beitrag zur Klinik und pathologischen Anatomie der Westphal-Strumpellschen Pseudosklerose. Z Gesamte Neurol Psychiatr 8:183, 1912. Weaver LK: Carbon monoxide poisoning. N Engl J Med 360:1217, 2009. Weaver LK, Hopkins RO, Chan KJ, et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 347:1057, 2002. Wegierko J: Typical syndrome of clinical manifestations in diabetes mellitus with fatal termination in coma without ketotic acidemia: So-called third coma. Pol Tyg Lek (Wars) 11:2020, 1956. Weiner WJ, Klawans HL: Hyperthyroid chorea, in Vinken PJ, Bruyn BW (eds): Handbook of Clinical Neurology. Vol 27: Metabolic

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and Deficiency Diseases of the Nervous System. Part I. Amsterdam, North-Holland, 1976, pp 279–281. Wijdicks EFM, Plevak DJ, Rakela J, Wiesner RH: Clinical and radiologic features of cerebral edema in fulminant hepatic failure. Mayo Clin Proc 70:119, 1995. Wilkinson DS, Prockop LD: Hypoglycemia: Effects on the nervous system, in Vinken PJ, Bruyn BW (eds): Handbook of Clinical Neurology. Vol 27: Metabolic and Deficiency Diseases of the Nervous System. Part I. Amsterdam, North-Holland, 1976, pp 53–78. Wilson SAK: Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 34:295, 1912. Winkelman MD, Ricanati ES: Dialysis encephalopathy: Neuropathologic aspects. Hum Pathol 17:823, 1986. Wright DG, Laureno R, Victor M: Pontine and extrapontine myelinolysis. Brain 102:361, 1979. Young E, Bradley RF: Cerebral edema with irreversible coma in severe diabetic ketoacidosis. N Engl J Med 276:665, 1967. Zieve L: Pathogenesis of hepatic encephalopathy. Metab Brain Dis 2:147, 1987.

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40 Diseases of the Nervous System Caused by Nutritional Deficiency

Among nutritional disorders, those of the nervous system occupy a position of special interest and importance. The early studies of beriberi at the turn of the 20th century were largely responsible for the discovery of thiamine and, consequently for the modern concept of diseases of nutritional deficiency. A series of notable achievements in the science of nutrition followed the discovery of vitamins. Despite such progress, diseases caused by nutritional deficiency, and particularly those of the nervous system, continue to represent a worldwide health problem of serious proportions. In communities where the diet consists mainly of highly milled rice, there is still a significant incidence of beriberi. In some countries, deficiency diseases are endemic, the result of chronic dietary deprivation. And the ultimate effects on the nervous system of intermittent mass starvation remain an alarming medical and humanitarian crisis. In addition to nutritional deprivation from poverty, other clinical circumstances in which nutritional deficiency can arise are alcoholism, dietary faddism, impaired absorption of dietary nutrients that occurs in conditions such as celiac sprue and pernicious anemia, and the wasting syndromes of cancer and HIV. Surgical excision of portions of the gastrointestinal tract for the treatment of obesity has emerged has an important cause of nutritional deficiency. Finally, there are iatrogenic deficiencies induced by the use of vitamin antagonists or certain drugs, such as methotrexate or isonicotinic acid hydrazide (INH), which interferes with the enzymatic function of pyridoxine.

General Considerations The term deficiency is used throughout this chapter in its strictest sense to designate disorders that result from the lack of an essential nutrient or nutrients in the diet or from a conditioning factor that increases the need for these nutrients. The most important of these are the vitamins, especially members of the B group—thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), and cobalamin (B12). While some disorders can be attributed to a single vitamin deficiency, such as thiamine deficiency causing Wernicke disease and vitamin B12 deficiency causing subacute combined degeneration (SCD) of the spinal cord, other disorders are the result of multiple nutritional deficiencies. Characteristic of nutritional diseases is the potential for involvement of both

the central and peripheral nervous systems, an attribute shared only with certain metabolic disorders. In many cases, vitamin deprivation occurs in the context of general undernutrition, and multisystem effects such as circulatory abnormalities and loss of subcutaneous fat and muscle bulk are usually associated. A total lack of vitamins, therefore, as occurs in starvation, is rarely associated with the classic deficiency syndromes of beriberi or pellagra. In other words, a certain amount of food is necessary to produce the disorders associated with a single vitamin deficiency. In a similar way, excessive intake of carbohydrates relative to the supply of thiamine favors the development of a thiamine-deficiency state. All deficiency diseases, including those of the nervous system, are influenced by factors such as exercise, growth, pregnancy, neoplasia, and systemic infection, which increase the need for essential nutrients, and by disorders of the liver and the gastrointestinal tract, which may interfere with the synthesis and absorption of these nutrients. As already mentioned, alcoholism is an important factor in the causation of nutritional diseases of the nervous system. Alcohol acts mainly by displacing food in the diet but also by adding carbohydrate calories (alcohol is burned almost entirely as carbohydrates), thus increasing the need for thiamine. There is some evidence as well that alcohol impairs the absorption of thiamine and other vitamins from the gastrointestinal tract. In infants and young children, a reduction in protein and caloric intake (so-called protein-calorie malnutrition) has a devastating effect on body growth. Whether or not protein-calorie malnutrition also hinders the growth of the brain, with consequent effects on intellectual and behavioral development, cannot be answered as readily. The data bearing on this matter are discussed in the last part of this chapter. Some comments will also be made in this chapter about the rare hereditary vitamin-responsive diseases. There are several distinctive neurologic disorders in which nutritional deficiency may partly contribute are discussed in other chapters. These include “alcoholic” cerebellar degeneration (Chap. 41) and central pontine and extrapontine myelinolysis (Chap. 39). Deficiencies of trace elements, because of their rarity, are not discussed; only iodine deficiency (cretinism) is of much importance in humans, and it was discussed in Chap. 39 on acquired metabolic diseases.

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WERNICKE-KORSAKOFF SYNDROME (THIAMINE [B1] DEFICIENCY) Wernicke disease and the Korsakoff amnesic state are common neurologic disorders that have been recognized since the 1880s. Wernicke disease is characterized by nystagmus, abducens and conjugate gaze palsies, ataxia of gait, and confusion. These symptoms develop acutely or subacutely and usually occur in varying combinations. Wernicke disease is specifically the result of a deficiency of thiamine. The Korsakoff amnesic state (Korsakoff psychosis) is a disorder in which retentive memory is impaired out of proportion to all other cognitive functions in an otherwise alert and responsive patient. This amnesic disorder, like Wernicke disease, is most often associated with the thiamine deficiency of alcoholism and malnutrition, but it may be a symptom of various other non-nutritional diseases that have their basis in structural lesions of the medial thalami or the hippocampal portions of the temporal lobes, such as infarction in the territory of branches of the posterior cerebral arteries, hippocampal damage after cardiac arrest, third ventricular tumors, and herpes simplex encephalitis. An almost equivalent type of memory disturbance may also follow acute lesions of the basal septal nuclei of the frontal lobe. Transient impairments of retentive memory of the Korsakoff type may be the salient manifestations of temporal lobe epilepsy, concussive head injury, and a transient global amnesia. The anatomic basis of the Korsakoff amnesic syndrome is described in Chap. 20. In the nutritionally deficient patient, Korsakoff amnesia is usually associated with and immediately follows the occurrence of Wernicke disease. For this reason and others elaborated in the following text, the term Wernicke disease or Wernicke encephalopathy is applied to a symptom complex of ophthalmoparesis, nystagmus, ataxia, and an acute apathetic–confusional state. If an enduring defect in learning and memory results, as it often does, the symptom complex is designated as the Wernicke-Korsakoff syndrome. It is perhaps in part due to the emphasis in previous editions of this book that alcoholism has been inordinately associated with this disease complex. The disease arises in many other clinical settings. One of Wernicke’s original cases, for example, occurred in a woman with hyperemesis gravidarum and such instances are still found. However, bariatric surgery, cancer chemotherapy, inanition in HIV and from anorexia nervosa, and even in the frailty of older age, in nutritionally susceptible persons, starvation for economic and social reasons all may give rise to thiamine deficiency. Even the elderly and frail who subsist for years on “tea and toast” can acquire the disease. In addition, there are common medical circumstances in which a subclinical thiamine deficiency becomes manifest. Perhaps the most important of these is a carbohydrate load, particularly the administration of intravenous glucose to a malnourished individual; other precipitants are unbalanced intravenous hyperalimentation, refeeding syndrome, thyrotoxicosis, and hypomagnesemia.

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Autopsy studies demonstrate that many cases of Wernicke disease are undiagnosed. As summarized in the review by Sechi and Serra of published series from several countries, there is a discrepancy between the detection of the process in autopsy series, 0.5 to 3 percent, and the prevalence of the clinical diagnosis, 0.04 to 0.13 percent, indicating that approximately three-quarters of cases are not recognized during life. Historical note  In 1881, Carl Wernicke first described an illness of sudden onset characterized by paralysis of eye movements, ataxia of gait, and mental confusion. His observations were made in 3 patients, of whom 2 had alcohol dependency and malnutrition and 1 was a young woman with persistent vomiting following the ingestion of sulfuric acid. In each of these patients, there was progressive stupor and coma culminating in death. The pathologic changes described by Wernicke consisted of punctate hemorrhages affecting the gray matter around the third and fourth ventricles and aqueduct of Sylvius; he considered these changes to be inflammatory in nature and confined to the gray matter, hence his designation “polioencephalitis hemorrhagica superioris.” In the belief that Gâyet had described an identical disorder in 1875, the term Gâyet-Wernicke is used frequently by French authors. Such a designation is hardly justified insofar as the clinical signs and pathologic changes in Gâyet’s patients differed from those of Wernicke’s patients in all essential details. The first comprehensive account of this disorder was given by the Russian psychiatrist SS Korsakoff in a series of articles published between 1887 and 1891 (for English translation and commentary, see Victor and Yakovlev). Korsakoff stressed the relationship between “neuritis” (a term used at that time for all types of peripheral nerve disease) and the disorder of memory seen in patients with alcoholism, which he believed to be “two facets of the same disease” and which he called “psychosis polyneuritica.” But he also made the point that neuritis need not accompany the amnesic syndrome and that both disorders could affect nonalcoholic as well as alcoholic patients. His clinical descriptions were remarkably complete and have not been surpassed to the present day. It is of interest that the relationship between Wernicke disease and Korsakoff polyneuritic psychosis was appreciated neither by Wernicke nor by Korsakoff. It was Murawieff, in 1897, who first postulated that a single cause was responsible for both. The intimate clinical relationship was established by Bonhoeffer in 1904, who stated that in all cases of Wernicke disease, he found neuritis and amnesic psychosis. Confirmation of this relationship on pathologic grounds came much later. For further details, the reader is referred to the extensive monograph by Victor and colleagues (1989).

Clinical Features The incidence of the Wernicke-Korsakoff syndrome cannot be stated with precision, but it had been a common disorder, as noted in the introductory comments. At the Cleveland Metropolitan General Hospital, for example, in a consecutive series of 3,548 autopsies in adults (for the period 1963 to 1976), our colleague M. Victor (1990) found

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Chapter 40 Diseases of the Nervous System Caused by Nutritional Deficiency

pathognomonic lesions in 77 cases (2.2 percent). The disease affects males slightly more often than females, and the age of onset is fairly evenly distributed between 30 and 70 years. In the past few decades, the incidence of the Wernicke-Korsakoff syndrome has fallen in the alcoholic population, but it is being recognized with increasing frequency among nonalcoholic patients in a variety of clinical settings that are prone to include malnutrition, including iatrogenic ones. The triad of clinical features described by Wernicke of ophthalmoplegia (with nystagmus), ataxia, and disturbances of mentation and consciousness is still clinically useful provided that the signs are carefully sought, and one recognizes that all features will not be present. The disease may begin with ataxia, followed in a few days or weeks by mental confusion, or there may be confusion alone or the more or less simultaneous onset of ataxia, nystagmus, and ophthalmoparesis with or without confusion. In approximately one-third of cases, one component of this triad may be the sole manifestation of the disease. Timely treatment with thiamine can prevent the permanent Korsakoff-amnesic component of the disease. A tabular representation of the various features is shown in Table 40-1, adapted from the series of 131 autopsied proved cases described by Harper and colleagues. The notable aspects are that all 3 of the typical signs were present in only 16 percent; 1 sign in 37 percent, usually confusion alone; 2 signs in 28 percent; and no signs reported or detected during life in 19 percent. A description of each of the major manifestations follows. Eye movement abnormalities  The diagnosis of Wernicke disease is made most readily on the basis of the ocular signs. These consist of (1) nystagmus that is both horizontal and vertical and mainly gaze-evoked, (2) weakness or paralysis of the lateral rectus muscles, and (3) weakness or paralysis of conjugate gaze. Usually, there is some combination of these abnormalities (see Chap. 13). Nystagmus is the most frequent eye movement abnormality seen in Wernicke’s disease, followed in frequency by

Table 40-1 CLINICAL FEATURES OF WERNICKE-KORSAKOFF DISEASE CLINICAL PRESENTATION

One Sign

Two Signs

Three Signs No Signs

Confusion Eye Movement Abnormalities Ataxia Confusion + Ataxia Confusion + Eye Movement Abnormalities Eye Movement Abnormalities + Ataxia Confusion + Eye Movement Abnormalities + Ataxia

INCIDENCE

34% 2.1% 1.0% 17.5% 8.2% 2.1% 16.5% 18.6%

(Adapted from Harper CG, Giles M, Finlay-Jones R: J Neurol Neurosurg Psychiatry. 49:341–345, 1986.)

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lateral rectus weakness, which is bilateral but not necessarily symmetrical. With complete paralysis of the lateral rectus muscles, nystagmus is absent in the abducting eyes and it becomes evident as the weakness improves under treatment. The palsy of conjugate gaze varies from merely a paretic nystagmus on extreme gaze to a complete loss of ocular movement in horizontal or vertical movements. Horizontal conjugate gaze palsy is more common than vertical gaze palsy, and isolated paralysis of downward gaze is a known but unusual manifestation. A pattern that simulates internuclear ophthalmoplegia has also been seen. In advanced stages of the disease, there may be a complete loss of ocular movements and the pupils, which are otherwise usually spared, may become miotic and nonreacting. Ptosis, small retinal hemorrhages, involvement of the near– far focusing mechanism, and evidence of optic neuropathy occur occasionally, but neither we nor our colleagues have observed papilledema that was included in Wernicke’s original description. These ocular signs are highly characteristic of Wernicke disease and the disappearance of nystagmus and an improvement in ophthalmoparesis within hours or a day of the administration of thiamine confirms the diagnosis. Ataxia  In the acute stage of the disease, the ataxia of stance and gait may be so severe that the patient cannot stand or walk without support. Lesser degrees are characterized by a wide-based stance and a slow, uncertain, short-stepped gait; the mildest degrees are apparent only in tandem walking. In contrast to the gross disorder of locomotion is a relatively infrequent limb ataxia and of intention tremor; when present, they are more likely to be elicited by heel-to-knee than by finger-to-nose testing. Dysarthric, cerebellar-type scanning speech is present only rarely. Disturbances of consciousness and mentation These occur in some form in all but 10 percent of patients who have clinical signs. From Table 40-1, it can also be appreciated that when there is only one sign of Wernicke disease, it is usually a confusional state. Several related types of disturbed mentation and consciousness are recognized. By far, the most common disturbance is a global confusional state. The next following in frequency is memory loss discussed as follows. The patient is apathetic, inattentive, and indifferent to his surroundings. Spontaneous speech is minimal and many questions are left unanswered, or the patient may suspend conversation and drift off to sleep, although he can be aroused without difficulty. Such questions as are answered betray disorientation in time and place, misidentification of those around him, and an inability to grasp the immediate situation. Many of the patient’s remarks may be irrational and lack consistency from one moment to another. If the patient’s interest and attention can be maintained long enough to permit adequate testing, one finds that memory and learning ability are also impaired, in this way blending into the Korsakoff state. In response to the administration of thiamine, the patient rapidly becomes more alert and attentive and more capable of taking part in mental testing. If, however, the state persists for a longer duration before thiamine is administered, the most

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prominent lasting abnormality becomes one of retentive memory (Korsakoff-amnesic state). Although drowsiness is a common feature of the Wernicke confusional state, more significant stupor and coma are rare as initial manifestations. If, however, the early signs of the disease are not recognized and the patient remains untreated, a progressive depression of the state of consciousness occurs with stupor, coma, and death in a matter of a week or two, just as occurred in Wernicke’s original cases. Autopsy series of Wernicke disease are heavily weighted with cases of this latter type, often undiagnosed during life (Harper; Torvik and colleagues). Some patients are alert and responsive from the time they are first seen and already show the characteristic features of the Korsakoff amnesic state. In a small number of such patients, the amnesic state is the only manifestation of the syndrome, and no ocular or ataxic signs (other than possibly nystagmus) can be discerned. The amnesic state  As indicated in Chap. 20, the core of the amnesic disorder is a defect in learning (anterograde amnesia) and a loss of past memories (retrograde amnesia). The defect in learning can be remarkably severe. The patient may be incapable, for example, of committing to memory the simplest of facts (such as the examiner’s name, the date, and the time of day) despite countless attempts; the patient can repeat each fact as it is presented, indicating that he understands what is wanted of him and that “registration” is intact, but by the time the third fact is repeated, the first may have been forgotten. However, certain nonverbal learning may take place; for example, with repeated trials, the patient may learn complex tasks such as mirror writing or how to negotiate a maze, despite no recollection of ever having been confronted with these tasks. Anterograde amnesia is always coupled with a disturbance of past or remote memory (retrograde amnesia). The latter disorder is usually severe in degree, although not complete, and covers a period that antedates the onset of the illness by up to several years. A few isolated events and information from the past are retained, but these are related without regard for the intervals that separated them or for their proper temporal sequence. Usually, the patient “telescopes” events into a brief period of time; sometimes, the opposite occurs. This aspect of the memory disorder becomes prominent as the initial confusional stage of the illness subsides. It is probably true that memories of the recent past are more severely impaired than those of the remote past (the rule of Ribot); language, computation, knowledge acquired in school, and all habitual actions are preserved. This is not to say that all remote memories are intact. As discussed in Chap. 20, these are not as readily tested as more recent memories, making the two difficult to compare. It is our impression that there are gaps and inaccuracies in memories of the distant past in practically all cases of the Korsakoff amnesic state and serious impairments in many. The cognitive impairment of the Korsakoff patient is not exclusively one of memory loss. Psychologic testing discloses that certain cognitive and perceptual functions that depend little or not at all on retentive memory are also impaired. As a rule, the Korsakoff patient has no insight into his illness and is characteristically apathetic

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and inert, lacking in spontaneity and initiative, and indifferent to everything and everybody around him. However, the patient has a relatively normal capacity to reason with data immediately before him. Confabulation had in the past been considered to be a specific feature of Korsakoff psychosis, but the validity of this view depends largely on how one defines confabulation, and there is no uniformity of opinion on this point. The observations of Victor and his colleagues (1959) do not support the oft-repeated statement that the Korsakoff patient fills the gaps in his memory with confabulation. In the sense that gaps in memory exist and that whatever the patient supplies in place of the correct answers fill these gaps, the statement is incontrovertible. It is hardly explanatory, however. The implication that confabulation is a deliberate attempt to hide the memory defect, out of embarrassment or for other reasons, is incorrect. In fact, the opposite seems to pertain: As the patient improves and becomes more aware of a defect in memory, the tendency to confabulate diminishes. Furthermore, confabulation can be associated with both phases of the Wernicke-Korsakoff syndrome: The initial one in which profound general confusion dominates the disease and the convalescent phase in which the patient recalls fragments of past experience in a distorted fashion. Events that were separated by long intervals are juxtaposed or related out of sequence so that the narrative has an implausible or fictional aspect. In the chronic state of the disease, confabulation is usually absent. These and other aspects of confabulation are discussed fully in the monograph by Victor and colleagues (1959). Other clinical abnormalities  Approximately 15 percent of patients show signs of alcohol withdrawal—that is, hallucinations and other disorders of perception, confusion, agitation, tremor, and overactivity of autonomic nervous system function. These symptoms are evanescent in nature and usually mild. As Korsakoff pointed out, signs of peripheral neuropathy are common, found in more than 80 percent of patients with the Wernicke-Korsakoff syndrome. In most, the neuropathic disease is mild and does not account for the disorder of gait, but in some, it may be severe and particularly painful. In a small number, retrobulbar optic neuropathy is added. Despite the frequency of peripheral neuropathy, overt signs of beriberi heart disease are rare. However, indications of disordered cardiovascular function, such as tachycardia, exertional dyspnea, postural hypotension, and minor electrocardiographic abnormalities, are frequent; occasionally, the patient dies suddenly following only slight exertion. These patients may show an elevation of cardiac output associated with low peripheral vascular resistance and abnormalities that revert to normal after the administration of thiamine. Postural hypotension and syncope are common findings in Wernicke disease and are probably a result of impaired function of the autonomic nervous system, more specifically to a defect in the sympathetic outflow (Birchfield). There may be mild hypothermia, loss of libido, and erectile dysfunction. Patients with the Korsakoff amnesic state may have demonstrably impaired olfactory discrimination. This deficit, like the notable apathy present in most Wernicke’s

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Chapter 40 Diseases of the Nervous System Caused by Nutritional Deficiency

patients, is probably attributable to a lesion of the mediodorsal nucleus of the thalamus and its connections, and not to a lesion of the peripheral olfactory system (Mair and colleagues). Vestibular function, as measured by the response to standard ice-water caloric tests, is universally impaired in the acute stage of Wernicke disease (Ghez), but vertigo is not a complaint. This vestibular paresis probably accounts for the severe disequilibrium in the initial stage of the illness.

Laboratory Findings The acute lesions of the Wernicke-Korsakoff syndrome in the mammillary bodies and other medial thalamic and periaqueductal areas can be demonstrated in most cases by magnetic resonance imaging (MRI) (Donnal and colleagues; Varnet and colleagues). The changes are most apparent on the fluid-attenuated inversion recovery (FLAIR), T2, and diffusion-weighted sequences (if there is necrosis), but they may also enhance following the administration of contrast material, as shown in Fig. 40-1. It is not clear to what extent gradient-echo or susceptibilityweighted MRI can be expected to consistently reveal the small hemorrhagic lesions of the diencephalon and periventricular areas. Imaging is particularly useful in patients in whom stupor or coma has supervened or in whom ocular and ataxic signs are otherwise inevident (Victor, 1990), but in milder cases, a normal MRI does not preclude the diagnosis. The typical MRI changes are observed in

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only 58 percent of cases (Weidauer and colleagues). In the chronic state, the mammillary bodies may be shrunken if measured by volumetric techniques (Charness and DeLaPaz). The cerebrospinal fluid (CSF) in uncomplicated cases of the Wernicke-Korsakoff syndrome is normal or shows only a modest elevation of the protein content. Protein values greater than 100 mg/dL or a pleocytosis indicates the presence of a complicating illness such as subdural hematoma, meningeal infection, or encephalitis. Measurements of serum thiamine and red blood cell transketolase have been explored as aids to diagnosis but are not sufficiently sensitive for clinical use and they are not readily available. Before treatment with thiamine, patients with Wernicke disease show a marked reduction in functional transketolase activity. Restoration of these values and of thiamine di- and triphosphate toward normal occurs within a few hours of the administration of thiamine, and completely normal values are usually attained within 24 h. There are suggestions that there is a hereditary factor in the susceptibility of Wernicke-Korsakoff disease and possibly explains why only a small proportion of nutritionally deficient alcoholic patients develop this disease. Candidates for this variability have been proposed to be in transketolase activity or in the thiamine transporter gene, possibly on an epigenetic basis, but other genetic regions have been studied and no consistent genetic associations have emerged. Approximately half of the patients with WernickeKorsakoff disease show EEG abnormalities, consisting of diffuse mild to moderate slow activity. Total cerebral blood flow and cerebral oxygen and glucose consumption may be reduced in the acute stages of the disease and may still be present after several weeks of treatment (Shimojyo and colleagues). These observations indicate that significant reductions in brain metabolism need not be reflected in EEG abnormalities or in depression of the state of consciousness and that the latter is more a function of the location of the lesion than of the overall degree of metabolic defect.

Course of the Illness

Figure 40-1.  Axial T1-postgadolinium image of a 63-year-old woman with Wernicke encephalopathy showing abnormal enhancement of the mammillary bodies (arrow).

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The mortality rate in the acute phase of Wernicke disease was 17 percent in the series of patients collected by Victor and colleagues (1989) many decades ago. The fatalities were attributable mainly to hepatic failure and infection (pneumonia, pulmonary tuberculosis, and septicemia being at that time the most common). Some deaths were undoubtedly a result of the cerebral or cardiac effects of thiamine deficiency that had reached an irreversible stage. Most patients respond in a fairly predictable manner to the administration of thiamine, as detailed further on. The most dramatic improvement is in the ocular manifestations. Recovery often begins within hours or sooner after the administration of thiamine and practically always within several days. This effect is so constant that a failure of the nystagmus and ocular palsies to respond to thiamine should raise doubts about the diagnosis of Wernicke disease. Horizontal nystagmus sometimes disappears in minutes. Sixth-nerve palsies, ptosis, and vertical gaze palsies recover completely within a week or two in most cases,

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but vertical nystagmus may sometimes persist for several months. Horizontal gaze palsies usually recover completely, but in 60 percent of cases, a fine horizontal nystagmus remains as a permanent sequela. In this respect, horizontal nystagmus is unique among the ocular signs. In comparison with the ocular signs, improvement of ataxia is delayed. Approximately 40 percent of patients recover completely from ataxia. The remaining patients recover incompletely or not at all and are left with a slow, shuffling, wide-based gait and inability to walk tandem. The residual gait disturbances and horizontal nystagmus provide a means of identifying obscure and chronic cases of dementia as alcoholic-nutritional in origin. Vestibular function improves at about the same rate as the ataxia of gait, and recovery is usually but not always complete. The early symptoms of apathy, drowsiness, and global confusion invariably recede, and as they do the defect in memory and learning stands out more clearly. However, the memory disorder, once established, recovers completely or almost completely in only 20 percent of patients. The remainder is left with varying degrees of permanent Korsakoff amnesia. It is apparent from the foregoing account that Wernicke disease and Korsakoff amnesia are not separate diseases but that the ocular and ataxic signs and the transformation of the global confusional state into an amnesic syndrome are successive stages in a single disease process. In the series of Victor and colleagues (1989), of 186 patients who survived the acute illness, 157 (84 percent) showed this sequence of clinical events. As a corollary, a survey of patients with alcoholism and Korsakoff amnesia in a psychiatric hospital disclosed that in most patients, the illness had begun with the symptoms of Wernicke disease and that approximately 60 percent of them still showed some ocular or cerebellar stigmata of Wernicke disease many years after the onset. The same continuum cannot be invoked to explain alcoholic-nutritional cerebellar degeneration that arises as an independent illness rather than the persistent ataxia of Wernicke disease (see further on and Victor and Adams [1961] and monograph by Victor and Adams).

Neuropathologic Findings Patients who die in the acute stages of Wernicke disease show symmetrical lesions in the paraventricular regions of the thalamus and hypothalamus, mammillary bodies, periaqueductal region of the midbrain, floor of the fourth ventricle (particularly in the regions of the dorsal motor nuclei of the vagus and vestibular nuclei), and superior cerebellar vermis. Lesions are consistently found in the mammillary bodies and less consistently in other areas. The microscopic changes are characterized by varying degrees of necrosis of parenchymal structures. Within the area of necrosis, nerve cells are lost, but usually, some remain; some of these are damaged, but others are intact. Myelinated fibers are more affected than neurons. These changes are accompanied by a prominence of the blood vessels, although in some cases, there appears to be a primary endothelial proliferation and evidence of recent or old petechial hemorrhage. In the areas of parenchymal damage, there is astrocytic and microglial proliferation. Discrete hemorrhages were found in only 20 percent

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of Victor’s (1989) cases, and many appeared to be agonal rather than acquired earlier during the acute illness. The cerebellar changes consist of degeneration of all layers of the cortex, particularly of the Purkinje cells; usually, this lesion is confined to the superior parts of the vermis, but in advanced cases, the most anterior parts of the anterior lobes are involved as well. Of interest is the fact that the lesions of Leigh encephalomyelopathy, a mitochondrial disorder implicating pyruvate metabolism, bear a resemblance to those of Wernicke disease but have slightly different distribution and histologic characteristics. The ocular muscle and gaze palsies are attributable to lesions of the sixth- and third-nerve nuclei and adjacent tegmentum, and the nystagmus to lesions in the regions of the vestibular nuclei. The latter is also responsible for the loss of caloric responses and probably for the gross disturbance of equilibrium that characterizes the initial stage of the disease. The lack of significant destruction of nerve cells in these lesions accounts for the rapid improvement and the high degree of recovery of oculomotor and vestibular functions. The persistent ataxia of stance and gait is caused by the lesion of the superior vermis of the cerebellum; ataxia of individual movements of the legs is attributable to an extension of the lesion into the anterior parts of the anterior lobes. Hypothermia, which occurs sometimes as an early feature of Wernicke disease, is probably attributable to lesions in the posterior and posterolateral nuclei of the hypothalamus (experimentally placed lesions in these parts have been shown to cause hypothermia or poikilothermia in monkeys). The topography of the neuropathologic changes in patients who die in the chronic stages of the disease, when the amnesic symptoms are established, is much the same as the changes in the acute stages of Wernicke disease. Apart from the expected differences in age of the glial and vascular reactions, the only important difference has to do with the involvement of the medial dorsal and anterior nuclei of the thalamus. The medial parts of these nuclei were consistently involved in the patients who had shown the Korsakoff amnesic state during life; they were not affected in patients who had had no persistent amnesic symptoms in the series of Victor and colleagues (1989). The mammillary bodies were affected in all the patients, both those with the amnesic defect and those without. These observations suggest that the lesions responsible for the memory disorder are those of the thalami, predominantly of parts of the medial dorsal nuclei (and their connections with the medial frontal and temporal lobes and amygdaloid nuclei), and not those of the mammillary bodies, as is frequently stated. It is notable that the hippocampal formations, the site of damage in most other types of Korsakoff memory loss, are intact.

Treatment of the Wernicke-Korsakoff Syndrome Wernicke disease constitutes a medical emergency; its recognition (or even the suspicion of its presence) requires the administration of thiamine. The prompt use of thiamine prevents the progression of the disease and reverses those lesions that have not yet progressed to the point of fixed structural change. As emphasized earlier, in patients

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Chapter 40 Diseases of the Nervous System Caused by Nutritional Deficiency

who show only ocular signs and ataxia, the administration of thiamine is crucial in preventing the development of an irreversible amnesic state. Although 2 to 3 mg of thiamine may be sufficient to modify the ocular signs, particularly suppression of nystagmus, much larger doses are needed to sustain improvement and replenish the depleted thiamine stores—initially, 50 to 200 mg intravenously and a similar dose mg intramuscularly—the latter being repeated each day until the patient resumes a normal diet. Certain writings indicate that initial doses of 500 mg are necessary to fully reverse the manifestations of Wernicke disease and prevent progression to the point of Korsakoff syndrome. It appears that these higher doses, given for several days parenterally, are needed to replete vitamin levels in alcoholic and nutritionally deprived patients (see the articles by Thomson and colleagues and guidelines from the Royal College of Physicians and the European Federation of Neurological Societies [EFNS]). The risks of administering parenteral thiamine have probably been overstated; anaphylactic reactions occurred in 0.1 percent of the series of Wrenn and colleagues and minor reactions in 1 percent. To avoid precipitating Wernicke disease, it has become standard practice in emergency departments to administer 100 mg or more of thiamine in malnourished or alcoholic patients if intravenous fluids that contain glucose are being infused. Magnesium is given as well because it is required as a cofactor for thiamine activity. It is similarly advisable to give B vitamins to alcoholic patients who are seen for other reasons in the emergency department so as to raise body stores of thiamine and other vitamins. The patient with chronic alcoholism (or the nonalcoholic patient with persistent vomiting) exhausts thiamine in a matter of 7 or 8 weeks, during which time the administration of glucose may serve to precipitate Wernicke disease or cause an early form of the disease to progress rapidly. The further management of Wernicke disease involves the use of a balanced diet and all the B vitamins, as the patient is usually deficient in more than thiamine alone. A different problem in management may arise once the patient has recovered from Wernicke disease and the amnesic syndrome becomes prominent. Only a minority of such patients (fewer than 20 percent in Victor’s series) recover entirely; moreover, the time of recovery may be delayed for several weeks or even months, and then it proceeds very slowly over a period of many months. The extent to which the amnesic symptoms will recover cannot be predicted during the acute stages of the illness. Interestingly, some patients with alcoholism who develop Korsakoff syndrome, once more or less recovered, seldom demand alcohol but will drink it if it is offered.

Infantile Wernicke–Beriberi Disease This designates an acute and frequently fatal disease of infants. It affects only breast-fed infants, usually in the second to the fifth months of life. Acute cardiac symptoms dominate the clinical picture, but neurologic symptoms (aphonia, strabismus, nystagmus, spasmodic contraction of facial muscles, and convulsions) have been described in many of the cases. This syndrome can be reversed

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dramatically by the administration of thiamine, so some authors prefer to call it acute thiamine deficiency in infants. In the few neuropathologic studies that are available, changes like those of Wernicke disease in the adult have been described. Occasionally, there are outbreaks of this condition due to inadequately formulated baby foods that lack thiamine. Infantile beriberi bears no consistent relationship to beriberi in the mother. Infants of mothers with overt signs of beriberi may be quite normal. The absence of beriberi in the mothers of affected infants suggests that infantile beriberi might be due to the result of a toxic factor in breast milk, but such a factor, if it exists, has never been isolated. Rarely, the clinical manifestations of beriberi in infancy represent an inherited (autosomal recessive) thiaminedependent state, responding to the continued administration of massive doses of thiamine (Mandel and colleagues; see also Table 40-4, further on).

NUTRITIONAL POLYNEUROPATHY (NEUROPATHIC BERIBERI) (SEE ALSO CHAP. 43) Beriberi is a distinct clinical entity characterized by a predominantly cardiac disorder occurring among people whose diet is dominated by polished rice. The milling process, or “polishing,” removes the husk that contains most of the vitamin nutrients. In fact, beriberi is not confined to any particular part of the world. In addition to affecting the heart, it also affects the peripheral nerves (which may be affected separately), with or without edema, the latter feature providing the basis for the old division into “wet” and “dry” forms. The cardiac manifestations range from tachycardia and exertional dyspnea to acute and rapidly fatal heart failure, the latter being the most dramatic but uncommon manifestation of beriberi. Here we emphasize the peripheral neuropathy associated with beriberi. The notion that the neurologic manifestation of beriberi is essentially a peripheral neuropathy was established in the late nineteenth century by the studies of the Dutch investigators Eijkman, Pekelharing and Winkler, and Grijns. Only after beriberi gained acceptance as a nutritional disease (following Funk’s discovery of vitamins in 1911) was it suspected that the neuropathy of alcoholic patients was also nutritional in origin. The similarity between beriberi and alcoholic neuropathy was commented upon by several authors, but it was Shattuck, in 1928, who first discussed the relationship of the two disorders. He suggested that “polyneuritis of chronic alcoholism was caused chiefly by failure to take or assimilate food containing a sufficient quantity B vitamins and might properly be regarded as true beriberi.” Convincing evidence that “alcoholic neuritis” is not a result of the neurotoxic effect of alcohol was supplied by Strauss. He allowed 10 patients to continue their daily consumption of whiskey while they consumed a well-balanced diet supplemented with yeast and vitamin B concentrates; the peripheral nerve symptoms improved in every case. The observations made by Victor (1984) support Strauss’s contention that alcoholic polyneuropathy is essentially a nutritional disease.

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Clinical Features The symptomatology of nutritional polyneuropathy is diverse. In fact, many patients are asymptomatic and evidence of peripheral nerve disease is found only by clinical or electromyographic examination. The mildest neuropathic signs are thinness and tenderness of the leg muscles, loss or depression of the Achilles and perhaps the patellar reflexes, and at times, a patchy blunting of pain and touch sensation over the feet and shins. Most patients, however, are symptomatic and have weakness, paresthesias, and pain as the usual complaints. The symptoms are insidious in onset and slowly progressive, but occasionally they seem to evolve or to worsen rapidly over a matter of days. The initial symptoms are usually referred to the distal portions of the limbs and progress proximally if the illness remains untreated. The feet are always affected earlier and more severely than the hands. Usually, some aspect of motor disability is part of the chief complaint, but in about one-third of the patients, the main complaints are pain and paresthesias. It is this painful syndrome that has been the most prominent feature in the patients we have encountered. The discomfort takes several forms: a dull, constant ache in the feet or legs; sharp and lancinating pains, momentary in duration, like those of tabes dorsalis; sensations of cramping or tightness in the muscles of the feet and calves; or band-like feelings around the legs. Coldness of the feet is a common complaint but is not corroborated by palpation. Far more distressing are feelings of heat or “burning” affecting mainly the soles, less frequently the dorsal aspects of the feet. These dysesthesias fluctuate in severity and characteristically are worsened by contactual stimuli, sometimes to the point where the patient cannot walk or bear the touch of bedclothes, despite the relative preservation of motor power (allodynia). The term burning feet has been applied to this syndrome, but it is not particularly apt, as the patient also complains of other types of paresthesias, dysesthesias, and pain, and these symptoms may involve the hands as well as the feet. Examination discloses varying degrees of motor, sensory, and reflex loss. As the symptoms suggest, the signs are symmetrical, more severe in distal than in proximal portions of the limbs, and often confined to the legs. In some cases, the disproportionate affection of motor power may be striking, taking the form of a foot- and wrist-drop, but the proximal muscles are usually affected as well (indicated, for example, by climbing stairs or by difficulty in arising from a squatting position). In a few patients, the weakness appears to be most severe in the proximal muscles. Absolute paralysis of the legs had been observed in the past only rarely; immobility caused by contractures at the knees and ankles in neglected patients was a more common occurrence. Tenderness of muscles on deep pressure is a highly characteristic finding elicited most readily in the muscles of the feet and calves. In the arms, tendon reflexes are sometimes retained despite a loss of strength in the hands. In patients in whom pain and dysesthesias are prominent and motor loss is slight, the reflexes at knee and ankle may be retained or even of greater than average briskness. This attests to the predominant affection of the small nerve fibers.

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Excessive sweating of the soles and dorsal aspects of the feet and of the volar surfaces of the hands and fingers is a common manifestation of alcohol-induced nutritional neuropathy. Postural hypotension is also sometimes associated, indicative of involvement of the peripheral sympathetic nerve fibers. Sensory loss or impairment may involve all the modalities, although one may be affected out of proportion to the others, usually pain and temperature. One cannot predict from the patient’s symptoms which mode of sensation might be affected disproportionately. In patients with impairment of superficial sensation (i.e., touch, pain, and temperature), the border between impaired and normal sensation is not sharp but shades off gradually over a considerable vertical extent of the limbs. Patients in whom pain is an outstanding symptom do not constitute a distinct group in terms of their neurologic signs. Pain and dysesthesias may be prominent in patients with either severe or slight degrees of motor, reflex, and sensory loss. The term hyperesthetic is used commonly to designate the exquisitely painful form of neuropathy but is not well chosen; as pointed out in Chap. 7, one is usually able, by using finely graded stimuli, to demonstrate an elevated threshold to painful, thermal, and tactile stimuli in the “hyperesthetic” zone. Once the stimulus is perceived, however, it has a painful and diffuse unpleasant quality (hyperpathia). Tactile evocation of pain or burning is an example, as mentioned, of allodynia. In most patients with nutritional polyneuropathy, only the limbs are involved and the abdominal, thoracic, and bulbar muscles are usually spared; however, we have encountered 2 cases in which there was a sensory loss in the pattern of an escutcheon over the anterior thorax and abdomen. In the most advanced instances of neuropathy, hoarseness and weakness of the voice and dysphagia as a result of degeneration of the vagus nerves may be added to the clinical picture. Some idea of the incidence of the motor, reflex, and sensory abnormalities and the combinations in which they occur can be obtained from Table 40-2, which is based on Victor’s (1984) examination of 189 nutritionally depleted alcoholic patients. Noteworthy is the fact that only 66 (35 percent) of the 189 patients showed the clinical picture of polyneuropathy in its entirety, that is, a symmetrical Table 40-2 CLINICAL FINDINGS IN NUTRITIONAL POLYNEUROPATHY NEUROPATHIC ABNORMALITY

Loss of reflexes alone Loss of sensation alone Weakness alone Weakness and sensory loss Reflex and sensory loss Sensory, motor, and reflex loss Data incomplete

LEGS (189 CASES)

ARMS (57 CASES)

45 (24)a 10 (5) — 2 (1)

6 (10)b 10 (18) 5 (9) 10 (18)

40 (21) 66 (35)

2 (3) 17 (30)

26 (14)

7 (12)

a

Figures in parentheses indicate percent of 189 cases. b Figures in parentheses indicate percent of 57 cases.

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impairment or loss of tendon reflexes, sensation, and motor power affecting legs more than the arms and the distal more than the proximal segments of the limbs. In the remaining patients, the motor-reflex-sensory signs occurred in various combinations. Stasis edema and pigmentation, glossiness, and thinness of the skin of the lower legs and feet are common findings in patients with any severe form of neuropathy. Major dystrophic changes, in the form of perforating plantar ulcers and painless destruction of the bones and joints of the feet (“Charcot forefeet”), have been described but are rare. Repeated trauma to insensitive parts and superimposed infection is thought to be responsible for the neuropathic arthropathy, as discussed in Chaps. 7 and 43. The CSF is usually normal, although a modest elevation of protein content is found in a small number. Findings of nerve conduction studies include mild to moderate degrees of slowing of motor and sensory conduction and a marked reduction in the amplitudes of sensory action potentials; the motor conduction velocities in distal segments of the nerves may be reduced, while conduction in proximal segments is normal. Denervated muscles show fibrillation potentials in a pattern that is consistent with more severe involvement peripherally.

Pathologic Features The essential change is one of axonal degeneration, with the destruction of both axon and myelin sheath. Segmental demyelination occurs only in a small proportion of fibers. The most pronounced changes are observed in the distal parts of the longest and largest myelinated fibers in the crural and, to a lesser extent, brachial nerves. In advanced cases, the changes extend into the anterior and posterior nerve roots. The vagus and phrenic nerves and paravertebral sympathetic trunks may be affected in advanced cases. Anterior horn and dorsal root ganglion cells undergo chromatolysis, indicating axonal damage. Secondary changes in the posterior columns are seen in some cases.

Pathophysiology The nutritional factor(s) responsible for the neuropathy of alcoholism and beriberi has not been defined precisely. Because of the difficulty in producing peripheral neuropathy in mammals by means of a thiamine-deficient diet, the idea that thiamine is the antineuritic vitamin was questioned in the past. Very few of the animal experiments undertaken to settle this point were satisfactory from a nutritional and pathologic point of view. Nevertheless, several studies in birds and humans do indeed indicate that uncomplicated thiamine deficiency may result in peripheral nerve disease. The necessity of either accepting or rejecting the specific role of thiamine became less urgent when it was demonstrated, in both animals and humans; a deficiency of pyridoxine or of pantothenic acid could also result in degeneration of the peripheral nerves, and therefore, there were alternative reasons for nutritional polyneuropathy (Swank and Adams). The question of whether polyneuropathy in the alcoholic patient might be a result of the direct toxic effects of alcohol and not of a nutritional deficiency has been raised from time to time (see the preceding text, and

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Denny-Brown, and Behse and Buchthal). The evidence for this view is not compelling, either on clinical or on experimental grounds, as already mentioned (see reference to Strauss in the introductory section on nutritional neuropathy). The data subsequently presented by Koike and colleagues, ostensibly in favor of the existence of a true alcoholic neuropathy, in our view, present no convincing support of a direct toxic effect of alcohol. In the end, we view alcoholic–beriberi neuropathy as a multiple B-vitamin deficiency. The interested reader will find a detailed critique of this subject in the chapters by Victor (1970) and by Windebank.

Treatment and Prognosis The first consideration is to supply adequate nutrition over a long period in the form of a balanced diet supplemented with B vitamins (equally important is to make certain that the patient follows the prescribed diet). If persistent vomiting or other gastrointestinal complications prevent the patient from eating, parenteral feeding becomes necessary; the vitamins may be given intramuscularly or added to intravenous fluids. Where pain and sensitivity of the feet are the major complaints, the pressure of bedclothes may be avoided by placing a cradle support over the legs. Aching of the limbs may be related to their immobility, in which case they should be moved passively on frequent occasions. Aspirin or acetaminophen is usually sufficient to control hyperpathia and allodynia; occasionally, codeine or methadone must be added. Obviously, opiates and addicting synthetic analgesics should be avoided if possible, but we have resorted to fentanyl patches for short periods in a few severely affected patients. Some of our patients with severe burning pain (similar to causalgia) in the feet had in the past been helped temporarily by blocking the lumbar sympathetic ganglia or by epidural injection of analgesics. The response to phenytoin, carbamazepine, and gabapentin has been inconsistent, but they are widely used. Adrenergic-blocking medication has been of little value and mexiletine, in our experience, of uncertain benefit. The regeneration of peripheral nerves, which may take many months, will be of little avail if the muscles have been allowed to undergo contracture and the joints to become fixed. In cases of severe paralysis, molded splints should be applied to the arms, hands, legs, and feet during periods of rest. Pressure on the heels and elbows can be avoided by padding the splints and by turning the patient frequently or by asking the patient to do so. As function returns, more vigorous physiotherapeutic measures can be undertaken. Recovery from nutritional polyneuropathy is a slow process. In the mildest cases, there may be a considerable restoration of motor function in a few weeks. In severe forms of the disease, many months may pass before the patient is able to walk unaided. The sensory features and pain, in particular, may be slower to recover, having taken over a year in one of our recently observed patients. The slowness of recovery creates a special problem for the alcoholic patient, in whom the great danger to continued recovery is the resumption of drinking and inadequate diet.

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RIBOFLAVIN DEFICIENCY (VITAMIN B2 DEFICIENCY) Whether or not riboflavin deficiency leads to neurologic symptoms has been controversial. In the past, there were claims that glossitis, cheilosis, and neuropathy were caused by riboflavin deficiency, but its effects were never isolated. It is a component of general malnutrition, making it difficult to separate the cause of various disorders. Night blindness seems, however, to be caused by B2 deficiency. Antozzi and colleagues reported that a metabolic disorder similar to the Reye syndrome can be caused by riboflavin deficiency and is correctable by the administration of riboflavin alone. The affected infants in their studies were hypoglycemic, hypotonic, and episodically weak and unresponsive. Generally, 15 mg per day in divided doses is used for replacement, but restoration of a normal diet is paramount. There have also been recorded instances of disease in older children and adults, manifesting as a type of lipid storage polymyopathy as a result of either a deficiency or malabsorption of riboflavin (Antozzi and colleagues). Presumably, a disorder of flavin metabolism had caused an impairment of both beta-oxidation of fatty acids and respiratory chain I and II complexes. Serum creatine phosphate was normal in these individuals, but carnitine was reduced. The oral administration of 200 mg of riboflavin and 4 g of carnitine per day relieved the symptoms. We have seen one case with a significant recovery after supplementation was instituted.

PELLAGRA (NIACIN, NICOTINIC ACID, B3 DEFICIENCY) In the early 1900s, pellagra attained epidemic proportions in the southern United States and in the alcoholic population of large urban centers. Since 1940, it has diminished greatly because of the general practice of enriching bread with niacin. Nevertheless, among vegetarian, maizeeating people, pellagra is still a common disease (Bomb and colleagues; Shah and colleagues; Ronthal and Adler). In developed countries, pellagra is practically confined to malnourished alcoholic patients (Ishii and Nishihara; Spivak and Jackson; Serdaru and colleagues).

Clinical Features In its fully developed form, pellagra affects the skin, alimentary tract, and hematopoietic and nervous systems. The early symptoms may be mistaken for those of a psychiatric disorder. Insomnia, fatigue, nervousness, irritability, and feelings of depression are common complaints; taken together, they have the character of neurasthenia. Examination discloses mental dullness, apathy, and a mild impairment of memory. Sometimes an acute confusional psychosis dominates the clinical picture. Untreated, these symptoms may progress to a dementia. Pellagra may not only produce mental impairment but occasionally result from it by virtue of anorexia and refusal of food.

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The dermatologic feature, often the aspect that permits one to make a confident diagnosis, is a scaly dermatitis in sunexposed areas, followed by hyperpigmentation of these areas. Diarrhea and glossitis or other forms of mucous membrane disorder may be accompaniments (hence the alliterative triad dementia-dermatitis-diarrhea). The spinal cord manifestations have not been clearly delineated, but in general, the signs are referable to both posterior and lateral columns, predominantly the former, and thereby simulating SCD. Signs of peripheral neuropathy are relatively less common and are indistinguishable from those of neuropathic beriberi.

Pathologic Changes These are most readily discerned in the large cells of the motor cortex (Betz cells) and to a lesser extent in the smaller pyramidal cells of the cortex, the large cells of the basal ganglia, the cranial motor and cerebellar dentate nuclei, and the anterior horn cells of the spinal cord. The affected neurons are swollen and rounded, with eccentric nuclei and loss of the Nissl bodies that have the appearance of a secondary axonal reaction. However, in the pathologic material presented by Hauw and associates, these chromatolytic changes were most pronounced in the brainstem nuclei (upper reticular and pontine) and not in the Betz cells. They concluded that the neuronal changes were not caused by a retrograde axonal lesion but did not comment on the status of the spinal cord or nerves. The few studies of the peripheral nerves in pellagra have disclosed changes like those in alcoholics and other patients with nutritional deficiency. The spinal cord lesions in pellagra take the form of a symmetrical degeneration of the dorsal columns, especially of Goll, and to a lesser extent of the corticospinal tracts. The posterior column degeneration is likely to be secondary to degeneration of the dorsal root ganglion cells or posterior roots. The exact mechanisms underlying the corticospinal tract degeneration have not been elucidated.

Etiology It has been known since 1937 when Elvehjem and coworkers showed that nicotinic acid cured black tongue, a pellagra-like disease in dogs, that this vitamin is effective in the treatment of pellagra. Many years before, Goldberger had demonstrated the curative effects of dietary protein and proposed that pellagra was caused by a lack of specific amino acids. Now it is known that pellagra may result from a deficiency of either nicotinic acid or tryptophan, the amino acid precursor of nicotinic acid. One milligram of nicotinic acid is formed from 60 mg of tryptophan, a process for which pyridoxine is essential. The relationship of niacin to tryptophan metabolism explains the frequent occurrence of pellagra in persons who subsist mainly on corn, which contains only small amounts of tryptophan and niacin, some of the niacin being in bound form and unavailable for absorption. It should be pointed out that in experimental subjects, only the cutaneous-gastrointestinal-neurasthenic manifestations of pellagra have been produced by diets that are tryptophan or niacin deficient; neurologic abnormalities have not resulted from these diets (Goldsmith). As a corollary, only the dermal, gastrointestinal, and neurasthenic

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manifestations respond to treatment with niacin and tryptophan; neurologic disturbances in affected individuals have proved to be recalcitrant to prolonged treatment with the vitamin, although the peripheral nerve disorder may subsequently respond to treatment with thiamine. In monkeys, degeneration of peripheral nerves and the cerebrocortical changes of pellagra were induced by a deficiency of pyridoxine (Victor and Adams, 1956). Swank and Adams described degeneration of the peripheral nerves in pyridoxine- and pantothenic acid-deficient swine, and Vilter and colleagues produced polyneuropathy in human subjects rendered pyridoxine deficient; these subjects also showed seborrheic dermatitis and glossitis (indistinguishable from that of niacin deficiency) and the cheilosis and angular stomatitis that are usually attributed to riboflavin deficiency. The foregoing observations indicate that certain lingual and cutaneous manifestations of pellagra may be produced by a deficiency of pyridoxine or other B vitamins and that the neurologic manifestations of pellagra are most likely caused by pyridoxine deficiency. In the special case of Hartnup disease in infants (which resembles pellagra in most respects including the dermatitis), a secondary niacin deficiency is believed to result from the high excretion of indicans and indole metabolites (see Chap. 36).

Treatment The administration of niacin 500 mg per day for approximately 3 weeks reverses the process. If the patient is unable to take oral medications, intravenous doses of 100 mg per day for 5 to 7 days are utilized. If the patient is simultaneously deficient in pyridoxine, as for example, when INH is used for tuberculosis treatment, the pyridoxine must also be replaced in order to allow the conversion of dietary tryptophan to endogenous niacin.

Nicotinic Acid-Deficiency Encephalopathy Under this title, Jolliffe and coworkers, in 1940, described an acute cerebral syndrome in alcoholic patients consisting of clouding of consciousness, progressing to extrapyramidal rigidity and tremors (“cogwheel” rigidity) of the extremities, uncontrollable grasping and sucking reflexes, and coma. Some of their patients showed overt manifestations of nutritional deficiency, such as Wernicke disease, pellagra, scurvy, and polyneuropathy. These authors concluded that the encephalopathy represented an acute form of nicotinic acid deficiency, as most of their patients recovered when treated with a diet of low vitamin B content supplemented by intravenous glucose and saline and large doses of nicotinic acid. Sydenstricker and colleagues (1938) had previously reported the salutary effects of nicotinic acid on the unresponsive state observed in elderly undernourished patients, and Spillane (1947) described a similar syndrome and response to nicotinic acid in the indigent Arab population of the Middle East. The status of this syndrome and its relation to pellagra are uncertain. The clinical, nutritional, and pathologic features were never delineated precisely. Serdaru and associates reported 22 presumed examples of this syndrome in the alcoholic population of the Salpêtriére clinic in Paris,

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all diagnosed retrospectively after the finding in postmortem material of pellagra-like changes in nerve cells. The prominent features were confusional states, paratonic rigidity, ataxia, and polymyoclonia, a picture somewhat like that described by Jolliffe and coworkers. Skin lesions were absent. We have not encountered identical cases among the undernourished patients in the alcoholic population.

PYRIDOXINE (VITAMIN B6) DEFICIENCY Pyridoxine deficiency or excess has been associated with a sensory polyneuropathy. The occurrence of neuropathy caused by INH was recognized in the early 1950s, soon after the introduction of this drug for the treatment of tuberculosis. It was characterized by paresthesia and burning pain of the feet and legs, followed by weakness of these parts and loss of ankle reflexes. Rarely, with continued use of the drug, the hands were affected as well. The nature of INH-induced neuropathy was clarified by Biehl and Vilter, who found that isoniazid causes a marked excretion of pyridoxine and that the administration of pyridoxine in conjunction with INH prevents the development of neuropathy. Because of this simple preventive measure, very few examples of INH-induced neuropathy are now observed. Hydralazine, closely related in structure to INH, when used in the past caused the formation of pyridoxalisoniazid complexes (hydrazones), which make pyridoxal (the main form of vitamin B6) unavailable to the tissues. The neuropathy responds favorably to discontinuation of the drug and the administration of pyridoxine. Pyridoxine deficiency also leads to homocystinemia because the vitamin is a coenzyme for the conversion of homocystine to cystathionine. Vascular thrombosis may result from the excess homocystine. Severe pyridoxine deficiency in animals and humans also causes seizures. This was first observed in swine by Swank and Adams and later in infants who were maintained on a milk formula lacking in pyridoxine. A pyridoxine-responsive seizure disorder (pyridoxine dependency) of the neonatal period is discussed in Chap. 15.

Treatment For pyridoxine deficiency caused by malnutrition, the treatment is 50 mg per day orally for several weeks, followed by 2 mg per day and resumption of a normal diet. When the deficiency results from a pyridoxine antagonist such as INH, penicillamine, hydralazine, or cycloserine, the treatment is 50 mg per day, only when the antagonist is in use. Treatment for the inherited form with convulsions is discussed in the section on neonatal seizures in Chap. 15. Lifelong supplementation is required after the seizures are aborted with a large intravenous dose of the vitamin.

Pyridoxine Toxicity Paradoxically, the consumption of large amounts of pyridoxine (mainly by vitamin faddists) may also cause a sensory peripheral neuropathy or ganglionopathy (Schaumburg and colleagues; Albin and colleagues).

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There is no weakness; the symptoms, including ataxia and areflexia, are purely sensory and can be quite disabling. Symptoms may extend to the trunk, scalp, and face. Improvement is the rule when the drug is withdrawn. This disorder is probably a direct toxic effect of pyridoxine on dorsal root ganglion cells.

FOLATE (B9 DEFICIENCY) Despite the frequency of folic acid deficiency and its hematologic effects, its role in the pathogenesis of nervous system disease has not been established beyond doubt (see reviews by Crellin and colleagues and by Carney). However, folate antagonists such as methotrexate are known to cause a neuropathy that is probably predicated on the vitamin deficiency. The polyneuropathy that occasionally complicates the chronic administration of phenytoin has also been attributed, on uncertain grounds, to folate deficiency. Botez and colleagues have described a group of 10 patients with sensorimotor polyneuropathy (4 also had spinal cord disease), presumably because of intestinal malabsorption; all the patients improved over several months while receiving large doses of folic acid. This experience is unique, however. The possible role of folate deficiency in the pathogenesis of spinal cord disease was mentioned previously in relation to vitamin B12 deficiency, and its putative role in psychiatric disease has been discussed by Carney. In such cases of folate deficiency, if SCD or mental changes occur, they must be rare. The folate deficiency of pregnancy is a special case that is known to increase the incidence of neural tube defects. For nutritional folate deficiency, which is difficult to separate from the lack of other vitamins, replacement is with 1 mg per day. In pregnant women, higher doses are used, separately from a multivitamin preparation in order to avoid vitamin A toxicity. When the folate antagonist methotrexate is the underlying cause, supplemental folinic acid (leukovorin, citrovorum factor) is given orally.

Pantothenic Acid Deficiency A predominantly sensory neuropathy also has been induced, again in swine, by Swank and Adams, and later in humans by a deficiency of pantothenic acid (a constituent of coenzyme A [CoA]), as reported by Bean and colleagues. In some patients, the administration of pantothenic acid has reportedly reversed the painful dysesthesias of the “burning foot” syndrome.

VITAMIN B12 (COBALAMIN) DEFICIENCY (SUBACUTE COMBINED DEGENERATION) The spinal cord, brain, optic nerves, and peripheral nerves are all affected by vitamin B12 (cobalamin) deficiency, giving rise to a classic neurologic syndrome in which the spinal cord is usually affected first and often exclusively. The term subacute combined degeneration (SCD) is customarily

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reserved for the spinal cord lesion of vitamin B12 deficiency and serves to distinguish it from other types of spinal cord diseases that happen to involve the posterior and lateral columns. Whether a peripheral neuropathy is a primary component of the disease or is secondary to damage of the posterior root fibers of entry in the dorsal cord has been debated, but the available pathologic evidence favors the latter, except perhaps for a few advanced cases, in which other nutritional deficiencies could have been responsible. The hematologic effects of vitamin B12 deficiency, when they result from pernicious anemia, are distinctive insofar as they usually result not from a dietary lack of vitamin B12 but from the failure to transfer minute amounts of this nutrient across the intestinal mucosa, “starvation in the midst of plenty,” as Castle aptly put it. This failure derives from the chronic absence of an intrinsic factor, which is secreted (along with hydrochloric acid) by the parietal cells of the gastric mucosa and transports cobalamin (“extrinsic factor”) to the ileum, where it is absorbed into the portal venous system. This is referred to as a conditioned deficiency, as it is conditional on the lack of an intrinsic factor. Minot and Murphy’s clinical experiment that showed the cure of the neurologic process by the feeding of liver, or parenteral liver extract that contained an “extrinsic factor” later found to be cobalamin, was a remarkable feat of translational medicine. It was Castle, experimenting on himself, who isolated the “intrinsic factor” that facilitates absorption of the vitamin. The hematologic and neurologic manifestations of vitamin B12 deficiency often complicate many of the malabsorptive disorders, including poor nutrition in the elderly, especially those with atrophic gastritis, but also individuals of any age with celiac sprue; gastric or ileal resections; overgrowth of intestinal bacteria in “blind loops,” anastomoses, diverticula, and other conditions resulting in intestinal stasis; and infestation with cobalamin-metabolizing fish tapeworm (Diphyllobothrium latum). Uncommon instances of vitamin B12 deficiency are observed in lactovegetarians and in infants nursed by mothers deficient in vitamin B12; vitamin B12 deficiency may also be a result of a rare genetic defect of methylmalonyl-CoA mutase, as discussed further on. It should be further commented that interference with methionine synthetase, a methylcobalamin-dependent enzyme, can be produced by exposure to nitrous oxide (N2O). Chronic exposure can produce the entire subacute combined syndrome, but more often, an individual is marginally deficient, often but not always elderly, and even short exposure may then induce symptoms. A megaloblastic anemic state, as well as the neurologic features of SCD, is thereby induced by the gas. This illness, cleverly named “anesthesia paresthetica” by Kinsella and Green, arises in operating room personnel (we have seen it in several anesthesia nurses), occasionally in dentists, and in abusers of the gas (whippets) to obtain a “high.” Their serum B12 levels are usually in the low-normal range, and measurements of methylmalonic acid are greatly elevated (see further on).

Clinical Manifestations Symptoms of nervous system disease occur in the majority of patients with pernicious anemia and in most with B12

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deficiency of other sources. The patient first notices mild general weakness and paresthesias consisting of tingling, “pins and needles” feelings, or other vaguely described sensations. The paresthesias involve the hands and feet, more often and first in the hands, and tend to be constant and steadily progressive and the source of much distress. As the illness progresses, the gait becomes unsteady and stiffness and weakness of the limbs, especially of the legs, develop. If the disease remains untreated, an ataxic paraplegia evolves with variable degrees of spasticity. Early in the course of the illness, when only paresthesia is present, there may be no objective sign. Later, examination discloses a disorder of the posterior and lateral columns of the spinal cord, predominantly of the former. Loss of vibration sense is the most consistent sign; it is more pronounced in the feet and legs than in the hands and arms and frequently extends over the trunk. Position sense is usually impaired in parallel. The motor signs, usually limited to the legs, include a mild symmetrical loss of strength in proximal limb muscles, spasticity, enhanced tendon reflexes, clonus, and extensor plantar responses. At first, the patellar and Achilles reflexes are diminished as frequently as they are increased; they may even be absent. This is most likely the result of neuropathy due to multiple vitamin deficiencies as cases of pure cobalamin loss, for example, due to N2O, almost never obliterate the tendon reflexes. This controversy regarding the presence of polyneuropathy as a component of SCD has already been alluded to. The gait at first is predominantly ataxic, later ataxic and spastic. Loss of superficial sensation below a segmental level on the trunk should suggest an alternative diagnosis involving the spinal cord. However, two of our patients have described a band-like sensation around the thorax. A defect of cutaneous sensation may take the form of impaired tactile, pain, and thermal sensation over the limbs in a distal distribution, implicating the small fibers of the peripheral nerves or the spinothalamic tracts, but such findings are relatively uncommon. The Lhermitte phenomenon (paresthesia down the spine or across the shoulders induced by a rapid flexion of the neck) may be reported by some patients but is more often allied with multiple sclerosis. The nervous system involvement in SCD is roughly symmetrical and distal, and sensory disturbances precede the motor ones; predominantly motor involvement from the beginning and a definite asymmetry of motor or sensory findings maintained over a period of weeks or months or prominent truncal or facial symptoms should always cast doubt on the diagnosis. Cognitive symptoms and signs are frequent, ranging from irritability, apathy, somnolence, suspiciousness, and emotional instability to a marked confusional or depressive psychosis or dementia. Lindenbaum and coworkers have reported cases in which neuropsychiatric symptoms, responsive to vitamin B12, were present without spinal cord or peripheral nerve abnormalities. In our clinical material, symptoms of dementia or psychosis have not been frequent and always followed the spinal cord disorder. Perhaps a slight degree of mental illness is all that is seen in the early stages.

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Visual impairment caused by optic neuropathy occasionally may be an early or sole manifestation of pernicious anemia; examination discloses roughly symmetrical centrocecal scotomata and optic atrophy in the most advanced cases. That visually evoked potentials may be abnormal in vitamin B12-deficient patients without clinical signs of visual impairment suggests that the visual pathways are affected more often than is evident from the neurologic examination alone. A small number of patients have symptoms of autonomic dysfunction, including urinary sphincteric symptoms and impotence. The CSF is usually normal; in some cases, there is a moderate increase in protein. The nerve conduction studies may show slowing of sensory conduction or reducedamplitude sensory potentials, but they are as often normal in early cases. Frequently, according to Hemmer and colleagues, somatosensory evoked potentials are delayed or absent; these changes are known to recover with treatment. Quite remarkable in corresponding to the locus of pathologic change, as these and other authors have indicated, is the finding on MRI of a T2 hyperintensity that demarcates the posterior columns of the cord and sometimes the lateral columns, as shown in Fig. 40-2. In a few of our patients, these have taken the form solely of welldefined linear changes over a long extent of the posterior columns of the cervical cord.

Neuropathologic Changes The pathologic process takes the form of a diffuse, although uneven, degeneration of white matter of the spinal cord and occasionally of the brain. The earliest histologic event is swelling of myelin sheaths, characterized by the formation of intramyelinic vacuoles and the separation of myelin lamellae. This is followed by a coalescence of small foci of tissue destruction into larger ones, imparting a vacuolated, sieve-like appearance to the tissue, an appearance also observed in HIV myelopathy and rarely in lupus erythematosus. The myelin sheaths and axis cylinders are both involved in the degenerative process, the former more obviously and perhaps earlier and more severely than the latter. There is relatively little fibrous gliosis in the early lesions, but in more chronic ones, particularly those in which considerable tissue is destroyed, the gliosis is pronounced. The changes begin in the posterior columns of the lower cervical and upper thoracic segments of the cord and spread from this region up and down the cord as well as forward into the lateral and anterior columns. The lesions are not limited to systems of fibers within the posterior or lateral columns but are scattered irregularly through the white matter, thereby representing a myelinopathy. In rare instances, foci of spongy degeneration are found in the optic nerves and chiasm and in the central white matter of the brain (Adams and Kubik). The peripheral nerves may show a loss of myelin, but there is no unequivocal evidence that axons are significantly affected. Agamanolis and colleagues (1978) showed that monkeys sustained on a vitamin B12-deficient diet for a prolonged period develop neuropathologic changes indistinguishable from those of SCD in humans. The time

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Figure 40-2.  Sagittal (left image) and axial (right image) T2 MRI of the cervical spine in subacute combined degeneration (SCD) showing abnormal hyperintensity in the posterior columns. The patient had markedly reduced vibration and position sense and a Romberg sign; the tendon reflexes were preserved and there were no corticospinal tract or peripheral nerve signs.

required for the production of nervous system changes in monkeys, 33 to 45 months, is comparable to the time required to deplete the vitamin B12 stores of patients with pernicious anemia in whom parenteral vitamin B12 therapy had been discontinued. It is noteworthy that vitamin B12deprived monkeys do not become anemic despite the prolonged period of vitamin B12 deficiency. Also in distinction to the human condition, involvement of the optic nerves is particularly severe in the monkey and probably precedes the degeneration of the spinal cord. The optic nerve lesions appear first in the papillomacular bundles, in the retrobulbar portions of the nerves; it subsequently spreads beyond the confines of this bundle and caudally in the optic nerves, chiasm, and tracts. These changes are much the same as those of “Tobacco–Alcohol Amblyopia” (see the section on this subject further on). The peripheral nerves are not affected in the experimentally produced vitamin B12 deficiency. Paresthesia, impairment of deep sensation, and ataxia are caused by lesions in the posterior columns. Weakness, spasticity, increased tendon reflexes, and Babinski signs depend on the involvement of the corticospinal tracts. The spinothalamic tracts may rarely be involved in the pathologic process, which explains the rare finding of a sensory level for pain and temperature on the trunk. The distal and symmetrical impairment of superficial sensation and loss of tendon reflexes that occur in advanced cases, however, may be explained by the involvement of peripheral nerves

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and are then reflected in nerve conduction studies (see further on, under “Diagnosis”).

Pathogenesis Methylcobalamin is an essential cofactor in the conversion of homocysteine to methionine. An impairment of this reaction caused by a deficiency of cobalamin is thought to cause a failure of DNA synthesis, accounting for the hematologic abnormalities, particularly for the production of megaloblasts. However, because neurons do not divide, this sequence of chemical events does not explain the central nervous system abnormalities. One of the better-understood functions of vitamin B12 is its role as a coenzyme in the methylmalonyl-CoA mutase reaction. In this reaction, which is a key step in propionate metabolism, methylmalonyl-CoA is transformed to succinyl-CoA, which subsequently enters the Krebs cycle. A lack of the cobalamin-dependent enzyme methylmalonyl-CoA mutase leads to the accumulation of methylmalonyl-CoA and its precursor, propionyl-CoA. According to this mechanism, propionyl-CoA displaces succinyl-CoA, which is the usual primer for the synthesis of even-chain fatty acids; this results in the anomalous insertion of oddchain fatty acids into membrane lipids, such as are found in myelin sheaths. Conceivably, this biochemical abnormality underlies the lesions of myelinated fibers that characterize the disease. However, Carmel and associates described a hereditary form of cobalamin deficiency in

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which methylmalonyl-CoA mutase activity was normal, despite the presence of typical neurologic abnormalities. In their view, the primary failure is one of methylation of homocysteine to methionine, that is, a failure of the methionine synthetase reaction, for which the coenzyme methylcobalamin is necessary. Evidence for the latter view comes also from the observations mentioned earlier that prolonged administration of N2O may produce not only megaloblastic changes in the marrow (Amess and colleagues) but also a sensorimotor polyneuropathy, often combined with signs of involvement of the posterior and lateral columns of the spinal cord (Layzer). Probably N2O produces its effects by inactivating the methylcobalamin-dependent enzyme, methionine synthetase. These and other hypotheses are discussed by Jandl, Carmel and colleagues, and by Beck (1988). The role of folate deficiency in the genesis of SCD is less certain. One known clinical mistake has been to treat pernicious anemia by giving folic acid; this corrects the anemia but may worsen or even evoke the spinal cord lesions. Nevertheless, there have been a few reported examples of cerebral and spinal cord lesions indistinguishable from those caused by vitamin B12 deficiency in patients with defective folate metabolism, both in adults with acquired deficiency (Pincus) and in children with an inborn error of metabolism (Clayton and colleagues). The current view, however, is that folate deficiency alone does not produce SCD.

Diagnosis The main differential diagnostic considerations of the combined sensory and motor features are cervical spondylosis (see Chaps. 10 and 42), multiple sclerosis of the cervical cord (see Chap. 35), non-B12-deficient combined system disease caused by low levels of serum copper (see Chap. 42), and rarities such as the female carrier state of adrenoleukodystrophy (see Chap. 36). The myelopathy associated with copper deficiency affects the posterior and lateral columns subacutely in a manner identical to that of SCD but unassociated with any form of B12 deficiency or related enzyme derangement. Somewhat to our surprise, the copper disorder has been as frequent as the classic type caused by B12 deficiency in our clinics. One remarkable circumstance, with which we have had experience, is the creation of severe SCD including paralysis in a B12-deficient patient whose myelopathic symptoms were misattributed to cervical spondylosis and who had an operation in which N2O was used as anesthesia. The chief obstacle to early diagnosis of SCD is the lack of parallelism that may exist between the hematologic and neurologic signs, particularly in patients who have taken dietary or medicinal folate. Anemia may also at times be absent, sometimes for many months, even in patients who have not taken folate. For example, in a retrospective study of 141 patients with neuropsychiatric abnormalities caused by cobalamin deficiency, there were 19 patients in whom both the hematocrit and mean red blood cell volume were normal (Lindenbaum and colleagues); in these patients, subtle morphologic abnormalities such as hypersegmented polymorphonuclear leukocytes and megaloblastosis in

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bone marrow smears were almost always found if carefully sought.

Laboratory Diagnosis Serum cobalamin should be measured whenever the diagnosis of vitamin B12 deficiency is in question. Microbiologic assay (using Euglena gracilis) is the most accurate measurement, but the method is time-consuming and cumbersome and has been replaced by a commercial radioisotope dilution assay (the inexpensive chemiluminescence assay is an alternative but slightly less dependable). With the radioassay, a serum B12 level below 100 pg/mL is usually associated with neurologic symptoms and signs of vitamin B12 deficiency. A level below 200 pg/mL that is unassociated with symptoms calls for further investigation of cobalamin deficiency. However, even serum levels of 200 to 300 pg/mL may still be associated (in 5 to 10 percent of cases) with cobalamin deficiency. High serum concentrations of cobalamin metabolites, methylmalonic acid (normal range, 73 to 271 nmol/L), and homocysteine (normal range 5.4 to 16.2 mmol/L) are additional reliable indicators of an intracellular cobalamin deficiency and can be used to corroborate the diagnosis in cases of low-mid-range B12 levels (Allen and colleagues; Lindenbaum and colleagues). It must be emphasized that the serum cobalamin level is not a measure of total-body cobalamin. In a patient who stops absorbing ingested cobalamin, the serum levels may remain in the normal range for months or years despite decreasing tissue reserves. In patients who have received vitamin B12 parenterally, the 2-stage Schilling test is a more reliable indicator of cobalamin deficiency because it uncovers a defect in absorption of the vitamin; however, the Schilling test has been largely supplanted for routine diagnosis by the measurement of antibodies to intrinsic factor and parietal cells. Achlorhydria is almost invariably present in patients with pernicious anemia; its presence can be inferred by measuring the serum gastrin level. Antibodies to gastric parietal cells are also present in as many as 90 percent of patients with cobalamin deficiency, specifically in those with pernicious anemia as opposed to those with diminished B12 intake, but this test, although diagnostically specific, is positive in only 60 percent of cases. A relationship between helicobacter gastritis and autoimmunity against gastric parietal cells is being explored. Low cobalamin levels with or without the clinical signs of deficiency may occur in patients with atrophic gastritis or after subtotal gastrectomy as mentioned. The malabsorption in such cases is thought to be because of a failure to extract cobalamin from food rather than a failure of the intrinsic factor mechanism (“food-cobalamin malabsorption”). Because the absorption of free cobalamin is normal, the Schilling test is unimpaired (Carmel, 1990). Infection of the gastric mucosa with Helicobacter pylori has been implicated in some cases. There are also rare inherited defects in the gene for the intrinsic factor that render it ineffective. The results of nerve conduction tests have varied in vitamin B12-deficient patients. Early in the course of SCD, nerve conduction may be normal, but some patients have

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slowing of distal sensory conduction; others have found reduced amplitudes and minor signs of denervation, suggestive of axonal change. This again raises the controversy regarding the presence of a peripheral nerve disorder in uncomplicated B12 deficiency. Authoritative texts indicate that neuropathy is present, but certainly, such involvement is not integral to the disease as many patients with prominent neurological manifestations, particularly early in the course, have normal nerve conduction studies. In patients with normal peripheral nerve studies, the somatosensory evoked potentials usually show abnormalities attributable to central conduction delays, implicating the posterior columns as the cause of the sensory symptoms (Fine and Hallett). In advanced cases, motor conduction and late responses may be affected to a slight degree. These ambiguities reflect the inconsistent and poorly understood role of the peripheral neuropathic component of this disease. The MRI lesions in the posterior columns were described earlier; they extend through the cervical and upper thoracic cords and, less often, to the lateral columns. The frequency of these findings, however, is not known, and their absence cannot be considered evidence against the diagnosis.

Treatment The diagnosis of pernicious anemia demands the administration of vitamin B12 and the continuation of treatment for the rest of the patient’s life. In cases of pernicious anemia, the patient is given 1,000 μg of cyanocobalamin or hydroxocobalamin intramuscularly each day for several days. The usual approach is to repeat the injection weekly for a month and then monthly for an indefinite period. Although most of the injected cobalamin is excreted, these patients must be given excessive doses of the vitamin because the repletion of cobalamin tissue stores is a function of the dose. In recent years, the notion that all forms of B12 deficiency must be circumvented by parenteral administration of the vitamin has been questioned and the use of oral cobalamin 500 to 1,000 μg daily has been used as an alternative, particularly for maintenance treatment. Several studies have indicated the effectiveness of this approach in elderly patients with poor B12 absorption and in persons with restricted diets, such as vegans, but we would nonetheless express some reservations regarding the use of oral replacement in the treatment of manifest SCD with neurologic manifestations. The most important factor influencing the response to treatment is the duration of symptoms; age, sex, and the degree of anemia are of lesser importance. The greatest improvements occur in patients whose disturbance of gait has been present for less than 3 months and recovery is usually complete if therapy is instituted within a few weeks after the onset of symptoms. All neurologic symptoms and signs may improve, mostly during the first 3 to 6 months of therapy, and then at a slower tempo during the ensuing year or even longer. In practically all instances, there is some degree of improvement after treatment, although in cases of the longest duration, the best that can be accomplished is an arrest of progression.

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DISORDERS CAUSED BY DEFICIENCIES OF FAT-SOLUBLE VITAMINS Vitamin E Deficiency This occurs in two types: a defect in intestinal absorption and an inherent hepatic enzyme deficiency that blocks the incorporation of vitamin E into lipoprotein. A rare neurologic disorder of childhood, sometimes later in life, consisting essentially of spinocerebellar degeneration in association with polyneuropathy and pigmentary retinopathy, has been attributed to a deficiency of vitamin E consequent to prolonged intestinal fat malabsorption (Muller and colleagues; Satya-Murti and colleagues). The same mechanism has been proposed to explain the neurologic disorders that sometimes complicate abetalipoproteinemia (see Chap. 36), fibrocystic disease (Sokol and colleagues), celiac sprue disease, and extensive intestinal resections, intrinsic bowel syndromes, or cholestatic liver disease that cause malabsorption, even decades after the onset of surgery or of the medical disorder (Harding and colleagues). Vitamin E deficiency has also been observed in young children with chronic cholestatic hepatobiliary disease (Rosenblum and colleagues). Ataxia, loss of tendon reflexes, ophthalmoparesis, proximal muscle weakness with elevated serum creatine kinase, and decreased sensation are the usual manifestations of vitamin E deficiency. These symptoms are referable to parts of the nervous system and musculature that are found to be diseased in animals deprived of vitamin E: degeneration of Clark columns, spinocerebellar tracts, posterior columns, nuclei of Goll and Burdach, and sensory roots (Nelson and colleagues). Local differences in the natural concentration of vitamin E in various parts of the nervous system and musculature are believed to account for the distribution of the lesions. In affected children, neurologic function improves after long-term daily supplementation with high doses of vitamin E. In addition to abetalipoproteinemia, there exists a form of spinocerebellar degeneration attributable to an inherited but conditioned deficiency of vitamin E that may closely mimic the phenotype of Friedreich ataxia (“familial isolated vitamin E deficiency” as discussed in Chap. 38). The onset is usually in early adolescence, but there is variability, particularly among different families. In these patients, absorption and transport of vitamin E to the liver is normal, but hepatic incorporation of tocopherol (the active form of vitamin E) into very-low-density lipoproteins is defective (Traber and colleagues). The abnormality has been traced to a mutation in TTPA, the gene encoding α-tocopherol transfer protein (Gotoda and colleagues). In a sense, this is a vitamin deficiency conditioned by a genetic mutation. The mutations and clinical manifestations have been variable, as pointed out in a study of 41 patients in 27 families (Cavalier and colleagues). The age of onset ranged from 2 to 52 years, but generally before age 20. Unexpected features such as head titubation and dystonia occurred in some cases, but unlike Friedreich ataxia, cardiomyopathy was rare. An important feature of

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these cases is that chronic oral administration of large doses of vitamin E can halt and even reverse the progression of the ataxia (Gabsi and colleagues).

Vitamins A and D Deficiencies Neurologic disorders caused by a lack or excess of these fat-soluble vitamins have been reported, but they are rare. Vitamin A deficiency sometimes occurs with malabsorption syndromes, causing impairment of vision. Excess of vitamin A may provoke the syndrome of intracranial hypertension or pseudotumor cerebri (see Chap. 29). Vitamin D deficiency is associated with hypoparathyroidism or a malabsorption state that leads to hypocalcemia, proximal muscle weakness, and rickets.

NUTRITIONAL SYNDROMES OF UNCERTAIN ETIOLOGY Several related conditions of nutritional deficiency overlap in their presentations and have in common an uncertainty as to the primary cause. In all likelihood, there is a combination of factors, perhaps conditioned by genetic susceptibility. Here we refer especially to a syndrome of spastic ataxia, blindness, and a severe painful neuropathy with glossitis, but there are other derivative syndromes that we discuss in this section.

Nutritional Spinal Spastic and Ataxic Syndrome This syndrome is observed occasionally in nutritionally depleted alcoholics. The main clinical signs are spastic weakness of the legs, with absent abdominal and increased tendon reflexes, clonus, extensor plantar responses, and a loss of position and vibratory senses. In our experience, this syndrome has usually been associated with other nutritional disorders such as Wernicke disease and peripheral and optic neuropathy. In prisoner-of-war camps, the “spastic syndrome” was observed in association with mental and emotional changes and dimness of vision, and at times with widespread muscular rigidity, confusion, coma, and death. The latter syndrome has never been studied pathologically, so that it is impossible to state whether the lesions are the same as or different from those of pellagra or from Strachan syndrome, described further on. The syndromes of tropical spastic paraparesis and of lathyrism, another form of spastic paraplegia common in India and certain parts of Africa, were for many years suspected of being nutritional in origin but are now known to be caused by a virus and a toxin, respectively. These and other types of tropical spastic paraplegia are discussed in greater detail with the spinal cord diseases (see Chap. 42). A chronic tropical disease of the peripheral nerves, called “ataxic neuropathy of Nigeria,” has been attributed to the ingestion of inadequately detoxified cassava (Osuntokun) that contains cyanide. Another form of spastic ataxia, called “konzo,” has been attributed to the production of cyanide by an ingested toxic glycoside in individuals who are protein deficient. The differential diagnosis of

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progressive spastic ataxia is quite broad and includes multiple sclerosis.

Nutritional Optic and Peripheral Neuropathy, “Tobacco–Alcohol Amblyopia,” and Strachan Syndrome (See Also Chap. 12) These terms refer to a characteristic form of visual impairment that results from nutritional deficiency. The defect in vision is the result of a lesion of the optic nerves, more or less confined to the region of the papillomacular bundle. Typically, the patient complains of dimness or blurring of vision for near and distant objects, evolving gradually over a period of several days or weeks. Examination discloses a reduction in visual acuity because of the presence of central or centrocecal scotomata, which are larger for colored than for white test objects. Pallor of the temporal portion of the optic disc is observed in some cases. These abnormalities are bilateral and roughly symmetrical and, if untreated, may progress to blindness and irreversible optic atrophy. With normal diet and vitamin supplements, improvement occurs in almost all cases but the most chronic ones; the degree of recovery depends on the severity of the amblyopia and particularly on its duration before therapy is instituted. Although the precise deficiency responsible for this disease cannot be determined, its nutritional basis was established beyond doubt during World War II and the Korean War, when innumerable instances were observed in prisoners of war who had been confined for prolonged periods under conditions of severe dietary deprivation. Fisher described the optic nerve lesions in 4 such patients who had died of unrelated causes between 8 and 10 years after the onset of amblyopia. In each case, there was a loss of myelin and axis cylinders restricted to the region of the papillomacular fibers. Of the 4 cases, 3 also showed demyelination of the posterior columns of the spinal cord, no doubt an expression of the associated sensory polyradiculopathy. In the Western world, a visual disorder indistinguishable clinically and pathologically from that observed in prisoners of war is observed infrequently, mainly among undernourished alcoholics. For many years this had been referred to as tobacco–alcohol amblyopia, with the implication that the visual loss is a result of the toxic effects of alcohol, tobacco, or both. Actually, the evidence strongly suggests that so-called tobacco–alcohol amblyopia is more likely caused by nutritional deficiency than by toxic exposure. A specific nutrient has not been identified, however. There are data in humans and animals that under certain conditions a deficiency of one or more of the B vitamins: thiamine, vitamin B12, and perhaps riboflavin, may cause degenerative changes in the optic nerves, a situation that pertains in the peripheral nerves as well. Part of the confusion in delineating a specific cause has been sporadic outbreaks of optic neuropathy in underdeveloped countries that may have been caused by a disseminated ingested toxin, as described further on. The pathology of the optic nerve in amblyopia in patients with alcoholism has been described by Victor and colleagues (1960).

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In the 1960s, a popular theory held that the combined effects of vitamin B12 deficiency and chronic poisoning by cyanide (generated in tobacco smoke) were responsible for “tobacco amblyopia.” Vitamin B12 deficiency is a rare but undoubted cause of optic neuropathy, as noted further on, but the notion that cyanide or other substances in tobacco smoke have a damaging effect on the optic nerves is unsupported. Instances of Leber hereditary optic atrophy, a mitochondrial disorder, may also be mistaken for “tobacco–alcohol amblyopia,” an error that should be made less often because Leber disease can now be identified by mitochondrial DNA testing. Recent outbreaks of an apparently nutritional or perhaps toxic optic neuropathy occurred in Cuba during the period of 1991 to 1993 and in Tanzania. In both instances, the optic neuropathy was frequently associated with peripheral neuropathy. The association of this epidemic with widespread dietary deprivation and the salutary response of both optic and peripheral nerve symptoms to treatment with B vitamins suggests a nutritional causation (see Centers for Disease Control and Prevention and the report of the Cuba Neuropathy Field Investigation Team), but a toxic cause could not be excluded. Shortly thereafter, Plant and colleagues reported on a similar outbreak of optic and peripheral neuropathy from Tanzania. There remains to be considered a neuropathic syndrome that almost certainly is nutritional in origin but does not conform clinically to beriberi or pellagra, the classic deficiency diseases. This syndrome was originally observed by Strachan in 1897 among Jamaican sugarcane workers. The main symptoms in his patients were pain, numbness, and paresthesias of the extremities; objectively, there was ataxia of gait, weakness, wasting, and loss of deep tendon reflexes and sensation in the limbs. Dimness of vision and impairment of hearing were common findings, as were soreness and excoriation of the mucocutaneous junctions of the mouth. This disorder, originally known as “Jamaican neuritis,” was quickly recognized in other parts of the world, particularly in the undernourished populations of tropical countries. Subsequently, many cases of this syndrome were observed in the besieged population of Madrid during the Spanish Civil War and during World War II among prisoners of war in North Africa and the Far East. The clinical descriptions from these varied sources are not entirely uniform, but certain features are common to all of them and occur with sufficient frequency to allow the delineation of the neurologic syndrome; it appears to be almost identical to the one described by Strachan. The core disorder is combined optic and peripheral neuropathy. The latter consists mainly of sensory symptoms and signs, and the former of the subacute evolution of failing vision, which, if untreated, progresses to complete blindness and pallor of the optic discs. Deafness and vertigo are uncommon, but in some outbreaks among prisoners of war, these symptoms were frequent enough to earn the epithet “camp dizziness.” In all these respects, the syndrome differs from beriberi. Along with the neurologic signs, there may be varying degrees of stomatoglossitis, corneal degeneration, and genital dermatitis (the orogenital syndrome).

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The mucocutaneous lesions are unlike those of pellagra and riboflavin deficiency. There have been only a few neuropathologic studies of this syndrome. Aside from the changes in the papillomacular bundle of the optic nerve, which are similar to the deficiency amblyopia discussed previously, the most consistent abnormality has been a loss of myelinated fibers in each column of Goll adjacent to the midline. Fisher interpreted this change to indicate a degeneration of the central processes of the bipolar sensory neurons of the dorsal root ganglia (i.e., the dorsal roots). The fact that the primary sensory neuron is the main site of the neuropathic disorder is consistent with the predominantly sensory symptomatology. We find it difficult to draw a sharp dividing line between the nutritional peripheral (and optic) neuropathy described previously and the Strachan syndrome.

“Alcoholic” Cerebellar Degeneration This term refers to a common and uniform type of degeneration of the vermian and anterior lobes of the cerebellum in those with alcohol use disorder. Its incidence was in the past about twice that of Wernicke disease, and like the latter, it is considerably more frequent in men than in women. It is characterized clinically by a wide-based stance and gait, varying degrees of instability of the trunk, and ataxia of the legs, the arms being affected to a lesser extent and often not at all. Nystagmus and dysarthria are infrequent. In addition to an ataxic (intention) tremor, there may be a tremor of the fingers or hands resembling one of the two types of parkinsonian tremor but appearing only when the limbs are placed in certain sustained postures. Mauritz and coworkers demonstrated that the instability of the trunk in these cases consists of a specific 3-Hz rhythmic swaying in the anteroposterior direction; by contrast, patients with lesions of the cerebellar hemispheres show only slight postural instability without directional preponderance. In most cases, the cerebellar syndrome evolves over a period of several weeks or months, after which it remains unchanged for many years. In others, it develops more rapidly or more slowly, but in these cases also, the disease eventually stabilizes. Occasionally, the cerebellar disorder progresses in a saltatory manner, the symptoms worsening in relation to a severe infectious illness or an attack of delirium tremens. The pathologic changes consist of degeneration of all the neurocellular elements of the cerebellar cortex but particularly of the Purkinje cells in the anterior and superior aspects of the vermis. The cerebellar atrophy is readily visualized by CT (Fig. 40-3) and MRI. Two particular forms of this syndrome have not been emphasized sufficiently. In one, the clinical abnormalities are limited to an instability of station and gait, individual movements of the limbs being unaffected. The pathologic changes in such cases are restricted to the anterosuperior portions of the vermis. A second type is strikingly acute but transient. Here, except for their reversibility, the cerebellar symptoms are identical to those that characterize the chronic, fixed form

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Marchiafava-Bignami Disease (Degeneration of the Corpus Callosum) In 1903, the pathologists Marchiafava and Bignami described a unique alteration of the corpus callosum in three alcoholic patients. In each case, coronal sectioning of the fixed brain disclosed a pink-gray discoloration of the central portion of the corpus callosum throughout its longitudinal extent. Microscopically, the lesion proved to be confined to the middle lamina (which makes up about two-thirds of the thickness of the corpus callosum), in which there was a loss of myelin and, to some degree, a loss of axis cylinders; macrophages were abundant in the altered zone, and astrocytic proliferation had followed. The clinical observations in these patients were few and incomplete. In 1907, Bignami described a case in which the corpus callosum lesion was accompanied by a similar lesion in the central portion of the anterior commissure. These early reports were followed by a spate of articles that confirmed and amplified the original clinical and pathologic findings. By 1922, about 40 cases of this disorder had been described in Italian literature (Mingazzini). With one exception, all the reported cases were in males, and all these men were insatiable drinkers. They drank red wine for the most part, but other forms of liquor as well. Beginning in 1936, with the report of King and Meehan, the disease came to be recognized throughout the world, and the notions that it had a predilection for drinkers of red wine and a special national predisposition or geographic locale were abandoned. The location of the white matter lesion was later appreciated by MRI to be variable with only a propensity for the corpus callosum. Figure 40-3.  Axial CT from a 60-year-old alcoholic patient showing the prominence of midline cerebellar sulci (upper image). A broadbased gait and ataxia of the legs had been present for many years. Death was from myocardial infarction. The cerebellum, cut in the midsagittal plane (lower image), shows folial atrophy of the anterosuperior vermis, characteristic of alcoholic cerebellar degeneration.

of the disease. In this transient type, the derangement is only one of function and has probably not progressed to the point of fixed structural changes. These forms of cerebellar disease, and particularly the restricted and reversible varieties, cannot be distinguished from the cerebellar manifestations of Wernicke disease either on pathologic or on clinical grounds. It is our opinion that the cerebellar ataxia of Wernicke disease and that referred to as alcoholic cerebellar degeneration are based on the same disease process, the former term being applicable when the cerebellar abnormalities are associated with ocular and cognitive signs and the latter when the cerebellar syndrome stands alone and becomes persistent. Alcoholic cerebellar degeneration is, in all likelihood, a result of nutritional deficiency and not of the toxic effects of alcohol, for reasons already indicated. Insofar as the cerebellar ataxia usually improves to some extent under the influence of thiamine alone (see earlier, under “Wernicke-Korsakoff Syndrome [Thiamine (B1) Deficiency]”), it is likely that a deficiency of this vitamin is in whole or partly responsible for the cerebellar lesion, but this has not been proven.

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Pathologic Features Marchiafava-Bignami disease is more readily defined by its pathologic than its clinical features. The principal alteration, as mentioned, is usually in the middle portion of the corpus callosum, which on gross examination appears rarefied and sunken and reddish or gray-yellow in color, depending on its age. In the anterior portion of the corpus callosum, the lesion tends to be more severe in the midline than in its lateral parts; in the splenium, however, the opposite may pertain. The most chronic lesion takes the form of a centrally placed gray cleft or cavity, with the collapse of the surrounding tissue and a reduction in thickness of the corpus callosum. Microscopically, corresponding to the gross lesions, one observes clearly demarcated zones of demyelination, with variable involvement of the axis cylinders and an abundance of fatty macrophages with gliosis at the margins. Inflammatory changes are absent. Infrequently, lesions of similar nature are found in the central portions of the anterior and posterior commissures and the brachia pontis. These zones of myelin destruction are surrounded by a rim of intact white matter. The predilection of this disease process for commissural fiber systems has been stressed, but it is certainly not confined to these fibers. Symmetrically placed lesions have been observed in the columns of Goll, superior cerebellar peduncles, and cerebral hemispheres, involving the centrum semiovale and extending, in some cases, into the adjacent convolutional white matter. As a rule, the internal

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capsule and corona radiata, subcortical arcuate fibers, and cerebellum are spared. In several cases, the lesions of deficiency amblyopia (see earlier) have been added; in others, the lesions of Wernicke disease. Many of the reported cases, as first pointed out by Jequier and Wildi, have involved cortical lesions of a special type: The neurons in the third layer of the frontal and temporal lobe cortices had disappeared and were replaced by a fibrous gliosis. Morel, who first described this cortical laminar sclerosis, did not observe its association with Marchiafava-Bignami disease. However, when Jequier and Adams reviewed his original cases (unpublished), all had Marchiafava-Bignami disease. In a subsequent report by Delay and colleagues comprising 14 cases of cortical laminar sclerosis, the cortical lesion was also consistently associated with a corpus callosum lesion. We believe the cortical lesions are best explained as secondary to the callosal degeneration.

Clinical Features The disease affects persons in middle and late adult life. With few exceptions, the patients have been males and severe chronic alcoholics. The clinical features of the illness are otherwise quite variable, and a clear-cut syndrome has not emerged. Many patients have presented in a state of terminal stupor or coma, precluding a detailed neurologic assessment. In others, the clinical picture was dominated by the manifestations of chronic inebriation and alcohol withdrawal, namely tremors, seizures, hallucinosis, and delirium tremens. In some of these patients, following the subsidence of the withdrawal symptoms, no signs of neurologic disease could be elicited, even in the end stage of the disease, which lasted for several days to weeks. In yet another group, a progressive dementia has been described, evolving slowly over a year before death. Emotional disorders, dysarthria, slowing and unsteadiness of movement, transient sphincteric incontinence, hemiparesis, and apractic or aphasic disorders have been reported. The last stage of the disease is characterized by physical decline, seizures, stupor, and coma. An impressive feature of these varied neurologic deficits in some patients has been their tendency toward remission when nutrition is restored. In 2 cases that have come to our attention, the clinical manifestations were essentially those of bilateral frontal lobe disease: motor and mental slowness, apathy, prominent grasping and sucking reflexes, gegenhalten, incontinence, and a slow, hesitant, wide-based gait. In both these cases, the neurologic abnormalities evolved over a period of about 2 months, and both patients recovered within a few weeks of hospitalization. Death occurred several years later as a result of liver disease and subdural hematoma, respectively. In each case, the autopsy disclosed an old lesion typical of Marchiafava-Bignami disease confined to the central portion of the most anterior parts of the corpus callosum, but one had to look closely to see the gray line of gliosis. In view of the great variability of the clinical picture and the obscuration in many patients of subtle mental and neurologic abnormalities by the effects of chronic inebriation and other alcoholic neurologic disorders, the

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diagnosis of Marchiafava-Bignami disease is understandably difficult. In fact, it is rarely made during life, but CT and MRI have disclosed typical but unsuspected examples (see Kawamura and colleagues). In some cases studied sequentially, MRI has disclosed demyelination, swelling, and necrosis of the corpus callosum with extension toward the subcortical white matter. In a few cases, these findings have reversed over time after vitamin therapy, leaving residual callosal atrophy (Gambini and colleagues). The occurrence, in a chronic alcoholic, of a frontal lobe syndrome or a symptom complex that points to a diagnosis of frontal or corpus callosum tumor but in whom the symptoms remit should suggest the diagnosis of Marchiafava-Bignami disease. The image appearance may be easily mistaken for multiple sclerosis, gliomatosis cerebri, or progressive multifocal leukoencephalopathy.

Pathogenesis and Etiology Originally, Marchiafava-Bignami disease was attributed to the toxic effects of alcohol, but this is an unlikely explanation in view of the prevalence of alcoholism and the rarity of corpus callosum degeneration. Furthermore, the distinctive callosal lesions have not been observed with other neurotoxins. Very rarely, undoubted examples of Marchiafava-Bignami disease have occurred in abstainers, so that alcohol cannot be an indispensable factor. A nutritional etiology has been invoked, but the putative factor that is deficient has not been determined. This view is underscored by reports of improvement in a few, but not all, cases following the administration of thiamine. The mechanisms involved in the selective demyelination and noninflammatory necrosis of particular areas of the white matter remain to be elucidated. Perhaps, when its mechanism becomes known, Marchiafava-Bignami disease, like central pontine myelinolysis (which it resembles histologically), will have to be considered in a chapter other than one on nutritional disease.

PROTEIN-CALORIE MALNUTRITION AND DEVELOPMENTAL DELAY (SEE ALSO CHAP. 37) There is increasing evidence that severe dietary deprivation during critical phases of brain development may result in permanent impairment of cerebral function and in developmental delay. Because there are an estimated 100 million children in the world who are undernourished and suffer from varying degrees of protein, calorie, and other dietary inadequacies, this is one of the most pressing problems in medicine and society. The literature is too large to review here, but excellent critiques have been provided by Winick, Birchfield and coworkers, Latham, and Dodge and colleagues. In contrast to the devastating effect of protein-calorie malnutrition on body growth, brain weight is only slightly reduced. Nevertheless, on the basis of experiments in dogs, pigs, and rats, it is evident that prenatal and early postnatal malnutrition retards cellular proliferation in the brain. All cells are affected, including oligodendroglia, with a proportional reduction in myelin. Also, the process of dendritic

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branching may be retarded by early malnutrition. A limited number of studies in humans suggest that protein-calorie malnutrition has a similar effect on the brain during the first 8 months of life. In animals, varying degrees of recovery from the effects of early malnutrition are possible if normal nutrition is reestablished during the vulnerable periods. Presumably, this is true for humans as well, although proof is difficult to obtain. In every series of severely undernourished infants and young children who have been observed for a period of many years, a variable proportion has been developmentally delayed to a modest degree; the majority recovers, however (Galler). Unfortunately, the neurologic and intellectual consequences of protein-calorie malnutrition have defied accurate assessment because of the difficulty of isolating the effects of severe malnutrition from those of infection, social deprivation, genetic mechanisms, and other factors.

Nutritional Deficiencies Secondary to Malabsorption The vitamins known to be essential to the normal functioning of the central and peripheral nervous systems cannot be synthesized by the human organism. Each is ingested as an essential part of the normal diet and absorbed in certain regions of the gastrointestinal tract. Impairment or failure of absorption caused by diseases

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of the gastrointestinal tract gives rise to several malabsorption syndromes, some of which have already been referred to, for example, malabsorptive vitamin E deficiency. In these diseases, the site of the block in transport from the intestinal lumen varies; it may be at the surface of the enterocytes or at their interface with the lymphatic channels and portal capillaries. Table 40-3, which is modified from Pallis and Lewis, lists the main malabsorptive diseases and their relationships to intestinal abnormalities. Of all these diseases, celiac sprue (gluten enteropathy) is the most common. The neurologic complications of this disorder, in our experience, have taken the form of a symmetrical, predominantly sensory polyneuropathy, as described in Chap. 43. However, other complications have been described, notably a progressive cerebellar syndrome with cortical, dentatal, and olivary cell loss. The cerebellar changes may be coupled with a symmetrical demyelination of the posterior columns, producing a spinocerebellar disorder similar to that of vitamin E deficiency, but in the latter case, vitamin E supplementation has no consistent effect. Others have remarked on a high incidence of depression and other psychiatric disturbances in adult patients with celiac sprue, as also discussed in Chap. 39. Unexplained seizures are also said to occur. Polyneuropathy and SCD of the spinal cord manifesting many years after gastrectomy are encountered only rarely.

Table 40-3 MECHANISMS WHEREBY MALABSORPTION MAY BE RELATED TO NEUROLOGIC DISEASE GASTROINTESTINAL DEFECT

Localized gastric lesions:   Pernicious anemia   Congenital lack of intrinsic factor   Partial gastrectomy   Lesions of small intestine:   Predominantly proximal     Predominantly distal:  Diffuse Bacterial contamination of small bowel (jejunal diverticulosis, blind-loop syndrome, strictures) Congenital absorptive defect         Transmucosal transport disorders associated with steatorrhea:     Endocrine causes  Postirradiation   Drug induced Defective synthesis of chylomicrons with prolonged intestinal malabsorption Infiltration of villous cores Competition for essential nutrients (e.g., fish tapeworm)

SUBSTANCE MALABSORBED

ASSOCIATED NEUROLOGIC DISORDER

  Vitamin B12 Vitamin B12 Vitamin B12 Vitamin D   ? Water-soluble vitamins Vitamin D Folic acid Vitamin B12   Vitamin B12

  Myelopathy, optic neuropathy, etc. Myelopathy, neuropathy, etc. Myelopathy, neuropathy, etc. Osteomalacic myopathy   ? Hypovitaminosis B ? Osteomalacic myopathy Probably none Neuropathy, myelopathy, etc. Myoclonus, ataxia, etc. Neuropathy, myelopathy, etc.

“Neutral” amino acids Tryptophan Methionine Folic acid Vitamin B12 Fat-soluble vitamins

Hartnup disease “Blue diaper” syndrome “Oast-house” urine disease Mental retardation, seizures, ataxia, choreoathetosis Neuropathy, myelopathy Xerophthalmia

        Vitamin E (carrier lipoprotein not synthesized in liver) Fats (defective chylomicron release) Vitamin B12

Keratomalacia ? Osteomalacic myopathy     Bassen-Kornzweig disease, spinocerebellar degeneration with polyneuropathy Encephalopathy of Whipple disease Neuropathy, myelopathy

Source: Reproduced by permission from Pallis CA, Lewis PD. The Neurology of Gastrointestinal Disease. Philadelphia: Saunders; 1974.

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Table 40-4 VITAMIN-RESPONSIVE INHERITED DISORDERS AFFECTING THE NERVOUS SYSTEM VITAMIN

DISORDER

THERAPEUTIC DOSE

ENZYMATIC DEFECT

Thiamine (B1)

Branched-chain ketoaciduria

5–20 mg

     

Lactic acidosis Pyruvic acidemia Anemia

5–20 mg 5–20 mg 50 mg

Branched-chain ketoacid decarboxylase Pyruvate carboxylase Pyruvate dehydrogenase —

Pyridoxine (B6)

Homocystinuria

>25 mg

Cystathionine synthase

    Cobalamin (B12)

Infantile convulsions Xanthurenic aciduria Methylmalonic aciduria

10–50 mg 5–10 mg 1,000 g

 

Methylmalonic aciduria and homocystinuria Megaloblastic anemia Formiminotransferase deficiency Homocystinuria and hypomethioninemia b-Methylcrotonylglycinuria Propionic acidemia Hartnup disease

>500 g

Glutamic acid decarboxylase Kynureninase Methylmalonyl-CoA mutase apoenzyme Defects in synthesis of adenosylcobalamin and methylcobalamin Folate deficiency Intestinal malabsorption of formiminotransferase N5, N10-Methylenetetrahydrofolate reductase b-Methylcrotonyl-CoA carboxylase Propionyl-CoA carboxylase Intestinal malabsorption of tryptophan

Folic acid     Biotin   Nicotinamide

5 mg >10 mg ↑5–10 mg ↑5–10 mg >400 mg

NEUROLOGIC MANIFESTATIONS

Lethargy, coma Mental retardation Cerebellar ataxia Same as thiamine-deficient beriberi of infancy and childhood Mental retardation, cerebrovascular accidents, psychoses Seizures Mental retardation Lethargy, coma, psychomotor retardation Developmental arrest, cerebellar ataxia Mental retardation Mental retardation Schizophrenic syndrome Mental retardation Lethargy, coma Cerebellar ataxia

Source: Adapted from Rosenberg and from Matsui SM, Mahoney MJ, Rosenberg LE: The natural history of inherited methylmalonic acidemias. N Engl J Med 308:857, 1983.

The neurology of gastrointestinal disease has also been reviewed by Perkin and Murray-Lyon.

INHERITED VITAMIN-RESPONSIVE NEUROLOGIC DISEASES (SEE TABLE 40-4 AND CHAP. 36) Although humans lack the capacity to synthesize essential vitamin molecules, they are nonetheless able to use them in a series of complex chemical reactions involved in intestinal absorption, transport in the plasma, entry into the organelles of many organs, activation of the vitamin into coenzyme, and, finally, their interaction with certain specific apoenzyme proteins. This compels consideration

of another aspect of nutrition wherein one or more of these steps in vitamin utilization may be defective because of a genetic abnormality. Under these circumstances, the signs of vitamin deficiency result not from vitamin deficiency in the diet but from a genetically deranged control mechanism. In some instances, the defect is only quantitative, and by loading the organism with a great excess of the vitamin in question, the biochemical abnormality can be overcome. The aforementioned special type of vitamin E deficiency that results from an inherited inability to incorporate the vitamin into lipoproteins falls into this category, the diseases of which, being of hereditary type, have already been described in Chap. 36. Rosenberg has listed the most important of these hereditary vitaminresponsive diseases, which we have abstracted for the reader in Table 40-4.

References Adams RD, Kubik CS: Subacute degeneration of the brain in pernicious anemia. N Engl J Med 231:2, 1944. Agamanolis DP, Victor M, Harris JW, et al: An ultrastructural study of subacute combined degeneration of the spinal cord in vitamin B12 deficient rhesus monkeys. J Neuropathol Exp Neurol 37:273, 1978. Albin RL, Albers JW, Greenberg HS, et al: Acute sensory neuropathy-neuronopathy from pyridoxine overdosage. Neurology 37:1729, 1987.

Ropper_Ch40_p1153-p1176.indd 1174

Allen RH, Stabler SP, Savage DG, Lindenbaum J: Diagnosis of cobalamin deficiencies: I. Usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 34:90, 1990. Amess JAL, Burman JF, Nancekievill DG, Mollin DL: Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 2:339, 1978. Antozzi C, Garavaglia B, Mora M, et al: Late-onset riboflavinresponsive myopathy with combined multiple acyl coenzyme

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Chapter 40 Diseases of the Nervous System Caused by Nutritional Deficiency A dehydrogenase and respiratory chain deficiency. Neurology 44:2153, 1994. Bean WB, Hodges RE, Daum KE: Pantothenic acid deficiency induced in human subjects. J Clin Invest 34:1073, 1955. Beck WS: Cobalamin and the nervous system. N Engl J Med 318:1752, 1988. Behse F, Buchthal F: Alcoholic neuropathy: Clinical, electrophysiological, and biopsy findings. Ann Neurol 2:95, 1977. Biehl JP, Vilter RW: The effect of isoniazid on vitamin B6 metabolism and its possible significance in producing isoniazid neuritis. Proc Soc Exp Biol Med 85:389, 1954. Bignami A: Sulle alterazione del corpo calloso e della commissura anteriore ritrovate in un alcoolista. Policlinico [Prat] 14:460, 1907. Birchfield RE: Postural hypotension in Wernicke’s disease: A manifestation of autonomic nervous system involvement. Am J Med 36:404, 1964. Bomb BS, Bedi HK, Bhatnagar LK: Post-ischaemic paresthesiae in pellagrins. J Neurol Neurosurg Psychiatry 40:265, 1977. Botez MI, Peyronnard J, Charron L: Polyneuropathies responsive to folic acid therapy. In: Botez MI, Reynolds EH (eds): Folic Acid in Neurology, Psychiatry, and Internal Medicine. New York, Raven Press, 1979, pp 401–412. Carmel R: Subtle and atypical cobalamin deficiency states. Am J Hematol 34:108, 1990. Carmel R, Watkins D, Goodman SI, Rosenblatt DS: Hereditary defect of cobalamin metabolism (cb1G mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 318:1738, 1988. Carney MWP: Neuropsychiatric disorders associated with nutritional deficiencies. CNS Drugs 3:279, 1995. Cavalier L, Ouachi K, Kayden H, et al: Ataxia with isolated vitamin E deficiency: Heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 62:301, 1998. Centers for Disease Control and Prevention: Epidemic neuropathy—Cuba, 1991–1994. MMWR Morb Mortal Wkly Rep 43:183, 189, 1994. Charness ME, DeLaPaz RL: Mamillary body atrophy in Wernicke’s encephalopathy: Antemortem identification using magnetic resonance imaging. Ann Neurol 22:595, 1987. Clayton PT, Smith I, Harding B, et al: Subacute combined degeneration of the cord, dementia, and parkinsonism due to an inborn error of metabolism. J Neurol Neurosurg Psychiatry 49:920, 1986. Crellin R, Bottiglieri T, Reynolds EH: Folate and psychiatric disorder: Clinical potential. Drugs 45:623, 1993. Cuba Neuropathy Field Investigation Team: Epidemic optic neuropathy in Cuba—clinical characterization and risk factors. N Engl J Med 333:1176, 1995. Delay J, Brion S, Escourolle R, Sanchez A: Rapports entre la degenerescence du corps calleux de Marchiafava-Bignami et la sclerose laminaire corticale de Morel. Encephale 49:281, 1959. Denny-Brown DE: The neurological aspects of thiamine deficiency. Fed Proc 17(Suppl 2):35, 1958. Dodge PR, Prensky AL, Feigin R: Nutrition and the Developing Nervous System. St. Louis, Mosby, 1975. Donnal JF, Heinz ER, Burger PC: MR of reversible thalamic lesions in Wernicke syndrome. AJNR Am J Neuroradiol 11:893, 1990. Elvehjem CA, Madden RJ, Strong FM, Woolley DW: Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J Am Chem Soc 59:1767, 1937. Fine EJ, Hallett M: Neurophysiological study of subacute combined degeneration. J Neurol Sci 45:331, 1980. Fisher CM: Residual neuropathological changes in Canadians held prisoners of war by the Japanese. Can Serv Med J 11:157, 1955.

Ropper_Ch40_p1153-p1176.indd 1175

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Gabsi S, Gouider-Khouja N, Belal S, et al: Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol 8:477, 2001. Galler JR: Malnutrition—a neglected cause of learning failure. Postgrad Med 80:225, 1986. Galvin R, Bråthen G, Ivashynka A, et al: EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol 17:1408, 2010. Gambini A, Falini A, Moiola L, et al: Marchiafava-Bignami disease: Longitudinal MR imaging and MR spectroscopy study. AJNR Am J Neuroradiol 24:249, 2003. Ghez C: Vestibular paresis: A clinical feature of Wernicke’s disease. J Neurol Neurosurg Psychiatry 32:134, 1969. Goldsmith GA: Niacin-tryptophan relationships in man and niacin requirement. Am J Clin Nutr 6:479, 1958. Gotoda T, Arita M, Arai H, et al: Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the α-tocopherol-transfer protein. N Engl J Med 333:1313, 1995. Harding AE, Mathews S, Jones S, et al: Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med 313:32, 1985. Harper C: The incidence of Wernicke’s encephalopathy in Australia—a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 46:593, 1983. Harper CG, Giles M, Finlay-Jones R: Clinical signs in the Wernicke-Korsakoff complex: A retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 49:341, 1986. Hemmer B, Glocker FX, Schumacher M, et al: Subacute combined degeneration: Clinical, electrophysiologic, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 65:822, 1998. Ishii N, Nishihara Y: Pellagra among chronic alcoholics: Clinical and pathological study of 20 necropsy cases. J Neurol Neurosurg Psychiatry 44:209, 1981. Jequier M, Wildi E: Le syndrome de Marchiafava-Bignami. Schweiz Arch Neurol Psychiatr 77:393, 1956. Jolliffe N, Bowman KM, Rosenblum LA, Fein HD: Nicotinic acid deficiency encephalopathy. JAMA 114:307, 1940. Kawamura M, Shiota J, Yagishita T, Hirayama K: MarchiafavaBignami disease: Computed tomographic scan and magnetic resonance imaging. Ann Neurol 18:103, 1985. King LS, Meehan MC: Primary degeneration of the corpus callosum (Marchiafava’s disease). Arch Neurol Psychiatry 36:547, 1936. Kinsella LJ, Green R: “Anesthesia paresthetica”: Nitrous oxideinduced cobalamin deficiency. Neurology 45:1608, 1995. Koike H, Iijima M, Sugiura M, et al: Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann Neurol 54:19, 2003. Latham MC: Protein-calorie malnutrition in children and its relation to psychological development and behavior. Physiol Rev 54:541, 1974. Layzer RB: Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 2:1227, 1978. Lindenbaum J, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:1720, 1988. Mair RG, Capra C, McEntee WJ, Engen T: Odor discrimination and memory in Korsakoff ’s psychosis. J Exp Psychol 6:445, 1980. Mandel H, Bernat M, Hazani A, Naveh Y: Thiamine-dependent beriberi in the thalamic-responsive anemia syndrome. N Engl J Med 311:836, 1984. Marchiafava E, Bignami A: Sopra un alterazione del corpo calloso osservata in soggetti alcoolisti. Riv Patol Nerv Ment 8:544, 1903.

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Mauritz KH, Dichgans J, Hufschmidt A: Quantitative analysis of stance in late cortical cerebellar atrophy of the anterior lobe and other forms of cerebellar ataxia. Brain 102:461, 1979. Mingazzini G: Der Balken. Berlin, Springer-Verlag, 1922. Morel F: Une forme anatomo-clinique particuliere de l’alcoolisme chronique: Sclerose corticale laminaire alcoolique. Rev Neurol 71:280, 1939. Muller DPR, Lloyd JK, Wolff OH: Vitamin E and neurological function. Lancet 1:225, 1983. Nelson JS, Fitch CD, Fisher VW, et al: Progressive neuropathologic lesions in vitamin E deficient rhesus monkey. J Neuropathol Exp Neurol 40:166, 1981. Osuntokun BO: Cassava diet, chronic cyanide intoxication and neuropathy in the Nigerian Africans. World Rev Nutr Diet 36:141, 1981. Pallis CA, Lewis PD: The Neurology of Gastrointestinal Disease. Philadelphia, Saunders, 1974. Perkin CD, Murray-Lyon I: Neurology and the gastrointestinal system. J Neurol Neurosurg Psychiatry 65:291, 1998. Pincus JH: Folic acid deficiency: A cause of subacute combined system degeneration. In: Botez MI, Reynolds EH (eds): Folic Acid in Neurology, Psychiatry, and Internal Medicine. New York, Raven Press, 1979, pp 427–433. Plant GT, Mtanda AT, Arden GB, Johnson GJ: An epidemic of optic neuropathy in Tanzania: Characterization of the visual disorder and associated peripheral neuropathy. J Neurol Sci 145:127, 1997. Ronthal M, Adler H: Motor nerve conduction velocity and the electromyograph in pellagra. S Afr Med J 43:642, 1969. Rosenberg LE: Vitamin-responsive inherited diseases affecting the nervous system. In: Plum F (ed): Brain Dysfunction in Metabolic Disorders. Vol 53. New York, Raven Press, 1974, pp 263–270. Rosenblum JL, Keating JP, Prensky AL, Nelson JS: A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med 304:503, 1981. Satya-Murti S, Howard L, Krohel G, Wolf B: The spectrum of neurologic disorder from vitamin E deficiency. Neurology 36:917, 1986. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: A new megavitamin syndrome. N Engl J Med 309:445, 1983. Sechi G, Serra A: Wernicke’s encephalopathy: New clinical settings and recent advances in diagnosis and management. Lancet Neurol 6:442, 2007. Serdaru M, Hausser-Hauw C, Laplane D, et al: The clinical spectrum of alcoholic pellagra encephalopathy. Brain 111:829, 1988. Shah DR, Singh SV, Jain IL: Neurological manifestations in pellagra. J Assoc Physicians India 19:443, 1971. Shattuck GC: Relation of beriberi to polyneuritis from other causes. Am J Trop Med Hyg 8:539, 1928. Shimojyo S, Scheinberg P, Reinmuth OM: Cerebral blood flow and metabolism in the Wernicke-Korsakoff syndrome. J Clin Invest 46:849, 1967. Sokol RJ, Butler-Simon N, Neubi JE, et al: Vitamin E deficiency neuropathy in children with fat malabsorption: Studies in cystic fibrosis and chronic cholestasis. Ann N Y Acad Sci 570:156, 1989. Spillane JD: Nutritional Disorders of the Nervous System. Baltimore, Lippincott Williams & Wilkins, 1947. Spivak JL, Jackson DL: Pellagra: An analysis of 18 patients and a review of the literature. Johns Hopkins Med J 140:295, 1977. Strachan H: On a form of multiple neuritis prevalent in the West Indies. Practitioner 59:477, 1897.

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Strauss MB: Etiology of “alcoholic” polyneuritis. Am J Med Sci 189:378, 1935. Swank RL, Adams RD: Pyridoxine and pantothenic acid deficiency in swine. J Neuropathol Exp Neurol 7:274, 1948. Sydenstricker VP, Schmidt HL Jr, Fulton MC, et al: Treatment of pellagra with nicotinic acid: Observations in 45 cases. South Med J 31:1155, 1938. Thomson AD, Cook CC, Touquet R, et al: The Royal College of Physicians report on alcohol: Guidelines for managing Wernicke’s encephalopathy in the accident and emergency department. Alcohol Alcohol 37:513, 2002. Torvik A, Lindboe CF, Rogde S: Brain lesions in alcoholics: A neuropathological study with clinical correlations. J Neurol Neurosurg Psychiatry 56:233, 1982. Traber MG, Sokol RJ, Burton GW, et al: Impaired ability of patients with familial isolated vitamin E deficiency to incorporate α-tocopherol into lipoproteins secreted by the liver. J Clin Invest 85:397, 1990. Varnet O, De Seze J, Soto-Ares G, et al: Encéphalopathie de Gayet-Wernicke: Intérêt diagnostique et pronostique de l’Imagerie par Résonance Magnétique. Rev Neurol 158:1181, 2002. Victor M: Polyneuropathy due to nutritional deficiency and alcoholism. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds): Peripheral Neuropathy, 2nd ed. Philadelphia, Saunders, 1984, pp 1899–1940. Victor M: Tobacco amblyopia, cyanide poisoning and vitamin B12 deficiency: A critique of current concepts. In: Smith JL (ed): Miami Neuro-ophthalmology Symposium. Vol 5. Hallandale, FL, Huffman, 1970, pp 33–48. Victor M: MR in the diagnosis of Wernicke-Korsakoff syndrome. AJNR Am J Neuroradiol 11:895, 1990. Victor M, Adams RD: Neuropathology of experimental vitamin B6 deficiency in monkeys. Am J Clin Nutr 4:346, 1956. Victor M, Adams RD: On the etiology of the alcoholic neurologic diseases with special reference to the role of nutrition. Am J Clin Nutr 9:379, 1961. Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders due to Alcoholism and Malnutrition, 2nd ed. Philadelphia, Davis, 1989. Victor M, Adams RD, Mancall EL: A restricted form of cerebellar degeneration occurring in alcoholic patients. Arch Neurol 1:577, 1959. Victor M, Mancall EL, Dreyfus PM: Deficiency amblyopia in the alcoholic patient: A clinicopathologic study. Arch Ophthalmol 64:1, 1960. Victor M, Yakovlev PI: S.S. Korsakoff ’s psychic disorder in conjunction with peripheral neuritis: A translation of Korsakoff ’s original article with brief comments on the author and his contribution to clinical medicine. Neurology 5:394, 1955. Vilter RW, Mueller JF, Glazer HS, et al: The effect of vitamin B6 deficiency induced by deoxypyridoxine in human beings. J Lab Clin Med 42:335, 1953. Weidauer S, Nichtweiss M, Lanfermann H, et al: Wernicke’s encephalopathy: MR findings and clinical presentation. Eur Radiol 13:1001, 2003. Windebank AJ: Polyneuropathy due to nutritional deficiency and alcoholism. In: Dyck PJ, Thomas PK, et al (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, Saunders, 1993, pp 1310–1321. Wrenn KD, Murphy F, Slovis CM: A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 18:867, 1989.

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41 Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents

Subsumed under this title is a diverse group of disorders of the nervous system that result from alcohol, drugs, and other injurious or poisonous substances. The neurologist must be concerned with the myriad of chemical agents that may adversely affect the nervous system; they abound in the environment as household products, insecticides, industrial solvents, and other poisons, as well as substances that may have therapeutic value but are used for their “recreational” psychotropic effects or are conventional medications with known toxic effects. Among the neurotoxins are those generated by bacteria and other infectious organisms, as well as toxins found in nature, such as marine toxins. Together, the effect of these agents and toxins on the nervous system constitutes the field of neurotoxicology. It would hardly be possible within one chapter to discuss the innumerable drugs and toxins that affect the nervous system. The interested reader is referred to a number of comprehensive monographs and references such as Casarett and Doull’s Essentials of Toxicology, edited by Klaassen and Watkins. The scope of this chapter is also limited because the therapeutic and adverse effects of many drugs are considered elsewhere in this volume in relation to particular symptoms and diseases. For example, the adverse effects of some antibiotics on cochlear and vestibular function and on neuromuscular transmission are discussed in Chaps. 14 and 46, respectively. Many of the undesirable side effects of the common drugs used in the treatment of extrapyramidal motor symptoms, pain, headache, seizure, sleep disorders, psychiatric illnesses, and so forth are also considered in the chapters dealing with each of these disorders and in the chapters that cover psychiatric diseases. Cyanide and carbon monoxide poisoning are discussed in relation to anoxemic encephalopathy (see Chap. 39). A number of therapeutic agents that predictably damage the peripheral nerves (e.g., cisplatin, disulfiram, vincristine) are mentioned in this chapter but are discussed further in Chap. 43, and those that affect muscle are included in Chap. 45. The presentation of this subject is introduced by some general remarks on the action of drugs on the nervous

system and is followed by discussion of the main classes of agents that affect nervous function: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Alcohol and alcoholism Opiates, opioids, and synthetic analgesic drugs Sedative-hypnotic drugs Antipsychosis drugs Antidepressant drugs Stimulants Psychoactive drugs and hallucinogens Bacterial toxins Plant poisons venoms, bites, and stings Heavy metals and industrial toxins Antineoplastic and immunosuppressive agents Antibiotics

GENERAL PRINCIPLES OF NEUROTOXICOLOGY The rational use of any drug requires knowledge of the best route of administration, the drug’s absorption characteristics, its distribution in the nervous system and other organs, and its biotransformations and excretion (pharmacokinetics). Because every drug, if given in excess, has some adverse effects, therapeutics and toxicology are inseparable. All systems of neurons are not identical; each has its own vulnerabilities to particular drugs and toxic agents. This principle, originally enunciated by Oskar and Cecile Vogt in their theory termed pathoclisis is now embodied as “selective vulnerability.” For example, selective vulnerability explains the production of parkinsonism by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in which a synthetic toxin affects a progressive loss of melanin-bearing dopaminergic nigral neurons (see Chap. 38). Another example is the preferential effects of anesthetics on the neurons of the upper brainstem reticular formation. Not only may certain groups of nerve cells be selectively destroyed by a particular agent, but particular parts of their structure may be altered as well. Drugs may be targeted even to the terminal axons, dendrites,

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neurofilaments, or receptors on pre- and postsynaptic surfaces of neurons or to certain of their metabolic activities, whereby they synthesize and release neurotransmitters or maintain their cellular integrity by the synthesis of RNA, DNA, and other proteins. An intriguing extension of this theme relates to the manner in which certain drugs or toxins affect individuals differently with a genetic disposition by way of single nucleotide polymorphisms; this is the field of pharmacogenetics. The same mechanisms by which drugs and toxins act on particular steps in the formation, storage, release, uptake, catabolism, and resynthesis of neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine, and other catecholamines cannot be separated from their toxic effects. These transmitters and modulating agents, by attaching to receptors at neuronal synapses, are able to increase or decrease the permeability of ion channels and stimulate or inhibit second cytoplasmic messengers (cyclic adenosine monophosphate [cAMP] and G-proteins) (Johnston and Gross). For example, drugs such as L-dopa, tryptophan, and choline enhance the synthesis of dopamine, serotonin, and acetylcholine, respectively, and may impart toxic effects through these same mechanisms. Baclofen modulates the release of gammaaminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system. Botulinum toxin prevents the release of acetylcholine in the neuromuscular junction and tetanus toxin does the same on GABA in Renshaw cells of the spinal cord. Benzodiazepines, bromocriptine, and methylphenidate are viewed as receptor agonists; the phenothiazines and anticholinergics act as receptor antagonists. Certain drugs enhance the activity of neurotransmitters by inhibiting their reuptake as, for example, the class of antidepressant drugs that has a relatively selective influence on the reuptake of serotonin. Others deplete existing neurotransmitters, and another class of drugs promotes the release of preformed synaptic transmitters; amphetamines and modafinil are examples in this class. One must not assume that these are the exclusive modes of action of each of these drugs; for example, cocaine acts as a direct stimulant and through the inhibition of reuptake of catecholamines. Furthermore, drugs have off-target effects in areas other than the central nervous system; this is particularly true of therapeutic medications that have gastrointestinal side effects and, of course, the obverse is true in daily practice as so many drugs used for treatment of diseases in visceral organs cause confusion, seizures, sensory symptoms, or weakness but their effects on the nervous system. To enter the extracellular compartment of the nervous system, a drug or toxic agent must transgress the tight capillary–endothelial barrier (blood–brain barrier) and the barrier between the blood and cerebrospinal fluid (blood–CSF barrier). Intrathecal injection circumvents these barriers, but then the agent tends to concentrate in the immediate subpial and subependymal regions. The process of movement from plasma to brain is by diffusion through capillaries or by facilitated transport. The solubility characteristics of the drug determine its rate of diffusion. In the following discussion on neurotoxins, the reader will appreciate a number of phenomena: tolerance

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(lessening effect of increasing dose), dependence and addiction (insatiable need), habituation, drug-seeking behaviors, and abstinence with its associated withdrawal effects. Particularly difficult in reference to drugs such as nicotine is the separation of habituation from addiction, that is, of psychologic dependence from physical dependence (see further on). The few examples given earlier are intended to provide a glimpse of the complex interactions between chemical agents and the cells of the nervous system. For more specific information, the reader is referred to authoritative textbooks of pharmacology such as Goodman and Gilman’s The Pharmacological Basis of Therapeutics, edited by Brunton and Knollmann.

ALCOHOL AND ALCOHOLISM Intemperance in the use of alcohol creates many problems in modern society, the importance of which can be judged by the emphasis it has received in contemporary writings, both literary and scientific. These problems may be divided into three categories: psychological, medical, and sociological. The main psychologic issue regards why a person drinks excessively, often with full knowledge that such action will result in physical injury and even death. The medical problem embraces all aspects of alcoholic dependence and habituation as well as the diseases that result from the abuse of alcohol. The sociologic problem encompasses the effects of sustained drinking on the patient’s work, family, and community. Some idea of the enormity of these problems can be gleaned from figures supplied by the United States Department of Health and Human Services, which indicate that up to 40 percent of medical and surgical patients have alcohol-related problems and that these patients account for 15 percent of all healthcare costs. Several surveys have suggested a rate of alcohol dependence of 3 to 5.5 percent of adults. A minimum of 3 percent of deaths in the United States are attributable to alcohol-related causes. More striking, but not at all surprising, is the fact that alcohol intoxication is involved in approximately 45 percent of fatal motor vehicle accidents and 22 percent of boating accidents. It requires little imagination to conceive the havoc wrought by alcohol in terms of suicide, accidents, crime, mental and physical disease, and disruption of family life. Finally, the problems engendered by excessive drinking cannot easily be separated from one another.

Etiology of Alcoholism (Alcohol Use Disorder) The cause of alcoholism as an addiction, or the less judgmental term “alcohol use disorder,” remains as obscure as it is for other forms of dependence and addiction, although environmental, cultural, and genetic factors are clearly implicated. No single personality type has been shown to predict reliably who will become addicted to alcohol. Similarly, no particular aspect of alcohol metabolism has been found to account for the development of addiction, with the possible exception of aldehyde dehydrogenase (see further on). Some persons drink excessively and

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Chapter 41 Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents

become alcoholic in response to a profoundly disturbing personal or family problem, but most do not. Alcoholism may develop in response to a depressive illness, more so in women than in men, but far more often depression is a consequence of drinking. Social and cultural influences are undoubtedly important in the genesis of alcoholism, however, no ethnic or racial group and no social or economic class are exempt. The importance of genetic factors in alcoholism has been amply identified. A study has been done in adopted Danish men whose biologic parents were alcoholic and control subjects whose biologic parents were not alcoholic (Goodwin and coworkers). All had been adopted before the age of 5 weeks and had no knowledge of their biologic parentage. Twenty percent of the offspring of biologic alcoholic parents, but only 5 percent of the control subjects, had become alcoholics by the age of 25 to 29 years. A Swedish adoption study (Bohman) and one in the United States (Cadoret and colleagues) corroborate these findings. Family studies disclose a three- to fourfold increased risk for alcoholism in sons and daughters of alcoholics, and twin studies show a twofold higher concordance rate for alcoholism in monozygotic than in dizygotic pairs. Details of these studies can be found in comprehensive reviews of the genetics of alcoholism many years ago but no less valid today (Grove and Cadoret; and Schuckit and Winokur). The search goes on for a biologic trait, or marker, that would identify those who are genetically vulnerable to the development of alcoholism, but none has proved to be sufficiently practical or sensitive to identify all such persons (Reich). Existing in parallel to these biological aspects is a vast and qualitatively varied epidemiologic literature on the ostensible health benefits of moderate alcohol intake. Effects on rates of myocardial infarction and all-cause mortality, sometimes different in men compared to women, have been claimed and disclaimed over the past century, often resulting in fads with limited medical credibility (such as the health benefits of red wine, which the authors personally but not professionally endorse). All that can be said is that studies are hopelessly confounded by social and other factors and in our opinion, no statement can be made that serves the public health.

Pharmacology and Physiology of Alcohol Ethyl alcohol, or ethanol, is the active ingredient in beer, wine, whiskey, gin, vodka, and other alcoholic beverages. The stronger spirits contain enanthic ethers, which provide flavor but have no important pharmacologic properties. In some preparations, impurities such as amyl alcohol (fusel oil) and acetaldehyde act like alcohol but are more toxic. Alcohol is metabolized chiefly by oxidation, less than 10 percent being excreted chemically unchanged in the urine, perspiration, and breath. The energy liberated by the oxidation of alcohol (7 kcal/g) can be utilized as completely as that derived from the metabolism of other carbohydrates. However, calories from alcohol are empty of nutrients such as proteins and vitamins and cannot be used in the repair of damaged tissue. All ingested alcohol, except that metabolized by alcohol dehydrogenase (ADH) in the stomach wall, is carried by the portal system to the

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liver. Here several enzyme systems independently oxidize alcohol to acetaldehyde. The most important of these, accounting for 80 to 90 percent of ethanol oxidation in vivo, are ADH and its isoenzymes. This reaction leads to the formation of acetaldehyde and the reduction of nicotinic acid dehydrogenase (NAD) to nicotinamide adenine dinucleotide (NADH). A second pathway of lesser importance involves catalase, which is located in the peroxisomes and mitochondria; a third uses the “microsomal ethanol oxidizing system” (MEOS), located mainly in the microsomes of the endoplasmic reticulum. The details of the process by which acetaldehyde is metabolized are still not settled. Most likely it is converted by aldehyde dehydrogenase to acetate. Acetaldehyde has a number of unique biochemical effects that are not produced by alcohol alone. Persons who flush easily after ingestion of alcohol (Chinese, Japanese, and other Asians) differ from “nonflushers” with respect to the metabolism of acetaldehyde rather than to the metabolism of alcohol. The flushing reaction has been traced to a deficiency of aldehyde dehydrogenase activity (Harada and colleagues). The low rate of alcoholism among Asians is said to be related to the flushing reaction (which is, in effect, a modified alcohol–disulfiram reaction; see further on), but this can hardly be the case, as North American Indians, a group with a high incidence of alcoholism, show the same reaction. A scale relating various degrees of functional impairment to blood alcohol levels in nonhabituated persons was constructed many years ago by Miles. At a blood alcohol level of 30 mg/dL, a mild euphoria was detectable, and at 50 mg/dL, mild incoordination. At 100 mg/dL, ataxia was obvious; at 200 mg/dL, there was confusion and a reduced level of mental activity; at 300 mg/dL, the subjects were stuporous; and a level of 400 mg/dL—accompanied by deep anesthesia—was potentially fatal. These figures are valid provided that the alcohol content in the blood rises steadily over a 2-h period and there has not been previous regular exposure to alcohol. For all practical purposes, once the absorption of alcohol has ended and equilibrium has been established with the tissues, ethanol is oxidized at a constant rate, independent of its concentration in the blood (about 150 mg alcohol per kilogram of body weight per hour, or about 1 oz of 90-proof whiskey per hour). Actually, slightly more alcohol is metabolized per hour when the initial concentrations are very high, and repeated ingestion of alcohol may facilitate its metabolism, but these increments are of little clinical significance. In contrast, the rate of oxidation of acetaldehyde does depend on its concentration in the tissues. This fact is of importance in connection with the drug disulfiram, which acts by raising the tissue concentration necessary for the metabolism of a certain amount of acetaldehyde per unit of time. The patient taking both disulfiram and alcohol will accumulate an inordinate amount of acetaldehyde, resulting in nausea, vomiting, and hypotension, sometimes so pronounced in degree as to be fatal. Certain other drugs—notably the sulfonylureas, metronidazole, and furazolidone—have effects like those of disulfiram but are less potent. Alcohol acts directly on neuronal membranes in a manner akin to that of the general anesthetics. These agents,

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as well as barbiturates and benzodiazepines, are lipidsoluble and are thought to dissolve in the cell membranes (in direct relation to the degree of their lipid solubility). One theory has been that with continued ingestion of alcohol, the neuronal membranes ostensibly “rigidify” and become resistant to the fluidizing effect of alcohol (Chin and Goldstein; Harris and colleagues). It is unlikely, however, that these changes in the physical properties of cell membranes are in themselves sufficient to alter cell function. Probably of greater importance are the effects of alcohol on membrane receptor systems that regulate ion channels, particularly chloride and calcium channels. One likely site that relates to the acute intoxicating effects of alcohol is a receptor for the inhibitory neurotransmitter GABA and its associated chloride-ion channel. Benzodiazepine antagonists appear to block the potentiation by alcohol of GABAinduced chloride flux. Like the GABA-chloride channel, the N-methyl-d-aspartate (NMDA) receptors, which transduce signals carried by glutamate (the major excitatory transmitter in the brain), are sensitive to extremely low concentrations of alcohol. There is also evidence that alcohol selectively potentiates serotonin receptor-ion currents, and the activity of this receptor has been implicated in alcoholand drug-seeking behavior and addiction. The effect of chronic administration of alcohol is to increase the number of neuronal calcium channels in the cell membrane. Moreover, calcium channel blockers, given during chronic administration, prevent both the increase in neuronal calcium channels and the development of tolerance to alcohol (Dolin and Little). The significance of these findings has been demonstrated by Little and colleagues, who showed that calcium channel blockers, given to chronically intoxicated animals after withdrawal, prevent withdrawal convulsions. The molecular mechanisms involved in alcohol intoxication and tolerance are obviously more complex than the foregoing remarks would indicate (Charness; and Samson and Harris). There is now a vast literature on this subject, much of it contradictory, and a unified concept of the role of neurotransmitters and their receptors and modulators in the production of alcohol intoxication and tolerance has yet to emerge. The part played by internal cellular messengers, which have attracted much attention in the field of addiction, is also currently under investigation. Alcohol tolerance A scale of blood concentrations such as the one previously described has virtually no value in the chronic alcoholic patient, as it does not take into account the phenomenon of tolerance. It is common knowledge that a habituated person can drink more and show fewer effects than the moderate drinker or abstainer. This phenomenon accounts for the surprisingly large amounts of alcohol that the chronic drinker can consume without showing significant signs of drunkenness. Soberappearing alcoholics may have blood alcohol levels of 400 to 500 mg/dL. This aspect of tolerance must be considered in judging the significance of a single estimation of the blood alcohol concentration as an index of functional capacity. The mechanisms that underlie tolerance and addiction are just beginning to be understood. There is little evidence that an enhanced rate of alcohol metabolism can adequately account for the degree of tolerance

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observed in alcoholics. An increase of neuronal adaptation to alcohol is a more likely explanation. Theoretically, the factors that are operative in this adaptation are the increasing resistance of neuronal membranes to the effects of alcohol and an increase in the number of neuronal calcium channels in the cell membrane.

Clinical Effects of Alcohol on the Nervous System Alcohol functions as a central nervous system (CNS) depressant. Some of the early effects of alcohol, such as garrulousness, aggressiveness, excessive activity, and increased electrical excitability of the cerebral cortex—all of them suggestive of cerebral stimulation—are thought to be caused by the inhibition of certain subcortical structures (possibly the high brainstem reticular formation) that ordinarily modulate cerebrocortical activity. Similarly, the initial hyperactivity of tendon reflexes may represent a transitory escape of spinal motor neurons from higher inhibitory centers. With increasing amounts of alcohol, however, the depressant action affects the cortical as well as other brainstem, cerebellar and spinal neurons. All motor functions—whether the simple maintenance of a standing posture, gait, the control of speech and eye movements, or highly organized and complex motor skills—are adversely affected by alcohol. The movements involved in these acts are not only slower than normal but also more inaccurate and random in character and therefore less well adapted to the accomplishment of specific ends. Alcohol also impairs the efficiency of mental function by interfering with the speed of perception and the ability to persist in mental processing. The learning process is slowed and rendered less effective. Facility in forming associations, whether of words or of figures, and the ability to focus, sustain attention, and concentrate is reduced. Finally, alcohol impairs the faculties of judgment and discrimination and, all in all, the ability to think and reason clearly. A number of neurologic disorders are characteristically associated with alcoholism. The factor common to all of them, of course, is the abuse of alcohol, but the mechanism by which alcohol produces its effects varies widely from one group of disorders to another and in many cases, the essential problem is one of nutritional deficiency as discussed in the preceding chapter. The classification that follows is based for the most part on known mechanisms. I. Alcohol intoxication—drunkenness, coma, paradoxical excitement (“pathologic intoxication”), “blackouts” II. Abstinence or withdrawal syndrome—tremulousness, hallucinosis, seizures, delirium tremens III. Nutritional diseases of the nervous system accompanying alcoholism (see Chap. 40) A. Wernicke-Korsakoff syndrome B. Polyneuropathy C. Optic neuropathy (“tobacco-alcohol amblyopia”) D. Pellagra IV. Diseases of uncertain pathogenesis associated with alcohol use disorder A. Cerebellar degeneration B. Marchiafava-Bignami disease

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C. Central pontine myelinolysis (osmotic demyelination syndrome) D. “Alcoholic” myopathy and cardiomyopathy E. Alcoholic dementia F. Cerebral atrophy V. Fetal alcohol syndrome VI. Neurologic disorders resulting from cirrhosis and portal–systemic shunts (see Chap. 39) A. Hepatic stupor and coma B. Chronic hepatocerebral degeneration VII. Traumatic brain lesions acquired during intoxication— subdural hematoma, cerebral contusion

Alcohol Intoxication and Related Disorders The usual manifestations of alcohol intoxication are so commonplace that they require little elaboration. They consist of varying degrees of exhilaration and excitement, loss of restraint, irregularity of behavior, loquacity and slurred speech, incoordination of movement and gait, irritability, drowsiness, and, in advanced cases, sleepiness, stupor, and coma. There are several complicated types of alcohol intoxication, which are considered below. Unlike the anesthetics, the margin between the dose of alcohol that produces surgical anesthesia and that which dangerously depresses respiration is a narrow one, a fact that adds an element of urgency to the diagnosis and treatment of alcoholic coma. One must also be alert to the possibility that other sedative-hypnotic drugs may have potentiated the depressant effects of alcohol. Another treacherous situation is that of traumatic brain injury that is complicated by intoxication, a circumstance that is prone to misinterpretation because of uncertainty as to the main cause of stupor or coma.

Pathologic Intoxication Despite what has been said earlier, on rare occasions, alcohol has an exclusively excitatory rather than a sedative effect. This reaction has been referred to in the past as pathologic, or complicated, intoxication, and as acute alcoholic paranoid state and is debated as being a genuine entity but we can attest to its existence in several patients we have observed. Because all forms of intoxication are pathologic, atypical intoxication or idiosyncratic alcohol intoxication are more appropriate designations, nevertheless, the term pathologic intoxication is still used. The boundaries of this syndrome have never been clearly drawn. In the past, variant forms of delirium tremens and epileptic phenomena, as well as psychopathic and criminal behavior, were indiscriminately included. Now the term is generally used to designate an outburst of blind fury with assaultive and destructive behavior. Often the patient is subdued only with difficulty. The attack terminates with deep sleep, which occurs spontaneously or in response to parenteral sedation; on awakening, the patient has no memory of the episode. Lesser degrees are also known wherein the patient, after several drinks, repeatedly commits gross social indiscretions. Allegedly this reaction

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may follow the ingestion of a small amount of alcohol, but in some of the patients we have observed the amount has often been substantial. Unlike the usual forms of alcohol intoxication and withdrawal, the atypical form has not been produced in experimental subjects, and the diagnosis depends on the aforementioned arbitrary criteria. Pathologic intoxication has been ascribed to many factors, but there are no meaningful data to support any of them. However, an analogy may be drawn between pathologic intoxication and the paradoxical reaction that occasionally follows the administration of barbiturates or other sedative drugs. The few patients we have seen, mostly young men of college age or slightly older, have been docile and seemingly well-adjusted when not drinking. Usually, they have avoided alcohol after a first episode of this sort, but there have been exceptions. The main disorders to be distinguished from pathologic intoxication are temporal lobe seizures that occasionally take the form of outbursts of rage and violence and the explosive episodes that characterize the behavior of certain sociopaths. The diagnosis in these cases may be difficult and depends on eliciting the other manifestations of temporal lobe epilepsy or sociopathy. Pathologic intoxication may require the use of restraints and the parenteral administration of sedative or antipsychosis agents.

Alcoholic “Blackouts” In the language of the alcoholic, the term blackout refers to an interval of time, during a period of severe intoxication, for which the patient later has no memory—even though the state of consciousness, as observed by others, was not grossly altered during that interval. However, a systematic assessment of mental function during the amnesic period has usually not been made. A few observations indicate that it is short-term (retentive) memory rather than immediate or long-term memory that is impaired; this feature and the subsequent amnesia for the episode are vaguely reminiscent of the disorder known as transient global amnesia (see Chap. 20) but without the incessant repetitive questioning and competence in nonmemory mental activities that characterize the latter. Blackouts may occur at any time in the course of alcoholism, even during the first drinking experience, and they certainly have happened in persons who never became alcoholic. The salient facts are that there is a degree of intoxication that interferes with the registration of events and the formation of memories during the period of intoxication and that the amount of alcohol consumed in moderate social drinking will only rarely produce this effect.

Treatment of Severe Alcohol Intoxication Coma caused by alcohol intoxication represents a medical emergency. The main objective of treatment is to prevent aspiration and respiratory depression. One would like to lower the blood alcohol level as rapidly as possible. The previously favored administration of fructose or of insulin and glucose for this purpose is now known to be of little value. Analeptic drugs such as amphetamine and various mixtures of caffeine and picrotoxin are antagonistic

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to alcohol only insofar as they are overall nervous system excitants, but they do not hasten the oxidation of alcohol and are not clinically useful. The use of hemodialysis is often considered in comatose patients with extremely high blood alcohol concentrations (> 500 mg/dL), particularly if accompanied by acidosis, and in those who have concurrently ingested methanol or ethylene glycol or some other dialyzable drug.

Methyl, Amyl, and Isopropyl Alcohols and Ethylene Glycol Poisoning with alcohols other than ethyl alcohol is a rare but catastrophic occurrence. Amyl alcohol (fusel oil) and isopropyl alcohol are used as industrial solvents and in the manufacture of varnishes, lacquers, and pharmaceuticals; in addition, isopropyl alcohol is readily available as a rubbing alcohol. Intoxication may follow the ingestion of these alcohols or inhalation of their vapors. The effects of both are much like those of ethyl alcohol, but more toxic. They also have in common the generation of acidosis, usually with an anion gap, and if a sample of serum is obtained soon after the ingestion, an osmolar gap that represents the molecules of the circulating alcohol is seen. Methyl alcohol (methanol, wood alcohol) is a component of antifreeze and many combustibles and is used in the manufacture of formaldehyde, as an industrial solvent, and as an adulterant of alcoholic beverages, the latter being the most common source of methyl alcohol intoxication. The oxidation of methyl alcohol to formaldehyde and formic acid proceeds relatively slowly; thus, signs of intoxication do not appear for several hours or may be delayed for a day or longer. Many of the toxic effects are like those of ethyl alcohol, but in addition severe methyl alcohol poisoning may produce serious degrees of acidosis (with an anion gap). The characteristic features of this intoxication, however, are damage to retinal ganglion cells—giving rise to scotomata and varying degrees of blindness, dilated unreactive pupils, and retinal edema—and bilateral degeneration of the putamens, readily visible on brain scans. Survivors may be left blind or, less often, with putamenal necrosis and dystonia or parkinsonism (McLean and colleagues). The most important aspect of treatment is the intravenous administration of large amounts of sodium bicarbonate to reverse acidosis. Hemodialysis and 4-methylpyrazole (see later) may be useful adjuncts because of the slow rate of oxidation of methanol. Ethylene glycol, an aliphatic alcohol, is a commonly used industrial solvent and the major constituent of antifreeze. In the latter form, it is sometimes consumed by alcoholics (5,000 cases of poisoning annually in the United States) and in suicide attempts with disastrous results. At first the patient merely appears drunk, but after a period of 4 to 12 h, hyperventilation and severe metabolic acidosis develop, followed by confusion, convulsions, coma, and renal failure and death in rapid succession. Cerebrospinal fluid lymphocytosis is a common but not invariable feature. The metabolic acidosis is a result of the conversion of ethylene glycol by ADH into glycolic acid, thus producing an anion gap that reflects the presence of this additional substance in the blood. (The anion gap has been defined in different

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ways, but the most convenient is the difference between the positive ion Na+ and the sum of negative ions, Cl− plus HCO3− [venous CO2 is used for the latter]; a value greater than 12 is considered a gap.) The cause of the renal toxicity is less clear—probably it is a result of the formation of oxalate from glycolate and the deposition of oxalate crystals in renal tubules. (One of our recent patients had hippurate crystals in the urine, a finding that is more characteristic of toluene ingestions.) These crystals appear in the urine and sometimes in the cerebrospinal fluid and aid in diagnosis.

Treatment of Nonethanol Alcohol Intoxication The treatment of ethylene glycol poisoning has, until relatively recently, consisted of hemodialysis and the intravenous infusion of sodium bicarbonate and ethanol, the latter serving as a competitive substrate for ADH. However, the use of ethanol in this regimen is problematic. Some workers have advocated the use of intravenous 4-methylpyrazole (fomepizole), which is a more effective inhibitor of ADH than is alcohol (Baud and colleagues; Brent and colleagues; Jacobsen). This form of treatment is recommended for methanol poisoning as well. Generally, for either methanol or ethylene glycol, a plasma level of the alcohol above 20 mg/dL, or above 10 mg/dL when combined with an osmolal gap over 10 is considered appropriate to institute the drug. In the case of ethylene glycol, oxaluria and acidosis are additional factors that may oblige treatment. Dialysis remains an essential therapy if cerebral and renal damage is not too advanced. Some patients who recover from the acute renal and metabolic effects are left with multiple cranial nerve defects, particularly of the seventh and eighth nerves. The latter abnormalities develop 6 to 18 days after the ingestion of ethylene glycol and have been attributed to the deposition of oxalate crystals along the cisternal portions of the affected nerves (Spillane and colleagues).

The Alcohol Abstinence, or Withdrawal, Syndrome This is the well-known symptom complex of tremulousness, hallucinations, seizures, confusion, and psychomotor and autonomic overactivity. Although a sustained period of chronic inebriation is the most obvious factor in the causation of these symptoms, they become manifest only after a period of relative or absolute abstinence from alcohol—hence the designation abstinence, or withdrawal, syndrome. Figure 41-1 illustrates this concept. Each of the major manifestations of the withdrawal syndrome may occur in more or less pure form and are so described below, but usually they occur in combination. Major withdrawal symptoms are observed mainly in the binge, or periodic, drinker, although the steady drinker is not immune if for some reason he stops drinking, such as during a hospital admission for surgery or a medical illness. The full syndrome, depicted further on, is called delirium tremens. In several places in the book it has been commented that the adoption of the general term delirium for all forms of mental confusion is perhaps unfortunate because it buries the richness of the full-blown and diagnostic delirium tremens syndrome.

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Days after cessation of drinking Figure 41-1.  Relation of acute neurologic disturbances to cessation of drinking (based on 50 cases). The shaded drinking period is greatly foreshortened and not intended to be quantitative. The periodic notching in the baseline represents the tremulousness, nausea, and so on that occur following a night’s sleep. The time relations of the various groups of symptoms to withdrawal are explained in the text. (Reproduced with permission from Victor M, Adams RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis. 1953;32:526-573.)

Tremulousness The most common single manifestation of the abstinence syndrome is tremulousness, often referred to as “the shakes” or “the jitters,” combined with general irritability and gastrointestinal symptoms, particularly nausea and vomiting. These symptoms first appear after several days of drinking, usually in the morning after a night’s abstinence. The patient “quiets his nerves” with a few drinks and is then able to drink for the rest of the day without undue distress. The symptoms return on successive mornings with increasing severity. The symptoms then become augmented, reaching their peak intensity 24 to 36 h after the complete cessation of drinking. Generalized tremor is the most obvious feature. It is of fast frequency (6 to 8 Hz), slightly irregular, and variable in severity, tending to diminish when the patient is in quiet surroundings and to increase with motor activity or emotional stress. The tremor may be so violent that the patient cannot stand without help, speak clearly, or eat without assistance. Sometimes there is little objective evidence of tremor, and the patient complains only of being “shaky inside.” Within a few days, flushed facies, anorexia, tachycardia, and tremor characteristic of the mild withdrawal syndrome subside to a large extent, but overalertness, tendency to startle easily, and jerkiness of movement may persist for a week or longer. Feelings of uneasiness may

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not leave the patient completely for 10 to 14 days. Certain electrophysiologic abnormalities (diminished amplitudes of sensory evoked potentials and prolonged latencies and conduction velocities of auditory brainstem potentials) remain altered long after the clinical abnormalities have subsided (Porjesz and Begleiter).

Hallucinations Symptoms of disordered perception occur in about onequarter of withdrawing hospitalized tremulous patients. The patient may complain of “bad dreams”—nightmarish episodes associated with disturbed sleep—which he finds difficult to separate from real experience. Sounds and shadows may be misinterpreted, or familiar objects may be distorted and assume unreal forms (illusions). There may also be more overt hallucinations, which are purely visual in type, mixed visual and auditory, tactile, or olfactory, in this order of frequency. There is little evidence to support the popular belief that certain visual hallucinations (bugs, pink elephants) are specific to alcoholism. Actually, the hallucinations comprise the full range of visual experience. They are more often animate than inanimate; persons or animals may appear singly or in panoramas, shrunken or enlarged, natural and pleasant, or distorted, hideous, and frightening. The hallucinosis may be an isolated phenomenon lasting for a few hours, and it may later be attended by other withdrawal signs.

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Acute and Chronic Auditory Hallucinosis A special type of alcoholic psychosis in chronic alcohol use disorder consisting of a more or less pure auditory hallucinosis has been recognized for many years. Kraepelin referred to it as the “hallucinatory insanity of drunkards,” or “alcoholic mania.” A report of 75 such cases was made many years ago by Victor and Hope. The central feature of the illness, in the beginning, is the occurrence of auditory hallucinations despite an otherwise clear sensorium during the withdrawal period; that is, the patients are not disoriented or obtunded, and they have an intact memory. The hallucinations may take the form of unstructured sounds such as buzzing, ringing, gunshots, or clicking (the elementary hallucinations of Bleuler), or they may have a musical quality, like a low-pitched hum or chant. The most common hallucinations, however, are human voices. When the voices can be identified, they are often attributed to the patient’s family, friends, or neighbors—rarely to God, radio, or television, in these ways closely simulating one aspect of the schizophrenic state. The voices may be addressed directly to the patient, but more frequently, they discuss him in the third person. In most cases, the voices are maligning, reproachful, or threatening in nature and are disturbing to the patient; a significant proportion, however, are not unpleasant and leave the patient undisturbed. To the patient, the voices are clearly audible and intensely real, and they tend to be exteriorized; that is, they come from behind a radiator or door, from the corridor, or through a wall, window, or floor. Another feature of auditory hallucinosis is that the patient’s response is more or less understandable in light of the hallucinatory content. The patient may call on the police for protection or erect a barricade against invaders; he may even attempt suicide to avoid what the voices threaten. The hallucinations are most prominent during the night, and their duration varies greatly: they may be momentary, or they may recur intermittently for days on end and, in exceptional instances, for weeks or months. While hallucinating, most patients have no appreciation of the unreality of their hallucinations. With improvement, the patient begins to question the inauthenticity and may be reluctant to talk about them and may even question his own sanity. Full recovery is characterized by the realization that the voices were imaginary and by the ability to recall, sometimes with remarkable clarity, some of the abnormal thought content of the psychotic episode. A unique feature of this alcoholic psychosis is its evolution, in a small proportion of the patients, to a state of chronic auditory hallucinosis. The chronic disorder begins like the acute one, but after a short period, perhaps a week or two, the symptomatology begins to change. The patient becomes quiet and resigned, even though the hallucinations remain threatening and derogatory. Ideas of reference and influence and other poorly systematized paranoid delusions become prominent. There are, however, important differences between the two disorders: the alcoholic illness develops in close relation to a drinking bout and the past history rarely reveals schizoid personality traits. Moreover, alcoholic patients with hallucinosis

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are not distinguished by a high incidence of schizophrenia within their families (Schuckit and Winokur; Scott), and a large number of such patients, whom our colleagues Victor and Adams evaluated long after their acute attacks, did not show signs of schizophrenia. There is some evidence that repeated attacks of acute auditory hallucinosis render the patient more susceptible to the chronic state. Similar forms of chronic auditory hallucinosis are discussed in Chap. 14 in relation to deafness.

Withdrawal Seizures (“Rum Fits”) In the setting of alcohol withdrawal either as relative or absolute abstinence following a period of chronic inebriation, convulsive seizures are common. More than 90 percent of withdrawal seizures occur during the 7- to 48-h period following the cessation of drinking, with a peak incidence between 13 and 24 h. During the period of seizure activity, the EEG is usually abnormal, but it reverts to normal in a matter of days, even though the patient may go on to develop delirium tremens. During the period of seizure activity and for days afterward, the patient is unusually sensitive to stroboscopic stimulation; almost half the patients respond with generalized myoclonus or a convulsive seizure (photoparoxysmal response). Seizures occurring in the abstinence period have a number of other distinctive features. There may be only a single seizure, but in the majority of cases the seizures occur in bursts of 2 to 6 over a day, occasionally even more; only 2 percent of patients studied by Victor (1968) developed status epilepticus. The seizures are generalized and convulsive. Focal seizures should always suggest the presence of a focal brain lesion (most often traumatic) in addition to the effects of alcohol. Twenty-eight percent of Victor’s patients with generalized withdrawal seizures went on to develop delirium tremens (see Victor, Adams and Collins, the percentage has been less in other series); almost invariably, the seizures preceded the delirium. The postictal confusional state may blend imperceptibly with the onset of the delirium, or the postictal state may have cleared over several hours or even a day or longer before the delirium sets in. Seizures of this type typically occur in a patient whose drinking history has extended over a period of many years and must be distinguished from other forms of seizures that have their onset in adult life. This serves to distinguish them from seizures that occur in the interdrinking period, long after withdrawal has been accomplished. It is important to note that the common idiopathic or posttraumatic forms of epilepsy are also influenced by alcohol. In these types of epilepsy, a seizure or seizures may be precipitated by only a short period of drinking (e.g., a weekend, or even one evening of heavy social drinking); perhaps unsurprisingly in these circumstances, the seizures occur not when the patient is intoxicated but usually the morning after, in the “sobering-up” period. Except for the transient dysrhythmia in the withdrawal period, the incidence of EEG abnormalities in patients who have had withdrawal seizures is no greater than in normal persons, in sharp contrast to the EEGs of nonalcoholic patients with recurrent seizures.

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Treatment and Prevention of Withdrawal Seizures Most patients during withdrawal do not require antiepileptic drugs, as the entire episode of seizure activity— whether a single seizure or a brief flurry of seizures—may have terminated before the patient is brought to medical attention. The parenteral administration of diazepam or sodium phenobarbital early in the withdrawal period does, however, prevent withdrawal fits in patients with a previous history of this disorder, as well as in those who might be expected to develop seizures on withdrawal of alcohol. This approach has been supported by the observations that intravenous lorazepam (2 mg in 2 mL of normal saline) was effective in preventing recurrent seizures after a first seizure in the same withdrawal period. In one series, only 3 of 100 patients so treated had a second seizure within 48 h, compared to 21 of 86 untreated patients (D’Onofrio and colleagues). The long-term administration of anticonvulsants is neither necessary nor practical: if such patients remain abstinent, they will be free of seizures; if they resume drinking, they often abandon their medications. Furthermore, it is not certain that continued administration of anticonvulsants dependably prevents abstinence seizures. The rare instances of status epilepticus should be managed like status of any other type (see Chap. 15). In alcoholics with a history of idiopathic or posttraumatic epilepsy, the goal of treatment, often not attainable, should be abstinence from alcohol, because of the tendency of even short periods of drinking to precipitate seizures. Such patients probably need to be maintained on anticonvulsant drugs. Withdrawal seizures are also discussed in Chap. 15 on Epilepsy and Other Seizure Disorders.

Delirium Tremens (“DTs”) and Related Disorders This is the most dramatic and grave of all the acute alcoholic illnesses. It is characterized by profound confusion, delusions, vivid hallucinations, tremor, agitation, and sleeplessness, as well as by the signs of increased autonomic nervous system activity—that is, dilated pupils, fever, tachycardia, and profuse perspiration. The clinical features of delirium are presented in detail in Chap. 19 as they relate to delirium tremens (DTs) and to other illnesses that simulate it. Delirium tremens develops in one of several settings. The patient, an excessive and steady drinker for many years, may have been admitted to the hospital for an unrelated illness, accident, or operation and, after 2 to 4 days, occasionally even later, becomes delirious. Or, following a prolonged drinking binge, the patient may have experienced several days of tremulousness and hallucinosis or one or more seizures and may even be recovering from these symptoms when delirium tremens develops, rather abruptly as a rule. As to the frequency of delirium tremens, in the past Foy and Kay reported an incidence of 0.65 percent of all patients admitted for other reasons to a large general hospital. Among 200 consecutive alcoholics admitted to a city hospital in the 1990s, 24 percent developed delirium tremens; of these, 8 percent died (Ferguson and colleagues)— figures that are considerably higher than those recorded

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in our hospitals (see in the following text). Of course, the reported incidence of delirium tremens will vary greatly, depending on the population served by a particular hospital. In most cases, delirium tremens is benign and shortlived, ending as abruptly as it begins. Consumed by relentless activity and wakefulness for several days, the patient falls into a deep sleep and then awakens lucid, quiet, and exhausted, with virtually no memory of the events of the delirious period. Less commonly, the delirious state subsides gradually with intermittent episodes of recurrence. In either event, when delirium tremens occurs as a single episode, the duration is 72 h or less in more than 80 percent of cases. Less frequently still, there may be one or more relapses, several episodes of delirium of varying severity being separated by intervals of relative lucidity—the entire process lasting for several days or occasionally for as long as 4 to 5 weeks. In the past, approximately 15 percent of cases of delirium tremens ended fatally, but the figure now is closer to 5 percent. In many of the fatal cases there is an associated infectious illness or injury, but in others, no complicating illness is discernible. Many of the patients die in a state of hyperthermia; in some, death comes so suddenly that the nature of the terminal events cannot be determined. Reports of series of cases with a negligible mortality rate in delirium tremens can usually be traced to a failure to distinguish between delirium tremens and the minor forms of the withdrawal syndrome, which are far more common and practically never fatal. We make note here of our experience with delirium following the withdrawal of barbiturates (Romero and colleagues), which is almost identical to the DTs, including the abrupt cessation of symptoms, as discussed in the section on “Barbiturate Abstinence, or Withdrawal, Syndrome” further on. There are also alcohol withdrawal states, closely related to delirium tremens and about as frequent, in which one facet of the delirium tremens complex assumes prominence, to the virtual exclusion of the other symptoms. The patient may simply exhibit a transient state of quiet confusion, agitation, or peculiar behavior lasting several days or weeks. Or there may be a vivid hallucinatory–delusional state and abnormal behavior consistent with the patient’s false beliefs. Unlike typical delirium tremens, the atypical states usually present as a single circumscribed episode without recurrences, are only rarely preceded by seizures, and do not end fatally. Pathologic examination is singularly unrevealing in patients with delirium tremens. Cerebral edema been absent in the authors’ pathologic material except when shock or hypoxia had occurred terminally. There have been no significant microscopic changes in the brain, which is what one might expect in a disease that is essentially reversible. The EEG findings have been discussed in relation to withdrawal seizures.

Pathogenesis of the Tremulous-HallucinatoryDelirious Disorders Prior to 1950, it was the common belief that these symptoms represented the most severe forms of alcohol intoxication—an idea that fails to satisfy the simplest

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clinical logic. The symptoms of toxicity—consisting of slurred speech, uninhibited behavior, staggering gait, stupor, and coma—are in themselves distinctive and, in a sense, the opposite of the symptom complex of tremor, fits, and delirium. It is evident, from observations in both humans and experimental animals, that the most important and the one obligate factor in the genesis of delirium tremens and related disorders is the withdrawal of alcohol following a period of sustained chronic intoxication. Furthermore, the emergence of withdrawal symptoms depends on a rapid decline in the blood alcohol level from a previously higher level and not necessarily on the complete disappearance of alcohol from the blood. The mechanisms by which the withdrawal of alcohol produces symptoms are incompletely understood. In all but the mildest cases, the early phase of alcohol withdrawal is attended by a drop in serum magnesium concentration and a rise in arterial pH—the latter based on respiratory alkalosis (Wolfe and Victor). Possibly the compounded effect of these two factors, both of which are associated with hyperexcitability of the nervous system, is responsible in part for seizures and for other symptoms that characterize the early phase of withdrawal. However, these factors alone are not explanatory. The molecular mechanisms that are thought to be operative in the genesis of alcohol tolerance and withdrawal have been mentioned earlier. The GABA-ergic system has been most strongly implicated, in part because the receptors for this inhibitory transmitter are downregulated by chronic alcohol use, but the situation is not nearly so simple, insofar as the excitatory glutaminergic system is also inhibited by alcohol. Laboratory findings  Rarely, blood glucose is seriously depressed in the alcohol withdrawal states. Ketoacidosis with normal blood glucose is another infrequent finding. Disturbances of electrolytes are of varying frequency and significance. Serum sodium levels are altered infrequently and are more often increased than decreased. The same is true for chloride and phosphate. Serum calcium and potassium are lowered in about one-quarter of patients. Most patients show some degree of hypomagnesemia, low PCO2, and high arterial pH—abnormalities that are probably important in the pathogenesis of withdrawal symptoms (see later). Abnormalities of the CSF occur unpredictably (it is usually normal), as do changes on brain imaging studies; they may indicate the presence of some medical or surgical complication. Enlargement of the third and lateral ventricles is a common finding (see later). The MRI is normal unless there is an incipient Wernicke disease, in which case lesions in the periaqueductal region and hypothalamus may be evident, as described in the previous chapter.

Treatment of Delirium Tremens and Minor Withdrawal Symptoms (See also Chap. 19 on Delirium and Other Confusional States) The treatment of delirium tremens begins with a search for associated injuries (particularly head injury with cerebral lacerations or subdural hematoma), infections (pneumonia or meningitis), pancreatitis, and liver disease. Because of the frequency and seriousness of these complications, appropriate imaging should be considered in most

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instances, and lumbar puncture should be performed if there is suspicion of meningitis. In severe forms of delirium tremens, the temperature, pulse, and blood pressure should be measured at frequent intervals in anticipation of peripheral circulatory collapse and hyperthermia, which, added to the effects of injury and infection, are the usual causes of death in this disorder. In the case of hypotension, one must act quickly, using intravenous fluids and, if called for, vasopressor drugs. The occurrence of hyperthermia demands the use of a cooling mattress or evaporative cooling in addition to specific treatment for any infection that may be present. An additional important element in treatment is the correction of fluid and electrolyte imbalance, particularly hypokalemia and hypomagnesemia. Severe degrees of agitation and perspiration may require the administration of up to 5 L of fluid daily, of which at least 1,500 to 2,000 mL should be normal saline. The specific electrolytes and the amounts that must be administered are governed by the laboratory values for these electrolytes. If the serum sodium is extremely low, one must be cautious in raising the level lest an osmotic demyelination syndrome be induced (see Chap. 39). In the rare case of hypoglycemia, the administration of glucose is an urgent matter. Patients who present with severe alcoholic ketoacidosis and normal or only slightly elevated blood glucose concentrations usually recover promptly, without the use of insulin. It must be emphasized, as it was in Chap. 40, that a special problem attends the use of glucose solutions in alcoholic patients. The administration of intravenous glucose may serve to consume the last available reserves of thiamine and precipitate Wernicke disease. Typically, these patients have subsisted on a diet disproportionately high in carbohydrate (in addition to alcohol, which is metabolized entirely as carbohydrate) and low in thiamine, and their body stores of B vitamins may have been further reduced by gastroenteritis and diarrhea. For this reason it is good practice to add B vitamins, specifically thiamine (which may also be supplemented by intramuscular injection), in all cases requiring parenterally administered glucose—even though the alcoholic disorder under treatment, for example, delirium tremens, is not primarily caused by vitamin deficiency. With respect to the use of medications to treat the withdrawal syndromes, it is important to distinguish between mild symptoms, which are essentially benign and responsive to practically any sedative drug, and full-blown delirium tremens. There is no certain way to predict whether a patient with the early signs of withdrawal will progress to delirium tremens. In the latter state, the object of therapy is to blunt the psychomotor and autonomic overactivity, prevent exhaustion, and facilitate the administration of parenteral fluid and nursing care; one should not attempt to suppress agitation “at all costs,” as doing so requires an amount of drug that might depress respiratory drive. A variety of drugs are effective in controlling withdrawal symptoms. The more popular ones have been diazepam, and the ancillary medications, clonidine and beta-adrenergic blockers, and a number of both older and newer anticonvulsant drugs such as gabapentin, which

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may reduce the requirement for sedative drugs. There is little to choose among the primary sedative drugs in respect to their therapeutic efficacy. More importantly, there are few data to indicate that any one of them can prevent hallucinosis or delirium tremens, or shorten the duration, or alter the mortality rate of the latter disorder (Kaim and colleagues). A summary of the medication management of withdrawal has been given by Kosten and O’Connor. In general, phenothiazine drugs should be avoided because they may reduce the threshold to seizures. Probably, the use of any of the diazepine medications is as effective as a single dose of lorazepam in prophylactically suppressing seizures (see earlier discussion). If parenteral medication is necessary, we have used 10 mg of diazepam given intravenously and repeated once or twice at 20- to 30-min intervals until the patient is calm but awake; we also favor midazolam in closely controlled circumstances when hyperactivity and hallucinosis are extreme. Beta-adrenergic-blocking agents, such as propranolol, labetalol, and atenolol are helpful in reducing heart rate, blood pressure, and the tremor to some extent. Lofexidine, an alpha2-agonist that blocks autonomic outflow centrally, and clonidine may be similarly effective in reducing the severity of withdrawal symptoms, but clinical trials have given conflicting results for lofexidine and they are not recommended as the sole treatments. Glucocorticoids have no place in the treatment of the withdrawal syndrome and potent agents such as propofol or dexmedetomidine are usually not necessary.

Wernicke-Korsakoff Syndrome and Alcoholic– Nutritional Diseases (See Chap. 40) Alcohol use disorder provides the ideal setting for the development of nutritional diseases of the nervous system. Although only a small proportion of alcoholics develop nutritional diseases, the overall number of these diseases is substantial because of the frequency of alcoholism. The importance of the alcohol-induced deficiency diseases relates to the fact that they are preventable and, if neglected, may lead to permanent disability. These illnesses, particularly the Wernicke-Korsakoff syndrome, are discussed fully in Chap. 40. Contrary to popular opinion with regard to the prevention of Wernicke disease, the content of thiamine in American beer and other liquors is so low as to have little nutritional preventive value (Davidson). (Some other B vitamins are the byproducts of yeast fermentation in production of beer).

Disorders of Uncertain Pathogenesis Associated With Alcohol Use Disorder Also discussed in Chap. 40 are alcoholic cerebellar degeneration and Marchiafava-Bignami disease. The former is almost certainly of nutritional origin; in the latter, a nutritional–metabolic etiology seems likely but has not been established. Central pontine myelinolysis (osmotic demyelination), although frequently observed in alcoholics, is more appropriately considered with the acquired metabolic disorders, usually the too rapid correction of hyponatremia (see Chap. 39). Certain disorders of skeletal

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and cardiac muscle associated with alcoholism (acute alcoholic myopathy and cardiomyopathy) are described in Chap. 45, with myopathies caused by drugs and toxins. There remain to be discussed several diverse disorders that have been attributed to alcoholism but whose causal relationship to alcohol abuse, nutritional deficiency, or some other relevant factor is not clear.

Alcoholic Dementia and Cerebral Atrophy The term alcoholic dementia is used widely and often indiscriminately to designate a presumably distinctive form of dementia that is attributable to the chronic, direct effects of alcohol on the brain. Unfortunately, a syndrome subsumed under the title of alcoholic dementia and its many synonyms that appear in the older literature (alcoholic deteriorated state, chronic alcoholic psychosis, chronic or organic brain syndrome due to alcohol) has never been delineated satisfactorily, either clinically or pathologically. In the Comprehensive Textbook of Psychiatry, it has been defined as “a gradual disintegration of personality structure, with emotional lability, loss of control, and dementia” (Sadock and Sadock). Purported examples of this state show a remarkably diverse group of symptoms, including jealousy and suspiciousness; coarsening of moral fiber and other personality and behavioral disorders; deterioration of work performance, personal care, and living habits; and disorientation, impaired judgment, and defects of intellectual function, particularly of memory. There have been many attempts to redefine alcoholic dementia. Cutting, as well as Lishman, expressed the view that the term Korsakoff psychosis should be limited to patients with a fairly pure disorder of memory of acute onset and that patients with more global symptoms of intellectual deterioration, of gradual evolution, be considered to have alcoholic dementia. These are rather weak diagnostic criteria. As pointed out in Chap. 40, Korsakoff psychosis may have an insidious onset and gradual progression, and patients with this disorder, in addition to an amnesic defect, characteristically show disturbances of cognitive functions that depend little or not at all on memory. More importantly, in none of the patients designated by these authors as having alcoholic dementia was there a neuropathologic examination, without which the clinical assessment must remain arbitrary and imprecise. The pathologic changes that purportedly underlie primary alcoholic dementia are even less precisely defined than the clinical syndrome. Courville, whose writings have been quoted most frequently in this respect, described a series of cerebral cortical changes that he attributed to the toxic effects of alcohol. Some of them turn out on close inspection to be quite nonspecific, reflecting nothing more than the effects of aging or the insignificant artifacts of tissue fixation and staining. That the mean brain weight is decreased in alcoholics and the pericerebral space is increased in volume (Harper and Blumbergs, and Harper and Kril)—findings that do no more than confirm the brain shrinkage that is demonstrable by brain imaging studies in many alcoholics and is to some extent reversible with sustained abstinence (see later).

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Most cases that come to autopsy with the label of alcoholic dementia have proved simply to have the lesions of the Wernicke-Korsakoff syndrome. Traumatic lesions of varying degrees of severity are commonly added. Other cases show the lesions of Marchiafava-Bignami disease, hepatic encephalopathy, subdural hematomas, or an unrelated communicating hydrocephalus, Alzheimer disease, ischemic necrosis, or some other disease quite unrelated to alcoholism. Practically always in our material, the clinical state can be accounted for by one or a combination of these disease processes and there has been no need to invoke a hypothetical toxic effect of alcohol on the brain. This has also been the experience of Torvik and associates; with a few exceptions, such as coincidental Alzheimer disease, all their cases that had been diagnosed as having alcoholic dementia turned out, on neuropathologic examination, to have the chronic lesions of Wernicke-Korsakoff disease. In brief, the most serious flaw in the concept of a primary alcoholic dementia is that it lacks a distinctive, welldefined pathology. Until such time as the morphologic basis is established, its status must remain ambiguous. A more detailed discussion of this subject and of so-called alcoholic cerebral atrophy can be found in the review by Victor (1994). Alcoholic cerebral atrophy likewise does not constitute a well-defined entity. The concept was the product originally of pneumoencephalographic studies. Relatively young alcoholics, some with and some without symptoms of cerebral disease were often found to have enlarged cerebral ventricles and widened sulci, mainly of the frontal lobes (Brewer and Perrett and of Haug). Similar findings have been reported in brain imaging studies of chronic alcoholics (Carlen and colleagues). The clinical correlates of these radiologic findings are unclear. Wilkinson demonstrated that in clinically normal alcoholics, the radiologic measures of “brain atrophy” were age-related; once the age factor was removed, the imaging findings in these subjects did not differ significantly from those in nonalcoholic controls. It may indeed be the case that chronic exposure to alcohol induces cerebral atrophy, but this requires confirmation. The idea of alcoholic atrophy is open to criticism mainly on the grounds that dilated ventricles have in fact been reversible to a considerable extent when abstinence is maintained (Carlen and colleagues; Lishman; Zipursky and colleagues; Schroth and colleagues).

Fetal Alcohol Syndrome That parental alcoholism may have an adverse effect on the offspring has been a recurrent theme in medical writings. Probably the first allusion to such a relationship was that of Sullivan in 1899, who reported that the mortality among the children of drunken mothers was more than two times greater than that among children of nondrinking women of “similar stock.” This increased mortality was attributed by Sullivan and later by Haggard and Jellinek to postnatal influences such as poor nutrition and a chaotic home environment, rather than to the intrauterine effects of alcohol. The idea that maternal alcoholism could damage the fetus was generally rejected and relegated to the category of superstitions about alcoholism or the claims of temperance ideologues.

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In the late 1960s, the effects of alcohol abuse on the fetus were rediscovered, so to speak. Lemoine and associates in France, and then Ulleland and Jones and Smith in the United States, described a distinctive pattern of abnormalities in infants born of severely alcoholic mothers. They stated that the affected infants are small in length in comparison to weight, and most of them fall below the third percentile for head circumference. They are distinguished also by the presence of short palpebral fissures (shortened distance between inner and outer canthi) and epicanthal folds; maxillary hypoplasia, micrognathia, indistinct philtrum, and thin upper lip; and longitudinally oriented palmar creases, flexion deformities of the fingers, and a limited range of motion of other joints. Minor anomalies (usually spontaneously closing cardiac septal defects), anomalous external genitalia, and cleft lip and palate are much more frequent than in the general population. All of these features have similarities to the syndrome described in a proportion of infants whose mothers had taken anticonvulsants during pregnancy, the “fetal anticonvulsant (antiepileptic) syndrome” (see Chap. 15). The newborn infants suck and sleep poorly, and many of them are irritable, restless, hyperactive, and tremulous; these last symptoms resemble those of alcohol withdrawal except that they persist. The first long-term study of children with what has come to be called fetal alcohol syndrome (FAS) was reported by Jones and coworkers. Among 23 infants born to alcoholic mothers, there was a neonatal mortality of 17 percent; among the infants who survived the neonatal period, almost half failed to achieve normal weight, length, and head circumference or remained mentally retarded to a varying degree, even under optimal environmental conditions. Several large groups of severely affected children have now been observed for 20 years or longer (Streissguth). Distractibility, inattentiveness, hyperactivity, and impairment of fine motor coordination are prominent features in early childhood. Most such children fall into the category of attention-deficit hyperactivity disorder. Slow growth of head circumference is a consistent finding throughout infancy and childhood. The physical stigmata of the syndrome become less distinctive after puberty, but practically all adolescents are left with some degree of mental retardation and behavioral abnormalities. The pathologic changes that underlie the syndrome have been studied in a small number of cases and no uniform change has emerged. Of some interest are observations that demonstrate a profound effect of alcohol exposure on the deletion of millions of neurons in the developing rat brain by a mechanism of apoptosis (Ikonomidu and coworkers). The main vulnerability occurs during periods of synaptogenesis, which in humans extends from the sixth month of gestation onward. It is noteworthy that infants born to nonalcoholic mothers who had been subjected to severe dietary deprivation during pregnancy (during World War II) were small and often premature, but these infants did not show the pattern of malformations that characterizes FAS. Alcohol readily crosses the placenta in humans and animals; in the mouse, rat, chick, miniature swine, and beagle dog,

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alcohol has been shown to have both embryotoxic and teratogenic effects. Thus, the evidence to date favors a toxic effect of alcohol, although a possible toxic effect of acetaldehyde and smoking and a possible contributory role for nutritional deficiency have not been totally excluded. Unequivocal cases of FAS observed to date have occurred mainly in infants born to severely alcoholic mothers (some of them with delirium tremens and liver disease) who continued to drink heavily throughout pregnancy. It is important to state that a relationship to lesser degrees of alcohol intake is far less secure. Data derived from the collaborative study sponsored by the National Institutes of Health indicate that about one-third of the offspring of women who are heavy drinkers have FAS. The worldwide incidence of FAS is estimated to be 1.9 per 1,000 live births (Abel and Sokol) and has been pronounced by some as the leading known cause of developmental delay in the western world. The degree of maternal alcoholism that is necessary to produce the syndrome and the critical stage in gestation during which it occurs is still vague. The various teratogenic effects described earlier are estimated to occur in the embryonic period, that is, in the first 2 months of fetal life. Other nonteratogenic effects appear to be related to periods during gestation when the fetus is exposed to particularly high alcohol levels. A comprehensive and still not outdated account of alcohol-related birth defects and the controversial issues surrounding this subject is contained in a special issue of Alcohol Health and Research World, published by the National Institutes of Health (Vol. 18, 1994).

Neurologic Complications of Alcoholic Cirrhosis and Portal–Systemic Shunts This category of alcoholic disease is discussed in Chap. 39, in connection with the acquired metabolic disorders of the nervous system.

Treatment of Alcohol Dependence Following recovery from the acute medical and neurologic complications of alcoholism, the patient still must face the underlying problem of alcohol dependence. To treat only the medical complications and leave the management of the drinking problem to the patient alone is shortsighted. Almost always, drinking is resumed, with a predictable recurrence of medical illness. For this reason, the medical profession must be prepared to deal with the addiction or at least to initiate treatment. The problem of excessive drinking is formidable but not nearly as hopeless as it is generally made out to be (see review of O’Connor and Schottenfeld). A common misconception among physicians is that specialized training in psychiatry and an inordinately large amount of time are required to deal with the addictive drinker. Actually, a successful program of treatment can be initiated by any interested physician, using the standard techniques of history taking, establishing rapport with the patient, and setting up a schedule of frequent visits, although not necessarily for prolonged periods. Our position on this matter was reinforced by a controlled study of problem drinkers in whom treatment was equally successful whether carried

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out by general practitioners or by specialists (Drummond and colleagues). It appears that the requisite for successful treatment is total abstinence from alcohol; for all practical purposes, this represents the only permanent solution. There are individuals who have been able to reduce their intake of alcohol and eventually to drink in moderation, but they represent a small proportion of the population. Patients should be made fully aware of the medical and social consequences of continued drinking. They must also be made to understand that because of some constitutional peculiarity (like that of the diabetic, who cannot handle sugar) they are incapable of drinking in moderation. Ideally, these facts should be presented in much the same way as one would explain the essential features of any other disease; there is nothing to be gained from adopting a punitive or moralizing attitude. A number of methods have proved valuable in the short- and long-term management of alcoholic patients. Detoxification clinics and special hospital units for the treatment of alcoholism are now available. The physician should be aware of the community resources available for the management of this problem and should be prepared to take advantage of them in appropriate cases. Most inpatient programs include individual and group counseling, didactics about the illness and recovery, and family intervention. Outpatient treatment (of individuals or groups) is widely available, either from specialized facilities or from specialized therapists in general mental health facilities; family counseling is usually offered as well and is often beneficial. Most professional alcoholism treatment in the United States includes an introduction to the methods and utilization of Alcoholics Anonymous (AA; see in the following text). Disulfiram, much less used in recent years, interferes with the metabolism of alcohol, so that a patient who takes both alcohol and disulfiram accumulates an inordinate amount of acetaldehyde in the tissues, resulting in nausea, vomiting, and hypotension, sometimes pronounced in degree. It is no longer considered necessary to demonstrate these effects to patients; it is sufficient to warn them of the severe reactions that may result if they drink while they have the drug in their bodies. The opioid antagonist naltrexone (50 mg/d orally) or a long-acting injectable formulation has also been used for this purpose, with overall favorable results in trials. The depot injectable form has the advantage of improving compliance in this population that is difficult to treat and to retain in clinical trials (Anton 2008). In Europe, modest success has been achieved with the GABA and glutamate modulator acamprosate (2,000 mg daily) but some trials have shown it to be ineffective. Putatively, a novel approach has been to block the addicting effects of alcohol on the mesolimbic dopaminergic system by the use of anticonvulsants such as topiramate. A reduction in alcoholic intake in patients taking this drug has been demonstrated in a small trial, in comparison to placebo, albeit over only a 12-week period. The use of these medications and the possible reasons for conflicting results between studies are discussed (Swift). A complex randomized trial conducted compared naltrexone, cognitive-behavioral therapy, and both, and

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found that abstinence was most likely, in the short period of 4 months, with the drug alone or when combined with the psychological therapy; those who received the cognitive therapy but neither naltrexone or a placebo pill did somewhat worse (Anton and colleagues, 2006). All of these alternatives require further verification Treatment with disulfiram is instituted only after the patient has been sober for several days, preferably longer. It should not be given to patients with cardiac or advanced liver disease. Should the patient drink while taking disulfiram, the ensuing reaction is usually severe enough to require medical attention, and a protracted spree can thus be prevented. Disulfiram may cause a polyneuropathy if continued over months or years, but this is a rare complication. Alcoholics Anonymous, an informal fellowship of recovering alcoholics, has perhaps proven to be the single most effective force in the rehabilitation of alcoholic patients. The philosophy of this organization is embodied in its “12 Steps,” a series of principles for sober living that guide the patient to recovery. The AA approach stresses in particular the practice of making restitution, the necessity to help other alcoholics, trust in a higher power, the group confessional, and the belief that the alcoholic alone is powerless over alcohol. Although accurate statistics are lacking, it is said that about one-third of the members who express more than a passing interest in the program attain a state of long-sustained or permanent sobriety. The methods used by AA are not acceptable to every patient, but most who persist in its activities appear to benefit; in particular, the physician should not accept a patient’s initial negative reaction as a reason to abandon AA as a mode of treatment. Finally, it should be noted that alcohol dependence is very frequently associated with psychiatric diseases of other types, particularly sociopathy and affective illness (the term dual diagnosis is used by psychiatrists to denote this combination of psychopathologies). In the latter case, the prevailing mood is far more often one of depression than of mania and is more often encountered in women, who are more apt to drink under these conditions than men. In these circumstances, expert psychiatric help should be sought, preferably from someone who is also familiar with addictive diseases. Attempts are being made to treat alcohol addiction with invasive methods such as deep brain stimulation of various sites, but these can only be considered experimental at this time. The role of physicians in caring for patients with alcohol problems has been outlined by several governmental agencies and is summarized in the review by O’Connor and Schottenfeld.

OPIATES AND SYNTHETIC ANALGESIC DRUGS The opiates, or opioids, strictly speaking, include all the naturally occurring alkaloids in opium, which is prepared from the seed capsules of the poppy Papaver somniferum. For clinical purposes, the term opiate refers only to the alkaloids that have a high degree of analgesic activity, characterized by morphine. The terms opioid and

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narcotic-analgesic designate drugs with actions similar to those of morphine. Compounds that are chemical modifications of morphine include diacetylmorphine, or heroin, hydromorphone (Dilaudid), codeine, hydrocodone, oxycodone (OxyContin), and from the Victorian era, laudanum and paregoric. A second class of opioids comprises the purely synthetic analgesics: meperidine (Demerol) and its congeners, notably fentanyl, methadone, levorphanol, propoxyphene (Darvon, no longer widely available), loperamide (the active ingredient in Imodium), and diphenoxylate (the main component of Lomotil). The synthetic analgesics are similar to the opiates in both their pharmacologic effects and patterns of abuse, the differences being mainly quantitative. Opioids activate G-coupled transmembrane receptors, meaning they influence neuronal activity through the intermediate of cAMP; the receptor types are denominated as mu, delta, and kappa. An understanding of the clinical effects of opioids is clarified by the knowledge that these receptors are concentrated in the thalamus and dorsal root ganglia (mu receptors, pain), amygdala (affect) and brainstem raphe (alertness), and Edinger-Westphal nuclei (pupillary miosis). Receptors in the brainstem, also of the mu type, are involved in modulating respiratory responses to hypoxia and hypercarbia (respiratory suppression). Receptors are also widely distributed in neural components of other organs, particularly the gastrointestinal tract, accounting for constipation that is an effect of the administration of this class of drugs. The clinical effects of the opioids are considered from two points of view: acute poisoning and addiction.

Opioid Overdose Because of the common, and particularly the illicit, use of opioids, poisoning is a frequent occurrence. This happens also as a result of ingestion or injection accidentally or with suicidal intent, errors in the calculation of dosage, the use of a substitute or contaminated street product, or unusual sensitivity. Children exhibit an increased susceptibility to opioids, so that relatively small doses may prove toxic. This is true also of adults with myxedema, Addison disease, chronic liver disease, and pneumonia. Acute poisoning may also occur in persons who are unaware that opioids available from illicit sources vary greatly in potency and that tolerance for opioids declines quickly after the withdrawal of the drug; on resumption of the habit, a formerly well-tolerated dose can be fatal. Unresponsiveness, shallow respirations, slow respiratory rate (e.g., 2 to 8 per min) or periodic breathing, pinpoint pupils, bradycardia, and hypothermia are the well-recognized clinical manifestations of acute opioid poisoning. In the advanced stages, the pupils paradoxically dilate, the skin and mucous membranes become cyanotic, and the circulation fails. Later in the course, pulmonary edema may arise, or aspiration pneumonia may become evident (Boyer). The immediate cause of death is usually respiratory depression with consequent hypoxemia. Patients who suffer a cardiorespiratory arrest are sometimes left with all the known residua of hypoxemic encephalopathy (see Chap. 39). Mild degrees of intoxication are

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reflected by anorexia, nausea, vomiting, constipation, and loss of sexual interest. Toxicology screens for opiates may be useful but action must be taken before the results of these tests are completed.

Treatment of Overdose This consists of the support of ventilation and administration of naloxone (Narcan), or the longer-acting nalmefene, both specific antidotes to the opiates and also to the synthetic analgesics. The dose of naloxone in adults is usually 0.4 to 0.5 mg and repeated in larger increments (the second dose is typically 2 mg) every 2 min to a dose of 15 mg intravenously as outlined by Boyer. For children, a higher initial dose of 0.1 mg/kg is recommended. Intranasal preparations of 2 mg and 4 mg are available for emergency treatment but are less consistently effective than the intravenous preparation. The improvements in circulation and respiration and reversal of miosis are usually dramatic. Failure of naloxone to produce such a response should cast doubt on the diagnosis of opioid intoxication. A narcotic withdrawal response may be seen, often with hypertension and tachycardia, and can be dramatic and resistant to treatment. If an adequate respiratory and pupillary response to naloxone is obtained, the patient should nonetheless be observed for up to 24 h and further doses of naloxone (50 percent higher than the ones previously found effective) can be given intramuscularly as often as necessary. Naloxone has less direct effect on consciousness, however, and the patient may remain drowsy for many hours. This is usually not harmful provided respiration is well maintained. Although nalmefene has a plasma half-life of 11 h, compared to 60 to 90 min for naloxone, it has no clear advantage in emergency practice. Gastric lavage may be a useful measure if the drug was taken orally. This procedure may be efficacious many hours after ingestion, as one of the toxic effects of opioids is ileus, which causes some of the drug to be retained in the stomach. Once the patient regains consciousness, complaints such as pruritus, sneezing, tearing, piloerection, diffuse body pains, yawning, and diarrhea may appear often with tachycardia and varying degrees of hypertension. These are the recognizable symptoms of the opioid abstinence, or withdrawal, syndrome described later. Consequently, an antidote must be used with great caution in an addict who has taken an overdose of opioid, because in this circumstance, it may precipitate withdrawal phenomena. Nausea and severe abdominal pain, presumably because of pancreatitis (from spasm of the sphincter of Oddi), are other troublesome symptoms of opiate use or withdrawal. Seizures are rare.

Opioid Addiction (Opioid Use Disorder) Just 50 years ago there were an estimated 60,000 persons addicted to narcotic drugs in the United States, exclusive of those who were receiving drugs because of incurable painful diseases. This represented a relatively small public health problem in comparison with the abuse of alcohol and barbiturates. Moreover, opioid addiction was of serious proportions in only a few cities—New York, Chicago,

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Los Angeles, Washington DC, and Detroit. Since the late 1960s, a remarkable increase in opioid addiction has taken place. According to statistics from the Centers for Disease Control and Prevention (CDC), as of 2016, 66 percent of the more than 63,000 drug overdose deaths in the United States involved an opioid (including both prescribed and illicit opioids) and on average, 115 Americans die every day from an opioid overdose. A serial rise in opioid-related deaths is traceable to three trends: increased prescribing of opioids (natural and semisynthetic opioid and methadone) in the 1990s, increased overdose deaths involving heroin around 2010, and increased overdose deaths involving synthetic opioids such as fentanyl around 2013. The precise number of opioid addicts is unknown but is estimated by the Drug Enforcement Administration to be well more than 500,000. The problem assumes enormous importance when one recognizes that a significant number of addicts are seropositive for HIV hepatitis viruses and thus a source of transmission to each other, to newborns, and to the nonaddicted population.

Etiology and Pathogenesis A number of factors—socioeconomic, psychologic, and pharmacologic—contribute to the genesis of opioid addiction. The most susceptible to opioid addiction are young men living in economically depressed areas of large cities, but significant numbers of addicts are found in suburbs and in small cities, and among affluent populations as well. The onset of opioid use is often in adolescence; fully twothirds of addicts start using the drugs before the age of 21. Some have psychiatric disturbances, conduct disorder, and sociopathy being the most common (“dual-diagnosis,” in psychiatric jargon) but vulnerability to addiction is not confined to one personality type. Using the Lexington Personality Inventory, a group of 837 opioid-dependent individuals was examined and found to have evidence of antisocial personality in 42 percent, emotional disturbance in 29 percent, and thought disorder in 22 percent; only 7 percent were free of such disorders (Monroe and colleagues). We are uncertain if these figures still pertain to the large number of young addicts. Social association with other addicts is an additional explanation for becoming addicted. In this sense, opioid addiction is contagious, and partly as a result of this pattern, opioid addiction has attained epidemic proportions. Opioid use disorder consists of three recognizable features: (1) intoxication, or “euphoria,” (2) pharmacogenic dependence or drug-seeking behavior (addiction), and (3) the propensity to relapse after a period of abstinence. Some of the symptoms of opioid intoxication have already been considered. In patients with severe pain or pain-anticipatory anxiety, the administration of opioids produces a sense of unusual well-being, a state that had traditionally been referred to as morphine euphoria. It should be emphasized that only a negligible proportion of such persons continue to use opioids habitually after their pain has subsided. The majority of potential addicts are not suffering from painful illnesses at the time they initiate opioid use, and the term euphoria is probably not an apt description of the initial effects. These persons, after several repetitions, are presumably attracted to a “high,” despite the subsequent

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recurrence of unpleasant, or dysphoric, symptoms (nausea, vomiting, and faintness as the drug effect wanes) but the internal experience that leads to overuse is probably more complex. These are intertwined with the characterization of the disorder as a disease rather than an affliction of another description that has both sociological and patient culpability aspects that are presumably not helpful. On the other hand, some workers in the field have expressed the opinion that addictions are learned behaviors, more so than due to brain changes (Lewis). The pharmacologic (in contrast to psychologic) criteria of opioid use disorder, as indicated earlier in regards to alcohol use disorder, are tolerance and physical dependence. The latter refers to the symptoms and signs that become manifest when the drug is withdrawn following a period of continued use. These symptoms and signs constitute a specific clinical state, termed the abstinence or withdrawal syndrome (see later). The mechanisms that underlie the development of tolerance and physical dependence are not fully understood. However, it is known that opioids activate an opioid antinociceptive system (enkephalins, dynorphins, endorphins), which are opioid receptors and are located at many different levels of the nervous system (these were referred to earlier and are described in Chap. 7; see also the review of Fields). The desensitization of opioid receptors, probably mainly the mu type, accounts for tolerance through a mechanism of uncoupling of the receptor from the G-protein complex. The repeated self-administration of the drug is the most important factor in the genesis of dependence aspect of addiction. Regardless of how one characterizes the state of mind that is produced by episodic exposure to the drug, the individual quickly discovers the need to increase the dose to obtain the original effects (tolerance). Although the initial effects may not be fully recaptured, the progressively increasing dose of the drug does relieve the discomfort that arises as the effects of each injection wear off. In this way, a new pharmacogenically induced need is developed, and the use of opioids becomes self-perpetuating. At the same time a marked degree of tolerance is produced, so that enormous amounts of drugs, for example, 5,000 mg of morphine daily, can eventually be administered without the development of toxic symptoms. The diagnosis of addiction is usually made when the patient admits to using and needing drugs. Should the patient conceal this fact, one relies on collateral information such as miosis, needle marks, emaciation, abscess scars, or chemical analyses. Meperidine addicts are likely to have dilated pupils and twitching of muscles. The finding of morphine or opiate derivatives (heroin is excreted as morphine) in the urine is confirmatory evidence that the patient has taken or has been given a dose of such drugs within 24 h of the test. The diagnosis of opiate addiction is also at once apparent when the treatment of acute opiate intoxication precipitates a characteristic abstinence syndrome.

The Opioid Abstinence Syndrome The intensity of the abstinence or withdrawal syndrome depends on the dose of the drug and the duration of use. The onset of abstinence symptoms in relation to the last

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exposure to the drug, however, is related to the pharmacologic half-life of the agent. With morphine, most individuals receiving 240 mg daily for 30 days or more will show moderately severe abstinence symptoms following withdrawal. Mild signs of opiate abstinence can be precipitated by narcotic antagonists in persons who have taken as little as 15 mg of morphine or an equivalent dose of methadone or heroin for 3 days. The abstinence syndrome that occurs in the morphine addict may be taken as the prototype. The first 8 to 16 h of abstinence usually pass asymptomatically. At the end of this period, yawning, rhinorrhea, sweating, piloerection, and lacrimation are manifest. Mild at first, these symptoms increase in severity over a period of several hours and then remain constant for several days. The patient may be able to sleep during the early abstinence period but is restless, and thereafter insomnia remains a prominent feature. Dilatation of the pupils, recurring waves of “gooseflesh,” and twitching of the muscles appear. The patient complains of aching in the back, abdomen, and legs and of “hot and cold flashes”; he frequently asks for blankets. At about 36 h the restlessness becomes more severe, and nausea, vomiting, and diarrhea usually develop. Temperature, respiratory rate, and blood pressure are elevated. All these symptoms reach their peak intensity 48 to 72 h after withdrawal and then gradually subside. The opioid abstinence syndrome is rarely fatal (it is life-threatening only in infants). After 7 to 10 days, the clinical signs of abstinence are no longer evident, although the patient may complain of insomnia, nervousness, weakness, and muscle aches for several more weeks, and small deviations of a number of physiologic variables can be detected with refined techniques for up to 10 months (protracted abstinence). Habituation, the equivalent of emotional or psychologic dependence, refers to the substitution of drug-seeking activities for all other aims and objectives in life. It is this feature that fosters relapse to the use of the drug long after the physiologic (“nonpurposive”) abstinence changes seem to have disappeared. The cause of relapse is not fully understood. Theoretically, fragments of the abstinence syndrome may remain as a conditioned response, and these abstinence signs may be evoked by the appropriate environmental stimuli. Thus, when a “cured” addict returns to a situation where narcotic drugs are readily available or in a setting that was associated with the initial use of drugs, the incompletely extinguished drug-seeking behavior may reassert itself. The characteristics of addiction and of abstinence are qualitatively similar with all drugs of the opiate group as well as the related synthetic analgesics. The differences are quantitative and are related to the differences in dosage, potency, and length of action. Heroin is 2 to 3 times more potent than morphine but the heroin withdrawal syndrome encountered in hospital practice is usually mild in degree because of the low dosage of the drug in the street product. Dilaudid (hydromorphone) is more potent than morphine and has a shorter duration of action; hence the addict requires more doses per day, and the abstinence syndrome comes on and subsides more rapidly. Abstinence symptoms from codeine, while definite, are less severe than those from morphine. The addiction liabilities

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of propoxyphene, a weak opioid, are negligible. Abstinence symptoms from methadone are less intense than those from morphine and do not become evident until 3 or 4 days after withdrawal; for these reasons methadone can be used in the treatment of morphine and heroin dependency (see further on). Meperidine addiction is of particular importance because of its high incidence among physicians and nurses. Tolerance to the drug’s toxic effects is not complete, so the addict may show tremors, twitching of muscles, confusion, hallucinations, and sometimes convulsions. Signs of abstinence appear 3 to 4 h after the last dose and reach their maximum intensity in 8 to 12 h, at which time they may be worse than those of morphine abstinence. As to the biologic basis of addiction and physical dependence, our understanding is still very limited. Experiments in animals have provided insights into the neurotransmitter and neuronal systems involved. As a result of microdialyzing opiates and their antagonists into the central brain structures of animals, it has been tentatively concluded that mesolimbic structures, particularly the nucleus accumbens, ventral tegmentum of the midbrain, and locus ceruleus are activated or depressed under conditions of repeated opiate exposure. Thus, chronic opiate usage increases the levels of intracellular messengers (G-proteins) as noted earlier that drive cAMP activity in the locus ceruleus and in the nucleus accumbens; blocking the expression of these proteins markedly increases the self-administration of opiates by addicted rats. As in alcoholism, certain subtypes of the serotonin and dopamine receptors in limbic structures have been implicated in the psychic aspects of addiction and habituation. These same structures are conceived as a common pathway for the impulse to human drives such as sex, hunger, and psychic fulfillment. Camí and Farré reviewed the neurochemical mechanism of addiction.

Treatment of the Opioid Abstinence Syndrome Views on the nature of drug addiction and appropriate methods of treatment are as much national and sociologic as they are biologic. One approach that has achieved some degree of success over the past 40 years has been the substitution of methadone for opioid, in the ratio of approximately 1 mg methadone for 3 mg morphine, 1 mg heroin, or 20 mg meperidine. Because methadone is long acting and effective orally, it needs to be given only twice daily by mouth—10 to 20 mg per dose being sufficient to suppress abstinence symptoms. After a stabilization period of 3 to 5 days, this dosage of methadone is reduced, and the drug is withdrawn over a similar period. An alternative but probably less effective method has been the use of clonidine (0.2 to 0.6 mg bid for a week), a drug that counteracts most of the noradrenergic withdrawal symptoms; however, the hypotension that is induced by this drug may be a problem (Jasinski and colleagues). In Europe, addicts who could not be detoxified and kept free of drugs by any other means have been given diacetylmorphine, the active ingredient in heroin, with some success when compared in clinical trials to methadone (Oviedo-Joekes and colleagues). Special settings that are capable of medical reversal of overdose are required but the notion of overall reduction in personal and societal

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harm seems to be attained by even this seemingly extreme measure. There is a movement to open more safe injection sites with the goal of reducing overdose deaths and disease transmission but it has met with societal resistance. A rapid detoxification regimen that is conducted under general anesthesia was popular in a number of centers as a means of treating opiate addiction has now been largely abandoned for reasons of safety but it could be resurrected if other more conventional approaches continue to be futile. The technique consisted of administering increasing doses of opioid receptor antagonists (naloxone or naltrexone) over several hours while the autonomic and other features of the withdrawal syndrome were suppressed by the infusion of propofol or a similar anesthetic, supplemented by intravenous fluids. Medications such as clonidine and sedatives were also given in the immediate postanesthetic period. There are substantial risks involved in this procedure and several deaths have occurred for which reason it has been all but abandoned. Furthermore, a number of patients continue to manifest signs of withdrawal after the procedure and require continued hospitalization. Treatment of opiate habituation  This is in some ways far more demanding than the treatment of opioid withdrawal and can be accomplished in special facilities and programs that are devoted wholly to the problem but are now available through trained primary care practices and may in the future be handled by pharmacists. The use of outpatient sublingual buprenorphine for the treatment of opioid (and cocaine) abuse has become more ubiquitous; this drug has both opioid agonist and antagonist properties; it mutes the effect of withdrawal, also serves as an aversive agent, and its abuse potential is relatively low. A randomized trial (Fudala and colleagues) has demonstrated the superiority over methadone of a combination of buprenorphine and naloxone combined with brief counseling in keeping opioid addicts in treatment and abstinent of abused drugs. This approach has been available in Europe for many years and has been adopted in the United States under a Department of Health–supervised program for primary care offices. In addition, there is evidence, based on animal experiments and experience with small numbers of individuals that it may be useful for the treatment of dual dependence on cocaine and opiates (see Mello and Mendelson), but this has not been confirmed in other clinical trials. Among the most well-known treatment methods has been ambulatory methadone maintenance clinics, where more than 100,000 former heroin addicts are participating in rehabilitation programs approved by the FDA. Methadone, in a dosage of 60 to 100 mg daily (sufficient to suppress the craving for heroin), is given under supervision day by day (less often with long-acting methadone) for months or years. Various forms of psychotherapy and social service counseling often administered by former heroin addicts are integral parts of the program. The results of methadone treatment are difficult to assess and vary considerably from one program to another. Even the most successful programs suffer an attrition rate of approximately 25 percent when they are evaluated after several years. Of the patients who remain, the majority achieves a degree of social rehabilitation, that is, they

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are gainfully employed and no longer engage in criminal behavior. The usual practice of methadone programs is to accept only addicts older than age 16 years with a history of heroin addiction for at least 1 year. This leaves many adolescent addicts untreated. The number of opioid dependent persons who can fully withdraw from methadone and maintain a drug-free existence is very small. This means that many individuals now enrolled in methadone programs are committed to an indefinite period of methadone maintenance and the effects of such a regimen are uncertain. An alternative method of ambulatory treatment of the opiate addict involves the use of narcotic antagonists, of which naloxone and naltrexone are the best known. The physical effects of abusing narcotics are thereby partially blocked, and there may be some degree of aversive conditioning if withdrawal symptoms are produced. Naltrexone is favored because it has a longer effect than naloxone, is almost free of agonist effects, and can be administered orally. Similar results have also been achieved with cyclazocine in a small number of highly motivated patients; this drug is administered orally in increasing amounts until a dosage of 2 mg/70 kg body weight is attained. The drug is taken bid (for 2 to 6 weeks) and is then withdrawn slowly.

Medical and Neurologic Complications of Opioid Use In addition to the toxic effects of the opioid itself, the addict may suffer a variety of neurologic and infectious complications resulting from the injection of contaminated adulterants (quinine, talc, lactose, powdered milk, and fruit sugars) and of various infectious agents (injections administered by unsterile methods). The most important of these is HIV infection, but septicemia, endocarditis, and viral hepatitis may also occur. Particulate matter that is injected with heroin or a vasculitis that is induced by chronic heroin abuse may cause stroke by an incompletely understood occlusion of cerebral arteries, with hemiplegia or other focal cerebral signs. Amblyopia, probably as a result of the toxic effects of quinine in the heroin mixtures, has been reported, as well as transverse myelopathy and several types of peripheral neuropathy. The spinal cord disorder expresses itself clinically by the abrupt onset of paraplegia with a level on the trunk below which motor function and sensation are lost or impaired and by urinary retention. Pathologically, there is an acute necrotizing lesion involving both gray and white matter over a considerable vertical extent of the thoracic and occasionally the cervical cord. In some cases, a myelopathy has followed the first intravenous injection of heroin after a prolonged period of abstinence. We have also seen cases of cervical myelopathy from heroin-induced stupor and a prolonged period of immobility with the neck hyperextended over the back of a chair or sofa. In addition, we and others have observed instances of a subacute progressive cerebral leukoencephalopathy after heroin use, similar to ones that occurred in Amsterdam in the 1980s, the result of inhalation of heroin or an adulterant (Wolters and colleagues; Tan and colleagues). Most instances of this leukoencephalopathy are the result of inhalation of heated heroin vapor in a practice known as chasing the dragon. The clinical presentation has varied but

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generally includes stupor, coma, and death, after a latent period of hours or days. In one of our patients, the white matter changes were concentrated in the posterior regions of the hemispheres and in the internal capsules and, in one striking case, in the cerebellar white matter. The MRI is fairly characteristic—widespread white matter hyperintensity involving supratentorial and infratentorial structures, with a predilection for corticospinal fibers above and below the internal capsules, and with sparing of subcortical U-fibers and gray matter structures. The white matter is vacuolated (Ryan and colleagues), with an appearance that simulates the spongiform change of prion disease. The pathophysiology is unknown but mitochondrial damage has been suggested. A similar leukoencephalopathy has also been reported in cocaine users, although a hypertensive encephalopathy or an adrenergic-induced vasculopathy may have played a role in these cases. Damage to single peripheral nerves at the site of injection of heroin and from compression is a relatively common occurrence. However, bilateral compression of the sciatic nerves, the result of sitting or lying for a prolonged period in a stuporous state or in the lotus position, has occurred in several of our patients. In sciatic compression of this type, the peroneal branch has been more affected than the tibial, causing foot-drop with less weakness of plantar flexion. More difficult to understand in heroin abusers is the involvement of other individual nerves, particularly the radial nerve, and painful affection of the brachial plexus, apparently unrelated to compression and remote from the sites of injection. Possibly in some instances there was a vasculitis affecting peripheral nerves. An acute generalized myonecrosis with myoglobinuria and renal failure has been ascribed to the intravenous injection of adulterated heroin. Brawny edema and fibrosing myopathy (Volkmann contracture) are the sequelae of venous thrombosis resulting from the administration of heroin and its adulterants by the intramuscular and subcutaneous routes. Occasionally, there may be massive swelling of an extremity into which heroin had been injected subcutaneously or intramuscularly; infection and venous thrombosis appear to be involved in its causation. The diagnosis of drug addiction always raises the possibility of an assortment of infectious complications: HIV, syphilis, abscesses and cellulitis at injection sites, septic thrombophlebitis, hepatitis, and periarteritis from circulating immune complexes. Tetanus, endocarditis (mainly caused by Staphylococcus aureus), spinal epidural abscess, meningitis, brain abscess, and tuberculosis are well-known but have seemingly occurred less frequently in recent years.

SEDATIVE-HYPNOTIC DRUGS This class of drugs consists of two main groups. The first includes the barbiturates, meprobamate, and chloral hydrate. These drugs are now little used, having been largely replaced by a second group, the benzodiazepines, the most important of which are chlordiazepoxide (Librium), lorazepam (Ativan), alprazolam (Xanax), clonazepam

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(Klonopin), and diazepam (Valium). Closely related are the nonbenzodiazepine hypnotics, typified by zolpidem (Ambien). The advantages of the benzodiazepine drugs are their relatively low toxicity and addictive potential and their minimal interactions with other drugs.

Barbiturates In the past, about 50 barbiturates were marketed for clinical use, but now only a few are encountered: pentobarbital (Nembutal), secobarbital (Seconal), amobarbital (Amytal), thiopental (Pentothal), and phenobarbital. The first three were the ones most commonly abused. Barbiturates are also a component of combination preparations for the treatment of migraine (e.g., butalbital in Fiorinal).

Mechanism of Action All the common barbiturates are derived from barbituric acid; the differences among them depend on variations in the side chains of the parent molecule. The potency of each drug is a function of the ionization constant and lipid solubility. The higher its lipid solubility, the greater the drug’s central nervous system potency and the quicker and briefer its action. The lowering of plasma pH increases the rate of entry of the ionized form into the brain. The action of barbiturates is to suppress neuronal transmission, presumably by enhancing GABA inhibition at pre- and postsynaptic receptor sites, and to reduce excitatory postsynaptic potentials. The major points of action in the CNS are similar to those of alcohol and other coma-producing drugs; impaired consciousness or coma relates to inactivation of neurons in the reticular formation of the upper brainstem. The liver is the main locus of drug metabolism and the kidney is the method of elimination of the metabolites. The clinical problems posed by the barbiturates are different depending on whether the intoxication is acute or chronic.

Acute Barbiturate Intoxication Although the decreased use and availability of these drugs (many are no longer manufactured) has made overdose far less common than in the past, the syndrome bears emphasis so that it is not missed. The symptoms and signs vary with the type and amount of drug as well as with the length of time that has elapsed since it was ingested. Pentobarbital and secobarbital produce their effects quickly and recovery is relatively rapid. Phenobarbital induces coma more slowly and its effects tend to be prolonged. In the case of long-acting barbiturates, such as phenobarbital, the hypnotic-sedative effect lasts 6 h or more after an average oral dose; with the intermediate-acting drugs such as amobarbital, 3 to 6 h; and with the short-acting drugs, pentobarbital, less than 3 h. The ingestion by adults of more than 3 g of these drugs at one time will prove fatal unless intensive treatment is applied promptly. The potentially fatal dose of phenobarbital is 6 to 10 g. The lowest plasma concentration associated with lethal overdosage of phenobarbital or barbital has been approximately 60 mg/mL and that of amobarbital and pentobarbital, 10 mg/mL. Severe intoxication occurs with the ingestion of 10 to 20 times the oral hypnotic dose. The patient cannot be

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roused by any means, that is, the patient is comatose. Respiration is slow and shallow or irregular, and pulmonary edema and cyanosis may be present. The tendon reflexes are usually, but not invariably, absent. Most patients show no response to plantar stimulation, but in those who do, the responses are extensor. With deep coma, the corneal and gag reflexes may also be abolished. Ordinarily, the pupillary light reflex is retained in severe intoxication and is lost only if the patient is asphyxiated; but in advanced cases, the pupils become miotic and poorly reactive, simulating opiate intoxication. At this point respiration is greatly depressed and oculocephalic and oculovestibular reflex responses are usually abolished. In the early hours of coma, there may be a phase of flexor or extensor posturing or rigidity of the limbs, hyperactive reflexes, ankle clonus, and extensor plantar signs; persistence of these signs indicates that anoxic damage has been added. The temperature may be subnormal, the pulse is faint and rapid, and the blood pressure is greatly reduced. Failure of respiration to quicken on painful stimulation is an ominous sign. There are few conditions other than barbiturate intoxication that cause a flaccid coma with small reactive pupils, hypothermia, and hypotension. A pontine hemorrhage may do so, but a hysterical trance or catatonic stupor does not present a problem in differential diagnosis. Serum toxicology studies provide a reliable means of identifying the type and amount of barbiturate in the blood. A patient who has also ingested alcohol may be comatose with relatively low blood barbiturate concentrations. Contrariwise, the barbiturate addict may show only mild signs of intoxication with very high blood barbiturate concentrations. Management  In mild or moderate intoxication, recovery is the rule and special treatment is not required except to prevent aspiration. If the patient is unresponsive, special measures must be taken to maintain respiration and prevent infection. An endotracheal tube should be inserted, with suctioning as necessary. Any risk of respiratory depression or underventilation requires the use of a mechanical ventilator. Hemodialysis or hemofiltration with charcoal may be used in comatose patients who have ingested long-acting barbiturates and these treatments are particularly advisable if anuria or uremia has developed. Occasionally, in the case of a barbiturate addict who has taken an overdose of the drug, recovery from coma is followed by the development of abstinence symptoms, as described later.

Barbiturate Abstinence, or Withdrawal, Syndrome Immediately following withdrawal, the patient seemingly improves over a period of 8 to 12 h, as the symptoms of intoxication diminish. Then a new group of symptoms develops, consisting of nervousness, tremor, insomnia, postural hypotension, and weakness. With chronic phenobarbital or barbital intoxication, withdrawal symptoms may not become apparent until 48 to 72 h after the final dose or it does not occur at all because of the slow metabolism and long half-life of these drugs. Generalized seizures with loss of consciousness may occur, usually between the second and fourth days of abstinence, but occasionally as long as 6 or 7 days after withdrawal. There may be

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a single seizure, several seizures, or, rarely, status epilepticus. Characteristically, in the withdrawal period, there is a greatly heightened sensitivity to photic stimulation, to which the patient responds with myoclonus or a seizure accompanied by paroxysmal changes in the EEG. The convulsive phase may be followed directly by a delusionalhallucinatory state or, as occurred in one of our cases (Romero and colleagues), a full-blown delirium indistinguishable from delirium tremens. Death has been reported under these circumstances. The abstinence syndrome may occur in varying degrees of completeness; some patients have seizures and recover without developing delirium, and others have a delirium without preceding seizures.

Chloral Hydrate This is one of the oldest and one of the safest, most effective, and most inexpensive of the sedative-hypnotic drugs but is no longer available in the United States. After oral administration, chloral hydrate is reduced rapidly to trichloroethanol, which is responsible for the depressant effects on the CNS. A significant portion of the trichloroethanol is excreted in the urine as the glucuronide, which may give a false-positive test for glucose. Tolerance and addiction to chloral hydrate develop only infrequently; for this reason, it was in the past commonly used for insomnia. Poisoning with chloral hydrate was a rare occurrence and resembled acute barbiturate intoxication except for the finding of miosis, which is said to characterize the former. Treatment follows along the same lines as for barbiturate poisoning. Death from poisoning is because of respiratory depression and hypotension; patients who survive may show signs of liver and kidney failure. Combining alcohol and chloral hydrate, the popular “Mickey-Finn” of detective stories in the mid-last century, produced severe intoxication and amnesia. Paraldehyde, another member of this group of sedative drugs, is also no longer being manufactured in the United States.

Benzodiazepines With the introduction of chlordiazepoxide in 1960 and the benzodiazepine drugs that followed (particularly diazepam), the older sedative drugs (barbiturates, paraldehyde, chloral hydrate) have become virtually obsolete. Indeed, the benzodiazepines are among the most commonly prescribed drugs in the world today. According to Hollister (1990), 15 percent of all adults in the United States use a benzodiazepine at least once yearly and about half this number use the drug for a month or longer. The benzodiazepines have been prescribed frequently for the treatment of anxiety and insomnia, and they are especially effective when the anxiety symptoms are severe. Also, they have been used to control overactivity and destructive behavior in children and the symptoms of alcohol withdrawal in adults. The benzodiazepines possess anticonvulsant properties, and the intravenous use of diazepam, lorazepam, and midazolam is an effective means of controlling status epilepticus, as described in Chap. 15. Diazepam in massive doses has been used with considerable success in the

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management of muscle spasm in tetanus and in the “stiff man” syndrome (see Chap. 45). Other benzodiazepine drugs are lorazepam (Ativan), triazolam (Halcion), clorazepate (Tranxene), temazepam (Restoril), oxazepam (Serax), alprazolam (Xanax), and other newer varieties, all widely used in the treatment of insomnia (see Chap. 18), and clonazepam (Klonopin), which is useful in the treatment of myoclonic seizures (see Chap. 15) and intention myoclonus (see Chap. 4). Midazolam (Versed), a short-acting parenteral agent, is given frequently to achieve the brief sedation required for procedures such as MRI or endoscopy and is also useful in the treatment of status epilepticus. Many other benzodiazepine compounds have appeared in recent years, but a clear advantage over the original ones remains to be demonstrated (Hollister, 1990). The benzodiazepine drugs, like barbiturates, have a depressant action on the CNS by binding to specific receptors on GABA inhibitory systems. The newer nonbenzodiazepine sleeping medication differs from the benzodiazepines structurally but is pharmacologically similar in binding to similar GABA-ergic receptors. The benzodiazepines act in concert with GABA to open chloride ion channels and hyperpolarize postsynaptic neurons and reduce their firing rate. The primary sites of their action are the cerebral cortex and limbic system, which accounts for their anticonvulsant and anxiolytic effects. While relatively safe in the recommended dosages, they are far from ideal. They frequently cause unsteadiness of gait and drowsiness and at times syncope, confusion, and impairment of memory, especially in the elderly. If taken in large doses, the benzodiazepines can depress the state of consciousness, resembling that of other sedative-hypnotic drugs, but with less respiratory suppression and hypotension. Nevertheless, data from the National Poison Data System showed tens of thousands of intubations and thousands of deaths in the United States in the last few decades due to benzodiazepine overdose (Bryant and colleagues). Flumazenil, a specific pharmacologic antagonist of the CNS effects of benzodiazepines, rapidly but briefly reverses most of the symptoms and signs of benzodiazepine overdose (Krisanda). It acts by binding to CNS diazepine receptors and thereby blocking the activation of inhibitory GABA-ergic synapses. Whether flumazenil is diagnostically useful in cases of coma of unknown etiology and in hepatic encephalopathy has been debated. Signs of physical dependence and true addiction, although relatively rare, undoubtedly occur in chronic benzodiazepine users, even in those taking therapeutic doses. The withdrawal symptoms are much the same as those that follow the chronic use of other sedative drugs (anxiety, jitteriness, insomnia, seizures) but may not appear until the third day after the cessation of the drug and may not reach their peak of severity until the fifth day (Hollister, 1990). In chronic benzodiazepine users, the gradual tapering of dosage over a period of 1 to 2 weeks minimizes the withdrawal effects. However, we have observed numerous cases over the years in which the cessation of moderate doses of chronically used diazepines has resulted in one or more seizures. This is likely to happen when the patient is hospitalized for other reasons and the accustomed sleeping or anxiolytic medication is omitted.

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Buspirone A class of antianxiety agents, exemplified by the selective 5-HT1A receptor serotonergic agonist buspirone, is chemically and pharmacologically different from the benzodiazepines, barbiturates, and other sedatives. Its distinctive nature is confirmed by the observation that it does not block the withdrawal syndrome of other sedative-hypnotic drugs. Because of its apparently reduced potential for abuse and tolerance, it is not included in the list of controlled pharmaceutical substances in the United States but adverse interactions with monoamine oxidase (MAO) inhibitors are known. Its use with other psychotropic drugs is still under investigation (see Chap. 47).

Propofol Also mentioned here, because neurologists are often asked to consult on these cases, is a curious effect of the anesthetic propofol. Seizures and myoclonic-like movements have been seen in a small number of individuals, presumably as an idiosyncratic effect. Sometimes these take the form of less-organized twitching, opisthotonus, or involuntary movements. Some inhaled anesthetics such as enflurane can cause seizures in susceptible patients. In our own experience, the seizures have occurred in the first hour after emergence from anesthesia, but as many cases are reported with seizures occurring during induction, emergence, and after the use of the drug (Walder and colleagues).

ANTIPSYCHOSIS DRUGS In the mid-1950s, a large series of pharmacologic agents, originally referred to tranquilizers (later, as psychotropic or neuroleptic drugs), came into prominent use, mainly for the control of schizophrenia, psychotic states associated with “organic brain syndromes,” and affective disorders (depression and bipolar disease). The mechanisms by which these drugs ameliorate disturbances of thought and affect in psychotic states are not fully understood, but presumably they act by blocking the postsynaptic mesolimbic dopamine receptors of which there are four subtypes, termed D1 through D4 on neuronal membranes (see Table 4-2, and discussion of dopamine receptor subtypes). The D2 receptors are located mainly in the frontal cortex, hippocampus, and limbic cortex, and the D1 receptors are in the striatum, as discussed in Chap. 4. The blockade of dopamine receptors in the striatum is probably responsible for the parkinsonian side effects of this entire class of drugs, and the blockade of another dopaminergic (tuberoinfundibular) system, for the increased prolactin secretion by the pituitary. These drugs also produce some adrenergic-blocking effect. The newer “atypical” antipsychotic drugs, exemplified by clozapine, apparently achieve the same degree of D2 and D3 blockade in the temporal and limbic lobes while exhibiting substantially less antagonistic activity in the striatum—accounting also for their lesser parkinsonian side effects. These drugs also block subsets of serotonin receptors.

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Since the introduction of phenothiazine chlorpromazine in the 1950s as an anesthetic agent and the serendipitous discovery of its antipsychotic effect, a large number of antipsychotic drugs have been marketed for clinical use. No attempt is made here to describe or even list all of them. Some have had only an evanescent popularity and others have yet to prove their value. Chemically, these compounds form a heterogeneous group. Eight classes of them are of particular clinical importance: (1) the phenothiazines; (2) the thioxanthenes; (3) the butyrophenones; (4) the rauwolfias alkaloids; (5) an indole derivative, loxapine, and a unique dihydroindolone, molindone; (6) a diphenylbutylpiperidine, pimozide; (7) dibenzodiazepines, typified by clozapine and olanzapine; and (8) a benzisoxazole derivative, risperidone. Molindone and loxapine are about as effective as the phenothiazines in the management of schizophrenia and their side effects are similar, although claims have been made that they are less likely to induce tardive dyskinesias and seizures. Their main use is in patients who are not responsive to the older drugs or who suffer intolerable side effects from them. The antipsychotic agents in the class of clozapine (which is less used than other agents in the class because of cases of aplastic anemia) have attracted great interest, because—as already mentioned—they are associated with relatively fewer extrapyramidal side effects. For this reason, they are particularly favored in controlling the confusion and psychosis of parkinsonian patients. The other new class of drugs, of which risperidone is the main example, also has fewer extrapyramidal side effects than the phenothiazines and a more rapid onset of action than the traditional antipsychotic medications. All of these newer medications produce the “metabolic syndrome” of weight gain, adverse lipid changes, and glucose intolerance. Pimozide may be useful in the treatment of haloperidol-refractory cases of Gilles de la Tourette syndrome (see Chap. 4); its main danger is its tendency to produce cardiac arrhythmias.

Phenothiazines This group comprises chlorpromazine (Thorazine), promazine (Sparine), triflupromazine (Vesprin), prochlorperazine (Compazine), perphenazine (Trilafon), fluphenazine (Permitil, Prolixin), thioridazine (Mellaril), mesoridazine (Serentil), and trifluoperazine (Stelazine) and others. In addition to their psychotherapeutic effects, these drugs have a number of other actions, so that certain members of this group are used as antiemetics (prochlorperazine) and antihistaminics (promethazine). The phenothiazines have had their widest application in the treatment of the major psychoses, namely schizophrenia and, to a lesser extent, bipolar psychosis, but they are being replaced by newer agents with fewer side extrapyramidal effects (but with problematic issues of their own). Under the influence of these drugs, many patients who would otherwise have been hospitalized were able to live at home and even work productively. In the hospital, the use of these drugs has facilitated the care of hyperactive, delirious, and combative patients (see Chaps. 48 and 49 for details of this clinical use).

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Side effects of the phenothiazines are frequent and often serious. Shared by the entire class is a tendency to cause the metabolic syndrome with weight gain, hyperglycemia, and hyperlipidemia. All of them may cause a cholestatic type of jaundice, agranulocytosis, seizures, orthostatic hypotension, skin sensitivity reactions, mental depression, and, most importantly, immediate or delayed extrapyramidal motor disorders. The neuroleptic malignant syndrome is the most extreme complication and is discussed separately further on and in Chap. 49. The following types of extrapyramidal symptoms, also discussed in Chap. 4, have been noted in association with all of the phenothiazines as well as the butyrophenones, and to a lesser extent with metoclopramide and pimozide, which block dopaminergic receptors. These are summarized in Table 49-1. 1. A parkinsonian syndrome is the most common complication—masked facies, slight symmetric tremor, reduced blinking, generalized rigidity, shuffling gait, and slowness of movement. These symptoms may appear after several days of drug therapy but more often after several weeks. Suppression of dopamine in the striatum (similar to the effect of loss of dopaminergic nigral cells that project to the striatum) is presumably the basis of the parkinsonian signs. 2. Acute dyskinetic and dystonic reactions, taking the form of involuntary movements of lower facial muscles (mainly around the mouth) and protrusion of the tongue (buccolingual or oral-masticatory syndrome), dysphagia, torticollis and retrocollis, oculogyric crises, and tonic spasms of a limb. These complications usually occur early in the course of administration of the drug, sometimes after the initial dose, in which case they recede dramatically on immediate discontinuation of the drug and the intravenous administration of diphenhydramine hydrochloride or benztropine. 3. Akathisia, which is an inner restlessness reflected by a persistent shifting of the body and feet and an inability to sit still, such that the patient paces the floor or jiggles the legs constantly (see Chap. 4). Of all the phenothiazines, molindone has a tendency to cause akathisia. This disorder often responds to oral propranolol. 4. Tardive dyskinesias are a group of late and persistent complications of neuroleptic therapy, which may continue after removal of the offending drug, that comprises lingual-facial-buccal-cervical dyskinesias, choreoathetotic and dystonic movements of the trunk and limbs, diffuse myoclonus (rare), perioral tremor (“rabbit” syndrome), and dysarthria or anarthria. Snyder postulated that the movements are because of hypersensitivity of dopamine receptors in the basal ganglia, secondary to prolonged blockade of the receptors by antipsychotic medication. As many as 40 percent of patients receiving long-term antipsychotic medication may develop tardive dyskinesia of some degree. The effect is likely a result of subcellular pathophysiologic alterations in the basal ganglia. Treatment is discussed later. 5. The neuroleptic malignant syndrome is discussed separately later because of its gravity and requirement for specific treatment.

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Butyrophenones Haloperidol (Haldol) is the only member of this group approved for use as an antipsychotic in the United States. It has much the same therapeutic effects as the phenothiazines in the management of acute psychoses and shares most of the side effects as the phenothiazines but exhibits little or no adrenergic blocking action. It is an effective substitute for the phenothiazines in patients who are intolerant of the latter drugs, particularly of their autonomic effects. It is also one of the main drugs for the treatment of Gilles de la Tourette syndrome (the other being pimozide; see Chap. 4) and the movement disorder of Huntington chorea. It has been widely used in critical care practice to reduce the duration of delirium but at least one randomized trial has failed to show that it is any different than treatment with placebo (Girard and colleagues).

Treatment of Neuroleptic Side Effects As indicated earlier, acute dystonic spasms usually respond to cessation of the offending drug and to the administration of diphenhydramine. Administration of antiparkinsonian drugs of the anticholinergic type (trihexyphenidyl, procyclidine, and benztropine) may hasten recovery from some of the acute symptoms. The purely parkinsonian syndrome usually improves as well, but the tardive dyskinesias stand apart because they may persist for months or years and may be permanent. Oral, lingual, and laryngeal dyskinesias of the tardive type are affected relatively little by any antiparkinsonian drugs. Amantadine in doses of 50 to 100 mg tid has been useful in a few of the cases of post-phenothiazine dyskinesia. Other drugs such as benztropine have been tried in the treatment of regional and more generalized tardive dyskinesia with uncertain results. Nevertheless, there is a tendency for most of the obstinate forms to subside slowly even after several years of unsuccessful therapy. Once a tardive syndrome has been identified, an immediate tapering of the offending medication is recommended, though the efficacy of this strategy has not been evaluated prospectively, and furthermore there is risk of exacerbation of psychotic symptoms. Substitution of the offending medication with one of the second-generation “atypical” antipsychotic medications is a reasonable strategy, though the reduced dyskinetic effects of these medications is only relative.

Neuroleptic Malignant Syndrome This is the most dreaded complication of phenothiazine and haloperidol use; rare instances have been reported after the institution or the withdrawal of L-dopa and similar dopaminergic agents, as well as a few instances reported with the newer antipsychosis drugs. Its incidence has been calculated to be only 0.2 percent of all patients receiving neuroleptics (Caroff and Mann) but its seriousness is underscored by a mortality rate of 15 to 30 percent if not recognized and treated promptly. It may occur days, weeks, or months after neuroleptic treatment is begun. The syndrome consists of hyperthermia, rigidity, stupor, unstable blood pressure, diaphoresis, and other signs

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of sympathetic overactivity, high serum creatine kinase (CK) values (up to 60,000 units), and, in some cases, renal failure because of myoglobinuria. The syndrome was first observed in patients treated with haloperidol, but since then other neuroleptic drugs have been incriminated, particularly the highly potent thioxanthene derivatives and the phenothiazines—chlorpromazine, fluphenazine, and thioridazine—but also, on rare occasions, the less potent drugs that are used to control nausea, such as promethazine. It has become evident that the newer antipsychotic drugs, and specifically olanzapine, are also capable of inducing the syndrome but the risk in comparison to the first generation of antipsychotic drugs has not been established. If treatment of the neuroleptic malignant syndrome is started early, when consciousness is first altered and the temperature is rising, bromocriptine in oral doses of 5 mg tid (up to 20 mg tid) will terminate the condition in a few hours. If oral medication can no longer be taken because of the patient’s condition, dantrolene, 0.25 to 3.0 mg intravenously, may be lifesaving. Once coma has supervened, shock and anuria may prove fatal or leave the patient in a vegetative state. The rigors during high fever may cause muscle damage and myoglobinuria, and shock may lead to hypoxemic-ischemic brain injury. One pitfall is to mistake neuroleptic malignant syndrome for worsening of the psychosis and inadvisably administer more antipsychosis medication. Meningitis, heat stroke, lithium intoxication, catatonia, malignant hyperthermia, and acute dystonic reactions figure in the differential diagnosis. Of course, neuroleptic medication must be discontinued as soon as any of the severe extrapyramidal reactions are recognized. It has been common practice to avoid future administration of the offending neuroleptic but the risk of using another class of antipsychotic agents has not been fully addressed. The syndrome has also been seen after withdrawal of medications for Parkinson disease (L-Dopa and dopamine agonists) an rarely after only dose reductions or changes between agents. The neuroleptic malignant syndrome bears an uncertain relationship to malignant hyperthermia by way of its clinical aspects but also in its response to bromocriptine and dantrolene (see later). Malignant hyperthermia in susceptible individuals is triggered by inhalation anesthetics and skeletal muscle relaxants (see Chap. 45). This disorder was described before the introduction of neuroleptic drugs, and in a small proportion of cases, has been related to a mutation of the ryanodine receptor gene. A genetic factor may underlie a small number of cases of the neuroleptic malignant syndrome (a polymorphism in the D2 receptor gene; see Suzuki and colleagues) possibly provoked by fatigue and dehydration. There is no evidence that the occurrence of one of these syndromes confers a susceptibility to the other.

ANTIDEPRESSION DRUGS Four classes of drugs—the MAO inhibitors, the tricyclic compounds, the serotonergic drugs, and lithium—are particularly useful in the treatment of depressive illnesses.

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The adjective antidepressant refers to their therapeutic effect and is employed here in deference to common clinical practice. Antidepressive or antidepression drugs would be preferable, as the term depressant still has a pharmacologic connotation that does not necessarily equate with the therapeutic effect.

Monoamine Oxidase Inhibitors The observation that iproniazid, an inhibitor of MAO, had a mood-elevating effect in tuberculous patients initiated a great deal of interest in compounds of this type and led quickly to their exploitation in the treatment of depression. Iproniazid proved exceedingly toxic to the liver, as were several subsequently developed MAO inhibitors; but other drugs in this class, much better tolerated, are still available. These include isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate), the latter two being the more frequently used. Tranylcypromine, which bears a close chemical resemblance to dextroamphetamine, may produce unwanted stimulation, but the most common adverse effect of all the MAO inhibitors is postural hypotension. Also, interactions with a wide array of other drugs and ingested substances may induce severe hypertension. Monoamine oxidase is located on the outer surface of the mitochondria in neurons and is used in the catabolism of catecholamines. In the gut and liver, the isoenzyme MAO-A normally serves to deaminate phenethylamine, tyramine, and tryptamine—all of which are products of protein catabolism. Inhibition of MAO-A allows these dietary amines, which have an amphetamine-like action, to enter the systemic circulation in increased quantities, thus releasing norepinephrine from sympathetic nerve endings and increasing heart rate and blood pressure. Most antidepressant medications are of this class. Medications used in Parkinson disease (see Chap. 38) inhibit the MAO-B isoenzyme, which deaminates phenylethylamine and trace amines, with a correspondingly lower risk of causing hypertension. More relevant to their action as antidepressants, the MAO inhibitors have in common the ability to block the intraneuronal oxidative deamination of naturally occurring amines (norepinephrine, epinephrine, dopamine, and serotonin) and it has been suggested that the accumulation of these substances is responsible for the antidepressant effect. However, many enzymes other than monoamine oxidase are inhibited by MAO inhibitors, and the latter drugs have numerous actions unrelated to enzyme inhibition. Furthermore, many agents with antidepressant effects like those of the MAO inhibitors do not inhibit MAO. Therefore, one cannot assume that the therapeutic effect of these drugs has a direct relation to MAO inhibition in the brain. The MAO inhibitors must be dispensed with caution and awareness of their potentially serious side effects. They may at times cause excitement, restlessness, agitation, insomnia, and anxiety, occasionally with the usual dose but more often with an overdose. Mania and convulsions may occur (especially in epileptic patients). Other side effects are muscle twitching and involuntary movements,

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urinary retention, skin rashes, tachycardia, jaundice, visual impairment, enhancement of glaucoma, impotence, sweating, muscle spasms, paresthesias, and a serious degree of orthostatic hypotension. Patients taking MAO-A inhibitors must be warned against the use of phenothiazines, CNS stimulants, and tricyclic and serotoninergic antidepressants (see later), as well as sympathomimetic amines and tyramine-containing foods. The combination of a MAO inhibitor and any of these drugs or amines may induce hypertension, atrial and ventricular arrhythmia, pulmonary edema, stroke, or death. Sympathomimetic amines are contained in some commonly used cold remedies, nasal sprays, nose drops, and certain foods—aged cheese, beer, red wine, pickled herring, sardines, sausages, and certain preserved meat or fish. Exaggerated responses to the usual dose of meperidine (Demerol) and other narcotic drugs have also been observed sporadically; in these cases, respiratory function may be depressed to a serious degree, and hyperpyrexia, agitation, and pronounced hypotension may occur as well, sometimes with fatal issue. Unpredictable side effects may also accompany the simultaneous administration of barbiturates and MAO inhibitors. The abrupt occurrence of severe occipital headache, nausea, vomiting, pupillary dilatation, or visual blurring should suggest a hypertensive crisis. Treatment is with intravenous phentolamine 5 mg, nitroprusside, labetalol, or a calcium channel blocker administered slowly to prevent hypotension. Overdosage of MAO inhibitors may lead to coma, for which there is no treatment other than supportive care. The therapeutic use of MAO inhibitors for depression is discussed in Chaps. 47 and 48, and MAO-B inhibitors for Parkinson disease, in Chap. 38.

decreased appetite and libido. The side effects of the tricyclic drugs are less frequent and far less serious than those of the MAO inhibitors. The tricyclic compounds are also potent anticholinergic agents, which account for their most prominent and bothersome side effects—orthostatic hypotension, urinary bladder weakness, drowsiness, confusion, blurred vision, and dry mouth. They may also occasionally produce CNS excitation—leading to insomnia, agitation, and restlessness—but usually these effects are readily controlled by small doses of benzodiazepines given concurrently or in the evenings. As indicated earlier, the tricyclic drugs should not be given with a MAO inhibitor; serious reactions have occurred when small doses of imipramine were given to patients who had discontinued the MAO in the previous days or weeks. Both the MAO inhibitors and the tricyclic antidepressants are dangerous drugs when taken in excess. Tricyclic compounds are a cause of accidental poisoning and suicide of depressed patients. It is common for the intoxicated patient to have taken several drugs, in which case chemical analyses of the blood and urine are particularly helpful in determining the drugs involved and in sorting out therapeutic and toxic concentrations. Mortality from overdose is mostly a result of cardiac rhythm disturbances, particularly tachyarrhythmias, and impaired conduction (atrioventricular block). Treatment consists of gastric aspiration and instillation of activated charcoal and the addition of physostigmine to reverse serious arrhythmias; the short duration of action of physostigmine requires that frequent doses be given. Dialysis is of no value because of the low plasma concentrations of the drug.

Tricyclic Antidepressants

Serotonin Reuptake Inhibitors and Related Drugs

Soon after the first successes with MAO inhibitors, another class of tricyclic compounds appeared. The mode of action of these agents is not fully understood, but there is evidence that they block the reuptake of amine neurotransmitters, both norepinephrine and serotonin. Blocking this amine pump mechanism (called the presynaptic plasma transporter), which ordinarily terminates synaptic transmission, permits the persistence of neurotransmitter substances in the synaptic cleft and does no more than support the hypothesis that endogenous depression is associated with a deficiency of noradrenergic or serotonergic transmission. These medications have been divided into classes of tertiary amines (imipramine, amitriptyline and doxepin, trimipramine), which have activity as reuptake inhibitors of norepinephrine and serotonin, and the secondary amines (desipramine, amoxapine, maprotiline, nortriptyline, protriptyline), which have a preferential effect on reuptake of norepinephrine. Subsequently, a number of additional antidepressant drugs were introduced. The tricyclic antidepressants and the serotonergic drugs discussed in the next section, are presently the most effective drugs for the treatment of patients with depressive illnesses, the former being particularly useful for those with anergic depressions, early morning awakening, and

The selective serotonin reuptake inhibitors (SSRIs) constitute a newer class of antidepressants; paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) are common examples, but new ones continue to be developed. Of the several related drugs such as venlafaxine (Effexor), nefazodone (Serzone), mirtazapine (Remeron), citalopram (Celexa), trazodone (Desyrel), and bupropion (Wellbutrin), each has a novel structure that is not analogous to that of the other categories of antidepressants. They are believed to act similarly to the SSRI class by inhibiting the reuptake of serotonin and norepinephrine. This results in a potentiation of the actions of these neurotransmitters. Because they do not bind as avidly as tricyclic drugs to the muscarinic and adrenergic receptors in the brain, they produce fewer side effects, but some patients complain of anxiety or insomnia when they are first introduced. These drugs share the same side effects to varying degrees, including the danger of concomitant MAO inhibitor administration. The risk of seizures related to the taking of certain of these medications has been much discussed. For the most part, the risk is quite small but there is little information to guide their use in known epileptics. Several studies suggest that the frequency of convulsions may increase in such patients. Bupropion has been particularly associated with

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seizures in about 0.5 percent of patients treated at higher dose levels (over 400 mg/d) and this drug should not be used in individuals with a history of seizures. The SSRI drugs may be effective in a shorter time than the tricyclic agents and are popular at the moment, but their long-term therapeutic usefulness in comparison with their predecessors remains to be determined (Richelson). Fluoxetine has also been used in a group of autistic children (see “Course, Treatment, and Prognosis” under “Autism” in Chap. 37). Constipation, dry mouth, and reduced sexual potency are to be expected in some, but varying degrees. Hyponatremia is a rare complication.

Serotonin Syndrome The symptoms of a “serotonin syndrome” that results from excessive intake of the above listed drugs or from the concurrent use of MAO inhibitors include confusion and restlessness, tremor, tachycardia, hypertension, clonus and hyperreflexia, shivering, and diaphoresis (Boyer and Shannon). The long list of other medications, when used concurrently with SSRIs can produce the syndrome (including “triptans” for migraine), are noted in this reference. The treatment is discontinuation of the medication, reduction of temperature and hypertension, benzodiazepines to control agitation, and in severe cases, the addition of cyproheptadine, a 5-HT2A receptor blocker. The typical dose is 4 to 8 mg every 4 to 6 h (or a higher initial dose); tablets are crushed and administered by nasogastric tube. Atypical antipsychosis agents with similar serotonin antagonist activity have also been used as treatment (olanzapine, chlorpromazine).

Lithium The discovery by Cade in 1949 of the therapeutic effects of lithium salts in mania has led to its widespread use in the treatment of bipolar disease (bipolar disorder). The drug has proved relatively safe if blood levels are monitored. Its value is much more certain in treatment of the manic phase of bipolar disorder and prevention of recurrences of cyclic mood shifts than it is in treatment of anxiety and depression. Guidelines for the clinical use of lithium are given in Chap. 48. Its mechanism of action is unclear but there is experimental evidence that lithium blocks the stimulus-induced release of norepinephrine and dopamine and enhances the reuptake of this amine—the opposite in a sense, of what occurs with the other classes of antidepressants. With blood levels of lithium in the upper therapeutic range (therapeutic 0.6 to 1.2 mEq/L), it is not uncommon to observe a fast-frequency action tremor or asterixis, together with nausea, loose stools, fatigue, polydipsia, and polyuria. These symptoms usually subside with time. Above a level of 1.5 to 2 mEq/L, particularly in patients with impaired renal function or in those taking a thiazide diuretic, serious intoxication becomes manifest—clouding of consciousness, confusion, delirium, dizziness, nystagmus, ataxia, stammering, diffuse myoclonic twitching, and nephrogenic diabetes insipidus. Vertical (downbeating) nystagmus and opsoclonus (see Chap. 13) may also be prominent. A variety of skin problems is common including worsening of acne vulgaris. An uncommon toxic effect is

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the development of goiter but most patients remain euthyroid although the thyroid-stimulating hormone (TSH) levels may increase slightly. The goiter usually requires no treatment but it is possible to administer thyroid hormone to cause the thyroid enlargement to regress. The myoclonic state, particularly when combined with confusion and sharp waves in the EEG, may mimic Creutzfeldt-Jakob disease (see Chap. 32) but there should be no problem in diagnosis if the setting of the illness and the administration of lithium are known. At blood lithium concentrations above 3.5 mEq/L, these symptoms are replaced by stupor and coma, sometimes with convulsions, and may prove fatal. Discontinuing lithium in the intoxicated patient, which is the initial step in therapy, does not result in immediate disappearance of toxic symptoms. This may be delayed by a week or two, and the diabetes insipidus may persist even longer. Fluids, sodium chloride, aminophylline, and acetazolamide promote the excretion of lithium. Lithium coma may require hemodialysis, which has proved to be the most rapid means of reducing the blood lithium concentration.

STIMULANTS Drugs that act primarily as CNS stimulants assume clinical importance for several reasons, mainly in their use for sleep disorders and attention deficit disorder. Some members of this group, the amphetamines, are abused and others are not infrequent causes of poisoning. Their main mechanism of action is the release of endogenous catecholamine from vesicles in the presynaptic terminals.

Amphetamines and Related Agents The amphetamines (d-amphetamine, d,l-amphetamine, pemoline, methamphetamine, methylphenidate) are analeptics (CNS stimulants) and in addition have significant hypertensive, respiratory-stimulant, and appetitedepressant effects. They are effective in the management of narcolepsy but have been more widely and sometimes indiscriminately used for weight loss, the abolition of fatigue, and the treatment of hyperactivity in children (see Chap. 37 for full discussion). Undoubtedly, they are able to reverse fatigue, postpone the need for sleep, and elevate mood but these effects are not entirely predictable and the user must compensate for the period of wakefulness with even greater fatigue and often with depression that follows. The intravenous use of a high dose of amphetamine produces an immediate feeling of ecstasy. Because of the ease with which amphetamines can be procured, instances of acute and chronic intoxication are not uncommon. Methamphetamine is frequently abused in this category, as intravenous “crystal” or smoked as “ice.” The toxic signs are essentially an exaggeration of the activating effects—restlessness, excessive speech and motor activity, tremor, and insomnia. Severe intoxication gives rise to hallucinations, delusions, and changes in affect and thought processes—a state that may be indistinguishable from paranoid schizophrenia. An amphetamine-associated vasculopathy and

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intracerebral and subarachnoid hemorrhage are wellrecognized but rare complications of chronic or acute intoxication (Harrington and colleagues and Chap. 33). Similar cerebrovascular complications may appear with sympathomimetic agents contained in over-the-counter cold medications and in dieting aids. Phenylpropanolamine has been implicated most often but ephedrine, cocaine (see in the following text), and similar agents rarely have the same effects and induce a vasculopathy. The pathogenesis of the vascular lesion is unknown (both vasospasm and arteritis have been reported). The chemically related compound, ecstasy, (3,4-methylenedioxmethampetamine, MDMA) is in this general amphetamine category, although it is often considered with the psychoactive drugs and is commented on below. Chronic use of amphetamines can lead to a high degree of tolerance and psychologic dependence. Withdrawal of the drug after sustained oral or intravenous use is regularly followed by a period of prolonged sleep (a disproportionate amount of which is rapid eye movement sleep), from which the patient awakens with a ravenous appetite, muscle pains, and feelings of profound fatigue and depression. Treatment consists of discontinuing the use of amphetamine and administering antipsychosis drugs. Hypertension may need to be treated until the effect of the drug has waned.

Cocaine The conventional use of cocaine as a local anesthetic, mainly in the past, has been overshadowed by its illicit and widespread use as a stimulant and mood elevator. Cocaine is abused intranasally (“snorted”), smoked, or injected intravenously or intramuscularly. There has been an alarming escalation in the use of cocaine, mainly because a relatively pure and inexpensive form of the free alkaloid base (“crack”) became readily available in the 1980s. This form of cocaine is heat-stable and therefore suitable for smoking. According to the National Household Survey on Drug Abuse, there are an estimated 600,000 frequent cocaine users in the United States. (Frequent use was arbitrarily defined as use on 51 or more days during the preceding year.) The number of occasional users (less than 12 days in the preceding year) was 2.4 million. These figures are probably subject to significant underreporting. A sense of well-being, euphoria, loquacity, and restlessness are the familiar effects. Pharmacologically, cocaine is thought to act like the tricyclic antidepressants; that is, it blocks the presynaptic reuptake of biogenic amines, thus producing vasoconstriction, hypertension, and tachycardia and predisposing to generalized tremor, myoclonus, seizures, and psychotic behavior. It has an additional weaker action, similar to amphetamines, of causing the release of endogenous monoamines. The cocaine abuser readily develops psychologic dependence and habituation, that is, an inability to abstain from frequent compulsive use. The manifestations of physical dependence are more subtle and difficult to recognize. Nevertheless, abstinence from cocaine following a period of chronic abuse is regularly attended by insomnia, restlessness, anorexia, depression, hyperprolactinemia, and signs of dopaminergic

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hypersensitivity—a symptom complex that constitutes an identifiable withdrawal syndrome. With the increasingly widespread use of cocaine, a variety of complications continues to emerge (Cregler and Mark). The symptoms of severe intoxication (overdose), noted above, may lead to coma and death and require emergency treatment in an intensive care unit, along the lines indicated for the management of other forms of coma. Seizures often occur in this setting and are treated more effectively with benzodiazepines than with standard anticonvulsant drugs. Spontaneous subarachnoid or intracerebral hemorrhage and cerebral infarction have rarely followed the intranasal use and smoking of cocaine (Levine and colleagues). These complications could be the result of acute hypertension induced by the sympathomimetic actions of cocaine, and the incidence of vascular malformations appears to be higher in those patients who have a cerebral hemorrhage (see Chap. 33). Cocaine and amphetamines also, on occasion, produce a state of generalized vasospasm leading to multiple cortical infarctions and posterior white matter changes that are evident on imaging studies, essentially a form of hypertensive, or posterior reversible encephalopathy (PRES) (Altura and Altura, and also Chap. 33). A case series has described 39 patients who developed acute rhabdomyolysis after cocaine use; 13 of these had acute renal failure, severe liver dysfunction, and disseminated intravascular coagulation and 6 of them died (Roth and colleagues). Some reports indicate that cocaine use during pregnancy may cause fetal damage, abortion, or persistent signs of toxicity in the newborn infant. Anxiety, paranoia, and other manifestations of psychosis may develop within several hours of cocaine use. These complications can be treated with antipsychosis drugs, for example, haloperidol.

Khat and Cathionine Stimulants The psychostimulant khat is used widely in certain countries, almost as a cultural norm in restricted populations, mainly in the Far East. The khat leaf is chewed to release cathionine that produces euphoria by an amphetaminelike effect. A chemically designed congener, the N-methyl analog of cathionine, or methcathinone (“Jeff,” “Cat,” “mulka,” and other street names), is manufactured from over-the-counter cold medications such as ephedrine, pseudoephedrine, and phenylpropanolamine and is frequently abused. Potassium permanganate may be used to reduce the basic substances and is a source of a manganese-induced extrapyramidal syndrome. Furthermore, entirely synthetic cathinones, often called “bath salts,” although they have no relation to that original product, are amphetamine-like substances that are taken orally or nasally and produce rapid activation of behavior and sympathetic hyperactivity.

PSYCHOACTIVE DRUGS AND HALLUCINOGENS Included in this category is a heterogeneous group of drugs, the primary effect of which is to alter perception, mood, and thinking out of proportion to other aspects of

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cognitive function and consciousness. This group of drugs comprises lysergic acid diethylamide (LSD), phenylethylamine derivatives (mescaline or peyote), psilocybin, certain indolic derivatives, cannabis (marijuana), phencyclidine (PCP), and a number of other compounds. They are also referred to as psychoactive or psychotomimetic drugs or as hallucinogens and psychedelics.

Marijuana Marijuana is the most commonly used illicit drug in the United States and in many jurisdictions it is no longer “illicit.” The effects, when taken by inhaling the smoke from cigarettes or pipe, are prompt in onset and evanescent. With low doses, the symptoms are like those of mild alcohol intoxication (drowsiness, euphoria, and perceptual distortions). With increasing amounts, the effects may become similar to hallucinogens (see later); they may be quite disabling for many hours. With even larger doses, severe depression and stupor may occur, but death is rare (Hollister, 1988). No definite damage to the nervous system has been found after chronic use. Increasingly, individuals have used marijuana to assuage anxiety, similar to the use of alcohol for this purpose. It then may lead to dependence. This agent and its derivatives activate the CB1 receptor, mainly on GABA-ergic neurons in the hippocampus, amygdala, and cortex. Activation of the receptor inhibits the release of oligopeptide neurotransmitters and monoamines. They also have complex electrophysiologic effects on neurons. Reverse tolerance to marijuana (i.e., increasing sensitization) may be observed initially, but on continued use, tolerance to the euphoriant effects develops. In one of the few experimental studies of chronic marijuana use, the subjects reported feeling “jittery” during the first 24 h after abrupt cessation of smoking marijuana, although no objective withdrawal signs could be detected. Chronic intoxicated users demonstrate reduced cognitive performance, but according to Iverson, a persistent cognitive decline has not been shown definitely. The mild antiemetic effects of marijuana coupled with euphoria have led to its therapeutic use to ameliorate the effects of chemotherapy. Putative effects on spasticity and, more popularly on neuropathic pain have not been fully substantiated (see commentaries by Caulley, Caplan, and Ross).

Synthetic Cannabinoids With the cathionines discussed above, this is a newer class of synthetic drugs; they go by street names of “Spice,” “K2,” “K4,” and many others. These agents bind even more avidly to cannabinoid receptors than does the original drug (marijuana) and produce a heightened stimulant effect. Agitation, delusions, and paranoia result, a veritable psychosis, and some patients we have admitted have been physically almost uncontrollable, only to awaken and have entirely normal affect and cognition. Because the synthetic agents are chemically quite different from cannabis, they do not appear on conventional toxicology-drug screens. Small regional outbreaks of “zombie”-like behavior have been attributed to these agents and the difficulty in rapidly identifying the agent has been highlighted (Adams

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and colleagues). Treatment of intoxication is generally by diazepines and haloperidol but often to little avail until the drug is metabolized.

Mescaline, LSD, and Psilocybin These agents produce much the same clinical effects if given in comparable amounts. The perceptual changes are the most dramatic: the user describes vivid visual hallucinations, alterations in the shape and color of objects, unusual dreams, and feelings of depersonalization. An increase in auditory acuity has been described but auditory hallucinations are rare. Cognitive functions are difficult to assess because of inattention, drowsiness, and inability to cooperate in mental testing. The somatic symptoms consist of dizziness, nausea, paresthesia, and blurring of vision. Sympathomimetic effects—pupillary dilatation, piloerection, hyperthermia, and tachycardia—are prominent, and the user may also show hyperreflexia, incoordination of the limbs, and ataxia. Tolerance to LSD, mescaline, and psilocybin develops rapidly, even on a once-daily dosage. Furthermore, subjects tolerant to any one of these three drugs are crosstolerant to the other two. Tolerance is lost rapidly when the drugs are discontinued and no characteristic signs of physical dependence ensue. In this sense, addiction does not develop, although users may become psychologically dependent on the drugs. These drugs are taken regularly by “drugheads” (a colorful term we have retained from the original authors of this book to describe individuals who use any agent that alters consciousness) and by college and high school students for a way of socializing, for conformity, or for reasons that even they cannot ascertain. The use of these drugs may be attended by a number of serious adverse reactions taking the form of acute panic attacks (“bad trip”), long-lasting psychotic states resembling paranoid schizophrenia, and flashbacks (spontaneous recurrences of the original LSD experience, sometimes precipitated by smoking marijuana and accompanied by panic attacks). Serious physical injury may follow on impairment of the user’s critical faculties. Numerous claims have been made that LSD and related drugs are effective in the treatment of mental disease and a wide variety of social ills, and that they have the capacity to increase one’s intellectual performance, creativity, and self-understanding. To date, no acceptable studies validate any of these claims. Recently, interest has been revived in the use of these drugs, particularly psilocybin as treatment for mental disorders such as depression. Small series suggest benefit in selected populations, who express interest in this approach (See Chap. 48).

Phencyclidine (“Angel Dust”) and “Ecstasy” During the early 1970s, the abuse of PCP and its analogues was a significant problem. The popularity of these drugs has dropped, but some illicit use continues because they are relatively cheap, easily available, and quite potent. (Their manufacture as a veterinary anesthetic was stopped in 1979.) PCP is taken in the form of a granular powder, frequently

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mixed with other drugs, and is smoked or snorted. It is usually classified as a hallucinogen, although it also has stimulant and depressant properties. The effects of intoxication are like those of LSD and other hallucinogens, and resemble those of an acute schizophrenic episode, which may last several days to a week or longer. After the ingestion of a large amount (10 mg or more) of PCP, it is present in the blood and urine for only a few hours sometimes making its detection difficult. Toxicity from the illicit use of “ecstasy” (methylenedioxymethamphetamine [MDMA]) during parties (“raves”) has increased as a result of its ill-founded reputation for safety. It appears to cause a release of both serotonin and dopamine in the brain and produces an elated state similar to the effects of cocaine. Seizures, cerebral hemorrhages, and psychosis have been reported in previously healthy individuals (Verebey and colleagues).

BACTERIAL TOXINS The most important diseases in this category are tetanus, botulism, and diphtheria. Each is caused by an extraordinarily powerful bacterial toxin that acts primarily on the nervous system.

Tetanus The cause of this disease is the anaerobic, spore-forming rod Clostridium tetani. The organisms are found in the feces of some humans and many animals, particularly horses, from which they readily contaminate the soil. The spores may remain dormant for many months or years, but when they are introduced into a wound, especially if a foreign body or purulent bacteria are present, they are converted into their vegetative forms, which produce the exotoxin tetanospasmin. In low-income countries, tetanus is still a common disease, particularly in newborns, in whom the spores are introduced via the umbilical cord (tetanus neonatorum). In the United States, the incidence rate of tetanus is about 1 per million people per year. Injection of contaminated heroin has emerged as another cause. Approximately 67 percent of all injuries leading to tetanus occur from deep scratches and puncture wounds in the home, and approximately 20 percent from deep scratches and puncture wounds in gardens and on farms. Since 1903, when Morax and Marie proposed their theory of centripetal migration of the tetanus toxin, it has been taught that spread to the nervous system occurs via the peripheral nerves, the toxin ascending in the axis cylinders or the perineural sheaths. Modern studies, using fluorescein-labeled tetanus antitoxin, have disclosed that the toxin is also widely disseminated via blood or lymphatics, probably accounting for the generalized form of the disease. However, in local tetanus (see Chap. 45), the likely mode of spread to the CNS is indeed by retrograde axonal transport.

Mode of Action of Tetanus Toxin Like botulinum toxin, the tetanus toxin is a zinc-dependent protease. It blocks neurotransmitter release by cleaving

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surface proteins of the synaptic vesicles, thus preventing the normal exocytosis of neurotransmitter. The toxin interferes with the function of the reflex arc by the blockade of inhibitory transmitters, mainly GABA, at presynaptic sites in the spinal cord and brainstem. The Renshaw cell, the source of recurrent inhibition of spinal and brainstem motor neurons, is preferentially affected. Elicitation of the jaw jerk, for example, is normally followed by the abrupt suppression of motor neuron activity, manifested in the electromyogram (EMG) as a “silent period” (see further on). In the patient with tetanus, there is a failure of this inhibitory mechanism, with a resulting increase in activation of the neurons that innervate the masseter muscles (trismus, or lockjaw). Of all neuromuscular systems, the masseter innervation seems to be the most sensitive to the toxin. Not only do afferent stimuli produce an exaggerated effect, but they also abolish reciprocal innervation, allowing both agonists and antagonists to contract, giving rise to the characteristic muscular spasm of tetanus (see below). In addition to its generalized effects on the motor neurons of the spinal cord and brainstem, there is evidence that the toxin acts directly on skeletal muscle at the point where the axon forms the endplate (accounting perhaps for localized tetanus) and also on the cerebral cortex and the sympathetic nervous system in the hypothalamus. Many of these features have been reviewed by Sanford. The incubation period varies greatly, from one or two days after exposure to a month or longer. Long incubation periods are associated with mild and localized types of the disease.

Clinical Features There are several clinical types of tetanus, usually designated as local, cephalic, and generalized. Generalized tetanus  This is the most common form. The interval from exposure in a wound to clinical manifestations is usually several days to 2 weeks (said to average 10 days) but varies depending on the type of wound and inoculum. It may begin as local tetanus that becomes generalized after a few days, or it may be diffuse from the beginning. Trismus is frequently the first manifestation. In some cases, this is preceded by a feeling of stiffness in the jaw or neck, slight fever, and other general symptoms of infection. The localized muscle stiffness and spasms spread quickly to other bulbar muscles as well as those of the neck, trunk, and limbs. A state of unremitting rigidity develops in all the involved muscles: the abdomen is board-like, the legs are rigidly extended, and the lips are pursed or retracted (risus sardonicus); the eyes are partially closed by contraction of the orbicularis oculi, or the eyebrows are elevated by spasm of the frontalis. Superimposed on this persistent state of enhanced muscle activity are paroxysms of tonic contraction or spasm of muscles (tetanic seizures or “convulsions”), which occur spontaneously or in response to the slightest external stimulus (Weinstein). They are agonizingly painful. Consciousness is not lost during these paroxysms. The tonic contraction of groups of muscles results in opisthotonos or in forward flexion of the trunk, flexion and adduction of the arms, clenching of the fists, and extension of the legs. Spasms of

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the pharyngeal, laryngeal, or respiratory muscles carry the constant threat of apnea or suffocation. Fever and pneumonia are common complications. Large swings in blood pressure and heart rate as well as profuse diaphoresis are typical, mainly in response to the intense muscular contractions but they may also be related to the action of the toxin on the CNS. Death is usually attributable to asphyxia from laryngospasm, to heart failure, or to shock, the latter resulting from the action of the toxin on the hypothalamus and sympathetic nervous system. Generalized spasms and rigidity of trunk and limbs developing in a neonate a few days after birth should suggest the diagnosis of tetanus. This form of tetanus occurs when there has been inadequate sterile treatment of the umbilical cord stump in a neonate born to an unimmunized mother. Local tetanus  This is the most benign form. The initial symptoms are stiffness, tightness, and pain in the muscles in the neighborhood of a wound, followed by twitchings and brief spasms of the affected muscles. Local tetanus occurs most often in relation to a wound of the hand or forearm, rarely in the abdominal or paravertebral muscles. Gradually, some degree of continuous involuntary spasm becomes evident. There is sustained tautness of the affected muscles and resistance of the part to passive movement. Superimposed on this background of more or less continuous motor activity are brief, intense spasms, lasting from a few seconds to minutes and occurring spontaneously or in response to all variety of stimulation (Struppler and colleagues). Early in the course of the illness there may be periods when the affected muscles are palpably soft and appear to be relaxed. A useful diagnostic maneuver at this stage is to have the patient perform some repetitive voluntary movements, such as opening and closing the hand, in response to which there occurs a gradual increase in the tonic contraction and spasms of the affected muscles, followed by spread to neighboring muscle groups (recruitment spasm). Even with mild localized tetanus there may be slight trismus, a useful diagnostic sign. Symptoms may persist in localized form for several weeks or months. Gradually the spasms become less frequent and more difficult to evoke, and they finally disappear without residue. Complete recovery is to be expected, as there are no pathologic changes in muscles, nerves, spinal cord, or brain, even in the most severe generalized forms of tetanus. Cephalic tetanus This form of tetanus follows wounds of the face and head. The incubation period is short, 1 or 2 days as a rule. The affected muscles (most often facial) are weak or paralyzed. Nevertheless, during accessions of tetanic spasm, the palsied muscles are seen to contract. Apparently, the disturbance in the facial motoneurons is sufficient to prevent voluntary movement but insufficient to prevent the strong reflex impulses that elicit facial spasm. The spasms may involve the tongue and throat, with persistent dysarthria, dysphonia, and dysphagia. Ophthalmoparesis is known to occur but is difficult to verify because of severe blepharospasm. In a strict sense, these cephalic forms of tetanus are examples of local tetanus that frequently becomes generalized. Many cases prove fatal.

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Diagnosis This is made from the clinical features and a history of preceding injury. The latter is sometimes disclosed only after careful questioning, the injury having been trivial, forgotten, and entirely healed. The organisms may or may not be recovered from the wound by the time the patient receives medical attention; other laboratory tests, apart from the EMG, are of little value. Serum CK may be moderately elevated if the rigidity is generalized. The EMG recorded from muscles in spasm shows continuous discharges of normal motor units like those recorded from a forceful voluntary muscle contraction. Most characteristic of tetanus, as mentioned earlier, is a loss of the physiologic silent period that occurs 50 to 100 ms after reflex contraction. This pause, normally produced by the recurrent inhibition of Renshaw cells, is blocked by tetanus toxin. In generalized tetanus the loss of the silent period can almost always be demonstrated in the masseter, and it is found in a muscle affected by local tetanus. Interestingly, the silent period is preserved in the stiff man syndrome (see Chap. 45). Tetany caused by hypocalcemia, the spasms of strychnine poisoning or black widow spider bite, trismus as a result of painful conditions in and around the jaw, the dysphagia of rabies, hysterical spasms, rigidity and dystonic spasms caused by neuroleptic drugs, and the spasms of the stiff man syndrome all resemble the spasms of tetanus but should not be difficult to distinguish when all aspects of these disorders are considered. Nonetheless, the diagnosis is difficult to bring to mind in a nonendemic area. The death rate from tetanus is approximately 50 percent overall; it is highest in newborns, heroin addicts, and patients with the cephalic form of the disease. The patient usually recovers if there are no severe generalized muscle spasms during the course of the illness or if the spasms remain localized.

Treatment This is directed along several lines. The widespread use of immunization is the best defense against the disorder as noted below. Washing a deep wound liberally is usually protective. At the outset, a single dose of antitoxin (3,000 to 6,000 U of tetanus human immune globulin) is given along with a 10-day course of penicillin (1.2 million U of procaine penicillin daily), metronidazole (500 mg q6h intravenously or 400 mg rectally), or tetracycline (2 g daily). These drugs are effective against the vegetative forms of C. tetani. Immediate surgical treatment of the wound (excision or debridement) is imperative, and the tissue around the wound should be infiltrated with antitoxin. Survival once spasms begin depends on expert and constant nursing in an intensive care unit and may be necessary for weeks. Tracheostomy is a requisite in patients with recurrent generalized tonic spasms and should not be delayed until apnea or cyanosis has occurred. The patient must be kept as quiet as possible to avoid stimulusinduced spasms. This requires a darkened, quiet room, and the judicious use of sedation. The benzodiazepines are the most useful drugs for both sedation and muscle relaxation; diazepam 120 mg/d or more can be given in frequent

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divided doses if ventilatory support is available; alternatively, midazolam or propofol can be used in a continuous intravenous infusion. Short-acting barbiturates and chlorpromazine may also be useful, as may be morphine. Intrathecal baclofen and continuous atropine infusions have been used with success in severe cases, and intramuscular injections of botulinum toxin may be used for trismus and local spasm. The aim of therapy is to suppress muscle spasms and to keep the patient drowsy to avoid the horrible discomfort of the spasms. All treatments and manipulations should be kept to a minimum and coordinated so that the patient may be sedated beforehand. Failure of these measures to control the tetanic paroxysms requires that intravenous administration of neuromuscular blocking agents such as pancuronium or vecuronium be used to abolish all muscle activity; appropriate sedative medication is instituted for as long as necessary, breathing being maintained by mechanical ventilation. Many intensive care units favor the use of neuromuscular paralytic drugs in all but the mildest cases. Further details concerning treatment can be found in the review by Farrar and colleagues. All persons should be immunized against tetanus and receive a booster dose of toxoid every 10 years—a practice that is frequently neglected in the elderly. (Some authorities indicate protection is longer). Injuries that carry a threat of tetanus should receive toxoid if the patient has not received a booster injection in the preceding year, and a second dose of toxoid is needed 6 weeks later. If the injured person has not received a booster injection since the original immunization, an injection of both toxoid and human antitoxin is used; the same applies to injured persons who have never been immunized. An attack of tetanus does not confer permanent immunity and persons who recover should be immunized.

Diphtheria Diphtheria, an acute infectious disease caused by Corynebacterium diphtheriae, is now quite rare in the United States and Western Europe. The faucial-pharyngeal form of the disease, which is the most common clinical type, is characterized by the formation of an inflammatory exudate of the throat and trachea; at this site, the bacteria elaborate an exotoxin, which affects the heart and nervous system in approximately 20 percent of cases. The involvement of the nervous system follows a predictable and biphasic pattern (Fisher and Adams). It begins locally, with palatal paralysis (nasal voice, regurgitation, and dysphagia) between the 5th and 12th days of illness. At this time or shortly afterward, other cranial nerves (trigeminal, facial, vagus, and hypoglossal) may also be affected. Ciliary body paralysis with loss of accommodation and blurring of vision but with preserved light reaction usually appears in the second or third week (the opposite of the Argyll Robertson reaction). Rarely, the extraocular muscles are weakened. The cranial nerve signs may clear without further involvement of the nervous system, or a delayed sensorimotor polyneuropathy may develop between the fifth and eighth weeks of the disease. The latter varies in severity from a mild, predominantly distal polyneuropathy of the limbs to a rapidly evolving, ascending paralysis,

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like that of the Guillain-Barré syndrome; CSF findings are similar as well (acellular fluid with elevated protein). The neuropathic symptoms progress for a week or two, and if the patient does not succumb to respiratory paralysis or cardiac failure (cardiomyopathy), these conditions stabilize and then improve slowly and more or less completely. The early oropharyngeal symptoms, the ciliary paralysis with relatively retained pupillary response to light, and subacute evolution of a delayed symmetrical sensorimotor peripheral neuropathy distinguish diphtheria from other forms of polyneuropathy. The long latency between the initial infection and the involvement of the nervous system has no clear explanation. In experimental animals, Waksman and colleagues many years ago demonstrated that the toxin reaches the Schwann cells in the most vascular parts of the peripheral nervous system within 24 to 48 h of infection but its metabolic effect on cell membranes extends over a period of weeks. The toxin produces demyelination in the proximal parts of spinal nerves, in dorsal root ganglia, and in spinal roots. The cardiac musculature and the conducting system of the heart undergo mild focal necrosis. The source of diphtheritic infection may be extrafaucial—a penetrating wound, skin ulcer, or infection of the umbilicus in the neonate. The systemic and neurologic complications of faucial diphtheria can also be observed in the extrafaucial form of the disease (wound infection) after a similar latent period. It is probable, therefore, that the toxin reaches neural sites via the bloodstream; but in addition, some action is exerted locally, as evidenced by palatal paralysis in faucial cases and by initial weakness and sensory impairment in the neighborhood of the infected wound. Although the infection is treated with penicillin or erythromycin, there is no specific treatment for the neurologic complications of diphtheria. It is generally agreed that the administration of antitoxin within 48 h of the earliest symptoms of the primary diphtheritic infection lessens the incidence and severity of the peripheral nerve complications. The polyneuropathy of diphtheria is discussed further in Chap. 43 (McDonald and Kocen).

Botulism Botulism is a rare form of food-borne illness caused by the exotoxin of Clostridium botulinum. Outbreaks of poisoning are most often caused by ingested bacteria contained in home-preserved than in commercially canned products, and vegetables and home-cured ham are incriminated more commonly than are other food products. Very rarely, a contaminated wound is the source of infection. Although the disease is ubiquitous, five western states (California, Washington, Colorado, New Mexico, and Oregon) account for more than half of all reported outbreaks in the United States. Neonatal and infantile forms of the disease have been reported. These are a result of absorption of the toxin formed by germination of ingested spores (rather than ingestion of preformed toxin), an important source of which is contaminated natural (raw) honey. A few adult cases may have a similar source. It is now well established based on observations in both animals and humans that the primary site of action of

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toxin is at a neuromuscular junction, more specifically on the presynaptic membrane. The toxin interferes with the release of acetylcholine from peripheral motor nerves at the neuromuscular synapse. The physiologic defect is similar to the one that characterizes the myasthenic syndrome of Lambert-Eaton (see Chap. 46) but different from that of myasthenia gravis. Symptoms usually appear within 12 to 36 h of ingestion of the tainted food. Anorexia, nausea, and vomiting occur in most patients. As a rule, blurred vision and diplopia are the initial neural symptoms; their association with ptosis, strabismus, and extraocular muscle palsies, particularly of the sixth nerve, may at first suggest a diagnosis of myasthenia gravis. In botulism, however, accommodation is lost, and the pupils are often unreactive to light. Other symptoms of bulbar involvement—nasality of voice, hoarseness, dysarthria, dysphagia, and an inability to phonate—follow in quick succession. These, in turn, are followed by progressive weakness of the muscles of the face, neck, trunk, and limbs, and by respiratory insufficiency. Despite the oropharyngeal weakness, it is not unusual for the gag reflex to be retained. Tendon reflexes are lost in cases of severe generalized weakness. These symptoms and signs evolve rapidly, over 2 to 4 days as a rule, and may be mistaken for those of the Guillain-Barré syndrome. Sensation remains intact, however, and the spinal fluid shows no abnormalities. Severe constipation is characteristic of botulism, perhaps as a result of paresis of smooth muscle of the intestine. Consciousness is retained throughout the illness unless severe degrees of anoxia develop as a result of respiratory failure. In the past, the mortality was greater than 60 percent, but it has declined greatly in recent decades, with improvements in the intensive care of acute respiratory failure and the effectiveness of C. botulinum antitoxins. The clinical diagnosis can be confirmed by electrophysiologic studies. Specifically, there is reduced amplitude of evoked muscle potentials and an increase in amplitude with rapid repetitive nerve stimulation (the opposite of what is found in myasthenia gravis). In patients who recover, improvement begins within a few weeks, first in ocular movement, then in other cranial nerve functions. Complete recovery of paralyzed limb and trunk musculature may take many months. The three types of botulinum toxins—A, B, and E— cannot be distinguished by their clinical effects alone, so the patient should receive the trivalent antiserum as soon as the clinical diagnosis is made. This antitoxin can be obtained from the Centers for Disease Control and Prevention in Atlanta, Georgia. An initial dose of 10,000 U is given intravenously after intradermal testing for sensitivity to horse serum, followed by daily doses of 50,000 U intramuscularly until improvement begins. Penicillin or metronidazole are given to eradicate the organism in a wound (but are not as useful if the exogenous preformed toxin has been ingested). Guanidine hydrochloride (50 mg/kg) has been somewhat useful in reversing the weakness of limb and extraocular muscles. Antitoxin and guanidine probably change the course of the illness relatively little and recovery depends on the effectiveness of respiratory care,

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maintenance of fluid and electrolyte balance, prevention of infection, and so on. The therapeutic injection of small quantities of botulinum toxin into a muscle affected by dystonia or spasticity will weaken it for weeks to months (see Chap. 4). Mild symptoms of botulism can occur with relatively large therapeutic doses, mainly affecting the oropharyngeal and ciliary muscles, and was more common a few decades ago when experience was limited. Cases are still seen after “botox parties” or illicit non-physician use.

PLANT POISONS, VENOMS, BITES, AND STINGS Ergotism Ergotism is the name applied to poisoning with ergot, a drug derived from the rye fungus Claviceps purpurea. Ergot is used therapeutically to control postpartum hemorrhage caused by uterine atony; one of its alkaloids, ergotamine, had been used in the treatment of migraine. Less so now (see Chap. 9), and a class of dopamine agonists, now less used in the treatment of Parkinson disease, has ergot activity (see Chap. 38). Chronic and repeated use of the drug is the usual cause. Two types of ergotism are recognized: gangrenous, which is caused by a vasospastic, occlusive process in the small arteries of the extremities, and convulsive, or neurogenic, ergotism. The latter is characterized by fasciculations, myoclonus, and spasms of muscles, followed by seizures. In nonfatal cases, a tabes-like neurologic syndrome may develop, with loss of knee and ankle jerks, ataxia, and impairment of deep and superficial sensation. The pathologic changes consist of degeneration of the posterior columns, dorsal roots, and peripheral nerves, but they have been poorly described. The relation of these changes to ergot poisoning is not clear, because most of the cases occurred in areas where malnutrition was endemic.

Lathyrism Lathyrism is a neurologic syndrome characterized by the relatively acute onset of pain, paresthesia, and weakness in the lower extremities, progressing to a permanent spastic paraplegia. It is a serious medical problem in India and in some North African countries and is probably caused by a toxin contained in the chickling vetch pea, Lathyrus, a legume that is consumed in excess quantities during periods of famine. This disorder is discussed further with the spinal cord diseases (see Chap. 42).

Konzo (Environmental Cyanide Poisoning, See Also Chap. 42) This is caused by ingestion of cyanide, usually from insufficiently processed roots of the bitter cassava. The illness is a rapid upper motor syndrome (paraplegia, tetrapelgia) and usually irreversible. It is most common in rural Africa and peaks in incidence during times of food shortage and drought, when cassava is utilized as a food substitute and there is insufficient water to allow for adequate processing

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of the roots. Efforts are directed toward education and providing resources for processing.

Mushroom Poisoning The gathering of wild mushrooms, a popular pastime in late summer and early fall, always carries with it the danger of poisoning. As many as 100 species of mushrooms are poisonous. Most of them cause only transient gastrointestinal symptoms but some elaborate toxins that can be fatal. The most important of these toxins are the cyclopeptides, which are contained in several species of Amanita phalloides and muscaria and account for more than 90 percent of fatal mushroom poisonings. These toxins disrupt RNA metabolism, causing hepatic and renal necrosis. Symptoms of poisoning with Amanita usually appear between 10 and 14 h after ingestion and consist of nausea, vomiting, colicky pain, and diarrhea, followed by irritability, restlessness, ataxia, hallucinations, convulsions, and coma. The important clinical features have been reviewed by Koppel. There may be added evidence of a neuromyopathy presenting as flaccid areflexic paralysis, high serum CK, diminished EMG potentials, and fiber necrosis. Other important mushroom toxins are methylhydrazine (contained in the Gyromitra species) and muscarine (Inocybe and Clitocybe species). The former gives rise to a clinical picture much like that caused by the cyclopeptides. The symptoms of muscarine poisoning, which appear within 30 to 60 min of ingestion, are essentially those of parasympathetic stimulation—miosis, lacrimation, salivation, nausea, vomiting, diarrhea, perspiration, bradycardia, and hypotension. Tremor, seizures, and delirium occur in cases of severe poisoning. The mushroom toxins have no effective antidotes. If vomiting has not occurred, it should be induced with ipecac, following which activated charcoal should be administered orally to bind what toxin remains in the gastrointestinal tract. A local poison control center may help identify the poisonous mushroom and its toxin. Even more important, the gathering and ingestion of field varieties of mushrooms should be left to those absolutely certain of their identity.

Buckthorn Poisoning A rapidly progressive and sometimes fatal paralysis follows the ingestion of the small fruit of the buckthorn shrub that is indigenous to northern Mexico and the neighboring southwestern parts of the United States. The responsible toxin causes a predominantly motor polyneuropathy, probably of axonal type. Except for a normal CSF protein concentration, the disorder closely resembles GuillainBarré syndrome and tick paralysis (see later), and its recognition depends on awareness of ingestion of the fruit in endemic areas.

Neurotoxin Fish Poisoning (Ciguatera) Ingestion of marine toxins that block neural sodium channels is a common form of poisoning throughout coastal areas and islands of the world. It results from eating fish

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that have fed on toxin-containing microscopic dinoflagellates. Reef fish and shellfish ingest high concentrations of these organisms during periodic upswings in the population of the dinoflagellates. They may be so profuse as to color the surrounding water (red tide). Although the toxins differ (tetrodotoxin—fugu, puffer fish; ciguatoxin—snails; saxitoxin and brevetoxin— shellfish), the neurologic and gastrointestinal symptoms that follow the ingestion of poisoned fish are similar. The initial symptoms are diarrhea, vomiting, or abdominal cramps coming on minutes to hours after the ingestion. These are followed by paresthesias that begin periorally and then involve the limbs distally. Hot and cold sensory stimuli (e.g., ice cream) are characteristically associated with electricallike or burning paresthesias in the mouth. Muscle aches and shooting pains are also mentioned by most patients. In puffer fish poisoning, and in advanced stages of poisoning from other fish, weakness occurs, and there have been a few reports of coma and of respiratory failure. The recognition of this type of fish poisoning is straightforward in endemic areas, in some of which there is a seasonal clustering of cases. In tourists returning home from endemic areas, and in persons consuming imported fish, the illness may be mistaken for Guillain-Barré syndrome. Prominent perioral paresthesias should suggest the correct diagnosis. Supportive treatment is all that is required but treatment with intravenous mannitol is said to hasten recovery. Pearn has reviewed the biochemistry and physiologic and clinical effects of the various marine toxins and points out a form of chronic intoxication that is apparently endemic in certain island communities. The main chronic effects are severe fatigue and asthenic weakness. The problem of distinguishing this syndrome from depression is acknowledged by the author and the cases on which we have consulted locally almost always fall into the psychiatric category. One of our patients developed chronic paresthesias.

Venoms, Bites, and Stings Although relatively rare, they are nonetheless important causes of mortality. The venoms of certain species of snakes, lizards, spiders (especially the black widow spider, see Chap. 46), and scorpions contain neurotoxins that may cause a fatal depression of respiration and curare-like paralysis of neuromuscular transmission. In the United States, there are approximately 8,000 poisonous snake bites per year. Some, such as the coral snake envenomation, are neurotoxic, producing pupillary dilatation, ptosis, ocular palsies, ataxia, and respiratory paralysis. Others (rattlesnakes, water moccasin snakes) cause tissue necrosis and circulatory collapse. These are reviewed by Gold and colleagues. The serious effects of Hymenoptera stings (bees, wasps, hornets, and fire ants) are mainly the result of hypersensitivity and anaphylaxis. Several instances of cerebral and myocardial infarction have been reported after bee and wasp stings (Crawley and colleagues). A substantial inception has been the development of an antivenom for scorpion stings that can be administered in parallel with diazepines to children and results in more

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rapid resolution of paralysis and respiratory failure (Boyer and colleagues). All of these disorders are discussed in detail in Harrison’s Principles of Internal Medicine.

Tick Paralysis This rare condition is the result of a toxin secreted by the gravid tick (holocyclotoxin, produced in the tick’s salivary glands). In Canada and the northwestern United States, the wood tick Dermacentor andersoni is mainly responsible; in the southeastern United States it is Dermacentor variabilis, a dog tick; the tick in Australia is the Ixodes holocyclus, but various other ticks occasionally may have the same effect. Most cases occur in children because their small body mass renders them susceptible to the effects of relatively small amounts of the toxin. The illness arises almost exclusively in the spring when the mature gravid ticks are most plentiful. The illness is more common and is generally more severe in cases on the Australian continent than it is in North America. Clinical manifestations require that the tick be attached to the skin for several days. The neurotoxin causes a generalized, flaccid, areflexic paralysis, appearing over 1 or 2 days and thereby mimicking the Guillain-Barré syndrome. In a few cases, several days of ataxia and areflexia precede the paralysis but sensory loss tends to be minimal. External ophthalmoplegia, which occurred in 5 of the 6 children described by Grattan-Smith and colleagues, is exceptional, judging by other reports; internal ophthalmoplegia and pharyngeal weakness are also known to occur, and while not typical, raise the possibility of botulism or diphtheria. The CSF is normal and electrophysiologic studies show reduction in the amplitude of the muscle action potentials but normal or only slightly slowed nerve conduction. Prominent ptosis and neck weakness may also raise the question of a neuromuscular process, but repetitive stimulation testing is normal or evokes only a slight decrement or increment in some cases. The ticks tend to attach to the hairlines or in the matted hair of the scalp, neck, and pubis, where a careful search will reveal them (for which reason nurses and electroencephalography technicians often are most likely to find them; see Felz and colleagues). The diagnosis is much in the awareness of clinicians in endemic areas during the tick season, for they are gratified with rapid and dramatic improvement when the tick is removed. The paralysis has been reported to become transiently worse after tick removal in some of the Australian cases. From a neurologic point of view, Lyme disease is a far more common tick-borne disorder. The causative agent is Borrelia burgdorferi, a spirochetal organism. The disorder is discussed fully with other infectious diseases in Chap. 31 and in Chap. 43, with the neuropathies.

HEAVY METALS AND INDUSTRIAL TOXINS Lead The causes and clinical manifestations of lead poisoning are quite different in children and adults.

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Lead Poisoning in Children In the United States, this disease has been identified most often in 1- to 3-year-old children who inhabit urban slum areas where old, deteriorated housing prevails. (Lead paint was used in most houses built before 1940 and in many built before 1960.) The chewing of leaded paint is promoted by compulsive ingestion (pica) from windowsills and painted plaster walls. The development of an acute encephalopathy is the most serious complication, resulting in death in 5 to 20 percent of cases and in permanent neurologic and mental deficits in more than 25 percent of survivors. Clinical manifestations  These develop over a period of 3 to 6 weeks. The child becomes anorectic, less playful and less alert, and more irritable. These symptoms may be misinterpreted as a behavior disorder or a manifestation of mental retardation. Intermittent vomiting, vague abdominal pain, clumsiness, and ataxia may be added. If these early signs of intoxication are not recognized and the child continues to ingest lead, more flagrant signs of acute encephalopathy may develop—most frequently in the summer months, for reasons that are not understood. Vomiting becomes more persistent, apathy progresses to drowsiness and stupor interspersed with periods of hyperirritability, and, finally, seizures and coma supervene. This syndrome may evolve in a period of a week or less, most rapidly in children younger than 2 years of age; in older children, it is more likely to develop in recurrent and less severe episodes. This clinical syndrome must be distinguished from tuberculous meningitis, viral meningoencephalitis, and the various conditions causing acute increased intracranial pressure. Usually, in lead encephalopathy, the CSF is under increased pressure with manifest papilledema, and there may be a slight lymphocytic pleocytosis and elevated protein but normal glucose values. It follows that lumbar puncture should be done with caution and only if it is essential for diagnosis. Diagnosis  Because the symptoms of plumbism are nonspecific, the diagnosis depends on an appreciation of the potential causative factors and the results of certain laboratory tests. Lead lines at the metaphyses of long bones and basophilic stippling of red cells are seen but are too inconstant to be relied on, but basophilic stippling of bone marrow erythroblasts is uniformly increased. Impairment of hemoglobin synthesis, which is exquisitely sensitive to the toxic effects of lead, results in the increased excretion of urinary coproporphyrin (UCP) and of Δ-aminolevulinic acid (ALA). These urinary indices and the lead concentrations in the serum bear an imperfect relationship to the clinical manifestations. In the test for UCP, which had in the past been performed in the clinic and emergency department, a few milliliters of urine are acidified with acetic acid and shaken with an equal volume of ether; if coproporphyrin is present, the ether layer will reveal a reddish fluorescence under a Wood lamp. This test is strongly positive when the whole blood concentration of lead exceeds 80 mcg/dL. The availability of chemical assays for these chemicals has made diagnosis easier, although not always as rapid. The diagnosis can be confirmed by promoting lead excretion with calcium disodium edetate (CaNa2 ethylenediaminetetraacetic acid [EDTA]), given in three doses

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(25 mg/kg) at 8-h intervals. Excretion of over 500 mg in 24 h is indicative of plumbism. The measurement of zinc protoporphyrin (ZPP) in the blood is another reliable means of determining the presence and degree of lead exposure. The binding of erythrocyte protoporphyrin to zinc occurs when lead impairs the normal binding of erythrocyte protoporphyrin to iron. Elevated ZPP can also be induced when access to iron is limited by other conditions, such as iron deficiency anemia. At blood lead concentrations of 70 mcg/dL symptoms may be minimal, but acute encephalopathy may occur abruptly and unpredictably, for which reason the child should be hospitalized for chelation therapy (see in the following text). Some children with a blood lead level of 50 mcg/dL may have symptoms of severe encephalopathy, whereas others may be asymptomatic. In the latter case, an attempt should be made to discover and remove the source of lead intoxication and the child should be reexamined at frequent intervals. The seriousness of lead encephalopathy is indicated by the fact that most of the children who become stuporous or comatose remain mentally retarded despite treatment. The physician’s aim, therefore, is to institute treatment before the severe symptoms of encephalopathy have become manifest. Pathology  In children who die of acute lead encephalopathy, the brain is massively swollen, with herniation of the temporal lobes and cerebellum, multiple microscopic ischemic foci in the cerebrum and cerebellum, and endothelial damage and deposition of proteinaceous material and mononuclear inflammatory cells around many of the small blood vessels. There are also hyperplastic changes in arteries and arterioles and in some places, perivascular infiltrates of lymphocytes and mononuclear cells. In the territories of some of these vessels there are foci of ischemic necrosis with surrounding glial reaction appropriate for the age of the lesion. Similar changes are present in the kidneys. Treatment  The plan of therapy includes the establishment of urinary flow, following which intravenous fluid therapy is restricted to basal water and electrolyte requirements. In cases of acute encephalopathy, combined chelation therapy with 2,3-dimercaprol (British anti-Lewisite [BAL]; 12 to 24 mg/kg) and CaNa2 EDTA (0.5 to 1.5 g/m2 body surface area) for 5 to 7 days. This is followed by a course of oral penicillamine (40 mg/kg, not exceeding 1 g/d). In acute cases, the goal is to reduce the serum lead levels below 40 mcg/dL. Once the absorption of lead has ceased, chelating agents remove lead only from soft tissues and not from bone, where most of the lead is stored. Any intercurrent illness may result in a further mobilization of lead from bones and soft tissues and an exacerbation of symptoms of lead intoxication. Repeated doses of mannitol may be used for relief of cerebral edema. Microcytic hypochromic anemia is treated with iron once the chelating agents have been discontinued. Seizures are best controlled with intravenous diazepam or midazolam. Prevention  The prevention of reintoxication (or initial intoxication) demands that the child be removed from the source of lead. Although this is axiomatic, it is often difficult to accomplish, despite the best efforts of local health

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departments and hospital and city social workers. Nevertheless, an attempt to eliminate the environmental factor must be made in each case. Such attempts, among other things, have resulted in a marked decrease in the incidence of acute lead encephalopathy in the past two decades. Although florid examples of this encephalopathy are now uncommon, undue exposure to lead (blood levels greater than 30 mcg/dL) remains inordinately prevalent and a continuing source of concern to public health authorities. As to the levels that pose a danger to the child, there is still some uncertainty. A review of the evidence up to 1980, concluded that persistent blood levels above 40 mcg/dL may cause slight cognitive impairment and, less certainly, an increased risk of behavioral difficulties (Rutter). Others have reported, from a prospective study of 172 children, that even lower levels may induce a decline in IQ at 3 and 5 years of age (Canfield and colleagues). These data require confirmation before general acceptance. Further compounding the problem of interpreting low-level lead exposure in children with blood lead concentrations below 45 mcg/dL is the observation that treatment with succimer, while successful in reducing lead levels, did not improve cognitive or behavioral function (Rogan and colleagues). The oral lead chelator succimer is approved for outpatient treatment of asymptomatic children with blood lead levels higher than 45 mcg/dL. A 3-week course of treatment is given, with weekly monitoring of blood lead levels to identify lead mobilization from bones and soft tissues (Jorgensen). In 1988, based on epidemiologic and experimental studies in the United States, Europe, and Australia, the Agency for Toxic Substances and Disease Registry set a much lower threshold for neurobehavioral toxicity (10 to 15 mcg/dL). It estimated that 3 to 4 million American children have blood levels in excess of this amount. Needleman and colleagues studied the long-term effects of low doses of lead in asymptomatic children, 132 of whom had had demonstrable levels of lead in the dentin of shed teeth (average 24 mg/dL). Eleven years later, the children were found to have behavioral abnormalities proportionate to their early lead levels. In comparison to a normal population, more had dropped out of school and more had lower vocabulary and grammatical reasoning scores, more reading difficulty, poorer hand-eye coordination performance, slower finger-tapping rates, and longer reaction times. The authors claimed to have eliminated other confounding variables such as lower social class and genetic factors. These findings are similar to those of long-term studies (Baghurst and colleagues; Mahaffey). There are not adequate pathologic or MRI studies of such cases.

Lead Intoxication in Adults Lead intoxication in adults is much less common than in children. The hazards to adults are the result of inhaling the dust of inorganic lead salts and the fumes from the burning of objects containing lead or involvement in processes that require the remelting of lead. Painting, printing, pottery glazing, lead smelting, welding, and storage battery manufacturing are the industries in which these hazards are likeliest to occur. In the past, miners and brass foundry and garage workers (during automobile radiator repair,

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when soldered joints are being heated; see Goldman and colleagues) were the ones most at risk. Currently, other, sometimes idiosyncratic, sources are more common. For example, the authors have encountered a case of lead encephalopathy in a man of Indian origin who was taking large amounts of an Ayurvedic herbal remedy for arthritis. The first manifestation was a series of generalized seizures followed by a fluctuating encephalopathy. His serum lead level was 70 mcg/dL, and 24-h urine collection contained 1,550 mg of lead (normal being less than 400 mg). There was a T2-weighted hyperintensity in the cerebral cortex. Whitfield and colleagues reviewed 23 instances of lead encephalopathy in adults. At the time of their report most cases were caused by moonshine (homemade whiskey from lead-lined stills). More recently, most cases have been from various herbal medications, as already mentioned. Combined lead and arsenic poisoning from herbal compounds is also known. The usual manifestations of lead poisoning in adults are colic, anemia, and peripheral neuropathy. Encephalopathy of the type described above is decidedly rare. Lead colic, frequently precipitated by an intercurrent infection or by alcohol intoxication, is characterized by severe, poorly localized abdominal pain, often with rigidity of abdominal muscles but without fever or leukocytosis. The pain responds to the intravenous injection of calcium salts, at least temporarily, but responds poorly to morphine. Mild anemia is common. A black line of lead sulfide may develop along the gingival margins. Peripheral neuropathy, usually a bilateral wrist drop, is a rare manifestation and is discussed in Chap. 43. The diagnostic tests for plumbism in children are generally applicable to adults, with the exception of bone films, which are of no value in the latter. Also, the treatment of adults with chelating agents follows the same principles as in children. Intoxication with tetraethyl and tetramethyl (organic) lead, used as additives in gasoline, is caused by inhalation of gasoline fumes. It occurs most often in workers who clean gasoline storage tanks. Insomnia, irritability, delusions, and hallucinations are the usual clinical manifestations, and a maniacal state may develop. The hematologic abnormalities of inorganic lead poisoning are not found, and chelating agents are of no value in treatment. Organic lead poisoning is usually reversible, but fatalities have been reported. The pathologic changes have not been well described.

Arsenic In the past, medications such as Fowler solution (potassium arsenite) and the arsphenamines, used in the treatment of syphilis, were frequent causes of intoxication, but now the most common cause is the suicidal or accidental ingestion of herbicides, insecticides, or rodenticides containing copper acetoarsenite (Paris green) or calcium or lead arsenate. In rural areas, arsenic-containing insecticide sprays are a common source of poisoning. Arsenic is used also in the manufacture of paints, enamels, and metals; as a disinfectant for skins and furs; and also in galvanizing, soldering, etching, and lead plating. Occasional cases of poisoning

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are reported in relation to these occupations. Arsenic is still contained in some topical creams and oral solutions that are used in the treatment of psoriasis and other skin disorders and in some herbal remedies. Arsenic exerts its toxic effects by reacting with the sulfhydryl radicals of certain enzymes necessary for cellular metabolism. The effects on the nervous system are those of an encephalopathy or peripheral neuropathy. The latter may be the product of chronic poisoning or may become manifest between 1 and 2 weeks after recovery from the effects of acute poisoning. It takes the form of a distal axonopathy that is described in Chap. 43 (Heyman and colleagues). In cases of arsenical polyneuropathy we have cared for, a distal sensorimotor areflexic syndrome developed subacutely. At autopsy there was a dying back pattern of myelin and axons with macrophage and Schwann cell reactions and chromatolysis of motor neurons and sensory ganglion cells. The CNS appeared normal. The symptoms of encephalopathy (headache, drowsiness, mental confusion, delirium, and convulsive seizures) may also occur as part of acute or chronic intoxication. In the latter case, they are accompanied by weakness and muscular aching, hemolysis, chills and fever, mucosal irritation (in patients exposed to arsine gas), diffuse scaly desquamation, and transverse white lines, 1 to 2 mm in width, above the lunula of each fingernail (Mees lines). Acute poisoning by the oral route is associated with severe gastrointestinal symptoms, shock and death in a large proportion of patients. The CSF is normal. Examination of the brain in such cases discloses myriads of punctate hemorrhages in the white matter. Microscopically, the lesions consist of capillary necrosis and of pericapillary zones of degeneration, which, in turn, are ringed by red cells (brain purpura). These neuropathologic changes are not specific for arsenical poisoning but have been observed in such diverse conditions as pneumonia, gram-negative bacillary septicemia from urinary tract infections, sulfonamide and phosgene poisoning, dysentery, disseminated intravascular coagulation, and others. The diagnosis of arsenical poisoning depends on the demonstration of increased levels of arsenic in the hair and urine. Several of the aspects of testing have been reviewed by Moyer. Arsenic is deposited in the hair within 2 weeks of exposure and may remain fixed there for long periods. Concentrations of more than 0.1 mg arsenic per 100 mg hair are indicative of poisoning. Arsenic also remains within bones for long periods and is slowly excreted in the urine and feces. Excretion of more than 0.1 mg arsenic per liter of urine is considered abnormal; levels greater than 1 mg/L may occur soon after acute exposure. We would caution, however, that individuals who consume fish on a regular basis, as occurs in coastal regions, may have slightly or moderately elevated levels of arsenic and that various conditions such as neuropathy and amyotrophic lateral sclerosis (ALS) may be mistakenly attributed to this innocuous finding. The levels return to normal within a few months of abstaining from fish. The CSF protein level may be raised (50 to 100 mg/dL). Treatment  Acute poisoning is treated by gastric lavage, vasopressor agents, dimercaprol (BAL), maintenance of renal perfusion, and exchange transfusions if massive hemoglobinuria occurs. Once polyneuropathy

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has occurred, it is little affected by treatment with BAL, but other manifestations of chronic arsenical poisoning respond favorably. There has been a gradual recovery from the polyneuropathy under our care.

Manganese Manganese poisoning results from the chronic inhalation and ingestion of manganese particles and occurs in miners of manganese ore and in workers who separate manganese from other ore. Several clinical syndromes have been observed. The initial stages of intoxication may be marked by a prolonged confusional-hallucinatory state. Later, the symptoms are predominantly extrapyramidal. They are often described as parkinsonian in type, but in the patients seen by the authors, the resemblance was not close: an odd gait (“cock” walk), dystonia and rigidity of the trunk, postural instability, and falling backward were features seen in two South American miners. Others, however, have reported stiffness and awkwardness of the limbs, often with tremor of the hands, “cogwheel” phenomenon, gross rhythmic movements of the trunk and head, and retropulsive and propulsive gait. Corticospinal and corticobulbar signs may be added. Progressive weakness, fatigability, and sleepiness as well as psychiatric symptoms (manganese madness) are other clinical features. Rarely, severe axial rigidity and dystonia, like those of Wilson disease, are said to have been the outstanding manifestations. The emergence of an extrapyramidal syndrome from the use of illicit drugs that are synthesized with potassium permanganate has already been mentioned in relation to the cathionine stimulants. The differences between manganism and conventional parkinsonism have been reviewed (Calne and colleagues). Neuronal loss and gliosis, affecting mainly the pallidum and striatum but also the frontoparietal and cerebellar cortex and hypothalamus, have been described, but the pathologic changes have not been carefully studied.

Treatment The neurologic abnormalities have not responded to treatment with chelating agents. In the chronic dystonic form of manganese intoxication, dramatic and sustained improvement has been reported with the administration of l-dopa; patients with the more common parkinsonian type of manganese intoxication have shown only slight, if any, improvement with l-dopa.

Mercury Mercury poisoning arises in two forms, one caused by inorganic compounds (elemental or mercury salt) and the other, more dangerous, caused by organic mercury. The sources of potential exposure have been reviewed (Clarkson). In past centuries, organic mercury poisoning was ubiquitous as a result of treatment for syphilis and neurosyphilis. The affected individual drooled profusely, lost their teeth, developed painful neuropathy (not named as such at the time). Among the organic compounds, methylmercury gives rise to a wide array of serious neurologic symptoms that may be delayed for days or weeks after exposure, including tremor of the extremities, tongue,

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and lips; mental confusion; and a progressive cerebellar syndrome, with ataxia of gait and arms, intention tremor, and dysarthria. Choreoathetosis and parkinsonian facies have also been described. Changes in mood and behavior are prominent, consisting at first of subjective weakness and fatigability and later of extreme depression and lethargy alternating with irritability. This delayed form of subacute mercury poisoning has been reported in chemical laboratory workers after exposure to methyl mercury compounds. These agents, particularly dimethylmercury, are extremely hazardous because they are absorbed transdermally and by inhalation, allowing severe toxicity to occur with even brief contact. In a tragic and fatal case of a chemist, a rapidly progressive ataxia and stupor progressing to coma developed 154 days after exposure (Nierenberg and colleagues). Cerebellar function was most severely impaired, and visual function was affected. The pathologic changes are characterized by a striking degeneration of the granular layer of the cerebellar cortex, with relative sparing of the Purkinje cells and neuronal loss and gliosis of the calcarine cortex and to a lesser extent of other parts of the cerebral cortex, similar to the Minamata disease cases described below. The chronic form of inorganic mercury poisoning occurs in persons exposed to large amounts of the metal used in the manufacture of thermometers, mirrors, incandescent lights, x-ray machines, and vacuum pumps. Because mercury volatilizes at room temperature, it readily contaminates the air and then condenses on the skin and respiratory mucous membranes. Nitrate of mercury, used formerly in the manufacture of felt hats (“mad hatters”), and phenyl mercury, used in the paper, pulp, and electrochemical industries, are other sources of intoxication. Paresthesias, lassitude, confusion, incoordination, and intention tremor are characteristic, and, with continued exposure, a delirious state occurs. Headache, various bodily pains, visual and hearing disorders, and corticospinal signs may be added, but their pathologic basis is unknown. The term erethism was coined to describe the timidity, memory loss, and insomnia that were said to be characteristic of chronic intoxication. If the exposure is more than a minimal degree over a long period, gastrointestinal disturbances are prone to occur (anorexia, weight loss), as well as stomatitis and gingivitis with loosening of the teeth. Acute exposure to inorganic mercury in larger amounts is even more corrosive to the gastrointestinal system and produces nausea, vomiting, hematemesis, abdominal pain, and bloody diarrhea, as well as renal tubular necrosis. Isolated instances of polyneuropathy associated with exposure to mercury have also been reported (Albers and colleagues; Agocs and colleagues) and may be responsible for the paresthesias that accompany most cases, as well as the acrodynic syndrome described below. The polyneuropathy associated with mercury poisoning is discussed in Chap. 43. The presence of mercury in industrial waste has contaminated many sources of water supply and fish, which are ingested by humans and cause mercurial poisoning. So-called Minamata disease is a case in point. Between 1953 and 1956, a large number of villagers living near Minamata Bay in Kyushu Island, Japan, were afflicted with a

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syndrome of chronic mercurialism, traced to the ingestion of fish that had been contaminated with industrial wastes containing methylmercury (Harada and colleagues). Concentric constriction of the visual fields, hearing loss, cerebellar ataxia, postural and action tremors, and sensory impairment of the legs and arms and sometimes of the tongue and lips were the usual clinical manifestations. The syndrome evolved over a few weeks. Pathologically there was diffuse neuronal loss in both cerebral and cerebellar cortices, most marked in the anterior parts of the calcarine cortex and granule cell layer of the cerebellum. CT scans in survivors, years after the mass poisoning, disclosed bilaterally symmetrical areas of decreased attenuation in the visual cortex and diffuse atrophy of the cerebellar hemispheres and vermis, especially the inferior vermis (Tokuomi and colleagues). A painful neuropathy of children (acrodynia) has been traced to mercury exposure from interior latex paint, to calomel (mercurous chloride), to teething powders, and to a mercuric fungicide used in washing diapers (Agocs and colleagues; Clarkson). Mercury has been removed from these products. Albers and colleagues observed the appearance of symptoms (mild decrease in strength, tremor, and incoordination) 20 to 35 years after exposure to elemental mercury. These authors believed that the natural neuronal attrition with aging had unmasked the neurologic disorder, a theory that we cannot validate. The authors believe it worth mentioning that there is no convincing evidence linking typical dietary ingestion of fish containing metallic compounds such as mercury or arsenic and any neurologic or developmental disease. Levels of both inorganic forms are found in the blood of persons who ingest considerable amounts of fish and often lead to incorrect attribution of neuropathy and other neurological disorders. The inhalation of vaporized mercury as a result of extensive dental work, or simply the presence of a large number of fillings (“amalgam illness”), is alleged to affect the peripheral nerves or to cause fatigue, but the connection is also doubtful as is the alleged relationship between vaccines containing mercury preservatives (thiomersal) and autism. Treatment  Treatment consists of removal from the source of mercury exposure, and for acute inorganic mercury poisoning, chelation therapy with penicillamine or dimercaprol (BAL). No chelator for methylmercury or ethylmercury is approved by the FDA. In the treatment of chronic mercury poisoning, penicillamine has been the drug of choice, because it can be administered orally and appears to chelate mercury selectively, with less effect on copper, which is an essential element in many metabolic processes.

Phosphorus and Organophosphate Poisoning Nervous system function may be deranged as part of acute and frequently fatal poisoning with inorganic phosphorus compounds (found in rat poisons, roach powders, and match heads). More important clinically is poisoning with organophosphorus compounds, the best known of which is triorthocresyl phosphate (TOCP). Organophosphates are widely used as insecticides. Since 1945, approximately 15,000 individual compounds

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in this category have come into use. Certain ones, such as tetraethylpyrophosphate, have been the cause of major outbreaks of neurologic disorder, especially in children. These substances have an acute anticholinesterase effect but no delayed neurotoxic action. Chlorophos, which is a 1-hydroxy-2,2,2-trichlorethylphosphonate, is an exception; it has both an acute and delayed action, as does TOCP. The immediate anticholinesterase effect manifests itself by headache, vomiting, sweating, abdominal cramps, salivation, wheezing (secondary to bronchial spasm), miosis, and muscular weakness and twitching. Most of these symptoms can be reversed by administration of atropine and pralidoxime. The delayed effect manifests 2 to 5 weeks following acute organophosphorus insecticide poisoning. This takes the form of a distal symmetrical sensorimotor (predominantly motor) polyneuropathy, progressing to muscle atrophy (see Chap. 43). Recovery occurs to a variable degree and then, in patients poisoned with TOCP, signs of corticospinal damage become detectable. The severity of paralysis and its permanence vary with the dosage of TOCP. Whether a polyneuropathy can arise without the preceding symptoms of cholinergic toxicity is debated; however, based on a review of the subject and a study of 11 patients exposed to these agents, three 3 of whom later acquired sensory neuropathy, Moretto and Lotti express the view that such an occurrence must be rare. In addition to the acute and delayed neurotoxic effects of organophosphorus, an intermediate syndrome has been described (Senanayake and Karalliedde). Symptoms appear 24 to 96 h after the acute cholinergic phase and consist of weakness or paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory muscles. Respiratory paralysis may prove fatal. In patients who survive, the paralytic symptoms last for 2 to 3 weeks and then subside. The intermediate and delayed symptoms do not respond to atropine or other drugs. Several striking outbreaks of TOCP poisoning have been reported. During the latter part of the prohibition era and to a lesser extent thereafter, outbreaks of so-called jake paralysis were traced to drinking an extract of Jamaica ginger that had been contaminated with TOCP. Adams had examined several “ginger jake” patients many years later and related to us that he found only signs of corticospinal disease. Presumably in the early stage of this disease they were obscured by the neuropathy. Another outbreak occurred in Morocco in 1959, when lubricating oil containing TOCP was used deliberately to dilute olive oil. Several other outbreaks have been caused by the ingestion of grain and cooking oil that had been stored in inadequately cleaned containers previously used for storing TOCP. The effect of TOCP on the peripheral nervous system has been studied extensively in experimental animals. In cats, there occurs a dying back from the terminal ends of the largest and longest medullated motor nerve fibers, including those from the annulospiral endings of the muscle spindles (Cavanagh and Patangia). The long fiber tracts of the spinal cord show a similar dying-back phenomenon. Abnormal membrane-bound vesicles and tubules were observed by Prineas to accumulate in axoplasm before degeneration. These effects have been traced to the

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inhibitory action of TOCP on esterases. There is still uncertainty as to the details of these reactions, and no treatment for the prevention or control of the neurotoxic effects has been devised.

Thallium In the late nineteenth century, thallium was used medicinally in the treatment of venereal disease, ringworm, and tuberculosis, and later in rodenticides and insecticides. Poisoning was fairly common. Sporadic instances of poisoning still occur, usually as a result of accidental or suicidal ingestion of thallium-containing rodenticides and rarely from overuse of thallium-containing depilatory agents. Patients who survive the effects of acute poisoning develop a rapidly progressive and painful sensory polyneuropathy, optic atrophy, and occasionally ophthalmoplegia—followed, 15 to 30 days after ingestion, by diffuse alopecia (see Chap. 43). The latter feature should always suggest the diagnosis of thallium poisoning, which can be confirmed by finding this metallic element in the urine. The main clinical features have been reviewed by Bank and colleagues. Two of our patients with thallium poisoning had a severe sensory and mild motor polyneuropathy and alopecia, from which they were recovering months later. It is not uncommon for the neuropathy to have a painful component involving acral regions. The condition can end fatally. The use of potassium chloride by mouth may hasten thallium excretion.

Other Metals Iron, antimony, tin, aluminum, zinc, barium, bismuth, copper, silver, gold, platinum, and lithium may all produce serious degrees of intoxication. The major manifestations in each case are gastrointestinal or renal, but certain neurologic symptoms—notably headache, irritability, confusional psychosis, stupor, coma, and convulsions—may be observed in any of these if the poisoning is severe, often as a terminal event. Gold preparations, which are still used occasionally in the treatment of arthritis, may, after several months of treatment, give rise to focal or generalized myokymia and a rapidly progressive, symmetrical polyneuropathy (Katrak and colleagues). The adverse effects of platinum are discussed later, with the antineoplastic agents. Lithium was discussed earlier. Mentioned here is a novel but quite rare cobaltchromium metallosis due to the leaching of metals from prosthetic hips into surrounding tissues. A painful sensorimotor polyneuropathy has been reported, in some patients accompanied by hearing loss. Although only a few cases have been documented, the process has attracted considerable attention and our only encounter with it has been the ill-advised revision of hip implants for nondescript sensory symptoms, similar to the peculiar obsession with removing dental fillings for erroneously diagnosed mercury poisoning. Attention already has been drawn to the possible causative role of aluminum intoxication in so-called dialysis dementia or encephalopathy (see Chap. 39). Removal

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of aluminum from the water used in renal dialysis has practically eliminated this disorder. It should be noted that the neuropathologic changes in experimental aluminum intoxication (see later) are not those observed in dialysis dementia. Perl and colleagues have reported the accumulation of aluminum in tangle-bearing neurons of patients with Alzheimer disease and in the Guamanian Parkinson–dementia–ALS complex. However, analysis of neuritic plaques by nuclear microscopy, without using chemical stains, failed to demonstrate the presence of aluminum (Landsberg and colleagues). The significance of these findings remains to be determined. A progressive neurologic disorder consisting of intention tremor, incoordination, and spastic paraparesis has been described in three patients who had worked for more than 12 years in the same pot room of an aluminum smelting plant (Longstreth and colleagues). Similar cases clearly attributable to aluminum intoxication have not been reported, however. Organic compounds of tin may seriously damage the nervous system. Diffuse edema of the white matter of the brain and spinal cord has been produced experimentally with triethyltin. Presumably, this was the basis of the mass poisoning produced by a triethyltin-contaminated drug called Stalinon. The illness was characterized by greatly elevated intracranial pressure and by a spinal cord lesion in some cases (Alajouanine and colleagues). Trimethyltin intoxication is much rarer; seizures are the main manifestation. Experimental studies in rats have shown neuronal loss in the hippocampus, largely sparing the Sommer sector, with later involvement of neurons in the pyriform cortex and amygdala (LeQuesne). A stereotyped episodic encephalopathy has been associated with bismuth intoxication, usually arising from the ingestion of bismuth subgallate. Large outbreaks have been reported in Australia and France (Burns and colleagues; Buge and colleagues). The onset of the neurologic disturbance is usually subacute, with a mild and fluctuating confusion, somnolence, difficulty in concentration, tremulousness, and sometimes hallucinations and delusions. With continued ingestion of bismuth, there occurs a rapid (24 to 48 h) worsening of the confusion and tremulousness, along with diffuse myoclonic jerks, seizures, ataxia, and inability to stand or walk. These symptoms regress over a few days to weeks when the bismuth is withdrawn, but some patients have died of acute intoxication. High concentrations of bismuth were found in the cerebral and cerebellar cortices and in the nuclear masses throughout the brain. These concentrations can be recognized as hyperdensities on a CT scan (Buge and colleagues).

Industrial Toxins Some of these, the heavy metals, already have been considered. In addition, a large number of synthetic organic compounds are widely used in industry and are frequent sources of toxicity, and the list is constantly being expanded. The reader is referred to the references at the end of the chapter, particularly to the text edited by Spencer and Schaumburg, for details concerning these compounds. Here we can do little more than enumerate the most important ones: chlorinated diphenyls (e.g., dichlorodiphenyltrichloroethane [DDT]) or chlorinated polycyclic compounds (Kepone),

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used as insecticides; diethylene dioxide (Dioxane); carbon disulfide; the halogenated hydrocarbons (methyl chloride, tetrachloroethane, carbon tetrachloride, trichloroethylene, and methyl bromide); naphthalene (used in moth repellants); benzine (gasoline); benzene and its derivatives (toluene, xylene, nitrobenzene, phenol, and amyl acetate [banana oil]); and the hexacarbon solvents (n-hexane and methyl-n-butyl ketone). With a few exceptions, the acute toxic effects of these substances are much the same from one compound to another. In general, the primary effect is on nonneurologic structures. Neural symptoms consist of varying combinations of headache, restlessness, drowsiness, confusion, delirium, coma, and convulsions, which, as a rule, occur late in the illness or preterminally. Some of these industrial toxins (carbon disulfide, carbon tetrachloride and tetrachloroethane, acrylamide, n-hexane, and diethylene glycol [Sterno; see Rollins and colleagues]) may cause polyneuropathy, which becomes evident with recovery from acute toxicity. Extrapyramidal symptoms may result from chronic exposure to carbon disulfide. A syndrome of persistent fatigue, lack of stamina, inability to concentrate, poor memory, and irritability has also been attributed to chronic exposure to solvents, but these symptoms are quite nonspecific, and evidence for such a syndrome is unsupported by convincing experimental or epidemiologic studies. Of the aforementioned industrial toxins, the ones most likely to cause neurologic disease are toluene (methyl benzene) and the hexacarbons (see editorial on this subject in references). The chronic inhalation of fumes containing toluene (usually in glue, contact cement, or certain brands of spray paint) may lead to severe and irreversible tremor and cerebellar ataxia, affecting movements of the eyes (opsoclonus, ocular dysmetria) and limbs, as well as stance and gait. Cognitive impairment is usually associated; corticospinal tract signs, progressive optic neuropathy, sensorineural hearing loss, and hyposmia occur in some patients. Generalized cerebral atrophy and particularly cerebellar atrophy are evident in imaging studies (Fornazzari and colleagues; Hormes and colleagues). Also, it has become apparent that acute toluene intoxication is an important cause of seizures, hallucinations, and coma in children (King and colleagues). The prolonged exposure to high concentrations of n-hexane or methyl-n-butyl ketone may cause a sensorimotor neuropathy, so-called glue-sniffer’s neuropathy (see Chap. 43). These solvents are metabolized to 2,5-hexanedione, which is the agent that damages the peripheral nerves. The neuropathy may result from exposure in certain industrial settings (mainly the manufacture of vinyl products) or, more often, from the deliberate inhalation of vapors from solvents, lacquers, glue, or glue thinners containing n-hexane (see also Chap. 43). Impure trichloroethylene, through its breakdown product dichloroacetylene, has a predilection for the trigeminal nerve, which can be damaged selectively. Hydrogen peroxide poisoning, usually by accidental ingestion, causes multiple small cerebral infarcts through a mechanism of gas embolus (Ijichi and colleagues). Most cases have been reversible. According to Humberson and colleagues (cited by Ijichi and colleagues) 120 mL of 35 percent hydrogen peroxide releases 14 L of oxygen on contact with

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organic tissue. The lung is involved, and the unmistakable brain lesions consist of tiny gas bubbles concentrated in parasagittal watershed areas.

ANTINEOPLASTIC AND IMMUNOSUPPRESSIVE AGENTS The increasing use of potent antineoplastic agents has given rise to a diverse group of neurologic complications, the most important of which are summarized here. A more detailed account of the neurologic complications of these agents can be found in appropriate chapters of the book. The neurotoxic effects of certain agents used in the treatment of brain tumors are specifically considered in Chap. 30.

Vincristine This drug is used in the treatment of acute lymphoblastic leukemia, lymphomas, and some solid tumors. Its most important toxic side effect, and the one that limits its use as a chemotherapeutic agent, is a peripheral neuropathy. Paresthesias of the feet, hands, or both may occur within a few weeks of the beginning of treatment; with continued use of the drug, a progressive symmetrical neuropathy evolves (mainly sensory with reflex loss). Cranial nerves are affected less frequently, but ptosis and lateral rectus, facial, and vocal cord palsies have been observed. Autonomic nervous system function may also be affected: constipation and impotence are frequent complications; orthostatic hypotension, atonicity of the bladder, and adynamic ileus are less frequent. The polyneuropathy caused by vincristine is described more fully in Chap. 43. Inappropriate antidiuretic hormone secretion and seizures have been reported but are uncommon. Although rarely noted in the literature, the authors have seen an instance of reversible posterior leukoencephalopathy with cortical blindness and headache after a single dose of vincristine, identical to the syndrome reported with the use of calcineurin inhibitors (see further on). The neural complications of vinblastine are similar to those of vincristine but are usually avoided because bone marrow suppression limits the dose of the drug that can safely be employed. Vinorelbine is a more recently introduced semisynthetic vinca alkaloid. It has much the same antitumor activity as vincristine but is supposedly less toxic.

Cisplatin and Oxilaplatin Cisplatin, a heavy metal that inhibits DNA synthesis, is effective in the treatment of gonadal and head and neck tumors, as well as carcinoma of the bladder, prostate, and breast. The dose-limiting factors in its use are nephrotoxicity and vomiting and a peripheral neuropathy (see Chap. 43). The latter manifests itself by numbness and tingling in fingers and toes, sometimes painful—symptoms that are being observed with increasing frequency. This toxic manifestation appears to be related to the total amount of drug administered, and it usually improves slowly after it has been discontinued. Biopsies of peripheral nerve have

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shown a primary axonal degeneration. Approximately onethird of patients receiving this drug also experience tinnitus or high-frequency hearing loss or both. Ototoxicity is also dose related, cumulative, and only occasionally reversible. Retrobulbar neuritis occurs rarely. Seizures associated with drug-induced hyponatremia and hypomagnesemia have been reported.

Paclitaxel and Docetaxel (Taxanes) Taxol (paclitaxel) and Taxotere (docetaxel) are anticancer drugs derived from the bark of the western yew. Both are particularly useful in the treatment of ovarian and breast cancer, but they have a wide range of antineoplastic activities. A purely or predominantly sensory neuropathy is a common complication. These drugs are thought to cause neuropathy by their action as inhibitors of the depolymerization of tubulin, thereby promoting excessive microtubule assembly within the axon. The neuropathy is dose-dependent, occurring with doses greater than 200 mg/m2 of paclitaxel and at a wide range of dose levels for docetaxel (generally greater than 600 mg/m2). Symptoms may begin 1 to 3 days following the first dose and affect the feet and hands simultaneously. Autonomic neuropathy (orthostatic hypotension) may occur as well. The neuropathy is axonal in type, with secondary demyelination, and is at least partially reversible after discontinuation of the drug.

Procarbazine This drug, originally synthesized as a MAO inhibitor, is now an important oral agent in the treatment of Hodgkin disease and other tumors. It has also proved to be especially effective in the treatment of oligodendrogliomas. Neural complications are infrequent and usually take the form of somnolence, confusion, agitation, and depression. Diffuse aching pain in proximal muscles of the limbs and mild symptoms and signs of polyneuropathy occur in 10 to 15 percent of patients treated with relatively high doses. A reversible ataxia has also been described. Procarbazine, taken in conjunction with phenothiazines, barbiturates, narcotics, or alcohol, may produce serious degrees of oversedation. Other toxic reactions, such as orthostatic hypotension, are related to its inhibition of MAO. l-Asparaginase

This enzymatic inhibitor of protein synthesis is used in the treatment of acute lymphoblastic leukemia. Drowsiness, confusion, delirium, stupor, coma, and diffuse EEG slowing are the common neurologic effects and are dose-related and cumulative. They may occur within a day of onset of treatment and clear quickly when the drug is withdrawn, or they may be delayed in onset, in which case they persist for several weeks. These abnormalities are at least in part attributable to the systemic metabolic derangements induced by l-asparaginase, including liver dysfunction. In recent years, increasing attention has been drawn to cerebrovascular complications of l-asparaginase therapy, including ischemic and hemorrhagic infarction and cerebral venous and dural sinus thrombosis (Fineberg and

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Swenson). These cerebrovascular complications are attributable to transient deficiencies in plasma proteins that are important in coagulation and fibrinolysis.

5-Fluorouracil This is a pyrimidine analogue, used mainly as a secondary treatment of cancer of the breast, ovary, and gastrointestinal tract. A small proportion of patients receiving this drug develop dizziness, cerebellar ataxia of the trunk and the extremities, dysarthria, and nystagmus—symptoms that are much the same as those produced by cytarabine (ara-C; see in the following text). These abnormalities must be distinguished from metastatic involvement of the cerebellum and paraneoplastic cerebellar degeneration. The drug effects are usually mild and subside within 1 to 6 weeks after discontinuation of therapy. The basis of this cerebellar syndrome is unknown.

Methotrexate (See Also Chap. 30) Administered in conventional oral or intravenous doses, methotrexate (MTX) is not usually neurotoxic. However, given intrathecally to treat meningeal leukemia or carcinomatosis, MTX commonly causes aseptic meningitis, with headache, nausea and vomiting, stiff neck, fever, and cells in the spinal fluid. Very rarely, probably as an idiosyncratic response to the drug, intrathecal administration results in an acute paraplegia that may be permanent. The pathology of this condition has not been studied. The most serious and more common of the neurologic problems associated with systemic MTX chemotherapy is leukoencephalopathy or leukomyelopathy, especially when it is given in combination with cranial or neuraxis radiation therapy. This develops several months after repeated intrathecal or high systemic doses of the drug, and a few milder cases are known to have occurred without radiation treatments, that is, with oral or intravenous MTX alone (Worthley and McNeil). We have seen one such instance in a woman receiving oral MTX for a systemic vasculitis; no alternative explanation for widespread white matter changes and mild dementia could be discerned. Nonetheless, this must be quite uncommon. The full-blown syndrome consists of the insidious evolution of dementia, pseudobulbar palsy, ataxia, focal cerebral cortical deficits, or paraplegia. Milder cases show only radiographic evidence of a change in signal intensity in the posterior cerebral white matter (“posterior leukoencephalopathy”) that is similar to the imaging findings that follow cyclosporine use (see further on) and hypertensive encephalopathy (Fig. 41-2). In severe cases, the brain shows disseminated foci of coagulation necrosis of white matter, usually periventricular, which can be detected with CT and MRI. Mineralizing microangiopathy (fibrosis and calcification of small vessels, mainly in the basal ganglia) is yet another complication of MTX therapy. It may occur with MTX treatment or with cranial irradiation but is particularly common when both forms of treatment are combined. The present authors have the impression that the severe necrotic lesions possess features comparable to

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of cerebellar degeneration in a considerable proportion of cases (4 of 24 reported by Winkelman and Hines). Ataxia of gait and limbs, dysarthria, and nystagmus develop as early as 5 to 7 days after the beginning of high-dose treatment and worsen rapidly. Postmortem examination has disclosed a diffuse degeneration of Purkinje cells, most marked in the depths of the folia, as well as a patchy degeneration of other elements of the cerebellar cortex. Other patients receiving high-dose ara-C have developed a mild, reversible cerebellar syndrome with the same clinical features. Because patients older than 50 years are said to be far more likely to develop cerebellar degeneration than those younger than 50 years, the former should be treated with a lower dosage (Herzig and colleagues).

Calcineurin Inhibitors (Cyclosporine, Tacrolimus, Sirolimus)

Figure 41-2.  Toxic reversible posterior leukoencephalopathy (PRES). Axial T2-fluid-attenuated inversion recovery (FLAIR) MRI in a patient with cortical blindness and severe headache days after receiving vincristine. This syndrome and radiographic findings are more typical following the use of cyclosporine, FK-506, and other chemotherapies. Compare this image to the similar conditions of hypertensive encephalopathy and toxemia shown in Fig. 33-35.

(and therefore may be the result of ) the coagulative necrosis of radiation encephalopathy.

The Nitrosoureas Carmustine (BCNU) and lomustine (CCNU) are nitrosoureas used to treat malignant cerebral gliomas. They are not neurotoxic when given in conventional intravenous doses, but intracarotid injection of the drugs may cause orbital, eye, and neck pain, focal seizures, confusion, and possibly focal neurologic deficits. Postmortem examinations of patients who had been treated with intravascular BCNU have disclosed a diffuse vasculopathy characterized by fibrinoid necrosis and microthrombi and diffuse foci of swollen axis cylinders and myelin vacuolization (Burger and colleagues; Kleinschmidt-de Masters).

Cytarabine (Ara-C) This drug, long used in the treatment of acute nonlymphocytic leukemia, is not neurotoxic when given in the usual systemic daily doses of 100 to 200 mg/m2. The administration of very high doses (up to 30 times the usual dose) induces remissions in patients’ refractory to conventional treatments. It also may produce, however, a severe degree

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These immunosuppressive drugs are used to prevent transplant rejection and to treat aplastic anemia and certain intrinsic immune diseases. Tremor is perhaps the most frequent side effect and myoclonus may be added. Sometimes these impart a stuttering character to speech. Headache and insomnia are common. Seizures may be a manifestation of toxicity, but the cause may lie with the other complications of organ transplantation and immunosuppression. Wijdicks has reviewed the neurologic effects of these drugs. A posterior leukoencephalopathy syndrome (PRES, see Chap. 33) resembling hypertensive encephalopathy— headache, vomiting, confusion, seizures, and visual loss (cortical blindness)—may follow the use of either drug and with an expanding list of other agents including some of the new monoclonal antibodies used in the treatment of cancer and autoimmune diseases (Table 41-1). There does not seem to be a consistent dose-response effect, drug levels often being in the therapeutic range. Table 41-1 NON-VASCULAR CAUSES OF REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY (PRES, SEE ALSO CHAP. 33) Methotrexate (intravenous and rarely oral) Calcineurin inhibitors (cyclosporine, tacrolimus, sirolimus) Cyclophosphamide Interferon (intravenous) l-Asparaginase Vincristine Cisplatin Cytarabine Gemcitabine Doxorubicin Etoposide Intravenous immunoglobulin Granulocyte colony-stimulating factor Erythropoetin Rituximab Surafinib Sunitinib Bevacizumab Combination chemotherapies, particularly those including cyclophosphamide or cytarabine

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The appearance on CT and MRI of nearly symmetrical changes mainly in the posterior white matter conform to the pattern that is seen in hypertensive encephalopathy (reversible posterior leukoencephalopathy [RPLE] or PRES). Lesions may also appear subcortically in the frontal and parietal lobes as well as in deep structures and the brainstem. Interferon treatment for malignant melanoma and a number of other chemotherapeutic agents have been associated with the same condition. Several such cases have been described and it has been suggested that cyclosporine alters the blood–brain barrier and that the fluid overload and hypertension which accompanies the use of cyclosporine underlies the radiologic changes (Hinchey and colleagues). A variety of psychotic syndromes with delusions, paranoia, and visual hallucinations also have been ascribed to the use of these drugs (Wijdicks).

Thalidomide Despite the catastrophic effects of thalidomide on the developing fetus (following its introduction as a soporific in 1957), this drug has now found several specific uses in the treatment of immunologic, neoplastic, and infectious diseases. It is effective in the treatment of leprosy, erythema nodosum, and the oral ulcerations of AIDS and Behçet disease. Experimental uses include suppression of graft-versus-host reactions and inhibition of blood vessel proliferation in vascular tumors such as renal cell cancer. A dose-dependent sensory neuropathy is the limiting factor in its use, and serial electrophysiologic testing is recommended if the medication is to be prescribed for protracted periods. Of course, it must not be given to a woman who is or might be pregnant.

Immune Checkpoint Blockade Therapy A relatively new strategy for treating certain cancers involves increasing the activity of host antitumor immunity through inhibition of intrinsic down-regulators of T-cell immunity. Several drugs have been approved for the treatment of melanoma, non-small-cell lung cancer, and other malignancies; these include pembrolizumab, ipilimumab, nivolumab, and others. These drugs are monoclonal antibodies that target immune down-regulators such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). The inhibition of intrinsic immune downregulation results in an increase in immune activity that is accompanied by inflammation (Postow and colleagues). This inflammation can adversely affect any organ; from a neurological perspective, the main problems encountered are encephalitis, aseptic meningitis, hypophysitis, uveitis, and a Guillain-Barré type of generalized neuropathy. We have encountered cases of the last of these with widely varying severity but most have slowly, if incompletely, improved. These problems typically occur a few weeks to months after therapy is initiated. The susceptibility to these complications is variable and it is unclear whether the presence of complications correlates with improved treatment efficacy. The excessive inflammation can be treated with glucocorticoids or, if needed, additional immunosuppressive agents.

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Chimeric Antigen Receptor T-Cell (CAR-T-Cell) Therapy Another strategy for treating certain malignancies, mostly hematologic, involves the use of host T-cells that have been genetically engineered to express an antigen receptor that binds specifically to tumor cells. This binding facilitates cytotoxic destruction of tumor cells by the modified T-cells, and several trials have demonstrated not only a favorable response rate in patients with otherwise refractory malignancies but also occasional durable remissions. The most common toxicity associated with CAR-T-cell therapy is a cytokine-release syndrome that can manifest on a spectrum from mild constitutional symptoms to severe multi-organ dysfunction including, rarely, hemophagocytic lymphohistiocytosis. An encephalopathy termed CAR-Tcell-related encephalopathy syndrome (CRES) is the second most common toxicity and is associated with a confusional state and seizures that result from cerebral edema and elevated intracranial pressure. The disorder most often occurs about 5 days after initiation of therapy, coincident with other cytokine-release symptoms, but may occur later as well. Efforts aimed at identifying and grading the symptoms have been established (Neelapu and colleagues). Current recommendations include obtaining a baseline brain MRI and initiating seizure prophylaxis before initiation of CAR-T-cell therapy, and frequent neurological assessments thereafter. Symptoms of cytokine-release syndrome and CRES can be managed with glucocorticoids, though at the expense of suppressing T-cell function. Interestingly, a high serum level of interleukin-6 (IL-6), one of the many cytokines released by activated T-cells, has been associated with more severe neurotoxicity. Antibody drugs that bind to and inhibit the IL-6 receptor, such as tocilizumab, have been shown to reduce CRES, particularly in the early period following initiation of CAR-T-cell therapy.

ANTIBIOTICS Numerous antibiotics, cardioactive medications, and other drugs may have adverse effects on the central or peripheral nervous system. Some of the latter are addressed in Chap. 43. Here we mention mainly that penicillin and its derivatives such as imipenem, and to a lesser degree, the cephalosporins, are capable of causing seizures when high serum concentrations are attained. Cefepime, for example, has often been presumptively implicated in otherwise unexplained encephalopathies in patients we see as consultants on the wards and ICU. This complication is favored in most instances by concomitant renal failure. Other important examples of antibiotic toxicity are optic neuropathy caused by ethambutol toxicity; ototoxicity and neuromuscular blockade from aminoglycoside and fluoroquinolone antibiotics; peripheral neuropathy, encephalopathy, and an Antabuse-like reaction to alcohol in patients taking metronidazole; a metronidazoleinduced polyneuropathy, isoniazid (INH) neuropathy and optic neuropathy, and possibly a peripheral neuropathy caused by chloramphenicol.

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There has been reported a curious and reversible cerebellar syndrome caused by metronidazole with MRI signal changes in the dentate nuclei, or more widespread signal changes in other parts of the brainstem and cerebral white matter (Woodruff and colleagues; Kim and coworkers). Dysarthria, confusion, and gait ataxia seem to form the core of the clinical syndrome but imaging changes may be found coincidentally as well. The most notorious toxic consequences with this group of drugs were seen with clioquinol, which was sold as Entero-Vioform and was used in many parts of the world to prevent traveler’s diarrhea and as a treatment for chronic gastroenteritis. In 1971, clinical observations

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began to appear in medical journals of a subacute myeloopticoneuropathy (SMON). During the 1960s, more than 10,000 cases of this disease were collected in Japan by Tsubaki and colleagues. Usually the illness began with ascending numbness and weakness of the legs, paralysis of sphincters, and autonomic disorder. Later, vision was affected. The onset was acute in about two-thirds of the cases and subacute in the remainder. The occurrence of these neurologic complications was found to be related to the prolonged use of clioquinol. In Japan, the drug was withdrawn from the market, and the incidence of SMON immediately fell, supporting the theory that it was caused by the drug. Recovery was usually incomplete.

References Abel EL, Sokol RJ: Incidence of fetal alcohol syndrome and economic impact of FAS-related anomalies. Drug Alcohol Depend 19:51, 1987. Adams AJ, Banister SD, Irizarry L, et al: “Zombie” outbreak caused by the synthetic Cannabinoid AMB-FUBINACA in New York. N Engl J Med 376:23, 2017. Agency for Toxic Substances and Disease Registry: The Nature and Extent of Lead Poisoning in Children in the United States: A Report to Congress. Atlanta, GA, Department of Health and Human Services, 1988. Agocs MM, Etzel RA, Parrish RG, et al: Mercury exposure from interior latex paint. N Engl J Med 323:1096, 1990. Alajouanine TH, Derobert L, Thieffry S: Etude clinique d’ensemble de 210 cas d’intoxication par les sels organiques d’étain. Rev Neurol (Paris) 98:85, 1958. Albers JW, Kallenbach LR, Fine LJ, et al (The Mercury Workers Study Group): Neurological abnormalities associated with remote occupational elemental mercury exposure. Ann Neurol 24:651, 1988. Altura BT, Altura BM: Phencyclidine, lysergic acid diethylamide and mescaline: Cerebral artery spasms and hallucinogenic activity. Science 212:1051, 1981. Anton RF: Naltrexone for the management of alcohol dependence. N Engl J Med 359:715, 2008. Anton RF, O’Malley SS, Ciraulo DA, et al: Combined pharmacotherapies and behavioral interventions for alcohol dependence. JAMA 295:2003, 2006. Baghurst PA, McMichael AJ, Wigg NR, et al: Environmental exposure to lead and children’s intelligence at the age of seven years—the Port Pirie Cohort Study. N Engl J Med 327:1279, 1992. Baldessarini RJ: Drugs and the treatment of psychiatric disorders: Depression and mania. In: Hardman JG, Limbrin LE, Gilman GA, et al (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 485–520. Bank WJ, Pleasure DE, Suzuki D, et al: Thallium poisoning. Arch Neurol 26:456, 1972. Baud FJ, Galliot M, Astier A, et al: Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole. N Engl J Med 319:97, 1988. Bohman M: Some genetic aspects of alcoholism and criminality. Arch Gen Psychiatry 35:269, 1978. Boyer EW: Management of opioid analgesic overdose. N Engl J Med 367:2, 2012.

Ropper_Ch41_p1177-p1222.indd 1219

Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352:1112, 2005. Boyer LV, Theodorous AA, Berg, RA, et al: Antivenom for critically ill children with neurotoxicity from scorpion stings. N Engl J Med 360:2090, 2009. Brent JB: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 360:2216, 2009. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 340:832, 1999. Brewer C, Perrett L: Brain damage due to alcohol consumption: An air-encephalographic, psychometric and electroencephalographic study. Br J Addict 66(3):170, 1971. Brunton L, Knollmann B: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th ed. New York, McGraw Hill 2022. Bryant SM, Welker KI, Khattar N: Treatment of benzodiazepine dependence. N Engl J Med 376:2387, 2017. Buge A, Supino-Viterbo V, Rancurel G, Pontes C: Epileptic phenomena in bismuth toxic encephalopathy. J Neurol Neurosurg Psychiatry 44:62, 1981. Burger PC, Kamenar E, Schold SC, et al: Encephalomyelopathy following high-dose BCNU therapy. Cancer 48:1318, 1981. Burns R, Thomas DQ, Barron VJ: Reversible encephalopathy possibly associated with bismuth subgallate ingestion. Br Med J 1:220, 1974. Cadoret RJ, Cain C, Grove WM: Development of alcoholism in adoptees raised apart from alcoholic biologic relatives. Arch Gen Psychiatry 37:561, 1980. Calne DB, Chu NS, Huang CC, et al: Manganism and idiopathic parkinsonism: Similarities and differences. Neurology 44:1583, 1994. Camí J, Farré M: Drug addiction. N Engl J Med 349:975, 2003. Canfield RL, Henderson CR, Cery-Slechata DA, et al: Intellectual impairment in children with blood lead concentrations below 10 g per deciliter. N Engl J Med 348:1517, 2003. Carlen PL, Wortzman G, Holgate RC, et al: Reversible cerebral atrophy in recently abstinent chronic alcoholics measured by computed tomography scans. Science 200:1076, 1978. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 77:185, 1993. Caulley L, Caplan B, Ross E. M.D. Medical marijuana for chronic pain. N Engl J Med 379:1575, 2018. Cavanagh JB, Patangia GN: Changes in the central nervous system of the cat as a result of tri-o-cresyl phosphate poisoning. Brain 88:165, 1965.

08/02/23 9:49 AM

1220

Part 4 MAJOR CATEGORIES OF NEUROLOGIC DISEASE

Charness ME: Molecular mechanisms of ethanol intoxication, tolerance, and physical dependence. In: Mendelson JH, Mello NK (eds): Medical Diagnosis and Treatment of Alcoholism. New York, McGraw-Hill, 1992, pp 155–199. Chin JH, Goldstein DB: Drug tolerance in biomembranes: A spin label study of the effects of ethanol. Science 196:684, 1977. Clarkson TW: The toxicology of mercury—current exposures and clinical manifestations. N Engl J Med 349:1731, 2003. Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 8th ed. New York, Oxford University Press, 2002. Courville CB: Effects of Alcohol on the Nervous System of Man. Los Angeles, San Lucas Press, 1955. Crawley F, Schon F, Brown M: Cerebral infarctions: A rare complication of wasp sting. J Neurol Neurosurg Psychiatry 66:550, 1999. Cregler LL, Mark H: Medical complications of cocaine abuse. N Engl J Med 315:1495, 1986. Cutting J: The relationship between Korsakov’s syndrome and “alcoholic” dementia. Br J Psychiatry 132:240, 1978. Davidson CS: Nutrient content of beers and ales. N Engl J Med 264:185, 1961. Dolin SJ, Little HJ: Are changes in neuronal calcium channels involved in ethanol tolerance? J Pharmacol Exp Ther 250:985, 1989. D’Onofrio G, Rathlev NK, Ulrich AS, et al: Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 340:915, 1999. Drummond DC, Thom B, Brown C, et al: Specialist versus general practitioner treatment of problem drinkers. Lancet 336:915, 1990. Farrar JJ, Yen LM, Cook T, et al: Tetanus. J Neurol Neurosurg Psychiatry 69:292, 2000. Felz MW, Smith CD, Swift TR: A six-year-old girl with tick paralysis. N Engl J Med 342:90, 2000. Ferguson JA, Suelzer CJ, Ecjert GJ, et al: Risk factors for delirium tremens development. J Gen Intern Med 11:410, 1996. Fields HL: Pain. New York, McGraw-Hill, 1987. Fineberg WM, Swenson MR: Cerebrovascular complications of l-asparaginase therapy. Neurology 38:127, 1988. Fisher CM, Adams RD: Diphtheritic polyneuritis: A pathological study. J Neuropathol Exp Neurol 15:243, 1956. Fornazzari L, Wilkinson DA, Kapur BM, Carlen PL: Cerebellar, cortical and functional impairment in toluene abusers. Acta Neurol Scand 67:319, 1983. Foy A, Kay J: The incidence of alcohol-related problems and the risk of alcohol withdrawal in a general hospital population. Drug Alcohol Rev 14:49, 1995. Fudala PJ, Bridge TP, Herbert S, et al: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 349:949, 2003. Girard TD, Exline MC, Shannon S, et al: Haloperidol and Ziprasidone for treatment of delirium in critical illness. N Engl J Med 379:2506, 2018. Gold BS, Dart RC, Barish RA: Bites of venomous snakes. N Engl J Med 347:347, 2002. Goldman RH, Baker EL, Hannan M, Kamerow DB: Lead poisoning in automobile radiator mechanics. N Engl J Med 317:214, 1987. Goodwin DW, Schulsinger F, Moller N, et al: Drinking problems in adopted and nonadopted sons of alcoholics. Arch Gen Psychiatry 31:164, 1974. Grattan-Smith PJ, Morris JG, Johnston HM, et al: Clinical and neurophysiological features of tick paralysis. Brain 120:1975, 1997. Grove WM, Cadoret RJ: Genetic factors in alcoholism. In: Kissin B, Begleiter H (eds): The Biology of Alcoholism. Vol 7. The Pathogenesis of Alcoholism. New York, Plenum Press, 1983, pp 31–56.

Ropper_Ch41_p1177-p1222.indd 1220

Haggard HW, Jellinek EM: Alcohol Explored. Garden City, NY, Doubleday Doran, 1942. Harada M: Minamata disease: Methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 25:1, 1995. Harada S, Agarwal DP, Goedde HW: Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet 2:982, 1981. Harper CG, Blumbergs PC: Brain weights in alcoholics. J Neurol Neurosurg Psychiatry 45:838, 1982. Harper CG, Kril JJ: Brain atrophy in chronic alcoholic patients: A quantitative pathologic study. J Neurol Neurosurg Psychiatry 48:211, 1985. Harrington H, Heller A, Dawson D: Intracerebral hemorrhage and oral amphetamine. Arch Neurol 40:503, 1983. Harris RA, Baxter DM, Mitchell MA, et al: Physical properties and lipid composition of brain membranes from ethanol tolerantdependent mice. Mol Pharmacol 25:401, 1984. Haug JO: Pneumoencephalographic evidence of brain damage in chronic alcoholics: A preliminary report. Acta Psychiatr Scand 203(Suppl):135, 1968. Herzig RH, Hines JD, Herzig GP: Cellular toxicity with high-dose cytosine-arabinoside. J Clin Oncol 5:927, 1987. Heyman A, Pfeiffer JB Jr, Willett RW, Taylor HM: Peripheral neuropathy caused by arsenical intoxication. N Engl J Med 254:401, 1956. Hinchey J, Chaves C, Appigani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334:494, 1996. Hollister LE: Cannabis. Acta Psychiatr Scand 78(Suppl 345):108, 1988. Hollister LE: Clinical Pharmacology of Psychotherapeutic Drugs, 3rd ed. New York, Churchill Livingstone, 1990. Hormes JT, Filley CM, Rosenberg NL: Neurologic sequelae of chronic solvent vapor abuse. Neurology 36:698, 1986. Ijichi T, Iton T, Sakai R, et al: Multiple brain gas embolism after ingestion of concentrated hydrogen peroxide. Neurology 48:277, 1997. Ikonomidu C, Bittigan P, Ishimaru M, et al: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287:1058, 2000. Iverson L: Cannabis and the brain. Brain 126:1252, 2003. Jacobsen D: New treatment for ethylene glycol poisoning. N Engl J Med 340:879, 1999. Jasinski DR, Johnson RE, Kocher TR: Clonidine in morphine withdrawal. Arch Gen Psychiatry 42:1063, 1985. Johnson BA, Ait-Daoud N, Bowden CL, et al: Oral topiramate for treatment of alcohol dependence: A randomised controlled trial. Lancet 361:1677, 2003. Johnston MV, Gross RA: Fundamentals of drug therapy in neurology. In: Johnston MV, Gross RA (eds): Principles of Drug Therapy in Neurology, 2nd ed. Oxford, UK, Oxford University Press, 2008, pp 3–32. Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 2:999, 1973. Jones KL, Smith DW, Streissguth AP, Myrianthopoulos NC: Outcome in offspring of chronic alcoholic women. Lancet 1:1076, 1974. Jorgensen FM: Succimer: The first approved oral lead chelator. Am Fam Physician 48:1496, 1993. Kaim SC, Klett CJ, Rothfeld B: Treatment of acute alcohol withdrawal state: A comparison of four drugs. Am J Psychiatry 125:1640, 1969. Katrak SM, Pollock M, O’Brien CP, et al: Clinical and morphological features of gold neuropathy. Brain 103:671, 1980. Kim E, Na DG, Kim EY, et al: MR imaging of metronidazoleinduced encephalopathy: Lesion distribution and diffusionweighted imaging findings. AJNR 28:1652, 2007.

08/02/23 9:49 AM

Chapter 41 Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents King MD, Day RE, Oliver JS, et al: Solvent encephalopathy. Br Med J 283:663, 1981. Klaassen CD, Watkins J: Casarett and Doull’s: Essentials of Toxicology, 4th ed. New York, McGraw-Hill, 2021. Kleinschmidt-de Masters BK: Intracarotid BCNU leukoencephalopathy. Cancer 57:1276, 1986. Koppel C: Clinical symptomatology and management of mushroom poisoning. Toxicon 31:1513, 1993. Kosten TR, O’Connor PG: Management of drug and alcohol withdrawal. N Engl J Med 348:1786, 2003. Krisanda TJ: Flumazenil: An antidote for benzodiazepine toxicity. Am Fam Physician 47:891, 1993. Landsberg JP, McDonald B, Watt F: Absence of aluminum in neuritic plaque cores in Alzheimer’s disease. Nature 360:65, 1992. Lemoine P, Harousseau H, Borteyru JP, Menuet JC: Les enfants de parents alcooliques: Anomalies observées à propos de 127 cas. Ouest-Med 25:477, 1968. LeQuesne PM: Metal neurotoxicity. In: Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System, 2nd ed. Philadelphia, Saunders, 1992, pp 1250–1258. LeQuesne PM: Toxic substances and the nervous system: The role of clinical observation. J Neurol Neurosurg Psychiatry 44:1, 1981. Levine SR, Brust JCM, Futrell N, et al: Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med 323:699, 1990. Lewis M: Brain changes in addiction as learning, not disease. N Engl J Med 379:1551, 2018. Lishman WA: Cerebral disorder in alcoholism: Syndromes of impairment. Brain 104:1, 1981. Little HJ, Dolin SJ, Halsey MJ: Calcium channel antagonists decrease the ethanol withdrawal syndrome. Life Sci 39:2059, 1986. Longstreth WT, Rosenstock L, Heyer NJ: Potroom palsy? Neurologic disorder in three aluminum smelter workers. Arch Intern Med 145:1972, 1985. Mahaffey KR: Exposure to lead in childhood. N Engl J Med 327:1308, 1992. McDonald WI, Kocen RS: Diphtheritic neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, et al (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, Saunders, 1993, pp 1412–1423. McLean DR, Jacobs H, Mielke BW: Methanol poisoning: A clinical and pathological study. Ann Neurol 8:161, 1980. Mello NK, Mendelson JH: Buprenorphine treatment of cocaine and heroin abuse. In: Cowan A, Lewis JW (eds): Buprenorphine: Combatting Drug Abuse With a Unique Opioid. Wilmington, DE, Wiley-Liss, 1995, pp 241–287. Miles WR: Psychological effects of alcohol and man. In: Emerson H (ed): Alcohol and Man. New York, Macmillan, 1932, p 224. Monroe JJ, Ross WF, Berzins JI: The decline of the addict as “psychopath”: Implications for community care. Int J Addict 6:601, 1971. Moretto A, Lotti M: Poisoning by organophosphorus insecticides and sensory polyneuropathy. J Neurol Neurosurg Psychiatry 64:463, 1998. Moyer TP: Testing for arsenic. Mayo Clin Proc 68:1210, 1993. Needleman HL, Schell A, Bellinger D, et al: The long-term effects of exposure to low doses of lead in childhood: An 11-year follow-up report. N Engl J Med 322:83, 1990. Neelapu SS, Tummala S, Kebriaei P, et al: Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol 15:47, 2018. Nierenberg DW, Nordgren RE, Chang MB, et al: Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 338:1672, 1998.

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Oviedo-Joekes E, Brissette S, Marsh DC, et al: Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med 361:777, 2009. Pearn J: Neurology of ciguatera. J Neurol Neurosurg Psychiatry 70:4, 2001. Perl DP, Gajdusek DC, Garruto RM, et al: Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Science 217:1053, 1982. Porjesz B, Begleiter H: Brain dysfunction and alcohol. In: Kissin B, Begleiter H (eds): The Biology of Alcoholism. Vol 7: The Pathogenesis of Alcoholism. New York, Plenum Press, 1983, pp 415–483. Postow MA, Sidlow R, Hellman MD: Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158, 2018. Prineas J: The pathogenesis of the dying-back polyneuropathies. J Neuropathol Exp Neurol 28:571, 1969. Reich T: Biologic-marker studies in alcoholism. N Engl J Med 318:180, 1988. Richelson E: Pharmacology of antidepressants—characteristics of the ideal drug. Mayo Clin Proc 69:1069, 1994. Rogan WJ, Dierich KN, Ware JH, et al: The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 344:1421, 2001. Rollins YD, Filley CM, McNut JT, et al: Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno) ingestion. Neurology 59:1460, 2002. Romero CE, Barohn JD, Knox AD, et al: Barbiturate withdrawal following Internet purchase of Fioricet. Arch Neurol 61:1111, 2004. Roth D, Alarcon FJ, Fernandez JA, et al: Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 319:673, 1988. Rutter M: Raised lead levels and impaired cognitive/behavioural functioning: A review of the evidence. Dev Med Child Neurol 22(Suppl 42):1, 1980. Ryan A, Molloy FM, Farrell MS, et al: Fatal toxic leukoencephalopathy: Clinical, radiological, and necropsy findings in two patients. J Neurol Neurosurg Psychiatry 76:1014, 2005. Sadock BJ, Sadock VA (eds): Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia, Lippincott Williams & Wilkins, 2009. Samson HH, Harris RA: Neurobiology of alcohol abuse. Trends Pharmacol Sci 13:206, 1992. Sanford JP: Tetanus—forgotten but not gone. N Engl J Med 332:812, 1995. Schroth G, Naegele T, Klose U, et al: Reversible brain shrinkage in abstinent alcoholics, measured by MRI. Neuroradiology 30:385, 1988. Schuckit MA, Winokur G: Alcoholic hallucinosis and schizophrenia: A negative study. Br J Psychiatry 119:549, 1971. Scott DF: Alcoholic hallucinosis: An aetiological study. Br J Addict 62:113, 1967. Senanayake N, Karalliedde L: Neurotoxic effects of organophosphate insecticide. N Engl J Med 316:761, 1987. Snyder SH: Receptors, neurotransmitters and drug responses. N Engl J Med 300: 465, 1979. Spencer PS, Schaumburg HH (eds): Experimental and Clinical Neurotoxicology, 2nd ed. New York, Oxford, 2000. Spencer PS, Schaumburg HH: Organic solvent neurotoxicity. Scand J Work Environ Health 11(Suppl 1):53, 1985. Spillane L, Roberts JR, Meyer AE: Multiple cranial nerve deficits after ethylene glycol poisoning. Ann Emerg Med 20:208, 1991. Streissguth AP: A long-term perspective of FAS. Alcohol Health Res World 18:74, 1994.

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Struppler A, Struppler E, Adams RD: Local tetanus in man. Arch Neurol 8:162, 1963. Sullivan WC: A note on the influence of maternal inebriety on the offspring. J Mental Sci 45:489, 1899. Suzuki A, Kondo T, Otani K, et al: Association of the TagIA polymorphism of the dopamine (D2) receptor gene with predisposition to neuroleptic syndrome. Am J Psychiatry 158:1714, 2001. Swift RM: Drug therapy for alcohol dependence. N Engl J Med 340:1482, 1999. Tan TP, Algra PR, Valk J, Wolters EC: Toxic leukoencephalopathy after inhalation of poisoned heroin: MR findings. AJNR Am J Neuroradiol 15:175, 1994. Tokuomi H, Uchino M, Imamura S, et al: Minamata disease (organic mercury poisoning): Neuroradiologic and electrophysiologic studies. Neurology 32:1369, 1982. Torvik A, Lindboe CF, Rogde S: Brain lesions in alcoholics. J Neurol Sci 56:233, 1982. Tsubaki T, Honmay Y, Hoshl M: Neurological syndrome associated with clioquinol. Lancet 1:696, 1971. Ulleland C: The offspring of alcoholic mothers. Ann N Y Acad Sci 197:167, 1972. Verebey K, Alrazi J, Jaffe JH: The complications of ‘ecstasy’(MDMA). JAMA 259:1649, 1988. Victor M: Alcoholic dementia. Can J Neurol Sci 21:88, 1994. Victor M: The pathophysiology of alcoholic epilepsy. Res Publ Assoc Res Nerv Ment Dis 46:431, 1968. Victor M, Adams RD: The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 32:526, 1953. Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syndrome and Other Disorders Due to Alcoholism and Malnutrition. Philadelphia, Davis, 1989.

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Victor M, Hope J: The phenomenon of auditory hallucinations in chronic alcoholism. J Nerv Ment Dis 126:451, 1958. Waksman BH, Adams RD, Mansmann HC: Experimental study of diphtheritic polyneuritis in the rabbit and guinea pig. J Exp Med 105:591, 1957. Walder B, Tramer MR, Seeck M: Seizure-like phenomena and propofol. A systematic review. Neurology 58:1327, 2002. Weinstein L: Current concepts: Tetanus. N Engl J Med 289:1293, 1973. Whitfield CL, Chien L, Whitehead JD: Lead encephalopathy in adults. Am J Med 52:289, 1972. Wijdicks EFM: Neurologic manifestations of immunosuppressive agents. In: Wijdicks EFM (ed): Neurologic Complications in Organ Transplant Recipients. Boston, Butterworth-Heinemann, 1999. Wilkinson DA: Examination of alcoholics by computed tomographic scans: A critical review. Alcohol Clin Exp Res 6:31, 1982. Winkelman MD, Hines JD: Cerebellar degeneration caused by high-dose cytosine arabinoside: A clinicopathological study. Ann Neurol 14:520, 1983. Wolfe SM, Victor M: The relationship of hypomagnesemia and alkalosis to alcohol withdrawal symptoms. Ann N Y Acad Sci 162:973, 1969. Wolters EC, Van Wijngaarden GK, Stam FC, et al: Leukoencephalopathy after inhaling “heroin” pyrolysate. Lancet 2:1233, 1982. Woodruff BK, Wijdicks EF, Marshall WF: Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med 346:68, 2002. Worthley SG, McNeil JD: Leukoencephalopathy in a patient taking low dose oral methotrexate therapy for rheumatoid arthritis. J Rheumatol 22:335, 1995. Zipursky RB, Lim KO, Pfefferbaum A: MRI study of brain changes with short-term abstinence from alcohol. Alcohol Clin Exp Res 13:664, 1989.

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PA R T

5

DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

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42 Diseases of the Spinal Cord

Diseases of the nervous system may be confined to the spinal cord, where they produce very distinctive syndromes. These relate to the special anatomic features of the cord, such as its prominent function in sensorimotor conduction and relatively primitive reflex activity; its long, cylindrical shape; its small cross-sectional size; the peripheral location of myelinated fibers next to the pia; the special arrangement of its blood vessels; and its intimate relationship to the vertebral column. Woolsey and Young estimated that approximately 30 diseases are known to affect the spinal cord, of which half are seen with regularity. These processes express themselves in readily recognizable ways, and, as will be evident, certain diseases preferentially produce special syndromes. This syndromic grouping of spinal cord disorders greatly facilitates clinical diagnosis. The main syndromes considered in this chapter are idealized patterns of the results of damage within the cord: (1) a complete or almost complete sensorimotor myelopathy that involves most or all of the ascending and descending tracts, effectively a transverse myelopathy causing paralysis and sensory loss marked by a distinct level on the body demarcating normal from absent sensation below (sensory level); (2) a combined painful radicular and transverse cord syndrome; (3) the hemicord (Brown-Séquard) syndrome of paralysis one side of the body and loss of pain and temperature sensation on the other side, usually with a hemisensory level; (4) a ventral cord syndrome of paralysis and loss of pain and temperature below a level, sparing posterior column function; (5) a foramen magnum syndrome of sequential paralysis of the limbs; (6) a central cord or syringomyelic syndrome, in which pain and thermal sensation are lost over several segments of innervation; (7) a syndrome of the conus medullaris of leg weakness, sensory loss in the perinium and sphincter dysfunction; and (8) a syndrome of the cauda equina of pain, variable leg weakness, radicular leg pain and later sphincter dysfunction. In addition, important distinctions and further recognizable patterns are made between lesions within the cord (intramedullary) and those that compress the cord from without (extramedullary). Some of the anatomic and physiologic considerations pertinent to an understanding of disorders of the cord and of the spine can be found in Chaps. 3, 8 (Fig. 8-7), and Chap. 10, on motor paralysis, somatic sensation, and back pain, respectively.

MYELOPATHY CAUSED BY TRAUMA AND OTHER PHYSICAL FACTORS This syndrome is best considered in relation to trauma, its most frequent cause, but it occurs also from other acute damage including infarction or hemorrhage and with rapidly advancing compressive, necrotizing, demyelinative, or inflammatory lesions. For convenience, we have included in this group radiation myelopathy, which is transverse but evolves subacutely.

Traumatic Injuries of the Spine and Spinal Cord Throughout medical history, advances in the understanding of spinal cord disease have coincided largely with periods of warfare. The first thoroughly documented study of the effects of sudden total cord transection was by Theodor Kocher in 1896, based on his observations of 15 patients. During World War I, Riddoch, and later Head and Riddoch, gave what are now considered the classic descriptions of spinal transection in humans; Lhermitte and Guillain and Barré are credited with refining those observations. Little could be done for patients in that era and fully 80 percent died in the first few weeks (from infections); survival was possible only if the spinal cord lesion was partial. World War II marked a turning point in the understanding and management of spinal injuries. The advent of antibiotics and the ability to control skin, bladder, and pulmonary infections permitted the survival of unprecedented numbers of soldiers with cord injuries and provided the opportunity for long-term observation. In special centers, the care and rehabilitation of paraplegic patient were brought to a high level. Studies conducted in these centers greatly enhanced our knowledge of the functional capacity of the chronically isolated spinal cord.

Mechanisms of Spinal Injury The usual circumstances of spinal cord injury, in approximate order of frequency in civilian practice, are motor vehicle and motorcycle accidents, falls, gunshot or stab wounds, diving accidents, crushing industrial injuries, and birth injuries. In the United States, the annual incidence of spinal cord injury has been given as approximately 5 cases

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per 100,000 population; males predominate (4:1). Each year, approximately 3,500 persons die in relation to their spinal injury, and another 5,000 are left with complete or nearly complete loss of spinal cord function. The underlying mechanism in most traumatic spinal cord injuries is disruption of the surrounding vertebral spinal column through fracture, dislocation, or disc protrusion, the spinal canal is suddenly narrowed, thereby compressing the cord (Ropper and Ropper). The vertebral column is almost invariably injured at the same time, which presents its own set of problems regarding the stability of the spine, and often, there is an associated cranial injury, as pointed out in Chap. 34. A useful classification of vertebral column injuries divides them into fracture–dislocations, pure fractures, and pure dislocations. Except for bullet, shrapnel, and stab wounds, a direct blow to the spine is a relatively uncommon cause of serious spinal cord injury. In general medical practice, most fractures and dislocations of the spinal column are the result of force applied at a distance from the site of the disruption of the spinal column. All three types of spinal injury are typically produced by a vertical compression of the spinal column, to which either anteroflexion or retroflexion (hyperextension) is added. The most important variables in the mechanics of vertebral injury are the structure of the bones and ligaments at the level of the injury and the intensity, direction, and point of impact of the force. The main elements of the spine are illustrated in Chap. 10. Approximately 20 percent of spinal column injuries affect more than one level and the cervical spine is most vulnerable because it is the most mobile and does not have the support of the thoracic cage or the bulk of muscles and bones of the lumbar spine. Therefore, blows to the head may result in cervical spinal injuries. The cranium itself constitutes a load on the fulcrum of the neck; forceful rotation about the neck can cause transient or persistent dislocation of vertebral bodies or fracture of elements of the vertebrae that destabilize the neck or cause disc protrusion, transiently or persistently narrowing the spinal canal. This mechanism blends into “whiplash” injury, which is discussed further on and in Chap. 10. If a hard object at high velocity strikes the cranium, a skull fracture occurs, the force of the injury being absorbed mainly by the elastic quality of the skull. If the traumatizing force is relatively soft yet unyielding or is applied slightly more slowly, the cervical spine will be the part injured. If the neck happens to be rigid and straight and the force is applied quickly to the head, the atlas and the odontoid process of the axis may fracture. In the case of cervical flexion injury, the head has usually been bent sharply forward when the force is applied. The cervical vertebrae are forced together at the level of maximum stress, driving the anteroinferior edge of the upper vertebral body into the one below, sometimes splitting it in two and tearing of the interspinous and posterior longitudinal ligaments. The posterior part of the fractured body is displaced backward and compresses the cord. Less severe degrees of anteroflexion injury produce only dislocation of adjacent cervical vertebrae at one of several levels, but even this may transiently compress the cord and

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cause injury. Pre-existing narrowing of the spinal canal by cervical spondylosis, ankylosing spondylitis, or by a congenital narrowness of the canal greatly increases vulnerability to the effects of anteroflexion and, to some extent, to retroflexion injuries. In cervical hyperextension injuries, the mechanism is one of the vertical compression of the spinal column with the head in an extended position. Stress is mainly on the posterior elements (the laminae and pedicles) of the midcervical vertebrae (C4 to C6), or sometimes at higher levels, which may be fractured unilaterally or bilaterally, and to a lesser extent on the anterior ligaments (see the named fractures in these regions further on). This ligamentous disruption in the spinal architecture allows for the displacement of one vertebral body upon the adjacent one and compresses the cord between the laminae of the lower vertebra and the body of the one above. Spinal cord trauma may also occur from hyperextension injury without apparent damage or misalignment of the vertebrae. In these instances, the cord damage, which can be minor or profound and permanent, is considered to be caused by a sudden inward bulge of the ligamentum flavum or by transient dislocation at the time of injury, which is permitted because of ligamentous disruption; when viewed with imaging studies after the injury, the vertebral bodies are found to have remained aligned. In such cases, rupture of the supporting ligamentous elements and spinal instability can be revealed by gentle flexion and extension of the neck under imaging observation, which demonstrates the movement of a vertebra in relation to an adjacent one. CT and plain lateral spine films are usually satisfactory means of demonstrating the spinal column injury but tearing and bulging of ligaments from vertebral dislocation are more dependably demonstrated by magnetic resonance imaging (MRI). Another potential mechanism of cord and spinal root injury involving extremes of extension and flexion of the neck is so-called whiplash or recoil injury, most often attributed to sudden deceleration or acceleration during an automobile accident. When a vehicle is struck sharply from behind, the head of the occupant is flung back uncontrollably, or if a fast-moving vehicle stops abruptly, there is sudden forward flexion of the neck, followed by retroflexion. Under these conditions, the occipitonuchal and sternocleidomastoid muscles and other supporting structures of the neck and head are affected much more often than is the spinal column. Nevertheless, in rare instances, quadriparesis, temporary or permanent, apparently results from a violent whiplash injury. The mechanism of neural injury in these circumstances is not clear; perhaps there is a transient posterior dislocation of a vertebral body, a momentary buckling of the ligamentum flavum, or retropulsion of the intervertebral disc into the spinal canal. Other ostensible results of whiplash, such as dizziness, are controversial and are discussed in Chap. 10. However, a comment to be made regarding whiplash is that all manner of neurologic symptoms has been uncritically attributed to it, often with implications for medicolegal and disability determinations. As mentioned, the presence of a congenitally narrow cervical spinal canal or of acquired spinal diseases such as cervical spondylosis, rheumatoid arthritis, or ankylosing

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Chapter 42 Diseases of the Spinal Cord

spondylitis adds greatly to the hazard of damage to the cord or roots. Neck trauma of almost any configuration may aggravate preexisting spondylotic symptoms, depending on the extent of spondylosis and degree of trauma. There are, in addition, examples of spinal cord compression from prolonged static hyperextension of the cervical spine during a protracted period of stupor, accounting for quadriplegia following a period of unresponsiveness due to opiate or sedative drug overdose (Ell et al). Arterial hypotension with hypoperfusion of the cord may be an added factor in some instances. A special type of spinal cord injury, occurring most often in wartime, is one in which a high-velocity missile penetrates the vertebral canal and damages the spinal cord directly. In some cases, the missile strikes the vertebral column without entering the spinal canal but, due to the shock wave, disrupts and virtually shatters the intradural contents or produces lesser degrees of spinal cord dysfunction; or, the transmitted shock wave from a bullet passing nearby the vertebral column causes paralysis of spinal cord function that is often reversible in a day or two (spinal cord concussion, described further on). Acute traumatic paralysis may also be the indirect consequence of a vascular mechanism, mainly through infarction from fibrocartilaginous emboli arising in an intervertebral disc that has ruptured into a radicular artery or vein of the cord or from traumatic dissecting aneurysm of the aorta that occludes the segmental arteries of the spinal cord (Weisman and Adams; Kneisley). One striking variant of this type of vascular injury is infarction of the upper cervical cord, resulting in hemi-, tri-, or tetraplegia, from dissection of one or both vertebral arteries and occlusion of their tributary anterior spinal arteries at the cervicomedullary junction. Vertebral fracture and dislocation  An analysis from a long-past but still instructive era, by Jefferson of 2,000 cases of spinal injury collected from the medical literature up to 1927 showed that most vertebral injuries occurred at the levels of the first and second cervical, fourth to sixth cervical, and eleventh thoracic to second lumbar vertebrae. Industrial accidents most often involve the thoracolumbar vertebrae. Impact to the head with the neck flexed or sharply retroflexed, as mentioned earlier, was the main cause of injuries to the cervical region. These are not only the most mobile portions of the vertebral column but also the regions in which the cervical and lumbar enlargements of the cord greatly reduce the space between neural and bony structures. The thoracic cord is relatively small and its spinal canal is capacious; additional protection at these levels is provided by high and overlapping articular facets, making dislocation difficult, and by limitations in anterior displacement of vertebral bodies imposed by the thoracic cage. Several configurations of vertebral fractures are common enough that they have been designated by eponyms or descriptive terms. The knowledgeable clinician has some familiarity with them and they are summarized in Table 42-1. They include Jefferson fracture, hangman’s fracture, Chance fracture, atlanto-axial fracture (C1-C2) and the more common atlanto-occipital fracture–dislocation, including fracture of the dens of C2. Regarding hangman’s fracture, contrary to the popular notion, most penal hangings do not

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cause vertebral bony disruption (the mechanism may vary and are still a subject of inquiry) and death is instead by strangulation or occlusion of the carotid and vertebral arteries. Suicidal hanging causes mainly strangulation. A more common mechanism for hangman’s fracture is an elderly person who falls and strikes the chin, causing hyperextension of the neck. Most fatal cases of cervical spine injury are from fracture–dislocations of the upper cervical spine (C1 to C3 vertebrae, encompassing atlanto-occipital and atlantoaxis dislocations with sudden respiratory paralysis).

Acute Evaluation of the Spine-Injured Patient The level of spinal cord damage and, by implication, the level of disruption of the spinal column can be determined from clinical findings. Diaphragmatic paralysis occurs with lesions of the upper three cervical segments (transient arrest of breathing from brainstem paralysis is common in severe head injury). Complete paralysis of the arms and legs usually indicates a fracture or dislocation at the fourth to fifth cervical vertebrae. If the legs are paralyzed and the arms can still be abducted and flexed, the lesion is likely to be at the fifth to sixth cervical vertebrae. Paralysis of the legs and only the hands but not the proximal arms indicates a lesion at the sixth to seventh cervical level. Below the cervical region, the spinal cord segments and roots are not directly opposite their similarly numbered vertebrae (Fig. 42-1). The spinal cord ends at the first lumbar vertebra, usually at its rostral border. Vertebral column lesions below this point give rise predominantly to cauda equina syndromes; these carry a better prognosis than injuries to the lower thoracic vertebrae, which involve both cord and multiple roots. The level of sensory loss on the trunk, as determined by perception of pinprick, is an accurate guide to the level of the lesion, with a few qualifications. (See Figs. 8-1, 8-3, and 8-4 for maps of the sensory dermatomes.) Lesions of the lower cervical cord, even if complete, may spare sensation down to the nipple line because of the contribution of the C3 and C4 cutaneous branches of the cervical plexus, which variably innervate skin below the clavicle. Or a lesion that involves only the outermost fibers of the spinothalamic pathways results in a sensory level (to pain and temperature) well below the level of the lesion. In all cases of spinal cord and cauda equina injury, the prognosis for recovery is more favorable if any movement or sensation is elicitable during the first 48 to 72 h. If the spinal column can be examined safely, it should be inspected and palpated for angulations or irregularities and gently percussed to detect underlying bony injury. Collateral injury of the thorax, abdomen, and long bones should be sought and cranial injury is a concern if the mechanism of direct spinal impact is not known from the history. A neurologic examination with recording of motor, sensory, and sphincter function is necessary to follow the clinical progress of spinal cord injury. A common practice is to define the injury according to the standards of the American Spinal Injury Association and to assign the injury to a point on the ASIA Impairment, or AIS (a derivative of the formerly used Frankel scale). The level of the cord injury is appended to the classification of injuries graded as severity

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Table 42-1 MAJOR VERTEBRAL FRACTURES AND DISLOCATIONS NOMENCLATURE

MECHANISM

IMAGING

Atlanto-occipital dislocation

Rotatory force to head

Unstable

Common in children; fatal if severe

Atlanto-axial dislocation

Rotatory mechanism common in children; flexion in adults Axial downward force on vertex of head

Displacement of occipital condyles in relation to lateral masses of C1 Dislocation of C1-C2 facet

Unstable

Varies from asymptomatic to severe myelopathy

Bilateral anterior and posterior arch fractures

Stable

Fracture through C2b: Type 1: tip of dens Type 2: base of dens Type 3: body of C2 Fractures through pedicles of C2 Dislocation (perched or jumped) of facets with reversal of normal “shingled” appearance

Type 2 most “unstable” and unlikely to heal spontaneously Usually stable

Usually asymptomatic; transverse ligament may be disrupted Varies from asymptomatic to tetraparesis

Fracture through vertebral body with loss of height Same as burst fracture but includes fractures through facets and posterior elements Wedging of anterior vertebral body, no loss of height and no subluxation

Variable

Jefferson fracture (C1) Odontoid (dens) fractures (C2)

Hyperflexion

Hangman’s fracture (C2)

Hyperextension with axial loading Severe flexion

Subaxial fracture-dislocation

Burst fracture (thoracolumbar) Chance fracture (thoracolumbar) Compression (wedge) fracture (thoracolumbar)

Axial loading Flexion of lower thoracic spine— “seat-belt” injury Hyperflexion

STABILITY

Poor

Variable Usually stable

CLINICAL EFFECTSa

Most are asymptomatic Occurs at any level C3 to T1; common cause of traumatic tetra- and quadriplegia; vertebral artery dissection Root compression from retropulsion of bone fragment Commonly asymptomatic Local pain, rarely neurologic deficit

a

Pain at the site of the fracture or dislocation is common to all these injuries. These features are in addition to local pain over the site of the vertebral injury.

b

of A through E. A paraphrased version that we have found useful is presented here with comments regarding functional ability from the Frankel scale: A. Complete: No sensory or motor function below the level of the lesion including in the sacral segments. B. Sensory incomplete: Sensory function is preserved, but motor function is lost below the zone of injury. C. Motor incomplete (first grade): Motor function is reduced in more than half of key muscles below the level of the lesion; this usually renders the patient unable to walk. (Reduced motor function is defined as active movement in a full range of motion only if gravity is eliminated.) D. Motor incomplete (second grade): Motor function is reduced in fewer than half of key muscles below the level of the lesion; this usually allows standing and walking. E. Normal: Reflexes may be abnormal. Obviously, groups C, D, and E have a more favorable prognosis for recovery of ambulation than groups A and B. Even minimal preserved of sensation at the outset of injury (grade B), which is usually in the perineum, is associated with a better outcome than AIS grade A. In cases of suspected spinal injury, the immediate concern is that movement (especially flexion) of the cervical spine be avoided. The patient should ideally be placed supine on a firm, flat surface (with one person assigned, if possible, to keeping the head and neck immobile) and should be transported by a vehicle that can accept the litter.

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The board may be placed under the patient, gently rolling him to one side with the head, neck, and body held in alignment. If moving the patient is not feasible, the neck may be immobilized in place with a form collar or an equivalent device that is contrived at the scene, or even the examiner’s hands held firmly along the cervical spine. The patient should ideally be transported by an ambulance equipped with spine boards, to which the head is fixed by straps. This provides a more effective means of immobilization than sandbags or similar objects placed on each side of the head and neck. On arrival at the hospital, it is prudent to have the cervical spine remain immobilized until a lateral film or a CT or MRI of the cervical spine can be obtained, with the qualifications below. Several schemes have been devised for determining which patients may require imaging after spinal injury; these are similar to “rules” for the use of imaging in head injury that are discussed in Chap. 34. Two widely cited ones for spinal injury are from the NEXUS group (Hoffman et al) and the “Canadian C-spine Rule” (Stiell et al). The former identifies those at low risk for spinal cord injury on the basis of the absence of posterior midline cervical-spine tenderness, no evidence of intoxication, a normal level of alertness (thereby allowing accurate reporting of the circumstances of injury and the presence of neck pain and broadly indicating there has not been serious brain injury), no focal neurologic deficit, and no other painful injuries that distract the patient from reporting neck pain. The Canadian rule may be slightly more sensitive and specific (this has been disputed); it is

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Chapter 42 Diseases of the Spinal Cord

I C1 II II 2 III 3 III 4 IV 5 IV V V 6 7 VI VI 8 VII VII T1 I

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Pathology of Traumatic Spinal Cord Injury

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As a result of squeezing or shearing of the spinal cord, there is a destruction of gray and white matter and a variable amount of hemorrhage, chiefly in the more vascular central parts. These changes, designated as traumatic necrosis of the cord, are maximal at the level of injury and at one or two segments above and below it. Rarely is the cord cut in two, and seldom is the pia-arachnoid lacerated. Separation of the components of traumatic necrosis, such as hematomyelia, concussion, contusion, and hematorrhachis (bleeding into the spinal canal), is not of great value either clinically or pathologically. As the lesion heals, it leaves a gliotic focus or cavitation with variable amounts of hemosiderin and iron pigment. Progressive cavitation (traumatic syringomyelia) may develop after an interval of months or years and, as the cavity enlarges beyond the main lesion, lead to a delayed central or incomplete transverse cord syndrome. In some instances, the lesion is virtually restricted to the centrally situated gray matter, giving rise to segmental weakness and sensory loss in the arms with few long tract signs. This is the central cervical cord syndrome, also called the Schneider syndrome (see further on; Schneider et al). Fragments of the central cord syndrome commonly occur as transient phenomena that reverse over several days.

3 4 5 6

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based on three high-risk criteria: age older than 65 years, a dangerous mechanism of injury, and limb paresthesias; and on any of six features that are associated with low-risk of cord injury: simple rear-end motor vehicle collision, sitting position in the emergency department, being ambulatory at any time after injury, delayed (not immediate) onset of neck pain, absence of midline cervical-spine tenderness, coupled with the ability to turn the head 45 degrees in both directions without pain.

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Figure 42-1.  The relationship of spinal segments and roots to the vertebral bodies and spinous processes. The cervical roots (except C8) exit through foramina above their respective vertebral bodies, and the other roots issue below these bodies. (Reproduced with permission from Haymaker W, Woodhall B: Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.)

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Experimental Spinal Cord Injury Investigation of the pathophysiology of acute spinal cord injury dates from the experimental studies of Allen in the early 1900s. His method consisted of dropping graded weights onto the dura-covered thoracic cord of surgically prepared animals. The technique was refined over the years by precise measurements of the velocity, force, and direction of the dropped weights. This type of impact on the cord, of sufficient severity to render the animal immediately paraplegic and abolish sensory-evoked responses from structures below the lesion, indicates that action potentials can no longer be conducted across the injured spinal cord segment. No histologic changes, by either light or electron microscopy, can be detected for several minutes after impact. The earliest tissue alterations consist of hyperemia and small hemorrhages in the central gray matter. By 1 h, the microscopic hemorrhages coalesce and become macroscopically visible. Tissue oxygen saturation is diminished in the region. Within 4 h, the central part of the cord swells and a spreading edema pervades the surrounding white matter; however, necrosis may not be evident for up to 8 h, an observation that has led to numerous strategies designed to spare the neurons and long tracts. Surgical intervention to minimize white matter edema— such as laminectomy and myelotomy—spinal cord cooling,

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hyperbaric exposure, and the administration of pharmacologic measures have been tried but, for the most part, have had no meaningful effects on the evolving lesion. Certain mechanisms that are thought to be operative in the death of cerebral neurons exposed to ischemia or to traumatic forces have also been invoked in spinal cord injury but with limited evidence to support this commonality. These potentially include release of excitotoxins such as glutamate and exposure of neurons to calcium and free radicals. Despite early experiments implicating neurotransmitters or opioid-like substances as neurotoxins, later work failed to substantiate this or other similar secondary mechanisms. One problem with the experimental work is that it only imperfectly reproduces spinal injury in humans. Most recent work in the field of spinal cord injury has been on regeneration of spinal tissue across gaps in the cord using stem cells, gene therapy, and tissue scaffolding made of artificial or in vitro cell structures. None has yet proved satisfactory for clinical implementation.

Clinical Effects of Spinal Cord Injury When the spinal cord is suddenly and severely impacted, three disorders of function are at once evident: (1) all voluntary movement in parts of the body below the lesion is immediately lost; (2) sensation from the lower parts of the body is abolished; and (3) reflex functions in segments of the isolated spinal cord are suspended. The last effect, termed spinal shock, involves tendon as well as autonomic reflexes. This state is of variable duration (1 to 6 weeks but sometimes far longer) and is so dramatic that Riddoch used it as a basis for dividing the clinical effects of spinal cord transection into two stages, that of spinal shock with areflexia followed by a stage of heightened reflex activity. The separation of these stages is not as sharp as this statement might imply. Less complete or less sudden lesions of the cord result in little or no spinal shock. The features of complete functional spinal cord transection are now presented in detail because of their practical value and the special place they occupy in classic neurology. Spinal shock  The loss of motor function at the time of injury, tetraplegia with lesions of the fourth to fifth cervical segments or above, and paraplegia with lesions of the thoracic cord, are accompanied by immediate atonic paralysis of bladder and bowel, gastric atony, loss of sensation below a level corresponding to the spinal cord lesion, muscular flaccidity, and almost complete suppression of spinal segmental reflex activity below the lesion. As a result of their sudden separation from higher levels of control, the neural elements below the lesion essentially fail to perform their normal function. As dramatic as this state of reflex paralysis is, its physiologic basis is incompletely understood. Also impaired in the segments below the lesion is the control of autonomic function. Vasomotor tone, sweating, and piloerection in the lower parts of the body are temporarily abolished. As a result, there may be severe systemic hypotension that itself contributes to spinal cord damage. The lower extremities lose heat if left uncovered, and they swell if dependent. The skin over time becomes dry and pale, and ulcerations may develop over bony prominences. The sphincters of the bladder and the rectum remain

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contracted to some degree because of the loss of the normal inhibitory influence of higher centers, but the detrusor of the bladder and smooth muscle of the rectum become atonic. Urine accumulates until the intravesicular pressure is sufficient to overcome the sphincters, causing overflow incontinence. There is also passive distention of the bowel, retention of feces, and absence of peristalsis (paralytic ileus). Genital reflexes (penile erection, bulbocavernosus reflex, contraction of dartos muscle) are abolished or profoundly depressed. The duration of the stage of spinal shock varies. In a small number (e.g., 5 of Kuhn’s 29 patients) it is permanent, or only fragmentary reflex activity is regained, even many years after the injury. In such patients, the spinal segments below the level of transection may have themselves been injured, perhaps by a vascular mechanism, although this explanation is unproven. More likely, there is a loss of the brainstem–spinal facilitatory mechanisms and an increase in inhibitory activity in the isolated segments. In other patients, minimal genital and flexor reflex activity can be detected within a few days of the injury and minimal reflex activity appears within a period of 1 to 6 weeks. Usually, the bulbocavernosus reflex is the first to return. Contraction of the anal sphincter can be elicited by plantar or perianal stimulation, and other genital reflexes reappear at about the same time. The F-waves, electrophysiologic responses that reflect the functioning of the motor neurons of the isolated segment of the cord, are suppressed until spasticity supervenes, at which time they become overly easy to elicit. Noxious stimulation of the plantar surfaces evokes a tremulous twitching and brief flexion or extension movements of the great toes. The explanation for spinal shock, which is brief in submammalian animals and longer lasting in higher mammals, especially in primates, is believed to be the sudden interruption of suprasegmental descending fiber systems that normally keep the spinal motor neurons in a continuous state of readiness. In the cat and monkey, Fulton found the facilitatory tracts in question to be the reticulospinal and vestibulospinal. Subsequent studies showed that in monkeys, some degree of spinal shock could result from the interruption of the corticospinal tracts alone. This is probably not a significant factor, however, at least in humans, because spinal shock does not result from acute cerebral and brainstem lesions that interrupt the corticospinal tracts. Stage of heightened reflex activity This is the more familiar condition of spasticity that emerges some time after spinal injury and is also typical of most of the nontraumatic subacute myelopathies that have developed more slowly than traumatic injuries and have not had a period of spinal shock. A few weeks after an acute traumatic injury, all reflex responses, which are initially minimal and unsustained, become stronger and more easily elicitable and, as time passes, come to include additional and more proximal muscles. Gradually, the typical pattern of heightened flexion reflexes emerges: dorsiflexion of the big toe (Babinski sign); fanning of the other toes; and later, flexion or slow withdrawal movements of the foot, leg, and thigh with contraction of the tensor fascia lata muscle (the last several

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Chapter 42 Diseases of the Spinal Cord

features referred to as “triple flexion”). Tactile stimulation of the foot may suffice as a stimulus, but a painful stimulus is more effective. The Achilles reflexes and then the patellar reflexes return. Retention of urine becomes less complete, and at irregular intervals, urine is expelled by spontaneous contractions of the detrusor muscle. Reflex defecation also begins. After several months the withdrawal reflexes become greatly exaggerated, to the point of flexor spasms, and they may be accompanied by profuse sweating, piloerection, and automatic emptying of the bladder (occasionally of the rectum). This is the “mass reflex,” which can be evoked by stimulation of the skin of the legs or by some interoceptive stimulus, such as a full bladder. Varying degrees of heightened flexor reflex activity may last for years or indefinitely. Heat-induced sweating is defective, but reflex-evoked (“spinal”) sweating may be profuse (see Kneisley). In such cases, the lateral horn cells in much of the thoracic cord are still viable and have been disinhibited. Above the level of the lesion, thermoregulatory sweating may be exaggerated in order to compensate for the loss of evaporative cooling of lower segments, and there is cutaneous flushing, hypertension that causes pounding headache and reflex bradycardia. This syndrome (“autonomic dysreflexia”) is episodic and occurs in response to a certain stimuli, such as a distended bladder or rectum. It has been ascribed to the reflex release of adrenaline from the adrenal medulla and of norepinephrine from the disinhibited sympathetic terminals caudal to the lesion but is exaggerated by defective baroreceptor compensatory reflexes, as discussed in Chap. 25. Extensor reflexes and tone eventually develop in most cases (18 of 22 of Kuhn’s patients who survived more than 2 years), but their appearance does not lead to the abolition of the exaggerated flexor reflexes. The overactivity of extensor muscles may appear as early as 6 months after the injury, but this only happens, as a rule, after the flexor responses are fully developed. Extensor responses are at first manifest in certain muscles of the hip and thigh and later of the leg. In a few patients, extensor reflexes are organized into support reactions sufficient to permit spinal standing. Kuhn observed that extensor movements were at first provoked most readily by a sudden shift from a sitting to a supine position and later by proprioceptive stimuli (squeezing of the thigh muscles) and tactile stimuli from wide areas. Marshall, in a study of 44 patients with chronic spastic paraplegia of spinal origin, found all possible combinations of flexor and extensor reflexes; the type of reflex obtained was determined by the intensity and duration of the stimulus (a mild prolonged noxious stimulus evoked an ipsilateral extensor reflex; an intense brief stimulus, a flexor response). From these observations, one would suspect that the ultimate posture of the legs—flexion or extension—does not depend solely on the completeness or incompleteness of the spinal cord lesion, as originally postulated by Riddoch. The development of paraplegia in flexion (extreme flexion of the hips and knees, as in a fetal position) relates also to the level of the lesion, being seen most often with cervical lesions and progressively less often with more caudal ones. Greatly troubling to the spinal patient

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are repeated flexor spasms, which are more frequent with higher lesions of the cord, and the ensuing contractures ultimately produce a fixed flexor posture. Furthermore, the reduction of flexor spasms by elimination of nociceptive stimuli (infected bladder, decubitus, etc.) favors an extensor posture of the legs (paraplegia in extension). According to Guttmann, the positioning of the limbs during the early stages of paraplegia influences their ultimate posture. Thus, prolonged fixation of the paralyzed limbs in adduction and semiflexion favors subsequent paraplegia in flexion. Placing the patient prone or placing the limbs in abduction and extension facilitates the development of predominantly extensor postures. Nevertheless, strong and persistent extensor postures are usually observed only with partial lesions of the spinal cord. Several sensory phenomena are expected after functional cord transection. The main one, of course, is the loss of all sensibility below the lesion, that is, a sensory level. Of some interest is the fact that many patients report sensory symptoms in segments of the body below the level of their transection. Thus, a tactile stimulus above the level of the lesion may be felt below the transection (a type of synesthesia). Patients describe a variety of paresthesias, the most common being a dull, burning pain in the lower back and abdomen, buttocks, and perineum. We have encountered several patients in whom aching testicular or rectal pain was a very distressing problem. The pain may be intense and last for a year or longer, after which it gradually subsides. It persists after rhizotomy but can be abolished by anesthetizing the stump of the proximal (upper) segment of the spinal cord (Pollock and coworkers). Transmission of sensation over splanchnic afferents to levels of the spinal cord above the lesion, the conventional explanation, is therefore not the most plausible one. The overactivity of sensory systems in the isolated segments of the spinal cord has several explanations. One assumes that suprasegmental inhibitory influences have been removed by the transection, so that afferent sensory impulses evoke exaggerated nocifensive and phasic and tonic myotatic reflexes. But isolated neurons also become hypersensitive to neurotransmitters. Since the early experiments of Cannon and Rosenblueth, it has been known that section of sympathetic motor fibers leaves the denervated structures hypersensitive to epinephrine and to acetylcholine. Various combinations of residual deficits (of lower and upper motor neurons and sensory neurons) are to be expected. High cervical lesions, for example, may result in extreme and prolonged tonic spasms of the legs because of the release of tonic myotatic reflexes. Under these circumstances, attempted voluntary movement may excite intense contraction of all flexor and extensor muscles lasting for several minutes. Segmental damage in the low cervical or lumbar gray matter, destroying inhibitory Renshaw neurons, may release activity of remaining anterior horn cells, leading to spinal segmental spasticity. Any residual symptoms persisting after 6 months are likely to be permanent, although in a few patients, some return of function (particularly sensation) is possible after this time. Loss of motor and sensory function above the

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lesion, coming on years after the trauma, is the result of an enlarging cavity in the proximal segment of the cord (see further on, under “Syringomyelia [Syrinx]”).

Transient Cord Injury (Spinal Cord Concussion) These terms refer to a transient loss of motor sensory function of the spinal cord that recovers within minutes or hours but may persist in mild form for days or more. In most instances, the symptoms rapidly diminish and few neurologic abnormalities may be found at the time of the first examination. There are a number of such transient syndromes: bibrachial weakness; quadriparesis (occasionally hemiparesis); paresthesias and dysesthesias in a similar distribution to the weakness; or sensory symptoms alone (“burning hands syndrome”). In the first and last of these, transient dysfunction of the central gray matter of the cervical cord is implicated. It is assumed that the cord undergoes some form of elastic deformation when the cervical spine is compressed or hyperextended; however, the same effects can be produced by direct blows to the spine or forceful falls flat on the back and occasionally, by a sharp fall on the tip of the coccyx. Little is known of the physiologic mechanisms that underlie these reversible syndromes. Spinal cord concussion from direct impact is observed most frequently in athletes engaged in contact sports (football, rugby, and hockey). An incomplete and reversible myelopathy is referable to the site and level of the injury. A congenitally narrow cervical canal is thought to predispose to spinal cord concussion and to increase the risk of recurrence. As with cerebral concussion, particularly if there have been previous concussions, a difficult decision arises—whether to allow the resumption of competitive sports. There are no reliable data on which to base this decision, only guidelines that tentatively allow continued participation, after an unspecified period of rest, if the deficit has been brief. It is, however, advisable in most cases to be certain that spinal instability has not been induced by the injury. This can be ascertained from flexion and extension x-ray images of the affected spinal region. The subject is reviewed by Zwimpfer and Bernstein. In athletic contact injury, unilateral arm and hand paresthesias are more common than symptoms of both arms, but they are usually from stretching of the brachial plexus on one side (a “stinger”), rather than from a cord injury. Central cord syndrome (Schneider syndrome) and cruciate paralysis A special form of acute cervical cord injury implicates mainly central cord damage, resulting in the loss of motor function solely or more severely in the upper limbs than in the lower ones, and it particularly affects the hands. Bladder dysfunction with urinary retention occurs in some cases and sensory loss is often slight (hyperpathia over the shoulders and arms may be the only sensory abnormality). Many of these instances are reversible, but damage to the centrally situated gray matter may leave an atrophic, areflexic paralysis of the arms and hands and a segmental loss of pain and thermal sensation from interruption of crossing pain and thermal fibers. Retroflexion injuries of the head and neck are the ones most often associated with the central cord syndrome, but other

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causes include hematomyelia, fibrocartilaginous embolism, and infarction from dissection of the vertebral artery in the medullary-cervical region as mentioned earlier in the chapter. Approximately 4 percent of patients who survive injuries of the very rostral cervical cord demonstrate a limited form of the central cord syndrome (Dickman and colleagues; originally recognized by Nielson and named by Bell, “cruciate paralysis.”) The weakness is very selective, being practically limited to the arms, a feature that is attributable to the segregation within the pyramidal decussation of corticospinal fibers to the arms (being rostral) and to the legs (more caudally situated). The arm weakness may be asymmetrical or even unilateral and sensory loss is inconsistent. The patients described have had contusions of the C1-C2 region. Whether the lesion lies strictly within the decussating corticospinal tract or involves central gray matter is not always clear; MRI findings have implicated the latter (Inamasu et al).

Management of Spinal Injury For some time, many centers administered methylprednisolone in high dosage beginning within 8 h of the injury and continued for 23 h. This measure, according to the multicenter National Acute Spinal Cord Study (Bracken et al, 1990), resulted in a slight improvement in both motor and sensory function. The therapeutic value of this measure has since been questioned after reanalysis of the data (Nesathurai; Hurlbert) and from other studies and it is no longer considered essential; most centers now eschew the use of glucocorticoids after spinal cord injury. Hypotension, a risk factor for poor clinical outcome, is treated with infusions of normal saline and may require the transient use of pressor agents. The use of hypothermia with cooling blankets or the infusion of cooled saline has undergone periods of popularity to protect spinal tissue but has not been validated. Imaging examinations are undertaken to determine the alignment of vertebrae and pedicles, fracture of the pedicle or vertebral body, compression of the spinal cord or cauda equina as a consequence of malalignment or bone debris in the spinal canal, and the presence of tissue damage within the cord. CT is favored to show bony injury and displacement and MRI is suited to displaying the cord injury, but if neither is available, myelography with CT scanning is an alternative. Instability of the spinal elements can often be inferred from dislocations or from certain fractures of the pedicles, pars articularis, or transverse processes, but gentle flexion and extension of the injured areas must sometimes be undertaken and plain films obtained in each position to determine if there is instability of the spinal column. If a cervical spinal cord injury is associated with a vertebral dislocation, traction on the neck may be necessary to secure proper alignment and maintain immobilization. Depending on the nature of the injury, this had been accomplished by the use of a halo brace, which provides the rigid external fixation of the cervical spine. This type of fixation was usually continued for 4 to 6 weeks, after which a rigid collar may be substituted. However, modern techniques of internal fixation and realignment of the spinal

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column (“instrumentation”) are no more often used is possible because they liberate the patient from an external and uncomfortable device. Concerning the early surgical management of traumatic spinal cord injury, there have been two perspectives. One advocates reduction and alignment of the dislocated vertebrae by traction and immobilization until skeletal fixation is obtained and then rehabilitation. The other approach, represented historically by Munro and later by Collins and Chehrazi, proposed early surgical decompression, correction of bony displacements, and removal of herniated disc tissue and intra- and extramedullary hemorrhage; often, the spine is fixed at the same time by a bone graft or other form of stabilization (see review by Ropper and Ropper). The latter approach of acute decompressive surgery remains contentious to the present day. The MRI has altered these empirical approaches by allowing early demonstration of hematomas and other sources of compression that may be amenable to acute surgery. With clinical evidence of a complete spinal cord lesion, most surgeons do not favor early surgery, but fixation of unstable segments is undertaken at a later time in order to facilitate rehabilitation. The results of the conservative and aggressive surgical plans of management for incomplete cord injuries have been difficult to compare, particularly in respect to the timing of surgical procedures, and have not been well evaluated with modern clinical trials. Collins, a participant in the National Institutes of Health (NIH) study of acute management of spinal cord injury decades ago, concluded that the survival rate was increased as a result of early surgical stabilization of fractures and fixation of the spine. Others have not been able to document a reduction in neurologic disability and have increasingly been inclined toward nonoperative management of both complete and partial spinal cord lesions (Clark; Murphy et al). Some North American neurosurgeons take the less aggressive stance, delaying operation or operating only on patients with compound wounds or those with progression or worsening of the neurologic deficit despite adequate reduction and stabilization. In each case, the approach is guided by the specific aspects of the injuries; ligamentous disruption, presence of hematoma, misalignment-displacement of spinal segments, instability of the injury, and fracture type. The greatest medical risks to the patient with spinal cord injury occur in the first days and weeks when gastric dilatation, ileus, shock, and infection are threats to life. The mortality rate falls rapidly after 3 months; beyond this time, 86 percent of paraplegics and 80 percent of quadriplegics will survive for 10 years or longer (Messard and colleagues). In children, the survival rate is even higher; the cumulative 7-year survival rate in spinal cord–injured children (who had survived at least 24 h after injury) has been 87 percent in one study (DeVivo and colleagues). Advanced age at the time of injury and being rendered completely quadriplegic have been the worst prognostic factors. The aftercare of patients with paraplegia, in addition to substantial psychological support to allow accommodation to new limitations while encouraging a productive life, is concerned with the management of bladder and bowel disturbances, care of the skin, prevention of pulmonary

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embolism, and maintenance of nutrition. At first, continual catheterization is necessary; then, after several weeks, the bladder can be managed by intermittent catheterization once or twice daily, using a scrupulous aseptic technique. Bacteriuria alone is common and does not require treatment with antibiotics unless there is associated pyuria. Morning suppositories and periodically spaced enemas are effective means of controlling fecal incontinence. Chronic pain (present in 30 to 50 percent of cases) requires the use of nonsteroidal anti-inflammatory medication, injections of local anesthetics, and transcutaneous nerve stimulation. A combination of carbamazepine or gabapentin and either clonazepam or tricyclic antidepressants may be helpful in cases of burning leg and trunk pain. Remaining pain may require more aggressive therapy, such as epidural injections of analgesics or corticosteroids or an implanted spinal cord stimulator that is applied to the dorsal columns or an analgesic pump, but often even these measures are ineffective. Fentanyl transcutaneous patches may be tried. Spasticity and flexor spasms may be troublesome; oral baclofen, diazepam, or tizanidine may provide some relief. In permanent spastic paraplegia with severe stiffness and adductor and flexor spasms of the legs, intrathecal baclofen, delivered by an automated pump, has also been helpful. The drug is believed to act at the synapses of spinal reflexes (Penn and Kroin). Selective injection of botulinum toxin may provide relief of some spastic deformities and of spasms. One must be alert to the threat of pulmonary embolism from deep-vein thrombi, although the incidence is surprisingly low after the first several months. Physical therapy, muscle reeducation, and the proper use of assistive devices are all important in the rehabilitation of the patient. Recent advances that combine epidural stimulation of the lumbosacral cord with intensive treadmill training have allowed some paraplegic patients to attain standing and some degree of over-ground walking (Angeli et al). Nerve grafting from spinal motor roots above the injury to nerves below and various forms of robotic and cerebral signaling to muscles has been tried.

Radiation Injury of the Spinal Cord Delayed necrosis of the spinal cord and brain are recognized sequela of radiation therapy for tumors in the thorax and neck. Mediastinal irradiation for Hodgkin disease or for other lymphomas had been, in the past, a typical setting for the development of these complications up to decades later. A lower motor neuron syndrome, presumably a result of injury to the gray matter of the spinal cord, may also follow radiation therapy in which the cord was inside the zone of treatment, as described in the following text.

Transient Radiation Myelopathy An “early” type of radiation myelopathy (appearing 3 to 6 months after radiotherapy) is characterized mainly by spontaneous uncomfortable sensations in the extremities. The paresthesias may be evoked by neck flexion (Lhermitte symptom). In one of our patients there was impairment of vibratory and position sense in the legs, but no weakness or signs of spinothalamic tract damage. The sensory abnormalities disappear after a few months and, according to Jones, are

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not followed by the delayed progressive radiation myelopathy described in the following text. The pathology of early and transient radiation myelopathy has not been fully elucidated, but there is a spongy appearance of the white matter with demyelination and depletion of oligodendrocytes.

Delayed Progressive Radiation Myelopathy This is one of the most dreaded complications of radiation therapy. It is a progressive myelopathy that follows, after a variable latent period, the radiation of malignant lesions in the vicinity of the spinal cord. The incidence of this complication is difficult to determine because many patients die of their malignant disease before the myelopathy has fully evolved, but it was in previous eras of delivery of radiation estimated to be between 2 and 3 percent (Palmer). Patients who have undergone hyperthermia as an adjunctive treatment for cancer are particularly vulnerable to radiation myelopathy (Douglas and colleagues). Clinical features  The neurologic disorder first appears 6 months or more after the course of radiation therapy, usually between 12 and 15 months (latent periods as long as 60 months or longer have been reported). The onset is insidious, usually with sensory symptoms—paresthesias and dysesthesias of the feet or a Lhermitte phenomenon, and similar symptoms in the hands in cases of cervical cord damage. Weakness of one or both legs usually follows sensory loss. Initially, local pain is absent, in distinction to the effects of spinal metastases. In some cases, the sensory abnormalities are transitory as in the syndrome described above; more often, additional signs make their appearance and progress, at first rapidly and then more slowly and irregularly, over a period of several weeks or months, with involvement of the corticospinal and spinothalamic pathways. The neurologic disturbance may take the form of a Brown-Séquard syndrome, but with progression, it is usually overtaken by a transverse myelopathy. Yet another myelopathic radiation syndrome has been described, namely, a slowly evolving amyotrophy, with weakness and atrophy of muscles and areflexia in parts of the body supplied by anterior horn cells of the radiated spinal segments (Reagan and coworkers). Most patients with this form of the disease die within a year of onset. This syndrome is reminiscent of the delayed motor neuron myelopathy following electrical or lightning injury of uncertain nature, described in the next section. There is also an unusual paraneoplastic variety of poliomyelopathy and an even less common necrotic myelopathy mentioned in the following text and in Chap. 30. The cerebrospinal fluid (CSF) in delayed progressive radiation transverse myelopathy is normal except for a slight elevation of protein content in some cases. MRI of the affected segments of cord demonstrates abnormal signal intensity, decreased in T1-weighted and increased in T2-weighted images. Early in the course of the myelopathy, the cord may be swollen, and there is often heterogeneous enhancement with gadolinium infusion. The location of the lesion corresponds to the irradiated portal, which can be identified by the radiation effect on the marrow of the overlying vertebral bodies. The spinal cord lesion tends to be more extensive in rostral–caudal dimension than the

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usual vascular or demyelinative myelopathy. These are important points to establish because a mistaken diagnosis of intraspinal tumor or of a dural arteriovenous fistula may lead to an unnecessary operation or further irradiation. Pathologic findings Corresponding with the level of the radiated area and extending over several segments, there is an irregular zone of coagulation necrosis involving both white and gray matter, the former to a greater extent than the latter. Varying degrees of secondary degeneration are seen in the ascending and descending tracts. Vascular changes—necrosis of arterioles or hyaline thickening of their walls and thrombotic occlusion of their lumens—are prominent in the most severely damaged portions of the cord. Most neuropathologists have attributed the parenchymal lesion to the blood vessel changes; others believe that the degree of vascular change is insufficient to explain the necrosis (Malamud et al; Burns et al). Certainly, the most severe changes in the cord are consistent with infarction, but the insidious onset and slow, steady progression of the disorder and the coagulative nature of the necrosis would then have to be explained by a steady succession of vascular occlusions. Exceptional instances in which a transverse myelopathy has developed within a few hours of radiation treatment (as described by Reagan et al), are more readily explained by thrombotic occlusion of a large spinal artery. Neurologists associated with cancer treatment centers are sometimes confronted with a patient who exhibits the late development (up to 10 to 15 years after radiation) of a slowly progressive sensorimotor paralysis of only one limb (motor weakness predominates) or one region of the body. This usually represents damage in the peripheral nervous system. Examples that we have encountered are multiple cranial neuropathies after radiation of nasopharyngeal tumors, cervical and especially brachial neuropathies after laryngeal and breast cancers, and lumbosacral plexopathies and cauda equina damage with pelvic radiation. These are discussed further in Chap. 43, on diseases of the peripheral nerves. Treatment and prevention Tolerance of the adult human spinal cord to radiation, taking into account the volume of tissue irradiated, the duration of the irradiation, and the total dose (Kagan and colleagues). Radiation injury could be avoided if the total dose was kept below 6,000 cGy and was given over a period of 30 to 70 days, provided that each daily fraction did not exceed 200 cGy and the weekly dose was not in excess of 900 cGy. Forewarned with this knowledge, radiation therapy specialists have the impression that the incidence of this complication is decreasing, especially as newer stereotactic methods of delivering radiation have been introduced. If the underlying neoplasm is likely to be imminently fatal, palliative radiation can exceed these limits. Several case reports remark on temporary improvement in neurologic function after the administration of glucocorticoids for radiation myelopathy. This therapy may be tried because, in some patients, it appears to arrest the process short of complete destruction of all sensory and motor tracts. Claims have also been made of regression of early symptoms in response to the administration of

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heparin split products and of hyperbaric oxygen, but benefit from these and other putative neuronal sparing agents have not been confirmed.

Spinal Cord Injury Caused by Electric Currents and Lightning Among acute physical injuries to the spinal cord, those caused by electric currents and lightning, despite their rarity, are of interest because they produce unusual clinical syndromes. Electrical forces can also injure the brain and peripheral nerves; these effects are noted only briefly here because they are infrequent. It is the spinal cord that is most consistently and severely damaged.

Electrical Injuries In the United States, inadvertent contact with electric current causes approximately 1,000 deaths annually and many more nonfatal but serious injuries. About one-third of fatal accidents result from contact with household currents; in these and other instances, the body serves as a conduit to ground and ground fault protectors (interrupters) in modern electrical wiring are meant to limit the duration of exposure. The factor that governs the damage to the nervous system is the amount of current, or amperage, with which the victim has contact, not simply the voltage, as is generally believed. In any particular case, the duration of contact with the current and the resistance offered by the skin to current (greatly reduced if the skin is moist or a body part is immersed in water) are of importance. The physics of electrical injuries is much more complex than these brief remarks indicate (for a full discussion, see the reviews by Panse and by Winkelman). Any part of the peripheral or central nervous system (CNS) may be injured by electric currents and lightning. The effects may be immediate, which is understandable, but of greater interest are the instances of neurologic damage that occur after a delay of 1 day to 6 weeks (1 week on average) and a rarer syndrome (the existence of which has been disputed) of anterior horn cell damage that arises after many years. The immediate effects are the result of direct heating of nervous tissue, but the pathogenesis of the ostensible delayed effects is not understood. They have been attributed to vascular occlusive changes induced by the electric current, a mechanism proposed to underlie the similar delayed effects of radiation therapy (see earlier). However, the latent period is measured in many months or a few years rather than in days and the course is more often progressive than self-limited. Moreover, the few postmortem studies of myelopathy as a consequence of electrical injury have disclosed widespread demyelination of long tracts, to the point of tissue necrosis in some segments, and relative sparing of the gray matter, but no abnormalities of the blood vessels. There may also be spinal fracture from vigorous muscle contraction. An extraordinary syndrome of focal muscular atrophy occurring with a delay of weeks to years after an electric shock has been described under the title spinal atrophic paralysis (Panse). It occurs when the path of the current, usually of low voltage, is from arm to arm (across the

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cervical cord) or from an arm to leg. It’s nature (and existence) has also been debated. When the head is one of the contact points, the patient becomes unconscious or suffers tinnitus, deafness, or headache for a short period following the injury. Pain and paresthesias occur immediately in the involved limb, but these symptoms are transient. Mild weakness, also unilateral, is immediate, followed in several weeks or months by muscle wasting, most often taking the form of segmental muscular atrophy. The syndrome simulates a regional form of amyotrophic lateral sclerosis or transverse myelopathy (most patients have some degree of weakness and spasticity of the legs). However, we have encountered cases of asymmetric and profound atrophic weakness of the arms that began almost two decades after the shock and progressed over many years without long tract signs, both with presumed diagnosis of amyotrophic lateral sclerosis. In contrast to injuries caused by high current, which affects mainly the spinal white matter, it is the gray matter that is injured in cases of spinal atrophic paralysis, at least as judged from the clinical effects. In a small number of surviving patients, after an asymptomatic interval of days to months, there has been an apoplectic onset of hemiplegia with or without aphasia or a striatal or brainstem syndrome, presumably because of thrombotic occlusion of cerebral vessels with infarction of tissue, but this condition has not been well studied. The separate issue of the relationship of electrical shock exposure and the later development of typical ALS is controversial. Most series are hampered by retrospective acquisition of data about the shock. Although we have encountered a few remarkable instances of this association, including two, who developed severe amyotrophy of the limb that was in contact with the electrical source many years before, as alluded to above, a relationship to typical motor neuron disease has been considered coincidental.

Lightning Injuries The factors involved in injuries from lightning are less welldefined than those from electric currents, but the effects are much the same. Direct strikes are often fatal; nearby strikes may produce neurologic damage. Topographic prominences such as trees, hills, and towers are struck preferentially, so these should be avoided; a person caught in the open has been advised to curl up on the ground, lying on one side with legs close together. Arborescent red lines or burns on the skin indicate the point of contact of the energy generated by direct or nearby lightning. The path through the body can be approximately deduced from the clinical sequelae. Death is a result of ventricular fibrillation or of the effects of intense desiccating heat on the brain. Lightning that strikes the head is particularly dangerous, proving fatal in 30 percent of cases. Most persons struck by lightning are initially unconscious, irrespective of where they are struck. In those who survive, consciousness is usually regained rapidly and completely. Rarely, unconsciousness or an agitated-confusional state may persist for a week or two. Persistent seizures are surprisingly rare. There may be a disturbance of sensorimotor function of a limb or all the limbs, which may be pale and

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cold or cyanotic. As a rule, these signs are also evanescent, but in some instances, they persist, or an atrophic paralysis of a limb or part of a limb makes its appearance after a symptom-free interval of several months, as in the case of electrical injury. A severe, predominantly motor polyneuropathy has been reported after a variable interval, and while it bears similarities to the motor neuron disorder ostensibly associated with electrical injury discussed in the section above, there is a more persuasive relationship to the less common event of lightning. There are also a few cases on record of recovery from generalized polyneuropathy after lightning injury, but our experience with one case was of profound generalized axonal damage with little recovery (see Chap. 43).

Myelopathy Following Spinal Anesthesia This subject is introduced here with the other forms of spinal cord injury for want of a better way to categorize it. A transient and often asymmetric paraparesis is known to occur following prolonged spinal anesthesia, but this is probably the result of a temporary effect of the injected agents on the cauda equina roots (see Chap. 43). A more serious and permanent injury has been caused by inadvertent injection of anesthetic directly into the conus medullaris (Hamandi et al; Wilkinson et al). The patient reports leg weakness and numbness on one side immediately with the injection or upon awakening if sedation has been used. The MRI reveals an eccentrically placed traumatic lesion within the caudal spinal cord. Although this complication is rare, it has occurred even when experienced anesthesiologists perform the procedure; misidentification of the L3-L4 spinal interspace has been cited as the problem. Flat-tipped needles are considered to be as likely to cause injury to the conus as are ones with sharp beveled tips. In the past arachnoiditis from irritative contrast agents, no longer used to any great extent, caused myelopathy (see Chap. 10).

INFLAMMATORY AND INFECTIOUS MYELOPATHIES (MYELITIS) In the nineteenth century, almost every disease of the spinal cord was labeled myelitis. Morton Prince, writing in Dercum’s Textbook of Nervous Diseases in 1895, referred to traumatic myelitis, compressive myelitis, and so on, obviously giving a rather imprecise meaning to the term. Gradually, knowledge of neuropathology advanced, and one disease after another was removed from this category until only the verifiably inflammatory ones remained. The spinal cord is known to be the locus of a limited number of infective and noninfective inflammatory processes, some causing selective destruction of neurons, others affecting primarily white matter (tracts), and yet another group involving the meninges and white matter or leading to a necrosis of both gray and white matter. Other special terms, qualifying myelitis, are used to indicate more precisely the distribution of the process: if confined to gray matter, the proper expression is poliomyelitis; if to white

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matter, leukomyelitis. If approximately the whole cross-sectional area of the cord is involved at one or more levels, the process is called transverse myelitis (although the term is still used more broadly for many myelitides); if the lesions are multiple and widespread over a long vertical extent, the modifying adjectives diffuse or disseminated are used and longitudinally extensive myelopathy has been introduced to denote a form of necrotic myelopathy that is associated in most cases with circulating autoantibodies (see Chap. 35). The term meningomyelitis refers to combined inflammation of meninges and spinal cord and meningoradiculitis to combined meningeal and root involvement. An inflammatory process limited to the spinal dura is called pachymeningitis, and if infected material collects in the epidural or subdural space, it is called epidural or subdural spinal abscess or granuloma, as the case may be. The adjectives acute, subacute, and chronic denote the tempo of evolution of myelitic symptoms—namely, more or less within days, 2 to 6 weeks, or more than 6 weeks, respectively. The main causes of myelitis are listed below.

Classification of Inflammatory Diseases of the Spinal Cord I. Viral myelitis (Chap. 32) A. Enteroviruses (groups A and B coxsackievirus, poliomyelitis, others) B. Herpes zoster C. Myelitis of HIV infection D. Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex E. Rabies F. Arboviruses-Flaviviruses (Japanese, West Nile, etc.) G. HTLV-I (human T-cell lymphotropic virus type I; tropical spastic paraparesis) II. Myelitis secondary to bacterial, fungal, parasitic, and primary granulomatous diseases of the meninges and spinal cord (Chap. 31) A. Mycoplasma pneumoniae B. Lyme disease C. Pyogenic myelitis 1. Acute epidural abscess and granuloma 2. Abscess of spinal cord D. Tuberculous myelitis (Chap. 31) 1. Pott disease of the spine with secondary cord compression 2. Tuberculous meningomyelitis 3. Tuberculoma of spinal cord E. Parasitic and fungal infections producing epidural granuloma, localized meningitis, or meningomyelitis and abscess, especially certain forms of schistosomiasis (Chap. 32) F. Syphilitic myelitis (Chap. 31) 1. Chronic meningoradiculitis (tabes dorsalis) 2. Chronic meningomyelitis 3. Meningovascular syphilis 4. Gummatous meningitis including chronic spinal pachymeningitis G. Sarcoid myelitis (Chap. 31)

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III. Myelitis of noninfectious inflammatory type (Chap. 35) A. Postinfectious and postvaccinal myelitis B. Acute and chronic relapsing or progressive multiple sclerosis (MS) C. Neuromyelitis optica spectrum disorder (NMOSD, subacute necrotizing myelitis, anti-myelin oligodendrocyte glycoprotein (MOG), Devic disease; longitudinally extensive myelopathy) due to antibodies against aquaporin (Chap. 35) D. Myelopathy with lupus or other forms of connective tissue disease and antiphospholipid antibody E. Paraneoplastic myelopathy and poliomyelitis (Chap. 30) From this outline, it is evident that many different and totally unrelated diseases are under consideration and that a general description cannot possibly encompass such a diversity of processes. Overall, myelitis caused by multiple sclerosis and postinfectious processes is the most common cause in practice. This was the case in several series (de Seze and colleagues (2001a); Nowak and coworkers). Many of the myelitides are considered elsewhere in this volume in relation to the diseases of which they are a part, mainly multiple sclerosis. Here it is only necessary to comment on the principal categories and to describe a few of the common subtypes.

Viral Myelitis (See Also Chap. 32) The enteroviruses, of which Coxsackie and poliomyelitis are examples, herpes zoster, arboviruses such as West Nile and the equine encephalitic viruses, and HIV are the important members of this category. The enteroviruses, in particular, have an affinity for neurons of the anterior horns of the spinal cord and the motor nuclei of the brainstem (i.e., they can be neuronotropic and cause a disease that can be generically termed poliomyelitis), and herpes zoster virus has a clear affinity for the dorsal root ganglia that may spread to the adjacent cord; hence the disturbances of function are in terms of motor and sensory neurons, respectively, not of spinal tracts. We have cared for several patients who have had destruction of anterior horn cells as a consequence of an enterovirus other than poliomyelitis virus (see further on). West Nile virus shows the same proclivity to damage anterior horn cells. The onset of these conditions is acute and takes the form of a febrile meningomyelitis. Although there are fever, systemic symptoms, and sometimes, cutaneous features (in the case of zoster), it is the nervous system disorder that is most significant. The patient suffers the effects of motor neuron infection, and some degree of improvement nearly always follows as neurons recover. Later in life, possibly as the neuronal loss of aging reduces the number of anterior horns, there may be an apparent increased loss of strength in muscles originally weakened by poliomyelitis (“postpolio” syndrome). Relatively infrequent examples of more or less transverse myelitis caused by herpes simplex virus (HSV types 1 and 2), varicella-zoster virus (VZV), CMV, EBV, any of the hepatitis viruses, and SV70 virus (causing epidemic conjunctivitis) have been reported, some in patients with immunodeficiency states, mainly AIDS. The situation is

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complex clinically, as most of these agents may also elicit a postinfectious variety of myelitis, described further on in this chapter and in Chaps. 32 and 35. HSV type 2 and CMV infections may also produce an acute lumbosacral radiculitis with urinary retention (Elsberg syndrome). A few cases of zoster myelitis have shown evidence of extensive inflammatory necrosis of the spinal cord with involvement of sensory and motor tracts, causing acute paraplegic and tetraplegic transverse syndromes. Pleocytosis in the CSF and isolation of the viral DNA from the CSF confirm the diagnosis of a primary viral infection, as discussed in Chap. 32. There are other rare forms of poliomyelitic reactions of unknown, possibly viral etiology. A rare syndrome in children of acute flaccid myelitis has evinced interest, but circumstantial evidence for enterovirus D68 etiology has been found (Vogt et al). Most children have had mild respiratory syndrome or fever days before the neurological disorder, leading to the reasonable assumption of a viral cause. Support for this is found in antibodies in the CSF directed at enteroviruses and in cases that appear in temporal outbreaks in some years. One such condition presents as acute febrile or afebrile meningomyelitis and leaves all the limbs paralyzed and flaccid, sparing the brainstem and affecting the diaphragm to a variable extent. Several such patients have harbored cancer or Hodgkin disease, and the pathology was more typical of a poliomyelitic viral infection rather than of the usual paraneoplastic syndromes (Chap. 30). Involvement of the white matter with sensory and motor paralysis below the level of a lesion has also been reported in so-called dumb rabies (in contrast to the usual form of “mad” or “furious” rabies encephalitis), and in an infection transmitted by the bite of a monkey, called the B virus. These are decidedly rare. More common are the viral myelopathy of HIV-AIDS and of HTLV-I infection. With these exceptions, one may say that myelitis that expresses itself mainly by dysfunction of motor and sensory tracts will usually prove not to be viral in origin but rather to one of the disease processes in category III (noninfectious, inflammatory) of the preceding classification, for example, multiple sclerosis. The unique myelopathies of HIV and of human HTLV infections are described in the following text.

Vacuolar Myelopathy with HIV (See Also “HIV Myelopathy” in Chap. 32) As the neurology of HIV infection has been elucidated, the clinical and pathologic characteristics of the associated myelopathy have been studied. The frequency of this condition is impressive—it was present in 20 of 89 successive cases of AIDS in which a postmortem examination was performed (Petito and colleagues). Often, the clinical symptoms and signs of spinal cord disease are obscured by a neuropathy or one or more of the cerebral disorders that complicate HIV infection directly or due to an opportunistic infection (CMV, toxoplasmosis, progressive multifocal leukoencephalopathy [PML]). In 5 cases of severe vacuolar myelopathy in the aforementioned series, there was leg or leg and arm weakness, often asymmetrical and developing over a period of weeks, to which the signs of sensory tract involvement and sphincteric disorder were added. A sensory ataxia has also been a common early feature in

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our experience. The CSF shows a small number of lymphocytes, a slight elevation of protein, and, occasionally, bizarre giant cells. The white matter of the spinal cord is vacuolated, by which is meant a ballooning within myelin sheaths of the long tracts. The changes are most severe in thoracic segments, with the posterior and lateral columns are affected diffusely. Axons are involved to a lesser degree, and lipidladen macrophages are present in abundance. Similar vacuolar lesions may be seen in the brain in some cases. The vacuolar pathology in the white matter of the spinal cord resembles subacute combined degeneration, but levels of vitamin B12 and folic acid are normal. (A similar lesion was found in one of our patients with myelopathy from chronic lupus erythematosus.) The antiretroviral drugs that slow the progress of HIV, with the exception of a few cases, seem to have little effect on the myelopathy and one can only resort to symptomatic treatment of spasticity.

Tropical Spastic Paraparesis Caused by Human T-Cell Lymphotropic Virus Type I (HTLV-I) This disease was brought to the attention of neurologists 50 years ago through the observations and writings of Cruickshank. However, it is only more recently that a chronic infective-inflammatory disease of the spinal cord caused by the retrovirus HTLV-I has been discovered and its connection to what had been called tropical myelitis appreciated. The implications of this discovery are potentially broad and extend even to the demyelinative and possibly the degenerative diseases. Spinal cord disease of this type has been reported from the Caribbean islands, southeastern United States, southern Japan, South America, and Africa. The clinical picture is one of a slowly progressive paraparesis with increased tendon reflexes and Babinski signs; disorder of sphincteric control is usually an early feature, but symmetric paresthesias, reduced vibratory and position senses and ataxia follow over several months or years. A few patients have had an associated polyneuropathy, as in Cruickshank’s early cases. The upper extremities are usually spared (except for lively tendon reflexes), as are cerebral and brainstem functions. The CSF contains small numbers of T-lymphocytes (10 to 50/mm3), normal concentrations of protein and glucose, and an increased content of immunoglobulin (Ig) G with antibodies to HTLV-I. The diagnosis is confirmed by the detection in the serum of the antibodies to the virus. Thinness of the spinal cord is evident on MRI and subcortical cerebral white matter lesions may be seen as well. Neuropathologic study has documented an inflammatory myelitis with focal spongiform, demyelinative, and necrotic lesions, perivascular and meningeal infiltrates of inflammatory cells, and focal destruction of gray matter. The posterior columns and corticospinal tracts are the main sites of disease, most evident in the thoracic cord. Because of slow evolution, the clinical picture can easily be confused with that of progressive spastic paraplegia of the heredofamilial variety, sporadic motor neuron disease, or the chronic phase of multiple sclerosis. There are

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also similarities with the AIDS myelopathy described earlier, but the other features of HIV infection are absent. Infusion of the anti-CCR4 T-cell antibody used in the treatment of T-cell leukemia caused by the same virus implicated in the myelopathy, mogamulizumab, has been shown in preliminary studies to reduce viral load and improve spasticity and motor function (Sato et al).

Myelitis Secondary to Bacterial, Fungal, Parasitic, and Granulomatous Diseases (See Also Chap. 31) With few exceptions, this class of spinal cord disease seldom offers difficulty in diagnosis. In most cases, an inflammatory reaction in the meninges, reflected in CSF pleocytosis, is only one manifestation of a generalized (systemic) disease process. The spinal lesion may involve primarily the pia-arachnoid (leptomeningitis), the dura (pachymeningitis), or the epidural space, for example, taking the form of a compressive abscess or granuloma; or it may reside in the adjacent spinal bones. In some acute forms, both the spinal cord and meninges are simultaneously affected, or the cord lesions may predominate. Chronic spinal meningitis may involve the pial arteries or veins; and as the inflamed vessels become thrombosed, infarction (myelomalacia) of the spinal cord results. Chronic meningeal inflammation may provoke a progressive constrictive pial fibrosis (a type of spinal arachnoiditis) that virtually strangulates the spinal cord. In certain cases, spinal roots become progressively damaged, especially the lumbosacral ones, which have a long meningeal exposure. Posterior roots, which enter the subarachnoid space near arachnoidal villi (where CSF is resorbed), tend to suffer greater injury than anterior ones (as happens in tabes dorsalis). Interestingly, there are cases of chronic cerebrospinal meningitis that remain entirely without symptoms until the spinal cord or roots become involved. The infrequent but curious bacterial myelitis associated with M. pneumoniae has come to be viewed as a postinfectious immune disease, as discussed in Chap. 31. However, portions of the DNA from this organism have been found in the spinal fluid early in the course of illness in some cases, suggesting the possibility of a direct bacterial infection of the spinal cord. It is not known whether antibiotic treatment alters the course of the illness. Syphilitic myelitis in its several forms, including tabes dorsalis, is also discussed in Chap. 31. Bacterial abscess of the spinal cord is rare, especially in comparison to an epidural spinal abscess, and it is recognized by MRI. At times, it stands as a single pyogenic metastasis from a distant infection and subsequent bacteremia, but more often, there has been spread from a contiguous infected surgical site or a fistulous connection with a superficial paraspinal abscess. Vertebral osteomyelitis is addressed further on in relation to an epidural abscess.

Sarcoid Myelitis (See Also Sarcoidosis in Chap. 31) Sarcoid granulomas may occur as one or more intramedullary spinal cord masses, as in the cases reported by Levivier and colleagues. In our experience, the granulomatous lesion, which may be focal or multifocal, simulates demyelinative disease with respect to its tendency to relapse and

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remit and in its response to corticosteroids. An asymmetrical ascending paraparesis and bladder disturbance have been the main features in our patients. Usually, there is evidence of systemic sarcoidosis and the CSF is abnormal (increase in cells and protein; glucose usually normal), but we have encountered a few instances of sarcoid restricted to the spinal cord before it was evident in the mediastinum (i.e., thoracic CT failing to demonstrate hilar adenopathy or diffuse parenchymal lung disease). Elevation of the spinal fluid IgG concentration and oligoclonal bands may be found, but they are not consistent features; often, there are activated histiocytes in the CSF. The use of angiotensin-converting enzyme levels in the CSF to distinguish sarcoidosis from multiple sclerosis suffers from the lack of normative values for this test, but it is reported in some small series to be elevated in two-thirds of patients with CNS sarcoid. The MRI is abnormal and the conus or other portions of the cord have intramedullary lesions. The most characteristic finding, however, is a multifocal-subpial nodular enhancement of the meninges adjacent to a lesion within the cord or nerve roots—a picture that resembles neoplastic meningeal infiltration. The diagnosis can be confirmed by mediastinal lymph node biopsy or by the less desirable method of biopsy of the spinal meninges, spinal roots and affected subpial cord. On occasion, other rare granulomatous conditions cause an intrinsic or, more often, extrinsic compressive myelopathy; these include brucellosis, xanthogranulomatosis, and eosinophilic granuloma. The diagnosis may be suspected if the systemic disease is apparent at the time, but usually, only the histology of a surgical specimen reveals the underlying process.

Syphilitic Meningomyelitis (See also Chap. 31) At one time very prevalent, these cases are now rarely seen in high- and moderate income countries. As in multiple sclerosis, the degree of ataxia and spastic weakness is variable. A few patients have an almost pure state of spastic weakness of the legs, requiring differentiation from motor system disease and familial spastic paraplegia. Such a syndrome, formerly called Erb spastic paraplegia and attributed to meningovascular syphilis, is now recognized as being nonspecific and more often caused by demyelinating disease. In a minority of chronic syphilitic patients, sensory ataxia and other posterior column signs predominate (i.e., simulating tables dorsalis). Ventral roots are involved in chronic meningeal inflammation, giving rise to signs of segmental amyotrophy—hence the term syphilitic amyotrophy of the upper extremities with spastic paraplegia. Confirmation of this now infrequent diagnosis depends on finding a lymphocytic pleocytosis, an elevated protein and gamma globulin, and a positive serologic or fluorescent treponemal antigen reaction in the CSF. Other aspects of this disease and treatment are discussed under “Spinal Syphilis” in Chap. 31. Tabes dorsalis is, of course, another important but separable form of syphilitic myelitis, as just noted.

Spinal Epidural Abscess This condition is worthy of emphasis because the diagnosis is often missed or mistaken for another disease, sometimes

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with disastrous results. Children or adults may be affected. Infection of the epidural space has a wide variety of sources. Staphylococcus aureus is the most frequent etiologic agent, equally distributed between methicillin resistant and methicillin sensitive types, followed in frequency by streptococci, gram-negative bacilli, and anaerobic organisms. An injury to the back, often trivial at the time, furunculosis or other skin or wound infection, or bacteremia may permit seeding of the spinal epidural space or of a vertebral body. This gives rise to osteomyelitis with extension to the epidural space. Occasionally, the spread is from an infected disc. Diabetes and recently treated cancer may be risk factors. Another source is bacteremia following the use of nonsterile needles or the injection of contaminated drugs. The thoracic spine is the most frequently affected, perhaps simply because of its greater length compared to the other portions of the spine. Organisms may be introduced into the epidural space during spinal surgery or rarely via a lumbar puncture needle during epidural or spinal anesthesia or from epidural injections of steroid or other therapeutic agents; the localization is then over the lumbar and sacral roots. In these cases of cauda equina epidural abscess, back pain may be severe but neurologic symptomatology is minimal unless the infection extends upward to the upper lumbar and thoracic segments of the spinal cord. It must be acknowledged that some, even fulminant, cases have no clear source in the body for the bacterial abscess, but most of these instances occur in patients who are diabetic or have cancer, even if the latter has been adequately treated. At first, the purulent process in the cervical or thoracic region is accompanied only by low-grade fever and aching local back pain, usually intense, in most cases, followed within a day or several days by radicular pain. Headache and nuchal rigidity are sometimes present; more often, there are just persistent pain and a disinclination to move the back. After several days, there may be a rapidly progressive paraparesis associated with sensory loss in the lower parts of the body and sphincteric paralysis. In some cases, the evolution of myelopathy is more gradual. Examination discloses the signs of a complete or partial transverse cord lesion, including, at times, the elements of spinal shock if paralysis has evolved rapidly. Percussion of the spine usually elicits tenderness over the site of the infection. A distinction is often made between this typical acute or subacute form of abscess and a more indolent type that is due to a partially granulomatous lesion over several segments of the spine. This form does not always require surgical treatment, as detailed in the following text. Diagnosis  The diagnosis can usually be ascertained from MRI (Fig. 42-2), but care must be taken to obtain images from levels rostral and caudal enough to detect the infected collection. There may be an enhancement of the margins of the purulent collection after several days. If an abscess is known to be present, lumbar puncture should generally not be performed, however, if the CSF space is inadvertently breached, the CSF usually contains white cells but of surprisingly small number (fewer than 100/mm3), both polymorphonuclear leukocytes and lymphocytes, unless of course, the needle penetrates the abscess, in which case pus is obtained. The CSF protein

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Figure 42-2.  MRI of spinal epidural abscess compressing the dorsolateral cervical spinal cord. Sagittal (left) and axial (right) T1 gadoliniumenhanced images show the peripherally enhancing pyogenic collection (arrows), which extends over several vertebral segments.

content is typically high (100–400 mg/100 mL or more), but the glucose is normal. Elevation of the sedimentation rate, C-reactive protein, and peripheral neutrophilic leukocytosis are additional indicators of the diagnosis. The last of these tests is abnormal in two-thirds of cases. Blood cultures demonstrate the organism in a similar proportion. Cultures from the CSF are infrequently positive. The decades old series reported by Baker and colleagues is still a valuable reference (see also Darouiche; Ropper and Ropper). The differential diagnosis includes other forms of spinal cord compression and, in cases with areflexic spinal shock, tetraparesis and respiratory failure, Guillain-Barré syndrome. Treatment  The foregoing clinical findings and signs of a myelopathy generally call for MRI to be performed relatively quickly or CT myelography, if MRI is not possible, to demonstrate the mass of the abscess and to determine its level. If not treated surgically by laminectomy and drainage before the onset of paralysis, the spinal cord lesion, which is probably partly a result of venous ischemia, becomes more or less irreversible. Broad-spectrum antibiotics in large doses must be given initially and the choice of treatment is then refined based on cultures from the abscess or the blood, or on a presumed source of bacteria, usually found to be staphylococcus. When osteomyelitis of a vertebral body is the primary abnormality, the epidural extension may implicate only a few spinal sensory and motor roots, leaving long tracts and other intramedullary structures intact. In some cases with cervical epidural abscesses, stiff neck, fever, and deltoidbiceps weakness are the main neurologic abnormalities.

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Having emphasized the urgency of treatment, there are instances of small epidural abscesses that do not compress the cord and are limited to one or two levels for which it has been possible for some patients to avoid surgery by administering antibiotics alone. Also, lumbar epidural abscess and cauda equina compression without neurologic signs may be, in some cases, treated with antibiotics, although many surgeons favor drainage, which must be undertaken in any case if osteomyelitis develops. Antibiotics are continued for several weeks, and the patient should be examined at regular intervals and have sequential MRI scans of the affected region. Even after apparently successful drainage and antibiotic treatment of an epidural abscess, there may be a slowly progressive and then static syndrome of partial spinal cord compression. This is the result of formation of a fibrous and granulomatous reaction at the operative site. Distinguishing this sterile inflammatory mass from residual epidural abscess is difficult, even with enhanced MRI, but persistent fever, leukocytosis, and an elevated sedimentation rate, C-reactive and peripheral white blood cell count suggest that surgical drainage of the abscess was incomplete. Spinal subdural abscess due to bacterial infections also occur and, clinically, are virtually indistinguishable from epidural ones on clinical grounds. The MRI will usually clarify the situation, but a clue is provided by the CT myelogram, in which the subdural lesion has a less sharp margin and usually a greater vertical extent than the usual epidural abscess. The epidural and subdural infections, if they smolder owing to delayed diagnosis or inadequate therapy, may also evolve into a local chronic adhesive meningomyelitis.

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Subacute pyogenic infections and granulomatous infections (tuberculous, fungal) may also arise in the spinal epidural space, as noted further on.

Vertebral Bacterial Osteomyelitis This process is presented in juxtaposition to epidural abscess, with which it is closely aligned. As with other forms of osteomyelitis, vertebral infection is typically due to hematogenous implantation of bacteria during episodes of bacteremia, or it is associated with the exogenous introduction of bacteria during spinal surgery, particularly if catheters or other devices, including for spinal stabilization, are incorporated. In the case of postsurgical infection, coagulase-negative staphylococci or propionibacterium are almost always implicated, whereas with bacteremia, a number of low-virulence organisms, including staphylococcus, are found and multiple organisms may be involved. The source of bacteremia may be urinary infection, endocarditis, or intravenous drug abuse, but many affected individuals also have diabetes, are immunosuppressed, have cancer, or are receiving dialysis for renal failure. In the group of immunocompromised patients, unusual or endemic organisms such as Brucella may be found. However, in almost half of the patients who have not had surgery, no source is identified. Approximately one-fifth of cases have an associated epidural abscess, as discussed above. This is often indicated by an increase in local back pain or extremely severe pain from the onset. The lumbar spine is the region most affected (in contrast to the frequent thoracic distribution of epidural abscess). The typical presentation is relatively nondescript with back pain, elevated white blood cell count, and C-reactive protein level. Fever, however, is inconsistent. Several types of imaging studies may be used to demonstrate the infection; however, MRI more dependably than CT shows edema within the bone marrow, and if there is the destruction of the disc adjacent to an effective vertebral body, infection is almost certain. Technetium bone scans were popular for the demonstration of osteomyelitis in general, but the findings may be nonspecific. A well-known adage is that neoplasms affecting the vertebral body do not cross the disc space, whereas infections do so. A point of contention has been the need for biopsy of the affected bone when blood cultures are negative, and no obvious source of infection in the body can be found. This procedure is generally suggested, although an extension of the infection from the vertebral body to the paravertebral or epidural spaces may also be performed under CT guidance. Initiating therapy with oral fluoroquinolones, with or without rifampin, has been suggested as a broad approach while the specific infecting bacteria are identified. Therapy is generally continued for at least 4 to 6 weeks, if not longer, but no clear guidance is available on the appropriate duration. Surgical removal of infected bone is generally not undertaken unless the osteomyelitis is the result of implanted hardware during previous spinal surgery. Almost invariably, this hardware must be removed. Surveillance for persistent infection after treatment is probably appropriate, but the MRI has not proven useful for this purpose.

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Inflammatory markers in the blood are apparently more dependable. A thorough review of this subject can be found in the clinical practice article by Zimmerli.

Spinal Cord Abscess Purulent collections within the substance of the cord were first described by Hart in 1830, and although it is rare, 73 cases had been reported by 1994 (Candon and Frerebeau). In some instances, the patient was known to have had a systemic bacterial infection, septicemia, or endocarditis; in others, there was a contiguous abscess in the skin or subcutaneous tissues with a fistula to the spinal cord through an intervertebral foramen. Spinal cord abscess is a rare complication of spinal dysraphism or of a developmentally open dorsal fistulous tract. The symptoms are indistinguishable from those of epidural abscess, namely, spinal and radicular pain followed by sensory and motor paralysis; the CSF findings are also the same. described a patient Cases have been described in which surgical drainage of an encapsulated intramedullary abscess led to recovery (Woltman and Adson), including in a case caused by Listeria monocytogenes, which was successfully drained and the meningeal infection suppressed by ampicillin and chloramphenicol (Morrison et al). There was no way to be certain of this diagnosis prior to the availability of MRI.

Tuberculous Spinal Osteomyelitis (Pott Disease) Tuberculous osteomyelitis of the spine with kyphosis (Pott disease) is well known in regions of endemic tuberculosis. Children and young adults are most often affected. The osteomyelitis is the result of reactivation of tuberculosis at a site previously established by hematogenous spread. An infectious endarteritis causes bone necrosis and collapse of a thoracic or upper lumbar (less often cervical) vertebral body resulting in a characteristic angulated kyphotic deformity (Fig. 42-3); any degree of additional rotary instability allows the emergence of a gibbus deformity. Most patients have some active tuberculous infection as evidenced by fever, night sweats, and other constitutional symptoms; the sedimentation rate is invariably elevated, but the degree may be slight. A compressive myelopathy occurs in some cases as a result of the spinal deformity, but it is infrequent and an epidural tuberculous abscess is a more common cause of cord compression (see in the following text). What is surprising to us about Pott disease is the excellent result that may be obtained by external stabilization of the spine and long-term antituberculous medication. A recent young patient of ours was saved from an operation by the intercession by telephone of his father, a physician from India. Although there is some controversy regarding spinal surgery, it is certainly required in the presence of severe deformities or a compressive myelopathy, as noted in Chap. 31.

Tuberculous Myelitis and Epidural Abscess Solitary tuberculoma of the spinal cord as part of a generalized infection is a rarity. More often, pus or caseous granulation tissue extrudes from an infected vertebra and gives rise to an epidural compression of the cord (Pott paraplegia, as distinct from Pott disease). Occasionally tuberculous meningitis may result in pial arteritis and spinal cord infarction. The paraplegia may appear before

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gray and white matter, with ova in arteries and veins leading to vascular obstruction and ischemia (Scrimgeour and Gajdusek). Less often, a localized granuloma gives rise to a cord syndrome, and rarely, the disease takes the form of acute transverse myelitis with massive necrosis of cord tissue (Queiroz et al). A pruritic “swimmer’s itch” at the site of entry of the parasite is reported by many patients in the days prior to the myelopathy. In an often-cited review, the latency between exposure and symptoms was 38 days to several years (Scrimgeour and Gajdusek). We have cared for patients over the years in whom the spinal cord in the low thoracic and lumbar region was infected approximately 3 weeks after they swam in contaminated water during an east African vacation and then returned home to the United States The CSF showed only a slight elevation of protein, but in almost all cases there is a pronounced pleocytosis ranging from 5 to 500 lymphocytes/mm3 and the glucose is normal or minimally reduced. Systemic and CSF eosinophilia are variable so they are not dependable for diagnosis. The diagnosis is confirmed by the finding of elevated titers of antibodies directed against the schistosome in the CSF or blood. There are usually oligoclonal bands of IgG in the CSF as well. The parasite can sometimes be found in biopsies of the rectosigmoid mucosa. The administration of praziquantel arrested the course of the illness, but all but one of our patients was left disabled. Figure 42-3.  Sagittal T2-weighted MRI in Pott tuberculous spine disease. The angulated deformity of the thoracic spine is highly characteristic. (Courtesy of Dr. Randall Edgell, New York University Medical Center.)

the tuberculous meningitis is diagnosed. All these forms of tuberculosis are infrequent in the United States and Western Europe, but we see a new case every several years in a patient who had spent his earlier life in India or Africa. Additional comments can be found in Chap. 31.

Myelitis Caused by Fungus and Parasitic Diseases A wide variety of fungal and parasitic agents may involve the spinal meninges. Such infections are rare, and some do not occur at all in the United States or are limited to certain geographic areas, particularly among immigrant populations. Actinomyces, Blastomyces, Coccidioides, and Aspergillus may invade the spinal epidural space via intervertebral foramina or, by extension, from a vertebral osteomyelitic focus. Cryptococcus, which causes meningoencephalitis and, rarely, a cerebral granuloma, in our experience, seldom causes spinal lesions. Hematogenous metastases to the spinal cord or meninges may occur in both blastomycosis and coccidioidomycosis. Occasionally an echinococcal infection of the posterior mediastinum may extend to the spinal canal (epidural space) via intervertebral foramina and compress the spinal cord. Schistosomiasis (bilharziasis) is a recognized cause of myelitis in Asia, Africa, and South America. The spinal cord is a target for all three common forms of Schistosoma: S. haematobium, S. japonicum, and S. mansoni, but most particularly the last of these (see “Schistosomiasis” in Chap. 31). The schistosomal ova evoke an intense granulomatous myelomeningoradiculitis. The lesions are destructive of

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Noninfectious Inflammatory Myelitis (Multiple Sclerosis and Acute and Subacute Transverse Myelitis) (See Chap. 35) The spinal cord disorders that make up this category take the form of a leukomyelitis based on either demyelination or necrosis of portions of the spinal cord. The critical factor in their pathogenesis appears to be a disordered immune response, in some cases, as a response to an infection, and in others, such as multiple sclerosis, an idiopathic immune disorder. Varied clinical syndromes are produced, and the basic disease is classified in textbooks under headings such as acute transverse myelitis, postinfectious myelitis, postvaccinal myelitis, acute MS, neuromyelitis optica, and necrotizing myelitis. While each of these conditions may affect other parts of the nervous system (most often the optic nerves and brain), often the only manifestations are spinal. The aforementioned myelopathies are characterized by various degrees of inflammatory destruction, usually with lymphocytes congregating around venules in the cord, but they are sufficiently distinct to justify their separate classification. Nonetheless, transitional cases sharing the clinical and pathologic attributes of more than one disease are encountered in any large clinical practice and pathologic collection. The subjects of multiple sclerosis, neuromyelitis optica and other primarily inflammatory myelitides are also discussed in Chap. 35. Some of the main points are recapitulated here.

Postinfectious and Postvaccinal Myelitides (See Also Chap. 35) The characteristic features of these diseases are their temporal relationship following a viral infection or vaccination with the delayed development of neurologic signs

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over the period of a few days, and a monophasic course, that is, a single attack with variable degrees of recovery and no recurrence. These processes may involve the brain as well as the spinal cord, in which case the process is properly designated as acute disseminated encephalomyelitis (ADEM). On the basis of the clinical features of disseminated postinfectious encephalomyelitis and the animal model of experimental allergic encephalomyelitis (EAE), postinfectious myelitis is presumed to be immunologic in nature, reflecting an attack that is more or less confined to spinal cord myelin as described in more detail in Chap. 35. The usual history in these cases is of weakness and numbness of the feet and legs (less often of the hands and arms), which typically develop over a few days, and for the sensory symptoms to ascend from the feet to the trunk. Paresthesias in the feet and legs, which simulate a polyneuropathy, are common early symptoms. Sphincteric disturbances and backache are also common in the first days but as often arise later. A slight asymmetry of the symptoms and signs, a sensory level on the trunk, or a Babinski sign clearly marks the disease as a myelopathy and serves to distinguish it from a rapidly progressive polyneuropathy such as the Guillain-Barré syndrome. Back pain of varying degrees and headache and stiff neck may or may not be present. In about half of cases, the patient can identify a recent infectious illness, usually a mundane upper respiratory syndrome, but the fever has usually abated when the neurologic symptoms begin. The illness evolves over several days, sometimes a single day, or on the other extreme, over 1 or 2 weeks. Despite the term transverse myelitis, fewer than half of cases demonstrate a truly “transverse” involvement of the cord; more often, there is an incomplete corticospinal and spinothalamic syndrome affecting

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one side more than the other. As discussed further on, it is usually not possible to distinguish an acute episode of postinfectious myelitis from the first attack of multiple sclerosis, but a well-defined preceding infection with certain organisms favors the former process. The latency between infection and myelitis is an uncertain matter, but there are well-documented instances in which the febrile episode blends into the neurologic syndrome and others in which the latency has been 2 weeks; considerably longer intervals make the association suspect. Almost invariably, the CSF contains lymphocytes and other mononuclear cells in the range of 10 to 50/mm3 (sometimes higher), with slightly raised protein and normal glucose content. However, there may be only 3 or 4 cells/ mm3, or none, making the inflammatory aspect less clear. Oligoclonal bands are usually absent. In most instances that have come under our care, the MRI has shown slight T2 signal abnormalities and minimal gadolinium enhancement extending over 2 or 3 spinal segments. Although the cord may be swollen in these regions (Fig. 42-4), several of our patients with mild and partial myelitis have had normal MRI studies. Clinical variants of this syndrome are frequent in our experience, including an almost pure paresthetic illness with posterior column dysfunction and the converse; a symmetrical paraparesis with analgesia below a level on the trunk but without the involvement of deep sensation (a syndrome more typically associated with infarction in the territory of the anterior spinal artery); a syndrome of variable sensory loss involving the leg and groin on one side or both; a purely lumbosacral or sacral myelopathy (conus syndrome with saddle analgesia and sphincter disturbances); and a partial Brown-Séquard syndrome.

B

Figure 42-4.  T2-weighted MRI of acute postinfectious myelitis in the sagittal (A) and axial (B) planes. There is abnormal T2 hyperintensity within the dorsal spinal cord and the cord is mildly enlarged. Mild enhancement following gadolinium infusion was noted (not shown).

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The progressive necrotic myelopathy of neuromyelitis optica and its variants are considered separately further on., In the past, postinfectious myelitis was most often observed in relation to the common exanthems (rubella, rubeola, varicella). The neurologic signs appeared as the rash was fading, often with a slight recrudescence of fever. Practically all human viruses have at one time or another been found to have preceded acute myelitis; however, the DNA viruses such as Epstein-Barr and cytomegalovirus are most common, and hepatitis B, varicella, and entero- and rhinoviruses have been detected from time to time. Mycoplasma is almost unique in being a bacterial trigger of the disease, but as noted earlier, there is uncertainty regarding its ability to cause direct infection rather than a postinfectious immune reaction. In most instances of postinfectious myelitis, the connection to a preceding infection is presumed but cannot be proved. Only the associations with EBV, CMV, and Mycoplasma seem fairly certain based on the regularity of their occurrence, but it may simply reflect the relative ease with which a recent infection can be documented by serologic tests. The list of antecedent infections is otherwise much the same as for the Guillain-Barré syndrome with the notable difference of Campylobacter jejuni, which has not led to myelitis but is a known precedent to acute polyneuropathy. It can be reasonably assumed that, for example, pharyngitis, respiratory infection, and conjunctivitis, with or without fever, was a likely trigger for myelitis and the finding of abnormal liver function tests or severe pharyngitis with cervical adenopathy usually indicates EBV or less often, CMV infection. More difficult to understand is a large number of cases of myelitis, including autopsy-proven ones, in which the disease develops without an apparent antecedent infection. There is always understandable uncertainty in such cases as to whether the illness is the opening phase of multiple sclerosis of the type described below under “Acute Demyelinating Myelitis of Multiple Sclerosis.” In the numerous cases of transverse myelitis under our care, fewer than half have shown other signs of MS after 10 to 20 years (this is a far lower incidence than disseminated multiple sclerosis following a bout of optic neuritis). There is also an isolated form of relapsing myelitis, sometimes but not always triggered by an infection that does not manifest lesions elsewhere in the neuraxis and therefore has an ambiguous relationship to MS. Further discussion of acute transverse myelitis in relation to other demyelinating diseases can be found below and in Chap. 35. The pathologic changes in postinfectious myelitis take the form of numerous subpial and perivenular zones of demyelination, with perivascular and meningeal infiltrations of lymphocytes and other mononuclear cells, and para-adventitial pleomorphic histiocytes and microglia. Taken in isolation, these pathologic changes cannot be distinguished from those of MS. Treatment  Once symptoms begin, it is not clear if any treatment is of consistent value. One’s first impulse, assuming the mechanism to be autoimmune, is to administer high doses of corticosteroids, a practice we have followed without conviction. We have also used plasma exchange or intravenous immune globulin in several patients with

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uncertain results, although this approach was seemingly helpful in a few patients who had an explosive clinical onset and it is used in cases of neuromyelitis optica spectrum myelopathy. More recently, trials of monoclonal antibodies targeting the interleukin-6 receptor have demonstrated benefits in preventing relapses (Yamamura et al). The prognosis of this illness is better than the initial symptoms might suggest. Invariably, the myelitic disease improves, sometimes to a surprising degree, but there are examples in which the sequelae have been severe and permanent. Pain in the midthoracic region or an abrupt, severe onset usually indicates a poor prognosis (Ropper and Poskanzer). The authors have several times given a good prognosis for long-term recovery and assurance that no relapse will occur, only to witness a recrudescence of other symptoms at a later date, indicating that the original illness was probably multiple sclerosis.

Acute Demyelinating Myelitis of Multiple Sclerosis (Chap. 35) The lesions of acute MS share many of the features of the postinfectious type, as noted above. However, the clinical manifestations of the former tend to evolve more slowly over a period of 1 to 3 weeks or even longer. Also, a relation to antecedent infections is not often seen in MS. Only the occurrence of subsequent attacks or additional lesions revealed by MRI or evoked potentials indicates that the basic illness is one of chronic recurrent demyelination. The most typical clinical expression of demyelinating myelitis is a numbness that spreads over one or both sides of the body from the sacral segments to the feet, anterior thighs, and up over the trunk, with coincident but variable and usually asymmetric weakness and then paralysis of the legs. As this process becomes complete, the bladder is also affected. The sensorimotor disturbance may extend to involve the arms, and a sensory level can be demonstrated on the upper parts of the trunk. The CSF may show a mild lymphocytosis, as in the postinfectious variety, but it is as often normal. Oligoclonal bands may be absent with the first attack. As a general rule, acute spinal MS is relatively painless and without fever, and the patient usually improves, with variable residual signs. The differential diagnosis of demyelinating myelitis is considered more fully in Chap. 35. Treatment  Corticosteroids, as outlined for the treatment of MS in Chap. 35, may lead to a regression of symptoms, sometimes with relapse when the medication is discontinued (after 1 to 2 weeks). Other patients, however, show no apparent response, and a proportion of cases have even continued to worsen while the medication was being given. Plasma exchange and intravenous immune globulin have reportedly been beneficial in individual cases, particularly in those with an explosive onset (see later). The results in our patients have been too variable to interpret.

Neuromyelitis Optica Spectrum Disorder (NMOSD), Acute and Subacute Necrotizing Myelitis, Devic Disease (See Chap. 35) This traditional combination of spinal cord necrosis and optic neuritis corresponds to the syndrome described

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by Devic in 1894 and named by him neuromyelitis optica (Devic disease). In every large center, examples of this disorder are found among the many patients who present with a subacute paraplegia or quadriplegia, sensory loss, and sphincter paralysis. Sometimes the neurologic signs may erupt so precipitously that a vascular lesion is assumed, however, in most other cases, the disease evolves at a slower and usually stepwise pace over several weeks or months. In its fullest form, it produces necrotizing myelopathy that is distinguished from the more common types of transverse myelitis by persistent and profound flaccidity of the legs (or arms if the lesion is cervical), areflexia, and atonicity of the bladder—all reflecting a widespread necrosis that involves both the gray and white matter of the spinal cord over a considerable contiguous vertical extent. The NMO/Devic disorder has been expanded to encompass a spectrum of syndrome (NMO spectrum disorder, NMOSD), as discussed in Chap. 35 that includes brainstem encephalitis, isolated optic neuritis, and partial forms of transverse myelitis, any of which may be monophasic or recurrent. Nearly all neurologists agree that a similar clinical syndrome involving the optic nerve and spinal cord (usually without necrosis) may also be caused by postinfectious encephalomyelitis or by MS, however, the finding by Lennon and colleagues of a specific serum IgG antibody in half of the cases of Devic disease was a notable advance and established NMOSD as an independent disorder. The antibody is directed against the aquaporin water channel (AQP-4) in capillaries of the cord, brainstem, and cerebellum and its role in the pathogenesis of the disease resolves the decades old uncertainty regarding a distinction between Devic disease and forms of multiple sclerosis, in which the antibody is not present. Approximately 75 percent of cases of NMOSD are associated with anti-AQP-4 antibodies, higher in women than men, and a smaller proportion has antibodies against MOG. The most characteristic clinical pattern is of acute attacks affecting one or more of six typical sites: optic nerves, spinal cord, area postrema of the dorsal medulla, diencephalon, brainstem, or cerebrum. However, the initial episode affects the optic nerve(s) or spinal cord in 85 percent of cases. Most cases relapse, but at highly variable intervals of months or years and these cause considerable disability in most untreated cases. In addition to the myelopathy, repetitive vomiting from damage to the area postrema is a distinctive mark of the disorder. In children, hemiparesis and other focal cerebral signs, even seizures, may predominate. Areas may be affected simultaneously or in rapid succession and unlike multiple sclerosis, the damage does not remit to any great extent. More so than with postinfectious transverse myelitis, the MRI reveals extensive signal changes and gadolinium enhancement, usually occupying three or more contiguous spinal segments; called a longitudinally extensive lesion, as alluded to earlier (Fig. 42-5). The optic neuropathy tends to occupy the full length of the nerve, unlike the spotty changes in MS. A dorsal medullary lesion on MRI is highly confirmatory of NMOSD. Imaging studies performed weeks or more after the onset of symptoms may show only

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Figure 42-5.  MRI of necrotic myelopathy in a patient with neuromyelitis optica spectrum disorder. Note the long extent of the lesion and thinning of the cord as the acute illness subsides.

atrophy of the involved segments of the cord. Persistent swelling of the affected region is more suggestive of spinal cord tumor or another type of inflammation, but the duration of cord swelling in NMO may extend for weeks. The electromyogram (EMG) often shows denervation of several contiguous myotomes, reflecting damage to the gray matter of those segments. A few or up to several hundred mononuclear cells per cubic millimeter and increased protein may be found in the CSF initially, but oligoclonal banding is usually absent, further distinguishing the disorder from multiple sclerosis. Some cases show only an elevated protein concentration. In cases coming to postmortem examination at variable times after the onset of symptoms, the lesion has proved to be necrotizing myelitis with widespread loss of spinal cord tissue. The pattern of tissue destruction appears, at least in part, infarctive and predominantly in the central cord, that is, not respecting the borders of gray and white matter. However, areas of residual inflammation and demyelination are often detected at the edges of the destructive lesions. Older lesions leave the spinal cord cavitated or collapsed over a vertical extent of 5 to 20 cm, with conical extensions of necrosis into the gray matter above and below the area of transverse damage. The diagnosis of NMOSD is based on the presence of one or more of the typical acute syndromes, antiAQP4IgG, and MRI lesions. There are, however, seronegative cases and the diagnosis then rests on clinical judgment. A similar disorder that is attached to antibodies against

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MOG, occurring mainly in children, is considered by most investigators as separate entity. Despite clinical similarities, MRI of the cord tends to show almost exclusive grey matter damage with anti-MOG, more diffuse and broadly centrally placed lesions in NMOSD, and wedge-shaped lesions in MS. The NMOSD picture is clouded by the presence of other autoantibodies in almost half of cases and the presence of a nameable autoimmune disorder, including systemic lupus, Sjogren syndrome and thyroiditis in almost one-third. Authorities in the field consider NMOSD to be the more common fundamental cause of CNS lesions in these instances. Almost 5 percent are paraneoplastic. Treatment is aimed at quelling the acute attack with intravenous glucocorticoids and preventing relapses with immunosuppressive drugs or monoclonal antibodies (e.g., eculizumab, inebilizumab, satralizumab) and is discussed more fully in Chap. 35.

Foix-Alajouanine Myelopathy Under the title “Subacute Necrotic Myelitis,” Foix and Alajouanine, and later Greenfield and Turner, and Hughes described a disorder mainly of adult men characterized by amyotrophic paraplegia that ran a progressive course over several months. The defining feature, one that still gives rise to lively polemical discussions, is severe necrosis of both gray and white matter in the lumbosacral region and a marked increase in the number of small vessels, their walls thickened, cellular, and fibrotic (“angiodysplastic”), yet without vascular occlusion. The veins are also thickened and surrounded by lymphocytes, mononuclear cells, and macrophages. As such, the disorder could be included under the vascular myelopathies discussed in the next section. These findings have been difficult to interpret and their relationship to the group of arteriovenous malformations (AVMs) and fistulas, discussed later, has been unclear, but we are inclined to the view of Antoni and others who were impressed with the prominence of large arteries and veins and have reinterpreted this pathologic process as an AVM. In many other cases of necrotic myelopathy that are not associated with a true vascular malformation, particularly those in the NMO spectrum just described above, the vascular changes simply reflect a neovascular response to necrosis or may be examples of neuromyelitis optica. A similar syndrome is produced by a rare idiopathic necrotizing vasculitis that is confined to the spinal cord (Caccamo et al). In these cases, there is a persistent and marked pleocytosis and some clinical stabilization with corticosteroids. These may be cases of NMOSD. One of our young male patients with this type of subacute necrotizing myelitis, responsive to corticosteroids, had mononuclear cells in the spinal fluid persistently over a year and died as a result of fulminant inflammatory cerebral hemorrhages. There were multiple occlusions of small vessels surrounding the spinal cord and a vasculitis. Polyarteritis nodosa and necrotizing arteritis only rarely involve the spinal cord. Schistosomiasis, as mentioned earlier, may produce necrotizing myelitis of the lumbosacral region.

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Myelitis (Myelopathy) With Rheumatologic Disease This is an interesting and varied group of spinal cord disorders that are thought to be inflammatory, but their nature has not been fully elucidated in part because of a paucity of pathologic material. An inflammatory vasculopathy has been implicated, similar to what is imputed for cerebral lesions in rheumatologic disorders, but there are also areas of noninflammatory and nonvasculitic demyelination that simulate multiple sclerosis. The imaging features and response to treatment are likewise varied.

Lupus Myelopathy A rapidly evolving or subacute myelopathy occurs in association with systemic lupus erythematosus. As mentioned, the process is presumed to arise from a microvasculitis or an autoantibody. In a review of 45 cases in which patients with lupus developed transverse myelitis over a period of days, there was back pain at the level of sensory loss (the cases we have seen have been painless) and pleocytosis and elevation of CSF protein (Propper and Bucknall). The MRI initially has generally demonstrated segmental swelling of the spinal cord. Postmortem examinations have disclosed widespread vasculopathy of small vessels with variable inflammation and myelomalacia, and, rarely, vacuolar myelopathy. Whether demyelination (so-called lupoid sclerosis due to an antibody) can occur independently of a vasculopathy has not been clear to us. Some but not all cases also have circulating antiphospholipid antibody; the relationship of these antibodies to the myelopathy and to microvascular occlusion is uncertain (see also “Antiphospholipid Antibody Syndrome” in Chap. 33 and further discussion in Chap. 35). The incidence of lupus myelopathy is not known; it must be rare, but one such case is admitted to our service, in a hospital with an active rheumatology division, about every year.

Sjögren Syndrome Myelopathy In addition to well-described posterior root ganglionopathy and sensory neuritis, an inflammatory myelitis has been associated with Sjögren syndrome. In most instances, the patient has had overt symptoms of Sjögren disease, including the sicca complex, and in others, the association has been established through serologic testing or by the finding of inflammatory infiltration of minor salivary glands (obtained by biopsy). In many reported cases, the myelopathy has simulated the myelitis of MS, even to the extent of including episodes of optic neuritis (Williams and colleagues; de Seze and coworkers, 2001b). The myelitis has been, in different cases, acute, chronic, or relapsing and displayed MRI changes in the cord that would otherwise be considered to be postinfectious or demyelinating myelitis were it not for the presence of Sjogren syndrome. The spinal fluid formula has also varied but generally does not contain oligoclonal bands. Treatment with prednisone and cyclophosphamide or methotrexate has been suggested and was seemingly successful in several of our patients. There is little pathologic material on which to judge the association, but the presence of other inflammatory lesions of the central and peripheral nervous system in Sjögren disease makes the existence of myelitis plausible.

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Antibody tests (anti-SS-A [Ro] and SS-B [La]) and possibly a biopsy of the minor salivary glands (at the junction of mucosa and epidermis of the lower lip) are justified in patients with unusual myelopathies or in those with sicca symptoms; however, screening in this manner of all cases that otherwise suggest MS or postinfectious myelitis may be excessive. This subject has been reviewed (Berkowitz) and is discussed in Chap. 35, in relation to multiple sclerosis. There is also the rare occurrence of nondescript myelitis with scleroderma, as mentioned above (systemic sclerosis), some cases of which have been of the longitudinally extensive type. The authors of most reports acknowledge the difficulty in distinguishing between the myelopathies of various connective tissue diseases. There may be some response to corticosteroids and other immunosuppressive medications. Myopathy and neuropathy, particularly trigeminal neuritis, are more common manifestations of scleroderma.

Behçet Syndrome Myelopathy (See Also Chap. 33) This vascular and inflammatory disease is usually considered in the context of cerebral venous thrombosis and other forms of stroke, but in addition to the typical findings of orogenital ulcers and uveitis, it has varied manifestations in the nervous system in about 5 percent of cases (neuro-Behçet’s syndrome). Among these is a myelopathy that may relapse like MS and may occur at single or multiple sites in the cord or simulate neuromyelitis optica in causing a longitudinally extensive lesion. The lesions may take up gadolinium on MRI and a peculiar imaging “bagel sign” has been described (Uygunoglu and colleagues), consisting of central hypointense area with a hyperintense rim. The clinical syndrome and imaging changes are said to resolve with glucocorticoids.

Paraneoplastic Myelitis (See Also Chap. 30) A subacute necrotic myelitis developing in conjunction with bronchogenic carcinoma was first brought to notice by Mancall and Rosales in 1964. Many cases have since been recorded in association with lymphomas and carcinomas, but the disease must be rare. Actually, in cancer patients, intramedullary metastasis, quite infrequent to begin with, is more common as a cause of intrinsic myelopathy, and, of course, a compressive lesion from cancer is far more frequent than either of these conditions. The clinical syndrome consists of a progressive, usually painless, loss of motor and then sensory function, usually with sphincter disorder, over weeks. Imaging studies demonstrate an area of T2 signal change in the cord, occupying one or several contiguous segments, similar to neuromyelitis optica (Devic disease); some have slight enhancement with gadolinium or rarely, imaging may be normal. This is in distinction to the nodular enhancing appearance of an intramedullary metastasis or of extradural metastatic disease with cord compression. Longitudinally extensive paraneoplastic myelopathy has been associated with a variety of paraneoplastic autoantibodies or, rarely, anti-aquaporin antibody but a causal link with antibodies is uncertain. However, this myelopathy does not seem to be a component of the anti-Hu–associated encephalitis-neuropathy spectrum.

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The CSF may contain a few mononuclear cells and a slightly increased protein, or it may be normal. The lesions are essentially of necrotic type and respect neither gray nor white matter, but the latter is more affected. There is little or no evidence of an infective-inflammatory or ischemic lesion, for the blood vessels, apart from a modest cuffing with mononuclear cells are normal. No tumor cells are visible in the CSF, meninges, or spinal cord tissue, and no virus has been isolated. In some cases of paraneoplastic myelopathy, the pathologic changes are more chronic, confined to the posterior and lateral columns, and often associated with paraneoplastic diffuse loss of cerebellar Purkinje cells. This latter syndrome may have a special association with ovarian carcinoma but has been observed with carcinoma of other types and with Hodgkin disease, as discussed in Chap. 30. Most of the reported cases of these types have ended fatally. Steroids and plasma exchanges have been of no clear value. Treatment of the underlying systemic tumor or immunosuppression has failed in most cases to alter the myelopathy (Flanagan and colleagues, 2011). A rare variety of anterior horn cell destruction that resembles motor neuron diseases is known to occur with certain lymphomas; it is also discussed with the paraneoplastic syndromes in Chap. 30.

Subacute Spinal Neuronitis (Propriospinal Myoclonus) Two distinct entities seem to be encompassed under this name, both rare; a progressive myelopathy and a regional disorder, mainly of the abdominal muscles. Whitely and colleagues drew attention to the process characterized clinically by tonic rigidity and intermittent myoclonic jerking of the trunk and limb muscles and by painful spasms of these muscles evoked by sensory or emotional stimuli. Their cases were progressive and eventually involved the limbs. In the few well-studied cases of this type, the brunt of the pathologic process has fallen on the cervical portion of the spinal cord. Widespread loss of internuncial neurons with relative sparing of the anterior horn cells, reactive gliosis and microglial proliferation, conspicuous lymphocytic cuffing of small blood vessels, and scanty meningeal inflammation have been the main findings. Involvement of the white matter is less marked. The pathophysiology of the rigidity in these cases is presumed to be because of the impaired function (or destruction) of Renshaw cells, with the release of tonic reflexes (Penry et al). The painful spasms and dysesthesias relate in some way to neuronal lesions in the posterior horns of the spinal cord and dorsal root ganglia. Whitely and Lhermitte and their coworkers proposed that these cases probably represent an obscure form of viral myelitis. The cases we have observed have been of the type that remained confined to several contiguous spinal segments, usually the upper abdomen and lower thorax, (Brown and colleagues). Some patients report a premonitory sensation before the abdominal jerking, or there is worsening with the supine position. Whether these represent the same disease as the one noted above is unclear, but the segmental, abdominal variety is now a firmly established entity, albeit also idiopathic, as described in a series by Roze et al

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and discussed under “Spinal or Segmental Myoclonus” in Chap. 4. The CSF may be normal or show a mild lymphocytosis and increase in protein content. Myoclonic jerking of the trunk and limbs in a focal or segmental distribution is probably a result of neuronal damage of this same type that is limited to a few segments of the spinal cord. Clonazepam, various antiseizure and antispasticity drugs in combination may partially suppress the myoclonus, and local injection of botulinum toxin has improved the symptoms in some. A similar syndrome in a few cases has followed vertebral or spinal artery angiography (see later). A paraneoplastic variety usually associated with breast cancer has been proposed, as in the case described by Roobol and colleagues, but its nature has not been fully elucidated.

Spinal Arachnoiditis (Chronic Adhesive Arachnoiditis; See also Chap. 10) This is now a relatively uncommon spinal cord disorder that was introduced in relation to the subject of low back pain in Chap. 10. It is characterized by a combination of painful root and spinal cord symptoms that may mimic intraspinal tumors. There is opacification and thickening of the arachnoidal membranes and adhesions between the arachnoid and dura—the result of proliferation of connective tissue. The subarachnoid space is unevenly obliterated. In this sense, the term arachnoiditis is not entirely appropriate, although it seems likely that the connective tissue overgrowth is a reaction to an antecedent arachnoidal inflammation. Some forms of arachnoiditis were traced to syphilis or to a subacute, therapeutically resistant meningitis of another type. Most others in the past followed the introduction of a variety of substances, most no longer used, into the subarachnoid space for diagnostic or therapeutic purposes or following spinal anesthesia, soon afterward or after an interval of weeks, months, or even years. This complication was eventually traced to a detergent that had contaminated vials of procaine. More pernicious, however, has been a delayed meningomyelopathy that developed within a few months or years of the inciting event, causing spastic paralysis, sensory loss, and incontinence of sphincters. There are also cases on record in which an epidural or similar catheter has accidentally penetrated the cord and caused traumatic partial myelopathy, as mentioned earlier. Still seen regularly is a restricted form of arachnoiditis that complicates a series of operations for lumbar discs or the spinal injection of methylene blue. Less convincing are cases attributed to closed spinal injuries. In many cases, no provocative factor can be recognized. There is reportedly a familial form (Duke and Hashimoto), but we have had no experience with it. Clinical manifestations  Symptoms may occur in close temporal relation to an acute arachnoidal inflammation or may be delayed for weeks, months, or even years, as indicated above. The most common mode of onset is with pain in the distribution of one or more sensory nerve roots, first on one side, then on both, in the lumbofemoral regions. The pain has a burning, stinging, or aching quality and is persistent. Abnormalities of tendon reflexes are common, but weakness and atrophy, the results of damage to anterior

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roots, are less frequent. In thoracic lesions, symptoms of root involvement may antedate those of cord compression by months or years. Sooner or later, however, there is the involvement of the spinal cord, manifest by a slowly progressive spastic ataxia with sphincter disturbances. The localized lumbar arachnoiditis associated with repeated disc surgery (the common variety seen in pain clinics) is characterized by back and or leg pain with other inconstant signs of radiculopathy (loss of tendon reflexes, weakness, and variable degrees of sensory loss), usually bilateral. The CSF is abnormal during the acute stage in practically all cases that ultimately result in adhesive arachnoiditis. In some, there is a moderate lymphocytic pleocytosis, occurring soon after the inciting event. In the localized lumbar arachnoiditis, referred to earlier, the CSF may be normal or show only a slight increase in protein content. The prominent finding with imaging is a partial or complete obliteration of the spinal subarachnoid space. The loculated myelographic appearance of arachnoiditis is characteristic (patchy dispersion of the column of dye and a “candle-guttering” appearance that was most evident in the past with oil-based contrast media); MRI reveals a loss of the normal ring of CSF or localized loculations of CSF (see Fig. 10-5). Treatment  In the early stages of arachnoiditis, corticosteroids have been given to control the inflammatory reaction and to prevent the progress of the disease, but their value is questionable. Surgery may be effective in the case of localized “cyst” formation and cord compression. For chronic adhesive lumbar arachnoiditis in which diffuse back and limb pain is the most distressing symptom, there has been little effective surgical or medical treatment, although relief has reportedly been provided in isolated instances by painstaking microsurgical dissection of the lumbar roots. In some cases, the loculations return. Administration of corticosteroids, systemic and epidural, has not been consistently beneficial but may be tried. Immune-suppressant medication such as azathioprine or interferons has been tried but not studied systematically. Transcutaneous stimulator treatment and gabapentin have also been used with inconsistent results.

VASCULAR DISEASES OF THE SPINAL CORD In comparison with the brain, the spinal cord is an uncommon site of vascular disease. Blackwood, in a review of 3,737 necropsies at the National Hospital for Nervous Diseases, London, during the period 1903 to 1958, found only 9 cases of spinal cord infarction, but in general hospitals, the incidence (e.g., judged on clinical grounds in our hospital) is higher. The spinal arteries tend not to be susceptible to atherosclerosis, and emboli rarely lodge there. Of all the vascular disorders of the spinal cord, infarction as a result of aortic disease, dural fistula, bleeding, and AVM are the only ones that are encountered with any regularity, but even taken together, they are infrequent in comparison to demyelinating myelitis or compression of the cord by the tumor. In current practice, most cases of

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infarction have developed in relation to operations on the aorta, usually the thoracic portion, where the vessel must be clamped for some period. The dural arteriovenous fistulas that cause spinal cord swelling are being recognized increasingly as their clinical syndromes are exposed and vascular imaging of small spinal arteries becomes more sophisticated. They have probably overtaken in frequency cord infarction in this category of disease. An understanding of these disorders requires knowledge of the blood supply of the spinal cord.

Vascular Anatomy of the Spinal Cord The blood supply of the spinal cord is derived from a series of segmental vessels arising from the aorta and from branches of the subclavian and internal iliac arteries. The most important branches of the subclavian are the vertebral arteries, small branches of which give rise to the rostral origin of the anterior spinal artery and to smaller posterolateral spinal arteries that together constitute the major blood supply to the cervical cord. The thoracic and lumbar cord is nourished by segmental arteries arising from the aorta and internal iliac arteries. Segmental branches of the lateral sacral arteries supply the sacral cord. A typical segmental artery divides into an anterior and a posterior ramus (Fig. 42-6). Each posterior ramus gives rise to a spinal artery, which enters the vertebral foramen, pierces the dura, and supplies the spinal ganglion and roots through its anterior and posterior radicular branches. Most anterior radicular arteries are small and some never reach the spinal cord, but a variable number (4 to 9), arising at irregular intervals, are much larger and supply most of the blood to the spinal cord. Tributaries of the radicular arteries supply blood to the vertebral bodies and surrounding ligaments. The venous drainage is into the posterior veins forming the spinal plexus. Their importance relates to the pathogenesis of fibrocartilaginous embolism (see further on). Lazorthes, in his review of the circulation of the spinal cord, divided the radiculomedullary arteries into three groups: (1) upper or cervicothoracic, which are derived from the anterior spinal arteries and branches of the thyrocervical and costovertebral arteries; (2) intermediate or middle thoracic (T3 to T8 cord segments), usually from a single T7 radicular artery; and (3) lower or thoracolumbar, from a large T10 or L1 anterior radicular artery, better known as the artery of Adamkiewicz. This artery supplies the lower two-thirds of the cord, but in any individual, the precise area supplied by this or any other anterior radiculomedullary artery varies greatly and one cannot predict what portion or proportion of cord will be infarcted if one of these vessels is occluded. The junction between the vertebral spinal and aortic circulations typically lies at the T2-T3 spinal segment, but most ischemic lesions lie well below this level. The anterior medullary arteries form the single anterior spinal artery, which runs the full length of the cord in its anterior sulcus and gives off direct penetrating branches via the central (sulco-commissural) arteries. These penetrating branches supply most of the anterior gray columns

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Penetrating A.

Posterior Spinal A.

Sulcal A.

Radiculomedullary artery of Adamkiewicz (at T10-L1 level)

Anterior Spinal A.

Radicular A.

Segmental A.

Aorta

Figure 42-6.  Anterior view of the spinal cord with its segmental blood supply from the aorta. (Reproduced with permission from Prasad S, Price RS, Kranick SM, et al: Clinical reasoning: a 59-year-old woman with acute paraplegia. Neurology. 2007;69(24):E41-E47.)

and the ventral portions of the dorsal gray columns of neurons (see Fig. 42-6). The peripheral rim of the white matter of the anterior two-thirds of the cord is supplied from a pial radial network, which also originates from the anterior median spinal artery. Thus, the branches of the anterior median spinal artery supply roughly the ventral two-thirds of the spinal cord. Infarction of the region supplied by this artery gives rise to an anterior spinal cord syndrome that consists of loss of pain and temperature and paralysis below the level of the lesion, but with sparing of proprioception and vibration sense that correspond to the transaction of the spinothalamic and corticospinal tracts but not of the posterior columns. The posterior medullary arteries form the paired posterior spinal arteries that supply the dorsal third of the cord by means of direct penetrating vessels and a plexus of pial vessels (similar to that of the ventral cord, with which it anastomoses freely). Within the cord substance, then, there is a “watershed” area of capillaries where the penetrating branches of the anterior spinal artery meet the penetrating branches of the posterior spinal arteries and the branches of the circumferential pial network. All spinal segments, because of the variable size of collateral arteries, do not have the same abundance of circulatory protection.

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Normally there are 8 to 12 anterior medullary veins and a greater number of posterior medullary veins arranged fairly close to one another at every segmental level. They drain into radicular veins. In addition, a network of valveless veins extends along the vertebral column from the pelvic venous plexuses to the intracranial venous sinuses without passing through the lungs (Batson plexus) and is considered a route for metastatic disease from the pelvis.

Infarction of the Spinal Cord Ischemic infarction of the spinal cord usually involves the territory of the anterior spinal artery, that is, a variable vertical extent of the ventral two-thirds of the spinal cord. Infarctions in this territory are relatively uncommon, as already mentioned, representing 1.2 percent of all strokes (Sandson and Friedman). The resulting clinical abnormalities are generally referred to as the anterior spinal artery syndrome, described by Spiller in 1909. Atherosclerosis and thrombotic occlusion of the anterior spinal artery are quite uncommon, as noted, and infarction in the territory of this artery is more often secondary to disease of the extravertebral collateral artery or to disease of the aorta, either advanced atherosclerosis, a dissecting aneurysm, or intraoperative surgical occlusion—which compromises the important segmental spinal arteries at their origins. An ischemic myelopathy has been reported in cocaine users, preceded sometimes by episodes of cord dysfunction resembling transient ischemic attacks. Cardiac and aortic surgery, which requires clamping of the aorta for more than 30 min, and aortic arteriography may also be complicated by infarction in the territory of the anterior spinal artery; more often in these circumstances, damage to central neuronal elements is greater than that to anterior and lateral funiculi, as described in the following text. Rarely, polyarteritis nodosa may cause occlusion of a spinal medullary artery. Systemic cholesterol embolism arising from a severely atheromatous aorta may have the same effect. This latter type of embolism is prone to occur after surgical procedures, angioplasty, or cardiopulmonary resuscitation. For unexplained reasons, the spinal cord infarction sometimes follows one of the aforementioned procedures by up to 3 weeks, as emphasized in Dahlberg’s series of cases (Dahlberg et al). In almost all such patients, other evidence of widespread embolism can be expected. Infarction may also result from systemic hypotension, the most vulnerable part being of the thoracic segments of the cord. One of our patients had cord infarction during a bout of diabetic coma. Among the most curious causes of cervical cord, infarction is dissection of the extracranial vertebral arteries, either unilateral or bilateral. The resultant ischemia in the territories of the anterior spinal arteries causes anterior and central cervical cord ischemia. In two cases of this nature that have been brought to our attention, there were an asymmetric brachial diplegia and a suspended sensory loss preceded by intense radicular and neck pain. There are numerous other case reports, although the cause of vertebral artery dissections has not always been clear (Weidauer and colleagues). A few patients have vertigo at the onset, directing attention to vertebral artery

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and lateral medullary damage. We have also encountered instances of myelomalacia in young adults in whom no aortic or spinal arterial disease could be demonstrated. Possibly, these were because of the embolization of disc material (nucleus pulposus) into the local vasculature (see further on). A quite different progressive ischemic necrosis of the cord can occur in the neighborhood of an AVM or dural fistula and is considered later in this chapter (see also the section on Foix-Alajouanine Myelopathy, described earlier). Despite the elucidation of these causes of spinal cord infarction, a large group in any series has no identifiable cause; for example, an etiology could be established in only 7 of 27 consecutive cases in one series (Novy and colleagues). The clinical manifestations of spinal arterial occlusion will, of course, vary with the level and portions of the cord that are infarcted, but common to practically all cases of infarction in the territory of the anterior spinal artery is a pain in the neck or back and the development of paralysis and loss of pain and thermal sensations below the level of the lesion, accompanied by paralysis of sphincteric function. Except in high cervical lesions, the sensory changes are dissociated, that is, pain and temperature sensations are lost (because of interruption of the spinothalamic tracts), but vibration and position sense are unimpaired (a result of sparing of posterior columns). Rarely, infarction is preceded by spinal transient ischemic attacks, as has been emphasized in cases related to cocaine use. The symptoms may develop instantaneously or, more often in our experience, over 1 or 2 h; in any case, more rapidly than in the inflammatory myelitides. Radicular pain corresponding to the upper level of the lesion is sometimes a complaint. Paralysis is usually bilateral, occasionally unilateral, and rarely complete. Also reported is a bibrachial paralysis as a fragment of the anterior spinal artery syndrome, as mentioned earlier. In cases that cause a complete transverse myelopathy, the limbs are initially flaccid and areflexic, as in spinal shock from traumatic lesions, followed after several weeks by the development of spasticity and the return of a degree of voluntary bladder control (unless sacral segments have been infarcted). Many patients regain a substantial degree of motor function, mainly in the first month but extending over a year (Sandson and Friedman; Cheshire et al; Novy et al). Infarction in the territory of the posterior spinal arteries is uncommon and the corresponding syndrome is not stereotyped; only 2 of 27 cases from the series by Novy and colleagues had this pattern. It may occur with surgery or trauma of the spine or rarely with vertebral artery dissections. Some, but not all, spinal cord infarctions are detected by MRI (Fig. 42-7). After a few days, there are obvious lesions on the T2 sequences, presumably reflecting edema that extends over several levels. There may be slight enhancement after infusion of gadolinium. It is notable, however, that the MRI taken in the first hours or day is often normal, including sometimes diffusion weighted images. The reason for the delay in the appearance of the imaging findings is not known. In the chronic stages, the infarcted region collapses and has an attenuated signal on MRI.

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Figure 42-7.  Cervical spinal cord infarct: Sagittal (left) and axial (right) T2 MRI of a man who experienced sudden onset of bilateral flaccid arm weakness. Note the abnormal T2 hyperintensity restricted to the ventral spinal cord, including both ventral horns.

Dissecting aneurysm of the aorta, which is characterized by intense interscapular and/or chest pain (occasionally it is painless), widening of the aorta, and signs of impaired circulation to the legs or arms and various organs, gives rise to a number of myelopathic syndromes. The neurologic picture was first described by Kalischeri in 1914 and the aortic lesion leading to dissection, according to Erdheim, was a medionecrosis. The spinal syndromes of aortic dissection, according to Weisman and Adams, are (1) paralysis of the sphincters and both legs with sensory loss below T6; (2) ischemic infarction of the cord confined to the gray matter, in which case there is an abrupt onset of muscle weakness or myoclonus and spasms in the legs but no pain or sensory loss; (3) obstruction of the origin of a common carotid artery with hemiplegia; and (4) less commonly, obstruction of a brachial artery with a sensorimotor neuropathy of the limb. With regard to aortic aneurysm surgery, paraplegia is uncommon after procedures performed on the infrarenal segment but occurs as frequently as 5 to 10 percent following the repair of thoracoabdominal aneurysms. Again emphasized here is the not easily explained observation that up to a quarter of these myelopathies do not appear for several days postoperatively (8 days in one of our patients) (Lintott and colleagues). In the past, aortography was sometimes complicated by an acute myelopathy; we had observed a number of such cases that were similar to those in a review of 43 instances (Killen and Foster). The most striking examples, fortunately rare, are now the result of complications of vertebral angiography, resulting in high cervical infarction,

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similar in most ways to the aforementioned spinal infarction from extracranial dissection of the vertebral artery. The onset of sensorimotor paralysis is immediate, and the effects are often permanent. The syndrome of painful segmental spasms, spinal myoclonus, and rigidity, as mentioned earlier, has also been observed under these conditions. It was presumed that vascular spasm and occlusion resulted in infarct necrosis. The frequency of this complication was greatly reduced by the introduction of less toxic contrast media. Treatment  Whether the acute effects of spinal infarction can be modified by high-dose corticosteroids, agents that increase blood flow, or anticoagulation is not known. There are case reports of improvement in paraplegia following aortic dissection by the use of CSF drainage (Blacker and colleagues; Killen and associates), but other factors may have contributed. Many surgical services insert a spinal drain prior to aortic procedures in order to reduce spinal fluid pressure, ostensibly reducing the incidence of cord infarction. There may be gradual improvement after spinal cord infarction (Robertson and colleagues), but most patients remain with substantial difficulties.

Surfer’s Myelopathy This unusual nontraumatic athletic problem has been described by Thompson and colleagues from Hawaii. It mainly affects novice surfers who were prone for prolonged times on the surfboard and then engaged in vigorous movements, followed by assuming a standing position. Within an hour of surfing, there was characteristic severe

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upper lumbar or thoracic pain followed by progressive paraparesis or paraplegia, and urinary retention. In several reports, MRI showed signal changes in a long extent of the thoracic spinal cord and when the proper imaging sequences have been performed, some cases have restricted diffusion in the affected region. On the basis of the latter finding and preservation of proprioception in some patients (implicating ischemia of the anterior portion of the spinal cord), a vascular mechanism has been proposed. Improvement has been inconsistent (Chang and colleagues).

Hemorrhage of the Spinal Cord (Hematomyelia) and Spinal Canal Hemorrhage into the spinal cord is rare compared with the frequency of cerebral hemorrhage. The apoplectic onset of symptoms that involve spinal tracts (motor, sensory, or both), associated with blood and xanthochromia in the spinal fluid, are the identifying features of hematomyelia. Aside from trauma, hematomyelia is usually traceable to a vascular malformation or a bleeding disease and particularly to the administration of anticoagulants. Actually, most vascular malformations of the spinal cord do not cause hemorrhage but instead produce a progressive, presumably ischemic myelopathy as described later and mentioned in the earlier section on the Foix-Alajouanine type of subacute necrotic myelopathy. The same causes (anticoagulation, blood dyscrasia with coagulopathy, and AVM) may underlie bleeding into the epidural or subdural space and give rise to a rapidly evolving compressive myelopathy. In some cases, one cannot ascertain the source of the bleeding, even at autopsy (Leech and coworkers). Epidural or subdural bleeding, like epidural abscess, represents a neurologic emergency and calls for immediate localization by imaging and, in some cases, surgical evacuation. Advances in the techniques of selective spinal angiography and microsurgery have permitted the visualization and treatment of vascular lesions that cause bleeding with a precision not imaginable a few decades ago. These procedures make it possible to distinguish among the several types of vascular malformations, arteriovenous fistulas, and vascular tumors, such as hemangioblastomas, and to localize them accurately to the spinal cord, epidural or subdural space, or vertebral bodies. This subject is discussed further on.

Vascular Malformations and Dural Fistulas of the Spinal Cord Lesions that cause ischemic (and hemorrhagic) myelopathy lesions are true AVMs, implying a congenital connection between the two sides of the circulation and others are more limited fistulas in the dura, probably mostly acquired for various reasons. The distinction is in the size of the nidus of communication between an artery and a vein and the size and location of feeding and draining vessels. The classification of spinal AVMs is confusing, in part because the enlarged draining veins by which the lesions were formerly identified are probably secondary features. A more

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useful categorization reflects the appearance and location of the malformation: (1) AVMs that are strictly intramedullary or that also involve the meninges and surrounding structures, such as the vertebral bodies, to a limited extent; (2) a variety of intradural perimedullary fistulas that lie on the pial and subpial surface of the cord (these probably conform most closely to the lesion described by Foix and Alajouanine discussed in the earlier section “Foix-Alajouanine Myelopathy”); and (3) probably the most common vascular malformation of the cord in current practice, dural fistulas. As mentioned, the last of these types may be acquired from local venous occlusions and the other types do not originate in this way and are likely to be developmental as in the cerebrum. Once recognized, treatment of a spinal cord malformation of any type may be an urgent matter, especially in cases with rapid clinical deterioration and impending paralysis. Dural arteriovenous fistula The entity is addressed first because it has emerged as the most common type, at least in our practices. Fistulas within the dura that overlies the spinal cord are capable of causing myelopathy, sometimes several segments distant from the vascular lesion. Most are situated in the region of the low thoracic cord or the conus and have a limited venous draining system. Some are in a dural root sleeve and drain into the normal perimedullary coronal venous plexus. Men seem to be affected disproportionately. The presenting clinical features in our patients have included slowly progressive bilateral but asymmetric leg weakness with variable sensory loss. The most common initial symptoms have been gait imbalance, numbness, and paresthesias in the lumbar region (Jellema and colleagues). As the process progressed, the majority has developed urinary problems, leg weakness, and numbness in the legs and buttocks. The degree of leg weakness varied greatly and back pain in their series was infrequent and has not been a consistent feature in the patients under our care. The myelopathy may have a subacute or saltatory evolution, presumably from fluctuating venous congestion within the cord. A claudicatory syndrome has also been reported. Characteristically, activities that increase venous pressure (Valsalva maneuver, exercise) transiently amplify the symptoms or produce irreversible, stepwise worsening. One remarkable such case involved a baritone opera singer whose legs gave way repeatedly while singing (Khurana et al). A few of our patients have reported transient symptoms upon standing. Many cases occur, however, without a stepwise progression or elicitable worsening. As mentioned, many cases have been painless, although most of our patients have had a moderate spinal ache or sciatica. In contrast to the larger parenchymal arteriovenous lesions, these bleed only rarely. The spinal fluid is normal or shows a slight elevation of protein. The disease can sometimes be inferred from the MRI appearance of a characteristic swelling of one or a few adjacent segments of the lower cord that represents venous congestion and edema, as discussed further on, and the fistula may be apparent on MRI as serpiginous flow voids, but selective arterial injections are usually required to demonstrate and treat the fistula as noted below under Diagnosis.

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Intramedullary AVM  The true spinal cord AVM, previously referred to as angioma racemosum venosum or dorsal extramedullary arteriovenous malformation, is typically located on the dorsal surface of the lower half of the spinal cord and occurs most often in middle-aged and elderly men (23 of 25 of Logue’s patients were male). However, this lesion may occur at any age and at any location in the cord and may be quite widespread. In a few cases, there has been an overlying dermatomal nevus. The clinical picture was well described by WyburnMason. Acute cramp-like, lancinating pain, sometimes in a sciatic distribution, is often a prominent early feature. It may occur in a series of episodes over a period of several days or weeks; sometimes, it is worse in recumbency. Almost always, there is weakness or paralysis of one or both legs and numbness and paresthesias in the same distribution with a highly variable duration of evolution; an abrupt apoplectic onset is known, or the neurologic signs may appear over months, most cases conforming to the middle of these extremes. Wasting and weakness of the legs may introduce the disease in some instances, with uneven progression, sometimes in a series of abrupt episodes. Severe disability of gait is usually present within 6 months, and half of the patients described by Aminoff and Logue were chair-bound within 3 years; the average survival in the past was 5 to 6 years, but the disorder has rarely been fatal in our patients. These lesions only infrequently give rise to intramedullary or subarachnoid hemorrhage. The spinal fluid shows high protein but little or no cellular reaction. When viewed directly, the dorsal surface of the lower cord may be covered with a tangle of veins, some involving roots and penetrating the surface of the cord. The progression of symptoms is presumably a result of chronic venous hypertension and secondary intramedullary ischemic changes, and the abrupt episodes of worsening are attributed to the thrombosis of vessels, all on uncertain grounds because angiographic studies sometimes show only a single or a few such dilated draining vessels. Furthermore, there is insufficient pathologic material to determine whether some of the more prominent venous anomalies represent true venous angiomas (probably they do not). Intradural perimedullary and subpial AVM  The pial fistulous arteriovenous communication that involves the superficial aspect of the cord to a variable extent is the least frequent in this category but probably of a similar nature to the dural type; it may be related (or identical) to the vascular lesion in the earlier discussed FoixAlajouanine process. In contrast to dorsal AVMs, these fistulas tend to involve the lower thoracic and upper lumbar segments or the anterior parts of the cervical enlargement. The patients are often younger and the sexes are equally affected. The clinical syndrome may take the form of slow spinal cord compression, sometimes with a sudden exacerbation, or the initial symptoms may be apoplectic in nature, either because of thrombosis of a vessel or of a hemorrhage from an associated draining vein that dilates to aneurysmal size and bleeds into the subarachnoid space or cord (hematomyelia and subarachnoid hemorrhage); the latter complication occurred in 7 of 30 cases reported by Wyburn-Mason.

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Diagnosis  These lesions—dural or parenchymal— may be apparent on MRI or CT myelography by the presence of one or more enlarged and serpiginous draining vessels in the subarachnoid space; just as often, they are not visualized by these methods (Jones et al). For this reason, the possibility should come to mind that an otherwise unexplained myelopathy with signs of congestion of the cord on MRI may be the result of a vascular malformation. However, several studies, such as the one by Toossi and colleagues, have suggested that the absence of both T2 hyperintensity and flow voids on MRI makes the presence of a dural fistula unlikely and spares the patient from the need for angiography. Imaging features that have been emphasized with dural fistulas include enlargement of the spinal cord at the level of the lesion and T2 bright signal of the swollen cord over several segments, but these are not invariable. Infrequently, the draining surface vessels are evident on MRI (Fig. 42-8A). Because of the slow blood flow within the vascular lesion, the affected region may have a hypointense T1 signal. The presence of peripherally located regions of T2 hypointense signal changes has been commented on (Hurst and Grossman). Many of these changes are reversed by surgical or endovascular interventions that ablate the malformation. There is a variable enhancement, although, with increasingly improved MRI techniques, more fistulas are becoming apparent. Some remarkable ones appear as multiple small enhancing areas that are like hairs standing on end, coating the cord over several levels. The diagnosis is usually established through selective angiography, which shows the fistula in the dura overlying the cord or on the surface of the cord itself, but the most conspicuous finding is often the associated early draining vein (Fig. 42-8B). Demonstration of the fistula requires the injection of feeding vessels at numerous levels above and below the suspected lesion because the main artery of origin is often some distance away from the malformation. The small angiodysplastic vessels of the Foix-Alajouanine lesion may not be opacified with angiography. In rare instances, the fistula or high-flow AVM lies well outside the cord, for example, in the kidney, and gives rise to myelopathy, presumably by raising venous pressures within the cord. Other rare vascular anomalies of the cord  In the Klippel-Trenaunay-Weber syndrome, a sometimes extensive vascular malformation of the spinal cord is associated with a cutaneous vascular nevus overlying the AVM or in a limb supplied by the affected cord level; when the malformation lies in the low cervical region, there may be enlargement of finger, hand, or arm (the hemangiectatic hypertrophy of Parkes Weber; neurofibromatosis is another cause of limb enlargement). Spinal segmental and tract lesions may occur at any age, but the patients we have observed were young adults. Vascular occlusion or hemorrhage was responsible for the myelopathy. Some of these vascular lesions have been treated by defining and ligating their feeding vessels. In a few reported cases, it has been possible to extirpate the entire lesion, especially if it occupied the surface of the cord. Other rare vascular anomalies of the spinal cord include aneurysm of a spinal artery with coarctation of the

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A

B

Figure 42-8.  Dural arteriovenous fistula of the cord. A. Sagittal T2-weighted MRI of the lower spinal cord of a 50-year-old man with progressive myelopathy. Cord edema (T2 hyperintensity at the conus medullaris) and multiple vascular flow voids surrounding the spinal cord and extending up to the mid-thoracic vertebral levels are seen, both the result of the arteriovenous fistula. B. Angiographic injection of the left T12 radicular artery from the patient whose MRI is shown in A, demonstrating abnormal early filling of draining veins surrounding the spinal cord, confirming the presence of an arteriovenous fistula. The fistula was repaired and the patient’s symptoms partially improved.

aorta and telangiectasia of the cord, which may or may not be associated with the hereditary hemorrhagic type of Osler-Rendu-Weber. Over the years, the authors have had under their care patients with the latter disease who developed acute hemorrhagic lesions of the spinal cord. We have also observed several cavernous hemangiomas of the spinal cord. In two of our patients, an angiographically negative solitary cavernous angioma was the source of an acute partial transverse myelopathy. The lesions were clearly demonstrable only in the T2-weighted MR images (McCormick and associates). Characteristically, the angiomas cause partial syndromes and are followed by considerable recovery of function just as when they occur in the brain. There may or may not be blood in the CSF. Rarely the same disease is responsible for one or more hemorrhagic lesions of the brain. The association of cavernous angiomas with arteriovenous fistulas of the lung is a rare finding, and the latter may be a source of brain abscess. In coarctation of the aorta, the circulation to the lower part of the spinal cord may be deficient, with resultant paresis of the legs, sensory loss, and sphincteric impairment. Or there may be intracranial subarachnoid hemorrhage from a ruptured saccular aneurysm, an associated condition in a small number of cases. Treatment  The rate of progression of the myelopathy from these lesions varies greatly, partly dependent on the pathology. In some cases, as already noted, it may

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become a matter of some urgency to reverse the venous congestion and avoid infarction of the cord. Other lesions require a more measured approach. By occluding the feeding artery of a spinal AVM or fistula, which is often single, and thereby eliminating the excess pressure in veins, the course of disease can be arrested and pain reduced (Symon et al). In most of our patients, there has been postoperative improvement in the neurologic deficit over a few weeks or months. In cases of larger racemose AVMs, stripping the enlarged veins along the dorsal cord is no longer considered necessary and may be dangerous. Increasingly, one resorts to obliteration of a fistula or a reduction of the AVM by the use of endovascular techniques and various types of embolic particles. The procedure is long and painstaking, for the operator must identify and embolize all the feeding vessels of the malformation; general anesthesia is required in most cases. This approach has certain drawbacks; recanalization occurs months later in some instances, as does distal occlusion of the venous drainage system with worsening of the myelopathy. For these reasons, surgical ligation of the arterial supply is still preferred as the initial procedure for larger AVMs. Some surgeons advise a staged approach in which the size of the malformation is first reduced by endovascular techniques, thereby making the surgery less complicated. Intradural fistulas are usually treated by endovascular methods, but they can be excised if visualized

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intraoperatively. Interventional techniques have also been used to advantage in intramedullary malformations, either as the sole treatment or in combination with surgery. Focused radiation has been tried, but the results have been difficult to evaluate.

Fibrocartilaginous Embolism This disorder came to attention after a case was described of an adolescent boy who died of sudden paralysis after a fall in a seated position. Postmortem examination revealed extensive myelomalacia as a result of occlusions of numerous spinal vessels by emboli of nucleus pulposus material (Naiman and coworkers). The clinical picture is essentially one of spinal apoplexy; after spinal trauma of even a mild degree, the patient experiences the abrupt onset of pain in the back or neck, accompanied by the signs of a transverse cord lesion affecting all sensory, motor, and sphincteric functions and evolving over a period of a few minutes to 1 h or more. Occasionally, the syndrome spares the posterior columns, thus simulating an anterior spinal artery occlusion. The CSF is normal. As with other types of cord infarction, the changes may not appear on MRI for a day or more. In some of the reported instances, there was said to have been no excessive activity or spinal trauma preceding the spinal cord symptoms. However, this has not been true of our patients, most of who had been participating in some strenuous activity, but often earlier in the day rather than at the time of the paraplegia. Others had fallen and injured themselves on preceding days; a direct blow to the back during contact athletic sports was the antecedent event in several others and is the easiest-to-understand cause. At autopsy, numerous small arteries and veins within the spinal cord are occluded by fibrocartilage, with necrosis of the spinal cord over 1 or 2 segments. A ruptured disc of the usual type is usually not found in these patients, but high-resolution radiographs have exposed a discontinuity of the cortical bone of the vertebral body adjacent to a collapsed disc and herniation of disc tissue into a vertebral body in a few instances (Tosi et al). The explanation is ostensibly that the high intravertebral pressure forces nucleus pulposus material into venules and arteries of the marrow of the vertebral body and thence into the adjacent radicular vessels (Yogananden and colleagues). This mechanism has probably been overlooked in some otherwise unexplained cases of acute ischemic myelopathy.

Caisson Disease (Decompression Sickness, “Bends”) This extraordinary myelopathy, which is well known to the scuba diving community, is observed in persons who are subjected to high underwater pressure and then ascend too rapidly. It affects mainly the upper thoracic spinal cord as a result of nitrogen bubbles that form and are trapped in spinal vessels. There may be little or no involvement of the brain. Haymaker, who provided the most complete account of the neuropathologic changes, observed ischemic lesions mainly in the white matter of the upper thoracic cord; the posterior columns were more affected than lateral and anterior ones. We have encountered instances in which

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an almost complete transverse myelopathy was evident soon after the patient resurfaced, but the syndrome then improved, leaving the patient with an asymmetrical and incomplete albeit permanent residual deficit. The smallest degree of damage is manifest as a minor myelopathy that affects the anterior or the posterior funiculi, leaving either spasticity or numbness of the legs. Immediate treatment consists of recompression in a hyperbaric chamber; later treatment is symptomatic, with antispasticity drugs and physical therapy.

Spinal Subdural Hemorrhage This is an unusual process, but we have reported cases that presented with excruciating thoracic back pain of such severity as to cause a bizarre, almost psychotic reaction (Swann and Ropper). The neck becomes slightly stiff, and there may be a headache, suggesting subarachnoid hemorrhage. However, signs of myelopathy do not appear, indicating that the bleeding is confined to the pliable subdural spaces surrounding the cord, thereby allowing the blood to spread over several segments. Lumbar puncture yields a distinctive dark yellowbrown spinal fluid that resembles, to us, used motor oil. The color is imparted by methemoglobin and reflects the presence of an adjacent, decomposing walled-off clot. Usually, there are also red blood cells in the CSF, suggesting seepage into the subarachnoid space from the adjacent collection. MRI or CT myelography shows a subdural collection with characteristically smooth borders. When drained operatively, this is found to be clotted blood. Usually, no vascular malformation is demonstrable and the cause remains obscure. Trauma or anticoagulation underlies a few cases, but many are spontaneous. The symptoms resolve in 1 or 2 weeks after the removal of the subdural hematoma. Small collections may be managed without surgery, in which case corticosteroids may be helpful in reducing the pain. The syndrome of spinal subarachnoid hemorrhage has been mentioned earlier and is also covered in Chap. 33 under “Other Causes of Intracranial Bleeding and Multiple Cerebral Hemorrhages.”

MYELOPATHIES CAUSED BY DISORDERS OF THE SPINAL COLUMN The gradual development of weakness in the legs is the common manifestation of many diseases of the spinal cord. A syndrome of this type, including ataxia of gait beginning insidiously in late childhood or adolescence and progressing steadily, is usually indicative of hereditary spinocerebellar degeneration (Friedreich ataxia) or one of its variants (see Chap. 38). In early adult life, MS is the most frequent cause and HIV myelopathy is being increasingly recognized; syphilitic meningomyelitis, formerly of great importance, is now uncommon. In middle and late adult life, cervical spondylosis, subacute combined degeneration of the cord (vitamin B12 deficiency), combined system degeneration of the nonpernicious anemia type, some associated with low levels of serum copper, radiation

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myelopathy, tropical spastic paraplegia, spinal arachnoiditis, and thoracic spinal tumor, particularly meningioma, are the important diagnostic considerations for the slowly progressive cord syndrome. In most forms of subacute and chronic spinal cord disease, spastic paraparesis is more prominent than posterior column ataxia, Friedreich ataxia and the myelopathy caused by vitamin B12 deficiency being notable exceptions. Broadly speaking, most acute or subacute myelopathies in adults are due to neoplastic compression from tumor in adjacent bones of the spinal column (a subject afforded a section of its own below), and most chronic instances are due to cervical spondylosis, but in both cases, the differential diagnosis is broad.

Cervical Spondylosis with Myelopathy (Spondylitic Myelopathy) (See Also Chap. 10) It has been stated, correctly in our opinion, that this is the most frequently observed myelopathy in general practice. It is a degenerative disease of the spine involving the lower and midcervical vertebrae that narrows the spinal canal and intervertebral foramina and causes progressive injury of the spinal cord, roots, or both. Historical note Key, in 1838, probably gave the first description of a spondylotic bar or ossified protrusion into the spinal canal. In two cases of compressive myelopathy with paraplegia, he found “a projection of the intervertebral substance and posterior ligament of the spine, which was thickened and presented as a firm ridge that had lessened the diameter of the canal by nearly a third.” The ligament, where it passes over the posterior surface of the intervertebral substance, was found to be “ossified.” In 1892, Horsley performed a cervical laminectomy on such a patient, removing a “transverse ridge of bone” compressing the spinal cord at the level of the sixth cervical vertebra. Thereafter, operations were performed in many cases of this sort, and the tissues removed at operation were repeatedly misidentified as benign cartilaginous tumors or “chondromata.” In 1928, Stookey described the pathologic effects upon the spinal cord and roots of these “ventral extradural chondromas.” Peet and Echols, in 1934, were probably the first to suggest that the so-called chondromata represented protrusions of disc material. But this idea never gained wide credence until the publication, in the same year, of the classic article on the ruptured intervertebral disc by Mixter and Barr. Although their names are associated with the lumbar disc syndrome, 4 of their original 19 cases were instances of cervical disc disease. It was C.S. Kubik who identified the extruded material as nucleus pulposus from surgical specimens obtained by Mixter and Barr at operation. Also of importance is Gowers’ account, in 1892, of vertebral exostoses, in which he described osteophytes that protrude from the posterior surfaces of the vertebral bodies and encroach upon the spinal canal, causing slow compression of the cord as well as bony overgrowth in the intervertebral foramina, giving rise to radicular pain. Gowers correctly predicted that these lesions would offer a more promising field for the surgeon than would other kinds of vertebral tumors.

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For some reason, there was little awareness of the frequency and importance of spondylotic myelopathy for many years after these early observations had been made. All the interest was in the acute ruptured disc. Finally, it was Russell Brain who, in 1948, put cervical spondylosis on the neurologic map, so to speak. He drew a distinction between acute rupture and protrusion of a cervical disc (often traumatic and more likely to compress the nerve roots than the spinal cord) and chronic spinal cord and root compression consequent to disc degeneration and associated osteophytic outgrowths (hard disc), as well as changes in the surrounding joints and ligaments. In 1957, Payne and Spillane documented the importance of a developmentally smaller-than-normal spinal canal in the genesis of myelopathy in patients with cervical spondylosis. These reports were followed by a spate of articles on the subject (Wilkinson).

Clinical Features The characteristic syndrome consists of combinations in varying degrees of: (1) painful, stiff neck or pain in the neck, shoulders, and upper arms (brachialgia) that may be aching or radicular (stabs of sharp and radiating pain evoked by movement), asymmetric or unilateral; (2) numbness and paresthesias of the hands; and (3) spastic leg weakness with Babinski signs, unsteadiness of gait, and a Romberg sign. The numbness and paresthesias are occasionally the earliest symptoms and typically involve the distal limbs, especially the hands. Variations of these symptoms are elaborated below. Each of the components may occur separately, or they may occur in combination, particularly myelopathy with radiculopathy. With reference to the most common of these symptoms, neck and shoulder pain, in any sizable group of patients older than 50 years of age, approximately 40 percent will be found at times to have some clinical abnormality of the neck, usually crepitus or pain, with restriction of lateral flexion and rotation (less often of extension). A survey in the pre-CT and pre-MRI era of 50 patients older than 50 years of age and none with neurologic complaints found that 75 percent showed radiologic evidence of narrowing of the cervical spinal canal as a result of osteophytes of the posterior vertebral bodies or osteoarthropathy at the apophyseal joints; thickening of the ligaments (Pallis and colleagues). However, only half of the patients with radiologic abnormalities showed physical signs of root or cord involvement such as changes in the tendon reflexes in the arms, briskness of reflexes and impairment of vibratory sense in the legs, or Babinski signs. The occasional finding of a Babinski sign in older individuals who had never had a stroke or complained of neurologic symptoms is often explained by an otherwise inevident cervical osteophyte (Savitsky and Madonick). Pain in this disorder is usually centered at the base of the neck or higher, often radiating to an area above the scapula. When brachialgia is also present, it takes several forms: a sharp pain in the pre- or postaxial border of the limb, extending to the elbow, wrist, or fingers; or a persistent dull ache in the forearm or wrist, sometimes with a burning sensation. Discomfort may be elicited by coughing, Valsalva

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maneuver, neck extension, or neck flexion may induce electrical feelings down the spine (Lhermitte symptom). Rarely, the pain is referred substernally. As to the sensory features (which may occasionally be absent), numbness, tingling, and prickling of the hands and soles of the feet and around the ankles are the most frequent complaints. Some patients complain of numbness or paresthesias, most often in one or two digits, a part of the palm, or a longitudinal band along the forearm. Slight clumsiness or weakness of a hand is another complaint. A feeling as if “wearing gloves,” “swollen,” or the hands “coated with glue” are common descriptions. Several of our patients have complained of paresthesias in the distal limbs and trunk for years before there was any indication of motor involvement. In advanced cases, there may be a vague sensory level at or just above the clavicles. Impaired vibratory sensation and diminished position sense in the toes and feet (all indicative of a lesion of the posterior columns), as well as the Romberg sign, are the most conspicuous sensory findings. This imparts a “tabetic” unsteadiness to the gait. Sensory defects tend to be asymmetrical. (It is noteworthy that symmetric sensory symptoms and signs of identical type are seen with subacute combined degeneration from vitamin B12 deficiency.) Less frequently, paresthesias and dysesthesias in the lower extremities and trunk may be the principal symptoms; even less often, there are sensory complaints on the face, ostensibly corresponding to compression of the trigeminal sensory tract in the upper cervical cord. Rarely the sensorimotor pattern takes the form of a Brown-Séquard syndrome. The third part of the typical syndrome, spastic legs from compressive myelopathy, most often manifests as a complaint of weakness of a leg or of getting upstairs and slight unsteadiness of gait. The entire leg or the quadriceps feels stiff and heavy and gives out quickly after exercise. Mobility of the ankle may be reduced, and the advancing toe of the shoe scrapes the floor. On examination, slight hypertonicity of the legs is usually more evident than weakness, and the tendon reflexes are increased (ankle jerks may not share in this change in the elderly). Although the patient may believe that only one leg is affected, it is commonly found that both plantar reflexes are extensors, the one on the side of the stiffer leg being more clearly so. Less often, both legs are equally affected. As the compression continues, walking becomes unsteady because of the addition of sensory ataxia. The biceps and brachioradialis reflexes on one or both sides may be depressed, sometimes in association with an increase in the triceps and finger reflexes. The hand or forearm muscles may undergo atrophy; in a few cases, the atrophy of hand muscles is severe. In such cases, the spondylotic compression, as judged by MRI or CT myelography, may be confined to the high cervical cord, well above the levels of the motor neurons that innervate these muscles. In patients with sensory loss, pain and thermal sensation often appear to be affected more than tactile sense. An unexpected Babinski sign has already been mentioned, and a few fasciculations may be seen, especially in proximal arm muscles. Another unusual feature in advanced stages of cervical cord compression is the appearance of mirror movements of the hands, in which effortful attempts

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to make refined movements of the fingers of one hand causes the opposite hand to move similarly. As the myelopathy progresses, sometimes intermittently, both legs become weaker and more spastic. Sphincteric control may then be altered; slight hesitancy and precipitancy of micturition are the usual complaints; frank incontinence is infrequent. In the more advanced form of this condition, walking requires the aid of a cane or canes or a walker; in some cases, all locomotion ultimately becomes impossible, especially in elderly patient. Abrupt worsening, even paraplegia or quadriplegia, may follow forceful traumatic flexion or extension injuries of the neck, as indicated later.

Pathologic Changes The fundamental lesion of the spinal column is probably generated initially by a fraying of the annulus fibrosus with the extrusion of disc material into the spinal canal. The disc becomes covered with fibrous tissue or partly calcified, thereby forming a transverse osteophytic “spondylitic bar,” or there may be simply central bulging of the annulus without extrusion of nuclear material. The latter, unlike ruptured discs that occur mainly at the C5-C6 or C6-C7 interspace, often involve higher interspaces and may occur at several adjacent levels. The dura may be thickened and adherent to the posterior longitudinal ligament at affected levels. The underlying pia-arachnoid is also thickened and the adjacent ligamentous hypertrophy contributes to the compression of the cord or the nerve roots. This series of pathologic changes is often ascribed to a type of hypertrophic osteoarthritis. However, osteophyte formation and ridging are so frequently observed in patients who have no other signs of arthritic disease that this explanation is surely not totally correct. Subclinical trauma in persons who are structurally susceptible to spondylosis is more likely to be the cause of bar formation, in the authors’ opinion. When a cervical nerve root is compressed by lateral osteophytic overgrowth, the dural sleeve is thickened and truncated and the root fibers are damaged. Usually, the fifth, sixth, or seventh cervical roots are affected in this way, both the anterior and posterior, or only the anterior, on one or both sides. A small neuroma may rarely appear proximal to the site of anterior root compression. The dura is ridged, and the underlying spinal cord is flattened. The root lesions may lead to secondary wedgeshaped areas of degeneration in the lateral parts of the posterior columns at higher levels. The most marked changes in the spinal cord are at the level(s) of compression. There are zones of demyelination or focal necrosis at the points of attachment of the dentate ligaments (which tether the spinal cord to the dura) and areas of rarefaction in the posterior and lateral columns, as well as loss of nerve cells. Ventral gray matter lesions, often asymmetrical, are attributed by Hughes to ischemia.

Pathogenesis The vulnerability of the cervical spine to degenerative change has no ready explanation. Most likely, it is related in some way to the high degree of mobility of the lower

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cervical vertebrae, which is accentuated by their location next to the relatively immobile thoracic spine. The mechanism of spinal cord injury would seem to be one of simple compression and ischemia. When the spinal canal is developmentally narrow in its anteroposterior dimension at one or several points, the space available for the spinal cord becomes insufficient. A small canal certainly makes an individual more subject to the compressive effects of spondylosis. The range acquired of narrowing of the canal that produces symptomatic cervical spondylosis is generally from 7 to 12 mm (normal canal diameter: 17–18 mm). Consequently, one must consider several additional mechanisms by which the cord might be damaged. The effects of the natural motions of the spinal cord during flexion and extension of the neck are probably important in this respect. Adams and Logue confirmed the observation of O’Connell that, during full flexion and extension of the neck, the cervical cord and dura move up and down. The spinal cord is literally dragged over protruding osteophytes and hypertrophied ligaments; conceivably, it is this type of intermittent trauma that causes progressive injury. It has also been shown that the spinal cord, displaced posteriorly by osteophytes, is compressed by the infolding of the posterolateral ligamentum flavum each time the neck is extended (Stoltmann and Blackwood). Segmental ischemic necrosis resulting from intermittent compression of spinal arteries or from compression of the anterior spinal artery has also been postulated. Most neuropathologists favor the idea of intermittent cord compression between osteophytes anteriorly and ligamentum flavum posteriorly, with an added vascular element accounting for the scattered lesions deep in the cord. Trauma from sudden extreme extension, as in a fall, severe whiplash injury, or chiropractic manipulation, or from a lesser degree of retraction of the head during myelography, tooth extraction, or a tonsillectomy may be operative in individual cases, particularly in patients with congenitally narrow canals. The lateral extension of the osteophyte and hypertrophy of the adjacent facet joint together compress the nerve root as it is entering its spinal foramen. Sometimes these are the main changes and cause only a radiculopathy, as discussed in Chap. 10.

Diagnosis When pain and stiffness in the neck, brachialgia, either in the form of aching or a more distinctive radicular pain, and sensorimotor-reflex changes in the arms are combined with signs of myelopathy, there is little difficulty in diagnosis. When the neck and arm changes are inconspicuous or absent, the diagnosis becomes more difficult. The myelopathy must then be distinguished from the late, progressive form of spinal multiple sclerosis. Because posterior vertebral osteophytes and other bony alterations are frequent in the sixth and seventh decades of life, the question that must be answered in any given case is whether the vertebral changes are adequately severe to cause the neurologic abnormality. The finding of some degree of sensorimotor or reflex change corresponding only to the level of the spinal abnormalities is a point that always favors spondylotic

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Figure 42-9.  Sagittal T2 MRI in a patient with symptomatic cervical spondylosis. The spinal cord is severely compressed at the C5-C6 intervertebral disc space. Faint abnormal T2 hyperintensity of the spinal cord can be seen at the point of compression. Following surgical decompression, the patients myelopathic symptoms partially improved.

myelopathy. A lack of such corresponding changes and the presence of oligoclonal bands and signs of lesions in the optic nerves and brain indicate demyelinating myelopathy. The detailed findings on both MRI and CT myelography become critical in such cases (Fig. 42-9). The MRI may overestimate the degree of cord compression by an osteophyte, but clear deformation of the cord into the shape of a kidney bean and obliteration of the surrounding CSF spaces in the transverse image support the diagnosis of spondylotic compression. To confidently attribute neurologic symptoms to spondylosis, there should be considerable encroachment on and obliteration of the circumferential CSF space at that level, not simply an impingement or slight deformation of the normal oval shape of the cord. Signal changes within the body of the cord underlying or within a half segment of the compression are seen in advanced cases and usually indicate a degree of irreversibility of at least the sensory symptoms. Curiously, these signal changes may be one or two levels above or below the site of main compression. A purportedly specific imaging sign of a transverse “pancake-like” gadolinium enhancement at and just caudal to the site of maximal compression has been suggested (Flanagan and colleagues, 2014). However, serious symptoms may occur even without changes in the intrinsic MRI signal. Contrast myelography with the patient supine and lateral views taken during flexion and extension of the neck may be useful diagnostic procedures in uncertain cases.

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It has been stated that spondylotic myelopathy may simulate amyotrophic lateral sclerosis (amyotrophy of arms and spastic weakness of the legs). This has seldom been a diagnostic problem. Although brachial and shoulder fasciculations with muscle atrophy may be combined with hyperreflexia in spondylosis, the widespread denervation and progressive course of ALS are not in evidence. We have observed only a few patients with spondylotic myelopathy who exhibited an absolutely pure motor syndrome, that is, one in which there was no cervical or brachial pain and no sensory symptoms in the arms or impairment of vibratory or position sense in the legs. Likewise, a pure spastic paraparesis is more likely to be a manifestation of MS, hereditary spastic paraplegia, motor neuron disease (primary lateral sclerosis type), HTLV-I myelopathy, or the carrier state of adrenoleukodystrophy or other intrinsic myelopathy. When imbalance, both perceived by the patient and observed in tests of walking, is a major symptom, spondylosis must be differentiated from acquired large-fiber polyneuropathies, particularly inflammatory or immune types and the more benign sensory neuropathy of the aged (see discussion of this entity in Chap. 43). Loss of tactile sensation in the feet and loss of tendon reflexes are characteristic of the latter; examination of the tendon reflexes distinguishes neuropathy from myelopathy. Subacute combined degeneration of the spinal cord because of vitamin B12 deficiency or low serum copper, HIV and HTLV-I myelopathy, ossification of the posterior longitudinal ligament, and spinal cord tumor (discussed further on) are usually listed among the conditions that might be confused with spondylotic myelopathy. The gait abnormality produced by spondylotic myelopathy may also be mistaken for that of normal-pressure hydrocephalus; a marked increase of imbalance with the removal of visual cues (Romberg sign) is a feature of spondylosis but not of hydrocephalus, and the short-stepped and magnetic quality of walking, that is, characteristic of hydrocephalus is not seen in cervical myelopathy (see Chap. 29 for discussion of NPH). Incontinence occurs only in advanced cases of spondylotic myelopathy but usually follows soon after gait deterioration in hydrocephalus. The special problems of spondylotic radiculopathy, which may accompany or occur independently of the myelopathy, are discussed in Chap. 10.

Treatment The slow, intermittently progressive course of cervical myelopathy with long periods of relatively unchanging symptomatology makes it difficult to evaluate the effects of treatment. Assuming that the prevailing view of the mechanism of cord and root compression is correct, the use of a soft collar to restrict anteroposterior motions of the neck seems reasonable. This form of immobilization may be sufficient to reduce discomfort in the neck and arms; only exceptionally in our experience, however, has arm and shoulder pain alone been sufficiently severe and persistent to require surgical decompression unless there is, in addition, a laterally protruded disc or osteophytic constriction of a root foramen. Many patients

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have been dissatisfied with the results of this passive approach and are unable to wear a collar for prolonged periods. If osteophytes have narrowed the spinal canal at several interspaces, a posterior decompressive laminectomy with severance of the dentate ligaments helps to prevent further injury, but the procedure has been partly supplanted by anterior approaches to decompression of the spinal canal. The results of a posterior procedure in relieving symptoms are fairly satisfactory (Epstein and Epstein); in fully two-thirds of the patients, improvement in the function of the legs occurs, and in most of the others, progression of the myelopathy is halted. The operation carries some risk; rarely, an acute quadriplegia—presumably a result of manipulation of the spinal cord and damage to spinal arteries—has followed the surgical procedure. When only one or two interspaces are the site of osteophytic compression, their removal by an anterior approach (anterior cervical discectomy and fusion, or “ACDF”) has apparently given better results and carries less risk. Even with modern surgical techniques, most series indicate that once symptomatic, the outcome varies and that a significant proportion of patients, even after adequate decompression and initial improvement, have persistent symptoms or undergo some degree of later functional deterioration (see also Chap. 10). This creates a conundrum for the physician in advising the patient about the correct time to undertake surgical decompression. Nonetheless, certain clinical observations pertain and may be used as guides to treatment. Any degree of spasticity, sphincter disturbance, or loss of sensation in the hands will not improve or will improve little, and indeed usually worsens over months without surgery. Hand weakness and muscular atrophy that is the result of radicular compression will improve with decompression of the appropriate root by one of several surgical approaches, but weakness that is from central cord damage requires decompression to halt the process and probably should not be delayed more than a few weeks once it is apparent that this is the problem. Usually, such patients have MRI signal changes within the substance of the cervical cord in apposition to an osteophytic bar.

Lumbar Stenosis (See also Chap. 10) This is another spondylotic abnormality seen with particular frequency in older individuals, especially men. As most disease in this category is at the L3 to L5 levels, there is, of course, no myelopathy, however, there is a fair degree of concordance with simultaneous cervical spondylosis. Usually, it declares itself by numbness and weakness of the legs, sometimes with poor control of sphincters. Many texts state that there may be little or no pain or only a spinal ache that fluctuates from day to day, but in our experience, the majority of patients have constant backache and sciatica. A notable feature is the induction or aggravation of the neurologic symptoms upon standing and walking (neurologic claudication). This topic is discussed in “Lumbar Stenosis” in Chap. 10, which should be consulted for a detailed discussion.

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Ankylosing Spondylitis This condition of the spine is a result of inflammation at the sites of ligamentous insertions into the bone that leads to an intense calcification. The sacroiliac joints and lumbar spine are most affected, as discussed in Chap. 10, but as the disease advances, the entire spine becomes fused and rigid. The biomechanics of the rigid spine makes it susceptible to fracture. The most common complication is a spinal stenosis and cauda equina syndrome. Bartleson and associates described 14 patients (and referred to 30 others in the medical literature) who, years after the onset of spondylitis, developed sensory, motor, reflex, and sphincteric disorders referable to L4, L5, and the sacral roots. Surprisingly, the spinal canal was not narrowed, but instead, the caudal sac was actually dilated. There is tentative evidence that enlargement of the lumbar dural sac is caused by a defect in resorption of the CSF (Confavreux and coworkers). There are usually arachnoidal diverticula on the posterior root sleeves, but no other explanation can be given for the radicular symptoms and signs. Surgical decompression has not benefited most patients, nor has corticosteroid therapy. This condition occasionally occurs at higher levels and gives rise to a myelopathy. Our experience includes several cases with symptoms related to the cervical roots. A hazardous complication of ankylosing spondylitis is compression of the cord from seemingly minor trauma that has resulted in fracture–dislocation of the cervical (or lumbar) vertebrae. Most unstable fractures associated with ankylosing spondylitis that require surgical fixation have been in the cervical region, and several patients have fracture–dislocations at two levels (Fox and colleagues). The instability at the upper spinal levels may be difficult to detect by imaging, and caution should be observed in allowing patients to resume full activity after a neck injury if the cervical spine is involved by ankylosing spondylitis. Careful flexion and extension radiograph views usually, but not always, demonstrate the instability. As mentioned briefly earlier, multiple arachnoid cysts in the thoracic or lumbar region are associated with ankylosing spondylitis (and with Marfan syndrome).

Rheumatoid Arthritis of the Spine The spinal changes of rheumatoid arthritis differ somewhat from those of ankylosing spondylitis, although the latter too may be a cause of atlantoaxial dislocation (see further on under “Anomalies at the Craniocervical Junction”). The ligaments that attach the odontoid to the atlas and to the skull and the joint tissue are weakened by the destructive inflammatory process. The subsequent dislocation of the atlas on the axis may remain mobile or become fixed and give rise to an intermittent or persistent paraparesis or quadriparesis. Similar effects may result from a forward subluxation of C4 on C5 (Nakano et al). Atlantoaxial dislocation is known to be a cause of collapse and sudden death. If the upper cervical cord is compressed, the odontoid process must be removed and C1-C2 decompressed and stabilized. Other levels of the spine are less frequently affected.

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Ossification of the Posterior Longitudinal Ligament (OPLL) Compressive cervical myelopathy caused by this process occurs mostly in patients of Japanese extraction (approximately 3% incidence in Japan) and elsewhere in the Pacific rim and was demonstrated to us as an almost mundane finding by colleagues in Hawaii. The clinical signs are much the same as those of cervical spondylosis, but the radiologic appearance of cancellous bone along a segment of the posterior longitudinal ligament is unique. The ligamentous calcification can be seen on plain X-ray films, CT, and MRI as a vertical longitudinal row of calcification and may be mistaken for spondylotic change. The ossified areas may enlarge enough to form islands of bone marrow. Laminoplasty with enlargement of the spinal canal has been successful.

Cervical Dural Sac Myelopathy (Hirayamn persons a Disease) This unusual myelopathy has usually been considered in discussions of motor neuron disorders because of its characteristic features of chronic wasting of one, or less often, or both hands and forearms without sensory changes or long tract signs. It appears, however, that the damage in this disease is from intermittent compression of the lower cervical cord and gradual deterioration of the motor neurons in the anterior grey matter. Hirayama’s group pointed out that in the young men who were affected, the mechanism of cord damage is a buckling of the dorsal dural sac and an intermittent anterior displacement and ligamentous compression of the cord during flexion of the neck. Although the disorder is highlighted as occurring mainly in Asia, we continue to sporadically see cases in young men from the United States. The muscles innervated by C7, C8, and T1, encompassing mainly the hand and forearm, are affected on one side or bilaterally but almost always markedly asymmetrically. There are few or no fasciculations and no sensory changes; the painless loss of power and muscle bulk proceeds smoothly over several years, giving the impression of a degenerative condition. MRI or CT myelogram performed with the neck flexed, as described by Hirayama and Tokumaru, shows the cervical cord to be atrophic with signal changes in the anterior parts of the cord and confirms the diagnosis of compression by the buckled dura. We have examined several such patients and can corroborate their claim from observation of MRI with the patient placed in a flexed-neck position. Presumably, this configuration causes ischemia of the anterior gray matter, but this has not been proved. Others have reported the syndrome in the absence of this structural configuration (Willeit et al). Two of our young male patients had long swan-like necks. What is important about this process is the degree of recovery afforded by ligamentous sectioning and by similar surgical approaches that accomplish decompression of the lower cervical cord, but outcomes have not been well studied in a systematic manner.

Paget Disease of the Spine (Osteitis Deformans) Enlargement of the vertebral bodies, pedicles, and laminae in Paget disease may result in a narrowing of the spinal canal. The clinical picture is one of cord compression.

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The plasma alkaline phosphatase concentration is high, and the typical bone changes are seen in radiographs. Usually, several adjacent vertebrae of the thoracic spine are affected, but other parts of the skeleton are also involved (see later), which facilitates diagnosis. Posterior surgical decompression leaving the pedicles intact is indicated if there is sufficient stability of the vertebral bodies to prevent collapse. Medical management includes the use of nonsteroidal anti-inflammatory drugs for persistent pain; calcitonin to reduce pain and plasma levels of alkaline phosphatase; and cytotoxic drugs such as plicamycin and etidronate disodium to reduce bone resorption.

Herniation of the Cord Through a Dural Tear Violent trauma to the spinal canal or skull, such as a fall or blow to the back, can cause arachnoidal and dural tears. The associated neural injury dominates the picture and the dural tear may require repair so as to minimize the development of meningitis. More difficult to understand is the occurrence of spinal cord herniation through a spontaneous rent in the adjacent dura, usually with no preceding injury. We have encountered numerous such instances, suggesting the condition is not rare. In the typical case, a vertically oriented tear of limited extent occurs in the ventral dura overlying the midor high-thoracic region, and a segment of the spinal cord protrudes through it into the epidural space. The result is a painless, subacute, and incomplete spinal cord syndrome, which reaches a plateau and leaves the patient with an asymmetrical spastic paraparesis and variable sensory loss. There are reports of a Brown-Séquard hemi-cord syndrome and variations of it as described (Watters and colleagues). Orthostatic headache of low-CSF pressure is not usually part of the syndrome. MRI or CT myelography demonstrates the protruded segment of the cord where it buckles through the dura. Presumably, the herniation creates a sufficient degree of local ischemia or mechanical disturbance to account for the myelopathic symptoms. Surgical restoration of the cord to its proper position and repair of the tear has resulted in partial or complete return of neurologic function (Vallee et al). As to the cause of this condition, a congenital duplication of the dural membranes combined with herniation through the inner layer has been observed in some cases at operation. The abnormal configuration of the membrane has been proposed as a cause of the propensity for the fibers to separate and create an aperture.

Congenital Anomalies at the Craniocervical Junction Of these, congenital fusion of the atlas and foramen magnum is the most common. In a large series of patients with bony abnormalities at the craniocervical junction, this partial or complete bony union of the atlas and occipital bone was found in 28 percent of cases (McCrae). It has also been noted that whenever the anteroposterior diameter of the canal behind the odontoid process was less than 19 mm, there tend to be signs of spinal cord compression. Fusion of the second and third cervical vertebrae is a common associated anomaly but does not seem to be of clinical significance. There is a

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considerable crossover with the foreshortened neck of the Klippel-Feil syndrome mentioned in the following text. Abnormalities of the odontoid process There may be complete separation of the odontoid from the axis or chronic atlantoaxial dislocation (atlas displaced anteriorly in relation to the axis). These abnormalities may be congenital or the result of injury and are known causes of acute or chronic spinal cord compression and stiffness of the neck. In all the congenital anomalies of the foramen magnum and the upper cervical spine, there is a high incidence of syringomyelia. Up to a third of all patients with syringomyelia and syringobulbia show such bony anomalies, but this is considerably higher than in our experience. All patients whose symptoms might be explained by a lesion in the cervicocranial region (particularly patients in whom MS and foramen magnum tumor are suspected) require careful imaging examination. In mucopolysaccharidosis IV, or the Morquio syndrome (Chap. 36), a typical feature is the absence or severe hypoplasia of the odontoid process. This abnormality, combined with laxity or redundancy of the surrounding ligaments, results in atlantoaxial subluxation and compression of the spinal cord. Affected children refuse to walk or develop spastic weakness of the limbs. Early in life, they excrete an excess of keratan sulfate, but this may no longer be detectable in adult life. In certain of the mucopolysaccharidoses, we have also seen a true pachymeningopathy with great thickening of the dura in the basal cisterns and high cervical region with spinal cord compression. Surgical decompression and spinal immobilization have been curative. Achondroplasia  This dominantly inherited form of dwarfism is caused by a mutation in one of the fibroblastic growth factors, which causes a failure of conversion of fetal cartilage to bone at the growth plate. It occasionally results in great thickening of the vertebral bodies, neural arches, laminae, and pedicles because of increased periosteal bone formation. The spinal canal is narrowed in the thoracolumbar region, often with kyphosis, leading sometimes to a progressive spinal cord or cauda equina syndrome. Another complication, which results from a small foramen magnum, is hydrocephalus (or markedly widened subarachnoid spaces). In young children, a syndrome of central apnea and spasticity of the legs is characteristic. These complications may require ventricular shunting. Narrowing of the lumbar canal tends to present later in life. Platybasia and basilar invagination  Platybasia refers to a flattening of the base of the skull (the angle formed by the intersection of the plane of the clivus and the plane of the anterior fossa is greater than 135 degrees). Basilar impression or invagination has a somewhat different meaning, namely, an upward bulging of the occipital condyles; if the condyles, which bear the thrust of the spine, are displaced above the plane of the foramen magnum, basilar invagination is present. Each of these abnormalities may be congenital or acquired (as in Paget disease); frequently, they are combined. They give rise to a characteristic shortness of the neck and a combination of cerebellar and spinal signs. A normal-pressure hydrocephalus may also develop.

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In the Klippel-Feil syndrome, there is a fusion of the upper cervical vertebrae or of the atlas to the occiput. The anomaly is easily identified by substantial foreshortening of the neck. Affected individuals are susceptible to compression of the cervical cord after minor trauma. Many such patients demonstrate mirror movements of their hands, comparable to those described earlier in cervical spondylosis.

Dysraphic Syndromes (Spina Bifida) and Tethered Cord These are described in Chap. 37 but should be considered in cases of chronic and progressive syndromes of the cauda equina and conus medullaris. In tethered cord, a progressive cauda equina syndrome with prominent urinary difficulties and varying degrees of spasticity are the usual presentations.

NUTRITIONAL AND TOXIC MYELOPATHIES Subacute Combined Degeneration of the Spinal Cord (See Chap. 40) This form of nutritional spinal cord disease is caused by vitamin B12 deficiency and is fully described in Chap. 40. Almost invariably, it begins with bilateral symptoms and signs of posterior column involvement in the hands (paresthesias and reduced touch, pressure, and joint sensibility), which, if untreated, is followed within a matter of several weeks or months by progressive spastic paraparesis because of involvement of the corticospinal tracts to which a vague sensory level on the trunk may be added. Particular importance attaches to the fact that this is a treatable disease and that the degree of reversibility is dependent upon the duration of symptoms before specific treatment is begun.

Copper Deficiency Myelopathy (Combined System Disease of Nonpernicious Anemia Type) This refers to a metabolic disease of the spinal cord caused by low copper, affecting the posterior and lateral columns, in this sense, also a combined system degeneration (Kumar and colleagues). A homologous disease exists as “swayback” in lambs. A deficiency of vitamin B12 is not causative but may coexist in some cases, probably on the basis of a shared inadequacy of dietary intake. Women are more often affected than men. Imbalance is the most common presenting complaint. Posterior column signs and gait ataxia tend to predominate, but a degree of spasticity is usually conjoined, and there may be Babinski signs and reduced ankle reflexes. The problem is typically one of impaired absorption of copper, for example, after gastric bypass or bowel surgery, which together account for half of the cases. Of importance in causation in some patients is excess zinc intake in the form of health supplements, coin swallowing, and denture creams (see Nations et al). There is usually an associated hypocupremic anemia with ringed sideroblasts and leukopenia with vacuolated myeloid precursors in the marrow that may be mistaken for a myelodysplastic process. The idiopathic

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variety has certain similarities to the disorder of copper mobilization in Menkes disease, but the disordered enzyme responsible for the latter has been normal. As reported by others, in a recent case on our service without explanation for the discovered copper deficiency, an MRI of the cervical cord revealed distinctive signal changes in both the posterior and lateral columns, identical to those of B12 deficiency, and these were no longer present after copper treatment. Most affected patients have abnormal somatosensory evoked potentials with delays in central conduction. Treatment  Oral copper supplementation, 2 mg/d for at least several months, seems effective in most patients, but some do not improve and the appropriate duration of treatment is unknown. Some patients relapse after an initial improvement even with continued administration or when copper supplementation is stopped. The gluconate, sulfate, or chloride preparations of copper may be used, although there has been concern about the bioavailability of the first-named compound. Intravenous therapy as a way of initially replenishing copper stores has been introduced, but the need for such treatment is uncertain. Zinc supplements must, of course, be discontinued, as they lower copper levels. There remains a group of subacute ataxic-spastic myelopathies that ostensibly are not caused by multiple sclerosis or by B12 or copper deficiency and we have been unable to properly categorize them; presumable some are nevertheless due to multiple sclerosis. Progressive spastic or spastic-ataxic paraparesis of a chronic, irreversible type may also develop in conjunction with chronic, decompensated liver disease; with AIDS; in cases of adrenoleukodystrophy, particularly in the symptomatic female heterozygote; in tropical spastic paraplegia (HTLV-I); radiation myelopathy; and adhesive spinal arachnoiditis, which was discussed above.

Lathyrism (See Also Chap. 41) From the interesting historical review of Dastur, one learns that this disease was known to Hippocrates, Pliny, and Galen in Europe, to Avicenna in the Middle East, and to the ancient Hindus. The term lathyrism was applied by Cantani, in Italy, because of its recognized relationship to the consumption of Lathyrus sativus (chickling vetch, vetch pea, or grass pea). In general medicine, the disorder is more closely associated with aortic dissection and the myelopathy has been termed neurolathyrism. The disease is still common in some parts of India and Africa. In these districts, during periods of famine when wheat and other grains are in short supply, the diet may, for months, consist of flour made of the grass pea. In individuals so exposed, a gradual weakening of the legs accompanied by spasticity and cramps occurs. Paresthesias, numbness, formication in the legs, and frequency and urgency of micturition, erectile dysfunction, and sphincteric spasms are added. The upper extremities may exhibit coarse tremors and involuntary movements. These symptoms, once established, are more or less permanent but not progressive, and most of the patients live out their natural life span.

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Only two reports on the neuropathology of lathyrism were known to Dastur, one by Buzzard and Greenfield in England, the other by Filiminoff in Russia. Both of their patients had been in a stationary paraplegic state for years. Greenfield noted a loss of ascending and descending tracts in the spinal cord, particularly the corticospinal and direct spinocerebellar tracts. Filiminoff observed a loss of myelinated fibers in the lateral and posterior columns. Unlike the cases of Spencer and colleagues, there had been a loss of pain and thermal sensation in the upper extremities. The larger Betz cells had disappeared, while anterior horn cells were unaffected. Gliosis and thickening of blood vessels were seen in the degenerated tracts. The toxic nature of this disease, long suspected, has been confirmed (Spencer and colleagues). They extracted a neuroexcitatory amino acid, beta-N-oxalylamino-L-alanine (BOAA), from grass peas and were able to induce corticospinal dysfunction in monkeys by giving this substance with a nutritious diet. Subsequently, a primate model of lathyrism was developed by feeding monkeys a diet of L. sativus in addition to an alcoholic extract of this legume (Constantini and colleagues). These findings tend to negate the importance of several other factors that had been thought to be causative, namely, malnutrition, ergot contamination, and toxins derived from Vicia sativa, the common vetch that grows alongside the Lathyrus species. The African acute spastic paraplegia called konzo has a similar toxic pathogenesis; it is caused by cyanide-like compounds in flour made from cassava.

NEOPLASTIC AND PARANEOPLASTIC MYELOPATHIES Intraspinal Tumors (See also Chap. 30) Compression of the spinal cord by a metastatic tumor in the vertebral column is a common occurrence in many types of cancers. Primary tumors of the spinal cord are considerably less frequent. In a Mayo Clinic series of 8,784 primary tumors of the CNS, only 15 percent were intraspinal (Sloof et al). In contradistinction to brain tumors, the majority of intraspinal ones are benign and produce effects mainly by compression of the spinal cord rather than by invasion. Thus, a proportion of intraspinal tumors are amenable to surgical removal, and their early recognition, before irreversible neurologic changes have occurred, becomes a matter of utmost importance.

General Considerations of Neoplastic Compression of the Cord (See Also Chap. 30) Neoplasms and other space-occupying lesions within the spinal canal can be divided into two groups: (1) those that arise within the substance of the spinal cord, either as a primary neural neoplasm or as a metastasis and invade and destroy tracts and central gray structures (intramedullary) and (2) those arising outside the spinal cord (extramedullary), either from vertebral bodies and epidural tissues (extradural) or in the leptomeninges or roots (intradural). In a general hospital, the relative frequency

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of spinal tumors in these different locations is approximately 5 percent intramedullary, 40 percent intradural– extramedullary, and 55 percent extradural, the majority of the latter being metastatic cancers, as already mentioned. This percentage of extradural lesions is higher than that encountered in more specialized neurosurgical services (e.g., Elsberg’s figures of 7, 64, and 29 percent, respectively), probably because the latter do not include as many patients with extradural lymphomas, metastatic carcinomas, and the like, as are seen in general hospitals. Intraspinal tumors  The most common primary extramedullary tumors are the neurofibromas and meningiomas, which together constitute approximately half of all intraspinal neoplasms. They are more often intradural than extradural. Neurofibromas have a predilection for the lumbar and thoracic region, whereas meningiomas are more evenly distributed over the vertical extent of the cord (Fig. 42-10). The other primary extramedullary tumors are sarcomas, vascular tumors, chordomas, and epidermoid and similar tumors, in that order of frequency. Primary intramedullary tumors of the spinal cord have the same cellular origins as those arising in the brain (Chap. 30), although the proportions of particular cell types differ. Ependymomas, some of which arise from the filum terminale, make up 60 percent of spinal cord cases, and astrocytomas make up approximately 25 percent. The astrocytoma is the most common intramedullary tumor if one excludes tumors arising in the filum terminale (Fig. 42-11). Oligodendrogliomas are much less common. The remainder (approximately 15 percent) consists of a diverse group of nongliomatous tumors: lipomas, epidermoids, dermoids, teratomas, hemangiomas, hemangioblastomas, chordomas, schwannomas, and intraspinal metastatic carcinomas. The cavernous hemangioma may be a source of spontaneous hematomyelia. As indicated further on, there is a frequent association between intramedullary tumors (both gliomatous and nongliomatous) and syringomyelia. The basis of this relationship remains obscure. Spinal ependymomas arise from ependymal lining of the central canal of the spinal cord. The myxopapillary type originates from clusters of ependymal cells in the filum terminale. The myxopapillary ependymoma that originates in the filum terminale causes a special syndrome referable to both lumbar roots (cauda equina) and conus. As commented in Chap. 30, a combination of asymmetric or bilateral sciatic or anterior thigh pain, sphincter difficulty, and upper motor neuron signs is typical. These spinal tumors occur in adults as often as in children, quite different from intracranial ependymomas, which are mainly childhood tumors. Although they are considered to be benign, intraspinal spread can occur and local recurrence after resection occurs in 10 percent of cases, even decades after surgery (Rezai and colleagues). Treatment is with surgical removal and selective radiation if there has not been gross total removal; long-term survival is the rule. The main differential diagnosis is a spinal schwannoma (neurofibroma). Intramedullary growths invade as well as compress and distort fasciculi in the spinal cord white matter. As the cord enlarges from the tumor growing within it or is compressed

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Figure 42-10.  Sagittal (left) and axial (right) gadolinium-enhanced T1-weighted MRI of an intraspinal meningioma that displaced and compressed the spinal cord, causing incontinence and leg weakness. As in intracranial meningiomas, homogenous contrast enhancement and a dural attachment are seen.

Figure 42-11.  Sagittal T2-weighted MRI of a primary glioma of the thoracic spinal cord in a middle-aged man. Note the expansion of the spinal cord.

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by a tumor from without, the free space around the cord is eventually consumed, and the CSF below the lesion becomes isolated or loculated from the remainder of the circulating fluid above the lesion. This is marked by Froin syndrome (xanthochromia and clotting of CSF from greatly elevated protein content) and an interruption of the flow of contrast medium in the subarachnoid space (examination of CSF has been surpassed as a test by modern imaging). The most informative diagnostic procedure is an MRI, which demonstrates both the intramedullary extent of the tumor and the effect on the surrounding subarachnoid space. Secondary spinal cord tumors can also be subdivided into intramedullary and extramedullary types. Extradural metastases (carcinoma, lymphoma, myeloma) are the most common of all spinal tumors. They account for the largest group of patients who develop symptoms of myelopathy while being cared for in hospital and are, therefore, likely to be encountered in the course of neurologic consultations. Extradural metastases arise from hematogenous deposits or extend from tumors of the vertebral bodies or from a paraspinal tumor extending via the intervertebral foramina (Fig. 42-12). Secondary extramedullary tumor growths are far more often extradural than intradural. The intradural type takes the form of meningeal carcinomatosis or lymphomatosis and the rare primary melanoma of the meninges, which are considered in Chap. 30. Intramedullary metastases are not as rare as is generally believed. A retrospective autopsy study of 627 patients

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Figure 42-12. Sagittal T1-weighted MRI showing multiple spinal metastases from carcinoma of the lung. The metastases exhibit low signal intensity due to tumor replacement of bone marrow, which is normally T1 hyperintense.

Figure 42-13.  Sagittal T2 MRI of an intramedullary metastasis from breast cancer. The expansile lesion is at the T2 vertebral level (arrow) and the adjacent edema extends superiorly and inferiorly over a great length of the spinal cord.

with systemic cancer (Costigan and Winkelman) found 153 cases with CNS metastases, in 13 of which the metastases were located within the cord. In 9 of the 13 cases, the metastasis was deep in the cord, unassociated with leptomeningeal carcinomatosis; in 4 cases, the neoplasm seemed to extend from the pia. Bronchogenic carcinoma was the main source. Diagnosis is difficult but is aided greatly by MRI with gadolinium enhancement; there is generally extensive contiguous edema (Fig. 42-13). Differentiation is from meningeal carcinomatosis, radiation myelopathy, and paraneoplastic necrotizing myelopathy, which is the least common of these entities. Treatment is often ineffective unless radiation therapy is begun before paraplegia supervenes (Winkelman et al).

prominent initially; scoliosis and spastic weakness of the legs come later. Because of this somewhat unusual clinical presentation and the rarity of intraspinal lesions in childhood, spinal cord tumors in this age group may be overlooked. Sensorimotor spinal tract syndrome  The clinical picture is related predominantly to compression and less often to invasion and destruction of spinal cord tracts. The signs of compression consist of a combination of (1) an asymmetrical spastic weakness of the legs with thoracolumbar lesions and of the arms and legs with cervical lesions, (2) a sensory level on the trunk below which perception of pain and temperature is reduced or lost, (3) posterior column signs, and (4) a spastic bladder under weak voluntary control. The onset of the compressive symptoms is usually gradual and the course progressive over a period of weeks and months, frequently with back pain. With extradural tumors, paralysis usually develops over a period of days to several weeks, but the tempo of progression may be more rapid or more leisurely. The initial disturbance may be of motor or sensory function and the distribution may be asymmetrical. High cervical or foramen magnum lesions produce special clinical syndromes, as described in Chap. 3 and in the following text. With thoracic lesions, one leg usually becomes weak and stiff before the other one. Subjective sensory symptoms of the dorsal column type (tingling paresthesias) assume similar distributions. Pain and thermal senses are more likely to be affected than tactile, vibration, and position senses. Nevertheless, the posterior

Clinical Features Patients with spinal cord tumors are likely to present with one of three clinical syndromes: (1) a sensorimotor spinal tract syndrome, (2) a painful radicular-spinal cord syndrome, or (3) least often, an intramedullary syringomyelic syndrome. Some of the sensory features of these syndromes are depicted in Fig. 8-7 of Chap. 8. Pain and stiffness of the back may antedate signs of spinal cord disease or dominate the clinical picture in some cases of extramedullary tumor. The back pain is usually worse when the patient lies down or may become worse after several hours in the recumbent position and be improved by sitting up. In children, severe back pain associated with spasm of paravertebral muscles is often

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columns are frequently involved as the process progresses. Initially, the sensory disturbance is contralateral to the maximum motor weakness, but a sharply defined BrownSéquard hemicord syndrome is rarely observed. The bladder and bowel usually become paralyzed coincident with paralysis of the legs. If the compression is relieved, there is recovery from these sensory and motor symptoms, often in the reverse order of their appearance; the first part affected is the last to recover, and sensory symptoms tend to disappear before motor ones. Radicular-spinal cord syndrome Here, the syndrome of spinal cord compression is combined with radicular pain, that is, pain in the distribution of a sensory nerve root. The discomfort is described as knife-like or as a dull ache with superimposed sharp stabs of pain, which radiate in a distal direction, that is, away from the spine, and are intensified by coughing, sneezing, or straining. Segmental sensory changes (paresthesias, impaired perception of pinprick and touch) or motor disturbances (cramp, atrophy, fascicular twitching, and loss of tendon reflexes) and an ache in the spine, in addition to the radicular pain, are the usual manifestations. Tenderness of the spinous processes over the tumor is found by percussion in about half the patients. The segmental changes, particularly the sensory radicular ones, often precede the signs of spinal cord compression by months if the lesion is benign. Intramedullary syringomyelic syndrome No single symptom is unique to the intramedullary tumors. Some degree of pain, sometimes minor, is common and is almost invariably present with tumors of the filum terminale. Ependymomas and astrocytomas, the two most common intramedullary tumors, usually give rise to a mixed sensorimotor tract syndrome. When the intramedullary tumor involves the central gray matter, a central cord or syringomyelic syndrome may result. The main features are segmental or dissociated sensory loss, amyotrophy, early incontinence, and late corticospinal weakness. Sacral sparing of sensation may be found as described in Chap. 8 on the sensory syndromes but is of less value in distinguishing intramedullary from extramedullary lesions. A dissociation of thermal pain and tactile sensory loss over several contiguous segments on the trunk is a more dependable sign of an intramedullary lesion. Rarely, an extramedullary tumor may give rise to a syringomyelic sensory syndrome, possibly by causing vascular insufficiency in the central portion of the cord. Special spinal syndromes  Unusual clinical syndromes may be found in patients with tumors in the region of the foramen magnum, as discussed in Chap. 3. They produce quadriparesis with pain in the back of the head and stiff neck, weakness and atrophy of the hands and dorsal neck muscles, marked imbalance, and variable sensory changes or, if they spread intracranially, there may be signs of cerebellar and lower cranial nerve involvement. Slowly growing tumors in this region, such as meningiomas, characteristically produce an “around the clock” progression of weakness beginning in one limb and proceeding to the adjacent one in a clockwise or counterclockwise direction. Lesions at the level of the lowermost thoracic and the first lumbar vertebrae may result in mixed cauda equina and spinal

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cord symptoms. A Babinski sign indicates that the spinal cord is involved above the fifth lumbar segment. Lesions of the cauda equina alone, always difficult to separate from those of the lumbosacral plexuses and multiple nerves, are usually attended in the early stages by sciatic and other root pain and lumbar ache, which are variously combined with a bilaterally asymmetrical, atrophic, areflexic paralysis, radicular sensory loss, and sphincteric disorder. These must be distinguished from lesions of the conus medullaris (lower sacral segments of the spinal cord), in which there are early disturbances of the bladder and bowel (urinary retention and constipation), back pain, symmetrical hypesthesia or anesthesia over the sacral dermatomes, a lax anal sphincter with loss of anal and bulbocavernosus reflexes, impotence, and sometimes weakness of leg muscles. Sensory abnormalities may precede motor and reflex changes by many months. Very rarely, for unclear reasons, tumors of the thoracolumbar cord (intramedullary, as a rule) are associated with markedly elevated spinal fluid protein and hydrocephalus; these respond to shunting and removal of the spinal tumor (Feldman et al). Less often, these tumors are associated with a pseudotumor cerebri syndrome.

Differential Diagnosis Several problems arise in the diagnosis of spinal cord tumors in addition to several previously mentioned. In the early stages, neoplastic compression or invasion of the cord must be distinguished from other diseases that cause pain over certain segments of the body, for example, diseases affecting the gallbladder, pancreas, kidney, stomach and intestinal tract, and pleura. Localization of the pain to a dermatome; its intensification by sneezing, coughing, and straining, and sometimes by recumbency; and the finding of segmental sensory changes and minor alterations of motor, reflex, or sensory function in the legs will usually provide the clues to the presence of a spinal cord–radicular lesion. MRI will settle the diagnosis in most instances. The pain of tumor or blood clot in the retroperitoneal space may cause orthostatic and nocturnal back pain that is similar to that of spinal tumor. There is then the problem of locating the segmental level of the lesion. At first, the sensory and motor deficits may be most pronounced in those parts of the body farthest removed from the lesion, that is, in the feet or lumbosacral segments. Later the levels of the sensory and motor deficits ascend, but they may still be at a level several segments below the lesion. In determining the level of the lesion, the location of back pain, root pain, and atrophic paralysis are of greater help than the upper level of hypoalgesia. Once vertebral and segmental levels of the lesion are established, there remains the necessity of determining whether the lesion is extradural, intradural–extramedullary, or intramedullary and whether it is neoplastic. If there is a visible or palpable spinal deformity or imaging evidence of vertebral destruction, one may confidently assume an extradural localization. Even without these changes, one still suspects an extradural lesion if root pain developed early and is bilateral if pain and aching in the spine are prominent and percussion tenderness is marked, if motor symptoms below the lesion preceded sensory ones

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and if sphincter disturbances were late. However, to distinguish between intradural–extramedullary lesions and intramedullary lesions on clinical grounds alone is often difficult. The findings of segmental amyotrophy and sensory loss of dissociated type (loss of pain and temperature and preservation of tactile sensation) point to an intramedullary lesion. Extradural tumors, both primary and secondary, must be differentiated from cervical spondylosis, tuberculous granuloma, sarcoidosis, AVMs of the cord, spinal dural fistulas, and certain chronic pyogenic or fungal granulomatous lesions, as well as from lipomas in patients receiving corticosteroids for prolonged periods and from the necrotizing myelopathy associated with occult tumors or occurring independently of them. A number of rarer conditions of the vertebral bodies, such as bone cysts, chondromas, eosinophilic granuloma, chordomas, and giant cell tumors, must also be considered. In the thoracic region, a ruptured disc or eventration of the cord through a dural tear is always a possibility. In the region of the lower back, that is, over the cauda equina, one must also distinguish between tumor and protruded intervertebral disc. Here, an extradural tumor may produce mainly sciatic and low back pain with little or no motor, sensory, reflex, or sphincteric disturbances. With intradural–extramedullary lesions, the important diagnostic considerations are meningioma, neurofibroma, meningeal carcinomatosis, cholesteatoma, and teratomatous cyst, a meningomyelitic process, or adhesive arachnoiditis. Intramedullary lesions are usually gliomas, ependymomas, or vascular malformations or, in the context of a known carcinoma, intramedullary metastases. The definition of vascular malformations by means of selective spinal angiography was discussed in an earlier section. Normal protein in the CSF and negative MRI effectively exclude an intramedullary tumor.

as well as those who have surgical decompression (Gilbert et al). However, a comparison of five different radiation programs (Nieder and colleagues) suggested there is little difference between approaches. Radiosurgery techniques change so rapidly that it is difficult to determine and compare outcomes. The issue of radiosensitivity of any particular tumor has become only a relative one as high doses of focal radiation are being delivered in one or a few fractions by stereotactic techniques. Laminectomy and decompression are appropriate to prevent irreversible compressive effects for rapidly growing tumors that have caused recent and severe loss of function below the level of compression. Cases that have been allowed to progress can be operated on if paraplegia has occurred within 1 or perhaps 2 days and the overall state of the patient’s cancer makes survival likely for at least several weeks. An often-cited trial comparing radiation and surgery (Patchell and colleagues) suggested that ambulation is preserved for a longer time with surgery than without. All these comments refer to compression of the cord at a single level. If the maximal safe radiation dosage had previously been applied to the spinal column or the diagnosis can only be made from tissue obtained from the site of spinal compression, surgical palliation is usually undertaken. Intradural–extramedullary tumors are generally removed if this can be accomplished safely, and this applies to benign extradural tumors that are symptomatic as well. Laminectomy, decompression, excision in isolated cases, and radiotherapy constitute the treatment of intramedullary gliomas. Such patients may improve and lead useful lives for a decade or longer. Based on a large experience with intramedullary lesions, mainly gliomas in children and young adults, recommend a radical excision of the tumor (Constantini and colleagues), but this approach has not been subjected to a trial.

Treatment

Other Causes of Spinal Cord Compression

The main consideration in the management of epidural metastases is the need for early diagnosis, at a stage when only back pain is present and before neurologic symptoms and signs have appeared. Once these signs appear, especially sphincter disturbances, the results of treatment are less successful but may still result in good limb and bladder function. Epidural growths of carcinoma and lymphoma have been typically managed by the administration of high to moderate doses of corticosteroids and radiation of the region of tumor, although surgical options exist and provide faster decompression and the opportunity for stabilization of the spinal column. The choice of surgery or stereotactic radiation is complex, partly stylistic, and dependent on the likelihood of survival, as noted in the following text, and possibly by the radiosensitivity of the tumor (Ropper and Ropper). Treatment may be supplemented by either endocrine therapy (for carcinoma of breast and prostate) or antineoplastic drugs (for certain lymphomas and myelomas. Pain relief is sometimes difficult to attain and requires narcotics. Evidence has been presented that patients who receive high-dose corticosteroids (16–60 mg of dexamethasone) and fractionated radiation (500 cGy on each of the first 3 days and then spaced radiation up to 3,000 cGy) do,

Epidural fat deposition (epidural lipomatosis) with spinal cord compression occurs in Cushing disease and after the long-term use of corticosteroids, but also in the absence of these disorders. The clinical picture may suggest discogenic disease (Lipson et al). Copious amounts of normal adipose tissue are found at laminectomy and removal of this tissue is curative. Lowering the dose of steroid and caloric restriction may help mobilize the fat and relieve the symptoms. An intra-spinal lipoma is also a component of the developmentally tethered cord, but in this process, the essential problem is a conus medullaris myelopathy from stretching of the cord rather than compression (see Chap. 37 and Thomas and Miller.) Arachnoid diverticula—intra- or extradural outpouchings from the posterior nerve root—are rare causes of a radicular-spinal cord syndrome, first described by Bechterew in 1893. They tend to occur in the thoracic or lumbosacral regions. The symptoms, in order of decreasing frequency, are pain, radicular weakness and sensory disorder, gait disorder, and sphincteric disturbances (Zilluffo et al). The frequent association of arachnoid diverticula with osteoporosis, ankylosing spondylitis, and arachnoiditis makes it difficult to interpret the role of the

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diverticula themselves. Surgical obliteration of the pouches has yielded unpredictable results. They have attained clinical importance more often as the source of spontaneous CSF leaks and a low-pressure syndrome (see Chap. 29). Spinal cord compression with paraplegia may be caused by extramedullary hematopoiesis in cases of myelosclerosis, thalassemia, cyanotic heart disease, myelogenous leukemia, sideropenic anemia, and polycythemia vera. A similar phenomenon occurs with ossification of the posterior longitudinal ligament, as described earlier. Solitary osteochondromas of vertebral bodies and multiple exostoses of hereditary type are other reported causes of spinal cord compression (Buur and Morch). The clinical syndrome has been one of spastic paraparesis of several months’ progression.

Genetic and Degenerative Disorders of the Spinal Cord (See Chap. 38) These are too numerous and varied to address here and the reader is referred to Chapter 38 on Degenerative Diseases. There are, for example, several familial forms of progressive spastic paraplegia, some beginning in childhood, others in adult life. A lack of sensory symptoms and signs and sparing of sphincteric function until late in the illness are important diagnostic features. A number of adult cases are “complicated” in the sense that the spastic paraplegia is associated with cerebellar ataxia or dementia. By contrast, primary lateral sclerosis, a sporadic form of degenerative disease of the motor system, is characterized by a pure spastic paraplegia and bulbar spastic palsy either initially or with progression, the result of changes that are confined to the corticospinal pathways.

Syringomyelia (Syrinx) (See Also Chap. 37) Syringomyelia (from the Greek syrinx, “pipe” or “tube”) is defined as a chronic progressive degenerative or developmental disorder of the spinal cord, characterized clinically by painless weakness and wasting of the hands and arms (brachial amyotrophy) and segmental sensory loss of dissociated type (loss of thermal and painful sensation with sparing of tactile, joint position, and vibratory sense, as described later). The cause is a cavitation of the central parts of the spinal cord, usually in the cervical region, but extending upward in some cases into the medulla and pons (syringobulbia) or downward into the thoracic and even into the lumbar segments. Frequently, there are associated developmental abnormalities of the vertebral column (thoracic scoliosis, fusion of vertebrae, or Klippel-Feil anomaly), of the base of the skull (platybasia and basilar invagination), and there is a special relationship to developmental deformations of the cerebellum and brainstem (particularly type I Chiari malformation). A large proportion of cases of developmental syringomyelia have type I Chiari malformation, consisting of a descent of cerebellar tonsils below the foramen magnum, as discussed in Chap. 37. There is also a group of less frequent but well-described syringomyelias that derives from the acquired processes mentioned earlier such as intramedullary tumor (astrocytoma, hemangioblastoma, ependymoma) and from preceding traumatic or hemorrhagic necrosis of the spinal cord.

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Wider experience with the pathology of developmental syringomyelia has led to the following classification, modified from Barnett and colleagues, that unfortunately creates some confusion because it simulates the Roman numeral classification of the Chiari malformations, with which it is sometimes allied: Type I. Syringomyelia with obstruction of the foramen magnum and dilatation of the central canal (developmental type) A. With type I Chiari malformation B. With other obstructive lesions of the foramen magnum, usually bony anomalies Type II. Syringomyelia without the obstruction of the foramen magnum (idiopathic developmental type) Type III. Syringomyelia with other diseases of the spinal cord (acquired types) A. Spinal cord tumors (usually intramedullary, especially hemangioblastoma) B. Traumatic myelopathy C. Spinal arachnoiditis and pachymeningitis D. Secondary myelomalacia from cord compression (tumor, spondylosis), infarction, hematomyelia Type IV. Pure hydromyelia (developmental dilatation of the central canal), with or without hydrocephalus Historical note  Although pathologic cavitation of the spinal cord was recognized as early as the sixteenth century, the term syringomyelia was first used to describe this process in 1827 by Ollivier d’Angers (cited by Ballantine et al). Later, following the recognition of the central canal as a normal structure, it was assumed by Virchow (1863) and by Leyden (1876) that cavitation of the spinal cord had its origin in an abnormal expansion of the central canal, and they renamed the process hydromyelia. Cavities in the central portions of the spinal cord, unconnected with the central canal, were recognized by Hallopeau (1870); Simon suggested in 1875 that the term syringomyelia be reserved for such cavities and that the term hydromyelia be restricted to simple dilatation of the central canal. Thus, a century ago, the stage was set for an argument about pathogenesis that has not been settled to the present day.

Clinical Features The clinical picture varies in the four types listed above, the differences depending on the extent of the syrinx and on the associated pathologic changes, particularly those related to the Chiari malformation. When there is no Chiari malformation, the association of syringomyelia with an intramedullary tumor (type III), particularly ependymoma, should be suspected; there is a disassociated sensorimotor abnormality extending over many segments of the body. Most cases of syrinx cavity that we have seen in adults have been from ependymoma, but we have also encountered examples in which there was no Chiari malformation and long-term and repeated imaging did not demonstrate ependymoma. With von Hippel-Lindau disease, the diagnosis hinges on the finding of the characteristic hereditary hemangioblastoma in the syrinx and retinal and cerebellar vascular malformations. In posttraumatic cases, necrosis of the spinal cord that has been stable for months or years

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begins to cause pain and spreading sensory or motor loss, recognizable only in segments above the original lesion (Schurch et al). This occurred in approximately 3 percent of the traumatic myelopathy cases of Rossier and coworkers, more often in quadriplegics than in paraplegics. The posttraumatic syrinx is not as well delineated anatomically as the usual forms of syringomyelia but consists instead of several contiguous areas of glia-lined myelomalacia with differing degrees of cavitation. In some instances of progressive spinal cord symptoms occurring several years after spinal surgery, the lesion has proved to be one of arachnoiditis and cord atrophy and not a syrinx (Avrahami et al). In the typical type I developmental syrinx (idiopathic, Chiari-associated developmental syringomyelia), symptoms usually begin in early adult life (20 to 40 years). Males and females are equally affected. Rarely some abnormality is noted at birth, but usually, the first symptom appears in late childhood or adolescence. The onset is usually insidious and the course is irregularly progressive. In many instances, the symptoms or signs are discovered accidentally, for example, as a result of a painless burn or atrophy of the hand, and the patient cannot say when the disease began. Rarely, there is an almost apoplectic onset or worsening; there are cases on record of an aggravation of old symptoms or the appearance of new symptoms after a violent strain or paroxysm of coughing. Trauma is a less certain precipitant. Once the disease is recognized, some patients remain much the same for years, even decades, but more often, there is intermittent progression to the point of being chair-bound within 5 to 20 years. This extremely variable course makes it difficult to evaluate therapy. The precise clinical picture at any given point in the evolution of the disease depends on the cross-sectional and longitudinal extent of the syrinx, but certain clinical features are so common that the diagnosis can hardly be made without them. These traditionally cited elements are (1) segmental weakness and atrophy of the hands and arms, (2) loss of some or all tendon reflexes in the arms, and (3) segmental anesthesia of a dissociated type (loss of pain and thermal sense and preservation of the sense of touch) over the neck, shoulders, and arms. The last of these leads to one of the most characteristic features of syringomyelia: painless injuries and burns of the hands. Finally, there are in cases of extensive cavitation weakness and ataxia of the legs from the involvement of the corticospinal tracts (possibly at their decussation) and posterior columns in the cervical region. Kyphoscoliosis is added in many of the cases and in nearly one-quarter of them there is an overt cervicooccipital malformation (short neck, low hairline, odd posture of the head and neck, fused or missing cervical vertebrae, that is, Klippel-Feil abnormality). The particular muscle groups that are affected on the two sides may vary. Exceptionally, motor function is spared, and the segmental dissociated sensory loss and/or pain are the only marks of the disease. In a few of the cases, especially those with the Chiari malformation, the reflexes in the arms are preserved or even hyperactive, as might be expected with upper rather than lower motor neuron involvement. Or the shoulder muscles may be atrophic and the hands spastic. In the lower extremities, the weakness, if present, is of a spastic (corticospinal) type.

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The characteristic segmental sensory dissociation is usually bilateral, but a unilateral pattern affecting only one hand and arm is not unknown, and this is true of amyotrophy as well. The sensory loss is distributed in a “cape” or hemicape pattern, often extending to back of the head or the face and onto the trunk. Although tactile sensation is usually preserved, there are cases in which it is impaired, usually in the region of the densest analgesia over the trunk or hand. Exceptionally there is no sensory loss in the presence of amyotrophy, and cases have been recorded in which only a hydrocephalus and hydromyelia were present with spastic paraparesis. If tactile sensation is affected in the arms, joint position and vibratory sense also tend to be impaired. In the lower extremities and over the abdomen, there may be some loss of pain and thermal sensation proximally, but more often, there is a loss of vibratory and position sense, which is indicative of a posterior column lesion and is the basis of ataxia. A Horner syndrome may result from ipsilateral involvement of the intermediolateral cell column at the C8, T1, and T2 levels. Pain has been a symptom in about half of our patients with developmental types of syringomyelia. The pain is usually unilateral or more marked on one side of the neck, shoulder, and arm; it is of a burning, aching quality, mostly in or at the border of areas of sensory impairment. In a few patients, it involves the face or trunk. An aching pain at the base of the skull or posterior cervical region that is intensified by coughing, sneezing, or stooping (brief exertional pain) is often present, but, as Logue and Edwards point out, the pain of this type may be a feature of Chiari malformation without syringomyelia and in that case is probably attributable to compression or stretching of cervical roots. Syringobulbia is the lower brainstem equivalent of syringomyelia. Usually, the two coexist and the brainstem cavity is simply an extension of one in the upper cord, but occasionally the bulbar manifestations precede the spinal ones or, rarely, occur independently. The glial cleft or cavity is located most often in the lateral tegmentum of the medulla, but it may extend into the pons and, rarely, even higher. The symptoms and signs are characteristically unilateral and consist of nystagmus, analgesia, and thermoanesthesia of the face (numbness); wasting and weakness of the tongue (dysarthria); and palatal and vocal cord paralysis (dysphagia and hoarseness). Diplopia, episodic vertigo, trigeminal pain or facial sensory loss, and persistent hiccough are less common symptoms. For understandable reasons, the diagnosis of brainstem MS or motor neuron disease is often raised. Entire monographs have been devoted to the clinical and pathologic features of syringobulbia (Jonesco-Sisesti). When a Chiari malformation is associated with syringomyelia and syringobulbia, it may be difficult to separate the effects of the two disorders. A typical example is shown in Fig. 37-4. Clinical features that favor the predominance of Chiari malformation are nystagmus, cerebellar ataxia, exertional head and neck pain, prominent corticospinal and sensory tract involvement in the lower extremities, hydrocephalus, and craniocervical malformations. In syringomyelia without a Chiari malformation but with some other type of obstructive lesion at the foramen magnum, the clinical picture is much the same, and the nature of the foramen magnum lesion can be determined only by MRI or surgical exploration.

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Hydromyelia This refers to a dilatation of the central canal of the cord that is distinct from developmental syringomyelia. The relationship between hydromyelia and syringomyelia has been the source of endless debate, in part the result of the lack of a coherent pathophysiologic explanation for either process. At least one hypothesis for the origin of syringomyelia includes an initial dilatation of the central canal (see later). Our impression is that a relatively nonprogressive, well-defined, cylindrical enlargement of the central canal over a few thoracic segments is a frequent enough occurrence in the absence of clinical changes that it represents an independent entity. In the few cases of symptomatic hydromyelia that have come to our attention, there had usually been a long-standing congenital hydrocephalus complicated years later by progressive weakness and atrophy of the shoulders and the muscles of the arms and hands. More often, there is no associated obstruction at the upper cord and no hydrocephalus for which reason it is our impression that most cases are benign and relatively nonprogressive. Proof of the existence of pure hydromyelia in the past has been based on necropsy demonstration of an enormously widened central canal, with or without hydrocephalus. Hydromyelia is now easily diagnosable by MRI and numerous asymptomatic cases are being discovered, often causing unnecessary concern and neurologic consultation.

Pathogenesis of Type I Syringomyelia Experimental work in animals has indicated that there is a normal flow of CSF from the spinal subarachnoid space through perivascular spaces to the parenchyma of the cord and possibly into the central canal. It has been suggested that impediments to flow might explain the dilatation of the central canal or the creation of a parallel or attached syrinx cavity. One theory of the pathogenesis of developmental syringomyelia, of which Gardner was the main advocate, is that the normal flow of CSF from the central canal to the fourth ventricle and its outlets are prevented by an obstruction of the foramina of Luschka and Magendie. As a result, a pulse wave of CSF pressure that is generated by systolic pulsations of the choroid plexuses is transmitted into the cord from the fourth ventricle through the central canal. According to this theory, the syrinx consists essentially of a greatly dilated central canal with a diverticulum that ramifies from the central canal and dissects along gray matter and adjacent fiber tracts. The frequency with which syringomyelia is linked to malformations at the craniocervical junction, that is, to Chiari and other lesions that could interfere with the normal flow of CSF lends credence to this theory. There are many instances, however, in which Gardner’s hydrodynamic theory could not explain syringomyelia. In some cases, the foramina of Luschka and Magendie are found to be patent, and other abnormalities of the posterior fossa or foramen magnum that block CSF flow are not in evidence. Furthermore, in many cases, including several we have inspected at autopsy, serial histologic sections have failed to demonstrate a connection between the fourth ventricle and the syrinx in the spinal cord or of a widening of the central canal above the syrinx (see also Hughes). Gardner’s

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theory has been questioned on other grounds. The calculated pulse-pressure wave transmitted into the cord has been found to be of such low amplitude as to be unlikely to produce a syrinx (Ball and Dayan). Based on this, it has been theorized that the CSF around the cervical cord, under increased pressure during strain or physical effort because of subarachnoid obstruction at the craniocervical junction, tracks into the spinal cord along the Virchow-Robin spaces or other subpial channels. Over a prolonged period, abetted perhaps by traumatic lesions, small pools of fluid coalesce to form a syrinx. In their view, originally, the syrinx forms independently of the central canal, but eventually, the two may become connected, allowing secondary enlargement of the canal (hydromyelia ex vacuo) (Heiss and colleagues). The basis for this has been hypothesized to be the compressive effect of the cerebellar tonsils, which partially occlude the subarachnoid space at the foramen magnum and create pressure waves that compress the spinal cord from without and not from within; the pressure waves propagate syrinx fluid caudally with each heartbeat. This hardly exhausts the list of hypotheses that have been offered over the years, but none of them has been confirmed. The authors favor the type of hydrodynamic mechanism as postulated originally by Gordon Holmes and elaborated by Ball and Dayan. In this view, a relationship exists between basal cranial, cervical spine, the cerebellospinal Chiari malformation, syringomyelia, and disturbed hydrodynamics of perispinal CSF. Logue and Edwards documented several cases of syringomyelia in which the foramen magnum was obstructed by a lesion other than a Chiari formation, for example, by dural cyst, localized arachnoiditis, atlantoaxial fusion, simple cerebellar cyst, and basilar invagination (Williams has reviewed the numerous hypotheses of causation).

Diagnosis The clinical picture of syringomyelia is so characteristic that diagnosis is seldom in doubt. Now one can obtain spectacular demonstrations of the syrinx, either traumatic or developmental (Fig. 42-14), Chiari malformations, and other foramen magnum lesions by MRI of the sagittal planes of the brain and spinal cord (see Fig. 37-4). Also, hours after a CT myelogram, contrast material fills the syrinx and the central canal directly, possibly by diffusion from the surface of the cord. Certain rare polyneuropathies (amyloid, Tangier disease, and Fabry disease) that preferentially affect small fibers in the nerves of the upper extremities can reproduce the dissociated sensory loss that is characteristic of a syrinx (“pseudosyringomyelic” deficit), but motor abnormalities are not prominent in these neuropathic cases. These diseases are discussed in Chap. 43.

Treatment For cases originating in a tumor, typically ependymoma in adults, resection of the tumor and some degree of decompression of the syrinx cavity can be undertaken to prevent the progression of symptoms. The cyst fluid may be high in protein and viscid (unlike the low-protein fluid of the usual syrinx).

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Figure 42-14. Sagittal T2-weighted MRI showing a developmental syringomyelia without Chiari malformation. The cervical spinal cord is greatly expanded, but there were only signs of spinothalamic sensory loss over the arms.

The only therapy of lasting value for type I syringomyelia (related to Chiari malformation) is surgical decompression of the foramen magnum and upper cervical canal. Headache and neck pain are helped most; ataxia and nystagmus tend to persist, but these are related to the Chiari process. The cavity tends to at least cease enlarging. Radiation therapy, which was formerly recommended, is of no benefit. The operation advised by Gardner, of plugging the connection between the fourth ventricle and the central canal of the cervical cord, has been abandoned. There were complications of this operative procedure, and the results were no better than those obtained from simple decompression. The decompression operation also carries some risk, especially if there is an attempt to excise the tonsillar projections of the cerebellum. In one series, comprising 56 cases of type I syringomyelia, the occipitocervical pain was relieved by decompression in most patients, but the shoulder-arm pain usually persisted (Logue and Edwards). Upper motor neuron weakness of the legs and sensory ataxia were often improved, whereas the segmental sensory and motor manifestations of the syringomyelia were not. In the past, reported good results had been reported from decompression in 75 percent of type I cases of syringomyelia (Hankinson), but in a retrospective review of 141 adult patients, good surgical outcome was achieved in but only 50 percent of those with minor degrees of descent of the cerebellar tonsils and only 12 percent of those with major cerebellar ectopia (Stevens and colleagues). A distended syrinx also led to a more

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favorable outcome. Whether the long-term course of these diseases is altered has not been determined. Other surgical series of Chiari-syrinx are discussed and cited in Chap. 37. Syringotomy or shunting of the cavity has been performed in type I and some of the type II (idiopathic) cases, but the results have been unpredictable. Surgical series of both types (mainly type II) have stated that 30 percent had an excellent outcome (Love and Olafson) and others reported improvement of pain and motor weakness by stabilization of the spine and syringotomy with the placement of a T-tube within the syrinx (Schurch and coworkers). In a comprehensive study of 73 operated patients with a developmental syrinx (Sgouros and Williams, 1995), approximately half remained clinically stable for a 10-year period; 15 percent had serious complications from the surgery. Our experience with these patients who have had the procedure has not persuaded us of its lasting value; most, even those who reported some improvement originally, soon relapsed to their preoperative state, and the disease then progressed in the usual way. An enlarged cervical cord with progressive clinical worsening may nonetheless justify an attempt to shunt the cavity. Other comments are found in Chap. 37. Surgery for posttraumatic cases has given only slightly more favorable results. With incomplete myelopathy, syringotomy relieved the pain in a series of 10 patients (Shannon and associates). Where they found the myelopathy to be complete, the cord was transected and the upper stump excised. In a study of 57 such patients, decompressive laminectomy and reconstruction of the subarachnoid space as the most effective of the several procedures used in the management of traumatic cavities (Sgouros and Williams, 1996). An extensive review of surgical approaches to syringomyelia can be found in the article by Brodbelt and Stoodley, who tentatively recommend lysis of arachnoidal adhesions as preferable to shunting or filleting of the cord, but acknowledge that the current state of treatment is unsatisfactory. The infrequent case of symptomatic purely hydromyelia may benefit from ventriculoperitoneal shunts of hydrocephalus, and a few excellent results are reported. This procedure has also been attempted in type I developmental cases, with unimpressive results unless there is an associated hydrocephalus. Draining the central canal by amputation of the tip of the sacral cord has been unsuccessful and can be harmful. Most patients with hydromyelia do not require treatment.

CONCLUDING REMARKS ON DISEASES OF THE SPINAL CORD It is well to remind oneself that of the more than 30 diseases of the spinal cord, effective means of treatment are available for many of the common ones: spondylosis, extramedullary spinal cord tumors, epidural abscess, hematoma and granuloma (tuberculous, fungal, sarcoidosis), myelitis, syringomyelia, and subacute combined degeneration and other forms of nutritional myelopathy. Many inflammatory myelopathies respond to immune-modulating measures. The physician’s major challenge is to determine whether the patient has one of these treatable diseases.

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References Adams CBT, Logue V: Studies in cervical spondylotic myelopathy. Brain 94:557, 569, 1971. Allen AR: Surgery of experimental lesions of the spinal cord equivalent to crush injury of fracture dislocation of the spinal column: A preliminary report. JAMA 57:878, 1911. American Spinal Injury Association: Standards for Neurological Classification of Spinal Injury Patients. Chicago, American Spinal Injury Association, 1984. Aminoff MJ, Logue V: The prognosis of patients with spinal vascular malformations. Brain 97:211, 1974. Angeli CA, Boakye M, Morton RA, et al: Recovery of over-ground walking after chronic motor complete spinal cord injury. N Engl J Med 379:1244, 2018. Antoni N: Spinal vascular malformations (angiomas) and myelomalacia. Neurology 12:795, 1962. Avrahami E, Tadmor R, Cohn DF: Magnetic resonance imaging in patients with progressive myelopathy following spinal surgery. J Neurol Neurosurg Psychiatry 52:176, 1989. Baker AS, Ojemann RG, Swartz MN, Richardson EP Jr: Spinal epidural abscess. N Engl J Med 293:463, 1975. Ball MJ, Dayan AD: Pathogenesis of syringomyelia. Lancet 2:799, 1972. Ballantine HT, Ojemann RG, Drew JH: Syringohydromyelia. In: Krayenbuhl H, Maspes PE, Sweet WH (eds): Progress in Neurological Surgery. Vol 4. New York, Karger, 1971, pp 227–245. Barnett JHM, Foster JB, Hudgson P: Syringomyelia. Philadelphia, Saunders, 1973. Bartleson JO, Cohen MD, Harrington TM: Cauda equina syndrome secondary to long-standing ankylosing spondylitis. Ann Neurol 14:662, 1983. Bell HS: Paralysis of both arms from injury of the upper portion of the pyramidal decussation “cruciate paralysis.” J Neurosurg 33:376, 1970. Berkowitz AL, Samuels MS: The neurology of Sjogren’s syndrome and the rheumatology of peripheral neuropathy and myelitis. Pract Neurol 14:14, 2014. Blacker DJ, Wijkicks EFM, Rama Krishna G: Resolution of severe paraplegia due to aortic dissection after CSF drainage. Neurology 61:142, 2003. Blackwood W: Discussion of vascular disease of the spinal cord. Proc R Soc Med 51:543, 1958. Bracken MR, Shepard MJ, Collins WF, et al: Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. J Neurosurg 76:23, 1992. Brain WR: Discussion on rupture of the intervertebral disc in the cervical region. Proc R Soc Med 41:509, 1948. Brain WR, Northfield D, Wilkinson M: The neurological manifestations of cervical spondylosis. Brain 75:187, 1952. Brodbelt AR, Stoodley MA: Posttraumatic syringomyelia: A review. J Clin Neurosci 10:401, 2003. Brown P, Thompson PD, Rothwell JC, et al: Axial Myoclonus of propriospinal origin. Brain 114:197, 1991. Burns RJ, Jones AN, Robertson JS: Pathology of radiation myelopathy. J Neurol Neurosurg Psychiatry 35:888, 1972. Buur T, Morch MM: Hereditary multiple exostoses with spinal cord compression. J Neurol Neurosurg Psychiatry 46:96, 1983. Caccamo DV, Garcia JH, Ho K-L: Isolated granulomatous angiitis of the spinal cord. Ann Neurol 32:580, 1992. Candon E, Frerebeau P: Abcés bacteriens de la moelle épinière. Rev Neurol 150:370, 1994. Cannon WB, Rosenblueth A: The Supersensitivity of Denervated Structures. New York, Macmillan, 1949. Chang CWJ, Donovan DJ, Liem LK, et al: Surfer’s myelopathy. Neurology 79:2171, 2012.

Ropper_Ch42_p1223-p1275.indd 1272

Cheshire WP, Santos CC, Massey EW, Howard JF: Spinal cord infarction: Etiology and outcome. Neurology 47:321, 1996. Cilluffo JM, Gomez MR, Reese DF, et al: Idiopathic (congenital) spinal arachnoid diverticula. Mayo Clin Proc 56:93, 1981. Clark K: Injuries to the cervical spine and spinal cord. In: Youmans JR (ed): Neurological Surgery, 2nd ed. Philadelphia, Saunders, 1982, pp 2318–2337. Collins WF, Chehrazi B: Concepts of the acute management of spinal cord injury. In: Mathews WB, Glaser GH (eds): Recent Advances in Clinical Neurology. London, Churchill Livingstone, 1983, pp 67–82. Confavreux C, Larbre J-P, Lejeune E, et al: Cerebrospinal fluid dynamics in the tardive cauda equina syndrome of ankylosing spondylitis. Ann Neurol 29:221, 1991. Constantini S, Miller DC, Allen JC, et al: Radical excision of intramedullary spinal cord tumors: Surgical morbidity and longterm follow-up evaluation in 164 children and young adults. J Neurosurg 93:183, 2000. Costigan DA, Winkelman MD: Intramedullary spinal cord metastasis. J Neurosurg 62:227, 1985. Cruickshank EK: A neuropathic syndrome of uncertain origin. West Indian Med J 5:147, 1956. Dahlberg PJ, Frecentese DF, Cogbill TH: Cholesterol embolism: Experience with 22 histologically proven cases. Surgery 10:737, 1989. Darouiche RO: Spinal epidural abscess. N Engl J Med 355:2012, 2006. Dastur DK: Lathyrism. World Neurol 3:721, 1962. de Seze J, Stojkovic T, Breteau G, et al: Acute myelopathies. Clinical, laboratory and outcome profiles in 79 cases. Brain 124:1509, 2001a. de Seze J, Stojkovic T, Hachulla E, et al: Myélopathies et syndrome de Gougerot-Sjögren: Étude clinique, radiologique et profil évolutif. Rev Neurol 157:6, 2001b. DeVivo MJ, Kartus PT, Stover SI: Seven-year survival following spinal cord injury. Arch Neurol 44:872, 1987. Dickman CA, Hadley NM, Pappas CTE, et al: Cruciate paralysis: A clinical and radiologic analysis of injuries to the cervicomedullary spine. J Neurosurg 73:850, 1990. Douglas MA, Parks LC, Bebin J: Sudden myelopathy secondary to therapeutic total-body hyperthermia after spinal-cord irradiation. N Engl J Med 304:583, 1981. Duke RJ, Hashimoto S: Familial spinal arachnoiditis. Arch Neurol 30:300, 1974. Ell JJ, Uttley D, Silver JR: Acute myelopathy in association with heroin addiction. J Neurol Neurosurg Psychiatry 44:448, 1981. Elsberg CA: Surgical Diseases of the Spinal Cord, Membranes and Nerve Roots: Symptoms, Diagnosis and Treatment. New York, Hoeber-Harper, 1941. Epstein JA, Epstein NE: The surgical management of cervical spinal stenosis, spondylosis, and myeloradiculopathy by means of the posterior approach. In: Cervical Spine Research Society (ed): The Cervical Spine. Philadelphia, Lippincott, 1989, pp 625–669. Feldman E, Bromfield E, Navia B, et al: Hydrocephalic dementia and spinal cord tumor. Arch Neurol 43:714, 1986. Filiminoff IN: Zur pathologisch-anatomischen Charakteristik des Lathyrismus. Z Ges Neurol Psychiatry 105:76, 1926. Flanagan EP, Krecke KN, Marsh RW, et al: Specific pattern of gadolinium enhancement in spondylitic myelopathy. Ann Neurol 76:54, 2014. Flanagan EP, McKeon A, Lennon VA, et al: Paraneoplastic isolated myelopathy: Clinical course and neuroimaging clues. Neurology 76:2089, 2011.

08/02/23 9:51 AM

Chapter 42 Diseases of the Spinal Cord Foix C, Alajouanine T: La myelite necrotique subaigue. Rev Neurol 2:1, 1926. Fox MW, Onofrio BM, Kilgore JE: Neurological complications of ankylosing spondylitis. J Neurosurg 78:871, 1993. Fulton JF: Physiology of the Nervous System. London, Oxford University Press, 1943. Gardner WJ: Hydrodynamic mechanism of syringomyelia: Its relationship to myelocele. J Neurol Neurosurg Psychiatry 28:247, 1965. Gilbert RW, Kim J-H, Posner JB: Epidural spinal cord compression from metastatic tumor: Diagnosis and treatment. Ann Neurol 3:40, 1978. Greenfield JG, Turner JWA: Acute and subacute necrotic myelitis. Brain 62:227, 1939. Guttmann L: Spinal Cord Injuries: Comprehensive Management and Research. Oxford, UK, Blackwell, 1976. Hamandi K, Mottershead J, Lewis T, et al: Irreversible damage to the spinal cord following spinal anesthesia. Neurology 59:624, 2002. Hankinson J: Syringomyelia and the surgeon. In: Williams D (ed): Modern Trends in Neurology. Vol 5. Oxford, Butterworth, 1970, pp 127–148. Haymaker W: Decompression sickness. In: Scholz W (ed): Handbuch der Speziellen Pathologischen Anatomie und Histologie. Vol XIII/1B. Berlin, Springer-Verlag, 1957, pp 1600–1672. Head H, Riddoch G: The automatic bladder: Excessive sweating and some other reflex conditions in gross injuries of the spinal cord. Brain 40:188, 1917. Heiss JD, Patronas N, DeVroom HL, et al: Elucidating the pathophysiology of syringomyelia. J Neurosurg 91:553, 1999. Hirayama K, Tokumaru Y: Cervical dural sac and spinal cord in juvenile muscular atrophy of distal upper extremity. Neurology 54:1922, 2000. Hoffman JR, Mower WR, Wolfson AB, et al: Validity of a set of clinical criteria to rule out injury to the cervical spine in patients with blunt trauma. N Engl J Med 343:94, 2000. Holmes G: On the spinal injuries of warfare: Goulstonian lectures. Br Med J 2:769, 1915. Hughes JT: Pathology of the Spinal Cord, 2nd ed. Philadelphia, Saunders, 1978. Hugon J, Ludolph A, Roy DN, et al: Studies on the etiology and pathogenesis of motor neuron diseases: II. Clinical and electrophysiologic features of pyramidal dysfunction in macaques fed Lathyrus sativus and IDPN. Neurology 38:435, 1988. Hurlbert RJ: Methylprednisolone for acute spinal cord injury: An inappropriate standard of care. J Neurosurg 93:1, 2000. Hurst RW, Grossman RI: Peripheral spinal cord hypointensity on T2-weighted MR images: A reliable imaging sign of venous hypertensive myelopathy. AJNR Am J Neuroradiol 21:781, 2000. Inamasu J, Hori S, Ohsuga F, et al: Selective paralysis of the upper extremities after odontoid fracture: Acute central cord syndrome or cruciate paralysis? Clin Neurol Neurosurg 103:238, 2001. Jefferson G: Discussion on spinal injuries. Proc R Soc Med 21:625, 1927. Jellema K, Canta LR, Tijssen CC, et al: Spinal dural arteriovenous fistulas: Clinical features in 80 patients. J Neurol Neurosurg Psychiatry 74:1438, 2003. Jones A: Transient radiation myelitis. Br J Radiol 37:727, 1964. Jones BV, Ernst RJ, Tomsick TA, et al: Spinal dural arteriovenous fistulas: Recognizing the spectrum of magnetic resonance imaging findings. J Spinal Cord Med 20:43, 1997. Jonesco-Sisesti N: Syringobulbia: A Contribution to the Pathophysiology of the Brainstem. Translated into English, edited, and annotated by RT Ross. New York, Praeger, 1986. Kagan RA, Wollin M, Gilbert HA, et al: Comparison of the tolerance of the brain and spinal cord to injury by radiation. In: Gilbert HA, Kagan RA (eds): Radiation Damage to the Nervous System. New York, Raven Press, 1980.

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Khurana VG, Perez-Terzic CM, Petersen RC, Krauss WE: Singing paraplegia: A distinctive manifestation of a spinal dural arteriovenous malformation. Neurology 58:1279, 2002. Kidd D, Thorpe JW, Kiendall BE, et al: MRI dynamics of brain and spinal cord in progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 60:15, 1996. Killen DA, Foster JH: Spinal cord injury as a complication of contrast angiography. Surgery 59:962, 1966. Killen DA, Weinstein C, Reed W: Reversal of spinal cord ischemia resulting from aortic dissection. J Thorac Cardiovasc Surg 119:1049, 2000. Kneisley LW: Hyperhydrosis in paraplegia. Arch Neurol 34:536, 1977. Kocher T: Die Wirletzungen der Virbelsäule zugleich als Beitrag zur Physiologie des menschlichen Ruckenmarcks. Mitt Grenzgeb Med Chir 1:415, 1896. Kuhn RA: Functional capacity of the isolated human spinal cord. Brain 73:1, 1950. Kumar N, Crum B, Petersen RC, et al: Copper deficiency myelopathy. Arch Neurol 61:762, 2004. Lazorthes G: Pathology, classification and clinical aspects of vascular diseases of the spinal cord. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 12. Amsterdam, North-Holland, 1972, pp 492–506. Leech RW, Pitha JV, Brumback RA: Spontaneous haematomyelia: A necropsy study. J Neurol Neurosurg Psychiatry 54:172, 1991. Lennon VA, Wingerchuk DM, Kryzer RJ, et al: A serum autoantibody marker for neuromyelitis optica: Distinction from multiple sclerosis. Lancet 364:2106, 2004. Levivier M, Baleriaux D, Matos C, et al: Sarcoid myelopathy. Neurology 41:1529, 1991. Lintott P, Hafez HM, Stansby G: Spinal cord complications of thoracolumbar aneurysm surgery. Br J Surg 85:5, 1998. Lipson SJ, Naheedy MH, Kaplan MH: Spinal stenosis caused by epidural lipomatosis in Cushing’s syndrome. N Engl J Med 302:36, 1980. Logue V: Angiomas of the spinal cord: Review of the pathogenesis, clinical features, and results of surgery. J Neurol Neurosurg Psychiatry 42:1, 1979. Logue V, Edwards MR: Syringomyelia and its surgical treatment: An analysis of 75 cases. J Neurol Neurosurg Psychiatry 44:273, 1981. Love JG, Olafson RA: Syringomyelia: A look at surgical therapy. J Neurosurg 24:714, 1966. Malamud N, Boldrey EB, Welch WK, Fadell EJ: Necrosis of brain and spinal cord following x-ray therapy. J Neurosurg 11:353, 1954. Mancall EL, Rosales RK: Necrotizing myelopathy associated with visceral carcinoma. Brain 87:639, 1964. Marshall J: Observations on reflex changes in the lower limbs in spastic paraplegia in man. Brain 77:290, 1954. McCormick PC, Michelsen WJ, Post KD, et al: Cavernous malformations of the spinal cord. Neurosurgery 23:459, 1988. McCrae DL: Bony abnormalities in the region of the foramen magnum: Correlation of the anatomic and neurologic findings. Acta Radiol 40:335, 1953. Messard L, Carmody A, Mannarino E, Ruge D: Survival after spinal cord trauma: A life table analysis. Arch Neurol 35:78, 1978. Mixter WJ, Barr JS: Rupture of the intervertebral disc with involvement of the spinal canal. N Engl J Med 211:210, 1934. Morrison RE, Brown J, Gooding RS: Spinal cord abscess caused by Listeria monocytogenes. Arch Neurol 37:243, 1980. Morse SD: Acute central cervical spinal cord syndrome. Ann Emerg Med 11:436, 1982. Munro D: The rehabilitation of patients totally paralyzed below the waist. N Engl J Med 234:207, 1946. Murphy KP, Opitz JL, Cabanela ME, Ebersold MJ: Cervical fractures and spinal cord injury: Outcome of surgical and nonsurgical management. Mayo Clin Proc 65:949, 1990.

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Naiman JL, Donahue WL, Pritchard JS: Fatal nucleus pulposus embolism of spinal cord after trauma. Neurology 11:83, 1961. Nakano KK, Schoene WC, Baker RA, Dawson DM: The cervical myelopathy associated with rheumatoid arthritis: Analysis of 32 patients, with 2 postmortem cases. Ann Neurol 3:144, 1978. Nations SP, Boyer PJ, Love LA, et al: Denture cream. An unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology 71:639, 2008. Nesathurai S: Steroids and spinal cord injury: Revisiting the NASCIS 2 and NASCIS 3 trials. J Trauma 45:1088, 1998. Nieder C, Grosu AL, Andratschke NH, Molls M: Update of human spinal cord reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol Biol Phys 66:1446, 2006. Novy J, Carruzzo A, Maeder P, Bogousslavsky J: Spinal cord ischemia. Clinical and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 63:1113, 2006. Nowak DA, Mutzenbach S, Fuchs HH: Acute myelopathy. Retrospective clinical, laboratory, MRI and outcome analysis in 49 patients. J Clin Neurosci 11:145, 2004. O’Connell JEA: The clinical signs of meningeal irritation. Brain 69:9, 1946. Pallis C, Jones AM, Spillane JD: Cervical spondylosis. Brain 77:274, 1954. Palmer JJ: Radiation myelopathy. Brain 95:109, 1972. Panse F: Electrical lesions of the nervous system. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 7. Amsterdam, North-Holland, 1970, pp 344–387. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 366:643, 2005. Payne EE, Spillane JD: The cervical spine: An anatomicopathological study of 70 specimens (using a special technique) with particular reference to the problem of cervical spondylosis. Brain 80:571, 1957. Peet MM, Echols DH: Herniation of nucleus pulposus: Cause of compression of spinal cord. Arch Neurol Psychiatry 32:924, 1934. Penn RD, Kroin JS: Continuous intrathecal baclofen for severe spasticity. Lancet 2:125, 1985. Penry JK, Hoefnagel D, Vanden Noort S, Denny-Brown D: Muscle spasm and abnormal postures resulting from damage to interneurones in spinal cord. Arch Neurol 3:500, 1960. Petito CK, Navia BA, Cho ES, et al: Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with AIDS. N Engl J Med 312:874, 1985. Pollock LJ: Spasticity, pseudospontaneous spasm, and other reflex activities late after injury to the spinal cord. Arch Neurol Psychiatry 66:537, 1951. Pollock LJ, Brown M, Boshes B, et al: Pain below the level of injury of the spinal cord. Arch Neurol Psychiatry 65:319, 1951. Propper DJ, Bucknall RC: Acute transverse myelopathy complicating systemic lupus erythematosus. Ann Rheum Dis 48:512, 1989. Queiroz L de S, Nucci A, Facure NO, Facure JJ: Massive spinal cord necrosis in schistosomiasis. Arch Neurol 36:517, 1979. Reagan TJ, Thomas JE, Colby MY: Chronic progressive radiation myelopathy. JAMA 203:106, 1968. Rezai AR, Woo HL, Lee M, et al: Disseminated ependymomas of the central nervous system. J Neurosurg 85:618, 1996. Riddoch G: The reflex functions of the completely divided spinal cord in man, compared with those associated with less severe lesions. Brain 40:264, 1917. Robertson CE, Brown RD, Wijdicks EFM, Rabenstein AA: Recovery after spinal cord infarcts: Long-term outcome in 115 patients. Neurology 78:114, 2012.

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Roobol TH, Kazzaz BA, Vecht CJ: Segmental rigidity and spinal myoclonus as a paraneoplastic syndrome. J Neurol Neurosurg Psychiatry 50:628, 1987. Ropper AE, Cahill KS, Hanna JW, et al: Primary vertebral tumors: A review of epidemiologic, histologic, and imaging findings, Part I: Benign tumors. Neurosurgery 69:1171, 2011. Ropper AH, Poskanzer DC: The prognosis of acute and subacute transverse myelitis based on early signs and symptoms. Ann Neurol 4:51, 1978. Ropper AE, Ropper AH: Acute spinal cord compression. N Engl J Med 376:1358, 2017. Roze E, Bounolleau P, Ducreux D, et al: Propriospinal myoclonus revisited: Clinical, neurophysiologic, and neuroradiologic findings. Neurology 72:1301, 2009. Rossier AB, Foo D, Shillito J: Posttraumatic cervical syringomyelia. Brain 108:439, 1985. Sandson TA, Friedman SH: Spinal cord infarction: Report of 8 cases and review of the literature. Medicine (Baltimore) 68:282, 1989. Sato T, Coler-Reilly AL, Yagishita N, et al: Mogamulizumab (Anti-CCR4) in HTLV-1–associated myelopathy. N Engl J Med 378:529, 2018. Savitsky N, Madonick MJ: Statistical control studies in neurology: Babinski sign. Arch Neurol Psychiatry 49:272, 1943. Schneider RC, Cherry G, Pantek H: The syndrome of acute central cervical spinal cord injury. J Neurosurg 11:546, 1954. Schurch B, Wichmann W, Rossier AB: Posttraumatic syringomyelia (cystic myelopathy): A prospective study of 449 patients with spinal cord injury. J Neurol Neurosurg Psychiatry 60:61, 1996. Scrimgeour EM, Gajdusek DC: Involvement of the central nervous system in Schistosoma mansoni and S. haematobium infection. Brain 108:1023, 1985. Sgouros S, Williams B: A critical appraisal of drainage in syringomyelia. J Neurosurg 82:1, 1995. Sgouros S, Williams B: Management and outcome of posttraumatic syringomyelia. J Neurosurg 85:197, 1996. Shannon N, Simon L, Logue V: Clinical features, investigation, and treatment of posttraumatic syringomyelia. J Neurol Neurosurg Psychiatry 44:35, 1981. Sloof JH, Kernohan JW, MacCarty CS: Primary Intramedullary Tumors of the Spinal Cord and Filum Terminale. Philadelphia, Saunders, 1964. Spencer PS, Roy DN, Ludolph A, et al: Lathyrism: Evidence for role of the neuroexcitatory amino acid BOAA. Lancet 2:1066, 1986. Spiller WG: Thrombosis of the cervical anterior median spinal artery: Syphilitic acute anterior poliomyelitis. J Nerv Ment Dis 36:601, 1909. Stevens JM, Serva WA, Kendall BE, et al: Chiari malformation in adults: Relation of morphologic aspects to clinical features and operative outcome. J Neurol Neurosurg Psychiatry 56:1072, 1993. Stiell IG, Clement CM, McKnight RD, et al: The Canadian C-spine rule versus the NEXUS low-risk criteria in patients with trauma. N Engl J Med 349:2510, 2003. Stoltmann HF, Blackwood W: The role of the ligamenta flava in the pathogenesis of myelopathy in cervical spondylosis. Brain 87:45, 1964. Stookey B: Compression of the spinal cord due to ventral extradural cervical chondromas. Arch Neurol Psychiatry 20:275, 1928. Swann KW, Ropper AH, New PFJ, Poletti CE: Spontaneous spinal subarachnoid hemorrhage and subdural hematoma. J Neurosurg 61:975, 1984. Symon L, Kuyama H, Kendall B: Dural arteriovenous malformations of the spine: Clinical features and surgical results in 55 cases. J Neurosurg 60:238, 1984. Thomas JE, Miller RH: Lipomatous tumors of the spinal canal. Mayo Clin Proc 48:393, 1973.

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Chapter 42 Diseases of the Spinal Cord Thompson TP, Pearce J, Chong G, et al: Surfer’s myelopathy. Spine 29:E353, 2004. Toossi S, Josephson SA, Hetts SW, et al: Utility of MRI in spinal arteriovenous fistula. Neurology 79:25, 2012. Tosi L, Rigoli G, Beltramello A: Fibrocartilaginous embolism of the spinal cord: A clinical and pathogenetic consideration. J Neurol Neurosurg Psychiatry 60:55, 1996. Uygunoglu U, Zeydan B, Ozguler Y, et al: Myelopathy in Beçhet disease: The bagel sign. Ann Neurol 82:288, 2017. Vallee B, Mercier P, Menei P, et al: Ventral transdural herniation of the thoracic cord: Surgical treatment in four cases and review of the literature. Acta Neurochir (Wien) 141:907, 1999. Vogt MR, Wright PF, De Bussscher T, et al. Enterovirus D68 in the anterior horn cells of a child with acute flaccid myelitis. New Eng J Med 386:2059, 2022. Watters MR, Stears JC, Osborn AG, et al: Transdural spinal cord herniation. AJNR 19:1337, 1998. Weidauer S, Nichtweiss M, Lanfermann H, et al: Spinal cord infarction: MR imaging and clinical features in 16 cases. Neuroradiology 44:851, 2002. Weisman AD, Adams RD: The neurological complications of dissecting aortic aneurysm. Brain 67:69, 1944. Whitely AM, Swash M, Urich H: Progressive encephalomyelitis with rigidity. Brain 99:27, 1976. Wilkinson M: Cervical Spondylosis, 2nd ed. Philadelphia, Saunders, 1971. Wilkinson PA, Valentine A, Gibbs JM: Intrinsic spinal cord lesions complicating epidural anaesthesia and analgesia: Report of three cases. J Neurol Neurosurg Psychiatry 72:537, 2002.

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Willeit J, Kiechl S, Kiechl-Kohlendarfer U, et al: Juvenile asymmetric segmental spinal muscular atrophy (Hirayama’s disease): Three cases without evidence of “flexion myelopathy.” Acta Neurol Scand 104:320, 2001. Williams B: The cystic spinal cord. J Neurol Neurosurg Psychiatry 58:649, 1995. Williams CS, Butler E, Roman GC: Treatment of myelopathy in Sjögren syndrome with a combination of prednisone and cyclophosphamide. Arch Neurol 59:815, 2001. Winkelman MD: Neurological complications of thermal and electrical burns. In: Aminoff MJ (ed): Neurology and General Medicine. New York, Churchill Livingstone, 1994, pp 915–929. Winkelman MD, Adelstein DJ, Karlins NL: Intramedullary spinal cord metastases: Diagnostic and therapeutic considerations. Arch Neurol 44:526, 1987. Woltman HW, Adson AW: Abscess of the spinal cord. Brain 49:193, 1926. Woolsey RM, Young RR (eds): Neurologic Clinics: Disorders of the Spinal Cord. Philadelphia, Saunders, 1991. Wyburn-Mason R: Vascular Abnormalities and Tumors of the Spinal Cord and Its Membranes. St. Louis, Mosby, 1944. Yamamura T, Kleiter I, Fujihara K, et al: Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Engl J Med 381:2114, 2019. Yogananden N, Larson SJ, Gallagher M: Correlation of microtrauma in the spine with intraosseous pressure. Spine 19:435, 1994. Zimmerli W: Vertebral osteomyelitis. N Engl J Med 362:1022, 2010. Zwimpfer TJ, Bernstein M: Spinal cord compression. J Neurosurg 72:894, 1990.

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43 Diseases of the Peripheral Nerves

In this single chapter, an attempt is made to provide an overview of the very large subject of peripheral nerve disease. Because the structure and function of the peripheral nervous system are relatively simple, one might suppose that our knowledge of its diseases would be fairly complete. Such is not the case. For example, when a group of patients with chronic polyneuropathy was investigated intensively in a highly specialized center for the study of peripheral nerve diseases several decades ago, a suitable explanation for their condition could not be found in 24 percent (Dyck et al, 1981) and equally discouraging figures prevail in our clinics today despite the availability of genetic testing. Moreover, the physiologic basis of many neuropathic symptoms continues to be elusive and in several of the neuropathies, the pathologic changes have not been fully determined. However, rapidly advancing techniques in the fields of immunology and genetics are clarifying many neuropathic diseases. Also, effective forms of treatment for several peripheral neuropathies have been introduced, making accurate diagnosis imperative. For these reasons, clinicians find the peripheral neuropathies among the most challenging and gratifying categories of neurologic disease.

GENERAL CONSIDERATIONS It is important to have a clear concept of the extent of the peripheral nervous system (PNS) and the mechanisms by which it is affected by disease. The PNS includes all neural structures lying outside the pial membrane of the spinal cord and brainstem with the exception of the optic nerves and olfactory bulbs, which are special extensions of the brain. The nerves within the spinal canal and attached to the ventral and dorsal surfaces of the cord are the spinal roots, which continue to form the numbered spinal nerves; those attached to the ventrolateral surface of the brainstem are the cranial nerve roots, or cranial nerves. The dorsal, or posterior (afferent, or sensory), spinal roots consist of central axonal processes of the sensory and cranial ganglia. On reaching the spinal cord and brainstem, the roots extend for variable distances into the dorsal horns and posterior columns of the cord and into the spinal trigeminal and other tracts in the medulla and pons before synapsing with secondary sensory neurons,

as described in Chaps. 7 and 8 that are devoted to the neurology of pain and sensation. The peripheral axons of the dorsal root ganglion cells are the sensory nerve fibers (in some writings they are considered dendrites). They terminate as freely branching or specialized corpuscular endings—that is, the sensory receptors—in the skin, joints, and other tissues. The sensory nerve fibers vary greatly in size and the thickness of their myelin covering; based on these dimensions, they are classified as type A, B, or C, as discussed in Chap. 7. The ventral, or anterior (efferent, or motor), roots are composed of the emerging axons of anterior and lateral horn cells and motor nuclei of the brainstem. Large, heavily myelinated fibers traverse the spinal nerves and terminate on muscle fibers and smaller unmyelinated ones terminate in sympathetic or parasympathetic ganglia. From the autonomic ganglia arise the axons that terminate in smooth muscle, heart muscle and conducting system, and glands. Traversing the subarachnoid space, where they lack well-formed epineurial sheaths, the cranial and spinal roots (both sensory and motor) are bathed in and are susceptible to substances in the cerebrospinal fluid (CSF), the lumbosacral roots having the longest exposure to the CSF space (Fig. 43-1). The vast extent of the peripheral ramifications of cranial and spinal nerves is noteworthy, as are their thick protective and supporting sheaths of perineurium and epineurium that are endowed with a vascular supply through longitudinal arrays of richly anastomosing nutrient arterial branches. The perineurium comprises the connective tissue sheaths that surround and separate each bundle of nerve fibers (fascicles) of varying size, each fascicle containing several hundred axons. The sheath that binds and surrounds all the fascicles of the nerve is the epineurium. As the nerve root approaches the cord, the epineurium blends with the dura (see Fig. 43-1). The fine connective tissue covering of individual nerve fibers is the endoneurium. Longitudinally oriented and widely anastomotic endoneural vessels also nourish the nerve fibers and are susceptible to disease. The spinal nerves traverse narrow foramina (intervertebral and cranial) and a few pass through tight channels peripherally in the limbs (e.g., the median nerve between the carpal ligament and tendon sheaths of flexor forearm muscles that make up the carpal tunnel; the ulnar nerve

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in the cubital tunnel). These anatomic features explain the sites of susceptibility of certain nerves to compression and entrapment and to ischemic damage. The axons themselves contain a complex internal microtubular apparatus for maintaining the integrity of their membranes and for transporting substances such as neurotransmitters over long distances between the nerve cell body and the distant reaches of the nerve fiber. As mentioned earlier and discussed in Chap. 7 the long axons of sensory nerves could properly be considered to be dendrites but the term “axon” is in common use to denote all the neuronal processes of peripheral nerves. Nerve fibers (axons) are coated with short segments of myelin of variable length (250 to 1,000 μm), each of which is enveloped by a Schwann cell and its membrane that constitute the myelin sheath. In fact, the PNS may be accurately defined as the part of the nervous system that is invested by the cytoplasm and membranes of Schwann cells. Each myelin segment and Schwann cell has a symbiotic relationship with the axon but is morphologically independent. The structure of the axonal membrane in the gaps between segments of the myelin sheaths (nodes of Ranvier) is specialized, containing a high concentration of sodium channels and permitting the saltatory electrical conduction of nerve impulses as described in Chap. 2. Unmyelinated fibers, more numerous in peripheral nerves than myelinated ones, also arise from cells in dorsal root and autonomic ganglia. Small bundles of these naked (unmyelinated) axons are enveloped by a single Schwann cell; delicate tongues of Schwann cell cytoplasm partition these bundles and separate individual axons. Each sensory nerve fiber terminates in a specialized ending which is designed to be especially sensitive to certain natural stimuli as discussed in Chaps. 7 and 8.

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Figure 43-1.  Diagram showing the relationships of the peripheral nerve sheaths to the meningeal coverings of the spinal cord. The epineurium (EP) is in direct continuity with the dura mater (DM). The endoneurium (EN) remains unchanged from the peripheral nerve and spinal root to the junction with the spinal cord. At the subarachnoid angle (SA), the greater portion of the perineurium (P) passes outward between the dura mater and the arachnoid (A), but a few layers appear to continue over the nerve root as part of the root sheath (RS). At the subarachnoid angle, the arachnoid is reflected over the roots and becomes continuous with the outer layers of the root sheath. At the junction with the spinal cord, the outer layers of the root sheath become continuous with the pia mater (PM). (Reproduced with permission from Haller FR, Low FN. The fine structure of the peripheral nerve root sheath in the subarachnoid space in the rat and other laboratory animals. Am J Anat. 1971;131(1):1–19.)

Pathogenic Mechanisms in Peripheral Nerve Disease These features enable one to conceptualize the possible avenues by which disease may affect the peripheral nerves. Pathologic processes may be directed at any one of the several groups of nerve cells whose axons constitute the nerves, that is, the cells of the anterior or lateral horns of the spinal cord, the dorsal root ganglia, or the sympathetic and parasympathetic ganglia. Each of these cell types exhibits specific vulnerabilities to disease, and if destroyed—as, for example, the motor nerve cells in poliomyelitis—there is secondary degeneration of the axons and myelin sheaths of the peripheral fibers of these cells. Neuropathic symptoms are also induced by alterations of the function and structure of the ventral and dorsal columns of the spinal cord, which contain the fibers of exit and entry of anterior horn and dorsal root ganglion cells, respectively. The myelin of these centrally located fibers is constituted differently from that of the peripheral nerves, being enveloped by oligodendrocytes rather than Schwann cells and the nerve fibers are supported by astrocytes rather than fibroblasts. Because of the intimate relation of the nerve roots to the CSF and to specialized arachnoidal cells (the arachnoidal villi), a pathologic process in the CSF or leptomeninges may damage the exposed spinal roots. Diseases of the connective tissues affect the peripheral nerves that lie within their sheaths. Diffuse or localized arterial diseases may injure nerves by occluding their nutrient arteries. In a large category of immune-mediated neuropathies, the damage is the result of a cellular or humoral attack on various components of myelin. For example, a subset of these is characterized by the binding of circulating antibodies to the specialized regions at the nodes of Ranvier, causing a

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block of electrical conduction. A complement-dependent humoral immune reaction against the radicular or peripheral axon is also known. Toxic or immunologic agents that selectively damage the Schwann cells or their membranes cause demyelination of peripheral nerves, leaving axons relatively intact, or a toxin may specifically affect axons and dendrites by poisoning their cell bodies, the axolemma, or the lengthy and complex axonal transport apparatus. Finally, one might correctly suppose that axons of the motor or sensory nerves, sympathetic fibers of varying diameter and length, or the end organs to which they are attached would each have its own particular liability to disease. At present we can cite only a few examples of diseases that cause disease through these mechanisms exclusively: for example, diphtheria, in which the bacterial toxin acts directly on the membranes of the Schwann cells near the dorsal root ganglia and adjacent parts of motor and sensory nerves (the most vascular parts of the peripheral nerve); polyarteritis nodosa, which causes occlusion of vasa nervorum, resulting in multifocal nerve infarction; tabes dorsalis, in which there is a treponemal meningoradiculitis of the posterior roots (mainly of the lumbosacral segments); poisoning by arsenic, which combines with the axoplasm of the largest sensory and motor nerves via sulfhydryl bonds; and vincristine toxicity, which damages the microtubular transport system. Analogous anatomic pathways are probably implicated in other diseases by mechanisms that remain to be discovered.

Among the genetically determined neuropathies, the altered gene products are known in some cases to lead to defective myelination, which greatly slows conduction along nerves. In other genetic diseases it is known that structural components of the axon are disrupted, leading to axonal degeneration and impaired electrical conduction but many of the basic mechanisms by which these occur are still under study.

Pathologic Reactions of Peripheral Nerve Several distinct histopathologic changes are recognized in the peripheral nerve, although they are not diseasespecific and they may be present in varying combinations in any given case. The three main ones are segmental demyelination, wallerian degeneration, and axonal degeneration (diagrammatically illustrated in Fig. 43-2). The myelin sheath is the most susceptible element of the nerve fiber, for it may break down as part of a primary process involving the Schwann cells or of the myelin itself, or it may be damaged secondarily as a consequence of disease affecting its axon. Focal degeneration of the myelin sheath with sparing of the axon is called segmental demyelination. The characteristic change of segmental demyelination is the disappearance of the sheath over segments of variable length, bounded on each end by one side of a node of Ranvier and an adjacent preserved segment of myelin. This exposes long segments of the axon to the

NERVE CELL BODY NUCLEUS AXON INTERMODE NODE OF RANVIER SCHWANN CELL NUCLEUS MOTOR END PLATE MUSCLE NORMAL

WALLERIAN DEGENERATION

SEGMENTAL DEMYELINATION

AXONAL DEGENERATION

Figure 43-2.  Diagram of the basic pathologic processes affecting peripheral nerves. In wallerian degeneration, there is degeneration of the axis cylinder and myelin distal to the site of axonal interruption (arrow) and central chromatolysis. In segmental demyelination, the axon is spared. In axonal degeneration, there is a distal degeneration of myelin and the axis cylinder as a result of neuronal disease. Both wallerian and axonal degeneration cause muscle atrophy. Further details are found in the text. (Courtesy of Dr. Arthur Asbury.)

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interstitial environment. Myelin may also degenerate from axonal disease in a general process that may occur either proximal or distal to the site of axonal interruption. Common to many lesions of the peripheral nerve is wallerian degeneration, a reaction of both the axon and myelin distal to the site of disruption of an axon. Wallerian degeneration might be described as “dying forward,” a process in which the nerve degenerates from the point of axonal damage outward. In contrast, when the axon degenerates as part of a “dying-back” phenomenon in a more generalized metabolically determined polyneuropathy, it is termed axonal degeneration. Here, the axon is affected progressively from the distal-most site to the proximal, with dissolution of myelin that occurs roughly in parallel with the axonal change. One explanation for this process is that the primary damage is to the neuronal cell body, which fails in its function of synthesizing proteins and delivering them to the distal parts of the axon. Certain toxic and metabolic processes affect axons uniformly along their length or impair anterograde axonal transport to the periphery; the functional impairment is then proportional to the size and length of the blocked axons. Damage to an axon distal to its sensory ganglion, however, does not result in degeneration of the spinal root as the connection between sensory neurons and proximal axon is spared. This discrepancy has consequences in the interpretation of electrophysiologic studies, as discussed in Chap. 2 and later in this chapter. Destruction of a proximal spinal motor root results in a gradual dissolution of the distal motor nerve and its myelin sheath (a form of wallerian degeneration). The neuronal motor cell body that gives rise to the motor fiber undergoes characteristic retrograde morphologic changes described below but does not die. Similar destruction of the dorsal spinal root produces secondary wallerian degeneration of the posterior columns of the spinal cord, but not of the peripheral sensory nerve because the dorsal root ganglion cell maintains the integrity of the distal axon. In other words, destruction of axons results within several days in wallerian degeneration of the myelin distal to the point of injury but not transgressing the neuronal cell body (the obverse of the situation of destruction of the distal sensory fiber noted above). The myelin breaks down into blocks or ovoids in which lie fragments of axons (digestion chambers of Cajal). The myelin fragments are then converted, through the action of macrophages, into neutral fats and cholesterol esters and carried by these cells to the bloodstream. Certain diseases affect the neuron primarily rather than the axon and cause either a motor or sensory neuronopathy. In the former case, more properly considered a myelopathy, the anterior horn cell is affected by a disease process (motor neuron disease, or motor neuronopathy) and in the latter, the sensory ganglion cell (ganglionopathy) is destroyed. A type of wallerian distal degeneration of the respective nerve fibers follows. Some of these pathologic reactions are more easily understood if one considers certain features of cytoskeletal structure and function of nerve cells and their axons. The axon contains longitudinally oriented neurofilaments and microtubules, which are separated but interconnected

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by cross-bridges. Their main function involves the transport of substances from nerve cell body to axon terminal (anterograde transport) and from the distal axon back to the cell body (retrograde transport). Thus, when the axon is severed, organelles cannot be transmitted to the distal axon for the purpose of renewing membrane and neurotransmitter systems. By means of retrograde axonal transport, the cell bodies receive signals to increase their metabolic activity and to produce growth factors and other materials needed for axonal regeneration. In an incompletely defined way, the axon also creates a local environment that allows the Schwann cell to maintain the integrity of the adjacent myelin sheath. Loss of this trophic influence leads to the dissolution of the myelin sheath, but not of the Schwann cell itself, leaving the cell available to regenerate myelin. There are also highly characteristic histopathologic changes in the nerve cell body termed chromatolysis as a secondary consequence of axonal interruption. These retrograde changes consist of swelling of the cell cytoplasm and marginalization and dissolution of the Nissl substance. The important point again is that despite the destructive changes in the nerve fibers, the nerve cells, while altered in histologic appearance, are left intact with preservation of the apparatus required for recovery. In segmental demyelination, recovery of function may be rapid because the intact but denuded axon needs only to become remyelinated. The newly formed internodal segments are initially thinner than normal and of variable length. By contrast, recovery is much slower with wallerian or axonal degeneration, often requiring months to a year or more because the axon must first regenerate and then reinnervate the muscle, sensory organ, or blood vessel before function returns. When the regenerating axon first becomes myelinated, the internodal myelin segments are short, the length of one normal internode being replaced by 3 or 4 shorter new ones. Recurrent demyelination and remyelination lead to “onion bulb” formations and enlargement of nerves, the result of proliferating Schwann cells and fibroblasts that encircle the axon and its thin myelin sheath. If nerve cells are destroyed, no recovery of function is possible except by collateral regeneration of axons from intact nerve cells. Interruption of a nerve fiber by severing or by crude destruction usually prevents continuity from being reestablished. Regenerating axon filaments take aberrant courses and, with fibroblastic scar formation, they may form a disorganized clump of tissue termed pseudoneuroma. These relatively few pathologic reactions do not, in themselves, differentiate the many dozens of diseases of the peripheral nerves, but when they are considered in relation to the selective effects on various types and sizes of fibers, the topography of the lesions, and the time course of the process, they furnish criteria for fairly accurate diagnosis. Moreover, the identification of these basic reactions is of great value in the inspection of pathologic material obtained from biopsy or autopsy. There are additional special pathologic changes, not specifically neural in nature that characterize certain diseases of the peripheral nervous system. These involve inflammatory or vascular changes or deposition of material in the interstitium of the nerve. For example, acute

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demyelinative polyneuritis of the Guillain-Barré type is characterized by endoneurial infiltrations of lymphocytes and other mononuclear cells in the nerves, roots, and sensory and sympathetic ganglia. Deposition of amyloid in the endoneurial connective tissue and walls of vessels affecting the nerve fibers is the distinctive feature of inherited and acquired amyloid polyneuropathy. Diphtheritic polyneuropathy is typified by the demyelinative character of the nerve fiber change, the location of this change in and around the roots and sensory ganglia, the subacute course, and the lack of inflammatory reaction. Several neuropathies are characterized by the deposition of antibodies and complement on the myelin sheath or on elements of the axon. These changes can be demonstrated by immunohistopathologic techniques but have no histopathologic representations. However, most polyneuropathies (paraneoplastic, nutritional, porphyric, arsenical, and uremic) are topographically symmetrical and represent forms of axonal degeneration but cannot be easily distinguished from one another on histopathologic grounds but share the features of axonal degeneration. Concerning the pathology of the mononeuropathies, our knowledge is somewhat more complete. Compression of nerve or nerve roots, local or segmental ischemia, stretch, and laceration of nerves are understandable mechanisms, and their pathologic changes can be reproduced experimentally. Tumor infiltration and importantly, vasculitis with ischemic infarction of nerve, account for a proportion of cases. Of infections and granulomas localized to single nerves, leprosy, sarcoid, and herpes zoster represent identifiable disease states. For most of the acute mononeuropathies that are a result of transient compression, the pathologic changes have yet to be fully defined, as they are usually reversible states that provide no opportunity for complete pathologic examination. Experimental models of nerve compression indicate disruption of tubular transport and local demyelination. The common symptoms of compression such as paresthesias are explained, as discussed further on, by exposure of sodium channels along denuded axons and spontaneous and ectopic electrical discharges.

SYMPTOMATOLOGY OF PERIPHERAL NERVE DISEASE There are motor, sensory, reflex, autonomic, and trophic symptoms and signs that are typical of peripheral nerve disease. Grouping them into syndromes based on their temporal and topographic features has proved to be of great value in clinical diagnosis. Although motor, sensory, reflex, and trophic changes are taken together to determine specific diagnosis, each element of the neuropathic diseases is given in the following pages.

Impairment of Motor Function It is not surprising that weakness in various patterns and degrees is a feature of almost all neuropathies. The degree of weakness is proportional to the number of axons or

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motor neurons affected. Polyneuropathies that are the result of axonal damage are characterized foremost by a relatively symmetric distribution of weakness that is, moreover, distal because the pathologic changes begin in the far distal parts of the largest and longest nerves and advance along the affected fibers toward their nerve cell bodies (dying-back neuropathy, or “distal axonopathy”). The muscles of the feet and legs are typically affected earlier and more severely than those of the hands and forearms. In milder forms of axonal disease, only the feet and lower legs are involved. Truncal and cranial muscles are usually the last to yield, and then only in severe cases. This represents the “lengthdependent” pattern that is typical of axonal degeneration. The nutritional, metabolic, and toxic neuropathies assume this predominantly distal “axonal” pattern. An exception is porphyria, an axonal process in which there may be mainly proximal weakness. By contrast, in acquired demyelinating polyneuropathies, the multifocal nature of lesions and blockage of electrical conduction often leads to weakness of proximal limb and facial muscles before or at the same time as distal parts are affected. Another pattern of neuropathic weakness is one in which all the muscles of the limbs, trunk, and neck are involved almost simultaneously, often including respiratory paralysis, therefore making it impossible to determine if the axons or myelin, or both, have been damaged. The best characterized of these processes is the Guillain-Barré syndrome (GBS). Less common causes of generalized paralysis include diphtheria, tick paralysis, and certain toxic polyneuropathies. Fatalities, when they occur, are usually a result of respiratory failure. A predominantly bibrachial paralysis is an unusual presentation of neuropathic disease but may occur in the inflammatory-demyelinating polyneuropathies, as well as in Sjögren syndrome, chronic immune or paraneoplastic neuropathies, lead neuropathy, Tangier disease, and in a familial type of brachial neuritis. (A more frequent cause of bibrachial palsy is disease of the motor neurons themselves namely, motor system disease, or a lesion placed centrally in the cervical cord that damages these same neurons.) Paraparesis is not typical of the generalized polyneuropathies, but it is observed with infections and inflammations of the cauda equina, as occurs with Lyme disease, cytomegalovirus, herpes simplex, and with neoplastic infiltration of the nerve roots. Bifacial and other cranial nerve paralyses are likely to occur in GBS, neoplastic invasion, with connective tissue diseases, HIV and herpes virus infection, sarcoidosis, Lyme disease, or one of the rare metabolic neuropathies (e.g., Refsum, BassenKornzweig, Tangier, and Riley-Day). These are discussed in Chap. 44 on diseases of the cranial nerves and in respective chapters on infections and metabolic diseases of the nervous system. Atrophy of weak or paralyzed muscles is characteristic of chronic disease of the motor neuron or motor axon and conversely, demyelinating neuropathies relatively spare muscle bulk because of the absence of denervation. Atrophy proceeds slowly over several weeks and months, the degree being proportional to the number of damaged motor nerve fibers. The maximum degree of denervation atrophy after an acute injury to the axons occurs in 90 to

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120 days and reduces muscle volume by 75 to 80 percent. Atrophy may also be a consequence of disuse; it occurs over many weeks but in itself does not reduce muscle volume by more than 25 to 30 percent. In chronic axonal neuropathies, the degrees of paralysis and atrophy tend to correspond. As mentioned previously, atrophy does not coincide with weakness in acute paralysis caused by the demyelinative neuropathies in which the nerve fiber is relatively less affected than is the myelin. Ultimately in muscle atrophy, there is degeneration and loss of the denervated muscle fibers. This process begins in 6 to 12 months; in 3 to 4 years, most of the denervated fibers will have degenerated. If reinnervation takes place within a year or so, motor function and muscle volume may be restored.

Tendon Reflexes As a rule, neuropathies are associated with a reduction or loss of tendon reflexes. Most often, this is the result of an interruption of the afferent (sensory) portion of the monosynaptic reflex arc. The reflexes may be diminished if muscular function is impaired, but this occurs mainly in the case of extreme atrophy, in which there are too few muscle fibers to manifest a contraction. There are, of course, many other processes that reduce the tendon reflexes, but it is the neuropathies with which loss of reflexes is most closely associated. An exception is the group of small-fiber neuropathies, in which tendon reflexes may be retained, even with marked loss of perception of painful stimuli. This discrepancy is attributable to the dependence of the afferent component of the tendon reflex arc on the large, heavily myelinated fibers that originate in muscle spindles. Conversely, in neuropathies that affect the largest diameter and most heavily myelinated fibers, the tendon reflexes are diminished early and disproportionately to weakness. Slowing of conduction in sensory fibers may also abolish the reflex by dispersing the afferent volley of impulses initiated by the tendon tap. There is generally a concordance between areflexia and a loss of proprioceptive and jointposition senses; that is, the large nerve fibers from spindle afferents are of the same type and size as those mediating these forms of sensation. Furthermore, loss of sensory functions that are dependent on these large fibers in the presence of preserved reflexes implicates the central projections of the sensory ganglion cells, that is, a lesion in the posterior columns of the spinal cord that does not interrupt the afferent tendon reflex arc. Regional loss of a reflex is usually a sign of a radiculopathy.

Sensory Loss (See Also “Sensory Syndromes” in Chap. 8) Most polyneuropathies cause impairment of both motor and sensory functions, but one is often affected more than the other. In the toxic and metabolic neuropathies, sensory loss usually exceeds weakness. These differences are emphasized in the descriptions of individual peripheral nerve diseases in later parts of the chapter. In the axonal polyneuropathies, sensation is affected symmetrically in the distal segments of the limbs and more in the legs than in the arms, owing to the length-dependent

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nature of most diseases that affect peripheral nerves. In most types, all sensory modalities (touch-pressure, pain and temperature, vibratory and joint position senses) are impaired or eventually lost, although one modality is often affected disproportionately to the others; for example, temperature sensation (small afferent fibers) may be impaired more than joint position and vibration (larger fibers). As an axonal neuropathy worsens, there is spread of sensory loss from the distal to more proximal parts of the limbs and eventually, to the anterior abdomen, thorax, and the face. An “escutcheon” pattern of sensory loss over the anterior abdomen and thorax in severe axonal neuropathy may be mistaken for the sensory level of a spinal cord lesion if the back is not examined. Another characteristic form of sensory loss affects the trunk, scalp, and face and later, the trunk and limbs; this is the pattern of a sensory ganglionopathy that is the result of simultaneous dysfunction of all parts of the sensory nerve. Most often, universal sensory loss is attributable to an acquired disease affecting the sensory ganglia (sensory neuronopathy, ganglionopathy referred to above); a paraneoplastic process or certain toxic or immune diseases are usually responsible (e.g., Sjögren disease, scleroderma).

Paresthesias, Pain, and Dysesthesias These symptoms were described in Chaps. 7 and 8. Sensory symptoms tend to be especially marked in the hands and feet. “Pins and needles,” “falling asleep,” “stabbing,” “tingling,” “prickling,” “electrical,” and “Novocain-like” are the adjectives chosen by patients to describe these positive sensory experiences. In some neuropathies, paresthesias and numbness are the only symptoms and objective sensory loss is lacking or minimal. Certain neuropathies characteristically cause pain, which is described as burning, aching, sharp and cutting, or crushing and at times may resemble the lightning pains of tabes dorsalis. Perversion of sensation (allodynia) is also commonplace in some polyneuropathies—for example, tingling, burning, stabbing pain, or just an uncomfortable dysesthesia is induced by tactile stimuli. Under these conditions, a stimulus induces not only an aberrant sensation but also one that radiates to adjacent areas and persists after the stimulus is withdrawn. As remarked in Chap. 8, the reactions of a patient with allodynia may seem to indicate hypersensitivity (“hyperesthesia”), but more often the sensory threshold is actually raised and it is the sensory experience or response that is exaggerated (hyperpathia). Painful paresthesias and dysesthesias are particularly common in diabetic, alcoholic–nutritional, and amyloid neuropathies. Mainly they affect the feet (“burning feet”) and less often the hands. In herpes zoster, they are confined to dermatomal regions of the body. A particularly intense form of burning pain typifies the causalgia of a partial nerve lesion (usually traumatic) of the ulnar, median, posterior tibial, peroneal, or occasionally some other nerve (see Chap. 7 and further on in this chapter). The mechanism of thermal and painful dysesthesias is not fully understood. It has been theorized that a loss of large touch-pressure fibers disinhibits the pain-receiving nerve cells in the posterior horns of the spinal cord.

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An argument against this explanation is the lack of pain in Friedreich ataxia, in which the larger neurons degenerate, and in certain purely sensory polyneuropathies, where only the perception of tactile stimuli (large fibers) is lost. A more likely explanation, supported by microneurographic recordings, is that dysesthetic pain results from ectopic discharges arising at many sites along surviving intact or regenerating nerve fibers or their terminal receptors. It has been postulated, on uncertain grounds, that the deep, aching neuropathic pain of sciatica or brachial neuritis (nerve trunk pain) arises from irritation of the normal endings (nervi nervorum) in the sheaths of the nerve trunks themselves (Asbury and Fields). These considerations are discussed in Chap. 7.

Sensory Ataxia and Tremor Proprioceptive deafferentation with retention of a reasonable degree of motor function may give rise to ataxia of gait and of limb movement as discussed in Chap. 8. Dysfunction of the spinocerebellar fibers of the peripheral nerves is probably the source of the ataxia. Some of the most severe ataxias of this type occur with sensory ganglionopathy, as commented further on. Ataxia without weakness is also characteristic of tabes dorsalis, a purely posterior root disease, but this syndrome can be duplicated by a type of diabetic polyneuropathy, which affects posterior roots (diabetic pseudotabes) and by a variant of GBS (termed Fisher syndrome). The ataxia is indistinguishable from that caused by cerebellar diseases, but other features of cerebellar dysfunction such as dysarthria and nystagmus are lacking. Characteristic of the sensory-ataxic gait are brusque, flinging, slapping movements of the legs. Loss of proprioception may also give rise to small wavering, fluctuating movements of the outstretched fingers—called pseudoathetotic, or “dancing fingers.” An action tremor of fast-frequency type may also appear during certain phases of a polyneuropathy; Shahani and coworkers had the impression that it is a result of loss of input from the muscle-spindle afferents. Corticosteroid therapy enhances this fast tremor. A particularly severe form of slower action tremor is combined with clumsiness of movement in the neuropathies caused by the autoimmune, anti-myelin-associated glycoprotein (anti-MAG) polyneuropathy and in some cases of chronic inflammatory demyelinating polyneuropathy (CIDP). The tremor may be so coarse as to resemble the intention tremor of cerebellar disease and all movements are rendered useless. However, a tremor at rest is not found in these afferentsensory neuropathies. The neuropathic type of tremor is also discussed in Chap. 4.

Deformity and Trophic Changes In a few of the chronic polyneuropathies, the feet, hands, and even the spine may become progressively deformed. This is most likely to occur when the disease begins during childhood. Austin pointed out that foot deformity is found in 30 percent of patients with hereditary polyneuropathy, and spine curvature is found in 20 percent. In early life, the feet are pulled into a position of talipes equinus

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(plantar deviation) because of disproportionate weakness of the pretibial and peroneal muscles and the unopposed action of the calf muscles. Weakness of the intrinsic foot muscles during the period of life when the bones are forming allows the long extensors of the toes to dorsiflex the proximal phalanges and the long flexors to shorten the foot, heighten the arch, and flex the distal phalanges. The result is the claw foot—le pied en griffe—or pes cavus (high arches) when the process is less severe. These changes in the structure of the foot are valuable diagnostic indicators that a neuromuscular disease originated in early childhood or during intrauterine development. A congenital claw hand has a similar implication. Unequal weakening of the paravertebral muscles on the two sides of the spine during early development leads to kyphoscoliosis. Denervation atrophy of muscle can be considered the main trophic disturbance resulting from interruption of the motor nerves. However, there are numerous other changes. Analgesia of distal limb parts makes them susceptible to burns, pressure sores, and other forms of injury that are easily infected and heal poorly. In an anesthetic and immobile limb, the skin becomes tight and shiny, the nails curved and ridged, and the subcutaneous tissue thickened (“trophic changes”). Hair growth is diminished in denervated areas. If the autonomic fibers are also interrupted, the limb becomes warm and pink. Repeated injuries and chronic subcutaneous and osteomyelitic infections result in a painless loss of digits and the formation of plantar ulcers (mal perforant du pied). These are prominent features of the recessive form of hereditary sensory neuropathy and we have observed them in dominant forms as well. In tabes dorsalis and syringomyelia as well as certain familial and other chronic polyneuropathies, analgesic joints, when chronically traumatized, may first become deformed and then actually disintegrate in a process called Charcot arthropathy (Charcot joint). Apart from analgesia, a critical factor in these trophic changes may be aberrant neural regulation of the distal vasculature, which interferes with normal tissue responses to trauma and infection. Ali and colleagues have related the ulcer formation to loss of C fibers, which mediate both pain and autonomic reflexes. However, paralyzed limbs, even in hysteria, if left dependent, are often cold, swollen, and pale or blue. These are probably secondary effects of immobilization, as pointed out long ago by Lewis and Pickering. Erythema and edema, burning pain, and cold sensations surely can be evoked by peripheral nerve irritation, particularly of C and A-δ fibers as discussed in Chap. 7.

Autonomic Dysfunction Anhidrosis and orthostatic hypotension, two of the most frequent manifestations of autonomic failure, predominate in certain types of polyneuropathies. They occur frequently in amyloidosis and in other small-fiber polyneuropathies, especially diabetic, and in several congenital types. These are also the main features of an acute autonomic polyneuropathy called pandysautonomia (Young et al; Adams et al; Low et al) and can be prominent in some cases of GBS. The neuropathic dysautonomic conditions are described in detail in Chap. 25 and later in this chapter.

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Other manifestations of autonomic paralysis are small or medium-sized unreactive pupils that are unusually sensitive to certain drugs (see Chap. 13); lack of sweat, tears, and saliva; erectile dysfunction; weak bowel and bladder sphincters with urinary retention or overflow incontinence; and weakness and dilation of the esophagus and colon. As a result of vagal and other parasympathetic dysfunction, the normal variability of heart rate with respiration (sinus arrhythmia) is lost and there may be paralytic ileus or dyscoordinated peristalsis, as well as achlorhydria and hyponatremia. Some of these abnormalities are found in diabetic and amyloid polyneuropathy. They correspond to degeneration of small unmyelinated autonomic fibers in the peripheral nerves. In any neuropathy involving sensory nerves, there is loss of autonomic function in the same zones as sensory loss. This is not true of radicular diseases because the autonomic fibers join the spinal nerves from the sympathetic chain and parasympathetic ganglia more distally. Changes in sweating and cutaneous blood flow may be demonstrated by a number of special tests described in Chap. 25.

Fasciculations, Cramps, and Spasms (See Also Chap. 46) Fasciculations and cramps are not prominent features in most polyneuropathies and in this respect, there is a difference from diseases of the anterior horn cells where they are important features. There are exceptions, however. Chronic spinal motor root compression leads to fasciculations or painful spasms in the innervated muscles. Occasionally one observes a state of mild motor polyneuropathy that, on recovery, leaves the muscles in a state variably referred to as myokymia, continuous muscular activity, and neuromyotonia as discussed in Chap. 46. The affected muscles ripple and quiver and occasionally cramp. The use of the muscles increases this activity and there is a reduction in their contractile efficiency, which the patient senses as a stiffness and heaviness. In some instances, this apparently constitutes the entire neuropathic syndrome and may be relieved by carbamazepine or phenytoin. Other closely related phenomena are spasms or involuntary movements of the toes and feet. The latter, when the sole manifestation of disease, was referred to by Spillane and colleagues as the syndrome of painful legs and moving toes. It has been attributed to ectopic discharges in sensory roots, ganglia, or nerves, evoking both pain and organized movements (Nathan). This is but one of many causes of the nocturnal restless leg syndrome, but it does not explain the more common type of idiopathic restless leg nocturnal syndrome described in Chap. 18. Other possible mechanisms for cramps and spasms are ephaptic cross-transmission between adjacent axons denuded of myelin, segmental hyperactivity from deafferentation, and neuronal sprouting during reinnervation. Infrequently, the muscle activity induces odd postures or slow writhing movements that have been likened to dystonia (Jankovic and van der Linden). The pathophysiology of these asynchronous activities of motor neurons is not known. Stimulation of a motor nerve in these cases, instead of causing a brief burst of action potentials in the muscle, results in a

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prolonged or dispersed series of potentials lasting several hundred milliseconds. Evidently, branched axons involved in collateral innervation have unstable polarization that may last for years.

APPROACH TO THE PATIENT WITH PERIPHERAL NEUROPATHY The clinician is faced initially with several problems that can be solved sequentially when dealing with this group of diseases: (1) establishing the existence of disease of the peripheral nervous system and differentiating it from a process of the central nervous system, neuromuscular junction or the muscles; (2) distinguishing by clinical examination which of the main topographic syndromes is being displayed; (3) determining by examination and nerve conduction studies if the problem is predominantly motor or sensory or autonomic in nature or is of mixed type and whether the myelin sheath, the axon, or cell body (motor or sensory neurons) is the target of disease; and (4) assessing if the neuropathy is acquired or hereditary in nature. When taken together, these features limit the likely etiologic diagnoses from a vast list of possibilities.

Topographic and Clinical Patterns of Neuropathy (Tables 43-1 and 43-2) At the outset it must be determined whether the neurologic findings correspond to one of the following syndromic patterns: 1. Polyneuropathy 2. Radiculopathy or polyradiculopathy 3. Neuronopathy—motor or sensory 4. Mononeuropathy 5. Multiple mononeuropathies (mononeuropathy multiplex) 6. Plexopathy (involvement of multiple nerves in a plexus) A discussion of these patterns is given in Chap. 8, but the main facts are reviewed here. In polyneuropathy, a generalized process affecting the peripheral nerves, weakness is relatively symmetrical from the beginning and progresses bilaterally; reflexes are lost in affected parts but particularly at the ankles; sensory complaints and loss of sensation are most pronounced distally, and in the feet before the hands in most cases. Polyradiculopathy, a disease of multiple spinal roots, differs from polyneuropathy in that the neurologic signs are asymmetrical, with an erratic distribution that may, for example, be proximal in one limb and distal in another. Weakness and zones of sensory loss correspond to involvement of one or more spinal or cranial roots. Pain in the sensory distribution of the roots is a common feature. The common single radiculopathy, most often the result of root compression by disease of the spinal column, is identified by pain, sensory, motor, and reflex change solely in the distribution of one nerve root. The distinction from mononeuropathy (see later) is not always apparent and one must resort to a reference or to memorized knowledge

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Table 43-1 ACTIONS OF THE PRINCIPAL MUSCLES AND THEIR NERVE ROOT SUPPLY ACTION TESTED

ROOTSa

NERVES

MUSCLES

Cranial Closure of eyes, pursing of lips, exposure of teeth

Cranial 7

Facial

Elevation of eyelids, movement of eyes

Cranial 3, 4, 6

Closing and opening of jaw   Protrusion of tongue Phonation and swallowing

Cranial 5   Cranial 12 Cranial 9, 10

Oculomotor, trochlear, abducens Motor trigeminal   Hypoglossal Glossopharyngeal, vagus

Elevation of shoulders, anteroflexion and turning of head

Cranial 11 and upper cervical

Spinal accessory

Orbicularis oculi Orbicularis oris Levator palpebrae, extraocular Masseters Pterygoids Lingual Palatal, laryngeal, and pharyngeal Trapezius, sternomastoid

Brachial Adduction of extended arm Fixation of scapula Initiation of abduction of arm External rotation of flexed arm Abduction and elevation of arm up to 90° Flexion of supinated forearm Extension of forearm Extension (radial) of wrist Flexion of semipronated arm Adduction of flexed arm Supination of forearm Extension of proximal phalanges Extension of wrist (ulnar side) Extension of proximal phalanx of index finger Abduction of thumb

C5, C6 C5, C6, C7 C5, C6 C5, C6 C5, C6 C5, C6 C6, C7, C8 C6 C5, C6 C6, C7, C8 C6, C7 C7, C8 C7, C8 C7, C8 C7, C8

Brachial plexus Brachial plexus Brachial plexus Brachial plexus Axillary nerve Musculocutaneous Radial Radial Radial Brachial plexus Posterior interosseous Posterior interosseous Posterior interosseous Posterior interosseous Posterior interosseous

Extension of thumb

C7, C8

Posterior interosseous

Pronation of forearm Radial flexion of wrist Flexion of middle phalanges Flexion of proximal phalanx of thumb Opposition of thumb against fifth finger Extension of middle phalanges of index and middle fingers Flexion of terminal phalanx of thumb Flexion of terminal phalanx of second and third fingers Flexion of distal phalanges of ring and little fingers Adduction and opposition of fifth finger Extension of middle phalanges of ring and little fingers Adduction of thumb against second finger Flexion of proximal phalanx of thumb Abduction and adduction of fingers

C6, C7 C6, C7 C7, C8, T1 C8, T1 C8, T1 C8, T1

Median nerve Median nerve Median nerve Median nerve Median nerve Median nerve

Pectoralis major Serratus anterior Supraspinatus Infraspinatus Deltoid Biceps, brachialis Triceps Extensor carpi radialis longus Brachioradialis Latissimus dorsi Supinator Extensor digitorum Extensor carpi ulnaris Extensor indicis Abductor pollicis longus and brevis Extensor pollicis longus and brevis Pronator teres Flexor carpi radialis Flexor digitorum superficialis Flexor pollicis brevis Opponens pollicis First, second lumbricals

C8, T1 C8, T1

Anterior interosseous nerve Anterior interosseous nerve

Flexor pollicis longus Flexor digitorum profundus

C7, C8 C8, T1 C8, T1

Ulnar Ulnar Ulnar

Flexor digitorum profundus Hypothenar Third, fourth lumbricals

C8, T1 C8, Tl C8, T1

Ulnar Ulnar Ulnar

Adductor pollicis Flexor pollicis brevis Interossei

Hip flexion from semiflexed position Hip flexion from externally rotated position Extension of knee Adduction of thigh Abduction and internal rotation of thigh Extension of thigh Flexion of knee    

L1, L2, L3 L2, L3 L2, L3, L4 L2, L3, L4 L4, L5, S1 L5, S1, S2 L5, S1, S2    

Femoral Femoral Femoral Obturator Superior gluteal Inferior gluteal Sciatic    

Iliopsoas Sartorius Quadriceps femoris Adductor longus, magnus, brevis Gluteus medius Gluteus maximus Biceps femoris Semitendinosus Semimembranosus

Crural

(Continued)

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Table 43-1 ACTIONS OF THE PRINCIPAL MUSCLES AND THEIR NERVE ROOT SUPPLY (CONTINUED) ACTION TESTED

Dorsiflexion of foot (medial) Dorsiflexion of toes (proximal and distal phalanges) Dorsiflexion of great toe Eversion of foot Plantar flexion of foot Inversion of foot Flexion of toes (distal phalanges) Flexion of toes (middle phalanges) Flexion of great toe (proximal phalanx) Flexion of great toe (distal phalanx) Contraction of anal sphincter

ROOTSa

NERVES

L4, L5 L5, S1

Peroneal (deep) Peroneal (deep)

L5, S1 L5, S1 S1, S2 L4, L5 L5, S1, S2 S1, S2 S1, S2 L5, S1, S2 S2, S3, S4

Peroneal (deep) Peroneal (superficial) Tibial Tibial Tibial Tibial Tibial Tibial Pudendal

MUSCLES

Anterior tibial Extensor digitorum longus and brevis Extensor hallucis longus Peroneus longus and brevis Gastrocnemius, soleus Tibialis posterior Flexor digitorum longus Flexor digitorum brevis Flexor hallucis brevis Flexor hallucis longus Perineal muscles

a

Predominant root(s) supplying a particular muscle are indicated in bold italic type.

of the motor and sensory innervation patterns of roots and nerves as given in Figs. 8-1, 8-2, and 8-3 and on the overleafs of the book. Most helpful is the limitation of sensory loss to one of the dermatomes, but it so happens that there is an overlap between adjacent dermatomes and such a pattern is not easily discerned. Mononeuropathy is the most circumscribed form of peripheral nerve disease. It is reflected by weakness and sensory loss in the territory of a single peripheral nerve (Table 43-1). Specific features serve to differentiate mononeuropathy from a radiculopathy—for example, weakness in dorsiflexion and eversion of the foot is referable either to the peroneal nerve or to the L5 nerve root; however, if there is weakness of inversion of the foot, innervated by the tibial nerve, the fault must be with the L5 root, not with the peroneal nerve. Conversely, if inversion is spared in a foot drop, the lesion is in the peroneal nerve. The distribution of sensory loss also aids in distinguishing the two processes; for example, in the aforementioned case the region of sensory change corresponding to the L5 root extends almost up to the knee on the anterior surface of the foreleg whereas it ends a limited distance above the ankle in the case of a peroneal nerve lesion (see the sensory maps in Figs. 8-1, 8-2, and 8-3). At times, particularly in advanced stages, the accumulation of multiple mononeuropathies, termed mononeuropathy multiplex, may be difficult to differentiate from polyneuropathy as discussed further on. Plexopathies (brachial or lumbosacral) create the most confusing patterns of motor and sensory involvement; only one limb is affected, but the motor, sensory, and reflex loss does not conform to a pattern of several adjacent nerve roots or nerves. Knowledge of the innervation of the involved muscles at the level of the plexus usually clarifies the situation. In sensory neuronopathy, the ganglion cells rather than the peripheral sensory nerves are predominantly affected. This gives rise to symptoms and signs of sensory loss in both a proximal and distal distribution, including the scalp, thorax, abdomen, and buttocks as well as the extremities; sensory ataxia is a common accompaniment. There is no weakness, but movements may be awkward as

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a result of a sensory ataxia. Motor neuronopathy is essentially the obverse condition, a disorder of the anterior horn causing weakness, fasciculations, and atrophy in a widespread distribution and, therefore, not properly included as a process of the peripheral nerves. The apparent complexity of peripheral nerve disease is greatly simplified by recognizing that of the multitude of diseases, each manifests itself by one or another of abovedescribed topographic and sensory-motor patterns for which reason the pattern of neuropathy sets limits on the etiologic possibilities. In the analysis of a polyneuropathy, it is of further value to determine whether the process is predominantly motor with less sensory involvement or the converse, or purely sensory, motor, or mainly autonomic. The time course of the disease also informs diagnosis. An acute onset (i.e., rapid evolution) is nearly always an inflammatory, immunologic, toxic, or vascular polyneuropathy. The other extreme, a polyneuropathy evolving over many years, is indicative of a hereditary or, rarely, a metabolic disease. Most of the toxic, nutritional, and systemic diseases of nerve develop subacutely over several weeks and months. In addition to the patient’s report of the progress of symptoms, signs such as muscle atrophy signify a process of relatively long duration, at least several months. The etiologic diagnosis of polyneuropathy is next guided by deducing whether the myelin sheath or the axon is primarily involved (i.e., demyelinating or axonal neuropathy). The neurologic examination alone may be sufficient to make this distinction, but greater precision is attained from nerve conduction studies and needle examination of muscles (EMG). The latter test also helps separate primary disorders of muscle (myopathies) and neurogenic denervation of muscle or neuromuscular block (myasthenia). The electrical examinations of nerve and muscle described in Chap. 2 greatly reduce the number of possible diagnoses. These EMG and nerve conduction abnormalities may be so characteristic as to virtually define a neuropathy, for example, chronic demyelinative motor neuropathy with multifocal conduction block. Other useful laboratory procedures are (1) biochemical tests to identify metabolic, nutritional, or toxic states;

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(2) CSF examination (increase in protein and in cells that indicate radicular or meningeal involvement); (3) nerve, and occasionally accompanying muscle biopsy (the latter aids in the diagnosis of vasculitic causes of neuropathy); (4) measurement of immunoglobulins and antineural antibodies that relate to immune-mediated neuropathies; and (5) genetic testing for several of the inherited neuropathies. These are discussed in the context of each of the main diseases of nerve and in the later parts of Chap. 2. Once having established that the patient has a disease of the peripheral nerves and having ascertained its clinical and electrophysiologic pattern and time course, one is usually able to determine its cause. This is accomplished most readily by allocating the case in question to one of the categories listed in Table 43-2, which classifies the peripheral nerve diseases syndromically according to their mode

of evolution and clinical presentation. Our use of the terms acute, subacute, and chronic neuropathy must be explained. By acute, we mean evolution in terms of days, and by subacute, evolution in terms of weeks. Chronic is divided into two groups: one in which the neuropathy has progressed for a period of several months to a few years and another in which progression is over many years, most of which prove to have a genetic cause. It can be restated that these temporal properties are, with the topographic pattern, the main determinants in the categorization of neuropathy. Diseases of the peripheral nerves are considered in a more comprehensive fashion in the two-volume Peripheral Neuropathy, edited by Dyck and colleagues and in the text by Amato and Russell cited in the references. Also recommended are more concise monographs by Schaumburg and associates and by Asbury and Thomas, and the atlas on the pathology of peripheral nerve by King.

Table 43-2 THE PRINCIPAL NEUROPATHIC SYNDROMES AND THEIR MAIN CAUSES I. Syndrome of acute motor paralysis with variable disturbance of sensory and autonomic function A. Guillain-Barré syndrome (GBS; acute inflammatory demyelinating polyneuropathy [AIDP]); see also Table 43-3 B. Acute axonal form of GBS (AMAN) C. Acute sensory neuropathy and neuronopathy syndrome D. Diphtheritic polyneuropathy E. Porphyric polyneuropathy F. Certain toxic polyneuropathies (thallium, triorthocresyl phosphate) G. Rarely, paraneoplastic H. Acute pandysautonomic neuropathy I. Tick paralysis J. Critical illness polyneuropathy II. Syndrome of subacute sensorimotor paralysis A. Symmetrical polyneuropathies 1. Deficiency states: alcoholism (beriberi), pellagra, vitamin B12 deficiency, chronic gastrointestinal disease (see Chap. 40) 2. Poisoning with heavy metals and solvents: arsenic, lead, mercury, thallium, methyl n-butyl ketone, n-hexane, methyl bromide, ethylene oxide, organophosphates (TOCP, etc.), acrylamide (see Chap. 41) 3. Drug toxicity: isoniazid, ethionamide, hydralazine, nitrofurantoin and related nitrofurazones, disulfiram, carbon disulfide, vincristine, cisplatin, paclitaxel, chloramphenicol, phenytoin, pyridoxine, amitriptyline, dapsone, stilbamidine, trichloroethylene, thalidomide, clioquinol, amiodarone, adulterated agents such as l-tryptophan 4. Uremic polyneuropathy (see Chap. 39) 5. Subacute inflammatory polyneuropathy 6. Paraneoplastic polyneuropathy 7. HIV B. Asymmetrical neuropathies (mononeuropathy multiplex) 1. Diabetes 2. Polyarteritis nodosa and other inflammatory angiopathic neuropathies (eosinophilic polyangiitis, hypereosinophilic, rheumatoid, lupus, Wegener granulomatosis, isolated peripheral nervous system vasculitis); see also Table 43-3 3. Mixed cryoglobulinemia 4. Sjögren-Sicca syndrome 5. Sarcoidosis 6. Ischemic neuropathy with peripheral vascular disease 7. Lyme disease 8. HIV 9. Diabetes 10. Multifocal motor neuropathy (MMN) 11. Multifocal conduction block (MADSAM) C. Unusual sensory neuropathies 1. Wartenberg migrant sensory neuropathy 2. Sensory perineuritis D. Meningeal-based nerve root disease (polyradiculopathy) 1. Neoplastic infiltration 2. Granulomatous and infectious infiltration: Lyme, sarcoidosis 3. Spinal diseases: osteoarthritic spondylitis 4. Idiopathic polyradiculopathy (Continued)

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Table 43-2 THE PRINCIPAL NEUROPATHIC SYNDROMES AND THEIR CAUSES (CONTINUED) III. Syndrome of early chronic sensorimotor polyneuropathy A. Paraneoplastic: carcinoma, lymphoma, myeloma, and other malignancies B. Chronic inflammatory demyelinating polyneuropathy (CIDP) C. Paraproteinemias D. Uremia (occasionally subacute) E. Nutritional beriberi (usually subacute) F. Diabetes G. Connective tissue diseases H. Amyloidosis I. Leprosy J. Hypothyroidism K. Benign sensory form in the elderly IV. Syndrome of more chronic (late) polyneuropathy, genetically determined forms (see Table 43-6) A. Inherited polyneuropathies of predominantly sensory type 1. Dominant mutilating sensory neuropathy in adults 2. Recessive mutilating sensory neuropathy of childhood 3. Congenital insensitivity to pain 4. Other inherited sensory neuropathies, including those associated with spinocerebellar degenerations, Riley-Day syndrome, and the universal anesthesia syndrome B. Inherited polyneuropathies of mixed sensorimotor types 1. Peroneal muscular atrophy (Charcot-Marie-Tooth; CMT types 1 [demyelinating] and 2 [axonal] and CMTX [X-linked]) 2. Hypertrophic polyneuropathy of Dejerine-Sottas, adult and childhood forms (CMT3) 3. Roussy-Lévy polyneuropathy 4. Polyneuropathy with optic atrophy, spastic paraplegia, spinocerebellar degeneration, or dementia 5. Hereditary liability to pressure palsy (HNPP) C. Inherited polyneuropathies with a recognized metabolic disorder (see Chap. 36) 1. Refsum disease 2. Metachromatic leukodystrophy 3. Globoid-body leukodystrophy (Krabbe disease) 4. Adrenoleukodystrophy 5. Amyloid polyneuropathy 6. Porphyric polyneuropathy 7. Anderson-Fabry disease 8. Abetalipoproteinemia (Bassen-Kornzweig) 9. Tangier disease V. Neuropathy associated with mitochondrial diseases (see Chap. 36) VI. Syndrome of recurrent or relapsing polyneuropathy A. Porphyria B. Chronic inflammatory demyelinating polyneuropathy C. Certain forms of mononeuritis multiplex D. Beriberi or intoxications E. Refsum disease F. Tangier disease G. Repeated toxic exposures VII. Syndrome of mononeuropathy or plexopathy A. Brachial plexus neuropathies B. Brachial mononeuropathies C. Causalgia D. Lumbosacral plexopathies E. Crural mononeuropathies F. Migrant sensory neuropathy G. Entrapment neuropathies

SYNDROME OF ACUTE MOTOR PARALYSIS WITH VARIABLE DISTURBANCE OF SENSORY AND AUTONOMIC FUNCTION Several differences separate the polyneuropathies in this category: (1) acute inflammatory demyelinating or axonal polyneuropathy (GBS), (2) vasculitic polyneuropathies, (3) porphyria, (4) certain toxic polyneuropathies, and (5) acute sensory and autonomic polyneuropathies. Of these acute polyneuropathic diseases, the Guillain-Barré inflammatory-demyelinative syndrome, because of its

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frequency and gravity, is most demanding of the physician’s attention.

Guillain-Barré Syndrome (GBS, Landry-GuillainBarré-Strohl Syndrome, Acute Inflammatory Demyelinating Polyneuropathy, AIDP) This is the most common cause of acute or subacute generalized paralysis in practice. In past epochs it was exceeded in frequency only by polio. The disorder occurs in all parts of the world and in all seasons, affecting children and adults of all ages and both sexes. A mild respiratory or gastrointestinal infection or immunization precedes the

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neuropathic symptoms by 1 to 3 weeks in approximately 60 percent of cases. Typical is a nondescript upper respiratory infection, but almost every known febrile infection and immunization has at one time or another been reported to precede GBS (many probably coincidentally). It has been appreciated from serologic studies that the enteric organism Campylobacter jejuni is a frequent identifiable antecedent infection, but it accounts for only a small proportion of cases. Other common antecedent events or associated illnesses include viral exanthems in children and numerous other viral illnesses in adults and children, particularly the large viruses of the herpes family (cytomegalovirus [CMV], Epstein-Barr virus [EBV], HIV), and less often, bacterial infections other than Campylobacter (Mycoplasma pneumoniae, Lyme disease). There are less certain associations with lymphoma (particularly Hodgkin disease) and with systemic autoimmune diseases.

Historical Background The earliest description of an afebrile generalized paralysis is probably that of Wardrop and Ollivier, in 1834. Important landmarks were Landry’s report (1859) of an acute, ascending, predominantly motor paralysis with respiratory failure leading to death among peasants on his land; Osler’s (1892) description of “febrile polyneuritis”; and the account by Guillain, Barré, and Strohl (1916) of a benign polyneuritis with albuminocytologic dissociation in the CSF (increase in protein without cells). The first comprehensive account of the pathology of GBS was that of Haymaker and Kernohan (1949), who stressed that edema of the nerve roots was an important change in the early stages of the disease. Subsequently, Asbury and colleagues (1969) established that the essential lesion, from the beginning of the disease, was perivascular mononuclear inflammatory infiltration of the roots and nerves. More recently, it has been found that complement deposition on the myelin surface may be the earliest immunologic event. For details of the historical and other aspects of this disease, see the monographs by Ropper and colleagues (1991) and by Hughes (1990).

Incidence The incidence of GBS varies between 0.4 and 1.7 cases per 100,000 persons per year; the median taken from several studies is 1.1 may be most dependable. It is generally a nonseasonal and nonepidemic disease, but outbreaks had been recorded in rural China following exposure of children to C. jejuni through chicken feces deposited in rice paddies. Women appear to be slightly more susceptible. The age range in our series has been 8 months to 81 years, with attack rates highest in persons 50 to 74 years of age. Cases are known in infants and in the very aged. In addition to a seasonal increase in incidence after natural influenza outbreaks, the administration of the A/New Jersey (swine) influenza vaccine, given in the United States in late 1976, brought attention to a slight increase in postvaccinal incidence of GBS. Several, but not most subsequent influenza vaccination programs have been associated with a marginal increase in cases. Representative was the widely publicized worldwide H1N1 vaccination program, in which the calculated risk of

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developing GBS after vaccination was in the range 2 cases per 1 million doses of vaccine, barely above the baseline rate and appearing mostly in individuals over 50 years (De Wals et al). A survey of COVID-19 vaccine cases has suggested a possible slightly increased incidence after the adenoviral vaccine but not the mRNA vaccine but acquisition biases make any conclusions tentative (Hanson et al). GBS appears in temporal relationship to almost any other vaccination, but the association in these instances may be idiosyncratic and certainly infrequent. Trauma and surgical operations may precede the neuropathy, but a causal association to them also remains uncertain.

Symptomatology The typical case is readily identified. Paresthesias and slight numbness in the toes and fingers are the earliest symptoms; only infrequently are they absent throughout the illness. The major clinical manifestation is weakness that evolves more or less symmetrically over a period of several days to a week or two, or somewhat longer. The proximal as well as distal muscles of the limbs are involved, usually the lower extremities before the upper (thus the older term Landry’s ascending paralysis); the trunk, intercostal, neck, and cranial muscles may be affected later. Weakness progresses in approximately 5 percent of patients to total motor paralysis with respiratory failure within a few days. In severe cases, the ocular motor nerves are paralyzed and even the pupils may be unreactive. More than half of patients complain of pain and an aching discomfort in the muscles, mainly those of the hips, thighs, and back. These symptoms precede weakness and may be mistaken for the waning features of a viral illness, lumbar disc disease, back strain, and orthopedic diseases. A few patients describe burning in the fingers and toes, and if this appears as an early symptom, it may become a persistent problem. Despite sensory symptoms, sensory loss is variable during the first days and may initially be barely detectable so that the typical case has the character of a predominantly motor neuropathy. By the end of a week, vibration and joint position sense in the toes and fingers are usually reduced; when such loss is present, deep sensibility (touch-pressure-vibration) tends to be more affected than superficial (pain-temperature). Reduced and then absent tendon reflexes are consistent findings. Only the ankle reflexes may be lost during the first week of illness. At an early stage, the arm muscles are usually stronger than the leg muscles, and in a few cases, they are spared almost entirely. Facial diplegia occurs in more than half, sometimes bilaterally at the same time or sequentially over days. Other cranial nerve palsies, if they occur, usually come later, after the arms and face are affected; they are the initial signs in a variant pattern of disease as described further on. At the onset, there is no fever, and if lymphadenopathy or splenomegaly occurs, they are related to a preceding viral infection. Disturbances of autonomic function include sinus tachycardia and, less often, bradycardia, facial flushing, fluctuating hypertension and hypotension, loss of sweating, or episodic profuse diaphoresis; one or more are common in minor form and infrequently they become pronounced or persist for more than a week. Urinary retention occurs in

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approximately 15 percent of patients soon after the onset of weakness, but catheterization is seldom required for more than a few days. Numerous medical complications follow in severe cases as a result of immobilization and respiratory failure, as discussed further on under “Treatment.” The archetypical illness described in the preceding paragraphs is typically a result of the widespread inflammatory-demyelinating process within peripheral nerves. This is contrasted with an axonal form of GBS described just below.

Acute Axonal Form of Guillain-Barré Syndrome Attention was drawn by Feasby and colleagues (1986) to an acute areflexic polyneuropathy clinically similar to typical GBS but characterized pathologically by widespread and severe axonal degeneration. In their initial report they described five patients with a rapid evolution of polyneuropathy and slow and poor recovery. Unlike the common form of demyelinating GBS, muscle atrophy became apparent relatively early in the axonal form (within weeks). The defining feature was the presence of numerous electrically inexcitable motor nerves and signs of extensive denervation. This finding could also signify a distal demyelinating block from which complete recovery is possible (Triggs et al). Nevertheless, most cases of abrupt and severe denervating paralysis, particularly if postinfectious, are caused by the axonal form of GBS (Ropper, 1986b). Postmortem examinations have disclosed severe axonal degeneration in nerves and roots with minimal inflammatory changes and little demyelination, even early in the disease. Based on the deposits of complement and the presence of macrophages in the periaxonal space, a humoral antibody directed against some component of the axolemma was postulated by Griffin and associates (1995). Visser and colleagues reported similar findings in a series of acute motor polyneuropathies. The outbreaks of motor neuropathy that occur seasonally in rural China have many of the same characteristics. These cases appear to be triggered largely by C. jejuni infections. Some, but not all, sporadic instances of acute axonal GBS have been preceded by the same infection. It is noteworthy that infection with the same bacteria can also induce a typical demyelinating form of GBS. A proportion of axonal cases, perhaps up to one-fifth, are associated with circulating antibodies to the GM1 ganglioside of peripheral nerve, and some of these reflect recently preceding infection with C. jejuni. The acronyms AMAN (acute motor) and AMSAN (acute motor-sensory axonal neuropathy) are equivalents to axonal GBS. Another variant of this illness, of which we have seen several instances, has been an acute multifocal neuropathy with electrophysiologic motor conduction block that leaves the reflexes unaltered and has high titers of anti-GM1 antibody (Capasso et al). Most experience with the generalized axonal form of GBS indicates that recovery is prolonged and incomplete.

Variants of Guillain-Barré Syndrome (Table 43-3) Portions of the typical clinical picture of GBS appear in isolated or abortive form and are a source of diagnostic confusion. Whereas in most patients the paralysis ascends

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Table 43-3 VARIANTS OF GUILLAIN-BARRÉ SYNDROME Regional   Fisher syndrome of ophthalmoplegia, ataxia, and areflexia   Cervico-brachial-pharyngeal weakness, often with ptosis   Oculopharyngeal weakness   Predominant paraparesis   Bilateral facial or abducens weakness with distal paresthesias   Ophthalmoplegia with GQ1b autoantibodies System specific   Generalized ataxia without dysarthria or nystagmus   Pure sensory   Pure motor  Pandysautonomia   Axonal (AMAN)

from legs to trunk, to arms, and then to cranial regions, and reaches a peak of severity within 10 to 14 days, the pharyngeal-cervical-brachial muscles may be affected first or constitute the entire illness, causing difficulty in swallowing with neck and proximal arm weakness (Ropper, 1986a). Ptosis, often with ophthalmoplegia, may be added. The differential diagnosis then includes myasthenia gravis, diphtheria, and botulism and a lesion affecting the central portion of the cervical spinal cord and lower brainstem. A syndrome comprising partial or complete ophthalmoplegia with ataxia and areflexia represents a variant of GBS described by Fisher (and is called Fisher syndrome). A purely ophthalmoplegic form also exists; it may be coupled with the pharyngeal-cervical-brachial pattern mentioned earlier. Ophthalmoplegia, whether occurring alone or with weakness or ataxia of other parts, is almost uniformly associated with a specific antineural antibody, anti-GQ1b. The ophthalmoplegic pattern raises the diagnostic possibilities of myasthenia gravis, botulism, diphtheria, tick paralysis, and basilar artery occlusion. Bilateral but asymmetrical facial and abducens weakness coupled with distal paresthesias or with proximal leg weakness is one of several other variants in our experience (Ropper, 1994). The tendon reflexes may be absent only at the ankles or at the knees. Lyme disease and sarcoidosis are then considerations in diagnosis. Whether bifacial palsy alone represents a variant of GBS is uncertain, but almost every case in our experience has had an alternative explanation. Paraparetic, ataxic, and purely motor or purely sensory forms of the illness have also been observed. Less difficulty attends the correct diagnosis of GBS if paresthesias in the acral extremities, progressive reduction or loss of reflexes, and relative symmetry of weakness appear after several days. The laboratory tests, particularly nerve conduction studies that affirm the diagnosis of typical GBS, give similar but generally milder abnormalities if they are carefully sought in all these variant forms. In a few patients, the weakness continues to evolve for 3 to 4 weeks or longer. From this group, a chronic form of demyelinative neuropathy (CIDP) may emerge and an intermediate group that progresses for 4 to 8 weeks and then improves can be identified (see further on).

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Laboratory Findings The most important laboratory aids are the electrodiagnostic studies and CSF examination. The CSF is under normal pressure and is acellular or contains only a few lymphocytes in all but 10 percent of patients; in the latter group, 10 to 50 cells (rarely more) per cubic millimeter, predominantly lymphocytes, may be found. The number of cells then decreases in a matter of 2 to 3 days; persistent pleocytosis suggests an alternative or additional process producing aseptic meningitis such as neoplastic infiltration, HIV, sarcoidosis, or Lyme infection. We have been unable to relate pleocytosis in the spinal fluid with any of the clinical features of GBS or to the severity of illness. The protein content is usually normal during the first few days of illness, but then it rises, reaching a peak in 4 to 6 weeks and persisting at a variably elevated level for many weeks. The increase in CSF protein is probably a reflection of widespread inflammatory disease of the nerve roots, but high values have had no clinical or prognostic significance in our material, apart from a few exceptional cases of pseudotumor cerebri (Ropper and Marmarou). The dissociation between high protein and low numbers of cells has been given the descriptor albumincytologic dissociation, but this is by no means the only cause of this formula In a few patients (fewer than 10 percent), the CSF protein values remain normal throughout the illness. From our experience, there is a higher proportion of patients with normal or only slightly elevated protein values among those with Fisher syndrome and other restricted or axonal forms of GBS. Abnormalities of nerve conduction are early and dependable diagnostic indicators of GBS. In cases with a typical clinical and EMG/NCS presentation, one could probably dispense with the CSF analysis as a confirmatory test. The most frequent early electrodiagnostic findings are a reduction in the amplitude of muscle action potentials, slowed conduction velocity, and conduction block in motor nerves, singly or in combination (see Chap. 2). Prolonged distal latencies and reduced distal amplitudes (reflecting distal conduction block) and prolonged or absent F responses (indicating involvement of proximal parts of motor nerves and roots) are other important diagnostic findings, all reflecting focal areas of demyelination. The H reflex is almost always much delayed, or more often absent, but this does little more than confirm the loss of ankle reflexes. Although a limited electrodiagnostic examination may be normal early in the illness, a thorough study, which includes measurement of late responses, invariably shows disordered conduction in an affected limb within days of the first symptom. Features that indicate widespread axonal damage portend a poor and protracted recovery in both young and old patients as discussed above. The clinical, CSF, and electrodiagnostic criteria for GBS were assessed by Asbury and Cornblath and are discussed in detail in the monograph by Ropper and colleagues. Many patients with acute GBS have shown gadolinium enhancement of the cauda equina roots on magnetic resonance imaging (21 of 24 patients in our study) and this may serve as a useful test in complicated cases (Gorson et al, 1996). Beyond the close association between autoantibodies to GQ1b and Fisher syndrome or other variants that

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include ophthalmoplegia as mentioned previously other anti-ganglioside antibodies have become of interest in GBS. The acute motor axonal variety has a tendency to be associated with antibodies to GM1 or GD1a and the pharyngeal-cervical-brachial syndrome, to GT1a. Much of this work comes from the laboratory of Yuki, and his review article with Hartung is recommended for further explanations of potential autoimmune mechanisms. Abnormalities of liver function occur in fewer than 10 percent of patients, probably reflecting a recent or ongoing viral hepatitis, usually as a result of CMV or EBV infections (rarely one of the hepatitis viruses). T-wave and other electrocardiographic changes of minor degree are reported frequently but tend to be evanescent. The sedimentation rate is normal unless there is an additional process of infectious, neoplastic, or autoimmune nature, any of which can occasionally coexist with GBS. Hyponatremia occurs in a proportion of cases after the first week, but particularly in ventilated patients. This is usually attributable to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), but a natriuretic type also occurs, from an excess of atrial natriuretic factor (Wijdicks et al). Transient diabetes insipidus is a rare and unexplained complication. With regard to proteinuria ostensibly due to glomerulonephritis reported by several groups in cases of GBS, we have found it very infrequently.

Pathologic Findings These have had a relatively consistent pattern and form. Even when the disease is fatal within a few days, most cases show endoneural perivascular (mainly perivenous) lymphocytic infiltrates. Later, there is segmental demyelination and a variable degree of wallerian degeneration. The cellular infiltrates are scattered throughout the cranial nerves, ventral and dorsal spinal roots, dorsal root ganglia, and along the entire length of the peripheral nerves. Swelling of nerve roots at the site of their dural exit has been emphasized by some authors and theorized to cause root damage. Variations of this pattern have been observed, each perhaps representing a different immunopathology. For example, there may be widespread demyelinative changes and only a paucity of perivascular lymphocytes (Ropper and Adelman). In patients whose electrophysiologic tests display severe axonal damage early in the illness as discussed earlier, the pathologic findings corroborate the predominantly axonal nature of the disease with secondary myelin damage and usually little inflammatory response. An occasional case has shown an inflammatory process with primary axonal damage rather than demyelination (Honovar et al).

Pathogenesis and Etiology Most evidence supports a cell-mediated immunologic reaction directed at peripheral nerves but the humoral immune system is clearly implicated as well. Waksman and Adams demonstrated that experimentally induced peripheral nerve disease (experimental allergic neuritis [EAN]), clinically and pathologically indistinguishable from GBS, develops in animals 2 weeks after immunization with peripheral nerve homogenates. Brostoff and colleagues suggested that the antigen in this reaction is

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a basic protein, designated P2, found only in peripheral nerve myelin. Subsequent investigations by these authors indicated that the neuritogenic factor might be a specific peptide in the P2 protein. However, it has become evident that there is no dominant antigen–antibody reaction in GBS and it is likely that any number of myelin and axonal elements may be involved in inciting the immune reaction. Figure 43-3 diagrammatically illustrates the pathologic steps in this proposed reaction. As noted further on,

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complement also seems to be a necessary factor in the initial attack on myelin. Although the transmission of EAN by T cells sensitized to myelin is strong evidence of their role in GBS, antimyelin antibodies are probably involved in the initial part of the disease. The serum from patients with GBS damages myelin in tissue cultures and induces a characteristic (“vesicular”) form of myelin destruction. Subepineural injection of serum from GBS patients into the sciatic nerve

A

B

C

D

Figure 43-3.  Diagram of probable cellular events in acute inflammatory polyneuropathy (Guillain-Barré syndrome). A. Lymphocytes attach to the walls of endoneurial vessels and migrate through the vessel wall, enlarging and transforming as they do so. At this stage no nerve damage has occurred. B. More lymphocytes have migrated into the surrounding tissue. The first effect on the nerve is breakdown of myelin, the axon being spared (segmental demyelination). This change appears to be mediated by the mononuclear exudate, but the mechanism is uncertain. C. The lesion is more intense, polymorphonuclear leukocytes being present as well as lymphocytes. There is interruption of the axon in addition to myelin sheath damage; as a result, the muscle undergoes denervation atrophy and the nerve cell body shows central chromatolysis. If the axonal damage is distal, the nerve cell body will survive, and regeneration and clinical recovery are likely. If, as in D, axonal interruption has occurred proximally because of a particularly intense root or proximal nerve lesion, the nerve cell body may die and undergo dissolution. In this situation, there is no regeneration, only the possibility of collateral reinnervation of muscle from surviving motor fibers. (Reproduced with permission from Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine (Baltimore). 1969;48(3):173-215.)

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of rats leads to local demyelination and electrical conduction block. The studies by Koski and associates of complement-dependent myelin damage by immunoglobulin (Ig) M antimyelin antibodies in GBS provided evidence that antimyelin antibodies are able to initiate myelin destruction even through T cells and that macrophages are the ultimate effectors of the damage. Indeed, the very earliest change is the deposition of complement on the inner layer of myelin (Hafer-Macko and colleagues). As mentioned earlier, circulating autoantibodies directed at components of nerve ganglioside are detected but only inconsistently in patients with GBS, the most predictable one being anti-GQ1b, which is found in almost all patients with ophthalmoplegia. Approximately one-fifth of patients have anti-GM1 antibodies early in their course, corresponding in most instances to a predominantly motor presentation and to axonal damage, the highest titers being associated with cases that follow Campylobacter infections. Antibodies directed against GD1a or GT1b are associated in some cases with the pharyngeal-brachial-cervical variant. Thus it would seem that casting GBS exclusively as a humoral or as a cellular immune process is an oversimplification. These antibody reactions have been summarized in a review by Yuki and Hartung. An unanswered question is what incites the immune reaction isolated to peripheral nerves in humans. All attempts to identify a virus or microbial agent within nerves have failed and it is likely that a variety of agents—viral, bacterial (particularly C. jejuni), certain vaccines, and perhaps neural injury itself—are each capable, in susceptible individuals, of precipitating an immune response against components of autologous peripheral nerve. In outbreaks of Zika virus infection, there is a rise in cases of GBS as in the French Polynesian series reported by Cao-Lormeau and coworkers. The occurrence of GBS in patients with AIDS or with EBV or CMV infections simply indicates that these agents induce an autoimmune response without implicating a direct viral infection of nerve. However, the high frequency of the association with viruses such as these, and particularly Zika, suggests special antigen characteristics of organisms that cross-react with neural antigens. The observation that only one of many individuals who are infected with a particular pathogen go on to develop GBS suggests that host factors are significant (there is, however, little consistency of human leukocyte antigen [HLA] types in GBS patients). Whether the aforementioned antibodies against various gangliosides of peripheral nerve are pathogenically active is also uncertain. Several animal diseases—namely coonhound paralysis of dogs, Marek disease of chickens (a viral neuritis), and cauda equina neuritis of horses—resemble GBS superficially but do not share its main clinical or pathologic features.

Differential Diagnosis GBS is not only the most frequent acute generalized polyneuropathy seen in general hospitals but also the most rapidly evolving and potentially fatal form. Any polyneuropathy that brings the patient to the brink of death or to respiratory failure within a few days will usually be of this variety. Most cases, however, are more limited with

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paresthesias, limb weakness, and areflexia and slight or moderate reduction in vital capacity. Several other conditions must be considered. The immediate problem is to differentiate GBS from acute spinal cord disease marked by sensorimotor paralysis with a defined spinal level and prominent sphincter disturbances and from several neuromuscular diseases that can simulate GBS. There may be diagnostic difficulty in the case of an acute lesion of the cord in which tendon reflexes are initially lost (spinal shock), or with necrotizing myelopathy, where a permanent loss of tendon reflexes follows extensive destruction of spinal gray matter. Early and transient urinary retention occurs in a proportion of patients with GBS and causes additional diagnostic confusion with spinal disease. Several features are useful in distinguishing GBS from a cervical myelopathy: in GBS, the facial and respiratory muscles are usually involved if there is generalized paralysis; the fingertips should be paresthetic once sensory symptoms have ascended to the level of the midcalves; marked sensory loss proximal to the hands or feet or only of the trunk is unusual early in the illness; and tendon reflexes are almost invariably lost in limbs that are too weak to resist gravity. Of course, careful testing of sensation on the trunk and limbs will expose the cause of paralysis as spinal in origin. Tick paralysis, a disease of children in the United States but affecting both children and adults in Australia and elsewhere, may be nearly impossible to distinguish from GBS unless one finds the tick (see Chap. 41). In addition to an ascending generalized paralysis, both may cause ataxia and may paralyze eye movements, but sensory loss is not usually a feature of tick paralysis and the CSF protein is normal. Episodes of painful paralytic porphyria also bear a superficial resemblance to GBS. Predominant motor features in comparison to sensory ones is the major characteristic of GBS, for which reason the differential diagnosis also includes poliomyelitis, caused by the West Nile virus and by enteroviruses other than the polio agent. In these infectious cases, the illness is marked by fever, meningoencephalitic symptoms, early pleocytosis in the spinal fluid, and purely motor and usually asymmetrical areflexic paralysis, all unusual in GBS. Several times we were misled by cases of carcinomatous meningitis with painless polyradiculopathy that caused a subacute, and fairly symmetric but mainly distal weakness, similar to GBS. An irregular distribution of weakness between proximal and distal parts and between sides, the absence of facial weakness, and the appearance of symptoms sequentially in one limb after another suggest the presence of this type of neoplastic polyradiculopathy. Sciatica may occur as an early feature with either process but radicular pain in the arms is unusual in GBS. Examination of the spinal fluid usually settles the matter. A problem arises in distinguishing generalized GBS with ophthalmoparesis or the Fisher variant from basilar artery stroke. The presence of reactive pupils, areflexia, and F-wave abnormalities in GBS, and of lively reflexes and Babinski signs in the case of brainstem infarction, dependably separate the disorders. Ptosis and oculomotor weakness in GBS causes confusion with myasthenia gravis, but there are no sensory symptoms and the tendon reflexes are

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unimpaired in myasthenia gravis. The mandibular muscles remain relatively strong in GBS (Ropper 1984), whereas the exercised jaw hangs open in myasthenia. Botulism also simulates this cranial variant of GBS, but pupillary reflexes are lost early in botulism (pupillary paralysis occurs mainly in advanced cases of GBS) and there is usually a bradycardia, which is unusual for GBS. Ingestion of shellfish or reef fish contaminated with saxitoxin, ciguatoxin, or tetrodotoxin (ciguatera, neurotoxic shellfish poisoning) is another cause of facial-brachial paresthesias, weakness, tachypnea, and iridoplegia lasting up to a few days—symptoms that resemble the cranial nerve variants of GBS. A number of neuromuscular disorders in critically ill patients with systemic medical conditions are difficult to distinguish from GBS. These include the polyneuropathy of critical illness (see further on in the chapter); an accelerated neuropathy of renal failure that is seen mainly in diabetic patients receiving peritoneal dialysis (both discussed further on); acute hypophosphatemia induced by hyperalimentation; polymyopathy produced by the administration of high-dose corticosteroids; and the prolonged effects of neuromuscular blocking drugs, resulting in the accumulation of their metabolites in patients under conditions of renal failure and acidosis.

Treatment General medical care In severe cases, respiratory assistance and assiduous nursing are paramount, because the disease remits naturally over time and the outlook for recovery is favorable in most patients. About one-quarter of our patients have required mechanical ventilation but the proportion seems to be lower in recent epochs. Because a patient’s condition may deteriorate unpredictably and rapidly in the first days of illness, it may be advisable to admit virtually all but the mildest cases to the hospital for observation of respiratory, autonomic, and motor function. The comments that follow are applicable to most other forms of acute and subacute neuromuscular respiratory failure, including myasthenia gravis and high spinal cord injury. Measurement of maximal inspiratory force and expiratory vital capacity usually suffices for the bedside estimation of diaphragmatic strength and respiratory function. The trend of these measurements is a guide to the likelihood of respiratory failure. As had been observed in poliomyelitis, the strength of the neck muscles and trapezii, which share the same segmental innervation as the diaphragm, tends to parallel diaphragmatic power. A rough estimate of breathing capacity may be obtained by having the patient count quickly on one deep breath. The ability to reach 20 generally corresponds to a vital capacity of greater than 1.5 L. If a downward trend in these measurements is recognized and the vital capacity diminishes to below about 10 mL/kg, endotracheal intubation and mechanical ventilation are usually necessary (see further on). However, a fairly severe impairment of ventilation may occur before the first sign of dyspnea appears and before there is an elevation of arterial carbon dioxide content. Incipient respiratory failure may be evident by tachypnea and a decrease in arterial oxygen tension (Po2 less than 85 mm Hg) reflecting pulmonary atelectasis. When respiratory failure arises gradually as the patient weakens over days, there is slight

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tachycardia, diaphoresis, restlessness, and tachypnea. Attempts to forestall intubation and positive-pressure ventilation by using negative-pressure cuirass-type devices have been unsatisfactory in our experience. Patients with oropharyngeal weakness require intubation even earlier to prevent aspiration, but full mechanical ventilation is not always necessary at the same time. Patients in these circumstances should obviously be admitted to an intensive care unit staffed by personnel skilled in maintaining ventilation and airway patency. The other major aspects of the treatment in severely affected patients involve the management of autonomic instability and the prevention of the many general medical problems that attend any immobilizing critical illness. Hypotension from dysautonomia, which occurs in approximately 10 percent of paralyzed patients and a smaller proportion with lesser degrees of weakness, is treated by intravenous infusions of saline and by the use of vasopressor agents for brief periods. Extremes of hypertension are managed by short-acting and titratable antihypertensive medications, such as intravenous labetalol. The choice and dosing of an antihypertensive drug is important, as episodes of hypertension may be rapidly succeeded by precipitous declines in pressure. Severe autonomic problems are difficult to anticipate, but provocative maneuvers such as ocular pressure to elicit heart block are used in some units to identify patients at risk. In patients who are bedbound, prevention of electrolyte imbalances, gastrointestinal hemorrhage, and particularly pulmonary embolism (by the use of subcutaneous heparin or pneumatic compression boots) requires attention. Adynamic ileus is a problem in some cases, manifest by abdominal pain coincident with nasogastric increased tube feeding and by bloating; it may lead to bowel perforation even if feeding is discontinued. As mentioned, a number of patients become hyponatremic, usually from SIADH but occasionally from a natriuresis, and the drop in sodium is exaggerated by positive-pressure mechanical ventilation. The distinction between the two conditions that cause hyponatremia determines the course of treatment: fluid restriction in the case of SIADH or salt replacement in the case of sodium loss. Many patients have bizarre waking dreams or hallucinations after weeks of immobilization (oneiric hallucinations). A dependable mode of communication should be established by the nursing staff, preferably before the patient is intubated. A Plexiglas or opaque board with letters and phrases is useful for this purpose. Failure to effectively clear the tracheobronchial airways and the need for prolonged mechanical ventilation are the usual indications for tracheostomy. In most cases, this procedure can be postponed until the third week of intubation. However, patients who become rapidly quadriplegic and ventilator-dependent benefit from tracheostomy earlier. Once tracheostomy is performed, careful tracheal toilet and treatment of pulmonary and urinary tract infections by the use of appropriate antibiotics are required; prophylactic antibiotic treatment is not recommended. With tracheostomy and intensive care, the mortality from the disease can be reduced to approximately 3 percent (Ropper and Kehne; see further on under “Prognosis”).

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The decisions to wean and then discontinue respiratory aid and to remove the endotracheal or tracheostomy tube are based on the degree and timing of recovery of respiratory function. The weaning process generally begins when the vital capacity reaches approximately 10 mL/kg and comfortable breathing can be sustained for a few minutes. The relative merits of the numerous methods of delivering positive-pressure volume-cycled ventilation and its gradual withdrawal are not covered here, but there is little to favor one over the other and the reader is referred to the monograph Neurological and Neurosurgical Intensive Care by Ropper and colleagues. Physical therapy (passive movement and positioning of limbs to prevent pressure palsies and, later, mild resistance exercises) can begin once they can be comfortably undertaken. Plasma exchange and immune globulin  Specific treatment of the presumed immune disorder that underlies GBS includes IVIg or plasma exchange. Our practice has been to observe patients who are still able to walk unaided rather than institute treatment immediately but some clinicians institute treatment when symptoms and signs are milder. If the patient becomes unable to walk, shows a reduction in vital capacity, or has signs of oropharyngeal weakness, treatment is instituted promptly. This typically occurs at the fifth to tenth day after the appearance of the first symptoms, but may be as early as 1 day or as late as 3 weeks. The typical regimen of IVIg is approximately 0.4 g/kg per day for 5 consecutive days. It is easier to administer and possibly safer than plasma exchange because there is no need for large intravenous access. The results of the first trial of IVIG (van der Meché and colleagues) were corroborated in an international trial (see Plasma Exchange/ Sandoglobulin Guillain-Barré Syndrome Trial Group). The latter trial compared plasma exchange to IVIg and also evaluated their use sequentially. There was a tenuous trend toward a better outcome in patients who received plasma exchange and results were perhaps slightly better in a group who were treated with plasma exchange followed immediately by 5 days of immune globulin infusions; in both instances, however, the differences failed to attain statistical significance and the three modes of treatment were said to be equivalent. Renal failure, proteinuria, and aseptic meningitis, manifested most often by severe headache, are infrequent complications of IVIg. However, venous thrombosis at various sites has emerged as a risk of IVIG infusion, particularly at higher rates or with compressed timeframes. The only serious reactions we have encountered have been in a few patients who congenitally lacked IgA and in whom pooled gamma globulin caused anaphylaxis, and a few cases of inflammatory local venous thrombosis in the region of the infusion site. The pharmacokinetics of IVIg are variable among individuals and some groups have found an association between a high rate of clearance of the agent and poorer clinical outcome (Kuitwaard and colleagues). Randomized trials together comprising more than 500 patients have established the efficacy of plasma exchange administered during the evolving phase of GBS. In patients who are treated within 2 weeks of onset, there

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is an approximate halving of the period of hospitalization, of the duration of mechanical ventilation, and of the time required to achieve independent ambulation. However, in the largest trial, if the first plasma exchange was delayed for 2 weeks or longer after the onset of the disease, the procedure was of little value. Nonetheless, if a patient continues to progress in the third or fourth week of illness, it is probably still appropriate to institute the exchanges. The most important predictors of responsiveness to plasma exchange treatment are the same as for the overall prognosis, namely the patient’s age (responders are younger) and the preservation of motor compound muscle action potential amplitudes prior to instituting treatment (McKhann et al). One study has found that the condition of patients was better at 6 and 12 months after treatment as compared to untreated patients; other studies have been equivocal on this point and demonstrated mainly accelerated improvement. The usual regimen of plasma exchange removes a total of 200 to 250 mL/kg of plasma in four to six treatments on alternate days, or over a shorter period if there is no coagulopathy. The replacement fluid is saline combined with 5 percent albumin. The need for large-bore venous access usually requires the insertion of a doublelumen subclavian or internal jugular catheters and this may be the main source of complications (pneumothorax, infection, hemorrhage). In some patients, treatment can be instituted, and sometimes the entire course completed, through the antecubital veins. During and after the procedure, hypotension, hypoprothrombinemia with bleeding and cardiac arrhythmias may occur. Some units measure the level of fibrinogen, which is greatly reduced by exchanges, before the next exchange to gauge to the risk of potential hemorrhage. Reactions to the citrate that is used to prevent blood from clotting in the plasma exchange machine are common but can be obviated by the cautious addition of calcium to the intravenous return line. Hepatitis and HIV are not risks if plasma is replaced with albumin and saline rather than with pooled plasma. After the use of either plasma exchange or IVIg, 5 to 10 percent of patients who initially improve will have a relapse that becomes apparent several days or up to 3 weeks after completion of treatment. If there had been a response to the initial therapy, the same treatment may be repeated or the alternative treatment may be tried; either can be successful. A few such patients relapse repeatedly and have the course of chronic inflammatory demyelinating polyneuropathy (see further on). In some patients under our care, this form of the disease stabilized after several months in response to the administration of corticosteroids, with very gradual tapering of the dose over several months, or in combination with repeated courses of IVIg or plasma exchanges. The clinical improvement that follows the administration of IVIg or plasma exchange usually cannot be readily discerned in an individual patient; that is, it is apparent only by comparing large groups of treated and untreated patients. For this reason, it is not possible to judge that a patient who fails to improve or who worsens through the period of treatment has derived no benefit from therapy. The question

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nevertheless arises regarding further plasma exchanges or continued infusion of immune globulin in cases of continued worsening or lack of improvement. Further complicating the matter are the limited expectations for early improvement in cases of axonal GBS. Our advice has been to repeat either of the two immune treatments if a patient is clearly declining, particularly if there is evidence of demyelinating neuropathy on the NCS, and if the illness is not much longer than 4 weeks in duration. Performing plasma exchanges after the use of IVIg does not make sense to us (but this notion has not been tested); therefore, we either follow a series of exchanges with IVIg or, more often, repeat a course of IVIg as suggested by Farcas and colleagues. The value of glucocorticoids alone in the treatment of GBS has been discussed for decades. Many clinicians were persuaded of their benefit; however, two randomized controlled trials, one with conventional-dose prednisolone and the other with high-dose methylprednisolone, have failed to demonstrate beneficial effect (Hughes, 1991). Although corticosteroids can no longer be recommended as routine treatment for acute GBS, we have observed a few instances in which the administration of intravenous highdose corticosteroids seemingly halted the progress of an acute case.

Prognosis As already indicated, approximately 3 to 5 percent of patients do not survive the illness, even in the bestequipped hospitals. In the early stages, death is most often a result of cardiac arrest, sometimes related to dysautonomia, adult respiratory distress syndrome, pneumo- or hemothorax, or some type of accidental machine failure. Later in the illness, pulmonary embolism and infectious complications of prolonged immobilization and respiratory failure are the main causes of death. The majority of patients recover with mild motor deficits or sensory complaints in the feet or legs. In approximately 10 percent, however, the residual disability is pronounced; this occurs in those with the most severe and rapidly evolving form of the disease, when there has been evidence of widespread axonal damage and in those requiring early and prolonged mechanical ventilatory assistance. A fairly consistent predictor of residual weakness and muscle atrophy is the finding of greatly reduced amplitudes of muscle action potentials and widespread denervation, both indicative of axonal damage. The most common remaining difficulties are weakness of the lower leg muscles, numbness of the feet and toes, and mild bifacial weakness. A few patients are left with sensory ataxia that tends to be severe and quite disabling. Distal neuropathic pain and persistent autonomic problems occur but are also infrequent. All manner of other late symptoms are attributed with little evidence to the illness and should be addressed on their own merits—fatigue and asthenia, muscle cramps, dizziness, pain, and breathlessness. Depression has not been frequent. The speed of recovery varies, but its pace is steady. Often, it occurs within a few weeks or months; however, if axons have been damaged, their regeneration may require 6 to 18 months or longer. In our experience,

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little improvement can be expected in disabilities that have lasted 2 or more years. Some 5 to 10 percent of patients encounter one or more recurrences of the acute polyneuropathy. An illness that in the beginning appeared to be an acute inflammatory polyradiculoneuropathy may fail to stabilize and continue to progress steadily, or there may be an incomplete remission followed by a chronic, fluctuating, slowly progressive neuropathy. These more chronic forms of inflammatory neuropathy are described in a later section of this chapter.

Critical Illness Polyneuropathy An acute or subacute symmetrical polyneuropathy is a frequent development in critically ill and septic patients, particularly in those with failure of multiple organs (Zochodne et al). This neuropathy causes difficulty in weaning a patient from the ventilator, even as the underlying critical illness comes under control. The neuropathic process, predominantly of motor type, varies in severity from an electrophysiologic abnormality without overt clinical signs, to quadriparesis with respiratory failure. Sensory symptoms and signs are variable but tend to be mild. Usually, the cranial nerves are spared and there are few or no dysautonomic manifestations. In general, this type of polyneuropathy appears after several days or more of bacterial sepsis or other overwhelming infection (now called systemic inflammatory response syndrome [SIRS]) and multiple organ failure, and is preceded in most instances by a confusional state or a depressed state of consciousness (“septic encephalopathy”). The EMG and NCS findings of a primary axonal process with early denervation and a normal CSF distinguish this entity from the typical demyelinative form of GBS. Autopsy material has usually disclosed little or no inflammatory changes in the peripheral nerves. Differentiating critical illness polyneuropathy from critical illness myopathy (see just below) and from the axonal form of GBS is difficult and depends on the context in which the illness occurs. All of these processes that occur in the intensive care unit, when extreme, can eliminate the motor nerve action potentials and when this configuration is found, the problem is most often attributed to the neuropathy, although this is not always correct. The toxic effects of drugs and antibiotics and nutritional deficiency must be considered in causation, but rarely can they be established. The many systemic mediators of sepsis are toxic to the peripheral nervous system; tumor necrosis factor has been proposed as one such endogenous toxin in causing neuropathy. Critical illness polyneuropathy must also be distinguished from an incompletely understood acute quadriplegic myopathy (critical illness myopathy) that also complicates critical illness (see Chap. 45). High doses of glucocorticoids, particularly in combination with neuromuscular blocking agents, have been implicated. The acute myopathy, which affects both distal and proximal muscles, is sometimes heralded by an elevation in the serum creatine kinase (CK) concentration (at times up to several thousand units). Myopathic potentials in the EMG and a unique type of degeneration of myofilaments in all the muscles are found. This illness is described in more detail in Chap. 45.

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Acute Uremic Polyneuropathy In addition to the well-known chronic sensory polyneuropathy associated with chronic renal failure that is discussed later in the chapter, there is a more rapid (“accelerated”) process that has not been widely appreciated as a cause of acute and subacute weakness. Most patients in our series were diabetics with stable end-stage renal failure who had been treated by peritoneal dialysis for their long-standing kidney disease (Ropper, 1993). In contrast to the better characterized and less severe chronic uremic neuropathy, generalized weakness and distal paresthesias progress over 1 or more weeks until a bedbound state is reached. The illness simulates subacute GBS. More aggressive dialysis or a change to hemodialysis has little immediate effect, although kidney transplantation is curative. Electrophysiologic studies show demyelinating features (slowing of conduction velocity), but usually not conduction block. There is mildly or moderately raised CSF protein concentration (not unexpectedly, for there is usually an element of diabetic neuropathy). A few reported cases have responded to plasma exchange or gamma globulin. As with the more common chronic uremic neuropathy, the cause of the acute form is unknown.

Acute Sensory Neuronopathy (Acute Sensory Ganglionopathy) Attention was initially drawn to this entity by Sterman and colleagues in a report of three adult patients with rapidly evolving sensory ataxia, areflexia, numbness, and pain, beginning in the face and spreading to involve the entire body. In those instances, the symptoms began following the institution of penicillin for a febrile illness (antibiotics have subsequently been shown not to be associated with this process). Proprioception was profoundly reduced, but there was no weakness or muscle atrophy, despite generalized areflexia. The sensory deficit attained its maximum severity within a week, after which it stabilized and improved very little. Electrophysiologic studies showed absent or slowed sensory conduction, but there were no abnormalities of motor nerve conduction or signs of denervation. In two patients, the CSF protein content was elevated to 126 and 175 mg/dL. Followup observations (for up to 5 years) disclosed no neoplastic or immunologic disorder, the usual identifiable causes of such a sensory neuronopathy. Lacking pathologic material, it was assumed from the permanence of the condition that sensory neurons were destroyed (sensory neuronopathy). A subsequent series of 42 patients emphasized an asymmetrical and brachial pattern of symptoms in some patients and initial involvement of the face in others (Windebank and colleagues). In contrast to Sterman’s cases, the CSF was usually normal and most patients had some improvement or a spontaneous resolution of symptoms. In this and subsequent reports, as mentioned, antibiotics were not implicated. This clinical pattern should be viewed as a syndrome rather than as a disease. There are two main presentations: limb ataxia that does not have accompanying dysarthria or nystagmus, thus distinguishing it from a cerebellar

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disorder; and generalized facial and truncal numbness that involves proximal and distal sensory areas and may include the top of the head, trunk, buttocks, scrotum, and oral mucosal membranes. The latter syndrome must be delineated from an evolving polyneuropathy, the early proximal symptoms being the most salient identifying feature for a ganglionopathy as mentioned in the introductory sections of this chapter. All the just described processes are accompanied by areflexia, but this may not be fully developed in the case of ganglionopathy for several days or longer. The same pattern of sensory loss evolving in a subacute or chronic manner is well known to occur as a paraneoplastic illness, described further on in this chapter, but it can evolve over days, or in association with the Sjögren syndrome, scleroderma, lupus erythematosus, paraproteinemia, HIV and human T-cell lymphotropic virus type I (HTLV-I) infection. Certain drugs and other agents, especially cisplatin and excessive intake of pyridoxine, are also causes of a sensory neuronopathy. These are discussed again later, under “Drug-Induced Neuropathies and Neuronopathies.” A rare form of ataxic GBS involves solely the large sensory fibers and produces ataxia, thereby simulating an acute sensory neuronopathy. In GBS, however, there is usually some degree of proximal weakness and the sensory changes do not extend to the face and trunk.

Diphtheritic Polyneuropathy The neurotoxic effects of Corynebacterium diphtheriae and the mode of action of the exotoxin elaborated by the bacillus are described in Chap. 41. Local action of the exotoxin may paralyze pharyngeal and laryngeal muscles (dysphagia, nasal voice) within 1 or 2 weeks after the onset of the infection and shortly thereafter may cause blurring of vision because of paralysis of accommodation, but these and other cranial nerve symptoms may be overlooked. At this stage, the cranial neuropathy must be distinguished from that of GBS, botulism, and most of all, from myasthenia gravis. A polyneuropathy, appearing 5 to 8 weeks later, takes the form of an acute or subacute limb weakness with paresthesias and distal loss of vibratory and position sense. The weakness characteristically involves all extremities at the same time or may descend from arms to legs. The patient may be unable to stand or walk and occasionally the paralysis is so extensive as to impair respiration. The CSF protein is usually elevated (50 to 200 mg/dL). Deaths that occur after the pharyngeal infection has subsided are a result of cardiomyopathy or, less often, of severe polyneuropathy with respiratory paralysis. This type of polyneuropathy, now quite rare, should be suspected in the midst of an outbreak of diphtheritic infection, as occurred in Russia (Logina and Donaghy). The important pathologic change is one of segmental demyelination without inflammatory reaction of spinal roots, sensory ganglia, and adjacent spinal nerves. Anterior horn cells, axons, peripheral nerves distally, and muscle fibers remain normal (Fisher and Adams). Treatment  Diphtheria antitoxin, given within 48 h of the onset of the infection, reduces the incidence and

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severity of neuropathic complications. Antitoxin is probably of much less value once the polyneuropathy begins. Thereafter, treatment is purely symptomatic, along the lines indicated for GBS. The prognosis for full recovery is excellent once respiratory paralysis is circumvented.

Porphyric Polyneuropathy A severe, rapidly advancing, more or less symmetrical and mainly motor polyneuropathy—often with abdominal pain, psychosis (delirium or confusion), or convulsions— may be a manifestation of acute intermittent porphyria. This type of porphyria is inherited as an autosomal dominant trait and is not associated with cutaneous sensitivity to sunlight. The metabolic defect is in the liver and is marked by increased production and urinary excretion of porphobilinogen and of the porphyrin precursor Δ-aminolevulinic acid. The peripheral and central nervous systems may also be affected in another hepatic type of porphyria (the variegate type). In the latter, the skin is markedly sensitive to light and trauma, and porphyrins are at all times found in the stools. Both of these hepatic forms of porphyria must be distinguished from the rarer erythropoietic (congenital photosensitive) porphyria, in which the nervous system is not affected. The original study of acute intermittent porphyria was made by Waldenstrom in 1957. The initial and often the most prominent symptom is moderate to severe colicky abdominal pain. It may be generalized or localized and is unattended by rigidity of the abdominal wall or tenderness. Constipation and intestinal distention (ileus) are frequent. Attacks last for days to weeks and repeated vomiting may lead to inanition. In latent forms, the patient may be asymptomatic or complain only of slight dyspepsia. The disease can be identified after some time by its characteristic recurrent attacks, often precipitated by drugs such as sulfonamides, griseofulvin, estrogens, barbiturates, phenytoin, and the succinimide anticonvulsants. The possibility of sensitivity to these drugs must always be kept in mind when convulsions are being treated in the porphyric patient. The first attack rarely occurs before puberty, and the disease is most likely to threaten life during adolescence and early adulthood. In contrast, acute polyneuropathy that appears for the first time in mid- or late adult life is not likely to be porphyric. The neurologic manifestations are usually those of an acute polyneuropathy involving the motor nerves more severely than the sensory ones; less often, both sensory and motor nerves are affected more or less equally and sometimes autonomic nerves as well. The symptoms may begin in the feet and legs and ascend, or they may begin in the hands and arms (sometimes asymmetrically) and spread in a few days to the trunk and legs. Often, the weakness predominates in the proximal muscles of the limbs and limb girdle muscles, in which case there is loss of knee jerks with preservation of reflexes at the ankles. Sensory loss, often extending to the trunk, is present in half the cases. Facial paralysis, dysphagia, and ocular palsies are features of only the most severe cases. The CSF protein content is normal or slightly elevated.

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The course of the polyneuropathy is variable. In mild cases the symptoms regress in a few weeks. Severe cases may progress to a fatal respiratory or cardiac paralysis in a few days, or the symptoms may advance in a saltatory fashion over several weeks, resulting in a severe sensorimotor paralysis that improves only after many months. A disturbance of cerebral function (confusion, delirium, visual field defects, and convulsions) is likely to precede the severe, but not always the mild, forms of polyneuropathy, or there may be none of these central features. Cerebral manifestations subside in a few days or weeks, although one of our patients was left with a lasting homonymous hemianopia. Tachycardia and hypertension are frequent in the acute phase of the disease and fever and leukocytosis may occur in severe cases. In general, the prognosis for recovery is excellent, although relapse of the porphyria may result in cumulative damage to the peripheral nervous system (see discussion further on under “Diagnosis of Recurrent or Relapsing Polyneuropathy”). In summary, the most characteristic features of porphyric neuropathy are the relapsing nature, acute onset, abdominal pain, psychotic symptoms in some cases, predominant motor neuropathy, often with an early bibrachial distribution of weakness, truncal sensory loss, and tachycardia. Rarely, the neuropathy develops without other symptoms of porphyria. The pathologic findings in the peripheral nervous system vary according to the stage of the illness at which death occurs. In the first few days, the myelinated fibers may appear entirely normal, despite almost complete paralysis. If symptoms had been present for weeks, degeneration of both axons and myelin sheaths are found in most of the peripheral nerves. The relation between the abnormality of porphyrin biosynthesis in the liver and nervous dysfunction has never been explained satisfactorily. The diagnosis is confirmed by the demonstration of large amounts of porphobilinogen and Δ-aminolevulinic acid in the urine. The urine turns dark when standing as a consequence of the formation of porphobilin, an oxidation product of porphobilinogen. Treatment  The use of intravenous glucose and intravenous hematin (4 mg/kg daily for 3 to 14 days) is recommended as the most effective therapy. Other aspects of treatment include respiratory support, use of betablocking agents (labetalol) if tachycardia and hypertension are severe, continued intravenous glucose to suppress the heme biosynthetic pathway, and pyridoxine (100 mg bid) on the supposition that vitamin B6 depletion has occurred. Attempted prevention is of the utmost importance, since attacks can be precipitated by the aforementioned drugs as well as numerous others that are porphyrinogenic.

Acute Toxic Polyneuropathies (See Also Chap. 41) As indicated in Chap. 41, the peripheral nerves may be affected by a wide variety of toxins including metals, drugs, organophosphates, and industrial solvents. As a rule, the neuropathies induced by these agents fall into the subacute and chronic categories (to be discussed further on). However, certain drugs—notably triorthocresyl phosphate (TOCP) and other organophosphates, thallium and rarely,

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arsenic—produce a polyneuropathy that may be fatal in a matter of days. It should be stressed that organophosphate neuropathy can be identified in almost all instances by the severe cholinergic effects that are apparent immediately after exposure. Severe and permanent motor paralysis is caused by TOCP; this ultimately proves to be a result of involvement of both upper and lower motor neurons. Thallium salts, when taken in sufficient amount, produce a clinical picture resembling that of GBS or an acute sensory polyneuropathy. If the salts are taken orally, there is first abdominal pain, vomiting, and diarrhea, followed within a few days by pain and tingling in the toes and fingertips and then rapid weakening of muscles of the limbs, initially the distal ones. As the weakness progresses, the tendon reflexes diminish. Pain sensation is reduced more than tactile, vibratory, and position sense. Persistent acral pain with allodynia has been a major feature in three of the five patients we have examined; in two of our patients there was no weakness, only sensory loss and ataxia. All cranial nerves except the first and eighth may be affected; facial palsies, ophthalmoplegia, nystagmus, optic neuritis with visual impairment, and vocal cord palsies are additional abnormalities but only in the most severely affected patients. The CSF protein rises to more than 100 mg. Death may occur in the first 10 days as a result of cardiac arrest. The early onset of painful paresthesias, sensory loss, and pain localized to joints, back, and chest, as well as rapid loss of hair (after 1 or 2 weeks), all serve to differentiate this neuropathy from GBS, porphyria, and other acute polyneuropathies. Relative preservation of reflexes is noteworthy and rapidly evolving complete alopecia is a striking feature. Patients with lesser degrees of intoxication may recover completely within weeks or months. Thallium salts act like potassium and a high intake of potassium chloride hastens the excretion of thallium. Chelating agents are of unproven value but are usually included in treatment. Some cases of arsenical and possibly mercurial polyneuropathy may also develop acutely. More often these conditions evolve subacutely, for which reason they are discussed further on. As alluded to earlier and in Chap. 41, certain other toxic neuropathies, such as those related to organophosphate or diethylene chloride (Sterno) poisoning, may have an acute onset and progress over days. In regard to this category of polyneuropathy, many instances are imputed to toxins by both patients and unskeptical physicians with little substantiation. Before making such an attribution, it is useful to ask whether the clinical features are compatible with the known neurotoxicity of an environmental agent or drug; whether the severity of symptoms is consistent with degree of presumed exposure (real or imagined); whether the associated systemic signs of an intoxication are present; if other individuals similarly exposed are affected; and whether symptoms stabilize or improve once the patient is removed from the presumed source of exposure. Failure to satisfy these precepts generally signifies some other disorder.

Other Acute Polyneuropathies On occasion, a vasculitic polyneuropathy as an isolated process or associated with lupus erythematosus, polyarteritis

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nodosa, and related disorders may develop as rapidly as GBS and careful clinical and electrophysiologic testing are needed to distinguish them. Several of our patients with polyarteritis and one with eosinophilic granulomatosis with polyangiitis became completely paralyzed within a week and one died of intestinal perforation. However, most cases of neuropathy caused by vasculitis evolve more slowly, with the syndrome assuming an asymmetrical and multifocal distribution, for which reason it is described in the next section. There is no doubt that paraneoplastic neuropathies, discussed further in the subacute category, can evolve more rapidly than is typical for this process and thereby simulate GBS. We have observed a few patients with alcoholism, occult carcinoma, Hodgkin disease, and renal transplantation develop an acute polyneuropathy, as rapid in its evolution as GBS, and acute episodes of this type have also been described in patients with Refsum disease. An unusual neuropathy in burn patients has been described by Marquez and colleagues; separating it from the category of critical illness polyneuropathy is difficult.

Acute Autonomic Polyneuropathy (“Pure Pandysautonomia”) Since the first description of such a case by Young and colleagues and Adams and associates, a number of others have been recorded and summarized by Low and colleagues. The condition, probably a type of postinfectious polyneuropathy in the category of GBS, is described in detail in Chap. 25. Some success has been achieved, anecdotally, by treatment with IVIg. A subacute and more chronic form, also immune in nature, is described later under “Idiopathic Autonomic Neuropathy” and a paraneoplastic variety is known.

SYNDROME OF SUBACUTE SENSORIMOTOR PERIPHERAL NEUROPATHY Placed in this category are neuropathies that evolve over several weeks to months and, after reaching their peak of severity, tend to persist for a variable period. Admittedly, the dividing line between such cases and those that evolve over somewhat shorter or longer periods is indistinct; there are many diseases of nerve that overlap both the acute and the early chronic categories. In contrast to the acute polyneuropathies, however, most that are subacute have prominent sensory features and are of axonal type. The main exception is a subacute inflammatory– demyelinative type, essentially a slow form of GBS, evolving over 4 to 8 weeks (Hughes and coworkers). Similarly, some instances of diphtheritic neuropathy evolve subacutely. Despite these qualifications, in the end, a symmetrical polyneuropathy syndrome of subacute type most often proves to be caused by nutritional deficiency (often complicated by alcoholism), by a remote effect of cancer (paraneoplastic, as described later), by poisoning with arsenic, lead, or by the toxic effects of any number of drugs used for therapeutic purposes (cisplatin, nitrofurantoin, isoniazid, etc.). Occasionally other drugs,

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metals, and industrial solvents are incriminated; these are discussed in Chap. 41.

Nutritional Deficiency Neuropathy (See Chap. 40) In the Western world, nutritional polyneuropathy is usually associated with chronic alcoholism. As indicated in earlier discussions, all data point to the identity or at least close relationship between alcoholic neuropathy and neuropathic beriberi. A nutritional factor is responsible for both, although in any given case it remains unclear whether the deficiency is one of thiamine, nicotinic acid, pyridoxine, pantothenic acid, folic acid, or a combination of these B vitamins. Our colleague M. Victor, who devoted considerable attention to this subject, was never persuaded of the existence of a form of polyneuropathy attributable solely to the toxic effect of alcohol, although claims of such an entity continue to be made and the perception persists among most physicians that alcohol is directly damaging to nerves. Nutritional neuropathy and other neurologic complications of deficiency disorders (Strachan syndrome, pellagra, vitamin B12 deficiency, and malabsorption syndromes) are described fully in Chap. 40. A predominantly sensory neuropathy with burning pain is typical of most forms of severe nutritional deprivation.

Paraneoplastic Polyneuropathy and Sensory Ganglionopathy (See Chap. 30) Although capable of producing diverse clinical presentations, the remote effect of cancer most often takes the form of a predominantly distal, symmetrical sensory, or sensorimotor polyneuropathy. Weakness and atrophy, ataxia, and sensory loss of the limbs may advance over several weeks or months to the point where the patient is confined to a wheelchair or bed; usually the CSF protein concentration is mildly elevated. All these symptoms may occur months or even a year or longer before a malignant tumor is found, although usually the tumor is apparent and most often is a lung cancer. In most series, a mixed sensorimotor polyneuropathy has been 4 to 5 times more frequent than a purely sensory one. However, the latter is a more specific syndrome identified with lung cancer (described originally by DennyBrown); it is characterized by a loss of all modalities of sensation spreading from the distal to the proximal segments of the limbs and eventually to the trunk and face. There is loss of tendon reflexes, but motor power may be retained. It has also been appreciated that the sensory loss in the beginning may have a multifocal distribution. Another variety is characterized by initial sensory ataxia, similar to that discussed in the earlier section “Acute Sensory Neuronopathy (Sensory Ganglionopathy).” The illness reaches its peak in a few weeks or months and in a very few instances the development has been as rapid as that of GBS. The pathologic changes are those of an inflammatory and destructive sensory neuropathy and neuronopathy (ganglionitis) and are sometimes part of a more widespread disorder of the nervous system related to the antiHu antibody (also termed antinuclear neuronal antibody type 1 (ANNA-1); see Chap. 30). This polyneuropathy has

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proven to be most typical of small-cell cancer of the lung as mentioned. In a series of 71 patients with paraneoplastic sensory neuronopathy, more than half were associated with symptomatic inflammatory lesions in the temporal lobes (limbic encephalitis), the brainstem, and, rarely, the anterior horn neurons of the spinal cord (Dalmau and colleagues). Other distinctive paraneoplastic syndromes such as cerebellar degeneration and Lambert-Eaton myasthenic syndrome were combined with polyneuropathy in isolated cases and there were signs of dysautonomia in 28 percent. In other words, there are many cases of sensory neuropathy and neuronopathy that exist in parallel with various neoplasms, including some of our patients with lymphomas. The CSF protein is mildly elevated but usually acellular. Sensory potentials are usually absent in all nerves after a few weeks but may be spared early on. The localization of anti-Hu antibody to the several affected regions of the nervous system and to the tumor itself has led to speculation that the lung tumors are typically small or inevident because the antibody suppresses tumor growth. Almost all cases of paraneoplastic sensory neuropathy and a proportion of the more nondescript sensory predominant or sensorimotor paraneoplastic polyneuropathies also demonstrate anti-Hu antibodies, making this testing useful in distinguishing paraneoplastic varieties of sensory neuropathy and neuronopathy from those caused by postinfectious or immune disorders such as Sjögren syndrome and HIV infection. The finding of high antibody titers should lead to chest imaging and, in appropriate cases, bronchoscopic or positron emission tomography (PET) examinations to detect an underlying cancer. A rare vasculitic mononeuropathy multiplex that occurs with cancer is discussed further on. An unusual assortment of polyneuropathies has been associated with non-Hodgkin lymphomas of both T- and B-cell types and with several related conditions, such as Castleman disease (angiofollicular lymphoid hyperplasia), intravascular T-cell lymphoma (and the related lymphomatoid granulomatosis; see Chap. 30), hypersensitivity lymph node hyperplasia (angioimmunoblastic or immunoblastic lymphadenopathy), and Kimura disease (lymphoid hyperplasia with eosinophilia mainly involving skin). In most of these neuropathies, particularly the one associated with Castleman disease, there is a paraproteinemia, often polyclonal, thereby relating this group to the paraproteinemic neuropathies and to osteosclerotic myeloma, discussed later. In several of our patients, the neuropathic manifestations appeared simultaneously with lymph node enlargement in the groin, axilla, or thorax. Clinically, the illness may take the form of GBS, chronic demyelinating polyneuropathy, subacute motor polyneuropathy or anterior horn cell disease, lumbar and brachial plexopathy, or a polyradiculopathy—each occurring as a paralymphomatous condition clearly separable from cases of meningeal and neural infiltration by tumor. Corticosteroids have been helpful in some of our patients with the lymphoid diseases; in others, the neuropathy resolves spontaneously or with radiation of the lymph nodes but otherwise progresses for months. Experience with the more conventional types of neuropathy accompanying non-Hodgkin lymphoma have been summarized in several reports (Vallat and colleagues). Intravascular

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lymphoma, a widespread neoplastic and vascular disease (described in Chap. 30), may infiltrate the peripheral nerves in a multiple mononeuropathy pattern. The various forms of paraneoplastic polyneuropathy are manifest clinically in 2 to 5 percent of patients with malignant disease. The figures are higher if one includes the neuropathies accounted for by malnutrition and pressure palsies that occur in the later stages of cancer and those identified by EMG in asymptomatic patients (Henson and Urich). Carcinoma of the lung accounts for approximately half of the cases of paraneoplastic sensorimotor polyneuropathy and for 75 percent of those with pure sensory neuropathy (Croft and Wilkinson); nevertheless, these neuropathies may be associated with neoplasms of all types. Although anti-Hu binds to the peripheral nerve, the immunopathology of the paraneoplastic polyneuropathies has not been completely defined. In the purely sensory type, there is not only a loss of nerve cells in the dorsal root ganglia but also an inflammatory reaction (Horwich et al)—much the same changes as occur with the sensory neuronopathy of Sjögren syndrome. In the mixed sensorimotor polyneuropathy, degeneration is greater in the distal than it is in the proximal segments of the peripheral nerves, but it extends into the roots in advanced cases. Dorsal root ganglion cells may be reduced in number in both types. If the histologic examination is performed early in the course of the neuropathy, sparse infiltrates of lymphocytes are observed distributed in foci around blood vessels. No tumor cells are seen in the nerves or spinal ganglia, unlike the rare instances of carcinomatous and lymphomatous mononeuropathy multiplex, in which tumor cells actually infiltrate nerves. Degeneration of the dorsal columns and chromatolysis of anterior horn cells are secondary to changes in the peripheral nerves and roots. The prognosis of the paraneoplastic neuropathies is poor. Even though the polyneuropathy may stabilize or even remit to some extent on its own or with therapy, most patients succumb to the underlying tumor within a year. Treatment  If the tumor can be treated effectively, or ideally removed, the neuropathy may improve, the exception being pure sensory neuronopathy, which rarely does so. Treatment with plasma exchange, gamma globulin, or immunosuppression has had only a minimal effect, but there are anecdotal reports of success with each of these treatments applied early in the course. In one report, only 1 of 18 patients with a subacute sensory neuropathy improved and another became dependent for sustained improvement on immune globulin (Uchuya and colleagues); most of the others stabilized or worsened and the authors concluded that treatment was of doubtful value. Glucocorticoids have not been tested in a systematic way for paraneoplastic neuropathy and there is limited clinical evidence to support their use.

Subacute Toxic Neuropathies Arsenical Polyneuropathy Of the neuropathies caused by metallic poisoning, that caused by arsenic has been particularly well characterized. In cases of chronic poisoning, the neuropathic symptoms

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develop rather slowly, over a period of several weeks or months and have the same sensory and motor distribution as the nutritional polyneuropathies. Gastrointestinal symptoms, the result of ingestion of arsenic compounds, may precede the polyneuropathy, which is nearly always associated with anemia, jaundice, brownish cutaneous pigmentation, hyperkeratosis of palms and soles, and later with white transverse banding of the nails (Mees lines). The disease is accompanied by an excess of arsenic in the urine and hair. Pathologically, this form of arsenical neuropathy is categorized as of the dying-back (axonal degeneration) type. In patients who survive the ingestion of a single massive dose of arsenic, a more rapidly evolving polyneuropathy may appear after a period of 8 to 21 days as discussed earlier. Diagnosis and treatment of arsenical poisoning are discussed further in Chap. 41. Here it is emphasized that the ingestion of fish in many areas of the industrialized world gives high levels of blood and urine arsenic, but the metal is in the form of arsenobetaine, which has low toxicity and does not cause neuropathy.

Lead Neuropathy (Plumbism) This is an uncommon disorder. In adults, it occurs following chronic exposure to lead paint or fumes (from smelting industries or burning batteries) or from ingestion of liquor distilled in lead pipes. Its most characteristic presentation is a motor mononeuropathy in the distribution of the radial nerves (wrist and finger drop). In a few personally observed patients this was the main abnormality, but there was also a sensory loss in the radial territory of the hand. Less commonly, there is foot-drop occurring alone or in combination with weakness of the proximal arm and shoulder girdle muscles. As pointed out in Chap. 41, lead neuropathy seldom occurs in children, in whom poisoning usually results in an encephalopathy. Although the neuropathy has been known since ancient times, details of the pathobiology are still obscure. Axonal degeneration with secondary myelin change and swelling and chromatolysis of anterior horn cells has been described. Lead accumulates in the nerve and may be toxic to Schwann cells or to endothelial capillary cells, causing edema. The diagnosis is established by the history of lead exposure, the predominant and restricted motor involvement, associated medical findings (anemia, basophilic stippling of red blood cell precursors in the bone marrow, a “lead line” along the gingival margins, colicky abdominal pain, and constipation), and the urinary excretion of lead and coproporphyrins. Blood lead levels of more than 70 mg/dL are always abnormal. In patients with lower levels, doubling of the 24-h urinary lead excretion following an infusion of the chelating agent CaNa2 ethylenediaminetetraacetic acid (EDTA) indicates a significant degree of lead intoxication. Coproporphyrin in the urine is abnormal in any amount, but it may also be found in porphyria, alcoholism, iron deficiency, and other disorders as well as in lead intoxication. Treatment consists of terminating the exposure to lead and eliminating lead from the bloodstream and the bones by chelation as discussed in Chap. 41. For this purpose,

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penicillamine, which is generally safe and can be administered orally, is preferable to dimercaprol (British antiLewisite [BAL]) or EDTA.

Other Metals and Industrial Agents Chronic poisoning with thallium and sometimes with lithium, gold, mercury, and platinum (in the antineoplastic agents cisplatin and carboplatin as discussed further on) produces a sensorimotor polyneuropathy; these intoxications are discussed in Chap. 41 and the acute form was addressed earlier in the chapter. A predominantly motor neuropathy is induced by occupational exposure to metallic mercury and mercury vapor but any connection to the mercury content in dental amalgam has little credibility. Exposure to manganese, bismuth, antimony, zinc, and copper may give rise to systemic signs of poisoning; some of them affect the central nervous system (CNS) but one cannot be certain that any of them specifically involves peripheral nerves. The devastating encephalopathy of organic mercury toxicity does not, to our knowledge, cause neuropathy. As mentioned in Chap. 41, a predominantly motor polyneuropathy has been reported as a rare complication of gold therapy for rheumatoid arthritis. Most often the cumulative dose of gold had exceeded 1 g but in a few instances the neuropathy occurred with 0.5 g. Painful distal burning is the initial complaint with weakness and wasting following. The onset of weakness, although usually insidious, can be abrupt enough to simulate GBS. There have been trigeminal, facial, and oculomotor palsies. One of the unusual features, not shared with most other toxic neuropathies, is a marked rise in CSF protein concentration. A distal, symmetrical sensorimotor (predominantly sensory) neuronopathy may follow exposure to certain hexacarbon industrial solvents. These include n-hexane (found in contact cements, thus affecting individuals who inhale the vapors); methyl n-butyl ketone (used in the production of plastic-coated and color-printed fabrics); dimethylaminopropionitrile (DMAPN), used in the manufacture of polyurethane foam); the fumigant methyl bromide; and the gas sterilant ethylene oxide. Operating room personnel may be affected by the latter when the agent is absorbed through the skin, leaving a characteristic rash at exposed sites (usually the wrists, where a surgical gown ends). A mild peripheral neuropathy and CNS changes of memory loss and headaches have been reported from this agent by Brashear and colleagues. Nurses are also subject to a risk of nitrous oxide neurotoxicity and this usually takes the form of a myelopathy predicated on cobalamin deficiency. Most cases are caused by repeated use of the gas to induce euphoria. As with vitamin B12 deficiency, the syndrome may be mistaken for a neuropathy but nerve conduction studies fail to demonstrate one. The associated macrocytic anemia is reversed by the administration of B12, but the neurologic illness may be less responsive as discussed in Chap. 40. Whether folate deficiency, sometimes in the context of alcohol excess, and mostly in countries without folate fortification programs, causes polyneuropathy has been a matter of debate. A series by Koike and

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colleagues describes a mundane, sensory-predominant neuropathy. Triorthocresyl phosphate and acrylamide are potent peripheral nerve toxins. Both of these drugs cause a dyingback polyneuropathy with axonal degeneration and have been used experimentally to produce this effect. Vacor, a phenylnitrosourea rodenticide, taken as a suicidal agent, gives rise to a profound sensory and autonomic neuropathy with abdominal pain and hyperglycemia caused by acute pancreatitis. Detailed accounts of the clinical and experimental neurotoxicology of these agents can be found in the monograph by Spencer and colleagues.

Drug-Induced Neuropathies and Neuronopathies A large number of medications are potential sources of polyneuropathy of predominantly sensory type. Most are dose-dependent and are therefore more or less predictable after large cumulative doses of the drug have been given (e.g., in cancer chemotherapy) or after prolonged administration for other reasons. A more complete list than can be compiled here can be found in the review by England and Asbury. Antineoplastic drugs (See also Chap. 41)  Among chemotherapeutic agents in current use, particularly cisplatin, carboplatin, and bortezomib, are known to evoke a dose-dependent, predominantly sensory polyneuropathy, which begins several weeks after completion of therapy in at least half of the patients. Proprioception and vibratory sensation are most severely impaired. Some patients develop acrodynia and episodic color changes in the fingertips and toes suggesting that autonomic nerves are also involved; in severe cases there is sensory ataxia and pseudoathetosis. The severity of histopathologic changes in the peripheral nervous system corresponds to the concentration of platinum in these tissues, the highest being found in dorsal root ganglia. Secondary degeneration in the posterior columns is the basis for a Lhermitte symptom reported by some patients. The taxanes paclitaxel and the more potent docetaxel, both cited as inhibitors of the depolymerization of neurotubules, are used mainly in the treatment of ovarian cancer. They produce a sensory polyneuropathy similar to that of cisplatin. The nerve lesion regresses slowly with a reduction in dosage. Pathologic studies have shown a neuronopathy and distal axonopathy affecting mainly large fibers. For decades it has been known that peripheral neuropathy commonly complicates the use of vincristine, an antineoplastic agent most widely used in treatment of the lymphomas and leukemia. Paresthesias are the most common early symptom, and loss of ankle jerks is an early sign. Some degree of weakness usually precedes objective sensory loss; the extensor muscles of the fingers and wrists are affected; later the dorsiflexors of the toes and feet causing foot-drop become involved either early or late in the clinical course. With the dose regimens currently used, the weakness is usually mild, but in the past, some patients became quadriparetic and bedbound. Adults are more severely affected than are children, as are persons with preexisting polyneuropathies. The neuropathy is

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strictly dose-related and reduction in dosage is followed by improvement of neuropathic symptoms although this may take several months. Many patients are then able to tolerate vincristine in low dosage, such as 1 mg every 2 weeks, for many months. Thalidomide produces a similar sensory neuropathy. It is finding use in the treatment of inflammatory conditions such as Behçhet disease, graft versus host reactions, erythema nodosum, lepromatous eruptions, aphthous stomatitis in HIV patients and highly vascular tumors and certain tumors such as renal cell cancer. Antimicrobial drugs As mentioned in Chap. 41, isoniazid (INH)-induced polyneuropathy was a common occurrence in the early 1950s when this drug was first used for the treatment of tuberculosis. Symptoms of neuropathy appeared between 3 and 35 weeks after treatment was begun and affected approximately 10 percent of patients receiving therapeutic doses in the upper range (10 mg/kg daily). The initial symptoms are symmetrical numbness and tingling of the toes and feet spreading, if the drug is continued, to the knees and occasionally to the hands. Aching and burning pain in these parts then becomes prominent. In addition to sensory loss, examination usually discloses a loss of tendon reflexes and weakness in the distal muscles of the legs. Severe degrees of weakness and loss of deep sensation are observed only rarely. Isoniazid produces its effects on the peripheral nerves by interfering with pyridoxine metabolism, perhaps by inhibiting the phosphorylation of pyridoxine (the collective name for the B6 group of vitamins) and decreasing the tissue levels of its active form, pyridoxal phosphate. The administration of 150 to 450 mg of pyridoxine daily in conjunction with the isoniazid completely prevents the neuropathy. The same mechanism is probably operative in the neuropathies that occasionally complicate the administration of the isoniazid-related substances such as ethionamide, used sometimes in the treatment of tuberculosis and the now little-used antihypertensive agent hydralazine. Paradoxically, the taking of extremely high doses of pyridoxine over a prolonged period may actually cause a disabling, predominantly sensory ganglionopathy (Schaumburg et al, 1983). A relatively mild sensory neuropathy (acral paresthesia) associated with optic neuropathy occasionally complicates chloramphenicol therapy. The chronic administration of metronidazole may have the same effect (and can produce lesions in the deep cerebellum). The newer antimicrobial, linezolid, has been associated with a fairly severe sensory neuropathy in a few cases after prolonged use. A predominantly motor neuropathy has been reported with the chronic administration of dapsone, a sulfone used to treat leprosy and certain dermatologic conditions. Stilbamidine, used in the treatment of kala azar, may also induce a purely sensory neuropathy with a propensity to affect the trigeminal nerves. The introduction, in 1952, of nitrofurantoin for the treatment of bladder infections was soon followed by reports of neurotoxicity attributable to the drug. The earliest symptoms are pain and tingling paresthesias of the toes and feet, followed shortly by similar sensations in the fingers. If the drug is not discontinued, the disorder progresses to a severe, symmetrical sensorimotor polyneuropathy.

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Patients with chronic renal failure are particularly prone to neurotoxicity from nitrofurantoin because of diminished drug excretion resulting in high tissue levels. To make matters more complex, the uremic state itself may be responsible for a polyneuropathy so that the distinction between uremic and nitrofurantoin neuropathy may be impossible. Neuropathologic studies has disclosed an axonal degeneration in peripheral nerves and sensory roots (Lhermitte and colleagues). Cardiac drugs Amiodarone, a drug used for treating recalcitrant ventricular tachyarrhythmias, induces a motor-sensory neuropathy in about 5 percent of patients after several months of treatment. It may also cause a toxic myopathy. Perhexiline maleate for the treatment of angina pectoris may also cause a generalized, predominantly sensory polyneuropathy in a small proportion of patients. Hydralazine as a neurotoxic agent has already been mentioned. Affected persons show a striking neuronal lipidosis. Patients taking niacin to lower blood cholesterol levels may experience distal and truncal paresthesias, and a somewhat controversial neuropathy has also been identified. Other pharmaceutical agents causing polyneuropathy  The development of a sensorimotor neuropathy similar to that produced by INH may be associated with the chronic use of disulfiram in the treatment of alcoholism. Its neurotoxic effects have been attributed to the action of carbon disulfide, which is produced during the metabolism of the drug, and is known to cause polyneuropathy and sometimes an optic neuropathy in workers in the viscose rayon industry. Pathologic data, although scant, tend to discredit this notion, insofar as disulfiram evokes a wallerian type of axonal degeneration, whereas carbon disulfide neuropathy is characterized by swollen (giant) axons that are filled with neurofilaments (Bouldin et al). Some patients who have taken phenytoin for decades may lose ankle and patellar reflexes and acquire mild distal symmetrical impairment of sensation, slowed conduction velocity in the peripheral nerves of the legs and rarely, weakness of the distal musculature. The mechanism and frequency of this complication are not clear. The cholesterol-lowering statin drugs have been tentatively implicated in a painful, paresthetic distal axonal polyneuropathy with retained reflexes (Gaist et al) but the evidence for this association is weak; sometimes a period off the drug or a change to an alternative agent is all that can be tried but it should not preclude a search for alternative causes. More often the problem with statins is one of a toxic myopathy. Colchicine has long been known to cause a myopathy, but a few cases of predominantly axonal sensory neuropathy have also been reported (neuromyopathy). Among various other agents that cause toxic neuropathy are hydroxychloroquine and colchicine. The anesthetic agent trichloroethylene, as with the aforementioned stilbamidine, has a predilection for cranial nerves, particularly the fifth. The neurotoxicity is apparently caused by dichloroacetylene, formed as a product of trichloroethylene. The neuropathic potential of nitrous oxide has already been mentioned. Most of the group of tumor necrosis factoralpha (TNF-α) inhibitors may cause a polyneuropathy, including small-fiber neuropathy, but this category of agents do not appear to have a direct toxic effect on nerves

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but instead alter immune function in some way that results in a process that simulates chronic inflammatory demyelinating polyneuropathy (see further on). Residual effects of polyneuropathy were seen in patients with the toxic eosinophilia-myalgia syndrome; the problem was traced to the ingestion of adulterated l-tryptophan, which had been used in nonprescription drugs for insomnia. One patient under our care suffered permanent areflexic quadriplegia. There may be an eosinophilic infiltrate in nerves, but the neuropathy is probably the result of a direct toxic mechanism. A sensory neuropathy, resulting from excessive pyridoxine ingestion alluded to earlier, is still seen among individuals who take huge doses of vitamin supplements. Amitriptyline is capable of producing paresthesias, but the effect seems to be idiosyncratic and infrequent and not associated with a detectable neuropathy.

Diabetic Neuropathy Diabetes mellitus is the most common cause of polyneuropathy in general clinical practice, for which reason it is accorded a separate section. We are referring mainly to a generalized, predominantly sensory syndrome, but several focal or regional forms of peripheral nerve disease also result from diabetes and for convenience of exposition, are included here. In recent years, attention has also been directed to a possible association between a nondescript sensory polyneuropathy and impaired glucose tolerance, even without manifest diabetes, persistent hyperglycemia, or an elevation of hemoglobin A1c and rates of diabetic neuropathy are similar in type I and type 2 diabetes. A survey has made a case for such an association (Sumner and colleagues), but we remain uncertain about a close relationship between glucose intolerance alone and polyneuropathy. By statistically adjusting for relevant factors such as glycemic control and glycosylated hemoglobin, it has been suggested that some cardiovascular risk factors subsumed under the term “metabolic syndrome” (triglyceride levels, body mass, hypertension) are themselves risk factors for diabetic polyneuropathy (Tesfaye and colleagues). Approximately 15 percent of patients with diabetes have symptoms and signs of polyneuropathy, but nearly 50 percent of cross-sectional population samples have evidence of peripheral nerve damage as assessed by nerve conduction abnormalities. The duration of diabetes is perhaps the most important factor. Fewer than 10 percent of patients have clinically evident polyneuropathy at the time of discovery of diabetes, but this figure rises to 50 percent after 25 years. The presence of diabetic retinopathy is associated with higher incidences of neuropathy. It is not surprising, therefore, that neuropathy is most common in diabetics older than 50 years; it is infrequent in those younger than age 30 years and is rare in childhood. A study of diabetics in Rochester, Minnesota found that 54 percent with type 1 and 45 percent with type 2 diabetes had polyneuropathy (Dyck and colleagues 1993). The proportions were lower, close to 15 percent at the time of diagnosis in both groups, when patients were selected based on clinical symptoms alone rather than on the presence of changes in nerve conduction. In the syndromes described below

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both type 1 and type 2 diabetic patients are susceptible, the duration of diabetes being a major factor as mentioned. Several fairly distinct clinical syndromes of diabetic neuropathy have been delineated: (1) the most common is a distal, symmetrical, primarily sensory polyneuropathy affecting feet and legs in a chronic, slowly progressive manner; the others are (2) acute ophthalmoplegia that affects the third, and less often the sixth, cranial nerve on one side; (3) acute mononeuropathy of limbs or trunk including a painful thoracolumbar radiculopathy; (4) an acute or subacute painful, asymmetrical, predominantly motor, multiple neuropathy affecting the upper lumbar roots or the proximal leg muscles (“diabetic amyotrophy”); (5) a more symmetrical, proximal motor weakness and wasting, usually without pain and with variable sensory loss, pursuing a subacute or chronic course; and (6) autonomic neuropathy involving bowel, bladder, sweating, and circulatory reflexes. These forms of neuropathy often coexist or overlap, particularly the autonomic and distal symmetrical types and the subacute proximal neuropathies. Most of the syndromes listed are likely to be a result of ischemia or infarction of nerves or nerve fascicles, because of a diabetic microvasculopathy. All but the first are special types of mononeuropathy multiplex. The polyneuropathy is associated with occlusion of small endoneurial blood vessels (vasonervorum) but possibly also incorporate a poorly understood metabolic abnormality; however, other theories of causation abound. In recent years, an inflammatory process has been postulated as yet another mechanism of peripheral nerve damage. These aspects are discussed further on.

Distal Sensory Diabetic Polyneuropathy The distal, symmetrical, primarily sensory form of polyneuropathy is the most common type. It is usually a chronic process, sometimes unnoticed by the patient. The main complaints are persistent and often distressing numbness and tingling, usually confined to the feet and lower legs and worse at night. The ankle jerks are absent and, sometimes, the patellar reflexes as well. As a rule, sensory loss is confined to the distal parts of the lower extremities, but in severe cases the hands are involved and the sensory loss may even spread to the anterior trunk, simulating a sensory level of spinal cord disease (Said et al, 1983). Trophic changes in the form of deep ulcerations and neuropathic degeneration of the joints (Charcot joints) are encountered in the most severe and long-standing cases, presumably as a result of sensory analgesia, trophic changes, and repetitive injury. (Foot ulcerations are more common simply as a result of the microvascular disease of skin in diabetic patients.) Muscle weakness is usually mild, but in some patients a distal sensory neuropathy is combined with a proximal weakness and wasting of the types mentioned earlier. Treatment of the acral pain may be a major problem and is discussed further on. In another group of patients with diabetic polyneuropathy the clinical picture may be dominated instead by loss of deep sensation, ataxia, and atony of the bladder, with only slight weakness of the limbs, in which case it resembles tabes dorsalis (hence the term diabetic pseudotabes).

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The similarity to tabes dorsalis is even closer if lancinating pains in the legs, unreactive pupils, abdominal pains, and neuropathic arthropathy are present.

Acute Diabetic Mononeuropathies Among these, diabetic ophthalmoplegia is a common occurrence, usually in an older patient with well-established diabetes. It commonly presents as isolated, painful third nerve palsy with sparing of pupillary function. In the first autopsied patient reported by Dreyfus and colleagues, there was an ischemic lesion in the center of the retroorbital portion of the third nerve. Subsequently, a similar case was described by Asbury and colleagues (1970). Slightly less often, the sixth nerve on one side is involved as described in Chap. 13. Isolated involvement of practically any of the major peripheral nerves has been described in diabetes, but the ones most frequently affected are the femoral, sciatic, and peroneal nerves, in that order. Rarely is a nerve in the upper extremity affected. As mentioned, the acute mononeuropathies, both cranial and peripheral, are presumably a result of infarction of the nerve, but it is only in pathologic studies of the third nerve that this basis has been established. Recovery is the rule but may take many months. Whether facial nerve palsy can be a manifestation of diabetic neuropathy is uncertain, but it must be rare.

Diabetic Multiple Mononeuropathies and Radiculoplexus Neuropathy (Diabetic Lumbar Plexopathy; Diabetic Amyotrophy; Garland Syndrome) This category overlaps with the mononeuropathies. A syndrome of painful unilateral or less often, asymmetrical multiple neuropathies tends to occur in older patients with relatively mild or even unrecognized diabetes. Multiple nerves are affected in a random distribution (mononeuropathy multiplex). The mononeuropathies often emerge during periods of transition in the diabetic illness, for example, after an episode of hyper- or hypoglycemia, when insulin treatment is initiated or adjusted, or when there has been rapid weight loss. The most characteristic syndrome affects the lumbar roots. Pain, which can be severe, begins in the low back or hip and spreads to the thigh and knee on one side; the discomfort has a deep, aching character with superimposed lancinating jabs and there is a propensity for pain to be most severe at night. Weakness and later atrophy are evident in the pelvic girdle and thigh muscles, although the distal muscles of the leg may also be affected. The weakness can progress for days or weeks (rarely, months). The patellar reflex is lost on the affected side. Curiously, we have found the opposite patellar reflex to be absent in some patients, without explanation. Deep and superficial sensation may be intact or mildly impaired, conforming to either a multiple nerve or multiple adjacent root distribution (i.e., L2 and L3, or L4 and L5). The pain lasts for several days and then gradually abates. Motor recovery is the rule although months and even years may elapse before it is complete. The same syndrome may recur after an interval of months or years in the opposite leg. The EMG shows denervation in the lumbar and sometimes adjacent myotomes.

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This form of neuropathy has been referred to as diabetic amyotrophy, a term that draws attention to the muscle wasting facet of the syndrome, which may appear surprisingly early after pain. Garland’s name (also Bruns’s) has been attached to this diabetic lumbar radiculoplexopathy based on his thorough report (but he mistakenly attributed the condition to a spinal cord lesion). Clinical experience has shown that an identical painful lumbofemoral neuropathy may develop in nondiabetics; possibly this form is also vasculopathic or vasculitic. While lumbar disc herniation, retroperitoneal hematoma compressing upper lumbar roots, carcinomatous meningeal seeding, and neoplastic and sarcoid infiltration of the proximal lumbar plexus enter into the differential diagnosis, the diabetic type is usually so distinctive as to permit recognition on clinical grounds alone. A reexamination of this syndrome points out that there is considerable overlap between the chronic polyneuropathy of diabetes and this rapidly evolving regional disorder (Barohn and colleagues, 1991). This survey also points out a high incidence of involvement of the L5 root, but we find this difficult to reconcile with the frequent finding of hip flexor and quadriceps weakness in our patients. As with the diabetic mononeuropathies, the upper extremities are only rarely affected by this process. Also observed in diabetic patients is a relatively painless syndrome of proximal symmetrical leg weakness, wasting, and reflex loss of more insidious onset and gradual evolution as discussed by Pascoe and colleagues. The iliopsoas, quadriceps, and hamstrings are involved in varying degrees. The muscles of the scapulae and upper limbs, usually the deltoid and triceps, are affected less frequently. Sensory changes, if present, are distal, symmetrical, and usually mild. In an attempt to delineate these types of proximal diabetic neuropathies, it must be emphasized that they overlap and that distal parts of a limb may be involved to a mild degree and the evolution of symptoms varies. Whether the proximal and distal syndromes should be distinguished on pathologic or electrophysiologic grounds is not clear. A syndrome of thoracoabdominal radiculopathy characterized by severe pain and dysesthesia is also well described (Sun et al). Almost always the diabetes has been of long standing (Kikta et al). The pain is distributed over one or several adjacent segments of the chest or abdomen; it may be unilateral, or less often bilateral, and, as with the lumbar radiculoplexopathy, sometimes follows a period of recent weight loss. Superficial sensory loss can be detected over the involved area in most patients. The pathology of this state is not known, but it is presumed to be an ischemic radiculopathy. The EMG changes consist of fibrillations of the paraspinal and abdominal muscles in one or more adjacent myotomes, corresponding to the painful area. With control of the diabetes, or perhaps spontaneously, recovery eventually occurs but it may be protracted. The differential diagnosis includes preeruptive herpes zoster, sarcoid infiltration of nerve roots, and thoracic disc rupture. In all forms of diabetic polyneuropathy, the CSF protein may be elevated from 50 to 150 mg/dL and sometimes higher. The protein concentration is usually normal

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in cases of diabetic mononeuropathy. Whether a slight elevation of CSF protein, discovered incidentally, can be attributed to diabetes in the absence of a polyneuropathy is uncertain. Despite the finding of inflammatory infiltrates in the proximal diabetic neuropathy (see in the following text), a cellular reaction in the CSF should not be attributed to the diabetic neuropathies.

Autonomic Diabetic Neuropathy Symptoms of autonomic involvement include any combination of pupillary and lacrimal dysfunction, impairment of sweating and vascular reflexes, nocturnal diarrhea, atonicity of the gastrointestinal tract (gastroparesis) and bladder dilation, erectile dysfunction, and postural hypotension. The most striking examples in our experience include severe abdominal and limb pain in young type 1 diabetics, symptoms comparable to the crises of tabes dorsalis that required narcotics to control. The basis of this type of autonomic involvement is not well understood. Duchen and associates, who studied the sympathetic ganglia in diabetic patients with autonomic symptoms, described vacuoles and granular deposits in sympathetic neurons and little if any neuronal degeneration; there was also a loss of myelinated nerve fibers in the vagus and splanchnic nerves and the rami communicantes, as well as changes in neurons of the intermediolateral columns of the spinal cord.

Pathology and Pathophysiology of the Diabetic Neuropathies In the typical symmetrical diabetic distal sensory polyneuropathy, loss of myelinated nerve fibers is the most prominent finding. In addition, segmental demyelination and remyelination of remaining axons are apparent in teased nerve fiber preparations. The latter findings are probably too severe and widespread to be simply a reflection of axonal degeneration. Occasionally, repeated demyelination and remyelination lead to onion-bulb formations of Schwann cells and fibroblasts, as it does in the relapsing inflammatory neuropathies. Unmyelinated fibers are also reduced in number in most specimens. Similar scattered lesions are found in the posterior roots and posterior columns of the spinal cord, and in the rami communicantes and sympathetic ganglia. Under the electron microscope, the basement membranes of intraneural capillaries are thickened and duplicated. There are changes in the microvasculature of the nerves as well, similar to what is seen in other organs and in the skin of diabetics. As can be surmised from this discussion, uncertainties persist about the pathogenesis of the diabetic neuropathies. Both the cranial and peripheral mononeuropathies, as well as the painful, asymmetrical, predominantly proximal neuropathy of sudden onset, have been considered by most neuropathologists to be ischemic in origin, secondary to a vasculopathy of the vasa nervorum. Obliterative microvascular lesions have been well illustrated (Raff and coworkers) and corresponding multiple small infarcts were found in the nerve trunks in other studies. The observations of Dyck et al (1986b) and of Johnson and their associates also suggested that all forms of diabetic

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neuropathy had the same microvascular basis. The latter authors described multiple foci of fiber loss throughout the length of the peripheral nerves, beginning in the proximal segments and becoming more frequent and severe in the distal. This pattern of change differs from that observed in diffuse metabolic disease of Schwann cells and in the dying-back type of neuropathy. It had earlier been noted that the fascicular capillaries and epineural arterioles have thickened and hyalinized basement membranes, similar to the microvascular changes seen in the retina, kidney, and other organs (Fagerberg). But occlusion of vessels and frank infarction of nerve has not been observed in most cases of polyneuropathy for which reason a vascular pathogenesis remains unsettled. An alternative view has been offered in which several groups have found areas of perivascular inflammation and adjacent damage to nerve fascicles in the proximal radicular plexus syndrome (Dyck and colleagues, 2000; Said and coworkers, 2003). These findings have implications for possible treatment with glucocorticoid and anti-inflammatory drugs. Several biochemical findings implicated in diabetic polyneuropathy and their interpretations were reviewed by Brown and Greene, who advanced the idea that persistent hyperglycemia inhibits sodium-dependent myoinositol transport. Low levels of intraneural myoinositol reduce phosphoinositide metabolism and sodium-potassium adenosine triphosphatase (ATPase) activity. Others have emphasized a deficiency of aldose reductase and an elevation of polyols (particularly sorbitol) as being causally important. The role of factors other than hyperglycemia that are subsumed under the “metabolic syndrome” mentioned earlier is also unclear. In reviewing these studies, one can only conclude that a convincing biochemical pathogenesis for neuropathy in diabetes has yet to be formulated. Another group of novel findings holds that there is a reduction in trophic factors within diabetic nerves (nerve growth factor [NGF], vascular endothelial growth factor [VEGF], erythropoietin); partial reversal of the polyneuropathy has been obtained in animals by replacement of these factors through gene therapy. Trials addressing this mode of treatment are noted later. Treatment  The only preventive treatment for diabetic neuropathy is the maintenance of blood glucose concentration at close to normal range. The prevailing view, derived from long-term human studies, is that there is a relationship between peripheral nerve damage and inadequate regulation of the diabetes. This is supported by the findings of the National Diabetic Complications Trial, in which 715 patients with type 1 diabetes were followed for 6 to 10 years. There was a relation between strict glucose control by means of an intravenous insulin infusion system and a reduction or delay in the occurrence of painful neuropathic symptoms, retinopathy, and nephropathy. However, this came at the price of a threefold increase in hypoglycemic reactions (see also Samanta and Burden). Whether similar protective effects of glucose control apply to type 2 diabetes is not known, but for most patients rigid control is impractical. A number of small trials have been

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conducted with aldose reductase inhibitors based on theoretical considerations of the above-discussed metabolic changes. Some recent interest has also been directed at the therapeutic use of gangliosides, which are normal components of neuronal membranes and can be administered exogenously. These approaches have not entered routine practice. Treatment using gene transfer had been pursued by our group. In experimental models of diabetic neuropathy, the intramuscular administration of VEGF has had a beneficial effect on several measures of nerve conduction and on the histologic changes of diabetic nerve damage in the treated limb (Ropper et al, 2009). Whether this was mediated by a trophic influence on nerves and Schwann cells, or is the result of angiogenesis, is not known. With similar intentions, two trials of NGF injections in almost 500 patients gave equivocal results, the first being positive and the followup study not showing improvement. VEGF has resulted in improvement of sensory symptoms but not of nerve conduction or of the sensory examination in a trial we conducted (Apfel and colleagues). The distressing paresthesias of the distal extremities can be managed with amitriptyline, other tricyclic antidepressants, or one of the newer generation of antidepressants, duloxitine, gabapentin, or pregabalin but the response is usually incomplete. Shooting, stabbing pain also responds to some degree to antiepileptic drugs but only modest effects can be expected. Gabapentin or pregabalin may give reasonable results, perhaps in part because high doses are tolerated (Gorson et al, 1999). Topical creams with capsaicin, lidocaine or other substances, or compounds with several of these (including ketorolac, gabapentin, ketamine) have been found helpful by a few patients but do not have support in randomized trials. Nerve blocks and epidural injections have been helpful in very few patients. In the proximal asymmetrical, truncal, or ophthalmoplegic neuropathies, the severe pain usually lasts for only a short period and requires the judicious use of analgesics, as outlined in Chap. 7. Glucocorticoids have been used in painful lumbosacral plexopathies, based on the inflammatory component described earlier and may quickly reduce pain based on case reports but effects beyond this are uncertain. A trial published in abstract form gave uncertain results. Other forms of immune therapy including IVIG and plasma exchange have been tried in uncontrolled studies, with uncertain results. The course in patients with the distal, symmetrical sensory neuropathy is generally of slow progression, but in the other types improvement and eventual recovery may be expected over a period of months or years.

ASYMMETRICAL AND MULTIFOCAL POLYNEUROPATHIES (MONONEUROPATHY, OR MONONEURITIS MULTIPLEX) (TABLE 43-4) In addition to diabetes, several systemic conditions are accompanied by acute or subacute involvement of multiple individual nerves serially or almost simultaneously. This configuration gives rise to the distinctive clinical

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Table 43-4 CAUSES OF MONONEUROPATHY MULTIPLEX Common   Polyarteritis nodosa   Microscopic polyangiitis   Eosiniphilic granulomatosis with polyangiitis  Leprosya   Wegener granulomatosis  Diabetes   Hereditary liability to preserve palsies  Cryoglobulinemia  Sarcoidosis   Lyme disease  HIV Less Common  Paraneoplastic  Amyloidosis   Systemic lupus   Rheumatoid arthritis   Leukemia-lymphoma infiltration   Intravascular lymphoma   Sjögren syndrome a

Leprosy is the most common cause of this syndrome worldwide but infrequent in areas in which it is not endemic.

picture of mononeuropathy or mononeuritis multiplex. The most notable examples are associated with vasculitides that produce nerve infarction, the archetype being polyarteritis nodosa and other vasculitides and particularly a form of idiopathic vasculitis that is confined to the peripheral nervous system. The distinctive features of the multiple mononeuropathy syndromes are the acute or subacute evolution of complete or almost complete sensorimotor paralysis in the distribution of single peripheral nerves. In addition to vasculitis or the nerves, sarcoidosis, forms of HIV-related neuropathy, Leprosy and Lyme disease may become manifest in this fashion, probably from infiltration or inflammation of nerves rather than infarction. The diabetic mononeuropathies were addressed in the preceding section.

Vasculitic Neuropathies More than half of all cases of mononeuropathy multiplex can be traced to a systemic vasculitis involving the vasa nervorum. These are the main causes of mononeuritis multiplex. Included in this category are polyarteritis nodosa, the eosinophilic granulomatosis with polyangiitis (formerly called Churg-Strauss syndrome of allergic bronchial asthma and eosinophilia), rheumatoid arthritis, lupus erythematosus, scleroderma, cryoglobulinemia, granulomatosis with polyangiitis, and the aforementioned idiopathic variety of vasculitis that is confined to the peripheral nerves and has no systemic manifestations. In a series of 425 cases of vasculitis (Said, 2005) affecting the peripheral nerves, 24 percent were associated with polyarteritis nodosa, 23 percent with rheumatoid arthritis, and about 32 percent with other connective tissue diseases; in 21 percent there were no signs of vasculitis beyond the peripheral nerves. Elevation of the sedimentation rate, C-reactive protein and other serologic abnormalities are typical features but not

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invariable of this group. The most recent addition to the diagnostic list has been a microscopic polyangiitis that is different from the vasculitis of medium-sized vessels that characterizes the remainder of the group. This subject has been reviewed by Collins, who summarizes guidelines for diagnosis.

Polyarteritis Nodosa Almost 75 percent of cases of polyarteritis nodosa include involvement of the small nutrient arteries of peripheral nerves (these figures come from autopsy series), but a symptomatic form of neuropathy develops in about half this number. Nevertheless, involvement of the peripheral nerves may be the principal or first sign of the disorder, before the main systemic components of the clinical picture—abdominal pain, hematuria, fever, eosinophilia, hypertension, vague limb pains, and asthma—have not fully declared themselves or have been misinterpreted. Although characteristically a disease of multiple discrete mononeuropathies, the syndrome associated with polyarteritis nodosa may appear more or less generalized and symmetrical as a result of the accumulation of many small nerve infarctions; that is, it can simulate a polyneuropathy. In these cases, careful clinical and electrophysiologic examinations disclose elements of mononeuritis that have been engrafted on an otherwise generalized process. For example, an asymmetrical foot- or wrist-drop or a disproportionate affection of one nerve in a limb, such as ulnar palsy with relative sparing of function of the adjacent median nerve, are clues to the multifocal nature of the process. As often it takes form of random infarctions of two or more individual nerves. The onset is usually abrupt with symptoms of pain or numbness at a focal site along a nerve or in the distal distribution of an affected nerve, followed in hours or days by motor or sensory loss in the distribution of that nerve and then by involvement in a saltatory fashion of other peripheral nerves. Both the spinal and cranial nerves may be affected but far less often than the nerves in the limbs. Virtually no two cases are identical. The CSF is usually normal. Nerve biopsy, usually taken from the sural nerve, will in most cases show the necrotizing arteritis in medium-size vessels (fibrinoid necrosis of all three coats of the vessel walls), with infiltrating eosinophils and occlusion of vessels. Muscle biopsy may also show perivascular inflammation and necrosis, but the diagnostic yield is less than for biopsy of a nerve, particularly if a sample is taken from a clinically affected nerve. Based on the smaller size of affected vessels and the presence of perinuclear antinuclear cytoplasmic autoantibodies (p-ANCA), there has been differentiated a “microscopic” polyarteritis, or polyangiitis (Lhote and colleagues) distinct from the granulomatosis with polyangiitis and that is probably more common than previously appreciated. The diagnosis is made by nerve biopsy. Rapidly progressive glomerulonephritis and lung hemorrhage are the additional features of the latter disease, neuropathy occurring somewhat less frequently than in typical polyarteritis. Treatment  Based on the response to the systemic vasculitides with ANCA activity, mononeuritis multiplex caused by vasculitis has generally been treated with

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glucocorticoids and either rituximab 375 mg/m2 weekly for 4 weeks, or cyclophosphamide 1 g/m2 intravenously once a month for several months, but other equivalent regimens have been suggested. We have used intravenous methylprednisolone, 1.5 mg/kg, for several days, followed by oral treatment. It appears from clinical experience that glucocorticoids alone are often inadequate, but some clinicians have taken this approach initially. Azathioprine is a reasonable alternative if cyclophosphamide is not tolerated. Treatment usually must be continued for at least several months. In intractable cases and in those with systemic involvement, treatment with methotrexate may be indicated, or this may be used initially. Spontaneous remission and therapeutic arrest are known, but many cases have a fatal outcome from kidney and systemic complications. The infarctive nerve palsies and sensory loss of the mononeuropathies generally persist to a large degree even when the systemic disease is brought under control.

Eosinophilic Granulomatosis With Polyangiitis (ChurgStrauss, Allergic Granulomatosis) and Hypereosinophilic Syndrome These closely related systemic illnesses involve multiple individual peripheral nerves, much as in polyarteritis. A characteristic feature is the excess of circulating and tissue eosinophils (more so than in polyarteritis) and a tendency of the vasculitis to involve the lungs and skin, in contrast to the renal and bowel infarctions of polyarteritis nodosa. There is considerable degree of pathologic and clinical overlap between both polyarteritis and eosinophilic polyangiitis necrotizing vasculitis with the more benign hypereosinophilic syndrome that is less aggressive and has a greater tendency for eosinophilic infiltration of tissues other than nerve. One medication (zafirlukast, a leukotriene receptor antagonist) that has been used in Europe to treat asthma, has precipitated several cases of this disease. Rarely, the overall illness has apparently been preceded by treatment with a macrolide antibiotic (e.g., azithromycin), estrogen, or carbamazepine, but these associations are uncertain, and most cases are idiopathic. In this disease, rhinitis or asthma may be present for years and only later is there marked eosinophilia and organ infiltration, particularly an eosinophilic pneumonitis. The neuropathy that then develops in approximately threequarters of patients is usually preceded by fever and weight loss and takes the form of an acute, painful mononeuritis multiplex. A granular cytoplasmic pattern of antineutrophil cytoplasmic autoantibodies (c-ANCA) of the same type that occurs in granulomatosis with polyangiitis (formerly Wegener’s granuomatotis) is found in more than half of cases (see in the following text). The histologic feature in nerve biopsies is similar to polyarteritis nodosa, but the eosinophilic infiltration tends to be more intense. We have seen other types of cutaneous diseases with vasculitic mononeuritis, the most impressive being a massive leukocytoclastic vasculitis of the skin (necrotic polymorphonuclear cells surrounding venules) resulting in large confluent hemorrhagic lesions. The idiopathic eosinophilic syndrome comprises a heterogeneous group of disorders, the common features of which are a persistent and extreme degree of eosinophilia

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and eosinophilic infiltration of many organ systems. Neuropathy occurs in fewer than half of the cases, taking the form of a painful diffuse sensorimotor syndrome with axonal damage or of a mononeuritis multiplex (see Moore et al). The pathologic appearance is one of diffuse infiltration of the nerves by eosinophils rather than a vasculitis. The neuropathic effects are attributable to the infiltration itself or to a postulated tissue-damaging effect of the eosinophilic cell. Treatment  Both the polyangiitis form and the idiopathic hypereosinophilic syndrome are treated initially with high doses of corticosteroids, with which the peripheral eosinophilia, as well as tissue damage, may abate in several weeks or months. Further immunosuppressive treatment in the forms of rituximab as discussed previously, azathioprine, methotrexate, or cyclophosphamide has been used in fulminant or refractory cases, which includes most of the ones that we have seen. A trial of mepolizumab, an anti-interleukin-5 monoclonal antibody produced remission of the overall disease in over on-third of patients, almost half of whom had neuropathy, but details of the effect of treatment on neuropathy was not specifically commented on (Wechsler et al).

Granulomatosis With Polyangiitis This disorder, renamed from Wegener’s granulomatosis because of the eponymous individual’s association with Naziism, gives rise to asymmetrical multiple mononeuropathy indistinguishable from the other angiopathic neuropathies described earlier and probably based on the same mechanism, mononeuropathies of the lower cranial nerves directly as they exit the skull and pass through the retropharyngeal tissues. The frequency of peripheral nerve involvement is much lower than in the other of classic vasculitides and the affected vessels are of a smaller caliber than in polyarteritis nodosa. Nonetheless, it has been emphasized in a prospective analysis of 128 patients that 25 had evidence of mononeuritis multiplex, with the peroneal nerve most often involved, and an even greater number had distal polyneuropathy; however, the proportion of their cases in which neuropathy was the presenting or sole manifestation of disease was higher than in other series DeGroot and colleagues. The finding of circulating c-ANCA is relatively specific for Wegener granulomatosis and for eosiniophilic polyangiitis disease, as mentioned earlier (Specks et al), and helps to differentiate it from polyarteritis (which may be associated with p-ANCA) and from retropharyngeal carcinoma, chordoma, sarcoidosis, and herpes zoster. Granulomatosis with polyangiitis as it affects the lower cranial nerves is discussed in Chap. 44. Treatment is along the lines of glucocorticoids and rituximab or cyclophosphamide as already discussed.

Essential Mixed Cryoglobulinemia This process may be associated with a vasculitic mononeuritis multiplex as well as a more generalized polyneuropathy. In many cases, glomerulonephritis, arthralgia, and purpura are conjoined, reflecting the systemic nature of the vasculopathy, but the mononeuritis may occur in isolation. The evolution in the cases under our care has been slower than in the typical vasculitic neuropathies,

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sometimes taking weeks or months between attacks of mononeuropathy. The neurologic disorder may become quiescent for long periods, during which time considerable improvement may occur. There is no evident relationship between the mode of onset or severity of the neuropathy and the concentration of cryoprecipitable proteins in the serum. These proteins can be detected by cooling the serum and demonstrating a precipitation of IgG and IgM proteins that redissolve on warming to 37°C (98.6°F). To demonstrate this phenomenon the blood sample must be carefully transported to the laboratory in a warm water bath. An association of cryoglobulinemia with hepatitis C is well known, but many patients have had polyneuropathy from cryoglobulins but without the infection (essential cryoglobulinemia). Treatment  It had been suggested that the neuropathy can be stabilized by corticosteroids and cyclophosphamide (Garcia-Bragado and colleagues), but rituximab has been increasingly employed rather than cyclophosphamide and plasma exchange; the comparison between approaches has not been systematically tested. If the underlying problem is hepatitis C infection, pegylated alpha-interferon and ribavirin are usually administered as antiviral agents, with rituximab if the neuropathy is severe. It is too early to judge if protease inhibitors for the treatment of hepatitis C will reduce the occurrence and degree of polyneuropathy. Other aspects of the condition are discussed further under “Polyneuropathy Associated with Paraproteinemia” and “Other Vasculitic Neuropathies.”

Rheumatoid Arthritis Some 1 to 5 percent of patients with rheumatoid arthritis have vasculitic involvement of one or more nerves at some time in the course of their disease, apart from more mundane pressure neuropathies as a result of thickened tendons and destructive joint changes. The arteritis is of small-vessel fibrinoid type and immune globulins are demonstrable in the walls of vessels. Most of the affected patients under our care have had severe rheumatic disease for many years and were strongly seropositive (Pallis and Scott). In addition to the neuropathy, such patients often have rheumatoid nodules, skin vasculitis, weight loss, and fever. There are rarer forms of chronic progressive polyneuropathy that complicate rheumatoid arthritis; they are described further on. Treatment is aimed at the underlying rheumatologic condition.

Systemic Lupus Erythematosus Approximately 10 percent of patients with lupus exhibit symptoms and signs of peripheral nerve involvement, but only a small number occur before the established and advanced stages of the disease (i.e., rarely has it been the initial presentation). In our several patients, the polyneuropathy has taken the form of a symmetrical, progressive sensorimotor paralysis, beginning in the feet and legs and extending to the arms, evolving over a period of several days or weeks, thereby simulating GBS. In a few, weakness and areflexia were more prominent than the sensory loss; the latter involved mainly vibratory and position senses. A more common syndrome in our experience has been a progressive or relapsing disease that cannot be distinguished

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clinically from chronic inflammatory demyelinating polyneuropathy (discussed further on). Multiple mononeuropathies have also been reported, as has involvement of the autonomic nervous system. An elevation of CSF protein that is found in some instances suggests nerve root involvement. Sural nerve biopsies may show vascular changes consisting of endothelial thickening and mononuclear inflammatory infiltrates in and around the small vessels for which reason the disease is included here with the other vasculitic neuropathies. Axonal degeneration is the most common change, but a chronic demyelinating pathology has also been described (Rechthand et al). Vascular injury from deposition of immune complexes is the proposed mechanism of nerve damage.

Isolated (Nonsystemic) Vasculitic Neuropathy In contrast to the aforementioned disorders, which involve several tissues and organs in addition to the peripheral nerves, necrotizing vasculitis that simulates polyarteritis nodosa may be limited to the peripheral nerves. Cases of this type appear as often as all the other systemic vasculitic types together. This restricted form of mononeuritis multiplex usually presents as a subacute symmetrical or asymmetrical polyneuropathy with superimposed mononeuropathies or solely with multiple mononeuritis. Circulating antineutrophil cytoplasmic antibody (ANCA) is found in a few cases, but other tests for inflammatory and rheumatologic diseases are usually negative. In one, the sedimentation rate was mildly elevated, the mean being 38 mm/h, with only one-quarter having values greater than 50 mm/h (Collins and colleagues, 2003). The main diagnostic difficulty arises when the EMG performed early in the course of illness shows conduction block that simulates a demyelinating polyneuropathy. Biopsy, preferably of an affected nerve, should then settle the issue. Treatment  The neuropathy tends to be less aggressive (and nonlethal) than the systemic forms of vasculitic neuropathy and has usually responded to glucocorticoids without treatment with cyclophosphamide. However, in the aforementioned series, the use of cyclophosphamide for 6 months with glucocorticoids resulted in a more rapid remission and fewer relapses. An expert group has provided guidelines for treatment specifically of this condition that approximates this approach by adding an immunosuppressive agent to corticosteroids only if the disease behaves aggressively (Collins et al, 2010).

Other Vasculitic Neuropathies In the past, administration of pooled serum for the treatment of various infections led to brachial plexus neuritis or to an immune mononeuropathy multiplex, presumably from deposition of antibody–antigen complexes in the walls of the vasa nervorum. A similar “serum sickness” reaction occurred after certain viral infections associated with arthritis, rash, and fever. The neuropathy that arises with hepatitis C infection may be of this type, perhaps mediated by an associated cryoglobulinemia as mentioned earlier. Interferon, which has been effective in treating the hepatitis, may also ameliorate the neuropathy, but greater success has been achieved with cyclophosphamide. Pooled immunoglobulin for the treatment of diverse

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neuromuscular diseases such as GBS and myasthenia gravis has not, to our knowledge, led to a serum-sickness neuropathy, but one of our patients with underlying polyangiitis developed a fulminating vasculitic skin eruption while being treated with IVIg. In two cases of severe systemic vasculitis related to administration of hydralazine, we observed no neuropathic features; whether this applies to other drug-induced vasculitides is not known. Minocycline is another drug that has been associated in rare and uncertain instances with a vasculitis, including mononeuropathies. The increasing appearance of vasculitic neuropathy with HIV infection, including a type that is independent of CMV infection, has already been mentioned; such cases have tended to improve spontaneously or with corticosteroid therapy. In about half of these cases the CSF contains polymorphonuclear cells. From time to time a patient with a lymphoproliferative disorder such as Hodgkin disease will develop mononeuritis multiplex that is found by biopsy to be caused by vasculitis. A chronic demyelinating, nonvasculitic polyneuropathy is more common with lymphomas of any type as discussed earlier. A rare paraneoplastic variety of vasculitic neuropathy has also been described. A reported 2 of patients and review 13 previous ones (Oh) had as the most common underlying cancer of the small-cell lung type. Anti-Hu antibodies that are typical of paraneoplastic neurologic diseases from this cancer are generally not detected (see Chap. 31). Other solid tumors (renal, gastric, gynecologic) have been associated with a similar neuropathy but only in a few instances. Almost all have had slightly elevated protein concentration in the CSF but few showed a pleocytosis. At autopsy, the vasculitis was limited to nerve and muscle. The role of an obscure small-vessel vasculitis in otherwise idiopathic axonal polyneuropathies of elderly patients has been reported, but is in our view, controversial. We have not found, as others have, an unexpected vasculitis in the nerve biopsies of such patients (Chia and colleagues). The vasoocclusive and infiltrative condition of intravascular lymphoma often includes a syndrome of multiple painless mononeuropathies as part of a larger multifocal illness of the central and peripheral nervous system.

Other Asymmetric Multifocal Neuropathies Neuropathy of Critical Limb Ischemia A few patients with severe atherosclerotic ischemic disease of the iliac or leg arteries will be found to have localized sensory changes or diminished reflexes. Usually, the other effects of ischemia—claudication and pain at rest, absence of distal pulses and trophic skin changes—are so prominent that the neurologic changes are minor by comparison. In experimental studies, combined occlusion of the aorta and multiple limb vessels are required to produce neural ischemia because of the profusely ramifying vasculature. In our experience of 12 patients with a critically ischemic leg, there was a neuropathy with a pronounced distal predominance; sensory loss in the feet was worse than the symptoms might suggest and there was mild weakness of the toes and depression or loss of the ankle

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reflex (Weinberg et al). Although paresthesias, numbness, and deep aching pain at rest were characteristic, the patients were more limited by symptoms of their vascular claudication than by the neuropathic ones. Restoration of circulation to the limb by surgical or other means resulted in some improvement of the regional neuropathy. Reviews of the literature on this subject can be found in the writings of Eames and Lange. A poorly understood but presumably localized ischemic neuropathy occurs in the region of arteriovenous shunts (fistulas) that have been placed for the purpose of hemodialysis. Complaints of transient diffuse tingling of the hand are not uncommon soon after creation of the shunt but only a few patients develop persistent forearm weakness, numbness and burning in the fingers, reflecting variable degrees of ulnar, radial, and median nerve, and possibly also muscle, ischemia. The role of an underlying uremic polyneuropathy in facilitating this neuropathy has not been studied. A progressive, symmetrical polyneuropathy as a result of systemic cholesterol embolism has been described (Bendixen and colleagues). An inflammatory and possibly necrotizing arteritis surrounds embolic cholesterol material within small vessels and may account for the progression of symptoms. This neuropathic process is more often discovered at autopsy than it is in the clinic, being eclipsed during life by the cerebral manifestations of cholesterol embolism (Chap. 33). The peripheral part of the illness simulates the polyneuropathy of a small-vessel polyarteritis.

Sarcoid Neuropathies The generalized granulomatous disease of sarcoidosis infrequently produces subacute or chronic polyneuropathy, polyradiculopathy, or mononeuropathies. A painful, small-fiber sensory neuropathy has also been described by Hoitsma and colleagues. Any of the neuropathies may be associated with granulomatous lesions in muscles (polymyositis) or with signs of CNS involvement, most often of the stalk of the pituitary with diabetes insipidus or a myelopathy (see Chap. 31). Involvement of a single nerve with sarcoid most often implicates the facial nerve (facial palsy), but sometimes multiple cranial nerves are affected in succession (see Chap. 44). Next in frequency is weakness and reflex and sensory loss, appearing sequentially (polyradiculopathy), in the distribution of several spinal nerves or roots. The occurrence of large, irregular zones of sensory loss over the trunk is said to distinguish the neuropathy of sarcoidosis from other forms of mononeuropathy multiplex. This pattern particularly when accompanied by pain, resembles diabetic radiculopathy (see earlier in “Diabetic Multiple Mononeuropathies and Radiculoplexus Neuropathy”). Unlike the cases of sarcoid polyneuropathies we have seen (Zuniga et al), another series of 11 patients with sarcoid neuropathy (Said and colleagues, 2002), had only 2 that were known to have pulmonary granulomas before the onset of neuropathic symptoms; 6 had a focal or multifocal neuropathic syndrome (including 1 with a clinical and electrophysiologic pattern that simulated multifocal conduction block). The remainder had a nonspecific symmetric polyneuropathy, one of which had an acute onset. Facial diplegia was common in sarcoid, as is well known.

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The pathologic changes in nerve and muscle biopsy specimens consisted mainly of epineurial granulomas and endoneurial inflammatory infiltrates, but there were indications of necrotizing vasculitis in seven cases. Among the cases we studied, 6 of 10 had a subacute or chronic sensorimotor polyneuropathy. It is notable that few patients in that series had elevated levels of angiotensin-converting enzyme in the serum.

Lyme Neuropathies (See Also Chap. 31) The neuropathy that develops in 10 to 15 percent of patients with this disease takes several forms. Cranial nerve involvement is well known, uni- or bilateral facial palsy being by far the most frequent manifestation. Other cranial nerves may also be affected as may almost any of the spinal roots, mostly in the cervical or lumbar region. Even phrenic nerve palsy has been attributed to Lyme disease in a few cases. A concurrent mild or moderate aseptic meningoradiculitis (10 to 100 mononuclear cells/mm3) is characteristic (although this may also occur in HIV and CMV and other forms of neuritis). The CSF glucose is usually normal but has been slightly depressed in a few cases with multiple radiculopathies. Some of the CSF cells may have immature features suggesting a lymphomatous infiltration. (See further on and Chap. 31 for further details of the laboratory diagnosis.) There may be radicular pain not unlike that of cervical or lumbar disc or plexus disease. The triad of cranial nerve palsies, radiculitis, and aseptic meningitis is most characteristic of Lyme disease during its disseminated phase, that is, from 1 to 3 weeks after the tick bite or from the appearance of the typical rash. The disease tends to be seasonal in the period of maximal tick exposure. The special polyradiculitis form of Lyme is discussed further on. Besides the just described cranial neuropathies, the following are the main neuropathic syndromes of Lyme disease: (1) multiple mononeuropathies (involvement of a single major nerve in the limbs, resulting in an isolated foot- or wrist-drop—a distinctly rare pattern, or a thoracoor lumbar mononeuropathy causing sagging of the innervated body part); (2) lumbar or brachial plexopathy (the latter being well described but rare); (3) a predominantly sensory polyneuropathy in which paresthesias and loss of superficial sensation in the feet and legs are coupled with loss of ankle jerks; (4) a generalized axonal polyneuropathy (Loggigian et al), mainly sensory and sometimes accompanied by a mild encephalopathy; and (5) acute GBS (we have encountered only 2 such cases in more than 400 patients with Guillain-Barré but the syndrome appears to be more common in Europe following Borrelia infection). Electrophysiologic testing indicates that the various peripheral nerve syndromes frequently overlap. All of the preceding processes excepting the one that resembles GBS usually occur as subacute or late complications of Lyme disease, several months or, rarely, years after the initial infection (in untreated cases). These late neuropathic syndromes respond less favorably to treatment than do the acute ones, and have a less certain connection to the infection (see further on). As the disease is not fatal, there are few adequate pathologic studies of the peripheral nerves in Lyme disease. The infective agent has not been

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demonstrated in nerve tissue, but perivascular inflammation and vasculitic changes are found in small vessels within the nerves. Lyme polyradiculitis and Bannwarth syndrome This is perhaps the best characterized, but not the most common, type of Lyme neuropathy. A painful lumbosacral polyradiculitis had been described in Europe by the term Bannwarth syndrome (in France as Garin-Bujadoux syndrome). The pathogen in Europe is a Borrelia spirochete slightly different from the one that causes Lyme disease in North America. In Bannwarth syndrome there is an intense inflammatory reaction in the cauda equina, giving rise to sciatic and buttock pain and bladder dysfunction. Less frequently, a cervical polyradiculopathy occurs with shoulder and arm pain that cannot be distinguished on clinical grounds from brachial neuritis. Cases of Bannwarth syndrome from North American Lyme under our care have progressed subacutely over days or weeks and involved the L2-L3-L4 roots, first one leg, then the other, and, subsequently, the midcervical roots on one or both sides. Sparing of a proximal or distal part of a limb while the adjacent part is weakened gives rise to a striking syndrome. One or more thoracic radiculopathies may be added and cause local discomfort. The nerve conduction tests show preservation of sensory potentials, which marks the process as radicular. Headache and a marked pleocytosis (over 100 mononuclear cells/mm3) in the spinal fluid may accompany the pain and usually precedes the radiculopathies by days. Polymerase chain reaction for the detection of the organism in the CSF gives variable results, especially after several days of neurologic illness. A value above unity of CSF to serum anti-Lyme antibodies is probably a dependable indicator of acute or subacute disease, but there have been few systematic studies of this measurement. Oligoclonal bands in the CSF are common as a reflection of these antibodies. A similar syndrome of lumbar polyradiculitis may also be caused by the herpes and Epstein-Barr viruses or more often by an opportunistic CMV infection in a patient with HIV infection. Diagnosis  This is both aided, and at times confused, by serologic testing (see Chap. 31). The enzyme-linked immunosorbent assay (ELISA) is not altogether satisfactory because it frequently yields false-positive and, occasionally, false-negative results. Western blot testing of CSF is more specific. Information to the effect that the patient has lived in or visited an endemic area is useful, but far more compelling is evidence of a tick bite followed by the characteristic rash, or a well-defined history of nonneurologic manifestations of Lyme disease (cardiac, arthritic). Bifacial palsy in any of these clinical contexts also favors the diagnosis of Lyme. Treatment  Treatment of the Lyme neuropathic syndromes is now typically with oral doxycycline or amoxicillin for 3 to 4 weeks but intravenous antibiotics have also been used, usually ceftriaxone 2 g daily for 1 month. More prolonged or intravenous treatment has not been shown to be superior. Glucocorticoids have an uncertain role in the painful radicular syndromes, but we have used them in low doses and they relieved pain. In most series, there

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is recovery or virtually complete resolution of radicular symptoms in approximately 90 percent of patients, although this may take months. Facial palsies also tend to improve, but with a lower rate of complete resolution. It has been stated that many of the peripheral and cranial neuropathies improve even without treatment, but this has not been studied systematically.

Sjögren Disease–Associated Neuropathies This disease is a chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration of the exocrine glands, particularly the parotid and lacrimal glands, that results in keratoconjunctivitis sicca and xerostomia (dry eyes and mouth). These core features may be combined with arthritis or with a wide range of other abnormalities, notably lymphoma, vasculitis, IgM paraproteinemia, renal tubular defects (renal tubular acidosis), and, quite often, a predominantly sensory polyneuropathy (Kaplan et al). In one series, the neuropathy was the presenting problem in 87 percent of 54 patients with Sjögren disease (Grant and colleagues). The sicca symptoms are often mild and reported only on specific inquiry. A symmetrical sensory polyneuropathy or a sensory ganglionopathy are the most common patterns. Sensorimotor polyneuropathy, polyradiculoneuropathy, autonomic neuropathy, or mononeuropathy (most often of the trigeminal nerve, as described by Kaltrieder and Talal) are less common. We have observed yet another neuropathic syndrome taking the form of asymmetrical sensory loss, mostly of position sense and involving the upper limbs predominantly, in association with tonic pupils and trigeminal anesthesia that is probably a variant of ganglionopathy. The sensory polyneuropathies of the Sjögren syndrome are of particular interest to neurologists, as they will encounter most cases before other physicians do (Griffin et al). More than 80 percent of affected patients are older women. The polyneuropathic syndrome often begins with paresthesias of the feet, usually mild in degree. The main clinical features are subacute and widespread sensory loss that may include the trunk and sometimes, profoundly diminished kinesthetic sense, giving rise to sensory ataxia of the limbs and of gait that reflect a ganglionitis. Loss of pain and temperature sensation is variable; tendon reflexes are abolished. A nondescript large- or small-fiber distal sensory neuropathy is also known, for which reason testing for Sjögren-related serum antibodies is included in the general evaluation of polyneuropathies in older patients, and the heterogeneity of sensory neuropathy presentation has been emphasized by several authors. In time, some patients develop autonomic abnormalities such as bowel atony, urinary retention, loss of sweating, and pupillary changes. There is usually little or no pain, but there have been exceptions. Diagnosis  Sjögren disease–associated neuropathy or ganglionopathy should be suspected in an older woman with sensory neuropathy or neuronopathy, particularly if sicca symptoms are present. There may be telangiectasias over the bridge of the nose, on the lips, and fingers. The evaluation is aided by the Schirmer and Rose Bengal tests, which usually demonstrate a reduction of tearing. Even without this confirmatory test, we have found it advisable

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to perform a biopsy of the lip (at the epithelial–mucosal juncture) to detect inflammatory changes in the small salivary glands. This is a minor office procedure in most instances. The diagnosis of Sjögren syndrome from the biopsy requires at least 2 collections of 50 or more lymphocytes in a 4-mm2 specimen. Some patients have serologic abnormalities such as antinuclear antibodies (anti-Ro, also termed SS-A, and anti-La, or SS-B) or monoclonal immunoglobulins, particularly of the IgM subclass. The frequency of specific Sjögren-specific antibodies varies between series; they may be useful as screening tests, but the lip biopsy appears to be more sensitive. In our series of 20 cases with minor salivary gland biopsies that demonstrated inflammatory changes diagnostic of the syndrome, only 6 had serologic evidence of the disease and 2 had positive serologic tests but a negative biopsy (Gorson and Ropper, 2003). The sedimentation rate in our patients was often slightly elevated; however, only 5 of our 20 had a value greater than 40 mm/min and many have had normal or only slightly elevated C-reactive protein levels. The main differential diagnostic entity, if the neuropathy appears subacutely, is a paraneoplastic sensory ganglionitis. Several authoritative clinicians have stressed that a proportion of unexplained polyneuropathies in middle and late life are putatively caused by Sjögren syndrome (Mellgren; Leger and their colleagues). Typical Sjögren abnormalities were found in the lip biopsies of 7 of 32 patients with chronic axonal polyneuropathy that could not otherwise be classified. Several other studies have corroborated this finding of inflammatory disruption of the minor salivary glands in obscure neuropathies, particularly in older women and in some men. The diagnosis in our clinics has not been nearly as frequent in this group. Nonetheless, a search for Sjögren disease may be revealing in otherwise obscure sensory neuropathies. Nerve biopsies have variably revealed necrotizing vasculitis, inflammatory cell infiltrates, and focal nerve fiber destruction. Usually, the CSF protein is normal and there is no cellular reaction. The few times a dorsal root ganglion has been examined in autopsy material; there were infiltrates of mononuclear cells and lymphocytes and destruction of nerve cells. Treatment  Glucocorticoids in doses of approximately 60 mg daily of prednisone, cyclophosphamide (100 mg per day), and rituximab (1,000 mg per day, 2 weeks apart) have been used when the neuropathy is severe and are indicated when there is vasculitis involving renal and pulmonary structures. We have initially administered prednisone 60 mg daily, sometimes in tandem with intermittent plasma exchange, but with little evidence of response, before adding a second immunosuppressive agent. The review of the neurologic manifestations of Sjögren syndrome by Lafitte and by Berkowitz and colleagues are recommended.

Idiopathic Sensory Ganglionopathy (Chronic Ataxic Neuropathy) In addition to the subacute pansensory syndrome described previously and paraneoplastic, postinfectious, and toxic processes, there is a yet another more chronic idiopathic syndrome characterized by severe global

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sensory loss and ataxia (Dalakas). We have encountered several such patients resembling cases described in the literature but it must be a rare condition. In our patients, numbness and sensory findings progressed over months and spread to proximal parts of the arms and legs and then to the trunk. The face and top of the scalp were finally involved. Despite ataxia and complete areflexia, muscular power remained normal, and pain was not a problem. There are reports of fasciculations in a few patients, but not in the ones we have seen. Within a year, most of these patients became completely disabled from the ataxia, unable to walk or even feed themselves. Autonomic failure was another feature in a few and one of our patients became deaf. Extensive examinations for an occult cancer, paraproteinemia, Sjögren disease, Refsum disease, autoimmune diseases, and all potential causes of an ataxic neuropathy proved to be frustratingly negative. Of course, it is possible that some patients had an as yet undiscovered tumor underlying a paraneoplastic ganglionopathy. Yet other instances have had all the features of a truncal–limb sensory neuropathy, with little or no ataxia and only muted reflexes; these have had a more benign course but still no cause was found (Romero et al). In a review of 17 patients with idiopathic sensory ataxic neuropathy, there were antibodies against the ganglioside GD1 in only 1 case and the authors concluded that the majority was not caused by an immunologic mechanism (Illa and colleagues, 2001). The motor nerve conduction studies have been normal or slightly impaired, while the sensory potentials were eventually lost (but they may at first be normal). A puzzling feature in two patients has been an unexpected preservation of many sensory nerve potentials even after a year of illness. In these cases, the process presumably lay in the dorsal roots rather than in the ganglia. In a few instances the MRI has shown a change in the posterior columns of the spinal cord, certainly as a secondary phenomenon from the spinal nerve and root disease. The spinal fluid has generally contained a slightly elevated protein concentration with few or no cells, up to 18/mm3 in our cases. Pathologic examination of the sensory ganglia in a few cases has disclosed an inflammatory process identical to that of Sjögren disease. Our attempts at treatment using plasma exchanges, IVIg, corticosteroids, and immunosuppressive agents have been mostly unsuccessful. Also mentioned here is a subacute or chronic idiopathic small-fiber ganglionopathy that affects function primarily. These patients complain of pain and burning in proximal body parts, including the face, tongue, and scalp with reduced sensation of pinprick in affected areas. The reflexes may be preserved and vibration sensory perception may be preserved. Our experience with such patients and anecdotal responses to treatment have been summarized (Gorson and colleagues 2008). Whether such aberrant proximal sensory complaints as “burning mouth syndrome” (see Chap. 9) are allied with this entity is not clear but they may occur together.

Idiopathic Autonomic Neuropathy Under this term is collected a group of subacute and chronic dysautonomias that on extensive evaluation cannot be attributed to diabetes, amyloidosis, autoimmune

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disease, Fabry disease, HIV, toxin exposure, or another systemic disease. A few cases will be found to be due to one of several rare mutations in genes, of which four sites have been described so far (SPTLC1, HSN2, IKBKAP, NTRK1). A number of idiopathic cases, almost half in one series (Suarez and colleagues, 1994), have been acute in onset and conform most closely to the “pure pandysautonomia” condition described as a variant of GBS. Others follow a subacute or chronic course and about one-fourth of these have a serum antibody that is directed against the acetylcholine receptor of sensory ganglia (Klein et al). Orthostatic hypotension is the leading feature; in those with the previously mentioned antibody, pupillary changes and difficulty with accommodation, dry mouth and dry eyes, and gastrointestinal paresis were the most common findings according to Sandroni and colleagues. Perhaps a subgroup is in some way related to Sjögren syndrome as sicca symptoms are prominent, but these later features could just as well be a component of the autonomic failure. There is not enough information to determine if all these cases are accounted for by one process or to judge the effects of various immune treatments.

Migratory Sensory Neuritis (Wartenberg Syndrome) The defining features of this unusual syndrome are searing and pulling sensations involving small cutaneous areas, that are evoked by extending or stretching the limb, as happens when reaching for an object, kneeling, or pointing with the foot (Wartenberg). The pain is momentary but leaves in its wake a patch of circumscribed numbness. Cutaneous sensory nerves must be involved in some way and are irritated during such mechanical maneuvers. The areas involved are usually proximal to the most terminal sensory distribution of nerves encompassing, for example, a patch on the lateral side of the hand and the proximal fifth finger or a larger region over the patella (these were the sites affected in three of our patients). Recovery of the area of numbness takes several weeks, but it may persist if the symptoms are induced repeatedly. Except for these patches of cutaneous analgesia, the clinical examination is normal. Selected sensory nerves may show abnormalities in conduction, but nerve conduction studies are for the most part normal. The many areas that may be affected in a single patient and have been described (Matthews and Esiri) and there may be an increase in the endoneurial connective tissue in a biopsied sural nerve. The syndrome may come in episodes over many years, without symptoms between attacks. A spurious diagnosis of multiple sclerosis is often made. The pathology is not certain, but some form of fibrosis or inflammation of cutaneous nerves has been suggested, perhaps similar to the condition of perineuritis described below.

Sensory Perineuritis Under this title, Asbury and colleagues (1972) described a patchy, burning, painful, partially remitting distal cutaneous sensory neuropathy. The pathologic picture was one of inflammatory scarring restricted to the perineurium, with compression of the contained nerve fibers. As with the Wartenberg syndrome above, reflexes and motor function were unaffected. Digital nerves, as well as the medial and

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lateral branches of the superficial peroneal nerve, were the ones most often involved. A trigeminal and occipital distribution of painful sensory symptoms has been described (Matthews and Squier) and one of the patients of Asbury and coworkers also had symptoms on the scalp. A Tinel sign is characteristically elicited by tapping the skin overlying the involved cutaneous nerves and is indicative of partial nerve damage and regeneration. The differential diagnosis includes numerous other forms of painful sensory neuropathy, but the patchy and painful, and often burning, quality of symptoms distinguishes this process. The diagnosis can only be established with certainty by biopsy of a distal cutaneous branch of a sensory nerve. Perhaps some of the large group of patients with “burning” feet may have a small-fiber neuropathy that affects intradermal nerve fibers in a similar way (see further on). Since the original report, the fibrosing perineurial pathologic changes that characterize perineuritis have been described in a number of polyneuropathies, mainly in diabetic patients but also in those with cryoglobulinemia, nutritional diseases, and malignancies (Sorenson et al). However, these patients displayed diverse clinical patterns of neuropathy, mainly mononeuritis multiplex and demyelinating neuropathy. Nevertheless, the pathologic feature of perineuritis may be less specific than initially thought but a perineuritis clinical syndrome is still a useful concept. A proportion of the idiopathic cases seem to respond to corticosteroids.

Celiac-Sprue Neuropathy Among the multitude of odd neurologic manifestations attributed to this disease, the best-known ones are cerebellar ataxia and myoclonus. In addition, Hadjivassiliou and colleagues have reported patients with a range of neuromuscular disorders in whom the neurologic symptoms antedated the diagnosis of the bowel disorder. A nondescript sensorimotor neuropathy was the most frequent, but one patient had mononeuropathy multiplex and Chin and colleagues have reported a multifocal neuropathy pattern. In a small prospective survey of treated celiac disease, approximately one-quarter had evidence of a polyneuropathy by nerve conduction testing, but the clinical findings were scant (Luostarinen and colleagues). Antigliadin antibodies (simple antibodies directed against gluten), as well as more specific anti-transglutaminase antibodies and histologic examination of a duodenal biopsy are confirmatory of the diagnosis. It is not clear how many neuropathy cases with celiac disease could be attributed to nutritional deficiency. We have not encountered a definite instance despite attempts to detect the special sprue antibodies in the evaluation of over 200 cases of otherwise obscure polyneuropathy.

Neuropathies in People Living with HIV (See Also Chap. 32) Patients infected with HIV are prone to several types of neuropathies, including a predominantly sensory type that may be painful, a lumbosacral polyradiculopathy, cranial (mainly facial nerve) and limb mononeuropathies, CIDP, GBS, and a vasculitic mononeuritis multiplex—none of

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which differs from the idiopathic or conventional varieties except that there is often a pleocytosis in the spinal fluid. Almost unique and common patterns in this group are the CMV cauda equina neuritis syndrome and an acute or subacute painful infiltrative lymphocytic neuropathy— the diffuse infiltrative lymphocytosis syndrome (DILS; Moulingier et al). Polyneuropathy may also be induced by antiviral agents that are used in the treatment of HIV infection, as discussed in Chap. 32.

SYNDROME OF POLYRADICULOPATHY WITH AND WITHOUT MENINGEAL INFILTRATION These are among the most clinically complex diseases of the peripheral nerves. Involvement of multiple spinal nerve roots produces a distinctive or sometimes confusing constellation of findings, usually quite different from those of polyneuropathy and from multiple mononeuropathies. As described earlier, muscle weakness caused by polyradiculopathy is characteristically asymmetrical and variably distributed in proximal and distal parts of the limbs, reflecting a pattern of muscles that share common root innervations (e.g., the combination of weakness in hamstring and gastrocnemius, or of iliopsoas, quadriceps, and obturator). However, muscles with similar innervation are not necessarily affected to the same degree because of the disproportionate contribution of a given root to each muscle. Sensory loss tends also to be patchy and to involve both the proximal and distal aspects of a dermatome. Pain is common in a radicular pattern, but sometimes only in the distal distribution of the root or in the back. The sensory findings tend to be less prominent than the motor ones. In keeping with nerve root pattern, certain tendon reflexes may be spared; a normal ankle jerk combined with an absent knee jerk, or the opposite, are particularly suggestive of a polyradiculopathy (or a lumbar plexopathy). Pain often takes the form of sharp jabs projected into the innervated zone of the involved root. As with mononeuritis multiplex, the cumulative effect of multiple root lesions can simulate a polyneuropathy in which case the tendency for polyradiculopathy to involve proximal muscles is the most helpful distinguishing feature. A special pattern of polyradiculopathy occurs wherein all the sensory roots are involved, simulating tabes dorsalis. The clinical state is similar to that of a sensory ganglionopathy described earlier. Large- and small-fiber sensory loss is combined with ataxia while power is normal and there is no atrophy. A prominent feature is shooting and burning pain. We have occasionally found sensory loss over the anterior abdomen and thorax in these cases, a finding more typical of chronic dying-back axonal polyneuropathy. Some of the diseases that affect nerve roots predominantly already have been discussed. They can be grouped into three broad categories: (1) diseases of the spinal column that compress adjacent roots; (2) infiltrative diseases of the meninges that secondarily involve the roots as they course through the subarachnoid space, mainly neoplastic of granulomatous infiltrations such as sarcoid; and

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(3) intrinsic neuropathies, inflammatory, infectious, or diabetic, that have a predilection for the radicular portion of the nerves. An elevated CSF protein and a pleocytosis usually accompany neoplastic or inflammatory meningeal diseases; the others show variable formulas in the spinal fluid. Often what appears to be a polyneuropathy on clinical grounds will be found to have an electrophysiologic pattern of root disease at multiple spinal levels. McGonagle and colleagues estimated that polyradiculopathies accounted for 5 percent of all cases referred to their EMG laboratory and our experience approximates this. Consequently, careful EMG and nerve conductions testing is the most useful ancillary examination in cases of complex neuropathic syndromes because the pattern of muscle denervation can be ascertained with greater certainty than by clinical means and a common root pattern can then be logically derived. Of great confirmatory value is the preservation of sensory potentials in nerves that innervate regions of sensory loss and supply weak and denervated muscles. This proves that the lesion is located proximal to the dorsal root ganglion and spares the peripheral sensory axons. Loss of the F and H late responses is also typical of polyradiculopathies. The proximal location of the lesion can be further corroborated by early evidence of weakness and denervation in the paraspinal, gluteal, or rhomboid muscles, which are supplied by nerves that arise very proximally from the roots. In axonal cases of neuropathy, these proximal muscles are the last to be involved. Among the acute and subacute meningeal radiculopathies, neoplastic infiltration (carcinomatous and lymphomatous) is the most common. Others are Lyme disease, sarcoidosis, herpes virus, arachnoiditis, AIDS-related cauda equina neuritis of CMV infection, or independently, EBV meningoradiculitis. In the past, meningeal syphilis, of course, was a common cause (tabes dorsalis). Diseases of the spine, exemplified by lumbar and cervical spondylosis, commonly impinge on nerve roots, as discussed in Chap. 10. Metastatic carcinoma of the vertebral bodies may compress one or several adjacent roots by encroaching on posterolateral recesses of the canal and proximal neural foramina. Among rare causes of polyradiculopathy is a chronic lumbosacral syndrome associated with dural eventrations surrounding nerve roots, which may complicate ankylosing spondylitis. However, one is often confronted by a pattern of subacute or chronic polyradiculopathy and abnormal CSF formula for which extensive examination fails to identify any of the diseases enumerated above. This idiopathic form of polyradiculopathy comes to our attention several times yearly. Some will turn out to have a lymphomatous infiltration at autopsy for which reason we have on occasion asked a neurosurgeon to remove a midlumbar (L2 or L3) motor rootlet for examination. Also particularly difficult diagnostically is a polyradiculopathy that involves the motor roots exclusively or predominantly and is indistinguishable from motor neuron disease except for the absence of widespread denervation or of progressive upper motor neuron signs and differing from the immune motor neuropathies discussed further on by the absence of conduction block.

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SYNDROME OF CHRONIC SENSORIMOTOR POLYNEUROPATHY In these common syndromes, reduced sensation, weakness, muscular atrophy, and loss of tendon reflexes progress over a period of months or years. Within this large category, two groups are distinguished. In the first and less chronic of the two, the neuropathy appears over months or a year or two. Comprising this group are acquired processes such as certain metabolic and immune-mediated polyneuropathies. Paraneoplastic neuropathies may also fall into this category, although they are more often subacute in onset, being almost fully developed in a matter of weeks. Leprous neuritis is the one infectious member of this group and also the one exception to the rule that all chronic neuropathies are more or less symmetrical in pattern. The polyneuropathies that make up the second group are far more chronic than the first, evolving insidiously over many years or decades; these are mainly the genetically determined diseases of the peripheral nervous system caused by specific genetic mutations.

Acquired Forms of Chronic Polyneuropathy Polyneuropathy Associated With Paraproteinemia The occurrence of a chronic sensorimotor polyneuropathy in association with an abnormality of serum immunoglobulins is recognized with increasing frequency, but its boundaries are still not well established as will be apparent in the following discussion. The excess blood protein, called a paraprotein or “M-spike,” is usually in the form of a monoclonal immunoglobulin. It may be an isolated abnormality or a by-product of a plasma cell malignancy, specifically multiple myeloma, plasmacytoma, or Waldenström macroglobulinemia. Several lines of evidence suggest that a pathogenetically active antibody against components of myelin or axon is present in at least some of these cases. Special forms of neuropathy are also associated with amyloidosis. Both the acquired and genetic forms of amyloidosis are discussed further on. Neuropathy with monoclonal gammopathy of undeterminedsignificance(MGUS,“benign”monoclonalgammopathy)  The association of a nonneoplastic IgM monoclonal protein and a neuropathy was first described by Forssman and colleagues and was treated as coincidental until Kahn (1980) established a compelling statistical association between the two conditions. A more direct relationship was established by the finding of antiperipheral nerve antibodies in some patients who had such a protein in their blood. This category of polyneuropathy is associated with a monoclonal or sometimes polyclonal excess of immunoglobulin (IgG, IgM, or IgA, rarely others, mainly with a kappa light chain components; see Kyle and Dyck). These cases are far more common than those caused by a malignant plasma cell disorder. In our experience, monoclonal proteins underlie the largest group of otherwise unexplained neuropathies in adults. The polyneuropathy associated with monoclonal gammopathy affects mainly, but not exclusively, males in

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the sixth and seventh decades of life. The onset is insidious over weeks and months or more, with numbness and paresthesias of the feet and then of the hands, followed by a relatively symmetrical weakness and slight wasting of these muscles. In some patients, sensory signs predominate. The tendon reflexes, eventually lost or diminished, may be preserved in the early phases of the illness. The course is usually slowly progressive, sometimes static after a year or so, and rarely remitting and relapsing. The CSF typically shows an elevation of the protein in the range of 50 to 100 mg/dL, and this is not due to passive diffusion of the excess paraprotein into the CSF. Most cases of polyneuropathy with monoclonal gammopathy have a demyelinating or mixed axonal– demyelinating pattern on the EMG and nerve conduction studies, but once the illness is well established, most will have predominantly axonal features. With few exceptions we have been unable to distinguish the axonal and demyelinating groups on clinical grounds or by their response to therapy (Gorson et al 1997; Ropper and Gorson 1998). Sural nerve biopsies show a loss of myelinated fibers of all sizes; unmyelinated fibers are mostly spared; hypertrophic changes, reflecting cycles of demyelination and remyelination with fibrosis are present in about half the cases according to Smith and colleagues. They found the monoclonal IgM antibody bound to surviving myelin sheaths and Latov and coworkers have shown that the serum IgM fraction often displays antimyelin activity. Typically, the monoclonal protein in the blood is present in a concentration much less than 2 g/dL and there is no evidence of multiple myeloma or other malignant blood dyscrasia. It should be emphasized that routine serum protein electrophoresis (SPEP) fails to detect the majority of these paraproteins; immunoelectrophoresis (IEP) or the more sensitive immunofixation testing is required. The bone marrow aspirate shows a normal or only mildly increased proportion of plasma cells, which are the source of the paraprotein and the plasma cells are not morphologically atypical as they are in myeloma. Insofar as myeloma becomes manifest in perhaps one-quarter of patients many years after the gammopathy has been recognized, the condition is termed monoclonal gammopathy of undetermined significance (MGUS), although the older term benign monoclonal gammopathy is less cumbersome. The importance of excess immunoglobulin as a cause of neuropathy can be appreciated by noting that 6 percent of patients referred to the Mayo Clinic with chronic polyneuropathy of unknown cause and as many as 20 percent in our clinical material and in other series have proved to have a monoclonal paraproteinemia (of course, the majority of patients with a blood paraprotein do not develop neuropathy). Despite the fact that IgG is the most frequent paraprotein in adults, a polyneuropathy is associated somewhat more often with the IgM class. Combining three large series of patients with neuropathy and monoclonal paraproteinemias (62 patients of Yeung et al, Gosselin et al, and our patients as reported by Simovic et al), 60 percent had IgM, 30 percent IgG, and 10 percent with IgA subclass paraproteins. An identical but infrequent condition exists in which only the light chain component of an immunoglobulin is

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overproduced by the plasma cells and is found exclusively in the urine (similar to the Bence Jones protein of multiple myeloma). Four-fifths of patients have had a kappa light chain component, as mentioned previously, although lambda light chain has special significance as discussed further on in relation to plasmacytoma and the polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. In our experience and in that of others, patients with IgM paraprotein more often have severe sensory findings and a demyelinative type of nerve conduction abnormality when compared with the IgG group. However, with the exception of the special antiMAG syndrome (see later), we have not found the extent of difference in clinical features and response to treatment between the immunoglobulin subclasses that has been reported by others (Simovic et al). Although more than a dozen specific antibodies against myelin and other components of nerve have been identified among the paraproteins, the ones that give rise to the most distinctive clinical syndromes, present in 50 to 75 percent of patients with IgM-associated neuropathies, are those that react with a MAG, related glycolipids, or sulfatide components of myelin (the latter are referred to as sulfate-3-glucuronyl paragloboside [SGPG] and related sulfatides). Proprioceptive sensory loss with gait imbalance, tremor, and the Romberg sign are typical findings in the group with anti-MAG activity, while weakness and atrophy tend to appear later in the illness. Other IgM antineural antibodies have a more tentative connection to polyneuropathy. It is reasonable to assume that IgG monoclonal gammopathies are also capable of causing chronic neuropathies, but the evidence is less compelling and based mainly on the frequency of their presence in cases of otherwise unexplained polyneuropathy. Indeed, it has been suggested that in many reported instances the association with neuropathy with IgG paraproteinemia is coincidental. The anti-MAG illnesses are relentlessly progressive at various rates in most patients but in about 15 percent of our patients with anti-MAG antibody the illness has been mild and static for years at a time, even without treatment. Because of the risk of myeloma or Waldenström disease, bone marrow examination is generally performed sometime in the course and particularly if the concentration of the paraprotein exceeds 3 g/dL or climbs progressively over years, or if other hematologic changes such as unexplained anemia or thrombocytopenia develop. Treatment  In most cases of uncomplicated monoclonal gammopathy with polyneuropathy that are associated with IgG or IgA paraproteins, particularly if not of long standing, plasma exchange may produce transient improvement for several weeks to months (Dyck et al, 1991). The treatment regimen generally is a total volume of approximately 200 to 250 mL/kg exchanged in each of 4 to 6 treatments over about 10 days and the removed plasma replaced with a mixture of albumin and saline. In patients who have IgM serum activity against specific components of myelin (particularly anti-MAG), the results of treatment have been inconsistent and generally less favorable. Plasma exchange alone has effected transient improvement in half of cases but sustained

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improvement in only 10 to 20 percent of our patients. Series of plasma exchanges every 2 to 4 months has sometimes resulted in transient responses. According to some reports, the response to immunosuppression with intravenous cyclophosphamide or fludarabine, mycophenolate, or oral chlorambucil, when coupled with plasma exchanges, has been somewhat better, at times allowing a reduction in the frequency of exchanges but our experience has generally not affirmed this. Rituximab, which has the appeal of having a preferential effect on the B-cell lymphocyte population, after initial enthusiasm based on small series, has given conflicting and generally negative results in several trials, including of anti-MAG neuropathy, but it may be reasonable to try in intractable cases. Improvement with high-dose infused immune globulin (IVIg) has been transiently effective in some of our cases with typical paraproteinemia and in 20 percent of those with anti-MAG neuropathy but the illness nonetheless progresses in most patients (Gorson et al, 2001). In almost all instances, immunosuppression and plasma exchanges or IVIg, if used, must be repeated indefinitely at intervals of one to several months as determined by the clinical course. An indwelling catheter is then usually required to allow repeated venous access. This group of neuropathies responds poorly or not at all to glucocorticoids.

POEMS Syndrome, Osteosclerotic Myeloma, and Multiple Myeloma A neuropathy associated with multiple myeloma has already been mentioned; it complicates 13 to 14 percent of cases of multiple myeloma and has a disproportionately high association with the osteosclerotic form of the disease. An abnormal monoclonal globulin (mainly with the kappa light chain component in multiple myeloma but lambda in the osteosclerotic type) is found in the serum of more than 80 percent of patients with myelomatous neuropathy. In a special and small group of patients with osteosclerotic myeloma, there is a predominantly demyelinating sensorimotor polyneuropathy and systemic disease termed POEMS (i.e., polyneuropathy of moderate severity is associated with organomegaly, endocrinopathy, elevated M protein, and skin changes, mainly hypertrichosis and skin thickening). The same process has been referred to as the Crow-Fukase syndrome in Japan, where the disease is prevalent. In many cases there is lymphadenopathy attributable to the angiofollicular hyperplasia of Castleman disease. Another characteristic feature of the osteosclerotic-related polyneuropathy is a greatly elevated CSF protein. The presence of the disease can be suspected from the presence of demyelinating features on the nerve conduction studies, an immunoglobulin spike in the blood, sometimes polyclonal or biclonal rather than monoclonal and, as mentioned, possessing a lambda light chain component. The diagnosis requires the demonstration of one or more osteosclerotic lesions by a radiographic survey of the long bones, pelvis, spine, and skull as well as a PET study, which usually shows the osteosclerotic lesions as highly active (a bone scan is insensitive) and a bone marrow examination, which shows a moderate increase in the number of welldifferentiated plasma cells. In most of our patients there have been several discrete bone lesions concentrated in

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the ribs and spine; the skull and long bones may harbor such lesions as well, or there may be a single lesion, which is often situated in the spinal column. Biopsy of a bone lesion is justified. The organomegaly and skin changes are apparently the result of high levels of circulating VEGF that is produced by the tumor and is useful in confirming the diagnosis. Treatment of POEMS The neuropathy that complicates a solitary plasmacytoma may improve markedly following irradiation or resection of the bone lesion. Multiple lesions or cases with no apparent bone lesions, including those in the POEMS syndrome, may be treated with chemotherapy (melphalan and prednisone) and may lead to some improvement or stabilization in the neuropathy. Treatment with plasma exchange has yielded uncertain but generally positive short-term results in our patients. The value of plasma exchanged and IVIG have been difficult to affirm in trials. Drugs used to treat multiple myeloma have also been tried, with uncertain results. Autologous stem cell transplantation or bevacizumab (a monoclonal antibody directed against VEGF) have been used, also with mixed results (Kuwabara et al, 2008) and with some positive results in uncontrolled series (Karam et al). Waldenström macroglobulinemia  Macroglobulinemia was the term applied by Waldenström to a systemic condition occurring mainly in older persons and characterized by fatigue, weakness, and a bleeding diathesis. Immunoelectrophoretic examination of the blood disclosed a marked and mostly monoclonal increase in the IgM plasma fraction. About half of patients with Waldenström disease and polyneuropathy will have specific anti-MAG antibodies, similar to the approximately one-third of patients with nonmalignant IgM paraproteins. (An uncertain proportion of patients with a “benign” IgM paraprotein will, over the years, develop Waldenström disease.) A few patients with Waldenström hyperproteinemia have a hyperviscosity state manifest by diffuse slowing of the retinal and cerebral circulations, giving rise to episodic confusion, coma, impairment of vision, and sometimes strokes (Bing-Neel syndrome). Most reports attribute this syndrome to infiltration of neural by malignant plasma cells rather than to hyperviscosity. The polyneuropathy, when present, evolves over months or longer and may be asymmetrical, particularly at the onset, but becomes bilateral, mainly sensory, and distal. The pattern in our patients has been very slowly progressive, and initially limited to the feet and legs with sensory ataxia and loss of knee and ankle jerks. The CSF protein is usually elevated and the globulin fraction increased. In a case recorded by Rowland and colleagues, the polyneuropathy was purely motor and simulated motor neuron disease. Treatment is discussed further on. Cryoglobulinemia  As mentioned in the section on vasculitic neuropathies, cryoglobulin, a serum protein that precipitates on cooling, is usually of the IgG or IgM type and most often polyclonal. While cryoglobulinemia may occur without any apparent associated condition (essential cryoglobulinemia), it also accompanies a wide variety of disorders such as multiple myeloma, lymphoma, connective tissue disease, chronic infection, and particularly, hepatitis C. Peripheral neuropathy occurs in a small proportion both

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of the essential and symptomatic cases. Occasionally the neuropathy evolves over a period of a few days and remits rapidly. More often it takes the form of a distal symmetrical sensorimotor loss, which develops insidiously (76 percent of the cases in the series reported by Gemignani et al) in association with the Raynaud phenomenon and purpuric eruptions of the skin. Initially, the neuropathic symptoms may consist only of pain and paresthesias that may be precipitated by exposure to cold (as often, there is no cold sensitivity). Later, weakness and wasting develop, more in the legs than in the arms, and more or less in the same distribution as the vascular changes. In some cases there may be a mononeuropathy multiplex with severe denervation in the territory of the involved nerves (9 percent of the series reported (Gemignani et al; see also Garcia-Bragado et al). In a few cases, the two neuropathic syndromes have been combined. As remarked earlier, detection of cryoglobulin requires special handling of the blood sample. The specimen should be carried to the laboratory in a bath of warm water to prevent precipitation of the protein. Any of the paraproteinemic states may be associated with an amyloid polyneuropathy, a subject accorded a separate section later in the chapter. The pathology of the cryoglobulinemic and macroglobulinemic neuropathies has been incompletely studied and the mechanisms by which these disorders cause neuropathy are uncertain. One presumes that some component of the paraprotein acts as an antineural antibody or that deposition of the protein is in some way toxic to the nerves or to the endoneurial vessels. In our most thoroughly autopsied case, there was widespread distal axonal degeneration of nonspecific type without amyloid deposition or inflammatory cells; yet in other reported cases, amyloid has been found in the nerve and the neuropathy has been attributed directly to it. Immune deposits of IgM had impregnated the inner layers of the perineurium in one reported case (Ongerboer de Visser and colleagues. Others have made similar observations (Dalakas and Engel 1981b). In yet other instances, the neuropathy of cryoglobulinemia is a result of the intravascular deposition of cryoglobulins, causing a more acute vasculitic mononeuropathy multiplex, as discussed earlier (Chad et al). Treatment  In the Waldenstrom-related neuropathies, the use of prednisone, the alkylating agent chlorambucil, cyclophosphamide, and repeated plasma exchange has at times led to improvement both in the systemic and neuropathic symptoms, although recovery has been incomplete. The monoclonal antibody rituximab has been effective in small studies. The optimal treatment of cryoglobulinemic neuropathy has not been settled. We have used plasma exchange and added immunosuppression in the vasculitic variety of this disease.

Acquired Primary (Nonfamilial, AL) Amyloid Neuropathy A heredofamilial type of amyloidosis (familial amyloidosis [FA]) is well known and is described further on. In addition, there are numerous sporadic instances of a peripheral neuropathy caused by amyloid deposition. As in the familial variety, the heart, kidneys, and gastrointestinal tract may be involved. This acquired type of amyloid disease has also been called primary systemic amyloidosis to distinguish

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it from the variety associated with chronic diseases. The term is misleading in that in most cases the amyloid is derived from a circulating paraprotein, but the proportion of “benign” and malignant plasma cell sources of the protein varies from one report to another. For example, in a large series (Kyle and Bayrd), only 26 percent of patients with primary amyloidosis had a malignant plasma cell dyscrasia. This agrees with our own experience, but other series have found rates of myeloma as high as 75 percent. In any case, 90 percent of primary amyloidosis is the result of a monoclonal protein in the blood (rarely polyclonal). Macrophage enzymes cleave the larger immunoglobulin molecules and the light chains aggregate to form amyloid deposits in tissue, or the plasma cells may produce light chains directly (“light chain disease”). Lambda light chain predominates in the idiopathic variety of amyloidosis and kappa light chain is more common in myeloma. In a few cases, the light chain is found only in the urine (as Bence Jones protein). In primary amyloidosis there is no evidence of preceding or coexisting disease (except the association with paraproteinemia or multiple myeloma). Secondary amyloidosis (AA), an infrequent occurrence nowadays, is the result of chronic infection or other chronic disease outside the nervous system and, as a rule, is not associated with neuropathy (e.g., it is not cited in the large recent series by Lachmann and colleagues, 2007). In contrast, familial amyloidosis, a third variety, is almost invariably associated with neuropathy but is associated with a paraprotein in only a small proportion of cases and the amount of immunoglobulin is small (see “Inherited [Familial Amyloidosis] Amyloid Neuropathies” later). Primary amyloidosis is mainly a disease of older men, the median age at the time of diagnosis being 65 years. In our clinical material, the majority of the patients have had peripheral neuropathy, but this may reflect a referral bias as in other series, less than one-third were so affected (Kyle et al). The neuropathic symptoms and signs are similar to those of hereditary amyloid polyneuropathy discussed further on, but the progress of the disease is considerably more rapid. The initial syndrome is primarily sensory—numbness, paresthesias, and very often, acral pain—signs that are mainly characteristic of involvement of small-diameter sensory fibers (loss of pain and thermal sensation). It is the painful aspect and the autonomic features discussed later that distinguish this disease from the other paraproteinemic neuropathies and indeed, from most other polyneuropathies. Weakness follows, initially limited to the feet but becoming more extensive as the disease progresses and eventually spreads to the hands and arms. Only later is there loss of mainly large fibers that mediate sensations of touch, pressure, and proprioception. Twenty-five percent of patients have carpal tunnel syndrome from infiltration of the flexor retinaculum. Exceptionally, patterns other than the painful and sensory predominant polyneuropathy have been associated with amyloidosis; preferential involvement of motor nerves, lumbar roots, plexopathy, and amyloidomas involving single nerves (sciatic, facial, trigeminal) have been reported. Unusual cases of mononeuritis multiplex are difficult to explain.

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Autonomic involvement can be severe in amyloid neuropathy (familial or primary) and may become evident early in the course of the illness; several of our patients presented with disturbances of gastrointestinal motility such as episodic diarrhea and orthostatic dizziness or erectile dysfunction and bladder disturbances. The pupils may show a slow reaction to light, or there may be a reduction in sweating. An infiltrative amyloid myopathy also occurs as a rare complication of the disease; it presents as an enlargement and induration of many muscles, particularly those of the tongue (macroglossia), pharynx, and larynx. Progression of the illness is relatively rapid, the mean survival being 12 to 24 months. An indolent neuropathy that evolves over years is unlikely to be a result of amyloidosis, although we have seen such a case. Death is a result of the renal, cardiac, or gastrointestinal effects of amyloid deposits, the manifestations of which are already evident in more than half of the patients who present with neuropathy. A nephrotic syndrome is also characteristic. Analysis of the serum and urine, searching for an abnormal paraprotein, is the most useful screening test for amyloid neuropathy. Next in value is a microscopic examination of a biopsy of the abdominal fat pad, gingiva, or rectal mucosa for deposition of amyloid in tissue or blood vessels. Biopsy of the sural nerve or of the involved viscera has a high diagnostic yield; muscle tissue gives variable results. The liver biopsy is positive in virtually all cases of primary amyloid and the kidney shows amyloid infiltration in 85 percent. In several of our patients with a clinical syndrome typical of amyloid neuropathy but in whom amyloid was absent in the sural nerve, the diagnosis was established only after sequential biopsy of numerous sites (fat pad, kidney, liver). If the sural nerve is severely depopulated of nerve fibers, the amount of congophilic staining and the characteristic amyloid birefringence may be meager and yield a spuriously negative result. It is also critical to ensure the accuracy of congophilic staining by comparison with positive and negative control tissue from the same laboratory. The CSF has a normal or mildly elevated protein concentration, but this does not distinguish the neuropathic process from many others. It has been emphasized that 10 percent of patients who appear by all the usual criteria to have primary amyloidosis will be found to have a genetic type (Lachmann and colleagues 2002). However, as mentioned, only a small proportion of the latter group has a monoclonal gammopathy and it tends to be of low concentration (it has been estimated to occur in one-quarter of familial cases but we have not encountered it). This difference and the rapid progression of the primary acquired form assist in distinguishing it from the genetic type that is discussed further on. In addition to the more slowly evolving familial types, the differential diagnosis of acquired amyloid neuropathy includes the myelomatous varieties, toxic and nutritional small-fiber neuropathies, diabetic polyneuropathy, paraneoplastic polyneuropathy, Sjögren disease, and an idiopathic small-fiber sensory neuropathy, all of which cause pain and which we have encountered more frequently than amyloidosis. Treatment Of Acquired Amyloid Neuropathy  The prognosis of primary-acquired amyloidosis and its associated

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Chapter 43 Diseases of the Peripheral Nerves

neuropathy has been poor. Immunomodulation, immunosuppression (which may help the renal disease), or removal of amyloid by plasma exchange have been marginally effective with notable exceptions using daratumumab, bortezomib and cyclophosphamide (Kastritis et al). Another approach has been bone marrow suppression with high doses of melphalan followed by autologous stem cell replacement. Several such patients have survived for years with marked improvement in the neuropathy. Several small molecules designed to prevent the aggregation of amyloid fibrils have shown benefit in transthyretin amyloid. Novel treatments have emerged for the familial form of amyloid as discussed further on. Pain is a serious problem in the amyloid neuropathies that may be treated with transcutaneous fentanyl patches or with oral narcotic medications. Orthostatic hypotension responds to the use of leg stockings, midodrine, and mineralocorticoids, as well as sleeping with the bed elevated at the head so that the patient’s entire body is angled down toward the feet.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) This form of polyneuropathy was separated from acute inflammatory polyradiculopathy, or Guillain Barre syndrome, by Austin in 1958 based on a prolonged and relapsing course, enlargement of nerves, and responsiveness to corticosteroids. Excluding the duration of evolution, the acute and chronic forms are similar in many ways. Both are widespread polyradiculoneuropathies, usually with cytoalbuminologic dissociation of the CSF (raised protein concentration with few or no cells); both exhibit nerve conduction abnormalities characteristic of a demyelinating neuropathy (reduced conduction velocity and partial conduction block in motor nerves), and pathologically, both show similar multifocal perivenous inflammatory infiltrates. But there are also important differences, the most evident of which are the modes of evolution, responses to treatment, and prognosis. As a rule, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) begins insidiously and evolves slowly, either in a steadily progressive or stepwise manner, attaining its maximum severity after several months. From the beginning it may be asymmetrical or involve the arms predominantly. However, in a small proportion of patients (16 percent in the series of McCombe et al [1987b] and a smaller proportion in our own series) the disease at first emerges from a mild or moderate case of GBS, in which case the illness becomes relapsing or simply worsens slowly and progressively. An antecedent infection is usually not identified in patients with CIDP as it is in GBS. Furthermore, CIDP may be distinct immunologically from GBS, insofar as certain HLA antigens occur with greater frequency in patients with CIDP than they do in the normal population, whereas there are no clear HLA propensities in patients with GBS. Finally, in contrast to acute GBS, many cases of CIDP respond favorably to the administration of prednisone. An ambiguity is introduced here because, as mentioned in the section on GBS, a group of patients has been described with polyneuritis in whom weakness progressed steadily for 4 to 12 weeks and who responded to corticosteroids (subacute

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GBS), in such cases, blurring the distinction between GBS and CIDP (Hughes et al, 1992). Chronic symmetric sensorimotor loss and areflexia coupled with nerve conduction findings of demyelination essentially defines the illness. Elevated spinal fluid protein concentration is so frequent that it might be added as a diagnostic criterion. The typical findings in nerve conduction studies are of multifocal conduction block as described in Chap. 2; prolonged distal latencies (“distal block”); nerve conduction slowing to less than 80 percent of normal values in several nerves; loss of late responses; and dispersion of the compound muscle action potentials— all reflecting demyelination in motor nerves. One or several of these changes have been present in 75 percent of our patients (Gorson et al, 1997). In the early stages of the disease, demyelinating features must be carefully sought by testing multiple nerves at several sites along their courses. After several months there is often some degree of axonal change (30 percent of our series), but the fundamental process continues to be one of multiple foci of demyelination. A fairly dependable finding is the absence of denervation changes early in the illness despite weakness and reduced amplitude of the motor action potential (indicative of a demyelinating block to conduction at a proximal site). Several large series of CIDP cases decades ago are available. In a study of 53 patients in whom the neuropathy progressed for more than 6 months, the clinical course was monophasic and slowly progressive in about one-third, stepwise and progressive in another third, and relapsing in the remaining third (Dyck and colleagues, 1975). The periods of worsening or improvement were measured in weeks or months. Weakness of the limbs, particularly of the proximal leg muscles, or numbness, paresthesias, and dysesthesias of the hands and feet were the initial symptoms. In 45 of the 53 patients in that series, the signs were those of a mixed sensorimotor polyneuropathy with weakness of the shoulder, upper arm, and thigh muscles in addition to motor and sensory loss in the distal parts of the limbs. In five patients the neuropathy was purely motor, and in three, purely sensory. Cranial nerve abnormalities were distinctly unusual. Enlarged, firm nerves were found in six patients. Not emphasized in their series is the common occurrence of a cerebellar-like tremor in cases of long standing. In another series (McCombe et al 1987a and 1987b) comprising 92 patients, two major subgroups were recognized: relapsing and nonrelapsing ones. In our own series of now over 100 patients, we have been impressed with several variant patterns of clinical presentation. In approximately 10 percent, numbness and weakness of the hands preceded involvement of the feet, which is unusual in other polyneuropathies, and a sensory ataxic form, a purely motor form, and mononeuropathies superimposed on a mild generalized polyneuropathy each accounted for approximately 5 percent. As mentioned earlier, a small proportion of cases began as acute GBS but continue to progress or relapse in the following months (Gorson et al, 1997). Another comprehensive account of the disease have been given by Hughes and associates. All of these studies have included cases with clinical progression for longer than 8 or 12 weeks; thus

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CIDP has come to be defined in part by a progressive polyneuropathy of this duration. As might be imagined from the experience with GBS, there are variant syndromes that align with CIDP but have special clinical characteristics. The best characterized of these is multifocal conduction block (called multifocal acquired demyelinating sensory and motor neuropathy, or MADSAM). Also described is a polyradicular process that presents as an ataxic illness with large fiber attributable sensory loss and spared sensory nerve action potentials (see Sinnreich et al), and a slowly progressive distal neuropathy (distal acquired demyelinating symmetrical neuropathy; DADS). In the latter, there are distal sensory and sometimes motor, disturbances and greatly prolonged distal latencies in most patients, and two-thirds have an associated IgM monoclonal gammopathy with kappa light chain component; the illness responds poorly to treatment, aligning it clinically in some respects with the anti-MAG neuropathies but in most clinical and electrophysiologic features appearing to be a variant of CIDP (Katz et al). The status of a predominantly axonal polyneuropathy that clinically simulates CIDP and responds to some extent to the same immunomodulating treatments has been described (Uncini and colleagues and Gorson and Ropper). The present authors have the impression that it is an immune-mediated neuropathy comparable to CIDP but with preferential destruction of axons rather than of myelin. Its frequency as a cause of acquired polyneuropathy is unknown, but we see several new cases every year. Also recognized is the frequency (up to 25 percent of the patients in some series, less often in our experience) with which there was a parallel systemic condition such as paraproteinemia, lymphoma, an undifferentiated reactive adenopathy or lupus, in association with an inflammatory demyelinating polyneuropathy (even aside from the rare DADS process mentioned above). These associations create problems in nosology that can be reconciled by labeling a given instance as, for example, “CIDP with paraproteinemia” or “CIDP with lupus,” thus separating such cases from the idiopathic variety but the distinctions are tenuous. These symptomatic inflammatory polyneuropathies respond to corticosteroids, albeit unpredictably, and to treatment of the underlying disease. Laboratory features  The CSF protein is elevated in more than 80 percent of patients with CIDP, typically in the range of 75 to 250 mg/dL. In rare instances there is papilledema and a pseudotumor cerebri syndrome (see Chap. 29) in relation to extremely high levels of CSF protein (usually >1,000 mg/dL). Elevation of the CSF gamma globulin fraction and a mild lymphocytic pleocytosis are found in 10 percent of patients (often in those who are HIV-seropositive), a considerably higher percentage than in our series. In sural nerve biopsy material, half are found to have interstitial and perivascular infiltrates of inflammatory cells, although one expects that most nerves would show these changes if a sufficient number could be sampled. Some specimens show only demyelination, or in cases of long standing, severe depletion of all nerve fibers. As in GBS, the demyelination appears to be affected by T cells and macrophages within the endoneurium and perineurium. The loss of myelinated fibers is variable and many of

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the remaining fibers are seen to be undergoing wallerian degeneration or show changes of segmental demyelination or demyelination-remyelination. Onion-bulb formations are conspicuous in recurrent and relapsing cases. The few adequate autopsy studies have shown only minimal or patchy inflammation and a considerable degree of axonal damage, probably reflecting the long duration of illness before examination. The presence of endoneurial and subperineurial edema has been emphasized by Prineas and McLeod. Treatment  Several trials have shown a short-term benefit from the intravenous infusion of high doses of gamma globulin (IVIg, total 2 g/kg in divided infusions over 2 to 5 days, see Hahn et al, 1996b. More than half of our patients have responded to this treatment, albeit for only several weeks or months, after which the infusions must be repeated to maintain clinical improvement. A desire to spare patients the side effects of indefinite prednisone administration (see later) makes this mode of therapy a reasonable alternative, in some cases for almost 10 years without ill effects. Patients who require treatment at such short intervals as to be impractical have benefited from the addition of small doses of prednisone or of an immunosuppressive drug as described in the following text. The main drawbacks of IVIg are its expense and the several hours required for its infusion. Rare instances of nephrotic syndrome, aseptic meningitis, serum sickness, thrombotic venous, or arterial occlusion, including stroke and hypotension, have been reported, particularly if the infusion is too rapid. Half of patients with CIDP also respond well to plasma exchanges. In a prospective double-blinded trial (Dyck and colleagues, 1986a) found that plasma exchange administered twice weekly for 3 weeks had a beneficial effect on both neurologic disability and nerve conduction. The response to plasma exchange in our patients has been comparable to that obtained with IVIg and with steroids, but we have discerned that some patients respond to one type of treatment and not another. The effects of plasma exchanges in most patients subside in 10 to 21 days, or even less; in some, the response lasts longer (Dyck and colleagues, 1986a) and Hahn and colleagues, 1996a). For these reasons we have often tried plasma exchange or immune globulin before committing a patient to long-term treatment with prednisone. The relative ease of administering IVIg favors its use first, followed by a series of plasma exchanges if there is no improvement. When there is a clear response, 3 or 4 brief series of plasma exchanges or repeated infusions of immune globulin may suffice to bring the patient to an improved level of function. These treatments can be supplemented by small doses of prednisone when frequent infusions or exchanges become impractical. It has been our experience that in about one-third of cases, IVIg and plasma exchange cease to have benefit after repeated use for 1 or more years. The ideal regimen for either treatment has not been established and is often guided by the clinical examination and reports from the patient about return of symptoms after an interval of weeks or months after each treatment. One of the most difficult problems in this field is the lack of useful clinical measurements to guide treatment with IVIg and plasma exchange and even the proper

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Chapter 43 Diseases of the Peripheral Nerves

adjustment of the dose of corticosteroid. Often, one may be influenced by the patient’s fear of losing any ground and even slight changes in sensory or motor symptoms. Glucocorticoids were formerly the mainstay of therapy, but many patients become dependent on the medication and correspondingly suffer side effects. Our approach has been to use corticosteroids as an adjunct to one of the previously mentioned treatments, but other centers use them first. The usual regimen begins with 60 to 80 mg of prednisone daily that is tapered over months to the lowest effective dose, typically 25 to 40 mg. Without substantiation by a controlled trial, we have found that corticosteroids can be withdrawn without relapse in some patients by slow tapering over many months or a year. Attempts to withdraw the steroids more quickly have led to further cycles of relapse. A number of patients will have no response to glucocorticoids within the first 1 or 2 months but will improve if treatment is continued. Some investigators have found that the earliest improvement occurs only after 2 months of treatment and is maximal at approximately 6 months (Barohn and colleagues 1989). In addition to all the wellknown side effects, the drug may produce tremor or exaggerate the tremor caused by the neuropathy. Long remissions lasting several years have been reported with the use of pulses of orally administered high-dose or daily glucocorticoids (Eftimov and colleagues) using dexamethasone 40 mg per day for 4 days, repeated for 6 cycles, or daily prednisolone, 60 mg for 6 weeks. Should a sustained trial of prednisone therapy prove unsuccessful, a course of azathioprine (for at least 3 months), 3 mg/kg in a single daily dose, has been recommended (Dalakas and Engel, 1981a), but a controlled trial has failed to show benefit from this combination and we have had little success with it. When the preceding measures prove unsatisfactory, cyclophosphamide, mycophenolate, rituximab, or another similar immunosuppressive medication can be added, but we have been unable to draw any firm conclusions as to the effectiveness of these combined regimens. High-dose cyclophosphamide has proven helpful in several cases under our care, although it has often failed (Brannagan et al and Brannagan that lists the applicable clinical trials). The usual regimen is 50 mg/kg IV daily for 4 days followed by granulocyte-stimulating factor beginning on the tenth day until the absolute neutrophil count recovers. Individual reports of successful treatment by autologous stem cell transplantation after high-dose chemotherapy have appeared but 1 patient relapsed after 5 years (Vermuelen and van Oers). This may become an option in severe and treatment-resistant cases. We have no explanation for the remarkable improvement and continued good health of a few of our patients after a severe toxic bacterial infection (Ropper, 1996). It has been stated that patients with discrete relapses have a better prognosis than those with a progressive course. In one series (McCombe’s et al, 1987b), 73 percent were said to have eventually recovered, but the long-term outcome has generally been poor. In fewer than 10 percent of patients has the disease finally remitted; additionally, unexplained remission occurs occasionally. The 5-year followup of 38 patients (Kuwabara and colleagues) gives a

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figure of 49 percent with full or partial remission, far higher than in our series.

Multifocal Motor Neuropathy (MMN) and Multifocal Conduction Block Several polyneuropathies that share many of the features of CIDP have been delineated based on unique clinical, immune, or electrophysiologic attributes. These include particularly multifocal motor neuropathy (MMN) and multifocal conduction block (also called MADSAM, as mentioned earlier). The latter has as its main feature a block of mixed nerve conduction at focal sites in a limited number of nerves as described earlier. In multifocal motor neuropathy, only blocks in motor nerve conduction are evident. There are similarities in clinical features and response to treatment between the two entities, but the purely motor nature of MMN (Delmont et al), makes it useful to separate them. Multifocal motor neuropathy, but not multifocal conduction block, is associated in half or more of cases with a particular IgM antibody, anti-GM1, directed against a ganglioside component of peripheral myelin (Pestronk et al). For this reason, some view this illness as belonging to the class of paraproteinemic neuropathies (see earlier and Simmons et al) and it is distinctive enough clinically to be categorized separately. Its importance as a clinical entity lies in the similarity of the clinical picture to a purely lower motor neuron type of amyotrophic lateral sclerosis (ALS) and, unlike ALS, its potential responsiveness to treatment. The pathophysiologic role of anti-GM1 antibodies is displayed by a case of transplacental transmission of a motor neuropathy to a neonate (Attarian et al). Multifocal motor neuropathy and motor conduction block predominate in men. They usually begin with an acute or subacute motor mononeuropathy, manifest, for example, as weakness of the wrist or foot-drop, and are often joined insidiously by another focal motor palsy. The process is painless, unlike vasculitic mononeuritis multiplex, involves the nerve incompletely, and, in its usual form, is unaccompanied by any sensory symptoms such as paresthesias or numbness. Despite the initially demyelinating character of the disorder, there is almost always atrophy of the weakened muscle within months and there may be a few fasciculations, thus simulating ALS. Nevertheless, the weakness tends to be disproportionate to atrophy. Usually, the tendon reflex is lost or muted in an affected region, but for unexplained reasons, some patients have one or more brisk reflexes. Our experience has been that this latter reflex change does not reach the point of appearing “pathologic” and that clonus and Babinski signs are categorically not part of the illness, as they are in ALS. When there is an association of the motor features with sensory symptoms or sensory loss and there is slowing of sensory conduction in regions of motor conduction block (multifocal conduction block), the acronym MADSAM (multifocal acquired demyelinating sensory and motor neuropathy) has been used as noted earlier, but the disorder, while similar to multifocal conduction block, more resembles CIDP. This conforms to what had been called Lewis-Sumner syndrome (Lewis et al, 1982) based on the description by these authors and their colleagues of subacute, painless asymmetric, distal multiple

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mononeuropathies. The ulnar and median nerves were involved in their patients and there was motor conduction block and sensory slowing in affected nerves. Curiously, two of their five original patients had optic neuritis, a feature not reported subsequently. The disease is not directly connected to antibodies against GM1, but a few patients with the sensorimotor disorder will display them. Treatment  For multifocal motor conduction block and motor neuropathy, with or without anti-GM1 antibodies, IVIg infusions have been effective, albeit temporarily, in more than half of patients. Some authoritative clinicians favor the early addition of rituximab in treatment-resistant cases or when the frequency of infusions is unsustainable and if that fails, cyclophosphamide. Other immunemodulating drugs have been tried in small series with various results. There is no response to corticosteroids. The MADSAM illness responds similarly to corticosteroids, IVIg, or plasma exchange, similar to the effects of these approaches in CIDP.

Uremic Polyneuropathy Polyneuropathy is among the most common complications of chronic renal failure. Robson has estimated that neuropathy complicates end-stage renal failure in twothirds of patients who are about to begin dialysis therapy. Bolton’s figures from past decades are much the same; 70 percent of his patients being dialyzed regularly had polyneuropathy and in 30 percent of all his patients, it was moderate or severe in degree. As described originally by Asbury and associates (1963), the neuropathy takes the form of a painless, progressive, symmetrical sensorimotor paralysis of the legs and then of the arms. In some patients, the syndrome begins with burning dysesthesias of the feet or with sensations of creeping, crawling, and itching of the legs and thighs, which tend to be worse at night and are relieved by movement (comparable to “restless legs” syndrome described in Chap. 18). Renal failure that is accompanied by diabetes gives rise to a particularly severe form of polyneuropathy. The combination of muscle weakness and atrophy, areflexia, sensory loss, and the graduated, distally predominant distribution of the neurologic deficit in the limbs leaves little doubt about the neuropathic nature of the disorder. Usually the neuropathy evolves slowly over many months. Infrequent instances of a more acute sensorimotor polyneuropathy that have been reported occur mainly in diabetic patients receiving peritoneal dialysis as discussed earlier (Ropper, 1993; Asbury et al, 1963). A rare uremic polymyositis with hypophosphatemia has also been described. The neuropathy has been observed with all types of chronic kidney diseases. More important to the development of chronic neuropathy than the nature of the renal lesion are the duration and severity of the renal failure and symptomatic uremia. With long-term hemodialysis, the neuropathic symptoms and signs stabilize but improve in relatively few patients. In fact, rapid hemodialysis may worsen the polyneuropathy (or perhaps its symptoms) temporarily. Peritoneal dialysis appears to be more successful than hemodialysis in improving the neuropathy, but this observation has not been firmly established. Complete recovery,

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occurring over a period of 6 to 12 months, usually follows successful renal transplantation for reasons given later. The pathologic findings are those of a nonspecific and noninflammatory axonal degeneration. In rapidly progressive cases, there is a tendency for the large fibers to be more affected; this is evident particularly on electrophysiologic testing that shows slowing of nerve conduction velocities, but there is no conduction block as occurs in other acquired demyelinating polyneuropathies. In all types of uremic polyneuropathies, pathologic changes are most intense in the distal segments of the nerves with the expected chromatolysis of their cell bodies. The cause of uremic polyneuropathy is unknown. What has been called the “middle molecule” theory is plausible. The end stage of renal failure is associated with the accumulation of toxic substances in the range of 300 to 2,000 kDa molecular weight. Furthermore, the concentration of these substances, which include methyl guanidine and myoinositol, has been shown to correlate with the degree of neurotoxicity (Funck-Brentano et al). These toxins (and the clinical signs of neuropathy) are not greatly reduced by hemodialysis. In contrast, the transplanted kidney effectively eliminates substances of wide-ranging molecular weights, which would account for the almost invariable improvement of neuropathy after transplantation. As is the case with uremic encephalopathy, urea alone given to experimental animals and in controlled studies of humans, does not seem capable of inducing a metabolic neuropathy.

Alcoholic–Nutritional Polyneuropathy As described at length in Chap. 41, in virtually all patients with alcoholic–nutritional polyneuropathy who remain untreated with vitamin and protein restoration, the weakness and atrophy of the legs, and to a lesser extent the arms, may reach an extreme degree. Thus, this disease, although subacute in its evolution as described earlier in the chapter, becomes a frequent cause of chronic polyneuropathy. There are usually prominent sensory features and considerable acral pain and allodynia. Certain cases of diabetic neuropathy behave similarly.

Leprous Polyneuritis This is the best example of an infectious neuritis, caused by the direct invasion of nerves by the acid-fast Mycobacterium leprae. The disease is still frequent in India and Central Africa and there are many lesser endemic foci, including parts of South America and Florida, Texas, and Louisiana, which border the Gulf of Mexico. Limited outbreaks have been reported during treatment for HIV, with armadillos as the probable intermediate host. The initial lesion in leprosy is an innocuous-appearing skin macule or papule, which is often hypopigmented and lacking in sensation; it is caused by the invasion of cutaneous nerves by M. leprae. In patients with a degree of immunologic resistance to infection, the disease progresses no further than this stage, which is spoken of as indeterminate leprosy, or it may evolve in several ways, depending mainly on the resistance of the host. The bacilli may be locally invasive, producing a circumscribed epithelioid granuloma that involves cutaneous and subcutaneous nerves

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Chapter 43 Diseases of the Peripheral Nerves

and results in a characteristic hypopigmented patch of superficial numbness and sensory loss, particularly in cooler areas of skin noted below (tuberculoid leprosy). The underlying subcutaneous sensory nerves may be palpably enlarged. If a large nerve in the vicinity of the granuloma is invaded (the ulnar, median, peroneal, posterior auricular, and facial nerves are most frequently affected), a sensorimotor deficit in the distribution of that nerve is added to the patch of cutaneous anesthesia. In contrast to the limited tuberculoid variety of leprosy, lack of resistance to the organism permits the proliferation and hematogenous spread of bacilli and the diffuse infiltration of skin, ciliary bodies, testes, lymph nodes, and nerves (lepromatous leprosy). Widespread invasion of the cutaneous nerves produces a symmetrical pattern of pain and temperature loss involving the pinnae of the ears (earlobes) and nose, as well as the dorsal surfaces of hands, elbows, forearms, and feet and anterolateral aspects of the legs—a distribution that is determined by the relative coolness of these parts of the skin. This temperature-dependent pattern is the most characteristic feature of the disease, as pointed out by our colleague TD Sabin. The sensory maps he has drawn (Fig. 43-4) are typical of established cases. The process evolves over years. Eventually, the anesthesia spreads to involve most of the cutaneous surface. Extensive sensory loss is followed by impaired motor function owing to invasion of muscular nerves where they lie closest to the skin (the ulnar nerve is the most vulnerable). There is loss of sweating in areas of sensory loss but otherwise the autonomic nervous system is unaffected. In distinction to other polyneuropathies, tendon reflexes are usually preserved in leprosy despite widespread sensory loss. Probably this is the result of sparing of most of the muscular and larger sensory nerves. Because of widespread anesthesia, injuries may pass unrecognized, with resultant infections, trophic changes, and loss of tissue. Variations in host immunity result in patterns of disease having both tuberculoid and lepromatous characteristics (dimorphous leprosy). Erythema nodosum occurs in a few cases. The diagnosis can be made from a skin scraping or biopsy, but multiple samples are often required. The findings on nerve conduction studies are varied, but they usually include findings that are consistent with a generalized but heterogeneous sensorimotor polyneuropathy that includes features of demyelination such as slowed nerve conduction velocities, temporal dispersion and occasionally, conduction block. Treatment  All forms of leprosy require long-term treatment with sulfones (dapsone being the most commonly used), rifampin, and clofazimine. The skin lesions of lepromatous leprosy are responsive to thalidomide, which itself may cause a sensory neuropathy (Barnhill and McDougall). Reactivation of disease, or a conversion from the tuberculoid to the lepromatous pattern, may occur during times of reduced immunity.

Polyneuropathy With Hypothyroidism The status of this disorder is uncertain and the authors have not encountered a definite case. Although characteristic disturbances of skeletal muscle are known to complicate hypothyroidism, the demonstration of a

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Response to Pinprick Normal Diminished Absent

Ventral

Dorsal

Pinprick Normal Decreased Lost

Figure 43-4.  Patterns of sensory loss in leprosy. The localization of these areas to cooler portions of the body is unique to this disorder. There is almost universal analgesia but sparing of warmer regions such as the midline of the back, popliteal and antecubital spaces, lower abdomen and groin, and the head and neck. (From The New England Journal of Medicine, Sabin TD, Preservation of sensation in a cutaneous vascular malformation in lepromatous leprosy, 282: 1084-1085. Copyright © 1970 Massachusetts Medical Society. Reprinted with permission.)

definite polyneuropathy has been infrequent. However, a number of elderly myxedematous patients complain of weakness and numbness of the feet, legs, and, to a lesser extent, hands, for which no other explanation can be found. Loss of reflexes, diminution in vibratory, jointposition, and touch-pressure sensations, and weakness in the distal parts of the limbs are the usual findings (Dyck and Lambert). The neuropathic manifestations are seldom severe. Nerve conduction velocities are slowed and the protein content of the CSF is usually increased

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to more than 100 mg/dL. Possibly the latter finding is a reflection of the increased protein content of the serum in the hypothyroid state. The subjective improvement and complete or near-complete reversibility of neuropathic signs following treatment with thyroid hormones provides evidence of a hypothyroid etiology. In biopsies of nerve, an edematous protein infiltration of the endoneurium and perineurium, a kind of metachromatic mucoid material, has been seen. Dyck and Lambert (who should be credited for drawing attention to this neuropathy) noted segmental demyelination in teased fiber preparations. In electron-microscopic sections, a slight increase in glycogen, acid mucopolysaccharides, and aggregates of glycogen and cytoplasmic laminar bodies in Schwann cells have been observed by others. Polyneuropathy of sensorimotor type has also been observed in association with a syndrome of chronic lymphocytic thyroiditis and alopecia (Hart et al).

Idiopathic Small-Fiber Sensory Polyneuropathy (Numb, Burning Feet Syndrome) This, of course, does not have the status of a single entity, but all neurologists encounter numerous cases of a relatively nonprogressive idiopathic sensory polyneuropathy, mainly in older patients. Paresthesias of feet and lower legs, sensory loss, and absent ankle reflexes are the usual findings. The hands may be mildly affected, but leg weakness and imbalance are absent or minor. A painful variety is also known (see later). The most common situation in our experience has been one that affects elderly women with slowly progressive (over years) burning and numbness of the feet, ascending to the ankles or midcalves. There are few findings on examination. Often, there is only mild loss of pinprick and thermal sensation; ankle reflexes may or may not be reduced. There is little progression over the years. Most of these cases are idiopathic, but there is a broad differential diagnosis, including the diseases mentioned earlier (Mendell and Sahenk; Table 43-5 is adapted from their discussion). Table 43-5 CAUSES OF PAINFUL SENSORY NEUROPATHY Common  Nutritional   Idiopathic in the elderly  Diabetes  Vasculitis   Residue of Guillain-Barré syndrome   Renal failure   Connective tissue disease, especially Sjögren disease   Human immune deficiency virus Less common   Amyloidosis, familial and primary   Voltage-gated sodium channel mutation  Paraneoplastic  Sarcoidosis   Toxic neuropathy, esp. arsenic poisoning   Fabry disease  Perineuritis Source: Adapted from Mendell and Sahenk.

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Electrophysiologic tests are likewise normal or virtually so; a few show diminished sural nerve potentials and minor changes of motor amplitudes. When the causes listed in the table have been excluded, a substantial group of patients is left and are in need of symptomatic relief. Some have been helped by gabapentin or by antidepressants and analgesic cream applied nightly to the soles and toes. A few of the more severe cases have apparently responded to gamma globulin infusions, but these observations require corroboration (Gorson and Ropper, 1995). In a number of cases of burning feet, the intradermal sensory nerves in skin biopsy specimens are depleted, but the meaning of this finding is not certain (Periquet et al) and the clinical diagnosis of a small-fiber neuropathy in affected older patients can be inferred without this procedure. Identifiable causes for painful sensory neuropathy in the elderly include mainly diabetes, alcoholic–nutritional deficiency states, connective tissue disease, amyloidosis, and vasculitis. Presumably, in the idiopathic cases, there is a similar small-fiber neuropathy, but the common clinical situation is that an etiology cannot be found. An alternative cause in these neuropathies that are characterized mainly by painful burning is that there is an abnormality of the sodium channel that renders the sensory neurons or fibers hyperexcitable. In the experience of one group, 8 of 28 patients in whom no etiologic diagnosis for small-fiber neuropathy could be found, there were mutations in the gene (SCN9A) encoding voltage-gated sodium channel Nav1.7. The mutation caused a gain of function in this gene and allowed dorsal root ganglion neurons to become hyperexcitable (Faber at al). Yet another rare cause of this syndrome has been the finding of antibodies to peripherin, which is a dominantly inherited trait (Stogbauer et al).

GENETIC FORMS OF CHRONIC POLYNEUROPATHY A polyneuropathy that advances slowly, and particularly symmetrically, over 10 years or more is almost invariably genetic in origin. The neuropathic disease may be remarkably restricted, as in familial analgesia with foot ulcers, or extensive, as in familial peroneal muscular atrophy. The time of onset of these very chronic neuropathies is usually in early life but often cannot be dated with certainty by the patient or family. In infants, the condition may be mistaken for muscular dystrophy or infantile muscular atrophy until sensory testing becomes possible. In the developing child, whose musculature naturally increases in power and volume with age, it may be difficult to decide whether the disease is progressive but typically, there is trouble running or walking making it difficult to keep up with other children, repeated ankle injuries, toe catching, labeled as “clumsiness,” or falls. Strongly indicative of one of these conditions at any age are pes cavus, hammertoes, and, in extreme forms, talipes equinus. One of these deformities is commonly detected in most cases of inherited polyneuropathy.

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Chapter 43 Diseases of the Peripheral Nerves

In later life, some of the inherited neuropathies are manifest as trophic changes of skin and bone in distal parts of the limbs indicate involvement of small (pain) fibers and the presence of deformed and degenerated joints (Charcot joint). The mutilating effects are the result of repeated injury to analgesic parts and to a lack of autonomic vascular reflexes. Atrophy of muscle and trophic changes in the skin are generally more marked than in the acquired forms of polyneuropathy. The CSF protein content may be mildly or moderately elevated over a period of years. We retain the nomenclature Charcot-Marie-Tooth (CMT) disease (type 1), which shows slowed nerve conduction as a consequence of a disorder of myelin. A distinctive feature of hereditary neuropathy is the uniformity of the electrophysiologic changes, for example, a similar degree of slowing of nerve conduction velocity in all the nerves, a feature that distinguishes this group from most acquired neuropathies. The distinction between the demyelinating and axonal types of inherited neuropathies is based on the motor nerve (typically ulnar or median nerve) conduction velocities in the arms, with slowing to velocities below 38 m/s defining the demyelinating category. To the reader not immersed in neuromuscular diseases, the classification, nomenclature, and number of genes that give rise to this group of diseases is dizzying. One approaches the affected patient, however, in a more circumscribed way by noting that the dominantly inherited demyelinating types are designated CMT1 and the dominant axonal types, as Charcot Marie type 2 (CMT2). The group of myelinopathies with onset in infancy (also called Dejerine-Sottas disease or congenital hypomyelinating neuropathy), are subsumed under CMT3, whereas most recessively inherited neuropathies (both axonal and demyelinating) are termed CMT4. There are, in addition, forms with intermediate degrees of conduction slowing that are not easily classified. An older nomenclature uses the term hereditary motor-sensory neuropathies, or HMSNs, for the main CMT types. The hereditary sensory neuropathies (HSNs) and the hereditary sensory autonomic neuropathies (HSANs) are considered separate entities. This category includes a variety of metabolic neuropathies and types that do not fit into the CMT classification. Recent genetic findings have in some ways simplified the matter of classification and have permitted the creation of a nosology that more or less parallels the clinical one. The systems in Tables 43-2 and 43-6 represent an attempt to conciliate the clinical and genetic data. Of this large and varied group, only the sensorimotor Charcot-Marie-Tooth type is the one likely to be seen with any regularity by neurologists and general physicians. This group has become quite large as more individual mutations are discovered, but a small number accounts for the majority of cases. The commonly encountered varieties are indicated in italics in Table 43-6. The major forms of hereditary neuropathy are designated as subcategories of CMT disease, grouped by patterns of inheritance and described in more detail further on.

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Inherited Polyneuropathies of Mixed Sensorimotor-Autonomic Types Charcot-Marie-Tooth Disease Types 1 (Demyelinating) and 2 (Axonal) and Related Neuropathies (See Table 43-6) Clinical features These are the most common forms of inherited peripheral neuropathy and, indeed, among the most common of all inherited neurologic diseases. The early symptoms of childhood clumsiness and athletic imprecision are listed previously, to which are added foot deformities of high arches and hammer toes. There may have been ankle fractures, foot-drop, medical plantar foot calluses and a need for podiatric treatment at an early age, painless or foot ulcers. In adolescence, an “inverted champagne bottle” appearance of the forelegs may become apparent. The typical case of CMT has its onset during late childhood or adolescence, although neurologists are increasingly aware that some cases, particularly type 2, may not attract attention until middle life. CMT1 cases usually make their appearance during the first decade while the peak age of onset of CMT2 is in the second decade or even later. Both motor and sensory signs are said to be more severe in the first type (Harding and Thomas, 1980). Adult patients have difficulty dating the onset of symptoms, so much so that with milder forms, they may not even be aware of having a neuropathic illness. In some cases, the widespread nerve conduction changes only come to light when this test is performed for the diagnosis of an unrelated problem or when a parent becomes aware of their own neuropathy after their child proves to have the disease. Some types that present in adulthood may even have a subacute or seemingly acute presentation, particularly the myelin protein zero (MPZ) and the PMP22 deletion (hereditary liability to pressure palsies) types. Because the clinical description was provided in 1886 almost simultaneously by Tooth in England and by Charcot and Marie in France, all of their names have been attached to it, even though similar cases had been recorded earlier by Eulenberg (1856), Friedreich (1873), Ormerod (1884), and Osler (1880). The two important advances in our understanding of this disease since the original descriptions have been the separation of the main subtypes based on their electrophysiologic (EMG) features and the discovery of genetic mutations that cause most of these diseases. The frequency of the disease cannot be stated with precision because of its clinical heterogeneity, but the usually quoted prevalence is 1 in 2,500 of the population, the most frequent subtype occurring in 1 in 4,000. This class of neuropathies is characterized clinically, as discussed previously, by the pattern of heredity, the speed of motor nerve conduction, and special clinical characteristics including the age of onset of symptoms such as difficulty walking and certain appended neuropathic syndromic findings such as hearing loss. From a genetic perspective, the classification is based on the gene that is affected and the nature of the mutation; deletions and duplications are the most common, but many single nucleotide polymorphisms have also been identified.

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Table 43-6 CLASSIFICATION OF THE INHERITED PERIPHERAL NEUROPATHIESa  

PATHOLOGY

I.  Charcot-Marie-Tooth (CMT) and Related Disorders 1.  CMT1 (demyelinating, dominantly inherited) demyelinating CMT1A*

ONSET

c

PMP22 duplication

CMT1B*

demyelinating

c, a

Myelin protein P0 (MPZ)

CMT1C

demyelinating

a

CMT1D, CMT4E CMT1F, CMT2E

demyelinating demyelinating, axonal

c, a c, a

Lipopolysaccharide-induced TNF-α (LITAF) Transcription factor EGR2 Neurofilament light subunit (NEFL) or PMP22 point mutation Rho guanine exchange factor

Congenital hypomyelination demyelinating 2.  CMT2 (axonal, dominantly inherited) axonal CMT2A* CMT2A2 (alt) axonal CMT2B axonal CMT2C axonal CMT2D axonal

c

CMT2F axonal 3.  AR-CMT2—(recessively inherited axonopathy) AR-CMT2A axonal

c, a

4. CMT3 (Dejerine-Sottas disease)

c, a c, a a c, a a

 

demyelinating

5.  CMT4 (recessively inherited myelin-axonopathy) CMT4A demyelinating

inf

Early areflexia, distal weakness, sensory loss Early areflexia, distal weakness, sensory loss   May be severe and congenital   Mild or asymptomatic

Kinesin KIF1Bβ motor protein Mitofusin (MFN2) GTP-binding protein RAB7 TRPV4 Glycyl t-RNA synthetase (GARS) Heat shock protein (BSPB1)

      Vocal cord, diaphragm paralysis  

Nuclear membrane lamin (LMNA) PMP22 most common; also P0, EGR2 (see above)

 

May be rapidly progressive

Slow, motor predominant

 

CMT4B

demyelinating

c

CMT4B2

demyelinating

c, a

CMT4C CMT4D

demyelinating demyelinating

c c

CMT4F

demyelinating

c

demyelinating

c, a

Ganglioside-induced differentiation protein (GDAP1) Myotubularin-related protein (MTMR2) SET-binding factor (MTMR13)) SHT3TC2 Schwann cell protein NmycDRG1 (NDRG1) Nuclear membrane protein (periaxin; PRX) GJB1

axonal

c, a

Unknown

Focal, painful brachial plexitis

axonal

c

PMP22 gene deletion

Focal entrapments, chronic neuropathy

Serine palmitoyl transferase

Small-fiber sensory and distal motor deficits    

6.  CMT1 X (X-linked demyelinating)* 7. Recurrent brachial plexopathy (AD) 8.  HNPP*

c

CLINICAL AND THERAPEUTIC FEATURES

GENE

II.  Hereditary Sensory and Autonomic Neuropathy (HSAN) 1.  HSAN1 (AD) axonal a

Focally folded myelin   Early scoliosis Neuropathy + hearing loss Early onset, severe Similar to CMT1A

2.  HSAN2 (AR) 3. HSAN3 (Riley-Day, AR)

axonal axonal

inf inf

4.  HSAN4 (AR)

axonal

inf

Novel neuronal protein Kinase-associated protein (IKBKAP) TrkA/NGF receptor

5.  HSAN5 (AR) axonal III.  Familial Amyloid Polyneuropathies (AD) 1. Type 1—Portuguese axonal

inf

Nerve growth factor-beta

Absent pain

a

Transthyretin

Liver transplant may be beneficial Liver transplant may be beneficial   Lax skin and “bloodhound” face; corticospinal, posterior column deficits

2. Type 2—Indiana/Swiss

axonal

a

Transthyretin

3.  Type 3—Van Allen 4.  Type 4—Finnish

axonal axonal

a a

Apolipoprotein A1 Gelsolin

Congenital SN with anhidrosis

(Continued)

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Table 43-6 CLASSIFICATION OF THE INHERITED PERIPHERAL NEUROPATHIESa (CONTINUED) PATHOLOGY

ONSET

GENE

IV.  Hereditary Disorders of Lipid Metabolism Causing Neuropathy (AR) 1. Metachromatic leukodystrophy demyelinating inf-a Arylsulfatase A and B 2.  Krabbe disease demyelinating, inf-a β-galactosidase axonal 3.  Fabry disease axonal c α-galactosidase 4. Adrenomyeloneuropathy (XR/XD) 5.  Refsum disease

demyelinating, axonal demyelinating

inf-a

ABCD1 transporter

inf-a

Phytanoyl-αCoA-hydroxylase

6.  Tangier disease

axonal

a

ABC1

7. Bassen-Kornzweig

axonal

c

MTP

c c, a

Gigaxonin Porphobilinogen deaminase

axonal

 

 

demyelinating

inf, c

Myelin transcription factor SOX10

V.  Miscellaneous Inherited Neuropathies 1.  Giant axonal neuropathy (AR) axonal 2.  Porphyria (AR) axonal 3. “Mitochondrial” neuropathies (NARP) 4. Severe PNS, CNS demyelination (AD)

CLINICAL AND THERAPEUTIC FEATURES

  Early bone marrow transplant may be beneficial Heat-induced pain, macular rash Early bone marrow transplant may be beneficial Dietary restriction may ameliorate the disease Small-fiber neuropathy, facial weakness, very low HDL Acanthocytosis, cerebellar ataxia   May respond to hematin, glucose Retinitis pigmentosa CNS, PNS hypomyelination

a

Italicized types with an asterisk are the most common in practice. CMT1A accounts for approximately 40 percent of cases with an identifiable mutation; CMT1B and HNPP approximately 6 percent each, and CMT1X approximately 6 percent of affected males. a, adult onset; c, childhood onset; inf, infantile onset.

As a guide to the frequency of various types, Saporta and colleagues in a study of over 1,000 patients from neuromuscular clinics found that two-thirds of patients had a mutation detected by conventional means. When combined with the mode of inheritance, the most common type was the typical demyelinating variety of CharcotMarie-Tooth disease (CMT1A, 17p duplication), and fewer than 10 percent each had X-linked CMTX1, hereditary liability to pressure palsies (HNPP), CMT1B, or the main axonal type, CMT2A; together, these implicated only four genes and all other forms, derived from about 30 other mutations, accounted for under 1 percent each. This is informative in guiding genetic testing in clinical circumstances. Still, almost one-third of patients with a clear history of heredofamilial neuropathy had none of the currently detectable mutations. The chronic degeneration of peripheral nerves and roots results in distal muscle atrophy beginning in the feet and legs and later involving the hands. The extensor hallucis and digitorum longus, the peronei, and the intrinsic muscles of the feet are affected early in life and this muscle imbalance produces the bony changes of pes cavus and pied en griffe (high arches and hammertoes). Later, all muscles of the legs and sometimes the lower third of the thigh become weak and atrophic. The thin legs have been likened to those of a stork or, if the lower thigh muscles are affected, to an inverted champagne bottle. Eventually the nerves to the calf muscles degenerate and the ability to plantar flex the feet is lost. After a period of many years, atrophy of the hand and forearm muscles develops in some cases. The hands later become

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clawed. The wasting seldom extends above the elbows or above the middle third of the thighs. Paresthesias and cramps are present but only to a slight degree and there is always some impairment, usually also mild, of deep and superficial sensation in the feet and hands, shading off proximally. Rarely, the sensory loss is severe and perforating ulcers appear as they do in the pure sensory varieties of inherited neuropathy. The tendon reflexes are absent in the involved limbs. The illness progresses very slowly over decades, giving the impression of stabilization for long periods. Walking difficulty, which is ultimately the main disability, is caused by a combination of sensory ataxia and weakness. Foot-drop and instability of the ankles are additional handicaps. The feet and legs may ache after use and cramps may be troublesome as mentioned, but otherwise pain is unusual; the feet may become cool, swollen, and blue, secondary to inactivity of the muscles of the feet and legs and their dependent position. There is usually no disturbance of autonomic function. Fixed pupils, optic atrophy, and nystagmus and endocrinopathies, epilepsy, and spina bifida, which have been reported occasionally in association with peroneal muscular atrophy, probably represent coincidental congenital disorders. The distinguishing clinical feature between types 1 and 2, and this is present in only a minority of cases, is perhaps enlargement of the nerves in type 1, most easily appreciated by palpation of the greater auricular and peroneal nerves. The clinical heterogeneity of CMT disease has been alluded to in the previous discussion and is evident in the numerous mutations that give rise to

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similar chronic polyneuropathies. Restricted forms are known to affect only the peroneal and pectoral or scapular muscles (scapuloperoneal form). The differential diagnosis involves the distal muscular dystrophies, late forms of familial motor system disease, Friedreich ataxia, Roussy-Lévy syndrome (see later) and other familial polyneuropathies, and, in adult onset cases, CIDP and the paraproteinemic neuropathies, discussed earlier. Electrophysiologic features  Dyck and Lambert (1975) and Harding and Thomas (1980) have been credited with subdividing CMT into the two broad types based on the speed of motor nerve conduction in the ulnar or median nerves, as mentioned, slow (mean conduction velocity less than 38 m/s but often in the range of 20 m/s) in type 1, and normal or near-normal conduction in CMT2. Electromyographers appropriately refer to these, respectively, as the demyelinating and axonal types. In both, the compound muscle action potentials and sensory potentials are greatly reduced in amplitude, but in type 2 there are findings of denervation in the EMG. In type 1 there is severe and widespread slowing of nerve conduction, but the electrical conduction block that characterizes acquired demyelinating neuropathies is not found and, in distinction to almost most all acquired diseases of peripheral nerves, the electrophysiologic findings, particularly the pronounced slowing of conduction in CMT1, are uniform throughout the peripheral nervous system. Genetic features and genetic testing Aspects of the genetic causes of these diseases were addressed in the introductory comments and here it is emphasized that a few basic principles apply. First, only a small number of cases of Charcot-Marie-Tooth disease arise as de novo mutations (Hoogendijk et al). Second, different mutations in the same gene can give rise to more than one type of disease. Third, only four genes (PMP22, MPZ, GJB1, and MFN2) account for 92 percent of cases of CMT and this allows efficient testing in practice. The most prevalent form of the disease is CMT1A, which displays an autosomal dominant pattern of inheritance with almost complete penetrance; it is due to duplication of PMP 22 on chromosome 17p. Less often, CMT1 is autosomal recessive and even less frequently, X-linked dominant or X-linked recessive (see Table 43-6). Two common mutations in chromosomes 1 or 17 cannot be easily distinguished from one another on clinical grounds, but they have distinctive EMG features. The condition of hereditary liability to pressure palsies (HNPP) also displays an aberration on chromosome 17, but in the form of a deletion rather than a duplication of the gene for PMP22. This disease is discussed further on under “Brachial Plexus Neuropathies.” The X-linked variant is the result of a mutation of the gene for connexin-32, another component of myelin. In a large proportion of CMT cases, the genetic basis can be established with current available genetic testing. For example, a study using whole genome sequencing has identified heretofore unknown compound heterozygous alleles that produce CMT phenotypes (Lupski and colleagues), most rare, but demonstrating that the frequency

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of unidentified mutations will be continuously reduced. Among these rare forms is CMT associated with glomerulopathy attributable to mutations in IFN2 (Boyer et al). Undoubtedly, further studies of genes and gene products will continue to advance our understanding of the inherited neuropathies. Based on the finding that only a few mutations are implicated in the majority of cases of CMT, various algorithms have been designed, taking into account the degree of slowing of motor nerve conduction velocity and clinical features. For example, PMP22 testing is a reasonable first step if the patient has the typical clinical appearance of CMT1A and motor nerve conductions are slower than 38 m/s. If this shows no mutation and there is maleto-male transmission, screening for CMTX1 is performed, or if autosomal inheritance, for MPZ mutations (CMT1B). If these are unrevealing, a third step may be screening for point mutations in PMP22, SIMPLE, and EGR2. If the nerve conduction velocities are severely slowed, below 15 m/s, PMP22 duplication or MPZ mutations are likely to be present. Those with intermediate conduction velocities, between 35 and 45 m/s are likely to have CMT1X or CMT1B and mutations in the corresponding genes. It is worth again noting that only a third of CMT2 cases will have mutations found by current methods. These prescriptions for testing will change as new sequencing methods are introduced. Pathologic findings Degenerative changes in the nerves result in depletion of the population of large sensory and motor fibers, leaving only the condensed endoneurial connective tissue. As far as one can tell, axons and myelin sheaths are both affected, the distal parts of the nerve more than the proximal ones. In type I, the nerves may be enlarged, with “onion-bulb” formations of Schwann cells and fibroblasts, as in Dejerine-Sottas disease (CMT3; type III HMSN in the Dyck classification). This change can often be seen in sural nerve biopsies. Anterior horn cells are slightly diminished in number and some are chromatolyzed as a secondary change. Dorsal root ganglion cells suffer a similar fate. The disease involves sensory posterior root fibers with degeneration of the posterior columns of Goll more than of Burdach. The autonomic nervous system remains relatively intact. The muscles contain large fields of atrophic fibers (group atrophy). Some of the larger fibers have a target appearance and may show degenerative changes. All these muscle changes are typical of neurogenic denervation. Former claims of a coincidental myelopathy and degeneration of spinocerebellar and corticospinal tracts probably indicate that the associated disease was really Friedreich ataxia or some other combination of chronic myelopathy and neuropathy. Treatment  No specific treatment is known. Stabilizing the ankles by arthrodeses is indicated if foot-drop is severe and the disease has reached the point where it is not progressing. Pediatric orthopedic specialists have experience with several techniques to stabilize the joints of weakened limbs. Regular exercise, but avoiding excessive weight training, is usually prescribed. In mild and early cases, fitting the legs with light braces and the shoes with springs to overcome foot-drop can be helpful.

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Chapter 43 Diseases of the Peripheral Nerves

Hereditary Neuropathy With Pressure Palsies (HNPP, PMP22 Deletion) This unusual but distinctive process of multiple recurrent local neuropathies, first reported by Earl and colleagues, is caused by a deletion of the PMP22 gene, the one that is duplicated in the previously described CMT1A. In both CMT1A and hereditary neuropathy with pressure palsies (HNPP), the PMP22 gene is functionally normal and these disorders arise because the total amount of the protein is abnormal. In CMT1A the gene is duplicated on one chromosome, thereby increasing the total PMP22 protein; by contrast, in HNPP, the gene is deleted so that the PMP22 protein is at approximately half-normal levels. HNPP is transmitted as a dominant trait. In these individuals, the focal neuropathies and plexopathies are generally not painful (in contrast with related conditions of hereditary neuralgic amyotrophy discussed further on). Focal nerve lesions are often provoked by slight or even brief compression. In addition to recurrent focal nerve palsies, most individuals with HNPP have an underlying chronic but slowly progressive demyelinating sensorimotor neuropathy that is mild on clinical examination (e.g., not all cases show areflexia). Electrophysiologic studies are abnormal, but may be only subtly so, with some slowing of conduction and distal motor and sensory nerve abnormalities, particularly across sites of compression. Nerve biopsies from these patients are most remarkable for the presence of localized nerve sheath thickening with duplication of the myelin lamellae (so-called tomaculae, meaning sausage shaped).

Hypertrophic Neuropathy of Infancy (Dejerine-Sottas Disease, Congenital Hypomyelination, CMT3) This relatively rare but striking neuropathy is inherited as an autosomal recessive trait. It begins in childhood or infancy, earlier than the typical form of peroneal muscular atrophy. Walking is delayed in onset and then progressively impaired. Pain and paresthesias in the feet are early symptoms, followed by the development of symmetrical weakness and wasting of the distal portions of the limbs. Talipes equinovarus postures with clawfeet and later clawhands are common. All modalities of sensation are impaired in a distal distribution, and the tendon reflexes are absent. Miotic, unreactive pupils, nystagmus, and kyphoscoliosis have been observed in some cases. The trunk and other cranial nerves are spared. The ulnar, median, radial, posterior tibial, and peroneal nerves stand out like tendons and are easily followed with the gently roving finger. The enlarged nerves are not tender. Unlike other forms of hereditary neuropathy, the CSF protein is persistently elevated in Dejerine-Sottas disease, in all likelihood because the spinal roots are enlarged. Nerve conduction velocities are markedly reduced, even when there is little or no functional impairment. Patients are usually more disabled than those with peroneal muscular atrophy and are confined to wheelchairs at an early age. Treatment is purely symptomatic. It is important to emphasize that the occurrence of hypertrophic neuropathy is not confined to this particular inherited disease. If one groups all patients in whom the

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nerves are diffusely enlarged (incorrectly called “hypertrophic” as it is mainly a nonspecific reaction of the epineural and perineural connective tissue that contributes to the bulk of the nerves), several diseases, both genetic and acquired, are included. The identifying histologic lesion in these cases is the “onion bulb,” which consists of a whorl of overlapping, intertwined, attenuated Schwann cell processes that encircle naked or finely myelinated axons and of endoneurial fibrofilaments. Enlarged nerves have been described in cases of recurrent demyelinating polyneuritis (CIDP), familial amyloidosis, Refsum disease, CMT type I, and other diseases. As was first pointed out by Thomas, any pathologic process that causes recurrent segmental demyelination and subsequent repair and remyelination may have this effect. In some patients with a history of early childhood hereditary polyneuropathy, the nerves are not yet palpably enlarged, but the characteristic Schwann cell abnormalities are revealed in biopsy material from a cutaneous nerve.

Phenotype-Genotype Correlations in the Inherited Sensorimotor Polyneuropathies As the molecular basis of the inherited polyneuropathies has been elucidated, it has become clear that diverse mutations and molecular defects can give rise to the same clinical phenotype. From a neurobiologic perspective, it is intriguing that both Dejerine-Sottas and Roussy-Lévy syndromes are linked to a recessively inherited loss of the myelin protein P0, and that the salient clinical features of this disorder are manifestations of defective nerve myelination. However, it has also become apparent that nearly identical clinical syndromes are associated with mutations in the genes for PMP22 and for the Schwann cell DNA-binding protein EGR2. Moreover, while some mutations in the P0 gene cause infantile onset neuropathies with the DejerineSottas and Roussy-Lévy phenotypes, other mutations in the same gene cause adult onset neuropathies. Although the early-onset cases show marked slowing of nerve conduction, the adult ones have conduction velocities that are typically above 35 m/s. The infancy-onset cases reveal major disruptions of folding of compact myelin, whereas in the adult-onset cases subtle alterations in the myelin protein P0 lead to a slow, predominantly axonal degeneration in adult life. Many other insights into the genetic and structural alterations of this vast category of disease have been revealed and can be appreciated from reading subspecialty texts on the subject, including the chapters by Amato and Russell and the monograph by Klein, Duan, and Shy, and the study by Saporta and coworkers, which are recommended.

Inherited Polyneuropathies of Predominantly Sensory Type Common to the diseases comprising this group are insensitivity to pain, lancinating pains, and ulcers of the feet and hands, leading to osteomyelitis, osteolysis, stress fractures, and recurrent episodes of cellulitis. Because similar symptoms and signs occur in syringomyelia, leprosy, and tabes dorsalis, there is considerable uncertainty in older writings on this subject as to whether the reported cases were

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examples of one of these diseases or of hereditary neuropathy. According to Dyck and Lambert (1975), it was Leplat in 1846, who first described plantar ulcers (mal perforant du pied).

Mutilating Hereditary (Dominant) Sensory Polyneuro­pathy in Adults (Hereditary Sensory and Autonomic Neuropathy [HSAN] Type 1) The characteristic features of this group of polyneuropathies are an autosomal dominant mode of inheritance and onset of symptoms in the second decade or later. Characteristically this begins with subtle loss of sensation for painful stimuli in the feet (e.g., inability to feel the hot sand or hot water in a tub). As the disease evolves, there is involvement of the feet with calluses of the soles and, later, episodes of blistering, ulceration, and lymphangitis followed by osteomyelitis and osteolysis, shooting pains, distal sensory loss with greater affection of pain and thermal sensation than of touch and pressure, loss of sweating, diminution or absence of tendon reflexes, and only slight loss of muscle power. Over time, loss of pain sensation in the fingers leads to fingertip ulcerations, osteomyelitis, and amputations. The plantar ulcer overlying the head of a metatarsal bone is the most dreaded complication, because it often leads to osteomyelitis. Infection of the pulp of the fingers and paronychias are uncommon. Some patients have a mild pes cavus and weakness of the peroneal and pretibial muscles, with foot-drop and steppage gait. Lancinating pains may occur in the legs, thighs, and shoulders, and, exceptionally, the pain may last for days or longer and be as disabling as that of tabes dorsalis; however, in the majority of patients there is no pain whatsoever. Neural deafness was present in one of Denny-Brown’s patients. In that case, which was studied postmortem, there was a loss of small nerve cells in the lumbosacral dorsal root ganglia; the dorsal roots were thin, and the fibers in the posterior columns of the spinal cord and those in the peripheral nerves were diminished in number. Myelinated and unmyelinated fibers were both affected. Both axonal degeneration and segmental demyelination have been demonstrated in teased nerve preparations. Sensory nerve conduction may be absent or is uniformly slowed in every nerve tested. It must be emphasized that despite its categorization as a “sensory and autonomic neuropathy,” the most common, dominantly inherited form, termed HSAN1, also entails progressive, disabling, distal motor weakness, a consequence of ongoing axonopathy and denervation. HSAN1 is a consequence of a loss of function of the enzyme serine palmitoyltransferase, which is the rate-limiting step in the biosynthesis of sphingolipids.

Recessive Mutilating Sensory Polyneuropathy of Childhood Here the pattern of inheritance is autosomal recessive. Onset is in infancy and early childhood and walking is delayed; there is pes cavus deformity and the first movements are ataxic. Ulcerations of the tips of toes and fingers and repeated infections of these parts result in the formation of paronychias and whitlows. The tendon reflexes are absent, but power is well preserved. All sensory modalities

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are impaired (touch-pressure somewhat more than paintemperature), mainly in the distal parts of the limbs but also over the trunk. In addition, there are reports of several sibships in which multiple members had a sensory neuropathy manifest by a generalized insensitivity to pain of the type described later. The lesions and electrophysiologic findings are similar to those in the dominantly inherited sensory neuropathy described previously. In all types of hereditary sensory neuropathies, measures must be taken to prevent stress fractures, acral mutilation, and infection. This is more difficult in the small child who does not understand the problem. It is also now evident that some of the infantile hereditary sensory neuropathies are a result of a disruption of molecular signaling pathways for neurotropic substances, such as nerve growth factor, that are critical to neural development.

Congenital Insensitivity to Pain In congenital insensitivity or indifference to pain, a syndrome in which the patient throughout life is unreactive to the pain of injury, there is no loss of the ability to distinguish pinprick and other noxious stimuli from nonnoxious ones. Furthermore, the nervous system of such individuals seems to be normal. There is another variety characterized by universal analgesia (Swanson et al). This latter type is inherited as an autosomal recessive trait and at least one form involves the gene for a nerve growth factor receptor located on chromosome 1q immediately adjacent to the site of the mutation for Charcot-Marie-Tooth disease type 1B (see Table 43-6). During childhood, one patient (Swanson and colleagues) had high fever when the environmental temperature was raised and the other had orthostatic hypotension. One of the patients died in his twelfth year and was found to have an absence of small neurons in the dorsal root ganglia, an absence of Lissauer tracts, and a decrease in size of the descending spinal tracts of the trigeminal nerves. Sweat glands were present in the skin but were not innervated.

Multiple Symmetrical Lipomas With Sensorimotor Polyneuropathy Whereas the usual cutaneous lipomas have no neurologic accompaniments, this clinical curiosity, known as Launois-Bensaude disease, consists of symmetrical lipomas of the neck and shoulders that are associated with polyneuropathy and sometimes, deafness. A mitochondrial disorder of similar genetic origin as the MERRF syndrome (see Chap. 36) has been identified (see Neumann’s review for clinical details).

Polyglucosan Disease This interesting process was mentioned in Chap. 38 in relation to dementia in which it is pointed out that there is a multisystem neurologic disease characterized by the widespread deposition in nervous tissue of corpora amylacea, in this disease termed polyglucosan bodies. The main presentation of this disorder is of slowly progressive motor and pronounced sensory loss in the legs due to an axonal polyneuropathy, neurogenic bladder, and a degree of upper motor neuron signs that may also be evident. It is the early

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appearance of the urinary difficulties or the upper motor neuron features that mark the illness as unusual in relation to other polyneuropathies. Biopsy of the sural nerve demonstrates profuse deposition of the polyglucosan bodies in the endoneurium. When dementia occurs, either with the neuropathy or in isolation, the corpora amylacea are found throughout the cerebrum. The process is detailed by Robitaille and colleagues and an upper motor neuron presentation that simulates amyotrophic lateral sclerosis, by McDonald and coworkers. The bodies are made up largely of glucose polymers that are well known to occur in the aging brain and, when present in small numbers, have been assigned an innocuous meaning. In the usual type of polyglucosan disease, which is found in individuals of Ashkenazic Jewish origin, there is a deficiency in glycogen branching enzyme (GBE) that is shared with glycogenosis type IV, and infantile recessive process, Anderson disease. As such, it could be considered with the other neuropathies that have an identifiable metabolic cause, discussed as a group further on. However, a proportion of cases do not have the inherited GBE enzyme abnormality.

Riley-Day Familial Dysautonomia (See Also Chap. 25) This disorder, inherited as an autosomal recessive trait, affects predominantly children of Ashkenazic Jewish heritage. Familial dysautonomia is usually manifested soon after birth (poor sucking, failure to thrive, unexplained fever, episodes of pneumonia). Hyporeflexia and impairment or loss of pain and temperature sensation, with relative preservation of pressure and tactile sense, are the main manifestations. Motor fibers are probably involved as well, but only to a slight degree; this is shown more effectively by reduced motor conduction velocity in peripheral nerves than it is by weakness. At a later age, the neuropathy becomes overshadowed by other manifestations of the disease, notably repeated infections and abnormalities of the autonomic nervous system—lack of tears, corneal ulceration, fixed pupils, blotchiness of the skin, defective temperature control, cold hands and feet, excessive sweating, lability of blood pressure, postural hypotension, difficulty in swallowing, esophageal and intestinal dilation, emotional instability, recurrent vomiting, and stunted growth. The tongue lacks fungiform papillae. Nerve biopsy reveals a diminution of small myelinated and unmyelinated fibers, which explains the impairment of pain and temperature sensation. In autopsy material, sympathetic and parasympathetic ganglion cells and, to a lesser extent, nerve cells in the sensory ganglia are diminished in number. Patients excrete increased amounts of homovanillic acid and decreased amounts of vanillylmandelic acid and methoxyhydroxyphenylglycol. Weinshilboum and Axelrod demonstrated a decrease in serum dopamine β-hydroxylase, the enzyme that converts dopamine to norepinephrine. The disease is caused by a mutation in a gene that expresses a kinase-associated protein (see HSAN3 in Table 43-6). There is no treatment for the disease except to provide symptomatic relief of gastrointestinal symptoms and orthostatic fainting. Other examples of congenital polyneuropathy with absence of autonomic function, probably differing from

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the Riley-Day dysautonomia, have been reported. Some of these develop transient episodes of reflex sympathetic dystrophy. A congenital failure of development of neural elements derived from the neural crest has been postulated. Ataxia-telangiectasia and Chédiak-Higashi disease are other genetic diseases with a recognized metabolic abnormality that may cause a polyneuropathy. They are described in Chap. 36, with the hereditary metabolic disorders.

Other Forms of Inherited Sensory Neuropathy Included here are numerous disorders similar to the ones described in the preceding pages but caused by different mutations; neuropathy with cerebellar degeneration; and the neuropathies in which there are recognized metabolic abnormalities, including familial amyloidosis. Some years ago a young man and woman with universal anesthesia affecting head, neck, trunk, and limbs came to attention (Adams et al); all forms of sensation were absent. The patients were areflexic but retained nearly full motor power; their movements were ataxic. Autonomic functions were impaired but not abolished. In a sural nerve biopsy, nearly all fibers—large and small, myelinated and unmyelinated—had disappeared. Surprisingly, there were no trophic changes of any kind. A variant of the recessively inherited form of sensory neuropathy has been described, in which there was an associated neurotrophic keratitis and a selective loss of small myelinated fibers in sural nerve biopsies (Donaghy and coworkers). We continue to observe variant and unclassifiable cases of purely motor, sensory, or mixed types such as these every year and the presumtoin is that deeper or wider sequencing of the genome will reveal genetic variants, even if the pathophysiology of the disorder in each patient is not yet accessible.

Hereditary Areflexic Dystasia (Roussy-Lévy Syndrome) In 1926, Roussy and Lévy reported seven cases of a dominantly inherited ataxic and neuropathic malady that had not previously been described. Its close relation to Friedreich ataxia and the amyotrophy of Charcot-Marie-Tooth disease was recognized. Based on molecular genetic testing, these relationships been clarified. Most classifications group it with CMT1 based on the causative mutations and nerve conduction studies. The condition is a sensory ataxia with pes cavus and areflexia, affecting mainly the lower legs and progressing later to involve the hands. Some degree of sensory loss, mainly of vibratory and position sense, is described in all cases. Atrophy of the muscles of the legs and postural tremor eventually become prominent, but the patients do not have signs of cerebellar disease (dysarthria, tremor, nystagmus). Kyphoscoliosis, a feature typical of Friedreich disease, has been described in several cases. Although the feet may be cold or slightly discolored, no autonomic defects are documented and the nerves are not palpably enlarged. Electrocardiographic abnormalities similar to those of Friedreich ataxia have been noted in one family but are not usual. The onset in many patients is during infancy, possibly dating from birth, and the course is relatively benign; all descendants of the original Roussy-Lévy family were still able to walk during their seventh decade of life.

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On clinical and pathologic grounds, Dyck and Lambert (1975) placed the Roussy-Lévy kinships within the category of the demyelinating type of Charcot-Marie-Tooth disease (CMT1). The mode of inheritance of the two syndromes, their benign course, pattern of neurologic signs, slow nerve conduction, and biopsy features (demyelination of nerve fibers with onion-bulb formation) are much the same. This view has been reinforced by the genetic findings reported by Planté-Bordeneuve and colleagues. In affected members of the original Roussy-Lévy family, these investigators identified a point mutation in the domain of the myelin protein gene PO, the same gene that is implicated in Dejerine-Sottas disease. Most currently studied cases (there are few) have point mutations in PMP22 or MPZ. Based on limited pathologic study, there is no cerebellar degeneration; nevertheless, the shared clinical features with Friedreich ataxia are unmistakable and create diagnostic confusion before genetic testing.

Polyneuropathy With Cerebellar Degeneration (See “Predominantly Cerebellar Forms of Hereditary and Sporadic Ataxia” in Chap. 38) Several such cases of adult onset have come to our attention over the years. Unlike Friedreich disease, the ataxia is mild and there is no kyphoscoliosis, but pes cavus or hammertoe deformities are found, attesting to the early onset of the neuropathy. The lower legs become atrophic and findings characteristic of CMT such as absent ankle reflexes and mild to moderate loss of distal deep sensibility are present. There is no Romberg sign and no Babinski signs. The outstanding feature is a profound atrophy of the cerebellar hemispheres, and to some extent of the vermis, on MRI. Although the illness is slowly progressive, our patients, like those with Roussy-Lévy disease, have remained highly functional into late age, having difficulty mostly with maintaining balance when dancing or wearing high-heeled shoes. The EMG is consistent with CMT2. The electrocardiogram has been normal. Several, but not all, such patients have had a family history of a similar process, but the available genetic testing has failed to reveal the site of a mutation. As mentioned, the process can simulate Friedreich ataxia in some respects. The genetic basis is uncertain and various genotypes have been reported in single families.

Polyneuropathy With Spastic Paraplegia From time to time we have observed children and young adults with unmistakable progressive spastic paraplegia superimposed on a sensorimotor polyneuropathy of extremely chronic evolution. Sural nerve biopsy in two of our cases disclosed a typical “hypertrophic” polyneuropathy. In another case, only loss of nerve fibers was found. Cavanaugh and colleagues and Harding and Thomas (1984) reported similar patients. Our patients were severely disabled, being barely able to stand on their atrophic legs. An even more ambiguous form of disease was described by Vucic and colleagues in which there is typical CMT but with brisk reflexes. There were Babinski signs in half the patients and spastic dysphonia in a few others. The mutation is not known. Although few in number, some cases of chronic polyneuropathy are combined with optic atrophy, with or

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without deafness or retinitis pigmentosa, and Dyck and Lambert (1975) classed these in a separate group. Jaradeh and Dyck have also described a hereditary motor-sensory polyneuropathy with the later development of a parkinsonian or a choreic-dystonic syndrome that responded to l-dopa. Most cases of this type have had an autosomal recessive inheritance.

Hereditary Recurrent Brachial Plexopathy (Hereditary Neuralgic Amyotrophy) This entity, mentioned earlier in relation to hereditary neuropathy with pressure palsies because of the implication of a similar genetic locus, is discussed in the later section under “Brachial Neuritis, Brachial Plexitis (Neuralgic Amyotrophy, Parsonage-Turner Syndrome).”

Inherited Polyneuropathies With a Recognized Metabolic Disorder Refsum Disease (HMSN IV, PHYH, and PEX7 Mutations) This rare disorder, named after Refsum who made the first clinical observations, is inherited as an autosomal recessive trait and has its onset in late childhood, adolescence, or early adult life. It is slowly progressive but may be punctuated by acute or subacute worsening. Clinical diagnosis is based on a combination of clinical manifestations— retinitis pigmentosa, ataxia, and chronic polyneuropathy— coupled with the metabolic marker of the disease, an increase in blood phytanic acid. Phytanic acid accumulates because of a deficiency of the peroxisomal enzyme, phytanoyl-coenzyme A (CoA) hydroxylase. The deficiency is caused by mutations in 1 of 2 disparate genes. Cardiomyopathy and neurogenic deafness are present in most patients, and pupillary abnormalities, cataracts, and ichthyotic skin changes (particularly on the shins) are added features in some. Anosmia and night-blindness (nyctalopia) with constriction of the visual fields may precede the neuropathy by many years. The polyneuropathy is sensorimotor, distal, and symmetrical in distribution, affecting the legs more than the arms. All forms of sensation are reduced, often deep sensation more so than pain and thermal sense, and tendon reflexes are lost. The CSF protein is increased, sometimes markedly. Usually, the polyneuropathy develops gradually, although in some patients it has a subacute onset or, after being established for some time, a tendency to worsen fairly abruptly. Although the nerves may not be palpably enlarged, “hypertrophic” changes with onion-bulb formation are invariable pathologic features. The metabolic defect has been discovered to be in the utilization of dietary phytol; a failure of oxidation of phytanic acid—a branched-chain tetramethylated 16-carbon fatty acid—that accumulates in the absence of activity of the enzyme phytanoyl-CoAhydroxylase. The relation between the increased phytanic acid and the polyneuropathy is uncertain. Clinical diagnosis is confirmed by the finding of increased phytanic acid in the blood of a patient with a chronic, mainly sensory neuropathy; the normal level is less than 0.3 mg/dL but in patients with this disease, it constitutes 5 to 30 percent of the total fatty acids of the

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serum lipids. Urinary phytanic acid concentration is also raised. Genetic testing reveals the mutation, which is in PHYH in 90 percent of cases and in PEX7 in the others. Treatment  Diets low in phytol may be beneficial but this is difficult to judge, because after an acute attack there is sometimes a natural remission. The claimed effects of plasma exchange have also been difficult to interpret. In some patients there is a very slow progression of the disease, and in others, a more rapid progression with death from cardiac complications.

Mitochondrial Neuropathy Like cases of mitochondrial disease with neuropathy (e.g., Tuck and McLeod), we have observed several in which the clinical picture was almost identical to that of Refsum disease, but elevations in phytanic acid were not present. Mild ichthyosis, sensorineural deafness, ataxia of mixed tabetic-cerebellar type, areflexia, and retinitis pigmentosa were the main findings, conforming to the NARP syndrome described in Chap. 36. None of our cases had a family history of a similar disorder. Sural nerve biopsy showed loss of large fibers. There was an identifiable mitochondrial disorder in most of the recently studied cases, as described in Chap. 36. It should be remarked that most mutations of mitochondrial DNA cause a myopathy with multisystem disease, but not a neuropathy. The onset of the disease is in childhood or adolescence with slow progression.

Abetalipoproteinemia (Bassen-Kornzweig Syndrome, MTTP Mutation) (See Also Chap. 36) This rare autosomal recessive childhood disorder was described in Chap. 36 with the inherited metabolic disorders of the nervous system and commented on with neuroacanthocytosis in Chap. 38, although there is no relationship between the 2 processes. It is mentioned here because the brunt of the neurologic disorder falls on the peripheral nerves. Acanthocytosis of red blood cells is its identifying feature. The earliest neurologic finding is usually diminution or absence of tendon reflexes, detected as early as the second year of life. Later, when the child is first able to cooperate in sensory testing, a loss of vibratory and position sense is found in the legs. Cerebellar signs (ataxia of gait, trunk, and extremities; titubation of the head; and dysarthria), muscle weakness, ophthalmoparesis, Babinski signs, and loss of pain and temperature sense are the other characteristic neurologic abnormalities, in more or less this order of frequency. Developmental delay, usually mild, occurs in some patients. Irregular progression occurs over a few years, and many patients are unable to stand and walk by the time they reach adolescence. Skeletal abnormalities include pes cavus and kyphoscoliosis, which are secondary to the early onset neuropathy. Constriction of the visual fields and ring scotomata are manifestations of the macular degeneration and retinitis pigmentosa in some cases. Cardiac enlargement and congestive failure are serious late complications. Neuropathologic findings consist of demyelination of peripheral nerves and degeneration of nerve cells in the spinal gray matter and cerebellar cortex. Diagnosis is confirmed by the finding of red blood cell acanthocytes, low serum cholesterol, and low-density-lipoproteins.

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The disease is caused by defects in a triglyceride transfer protein, as discussed in Chap. 36. A deficiency of vitamin E, as a result of malabsorption, may be a factor, and large doses of the vitamin should be tried as therapy. A closely related disease, also with familial hypobetalipoproteinemia, was described by van Buchem and coworkers. It, too, is associated with malabsorption syndrome, ill-defined weakness, ataxia, dysesthesia of the legs, and Babinski signs. There is no sensory loss.

Tangier Disease (ABC1 Mutation) This is a rare, familial, small-fiber neuropathy of which we have seen a few cases, inherited as an autosomal recessive trait. It is named for the island off the Virginia coast where the first-described patients resided. The mutation eliminates the function of the adenosine triphosphate (ATP)cassette transporter protein, ABC1. It results in a deficiency of high-density lipoprotein, extremely low serum cholesterol, and high triglyceride concentrations in the serum. Perhaps based on these abnormalities, the patients are disposed to early and severe atherosclerosis. The presence of enlarged, yellow-orange (cholesterol-laden) tonsils is said to be a frequent manifestation (of course, previous tonsillectomies obviate this sign). About half of the reported cases have had neuropathic symptoms, taking the form of an asymmetrical sensorimotor neuropathy that fluctuates in severity. The sensory loss is predominantly for pain and temperature and extends over the entire body; at times it is limited to the face and upper extremities, simulating syringomyelia (“pseudosyringomyelia”). Tactile and proprioceptive sensory modalities tend to be preserved. The polyneuropathy may come in attacks—that is to say, it simulates a recurrent process. Muscular weakness, if present, affects either the lower or upper extremities or both, particularly the hand muscles, which may undergo atrophy and show denervation by EMG. In a small number of patients there has been facial diplegia out of proportion to weakness elsewhere. In one of our patients, the pain and temperature loss was restricted to the head, neck, and arms. Tendon reflexes are often lost or diminished. Transient ptosis and diplopia have been reported. Nerve conduction is slowed. Fat-laden macrophages are present in the bone marrow and elsewhere. No complete pathologic studies are available. There is no known treatment but dietary measures to reduce triglycerides may help, particularly in preventing atherosclerosis but the influence on the neuropathy is uncertain.

Fabry Disease (Anderson-Fabry Disease, GLA Mutation) (See Also Chap. 36) The genetic and metabolic aspects of this sex-linked disorder caused by deficiency of alpha-galactosidase A were considered with the inherited metabolic diseases. Here we offer some additional remarks about the painful neuropathic component. It bears commenting that 10 percent of heterozygous women display neuropathic symptoms, but usually of later onset and lesser degree than in males. The pain, which is usually the initial symptom in childhood and adolescence, often has a burning quality

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or occurs in brief lancinating jabs, mostly in the fingers and toes, and may be accompanied by paresthesias of the palms and soles. Changes in environmental temperature and exercise may induce pain in “crises,” an identifying feature. These abnormalities are a result of the accumulation of glycolipid (ceramide trihexoside) in peripheral nerves, both perineurally and intraneurally, as well as in cells of the spinal ganglia and the anterior and intermediolateral horns of the spinal cord. There is preferential loss of small myelinated and unmyelinated fibers and small neurons of dorsal root ganglia (Ohnishi and Dyck), and by autonomic changes in other cases. Involvement of the sensory ganglia and the associated degenerative changes in the afferent fibers are thought to be the likely cause of the thermally induced painful sensory phenomena (Kahn 1973). Later in the illness there is progressive impairment of renal function and cerebral and myocardial infarction. The characteristic dermal feature is the presence of numerous dark red macules and papules (angiokeratomas), up to 2 mm in diameter, over the trunk and limbs, most closely clustered over the thighs and lower trunk and around the umbilicus (angiokeratoma corporis diffusum). The comprehensive review by Brady and Schiffman is recommended. The responsible mutation has been identified in GLA. Treatment  Phenytoin, carbamazepine, gabapentin, or amitriptyline may be helpful in alleviating the pain and dysesthesias. As discussed in Chap. 36, enzyme replacement therapy has become available and seems to lead to partial remission of many of the features including the neuropathic ones.

Polyneuropathy of Acromegaly and Gigantism Nerve entrapment, particularly of the median nerve, is a well-known feature of acromegaly. Pickett and colleagues identified carpal tunnel syndrome in 56 percent of acromegalics. Also recognized as a complication of acromegaly, but not because of multiple nerve entrapments, is polyneuropathy characterized by paresthesia, loss of tendon reflexes in the legs, and atrophy of slight degree in the distal leg muscles. Sometimes there are enlarged nerves. In the case reported by Stewart, the enlargement was the result of hypertrophic changes in the endoneurial and perineurial tissues, similar to those that occur in other so-called hypertrophic neuropathies of inflammatory or heredofamilial origin. In cases of extreme gigantism, a more severe polyneuropathy has sometimes been reported, to the point of causing Charcot joints (Daughaday). Mentioned here is a case we have observed in which a severe and slowly progressive relatively symmetric motor neuropathy occurred in a patient with Pyle disease, a metaphyseal dysplasia that resembles acromegaly.

Metachromatic Leukodystrophy (ARSA Mutation, See Also Chap. 36) In this metabolic disease, the congenital absence of the degradative enzyme sulfatase leads to massive accumulation of sulfatide throughout the central and peripheral nervous systems and to a lesser extent in other organs. The abnormality is transmitted as an autosomal recessive trait. Progressive cerebral deterioration is the most obvious clinical feature, but hyporeflexia, muscular atrophy, and

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diminished nerve conduction velocity reflect the presence of a neuropathy. Early in the course of the illness, the weakness, hypotonia, and areflexia may suggest Werdnig-Hoffmann disease; in older children there may be a complaint of paresthesias and demonstrable sensory loss. Bifacial weakness has been reported but must be rare. Sensory and motor conduction velocities are greatly slowed similarly in all nerves. Metachromatically staining granules accumulate in the cytoplasm of Schwann cells in nerves as well as in the cerebral white matter. There is loss of peripheral myelinated fibers. The measurement of arylsulfatase A activity in peripheral leukocytes or urine and biopsies of sural nerves are used to establish the diagnosis, even early in the course of the illness.

Inherited (Familial Amyloidosis, TTR Amyloidosis) Amyloid Neuropathies (See Table 43-6) As noted earlier in the discussion of acquired (primary) amyloidosis, amyloid is a descriptive term for any of the proteins that are deposited in filamentous beta-pleated sheets; it can be derived from a number of precursor protein sources. Peripheral neuropathy is a common and often the most prominent manifestation of amyloidosis. The polyneuropathies are of two main types—those associated with familial amyloidosis (referred to as FA) and the other associated with primary (nonfamilial) systemic deposition of amyloid (termed AL), which is derived from a circulating monoclonal protein. The acquired type has been discussed earlier. The most notable difference between these two types is the absence of a significant amount of paraprotein in the inherited forms (see further on). The amyloidosis that is secondary to chronic infectious or inflammatory disease, referred to as AA, is an increasingly rare condition and, in any case, does not affect the nerves. In the following described most common familial amyloidoses, the amyloid is derived from an inherited abnormality of serum protein transthyretin (TTR, formerly called “prealbumin”). Several different amino acid substitutions have been identified in each type of amyloidosis. In the originally described Andrade type, methionine replaces valine at amino acid 30; therefore this has been referred to as transthyretin amyloidosis and as the TTR met 30 type. However, there are over 100 variants in the transthyretin gene that can give rise to amyloidosis. The familial amyloid polyneuropathies comprise several distinct groups, as enumerated in Table 43-6. The pattern of inheritance in all types is autosomal dominant; males and females are affected with equal frequency. Although a descriptive classification based on the ethnic or geographic origin of affected families is still in use and is retained in the narrative categorization below, it is now possible to categorize the diseases according to their genetic causes and the corresponding chemical structure of the amyloid protein that is deposited in tissue. The recent cloning of many of the amyloid protein genes has made possible not only the detection of the common transthyretin mutation but also DNA tests for some of the other types of familial amyloidoses. Lachmann and colleagues (2002 and 2007) emphasize the high frequency of genetic defects in amyloid precursor proteins and the finding in onequarter of cases of a low-level monoclonal gammopathy.

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Characteristic of all the amyloid polyneuropathies is the preferential involvement of small-diameter sensory and autonomic nerves and deposition of amyloid in various organs. Sensory loss, therefore, dominates the picture and pain and autonomic changes are prominent in most varieties of the disease. The following are the main recognized types of familial amyloid neuropathies. We retain the descriptive terms for convenience. 1. The Portuguese (Andrade) type. Andrade, in 1939, recognized that a chronic familial illness known as “foot disease” among the inhabitants of Oporto, Portugal, was a special type of amyloid polyneuropathy. He was not the first to have seen amyloid in degenerating nerve but deserves credit for identifying the disease as one of the heredofamilial polyneuropathies. By 1969 he had studied 148 sibships, comprising 623 individuals, among whom there were 249 with polyneuropathy. Descendants of this family have been traced to Africa, France, and Brazil. Other foci of the disease have been reported in Japan (Araki et al; Ikeda et al), the United States (Kantarjian and DeJong), Germany (Delank et al), Poland, Greece, Sweden, and northwest Ireland (Staunton et al). As far as one can tell, these are separate, unrelated probands in different ethnic groups.   The age of onset of this form of familial amyloid polyneuropathy is between 25 and 35 years. The disease progresses slowly and terminates fatally in 10 to 15 or more years. The initial symptoms are usually numbness, paresthesias, and sometimes pain in the feet and lower legs. Weakness is minimal, and the tendon reflexes, although diminished, may be retained early in the course of the illness. Pain and thermal sense are reduced more than tactile, vibratory, and position sense (a “pseudosyringomyelic”) pattern. Autonomic involvement is another important characteristic—loss of pupillary light reflexes and miosis, anhidrosis, vasomotor paralysis with orthostatic hypotension, alternating diarrhea and constipation, and erectile dysfunction. These autonomic changes tend to be more extensive than the sensory ones. Difficulty in walking also develops and has its basis in a combination of faulty position sense and mild muscle weakness. Later, tendon reflexes are abolished and the legs become thin. The nerves are not enlarged. Cranial nerve involvement (facial weakness and numbness, loss of taste) is a late manifestation and occurs in only a few cases.   The clinical details vary somewhat from case to case, even within a family. Cardiac enlargement and irregularities in cardiac rhythm as a result of bundle-branch or atrioventricular (AV) block occur early in some and late in others. A few patients have had severe amyloid cardiomyopathy from the onset (Ikeda et al). Weight loss may be pronounced owing to anorexia and disordered bowel function and the later development of a malabsorption syndrome. The liver may become enlarged (as it may in the acquired form). Vitreous opacities (veils, specks, and strands) may progress to blindness but this has been rare; in a few, there has been an impairment

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of hearing. Involvement of the CNS—manifest as behavioral abnormalities, cerebellar ataxia, and bilateral corticospinal signs—has also been reported in a few cases but their nature and pathologic basis is controversial (Ikeda et al). A nephrotic syndrome and uremia terminate life in some patients. The CSF may be normal or the protein content may be increased (50 to 200 mg/dL); the blood is normal except for anemia caused by amyloidosis of the bone marrow. This is probably the most common transthyretin mutation–derived amyloidosis. 2. Familial amyloidosis with carpal tunnel syndrome (Swiss type). Falls and coworkers, in 1955, and later Rukavina and associates described a large group of patients of Swiss stock living in Indiana who developed, in their fourth and fifth decades, a syndrome of acroparesthesias in the hands as a result of deposition of amyloid in the connective tissues and beneath the carpal ligaments. Similar kindreds of German descent were recognized in Maryland. There were sensory loss and atrophic muscle weakness in the distribution of the median nerves, which were compressed. Section of the carpal ligaments relieved the symptoms. In some of the patients, other nerves of the arms were said to have become involved later. Vitreous deposits have been observed frequently in this form of the disease. As with the Portuguese type, an abnormal transthyretin is the basis of the deposition of amyloid. 3. Iowa type. In 1969, van Allen described an Iowa kindred with onset, in their thirties, of a fairly severe sensorimotor neuropathy, involving the legs and then the arms. There was amyloid deposition in the testes, adrenal glands, and kidneys (the usual cause of death), as well as a high incidence of peptic ulcer disease. The amyloid in this disease is derived from a mutated apolipoprotein A1, in which there is an amino acid substitution. 4. Cranial neuropathy with corneal lattice dystrophy and facial palsies. This unusual form of amyloid neuropathy was first described in three Finnish families by Meretoja, hence the label “Finnish type.” Subsequently, it was reported from several different parts of the world in families of non-Finnish heritage. The disease usually begins in the third decade with lattice corneal dystrophy. Vitreous opacities are not observed, and visual acuity is little affected. Peripheral neuropathy may not be evident until the fifth decade, at which time the facial nerves, particularly their upper branches, become affected. The nerves of the limbs are involved even later and to a much lesser extent than in other amyloid neuropathies. In advanced cases there is a distinctive appearance of excessive skin folds about the face, facial diparesis, dysarthria, spasticity, and dense loss of posterior column function. At postmortem examination, deposits of amyloid are found in virtually every organ, mainly in the kidneys and blood vessels and in the perineurium of affected nerves. The amyloid fibrils are derived from the protein gelsolin. The latter is normally an actin-binding protein, but it is also an important constituent of basement membranes, which may explain the deposition of amyloid in the cornea and skin.

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Diagnosis of familial amyloid neuropathy  When the characteristic painful small-fiber type of sensory disturbance and autonomic changes are coupled with a family history of the same constellation, the diagnosis is not difficult. As noted in the earlier section on the acquired paraproteinemic neuropathy, the presence of a monoclonal (rarely polyclonal) immunoglobulin in the blood is found in only a limited number of patients with familial amyloid cases and it is usually just above the upper limit of normal for the immunoglobulin subclass. Otherwise the two types of amyloid diseases, FA and AL, are quite similar and, indeed, approximately 10 percent of cases considered by history and examination to be acquired will be found to have the genetic disorder (Lachmann et al 2002). The situation has been clarified by the availability of gene sequencing to detect mutations in transthyretin that are related to amyloidosis. Pathologic findings Amyloid deposits are demonstrable in the walls of blood vessels, the interstitial (endoneurial) tissues of the peripheral somatic and autonomic nerves, and in the spinal and autonomic ganglia and roots. There is a loss of nerve fibers, the unmyelinated and small myelinated fibers being more depleted than the large myelinated ones. The anterior horn and sympathetic ganglion cells are swollen and chromatolyzed because of involvement of their axons, and the posterior columns of the spinal cord degenerate, also on a secondary basis. The pathogenesis of the fiber loss in familial amyloidosis, as in the acquired type, is not fully understood. Based on their findings in a sporadic case of amyloid polyneuropathy with diabetes mellitus, Kernohan and Woltman suggested that amyloid deposits in the walls of the small arteries and arterioles interfered with the blood supply in the nerves and that amyloid neuropathy is essentially an ischemic process. In other cases, however, the vascular changes are relatively slight and the degeneration of the nerve fibers appears to be related to their compression and distortion by the endoneurial deposits of amyloid or, alternatively, there may be a direct toxic effect of the embedded amyloid. Amyloid also deposits in the tongue, gums, heart, gastrointestinal tract, kidneys, and many other organs, where it may act as a tissue toxin or has a mechanically disrupting effect on cells. Treatment  Novel approaches have been developed for the treatment or amelioration of genetic forms of a amyloid. A small molecule, tafamidis, that prevents the aggregation of amyloid fibrils by stabilizing it in a tetrameric form (Coelho et al, 2012) and interfering RNA therapy (RNAi) that reduces the production of mutant amyloid (Coelho et al, 2013) are both promising. Both have shown promise in halting or reversing familial amyloidosis (Adams et al 2018 and Benson et al). Beneficial effects have been shown in some aspects of the neuropathy but it is not clear if these are sustained. Whether the more provocative approach of gene editing by CRISPR-Cas9, which has been shown to reduce serum amyloid, will translate to clinical effects on neuropathy is being explored (Gillmore et al). Liver transplantation has proved curative of some of the familial amyloid polyneuropathies, but obviously it has no role in the acquired forms. More than 500 patients in one series had received liver transplants with a 77 percent rate

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of survival, equivalent to liver transplantation for other diseases (Herlenius and colleagues).

Problems in Diagnosis of the Chronic Polyneuropathies This is the group of peripheral nerve diseases that has given the present authors the most difficulty. The cause of acute and many of the subacute and relapsing forms of nerve disease usually can be established by widely available clinical and laboratory methods. It is the early and late chronic polyneuropathies that continue to baffle the neurologist and general physician, despite the value of EMG and nerve conduction studies and the respectable advances that have been made in the field of genetic testing.

Diagnosis of Early Chronic Polyneuropathy A sensorimotor paralysis, which evolves over several weeks (subacutely) or more slowly, over many months or a year or two, and involves legs more than arms and distal parts more than proximal should lead to a search for diabetes, occult neoplasia (carcinoma, lymphoma, multiple myeloma, or plasmacytoma), HIV, paraproteinemia (including amyloid neuropathy), systemic autoimmune disease, and CIDP. In our experience, the subacute and chronically evolving demyelinating neuropathies (over months) that have slowed motor conduction velocities, conduction block, and relatively normal needle EMG studies generally turn out to be CIDP or one of its variants, some with a paraproteinemia. Marked weakness and reduced muscle action potential amplitudes in the face of minimal denervation, even if present in only a few nerves, also indicate the presence of focal demyelination. Some of the mixed axonal–demyelinating cases in which one eventually arrives at a diagnosis will also be related to an immune (paraproteinemic) or inflammatory (CIDP) process. In exceptional cases, the neoplastic basis may remain hidden for as long as 2 or 3 years after the onset of polyneuropathy. An environmental toxin, endocrine disorder (except for diabetes), or nutritional cause is seldom identified, despite the frequent attribution of obscure polyneuropathies to such causes. Nonetheless, history of exposure to industrial or hobbyist toxins, sociopathy or psychopathy that would lead to toxin ingestion, or foreign travel should be sought and the evaluation should include testing for heavy metals in obscure cases. Unusual causes of nutritional deficiency such as celiac-sprue and other malabsorption syndromes (Whipple disease, Crohn disease, chronic hepatic disease, and particularly intestinal bypass surgery) have usually been obvious enough when present, so that the experienced clinician rarely overlooks them. Perhaps sprue is able to cause a neuropathy with minimal gastrointestinal symptoms. Vitamin B12 deficiency may be sought in cases of large-fiber neuropathy. A difficult problem is that of an older person with a mild, nonprogressive sensorimotor polyneuropathy, in whom there is evidence of mild hypothyroidism, marginally low vitamin B12 and folic acid levels in the blood, a somewhat unbalanced diet, perhaps an excessive alcohol intake, and an abnormal glucose tolerance response. It is easy to propose, but hard to prove, that any of these factors is

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relevant. Vitamin replacement can be undertaken nonetheless if no other cause is found. In the purely or predominantly sensory polyneuropathies not caused by diabetes—some painful, some not, and some with ataxia—an association with occult carcinoma, an IgM or other paraproteinemia, primary and familial amyloidosis, or Sjögren syndrome are the primary considerations. The problem of a mild sensory neuropathy in an elderly patient with or without burning feet was discussed earlier. When the symptoms are confined to the feet and legs, hereditary sensory neuropathy must always be considered if the condition is long standing. Intoxications with pyridoxine, metals, and idiosyncratic responses to therapeutic medications account for a few chronic sensory neuropathies. Despite all these considerations, we still regularly encounter patients in whom the cause is not disclosed by any of the available tests. We have watched helplessly as some of these patients were reduced to a bed and wheelchair existence and others suffered from pain until they became dependent on opiates. Table 43-7 lists the laboratory tests that we have found useful in the investigation of this group of neuropathies, with electrophysiology being the most valuable.

Diagnosis of Late Chronic Polyneuropathy The majority of these (evolving over years) prove to be genetic, either inherited or one of the infrequent sporadic mutations that are responsible for the genetic types. The observations of Dyck and coworkers (1981), referred to in the introduction to this chapter, are of interest in this respect. In a series of 205 patients who were referred to the Mayo Clinic with neuropathies of unknown cause, 86 were found to have an inherited form of disease. The proportion is presumably higher now that panels of genetic testing are available. With appropriate genealogic data, the diagnoses of the peroneal muscular atrophy of Charcot-Marie-Tooth disease can usually be made on clinical grounds alone (high arches, distal foreleg atrophy, chronicity, etc.). Sporadic cases are more difficult. Some of the patients who have consulted us in adulthood for an obscure polyneuropathy report having had operations on their feet and toes for these reasons, but the connection to a genetic neuropathy had not been previously made. Additional hints are frequent sprained ankles and the need to tape the ankles during adolescence to run or participate in sports. Dyck and associates (1981) found that direct examinations of the patients’ siblings, children, parents, and other close relatives were often successful in revealing a hereditary basis for the neuropathy. The absence of ankle reflexes or foot deformities, particularly pes cavus or prominent hammer toes, in relatives discloses the diagnosis. Genetic testing for the main forms of Charcot-MarieTooth disease is available from commercial laboratories and has increased the diagnostic certainty. A comment has already been made regarding the utility of such testing and the small number of mutations that give rise to over one-third of cases of inherited sensorimotor neuropathy. As already alluded to, individuals with a chronic demyelinating neuropathy, pes cavus or hammer toes, and a likely autosomal dominant pattern of inheritance probably

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Table 43-7 LABORATORY TESTS FOR THE INVESTIGATION OF SUBACUTE AND CHRONIC POLYNEUROPATHIES Distal Symmetric Polyneuropathiesa   Serum glucose, glucose tolerance test, hemoglobin A1c   Anti-Hu antibody   Immunoelectrophoresis of serum and urine   Antimyelin-associated glycoprotein (MAG) and SGPG  Anti-GM1 antibody (if evidence of multifocal motor conduction block)   Vitamin B12 and methylmalonic acid level   Human immune deficiency virus antibody   Lyme antibody Western blot   Heavy metal concentrations in blood and tissue   Blood urea nitrogen   Anti-gliadin and anti-transglutaminase antibodies   Vitamin E levels   Genetic testing for Charcot-Marie-Tooth disease and related hereditary neuropathies as indicated in text Mononeuropathy Multiplex   Sedimentation rate, C-reactive protein   p-ANCA, c-ANCA  Cryoglobulins  HIV   Angiotensin converting enzyme (ACE) and chest imaging for sarcoid  CMV   PMP22 deletion in appropriate circumstances   Consider nerve biopsy Sensory Ganglionopathy   Sedimentation rate, C-reactive protein  Anti-SSA/SSB   Anti-Hu and related paraneoplastic antibodies   Pyridoxine level if appropriate   Consider biopsy of minor salivary gland of lip Small-Fiber Painful Neuropathy   Serum glucose, glucose tolerance test, hemoglobin A1c  HIV   Transthyretin (TTR) mutation   Above listed testing pertaining to rheumatologic diseases   Heavy metal concentrations   Vitamin B levels and carotene   Alpha-galactosidase A concentration (Fabry disease)   Voltage-gated sodium channel sequencing (1.7)   Consider autonomic testing and skin biopsy for nerve fiber quantification   Consider abdominal fat pad biopsy for amyloidosis   Consider nerve biopsy for microscopic vasculitis a

Testing for each category of neuropathy is determined for Sjögren disease by clinical circumstances and results of electrophysiologic studies. See England et al, 2009.

have CMT1A and sequencing for PMP22 duplication may be undertaken. If there is male-to-male transmission, CMT1X is likely and the GJB1 gene may be investigated. If both genes lack causative mutations in a demyelinating case, CMT1B is possible, especially if motor nerve conduction velocities are very slow (below 15 m/s), and the MPZ gene is suspect. Whether testing beyond this, which would include the SIMPLE, PMP22, and EGR2 genes that occur in low frequency with CMT1A, is worthwhile depends on the clinical circumstances. Some cases of axonal, CMT2, will have one of several very low-frequency mutations that have been delineated. Numerous easily accessible algorithms

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for genetic testing have been published, similar to the guidance in the article by Saporta and colleagues, that are based on inheritance, nerve conduction velocity, and clinical features and we have not reproduced them here. Slowly progressive polyneuropathy with features of central nervous system degeneration, particularly cerebellar ataxia, most often has a genetic basis, but a small number are found to be the result of a genetic metabolic disorder such as a leukodystrophy. In contrast, a few young patients have come to our attention in whom a gradually progressive polyneuropathy that evolved over almost a decade turned out to be an acquired chronic inflammatory demyelinating condition rather than the expected genetic type. The absence of a family history of neuropathy or of high arches and heterogeneous slowing of both nerve conduction velocities and reductions in motor amplitudes on the nerve conduction studies provided hints to the acquired nature of the condition. Finally, it should be conceded again that even after the most assiduous clinical and laboratory investigation, a substantial proportion of chronic neuropathies remain unexplained.

Diagnosis of Recurrent or Relapsing Polyneuropathy Several types of neuropathies are particularly prone to recurrence: CIDP, Refsum disease, Tangier disease, and porphyria, the last of which may display attacks that recur spontaneously or are precipitated by the administration of various drugs. Repeated exposure to environmental toxins can do the same. Approximately 2 percent of patients with GBS have one or more relapses, in which the clinical and pathologic changes differ little between episodes. Some instances of mononeuritis multiplex, especially when associated with cryoglobulinemia, are also characterized by remissions and relapses over many years, although the remissions are incomplete. A common cause of relapse is the withdrawal of corticosteroids in CIDP patients who are dependent on these drugs; similarly, lapses in the treatment of paraproteinemic neuropathies cause similar fluctuations in symptoms. Enlargement of nerves may occur with repeated attacks from any of these diseases. It is self-evident that patients who have recovered from an episode of alcoholic–nutritional or toxic polyneuropathy will develop a recurrence if they again subject themselves to intoxication or nutritional deficiency. Neuropathic symptoms that fluctuate in relation to environmental factors such as cold (cryoglobulinemia), heat (Fabry and Tangier diseases), or intermittent exposure to heavy metal or other type of poisoning may simulate an inherently relapsing polyneuropathy.

PLEXOPATHIES AND MONONEUROPATHIES The diagnosis of this group of neuropathies rests on the finding of motor, reflex, and sensory changes confined to the territory of a single nerve; of several individual nerves affected in a random manner (mononeuritis or

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mononeuropathy multiplex); or of a plexus of nerves or part of a plexus (plexopathy). Certain neuropathies of this type—traceable mainly to polyarteritis nodosa or other vasculitides, leprosy, sarcoid, or diabetes—have already been discussed and are the main causes of the multiple mononeuropathy pattern. In addition to the signs of mononeuropathy multiplex, pain overlying the site of nerve infarction or distally is characteristic. The CSF protein is usually normal, and in certain of these diseases there is a CSF pleocytosis and slightly elevated protein (e.g., HIV, Lyme disease). Inflammatory neuropathy and the multifocal motor neuropathy caused by antibodies to GM1 also may be considered, because of their clinical similarity to this group. In identifying a process as caused by single or multiple mononeuropathies, the reader can refer to Table 43-1, which lists the roots, nerves, and muscles that are involved in particular movements, and to Table 43-4, which gives the main etiologies of mononeuropathy multiplex.

Brachial Plexus Neuropathies Brachial plexus neuropathies, or brachial plexopathies, comprise an interesting group of neurologic disorders. Most develop without apparent cause and manifest themselves by sensorimotor derangements ascribable to one or more of the cords of the plexus. Some are a result of infiltration by tumor, compression, obscure infections (possibly viral), and the delayed effects of radiotherapy. Of obvious cause are those that result from trauma, in which the arm is hyperabducted or the shoulder violently separated from the neck. Difficult births are an important source of such traction injuries to the plexus, but their nature is also readily evident. Rarely, the brachial plexus or other peripheral nerves may be damaged at the time of an electrical injury, either from lightning or from a household or industrial source (see “Electrical Injuries” in Chap. 41). Most common in this category is an idiopathic brachial plexus neuritis or plexitis of obscure origin, also called Parsonage-Turner syndrome, discussed in more detail further on. It stands apart as a special and fairly common clinical entity, often difficult to distinguish from other types of brachial and axillary pain. Some of these cases, surprisingly, are familial; others occur in small outbreaks, but most are sporadic. Direct compression of parts of the plexus by adjacent skeletal anomalies (cervical rib, fascial bands, narrowed thoracic outlet) represents another, if somewhat controversial, category of brachial plexus injury. A subcutaneous or intramuscular injection of vaccine or foreign serum was in the past sometimes followed by a brachial plexopathy (due to the aforementioned serum sickness reaction), usually a partial plexopathy. There are also plexus lesions of presumed toxic nature, such as following distal intravenous heroin injection. Granulomatous diseases such as sarcoid and secondary inflammatory processes related to lymphoma may implicate a plexus and an ischemic condition resulting from thrombosis of the subclavian artery or vein (Paget-Schrötter syndrome) is known. In assessing the type and degree of plexus injury, electrophysiologic testing is of particular importance. Early after a traumatic injury or other acute disease of the

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Chapter 43 Diseases of the Peripheral Nerves

plexus, the only electrophysiologic abnormality may be an absence of late responses (F wave). After 7 to 10 days or more, as the process of wallerian degeneration proceeds, sensory potentials are progressively lost and the amplitudes of compound muscle action potentials are variably reduced. Fibrillation potentials, indicative of denervation, then begin to appear in the corresponding muscles. Even later, usually after several weeks, signs of reinnervation can be detected. In more chronic cases, all of these features are evident when the patient is first studied. The pattern of denervated muscles allows a distinction to be made between a plexopathy, radiculopathy, and mononeuritis multiplex based on the known patterns of muscle innervation. If denervation changes are found in the paraspinal muscles, the source of weakness and pain is in the intraspinal roots, proximal to the plexus. In this case, the sensory potentials are retained. MRI may expose metastatic deposits of the plexus, but small nodular lesions may escape detection and one then defers to the clinical data if the circumstances suggest an infiltrative or compressive lesion. The anatomic plan of the brachial (and lumbosacral) plexus and their relations to blood vessels and bony structures (Fig. 43-5) and one of many detailed maps of the peripheral nerves should be consulted. We resort to the illustrations of individual nerves and plexuses that are well demonstrated in the monograph published by the Guarantors of Brain. For orientation, it is enough to remember that the brachial plexus is formed from the anterior and posterior divisions of cervical roots 5, 6, 7, and 8 and thoracic nerve root 1. The fifth and sixth cervical roots merge into the upper trunk, the seventh root forms the middle trunk, and the eighth cervical and first thoracic roots form the lower trunk. Each trunk divides into an anterior and posterior division. The posterior divisions of each trunk unite to form the posterior cord of the plexus. The anterior divisions of the upper and middle trunks unite to form the lateral cord. The anterior division of the lower trunk forms the medial cord. Two important nerves emerge from the upper trunk (dorsal scapular nerve to the rhomboid and levator scapulae muscles, and long thoracic nerve to the anterior serratus). The posterior cord gives rise mainly to the radial nerve. The medial cord gives rise to the ulnar nerve, medial cutaneous nerve to the forearm, and medial cutaneous nerve to the upper arm. This cord lies in close relation to the subclavian artery and apex of the lung and is the part of the plexus most susceptible to traction injuries and to compression by tumors that invade the costoclavicular space. The median nerve is formed by the union of parts of the medial and lateral cords.

Lesions of the Entire Brachial Plexus In this case, the entire arm is paralyzed and hangs uselessly at the side; the sensory loss is complete below a line extending from the shoulder diagonally downward and medially to the middle third of the upper arm. Biceps, triceps, radial, and finger reflexes are abolished. The usual cause is vehicular trauma that causes multiple root avulsion, especially motorcycle injury with extreme hyper extension of the shoulder.

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Upper Brachial Plexus Paralysis This is a result of injury to the distal fifth and sixth cervical roots, the most common causes of which are forceful separation of the head and shoulder during difficult delivery, pressure on the supraclavicular region during anesthesia, immune reactions to injections of foreign serum or vaccines, and idiopathic brachial plexitis (see later). The muscles affected are the biceps, deltoid, supinator longus, supraspinatus and infraspinatus, and, if the lesion is very proximal, the rhomboids. The arm hangs at the side, internally rotated and extended at the elbow. Movements of the hand and forearm are unaffected. The prognosis for spontaneous recovery is generally good, although this may be incomplete. Injuries of the upper brachial plexus and spinal roots incurred at birth (termed in older literature as Erb-Duchenne palsy) usually persist throughout life.

Lower Brachial Plexus Paralysis This is commonly the result of traction on the abducted arm in a fall or during an operation on the axilla, infiltration or compression by tumors extending from the apex of the lung (superior sulcus or Pancoast syndrome), or compression by cervical ribs or bands. Injury may occur during birth, particularly with breech deliveries (termed DejerineKlumpke paralysis). There is weakness and wasting of the small muscles of the hand and a characteristic clawhand deformity. Sensory loss is limited to the ulnar border of the hand and the inner forearm; if the first thoracic motor root is involved, there may be an associated paralysis of the cervical sympathetic nerves with a Horner syndrome. Invasion of the lower plexus by tumors is usually painful; postradiation lesions are more likely to cause paresthesias without pain (Lederman and Wilbourn, 1984).

Infraclavicular Lesions Involving Cords of the Brachial Plexus (See Fig. 43-5) A lesion of the lateral cord causes weakness of the muscles supplied by the musculocutaneous nerve and the lateral root of the median nerve; it manifests mainly as a weakness of flexion and pronation of the forearm. The intrinsic muscles of the hand innervated by the medial root of the median nerve are spared. A lesion of the medial cord of the plexus causes weakness of muscles supplied by the medial root of the median nerve and the ulnar nerve. The effect is that of a combined median and ulnar nerve palsy. A lesion of the posterior cord results in weakness of the deltoid muscle, extensors of the elbow, wrist, and fingers, and sensory loss on the outer surface of the upper arm. One group of infraclavicular injuries, often iatrogenic, results from damage to the subclavian or axillary vessels and the formation of pseudoaneurysms or hematomas. Small puncture wounds—as might occur with catheterization of the subclavian vein, anesthetic block of the brachial plexus, or transaxillary arteriography—are likely to produce this type of injury. As mentioned earlier, thrombosis of the vessels of the neurovascular subclavian bundle are a rare cause. Other frequent causes of injury to the cords are dislocation of the head of the humerus, direct axillary

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Figure 43-5.  Diagram of the brachial plexus: the components of the plexus have been separated and drawn out of scale. Note that peripheral nerves arise from various components of the plexus: roots (indicated by cervical roots 5, 6, 7, 8, and thoracic root 1); trunks (upper, middle, lower); divisions (anterior and posterior); and cords (lateral, posterior, and medial). The median nerve arises from the heads of the lateral and medial cords. (Reproduced with permission from Haymaker and Woodhall. Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders,1953.)

trauma (stab wounds), and supraclavicular compression during awkward positioning of the arm in an operation. Any cords of the plexus may be injured or they may be affected in various combinations.

Thoracic Outlet Syndrome This subject is discussed extensively in Chap. 10.

Brachial Neuritis, Brachial Plexitis (Neuralgic Amyotrophy, Parsonage-Turner Syndrome) This illness develops abruptly in an otherwise healthy individual; it may also complicate an infection, an

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injection of vaccine or antibiotic, childbirth, surgical procedures of any type, or the use of heroin. Magee and DeJong, in 1960, and Tsairis and coworkers, in 1972, reported large series of cases and amplified a wellknown clinical picture. The term neuralgic amyotrophy was applied to this symptom complex by Parsonage and Turner, who wrote extensively on the subject. Their term for the condition is appropriate, as the clinical and EMG findings suggest a lesion of the peripheral nerves of the shoulder girdle and upper arm rather than in the cords of the plexus. Actually, the site of the pathologic changes has not been established. Our patients have nearly all

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Chapter 43 Diseases of the Peripheral Nerves

been adults, ranging from 20 to 65 years of age. Males may be more susceptible. Beginning as an ache or deep burning in and around the shoulder that is typically centered over the deltoid, at the root of the neck or in the axilla and suspected at first of being only a muscle strain, the pain rapidly becomes very intense and may include a component of burning. The onset can be remarkably abrupt and occasionally awakens the patient from sleep. It is made worse by movements that involve the muscles in the region and the patient searches for a comfortable position. Narcotics are sometimes required to suppress the pain in the first days of illness. After a period of several days there is a rapid development of muscular weakness and thereafter, sensory and reflex impairment. With the development of weakness, the pain begins to subside. In a few cases, the neurologic disorder occurs with little or no antecedent pain. Possibly in some there is pain that is not followed by demonstrable weakness. A small proportion of cases are bilateral at the outset, or the opposite side is affected weeks later but most cases remain one sided. Unlike restricted radicular lesions, which almost never cause complete paralysis of a muscle because of overlapping innervations, certain muscles involved in brachial neuritis, such as the serratus anterior, deltoid, biceps, or triceps, may be totally or almost paralyzed, sometimes in isolation (see later). Rarely are all the muscles of the arm involved (4 of 99 cases of Tsairis et al). Most of the neurologic deficits in our patients have been localized around the shoulder and upper arm. Either the biceps or triceps reflex may be abolished. In a few cases there has been an additional median, radial, anterior, or posterior interosseous nerve palsy that can be detected and isolated by EMG to a site distal to the plexus (see later). Affected patients usually have no fever, leukocytosis, or increased sedimentation rate. Occasionally there is a mild pleocytosis (10 to 50 white blood cells/mm3) and slightly increased protein in the CSF, but most cases have a normal formula and sampling of CSF is not necessary for diagnosis. Recovery of paralysis and restoration of sensation are usually complete in 6 to 12 weeks, but sometimes not for a year or longer. In approximately 10 percent of cases there is residual weakness and wasting of the affected muscles and a similar number have had a recurrence sometime later on the same or the opposite side. A number of our elderly patients with this condition have had little recovery of motor function over 5 years. In a series of 246 cases described by van Alfen and colleagues that may be consulted for descriptions of the many clinical variations of this illness, they found that a considerable proportion had chronic pain and residual weakness. (Their series included idiopathic and hereditary brachial plexopathy, of the type addressed in the next section.) Motor nerve conduction (amplitude reduction) becomes impaired in 7 to 10 days, as described earlier. The lesions are presumably of axonal type, and electrophysiologic features of denervation follow. There are highly restricted forms that affect only one or two nerves of the brachial plexus, as mentioned earlier. The most common of these is probably an isolated palsy of the serratus anterior (long thoracic nerve). The suprascapular, axillary,

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posterior interosseus, and phrenic nerves are other occasional sites of solitary neuritis. In the case of a unilateral phrenic nerve paralysis, there is mild dyspnea on exertion and one hemidiaphragm is found to be elevated on the chest radiographs. When the process is not progressive and no mediastinal lesion can be detected with extensive imaging, a phrenic palsy can be assumed to fall into this idiopathic category. We have seen a Horner syndrome in association with brachial neuritis but this finding is always of greater concern as a sign an infiltrating neoplasm or granulomatous process. We have had experience with patients who had this syndrome following parvovirus B19 infection, as has been cited in the literature. Most of these cases had been preceded within days by an erythematous rash spreading from the limbs to the trunk and face, somewhat similar to the eruption of fifths disease caused by this virus in children. One of our patients had no premonitory features, but her child had just recovered from fifth disease (parvovirus) diagnosed by the pediatrician. Some patients have had preceding influenza-like symptoms and adenopathy as well or CMV infection (Duchowny and colleagues)or in persons living with HIV. A few outbreaks of brachial neuritis have been recorded and prompted the suggestion that the Coxsackievirus was the cause. Whether Lyme infection can cause brachial neuritis is unsettled, but we have seen at least one instance that was more of a cervical radiculopathy— there was a pleocytosis in the CSF. The therapeutic use of interleukin-2 and interferon has apparently precipitated a few cases. In the past, when animal antisera were in common use, this entity was frequent; in the modern era it has been seen rarely after injection of tetanus toxoid, typhoidparatyphoid vaccine, and triple vaccine (pertussis, diphtheria, and tetanus). There are several good summaries of cases in the literature (Maas and coworkers). Plexitis also occurs as an uncommon idiopathic complication of the postpartum state (Lederman and Wilbourn, 1996). Some of these are repetitive or bilateral and some are familial, but otherwise the plexopathy has no distinguishing features from the idiopathic type. The heredofamilial variety is described later. One must differentiate idiopathic brachial plexitis from the following conditions: (1) spondylosis or ruptured disc with root compression, particularly the C5 and C6 roots, in which paralysis is rarely as severe as it is in plexitis; (2) brachialgia from bursitis, labral tear, or rotator cuff syndrome; (3) polymyalgia rheumatica; (4) entrapment neuropathies, particularly of the subscapular or dorsal scapular nerve; (5) carcinomatous plexopathy; (6) radiation plexopathy; and (7) sarcoid and other granulomatous infiltrations. Dissection of the vertebral artery may rarely simulate the pain and weakness of brachial neuritis (Berroir et al). Pathologic data are sparse, but collections of intense mononuclear inflammation in fascicles of the plexus obtained by biopsy have been reported (Suarez and coworkers, 1996). Perivascular lymphocytes were found in the endoneurial space and, less so, in the epineurium. Therapy is purely symptomatic, but we have usually embarked on a course of glucocorticoids when the illness continued to advance over many weeks. These sometimes have a beneficial effect on pain and have also been

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successful in some cases of lumbosacral plexitis (see further one). Uncontrolled observations on the use of prednisolone in 50 patients have suggested that pain relief and motor outcome were better than in untreated patients (Eijk and coworkers).

Heredofamilial Brachial Plexopathy (Hereditary Neuralgic Amyotrophy, SEPN1 Mutation) Rarely, an acute and painful recurrent brachial neuropathy occurs in a familial pattern. The inheritance is autosomal dominant and the attacks, occur most commonly in the second and third decades of life. The authors have observed this syndrome in 3 generations of a family, some members having had 5 attacks at ages ranging from 3 to 45 years. We have had experience with the contemporaneous onset of brachial plexitis in an adult brother and sister who shared the same household but had no family history of a similar problem. A shared exposure to viral or environmental agents was suspected. Lower cranial nerve involvement and mononeuropathies in other limbs are conjoined in some instances (Taylor). Attacks may be spontaneous or precipitated by compression, slight stretching, or minor trauma to the region of the plexus. In one family, attacks have been triggered by events that activate the immune system (fevers, infections, surgical procedures). In several such families, there are subtle characteristic facial features including narrowed and horizontally positioned eyes and a long nasal bridge (Modigliani face). Cleft palate and unusual skin folds and creases have been observed in other kindreds (Jeannet et al). The typical course is usually benign with good recovery of each episode, but residual deficits may accumulate after recurrent attacks. In Dutch families affected by the disease, Alfen and colleagues have pointed out that some patients experience a more chronic and undulating course rather than discrete attacks. Examination of the sural nerves from two patients with familial recurrent brachial neuropathy showed, in teased single nerve fibers, sausage-like segments of thickened myelin and redundant loops of myelin with secondary constriction of the axon (Madrid and Bradley). In addition, nerve fibers showed a considerable degree of segmental demyelination and remyelination. They called this aberration of myelin formation “tomaculous” neuropathy (from tomaculum, “sausage”), changes that are now appreciated as valid but relatively nonspecific. The genetic basis for this is a mutation of SEPN1. Another cause of recurrent brachial palsy, or of derivative syndromes involving nerves in the arms, is HNPP, discussed in the earlier section on inherited neuropathies and due to a deletion in the PMP22 gene (“Hereditary Neuropathy With Pressure Palsies”). As commented there, the gene defect is also on chromosome 17, but it is not the one associated with familial brachial neuritis (see Chance et al). Some confusion has arisen because CMT1A, HNPP, and the familial brachial palsy disease all have chromosome 17 defects. Pressure palsies in HNPP are painless and there is usually an underlying and slowly advancing polyneuropathy. In some families, the distinction between hereditary neuralgic amyotrophy (HNA) and HNPP was unclear as the recurrent brachial plexopathies were painful

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(consistent with the former), but there was also a painless multifocal sensory neuropathy (consistent with the latter) (Thomas and Ormerod).

Brachial Neuropathy following Radiation Therapy This is usually a complication of irradiation of the axilla for carcinoma of the breast. In a group of 117 such patients who were treated with high-voltage, small-field therapy and had received either 6,300 or 5,775 cGy in divided doses, 73 percent developed weakness and sensory loss in the hand and fingers between 4 and 30 months after treatment, most of them after 12 months (Stoll and Andrews). In one autopsied case, the brachial plexus was ensheathed in dense fibrous tissue; distal to this zone, both myelin and axons had disappeared (wallerian degeneration), presumably as a result of entrapment of nerves in fibrous tissue; possibly a vascular factor was also operative. An analysis of the brachial plexus lesions in 100 patients with cancer, also found that doses exceeding 6,000 cGy were associated with radiation damage (Kori and coworkers). Usually, the upper plexus was involved and was sometimes associated with a painless lymphedema. Myokymic discharges and fasciculations are particularly suggestive of radiation damage. In patients who received lower doses, the development of brachial plexopathy usually indicated tumor infiltration; these lesions affected the lower plexus more than the upper; they were often painful and accompanied by Horner syndrome (Lederman and Wilbourn, 1984). Rarely, radiation may give rise many years later to a malignant tumor of nerve or the surrounding connective tissue, a sarcoma in two cases familiar to us. These high doses of radiation are no avoided or delivered in fractions that reduce the likelihood of damage to the plexus.

Herpes Zoster Plexitis, Neuritis, and Ganglionitis (See Chap. 32) This organism is perhaps the best-defined infectious cause of the above listed syndromes, but its identification is usually obvious based on the skin eruption of shingles and the disorder is usually confined to a single or two adjacent dermatomes in immunocompetent patients. Cases are known in which radicular pain precedes the eruption by many days or in which shingles do not appear, thereby simulating a herniated disc (zoster sine herpete). These conditions are discussed with the other viral infections of the nervous system in Chap. 32.

Brachial Mononeuropathies (See Table 43-1) Long Thoracic Nerve (of Bell) This nerve is derived from the fifth, sixth, and seventh cervical nerves and supplies the serratus anterior muscle, which fixates the lateral scapula to the chest wall. Paralysis of this muscle results in an inability to raise the arm over the head and winging of the medial border of the scapula when the outstretched arm is pushed forward against resistance. The nerve is injured most commonly by carrying heavy weights on the shoulder or by strapping the shoulder to the operating table. As stated earlier, the neuropathy may be the only

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Chapter 43 Diseases of the Peripheral Nerves

affected nerve in a brachial plexus neuropathy of either the inherited or idiopathic variety (Phillips).

Suprascapular Nerve This nerve is derived from the fifth (mainly) and sixth cervical nerves and supplies the supraspinatus and infraspinatus muscles. Lesions may be recognized by the presence of atrophy of these muscles and weakness of the first 15 degrees of abduction (supraspinatus) and of external rotation of the arm at the shoulder joint (infraspinatus). The latter muscle is tested by having the patient flex the forearm and then, pinning the elbow to the side, asking him to swing the forearm backward against resistance. This nerve is often involved as a result of a herniated C5-C6 disc (see Chap. 10), or as part of a brachial plexus neuropathy of either the sporadic or inherited type. It may be affected during infectious illnesses and may be injured in gymnasts, or as a result of local pressure from carrying heavy objects on the shoulder (“meatpacker’s neuropathy”). An entrapment syndrome has also been reported; it is characterized by pain and weakness on external rotation of the shoulder joint with atrophy of the infraspinatus muscle (Table 43-8). Decompression of the nerve where it enters the spinoglenoid notch relieves the condition.

Axillary Nerve This nerve arises from the posterior cord of the brachial plexus (mainly from the C5 root, with a smaller contribution from C6) and supplies the teres minor and deltoid muscles. It may be involved in dislocations of the shoulder joint, fractures of the neck of the humerus, disc protrusion, and brachial neuritis; in other instances, no cause may be apparent. The anatomic diagnosis depends on recognition Table 43-8 ENTRAPMENT NEUROPATHIES NERVE

SITE OF ENTRAPMENT

Suprascapular Lower trunk or medial cord of branchial plexus Median  Wrist  Elbow

Spinoglenoid notch Cervical rib or band at thoracic outlet   Carpal tunnel Between heads of pronator teres (pronator syndrome)a   Guyon’s canal (ulnar tunnel) Bicipital groove, cubital tunnel Radial tunnel—at point of entrance into supinator muscle (arcade of Frohse)a Inguinal ligament

Ulnar  Wrist  Elbow Posterior interosseous nerve Lateral femoral cutaneous (meralgia paresthetica) Obturator Posterior tibial Interdigital plantar (Morton metatarsalgia) a

Obturator canala Tarsal tunnel; medial malleolus– flexor retinaculuma Plantar fascia: between heads of third and fourth metatarsals

These are not well-defined syndromes and may be subject to overdiagnosis. Alternative diagnoses should be considered. For example, multifocal motor neuropathy and brachial neuritis account for cases that may be incorrectly attributed to radial tunnel syndrome and cases of distal sensory neuropathy may be attributed to tarsal tunnel syndrome.

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of paralysis of abduction of the arm (in testing this function, the angle between the side of the chest and the arm must be greater than 15 degrees and less than 90 degrees), wasting of the deltoid muscle, and slight impairment of sensation over the outer aspect of the shoulder.

Musculocutaneous Nerve The origin of this nerve is from the fifth and sixth cervical roots. It is a branch of the lateral cord of the brachial plexus and innervates the biceps brachii, brachialis, and coracobrachialis muscles. Lesions of the nerve result in wasting of these muscles and weakness of flexion of the supinated forearm. Sensation may be impaired along the radial and volar aspects of the forearm (lateral cutaneous nerve). Isolated lesions of this nerve are usually the result of fracture of the humerus.

Radial Nerve This nerve is derived from the sixth to eighth (mainly the seventh) cervical roots and is the distal extension of the posterior cord of the brachial plexus. It innervates the triceps, brachioradialis, and supinator muscles, and continues below the elbow as the posterior interosseous nerve, which innervates the extensor muscles of the wrist and fingers, the main abductor of the thumb (the abductor pollicis longus, which is easier to isolate than the median nerve innervated abductor pollicis brevis), and the extensors of the fingers at both joints. A complete proximal radial nerve lesion results in paralysis of extension of the elbow, flexion of the elbow with the forearm midway between pronation and supination (a result of paralysis of the brachioradialis muscle), supination of the forearm, extension of the wrist and fingers, and extension and abduction of the thumb in the plane of the palm. If the lesion is confined to the posterior interosseous nerve, only the extensors of the wrist and fingers are affected. Sensation is impaired over the posterior aspects of the forearm and over a small area on the radial aspect of the dorsum of the hand. The radial nerve may be compressed in the axilla (“crutch” palsy), but more frequently at a lower point, where the nerve winds around the humerus (see Table 43-8); pressure palsies incurred during an alcoholic stupor and fractures of the humerus commonly injure the nerve at the site of injury. It is susceptible to lead intoxication and is frequently involved as part of brachial neuritis and mononeuritis multiplex.

Median Nerve This nerve originates from the fifth cervical to the first thoracic roots but mainly from the sixth cervical root and is formed by the union of the medial and lateral cords of the brachial plexus. It innervates the pronators of the forearm, long finger flexors, and abductor and opponens muscles of the thumb and is a sensory nerve to the palmar aspect of the hand. Complete interruption of the median nerve results in inability to pronate the forearm or flex the hand in a radial direction, paralysis of flexion of the index finger and terminal phalanx of the thumb, weakness of flexion of the remaining fingers, weakness of opposition and abduction of the thumb in the plane at a right angle to the palm

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(abductor and flexor pollicis brevis), and sensory impairment over the radial two-thirds of the palm and dorsum of the distal phalanges of the index and third fingers. The nerve may be injured in the axilla by dislocation of the shoulder and in any part of its course by stab, gunshot, or other types of wounds, and like the radial nerve, is often a component of the mononeuritis multiplex syndrome. Incomplete lesions of the median nerve between the axilla and wrist may result in causalgia (see further on). Carpal tunnel syndrome (See also Chap. 10.)  Compression of the median nerve at the wrist (carpal tunnel syndrome) is the most common disorder affecting the median nerve and the most frequent nerve entrapment syndrome. The problem arises usually as a result of excessive use of the hands and occupational microtrauma. Infiltration of the transverse carpal ligament with amyloid (as occurs in multiple myeloma and amyloidosis) or thickening of connective tissue in rheumatoid arthritis, acromegaly, mucopolysaccharidosis, and hypothyroidism are less commonly identified causes. It is also common for the condition to make its appearance during pregnancy. In elderly individuals, the cause of the carpal tunnel syndrome is often not apparent. According to Kremer and colleagues, it was McArdle, in 1949, who first suggested that the cause of this syndrome was compression of the median nerve at the wrist and that the symptoms would be relieved by division of the flexor retinaculum forming the ventral wall of the carpal tunnel. Dysesthesias and pain in the fingers, referred to for many years as “acroparesthesia” came to be recognized as a syndrome of median nerve compression only in the early 1950s. The syndrome is essentially a sensory one; the loss or impairment of superficial sensation affects the palmar aspect of the thumb and the index and middle fingers (especially the index finger) and may or may not split the ring finger (splitting does not occur with a plexus or root lesion). The paresthesias are characteristically worse during the night. As pointed out in Chap. 10, the pain in carpal tunnel syndrome may radiate into the forearm and even into the region of the biceps and rarely, to the shoulder. Weakness and atrophy of the abductor pollicis brevis and other median-innervated muscles occur in only advanced cases of compression. Electrophysiologic testing confirms the diagnosis by demonstrating prolonged sensory conduction across the wrist and explains cases in which operation has failed (see the review by Stevens). Several provocative tests are useful. The Phalen maneuver consists of hyperflexion of the wrist for 30 to 60 s—usually performed by opposing the outer surfaces of the hands with the wrists flexed. The Tinel sign is elicited by lightly tapping the volar aspect of the wrist at the transverse carpal ligament (distal to the first wrist crease). Both of these tests are meant to elicit pain or paresthesias over the digits innervated by the median nerve. The sensitivity of these tests is close to 50 percent, but their specificity is considerably higher. Other tests involving prolonged pressure over the median nerve have been devised, but they are of uncertain value, for example, Durken’s test of the Phalen maneuver combined with digital compression of the nerve. Treatment  Surgical division of the carpal ligament with decompression of the nerve is curative but is required

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only in severe and protracted cases. Splinting of the wrist to limit flexion almost always relieves the discomfort but denies the patient the full use of the hand for some time. It is a useful temporizing measure for a few weeks, as is the injection of hydrocortisone into the carpal tunnel. Studies of oral corticosteroids give conflicting results. Treatment of an underlying condition such as arthritis, hypothyroidism and possibly diabetes, is often helpful. Some patients have benefited, paradoxically, from the stopping of corticosteroids or estrogen. Also, some practitioners favor the use of nonsteroid anti-inflammatory medication, but we have been generally unimpressed with the results. Often, splinting and local steroid injections are satisfactory in the short term, especially if the symptoms are of recent onset. Another less common site of compression of the median nerve is at the elbow, where the nerve passes between the two heads of the pronator teres, or just above that point behind the bicipital aponeurosis. It gives rise to the “pronator syndrome,” in which forceful pronation of the forearm produces an aching pain (see Table 43-8). There is weakness of the abductor pollicis brevis and opponens muscles and numbness of the first three digits and palm.

Ulnar Nerve This nerve is derived from the eighth cervical and first thoracic roots. It innervates the ulnar flexor of the wrist, the ulnar half of the deep finger flexors, the adductors and abductors of the fingers, the adductor of the thumb, the third and fourth lumbricals, and muscles of the hypothenar eminence. Complete ulnar paralysis is manifest by a characteristic clawhand deformity; wasting of the small hand muscles results in hyperextension of the fingers at the metacarpophalangeal joints and flexion at the interphalangeal joints. The flexion deformity is most pronounced in the fourth and fifth fingers, as the lumbrical muscles of the second and third fingers, supplied by the median nerve, counteract the deformity. Sensory loss occurs over the fifth finger, the ulnar aspect of the fourth finger, and the ulnar border of the palm. The ulnar nerve is vulnerable to pressure in the axilla from the use of crutches, but it is most commonly injured at the elbow by fracture or dislocation involving the joint. Delayed (tardive) ulnar palsy may occur many months or years after an injury to the elbow that had resulted in a cubitus valgus deformity of the joint. Because of the deformity, the nerve is stretched in its groove over the ulnar condyle and its superficial location renders it vulnerable to compression. A shallow ulnar groove, quite apart from abnormalities of the elbow joint, may expose the nerve to compressive injury from more innocuous situations such as prolonged resting of the arm on the side of a chair or even excessive flexion of the elbow. Anterior transposition of the ulnar nerve is a simple and effective form of treatment for these types of ulnar palsies. Compression of the nerve may occur just distal to the medial epicondyle, where it runs beneath the aponeurosis of the flexor carpi ulnaris (cubital tunnel). Flexion at the elbow causes a narrowing of the tunnel and constriction of the nerve. This type of ulnar palsy is treated by incising the aponeurotic arch between the olecranon and medial epicondyle. Yet another site of ulnar nerve compression is in the ulnar tunnel at the wrist.

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Prolonged pressure on the ulnar part of the palm may result in damage to the deep palmar branch of the ulnar nerve, causing weakness of small hand muscles but no sensory loss. This site is most often implicated in patients who hold tools or implements tightly in the hand for long periods (we have seen it in machinists and professional cake decorators). The lesion is localizable by nerve conduction studies. A syndrome of burning pain (causalgia) and associated symptoms (causalgia) may follow incomplete lesions of the ulnar nerve (or other major nerves of the limbs) and is described further on.

Lumbosacral Plexus and Crural Neuropathies The twelfth thoracic, first to fifth lumbar, and first, second, and third sacral spinal nerve roots compose the lumbosacral plexuses and innervate the muscles of the lower extremities (Fig. 43-6 and Table 43-1). The following are the common plexus and crural nerve palsies.

Lumbosacral Plexus Lesions Extending as it does from the upper lumbar area to the lower sacrum and passing near several lower abdominal and pelvic organs, this plexus is subject to a number of special injuries and diseases. The cause may be difficult to ascertain because the primary disease is often not within reach of the palpating fingers, either from the abdominal

L1

L1

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side or through the anus and vagina; even refined radiologic techniques may not reveal it. Diagnosis involves exclusion of spinal root (cauda equina) lesions by EMG, examination of CSF if root disease is likely, and MRI of the plexus. The clinical findings help to focus studies on the appropriate part of the lumbosacral plexus. The main effects of upper lumbar plexus lesions are weakness of flexion and adduction of the thigh and extension of the leg, with sensory loss over the anterior thigh and leg; these effects must be distinguished from the symptoms and signs of femoral neuropathy (see later). Lower plexus lesions weaken the posterior thigh, leg, and foot muscles and abolish sensation over the first and second sacral segments (sometimes the lower sacral segments also). Lesions of the entire plexus, which occur infrequently, cause weakness or paralysis of all leg muscles with atrophy, areflexia, and anesthesia from the toes to the perianal region and autonomic loss with warm, dry skin. The types of lesions that involve the lumbosacral plexus are rather different from those affecting the brachial plexus. Cancer, diabetes, and an idiopathic variety have dominated our material. Trauma is a rarity except with massive pelvic, spinal, and abdominal injuries because the plexus is so well protected. Occasionally, a pelvic fracture will damage the sciatic nerve as it issues from the plexus. In contrast, some part of the plexus may be damaged during surgical procedures on abdominal and pelvic organs, often for reasons that may not be entirely clear. For example,

Lumbosacral trunk

2

Superior gluteal n.

3

Inferior gluteal n.

2

Iliohypogastric n. Ilioinguinal n.

3

3 4 Inferior hemorrhoidal n.

Sciatic n.

Lateral cutaneous n. of thigh

4

Genitofemoral n.

4 Dorsal n. of penis 5

Femoral n.

Posterior cutaneous n. of thigh

Perineal n. Pudendal n.

Obturator n. Lumbosacral trunk

Figure 43-6.  Diagram of the lumbar plexus (left) and the sacral plexus (right). The lumbosacral trunk is the liaison between the lumbar and the sacral plexuses. (Reproduced with permission from Haymaker and Woodhall. Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.)

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hysterectomy has on a number of occasions led to neurologic consultation in our hospitals because of numbness and weakness of the anterior thigh. Either the cords of the upper part of the plexus or the femoral nerve were compressed by retraction against the psoas muscle, or in vaginal hysterectomy (when thighs are flexed, abducted, and externally rotated) the femoral nerve was compressed against the inguinal ligament. A similar injury may be associated with vaginal delivery (see further on). Lumbar sympathectomy has also been associated with upper plexus lesions, of which the most disabling sequelae are burning pain and hypersensitivity of the anterior thigh. Appendectomy, pelvic explorations, and hernial repair may injure branches of the upper plexus (ilioinguinal, iliohypogastric, and genitofemoral nerves), with severe pain and slight sensory loss in the distribution of one of these nerves. The pain may last for months or a year or more. The lumbar plexus may be compressed by an aortoiliac atherosclerotic aneurysm. Usually there is pain that radiates to the hip, the anterior thigh, and occasionally the flank. Slight weakness in hip flexion and altered sensation over the anterior thigh are found on examination. Plexus involvement with tumors is commonplace and presents special difficulties in diagnosis. Carcinoma of either the cervix or prostate may seed along the perineurial lymphatics and cause pain in the groin, thigh, knee, or back without much in the way of sensory, motor, or reflex loss. The pain is more often unilateral than bilateral. The CSF and spinal canal (by MRI) are normal. Testicular, uterine, ovarian, and colonic tumors or retroperitoneal lymphomas, by extending along the paravertebral gutter, implicate various parts of the lumbosacral plexus. Instances of endometriosis that involve the plexus have also been reported, in which case pain fluctuates in parallel with the menstrual cycle (a similar condition exists that implicates only the sciatic nerve). The neurologic symptoms are projected at a distance in the leg and may or may not be confined to the territory of any one nerve. Pelvic and rectal examinations may be negative, and CT scanning and MRI may be necessary to show such lesions. If all these examinations are negative, exploratory laparotomy may have to be undertaken. In cancer patients, it is sometimes difficult to distinguish the effects of radiation on the lumbosacral plexus from those of metastatic tumor, as is the case in relation to the brachial plexus. Again, the earliest symptom in metastatic lumbosacral plexopathy is usually pain, whereas in radiation plexopathy it is weakness (Thomas et al). Plexopathy from metastatic tumor is usually unilateral and detectable by CT scanning; radiation plexopathy is as often bilateral and changes are not evident in CT or MRI scans. Fasciculations and myokymia are more likely to be seen in patients with radiation plexopathy, which seemingly occurs more frequently in patients with diabetic neuropathy. Sarcoidosis is another cause and may be responsive to corticosteroids. Reference has already been made to femoral nerve injury during parturition, but other puerperal complications are also observed. Back pain in the latter part of pregnancy is, of course, common, but there are instances

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in which the patient complains of severe pain in the back of one or both thighs during labor and after delivery has numbness and weakness of the leg muscles with diminished ankle jerks. Parturitional lumbosacral plexus injuries occur with a frequency of 1 per 2,000 deliveries. This injury is usually unilateral and is manifest by pain in the thigh and leg and symptoms and signs of involvement of the superior gluteal and sciatic nerves (Feasby et al). The attribution of these symptoms to pressure of the fetal head on the sacral plexus(es) is conjectural. A limited plexopathy, occurring after difficult vaginal delivery, mainly impairs sensation in the perineum and sphincteric function (Ismael et al). The perineal muscles may show signs of denervation. Protrusion of an intervertebral disc may also occur during delivery and simulate plexus injury. Idiopathic lumbosacral plexitis In addition to the diabetic type detailed earlier in the chapter, an idiopathic neuralgic amyotrophy or lumbosacral plexitis, analogous to the brachial variety, has been observed. Bradley and coworkers have recorded such cases and their paper can be referred to for the clinical details. After causing widespread unilateral or bilateral sensory, motor, and reflex changes in a leg, lumbosacral plexitis may leave the patient with dysesthesias as troublesome as those that follow herpes zoster (which also may occur at this level). Loss of sweating and warmth of the feet indicate interruption of autonomic fibers by lesions in peripheral nerves rather than in roots. The sedimentation rate may be elevated. Dyck and colleagues (2000) inferred an autoimmune basis from biopsy material and immunosuppressant drugs were possibly beneficial in four of six cases reported by Bradley and coworkers. The outcome is variable with complete recovery being uncommon. Diabetic amyotrophy caused by involvement of the lumbar plexus and roots was discussed in an earlier section (“Diabetic Multiple Mononeuropathies and Radiculoplexus Neuropathy”).

Lateral Cutaneous Nerve of the Thigh (Meralgia Paresthetica) This sensory nerve originates from the second and third lumbar roots and supplies the anterolateral aspect of the thigh from the level of the inguinal ligament almost to the knee. The nerve penetrates the psoas muscle, crosses the iliacus, and passes into the thigh by coursing between the attachments of the lateral part of the inguinal ligament to just anterior to the anterior superior iliac spine. Compression (entrapment) may occur at the point where it passes between the two prongs of attachment of the inguinal ligament. Compression of the nerve results in uncomfortable paresthesias and sensory impairment in its cutaneous distribution, a common condition known as meralgia paresthetica (meros, “thigh”). Usually numbness and mild sensitivity of the skin are the only symptoms, but occasionally there is a persistent distressing burning pain. Perception of touch and pinprick are reduced in the territory of the nerve; there is no weakness of the quadriceps or diminution of the knee jerk. The symptoms are characteristically worsened in certain positions and after prolonged standing

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Chapter 43 Diseases of the Peripheral Nerves

or walking. Occasionally, for an obese person, sitting is the most uncomfortable position. Obesity, pregnancy, and diabetes mellitus may be contributory factors. Most often the neuropathy is unilateral, but Ecker and Woltman found 20 percent of their patients to have bilateral symptoms. Most of our patients with meralgia paresthetica request no treatment once they learn of its benign character. Weight loss and adjustment of restrictive clothing and belts or correction of habitual postures that might compress the nerve are sometimes helpful. A few with the most painful symptoms have demanded a neurectomy or section of the nerve, but it is always wise to perform a lidocaine block first, so that the patient can decide whether the persistent numbness is preferable. In one specimen of nerve obtained at operation, we found a discrete traumatic neuroma. Corticosteroid injections at the point of entrapment may have helped in a few cases, but this has not been studied in a systematic way.

Obturator Nerve This nerve arises from the third and fourth and to a lesser extent the second lumbar roots. It supplies the adductors of the thigh and contributes to the innervation of the internal and external rotators. The adductors have the added function of contributing to flexing the hip. The nerve may be injured by the fetal head or forceps during the course of a difficult labor or compressed by an obturator hernia. Rarely, it is affected with diabetes, polyarteritis nodosa, and osteitis pubis and by retroperitoneal spread of carcinoma of the cervix, uterus, and other tumors (Rogers et al).

Femoral Nerve This nerve is formed from the second, third, and fourth lumbar roots. Within the pelvis it passes along the lateral border of the psoas muscle and enters the thigh beneath the Poupart ligament, lateral to the femoral artery. Branches arising within the pelvis supply the iliacus and psoas muscles. Just below the Poupart ligament the nerve splits into anterior and posterior divisions. The former supplies the pectineus and sartorius muscles and carries sensation from the anteromedial surface of the thigh; the posterior division provides the motor innervation to the quadriceps and the cutaneous innervation to the medial side of the leg from the knee to the internal malleolus. The distinction between femoral neuropathy and a third lumbar root lesion is made by detecting weakness of the hip adductor (innervated by the obturator nerve) in the case of the root lesion. Following injury to the femoral nerve, there is weakness of extension at the knee, wasting of the quadriceps muscle, and failure of fixation of the knee. The knee jerk is abolished. If the nerve is injured proximal to the origin of the branches to the iliacus and psoas muscles, there is additionally weakness of hip flexion. The most common cause of femoral neuropathy is diabetes. The nerve may also be involved by pelvic tumors. Not uncommon is injury to the nerve during pelvic operations. Usually this is the result of improper placement of retractors, which may compress the nerve directly or indirectly by undue pressure on the psoas muscle. Bleeding

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into the iliacus muscle or the retroperitoneum, observed in patients receiving anticoagulants and in hemophilia patients, is a relatively common cause of isolated femoral neuropathy (Goodfellow et al). The presenting symptom of iliacus hematoma is pain in the groin spreading to the lumbar region or thigh, in response to which the patient assumes a characteristic posture of flexion and lateral rotation of the hip. A palpable mass in the iliac fossa and the signs of femoral nerve compression (quadriceps weakness and loss of knee jerk) follow in a day or two. Infarction of the nerve may occur in the course of diabetes mellitus and polyarteritis nodosa. Not infrequently acute femoral neuropathy is of indeterminate cause.

Sciatic Nerve (See Also Chap. 10) This nerve is derived from the fourth and fifth lumbar and first and second sacral roots, for which reason a ruptured disc at any of these levels may simulate sciatic neuropathy (sciatica). The sciatic nerve supplies motor innervation to the hamstring muscles and all the muscles below the knee through its two divisions, the tibial and peroneal nerves (see later); the sciatic nerve conveys sensory impulses from the posterior aspect of the thigh, the posterior and lateral aspects of the leg, and the entire sole. In complete sciatic paralysis, the knee cannot be flexed and all muscles below the knee are paralyzed. Weakness of gluteal muscles and pain in the buttock and posterior thigh point to nerve involvement in the pelvis. Lesions beyond the sciatic notch spare the gluteal muscles but not the hamstrings. Partial compressive lesions are more common and tend to involve peroneal-innervated muscles more than tibial ones, giving the impression of a peroneal palsy. Rupture of one of the lower lumbar intervertebral discs is the most common cause of sciatica, although it does, of course, not directly involve the sciatic nerve. The associated motor and sensory findings allow localization of the root compression (L4-L5 disc compressing L5 root: pain in posterolateral thigh and leg with numbness over the inner foot and weakness of dorsiflexion of the foot and toes; L5-S1 disc compressing S1 root: pain in posterior thigh and leg, numbness of lateral foot, weakness of foot plantar flexion and loss of ankle jerk), as discussed in Chap. 10. The sciatic nerve is commonly injured by fractures of the pelvis or femur, fracture/dislocation of the hip, gunshot wounds of the buttock and thigh, and the injection of toxic substances into the lower gluteal region. Total hip arthroplasty is another cause. Tumors of the pelvis (sarcomas, lipomas) or gluteal region may compress the nerve. Sitting for a long period with legs flexed and abducted (lotus position) under the influence of narcotics or barbiturates or lying flat on a hard surface in a sustained stupor may severely injure one or both sciatic nerves or branches thereof. The nerve may be involved by neurofibromas and infections and by ischemic necrosis in diabetes mellitus and polyarteritis nodosa. Cryptogenic forms of sciatica occur and in a referral practice, are more frequent than those of identifiable cause. Partial lesions of the sciatic nerve occasionally result in causalgia (see further on). The common Morton neuroma, typically between the third and fourth metatarsals, causes interdigital or

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intermetatarsal pain and can be detected by imaging. It is subject to surgical section. Also mentioned here is a distressingly painful compression of the plantar branches of the sciatic nerve.

Common Peroneal (Fibular) Nerve Just above the popliteal fossa the sciatic nerve divides into the tibial nerve (medial, or internal, popliteal nerve) and the common peroneal nerve (lateral, or external, popliteal nerve). The latter swings around the head of the fibula to the anterior aspect of the leg, giving off the superficial peroneal nerve that provides musculocutaneous branches (to the peroneal muscles) and to the deep peroneal nerve (formerly called anterior tibial nerve). Branches of the latter supply the dorsiflexors of the foot and toes (anterior tibialis, extensor digitorum longus and brevis, and extensor hallucis longus muscles) and carry sensory fibers from the dorsum of the foot and lateral aspect of the lower half of the leg. There was weakness of dorsiflexion of the foot (foot-drop) in all of the 116 cases of common peroneal neuropathy reported by Katirji and Wilbourn, and numbness of the dorsum of the foot was present in most cases. Weakness of eversion of the foot is usually demonstrable; because inversion is a function of the L5 root and the tibial nerve, it is spared in peroneal palsy, thereby allowing a distinction between foot-drop at the two sites. (Foot eversion should be tested with the ankle passively dorsiflexed.) Pain is variable. Pressure during an operation or sleep or from tight plaster casts, obstetric stirrups, habitual and prolonged crossing of the legs while seated, and tight knee boots are the most frequent causes of injury to the common peroneal nerve. The point of compression of the nerve is where it passes over the head of the fibula. Emaciation in patients with cancer or AIDS increases the incidence of these types of compressive injuries. The nerve may also be affected in diabetic neuropathy and injured by fractures of the upper end of the fibula. A Baker cyst, which consists of inflamed synovium extending into the retropopliteal space, may compress the nerve, and it may be damaged by muscle swelling or small hematomas behind the knee in asthenic athletes. The prognosis is generally good in cases of partial paralysis.

Tibial Nerve This, the other of the two divisions of the sciatic nerve (it divides in the popliteal fossa), supplies all of the calf muscles—that is, the plantar flexors and invertors of the foot and toes—after which it continues as the posterior tibial nerve. This nerve passes through the tarsal tunnel, an osseofibrous channel that runs along the medial aspect of the calcaneus and is roofed by the flexor retinaculum. The tunnel also contains the tendons of the tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles and the vessels to the foot. The posterior tibial nerve terminates under the flexor retinaculum and divides into medial and lateral plantar nerves (supplying the small muscles of the foot). Complete interruption of the tibial nerve results in a calcaneovalgus deformity of the foot, which can no longer be plantar-flexed and inverted. There is loss of sensation over the plantar aspect of the foot.

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The posterior tibial nerve may be compressed in the tarsal tunnel (an entrapment syndrome as discussed in the following text) by thickening of the tendon sheaths or the adjacent connective tissues or by osteoarthritic changes. Neuromuscular experts have expressed concern that this is one of the over diagnosed entrapment syndromes. Tingling pain and burning over the sole of the foot develop after standing or walking for a long time. Pain in the ankle or foot is added in some cases and the pain may be referred proximally along the sciatic nerve. Pressure over the nerve in the inferior malleolar region produces pain, which radiates to the terminal distributions of the nerve. Usually there is no motor deficit. Relief is obtained by severing the flexor retinaculum.

Entrapment Neuropathies Reference has been made in several places in the preceding material to the most frequently encountered entrapment neuropathies. A nerve passing through a tight canal is trapped and subjected to constant movement or pressure, forces not applicable to nerves elsewhere. The epineurium and perineurium become greatly thickened, strangling the nerve, with the additional possibility of demyelination. Function is gradually impaired, sensory more than motor, and the symptoms fluctuate with activity and rest. The most frequently compressed nerves are the median, ulnar, peroneal, tibial, and plantar in approximately that order. It is well to keep in mind the systemic processes that enhance pressure palsies by infiltration of the nerve or surrounding tissues. The main ones are hypothyroidism, amyloid, pregnancy, and hereditary liability to pressure palsies. Table 43-8 lists the common entrapment neuropathies and the locations of compression. Detailed accounts of these disorders are contained in the monographs of Dawson and colleagues and of Asbury and Gilliatt.

Complex Regional Pain Syndrome; Causalgia, Reflex Sympathetic Dystrophy (See Chaps. 7 and 10) One unfortunate result of partial injury to a peripheral nerve is the delayed appearance of severe pain roughly in the distribution of the affected nerve. This complex problem, which consists of burning pain termed causalgia and associated local trophic and autonomic changes that had been subsumed under the term reflex sympathetic dystrophy and now, complex regional pain syndrome, is discussed further in Chap. 7 in the context of other pain syndromes and in Chap. 10.

Traumatic Interruption of Nerves Although the management of such lesions is best delegated to specialized neurosurgeons, several aspects involve the neurologist. Surgical advances have allowed the successful apposition of severed nerve ends. The current recommendation is that end-to-end suturing of the stumps within 72 h should be undertaken to repair a sharp and clean division. In cases where the nerve is found on exploration to be bluntly severed with ragged ends, most surgeons recommend tacking the free ends

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to adjacent connective tissue planes and attempting the repair in 2 to 4 weeks. Most injuries, however, are blunt and retain some continuity of the nerve. If such continuity across the traumatized region can be demonstrated by electrophysiologic examination, operation is unnecessary. In the absence of improvement in the clinical and

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electrophysiologic features after several months (up to 6 months for plexus lesions), surgical repair may facilitate limited healing. Pain that appears months or years after injury suggests the development of a neuroma at the site of nerve section; a Tinel sign at that site aids in identifying this problem.

References Adams D, Gonzalez-Duarte A, O’Riordan WD, et al: Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379:11, 2018. Adams RD, Shahani BT, Young RR: A severe pansensory familial neuropathy. Trans Am Neurol Assoc 98:67, 1973. Alfen N, Van Engelen BG, Reinders JW, et al: The natural history of hereditary neurologic amyotrophy in the Dutch population. Two distinct types? Brain 12:718, 2000. Ali Z, Carroll M, Robertson KP, Fowler CJ: The extent of small fibre sensory neuropathy in diabetics with plantar foot ulceration. J Neurol Neurosurg Psychiatry 52:94, 1989. Amato AA, Russell JA: Neuromuscular Disorders. 2nd ed. New York, McGraw-Hill, 2015. Andrade C, Canijo M, Klein D, Kaelin A: The genetic aspect of the familial amyloidotic polyneuropathy: Portuguese type of paramyloidosis. Humangenetik 7:163, 1969. Apfel SC, Schwartz S, Adornato BT, et al: Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group. JAMA 284:2215, 2000. Araki S, Mawatari S, Ohta M, et al: Polyneurotic amyloidosis in a Japanese family. Arch Neurol 18:593, 1968. Asbury AK, Aldredge H, Hershberg R, et al: Oculomotor palsy in diabetes mellitus. A clinicopathologic study. Brain 93:555, 1970. Asbury AK, Arnason BGW, Adams RD: The inflammatory lesion in acute idiopathic polyneuritis. Medicine (Baltimore) 48:173, 1969. Asbury AK, Cornblath DR: Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol 27:S21, 1990. Asbury AK, Fields HL: Pain due to peripheral nerve damage: An hypothesis. Neurology 34:1587, 1984. Asbury AK, Gilliatt RW (eds): Peripheral Nerve Disorders. London, Butterworth, 1984. Asbury AK, Picard EH, Baringer JR: Sensory perineuritis. Arch Neurol 26:302, 1972. Asbury A, Thomas PK: Peripheral Nerve Disorders, 2nd ed. London, Butterworth & Heinemann, 1995. Asbury A, Victor M, Adams RD: Uremic polyneuropathy. Arch Neurol 8:113, 1963. Attarian S, Azulay J, Chabrol B, et al: Neonatal lower motor neuron syndrome associated with maternal neuropathy with anti-GM1 IgG. Neurology 63:379, 2004. Austin JH: Observations on the syndrome of hypertrophic neuritis (the hypertrophic interstitial radiculoneuropathies). Medicine (Baltimore) 35:187, 1956. Barnhill RL, McDougall AC: Thalidomide: Use and possible mode of action in reactional lepromatous leprosy and in various other conditions. J Am Acad Dermatol 7:317, 1982. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR: Chronic inflammatory polyradiculoneuropathy: Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol 46:878, 1989.

Ropper_Ch43_p1276-p1354.indd 1349

Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR: The BrunsGarland syndrome (diabetic amyotrophy). Revisited 100 years later. Arch Neurol 48:1130, 1991. Bendixen BH, Younger DS, Hair LS, et al: Cholesterol emboli neuropathy. Neurology 42:428, 1992. Benson MD, Waddington-Cruz M, Berk JL, et al: Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 379:22, 2018. Berkowitz AL, Samuels MA. The neurology of Sjogren’s syndrome and the rheumatology of peripheral neuropathy and myelitis. Pract Neurol 14:14, 2014. Berroir S, Sarazin M, Amarenco P: Vertebral artery dissection presenting as neuralgic amyotrophy. J Neurol Neurosurg Psychiatry 72:522, 2002. Bolton CF: Peripheral neuropathies associated with chronic renal failure. Can J Neurol Sci 7:89, 1980. Bouldin TW, Hall CO, Krigman MR: Pathology of disulfiram neuropathy. Neuropathol Appl Neurobiol 6:155, 1980. Boyer O, Nevo F, Plaisier E, et al: IFN2 mutations in Charcot-MarieTooth disease with glomerulopathy. N Engl J Med 365:2377, 2011. Bradley WG, Chad D, Verghese JP, et al: Painful lumbosacral plexopathy, with elevated sedimentation rate: A treatable inflammatory syndrome. Ann Neurol 15:457, 1984. Brady RO, Schiffman R: Clinical features of and recent advances in therapy for Fabry disease. JAMA 284:2771, 2000. Brannagan TH, Pradhan A, Heiman-Patterson T, et al: High-dose cyclophosphamide without stem-cell rescue for refractory CIDP. Neurology 58:1856, 2002. Brashear A, Unverzaght FW, Farber MO, et al: Ethylene oxide neurotoxicity: A cluster of 12 nurses with peripheral and central nervous system toxicity. Neurology 46:992, 1996. Brostoff SW, Levit S, Powers JM: Induction of experimental allergic neuritis with a peptide from myelin P2 basic protein. Nature 268:752, 1977. Brown MJ, Greene DA: Diabetic neuropathy: Pathophysiology and management. In: Asbury AK, Gilliatt RW (eds): Peripheral Nerve Disorders. Boston, Butterworth, 1984, pp 126–153. Cao-Lormeau VM, Blake A, Mons S, et al: Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study. Lancet 9:387, 2016. Capasso M, Caporale CM, Pomilio F, et al: Acute motor conduction block neuropathy. Another Guillain-Barré variant. Neurology 61:617, 2003. Cavanaugh NPC, Eames RA, Galvin RJ, et al: Hereditary sensory neuropathy with spastic paraplegia. Brain 102:79, 1979. Chad D, Periser K, Bradley WG, et al: The pathogenesis of cryoglobulinemic neuropathy. Neurology 32:725, 1982. Chance PF, Lensch MW, Lipe H, et al: Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: Two distinct entities. Neurology 44:2253, 1994. Chia L, Fernandez A, Lacroix D, et al: Contribution of nerve biopsy findings to the diagnosis of disabling neuropathy in the elderly. A retrospective review of 100 consecutive patients. Brain 119:1091, 1996.

10/02/23 3:44 PM

1350

Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

Chin RL, Tseng VG, Green PH, et al: Multifocal axonal polyneuropathy in celiac disease. Neurology 66:1923, 2006. Coelho T, Adams D, Silva A, et al: Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 369:819, 2013. Coelho T, Maia L Cotto F, Silva AM, et al. Tafamidis for transthyretin familial amyloid polyneuropathy. Neurology 79:785, 2012. Collins MP: The vasculitic neuropathies: An update. Curr Opin Neurol 25:573, 2012. Collins MP, Dyck PJ, Gronseth GS, Guillevin, et al: Peripheral Nerve Society Guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy: Executive summary. J Peripher Nerv Syst 15:176, 2010. Collins MP, Periquet MI, Mendell JR, et al: Nonsystemic vasculitic neuropathy: Insights from a clinical cohort. Neurology 61:623, 2003. Croft PB, Wilkinson M: The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma. Brain 88:427, 1965. Dalakas MC: Chronic idiopathic ataxic neuropathy. Ann Neurol 19:545, 1986. Dalakas MC, Engel WK: Chronic relapsing (dysimmune) polyneuropathy: Pathogenesis and treatment. Ann Neurol 9:134, 1981a. Dalakas MC, Engel WK: Polyneuropathy with monoclonal gammopathy: Studies of 11 patients. Ann Neurol 10:45, 1981b. Dalmau J, Graus F, Rosenbaum MK, Posner JB: Anti-Hu–associated paraneoplastic encephalomyelitis/sensory neuropathy: A clinical study of 71 patients. Medicine (Baltimore) 71:59, 1992. Daughaday WH: Extreme gigantism: Analysis of growth velocity and occurrence of severe peripheral neuropathy with neuropathic joints. N Engl J Med 297:1267, 1977. Dawson DM, Hallett M, Wilbourn, AJ: Entrapment Neuropathies, 3rd ed. Boston, Lippincott-Raven, 1999. De Wals P, Deceuninck G, Toth E, et al: Risk of Guillain-Barré syndrome following H1N1 influenza vaccination in Quebec. JAMA 308:175, 2012. DeGroot K, Schmidt DK, Arlt AC, et al: Standardized neurologic evaluation of 128 patients with Wegener granulomatosis. Arch Neurol 58:1215, 2001. Delank HW, Koch G, Kohn G, et al: Familiare amyloid Polyneuropathie typus Wohlwill-Corino Andrade. Arztl Forsch 19:401, 1965. Delmont E, Azulay JP, Giorgi R, et al: Multifocal motor neuropathy with and without conduction block. Neurology 67:592, 2006. Denny-Brown D: Hereditary sensory radicular neuropathy. J Neurol Neurosurg Psychiatry 14:237, 1951. Donaghy M, Hakin RN, Bamford JM, et al: Hereditary sensory neuropathy with neurotrophic keratitis. Description of an autosomal recessive disorder with a selective reduction of small myelinated nerve fibres and a discussion of the classification of the hereditary sensory neuropathies. Brain 110:563, 1987. Dreyfus PM, Hakim S, Adams RD: Diabetic ophthalmoplegia: Report of a case with postmortem study and comments on vascular supply of human oculomotor nerve. AMA Arch Neurol Psychiatry 77:337, 1957. Duchen LW, Anjorin A, Watkins PJ, Mackay JD: Pathology of autonomic neuropathy in diabetes mellitus. Ann Intern Med 92:301, 1980. Duchowny M, Caplan L, Siber G: Cytomegalovirus infection of the adult nervous system. Ann Neurol 5:458, 1979. Dyck PJ, Daube J, O’Brien P, et al: Plasma exchange in chronic inflammatory demyelinating polyneuropathy. N Engl J Med 314:461, 1986a. Dyck PJ, Karnes JL, O’Brien P, et al: The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann Neurol 19:440, 1986b.

Ropper_Ch43_p1276-p1354.indd 1350

Dyck PJ, Kratz KM, Karnes JL, et al: The prevalence by staged severity of various types of diabetic neuropathy, and nephropathy, in a population-based cohort. Neurology 43:817, 1993. Dyck PJ, Lais AC, Ohta M, et al: Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc 50:621, 1975. Dyck PJ, Lambert EH: Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory, and autonomic neurons. In: PJ Dyck, PK Thomas, EH Lambert (eds): Peripheral Neuropathy. Philadelphia, Saunders, 1975, pp 825–867. Dyck PJ, Lambert EH: Polyneuropathy associated with hypothyroidism. J Neuropathol Exp Neurol 29:631, 1970. Dyck PJ, Low PA, Windebank AJ, et al: Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med 325:1482, 1991. Dyck PJ, Oviatt KF, Lambert EH: Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 10:222, 1981. Dyck PJB, Engelstad J, Norell J, Dyck PJ: Microvasculitis in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN): Similarity to the diabetic variety (DLSRPN). J Neuropathol Exp Neurol 59:525, 2000. Eames RA, Lange LS: Clinical and pathologic study of ischaemic neuropathy. J Neurol Neurosurg Psychiatry 30:215, 1967. Earl CJ, Fullerton PM, Wakefield GS, Schutta HS: Hereditary neuropathy with liability to pressure palsies. Q J Med 33:481, 1964. Ecker AD, Woltman WH: Meralgia paresthetica: A report of one hundred and fifty cases. JAMA 110:1650, 1938. Eftimov F, Veremuelen M, Doorn PA, et al: Long-term remission of CIDP after pulsed dexamethasone or short-term prednisolone treatment. Neurology 78:1079, 2012. England JD, Asbury AK: Peripheral neuropathy. Lancet 363:2151, 2004. England JD, Gronseth GS, Franklin G, et al: Evaluation of distal symmetric polyneuropathy: The role of laboratory and genetic testing (an evidence-based review). Muscle Nerve 39:116, 2009. Faber CG, Hoeijmakers JG, Ahn HS, et al: Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 71:26, 2012. Fagerberg SE: Diabetic neuropathy: A clinical and histological study on the significance of vascular affections. Acta Med Scand 164(Suppl 345):1, 1959. Falls HF, Jackson JH, Carey JG, et al: Ocular manifestations of hereditary primary systemic amyloidosis. Arch Ophthalmol 54:660, 1955. Farcas P, Avnum L, Frisher S, et al: Efficacy of repeated intravenous immunoglobulin in severe unresponsive Guillain-Barré syndrome. Lancet 350:1747, 1997. Feasby TE, Burton SR, Hahn AF: Obstetrical lumbosacral plexus injuries. Muscle Nerve 15:937, 1992. Feasby TE, Gilbert JJ, Brown WF, et al: An acute axonal form of Guillain-Barré polyneuropathy. Brain 109:1115, 1986. Fisher CM: An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 255:57, 1956. Fisher CM, Adams RD: Diphtheritic polyneuritis: A pathological study. J Neuropathol Exp Neurol 15:243, 1956. Forssman O, Bjorkman G, Hollender A, Englund NE: IgM-producing lymphocytes in peripheral nerve in a patient with benign monoclonal gammopathy. Scand J Haematol 11:332, 1973. Funck-Brentano JL, Cueille GF, Man NK: A defense of the middle molecule hypothesis. Kidney Int 13(Suppl 8):S31, 1978. Gaist D, Jeppesen U, Andersen M, et al: Statins and risk of polyneuropathy: A case control study. Neurology 58:1333, 2002. Garcia-Bragado F, Bernandez JM, Navarro C, et al: Peripheral neuropathy in essential mixed cryoglobulinemia. Arch Neurol 45:1210, 1988.

10/02/23 3:44 PM

Chapter 43 Diseases of the Peripheral Nerves Garland H: Diabetic amyotrophy. Br Med J 2:1287, 1955. Gemignani F, Brindani F, Alferi S, et al: Clinical spectrum of cryoglobulinemic neuropathy. J Neurol Neurosurg Psychiatry 76:1410, 2005. Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 In vivo gene editing for transthyretin amyloidosis. N Engl J Med 385:493, 2021. Goodfellow J, Fearn CB, Matthews JM: Iliacus haematoma: A common complication of haemophilia. J Bone Joint Surg Br 49B:748, 1967. Gorson KC, Allam G, Ropper AH: Chronic inflammatory demyelinating polyneuropathy: Clinical features and response to treatment in 67 consecutive patients with and without monoclonal gammopathy. Neurology 48:321, 1997. Gorson KC, Herrmann DN, Thiagarajan R, et al: Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry 79:163, 2008. Gorson KC, Ropper AH: Axonal neuropathy associated with monoclonal gammopathy of undetermined significance. J Neurol Neurosurg Psychiatry 63:163, 1997. Gorson KC, Ropper AH: Idiopathic distal small fiber neuropathy. Acta Neurol Scand 92:376, 1995. Gorson KC, Ropper AH: Positive salivary gland biopsy, Sjögren syndrome and neuropathy: Clinical implications. Muscle Nerve 28:553, 2003. Gorson KC, Ropper AH, Mureillo M, Blair R: Prospective evaluation of MRI lumbosacral root enhancement in acute GuillainBarré syndrome. Neurology 47:813, 1996. Gorson KC, Ropper AH, Weinberg DH: Upper limb predominant, multifocal inflammatory demyelinating neuropathy. Muscle Nerve 22:758, 1999. Gorson KC, Ropper AH, Weinberg DH, Weinstein R: Treatment experience in patients with anti-myelin-associated glycoprotein neuropathy. Muscle Nerve 24:778, 2001. Gorson KC, Schott C, Rand WM, et al: Gabapentin in the treatment of painful diabetic neuropathy: A placebo-controlled, doubleblind, crossover trial. J Neurol Neurosurg Psychiatry 66:251, 1999. Gosselin S, Kyle RA, Dyck PJ: Neuropathy associated with monoclonal gammopathy of undetermined significance. Ann Neurol 30:54, 1991. Grant I, Hunder GG, Homburger HA, Dyck PJ: Peripheral neuropathy associated with sicca complex. Neurology 48:855, 1997. Griffin JW, Cornblath DR, Alexander B, et al: Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren’s syndrome. Ann Neurol 27:304, 1990. Griffin JW, Li CY, Ho TW, et al: Guillain-Barré syndrome in northern China: The spectrum of neuropathological changes in clinically defined cases. Brain 118:577, 1995. Guarantors of Brain: Aids to the Examination of the Peripheral Nervous System, 2nd ed. London, Baillière-Tindall, 1986. Guillain-Barré Study Group: Plasmapheresis and acute GuillainBarré syndrome. Neurology 35:1096, 1985. Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, et al: Neuromuscular disorder as presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 63:770, 1997. Hafer-Macko CE, Sheikh KA, Li CY, et al: Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann Neurol 39:625, 1996. Hahn AF, Bolton CF, Pillay N, et al: Plasma exchange therapy in chronic inflammatory demyelinating polyneuropathy. Brain 119: 1055, 1996a. Hahn AF, Bolton CF, Zochodne D, Feasby TE: Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. Brain 119:1067, 1996b.

Ropper_Ch43_p1276-p1354.indd 1351

1351

Hanson KE, Goddard K, Lewis N, et al: Incidence of GuilllainBarre syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Network Open 2022. doi:10.1001/ jamanetworkopen.2022.8879 Harding AE, Thomas PK: Peroneal muscular atrophy with pyramidal features. J Neurol Neurosurg Psychiatry 47:168, 1984. Harding AE, Thomas PK: The clinical features of hereditary motor and sensory neuropathy: Types I and II. Brain 103:259, 1980. Hart ZH, Hoffman W, Winbaum E: Polyneuropathy, alopecia areata, and chronic lymphocytic thyroiditis. Neurology 29:106, 1979. Haymaker W, Kernohan JW: The Landry-Guillain-Barré syndrome: Clinicopathologic report of fifty fatal cases and critique of the literature. Medicine (Baltimore) 28:59, 1949. Henson RA, Urich H: Cancer and the Nervous System. Oxford, UK, Blackwell, 1982, pp 368–405. Herlenius G, Wilczek HE, Larsson M, et al: Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: Results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 77:64, 2004. Hoitsma E, Marziniak M, Faber GC, et al: Small fibre neuropathy in sarcoidosis. Lancet 359:2085, 2002. Honovar M, Tharakan JK, Hughes RAC, et al: A clinico-pathological study of Guillain-Barré syndrome: Nine cases and literature review. Brain 114:1245, 1991. Hoogendijk JE, Hensels GW, Gabreel S, et al: De novo mutation in hereditary motor and sensory neuropathy, type 1. Lancet 339:1081, 1992. Horwich MS, Cho L, Porro RS, Posner JB: Subacute sensory neuropathy: A remote effect of carcinoma. Ann Neurol 2:7, 1977. Hughes R, Sanders E, Hall S, et al: Subacute idiopathic demyelinating polyradiculoneuropathy. Arch Neurol 49:612, 1992. Hughes RAC: Guillain-Barré Syndrome. London, Springer-Verlag, 1990. Hughes RAC: Ineffectiveness of high-dose intravenous methylprednisolone in Guillain-Barré syndrome. Lancet 338:1142, 1991. Ikeda S-I, Hanyu N, Hongo M, et al: Hereditary generalized amyloidosis with polyneuropathy: Clinicopathological study of 65 Japanese patients. Brain 110:315, 1987. Illa I, Rojas R, Gallardo E, et al: Chronic idiopathic sensory ataxic neuropathy: Immunological aspects of a series of 17 patients. Rev Neurol 157:517, 2001. Ismael SS, Amarenco G, Bayle B, Kerdraon J: Postpartum lumbosacral plexopathy limited to autonomic and perineal manifestations: Clinical and electrophysiologic study of 19 patients. J Neurol Neurosurg Psychiatry 68:771, 2000. Jankovic J, Van der Linden C: Dystonia and tremor induced by peripheral trauma: Predisposing factors. J Neurol Neurosurg Psychiatry 51:1512, 1988. Jaradeh S, Dyck PJ: Hereditary motor sensory neuropathy with treatable extrapyramidal features. Arch Neurol 49:175, 1992. Jeannet PY, Watts GD, Bird TD, Chance PF: Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy. Neurology 57:1963, 2001. Johnson PC, Doll SC, Cromey DW: Pathogenesis of diabetic neuropathy. Ann Neurol 19:450, 1986. Kahn P: Anderson-Fabry disease: A histopathological study of three cases with observations on the mechanism of production of pain. J Neurol Neurosurg Psychiatry 36:1053, 1973. Kahn SN, Riches PG, Kohn J: Paraproteinemia in neurological disease: Incidence, association and classification of monoclonal immunoglobulins. J Clin Pathol 33:617, 1980. Kaltrieder HB, Talal N: The neuropathy of Sjögren’s syndrome: Trigeminal nerve involvement. Ann Intern Med 70:751, 1961.

10/02/23 3:44 PM

1352

Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

Kantarjian AD, DeJong RN: Familial primary amyloidosis with nervous system involvement. Neurology 3:399, 1953. Kaplan JG, Rosenberg R, Reinitz E, et al: Invited review: Peripheral neuropathy in Sjögren’s syndrome. Muscle Nerve 13:573, 1990. Karam C, Klein CJ, Dispenzieri A, et al: Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome. Neurology 2015;84, 1981. Kastritis E, Palladini G, Minnema MC, et al: Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. New Eng J Med 385:46, 2021. Katirji MB, Wilbourn AJ: Common peroneal mononeuropathy: A clinical and electrophysiologic study of 116 lesions. Neurology 38:1723, 1988. Katz JS, Saperstein DS, Gronseth D, et al: Distal acquired demyelinating symmetric neuropathy. Neurology 54:615, 2000. Kernohan JW, Woltman HW: Amyloid neuritis. Arch Neurol Psychiatry 47:132, 1942. Kikta DG, Breuer AC, Wilbourn AJ: Thoracic root pain in diabetes: The spectrum of clinical and electromyographic findings. Ann Neurol 11:80, 1982. King R: Atlas of Peripheral Nerve Pathology. London, Arnold, 1999. Klein CJ, Duan X, Shy ME: Inherited neuropathies: Clinical overview and update. AANEM Monograph. Muscle Nerve 48:604, 2013. Klein CM, Vernino S, Lennon VA, et al: The spectrum of autoimmune autonomic neuropathies. Arch Neurol 53:752, 2003. Koike H, Takahashi M, Ohyama K, et al: Clinicopathologic features of folate-deficiency neuropathy. Neurology 84:1026, 2015. Kori SH, Foley KM, Posner JB: Brachial plexus lesions in patients with cancer: 100 cases. Neurology 31:45, 1981. Koski CL, Gratz E, Sutherland J, et al: Clinical correlation with anti-peripheral nerve myelin antibodies in Guillain-Barré syndrome. Ann Neurol 19:573, 1986. Kremer M, Gilliatt RW, Golding JSR, Wilson TG: Acroparaesthesiae in the carpal-tunnel syndrome. Lancet 2:590, 1953. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al: Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol 66:597, 2009. Kuwabara S, Misawa S, Kanai K, et al: Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome. Neurology 71:1691, 2008. Kuwabara S, Misawa S, Mori M, et al: Long-term prognosis of chronic inflammatory demyelinating polyneuropathy—a five-year followup of 38 cases. J Neurol Neurosurg Psychiatry 77:66, 2006. Kyle RA, Bayrd ED: Amyloidosis: Review of 236 cases. Medicine (Baltimore) 54:271, 1975. Kyle RA, Dyck PJ: Neuropathy associated with the monoclonal gammopathies. In: Dyck PJ, Thomas PK (eds): Peripheral Neuropathy, 4th ed. Philadelphia, Elsevier Saunders, 2005, pp 2255–2276. Kyle RA, Kelly JJ, Dyck PJ: Amyloidosis and neuropathy. In: Dyck PJ, Thomas PK (eds): Peripheral Neuropathy, 4th ed. Philadelphia, Elsevier Saunders, 2005, pp 2427–2451. Lachmann HJ, Booth DR, Booth SE, et al: Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 346:1786, 2002. Lachmann HJ, Goodman HJ, Gilbertson JA, et al: National history and outcome in systemic AA amyloidosis. N Engl J Med 356:2361, 2007. Lafitte C: Manifestations neurologique du syndrome de GougerotSjögren primitif. Rev Neurol 154:658, 1998. Latov N, Gross RB, Kastelman J, et al: Complement-fixing antiperipheral nerve myelin antibodies in patients with inflammatory polyneuritis and with polyneuropathy and paraproteinemias. Neurology 31:1530, 1981. Lederman RJ, Wilbourn AJ: Brachial plexopathy: Recurrent cancer or radiation? Neurology 34:1331, 1984.

Ropper_Ch43_p1276-p1354.indd 1352

Lederman RJ, Wilbourn AJ: Postpartum neuralgic amyotrophy. Neurology 47:1213, 1996. Leger JM, Bouche P, Cervera P, Hauw JJ: Primary Sjögren syndrome in chronic polyneuropathy presenting in middle or old age. J Neurol Neurosurg Psychiatry 59:1276, 1995. Lewis RA, Sumner AJ, Brown MJ, Asbury AK: Multifocal demyelinating neuropathy with persistent conduction block. Neurology 32:958, 1982. Lewis T, Pickering GW: Circulatory changes in the fingers in some diseases of the nervous system with special reference to the digital atrophy of peripheral nerve lesions. Clin Sci 2:149, 1936. Lhermitte F, Fritel D, Cambier J, et al: Polynevrites au cours de traitements par la nitrofurantoine. Presse Med 71:767, 1963. Lhote F, Cohen P, Genereau T, et al: Microscopic polyangiitis: Clinical aspects and treatment. Ann Med Interne (Paris) 147:165, 1996. Loggigian EL, Kaplan RF, Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 323:1438, 1990. Logina I, Donaghy M: Diphtheritic polyneuropathy: A clinical study and comparison with Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 67:433, 1999. Low PA, Dyck PJ, Lambert EH: Acute panautonomic neuropathy. Ann Neurol 13:412, 1983. Luostarinen L, Himanen S-L, Luostarinen M, et al: Neuromuscular and sensory disturbances in patients with well treated coeliac disease. J Neurol Neurosurg Psychiatry 74:490, 2003. Lupski JR, Reid JG, Gonzaga-Jauregui C, et al: Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 362:1181, 2010. Maas JJ, Beersma MFC, Haan J, et al: Bilateral brachial plexus neuritis following parvovirus B19 and cytomegalovirus infection. Ann Neurol 40:928, 1996. Madrid R, Bradley WG: The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy). J Neurol Sci 25:415, 1975. Magee KR, DeJong RN: Paralytic brachial neuritis. JAMA 174:1258, 1960. Marquez S, Turley JJ, Peters WJ: Neuropathy in burn patients. Brain 116:471, 1993. Matthews WB, Esiri M: The migrant sensory neuritis of Wartenberg. J Neurol Neurosurg Psychiatry 46:1, 1983. Matthews WB, Squier MV: Sensory perineuritis. J Neurol Neurosurg Psychiatry 51:473, 1988. McCombe PA, McLeod JG, Pollard JD, et al: Peripheral sensorimotor and autonomic polyneuropathy associated with systemic lupus erythematosus. Brain 110:533, 1987a. McCombe PA, Pollard JD, McLeod JG: Chronic inflammatory demyelinating polyradiculoneuropathy: A clinical and electrophysiological study of 92 cases. Brain 111:1617, 1987b. McDonald TD, Faust PL, Bruno C, et al: Polyglucosan body disease simulating amyotrophic lateral sclerosis. Neurology 43:785, 1993. McGonagle TK, Levine SR, Donofrio PD, Albers JW: Spectrum of patients with EMG features of polyradiculopathy without neuropathy. Muscle Nerve 13:63, 1990. McKhann GM, Griffin JW, Cornblath DR, et al: Plasmapheresis and Guillain-Barré syndrome: Analysis of prognostic factors and the effect of plasmapheresis. Ann Neurol 23:347, 1988. Mellgren SI, Conn DL, Stevens JC, Dyck PJ: Peripheral neuropathy in primary Sjögren’s syndrome. Neurology 39:390, 1989. Mendell JR, Sahenk Z: Painful sensory neuropathy. N Engl J Med 348:1243, 2003. Meretoja J: Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms: A previously unrecognized heritable syndrome. Ann Clin Res 1:314, 1969. Moore PM, Harley JB, Fauci AS: Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 102:109, 1985.

10/02/23 3:44 PM

Chapter 43 Diseases of the Peripheral Nerves Moulingier A, Authier F-J, Baudrimont M, et al: Peripheral neuropathy in human immunodeficiency virus-infected patients with the diffuse infiltrative lymphocytosis syndrome. Ann Neurol 41:438, 1997. Nathan PW: Painful legs and moving toes: Evidence on the site of the lesion. J Neurol Neurosurg Psychiatry 41:934, 1978. Oh S: Paraneoplastic vasculitis of the peripheral nervous system. Neurol Clin 15:849, 1997. Ohnishi A, Dyck PJ: Loss of small peripheral sensory neurons in Fabry disease. Arch Neurol 31:120, 1974. Ongerboer de Visser BW, Feltkamp-Vroom TM, Feltkamp CA: Sural nerve immune deposits in polyneuropathy as a remote effect of malignancy. Ann Neurol 14:261, 1983. Pallis CA, Scott JT: Peripheral neuropathy in rheumatoid arthritis. Br Med J 1:1141, 1965. Parsonage MJ, Turner JWA: Neuralgic amyotrophy: The shoulder girdle syndrome. Lancet 1:973, 1948. Pascoe MK, Low PA, Windebank AJ, Litchy WJ: Subacute diabetic proximal neuropathy. Mayo Clin Proc 72:1123, 1997. Periquet MI, Novak V, Collins MP, et al: Painful sensory neuropathy: Prospective evaluation using skin biopsy. Neurology 52: 1641, 1999. Pestronk A, Chaudhry V, Feldman EL, et al: Lower motor neuron syndromes defined by patterns of weakness, nerve conduction abnormalities, and high titers of antiglycolipid antibodies. Ann Neurol 27:316, 1990. Phillips LH: Familial long thoracic nerve palsy: A manifestation of brachial plexus neuropathy. Neurology 36:1251, 1986. Pickett JBE, Layzer RB, Levin SR, et al: Neuromuscular complications of acromegaly. Neurology 25:638, 1975. Planté-Bordeneuve V, Guichon-Mantel A, Lacroix C, et al: The Roussy-Lévy family: From the original description to the gene. Ann Neurol 46:770, 1999. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 349:225, 1997. Prineas JW, McLeod JG: Chronic relapsing polyneuritis. J Neurol Sci 27:427, 1976. Raff MC, Sangalang V, Asbury AK: Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 18:487, 1968. Rechthand E, Cornblath DR, Stern BJ, Meyerhoff JO: Chronic demyelinating polyneuropathy in systemic lupus erythematosus. Neurology 34:1375, 1984. Refsum S: Heredopathia atactica polyneuritiformis: A familial syndrome not hitherto described. Acta Psychiatr Scand Suppl 38:1, 1946. Robitaille Y, Carpenter S, Karpati G, Dimauro S: A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes. Brain 103:315, 1980. Robson JS: Uraemic neuropathy. In: Robertson RF (ed): Some Aspects of Neurology. Edinburgh, UK, Royal College of Physicians, 1968, pp 74–84. Rogers LR, Borkowski JW, Albers KH, et al: Obturator mononeuropathy caused by pelvic cancer: Six cases. Neurology 43:1489, 1993. Romero CE, Jacobs BJ, Ropper AH: Clinical characteristics of a mild sensory-fasciculatory syndrome. Neurology 62(Suppl 5): A519, 2004. Ropper AH: Preservation of jaw power in Guillain-Barre syndrome. Lancet 1(8383):961, 1984. Ropper AH: Unusual clinical variants and signs in Guillain-Barré syndrome. Arch Neurol 43:1150, 1986a. Ropper AH: Severe acute Guillain-Barré syndrome. Neurology 36:429, 1986b. Ropper AH: Accelerated neuropathy of renal failure. Arch Neurol 50:536, 1993.

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Ropper AH: Further regional variants of acute immune polyneuropathy. Arch Neurol 51:671, 1994. Ropper AH: Chronic demyelinating polyneuropathy: Improvement after sepsis. Neurology 46:848, 1996. Ropper AH, Adelman L: Early Guillain-Barré syndrome without inflammation. Arch Neurol 49:979, 1992. Ropper AH, Gorson KC: Neuropathies associated with paraproteinemias. N Engl J Med 338:1601, 1998. Ropper AH, Gorson KC, Gooch CL, et al: Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: A randomized, double-blinded trial. Ann Neurol 65:386, 2009. Ropper AH, Kehne SM: Guillain-Barré syndrome: Management of respiratory failure. Neurology 35:1662, 1985. Ropper AH, Marmarou A: Mechanism of pseudotumor in GuillainBarré syndrome. Arch Neurol 41:259, 1984. Ropper AH, Wijdick EFM, Truax BT: Guillain-Barré Syndrome. Philadelphia, Davis, 1991. Rowland LP, Defendini R, Sheman W, et al: Macroglobulinemia with peripheral neuropathy simulating motor neuron diseases. Ann Neurol 11:532, 1982. Rukavina JG, Block WD, Jackson CE, et al: Primary systemic amyloidosis: A review and an experimental genetic and clinical study of 29 cases with particular emphasis on the familial form. Medicine (Baltimore) 35:239, 1956. Sabin TD: Temperature-linked sensory loss: A unique pattern in leprosy. Arch Neurol 20:257, 1969. Said G, Lacroix C: Primary and secondary vasculitic neuropathy. J Neurol 252:633, 2005. Said G, Lacroix C, Lozeram P, et al: Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 126:376, 2003. Said G, Lacroix C, Planto-Bordenevue U, et al: Nerve granulomas and vasculitis in sarcoid peripheral neuropathy. Brain 125:264, 2002. Said G, Slama G, Selva J: Progressive centripetal degeneration of axons in small fiber type diabetic polyneuropathy: A clinical and pathological study. Brain 106:791, 1983. Samanta A, Burden AC: Painful diabetic neuropathy. Lancet 1:348, 1985. Sandroni P, Vernino S, Klein CM, et al: Idiopathic autonomic neuropathy. Comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol 61:44, 2004. Saporta, ASD, Sottile SL, Miller LJ, et al: Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 69:22, 2011. Schaumburg HH, Berger AR, Thomas PK: Disorders of Peripheral Nerves, 2nd ed. Philadelphia, Davis, 1992. Schaumburg HH, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse. N Engl J Med 309:445, 1983. Shahani BT, Young RR, Adams RD: Neuropathic tremor: Evidence on the site of the lesion. Electroencephalogr Clin Neurophysiol 34:800, 1973. Simmons Z, Albers JW, Bromberg MB, Feldman EL: Long-term follow-up of patients with chronic demyelinating polyradiculoneuropathy without and with monoclonal gammopathy. Brain 118:359, 1995. Simovic D, Gorson KC, Ropper AH: Comparison of IgM-MGUS and IgG-MGUS polyneuropathy. Acta Neurol Scand 97:194, 1998. Sinnreich M, Klein CJ, Daube JR, et al: Chronic immune sensory polyradiculopathy. Neurology 63:1662, 2004. Smith IS, Kahn SN, Lacey BW, et al: Chronic demyelinating neuropathy associated with benign IgM paraproteinemia. Brain 106:169, 1983. Sorenson EJ, Sima AAF, Blaivas M, et al: Clinical features of perineuritis. Muscle Nerve 20:1153, 1997.

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Specks U, Wheatley CL, McDonald TJ, et al: Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener’s granulomatosis. Mayo Clin Proc 64:28, 1989. Spencer PS, Schaumburg HH, Ludolph AC (eds): Experimental and Clinical Neurotoxicology. New York, Oxford University Press, 1999. Spillane JW, Nathan PW, Kelly RE, Marsden CD: Painful legs and moving toes. Brain 94:541, 1971. Staunton H, Dervan P, Kale R, et al: Hereditary amyloid polyneuropathy in northwest Ireland. Brain 110:1231, 1987. Sterman AB, Schaumberg HH, Asbury AK: The acute sensory neuropathy syndrome: A distinct clinical entity. Ann Neurol 7:354, 1980. Stevens JC: The electrodiagnosis of the carpal tunnel syndrome. Muscle Nerve 12:99, 1987. Stewart BM: The hypertrophic neuropathy of acromegaly: A rare neuropathy associated with acromegaly. Arch Neurol 14:107, 1966. Stogbauer F, Young P, Kuhlenbaumer G, et al: Autosomal dominant burning feet syndrome. J Neurol Neurosurg Psychiatry 67:78, 1999. Stoll BA, Andrews JT: Radiation induced peripheral neuropathy. Br Med J 1:834, 1966. Suarez CM, Fealy RD, Camilleri M, Low PA: Idiopathic autonomic neuropathy. Clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology 44:1675, 1994. Suarez GA, Giannini C, Bosch EP, et al: Immune brachial plexus neuropathy: Suggestive evidence for inflammatory-immune pathogenesis. Neurology 46:559, 1996. Sumner CJ, Sheth S, Griffin JW, et al: The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60:108, 2003. Sun SF, Steib EW: Diabetic thoracoabdominal neuropathy: Clinical and electrodiagnostic features. Ann Neurol 9:75, 1981. Swanson AG, Buchan GC, Alvord EC Jr: Anatomic changes in congenital insensitivity to pain: Absence of small primary sensory neurons in ganglia, roots and Lissauer’s tract. Arch Neurol 12:12, 1965. Taylor RA: Heredofamilial mononeuritis multiplex with brachial predilection. Brain 83:113, 1960. Tesfaye S, Chaturvedi N, Easton SE, et al: Vascular risk factors and diabetic neuropathy. N Engl J Med 352:341, 2005. Thomas JE, Cascino TL, Earle JD: Differential diagnosis between radiation and tumor plexopathy of the pelvis. Neurology 35:1, 1985. Thomas PK, Ormerod IE: Hereditary neurologic amyotrophy associated with a relapsing multifocal sensory neuropathy. J Neurol Neurosurg Psychiatry 56:107, 1993. Triggs WJ, Cros D, Gominak SC, et al: Motor nerve inexcitability in Guillain-Barré syndrome. Brain 115:1291, 1992. Tsairis P, Dyck PJ, Mulder DW: Natural history of brachial plexus neuropathy: Report on 99 cases. Arch Neurol 27:109, 1972. Tuck RR, McLeod JG: Retinitis pigmentosa, ataxia, and peripheral neuropathy. J Neurol Neurosurg Psychiatry 46:206, 1983. Uchuya M, Graus F, Vega F, et al: Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal antibodies. J Neurol Neurosurg Psychiatry 60:388, 1996. Uncini A, Sabatelli M, Mignogna T, et al: Chronic progressive steroid responsive axonal polyneuropathy: A CIDP variant or a primary axonal disorder. Muscle Nerve 19:365, 1996.

Ropper_Ch43_p1276-p1354.indd 1354

Vallat JM, DeMascarel A, Bordessoule D, et al: Non-Hodgkin malignant lymphomas and peripheral neuropathies C13 cases. Brain 118:1233, 1995. van Alfen N, van Engelen BGM: The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 129:438, 2006. van Allen MW, Frohlich JA, Davis JR: Inherited predisposition to generalized amyloidosis. Neurology 19:10, 1969. van Buchem FSP, Pol G, De Gier J, et al: Congenital b-lipoprotein deficiency. Am J Med 40:794, 1966. van der Meché FGA, Schmitz PIM, the Dutch Guillain-Barré Study Group: A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med 326:1123, 1992. van Eijk JJJ, van Alfen N, Berrevoets M, et al: Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: An observational study. J Neurol Neurosurg Psychiatr 80:1120, 2008. Vermuelen M, Van Oers MH: Relapse of chronic inflammatory demyelinating polyneuropathy 5 years after autologous stem cell transplantation. J Neurol Neurosurg Psychiatry 78:1154, 2007. Visser LH, Van der Meché FGA, Van Doorn PA, et al: GuillainBarré syndrome without sensory loss (acute motor neuropathy). Brain 118:841, 1995. Vucic S, Kennerson M, Zhu D, et al: CMT with pyramidal features. Neurology 60:696, 2003. Waksman BH, Adams RD: Allergic neuritis: An experimental disease of rabbits induced by the injection of peripheral nervous tissue and adjuvants. J Exp Med 102:213, 1955. Waldenstrom J: The porphyrias as inborn errors of metabolism. Am J Med 22:758, 1957. Wartenberg R: Neuritis, Sensory Neuritis, and Neuralgia. New York, Oxford University Press, 1958, pp 233–247. Wechsler ME, Akuthota P, Jayne D, et al: Mepolixumab or palcebo for esosinophilic granulomatosis with polyangiiiis. N Engl J Med 376:1921, 2017. Weinberg DH, Simovic D, Ropper AH, Isner J: Chronic ischemic monomelic neuropathy. Neurology 57:1008, 2001. Weinshilboum RM, Axelrod J: Reduced plasma dopamine-hydroxylase activity in familial dysautonomia. N Engl J Med 285:938, 1971. Wijdicks EF, Ropper AH, Nathanson JA: Atrial natriuretic factor and blood pressure fluctuations in Guillain-Barré syndrome. Ann Neurol 27:337, 1990. Windebank AJ, Blexrud MO, Dyck PJ, et al: The syndrome of acute sensory neuropathy: Clinical features and electrophysiologic and pathologic changes. Neurology 40:584, 1990. Yeung KB, Thomas PK, King RHM, et al: The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM and IgA paraproteinemias. J Neurol 238:383, 1991. Young RR, Asbury AK, Corbett JL, Adams RD: Pure pan-dysautonomia with recovery. Brain 98:613, 1975. Yuki N, Hartung H-P: Guillain-Barré syndrome. N Engl J Med 366:2294, 2012. Zochodne DW, Bolton CF, Wells GA: Critical illness polyneuropathy: A complication of sepsis and multiple organ failure. Brain 110:819, 1987. Zuniga G, Ropper AH, Frank J: Sarcoid peripheral neuropathy. Neurology 41:1558, 1991.

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44 Diseases of the Cranial Nerves

The cranial nerves occupy a special place in neurology because examination of their function and dysfunction can provide critical information localizing lesions to the brainstem or skull base. Certain of the cranial nerves and their disorders have already been discussed: namely, disorders of olfaction in Chap. 11; of vision and extraocular muscles in Chaps. 12 and 13; of cochlear and vestibular function in Chap. 14; and craniofacial pain in Chap. 9. There remain to be described the disorders of the facial (VII) nerve and of the lower cranial nerves (IX–XII), as well as certain diseases that affect the trigeminal (V) nerve. These are considered here.

The Fifth, or Trigeminal, Nerve Anatomic Considerations The fifth nerve (Fig. 44-1) is a mixed sensory and motor nerve. It conducts sensory impulses from the greater part of the face and head; from the mucous membranes of the nose, mouth, and paranasal sinuses; and from the cornea and conjunctiva. It also provides the sensory innervation of the dura in the anterior and middle cranial fossae. The cell bodies of the sensory part of the nerve lie in the Gasserian, or semilunar, ganglion. This, the largest sensory ganglion in humans, lies in the inferomedial part of the middle cranial fossa in a recess called Meckel’s cave. The central axons of the ganglion cells form the sensory root of the nerve. These fibers, on entering the lateral mid pons, divide into short ascending and long descending branches. The former are concerned mainly with tactile and light pressure sensation and synapse with second-order neurons in the principal sensory nucleus. Proprioceptive afferents from facial muscles and the masseter also ascend to terminate in the mesencephalic nucleus. The fibers that mediate pain and temperature sensation do not end in these nuclei but form long descending branches of the spinal trigeminal tract. This pathway, which contains both facilitatory and inhibitory fibers, together with its adjacent nucleus, extends from the junction of the pons and medulla to the uppermost segments (C2 or C3) of the spinal cord (as evidenced by the relief of facial pain after medullary trigeminal tractotomy). The spinal trigeminal nucleus in the upper cervical cord is a continuation of the spinal tract of Lissauer and substantia gelatinosa, while the main trigeminal sensory nucleus in the pons and medulla is a continuation of the

nucleus of the medial lemniscus. From both the principal sensory and spinal trigeminal nuclei, second-order fibers cross to the opposite side and ascend to the thalamus in a system of fibers called the trigeminothalamic or quintothalamic tract. These fibers come to lie in the most medial part of the spinothalamic tract and the lateral part of the medial lemniscus. In addition, the secondary trigeminal neurons project to the facial and hypoglossal nuclei bilaterally, the salivatory nuclei, the cuneate nuclei of the upper cervical segments, and other cranial nerve nuclei. The principal sensory and spinal trigeminal nuclei receive fibers from the reticular formation, the thalamus, the nucleus tractus solitarius, and the somatosensory cortex. The peripheral branches of the Gasserian ganglion form the three sensory divisions of the nerve. The first (ophthalmic) division passes through the cavernous sinus and superior orbital fissure; the second (maxillary) division also passes through the cavernous sinus and leaves the middle fossa through the foramen rotundum; and the third (mandibular) does not traverse the cavernous sinus and instead exits Meckel’s cave inferiorly through the foramen ovale. The motor portion of the fifth cranial nerve, which supplies the masseter and pterygoid muscles, has its origin in the trigeminal motor nucleus in the mid pons. The exiting fibers pass underneath (but not through) the gasserian ganglion and become incorporated into the mandibular nerve. The masseter and pterygoid muscles are used in chewing and are implicated in a number of brainstem reflexes, one of which is the jaw jerk. Tapping the chin with the jaw muscles relaxed stimulates proprioceptive afferents that terminate in the mesencephalic nucleus of the midbrain, which sends collaterals to the motor nucleus of the fifth nerve and causes the masseters to contract. This reflex is enhanced in spastic bulbar (pseudobulbar) palsy. Another pontine reflex that uses afferent trigeminal sensory nerves is the blink reflex. Tapping of the brow or bridge of the nose evokes bilateral blink through activation of the orbicularis oculi muscles (facial nerve efferents). Touching the eyelids and cornea (corneal reflex) does the same. Because of their wide anatomic distribution, complete interruption of both the motor and sensory fibers of the trigeminal nerve is rarely observed. In contrast, partial dysfunction of the trigeminal nerve, particularly of the sensory

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Mesencephalic nucleus Principal sensory nucleus

Motor nucleus N. V

Gasserian ganglion Motor root fibers I

Motor nucleus N. VII

II

III

Secondary trigeminal fibers

Spinal V Nucleus N. XII

Figure 44-1.  Scheme of the trigeminal nuclei and some of the trigeminal reflex arcs. I, ophthalmic division; II, maxillary division; III, mandibular division. (Originally from Ramon y Cajal S: La Textura del Sistema Nervista del Hombre y los Vertebrados, Madrid, Moya, as adapted from Carpenter MB, Sutin J: Human Neuroanatomy, 8th ed. Baltimore, Williams & Wilkins, 1982, by permission.)

part, is common, the main symptoms being facial numbness and pain. The various cranial nerve and brainstem syndromes in which the fifth nerve is involved are listed in Tables 30-5, 33-5, and 44-1, the last in relation to stroke syndromes of the brainstem that affect the nerve in its fascicular course or in its nucleus.

Diseases Affecting the Fifth Nerve A variety of diseases may affect the peripheral branches of the trigeminal nerves, the Gasserian ganglion, and the roots (sensory and motor). Hughes has summarized them and the main ones are described below. The role of the nerve in migraine is discussed in Chap. 9. Trigeminal neuralgia (See also “Trigeminal Neuralgia” in Chap. 9) The frequent and important disease of the trigeminal nerve is trigeminal neuralgia (tic douloureux). This condition has been known since ancient times, having been described by Arateus in the first century A.D., by John Locke in 1677, by Nicolaus Andre in 1756, and by John Fothergill in 1776 (according to Katusic et al). The overall incidence rate for both sexes combined is 4.3 per 100,000

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Nucleus spinal V

persons per year, but it is higher for women than for men (in a ratio of 3:2) and is much higher in the elderly. The mean age of onset is 52 to 58 years for the idiopathic form and 30 to 35 years for the symptomatic forms, the latter being caused by trauma or vascular, neoplastic, and demyelinating diseases. In recent years, mainly from the work of Jannetta, that a proportion of cases result from compression and secondary demyelination of trigeminal nerve rootlets by small branches of the basilar artery or veins (see Love and Coakham). The characteristic features of trigeminal neuralgia are its paroxysmal facial pain, its unilaterality, the tendency to involve the second and third divisions of the trigeminal nerve, an intensity that makes the patient grimace or wince (tic), the presence of a trigger point on the face, the lack of demonstrable sensory or motor deficit, and its response in more than half of the cases to antiepileptic drugs (AEDs). The diagnosis of trigeminal neuralgia and its differentiation from other forms of intermittent facial pain described below—as well as from cluster headache, dental neuralgia, temporomandibular joint pain, and atypical facial pain—is usually not difficult, especially if there is a trigger point and

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Table 44-1 EXTRAMEDULLARY CRANIAL NERVE SYNDROMES SITE

Sphenoidal fissure Lateral wall of cavernous sinus Retrosphenoidal space fossa Apex of petrous bone Internal auditory meatus Pontocerebellar angle Jugular foramen Posterior laterocondylar space Posterior retroparotid space Posterior retroparotid space

CRANIAL NERVES INVOLVED

EPONYMIC SYNDROME

USUAL CAUSE

III, IV, ophthalmic, V, VI III, IV, ophthalmic (occasionally maxillary), V, VI II, III, IV, V, VI

Foix Tolosa-Hunt (when caused by idiopathic inflammation) Jaccoud

Invasive tumors of sphenoid bone, aneurysms Aneurysms or thrombosis of cavernous sinus; invasive tumors from sinuses and sella turcica; sometimes recurrent, benign granulomatous reactions, responsive to steroids Large tumors of middle cranial

V, VI VII, VIII

Gradenigo  

V, VII, VIII, and sometimes IX IX, X, XI

 

Petrositis, tumors of petrous bone Tumors of petrous bone (dermoids, etc.), vestibular schwannoma Vestibular schwannomas, meningiomas

IX, X, XI, XII

Collet-Sicard

IX, X, XI, XII, and Horner syndrome X and XII, with or without XI

Villaret

Tumors (glomus jugulare), venous sinus thrombosis, and aneurysms Tumors of parotid gland, carotid body; secondary and lymph node tumors, tuberculous adenitis, carotid artery dissection Same as above, and granulomatous lesions (sarcoid, fungi)

Tapia

Parotid and other tumors of, or injuries to, the high neck

Vernet

(See also Tables 30-5 and 33-5.)

no demonstrable evidence of sensory or motor impairment. Furthermore, the vascular compressive form is difficult to diagnose without high-resolution neuroimaging or exposure at operation and most such cases are therefore characterized as idiopathic until revealed as vascular in causation. In rare instances, trigeminal neuralgia is preceded or accompanied by hemifacial spasm, a combination that Cushing called tic convulsif. This combination may be indicative of a tumor (cholesteatoma), an aneurysmal dilatation of the basilar artery or one of its branches, or an arteriovenous malformation that compresses both the trigeminal and facial nerves. Trigeminal neuralgia and glossopharyngeal neuralgia (pain in the tonsillar region) may also be combined in these conditions. Trigeminal neuropathies and neuritis Of the conditions that damage the branches of the trigeminal nerve, facial and cranial injuries, and fractures are probably the most common, but they do not usually come to the attention of neurologists. The most superficial branches of the nerve—the supratrochlear, supraorbital, and infraorbital— are the ones usually involved in trauma. The sensory loss is present from the time of the injury, and partial regeneration may be attended by constant pain. Of the various inflammatory and infectious diseases that affect the trigeminal nerves or ganglia, herpes zoster ranks first. Persistent pain after herpetic infection of the trigeminal nerve is a serious problem that at times can be difficult to treat effectively. This subject is discussed in Chap. 9 with other forms of facial pain. Middle ear infections and osteomyelitis of the apex of the petrous bone may spread to the ganglion and root, also implicating the sixth cranial (abducens) nerve (Gradenigo syndrome). HIV infection has not been clearly implicated in infection of the fifth nerve (as it has in the seventh nerve), but reactivation of latent herpes zoster is seen with AIDS.

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The trigeminal root may be compressed or invaded by intracranial meningiomas, vestibular schwannomas, trigeminal schwannomas, cholesteatomas, and chordomas and by tortuous branches of the basilar artery. Sinus tumors and metastatic disease may also infiltrate the nerve, causing pain and a gradually progressive sensory loss. Demyelination at the trigeminal root entry point into the pons is another well-characterized cause in some patients with multiple sclerosis (Fig. 44-2).

Figure 44-2.  Left-sided facial sensory loss due to demyelination of the trigeminal root entry zone in a patient with multiple sclerosis. Abnormal enhancement of the nerve root is seen on T1 postgadolinium MRI.

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The ophthalmic division of the trigeminal nerve may be damaged in the wall of the cavernous sinus in combination with the third, fourth, and sixth nerves by a variety of processes, including thrombosis of the cavernous sinus. Tumors of the sphenoid bone (myeloma, metastatic carcinoma, squamous cell carcinoma, and lymphoepithelioma of the nasopharynx) may involve branches of the trigeminal nerve at their foramina of entry or exit. Perineural infiltration of superficial branches of the nerve by squamous cell skin cancers of the face is discussed further under “Multiple Cranial Nerve Palsies.” The mandibular division of the nerve may be compressed by the roots of an impacted third molar (wisdom) tooth. Well known to clinicians is a sign of numbness of the chin and lower lip from infiltration of the mental nerve as the first indication of metastatic carcinoma of the breast, prostate, or multiple myeloma. Massey and colleagues have described the details of 19 such cases of the “numb chin” sign. Neurologists also encounter instances of slowly evolving unilateral or bilateral trigeminal neuropathy in which sensory impairment is confined to the territory of the trigeminal nerve, sometimes associated with pain, paresthesias, or disturbances of taste. This type of loss of facial sensation can also occur as part of a widespread sensory neuropathy or ganglionopathy that occurs as a paraneoplastic effect of cancer (see Chap. 30) or with Sjögren syndrome or disease. As common is an association between isolated trigeminal neuropathy and immune-mediated connective tissue diseases. Of 22 such cases described by Lecky and colleagues, 9 had either scleroderma or mixed connective tissue disease, and a similar number had either organ- or nonorgan-specific serum autoantibodies. Several specific antibody tests are used to establish the diagnosis of scleroderma. The symptoms may involve the other side of the face years later. Hughes has also described cases of trigeminal neuropathy with scleroderma, lupus erythematosus, and Sjögren disease. Some patients with Sjögren syndrome manifest the trigeminal neuropathy and the associated antibodies or inflammation of the minor salivary glands well before the characteristic sicca (dry) syndrome or other systemic manifestations of the disease. Pathologic data are limited but point to an inflammatory lesion of the trigeminal ganglion or sensory root. Spillane and Wells, many decades ago, discussed an isolated trigeminal neuropathy (it had been called Spillane’s trigeminal neuritis). Four of their 16 patients had an associated paranasal sinusitis, but subsequent reports have failed to substantiate a causal relationship between sinusitis and cranial neuritis. One wonders how many of these individuals had connective tissue disease. A less common form of idiopathic trigeminal sensory neuropathy has an acute onset and a tendency to resolve completely or partially, in much the same manner as Bell’s palsy, with which it is sometimes associated (Blau et al). A recurrent variety of acute trigeminal symptoms of uncertain origin has been reported in the dental literature. Rarely a patient’s facial numbness is a component of an upper cervical intervertebral disc syndrome that included numbness on the same side of the body. Presumably, the cervical spinal trigeminal nucleus or tract was compressed. Facial numbness, of course, also occurs with diverse conditions such as syringomyelia that affect the

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spinal nucleus of the trigeminal nerve but in these conditions, there are additional signs of brainstem or upper cervical cord disease. An idiopathic pure unilateral trigeminal motor neuropathy is known but is a clinical rarity. Chia described five patients in whom an aching pain in the cheek and unilateral weakness of mastication were the main features. Electromyography (EMG) showed denervation changes in the ipsilateral masseter and temporalis muscles. The outcome was favorable. Postcontrast MRI with thin slices can disclose enhancement at the trigeminal root entry zone in a variety of inflammatory, demyelinating, and neoplastic disorders. The function of the nerve may be studied by the recording of blink reflexes. A few laboratories have developed an evoked potential test, specifically of the trigeminal nerve.

The Seventh, or Facial, Nerve Anatomic Considerations The seventh nerve is mainly a motor nerve, supplying all the muscles concerned with a facial expression on one side. The sensory component is small (the nervus intermedius of Wrisberg); it conveys taste sensation from the anterior two-thirds of the tongue and, variably, cutaneous sensation from the anterior wall of the external auditory canal. The taste fibers at first traverse the lingual nerve (a branch of the trigeminal mandibular) and then join the chorda tympani, which conveys taste sensation via the facial nerve to the nucleus of the tractus solitarius. Secretomotor fibers originate in the superior salivatory nucleus and innervate the lacrimal gland through the greater superficial petrosal nerve and the sublingual and submaxillary glands by traveling through the chorda tympani and then forming the lingual nerve (Fig. 44-3). Several other anatomic facts are worth noting. The motor nucleus of the seventh nerve lies ventral and lateral to the abducens nucleus, and the intrapontine fibers of the facial nerve partly encircle and pass dorsolaterally to the abducens nucleus before emerging from the lower pons, just lateral to the corticospinal tract. The impression made by these looping fibers of the seventh nerve is visible in the floor of the upper fourth ventricle as a protuberance, the facial colliculus. In this region of the pons, infiltrative lesions affect the sixth and seventh nerves simultaneously. The facial nerve enters the internal auditory meatus with the vestibulocochlear nerve bundle and then bends sharply forward and downward around the anterior boundary of the vestibule of the inner ear. At this angle (genu) lies the sensory ganglion (named geniculate because of its proximity to the genu). The nerve continues in its own bony channel, the facial canal, within which, just distal to the geniculate ganglion, it provides a branch to the pterygopalatine ganglion, that is, the greater superficial petrosal nerve, which exits the skull through the vidian canal and innervates the lacrimal, nasal, and palatine glands. Somewhat more distally, it gives off a small motor branch to the stapedius muscle and is then joined by the chorda tympani, which carries parasympathetic fibers that become

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Lacrimal gland

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Trigeminal ganglion

I VI II

III

Major superficial petrosal nerve

Motor nucleus N. VII

Nasal and palatine glands Pterygopalatine ganglion

C

Chorda tympani Lingual nerve

Sup. salivatory nucleus

B

A

Nucleus fasc. solitarius

Geniculate ganglion Fasc. solitarius

Submandibular gang. Sublingual gland

Submandibular gland

Motor root N. VII

Figure 44-3.  Scheme of the seventh cranial (facial) nerve. The motor fibers are represented by the solid purple line originating in the motor nucleus of VII. Parasympathetic fibers are represented by regular dashes; special visceral afferent (taste) fibers are represented by long dashes and dots. A, B, and C denote lesions of the facial nerve at the stylomastoid foramen, distal to the geniculate ganglion, and proximal to the geniculate ganglion. Disturbances resulting from lesions at each of these sites are described in the text. (Reproduced with permission from Carpenter MB, Sutin J. Human Neuroanatomy, 8th ed. Baltimore, Williams & Wilkins, 1982.)

the lingual nerve, project to the submandibular ganglion, and innervate the submandibular and sublingual glands. The motor root of the facial nerve exits the skull at the stylomastoid foramen and then passes through the parotid gland and subdivides into five branches that supply the facial muscles, the stylomastoid muscle, the platysma, and the posterior belly of the digastric muscle. A complete interruption of the facial nerve at the stylomastoid foramen paralyzes all muscles of facial expression on the same side. The corner of the mouth droops, the creases and skin folds are effaced, the forehead is unfurrowed, the palpebral fissure is widened, and the eyelids will not close completely. Upon attempted closure of the lids, both eyes roll upward (Bell phenomenon), but the one on the paralyzed side remains visible because of lack of eyelid closure. The lower lid sags also, and the punctum falls away from the conjunctiva, permitting tears to spill over the cheek. Food and secretions collect between the teeth and cheek, and saliva may dribble from the corner of the mouth. The patient complains of heaviness or numbness and sometimes an aching pain in the face, but the sensory loss can usually not be demonstrated. Taste, however, is intact because the chorda tympani has separated from the main trunk of the facial nerve proximal to the stylomastoid foramen. If the lesion is in the facial canal above the junction with the chorda tympani but below the geniculate ganglion, all the preceding symptoms are present, but in addition, the taste is lost over the anterior two-thirds of

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the tongue on the same side. The nerve to the stapedius muscle is also usually involved with a lesion at this site and there is hyperacusis (sensitivity to sudden loud sounds). If the geniculate ganglion or the motor root proximal to it is damaged, lacrimation and salivation may be reduced. Lesions at this point may also affect the adjacent eighth nerve, causing deafness, tinnitus, or dizziness.

Bell’s Palsy The most common disease of the facial nerve is Bell’s palsy (incidence rate of 23 per 100,000 people annually, according to Hauser et al). The disorder affects men and women more or less equally and occurs at all ages and all times of the year. There is controversy regarding an increased incidence in women during the third trimester of pregnancy, particularly in the 2 weeks preceding delivery and in the first 2 weeks postpartum; up to a threefold increase has been cited by some authors, but others have failed to find this disproportion. Bell palsy is probably more common in diabetic patients and possibly in those with hypertension. Regarding the causation of Bell’s palsy, a viral agent has long been suspected and such a mechanism has been established with reasonable certainty for the majority of cases (Baringer, 1996). Burgess and colleagues identified the DNA of herpes simplex virus (HSV) in the geniculate ganglion of an elderly man who died 6 weeks after the onset of Bell’s palsy. Murakami and coworkers (1996), using the polymerase chain reaction (PCR), found HSV type I in the

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endoneurial fluid surrounding the seventh nerve in 11 of 14 cases of Bell’s palsy; the fluid was obtained during surgical decompression of the nerve in severe cases. The same investigators produced facial paralysis by inoculating HSV into the ears and tongues of mice; virus antigens were then found in the facial nerve and geniculate ganglion. Varicella zoster virus (VZV) was not found in any of their patients but was isolated from patients with the Ramsay Hunt syndrome, which refers to facial palsy associated with VZV reactivation causing a vesicular rash on the pinna of the ear, palate, and/or tongue (discussed further on). Patients with fractures or other infections of the temporal bone yielded neither HSV nor VZV gene sequences. As one might expect, the opportunity to examine the facial nerve in the course of Bell’s palsy occurs very rarely. Only a handful of such cases are on record, all showing varying degrees of degeneration of nerve fibers. One case was said to show inflammatory changes, but these may have been misinterpreted (see Karnes). The onset of Bell’s palsy is acute; about one-half of cases attain maximum paralysis in 48 h and practically all within 3 or 4 days. Pain behind the ear may precede the paralysis by a day or two and, in a few patients, is intense and persistent. Although a report by the patient of fullness or numbness in the face is common, in a small number, there is hypesthesia in one or more branches of the trigeminal nerve. The explanation of this finding is not clear. Impairment of taste is present in most patients, but it rarely persists beyond the second week of paralysis. This indicates that the lesion has extended proximal to the point at which the chorda tympani joins the facial nerve. Hyperacusis or distortion of sound is then experienced in the ipsilateral ear and, as mentioned, indicates paralysis of the stapedius muscle. The facial nerve in Bell’s palsy often displays the abnormal signal on gadolinium-enhanced MRI, although this may be difficult to appreciate in axial sections if the change is in the vertical part of the facial canal. There is a mild increase of lymphocytes and mononuclear cells in the CSF in a few instances. Cases with more pronounced contrast enhancement of the facial nerve apparently have a worse prognosis (Kress). The enhancement presumably reflects inflammation and swelling along the course of the facial nerve. Fully 70 percent of patients recover completely within a month or two and 85 percent achieve near-normal facial function, as reviewed by Gilden. Recovery of taste precedes recovery of motor function; if taste returns in the first week, it is a good prognostic sign. But early recovery of some motor function in the first 5 to 7 days is the most favorable sign. EMG may be of value in distinguishing temporary conduction defects from a pathologic interruption of nerve fibers; if there is evidence of denervation after 10 days, one may expect a long delay in the onset of recovery, measured in terms of months. Recovery then proceeds by axonal regeneration, a process that may take 2 years or longer and is often incomplete. Bell’s palsy recurs in approximately 8 percent of cases in several series, presumably as a result of reactivation of the latent herpes virus (van Amstel and Devriese; Pitts et al).

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The palsy reemerges during an infection or pregnancy, or for no apparent reason. The interval between episodes is unpredictable but averages about 10 years. Recurrent forms of facial paralysis also occur with Lyme disease and sarcoidosis and in a familial variety, as mentioned below. Treatment  Protection of the eye during sleep is generally employed in the management of Bell’s palsy. There is no evidence that surgical decompression of the facial nerve is effective, and it may be harmful. The administration of prednisone (40 to 60 mg/d, or an equivalent glucocorticoid) during the first week to 10 days after onset was shown to be beneficial in a randomized placebo-controlled trials by Sullivan and colleagues and by Engstrom and colleagues. Glucocorticoids are thought to decrease the possibility of permanent paralysis from swelling of the nerve in the tight facial canal. The finding of viral genome surrounding the seventh nerve suggested that antiviral agents might be useful in the management of Bell’s palsy. Most evidence from randomized trials, however, particularly the one conducted by Sullivan and colleagues, fails to support the use of these drugs alone or in combination with steroids. On the other hand, in one study Hato and colleagues suggested an additive benefit of treatment with valacyclovir and prednisolone compared to treatment with prednisolone alone, particularly in the group of patients presenting with complete facial palsy. An earlier trial by De Diego and colleagues did not affirm this. In appropriate circumstances, testing should be undertaken for infectious causes that would require alternative therapy (e.g., Lyme, HIV, and perhaps mycoplasma), but this is not routinely required. The treatment of facial palsy caused by VZV (Ramsay Hunt syndrome) with antiviral drugs is discussed later.

Other Causes of Facial Palsy Lyme disease (borreliosis) commonly involves the facial nerve, as indicated in Chap. 31. The mechanism is uncertain, but there is, so far, no evidence of direct spirochetal infection of the nerve. The diagnosis is likely when there has been a tick bite with well-documented erythema migrans or arthritis. Some Lyme-infected patients develop almost simultaneous facial palsy and mild distal sensory polyneuropathy. HIV infection is another wellknown infectious cause of facial palsy. The facial palsy of both Lyme and HIV infections is associated with a pleocytosis in the spinal fluid, for which reason serologic and CSF examination may be useful if there is suspicion of either process. Rarely, chicken pox in children may be followed in 1 to 2 weeks by facial paralysis. Tuberculous infection of the mastoid and middle ear or of the petrous bone is a cause of facial paralysis in parts of the world where this infection is particularly common. Facial palsy may occur during or soon after infectious mononucleosis and was observed occasionally in poliomyelitis. The facial nerve is also frequently involved in leprosy. Bilateral involvement of the facial nerve is commented on further on. The nerve is often involved in sarcoidosis, where the lesion is probably in the meninges, as discussed in the following section.

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The Ramsay Hunt syndrome, caused by herpes zoster of the geniculate ganglion, consists of a facial palsy associated with a vesicular eruption in the external auditory canal, other parts of the cranial integument, and mucous membrane of the oropharynx. This infection may be initially indistinguishable from Bell’s palsy as the vesicles may not become apparent for days. Often the eighth cranial nerve is affected as well, causing nausea, vertigo, and deafness. The virus can be detected even before the emergence of typical vesicles by collecting exudate from the skin of the pinna on a Schirmer strip (otherwise used to quantitate tearing) and applying PCR techniques (Murakami and colleagues). In this way, in a matter of a few hours, they documented VZV infection in 71 percent of patients with Ramsay Hunt syndrome without vesicles. Currently, treatment with acyclovir, valacyclovir, or famciclovir is recommended. The randomized trial by Whitley et al and the review by Sweeney and Gilden are recommended to the interested reader. Tumors of the parotid gland or ones that invade the temporal bone (carotid body, cholesteatoma, and dermoid) or granulomatosis including the earlier mentioned sarcoidosis, or pachymeningitis at the base of the brain may produce a facial palsy; the onset is insidious and the course progressive. Fractures of the temporal bone (usually with damage to the middle or internal ear), otitis media, and middle ear surgery are uncommon causes. The orientation of the petrous fracture determines the prognosis (see discussion in Chap. 34). Acoustic and vestibular Schwannomas, neurofibromas, glomus jugulare tumors, and aneurysmal dilatations of the vertebral or basilar artery may involve the facial nerve. Pontine lesions, most often vascular or neoplastic, cause facial palsy, usually in conjunction with other neurologic signs. Weakness of only a portion of the facial musculature, associated with numbness in the same region, may be the result of perineural tumor invasion by squamous cells or other skin cancers (see further on under “Multiple Cranial Nerve Palsies”). An autosomal dominant syndrome of facial palsy, multiple truncal café-au-lait spots, and mild developmental delay was described by Johnson and colleagues. Wilson and Hoxie have pointed out the frequent coexistence of facial asymmetry in adults with congenital or early onset superior oblique palsy and compensatory head tilt or torticollis.

Bilateral Facial Palsy Bell’s palsy may be bilateral, but only rarely is the involvement on the two sides simultaneous. The truly contemporaneous appearance of bilateral facial paralysis (facial diplegia) is most often a manifestation of the GuillainBarré syndrome (GBS) and may also occur in Lyme disease and, rarely, with HIV infection. There are numerous other causes of bilateral facial palsy, all of them infrequent. Keane (1994) listed the idiopathic (now presumably mainly viral) variety, GBS, and meningeal infiltration by tumor as the most common causes but also found 2 cases of syphilis among 43 patients. The bilateral syndrome has been reported in approximately 7 of every 1,000 patients with sarcoidosis. When acute in onset and associated with parotid

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gland swelling from sarcoidosis, it has been referred to as uveoparotid fever or Heerfordt syndrome. In typical cases of sarcoidosis, the paralysis on each side tends to be temporally separated by weeks or more. Mononucleosis may affect both sides of the face almost simultaneously; this is probably a form of GBS. Bifacial palsy is also a feature of the developmental disorder, Möbius syndrome (see Chap. 37). Less common is the inflammatory disorder known as Melkersson-Rosenthal syndrome, consisting of the triad of recurrent facial paralysis, facial (particularly labial) edema, and, less constantly, plication of the tongue. The syndrome begins in childhood or adolescence and may be familial. Biopsy of the lip or skin may reveal a granulomatous inflammation. The cause is not known, and, despite the cardinal feature of angioneurotic edema, complement levels are normal. A series of biopsied cases has been reported by Elias and colleagues. Causes of recurrent Bell’s palsy are summarized by Pitts and colleagues. Kennedy syndrome causes bifacial weakness in addition to bulbar palsy as the disease progresses; preceding facial fasciculations are characteristic. Facioscapulohumeral muscular dystrophy, as the name implies, incorporates facial weakness but would not be mistaken for Bell’s palsy (see Chap. 45). The same is true for the rare form of amyloidosis associated with crystal lattice deposits in the cornea that typically involves both facial nerves.

Facial Hemiatrophy (Parry-Romberg Syndrome) This obscure disorder occurs mainly in females and is characterized by a disappearance of fat in the dermal and subcutaneous tissues on one or both sides of the face, giving the appearance of facial paresis. It usually begins in adolescence or early adulthood and is slowly progressive. In its advanced form, the affected side of the face is gaunt and the skin thin, wrinkled, and rather dark; the hair may turn white and fall out, and the sebaceous glands become atrophic; the muscles and bones are not involved as a rule. The condition is a form of lipodystrophy, but the localization within a myotome suggests the operation of some neural factor (possibly a growth factor) of unknown nature. A variegated coloration of the iris and congenital oculosympathetic paralysis are found in some cases. Rarely, certain central nervous system abnormalities referable to the ipsilateral hemisphere (mainly focal seizures, migraine, trigeminal neuralgia, and ventricular dilatation) are conjoined (Hosten). The significance of these associations is unclear. Immunosuppressive treatment can stabilize the clinical course.

Aberrant Effects of Recovery From Facial Nerve Palsy If a peripheral facial paralysis has existed for some time and return of motor function has begun but is incomplete, a contracture with diffuse myokymic activity may appear. The palpebral fissure becomes narrowed, and the nasolabial fold deepens. Spasms of facial muscles may develop and persist indefinitely, being initiated by any facial movement. With the passage of time, the corner of the mouth and even the tip of the nose may become pulled to the affected side. Anomalous or aberrant regeneration of the seventh nerve fibers, following Bell’s palsy or other

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injuries, may result in other curious disorders that represent limited types of synkineses. If regenerating fibers originally connected with the orbicularis oculi become connected with the orbicularis oris, closure of the lids may cause a retraction of the corner of the mouth; conversely, aberrant regeneration of fibers may cause synkinetic eyelid closure during contraction of the orbicularis oris. If visceromotor fibers originally innervating the salivary glands later come to innervate the lacrimal gland, anomalous tearing occurs whenever the patient salivates; this phenomenon is referred to as “crocodile tears.” A similar mechanism explains gustatory sweating of the cheek and upper lip following injury to parasympathetic innervation of the parotid (Frey syndrome). An unusual congenital synkinesis sometimes occurs between motor trigeminal fibers and branches of the facial nerve, producing a “jaw-winking” phenomenon (also called Wartenberg or inverse Marcus-Gunn sign), in which jaw movements, especially lateral movements (engaging the pterygoid muscle), cause an involuntary closure of the eyelid ipsilateral to the movement.

Hemifacial Spasm Hemifacial spasm is a disorder of painless, irregular clonic contractions of facial muscles on one side. This condition usually develops in the fifth and sixth decades, affects women more than men, and often proves to be caused by a compressive lesion of the facial nerve, usually by a tortuous branch of the basilar artery that lies on the ventral surface of the pons and forms a loop under the proximal seventh nerve. Less often, the cause of compression is a fusiform basilar artery aneurysm or a vestibular schwannoma or meningioma. Multiple sclerosis is a rare cause. The spasm usually begins in the orbicularis oculi muscle and as the condition worsens, the contractions also occur in other muscles on that side of the face, including the platysma. Paroxysms may be induced or aggravated by voluntary and reflexive movements of the face. The pathophysiology of the spasm is believed to be focal demyelination at the site of nerve root compression by the vessel. The demyelinated axon is presumed to activate adjacent nerve fibers by ephaptic transmission (“artificial” synapse of Granit et al). Another possible source of the spasm is spontaneous ectopic excitation arising in injured fibers. Treatment  Medical treatment can be effective in some patients with hemifacial spasm. Alexander and Moses noted that carbamazepine in doses of 600 to 1,200 mg/d controls the spasm in two-thirds of the patients. Baclofen or gabapentin can be tried if carbamazepine fails. Many patients, however, cannot tolerate these drugs, have only brief remissions, or fail to respond. Serial injections with botulinum toxin injected into the orbicularis oculi and other facial muscles can be highly effective to reduce or eliminate the involuntary contractions without causing excessive weakness, and we have usually resorted to this treatment early in the course of the disorder. Some patients have been injected repeatedly for more than 5 years without apparent adverse effects. Failing these conservative measures to treat the condition, surgery may be appropriate.

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The work of Nielsen and Janetta demonstrates that microsurgical decompression of the root with the interposition of a pledget between the vessel and the facial nerve relieves the facial spasm in most patients. These results were corroborated by Barker and associates in a series of 705 patients followed postoperatively for an average period of 8 years; 84 percent achieved an excellent result. An even higher rate of benefit was obtained in a prospective series by Illingworth and colleagues (cure of 81 of 83 patients). Surgical decompression involves exploration of the posterior fossa and carries some risk. The facial muscles may be weakened, sometimes permanently. Another complication has been deafness as a result of injury of the adjacent eighth nerve. Also, there is a risk of recurrence of the spasms, usually within 2 years of the operation (Piatt and Wilkins). Tight dural closure is required to prevent CSF leakage from the posterior fossa.

Other Disorders of the Facial Nerve Facial myokymia is a fine rippling activity of all the muscles of one side of the face (discussed further in Chap. 46). It develops most often in the course of multiple sclerosis or a brainstem glioma and can be seen in some disorders of the neuromuscular junction (e.g., neuromyotonia). It has also occurred after other diseases of the facial nerve, for example, in GBS, in which case it is usually bilateral. The fibrillary nature of the involuntary movements and their arrhythmicity tend to distinguish them from the coarser intermittent facial spasms and contracture, tics, tardive dyskinesia, and focal motor seizures. The EMG pattern is one of spontaneous asynchronous discharge of adjacent motor units, appearing singly or in doublets or triplets at a rate varying from 30 to 70 cycles per second. The myokymia seen in the facial muscles is believed to result from demyelination of the intrapontine part of the facial nerve and possibly supranuclear disinhibition of the facial nucleus, but the observation of facial myokymia following some cases of GBS informs us that the abnormal movement may have its origin in a lesion at any point along the nerve. A clonic or tonic contraction of one side of the face may be the sole manifestation of a cerebral cortical seizure. When the seizure focus involves a very limited amount of motor cortex, demonstrable changes may not be evident on scalp EEG. Focal motor seizures, or epilepsia partialis continua, can often be difficult to extinguish despite multiple AEDs, though carbamazepine can be particularly helpful. Involuntary recurrent spasm of both eyelids (blepharospasm, as discussed in Chaps. 4 and 13) may occur with almost any form of dystonia but is most frequent in elderly persons as an isolated phenomenon, and there may be varying degrees of spasm of the other facial muscles. Although relaxants and tranquilizing drugs are of little help in this disorder, injections of botulinum toxin into the orbicularis oculi muscles can reduce excessive blinking. A few may be helped (paradoxically) by l-dopa. Baclofen, clonazepam, and tetrabenazine in increasing doses may be helpful as well. In the past, failing these measures, the periorbital muscles were destroyed by injections of doxorubicin or surgical myectomy. With the advent of botulinum treatment, there is no longer a need to resort to these

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Chapter 44 Diseases of the Cranial Nerves

extreme and irreversible measures. In some cases, blepharospasm subsides spontaneously. Rhythmic unilateral myoclonus, akin to palatal myoclonus (actually a tremor as noted in Chap. 4), may be restricted to facial, lingual, or laryngeal muscles. Hypersensitivity of the facial nerve occurs in hypocalcemic tetany; spasm of the facial muscles is elicited by tapping in front of the ear (Chvostek sign), but this phenomenon is also seen in many normal individuals.

The Ninth, or Glossopharyngeal, Nerve Anatomic Considerations This nerve arises from the lateral surface of the medulla by a series of small roots that lie just rostral to those of the vagus nerve. The glossopharyngeal, vagus, and spinal accessory nerves leave the skull together through the jugular foramen and are then distributed peripherally. The ninth nerve is mainly sensory, with cell bodies in the inferior, or petrosal, ganglion (the central processes of which end in the nucleus solitarius) and the small superior ganglion (the central fibers of which enter the spinal trigeminal tract and nucleus). Within the nerve are afferent fibers from baroreceptors in the wall of the carotid sinus and from chemoreceptors in the carotid body. The baroreceptors are involved in the regulation of blood pressure, and chemoreceptors are responsible for the ventilatory responses to hypoxia. The somatic efferent fibers of the ninth nerve are derived from the nucleus ambiguus, and the visceral efferent (secretory) fibers from the inferior salivatory nucleus. These fibers contribute in a limited way to the motor innervation of the striated musculature of the pharynx (mainly of the stylopharyngeus, which elevates the pharynx), the parotid gland, and the glands in the pharyngeal mucosa. A discussion of its role in swallowing is found in Chap. 25. It is commonly stated that the glossopharyngeal nerve mediates sensory impulses from the faucial tonsils, posterior wall of the pharynx, and part of the soft palate as well as taste sensation from the posterior third of the tongue. However, an isolated lesion of the ninth cranial nerve is a rarity, and therefore the effects are not fully known. In one personally observed case of bilateral surgical interruption of the ninth nerves, verified at autopsy, there had been no demonstrable loss of taste or other sensory or motor impairment. This suggests that the tenth nerve may be responsible for these functions, at least in some individuals. The role of the ninth nerve in the reflex control of blood pressure and ventilation has been alluded to earlier, but referable clinical manifestations from damage of this cranial nerve are infrequent except perhaps for syncope, as noted below. One may occasionally observe glossopharyngeal palsy in conjunction with vagus and accessory nerve involvement because of a tumor in the posterior fossa or an aneurysm or intracranial dissection of the vertebral artery, or thrombosis of the sigmoid sinus or internal jugular vein. The nerves may be compressed as they pass through the jugular foramen. Hoarseness as a result of vocal cord paralysis, some difficulty in swallowing, deviation of the soft palate to the sound side, anesthesia of the posterior wall of the pharynx, and weakness of the upper trapezius and

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sternomastoid muscles make up the clinical picture (see Table 44-1, jugular foramen syndrome). On leaving the skull, the ninth, tenth, and eleventh nerves lie adjacent to the cervical internal carotid artery, where they can be damaged (presumably made ischemic) by a dissection of that vessel.

Glossopharyngeal Neuralgia (Also Discussed in Chap. 9) This disorder, first described by Weisenburg in 1910, resembles trigeminal neuralgia in many respects except that the unilateral stabbing pain is localized to one side of the root of the tongue and throat. It is far less common than trigeminal neuralgia. Sometimes the pain overlaps the vagal territory beneath the angle of the jaw and external auditory meatus. It may be triggered by coughing, sneezing, swallowing, and pressure on the tragus of the ear. Temporary blocking of the pain by anesthetizing the tonsillar fauces and posterior pharynx with 10 percent lidocaine spray is diagnostic. Rarely, herpes zoster may involve the glossopharyngeal nerve. Fainting as a manifestation of vagoglossopharyngeal neuralgia is described in Chap. 9. The same antiepileptic and other drugs that are helpful in the treatment of tic douloureux may be used to treat glossopharyngeal neuralgia, but their efficacy is difficult to judge. Regarding vascular compression of the nerve as a cause of glossopharyngeal neuralgia, Resnick and colleagues have reported the results of microvascular decompression of the ninth nerve in 40 patients; in 32 of these, relief of symptoms was complete and was sustained during an average follow-up of 4 years; 3 patients remained with permanent weakness of structures ostensibly innervated by the ninth nerve. A similar high rate of success has been achieved by others. If syncope is associated with the pain, it can be expected to cease with abolition of the attacks of pain. Syncope can also occur when the ninth nerve is involved by tumors of the parapharyngeal space; most of these are squamous cell carcinomas and both the ninth and tenth nerves are implicated. Section of rootlets of the ninth nerve has reportedly reduced or abolished the episodes of fainting in these cases.

The Tenth, or Vagus, Nerve Anatomic Considerations This nerve has an extensive sensory and motor distribution and important autonomic functions. It has two ganglia: the jugular, which contains the cell bodies of the somatic sensory nerves (innervating the skin in the concha of the ear), and the nodose, which contains the cell bodies of the afferent fibers from the pharynx, larynx, trachea, esophagus, and thoracic and abdominal viscera. The central processes of these two ganglia terminate in the nucleus of the spinal trigeminal tract and the tractus solitarius, respectively. The motor fibers of the vagus are derived from two nuclei in the medulla—the nucleus ambiguus and the dorsal motor nucleus. The former supplies somatic motor fibers to the striated muscles of the larynx, pharynx, and palate; the latter supplies visceral motor fibers to the heart and other thoracic and abdominal organs. The distribution of vagal fibers is illustrated in Fig. 44-4, and their participation in swallowing is described in Chap. 25.

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Dorsal motor nucleus of vagus Nucleus ambiguus

Vagus n.

Glossopharyngeal n.

Spinal accessory n. Jugular foramen

Meningeal br. Auricular br.

Jugular ganglion Nodose ganglion (Muscles and mucosa of pharnyx, soft palate) (Cricothyroid m)

Pharyngeal branch Superior laryngeal br

(Mucosa and glands of larnyx and epiglottis)

Cervical vagus

Int. jugular v. Int. carotid a. Trachea and esophagus Laryngeal muscles

Recurrent laryngeal n. Superior cardiac rami Inferior cardiac rami Pulmonary branches

Figure 44-4. Anatomic features of the vagus nerve. Note the relationship to the spinal accessory and glossopharyngeal nerves at the jugular foramen and the long course of the left recurrent laryngeal nerve, which is longer than the right and hooks around the aortic arch (not shown).

Complete interruption of the intracranial portion of one vagus nerve results in a characteristic pattern of paralysis. The soft palate droops on the ipsilateral side and does not rise in phonation. The uvula often, but not always, deviates to the normal side on phonation. There is loss of the gag reflex on the affected side and of the curtain movement of the lateral wall of the pharynx, whereby the faucial pillars move medially as the palate rises in saying “ah.” The voice is hoarse, often nasal, and the vocal cord on the affected side lies immobile in a “cadaveric” position, that is, midway between abduction and adduction. With partial lesions, movements of abduction are affected more than those of adduction (Semon’s law). There may be a loss of sensation at the external auditory meatus and back of the pinna. Usually, no change in visceral function can be demonstrated with a unilateral lesion except by special autonomic testing. If the pharyngeal branches of both vagi are affected, as in diphtheria, the voice has a nasal quality,

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Distal vagus

Esophageal plexus

Anterior and posterior vagus nerves

Esophageal hiatus of diaphragm

and regurgitation of liquids through the nose occurs during the act of swallowing.

Diseases Affecting the Vagus Complete bilateral paralysis is said to be incompatible with life, and this is probably true if the nuclei are entirely destroyed in the medulla by poliomyelitis or some other disease. However, in the cervical region, both vagi were blocked with procaine in the treatment of intractable asthma in past days without mishap. Of interest in this regard, Johnson and Stern reported a case of bilateral vocal cord paralysis in association with familial hypertrophic polyneuropathy, and Plott relates three brothers with congenital laryngeal abductor paralysis caused by bilateral dysgenesis of the nucleus ambiguus. Bannister and Oppenheimer have called attention to defects of phonation and laryngeal stridor as early features of autonomic failure in multiple system atrophy

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(see Chap. 38). In some patients, stridor is a prominent feature of the illness, sometimes persisting for as much as a year before other features of the degenerative disease become evident. The vagus nerve may be implicated within the meninges by infectious, neoplastic, and inflammatory processes, within the medulla by vascular lesions (e.g., the lateral medullary syndrome of Wallenberg, as described in Chap. 33), and by motor neuron disease. Herpes zoster may attack this nerve, either alone or together with the ninth nerve as part of a jugular foramen syndrome. The vagus is often affected along with the glossopharyngeal nerve in spontaneous dissection of the carotid artery at the base of the skull. The nerves may be damaged in the course of thyroid surgery and may be involved in cases of advanced alcohol or diabetic neuropathy. Diabetes is probably the most common cause of bilateral vagal neuropathy, manifested by the loss of normal sinus arrhythmia. Finally, the vagus can be compressed by lesions of the jugular foramen as part of a multiple cranial nerve syndrome, as summarized in Table 44-1; metastatic tumors such as from the prostate or breast and jugular vein thrombosis are typical causes. A fact of some importance is that the left recurrent laryngeal nerve, because of its long course under the aortic arch, can become damaged as a result of lesions in the thorax. There is no dysphagia with lesions at this point in the nerve because the branches to the pharynx (but not to the larynx) have already been given off. For this reason, an aneurysm of the aortic arch, an enlarged left atrium, mediastinal lymph nodes from bronchogenic carcinoma, and a mediastinal or superior sulcus lung tumor are more frequent causes of an isolated (left) vocal cord palsy than intracranial diseases. It is estimated that in one-quarter to one-third of all cases of paralysis of the recurrent laryngeal nerve no cause can be established, that is, they are idiopathic. The highest incidence is in the third decade, and males are more susceptible than females. Of the 21 cases reported by Blau and Kapadia, 5 recovered completely and 5 partially within a few months; no other disease appeared in the 8-year period that followed. Berry and Blair described palsies of the superior and recurrent laryngeal nerves, occurring as part of isolated vagal neuropathies. A few were bilateral, and, again, the majority of the cases were idiopathic and had much the same prognosis as isolated palsies of the recurrent laryngeal nerve. Laryngeal neuralgia is a rare entity in which paroxysms of pain are localized over the upper portion of the thyroid cartilage or hyoid bone on one or both sides. The pain may be evoked by coughing, yawning, talking, or sneezing. In the case reported by Brownstone and coworkers, the symptoms were relieved by carbamazepine.

Neurologic Diagnosis of Vocal Cord Paralysis Clues from the history and examination can help determine the site of the lesion producing vocal cord palsy. If intramedullary, there are usually ipsilateral cerebellar signs, loss of pain and temperature sensation over the ipsilateral face and contralateral arm and leg, and an ipsilateral Bernard-Horner syndrome (see Table 33-3). If the lesion is extramedullary but intracranial, the glossopharyngeal

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and spinal accessory nerves are frequently involved as well (jugular foramen syndrome; see Table 44-1). If extracranial in the posterior lateral condylar or retroparotid space, there may be a combination of 9th, 10th, 11th, and 12th cranial nerve palsies and a Horner syndrome. Combinations of these lower cranial nerve palsies, which have a variety of eponymic designations (see Table 44-1), are caused by various tumors, both primary and metastatic, or by chronic inflammations or granulomas involving lymph nodes at the base of the skull. If there is no palatal weakness and no pharyngeal or palatal sensory loss, the lesion is below the origin of the pharyngeal branches, which leaves the vagus nerve high in the cervical region. The usual site of disease is then the mediastinum.

The Eleventh, or Spinal Accessory, Nerve Anatomic Considerations This is a purely motor nerve of spinal rather than cranial origin. Its fibers arise from the anterior horn cells of the upper 4 or 5 cervical segments and enter the skull through the foramen magnum. Intracranially, the accessory nerve travels for a short distance with the part of the tenth nerve that is derived from the caudalmost cells of the nucleus ambiguus; together, the two roots are referred to as the vagalaccessory nerve or the cranial root of the accessory nerve. The two roots together leave the skull through the jugular foramen. The vagus fibers then rejoin the main trunk of the vagus. The motor fibers derived from the upper cervical segments of the spinal cord form an “external ramus” and innervate the ipsilateral sternocleidomastoid and trapezius muscles. Only the somatic motor fibers constitute the accessory nerve in the strict sense. In patients with torticollis, however, division of the upper cervical motor roots or the spinal accessory nerve has often failed to ablate completely the contraction of the sternocleidomastoid muscle. This suggests a wider innervation of the muscle, perhaps by fibers of apparent vagal origin that join the accessory nerve for passage through the jugular foramen. The supranuclear innervation of the spinal accessory nuclei is apparently mainly ipsilateral as evidenced by contraversive turning of the head during a convulsion, the result of contraction of the ipsilateral sternocleidomastoid muscle. Whether this is attributable to a direct ipsilateral tract, or to double crossing of the supranuclear tracts, is not known. A complete lesion of the accessory nerve results in weakness of the sternocleidomastoid muscle and upper part of the trapezius (the lower part of the trapezius is innervated by the third and fourth cervical roots through the cervical plexus). Weakness of the sternocleidomastoid can be demonstrated by having the patient forcibly turn the head in the opposite direction against the examiner’s hand. When it is weak, little force will be generated and the examiner will feel that the sternocleidomastoid does not contract firmly beneath the fingers. This muscle can be further tested by having the patient press his head forward against resistance or lift his head from the pillow. Weakness of the trapezius can be demonstrated by asking the patient to shrug his shoulders; the affected side will be found to be weaker, and there will often be evident atrophy of the

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upper part of the trapezius. With the arms at the sides, the shoulder on the affected side droops and the scapula is slightly winged; the latter defect is accentuated with lateral movement of the arm (with serratus anterior weakness, winging of the scapula is more prominent and occurs on forward elevation of the arm). Motor neuron disease, poliomyelitis, syringomyelia, and spinal cord tumors may involve neurons of the spinal accessory nerve. In its intracranial portion, the nerve is usually affected along with the ninth and tenth cranial nerves by herpes zoster or by lesions of the jugular foramen (glomus tumors, neurofibromas, metastatic carcinoma, internal jugular vein thrombosis). Tumors at the foramen magnum may also damage the nerve. In the posterior triangle of the neck, the eleventh nerve can be damaged during surgical operations and by external compression or injury. Compressive and invasive lesions of the nerve may be visualized by CT or MRI of the posterior cervical space. A benign disorder of the eleventh nerve, akin to Bell’s palsy, has been described by Spillane and by Eisen and Bertrand. It begins with pain in the low lateral neck that subsides in a few days and is followed by weakness and atrophy in the distribution of the nerve. Also, a recurrent form of spontaneous accessory neuropathy has been described (Chalk and Isaacs). About one-quarter to onethird of eleventh nerve lesions are estimated to be of this idiopathic type; most, but not all, of the patients recover. Bilateral sternocleidomastoid and trapezius palsy, which occurs with primary disease of muscles—for example, polymyositis and muscular dystrophy—may be difficult to distinguish from a bilateral damage to the accessory nerves or the motor nuclei (progressive bulbar palsy).

The result is paralysis and atrophy of one side of the tongue, together with spastic paralysis and loss of vibration and position sense in the opposite arm and leg. Poliomyelitis and motor neuron disease may destroy the hypoglossal nuclei. The latter is the most common cause of a bilaterally atrophic and fasciculating tongue. Lesions of the basal meninges and of the occipital bones (tumor invasion, platybasia, invagination of the occipital condyles, Paget disease) may involve the nerve in its extramedullary course, and it is sometimes damaged in operations on the neck including carotid endarterectomy. Goodman and coworkers showed a dissecting aneurysm of the carotid artery to have compressed the hypoglossal nerve, with resultant weakness and atrophy of the tongue. Rare instances of temporal arteritis and Takayasu arteritis affecting the carotid artery and adjacent twelfth nerve have been described. Lance and Anthony have described the simultaneous occurrence of nuchal-occipital pain and ipsilateral numbness of the tongue, provoked by the sudden, sharp turning of the head and termed it the neck–tongue syndrome. The phenomenon has been attributed to compression in the atlantoaxial space of the second cervical root, which carries some of the sensory fibers from the tongue, via the hypoglossal nerve, to the C2 segment of the spinal cord. It is worth mentioning here that the tongue is often red and smooth in vitamin-deficiency states. Glossodynia (burning mouth syndrome discussed in Chap. 9), a condition most frequently seen in the elderly and in young women, may or may not be accompanied by redness and dryness but not by lingual weakness. A habit of tongue-thrusting and teethclenching is often associated. The ascription of these motor abnormalities to a psychogenic mechanism does not agree with the authors’ experience (see Quinn).

The Twelfth, or Hypoglossal, Nerve Anatomic Considerations This is also a pure motor nerve, which supplies the somatic musculature of the tongue. It arises as a series of rootlets that issue from the ventral medulla between the pyramid and inferior olivary complex. The nerve leaves the skull through the hypoglossal foramen and innervates the genioglossus muscle, which acts to protrude the tongue; the styloglossus, which retracts and elevates its root; and the hypoglossus, which causes the upper surface to become convex. Complete interruption of the nerve results in paralysis of one side of the tongue. The tongue curves slightly to the healthy side as it lies in the mouth, but on protrusion it deviates to the affected side, owing to the unopposed contraction of the healthy genioglossus muscle. By pushing against the patient’s tongue in the cheek, one can judge the degree of weakness. Patients with lesions of the hypoglossal nerve will have difficulty moving the tongue with natural facility, causing difficulty with handling food in the mouth as well as lingual dysarthria. Over time, the denervated side becomes wrinkled and atrophied, and fasciculations become apparent. Isolated lesions of the hypoglossal nerve roots are rare. Occasionally an intramedullary lesion, usually a stroke, damages the emerging fibers of the hypoglossal nerve, corticospinal tract, and medial lemniscus (see Table 33-3).

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SYNDROME OF BULBAR PALSY This syndrome is the result of weakness or paralysis of muscles that are supplied by the motor nuclei of the lower brainstem, that is, the motor nuclei of the fifth, seventh, and ninth to twelfth cranial nerves. (Strictly speaking, the motor nuclei of the fifth and seventh nerves lie outside the “bulb,” which is the old name for the medulla oblongata.) Involved are the muscles of the jaw and face; the sternocleidomastoids and upper parts of the trapezii; and the muscles of the tongue, pharynx, and larynx. If weakness develops rapidly, as may happen in GBS, diphtheria, or poliomyelitis, there is no time for muscle atrophy. Myasthenia gravis, inclusion body myopathy, and polymyositis on rare occasions may produce such a picture, but motor neuron disease is the most common cause. When the latter disease is isolated to the bulbar muscles, it has been called progressive bulbar palsy, as discussed in Chap. 38. This can also be a presentation of Kennedy bulbospinal atrophy. The chronic forms of motor neuron disease and the childhood form of Fazio-Londe disease result in marked wasting and fasciculation of the facial, tongue, sternocleidomastoid, and trapezius muscles. All of these disorders must be differentiated from pseudobulbar palsy, that is discussed in Chaps. 24 and 25.

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MULTIPLE CRANIAL NERVE PALSIES As one can readily understand, several cranial nerves may be affected by a single disease process. The first clinical problem that arises is whether the lesion lies within or outside the brainstem. Lesions lying on the surface of the brainstem, infiltrating the meninges, or situated at the base of the skull are characterized by involvement of adjacent cranial nerves (often occurring in succession) and by late and only slight, if any, involvement of the long sensory and motor pathways. These syndromes are discussed later and listed in Table 44-1 by their eponymic designations. The opposite is true of intramedullary, intrapontine, and intramesencephalic lesions; within the brainstem that involves cranial nerves and produces crossed sensory or motor paralysis (cranial nerve signs on one side of the body and tract signs on the opposite side, the historical aspects of which are reviewed by Silverman et al). In this way, a number of distinctive brainstem syndromes, to which eponyms have also been attached, are produced; these are listed in Table 33-5 because they are most often the result of brainstem stroke. The special problems of multiple cranial nerve palsies of the ocular motor nerves are addressed in Chap. 13. Involvement of multiple cranial nerves outside the brainstem may be the result of trauma; localized infections such as herpes zoster (subacute onset); Lyme disease as reported by Schmutzhard and colleagues; cytomegalovirus (CMV) infection in an HIV patient; Wegener granulomatosis, sarcoidosis, other types of granulomatous diseases, or compression by tumors and saccular aneurysms. The sequential painless affection of contiguous or noncontiguous nerves over several days or weeks is particularly characteristic of meningeal carcinomatosis or lymphomatosis. In the series of 79 cases accumulated by Keane (2005), tumor was by far the most common underlying cause of multiple cranial nerve palsies—particularly schwannomas, metastases, and meningiomas; trauma, infection, and vascular disease followed in frequency after neoplasm. The eighth nerve is commonly incorporated in these neoplastic meningeal infiltrations. Among the solid tumors that cause local compression of nerves, neurofibromas, schwannomas, meningiomas, cholesteatomas, carcinomas, chordomas, and chondromas have all been observed. Nasopharyngeal carcinoma (Schmincke tumor or lymphoepithelioma) may implicate several cranial nerves in succession by invading the base of the skull (mainly the fifth and sixth but also higher nerves; Fig. 44-5), as do basilar invagination and Chiari malformation. Several lower cranial nerves may be involved on one side by a carotid artery dissection. A successive involvement of all cranial nerves on one side has been referred to as Garcin syndrome or hemibasal syndrome. It has been reported in chondromas and chondrosarcomas of the clivus but may occur with nasopharyngeal carcinomas. Bone erosion is likely to be seen radiographically in these cases. Table 44-2 lists the main causes of multiple cranial nerve palsies of extramedullary origin in our experience. The question of viral infections of cranial nerves is always raised by acute neuropathies of the facial, trigeminal, and

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Figure 44-5. Nasopharyngeal carcinoma invading the anterior left side of the base of the skull and nasopharynx and causing third and fifth nerve palsies. Axial CT of the anterior skull base.

vestibulocochlear nerves, especially when the condition is bilateral, involves several nerves in combination, or is associated with a pleocytosis in the spinal fluid. Actually, the only proved viral etiologies in this group of cases are herpes simplex, herpes zoster, and CMV infections. Because neural deafness, vertigo, and other cranial nerve palsies have been observed in conjunction with the postinfectious encephalomyelitides of Mycoplasma, varicella, measles, rubella, mumps, and scarlet fever, they probably share an immune-mediated mechanism. Multiple or single cranial nerve palsies of abrupt onset may precede or accompany infectious mononucleosis and sometimes other viral or

Table 44-2 CAUSES OF EXTRAMEDULLARY MULTIPLE CRANIAL NERVE PALSIES Meningeal Processes   Carcinomatous and lymphomatous meningitis Sarcoidosis   and Wegener granulomatosis   Infectious radiculitis (tuberculous, fungal, syphilitic, Lyme)   Idiopathic pachymeningitis Lesions Affecting Nerves at the Skull Base   Metastasis of solid tumor or lymphomatous infiltration   Local spread from nasopharyngeal tumor, chordoma, sarcoma  Trauma   Vascular occlusion or dissection (carotid artery dissection,   jugular vein thrombosis)   Paget disease, basilar invagination, Arnold-Chiari, and other   bony disorders Processes Within Nerves   Perineural invasion of spindle cell, basal cell, parotid, and   squamous cell cancer   Granulomas and infectious diseases (Listeria, sarcoid, Wegener   granulomatosis, diphtheria, HIV, Lyme disease, CMV infection   in AIDS, Sjögren syndrome, idiopathic)   Herpes zoster and other viral and postinfectious inflammatory   lesions (GBS)   Mixed connective tissue disease Idiopathic   Tolosa-Hunt–like syndrome affecting nonorbital nerves   Post- and parainfectious

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mycoplasmal diseases. DeSimone and Snyder assembled a series of 20 such cases associated with mononucleosis; bilateral facial paralysis was the most common presentation, bilateral optic neuritis the next most common, and in 3 cases, 3 or 4 cranial nerves were involved. The prognosis is excellent. Some cases formerly thought to be postinfectious in nature may be true infections of the nerve. The same may be said of the single and multiple cranial nerve palsies that are sometimes associated with HIV and CMV infections. Treatment of the parainfectious cases is symptomatic; the prognosis for recovery is good in many cases. Quite often, one observes an acute or subacute form of multiple cranial neuropathy of undetermined cause. Juncos and Beal reported on 14 cases of this type, incorporating 6 welldocumented cases of the Tolosa-Hunt orbitocavernous sinus syndrome with oculomotor palsies. In the group that was not attributable to Tolosa-Hunt, the onset was with facial pain and headache (temporofrontal), followed within days by abducens palsy (12 of 14), oculomotor palsy (6 of 14), trigeminal palsy (5 of 14), and facial weakness (4 of 14), and less often by involvement of the eighth, ninth, and tenth cranial nerves (unilaterally in most instances). Increased CSF protein and pleocytosis occurred in several. The prompt relief of pain upon administration of steroids was similar to that obtained in the Tolosa-Hunt syndrome. The mode of recovery, which usually occurred within a few months, was also much the same in the two groups of patients. Juncos and Beal concluded that the clinical features of the two groups overlapped and that their separation into two syndromes was arbitrary. We have seen a relapsing form of this illness in young adults, responsive on each occasion to steroids and stabilizing after several years. Numerous tests of the CSF by PCR revealed no viruses. Conceivably, some of these cases represent variant forms of GBS, in as much as they may be preceded by a nonspecific infection and may at times be accompanied by areflexia or evanescent paresthesias and elevated CSF protein without pleocytosis. Others probably are examples of the entity described by Juncos and Beal, possibly reflecting a granulomatous process in the pachymeninges. As a more chronic affliction, numerous cases have been observed in which cranial nerves were affected sequentially over a period of many years (polyneuritis cranialis multiplex). Some were later found to have tuberculosis of cervical lymph nodes (presumably tuberculous scrofula), and a few others had had sarcoidosis. No cause

was determined in many. Symonds had a similar experience. It is usually worth obtaining a biopsy of an enlarged cervical lymph node in these circumstances. The cavernous sinus syndrome, discussed in Chaps. 31, 33, and elsewhere in the book, consists of various combinations of oculomotor palsies and upper trigeminal sensory loss, usually accompanied by signs of increased pressure or inflammation of the venous sinus. The third, fourth, fifth, and sixth cranial nerves are affected first on one side only, but any of the processes that infiltrate or obstruct the sinus may spread to the other side. The main causes are septic or aseptic thrombosis of the venous sinus due to trauma, hypercoagulable states, or infections in adjacent structures, carotid artery aneurysm, carotid-cavernous fistulae, and neoplastic infiltration. Keane (1996) summarized his experience with an astonishing 151 instances of cavernous sinus syndrome and found trauma and surgical procedures to be the most common causes, followed by neoplasms (specifically those originating in the nasopharynx), pituitary tumors, metastases, and lymphomas; our experience has tended more toward local infectious causes in diabetic patients and hypercoagulable states. A special cause of multiple cranial nerve palsies is an infiltration along the distal nerves in the skin and subcutaneous tissues by squamous cell carcinomas of the face, especially by spindle cell and other atypical varieties of tumor. A variant of malignant melanoma, “lentigo maligna,” may do the same but has more of a tendency to infiltrate along larger nerves to the base of the skull and cause larger areas of loss of facial sensation and pain, vertigo, and deafness. This type of perineural spread first causes very restricted unilateral palsies and sensory loss related to the superficial branches of the fifth and seventh cranial nerves in one region of the face and then extends to the base of the skull and to the ventral brainstem. According to Clouston and colleagues, who have presented five cases in detail, the initial symptoms are usually pain and numbness in the area underlying the skin lesion and facial weakness confined to the same regions of the face; this pattern is a result of the proximity of fifth and seventh nerve branches in the skin and subcutaneous tissues. Various combinations of oculomotor palsies may follow as a result of tumor entry into the orbit via the infraorbital branch of the maxillary nerve. Occasionally there is no pain. We have also observed a similar regional pattern of extracranial involvement of trigeminal and facial nerves with an infiltrative mixed-cell tumor of the parotid gland.

References Alexander GE, Moses H: Carbamazepine for hemifacial spasm. Neurology 32:286, 1982. Bannister R, Oppenheimer DR: Degenerative diseases of the nervous system associated with autonomic failure. Brain 95:457, 1972. Baringer JH: Herpes simplex virus and Bell palsy. Ann Intern Med 124:63, 1996. Barker FG, Jannetta PJ, Bissonette DJ, et al: Microvascular decompression for hemifacial spasm. J Neurosurg 82:201, 1995.

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Berry H, Blair RL: Isolated vagus nerve palsy and vagal mononeuritis. Arch Otolaryngol 106:333, 1980. Blau JN, Harris M, Kennet S: Trigeminal sensory neuropathy. N Engl J Med 281:873, 1969. Blau JN, Kapadia R: Idiopathic palsy of the recurrent laryngeal nerve: A transient cranial mononeuropathy. Br Med J 4:259, 1972. Brownstone PK, Ballenger JJ, Vick NA: Bilateral superior laryngeal neuralgia. Arch Neurol 37:525, 1980.

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Chapter 44 Diseases of the Cranial Nerves Burgess RC, Michaels L, Bale JF Jr, Smith RJ: Polymerase chain reaction amplification of herpes simplex viral DNA from the geniculate ganglion of a patient with Bell’s palsy. Ann Otol Rhinol Laryngol 103:775, 1994. Chalk C, Isaacs H: Recurrent spontaneous accessory neuropathy. J Neurol Neurosurg Psychiatry 53:621, 1990. Chia L-G: Pure trigeminal motor neuropathy. BMJ 296:609, 1988. Clouston PD, Sharpe DM, Corbett AJ, et al: Perineural spread of cutaneous head and neck cancer: Its orbital and central neurologic complications. Arch Neurol 47:73, 1990. De Diego JI, Prim MP, De Sarria MJ, et al: Idiopathic facial paralysis: A randomized, prospective, and controlled study using single-dose prednisone versus acyclovir three times daily. Laryngoscope 108:573, 1998. DeSimone PA, Snyder D: Hypoglossal nerve palsy in infectious mononucleosis. Neurology 28:844, 1978. Eisen A, Bertrand G: Isolated accessory nerve palsy of spontaneous origin: A clinical and electromyographic study. Arch Neurol 27:496, 1972. Elias MK, Mateen FJ, Weller CR, et al: The Melkersson-Rosenthal syndrome: A retrospective series of biopsied cases. J Neurol 260:138, 2013. Engstrom M, Berg T, et al: Prednisolone and valaciclovir in Bell’s palsy: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet Neurol 7(11):993–1000, 2008. Gilden DH: Bell’s palsy. N Engl J Med 351:1323, 2004. Goodman JM, Zink WL, Cooper DF: Hemilingual paralysis caused by spontaneous carotid artery dissection. Arch Neurol 40:653, 1983. Granit R, Leskell L, Skogland CR: Fibre interaction in injured or compressed region of nerve. Brain 67:125, 1944. Hato N, Yamada H, Kohno H: Valacyclovir and prednisolone treatment for Bell’s palsy: A multicenter, randomized, placebo-controlled study. Otol Neurotol 28(3):408–413, 2007. Hauser WA, Karnes WE, Annis J, Kurland LT: Incidence and prognosis of Bell’s palsy in the population of Rochester, Minnesota. Mayo Clin Proc 46:258, 1971. Hosten N: MR of brain involvement in progressive facial hemiatrophy (Romberg disease): Reconsideration of a syndrome. AJNR Am J Neuroradiol 15:145, 1994. Hughes RAC: Diseases of the fifth cranial nerve. In: Dyck PJ, Thomas PK, Lambert EH, et al (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, Saunders, 1993, pp 801–817. Illingworth RD, Porter DG, Jakubowski J: Hemifacial spasm: A prospective long-term follow up of 83 patients treated by microvascular decompression. J Neurol Neurosurg Psychiatry 60:73, 1996. Jannetta PJ: Posterior fossa neurovascular compression syndromes other than neuralgias. In: Wilkins RH, Rengachary SS (eds): Neurosurgery, 2nd ed. New York, McGraw-Hill, 1996, pp 3227–3233. Johnson VP, McMillin JM, Aceto T, Bruins G: A newly recognized neuroectodermal syndrome of familial alopecia, anosmia, deafness, and hypogonadism. Am J Med Genet 15:497, 1983. Johnson JA, Stern LZ: Bilateral vocal cord paralysis in a patient with familial hypertrophic neuropathy. Arch Neurol 38:532, 1981. Juncos JL, Beal MF: Idiopathic cranial polyneuropathy. Brain 110:197, 1987. Karnes WE: Diseases of the seventh cranial nerve. In: Dyck PJ, Thomas PK, Lambert EH, et al (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, Saunders, 1993, pp 818–836. Katusic S, Beard CM, Bergstralh E, Kurland LT: Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945–1984. Ann Neurol 27:89, 1990.

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Keane JR: Bilateral seventh nerve palsy: Analysis of 43 cases and review of the literature. Neurology 44:1198, 1994. Keane JR: Cavernous sinus syndrome: Analysis of 151 cases. Arch Neurol 53:967, 1996. Keane JR: Multiple cranial nerve palsies: Analysis of 79 cases. Arch Neurol 62:1714, 2005. Kress B, Griesbeck F, Stippich C, et al: Bell’s palsy: Quantitative analysis of MR imaging data as a method of predicting outcome. Radiology 230:504, 2004. Lance JW, Anthony M: Neck-tongue syndrome on sudden turning of the head. J Neurol Neurosurg Psychiatry 43:97, 1980. Lecky BRF, Hughes RAC, Murray NMF: Trigeminal sensory neuropathy. Brain 110:1463, 1987. Love S, Coakham HB: Trigeminal neuralgia. Pathology and pathogenesis. Brain 124:2347, 2001. Massey EW, Moore J, Schold SC Jr: Mental neuropathy from systemic cancer. Neurology 31:1277, 1981. Murakami S, Honda N, Mizobuchi M, et al: Rapid diagnosis of varicella zoster virus in acute facial palsy. Neurology 51:1202, 1998. Murakami S, Mizobuchi M, Nakashiro Y, et al: Bell palsy and herpes simplex virus: Identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med 124:27, 1996. Nielsen VK, Jannetta PJ: Pathophysiology of hemifacial spasm: Effects of facial nerve decompression. Neurology 34:891, 1984. Piatt JH, Wilkins RH: Treatment of tic douloureux and hemifacial spasm by posterior fossa exploration: Therapeutic implications of various neurovascular relationships. Neurosurgery 14:462, 1984. Pitts DB, Adour KK, Hilsinger RL: Recurrent Bell’s palsy analysis of 140 patients. Laryngoscope 98:535, 1988. Plott D: Congenital laryngeal-abductor paralysis due to nucleus ambiguus dysgenesis in three brothers. N Engl J Med 271:593, 1964. Quinn JH: Glossodynia. J Am Dent Assoc 70:1418, 1965. Resnick DK, Jannetta PJ, Bissonette D, et al: Microvascular decompression for glossopharyngeal neuralgia. Neurosurgery 36:64, 1995. Schmutzhard E, Stanek G, Pohl P: Polyneuritis cranialis associated with Borrelia burgdorferi. J Neurol Neurosurg Psychiatry 48:1182, 1985. Silverman JE, Liu GT, Volpe NJ, Galetta SL: The crossed paralyses. Arch Neurol 52:635, 1995. Spillane JD: Isolated unilateral spinal accessory nerve palsy of obscure origin. Br Med J 2:365, 1949. Spillane JD, Wells CEC: Isolated trigeminal neuropathy: A report of 16 cases. Brain 82:391, 1959. Sullivan FM, Swan IR, Donnan PR, et al: Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med 357:1598, 2007. Sweeney CJ, Gilden DH: Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 71:149, 2001. Symonds C: Recurrent multiple cranial nerve palsies. J Neurol Neurosurg Psychiatry 21:95, 1958. van Amstel AD, Devriese PP: Clinical experience with recurrences of Bell’s palsy. Arch Otorhinolaryngol 245:302, 1998. Whitley RJ, Weiss H, Gnann JW, et al: Acyclovir with and without prednisone for the treatment of herpes zoster: A randomized, placebo-controlled trial. Ann Intern Med 125:376, 1996. Wilson ME, Hoxie J: Facial asymmetry in superior oblique muscle palsy. J Pediatr Ophthalmol Strabismus 30:315, 1993.

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45 Diseases of Muscle

Skeletal, or voluntary, muscle constitutes the principal organ of motion, as well as a vast metabolic reservoir. Disposed in more than 600 separate muscles, this tissue makes up as much as 40 percent of the weight of adult human beings. An intricacy of structure and function undoubtedly accounts for its diverse susceptibility to disease, for which reason the main anatomic and clinical facts are provided as an introduction to the muscle diseases. A single muscle is composed of thousands of muscle fibers that extend for variable distances along its longitudinal axis. Each fiber is a relatively large and complex multinucleated cell varying in length from a few millimeters to several centimeters (34 cm in the human sartorius muscle) and in diameter from 10 to 100 μm. Some fibers span the entire length of the muscle; others are joined end to end by connective tissue. Each muscle fiber is enveloped by an inner plasma membrane (the sarcolemma) and an outer basement membrane. The multiple nuclei of each fiber, which are oriented parallel to its longitudinal axis and may number in the thousands, lie beneath the plasma membrane (sarcolemma); hence they are termed subsarcolemmal, or sarcolemmal nuclei. The cytoplasm (sarcoplasm) of the cell is abundant, and it contains myofibrils and various organelles such as mitochondria and ribosomes. Each myofibril is enveloped in a membranous net, the sarcoplasmic reticulum (SR; Fig. 45-1). Extensions of the plasma membrane into the fiber form the transverse tubular system (T tubules), which are extracellular channels of communication with the intracellular sarcoplasmic reticulum. The SR and T tubules are anatomically independent but functionally related membrane systems. The junctional gap between the T tubules and SR is occupied by protein formations that are attached to the SR and are referred to as junctional feet; the latter have been identified as ryanodine receptors and are responsible for the release of calcium from the SR, which is a critical step in exciting the muscle (Franzini-Armstrong). The myofibrils themselves are composed of longitudinally oriented interdigitating filaments (myofilaments) of contractile proteins (actin and myosin), additional structural proteins (titin and nebulin), and regulatory proteins (tropomyosin and troponin). The series of biochemical events by which these proteins, under the influence of calcium ions, accomplish the contraction and relaxation of muscle is described in Chap. 2. Droplets of stored fat,

glycogen, various proteins, many enzymes, and myoglobin, the latter imparting the red color to muscle, are contained within the sarcoplasm or its organelles. The individual muscle fibers are surrounded by delicate strands of connective tissue (endomysium), which provide their support and permit unity of action. Capillaries, of which there may be several for each fiber, and nerve fibers lie within the endomysium. Muscle fibers are bound into groups or fascicles by sheets of collagen (perimysium), which also bind together groups of fascicles and surround the entire muscle (epimysium). The latter connective tissue tunics are richly vascularized, with different types of muscle having different arrangements of arteries and veins. The muscle fibers are attached at their ends to tendon fibers, which, in turn, connect with the skeleton. By this means, muscle contraction maintains posture and imparts movement. Other notable characteristics of muscle are its natural mode of contraction, that is, through neural innervation— and the necessity of intact innervation for the maintenance of its normal tone and trophic state. Each muscle fiber receives a nerve twig from a motor nerve cell in the anterior horn of the spinal cord or nucleus of a cranial nerve; the nerve twig joins the muscle fiber at the neuromuscular junction or motor endplate. As was pointed out in Chaps. 2 and 3, groups of muscle fibers with a common innervation from one anterior horn cell constitute the motor unit, which is the basic physiologic unit in all reflex, postural, and voluntary activities. Embedded in the surface membrane are several types of ion channels that are responsible for maintaining the electrical potential and propagating depolarizing currents across the muscle membrane (diseases of these channels are discussed in Chap. 46). Also constituting a large part of the membrane is a series of anchoring structural proteins, the nature of which have been thoroughly elucidated in the past few decades. Pathologic configurations of these proteins are described in detail in relation to the muscular dystrophies. In addition to motor nerve endings, muscle contains several types of sensory endings, all of them mechanoreceptors: Free nerve endings subserve the sensation of deep pressure-pain; Ruffini and Pacinian corpuscles are pressure sensors; and the Golgi tendon organs and muscle spindles are tension receptors and participate in the

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Triad Terminal cisternae T system

Sarcoplasmic reticulum T system

A Z I

M H A

Myosin

maintenance of muscle tone and reflex activity. The Golgi receptors are located mainly at the myotendon junctions; Pacinian corpuscles are localized in the tendon but are also found sparsely in muscle itself. Muscle spindles are specialized groups of small muscle fibers that regulate muscle contraction and relaxation, as described in Chap. 2. All of these receptors are present in the highest density in muscles that are involved in fine movements. Muscles are not equally susceptible to disease, despite the apparent similarity of their structure. In fact, practically no disease affects all muscles in the body and each pathologic entity has a characteristic topography within the musculature. The topographic differences between diseases provide incontrovertible evidence of structural or physiologic differences between muscles that cannot be appreciated by the light or electron microscope. The factors responsible for the selective vulnerability of certain muscles are not fully understood but several explanations are possible. One may relate simply to fiber size; consider, for example, the large diameter and length of the fibers of the glutei and paravertebral muscles in comparison with the smallness of the ocular muscle fibers. The number of fibers composing a motor unit may also be of significance; in the ocular muscles, a motor unit contains only 6 to 10 muscle fibers (some even fewer), but a motor unit of the gastrocnemius contains as many as 1,800 fibers. Also, the eye muscles have a much higher metabolic rate and a richer content of mitochondria than the large trunk muscles. Differences in patterns of vascular supply may permit some muscles to withstand the effects of vascular

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Actin

Figure 45-1.  Schematic of the major subcellular components of a myofibril. The transverse (T) system, which is an invagination of the plasma membrane of the cell, surrounds the myofibril midway between the Z lines and the center of the A bands; the T system is approximated to, but apparently not continuous with, dilated elements (terminal cisternae) of the sarcoplasmic reticulum on either side. Thus, each sarcomere (the repeating Z-line-to-Z-line unit) contains two “triads,” each composed of a pair of terminal cisternae on each side of the T tubule. (Reproduced with permission from Peter JB, Skeletal Muscle: Diversity and mutability of its histochemical, electronmicroscopic, biochemical and physiologic properties. In Pearson CM, Mostofi FK (eds): The Striated Muscle. Baltimore, Williams & Wilkins, 1973:1-18.)

occlusion better than others. Histochemical studies of skeletal muscles have disclosed that within any 1 muscle, there are subtle metabolic differences between fibers, certain ones (type 1 fibers) being richer in oxidative and poorer in glycolytic enzymes and others (type 2 fibers) having the opposite distribution. The distribution of certain structural proteins may alter the topography of disease expression; for example, the eye muscles do not contain dystrophin, a submembrane protein that is deficient in Duchenne muscular dystrophy, which explains the muscles’ lack of involvement in this disease. The endomysial fibroblasts of eye muscles contain an abundance of glycosaminoglycans, which renders them susceptible to thyroid diseases. Diseases of the neuromuscular junction show a distribution of weakness in relation to the density of these junctions in different muscles. Doubtless other differences will be discovered. Normal muscle is endowed with a population of embryonic muscle precursor cells, known as satellite cells, and, as a result, it possesses a remarkable capacity to regenerate, a point often forgotten. It has been estimated that enough new muscle can be generated from a piece of normal muscle the size of a pencil eraser to provide normal musculature for a 70-kg adult. However, with complete destruction of the muscle fiber, this regenerative capacity is greatly impaired. Inflammatory and metabolic destructive processes are usually followed by fairly complete restoration of the muscle cells, provided that some part of each fiber has survived and the endomysial sheaths of connective tissue have not been severely disrupted. Unfortunately,

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many pathologic processes of muscle are chronic and unrelenting. Under such conditions, any regenerative activity fails to keep pace with the disease and the loss of muscle fibers becomes permanent. The bulk of the muscle is then replaced by fat and collagenous connective tissue, as occurs typically with the muscular dystrophies.

THE DEVELOPMENT AND AGING OF MUSCLE (SEE ALSO CHAP. 28) The accepted view of the embryogenesis of muscle is that muscle fibers form by fusion of myoblasts soon after the latter differentiate from somatic mesodermal cells. Muscle connective tissue derives from the somatopleural mesoderm. After fusion of the myoblasts, a series of cellular events including the sequential activation of myogenic transcription factors leads to myofibril formation. The newly formed fibers are thin, centrally nucleated tubes (appropriately called myotubes) in which myofilaments begin to be produced from polyribosomes. As myofilaments become organized into myofibrils, the nuclei of the muscle fiber are displaced peripherally to a subsarcolemmal position. Once the nuclei assume a peripheral position, the myofiber is fully formed. A complete understanding of the mechanisms whereby myoblasts seek one another, the manner in which each of a series of fused nuclei contributes to the myotube, the formation of actin and myosin fibrils, Z-discs, and the differentiation of a small residue of satellite cells on the surface of the fibers continues to emerge (as reviewed, e.g., by Rubenstein and Kelly). The mechanisms that determine the number and arrangement of fibers in each muscle are not as precisely understood. Presumably, the myoblasts themselves possess the genetic information that controls the program of development, but within any given species there are wide individual variations that account for obvious differences in the size of muscles and their power of contraction. The number of fibers assigned to each muscle is probably attained by birth, and growth of muscle thereafter depends mainly on the enlargement of fibers. Although the nervous system and musculature develop independently, muscle fibers continue to grow after birth only when they are active and under the influence of nerve. Measurements of muscle fiber diameters from birth to old age show the growth curve ascending rapidly in the early postnatal years and less rapidly in adolescence, reaching a peak during the third decade. After puberty, growth of muscle is less significant in females than in males, and such differences are greater in the arm, shoulder, and pelvic muscles than in the leg; growth in ocular muscles is about equal in the two sexes. At all ages, disuse of muscle decreases fiber size by as much as 30 percent, and overuse increases the size by about the same amount (work hypertrophy). Normally, type 1 (oxidative enzyme-rich) fibers are slightly smaller than type 2 (phosphorylative enzyme-rich) fibers; the numerical proportions of the two fiber types vary in different muscles in accordance with the natural functions of that muscle. The exercising of young animal muscle causes a hypertrophy of high-oxidative type 1 fibers and an

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increase in the proportion of low-oxidative type 2 fibers; aging muscle lacks this capacity; exercise produces only an increase in the proportion of type 2 fibers (Silbermann et al). No such data are available in humans, but clinical observation suggests that with aging, the capacity of muscle to respond to intense, sustained exercise is diminished. During late adult life, the number of muscle fibers diminishes and variation in fiber size increases as mentioned in Chap. 28 on aging. The variations are of two types: group atrophy, in which clusters of 20 to 30 fibers are all reduced in diameter to about the same extent, and random single-fiber atrophy. Also, muscle cells, like other cells of postmitotic type, are subject to aging changes (lipofuscin accumulation, autophagic vacuolization, enzyme loss) and to death. Group atrophy, present to a slight degree in the gastrocnemii of almost all individuals older than 60 years, represents denervation effect from an agingrelated loss of lumbar motor neurons and peripheral nerve fibers (Tomlinson and colleagues, and also Chap. 28). Denervation from spinal motor neuron or nerve disease at every age has roughly the same effect; namely, atrophy of muscle fibers (first in random distribution, then in groups) and later, degeneration. Muscle necrosis at all ages excites a regenerative response from sarcolemmal and satellite cells in any intact parts of the fibers. If this occurs repeatedly, the regenerative potential wanes, with ultimate death of the fiber leading to permanent depopulation of fibers with the expected muscle weakness.

APPROACH TO THE PATIENT WITH MUSCLE DISEASE The number and diversity of diseases of striated muscle greatly exceed the number of symptoms and signs by which they express themselves clinically; thus, different diseases share certain common symptoms and syndromes. To avoid excessive repetition in the description of individual diseases, we discuss here, in one place, the broad clinical manifestations of muscle disease. The physician is initially put on the track of a myopathic disease by eliciting complaints of muscle weakness or fatigue, pain, limpness or stiffness, spasm, cramp, twitching, or a muscle mass or change in muscle volume. Of these, the symptom of weakness is by far the most frequent and at the same time the most elusive. When speaking of weakness, the patient often means excessive fatigability and poor endurance. As discussed in Chap. 23, fatigue is an abstruse symptom, always requiring careful analysis and interpretation. When not attended by manifest reduction in muscle power, it is usually nonmuscular in origin. It may, on medical investigation, prove to be a systemic manifestation of infection, metabolic or endocrine disorder, severe anemia, reduced cardiopulmonary function, or neoplasia. More often, when expressed as a feeling of poor endurance, weariness, and disinclination to undertake or sustain mental and physical activity, it may be indicative of chronic anxiety and depression. On the other hand, a rare example of a physiologic muscle disorder that simulates lassitude is lifelong exercise intolerance,

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often accompanied by muscle cramps during exercise, which has been traced to mutations in the cytochrome b gene of the mitochondrial DNA (Andreu et al).

Evaluation of Muscle Weakness and Paralysis Rather than relying on the patient’s report to distinguish between fatigability and weakness, it is more informative to observe the patient during the performance of certain common activities such as walking, climbing stairs, and arising from a sitting, kneeling, squatting, or reclining position or using the arms over the head. Difficulty in performing these tasks signifies weakness rather than fatigue. Sometimes, the weakness of a group of muscles becomes manifest only after a period of activity; for example, the feet and legs may “drag” only after the patient has walked a long distance. The physician, on being told this by the patient, should attempt to conduct the examination under circumstances that duplicate the complaints. Of course, these impairments of muscle function may be caused by a neuropathic or central nervous system (CNS) disturbance rather than of a myopathic one, but usually these conditions can be separated by the basic methods indicated further on in this chapter and in Chaps. 3 and 23. Reduced strength of muscle contraction—manifest by diminished power of single contractions against resistance (peak power) and during the sustained performance of prolonged or repetitive movements (i.e., endurance)—are the indubitable signs of muscle or neuromuscular disease. In such testing, the physician may encounter difficulty in enlisting the patient’s cooperation. The tentative, hesitant performance of the asthenic or suggestible individual, or the hysteric or malingerer, poses difficulties that can be surmounted by experience and by the techniques described in Chap. 3. In infants and small children, who cannot follow commands, one assesses muscle power by the resistance to passive manipulation or by observing performance while the child is engaged in natural activities. The patient may be reluctant to fully contract the muscles in a painful limb; indeed, pain itself causes a reflex diminution in the power of contraction (algesic paresis). Estimating the strength of isometric contractions that do not require the painful part to be moved is a way around this difficulty. Ascertaining the extent and severity of muscle weakness requires a systematic examination of the main groups of muscles. The patient is asked to contract each group with as much force as possible, while the examiner opposes the movement and offers a graded resistance in accordance with the degree of residual power (isokinetic contraction). Alternatively, the patient is asked to produce a maximal contraction and the examiner estimates power by the force needed to overcome or “break” it (isometric contraction or maximum voluntary isometric contraction). If the weakness is unilateral, one has the advantage of being able to compare it with the strength on the normal side. If it is bilateral, the physician must refer to his concept of what constitutes normalcy based on experience in muscle testing. As mentioned, one can distinguish true weakness from unwillingness to cooperate, feigned or neurasthenic weakness, and inhibition of movement by pain.

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To quantitate the degree of weakness, a rating scale may be required. Widely used is the one proposed by the Medical Research Council (MRC) of Great Britain, which recognizes 6 grades of muscle strength as follows: 0—Complete paralysis 1—Minimal contraction 2—Active movement only with gravity eliminated 3—Full movement against gravity but cannot offer resistance to manual muscle opposition 4—Active movement against gravity and resistance but can be overcome by manual muscle opposition 5—Normal strength Further gradations may be added, specified as 4+ for barely detectable weakness and 4– for easily detected weakness, 3+ and 3−, and so on. The ocular, facial, lingual, pharyngeal, laryngeal, cervical, shoulder, upper arm, lower arm and hand, truncal, pelvic, thigh, and lower leg and foot muscles are examined sequentially. It is most convenient to compare power generated by the same muscle from each side. To fully and properly use tools such as the MRC scale and to detect mild weakness, muscles such as the neck flexors and extensors must be tested with the patient in the prone and supine positions. The anatomic significance of each of the actions tested, that is, what roots, nerves, and muscles are involved, can be determined by referring to Table 45-1. A practiced examiner can survey the strength of these muscle groups in 2 to 3 min. A word of caution is in order: In manually resisting the patient’s attempts to contract the large and powerful trunk and girdle muscles, the examiner may fail to detect slight degrees of weakness, particularly in well-muscled individuals. These muscle groups are best examined by having the patient use the muscle groups for their intended purposes: squat and kneel and then assume the erect posture, arise from and, walk on toes and heels, and lift a heavy object (e.g., this textbook) over his head. The strength of muscles of the hand can be quantified with a dynamometer; for research purposes, similar but more sophisticated devices exist for other muscle groups (Fenichel et al). Nonetheless, the examiner should not dismiss the patient’s complaint of weakness simply if it cannot be substantiated by the examination.

Changes in the Contractile Process These processes relate to qualitative changes in muscle contraction. In the myasthenic states there is a rapid failure of contraction in the affected muscles during sustained or repetitive activity. For instance, after the patient looks upward at the ceiling for a few minutes, the eyelids progressively droop; closing the eyes and resting the levator palpebrae muscles cause the ptosis to lessen or disappear. Similarly, holding the eyes in a far lateral position will induce diplopia and strabismus. These effects, in combination with restoration of power by the administration of neostigmine or edrophonium, are the most valuable clinical criteria for the diagnosis of myasthenia gravis, as described in Chap. 46.

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Table 45-1 DUCHENNE/BECKER, EMERY-DREIFUSS, LIMB-GIRDLE, AND RELATED MAJOR MUSCULAR DYSTROPHIES INHERITANCE TYPE

X-linked recessive Duchenne/Becker   Emery-Dreifuss

GENE/PROTEIN

Scapuloperoneal Autosomal dominant LGMD 1A

  DMD/Dystrophin   EMD and others/ Emerin FHL1 and others   Myotilin

LGMD 1B   LGMD 1C LGMD 1D LGMD 1E Autosomal recessive LGMD 2A LGMD 2B   LGMD 2C–F LGMD 2G LGMD 2H LGMD 2I   LGMD 2J LGMD 2M

LMNA/Lamin A/C   CAV3/Caveolin-3 6p Desmin   CPN3/Calpain-3 DYSF/Dysferlin   α, β, γ, δ-sarcoglycans Telethonin TRIM32 FKRP/Fukutin   TTN/Titin POMGNT1

ONSET DECADE

 

CK ELEVATION

  1st   2nd–3rd

10–50 ×   5×

    3rd–4th

    2×

1st–2nd   1st 3rd–5th 1st   1st–2nd 2nd–3rd   1st–3rd 2nd 1st–3rd 1st–3rd   1st–3rd Birth

3–5 ×   4–25 × 2–4 × Nl   3–15 × 10–50 ×   5–40 × 3–17 × 2–25 × 10–30 ×   2×  

REGIONS AFFECTED

  Proximal, then distal muscles Cardiac muscle Proximal muscles, joint contractures; cardiac arrhythmias Scapular-peroneal   Distal greater than proximal weakness, vocal cords, pharynx; allelic with myofibrillar myopathy Resembles Emery-Dreifuss disease Proximal muscles and heart, joint contractures Proximal muscles Proximal muscles; cardiomyopathy Proximal muscles   Proximal and distal muscles Proximal and distal muscles Allelic to Miyoshi myopathy Phenotype of Becker dystrophy Proximal greater than distal muscles Proximal greater than distal muscles Proximal greater than distal muscles FKRP defects also cause CMD Proximal and sometimes distal muscles Mutations also associated with muscleeye-brain diseases

CK, creatine kinase; CMD, childhood muscular dystrophy; FKRP, fukutin-related protein; LGMD, limb-girdle muscular dystrophy; Nl, normal.

The opposite of the myasthenic phenomenon, an increment in power with a series of several voluntary contractions is a feature of the Lambert-Eaton myasthenic syndrome, which is associated in approximately 50 percent of cases with small cell carcinoma of the lung. The same increment occurs in botulism. In both instances there is an increase in the amplitude of compound muscle action potentials on the nerve conduction studies obtained following brief exercise (10 to 15 s), or at high rates of repetitive nerve stimulation (20 to 50 Hz), as described in Chap. 46. Other abnormalities may be discovered by observing the speed and efficiency of contraction and relaxation during one or a series of maximal actions of a group of muscles. In myxedema, for example, stiffness and slowness of contraction in a muscle such as the quadriceps may be seen on change in posture (contraction myoedema) and by direct percussion of a muscle, and there is an associated prolonged duration of the tendon reflexes. Slowness in relaxation of muscles is another feature of hypothyroidism, accounting for the complaint of uncomfortable tightness of proximal limb muscles. A curious rippling phenomenon in muscles may be the result of several processes and occurs as an inherited autosomal dominant trait. After a period of relaxation, stiffening and rippling occur in the contracting or stretched muscles. A prolonged failure of relaxation following contraction of a muscle is characteristic of myotonia, which typifies certain diseases: myotonia congenita, myotonic dystrophy, and paramyotonia congenita (attached to Eulenburg’s name).

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True myotonia, with its prolonged discharge of membrane action potentials, requires strong contraction to elicit, is more evident after a period of relaxation, and tends to disappear with repeated contractions as discussed further in relation to the ion channel disorders of muscle in Chap. 46. This persistence of contraction is demonstrable also by tapping a muscle (percussion myotonia), a phenomenon easily distinguished from the electrically silent local bulge (myoedema) induced by tapping the muscle of a myxedematous or cachetic patient. It is also distinguished from the brief fascicular contraction that is induced by tapping a normal or partially denervated muscle, referred to as idiomuscular contraction. In paramyotonia congenita one observes paradoxical myotonia, which refers to an increase in the degree of myotonia during a series of contractions (the reverse of what happens in the usual type of myotonia). The effect of cold on muscle contraction may also prove informative; either paresis or myotonia, lasting for a few minutes, may be evoked or enhanced by cold. This is most prominent in paramyotonia, but it may occur to some degree in all the other myotonic disorders. Also, a cold pack applied to a ptotic eyelid of myasthenia will often reduce the weakness. Myotonia and myoedema must also be distinguished from the recruitment and spread of involuntary spasm induced by strong and repeated contractions of limb muscles in patients with mild or localized tetanus, with the “stiff man” syndrome and with dystonias of various types. These are not primary muscle phenomena but are neural

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Chapter 45 Diseases of Muscle

in origin, a result of an abolition of inhibitory mechanisms and also taken up in Chap. 46. In practice, the term contracture is applied to describe fixed muscle shortening. Several distinct types can be recognized. In physiologic contracture, a group of muscles, after a series of strong contractions, remain shortened for many minutes because of failure of the metabolic mechanism necessary for relaxation. In this shortened state, the electromyogram (EMG) remains relatively silent, in contrast to the high-voltage, rapid discharges observed with cramp, tetanus, and tetany. True physiologic contracture occurs in McArdle disease (phosphorylase deficiency), phosphofructokinase deficiency, and possibly in other conditions, where phosphorylase seems to be present but nonfunctional. Yet another type of exercise-induced contracture, described originally by Brody, has been attributed to an autosomal recessive deficiency of calcium adenosine triphosphatase in the sarcoplasmic reticulum in type 2 muscle fibers (Karpati and coworkers). True contracture needs to be distinguished from paradoxical myotonia (see earlier) and from cramp, which in certain conditions (dehydration, tetany, pathologic cramp syndrome, amyotrophic lateral sclerosis [ALS]) can also be initiated by one or a series of strong voluntary muscle contractions. It is appropriate here to comment on pseudocontracture (myostatic or fibrous contracture), for which the term contracture is also often used in general medicine. This is the common form of muscle and tendon shortening that follows prolonged fixation and inactivity of the normally innervated muscle (as occurs in a broken limb immobilized by a cast or weakness of a limb that is allowed to remain immobile). Here the shortened state of the muscle and tendons has no clearly established anatomic, physiologic, or chemical basis. Fibrosis of muscle, a state following chronic fiber loss and immobility of muscle, is another cause of muscle shortening. Depending on the predominant position, certain muscles are both weakened and shortened. Flexor fibrous contracture of the arms is a prominent feature of the Emery-Dreifuss form of muscular dystrophy. It also accounts for the rigidity and kyphoscoliosis of the spine, which are so frequently a part of myopathic diseases. The latter state is distinguished from ankylosis by the springy nature of the resistance, coincident with increased tautness of muscle and tendon during passive motion, and from Volkmann contracture, in which there is fibrosis of muscle and surrounding tissues as a result of ischemic injury, usually after a fracture of the elbow. Arthrogryposis is another form of fibrous contracture that is found in newborns, involving multiple muscle groups; it occurs in association with several diseases that have two features in common: an onset during intrauterine life and an alteration of the neural or muscular apparatus that results in muscular weakness. In other words, contractures and fixity of the limbs in arthrogryposis are the result of reduced mobility of the developing joints, consequent on muscle weakness during fetal development. Most often the cause is a loss or failure of development of anterior horn cells, as in Werdnig-Hoffman disease, but the abnormality may be in the nerve roots, peripheral nerves, or motor endplates, or in the muscle itself. The rigid spine syndrome (RSS) in children is yet another form of fibrous

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contracture, presumably the result of an unusual axial muscular dystrophy. Notably, most primary muscle diseases are painless. When pain is prominent and continuous during rest and activity, there will usually be evidence of disease of the peripheral nerves, as in alcoholic–nutritional neuropathy, or of adjacent joints and ligaments (rheumatoid arthritis, polymyalgia rheumatica). Pain tends not to be prominent in polymyositis and dermatomyositis, and its presence usually indicates coincident involvement of connective tissues and joint structures. (e.g., fasciitis). Hypothyroidism, hypophosphatemia, and hyperparathyroidism are other sources of a myalgic myopathy. Certain drugs produce muscle aches in susceptible individuals. They include the “statin” lipid-lowering drugs, clofibrate, captopril, lithium, colchicine, beta-adrenergic blocking drugs, penicillamine, cimetidine, suxamethonium, and numerous others (see the table contained in the review by Mastaglia and Laing). Pain localized to a group of muscles is more often a feature of torticollis and dystonias. There are probably a limited number of mechanisms of muscle pain. Prolonged and sustained contraction gives rise to a deep aching sensation. Contraction under ischemic conditions—as when the circulation is occluded by a tourniquet or from atherosclerotic vascular disease— induces pain; the pain of intermittent claudication is presumably of this type and is not accompanied by cramp. It was postulated that lactic acid or some other metabolite accumulates in muscles and activates pain receptors, but there is also evidence to the contrary. The delayed pain, swelling, and tenderness that occur after sustained exercise of unconditioned muscles are evidently a result of fiber necrosis (Armstrong). Muscle biopsy infrequently reveals the cause of these painful syndromes, but it may be undertaken in cases of suspected metabolic or dystrophic muscle disease. Biopsy may be most likely to be helpful if there is exercise-induced muscle pain and the creatine kinase (CK) concentration is greatly elevated, although even then two-thirds of these patients can have either normal or nonspecific findings on the biopsy (Filosto and colleagues). Benign fasciculations, a common finding in otherwise normal individuals, can be identified by the lack of muscular weakness and atrophy and by the small-size muscle fascicles involved and repetitive appearance in only one or a few regions. The recurrent twitches of the eyelid or muscles of the thumb experienced by most normal persons are often referred to inaccurately as “live flesh” or myokymia but are benign fasciculations of this type. Individuals with truly benign fasciculations have normal EMGs (i.e., they have no fibrillations) as demonstrated in a large series of such patients studied and followed for many years by Blexrud and colleagues. Myokymia is a less common condition, in which there are repeated twitchings and rippling of a muscle at rest. Muscle cramps, despite their common occurrence, are a poorly understood phenomenon. They occur at rest or with movement (action cramps), and they are frequently reported in motor system disease, tetany, dehydration after excessive sweating and salt loss, metabolic disorders (uremia and hemodialysis, hypocalcemia, hypothyroidism,

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and hypomagnesemia), and certain muscle diseases (e.g., rare cases of Becker muscular dystrophy and congenital myopathies). A familial (X-linked recessive) type of myalgia and cramps associated with deletion of the first third of the dystrophin gene, which is the one implicated in Duchenne dystrophy, has been reported, occurring without weakness or evidence of dystrophy (Gospe and colleagues). Lifelong, severe cramping of undetermined type has also been seen in a few families. The dramatic Satoyoshi syndrome is characterized by continuous, painful leg cramps, alopecia universalis, and diarrhea (described further on). Far more frequent than all these types of cramping, and experienced at one time or another by most normal persons, is the benign form (idiopathic cramp syndrome) in which no other neuromuscular disturbance can be found. Most often benign cramps occur at night and affect the muscles of the calf and foot, but they may occur at any time and involve any muscle group. Some patients state that cramps are more frequent when the legs are cold and daytime activity has been excessive. In others, the cramps are provoked by the abrupt stretching of muscles, are very painful, and tend to wax and wane before they disappear. The EMG counterpart is a high-frequency discharge. Although of no pathologic significance, the cramps in extreme cases are so persistent and readily provoked by innocuous movements as to be disabling. Cramps of all types need to be distinguished from sensations of cramp without muscle spasm. The latter is a dysesthetic phenomenon in certain polyneuropathies. The disorders that simulate cramps, such as stiff-man syndrome and other forms of continuous muscle fiber activity that have various bases, are discussed in Chap. 46. Contrasted to cramp is the already described physiologic contracture, observed in McArdle disease and related metabolic myopathies, in which increasing muscle shortening and pain gradually develop during muscular activity. Unlike cramping, physiologic contracture does not occur at rest, the pain is less intense, and the EMG of the contracted muscle at the time is relatively silent. Continuous spasm intensified by the action of muscles and with no demonstrable disorder at a neuromuscular level is a common manifestation of localized tetanus and also follows the bite of the black widow spider. There may also be difficulty distinguishing cramps and spasms from the early stages of a dystonic illness. Altered structure and function of muscle are not accurately revealed by palpation. Of course, the difference between the firm, hypertrophied muscle of a wellconditioned athlete and the slack muscle of a sedentary person is as apparent to the palpating fingers as to the eye, as is also the persistent contraction in tetanus, cramp, contracture, fibrosis, and extrapyramidal rigidity. The muscles in dystrophy are said to have a “doughy” or “elastic” feel, although this may be difficult to judge. In the Pompe type of glycogen storage disease, attention may be attracted to the musculature by an unnatural firmness and increase in bulk. The swollen, edematous, weak muscles in acute rhabdomyolysis with myoglobinuria or severe polymyositis may feel taut and firm but are usually not tender. Areas of tenderness in muscles that otherwise function normally, a state called myogelosis, have been attributed to fibrositis or fibromyositis.

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Topographic Patterns of Myopathic Weakness In almost all the diseases under consideration, some muscles are affected and others spared, each disease displaying its own pattern. Restated, the topography or distribution of weakness tends to be alike in all patients with the same disease. As a general rule, muscle diseases are identified by a predominantly proximal weakness that is symmetric, but the configurations differ in important ways. The specific pattern of weakness is as important a diagnostic attribute of muscular disease as for the various diseases of the peripheral nervous system discussed in Chap. 43. Ocular palsies presenting as ptosis, diplopia, and strabismus  Primary diseases of muscle do not involve the pupil, and in most instances their effects are bilateral. In lesions of the third, fourth, or sixth cranial nerves, a neural origin is disclosed by the pattern of ocular muscle palsies, abnormalities of the pupil, or both. When weakness of the orbicularis oculi (muscles of eye closure) is added to weakness of eye opening (levator palpebrae; ptosis), it nearly always signifies myasthenia gravis. The rare primary disease of ocular muscle (progressive external ophthalmoplegia) is usually symmetric and does not produce diplopia. Other causes of subacute and chronic development of relatively pure weakness of the muscles of eye movement are oculopharyngeal dystrophy and exophthalmic (hyperthyroid) ophthalmopathy. In PEO, the muscles, including the levators of the eyelids, become paralyzed almost symmetrically over a period of years. This disorder typically represents mitochondrial myopathy. Oculopharyngeal dystrophy involves primarily the levators of the eyelids and, to a lesser extent, other eye muscles and pharyngealupper esophageal striated muscles. It begins in middle or late adult life and later, and—like PEO—tends only decades later to involve girdle and proximal limb muscles. There are several other less common chronic myopathies in which external ophthalmoplegia is associated with involvement of other muscles or organs, namely, the KearnsSayre syndrome (retinitis pigmentosa, heart block, short stature, generalized weakness, and ovarian hypoplasia); the congenital ophthalmoplegia of the Goldenhar-Gorlin syndrome (Aleksic et al); other congenital myotubular and mitochondrial myopathies; and nuclear ophthalmoplegia with bifacial weakness (Möbius syndrome). Rarely, eye muscle weakness may occur at a late stage in a few other dystrophies. Ptosis has a wider diagnostic range than ophthalmoplegia that includes myotonic dystrophy. Although not a regular feature of the disease, ophthalmoparesis can occur in the Lambert-Eaton myasthenic syndrome. Ptosis is variable in all of these conditions. When present in infantile myopathic disease, it is frequently a marker of the congenital myasthenic syndromes. The periorbital edema of Trichinosis is a rare cause, associated also with periorbital edema. Bifacial palsy presenting as an inability to smile, to expose the teeth, and to close the eyes Varying degrees of bifacial weakness are observed in myasthenia gravis, usually conjoined with ptosis and ocular palsies. On occasion, weakness of facial muscles may be combined with myasthenic weakness of the masseters and other

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bulbar muscles without involvement of ocular muscles. Facial weakness and ptosis are features of myotonic dystrophy. More severe or complete facial palsy occurs in facioscapulohumeral dystrophy, sometimes presenting several years before weakness of the shoulder girdle muscles. Bifacial weakness is also a feature of certain congenital myopathies (centronuclear, nemaline), Kennedy disease (bulbospinal motor neuron disease), and the Möbius syndrome of the absence of the facial nuclei (in combination with abducens palsies). Advanced scleroderma, Parkinson disease, or a pseudobulbar state can immobilize the face to the point of simulating myopathic or neuropathic paralysis, but always in a context that makes the cause obvious. Bulbar (oropharyngeal) palsy presenting as dysphonia, dysarthria, and dysphagia with or without weakness of jaw or facial muscles  Myasthenia gravis is the most frequent cause of this syndrome and must also be considered whenever a patient presents with the solitary finding of a hanging jaw or fatigue of the jaw while eating or talking; usually, however, ptosis and ocular palsies are conjoined. Dysphagia and dysphonia may be early and prominent signs of polymyositis, as well as inclusion body myositis (IBM), and may appear in patients with myotonic dystrophy, because of upper esophageal atonia. Combinations of these palsies are not typically of muscular or neuromuscular origin but instead are observed as an acute syndrome in brainstem stroke, at the outset of Guillain-Barré syndrome, or in botulism. Diphtheria and bulbar poliomyelitis are now rare diseases that may present in this way. Progressive bulbar palsy (motor neuron disease) may be the basis of this syndrome (see Chap. 38); the last of these diagnoses is most obvious when the tongue is withered and twitching. Syringobulbia, basilar invagination of the skull, and certain types of Chiari malformation may reproduce some of the findings of bulbar palsy by involving the lower cranial nerves. Cervical palsy presenting with inability to hold the head erect or to lift the head from the pillow (hanging, or dropped, head syndrome, camptocormia)  This is caused by weakness of the posterior neck muscles and of the sternocleidomastoids and other anterior neck muscles. In advanced forms of this syndrome, the head may hang with chin on chest unless the patient holds it up with the hands. There may be difficulty differentiating the condition from a dystonic anterocollis; in the latter there is palpable tonic spasm of the sternomastoid and posterior neck muscles. A pattern of neck and spine extensor weakness also occurs in advanced Parkinson disease. A common error in all these cases is to attribute the problem to structural disease of the cervical spine. This topographic pattern occurs most often in inflammatory myopathies and IBM, in which cases it is often combined with mild dysphagia, dysphonia, and weakness of girdle muscles. The same symptom may be a feature of motor neuron disease and is infrequently the presenting feature of that process. Myasthenic patients commonly complain of an inability to hold up their heads late in the day; both flexors and extensors of the neck are found to be weak. Occasionally, this pattern of weakness is observed in patients with nemaline rod myopathy. Cases of hanging

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head have appeared many years after local radiation of the neck and thorax (for example, to treat Hodgkin disease) and with syringomyelia (Rowin and colleagues; Nalini and Ravishankar). Neck extensor weakness is also often observed in elderly persons, sometimes with severe but relatively nonprogressive weakness accompanied by only mild weakness of shoulder girdle and proximal arm muscles. The designation “isolated neck extensor myopathy” in preference to “dropped head syndrome” (Katz and colleagues). What has been referred to as a bent spine syndrome (for which the term camptocormia is also used) is probably the same entity and may follow after years of the condition affecting the neck, or it may surface independently (Umapathi and colleagues; Azher and Jankovic). Mutations in RYR1 that encode for ryanodine receptor may be a common cause of late-onset axial myopathy and neck extensor weaknessbent spine syndrome (Løseth et al). Mutations in RYR1 are also associated with the central core congenital myopathy or malignant hyperthermia as noted in a later section. The major types of progressive muscular dystrophies, when advanced, usually affect the anterior neck muscles severely. Syringomyelia, spinal accessory neuropathy, some form of meningoradiculitis, and loss of anterior horn cells in conjunction with systemic lymphoma or carcinoma may differentially paralyze the various neck muscles. Weakness of respiratory and trunk Muscles Usually the diaphragm, chest, and trunk muscles are affected in association with shoulder and proximal limb muscles, but occasionally, isolated weakness of the respiratory muscles is the initial or the dominant manifestation of a muscle disease. Dyspnea and diminished vital capacity first bring the patient to the pulmonary clinic. The main causes are motor neuron disease, myasthenia gravis and less often glycogen storage disease (such as acid maltase deficiency—Pompe disease), mitochondrial myopathies, and nemaline myopathy. Dermatomyositis may cause respiratory weakness, but pulmonary difficulty is more often the result of an associated interstitial lung disease that may be amyopathic (lacking in muscle weakness). Unilateral paralysis of the diaphragm may result from compression of the phrenic nerve in the thorax by tumor or aortic aneurysm; an idiopathic or postinfectious variety may be related to brachial plexitis (see Chap. 43). The diaphragm and accessory muscles may be severely affected in some types of muscular dystrophies, but usually in association with pelvocrural and shoulder muscle weakness. Nocturnal dyspnea, sleep apnea, and respiratory arrest may occur, particularly in myasthenics and in patients with glycogen storage myopathies, and respiratory failure may threaten life in severe myasthenia gravis, Guillain-Barré syndrome, and poliomyelitis. As a general observation, in the acute neuromuscular paralyses, the cervical and shoulder muscles and the diaphragm, all of which share a common innervation, show a similar degree of weakness. Asking the patient to count aloud on one maximal breath can help detect diaphragmatic weakness (counting to 20 equates with a vital capacity of approximately 2 L). Paradoxical inward movement of the abdomen with inspiration is another sign of diaphragm weakness. Disorders of breathing and ventilation are discussed in Chap. 25 that discusses respiratory control and

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Chap. 43 in relation to its most dramatic presentation in the Guillain-Barré syndrome. Bibrachial palsy and the dangling-arm ( flail-arm) syndrome  Weakness, atrophy, and fasciculations of the hands, arms, and shoulders characterize the common form of motor neuron disease, ALS. Primary diseases of muscle hardly ever weaken these parts disproportionately. A diffuse weakness of both arms and the shoulder muscles may occur in the early stages of Guillain-Barré syndrome, paraneoplastic neuropathy, and amyloid polyneuropathy, in special forms of immunoglobulin (Ig) M-related paraproteinemic, or in inflammatory polyneuropathy (e.g., brachial neuritis) and porphyric polyneuropathy. A lesion affecting the central portion of the spinal cord in the cervical region produces this same pattern, but in that case there is an associated loss of pain and thermal sensation in the upper limbs and shoulders, signs that exclude disease of muscle. Proximal limb-girdle palsies presenting as inability to raise the arms or to arise from a squatting, kneeling, or sitting position  This is the common pattern of a number of myopathies. Polymyositis, IBM, dermatomyositis, and the muscular dystrophies most often manifest themselves in this fashion. The endocrine and the acquired metabolic myopathies (e.g., Cushing disease, hyperthyroidism, and steroid or statin administration) are other typical causes. Proximal limb weakness is a feature of myasthenia but almost always after the development of ocular or pharyngeal involvement. The childhood Duchenne, Becker, and limb-girdle types of dystrophies tend first to affect the muscles of the pelvic girdle, gluteal region, and thighs, resulting in a lumbar lordosis and protuberant abdomen, a waddling gait, and difficulty in arising from the floor and climbing stairs without the assistance of the arms. Climbing up by placing the hands on the thighs (Gower sign) is particularly characteristic of the dystrophies. Facioscapulohumeral dystrophy affects the muscles of the face and shoulder girdles foremost, and it is manifest by incomplete eye closure, inability to whistle and to raise the arms above the head, winging of the scapulae, and thinness of the upper arms with preserved forearm bulk (“Popeye” effect). Certain early or mild forms of dystrophy may selectively involve only the peroneal and scapular muscles. In milder forms of polymyositis, weakness may be limited to the neck muscles or to the shoulder or pelvic girdles. A number of other diseases of muscle may express themselves by a disproportionate weakness of girdle and proximal limb musculature. An intrinsic metabolic myopathy, such as the adult form of acid maltase deficiency and the familial types of periodic paralysis, may affect only this region. The congenital myopathies (central core, nemaline, myotubular) cause a relatively nonprogressive weakness of girdle muscles more than distal ones. Proximal muscles are occasionally implicated in spinal muscular atrophy or lateonset type and in Kennedy bulbospinal atrophy. Bicrural palsy presenting as lower leg weakness with inability to walk on the heels and toes, or as paralysis of all leg muscles  With the exception of certain distinctive distal types of muscular dystrophies, this pattern, usually due to weakness of peroneal, anterior tibial, and thigh muscles, is

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usually not a result of myopathy. Symmetrical weakness of the lower legs is more often caused by polyneuropathy. In cases of total leg and thigh weakness, one first considers a spinal cord disease. Motor neuron disease may begin in the legs, asymmetrically and distally as a rule, and affect them disproportionately to other parts of the body. Thus the differential diagnosis of distal or generalized leg weakness involves more diseases than are involved in the restricted paralyses of other parts of the body. Isolated quadriceps femoris weakness  Isolated quadriceps femoris weakness may be the expression of several diseases. In adults, the most common cause is IBM (where it may be unilateral or asymmetrical) or, a restricted form of Becker muscular dystrophy. In thyrotoxic and steroid myopathies, the major effects are on the quadriceps muscles. If unilateral or bilateral with loss of patellar reflex and sensation over the inner leg, this condition is most often the result of a femoral neuropathy, as occurs from diabetes, or of an upper lumbosacral plexus lesion. Injuries to the hip and knee cause rapid disuse atrophy of the quadriceps muscles. A painful condition of infarction of the muscle on 1 side is seen in diabetic patients. Distal bilateral limb palsies presenting as foot-drop with steppage gait, weakness of all lower leg muscles, and later wrist-drop and weakness of hands  The principal cause of this syndrome is a familial polyneuropathy, mainly of the Charcot-Marie-Tooth type (see Chap. 43); the course is over decades. Also presenting in this way are paraproteinemic and inflammatory polyneuropathies, with or without motor conduction block and exceptionally, some forms of familial progressive muscular atrophy and distal types of progressive muscular dystrophy, and sarcoid myopathy. In myotonic dystrophy, there may be weakness of the leg muscles as well as the forearms, sternocleidomastoids, face, and eyes. With these exceptions, the generalization that girdle weakness without sensory changes is indicative of myopathy and that distal weakness is indicative of neuropathy is clinically useful. Generalized paralysis of limb muscles, involved either in attacks or as a chronic persistent, progressive deterioration (see also Chap. 46)  When acute in onset and episodic, this syndrome is usually a manifestation of familial or acquired hypokalemic or hyperkalemic periodic paralysis. One variety of the hypokalemic type is associated with hyperthyroidism, another with hyperaldosteronism. Attacks of porphyric neuropathy and of Refsum disease with generalized weakness have an episodic nature. Widespread paresis (rather than paralysis) that has an acute onset and lasts many weeks is at times a feature of a severe form of idiopathic or parasitic (trichinosis) polymyositis and, rarely, of the toxic effects of certain pharmaceutical agents, particularly those used to treat hypercholesterolemia. Idiopathic polymyositis and, rarely, IBM may involve all limb and trunk muscles, but usually spare the facial and ocular muscles, whereas the weakness in trichinosis is mainly in the ocular and lingual muscles. In infants and young children, a chronic and persistent generalized weakness of all muscles, except those of the eyes, always raises the question of Werdnig-Hoffman spinal muscular atrophy or, if milder in degree and relatively nonprogressive, of one of the congenital myopathies or polyneuropathies. In these

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diseases of infancy, paucity of movement, hypotonia, and retardation of motor development may be more obvious than weakness, and there is arthrogryposis at birth. Paralysis of single muscles or a group of muscles  This is usually neuropathic, less often spinal or myopathic. Muscle disease does not need to be considered except in certain instances of pressure-ischemic necrosis of muscle as a result of local pressure or infarction, as in monoplegic alcoholic myopathy or in diabetic muscle infarction. The weakness of IBM has a preference for certain sites, specifically parts of the quadriceps, or of the forearm muscles, particularly the long finger flexors (flexor digitorum profundus), and also therefore enters into consideration. From this exposition of the topographic aspects of weakness, one can appreciate that each neuromuscular disease exhibits a predilection for particular groups of muscles. Apart from these patterns that suggest certain possibilities of disease and exclude others, diagnosis depends on the age of the patient at the time of onset and tempo of progression, the coexistence of medical disorders, certain laboratory findings (serum concentrations of muscle enzymes, EMG, and biopsy findings), and genetic determinants. The symptoms and signs of muscle disease are considered in this chapter mainly in connection with the age of the patient at the time of onset, their mode of evolution, and the presence or absence of familial occurrence. Because many muscle diseases are hereditary, a careful family history is important. The pattern of inheritance has diagnostic significance and, if genetic counseling or prenatal diagnosis is a consideration, a detailed genealogic tree becomes essential. When historical data are insufficient, it is often necessary to examine siblings and parents of the proband. The molecular genetics and other genetic aspects of the heritable muscle diseases, subjects of intense interest in recent years, are discussed at appropriate points in the chapter. In summary, the clinical recognition of myopathic diseases is facilitated by a prior knowledge of a few topographic syndromes, the age of the patient at the onset of the illness, a familial occurrence of the same or similar illnesses, and of the medical setting in which weakness evolves. Diagnostic accuracy is aided by the intelligent use of the laboratory examinations discussed in Chap. 2, particularly the muscle enzymes, EMG, and muscle biopsy.

THE INFECTIOUS MYOPATHIES The discovery that striated skeletal muscle and cardiac muscle could be the sole targets of a number of infectious agents came about during the era of the development of microbiology and occupied the attention of many prominent clinicians, including Osler. As these diseases were being characterized, however, a number of other inflammatory states affecting muscle were found for which there was no infectious cause. This group of idiopathic inflammatory myopathies figures so prominently in clinical myology that we devote a separate section to the subject. First, the infections of muscle are described.

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Parasitic Myositis Included here are trichinosis, toxoplasmosis, parasitic and fungal infections, and a number of viral infections.

Trichinosis This parasitic disease is caused by the nematode Trichinella spiralis. Its general features are discussed in Chap. 31. Regarding the myopathic aspect of the illness, the authors have been most impressed with the ocular muscle weakness, which results in strabismus and diplopia; with weakness of the tongue, resulting in dysarthria; and with weakness of the masseter and pharyngeal muscles, which interferes with chewing and swallowing. Any weakness of limb muscles is usually mild and more severe proximally than distally. However, the diaphragm may be involved, as well as the myocardium. The affected muscles are slightly swollen and tender in the acute stage of the disease. Often, there is conjunctival, orbital, and facial edema, sometimes accompanied by subconjunctival and subungual splinter hemorrhages. As the trichinae become encysted over a period of a few weeks, the symptoms subside and recovery is complete. Many, perhaps the majority, of infected patients are asymptomatic throughout the invasive period, and as much as 1 to 3 percent of the population in certain regions of the country will be found at autopsy to have calcified trichinella cysts in their muscles with no history of parasitic illness. Heavy infestations have been known to end fatally, usually from cardiac and diaphragmatic involvement. In these more massive infections, the brain also may be involved, probably by emboli that arise in the heart from an associated myocarditis. Diagnosis  Clinically, one should suspect the disease in a patient who presents with a puffy face and tender muscles. Eosinophilia is practically always present in the peripheral blood (>700 cells/mm3), although the sedimentation rate is often normal. The CK level is moderately elevated. A skin test using Trichinella antigen is available, but it is unreliable. The enzyme-linked immunosorbent assay (ELISA) blood test is more accurate, but it becomes positive only after 1 or 2 weeks of illness. Biopsy of almost any muscle (usually the deltoid or gastrocnemius), regardless of whether it is painful or tender, is probably the most reliable confirmatory test. More than 500 mg of muscle may be required to demonstrate larvae, but smaller specimens will almost invariably show an inflammatory myopathy. Muscle fibers undergo segmental necrosis, and the interstitial inflammatory infiltrates contain a predominance of eosinophils. This accounts for the edema, pain, and tenderness of heavily infested muscles. The capsules of the larvae gradually thicken in the first month of the infection and then calcify. The EMG may exhibit profuse fibrillation potentials, a phenomenon attributed on theoretical grounds to the disconnection of segments of muscle fibers from their motor endplates (Gross and Ochoa). Treatment  No treatment is required in most cases. In patients with severe weakness and pain, a combination of thiabendazole, 25 to 50 mg/kg daily in divided doses for 5 to 10 days, and prednisone, 40 to 60 mg/d, is recommended. Albendazole, in a single oral dose of 400 mg daily, or mebendazole are equally effective but usually

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more expensive. Recovery, as mentioned, is complete as a rule, except in rare patients with cerebral infarcts. Other aspects of this parasitic infestation are discussed in Chap. 31.

Toxoplasmosis This is an acute or subacute systemic infection caused by the encephalitozoon Toxoplasma gondii. Most Toxoplasma infections in immunocompetent patients, which occur in up to 10 to 30 percent of the population, are asymptomatic, but there may be fever and varying degrees of involvement of the skin, lymph nodes, retina, myocardium, liver, brain, and muscle. In one such case studied by our colleagues, Toxoplasma organisms and pseudocysts were detected in skeletal muscle (Kass et al); wherever a parasitic pseudocyst had ruptured, there was focal inflammation. Some muscle fibers had undergone segmental necrosis, but this was not prominent (one contained the organism), accounting for the relative paucity of muscle symptoms. With the emergence of HIV, toxoplasmic infections of both the brain and also sometimes skeletal muscle have become more common although the latter is less common than primary HIV myopathy and treatment-related muscle diseases (Gherardi et al). The subject of HIV is discussed in Chap. 31 and toxoplasmic infection is discussed in greater detail in Chap. 32. The myopathy, which occurs with variable fever, lymphopenia, and failure of other organs, consists of weakness, wasting, myalgia, and elevated CK levels. Presumably, the immunocompromised patient is unable to respond to protozoan infections, allowing latent infections to be reactivated. Sulfadiazine in combination with pyrimethamine or trisulfapyrimidine, which acts synergistically against the toxoplasmic trophozoites, improves the muscle symptoms and reduces serum CK. Folic acid is given in addition.

Other Parasitic and Fungal Infections of Muscle Echinococcosis, cysticercosis, trypanosomiasis (Chagas disease), sparganosis, toxocariasis, and actinomycosis have all been known to affect skeletal muscle on occasion, but the major symptoms relate more to involvement of other organs (Banker). Only cysticercosis may first claim the attention of the clinical myologist because of a dramatic pseudohypertrophy of thigh and calf muscles. Hydatids infest the paravertebral and lumbar girdle muscles in 5 percent of cases and may lead to their enlargement. Coenurosis and sparganosis are causes of movable lumps in the rectus abdominis, thigh, calf, and pectoralis muscles. Protozoan infections of muscle—microsporidiosis, African and American trypanosomiasis—which occurred only rarely until a few decades ago, are now being observed in immunodeficient (HIV-infected) individuals in endemic areas.

Viral Infections of Muscle HIV and Human T-Lymphotropic Virus Type I Myositis HIV and human T-lymphotropic (or leukemia) virus type I (HTLV-I) are increasingly common causes of viral myositis (Engel and Emslie-Smith). Moreover, as discussed further on, zidovudine (ZVD), a drug included in many regimens

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to treat HIV infections, may itself induce a myopathy with myalgia and weakness that is, at times, indistinguishable from HIV myopathy (Dalakas et al). An inflammatory, and presumed infectious, myopathy may develop early in the course of HIV infection but is rarely the initial manifestation. The pattern is like that of idiopathic polymyositis with painless weakness of the girdle and proximal limb muscles. Reflexes are diminished in most cases, but this is difficult to interpret in view of the high incidence of concomitant polyneuropathy. Serum CK is elevated, and the EMG shows an active myopathy with fibrillations, brief polyphasic motor units, and complex repetitive discharges. The myopathologic changes in AIDS are also like those of idiopathic polymyositis described further on. In addition, in some cases electron microscopy discloses the presence of nemaline (rod) bodies within type 1 fibers, similar to those observed in the congenital form of nemaline myopathy discussed further on. As implied earlier, the pathogenesis of the HIV myopathy has not been firmly established as there is scant evidence of a direct viral infection of the muscle fibers. An immune basis has been suggested in view of a response to corticosteroids, plasma exchange, and gamma globulin, comparable to the beneficial effects in the idiopathic variety of polymyositis. Corticosteroids in doses similar to those used in the treatment of idiopathic polymyositis are effective in ameliorating the weakness, but they entail special risks in immunocompromised patients. The clinical features of putative ZVD-induced myopathy are much the same as those of HIV myopathy except that moderate pain is said to be characteristic of the druginduced variety. The myopathy has been attributed to the mitochondrial toxicity of the drug, which may account for the presence of “ragged red” fibers in biopsy specimens. The onset of symptoms appears to be related to the sustained administration of high doses of the drug (1,200 mg daily for a year or longer). Cessation or reduction in dosage of the drug diminishes the muscular discomfort within weeks, but strength recovers more slowly. Distinguished from the HIV- and ZVD-related inflammatory myopathies is the severe generalized muscle wasting that characterizes advanced, cachectic AIDS. Muscle enzymes are normal and strength is affected little, especially considering the loss of muscle bulk. Histologically, there is atrophy of type 2 fibers. The pathogenesis of this cachectic syndrome is uncertain; it has been attributed to a multiplicity of systemic factors, including circulating catabolic cytokines, just as in other wasting syndromes such as cancer. A myopathy caused by HTLV-I infection also simulates polymyositis in its clinical and histologic features. The illness occurs most often in endemic areas but is less common than the myelopathy that is associated with the virus.

Other Viral Myopathies In most patients with pleurodynia (epidemic myalgia, Bornholm disease), muscle biopsies disclose no abnormalities and there is no clear explanation of the pain. However, group B Coxsackie virus has been isolated from striated muscle of a few patients with this disorder.

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A necrotizing myositis has been suspected in a number of patients with influenza; under the electron microscope, some muscle fibers contain structures with the features of influenza virions. Malaise, myalgia, and slight weakness and stiffness were the clinical manifestations. Because of the myalgia, it is difficult to know how much of the weakness is only apparent. Recovery has been complete within a few weeks. In one patient with generalized myalgia and myoglobinuria, the influenza virus was isolated from muscle (Gamboa et al). These observations suggest that the intense muscle pain in certain viral illnesses might be the result of a direct viral infection of muscle. However, there are many cases of influenzal myalgia, mainly of the calves and thighs (Lundberg; Antony and coworkers), in which it was not possible to establish that there was a muscular disorder at all. In the condition described as epidemic neuromyasthenia (benign myalgic encephalomyelitis, Icelandic disease), in which influenza-like symptoms were combined with severe pain and weakness of muscles, a viral cause was postulated, but an organism was never isolated. The illness has been absorbed into the large and indistinct category of chronic fatigue syndrome (discussed in Chap. 23). Echo 9, adenovirus 21, herpes simplex, Epstein-Barr virus, coxsackievirus, and Mycoplasma pneumoniae are other causes of sporadic myositis with rhabdomyolysis (Mastaglia and Ojeda). In these infections the nonmyopathic aspects of the disease usually predominate; in some of them, the evidence of invasion of muscle has not been fully substantiated, as in many instances a nonspecific (Zenker-type) degeneration could have explained the muscle findings. The existence of a postinfectious type of myositis is also unsettled and this uncertainty pertains to muscle ailments that have been casually associated with COVID. COVID (SARS-CoV-2) infection has been associated with myositis, but histopathologic analysis has shown immune-mediated inflammatory changes related to release of cytokines but has not shown direct viral tissue invasion (Suh).

IMMUNE-INFLAMMATORY MYOPATHIES These are common diseases that affect primarily the striated muscle and skin and sometimes connective tissues. The term used to describe the disease reflects the tissues involved. If the inflammatory changes are restricted clinically to the striated muscles, the disease has traditionally been called polymyositis (PM); if, in addition, the skin is involved, it has been called dermatomyositis (DM), although the two diseases are probably immunopathologically distinct and some authorities question the existence, or at least the frequency, of an independent idiopathic polymyositis (Dalakas). Either may be associated with a rheumatologic disorder, in which case the designation is PM or DM with rheumatoid arthritis, rheumatic fever, lupus erythematosus, scleroderma, Sjögren syndrome, or mixed connective tissue disease, as the case may be. There is also an important but inconsistent relationship of these myositides and systemic carcinoma, as discussed

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further on. However, the largest advance broadly in the field of inflammatory myopathies has been the delineation of several specific antibodies that associate with certain clinical and histopathologic features. In fact, the terms polymyositis and dermatomyositis are beginning to lose their meaning as specific entities and traditional diagnostic criteria are being replaced. Both diseases, as traditionally defined, were described the nineteenth century. Polymyositis was first described by Wagner in 1863 and 1887, and DM was established as an entity by Unverricht in a series of articles written from 1887 to 1891. A classification introduced in the monograph of Walton and Adams included categories associated with neoplasia and with connective tissue diseases (Kakulas and Adams; Engel and colleagues). It is mentioned above and emphasized further on that there is disagreement regarding the frequency of PM as an independent entity. Many cases so classified may be the result of DM, an immune necrotizing myopathy commented on below, or of IBM, or are related to an underlying connective tissue disease (Amato and Griggs). Even other cases are examples of muscular dystrophy with secondary inflammatory changes, an error made infrequently with modern pathology techniques. The main point of controversy has been the proposal that isolated PM is rare and overdiagnosed (van der Muelen et al) but this may be obviated by newer classifications based on circulating autoantibodies. Inflammatory myopathy coexists with numerous systemic diseases as discussed, and some authors consider it to be a syndrome rather than a disease. Despite the above descriptions, dermatomyositis is a heterogeneous syndrome associated with several antibodies: anti–transcription intermediary factor 1-γ (antiTIF1-γ), anti–complex nucleosome remodeling histone deacetylase (anti-Mi2), anti–melanoma differentiation gene 5 (anti-MDA-5), anti–nuclear matrix protein 2 (antiNXP-2), anti–small ubiquitin-like modifier-activating enzyme (anti-SAE), and anti-aminoacyl tRNA synthetases (anti-ASAs), each as mentioned associated with a clinical syndrome and histopathologic appearance. It had been hypothesized the typical idiopathic inflammatory myopathy is caused by complement-mediated microangiopathy, but there is evidence that the microvasculopathy, skin, and muscle damage may be due to toxicity from type I interferon-mediated pathways, most likely IFN-beta, and the complement deposition on capillaries is secondary. This has implications for treatment.

Dermatomyositis This is the representative example of inflammatory myopathy. The onset is usually insidious and the course progressive over a period of several weeks or months. It may develop at almost any age and in either sex; however, the majority of patients are 30 to 60 years of age, and a smaller group shows a peak incidence at 15 years of age; women predominate in all age groups. A febrile illness or benign infection may precede the weakness, but in most patients the first symptoms develop in the absence of these or other apparent initiating events.

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The usual mode of onset is mainly painless weakness of the proximal limb muscles, especially of the hips and thighs and to a lesser extent the shoulder girdle and neck muscles. Often, the patient cannot easily determine the time of onset of weakness. Certain actions—such as arising from a deep or low chair or from a squatting or kneeling position, climbing or descending stairs, walking, putting an object on a high shelf, or combing the hair—become increasingly difficult. Pain of an aching variety in the buttocks, calves, or shoulders is experienced by approximately 15 percent of patients, and it may indicate a combination of myositis and rheumatoid arthritis, tendonitis, or other rheumatologic disorder. When the patient is first seen, many of the muscles of the trunk, shoulders, hips, upper arms, and thighs are usually involved. The posterior and anterior neck muscles (the head may loll) and the pharyngeal, striated esophageal, and laryngeal muscles (dysphagia and dysphonia) may be involved as well. In restricted forms of the disease, only the neck or paraspinal muscles (camptocormia) may be implicated. Ocular muscles are not affected but there are rare instances of combined myositis and myasthenia gravis. The facial, tongue, and jaw muscles are only occasionally affected, and the distal muscles, namely the forearm, hand, leg, and foot are spared in 75 percent of cases. The respiratory muscles are weakened to a minor degree and in only an exceptional case is there dyspnea, the cause of which is revealed only by an intercostal muscle biopsy (Thomas and Lancaster). Occasionally, the early symptoms predominate in one proximal limb before becoming generalized. As emphasized further on, onset after age 50 years, normal CK, or aberrant patterns of weakness, such as early wrist or finger flexor, quadriceps, or ankle dorsiflexor involvement, are indicative of IBM (see further on). The muscles are usually not tender, and atrophy and reduction in tendon reflexes, although sometimes present, are far less pronounced than they are in patients with chronic denervation atrophy, IBM, or Lambert-Eaton myasthenic syndrome (the last of these is discussed in Chap. 46). As the weeks and months pass, the weakness and muscle atrophy progress unless treatment is initiated. Without physical therapy, fibrous contracture of muscles eventually develops. Some elderly individuals with a particularly chronic form of the disease may present with severe atrophy and fibrosis of muscles; the response to treatment in such cases is poor. Most often, the skin changes precede the muscle syndrome and take the form of a localized or diffuse erythema, maculopapular eruption, scaling eczematoid dermatitis, or exfoliative dermatitis. Sometimes, skin and muscle changes evolve together over a period of 3 weeks or less. A characteristic form of the skin lesions are patches of a scaly roughness over the extensor surfaces of joints (elbows, knuckles, and knees) with varying degrees of pink-purple coloration. Red, raised papules may be present over exposed surfaces such as the elbows, knuckles, and distal and proximal interphalangeal joints (Gottron papules— applied in some writings to all the skin changes over the knuckles and extensor prominences); these are particularly prominent in DM of childhood. Also typical is a lilaccolored (heliotrope) change in the skin over the eyelids,

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on the bridge of the nose, on the cheeks, and over the forehead; it may have a scaly component. Itching may be a troublesome symptom in regions of the other skin eruptions. A predominance of rash over the neck and upper shoulders has been termed the V sign, while rash over the shoulders and upper arms, the shawl sign. This distribution suggests that the skin changes reflect heightened photosensitivity (a feature shared with pellagra). Periorbital and perioral edema are additional findings but mainly in fulminant cases. Skin changes may be transient and in some instances are restricted to one or more patches of dermatitis; they are difficult to appreciate in dark-skinned individuals. Evanescent and restricted skin manifestations are emphasized because they are frequently overlooked and provide clues to diagnosis. In the healing stage, the skin lesions leave whitened atrophic scars with a flat, scaly base. Dilated capillary loops at the cuticular nail beds may be seen but are more characteristic of the childhood type discussed further on. In contrast to PM, DM affects children and adults about equally. Among adults, DM is more frequent in women, whereas in childhood males and females are affected equally. Other physical signs include periarticular and subcutaneous calcifications that are common in the childhood form. Signs of associated connective tissue disease are more frequent than in pure PM (see further on). The Raynaud phenomenon has been reported in nearly onethird of the patients and a similar number have dilated or thrombosed nail fold capillaries. Whether this signifies the presence of a systemic autoimmune tissue disease has not been clarified. Others subsequently develop a mild form of scleroderma, and an associated esophageal weakness is demonstrated by fluoroscopy in up to 30 percent of all patients. The superior constrictors of the pharynx may be involved, but cinefluoroscopy may be necessary to demonstrate the abnormality.

Polymyositis In recent years the term polymyositis has fallen out of favor, and many cases that would previously have been generally classified as PM are now more specifically classified (for example as the antisynthetase syndrome, an overlap myositis (with another connective tissue disease), or immunemediated necrotizing myopathy (IMNM). IMNM is now understood to have distinct histopathological features, but in the past these cases would commonly have been labeled as PM. To the extent that polymyositis still exists as its own clinical diagnostic entity, it is an idiopathic subacute or chronic and symmetrical weakness of proximal limb and trunk muscles without dermatitis. In both PM and DM, there may be involvement of organs other than muscle. Cardiac manifestations have been observed, often taking the form of relatively minor electrocardiographic (ECG) changes, but several patients have had arrhythmias with clinical consequences. Among the rare fatal cases, about half have shown necrosis of myocardial fibers at autopsy, usually with only modest inflammatory changes. Interstitial lung disease is another known association in a few cases; its frequency ranges from 10 to 47 percent in

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different series and up to 70 percent in one subtype with anti-Jo antibodies (see further on under “Laboratory Diagnosis of PM and DM”). A low-grade fever occurs rarely, especially if joint pain coexists. Carcinoma with adult inflammatory myopathy  At one time this was a controversial subject and in some respects it remains so because of widely varying incidences of concurrence between systemic malignancy with PM and DM (see Engel et al; Buchbinder and Hill). In one series, 9 percent of 396 patients with PM were found to have carcinoma, either at the time of diagnosis of the muscle disease or within 5 years (Sigurgeirsson and colleagues). It has been reported that 29 percent of a group of DM patients had an associated carcinoma; this figure rose to 40 percent if the patient was older than 40 years, and to 66 percent if the patient was both male and older than 40 years (DeVere and Bradley). This, however, is higher than reported in most other series. The relationship between myositis and malignancy is not understood; nonetheless, the connection appears valid, even if of uncertain frequency. The neoplastic processes linked most often with myositis are lung and colon cancer in men and breast and ovarian cancer in women; however, tumors have been reported in nearly every organ of the body. In about half the cases, myositis antedates the clinical manifestations of the malignancy, sometimes by 1 to 2 years, an interval that has brought the association into question by several authors. The morbidity and mortality of patients with this combination is usually determined by the nature of the underlying tumor and its response to therapy. Occasionally, excision of the tumor is attended by remission of the myositis, but information on this point comes mostly from sporadic reports.

Dermatomyositis of Childhood Idiopathic myositis occurs in children, but less frequently than in adults. Some cases tend to be relatively benign but otherwise do not differ from the syndrome in adults. More frequently, there is a distinctive illness, which differs in some respects from the usual adult form of the disease (Banker and Victor). In these children and adolescents, there is greater involvement of blood vessels in the connective tissue of multiple organs, as well as in skin and muscle. This childhood form of DM begins, as a rule, with typical skin changes accompanied by anorexia and fatigue. Erythematous discoloration of the upper eyelids (the previously noted heliotrope rash), frequently with facial edema, is another characteristic early sign. The erythema spreads to involve the periorbital regions, nose, malar areas, and upper lip as well as the skin over the knuckles, elbows, and knees. Cuticular overgrowth, subungual telangiectasia, and ulceration of the fingertips may be found. Capillary prominence in the nail beds and avascular regions in the cuticle are said to be characteristic but need to be sought with a magnifying lens or ophthalmoscope (these signs are also seen in the “CREST” [calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, telangiectasia] form of scleroderma). Symptoms of weakness, stiffness, and pain in the muscles usually follow but may precede the skin manifestations.

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The weakness is generalized but always more severe in the muscles of the shoulders and hips and proximal portions of the limbs. A tiptoe gait, the result of fibrous contractures of flexors of the ankles, is a common late abnormality. Tendon reflexes are depressed or abolished, but only commensurate with the degree of muscle weakness. Intermittent low-grade fever, substernal and abdominal pain (like that of peptic ulcer), melena, and hematemesis from bowel infarction may occur, the result of an accompanying systemic vasculitis. The mode of progression of DM of childhood, like that of the adult form, is variable. In fulminant cases, the weakness appears rapidly, involving all the muscles including those of chewing, swallowing, talking, and breathing and leading to total incapacitation. Perforation of the gastrointestinal tract from bowel infarction may be the immediate cause of death, as it has been in two of our patients. In others, there is slow progression or arrest of the disease and, in a small number, there is a remission of weakness. Flexion contractures at the elbows, hips, knees, and ankles and subcutaneous calcification and ulceration of the overlying skin, with extrusion of calcific debris are manifestations in the late, untreated stages of the disease.

Systemic Autoimmune (Rheumatologic) Diseases With Polymyositis and Dermatomyositis In both PM and DM, the inflammatory changes are often not confined to muscle but are associated with systemic autoimmune diseases such as rheumatoid arthritis, scleroderma, lupus erythematosus, or combinations thereof (mixed connective tissue disease); the same muscle changes are associated less often with the Sjögren syndrome. Conversely, in the aforementioned immune diseases, inflammatory muscle changes are frequently found but in only a limited number of muscles and often asymptomatically. The incidence of these “crossover” or overlap cases cannot be stated with certainty. A true necrotizing–inflammatory myopathy has been reported in up to 8 percent of cases of lupus erythematosus (far higher than in our experience), and an even smaller proportion of cases of systemic sclerosis, rheumatoid arthritis, and Sjögren syndrome. The treatment of rheumatoid arthritis with D-penicillamine increases the incidence of, or perhaps independently precipitates, a myositis. Also notable is the sporadic concurrence of myositis with other autoimmune diseases such as myasthenia gravis and Hashimoto thyroiditis and less often, with a monoclonal paraprotein in the blood; it is not clear whether these are coincidental, but it is likely that they reflect an underlying genetic propensity to autoimmune disease. In the overlap syndromes that incorporate autoimmune disease and myositis, there is usually greater muscular weakness and atrophy than can be accounted for by the muscle changes alone. Inasmuch as arthritis or periarticular inflammation may limit motion because of pain, result in disuse atrophy, and also at times cause a vasculitic polyneuropathy, the interpretation of diminished strength in these autoimmune diseases is not simple. Malaise, aches, and pains are common and attributable mostly to the systemic disease. Sometimes the diagnosis of myositis

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must depend on muscle biopsy, EMG findings, and measurements of muscle enzymes in the serum. In these complicated cases, myositis may accompany the connective tissue disease or occur many years later. It is worth noting that PM may occur during pregnancy and that rarely the fetus is affected (most often the fetus and neonate are normal) with elevated CK levels for months postpartum (Messina et al).

Laboratory Diagnosis of PM and DM In the majority of patients, serum levels of CK and other muscle enzymes, such as aldolase, are elevated. Serum CK levels tend to be higher in PM than in DM because of the widespread single-fiber necrosis in the former (as described in the following section on pathologic changes). However, in DM, if there are infarcts in muscle, CK levels will be moderately elevated as well. The sedimentation rate is normal or mildly elevated in both diseases. It has been appreciated that some cases of PM and DM are associated with autoantibodies in the blood. Some of these are undoubtedly nonspecific markers of an autoimmune or inflammatory state (Brouwer et al), but others may be of pathogenetic significance or are markers for syndromes with multiorgan damage that extends beyond muscle. Tests for circulating rheumatoid factor or antinuclear antibody (ANA) are positive in fewer than half of cases. A high titer of ANA, in conjunction with elevated antiribonuclear antibodies, suggests the coexistence of systemic lupus or mixed connective tissue disease. It must be emphasized, however, that absent or low-titer ANA and a normal sedimentation rate do not exclude the diagnosis of PM, a fact that limits their diagnostic usefulness. Other antibodies can be found on occasion that are directed against constituents of a nucleolar protein complex (PM-Scl) and ribonucleoproteins (Ro/SS-A and La/SS-B). Of greater interest are the findings that 20 to 30 percent of patients with DM have antibodies against various cellular components of muscle, in particular, antibodies directed against cytoplasmic transfer ribonucleic acid (tRNA) synthetases (anti-Jo1), or against the tRNA itself. These are found when the myositis is coupled with an expanded illness that involves other tissues. The clinical disorders associated with these antibodies usually combine myositis with (1) interstitial lung disease (2) arthritis, (3) Raynaud syndrome, and (4) thickening of the skin of the hands (“mechanic’s hands”). Following from the designation of the main type of antibody, these have been termed synthetase syndromes. A proportion of cases of severe, necrotizing inflammatory myositis show specific antibodies that are directed against a cytoplasmic ribonucleoprotein complex (SRP), or against a protein complex that is a nuclear helicase (Mi-2). These are now classified as separate entities from DM and in some series have carried a heightened risk of cardiac muscle inflammatory involvement. Similarly, in the category of necrotizing inflammatory myositis, a proportion of patients display antibodies to HMGCR, the target of statin drugs, but may also be present without exposure to these drugs. Although these various autoantibodies, with the possible exception of anti-Jo1, have not been especially useful as primary diagnostic tools, they do have a role in

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refining diagnosis. For example, a positive Jo1 antibody, although too uncommon to use as a screening test, argues against the diagnosis of inclusion body myopathy (which has been associated with a different set of autoantibodies as discussed further on) and its presence raises concern about the later development of interstitial lung disease. The presence of these antibodies also underscores the role for the humoral immune system in the pathogenesis of inflammatory myositis and raises opportunities for investigation discussed as follows. Myoglobinuria can be detected in the majority of patients with most forms of myositis, particularly a necrotizing form, provided that a sensitive immunoassay procedure is used, but this test is not routinely performed. The EMG is quite helpful in diagnosis but has been normal in a small proportion of our patients, even when many muscles are sampled. A typical “myopathic pattern” is disclosed, that is, many abnormally brief action potentials of low voltage in addition to numerous fibrillation potentials, trains of positive sharp waves, occasional polyphasic units, and myotonic activity—all but the brief potentials possibly reflecting irritability of the muscle membranes (see Chap. 46). These findings are most apparent in weak muscles and are almost always seen when proximal weakness is well developed but they also may be observed in clinically unaffected areas. Indolent and chronic cases in which fibrosis of muscle and wasting have supervened may show polyphasic units that simulate denervation–reinnervation changes, juxtaposed with myopathic motor units. The EMG is also helpful in choosing a muscle for biopsy sampling but care must be taken not to obtain tissue from precisely the same site as a recent EMG needle insertion as a spurious histopathologic appearance of muscle damage may be obtained in this region (see the following text). Our approach has been to perform the needle EMG examination on one side of the body and biopsies on the other side. As stated earlier, the ECG is abnormal in some cases and this finding may suggest the need for vigilance regarding cardiac symptoms and arrhythmias. The results of magnetic resonance imaging (MRI) of muscle have been interesting and may aid the clinician in that abnormalities in T1, T2, and STIR signal intensity define regions of increased water content and inflammation and spectroscopic studies demonstrate regional deficits in energy production. Although MRI cannot at this time replace a biopsy for diagnosis, it can refine the distribution of lesions and aid in targeting the muscle biopsy, as well as provide a useful index of the efficacy of drug therapy. In some cases, MRI can distinguish IBM from either PM or metabolic muscle disease (Lodi et al; Dion et al).

Pathologic Changes in PM and DM Because of the scattered distribution of inflammatory lesions and destructive changes, only part (or none) of the complex of pathologic changes may be divulged in any single biopsy specimen. Because of this limitation, more than one site of biopsy or multiple samples through one incision is advisable. In DM, there are several distinctive histopathologic changes (Casal-Dominguez and colleagues.) In contrast to the evident necrosis of single fibers of PM, DM is

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characterized by perifascicular muscle fiber atrophy (referring to changes at the periphery of a fascicle, for reasons noted below). Moreover, the inflammatory infiltrates in DM predominate in the perimysial connective tissue, whereas in PM they are scattered throughout the muscle and are most prominent in relation to the muscle fiber membrane and the endomysium. The muscle lesions in dermatomyositis of childhood are similar to those of the adult form, only greatly accentuated. In a biopsy sample, the diagnosis can be inferred from the perifascicular pattern of degeneration and atrophy of muscle fibers. The principal changes in idiopathic PM consist of widespread destruction of segments of muscle fibers with an inflammatory reaction, that is, phagocytosis of muscle fibers by mononuclear cells and infiltration with a varying number of lymphocytes and lesser numbers of other mononuclear and plasma cells. Evidence of regenerative activity of muscle, mainly in the form of proliferating sarcolemmal nuclei, basophilic (RNA-rich) sarcoplasm, and new myofibrils, is evident in damaged regions. Many of the residual muscle fibers are small, with increased numbers of sarcolemmal nuclei. Some of the small fibers are found in clusters, the result of splitting of regenerating fibers. Either the degeneration of muscle fibers or an infiltration of inflammatory cells may predominate in any given biopsy specimen, although both types of changes are in evidence at autopsy. In a single section from a biopsy sample, there may be only necrosis and phagocytosis of individual muscle fibers without infiltrates of inflammatory cells, or the reverse may be observed. However, in serial sections, muscle necrosis is shown to be adjacent to inflammatory infiltrates. Repeated attacks of a necrotizing myositis exhaust the regenerative potential of the muscles so that fiber loss, fibrosis, and residual thin and large fibers in haphazard arrangement may eventually impart a dystrophic appearance. For all these reasons, the pathologic picture can be correctly interpreted only in relation to clinical and other laboratory data (Dalakas and Hohlfeld). Even more distinctive of DM are microvascular changes in muscle. Endothelial alterations (tubular aggregates in the endothelial cytoplasm) and occlusion of vessels by fibrin thrombi may be appreciated, with associated zones of infarction. The same vascular changes underlie the lesions in the connective tissue of skin, subcutaneous tissue, and gastrointestinal tract when they are present. The perifascicular muscle fiber atrophy had in the past been attributed to an ischemic process set up by capillary occlusion, but recent evidence suggests otherwise (see Bohan and Peter; Greenberg and Amato).

Etiology and Pathogenesis Immunopathologic studies have substantiated an autoimmune mechanism and suggested that PM, DM, and necrotizing myositis can be distinguished from one another based on their immunopathologic characteristics (Dalakas). In DM, immune complexes, IgG, IgM, complement (C3), and membrane-attack complexes are deposited in the walls of venules and arterioles, indicating that the immune response is directed primarily against intramuscular blood vessels (Whitaker and Engel; Kissel et al).

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Such a response is lacking in PM (and in IBM, discussed further on). The two disorders have been shown to differ based on the subsets and locations of lymphocytes that make up the intramuscular inflammatory aggregates (Engel and Arahata). However, the deposition of these complexes may be a secondary event as our colleagues Greenberg and Amato propose. In PM, there are a large number of activated T cells, mainly of the CD8 class, whereas B cells are sparse. Moreover, T cells, accompanied by macrophages, enclose and invade nonnecrotic muscle fibers. In DM, very few fibers are affected in this manner, and the percentage of B cells at all sites is significantly higher than it is in PM. These data suggest that the effector response in DM may be predominantly humoral, whereas in PM the response is composed of cytotoxic T cells, clones of which have been sensitized to a yet undefined antigen on the muscle fiber.

Treatment Most clinicians agree that glucocorticoids (e.g., prednisone, 1 mg/kg, as a single daily dose orally, or intravenously) are a reasonable first therapy for both PM and DM. The response to treatment is monitored by testing of strength and measurement of CK (not by following the erythrocyte sedimentation rate [ESR]). In patients who respond clinically, the serum CK decreases before the weakness subsides; with relapse, the serum CK rises before weakness returns. Once the CK level normalizes and strength improves, typically several weeks or longer, one approach is to reduce the dosage gradually—by no more than 5 mg every 2 weeks— toward 20 mg daily. It is then appropriate to attempt to control the disease with an alternate-day schedule with double this amount (i.e., prednisone, 40 mg every other day) to reduce the side effects of the drug. After cautious reduction of prednisone over a period of 6 months to 1 year or longer, the patient can usually be maintained on doses of 7.5 to 20 mg daily, with the aim of eventual discontinuation of the drug. Corticosteroids should not be discontinued prematurely, for the relapse that may follow is often more difficult to treat than the original illness. Some clinicians prefer to add an immunosuppressive agent at this time rather than wait for failure of glucocorticoids or as a means of reducing steroid dependence, as discussed below. In acute and particularly severe cases, treatment may be facilitated by the use initially of high-dose methylprednisolone (1 g intravenously each day for 3 to 5 days). This form of treatment should be regarded as a temporary measure until oral prednisone or a more fast-acting treatment becomes effective. Alternatively, or sometimes in tandem with this approach in severe cases, intravenous immunoglobulin (IVIg) or plasma exchanges may be instituted. In patients with DM who respond poorly to corticosteroids and other immunosuppressants or are severely affected early on, the addition of IVIg infusions often proves helpful, although several courses of treatment at monthly intervals may be required to achieve sustained improvement. In several controlled studies of small numbers of patients with DM, practically all showed improvement in muscle strength and in skin changes, and a reduction in CK concentration (Dalakas 1997; Mastaglia et al). A randomized controlled trial in 95 patients corroborates these reports and

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emphasizes potential adverse events such as infusion reactions and venous thrombosis (Aggarwal et al). A complex composite scoring system has been devised for trials of inflammatory myopathy but aspects of it may be opaque to non-specialist clinicians. It is noteworthy from our experience that IVIg has seldom been effective in PM or DM when used alone or as initial therapy. These options are discussed in the review by Dalakas (2015). The proper use of these treatments in crossover cases with connective tissue disease has not been established. Some patients who cannot tolerate, or are refractory to, prednisone may respond favorably to oral azathioprine with care being taken to avoid severe leukopenia. Methotrexate is currently favored by many groups over azathioprine as an adjunct to steroids (5 to 10 mg/week in 3 divided oral doses, increased by 2.5 mg/week, to a total dose of 20 mg weekly). Methotrexate or azathioprine should generally be given along with the lowest effective doses (15 to 25 mg) of prednisone. Although one study failed to show efficacy (Oddis et al), in cases that have been refractory to corticosteroids and methotrexate, we and our colleagues have had success with rituximab intravenously, 750 mg/m2, repeated in 2 weeks and sometimes required every 6 to 18 months. Some clinicians favor, from the beginning, a combination of prednisone in low dosage and one of these immunosuppressant drugs, and this approach is generally necessary when myocarditis or interstitial pneumonitis is coupled with DM. It has been suspected that patients with anti-Jo or other antibodies may respond more favorably. Mycophenolate mofetil has also been introduced and has allowed a reduction in steroid dose within several months in both PM and DM, according to a number of anecdotal reports, but has not proven clearly effective in a randomized trial; the reasons for this failure are being actively discussed and we have not abandoned its use. Cyclosporine has also been used in recalcitrant cases; it has few advantages over other immunosuppressant drugs and has a number of potentially serious side effects, including nephrotoxicity. Cyclophosphamide, which is a useful drug in the treatment of Wegener granulomatosis, polyarteritis, and other vasculitides, is said to be of lesser value in PM, but it may be useful in refractory cases and has perhaps the highest toxicity of the immunosuppressive medications that are used for inflammatory myopathies; we no longer use it with any regularity.

Prognosis Except for patients with malignancy, the prognosis in adult PM and DM is generally favorable. Only a small proportion of patients with PM succumb to the disease and then usually from a secondary pulmonary complication or from myocarditis as already mentioned. Several of our patients have had severe aspiration pneumonias as a result of their dysphagia. The period of activity of disease varies considerably but is typically 2 to 3 years in both the child and adult. As indicated earlier, the majority improves with corticosteroid therapy, but many are left with varying degrees of weakness of the shoulders and hips. Approximately 20 percent of our patients have recovered completely after steroid therapy and long-term remissions have been achieved after withdrawal of medication in about an equal

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number. The extent of recovery is roughly proportional to the acuteness and severity of the disease and the duration of symptoms prior to institution of therapy. Patients with acute or subacute PM in whom treatment is begun soon after the onset of symptoms have the best prognosis. In one series, in which patients were treated early, there was remission in more than 50 percent of cases (DeVere and Bradley), whereas another series reported a far lower rate in patients who were treated more than 2 years after onset of the disease (Riddoch and Morgan-Hughes). Those patients who have come to our attention after a long period of proximal weakness and with substantial muscle atrophy have not recovered completely, although some improvement occurred over years. Even in patients who have a coexistent malignancy, muscle weakness may lessen and serum enzyme levels decline in response to corticosteroid therapy, but weakness returns after a few months and may then be resistant to further treatment. As already stated, if the tumor is successfully removed, muscle symptoms may remit, but this experience has not been uniform. The overall mortality after several years of illness had in the past approximated 15 percent, being higher in childhood DM, in PM with rheumatologic diseases, and, of course, when a malignancy is found. Recent figures give more optimistic results.

Inclusion Body Myositis (IBM) IBM is the third major form of idiopathic myopathy and, depending on the care taken with histologic diagnosis, is the most common one in patients older than 50 years. It is often identifiable by certain topographic features of the weakness described below. There is consensus that the disease is immune-mediated, even when the inflammatory component is not prominent in biopsy material. A source of confusion has been the separate entity of inclusion body myopathy, a largely hereditary, pauciinflammatory process, which displays a different pattern of weakness from IBM. Its defining pathologic features, intracytoplasmic and intranuclear inclusions, were first described in 1965 by R.D. Adams and colleagues, who also drew attention to a number of clinical attributes now considered characteristic. By 1994, only 240 sporadic cases had been recorded in the medical literature (Mikol and Engel), but the diagnosis is now made so frequently that this low number almost certainly reflects the misidentification of IBM as PM in the past. Garlepp and Mastaglia concluded that more than one-third of cases of inflammatory myopathy, especially in men, are IBM. Moreover, as alluded to, the majority of myopathies in patients older than 50 years, not attributable to medication toxicity, are probably due to IBM. A set of clinical and pathologic diagnostic criteria for the disease have been proposed by Griggs and coworkers and are useful for research purposes. The myositis, as alluded to, predominates in men (in a ratio of 3:1) and has its onset in middle or late adult life. Diabetes, any one of a variety of autoimmune diseases, and a relatively mild polyneuropathy are associated in approximately 20 percent of sporadic cases of IBM, but

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associations with malignancy or systemic autoimmune disease have not been established.

Clinical Manifestations The illness is more variable but generally more focal in presentation than is PM and DM. It is characterized by a steadily progressive, painless muscular weakness and modest atrophy, which is usually distal in the arms and both proximal and distal in the legs. In approximately 20 percent of cases, the disease begins with focal weakness of the quadriceps, finger or wrist flexors, or lower leg muscles on one or both sides, and gradually spreads to other muscle groups after many months or years. Selective weakness of the flexor pollicis longus is a particularly characteristic pattern of involvement, and isolated quadriceps weakness or neck extensor weakness should also bring the diagnosis to mind, although IBM is not the exclusive cause of these patterns. In most patients, the deltoids are spared and the thumb flexors are weak, the opposite pattern to PM and DM. The tendon reflexes are normal initially but diminish in about half the patients, especially the knee jerks, as the disease progresses. Interestingly, the knee jerks may be depressed or lost even without much in the way of quadriceps weakness; this is not the case in PM, in which the reflexes are spared until the muscle is extremely weak. These clinical features are well displayed in the series reported by Amato and colleagues. Dysphagia is common (Wintzen et al). Selective or asymmetric involvement of distal muscles, when it occurs, erroneously suggests the diagnosis of motor neuron disease (the reflexes are not, however, enhanced as they are in ALS).

Laboratory and Muscle Biopsy Features The CK is normal or slightly elevated, generally showing lower levels than in cases of PM with comparable amounts of weakness. EMG abnormalities are much like those found in PM, as discussed earlier. In addition, a small proportion of IBM patients display a more typically neuropathic EMG pattern, mainly with long-duration polyphasic potentials because of the chronicity of the disease, in the distal limb muscles. However, the EMG changes tend to be restricted to weakened muscles, a distinction from ALS. The diagnosis depends on the clinical features and is supported by the muscle biopsy. There are structural abnormalities of muscle fibers and inflammatory changes. The latter are similar to, but usually of lesser severity than, those observed in idiopathic PM. (The infiltrating cells are mainly T cells of the CD8 type.) The denominative finding is of intracytoplasmic, subsarcolemmal vacuoles, and eosinophilic inclusions in both the cytoplasm and nuclei of degenerating muscle fibers. The vacuoles contain, and are rimmed by, basophilic granular material, called “rimmed vacuoles.” Special stains, particularly Gomori trichrome on frozen sections, and extensive inspection of biopsy specimens are required to disclose the rimmed vacuoles, for they are infrequent, widely dispersed, and easily overlooked. The inclusions may be congophilic, and often stain for TDP-43, p62, SM1-31, and, particularly, beta amyloid. As noted in subsequent sections similar inclusions are found in a number of other muscle diseases and are not in and of themselves diagnostic, especially without

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the destructive and mildly inflammatory changes of IBM. Moreover, the clinical context of these other diseases usually causes little difficulty in identifying the inclusions as ancillary and minor abnormalities on the biopsy. Of clinical utility has been the introduction of testing for cytosolic antibodies (anti-cN1; NT5C1A) that are found in two-thirds of patients with IBM. They appear to be specific and assist in particular by differentiating this disease from the other inflammatory myopathies and in its detection when there is a pattern of weakness that is not typical of an inflammatory myopathy. Testing other antibodies such as anti-Jo is probably suited to confirming cases that have the elements of a larger syndrome that includes, for example, interstitial lung disease. Ultrastructural studies show that the protein inclusions accumulate at or near foci of abnormal tubulofilamentous structures in both the nuclei and cytoplasm. The nature of these diverse changes is obscure. The tubulofilamentous inclusions suggested to earlier investigators a viral origin, but an agent has never been isolated and serologic studies have failed to substantiate an infectious causation.

Treatment IBM has not responded in any consistent fashion to treatment with corticosteroids or other immunosuppressive drugs. Indeed, the disease should be suspected in recalcitrant cases of apparent PM or DM. The level of CK and the degree of leukocyte infiltration of muscle often diminish with corticosteroid treatment despite a lack of clinical improvement. On this basis, it has been suggested that the inflammatory response is not a primary cause of muscle destruction (Barohn and coworkers). In a few cases there has been brief improvement in response to glucocorticoids or IVIg, especially in weakened muscles involved in swallowing, but the gains have been unsustained and serial histopathologic examinations have detected no change. Two controlled trials have failed to show a benefit of IVIg. Plasma exchange and leukocytapheresis have also been tried, with generally discouraging results. In a preliminary trial of bimagrumab, an antibody directed to signaling of TGF-β receptor, has shown some improvement of muscle mass but a definitive clinical demonstration of effect has not been tested (Amato et al, 2014). The disease in most patients is relentlessly progressive over many years, sometimes very slowly, and no method of treatment has so far altered the long-term prognosis. Sometimes, the process remains fairly restricted in scope or severity for up to a decade, thereby creating less disability than in cases that become generalized.

Problems in Diagnosis of Inflammatory Myopathy The main issue here is differentiation of DM and PM from inclusion body myopathy. The specific problem of determining which patients with DM or PM should have an extensive evaluation for a systemic malignancy and for connective tissue disease has been partially settled. We have adopted the practice of careful inspection of the chest radiograph, routine blood tests and stool examination for blood for all patients, and of undertaking a more extensive evaluation in patients older than 55 years and in smokers of any age. The evaluation of patients over 55 and smokers

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includes chest and abdominal computed tomographic (CT) scans, colonoscopy, pelvic ultrasound, cancer antigen (CA)-125, carcinoembryonic antigen (CEA), as well as other tests. In patients with recent weight loss, anorexia, or other symptoms suggestive of malignancy, we have included upper endoscopy and resorted to a body positron emission tomography scanning. In addition to these main issues of distinguishing PM and DM from IBM, currently aided by antibody testing, we call attention to the following problems that we have encountered in connection with diagnosis: 1. The patient with proximal muscle weakness is incorrectly diagnosed as having progressive muscular dystrophy (actually, the opposite pertains more often). Points in favor of myositis are (1) lack of family history (although many dystrophies have recessive inheritance); (2) older age at onset; (3) rapid evolution of weakness; (4) evidence, past or present, of other connective tissue diseases; (5) high serum CK values (again, can be high in certain dystrophies); (6) marked degeneration and regeneration in muscle biopsy; and, finally, if there is still doubt, (7) unmistakable improvement with corticosteroid therapy. 2. The patient with a systemic autoimmune disease (rheumatoid arthritis, scleroderma, lupus erythematosus, Sjögren syndrome) is suspected of having PM in addition. Pain in these conditions prevents strong exertion (algesic pseudoparesis). Points against the coexistence of myositis are (1) the inability to document weakness out of proportion to muscle atrophy and the presence of pain on passive movement of the limbs; (2) normal EMG; (3) normal serum CK; and (4) normal muscle biopsy except possibly for areas of infiltration of chronic inflammatory cells in the endomysial and perimysial connective tissue (interstitial myositis). 3. When muscle pain is a prominent feature, polymyalgia rheumatica must be differentiated. This latter syndrome is characterized by pain, stiffness, and tenderness in the muscles of the neck, shoulders, and arms, and sometimes of the hips and thighs; even passive motion of the limbs causes pain because of the periarticular locus of this disease. A high sedimentation rate, usually above 65 mm/h, is a diagnostic feature, but more typically the value is close to 100 mm/h, levels higher than in myositis. Biopsy of the temporal artery frequently discloses a giant cell arteritis. CK levels—and, of course, muscle biopsy—are normal. Rapid disappearance of pain with administration of small doses of prednisone is also diagnostic of polymyalgia rheumatica (see Chap. 9). 4. The patient has restricted muscle weakness. Weakness or paralysis of the posterior neck muscles, with inability to hold up the head, restricted bilateral quadriceps weakness, and other limited pelvocrural palsies are examples. Most often, the head-hanging or head-lolling syndrome proves to be caused by PM, and the other syndromes are caused by restricted forms of dystrophy or by motor neuron disease. IBM is the main alternative consideration in cases of neck or quadriceps weakness, particularly if the latter weakness is asymmetric; muscle enzymes in the serum are normal or slightly elevated. EMG and biopsy are helpful in diagnosis.

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5. The patient has diffuse myalgia and fatigability. Most such patients have proved to be depressed and only rarely to have a myopathy. A few will be found to be caused by a toxic myopathy, particularly from one of the statin class of drugs. Hypothyroidism, McArdle disease, hyperparathyroidism, steroid myopathy, adrenal insufficiency, and early rheumatoid arthritis must be excluded by appropriate studies. Features that virtually exclude a myositis are (1) lack of reduced peak power of contraction and (2) normal EMG, serum enzymes, and muscle biopsy. 6. Trichinosis, toxoplasmosis, HIV, and other infectious causes of myositis can simulate acute immune myositis as described in the early parts of this chapter. Occasionally, the diagnosis of sarcoidosis is made from the muscle biopsy, but the myopathic features (weakness and pain) tend to be minor.

Other Inflammatory Myopathies There are a large number of unrelated myositides and rare forms of focal myositis or relatively minor changes in muscle that occur in the course of inflammatory diseases of blood vessels or systemic infections and, curiously, with certain tumors such as thymoma. Most of these do not warrant extensive consideration and are described in detail in monographs devoted to muscle disease (Banker). A type of fasciitis that is characterized by pronounced infiltration of macrophages has been related to vaccinations that contain the aluminum compound, but the myositis does not seem to be related to this aforementioned entity (Bassez et al). Three inflammatory myopathic diseases, however, are distinctive and of interest to neurologists: (1) eosinophilic myositis, fasciitis, and myalgia syndrome, (2) orbital myositis, and (3) sarcoidosis of muscle.

Eosinophilic Myositis and Fasciitis This term has been applied to four overlapping clinical entities: (1) eosinophilic fasciitis, (2) eosinophilic monomyositis (sometimes multiplex), (3) eosinophilic PM, and (4) the eosinophilia-myalgia syndrome. Eosinophilic fasciitis This condition, mistakable for PM, was reported by Shulman in 1974. He described two men with a scleroderma-like appearance of the skin and flexion contractures at the knees and elbows associated with hyperglobulinemia, elevated sedimentation rate, and eosinophilia. Biopsy revealed greatly thickened fascia, extending from the subcutaneous tissue to the muscle and infiltrated with plasma cells, lymphocytes, and many eosinophils; the muscle itself appeared normal and the skin lacked the characteristic histologic changes of scleroderma. One of Shulman’s patients recovered in response to prednisone. The many reports that followed have substantiated and amplified Shulman’s original description. The disease predominates in men in a ratio of 2:1. Symptoms appear between the ages of 30 and 60 years and are often precipitated by heavy exercise (Michet et al). There may be low-grade fever and myalgia followed by the subacute development of diffuse cutaneous thickening and

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limitation of movement of small and large joints. In some patients, proximal muscle weakness and eosinophilic infiltration of muscle can be demonstrated (Michet et al). Repeated examinations of the blood disclose an eosinophilia in most but not all patients. The disease usually remits spontaneously or responds well to corticosteroids. A small number relapse and do not respond to treatment and some have developed aplastic anemia and lympho- or myeloproliferative disease. Eosinophilic monomyositis Painful swelling of a calf muscle or, less frequently, some other muscle has been the chief characteristic of this disorder. Biopsy discloses inflammatory necrosis and edema of the interstitial tissues; the infiltrates contain large but variable numbers of eosinophils. The disorder was typified by one of our patients, a young woman who developed such an inflammatory mass first in one calf and, 3 months later, in the other. The response to prednisone was dramatic; the swelling and pain subsided in 2 to 3 weeks and her power of contraction was then normal. When the connective tissue and muscle are both damaged, a chaotic regeneration of fibroblasts and myoblasts may result, forming a pseudotumorous mass that may persist indefinitely. Eosinophilic polymyositis  Layzer and associates described an eosinophilic disorder that they classified as “subacute polymyositis.” Their patients were adults in whom predominantly proximal weakness evolved over several weeks. The features of the muscle disorder were typical of PM except that the inflammatory infiltration was predominantly eosinophilic and the muscles were swollen and painful. Moreover, the muscle disorder was part of a widespread systemic illness typical of the hypereosinophilic syndrome. The systemic manifestations included a striking eosinophilia (20 to 55 percent of the white blood cells), cardiac involvement (conduction disturbances and congestive failure), vascular disorder (Raynaud phenomenon, subungual hemorrhages), pulmonary infiltrates, strokes, anemia, neuropathy, and hypergammaglobulinemia. There was a favorable response to corticosteroids in two patients, but in a third the outcome was fatal in 9 months. Layzer and coworkers noted that a lack of necrotizing arteritis distinguished this process from polyarteritis nodosa and Churg-Strauss disease. No infective agent was isolated. An allergic mechanism seems possible, and in the present authors’ view one cannot exclude an angiitis as a cause of the muscle lesions. The last two of these previously mentioned syndromes (eosinophilic monomyositis and polymyositis) have overlapping features as shown by Stark’s cases, in which a monomyositis was accompanied by several of the systemic features described by Layzer and colleagues. An uncertain proportion of cases are attributable to mutations in CAPN3, the gene for calpain-3 (Krahn et al). Moreover, some cases of eosinophilic polymyositis without systemic features have been found to be limb-girdle muscular dystrophy 2A, also due to a calpain mutation (i.e., both are considered to be “calpainopathies”). Patients with the dystrophic process, who also have a peripheral eosinophilia, probably have eosinophilic myositis. Eosinophilia-Myalgia syndrome Beginning in 1980, sporadic reports documented a lingering systemic illness

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characterized by severe generalized myalgia and eosinophilia of the peripheral blood following the ingestion of contaminated l-tryptophan. In late 1989 and early 1990, an outbreak occurred of this eosinophilia-myalgia syndrome, as the illness came to be called. More than 1,200 cases were reported to the Centers for Disease Control and Prevention (Medsger) and we examined several of them. The outbreak was ultimately traced to the use of nonprescription l-tryptophan tablets used as a sleep aid supplied by a single manufacturer and contaminated by ethylidenebis-tryptophan and methyltetrahydro-beta-carboline-carboxylic acid, both close chemical relatives of l-tryptophan (Mayeno et al, 1990, 1992). The onset of the muscular illness was relatively acute, with fatigue, low-grade fever, and eosinophilia (>1,000 cells/mm3). Muscle pain and tenderness, cramps, weakness, paresthesias of the extremities, and induration of the skin were the main clinical features. A severe axonal neuropathy with slow and incomplete recovery was associated in some cases. Biopsies of the skin fascia, muscle, and peripheral nerve disclosed a microangiopathy and an inflammatory reaction in connective tissue structures; changes like those observed in scleroderma, eosinophilic fasciitis, and in the toxic oil syndrome. The latter syndrome, caused by the ingestion of contaminated rapeseed oil, occurred in an outbreak in Spain in 1981 and gave rise to a constellation of clinical and pathologic changes that were essentially identical to those caused by contaminated L-tryptophan (Ricoy et al; see also Chap. 41). The two toxins are also closely linked chemically and there have been other more limited outbreaks of the toxic neuropathy, usually from adulterated cooking oil. The cutaneous lesions and eosinophilia of this syndrome responded to treatment with prednisone and other immunosuppressive drugs, but other symptoms persisted. Severe axonal neuropathy in our patients improved incompletely over several years, leaving one chair-bound with severe distal atrophic weakness after 15 years. Although this exact problem is no longer likely to be seen by physicians, it serves as a model for future peculiar myopathic syndromes from adulterated drugs that otherwise would seem innocuous.

Acute Orbital Myositis Among the many cases of orbital inflammatory disease (pseudotumor of the orbit and Tolosa-Hunt syndrome, as described in Chap. 13), there is a small group in whom the inflammatory process appears to be localized to the extraocular muscles. To this group, the term acute orbital myositis has been applied. The abrupt onset of orbital pain that is made worse by eye motion, redness of the conjunctiva adjacent to the muscle insertions, diplopia caused by restrictions of ocular movements, lid edema, and mild proptosis are the main clinical features and, admittedly, the distinctions from orbital pseudotumor are not clear. It may spread from one orbit to the other. The ESR is usually elevated and the patient may feel generally unwell, but only rarely can the ocular disorder be related to a systemic autoimmune disease or any other specific systemic disease. CT and MRI have proved to be particularly useful in demonstrating the swollen ocular muscles or muscle,

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and in separating orbital myositis from the other remitting inflammatory orbital and retroorbital conditions (Dua et al). As a rule, acute orbital myositis resolves spontaneously in a matter of a few weeks, although it may recur in the same or the opposite eye. Administration of steroids appears to hasten recovery.

Sarcoid Myopathy, Granulomatous Myositis, and Localized Nodular Myositis There are undoubted examples of muscle involvement in patients with sarcoidosis, but they seem to be less frequent and less certain than would appear from the medical literature. In some cases, sarcoid myopathy becomes evident as a slowly progressive, occasionally fulminant, painless proximal or distal weakness. The CK levels are elevated. Muscle biopsy discloses numerous noncaseating granulomas. However, such lesions may also be found in patients with sarcoidosis who have no weakness. Treatment with moderate doses of corticosteroids (prednisone, 25 to 50 mg daily) is usually effective in symptomatic cases, but an additional immunosuppressive agent, such as cyclosporine, may have to be instituted if improvement is not evident in several weeks. Much more puzzling have been cases of myopathy with the clinical features of idiopathic polymyositis and the presence of noncaseating granulomas in the muscle biopsy but with no evidence of sarcoidosis of the nervous system, lungs, bone, skin, or lymph nodes. Such cases call into question the validity of a muscle granuloma as a criterion of sarcoidosis, but the matter cannot be settled until we have a better definition and etiology for sarcoidosis. These cases are presently classified as granulomatous myositis and, if limited to one or a small group of muscles, localized nodular myositis (Cumming et al). In a syndrome described by Namba and colleagues, this type of myositis was combined with myasthenia gravis, myocarditis, and thyroiditis. The muscle process has, on a few occasions, also been associated with Crohn disease. Electron microscopy has disclosed muscle fiber invasion by lymphocytes, suggesting a cell-mediated immune reaction. Very rarely, a granulomatous myositis may complicate tuberculosis or syphilis.

THE MUSCULAR DYSTROPHIES (TABLES 45-1 THROUGH 45-3) The muscular dystrophies are a group of progressive hereditary degenerative diseases of skeletal muscles. The intensity of the degenerative changes in muscle and the cellular response and nature of the regenerative changes distinguish the dystrophies histologically from other diseases of muscle and also have implications regarding their pathogenesis. The category of more benign and relatively nonprogressive myopathies—each named from its special histopathologic appearance, such as central core, nemaline, mitochondrial, and centronuclear diseases— present greater difficulty in classification. Like the dystrophies, they are primarily diseases of muscle and are often heredofamilial in nature, but they are placed in a separate

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category because of a nonprogressive or slowly progressive course and their distinctive histochemical and ultrastructural features. The current clinical classification of the muscular dystrophies is based mainly on the distribution of the dominant muscle weakness and the responsible mutation but several of the classical types have retained their eponymic designations: Duchenne, Becker, Emery-Dreifuss, LandouzyDejerine, Miyoshi, Welander, Fazio-Londe, and Bethlem are among the ones that still have utility in shorthand. To these are added myotonic dystrophy and a group of so-called congenital muscular dystrophies, usually severe in degree. The extraordinary depth of information regarding the molecular nature of the dystrophies is one of the most gratifying developments of modern neuroscience. The majority of the dystrophies are caused by changes in structural elements of the muscle cell, mainly in its membrane, but other important mechanisms also are being identified. In keeping with the outlook expressed throughout the book, we adhere to a clinical orientation in describing the muscular dystrophies but make clear that treatment in the future could be determined based on understanding of molecular mechanisms. Each of the muscular dystrophies is described in accordance with this scheme. The differentiation of dystrophic diseases of muscle from those secondary to neuronal degeneration was an achievement of neurologists of the second half of the nineteenth century. Isolated cases of muscular dystrophy had been described earlier, but no distinction was made between neuropathic and myopathic disease. In 1855, Duchenne described the progressive muscular atrophy of childhood that now bears his name. However, it was not until the second edition of his monograph in 1861 that the “hypertrophic paraplegia of infancy” was recognized as a distinct syndrome. By 1868, he was able to write a comprehensive description of 13 cases and recognized that the disease was muscular in origin and restricted to males. Gowers in 1879 gave a masterful account of 21 personally observed cases and called attention to the characteristic way in which such patients arose from the floor (Gowers sign). Erb, in 1891, crystallized the clinical and histologic concept of a group of diseases caused by primary degeneration of muscle, which he named muscular dystrophies. The first descriptions of facioscapulohumeral dystrophy were published by Landouzy and Dejerine in 1894; of progressive ocular myopathy by Fuchs in 1890; of myotonic dystrophy by Steinert and by Batten and Gibb in 1909; of distal dystrophy by Gowers in 1888, Milhorat and Wolff in 1943, Welander in 1951, and Miyoshi and colleagues in 1986; and of oculopharyngeal dystrophy by Victor and associates in 1962. References to these and other writings of historical importance can be found in the works of Kakulas and Adams, of Walton and colleagues, and of Engel and Franzini-Armstrong, and most recently of Amato and Russell. In the more recent history of the dystrophies, the most notable event was the discovery by Kunkel, in 1986, of the dystrophin gene and its protein product. Since then, there has been an extraordinary accumulation of moleculargenetic, ultrastructural, and biochemical information about the muscular dystrophies, which has broadened our

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understanding of their mechanisms. It has also clarified a number of uncertainties as to their clinical presentations and has necessitated a revision of an older classification.

Duchenne Muscular Dystrophy (DMD Mutation) This is the most frequent and prototypic early onset muscular dystrophies. It begins in early childhood and runs a relatively rapid, progressive course. The incidence is in the range of 13 to 33 per 100,000 yearly or about 1 in 3,300 live male births. There is a strong familial liability as the disease is transmitted as an X-linked recessive trait, occurring almost exclusively in males, and involving the DMD gene and the protein dystrophin. Careful examination of the mothers of affected boys shows slight muscle involvement in as many as half of them (Roses and coworkers). Approximately 30 percent of patients have no family history of the disease and these represent spontaneous mutations. Rarely, a severe proximal Duchenne-type muscular dystrophy occurs in young girls. This may have several explanations. The female may have only 1 X chromosome, as occurs in the Turner (XO) syndrome, and that chromosome carries the Duchenne gene, or the Lyon principle may be operative; that is, there is inactivation of the unaffected paternal X chromosome allowing expression of the mutated Duchenne protein from the maternal chromosome in a large proportion of embryonic cells (mosaicism). It so happens that most childhood dystrophies in girls prove to be of an entirely different type that is caused by an autosomal recessive mutation causing a limb-girdle dystrophy as discussed further on.

Clinical Features Duchenne muscular dystrophy is usually recognized by the third year of life and almost always before the sixth year. Nearly half of children show evidence of disease before beginning to walk. A greatly elevated CK may be the clue. In another group of young children, an indisposition to walk or run normally at the expected time brings them to medical attention or, having achieved these motor milestones, they appear less active than expected and are prone to falls. Increasing difficulty in walking, running, and climbing stairs, excessive lumbar lordosis, and waddling gait become more obvious as time passes. The iliopsoas, quadriceps, and gluteal muscles are involved initially; then the pretibial muscles weaken (foot-drop and toe walking). Muscles of the pectoral girdle and upper limbs are affected after the pelvicrural ones; the serrati, lower parts of pectorals, latissimus dorsi, biceps, and brachioradialis muscles are affected, more or less in this order. Enlargement of the calves and certain other muscles is progressive in the early stages of the disease but most of the muscles, even the ones that are originally enlarged, eventually decrease in size; only the gastrocnemii, and to a lesser extent the lateral vasti and deltoids, are consistently large and this peculiarity may attract attention before the weakness becomes evident. The enlarged muscles have a firm, resilient (“rubbery”) feel and are slightly weaker and more hypotonic than healthy ones. Thus the muscle enlargement is a pseudohypertrophy. Rarely, all muscles are at first large and strong, even the facial muscles, as in

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one of Duchenne’s cases (from the marble statue, Farnese Hercules); histologically, this is a true muscle hypertrophy. Muscles of the pelvic girdle, lumbosacral spine, and shoulders become weak and wasted, accounting for certain clinical peculiarities. Weakness of abdominal and paravertebral muscles accounts for a lordotic posture and protuberant abdomen when standing and the rounded back when sitting. Weakness of the extensors of the knees and hips interferes with equilibrium and with activities such as climbing stairs or rising from a chair or a stooped posture. In standing and walking, the patient places his feet wide apart to increase his base of support. To rise from a sitting position, he first flexes his trunk at the hips, puts his hands on his knees, and pushes the trunk upward by working the hands up the thighs. In rising from the ground, the child first assumes a four-point position by extending the arms and legs to the fullest possible extent and then works each hand alternately up the corresponding thigh (the sign traditionally attached to Gowers’ name). In getting up from a recumbent position, the patient turns his head and trunk and pushes himself sideways to a sitting position. S.A.K. Wilson used an alliterative phrase to describe the characteristic abnormalities of stance and gait: The patient “straddles as he stands and waddles as he walks.” The waddle is the result of bilateral weakness of the gluteus medius. Many affected boys have a tendency to walk on their toes as a consequence of contractures in the gastrocnemii muscles. Calf pain is frequent. Weakening of the muscles that fix the scapulae to the thorax (serratus anterior, lower trapezius, rhomboids) causes winging of the scapulae, and the scapular angles can sometimes be seen above the shoulders when one is facing the patient. Later, weakness and atrophy spread to the muscles of the legs and forearms. The muscles that are preferentially affected among these are the neck flexors, wrist extensors, brachioradialis, costal part of the pectoralis major, latissimus dorsi, biceps, triceps, and anterior tibial and peroneal muscles. The ocular, facial, bulbar, and hand muscles are usually spared, although weakness of the facial and sternocleidomastoid muscles and of the diaphragm occurs in the late stages of the disease. As the trunk muscles atrophy, the bones stand out like those of a skeleton. The space between the lower ribs and iliac crests diminishes with atrophy and weakness of the abdominal muscles. The limbs are usually loose and slack, but as the disability progresses, fibrous contractures appear as a result of the limbs remaining in one position and the imbalance between agonists and antagonists. Early in the ambulatory phase of the disease, the feet assume an equinovarus position as a result of shortening of the posterior calf muscles, which act without the normal opposition of the pretibial and peroneal muscles. Later, the hamstring muscles become permanently shortened because of a lack of counteraction of the weaker quadriceps muscles. Similarly, contractures occur in the hip flexors because of the relatively greater weakness of hip extensors and abdominal muscles. This leads to a pelvic tilt and compensatory lordosis to maintain standing equilibrium. The consequences of these contractures account for the habitual posture of the patient with Duchenne dystrophy: lumbar lordosis, hip flexion and abduction, knee flexion, and plantar flexion.

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As they become severe, these contractures contribute importantly to the eventual loss of ambulation. Scoliosis, as a result of unequal weakening of the paravertebral muscles, and flexion contractures of the forearms appear, usually after walking is no longer possible. The tendon reflexes are diminished and then lost as muscle fibers disappear, the ankle reflexes being the last to go. The bones are thin and demineralized, and the appearance of ossification centers is delayed. Smooth muscles are spared, but the heart is affected by various types of arrhythmias. The ECG shows prominent R waves in the right precordial leads and deep Q waves in the left precordial and limb leads, the result of cardiac fiber loss and replacement fibrosis of the basal part of the left ventricular wall (Perloff et al). Death is usually the result of pulmonary infections and respiratory failure and sometimes, of cardiac decompensation. Patients with Duchenne dystrophy usually survive until late adolescence, but not more than 20 to 25 percent live beyond the twenty-fifth year. The last years of life are spent in a wheelchair; finally the patient becomes bedfast. Mild degrees of developmental delay as mentioned, which is nonprogressive, are observed in many cases. The average IQ is 85 and approximately one-quarter have an IQ below 70, but the range has been 40 to 130. As mentioned earlier, female carriers of the disease (i.e., the mothers of affected boys) and described slight weakness and enlargement of the calves as well as elevated CK values and abnormalities of the electromyelogram (EMG) and muscle biopsy, all slight in degree, in more than half; as mentioned, this is far higher than in our experience and that of our colleagues. A small number of female carriers manifest a moderate myopathy that may mimic limbgirdle dystrophy (see further on). The muscle fibers of such patients (referred to as manifesting or symptomatic carriers) show a mosaic immunostaining pattern mentioned earlier, some fibers containing dystrophin and others lacking it (Hoffman et al, 1988). This diagnostic information is particularly helpful in genetic counseling. The serum CK values are 25 to 200 times normal, which, with the EMG and muscle biopsy findings, help exclude spinal muscular atrophy. The EMG shows fibrillations, positive waves, low-amplitude and brief polyphasic motor unit potentials, and, sometimes, high-frequency discharges. The female carrier may occasionally display the same abnormalities, but to a much milder degree. The molecular and genetic bases of the disease are discussed further on.

Becker Muscular Dystrophy This milder dystrophy is closely related to the Duchenne type clinically, genetically, and ultrastructurally, involving the same DMD gene as in the Duchenne type. It had long been noted that mixed with the Duchenne group were relatively benign cases. In 1955, Becker and Keiner proposed that the latter be separated as a distinct entity, now called Becker muscular dystrophy. The incidence is difficult to ascertain, but it has been estimated as 3 to 6 per 100,000 male births. Like the Duchenne form, it is an X-linked disorder, practically limited to males and transmitted

Ropper_Ch45_p1370-p1431.indd 1392

by females. It causes weakness and hypertrophy in the same muscles as Duchenne dystrophy, but the onset is much later (mean age: 12 years; range: 5 to 45 years). While boys with Duchenne dystrophy are usually dependent on a wheel-chair by early in the second decade, it is not uncommon for those with Becker dystrophy to walk well into adult life. In comparison to Duchenne dystrophy, those with Becker and intermediate types retain their ability to raise the head fully off the bed. We have, for example, encountered patients who served in the military with the disease undetected. If maternal uncles are affected by the disease and are still walking, the diagnosis is relatively easy. Mentation is usually normal and cardiac involvement is far less frequent than in Duchenne dystrophy, but there are cases that present with a cardiomyopathy and we have been made aware of two brothers who had cardiac transplantation before the disease was detected. Kuhn and associates have reported a genealogy in which early myocardial disease and cramping myalgia were prominent features. The molecular-genetic basis of this form is discussed below.

Pathology of Duchenne and Becker Dystrophies In the early stages of Duchenne dystrophy, the most distinctive features are prominent segmental degeneration and phagocytosis of single muscle fibers or groups of fibers and evidence of regenerative activity (basophilia of sarcoplasm, hyperplasia and nucleation of sarcolemmal nuclei, and the presence of myotubes and myocytes). The necrosis excites a regenerative or restorative process, which explains the forking of fibers and clustering of small fibers with prominent nuclei. The necrotic sarcoplasm and sarcolemma are removed by mononuclear phagocytic (macrophage) cells. There may also be a few T lymphocytes in the region, suggesting inflammation. There is a hyalinization of the sarcoplasm of many degenerating and nondegenerating fibers. In longitudinal sections these are seen as “contraction bands,” expressive of the irritability of dystrophic muscle. This phenomenon may be present before there is any significant degree of degeneration and is more extensive in Duchenne than in any of the other dystrophies. Eventually, there are histologic changes that are common to all types of advanced muscular dystrophies: loss of muscle fibers, residual fibers of larger and smaller size than normal, all in haphazard arrangement, and the secondary reaction of an increase in lipocytes and fibrosis. Hypertrophy of muscle is apparently the result of work-induced enlargement of the remaining sound fibers in the face of adjacent fiber injury. However, examples of true hypertrophy of entire muscles prior to the first sign of weakness also occur and are difficult to explain. In these cases, large fibers may be present when at most there are only a few degenerating fibers. The more common feature of pseudohypertrophy is a result of lipocytic replacement of degenerated muscle fibers, but in its earlier stages, the presence of many enlarged fibers may contribute to the enlargement of muscle. Thus a true hypertrophy appears to give way to pseudohypertrophy. In the late stage of the dystrophic process, only a few scattered muscle fibers remain, almost lost in a sea of fat cells. It is notable that the late, or burned-out, stage of chronic polymyositis

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resembles muscular dystrophy in that the fiber population is depleted, the residual fibers are of variable size, and fat cells and endomysial fibrous tissue are increased; lacking only are the hypertrophied fibers of dystrophy. This resemblance confirms that many of the typical changes of muscular dystrophy are nonspecific, reflecting mainly the chronicity of the myopathic process.

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Laminin- 2 Collagen VI

Dystroglycan complex

Sarcoglycan complex Extracellular nNOS

Molecular Biology of Duchenne and Becker Dystrophies The first important development in our understanding of the Duchenne and Becker muscular dystrophies was the discovery by Kunkel of the mutation on the X chromosome in what was later named DMD and of its gene product, dystrophin (Hoffman et al, 1987). The protein is expressed in skeletal, cardiac, and smooth muscle, as well as in brain. To date, the dystrophin gene is the largest one known in humans, spanning more than 2 Mb of DNA. This is in part the explanation for the observation that one-third of affected boys have a spontaneous mutation in the gene. Most mutations are deletions and combined with the less frequent duplications, account for over two-thirds of cases. The biochemical assay of dystrophin and its histochemical demonstration near the sarcolemma have made possible the accurate diagnosis of the Duchenne and Becker phenotypes from biopsy material and have clarified the relationship between these two disorders. Whereas dystrophin is absent in patients with the Duchenne phenotype, it is present but structurally abnormal in the Becker type. Moreover, phenotypes that fall between the classic Duchenne and Becker forms exist and are characterized by a lower-than-normal amount of dystrophin. The Duchenne and Becker dystrophies and their intermediate forms are spoken of as dystrophinopathies. A slightly different form of dystrophin, originating in a different part of the gene, is found in neurons of the cerebrum and brainstem and in astrocytes, Purkinje cells, and Schwann cells at nodes of Ranvier (Harris and Cullen). A deficiency of cerebral dystrophin may in some yet unexplained way account for the mild cognitive developmental delay. It will be interesting to learn how such a deficiency might impair brain development and whether there is any connection to some cases of mental deficiency without muscular dystrophy. Figure 45-2 schematically represents the structural basis of the dystrophinopathies and certain of the limbgirdle and congenital dystrophies described further on. In normal skeletal and cardiac muscle, dystrophin is localized to the cytoplasmic surface of the sarcolemma, where it interacts with F-actin of the cytoskeleton (the filamentous reinforcing structure of the muscle cell). Dystrophin is also tightly bound to a complex of sarcolemmal proteins known as dystrophin-associated proteins (DAPs) and to dystrophin-associated glycoproteins (DAGs). Of special biologic importance in this complex are these proteins and a 156-kDa glycoprotein called dystroglycan. The latter actually lies just outside the muscle cell and links the sarcolemmal membrane to the extracellular matrix (the inner portion of the basement membrane) by binding with merosin, a subunit of laminin. The dystrophin–glycoprotein complex functions in this scheme as a transsarcolemmal structural

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Caveolin-3 Intracellular Integrin Dysferlin complex

Calpain F-Actin Dystrophin Golgi/Endoplasmic reticulum

SEPN1

POMT1 POMGnT1 Fukutin Fukutin-related peptide

Figure 45-2.  The molecular organization of the dystrophin-glycoprotein complex in the membrane and sarcolemma and endoplasmic reticulum-Golgi apparatus. These proteins are related to Duchenne, limb-girdle, Miyoshi, and certain congenital dystrophies. Details in text.

link between the subsarcolemmal cytoskeleton and the extracellular matrix. Moreover, each of these membranebinding proteins (adhalin, merosin, and laminin) is implicated in specific muscular dystrophies, as discussed later in this chapter. The loss of dystrophin leads to a parallel loss of DAPs and to disruption of the dystroglycan–protein complex. This change renders the sarcolemma susceptible to breaks and tears during muscle contraction, a hypothesis proposed first by Mokri and Engel and entirely consistent with the ultrastructural abnormalities that characterize Duchenne dystrophy. These authors demonstrated defects of the plasma membrane (sarcolemma) in a large proportion of nonnecrotic hyalinized muscle fibers, allowing ingress of extracellular fluid and calcium. The entrance of calcium is speculated to activate proteases and to increase protein degradation. The membrane defects and the associated alterations in the underlying region of the fiber represent the earliest and most basic pathologic change in Duchenne dystrophy and account for the leakage into the serum of CK and other enzymes of muscle.

Diagnosis of Duchenne and Becker dystrophies Analysis of the dystrophin gene in DNA obtained from white blood cells or from 50 mg of skeletal muscle can demonstrate the gene mutations in Duchenne and Becker patients and discriminate between these diseases. Also, immunostaining of muscle for dystrophin makes possible the differentiation of Duchenne, Becker, the carrier state, and other muscle disorders. An alternative method, developed by Byers and colleagues, uses an ELISA to measure the dystrophin levels in muscle biopsy samples. This testing is a rapid and relatively inexpensive tool for establishing the diagnosis of Duchenne and Becker muscular dystrophies and distinguishing them from unrelated disorders.

Other Rarer Dystrophinopathies Testing for the dystrophin protein has also brought to light several much rarer types of dystrophin abnormalities.

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One takes the form of a familial X-linked myalgic-crampmyoglobinuric syndrome, resulting from the deletion of the first third of the dystrophin gene (Gospe and coworkers). The muscle changes are mild and relatively nonprogressive. Another dystrophinopathy takes the form of an X-linked cardiomyopathy characterized by progressive heart failure in young persons without clinical evidence of skeletal muscle weakness; biopsy of skeletal muscle reveals reduced immunoreactivity to dystrophin (Jones and de la Monte). In yet another type, a glycerol-kinase deficiency is associated with varying degrees of adrenal hypoplasia, mental retardation, and myopathy.

Emery-Dreifuss Muscular Dystrophy (EMD and Other Mutations) This is a group of disorders that encompasses at least six different genetic types, the most common probably being an X-linked muscular dystrophy characterized by the special feature of muscle contractures. That process is relatively benign in comparison with the Duchenne dystrophy, at least in so far as most affected individuals live into adulthood. It was described originally by Emery and Dreifuss and subsequently by Hopkins and by Merlini and their colleagues. The primary gene defect is a deficiency of the protein emerin, a constituent of the nuclear membrane, encoded by EMD on the X chromosome (Fig. 45-3). However, also described are autosomal dominant forms with mutations in the gene for laminin A/C (called LGMD 1B, obviously affecting both girls and boys), an additional X-linked form due to mutations in FHL-1 as well as sporadic and dominant mutations of other genes encoding for entirely disparate proteins. Making a complete understanding of this syndrome even more complex is the recent appreciation that many of cases have none of these mutations. The age of onset varies from childhood to late adolescence or adulthood. Weakness affects first the upper arm Dystroglycans

Cytoplasm

Extracellular Intracellular

Dystrophin

Nucleus

-Actinin

Actin Titin

Nebulin

Emerin Nuclear pore Lamin A/C

Calpain Actin

Myosin

Myotilin Telethonin Contractile Proteins Z band in Sarcomere

Figure 45-3.  Expanded schematic of the nuclear and contractile proteins of the muscle. These proteins are referable to Emery-Dreifuss dystrophy and a number of the distal and the congenital dystrophies, as well as several of the limb-girdle dystrophies. Details in text.

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and pectoral girdle musculature and later the pelvic girdle and the distal muscles in the lower extremities. The distinguishing feature of the most typical form of the disease is the early appearance of contractures in the flexors of the elbow, extensors of the neck, and posterior calf muscles. Facial muscles are affected occasionally. There is no hypertrophy or pseudohypertrophy, and cognition is unaffected. However, severe cardiomyopathy with variable sinoatrial and atrioventricular conduction defects is a common accompaniment. The course of the myopathy is generally benign, more like that of Becker dystrophy, but weakness and contractures are severe in some cases and sudden cardiac death is a not infrequent occurrence. For this reason, close monitoring by a cardiologist and the prophylactic insertion of a pacemaker at the appropriate time may be lifesaving. The less common types of Emery-Dreifuss dystrophy, as mentioned, may have a scapuloperoneal (FHL-1 gene) or humeroperoneal (laminin mutation).

Facioscapulohumeral Muscular Dystrophy (FSH, Landouzy-Dejerine Muscular Dystrophy, DUX4 Mutation) This is a slowly progressive dystrophy involving primarily the musculature of the face and shoulders, often with long periods of nearly complete arrest. The pattern of inheritance is usually autosomal dominant. Almost all are of the facioscapulohumeral muscular dystrophy 1 (FSHD1) type; 5 to 10 percent are designated FSHD2, for which the mutation has recently been identified. The clinical presentations are very similar. Although less common than the Duchenne and myotonic dystrophies, FSH is not rare (an estimated yearly incidence rate of 5:100,000) and we have seen 1 or more cases yearly. The age of onset is usually between 6 and 20 years, but cases beginning in early adult life are occasionally encountered. Weakness and atrophy of the involved muscles are the major physical findings; pseudohypertrophy occurs only rarely and is slight. As a rule, the first manifestations are difficulty in raising the arms above the head and winging of the scapulae, although bifacial weakness may have initially attracted attention, even in early childhood. There is involvement especially of the orbicularis oculi, the zygomaticus, and the orbicularis oris, whereas the masseters, as well as the temporalis, extraocular, pharyngeal, and respiratory muscles are spared. There is an inability to close the eyes firmly, to purse the lips, and to whistle; the lips have a peculiar looseness and tendency to protrude. The lower parts of the trapezius muscles and the sternal parts of the pectorals are almost invariably affected. By contrast, the deltoids may seem to be unusually large and strong, an appearance that may be mistaken for pseudohypertrophy. The advancing atrophic process involves the sternocleidomastoid, serratus magnus, rhomboid, erector spinae, latissimus dorsi, and eventually the deltoid muscles as well. The bones of the shoulders become prominent; the scapulae are winged and elevated (“angel-wing” appearance), and the clavicles stand out. The anterior axillary folds slope down and out as a result of wasting of

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Chapter 45 Diseases of Muscle

the pectoral muscles. Usually the biceps waste less than the triceps, and the brachioradialis muscles even less, so that the upper arm may be thinner than the forearm (“Popeye” effect). Pelvic muscles are involved later and to a milder degree, giving rise to a slight lordosis and pelvic instability. The pretibial muscles weaken, and foot-drop is added to the waddling gait. The Beevor sign, an upward movement of the umbilicus on flexing the neck as a result of weakness of the lower abdominal muscles, is reportedly common (Awerbuch et al), but we have not seen it in early cases. Life expectancy is said to not be shortened. Initially, and even throughout the course, the muscular weakness may be asymmetrical (winging of only one scapula). Many of the patients with milder degrees of this form of dystrophy are unaware that they have the disease. This was true of nearly half of the large series of patients described in the Utah Mormon population (Tyler and Stephens). At any point, the disease may become virtually arrested. Nevertheless, 15 to 20 percent of patients eventually require a wheelchair (Tawil et al). An interesting feature of this group of diseases is the occasional congenital absence of a muscle (amyoplasia of one pectoral, brachioradialis, or biceps femoris) or part of a muscle in patients who later develop the typical features of the disease. The external ocular muscles are known to occasionally become affected late in the illness. Although cardiac involvement is rare, in a few cases tachycardia, cardiomegaly, and arrhythmias have occurred. Mental function is normal. Serum CK values are normal or slightly elevated. At a molecular level, FSHD1 has been found to have a consistent association with deletions of variable size on DUX4, located at the tip of chromosome 4q. This disorder is a consequence of alterations of a noncoding portion of DNA. Deletions in a repeated segment interfere with the structure of chromatin and allow the expression of normally inactive genes such as DUX4. Only patients with an allele that contains a repeat segment FSHD2 (called D4Z4 repeats) are susceptible to the disease. An entirely different mutation in a gene that maintains the structural integrity of chromatin accounts for the less common FSHD2; this change results in hypomethylation of the D4Z4 segments (an epigenetic mechanism) and is therefore also dependent on the permissive repeat allele. A variant in which only the shoulder and arm muscles are affected, sparing the face, and a form with bilateral foot-drop are known (Krasnianski et al). In some cases, usually with severe deletions at the FSH locus on chromosome 4, there is an early onset, relatively rapid progression and an association with facial diplegia, sensorineural deafness, and, sometimes, exudative retinal detachment (Coats disease). Using fluorescein angiography, Fitzsimmons and others have found a variety of other retinal abnormalities: telangiectasia, occlusion, leakage, and microaneurysms; in the majority of cases, suggesting that these retinal abnormalities are an integral part of the disease. Less common manifestations of FSHD include isolated scapular winging or other focal weakness such as foot drop, sparing of facial muscles, a variant with limb-girdle weakness, and rare instances of progressive external ophthalmoplegia (PEO).

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Scapuloperoneal Muscular Dystrophy This is a heterogenous group of myopathies that share the denominative topographic distribution of weakness and atrophy, usually beginning in childhood but with wide variability. Beginning with Brossard in 1886, there were numerous reports of a distinctive pattern of progressive muscular weakness and wasting that involved the muscles of the neck, shoulders, and upper arms, and of the anterior tibial and peroneal groups, causing severe foot-drop. The nature of this disorder has been a matter of controversy, some writers claiming it to be a progressive muscular dystrophy and others, a muscular atrophy of spinal or neuropathic type. Probably both are correct in that either process can produce more or less the same pattern of weakness. A form of familial scapuloperoneal weakness and atrophy associated with areflexia and distal sensory loss (a spinalneuronopathic form) has been found to have a mutation in the desmin gene (Davidenkow; Munsat and Serratrice). The mutation in the most common form of the disease has been found in TRPV4 but others have been connected to FHL-1 on the X-chromosome (see Table 45-1). A mutation in TRIM32 has also causes this phenotype. The onset of symptoms in their six patients was in early or middle adult life, with difficulty in walking because of bilateral footdrop; symptoms referable to scapulohumeral involvement came later. Progression was slow, and none of the patients became severely incapacitated.

Limb-Girdle Muscular Dystrophies (LGMD, Scapulohumeral and Pelvifemoral Muscular Dystrophies, Erb Dystrophy) (See Table 45-1) There is a large group of patients with muscular dystrophy who do not fit into the Duchenne/Becker, facioscapulohumeral, or scapuloperoneal categories. Children of both sexes in this group lack the hypertrophy of calves and other muscles; adults with late-onset forms have either pelvic or shoulder girdle involvement or both, and their facial muscles are spared. Because Wilhelm Erb first called attention to these types of dystrophy, they were classified as the “limb-girdle dystrophies of Erb” (Walton and Nattrass). This clinically based grouping has been problematic from the time it was proposed because, like the scapuloperoneal group, it is heterogeneous, the only unifying feature being the presence of limb-girdle weakness with sparing of the facial muscles. The inheritance is variable, but the autosomal recessive forms are the most common. Either the shoulder girdle or pelvic girdle muscles may be first affected (traditionally these forms had been referred to as the Erb juvenile atrophic and Leyden-Möbius types, respectively). Weakness and atrophy may become evident during either late childhood or early adult life and spread from shoulders to hips or vice versa. The status of this group of limb-girdle muscular dystrophies (LGMDs) as a clinical–genetic entity is being steadily revised. The delineation of the progressive spinal muscular atrophies and the congenital and metabolic myopathies has considerably narrowed the category of limb-girdle dystrophies as originally described. With the application of molecular genetic techniques, progress in this direction

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accelerated greatly. The now well-populated class of limbgirdle dystrophies is classified as LGMD1 for the autosomal dominant types, and LGMD2 for the recessive types, and further subclassified based on the specific genotype. At the time of this writing, over 25 forms of autosomal recessive and 6 forms of autosomal dominant limb-girdle dystrophies have been defined, most with an identifiable mutation and a protein that in most cases is a constituent of the sarcolemmal, sarcomeric, or nuclear membrane structural protein (Bushby). The later the onset of these disorders, the more likely that the course will be benign. In these lesser-affected patients the EMG is myopathic and the CK values are only moderately elevated and may be normal. More severe cases can have greatly elevated CK levels. Cardiac involvement occurs but is infrequent (mainly in the group classified as myofibrillar dystrophies), and mental function is normal, but there are exceptions including in cases of laminin A/C mutations (type 1B), FKRP (fukutinrelated protein mutation) mutations (type 2I), and in the sarcoglycanopathies. This information is summarized in Table 45-2 and discussion of the better-characterized types follows.

limb-girdle dystrophies. In most other ways, this disease reflects the heterogeneity of clinical presentation of the other subtypes of limb-girdle disease. A period of stabilization lasting several to 35 years is common, followed by a decade or more of progression that eventually involves the shoulder muscles. Most patients, particularly those with later onset, remained able to walk into their forties. Other features are variable, for example, dysphagia and ptosis; however, distal weakness is not seen and intelligence is normal. The defective FKRP gene is related in function to four other muscle genes in addition to fukutin (hence its name). All five of these genes are glycosyl transferases that attach sugar groups to proteins such as alpha-dystroglycan. The severity of the clinical phenotype is inversely related to the levels of glycosylation of alpha-dystroglycan. Defects in any of the five genes can cause developmental lesions in the brain in addition to muscle disease, although those associated with FKRP mutations are less common and less severe.

Limb-Girdle Muscular Dystrophy 2I (FKRP, Fukutin Mutation)

These entities comprise the best-defined group of limbgirdle dystrophy. Clinically they resemble severe Duchenne dystrophy in practically all respects, including the presence of calf hypertrophy, cardiomyopathy, and marked elevation of CK in the early stages of the illness. The obvious distinction from Duchenne dystrophy is the autosomal recessive pattern of inheritance (affection of both girls and boys in the same sibship). The largest and best-studied group of this severe, recessive pelvic-pectoral dystrophy (99 children in 28 families) has come from Tunisia (Ben Hamida et al). It also occurs commonly in other Arab countries and has been observed repeatedly in Brazil, but less so in Europe and North America. The basic defect is in 1 of 4 dystrophin-associated glycoproteins (DAGs)—a-, b-, g-, and d-sarcoglycan (see Fig. 45-2); α-sarcoglycan (designated 50 DAG) is

The discovery of the “fukutin-related protein” initially came about because mutant forms caused a severe congenital muscular dystrophy (CMD). It later became apparent that certain mutations also cause a common type of later onset limb-girdle dystrophy. As the designation “2” indicates, it is transmitted in an autosomal recessive manner. This is the most common form of limb-girdle dystrophy in patients of Northern European descent. In a series of 16 patients from 14 families, the an onset of proximal girdle weakness was usually in the second to fourth decades of life (but as early as age 2 years) (Poppe and colleagues). The majority of patients eventually had respiratory failure and several displayed varying degrees of congestive heart failure, features that also accompany some of the other

Severe Childhood Autosomal Recessive Muscular Dystrophy (Sarcoglycanopathies; LGMD 2C, D, E, and F)

Table 45-2 SELECTED MUSCULAR DYSTROPHIESa ONSET DECADE

CK ELEVATION

Myotonic dystrophy (DM1)

TYPE

Expanded intronic CTG repeat in myotonin kinase

GENE VARIANT

1st–2nd

1–2 ×

Proximal myotonic myopathy (DM2)

Expanded intronic CCTG repeat in zinc finger protein

1st–2nd

1–2 ×

Facioscapulohumeral dystrophy Oculopharyngeal dystrophy Bethlem myopathy     Myofibrillar myopathy

Multigene dysregulation at 4q telomere Exonic GCG expansion (alanine) in poly-A binding protein Collagen VI, subunits α 1-3     Myotilin, desmin, αβ-crystallin

1st–4th

1–2 ×

6th–7th

1–2 ×

1st–3rd     2nd–4th

1–4 ×     1–5 ×

REGIONS AFFECTED

Distal weakness, myotonia, cataracts Testicular atrophy, balding, cardiac arrhythmias Resembles myotonic dystrophy with prominent proximal muscle weakness but no infancy onset; less facial weakness Facial, scapular, anterior tibial muscles Hearing loss, ocular telangiectasias Oculopharyngeal and levator palpebrae muscles Proximal weakness Contractures in fingers, elbows, knees May present as CMD Allelic with LGMD-1A

a

All inherited in an autosomal dominant pattern. CCTG, cytosine, cytosine, thymine, guanidine; CMD, childhood muscular dystrophy; CTG, cytosine, thymine, guanidine; GCG, guanidine, cytosine, guanidine; LGMD, limb-girdle muscular dystrophy.

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also called adhalin, from the Arabic word adhal, meaning muscle. A primary deficiency of adhalin has been traced adhalin on chromosome 17q21 (Roberds et al). A primary defect in b-sarcoglycan (43 DAG) has been mapped to chromosome 4q12, of g-sarcoglycan (35 DAG) to the pericentromeric region of chromosome 13q, and of b-sarcoglycan (43 DAG) to chromosome 5q. Primary defects in 25 DAG may also lead to a deficiency of adhalin, but the latter is incomplete and represents a secondary effect, possibly explained by the proximity of the defective genes to the adhalin gene. Because of clinical similarities, there may be difficulty in distinguishing limb-girdle dystrophies (formerly termed severe childhood autosomal recessive muscular dystrophy [SCARMD]) from a dystrophinopathy (except that the former occur in females). In addition to the difference in inheritance, they can be readily diagnosed by showing a loss of sarcolemmal immunostaining for any of the dystrophin-associated glycoproteins but with preservation of staining for dystrophin itself. However, it is not possible on clinical grounds to distinguish one sarcoglycanopathy from another; this can be accomplished only by specific immunostaining.

Autosomal Recessive Muscular Dystrophy (LGMD 2A and B; Calpain-3) These forms of limb-girdle dystrophies have been described in large kindreds, in Indiana (among the Amish people), on the island of Réunion in the Indian Ocean, in Brazil, Great Britain, Italy and Spain, and elsewhere, affecting males and females equally. Both the shoulder and pelvic girdles are involved. The degree of weakness has varied considerably. In one form of the disease, called LGMD 2A, the abnormal gene codes for a calcium-activated neutral protease, or calpain (see Fig. 45-3). This “calpainopathy” is currently believed to account for approximately 40 percent of patients with LGMD. Frequently, and early in the course of disease, there are Achilles tendon contractures and very high serum CK levels (at least 10 times normal), features that may permit distinction from the sarcoglycanopathies. Yet another fairly common recessive limb-girdle dystrophy of slow progression is caused by a mutation in the gene for the protein dysferlin, which localizes to the muscle fiber membrane. Noteworthy is the fact that this same protein is involved in the distal form of Miyoshi muscular dystrophy described further on. Early involvement of the gastrocnemius muscle (inability to walk on tiptoe) and extraordinarily high levels of CK, as in calpainopathy, are clues to the latter disease.

Autosomal Dominant Limb-Girdle Dystrophies (LGMD 1A-1E) Several dystrophies with the LGMD phenotype are inherited as autosomal dominant traits. For example, LGMDA 1A is an autosomal dominant limb-girdle dystrophy of late onset that was described in a large North Carolina family (49 affected members in a pedigree of 218 persons). The mean age at onset was 27 years. Proximal leg weakness, with or without proximal arm weakness, and elevated CK values were the main clinical characteristics. The primary

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defect is in a gene encoding the protein myotilin (see Fig. 45-3) (Speer and colleagues). LGMDA 1A is allelic to a form of myofibrillar myopathy. LGMD 1B is a dominantly inherited disorder arising from mutations in the gene encoding the nuclear membrane protein lamin A/C (Fig. 45-3). Mercuri and colleagues note that the phenotypes of these mutations vary widely. The muscle disorders range from severe cases that mimic CMD to milder ones with features of limb-girdle dystrophy or Emery-Dreifuss muscular dystrophy. The diverse, nonmuscular manifestations of lamin A/C mutations include a cardiomyopathy, a form of lipodystrophy, a syndrome of accelerated aging (Hutchinson-Gilford progeria), and a recessively inherited axonal neuropathy.

Progressive External Ophthalmoplegia (Kearns-Sayre Syndrome) (See Also “Progressive External Ophthalmoplegia [PEO] and Kearns-Sayre Syndrome” Under Mitochondrial Myopathies in Chap. 36) This has proved to be a confusing group of processes characterized by slowly progressive myopathy primarily involving and often limited to the extraocular muscles. Usually, the levators of the eyelids are the first to be affected, causing ptosis, followed by progressive balanced ophthalmoparesis. This disorder usually begins in childhood, sometimes in adolescence, and rarely in adult life (as late as 50 years). Several types have been described. The most common one arises from either deletions or point mutations in mitochondrial DNA and are discussed in Chap. 37 with other metabolic disorders. However, when the foregoing PEO categories are eliminated, there remains a distinctly different category of dominantly inherited PEO. Males and females are equally affected; the pattern of inheritance is autosomal dominant in some and recessive or uncertain in others. Once started, the disease progresses relentlessly until the eyes are motionless. Simultaneous involvement of all extraocular muscles permits the eyes to remain in a central position, so that strabismus and diplopia are uncommon (in rare instances, one eye is affected before the other). The pupillary responses and accommodation are normal. As the patient attempts to raise his eyelids and to see under them, the head is thrown back and the frontalis muscle is contracted, wrinkling the forehead (hutchinsonian facies). The eyelids are abnormally thin due to atrophy of the levator muscles. The orbicularis oculi muscles are frequently involved in addition to the extraocular muscles. Thus, in PEO, as in myasthenia gravis and myotonic dystrophy, there can be a characteristic combination of weakness of eye closure and eye opening, a combination that is nearly always myopathic. Other facial muscles, masseters, sternocleidomastoids, deltoids, or peronei are variably weak and wasted in approximately 25 percent of cases. The characteristic feature of PEO is that ptosis and ocular paralysis precede involvement of other muscles by many years. Given that there is considerable clinical overlap between the mitochondrial syndrome and dominantly inherited PEO, it is not surprising that some of the

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dominantly inherited gene defects causing PEO result in disturbances in mitochondrial DNA. Mutations in three nuclear genes have been implicated. (These are twinkle, a mitochondrial DNA binding protein; ANT1, an adenine nucleotide transporter in the intermembrane space in the mitochondrion; and POLG, a subunit of the mitochondrial DNA polymerase.) There are also recessively inherited instances of familial PEO, one of which involves a nuclear gene.

Oculopharyngeal Dystrophy (PABPN1 Mutation, See Table 45-2) Oculopharyngeal dystrophy is inherited as an autosomal dominant trait and is unique in its late onset (usually after the forty-fifth year) and the restricted muscular weakness, manifest mainly as a bilateral ptosis and dysphagia. E.W. Taylor first described the disease in 1915 and assumed that it was caused by a nuclear atrophy (oculomotor-vagal complex). However, Victor and colleagues, in 1962, showed that the descendants of Taylor’s cases had a late-life dystrophy (myopathic EMG and biopsy). One of the families described by Victor, Hayes, and Adams was subsequently traced by Barbeau through 10 generations to an early French-Canadian immigrant, who was the progenitor of 249 descendants with the disease. Other families showing a dominant (rarely recessive) pattern of inheritance and a number of sporadic cases have been observed in many parts of the world. Difficulty in swallowing and change in voice are associated with slowly progressive ptosis. Swallowing becomes so difficult that food intake is limited, resulting in cachexia, which can be ameliorated by cutting the cricopharyngeus muscles, or, if that fails, by a gastrostomy or nasogastric tube. Later in the disease, in some families the external ocular muscles and shoulder and pelvic muscles become weakened and atrophic to a varying extent. In the few autopsied cases, a loss of fibers of modest proportions was widespread in these and many other muscles. Rimmed vacuoles in the sarcoplasm and, by electron microscopy, intranuclear tubular filaments are characteristic but not specific histologic findings (these features are seen in other myopathies, particularly in inclusion body myositis). The brainstem nuclei and cranial nerves are normal. As in the other mild and restricted muscular dystrophies, the serum CK and aldolase levels are normal and the EMG is altered only in the affected muscles. The gene product of the mutated gene, PABN1, is a protein that binds to RNA (poly-A binding protein). The defect is an expansion of a string of alanines. Normally, there are six repeats; in dominantly inherited oculopharyngeal dystrophy, there are 8 to 13 repeats; in the recessively inherited form there are seven repeats on each allele. Thus this represents one of the most subtle nucleotide expansion diseases yet discovered.

Myotonic Dystrophy Types 1 and 2 There are two types of myotonic dystrophies (DM1 and DM2/PROMM). Type 1 (DM1) is the most common adult muscular dystrophy. It was described in 1909 by Steinert,

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who considered it to be a variant of congenital myotonia (Thomsen disease; see Chap. 46) and in the same year by Batten and Gibb, who recognized it as a unique clinical entity. DM1 is distinguished by an autosomal dominant pattern of inheritance with a high level of penetrance, special topography of the muscle atrophy, associated obvious myotonia, and occurrence of dystrophic changes in nonmuscular tissues (lens of eye, testicle and other endocrine glands, skin, esophagus, heart, and, in some cases, the cerebrum). Certain muscles, the levator palpebrae, facial, masseter, sternocleidomastoid, and forearm, hand, and pretibial muscles, are consistently involved in the dystrophic process. It is possible that Gowers’ famous case of an 18-year-old youth with weakened and wasted anterior tibial and forearm muscles and sternocleidomastoids, in conjunction with paresis of the orbicularis and frontalis muscles, was an example of this disease. Despite some clinical variability of myotonic dystrophy, the defective gene in the first type has been the same in every population that has been studied. At this locus on chromosome 19q there is a specific molecular defect, an unstable trinucleotide sequence (CTG) in the DMPK gene that is longer in affected individuals than it is in healthy siblings or unaffected subjects. Whereas healthy individuals will have 5 to 30 CTG repeats, patients with myotonic dystrophy have 50 to 2,000. Longer sequences are associated with more severe disease, and they increase in size through successive generations lead to earlier occurrence (genetic anticipation), particularly in DM1. The CTG repeats reside within the myotonin protein kinase gene. It is of considerable interest that these CTG repeating segments do not code for a protein (i.e., they are intronic), quite unlike conditions such as Huntington disease in which the triplet expansion codes for amino acid sequences within a protein. The milder type 2 myotonic dystrophy (DM2) is caused by an expanded triplet repeat in the CNBP gene on chromosome 3, as discussed further on under “Proximal Myotonic Myopathy (PROMM, DM2).” A critical element in the pathogenesis of this disease in both types is the intranuclear accumulation of the expanded RNA sequences; these disrupt the regulation of alternative splicing of mRNA and perturb the expression of many genes, thus the multiple systems affected clinically.

Clinical Features of Myotonic Dystrophy 1 (DM1, DMPK Mutation) In most instances of myotonic dystrophy, the weakness and muscular wasting do not become evident until early adult life, but they may present in childhood, usually with facial weakness and ptosis. Myotonia is perhaps more obvious and earlier in this disorder than in most others that display the sign as one component. Myotonic dystrophy is, for example, far more common than myotonia congenita. Myotonia combined with distal weakness in DM1 stands out from other myopathies. Cardiac arrhythmias, sometimes evident on in conduction defects in EKG, are common as noted below. A severe neonatal (congenital) form of the disease is well known and is described separately further on.

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In the common early adult form of the disease, the small muscles of the hands along with the extensor muscles of the forearms are often the first to become atrophied. Difficulty grasping (due to weakness of hand muscles) and then releasing objects (because of the myotonia) is typical. In other cases, ptosis of the eyelids and thinness and slackness of the facial muscles may be the earliest signs, preceding other muscular involvement by many years. Atrophy of the masseters leads to narrowing of the lower half of the face, and the mandible is slender and malpositioned so that the teeth do not occlude properly. This, along with the ptosis, frontal baldness, and wrinkled forehead, imparts a distinctive appearance that, once seen, can be recognized at a glance (“hatchet” face). The sternocleidomastoids are almost invariably thin and weak and are associated with an exaggerated forward curvature of the neck (“swan neck”). Atrophy of the anterior tibial muscle groups, leading to foot-drop, is an early sign in some families. Pharyngeal and laryngeal weakness results in a weak, monotonous, nasal voice. The uterine muscle may be weakened, interfering with normal parturition, and the esophagus is often dilated because of loss of muscle fibers in the striated as well as smooth muscle parts. Megacolon occurs in some patients. Diaphragmatic weakness and alveolar hypoventilation, resulting in chronic bronchitis and bronchiectasis, are common late features, as are cardiac abnormalities; the latter are most often a result of disease of the conducting apparatus, giving rise to bradycardia and a prolonged P-R interval. Patients with extreme bradycardia atrial tachyarrhythmia or high degrees of atrioventricular block may die suddenly; for such individuals, insertion of a pacemaker is often recommended (Moorman et al; Groh et al). Mitral valve prolapse and left ventricular dysfunction (cardiomyopathy) are less frequent abnormalities. In this disorder, as in Emery-Dreifuss dystrophy, careful assessment by a knowledgeable cardiologist is required. The disease progresses slowly, with gradual involvement of the proximal muscles of the limbs and muscles of the trunk. Tendon reflexes are lost or much reduced. Contracture is rarely seen, and the thin, flattened hands are consequently soft and pliable. Most patients are confined to a wheelchair or bed within 15 to 20 years of the first signs, and death occurs before the normal age from pulmonary infection, heart block, or heart failure. The phenomenon of myotonia, which expresses itself in prolonged idiomuscular contraction following brief percussion or electrical stimulation and in delay of relaxation after strong voluntary contraction, is the third striking attribute of the disease (the other two being the facial, ptotic, and limb weakness, and the cardiac-autoimmune features). Not as widespread or severe as in myotonia congenita, it is, nonetheless, easily elicited in the hands and tongue in almost all cases, and in the proximal limb muscles in half of the cases. Gentle movements do not evoke it (eye blinks, movements of facial expression, and the like are not impeded), whereas strong closure of the lids and clenching of the fist are followed by a long delay in relaxation. Myotonia may precede weakness by several years. Indeed, Maas and Paterson have claimed that many cases diagnosed originally as myotonia congenita eventually

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proved to be examples of myotonic dystrophy. Of interest is the fact that in congenital or infantile cases of myotonic dystrophy, the myotonic phenomenon is not elicited until later in childhood, after the second or third year of life. The child often becomes accustomed to the myotonia and does not complain about it. The relation of myotonia to the dystrophy is not direct. Certain muscles that show the myotonia best (tongue, flexors, of fingers) are seldom weak and atrophic. Moreover, there may be little or no myotonia in certain families that show the other characteristic features of myotonic dystrophy. The muscle hypertrophy that is characteristic of myotonia congenita is not a feature of myotonic dystrophy. The fourth major characteristic of the disease is the dystrophic change in nonmuscular tissues. The most common of these is lenticular opacities, found by slit-lamp examination in 90 percent of patients. At first dust-like, they then form small, regular opacities in the posterior and anterior cortex of the lens just beneath the capsule; under the slit lamp they appear blue, blue-green, and yellow, and are highly refractile. Microscopically, the crystalline material (probably lipids and cholesterol, which cause the iridescence) lies in vacuoles and lacunae among the lens fibers. In older patients, a stellate cataract slowly forms in the posterior cortex of the lens. Mild to moderate degrees of developmental cognitive delay are common in DM1, and the brain weight in several of our patients was 200 g less than that in normal individuals of the same age. Late in adult life, some patients become suspicious, argumentative, and forgetful. In some families, a hereditary sensorimotor neuropathy may be added to the muscle disease (Cros et al). Other nonspecific abnormalities, such as hyperostosis of the frontal bones and calcification of the basal ganglia, both readily discerned by CT, seem to be more common in patients with myotonic dystrophy than they are in healthy persons. Progressive frontal alopecia, beginning at an early age, is a characteristic feature in both men and women with this disease. Testicular atrophy with androgenic deficiency, reduced libido or impotence, and sterility are additional frequent manifestations. In some patients gynecomastia and elevated gonadotropin excretion are found. Testicular biopsy shows atrophy and hyalinization of tubular cells and hyperplasia of Leydig cells. (Thus all the clinical characteristics of the Klinefelter syndrome may be present but without the “sex chromatin” mass [Barr body].) Ovarian deficiency occasionally develops in the female patient, but it is seldom severe enough to interfere with menstruation or fertility. The prevalence of clinical or chemical diabetes mellitus is slightly increased in patients with myotonic dystrophy, but an increased insulin response to a glucose load has proved to be a common abnormality. Numerous surveys of other endocrine functions have yielded little significance. Finally, heart block, atrial and ventricular tachycardias, unexplained cardiomyopathy with heart failure, and sudden death are well-known in the disorder and require repeated EKG evaluation. Insertion of a pacemaker has become common. We have been impressed with the variability of clinical expression. In many patients, intelligence has been

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unimpaired and the myotonia and muscle weakness have been so mild that the patients were unaware of any difficulty. In a large Labrador kinship, 27 of 133 patients had only a partial syndrome and only minor muscle symptoms at the time of examination (Pryse-Philips and associates).

Pathologic Features In addition to displaying most of the common findings of muscular dystrophy, there are several highly unusual myopathologic features. Peripherally placed sarcoplasmic masses and circular bundles of myofibrils (ringbinden) are found. There is hypertrophy of type 1 fibers with centrally placed nuclei (this may be a marked finding) and many atrophic fibers show nuclear clumping. In many of the muscle spindles there is an excess of intrafusal fibers (particularly in the congenital form). Many of the terminal arborizations of the peripheral nerves are unusually elaborate and elongated.

Congenital Myotonic Dystrophy Brief reference was made earlier to this inherited, distinctive, and potentially lethal form of myotonic dystrophy. Harper’s (1975) study of 70 personally observed patients and 56 others gathered from the medical literature suggests this disease exists in every pediatric neurology service. Profound hypotonia and facial diplegia at birth are the most prominent clinical features; myotonia is notably absent. Drooping of the eyelids, the tented upper lip (“carp” mouth), and the open jaw impart a characteristic appearance, which allows immediate recognition of the disease in the newborn infant and child. Difficulty in sucking and swallowing, bronchial aspiration (because of palatal and pharyngeal weakness), and respiratory distress (because of diaphragmatic and intercostal weakness and pulmonary immaturity) are present in varying degrees; the latter disorders are responsible for a previously unrecognized group of neonatal deaths (24 such deaths among siblings of affected patients in Harper’s study). In surviving infants, delayed motor and speech development, swallowing difficulty, mild to moderately severe mental retardation, and talipes or generalized arthrogryposis are common. Once adolescence is attained, the disease follows the same course as the later form. As stated earlier, clinical myotonia in the congenital form of the disease becomes evident only later in childhood, although EMG study may disclose myotonic discharges in early infancy. The diagnosis may be suspected by the simple test of eliciting myotonia in the mother. ECG changes occur in one-third of the patients. In the congenital form of this disease the affected parent is always the mother with type 1 (DM1) myotonic dystrophy, in whom the disease need not be severe. Electrophysiologic testing will bring out the myotonia in the mother if it is inevident on percussion of muscle. (In cases of adult-onset, transmission is maternal or paternal.) These data suggest that in addition to inheriting the myotonic dystrophy gene, the congenital cases also receive some maternally transmitted factor, possibly methylation of DNA that allows expansion of the trinucleotide repeat in oocytes. The prenatal diagnosis of myotonic dystrophy is readily accomplished by examination for CTG repeats in the amniotic fluid or in a biopsy of chorionic villi.

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However, it is not possible to predict whether a fetus with an expanded mutation will have congenital myotonic dystrophy or later-onset myotonic dystrophy.

Proximal Myotonic Myopathy (DM2, PROMM, CMBP Mutation) This myopathy is characterized by autosomal dominant inheritance (unlike the limb-girdle dystrophies, the numeral 2 denotes the second type of DM, not recessive inheritance), with proximal muscle weakness, myotonia, and cataracts (Ricker and colleagues). Seventeen families containing 50 affected members were studied by these authors. Onset was between 20 and 40 years of age, with intermittent myotonic symptoms of the hands and proximal leg muscles, followed by a mild, slowly progressive weakness of the proximal limb muscles without significant atrophy. In contrast to DM1, cataracts developed in onehalf of their patients and cardiac arrhythmias in only two. Onset in infancy, ptosis, weakness of facial, jaw, and distal limb muscles, and mental abnormalities were notably absent, further distinguishing PROMM from the conventional (DM1) form of myotonic dystrophy. Histologically, there are many fibers with multiple (5 to 10 or more) internalized nuclei, without ringbinden or subsarcolemmal masses. In addition, there are atrophic fibers with nuclear clumps. Analysis of leukocyte and muscle DNA discloses no expansion of the CTG component of the myotonic dystrophy gene. Rather, the gene defect for this disease has been mapped to the CNBP gene on chromosome 3q where there is an expansion of a CCTG repeats. Like the expanded CTG repeat in myotonic dystrophy, the CCTG expansion in PROMM is associated with intranuclear accumulation of the expanded RNA transcript, and like the CTG repeats of myotonic dystrophy, the CCTG segments do not code for a protein.

Distal Muscular Dystrophies (Welander, Miyoshi, and Other Types) (See Table 45-3) Included in this group are several slowly progressive distal myopathies with onset principally in adult life. Weakness and wasting of the muscles of the hands, forearms, and lower legs, especially the extensors, are the main clinical features. Although such cases had been reported by Gowers and others, their differentiation from myotonic dystrophy and peroneal muscular atrophy was unclear until relatively recently. Several types of distal dystrophies are inherited as autosomal dominant traits. A different dominantly inherited distal dystrophy was described by Welander in a study of 249 patients from 72 Swedish pedigrees (not to be confused with the KugelbergWelander juvenile spinal muscular atrophy affecting proximal muscles; see Chap. 38). Weakness developed first in the small hand muscles and then spread to the distal leg muscles, causing a steppage gait. Fasciculations, cramps, pain, sensory disturbances, and myotonia were notably absent. Some patients have a low-grade sensory neuropathy, suggesting that pathology in this disorder may not be exclusively in muscle. Cataracts appeared after the age of 70 years in 3 patients and can be discounted as having special significance. No endocrine disorders were detected.

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Table 45-3 DISTAL MUSCULAR DYSTROPHIES INHERITANCE DISORDER

GENE

ONSET DECADE

CK ELEVATION

REGIONS AFFECTED

Autosomal recessive Miyoshi myopathy (LGMD 2B)  

  Dysferlin

  2nd–3rd

  10–50 ×

 

 

 

 

 

 

 

Nonaka myopathy with rimmed vacuoles (familial IBM)

GNE kinase–epimerase UDP-N-acetylglucosamine2-epimerase/N-mannosamine kinase   TIA1     TTN/Titin   X-linked (see Table 45-1)

2nd–3rd

3–10 ×

  4th–5th     4th–8th   3rd–6th

  2–3 ×     2–4 ×   2–10 ×

  Weakness begins in hands Slow progression Spares cardiac muscle Onset in tibial distribution No cardiac involvement Scapuloperoneal weakness

    Desmin/ab crystallin   MYHC-1 (MYH7) ZASP  

    3rd–4th   2nd–3rd 2nd–3rd  

    2–3 ×   3× 2×  

Hyaline bodies in muscle Early onset of foot-drop Onset of distal weakness, slowly progressive Cardiac arrhythmias (sometimes fatal) Anterior tibial (early foot-drop) Anterior tibial Cardiomyopathy common

Autosomal dominant Welander distal dystrophy     Tibial muscular dystrophy   Scapuloperoneal dystrophy     Desmin myopathy   Gower-Laing Markesbery-Griggs  

  Begins in gastrocnemius muscles, rarely, in anterior tibial muscles Identical genetic defects may cause LGMD-2B Involves multiple muscle groups, spares heart Distal more than proximal weakness Quadriceps sparing Spares heart

IBM, inclusion body myopathy.

Dystrophic changes were demonstrated in 3 autopsies and 22 biopsy specimens. Some muscle biopsy material has shown rimmed vacuoles and inclusions that are similar to inclusion body myopathy. Progression of the disease was very slow; after 10 years or so, some wasting of proximal muscles was seen in a few of the patients. Welander dystrophy has been linked to mutations in T1A1 on chromosome 2p13, near the locus for the below described Miyoshi myopathy. Markesbery and colleagues reported a late-onset distal myopathy in which weakness began in the distal leg muscles (tibialis anterior) and later spread to the hands; there was also cardiomyopathy and heart failure. A mutation in the ZASP gene has been found. Very similar distal myopathies have been described in Finnish patients by Udd and colleagues and caused by dominant mutations in the “titin” gene. A form beginning in childhood has been described and attributed to a mutation in the gene (MYHC7) that codes for myosin heavy chain 1 protein. The characteristic feature in all these cases is progressive bilateral foot-drop.

Miyoshi Dystrophy (DYSF Mutation) A type of distal dystrophy characterized by autosomal recessive pattern of inheritance is particularly prevalent in Japan (Miyoshi et al), but numerous cases exist in all parts of the world. The Miyoshi myopathy is the one we have encountered most often among the distal muscular dystrophies. Onset of the disease is in early adult life, with weakness and atrophy of the leg muscles most prominent in the

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peroneal or the gastrocnemius and soleus muscles. Over many years the weakness extends to the thighs, gluteal muscles, and arm muscles, including the proximal ones. Serum CK concentrations are greatly increased in the early stages of the disease. In this type of dystrophy the mutation in DYSF leads to an absence of the muscle protein dysferlin, a membrane protein that does not interact with any of the dystrophin-binding elements. Whereas dystrophin and its binding partners are believed to confer tensile strength, dysferlin and its associated proteins (e.g., the annexins) function in calcium-mediated membrane repair (Lennon et al). As mentioned earlier, limb-girdle dystrophy 2B has been linked to the same chromosomal locus and it also lacks the dysferlin protein. It is also striking that different family members with the same dysferlin mutation can have disease onset in either a proximal (LGMD) or distal (Miyoshi) pattern, suggesting that additional factors modify the pattern of weakness produced by dysferlin deficiency. We have encountered a family in which two individuals with dysferlin mutations had proximal weakness at onset while another sibling with the same disease had anterior tibial weakness. An apparently separate form of distal myopathy with autosomal dominant inheritance and onset before 2 years of age has been described. Whether these infantile-onset cases represent a true muscular dystrophy has not been established. Several even rarer distal myopathies with linkage to specific genetic sites have been described, but most are not well-enough characterized to require elaboration here (Illa; Amato and Russell).

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Congenital Muscular Dystrophy (Fukuyama, Walker-Warburg, Merosin Deficient, Rigid Spine, and Other Types) (Table 45-4) Early in the twentieth century there were scattered reports of congenital myopathy, some of which may have represented congenital myotonic dystrophy or one of the congenital myopathies described later. In 1957, Banker and associates described 2 patients (siblings), 1 dying 1.5 h after birth and the other dying at the age of 10 months of a congenital muscular dystrophy (CMD) with arthrogryposis. The pathologic changes consisted of muscle fiber degeneration, variation in fiber size, fibrosis, and fat cell replacement. The central and peripheral nervous systems were intact. The severity of the degenerative changes was such that a developmental disorder of muscle could be excluded. Pearson and Fowler, in 1963, reported a brother and sister with similar clinical and pathologic findings, and Walton and colleagues described yet another patient, 4 years of age. By 1967, Vassella and colleagues were able to collect 27 cases from the medical literature and to add 8 cases of their own. The high incidence of sibling involvement pointed to an autosomal recessive inheritance. Preceding the modern genetic findings, in 1976, Bethlem and van Wijngaarden described an autosomal dominant, early onset limb-girdle dystrophy in 28 members of 3 unrelated Dutch families. Flexion contractures of the elbows, ankles, and hyperextensible interphalangeal joints of the fingers were present from the beginning stages of weakness, but neither the weakness nor the contractures were disabling. Also unlike Emery-Dreifuss dystrophy, contractures of the neck and spine were not present. Uniformity of clinical expression, slow progression with

long periods of arrest, and normal longevity are other important features of the illness. Mohire and coworkers have proposed the designation Bethlem myopathy. A milder form that is allelic with the Bethlem type is termed Ulrich myopathy; many of these patients survive into their fifties because of the slow progression of disease. Defined as a muscle dystrophy already present at birth, often with contractures of proximal muscles and trunk, the severity of the weakness and degree of progression have varied widely. Of the 8 cases reported by Rotthauwe and colleagues, 1 had a benign course, but the others all had weakness and hypotonia at birth, and difficulty in sucking and swallowing had interfered with nutrition. Their oldest patients, 14 and 23 years of age, and several others had walked, but at a late age. In a Finnish series, congenital dystrophy accounted for 9 percent of the 160 cases of neuromuscular disease seen at their hospital over a decade (Donner and associates). The weakness and hypotonia were generalized, and three had ECG abnormalities. The CK values were elevated and the EMGs were myopathic. This group of dystrophies began to come into focus in the 1960s with a series of articles from Japan relating the details in more than 100 patients with congenital dystrophy (Fukuyama et al). Although it is the second most common muscular dystrophy in Japan, it is rare elsewhere. The special feature of these cases was the coexistence of severe mental retardation and developmental anomalies of the cerebral cortex. Hyperlucency in the periventricular white matter (by CT) was frequently observed. In another group of cases, CMD was associated with lissencephaly as well as cerebellar and retinal malformations (WalkerWarburg syndrome; see Dobyns et al). In a series reported by Santavuori and coworkers, CMD was associated with

Table 45-4 CONGENITAL MUSCULAR DYSTROPHIES (CMD) DISORDER

Merosin deficiency   Fukutin CMD (LGMD 2I)       Muscle-eye brain disease         Walker-Warburg disease       Rigid spine syndrome     Integrin CMD   LARGE CMD

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GENE/PROTEIN

CK ELEVATION

REGIONS AFFECTED

LAMA2/Merosin   FKRP/Fukutin

5–35 ×   10–50 ×

Hypotonia, diffuse weakness, slow motor development Cognitive function largely spared Hypotonia, diffuse weakness, slow motor development

      POMGnT1I/N-acetylglucosaminyl-transferase         POMT1/O-Mannosyltransferase 1       SEPN1/Selenoprotein     Integrin α-7   LARGE

      5–20 ×

Mental retardation, seizures common MRI: hypomyelination, hydrocephalus Cognitive function largely spared Hypotonia, diffuse weakness, slow motor development

        5–20 ×

Mental retardation, seizures common Cataracts, retinal dysplasias, retinitis, glaucoma Hypoplasia of optic nerve MRI: hypomyelination, hydrocephalus, lissencephaly Hypotonia, diffuse weakness, slow motor development

      Nl     1–2 ×   Nl

Mental retardation, seizures common Cataracts, retinal dysplasias, retinitis, glaucoma MRI: hypomyelination, hydrocephalus, lissencephaly Hypotonia, restricted flexion of the neck and spine Contractures at multiple joints, normal heart Cognitive function largely spared Hypotonia, diffuse weakness, slow motor development Slowed motor development ± mental retardation Profound mental retardation, cerebral white matter changes

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retinal degeneration and optic atrophy, hydrocephalus, pachygyria-polymicrogyria, and hypoplastic or absent septum pellucidum and corpus callosum (“muscle-eye-brain” [MEB] disease). Lebenthal and colleagues later described a large Arab pedigree with CMD and patent ductus arteriosus. Some patients had contractures at birth; in others, contractures developed at a later age. The EMG disclosed a myopathic pattern and CK levels were moderately elevated. In recent years, the classification and relationships of the congenital muscular dystrophies have been clarified to some extent by a number of genetic studies (see Table 45-4). Remarkably, the major congenital muscular dystrophies share an important biologic attribute: each involves either an abnormality of a protein that binds to the dystrophin complex (e.g., laminin α2 or merosin) or an abnormality of a protein in the Golgi apparatus that is important in processing proteins (such as the dystroglycans and sarcoglycans) that interact with the dystrophin complex (see Figs. 45-2 and 45-3). The most frequent congenital dystrophy in the white population is the “Occidental” type, so called because it is characterized exclusively by muscle involvement. There are occasionally abnormal white matter signals on MRI. In approximately 50 percent of such patients, merosin is completely absent (“merosin-negative” cases) (Tomé and colleagues). Merosin, the predominant isoform of α-laminin in the basement membrane of the muscle fiber, is closely bound to alpha-dystroglycan, which in turn is bound to the dystrophin cytoskeleton (see Fig. 45-2). An absence of merosin interrupts this linkage and leads to muscle degeneration. The diagnosis of merosin deficiency can be made prenatally by immunostaining chorionic villi cells, and postnatally by staining skeletal muscle biopsy material. In most cases that are merosin deficient, the disorder is genetically linked to the merosin (laminin α2) gene that either alters or prevents expression of the protein. An additional member of the group of merosin-positive congenital muscular dystrophies is termed rigid spine syndrome (RSS). The syndrome consists of (1) infantile hypotonia with early weakness of neck muscles and poor head control; (2) stabilization with only slight decrease in muscle strength but marked loss of muscle bulk; (3) prominent contractures of spinal muscles resulting in scoliosis and rigidity in flexion and, to a lesser extent, contractures of limb joints; (4) respiratory insufficiency with onset before adolescence; and (5) normality of intellectual and cardiac function (Dubowitz; Flanigan and coworkers). This unusual CMD with RSS (CMD-RSS) arises from mutations in a gene encoding a so-called selenoprotein. In the Fukuyama type of CMD, as noted previously, fukutin is one of 5 genes whose mutations alter protein glycosylation, deranging function of both muscle and brain. Thus, the genes for MEB and the Walker-Warburg syndrome are also glycosyltransferases (respectively, POMGnT1 and POMT1), as is the aforementioned fukutin-related peptide. It has been shown that another form of CMD follows mutations of another glycosylation gene (known as LARGE).

Myofibrillar Myopathy The field of chronic and congenital myopathies has been muddied by a plethora of reports describing curious inclusions in muscle fibers under a bewildering array of

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terms: myopathy with inclusion bodies, atypical myopathy with myofibrillar aggregates; cytoplasmic body myopathy; spheroid body myopathy; myopathy with characteristic sarcoplasmic bodies and skeleton (desmin) filaments; and others. Implied by these reports is the notion that each of these structural abnormalities represented a new and distinctive myopathy. More recently, it has been demonstrated that most of these changes are the consequence of a single pathologic process, a focal dissolution of myofibrils, followed by an accumulation of degradative products (Nonaka and Engel; Ozawa and colleagues). The term myofibrillar myopathy has been proposed to encompass the entire spectrum of these pathologic changes. Most authorities now consider this to be a muscular dystrophy because mutations have been found in genes for several muscle constituent proteins. Mutations of one of the proteins that relate to the Z-disc (the connection between adjacent sarcomeres, which are the structural units of the myofibril) of muscle are the unifying feature. Some of these abnormalities can be traced to a dominant mutation in the genes coding for the filament proteins myotilin, also implicated in one of the limb-girdle dystrophies, in desmin, and in the chaperone protein αβcrystallin (Selcen and colleagues). Presumably, mutations in either gene predispose to protein aggregation, the former by destabilizing desmin and the latter by altering the capacity of the αβ-crystallin to facilitate normal desmin folding. The diagnosis of myofibrillar myopathy is usually made in adult life by muscle biopsy. Men and women are equally affected. Slowly progressive weakness of the muscles of limbs and trunk is the main clinical feature. Both proximal and distal muscles are affected, more in the legs than in the arms. Hyporeflexia is usual. Cardiac involvement, usually abnormalities of conduction, is present in approximately 25 percent of the patients. The pattern of inheritance is most often autosomal dominant, but autosomal recessive and X-linked patterns also have been described. An astonishing 63 patients were studied by Selcen and associates; their article can be consulted for further details. Genetically there is considerable heterogeneity. At the time of writing, several chromosomal loci for myofibrillar myopathy have been documented (desmin, myotilin, ZASP, αβ-crystallin, BAG3, filamin C, DNAJB6, TNP03) and more are likely to exist (Engel and Franzini-Armstrong).

Problems in Diagnosis of the Muscular Dystrophies The following are some of the common problems that arise in the diagnosis of muscular dystrophy: 1. The diagnosis of muscular dystrophy in a child who has just begun to walk or in whom walking is delayed. Tests of peak power on command cannot be used with reliability in small children. The most helpful points in identifying Duchenne dystrophy are (1) unusual difficulty in climbing stairs or arising from a crouch or from a recumbent position on the floor, showing greater weakness at the hips and knees than at the ankles; (2) unusually large, firm calves; (3) male sex; (4) high serum CK, aldolase, and myoglobin levels; (5) myopathic EMG; (6) biopsy findings; and (7) special methods of testing for dystrophin protein.

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2. The adult patient with diffuse or proximal muscle weakness of several months’ duration, raising the question of polymyositis versus dystrophy. Even biopsy may be misleading in showing a few inflammatory foci in an otherwise dystrophic picture. As a rule, polymyositis evolves more rapidly than dystrophy. It may be associated with higher CK and aldolase values than most of the dystrophies except the Duchenne and distal Miyoshi types. With these points in mind, if immunostaining of a muscle biopsy fails to reveal the diagnosis of a dystrophy, there may still be uncertainty, in which instance a trial of prednisone may be indicated for a period of 6 months. Unmistakable improvement favors polymyositis; questionable improvement (physician’s and patient’s judgment not in accord) leaves the diagnosis unsettled but suggests inclusion of body myositis or a dystrophy. Pompe disease, a treatable metabolic glycogen storage myopathy discussed elsewhere in this chapter, may simulate Becker or limb-girdle dystrophy in an adult or child. Clues to the diagnosis are early respiratory involvement, myotonic or pseudomyotonic discharges in the EMG. Muscle biopsy with immunohistochemistry establishes the diagnosis, but the standard stains may be unrevealing. 3. An adult with a very slowly evolving proximal weakness. In addition to facioscapular and limb-girdle dystrophies, myositis and inclusion body myopathy, several of the congenital polymyopathies may begin to cause symptoms or to worsen in adult years. These include central core and nemaline myopathy. Examples have been reported in the adult of mild forms of acid maltase or debrancher enzyme deficiency with glycogenosis, progressive late-stage hypokalemic polymyopathy, mitochondrial myopathy, the abovementioned Pompe disease, and carnitine myopathy. Muscle biopsy and histochemical staining of the muscle usually provide the correct diagnosis. 4. The occurrence of subacute or chronic symmetrical proximal weakness in a child or adolescent that raises the question of spinal muscular atrophy as well as of polymyositis and muscular dystrophy. EMG and muscle biopsy settle the matter by distinguishing neuropathic from myopathic changes. Some of the same problems arise in an adult with distal dystrophy. 5. Weakness of a shoulder or one leg with increasing atrophy. This is usually a result of a radiculopathy or mononeuritis, the beginning of motor system disease (progressive spinal muscular atrophy), but rarely may be the early stage of a muscular dystrophy. The first two diseases may develop silently, in mild form, and attract notice only when wasting begins (denervation atrophy takes 3 to 4 months to reach its peak). Points in favor of these acquired diseases are (1) acute or subacute onset and pain; (2) confinement of the disease to muscles originally affected and sparing of other muscles; and (3) an EMG showing denervation effects. Facioscapulohumeral dystrophy may begin with asymmetrical shoulder weakness. Biopsy is seldom performed under such circumstances, because, by temporizing, the problem eventually settles itself. Invariably muscle dystrophy becomes bilateral and symmetrical; mononeuritis

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stabilizes or recovers; motor neuron disease declares itself by the presence of fasciculations and relatively rapid progression of weakness. 6. The distinctions, in the child or adolescent, between dystrophy and one of the congenital or metabolic myopathies are considered later in this chapter.

Treatment of the Muscular Dystrophies There has, until recently, been no specific treatment for any of the muscular dystrophies that alters the course of unrelenting progression of weakness and wasting. The various vitamins, amino acids, testosterone, and drugs, such as penicillamine, recommended in the past, have all proved to be ineffective. The administration of prednisone or deflazacort has been shown to slightly slow the progression of Duchenne dystrophy for a period of up to 3 years (Fenichel et al). The optimal dose is 0.75 mg/kg given daily, but it must often be reduced because of intolerable side effects (weight gain, behavioral and gastrointestinal disorders). In recent years, there has been considerable progress in the development of genetic therapies that involve exon skipping to increase dystrophin expression (Sun; van Deutekom and colleagues; Goermans and coworkers). Eteplirsen is an exon 51 skipping drug, administered intravenously, that can be used in patients with mutations proven in that region of the DMD gene. Golodirsen and Viltolasren are antisense oligonucleotides that modify the splicing of exon 53 of the dystrophin pre-messenger RNA, leading to increased dystrophin translation in patients with mutations affecting that region of the gene. Casimersen can be used in patients mutations amenable to exon 45 skipping. Finally, ataluren is an oral drug that promotes ribosomal read-through of nonsense stop mutations to promote translation of functioning dystrophin protein. The clinical studies fully evaluating these drugs are somewhat small, but each has become approved for use in certain regions of the world. Another strategy that has been used is the injection of human myoblasts, stem cells, or satellite cells that contain a full complement of dystrophin and other structural elements into the muscles of patients with muscular dystrophy (Blau). There is an analogous effort to use the technology of viral-mediated gene delivery to allow gene and protein replacement in the recessively inherited dystrophies. Respiratory failure occurs in virtually all patients affected with Duchenne dystrophy after they become wheelchair-bound, as well as in some of the other dystrophic diseases. It may be so insidious as to become evident only as sleep apnea, as retention of carbon dioxide that causes morning headache, or as progressive weight loss that reflects the excessive work of breathing. If there are frequent episodes of oxygen desaturation, some improvement in daytime strength and alertness can be attained by assisting ventilation at night. This may be accomplished in the early stages of disease by a negative-pressure cuirasstype of device that expands the chest wall periodically or, more conveniently, by nasal-positive pressure (NIPPV [noninvasive positive-pressure ventilation] or BiPAP [bilevel positive airway pressure]). Later, positive-pressure

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Chapter 45 Diseases of Muscle

ventilation through a fenestrated tracheostomy is required that allows nighttime ventilation but leaves the patient free to speak and breathe during the day. With regard to earlier or anticipatory treatment, in patients free of respiratory failure with vital capacities between 20 and 50 percent of predicted values, a randomized trial of nasal mechanical ventilation failed to demonstrate improvement or prolonged survival (Raphael et al). There has been a clinical impression that even more severely affected patients can be managed at home for prolonged periods with respiratory assistance. Needless to say, the common complications of muscular dystrophy—pulmonary infections and cardiac decompensation—must be treated symptomatically. Surgical management of cataracts is indicated when they become mature. As noted earlier, a vital element in the care of patients with certain of the dystrophies is monitoring for early evidence cardiac arrhythmias. In disorders such as myotonic dystrophy, Emery-Dreifuss dystrophy, the myofibrillar myopathies, and some of the mitochondrial disorders, it is imperative that cardiac status should be evaluated on a regular basis (typically yearly) with ECG and echocardiography and periodically with 24-h rhythm monitoring if the ECG is abnormal or the patient reports episodic symptoms referable to an arrhythmia such as lightheadedness, palpitations, or dyspnea. The timely use of cardiac pacemakers or defibrillators, implemented at the earliest sign of arrhythmia or prophylactically, is often needed in this patient population to reduce the chance of sudden death. Mexiletine has been shown to reduce myotonia, especially in DM2 and the nondystrophic myotonias but, like quinine that caused rare cardiac arrhythmias, is also now out of favor by some clinicians (Statland and coworkers). Further discussion of myotonia and its treatment can be found in Chap. 46. Testosterone has been found to increase muscle mass in patients with myotonic dystrophy, but was of no value in preserving strength or lessening myotonia (Griggs et al, 1989). Maximal resistance exercises, if begun early, can strengthen muscles in Duchenne, limb-girdle, and facioscapulohumeral dystrophies (Vignos). One study of this intervention showed that none of the muscles was weaker at the end of a year than at the beginning. Cardiorespiratory function after endurance exercise was not significantly improved. Contractures were reduced by passive stretching of the muscles 20 to 30 times a day and by splinting at night. If contractures have already formed, fasciotomy and tendon lengthening are indicated in patients who are still ambulating, but this is not recommended early in the course of the disease. Maintenance of ambulation and upright posture will delay scoliosis. In general, preventive measures are more successful than restorative ones. From such observations it may be concluded that two factors are of importance in the management of patients with muscular dystrophy: avoiding prolonged bed rest and encouraging the patient to maintain as full and normal a life as possible. These help prevent the rapid worsening associated with inactivity and conserve a healthy attitude of mind. Obesity should be avoided; this requires careful attention to diet. Swimming is a useful exercise. Massage and electrical stimulation are probably worthless.

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The education of children with muscular dystrophy should continue, with the aim of preparing them for a sedentary occupation. Prevention by prenatal counseling is available for most dystrophies, but proper diagnosis is essential. Special centers provide the genetic and psychological services necessary to carry this out properly.

THE METABOLIC MYOPATHIES Two main classes of metabolic diseases of muscle are recognized—one is traceable to a primary, or hereditary, metabolic abnormality of the muscle itself; another in which the myopathy is secondary to a disorder of endocrine function, that is, to disease of the thyroid, parathyroid, pituitary, or adrenal gland. Yet a third group of myopathies is the result of a large variety of myotoxic drugs and other chemical agents; they are addressed separately. The hereditary metabolic myopathies are of special interest because they reveal certain aspects of the complex chemistry of muscle fibers. Indeed, each year brings to light some new genetically determined enzymopathy of muscle. As a consequence, a number of diseases formerly classified as dystrophic or degenerative have been added to the enlarging list of metabolic myopathies. There are now so many of them that only the most representative can be presented in a textbook of neurology.

The Nature of Primary Metabolic Myopathies The chemical energy for muscle contraction is provided by the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP); ATP is restored by phosphocreatine and ADP acting in combination. These reactions are particularly important during brief, high-intensity exercise. During periods of prolonged muscle activity, rephosphorylation requires the availability of carbohydrates, fatty acids, and ketones, which are catabolized in mitochondria. Glycogen is the main sarcoplasmic source of carbohydrate, but blood glucose also moves freely in and out of muscle cells as needed during sustained exercise. The fatty acids in the blood, derived mainly from adipose tissue and intracellular lipid stores, constitute the other major source of energy. Carbohydrate is metabolized during aerobic and anaerobic phases of metabolism; the fatty acids are metabolized only aerobically. Resting muscle derives approximately 70 percent of its energy from the oxidation of long-chain fatty acids. As stated earlier, the circumstances during exercise are somewhat different. During a short period of intense exercise, the muscle uses carbohydrate derived from glycogen stores; myophosphorylase is the enzyme that initiates the metabolism of glycogen. With longer aerobic exercise, blood flow to muscle and the availability of glucose and fatty acids are increased. At first, glucose is the main source of energy during exercise; later, with exhaustion of glycogen stores, energy is provided by oxidation of fatty acids. Thus, muscle failure at a certain phase of exercise is predictive of the type of energy failure. A rising blood concentration of gamma-hydroxybutyrate reflects the increasing

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Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

oxidation of fatty acids, and an increase in blood lactate reflects the anaerobic metabolism of glucose. The cytochrome oxidative mechanisms are essential in both aerobic and anaerobic muscle metabolism; these mechanisms are considered in Chap. 36 in relation to the mitochondrial diseases in which muscle tissue is prominently involved, and they are referred to here only briefly. It follows from these observations that the efficiency and endurance of muscular contraction depend on a constant supply of glycogen, glucose, and fatty acids, and on the adequacy of the enzymes committed to their metabolism. Biochemical derangements in the storage, breakdown, or utilization of these substrates give rise to a large number of muscle disorders, the most important of which are elaborated in the following pages.

Glycogen Storage Myopathies An abnormal accumulation of glycogen in the liver and kidneys was described by von Gierke in 1929; shortly thereafter, Pompe (1932) reported a similar disorder involving cardiac and skeletal muscle. Major contributions to our understanding of glycogen metabolism were made by McArdle, by Cori and Cori, and by Hers, who discovered the deficiency of acid maltase in Pompe disease and enunciated the concept of inborn lysosomal diseases (see Chap. 36). Since then, many nonlysosomal enzyme deficiencies of muscle and other organs have been identified and have become the basis of the classification presented in Table 45-5. These enzymatic deficiencies alter the metabolism of many cells, but most strikingly those of the liver, heart, and skeletal muscle. In about half of affected individuals, a chronically progressive or intermittent myopathic syndrome is the major manifestation of the disease. It is a curious fact, that with the exception of the rare phosphoglycerate kinase deficiency (X-linked recessive inheritance), all the glycogenoses are inherited as autosomal recessive traits. The most impressive and common of these glycogen storage diseases from the standpoint of the clinical neurologist are 1,4-glucosidase (acid maltase) and myophosphorylase deficiencies.

Acid Maltase Deficiency (Glycogenosis Type II; Pompe Disease and Related Disorders, GAA Mutation) A deficiency of the enzyme acid maltase (also called acid alpha-glucosidase and due to mutations in the GAA gene) takes three clinical forms, of which the first (Pompe disease) is the most serious. Pompe disease typically develops in infancy, between 2 and 6 months; dyspnea and cyanosis call attention to enlargement of the heart, and the liver may be enlarged as well. The skeletal muscles are weak and hypotonic, although their bulk may be increased. The tongue may be enlarged, giving the infant a cretinoid appearance. Hepatomegaly, while often present, is not pronounced. Exceptionally, the heart is normal in size and the CNS and muscles bear the brunt of the disorder. The clinical picture then resembles infantile spinal muscular atrophy (Werdnig-Hoffmann disease) and, to add to difficulty in differential diagnosis, there may be fasciculations. The infantile disease is rapidly progressive and ends fatally in a few months. The EMG shows

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myopathic changes, but there are, in addition, fibrillation potentials, heightened insertional activity, and pseudomyotonia. Large amounts of glycogen accumulate in muscle, heart, liver, and neurons of the spinal cord and brain. All tissues lack acid maltase (also called alphaglucosidase) because of a mutation in its gene. In the second (childhood) form, onset is during the second year, with delay in walking and slowly progressive weakness of shoulder, pelvic girdle, and trunk muscles. The toe walking, waddling gait, enlargement of calf muscles, and lumbar lordosis resemble those of Duchenne dystrophy. Cardiomyopathy is exceptional, hepatomegaly is less frequent than in the infantile form, and developmental delay is present in a minority. Death occurs between 3 and 24 years of age, usually from ventilatory failure and recurrent pulmonary infections. In the third, or adult, form there is a more benign truncal and proximal limb myopathy that is slowly progressive over many years and death is usually the result of weakness of respiratory muscles. At times, the only severe weakness is of the diaphragm, as in the case reported by Sivak and colleagues, making adult acid maltase deficiency part of a select group of neuromuscular disorders that may present in this way (along with motor neuron disease, nemaline myopathy, and myasthenia gravis). The liver and heart are not enlarged. CK values can be normal or slightly increased. The EMG discloses a number of abnormalities— brief motor unit potentials, fibrillation potentials, positive waves, bizarre high-frequency discharges, and occasional myotonic discharges (without clinical evidence of myotonia). The disease must be differentiated from other chronic adult myopathies, including polymyositis and the endocrine myopathies, and from motor neuron disease. Aside from the elevation of the muscle-derived enzymes CK and of aldolase, blood studies are normal. A simply implemented dried blood spot screening test for alpha-glucosidase has been developed and, if it shows that there is no enzyme detectable, a biopsy can be omitted and the clinician can proceed to genetic testing. This screening test is particularly important in babies with suspected disease, as they are susceptible to general anesthesia that may be used to accomplish a biopsy. The diagnosis of acid maltase deficiency in early onset cases is readily confirmed by muscle biopsy, but lateronset cases may show only nonspecific changes. The main features, when found, are vacuoles containing periodic acid-Schiff (PAS)–positive diastase-digestible material; they stain intensely for acid phosphatase. The glycogen particles lie in aggregates; electron microscopy shows some of them to occupy lysosomal vesicles and others, to lie free. The myofibrils are disrupted and some muscle fibers degenerate. Glycogen accumulation is more pronounced in type 1 fibers. The earlier mentioned blood-spot test is useful in cases, particularly those of late onset, that have the typical characteristics of disease but display only nonspecific histopathologic changes. As indicated earlier, in the more severe infantile form of acid maltase deficiency, heart muscle and the large neurons of the spinal cord and brainstem may also accumulate glycogen and degenerate. The difference in severity between infant and adult forms relates to the completeness

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Chapter 45 Diseases of Muscle

of enzyme deficiency, but possibly other factors are also at work as more than one of the three types may occur in the same family. Treatment  The adult who is threatened by respiratory failure should be observed frequently with measurements of vital capacity and blood gases. A low-carbohydrate, high-protein diet may be beneficial (Umpleby and coworkers). Respiratory support (rocking bed, nasal positive pressure, cough-assist devices, and negative-pressure cuirass) may prolong life. Enzyme replacement therapy is available to treat Pompe disease. Recombinant acid alpha-glucosidase has been shown to prolong survival in the typical infantile Pompe case, but the benefits are modest in later-onset cases, although walking was improved and pulmonary function stabilized in one series (van der Ploeg et al). The agent is injected intravenously every 2 weeks. The same approach has been used in cases of infantile onset (Kishani et al).

Myophosphorylase Deficiency (Type V Glycogenosis; McArdle Disease, PYGM Mutation) and Phosphofructo­ kinase Deficiency (Type VII Glycogenosis; Tarui Disease, PFKM Mutation) These disorders are considered together because they are clinically virtually identical and both express themselves by the development of muscle cramps after exercise (actually true physiologic contractures, as described in Chap. 46). In both diseases, an otherwise normal child, adolescent, or adult begins to complain of weakness and stiffness and sometimes pain on using the limbs. Muscle contraction and relaxation are normal when the patient is in repose, but strenuous exercise, either isometric (carrying heavy weights) or dynamic (climbing stairs or walking uphill), causes the muscles to shorten (contracture), a result of their inability to relax. After vigorous exercise, episodes of myoglobinuria are common, in some cases resulting in renal failure. With mild sustained activity, the patient experiences progressive muscle fatigue and weakness, which diminish following a brief pause. The patient can then resume his activities at the original pace (“second-wind” phenomenon). During the second-wind phase, the patient copes with his symptoms by increasing cardiac output and substituting free fatty acids and bloodborne glucose for muscle glycogen (Braakhekke et al). The primary abnormality in McArdle disease is a deficiency of myophosphorylase, which prevents the conversion of glycogen to glucose-6-phosphate. Phospho­ fructokinase deficiency (Tarui disease) interferes with the conversion of glucose-6-phosphate to glucose-1-phosphate; the defect in the latter condition is also present in red blood cells (Layzer et al). The mutations for the conditions are named above and located on different chromosomes and analysis of DNA from the patient’s leukocytes can be used for genetic diagnosis. The muscle (M) subunit of the phosphofructokinase protein in Tarui disease is at fault. This defect predominates in Ashkenazi Jewish men. Clinical variations of these disorders, particularly in severity and age of onset, are well known. Some patients, with no previous symptoms of cramps or myoglobinuria, develop progressive weakness of limb muscles in the sixth

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or seventh decade. One of these older patients came to our attention because of chronically elevated levels of CK and mild muscle cramping after climbing stairs. In others, rapidly progressive weakness became evident in infancy, with early death from respiratory failure. Curiously, these extreme forms are not directly related to severity of the enzyme deficiencies. The contracted muscles, unlike muscles in other involuntary spasms, no longer use energy and they are more or less electrically silent (i.e., no electrical activity is recorded from maximally contracted muscle during the cramps). Moreover, the muscle does not produce lactic acid. The shortened state is spoken of as physiologic contracture as discussed in the introductory sections of this chapter. Ischemia contributes to this condition by denying glucose to the muscle, which then cannot function adequately on fatty acids and nonglucose substrates. These features are the basis of the forearm ischemic exercise test, which, although controversial in its use and sensitivity, may be helpful if performed carefully. An indwelling catheter is placed in the antecubital vein and a basal blood sample is obtained. Above the elbow, a sphygmomanometer cuff is inflated to exceed arterial pressure. After 1 min of vigorous hand exercise (30 hand closures against an ergometer), blood samples are obtained at 1 and 3 min. Normal individuals show a 3- to 5-fold increase in blood lactate. In patients with either McArdle or Tarui disease, the lactate fails to rise. This procedure has reportedly caused a localized rhabdomyolysis (Meinck et al), for which reason Griggs and associates recommend that the test be carried out without a blood pressure cuff. Problems with consistency in conducting the test and in processing blood samples for lactate limit its validity unless it is performed by experienced individuals and laboratories. Definitive diagnosis depends more on the histochemical stains of biopsied muscle, which reveal an absence of phosphorylase activity (in McArdle disease) or of phosphofructokinase activity (in Tarui disease). Genetic analysis, can be used to corroborate the diagnosis, but it is unnecessary if the histochemical tests are definitive. Treatment  The main treatment is a planned reduction and intermittency in physical activity. Sucrose, taken as 75 g in a beverage, has been shown to cause a shortlived improvement in exercise tolerance, and it has been proposed that exercise-induced rhabdomyolysis can be avoided by a well-timed drink (Vissing and Haller). Fructose and creatine taken orally are also said to be helpful in some cases, but the reported results are not as impressive as they are for sucrose. Improvement has also been described after the administration of glucagon (Kono et al) and with a high-protein diet (Slonim and Goans), but these effects are not consistent.

Other Forms of Glycogenosis (See Table 45-5) Of the remaining glycogen storage diseases, type III (debranching enzyme deficiency; Cori-Forbes disease, AGL Mutation) affects muscle but only inconsistently. The childhood form is characterized mainly by a benign hepatopathy, sometimes accompanied by diminished muscle strength and tone. An adult form beginning in the third and fourth decades presents with proximal and distal myopathy. The course is slowly progressive and may

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MYOGLOBINURIA

      +   + + + + + +

ORGANOMEGALY

+

    ±

+

 

 

+ +    

+ + + +

+

+

 

     

 

POSITIVE ISCHEMIC EXERCISE TEST

Ad-A

A

I, C-A

I C A C-A I-C C, Ad, A C-A I, C, Ad, A

ONSET OF DISEASEb

Muscle Muscle, RBC Muscle Muscle

Muscle, RBC

Muscle, WBC, chorionic villus, amniotic fluid Muscle Muscle Muscle, WBC, fibroblasts Muscle, WBC fibroblasts amniotic fluid Muscle, WBC

ENZYME-DEFICIENT CELLS FOR ASSAY

 

 

 

+     + +     +

HYPOTONIA

       

 

 

 

+ +  

+

MEMBRANE-LINED VACUOLES WITH GLYCOGEN

+

+

+

          + + +

EXERCISE INTOLERANCE (MYALGIA, CRAMPS, STIFFNESS, ± MYOGLOBINURIA)

+ ± + +

+

+

+

+ + +

       

 

 

+

+ +  

+

INTRA-AND EXTRAVACUOLAR ACID PHOSPHATASE

INCREASED GLYCOGEN IN SUBSARCOLEMMA AND INTERMYOFIBRILLAR AREAS

+

 

 

+

+ + + + + + + +

MYOPATHY ± ATROPHY

+

 

 

          + +  

EARLY FATIGUE AND SECOND WIND

       

+

 

+

     

 

AMYLOPECTIN DEPOSITS

 

 

 

+ + +          

SEVERE RESPIRATORY MUSCLE WEAKNESS

HISTOCHEMISTRY

Absence of myophos-phorylase Absence of phosphofructokinase        

 

     

 

 

 

 

      + + + +  

CONTRACTURES

b

All types: elevated creatine kinase (CK); myopathic electromyogram, with increased irritability and myotonia. A, adult; Ad, adolescence; C, childhood; I, infancy. Additional features (not charted above): feeding difficulties, II Pompe; retarded growth, III; neurologic abnormalities, II Pompe, IX; seizures, VIII, IX; hypoglycemic seizures, III; jaundice, VII, IX; cirrhosis, IV; generalized scaling erythema, XI; firm consistency of muscle, II Pompe; elevated serum aspartate aminotransferase and lactic dehydrogenase, II; elevated serum bilirubin, VII, IX; failure of lactate dehydrogenase to rise proportionally to elevation of CK, XI; fasting hypoglycemia, III; hemolytic anemia and reticulocytosis, VII, IX; hemoglobinuria, IX; excessive rise in serum pyruvates during ischemic exercise test, XI.

a

XI

X

IX

Acid maltase Acid maltase Acid maltase Debrancher Branching Myophosphorylase Phosphofructokinase Phosphorylase B kinase Phosphoglycerate kinase Phosphoglycerate mutase Lactic dehydrogenase

DEFECTIVE ENZYME

II (Pompe) II II III (Cori-Forbes) IV (Andersen) V (McArdle) VII (Tarui) VIII

GLYCOGENOSIS TYPE (PROPER NAME)

THE GLYCOGENOSES AFFECTING SKELETAL MUSCLEa

Table 45-5

Chapter 45 Diseases of Muscle

be associated with wasting of the leg and hand muscles. Several patients have developed weakness during adult life complained of rapid fatigue and aching of muscles, occurring with exertion and first noticed at an early age. Serum CK values were elevated and the EMG showed a myopathic picture as well as increased insertional activity, pseudomyotonic discharges, and fibrillation potentials. Rarely in the adult form, glycogen also accumulates in the peripheral nerves, giving rise to mild symptoms of polyneuropathy. The enzymatic defect is one of amylo-1, 6-glucosidase deficiency. Disturbance of skeletal muscle is even less prominent in type IV glycogenosis (branching enzyme deficiency, or Andersen disease, which is also implicated in the polyglucosan disease that causes a special neuropathy discussed in Chap. 43, a motor system disease with flaccid bladder, or a leukoencephalopathy with dementia). This is a progressive disease of infancy and early childhood, characterized by cirrhosis and chronic hepatic failure, usually with death in the second or third year. Hepatomegaly as a result of accumulation of an abnormal polysaccharide is a universal finding. Muscle weakness and atrophy, hypotonia, and contractures occur less regularly and are overshadowed by the liver disease. The diagnostic hallmark of the myopathy is the presence of basophilic, intensely PAS-positive polysaccharide granules in skin and muscle. The remaining nonlysosomal glycogenoses (types VIII through XI) need only be mentioned briefly. They are all rare and clinically heterogeneous, and a myopathy— characterized by intolerance to exercise, cramps, myoglobinuria, elevated CK, and, sometimes, renal failure—has been observed in a small proportion of them. Phosphoglycerate kinase deficiency (type IX glycogenosis, PGK1 mutation) differs in that it is inherited as a sex-linked recessive trait localized to chromosome Xq13. Hemolytic anemia—becoming evident soon after birth—mental retardation, seizures, and tremor are other features that set this glycogenosis apart from the others. The myopathic features of the lysosomal and nonlysosomal glycogenoses are listed in Table 45-5 (Griggs and associates; Engel and Franzini-Armstrong).

Disorders of Lipid Metabolism Affecting Muscle (Lipid Myopathies) Although it has long been known that lipids are an important source of energy in muscle metabolism (along with glucose), it was only in 1970 that W.K. Engel and associates reported the abnormal storage of lipid in muscle fibers attributable to a defect in the oxidation of longchain fatty acids. The subjects of their report were twin sisters who had experienced intermittent cramping of muscles associated with myoglobinuria after vigorous exercise. In 1973, A.G. Engel and Angelini described a young woman with progressive myopathy, lipid storage predominantly in type 1 muscle fibers, and a deficiency of muscle carnitine, a cofactor required for the oxidation of fatty acids. Since that time, highly sophisticated biochemical techniques have greatly expanded the study of fatty acid metabolism and the identification of many of the primary defects.

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Carnitine (β-hydroxy-gamma-N-trimethylaminobutyrate), derived from lysine and methionine, plays a central role in the metabolism of fatty acids. Approximately 75 percent of carnitine comes from dietary sources (red meat and dairy products); the remainder is synthesized in the liver and kidneys. Practically all of the body carnitine is stored in muscle, where it has two main functions: (1) transporting long-chain fatty acylcoenzyme As (CoAs) from the cytosol compartment of the muscle fiber into the mitochondria, where they undergo beta-oxidation, and (2) preventing the intramitochondrial accumulation of acyl-CoAs, thus protecting the muscle cell from the membrane-destabilizing effects of these substances. To be oxidized, the long-chain fatty acids undergo a series of biochemical transformations. First they are activated to corresponding acyl-CoA esters by acyl-CoA synthetase, which is located on the outer mitochondrial membrane. Because the inner mitochondrial membrane is impermeable to acyl-CoA esters, they are transferred into the mitochondria as acylcarnitine esters. This is accomplished by carnitine palmitoyltransferase I (CPT I), also located on the outer mitochondrial membrane. A second carnitine palmitoyltransferase (CPT II), bound to the inner face of the inner mitochondrial membrane, reconverts the acylcarnitines to fatty acyl-CoAs, which undergo betaoxidation within the mitochondrial matrix (DiMauro and colleagues; DiDonato and Taroni). Isoforms of CPT are critically involved in this process at the inner and outer membranes of the mitochondria. Despite the many biochemical abnormalities that have been identified in the fatty acid metabolic pathways, there are essentially three clinical patterns by which these defects are expressed: 1. One constellation of symptoms referred to as the encephalopathic syndrome has its onset in infancy or early childhood. Its very first manifestation may be sudden death (sudden infant death syndrome [SIDS]), or there may be vomiting, lethargy and coma, hepatomegaly, cardiomegaly, muscular weakness, and hypoketotic hypoglycemia, with prominent hyperammonemia, that is, a Reye-like syndrome. Undoubtedly, instances of this syndrome have not been recognized as abnormalities of fatty acid metabolism but have been designated incorrectly as the Reye syndrome or as SIDS. They are discussed in Chap. 36 with other inherited metabolic disorders. 2. A second (myopathic) syndrome appears in late infancy, childhood, or adult life and takes the form of a progressive myopathy, with or without cardiomyopathy. The myopathy may follow episodes of hypoketotic hypoglycemia or may develop de novo. 3. The third syndrome is one that usually begins in the second decade of life and is induced by a sustained period of physical activity or fasting. It is characterized by repeated episodes of rhabdomyolysis with or without myoglobinuria. 4. Summarized in the following text are the main disorders of fatty acid metabolism that affect skeletal muscle; these are rare but interesting diseases.

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Primary Systemic Carnitine Deficiency (SLC22A5 Mutation) To date, this is the only form of carnitine deficiency that can be considered primary (see further on for discussion of the secondary types). Its main clinical features are progressive lipid storage myopathy and cardiomyopathy, sometimes associated with the signs of hypoketotic hypoglycemia. There is no dicarboxylic aciduria, in distinction to the secondary beta-oxidation defects, in all of which dicarboxylic aciduria is present. The cardiomyopathy, which is fatal if untreated, responds to oral administration of L-carnitine, 2 to 6 g/d. This disorder is inherited as an autosomal recessive trait. In these families there is frequently a history of sudden unexplained death in siblings, so that early identification of affected children is essential.

Carnitine Palmitoyltransferase Deficiency (CPT1A Mutation) This disease is also inherited as an autosomal recessive trait and the gene encoding carnitine palmitoyltransferase (CPT) has been identified. There are three types: types I, IIA, and IIB. Type I is the most common. It affects males predominantly, beginning in the second decade of life. Attacks of myalgia, cramps, and muscle weakness, “tightness,” and stiffness are precipitated by sustained (although not necessarily intense) exercise and less often by a prolonged period of fasting. Fever, anesthesia, drugs, emotional stress, and cold have been additional but rare precipitating events. The attacks vary greatly in frequency. They are usually accompanied by myoglobinuria, with resultant renal failure in about one-fourth of cases (DiMauro et al, 1973). Rest does not abort the attacks and, once initiated, there is no second-wind phenomenon. There are no warning signs of an impending attack. Any muscle group may be affected. Persistence of weakness after an attack is uncommon. Serum CK rises to high levels not only during attacks but also after vigorous exercise without myoglobinuria. A mild form is more likely to occur in females. In type I deficiency, necrosis of muscle fibers, particularly type I fibers, occurs during attacks, followed by regeneration. Between attacks, the muscle appears normal. In type IIA, lipid bodies accumulate in the liver, and in type IIB, excess lipid is detected in heart, liver, kidneys, and skeletal muscle. CPT is either undetectable or greatly reduced in muscle, and assays are now available for the measurement of CPT I and II in circulating lymphocytes and cultured fibroblasts. Testing for the mutation is available. Treatment  A high-carbohydrate, low-fat diet, ingestion of frequent meals, and additional carbohydrate before and during exercise appear to reduce the number of attacks. Patients need to be instructed about the risks of prolonged exercise and skipped meals. Recently, the use of bezafibrate, a drug used for dyslipidemia, has been helpful in patients with mild CPT II.

Secondary Systemic Carnitine Deficiency This is occasionally the result of severe dietary deprivation or impaired hepatic and renal function. Such instances have been observed in patients with alcoholic–nutritional

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diseases and kwashiorkor, in premature infants receiving parenteral nutrition, in patients with chronic renal failure undergoing dialysis, and rarely, as a complication of valproate therapy. However, most cases of systemic carnitine deficiency are a result of defects of beta-oxidation, described as follows.

Other Lipid Myopathies Carnitine acylcarnitine translocase deficiency  This condition causes muscular weakness, cardiomyopathy, hypoketotic hypoglycemia, and hyperammonemia, which develop in early infancy and usually lead to death in the first month of life. Long-chain acyl-CoA dehydrogenase deficiency (ACLDVL mutation)  The presentation is in infancy, with recurrent episodes of fasting hypoglycemic coma, muscle weakness, and myoglobinuria, and sometimes sudden death. Survivors may develop a progressive myopathy. Administration of carnitine improves the cardiac disorder and prevents metabolic attacks. Medium-chain acyl-CoA dehydrogenase deficiency (ACADM mutation)  This is a cause of SIDS and a Reye-like syndrome. About half of survivors develop a lipid-storage myopathy in childhood or adult life. The abnormal gene has been mapped to chromosome 1p31. Oral L-carnitine may be of therapeutic value. Short-chain acyl-CoA dehydrogenase deficiency This myopathy in a limb-girdle distribution may appear initially in older children and adults, or it may follow episodic metabolic disorders in infancy. Long-chain hydroxyacyl-CoA dehydrogenase deficiency  This is a disease of infancy marked by episodes of Reyelike syndrome, hypoketotic hypoglycemia, lipid storage myopathy, cardiomyopathy, and sometimes sudden death. Short-chain hydroxyacyl-CoA dehydrogenase deficiency  This presents as an episodic disorder such as the one described previously, long-chain hydroxyacyl-CoA dehydrogenase deficiency (HAD), but its onset is in adolescence. Recurrent attacks may be associated with myoglobinuria. Multiple acyl-CoA dehydrogenase deficiency; glutaric aciduria type II  Some cases are caused by a deficiency of electron transfer flavoprotein (ETF) and others by a deficiency of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). In the severest form of multiple acyl-CoA dehydrogenase deficiency (MADD), infants are born prematurely and many die within the first week of life; added to the common metabolic abnormalities are multiple congenital defects and a characteristic “sweaty feet” odor. In less severe cases, the congenital anomalies are absent. In the least severe form, the onset may be in late infancy (with episodic metabolic disturbances) or in childhood or adult life (with a lipid storage myopathy and a deficiency of serum and muscle carnitine). The prenatal diagnosis of glutaric aciduria type II (GA II) is suggested by the finding of large amounts of glutaric acid in the amniotic fluid. In the milder forms of the disease, oral riboflavin (100 to 300 mg/d) may be helpful. Muscle coenzyme Q10 deficiency This condition presents as a slowly progressive lipid storage myopathy from early childhood. The basic defect is in coenzyme Q10 in the respiratory chain of muscle mitochondria.

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Chapter 45 Diseases of Muscle

The administration of coenzyme Q10 has improved the myopathic weakness. Neutral lipid storage diseases (Chanarin-Dorfman disease, PNPLA2 mutation)  These abnormalities of lipid metabolism are distinct from the beta-oxidation defects; they occur in two forms, Chanarin disease, which is characterized by ichthyosis, and a form without skin changes. A progressive myopathy is combined with neurologic manifestations, such as developmental delay, ataxia, neurosensory hearing loss, and microcephaly. The lipid material is stored in muscle as triglyceride droplets that are nonlysosomal and non–membrane-bound.

ENDOCRINE MYOPATHIES Thyroid Myopathies Several myopathic diseases are related to alterations in thyroid function: (1) chronic thyrotoxic myopathy; (2) exophthalmic ophthalmoplegia (Graves disease); (3) myasthenia gravis associated with thyrotoxicosis; (4) periodic paralysis associated with thyrotoxicosis; and (5) muscle hypertrophy and slow muscle contraction and relaxation associated with myxedema and cretinism.

Chronic Thyrotoxic Myopathy This disorder, first noted by Graves and Basedow in the early nineteenth century, is characterized by progressive weakness and wasting of the skeletal musculature, occurring in conjunction with overt or covert (“masked”) hyperthyroidism. The thyroid disease is usually chronic and the goiter is usually of the nodular rather than the diffuse type. Exophthalmos and other classic signs of hyperthyroidism are often present but need not be. This complication of hyperthyroidism is most frequent in middle age, and men are more susceptible than women. Some degree of myopathy has been found when sought in more than 50 percent of thyrotoxic patients, although the manifestations may be subtle. The onset is insidious, and the weakness progresses over weeks and months. The muscular disorder as noted is most often mild in degree, but it may be so severe as to suggest progressive spinal muscular atrophy (motor system disease). Muscles of the pelvic girdle and thighs are weakened more than others (Basedow paraplegia), although all are affected to some extent, even the bulbar muscles and, albeit rarely, the ocular ones. However, the shoulder and hand muscles show the most conspicuous atrophy (not an obligatory feature). Tremor and twitching during contraction may occur, but we have not seen fasciculations. The tendon reflexes are of average briskness, possibly more lively than normal. Both the contraction and relaxation phases of the tendon reflexes are shortened, but usually this cannot be detected by the clinician. Serum concentrations of muscle enzymes are not increased and may be reduced. The EMG is typically normal, although the action potentials may be abnormally brief or polyphasic. Biopsies of muscle, except for slight atrophy of both types 1 and 2 fibers and an occasional degenerating fiber, have been normal. Muscle power and

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bulk are gradually restored when thyroid hormone levels are reduced to normal levels.

Exophthalmic Ophthalmoplegia (Graves Ophthalmo­ pathy) (See discussion in Chap. 13) This refers to the cooccurrence of weakness of the ocular muscles and exophthalmos in patients with Graves disease (pupillary and ciliary muscles are always spared). The exophthalmos varies in degree, sometimes being absent at an early stage of the disease, and it is not in itself responsible for the muscle weakness. Often there is some degree of orbital pain. Both the exophthalmos and the weakness of the extraocular muscles may precede the signs of hyperthyroidism, be associated with the other classic features of hyperthyroidism (tachycardia, weight loss, tremor), or may follow effective treatment of the disorder. The eye signs, both ocular paresis and exophthalmos, become apparent over days or weeks and may occasionally be unilateral, especially at the onset. Any of the external eye muscles may be infiltrated, usually one more than others, accounting for strabismus and diplopia; the inferior and medial recti are the most frequently affected, but upward movements are usually limited as well. The typical but not invariable sign of lid retraction imparts a staring appearance. Subtle exophthalmos can be appreciated by standing above and behind the seated patient and observing the relative positions of the lids and the eyelashes. Conjunctival edema and vascular engorgement over the insertions of the medial and lateral rectus muscles can be appreciated by inspecting and palpating the globe in its extreme lateral positions. These swollen muscles are easily visible on orbital ultrasonography, CT, and MRI. The differential diagnosis of this imaging appearance is from orbital pseudotumor, a usually painful condition, which is discussed in Chap. 13. Examination of the eye muscles in biopsy and autopsy material has shown prominent fibroblasts, many degenerated fibers, and infiltrations of lymphocytes, mononuclear leukocytes, and lipocytes; hence the term infiltrative ophthalmopathy. These histopathologic findings are suggestive of an autoimmune disease—a hypothesis supported by the finding of serum antibodies that react (inconsistently) with extracts of eye muscles (Kodama et al). Possibly the antibodies target glycosaminoglycans of the orbital fibroblasts. A sensitivity of muscle fibers to beta-adrenergic activity caused by excessive thyroid hormone has also been postulated. Other factors are almost certainly involved, such as the small size of oculomotor motor units, the absence of dystrophin, and the rich mitochondrial content. Treatment  Because the ophthalmoparesis often runs a self-limited course, as does the exophthalmos, therapy is difficult to evaluate. Certainly the maintenance of a euthyroid state seems desirable (Dresner and Kennerdell). If the exophthalmos is slight, topical applications of adrenergic blocking agents (guanethidine eye drops, 5 percent) and ophthalmic ointment to prevent corneal drying are adequate. Severe exophthalmos, marked by periorbital and conjunctival edema, and the extraocular muscle weakness may be partially controlled by high doses of corticosteroids (about 80 mg/d prednisone). Because of the hazards of protracted corticosteroid therapy, this approach should be

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Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

reserved for patients who would otherwise require surgical intervention to decompress the contents of the orbit. In a number of such cases, it has been possible for the patient treated with corticosteroids to weather the crisis for several weeks or more and avoid the damaging effects of extreme exophthalmos and risks of surgery. Exophthalmos of a degree that threatens to injure the cornea or cause blindness requires tarsorrhaphy or decompression by removal of the roof of the orbit. Teprotumumab is a monoclonal insulin growth factor-receptor antagonist that substantially improves outcomes in patients with more severe disease (Douglas).

Thyrotoxic Hypokalemic Periodic Paralysis This disorder closely resembles familial hypokalemic periodic paralysis (as described in Chap. 46). It consists of attacks of mild to severe weakness of the muscles of the trunk and limbs; usually the cranial muscles are spared. The weakness develops over a period of a few minutes or hours and lasts for part of a day or longer. In some series of patients with periodic paralysis, as many as half have had hyperthyroidism and most of them have been Asian males. Unlike the typical hypokalemic form, thyrotoxic periodic paralysis is not a familial disorder and its onset is usually in early adult life. Nevertheless, in most of the thyrotoxic cases, the serum potassium levels have been low during the attacks of weakness and the administration of 100 to 200 mg of potassium chloride has terminated the episodes. Propranolol in doses of 160 mg daily in divided doses is also helpful in preventing the episodes. More importantly, effective treatment of the hyperthyroidism abolishes the periodic attacks of weakness in more than 90 percent of cases. A mutation in the potassium channel, Kir2.6, has been found to confer susceptibility to the disease. Other aspects of periodic paralysis are discussed in Chap. 46.

Myasthenia Gravis With Hyperthyroidism Myasthenia is discussed fully in Chap. 46. Here only a few remarks are made on its special relationship to thyrotoxicosis. Myasthenia gravis in its typical autoimmune, anticholinesterase-responsive form may accompany hyperthyroidism or rarely, hypothyroidism, which are also autoimmune in nature. Approximately 5 percent of patients with myasthenia have hyperthyroidism and the frequency of myasthenia gravis in patients, while low, is 20 to 30 times higher in hyperthyroidism than in the general population. Either condition may appear first, or they may coincide. The weakness and atrophy of chronic thyrotoxic myopathy may be added to that of the myasthenia without appearing to affect the requirement for or response to anticholinesterase medications. By contrast, hypothyroidism, even of mild degree, seems to aggravate the weakness of myasthenia gravis, greatly increasing the need for pyridostigmine and at times inducing a myasthenic crisis. In these cases, thyroxine is beneficial and, with respect to myasthenia, restores the patient to the status that existed before the onset of thyroid insufficiency. The myasthenia should probably be regarded as an autoimmune disease independent of the thyroid disease and each must be treated separately.

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Hypothyroid Myopathy Abnormalities of skeletal muscle consisting of diffuse myalgia and increased volume, stiffness, and slowness of contraction and of relaxation are common manifestations of hypothyroidism, whether in the form of myxedema or cretinism. These changes probably account for the relatively large tongue and dysarthria that one observes in myxedema. Weakness, however, is not a prominent feature. The presence of action myospasm and myokymia (both of which are rare) and of percussion myoedema and slowness of both the contraction and relaxation phases of tendon reflexes assists the examiner in making a bedside diagnosis. The administration of thyroxine corrects the muscle disturbance. Cretinism in association with these muscle abnormalities is known as the Kocher-Debré-Semelaigne syndrome, and myxedema in childhood or adult life with muscle hypertrophy is the Hoffmann syndrome; the latter simulates hypertrophia musculorum vera and myotonia congenita. In neither cretinism nor myxedema, however, is there evidence of true myotonia, either by clinical testing or by EMG, although muscle action potentials are myopathic and often show bizarre high-frequency discharges. Serum transaminase values are normal but CK levels are usually elevated, often markedly so. Muscle biopsies have disclosed only the presence of large fibers or an increase in the proportion of small fibers (either type 1 or 2) and slight distention of the sarcoplasmic reticulum and subsarcolemmal glycogen (probably all a result of disuse atrophy).

Pathogenesis of the Thyroid Myopathies How thyroid hormone affects the muscle fiber is still a matter of conjecture. Clinical data indicate that thyroxine influences the contractile process in some manner but does not interfere with the transmission of impulses in the peripheral nerve across the myoneural junction or along the sarcolemma. In hyperthyroidism an undefined functional disorder enhances the speed of the contractile process and reduces its duration, the net effect being fatigability, weakness, and loss of endurance of muscle action. In hypothyroidism, muscle contraction is slowed, as is relaxation, and its duration is prolonged. The speed of the contractile process is related to the quantity of myosin adenosine triphosphatase (ATPase), which is increased in hyperthyroid muscle and decreased in hypothyroid muscle. The speed of relaxation depends on the rate of release and reaccumulation of calcium in the endoplasmic reticulum. This is slowed in hypothyroidism and increased in hyperthyroidism (Ianuzzo et al). The myopathic effects of hypothyroidism need to be distinguished from those of a neuropathy, which may rarely complicate hypothyroidism (see Chap. 43).

Corticosteroid Myopathies The widespread use of adrenal corticosteroids has created a class of muscle diseases similar to the one that occurs in the Cushing disease as described many decades ago by Müller and Kugelberg. A deficiency of corticosteroids, as occurs in Addison disease, also causes generalized weakness and asthenia, but without an identifiable muscle disease.

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Chapter 45 Diseases of Muscle

Corticosteroid and Cushing Disease Myopathy The prolonged use of corticosteroids causes the proximal limb and girdle musculature to become weak to the point of causing difficulty in elevating the arms and arising from a sitting, squatting, or kneeling position; walking upstairs may also be hampered. Some individuals seem to be more susceptible than others. The problem often arises of distinguishing an iatrogenic steroid-induced myopathy from the weakness produced by a primary neuromuscular disorder that is being treated with these medications such as one of the myositides or myasthenia. In some of our myasthenic patients, the use of high-dose corticosteroids has resulted in a selective, rapid, and severe weakness of the hip flexors. The EMG is normal or mildly myopathic, with small and abundant action potentials but no fibrillations. Biopsies disclose only a slight variation in fiber size with atrophic fibers, mainly of type 2b, but little or no fiber necrosis and no inflammatory cells. Under electron microscopic examination there are aggregates of mitochondria, accumulations of glycogen and lipid, and slight myofibrillar loss that suggest more disuse atrophy than they do a primary muscle disorder. The serum CK and aldolase are usually normal. These changes are the same in Cushing disease and an otherwise unexplained proximal myopathy with these features suggests that diagnosis (Cushing disease and Cushing syndrome). There is an imprecise correlation between the total dose of corticosteroid administered and the severity of muscle weakness. Nevertheless, in patients who develop this type of myopathy, the corticosteroid dosage has usually been high and sustained over a period of months or years. All corticosteroids may produce the disorder, although fluorinated ones, on uncertain evidence, are said to be more culpable than others. Discontinuation or reduction of corticosteroid administration leads to gradual improvement and recovery; alternate-day regimens may also allow recovery, albeit gradually. As the foregoing discussion implies, the mechanism by which corticosteroids cause muscle weakness is not known. In corticosteroid-treated animals, there is a measurable decrease in the uptake of amino acids and protein synthesis by muscle, but the underlying pathways have not been elucidated. This has even greater bearing on the next discussed subject.

Critical Illness Myopathy (Acute Steroid Myopathy; Acute Quadriplegic Myopathy) In addition to the proximal myopathy induced by the longterm use of steroids, an acute and far more severe myopathy has been recognized in critically ill patients. It was described initially with cases of severe asthma in patients who were exposed to high doses of steroids for treatment. Subsequently, this acute myopathy has been recognized with all types of critical systemic diseases and organ failure, again, usually in the context of the administration of high doses of corticosteroids but in a few cases, with sepsis and shock without exposure to this class of medication. Moreover, the use of neuromuscular blocking agents appears to play an important complementary role in the genesis of the myopathy, being reported as a factor in more than

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80 percent of cases; it is uncertain whether these agents alone, without sepsis or organ failure, can produce a similar process (see reviews by Gorson and Ropper, Lacomis et al, and Barohn et al). Patients who acquire this problem may have been exposed to high doses of corticosteroids for only brief periods. Exceptional instances have been reported in which the myopathy was induced by doses as low as 60 mg prednisone administered for 5 days, but we have not encountered such a case. The degree and type of simultaneous exposure to neuromuscular blocking agents have varied, but the doses have generally also been quite high, falling in the range of a total dose of 500 to 4,000 mg of pancuronium or an equivalent, over several days. The severe generalized muscle weakness usually becomes evident when the systemic illness subsides, often as attempts are made to wean the patient from the ventilator. The tendon reflexes are normal or diminished, and there may be confounding features of a “critical illness polyneuropathy,” which is discussed in Chap. 43. Most of our patients with acute myopathy have recovered over a period of 6 to 12 weeks after the corticosteroid agent has been greatly reduced in dose or withdrawn, but a few have remained weak for as long as a year. Serum CK is elevated, at least early in the process. The EMG discloses the characteristic features of a myopathy; often there are fibrillations as well, theorized to be a result of separation of the motor endplate region from intact segments of muscle fibers. A concurrent polyneuropathy and any residual effects of neuromuscular blockade can be excluded by appropriate electrophysiologic studies. Muscle biopsy shows varying degrees of necrosis and vacuolation affecting mainly type 2 fibers. The identifying histologic feature is a striking loss of thick (myosin) filaments. Severe degrees of muscle necrosis occur and have been accompanied by massively elevated CK levels and by myoglobinuria with renal failure. Several experimental observations may explain the apparent additive effect on muscle of corticosteroids and neuromuscular blocking agents. Animals exposed to high doses of steroids soon after experimental denervation of a muscle display a selective loss of myosin, the characteristic finding of acute steroid myopathy. Myosin depletion is reversed by reinnervation but not by withdrawal of the corticosteroids. Furthermore, denervation of muscle has been found to induce an increase in glucocorticoid receptors on the surface of the muscle. On this basis, it has been postulated that exposure to neuromuscular blocking agents creates a functional denervation, rendering the muscle fiber vulnerable to the damaging effects of steroids (Dubois and Almon). It is curious that this myopathy has not been seen after high-dose corticosteroid administration for neurologic diseases such as multiple sclerosis, but the observation of Panegyres and colleagues of a patient with myasthenia who developed a severe, myosin-depleted myopathy following high doses of methylprednisolone supports such a dual action of denervation (at the postsynaptic membrane) and glucocorticoids. Whether it also explains the more common circumstance of clinical worsening of myasthenia gravis that sometimes accompanies the initial administration of corticosteroid treatment is also not clear.

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Adrenocortical Insufficiency Generalized weakness and fatigability are characteristic of adrenocortical insufficiency, whether primary in type, that is, because of Addison disease (infectious, neoplastic, or autoimmune destruction of the adrenal glands or adrenal hemorrhage), or secondary to a pituitary deficiency of adrenocorticotropic hormone (ACTH). The weakness and fatigability, however, are probably related to mostly water and electrolyte disturbances and hypotension, not to a primary disorder of muscle. Perhaps there is also an element of reduced central drive of motor activity. Biopsy has not disclosed any abnormalities of muscle and postmortem examination in one case showed no changes. Likewise, the EMG is normal, and the tendon reflexes are retained. Addisonian weakness responds (as does hyperkalemic paralysis) to glucocorticoid and mineralocorticoid replacement.

Primary Aldosteronism Production of excess aldosterone by adrenal adenomas has been the subject of many articles, one of the earliest and most notable being that of Conn muscular weakness has been observed in 75 percent of the reported cases of hyperaldosteronism. In nearly half of those with muscle weakness there was either hypokalemic periodic paralysis or tetany. Chronic potassium deficiency may express itself either by periodic weakness or by a chronic myopathic weakness. An associated severe alkalosis causes the tetany. As in the weakness of Addison disease, there is no structural disorder of muscle, except perhaps for vacuolation, which is the result of severe hypokalemia.

Diseases of Parathyroid Glands and Vitamin D Deficiency A proportion of patients with parathyroid adenomas complain of weakness and fatigability. Vicale described the first example of this disorder and remarked on the muscular atrophy and weakness and the pain on passive or active movement. The tendon reflexes were retained. A few scattered muscle fibers had undergone degeneration, but claims for a denervative muscle process are disputed. We have not been impressed with either a myopathy or neuropathy in this disease. In hypoparathyroidism, muscle cramping is prominent, but there are no other neuromuscular manifestations. In both hypoparathyroidism and pseudohypoparathyroidism— the latter with characteristic skeletal abnormalities and, in some instances, mental slowness—the most important muscle abnormality is tetany. This is a result of low ionized serum calcium, which depolarizes axons more than muscle fibers. Osteomalacia, as a result of vitamin D deficiency and disorders of renal tubular absorption, often includes muscle weakness and pain as common complaints, similar to those in patients with primary hyperparathyroidism and with uremia (see Layzer for further comment). A chronic proximal myopathy can occur in conjunction with hypophosphatemia associated with solitary bone cysts. In two of our patients, removal of the cyst restored serum phosphorus levels and cured the generalized

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muscle weakness. Also known is an uncommon syndrome of severe hypophosphatemia and generalized bone pain in association with usually benign mesenchymal tumors of soft tissue and bone (oncogenic hypophosphatemia). These tumors express a fibroblast growth factor that induces renal wasting of phosphorous. Hypophosphatemic myopathic weakness has been noted in critical care units, precipitated by hyperalimentation solutions; the onset of weakness can be so abrupt in this circumstance, as to simulate the Guillain-Barré syndrome. The oral administration of phosphates to raise serum phosphorus cures the nonneoplastic cases. Presumably phosphorus depletion limits the phosphorylation reactions and the synthesis of ATP in muscle.

Weakness in Acromegaly Proximal muscle weakness and atrophy have been recorded as late developments in many acromegalic patients. Formerly thought to be caused by neuropathy, these symptoms in acromegaly have been convincingly shown to be the result of a generalized myopathy (Mastaglia and colleagues). The serum CK is slightly elevated in some cases, and myopathic potentials are observed in the EMG. Biopsy specimens have shown atrophy and reduced numbers of type 2 fibers, but necrosis of only a few fibers. Treatment of the pituitary adenoma and correction of the hormonal changes restores strength. A mild peripheral neuropathy of sensorimotor type has also been reported in a few patients with acromegaly but is far less frequent than carpal tunnel syndrome and other focal entrapments in this disease.

MITOCHONDRIAL MYOPATHIES (SEE CHAP. 36) The genetic aspects of mitochondrial diseases and the diverse and overlapping clinical syndromes that constitute this category—including the myopathic ones—are discussed in Chap. 36. The histologic change termed ragged red fibers reflects the mitochondrial changes of this class of diseases and is common to many of them, even without manifest symptoms of muscle disease.

MYOPATHIES CAUSED BY DRUGS AND TOXINS; RHABDOMYOLYSIS (SEE CHAP. 41) A vast number of drugs and other chemical agents have been identified as myotoxic (See Table 45-6). In 1989, Curry and colleagues found reports (in the English literature alone) of approximately 100 drugs that had caused rhabdomyolysis and myoglobinuria, mostly acting in an idiosyncratic manner, and the list continues to grow. Additional myotoxic agents that can be expected to appear as new drugs are introduced. Because it is impractical to describe all the implicated drugs and toxins individually, they are broadly categorized and their main features listed in Chap. 41. Exogenous agents may produce myopathic changes in several ways. They may act directly on muscle cells, either diffusely or locally, as occurs with intramuscular injections, or the muscle damage can be a result of diverse secondary

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Chapter 45 Diseases of Muscle

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Table 45-6 FEATURES OF TOXIN-INDUCED MYOPATHIES MYOPATHIC SYNDROME

AGENT

CLINICAL FEATURES

PATHOLOGY

LABORATORY FINDINGSa

Acute/subacute painful proximal myopathy; tendon reflexes usually preserved

Necrosis, regeneration

CK ↑↑, myoglobinuria +/−

 

 1.  Statin drugs-immune mechanism  2. Alcohol excess  3. Clofibrate, gemfibrozil  4.  Amphetamine derivatives  5. Hypervitaminosis E

5. Painless

 

   

 6. Organophosphates  7. Snake venoms

 

 8.  High-dose corticosteroids in critical illness  9.  Mushroom poisoning (Amanita phalloides) 10. Cocaine 1. Acute (high IV steroid doses, ventilated patients on pancuronium) 2. Myasthenics   3. Chronic

  7. Severe, acute intoxication 8. Neuromuscular blockers implicated  

5. Paracrystalline inclusion bodies      

 

9.  Loss of myosin

 

  1. Necrosis of mainly type 2 fibers; loss of myosin; vacuolar changes

  CK ↑↑, myoglobinuria +

  2.  Type 2 fiber atrophy

  Blood lymphocytosis

Necrosis, regeneration, vacuolization

CK ↑↑, myoglobinuria +/−, hypokalemia

Chloroquine: vacuole formation, optically dense structures

CK ↑

  Focal mitochondrial loss, vacuoles Vacuolar myopathy (rimmed vacuoles)

  CK ↑

Inflammation, necrosis, regeneration

CK ↑, myoglobinuria +/−

Vasculitis, connective tissue infiltration

Eosinophilia

Ragged red fibers, necrosis, regeneration      

CK normal or ↑

  Focal necrosis

  CK ↑

Marked fibrosis and myopathic changes

Normal

Necrotizing myopathy (rhabdomyolysis)

    Steroid myopathy

    Hypokalemic myopathy

Amphiphilic cationic drug myopathy (lysosomal storage, “lipidosis”)   Impaired protein synthesis Antimicrotubular myopathy Inflammatory myopathy Fasciitis, perimyositis, microangiopathy Mitochondrial myopathy Various       Local myopathy due to IM injections  

  Severe proximal and distal weakness

  2 and 3. Proximal atrophy, weakness 1. Diuretics Weakness may be 2. Laxatives periodic, reflexes 3. Licorice, carbenoxolone may be depressed or 4. Amphotericin B, toluene absent, rarely severe 5.  Alcohol abuse myoglobinuria 1. Chloroquine (>500 mg), Proximal muscle pain hydroxychloroquine, quinaand weakness, sensocrine, plasmocid rimotor neuropathy, 2. Amiodarone cardiomyopathy 3. Perhexiline   Ipecac syrup, emetine Myalgia, proximal weakness, cardiomyopathy 1. Colchicine Proximal weakness, 2. Vincristine peripheral neuropathy; CK may be normal 1. D-Penicillamine Proximal muscle pain, 2. Procainamide weakness, skin changes 3. Cimetidine? Ciguatera toxin? possible 1.  Toxic oil syndrome Myalgia, skin changes, 2. Eosinophilia-myalgia peripheral neuropasyndrome thy, other systems also affected 1. Zidovudine Proximal myalgia and 2. Germanium weakness 1. Cyclosporine   2. Labetalol   3. Anthracycline antibiotics 3. Humans: only cardiomyopathy 4.  Rifampin, amiodarone   1. Acute: IM injection of variLocal pain, swelling, ous drugs—e.g., cephalothin, sometimes abscess lidocaine, diazepam formation 2. Chronic: Repeated IM Induration and contracinjections—e.g., pethidine, ture of injected muscles pentazocine, intravenous drug abuse, antibiotics (in children)

   

CK ↑

     

CK (serum creatinine kinase): ↑ (mild), ↑↑ (moderate), ↑↑↑ (marked) elevations; myoglobinuria: +/− (may be present). Source: Reproduced with permission from Sieb JP: Myopathies due to drugs, toxins, and nutritional deficiency; In Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York: McGraw-Hill, 2004. a

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Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

factors—electrolyte disturbances (hypokalemia), renal failure, excessive energy requirements of muscle (as occur with drug-induced seizures and malignant hyperthermia), or inadequate delivery of oxygen and nutrients. Of course, there is a derivative category of drug-induced coma with compressive-ischemic injury to muscle. However, the most important group is that of direct toxic effects on the muscle membrane on the internal apparatus of the cell. Several clinical features mark a myopathy as toxic in nature: lack of preexisting muscular symptoms; a predictable delay in onset of symptoms after exposure to a putative toxin; the lack of any other cause for the myopathy; and often, complete or partial resolution of symptoms after withdrawal of the toxic agent. Pathologically, this group of disorders is characterized by nonspecific myopathic changes, which in most severe degrees take the form of myonecrosis (rhabdomyolysis) and resultant myoglobinuria. This necrotizing muscle syndrome is the most frequent and serious myotoxic syndrome. In any disease that results in rapid destruction of striated muscle fibers (rhabdomyolysis), myoglobin and other muscle proteins enter the bloodstream and appear in the urine. The latter is “cola”-colored (burgundy red or brown), much like the urine in hemoglobinuria. In hemoglobinuria, however, the serum is pink, because hemoglobin (but not myoglobin) is bound to haptoglobin, and this complex is not excreted in the urine as readily as myoglobin; also in addition, the hemoglobin molecule is three times as large as the myoglobin molecule. (The hemoglobin–haptoglobin complex is removed from the blood plasma over a period of hours and haptoglobin may be depleted, so that hemoglobinuria is present without grossly evident hemoglobinemia.) Differentiation of the two pigments in urine is difficult; both are guaiac-positive and may be detected by the “dipstick” test that can be used to advantage at the bedside in appropriate circumstances. Only small differences are seen on spectroscopic examination. The most sensitive means of detecting myoglobin is by radioimmunoassay. It should be mentioned that porphyrins are another cause of discoloration of the urine. The clinical picture in porphyria is one of a polyneuropathy and not a myopathy. Many of the causes of myonecrosis have already been mentioned in this chapter, including acute inflammatory myopathy, several types of glycogenoses, CPT deficiency, and as a result of poisoning or therapeutic use of a vast array of drugs (including the combination of steroids and pancuronium in critically ill patients, discussed earlier), environmental toxins, and venoms. Myoglobinuria is an important feature of many other medical conditions: crush injury; extensive infarction of muscle that occurs in cases of vascular disease and of diabetes; in cases of severe acute alcohol intoxication, excessive use or repeated injury to muscles in status epilepticus, generalized tetanus, malignant hyperthermia, malignant neuroleptic syndrome, prolonged marching, electrical and lightning injuries; or simply excessive exercise—although muscle necrosis after exercise suggests an underlying metabolic disease of muscle. Regardless of the cause of the rhabdomyolysis, the affected muscles become painful and tender within a few hours and their power of contraction is diminished.

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Sometimes, the skin and subcutaneous tissues overlying the affected muscles (nearly always of the limbs and sometimes of the trunk) are swollen and congested. There is a marked elevation of CK in the serum and there may be a low-grade fever and a reactive leukocytosis. If myoglobinuria is mild, recovery occurs within a few days and there is only a residual albuminuria. When severe, renal damage may ensue and lead to anuric renal failure requiring dialysis. The mechanism of the renal damage is not entirely clear; it is not simply a mechanical obstruction of tubules by precipitated myoglobin (although this does occur). Treatment of myoglobinuria Alkalinization of the urine by ingestion or infusion of sodium bicarbonate is said to protect the kidneys by preventing myoglobin casts, but in severe cases it is of doubtful value and the sodium may actually be harmful if anuria has already developed. Diuresis induced by mannitol or by loop diuretics such as furosemide and by the administration of intravenous fluids reduces the chances of anuric renal failure if given in time. Therapy is much the same as for the anuria that follows shock (see Harrison’s Principles of Internal Medicine). In cases of focal muscle injury, for example, as occurs in diabetics or from vascular occlusion, surgical decompression of the overlying fascia and skin may be necessary to prevent ongoing ischemia, the “compartment syndrome.”

Statin-Induced Myopathy With the widespread use of these lipid-lowering medications, myotoxicity has become a well-described but possibly overrated problem. Symptoms range in severity from mild muscular aches with slightly elevated CK concentrations in the serum to a rare but potentially fatal rhabdomyolytic syndrome. (Myalgias alone are as common in patients taking placebo as in those taking statins). The incidence of true myopathy with statins has been estimated to be approximately 1 in 10,000 people treated per year. There appear to be two types of myopathy—one idiosyncratic and associated with direct toxicity and another, now thought to be more common, due to an antibody reaction. The first generation of these drugs were fungal metabolites (lovastatin, pravastatin, simvastatin) and were infrequently implicated in muscle damage, but the newer synthetic ones (atorvastatin, fluvastatin, cerivastatin) are more frequently toxic, especially when given with gemfibrozil (which has reportedly led to a small number of deaths from myoglobinuric renal failure and has been removed from the market). Few cases are this dramatic. The subject has been reviewed by Thompson and associates and by Mammen. Drugs in the statin class with higher lipid solubility appear to have a greater potential for toxicity as a result of their increased muscle penetration. In addition to the direct toxicity, there is an autoantibody syndrome directed against HMGCo-A reductase, which may be induced by statins (of any type) or occur spontaneously and may cause necrotizing myopathy as discussed in an earlier section (Mammen). The mechanism of directly toxic muscle damage is not well understood, but it is likely that inherent enzymatic defects are present in a proportion of the severe cases and that others are due to the aforementioned autoimmune

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Chapter 45 Diseases of Muscle

process (Farmer). A novel insight derived from genomewide screening has been that variants in a gene (SLCO1B1) that codes for an organic anion-transporting polypeptide confers a risk of statin myopathy (4.5-fold for a heterozygous state and 17 times for the homozygous state; see the study by The SEARCH Collaborative Group). In addition, the chronic use of statin drugs reduces levels of both ubiquinone and small guanosine triphosphate (GTP)–binding proteins, also plausible factors in statin-induced muscle toxicity. A clinical problem arises when the CK level is elevated, but the patient taking one of these medications has no muscular symptoms. It has been our general practice to continue the medication if the elevation of CK is in the low range and does not rise over time, and if the medication is considered necessary. If alternative and safe means of lowering the lipid level are available, they should be tried in lieu of a statin, but each patient’s circumstances differ. A similarly vexing and not uncommon problem is myopathic symptoms such as muscle stiffness, tenderness, and weakness with normal CK concentrations in patients taking a drug in this class; a trial of discontinuing the medication might be appropriate (Phillips and colleagues). Finally, we have encountered a number of patients whose CK levels have remained high for months or longer after the medications have been stopped. In a few, CK elevations have remained over years, but we have had no way to ensure that the test was not abnormal before taking the statin. As a rule, statins should be discontinued if the muscle disorder is serious. Treatment of the immune type of myopathy is complex as the syndrome may persist after discontinuation of the drug. In some instances, discontinuation is followed by spontaneous improvement but others may require glucocorticoids administration or an immunosuppressive agent such as mycophenylate or azathioprine. If there is no response, intravenous immunoglobulin or rituximab may be tried, although there have not been adequate trials to determine the best course of action (Mammen).

Colchicine Myoneuropathy This condition is included here as much for its curious histopathologic features as for its clinical interest. The drug, used widely in the treatment of gout, often gives rise to a mild subacute proximal muscular weakness but has also produced an acute necrotizing myopathy. Most instances of the latter have occurred in patients with a degree of renal failure, which allows accumulation of the drug (even though the drug is metabolized predominantly by the liver). In rare instances the myopathy has affected the cranial musculature and the diaphragm. Many cases also show clinical or electrophysiologic evidence of a polyneuropathy, leading to the term colchicine myoneuropathy (Kuncl and colleagues). The reflexes are diminished and there is mild distal sensory loss. Rare cases of colchicine-induced hypokalemic periodic paralysis and also of myotonia have been reported. The serum CK concentration may be elevated or normal. The muscle biopsy shows elements of both myopathic and neuropathic disease, with the special feature in muscle of rimmed vacuoles on the Gomori trichrome stain that are

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more central in the muscle fibers than those seen with inclusion body myositis. The mechanism of the muscle damage is unknown but is probably attributable to the drug’s interference with tubulin, a protein required for the polymerization of microtubules in muscle and nerve. Weakness resolves in a matter of days or weeks when the drug is discontinued, but the neuropathic features may remain. Other drugs that cannot be compactly summarized but may produce a toxic myopathy or neuromyopathy include amiodarone, chloroquine, and hydroxychloroquine as mentioned in Chap. 41.

Alcohol Myopathy (See Also Chap. 41) Several forms of muscle weakness have been ascribed to alcoholism. In one type, a painless and predominantly proximal weakness develops over a period of several days or weeks in the course of a prolonged drinking bout and is associated with severe degrees of hypokalemia (serum levels < 2 mEq/L). The urinary excretion of potassium is not significantly increased, and depletion is probably the result of vomiting and diarrhea. In addition, serum levels of liver and muscle enzymes are markedly elevated. Biopsies from severely weakened muscles show single-fiber necrosis and vacuolation. Treatment consists of the administration of potassium chloride intravenously (about 120 mEq daily for several days), after which oral administration suffices. Strength returns gradually in 7 to 14 days, and enzyme levels return to normal concomitantly. A more dramatic myopathic syndrome, occurring acutely at the height of a prolonged drinking bout and appropriately termed acute alcoholic myopathy, is manifest by severe pain, tenderness, and edema of the muscles of the limbs and trunk, accompanied in severe cases by renal damage (Hed et al). Hypokalemia is not implicated. The myonecrosis is generalized in some patients, and remarkably focal in others. A swollen, painful, tender limb or part of a limb may give the appearance of a deep venous thrombosis or lymphatic obstruction. Myonecrosis is reflected by high serum levels of CK and aldolase and the appearance of myoglobin in the urine, leading in the most severe cases to fatal myoglobinuric renal failure. Indeed, in a general hospital, alcoholism is one of the most common causes of rhabdomyolysis and myoglobinuria, rivaled only by status epilepticus and trauma. Some patients recover within a few weeks, but others require several months, and relapse during another drinking spree occurs frequently. Restoration of motor power occurs with muscle regeneration but may be hindered by polyneuropathy and other syndromes of neuromuscular disability associated with alcoholism. Rhabdomyolysis has been produced experimentally in rats by subjecting the animals to a brief fast following a 2- to 4-week exposure to alcohol, suggesting that a similar mechanism may be operative in alcoholic individuals (Haller and Drachman). A third form of acute muscular disorder in alcoholics consists of severe muscular cramps and diffuse weakness in the course of a sustained drinking bout (Perkoff and his associates). They noted a number of biochemical abnormalities in these patients, as well as in asymptomatic alcoholics who had been drinking heavily for a sustained period

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Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

before admission to the hospital: elevated serum levels of CK, myoglobinuria, and a diminished rise in blood lactic acid in response to ischemic exercise. From time to time in alcoholics one observes the subacute or chronic evolution of painless weakness and atrophy of the proximal muscles of the limbs, especially of the legs, with only minimal signs in the distal segments of the legs and feet. Cases such as these have been referred to as chronic alcoholic myopathy, implying a direct toxic effect of alcohol on muscle, but the data are insufficient to warrant such an assumption. Some of these cases have shown necrosis of individual muscle fibers and other signs of polymyositis; most cases prove to be neuropathic in nature (Faris and Reyes). Treatment follows along the lines indicated for nutritional-alcoholic neuropathy, and complete recovery can be expected if the patient abstains from alcohol and maintains adequate nutrition.

THE CONGENITAL MYOPATHIES Included under this section are two sizable groups of muscle diseases: one is an assemblage of congenital deformities that involve muscle and the other is a unique class of congenital myopathies. Insofar as all of the disorders comprising these categories are congenital, it may be helpful by way of introduction to refer briefly the main facts about the natural development and aging of muscle in the introductory section of this chapter. These diseases are of particular importance in pediatric neurology, for most of them usually present at an early age.

Congenital Deformities of Muscle Arthrogryposis (Table 45-7) This disorder of multiple congenital contractures, now referred to as arthrogryposis (literally, curved joints), has been estimated to occur once in 3,000 births. The deformities result from a lack of movement during fetal development and are therefore produced by any disorder that immobilizes the developing embryo, whether from a lack of anterior horn cells, peripheral nerves, the motor end plate (as in an infant born to a myasthenic mother), or diseases of muscle. Often, there are associated developmental defects of the nervous system and somatic structures, low-set ears, wide and flat nose, micrognathia, and higharched palate; less often, there are short neck, congenital heart disease, hypoplasia of the lungs, and cryptorchidism. Table 45-7 THE MAIN CAUSES OF ARTHROGRYPOSIS Werdnig-Hoffmann motor neuron disease Myotonic dystrophy Congenital myasthenia (see Chap. 46) Congenital myopathy Congenital muscular dystrophy Neonatal neuropathy Prader-Willi syndrome Amyoplasia (focal arthrogryposis)

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Of the many conditions that underlie arthrogryposis, developmental abnormalities of the anterior horn cells, mainly Werdnig-Hoffmann disease as discussed in Chap. 38, is by far the most common. A failure in development of anterior horn cells results in an uneven smallness and paresis of limb muscles. The unopposed contraction of relatively normally innervated muscles sets the fixed deformities. In a less common group of myopathic causes of arthrogryposis, the nervous system is usually intact and the disease is that of a congenital myopathy or congenital dystrophy. It has been observed that in the myopathic variety the limbs are fixed in a position of flexion at the hips and knees and adduction of the legs, in contrast to the variable postures of the myelopathic (anterior horn cell) form. In addition to these two well-recognized causes of arthrogryposis, occasional cases are attributable to a neonatal neuropathy, neonatal myasthenia gravis, or to the PraderWilli syndrome (causing intrauterine hypotonia). An infant with arthrogryposis should be evaluated with an EMG that is interpreted by an experienced electromyographer, and by a biopsy of muscle for the detection of group atrophy and of the congenital myopathies described further on in this chapter. Both these tests are difficult to interpret in the incompletely formed nervous system of the premature infant. In many circumstances, it is valuable to delay the tests until several weeks of postterm development when the results are usually clearer. Sometimes, the electrophysiologic and biopsy tests may have to be repeated after several weeks or more to give a definitive diagnosis. If the initial evaluations are unrevealing, an imaging study of the brain to detect cerebral malformations (and sequencing of the PWCR locus chromosome 5 for Prader-Willi syndrome) may prove useful.

Congenital Focal Fibrous Contractures This term refers to a fixation of limb posture as a result of a developmental lack or destruction of muscles, with shortening and fibrosis of supporting tissue and ligaments. A surprising number of deformities in infants and children are traceable to this type of defect. The most common are congenital clubfoot (talipes), congenital torticollis (wryneck), congenital elevation of the scapula (Sprengel deformity), and congenital dislocation of the hips. In all these conditions, the postural distortion is produced and maintained either by a weakened, fibrotic muscle or by a normal one that is contracted and shortened because of the absence of a countervailing antagonist. Trauma to a muscle during intrauterine life or at birth may lead to fibrosis and to fibrous contracture in some cases. Congenital clubfoot Here the deformity may be one of plantar flexion of the foot and ankle (talipes equinus), inversion (talipes varus or clubfoot), eversion (talipes valgus or splayfoot), or dorsiflexion of foot at the ankle (talipes calcaneus). Approximately 75 percent of cases are of the equinovarus clubfoot variety (i.e., the foot turns downward and inward). Usually both feet are affected. Multiple incidences may occur in one family. Several explanations of cause and pathogenesis have been offered: fetal malposition, an embryonic abnormality of tarsal and metatarsal bones, a primary defect in nerves or anterior horn cells of the spinal cord, or a congenital dystrophy of muscle.

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No one theory explains all cases, and available pathologic data exclude a single cause and pathogenesis. In some instances, clubfoot is the only recognizable congenital abnormality, but as often it occurs as a manifestation of generalized arthrogryposis and is an indicator of a more widespread intrauterine involvement of the CNS. (See Kakulas and Adams and also Banker for pertinent literature on the subject.) Congenital torticollis (Wryneck)  This disorder begins during the first months of life and, unlike the torticollis of adults discussed in Chap. 4, it is not the result of a dystonia but instead is caused by congenital shortening of the sternocleidomastoid muscle, which is firm and taut. The head is inclined to one side and the occiput slightly rotated to the side of the affected muscle. This disorder is nonfamilial and is ascribed to injury to the sternocleidomastoid at birth. Whether the injury is a purely mechanical one to the muscle itself or is caused by ischemia stemming from arterial or venous occlusion (or an entirely different cause) is not clear. Congenital torticollis often gives rise to a sternocleidomastoid enlargement (a pseudotumor) that appears, on exploration, as a pale, spindle-shaped swelling of the muscle belly. The histologic findings are similar to those of Volkmann contracture, that is, replacement of the muscle fibers by relatively acellular connective tissue, suggesting that an ischemic mechanism underlies the defect in at least some cases.

Congenital Absence of Muscles (Amyoplasia) It is well known that some individuals are born without certain individual muscles. This pertains not only to certain inconstant and functionally unimportant muscles, such as the palmaris longus, but also to more substantial ones. The muscles found to be absent most frequently are the pectoralis, trapezius, serratus anterior, and quadriceps femoris, but many single muscles may be missing in isolated cases. Congenital absence of muscle is usually associated with congenital anomalies of neighboring nonmuscular

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tissues. For example, congenital absence of the pectoral muscle is accompanied by aplasia or hypoplasia of the mammary structures or of syndactyly and microdactyly. Agenesis of the pectoral muscle may also be associated with scoliosis, webbed fingers, and underdevelopment of the ipsilateral arm and hand (Poland syndrome). Another unusual constellation consists of congenital absence of portions of the abdominal muscles (“prune belly”), often in association with arthrogryposis and a defect of ureters, bladder, and genital organs. Amyoplasia also occurs in a few cases of facioscapulohumeral dystrophy.

Restricted Nuclear Amyotrophies In another group of restricted palsies, the essential abnormality is in the CNS (nuclear amyotrophies). One of the most frequent is congenital ptosis as a result of an inborn defect of the innervation of the levator palpebrae muscles. Complete paralysis of all muscles supplied by the oculomotor nerve, apparently a result of hypoplasia of the third nerve nuclei, may be observed in several members of a family and occasionally in only one member. Bilateral abducens palsy is often associated with bifacial palsy in the newborn and is known as the Möbius syndrome; this usually nonfamilial anomaly, the cause of which is thought to be a nuclear hypoplasia or aplasia, is discussed with the developmental disorders in Chap. 37. In these familial nuclear amyotrophies, the muscles develop independently of the nervous system but have no prospect of surviving because of failure of innervation. It is, therefore, a kind of congenital denervation hypotrophy. Of course, a primary dystrophy may also give rise to bifacial weakness, as in FSHD.

Congenital Structural Myopathies (Table 45-8) Beginning in 1956, with the account by Shy and Magee of a patient whose muscle fibers showed a peculiar central densification of sarcoplasm (“cores”), a new class of

Table 45-8 THE MAIN CONGENITAL MYOPATHIES TYPE

GENETICS

ONSET DECADE

CK ELEVATION

Ryanodine receptor (RYR1)       a-Tropomyosin Nebulin

1st–2nd

1–10 ×

      1st–2nd

      1–2 ×

   

Coflin-2 b-Tropomyosin

   

   

      Myotubular myopathy

      X-linked AD, AR,

Ryanodine receptor Troponin T1 a-Actin Myotubularin Dynamin-2

      1st

      1–4 ×

 

 

MYF6

 

 

Central core disease

AD, AR

      Nemaline rod myopathy

      AD, AR

   

GENE

REGIONS AFFECTED

Diffuse myopathy presenting in infancy Proximal myopathy beginning in adolescence   Risk of malignant hyperthermia May include mental retardation Diverse phenotypes May present as severe congenital myopathy or as childhood-onset myopathy   May include facial weakness, high-arched palate, and high pedal arches       Proximal and distal weakness May include facial weakness, ophthalmoparesis, ptosis  

AD, autosomal dominant; AR, autosomal recessive; CK, creatine kinase.

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hereditary diseases of muscle was delineated. The more common and better-defined members of this group are the central core, nemaline (rod-body), myotubular, and centronuclear myopathies. A variety of other types of congenital myopathy have been described, but they are relatively uncommon and some are of dubious specificity; they are mentioned only briefly. As the names imply, in each of these diseases there is no loss of muscle fibers, but within each fiber there is a distinctive morphologic abnormality. These processes usually express themselves early in life by a lack of muscle bulk, hypotonia, weakness of the limbs, and often, with additional but subtle dysmorphic features of other parts of the body. Further study has revealed that the diseases of this group are not confined to infancy and early childhood and some of them, especially those present at birth, are not as benign as their early descriptions implied. Each of the entities mentioned earlier has been observed at a later age, even in middle adult life. Indeed, if the disease is mild, there is often no way of deciding whether it has been present since birth. The characteristic feature of most of these myopathies, in addition to usual early onset, is lack of progression or extremely slow progression, in contrast to the more rapid pace of many muscular dystrophies, Werdnig-Hoffmann disease, and of other forms of hereditary motor system disease of childhood and adolescence. Exceptionally, an example of more rapid progression of a congenital myopathy has been reported, and prior to the use of histochemical and electron microscopic techniques such patients were usually considered to have a “benign muscular dystrophy.” Familial occurrence has also been established in some types, so the clinical line of separation between this group of diseases and some of the more slowly progressive muscular dystrophies may in certain cases remain ambiguous. There is no specific treatment for any of the congenital myopathies. The characteristic lesions in the congenital myopathies are revealed most clearly by the systematic application of histochemical stains to frozen sections of muscle biopsy tissue and by phase and electron microscopy. Some of the abnormalities are also disclosed by the conventional stains used in light microscopy, but as a group their identification has been the product of newer histologic techniques. A word of caution is in order about the specificity of some of the morphologic changes and the classifications of the congenital myopathies based on these changes. It is inadvisable to assume that a change in a single organelle or a subtle change in the sarcoplasm of a muscle fiber can be relied on to characterize a pathologic process. Indeed, as more careful studies have been made of this class of disease, the specificity of some of the changes has come to be questioned. For example, central cores are sometimes found in the same muscle as nemaline bodies, and so on, and each of the denotative lesions has been reported in association with other systemic diseases and even as a result of certain medications. Nevertheless, the prominence of the morphologic change in any individual case, along with certain characteristic clinical features, permits an accurate diagnosis to be made.

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Central Core Myopathy (RYR1 Mutation) In the original family described by Shy and Magee, five members (four males) in three successive generations were affected, suggesting an autosomal dominant pattern of inheritance. The youngest was 2 years old; the oldest, 65 years. In each there was weakness and hypotonia soon after birth (again, “floppy infant”) and a general delay in motor development, particularly in walking, which was not achieved until the age of 4 to 5 years. These patients had difficulty in rising from a chair, climbing stairs, and running. The weakness was greater in proximal than in distal muscles, although the latter did not escape, and shouldergirdle muscles were affected less than those of the pelvic girdle. Facial, bulbar, and ocular muscles were spared. The tendon reflexes were hypoactive and symmetrical. Muscle atrophy was not a prominent feature, although poor muscular development was present in one patient and has since been reported in others. There were no fasciculations, cramps, or myotonia, but cramps following exercise have been described in other families. The ECGs were normal. Almost all cases studied in the modern era have been due to variants in the ryanodine receptor 1 (RYR1), which is also implicated in the causation of a small number of cases of malignant hyperthermia (see Chap. 41) and of the rare recessively inherited condition of minicore disease (multiple, or multi-minicore), a congenital myopathy that may include ophthalmoplegia. The disease, therefore, has remarkable attribute in that every patient is a potential candidate for the development of malignant hyperthermia and should wear a medical alert bracelet or be otherwise identified to indicate vulnerability to this anesthetic-induced complication. The disease is rare, but as additional cases have been discovered, milder forms have come to be recognized, and in some of them the symptoms first appeared in adult life. Originally these patients were thought to have limbgirdle dystrophy because of the disproportionate involvement of proximal muscles. In other families, such as the one reported by Patterson and colleagues, the disease was first recognized in middle adult life with the rapid evolution of a proximal myopathy. Dislocation of the hips, pes cavus or pes planus, and kyphoscoliosis has been found in a few children, but arthrogryposis is rare. In the majority of cases, the progress of the disease is extremely slow, with slight worsening over many years. These represent the two extremes of the process. The EMG reveals brief, small-amplitude motor unit potentials with a normal interference pattern. Serum concentration of CK is normal or only slightly elevated, as it is in all the congenital myopathies. Pathologically, the majority of the muscle fibers appears normal in size or enlarged, and no focal destruction or loss of fibers can be found. The unique feature of the disease is the presence in the central portion of each muscle fiber of a dense, amorphous condensation of myofibrils or myofibrillar material. This altered zone characteristically lacks mitochondria and other organelles and gives a reduced positive PAS reaction and a dark blue coloration with the Gomori trichrome stain, contrasting with the normal blue-green color of the peripheral myofibrils.

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Chapter 45 Diseases of Muscle

Within the core, there is a lack of phosphorylase and oxidative enzymes. Most of the cores are in type 1 fibers, which predominate in muscle biopsies. These cores run the length of the muscle fiber, thus differing from the multiple cores or minicores that are seen in oculopharyngeal and multiminicore myopathy.

Nemaline (Rod-Body) Myopathy (Various Mutations) This disorder also expresses itself by hypotonia and impaired motility in infancy and early childhood, but unlike the case in central core disease, the muscles of the trunk and limbs (proximal greater than distal), as well as the facial, lingual, and pharyngeal muscles, are strikingly thin and hypoplastic. Several forms have been observed. One is congenital, with generalized weakness in the neonatal period, making breathing and feeding difficult. The limbs are flaccid and flexic (again “floppy” infant). Pneumonia and death occur within weeks to months. In forms that permit longer survival, the weakness is less severe, involving mainly the proximal muscles. Tendon reflexes are diminished or absent. The young child with this disease usually suffers from inanition and frequent respiratory infections, which may shorten life. Strength slowly improves with growth, the latter process evidently counteracting the advance of the disease. A slender appearance, narrow face, open mouth, narrow, arched palate, and kyphoscoliosis are regular but not invariable accompaniments of nemaline myopathy. These dysmorphic features are not typical of the other congenital polymyopathies. Pes cavus or clubfoot may be added. Some of the milder cases reach adulthood, at which time a cardiomyopathy may threaten life. A.G. Engel, as well as W.K. Engel and Reznick, observed individuals who first showed signs of the disease in middle age; the weakness was mainly in proximal muscles and the dysmorphic and skeletal abnormalities of the childhood form were lacking. The EMG is “myopathic,” and serum enzymes are normal or only slightly elevated. Cases of nemaline myopathy have come to attention during adulthood because of disproportionate involvement of the respiratory muscles, a feature shared with the adult appearance of acid maltase deficiency. Usually, these patients have had a history of poor physical performance throughout their earlier life. An unexplained accompanying monoclonal gammopathy has appeared in case reports of late-onset nemaline myopathy and probably represents a separate process that is more than chance occurrence. In the series of late-onset cases described by Chahin and colleagues, 7 of 14 cases had an abnormal blood protein and these authors suggested that the prognosis may be less favorable than in those lacking the protein. The patients who have been shown with this combination of adult proximal weakness and monoclonal protein had no dysmorphic features, suggesting that these cases are different from the typical genetically determined nemaline myopathy described as follows. Nemaline myopathy appears to be genetically heterogeneous but about 20 percent are due to mutations in ACTA1. The pattern of inheritance is most often autosomal

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dominant with variable penetrance. In some families there has been an autosomal recessive or an X-linked pattern of inheritance. Studies of the various gene defects have begun to clarify the uncertainties about inheritance and explain the relationships between the different forms of the disease. The genes implicated in nemaline myopathy include those for alpha-tropomyosin, beta-tropomyosin, alphaactin, nebulin, troponin, coflin-1, and the ryanodine receptor (the last of these is more commonly implicated in central core disease, as mentioned above). The disease is so named for the rods or coils of threadlike structures in pathology material. Frozen muscle tissue stained with Gomori trichrome discloses the characteristic lesion, which can be seen under the light microscope. Myriads of bacillus-like rods, singly and in small packets, are seen beneath the plasma membrane of the muscle fiber. They are composed of material that resembles that of Z bands under the electron microscope, and often actin filaments are attached, just as they are to Z bands. The type 1 fibers, which usually predominate, are smaller than normal, as in central core disease. The size of the motor neurons has been reported to be reduced. Weakness is probably related to smallness and reduction in the number of muscle fibers and possibly to focal interruption of their cross-striations, particularly of the Z bands.

Centronuclear (Myotubular) Myopathy In this familial disease, hypotonia and weakness become manifest soon after birth or in infancy or early childhood. In the mildest form, the diagnosis does not become evident until adult years. All the striated skeletal muscles are involved to some degree, but distinctive features are ptosis and ocular palsies combined with weakness of facial, masticatory, lingual, pharyngeal, laryngeal, and cervical muscles in most of the infants with this disease, but not in adults. In the limbs, distal weakness keeps pace with proximal weakness. The limbs remain thin and are flexic throughout life. Motor development is secondarily slowed, though some improvement with maturation can occur. Later, however, motor functions that had been acquired may be lost as the disease slowly advances. Several patients have shown signs of cerebral abnormality with seizures and an abnormal electroencephalogram (EEG), but it is not clear whether this is truly part of the disease. Needle EMG examination shows the usual myopathic pattern as well as both positive sharp waves and fibrillation potentials in some cases. Abundant spontaneous activity should suggest the diagnosis of centronuclear myopathy (Griggs et al). This disorder can be classified into three types, based on severity, mode of presentation, and genetic pattern: (1) a severe neonatal X-linked recessive type, now known to be associated mainly with mutations in myotubularin, MTM1; (2) a less severe early infantile, late-infantile, or childhood autosomal recessive type associated with BIN1, RYR1, or titin; and (3) a still milder late childhood–adult autosomal dominant type associated in some cases with mutations in DYN2 (dynamin) or MYF6, a helix-loop-helix protein that appears to function as a myogenic transcription factor (Heckmatt and colleagues).

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The outstanding pathologic features of the disease are the smallness of muscles and their constituent fibers and central nucleation. In one group of centronuclear myopathies, there is hypotrophy of type 1 fibers (Bethlem et al; Karpati et al). Surrounding most of the centrally placed nuclei is a clear zone, in which there is a lack of organization of contractile elements. Because of central nucleation, the disease has incorrectly been referred to as myotubular myopathy, implying an arrest in development of muscle at the myotubular stage. Actually, the nature of the pathologic process is obscure. The small, centrally nucleated fibers do not really resemble typical myotubes. There is evidence from electron microscopic studies of changes in the central parts of the fibers (lack of enzymatic activity in the clear zones surrounding the nuclei), leading in all probability to fiber loss. Such changes argue against a purely developmental abnormality.

histochemical alterations observed in many infants and children with congenital developmental abnormalities, delays in motor development, and other conditions. Other putative congenital myopathies include so-called reducing body, trilaminar, and cap disease; zebra body; and familial myopathy with lysis in type 1 fibers, among others. They most likely also represent nonspecific reactions in muscle or fixation artifacts; as yet there is no evidence that any one of them represents a clinicopathologic entity.

Myofibrillar Myopathy This entity, more a group of myopathies, was formerly included among the congenital myopathies but now clearly belongs in the category of dystrophies and is discussed in an earlier section on that class of diseases. As stated in the introductory section, there is currently no treatment for any of the congenital myopathies.

Myopathy With Tubular Aggregates The accumulation of tubular aggregates in the subsarcolemmal or more interior regions of muscle fibers was first observed in patients with hypokalemic periodic paralysis and myotonia congenita, and later with a number of diverse conditions, such as chronic drug intoxication, hypoxia, and congenital myasthenic syndromes. However, tubular aggregates are also the defining feature of several rare and purely myopathic syndromes: (1) a slowly progressive muscular weakness, in a limb-girdle distribution, with onset in childhood or early adult life; inheritance is either autosomal dominant or recessive in type; (2) a childhood onset of proximal weakness, easy fatigability, and myasthenic features; heredity is autosomal recessive. This syndrome may respond to pyridostigmine; and (3) muscle pain, cramps, and stiffness induced by exercise; the cases to date have been sporadic. The histologic changes are readily overlooked in paraffin sections. Frozen sections show masses of material that is basophilic with hematoxylin and eosin and bright red with Gomori trichrome and shows an intense reaction with reduced form of nicotinamide adenine dinucleotide (NADH) dehydrogenase. By electron microscopy, the bundles of tubular aggregates are sharply demarcated from myofibrils.

Other Congenital Myopathies The foregoing congenital myopathies—central core, nemaline, centronuclear, and tubular aggregate types—are fairly well-defined clinicopathologic entities. Other less common types have been described, each named according to a distinctive morphologic alteration of organelles in muscle fibers in histochemical and electron microscopic preparations. In none of these additional types has the pattern of inheritance or the gene locus been identified. Some of these myopathies (multicore [minicore], fingerprint body, sarcotubular) have been reported in only a few cases, quite insufficient to allow their categorization as disease entities. Two other types, congenital fiber type disproportion and congenital fiber type predominance, originally designated as congenital myopathies, have proved to be nonspecific

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THE SPINAL MUSCULAR ATROPHIES OF INFANCY AND CHILDHOOD (SEE CHAP. 38) Obviously this important group of diseases, appearing as they do in the same periods of life as the congenital myopathies and of certain of the congenital muscular dystrophies, must figure in the differential diagnosis of early onset muscle weakness, hypotonia, and of arthrogryposis. Indeed, they represent the main problems faced by the clinician studying neuromuscular diseases of the infant. Their hereditary nature, their progression to fatal outcome or delayed motor attainments, and their tendency in certain instances to produce disabling contractures are shared with the primary muscle diseases. The proper application of current laboratory techniques sets them apart in most instances. In deference to their neuronal origin, we have placed them with the other degenerative diseases in Chap. 38.

DISORDERS OF MUSCLE CHARACTERIZED BY CRAMP, SPASM, PAIN, AND LOCALIZED MASSES (SEE ALSO CHAP. 46) Quite apart from spasticity and rigidity, which are caused by a disinhibition of spinal motor mechanisms, there are forms of muscular stiffness and spasm that can be traced to abnormalities of the lower motor neuron and its spinal inhibitory mechanisms or to the sarcolemma of the muscle fiber. Muscles may go into spasm because of an unstable depolarization of motor axons, sending volleys of impulses across neuromuscular junctions—as occurs in myokymia, hypocalcemic tetany, and pseudohypoparathyroidism. In other states, the innervation of muscle is normal, but contraction persists despite attempts at relaxation (myotonia). Or, after one or a series of contractions, the muscle may be slow in decontracting, as occurs in paradoxical myotonia and hypothyroidism. In the contracture of McArdle phosphorylase deficiency

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and phosphofructokinase deficiency, muscle, once contracted, lacks the energy to relax. In yet another type of muscle stiffness, the muscle may ripple or respond to percussion by mounding and rapidly contracting and relaxing. Cramping should also be differentiated from restless leg syndrome (see Chap. 18), which is primarily a nocturnal disorder but may carry over into the daytime hours. Each of these conditions evokes the complaint of cramp or spasm, which is variably painful and interferes with free and effective voluntary activity. Each condition has its own identifying clinical and EMG characteristics and most of them respond favorably to therapy.

Muscle Cramp (See Also Chap. 46) This subject was introduced at the beginning of this chapter, where it is pointed out that everyone at some time or other experiences muscle cramps. Cramps often occur during the night, after a day of unusually strenuous activity; less frequently they occur during the day, either during a period of relaxation or occasionally after a strong voluntary contraction or postural adjustment. A random restless or stretching movement may induce a hard contraction of a single muscle (most frequently of the foot or leg) that cannot be voluntarily relaxed. The muscle is visibly and palpably taut and painful, and the condition is readily distinguished from an illusory cramp, in which the sensation of cramp is experienced with little or no contraction of muscle. The latter phenomenon may occur in normal persons as well as in those with peripheral nerve diseases. Massage and vigorous stretch of the cramped muscle will cause the spasm to yield, although for a time the muscle remains excitable and subject to recurrent cramps. Visible fasciculations may precede and follow the cramp, indicating excessive excitability of the terminal branches of motor neurons supplying the muscle. Sometimes the cramp is so intense that the muscle is injured; it remains sore to touch and painful on use for a day or longer. Cramps of precordial chest muscles or diaphragm may arouse fear of heart or lung disease. In the EMG, the cramp is marked by bursts of high-frequency, high-voltage action potentials, and the precramp phase shows runs of activity in motor units. Why cramps should be painful is not known; probably the demands of the overactive muscle exceed metabolic supply, causing a relative ischemia and accumulation of metabolites. Overwork of muscle with or without impairment of circulation is also painful. Between cramps, the muscles are normal clinically and electromyographically. Cramps are known to increase in frequency under certain conditions and with certain diseases. They are common during pregnancy for reasons not fully understood. Dehydration and excessive sweating predispose to cramping and are a constant threat to athletes. Exertional cramps are elicited more easily than usual in motor system disease, hypothyroidism, and in chronic polyneuropathies. Focal cramping occurs after partial nerve or root injury. For example, the calf muscle on one side is subject to severe recurrent cramps after decompression of the S1 root for lumbar disc disease; in extreme cases, the muscle hypertrophies after long periods of intermittent cramping. Patients undergoing hemodialysis are subject to cramps,

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which can be suppressed by intravenous hypertonic saline or hypertonic glucose. The mechanism of muscle cramping is obscure. Several enzymes have been implicated, controversially but often included among these is myoadenylate. This enzyme, which is present in high concentration in muscle, is thought to function primarily during aerobic exercise and facilitate the regeneration of ATP from ADP through the action of adenylate kinase. However, low levels of this enzyme are not specific, occurring in such unrelated disorders as hypokalemic periodic paralysis and spinal muscular atrophy (see Layzer for details). Quinine sulfate (300 mg at bedtime and repeated in 4 h if necessary, or 300 mg tid for idiopathic diurnal cramping) had been an effective medication but is no longer widely used because of a low risk of ventricular arrhythmia. Some patients, nonetheless, seek relief from the use of quinine water, some brands of which still contain the chemical. Diphenhydramine hydrochloride (Benadryl) 50 mg or procainamide 0.5 to 1.0 g are alternatives. Phenytoin, carbamazepine, and other antiepileptic drugs, and clonazepam may be useful in alleviating repeated daytime cramping.

Tetany, Pseudotetany, and Related Cramp Syndromes As pointed out earlier, a reduction in ionizable calcium and magnesium is associated with involuntary cramp-like spasms; in their mildest form they appear as distal carpopedal spasms, but they may involve any of the muscles except the extraocular ones. Under these circumstances, stimulation of a muscle through its nerve at high frequencies (15 to 20 times per second) reproduces spasms, and hyperventilation and ischemia increase the tendency. Indeed, the Trousseau sign—carpal spasms with occlusion of the blood supply to the arm—takes advantage of the latter phenomenon. Hypocalcemic tetany is attributable to an unstable depolarization of the axonal membrane of the nerve fiber. This mechanism is affirmed by (1) the sensitivity of nerve to percussion (e.g., tapping over the facial nerve near its foramen of exit induces a facial twitch, or Chvostek sign), (2) fast-frequency doublets and triplets of motor unit potentials in the EMG indicating excessive neural excitability, (3) evocation of spasm by application of a tourniquet to proximal parts of a limb (causing ischemia of segments of nerve beneath the tourniquet), and (4) the associated tingling, prickling paresthesias from excitation of sensory nerve fibers. Hypocalcemia also causes a lesser change in the muscle fibers themselves; hence nerve block does not completely eradicate tetany. Of note, however, the Chvostek sign is found in some normal individuals, without obvious explanation. The previously described idiopathic benign cramps resemble tetany but without measurable hypocalcemia (pseudotetany). Just as in tetany, in about half of cases of benign cramp, stimulation of nerve at 15 or more times per second produces repetitive discharges. Biopsies have disclosed no abnormalities of the muscle fibers except for a few ringbinden (circumferential bands of myofibrils encircling a normal core of longitudinally oriented myofibrils). Calcium and diazepam are of no therapeutic value, but

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some patients respond to phenytoin, quinine (no longer widely used because of the risk of arrhythmia), procainamide, or chlorpromazine. A familial (autosomal dominant) form of the benign cramp syndrome has been reported; the cramps affected the distal limb muscles, began in childhood and adolescence, and persisted throughout life. Another such family with cramps beginning somewhat later in life and affecting the anterior neck, arm, and abdominal muscles as well as those of the thigh and calf has been described. Also, a familial myalgic-cramp syndrome alluded to early in this chapter has been associated with deletion of part of the dystrophin gene (but with little or no dystrophic weakness). A tendency to cramp and pain has also been noted in a number of the congenital myopathies and in some families with Duchenne and Becker dystrophies.

Satoyoshi Syndrome Satoyoshi described a group of patients who, in addition to widespread and severe cramping of muscle, developed universal alopecia, amenorrhea, intestinal malabsorption with frequent diarrhea, and some developed epiphyseal destruction and retarded growth. Most Japanese patients he described were younger than 20 years, but the two cases we have observed in whites were middle-aged. The serum calcium in these patients is normal, and the EMG shows only high-frequency discharges that are characteristic of cramps. A patient of ours with this condition had decades of chronic diarrhea, alopecia, and continuous, extremely painful calf cramps that had the gross appearance of fasciculations. This triad virtually identifies the disease. The cause of the disorder is obscure but is tentatively presumed to be autoimmune. Glucocorticoids, particularly in high doses over short periods, have been tried with some success; dantrolene has also been used and we had the impression that plasma exchange may have been helpful in one case.

Continuous Muscle Fiber Activity Due to Disorders of Nerve and Distal Axons (See Chap. 46) While the main manifestations of this group of disorders, muscular cramps, would seem to belong in this chapter on muscle diseases, they are, in fact, related to disorders of motor nerves, axons, and their terminal arborizations. For this reason, they appear in Chap. 46 on channelopathies and in Chap. 43, with disorders of the peripheral nerves.

MYALGIC STATES Many of the muscle diseases described previously are associated with aching and discomfort. These are particularly prominent in conditions that are accompanied by cramp and biochemical contracture (phosphorylase and phosphofructokinase deficiency). Ischemia of muscle—that is, intermittent claudication—is also painful, as is dystonia in some cases. Muscle weakness that imposes persistent abnormal postures on the limbs may cause stretch injury to muscles and tendons. This is observed in a number of

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the congenital myopathies and dystrophies. In all these conditions, clinical study will usually disclose the source or sources of the pain. Diffuse muscle pain, which merges with malaise, is a frequent expression of a large variety of systemic infections—for example, influenza, brucellosis, dengue, Colorado tick fever, measles, malaria, relapsing fever, rheumatic fever (in which it was called “growing pains”), salmonellosis, toxoplasmosis, trichinosis, tularemia, and Weil disease. When the pain is intense, especially if it is localized to one side of the lower chest and abdomen, the most likely diagnostic possibility is epidemic myalgia (also designated as pleurodynia, “devil’s grip,” and Bornholm disease caused by Coxsackievirus infection). Poliomyelitis may be accompanied by intense pain at the onset of neurologic involvement, and later the paralyzed muscles may ache. This is true also of the Guillain-Barré syndrome, in which the pain may precede weakness by several days. Little is known about the pathologic basis of the muscular pain in these diseases; it is not a result of muscle inflammation and is probably produced by circulating cytokines that are common to most systemic infections. Mild muscle pain is a frequent but not a necessary accompaniment of polymyositis and dermatomyositis.

Polymyalgia Rheumatica (See Chap. 10) The major consideration in elderly and middle-aged patients with pain in proximal muscles of the limbs is polymyalgia rheumatica. This subject is mentioned briefly in other sections of this book in relation to back and extremity pain (see Chap. 10) and to temporal arteritis, to which it is closely connected (see Chap. 9). The muscular soreness may be diffuse or asymmetrical, particularly in the proximal arms and shoulders. Every movement is reported as stiff and painful. The periarticular tissues and their muscular attachments are affected primarily and may be tender, but this is difficult to interpret, because tenderness in these regions may be found in healthy individuals. The sedimentation rate is elevated in the majority of patients, and a 48-h trial of prednisone, by completely alleviating muscle pain, confirms the diagnosis. In the context of muscle pain, systemic symptoms such as weight loss, headache, and fatigue, as well as mild anemia, are particularly suggestive of polymyalgia rheumatica.

Fibromyalgia This would appear, by definition, to represent an inflammation or other affection of the fibrous tissues of the muscles, fascia, and aponeuroses. Unfortunately, the pathologic basis of this state remains obscure. Only some clinical facts can be stated. During the first movements after a period of inactivity, a muscle or group of muscles may become painful and tender, particularly after exposure to cold, dampness, or minor trauma, but often for no reason that can be discerned. One looks in vain for signs of tendinous, muscular, or arthritic disease. The neck and shoulders are the most common sites. Tender areas, up to several centimeters in diameter, can be palpated within the muscles (“fibrositic nodules” by experts), and active

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contraction or passive stretching of the involved muscles increases the pain—points said to be of diagnostic value, but disputed. Often, symptoms such as mental and physical fatigue, insomnia, and headache are associated and raise the suspicion of an anxiety state or depression. In a few instances the condition clears up in a few weeks; local heat and massage and local injections of anesthetics or steroids are found to give comfort while symptoms are present, but most often it becomes a chronic condition. The chronic form of fibromyalgia presents far greater problems, usually disabling the patient and causing a change in accustomed habits and employment as discussed in Chap. 10. It has become one of the prime diagnoses made by rheumatologists and physiatrists, but the patient may first come to the attention of a neurologist. Most definitions of the syndrome have been circular or somewhat arbitrary. Those now in general use are similar to the one proposed by a committee of the American College of Rheumatology. The basis for diagnosis is the presence of widespread pain, including focal areas of pain (trigger points) that can be produced by 4 kg of digital pressure in 11 of 18 typical locations over muscles, tendons, or bone—these are concentrated around the shoulders and paraspinal regions—and there is no requirement for the presence of the several common systemic complaints that accompany the illness in most patients (fatigue, difficulty concentrating, sleeping difficulty, or anxiety). In the past, similar pains were associated with cases of irritable bowel or irritable bladder syndromes, dysmenorrhea, chronic headache, and cold intolerance. Depending on how broad a definition one allows for the widespread pain and painful trigger points, most or all patients in our experience manifest many of the same complaints as those with the chronic fatigue syndrome, which is discussed in Chap. 24. Writers on the subject, however, have pointed out that in the majority of patients, formal assessment by modern criteria fails to confirm the presence of depression, and that when depression coexists with the muscular complaints, the two are discordant temporally and in severity. While we acknowledge that antidepressants often give disappointing results and that in our practice there have been a number of patients with fibromyalgia who do not have any other manifestations of depression, they have been the exceptions. The literature eschews the use of corticosteroids for treatment of the pain, but we have had occasion to see patients whose symptoms were relieved when these medications were used for other purposes. Fibromyalgia remains a problematic illness, defined largely by a pattern of pain that justifies its name. Despite attempts to objectify the physical symptoms, psychiatric factors should not be overlooked. This condition is a favorite illness with physiotherapists, who claim that their physical measures are helpful, as they may well be. Rarely, a similar syndrome is the forerunner of what proves, after some days, with the onset of neurologic signs, to be a radiculitis, brachial neuritis, or outbreak of herpes zoster.

Other Myalgic States An impressive polymyalgia follows excessive exercise. Often, the patient observes that aching pain occurs not at

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the time of activity but some hours or even a day or two later, resembling the discomfort following the excessive use of unconditioned muscles. The muscles are sore and there is an intolerance of exercise and physical exertion. The serum CK concentration is mildly to moderately elevated. This is a natural phenomenon and is self-limiting. When such a state persists indefinitely and a program of conditioning exercises does not alleviate the pain, it represents a special category of disease. In a few instances an increased sedimentation rate or other laboratory aids may clarify the diagnosis, and muscle biopsy may reveal a nonspecific interstitial nodular myositis or the giant cell arteritis associated with polymyalgia rheumatica. Whether or not patients on lipid-lowering statin medications are particularly susceptible to this problem is not clear. A few individuals go on to have the features of the previously described fibromyalgic syndrome. However, this cluster of symptoms most often occurs without explanation, and one can only suspect an obscure infection or a subtle aberration of muscle metabolism, presently impossible to demonstrate. Reference has been made in the literature to the controversial finding of a myoadenylate deaminase deficiency in some of these cases. There is also a group of patients who have idiopathic leg pain during rest after activity. Some families afflicted in this way are forced to live a sedentary existence. The condition does not respond to analgesics. In 2 cases, a deficiency of calcium ATPase was found and reportedly alleviated by a calcium channel blocker such as verapamil, 120 mg (Walton). It must be distinguished from the syndromes of painful legs and moving toes, and from the restless leg syndrome discussed in Chap. 18. Before dismissing vague muscle aches as an excessive somatic concern, hypothyroidism, hyperparathyroidism, and renal tubular acidosis, hypophosphatemia, hypoglycemia, and the intrinsic phosphorylase or phosphofructokinase defects should be considered. Patients with these latter diseases often complain of soreness, stiffness, and lameness after strenuous muscular effort. The most valuable screening tests are the sedimentation rate and serum CK concentration. Some patients probably have an obscure metabolic myopathy, presently undiagnosable. In every reported series, such as that of Serratrice and coworkers, half of the cases with diffuse myalgia are of this uncertain type. This coincides with, or is more optimistic than, our own experience.

LOCALIZED MUSCLE MASSES Masses may be found in one or many muscles in a variety of clinical settings, and the clinical findings in each one have a different significance. Muscle or tendinous rupture is usually caused by a violent strain attended by an audible snap and then a bulge, which appears when the muscle contracts. A very focal weakening in contractile power and mild discomfort are usually noted by the patient. The biceps brachii and soleus muscles are most often affected. Treatment is by surgical repair; if that is delayed, little can be done for the condition.

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Hemorrhage into muscle may occur as a consequence of trauma, as a complication of the use of anticoagulants, in hematologic diseases, in severe myotonia, or after a minor trauma to a patient with Zenker degeneration of muscle who is convalescing from typhoid fever or some other infection. Runners may acquire painful localized hematomas in leg muscles. Tumors of muscle include desmoid tumor (a benign massive growth of fibrous tissue observed most often in parturient women and after surgery), rhabdomyosarcoma (a highly malignant tumor with strong liability to local recurrence and metastasis), liposarcoma, and angioma. Large neurofibromas or neurofibrosarcomas beneath large muscles such as the hamstring may be difficult to differentiate by physical examination or MRI from masses within the muscle. Pseudotumorous growths, sometimes massive, may follow injury to a muscle. Interlacing regenerating muscle fibers and fibroblasts compose the mass. Excision of the entire muscle had been undertaken in several cases in the belief that the growth was a rhabdomyosarcoma, whereas it is actually a benign reaction to trauma (Kakulas and Adams). Metastasis to muscle occurs, most often lymphomatous in our experience. Thrombosis of arteries or, more often, of veins causes congestion and infarction of muscle. A special type of muscle infarction occurs in patients with complicated and poorly controlled diabetes mellitus (Banker and Chester). Usually it involves the anterior thigh, and occasionally other muscles of the lower limb. The symptoms are the sudden onset of pain and swelling of the thigh, with or without the formation of a tender, palpable mass. Recurrent infarction of the same or opposite thigh is characteristic. The stereotypical clinical picture and the striking MRI appearance obviate the need for diagnostic muscle biopsy. Extensive infarction of muscle is due to the occlusion of many medium-sized muscular arteries and arterioles, most likely the result of embolization of atheromatous material from eroded plaques in the aorta or iliac arteries. Recognition of this complication and immobilization of the limb are of prime practical importance, as muscle biopsy and early ambulation may cause serious hemorrhage into the infarcted tissue. The pretibial, or compartment syndrome, also well recognized, follows direct trauma or excessive activity (marching, exercising of unconditioned muscles) or ischemic infarction due to arterial occlusion. There is swelling of the extensor hallucis longus, extensor digitorum longus, and anterior tibial muscles. Being tightly enclosed by the bones and pretibial fascia, the swelling leads to ischemic necrosis and myoglobinuria. Permanent weakness of this group of muscles can be prevented by incising the pretibial fascia and thereby decompressing the affected muscles. A similar compartment syndrome can occur in the forearm.

Myositis Ossificans This condition involves the deposition of bone within the substance of a muscle. Two types are recognized. One is a localized form that appears in a single muscle or group of muscles after trauma, and the other is a progressive,

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widespread ossifying process, entirely unrelated to trauma, in many muscles of the body. Localized (traumatic) myositis ossificans After a muscle tear, a single blow to the muscle, or repeated minor trauma, a painful area develops in the muscle. It is gradually replaced by a mass of cartilaginous consistency, and within 4 to 7 weeks a solid mass of bone can be felt and seen in CT or radiographs. This most frequently happens in vigorous adult men. The inner thigh muscles (in those who ride horses) and to a lesser extent the pectoralis major and biceps brachii are the most frequent locations. The mass tends to subside after several months if the patient desists from the activity that produced the trauma. Generalized myositis ossificans This disease, first described by Munchmeyer in 1869, has since been referred to by his name or as myositis ossificans progressiva. It is rare, although Lutwak, in 1964, was able to collect 264 cases from the literature. The cause is unknown, but the disease is probably inherited as an autosomal dominant trait. It consists of widespread bone formation along the fascial planes of muscles and has its onset in infancy and childhood in 90 percent of cases. Biopsies of indurated swellings have revealed extensive proliferation of interstitial connective tissue in which little inflammatory cell reaction is found. Within a few weeks, the connective tissue becomes less cellular and retracts, compressing the adjacent muscle fibers. Osteoid and cartilage formation occur at a later stage, developing in the connective tissue and enclosing relatively intact muscle fibers. Nearly 75 percent of all reported cases have been associated with congenital anomalies, the most frequent of which is a failure of development of the great toes or thumbs and less often, other digits. Less frequently, there is hypogenitalism, deafness, and an absence of upper incisors. The first symptom is often a firm swelling and tenderness in a paravertebral or cervical muscle. There is, in addition, a mild discomfort during muscle contraction, and the overlying skin may be reddened and slightly swollen. Trauma may be recalled as the initiating factor, but as the months pass, other muscles not injured in any recognizable way become similarly involved. At first, radiographs reveal no important changes, but within 6 to 12 months, calcium deposits are observed, and one can feel stony-hard masses within the muscles. As the disease advances, limitation of movement and deformities become increasingly evident. Calcified bridges between adjacent muscles and across joints lead to rigidity of the spine, jaw, and limbs; scoliosis; and limited expansion of the thorax. Ultimately, the patient is virtually “changed to stone.” A genetic basis for one type, fibrodysplasia ossificans progressiva, has been determined. The principal problem in diagnosis is to differentiate generalized myositis ossificans from calcinosis universalis. The latter usually occurs in relation to scleroderma or polymyositis and is characterized by calcium deposits in the skin, subcutaneous tissues, and connective tissue sheaths around the muscles; in myositis ossificans, there is actual bone formation within the muscles. The pathologic data are often too meager to justify this sharp distinction.

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The prolonged ingestion of large doses of vitamin D may also result in the deposition of masses of calcium salts around muscles, joints, and subcutaneous tissue. Calcific deposits, perhaps true ossification, may occur in the soft tissues around the hips and knees of paraplegics and rarely following a hemiplegia (“paralytic myositis ossificans”) or other causes of prolonged immobilization such as casting. Myositis ossificans may undergo spontaneous remissions and may stabilize for many years, during which the patient is capable of adequate function. In other cases, progression leads to marked debilitation and respiratory embarrassment, the final illness often being a terminal pneumonia or other infection. The molecular basis for myositis ossificans is unknown, but it has been suggested that one causative defect is the overexpression of bone morphogenic protein. In mice, the forced expression of this protein induces heterotopic bone

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formation. It is likely that the primary problem arises either because of inappropriate expression of one element of the protein or of excessive binding between signaling proteins and their receptors.

Treatment The administration of a diphosphonate (ethane-1-hydroxy1,1-diphosphate [EHDP], 10 to 20 mg/kg orally), a compound that inhibits the deposition of calcium phosphate, has been said to cause regression of new swellings and to prevent calcification. Some of the calcium deposits in calcinosis universalis have receded in response to prednisone, and because of the unclear relationship of this disease to generalized myositis ossificans, it is probably advisable to try this form of therapy as well. Excision of bony deposits may be undertaken if it is certain that they are the cause of particular disabilities.

References Adams RD: Thayer lectures: I. Principles of myopathology: II. Principles of clinical myology. Johns Hopkins Med J 131:24, 1972. Adams RD, Kakulas BA, Samaha FA: A myopathy with cellular inclusions. Trans Am Neurol Assoc 90:213, 1965. Aggarwal R, Charles-Schoeman C, Schessl J, et al: Trial of IVIG in dermatomyosisits. N Engl J Med 387:1264–1278, 2022. Aleksic S, Budzilovich C, Choy A: Congenital ophthalmoplegia in oculoauriculovertebral dysplasia hemifacial microsomia (Golden-har-Gorlin syndrome). Neurology 26:638, 1976. Amato AA, Griggs RC: Unicorns, dragons, polymyositis, and other mythological beasts. Neurology 61:288, 2003. Amato AA, Gronseth GS, Jackson CE, et al: Inclusion body myositis: Clinical and pathological boundaries. Ann Neurol 40:581, 1996. Amato AA, Russell J: Neuromuscular Disease. New York, McGraw-Hill, 2008. Amato AA, Sivakumar K, Goyal N, et al: Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 83:2239, 2014. Andreu AL, Hanna MG, Reichman H, et al: Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 341:1037, 1999. Antony JH, Procopis PG, Ouvrier RA: Benign acute childhood myositis. Neurology 29:1068, 1979. Armstrong RB: Mechanisms of exercise-induced, delayed onset muscular soreness: A brief review. Med Sci Sports Exerc 16:529, 1984. Awerbuch GI, Nigro MA, Wishnow R: Beevor’s sign and facioscapulohumeral dystrophy. Arch Neurol 47:1208, 1990. Azher SN, Jankovic J: Camptocormia. Pathogenesis, classification, and response to therapy. Neurology 65:355, 2005. Banker BQ: Congenital deformities, in Engel AG, FranziniArmstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1931–1962. Banker BQ: Dermatomyositis of childhood: Ultrastructural alterations of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 34:46, 1975. Banker BQ: Other inflammatory myopathies, in Engel AG, Franzini-Armstrong C (eds): Myology, 2nd ed. New York, McGraw-Hill, 1994, pp 1461–1486.

Ropper_Ch45_p1370-p1431.indd 1427

Banker BQ: Parasitic myositis, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1419–1444. Banker BQ, Chester CS: Infarction of thigh muscle in the diabetic patient. Neurology 23:667, 1973. Banker BQ, Victor M: Dermatomyositis (systemic angiopathy) of childhood. Medicine (Baltimore) 45:261, 1966. Banker BQ, Victor M, Adams RD: Arthrogryposis multiplex due to congenital muscular dystrophy. Brain 80:319, 1957. Barbeau A: The syndrome of hereditary late onset ptosis and dysphagia in French Canada, in Kuhn EE (ed): Progressive Muskeldystrophies, Myotonie, Myasthenie. New York, Springer-Verlag, 1966. Barohn RJ, Amato AA, Sahenk Z, et al: Inclusion body myositis: Explanation for poor response to immunosuppressive therapy. Neurology 45:1302, 1995. Barohn RJ, Jackson CE, Rogers SJ, et al: Prolonged paralysis due to non-depolarizing neuromuscular blocking agents and corticosteroids. Muscle Nerve 17:647, 1994. Bassez G, Authier FJ, Lechat-Zakman E, et al: Inflammatory myopathy with abundant macrophages (IMAM). A condition sharing similarities with cytophagic histiocytic panniculitis and distinct from macrophagic myofasciitis. J Neuropathol Exp Neurol 62:464, 2003. Batten FE, Gibb HP: Myotonia atrophica. Brain 32:187, 1909. Becker PE, Keiner F: Eine neue X-chromosomale muskeldystrophie. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 193:427, 1955. Ben Hamida M, Fardeau M, Attia N: Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve 6:469, 1983. Bethlem J, Arts WF, Dingemans KP: Common origin of rods, cores, miniature cores, and focal loss of cross-striations. Arch Neurol 35:555, 1978. Bethlem J, van Wijngaarden GK: Benign myopathy with autosomal dominant inheritance: A report on three pedigrees. Brain 99:91, 1976. Blau HM: Cell therapies for muscular dystrophy. N Engl J Med 359:1403, 2008. Blexrud MD, Windebank AJ, Daube JR: Long-term follow-up of 121 patients with benign fasciculations. Ann Neurol 34:622, 1993.

10/02/23 2:16 PM

1428

Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl J Med 292:403, 1975. Braakhekke JP, De Bruin MI, Stegeman DF, et al: The second wind phenomenon in McArdle’s disease. Brain 109:1087, 1986. Brody I: Muscle contracture induced by exercise: A syndrome attributable to decreased relaxing factor. N Engl J Med 281:187, 1969. Brouwer R, Hensgstman GJD, Egberts WV, et al: Autoantibody profiles in the sera of European patients with myositis. Ann Rheum Dis 60:116, 2001. Buchbinder R, Hill CL: Malignancy in patients with inflammatory myopathy. Curr Rheumatol Rep 4:415, 2002. Bushby KMD: Making sense of the limb girdle muscular dystrophies. Brain 122:1403, 1999. Byers TJ, Neumann PE, Beggs AH, Kunkel LM: ELISA quantitation of dystrophin for the diagnosis of Duchenne and Becker muscular dystrophies. Neurology 42:570, 1992. Casal-Dominguez M, Pinal-Fernandez I, Pak K, et al: Performance of the 2017 European Alliance of Associations for Rheumatology/ American College of Rheumatology Classification Criteria for Idiopathic Inflammatory Myopathies in Patients With MyositisSpecific Autoantibodies. Arthritis Rheumatol, 74:508, 2022. Chahin N, Selcen D, Engel AG: Sporadic late onset nemaline myopathy. Neurology 65:1158, 2005. Cori GT, Cori CF: Glucose-6-phosphatase of the liver in glycogen storage disease. J Biol Chem 199:661, 1952. Cros D, Harnden P, Pouget J, et al: Peripheral neuropathy in myotonic dystrophy: A nerve biopsy study. Ann Neurol 23:470, 1988. Cumming WJK, Weiser R, Teoh R, et al: Localized nodular myositis: A clinical and pathological variant of polymyositis. Q J Med 46:531, 1977. Curry SC, Chang D, Connor D: Drug- and toxin-induced rhabdomyolysis. Ann Emerg Med 18:1068, 1989. Dalakas MC: Intravenous immune globulin therapy for neurological diseases. Ann Neurol 126:721, 1997. Dalakas MC: Inflammatory muscle disease. N Engl J Med 372:1734, 2015. Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis. Lancet 362:971, 2003. Dalakas MC, Illa I, Pezeshkpour GH, et al: Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322:1098, 1990. Davidenkow S: Scapuloperoneal amyotrophy. Arch Neurol Psychiatry 41:694, 1939. DeVere R, Bradley WG: Polymyositis, its presentation, morbidity and mortality. Brain 98:637, 1975. DiDonato S, Taroni F: Disorders of lipid metabolism, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1587–1622. DiMauro S, Melis-DiMauro P: Muscle carnitine palmitoyltransferase deficiency and myoglobinuria. Science 182:929, 1973. Dion E, Cherin P, Payan C, et al: Magnetic resonance imaging criteria for distinguishing between inclusion body myositis and polymyositis. J Rheumatol 29:1897, 2000. Dobyns WB, Pagon R, Armstrong D, et al: Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 32:195, 1989. Donner M, Rapola J, Somer H: Congenital muscular dystrophy: A clinicopathological and follow-up study of 13 patients. Neuropediatrie 6:239, 1975. Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, et al: Teprotumumab for the treatment of active thyroid eye disease. NEJM 382:341, 2020. Dresner SC, Kennerdell JS: Dysthyroid orbitopathy. Neurology 35:1628, 1985. Dua HS, Smith FW, Singh AK, Forrester JV: Diagnosis of orbital myositis by nuclear magnetic resonance imaging. Br J Ophthalmol 71:54, 1987.

Ropper_Ch45_p1370-p1431.indd 1428

Dubois DC, Almon RR: A possible role for glucocorticoids in denervation atrophy. Muscle Nerve 4:370, 1981. Dubowitz V: Rigid spine syndrome: A muscle syndrome in search of a name. Proc R Soc Med 66:219, 1973. Emery AEH, Dreifuss FE: Unusual type of benign X-linked muscular dystrophy. J Neurol Neurosurg Psychiatry 29:338, 1966. Engel AG: Myofibrillar myopathy. Ann Neurol 46:681, 1999. Engel AG, Angelini C: Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: A new syndrome. Science 179:899, 1973. Engel AG, Angelini C, Gomez MR: Fingerprint body myopathy. Mayo Clin Proc 47:377, 1972. Engel AG, Arahata K: Mononuclear cells in myopathies: Quantitation of functionally distinct subsets, recognition of antigenspecific cell-mediated cytotoxicity in some diseases and implications for the pathogenesis of the different inflammatory myopathies. Hum Pathol 17:704, 1986. Engel AG, Emslie-Smith AM: Inflammatory myopathies. Curr Opin Neurol Neurosurg 2:695, 1989. Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004. Engel AG, Hohlfeld R, Banker BQ: The polymyositis and dermatomyositis syndromes, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1321–1366. Engel AG, Ozawa E: Dystrophinopathies, in Engel AG, FranziniArmstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 961–1026. Engel WK, Reznick JS: Late onset rod-myopathy: A newly recognized, acquired, and progressive disease. Neurology 16:308, 1966. Engel WK, Vick NK, Glueck J, Levy RI: A skeletal muscle disorder associated with intermittent symptoms and a possible defect in lipid metabolism. N Engl J Med 282:697, 1970. Faris AA, Reyes MG: Reappraisal of alcoholic myopathy: Clinical and biopsy study on chronic alcoholics without muscle weakness or wasting. J Neurol Neurosurg Psychiatry 34:86, 1971. Farmer JA: Learning from the cerivastatin experience. Lancet 358:1383, 2001. Fenichel GM, Cooper DO, Brooke MH (eds): Evaluating muscle strength and function: Proceedings of a workshop. Muscle Nerve 13(Suppl):S1:57, 1990. Fenichel GM, Florence JM, Pestronk A, et al: Long-term benefit from prednisone therapy in Duchenne muscular dystrophy. Neurology 41:1874, 1991. Filosto M, Tonin P, Vattemi et al: The role of muscle biopsy in investigating isolated muscle pain. Neurology 68:181, 2007. Fitzsimmons RB, Gurwin EB, Bird AC: Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy. Brain 110:631, 1987. Flanigan KM, Kerr L, Bromberg MB, et al: Congenital muscular dystrophy with rigid spine syndrome: A clinical, pathological, and genetic study. Ann Neurol 47:152, 2000. Franzini-Armstrong C: The membrane systems of muscle cells, in Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 232–256. Fukuyama Y, Osawa M, Saito K (eds): Congenital Muscular Dystrophies. Amsterdam, Elsevier, 1997. Gamboa ET, Eastwood AB, Hays AP, et al: Isolation of influenza virus from muscle in myoglobinuric polymyositis. Neurology 29:556, 1979. Garlepp MJ, Mastaglia FL: Inclusion body myositis. J Neurol Neurosurg Psychiatry 60:251, 1996. Gherardi R, Baudrimont M, Lionnet F, et al: Skeletal muscle toxoplasmosis in patients with acquired immunodeficiency syndrome: A clinical and pathological study. Ann Neurol 32:535, 1992.

10/02/23 2:16 PM

Chapter 45 Diseases of Muscle Goermans NM, Tulinius M, van der Akker JT, et al: Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N Engl J Med 364:1513, 2011. Gorson KC, Ropper AH: Generalized paralysis in the intensive care unit: Emphasis on the complications of neuromuscular blocking agents and corticosteroids. J Int Care Med 11:219, 1996. Gospe SM, Lazaro RP, Lava NS, et al: Familial X-linked myalgia and cramps: A nonprogressive myopathy associated with a deletion in the dystrophin gene. Neurology 39:1277, 1989. Gowers WR: Pseudohypertrophic Muscular Paralysis. London, Churchill Livingstone, 1879. Gowers WR: A lecture on myopathy, a distal form. Br Med J 2:89, 1902. Greenberg SA, Amato AA: Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol 17:359, 2004. Griggs RC, Askanas V, DiMauro S, et al: Inclusion body myositis and myopathies. Ann Neurol 38:705, 1995. Griggs RC, Mendell JR, Miller RG: Evaluation and Treatment of Myopathies. Philadelphia, Davis, 1995. Griggs RS, Pandya S, Florence JM, et al: Randomized controlled trial of testosterone in myotonic dystrophy. Neurology 39:219, 1989. Groh WJ, Groh MR, Saha C, et al: Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 358:2688, 2008. Gross B, Ochoa J: Trichinosis: A clinical report and histochemistry of muscle. Muscle Nerve 2:394, 1979. Haller RG, Drachman DB: Alcoholic rhabdomyolysis: An experimental model in the rat. Science 208:412, 1980. Harley HG, Brook JD, Rundle SA, et al: Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355:545, 1992. Harper PS: Congenital myotonic dystrophy in Britain. Arch Dis Child 50:505, 514, 1975. Harper PS: Myotonic Dystrophy. Philadelphia, Saunders, 1979. Harris JB, Cullen MJ: Ultrastructural localization and possible role of dystrophin, in Kakulas BA, Howell JM, Rosas AD (eds): Duchenne Muscular Dystrophy. New York, Raven Press, 1992. Heckmatt JZ, Sewry CA, Hodes D, Dubowitz V: Congenital centronuclear (myotubular) myopathy. Brain 108:941, 1985. Hed R, Lundmark C, Fahlgren H, Orell S: Acute muscular syndrome in chronic alcoholism. Acta Med Scand 171:585, 1962. Hers HG: Alpha-glucosidase deficiency in generalized glycogen storage disease (Pompe’s disease). Biochem J 86:11, 1963. Hoffman EP, Arahata K, Minetti C, et al: Dystrophinopathy in isolated cases of myopathy in females. Neurology 42:967, 1992. Hoffman EP, Brown RH Jr, Kunkel LM: Dystrophin: The protein product of the Duchenne muscular dystrophy locus. Cell 51:919, 1987. Hoffman EP, Fischbeck KH, Brown RH, et al: Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N Engl J Med 318:1363, 1988. Hopkins LC, Jackson JA, Elias LJ: Emery-Dreifuss humeroperoneal muscular dystrophy: An X-linked myopathy with unusual contractures and bradycardia. Ann Neurol 10:230, 1981. Ianuzzo D, Patel P, Chen V, et al: Thyroidal trophic influence on skeletal muscle myosin. Nature 270:74, 1977. Illa I: Distal myopathies. J Neurol 247:169, 2000. Jones HR, de la Monte SM: Case records of the Massachusetts General Hospital: Case 22-1998. N Engl J Med 339:182, 1998. Kakulas BA, Adams RD: Diseases of Muscle: Pathological Foundations of Clinical Myology, 4th ed. Philadelphia, Harper & Row, 1985. Karpati G, Carpenter S, Nelson RF: Type 1 muscle fiber atrophy and central nuclei. J Neurol Sci 10:489, 1970.

Ropper_Ch45_p1370-p1431.indd 1429

1429

Karpati G, Charuk J, Carpenter S, et al: Myopathy caused by a deficiency of Ca-adenosine triphosphatase in sarcoplasmic reticulum (Brody’s disease). Ann Neurol 20:38, 1986. Kass EH, Andrus SB, Adams RD, et al: Toxoplasmosis in the human adult. Arch Intern Med 89:759, 1952. Katz JS, Wolfe GI, Burns DK, et al: Isolated neck extensor myopathy: A common cause of dropped head syndrome. Neurology 46:917, 1996. Kearns TP, Sayre GP: Retinitis pigmentosa, external ophthalmoplegia and complete heart block. Arch Ophthalmol 60:280, 1958. Kissel JT, Mendell JR, Rammohen KW: Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 314:329, 1986. Kishani PS, Corzo D, Nicolino M, et al: Recombinant human α-glucosidase. Major clinical benefits in infantile-onset Pompe disease. Neurology 68:99, 2007. Kodama K, Sikorska H, Bandy-Dafoe P, et al: Demonstration of circulating autoantibody against a soluble eye-muscle antigen in Graves’ ophthalmopathy. Lancet 2:1353, 1982. Kono N, Mineo I, Sumi S, et al: Metabolic basis of improved exercise tolerance: Muscle phosphorylase deficiency after glucagon administration. Neurology 34:1471, 1984. Krahn M, de Munain AL, Streichenberger N, et al: CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol 59:905, 2006. Krasnianski M, Eger K, Neudeckers S, et al: Atypical phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35 deletion. Arch Neurol 60:1421, 2003. Kugelberg E, Welander L: Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. Arch Neurol Psychiatry 75:500, 1956. Kuhn E, Fiehn W, Schroder JM, et al: Early myocardial disease and cramping myalgia in Becker type muscular dystrophy: A kindred. Neurology 29:1144, 1979. Kuncl RW, Duncan G, Watson D, et al: Colchicine myopathy and neuropathy. N Engl J Med 316:1562, 1987. Kunkel LM: Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature 322:73, 1986. Lacomis D, Giuliani MJ, Van Cott A, Kramer DJ: Acute myopathy of intensive care: Clinical, electromyographic, and pathological aspects. Ann Neurol 40:645, 1996. Layzer RB: Neuromuscular Manifestations of Systemic Disease. Philadelphia, Davis, 1985. Layzer RB, Rowland LP, Ranney HM: Muscle phosphofructokinase deficiency. Arch Neurol 17:512, 1967. Layzer RB, Shearn MA, Satya-Murti S: Eosinophilic polymyositis. Ann Neurol 1:65, 1977. Lebenthal E, Shochet SR, Adam A, et al: Arthrogryposis multiplex congenita: 23 cases in an Arab kindred. Pediatrics 46:891, 1970. Lennon N, Kho A, Bacskai BJ, et al: Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound healing. J Biol Chem 278(50):50466, 2003. Lodi R, Taylor DJ, Tabrizi SJ, et al: Normal in vivo skeletal muscle oxidative metabolism in sporadic inclusion body myositis assessed by 31P-magnetic resonance spectroscopy. Brain 121:2119, 1998. Løseth S, Voermans NC, Torbergsen T, et al. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol 260:1504, 2013. Lundberg A: Myalgia cruris epidemica. Acta Paediatr Scand 46:18, 1957. Maas O, Paterson AS: Myotonia congenita, dystrophia myotonica, and paramyotonia. Brain 73:318, 1950. Mammen AL: Statin-associated autoimmune myopathy. N Engl J Med 374:664, 2016.

10/02/23 2:16 PM

1430

Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

Markesbery WR, Griggs RC, Leach RP, Lapham LW: Late onset hereditary distal myopathy. Neurology 23:127, 1974. Mastaglia FL, Barwich DD, Hall R: Myopathy in acromegaly. Lancet 2:907, 1970. Mastaglia FL, Laing NG: Investigation of muscle disease. J Neurol Neurosurg Psychiatry 60:256, 1996. Mastaglia FL, Ojeda VJ: Inflammatory myopathies. Ann Neurol 17:278, 317, 1985. Mastaglia FL, Phillips BA, Zilko PJ: Immunoglobulin therapy in inflammatory myopathies. J Neurol Neurosurg Psychiatry 65:107, 1998. Mayeno AN, Belongia EA, Lin F, et al: 3-(phenylamino)alanine, a novel aniline derived amino acid associated with the eosinophilia-myalgia syndrome: A link to the toxic oil syndrome? Mayo Clin Proc 67:1134, 1992. Mayeno AN, Lin F, Foote CS, et al: Characterization of “peak E,” a novel amino acid associated with eosinophilia-myalgia syndrome. Science 250:1707, 1990. McArdle B: Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 10:13, 1951. Medsger TA Jr: Tryptophan-induced eosinophilia-myalgia syndrome. N Engl J Med 322:926, 1990. Meinck HM, Goebel HH, Rumpf KW, et al: The forearm ischaemic work test—hazardous to McArdle patients? J Neurol Neurosurg Psychiatry 45:1144, 1982. Mercuri E, Pope M, Quinlivan R, et al: Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene. Arch Neurol 61:690, 2004. Merlini L, Granata C, Dominici P, Bonfiglioli S: Emery-Dreifuss muscular dystrophy: Report of five cases in a family and review of the literature. Muscle Nerve 9:481, 1986. Messina S, Fagiolari G, Lamperti C, et al: Women with pregnancyrelated polymyositis and high serum CK levels in the newborn. Neurology 58:482, 2002. Michet CJ Jr, Doyle JA, Ginsburg WW: Eosinophilic fasciitis: Report of 15 cases. Mayo Clin Proc 56:27, 1981. Milhorat AT, Wolff HG: Studies in diseases of muscle: XIII. Progressive muscular dystrophy of atrophic distal type; report on a family; report of autopsy. Arch Neurol Psychiatry 49:655, 1943. Miyoshi K, Kawai H, Iwasa M, et al: Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Brain 109:31, 1986. Mohire MD, Tandan R, Fries TJ, et al: Early-onset benign autosomal dominant limb-girdle myopathy with contractures (Bethlem myopathy). Neurology 38:573, 1988. Mokri B, Engel AG: Duchenne dystrophy: Electron microscopic findings pointing to a basic or early abnormality in the plasma membrane of the muscle fiber. Neurology 25:1111, 1975. Moorman JR, Coleman RE, Packer DL, et al: Cardiac involvement in myotonic muscular dystrophy. Medicine (Baltimore) 64:371, 1985. Müller R, Kugelberg E: Myopathy in Cushing’s syndrome. J Neurol Neurosurg Psychiatry 22:314, 1959. Munsat TL, Serratrice G: Facioscapulohumeral and scapuloperoneal syndromes, in Vinken PJ, Bruyn GW, Klawans H (eds): Handbook of Clinical Neurology. Vol 18 (new series). Amsterdam, Elsevier Science, 1992, pp 161–176. Nalini A, Ravishankar S: “Dropped head syndrome” in syringomyelia: Report of two cases. J Neurol Neurosurg Psychiatry 76:290, 2005. Namba T, Brunner MG, Grog N: Idiopathic giant cell polymyositis: Report of a case and review of the syndrome. Arch Neurol 31:27, 1974. Nonaka I, Sunohara N, Satoyoshi E, et al: Autosomal recessive distal muscular dystrophy: A comparative study with distal myopathy with rimmed vacuole formation. Ann Neurol 17:52, 1985.

Ropper_Ch45_p1370-p1431.indd 1430

Oddis CV, Reed AM, Aggarwal R, et al: Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum 65:314, 2013. Panegyres PK, Squier M, Mills KR, Newsom-Davis J: Acute myopathy associated with large parenteral dose of corticosteroid in myasthenia gravis. J Neurol Neurosurg Psychiatry 56:702, 1993. Patterson VH, Hill TRG, Fletch PJH, Heron JR: Central core disease: Clinical and pathological progression within a family. Brain 102:581, 1979. Pearson CM, Fowler WG: Hereditary nonprogressive muscular dystrophy inducing arthrogryposis syndrome. Brain 86:75, 1963. Perkoff GT, Hardy P, Velez-Garcia E: Reversible acute muscular syndrome in chronic alcoholism. N Engl J Med 274:1277, 1966. Perloff JK, Roberts WC, DeLeon AC, et al: The distinctive electrocardiogram of Duchenne’s muscular dystrophy. Am J Med 42:179, 1967. Peter JB. Skeletal muscle: Diversity and mutability of its histochemical, electron-microscopic, biochemical and physiologic properties. In Pearson CM, Mostofi FK (eds): The Striated Muscle. Baltimore, Williams & Wilkins, 1973, pp 1–18. Phillips PS, Haas RH, Banny KHS, et al: Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 137:581, 2002. Poppe M, Cree L, Bourke J, et al: The phenotype of limb-girdle muscular dystrophy type 2I. Neurology 60:1248, 2003. Pryse-Philips W, Johnson GJ, Larsen B: Incomplete manifestations of myotonic dystrophy in a large kinship in Labrador. Ann Neurol 11:582, 1982. Raphael JC, Chevret S, Chastang C, et al: Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation Assistance in Duchenne de Boulogne Muscular Dystrophy. Lancet 343:1600, 1994. Ricker K, Koch MC, Lehmann-Horn F, et al: Proximal myotonic myopathy: A new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44:1448, 1994. Ricoy JR, Cabello A, Rodriguez J, Tellez I: Neuropathological studies on the toxic syndrome related to adulterated rapeseed oil in Spain. Brain 106:817, 1983. Riddoch D, Morgan-Hughes JA: Prognosis in adult polymyositis. J Neurol Sci 26:71, 1975. Roberds SL, Leturcq F, Allamand V, et al: Missense mutation in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell 78:625, 1994. Roses MS, Nicholson MT, Kircher CS, Roses AD: Evaluation and detection of Duchenne’s and Becker’s muscular dystrophy carriers by manual muscle testing. Neurology 27:20, 1977. Rotthauwe HW, Mortier W, Beyer H: Neuer Typ einer recessiv X-chromosomal verebten Muskeldystrophie: Scapulo-humerodistale Muskeldystrophie mit fruhzeitigen Kontrakturen und Herzrhythmusstorungen. Humangenetik 16:181, 1972. Rowin J, Cheng G, Lewis SL, Meriggoli MN: Late appearance of dropped head syndrome after radiotherapy for Hodgkin’s disease. Muscle Nerve 34:666, 2006. Rubenstein NA, Kelly AM: The diversity of muscle fiber types and its origin during development, in Engel AG, FranziniArmstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 87–103. Santavuori P, Somer H, Sainio A, et al: Muscle-eye-brain disease (MEB). Brain Dev 11:147, 1989. SEARCH Collaborative Group, The. SLCO1B1 variants and statininduced myopathy—a genomewide study. N Engl J Med 359:789, 2008.

10/02/23 2:16 PM

Chapter 45 Diseases of Muscle Selcen D, Ohno K, Engel AG: Myofibrillar myopathy—clinical, morphological and genetic studies in 63 patients. Brain 127:439, 2004. Shulman LE: Diffuse fasciitis with hyperglobulinemia and eosinophilia: A new syndrome? J Rheumatol 1(Suppl):46, 1974. Shy GM, Magee KR: A new congenital non-progressive myopathy. Brain 79:610, 1956. Sigurgeirsson B, Lindelof B, Edhag O, Allander E: Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 326:363, 1992. Silbermann M, Finkelbrand S, Weiss A, et al: Morphometric analysis of aging skeletal muscle following endurance training. Muscle Nerve 6:136, 1983. Sivak ED, Salanga VD, Wilbourn AJ, et al: Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis. Ann Neurol 9:613, 1981. Slonim AE, Goans PJ: Myopathy in McArdle’s syndrome. Improvement with a high-proten diet. N Engl J Med 312:355, 1985. Speer MC, Yamaoka LH, Gilchrist JH, et al: Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: Linkage of an autosomal dominant form to chromosome 5q. Am J Hum Genet 50:1211, 1992. Stark RJ: Eosinophilic polymyositis. Arch Neurol 36:721, 1979. Statland JM, Bundy BN, Wang Y, et al for the Consortium for Clinical Investigation of Neurologic Channelopathies: Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: A randomized controlled trial. JAMA 308:1357, 2012. Steinert TH: Über das klinische und anatomische Bild des Muskelschwunds der Myotoniker. Dtsch Z Nervenheilkd 37:58, 1909. Suh J, Mukerji SS, Collens SI, Padera RF Jr, Pinkus GS, Amato AA, et al: Skeletal muscle and peripheral nerve histopathology in COVID-19. Neurol 97:e849, 2021. Sun C, Shen L, Zhang Z, Xie X. Therapeutic strategies for duchenne muscular dystrophy: an update. Genes 11:837, 2020. Tawil R, Figlewicz DA, Griggs RC, et al: Facioscapulohumeral dystrophy: A distinct regional myopathy with a novel molecular pathogenesis. Ann Neurol 43:279, 1998. Thomas MR, Lancaster R: Polymyositis presenting with dyspnea, greatly elevated muscle enzymes but no apparent muscular weakness. Br J Clin Pract 44:378, 1990. Thompson PD, Clarkson P, Karas RH: Statin-associated myopathy. JAMA 289:1681, 2003. Tomé FMS, Evangelista T, Leclerc A, et al: Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III 317:351, 1994. Tomlinson BF, Walton JN, Rebeiz JJ: The effects of aging and cachexia on skeletal muscle: A histopathologic study. J Neurol Sci 8:201, 1969. Tonin P, Lewis P, Servidei S, DiMauro S: Metabolic causes of myoglobinuria. Ann Neurol 27:181, 1990.

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Tyler FH, Stephens FE: Studies in disorders of muscle: II. Clinical manifestations and inheritance of facioscapulohumeral dystrophy in large family. Ann Intern Med 32:640, 1950. Udd B, Partanen J, Halonen P, et al: Tibial muscular dystrophy. Late adult-onset distal myopathy in Finnish patients. Arch Neurol 50:604, 1993. Umapathi T, Chaudry V, Cornblath D, et al: Head drop and camptocormia. J Neurol Neurosurg Psychiatry 73:1, 2002. Umpleby AM, Wiles CM, Trend PS, et al: Protein turnover in acid maltase deficiency before and after treatment with a high protein diet. J Neurol Neurosurg Psychiatry 50:587, 1987. van der Muelen MFG, Bronner IM, Hoogendijk JE, et al: Polymyositis: An overdiagnosed entity. Neurology 61:316, 2003. van der Ploeg AT, Clemens PR, Corzo D, et al: A randomzied study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 362:1396, 2010. van Deutekom, Janson AA, Ginjaar IB, et al: Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357:2677, 2007. Vassella F, Mumenthaler M, Rossi E, et al: Congenital muscular dystrophy. Dtsch Z Nervenheilkd 190:349, 1967. Vicale CT: The diagnostic features of a muscular syndrome resulting from hyperparathyroidism, osteomalacia owing to renal tubular acidosis, and perhaps to related disorders of calcium metabolism. Trans Am Neurol Assoc 74:143, 1949. Victor M, Hayes R, Adams RD: Oculopharyngeal muscular dystrophy: A familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 267:1267, 1962. Vignos PJ: Physical models of rehabilitation in neuromuscular disease. Muscle Nerve 6:323, 1983. Vissing J, Haller RG: The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 349:2503, 2003. Walton JN: The idiopathic inflammatory myopathies and their treatment. J Neurol Neurosurg Psychiatry 54:285, 1991. Walton JN, Adams RD: Polymyositis. London, Livingstone, 1958. Walton JN, Karpati G, Hilton-Jones D (eds): Disorders of Voluntary Muscle, 6th ed. Edinburgh, UK, Churchill Livingstone, 1994. Walton JN, Nattrass FS: On the classification, natural history and treatment of myopathies. Brain 77:169, 1954. Welander L: Myopathia distalis tarda hereditaria. Acta Med Scand 141(Suppl 265):1, 1951. Whitaker JN, Engel WK: Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N Engl J Med 286:333, 1972. Wintzen AR, Bots GTH, DeBakker HM, et al: Dysphagia in inclusion body myositis. J Neurol Neurosurg Psychiatry 51:1542, 1988. Wohlfart G, Fex J, Eliasson S: Hereditary proximal spinal muscle atrophy simulating progressive muscular dystrophy. Acta Psychiatr Neurol Scand 30:395, 1955.

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46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity Disorders of the neuromuscular junction, myotonias, and other disorders of persistent muscle fiber activity are discussed together because they can all cause weakness or changes in salience of the musculature but are not strictly speaking disease of muscle, instead having their origins in problems with the terminal motor axons or neuromuscular junction. Their pathophysiology and clinical features sometimes overlap with immune mechanisms that underlie a number of them.

DISORDERS OF THE NEUROMUSCULAR JUNCTION Several disorders of the neuromuscular junction exist the most common of which is myasthenia gravis. Most of these disorders exhibit the characteristic and striking features of fluctuating weakness and fatigability of muscle. Some degree of weakness is usually present at all times, but it is made worse by activity. The weakness and fatigability reflect physiologic abnormalities of the neuromuscular junction that are demonstrated by clinical signs and by special electrophysiologic testing. As an aid to understanding the diseases discussed in this chapter, the reader should consult the discussion of the structure and function of the neuromuscular synapse given in Chap. 2.

Myasthenia Gravis The cardinal feature of myasthenia gravis, usually referred to simply as myasthenia, is fluctuating weakness of voluntary (skeletal) muscles, particularly those innervated by motor nuclei of the brainstem, that is, ocular, masticatory, facial, deglutitional, and lingual. Manifest weakening during continued activity, quick restoration of power with rest, and dramatic improvement in strength following the administration of anticholinesterase drugs such as neostigmine are the other notable characteristics. Myasthenia is an immune disease in which circulating antibodies against components of the motor postsynaptic membrane and subsequent structural changes in that membrane explain virtually all the features of the disease. Historical note Several students of medical history affirm that Willis, in 1672, gave an account of a disease that

could be none other than myasthenia gravis. Others give credit to Wilks (1877) for the first description and for having noted that the medulla was free of disease, in distinction to other types of bulbar paralyses. The first reasonably complete accounts were those of Erb (1878), who characterized the disease as a bulbar palsy without an anatomic lesion, and of Goldflam (1893); for many years thereafter, the disorder was referred to as the Erb-Goldflam syndrome. Jolly (1895) was the first to use the name myasthenia gravis, to which he added the term pseudoparalytica to indicate the lack of structural changes at autopsy. Also, it was Jolly who demonstrated that myasthenic weakness could be reproduced in affected patients by repeated faradic stimulation of the motor nerve and that the “fatigued” muscle would still respond to direct galvanic stimulation of its membrane. Interestingly, he suggested the use of physostigmine as a form of treatment, but there the matter rested until Reman, in 1932, and Walker, in 1934, demonstrated the therapeutic value of the drug. The relationship between myasthenia gravis and tumors of the thymus gland was first noted by Laquer and Weigert in 1901, and in 1949, Castleman and Norris gave the first detailed account of the pathologic changes in the gland. In 1905, Buzzard published a careful clinicopathologic analysis of the disease, commenting on both the thymic abnormalities and the infiltrations of lymphocytes (called lymphorrhages) in muscle. In 1973 and subsequently, the autoimmune nature of myasthenia gravis was established through a series of investigations by Patrick and Lindstrom, Fambrough, Lennon, and A.G. Engel (1977) and their colleagues (see in the following text). The clear demonstration of an immunologic mechanism operative at the neuromuscular junction was the most significant development in our understanding of myasthenia gravis. Patrick and Lindstrom discovered that repeated immunization of rabbits with AChR protein obtained from the electric eel caused muscular weakness (contrary to what is stated in some books, their discovery was not accidental). Lennon and colleagues recognized this model as being similar to that of myasthenia gravis. Soon thereafter, Fambrough and coworkers demonstrated that the basic defect in myasthenia gravis was a marked reduction in the number of ACh receptors on the postsynaptic membrane of the neuromuscular junction. These

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observations were followed by the creation of an experimental model of the disease and the demonstration that experimentally induced myasthenia had clinical, pharmacologic, and electrophysiologic properties identical with those of human myasthenia gravis (Engel et al, 1976a). It was also shown that humoral antibodies directed against protein components of AChR could transfer the myasthenic weakness to normal animals and that the weakness, as well as the physiologic abnormalities, could be reversed by the administration of anticholinesterase drugs. Thus, the accumulated evidence satisfied the criteria for the diagnosis of an autoantibody-mediated disorder (Drachman, 1990). Epidemiology  Certain epidemiologic features of the disease are of clinical interest. Its prevalence is variously estimated to be from 43 to 84 per million persons and the annual incidence rate is approximately 1 per 300,000. The disease may begin at any age, but onset in the first decade is relatively rare (only 10 percent of cases begin in children younger than 10 years of age). The peak age of first symptoms is between 20 and 30 years in women and between 50 and 60 years in men. Under the age of 40, females are affected two to three times as often as males, whereas in later life, the incidence in males is higher (3:2). Of patients with thymomas, the majority is older (50 to 60 years) and males predominate. Familial occurrence of myasthenia is known, but it is rare. Many such cases prove to have one of the genetically determined myasthenic syndromes and not the acquired autoimmune form of disease (see further on). More common is a family history of one of the autoimmune diseases enumerated earlier. For example, in one series, 30 percent had a maternal relative with a connective tissue disease, suggesting that myasthenia gravis patients inherit a susceptibility to autoimmune disease (Kerzin-Storrar and associates). There have also been reports of the concurrence of myasthenia and multiple sclerosis, but this association is less certain. There is an increased representation of HLA-B8 and -DR3 haplotypes, as occurs in other autoimmune diseases, which are discussed further on.

Clinical Manifestations Myasthenia gravis, as the name implies, formerly had a grave prognosis, perhaps less so today but still associated with considerable morbidity. As mentioned, repeated or persistent activity of a muscle group exhausts contractile power, leading to a progressive paresis, and rest restores strength, at least partially. These features, concentrated in the palpebral, ocular, and the oro-facial-lingual muscles, are the identifying attributes of the disease and their demonstration is usually enough to establish the diagnosis on clinical grounds. The special vulnerability of the neuromuscular junctions in certain muscles gives myasthenia its highly characteristic clinical appearance. Usually, the eyelids and the muscles of eye movement, and somewhat less often, of the face, jaws, throat, and neck, are the first to be affected. Infrequently, the initial complaint is referable to the limbs or to breathing. Specifically, weakness of the levator palpebrae or extraocular muscles is the initial manifestation of the disease in about half the cases, and these muscles

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are involved eventually in more than 90 percent. Ocular palsies and ptosis are usually accompanied by weakness of eye closure, a combination that is virtually always indicative of the disease, although it may be observed in certain muscular dystrophies. Diplopia is quite common in myasthenia, but it does not correspond to the innervatory pattern of a nerve; instead, it is the result of asymmetrical weakness of several muscles in both eyes. As the disease advances, it spreads insidiously from the cranial to the limb and axial muscles, but there are instances of fairly rapid development, sometimes initiated by an infection, usually respiratory. In rare cases, the distal extremity muscles may be involved, such as the “myasthenic hand” described by Janssen and colleagues. Symptoms may first appear during pregnancy or, more commonly, during puerperium or in response to paralytic drugs used during general anesthesia. Particular ocular signs are highly characteristic of myasthenia. For example, sustained upgaze (for 30 or more seconds) will usually induce or exaggerate ptosis and may uncover myasthenic ocular motor weakness, thereby marking it as “fatigable.” Another characteristic sign, not as frequently elicitable as fatigable ptosis, was described by Cogan and is a twitching of the upper eyelid that appears a moment after the patient moves the eyes from a downward to the primary position (“lid-twitch” sign). Or, after sustained upward gaze, one or more twitches may be observed upon closure of the eyelids or during horizontal movements of the eyes. Repeated ocular versions when tracking a target or by an optokinetic stimulus may disclose progressive paresis of the muscles that carry out these movements. Unilateral painless ptosis without either ophthalmoplegia or pupillary abnormality in an adult will most often prove to be due to myasthenia. Usually, there is subtle ptosis of the other eye that can be revealed by manually elevating the more affected eyelid. Attempts by the patient to overcome ptosis may impart a staring expression of the opposite eye. Bright sunlight is said to aggravate the ocular signs and cold to improve them. The application of an ice pack over the eye often relieves the ptosis for a brief period. Muscles of facial expression, mastication, swallowing, and speech are affected in 80 percent of patients at some time in the illness, and in 5 to 10 percent, these are the first or only muscles to be involved. Less frequent is early involvement of the flexors and extensors of the neck, muscles of the shoulder girdle, and flexors of the hips. (This pattern may be associated with a special autoantibody, as will be discussed later.) Of the trunk muscles, the erector spinae are the most frequently affected. In the most advanced cases, all muscles are weakened, including the diaphragmatic, abdominal, and intercostal, and even the external (skeletal muscle) sphincters of the bladder and bowel. As the disease progresses, the involvement of any group of muscles closely parallels their degree of weakness early in the disease. The clinical rule also holds that the proximal muscles are far more vulnerable than distal ones, as they are in most other forms of myopathy. Another characteristic and understandable feature of myasthenic weakness is its tendency to increase as the day

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wears on or with repeated use of an affected muscle group but curiously, patients seldom volunteer this information. A few patients report paradoxical worsening on awakening, especially if they have not taken medication during the night, but a larger proportion of patients are close to asymptomatic after a night’s rest. In general terms, therefore, myasthenia gravis may be conceived as a fluctuating and fatigable oculofaciobulbar palsy. Other features result from the topography and fatigability of the disease. The natural smile becomes transformed into a snarl; the jaw may sag so that it must be propped up by the patient’s hand; chewing tough food may be difficult and the patient may have to terminate a meal because of the inability to masticate and swallow. It may be more difficult to eat after talking, and the voice fades and becomes nasal after sustained conversation. Women may complain of inability to fix their hair or makeup because of fatigue of the shoulders or of difficulty in applying lipstick because they are unable to purse and roll their lips. Weakness of the neck muscles causes fatigue in holding up the head. In cases with generalized weakness, there is difficulty in retaining flatus because of the weakness of the external rectal sphincter. A peculiarity of myasthenic muscle contraction that may be observed occasionally is a sudden lapse of sustained posture or interruption of movement resulting in a kind of irregular tremor similar to that of normal muscle nearing the point of exhaustion. A dynamometer demonstrates the rapidly waning power of contraction of a series of hand grips and repetitive stimulation of a motor nerve at slow rates while recording muscle action potentials shows the same decremental strength in a quantitative fashion (see Fig. 2-15A and in the following text). Weakened muscles in myasthenia gravis undergo atrophy to only a minimal degree or not at all. Tendon reflexes are seldom altered. Even repeated tapping of a tendon does not usually tax muscles to the point where contraction fails. Smooth and cardiac muscles are not involved and other neural functions are preserved. Weakened muscles, especially those of the eyes and back of the neck, may ache, but the pain is seldom an important complaint. Paresthesias of the face, hands, and thighs are reported infrequently but are not accompanied by demonstrable sensory loss. The tongue may display one central and two lateral longitudinal furrows (trident tongue), as pointed out originally by Buzzard; the tongue may be atrophic in the MuSK (muscle-specific tyrosine kinase) form of disease. Patients with MuSK antibody, mostly women, have a special clinical syndrome of prominent oculobulbar weakness (Scuderi et al), or severe disease characterized by respiratory crises (see also Evoli et al). Others have reported a different pattern of mainly neck and proximal weakness that simulates a myopathy. Many of these patients are inadequately responsive to anticholinesterase treatment. Clinical grading To facilitate the clinical staging of therapy and prognosis, the classification introduced by Osserman remains useful; it can be found in his monograph cited in the references and in previous editions of this book. This system has been replaced by a scheme

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suggested by a task force of the Myasthenia Gravis foundation, as reproduced here (Jaretzki et al). Class I  Any ocular muscle weakness May have weakness of eye closure All other muscle strength is normal Class II Mild weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity IIa Predominantly affecting limb, axial muscles, or both May also have lesser involvement of oropharyngeal muscles IIb  Predominantly affecting oropharyngeal muscles, respiratory muscles, or both May also have lesser or equal involvement of limb, axial muscles, or both Class III Moderate weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity IIIa Predominantly affecting limb, axial muscles, or bothMay also have lesser involvement of oropharyngeal muscles IIIb Predominantly affecting oropharyngeal muscles, respiratory muscles, or both May also have lesser or equal involvement of limb, axial muscles, or both Class IV Severe weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity IVa  Predominantly affecting limb and/or axial muscles May also have lesser involvement of oropharyngeal muscles IVb Predominantly affecting oropharyngeal muscles, respiratory muscles, or both May also have lesser or equal involvement of limb, axial muscles, or both Class V Intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb. Others have proposed a classification based on a constellation of the age of onset, presence or absence of thymoma, antibody level against acetylcholine receptor (AChR), and association with human leukocyte antigen (HLA) haplotypes (Compston and colleagues). This system is as follows: (1) myasthenia gravis with thymoma— no sex or HLA association, high AChR antibody titer; (2) onset before age 40, no thymoma—female preponderance and an increased association with HLA A1, B8, and DRW3 antigens; (3) onset after age 40, no thymoma— male preponderance, increased association with HLA A3, B7, and DRW2 antigens, low AChR antibody titer. The last group includes a proportion of older men with purely ocular symptoms (formerly Osserman type I). Classifications such

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as these are meant to capture certain types and contexts of myasthenia more than to convey the severity of illness.

Course and Prognosis The course of the illness is extremely variable. Rapid spread from one muscle group to another occurs in some, but in others, the disease remains unchanged for years before progressing or there is no progression. Remissions may take place without explanation, usually in the first years of illness, but these happen in less than half the cases and seldom last longer than a month or two. If the disease remits for a year or longer and then recurs, it then tends to be steadily progressive. Relapse may also be occasioned by the same events that, in some cases, preceded the onset of the illness, especially infections. The risk of severe respiratory compromise or death from generalized myasthenia gravis is greatest in the first year after the onset of the disease (Simpson). The second period of danger in progressive cases is from 4 to 7 years after onset. After this time, the disease tends to stabilize and the risk of severe relapse diminishes. Fatalities relate mainly to the respiratory complications of pneumonia and aspiration. The mortality rate in the first years of illness, formerly in excess of 30 percent, is now less than 5 percent, and with appropriate therapy, virtually all patients lead normal lives. An aspect of interest is the timing and frequency of conversion from ocular and restricted oropharyngeal patterns of weakness to more widespread involvement including the diaphragm. An increasing duration of purely ocular myasthenia is associated with a decreasing risk of late generalization of weakness (Bever and coworkers). In a retrospective study of 108 patients, it was found that only 15 percent of the observed instances of generalization occurred more than 2 years after isolated ocular manifestations. Later age at onset was also associated with a higher incidence of fatal respiratory crises. In general, patients whose disease begins at a younger age run a more benign course. Analysis of the course of an astonishing 1,036 patients for a mean duration of 12 years showed that the clinical manifestations remained confined to the extraocular muscles and orbicularis oculi in 16 percent (Grob and colleagues). Their data further indicated that localized ocular myasthenia present for only a month was associated with a 60 percent likelihood that the disease would generalize, but in those cases that remained restricted for more than a year, only 16 percent became generalized. Also informative in this series was that in 67 percent the disease attained its maximum severity within a year of onset, and in 83 percent, within 3 years. In contrast, in another study of 37 consecutive cases with only ocular signs, 17 had more widespread weakness within a period of 6 years (Weinberg et al). It has been stated that the progression of symptoms is more rapid in male than in female patients. Occasionally, isolated muscle groups may occasionally remain permanently weak even when the ocular and generalized weakness has resolved. The muscles most often affected in this way are the anterior tibialis, triceps, and portions of the face. The long-term outlook for children with myasthenia is better than it is for adults, and their life expectancy is

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only slightly reduced. Among a group of 149 children for an average of 17 years; 85 of them had thymectomies, one of the main treatments for myasthenia as discussed further on (Rodriguez and colleagues). Approximately 30 percent of the nonthymectomized and 40 percent of the thymectomized patients underwent remission and were free of symptoms, usually in the first 3 years of illness. Those children with bulbar symptoms and no ocular or generalized weakness had the most favorable outcome.

Thymic and Systemic Disorders Associated With Myasthenia A nonneoplastic lymphofollicular hyperplasia of the thymic medulla occurs in 65 percent or more of cases of myasthenia and thymic tumors occur in 10 to 15 percent. Thymomas with malignant characteristics may spread locally in the mediastinum and to regional lymph nodes, but they rarely metastasize beyond these structures; when they do, the lungs and liver are usually affected. It should be emphasized that thymic enlargement and tumors may be missed in plain films of the chest and should be sought by CT with contrast. A striking degree of hyperplasia of the medulla of the thymus characterized by lymphoid follicles with active germinal centers is found in the majority of cases. Hyperplasia is even more frequent in younger patients in the third and fourth decades. The cells in the centers of the follicles are histiocytes surrounded by helper T lymphocytes, B lymphocytes, and plasma cells; immunoglobulin G (IgG) is elaborated in the germinal follicles. These resemble the cellular reaction observed in the thyroid tissue of Hashimoto thyroiditis. Because the latter disease has been reproduced in animals by injecting extracts of thyroid with Freund adjuvants, it had long ago been suggested that the so-called thymitis of myasthenia gravis is the result of a similar autoimmune sensitization, but the inciting events for this process are entirely unknown. Immunosuppression with steroids causes the involution of the thymus. With regard to thymic tumors, two forms have been described: one composed of histiocytic cells like the reticulum cells in the center of the follicles, and the other predominantly lymphocytic and considered to be lymphosarcomatous. Some of the tumors have a high proportion of spindle-shaped cells. Overlapping types have been common. Thymic tumors may be unattended by myasthenia, though myasthenia has eventually developed in all of the cases under our observation, sometimes 15 to 20 years after the tumor was removed surgically. The severity of myasthenic symptoms is said to be no different in patients with thymoma than it is from that in patients without a tumor (Bril and colleagues), but our impression has been that patients with tumors, particularly children, often have a peculiar clinical course. For example, we have observed unexpected sudden remissions and severe relapses, as well as resistance to medications. Many contemporary studies, including more than 40 autopsies at our hospitals, have confirmed Erb’s original contention that myasthenia gravis is a disease without a central nervous system lesion. The brain and spinal cord are normal unless damaged by hypoxia and hypotension from cardiorespiratory failure. Furthermore, the muscle

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fibers are generally intact, although in fatal cases with extensive paralysis, isolated fibers of esophageal, diaphragmatic, and eye muscles may undergo segmental necrosis with variable regeneration (Russell). Scattered aggregates of lymphocytes (lymphorrhages) are also observed, as originally noted by Buzzard, but none of these changes in muscle explains the widespread and severe weakness. The main ultrastructural alterations occur in the motor endplate. These changes, elegantly demonstrated by A.G. Engel and associates (1976a, 1977, 1987), consist of a reduction and simplification in the surface area of the postsynaptic membrane (sparse, shallow, abnormally wide, or absent secondary synaptic clefts) and a widening

of the synaptic cleft (Fig. 46-1). The number and size of the presynaptic vesicles and their quanta of acetylcholine (ACh) are normal. The observation of regenerating axons near the junction, the many simplified junctions, and the absence of nerve terminals supplying some postsynaptic regions suggested to Engel and coworkers (1976a, 1977, 1987) that there was an active process of degeneration and repair of the neuromuscular junction, particularly of the postsynaptic side. Although not directly relevant to myasthenia, it is of interest that a number of curious neurologic disorders occur in association with thymoma. Among our own patients were two with “limbic encephalitis” with memory

A

B Figure 46-1.  A. Endplate from a patient with myasthenia gravis. The terminal axon contains abundant presynaptic vesicles, but the postsynaptic folds are wide and there are few secondary folds. The loose junctional sarcoplasm is filled with microtubules and ribosomes. The synaptic cleft (asterisk) is widened. (From Santa et al by permission.) B. Normal endplate for comparison. (Courtesy of Dr. A.G. Engel.)

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loss and confusion that could not be differentiated from the paraneoplastic variety of encephalitis (see Chap. 30), 1 case of midbrain encephalitis, 1 of Morvan’s fibrillary chorea (see further on), and 1 of aplastic anemia. Some of these neurologic processes are associated with antibodies directed against voltage-gated potassium channels (VGKC). Such cases appear in the literature, and all are considered to have a humoral immune basis. Of biologic and even greater clinical importance is the coexistence of myasthenia gravis and other autoimmune diseases. Thyrotoxicosis with periodic paralysis (5 percent of myasthenic patients), lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, mixed connective tissue disease, anticardiolipin antibody, and (curiously) polymyositis have all been associated with myasthenia more often than can be explained by chance. A proportion of young women with myasthenia have moderately elevated titers of antinuclear antibody without the clinical manifestations of systemic lupus.

Etiology and Pathogenesis Myasthenic weakness and fatigue are a result of the failure of effective neuromuscular transmission on the postsynaptic side. The greatly reduced number of receptors and the competitive activity of anti-AChR antibodies produce postsynaptic potentials of insufficient amplitude to discharge some muscle fibers. Blocked transmission at many endplates results in a reduction in the contractile power of the muscle. This deficiency is reflected first in the ocular and cranial muscles that are both the most continuously active and have the fewest AChRs per motor unit. Fatigue is understandable as the result of the normal decline in the amount of ACh released with each successive impulse. Antibodies to AChR protein are present in more than 85 percent of patients with generalized myasthenia and in 60 percent of those with ocular myasthenia (NewsomDavis, 1992). The presence of receptor antibodies has proved to be a reasonably sensitive and reliable test of the disease, as discussed later. The manner in which the antibodies that are directed against proteins in the intracellular compartment (such as anti-MuSK discussed later) causes weakness is not known. Neuromuscular transmission is therefore impaired in several ways: (1) the antibodies block the binding of ACh to the AChR; (2) serum IgG from myasthenic patients has been shown to induce an increase in the degradation rate of AChR. This may be the result of the capacity of antibodies to cross-link the receptors; (3) antibodies cause a complement-mediated destruction of the postsynaptic folds (Engel and Arahata). Although the evidence that an autoimmune mechanism is responsible for the functional disorder of muscle in myasthenia gravis is incontrovertible, the source of the autoimmune response has not been established. Because most patients with myasthenia have thymic abnormalities and a salutary response to thymectomy, it is logical to implicate the lymphoid reaction in this gland in the pathogenesis of the disease. Both T and B cells from the myasthenic thymus are particularly responsive to the AChR, more so than analogous cells from peripheral blood.

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Moreover, the thymus contains “myoid” cells (resembling striated muscle) that bear surface AChR. It is not known with certainty that thymic myoid cells are the source of immunologic stimulation in myasthenia gravis. The most obvious objection is that such cells are even more abundant in the normal than in the myasthenic thymus (according to Schluep et al). Another suggested pathogenesis, yet unconfirmed, is that a virus with a tropism for thymic cells might alter such cells and induce antibody formation. A viral infection might, at the same time, have a potential for oncogenesis, accounting for thymic tumors, but this is all speculative. Scadding and associates have suggested a different mode of thymic involvement; they have shown that thymic lymphocytes from patients with myasthenia gravis can synthesize anti-AChR antibody, both in culture and spontaneously.

Diagnosis In patients who present with a changeable, specifically fatigable, diplopia or ptosis and the typical myasthenic facies—unequally drooping eyelids, relatively immobile mouth turned down at the corners, a smile that looks more like a snarl, a hanging jaw supported by the hand— the diagnosis can hardly be overlooked. However, only a few patients display this fully developed syndrome. Ptosis, diplopia, difficulty in speaking or swallowing, or weakness of the limbs is at first mild and inconstant and may be mistaken for cerebrovascular disease. However, the finding that sustained activity of small cranial muscles results in weakness (e.g., increasing droop of eyelids while looking at the ceiling or diplopia when fixating in lateral or vertical gaze or reading for 2 to 3 min) and that contraction improves after a brief rest is virtually diagnostic, even in the early stages of the disease. Any other affected group of muscles may be tested in a similar fashion. The characteristic ocular signs have already been described. For confirmation, the measurement of specific antibody (anti-AChR), electromyography, and certain pharmacologic tests described below are necessary. Several special clinical problems and associated conditions are summarized further on. Electrophysiologic testing Characteristic of myasthenia is a rapid reduction in the amplitude of compound muscle action potentials during a series of repetitive stimulations of a peripheral nerve at a rate of 3 per second (decrementing response as shown in Fig. 2-15A). Reversal of this response by neostigmine or edrophonium has been a reliable confirmatory finding in most cases. A decremental response to stimulation can usually be obtained most often from the proximal limb muscles followed by the facial and, to a lesser extent, the hand muscles, which may or may not be clinically weak. During a progressive phase of the disease or during corticosteroid therapy, a slight initial incrementing response may be obtained, not to be confused with the marked incrementing response after voluntary contraction that characterizes the Lambert-Eaton syndrome (see further on). Single-fiber electromyography (EMG) represents an even more sensitive method of detecting the defect in neuromuscular transmission. This technique demonstrates an inconstancy of the normally invariant interval between the

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firing of muscle fibers connected to the same motor unit (“jitter”—see “Single-Fiber Electromyography” in Chap. 2) or complete blocking of successive discharges from single muscle fibers belonging to the same motor unit. The test requires a great deal of cooperation from the patient and that contraction of a muscle be sustained at just the right amplitude in order to isolate single muscle fibers from the same unit. It is also possible to detect such pairs of fibers by electrical stimulation of a nerve. Nerve conduction velocities and distal motor latencies are normal unless there is a coincident polyneuropathy. Neostigmine test  Almost as valuable as electrophysiologic testing is testing with the cholinesterase inhibitors neostigmine and, in the past, edrophonium, a more rapidly acting agent. These drugs prolong and exaggerate the effects of ACh in the synapse and thereby produce an increment in muscle power in the patient with myasthenia. Edrophonium is variably available in the United States at the time of this writing, but neostigmine affords a longer time for observation, as noted in the next paragraph. The tests are performed in the following manner. After the estimation of strength in a cranial (usually the levator palpebrae or an extraocular muscle) or limb muscle (by dynamometry), or vital capacity, neostigmine is injected intramuscularly in a dose of 1.5 mg. Atropine sulfate (0.8 mg) is generally given several minutes in advance to counteract the unpleasant muscarinic effects of neostigmine (salivation, sweating, bronchorrhea, borborygmi, bowel cramps, and, sometimes, diarrhea). Neostigmine may alternatively be given intravenously in a dose of 0.5 mg, but its effect is often too brief to be as useful. After intramuscular injection of neostigmine, objective improvement occurs within 10 to 15 min, reaches its peak at 20 min, and lasts up to 1 h, allowing for careful verification of the neurologic improvement. Many neurologists perform this test twice, once with an injection of saline as a control. Alternatively, 1 mg (0.1 mL) of edrophonium is given intravenously; if this dose is tolerated and no definite improvement in strength occurs after 45 s, another 4 to 9 mg is injected. A total dose of 10 mg is rarely necessary. Most patients who respond do so after 3 to 5 mg has been administered. The mild muscarinic effects of edrophonium are blocked by pretreatment with atropine 0.8 mg subcutaneously as for neostigmine. The clinical effect of improved ptosis, extraocular movements, oropharyngeal function, arm and shoulder abduction, or vital capacity persists for no more than 5 min with edrophonium and 60 min with neostigmine. One caution: with either drug, some patients deteriorate immediately, but briefly, as a result of an increase in pulmonary secretions. A positive test consists of visible (objective) improvement in muscle contractility, fusion of diplopia, or resolution of fatigable ptosis. Dynamometry and measurement of forced vital capacity serve as more objective markers of improvement or lack of effect. The report of subjective improvement alone is not dependable and one must be distrustful of equivocal test results, which may occur with ocular palsies due to tumors, thyroid disease, Guillain-Barré syndrome (GBS), progressive supranuclear palsy, or carotid aneurysms (pseudoocular myasthenia).

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A negative test with an anticholinesterase agent does not entirely exclude myasthenia gravis but is a strong point against the diagnosis. In a small number of patients with periodic and purely ocular symptoms who later prove to have myasthenia gravis, the edrophonium and neostigmine tests (and electrophysiologic studies and AChR antibody measurements) may be entirely normal during the first or even after several acute episodes. Only later, for inexplicable reasons, do these tests become positive. Finally, the anticholinesterase-inhibiting drugs carry a small risk of inducing ventricular fibrillation and cardiac arrest so that testing should be carried out where emergency support is accessible. Measurement of receptor antibodies in blood The detection of anti-AChR antibodies provides a reasonably sensitive and highly specific test for the diagnosis of myasthenia. The radioimmunoassay method of detection is accurate and widely used. Serum antibodies are found in 80 to 90 percent of patients with generalized myasthenia gravis and in approximately 60 percent of those whose symptoms are restricted to the ocular muscles (Vincent and Newsom-Davis). For the most part, adults with myasthenia whose sera are persistently negative for AChR antibodies do not differ clinically or electromyographically from those with antibodies with the exception noted below. Persistently negative AChR antibody tests are more frequently found in patients with ocular myasthenia than in patients with generalized weakness. Patients with thymoma and severe generalized myasthenia are practically always seropositive. Interestingly, the antibody titers usually remain elevated during clinical remissions. Instances of “seronegative” disease are sometimes due to antibody production against unusual muscle epitopes that are located on or near the AChR; their detection requires a special panel of tests. However, the majority of such cases have been ascribed to IgG antibodies directed against an intracellular muscle-specific kinase (MuSK). This enzyme plays a role in supporting the normal structure of the postsynaptic membrane and in the arrangement of AChR, but its main function may be in developmental synaptic differentiation. The illness is possibly acquired late in life because of the high rate or turnover of the neuromuscular junction, with newly formed junctions being physiologically inadequate. The associated clinical syndrome differs from typical myasthenia and was discussed earlier. Also of interest, but not currently used in routine diagnosis, is the presence of antibodies directed against striated muscle in almost half of myasthenic patients and an even higher incidence (stated to be 85 percent) in patients who also have a thymoma. Rare instances of seronegative myasthenia with antibodies directed to cortactin, a protein in the pathway of MuSK has been described (Cortes-Vicente et al). Each of the commonly used diagnostic tests, electrophysiology, edrophonium, and antibodies, proves to be about equally reliable. Kelly and coworkers obtained positive results with single-muscle-fiber recording in 79 percent, with the antireceptor antibody test in 71 percent, and with the edrophonium test in 81 percent. Combined, they confirmed the diagnosis in 95 percent of clinically suspected cases. Presumably, had the anti-MuSK receptor

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

antibody test been available, the sensitivity of serologic diagnosis would have been higher. In keeping with the observation of some myasthenic patients that their weakness improves in the cold, a test has been devised in which an ice pack is placed over a ptotic eyelid for 2 min or to the limit of the patient’s tolerance. Sethi and colleagues found that ptosis was diminished in 8 of 10 patients. In our patients, this effect has not been as consistently evident, but it may be a useful adjunctive test. Other diagnostic tests performed routinely in essentially all patients with myasthenia gravis include CT of the chest (for the detection of thymic enlargement or thymoma), tests of thyroid function for reasons discussed further on, and in cases of uncertain diagnosis, magnetic resonance imaging of the cranium and orbits to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.

Special Diagnostic Problems We have encountered the following clinical problems in myasthenia: 1. The concurrence of myasthenia gravis and thyrotoxicosis. Thyrotoxicosis may produce a characteristic ocular myopathy and there is a tentative relation to periodic paralysis, as indicated in Chap. 45. There is no definite evidence that thyrotoxicosis aggravates myasthenia gravis; some clinicians have even observed an inverse relationship between the severity of the two conditions. Hypothyroidism, however, does worsen the myasthenic symptoms. The ophthalmoplegia of thyrotoxicosis can usually be distinguished by the presence of associated exophthalmos (early in the disease, exophthalmos may be absent), lack of ptosis, and the lack of definitive response to neostigmine. Polymyositis and inclusion body myopathy are differentiated from myasthenia by lack of involvement of extraocular muscles, but they may affect oropharyngeal muscles, as does myasthenia. Finding the signs of these diseases in combination with those of myasthenia indicates a concurrence of two independent autoimmune diseases. 2. The patient with depression who complains of nonspecific weakness when actually referring to fatigability. There is no ptosis, strabismus, or dysphagia, though an anxious individual may complain of diplopia (usually of momentary duration when drowsy) and also of tightness in the throat (globus hystericus). A number of such patients claim improvement with neostigmine, but the objective reversal is always uncertain. Conversely, myasthenia is as often mistaken for hysteria or other emotional illness, mainly because the physician is unfamiliar with myasthenia (or with hysteria) and has been overly impressed with the precipitation of the illness by an emotional crisis. Furthermore, fatigability is a feature of all of these conditions, but only in the psychiatric ones does it extend to the sphere of mental endurance. Those with myasthenia do not usually complain of fatigue of the mind, whereas these are frequent complaints in psychiatric conditions. A similar problem arises frequently in our services in judging breathlessness due to anxiety or cardiopulmonary disease in a patient with presumed

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myasthenia. Careful appraisal of the breathing pattern and determination of the vital capacity or other spirometric measurements are helpful here. 3. Progressive external ophthalmoplegia and other restricted myopathies, including congenital myasthenic states. These may be mistaken for long-established myasthenia gravis. It should be emphasized that the extraocular muscles and levator palpebrae may be permanently damaged by myasthenia and cease to respond to neostigmine. Another possibility is that restricted ocular myasthenia may not respond to anticholinesterase drugs from the beginning and the diagnosis of myasthenia is erroneously excluded. One must then turn to other muscles for clinical and electromyographic and serologic confirmation of the diagnosis. 4. Myasthenia with dysarthria and dysphagia but without ptosis or obvious strabismus. These may be confused with multiple sclerosis, polymyositis, inclusion body myopathy, stroke, motor neuron disease, or some other neurologic disease. Testing with an anticholinesterase inhibitor, single-fiber and repetitive stimulation recording, and measurement of antibodies usually clarifies the matter. 5. The initial manifestations of botulism—blurred vision, diplopia, ptosis, strabismus, and ophthalmoparesis— may be mistaken for myasthenia gravis of acute onset. In botulism, however, the pupils are usually large and unreactive, and the eye signs are followed in rapid succession by the involvement of bulbar, trunk, and limb muscles. 6. Similarly, the oculopharyngeal-brachial and variants of GBS in the early stages have many of the features of myasthenia, including ptosis, that may be partially responsive to anticholinesterase drugs. The loss of tendon reflexes, acral paresthesias, and areflexia, or the development of ataxia in the limbs make the diagnosis of GBS at once apparent and detailed electrophysiologic testing distinguishes the two conditions. 7. Intoxication with organophosphate insecticides, because of their capacity to induce a cholinergic crisis, may be confused with a myasthenic crisis (see further on). Certain other small clinical points may be helpful in differentiating myasthenia from other diseases that affect the cranial musculature. A hanging jaw and hanging head are indicative of myasthenia, whereas complete or asymmetric facial paresis is typical of GBS. Botulism usually affects the pupillary convergence reaction, and GBS does so only when there is complete internal and external ophthalmoplegia; diphtheria affects mainly the accommodative reaction early on. The question of midbrain stroke as a consequence of basilar artery occlusion arises in a case with total ophthalmoplegia; it should be recalled that the level of consciousness is usually reduced if vertical gaze and pupillary reactions are lost in cases of basilar artery stroke; such is not the case in neuromuscular diseases. The myasthenic syndrome of Lambert-Eaton, discussed further on, only occasionally affects the ocular muscles but is identified by its other clinical and electrophysiologic features. Ocular paresis, as may occur in nemaline polymyopathy, oculopharyngeal dystrophy, and thyrotoxic ophthalmic

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disease, come on too slowly in most cases to be confused with myasthenia gravis. On occasion, the eye movements in myasthenia simulate an internuclear ophthalmoplegia or other “central” sign, even to the extent of including nystagmus in an abducting eye.

Treatment The treatment of this disease involves the careful use of two groups of drugs—anticholinesterases and immunosuppressants including corticosteroids and, in special acute circumstances, plasma exchange and intravenous immune globulin (IVIg). An elective thymectomy is appropriate in many patients, as discussed below. Consensus guidelines for the treatment of myasthenia were issued in 2016 (Sanders et al). Anticholinesterase drugs  The two drugs that give the best results in ameliorating myasthenic weakness are neostigmine (Prostigmin) and pyridostigmine (Mestinon), the latter being preferred by most clinicians and patients. The usual dose of pyridostigmine is 30 to 90 mg given every 6 h (typically a 60-mg pill is tried first); the oral dose of neostigmine ranges from 7.5 to 45 mg given every 2 to 6 h. Extended-action forms of both drugs are available but are given at bedtime mainly to patients who complain of weakness during the night or early morning hours. The dosage of these drugs and their frequency of administration vary considerably from patient to patient, but the maximal useful dosage of pyridostigmine rarely exceeds 120 mg given every 3 h (Drachman, 1990). Table 46-1 lists the approximate dose-equivalents of these various drugs. For mild cases, and for patients in partial remission after thymectomy, and for some patients with purely ocular myasthenia, the use of anticholinesterase drugs may be the only form of therapy necessary for some period of time. Although these drugs seldom relieve symptoms completely (the response of ocular symptoms is typically incomplete), most such patients are able to function well. Glucocorticoids  For the patient with moderate to severe generalized weakness who is responding inadequately to anticholinesterase drugs, the long-term administration of corticosteroids is the most consistently effective form of treatment, as described in a large series of patients (Pascuzzi and colleagues). Small doses of corticosteroids (prednisone 15 to 25 mg daily) alone or in combination with azathioprine are also often adequate to control ocular myasthenia. However, one must be prepared to contend with the side effects of long-term glucocorticoid Table 46-1 DOSE-EQUIVALENTS FOR DRUGS USED IN THE TREATMENT OF MYASTHENIA GRAVIS DOSE EQUIVALENT

Pyridostigmine (Mestinon) Neostigmine oral (Prostigmin) Neostigmine IM Neostigmine IV

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ONSET

TIME TO MAXIMUM RESPONSE

60 mg (oral)

40 min

1h

15 mg

1h

1.5 h

1.5 mg 0.5 mg

30 min Immediate

1h 20 min

therapy and we hesitate to undertake such a program in children or patients with severe diabetes or other diseases that are likely to be aggravated. Because recent experience with the newer immunosuppressive agents was not incorporated into most prior series, the uniform use of steroids might not be correct. The usual form of steroid therapy is prednisone (or corresponding doses of prednisolone), beginning with 15 to 20 mg/d and increasing the dose gradually until a satisfactory clinical response is obtained or until a daily dose of 50 to 60 mg is reached. It is important to be aware that with higher doses or more rapid elevations of the doses, worsening of weakness in the first weeks may occur and hospitalization and careful observation for respiratory difficulty may be advisable. Improvement after the initiation of corticosteroids occurs over a few weeks. Once the maximal effect from prednisone has been attained, the dosage can be reduced gradually over months to the lowest point at which it is still effective. Our practice has been to then attempt to institute an alternate-day schedule, which diminishes the side effects; some patients have done better with a modest difference in dose from 1 day to the next, rather than omitting a dose entirely on alternate days. Potassium supplements and antacids should be prescribed if needed, as with any chronic corticosteroid regime and consideration should be given to prophylaxis with antibiotics for Pneumocystis infection and bisphosphonate for osteoporosis if long-term treatment is anticipated. At the outset of steroid therapy, anticholinesterase drugs are given simultaneously; as the patient improves, the dosage of the latter may be adjusted downward. Azathioprine and other immunosuppressive drugs   Azathioprine is a useful adjunct to steroids in patients who cannot tolerate or fail to respond to prednisone. It has been possible to manage the disease reasonably well in a few patients with azathioprine alone, but there is no study to support this practice (see Palace et al, 1998). Treatment typically begins with 50 mg (1 tablet) bid for a few days; if this is tolerated, the dosage is raised to 2 to 3 mg/kg/d (150 to 250 mg daily). However, improvement occurs much more slowly than with corticosteroids and a significant response may not be evident for many months to a year (Witte et al). Liver function tests and blood cell count should be checked regularly. The Myasthenia Gravis Clinical Study Group found that the most severe forms of the disease, particularly those resistant to either prednisone or azathioprine alone, benefit from the combination of the two medications. Azathioprine is a prodrug of mercaptopurine, which is metabolized principally by thiopurine methyltransferase (TPMT). Approximately 3 per 100,000 persons are deficient in the enzyme, for which reason, some clinicians measure its level before initiating azathioprine in order to avoid bone marrow toxicity; it has not been our practice to do so. There are many variant alleles of TPMT and a larger number of patients have a partial deficiency of the enzyme or even excessive enzyme activity, but it has not been clear how to utilize this information in myasthenia. Azathioprine interacts with other drugs such as allopurinol and warfarin. Cyclosporine is another immunosuppressive drug that has shown benefits in clinical trials (Tindall et al). It is

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

given in 2 divided doses daily, to a total of 6 mg/kg, but not often used currently because of serious side effects (hypertension, nephrotoxicity) and its high cost. Mycophenolate is currently being used as an adjunct to corticosteroids and has been beneficial in several small trials but failed to demonstrate a similar effect in larger controlled studies. The clinical improvement, when it does occur, has generally occurred sooner than it does with azathioprine (Meriggioli et al). Diarrhea was the main adverse effect. Several experts in the field believe that mycophenolate is preferable to most of the adjunctive medications and, in some milder cases, may be effective alone but reconciling this view with recent failed trials is vexing. Cyclophosphamide may be administered in intravenous pulses in severe cases, but the appropriate use of this potent agent is not clear and we have resorted to it infrequently (De Feo and coworkers). A regimen of high-dose cyclophosphamide (50 mg/kg/d for 4 consecutive days) followed by granulocyte-stimulating factor to “reboot” the immune system can also be considered in refractory cases (Drachman and colleagues). This approach has risks but may be justified if all other measures have failed. Liver function and white blood cell count require monitoring. On the basis of pilot trials, many other drugs, for example, tacrolimus, rituximab, and etanercept, have come into use in patients who are dependent on or resistant to corticosteroids, including those with antibodies to MuSK (Ponseti and colleagues; Diaz-Manera et al). Preliminary trial results have been reported with the use of an agent that blocks the neonatal IgG-Fc fragment (efgartigimod) and reduces antibody production (Howard et al), particularly in antiacetylcholine receptor antibody positive patients. Plasma exchange and intravenous immune globulin  For severe myasthenia that is refractory to treatment with anticholinesterase drugs and prednisone or during an acute period of worsening, one must resort to other measures. Striking temporary remissions (2 to 8 weeks) may be obtained by the use of plasma exchange. This form of treatment may be lifesaving during a myasthenic crisis. It also finds use before and after thymectomy and at the start of immunosuppressive drug therapy. Plasma exchange is also helpful in limiting the aforementioned weakness that is often induced by the institution of high-dose corticosteroids. The number and volume of exchanges required in these circumstances are somewhat arbitrary, but they tend to be less than those required for GBS; several exchanges of 2 to 3.5 L each (totaling approximately 125 mL/kg) performed over a week usually suffice. The removed plasma is replaced with albumin and saline. It has been estimated that a 2-L exchange will remove 80 percent of circulating antibodies and that this will be reflected in reduced ACh antibody levels in 3 to 5 days. There is only an approximate correlation between a reduction in the titer of anti-AChR antibody and the degree of clinical improvement. In a crisis requiring plasma exchanges and mechanical ventilation, it has been our practice to discontinue or curtail the use of anticholinesterase drugs and resume them as the patient is being weaned from the ventilator. Also, it may be that sensitivity to these drugs may be enhanced in the hours after an exchange so that their dosages must be adjusted accordingly.

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A small number of patients respond so well to plasma exchange and find the side effects of steroids so intolerable that they choose to be maintained with 2 to 3 exchanges every several weeks or months. Immuno–adsorption, a technique similar to plasma exchange that removes antibodies and immune complexes by passing blood over a tryptophan column, is less cumbersome than conventional plasma exchange and has been effective, but experience with this procedure is limited. IVIg is similarly, and possibly equivalently, useful in the short-term control of acutely worsening myasthenia. It’s ease of administration favors it over plasma exchange. The usual dose is 2 g/kg given in divided doses over 3 to 5 days. Several small series suggest that the effect is equivalent to a series of plasma exchanges. However, plasma exchange and immune globulin have been subjected to only limited systematic study or comparison, and while these treatments are invaluable in deteriorated patients or those in crisis, they offer only short-term benefits. In two separate small studies, no difference was identified between IVIg and plasma exchange in myasthenic exacerbations, most cases of which were less severe than a typical crisis (Gajdos and colleagues, 1997; Barth et al). Also, no difference was identified in a trial of IVIg 1 g/kg/d given for 1 or 2 days. Thymectomy  This operation, first introduced by Blalock, is considered an appropriate procedure for many patients with generalized myasthenia gravis between puberty and 55 years of age. The surgery is performed electively and not during an acute deterioration of myasthenia. The remission rate after thymectomy is approximately 35 percent provided that the procedure is done in the first year or 2 after onset of the disease, and another 50 percent will improve to some extent (Buckingham et al). The remission rate is progressively lower, but not negligible if the operation is postponed beyond this time. In patients with myasthenia restricted to the ocular muscles for a year or longer, the prognosis is so good that thymectomy is unnecessary. The response to thymectomy is not evident for several months and is usually maximal by approximately 3 years. In favorably responding cases, levels of circulating receptor antibody are reduced or disappear entirely. If possible, thymectomy should be postponed until puberty because of the importance of the gland in the development of the immune system, but juvenile myasthenia is also quite responsive. The results are not as predictable in patients who harbor a thymoma. A randomized trial has affirmed the usefulness of thymectomy (Wolfe and colleagues). Beyond the demonstration of effect of the procedure over 3 years when coupled with alternate day prednisone compared to alternate-day prednisone alone, certain of the outcomes of the trial were instructive but tentative due to the small number of patients enrolled: medical complications were lower in the surgical group as a result of reduced requirement for prednisone and immunosuppressive drugs, and the effects of the operation were clearer in women than in men. Viewing the Kaplan-Meier curves from that trial, it appears broadly that the effect of thymectomy was maximal at approximately 6 months and remained stable thereafter.

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A suprasternal approach for removal of the gland has been developed and results in less postoperative pain and morbidity than occurs with a transsternal thoracotomy, but the transsternal operation may be preferable because it assures a more complete removal of thymic tissue. Thymectomy is best performed in a hospital where there is close collaboration between the thoracic surgeon and the neurologist. If the patient is weak preoperatively, a course of plasma exchange or immune globulin may be given preceding the surgical procedure. Large “stress doses” of corticosteroids seem to be unnecessary in most patients who have been taking these medications chronically. After operation, respiratory assistance must be available if needed. Neostigmine intramuscularly may be given every 3 to 6 h postoperatively. Usually, the dose requirement is about 75 percent of that taken before surgery. As improvement occurs, oral medications are resumed as remission is not anticipated for many months or longer, as noted above. Thymectomy may also be a safe and effective treatment in elderly patients with myasthenia. In a study of 12 such individuals, complete remission in 9 and clinical improvement in the remainder (Olanow and associates). The improvement in older patients is less convincing than it is in the younger group, in part because the thymus is atrophic. Nonetheless, some of our patients who were older than age 60 years did benefit. The abovementioned clinical trial did not include patients over the age 65 years. Removal of the thymus gland is also indicated in practically all patients in whom thymoma is detected by CT of the chest. The tumor can be locally invasive but rarely metastasizes. The operative approach is through the anterior thorax, with adequate exposure to remove all the tumor tissue. If the tumor cannot be removed completely, the remaining tissue should be treated with focused radiation. Local spread and lymph node invasion have been treated with combinations of chemotherapy including cisplatin, but it is not very satisfactory. Park and colleagues concluded from a large retrospective study of metastatic cases that chemotherapy offers some benefit in terms of survival, but this remains controversial. Despite this endorsement of thymectomy for generalized myasthenia, it has remained an unproven therapy by a modern trial and attempts to recruit patients for such an endeavor have been difficult.

Myasthenic and Cholinergic Crisis A rapid and severe deterioration of the myasthenia, termed myasthenic crisis, can bring the patient to the brink of respiratory failure in a matter of hours. A respiratory infection or excessive use of sedative medications or drugs with a potential for blocking neuromuscular transmission may precede the myasthenic crisis. We have encountered numerous cases in which oropharyngeal weakness has led to aspiration pneumonia, which, in turn, precipitated a crisis. Just as often, a precipitating event is not evident. Rarely a respiratory arrest is the first manifestation of crisis. Such events may occur at any time after the diagnosis of myasthenia, but half are evident within 12 to 18 months. In an early but still salient experience with 53 patients in myasthenic crisis at the Columbia-Presbyterian Medical Center, pneumonia was

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the most frequent precipitating event, but no cause could be determined in almost one-third of cases (Thomas et al). Incipient respiratory failure is usually marked by a reduction of vital capacity, often accompanied by restlessness, anxiety, diaphoresis, or tremor. Once the diaphragm fails, movements of the chest wall and abdomen become paradoxical (the abdomen moves inward during inspiration) or there may be shallow excursions of the chest, alternating with paradoxical movements as discussed in Chap. 25, where the characteristics of neuromuscular respiratory failure are described. In an emergency, after clearing the airway, such a patient can be supported briefly by a tight-fitting face mask and manual bag (Ambu) breathing. The chest wall will be very compliant as a result of muscular weakness. Management of the crisis entails timely and careful intubation followed by mechanical ventilation in a critical care unit that is equipped to attend to the medical and neurologic needs of such patients (Ropper). Respiratory failure in a few patients can be managed by the use of bilevel positive airway pressure (BIPAP), according to Rabinstein and Wijdicks, but in our experience, this has not been consistently effective in avoiding endotracheal intubation. One must cope with both the oropharyngeal weakness and secretions that endanger the airway and the diaphragmatic weakness. Anticholinesterase drugs, which exaggerate secretions, are best withdrawn at the time of intubation. A useful maneuver is to allow the patient to remain off cholinergic drugs for several days while on a ventilator; there is often a heightened response to the reinstitution of medications after this period. The use of plasma exchange or intravenous gamma globulin, as described earlier, is equivalently effective in hastening improvement and weaning from the ventilator. Some of our colleagues have used highdose corticosteroid infusions in these circumstances, but this measure has not been particularly successful in our unit and, in the short run, carries the risk of inducing worsening of the weakness (Panegyres et al). Patients with myasthenic crisis generally respond to plasma exchange or to immunoglobulin infusions in 1 or 2 days, but more often, a week or more is required for recovery after a full course of 4 to 5 exchanges or 3 to 5 g/kg IVIg given in divided daily doses. Whether the previously mentioned studies (e.g., Gajdos et al, 1997 and 2005) comparing the two treatments and comparing doses of IVIg in myasthenic exacerbations are pertinent to the crisis is unknown, but we almost always institute one or the other soon after it as it is apparent that respiratory failure is imminent or worsening. It is generally best to wait 2 or 3 weeks before committing a patient to tracheostomy. When weaning from the ventilator is anticipated, anticholinesterase agents are reintroduced slowly, and treatment with corticosteroids can be instituted if necessary. Oral doses of 60 mg pyridostigmine or 15 mg neostigmine are roughly equivalent to 0.5 to 1 mg neostigmine intravenously and 1.5 to 2 mg intramuscularly, as noted in Table 46-1. Most patients with myasthenic crisis take several weeks to recover, and a few of our patients have remained ventilator-dependent for months. In the extensive experience of 53 patients from Columbia-Presbyterian, half of the patients could be safely extubated within 2 weeks

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

and three-quarters by a month (Thomas et al). There were 7 deaths among 53 patients, reflecting the gravity of this syndrome even in the modern era of intensive care. Atelectasis, severe anemia, congestive heart failure, and clostridial diarrhea (associated with antibiotic use) portend a prolonged period of generalized weakness and intubation. From time to time, one encounters a patient in whom respiration and ambulation do not improve for many months after a myasthenic crisis. In our experience, these have been middle-aged or older patients, usually women, in whom an element of hyperthyroidism or hypothyroidism may have been operative. They become wasted as the proximal limb and axial muscles, including the diaphragm, fail to recover their power, even though the ocular and oropharyngeal muscles improve. The role of corticosteroids in producing a concomitant proximal myopathy is a consideration that can be solved by careful electrophysiologic examination. If the response to anticholinesterase drugs is poor and progressively larger doses are not relieving symptoms, there is consideration of a cholinergic crisis. In our own experience with more than 80 patients of severe myasthenia in an intensive care unit, we have been persuaded of the occurrence of a cholinergic crisis only rarely. This consists of a relatively rapid increase in muscular weakness, usually coupled with the adverse muscarinic effects of the anticholinesterase drug (nausea, vomiting, pallor, sweating, salivation, bronchorrhea, colic, diarrhea, miosis, bradycardia). An impending cholinergic effect is betrayed by the constriction of pupils. If the blood pressure falls with bradycardia, 0.6 mg atropine sulfate may be given slowly by the intravenous route. Neostigmine or repetitive stimulation may be used to determine whether or not weakness is to the result of an excess of anticholinesterase medications. However, this test has been misleading and undoubtedly has contributed to an overestimation of the frequency and importance of the cholinergic crisis. Infection, or the natural course of the disease, has been a far more common cause of acutely worsening weakness and respiratory failure. The only recourse in cases of long-standing and severe, intractable myasthenia is to continue an average dose of corticosteroids, immunosuppressive, and anticholinesterase medications with intermittent trials of immune globulin or plasma exchanges. This is also a desperate situation in which high-dose cyclophosphamide followed by a granulocyte-stimulating factor, as mentioned earlier, may result in slow improvement. Other agents such as rituximab may be tried. Whether thymectomy, undoubtedly risky in these sick patients, effects severe and longestablished myasthenia is not known, but its effects, in any case, would be delayed. Management of anesthesia and pregnancy in the myasthenic patient Surgical procedures of any type are often sufficiently stressful to produce decompensation of the disease. If the patient is unable to take medications orally, anticholinesterase agents may be given intramuscularly (approximately 1/30 of the oral dose of pyridostigmine and 1/10 the oral dose of neostigmine listed in Table 46-1). If corticosteroids were being used, they may be continued and the dose generally left unchanged; large “stress” doses are generally unnecessary, as mentioned earlier in

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the discussion of thymectomy. Neuromuscular blocking agents of the noncompetitive type may have a very prolonged effect in these patients and should be avoided as part of the anesthetic regimen. If they are necessary for some reason, a period of mechanical ventilation should be anticipated. In contrast, the dose of succinylcholine (which is not recommended) required to produce muscle relaxation may be larger than usual. Any drug, the use of which is contemplated in anesthetic and postsurgical management, should be checked against the list of agents that are capable of exaggerating myasthenic weakness (see further on). Pregnancy is usually uncomplicated in patients with myasthenia, but some women who are partially treated for myasthenia and have generalized weakness may have difficulty in assisting with vaginal delivery. However, the use of intravenous cholinesterase inhibitors is contraindicated because of the possibility of inducing uterine contractions, and cytotoxic drugs are generally avoided during pregnancy because of the potential for fetal abnormalities. Also, magnesium is not recommended for the treatment of eclampsia because its neuromuscular blocking effects may worsen myasthenic weakness. Delivery usually proceeds normally, and breast-feeding is not thought to be a problem with regard to the transmission of AChR antibodies. Almost half of women with myasthenia have an exacerbation of varying degrees in the several weeks postpartum. A rapidly dropping level of alpha-fetoprotein has been implicated as this protein inhibits the binding of antiacetylcholine antibodies to postsynaptic receptors. The issues of neonatal myasthenia and of reduced intrauterine movements with arthrogryposis are considered later.

Other Disorders of Neuromuscular Transmission (Table 46-2) Considered here are several disorders of neuromuscular transmission characterized clinically by muscular weakness and fatigability but differing in mechanism from autoimmune myasthenia gravis. The Lambert-Eaton myasthenic syndrome, neonatal myasthenia, congenital myasthenic syndromes, and myasthenic syndromes induced by drugs and toxins are the main disorders in this group. Two additional important diseases—botulism and organophosphate poisoning—are described in Chap. 41.

The Myasthenic-Myopathic Syndrome of Lambert-Eaton (Lambert-Eaton Syndrome) This special form of neuromuscular disorder that in a few ways simulates myasthenia gravis is observed most often in patients with small cell carcinoma of the lung, was first described by Lambert, Eaton, and Rooke in 1956 and further by Eaton and Lambert in 1957. Unlike myasthenia gravis, the muscles of the trunk, shoulder girdle, pelvic girdle, and lower extremities are the ones that become weak and fatigable. The first symptoms are difficulty in arising from a chair, climbing stairs, and walking; the shoulder muscles are usually affected later. Although ptosis, diplopia, dysarthria, and dysphagia may occur, presentation with these symptoms is distinctly unusual. Increasing weakness after

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Table 46-2 MAJOR DISORDERS OF THE NEUROMUSCULAR JUNCTION MYASTHENIC SYNDROMES

CAUSAL AGENT OR GENE DEFECT

ONSET DECADE

TREATMENT

CLINICAL FEATURES

ACQUIRED MYASTHENIC SYNDROMES

Presynaptic Botulism (Chap. 41)

Any

Supportive; ventilation

Lambert-Eaton myasthenic syndrome

Peptide toxin from Clostridium botulinum Autoimmune reduction in calciummediated quantal release

Midlife

3,4-DAP Possibly IVIg

Synaptic Insecticides (Chap. 41)

Organophosphates (inhibits AChE)

Any

Remove toxins Atropine

Miosis, diarrhea, cramps, weakness Delayed sensorimotor neuropathy

Autoimmune attack on postsynaptic membrane Antibodies to AChR or MuSK protein Multiple peptide toxins that lyse muscle, bind Na channels, K channels (acting both post- and presynaptically)

Adult

AChE inhibitors, IVIg

Diplopia, ptosis

Any

Other immunosuppressants Supportive Possibly AChE inhibitors

Limb weakness with exertion Acute weakness

Postsynaptic Myasthenia gravis Snake venom toxins (Chap. 41)

exertion stamps the condition as myasthenic, but in direct contrast to myasthenia gravis, there may be a temporary increase in muscle power during the first few contractions. The tendon reflexes are often diminished, but complete abolition of the reflexes should raise the question of an associated carcinomatous polyneuropathy. Fasciculations are not seen. An instructive review of this disease consisting of 50 well-studied cases described proximal leg weakness in all, arm weakness in 39, diplopia in 25, ptosis in 21, and dysarthria in 12. Symptoms were paresthesias, aching pain (suggesting arthritis), and a number of autonomic disturbances, such as dryness of the mouth, constipation, difficult micturition, and impotence (O’Neill and colleagues). This latter group of symptoms gives the syndrome an unmistakable stamp, as discussed further on under “Diagnosis.” One should not be surprised to find other neurologic manifestations of neoplasia (e.g., polyneuropathy, polymyositis or dermatomyositis, multifocal leukoencephalopathy, cerebellar degeneration, as discussed in Chap. 30). The onset of weakness is subacute and the course variably progressive. Males are affected far more often than females (5:1). The weakness may precede discovery of the tumor by months or years. Approximately 60 percent of cases are associated with small cell lung cancer, but small numbers have also occurred with carcinoma of the breast, prostate, stomach, and rectum and with lymphomas; in about one-third of patients, no tumor is found. Some cases are associated with other autoimmune diseases, but most are paraneoplastic or idiopathic. The condition may occur in children, usually with no relation to tumor. In tumor cases, death usually occurs in a few months or years from the effect of the neoplasm; the idiopathic ones fluctuate over the years. The response to neostigmine and pyridostigmine is poor or at least unpredictable, and this finding in a myasthenic patient should bring the diagnosis of Lambert-Eaton

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Blurred vision, dysphagia, limb weakness Truncal weakness, dysautonomic features Two-thirds have cancer

syndrome to mind. In contrast, d-tubocurarine, suxamethonium chloride, gallamine, and other muscle relaxants have a deleterious effect and may cause fatality, just as in myasthenia gravis. Conventional electrodiagnostic studies show no abnormality in the peripheral nerves. A single stimulus of nerve may evoke a low-amplitude muscle action potential (in contrast to myasthenia gravis, in which it is normal or nearly so) whereas at fast rates of stimulation (50 per second as shown in Fig. 2-15B) or following strong voluntary contraction (for 15 s or longer) there is a marked increase in the amplitude of action potentials (incrementing response hence the term “inverse myasthenia,” which has been applied to Lambert-Eaton myasthenic syndrome [LEMS]). Single-fiber recordings show an increase in “jitter” as in myasthenia gravis, as described in Chap. 2. Elmquist and Lambert, from a series of studies of excised muscle, deduced that there is a defect in the release of ACh quanta from the presynaptic nerve terminals, akin to the effects of botulinum toxin, magnesium excess, and neomycin. The presynaptic vesicles themselves appear to be normal in morphology and content. Also, in contrast to myasthenia gravis, the surface area of the postsynaptic receptor membrane in this syndrome is actually increased (Engel, 1976b). The physiologic mechanism in Lambert-Eaton myasthenic syndrome is a loss of voltage-gated calcium channels on the presynaptic motor nerve terminal. The calcium channels become cross-linked and aggregated by IgG autoantibodies, ultimately reducing the number of functioning channels (Fukunaga et al). These antibodies against a specific component of the presynaptic membrane have the effect of reducing the presynaptic release of ACh, virtually the opposite of myasthenia gravis. A serologic test for these antibodies (anti-VGKC) is available and is performed to confirm the diagnosis. Even in patients without detectable antibodies against

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

voltage-gated calcium channels, passive transfer experiments indicate the presence of a circulating factor with similar activity. Muscle biopsy is normal or shows only the same slight, nonspecific changes as in myasthenia gravis. The thymus is, of course, normal. Recognition of the Lambert-Eaton syndrome should lead to a search for an occult tumor, particularly of the lung. A positron emission tomography (PET) scan of the body may be useful for this purpose, although CT of the lungs is usually adequate. If found, it should be treated; this alone may result in improvement in the neurologic syndrome. If none is found, the search should be repeated at regular intervals, as the tumors at first are small and may be inapparent even at autopsy. Numerous cases of the more typical paraneoplastic syndromes discussed in Chap. 30, such as cerebellar degeneration, may coexist with the Lambert-Eaton syndrome, most of them are a result of small cell lung cancer (see Mason and colleagues), while others are a result of idiopathic antibodies to the calcium channels. Treatment  Most patients with this disorder benefit mildly or moderately from the administration of 3,4-diaminopyridine (3,4-DAP), an agent that blocks potassium channels in the distal motor terminal, thus prolonging depolarizations and enhancing the release of ACh vesicles. The drug is given as 20 mg, up to 5 times a day, either alone or in conjunction with pyridostigmine (Lundh et al). It is not approved by the FDA in the United States and must be obtained from specialty pharmacies but, nonetheless, has replaced the formerly used guanidine hydrochloride that had hematologic and renal toxicity with long-term use. With regard to long-term relief, numerous regimens have been tried and favored by different groups. Several groups have claimed the best results in nontumor cases with repeated courses of plasmapheresis in combination with prednisone and azathioprine or prednisone alone (Streib and Rothner; Dau and Denys). IVIg has also been effective in a few reported cases. The benefit is a result of a reduction in calcium channel autoantibodies, but the mechanism whereby IVIg produces this effect could not be established (Bain and coworkers). Many clinicians prefer alternate-day administration of prednisone and azathioprine (prednisone 25 to 60 mg/d, and azathioprine 2–3 mg/kg body weight daily) supplemented intermittently as needed by IVIg. The response to treatment tends to be slow, over a period of months and sometimes up to a year. Some patients recover fully; in others, restoration of power is incomplete. The oral potassium channel blocker, amifampridine, has been approved for the treatment of LEMS in 6 to 17-year-olds and is supported by several clinical trial results (Oh et al). It has been tried as well in adults with LEMS and in congenital myasthenic syndromes but with less compelling evidence. Diagnosis  A syndrome of symmetrical weakness and fatigability of proximal muscles coupled with dry mouth, sphincter disturbances, aching muscles, and diminished reflexes are diagnostic. The illnesses with which it might be confused are myasthenia gravis, inclusion body myopathy, and polymyositis. There is a superficial resemblance to hysterical paralysis, where the patient may do better with encouragement on making a succession of voluntary

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contractions, and arthritis, where pain hampers the first movements more than the successive ones. Then the electrodiagnostic and specific serologic tests are of value.

Neonatal Myasthenia Gravis An estimated 10 to 20 percent of babies born to mothers with myasthenia show transient signs of myasthenia (hypotonia, weak cry, and suck). This transitory phenomenon is apparent at birth and has a mean duration of about 2 to 5 weeks; recovery is usually complete within 2 months of birth (rarely longer), without later relapse. Uncommonly, the mother with myasthenia reports reduced intrauterine movements, suggesting a dangerous degree of myasthenia in the fetus. A few of these children will be born with arthrogryposis, the result of a sustained period of intrauterine immobility, and this complication tends to recur in subsequent births. It has long been assumed that neonatal myasthenia is a result of the passive transplacental transfer of AChR antibodies. This explanation is not entirely satisfactory insofar as maternal AChR antibodies are transferred from mother to fetus in all AChR antibody-positive pregnancies and the incidence and severity of neonatal myasthenia gravis do not correlate with the severity or duration of the mother’s illness or with the serum level of the maternal AChR antibody. In fact, neonatal myasthenia may occur when the mother is in remission. Administration of plasma exchange and anticholinesterase drugs to the infant may be useful in hastening recovery from neonatal myasthenia.

Congenital Myasthenic Syndromes (See Table 46-3) The congenital myasthenic syndromes are inherited defects in components of the presynaptic, synaptic, or postsynaptic junctional apparatus (Table 46-3). In the 1970s and 1980s, after the autoimmune basis of myasthenia gravis was established and its morphologic and physiologic features defined, the differences between this disease and familial infantile forms became evident. Since then, at least eight distinct and rare congenital myasthenic syndromes have been delineated on the basis of their electrophysiologic and ultrastructural features, and a number of others have been partially characterized. Broadly speaking, the defects involve resynthesis or packaging of ACh or a paucity of synaptic vesicles (presynaptic); deficient quantal release; a deficiency of endplate ACh esterase (synaptic); or kinetic abnormalities in the AChR channels or AChR deficiency (postsynaptic). It has been estimated that in three-fourths of the cases, the defect is postsynaptic. These disorders are distinguished by neonatal onset, fluctuating and sometimes progressive weakness that may be quite severe, sometimes pronounced muscle hypotrophy, persistent ptosis, and seronegativity for anti-AChR and anti-MuSK antibodies. Moreover, heritability (typically autosomal recessive) is suggested by the familial occurrence of the disorders among siblings. The most important clue to the disease in the neonate is an increase in ptosis and in bulbar and respiratory weakness

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Table 46-3 HEREDITARY AND CONGENITAL MYASTHENIC SYNDROMES MYASTHENIC SYNDROME

CAUSAL AGENT OR GENE DEFECT

ONSET DECADE

TREATMENT

CLINICAL FEATURES

Presynaptics

Episodic apnea

Choline acetyltransferase

1st

AChE inhibitors

Mild episodes of weakness; recurrent apnea

Paucity of synaptic vesicles Reduced quantal release of acetylcholine

Unknown

1st

Apnea monitor AChE inhibitors

Ptosis common Recurrent, sometimes pronounced weakness

Unknown

1st

AChE inhibitors and 3,4-aminopyridine

Wasting, respiratory failure, dysmorphism

AChE Collagen tail for AChE DOK-7 mutation

1st

Diffuse weakness, ptosis

1st

None Avoid AChE inhibitors None

Slow channel syndrome

AChR subunits

1st to 6th

Quinidine, AChE inhibitors

Fast channel syndrome

AChR subunits

1st

Avoid 3,4-DAP 3,4-DAP

Primary AChR deficiency Rapsyn deficiency Plectin deficiency Escobar syndrome

AChR subunits

1st

AChE inhibitors, 3,4-DAP

Rapsyn Plectin Defective fetal γ-AChR subunit

1st 1st In-utero

AChE inhibitors, 3,4-DAP 3,4-DAP Maturity with replacement of γ - with e-AChR subunit

Ptosis, diffuse weakness, delayed motor milestones Often show atrophy of dorsal forearms Ptosis, recurrent weakness, motor development delays Ptosis, recurrent weakness, motor development delays Ptosis, recurrent weakness Myasthenic features, epidermolysis bullosa Arthrogryposis, respiratory failure, pterygium (webbing of skin)

Synaptic

AChE deficiency DOK-7 “synopathy”

Limb-girdle, ptosis

Postsynaptic

AChE, acetylcholinesterase; AChR, acetylcholine receptor; DAP, diaminopyridine; .

with crying. Later in infancy, these symptoms, as well as fluctuating ocular palsies and abnormal fatigability, are brought out by other types of sustained activities. Motor milestones may be delayed. In some cases, myasthenic weakness and fatigability do not become evident until the second and third decades of life. Testing with anticholinesterase drugs is inconsistently positive in a few forms of congenital myasthenia, as mentioned further on, but it usually is negative. Two of the congenital myasthenic diseases—fast channel syndrome and slow channel syndrome—are consequences of mutations in AChR subunits that accelerate (fast channel) and slow (slow channel) the kinetics of gating of receptor channel (Croxen et al). Another wellcharacterized type, usually causing arthrogryposis and recurrent apneic spells but occasionally having an adultonset (as late as 48 years), has been traced to mutations in the “rapsyn” gene. The rapsyn protein plays a role in maintaining the integrity of the postsynaptic membrane (see Burke et al). Deficiency of the enzyme required to synthesize and package ACh in vesicles (choline acetyltransferase) causes a congenital myopathy with episodes of stress-induced apnea. In another type, the synaptic vesicles form poorly and are reduced in number. Being largely presynaptic defects, both of these disorders respond to acetylcholine esterase (AChE) inhibitors. In comparison, children with congenital myasthenia as a result of deficiency of AChE deteriorate markedly if given AChE inhibitors. Three disorders affecting postsynaptic structures (the fast-channel syndrome, AChR deficiency, and the myasthenic syndromes associated with deficiencies of rapsyn and plectin) also respond to AChE inhibition and 3,4-DAP,

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although both agents are hazardous in individuals with the slow-channel syndrome. Another form of congenital myasthenia is caused by a recessive mutation in DOK-7 that causes a simplified structure of the synapse but no alteration in AChRs (Beeson et al). The clinical features are of a limb-girdle pattern of weakness that causes a delay in walking after the child has reached other normal motor milestones and of ptosis from an early age (Palace and colleagues). A further category of congenital syndromes of defects in the presynaptic quantal release of ACh linked to an intriguing prenatal myasthenic disease called Escobar syndrome (arthrogryposis, pterygia, and respiratory distress) has been traced to mutations in the gamma subunit of the AChR, a component expressed only in fetal life and replaced with maturity by the epsilon subunit (Milone and colleagues; Hoffmann and coworkers). The studies of A.G. Engel have systematically defined and classified these disorders in a series of extensive investigations of more than 100 cases (Engel et al, 2003).

Myasthenic Weakness Caused by Antibiotics, Other Drugs, and by Environmental Toxins (See Chap. 41 and Table 46-2) Many drugs can cause a myasthenic syndrome or a worsening of myasthenia gravis by their action on pre- or postsynaptic structures. In the case of a nonmyasthenic patient, this is most likely to happen in the presence of hepatic or renal disease that allows excessive accumulation of the causative agent. The myasthenic state in these conditions is acute and lasts hours or days, with full recovery provided that the patient does not succumb to respiratory failure.

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

The ocular, facial, and bulbar muscles are involved, just as in native myasthenia. The treatment is to provide respiratory support, discontinue the offending drug, and attempt to reverse the conduction block at the motor endplate by infusions of calcium gluconate, potassium, and anticholinesterases (Argov and Mastaglia). There are more than 30 drugs in current clinical use (other than anesthetic agents) that may, under certain circumstances, interfere with the neuromuscular transmission in otherwise normal individuals. Of these, the most important is the aminoglycoside and quinolone antibiotics. Myasthenic weakness has been reported with 18 different antibiotics, but particularly neomycin, kanamycin (less so with gentamicin), colistin, streptomycin, polymyxin B, and certain tetracyclines (McQuillen et al; Pittinger et al). It has been shown that these drugs impair transmitter release by interfering with calcium ion fluxes at nerve terminals. The fluorinated quinolones (fluoroquinolones)—typified by ciprofloxacin—affect both pre- and postsynaptic activity. They are especially hazardous when given to patients with myasthenia, but they may be used if necessary to treat infections in patients who are already receiving ventilatory support. Other agents—particularly the organophosphate insecticides and nerve gases—cause paralysis by binding to cholinesterase and blocking the hydrolysis of ACh. The endplate remains depolarized and is refractory to neural stimuli. The most notable of these agents are (1) botulinum toxin, which binds to cholinergic motor endings, blocking quantal release of ACh; (2) black widow spider venom, which causes a massive release of ACh, resulting in muscular contraction and then paralysis from a lack of ACh; (3) d-tubocurarine, which binds to AChR; (4) suxamethonium and decamethonium, which also bind to AChR; (5) organophosphates, which bind irreversibly to AChE; and (6) malathion and parathion, which inhibit AChE. The actions of all these agents except for the organophosphate “nerve gases” are transitory. The administration of d-penicillamine has also caused an unusual type of myasthenia. The weakness is typical in that rest increases strength—as do neostigmine and edrophonium—and the electrophysiologic findings are also the same. In such cases, anti-AChR antibodies can be identified in the serum; hence, one must assume that this is a form of induced autoimmune myasthenia gravis (Vincent and associates). In these respects, it differs from the weakness caused by aminoglycosides (Swift). Rarely, typical autoimmune myasthenia gravis develops as part of a chronic graft-versus-host disease in long-term (2- to 3-year) survivors of allogeneic marrow transplants. A large group of naturally occurring environmental neurotoxins is known to act at the neuromuscular junction and to induce muscle paralysis of a pattern like that of myasthenia gravis. Venoms of certain snakes, spiders, and ticks are common and well-known animal poisons, as are ciguatera and related toxins (from fish that have ingested certain dinoflagellates), curare (from plants), and Clostridium botulinum—all of which are discussed in Chap. 41. Poisoning by these natural neurotoxins constitutes an important public health hazard in many parts of the world (Senanayake and Roman).

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MYOTONIAS, PERIODIC PARALYSES, AND STATES OF PERSISTENT MUSCLE FIBER ACTIVITY (CHANNELOPATHIES) Myotonias were historically categorized as a special group of muscle diseases unified by the clinical sign of myotonia and were aligned in older classifications with muscular dystrophies. This view was based on myotonia as it was understood in the classic form of myotonic dystrophy, a subject discussed in Chap. 45. Similarly, before fundamental knowledge of their mechanism was revealed, periodic paralyses (better called episodic paralysis) were considered to be metabolic diseases of muscle. However, it has become evident that most diseases that feature prominent myotonia and the processes that cause episodic muscular paralysis are neither degenerative nor dystrophic. Clinical and electrophysiologic studies show that myotonia is an elemental feature of many nondystrophic conditions, foremost among them are the hyperkalemic form of periodic paralysis and myotonia congenita. Most of these diseases are caused by mutations in genes that code for chloride, sodium, calcium, or potassium ion channels in the muscle membrane, and they are referred to as ion channel diseases or channelopathies (see Ryan and Ptácek). Within this group, there are also instances of muscle conditions that display no myotonia but only periodic paralysis. Given that these are disorders of muscle membrane excitability, it is not surprising that the primary defects are in voltage-dependent ion channels. By analogy, it was anticipated that ion channelopathies would be implicated in 2 other categories of disease in which there is altered membrane excitability, namely epilepsies and certain cardiac arrhythmias, and indeed, this has proven to be the case (see discussion in Chap. 15 on the epilepsies). In the process, several new forms of nondystrophic myotonia have been defined. Molecular studies have identified the fundamental defects in myotonias and episodic paralyses and clarified their relationships (Rüdel and associates; Hanna and colleagues; Cannon; Heatwole and colleagues). Table 46-4 summarizes the main features of the ion channel diseases affecting muscle and the individual members of the group are described as follows.

Chloride Channel Diseases Myotonia Congenita (Thomsen Disease) This is an uncommon disease of skeletal muscle that begins in early life and is characterized by myotonia, muscular hypertrophy, nonprogressive course, and dominant inheritance. It is distinctly different from myotonic dystrophy, which is characterized by a progressive degeneration of muscle fibers and has a different genetic basis. Thomsen disease is caused by one of several inherited molecular defects in the voltage-dependent chloride channel gene (CLCN1) (see Koch et al). It is interesting that most mutations behave as dominant traits, whereas others have either a dominant or recessive pattern of inheritance (see Table 46-4). The physiologic mechanism whereby these

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+ — + ++ Increased 2–3 times Increased

++ — Normal to borderline Normal Normal — Mexiletine if required for myotonia

Normal — Mexiletine if required for myotonia

Normal

++ — — — + + ++ +

++ — — — + + ++ +

During attack, glucose and calcium; for prevention, acetazolamide CHO, low-K diet

Normal ++

Increased

++ + — ++ + ++ + +

—

+/– +/– +/– +++ First decade

Hyperkalemic periodic paralysis Dominant SCN4A Alpha subunit

SODIUM

++ +++ — — Late childhood or earlier —

Generalized myotonia (Becker) Recessive CLCN1 CLC1

CHLORIDE

++ ++ — — Congenital to late childhood —

Myotonia congenita (Thomsen) Dominant CLCN1 CLC1

CHLORIDE

CHO, carbohydrates; +, mild; ++, moderate; +++, severe.

Serum K between attacks Significant myopathology (vacuolar myopathy) Treatment

Serum K during attack

Precipitating factors Increases with exercise Appears after exercise Fasting Carbohydrate load Potassium load Cold Pregnancy “Warmup” phenomenon Involvement of cranial muscles Muscle hypertrophy Permanent myopathy Serum CK during attack

Myotonia (electrical) Myotonia (clinical) Paramyotonia (clinical) Episodic paralysis Onset

Inheritance Gene Channel protein

Disease

CHANNEL AFFECTED

THE MAIN INHERITED MYOTONIAS AND PERIODIC PARALYSES (THE CHANNELOPATHIES)

Table 46-4

Mexiletine if needed for myotonia

Normal —

Normal

— — Increased 5–10 times

— — — +/– +++ ++ — ++

++ — +++ +/– Paramyotonia at birth +++

Paramyotonia congenita (Eulenburg) Dominant SCN4A Alpha subunit

SODIUM

KCl during and acetazolamide between attacks

Normal ++

— ++ Normal to slightly increased Decreased

++ — + — + + + —

Hypokalemic periodic paralysis Dominant DHP receptor Dihydropyridine receptor — — — +++ Late childhood to third decade —

CALCIUM

Normal Rhabdomyolysis, cores Intravenous dantrolene

— — Markedly increased Normal

— — — — — — — —

—

Malignant hyperthermia Dominant RYR1 Ryanodine receptor — — — — All ages

CALCIUM

Acetazolamide

High, low, or normal Normal Tubular aggregates

— + Normal

— — — — — ? — ++

+

Dominant KCNJ2 Inward rectifying K channel — — — + Childhood

Andersen disease

POTASSIUM

Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

mutations alter ion fluxes across the muscle membrane and cause myotonia is described further on. History  The disorder was first brought to the attention of the medical profession in 1876 by Julius Thomsen, a Danish physician who himself suffered from the disease, as did 20 members of his family over 4 generations. His designation of ataxia muscularis was not correct, but his description left no doubt as to the nature of the condition in that it featured “tonic cramps in voluntary muscles associated with an inherited psychical indisposition.” The latter aspect of the condition was not borne out by subsequent studies and is now thought to be his erroneous speculation as to causality. In 1881, Strümpell assigned the name myotonia congenita to the disease, and in 1883, Westphal referred to it as Thomsen’s disease. Erb provided the first description of its pathology and called attention to two additional unique features: muscular hyperexcitability and hypertrophy. In 1923, Nissen, Thomsen’s great-nephew, extended the original genealogy to 35 cases in 7 generations, and in 1948, Thomasen’s monograph is still a useful clinical reference. Myotonia, a tonic spasm of muscle after forceful voluntary contraction, stands as the cardinal feature and is best represented in this disease. As emphasized in Chaps. 2 and 45, this phenomenon reflects the electrical hyperexcitability of the muscle membrane. The electrophysiologic representation of the spasm is shown in Fig. 2-19, and a description of the physiology can be found in Chap. 2. It is most pronounced after a period of inactivity. Repeated contractions “wear it out,” so to speak, and the later movements in a series become more swift and effective. Rarely, the converse is observed—where only the later movements of a series induce myotonia (myotonia paradoxica); usually, this is a feature of another condition, cold-induced paramyotonia congenita (see further on). Unlike cramp, the myotonic spasm is painless, but after prolonged activity, nocturnal myalgia (a pinching-aching sensation in the overactive muscles) may develop and prove distressing. Close observation reveals a softness of the muscles during rest and the initial contraction appears not to be significantly slowed. The disease, myotonia congenita, as mentioned above, is usually inherited as a dominant trait so that most often, other members of the family have been affected. Its congenital nature may be evident even in the crib, where the infant’s eyes are noted to open slowly after it has been crying or sneezing and its legs are conspicuously stiff as the child tries to take its first steps. In other cases, the myotonia becomes evident only later in the first or second decade. The muscles are generously proportioned and may become hypertrophied but seldom to the degree observed in the recessive form of the disease described further on. Despite their muscular appearance, these patients do not do well in athletic pursuits as a result of myotonia. When severe, myotonia affects all skeletal muscles but is especially prominent in the lower limbs. Attempts to walk and run are impeded to the extent that the patient stumbles and falls. Other limb and trunk muscles are also thrown into spasm, as are those of the face and upper limbs. One of the characteristic features is grip myotonia in which the patient is unable to release a handshake and must slowly

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open the fingers one at a time. Occasionally a sudden noise or fright may cause generalized stiffness and falling. Small, gentle movements such as blinking or elicitation of a tendon reflex do not initiate myotonia, whereas strong closure of the eyelids, as in a sneeze, sets up a spasm that may prevent the complete opening of the eyes for many seconds. Spasms of extraocular muscles occur in some instances, leading to strabismus. If the patient has not spoken for a time, there is sometimes striking dysarthria. Arising at night, the patient cannot walk without first moving the legs for a few minutes. After a period of rest, the patient may have difficulty in arising from a chair or climbing stairs. Loosening of one set of muscles after a succession of contractions does not prevent the appearance of myotonia in another area, nor in the same ones if used in another pattern of movement. Smooth and cardiac muscles are not affected and intelligence is normal. Lacking also are the narrow face, frontal balding, cataracts, and endocrine changes typical of myotonic dystrophy that is discussed in Chap. 45. Myotonia that is evident in infancy is far more likely to represent myotonia congenita than myotonic dystrophy, in which myotonia rarely has its onset in the first few years of life. Myotonia can also be induced in most cases by tapping a muscle belly with a percussion hammer (percussion myotonia). Unlike the lump or ridge produced in hypothyroid or cachectic muscle (myoedema), the myotonic contraction involves an entire fasciculus or an entire muscle and, unlike the phenomenon of idiomuscular irritability (contraction of a fascicle in response to striking the muscle), it persists for several seconds. If tapped, the tongue shows a similar reaction. An electrical stimulus delivered to the motor point in a muscle induces a prolonged contraction (Erb myotonic reaction). In Thomsen disease, as in virtually all forms of myotonia, the stiffness is somewhat exaggerated in the cold. On a cold day, affected individuals may have a prolonged grimace with closed eyes after a sneeze. We encountered two brothers with this disorder who described diving into a cool swimming pool on a hot summer day and having to lie nearly motionless at the bottom of the pool for several seconds until the muscle stiffness abated enough to allow them to swim to the top. However, as mentioned, prominent cold-induced myotonia is more characteristic of paramyotonia congenita (see later). Biopsy reveals no abnormality other than enlargement of muscle fibers, and this change occurs only in hypertrophied muscles. As often happens in fibers of increased volume, central nucleation is somewhat more frequent than it is in normal muscle. The large fibers contain increased numbers of normally structured myofibrils. In well-fixed biopsy material examined under the electron microscope, no significant morphologic changes have been identified (Schröder and Adams). Myotonia levior was the name applied by DeJong to a dominantly inherited form of myotonia congenita in which the symptoms are milder and of later onset than those of Thomsen disease. In 2 patients of a myotonia levior family, a mutation of the same chloride ion channel (CLCN1) that is implicated in Thomsen’s disease has been identified (Lehmann-Horn and coworkers, 1995). Thus it appears that myotonia levior is simply a mild form of Thomsen disease.

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Diagnosis  In patients who complain of spasms, cramping, and stiffness, myotonia must be distinguished from several of the disorders of persistent muscle activity described further on and in Chap. 45. None of these disorders displays percussion myotonia or the typical electromyogram (EMG) abnormality of myotonic discharge. The only possible exceptions are the Schwartz-Jampel syndrome of hereditary stiffness combined with short stature and muscle hypertrophy and stiff man syndrome, which are discussed further on and in Chap. 45. Uncertainty in diagnosis arises in patients who have only myotonia in early life and later prove to have classic (type 1) myotonic dystrophy or who notice myotonia in adulthood with mild proximal weakness and are found to have type 2 myotonic dystrophy. The myotonia in myotonic dystrophy is usually mild and in several families that we have followed, some degree of weakness and the typical facies of myotonic dystrophy could be appreciated even in early childhood. This is not the case in the less-frequent type 2 myotonic dystrophy in which there are no dysmorphic features (also called proximal myotonic myopathy [PROMM]; see Chap. 45 and further on). In paramyotonia congenita there is also myotonia of early onset, but, again, it tends to be mild, involving mainly the orbicularis oculi, levator palpebrae, and tongue; the diagnosis of paramyotonia is seldom in doubt because of the worsening with continued activity and prominent cold-induced episodes of myotonia and paralysis. In patients with very large muscles, one must consider not only myotonia congenita but also familial hyperdevelopment, hypothyroid myopathy, the Bruck-de Lange syndrome (congenital hypertrophy of muscles, mental retardation, and extrapyramidal movement disorder), Becker myotonia, Duchenne dystrophy, and most of all, hypertrophic myopathy (hypertrophia musculorum vera); this last disease is of interest because the aberrant protein (myostatin) and gene defect have been characterized. Muscle hypertrophy is not a feature of myotonic dystrophy. The demonstration of myotonia by percussion and EMG study usually resolves the problem, although, in exceptional cases of Thomsen disease, the persistence of contraction may be difficult to demonstrate. In hypothyroidism, the EMG may show bizarre highfrequency (pseudomyotonic) discharges; however, true myotonia does not occur, myoedema is prominent, and, along with other signs of thyroid deficiency, there is slowing of contraction and relaxation of tendon reflexes not seen in myotonia congenita. Treatment  Quinine is effective in reducing myotonia but is now used infrequently because of the (low) risk of causing torsade de pointes. Procainamide, 250 to 500 mg qid, and mexiletine, 100 to 300 mg tid, are beneficial in relieving the myotonia, but they, too, have fallen out of favor for various reasons. Phenytoin, 100 mg tid, is useful in some cases. The cardiac antiarrhythmic drug tocainide (1,200 mg daily) has also proved effective, but it sometimes causes agranulocytosis and is no longer recommended. A trial has shown that mexiletine may be useful in a group of rare nondystrophic myotonias (Statland et al).

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Generalized Myotonia (Becker Disease) This is the second form of congenital myotonia, inherited as an autosomal recessive trait. Like the dominant Thomsen form, it is caused by an allelic mutation of the gene encoding the chloride ion channel of the muscle fiber membrane. The clinical features of the dominant and recessive types are similar except that myotonia in the recessive type does not become manifest until 10 to 14 years of age, or even later, and tends to be more severe in the dominantly inherited variety. The myotonia appears first in the lower limbs and spreads to the trunk, arms, and face. Hypertrophy is invariably present. There may be associated mild distal weakness and atrophy; this was found in the forearms in 28 percent of Becker’s 148 patients and in the sternocleidomastoids in 19 percent. Dorsiflexion of the feet was limited and fibrous contractures were common. Weakness may also be present in the proximal leg and arm muscles. The most troublesome aspect of the disease is the transient weakness that follows initial muscle contraction after a period of inactivity. Progression of the disease continues until about 30 years of age, and the course of the illness thereafter remains unchanged (Sun and Streib). In contrast to Thomsen disease, creatine kinase (CK) may be elevated. Testicular atrophy, cardiac abnormality, frontal baldness, and cataracts—the features that characterize myotonic dystrophy—are conspicuously absent.

Sodium Channel Diseases The main diseases in this category are hyperkalemic periodic paralysis and paramyotonia congenita. The derivative disorders normokalemic periodic paralysis, acetazolamideresponsive myotonia, myotonia fluctuans, and myotonia permanens are variants of hyperkalemic periodic paralysis. All of them are caused by mutations in the gene encoding the alpha subunit of the membrane-bound voltage-gated sodium channel in skeletal muscle (SCN4A).

Hyperkalemic Periodic Paralysis The essential features of this disease are an episodic generalized weakness of fairly rapid onset and a rise in serum potassium during attacks. Weakness appearing after a period of rest that follows exercise is particularly characteristic. This type of periodic paralysis was first described and distinguished from the more common (hypokalemic) form by Tyler and colleagues in 1951. Five years later, Gamstorp described two additional families with the disorder and named it adynamia episodica hereditaria. As further examples were reported, it was noted that in many of them, there were minor degrees of myotonia, which brought the condition into relation with paramyotonia congenita (see further on). Hyperkalemic periodic paralysis is associated with a defect in the alpha subunit of the sodium channel gene (Fontaine et al, 1990). It is now appreciated that there are distinct variants of hyperkalemic periodic paralysis that are genetically distinct. All are associated with membrane hyperexcitability because of delays in sodium channel inactivation following membrane depolarization, as discussed later.

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

Clinical Manifestations The pattern of inheritance is autosomal dominant, as noted, with onset usually in infancy and childhood. Characteristically, attacks of weakness occur before breakfast and later in the day, particularly when resting following exercise. In the latter case, the weakness appears after 20 to 30 min of becoming sedentary. The patient notes difficulty that begins in the legs, thighs, and lower back and spreads to the hands, forearms, and shoulders over minutes or more. Only in the severest attacks are the neck and cranial muscles involved; respiratory muscles are usually spared. As the muscles become inexcitable, tendon reflexes are diminished or lost. Attacks usually last 15 to 60 min, and recovery can be hastened by mild exercise. After an attack, mild weakness may persist for a day or 2. In severe cases, the attacks may occur every day; during late adolescence and the adult years, when the patient becomes more sedentary, the attacks may diminish and even cease entirely. In certain muscle groups, if myotonia coexists, it is difficult to separate the effects of weakness from those of myotonia. Indeed, when an attack of paresis is prevented by continuous movement, firm, painful lumps may form in the calf muscles. Usually, however, the presence of myotonia can only be detected electromyographically. Some patients with repeated attacks may be left with permanent weakness and wasting of the proximal limb muscles. During the attack of weakness, serum K rises, often, but not always, up to 5 to 6 mmol/L. This is associated with increased amplitude of T waves in the electrocardiogram (ECG) and a fall in the serum Na level (because of the entry of Na into the muscle). With increased urinary excretion of K, the serum K falls and the attack terminates. Between attacks, serum K is usually normal or only slightly elevated. The attacks of paralysis are virtually alike in all clinical variants of the disease. In the paramyotonic form discussed below, the attacks are associated with paradoxical myotonia (myotonia induced by exercise and also by cold). The provocative test, undertaken under careful supervision when the patient is functioning normally, consists of the oral administration of 2 g of KCl in a sugar-free liquid repeated every 2 h for 4 doses if that many are necessary to provoke an attack. The test is given in the fasting state, ideally just after exercise. The weakness typically has a latency of 1 to 2 h after the administration of K. The patient must be carefully monitored by ECG and frequent serum estimations of serum potassium. The test should never be undertaken in the presence of an attack of weakness, or when there is reduced renal function, or in those with diabetes requiring insulin. The treatment of this syndrome is the same as that for paramyotonia congenita, described further on. Normokalemic periodic paralysis This form of episodic paralysis resembles the hyperkalemic form in practically all respects except that serum potassium does not increase out of the normal range, even during the most severe attacks. However, some patients with normokalemic periodic paralysis are sensitive to potassium loading (Poskanzer and Kerr); other kindreds are not (Meyers et al). The disorder is also transmitted as an autosomal dominant trait and the basic defect has proved to stem from the same

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mutation as that of hyperkalemic periodic paralysis of which it may be considered a variant.

Paramyotonia Congenita (Eulenburg Disease) Clinical manifestations  In this disease, attacks of periodic paralysis are associated with myotonia, which may be paradoxical in type—that is, developing during exercise and worsening as the exercise continues. In addition, a widespread myotonia, often coupled with weakness, is induced by exposure to cold. In some patients, the myotonia can be elicited even in a warm environment. The weakness may be diffuse, as in hyperkalemic periodic paralysis, or limited to the part of the body that is cooled. As commented in the earlier sections, cold exaggerates many types of myotonia to some extent, but this property is most characteristic of paramyotonia, and it is in this condition that cold-induced weakness persists for up to several hours once started, even after the body is rewarmed. Percussion myotonia can be evoked in the tongue and thenar eminence. Myotonia that is constantly present in a warm environment diminishes with repeated contraction, whereas myotonia induced by cold increases with repeated contraction (paradoxical myotonia) (Haass and colleagues). Like hyperkalemic periodic paralysis, paramyotonia congenita is transmitted in an autosomal dominant manner and both diseases have been linked to the same gene (SCN4A), which encodes the alpha subunit of the muscle membrane sodium channel; the two mutations are allelic. Laboratory findings In both hyperkalemic periodic paralysis and paramyotonia congenita, the serum K is usually above the normal range during bouts of weakness, but paralysis has been observed at levels of 5 mEq/L and lower. Each patient appears to have a critical level of serum K, which, if exceeded, will be associated with weakness. (This has led some authors to term the periodic paralysis as potassium dependent.) The administration of KCl, raising serum K to above 7 mEq/L, a level that has no effect on normal individuals, invariably induces an attack. As mentioned earlier, the ECG must be monitored during such provocative testing. The EMG shows myotonic discharge in all muscles, even at normal temperatures. The CK may be elevated. In vitro studies of muscle from patients with coldinduced stiffness and weakness have shown that as the temperature is reduced, the muscle membrane is progressively depolarized to the point where the fibers are inexcitable (Lehmann-Horn et al, 1987). A sodium channel blocker (tetrodotoxin) prevents the cold-induced depolarization. In patients with paramyotonia, but not in those with hyperkalemic periodic paralysis, a diminution of the compound muscle action potential in response to the cooling of muscle occurs, largely settling the argument as to whether the two syndromes (hyperkalemic paralysis and paramyotonia) are the same or different (Subramony and colleagues). Some patients with paramyotonia, like those with certain other forms of periodic paralysis, may, in later life, slowly develop a myopathy that causes persistent weakness. In some cases, this is sufficiently severe that it mimics

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the pattern of late-onset limb-girdle muscular dystrophy. However, in the case of paramyotonia there are relatively few histologic changes, primarily vacuoles in some of the muscle fibers and minimal evidence of myofiber degeneration. Treatment  Most patients with hyperkalemic periodic paralysis and its variants benefit from prophylactic use of the carbonic anhydrase inhibitor acetazolamide, 125 to 250 mg bid or tid (paradoxically, as it has a tendency to produce potassium retention). Acetazolamide reduces the frequency of attacks and may provide some relief from myotonia. There are no controlled studies of acetazolamide in these disorders, but trials of the related carbonic anhydrase inhibitor, dichlorphenamide demonstrated a reduced frequency of paralytic spells in both hyperand hypokalemic forms of periodic paralysis (Tawil et al; Sansone et al, 2016). However, in some patients, the attacks of hyperkalemic paralysis and of paramyotonia congenita are too infrequent, too brief, or too mild to require continuous treatment. The administration of diuretics such as hydrochlorothiazide (0.5 g daily), keeping the serum K below 5 mEq/L, also prevents attacks but risks inducing dangerous degrees of hypokalemia. When the myotonia is more troublesome than the weakness, mexiletine 200 mg tid is perhaps the best alternative because it prevents both cold- and exercise-induced myotonia, but it does not influence the frequency of acute attacks. Some additional benefits may be gained by adding inhaled beta-adrenergic agonists such as albuterol or salbutamol. Some studies suggest that one agent in this class, clenbuterol, may have a direct effect in blocking the sodium channel, independent of its activation of adrenergic receptors. Procainamide or the lidocaine derivative tocainide, in doses of 400 to 1,200 mg daily, is also useful for myotonia (tocainide carries a small risk of agranulocytosis). For the treatment of an acute and severe episode, intravenous calcium gluconate (1–2 g) often restores power. If, after a few minutes, this treatment is unsuccessful, intravenous glucose or glucose and insulin and hydrochlorothiazide should be tried so as to reduce the serum potassium concentration.

Other Sodium Channel Disorders Several other clinical presentations of hereditary periodic paralysis have been linked to mutations of the gene encoding the alpha subunit of the skeletal muscle sodium channel and probably represent variants of the disease. One of these has been designated myotonia fluctuans because muscle stiffness fluctuated in severity from day to day (Ricker and colleagues, 1994). In other respects, the clinical features resemble those of myotonia congenita, including provocation of attacks of myotonia by exercise. The muscle stiffness is only slightly sensitive to cold but is markedly aggravated by the ingestion of potassium and, interestingly, never progresses to muscular weakness or paralysis. Myotonia permanens is the name given to a severe, persistent myotonia and marked hypertrophy of muscles, particularly of the neck and shoulders. The EMG discloses continuous muscle activity. This disease was discovered in the course of genotyping a patient who earlier had been reported as

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an example of “myogenic” Schwartz-Jampel syndrome, but it affects the same channel as in hyperkalemic periodic paralysis (Spaans and associates). Trudell and colleagues studied 14 patients from a large kindred with autosomal dominant myotonia, the main feature of which was periodic worsening of myotonia accompanied by muscle pain and stiffness, most severe in the face and hands. The symptoms were enhanced by cold (suggesting paramyotonia) and severe stiffness and palpable rigidity followed within 15 min of the ingestion of potassium, but neither of these measures provoked muscle weakness. Muscle biopsy disclosed a normal ratio of types 1, 2A, and 2B fibers, further distinguishing this disorder from typical myotonia congenita, where 2B fibers may be reduced in number. All patients in this family who were treated with the carbonic anhydrase inhibitor acetazolamide had a dramatic resolution of symptoms within 24 h, hence the name acetazolamide-responsive myotonia. This disorder has been linked to the same molecular alteration of the sodium channel gene as occurs in hyperkalemic periodic paralysis (Ptácek et al, 1994b). Rosenfeld and coworkers described yet another form of painful congenital myotonia attributable to a novel mutation in the sodium channel alpha-subunit gene (SCN4A). Affected members of this family experienced debilitating pain, particularly severe in the intercostal muscles. Also, the pain was resistant to treatment with acetazolamide and other antimyotonic drugs (mexiletine and tocainide) and could not be provoked by ingestion of potassium-rich foods, differing from even rarer similar cases that are acetazolamide responsive. Finally, in regard to disorders of the sodium channel, it should be mentioned that the marine toxins (ciguatoxin, tetrodotoxin, saxitoxin) discussed in Chap. 41, produce their effects on the peripheral and central nerves by blocking sodium channels but have a little obvious effect on muscle function.

Pathophysiology of Myotonia and Hyperkalemic Periodic Paralysis (See Also Chap. 2) In both myotonia congenita and hyperkalemic paralysis, the absence of major morphologic changes and the prominence of the myotonic phenomenon in individual muscle fibers are consistent with a disorder of the sodium channel. This is also compatible with the observation that myotonia persists after the administration of curare, thereby exonerating neural input as the source of myofiber hyperexcitability. The electromyographic pattern of a myotonic muscle reveals highly characteristic discharges that persist following the cessation of voluntary contraction. The tension of the myotonic muscle fibers is slow to diminish as a result of these greatly prolonged trains of muscle action potentials (see Fig. 2-19). Some of these afterdischarge potentials are the size of fibrillations, but others are as large as normal motor units. Thus myotonia can be distinguished electrophysiologically from contracture (e.g., that encountered in McArdle disease, in which the muscle is electrically silent). In experiments conducted in the 1940s, Denny-Brown and Foley, stimulating single muscle fibers directly, found that

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

myotonic discharges could be elicited only by a volley of stimuli and not by a single stimulus. They also noted that the series of myotonic potentials progressively diminished in size. Percussion elicits myotonia by imparting a brief but relatively intense repetitive excitation of the muscle membrane. The biophysical basis of myotonia is now well understood in terms of the functioning of chloride and sodium channels in the muscle membrane and internal structures. The correspondence between mathematical models of the electrical properties of the membrane and the clinical features of the myotonic and periodic paralyses is quite remarkable. During the normal action potential in all neural and muscular tissue, membrane depolarization is terminated by two events: the depolarization-induced inactivation of the sodium channel (which ends the inward sodium current) and the subsequent action of the outward potassium current. In muscle, the termination of an action potential requires an additional factor. Because of its large size, excitation of the muscle fiber involves depolarization that propagates not only along the cell surface but also radially into the center of the muscle cell through the transverse tubules (T tubules). The tubules are very narrow structures whose internal spaces are in continuity with the extracellular space. When the repolarizing outward potassium current is activated, potassium ions flood into the tubules from the muscle cytoplasm. By itself, this tubular K accumulation would depolarize the muscle membrane and prolong excitation. Normally, this does not occur because there is a large opposing chloride conductance in the tubules that counteracts the influence of potassium accumulation. The first clues to the importance of the chloride channel in this electrical stabilizing process were demonstrated in vitro studies of myotonic goat muscle that showed reduced chloride conductance in the transverse tubular system (Bryant, 1979). Subsequent studies of muscle from patients with myotonia congenita demonstrated a similarly low chloride conductance (Lipicky and Bryant). That a mutation in a muscle chloride channel could produce myotonia was confirmed in a mouse model by Jentsch and Steinmeyer and colleagues (see Koch et al), who subsequently also described the first human chloride channel (CLCN1) mutations. As indicated, an essential event for normal repolarization of an excitable membrane is the rapid inactivation of the inward sodium current. This process of rapid, complete sodium channel inactivation is impaired by the sodium channel mutations implicated in hyperkalemic periodic paralysis. The mutations cause imperfect inactivation of the channel and lead to aberrant and early reopenings. Repolarization is then incomplete, rendering the muscle cell more readily re-excited; it is this hyperexcitability that causes the myotonia of hyperkalemic periodic paralysis. The problem becomes self-reinforcing because, as the membrane fails to repolarize fully, its electrolytic inactivation becomes increasingly less effective. If this process is not aborted, the result is such excessive depolarization that the muscle cell ultimately becomes unexcitable—a state that corresponds to the paralytic phase of hyperkalemic periodic paralysis. These features are evident in

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hyperkalemic muscle in vitro (Cannon et al) and can be recapitulated in computer simulations of aberrant channels. Presumably, over several hours, a variety of compensatory mechanisms (e.g., activation of Na-K adenosine triphosphatase [ATPase] pumps) restores the baseline excitability of the muscle membrane.

Calcium Channel Diseases Hypokalemic Periodic Paralysis This is the best-known form of periodic paralysis. The history of the disease is difficult to trace, but the first unmistakable account was probably that of Hartwig in 1874, followed by the accounts of Westphal (1885) and Oppenheim (1891). Goldflam (in 1895) first called attention to the remarkable vacuolization of the muscle fibers that is characteristic of the process (Talbott; Layzer; LehmannHorn and associates, 2004). In 1937, Aitken and associates described the occurrence of low serum potassium during attacks of paralysis and the reversal of the paralysis by the administration of potassium, thus setting the stage for subsequent differentiation from the hyperkalemic forms of periodic paralysis. The usual pattern of inheritance is autosomal dominant with reduced penetrance in women (male-to-female ratio of 3 or 4:1). The mutation was localized to a region containing the gene that encodes the alpha subunit of the calcium channel of skeletal muscle and missense mutations in the responsible gene (CACNA1S) have been identified (Fontaine and coworkers, 1990 and 1994). The subunit, which is part of the dihydropyridine receptor complex, is located in the transverse tubular system. This region is believed to act both as a voltage sensor that controls calcium release from the sarcoplasmic reticulum, thus mediating muscle excitation– contraction coupling, and as a calcium-conducting pore. How precisely the reduced calcium channel function relates to hypokalemia-induced attacks of muscle weakness is not fully known, but most of the mutations affect the protein in a way that would allow a cation leak (Matthews et al). Approximately 10 percent of cases, however, are due to a mutation in the earlier discussed sodium channel, SCN4A. Clinical manifestations  In our experience, this disease has become clinically apparent after adolescence and has been much more severe in males. We note, however, that in Talbott’s review of 152 cases, there were 40 in which symptoms began before the 10th year of life and 92 before the 16th year. The typical attack comes on during the second half of the night or the early morning hours, after a day of unusually strenuous exercise; a meal rich in carbohydrates favors its development. Excessive hunger or thirst, dry mouth, palpitation, sweating, diarrhea, nervousness, and a sense of weariness or fatigue are mentioned as prodromata but do not necessarily precede an attack. Usually, the patient awakens to discover a mild or severe weakness of the limbs. However, diurnal attacks also occur, especially after a nap that follows a large meal. The attack evolves over minutes to several hours; at its peak, it may render the patient so helpless as to be unable to call for assistance. Once established, the weakness lasts a few hours if mild or several days if severe.

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The distribution of the paralysis varies. Limbs are affected earlier and often more severely than trunk muscles, and proximal muscles are possibly more susceptible than distal ones. The legs are often weakened before the arms, but exceptionally the order is reversed. The muscles most likely to escape are those of the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters, but on occasion, even these may be involved. When the attack is at its peak, tendon reflexes are reduced or abolished and cutaneous reflexes may also disappear. As the attack subsides, strength generally returns first to the muscles that were last to be affected. Headache, exhaustion, diuresis, and occasionally diarrhea may follow the attack. Myotonia is not seen; indeed, clinical or EMG evidence of myotonia essentially excludes the diagnosis of hypokalemic periodic paralysis. Attacks of paralysis tend to occur every few weeks and tend to lessen in frequency with advancing age. Rarely, death may occur from respiratory paralysis or derangements of the conducting system of the heart. Such fatal cases were reported mainly in the era before modern intensive care. Atypical forms include weakness of one limb or certain groups of muscles, bibrachial palsy (inability to lift one’s arms or to comb one’s hair), and transient weakness during accustomed activities such as walking. Some of our patients had a talipes deformity from early life. During middle adult life, a number of patients have developed a severe, slowly progressive proximal myopathy, with vacuolated and degenerated fibers and myopathic action potentials, in some instances long after attacks of periodic paralysis had ceased. Laboratory findings  The attacks are accompanied by a reduction in serum K levels, as low as 1.8 mEq/L, but usually at levels that would not be associated with muscle weakness in normal subjects. The fall in serum K is associated with little or no increase in urinary K excretion. Presumably, large quantities of K enter the muscle fibers during an attack, but this explanation may not be complete. Some episodes occur with near-normal levels of K, and weakness persists for a time after the serum level has been restored. The serum K levels return to normal during recovery. Although the shifts in K are of undoubted importance in the pathogenesis of muscle weakness, the marked sensitivity to small reductions of serum K suggests that other factors are operative and that the fall in K may be a secondary phenomenon. As in hyperkalemic paralysis, the muscular weakness in this disease is associated with a decrease in the amplitude, and eventual loss, of muscle action potentials, and there is a failure of excitation by supramaximal stimulation of peripheral nerve or by strong voluntary effort. A decline in strength precedes the loss of motor unit potentials and the failure of propagation of action potentials over the surface of the fiber. The polarization potentials of muscle fibers measured by intracellular recordings are initially normal despite the failure of impulse propagation by the sarcolemma. One would expect the muscle fiber to be hyperpolarized as K moves into it, but it actually becomes depolarized, likely due to increased Na conductance (Rüdel and associates). ECG changes also begin at levels of K that are slightly below normal (about 3 mEq/L); they

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consist of prolonged PR, QRS, and QT intervals and flattening of T waves. Diagnosis at a time when the patient is normal may be facilitated by provocative tests. With the patient carefully monitored, including the use of ECG, the oral administration of 50 to 100 g of glucose or loading with 2 g of NaCl every hour for 7 doses, followed by vigorous exercise, brings on an attack, which then can be terminated by 2 to 4 g of oral KCl (the opposite of what pertains in hyperkalemic periodic paralysis). Pathologic changes  The muscle fibers are uniformly somewhat large, but the most striking change, particularly in the late degenerative phases of the disease, is vacuolization of the sarcoplasm. The myofibrils are separated by round or oval vacuoles containing clear fluid, presumably water, and a few periodic acid-Schiff (PAS)-positive granules. There are pathologic changes in myofibrils and mitochondria as well, and focal increases in muscle glycogen. Isolated muscle fibers may undergo segmental degeneration. Electron microscopic studies have shown that the vacuoles arise as a result of proliferation and degeneration of membranous organelles within the sarcoplasmic reticulum and transverse tubules (Engel, 1970). Treatment  A low-sodium diet (less than 160 mEq/d), avoidance of large meals and of exposure to cold, and acetazolamide 250 mg tid may be helpful in preventing attacks. That acetazolamide reduces attacks is somewhat surprising as it is kaluretic, but it may work through the production of acidosis; a few patients have worsened with the drug. Patients who are unresponsive to acetazolamide may be treated with the more potent carbonic anhydrase inhibitor, dichlorphenamide, 50 to 150 mg/d, or with the potassium-sparing diuretics spironolactone or triamterene (both in doses of 25–100 mg/d), but caution must then be exercised with the simultaneous administration of oral potassium supplements. The daily administration of 5 to 10 g of KCl orally in an unsweetened aqueous solution prevents attacks in many patients, and apparently, this program can be maintained indefinitely. If this approach fails, a low-carbohydrate, low-salt, high-K diet combined with a slow-release K preparation may be effective. For an acute attack, 0.25 mEq KCl/kg should be given orally, or if this is not tolerated, some other K salt may be tried. This dose may be insufficient and if there is no improvement in 1 or 2 h, KCl may have to be given intravenously: 0.05 to 0.1 mEq/kg initially in a bolus at a safe rate, followed by 20 to 40 mEq KCl in 5 percent mannitol, avoiding glucose or NaCl as the carrier solution. For the late-progressive polymyopathy that follows many severe attacks of periodic paralysis, strength can be restored with long-term administration of dichlorphenamide (Dalakas and Engel). Regular exercise (not too strenuous) to keep the patient fit is desirable.

Secondary Kalemic Periodic Paralyses In addition to the hereditary kalemic paralyses described earlier, transitory episodes of weakness are associated with a number of acquired derangements of potassium metabolism (mainly hypokalemia); these include thyrotoxicosis, aldosteronism, 17α-hydroxylase deficiency (Yazaki et al), barium poisoning (Lewi and Bar-Khayim), glycyrrhizic

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acid ingestion (a substance in licorice that has mineralocorticoid activity), and abuse of thyroid hormone (Layzer). Other forms of secondary hypokalemic weakness occur in patients with chronic renal disease (including renal tubular acidosis from Sjogren syndrome) and adrenal insufficiency or loss of potassium, as occurs with excessive use of diuretics or laxatives (the most common cause in practice). Renal failure with hyperkalemia can also induce considerable weakness.

Thyrotoxicosis With Periodic Paralysis This is a special form of secondary hypokalemic periodic paralysis and occurs mainly in young adult males (despite the higher incidence of thyrotoxicosis in women), with a strong predilection for those of Japanese and Chinese origin (Pothiwala). A study in Japan showed that 8.9 percent of men with thyrotoxicosis had periodic paralysis, but this was the case in only 0.4 percent of women (Okinaka and associates); in China, the corresponding figures were 13.0 and 0.17 percent (McFadzean and Yeung). The paralytic disorder is unrelated to the severity of hyperthyroidism. In patients with familial forms of periodic paralysis, the induction of hyperthyroidism is said not to increase the frequency or intensity of attacks. Therefore, it seems likely that thyrotoxicosis has unmasked another type of hereditary periodic paralysis, although a familial occurrence in thyrotoxic cases is exceptional. Clinically, the attacks of paralysis are much the same as those of familial hypokalemic type except for a greater liability to cardiac irregularity. As in the familial form, the paralyzed muscles are electrically inexcitable. Potassium chloride restores power in paralytic attacks, and treatment of hyperthyroidism prevents their recurrence.

Hypokalemic Weakness in Primary Aldosteronism (Conn Syndrome) Hypokalemic weakness because of hypersecretion of the major adrenal mineralocorticoid aldosterone was first described by Conn and associates in 1955. In primary aldosteronism, the cause of the hypersecretion is in the adrenal gland itself, usually an adrenal cortical adenoma, less often adrenal cortical hyperplasia. Although the disorder is uncommon (occurring in approximately 1 percent of unselected hypertensive patients), its recognition is essential for effective treatment. Persistent aldosteronism is frequently associated with hypernatremia, polyuria, and alkalosis, which predispose to attacks of tetany as well as to hypokalemic weakness. In an analysis of 145 patients with primary aldosteronism, it was found that persistent muscular weakness was a major complaint in 73 percent; intermittent attacks of paralysis occurred in 21 percent; and tetany in another 21 percent (Conn and associates 1964). These manifestations were much more frequent in women than in men, in contrast to the preponderance of men among patients with hypokalemic periodic paralysis of familial type. Rarely, as already noted, primary aldosteronism is produced by the chronic ingestion of licorice; this is due to its content of glycyrrhizic acid, a potent mineralocorticoid (Conn et al, 1968). The muscle fibers of patients with primary aldosteronism show necrosis and vacuolation. Ultrastructurally, the necrotic areas are characterized by the dissolution of

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myofilaments with degenerative vacuoles; nonnecrotic fibers contain membrane-bound vacuoles and show dilatation of the sarcoplasmic reticulum and abnormalities of the transverse tubular system, suggesting that vulnerability of the latter structures may be responsible for the muscle fiber necrosis (Atsumi et al).

Malignant Hyperthermia This dramatic syndrome is observed during general anesthesia in susceptible individuals, some of whom clearly have a channelopathy. It is characterized by rapidly rising body temperature, extreme muscular rigidity, and a high mortality rate. Since the original report by Denborough, as larger experience was gained with this entity, it proved in some cases to be a metabolic myopathy inherited as a dominant trait, rendering the individual vulnerable to any volatile anesthetic agent, particularly halothane, and to the muscle relaxant succinylcholine. The fundamental cause, in a proportion of cases, is an aberration in a component of the ryanodine calcium channel. Malignant hyperthermia has been estimated to occur approximately once in the course of every 50,000 administrations of general anesthesia.

Clinical Manifestations The full clinical picture is striking, but anesthesiologists have become adept at detecting its earliest stages and aborting the process. As halothane or similar inhalational anesthesia is induced, or succinylcholine is given for muscular relaxation, the jaw muscles unexpectedly become tense rather than relaxed and soon rigidity extends to all of the muscles. Thereafter, the body temperature rises to 42°C or 43°C and there is tachypnea and tachycardia. Blood pH may fall to 7 or below. There may be gross myoglobinuria and serum CK reaches extraordinarily high levels. Circulatory collapse and death may ensue in approximately 10 percent of cases, or the patient may survive with gradual recovery. In some cases, there is the same sequence of events (increased temperature and acidosis) without muscular spasm. In cases of early death, the muscle may appear normal by light microscopy. With survival for several days, samples of muscle reveal scattered segmental necrosis and phagocytosis of sarcoplasm without inflammation. Patients with a particular congenital myopathy (central core myopathy), and those with King-Denborough syndrome, mentioned later, have a propensity to malignant hyperthermia, as noted in Chap. 45.

Pathophysiology and Etiology The pathogenesis of malignant hyperthermia has been the subject of numerous investigations. During the rigor phase, oxygen consumption in muscle increases threefold and serum lactate, 15- to 20-fold. Muscle from most affected individuals is abnormally sensitive to caffeine, which induces contracture in vitro. It has been postulated that halothane acts in a manner similar to caffeine—that is, to release calcium from the sarcoplasmic reticulum and prevent its reaccumulation, thus interfering with the relaxation of the muscle. The essential physiologic change is one of increased intracellular calcium.

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Insight into the disease has been gained from a breed of pigs, inbred for muscular development, in which muscle spasm (true contracture) and hyperthermia follow the administration of anesthetic agents. These swine have an inherited defect in the ryanodine receptor, a protein component of the calcium channel of the sarcoplasm that is sensitive to both caffeine and ryanodine. However, one of several similar defects in ryanodine is found in somewhat fewer than 20 percent of people with susceptibility to malignant hypothermia. It is presumed that other yet unidentified allelic mutations of this receptor protein or another that controls the structure of the calcium channel account for the remainder of cases. The cause of the high fever is unknown; it is probably caused by muscle spasm, but the effect of the anesthetic on heat-regulating centers has not been excluded. Clues as to which patients are at risk for this condition come from several sources. Other members of the family may have difficulties or have died during anesthesia. Some susceptible individuals exhibit myopathic and musculoskeletal abnormalities (Isaacs and Barlow). One such dysmorphic constellation consists of short stature, ptosis, strabismus, highly arched palate, dislocated patellae, and kyphoscoliosis, which have been present in several families (King-Denborough syndrome, see Denborough et al). As mentioned just above and in Chap. 45 on the congenital myopathies, central core (sometimes called multicore) myopathy is frequently complicated by malignant hyperthermia. This is understandable insofar as both disorders have been linked to the gene encoding the ryanodine receptor; the two diseases are a result of allelic variations (Quane et al). It has been pointed out that another rare muscle disease (Evans myopathy, named after the affected family) may also be a predisposing condition. It is inherited as an autosomal trait and may be asymptomatic until the anesthetic reaction, but some patients have wasting of the distal thigh muscles and an elevation of serum CK concentration (see Harriman et al). Diagnostic testing Various tests for susceptibility to malignant hyperthermia can be considered in the appropriate circumstances. One method involves in vitro exposure of a muscle biopsy specimen to halothane and to caffeine and the detection of muscle contracture with both agents (Denborough). This test may be considered in individuals with a suspected prior episode of malignant hyperthermia (after 6 months) and in those with a family member with a prior episode but without a known genetic mutation. It is performed only in a few centers, which are listed at http:// www.mhaus.org. Genetic testing of the RYR1, CACNA1s, and STAC3 genes may also be considered, particularly in individuals with a confirmed or highly suspicious episode or those with a positive caffeine halothane contracture test.

Treatment This consists of discontinuation of anesthesia at the first hint of masseter spasm or rise of temperature. The intravenous administration of dantrolene, which inhibits the release of calcium from the sarcoplasmic reticulum, may be lifesaving. An infusion of 1 mg/kg is given initially and increased slowly until symptoms subside, the total dosage not exceeding 10 mg/kg. Other measures should include body cooling,

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intravenous hydration, sodium bicarbonate infusion to correct acidosis, and mechanical hyperventilation to decrease acidosis. Thereafter, halothane and other volatile anesthetic agents and succinylcholine should be avoided in such individuals and surgical procedures, if necessary, should be done with other agents, such as propofol, nitrous oxide, fentanyl, thiopental (or other barbiturate), or local anesthesia. Intravenous dantrolene (2.5 mg/kg given slowly 1 h prior to anesthesia) prevents the syndrome, but this is not a preferred option in patients with the disorder.

Neuroleptic Malignant Syndrome This state, in which hyperthermia occurs as an idiosyncratic reaction to neuroleptic drugs, is also accompanied by widespread myonecrosis. It shares some features with malignant hyperthermia but is a distinct entity, as discussed in Chap. 41.

Potassium Channel Diseases The discovery of several types of seizure disorders based on inherited defects of the potassium channel has elicited considerable interest and only recently was it appreciated that one form of periodic paralysis, Andersen disease, is associated with the VGKC.

Andersen-Tawil Disease Andersen and coworkers first drew attention to a distinct form of potassium-sensitive periodic paralysis characterized by the triad of periodic potassium-sensitive weakness, ventricular dysrhythmias with long QT syndrome, and dysmorphic features (micrognathia, short stature, scaphocephaly, hypertelorism, broad nose, low-set ears, and short index fingers). Sometimes called “Andersen disease,” it is not to be mistaken for the glycogen storage disease of the same name, which is discussed in Chap. 45. A study of five kindreds pointed out that attacks of paralysis can be associated with hypo-, normo-, or hyperkalemia and that a prolonged QT interval is an integral feature of the disease (and sometimes the only sign in a given family) (Sansone and colleagues, 1997). Most cases of Andersen disease are a consequence of dominant-negative mutations in the gene KCNJ2 that encodes a type of K channel (Plaster and colleagues). In vitro studies indicate that the mutation impairs the ability of preformed channels to migrate to the membrane surface and also impedes the current-carrying capacity of the potassium channel system. This defect would be expected to impair the repolarization of the muscle membrane, thereby making both skeletal and cardiac muscle hyperexcitable.

Morvan Syndrome (Chorée Fibrillaire) This disease is characterized by continuous muscle fiber activity, sometimes referred to as “neuromyotonia,” and therefore may also be considered among similar disorders of constant muscle activity that are discussed further in the chapter. It is associated with specific antibodies directed against VGKC. One of these antibodies is anti-contactinassociated protein-like 2 (Caspr2) antibodies that produce a syndrome of neuromyotonia, often associated with some

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity

combination of memory loss and confusion, sleep disturbances, neuropathic pain, autonomic instability, and focal seizures (Irani and colleagues; Serratrice and Azulay; Thieben and colleagues). This disorder is most common in older men with a median age of 65 years. The presentation tends to be more slower than other autoimmune encephalitis syndromes, often presenting over the course of many months. In some patients, there is isolated neuromyotonia without the other clinical features. It is typically not associated with cancer and most patients have good responses to immunotherapy (Ligouri and colleagues). Some cases have an associated thymoma and its removal may be curative.

OTHER DISEASES AFFECTING MUSCLE MEMBRANE EXCITABILITY In addition to the above disorders, various seizure syndromes (see Chap. 15) and a category of spinocerebellar ataxias are also attributable to mutations of ion channels and are addressed in other sections of the book. Also mentioned here for completeness are several diseases that result from secondary dysfunction of these same ion channels. Most of these conditions are acquired and autoimmune in nature, for example, the Lambert-Eaton myasthenic syndrome that results from an autoimmune attack on calcium channels discussed earlier, the Isaac syndrome that results from an autoimmune attack on potassium channels, producing neuromyotonia, anti-VGKC and antiNMDA encephalitis (see Chap. 30), and erythromelalgia that implicates a sodium channel (see Chap. 10). Thus, ion channels, being ubiquitous in all excitable tissues, might be expected to produce a large variety of diseases that affect central and peripheral nervous structures. Despite this, each of the genetic and acquired processes has remarkably specific features that are pertinent only to the channel as expressed in a single tissue.

Physiologic Contracture Caused by Phosphorylase Deficiency (McArdle Disease) and Phosphofructokinase Deficiency (Tarui Disease) Contractures are examples of an entirely different type of painful shortening and hardness of muscle. In both these diseases, an otherwise healthy child, adolescent, or adult begins to complain of weakness and stiffness, and sometimes pain on using the limbs. Muscle contraction and relaxation are normal when the patient is in repose, but strenuous activity, especially under conditions of ischemia, causes the muscles to shorten gradually because of a failure of relaxation. The contracted muscles in these disorders—unlike muscles in cramp, continuous muscular activity syndromes, or myotonia and other involuntary spasms—no longer use energy, for which reason they are almost silent electrically in the EMG. This condition is spoken of as physiologic contracture. McArdle and Tarui diseases are discussed more fully in a later section.

Pseudomyotonia This phenomenon is observed in hypothyroidism, where the muscle fibers contract and relax slowly, a response

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readily demonstrated in the tendon reflexes, particularly the Achilles reflex. The muscles are large and subject to myoedema. When contracted, they may show waves of slow contraction. The basis of this disorder appears to be slowness in the reaccumulation of calcium ions in the endoplasmic reticulum and in the disengagement of actin and myosin filaments. The EMG may show afterpotentials following voluntary contraction, but they do not resemble the typical waning discharges (“myotonic runs”; Fig. 2-19) of true myotonia. A closely related syndrome, wherein painless contracture is induced by exercise, consists of normal muscle contraction is normal, but the relaxation phase becomes increasingly slow during exercise (Lambert and Goldstein; Brody). The slow relaxation has also been attributed to a decreased uptake of calcium by the sarcoplasmic reticulum. In some cases, the disease is transmitted as a recessive trait with a mutation that impairs the function of a sarcoplasmic reticular calcium ATPase. In other instances, the disease is transmitted as a dominant trait that is not genetically linked to calcium ATPase. This latter process may be more closely aligned with muscular dystrophies and is mentioned in Chap. 45 under that heading.

Tetanus (See Tetanus in Chap. 41) This toxic disorder is characterized by persistent spasms of skeletal muscles, owing to the effect of the tetanus toxin on spinal neurons (Renshaw and other cells), the natural function of which is to inhibit the motor neurons. As the condition develops, activities that normally excite the neurons (i.e., voluntary contraction and startle from visual and auditory stimulation) all evoke involuntary spasms. Sleep tends to quiet them, and they are suppressed by spinal anesthesia and curare. The EMG shows the expected interference pattern of muscle action potentials. Once the muscle is involved in persistent contraction, it is said that the shortened state is not abolished by procaine block or severance of nerve (in animals), but this type of myostatic contracture has not been demonstrated in humans. The effect of tetanus toxin on the spinal inhibitory neurons is analogous to that of strychnine. There is also an action of the toxin at the neuromuscular junction, which has been more difficult to evaluate in the face of its powerful central action. Having injected this toxin locally in animals, Price and associates demonstrated its localization at motor endplates. It binds with ganglioside in the axon membrane and is transported by retrograde flow to the spinal cord, where it induces local tetanus effects. Neurons that innervate slow-twitch type 1 muscle fibers are more sensitive than those supplying fast-twitch type 2 fibers. Presynaptic vesicles increase in number, ACh is blocked, and terminal axon injury may paralyze muscle fibers. Fibrillation potentials and axonal sprouting follow. The similarities to stiff person syndrome are mentioned further on.

Black Widow Spider Bite (See also Chap. 41) The toxin produced by this spider within a few minutes of the bite leads to a striking syndrome of cramps and spasms and then a painful rigidity of abdominal, trunk,

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and leg muscles. The spasms are followed by weakness. There is also vasoconstriction, hypertension, and autonomic hyperactivity. If death does not occur in the first 24 to 48 h, recovery is complete. The spider venom has a presynaptic localization and rapidly releases quanta of ACh. The vesicles became depleted. There is some evidence that the venom prevents endocytosis of the vesicles by inserting itself into the presynaptic membranes, causing a disturbance of ionic conductance channels (Swift). Treatment consists of calcium gluconate infusions and diazepine. Intravenous magnesium sulfate also helps to reduce the release of ACh and control the convulsions that sometimes occur. There is antiserum that is available in regions where such envenomation is frequent; it shortens the illness considerably.

States of Persistent Muscle Activity This is an interrelated group of clinical states, all characterized by some degree of regional continuous muscular activity that, in some cases, cannot be fully differentiated from one another. From a clinical perspective, we have found it is useful to categorize them into groups that are caused by (1) hyperexcitability of the peripheral motor nerves (fasciculations and myokymia), (2) centrally mediated hyperexcitability of motor output (Isaacs syndrome, stiff man syndrome), and (3) nonmyotonic hyperexcitability of muscle (rippling muscle disease, Schwartz-Jampel syndrome).

Hyperexcitability of Peripheral Nerve This comprises a set of disorders in which peripheral motor nerve activity is augmented such that there are excessive, sometimes sustained contractions of the motor unit. Its mildest manifestation is benign fasciculation. In more severe form, the manifestations include neuromyotonia, Isaacs disease, and a disease of potassium-gated ion channels (Morvan disease, or Morvan fibrillary chorea discussed below) that may also involve the brain. These processes are not generally familial and several lines of investigation suggest an acquired autoimmune nature (Newsom-Davis). For example, all but benign fasciculations are associated more often than might be expected with other autoimmune diseases such as myasthenia gravis and some respond to autoimmune therapies such as plasmapheresis, the patient’s serum possesses antibodies to either VGKCs as mentioned or, less frequently, to nicotinic ACh receptors (Vernino and Lennon).

Benign Fasciculations A few random fasciculations in the muscles of the calf, small muscles of the hand or of the face, or elsewhere are seen in most normal individuals. They are of little significance but can be a source of worry to physicians and patients who have read that fasciculations are an early sign of amyotrophic lateral sclerosis. A simple clinical rule is that fasciculations in relaxed muscle are not indicative of motor system disease unless there is associated weakness, atrophy, or reflex change. Healthy individuals experience intermittent twitching of a muscle (or even part of a muscle), such as one of the

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muscles of the thenar eminence, eyelids, calves, or orbicularis oculi. They may continue for days. Electromyographically, benign fasciculations tend to be more constant in location and more frequent and rhythmic than the ominous fasciculations of amyotrophic lateral sclerosis, but such distinctions are not entirely reliable. The physiology of fasciculations is discussed in Chap. 2 and illustrated in Fig. 2-20. Quantitative study of the motor unit size may be helpful in these circumstances by demonstrating normally modeled units in the benign form and abnormally large units because of reinnervation in the case of motor neuron disease. Occasionally, benign fasciculations are widespread and may last for months or even years. In several of our patients, they have recurred in bouts separated by months and lasting several weeks. No reflex changes, sensory loss, nerve conduction, EMG abnormality (other than fasciculations), or increase in serum muscle enzymes are found. Low energy and fatigability in some of these patients may suggest an endogenous depressive illness, yet the fasciculations are not explained by this mechanism. Patients commonly report a sense that the muscles affected by the twitching are weak, but this cannot be confirmed by testing and several of our patients, curiously most of whom have been physicians, complained of equally troubling migratory zones of paresthesias. Pain of aching or burning type may increase after activity and cease during rest. Fatigue and a sense of weakness are frequent complaints. We suspect that this fasciculatory state reflects a disease of the terminal motor nerves, for a few of our patients have shown slowing of distal latencies, and Cöers and associates have found degeneration and regeneration of motor nerve terminals in similar cases. However, most such cases are of benign nature and settle down in a matter of weeks or months. Large series show that the condition, even after years, does not progress to spinal muscular atrophy, polyneuropathy, or amyotrophic lateral sclerosis (Hudson and colleagues; Blexrud et al). It should be acknowledged, however, that there are infrequent patients with seemingly benign fasciculations in whom the EMG shows some abnormal features (e.g., rare fibrillations) in numerous muscles and who later develop the other features of motor neuron disease. Carbamazepine, and to a lesser extent phenytoin and other antiepileptic drugs, has been helpful in reducing the fasciculations and sensations of weakness in a proportion of cases and numerous other medications have been reportedly helpful.

Cramp-Fasciculation Syndrome This is probably a variant of the above-described benign entity in which fasciculations are conjoined with cramps, stiffness, and systemic features such as exercise intolerance, fatigability, and muscle aches. Although affected individuals may be to some degree disabled by these symptoms, the prognosis is good. The salient finding on physiologic studies is that stimulation of peripheral nerves results in sustained muscle firing due to prolonged trains of action potentials in the distal motor nerve. This phenomenon may be brought out in special electrophysiologic testing (Tahmoush and colleagues). In effect, this is a mild form of neuromyotonia, which is described

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further on. In a small number of patients with crampfasciculation syndrome, it is possible to demonstrate the presence of autoantibodies directed against voltage-gated axonal potassium channels. Carbamazepine or gabapentin may be beneficial. There are, in addition to these benign states, several syndromes of abnormal muscle activity. The main ones are myokymia, a state of successive contractions of motor units imparting an almost continuous undulation or rippling of the overlying body surface, and several syndromes of continuous muscle fiber activity described below.

Myokymia This state of abnormal rippling muscle activity may be generalized or limited to one part of the body such as the muscles of the shoulders or of the lower extremities. It is observed most often with demyelination of peripheral nerve following injury, and thus it is neuropathic in nature. The common underlying conditions are multiple sclerosis or GBS affecting the facial nerve and radiation damage to the brachial or lumbar plexus. In the EMG, myokymic discharges consist of repetitive firing of 1 motor unit, firing at 5 to 60 Hz and recurring regularly at 0.2- to 10-s intervals. The driving impulses arise in the most peripheral parts of the axon of chronically damaged nerves. In some patients, cramping is associated, and those muscles about to cramp may twitch or show premonitory spontaneous rippling contractions; the cramping may be associated with sweating. Thus, myokymia, fasciculation, and cramping seem to be related but not clinically identical conditions.

Continuous Muscle Fiber Activity (Isaac Syndrome) The relation of myokymia to the state called continuous muscle fiber activity is ambiguous. Sporadically in the neurologic literature, there have been descriptions of patients whose muscles, at some point, begin to “work” continuously (see Isaacs). Terms such as neuromyotonia and widespread myokymia with delayed muscle relaxation are additional names that have been applied to what is essentially the same condition. At the moment, there is little reason to distinguish one from another except in gradations of severity. In each case, the excessive and spontaneous activity can be attributed to hyperexcitability of terminal parts of motor nerve fiber, possibly as a result of a partial loss of motor innervation and compensatory collateral sprouting of surviving axons (Cöers et al; Valli et al). The association of this type of disorder to anti-voltage gated potassium channels has been mentioned in relation to thymoma and to Morvan’s syndrome. Twitching, spasms, and rippling of muscles (myokymia) are evident, the latter being the main clinical sign. In advanced cases, there is generalized muscle stiffness and a sense of weakness. Complaints of muscle aching are usual, but severe myalgia is uncommon. The tendon reflexes may be reduced or abolished. Any muscle group may be affected. The stiffness and slowness of movement make walking laborious (“armadillo” syndrome); in extreme cases, all voluntary movement is blocked. The muscle activity persists

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throughout sleep. The continuous visible and painful cramps of the above-described Satoyoshi disease may be difficult to distinguish from myokymia clinically, but they represent a different phenomenon. General and spinal anesthesia do not always suppress the muscular activity, but curare does; nerve block usually has no effect or may reduce the activity, as in the case described by Lütschg and colleagues. The EMG findings are much the same as those described earlier. Special types of myokymia arise in childhood or adult life, sometimes in association either with a polyneuropathy or rarely with an inherited type of episodic ataxia that is variably responsive to acetazolamide or remits spontaneously (see Chap. 5). An inherited form of continuous muscle fiber activity has been traced to a mutation of the peripheral nerve K channel (Gutmann and Gutmann). In addition to the association with polyneuropathy, a state of continuous muscular activity has also been described in association with lung cancer and thymoma, in which cases an immune mechanism has been inferred, as noted above in Morvan syndrome (see reviews by Newsom-Davis and Mills and the discussion of paraneoplastic syndromes in Chap. 30). Treatment  Phenytoin or carbamazepine often abolishes the continuous muscular activity and cause a return of reflexes. Acetazolamide has been helpful in other cases (Celebisoy et al). Many of the idiopathic cases will improve spontaneously after several years, however, plasma exchange may be tried if the symptoms are intractable.

Stiff Person Syndrome This is a condition of persistent and intense spasms, particularly of the proximal lower limbs and lumbar paraspinal muscles. It was originally described by Moersch and Woltman in 1956 as stiff man syndrome. Since then, many examples have been reported all over the world and the term stiff person syndrome has been used to indicate its occurrence in both women and men. For lack of a better place in the book to discuss it, it is included here with other processes that cause muscular spasms and cramps. The onset is insidious, usually in middle life. No genetic predisposition is known. At first, the stiffness and spasms are intermittent, then gradually, they become more or less continuously active in the proximal leg and axial trunk muscles and increasingly painful. The spasms impart a robotic appearance to walking and an exaggerated lumbar lordosis. Attempts to move an affected part passively yield an almost rock-like immobility, perceptibly different from spasticity, paratonia, or extrapyramidal rigidity. Muscles of respiration and swallowing and those of the face may be involved in advanced cases, but trismus, a common feature of tetanus, does not occur. We have observed brief periods of cyanosis and respiratory arrest during episodes of intense spasm, and one of our patients died during such an episode. The eye muscles are rarely affected. As the illness progresses, any noise or other sensory stimulus or attempted passive or voluntary movement may precipitate painful spasms of all the involved musculature. The tendon reflexes are normal if they can be tested. The affected muscles, particularly the lumbar paraspinals and

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glutei, are extremely taut when palpated and eventually, they become hypertrophied. It is this axial spasm that is most characteristic of the disease and gives rise to a characteristic lumbar lordosis. We have experience with one unusual instance of this disease that caused the obverse, namely, flexion spasm of the abdominal musculature with a bent-over camptocormia. A similar stiffness of one limb (stiff limb syndrome) has been differentiated from the generalized variety (Barker et al; Saiz et al; Brown et al), but most of the localized cases have antibodies to glutamic acid decarboxylase (GAD), as described below. The limited form of the condition begins in 1 leg and spreads to its opposite but remains isolated to the lower extremities, similar to localized tetanus. A central origin of the muscle spasms is indicated by their disappearance during sleep, during general anesthesia, and with a proximal nerve block. The electrophysiologic features differ from those of myokymia and continuous muscle fiber activity syndrome in that the EMG in stiff man syndrome consists entirely of activated but normally configured motor units, with no evidence of distal motor nerve disturbance. Of interest is the finding that about two-thirds of the cases of stiff man syndrome display circulating autoantibodies that are reactive with GAD, the synthesizing enzyme for gamma-aminobutyric acid (GABA; Solimena et al). On several occasions, the test for this antibody has become positive after samples taken over 2 years were negative. An antibody to the glycine receptor (GlyR) has been identified in a subset of patients with stiff man syndrome with antiGAD antibodies (McKeon and colleagues), rare cases of which have included a fatal encephalopathy and myoclonus (Turner et al) and a few patients with a special cervical pattern of stiffness have had anti-amphiphysin antibodies (Murinson and Guarnaccia). In all these rare cases, antiGAD antibody is usually also present and paraneoplastic versions of each syndrome are known, as commented below. Reduced spinal GABA presumably creates an imbalance between the spinal inhibitory (gabanergic) input and the excitatory input to alpha motor neurons. This interpretation is supported by the fact that the spasms worsen under the influence of drugs that enhance aminergic activity, thereby facilitating long-latency spinal reflexes or that inhibit catecholaminergic or gabanergic transmitters. An autoimmune mechanism is further suggested by the high incidence of insulin-dependent diabetes (present eventually in almost all the cases under our care) with detectable antibodies to islet cells; a few patients have thyroiditis, pernicious anemia, or immune-mediated vitiligo. There are rare paraneoplastic varieties of stiff man syndrome, mostly accompanying breast cancer and associated in some cases with circulating antibodies directed against amphiphysin or gephyrin, proteins associated with synaptic GABA receptors. Some of the cases related to the antiamphiphysin antibodies also display more conventional types of paraneoplastic neurologic disorder such as encephalopathy or opsoclonus (see Chap. 30). Also reported, perhaps not surprisingly, have been instances of a variable cerebellar syndrome with stiff-man and high titers of anti-GAD antibodies (Rakoevic et al).

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The stiff man syndrome must be distinguished from tetanus (see “Tetanus” in Chap. 41 and further on), Isaacs syndrome, and the rare syndrome of subacute myoclonic spinal neuronitis, described in Chaps. 32 and 42. In both the stiff man syndrome and myoclonic spinal neuronitis, the intense spasms and stiffness of muscles are a result of the disinhibition of interneurons in the gray matter of the spinal cord. The syndromes of continuous muscle activity are usually distinguishable clinically and electromyographically from extrapyramidal and corticospinal abnormalities such as dystonia, dyskinesia, and rigidity, although early phases of axial dystonic disorders and stiff man syndrome have similarities.

Treatment In the stiff man syndrome, diazepam in doses of up to 50 to 250 mg/d, increased gradually, is most effective; clonazepam, vigabatrin, or baclofen is sometimes effective as well. In keeping with the presumed autoimmune mechanism of most cases, plasma exchange, high-dose corticosteroids, or intravenous gamma globulin are helpful in some patients, albeit for only several weeks or months before another infusion is required. Several of our patients have required intravenous gamma globulin for several years at intervals of 6 to 12 weeks but nevertheless became disabled if the dose of diazepam was reduced below 100 mg/d. A small randomized trial of IVIg has demonstrated the efficacy of this treatment, with benefits varying in duration from 6 weeks to 1 year (Dalakas and colleagues, 2001). The typical dose is 0.4 mg/kg daily for 4 or 5 consecutive days. Immunosuppression with rituximab is being used increasingly on the basis of case reports and small series, but a small randomized trial has been negative (Dalakas et al, 2017). For intractable cases, particularly when one limb is involved, propofol has been anecdotally effective in doses that do not produce sedation (Hattan et al).

Congenital Neonatal Rigidity A “stiff infant” syndrome, observed by Dudley and colleagues in four families of mixed heritage, probably should be included in this general category. The condition came to medical attention because of respiratory distress as the result of a generalized muscular rigidity beginning at about 2 months of age. The rigidity spread slowly from cervical muscles to those of the trunk and limbs, and, as it persisted, slight hypertrophy developed. The use of respiratory aid and a feeding gastrostomy enabled the infants to survive. The rigidity slowly diminished in the second year of life. The clinical course was unlike that of tetanus. In fatal cases, there were zones of fiber loss, with fibrosis in skeletal and cardiac muscles and a greater than normal variation in fiber size. Altered Z lines were observed with electron microscope in some fibers.

Primary Hyperexcitability of Muscle At least three varieties of primary muscle disorders are known, not myotonic in nature, that produce continuous muscle activity. The first described below is because of a defect in the muscle membrane; the second has been found to be a disease of the extracellular matrix of muscle.

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The third disorder, Brody disease, is only mentioned here for completeness as it is quite rare, even in comparison to the other unusual disorders in this section.

Rippling Muscle Disease Ricker and Burns and their associates described a rare familial disorder (autosomal dominant) in which muscles display an unusual sensitivity to stretch, manifest by rippling waves of muscle contraction. Percussion of muscles yields a pronounced and painful local mounding. The activation is a type of myokymia. Similar familial and sporadic cases have been traced to a defect in caveolin, a protein otherwise implicated in one of the muscular dystrophies (Vorgerd). An autoimmune process was implicated in some other cases (Ashok Muley and Day). The EMG discloses neither myotonic discharges nor the action potentials of cramp, indicating that the basic abnormality is in the muscle membrane.

Schwartz-Jampel Syndrome A syndrome characterized by continuous muscle fiber activity with stiffness and blepharospasm, accompanied by obvious dysmorphic features (dwarfism, pinched face with low-set ears, blepharophimosis, high-arched palate, receding chin, diffuse metaphyseal and epiphyseal

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bone dysplasia with flattened vertebrae), was described by Schwartz and Jampel in 1962. It has been reported under other names including myotonic chondrodystrophy. There may be percussion myotonia. Intelligence is usually preserved. The stiff muscles disturb gait most obviously. The muscle stiffness is the result of frequent, almost continuous muscle activity with a combination of normal motor units and high-frequency discharges and afterdischarges similar to those seen in Isaacs syndrome. The discharges can be demonstrated to arise from muscle fibers themselves as the activity is not obliterated by curare. Agents such as procainamide, which block sodium channels in muscle, inhibit the discharges, just as they do in some other myotonic disorders (Spaans and associates). The disorder is usually inherited as an autosomal recessive trait that is caused by mutations in perlecan, a heparin-sulfate proteoglycan that is bound to the basement membranes of skeletal muscle and cartilage. Loss of function of the protein perturbs the organization of the basement membrane leading to an altered clustering of ACh esterase and abnormal expression of ion channels. Electron microscopic studies of muscle have yielded inconsistent findings: dilated T system, Z-band streaming, dilatation of mitochondria, and signs of denervation (Fariello and colleagues).

References Aitken RS, Allot EN, Casteldon LI, Walker M: Observations on a case of familial periodic paralysis. Clin Sci 3:47, 1937. Andersen ED, Krasilnikoff PA, Overvad H: Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. Acta Paediatr Scand 60:559, 1971. Argov Z, Mastaglia FL: Disorders of neuromuscular transmission caused by drugs. N Engl J Med 301:409, 1979. Ashok Muley S, Day JW: Autoimmune rippling muscle. Neurology 61:869, 2003. Atsumi T, Ishikawa S, Miyatake T, Yoshida M: Myopathy and primary aldosteronism: Electron microscopic study. Neurology 29:1348, 1979. Bain PG, Motomura M, Newsom-Davis J, et al: Effects of intravenous immunoglobulin on muscle weakness and calcium channel auto-antibodies in the Lambert-Eaton myasthenic syndrome. Neurology 47:678, 1996. Barker RA, Reeves T, Thom M, et al: Review of 23 patients affected by the stiff man syndrome: Clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 65:633, 1998. Barth D, Nabavi Nouri M, Ng E, et al: Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 76:2017, 2011. Becker PE: Genetic approaches to the nosology of muscle disease: Myotonias and similar diseases: Part 7. Muscle. In: Bergsma D (ed): The Clinical Delineation of Birth Defects. Baltimore, MD, Williams & Wilkins, 1971. Beeson D, Higuchi O, Palace J, et al: Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313:1975, 2006. Bever CT Jr, Aquino AV, Penn AS, et al: Prognosis of ocular myasthenia. Ann Neurol 14:516, 1983. Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region: Report of a case in which the tumor was removed. Ann Surg 110:544, 1939.

Ropper_Ch46_p1432-p1466.indd 1461

Blexrud MD, Windebank AJ, Daube JR: Long term follow-up of 121 patients with benign fasciculations. Neurology 34:622, 1993. Bryant SH: Myotonia in the goat. Annals of the New York Academy of Sci 317:314-325, 1979. Bril V, Kojic J, Dhanani A: The long-term clinical outcome of myasthenia gravis in patients with thymoma. Neurology 51:1198, 1998. Brody IA: Muscle contracture induced by exercise: A syndrome attributable to decreased relaxing factor. N Engl J Med 281:187, 1969. Brown P, Rothwell PJ, Marsden CD: The stiff leg syndrome. J Neurol Neurosurg Psychiatry 62:31, 1997. Buckingham JM, Howard FM Jr, Bernatz PE, et al: The value of thymectomy in myasthenia gravis: A computer-assisted matched study. Ann Surg 184:453, 1976. Burke G, Cossins J, Maxwell S, et al: Rapsyn mutation in hereditary myasthenia. Distinct early and late phenotypes. Neurology 61:826, 2003. Burns RJ, Bretag AH, Blumbergs PC, Harbord MG: Benign familial disease with muscle mounding and rippling. J Neurol Neurosurg Psychiatry 57:344, 1994. Buzzard EF: The clinical history and postmortem examination of 5 cases of myasthenia gravis. Brain 28:438, 1905. Cannon SC: An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul Disord 12:533, 2002. Cannon SC, Brown RH Jr, Corey DP: Theoretical reconstruction of myotonia and paralysis caused by incomplete inactivation of sodium channels. Biophys J 65:270, 1993. Celebisoy N, Cologlu Z, Akbaba Y, et al: Continuous muscle fibre activity: A case treated with acetazolamide. J Neurol Neurosurg Psychiatry 64:256, 1998. Cöers C, Telerman-Toppet N, Durda J: Neurogenic benign fasciculations, pseudomyotonia, and pseudotetany. Arch Neurol 38:282, 1981.

08/02/23 9:57 AM

1462

Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

Cogan DG: Myasthenia gravis: A review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol 74:217, 1965. Compston DAS, Vincent A, Newsom-Davis A, Batchelor JR: Clinical, pathological, HLA antigen, and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 103:579, 1980. Conn JW, Knopf RF, Nesbit RM: Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107:159, 1964. Conn JW, Rovner DR, Cohen EL: Licorice-induced pseudoaldosteronism: Hypertension, hypokalemia, aldosteronopenia and suppressed plasma renin activity. JAMA 205:492, 1968. Cortes-Vicente E, Gallardo E, Martinez MA, et al: Clinical characteristics of patients with double-seronegative myasthenia gravis and antibodies to cortactin. JAMA Neurol 73:1099, 2016. Croxen R, Hattan C, Shellay C, et al: Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology 59:162, 2002. Dalakas MC, Engel WK: Treatment of “permanent” muscle weakness in familial hypokalemic periodic paralysis. Muscle Nerve 6:182, 1983. Dalakas MC, Fugii M, Li M, et al: High dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 345:1870, 2001. Dalakas MC, Rakocevic G, Dambrosia JM, et al: A double-blind, placebo controlled study of rituximab in patients with stiff person syndrome. Ann Neurol 82:271, 2017. Dau PC, Denys EH: Plasmapheresis and immunosuppressive therapy in the Eaton-Lambert syndrome. Ann Neurol 11:570, 1982. De Feo LG, Schottlender J, Martelli NA, et al: Use of intravenous pulsed cyclophosphamide in severe generalized myasthenia gravis. Muscle Nerve 26:31, 2002. DeJong JGY: Myotonia levior. In: Kuhn E (ed): Progressive Muskeldystrophie-Myotonie-Myasthenie. Heidelberg, Springer, 1966, pp 255–259. Denborough MA: Malignant hyperthermia. Lancet 352:1131, 1998. Denborough MA, Forster JF, Lovell RR: Anaesthetic deaths in a family. Br J Anaesth 1962:34, 395. Denny-Brown D, Nevin S: The phenomenon of myotonia. Brain 64:1, 1941. Diaz-Manera J, Matinez-Hernandez E, Querol L, et al: Long-lasting effect of rituximab in MuSK myasthenia. Neurology 78:189, 2012. Drachman DB: How to recognize an antibody-mediated autoimmune disease: Criteria. Res Publ Assoc Res Nerv Ment Dis 68:183, 1990. Drachman DB: Myasthenia gravis. N Engl J Med 298:136, 186, 1978. Drachman DB: Myasthenia gravis. N Engl J Med 330:1797, 1994. Drachman DB, Jones RJ, Brodsky RA: Treatment of refractory myasthenia: “Rebooting” with high dose cyclophosphamide. Ann Neurol 53:29, 2003. Eaton LM, Lambert EH: Electromyography and electric stimulation of nerves and diseases of motor unit: Observations on myasthenic syndrome associated with malignant tumors. JAMA 163:1117, 1957. Elmquist D, Lambert EH: Detailed analysis of neuromuscular transmission in a patient with the myasthenic syndrome, sometimes associated with bronchial carcinoma. Mayo Clin Proc 43:689, 1968. Engel AG: Evolution and content of vacuoles in primary hypokalemic periodic paralysis. Mayo Clin Proc 45:774, 1970. Engel AG (ed): Myasthenia Gravis and Myasthenic Disorders. New York, Oxford University Press, 1999. Engel AL, Arahata K: The membrane attack complex of complement at the endplate in myasthenia gravis. Ann N Y Acad Sci 505:326, 1987.

Ropper_Ch46_p1432-p1466.indd 1462

Engel AG, Lambert EH, Howard FM: Immune complexes (IgG and C3) at motor end-plate in myasthenia gravis. Mayo Clin Proc 52:267, 1977. Engel AG, Lambert EH, Santa T: Study of long-term anticholinesterase therapy. Neurology 23:1273, 1973. Engel AG, Ohno K, Sine SM: Congenital myasthenic syndromes: Progress over the past decade. Muscle Nerve 27:4, 2003. Engel AG, Tsujihata M, Lambert EH, et al: Experimental autoimmune myasthenia gravis: A sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations. J Neuropathol Exp Neurol 35:569, 1976a. Engel AG, Tsujihata M, Lindstrom JM, Lennon VA: The motor end plate in myasthenia gravis and in experimental autoimmune myasthenia gravis. Ann N Y Acad Sci 274:60, 1976b. Evoli A, Tonali P, Padua L, et al: Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 126:2304, 2003. Fambrough DM, Drachman DB, Satyamurti S: Neuromuscular junction in myasthenia gravis: Decreased acetylcholine receptors. Science 182:293, 1973. Fariello R, Meloff K, Murphy EG, et al: A case of Schwartz-Jampel syndrome with unusual muscle biopsy findings. Ann Neurol 3:93, 1978. Fontaine B, Khurana TS, Hoffman EP, et al: Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 250:1000, 1990. Fontaine B, Vale Santos JM, Jurkat-Rott JK, et al: Mapping of hypokalemic periodic paralysis (hypo PP) to chromosome 1q31-q32 by a genome-wide search in three European families. Nat Genet 6:267, 1994. Fukunaga H, Engel AG, Osane M, et al: Paucity and disorganization of presynaptic membrane active zones in the LambertEaton myasthenic syndrome. Muscle Nerve 5:686, 1982. Gajdos P, Chevret S, Clair B, et al: Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol 41:789, 1997. Gajdos P, Tranchant C, Clair B, et al: Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: A randomized double-blind clinical trial. Arch Neurol 62:1689, 2005. Gamstorp I: Adynamia episodica hereditaria. Acta Paediatr Scand 45(Suppl 108):1, 1956. Greer M, Schotland M: Myasthenia gravis in the newborn. Pediatrics 26:101, 1960. Grob D, Brunner NG, Namba T: The natural course of myasthenia gravis and effect of therapeutic measures. Ann N Y Acad Sci 377:652, 1981. Gutmann L, Gutmann L: Axonal channelopathies: An evolving concept in the pathogenesis of peripheral nerve disorders. Neurology 47:18, 1996. Haass A, Ricker K, Rüdel R, et al: Clinical study of paramyotonia congenita with and without myotonia in a warm environment. Muscle Nerve 4:388, 1981. Hanna MG, Wood NW, Kullmann DM: Ion channels and neurological disease: DNA based diagnosis is now possible, and ion channels may be important in common paroxysmal disorders. J Neurol Neurosurg Psychiatry 65:427, 1998. Harriman DGF, Summer DW, Ellis FR: Malignant hyperthermia myopathy. Q J Med 42:639, 1973. Hattan E, Angle MR, Chalk C: Unexpected benefit of propofol in stiff-person syndrome. Neurology 70:1641, 2008. Heatwole CR, Statland JM, Logigian EL: The diagnosis and treatment of myotonic disorders. Muscle Nerve 47:632, 2013. Hoffmann K, Muller JS, Stricker S, et al: Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am J Hum Genet 79:303, 2006.

08/02/23 9:57 AM

Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity Howard JF, Bril V, Vu T, et al: Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled trial. Lancet Neurol 20:526, 2021. Hudson AJ, Brown WF, Gilbert JJ: The muscular pain-fasciculation syndrome. Neurology 28:1105, 1978. Irani SR, Pettingill P, Kleopa KA, et al: Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 72:241, 2012. Isaacs H: Continuous muscle fibre activity in an Indian male with additional evidence of terminal motor fibre abnormality. J Neurol Neurosurg Psychiatry 30:126, 1967. Isaacs H, Barlow MB: Malignant hyperpyrexia. J Neurol Neurosurg Psychiatry 36:228, 1973. Janssen JC, Larner AJ, Harris J, et al: Myasthenic hand. Neurology 51:913, 1998. Jaretzki A 3rd, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000;55(1):16–23. Kelly JJ, Daube JR, Lennon VA: The laboratory diagnosis of mild myasthenia gravis. Ann Neurol 12:238, 1982. Kerzin-Storrar L, Metcalfe RA, Dyer PA: Genetic factors in myasthenia gravis: A family study. Neurology 38:38, 1988. Koch MC, Steinmeyer K, Lorenz C, et al: The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257:797, 1992. Lambert EH, Eaton LM, Rooke ED: Defect of neuromuscular transmission associated with malignant neoplasm. Am J Physiol 187:612, 1956. Lambert EH, Goldstein NP: An unusual form of “myotonia.” Physiologist 1:51, 1957. Lambert EH, Lindstrom JM, Lennon VA: End-plate potentials in experimental autoimmune myasthenia gravis in rats. Ann N Y Acad Sci 274:300, 1976. Layzer RB: Neuromuscular Manifestations of Systemic Disease. Philadelphia, Davis, 1985. Lehmann-Horn F, Mailänder V, Heine R, George AL: Myotonia levior is a chloride channel disorder. Hum Mol Genet 4:1397, 1995. Lehmann-Horn F, Rüdel R, Jurkat-Rott K: Nondystrophic myotonias and periodic paralyses. In: Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York, McGraw-Hill, 2004, pp 1257–1300. Lehmann-Horn F, Rüdel R, Ricker K: Membrane defects in paramyotonia congenita (Eulenburg). Muscle Nerve 10:633, 1987. Lennon VA: Immunologic mechanisms in myasthenia gravis— a model of a receptor disease. In: Franklin E (ed): Clinical Immunology Update—Reviews for Physicians. New York, Elsevier/North-Holland, 1979, pp 259–289. Lennon VA, Lindstrom JM, Seybold ME: Experimental autoimmune myasthenia gravis in rats and guinea pigs. J Exp Med 141:1365, 1975. Lewi Z, Bar-Khayim Y: Food poisoning from barium carbonate. Lancet 2:342, 1964. Ligouri R, Vincent A, Clover L, et al: Morvan’s syndrome: Peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124:2417, 2001. Lipicky RJ, Bryant SH: Ion content, potassium flux, and cable properties of myotonic, human, external intercostal muscle. Trans Am Neurol Assoc 96:34, 1971. Lundh H, Nilsson O, Rosen I: Treatment of Lambert-Eaton syndrome: 3,4-Diaminopyridine and pyridostigmine. Neurology 34:1324, 1984. Lütschg J, Jerusalem F, Ludin HP, et al: The syndrome of “continuous muscle fiber activity.” Arch Neurol 35:198, 1978.

Ropper_Ch46_p1432-p1466.indd 1463

1463

Mason WP, Graus F, Land B, et al: Small-cell lung cancer, paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome. Brain 120:1279, 1997. Matthews E, Labrum R, Sweeney MG, et al: Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72:1544, 2009. McFadzean AJS, Yeung R: Periodic paralysis complicating thyrotoxicosis in Chinese. Br Med J 1:451, 1967. McKeon B, Martinez-Hernandez E, Lancaster E, et al: Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 70:44, 2013. McQuillen MP, Cantor HE, O’Rourke JR: Myasthenic syndrome associated with antibiotics. Arch Neurol 18:402, 1968. Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al: Mycophenolate mofetil for myasthenia gravis. Neurology 61:1438, 2003. Meyers KR, Gilden DH, Rinaldi CF, Hansen JL: Periodic muscle weakness, normokalemia, and tubular aggregates. Neurology 22:269, 1972. Mills KR, Edwards RHT: Investigative strategies for muscle pain. J Neurol Sci 58:73, 1983. Milone M, Fukada T, Shen XM, et al: Novel congenital myasthenic syndromes associated with defect in quantal release. Neurology 66:1223, 2006. Moersch FP, Woltman HW: Progressive fluctuating muscular rigidity (“stiff-man syndrome”): Report of a case and some observations in 13 other cases. Mayo Clin Proc 31:421, 1956. Murinson BB, Guarnaccia JB: Stiff-person syndrome with antiamphiphysin antibodies. Neurology 71:1955, 2008. Myasthenia Gravis Clinical Study Group: A randomized clinical trial comparing prednisone and azathioprine in myasthenia gravis: Results of the second interim analysis. J Neurol Neurosurg Psychiatry 56:1157, 1993. Newsom-Davis J: Diseases of the neuromuscular junction. In: Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System, 2nd ed. Philadelphia, Saunders, 1992, pp 197–212. Newsom-Davis J: Neuromyotonia. Rev Neurol 160:85, 2004. Newsom-Davis J, Mills KR: Immunological associations of acquired neuromyotonia (Isaacs’ syndrome). Brain 116:453, 1993. Nissen K: Beiträge zur Kenntnis der Thomsen’schen Krankheit (Myotonia congenita), mit besonderer Berücksichtigung des hereditären Momentes und seinen Beziehungen zu den Mendelschen Vererbungsregeln. Z Klin Med 97:58, 1923. Oh SJ, Schcherbakova N, Kostera-Pruszczyk A, et al: Amifampridine phosphate is effective and safe in a phase 3 clinical trial in LEMS. Muscle Nerve 53:717, 2016. Okinaka S, Shizume K, Iinos S, et al: The association of periodic paralysis and hyperthyroidism in Japan. J Clin Endocrinol Metab 17:1454, 1957. Olanow CW, Lane RJM, Roses AD: Thymectomy in late-onset myasthenia gravis. Arch Neurol 39:82, 1982. O’Neill JH, Murray NM, Newsom-Davis J: The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 14:577, 1988. Osserman KE: Myasthenia Gravis. New York, Grune & Stratton, 1958. Palace J, Lashley D, Newsom-Davis J, et al: Clinical features of the DOK-7 neuromuscular junction synaptopathy. Brain 130:1507, 2007. Palace J, Newsom-Davis J, Lecky B: A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 50:1778, 1998. Panegyres PM, Squier M, Mills KR, Newsom-Davis J: Acute myopathy associated with large parenteral dose of corticosteroid in myasthenia gravis. J Neurol Neurosurg Psychiatry 56:702, 1993. Park HS, Shin DM, Lee JS, et al: Thymoma. A retrospective study of 87 cases. Cancer 73:2491, 1994.

08/02/23 9:57 AM

1464

Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE

Pascuzzi RM, Coslett HB, Johns TR: Long-term corticosteroid treatment of myasthenia gravis: Report of 116 cases. Ann Neurol 15:291, 1984. Patrick J, Lindstrom JP: Autoimmune response to acetylcholine receptor. Science 180:871, 1973. Patrick J, Lindstrom JP, Culp B, McMillan J: Studies on purified eel acetylcholine receptor and antiacetylcholine receptor antibody. Proc Natl Acad Sci U S A 70:3334, 1973. Pittinger CB, Eryase Y, Adamson R: Antibiotic-induced paralysis. Anesth Analg 49:487, 1970. Plaster NM, Tawil R, Tristani-Firouzi M, et al: Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511, 2001. Ponseti JM, Azem J, Fort JM, et al: Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis. Neurology 64:1641, 2005. Poskanzer DC, Kerr DNS: A third type of periodic paralysis with normokalemia and favorable response to NaCl. Am J Med 31:328, 1961. Price DL, Griffin JW, Peck K: Tetanus toxin: Evidence for binding at presynaptic nerve endings. Brain Res 121:379, 1977. Ptácek LJ, Tawil R, Griggs RC, et al: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863, 1994a. Ptácek LJ, Tawil R, Griggs RC, et al: Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 44:1500, 1994b. Quane KA, Healy JMS, Keating KE, et al: Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 5:51, 1993. Rabinstein A, Wijdicks EFM: BiPAP in acute respiratory failure due to myasthenic crisis may prevent intubation. Neurology 59:1647, 2002. Rakoevic G, Raju R, Semino-Mora C, et al: Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 67:1068, 2006. Reman L: Zur pathogenese und therapie der myasthenia gravis pseudoparalytica. Dtsch Z Nervenheilkd 128:66, 1932. Ricker K, Moxley RT, Heine R, Lehmann-Horn F: Myotonia fluctuans: A third type of muscle sodium channel disease. Arch Neurol 51:1095, 1994. Ricker K, Moxley RT, Rohkamm R: Rippling muscle disease. Arch Neurol 46:405, 1989. Robertson WC, Chun RWM, Kornguta SE: Familial infantile myasthenia. Arch Neurol 37:117, 1980. Rodriguez M, Gomez MR, Howard FM: Myasthenia gravis in children: Long-term followup. Ann Neurol 13:504, 1983. Ropper AH, Gress DR, Diringer MN, et al (eds): Neurological and Neurosurgical Intensive Care, 4th ed. Baltimore, Lippincott Williams Wilkins, 2004, pp 299–311. Rosenfeld J, Sloan-Brown K, George AL: A novel muscle sodium channel mutation causes painful congenital myotonia. Ann Neurol 42:811, 1997. Rüdel R, Lehmann-Horn F, Ricker K, et al: Hypokalemic periodic paralysis: In vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7:110, 1984. Russell DS: Histological changes in myasthenia gravis. J Pathol Bacteriol 65:279, 1953. Ryan DP, Ptácek LJ: Episodic neurological channelopathies. Neuron 68:282, 2010. Saiz A, Graus F, Valldeoriola F, et al: Stiff-leg syndrome: A form of stiff-man syndrome. Ann Neurol 43:400, 1998. Sanders DB, Wolfe GI, Benetar M, et al: International consensus guidelines for management of myasthenia gravis. Neurology 87:419, 2016.

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Sansone VA, Burge J, McDermott MP, et al: Randomized placebocontrolled trial of dichlorphenamide in periodic paralysis. Neurology 86:1408, 2016. Sansone V, Griggs RC, Meola G, et al: Andersen’s syndrome: A distinct periodic paralysis. Ann Neurol 42:305, 1997. Santa T, Engel AG, Lambert EH: Histometric study of neuromuscular junction ultrastructure: I. Myasthenia gravis. Neurology 22:71, 1972. Satoyoshi E: A syndrome of progressive muscle spasm, alopecia and diarrhea. Neurology 28:458, 1978. Scadding GK, Vincent A, Newsom-Davis J, Henry K: Acetylcholine receptor antibody synthesis by thymic lymphocytes: Correlation with thymic histology. Neurology 31:935, 1981. Schluep M, Willcox N, Vincent A, et al: Acetylcholine receptors in human thymic cells in situ: An immunohistological study. Ann Neurol 22:212, 1987. Schröder JM, Adams RD: The ultrastructural morphology of the muscle fiber in myotonic dystrophy. Acta Neuropathol 10:218, 1968. Schwartz O, Jampel R: Congenital blepharophimosis associated with a unique generalized myopathy. Arch Ophthalmol 68:52, 1962. Scuderi F, Marino M, Colonna L, et al: Anti-p110 autoantibodies identify a subtype of “seronegative” myasthenia gravis with prominent oculobulbar involvement. Lab Invest 82:1139, 2002. Senanayake N, Roman GC: Disorders of neuromuscular transmission due to natural environmental toxins. J Neurol Sci 107:1, 1992. Serratrice G, Azulay JP: Que reste-t-il de la chorée fibrillaire de Morvan? Rev Neurol (Paris) 150:257, 1994. Sethi KD, Rivner MH, Swift TR: Ice pack test for myasthenia gravis. Neurology 37:1383, 1987. Simpson JA: Myasthenia gravis: A new hypothesis. Scott Med J 5:419, 1960. Solimena M, Folli F, Aparisi R, et al: Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322:1555, 1990. Spaans F, Theunissen P, Reekers AD, et al: Schwartz-Jampel syndrome: 1. Clinical, electromyographic, and histologic studies. Muscle Nerve 13:516, 1990. Statland JM, Bundy BM, Wang Y, et al: Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia. JAMA 308:1357, 2012. Streib EW: Paramyotonia congenita: Successful treatment with tocainide: Clinical and electrophysiologic findings in seven patients. Muscle Nerve 10:155, 1987. Streib EW, Rothner D: Eaton-Lambert myasthenic syndrome: Long-term treatment of 3 patients with prednisone. Ann Neurol 10:448, 1981. Subramony SH, Wee AS, Mishra SK: Lack of cold sensitivity in hyperkalemic periodic paralysis. Muscle Nerve 9:700, 1986. Sun SF, Streib EW: Autosomal recessive generalized myotonia. Muscle Nerve 6:143, 1983. Swift TR: Disorders of neuromuscular transmission other than myasthenia gravis. Muscle Nerve 4:334, 1981. Tahmoush AJ, Alonso RJ, Tahmoush GP, et al: Cramp-fasciculation syndrome: A treatable hyperexcitable peripheral nerve disorder. Neurology 41:1021, 1991. Talbott JH: Periodic paralysis: A clinical syndrome. Medicine (Baltimore) 20:85, 1941. Tawil R, McDermott MP, Brown RH Jr, et al: Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol 47:46, 2000. Thieben MJ, Lennon VA, Askanit AJ, et al: Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 62:1177, 2004.

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Chapter 46 Disorders of the Neuromuscular Junction, Myotonias, and Disorders of Persistent Muscle Fiber Activity Thomas CE, Mayer SA, Gungor Y, et al: Myasthenic crisis: Clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 48:1253, 1997. Thomasen E: Myotonia, Thomsen’s Disease, Paramyotonia, Dystrophia Myotonica. Aarhus, Denmark, Universitetsforlaget i Aarhus, 1948. Thomsen J: Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer disposition (Ataxia muscularis?). Arch Psychiatr Nervenkr 6:706, 1876. Tindall RSA, Phillips JT, Rollins JA, et al: A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci 681:539, 1993. Turner MR, Irani SR, Leite MI, et al: Progressive encephalomyelitis with rigidity and Myoclonus. Neurology 77:439, 20011. Trudell RG, Kaiser KK, Griggs RC: Acetazolamide-responsive myotonia congenita. Neurology 37:488, 1987. Tyler FH, Stephens FE, Gunn FD, Perkoff GT: Studies on disorders of muscle: VII. Clinical manifestations and inheritance of a type of periodic paralysis without hypopotassemia. J Clin Invest 30:492, 1951. Valli G, Barbieri S, Stefano C, et al: Syndromes of abnormal muscular activity: Overlap between continuous muscle fiber activity and the stiff-man syndrome. J Neurol Neurosurg Psychiatry 46:241, 1983. Vernino S, Lennon VA: Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle Nerve 26:702, 2002.

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Vincent A, Newsom-Davis J: Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: Results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 48:1246, 1985. Vincent A, Newsom-Davis J, Martin V: Antiacetylcholine receptor antibodies in d-penicillamine associated myasthenia gravis. Lancet 1:1254, 1978. Vincent A, Wray D (eds): Neuromuscular Transmission. Basic and Applied Aspects. New York, Manchester Press, 1990. Vorgerd M, Ricker K, Ziemssen W, et al: A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. Neurology 57:2273, 2001. Walker MB: Treatment of myasthenia gravis with physostigmine. Lancet 1:1200, 1934. Weinberg DH, Rizzo JF, Hayes MT, et al: Ocular myasthenia gravis: Predictive value of single-fiber electromyography. Muscle Nerve 22:1222, 1999. Witte AS, Cornblath DR, Parry GJ, et al: Azathioprine in the treatment of myasthenia gravis. Ann Neurol 15:602, 1984. Wolfe GI, Kaminski HJ, Aban IB, et al: Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 375:511, 2016. Yazaki K, Kuribayashi T, Yamamura Y, et al: Hypokalemic myopathy associated with a 17α-hydroxylase deficiency: A case report. Neurology 32:94, 1982.

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PA R T

6

PSYCHIATRIC DISORDERS

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47 Anxiety, “Functional” and Personality Disorders

The relationship between psychiatry and neurology, at one time unified specialties, has been problematic for well over a century. With the emergence of numerous theories of the nature of mental life and of the mind, came corresponding systems for the treatment of psychiatric disease. Most of these systems, typified in the past by psychoanalysis, seemed to have little in common with neurologic ideas about the structure and function of the brain. Freed from the model of the main mental disease that was the result of structural damage to the brain, syphilitic general paresis, psychiatry was able to turn to matters that were less anchored in medicine. With the emergence of a biologic psychiatry based on neurochemistry, genetics, and functional imaging of the brain, it would seem that the gap between diseases of the mind and of the brain is closing. However, neurologists should view some of these modern ideas with at least some skepticism. For example, the observation of brain function by the use of imaging methods, and disruption of that function in disease, is not the equivalent of the disease itself and certainly cannot capture the experience through which mental disease is manifest. To dissociate an individual’s personal history and experiences, aspects of life that probably cannot be quantified or visualized, from diseases of the mind remains an artifice now, as it was in the time of the classic philosophers. This potential division between mind and brain, or “dualism,” is particularly apparent when one begins to analyze the normal internal stream of thought that dominates daily life rather than the disordered thoughts of mental disease states. Hughlings Jackson was of the opinion that the brain provides a platform for thinking but is not explanatory of it, a property of mind he termed “emergent.” This leaves open the possibility of a science of the mind that is separate from the science of the brain. Moreover, the separation of quirks of personality and character traits, probably reflecting the biologic diversity of the development of the brain, from genuine disease will remain eternally problematic. Even the margins between disease and mental dysfunction in everyday life have been disputed and have given rise to numerous “shadow syndromes” of psychologic origin that are subject to change with popular culture and fashion. This serves as an appropriate introduction to a chapter that formerly used the term “Neuroses” and has been mostly renamed “Anxiety Disorders” in acquiescence to

modern terminology. Likewise, what had been called “hysteria” for over a century, has pejorative connotations and is biologically incorrect (in so far as symptoms were attributed to a wandering uterus), and has been ambiguously renamed “functional disorder” or “psychogenic disorder,” both meant to strongly imply to the absence of an anatomical explanation but this is no to say the patient has volitional control over the symptoms. In every society, there are many troubled individuals who are neither mentally ill nor developmentally impaired. They differ from other people in being plagued by feelings of inferiority or self-doubt, suspicion about the motives of others, low energy, inexplicable fatigue, shyness, irritability, moodiness, sense of guilt, or unreasonable worries and fears. They suffer as a result of these feelings or they behave in ways that are upsetting to those around them and to society at large. Yet none of these conditions precludes partaking in the everyday life, such as attending school, working, marrying, and raising a family. As these conditions were more carefully documented in the early part of the last century, they came to be called neuroses, and those that created societal difficulties were called psychopathies, and more recently, personality disorders and sociopathies. The question of the purity and homogeneity of these mental states creates an ongoing polemic in psychiatry, medicine and society. The neuroses as a group appeared to be so diverse as to require subdivision in former editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) into no less than seven different types before the term was expunged in 1980. We take a neutral position on the value of DSM not out of iconoclasm but because the definitions in that system are changed frequently, are subject to considerable controversy, and often do not accord with neurobiologic ideas of brain function. In any case, readers may wish to consult the most current DSM where appropriate, to gain insight into the evolving thinking of the psychiatric community. Even in the modern era, a discussion of non-psychotic mental disorders is not complete without including the ideas of Sigmund Freud and his psychoanalytically minded colleagues. Freud separated neuroses and psychoneuroses and both subjects became enmeshed in psychoanalytic theory. The assumption about neurosis was that an undercurrent of anxiety arising from unconscious conflict explained the neuroses as well as the psychopathies.

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The term psychoneurosis was reserved for neurosis that had an additional aspect based in a brain (physical) trait—but the two differed very little. Later, psychiatrists uncommitted to psychoanalytic theory attributed these states to social forces leading to maladaptive behavior from childhood. Many of these notions were not acceptable to biologically oriented physicians, with the result that the term psychoneurosis was expunged from later editions of the DSM, and neurosis was replaced by anxiety disorders, phobic states, and obsessivecompulsive disorder as alluded to above. These terms are at present applied to mental disorders with the following characteristics: (1) symptoms that are distressing to the affected individual and regarded by the person as unacceptable or alien; (2) intactness of reality testing (the patient’s evaluation of the relationship between himself and the outside world); (3) symptomatic behavior that does not seriously violate social norms, although personal functioning may be moderately impaired; (4) a disturbance that has its onset early in life and is enduring—not a transitory reaction to stress; and (5) the absence of a discernible medical cause or structural disease of the brain. The foregoing definition of anxiety and its allied disorders has the virtue of being descriptive without committing one to any theory of causation. The genesis of the anxiety, phobic, and obsessive states remains elusive. It is generally conceded that they do not arise de novo. The antecedents are thought in some quarters to be abnormalities in personality development, strongly influenced by genetic factors and molded by stressful events in the life of the individual (Noyes et al), introduced by Engel in 1977 as the biopsychosocial theory of mental health and mental illness. Traits of this nature undoubtedly arise in several individuals from the same family. Thus, any discussion requires a brief digression into the origins of normal personality development and departures from it. It is clear from the interactions of daily life that minor forms of anxiety contribute to the makeup of the normal personality.

PERSONALITY DISORDERS Chapter 27 introduced the concept of personality and its development. There it was pointed out that the term embraces the totality of a person’s mental attributes, observable behavior, and reportable subjective experience—the sum of which distinguishes one individual from all others. It includes elements of what might be called the individual’s character that is defined by intelligence, drives, temperament, and sentiments—in short, all forces from within the organism that determine a person’s reactions to the prevailing environment. The term character is almost synonymous with personality but is less useful in medicine because of its emphasis on interpersonal and ethical aspects and its moralistic connotation. Pertinent to this subject matter is the assumption that in approximately 15 percent of the general population, certain personality traits are so pronounced as to be distressing to the individual and disturbing to others, even though the patient is not manifestly sociopathic or psychotic. The roots of personality features such as boldness and timidity, novelty seeking and excitability, level of energy and motor activity, fearfulness and fearlessness, social

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adaptability and rigidity or stubbornness are already evident in the first months of life. Monozygotic twins are alike (but not absolutely identical) in these respects, even when reared apart. Gesell and his colleagues, in their studies of infants in the middle of the last century (see Chap. 27), observed individual differences that are apparently innate; each of these characteristics is likely to be at least partly genetically determined. The personalities that result are as individual as fingerprints. One example of a biologic and genetic basis of a human personality trait, albeit to a limited degree, has been found in the expression of thrill seeking, exploration, and excitability. For example, early work in the field pointed to polymorphisms of a dopamine receptor gene accounts in small measure for the genetic variability of this personality type (Cloninger and colleagues, 1996). Findings such as these have been reproduced for similar polymorphisms that contribute to the traits of timidity, anxiety, and obsessiveness. The notion, expressed by authors such as Kandel, that genetics will explain a large part of mental function and mental illness sounds reasonable enough, but the data to establish this are far from complete. The interesting and somewhat related construct of a “national character” is embedded in social discourse but has not been extensively studied. It is mentioned here to allow for a more complete picture of the concept of character. A survey has indicated that mean personality traits in 49 cultures do not correspond to general stereotypes and are therefore probably simply contrivances for maintaining national identity (Terracciano and colleagues). Similar comments can be proffered regarding sex differences in personality that are embedded in cultural stereotypes but these sex personality profiles have more data to suggest a degree of uniformity and validity in differences between men and women in all cultures. An unsolved problem is whether each of the personality types accepted by the American Psychiatric Association is predictive or determinative of a later mental disorder. (DSM-5 lists 10 types of personality disorder; Table 47-1 lists 12 that are more granular). In this regard, two broad groups of personality disorders can be recognized. In one group— comprising the paranoid, schizoid, cyclothymic, and obsessive-compulsive personality types—there are similarities to major types of psychiatric illness. Thus, among patients who develop paranoid schizophrenia, a considerable number will have had attributes described under “paranoid” or “schizoid” personality type.” In fact, it may be difficult to judge where the personality disorder leaves off and the schizophrenic illness began. Similarly, it may be that from several family studies that the cyclothymic personality is related to bipolar disease. Obsessive-compulsive personality is related not only to obsessive-compulsive disorder, as one might expect, but also to depressive disease. The notion of clusters of personality traits has been introduced and may be more useful in clinical work than are the discrete personality types (Tyrer). The co-occurrence of types of personality disorders is common has led to an new classification system using a “dimensional” approach that gauges the maladaptive aspects of behavior that are shared across types (Sharp). Borderline personality (see below) anchors many of the other types. Perhaps most problematic in classification, but seen regularly in medical practice, is the “borderline personality

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Table 47-1 PERSONALITY DISORDERS TYPE

Paranoid Cyclothymic Schizoid Explosive Obsessive-compulsive (anankastic) Hysterical Asthenic Passive-aggressive Inadequate Antisocial Passive-dependent Immature Borderline Narcissistic

CHARACTERISTICS

Chronic wariness, suspiciousness, litigiousness, hypersensitivity, jealousy, envy; lack of insight or humor, tendency to blame others; sense of self-importance and entitlement Recurring periods of depression (low energy, pessimism, hopelessness, despair) and elation (high energy, ambition, enthusiasm, optimism) not readily explained by circumstances Isolation, seclusiveness, secretiveness, discomfort in relationships; often eccentric and lacking in energy; few friends; detachment; inability to express ideas and feelings, especially anger Outbursts of rage and aggression not in keeping with usual personality, often in response to minor provocation; sense of loss of control followed by regret Chronic worries about standards; excessive concern about self-image; tension in relationships, leading to isolation; inability to relax and excessive inhibitions; overly meticulous, conscientious, and perfectionist; predisposition to depression and obsessive-compulsive neurosis Immaturity, histrionic behavior, excitability, emotional instability, sexualization of relationships, low frustration tolerance, and shallow interpersonal ties; dependency Chronic weakness, easy fatigability, sense of vulnerability, oversensitive to physically and emotionally taxing situations, little ambition or aggression; low energy level; anhedonia Obstructive behavior, stubbornness, intentional errors or omissions; intolerance of authority with struggles over control, often creating difficulties in medical settings; externalization of conflicts and blaming others for untoward events Chronic inability to meet ordinary life demands in the absence of mental retardation; severe dependency on others; tendency to become institutionalized or to become dependent on institutions Unsocialized or antisocial behavior in conflict with society; selfishness, callousness, impulsiveness, lack of loyalty, and little guilt; low frustration tolerance; tendency to blame others, long history of interpersonal and social difficulties and arrests Lack of self-confidence, indecisiveness, tendency to cling to and seek support from others Ineffectual responses to social, psychologic, and physical demands; lack of stamina; poor adaptation to ordinary situations; a “loser” Poorly regulated emotions, self-injury, dysphoria, unstable interpersonal relationships Grandiosity, fantasies of power, success, idealized love, and belief that he or she is special or unique and can only be understood by or associate with others of high status

disorder.” As with other personality types, the pattern of behaviors is pervasive and lifelong in the affected individual. An ensemble of poorly regulated emotions, impulsive and aggressive actions, and repeated self-injury form the core aspects of the disorder. These patients typically express a range of emotional “pains” and a sense of dysphoria, often rapidly changing from one mood to another without provocation. Interpersonal relationships are unstable as a result of fear of being left alone combined with argumentativeness. These are among the most distressing individuals for families and physicians to deal with and little success has been achieved in treatment. The potential biologic roots of the borderline personality disorder are difficult to determine (Lieb and colleagues) and difficulties in treating these people are well known (Gunderson), currently limited mainly to various types of insight-oriented psychotherapies. As all personality disorders involve problems in selfregulation and maintenance of stable relationships an approach to understanding and classification, as alluded to above, has been to assess the severity of maladaptive traits such as disordered self-identity and interpersonal functioning across domains of functioning such as detachment, antagonism and psychoticism (Sharp). The defining features of the personality disorders therefore fall short of meeting the criteria for serious mental illness. Yet, an understanding of these personal peculiarities may be of great help to the physician. This knowledge makes it possible to appreciate their role as sources of perennial complaint, self-concern, and family discord, and to explain a patient’s reactions that have interfered with diagnostic and therapeutic procedures during a medical illness. It is, however, quite common for

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extremes of personality to create depression and anxiety, either of which is amenable to medical and psychotherapeutic treatment. As a final comment, one should never underestimate the power of maturation to ameliorate the turmoil of adolescence and to settle the young mind.

ANXIETY DISORDERS (SEE ALSO CHAP. 23) Although considered to be the most frequent of mental disturbances, the anxiety disorders are among the least understood. They were established as clinical entities in the late 19th century, but there are still major unresolved issues with respect to their nature, classification, and etiology. Descriptively, they are meant to include (1) anxiety disorder; (2) phobic disorder, which includes phobia of illness, social phobia, and agoraphobia; (3) obsessive-compulsive states; (4) functional disorder (formerly hysteria); and (5) hypochondriasis. Older classifications included additional types called neurasthenia (dysthymia or depressive neurosis), which is now considered with the depressive illnesses, and “depersonalization neurosis” (dissociative disorders), which is a form of functional illness. Although each of these syndromes is clinically separable when occurring in pure form, experience shows that many patients suffer from symptoms of more than one type. In recent classifications, all the neuroses have been again subsumed in three broad categories: (1) anxiety disorders (which include panic states, with and without agoraphobia, and the phobic and obsessive-compulsive neuroses); (2) somatoform disorders

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(comprising hysterical neurosis, or conversion disorder, and hypochondriasis); and (3) dissociative disorders. An interesting view of the relative frequency and expression of mental disorders of the day (but still pertinent) was provided by an analysis of 1,045 consecutive psychiatric consultations at the New England Center Hospital during the years 1955 and 1956 in which the dominant psychiatric syndrome in approximately 20 percent of patients was an anxiety state. Other epidemiologic studies continued to disclose a strikingly high incidence of anxiety disorders in the general population (Winokur and Coryell). Lifetime prevalence figures indicate that at least 11 percent of the population is so affected—that is, an estimate of 25 million persons in the United States. Such information as is available suggests that the incidence of the anxiety disorders is much the same in an urban population (midtown New York) as it is in a rural one (Stirling County, Nova Scotia), indicating that socioeconomic, racial, and cultural factors may be of limited importance. Furthermore, in times of calamity or societal stress, such as the bombing of London, or the (of course, not comparable) COVID epidemic the incidence of neurotic symptoms was said not to have increased. Thus, it is probably an oversimplification to view neuroses as merely by-products of life in civilized society or reactions to environmental stress (see also Chap. 23). This raises the issue alluded to earlier and discussed more extensively further on;, the role of background personality traits in promoting extreme and persistent anxiety after a traumatizing event (posttraumatic stress disorder, PTSD; see Chap. 23). The symptoms of the anxiety disorders typically arise in late childhood, adolescence, or early adult life. Admittedly, symptoms may be recognized for the first time after this age, but a good clinical rule is to suspect any mental illness that appears for the first time after the age of about 40 years to be either a depression or a dementia rather than a personality trait or disorder.

ANXIETY AND PANIC ATTACKS As mentioned, the term anxiety neurosis was introduced by Freud to describe a syndrome of general irritability, anxious expectation, anxiety attacks, and somatic accompaniments or equivalents of anxiety (breathlessness, chest pain, asthenia). In anxiety disorders, this symptom complex constitutes the entire illness. However, parts or all of this constellation also appear with many psychiatric diseases—bipolar disease, schizophrenia, hysteria, and phobic neurosis. Its closest link is with depression, which it resembles in another respect, namely, a strong hereditary factor, as pointed out by Cohen and White in 1949.

Clinical Presentation Anxiety disorder in its fullest form is a chronic state, punctuated by recurrent attacks of acute anxiety or panic. The acute attacks are the hallmark of the disorder, and some psychiatrists were in the past reluctant to make a diagnosis of anxiety (neurosis) in their absence. Because of the clinical features of panic attacks and particularly their

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episodic nature, which can simulate an acute medical condition, they are of special interest to neurologists and general physicians. At times, anxiety may be inferred from observing the activities of young children and is reported as a form of nervousness by older children and adolescents, but more often in this age group there are physical complaints at times of transition or stress. The most extreme form of anxiety is the panic attack. In their full form they are prone to begin after adolescence. They generally begin with ill-defined distressing feelings that may include dread and foreboding. The patient is assailed by a sense of strangeness, becomes frightened, in extreme cases by the prospect of imminent death (angor animi) or of losing his mind or losing self-control. There may be a feeling of smothering. “I am dying” or “I can’t breathe” are characteristic expressions of alarm and panic. The heart races, breathing comes in rapid gasps, the pupils may be dilated, and the patient may sweat or tremble. The palpitation and breathing difficulties are so prominent that a cardiologist is often consulted. Some of our psychiatric colleagues have identified breathlessness or a suffocating feeling as central to the diagnosis of panic (and attribute psychologic meaning to the symptom), but this is not sustained by our observations of affected patients. The symptoms abate spontaneously after 15 to 30 min, leaving the patient shaken, tense, perplexed, and often embarrassed. There is no confusion, and after the episode there is full memory of the event. Most anxiety attacks are of lesser severity with complaints of apprehension, slight faintness, palpitations, or a feeling of postural instability referred to by the patient as dizziness. Breathlessness, vague chest or upper abdominal discomfort, a palpitating sensation as if the heart were beating too hard, and a generalized “washed out” feeling (asthenia) are other common symptoms. More than 50 years ago Cohen and White listed the following symptoms in order of frequency in the patients they observed with anxiety attacks: palpitation, 97 percent; easy fatigue, 93 percent; breathlessness, 90 percent; nervousness, 88 percent; chest pain, 85 percent; sighing, 79 percent; dizziness, 78 percent; apprehensiveness, 61 percent; headache, 58 percent; paresthesias, 58 percent; weakness, 56 percent; insomnia, 53 percent; unhappiness, 50 percent. What is evident from this listing is that the experience of anxiety is a polysymptomatic physical syndrome. This was the basis of the James-Lang theory of emotion—that the physical-sensory experience was the central one and the emotional experience followed. It is not surprising, therefore, that many patients with chronic or recurrent symptoms first consult a physician not with a complaint of “anxiety” but with symptoms referable to the cardiorespiratory system or gastrointestinal system (dyspepsia, loss of appetite, or “irritable colon”). Many patients experience a constant uneasiness that the spells may reoccur, especially in public; hence the patient may be fearful of leaving home lest help not be available should an attack occur (agoraphobia). Except in minor details, it is notable that the attacks are alike in any one individual. Between attacks, most patients feel relatively well but many complain of the symptoms of anxiety and asthenia in lesser but persistent fashion.

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Chapter 47 Anxiety, “Functional” and Personality Disorders

Hyperventilation is a special, although not invariable, feature of the anxiety attack. Hyperventilation itself, by reducing the PCO2, will cause giddiness, paresthesias of the fingers, tongue, and lips, and, at times, frank tetany. However, contrary to what is stated in some textbooks, in only a minority of patients does a 3-min period of deep breathing reproduce the symptoms of an anxiety or panic attack. Nonetheless, this maneuver may be used to assist the patient in describing certain aspects of an attack. Attacks in minor form, without the full force of the physical accompaniments may occur at infrequent intervals or several times a day. Much to the patient’s surprise, they usually occur in situations where there are no easily recognizable sources of fear, as when the patient is sitting quietly at home or has just awakened from sleep. In other instances, a trying or upsetting experience induces an attack, which is nonetheless excessive for the condition that provoked it. In some patients, attacks are brought on consistently by confinement to a closed space (claustrophobia)—an elevator, for example—or by crowded surroundings, as in a church, restaurant, or theater. An anxiety state frequently follows an accident and then may be a source of ongoing disability (Modlin), a condition more akin to posttraumatic stress disorder. Similar spells of anxiety are also a prominent feature of the postconcussive and posttraumatic stress syndromes. From the patient’s life history, two patterns of anxiety disorder are discernible. In one, there is a nearly lifelong history of poor exercise tolerance, little stamina, and inability to do heavy physical work or participate in vigorous sports, tenseness, nervousness, and intolerance of crowds, that is, what had in the past been called neurasthenia (or nervous exhaustion), named by the neurologist George Beard in 1869 and renamed innumerable times by others as a result of its widespread applicability in all branches of medicine. When these symptoms arose during military service, they were designated, since the American Civil War as neurocirculatory asthenia, “irritable heart,” or “soldier’s heart.” The course of anxiety traits is variable. A 20-year follow-up study showed that symptoms were still present in 88 percent but persisted in being moderately or severely disabling in only 15 percent (Wheeler and associates). Most affected patients were able to work and to enjoy a reasonably normal family and social life. Their only liability to further psychiatric illness was to later anxious depression, whereas so-called psychosomatic illnesses and other psychiatric illnesses did not occur more frequently than in the general population. Those with uncomplicated anxiety neurosis rarely commit suicide.

Etiology and Pathogenesis Anxiety disorder has been attributed to a genetic propensity, to a “constitutional weakness” of the nervous system, to social and psychologic factors, and to physiologic and biochemical derangements; but none of these factors provides a completely satisfactory explanation of the primary problem. The onset of both acute and chronic anxiety, as mentioned, is rare before 18 years or after 35 to 40 years of age

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(average age of onset 25 years). The condition in some series is twice as frequent in women as in men and there is clearly a high familial incidence. In one study (Wheeler et al) there was a prevalence of 49 percent among the grown children of patients with anxiety neurosis, compared with 5 percent in the general population. There was a concordance rate of 40 percent in identical twins, compared with 4 percent in dizygotic twins in one study (Slater and Shields). Among the relatives of index cases, mothers suffered from anxiety neurosis more often than did fathers; in the latter, alcoholism was more frequent than in the population at large (Modlin). A clear pattern of inheritance has not been established, but it approximates that of autosomal dominance with incomplete penetrance. The psychodynamic theories that attempted to provide a unified explanation of these diverse anxiety states (Nemiah) cannot be totally dismissed. The symptoms of an anxiety resemble those of fear in many ways, although nearly always the former is longer in duration and less distinct. The most important difference, however, is that the cause of fear is known to the patient, whereas that of anxiety is not. The most extreme but not inconceivable interpretation of anxiety is the James-Lange theory of emotion, mentioned earlier, which attributes the psychologic experience entirely to the accompanying physical symptoms. On the physiologic and biochemical side, it has been observed that anger provokes an excessive secretion of norepinephrine, whereas fear is accompanied by increased secretion of epinephrine. Actually, fear activates the autonomic nervous system as a whole and the increase in epinephrine is more than counterbalanced by a parasympathetic discharge. Attention has been focused on overactivity of the locus ceruleus and upper brainstem nuclei as possible anatomic substrates of anxiety (Judd et al). Other studies have implicated serotonergic centers. Evidently, the responsiveness of the autonomic nervous system in these patients remains heightened and a number of stimuli (cold, pain, muscular effort) may produce abnormal responses in pulse, respiration, oxygen consumption, and work performance. An interesting but not uniformly affirmed abnormality (noted by Cohen et al) was that the blood lactic acid levels in response to exercise are higher than normal. The presence of these changes does not necessarily mean that they are causal; they are as likely secondary to other factors such as poor physical condition and apprehension associated with the syndrome. Nevertheless, some investigators have found that infusions of lactic acid can trigger panic attacks in persons with anxiety neurosis (Liebowitz et al). Subsequently, numerous other theories of causation have been proposed based on the reported provocation of panic attacks by a number of different substances—carbon dioxide, yohimbine, gamma-aminobutyric acid (GABA), isoproterenol, and others. None provides a comprehensive biologic explanation for anxiety or panic attacks. Studies correlating cerebral function and blood flow indicate that when panic is induced by an intravenous injection of sodium lactate, there is an immediate increase in blood flow to the cortex of both temporal lobes. In states of fear, the tips of the temporal lobes and the amygdaloid nuclei are known to become activated. In the relaxed

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period between panic attacks, the right limbic system and the parahippocampal gyrus have been abnormally active in some studies. As with the aforementioned biochemical models, these seem to be more reflections of brain activity in response to the psychic experience than they are explanations. Nevertheless, parts of the limbic system are presumably involved in an essential way in the production and perpetuation of anxiety and its related states. The discovery that the benzodiazepines bind to specific sites of the GABA receptor complex and that the sedative and amnesic effects (α1 subunit) of these drugs seem to be separable from their anxiolytic effects (α2 subunit) raises the possibility that abnormalities of the GABA system directly underlie anxiety. However, there is only indirect evidence for this mechanism. Of potentially greater importance is the finding of genetic polymorphisms that relate to the presence of anxiety states, such as one in the serotonin transporter gene (Lesch et al). It has been estimated that allelic differences in this gene contribute perhaps 10 percent to the overall anxiety tendency. One presumes that there are numerous additional genes that participate in a similar way. Others have not found this association or have found it only in patients with generalized anxiety and not in those with panic attacks. Consequently, the relationship of genetic polymorphisms to anxiety states cannot be stated at this moment, but a heritable component seems highly likely.

Differential Diagnosis Shorn of the psychologic components of apprehension and fear, the anxiety and panic attack consists essentially of an excessive autonomic, mainly sympathetic, discharge. Some of the autonomic symptoms are therefore duplicated by pheochromocytoma. The prominence of chest discomfort and respiratory distress during an acute anxiety attack may be mistaken for myocardial ischemia, in which case the patient is often subjected to a series of studies of cardiac function. Another form of the illness—in which nondescript dizziness, vague difficulty with visual clarity, and fear of losing consciousness are the most prominent features—may be mistaken for a vestibular problem (see “Nonvertiginous Types of Dizziness” in Chap. 14) or for epilepsy. In contrast, headache is surprisingly, an infrequent experience and the diagnosis should be suspect if it is a prominent feature. Other medical diseases that may be brought to mind by isolated elements of an anxiety state are pulmonary embolism, cardiac arrhythmias, hypoglycemia, hypoparathyroidism, alcohol, drug, nicotine withdrawal and especially, complex partial seizures. The autoantibody syndrome associated with NMDA antibodies and some instances without these antibodies may have anxiety as its opening feature. In regard to seizures as imitators of anxiety, however, loss of consciousness, incontinence, and clonic or myoclonic movements do not occur in anxiety spells. Adherence to the diagnostic criteria of these disease states readily permits their differentiation from acute anxiety, but diagnosis may be difficult if the symptoms are brief. Of equal importance is the relationship of anxiety to depression. A large proportion of patients with depression

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have symptoms of anxiety. Indeed, some psychiatrists believe that anxiety disorder is accounted for mainly by a variant of depression. As has been mentioned, an anxiety state appearing for the first time after the 40th year usually proves to be primarily a depression, although it may be that a predisposing personality trait is involved. The presence of symptoms such as overwhelming fatigue, self-deprecation, and feelings of hopelessness and, of course, ideas of self-destruction make depression the fundamental diagnosis, with anxiety an associated feature (anxious depression). As mentioned, a very small number of patients with a condition diagnosed as pure anxiety neurosis have committed suicide, but this does not hold if depression is the central illness. Schizophrenia may also make itself apparent initially with prominent anxiety symptoms. Here the diagnosis rests on finding the characteristic thought disorder of schizophrenia, which may emerge only with time and after several interviews.

Treatment Anxiolytics and antidepressants are generally effective in suppressing panic attacks and creating a sense of wellbeing but their continued use comes with risks of dependence and withdrawal. Among these, the benzodiazepine alprazolam had been favored by some psychiatrists, but lorazepam and clonazepam are almost as effective and are considered less likely to cause dependence, but this has not been clearly documented. In mild cases, the benzodiazepines may be used intermittently rather than several times daily, but they tend to be less useful once a panic attack has become established. Panic attacks tend to recur when the medications are discontinued, even after prolonged (6 to 12 months) administration. Any reduction in the amount of these medications should be gradual as withdrawal symptoms simulate panic or anxiety spells. Tricyclic antidepressants and drugs that raise serotonin concentrations in the nervous system (selective serotonin reuptake inhibitors [SSRIs]) may also be effective in the prevention of panic attacks and agoraphobia, but their onset of action is delayed for weeks. They become useful for symptoms of anxiety that recur or persist for more than several months. The doses are similar to those used to treat depression, and small differences between the agents in this class do not seem to be clinically important (see Chap. 48). Buspirone, a specific serotonin 5-HT2 agonist, has been promoted as effective in the treatment of anxiety and as a surrogate for benzodiazepines, but to us, its benefit has seemed to be slight. It is important to point out that during the initial weeks of administration of antidepressants, the underlying anxiety symptoms may worsen, and an anxiolytic may be required until the antidepressant becomes effective. Propranolol, 10 to 20 mg tid, or a longacting form of adrenergic blocker, can reduce many of the autonomic accompaniments of anxiety and is useful to some patients. Psychiatric consultation is, of course, invaluable. Behavioral therapy (progressive exposure of the patient to panic-provoking situations) is said to be beneficial,

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particularly if agoraphobia is a major symptom. Relaxation activities, including biofeedback and meditation, help many patients, although persistence is required in performing these exercises at least once daily and they are less helpful once a panic attack has begun. Cognitive-behavioral therapy, which is discussed in relation to the treatment of depression in Chap. 48, also appears to be useful in the treatment of panic disorder (Andreasen and Black). A cardiac consultation and some simple tests (electrocardiogram, chest films) are often needed to reinforce to the patient the benign nature of the cardiac and respiratory symptoms and to alleviate fear of heart disease. These and other concepts of the treatment of anxiety were discussed decades ago by Goodwin and Guze and are still valid. Anxiety symptoms arising in relation to a particular threatening event in an individual not previously prone to anxiety carry the best prognosis, but the symptoms may be prolonged, a feature of posttraumatic stress disorder.

PHOBIC DISORDER In this state, patients are overwhelmed by an intense and irrational fear of some animal, object, social situation, or disease. Although acknowledging that there are no grounds for a particular fear (hence it is not a delusion) and that such provocative stimuli are for the most part innocuous, the patient is nonetheless powerless to suppress it. This disorder was known to Hippocrates, who drew a distinction between normal and morbid fears. Westphal, in 1871, was the first to give morbid fears the status of a disease. Unlike an anxiety attack, a phobia focuses on a specific object or situation. The patient is chronically fearful of a particular animal or situation and becomes extremely anxious or panic stricken and incapacitated when placed in a situation that evokes the phobia. These situations are avoided at all costs. As a result, it may be impossible for the patient to leave the house or neighborhood unaccompanied or at all, mingle in a crowd, walk across a bridge, or travel by air. This fear of being in places or situations from which escape might be difficult or extremely embarrassing is spoken of as agoraphobia. (Agoraphobia, however, is a secondary feature of other psychiatric disorders, the most frequent being anxiety with panic attacks as already mentioned.) The most common phobia—and one that is not disabling for the most part—is claustrophobia, the fear of being confined in a closed space such as an elevator or a magnetic resonance scanner. Other phobias are those of high places, dogs, cats, insects, dirt, sprays and other contaminants, air travel, HIV, cancer, insanity, and death. Feelings of helplessness, pessimism, and despondency, the hallmarks of a depressive illness, result after years of phobic suffering. Often there are obsessive-compulsive tendencies as well, and some patients are hypochondriacal. Phobias are essentially obsessive fears and are somehow allied with anxiety disorders. The present authors have observed a number of patients whose phobic (or obsessive-compulsive) states became greatly exaggerated as an endogenous depression developed. Recovery from

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the depression returned them to their earlier and milder phobic state.

OBSESSIVE-COMPULSIVE DISORDER Like the pure phobic states, a state dominated by obsessions (thoughts) and compulsions (acts) is infrequent, occurring in less than 5 percent of patients seeking help in a psychiatric outpatient clinic, but it can be extremely disabling. Minor compulsions (e.g., not stepping on cracks in the sidewalk), like minor phobias, are common in children, cause little or no distress, and disappear in later life. A few, such as rechecking a locked door or a gas stove, may persist throughout life. Also, certain habits and rigid, obsessional ways of thinking, stubbornness, extreme punctuality, and excessive attention to detail may be persistent but excite little attention medically unless they interfere with a diagnostic procedure or the treatment of a medical disease. Obsessive-compulsive disorder begins in adolescence or early adult years, although treatment may not be sought until middle age. The two sexes are equally affected. The onset is usually gradual and often cannot be accurately dated, but in some cases, it is precipitated by a particular event in the patient’s life, such as the death of a relative. The family history often discloses a high incidence of obsessional or phobic personality in other members. There is usually a prevailing undercurrent of insecurity and anxiety. Obsessions are imperative and distressing thoughts that persist in the patient’s mind despite a desire to resist and to get rid of them. They take various forms; among them are intellectual obsessions, in which phrases, rhymes, ideas, or vivid images (these are often absurd, blasphemous, obscene, and sometimes frightening) constantly intrude into consciousness; impulsive obsessions, in which the mind is dominated by an impulse to kill oneself, to stab one’s children, or to perform some other objectionable act; and inhibiting obsessions, in which every act must be ruminated on and analyzed before it is carried out—a state that is cleverly called doubting mania. Every effort at distraction fails to rid the patient of the obsessive thought. It engulfs the individual’s mind, rendering the person dysphoric and, often, inefficient. Probably the most disturbing obsessions are the impulsive ones, in which patients constantly struggle with the fear that they will put some terrible thought into action. Even as they tell of the obsession, they reveal a severe underlying anxiety and seek reassurance that they will not yield to it. Fortunately, such patients rarely obey their pathologic impulses. Phobias, as mentioned earlier, are considered by some authorities to be essentially obsessive fears and are included in this category of neurosis. Compulsions are acts that result from obsessions. These are single acts or a series of acts (rituals) that the patient must carry out to put his mind at ease. Examples are repeated checking of the gas jets or the locks on doors, adjusting articles of clothing, repeated hand washing, using a clean handkerchief to wipe objects that have been touched by others, tasting foods in specific ways, and touching or arranging objects in a particular sequence. The most common of these obsessions and compulsions center

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around contamination concerns that lead to repeated hand washing or bathing. Other obsessions and compulsions can be identified as clusters of thoughts that derive from the above-mentioned concern about harm to oneself or to others and consequent checking on others. Less common clusters involve excessive focus on symmetry, precision, and ordering, and on saving and hoarding. Certain motor disturbances—namely, habit spasms or tics—are, in a sense, motor compulsions. They consist of repetitious movements of the shoulders, arms, hands, and certain of the facial muscles (see Chap. 4). One feature that separates quasivoluntary tics from involuntary movements of extrapyramidal type is the patient’s feeling that the tics must be carried out to relieve an inner tension. Unlike compulsions, however, tics are not usually based directly on obsessive thoughts—except perhaps the Gilles de la Tourette syndrome, in which multiple tics are combined with compulsive utterances, often offensive ones (see later). In all these obsessions and compulsions and in the phobias, patients recognize the irrationality of their ideas and behaviors, yet are powerless to control them. It is this insight into the obsessional experience and the struggle against it that distinguish obsessions from delusions. After the condition has persisted for a time, they may become depressed and suffer from typical anxiety attacks.

Mechanisms of Obsessive Disorder For many years, psychodynamic conceptualizations held sway of obsessional states as the product of intrapsychic conflicts. Only relatively recently has a more reasonable neurobiologic model been advanced. These are largely derived from the findings of functional imaging, which have been quite consistent in demonstrating increased metabolic activity in the orbitofrontal cortex, cingulate, and, to a lesser extent, striatum. The orbitofrontal cortex and amygdala were reported to be shrunken in other cases. In a study of 13 patients who developed elements of obsessiveness and compulsive disorder after incurring focal brain lesions, lesions have been found in diverse loci, including the cingulate, frontal, and temporal cortices, as well as the basal ganglia (Berthier and colleagues). Additional insight into obsessive-compulsive disorder may be obtained from the many cases in which acquired striatal damage may be linked to obsessional behavior. One such entity is a poststreptococcal tic disorder termed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), discussed in Chap. 4. This disorder is presumably related to another extrapyramidal condition, Sydenham chorea, in which tics and similar movement disorders, as well as obsessive behavioral abnormalities, have long been known to coexist. Functional imaging studies in patients with PANDAS have yielded variable findings but generally there has been increased activity in the caudate nucleus and orbitofrontal cortex in association with the patient’s compulsive thoughts. The Gilles de la Tourette syndrome of multiple tics, including vocal ones, beginning in childhood or adolescence and lasting more than a year, has a strong

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component of obsessive-compulsive disorder in more than half of patients. Both disorders occur in a pattern of inheritance that is close to an autosomal dominant trait with incomplete penetrance (Kurlan). Because dopamine antagonists (Haldol was the first of these to be tried systematically, by Shapiro) have been beneficial in the management of the Tourette syndrome, a number of etiologic hypotheses revolve around serotonergic and dopaminergic neurotransmitter systems (Baxter). The neurochemical alterations in obsessive-compulsive disorder have been based in part on the responses to medications, notably to the serotonin reuptake inhibitors, as noted further on. These agents are found to be of therapeutic benefit, as are stereotactic neurosurgical lesions in the cingulate gyri (see further on). More extensive comments on the Gilles de la Tourette syndrome are found in Chap. 4.

Treatment This is best left to the experienced psychiatrist. At the least there should be a trial of therapy using behavioral modification techniques. In the case of phobic neurosis, the aim is to reduce the patient’s fear to the extent that exposure to the phobic situation can be tolerated. One form of therapy is systematic desensitization, which consists of increasing and graded exposure of the patient to the object or situation that arouses the fear. Psychotherapy can consist of repeated explanation, reassurance, and guidance in dealing with symptoms. As with phobic neurosis, several reports have indicated that compulsive rituals can sometimes be reduced by the techniques of behavior therapy as discussed in Chap. 48. Certain medications, particularly the SSRI types such as fluoxetine, are considered to be effective in reducing obsessions and compulsions in more than half of patients. The less selective agent, clomipramine, is also effective, as were the commonly used tricyclic antidepressants in the past, but clomipramine is not nearly as well tolerated as are the conventional SSRI drugs (Stein). In the past, cingulotomy produced symptomatic improvement in both phobic and obsessional neuroses and was considered a reasonable procedure. This measure is largely outdated as the implantation of electrical stimulating electrodes (deep brain stimulation) in this region or in the subthalamic nucleus has proved effective for intractable and disabling obsessive compulsive disorder but without affecting the degree of anxiety and at the expense of a moderate number of surgical complications (Mallet et al).

FUNCTIONAL NEUROLOGICAL DISORDERS (HYSTERIA, BRIQUET DISEASE; SOMATIZATION DISORDER; PSYCHOGENIC NEUROLOGIC DISORDER) This subject is of great importance to neurologists and general physicians because of its frequency. Any sense that this was a disorder of the Victorian era belies modern experience. What has changed for the better is the reduced stigmatization of the disorder and a more straightforward, non-judgmental approach to treatment.

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Although a disorder of this nature has been known since ancient times, many writers credit the first description of the syndrome to the French physician Briquet in 1859. Charcot later elaborated certain manifestations of the disease, particularly those with a theatrical aspect, and thereby interested Freud and Janet in the problem. Charcot demonstrated that the symptoms could be produced and relieved by hypnosis. There have been many extensive expositions of Charcot’s work in this field and his consideration of hysteria as an organic disease, perhaps allied with epilepsy but representing in any case a “functional” disorder of brain. One of the authors of this text has devoted a large part of a book to the subject (Ropper and Burrell). Charcot’s acolyte, Janet postulated a dissociative state of mind to account for certain features, such as trances and fugue states, a term that has reappeared in modern psychiatry. Freud and his followers conceived of hysterical symptoms as a product of “ego defense mechanisms” in which psychic energy, generated by unconscious sexual conflicts, was “converted” into physical symptoms. This latter concept was widely accepted, to the point where the term conversion became incorporated into the nomenclature of the neuroses and the terms conversion symptoms and conversion reaction came to be equated with the disease hysteria. We see no merit in this dichotomy, based on unsubstantiated psychodynamic theory, of a conversion type as separate from a dissociative type of hysteria, as claimed by the DSM classification (Nemiah). In clinical neurology one encounters two types of psychogenic neurologic disorders, both identified as having no possibility of explanation in disease of the nervous system: (1) a chronic illness marked by multiple and often dramatically presented symptoms and somatic abnormalities of “classic hysteria,” predominantly in women (there is potential sexism and acquisition bias in this categorization but we report our and our colleagues contemporary experience) and (2) an illness predominantly of men but also of women who develop physical symptoms or remain inexplicably disabled for the purpose of obtaining compensation, influencing litigation, avoiding military duty or imprisonment, or for the manipulation of some other interpersonal or societal situation. This latter state has been called compensation neurosis, compensation hysteria, or hysteria with sociopathy, in other words, malingering.

Briquet Syndrome There is also a chronic and episodic condition of repeated bouts of functional neurologic and medical symptoms in the past accounted for 1 to 2 percent of admissions to a neurologic service and a greater number of outpatient visits but now is represented mainly by psychogenic seizures and convulsions, “psychogenic nonepileptic seizures,” or PNES (see further on and Chap. 15). The more general chronic form that does not include epileptic-like attacks usually has its onset in the teens or early twenties, mainly in young women; a very few cases begin before puberty. Once established, the symptoms recur intermittently, although with reduced frequency, throughout the adult years even to an advanced age. No doubt there are cases of lesser severity

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in which symptoms occur only a few times or perhaps only once. The patient may be seen for the first time during middle life or later, and the earlier history may not at first be forthcoming. Careful probing almost invariably reveals that the earliest manifestations of the chronic form of illness had appeared before the age of about 25 years. Other important data are also revealed by eliciting a careful history. During late childhood and adolescence, the normal activities of the patient, including education, had often been interrupted by periods of ill-defined illness. In the past, rheumatic fever, and in the current era, chronic fatigue, Lyme disease, sick building syndrome, or multiple environmental allergy may be carried as explanatory diagnoses from other physicians or the patient’s research on the Internet. Later in life, problems in work adjustment and marriage are frequent. Notable in many cases is a high incidence of marital incompatibility, separation, and divorce. The patient’s life history is punctuated by symptoms that do not conform to recognizable patterns of medical and surgical disease. For these ailments, many forms of therapy including surgical operations may have been performed. In the past, rarely had adult life been reached without at least one abdominal operation for vague abdominal pain, persistent nausea and vomiting, or an obscure gynecologic complaint. Often the indications for the surgical procedures were unclear; moreover, the same symptoms or others often recurred to complicate the convalescence. The biographies of these patients are replete with disorders that center about menstrual, sexual, and procreative functions. Menstrual periods may be painfully prostrating, irregular, or excessive. Sexual intercourse may be painful or unpleasant. Pregnancies may be exceedingly difficult; the common vomiting of the first trimester may persist all through the gestational period, with weight loss and prostration; labor may be unusually difficult and prolonged, and all manner of unpredictable complications are said to have occurred during and after parturition. Briquet syndrome in its fullest form is a polysymptomatic disorder, implicating at some time and in some patients, almost every organ system. In a study of 50 unmistakable cases of hysteria (as compared with a control group of 50 healthy women), the most frequent symptoms were headache, blurred vision, lump in the throat, loss of voice, dyspnea, palpitation, anxiety attacks, anorexia, nausea and vomiting, abdominal pain, unusual food allergies, severe menstrual pain, urinary retention, painful intercourse, paresthesias, dizzy spells, nervousness, and easy crying (Purtell and colleagues). The mental examination of the patient with hysteria demonstrates a lack of precision in relating the details of the illness. Questions regarding the chief complaint usually elicit a narration of a series of incidents or problems, many of which prove to have little or no relevance to the question. Memory defects (amnesic gaps) are apparent while the history is being taken; the patient appears to have forgotten important segments of the history, some of which had been clearly described in the past and are part of the medical record. The description of symptoms is dramatic and not in accord with the facts as elicited

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from other members of the family. Often, a rather casual demeanor is manifest, the patient insisting that everything in her life is quite normal and controlled, when, in fact, the medical record is checkered with instances of dramatic and unexplained illness. This calm attitude toward a turbulent illness and seemingly disabling physical signs is so common that it had been singled out as an important characteristic of hysteria, la belle indifference. Other patients, however, are obviously tense and anxious and report frank anxiety attacks. Emotional reactions are superficial and scenes that are disturbing to others are quickly forgotten. Claims of early life sexual or physical abuse are common and often prove to be true, or sometimes are not valid; when present, they probably play a role in the genesis of some cases (see further on). The so-called stigmata of hysteria—that is, corneal anesthesia; absence of gag reflex; spots of pain and tenderness over the scalp, sternum, breasts, lower ribs, and ovaries—had in the past been suggested by the examiner and are not helpful in diagnosis. The relative value of various features of the history, examination and psychological profile that may be of value in diagnosis have been summarized (Lazare), and the psychiatric features are not definitive. The variation and pleomorphism of the physical signs are limited only by the patient’s ability to produce them by voluntary effort. Some features that were common in the past, such as arc de circle, in which the patient arches the back and supports the body by the heels and back of the head, however, are not possible to obtain except by voluntary means and probably can be considered characteristic, if rare. Sometimes the patient’s physical signs are an imitation of those of another member of the family (“folie à deux”) or are evoked by a stressful event in the patient’s personal life. However, this may not be disclosed at the time of the first examination. Although many in the past had commented on the rather youthful, girlish appearance and coquettish (“seductive”) manner of the patients, these by no means characterize patients in the current era.

Special Neurologic Syndromes of Functional Origin A few functional syndromes occur with regularity that physicians may expect to encounter them. Most are neurologic in nature. They constitute some of the most puzzling diagnostic problems in medicine.

Hysterical Pain This is a fraught area but pain due to functional disorder may involve any part of the body; generalized or localized headache, “atypical facial pain,” vague abdominal pain, and chronic back pain with camptocormia are the most frequent and troublesome. In many of these patients the response to analgesic drugs has been unusual or excessive, and some of them are addicted. The hysterical patient may respond readily to a placebo as though it were a potent drug, but it should be pointed out that this is a notoriously unreliable means of distinguishing hysterical pain from that of other diseases. A greater error is to mistake the pain of osteomyelitis or visceral tumor—before other symptoms have developed—for a manifestation of hysteria. There are

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several helpful diagnostic features of hysterical pain: (1) the patient’s inability to give a clear, concise description of the type of pain; (2) the location of the pain does not conform to the pattern of pain in the familiar medical syndromes; (3) the dramatic elaborations of its intensity (speaking in inflated metaphors—“like a giant knife stabbing”) and its effects on the body (“tearing my limb off”); (4) its persistence, either continuous or intermittent, for long periods of time; (5) the assumption of bizarre postures; and, most important; and (6) the coexistence of other clinical features or previous attacks of hysterical nature.

Functional Vomiting This is often combined with pain and tenderness in the lower abdomen and had many times in the past resulted in unnecessary appendectomies and removal of pelvic organs in adolescent girls and young women. The vomiting often occurs after a meal, leaving the patient hungry and ready to eat again; it may be induced by unpleasant circumstances. Some of these patients can vomit at will, regurgitating food from the stomach like a ruminant animal. Vomiting may persist for weeks with no cause being found. Weight loss may occur, but seldom to the degree anticipated. As remarked earlier, the usual first-trimester vomiting of pregnancy may continue throughout the entire 9 months. Anorexia may be a prominent associated symptom and must be differentiated from anorexia nervosa–bulimia, another closely related disease of young women. Factitious self-induced vomiting is more aligned with malingering.

Psychogenic Seizures (PNES), Trances, and Fugues (See Also Chap. 15) These conditions seem to be no less frequent than in the days of Charcot, when la grande attaque d’hysterie was often exhibited before medical audiences, but it is quite familiar to neurologists and one of the main concerns of epileptologists. To witness an attack is of great assistance in diagnosis but electroencephalogram (EEG) monitoring is often required for certainty. The lack of an aura, initiating cry, hurtful fall, or incontinence; the presence of peculiar movements such as grimacing, squirming, thrashing and flailing of the limbs, side-to-side motions of the head, arc de circle, and striking at or resisting those who offer assistance; the retention of consciousness during a motor seizure that involves both sides of the body; a long duration of the seizure, its abrupt termination by strong sensory stimulation, lack of postictal confusion, and failure to produce a rise in creatine kinase—are all typical of the psychogenic attack. Sometimes hyperventilation will initiate an attack and is therefore a useful diagnostic maneuver. Both epilepsy, particularly of frontal-lobe type, and functional seizures may occur in the same patient, a combination that invariably causes difficulty in diagnosis as discussed in Chap. 15. Hysterical trances or fugues, in which the patient wanders about for hours or days and carries out complex acts may simulate temporal lobe epilepsy or any of the conditions that lead to confusional psychosis. The most reliable point of differentiation comes from observation of the patient, who, if hysterical, is likely to indicate a degree of alertness and promptness of response not seen in temporal

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lobe seizures or confusional states. Following the episode, an interview with the patient—under the influence of hypnosis, strong suggestion, or midazolam (formerly used was amobarbital [Amytal])—will often reveal memories of what happened during the episode. This helps to exclude the possibility of an epileptic spell.

Functional Paralyses, Gait, Sensory Loss, and Tremors (See Also Chaps. 3, 4, and 6) Hysterical palsies may involve an arm, a leg, one side of the body, or both legs. If the affected limb can be moved at all, muscle action is weak and tremulous. Movements are slow, tentative, and poorly sustained; often it can be demonstrated that the strength of voluntary movement is proportional to the resistance offered by the examiner, thus imparting a “give-way” character, as noted in the discussion of these signs in Chap. 3. One can detect by palpation that agonist and antagonist muscles are contracting simultaneously, thereby holding the limb in place rather than opposing the examiner, and when the resistance is suddenly withdrawn, there is no follow-through or rebound, as is normally the case. Many other signs have been devised to demonstrate inconsistencies with normal physiologic principles and a purposive lack of cooperation. These are elaborated on in the literature (Stone and associates 2002b and 2013a, b). Discrepancies are usually found by testing an agonist, antagonist, or fixator movement while the patient is focused on making an effort with another group of muscles (e.g., the Hoover sign; see Chap 3). Muscular tone in the affected limbs is usually normal but slight resistance may sometimes be found. A seeming lack of effort and the absence of full compliance with the examiner’s requests during the testing of muscle strength, while common in hysterical patients, are not confined to them; one encounters such findings not infrequently during the examination of suggestible but nonhysterical patients who harbor a neurologic disease and in those with a painful condition in an adjacent joint. Walking and standing may be impossible (astasiaabasia) or the gait may be bizarre with collapsing legs that bring the patient to a squat, or a “skating” gait in which one foot is pushed ahead of the body. Other forms—some quite absurd such as the ability to walk only backwards, as noted in Chap. 6—are easily recognized as inconsistent with the makings of the nervous system in disease. Weakness and poor balance are combined elements in both the quadriparetic and hemiparetic forms. In an informative series of 60 cases of functional gait disorders, the hemiparetic and monocrural forms were twice as frequent as the quadriparetic (Keane). The gait disorder is sometimes difficult to describe because of its variability but is usually mistakenly called “ataxic” by inexperienced examiners. Sudden falls without voluntary protective movements and inconsistencies of balance are helpful features. Difficulty in walking and moving the legs that disappears when the patient is seated is, of course, not unique to hysteria; it also occurs in so-called frontal lobe gait apraxia and in ataxia from midline cerebellar lesions and in hydrocephalus. In a most remarkable and recalcitrant form of psychogenic movement disorder, maintenance of the limbs

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in a rigid or dystonic posture for a long time may result in a bed-bound, crippled state with severe flexion pseudocontractures of the limbs. We have seen one such case of 18 years’ duration. The tendon reflexes are usually normal if they can be tested, but with hysterical rigidity and muscular contractures, the abdominal and plantar reflexes may be suppressed. Anesthesia or hypesthesia is almost always inadvertently suggested by the physician’s examination. Seldom is sensory loss a spontaneous complaint, although “numbness” and paresthesias are not uncommon in hysterics. The sensory loss may involve one or more limbs below a sharp line (stocking and glove distribution), or may involve precisely one-half of the body, or vibratory sense may be lost over precisely one-half of the skull (a test favored to demonstrate hysterical hemianesthesia). Touch, pain, taste, smell, vision, and hearing may all be affected on that side, which is an anatomic impossibility from a single lesion. Other aspects of psychogenic sensory disturbance are discussed in Chap. 8. The closest syndrome is that produced by a thalamic infarction but this, too, is easily distinguishable from psychogenic hemianesthesia. The sometimesstated notion that hysterical paralysis and sensory deficits are more common on the left side is apparently untrue (Stone and colleagues, 2002a). The features of functional tremor and other movement disorders are described in Chap. 4. Emphasized here is the cessation of tremor with distracting tasks—for example, complex finger movement patterns on the side opposite the tremor (such as touching the fourth, second, and fifth fingers in sequence rapidly), or refixation of the eyes on a target, or walking on the outside of the heels. The ability of the examiner to “chase” the tremor to proximal or distal parts of the limb by holding and immobilizing one part is highly characteristic. Another fairly dependable but not invariable sign is worsening of a tremor with loading that is accomplished by placing a heavy object in the patient’s hand (most basal ganglionic and cerebellar tremors are muted by this maneuver). Some general characteristics of psychogenic movement disorders include a typically acute onset and rapid progression of the movements, distractibility, variability and the simultaneous occurrence of various abnormal movements and of unexplainable paralysis, sensory loss, or pain (Hinson and Haren). The movements are not explainable by characteristics of organic brain diseases, but as with all forms of functional disorder, it is not on this feature alone that the diagnosis can rest.

Functional Blindness (See Also Chap. 12) This dramatic event may affect one or both eyes and may be coupled with hemiparesis or appear in isolation. The symptoms usually develop suddenly, often after an altercation or other emotionally charged event. The patient stares straight ahead blandly when undisturbed but may squint or move the head as if straining to see when asked to view an object. Some such individuals can reduce reflexive blinking in response to a visual threat. The psychic nature of the problem may be recognized by a nurse or assistant who observes the patient reaching for a cup or phone. The preservation of vision is confirmed by the presence of normal

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pupillary reflexes and of optokinetic nystagmus, although one occasionally encounters a patient who has learned to suppress the latter response. A mirror passed slowly in the patient’s central vision often engages eye movements. Other similar maneuvers are favored by different examiners. The presence of visual evoked responses also confirms the intactness of retinooccipital connections. The condition is usually short-lived. To be distinguished from these disorders are cortical blindness and variants of the Balint syndrome are the main diagnostic considerations (see Chap. 21). Convergence spasm, occurring as an isolated phenomenon, is practically always of hysterical nature. A related phenomenon involves the self-administration of mydriatic eyedrops by healthcare personnel. The patient arrives on the emergency ward complaining of reduced vision (expected) or with headache and claiming to have an intracranial mass. This behavior is perhaps more sociopathic (or malingering) than hysterical.

Functional Amnesia Despite being a Hollywood trope, patients brought to a hospital not knowing their own identity, in a state of amnesia, are usually hysterical or sociopathic individuals involved in a crime or having experienced an embarrassing event that they wish to obscure (e.g., marital infidelity). Epileptic patients or victims of a concussion, transient global amnesia, or acute confusional psychosis do not arrive asking for help in establishing their identity. Moreover, the complete loss of memory for all previous life experiences by patients who are otherwise able to comport themselves normally is not observed in any other condition. In the Ganser syndrome patients essentially pretend to have become insane or demented. They may act in an absurd manner, simulating the way they believe that a deranged or demented person would act, and give senseless or approximate answers to every question asked of them (calling the color red, blue or answering 5 for 2 + 2).

Etiology and Pathogenesis Psychoanalytic theory, which held that both conversion and dissociative symptoms were based on particular psychodynamic mechanisms, is impossible to affirm or refute. Although subject to some questions of fabricated recall, the high rate of childhood sexual abuse in severe monosymptomatic cases of hysteria or fugue states has been commented on in literature and seems unassailable. An acknowledged history of childhood abuse related by the patient alerts the physician to the possibility of hysteria. Sociologic and educational factors may be important. A genetic causation must also be considered since family studies have disclosed that approximately 20 percent of first-degree relatives of female sufferers of functional disorders have the same illness, an incidence 10 times that in the general population. This supports, in some views, the idea that ongoing functional disorder is a disease and not merely a surfacing of a personality trait (Goodwin and Guze).

Pathophysiology of Hysteria Whether conversion symptoms are consciously produced by the patient or arise unconsciously, without the patient’s

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awareness, is a question that has been debated endlessly without resolution. Babinski attributed the symptoms to hypersuggestibility. In fact, he defined hysteria as an illness whose symptoms could be induced (and removed) by suggestion. The present authors place credence on the notion of hypersuggestibility, in keeping with older ideas and studies that emphasized susceptibility to hypnosis and suggestion. Fascinating in this regard were the observations of Charcot’s students that on their wards, the patients’ symptoms disappeared when he died. There is some evidence to support this idea, as many patients can be readily hypnotized and their symptoms temporarily eliminated by this procedure or by an interview and examination under the influence of midazolam (formerly drugs such as pentothal were used). The potentially condescending or deceptive aspects of undertaking these tests has evinced modern comment and has limited their use without assent of the patient. Some insights can be obtained from studies of functional imaging in functional paralysis (see also Chap. 3). In general, activity in the contralateral prefrontal cortex is suppressed when the patient with hysteria attempts to move a limb, suggesting a “choice” of an active attempt not to move the limb (Spence and colleagues, Carson and colleagues). The pattern of activation is different from volunteers who purposefully feign paralysis and do not demonstrate such reduced prefrontal activity. When the hysteric with unilateral sensory loss is stimulated on the affected limb, there is no activation of the contralateral sensory cortex but bilateral stimulation results in activation of the appropriate regions in both hemispheres (Ghaffar et al). Functional disorder and sociopathy may be related (Carothers). This relationship is also supported by family studies. First-degree male relatives of women with functional disorders have an increased incidence of sociopathy and alcoholism; among first-degree female relatives of convicted male felons, there is an increased prevalence of hysteria.

Diagnosis It should be emphasized that single bouts of isolated functional paresis, blindness, and anesthesia are common in neurologic practice and do not presage a chronic illness. The same is true for transient neurologic signs exhibited during the course of the examination, mainly pertaining to unusual or drifting sensory loss or asthenic weakness of a limb. With respect to the diagnosis of a life-long functional disorder (Briquet disease), the characteristic age of onset; the longitudinal history of recurrent multiple complaints as outlined earlier; the attitude of the patient and the manner of presenting symptoms; the incongruity of affect and clinical state; the discrepancy between the report of neurologic deficit and the signs; the impossibility of explaining the patient’s signs on an anatomic or physiologic basis; and the absence of symptoms and signs of other medical and surgical disease will permit diagnosis in the majority of cases. Certain tests designed to reveal normal functioning of a limb, of vision, and of gait already have been mentioned. As to the frequency of incorrect diagnosis in these disorders, an assessment of over 1,000 patients who were given the diagnosis of a functional disorder, only

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Chapter 47 Anxiety, “Functional” and Personality Disorders

0.4 percent were later found to have an organic explanation for their symptoms but surveys in specialty clinics for functional disorders have acquisition bias that inflates incidence figures (Stone and colleagues, 2009). In contrast, on record are studies in which patients with an initial diagnosis of hysteria by general physicians were followed for many years and in which up to one-third (far less in most series) turned out eventually to have an “organic condition” that, in retrospect, explained the symptoms (Couprie et al). The physician can be reassured that in most follow up studies of patients with so-called conversion disorder (exclusive of pseudoseizures), virtually none develops a neurologic lesion that in retrospect was related to the initial episode (Stone and colleagues, 2003). It is of interest that in the series cited, most patients had persistent functional disability from their conversion symptoms, even a decade later. When the diagnostic criteria in these cases are closely analyzed, it becomes apparent that the diagnosis was made solely by the “discrepancy method”—that is, the patient’s symptoms or signs were not deemed to be credible manifestations of disease, based mainly on the clinical experience of the examiner. Of course, this assumes that the examiner has a wide experience; unfortunately for the novice, many syndromes are difficult to identify and comprehend. However, when diagnosis is based on the totality of the clinical picture and not on the “discrepancy method,” it can be quite accurate. Projective tests (the Rorschach and Thematic Apperception Tests), which for a time were popular with dynamic psychiatrists, are apparently not helpful in diagnosis and are now used very little. The presence of extreme suggestibility and the tendency to dramatize symptoms as measured by one part of the Minnesota Multiphasic Personality Inventory and other psychometric tests is helpful in diagnosis but not pathognomonic; these traits appear under certain conditions in individuals who never develop hysteria.

Treatment of Functional Symptoms Here, opinions differ but modern approaches that are nonjudgmental, straightforward, and aimed at returning the patient to good function have great appeal. Treatment may be considered from two aspects: the recognition of childhood trauma and amelioration of any maladaptive long-standing traits and relieving recently acquired physical symptoms. Psychotherapists have attempted to modify traumatically induced personality traits through long-term reeducation, but their results are uninterpretable and there are no control studies for the few reports of therapeutic success. In less severe cases and especially in those in whom hysterical symptoms have appeared under the pressure of a major crisis, explanatory and supportive psychotherapy appears to be helpful, and the patients have been able to resume their roles in life and work. Acute symptoms can often be mitigated by persuasion and demonstration. One approach is to explain the nature of the illness and point out how common it is and offer support to reverse the main features. Reassurance that recovery is possible and that the patient seems to be in the process of recovering may be useful. It has been suggested that showing the patient objective evidence of the functional nature

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of weakness, such as Hoover sign, is useful demonstrating the correctness of the diagnosis and demonstrating its potential reversibility (Stone and Edwards). The earlier this is done after the development of symptoms, the more likely they are to be relieved. Sometimes a single symptom such as hemiparesis or tremor can be halted by a particular maneuver and this demonstration suffices to begin recovery. In chronically bedridden patients, pressure to get out of bed and resume function can be applied. Several approaches to discussing the symptomatology with the patient have been suggested. At one extreme is a confrontative approach in which the patient is told the symptoms are psychologic, or “in your head.” We have found this to be counterproductive and almost always provokes an angry response that does not aid clinical improvement. At the other extreme is complete avoidance on the part of the physician, an approach that is almost as unproductive. We prefer to ask the patient if the symptoms can in some way be the result of “stress” or an upsetting recent experience. On occasion, in private, we will inquire about childhood sexual abuse and often get an affirmative response from the patient, with later confirmation by a spouse or sibling. Very powerful is nonjudgmental but firm reassurance that there is no serious disease. We have found it useful to list the diseases that have been excluded by examination and testing: brain tumor, stroke, amyotrophic lateral sclerosis, multiple sclerosis, etc. This often evokes an acknowledgment by the patient that one of the diseases had been a preoccupying concern. We then indicate, without using psychologic terms, that the brain may at times adopt certain patterns of behavior that do not reflect structural damage, and, furthermore, that these patterns can be unlearned with physical therapy and time, as described in the following text. That the patient’s response to these conversations varies widely is not surprising. One group seems not to mind and to be relieved by the expression of concern and reassurance that there is no dangerous disease at the root of the problem. They can be sent for physical therapy and may do well in the short run. Another group is indignant and unlikely to consult the physician again; several in the past have refused to pay the doctor’s bill (before the era of insurance coverage) or written critical letters to hospital representatives. Many have objected to the explanation based on their own view, often derived from research on the Internet and with similarly afflicted persons, that Lyme disease, chronic viral infection, environmental toxins, allergies, etc., are to blame. A few of these cases have the flavor of a delusion. All that the physician can offer here is an openness to see and reexamine the patient in several months as “cure” has limited meaning in these instances and there is a high likelihood that such individuals will see a long list of doctors. The success of any of these programs over a long period is unknown. The eradication of recently acquired hysterical symptom is relatively common. The real test is whether it enables the patient to adjust satisfactorily to family and society and to perform daily activities effectively, and whether it prevents addiction, unnecessary medical treatments, and operations. Estimates of the recurrence rate of hysterical symptoms vary widely from 12 to 80 percent. In various series (Gatfield and Guze; Merskey), the recurrence of somatic symptoms of similar or of other types was

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as high as in sociopathies. We have seen a few patients with monosymptomatic hysteria (paraparesis, bizarre gait, crippling dystonia) that persisted for years on end regardless of treatment. The use of a wheelchair for more than several days has been a bad prognostic sign.

Hypochondriasis This is the preoccupation with bodily functions or physical signs and sensations, leading to the fear or belief of having serious disease. Hallmarks of this condition are the failure of repeated examinations to disclose any physical basis for the patient’s symptoms and the failure of reassurance to affect either the patient’s symptoms or his conviction of being sick. It is estimated that 85 percent of hypochondriasis is secondary to other mental disorders, chiefly depression, but also schizophrenia and anxiety neuroses. In approximately 15 percent of cases, however, there appears to be no associated illness (primary hypochondriasis). Most patients in this latter category are habitués of medical outpatient clinics, who are passed from specialist to specialist, perplexing and angering doctors along the way, because their symptoms defy both satisfactory diagnosis and cure. Related to hypochondriasis, but probably delusional are young adults who present with a fixed somatic belief regarding a peculiar symptom such as that the tongue is swollen, the jaw is not properly aligned, or the penis is ulcerated, when in fact no such abnormalities are present. The troubling aspect to the family and physician of such an illness is the persistence of the symptom and disability that extends for years, all tests having been negative. Probably these patients should be treated like schizophrenics, which many of them probably are. What to do with patients who are less severely affected but who have an unshakable belief that they have Lyme disease or environmental “allergies” as mentioned above depends on the context, but the likelihood of dissuasion is almost as poor as for the worst hypochondriac patients. The treatment of primary hypochondriasis is difficult unless the physician keeps in mind the personality of the patient and the therapeutic goals. A psychodynamic outlook would suggest that these patients need to retain their symptoms, so that the usual concept of “curing” is inapplicable. The presence of symptoms provides the context for a relationship with a physician, and it is the continuation of this relationship, which is often the only dependable contact in the patient’s life, which is the motivation for some hypochondriac patients. Such patients are best managed by general physicians who realize that these are patients who do not necessarily want or expect a cure, and who are content with small gains and the avoidance of unnecessary surgery.

SOCIOPATHY Of the abnormal personality types listed in Table 47-1, the antisocial type is the best defined and the one most likely to cause trouble in the family and community. It had been defined (in DSM) as a state in which the individual “is always in trouble, profiting not from experience or

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punishment, unable to empathize with family or friends or to maintain loyalties to any person, group, or code. He is likely to be shallow, callous, and hedonistic, showing marked emotional immaturity with lack of sense of responsibility, lack of judgment, and an ability to rationalize his behavior so that it appears warranted, reasonable and justified.” Since Prichard, in 1835, first described this condition under the term immoral insanity, there have been many attempts to give it a more precise definition and to avoid using it as a psychiatric wastebasket. At the turn of the century, Koch introduced the term psychopathic inferiority, implying that it was a constitutionally determined deviation in personality. Later the term psychopathic personality came into common use. In the past, many authors used this last term indiscriminately to embrace all forms of deviant personality. Subsequently, the term came to be used in a more restricted sense to define a subgroup of antisocial or aggressive psychopaths (antisocial personality disorder). Aubrey Lewis has given a lucid account of the history of the concept of sociopathy. A study of sociopathy based on a 30-year follow-up study of 524 cases from a child guidance clinic and 100 controls concluded that the behavior is intransigent over time (Robins). Investigations of psychiatric illness in large numbers of felons and their first-degree relatives are also instructive and emphasize the complexity of the problem (Cleckley; McCord and McCord; Guze and coworkers). Common to these individuals is unemotional and remorseless behavior. The following material and the preceding quotation are taken largely from these writings and from those of Reid.

Clinical Description This condition, unlike the majority of psychiatric disorders, is manifest by the age of 12 to 15 years, and frequently earlier. The manifestations of sociopathic behavior in children and adults are 5 to 10 times more frequent in males than they are in females. It consists essentially of deviant behavior in which individuals seem driven to cause difficulty in everything they do or behave in a way that most societies identify as grossly criminal. Norms imposed by family, school, religion, and society are broken. Seemingly, the sociopath acts on impulse, but after committing the unsocial act, he shows no remorse. The most frequent antisocial activities are theft, truancy, running away, associating with undesirable characters, indiscriminate sexual relations, repeated fighting, recklessness and impulsivity, lying without cause, vandalism, abuse of drugs and alcohol, and, later, inability to work steadily or keep a job. Criminality is intimately associated. Fire setting and cruelty to animals are particularly associated with future sociopathy according to several authors (the “callous youth” alluded to above). Of children or adolescents who exhibited 10 or more antisocial symptoms, 43 percent were categorized as sociopaths in adulthood (Robins et al). If only 8 or 9 of these traits were present, 29 percent were so grouped; if 6 or 7, 25 percent; and 3 to 5, 15 percent. Conversely, not a single adult sociopath was observed who did not manifest antisocial symptoms in earlier life. Interestingly, a number of other problems of childhood and adolescence—such

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Chapter 47 Anxiety, “Functional” and Personality Disorders

as enuresis, dirty appearance, sleepwalking, irritability, nail biting, oversensitivity, poor eating habits, nervousness, being withdrawn or seclusive, unhappiness, tics, and fears—were not predictive of adult sociopathy. At the same time, it should be noted that more than half the disturbed children in large studies (Robins) had lost most of their sociopathic traits by adulthood. This does not mean that they remained societally normal. Of those who did not become adult sociopaths, the most developed other adult psychiatric illnesses, particularly addiction to alcohol. Only in the group of children with fewer than three antisocial symptoms did a reasonable number (onethird) remain entirely well from a psychiatric point of view in adult life. Because sociopathic behavior in children may terminate spontaneously or evolve into other disorders, it is advised that the diagnosis of antisocial personality disorder be reserved for adults; the same behavior pattern in children is designated as conduct disorder. In most series, a search for evidence of encephalitis, often postulated in the past as the basis of sociopathy, was not revealing, nor was there any proof of other brain damage. In the current era, head trauma is often imputed as the cause of troublesome behavior in adolescents and young adults, but there is no basis for this view. EEG abnormalities, taking the form of mild to moderate bilateral slowing, are more frequent in criminals and sociopaths than they are in the normal population in some series, but the validity of this finding is uncertain. Some findings suggest a genetic predisposition to antisocial personality. In a Danish study of criminals, “inappropriate nonpsychotic impulse-ridden behavior” was found five times more frequently in first-degree biologic relatives than it was in the general population (Christiansen). Criminality was two times more frequent in monozygotic twins than it was in dizygotic twins. Further evidence of a genetic factor was provided in a study of adoptees who were separated at birth from antisocial biologic parents (Cadoret). A higher incidence of antisocial behavior was present in the adoptees than were in controls. Treatment  There is limited information as to the best approaches to treatment and the role of the medical profession has never been clear. Most psychiatrists have been discouraged by the results of psychotherapy, but whether behavioral therapy, psychoanalysis, or drugs have more to offer cannot be determined from available data. Medical efforts should be directed to evaluating the patient’s neurologic status, assessing his intelligence, and explaining the nature of the disorder to parents and social agencies, tasks best performed by a psychiatrist. It seems reasonable to approach minor criminal behavior early in life and to use peer counselling and guidance by organized groups to engage in juvenile delinquency. However, some of the substrate for these behaviors in disadvantaged socioeconomic circumstances is a larger societal problem.

Malingering This problem arises frequently in connection with both functional illness and sociopathy, and the physician should know how to deal with it. The term malingering refers to the conscious and deliberate feigning of illness or disability

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to attain a desired goal. It does not appear as an isolated phenomenon, and its occurrence must be interpreted as a sign of a serious personality disturbance, often one that prevents effective work or military service, as a means of obtaining recompense for an alleged injury, or avoiding the penal system, although noteworthy exceptions to this statement can be found. In the malingerer one may observe pain, hyperesthesia, anesthesia, limping gait, tremor, contracture, paralysis, amaurosis, deafness, stuttering, mutism, amnesia, pseudoconvulsions and fugues, jumping of limbs with touch, and unexplained skin lesions—in short, the same array of symptoms and signs, singly or in combination, as in the patients with functional disorders. Probably the medical profession has placed too great a reliance on degree of conscious awareness of deception. In such unstable and immature individuals, the terms conscious, unconscious, and deception are too uncertain to be useful. A particular form of sociopathy or malingering, which consists essentially of systematically and specifically deceiving the medical profession, has been called Munchausen’s syndrome—named (not altogether aptly) after a 17th-century German soldier, Baron von Munchausen, who invented incredible tales of adventure and daring. In an analysis of 59 cases (45 men, 14 women), the following characteristic features are common, which will be recognized by experienced neurologists: feigned severe illness of a dramatic and emergency nature; factitious evidence of disease, surreptitious interference with diagnostic procedures, or self-mutilation; a history of many hospitalizations (sometimes more than 100); extensive travel or visits to innumerable physicians; and, finally, regular departure from the hospital against medical advice (Ireland and colleagues).

Intermittent Explosive Disorder Designated by this title is an uncommon disorder, the characteristic feature of which is the occurrence of repetitive, unpredictable outbursts of violent, aggressive behavior disproportionate to the provoking situation. This condition needs to be set apart from the uncontrollable outbursts that sometimes are associated with dementia, developmental delay, autism, schizophrenia, drug addiction, alcoholism, or those that follow serious head injuries or other brain diseases. Neurologic opinions have been solicited on our services for patients afflicted with this condition, the question usually being one of seizures as a cause of the aberrant behavior. Some persons with intermittent explosive disorder have, from early childhood, reacted to frustration with a loss of self-control, striking out in blind rage at anyone who crossed them (episodic dyscontrol syndrome); as adults, they may inflict serious injury or kill. Lesser degrees are recognized as expressions of “hot temper.” Sometimes such behavior appears to be a continuation of the temper tantrums of earlier childhood. What is surprising in some of our patients has been a discrepancy between this episodic behavior and a pleasant and concerned, even contrite, demeanor at other times. Such patients are aware of the inappropriate nature of their behavior and its impact on others; they express remorse and may seek medical

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assistance to mute the outbursts. Others, of course, have no such insight and their anger episodes are simply an extension of their sociopathy. The causes of aggressive violence are poorly understood. There appears to be a heritable tendency (Cadoret et al, 1997); males predominate and a sex-linked form extending over several generations has been described. Polymorphisms of the androgen receptor have been implicated in several preliminary studies. In only a very small number of patients, a seizure disorder can be identified, particularly temporal lobe epilepsy, but the majority still appear to be constitutional in nature. A state of adrenergic hyperactivity has been suggested and supported to some extent by these patients’ response to propranolol, but this is not explanatory of the behavior (Elliott; Jenkins and Maruta; also see Chap. 25 discussion of the limbic system). Intense outbursts of anger and physical violence are also infrequent features of the diagnostic category of borderline personality disorder, the other manifestations of which include “a pervasive pattern of instability of mood, interpersonal relationships, and self-image.” Besides propranolol, lithium, carbamazepine, and phenytoin have been found to be helpful in controlling and preventing the explosive attacks in uncontrolled studies. We have noted the recent increased use by psychiatrists of serotonergic antidepressants in these patients but have no way to judge their effect.

ANOREXIA NERVOSA AND BULIMIA Anorexia nervosa is a behavioral disorder of previously healthy girls and young women living in affluent societies, mainly from upper and middle social classes, who become emaciated as a result of voluntary starvation. It is rare in Asian and African American women, and very uncommon in males. Richard Morton first described the condition in 1649, under the title of “nervous phthisis,” a “nervous consumption” resulting from “sadness and anxious cares”—a title that embodied enigmatic roots in psychologic derangements (Herzog and Becker). Bulimia (literally ox-hunger), to which it is closely related, was not identified as an eating disorder until the latter part of the 19th century. As a rule, anorexia nervosa begins shortly after puberty—sometimes later, but seldom after 30 years of age. Some of the patients were overweight in childhood, especially in the prepubertal period. Dieting is much talked about and may have been encouraged. In times when dieting and female thinness are considered normative or desirable, the disorder seems to be more common and lesser but transient forms of the disorder are frequent in high school- and college-age young women. Sometimes there appears to be a precipitating event, such as leaving home, disruption of family life, or other stress. Whatever the provocation, it leads to an obsessive refusal to eat. What is more important, the abnormal eating habits persist even when the patient has become painfully thin, and when counseled to eat normally she will use every artifice to starve herself. Food is hidden instead of being eaten, vomiting may be provoked after a meal, or the bowel may

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be emptied by laxatives. The patient shows no concern about her obvious emaciation and remains active, if not overactive in exercise. If left untreated, these patients may waste away, and approximately 5 percent have succumbed to some intercurrent infection or other medical complication, placing it among the lethal psychiatric conditions. One is struck with the degree of emaciation; it exceeds that of most of the known wasting diseases. Often 30 percent or more of the body weight may have been lost by the time the patient’s family insists on medical consultation. Bradycardia and hypotension are indicators for hospitalization. A fine lanugo covers the face, body, and limbs. The skin is thin and dry, without its normal elasticity, and the nails are brittle. The dental enamel is eroded. Pubic hair and breast tissue (except for loss of fat) are normal, and, in this respect, anorexia nervosa is unlike hypopituitary cachexia (Simmonds disease). Surprisingly, however, there are infrequently neurologic signs of nutritional deficiency. The patient is alert and cheerfully indifferent to her condition. Any suggestion that she is unattractively thin or seriously depleted is rejected. Amenorrhea is practically always present and may precede the extreme weight loss. Luteinizing hormone (LH) concentrations are reduced to pubertal or prepubertal levels. Clomiphene citrate fails to stimulate a rise in LH, as it does normally. Administration of gonadotropicreleasing factor raises the LH and follicle-stimulating hormone (FSH) levels, suggesting a hypothalamic disorder. The basal metabolic rate is low; triiodothyronine (T3) and thyroxine (T4) are low, while levels of physiologically inactive 3,3,5-triiodothyronine (reverse T3) are normal or increased. Plasma thyrotropin (thyroid-stimulating hormone [TSH]) and growth hormone levels are normal. Serum cortisol levels are usually normal; excretion of 17-hydroxysteroids is slightly reduced. In sum, there is evidence of hypothalamic–pituitary dysfunction, but this is probably secondary to starvation (and there are no definite changes in the pituitary gland in fatal cases (Scheithauer and colleagues). These endocrine abnormalities, most of which are probably secondary effects of weight loss have been summarized in various reviews (Becker and colleagues). Brain imaging shows slight to moderate enlargement of the lateral and third ventricles, which return to normal size when the disorder subsides. The etiology of anorexia nervosa is unknown, although there is no lack of hypotheses. A high concordance in monozygotic twins as compared with dizygotic twins has been noted (Holland and coworkers). Earlier signs of hysterical tendencies, obsessional personality traits, and depression are mentioned as being frequent in some series, but not in others. Certain polymorphisms in the serotonin transporter gene, of types different from those that have been tentatively attached to anxiety and to obsessive traits, have also been reported. These findings are difficult to interpret. A functional imaging study has shown activation of the left insula, amygdala, and cingulate when high-calorie drinks were imbibed by anorectic women (Ellison et al), but this conceivably may have reflected anxiety termed calorie fear rather than a specific biologic feature of the disease. Reports concerning the percentage of first-degree relatives of anorectic patients with bipolar disease are

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also inconsistent. An increased prevalence of neurosis or alcoholism has been noted in other members of the family. However, psychiatrists seem to agree that the patient does not have symptoms that conform to any of the major neuroses or psychoses. Certainly, loss of appetite, lack of self-esteem and interest in personal appearance, and self-destructive behavior—common features of anorexia nervosa—are also symptoms of depressive illness, yet most of the patients do not look or admit to being dejected. Moreover, endogenous depression affects both sexes. The pathologic fear of becoming fat and the obsession with weight might be interpreted as a phobic or obsessional neurosis. That anorexia nervosa is practically confined to females must figure in any acceptable explanation of the syndrome. Probably important is that anorexia nervosa has its onset in relation to menarche, at a time when the female exhibits rather large fluctuations in appetite and weight. This has suggested to some an imbalance between the satiety center, believed to lie in the ventromedial hypothalamus, and the feeding center, in the lateral hypothalamus. An association of anorexia with structural disease involving the appetite centers has not been established, although rare cases of acquired anorexia have been attributed to lesions of the lateral hypothalamus (Lewin and colleagues; White and Hain; Martin and Reichlin). A disorder of infants described under “diencephalic syndrome” causes progressive and ultimately fatal emaciation despite normal food intake in an otherwise alert and cheerful infant. The causative lesion has usually proved to be a lowgrade astrocytoma of the anterior hypothalamus or optic nerve region (Burr et al). Also interesting is a case in which profound and long-standing anorexia nervosa resolved after a left thalamic stroke (Dusoir et al). See Chap. 26 for further discussion and references. Treatment  Treatment at the moment consists of winning the patient’s confidence, supportive psychotherapy, assignment of one individual to sit with the patient as each meal is eaten, and a gradual increase of a balanced

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diet (Anderson). Extreme cases require hospitalization. If the patient refuses to eat, tube feeding may be lifesaving. As weight is gained over several weeks, the patient usually becomes more normal in attitude toward eating and will continue to recover on this regimen at home. Menses do not return until considerable weight has been gained (approximately 10 percent above the weight at the time of the menarche). Some of our colleagues report better success with such a regimen when imipramine or fluoxetine has been added; others have found these drugs to be ineffective except in patients with prominent symptoms of depression. The potentially devastating medical complications to which severely anorectic patients are prone and the need to evaluate and treat these problems at the same time that nutritional therapy is undertaken has been emphasized (Becker and colleagues). In particular, an electrocardiogram may disclose a prolonged QT interval—the presence of which contraindicates the use of tricyclic antidepressants and increases the risk of ventricular tachycardia. On average, about half of patients recover completely or almost completely (Steinhausen and Seidel). In the remainder, the outcome is generally unfavorable. They either relapse after an initial period of improvement or remain chronically anorectic. Many patients are said to lapse into a chronic dysfunctional state characterized by a persistent preoccupation with food, weight, dieting, and exercise. It is not generally appreciated that chronic anorexia nervosa significantly shortens life; after a mean follow-up period of 12 years, 11 percent of a group of 84 patients had died (Deter and Herzog), and 15 percent after 20 years (Ratnasuriya et al). Suicide is a contributor to this high mortality rate (Sullivan). The few adolescent boys with this syndrome recovered on antidepressant medication. In general, the therapeutic benefit of medications is considerably greater in cases of bulimia than in anorexia nervosa (Mehler).

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5). Arlington, VA, American Psychiatric Publishing, 2013. Anderson AE: Practical Comprehensive Treatment of Anorexia Nervosa and Bulimia. Baltimore, Johns Hopkins University Press, 1985. Andreasen NC, Black DW: Introductory Textbook of Psychiatry, 3rd ed. Washington, DC, American Psychiatric Press, 2001. Baxter LR: Neuroimaging in obsessive-compulsive disorder: Seeking the mediating neuroanatomy. In: Jenike MA, Baer L, Minichiello WE (eds): Obsessive-Compulsive Disorders: Theory and Management, 2nd ed. Chicago, Mosby-Year Book, 1990, pp 167–188. Beard G: Neurasthenia, or nervous exhaustion. Boston Med Surg J 18:270, 1868. Becker AE, Grinspoon SK, Klibanski A, Herzog DB: Eating disorders. N Engl J Med 340:1092, 1999.

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Berthier ML, Kulisevsky J, Gironell A, et al: Obsessive-compulsive disorder associated with brain lesions: Clinical phenomenology, cognitive function and anatomic correlates. Neurology 47:353, 1996. Briquet P: Traite Clinique et Therapeutique a l’Hysterie. Paris, Ballière, 1859. Burr IM, Slonim AE, Danish RK: Diencephalic syndrome revisited. J Pediatr 88:429, 1976. Cadoret RJ: Psychopathology in adopted-away offspring of biologic parents with antisocial behavior. Arch Gen Psychiatry 35:176, 1978. Cadoret RJ, Leve LD, Devor E: Genetics of aggressive and violent behavior. Psychiatr Clin North Am 20:301, 1997. Carothers JC: Hysteria, psychopathy and the magic word. Mankind Q 16:93, 1975. Carson AJ, Brown R, David AS, et al: Functional (conversion) neurological symptoms: Research since the millennium. J Neurol Neurosurg Psychiat 83:842, 2013.

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Christiansen KO: Crime in a Danish twin population. Acta Genet Med Gemellol (Roma) 19:323, 1970. Cleckley H: The Mask of Sanity. St. Louis, Mosby, 1955. Cloninger CR, Adolfsson R, Svrakic NM: Mapping genes for human personality. Nat Genet 12:3, 1996. Cloninger CR, Reich T, Guze SB: The multifactorial model of disease transmission: III. Familial relationship between sociopathy and hysteria (Briquet’s syndrome). Br J Psychiatry 127:23, 1975. Cohen ME, White PD: Life situations, emotions, and neurocirculatory asthenia (anxiety neurosis, neurasthenia, effort syndrome). Res Publ Assoc Res Nerv Ment Dis 29:832, 1949. Cohen ME, White PD, Johnson RE: Neurocirculatory asthenia, anxiety neurosis or the effort syndrome. Arch Intern Med 81:260, 1948. Couprie W, Wijdicks EFM, Rooijmans HGM, Van Gijn J: Outcome in conversion disorder: A follow-up study. J Neurol Neurosurg Psychiatry 58:750, 1995. Deter H-C, Herzog W: Anorexia nervosa in a long-term perspective: Results of the Heidelberg-Mannheim study. Psychosom Med 56:20, 1994. Dusoir H, Owens C, Forbes RB, et al: Anorexia nervosa remission following left thalamic stroke. J Neurol Neurosurg Psychiatry 76:144, 2005. Elliott FA: Propranolol for the control of belligerent behavior following acute brain damage. Ann Neurol 1:489, 1977. Ellison Z, Foong J, Howard R, et al: Functional anatomy of calorie fear in anorexia nervosa. Lancet 352:1192, 1998. Gatfield PD, Guze SB: Prognosis and differential diagnosis of conversion reactions: A follow-up study. Dis Nerv Syst 23:623, 1962. Gesell A (ed): The First Five Years of Life: A Guide to the Study of the Pre-School Child. New York, Harper & Row, 1940. Ghaffar O, Staines R, Feinstein A: Unexplained neurologic symptoms: An fMRI study of sensory conversion disorder. Neurology 67:2036, 2006. Goodwin DW, Guze SB: Psychiatric Diagnosis, 5th ed. New York, Oxford University Press, 1996. Gunderson JG: Borderline personality disorder. N Engl J Med 364:2037, 2011. Guze SB, Goodwin DW, Crane JB: Criminal recidivism and psychiatric illness. Am J Psychiatry 127:832, 1970. Herzog DB, Becker AE: Eating disorders. In: Nicholi AM (ed): The New Harvard Guide to Psychiatry, 3rd ed. Cambridge, MA, Belknap Harvard University Press, 1999, pp 400–414. Hinson VK, Haren WB: Psychogenic movement disorders. Lancet Neurol 5:695, 2006. Holland AJ, Sicotte N, Treasure J: Anorexia nervosa: Evidence for a genetic basis. J Psychosom Res 32:561, 1988. Ireland P, Sapira JD, Templeton B: Munchausen’s syndrome. Am J Med 43:579, 1967. Jenkins SC, Maruta T: Therapeutic use of propranolol for intermittent explosive disorders. Mayo Clin Proc 62:204, 1987. Jones AB, Llewellyn LJ: Malingering. Philadelphia, Lippincott, 1918. Judd FK, Brurrows GD, Norman TR: The biological basis of anxiety: An overview. J Affect Disord 9:271, 1985. Kandel ER: A new intellectual framework for psychiatry. Am J Psychiatry 155:457, 1998. Keane JR: Hysterical gait disorders: 60 cases. Neurology 39:586, 1989. Kurlan R: Tourette’s syndrome: Current concepts. Neurology 39:1625, 1989. Lazare A: Conversion symptoms. N Engl J Med 305:745, 1981. Lesch K-P, Bengel D, Heils A, et al: Association of anxiety-related traits with polymorphism in the serotonin transporter gene regulatory region. Science 274:1527, 1996.

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Lewin K, Mattingly D, Millis RR: Anorexia nervosa associated with hypothalamic tumour. Br Med J 10:629, 1972. Lewis A: Psychopathic personality: A most elusive category. Psychol Med 4:133, 1974. Lieb K, Zanarini MC, Schmal C, et al: Borderline personality disorder. Lancet 364:453, 2004. Liebowitz MR, Fryer AJ, Goerman JM, et al: Lactate provocation of panic attacks. Arch Gen Psychiatry 41:764, 1984. Mallet L, Polosan M Jaafari N, et al: Subthalamic nucleus stimulation in severe obsessive compulsive disorder. N Engl J Med 359:2121, 2008. Martin JB, Reichlin S: Clinical Neuroendocrinology, 2nd ed. Philadelphia, Davis, 1987. McCord W, McCord J: The Psychopath. Princeton, NJ, Van Nostrand, 1964. Mehler PS: Bulimia nervosa. N Engl J Med 349:875, 2003. Merskey H: The Analysis of Hysteria. London, Ballière Tindall, 1979. Modlin HC: Postaccident anxiety syndrome: Psychosocial aspects. Am J Psychiatry 123:1008, 1967. Nemiah JC: The psychodynamic basis of psychopathology. In: Nicholi AM Jr (ed): The Harvard Guide to Psychiatry. Cambridge, MA, Belknap Harvard University Press, 1999, pp 203–219. Noyes R, Clarkson C, Crowe R, et al: A family study of generalized anxiety disorder. Am J Psychiatry 144:1019, 1987. Purtell JJ, Robins E, Cohen ME: Observations on clinical aspects of hysteria. JAMA 146:902, 1951. Ratnasuriya RH, Eisler I, Szmukler GJ, Russell GFM: Anorexia nervosa: Outcome and prognostic factors after 20 years. Br J Psychiatry 158:495, 1991. Reid W (ed): The Psychopath: A Comprehensive Study of Antisocial Disorders and Behaviors. New York, Brunner-Mazel, 1978. Robins E, Purtell JJ, Cohen ME: Hysteria in men. N Engl J Med 246:677, 1952. Robins LN: Deviant Children Grown Up: A Sociological and Psychiatric Study of Sociopathic Personality. Huntington, NY, Krieger, 1974. Ropper AH, Burrell BD: How the Brain Lost Its Mind. New York, Avery, Penguin Press, 2019. Scheithauer BW, Kovacs KT, Jariwala LK, et al: Anorexia nervosa: An immunohistochemical study of the pituitary gland. Mayo Clin Proc 63:23, 1988. Sharp C: Personality disorders. New Eng J Med 387:916, 2022. Slater B, Shields J: Genetical aspects of anxiety. In: Lader MH (ed): Studies of Anxiety. London, Royal Medico-Psychological Association, 1969, pp 62–71. Spence SA, Crimlisk HL, Cope H, et al: Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement. Lancet 355:1243, 2000. Stein DJ: Obsessive-compulsive disorder. Lancet 360:397, 2002. Steinhausen HC, Seidel R: The Berlin follow-up study of eating disorders in adolescence, Part 2: Intermediate-term catamnesis after 4 years. Nervenarzt 65:26, 1994. Stone J, Carson A, Duncan R, et al: Symptoms “unexplained by organic disease” in 1144 new neurology out-patients: How often does the diagnosis change at follow-up? Brain. 132:2878, 2009. Stone J, Edwards M: Trick or treat? Showing patients with functional (psychogenic) motor symptoms their physical signs. Neurology 79:282, 2013a. Stone J, Reuber M, Carson A: Functional symptoms in neurology. Pract Neurol 13:104, 2013b. Stone J, Sharpe M, Carson A, et al: Are functional motor and sensory symptoms really more common on the left? A systematic review. J Neurol Neurosurg Psychiatry 73:578, 2002a.

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Chapter 47 Anxiety, “Functional” and Personality Disorders Stone J, Sharpe M, Rothwell PM, et al: The 12-year prognosis of unilateral functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 74:591, 2003. Stone J, Zeman A, Sharpe M: Functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry 73:241, 2002b. Sullivan PE: Mortality in anorexia nervosa. Am J Psychiatry 152:1073, 1995. Terracciano A, Abdel-Khalek AM, Ádám N, et al: National character does not reflect mean personality trait levels in 49 cultures. Science 310:96, 2005. Tyrer P: New approaches to the diagnosis of psychopathy and personality disorder. J R Soc Med 97:371, 2004.

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Wheeler EO, White PD, Reed EW, Cohen ME: Neurocirculatory asthenia (anxiety neurosis, effort syndrome, neurasthenia): A twenty-year follow-up study of one hundred and seventythree patients. JAMA 142:878, 1950. White LF, Hain RF: Anorexia in association with a destructive lesion of the hypothalamus. Arch Pathol 68:275, 1959. Winokur G, Coryell W: Anxiety disorders: The magnitude of the problem. In: Coryell W, Winokur G (eds): The Clinical Management of Anxiety Disorders. New York, Oxford University Press, 1991, pp 3–9.

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48 Depression and Bipolar Disorder

These disorders are ubiquitous in all societies and cause considerable suffering. These disorders, while manifesting themselves as changes in mental life, are nevertheless clearly mediated by brain function. They assume importance for psychiatrists and neurologists but are embedded in the practices of virtually all branches of medicine.

DEPRESSION Depression is perhaps the cause of more grief and misery than any other single disease to which humankind is subject. This view, expressed by Kline more than 50 years ago, is still shared by almost everyone in the field of mental health and the several forms of depression taken together are the most frequent of all psychiatric illnesses. The term “depression” denotes both a state of being and a more formally defined psychiatric disorder. The Global Burden of Disease Study 2019 affirms this view and estimates that depression is the fourth leading serious illness cause of disability in adolescents and young adults and a major contributor to self-harm and suicide deaths (GBD 2019). In a general hospital, as indicated in the previous chapter, depression accounted for an estimated 50 percent of psychiatric consultations and 12 percent of all admissions. Although depression has been known to physicians for more than 2,000 years (melancholia is described in the writings of Hippocrates), it has been difficult to separate the medical aspects (Kraepelinian concept) from the psychologic reaction (Meyerian concept). In other words, is it basically a biologic derangement or a response to psychosocial stress? A balanced position is that both are correct—that is, there are two basic substrates for depression: exogenous (an apparent cause) and endogenous (with no overt external cause), and that there is an interplay between them and biologic susceptibility to either one. The boundaries between a biological disease and the medicalization of everyday life are therefore blurred. However, clinical and physiological states of depression that do not accord with external circumstances, when prolonged or severe, constitute an illness and recurrent bouts can probably be said to constitute a disease. In respect to endogenous depression and the related condition of bipolar disease, genetic and neurochemical data cited further support the Kraepelinian view of a

disease state. Nevertheless, a lay concept persists, perpetuated by process-oriented psychiatrists, that events in one’s life, either distant or current, underlie all types of depressive illnesses. A potential consequence of this view is the assumption that an inability to deal with these stresses represents a personal failure of sorts, and this, in turn, may inhibit the acceptance of psychiatric help. It is in this subject of depression that the interplay between our ongoing internal conversation and brain states meets. As noted further on, the difficulties of daily life can entrain the circuits that correspond to depressive feeling and affect. Seeking causality in either direction is complicated and self-referential; for example, functional imaging that purports to show patterns of depression may be the brain representation of that activity and not its genesis. Of considerable consequence for clinical work, depressive states are often associated with obscure physical symptoms. For this reason, these manifestations of depression are likely to come first to the attention of general physicians. All fields of medical specialty, however, have depressive equivalents; the physical symptoms of depression may be mistakenly attributed to conditions such as anemia, low or high blood pressure, hypothyroidism, migraine, tension headaches, chronic pain syndrome, or chronic infection. Neurologists are most likely to encounter depressed patients who complain of fatigue and weakness, chronic headache, pain, and difficulty in thinking or remembering. In 249 “manic-depressive” patients, who were mainly depressed, compared to 50 hospitalized patients who had systemic medical diseases, the depressed patients had higher rates of headache, tinnitus, blurred vision, chest pain, palpitations, and a long list of other physical symptoms than the medically sick patients (Cassidy et al). Depression masquerading as chronic pain, fatigue, or some other medical condition had been called masked depression or depressive equivalent, terms we still find useful in explaining certain symptoms to patients. There are numerous reasons for separating the problem of endogenous depression from bipolar disease, defined as a life history of both mania and depressive episodes, but the distinction clinically may be difficult because the bipolar disease may be dominated by depressions, with manic or hypomanic episodes appearing as only a minor or infrequent problem. Foremost among the reasons to consider them separately are differences that

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have been highlighted in response to treatment. In keeping with modern notions, endogenous depression and bipolar disorder are presented separately in this chapter, but an understanding of either one is incomplete without knowledge of the other. Another important reason why physicians should be aware of depressive illness in all its forms is the danger of suicide, which may be attempted and successfully accomplished before the depression is recognized. Timely diagnosis may prevent such a tragedy—one that is all the more regrettable as some depressive illnesses can be successfully treated. As remarked in Chap. 23, the term depression embraces more than a feeling of sadness and unhappiness. It stands for a complex of disturbed feelings (mood or affective disorder)—which may include despair, hopelessness, sense of worthlessness, and thoughts of self-harm—associated with decreased energy and libido, loss of interest in personal affairs, impaired concentration, various abnormalities of behavior and appearance, and sometimes, prominent physical complaints. The most important of these include anxiety, insomnia, anorexia or overeating, headache, and various types of regional pain. At one extreme are depressive symptoms of psychotic proportions that incorporate paranoid or somatic delusions, which create chaos in the lives of patients and those close to them. At the other extreme are the common feelings of unhappiness, anhedonia (loss of pleasurable responses), discouragement, and resentment that may occur in almost everyone as a reaction to the disappointments of everyday life, such as loss of employment, failure to gain recognition, or unsuccessful social adjustment. The place in this nosology of the special case of postpartum depression has not been clear, and it is discussed in this chapter as well in the next one, as it is sometimes difficult to differentiate it from postpartum psychosis, a more dramatic and well-defined disorder. Some authors question the primacy of a primary biologic entity that is tied to the postpartum period (Brockington), but this diverges markedly from the general experience, in which varying degrees of depression are quite common in the weeks after delivery and cannot simply be attributed to psychosocial factors or sleep deprivation. As a purely phenomenological observation, an abnormally elevated mood, or mania, is about one-third as frequent as depression. It may develop as a relatively pure, recurrent clinical state, or, more often, may alternate or be intertwined with depression, in which case it was referred to as manic-depressive disease (now, bipolar disorder in the classification of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association). Hypomania and cyclothymic disorder have been the names given to milder forms of mania and bipolar disorder, respectively. The DSM classifications acknowledge the existence of a mixed schizoaffective state in which attributes of depression and schizophrenia are combined. Distinguishing these various types of depressive illnesses is of therapeutic as well as theoretical importance insofar as a particular type may respond better to one form of treatment than to another. Finally, the neurologist should bear in mind the possibility of an incipient dementia presenting

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as a depression, although the reverse, a masked depression causing difficulty with thinking and memory (pseudodementia) is more common in general practice.

Reactive Depressions and Depressions With Medical and Neurologic Diseases Patients reacting to a medical or neurologic illness seldom express feelings of sadness or despair without mentioning physical accompaniments such as easy fatigability, anxiety, headaches, dizziness, loss of appetite, reduced interest in life and love, trouble in falling asleep, or premature awakening. It follows that whenever these symptoms become manifest in the course of medical disease, they should arouse suspicion of a depressive reaction (Table 48-1). Chronic pain is a frequent somatic manifestation of depression. The pain may be based on an attendant disease but is prolonged, disabling, sometimes vague in nature, and recalcitrant to straightforward medical and surgical approaches. Furthermore, a depressed mood exacerbates and prolongs the pain of any type. All patients with chronic pain syndromes should be evaluated psychiatrically, as pointed out in Chap. 7.

Table 48-1 DEPRESSION SECONDARY TO NEUROLOGIC, MEDICAL, AND SURGICAL DISEASES AND DRUGS 1. Neurologic diseases a. Neuronal degenerations—Alzheimer, Huntington, frontotemporal dementia, Lewy-body disease, Parkinson disease, and multiple system atrophy b. Focal CNS disease—strokes, brain tumors, trauma, multiple sclerosis 2. Metabolic and endocrine diseases a. Corticosteroids, excess or withdrawal b. Hypothyroidism, rarely thyrotoxicosis c. Cushing syndrome d. Addison disease e. Pernicious anemia (vitamin B12 deficiency) 3. Myocardial infarction, open heart surgery, and other operations 4. Infectious diseases a. Brucellosis b. Viral hepatitis, influenza, pneumonia c. Infectious mononucleosis d. Whipple disease e. Creutzfeldt-Jakob disease 5. Cancer, particularly pancreatic and metastatic 6. Parturition 7. Medications a. Corticosteroids and ACTH b. Interferons c. Analgesics and anti-inflammatory agents (other than steroids)—indomethacin, phenacetin d. Certain antiseizure drugs e. Antibiotics, particularly cycloserine, ethionamide, griseofulvin, isoniazid, nalidixic acid, and sulfonamide f. Antihypertensive drugs—clonidine, propranolol (and certain other beta-adrenergic blockers) g. Cardiac drugs—digitalis, procainamide h. Disulfiram i. l-Dopa j. Methysergide k. Oral contraceptives 8. Alcoholism ACTH, adrenocorticotropic hormone; CNS, central nervous system.

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In several major medical illnesses, depressive symptoms occur with such frequency as to become almost part of the disease. Contrariwise, in certain chronic and occult diseases, symptoms econdary such as lassitude and fatigue may resemble and be mistaken for a depressive reaction. Hypothyroidism, infectious mononucleosis, hepatitis, lymphoma, myeloma, metastatic carcinoma, malnutrition, polymyalgia rheumatica, and frontal lobe tumors, especially frontal meningiomas, may simulate depression for weeks or months before the medical diagnosis becomes evident. A special relationship to occult pancreatic or other abdominal cancers has been suggested over the years, but it is difficult to understand. Sedative drugs, beta-adrenergic blocking agents, beta-interferons for the treatment of multiple sclerosis and hepatitis, and phenothiazines may also evoke a depressive reaction; corticosteroids can induce a peculiar psychiatric state in which confusion, insomnia, and either an elevation of mood or depression are combined, even to the point of psychosis. A depressed mood may also emerge during the tapering-off period of corticosteroid medication (a hypomanic state is more common in our experience during active use). In neurologic practice, there has been increased awareness of depression associated with the use of antiseizure medications, for example, levetiracetam. Of particular significance is the reactive depression that occurs on learning of a serious medical or neurologic disease. Often such an emotional reaction, which the physician may tend to ignore, is the dominant manifestation of a disease that threatens the life pattern and independence of the patient. Recognition by the patient that he has suffered a stroke or that he has cancer, multiple sclerosis, amyotrophic lateral sclerosis, or Parkinson disease is almost always followed by some degree of reactive depression, often with an element of anxiety. A prime example is depression that follows myocardial infarction (Wishnie et al). Usually, it begins toward the end of the patient’s stay in the hospital and attracts little attention. Once the patient is home, fatigability that approaches exhaustion may be the main complaint and interfere with accustomed activities and rehabilitation. It may be described as weakness and falsely attributed to heart failure. Symptoms of irritability, anxiety, and despondency are next in order of frequency, followed by insomnia and feelings of aimlessness and boredom. Although most of these patients ultimately recover without medical assistance, depression exacts a high toll in terms of mental suffering and some surveys suggest a relation of depression to poorer cardiovascular outcomes.

Depression Following Stroke and With Degenerative Neurologic Disease An analogous depressive reaction occurs in some patients after stroke. Some, but not all, studies have indicated that patients with left anterior cerebral lesions, involving predominantly the lateral frontal cortex or basal ganglia, have a greater frequency and severity of depression than do patients with lesions in other locations (Starkstein et al, 1987; Robinson). Lesions of the right hemisphere have not shown this correlation with depression but have a higher association with pathologic cheerfulness or mania, although these phenomena are rare. However, a British community-based study of stroke survivors failed to confirm these findings, perhaps because the infarcts

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were small in size (more than half the patients had never been admitted to hospital) and many patients were examined for the first time only at 6 and 12 months after their strokes (House and colleagues). The occurrence of psychotic depression with hallucinations and delusions has been reported in patients with right temporoparietal infarcts (Levine and Finkelstein). Our experience suggests an unsurprising relationship between the degree of motor and language disability and the severity of poststroke depression but a less predictable relationship to the location of the lesion. The possible predisposing effects of minor previous episodes of depression, family history of depressive illness, and medications have not been studied systematically. These issues are also incorporated into Chap. 33 on Cerebrovascular Disease. With regard to emotional reactions in degenerative brain diseases, Parkinson disease is complicated by a depressive reaction in approximately one-quarter of cases. Weakness and fatigability, already aspects of the motor syndrome, are added to the principal psychologic manifestations and the resulting therapeutic problem becomes formidable. Another hazard in Parkinson’s and in Lewy-body disease is the tendency for l-dopa itself to provoke a depression in a limited number of patients, sometimes with suicidal tendencies, paranoid ideation, and psychotic episodes. (The state of acute anxiety, sometimes extreme, that accompanies off periods in Parkinson’s disease is a well-known but separate phenomenon.) Huntington chorea is quite often associated with depression, even before the movement disorder and dementia become conspicuous. In one series, 10 of 101 patients with Huntington disease either committed suicide or attempted it, and this outcome is commented on in almost all large series of that disease. Alzheimer disease may be accompanied by depressive symptoms, in which instance, it is difficult or impossible early in the illness to evaluate the relative contributions of the mood disorder and dementia. In later stages, the overt signs of depression usually abate, even though various behaviors in the late stages of the disease are often imputed to depression.

Depression During and after Pregnancy The main risk for depression during pregnancy is a history of previous depressions. Certain epidemiologic factors also come into play, including a family history of depression, single motherhood, cigarette smoking, low income, youth, and domestic violence. The implications, however, of depression during pregnancy are great in that the fetus and neonate are at risk of suffering due to inadequate prenatal and postnatal care and there is an increased rate of miscarriage. Several pieces of controversial evidence suggest that maternal depression may affect fetal growth and infant temperament. Furthermore, postpartum depression is also more common in women with prenatal depression and may lead to similar difficulties with infant care. Postpartum depression is formally defined as a major depressive episode within 4 weeks of delivery, but this interval seems arbitrary. A distinction has been made between postpartum depression and mild depressive symptoms, which are common after delivery, but this also seems somewhat arbitrary. Estimates of this disorder are in the range of 10 percent of women after pregnancy, perhaps higher in low-income areas. The symptoms are generally

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Chapter 48 Depression and Bipolar Disorder

as expected for depression, including anxiety, irritability, and insomnia, and may blend into various preoccupations or suicidal ideation or worry about causing harm to the baby. Risk factors for postpartum depression include a history of mood disorders and depression during previous pregnancies. The theories for causation are not satisfactory and revolve around rapid declines in hormones. Most authorities recognize environmental factors as contributors in some cases as well. Most cases resolve, with or without treatment, but up to one-fifth of women may remain depressed for a year or longer (Stewart). Because of the potential seriousness of this disorder, screening by obstetricians and general practitioners has been emphasized and formal sales have been developed. As of the mid to earlier, there may be some crossover with postpartum psychosis, in which women become delusional, confused, and have disorganized thinking that may accompany either depressed or elevated mood. The treatment of depression during pregnancy has attracted considerable attention because of the potential risks to the fetus of the class of serotonin reuptake inhibitors (SSRIs). This is discussed in a later section. Treatment of postpartum depression includes psychological interventions for milder cases and serotonin reuptake inhibitor antidepressant medications in more severe cases if the disorder does not resolve. Newer steroid-like agents are being explored for treatment.

Clinical Presentation of Depression Fully developed endogenous depression may evolve within a few days, or more often, it emerges gradually, on a background of vague prodromal symptoms that had been present for months. Chapter 23 provides a detailed description of the symptoms and signs of depression. Here it need only be repeated that the patient expresses feelings of sadness, unhappiness, discouragement, hopelessness, and despondency, with a loss of self-esteem. Reduced energy and activity, typically expressed as mental and physical exhaustion, is almost always present to the point of catatonia in the most severe cases. As emphasized in Chap. 23, the most common cause in general practice of symptoms relating to reduced psychic and physical energy and drive (conation) is depression. There is usually heightened irritability, most often reported by a spouse or friends, as well as a lack of interest in activities that formerly were pleasurable. According to DSM, an abstract of the essential diagnostic criteria of endogenous depression (“major depressive syndrome”) consists of a (1) depressed-dysphoric mood nearly every day, (2) loss of interest or pleasure in all usual activities (including sexual activity) in combination with (3) disturbance of appetite and loss of weight; (4) insomnia or hypersomnia; (5) psychomotor retardation or agitation; (6) decreased energy and fatigue; (7) self-reproach, feelings of worthlessness or guilt; (8) indecisiveness, complaints of memory loss and difficulty in concentrating; and (9) thoughts of death or suicide or actual suicide attempts. In recent versions of DSM criteria (5th edition), five or more features are required, in contrast to the previous version, which required four items, and that the state should represent a departure from the previous functioning. This is a useful listing but simply recapitulates the

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Table 48-2 DIAGNOSTIC CRITERIA FOR MAJOR DEPRESSIVE EPISODE ADAPTED FROM DSMa Five more of the following symptoms are required during the same 2-week period with at least 1 of the first 2 included: Depressed mood most of the day, nearly everyday Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly everyday Significant weight loss without diet, or weight gain of more than 5% of body weight in a month, or decrease or increase in appetite nearly everyday Insomnia or hypersomnia nearly everyday Psychomotor agitation or retardation nearly everyday Fatigue or loss of energy nearly everyday Feelings of worthlessness or excessive or inappropriate guilt nearly everyday Diminished ability to think or concentrate or indecisiveness nearly everyday Recurrent thoughts of death, recurrent suicidal ideas without a specific plan, or suicide attempt or specific plan for committing suicide a

Appropriate exclusions are made for manic episodes that would mark the illness as bipolar, and special forms of depression due to grief, significant personal or social distress, and drugs or toxic substances are discussed in the text. Source: From the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5). Washington, DC, APA, 2013.

well-described emotional, conative, and physical aspects of endogenous depression. Several formalized diagnostic criteria have been devised for both screening and diagnosis of major depression (Table 48-2). These codify the clinical features discussed in previous paragraphs but separate major depression from bipolar disorder by requiring the absence of elements that suggest a manic or hypomanic episode and further exclude depression that is plausibly connected to personal distress or grieving due to a loss or the effects of a drug or toxic substance. The U.S. Preventive Services Taskforce Joint has recommended depression screening for all adult patients in primary care settings, and the Joint Commission has recommended screening for suicidal ideation. The depressed patient tends to move slowly; sighing is frequent, and speech is reduced. The mental life of such an individual may narrow to a single-minded concern about physical or mental health. In dialogue, the patient’s responses become so stereotyped that the listener can soon predict exactly what is going to be said. There is a poverty of ideation and sometimes a notable absence of insight. Consciousness is clear, and although there is no evidence of a schizophrenic type of thought disorder, delusional ideas, and less often hallucinations, may be prominent in some patients, justifying the term depressive psychosis. The delusions are generally congruent with the patient’s mood and are not as fixed or bizarre as those of schizophrenia or paranoia. In our experience, delusions are more common in older patients and tend to appear only after weeks or months of more typical symptoms of depression. Common ones in experience with our patients have been gas poisoning in the house, unaccustomed suspiciousness, alleged home break-ins, having inadequate money, or being stolen from or cheated. (Some of these arise in early dementia as well.) Hallucinations, when they occur, are usually transitory,

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vocal, and only vaguely accusatory; their presence should raise the possibility of an associated structural brain disease, drug intoxication, or alcoholic auditory hallucinosis. Frequently, agitation or irritability rather than physical inactivity and mental slowness are the principal behavioral abnormalities. The source of the agitation appears usually to be related to an underlying anxiety state. Pacing the floor and wringing the hands, particularly in the early morning hours, are characteristic. Such patients tend to be overly talkative and vexed in their manner of expression, irritable, shorttempered, impatient, and intolerant of minor problems— changes noted mainly by family members. Attempts at reassurance may meet with initial success, only to be dispelled in the next rush of doubts. These patients remain impervious to reason and logic with respect to their symptoms, even though they are reasonable and logical in other areas of their lives. At its worst, the illness takes the form of a depressive stupor; the patient becomes mute, indifferent to nutritional needs, and neglectful even of bowel and bladder functions (anergic depression). The condition in this extreme form is catatonic depression. Such patients must be fed and their other needs attended to until therapy (usually electroconvulsive therapy [ECT]) brings about improvement. The immediate concern in patients with mid- and latelife major depression is the potential for suicide, a topic addressed again further on. Because many of these individuals have reputations for being sound, dependable, and stable and may deny being depressed, one’s inclination is to doubt the possibility of self-destruction. Such patients should nonetheless be questioned forthrightly on this subject: Have there been thoughts of suicide? Do they feel that life is not worthwhile? Do they think themselves capable of committing suicide? Have they made such plans or made suicide attempts before? Is there a family history of suicide? Do they own a firearm? Are they fearful of dying? Do they have a strongly held religious view that proscribes suicide? These questions relate to features that have been shown to put depressed individuals at risk (or less risk) of suicide, but none are infallible guides to the risk of suicide. If, from their answers, they are judged to carry an imminent risk of suicide, they should be directed to a psychiatrist and generally admitted to a hospital. In recent years, it has come to be appreciated that the elderly are increasingly prone to suicide and that older white men have the highest rates of completed suicides (mainly with firearms). In some depressions, hypochondriacal preoccupation with bowel and digestive functions accounts for repeated visits to the physician. Persistent insomnia may be the major complaint of depressed patients. Early awakening is typical, and the morning hours are then the worst period of the day for the low emotional state. Other patients have difficulty falling asleep, especially if there is an associated anxiety state. A complaint in the male of loss of libido and erectile dysfunction is another monosymptomatic presentation; only with probing inquiry about other disturbances common to depression will the diagnosis become evident. Adherence to the aforementioned or similar diagnostic criteria (see Table 48-1) undoubtedly facilitates diagnosis, but not infrequently, a single one of these symptoms so dominates the clinical picture as to suggest the diagnosis

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of another disease state and obscure the presence of an underlying depression. As mentioned earlier, depressed patients who are referred to the neurologist tend to complain inordinately of physical and cognitive symptoms and to minimize or deny the emotional ones. Complaints of fatigue, weakness, malaise, or widespread aches and pains, for example, suggest a variety of medical diseases, such as anemia, Addison disease, hypothyroidism, chronic infection, polymyositis, or early rheumatoid arthritis. Quite often, the fatigue state is misinterpreted as muscular weakness, and this directs a medical search for neuromuscular disease. Similarly, complaints of persistent headache may suggest the presence of intracranial disease. Complaints of poor memory, inability to concentrate, and other cognitive impairments raise the question of dementia until it is found, by careful examination, that mental competence belies the patient’s appraisal of his own defects. Several psychologic scales are used to score the severity of depression, mainly for the purposes of clinical trials. They can also be helpful in clinical work as they are sensitive to one or another aspect of depression, but they do not supplant the clinical examination in determining if an individual is depressed or suicidal. They may be helpful in differentiating depression from dementia and in detecting depression in cases where physical complaints are more prominent than psychic ones. The tests most familiar to neurologists are the Hamilton and the Beck scales, but others have been validated and widely used.

BIPOLAR DISEASE AND MANIA Bipolar disease is a disorder of mood consisting of prolonged episodes of depression interrupted by or coexistent with episodes of mania. It was given the name manic-depressive disease by Kraepelin in 1896, and it was with him that our current clinical concept of this disorder originated. He viewed the manic and depressive attacks as opposite poles of the same underlying process and pointed out that, unlike dementia praecox (the prevalent name at the time, given by Pick, for schizophrenia), bipolar psychosis entails no intellectual deterioration. A traditional view of bipolar disease was that of a periodic or cyclic condition in which one major mood swing was followed by an equal but opposite excursion. This is seldom the case, however. Episodes of depression are more than twice as frequent as manic ones, and according to current experts, the most common form of the illness is characterized by episodic depression alone with many patients having several episodes of depression before their first period of mania. Recurrence of episodes of pure mania without interspersed episodes of depression is known to occur but is relatively less common. As a consequence, bipolar psychosis has currently been divided into two subtypes, one characterized predominantly by manic episodes, often with delusions or hallucinations (bipolar I), and another in the form of mainly episodes of depression interspersed with hypomania rather than overt mania (bipolar II). The bipolar I variety occurs in approximately 10 percent of patients with affective disorder. The biologic accuracy of

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this classification has not been critically determined and the older classification of unipolar versus bipolar (encompassing both types of cycling depression with mania) is, at times, easier to understand. In addition, there are mixed affective states, in which symptoms of both depression and mania occur within a single episode of the illness. A so-called rapid-cycling form of bipolar disease has also been recognized in which four or more circumscribed cycles of manias and depression occur in a year. Like other variants of the disease, it tends to have an aberrant or unpredictable response to medication. Still, other patients with affective elements of depression present with atypical features; for example, instead of anorexia, weight loss, and insomnia, they sleep and eat excessively. The prevalence of bipolar disease cannot be stated with precision, mainly because of varying criteria used for diagnosis. Certainly, depression and depressive episodes are ubiquitous and mania is less common. The apparent increase of the disease in the past 50 years probably reflects a growing awareness of the condition among both physicians and the laity. Studies of large groups of patients from relatively isolated areas of Iceland and the Danish islands of Bornholm and Samsø indicated that 5 percent of men and 9 percent of women developed symptoms of major depression, mania, or both at some time during their lives (Goodwin and Guze). Other studies, such as the one conducted by the National Comorbidity Survey, report lifetime prevalence for bipolar disorder in the United States as 4.5 percent (Merikangas et al). According to the Global Burden of Disease Study, the incidence of bipolar disease increased by about 50 percent between 1990 and 2013, but it is still considered rare by comparison to depression and to other medical diseases (Ferrari). Bipolar disease begins most frequently in early and middle adult years, with a peak age of onset stated to be around the age of 20 for both sexes. However, a significant proportion of patients experience the first attack in childhood, adolescence, or late adult life. A study of 997 persons older than age 65 years in North Carolina found symptoms of a major depressive illness in 3.7 percent (Blazer and Williams). The disease was two or three times more frequent among women. There is no known explanation for this sex difference, but some have speculated that just as many men are depressed, only they deny it or turn to alcohol. Patients in the bipolar group have an earlier age of onset, more frequent and shorter cycles of illness, and a greater prevalence of affective disorder among their relatives than do patients with unipolar depression (Winokur).

Clinical Presentation The manic state is in many ways the opposite of the depressed state, being characterized by a euphoric flight of ideas, motor and speech hyperactivity, and an increased appetite and sex urge. When such a state is fully developed, it qualifies as a psychosis. After a minimum of sleep, the patient awakes with enthusiasm and expectation. The manic individual appears to possess great drive and confidence yet lacks the ability to carry out plans. Often headstrong, impulsive, socially intrusive behavior is

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characteristic. Judgment may be so impaired that reckless investments are made; fortunes are spent in gambling or on extravagant shopping sprees. Setbacks do not perturb the patient but rather act as goads to new activities. Euphoria and expansiveness sometimes bubble over into delusions of power and grandeur, which, in turn, may make the patient offensively aggressive. Up to a point, the patient’s mirth and good spirits may be contagious, and others may join in; however, if the patient is thwarted, the warmth and good humor can suddenly change to anger. Irritability rather than elation may become the prevailing mood. The threshold for paranoid thinking is low, which makes the patient sensitive and suspicious. Personal neglect may reach the point of dishevelment and poor hygiene. In its most advanced form, a condition formerly described as “delirious mania,” the patient becomes totally incoherent and altogether disorganized in behavior. Such were the descriptions in some of the great literature of the 19th and early 20th centuries depicting the mania of neurosyphilis. At this stage, visual and auditory hallucinations and paranoid delusions may be rampant. Hypomania describes a milder degree of the disorder, but this term is also used loosely to depict behavior in a normally functioning individual who is unusually energetic and active. In this latter sense, hypomania is a personality trait found in some talented and productive persons and need not arouse concern unless it is excessive and out of character for the individual. A number of highly creative individuals have had bipolar disorders (Belmaker), but full-blown mania is uniformly destructive of careers and personal relationships. Such individuals are actually more creative when treated with appropriate medications. Even though many authors, such as Thomas Mann in his character of Adrian Leverkühn in Doctor Faustus, romanticized a link between madness and creativity, the linkage, in reality, goes only so far. First attacks of either depression or mania last an average of 6 months if untreated, although the duration varies greatly. With treatment, this can be reduced, according to some trials, by more than half in many patients. Although most episodes of bipolar disease subside in a matter of months, a significant number, remain chronic for longer periods. According to Winokur and colleagues, 14 percent of their bipolar patients had not recovered after 2 years, and 5 percent had not recovered after 5 years. Comparative figures for primary unipolar patients were 19 and 12 percent, respectively. Most depressed patients have one or more recurrences. Variables that are predictive of an unfavorable outcome are high degrees of anxiety, strongly positive family history of a similar psychiatric illness, and the presence of depression-provoking circumstances (Hirschfeld et al). Perhaps most important is the duration of illness before treatment, that is, earlier treatment is generally associated with a more favorable prognosis. Mania presenting as an encephalopathy The manic patient may be disoriented and slightly agitated, with a clouded sensorium. This extreme is not frequently encountered, but we have several times admitted patients to the neurology service with mania that presented in a manner suggesting an encephalopathy and global confusional state. The patient conducted himself pleasantly, without

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psychosis, pressured speech, or overactive motor behavior but with an inattentive, confusion as the dominant feature. Conditions such as herpes encephalitis, alcohol or drug withdrawal, stroke, and paraneoplastic encephalitis were considered until the patient began filling notebooks with writing, manifesting insomnia, and making connections between ideas and events that were individually valid but just outside the realm of likelihood. One patient insisted that one of us was also his wife’s cardiologist and another that one of the authors had scored a winning touchdown at a college football game at which he was present. Stories about public figures were factually correct but attached to the wrong person. The patient sat near the door to his hospital room and incessantly but pleasantly attracted our attention to speak to him every time one of us was in sight. At the same time, performance on orientation, arithmetic, and language tasks was normal.

ETIOLOGY OF DEPRESSION AND BIPOLAR DISEASE The following are the main theories, not mutually exclusive, that have been proposed to explain the origin of depression; for a detailed review of the subject, the reader is referred to the review by Belmaker and Agam.

Genetic Factors The capacity to experience sadness and depression is common to all people, but there is no question that some individuals are more liable to depression than others who are subjected to similar psychosocial forces. It has been estimated, using various genetic techniques, that as much as 40 percent of the risk of depression is heritable (lower than for schizophrenia and bipolar disease; in the latter, it has been estimated to be from 70 to 90 percent). Adopted children whose biologic parents had affective disorder are at greater risk of developing this disease than adoptees whose biologic parents were not affected (Mendlewicz and Rainer; Cadoret). The frequency of these illnesses is greatly increased in the relatives of affected patients (prevalence rate of 14 to 25 percent in first-degree relatives). Similarly, the risk of depression among first-degree relatives is increased (15 percent, in comparison to 1 to 2 percent risk in the general population). If several twin studies are taken together, 72 percent of monozygotic twins are concordant for bipolar disease, compared with 14 percent of same-sex dizygotic twins; comparative figures for unipolar disease are 40 percent and 11 percent, respectively (see Goodwin and Guze). All of these findings indicate a strong genetic factor. Genome-wide association studies have identified about three dozen loci that are seemingly associated with bipolar disease, but together they probably account for less than one-quarter of the overall heritability. One indication that specific genes may alter the susceptibility to depression has been allelic variations in the serotonin transporter gene (the main target of the selective serotonin antidepressants) that have been associated with a sevenfold increased risk of major depression (Ogilvie and colleagues). Not all studies agree on these points, and

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the complexity of interaction with genetic factors and the environment is demonstrated by a variant in the serotonin transporter that correlates with an increase in depression in response to stress (Caspi et al). Other hypotheses have postulated various susceptibility loci, but again, a single gene locus seems unlikely (see Sanders et al).

Anatomic Correlates Several lines of study, including those employing functional and network imaging, indicate that a few regions of the brain are implicated in the pathogenesis of the complex symptomatology of depression (Drevets). Hypometabolism in the left frontal cortex is among the most consistent findings. Also prominent in many studies are metabolic changes in the cingulate and orbitofrontal cortices, related parts of the medial limbic system, and the hippocampus. As with all functional imaging studies, it is difficult to know if the observed changes are the cause or simply the representation of activity that corresponds to the depressive state. An intriguing observation, and one that does not entirely accord with the above, has been observed during deep brain stimulation for the treatment of Parkinson disease (Bejjani and colleagues). A patient displayed transient but dramatic manifestations of depression only when high-frequency stimulation was delivered to the left substantia nigra. Positron emission tomography imaging during stimulation showed activation in the left orbitofrontal cortex and, less consistently, in the left amygdala, globus pallidus, thalamus, and right parietal lobe. In two other cases with no prior psychiatric symptoms, deep brain stimulation of the subthalamic nucleus induced a reversible manic state (Herzog et al; Kulisevsky et al). A hypomanic episode has been noted in the early stages of herpes encephalitis (Fisher), and numerous cases of temporary secondary mania have been reported after stroke and after brain trauma, the latter most often affecting the right temporal lobe. It is likely that the structures implicated in these cases are part of a larger and widely distributed network that is activated during depression. The results of network and connectome studies in depression have given interesting but broadly ambiguous results. One such study of focal brain lesions associated with depression found no consistent location but converged on a circuit that involved the dorsolateral prefrontal cortex (Padmanabhan et al). On the histologic level, several studies have shown depletion of, and changes in, the pyramidal neurons of the CA3 region of the hippocampus in both depression and stress, but the meaning of these findings is unclear (Sapolsky). They are referred to later in relation to neurogenesis (the appearance in adults of new neurons) in the temporal lobe and recovery from depression and these ideas which are speculative, are also mentioned in Chaps. 17 and 28. Based in part on observations in this field, a relationship has been suggested between depressive illness and the later development of dementia. Evolving work on alterations in the brain connectome in mania has given varied results but focuses on decreased activity between various brain hubs that are considered “rich” in connectivity and between the hemispheres

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(Collin et al), but these are not easily applicable concepts and will probably change as more investigation is performed.

Biochemical Theories It has been evident for decades that the biogenic monoamines (norepinephrine, serotonin, and dopamine) are in some way involved in the biology of depression. However, most of the neurochemical theories of depression suffer from the weakness that they have been the result of backward reasoning from the effects of antidepressants on various neurotransmitters to putative mechanisms. Following the observations that the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors exerted their effect by increasing norepinephrine and serotonin at central adrenergic receptor sites in the limbic system and hypothalamus and that depression-provoking drugs (such as reserpine) deplete biogenic amines at these sites, it was proposed that naturally occurring depressions might be associated with a deficiency of these substances. Furthermore, depressed patients and their first-degree relatives, as well as healthy individuals, develop a depressed mood after dietary depletion of the monoamine precursor tryptophan, and concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, are reduced in the cerebrospinal fluid during endogenous depression and the levels are elevated in manic states. Some neurochemical imaging studies corroborate these findings and others do not. Along similar lines, 5-hydroxyindoleacetic acid (5-HIAA), a deaminated metabolite of serotonin, is reduced in the cerebrospinal fluid of depressed patients (Carroll et al). Certain of the newer antidepressants act as selective SSRIs and ostensibly produce their salutary effects by increasing the amount of serotonin that is functionally active in the synapse (they also raise the concentrations of norepinephrine). For these reasons, serotonin and its neuronal pathways have also been implicated in the genesis of depression. However, the reader should be reminded that even recently, it was widely held that depletion of norepinephrine fulfilled this role. It is also not yet clear which neurochemical alterations are primary and which modulate other systems. For example, reports suggest that substance P plays an important role in the causation of depression (Kramer et al) and that blockade of substance P receptors has antidepressant effects. Why there is a delay of several weeks in the improvement of depression related to the taking of the various antidepressants is unexplained by any of the neurochemical models. Another set of observations that had captured interest implicates a disorder of hypothalamic–pituitary– adrenal axis function (Schlesser et al). It had been found several decades ago that the parenteral administration of 1 to 2 mg of dexamethasone failed to suppress serum cortisol secretion while the patient was ill with endogenous depression but suppressed this activity after recovery. In reactive depressions, there was a normal suppression of cortisol secretion. At one time, the dexamethasone suppression test was believed to separate the two large groups of depressed patients and to predict the response to drug therapy. However, subsequent studies have shown that the specificity of this test was

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far less than earlier reports had indicated (Amsterdam et al; Insel et al). Accumulated evidence indicates that 50 percent of severely depressed patients do not show suppression of cortisol secretion, and a positive test can be obtained in a significant number of patients with other psychiatric disorders. The failure of dexamethasone suppression had been attributed to hyperactivity in the hypothalamic-pituitary axis and a corresponding increase in secretion of corticotropinreleasing hormone, adrenocorticotropic hormone (ACTH), and glucocorticoids. Elevated levels of glucocorticoids had been theorized to impede neurogenesis in the medial temporal lobe and perhaps to explain or exaggerate the loss of hippocampal neurons demonstrated in some studies of the brains of deceased depressed patients. A proposal that ECT acts by elevating levels of neurotrophic factors is at least consistent with this view and with the hypothesis that one component of recovery from depression is in some way associated with restoration of normal neuronal architecture in regions of the hippocampus and the hypothalamus (Chen et al). Although highly speculative, perhaps some of these changes explain the delay in improvement after the administration of antidepression drugs. At the present time, it must be conceded that there is no reliable biologic test or biomarker, chemical or imaging, for depression. One must resort to clinical analysis not only for diagnosis but also for the differentiation of special types of depressive reactions.

Psychosocial Theories Many experienced psychiatrists emphasize the importance of psychosocial factors in the genesis of depressive illness. Among patients with primary depressive disorders, life events of a stressful nature were found to have occurred more frequently in the months preceding the onset of depression than in matched control groups. This has been equally true of patients with a family history of depression and of those without such a history. Nor do patients with endogenous depression differ in this respect from those with reactive depression. Left unanswered is the question of if and why some individuals are subject to a reactive depression; are they predisposed by psychologic, personality, or genetically transmitted factors of heightened vulnerability to the effects of psychosocial stress? One is tempted to conclude that many depressions attributed to psychosocial stress are contaminating a group of endogenous depressions. Psychiatrists have also failed to find a consistent correlation between depressive illness and personality type or a particular psychodynamic mechanism. The biopsychosocial theories of mental illness have the most appeal in explaining depression, but which elements are operative in any individual are difficult to discern.

TREATMENT Here, a distinction is made between the treatment approaches to depression and to bipolar disorder, including depressive disorders as a component of the latter. The use of medications for depression is now so widespread that all physicians should be familiar with them. It must be

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acknowledged, however, that reports on the magnitude of the effect on depression of these medications have been dominated by a few clinical trials conducted by pharmaceutical companies. Meta-analyses of several large studies on the therapeutic effects of antidepressants suggest that clinical improvement attributable to the drugs themselves occurs in approximately 50 percent of patients; an additional improvement in up to 25 percent is attributable to a placebo effect or, more likely, to the natural course of the disease. The remainder fails to improve in a timely manner or relapse while on medication. The incremental value of certain forms of psychotherapies in tandem with medications is discussed further on. Those untrained in psychiatry would be unwise to undertake the management of bipolar disease or a serious endogenous depression without the advice or assistance of a psychiatrist. On the other hand, if the symptoms are primarily neurologic (e.g., chronic headache, generalized weakness, and fatigability) and if there is a low risk of suicide, it may be appropriate for the experienced neurologist to institute treatment with antidepressant medication.

Antidepressant Medication In the management of bipolar and depressive disease, the main categories of drugs in general use are—the tricyclic antidepressants, the “atypical” or nontricyclic group of compounds, the MAO inhibitors, serotonin agonists (reuptake inhibitors), antipsychotic drugs, antiepileptic drugs, and lithium. The pharmacologic properties and modes of action of these drugs were considered in the context of their side effects in Chap. 41. Additional points of interest are mentioned here. Most psychiatrists currently prefer to begin treatment of patients with depression (not bipolar disease) with one of the functional serotonin agonists (reuptake inhibitors-SSRIs, or others, of a related group of serotonin-norepinephrine reuptake inhibitors. New drugs of similar type are appearing regularly. These drugs have less sedating and anticholinergic effects than the tricyclic antidepressants discussed below and may have a slightly faster onset of effect against depression. Certain side effects, such as loss of libido and erectile dysfunction, occur in a proportion of patients and are difficult to differentiate from the signs of depression. Other side effects occur in a proportion of patients, including insomnia or hypersomnia, weight gain or loss, gastrointestinal upset, increased anxiety as discussed in Chap. 47, blurred vision, and dizziness, among many others (see Chap. 41). The very consequential “serotonin syndrome” that occurs with overdose includes delirium, hypertension, tachycardia, diaphoresis, muscular rigidity, myoclonus, and clonus. The pupils may be dilated. This disorder and its treatment are discussed in Chap. 41. The contentious issues of these drugs inducing mania in undiscovered bipolar disease, precipitating suicide soon after the institution of these medications, and the use of these drugs in children are important ones that can only be addressed here cursorily. The overall rates of suicide among adolescents with depression were decreasing at the time of increasing use of SSRI agents (Ryan). The precipitation of a manic episode by serotonergic antidepressants in some patients with bipolar disorder seems a regular enough occurrence that this risk is no longer a point in question. Also emphasized is an increased risk of

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pulmonary hypertension in the babies of mothers exposed to SSRI during the pregnancy. The tricyclic antidepressants, in general, are equally effective, although an individual patient may have a better response or tolerance to one than to another. These drugs, taken at bedtime, may also be helpful in alleviating insomnia that accompanies depression. The therapeutic effect of tricyclic medication is generally not evident for 2 to 4 weeks after treatment has been initiated, and it is important that this be explained to the patient and family. Common side effects are orthostatic hypotension, dry mouth, constipation, tachycardia, urinary hesitancy or retention (especially in patients with prostatic hypertrophy), tremor, and drowsiness. Closed-angle glaucoma may decompensate. Caution should be exercised in elderly patients with cardiac disorders of all types because of the possibility of causing heart block or arrhythmia. The nontricyclic drugs appear to be as effective as the tricyclic agents in the treatment of depression without the adverse anticholinergic and cardiotoxic effects. If one of the SSRI or tricyclic and related drugs given in full doses for 4 to 6 weeks does not produce the desired effect, or as often happens, the patient is intolerant of the given drug, an alternative group, for example, an MAO inhibitor may be tried. In one of the many new “effectiveness” trials sponsored by the National Institutes of Mental Health, as distinguished from “efficacy” in randomized trials, failure of citalopram to accomplish remission of depression by changing to bupropion, sertraline, or venlafaxine was successful in 25 percent of cases (Rush et al). After discontinuing SSRIs, there a drug-free interval is advised of 1 to 2 weeks before instituting an MAO inhibitor in order not to provoke a serotonin syndrome. Some studies suggest that MAO inhibitors are superior in depression with atypical features such as increased appetite. The most serious risk of MAO inhibitors is hypertensive crisis; consequently, these drugs should be dispensed with caution in patients with hypertension and with cardiovascular or cerebrovascular disease. Patients taking these drugs are advised to avoid foods with a high tyramine content (aged cheese, many pickled foods, chicken liver, beer, wines, yeast extract) as well as medications containing sympathomimetic agents or l-dopa (decongestants, amphetamines, caffeine) and the aforementioned serotonin agonists. The use of the monoamine oxidase inhibitor (MAOI)-B drugs for the treatment of Parkinson disease (see Chap. 38) is also interdicted. Supplementation of antidepressants with antiepileptic medications as a “mood stabilizer” in depression is a popular approach with many psychiatrists. Valproate or gabapentin are often used, but also used are carbamazepine or phenytoin. There are few credible studies by which to judge the value of this strategy, and one randomized trial showed no benefit with respect to recovery of depression in bipolar disease (Sachs et al), but these drugs may provide some additional benefit if only as antianxiety agents. More persuasive are the data suggesting that antiepileptic drugs are useful in treatment of the manic state. Because many depressed patients are responsive to one class of drugs but not to another, the clinician is aided by information regarding which of these drugs has been helpful in past episodes. As mentioned, clinical response to antidepressant drugs is not expected for several weeks. Treatment,

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if successful, is usually continued for 6 to 9 months and combined with psychotherapy. The premature discontinuation of medications is a source of relapse, as demonstrated in a trial that compared maintenance to gradual discontinuation of antidepressants in primary care practices showed that relapse occurred in a higher proportion of patients who stopped medication (Lewis et al). However, the symptoms of antidepressant withdrawal, particularly anxiety, may mimic the symptoms of depression. If nothing else, this points out that discontinuation of antidepressants is best accomplished over many weeks or months. After all these drug manipulations fail, a common approach is to add aripiprazole or bupropion to existing antidepressants (“augmentation”). Approximately 25% of patients will have remission of depression. The side effects of antidepressants are given in tabular form and adapted for Table 48-3. Trials of lithium monotherapy or in combination with a mood stabilizer (often valproate) in bipolar disorder (Carvalho et al), but many of the trials are flawed or have limited generalizability. Also to be kept in mind are the side effects of the drugs used for bipolar disorder and the risks of some of the mood stabilizers in pregnancy.

There has been renewed interest in the guided use of psychedelic drugs, particularly psilocybin preparations, for depression. Randomized trials in very selected groups of patients, including with treatment resistant depression (failure of two to four antidepressants) (Goodwin et al) and a comparison to escitalopram (Carhart-Harris et al) both over only weeks of observation, suggest some benefit. The psychotherapeutic resources required and the inability to account for anticipation bias and unblinding of participants makes the practical application of these provocative observations with psychedelic compounds for depression difficult to gauge. There have also been explorations in major depressive disorder of modulators of GABA-A receptors that have given promising but preliminary results in the shortterm (Gunduz-Bruce et al).

Electroconvulsive Therapy and Transcranial Magnetic Stimulation What used to be called infelicitously “electroshock” therapy continues to be a highly effective treatment for severe endogenous depression or catatonic depression that has been unresponsive to other measures and can be used

Table 48-3 CLASSIFICATION AND SIDE EFFECTS OF ANTIDEPRESSANTS   FUNCTIONAL CLASSIFICATION

SIDE EFFECTS INSOMNIA AND AGITATION

SEDATION

Reuptake Inhibitors Selective serotonin reuptake inhibitors (SSRIs)  Fluoxetine ++ −/+  Paroxetine ++ −/+  Sertraline ++ −/+  Fluvoxamine ++ +  Citalopram ++ −/+  Escitalopram ++ −/+ Nonselective norepinephrine reuptake inhibitors  Desipramine + −/+  Nortriptyline + +  Maprotiline + −/+ Mixed or dual-action reuptake inhibitors   Older agents (TCAs)  Amitriptyline −/+ ++  Dothiepin −/+ ++  Imipramine ++ + Newer agents (non-TCAs)  Venlafaxine ++ −/+  Bupropion ++ −/+  Duloxetine −/+ + MAOIs  Phenelzine ++ +  Tranylcypromine ++ +  Isocarboxazid ++ −/+  Selegiline + −/+ Mixed-Action Newer Agents  Mirtazapine −/+ +++  Nefazodone −/+ ++  Trazodone −/+ +++

HYPOTENSION

ANTICHOLINERGIC EFFECTS

NAUSEA OR GASTROINTESTINAL EFFECTS

SEXUAL DYSFUNCTION

WEIGHT GAIN

−/+ −/+ −/+ −/+ −/+ −/+

−/+ + −/+ −/+ −/+ −/+

++ ++ ++ ++ ++ ++

++ ++ ++ ++ ++ ++

+ + + + + +

++ + +

+ + +

−/+ −/+ −/+

+ + +

+ + ++

++ ++ ++

+++ ++ ++

−/+ −/+ −/+

+ + +

++ ++ ++

−/+ −/+ −/+

−/+ + +

++ + +

++ −/+ −/+

−/+ −/+ −/+

++ ++ ++ +

+ + + +

+ + + +

++ ++ ++ +

+ + ++ +

+ + +

−/+ + −/+

−/+ + +

−/+ −/+ ++

+++ + +

−, none; +, mild; ++, moderate; +++, severe; TCA, tricyclic antidepressant. Source: From The New England Journal of Medicine, Mann JJ, The Medical Management of Depression, 353:1819-1834. Copyright © 2005 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

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to interrupt manic episodes. One of its advantages is the rapidity of onset of effect, making it useful in acute or critical situations of psychiatric disease, but there is little doubt that the treatment has been stigmatized as a result of popular conceptions. In major depressive disorder, rates of response have been estimated to be 60 to 80 percent, and rates of remission, 5 to 60 percent (Tor et al). The technique, if properly supervised, is considered to be safe and a comprehensive informed consent process is used. The risk of death with ECT has been estimated to be 2 per 100,000 treatments and the risk of medical events is extremely low (Kaster et al). The patient is anesthetized by an intravenous injection of a short-acting barbiturate, benzodiazepine, or propofol and is also medicated with a muscle relaxant. In the conventional method, an electrode is placed over each temple (or placed in the right unilateral or bifrontal regions), and a current of about 400 mA and 70 to 120 V is passed between them for 0.1 to 0.5 s. The machine itself has as the essential element a large capacitor that is discharged to produce an electrographic seizure. The paralytic agent prevents injurious muscle spasms. The patient is awake within 5 to 10 min and is up and about in 30 min. The mechanism by which ECT produces its effects is unknown, but it appears that an electrographic seizure is necessary for clinical effect in depression. Treatments are usually given every other day for 6 to 12 sessions. If there has been a therapeutic response, maintenance ECT at increasing intervals and concurrent administration of an antidepressant is usually employed with the goal of sustaining an antidepressant response with the fewest treatments necessary. One contraindication to the use of ECT is the presence of increased intracranial pressure, as may occur with a neoplasm or intracranial hematoma. Whether epilepsy is precipitated or worsened by ECT is debated, but the presence of epilepsy is generally considered a contraindication. This treatment should also be used cautiously in the presence of uncontrolled systemic hypertension or with a known sensitivity to the anesthetic agents that are used as premedication. The drawback of ECT is the production of impairment of recent memory for the period of treatment and for the days that follow, the degree of impairment related to the number of treatments given. Placing both electrodes on the nondominant side (unilateral ECT) or using lower amounts of current and a briefer pulse rather than a sine wave produces less memory disturbance and has been adopted in some situations because it is almost as effective. Cognitive and memory effects vary with electrode placement and duration of the electrical discharge that is used. Anterograde amnesia occurs immediately after treatment but resolves over weeks, whereas retrograde amnesia develops more gradually over the course of treatment and may take months to dissipate. There are rare cases of delirium following a treatment. Despite the short-term sequelae, neuropathological and imaging studies after ECT have not found damage, and cohort studies have not shown that dementia occurs later in life (Osler et al). With the recognition that transcranial magnetic motor stimulation sometimes produces an elevation of mood, it has been introduced as a potential substitute for ECT. The magnetic technique has the advantage of being free of any but minor physical effects, and because it produces no loss

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of consciousness, anesthesia and neuromuscular paralysis are not needed. Brief pulses of high-frequency stimuli are used. Few controlled studies have been performed and it is not as effective against severe or prolonged depressions and probably not at all for catatonia. Related methods, such as direct current stimulation of the cortex, have met with mixed but generally negative results (Brunoni et al). Until the advent of antidepressant drugs, ECT was the treatment of choice for the agitated depression of middle and late life and for catatonia. Following a course of 6 to 14 treatments, close to 90 percent of patients recovered within 2 months or less. Prior to the use of ECT, this type of depression might last for 2 years or longer before remission or suicide. Deep brain stimulation is under study for refractory depression.

Treatment of Bipolar Disease Lithium Carbonate After the extraordinary discovery by Cade in 1949, lithium has, for decades, until very recently, been the drug of choice in treating the manic phase of bipolar disease, and it is continued to be used in preventing relapses of bipolar disease and depression in some patients. The newer antipsychotic drugs discussed in the next chapter have overtaken lithium for the acute treatment of bipolar disease, with only limited evidence that they are superior. During an acute manic attack, hospitalization may be required to protect the manic patient from impulsive and aggressive behavior that might cause personal and interpersonal difficulty or jeopardize a career. Haloperidol or one of the newer antipsychotic agents (discussed in Chap. 49) or ECT (see earlier) can be used to control mania until lithium carbonate becomes effective, usually a matter of 4 or 5 days. The usual dosage of lithium is 1,200 to 2,400 mg daily in divided oral doses, which produces the desired serum level of 0.9 to 1.4 mEq/L. The serum level of lithium is checked regularly, both to ensure that a therapeutic dose is being taken and to limit toxicity (see later). The side effects of lithium are nausea and vomiting, diarrhea (especially if the dose is increased too rapidly), a feeling of mental dullness, action tremor, weakness, ataxia, slurred speech, blurred vision, dizziness, nystagmus (especially vertical or down beating), stupor, and coma. A confusional psychosis with polymyoclonus and ataxia that together simulate Creutzfeldt-Jakob disease (including periodic sharp waves in the electroencephalogram) may occur at toxic levels. In patients who do not tolerate lithium, carbamazepine, valproate, or another antiepileptic is sometimes substituted. A combination of lithium and a tricyclic or SSRI medication at the lowest effective level has been used as long-term preventive therapies for bipolar disease, and the same combination is useful for patients with mixed bipolar disorder in which depressive and manic manifestations occur within a single episode of illness. Concern that the use of lithium during pregnancy might lead to fetal cardiac malformations, particularly right ventricular outflow obstruction, was affirmed in one study but the rates were low (Paterno et al).

Antipsychotic Drugs Perhaps the most marked change in the treatment of acute episodes of bipolar disease is to initiate one of the

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Chapter 48 Depression and Bipolar Disorder

approved antipsychotic medications (quetiapine, fluoxetine) rather than lithium to bring both the depression and episodic cycling into mania under control. Failing this, a “mood stabilizing” drug such as lamotrigine or divalproex has been used. As mentioned earlier, there is scant evidence that these approaches are superior to lithium. The point to be made is that the use of conventional antidepressants is currently less popular in bipolar disease because of the risk of worsening depression to the point of a suicidal state or of inducing mania. Other combinations have been used such as olanzapine with a serotonergic antidepressant. These are summarized in the review by Frye. Taken together, the effectiveness of these new approaches serves to emphasize the importance of proper diagnosis of bipolar disease. Haloperidol may be necessary to control a dangerous manic episode while one of these medications becomes effective.

Psychotherapy In patients with depression or bipolar disease, careful explanations of the patient’s illness, reassurance that the illness is usually self-limited, and encouragement and instruction to the family are of value in helping both the patient and family to understand the illness and cope with it. At the same time, there should be vigilance for suicidality, admittedly a difficult task given its unpredictability. As a general rule, bipolar illness is best managed by a physician who is willing to follow the patient over a long period of time and is available to reevaluate the patient on suspicion of relapse. Although the prognosis for any individual attack is relatively good, it is wise to arrange for a plan of action that will be set in operation at the first hint of a recurrence. Tomes have been written about various psychodynamic approaches to psychotherapy and the authors are unable to comment authoritatively on them. A structured and problem-oriented approach to psychotherapy using “cognitive-behavioral” and “interpersonal” strategies has gained considerable popularity since its introduction in the 1970s by Beck. It draws to only a limited extent on psychoanalytic and other psychodynamic theories and has been used in patients with depression and in those with anxiety, chronic pain, and other disorders. Cognitivebehavioral therapy has been stated to be most effective in patients with mild to moderate (not chronic) depression, generalized anxiety and panic disorder, and obsessivecompulsive and phobic disorders (Blenkiron). Essentially, in the short term, the therapist provides the patient with information on the nature of the illness, its common symptoms, and the active interventions that are to be undertaken by the patient with the aid of the therapist to alter the specific misperceptions and the dysfunctional behaviors that spring from them. In one study of difficult-totreat chronic forms of depression, an antidepression drug (nefazodone), cognitive-behavioral therapy, or the combination, led remissions in approximately 50 percent of each of the first two groups and in 85 percent of the combined treatment cohort at 12 weeks (Keller and colleagues). This stands as one demonstration of the value of result-oriented psychotherapy. One derivative approach is “Acceptance and Commitment Therapy” (ACT), which aids in accepting the difficulties of life. The interested reader can find discussion of this subject in the current edition of Kaplan and Sadock’s

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Comprehensive Textbook of Psychiatry (Sadock and Sadock). Noteworthy is the opinion that behavioral-cognitive psychotherapy may be no better or worse than other forms of psychotherapy (Gabbard), but it has the virtues of relative brevity, uniformity of application, and straightforwardness that avoids blaming the patient, family, environment, or other external forces.

SUICIDE Some 30,000 suicides are recorded annually in the United States and attempted suicides exceed this number by approximately 10 times. Psychiatrists agree that these are conservative figures. Suicide is the eighth leading cause of death among adults in the United States and the second leading cause among persons between the ages of 15 and 24 years, rates that emphasize the importance of recognizing depression that has a high potential for self-destruction. Recent worldwide surveys show a wide variety of rates across ages and sex. With the exception of the Americas, suicide rates have seemingly declined over two decades but remain high in older people. Physicians are well advised to be familiar with the few imperfect clues to identify patients who intend to end their lives. Some of the questions that may be broached in an interview regarding depression were listed earlier, but particularly, “Do you think of hurting yourself or taking your own life?” and the follow-through query, “Do you have a plan?” Physicians should also be aware that many suicides are accomplished by taking an overdose of prescribed medications, for which reason caution needs to be exercised in their distribution and administration in depressed patients. Successful suicide is 3 times more common in men than in women and particularly common among men older than 40 years of age, and patients with a history of suicide in either mother or father carry a higher risk than those without such a history. A previous suicide attempt adds to the risk. Some workers view suicidal intent as a special form of depression or an important variant of it (Mann, 1998), and that certain individuals are by nature susceptible to attempt suicide as a result of biologic factors. In other words, suicide is not viewed as simply a cognitive response to extreme stress or despondency. Certainly, impulsivity, a frontal lobe phenomenon, seems to be an element of the suicidal act in many cases, but this also is difficult to anticipate and prevent. There is no way for the authors to judge these views, but proponents have pointed to indices of serotonin function that differ between depressed individuals who attempt suicide and those who do not all tentative observations. It has also been observed that the inception of modern antidepressant medications has not greatly altered the rates of suicide among depressed patients. Bipolar illness, endogenous depression, depression resulting from a debilitating disease (e.g., Huntington disease, cancer, and HIV), pathologic grief, and depression in an alcoholic or schizophrenic all carry the risk of suicide. In bipolar disease and endogenous depression, the risk of suicide over the lifetime of the patient is approximately 15 percent (Guze and Robins). In Robins’ series of 134 patients who committed suicide, 47 percent had a known depressive illness, and 25 percent were alcoholic. Other

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series have recorded even higher rates of depression, alcoholism, and drug abuse (Andreasen and Black). Despite the above comments regarding impulsivity, many suicides are planned. Furthermore, the intention of committing suicide is sometimes communicated to someone significant in the patient’s life. The message may be in the form of a direct verbal statement of intent, or it may be indirect, such as giving away a treasured possession or revising a will. As alluded to earlier, important deterrents to suicide are devout Catholicism or comparable religious belief against suicide, concern about the suffering it would cause the family, and fear of death sincerely expressed by the patient. However, no single one of these attributes stands out as entirely predictive of suicide. Tests and scales alluded to earlier have been devised to gauge suicide risk, but they seem to be as imperfect as clinical judgment. As a consequence, one is left with clinical judgment and an index of suspicion as the main guides. The only rule of thumb is that all suicidal threats are to be taken seriously, and patients who threaten to kill themselves should be evaluated quickly by a psychiatrist.

SPECIAL PROBLEMS IN PATIENTS WITH DEPRESSIVE ILLNESS In our experience, the following are some of the common and troublesome clinical situations in which it may prove difficult to recognize an underlying depression: 1. Patients with chronic pain. The association between chronic pain and depression has long been appreciated. This is far from a homogeneous group of affected individuals. The special case of chronic headache, confronted often by neurologists, is discussed below and in Chap. 9. In some patients with chronic pain, the symptoms and signs of depression are quite apparent, and it is certainly not unreasonable to attribute depression to chronic discomfort. If the pain has been present for less than 1 year and had its onset at the same time as other depressive symptoms, response to antidepressant treatment is likely to be favorable. Far more difficult to understand, and to manage, are patients with persistent pain as the only complaint; the head, face, and lower back are the most common loci. Weeks or months of unremitting daily tension-type headaches in the context of a normal examination are highly suggestive of depression at any age. If an exhaustive search for the source of the pain proves unsuccessful, the conclusion is finally reached that the pain is “psychogenic,” but this attribution of pain to some obscure psychologic mechanism is

hardly helpful. Nevertheless, in a fair proportion of such patients, that pain will be alleviated to some extent by antidepressant drugs is suggestive of a linkage of pain and depression, although determining a connection in any particular case is difficult and one cannot exclude an independent biological effect of these medications on pain. The problem may have been made even more difficult by repeated surgical operations as well as dependency on analgesic drugs, which in themselves deplete energy and have other adverse effects. Such patients are to be found among those disabled after multiple operations for ruptured intervertebral disc or arthritic hips or those with atypical facial pain. 2. Depression and alcoholism. These are commonly associated, and it is important to determine which is primary and which is secondary. In a series of patients with alcohol dependence reported many years ago, secondary depression occurred in 30 of 61 females and in 41 of 112 males; moreover, once the alcoholism was established, depression became evident much earlier in the women than in the men (Cadoret and Winokur). The opposite occurrence (the development of alcoholism on the background of a primary depression) is considered to be less common. Some early family studies suggest that the same genetic predisposition leads to depression in females and alcoholism and sociopathy in men (Winokur 1991). Whether there is a similar linkage between depression and drug addiction, for example, to opiates, is not clear, but it seems not in our experience. 3. Depression in childhood and adolescence. We have observed depressive states in children and they have often been misdiagnosed by both pediatricians and psychiatrists. The common manifestations have been chronic headache, refusal to go to school, withdrawal from social activities, anorexia, vomiting and weight loss, and scholastic failure. Puberty is a time of onset in many cases, and the disorder is frequent in late childhood and in high school and college students. It is worthwhile appreciating this fact and to avoid treating the child for some presumed nonaffective nervous symptoms, only to have the patient attempt suicide, but admittedly the diagnosis is difficult in this age group. 4. Anxiety, hypochondriasis, and pseudodementia. These are clinical circumstances in which an underlying depressive illness may not be immediately apparent but can be suspected, as discussed in Chap. 47. The complaint of severe chronic fatigue without medical explanation should raise the same suspicion (see Chap. 23). An elderly person with seemingly early signs of dementia may, on closer examination, turn out to have a severe depressive illness.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5). Washington, DC, APA, 2013. Amsterdam JD, Winokur G, Caroff SN, et al: The dexamethasone suppression test in outpatients with primary affective disorder and healthy control subjects. Am J Psychiatry 139:287, 1982.

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Andreasen NC, Black DW: Introductory Textbook of Psychiatry, 2nd ed. Washington, DC, American Psychiatry Press, 1995. Beck AT: Cognitive Therapy and the Emotional Disorders. New York, International Universities Press, 1976.

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Chapter 48 Depression and Bipolar Disorder Bejjani B-P, Damier P, Arnulf I, et al: Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 340:1476, 1999. Belmaker RH: Bipolar disorder. N Engl J Med 351:476, 2004. Belmaker RH, Agam G: Major depressive disorder. N Engl J Med 358:55, 2008. Blazer D, Williams CD: Epidemiology of dysphoria and depression in an elderly population. Am J Psychiatry 137:439, 1980. Blenkiron P: Who is suitable for cognitive behavioural therapy. J R Soc Med 92:222, 1999. Brockington I: Postpartum psychiatric disorders. Lancet 363:303, 2004. Brunoni AR, Moffa AH, Sampaio-Junior B, et al: Trial of electrical direct-current therapy versus escitalopram for depression. N Engl J Med 376:2523, 2017. Cade JF: Lithium salts in the treatment of psychotic excitement. Med J Aust 2:349, 1949. Cadoret RJ: Evidence for genetic inheritance of primary affective disorder in adoptees. Am J Psychiatry 135:463, 1978. Cadoret RJ, Winokur G: Depression in alcoholism. Ann N Y Acad Sci 233:34, 1974. Carhart-Harris R, Giribaldi B, Watts R, et al: Trial of psilocybin versus escitalopram for depression. New Eng J Med 384:1402, 2021. Carroll BJ, Feinberg M, Greden JF, et al: A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 38:15, 1981. Carvalho A, Firth J, Vieta E. Bipolar disorder. N Engl J Med 383:58, 2020. Caspi A, Sugden K, Morritt TE, et al: Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 301:386, 2003. Cassidy WL, Flanagan NB, Spellman M, Cohen ME: Clinical observations in manic-depressive disease. JAMA 164:1535, 1957. Chen B, Dowlatshahi D, MacQueen GM, et al: Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260, 2001. Collin G, van den Heuvel MP, Abramovic L, et al: Brain network analysis reveals affected connectome structure in bipolar I disorder. Hum Brain Mapp 37:122, 2016. Drevets WC: Neuroimaging and neuropathological studies of depression: Implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 11:240, 2001. Ferrari AJ, Stockings E, Khoo JP, et al: The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord 18:440, 2016. Fisher CM: Hypomanic symptoms caused by herpes simplex encephalitis. Neurology 47:1374, 1996. Frye MA: Bipolar disease—A focus on depression. N Engl J Med 364:51, 2011. Gabbard GD: Mood disorders: Psychodynamic aspects. In: Sadock BJ, Sadock VA (eds): Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1328–1338. GBD 2019 Disease and Injuries Collaborators. Global Burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A system2019 systematic analysis for the Global Burden of Disease Study 2019. Lancet 396:1204, 2020. Goodwin GM, Aaronson ST, Alvarez O, et al: Single-dose psilocybin for a treatment-resistant episode of major depression. New Eng J Med 387:1637, 2022. Goodwin DW, Guze SB: Psychiatric Diagnosis, 5th ed. New York, Oxford University Press, 1996. Gunduz-Bruce H, Silber C, Kaul I, et al: Trial of Sage-217 in patients with major depressive disorder. New Eng J Med 381:903, 2021.

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Guze SB, Robins E: Suicide and primary affective disorders. Br J Psychiatry 117:437, 1970. Herzog J, Reiff J, Krack P, et al: Manic episode with psychotic symptoms induced by subthalamic nucleus stimulation in a patient with Parkinson’s disease. Mov Disord 18:1382, 2003. Hirschfeld RMA, Klerman GL, Andreasen NC, et al: Psycho-social predictors of chronicity in depressed patients. Br J Psychiatry 148:648, 1986. House A, Dennis M, Warlow C, et al: Mood disorders after stroke and their relation to lesion location. Brain 113:1113, 1990. Insel TR, Kalin NH, Guttmacher LB, et al: The dexamethasone suppression test in patients with primary obsessivecompulsive disorder. Psychiatry Res 6:153, 1982. Kaster TS, Vigod SN, Gomes T, Sutradhar R, Wijeysundera DN, Blumberger DM: Risk of serious medical events in patients with depression treated with electroconvulsive therapy: A propensity score-matched, retrospective cohort study. Lancet Psychiatry 8:686, 2021. Keller MB, McCullough JP, Klein DN, et al: A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 342:1462, 2000. Kline N: Practical management of depression. JAMA 190:732, 1964. Kramer MS, Cutler N, Feighner J, et al: Distinct mechanisms for anti-depressant activity by blockade of central substance P receptors. Science 281:1640, 1998. Kulisevsky J, Berthier ML, Gironell A, et al: Mania following deep brain stimulation for Parkinson’s disease. Neurology 59:1421, 2002. Levine DN, Finkelstein S: Delayed psychosis after right temporoparietal stroke or trauma. Neurology 32:267, 1982. Lewis G, Marston L, Duffy L, et al. Maintenance or discontinuation of antidepressants in primary care. N Engl J Med 385:1275, 2021. Mann JJ: The neurobiology of suicide. Nat Med 4:25, 1998. Mendlewicz J, Rainer JD: Adoption study supporting genetic transmission in manic-depressive illness. Nature 268:327, 1977. Merikangas KE, Akisaki HS, Angst J, et al: Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey Replication. Arch Gen Psychiatry 64:543, 2007. Ogilvie AD, Battersby S, Bubb VJ, et al: Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 346:731, 1996. Osler M, Rozing MP, Christensen GT, et al. Electroconvulsive therapy and risk of dementia in patients with affective disorders: a cohort study. Lancet Psychiatry 5:348, 2018. Padmanabhan JL, Cooke D, Siddiqi S, et al. A human depression circuit derived from focal brain lesions. Biol Psychiatry 15:749, 2019. Paterno E, Huybrechts KF, Bateman BT, et al: Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med 376:2245, 2017. Robins E: The Final Months: A Study of the Lives of 134 Persons Who Committed Suicide. Oxford, UK, Oxford University Press, 1981. Robinson RG: Mood disorders secondary to stroke. Semin Clin Neuropsychiatry 2:244, 1997. Rush AJ, Trivedi MH, Wisniewski R, et al: Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354:1231, 2006. Ryan ND: Treatment of depression in children and adolescents. Lancet 366:933, 2005. Sachs GS, Nierenberg AA, Calabrese JR, et al: Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 356:1711, 2007. Sadock BJ, Sadock VA (eds): Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2017.

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Sanders AR, Detera-Wadleigh SD, Gershon ES: Molecular genetics of mood disorders. In: Charney DS, Nestler EJ, Bunney BS (eds): Neurobiology of Mental Illness. New York, Oxford University Press, 1999, pp 299–316. Sapolsky RM: Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 57:925, 2000. Schlesser MA, Winokur G, Sherman BM: Hypothalamic-pituitaryadrenal axis activity in depressive illness. Arch Gen Psychiatry 37:737, 1980. Starkstein SE, Robinson RG, Price TR: Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 110:1045, 1987. Stewart DE: Depression during pregnancy. N Engl J Med 365:1605, 2011.

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Thomson KC, Hendrie HC: Environmental stress in primary depressive illness. Arch Gen Psychiatry 26:130, 1972. Tor PC, Tan XW, Martin D, Loo C: Comparative outcomes in electroconvulsive therapy (ECT): A naturalistic comparison between outcomes in psychosis, mania, depression, psychotic depression and catatonia. Eur Neuropsychopharmacol 51:43, 2021. Winokur G: Mania and Depression: A Classification of Syndrome and Disease. Baltimore, MD, Johns Hopkins University Press, 1991. Winokur G, Coryell W, Keller M, et al: A prospective follow-up of patients with bipolar and primary unipolar affective disorder. Arch Gen Psychiatry 50:457, 1993. Wishnie HA, Hackett TP, Cassem NH: Psychological hazards of convalescence following myocardial infarction. JAMA 215:1292, 1971.

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49 Psychosis, Schizophrenia, Delusional, and Paranoid States

This chapter discusses disorders characterized by psychosis. The definition of this state has been difficult to attain with certainty. At its simplest, it reflects a continuous disconnection of thought processes from reality. At times, it has been defined largely by the presence of hallucinations or delusions. In DSM-5, psychosis is characterized by hallucinations, delusions, disorganized thinking, grossly disorganized motor behavior, or negative symptoms, which are defined in the following discussion. None of these captures the sometimes subtle but often bizarre ideas and behaviors of individuals with psychosis or the experience of communicating with them being in the presence of a person with psychosis. While psychosis is a core feature of schizophrenia, it can be fully expressed in a number of acute states such as drug intoxications. Some of these aspects are discussed in Chap. 19 on “Delirium and Other Acute Confusional States.”

SCHIZOPHRENIA Schizophrenia is among the most serious of all unsolved diseases. This was the opinion expressed 60 years ago in Medical Research: A Mid-Century Survey, sponsored by the American Foundation. Because of a worldwide lifetime prevalence of approximately 0.85 percent and particularly because of its onset early in life, its chronicity, and the associated social, vocational, and personal disabilities, the same conclusion is justified today (Carpenter and Buchanan). Schizophrenia has been found in every ethnic and social group so far studied. On average, 35 new cases per 100,000 population appear annually (Jablensky). The Global Burden of Disease Study derived from multiple sources (Charlson et al) gives estimates in 2016 of 0.28 percent of the world’s population, which do not vary greatly cross populations or regions. Estimates of the prevalence of schizophrenia and related psychotic disorders in the United States have been 0.25 to 0.64 percent. Despite the low incidence, the resultant number of years of life with disability are enormous. The incidence of schizophrenia has remained more or less the same over the past several decades. Males and females are affected with equal frequency. For unknown reasons, the incidence is higher in social classes showing high mobility and disorganization. It has been suggested

that this is a by-product of “downward drift”—a result of deteriorating function in those with the disease that forces them into the lowest socioeconomic stratum where one finds poverty, crowding, limited education, and associated disadvantages—and the same data have been used to support the idea that schizophrenia can be caused by such social factors. Schizophrenic patients occupy about half the beds in psychiatric hospitals—more hospital beds than are allocated to any other single disease—and they constitute 20 to 30 percent of all new admissions to psychiatric institutions (100,000 to 200,000 new cases per year in the United States). The age of admission generally is between 20 and 40 years, with a peak between 28 and 34 years. The economic burden created by this disease is enormous— the direct and indirect costs in the United States have been estimated to be over $50 billion. Neurologists and psychiatrists currently accept the idea that schizophrenia comprises a group of related disorders characterized by a particular type of disordered thinking, affect, and behavior. The syndrome by which these disorders manifest themselves differs from those of delirium, confusional states, dementia, and depression in ways that will become clear in the following pages. The diagnosis of schizophrenia depends on the recognition of characteristic psychologic disturbances largely unsupported by abnormal physical findings and laboratory data. This inevitably results in a degree of diagnostic imprecision. In other words, any group classified as schizophrenic will include patients with diseases that only resemble schizophrenia, whereas variant or incomplete cases of schizophrenia may not have been included. Moreover, there is not full agreement as to whether all the conditions that are called schizophrenia are the expression of a single disease process. In the United States, for example, paranoid schizophrenia had been considered a subtype of the common syndrome, whereas in some parts of Europe it is thought to be a separate disease.

Historical Background Present views of the disease now called schizophrenia originated with Emil Kraepelin, a Munich psychiatrist, who first clearly separated it from bipolar psychosis. He called it dementia praecox (adopting the term introduced earlier by Morel) to refer to a deterioration of mental function at

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an early age, from a previous level of normalcy. At first, Kraepelin believed that “catatonia” and “hebephrenia,” which had previously been described by Kahlbaum and by Hecker, respectively, as well as the paranoid form of schizophrenia, were separate diseases, but later he concluded that several subtypes were a single disease. He emphasized the characteristics of an onset in adolescence or early adult life and a chronic course, often ending in marked deterioration of personality as the defining attributes of all forms of the disease. Early in the twentieth century, the Swiss psychiatrist Eugen Bleuler substituted the term schizophrenia for dementia praecox. This was an improvement insofar as the term dementia was already being used to specify the clinical effects of another category of disease; unfortunately, however, the new name implied a “split personality” or “split mind.” By the “splitting” of psychic functions, Bleuler meant the lack of correspondence between ideation and emotional display—the inappropriateness of the patient’s affect in relation to his thoughts and behavior. In contrast, in bipolar disease, the patient’s mood and affect accurately express his morbid thoughts. Bleuler also introduced the term autism (“thinking divorced from reality”) as an aspect of the thought disorder. Bleuler believed that all the schizophrenic syndromes were composed of primary or basic symptoms, summarized by subsequent authors as the “four A’s” (loose associations, flat affect, ambivalence, and autism) and of secondary or “partial phenomena” such as delusions, hallucinations, negativism, and stupor. However interesting this formulation proved to be, the psychologic abnormalities are so difficult to define precisely that these divisions have come to be of only mnemonic value. Meyer, who introduced the “psychobiologic approach” to psychiatry, sought the origins of schizophrenia, as well as other psychiatric syndromes, in the personal and medical history of patients, emphasizing particularly their habitual reactions to life events. Freud viewed schizophrenia as a manifestation of a “weak ego” and an inability to control anxiety and instinctual forces—the result of a fixation of libido at an early (“narcissistic”) stage of psychosexual development. None of these theories has been corroborated, and none ever gained wide acceptance, particularly as the biological disease model of schizophrenia, propelled by successful pharmacologic treatment, defined a disease and not a psychologic disorder. A contemporary approach to schizophrenia, summarized below, has involved the isolation of its many pervasive mental and behavioral features into three clusters: (1) negative symptoms of diminished psychomotor activity (poverty of speech and spontaneous movement, flatness of affect); (2) a “disorganization” syndrome, or thought disorder (fragmentation of ideas, loosening of associations, tangentiality, and inappropriate emotional expression); and (3) reality distortion, comprising hallucinations and delusions, or positive symptoms (Liddle). The separation of behaviors into “positive” and “negative” symptoms was believed to be useful in distinguishing among the types of schizophrenias and perhaps to align the mental status with conventional physiologic analysis, but this view is an oversimplification (Andreasen). Although there is disagreement as to whether each of these features is primary

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or secondary, positive or negative, they have the value of lending themselves to objective study and scales have been devised to measure them.

Clinical Syndrome of Schizophrenia The central abnormalities in schizophrenia are hallucinations, mainly auditory, and a special disorder in the perception of one’s self in relation to the external world. Some patients with chronic schizophrenia, before the onset of a flagrant psychosis or when in remission, show none of the usual symptoms and—during brief testing of mental status—appear normal. But on longer observation, they are vague and preoccupied with their own thoughts. They seem unable to think in the abstract, to understand fully figurative statements, or are unable to separate relevant from irrelevant data. There is what has been called a circumstantiality and tangentiality about their thinking and remarks. They fail to communicate their ideas clearly. Their thinking no longer respects the logical limits of time and space so that parts of ideas are confused with the whole or are clustered together or condensed in an illogical way. In an analysis of a problem or a situation, there is a tendency to be overinclusive rather than underinclusive (as happens in dementia). In conversation and in writing, the trend of an argument or thought sequence is often interrupted abruptly, with a resulting disorder of verbal communication. Such disorders of thinking are reflected in the patient’s behavior. Over time there is a general deterioration in functioning, social withdrawal and bizarre actions, self-absorption, and aimlessness. In more severely affected patients with schizophrenia, thinking is even more disintegrated. They appear to be totally preoccupied with their inner psychic life (thus the early use of the term autism) and may do no more than utter a series of meaningless phrases or neologisms, or their speech may be reduced to a nonsensical “word salad.” They are unable to attend to any task or to concentrate, and their performance is interrupted by sudden “blocking” or by insertion of some extraneous idea or inexplicable act, somewhat like that observed in a severely confused or delirious patient. At times these patients are talkative and exhibit odd behavior; at other times they are quiet and idle. In the extreme, the patients are mute or assume and maintain imposed postures or remain immobile (catalepsy). With remission, they may remember much of what has happened or may have only fragmentary memories of events that occurred. Typical of schizophrenia is the patient’s expression of remarkably unusual experiences and ideas. The patient may express the thought that his body is somehow separated from his mind, that he does not feel like himself, that his body belongs to someone else, or that he is unsure of his own identity or even sex, experiences called depersonalization. Thought insertion, wherein it seems to the patient that an idea has been implanted into his mind, or thought withdrawal, wherein an idea has been extracted from his mind by an outside agency, may be other parts of this problem. Closely related, and characteristic of schizophrenia, are ideas of being under the control of some external agency or being made to speak or act in ways that are

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Chapter 49 Psychosis, Schizophrenia, Delusional, and Paranoid States

dictated by others, often through the medium of radar, telepathy, television, or the Internet (passivity feelings). Thought projection, the notion that external elements in the environment are being controlled by the patient’s mind, is similar. Frequently, there are ideas of reference— that the remarks or actions of others are subtly or overtly directed to the patient. Finally, the patient may feel that the world about him is changed or unnatural, or his perception of time may be altered, not in a brief episode like the jamais vu of a temporal lobe seizure, but continuously; this is the phenomenon of derealization. However, the bizarreness of these delusions, once considered a characteristic feature, has been removed from the diagnostic criteria for schizophrenia in the DSM (American Psychiatric Association) because of its nonspecificity and the difficulty determining exactly what constitutes bizarre. Auditory hallucinations are frequent and a core feature of the typical illness. They consist of voices that comment on the patient’s character and activities and are usually accusatory, threatening, or claiming control of the patient’s actions. The voices may or may not be recognized; they may belong to one person or two or more persons who converse with the patient or with one another. Seldom can the voices be localized to a point outside the patient. Instead, they seem to come from within, so that they cannot be distinguished from his own feelings and thoughts. Certain somatic hallucinations and delusions may predominate in any one individual. Visual, olfactory, and other types of hallucinations also occur but are much less frequent. The patient believes in the reality of these hallucinations and often weaves them into a delusional system. It should be reiterated here that hallucinations are a feature of several disparate neurologic processes, but in most people visual hallucinations predominate, whereas auditory hallucinations are more the hallmark of schizophrenia. Of interest in this regard is “The Report on the Census of Hallucinations” by Sidgwick in 1894 who suggested (cited by Frith) that almost 1 in 10 ostensibly normal respondents has experienced hallucinations, mostly visual. The main illnesses in which hallucinations and delusions are prominent are hallucinogenic drug ingestion and the Charles Bonnet syndrome (see Chap. 12). With respect to negative symptoms in schizophrenia, they have been divided into four groups (Liddle and Barnes): (1) flat affect, diminution in expressive gestures, latency of response, reduced spontaneous movements, apathy, restricted recreational activities, inability to feel intimate or close, and motor retardation; these negative symptoms, which have resemblances to frontal lobe behavioral syndromes, correlate with reduced blood flow in the frontal lobes and a poor prognosis; (2) disorganization of thought, incoherence, inappropriate affect, illogicality, bizarre behavior, aggression, agitation, and tangentiality; these abnormalities are nonfrontal; (3) hallucinations and delusions that the patient’s mind is being read and that thoughts are being extracted from his mind or being controlled or broadcasted, probably related to temporal lobe function; and (4) suspicion, hostility, and delusions of reference. These features can coexist in various combinations. However valid or invalid such subdivisions prove to be, they direct attention to the functional anatomy and

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physiology of particular neuronal systems in the brain (see further on; Friston et al). The behavior of the individual with schizophrenia who experiences these ideas and feelings is correspondingly altered. Early in the course of the illness, normal activities may be slowed or interrupted. No longer does the patient function properly in school or at work. Associates and relatives are likely to find the patient’s complaints and ideas disturbing. The patient may be idle for long periods— preoccupied with inner ruminations—and may withdraw socially. A panic or frenzy of excitement may lead to an emergency ward visit (a high degree of anxiety occurring for the first time in a young person should raise the suspicion of a developing schizophrenia), or the patient may become mute and immobile, that is, catatonic. Attacks of catatonia are infrequent, but lack of will, drive, assertiveness, and motor activity are characteristic of the disease. Over time, a deteriorated and dilapidated state occurs, which in the extreme results in an unkempt and malnourished state with which the public unfortunately associates schizophrenia. Individuals of this type may roam the streets and live in appalling conditions on the fringes of society where they are subject to the criminal behavior of others. That schizophrenia of all types carries a significant risk of suicide is not widely appreciated. In a follow up study of schizophrenic and bipolar patients, in each group the proportion of patients who had committed suicide was the same (approximately 10 percent) (Winokur and Tsuang) but this is not a uniformly held view. Suicide occurs most often among young patients with schizophrenia living apart from their families who may be frightened and overwhelmed by their symptoms and who experience the difficulties of independent existence. Sometimes suicide is a response to terrifying and commanding vocal hallucinations. The schizophrenic patient may also be homicidal, usually acting on a delusion that he has been wronged or is threatened by the victim. Incidents of this type are unpredictable and infrequent, but the presence of escalating paranoia should be a warning. Finally, whether a genuine dementia results from chronic schizophrenia has been much debated over the years but the mental deterioration differs somewhat from the neurologist’s conception of dementia. The notion of this type of “dementia praecox” has been discarded, but clinicians continue to encounter cases of progressive generalized, and sometimes severe, intellectual impairment in both acute and long-standing cases of schizophrenia; this has been true before and after the modern era of therapeutics. The problem was highlighted by a series that analyzed a frontotemporal type of dementia in eight patients after 9 to 30 years of schizophrenia with frontal or temporal hypoperfusion on functional imaging (de Vries and colleagues).

Diagnostic Criteria Included in the early definitions of the disease, both of Kraepelin and of Bleuler, were a characteristic premorbid personality, an insidious onset of the more flagrant symptoms in adolescence or early adult life, and a chronic but fluctuating course with a tendency to progressive

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deterioration. Both of these early investigators regarded hallucinations and delusions as secondary symptoms that could be absent, as in their category of “simple schizophrenia.” Embodied in both their definitions was the concept of disease characterized by a poor prognosis and, as stated earlier, a unique constellation of symptoms different from those of delirium, confusion, depression, mania, and dementia—which are manifestations of brain diseases. Many of their seminal ideas, and others discussed below, have been retained but most have been discarded in modern diagnostic criteria. Nevertheless, they established a lexicon for the clinical description and grading of schizophrenic disorders and all subsequent progress has been essentially to refine these ideas. For that reason, they are summarized here so that the student may appreciate the evolutionary nature of diagnostic criteria, as expressed through the Diagnostic and Statistical Manual of Mental Disorders (DSM). Attempts to apply the early criteria initially met with difficulty, especially when hallucinations and delusions were absent. To overcome this, Schneider proposed that the distinction between primary and accessory manifestations be abandoned. He attached more importance and reliability to the occurrence of auditory hallucinations, perceptual delusions (misinterpretation of what the patient hears and feels), and disturbances of thinking (experiences of alienation and influence). This constellation of symptoms, which was more precise and easy to recognize, came to be known as Schneider’s firstrank symptoms of active schizophrenia. The Schneider diagnostic criteria, when applied to a group of patients admitted to the hospital with a diagnosis of schizophrenia, served to distinguish those with better and worse prognosis (Taylor). Those without hallucinations, delusions, and thought control or projection responded more poorly to treatment and required a more prolonged period in the hospital and higher doses of neuroleptic drugs than did those with these features. The two groups correspond closely to two categories of schizophrenic disorders later separated based on prognosis (Robins and Guze). The Schneider-positive, poor-prognosis schizophrenia (also referred to in older literature as nuclear or process schizophrenia) corresponded closely to kraepelinian schizophrenia, while many of the Schneider-negative patients with good prognosis were probably suffering from some other nonschizophrenic illness such as bipolar disease (see Chap. 48). Having made these comments, it must be acknowledged that newer classifications of schizophrenia give these distinctions less credibility and point to marginal differences in outcome and responses to treatment. Feighner and colleagues, who drew up a set of diagnostic criteria for research in the major psychiatric syndromes (which were subsequently incorporated, until recently, into successive editions of the DSM) stated that the diagnosis of schizophrenia is tenable only in the presence of (1) a chronic illness of at least 6 months’ duration and a failure (after an acute episode) to return to the premorbid level of psychosocial adjustment, (2) delusions or hallucinations without significant confusion or disorientation (i.e., without clouding of consciousness), (3) verbal productions

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that are so illogical and confusing as to make communication difficult (if the patient is mute, diagnosis should be deferred), and (4) at least three of the following manifestations: (a) among adults, the lack of a partner or spouse; (b) poor premorbid social adjustment or work history; (c) family history of schizophrenia; or (d) onset of illness prior to age of 40 years. Important exclusions from certainty in the diagnosis of schizophrenia include the absence of a family history of bipolar disease, absence of an earlier illness with depressive or manic symptoms, and absence of alcoholism, drug abuse, or other organic disease. While the Feighner criteria are so strict as to exclude certain patients with a schizophrenic illness, those patients who are included will be found to constitute a fairly homogeneous group. After a 10-year period in one study that used these criteria (Morrison and colleagues) there was practically no need to change the diagnosis to another category of mental disease; in other words, they had reliably separated schizophrenia from schizophreniform psychosis (in which only the acute delusionalhallucinatory syndrome was present), and from bipolar psychosis. Newer diagnostic criteria are no less refined but achieve clarity by stating that a patient must have at least one of the symptoms of delusions, hallucinations, and disorganized speech (not thinking). Also in updated versions is the removal of the necessity for delusions to be “bizarre”, as already mentioned, and for there to be some elements of Schneiderian first-rank symptoms, namely an auditory experience of two or more voices conversing.

Subtypes of Schizophrenia Psychiatrists had in the past separated a number of subtypes of schizophrenia, although the usefulness of these distinctions has been questioned and most modern criteria eliminate them entirely because they have proved to have limited clinical and therapeutic importance. They are briefly reviewed here for their historical interest and because they allow an explication of some of the more interesting symptoms and signs of schizophrenia that are entirely descriptive but are still instructive and retain clinical interest. In what was called simple schizophrenia, the least florid form, the patient exhibits thought disorder, bland affect, social withdrawal, and reduction in speech and movement, all of which impair work performance. Poverty of psychomotor activity is the dominant feature and hallucinations and delusions are absent. These patients may attract notice in middle and high school because they behave in an odd manner, tending to remain by themselves (“loners”), making no effort to adjust to a social group at school or to find work, have dates, or later, to establish a family. Catatonic schizophrenia is still the most readily identifiable type because of the striking syndrome of catatonia, and while still distinctive, it is now, for unclear reasons, found to be infrequent. In most cases the onset is relatively acute. In others, after a long prodrome of slackening interest, apathy, and dreamy preoccupation, a state of dull stupor supervenes, with mutism, inactivity, refusal of food, and a tendency to maintain one

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Chapter 49 Psychosis, Schizophrenia, Delusional, and Paranoid States

position “like a mummy” (catalepsy). Like other forms of catatonia, this type of schizophrenia was the one most characterized by the retention of a posture: if a limb is lifted by the examiner, it will be held in that position for hours (flexibilitas cerea). Pinprick or pinch induces no reaction. Yet these patients may be fully aware of what is said to them or happening around them and will reproduce much of this information during a later spontaneous remission, a feature vividly recalled in the autobiographical novel “The Snake Pit” by Mary Jane Ward (although she would certainly by current standards have been diagnosed as bipolar instead of schizophrenic). Catatonia is recognized to be a feature of other mental disorders and is more frequent in severe involutional depression than in schizophrenia (the catatonic state is further discussed in Chap. 16 on Coma and Related Disorders of Consciousness). Disorganized, or hebephrenic, schizophrenia was believed by Kraepelin to be a particularly malignant form. It tended to occur at an earlier age than the other varieties, hence the prefix hebe (“youth”). The thought disorder is pronounced—there is a striking incoherence of ideas and a grossly inappropriate affect; the frequent occurrence of hallucinations and delusions leaves little doubt that the patient is psychotic. Paranoid schizophrenia was one of the most frequent and well-circumscribed types, even if now unattached from schizophrenia in the DSM-5 diagnostic criteria. The mean age of onset is in the early forties, later than that of the preceding types (Winokur). The central feature is the preoccupation with one or more delusions related to a single or to a limited ensemble of themes, accompanied by auditory hallucinations. More often than not, the delusional hallucinatory content is persecutory, but it may also be religious, depressive, grandiose, or bizarrely hypochondriacal in nature. It is mentioned again that these distinctions are interesting and have some heuristic value but not often mentioned in modern work,

Course of Schizophrenia Some patients with schizophrenia are subject to periodic exacerbations of their illness, sometimes at regular intervals. Remissions that allow functioning in society are more frequent and lasting when medication is given and prolonged institutionalization is avoided. A small proportion (approximately 10 percent), after an acute schizophrenic episode, have a long-lasting and fairly complete remission before lapsing into a chronic form of the illness. Unfortunately, these latter patients, at the time of their acute psychosis, cannot be distinguished from those few who will have a permanent remission. Modern therapeutic programs have vastly reduced the number of patients in mental hospitals. However, readmission rates have also risen (revolving-door phenomenon) and the total number of very young and very old patients in hospitals has even increased slightly. The life expectancy of schizophrenic patients is reduced, possibly because of the malnutrition, neglect, and exposure to infections that occur in some public institutions and from living on the streets or in marginal circumstances.

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Neurologic and Neuropsychologic Abnormalities in Schizophrenia The early findings of Kraepelin and of Bleuler, that many schizophrenic patients will, on detailed examination, show subtle and inconsistent neurologic changes, have been substantiated by many studies but these refer mainly to “soft neurologic signs” that are present in schizophrenia more often than in healthy populations. These include impersistence in motor and mental tasks, astereognosis and graphesthesia, sensory extinction, hyperreflexia and hyporeflexia, slight tendency to grasping, mild impairment of coordination and disturbances of balance, abnormal (choreiform) movements, abnormalities of motor activity, adventitious and overflow movements, anisocoria, slight esotropia, and faults in visual auditory integration. Features of this type have been present in up to half of patients and are vaguely correlated with the degree of cognitive disorder. Some of them are certainly the result of inattention. Also evident in about half of schizophrenic patients are subtle defects in ocular tracking movements (Levin et al) in the form of slowed smooth pursuit and intrusions of saccades during pursuit; some relatives of schizophrenic patients also show these eye signs when carefully tested. In contrast, “hard neurologic signs” (such as unilateral motor or sensory defects) are not seen unless they are the result of an additional neurologic disorder. Electroencephalographic (EEG) abnormalities have been detected in about one-third of patients, but are generally minor and their meaning is uncertain, especially if they have occurred after long-standing treatment. When EEG patterns were in the past a focus of research, they were found to be more frequent in schizophrenic patients who had a positive family history and in those with enlarged ventricles. Sophisticated psychometric testing has disclosed abnormalities, not so much in intelligence and memory (which are slightly reduced in 20 to 30 percent of cases), as in other psychologic functions. Alertness is not generally impaired, but the ability to maintain attention, as measured by continuous performance tasks, is reduced (Seidman). In tests of verbal and visual pattern learning, problem-solving, and memorizing, there is a surprising degree of impairment in both acute and chronic schizophrenic patients that is not easily attributable to previous treatment. In the acute schizophrenic patient, verbal memory was more affected than visual pattern memory and left-hemispheric functions were more reduced than right-hemispheric ones. Yet, in chronic schizophrenia, there is usually subtle evidence implicating bihemispheric impairment in respect to several cortical functions (Cutting and Flor-Henry).

Theories of Causation and Mechanism Although there is no agreement as to the fundamental cause of the disease, increasing evidence favors broad interactions between a genetic predisposition, neurotransmitter derangements, and early developmental events. One widely held hypothesis is that this disease reflects an underlying developmental disorder, determined either

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genetically or because of an environmental insult, leading to abnormalities of synaptic connectivity, prominently affecting the hippocampus and prefrontal cortex. With detailed analysis, many potential causes have been suggested, as summarized in reviews (Marder and Cannon).

Genetic Factors Several studies have estimated that genetic factors may account for upward of 80 percent of the risk of developing schizophrenia, more than for any other mental illness. Early studies showed that the frequency of disease in 5,000 siblings of schizophrenic patients was 11 percent, in contrast to slightly less than the approximately 1 percent in the general population noted above (Kallmann). In 90 sets of fraternal twins of whom one had schizophrenia, the incidence of disease in the other twin was also 11 percent, the same as in nontwin siblings; however, in 62 sets of monozygotic twins, the incidence in the second twin was 68 percent. The risk that a child of a schizophrenic parent will develop schizophrenia is the same as that for the sibling of a schizophrenic patient (i.e., 11 percent); if 1 sibling and 1 parent have schizophrenia, the risk is 17 percent. If both parents are schizophrenic the chances are 46 percent that the child will have the disease. Subsequent family and twin studies have confirmed these findings (Goodwin and Guze for a more complete tabulation). It is noteworthy, however, that the penetrance of this trait appears to be less than it is for bipolar disease but that genetic factors seem to play a larger role in patients whose schizophrenia manifests in their teenage years. Although the importance of genetic factors in the etiology of schizophrenia is undeniable, a mendelian pattern of inheritance has not been determined. Polymorphisms in several genes have been implicated as risk factors but only 1 percent of risk can be attributed collectively to single nucleotide variants. Such genes include those expressing neuregulin, dysbindin, catechol O-methyltransferase (COMT), proline dehydrogenase, and “disrupted in schizophrenia 1” (DISC1). Some provocative sites are rare alleles in genes that also are overrepresented in autism—NRXN1, SHANK3, CNTNAP2, and PRODH (McClellan and King). There are also a copy number variations at genetic “hotspots” that occur in schizophrenia, autism, and other developmental disorders. What has merged from large population studies using genomewide array screening, is that there are not likely to be common risk variants for schizophrenia (Lieberman and First). Many of the polymorphisms seem to be of recent evolutionary origin or have a substantial rate of arising de novo. Some of the more provocative findings have been of connections to loci in the major histocompatibility (MHC) gene loci, putatively creating an immune link to schizophrenia, one that is often cited but has no proof. The studies implicating these genes must be interpreted cautiously because the functional significance of the allelic variants is not defined. Nevertheless, considered together, they point to disorders both of neuronal development and neurotransmission.

Environmental and Developmental Factors There continues to be debate concerning the relative importance of genetic versus environmental factors in the causation of the disease. The lack of complete concordance

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between monozygotic twins and the fact that approximately 80 percent of schizophrenic patients have no other family members with the disease, indicate that factors other than genetic ones probably play a role. Some of these appear to be early events that occur in utero or infancy and alter normal developmental programs of brain structure. The neuropsychiatric literature contains tentative and only circumstantial evidence that schizophrenia is associated with overt brain injury during the intrauterine or neonatal period, but there is reportedly an increased incidence of obstetric complications during the gestational period and birth of schizophrenic patients. Also consistent with an early adverse environmental factor is the observation by several groups that in the northern latitudes, more schizophrenic persons are born in the winter months and to women who were exposed to influenza during midpregnancy—inviting speculation that a viral infection may have damaged the fetal brain. In one study being born in an urban region, particularly in February or March, carried with it a higher risk for developing the disease than having an affected parent or sibling (Mortensen and colleagues). Among 5,362 infants who were followed prospectively since their birth in 1946 by Jones and colleagues, the 30 individuals who later developed schizophrenia had been delayed in the attainment of motor milestones and speech and exhibited greater social withdrawal and schoolroom anxiety as well as lower scholastic achievement. Thus, it is possible that schizophrenic individuals are not entirely normal in early childhood, but whether their abnormalities are already early manifestations of schizophrenia or risk factors for the disease has not been determined.

Neuropathologic, Brain Imaging, and Neurophysiologic Findings Notably lacking in reports of developmental changes in schizophrenia, are accurate and modern neuropathologic data. Dunlap, in 1928, in a critical analysis, repudiated all earlier interpretations of cellular alterations that had been reported in the brains of schizophrenic patients. He pointed out that many of them, such as dark “sclerotic” nerve cells, were artifacts and that the presence of lipofuscin was a nonspecific age change. He also asserted that the neuronal loss described by Alzheimer was based on impression and could not be corroborated by quantitative methods. Similarly, the claim of Oscar Vogt of neuronal loss in the cortex was rejected by his contemporaries, Spielmeyer and Scholz, who were unable to find any consistent cellular abnormality in schizophrenia. Spielmeyer, in a critical study of the problem in 1930, concluded that such changes as had been described up to that time could not be clearly distinguished from the normal, and that the more marked changes in some cases were due to coincidental causes. Corsellis, based on yet another review of the neuropathologic data in 1976, found no reason to deviate from Spielmeyer’s view. The uncertain neuropathologic findings were responsible for the enigmatic categorization of schizophrenia as a “functional” disorder, that is, a disorder with no structural basis. Nevertheless, there has been a general sense that, while the number of neurons in the gray matter is normal, the pyramidal cells are smaller and more densely

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packed, resulting in a thinning of laminae II and III. These cytoarchitectonic changes have been the most difficult to interpret and to confirm. Capricious methods such as the rapid Golgi stain indicate that density of dendritic spines is decreased in the frontal and temporal cortex of chronic schizophrenic patients. Also, several studies with other labeling methods converge on the observation that affected individuals have fewer dendritic spines than agematched controls. More contemporary reports using special cell-labeling studies have found subtle cytoarchitectonic abnormalities in the brains of schizophrenic patients. For example, aberrant distribution of interstitial neurons in the frontal lobe white matter has been described (Akbarian and colleagues). These cells have their origin in the embryologic subplate that guides neuronal migration, and the inference is that the abnormally migrating cells have formed aberrant neuronal connections. The number of small neurons in one study was reduced in layers I and II of the anterior cingulate cortex (Benes and colleagues). These are gammaaminobutyric acid (GABA)–releasing (inhibitory) neurons. Other studies describe a paucity of gabanergic, inhibitory interneurons (so-called chandelier cells) in the prefrontal cortex (Woo et al). These observations suggest a developmental rather than an acquired lesion. The absence of gliosis supports but does not prove that the developmental disorder occurs prenatally Imaging by CT and subsequently MRI of the brain provided a new stimulus to the anatomic study of schizophrenia. Johnstone and coworkers were the first to describe ventricular enlargement and sulcal widening in 18 patients and correlate these findings with dulling of intellect and affect. In a study of 58 individuals with chronic schizophrenia younger than age 50 years, there was enlargement of the lateral ventricles in 40 percent (Weinberger and colleagues, 1979). In 15 pairs of monozygotic twins, one of whom had schizophrenia, the anterior hippocampi were found to be smaller and the lateral and third ventricles larger in the affected twin (Suddath et al). Others have demonstrated a reduction in the volume of gray matter in the posterior part of the left superior temporal gyrus, which includes Heschl gyri and the planum temporale (Shenton and colleagues). The degree of volumetric reduction correlated roughly with the severity of the thought disorder. Other MRI studies have shown a volumetric change in the gray matter of the left hippocampus, parahippocampal gyrus, and amygdala (in right-handed patients). Equally compelling is the finding that young individuals having two or more relatives with the disease, and therefore being at risk for developing schizophrenia, have volumetric brain changes detected by imaging studies (Lawrie et al); the left hippocampal– amygdaloid region is smaller than in healthy people, but slightly larger than in affected relatives. Neuropsychologic testing has disclosed deficits in attention and abnormalities of the P300 waves (cortical “eventrelated” potentials). These deficits are probably concordant with reduced cognitive activation activity in functional MRI, for example, decreased blood flow in the prefrontal areas during cognitive tasks (Weinberger et al, 1986). It is unclear, however, if these changes represent primary defects or are secondary to an inherent lack of motivation.

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Studies of regional glucose metabolism and postmortem norepinephrine measurements have yielded ambiguous data, although most show a reduction in glucose metabolism in the thalamus and frontal cortex. Several lines of investigation point to the medial part of the left temporal lobe and related limbic and frontal systems as being the focus of a developmental abnormality (see Tsuang et al and Friston et al for pertinent references). The inconsistent findings on functional imaging may be accounted for by correlations between certain blood flow patterns and specific symptoms (Sabri and colleagues). For example, the formal thought disorder corresponded to increased flow in the frontal and temporal regions, whereas delusions and hallucinations were associated with reduced flow in the cingulate, left frontal, and temporal areas. PET studies in schizophrenic patients while they were experiencing auditory hallucinations have found increased blood flow mainly in both thalami, left hippocampus, and right striatum, but also in the parahippocampal, orbitofrontal, and cingulate areas (Silbersweig and coworkers).

Alterations in Neurotransmitters When certain hallucinogens, such as mescaline and lysergic acid diethylamide (LSD), were first observed to induce hallucinations and abnormalities of thinking, it was hoped that they might provide experimental models of schizophrenia. This hope was never realized but there are instances, difficult to interpret, in which these drugs have induced a prolonged relapse in a schizophrenic patient. The psychosis caused by these drugs implicates serotonin (5-HT2A) systems, an idea now resurrected as noted below. Similarly, when methionine, a potent source of methyl groups, was observed to exacerbate the symptoms of some schizophrenic patients, it was thought that a primary metabolic fault had been discovered. More recently, a glutamine hypothesis has been offered and is being investigated. The dopamine hypothesis that held sway for decades and still has credibility was based on the response of psychotic symptoms to phenothiazine and related medications, which implicates the dopaminergic system of the temporal lobe (Carlsson). The evidence for this has been circumstantial but is supported by observations that antipsychotic drugs reduce the electrical activity of mesolimbic dopaminergic neurons in experimental models. Furthermore, there have been several demonstrations of increased concentrations of dopamine or its metabolite, homovanillic acid, in schizophrenic brains obtained at autopsy. The finding that dopamine receptors are organized in two systems, one limbic and the other cortical, has led to an expanded but speculative hypothesis that an excess of dopaminergic activity in the mesolimbic system gives rise to the positive symptoms of schizophrenia— that is, psychosis—whereas a diminished activity in the mesocortical system accounts for the negative symptoms. The involvement of the mesolimbic system, which plays a role in attention, has prompted further speculation that the thought disorder of schizophrenia is attributable to a breakdown of the normal “filtering” of stimuli reaching cognition. As mentioned earlier, it has been found that a variant in the gene for COMT that enhances metabolism of dopamine is overrepresented in schizophrenia, further

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incriminating a disorder of dopaminergic neurotransmission in the pathophysiology of this disease (Egan et al). However, the dopamine hypothesis has weaknesses, the most prominent of which is the relative ineffectiveness of dopamine-blocking drugs in alleviating many aspects of the disease that have been pointed out by several authors (e.g., Freedman). The complexity of dopamine systems and their interaction with other neurotransmitter circuits make a simplistic mechanism unlikely. Modifications of the dopamine hypothesis of psychosis have included deficiency of GABA or NMDA receptors (see below), both of which balance the dopamine (and glutamate) systems. A hypothesis based on changes in the serotoninergic system has been again proposed. As with the dopaminergic model, attention was drawn to mechanisms relating to a newer class of antipsychotics (clozapine, risperidone), which have major effects on the serotonin system and were found to ameliorate the psychosis. Several groups have reported alterations in serotonin receptors in the brains of schizophrenic patients (see later). A further connection is of an allelic variation in the gene on chromosome 13 encoding for a serotonin receptor (5-HT2A) that confers a susceptibility to schizophrenia (Williams and colleagues). The variation in this gene is insufficient to explain the disease in any one individual, if for no other reason than that many patients who are homozygous for the suspect allele do not develop schizophrenia. Perhaps a nearby region relating to the receptor may be at fault through linkage disequilibrium (see commentary by Harrison and Geddes). A third biochemical hypothesis derives from observations that a psychosis syndrome is produced by chronic ingestion of phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) antagonist and from the NMDA autoantibody syndrome. These implicate the glutaminergic system, but it must be pointed out that the dopaminergic and glutaminergic systems converge on certain cortical neurons and that glutaminergic release is modulated in several places in the brain by dopamine (Lieberman and First). A variety of physiologic and endocrine differences between schizophrenic and healthy subjects have been claimed. None has proved to be significant. Because psychoses may complicate corticosteroid administration and certain endocrine disorders (Cushing syndrome, thyrotoxicosis, see later), there have been many attempts to uncover such abnormalities in the schizophrenic patient; all have failed.

Psychosocial Hypotheses The notion that psychosocial factors play an important role in the genesis of schizophrenia was a recurrent theme in older psychiatric writings but is now given less credence. Prominent in these early writings was Freud’s view that the schizophrenic process represents a fixation at an early autoerotic stage of sexual development. There is no way of affirming or refuting this proposition, even if one adopts a Freudian view of psychodynamics. The same can be said for the many suggestions that disturbed intrafamily relationships engender schizophrenic traits or possibly provoke psychosis in genetically vulnerable persons. Behind all

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these suggestions is disturbance of interpersonal relations in the family that interfered with the normal maturation of personality. The extent to which these aberrations of family relationships are primary or secondary cannot be ascertained. The often-cited observations of Harlow on the deleterious effects of maternal and peer deprivation in primates opened the possibility that similar deprivations in humans may be responsible for the development of schizophrenia. However, such severe degrees of familial deprivation have rarely been documented in humans and when they were, as in some orphans, the effects were only transitory. Nevertheless, stressful life events coincide with the first onset of a psychosis syndrome in some patients destined to manifest schizophrenia. One of these events is entry to college but this happens to coincide with the typical time of onset of schizophrenic symptoms. Also, cannabis use has been noted to be common among individuals with schizophrenia or at a minimum, with an earlier onset of the disorder but a causal link cannot be established (Large et al). Similar considerations may pertain to the earlier mentioned use of psychedelic drugs.

Differential Diagnosis From a neurologic standpoint, the main initial distinction to be made is between an acute schizophrenia-like psychosis and the chronic disease, schizophrenia. A delusional-hallucinatory syndrome in which there is little if any disturbance of consciousness is characteristic of schizophrenia, but it may occur in the manic phase of bipolar disease, encephalitis, temporal lobe epilepsy, chronic amphetamine intoxication, withdrawal from alcohol, glucocorticoids, anti-NMDA encephalitis, and most often in the emergency department, from PCP, angel dust, LSD, and other drug intoxications. On rare occasions it is seen with postpartum psychosis (see further on) and with certain endocrine and metabolic disorders in which consciousness is not impaired. These distinctions are made by the premorbid history and the course of the illness. If the patient had been reclusive, withdrawn, and socially maladapted and does not seem to recover fully from the acute psychosis, then the diagnosis of schizophrenia is likely. Lacking these features, and in particular with a full remission, one assumes the occurrence of hypomania or of a toxic-metabolic psychosis, which can be detected by laboratory screening for drugs and endocrine diseases. Furthermore, it has been estimated that only 10 percent of patients with typical schizophrenia will have such an acute episode. Adherence to the criteria enumerated earlier, particularly to those devised by Feighner and colleagues will avoid most errors in diagnosis. Further complicating matters, is the status of acute schizophrenia and of the so-called schizothymic and schizoaffective states, which bring to light a nosologic problem. How biologically sound is the traditional separation of depressive disease, bipolar disease, and schizophrenia? The suggestion has been made that they are linked in some way by these transitional forms. Neurologists should keep an open mind about these and other theoretical problems that lack a firm genetic and neuropathologic basis.

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In addition to the acute schizophreniform psychosis, the authors have encountered difficulties in the diagnosis of neurological disorders simulating schizophrenia: 1. A patient with a healthy family and premorbid history with an acute illness having many of the typical features of schizophrenia but associated with confusion, forgetfulness, and/or clouding of consciousness. This type of illness combines the features of schizophrenia and a confusional state. This syndrome is characteristic of autoimmune encephalitis, particularly a form caused by anti-NMDA antibody (Chap. 35), of hallucinogenic drug use, particularly phencyclidine intoxication, glucocorticoid-induced psychosis, and thyrotoxic psychosis. Usually, recovery is complete with appropriate treatment, and schizophrenia is excluded by the fact that the patient remains well. 2. Adolescents and young adults whose social relationships are disorganized and who are unusually sensitive, resentful, rebellious, fearful, discouraged, in trouble with school authorities and the law, and using drugs. Such patients may be classified as having a borderline personality or sociopathy that appears to go back several years. These types of personality disorders and social maladjustments turn out not to be schizophrenia. 3. There is another related type of diagnostic problem, arising in an individual who has been only marginally competent because of personality problems and many vague neurotic and hypochondriacal symptoms, often requiring prolonged psychotherapy. Only a few such individuals will indeed later be found to have schizophrenia. 4. In a chronic delusional-hallucinatory state in a patient with chronic alcohol use disorder (chronic alcoholic hallucinosis); it will usually be disclosed that the illness began when alcohol was withdrawn, after a period of sustained drinking, and at first took the form of an acute auditory hallucinosis characterized by threatening, exteriorized auditory hallucinations to which the patient’s emotional reaction was appropriate. Only later do a few of these patients drift into a quiet hallucinatory, mildly paranoid state, with rather bland affect. Cases of this type with which we are familiar had their onset between 45 and 50 years of age, that is, much later than the usual age of onset of schizophrenia. 5. A patient who is confused or stuporous and seemingly catatonic-negativistic, refusing or unable to speak, to execute commands, or to be activated in any way. If signs of focal cerebral or brainstem disease are absent, one is tempted to make a diagnosis of catatonic schizophrenia, not appreciating that catatonia as a phenomenon may be indistinguishable from akinetic mutism (Chap. 16). It may also appear with widespread disease of the associational cortices and as mentioned earlier, with severe depression, certain confusional states, and hysteria. The authors have seen cases of hypoxic and other metabolic encephalopathies, Schilder disease, certain storage diseases, and Creutzfeldt-Jakob disease that were initially mistaken for schizophrenia because of failure to adhere to this principle. 6. A patient with temporal lobe epilepsy who, apart from intermittent psychomotor seizures, has long periods

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(weeks or months) of hallucinations, delusions, bizarre behavior, and disorganization of thinking. Such a disturbance may reflect a persistent state of temporal lobe seizures (temporal lobe status epilepticus), which in some cases has been demonstrated by depth electrodes to originate in the amygdaloid or other medial temporal areas. The nature of the disturbances of emotionality and mentation in such patients, a somewhat controversial subject, is discussed in Chaps. 15 and 24. 7. Patients with prominent depressive symptoms who have made repeated suicide attempts pose an exceptionally difficult problem. They were referred to in the past as schizothymic and to this day it is not certain whether they have schizophrenia, a chronic depressive illness (dysthymia), or both (“schizoaffective”). When in remission, patients with affective disorders are usually normal, whereas those with schizophrenia are not. 8. One should be hesitant to make the diagnosis of schizophrenia during childhood, although such a diagnosis has been entertained in children who have a variety of developmental and adjustment problems and who at some time become psychotic, that is, they become excited, depressed, or hallucinatory and express bizarre ideas. There is no evidence that such children go on to have schizophrenia later in life. And although what are thought to be “schizoid” traits may be recognized in childhood, a frank psychosis is hardly ever recorded at this age. Of particular importance in such children is to exclude the presence of metabolic errors, mental retardation, or an early onset depressive illness. Similarly, childhood autism and particularly its milder forms, such as Asperger syndrome discussed in Chap. 37, should not be confused with schizophrenia. That the incidence of schizophrenia is not increased in the families of autistic children supports the idea that the two are separate diseases. 9. The special problem of mania that manifests for the first time as a confusional-encephalopathic state was discussed in Chap. 48.

Treatment Treatment aims to suppress psychotic symptoms, ameliorate the disorder of thinking and the apathetic state, prevent relapse, and optimize social adjustment. The physician soon becomes accustomed to the pattern of the patient’s psychotic behavior and can help support the patient and his family during difficult periods. Relapse with psychosis may require hospitalization and drug therapy, especially if there is a possible hazard of injury or suicide or difficulty in management at home. Hospitalization aims to protect the patient, relieve the family of the need for constant vigilance and supervision, and ensure the administration of drugs until the exacerbation spends itself. If medication is successful in preventing progressive decompensation, the patient can many times return to the family and community but as often will need a supervised environment. It is invaluable to have a competent social worker or nurse maintain frequent contact with the patient and his family and ensure continuity of medication.

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In recent years a trend of early intervention with a first psychotic episode has gained favor. This includes a more thorough medical evaluation than had been typically conducted in the past and a team approach to reorienting the patient by providing straightforward cognitive behavioral or psychotherapy and family counseling. In some health systems, this has reduced the incidence of relapse. The modern era of treatment of schizophrenia began in 1952, with the incidental demonstration by the French surgeon Henri Laborit of the antipsychosis properties of chlorpromazine (while working as a military physician in Tunisia). Subsequently, many other phenothiazines have been used to treat chronic and acute psychosis but their use is limited by extrapyramidal side effects. Treatment currently consists essentially of the administration of one of several newer antipsychotic medications. The various classes of antipsychotic drugs, their mode of action, and neurologic (“neuroleptic”) side effects are discussed in Chap. 41. The second generation of “atypical” nonphenothiazine antipsychosis drugs that have complex effects on the dopamine and serotonin systems are now used in preference to the standard dopamine antagonists, the phenothiazines and the butyrophenones. They are “atypical” in that their extrapyramidal side effects are far less than that for the phenothiazines. They all serve to calm the patient, blunt emotional responses, and reduce hallucinosis and aggressive and impulsive behavior, leaving cognitive functions relatively intact. The main side effects, pertaining mostly to the phenothiazine group, are summarized in Table 49-1 and Chap. 41. The antipsychotic action of these drugs is more impressive in the short and intermediate term than over the long term, although some data suggest

that they are also of value in preventing relapses. Negative symptoms (apathy and withdrawal) respond less well than positive ones, and it is generally acknowledged that 10 to 20 percent of patients respond little or not at all to medication. Approximately one-quarter of patients will have a relapse while being treated with an effective drug and three-quarters of patients with non-adherence to a previously effective regimen will relapse. Clozapine, olanzapine, risperidone, quetiapine, and others listed in Table 49-2 are common atypical antipsychosis drugs with incompletely defined pharmacologic properties but with narrower affinities for certain receptors. In addition to their reduced extrapyramidal side effects, they produce clinical improvement in about half of patients who have proved to be unresponsive to other antipsychotic medications. These drugs bind to and inhibit serotonin receptors and, to some extent, dopamine receptors (Meltzer and Nash), but have a much lower affinity for striatal dopamine receptors, thus providing an advantage—the absence of immediate or tardive (delayed) extrapyramidal side effects. This has led most psychiatrists to use one of the newer drugs, rather than the phenothiazines, as a first choice. The addition of a second drug, specifically combining clozapine with risperidone, was not found to be useful in a trial (Honer and colleagues). Moreover, in another effectiveness trial sponsored by the National Institutes of Mental Health, (“CATIE” Investigators) found that most chronic patients with schizophrenia discontinued their antipsychosis drugs within 18 months. Among the medications they compared, olanzapine was slightly more effective than quetiapine, risperidone, and ziprasidone; of equal interest, the phenothiazine perphenazine was equivalent in efficacy and tolerability to the last 3 second-generation (atypical) drugs.

Table 49-1 EXTRAPYRAMIDAL SYNDROMES ASSOCIATED WITH TYPICAL NEUROLEPTIC-ANTIPSYCHOTIC AGENTS REACTION

Acute dystonias Parkinsonism Malignant syndrome

“Rabbit” syndrome Akathisia Tardive dyskinesias

FEATURES

MAXIMUM RISK

Muscle spasms; tongue, face, neck, back; terrifying; rarely fatal from asphyxia Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait Catatonia, stupor, fever, unstable pulse, blood pressure and respirations, elevated serum creatine kinase and myoglobin; can be fatal Rare perioral tremor; usually reversible Motor restlessness with anxiety and agitation

1–5 d or with each injection of decanoates Evolves slowly in 1–4 wk, often persists Days to weeks

Oral-facial dyskinesia choreoathetosis, variable dystonia; often slowly reversible; rarely progressive

Months to years Can start immediately and usually persists 6–120 mo; worse when drug stopped

PROPOSED MECHANISMS

TREATMENTS

Dopamine excess

Anticholinergic agents

Dopaminergic deficiency

Oral anticholinergics, amantadine; dopaminergics are too risky

Hypothalamic and extrapyramidal dysfunction likely; not muscle calcium influx problem as in hyperthermia of anesthesia Parkinsonism variant

Stop neuroleptic; expert intensive care; dantrolene or bromocriptine may help

Unknown; adrenergic component

Reduce dose or change drug propranolol; antiparkinson agents and benzodiazepines Prevention best; Tetrabenazine and similar drugs, reintroduction of offending drug and slow tapering, slow spontaneous remission

Dopaminergic excess likely

Oral anticholinergics

Note: Akathisia and early tardive dyskinesias are often overlooked unless specifically considered at examination. The risk of most reactions is greater with high potency, typical neuroleptics, and all but acute dystonia (young males at greatest risk for both acute and tardive dystonias) and akathisia (any age) are more likely in the elderly. Children may also be at elevated risk for parkinsonism as well as reversible neuroleptic withdrawal-associated dyskinesias. (THE HARVARD GUIDE TO PSYCHIATRY: THIRD EDITION, edited by Armand M Nicholi, Jr, MD, Cambridge, Mass.: The Belknap Press of Harvard University Press, Copyright © 1988, 1999 by the President and Fellows of Harvard College. Used by permission. All rights reserved.)

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Table 49-2 “ATYPICAL” ANTIPSYCHOTIC DRUGS WITH LIMITED EXTRAPYRAMIDAL SIDE EFFECTS MEDICATION

BRAND NAME

INITIAL DOSE

TARGET OR MAXIMAL DOSE

Olanzapine Quetiapine Clozapine Risperidone Ziprasidone Aripiprazole Amisolpride

Zyprexa Seroquel Clozaril Risperidol Geodon Abilify Solian

5 mg 25 mg bid 12.5 mg bid 1 mg bid 20 mg 5 mg 100 mg

10 mg 300 mg 300 mg 3 mg bid 160 mg 30 mg 1,000 mg

POTENTIAL SIDE EFFECTSa

Orthostatic hypotension, transaminase elevation, hyperprolactinemia Orthostatic hypotension, cataracts, transaminase elevation Agranulocytosis, transient fever, anticholinergic activity, hyperglycemia Orthostatic hypotension Less weight gain than others in this class. Prolongation of QT interval Less weight gain than others in this class. Prolongation of QT interval  

a

All have the potential to cause tardive dyskinesias and neuroleptic malignant syndrome (see Table 49-1), but these complications are less frequent than with phenothiazines and haloperidol. Weight gain is common with this class of drugs.

Approximately 1 percent of patients treated with one of the most effective drugs, clozapine, develop leukopenia in the first 18 months of treatment, which may be fatal due to overwhelming infections, for which reason monitoring of white blood cell count is incorporated into the treatment plan; there is less risk with the related agent, olanzapine, but leukopenia and agranulocytosis have been reported in rare instances with it as well. Orthostatic hypotension, tachycardia, fever, and hypersalivation may be troublesome in the first days and weeks of therapy with any agent in this class. Risperidone is a potent serotonin and dopamine-receptor antagonist. Low doses reportedly attenuate the negative symptoms of schizophrenia (apathy, emotional withdrawal, lack of social interaction) and the incidence of extrapyramidal side effects is low provided that the dosage is kept below 6 mg daily. Newer classes of agents that are being investigated include agonists 5-HT and trace amine-associated receptors that do not have D-2 activity (Koblan et al) and muscarinic cholinergic receptor agonists combined with peripheral muscarinic blockers to mitigate side effects (Brannan et al). These have only been tested in short-term trials and compared only to placebo. Table 49-2 summarizes typical dosages of some antipsychotic drugs. In the higher dose ranges, parkinsonian features may nevertheless appear. Tardive dyskinesias, however, are infrequent. Common to most of the drugs is weight gain and other aspects of the “metabolic syndrome” including hyperlipidemia and hyperglycemia. With long-term treatment this may accumulate to 20 percent of the patient’s original weight. In a few cases, the newer generation antipsychotics have induced some obsessive-compulsive symptoms. In one meta-analysis of extrapyramidal symptoms and various drugs, low-potency first-generation antipsychotics (excluding haloperidol) may have had similar complications to the new generation of drugs when dose-equivalent amounts are given (Leucht and colleagues). Many clinicians do not agree with this perspective. Several series have also suggested that the atypical antipsychosis drugs have a risk of ventricular arrhythmias and sudden death compared to conventional medications. However, other series indicate that the frequency of these complications, while increased approximately twofold compared to nonusers, are the same for older and newer drugs when adjusted for medication dose (Ray and colleagues). These comparisons are matters of

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ongoing debate; however, a “black-box” warning appears with these drugs in relation to increased mortality risk from cardiovascular events in the elderly. The precise cause(s) of this increase are not clear. Attempts are made to individualize and eventually lower the dosage until the patient’s behavior suggests that a relapse is imminent. Antidepressants and lithium have also been used in those schizophrenic patients with prominent affective symptoms. Electroconvulsive therapy (ECT), which may be effective, is now seldom used except in patients who are catatonic or severely agitated or who have prominent affective symptoms. To some extent, the acute extrapyramidal side effects of haloperidol and the phenothiazines can be mitigated by the simultaneous parenteral administration of antihistaminic drugs—for example, diphenhydramine, 25 mg tid—and the anticholinergic drugs used in the treatment of Parkinson disease—for example, benztropine, 0.5 to 1 mg bid. However, the latter drugs must be given cautiously for they may interfere with the action of the antipsychotic drugs and, if given in large doses, themselves induce a toxic confusional state. If it becomes necessary to treat the extrapyramidal side effects, it is usually possible to eliminate the anticholinergic drugs after 2 to 3 months without a return of motor symptoms. In chronically medicated patients, 20 to 40 percent of whom develop tardive dyskinesias, an increased dose of the antipsychotic drug may suppress the dyskinesia, but only temporarily. The most dreaded complication of pharmacotherapy is the neuroleptic malignant syndrome. The nature and management of this complication and of the more common problem of tardive dyskinesias are discussed in Chaps. 4 and 41.

Outcome of Schizophrenia This is a complex matter as a result of uncertain diagnosis early in a psychotic disorder, variation in socioeconomic and support systems across studies, duration of study, and differences in treatment patterns. Various studies estimate that between 4 and 30 percent of patients who recover from an acute psychotic episode will remain relatively well, even without treatment (Correll et al). So far, no dependable method of predicting outcome has been devised. As an approximation, with modern drug therapy and supportive psychiatric management, approximately 60 percent of schizophrenic patients will recover sufficiently to return

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to their homes and become socially adjusted to varying degrees (about half of this group can engage in some occupation). Approximately 30 percent remain severely disabled and 10 percent remain hospitalized.

DELUSIONAL DISORDER AND PARANOID DISORDER The term paranoid (para = beside, nous = mind) literally means a mind beside itself. It designates patients who show “fixed suspicions, persecutory delusions, dominant ideas or grandiose trends logically elaborated and with due regard for reality once the false interpretation or premise has been accepted. Further characteristics that differentiate pure paranoia from typical schizophrenia are formally correct conduct, adequate emotional reactions, and coherence of the train of thought” (Rosanoff ). In other words, in pure paranoia (delusional disorder in DSM), there is supposed to be no mental defect other than the delusional system—no dementia, hallucinations, or emotional disturbance. In past years, a large group of the mentally ill was classified as paranoid. But with advancing knowledge of mental illness, a decreasing number has been left in this category. The trouble that psychiatrists have taken to couch this definition in negatives implies that paranoia is frequently a feature of other forms of mental illnesses, notably schizophrenia, bipolar disease, Alzheimer disease, Lewy-body disease, toxic or alcoholic psychosis, and general paresis. This fact about paranoia was known from the beginning, when Heinroth originally described it in 1818 and classified it as a limited disorder of the intellect. Kraepelin, in agreement with the ideas of Kahlbaum, distinguished between paranoia and dementia praecox, but remarked that approximately 40 percent of patients who developed paranoia early in life went on to become schizophrenic. In DSM-IV, this disorder is classified as “delusional (paranoid) disorder” and defined it as a persistent delusion that is not part of any other mental disorder. Furthermore, the delusions are nonbizarre, that is, while improbable, they involve situations that could occur in real life, such as being followed, poisoned, infected, loved at a distance, deceived by a spouse, or having a disease. Figures on the frequency of isolated paranoia are probably not reliable because they are of necessity based on hospital records. Doubtless there are many individuals with mild forms of the disorder who have never crossed the threshold of a mental hospital. These individuals are relatively harmless and in their communities are judged to be “off,” eccentric, or simply odd. Males and females are equally affected. Among psychiatric hospital patients, true isolated paranoia has been rare, accounting for approximately 0.1 percent of admissions (Winokur).

Clinical Manifestations It would be difficult to give an account of all the ways in which patients with paranoia behave. A simple amalgam will suffice—that of a middle-aged man of uneasy,

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brooding, asocial, eccentric nature who gradually develops a dominating idea or belief of his own importance, of having in his possession special powers that make him the envy of others who become bent on persecuting him. As the delusion grows, he becomes more preoccupied, less efficient, and increasingly suspicious of others, with a tendency to interpret every one of their words, gestures, or actions as having some reference to himself. On examining such a person, one is impressed with his capacity for careful reasoning, even betraying good intelligence. Whatever the delusional theme—erotomania (a delusion that another person, usually of higher status, is in love with the patient), grandiose, jealous, persecutory, or somatic, the last being the most common—the patient’s arguments are logical and buttressed cogently by evidence. The patients express their false beliefs with certainty and conviction and are totally unaccepting of all arguments that impugn their rationality. Also, the views of such patients about matters other than their delusions can be quite sensible. The querulous patients with paranoia are the most problematic. They remain in the community, flooding the mails and emails with documents accusing people falsely of various misdeeds, incessantly writing to newspapers and websites, and expressing their opinions about anything and everything. As the years pass, the patient changes little, although a few such patients may later break down and begin to hallucinate and finally end in a deteriorated state much like that of schizophrenia. This trend supports Bleuler’s opinion that the illness is a variant of schizophrenia. Regarding causation, there have been several completely unverifiable ideas. The Freudian school attributed paranoia to repressed homosexuality and fixation at the narcissistic level. Meyer invoked a long-standing personality disorder, the paranoid constitution, using the term to refer to a lifelong tendency to hold biased views, to be overly concerned about what others think of the individual, and to attribute deliberate intentions to indifferent actions. There have been many discussions of proposed psychologic mechanisms of paranoia (Manschreck). The authors’ experience with pure paranoia in a general hospital has been limited. One sees deluded patients, to be sure, but usually their abnormal ideas have centered on self-persecution, health and bodily functions, infidelity of a spouse, theft of possessions, and the like. The claim that poisoning by carbon monoxide has left the person with ill-defined defects in concentration and other mental functions or the belief that there exists an unobservable parasitic skin infestation have been the most common delusions in our experience. Whether unshakable beliefs about Lyme disease or environmental toxins or multiple imagined allergies fit in this category is unclear. One of our patients, functioning normally in every other way, carried the unshakable idea that people were sneaking into her house at night when she was away and rearranging the furniture. She functioned extremely well through her eighties but had a schizophrenic sister. Also, several physicians under our care have woven extensive delusional ideas around tenuous scientific theories; these ideas have applied to personal life events as well as physical and psychologic symptoms and in some cases have resulted

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Chapter 49 Psychosis, Schizophrenia, Delusional, and Paranoid States

in bizarre regimens of self-medication. Rarely, a patient comes to the hospital for some other medical reason, and it is found that they have been living quietly in the community, preoccupied with a strange and outlandish delusional system, yet appearing neither depressed nor schizophrenic. Certainly, one often sees delusions in depressed patients who decompensate as their depression deepens. Sharply separated from the more or less pure delusional disorders are the ones that occur as part of a confusional state or delirium. Delusions occurring in the latter setting are characteristically bizarre, changeable, poorly systematized, and, with rare exceptions, transitory and are associated with many other aberrations of mental function. The same can be said for delusions that occur in the early stages of a dementing disease. Such events are common, of course, in elderly persons with an incipient or well-compensated dementia (called by Raymond Adams, “beclouded dementia”; see Chap. 19). Occasionally, one of the degenerative dementing diseases of middle and late life (Alzheimer, Huntington, and especially Lewy-body) presents first with a delusional disorder. Otherwise healthy persons without known mental illness may experience a brief delusional episode, notably after surgical procedure or the administration of sedative drugs or at times of extreme personal stress. In most, there are no subsequent mental problems, but a proportion of these older patients will be found to later develop dementia. There is also the frequent problem of varied delusions with manic states that are part of the bipolar disorder discussed in Chap. 48 in which the ideas tend not to be always so clearly persecutory, are usually multiple and disconnected to each other, and often reflect misidentification or distortion of memories. Certain drugs have a tendency to produce paranoia in otherwise nonpsychotic individuals; corticosteroids, phencyclidine, amphetamine, psychedelics, and cocaine are the main offenders seen in patients arriving in emergency departments, and anticholinergic drugs are often responsible in hospitalized patients. A few patients became depressed, sometimes profoundly, after use of interferon for multiple sclerosis and display delusional thinking. Some antiseizure drugs, among them levetiracetam, may have delusions or psychotic-like syndromes as part of an induced depression. These have all been called “organic delusions” (Cummings).

Management We have no way of determining whether psychotherapy has influenced these states of paranoia and delusion; our impression is not. In a general hospital, where most of our paranoid patients have been depressed, manic, or demented, we have several times been gratified by the effects of antidepressant or antipsychotic medication, with full knowledge of the potential risks discussed earlier. In the treatment of patients with pathologic jealousy, at least one report in an earlier era found phenothiazine drugs to be useful (Mooney) but this is anecdotal. From what has been said, the clinical analysis of patients with delusions requires a careful study of mood and cognitive function to rule out bipolar disease and dementia. If either of these two states exists, the treatment

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proceeds along the lines discussed in Chaps. 20 and 48. A matter of practical importance is for the physician to evaluate the nature of the delusional ideas and try to judge whether the patient is homicidal or suicidal. Occasionally, physicians and others have been killed or maimed by patients with paranoia who thought they were being mistreated.

POSTPARTUM PSYCHOSES (SEE ALSO POSTPARTUM DEPRESSION IN CHAP. 48) Parturition, associated as it is with many biologic disturbances such as the effects, drugs, eclampsia, hemorrhage, infection, and perhaps most prominently, an abrupt hormonal adjustment, is frequently associated with a disturbance of mood. Obstetricians have observed that a woman may feel extraordinarily well immediately postpartum, only to lapse in the following days into a weepy, depressed state in which she may be distressed by lack of feeling for her newborn infant. Usually this lasts for only a few days (“postpartum blues”), being quelled by the return home, responsibility for the infant, and nursing. In some patients, however, the depressive symptoms persist for months (see later). A few affected women have psychosis appended to a severe depression but there is apparently an independent entity of postpartum psychosis with no overt depression. As mentioned in the previous chapter, some authors have questioned the existence of a special depressive illness that is linked to the postpartum period, an opinion that is not supported by our clinical experience (see Brockington). Depression during pregnancy may be a separate entity and is noted in Chap. 48. The period after childbirth is therefore also one in which there is a potential disposition to psychosis. Opinion varies as to whether there is a special puerperal, or postpartum psychosis. Some psychiatrists believe that the psychotic break that may occur at this time is either a confusional-delirious state or a schizophreniform or depressive psychosis, and that these illnesses do not differ from those occurring at other times in life. Postpartum psychosis is therefore not easily categorized. It has its onset between 48 and 72 h or longer after a delivery that may have been complicated by excessive bleeding or infection but as often, is not. The patient alternates between periods of noisy hyperactivity and of mutism and inactivity. She is disoriented and incapable of thinking clearly. The baby is sometimes rejected as not belonging to her (instances of infanticide are not unknown). Although the illness has some features of delirium, it may merge with a schizophrenic or depressive type of psychosis that persists for months. In a series of such cases, approximately 40 percent were predominantly affective, 20 percent schizophreniform, and the remainder self-limited confusional psychoses (Boyd). Some experts have argued that a delirium with fluctuating attention and cognitive difficulties are characteristic of the disorder. There certainly may be perceptual alterations but the outstanding and most dangerous aspects in patients we have seen are suicidal and infanticidal thoughts. New approaches to the treatment of

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postpartum depression using “neuro-steroids” are being investigated but it is not clear if they will be applicable to postpartum psychosis. In the diagnosis of postpartum psychosis, one must keep in mind the possibility of eclampsia, the consequences of pituitary infarction, cerebral vein thrombosis or transitory stroke of arterial type, ergot-induced psychosis, and hypotensive-hypoxic cerebral injury. The treatment of such patients follows the methods described in Chap. 48 and in the following text.

THE ENDOCRINE PSYCHOSES One of the most provocative observations in contemporary psychiatry had been that healthy individuals may become psychotic when they develop hyper- or hypothyroidism or Cushing syndrome, or less often, adrenal insufficiency, or when they receive therapeutic doses of corticosteroids. If these conditions were no more than examples of druginduced psychosis, they would be interesting enough. The fact is, however, that they differ considerably from the usual toxic deliria or confusional states. The syndrome comprises features that are suggestive of bipolar disorder with psychosis or schizophrenia on the one hand and of confusional psychosis on the other. These endocrine psychoses have far-reaching medical significance, for they provide artificial models and a neurologic perspective of psychoses created by the manipulation of metabolic and exogenous factors. It is appropriate that they are in the last chapter in a neurology book.

Corticosteroid (Glucocorticoid) and Adrenocorticotropic Hormone Psychosis First described in arthritic patients being treated with cortisone, these syndromes now occur far less frequently than when corticosteroids were introduced into medical practice. The psychosis usually develops over a period of a few days after the patient has received the medication for a week or more. The features are extremely variable. Depression and insomnia are the most frequent early symptoms, but some patients become elated, agitated, excited, and talkative, as though under pressure to speak, whereas others are mute; or the prevailing emotional response may be one of anxiety and panic. Thinking may be slightly illogical, tangential, or incoherent. Hallucinations and sensory misinterpretations may appear. However, clouding of the sensorium and disorientation, the hallmarks of deliria and the confusional states, have been less prominent. Nevertheless, the state of awareness may not be altogether normal, and at times the patient is bewildered. If administration of the drug is discontinued as soon as symptoms appear, the psychosis subsides but only gradually over several days to weeks, with complete recovery. In patients with Cushing disease, mental changes are similarly known. In some patients there is a combination of affective disorder and impairment of cognitive function, usually apparent during mental status testing. Also, among athletes taking anabolic steroids, some develop affective

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and psychotic symptoms—reduced sleep, irritability, aggression, paranoid delusions, auditory hallucinations, and euphoria or depression. Mental changes in Addison disease are less frequent and more varied. Irritability, confusion, disorientation, and convulsions, with or without symptoms of hypoglycemia, have been the main features. Low energy from pituitary of adrenal failure simulates depression but may not have an affective component. The mechanisms are not well understood. From the few available studies, it has been deduced that the occurrence of psychosis is not related to the premorbid personality. Although the dosage of corticosteroid or adrenocorticotropic hormone (ACTH) has usually been high, there has been no definite correlation between the dosage and the occurrence, severity, and duration of psychosis. In a study of patients with systemic lupus erythematosus, 5 percent of patients became psychotic with steroid treatment, and for an obscure reason, only hypoalbuminemia was found by statistical analysis to be an associated factor and this is not entirely plausible (Chau and Chi). A history of anxiety or of a family history of psychiatric disease had only a marginal predictive value for steroid-induced psychosis. The notion held by many neurologists that dexamethasone is less frequently associated with psychosis than other corticosteroids is unproven. Lithium is often effective in controlling manic symptoms, allowing continuation of the corticosteroid therapy if necessary for the underlying medical condition (Falk et al).

“Thyroid Psychosis” A great deal has been written about the pervasive effects of abnormal thyroid function on all organs, including the neuromuscular apparatus and central nervous system. These are discussed in Chap. 39 with other acquired metabolic diseases of the nervous system, but mental changes with these endocrinopathies are not nearly as frequent or prominent as for adrenal and pituitary disorders. The hyperthyroid patient shows minor changes in emotions and mentation. Restlessness, irritability, apprehension, emotional lability, and at times even agitation and a generalized chorea may occur. Either of two trends may be observed in the relatively rare thyrotoxic patient who develops psychosis. There may be a mild manic state, with its characteristic increase in psychomotor activity, excessive talkativeness, and flight of ideas, or there may be depression, with its somber mood, weeping, and anxiety. Visual and auditory hallucinations may be present in both groups. Usually there is something more than simple mania or agitated depression, that is, some clouding of the sensorium with perplexity and confusion, suggestive of delirium. The condition is said to be related to the premorbid personality, some personality types being more vulnerable, but this is disputed. It can be stated that the psychiatric changes are not directly related to the severity of the thyrotoxicosis. Treatment of the hyperthyroidism does not result in prompt arrest of the psychic disorder; recovery usually takes place over a period of months. One must distinguish this illness from other types of recurrent psychoses that happen to be coincidental with or precipitated by hyperthyroidism and from the steroid-responsive

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Chapter 49 Psychosis, Schizophrenia, Delusional, and Paranoid States

encephalopathy called “Hashimoto encephalopathy” mentioned below. With myxedema there is a characteristic slowness and thickness of speech and in extremes, drowsiness, hypothermia, mental dullness, listlessness and apathy, irritability, and sometimes suspiciousness. The patient may sleep much of the time, having to be awakened for meals. A disturbance of memory and the lack of genuine symptoms of depression, such as feelings of hopelessness and loss of self-esteem, help to distinguish the mental disorder of myxedema from that of a depressive illness. Nevertheless, unless one thinks of myxedema in cases of psychomotor retardation, the diagnosis will be missed. Reduced cerebral

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blood flow and metabolism have been found in myxedema; with specific therapy, these functions are restored to normal within 2 to 3 weeks. An entirely different type of mental disturbance characterized by intermittent delirium and stupor often associated with myoclonus and autoimmune in nature may occur in patients with thyroiditis or at least, with the autoantibodies associated with this disorder (“Hashimoto encephalopathy,” Chap. 39). The illness is responsive to glucocorticoids. The diagnosis is confirmed by the finding of circulating antibodies to thyroglobulin and thyroid peroxidase but there are high rates of false positive tests, particularly in middle-aged and older women.

References Akbarian S, Kim JJ, Potkin SG, et al: Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. Arch Gen Psychiatry 53:425, 1996. American Foundation: Medical Research: A Mid-Century Survey. Boston, Little, Brown, 1956. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5). Washington, DC, APA, 2013. Andreasen NC: Symptoms, signs, and diagnosis of schizophrenia. Lancet 346:477, 1995. Benes FM, Davidson J, Bird ED: Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry 43:31, 1986. Bleuler E: Dementia Praecox or the Group of Schizophrenias. Zinkin J (trans). New York, International Universities Press, 1950. Boyd DA: Mental disturbances with childbearing. Am J Obstet Gynecol 43:148, 1942. Brockington I: Postpartum psychiatric disorders. Lancet 363:303, 2004. Brannan SK, Sawchak S, Miller AC, et al: Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med 384:717, 2021. Carlsson A: The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1:179, 1988. Carpenter WT, Buchanan RW: Schizophrenia. N Engl J Med 330:681, 1994. Charlson FJ, Ferrari AJ, Santomauro DF, et al: Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull 44:1195, 2018. Chau SY, Chi CM: Factors predictive of corticosteroid psychosis in patients with systemic lupus erythematosus. Neurology 61:104, 2003. Correll CU, Rubio JM, Kane JM: What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 17:149, 2018. Corsellis JAN: Psychoses of obscure pathology. In: Blackwood W, Corsellis JAN (eds): Greenfield’s Neuropathology. London, Edward Arnold, 1976, pp 903–915. Cummings JL: Organic delusions. Br J Psychiatry 46:184, 1985. Cutting J: Memory in functional psychoses. J Neurol Neurosurg Psychiatry 42:1031, 1979. de Vries PJ, Honer WG, Kemp PM, et al: Dementia as a complication of schizophrenia. J Neurol Neurosurg Psychiatry 70:588, 2001.

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Dunlap CR: The pathology of the brain in schizophrenia. Res Publ Assoc Res Nerv Ment Dis 5:371, 1928. Egan MF, Goldber TE, Kolachana BS, et al: Effect of COMT Val108/158 Met genotype on frontal lobe dysfunction and risk for schizophrenia. Proc Natl Acad Sci U S A 98:6917, 2001. Falk WE, Manke MW, Poskanzer DC: Lithium prophylaxis of corticotropin-induced psychosis. JAMA 241:1011, 1979. Feighner JP, Robins E, Guze SB, et al: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57, 1972. Flor-Henry P: Lateralized temporo-limbic dysfunction and psychopathology. Ann N Y Acad Sci 280:777, 1976. Frith C: The pathology of experience. Brain 127:239, 2004. Goodwin DW, Guze SB: Psychiatric Diagnosis, 5th ed. New York, Oxford University Press, 1996. Harlow H: Learning to Love. New York, Jason Aronson, 1974. Harrison PJ, Geddes JR: Schizophrenia and the 5-HT2A receptor gene. Lancet 347:1274, 1996. Honer WG, Thornton AE, Chen EY, et al: Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 354:472, 2006. Jablensky A: Epidemiology of schizophrenia: A European perspective. Schizophr Bull 12:52, 1986. Johnstone EC, Crow TJ, Frith CD, et al: The dementia of dementia praecox. Acta Psychiatr Scand 57:305, 1978. Jones P, Rodgers B, Murray R, Marmot M: Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 344:1398, 1994. Kallmann FJ: The genetic theory of schizophrenia: An analysis of 691 twin index families. Am J Psychiatry 103:309, 1946. Kane JM, Marder SR: Psychopharmacologic treatment of schizophrenia. Schizophr Bull 19:287, 1993. Koblan KS, Kent J, Hopkins SC, et al: A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med 382:1497, 2020. Kraepelin E: Robertson GM (ed): Dementia Praecox and Paraphrenia. Barclay RM (trans). Edinburgh, UK, Livingstone, 1919. Large M, Sharma S, Compton MT, et al: Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry 68:555, 2011. Lawrie SM, Whalley H, Kestelman JN, et al: Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 353:30, 1999. Leucht S, Wahlbeck K, Hamman J, et al: New generation antipsychotics versus low-potency conventional antipsychotics: A systematic review and meta-analysis. Lancet 361:1581, 2003.

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Part 6 PSYCHIATRIC DISORDERS

Levin S, Jones A, Stark L, et al: Identification of abnormal patterns in eye movements of schizophrenic patients. Arch Gen Psychiatry 39:1125, 1982. Liddle PF: The symptoms of chronic schizophrenia: A re-examination of the positive-negative dichotomy. Br J Psychiatry 151:145, 1987. Liddle PF, Barnes TRE: Syndromes of chronic schizophrenia. Br J Psychiatry 157:558, 1990. Lieberman JA, First MB: Psychotic disorders. N Engl J Med 379:270, 2018. Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209, 2005. Marder SR, Cannon TD: Schizophrenia. N Engl J Med 381:1753, 2019/ McClellan J, King M-C: Genomic analysis of mental illness. A changing landscape. JAMA 303:2523, 2011. Meltzer HY, Nash JF: Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43:587, 1991. Meyer A: Fundamental conceptions of dementia praecox. In: Collected Papers of Adolph Meyer. Vol 2. Baltimore, MD, Johns Hopkins University Press, 1950. Mooney H: Pathologic jealousy and psychochemotherapy. Br J Psychiatry 111:1023, 1965. Morrison J, Winokur G, Crowe R, Clancy J: The Iowa 500: The first follow-up. Arch Gen Psychiatry 29:677, 1973. Mortensen PB, Pedersen CB, Westergaard T, et al: Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med 340:603, 1999. Pearlson GD: Neurobiology of schizophrenia. Ann Neurol 48:556, 2000. Ray WA, Chung CP, Murray KT, et al: Atypical antipsychotic drugs and the risk of sudden death. N Engl J Med 360:225, 2009. Robins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. Am J Psychiatry 126:983, 1970. Rosanoff AJ: Manual of Psychiatry. New York, Wiley, 1920. Rosenthal D, Wender PH, Kety SS, et al: Parent-child relationships and psychopathologic disorder in the child. Arch Gen Psychiatry 32:466, 1975. Sabri O, Ekworth R, Schreckenberger M, et al: Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics. Lancet 349:1735, 1997.

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Schneider K: Clinical Psychopathology. Hamilton MW (trans). New York, Grune & Stratton, 1959. Seidman LJ: Schizophrenia and brain dysfunction: An integration of recent neurodiagnostic findings. Psychol Bull 94:195, 1983. Shenton ME, Kikinis R, Jolesz FA, et al: Abnormalities of the left temporal lobe and thought disorder in schizophrenia. N Engl J Med 327:604, 1992. Silbersweig DA, Stern E, Frith C, et al: A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176, 1995. Spielmeyer W: The problem of the anatomy of schizophrenia. J Nerv Ment Dis 72:241, 1930. Suddath RL, Christison GW, Torrey EF, et al: Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 322:789, 1990. Taylor MA: Schneiderian first-rank symptoms and clinical prognostic features in schizophrenia. Arch Gen Psychiatry 26:64, 1972. Tsuang MT, Faraone SV, Green AI: Schizophrenia and other psychotic disorders. In: Nicholi AM Jr (ed): The Harvard Guide to Psychiatry, 3rd ed. Cambridge, MA, Belknap Harvard University Press, 1999, pp 240–280. Waddington JL: Schizophrenia: Developmental neuroscience and pathobiology. Lancet 341:531, 1993. Ward, Mary Jane: The Snake Pit. Random House, New York. 1946. Weinberger DR, Berman KF, Zec RF: Physiologic dysfunction of the dorsolateral prefrontal cortex in schizophrenia: Regional cerebral blood flow evidence. Arch Gen Psychiatry 43:114, 1986. Weinberger DR, Torry EF, Neophytides AN, Wyatt RJ: Lateral cerebral ventricular enlargement in chronic schizophrenia. Arch Gen Psychiatry 36:735, 1979. Williams J, Spurlock G, McGuffin P, et al: Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. Lancet 347:1294, 1996. Winokur G: Delusional disorder (paranoia). Compr Psychiatry 18:511, 1977. Winokur G, Tsuang M: The Iowa 500: Suicide in mania, depression and schizophrenia. Am J Psychiatry 132:650, 1975. Woo TU, Whitehead RE, Melchitzky DS, et al: A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci USA 95:5341, 1998. Woods BT: Neurologic soft signs in psychiatric disorders. In: Joseph AB, Young RR (eds): Movement Disorders in Neurology and Neuropsychiatry. Cambridge, MA, Blackwell, 1992, pp 438–448.

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Index Note: Page numbers followed by f indicate figures; and page numbers followed by t indicate tables. A AA (Alcoholics Anonymous), 1190 AASM (American Academy of Sleep Medicine) sleep scoring system, 400, 403t ABC syndrome, 149 ABC1 mutation, 1333 ABCD1 mutation. See Adrenoleukodystrophy (ABCD1 mutation) ABCD2 Score, 790t, 791 Abdominal migraine, 183 Abducens (sixth) nerve anatomy of, 270–271, 271f disorders of, 270–271, 273, 274f, 275t, 277 in horizontal gaze, 265, 265f in multiple cranial nerve palsies, 1368 Abetalipoproteinemia (BassenKornzweig acanthocytosis), 973, 1333 Aβ (beta amyloid) protein, 1060, 1060f, 1061 Abiotrophy, 1052 Ablative surgery, for pain, 152–153 Abortive poliomyelitis, 758–759 Abscess brain. See Brain abscess epidural. See Epidural abscess spinal cord, 1238, 1241 subdural. See Subdural abscess Absence (petit mal) seizures atypical, 324–325 characteristics of, 324 diagnosis of, 339 EEG in, 31f, 33, 324 treatment of, 353 Absolute (perfect) pitch, 600 Abstinence syndrome. See Withdrawal Abulia, 366, 426, 466, 527 ACADM mutation (acyl-CoA dehydrogenase deficiency), 1410 Acalculia, 600, 1057 Acamprosate, 1189 Acanthocytosis Bassen-Kornzweig, 973, 1333 with chorea, 1091–1092 ACE (angiotensin-converting enzyme) inhibitors, 837, 903 Acebutolol, 397

Aceruloplasminemia (CP deficiency), 978 Acervuli, 569 Acetaldehyde metabolism, 1179 Acetaminophen for migraine, 187 for nutritional polyneuropathy, 1161 for pain, 151t Acetazolamide for cerebral edema, 646 for high-altitude sickness, 1131 in hypokalemic periodic paralysis treatment, 1454 for paramyotonia congenita, 1452 for pseudotumor cerebri, 632 Acetazolamide-responsive myotonia, 1452 Acetylcholine (ACh) age-related changes in, 612 in alpha motor neurons, 56 in autonomic nervous system, 535, 536 in basal ganglia, 77 Acetylcholine esterase (AChE) inhibitors, 1446 Acetylcholine receptor (AChR), 1446, 1446t Achilles reflex, 212, 213 Achlorhydria, 1167 Achondroplasia, 1261 Achromatopsia, 260, 482 Acid lipase deficiency, 950t Acid maltase deficiency (GAA mutation), 512, 1406–1407, 1408t Acid-base disorders, 1142 Acidemia glutaric, 946, 981 propionic, 945t, 946, 1072 pyruvic, 1174t Acidosis diabetic, 1134 metabolic, 1142, 1182 Acidurias, organic, 946 ACLDVL mutation (acyl-CoA dehydrogenase deficiency), 1410 Acoustic neuroma. See Vestibular schwannoma Acoustic-stapedial reflex, 298 Acquired immunodeficiency syndrome. See HIV infection

Acrocephalosyndactyly, 1002–1003 Acrocephaly, 999 Acromegaly clinical features of, 573, 677 diagnosis of, 677 pituitary adenoma and, 677 polyneuropathy in, 1334 treatment of, 678 weakness in, 1414 Acroparesthesias, 408, 420 Acrylamide poisoning, 1301 ACTH. See Adrenocorticotropic hormone Actin, 1370 Actinomyces, 1242 Actinomycosis, 729 Action potentials compound muscle, 39–40, 40f, 41t, 42f, 43–44 in EMG, 44–45, 44f sensory nerve, 40, 42f Acupuncture, 153, 209 Acute bacterial endocarditis (ABE), 712 Acute disseminated encephalomyelitis (ADEM) in children, 931 clinical features of, 931–932, 1243 CSF examination in, 931 differential diagnosis of, 744, 923 imaging in, 931–932, 932f mortality rates in, 930 pathogenesis of, 912, 931 postinfectious, 932 postvaccinal, 932–933 treatment of, 933 Acute inflammatory demyelinating polyneuropathy (AIDP). See Guillain-Barré syndrome Acute mountain sickness, 1131 Acute necrotizing encephalomyelopathy, 990. See also Subacute necrotizing encephalomyelopathy (Leigh disease) Acute necrotizing hemorrhagic encephalomyelitis (Hurst disease), 933–934, 933f Acyclovir, 197, 748, 753 Acyl-CoA dehydrogenase deficiency disorders, 1410 Adamantinoma, 674–675 Adamkiewicz artery, 1249, 1249f

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Index

Adams-Stokes-Morgagni syndrome, 393 ADAMTS13, 868 Addiction to alcohol. See Alcohol use and alcoholism to barbiturates, 1195 to chloral hydrate, 1196 headache in, 182 to meperidine, 1192 to opioids. See Opioid addiction (opioid use disorder) pain treatment in, 148 to propoxyphene, 1192 Addison disease, 576, 1142, 1414, 1516 ADEM. See Acute disseminated encephalomyelitis Adenoma parathyroid, 1414 pituitary acromegaly in, 677 age-linked, 675 amenorrhea-galactorrhea syndrome in, 677 apoplexy in, 679 bitemporal hemianopia in, 676 Cushing disease in, 677 diagnosis of, 676t, 677, 678f empty sella syndrome in, 678 endocrine system disorders with, 677 headache in, 676 optic neuropathy in, 258 treatment of, 575, 678–679 Adenoma sebaceum, 1013, 1015, 1015f Adenosine diphosphate (ADP), 1405 Adenosine triphosphatase (ATPase), 958 Adenosine triphosphate (ATP), 618, 785, 1405 ADH. See Antidiuretic hormone ADH (alcohol dehydrogenase), 1179 ADHD. See Attention-deficit hyperactivity disorder Adiadochokinesis, 115 Adie pupil, 288, 288t, 548, 551 Adiposogenital dystrophy, 572–573 Adolescent adjustment reaction, 603 Adolescents cognitive rest in, 900 depression in, 1500 dysphonia in, 506 failure of puberty in, 572 growth and development of anatomic basis of, 583, 584f intelligence, 590 motor, 586 sexual, 591–592

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inherited metabolic diseases in. See Children, inherited metabolic diseases in, of late childhood and adolescence Moyamoya disease in, 824–825 precocious puberty in, 572 schizophrenia in, 1511 seizures in causes of, 340f, 340t, 342 juvenile myoclonic epilepsy and, 325 temporal lobe, 328–329 treatment of, 342 sleep in, 399, 403f sociopathy in, 1482 stroke in, 827–829, 828t subacute sclerosing panencephalitis in, 762 toe walking in, 1113 ADP (adenosine diphosphate), 1405 Adrenal gland neuroendocrine syndromes related to, 575–576 sympathetic innervation of, 534, 536, 539 Adrenergic receptors, 536 Adrenocorticotropic hormone (ACTH) actions of, 539, 566t, 567 for adrenoleukodystrophy, 983 low levels of, 576, 1414 for MS, 925 in pituitary adenoma, 677 psychosis and, 1516 for tuberous sclerosis, 1017 Adrenoleukodystrophy (ABCD1 mutation) clinical subtypes of, 982 cortical blindness in, 982 differential diagnosis of, 960t genetic factors in, 982 in heterozygous female carriers of, 983 laboratory diagnosis of, 983 MRI in, 983, 983f onset of, 982 treatment of, 983 Adson maneuver, 224f Adson test, 224 Adult attention-deficit disorder, 602–603 Advanced-sleep-phase syndrome, 411 Aerocele, 882, 896 Affect in confusional states, 426 definition of, 520 pseudobulbar, 523–524, 523t Affective (mood) disorder, 1489. See also Depression

Afferent pathways in pain mechanisms peripheral, 135–136, 135t, 136f, 143, 157 spinal, 137–139, 138f, 139f visceral, in autonomic nervous system, 535–536 African trypanosomiasis, 414 AGA mutation (aspartylglycosaminuria), 950t, 970 Age-associated memory impairment (AAMI), 609 Age-related changes anatomic, 608t in brain, 611–612 in central nervous system neoplasm incidence, 643 in cerebrovascular disease, 773t in cognitive function, 439–440, 608–609 vs. degenerative changes, 1052–1053 in epilepsy, 322f, 340–343, 340f, 340t in equilibrium, 305 frailty and, 607, 608t in gait, 610 in hearing, 607 in learning, 609 macular degeneration, 252 in memory, 439–440, 608–609 in mental status examination, 609 in motor functions, 607, 610–611 in MS onset, 910 in muscles, 612–613, 1372 in nerves, 612–613 neurologic, 607–608, 608t in neurotransmitters, 612 in obsessive-compulsive disorder, 1475 in personality, 609–610 in pupil size, 286 in reflexes, 607–608 in seizures, 321, 322f, 340–343, 340f, 340t in sensory function, 163, 165, 234, 236, 607–608 in sleep, 399, 402, 403f in smell sense, 234, 607 in spine, 204 in taste sense, 236 in vibration sense, 608 in vision, 243 Ageusia, 233, 236–237, 237t Aggressive behavior, 517, 524–525, 526f, 529 Agitated delirium, 431–432. See also Delirium AGL mutation. See Debranching enzyme deficiency (Cori-Forbes disease, AGL mutation)

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Index Agnosia auditory, 471 Balint syndrome and, 260, 478, 483 color, 482 olfactory, 232, 235 pain perception in, 149 in parietal lobe lesions, 475–476 prosopagnosia, 481–482 tactile, 166–167 verbal auditory, 596 visual, 259–260, 481–483, 1129 visual object, 481 visual simultanagnosia, 482 Agoraphobia, 1472, 1474 Agrammatism, 466, 496 Agranular cerebral cortex, 462, 462f, 464 Agraphesthesia, 474, 475 Agraphia alexia with, 501 alexia without, 482, 484, 495t, 500–501 aphasic, 502 apraxic, 502 constructional, 502 lexical, 503 linguistic, 502–503 phonologic, 503 writing in, 502–503 Agyria. See Lissencephaly AICA (anteroinferior cerebellar artery), 803, 806 Aicardi syndrome, 999, 1004 AIDP (acute inflammatory demyelinating polyneuropathy). See Guillain-Barré syndrome AIDS. See HIV infection Air embolism, cerebral, 778 Akathisia antipsychotics and, 1512t causes of, 104, 426, 529 characteristics of, 104 phenothiazines and, 1198 Akinesia, 78, 465 Akinetic mutism, 366, 426 ALA (aminolevulinic acid), 1209 Alarm clock headache, 189–190 Albendazole, 733, 734, 1379 Alberta Stroke Program Early CT Score (ASPECTS), 790t, 791 Albinism, 245, 963 Albumin, in CSF, 17 Albuterol, 1452 Alcohol dehydrogenase (ADH), 1179 Alcohol use and alcoholism accidents caused by, 1178 aggressive behavior induced by, 526 blood alcohol levels in, 1179

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central pontine myelinolysis in. See Central pontine myelinolysis (CPM) cerebral atrophy in, 1187 clinical effects of, 1181–1182 dementia in, 1187–1188 depression in, 1179, 1500 etiology of, 1178–1179 fetal alcohol syndrome and, 1188–1189 genetic factors in, 1179 headache and, 174 incidence of, 1178 intoxication in blackouts and, 1181 coma and, 382t, 1181 gait in, 123, 124 pathologic, 1181 stuttering in, 598 treatment of, 1181–1182 mania in, 1184 myopathy in, 1417–1418 nutritional deficiencies in, 1153, 1187 cerebellar degeneration and, 1098, 1170–1171, 1171f Marchiafava-Bignami disease and, 1171–1172 optic neuropathy and, 1169–1170 pellagra and, 1162–1163 polyneuropathy and, 1299, 1322 spinal spastic and ataxic syndrome and, 1169 Wernicke-Korsakoff syndrome and. See Wernicke-Korsakoff syndrome optic neuropathy and, 256 pharmacology and physiology of, 1179–1180 in pregnancy, 1188–1189 psychiatric diseases and, 1190 psychosis in, 1184 schizophrenia in, 1511 smell sense and, 234 tolerance in, 1180 treatment of, 1189–1190 withdrawal from, 1182, 1183t auditory hallucinosis in, 1184 delirium in, 431–432, 1185. See also Delirium tremens hallucinations in, 1183 management of, 1186–1187 morning shakes in, 88, 1183 pathogenesis of, 1185–1186 seizures in, 343, 1184–1185 tremors in, 88, 1183 Alcoholics Anonymous (AA), 1190 Aldosterone deficiency, 511 Aldosteronism, primary (Conn syndrome), 1414, 1455

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Alemtuzumab, 926 Alertness, 362, 370–371 Alexander disease (GFAP mutation), 956, 959 Alexander’s law, 281 Alexia with agraphia, 501 definition of, 260 without agraphia, 482, 484, 495t, 500–501 Algesic paresis, 1373 Algodystrophy, 147 Alien hand, 65 Allergic reactions to antiepileptic drugs, 349 to gluten, 1146 Allesthesia, 161, 261 Allocortex, 460 Allodynia definition of, 142, 142t, 161 in peripheral neuropathy, 146, 1281 Alloesthesia, 162 Allopregnanolone, 355 Allopurinol, 980 Almotriptan, 187t Alogia, 466 Alpers disease, 956, 958, 959t Alpha coma, 34 Alpha motor neurons, 56, 62, 63 Alpha waves, in EEG, 29f, 32, 370 Alport syndrome, 304t Alprazolam, 1196 ALS. See Amyotrophic lateral sclerosis (ALS) Alteplase, 809 Alternate cover test, 275 Aluminum intoxication, 1214 Alzheimer disease. See also Dementia assessment of, 454 cerebral atrophy in, 1055–1056 clinical features of, 1056–1059 amnesia, 1057, 1058 anomic aphasia, 501–502, 1057 apraxia, 1057 cognitive function changes, 1057–1058 dysnomia, 1058 executive dysfunction, 1058 gait disorders, 129 loss of smell sense, 234 paranoia and personality changes, 1058 seizures, 1057 speech and language disorders, 1056, 1058 visuospatial disorientation, 1058 diagnosis of, 439, 439t, 1063–1064, 1063f diagnostic criteria for, 1058–1059 differential diagnosis of, 1064

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Index

Alzheimer disease (Cont.): Down syndrome and, 1011, 1061, 1062, 1078 EEG in, 35 epidemiology of, 1056 familial, 1056 genetic factors in, 1056, 1062–1063, 1062t head injury and, 1062 informing patient about, 454–455 management of, 454–455 memory in, 1057 neurofibrillary tangles in, 611–612, 1059–1062, 1059f neurotransmitter abnormalities in, 1062 Parkinson disease and, 1060, 1078 pathogenesis of, 1060–1063 pathology of, 1059–1060, 1059f prevalence and incidence of, 5, 6t risk factors for, 1056 treatment of, 1064–1065 Alzheimer Disease Assessment Scale-Cognitive, 454 Amanita, 1208, 1415t Amantadine, 1081t, 1083, 1084, 1198 Amaurosis definition of, 239 fugax, 194, 249, 782, 867 Leber, 257, 1004, 1115 Amblyopia deficiency, 256–257 definition of, 239 ex anopsia, 261 as opioid use complication, 1194 strabismus and, 261 tobacco-alcohol, 257, 1169–1170 Amebiasis, 733t Amebic meningoencephalitis, 731, 733t Amenorrhea, 1484 Amenorrhea-galactorrhea syndrome, 677 American Academy of Sleep Medicine (AASM) sleep scoring system, 400, 403t Amikacin, 704t Aminergic fibers, 115 Amino acids, in CSF, 18 Aminoacidopathies in early childhood with ataxia, seizures, and developmental delay, 963–964 Hartnup disease, 963, 1163 hereditary tyrosinemia, 963 phenylketonurias, 945t, 961–963 tyrosine hydroxylase deficiency, 963 in infants branched-chain aminoacidopathy, 947–948 vitamin-responsive, 945

Ropper_Index_1519-1606.indd 1522

Aminoglycosides, 1447 Aminolevulinic acid (ALA), 1209 Aminophylline, 344, 813 4-Aminopyridine, 927 Amiodarone, 1302 Amisulpride, 1513t Amitriptyline for diabetic neuropathy, 1306 for Fabry disease, 1334 for herpes zoster, 197 mechanism of action, 1200 for migraine prevention, 188 for pain, 150 polyneuropathy induced by, 1303 for postherpetic neuralgia, 753 side effects of, 1497t in tinnitus treatment, 300 Ammonia, in CSF, 18 Amnesia in Alzheimer disease, 1058 anatomic basis of, 448–449 anterograde, 445, 1156 classification of, 449, 450t dysnomia in, 472–473 functional, 1479 after head injury, 450, 881, 888, 898 in Korsakoff syndrome, 445–446, 1133, 1154, 1156, 1158 mental status examination in, 452, 453f nonorganic, 454 psychosis and, 330 retrograde, 445, 450, 884, 1156 in seizures, 328, 339 transient epileptic, 329, 450 transient global, 449–451, 451f in Wernicke-Korsakoff syndrome, 1156 Amobarbital, 1195 Amoxapine, 1200 Amoxicillin, 726 Amphetamines, 420, 1201–1202 Amphotericin B for amebic meningoencephalitis, 731 for coccidioidomycosis, 729 for cryptococcosis, 728 Ampicillin for bacterial meningitis, 703, 703t, 704t for Listeria infections, 707 Amusia, 471, 600 Amygdala anatomy of, 70, 71f in anxiety, 517 in autonomic regulation, 535 in emotions, 522, 525 Amyl acetate, 1215 Amyl alcohol, 1182 Amyloid angiopathy, 853, 855–856, 855f Amyloid hypothesis, 1061

Amyloid plaque, 611, 1059, 1059f Amyloid precursor protein, 1060, 1060f, 1062t Amyloidosis autonomic dysfunction in, 547 familial, 1326t, 1334–1336 oculoleptomeningeal, 637 primary, 547, 1317–1319 secondary, 1318 Amyoplasia, 1419 Amyotonia congenita, 1111 Amyotrophic lateral sclerosis (ALS) vs. cervical spondylosis, 1259 clinical features and evolution of, 1103–1104 with dementia, 1105 diagnosis of, 1106–1107 epidemiology of, 1102–1103 genetic defects associated with, 1107–1108, 1108t historical aspects of, 1102 imaging in, 1104, 1104f laboratory features of, 1104 pathology of, 1053, 1105 prevalence and incidence of, 5, 6t vs. spinal electrical injuries, 1235 treatment of, 1108–1109 Amyotrophy diabetic, 1304, 1346 neuralgic, 1340–1342, 1346 restricted nuclear, 1419 syphilitic, 1239 Analgesia definition of, 161 endogenous mechanisms in, 141 headache and, 174 stimulation-produced, 141 testing of, 9 Analgognosia, 149 Anarithmetia, 477, 600 Anarthria, 490, 504 Anatomic diagnosis, 3, 4 Andermann syndrome, 999 Andersen disease (branching enzyme deficiency), 1408t, 1409 Andersen-Tawil disease, 1448t, 1456 Anderson-Fabry disease. See Fabry disease (GLA mutation) Anemia fatigue in, 512 pernicious, 1164, 1167–1168 sickle cell, 829, 869 Anencephaly, 1001 Anergic depression, 518 Anesthesia coma in, 372 definition of, 161 dolorosa, 143 in myasthenia gravis, 1443

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Index spinal, 1236 testing of, 9 transient facial, 916 Aneurysm aortic, myelopathy after repair of, 1251 giant cerebral, 846, 847f headache in, 175 intracranial, unruptured, 846 mycotic, 846–847 of retinal vessels, 248 saccular, ruptured. See Subarachnoid hemorrhage, ruptured saccular aneurysm in ANF (atrial natriuretic factor), 572, 845 Angel dust, 1203–1204 Angelman syndrome, 1012 Anger, 524–525 Angiitis. See Vasculitis Angina, nocturnal, 420 Angiography in AVMs, 1253 in brain death, 369 catheter, 25 CT, 25, 26f in dural arteriovenous fistula, 1254f in hemangioblastoma of cerebellum, 667, 668f MR, 25, 26f risks and complications of, 25 in stroke, 87 Angiokeratoma corporis diffusum. See Fabry disease (GLA mutation) Angiomas, 1426 Angiomatosis with cerebral calcification (Sturge-Weber syndrome), 341, 1021–1023, 1022f Angioplasty, for carotid artery stenosis, 816 Angiostrongyloidiasis, 733t Angiotensin, 537, 545 Angiotensin-converting enzyme (ACE) inhibitors, 837, 903 Angor, 515 Angular gyrus, 491, 501 Anhidrosis, 551 Anisocoria, 288–289, 289f Ankylosing spondylitis, 207, 218–219, 1260 ANNA 2 (anti-Ri) antibodies, 684t, 688–689 ANNA-1 (antineuronal nuclear antibody type 1), 685, 1299 Anomia aphasia in, 495, 495t, 501–502 visual verbal color, 500 Anophthalmia, with mental retardation, 1003 Anorexia nervosa, 573, 1484–1485

Ropper_Index_1519-1606.indd 1523

Anosmia, 232–234, 232t, 881 Anosognosia in occipital lobe lesions, 480 in parietal lobe lesions, 475–476 Anoxia coma in, 382t hypoxic-ischemic encephalopathy in, 1127 in ischemic stroke, 85, 783 myoclonus in, 96 Antalgic gait, 123 Antalgic posture, 206 Anterior cerebral artery stroke syndromes, 796–798, 796f Anterior chamber of eye, 240 Anterior choroidal artery stroke syndrome, 798 Anterior lobe, cerebellum, 109, 110f, 110t, 117 Anterior spinal artery syndrome, 170 Anterograde amnesia, 445, 884, 1156 Anteroinferior cerebellar artery (AICA), 803, 806 Anthrax, 701, 708 Anti-AChR antibodies, in myasthenia gravis, 1438 Anti-amphiphysin, 684t Antibiotics. See also specific drugs for bacterial meningitis, 703–704, 704t, 705t for brain abscess, 715 for cerebral venous thrombosis, 755 for leptospirosis, 726 for Lyme disease, 726 for mycoplasmal infections, 706 in mycotic aneurysm treatment, 847 for septic thrombophlebitis, 711, 712 for subdural empyema, 710 toxicity of, 1218–1219 for tuberculous meningitis, 718–719 weakness induced by, 1446–1447 Anticholinergic drugs. See also specific drugs for Parkinson disease, 1081t, 1083, 1084 for PSP, 1090 Anticholinesterase drugs, 397, 1440. See also specific drugs Anticoagulants. See also specific drugs in cerebral hemorrhage, 853 for ischemic stroke prevention, 814, 815 for ischemic stroke treatment, 811 for nonbacterial thrombotic endocarditis, 866 reversal and resumption after cerebral hemorrhage, 838 Anticonvulsant drugs. See Antiepileptic drugs

1523

Anti-CRMP-5 antibodies, 684t, 686, 688–689 Antidepressant drugs. See also specific drugs for anxiety and panic attacks, 1474 autonomic dysfunction caused by, 549 classes of, 1199 classification of, 1497t confusional states induced by, 432 in depression treatment, 1496–1497 for herpes zoster, 753 in Huntington disease treatment, 1072 for insomnia, 408 mechanism of action, 1495 in migraine treatment, 188–189 for narcolepsy, 419 for pain, 150 for postherpetic neuralgia, 197 in schizophrenia treatment, 1513 seizures induced by, 344 side effects of, 1497t in spinal cord injury management, 1233 SSRIs. See Selective serotonin reuptake inhibitors (SSRIs) tricyclic. See Tricyclic antidepressants Antidiuretic hormone (ADH). See also Vasopressin in blood pressure control, 537 syndrome of inappropriate secretion of, 571–572, 1140–1141, 1290 Antiepileptic drugs. See also specific drugs for hypoxic-ischemic encephalopathy, 1130 for migraine treatment and prevention, 188–189 for pain, 150–151, 151t for posttraumatic seizure, 898–899 in pregnancy, 344–345 for seizures in children, 347, 348t, 353 combination therapy in, 347 discontinuation of, 350 dosage of, 348–349, 348t goals of, 346 half-life of, 348t, 349 indications for, 347t, 348t interaction with other drugs, 349 mechanism of action, 346–347, 347t, 350–353, 351f side effects of, 349, 350 teratogenic effects of, 345–346 for status epilepticus, 354–356, 354t for subarachnoid hemorrhage, 845

10/02/23 10:43 AM

1524

Index

Antigravity reflexes, 121–122 Anti-Hu antibodies, 684t, 686, 687, 688, 1300 Antihypertensive drugs, 511. See also specific drugs Anti-IgLON5, 413 Anti-Ma antibodies, 684t, 688–689 Antimicrobial drugs, 1302. See also specific drugs Antineoplastic agents, 1215–1218, 1301–1302 Antineuronal nuclear antibody type 1 (ANNA-1), 685, 1299 Anti-NMDA antibodies, 684t, 685–686, 688–689, 935 Antiphospholipid antibody disease, 786, 867–868, 923 Antiplatelet drugs, 814–815. See also specific drugs Antipsychotic drugs. See also specific drugs for bipolar disease, 1498–1499 classes of, 1197 extrapyramidal syndromes associated with, 1512, 1512t fatigue induced by, 511 in Lewy body dementia treatment, 1068 mechanisms of action, 1197 side effects of, 1513, 1513t. See also Neuroleptic malignant syndrome (NMS) tardive dyskinesia from, 101–102 Anti-Purkinje cell antibodies, 684t, 685, 687 Antirecoverin antibodies, 684t, 689 Antiretroviral therapy, 757 Anti-Ri (ANNA 2) antibodies, 684t, 688–689 Antisense oligonucleotides, 1072 Antisocial personality disorder, 1471t Antispasticity drugs, 63, 131. See also specific drugs Antithrombin III deficiency, 786 Antitoxin for botulism, 1207 for diphtheria, 1296–1297 for tetanus, 1205 Anti-VGKC antibodies, 684t, 685, 685f Anti-Yo antibodies, 684t, 685, 687 Anton syndrome, 260, 470, 480, 803, 1129 Anton-Babinski syndrome, 475–476 Anxietas, 515 Anxiety acute, 528 cause, mechanism and biological significance of, 517 definition of, 515 faintness and, 395

Ropper_Index_1519-1606.indd 1524

vs. fear, 1473 incidence of, 514–515 neurologic examination in, 10 PET in, 517 in PTSD, 516 in sleep disorders, 517 Anxiety disorders classification of, 1471 clinical presentation of, 1471–1472 depression and, 428, 1473–1474, 1500 differential diagnosis of, 1473–1474 etiology and pathogenesis in, 1473–1473 historical aspects of, 1469–1470 incidence of, 1471 panic attacks in, 515–516, 1472 treatment of, 1474 Anxiolytics, 516, 1474. See also specific drugs Aorta, coarctation of, 1254 Aortic aneurysm, 1251 Aortic stenosis, 394 Apallesthesia, 161 Apallic syndrome, 364 Apathy, 526–527, 529 Apert syndrome, 1003 Apex petrositis, 277 Apgar score, 585, 585t Aphasia agraphia in, 502 anomic, 495, 495t, 501–502 Broca. See Broca aphasia central, 485, 492 cerebral dominance in, 493 in children, 595 conduction, 485, 492, 495t, 498, 499 deep, 492 defective repetition in, 494–495 definition of, 490 differential diagnosis of, 444 dyscalculia in, 477 foreign accent syndrome and, 502 global, 495, 495t, 498–499 ictal, 326 jargon, 498 localization of lesions in, 491–492 logopenic, 1066 nonfluent, 496 primary progressive, 1065, 1066 progressive nonfluent, 1066 striatocapsular, 503 subcortical, 503 thalamic, 503 transcortical motor, 495, 495t, 496, 500 transcortical sensory, 495, 495t, 499–500 treatment of, 503–504 types of, 495–499, 495t Wernicke. See Wernicke aphasia word blindness and, 495t, 500–501

word deafness and, 301, 471, 485, 494, 495t, 500 word mutism and, 495t, 501 Aphemia, 495t, 501 Aphonia, 490 Aplasia, 302 Apnea in sleep, 415–417, 415t, 511 test, in brain death diagnosis, 368 Apneustic breathing, 379 Apo E, 1062t, 1063 Apolipoprotein E, 1060f, 1062t, 1063 Apophyseal joints, 203, 204f Apoplexy. See Stroke Apoplexy, pituitary, 258, 679, 881 Apoptosis in cortical development, 1000 in degenerative diseases, 1054 in hypoxic-ischemic encephalopathy, 1127 in ischemic stroke, 786 Apotemnophilia, 476 Apperception, 424, 481 Apraclonidine, 287, 544 Apractognosia, 477 Apraxia agraphia in, 502 in Alzheimer disease, 1057 in Broca aphasia, 496 Cogan oculomotor, 1025 congenital oculomotor, 269 constructional, 65, 477 definition of, 64, 465 developmental motor, 65 differential diagnosis of, 444 dressing, 65 ideational, 64 ideomotor, 64 oral-buccal-lingual, 65 in parietal lobe lesions, 474, 476–477 sympathetic (limb-kinetic), 64, 485 testing for, 65 Aprosodia, 494 Aquaporin-4, 728, 1245 Aqueduct of Sylvius, 623 Aqueous humor, 243 AR mutation (Kennedy syndrome), 1108t, 1112, 1361 Arachnoid cyst, 669, 671–672, 681 Arachnoid diverticula, 1267–1268 Arachnoid villi, 619 Arachnoiditis in bacterial meningitis, 697t chronic adhesive, 1248 clinical manifestations of, 1248 etiology of, 1238 lumbar, 217, 218f, 1248 opticochiasmatic, 636 regional, 636

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Index after spinal anesthesia, 1236 treatment of, 1248 Arboviral encephalitis, 745–746 Archicerebellum, 109, 110t Arcus senilis, 242 Area postrema, 561 Areflexia, 56, 723, 1331–1332 Arginase deficiency, 47, 946 Arginine vasopressin, 547 Argininosuccinase deficiency, 946 Argininosuccinic acid synthetase, 946 Argininosuccinic aciduria, 947 Argyll Robertson pupils, 288, 288t Argyrophilic grain disease, 1068 Aripiprazole, 1513t Arm pain in carpal tunnel syndrome, 225 in cervical disc herniation, 221 in epicondylitis, 225 origins of, 220, 225 in thoracic outlet syndrome, 223–224 Arm weakness, 1378 Arnold-Chiari malformation, 1008. See also Chiari malformations Around-the-clock paralysis, 681 Arousal, 361 Arrhythmias in deep breathing test, 541 syncope in, 387, 388 ARSA mutation. See Leukodystrophies, metachromatic ARSB mutation (Maroteaux-Lamy disease), 968t, 969 Arsenic poisoning, 1211–1212, 1298, 1300 Artemether, 732 Arteriography, cerebral, 87, 777 Arteriosclerosis cerebrovascular, 443 retinal, 247 Arteriovenous fistula, dural, 851–852, 852f, 1252, 1254f Arteriovenous malformations (AVMs) cerebral cavernous, 852–853, 853f clinical features of, 848–849 developmental venous anomaly in, 853, 853f dural fistula in, 851–852, 852f hemorrhage in, 847–848 imaging of, 849, 850f migraine in, 187 pseudotumor cerebri in, 631 treatment of, 849–851 spinal classification of, 1252 diagnosis of, 1253 dorsal extramedullary, 1253 incidence of, 1248

Ropper_Index_1519-1606.indd 1525

intradural perimedullary and subpial, 1253 intramedullary, 1253 treatment of, 1254–1255 Arteritis cranial. See Temporal arteritis Heubner, 721 intracranial granulomatous, 861–862, 861f Takayasu, 198, 394, 782, 862 Artery-to-artery embolism, 777 Artesunate, 732 Arthritis, degenerative, of lumbar spine, 217 Arthrogryposis, 1375, 1418, 1418t Articulation disorders, 504–507, 598 Articulatory muscles, spasm of, 597 Arylsulfatase deficiency (ARSA mutation). See Leukodystrophies, metachromatic ASAH1 mutation. See Lipogranulomatosis (Farber disease) Aseptic meningitis, acute. See Meningitis, viral (aseptic) Asomnia, 420 L-Asparaginase, 1216 Aspartate, 785 Aspartylglycosaminuria (AGA mutation), 950t, 970 ASPECTS (Alberta Stroke Program Early CT Score), 790t, 791 Asperger syndrome, 1045. See also Autism/autism spectrum disorders (Kanner-Asperger syndrome) Aspergillosis, 739 Aspergillus, 1242 Asphyxia, neonatal, 1027 Aspiration, 560–561 Aspiration pneumonia, 384 Aspirin for erythromelalgia, 149 for ischemic stroke prevention, 814 for migraine treatment, 187 for nutritional polyneuropathy, 1161 for pain, 151t Association areas of cerebral cortex, 464f Astasia-abasia, 131 Astereognosis, 166, 474, 475 Asterixis, 93, 1134–1135 Asthenia, 510, 511, 516, 647 Asthenic personality disorder, 1471t Asthenopia, 480 Astrocytes, 698, 1135 Astrocytoma brainstem, 679 in children, 651–652

1525

classification and grading of, 642t clinical features of, 651 diagnosis of, 649–650 genetic factors in, 643, 649, 651 giant cell, 670 incidence of, 641t, 643, 648 MRI in, 651, 651f pilocytic, 651 prognosis of, 649 recurrent, 650 spinal cord, 1263 treatment of, 651–652 Asyllabia, 500 Asymbolia for pain, 150 Asynergia, 115, 116 Ataluren, 1404 Ataxia cerebellar alcoholic, 1170 in celiac disease, 1146 of childhood, 750, 964, 1033 clinical features of, 116–117 in hyperthermia, 1146 with myxedema, 1145 progressive, 972–973. See also Degenerative diseases, with progressive ataxia congenital, 1032–1033 differential diagnosis of, 119t dysarthria in, 504–505 Friedreich. See Friedreich ataxia gait in, 118, 124, 124t, 465–466 generalized, 119 in Guillain-Barré syndrome, 1289 after head injury, 899 hemiparesis with, in lacunar stroke, 780 hereditary deafness with, 1117 hereditary spastic paraplegia with, 1114 in infants, 594 in metabolic disorders, 964 in MS, 916 in multiple system atrophy, 1087 neonatal, 1032–1033 noncerebellar sources of, 118–119 non-Friedreich, 964 in nutritional spinal spastic and ataxic syndrome, 1169 optic, 475, 483 in paraneoplastic cerebellar degeneration, 687 paroxysmal, 1096t, 1101 in peripheral neuropathy, 1282 polymyoclonus with opsoclonus and, 666 progressive. See Degenerative diseases, with progressive ataxia sensory, 118, 124t, 125–126, 1282

10/02/23 10:43 AM

1526

Index

Ataxia (Cont.): static, 1096 in tabetic syphilis, 722–723 thalamic, 119 tremors in, 91, 116–117 unilateral, 119 vertigo and, 118–119, 306 in Wernicke-Korsakoff syndrome, 1155, 1155f Ataxia-telangiectasia, 1024–1025, 1024f Atenolol, 188, 397 Atherosclerosis in carotid arteries, 779, 789, 817–818 cerebral, 612 diabetes mellitus in, 775–776 in fibromuscular dysplasia, 821 in ischemic stroke, 778–779, 782 treatment of, 811 Athetosis characteristics of, 82 definition of, 80 double, 82, 505, 1031 gait disorders in, 128 intention or action, 82 posthemiplegic, 82 Athletes, concussion in, 884, 900 Atlantoaxial dislocation, 221, 1228t, 1261 Atlanto-occipital dislocation, 1228t Atlas, in atlantoaxial subluxation, 221 ATN1 mutation (Dentatorubropallidoluysian atrophy, DRLPA), 1072, 1096t, 1100–1101 Atomoxetine, 602 Atonia, 56 Atovaquone, 732 ATP (adenosine triphosphate), 618, 785, 1405 ATP7A mutation (Menkes disease), 957–958, 960 ATP7B mutation. See Hepatolenticular degeneration (Wilson disease) ATPase (adenosine triphosphatase), 958 Atrial fibrillation, stroke in, 776–777, 814 Atrial natriuretic factor (ANF), 572, 845 Atrioventricular block, syncope in, 393 Atrophy alcoholic cerebral, 1188 bulbospinal muscular, 1108t, 1112 denervation, 1282 in motor function impairment, 1280–1281 multiple system. See Multiple system atrophy (MSA) muscle. See Muscle(s), atrophy of optic nerve. See Optic atrophy posterior cortical, 1066–1067

Ropper_Index_1519-1606.indd 1526

progressive muscular. See Degenerative diseases, with muscular weakness and wasting without sensory changes spinal muscular. See Spinal muscular atrophy (SMA) Sudeck, 147, 225 Atropine, 388, 397, 545, 553, 724 Atropine sulfate, 1438, 1443 ATRX mutations, 642t, 643 Attention assessment of, 7 in confusional states, 362–363, 424 parietal lobe in, sensory attention and, 166 Attentional matrix, 424 Attention-deficit hyperactivity disorder (ADHD) in adults, 602–603 in children, 600–602 dyslexia and, 601 imaging studies in, 601–602 in infants, 601 subsyndromes in, 601 treatment of, 602 ATXN3 mutation (Machado-JosephAzorean disease), 1096t, 1100 Audiometry, 49, 298, 309 Auditory agnosia, 471 Auditory cortex, 294f, 469 Auditory cortex lesions, 481–482 Auditory neglect, 478 Auerbach plexus, 539 Aura in migraine, 178t, 179, 186–188 in seizures, 237, 307 Autism/autism spectrum disorders (Kanner-Asperger syndrome) clinical features of, 1046 course, treatment, and prognosis of, 1047, 1201 definition of, 1045 etiology and pathology of, 1046–1047 genetic factors in, 1045–1046 prevalence of, 1045 Autistic savant, 438 Autoimmune diseases. See also specific diseases differential diagnosis of, 1388 MS and, 912 prevalence and incidence of, 6t Autoimmune encephalitis, 935, 935t Automatisms, 61 neonatal, 585, 586 in seizures, 328 in sleep, 412–413 Autonomic dysreflexia, 549

Autonomic nervous system. See also Parasympathetic nervous system; Sympathetic nervous system anatomy of, 531–536, 532f–533f in bladder regulation, 537–538, 538f, 544 in blood pressure regulation. See Blood pressure, autonomic regulation of in bowel function regulation, 539, 544 disorders of. See Autonomic nervous system disorders endocrine system interactions with, 535, 537 function tests of, 540t in lacrimal function, 543–544 neurotransmitters in, 536–537 pharmacologic tests of, 544 physiology of, 536–537 in sexual function, 544 in sudomotor function, 543, 551 in vasomotor reactions, 543 in visceral regulation, 535–536 Autonomic nervous system disorders autonomic failure in elderly, 548 in diabetes mellitus, 1305 drug-induced, 549 emergency and alarm reactions, 539 in Guillain-Barré syndrome, 545–546, 1288–1289 after head injury, 903–904 Horner syndrome. See Horner syndrome idiopathic neuropathy, 1312–1313 inherited, 547–548 multiple system atrophy. See Multiple system atrophy in peripheral neuropathy, 1282–1283 pure autonomic failure, 546–547 pure pandysautonomia, 545–546, 1298 Riley-Day syndrome. See Riley-Day familial dysautonomia in spinal cord trauma, 1230 stellate ganglion syndrome, 548–549 sympathetic storm, 549–551, 903–904 tests for, 539–545, 540t in tetraplegia and paraplegia, 549 Autoregulation, of cerebral blood flow, 783, 1126 Autoscopy, 470, 472 Autosomal inheritance, 941 Avellis syndrome, 802t AVMs. See Arteriovenous malformations Axillary nerve neuropathy, 1343 Axon reflex of Lewis, 140

10/02/23 10:43 AM

Index Axons diffuse injury of. See Diffuse axonal injury (DAI) pathologic processes in, 1278–1280, 1278f regeneration of, 1279 structure of, 1277 transport in, 1279 Azathioprine for antiphospholipid antibody disease, 868 for dermatomyositis, 1386 for Lambert-Eaton myasthenic syndrome, 1445 for myasthenia gravis, 1440 for NMO, 930 for polyarteritis nodosa, 1307 Azithromycin for cat scratch disease, 708 for Legionella infections, 708 for mycoplasmal infections, 706 AZT (zidovudine), 756, 1380, 1415t B Babbling, 590 Babes nodules, 749 Babinski sign in acute hydrocephalus, 625 in ALS, 1103 in brain herniation, 373, 374 in coma, 363, 376 in monoplegia, 66 in multiple system atrophy, 1087 testing of, 9 in upper motor neuron disorders, 62–63, 62f Babinski trunk-thigh test, 68 Bacillus anthracis, 708 Back pain in adhesive arachnoiditis, 217 anatomy and physiology in, 203–204, 204f in ankylosing spondylitis, 218–219 in cervical intervertebral disc herniation, 221 chiropractic manipulation for, 209 chronic and recurrent, 209 in coccydynia, 219 in congenital anomalies of lumbar spine, 215 diagnostic procedures in, 207–208 in facet syndrome, 217 in failed back syndrome, 220 in hemorrhage, intraspinal, 219 local, 205 in lumbar stenosis, 216–217 in MS, 916 in neoplastic diseases, 219

Ropper_Index_1519-1606.indd 1527

in osteoarthritis, 217 physical examination of, 206–207, 207f prevalence and incidence of, 6t pseudoradicular, 205 in psychiatric diseases, 219–220 in radiation-induced arachnoiditis, 218f radicular, 168, 205 referred, 205 in spinal infections, 219 in sprain and strain, 208–209 traumatic, 208–210 types of, 204–206 vertebral fractures and, 210 from visceral disease, 208 Baclofen in ALS treatment, 1109 mechanism of action, 63 for spasticity, 131, 928 in spinal cord injury management, 1233 for stiff man syndrome, 1460 Bacterial infections botulism, 1206–1207, 1293 brain abscess, 696 common organisms in, 696–697 CSF examination in, 14t, 16 diphtheria, 1206 encephalitis, 706–709 hematogenous spread of, 696 meningitis. See Meningitis, bacterial myelitis in, 1238 tetanus, 1204–1206 BAEPs (brainstem auditory evoked potentials), 35t, 36–37, 37f Balint syndrome, 260, 478, 483, 803 Ball valve obstruction, 671 Ballismus, 82–83 Ballistic movements, 54, 82–83, 116 Balo concentric sclerosis, 918 Baltic myoclonus, 95 Bamboo spine, 219 Bannwarth syndrome, 216, 725, 1311 Barbiturates abstinence (withdrawal) syndrome, 1195–1196 acute intoxication from, 1195 MAO inhibitors with, 1200 mechanism of action, 1195 in tetanus treatment, 1206 tremors and, 88 Bardet-Biedl syndrome, 572 Barthel Index, 790t, 791 Bartonella henselae (cat scratch disease), 251, 255, 708 Bartter syndrome, 304t Basal ganglia anatomy of, 53, 70–73, 71f, 72f calcification of, 980–981, 980f

1527

neuromodulators in, 77 pharmacology of, 75–77, 76t physiology of, 73–75, 74f–75f thalamus connections and, 73–75, 74f–75f Basal ganglia disorders in Huntington disease, 75f, 79. See also Huntington disease in Parkinson disease, 73, 74f, 75. See also Parkinson disease pathology of, 77–78 subcortical dementia, 442 symptoms of, 78–85 Basal-cell nevus syndrome, 1005 Basilar artery disorders branch occlusion, 806–807 coma in, 381t dissection, 824 migraine in, 181 occlusion, 279–280 stroke syndromes, 805–807 vertigo and, 315 Basilar impression, 924, 1261 Basilar invagination, 1261 Basilar membrane, 292, 293f Basket cells, 114, 114f, 115, 115f Bassen-Kornzweig acanthocytosis (abetalipoproteinemia), 973, 1333 Bath salts, 1202 Batten disease, 974. See also Neuronal ceroid lipofuscinoses Battle sign, 881 Baylisascariasis, 733t Becker disease (generalized myotonia), 1448t, 1450 Becker muscular dystrophy, 1374t, 1392–1393 Beclouded dementia, 433 Behavior aggressive, 517, 524–525, 526f, 529 in confusional states, 424–427 epilepsy and, 330 rejection, 476 violent, 524–525, 526f, 529 Behavioral development, of infants and children, 585–586 Behavioral disorders in Alzheimer disease, 1058 in anterior cerebral artery stroke syndrome, 797 in frontal lobe lesions, 465, 467–468 after head injury, 897–898 in Huntington disease, 1070 in inherited metabolic disease, 985–986 in Lesch-Nyhan disease, 980 observable aspects of, 424 of REM sleep, 410–411, 413 in temporal lobe lesions, 472

10/02/23 10:43 AM

1528

Index

Behçet disease clinical features of, 864 differential diagnosis of, 703 meningitis in, 743 vs. multiple sclerosis, 923 myelopathy in, 1247 nervous system involvement in, 864 treatment of, 864 Behr syndrome, 1114 Bell phenomenon, 268, 1359 Bell’s palsy causes of, 1359–1360 clinical features of, 1360 eyelid movements and blinking in, 285 incidence of, 1359 taste sense in, 236 treatment of, 1360 Bends, 1255 Benedikt syndrome, 802, 802t Benign paroxysmal positional vertigo (BPPV), 281, 310–313, 311f, 312f Benign senescent forgetfulness, 440, 609 Benign unilateral mydriasis, 288 Benzene, 1215 Benzine, 1215 Benzoate, 947 Benzodiazepines for anxiety and panic attacks, 1474 for insomnia, 408 mechanism of action, 1196 overdose, 1196 for PTSD, 516 in tetanus treatment, 1205–1206 tremors and, 88 withdrawal from, 343, 1196 Benztropine in Parkinson disease treatment, 1081t, 1083 for PSP, 1090 for side effects of haloperidol, 104 Benzyl ammonium chloride, 749 Bereitschaft “readiness” potential, 60 Beriberi infantile, 1159 neuropathic. See Nutritional deficiencies, polyneuropathy in Bernard-Horner syndrome. See Horner syndrome Beta waves, in EEG, 32–33 β-adrenergic antagonists for blood pressure management, 903 for essential tremors, 89 for migraine prevention, 188 for orthostatic hypotension, 397 β-amyloid protein, 1060, 1060f, 1061 β-endorphin, 141

Ropper_Index_1519-1606.indd 1528

Beta-galactosidase deficiency, 953. See also Gangliosidosis β-glucuronidase deficiency (Sly disease, GUSB mutation ), 968t, 969 Beta-keto acidemia, 946 Bethanechol, 553 Bethlem myopathy, 1396t, 1402 Betz cells, 56–57, 1162 Bezold-Jarisch reflex, 390 Bibrachial palsy, 1378 Bibrachial paralysis, 1280 Bicarbonate, in CSF, 17t Bicrural palsy, 1378 Bielschowsky sign, 273 Bier block, 152 Bifacial palsy, 1025, 1376–1377 Bilateral paralysis facial, 1361 vagal, 1364 Bilateral phrenic nerve paresis, 559 Bilevel positive airway pressure, 416, 559, 1109 Bilharziasis, 1242 Bilirubin in CSF, 16 in kernicterus, 1032 Bing-Neel syndrome, 1317 Binocular diplopia, 272 Binswanger disease, 129, 130, 443, 820, 826 Biofeedback, 153 Biopsy of brain, 50 of muscles, 50, 1375, 1385, 1387 of nerves, 50 of salivary gland, 1312 of skin, 50 Biopterin deficiency, 945 Biot breathing, 379 Biotin, 1174t Bipolar (manic-depressive) disease. See also Depression age of onset of, 1493 anatomic correlates of, 1494–1495 biochemical theories of, 1495 clinical features of, 1489, 1493–1494 definition of, 1492–1493 early signs of, 603 genetic factors in, 1494 incidence of, 6t, 1493 in medical or surgical illness, 434 prognosis of, 1493 subtypes of, 1492–1493 treatment of, 1498–1499 Bismuth intoxication, 1214 Bites black widow spider, 1447, 1457–1458 rabies in, 745, 749–750

tick in Lyme disease, 725. See also Lyme disease paralysis in, 1209, 1292 types of, 1208–1209 Bizarre ideation, 529 Bjerrum field defect, 243 Black widow spider bites, 1447, 1457–1458 Blackouts, alcoholic, 1181 Bladder, 537–539, 538f Bladder dysfunction in brainstem lesions, 552 in elderly, 610 in frontal lobe lesions, 465, 466, 552–553 in MS, 552, 917, 927–928 in paralysis, 552 reflex neurogenic, 552 after spinal cord injury, 1230–1231 in spinal cord lesions, 552 in spinal shock, 552 stretch injury, 552 tests for, 544 treatment of, 553 Blast injuries, 883, 896 Blastomyces/blastomycosis, 729, 1242 Blepharoclonus, 90 Blepharospasm, 84, 97, 100, 284, 1362–1363 Blind spot, 244 Blindisms, 480 Blindness color, 260 cortical , 259, 480, 803, 982 in degenerative diseases, 1114–1116 functional, 1479 gait in, 123 nonorganic, 259 in retinoblastoma, 666 in temporal arteritis, 861 transient, in head injury, 889 transient monocular, 249, 793 word, 495t, 500–501 Blindsight, 259, 480 Blink responses in, nerve conduction studies, 43 Blinking in coma, 378 disorders of, 284–285 in Parkinson disease, 1073 as reflex response, 284, 1355 Bloch-Sulzberger syndrome, 1005–1006 Blood cultures, 702 Blood oxygen level-dependent (BOLD) signals, 27, 27f Blood patch, for intracranial hypotension, 634

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Index Blood pressure autonomic regulation of mechanisms in, 537 orthostatic hypotension and, 392–393 in sympathetic hyperactivity, 550 testing of, 540–543, 541f, 542f in coma, 375 in Guillain-Barré syndrome, 545 management of, in increased intracranial pressure, 903 in Valsalva maneuver, 542–543 Blood vessels, as pain source, 140 Blood–brain barrier, 618, 912 Bobbing, ocular, 283 Bobble head syndrome, 624, 681 BOLD (blood oxygen level-dependent) signals, 27, 27f Borderline personality disorder, 1470–1471, 1471t Bornholm disease, 1380, 1424 Borrelia burgdorferi, 725. See also Lyme disease Bortezomib, 1301 Botulinum toxins for blepharospasm, 99 for dystonia, 99 for essential tremors, 89 mechanism of action, 1447 for migraine prevention, 189 for spasmodic dysphonia, 507 for spasmodic torticollis, 99 in spinal cord injury management, 1233 in tetanus treatment, 1205 for tics, 104 types of, 1207 for writer’s cramp, 101 Botulism clinical features of, 1207, 1444t epidemiology of, 1206 etiology of, 1206, 1444t vs. Guillain-Barré syndrome, 1293 vs. myasthenia gravis, 1439 treatment of, 1207, 1444t Botzinger complex, 556, 556f Bourneville disease. See Tuberous sclerosis (Bourneville disease) Bowel function/dysfunction, 539, 553 BPPV (benign paroxysmal positional vertigo), 281, 310–313, 311f, 312f Brachial plexus disorders anatomy of, 1339, 1340f atrophic monoplegia in, 66 hereditary recurrent, 1332 heredofamilial plexopathy, 1342 in heroin users, 1194 infraclavicular lesions, 1339–1340, 1340f

Ropper_Index_1519-1606.indd 1529

lesions of entire brachial plexus, 1339 mononeuropathies, 1342–1343, 1343t neuritis/plexitis, 1338, 1340–1342 neuropathies, 1338–1339, 1340–1342 pain in, 225, 1341 palsy, 1033–1034, 1378 paralysis, 1280, 1339 after radiation therapy, 1342 thoracic outlet syndrome, 223–225, 224f Brachycephalic head, 999 Bradykinesia, 78–79 Bradyphrenia, 425, 426, 467 Bragard sign, 206 Brain abscess of. See Brain abscess anatomy of, 459, 459f biopsy of, 50 CT of, normal, 20f displacement and herniation of in bacterial meningitis, 697t cerebellar, 646 increased intracranial pressure in, 621–622, 646 pressure cone in, 646 subfalcial, 646 transtentorial, 646 edema in. See Cerebral edema growth and development of in adolescents and children, 583, 584f embryonal and fetal, 581–582, 582t, 583f, 1001t in neonates and infants, 582–583, 584f, 585 herniation of, 373–374, 373f, 374t imaging of. See Imaging techniques iron accumulation in, degeneration with. See Neurodegeneration with brain iron accumulation (Hallervorden-Spatz disease) ischemia of, generalized, 820–821 MRI of, normal, 23f purpura, 854, 1140 radiation injury of, 689–691, 690f, 691f sarcoma of, 664 swelling, acute traumatic, 895 tumors. See Intracranial tumors Brain abscess clinical manifestations of, 714 coma in, 381t congenital heart disorders and, 713 as contraindication to LP, 701 diagnosis of, 714–715 etiology of, 713–714 formation of, 696 metastatic, 712 MRI in, 713f, 714–715

1529

pathogenesis of, 712–713, 713f pathology of, 714 treatment of, 715 Brain death apnea test in, 368 in children, 369 diagnosis of, 367–368 EEG in, 28, 33, 368 ethical issues in, 369 from hypoxic-ischemic encephalopathy, 1128 organ transplantation and, 369 respiration in, 555 Brain sand, 569 Brain stones, 1015–1016, 1016f Brain tumors. See Intracranial tumors Brain-sagging syndrome, 633 Brainstem in equilibrium, 305 eye movement pathways in, 264–266, 265f motor nuclei of, 53, 265 Brainstem auditory evoked potentials (BAEPs), 35t, 36–37, 37f, 298 Brainstem lesions astrocytomas, 679 bladder function in, 552–553 central sleep apnea in, 416 Cushing response in, 550 glioma, 679–680, 680f horizontal gaze palsy in, 268 infarction, 1143 intramedullary syndromes of, 801– 802, 802t metastatic, 660 nystagmus in, 282 paraneoplastic encephalitis, 684–685 sensory disorders in, 170–171 in severe head injury, 887 vertigo in, 315–316, 315t, 316t Branched-chain aminoacidopathies, 947–948 Branching enzyme deficiency (Andersen disease), 1408t, 1409 Branchio-oto-renal syndrome, 303t Breast cancer, 659, 1265f Breathholding spells, 392 Breathing. See Respiration Briquet syndrome, 148, 333, 1476–1477 Brivaracetam, 347t, 348t, 353 Broadbent’s law, 61 Broca aphasia clinical features of, 492, 495, 495t, 496 localization of lesions in, 497, 497f minimal, 504 mutism in, 496 sympathetic apraxia in, 485

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1530

Index

Broca area, 462, 464f, 491 Brodmann areas, 56–57, 58f, 459, 460f–461f, 462, 491f Bromocriptine for hepatic encephalopathy, 1137 for neuroleptic malignant syndrome, 1199 for Parkinson disease, 1082 for pituitary adenoma, 678 Brown-Séquard syndrome, 66, 169, 169f, 752 Brucella/brucellosis, 207, 708–709 Brudzinski sign, 699 Brueghel syndrome, 100 Bruit, carotid, 675, 789, 817–818 Buckthorn poisoning, 1208 Bulbar palsy causes of, 1366 progressive, 1102, 1105–1106, 1112–1113 spastic, 505 weakness patterns in, 1377 Bulbar speech, spastic, 598 Bulbospinal muscular atrophy, 1108t, 1112–1113 Bulimia, 414–415, 573, 1484–1485 Bulldog reflex, 1106 Buprenorphine, 1193 Bupropion, 344, 1200–1201, 1497t Burning feet syndrome causes of, 1324t characteristics of, 1324 gait in, 126 in nutritional polyneuropathy, 1160 pantothenic acid deficiency in, 1164 Burning mouth syndrome (glossodynia, stomatodynia), 200, 237, 1366 Burns central pontine myelinolysis in, 1143 encephalopathy with, 1140 Bursitis subacromial, 220, 225 trochanteric, 207 Burst fracture, 1228t Burst neurons, in horizontal gaze, 265–266 Buspirone, 1197 Butyrophenones, 1198 C Cacogeusia, 234, 237 Cacosmia, 234, 237 CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) genetic factors in, 827 imaging of, 827 migraine in, 182, 184

Ropper_Index_1519-1606.indd 1530

Café-au-lait spots, 1018, 1018f, 1020 Caffeine insomnia and, 408 for intracranial hypotension, 634 migraine and, 179, 188 Caisson disease, 1255 Calcification, basal ganglionic and cerebellar, 980–981, 980f Calcineurin inhibitors, 1217–1218 Calcium in CSF, 17t disorders of hypercalcemia, 1141–1142 hypocalcemia, 143, 948–949 homeostasis, 785 Calcium channel blockers in hypertensive encephalopathy treatment, 858 for ischemic stroke, 813 for migraine prevention, 189 for Raynaud syndrome, 551 in subarachnoid hemorrhage treatment, 845 Calcium channel disorders. See Channelopathies, calcium Calculating, precocious, 600 California virus encephalitis, 745 Call-Fleming syndrome, 204, 858–859 Callosal pathways, 500 Callosotomy, 356 Caloric testing in coma, 281, 378 for nystagmus, 281, 308 CAM-ICU (Confusion Assessment Method for the ICU), 433 cAMP (cyclic adenosine monophosphate), 76 Campylobacter jejuni, in GBS, 1288, 1292 Canadian criteria/rule for cervical spine trauma, 1228–1229 for CT after concussion, 888, 888t Canalolithiasis, 310, 313 Canavan-van Bogaert-Bertrand disease (spongy degeneration of infancy), 955, 956f, 959, 960t cANCA (cytoplasmic antineutrophil cytoplasmic antibodies), 862 Candidiasis, 739 Cannabinoids high-potency, 859 for seizures, 357 synthetic, 1203 Cannabis, 1203 Cannibalism, kuru and, 768 Cannon law, 544 Capsaicin, 753, 1306 Capsular warning syndrome, 781

CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), 827 Carbamazepine for Fabry disease, 1334 for neurosyphilis, 724 for nutritional polyneuropathy, 1161 for occipital neuralgia, 198 for pain, 151t for postherpetic neuralgia, 753 in pregnancy, 345 for seizures, 347t, 348t, 350, 352 side effects of, 352 for spasms in MS, 928 in spinal cord injury management, 1233 Carbamoyl phosphate synthetase, 946 Carbidopa, 409, 1081t, 1082–1083 Carbon dioxide, in apnea test, 368 Carbon disulfide, 1215, 1302 Carbon monoxide poisoning, 382t, 1130–1131, 1131f Carboplatin, 1301 Carcinoma metastatic. See Metastases nasopharyngeal transitional cell, 681 opsoclonus-myoclonus-ataxia syndrome in, 688 paraneoplastic encephalomyelitis in, 684–686, 684t, 685f Carcinomatosis meningitis, 661–662 Cardiac arrest in head injury, 890 in hypoxic-ischemic encephalopathy, 1130 seizures in, 344 somatosensory evoked potentials in, 38 Cardiac output in syncope, 388, 393–394 during Valsalva maneuver, 542–543 Cardiac surgery, stroke risk with, 830–831 Cardiovascular disorders with hypothalamic lesions, 574 in muscular dystrophy, 1405 Carmustine, 1217 Carnitine, 1409 Carnitine deficiency disorders, 1409–1410 Carotid arteries anatomy of, 784f, 785f, 792 atherosclerosis in, 779 bruit in, 675, 789, 817–818 dissection of, 821–822, 823f, 882, 889 embolism in, 777 ischemic stroke syndrome of, 792–793 ophthalmic branch of, 247

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Index revascularization surgery of, 811 stenosis of, 779, 816–818, 817f territory supplied by, 784f, 785f, 792 TIA in, 782 Carotid body tumors, 675 Carotid sinus syncope, 389, 391, 397–398 Carotid-cavernous fistula, 882 Carotidynia, 198 Carpal tunnel syndrome arm pain in, 225 diagnosis of, 1344 familial amyloidosis (Swiss type) with, 1335 treatment of, 1344 Carpenter syndrome, 1003 CAR-T-cell (chimeric antigen receptor T-cell) therapy, 1218 CAR-T-cell-related encephalopathy syndrome (CRES), 1218 Casimersen, 1404 Cassava, 1207–1208 Castleman disease, 663, 1299 Cat scratch disease (Bartonella henselae), 251, 255, 708 Catalepsy, 115, 367, 1507 Catamenial migraine, 174, 179, 183 Cataplexy, 417–419 Cataracts bilateral, 957 causes of, 243 congenital, 247 in galactosemia, 945 Catatonia, 367, 426 Catatonic depression, 1492 Catatonic schizophrenia, 1505, 1506–1507, 1511 Catechol-O-methyltransferase (COMT) inhibitors, 1081t, 1084 Cathinone stimulants, 1202 Cauda equina, 204 claudication in, 216 compression of in lumbar intervertebral disc herniation, 212 in lumbar stenosis, 216 pain in, 205 by tumors, 215–216 epidural abscess in, 1239 lesions of, 1266 Caudal regression syndrome, 1007 Caudate hemorrhage, 834 Caudate nucleus, 70, 71f, 1070 Causalgia, 142t, 147. See also Complex regional pain syndrome (CRPS) Causalgia-dystonia syndrome, 147 Cautious gait, 130 Cavernous malformations, 852–853, 853f

Ropper_Index_1519-1606.indd 1531

Cavernous sinus cranial nerves in, 269–271, 271f, 277 septic thrombophlebitis in, 711 thrombosis of, 865, 1357t tumors of, 682t Cavernous sinus syndrome, 277, 1368 CBGD (corticobasal-ganglionic degeneration), 1090–1091 CBS mutation (homocystinuria), 829, 945t, 984–985, 1174t Cefepime for bacterial meningitis, 703, 703t for brain abscess, 715 toxicity of, 344, 1218 Cefotaxime, 704t, 715 Ceftazidime, 703, 704t, 708 Ceftriaxone for bacterial meningitis, 703, 703t for brain abscess, 715 for leptospirosis, 726 for Lyme disease, 726 for neurosyphilis, 724 for Whipple disease, 709 Cefuroxime, 726 Celiac disease, 1146 Celiac-sprue neuropathy, 1313 Central achromatopsia, 482 Central aphasia, 485, 492 Central cervical cord syndrome, 1229 Central cord syndrome, 1232 Central core myopathy (RYR1 mutation), 1419t, 1420–1421 Central deafness, 297, 596 Central nervous system neoplasms. See also specific neoplasms biology of, 642–643 classification and grading of, 641–642, 642t genetic factors in, 642t, 643 incidence of, 640–641, 641t intracranial. See Intracranial tumors viruses and, 643 Central neurogenic hyperventilation, 379, 558 Central pontine myelinolysis (CPM) clinical features of, 1142–1143 etiology and pathogenesis of, 1143–1144 imaging in, 1143, 1143f pathologic features of, 1142 Central sleep apnea, 416 Central syndrome, 373 Centronuclear (myotubular) myopathy, 1419t, 1421–1422 Cephalalgia. See Cluster headache Cephalic tetanus, 1205 Cephalosporins for bacterial meningitis, 703, 703t for brain abscess, 715

1531

side effects of, 1218 for subdural empyema, 710 Ceramidase deficiency (lipogranulomatosis), 950t, 954 Cerebellar arteries, 803–805, 806–807 Cerebellar disorders ataxia. See Ataxia, cerebellar calcification of vessels, 980–981, 980f clinical features of, 115–118 cognitive features of, 118 coordination in, 116–117 decomposition of movement in, 115–116 degenerative in alcoholism, 117, 1170–1171, 1171f paraneoplastic, 686–688, 687f with polyneuropathy, 1332 differential diagnosis of, 119, 119t dysarthria in, 117, 494 equilibrium and gait in, 117, 123–124, 124t eye movements in, 117 after head injury, 899 hematoma, 837 hemorrhage, 834f, 835. See also Intracerebral hemorrhage herniation, 373–374, 373f, 646, 697t from hyperthermia, 1146 hypotonia in, 117–118 infarctions, 813 memory in, 118 metastases to, 660 movement disorders in, 115–118 myoclonus in, 118 nystagmus in, 117, 282 stance in, 124 tremors in, 86t, 91, 115–116 vertigo in, 307, 315, 315t, 316t Cerebellar fits, 646 Cerebellar-foramen magnum herniation, 646 Cerebellitis, acute, 750 Cerebellopontine angle tumors, 674, 682t Cerebellum anatomy of, 53, 109–115, 110f–115f, 110t anterior lobe of, 109, 110f, 110t, 117 connections to main motor pathways, 111 cortex of, 111, 114f deep nuclei of, 113 disorders of. See Cerebellar disorders efferent fibers of, 111 embryonal and fetal development of, 581–582, 582t in equilibrium, 305 in eye movements, 266–267

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1532

Index

Cerebellum (Cont.): flocculonodular lobe of, 109, 110f, 117 functions of, 109, 110t hemangioblastoma of, 667–668, 668f hemispheres of, 109, 110f, 110t input pathways of, 114–115 longitudinal zones of, 111 neuronal organization of, 113–115, 114f, 115f peduncles of, 109, 110f, 111–112, 111f, 111t physiology of, 109–111, 115f posterior lobe of, 109, 110f, 110t somatotopic organization of, 113 Cerebral arteries anatomy of, 784f, 785f anterior, stroke syndromes of, 796–798, 796f atheromatous plaque in, 778 in Churg-Strauss angiitis, 862 middle. See Middle cerebral artery (MCA) noninfectious inflammatory diseases of, 860 occlusion of, 785–786, 1194 in polyarteritis nodosa, 862 posterior. See Posterior cerebral artery (PCA) in stroke, 778–779 Cerebral atherosclerosis, 612 Cerebral atrophy, alcoholic, 1188 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. See CADASIL Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), 827 Cerebral blood flow autoregulation of, 783, 1126 critical threshold of, 784 in elderly, 612 in syncope, 390 in Wernicke-Korsakoff syndrome, 1157 Cerebral contusion. See Head injury, severe Cerebral cortex agranular, 462, 463f, 464 anatomy and physiology of, 459–462, 459f–461f, 463f–464f association areas of, 464f auditory areas of, 295, 469, 481–482 Brodmann areas of, 56–57, 58f, 459, 460f–461f, 462, 491f cell types in, 461

Ropper_Index_1519-1606.indd 1532

columnar organization of neurons in, 462 development of in children and adolescents, 584f, 585–586 embryonal and fetal, 581–582, 582t in neonates and infants, 582–583 disconnection syndromes of, 462, 464f, 483–485 epilepsy in disorders of, 338t fMRI of, 459 function tests of, 7–8 functional zones of, 458–459, 461f granular, 462, 463f, 464 heterotypical, 461 homotypical, 461–462 language areas of, 490–492, 491f layers of, 461–462, 461f lesions of. See Frontal lobe lesions; Occipital lobe lesions; Parietal lobe lesions; Temporal lobe lesions neuropsychologic tests of, 485 PET of, 459 precentral, 462 size of, 460 thalamus connections and, 73–75, 74f–75f, 139, 160 visual areas in, 247, 259–260, 462, 463f, 464f Cerebral edema cytotoxic, 644, 644f, 785, 1127 in head injury, 778, 887 in hepatic encephalopathy, 1136 increased intracranial pressure in, 621–622, 645–646 interstitial, 644, 645 after ischemic stroke, 812–813, 812f localized, 645 MRI of, 812f after severe head injury, 887 treatment of, 645–646, 812–813 vasogenic, 644, 644f Cerebral embolism air, 778 in arteriography, 778 artery-to-artery, 777 in carotid arteries, 777 diagnosis of, 776 from endocarditis, 777 fat, 778, 889 infarction from, 776–777 in ischemic stroke, 772, 776–778 in MCA. See Middle cerebral artery (MCA), ischemic stroke syndromes of migrating or traveling, 777 in mitral valve prolapse, 777–778 paradoxical, 777 from pulmonary veins, 778

after severe bone trauma, 778 after severe head injury, 887 TIA in, 782 from tumors, 778 Cerebral hemisphere dominance anatomic differences in, 493 assessment of, 492–494 in handedness, 492–494 in language, 489, 492–494 in speech and language disorders, 493–494 Cerebral palsy, 67, 1026. See also Congenital cerebral motor disorders Cerebral perfusion pressure, 620 Cerebral salt wasting, 572, 1141 Cerebral veins obstruction of, 629 thrombosis of, 864–866, 865f Cerebritis, 714 Cerebrohepatorenal (Zellweger) disease, 957, 959 Cerebrospinal fluid (CSF). See also Cerebrospinal fluid (CSF) examination absorption of, 619 albumin in, 17 amino acids in, 18 ammonia in, 18 appearance and pigments of, 15–16 bilirubin in, 16 cellularity of, 16 changes in solutes and other components in, 18–19 circulation of, 618–619, 619f composition of, 617–618 CT of, 19, 20f, 23f erythrocytes in, 14t, 15–16 formation of, 618 gamma globulin in, 17 glucose in, 14t, 18–19 gross appearance and pigments in, 15–16 hemoglobin in, 16 leaks, 634–635, 702, 882, 896 leukocytes in, 14t, 15–16 MRI of, 21f, 23f normal values in, 17t osmolarity of, 17t pH of, 17t physiology of, 617–621 pressure of, 15, 619–620. See also Intracranial hypotension; Intracranial pressure, elevated protein in, 14t, 16–17, 17t serologic and virologic tests, 18 sodium in, 618 urea in, 18 uric acid in, 18

10/02/23 10:43 AM

Index volume of, 618, 619–620 xanthochromia of, 16, 842 Cerebrospinal fluid (CSF) examination. See also Lumbar puncture (LP) in ALS, 1104 in arboviral encephalitis, 745 in bacterial meningitis, 700 in brain abscess, 714 characteristic findings in, 13, 14t cultures, 701 in ependymal disorders, 635–637 in glioma, 648 Gram stain, 701 in herpes simplex encephalitis, 747 in HIV encephalopathy, 755 in hydrocephalus, 13–14. See also Hydrocephalus indications for, 13–14, 14t in meningeal disorders. See Meningeal disorders in meningitis, 700–701 aseptic, 740 bacterial, 14t, 700–702 carcinomatous, 661–662 in children, 701 chronic, 742–743 fungal, 14t, 18, 727 tuberculous, 14t, 18, 717 viral, 14t, 16–18 in migraine with pleocytosis, 182–183 in MS, 14t, 17, 920 in neurosyphilis, 720 in normal-pressure hydrocephalus. See normal-pressure hydrocephalus in postinfectious myelitis, 1243 in pressure. See Intracranial pressure in primary CNS lymphoma, 658 in pseudotumor cerebri. See Pseudotumor cerebri in restless legs syndrome, 409 in seizures, 336 in septic thrombophlebitis, 711 special techniques for, 701–702 in spirochetal infections, 14t, 18 in stroke, 14t, 17 in subacute spongiform encephalopathy, 766 in subarachnoid hemorrhage, 14t, 15–16, 842 in subdural empyema, 709 in tabetic neurosyphilis, 723 Cerebrotendinous xanthomatosis (CYP27A mutation), 984 Cerebrovascular disease age-related changes in, 773t amyloid angiopathy, 853, 855–856, 855f

Ropper_Index_1519-1606.indd 1533

cavernous malformations, 852–853, 853f CSF examination in, 14t, 15–16 dementia in Alzheimer type, 870–871. See also Alzheimer disease arteriosclerotic, 43 infarction and, 443 multiinfarct, 1064 developmental venous anomaly, 853, 853f diffuse vasospasm, 859t dural arteriovenous fistula, 851–852, 852f focal neurologic deficits, 774 headache in, 175 hemorrhagic intracerebral. See Intracerebral hemorrhage subarachnoid. See Subarachnoid hemorrhage incidence of, 775 inevident or misconstrued syndromes of, 869–870 ischemic. See also Ischemic stroke Binswanger disease, 826 CADASIL, 826–827, 826f carotid artery dissection, 821–822, 823f fibromuscular dysplasia, 821 generalized, 820–821 intracranial artery dissection in, 824 Moyamoya disease, 782, 824–825, 825f vertebral artery dissection in, 803–804, 822–824 migraine and, 184–185 occlusion in, 778–779 PRES, 856–858 seizures in, 344 special clinical problems in, 869–871 stroke in. See Stroke syncope with, 394 vascular anatomy of, 758f, 784f vasculitis. See Vasculitis, cerebral vasospasm in, diffuse, 858–859, 859f Cerebrum, 458–459 Ceruloplasmin, deficiency of, 978 Cervical palsy, 1377 Cervical rib, 223, 224f Cervical spine/spinal cord disorders congenital anomalies, 1261–1262 intervertebral disc herniation management of, 223 MRI in, 222–223, 231f symptoms at different levels, 211t, 221–222 magnetic stimulation in, 38–39 metastatic disease, 225

1533

osteoarthritis, 221 rheumatoid arthritis, 221, 1260 spondylosis with myelopathy clinical features of, 223, 1256–1257 diagnosis of, 1258–1259, 1258f differential diagnosis of, 1259 historical aspects of, 1256 with lumbar stenosis, 205, 1259 pathogenesis of, 1257–1258 pathologic changes in, 1257 treatment of, 223, 1259 traumatic atlantoaxial dislocation, 221, 1228t, 1261 autonomic dysfunction in, 549 cruciate paralysis in, 1232 evaluation of, 1227–1229, 1229f flexion injury, 1226 fractures, 901, 1226, 1227, 1228t headache in, 176, 196 hyperextension injuries, 1226 management of, 1232–1233 whiplash injuries, 1226 treatment of, 223 Cervical subarachnoid puncture, lateral, 14 Cestode infections, 733–735, 733t, 734f CGRP receptor antagonists, 187, 188, 189, 191 CHA2DS2VASC-c (CHADS-VASC) Stroke Predictor Scale for Atrial Fibrillation, 791, 791t Chagas disease, 732 Chanarin-Dorfman disease (PNPLA2 mutation), 1411 Chance fracture, 1228t Channelopathies calcium hypokalemic periodic paralysis, 1448t, 1453–1454 hypokalemic weakness in primary aldosteronism, 1455 malignant hyperthermia, 574, 1199, 1448t, 1455–1456 secondary periodic paralyses, 1454–1455 seizures in, 334, 338t thyrotoxic periodic paralysis, 1437, 1447, 1455 chloride. See Myotonia congenita (Thomsen disease) potassium, 334, 338t, 1448t, 1456 sodium, 334, 338t, 1450–1453 hyperkalemic periodic paralysis, 1448t, 1450–1451 paramyotonia congenita (Eulenburg disease), 1448t, 1451–1452 Charcot joints, 723, 724, 1282, 1303, 1334

10/02/23 10:43 AM

1534

Index

Charcot-Marie-Tooth disease classification of, 1326t clinical features of, 90, 1325, 1327–1328 differential diagnosis of, 1328 EMG in, 1328 genetic features of, 1326t, 1328, 1337 pathologic findings in, 1360 treatment of, 1360 Charles Bonnet syndrome, 300, 481 Chemical meningitis, 742t, 743 Chemotherapy for brainstem glioma, 680 for glioblastoma, 650 for gliomatosis cerebri, 652 for malignant meningitis, 662 for medulloblastoma, 665 for neuroblastoma, 666 for oligodendroglioma, 653–654 for primary CNS lymphoma, 658 for tuberculous meningitis, 718–719 Cherry-red spot, retinal in central retinal artery occlusion, 249, 249f diseases associated with, 951t in myoclonus, 95 in Tay-Sachs disease, 951, 951f Cherry-red spot myoclonus syndrome, 975 Cheyne-Stokes breathing/respirations, 373, 374, 374t, 375, 378–379, 558 Chiari malformations clinical manifestations of, 1009–1010 differential diagnosis of, 924 headache in, 195–196, 1009 imaging of, 1009–1010, 1009f incidence of, 1008 morphology of, 1009 in sleep disorders, 410 syringomyelia and, 1268–1269 treatment of, 1010 Chickenpox, 751 Children ADEM in, 931 ADHD in. See Attention-deficit hyperactivity disorder (ADHD) arachnoid cyst in, 671 astrocytomas in, 651 ataxia in acute, 750, 972, 1033 progressive, in early childhood, 964 progressive, in late childhood, 972–975 ataxia-telangiectasia in, 1024 athetosis in, 82 autistic. See Autism/autism spectrum disorders (Kanner-Asperger syndrome) bacterial meningitis in, 698–699, 704

Ropper_Index_1519-1606.indd 1534

BAEPs in, 37 brain death in, 369 cataracts in, congenital, 247 Charcot-Marie-Tooth disease in, 1325 choreoathetosis in, 1031 clumsiness in, 589, 594 cognitive rest in, 900 CSF pressure in, 15 depression in, 1500 dermatomyositis in, 1383 developmental motor apraxia in, 65 dystonia in, 84 EEG in, 33 enuresis in, 603 ependymomas in, 654 fetal alcohol syndrome in, 1188–1189 Gilles de la Tourette syndrome in, 103–104 growing pains in, 145 growth and development of. See also Developmental diseases anatomic basis of, 583, 584f behavioral, 585–586 delays in, gait disorders and, 130–131 evaluation of, 589t intellectual, 438, 590. See also Developmental diseases language, 590–591 milestones in, 588t motor, 586 normal functions and delays in, 587t–588t personality and social adaptation, 592 physiology of, early, 585–586 sensory, 589, 594 sexual, 591–592 habit spasms in, 102–103 head injury in. See Head injury, in children hemiplegia in, 182, 183 Huntington disease in, 1070 hypoparathyroidism in, 1145 increased intracranial pressure in, 622 inherited metabolic diseases in of early childhood aminoacidopathies. See Aminoacidopathies aspartylglycosaminuria, 950t, 970 Cockayne syndrome, 970 diagnosis of, 971 fucosidosis, 950t, 970 Gaucher disease. See Gaucher disease (glucocerebrosidase deficiency) mannosidosis, 950t, 969–970

metachromatic leukodystrophy. See Leukodystrophies, metachromatic mucolipidoses, 950t, 969 mucopolysaccharidoses. See Mucopolysaccharidoses neuroaxonal dystrophy/ degeneration (PLA2G6 mutation), 965–966 neuronal ceroid lipofuscinoses. See Neuronal ceroid lipofuscinoses (Batten disease) Niemann-Pick disease. See Niemann-Pick disease (sphingomyelinase deficiency) opsoclonus-myoclonus syndrome, 966–967, 1033 progressive cerebellar ataxia, 964 signs of, 970–971 of late childhood and adolescence, 971–972 aceruloplasminemia, 978 basal ganglionic and cerebellar calcification, 980–981, 980f with changes in behavior and intellect, 985–986 with choreoathetosis and dystonia, 981 extrapyramidal syndrome. See Extrapyramidal motor system disorders, in inherited metabolic diseases Fabry disease. See Fabry disease familial polymyoclonus. See Polymyoclonus, familial homocystinuria. See Homocystinuria (CBS mutation) hypocupric myeloneuropathy, 978–979 leukodystrophies, 981–984. See also Leukodystrophies neurodegeneration with brain iron accumulation (Hallervorden-Spatz disease), 84, 99f, 979 osteopetrosis, 981 Parkinsonian syndromes. See Parkinsonian syndromes, in inherited metabolic diseases progressive cerebellar ataxias, 972–973 with seizures, 975–976. See also Children, seizures in with stroke, 984–985 sulfite oxidase deficiency, 948, 985

10/02/23 10:43 AM

Index intellectual and developmental disability in, 603–604, 604f intraspinal tumors in, 1265 lead poisoning in, 1209–1210 lead toxicity in, 631 learning disabilities in, 594–595 leukemia in, 662 malaria in, 732 medulloblastoma in, 665 mercury poisoning in, 1213 migraine in, 179, 181, 183 Moyamoya disease in, 824–825 MRI in, 24 MS in, acute, 918 muscular dystrophy in. See Muscular dystrophies myasthenia gravis in, 1435 neuroblastoma in, 666 neurologic examination in, 10 nocturnal enuresis in, 420 nystagmus in, 282 occult hydrocephalus in, 624 opsoclonus in, 283 opsoclonus-myoclonus-ataxia syndrome in, 688 PANDAS syndrome in, 104 paralysis in, 66, 67 parvovirus infections in, 741 periodic syndrome in, 181 progressive bulbar palsy in, 1112–1113 protein-calorie malnutrition in, 1153 pupil size in, 286 recessive mutilating sensory polyneuropathy in, 1330 retinoblastoma in, 666 Riley-Day syndrome in, 548–549 saccular aneurysms in, 838 schizophrenia in, 1511 seizures in, 320, 1038 antiepileptic drugs for, 347, 348t causes of, 340–342, 340f, 340t with centrotemporal spikes, 331 infantile spasms, 331 juvenile myoclonic epilepsy and, 325 ketogenic diet for, 357 with occipital spikes, 331 treatment of, 353 sleep in, 399, 402, 403f sociopathy in, 1482 somnambulism in, 412–413 speech and language disorders in. See Speech and language disorders spinal cord trauma in, 1233 springing pupils in, 288 strabismus in, 261, 272 strength testing of, 1373 stroke in, 827–829, 828t

Ropper_Index_1519-1606.indd 1535

subacute sclerosing panencephalitis in, 762 subdural empyema in, 709 toe walking in, 1113 torsion dystonia in, 1092 visual acuity testing in, 239–240 Chimeric antigen receptor T-cell (CAR-T-cell) therapy, 1218 Chiropractic manipulation in back pain, 209 Chloral hydrate, 1196 Chloramphenicol, 703, 703t, 730 Chloride, in CSF, 17t Chloride channel disorders. See Myotonia congenita (Thomsen disease) Chlorinated polycyclic compounds, 1214–1215 Chlorpromazine, 1206, 1512 Cholesteatoma, 314, 674 Cholesterol ester storage disease, 950t Choline (Cho), 25 Choline acetyltransferase, 1062 Cholinergic crisis, 1443 Cholinergic neurons, 404–405 Chondrodysplasia punctata, 1003 Chondrodystrophia calcificans congenita, 1003 Chondrosarcoma, 664 Chordoma, 680–681 Chorea acanthocytosis with, 1091–1092 benign hereditary, 81, 81t diseases associated with, 80–82, 81t drug-induced, 81, 81t gravidarum, 81t in HIV infection, 82 in Huntington disease. See Huntington disease hypotonia in, 80 in lupus erythematosus, 81 vs. movement disorders, 80 vs. myoclonus, 80–81 in paraneoplastic disorders, 81 in pregnancy, 81 senile, 1071 in streptococcal infection, 81 Sydenham, 81t, 82 Chorée fibrillaire (Morvan syndrome), 1456–1457 Choreiform syndrome, 602 Choreoathetosis vs. athetosis, 82 in basal ganglion disease, 77 in congenital lactic acidosis, 956 gait disorders in, 128 in infants and children, 1031 in metabolic disease, 981

1535

in Niemann-Pick disease, 966 paroxysmal, dystonia and, 85 phenytoin and, 352 Chorioepithelioma, 659 Chorioretinitis, 251, 1035 Choroid plexus in bacterial meningitis, 697t CSF formation in, 618 tumors of, 642t, 667 Choroidal artery stroke syndrome, 798 Chromatolysis, 1279 Chromosomal abnormalities, 940–941, 1010–1013. See also Down syndrome (trisomy 21); specific disorders Chronic ataxic neuropathy, 1312 Chronic fatigue syndrome, 149–150, 513–514 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) clinical features of, 1319–1320 vs. Guillain-Barré syndrome, 1319 in HIV infection, 756 laboratory features in, 1320 nerve conduction studies in, 1319 nonrelapsing, 1319 relapsing, 1319, 1338 treatment of, 1320–1321 Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), 934 Chronic mountain sickness (Monge disease), 1131 Chronic traumatic encephalopathy (punch-drunk syndrome), 899–900 Churg-Strauss disease, 862, 1307 CIDP. See Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Ciguatera, 163, 1208 Ciliary body paralysis, 1206 Ciliospinal pupillary reflex, 287 Cingulate gyrus, 522 Ciprofloxacin, 704t, 708, 1447 Circadian rhythms, 399, 411, 568 Circle of Willis aneurysms in, 839f regions supplied by, 792, 801, 801f saccular aneurysms in, 838–839 Circumduction, 126 Cisapride, 553 Cisplatin, 1215–1216, 1301 Cisternal puncture, 14 Citalopram, 1200, 1497t Citrullinemia, 946

10/02/23 10:43 AM

1536

Index

CJD (Creutzfeldt-Jakob disease). See Subacute spongiform encephalopathy Clarithromycin, 707 Clasp-knife phenomenon, 62 Clasp-knife spasticity, 79 Claude syndrome, 802, 802t Claudication, 205, 216 Claustrophobia, 1472 Claustrum, 70, 71f Cleft palate, 598 Climbing fibers, 114f, 115, 115f Clindamycin, 708 Clinical method of neurology. See Neurologic diagnosis Clioquinol, 1219 CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), 934 CLN mutation. See Neuronal ceroid lipofuscinoses (Batten disease) Clobazam, 347t, 348t Clofazimine, 1323 Clonazepam for anxiety disorders, 1472 for essential tremors, 89 for hypoxic-ischemic encephalopathy, 1130 indications for, 1196 for palatal tremor, 93 for seizures, 347t, 348t, 353 for somnambulism, 413 in spinal cord injury management, 1233 for stiff man syndrome, 1460 Clonidine, 104 Clonus, 63 Clopidogrel, 814 Clorazepate, 1196 Clostridium botulinum, 1206. See also Botulism Clostridium tetani, 1204. See also Tetanus Clozapine in Huntington disease management, 1071 in Lewy body dementia management, 1068 in Parkinson disease management, 1084 for schizophrenia, 1512–1513, 1513t side effects of, 1513, 1513t Clubfoot, 1418–1419 Clumsiness in children, 589, 594 in cortical-basal ganglionic degeneration, 1090 in lacunar stroke, 780

Ropper_Index_1519-1606.indd 1536

Cluster headache sleep patterns in, 408 symptoms of, 174, 178t, 189–190 treatment of, 178t, 191 variants of, 190–191 Cluttered speech, 598 CMAP (compound muscle action potential), 39–40, 40f, 41t, 42f, 43–44 CMBP mutation (proximal myotonic myopathy), 1396t, 1400 CMV. See Cytomegalovirus (CMV) infections CNTNAP2 gene, 598 Coats disease, 1395 Cobalamin. See Vitamin B12 Cobalt-chromium metallosis, 1214 Cocaine abuse of, 1202 confusional states induced by, 447 overdose, 1202 pupillary response to, 289, 544 spinal cord infarction from, 1250 in vasospasm, diffuse, 858–859 Coccidioides/coccidioidomycosis, 729, 1242 Coccydynia, 219 Cochlear nerve anatomy of, 292, 293f in central deafness, 297 injury of, 881–882 in sensorineural deafness, 297, 301 Cochleo-orbicular reflex, 302 Cockayne syndrome (ERCC mutation), 955, 970 Codeine, 151t Coenuriasis, cerebral, 734 Coenzyme Q10 deficiency, 1410–1411 Cogan oculomotor apraxia, 269, 1025 Cognitive function age-related changes in, 439–440, 608–609 in Alzheimer disease, 1057–1058 assessment of, 7 in cerebellar disease, 118 in cretinism, 1149 in frontal lobe lesions, 466–467 impairment of, 24 inherited metabolic diseases and changes in, 981–982 intelligence in, 436–439 intracranial tumors and changes in, 647 in lupus erythematosus, 863 mild impairment of, 439–440, 609, 1057–1058 in MS, 916 in tuberous sclerosis, 1014 in vitamin B12 deficiency, 1165 in Wernicke-Korsakoff syndrome, 1156

Cognitive rest, 900 Cogwheel phenomenon, 80, 90, 1074 COL4A1 mutations, 827 Colchicine, 1302, 1415t, 1417 Cold exposure, in Raynaud syndrome, 550–551 Cold pressor test, 543 Collapsin-responsive mediator protein-5 (CRMP-5), 684t Collet-Sicard syndrome, 682t, 1357t Collier sign, 266, 285 Colloid bodies in retina, 248 Colloid cyst, 193, 670–671, 671f Coloboma, 258 Color agnosia, 482 Color anomia, 482 Color blindness, 260 Color vision, 260 Colpocephaly, 1012 Coma acute hydrocephalus in, 379 in alcohol intoxication, 382t alpha, 35 anatomy and neurophysiology of, 370–371 in anoxia, 382t awake, 364 Babinski sign in, 363, 376 in barbiturate intoxication, 1195 in basilar artery disorders, 381t in brain abscess, 381t in brain death, 367–368 caloric testing in, 378 in carbon monoxide intoxication, 382t in cerebral hemorrhage, 381t classification of, 380–383 clinical approach to, 375–385 common causes of, 361, 362t, 380, 381t–382t, 383 in concussion, 372, 883 corneal reflex response in, 378 definition of, 361 dépassé, 367 in diabetes mellitus, 371, 382t differential diagnosis of, 380–383, 381t–382t drug-induced, 372, 376–377 in eclampsia, 381t EEG in, 32f, 34 in encephalitis, 381t, 748 eye and eyelid movements in, 377–378 hemiplegia in, 376 hepatic, 371, 382t, 1134 in hypercapnia, 382t in hypoglycemia, 382t increased intracranial pressure in, 379, 384 in infections, 382t

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Index laboratory procedures in, 379–380 LP in, 384 management of, 383–384 in meningitis, 381t in metabolic disorders, 371–372. See also Metabolic encephalopathy neurologic examination in, 10, 376–379 in opioid intoxication, 382t papilledema in, 379 pathologic anatomy of, 372–374 physical examination in, 375–376 in pontine hemorrhage, 835 posturing in, 378 prognosis of, 384–385 pupillary reactions in, 376–377 recurrent, 369 reflexes in, 363 respiration in, 375, 378–379 in sedative intoxication, 382t in seizures, 372, 382t vs. sleep, 363–364 spindle, 370, 410 spontaneous limb movements in, 376 stroke in, 870 in subarachnoid hemorrhage, 381t in subdural hematoma, 381t in toxic conditions, 371–372, 381t–382t in TTP, 381t in uremia, 382t vegetative state and, 364–365 Combat fatigue, 510 Comitant strabismus, 272 Common peroneal (fibular) nerve neuropathy, 1348 Communicating rami, 534 Compartment (pretibial) syndrome, 1426 Compensation claims anosmia in, 234 back pain in, 220 in concussion, 900 neck pain in, 221 pain complaints and, 148 Compensation neurosis. See Malingering Complex regional pain syndrome (CRPS) chronic pain in, 143 clinical features of, 147 definition of, 142, 142t facial pain in, 200 pathophysiology of, 147 after peripheral nerve injury, 1348 treatment of, 147 Complex repetitive discharges (CRDs), 47

Ropper_Index_1519-1606.indd 1537

Compound muscle action potential (CMAP), 39–40, 40f, 41t, 42f, 43–44 Compression fracture, 1228t Compulsions, 1475 Computed tomography (CT) in Alzheimer disease, 1063 angiography in, 25, 26f in arachnoid cyst, 671 in AVMs, 849, 850f in bacterial meningitis, 702 of brain, normal, 20f in central pontine myelinolysis, 1143 in colloid cyst of third ventricle, 671 in concussion assessment, 888, 888t of CSF, 19, 20f in cysticercosis, 734, 734f in ependymoma, 654 in epidural hematoma, 892, 892f in herpes simplex encephalitis, 747 in hypertensive encephalopathy, 856–857 in hypoparathyroidism, 1145 in hypoxic-ischemic encephalopathy, 1128, 1128f in intracerebral hemorrhage, 832, 834f in intracranial pressure management, 902 in meningioma, 655 vs. MRI, 19, 22t in MS, 921 of muscles, 49 vs. myelography, 19 of normal-pressure hydrocephalus, 626, 627f in paraneoplastic cerebellar degeneration, 687 in pregnancy, 22 in primary CNS lymphoma, 657–658 of pseudotumor cerebri, 630 risks of, 19, 22 in seizures, 336 in septic thrombophlebitis, 711 in severe head injury, 885–886, 886f of spine, 208 in stroke, 786 in subarachnoid hemorrhage, 841–842, 841f, 843f, 844f in subdural hematoma, 892, 893f, 894, 894f in tuberculous meningitis, 717 in tuberous sclerosis, 1015–1016, 1016f COMT (catechol-O-methyltransferase) inhibitors, 1081t, 1084 Conation, 424, 426 Concentric constriction, of visual fields, 242 Concentric sclerosis of Balo, 918

1537

Concussion amnesia in, 884, 888 assessment of, 888, 888t in athletes, 884, 900 in blast injuries, 883, 896 clinical manifestations of, 883–884 coma in, 372, 883 compensation claims in, 900 consciousness in, 882–883 definition of, 879–880 EEG in, 34 historical aspects of, 883 mechanism of, 883 of spinal cord, 1227, 1232 treatment of, 900 Conditioned nutritional deficiency, 1164 Conduction aphasia, 485, 492, 495t, 498, 499 Conduction block, 41–42, 1320 Conductive deafness, 297, 299, 300 Cones and rods, 244, 244f Confabulation, 446, 1156 Confrontational testing, of visual fields, 242 Confusion and confusional states affect in, 425–426 apperception in, 424 attention in, 363, 424 on awakening, 414 behavior in, 424–427 classification of, 430t clinical examination in, 429–430 in critical illness, 433 definition of, 361, 362, 428, 429 in delirium, 363, 428, 431–432 in dementia, 428, 429, 432–433 drug-induced, 432 EEG in, 429 in elderly, 432–433 emotional disturbances in, 425–426, 428–429 etiologies of, 430–431, 431t global, 428, 430t, 431 in head injury, 889 impulse disturbances in, 426–427 infectious, 433 insight loss in, 427 laboratory tests in, 430–431, 431t management of, 434 memory in, 363, 425 in metabolic encephalopathy. See Metabolic encephalopathy mood disturbances in, 425–426 in nonconvulsive status epilepticus, 433–444 perception in, 424–425 postoperative, 433 psychosis in, 430t, 431 seizures and, 431

10/02/23 10:43 AM

1538

Index

Confusion and confusional states (Cont.): in septic encephalopathy, 433 social behavior disorders in, 427 states of, 362–363 syndromes of, 431–434 terminology of, 428–429 thought process disturbances in, 425 in tuberculous meningitis, 717 in Wernicke-Korsakoff syndrome, 1155–1156, 1155f Confusion Assessment Method for the ICU (CAM-ICU), 433 Congenital cerebral motor disorders ataxias, 1032–1033 early detection of, 593 etiology of geminal matrix hemorrhage, 1026–1027, 1026f hypoxic-ischemic damage and neonatal encephalopathy, 1027–1028 neonatal hypoglycemia, 1030–1031 periventricular leukomalacia, 1027 extrapyramidal syndromes, 1031–1032 flaccid paralyses and floppy infant syndrome, 593, 1033–1034, 1033t spastic, 126, 1028–1030, 1030f terminology of, 1025–1026 treatment of, 1034 Congenital disorders anosmia, 233 cataracts, 247 central hypoventilation syndrome, 558 of cervical spine, 1261–1262 classification of, 997–998, 997t Cogan oculomotor apraxia, 269, 1025 of color vision, 260 craniocervical anomalies, 1261–1262 craniospinal deformities in. See Craniospinal deformities deafness, 301, 595–596 deafness in, 302 of heart, 713 hydrocephalus, 624 hypothalamic diabetes insipidus, 570 ichthyosis, hypogonadism, and mental retardation, 1005 inarticulation, 596–597 insensitivity to pain, 149, 1330 of lumbar spine, 215 of motor function. See Congenital cerebral motor disorders muscular dystrophies. See Muscular dystrophies myasthenic syndromes, 1445–1446, 1446t

Ropper_Index_1519-1606.indd 1538

myopathy. See Myopathy(ies) neonatal rigidity, 1460 neuroectodermatoses, 1013–1025, 1013t nystagmus, 282 oculomotor apraxia, 269 of optic nerve, 257 strabismus in, 263 tapetoretinal degeneration. See Leber hereditary optic atrophy (Leber amaurosis) word deafness, 596 Conjugate eye movements anatomy of, 263 in coma, 377–378 impairment of, 268–269 testing of, 267 Conn syndrome (primary aldosteronism), 1414, 1455 Connexin, 302, 303t Conradi-Hünermann syndrome, 1003 Consciousness in concussion, 882–883 content of, 361 definition of, 361 disorders of akinetic mutism, 366 brain death, 367–369 catatonia, 367 clinical approach to, 375–385 coma. See Coma EEG in, 34, 370 hypothalamic lesions in, 574–575 locked-in syndrome, 366, 557, 806 in metabolic disorders, 371– 372. See also Metabolic encephalopathy minimally conscious state, 365–366 syncope. See Syncope vegetative state, 364–365 in Wernicke-Korsakoff syndrome, 1155–1156 EEG and impaired, 369 level of, 361 in minor head injury, 887–889, 888t in panic attacks, 515 states of, 362–364 Constitutional asthenia, 511 Constraint therapy, 820 Constructional agraphia, 502 Constructional apraxia, 65, 477 Continuous positive airway pressure, 416, 559 Contraceptives, oral cerebral infarction risk and, 829–830 chorea and, 81, 81t migraine and, 179, 184 Contraction myoedema, 1374

Contractions, of muscles. See Muscle(s), contractions of Contractures, of muscles. See Muscle(s), contractures of Contrecoup lesion, 884, 889 Contusion, cerebral. See Head injury, severe Conus medullaris lesions, 1266 Convergence disorders, 1476 Convergence spasm, 269, 283, 1479 Convergent eye movements anatomy of, 263 insufficiency of, 269 nystagmus and, 283 spasm of, 269, 283 testing, 268 Conversion disorder, 333 Convexity subarachnoid hemorrhage, 847 Convulsions, 320. See also Seizures Cooing, 590 Coordination in cerebellar disease, 116–117 developmental disorders of, 594 tests of, 8 Copolymer I (glatiramer acetate), 926 Copper deficiency myelopathy, 978– 979, 1262 Coprolalia, 103, 505 Copy number variations, 940, 997 Corectopia, 377 Cori-Forbes disease (debranching enzyme deficiency, AGL mutation), 1407, 1408t, 1409 Cornea abnormalities of, 242 examination of, 240 Kayser-Fleischer ring of, 242, 976, 977f opacity, 242 reflexes, 284, 378, 1355 Corneal lattice dystrophy, with cranial neuropathy, 1335 Cornelia DeLange syndrome, 1005 Corpus callosum agenesis of, 999 degeneration of, 1171–1172 Cortical blindness , 259, 480, 803, 982 Cortical vein thrombosis, 344, 864–865 Corticobasal-ganglionic degeneration (CBGD), 1090–1091 Corticobulbar tract, 57f, 58. See also Upper motor neurons Corticoreticulospinal pathways, 61 Corticospinal tract. See also Upper motor neurons anatomy and physiology of, 53, 56–57, 57f disorders of, vs. extrapyramidal disorders, 70, 71t

10/02/23 10:43 AM

Index lacunar stroke in, 781 neurotransmitters of, 56 somatotopic organization of, 58–59 Corticosteroid myopathies, 1412–1413, 1415t Corticosteroid psychosis, 1147, 1516 Corticosteroids for acute necrotizing hemorrhagic encephalitis, 934 for ADEM, 933 anxiety caused by, 517 for autoimmune encephalitis, 935 for bacterial meningitis, 704 for Bell’s palsy, 1360 for cerebral edema, 645 in Churg-Strauss syndrome treatment, 1308 for CIDP, 1320 in cryoglobulinemia treatment, 1308 for cysticercosis, 734 for dermatomyositis, 1385 for glioblastoma, 650 for gliomatosis cerebri, 652 in granulomatous arteritis treatment, 862 in Guillain-Barré syndrome treatment, 1295 for herpes simplex encephalitis, 748 for hypereosinophilic syndrome, 1308 for hypoxic-ischemic encephalopathy, 1130 in intracranial pressure management, 903 in LP, 14 for metastatic intracranial tumor, 660 for MS, 924–925, 1244 for myasthenia gravis, 1440 for optic neuritis, 255, 925 for polyarteritis nodosa, 1307 for polymyositis, 1385 for primary CNS lymphoma, 658 for pseudotumor cerebri, 632 for radiation myelopathy, 1234 serous retinopathy and, 250 for Sjögren syndrome, 1312 in spinal cord injury management, 1233 for trichinosis, 733 for tuberculous meningitis, 719 Corticostriatospinal degenerations, 1091 Corticotropin-releasing factor (CRF), 539 Corticotropin-releasing hormone (CRH), 517, 567 Cortisol, 404, 516, 575 Corynebacterium diphtheriae, 1206, 1296 Costen syndrome, 199

Ropper_Index_1519-1606.indd 1539

Costoclavicular syndrome, 223 Costotransversitis, 207 Costovertebral angle, 207, 207f Cotton-wool patches, 247, 248 Coughing, headache and, 174, 194–195 Coup lesion, 884, 889 Cover and cover-uncover eye tests, 272 COVID-19 infection fatigue syndrome following, 513 myelitis following, 1381 neurologic features of, 745 Coxsackie virus, 741, 758, 760 CP mutation (aceruloplasminemia), 978 CPM. See Central pontine myelinolysis (CPM) CPT1A mutation (carnitine palmitoyltransferase deficiency), 1410 Crack cocaine, 858–859 Cramp-fasciculation syndrome, 1458–1459 Cramps action, 1375 characteristics of, 1423 diseases associated with, 1375–1376, 1423 EMG in, 1423 focal, 1423 in hypoparathyroidism, 1414 idiopathic, 1376 management of, 1423 mechanism of, 1423 musician’s, 101 with myalgia and myoglobinuria, 1394 occupational, 101 in peripheral neuropathy, 1283 in pseudotetany, 1423–1424 in Satoyoshi syndrome, 1376, 1424 in tetany, 1423 writer’s, 84, 98, 101 Cranial arteritis. See Temporal arteritis Cranial nerves abducens. See Abducens (sixth) nerve anatomy of, 1276 in bacterial meningitis, 697t, 698, 700 in basilar artery occlusion, 806 in cavernous sinus, 269–271, 271f, 277 in cranial pain, 174–175 facial. See Facial (seventh) nerve glossopharyngeal. See Glossopharyngeal (ninth) nerve hypoglossal (twelfth), 1366 injuries of, 881–882 in mononucleosis, 1368

1539

multiple, palsies of, 1367–1368, 1367f, 1367t neuralgia of, 196–199 oculomotor. See Oculomotor (third) nerve olfactory (first), 230–232, 231f optic. See Optic (second) nerve spinal accessory (eleventh), 99–100, 1365–1366 tests of, 7–8 trigeminal. See Trigeminal (fifth) nerve trochlear. See Trochlear (fourth) nerve vagus. See Vagus (tenth) nerve in vestibular schwannoma, 672–673 vestibulocochlear. See Vestibulocochlear (eighth) nerve viral infection of, 1367–1368 Cranial root, of accessory nerve, 1365 Craniectomy, decompressive, 904 Craniocerebral anomalies with syndactyly, 1002–1003 Craniocerebral trauma. See Head injury Craniocervical junction anomalies, 1261–1262 Craniofacial dysostosis, 1003 Craniofacial pain. See also Headache anatomy of, 174–175 mechanisms of, 175–176, 186–187, 196–200 Craniopharyngioma, 234, 641t, 674–675 Craniospinal deformities, 998 at birth and in early infancy, 998–999, 998t Chiari malformations. See Chiari malformations combined cerebral, cranial, and somatic abnormalities, 1002 craniocephalic–skeletal anomalies, 1003 dwarfism, 968, 1004–1005 oculoauriculocephalic anomalies, 1004 oculoencephalic defects, 1003–1004 syndactylic-craniocerebral anomalies, 1002–1003 developmental spinal defects, 1007–1008, 1008f in disturbances of neuronal migration and cortical development, 999–1000, 1001t anencephaly, 1001 lissencephaly, 1000, 1001–1002, 1001t, 1004 microcephaly. See Microcephaly pial surface disorders, 1002

10/02/23 10:43 AM

1540

Index

Craniospinal deformities (Cont.): dysraphism, 1006–1007, 1006f neurocutaneous anomalies with developmental delay, 1005–1006 teratologic, 1013 Craniosynostoses, 999 Craniotubular bone dysplasia and hyperostoses, 1003 Cranium embryonic development of, 998, 1001t sarcoma of, 664 CRDs (complex repetitive discharges), 47 Creatine kinase, 396 Creatine phosphate, 785 Creatinine, in CSF, 17t Creativity, 438–439 Credé maneuver, 552 Cremasteric reflex, 63 CRES (CAR-T-cell-related encephalopathy syndrome), 1218 Cretinism, 949, 1148–1149 Creutzfeldt-Jakob disease (CJD). See Subacute spongiform encephalopathy CRF (corticotropin-releasing factor), 539 CRH (corticotropin-releasing hormone), 517, 567 Cri-du-chat syndrome, 1011–1012 Crigler-Najjar syndrome, 1032 Criminality, sociopathy and, 1482 Crista ampulla, 293, 293f Critical illness myopathy, 1413 Critical illness polyneuropathy, 560, 1295–1296 Critical limb ischemia, 1309–1310 CRMP-5 (collapsin-responsive mediator protein-5), 684t Cross-dressing, 1084 Crouzon syndrome, 1003 Crow-Fukase syndrome, 1316 CRPS. See Complex regional pain syndrome (CRPS) Crying involuntary uncontrollable, 523–524, 523t, 528–529 in seizures, 328 Cryoglobulinemia, 1308, 1317 Cryoglobulins, 551 Cryptococcosis, 727–728, 757, 1242 CSF. See Cerebrospinal fluid CT. See Computed tomography Cubital tunnel syndrome, 346 Cupula, 293, 293f Cupulolithiasis, 310, 312

Ropper_Index_1519-1606.indd 1540

Cushing disease clinical features of, 575 diagnosis of, 575 mental changes in, 1516 myopathy in, 1413 in pituitary adenoma, 677 treatment of, 575–576 Cushing response, 550 Cushing syndrome, 575–576, 677, 1147 Cushing ulcer, 516, 574 Cutaneomuscular abdominal reflex, 63 Cyanide poisoning, 1207–1208 Cyanocobalamin, 1168 Cyclazocine, 1194 Cyclic adenosine monophosphate (cAMP), 76 Cyclic vomiting syndrome, 181, 562 Cyclizine, 309 Cyclophosphamide for CIPD, 1320 for cryoglobulinemia, 1308 for granulomatous arteritis, 862 for MS, 927 for myasthenia gravis, 1441 for NMO, 930 for polyarteritis nodosa, 1307 for polymyositis, 1386 for Sjögren syndrome, 1312 Cycloplegia, 273 Cyclosporine, 1217–1218, 1386, 1440–1441 Cyclothymic personality disorder, 1471t, 1489 CYP27A mutation (cerebrotendinous xanthomatosis), 984 Cyproheptadine, 189 Cyst arachnoid, 669, 671 in astrocytoma, 651 bone, in hypophosphatemia, 1414 colloid, 193, 670–671, 671f congenital, 1008 dermoid, 668, 683 epidermoid, 668, 674 suprasellar arachnoid, 681 suprasellar epidermoid, 674–675 synovial, 215 Tarlov, 215, 634 Cysticercosis, 733–734, 733t, 734f, 1380 Cystinuria, 945t Cytarabine, 1217 Cytochrome oxidase deficiency, 942 Cytoid bodies, 248 Cytokine-release syndromes, 1218 Cytomegalovirus (CMV) infections aseptic meningitis, 741 congenital, 1035–1036 diagnosis of, 742 in HIV infection, 757

Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA), 862 Cytotoxic edema, 644, 644f, 645, 785, 1127 D Dabigatran, 814 Dacrystic epilepsy, 328 DADS (distal acquired demyelinating symmetrical neuropathy), 1320 DAGs (dystrophin-associated glycoproteins), 1393, 1396–1397 DAI (diffuse axonal injury), 364, 891t Dancing eyes syndrome, 1033 Dancing fingers, 1282 Dandy-Walker syndrome, 623, 624, 1002, 1006, 1006f Dangling-arm syndrome, 1378 Dantrolene, 1199 Dapsone, 1302, 1323 Dawson fingers, 915f, 920 Daytime sleepiness, excessive, 415–417, 415t DBS (deep brain stimulation), 1085–1086, 1476 DCX mutation, 1001t, 1002 DDT (dichlorodiphenyltrichloroethane), 1214 de Morsier syndrome (septooptic dysplasia), 1004 Deafferentation pain, 143 Deafferented state, 366 Deafness assessment of, 297 bacterial infections in, 301 bilateral, 301 causes of, 301–302 central, 297, 596 conductive, 297, 299, 300 congenital, 301, 302, 595–596 cortical, 470–471 functional (hysterical), 302 hereditary syndromes of, 302, 303t–304t, 1116–1117 in infants, 594 in Ménière disease, 301, 309 in meningitis, 301 in middle ear disorders, 297, 300 in mitochondrial disorders, 302, 304t in neurosyphilis, 724 nonrecruiting, 298 recruiting, 298 sensorineural, 297 tinnitus in, 299 unilateral, 301 unilateral episodic, 301 word. See Word deafness

10/02/23 10:43 AM

Index Death. See also Brain death neocortical, 364 sudden unexplained, in epilepsy, 330 Debranching enzyme deficiency (Cori-Forbes disease, AGL mutation), 1407, 1408t, 1409 Decerebrate rigidity, 378 Decomposition of movements, in cerebellar disease, 115–116 Decompression, spinal cord, 1267 Decompression sickness, 1255 Decompressive craniectomy, 904 Decorticate posturing, 378 Dedifferentiation, 643 Deep aphasia, 492 Deep brain stimulation (DBS), 99, 1085–1086, 1476 Degenerative diseases vs. age-related changes, 1052–1053 apoptosis in, 1054 Binswanger disease, 129, 130, 443, 820, 826 with blindness, 1114–1115 Leber hereditary optic atrophy (Leber amaurosis), 257, 1004, 1115 retinitis pigmentosa, 242, 1115–1116 Stargardt disease, 1116 classification of, 1054–1055 clinical characteristics of, 1053 with congenital or progressive deafness, 302, 303t–304t, 1116–1117 of corpus callosum, 1171–1172 dementia in. See Dementia depression in, 1490 EEG in, 34–35 of frontal lobe, 441 hepatocerebral, 90, 1144–1145 with muscular weakness and wasting without sensory changes hereditary spastic paraplegia, 1113–1114, 1113t, 1332 motor neuron disease, 1095 amyotrophic lateral sclerosis. See Amyotrophic lateral sclerosis (ALS) primary lateral sclerosis, 1102, 1106, 1268 progressive bulbar palsy, 1105–1106 progressive muscular atrophy, 1105, 1107 spinal muscular atrophy. See Spinal muscular atrophy (SMA) neuronal loss in, 1052, 1059 pathologic features of, 1053–1054

Ropper_Index_1519-1606.indd 1541

with posture and movement abnormalities acanthocytosis with chorea, 1091–1092 corticobasal-ganglionic degeneration. See Corticobasal-ganglionic degeneration (CBGD) corticostriatospinal degenerations, 1091 dystonic disorders. See Dystonia/ dystonic disorders multiple system atrophy. See Multiple system atrophy (MSA) Parkinson disease. See Parkinson disease progressive supranuclear palsy. See Progressive supranuclear palsy (PSP) prevalence and incidence of, 6t with progressive ataxia cerebellar cortical ataxias, 1098, 1099f, 1332 classification of, 1095 dentatorubropallidoluysian atrophy (DRPLA), 1072, 1096t, 1100–1101 differential diagnosis of, 1101 in early childhood, 964 fragile X tremor–ataxic premutation syndrome, 1098–1099 Friederich ataxia. See Friedreich ataxia hereditary polymyoclonus, 1101–1102 inherited, 1095, 1096t Machado-Joseph-Azorean disease, 1096t, 1100 multiple system atrophy. See Multiple system atrophy (MSA) paroxysmal ataxias, 1096t, 1101 vitamin E deficiency in, 1096t, 1097, 1168 retinal, 251 with sensory and sensorimotor disorders Charcot-Marie-Tooth disease. See Charcot-Marie-Tooth disease Dejerine-Sottas syndrome, 171, 801, 1329 Riley-Day syndrome. See RileyDay familial dysautonomia of spine, 204 striatonigral, 79, 80 Deglutitional syncope, 392 Déjà vu, 328 Dejerine-Mouzon syndrome, 171

1541

Dejerine-Roussy syndrome (hypertrophic neuropathy of infancy), 171, 801, 1329 DeLange syndrome, 1005 Delayed posthypoxic encephalopathy and leukoencephalopathy, 1129, 1129f Delayed-sleep-phase syndrome, 411 Delirium. See also Hallucinations agitated, 431–432 in alcohol withdrawal, 431–432. See also Delirium tremens vs. confusion, 363 confusion in, 428, 430t, 431–432 definition of, 428 EEG in, 432 management of, 434 PET in, 432 states of, 361 Delirium tremens brain pathology in, 432 clinical features of, 363, 1185 EEG in, 35 incidence of, 1185 pathogenesis of, 1185–1186 treatment of, 1186–1187 Delta waves, in EEG, 30f, 33 Delusional disorder, 1514–1515 Delusions, 232, 235, 425 Dementia alcoholic, 1187–1188 in ALS, 1105 beclouded, 433 in Binswanger disease, 826 in cerebrovascular disease arteriosclerotic, 43, 443 characteristics of, 870–871 multiinfarct, 1064 in chronic hydrocephalus, 443 classification of, 442, 444t confusion in, 432–433 in cortical-basal ganglionic degeneration, 1090 definition of, 428, 436 in dialysis, 1139 differential diagnosis of, 439, 439t, 444–445, 1064 gait disorders in, 129, 130 gait in, 441 in Gerstmann-Sträussler- Scheinker syndrome, 767 head injury and, 443 in hepatic encephalopathy, 1135 hereditary multiinfarct. See CADASIL in HIV infection, 755, 755f in inflammatory disorders, 443 intelligence in, 458–459 language function in, 441 leukodystrophy, 443 management of, 454–455

10/02/23 10:43 AM

1542

Index

Dementia (Cont.): memory in, 442–443 mental status examination in, 452, 453f in metabolic disease, 1146–1149 multiinfarct, 1064 myoclonic, 96 with other neurologic features adult polyglucosan body disease, 1072 familial dementia with spastic paraparesis, 1072 Huntington disease. See Huntington disease paralytica, 722 pathogenesis of, 442–443 physical deterioration in, 441–442 prevalence and incidence of, 5, 5f progressive in Alzheimer disease. See Alzheimer disease in argyrophilic grain disease, 1068 in Lewy body dementia. See Lewy body dementia in lobar atrophies, 1065–1067 in neuroserpinopathy, 1068 reflexes in, 441 semantic, 1066–1067 senile. See Alzheimer disease signs of, 430 subcortical, 442, 916 subdural hematoma and, 443 in thyroid encephalopathies, 1147–1149 types of, 439, 439t Dementia praecox, 1503. See also Schizophrenia Demyelinating diseases CIDP. See Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) classification of, 908, 909t definition of, 908 GBS. See Guillain-Barré syndrome (GBS) inflammatory, 909t. See also Acute disseminated encephalomyelitis (ADEM); Multiple sclerosis (MS); Neuromyelitis optica (NMO) nerve conduction studies in, 43 osmotic, 1142 postinfectious, 255 Schilder-type, 918–919 Demyelination, 1278–1279, 1278f Dendrites, as sensory receptors, 155 Denervation hypersensitivity in, 146, 544 MUPs in, 47–48, 48f muscle atrophy in, 56, 66, 1282

Ropper_Index_1519-1606.indd 1542

Denny-Brown syndrome, 1117 Dental disorders, facial pain in, 199 Dentate nucleus, 111, 113, 113f, 116 Dentatorubral cerebellar atrophy with polymyoclonus, 975 Dentatorubropallidoluysian atrophy (DRLPA, ATN1 mutation), 1072, 1096t, 1100–1101 Depersonalization, 1504 Depression. See also Bipolar disease alcohol use in, 1179, 1500 anatomic correlates of, 1494–1495 anergic, 518 anxiety and, 528, 1473–1474, 1500 biochemical theories of, 1495 catatonic, 1492 in childhood and adolescence, 1500 clinical presentation of, 1491–1492 diagnostic criteria for, 1491, 1491t differential diagnosis of, 444–445 endogenous, 518 erectile dysfunction in, 555 etiology of, 1494–1495 fatigue in, 518 genetic factors in, 1494 hallucinations in, 1490 hypochondriasis and, 1500 incidence of, 518, 1488 irritability and, 517 masked, 1488 in medical and surgical disease, 1489–1491, 1489t degenerative diseases, 1490 Huntington disease, 1490 MS, 917, 927 myasthenia gravis, 1439 Parkinson disease, 1084, 1490 stroke, 819, 1490 neurologic examination in, 10 olfactory hallucinations in, 235 pain and, 145, 148, 1489, 1500 pain perception and, 141 postpartum, 1489, 1490–1491 in pregnancy, 1490 pseudodementia and, 1500 psychosis in, 1491 psychosocial theories of, 1495 reactive, 1489 states of, 1488 suicide and, 1492, 1499–1500 symptoms of, 517–518 treatment of, 1084, 1496–1498, 1497t. See also Antidepressant drugs Depressive equivalent, 1488 Derealization, 1504 Dermacentor andersoni, 1209 Dermatitis, 1162 Dermatomes, 136, 143, 144f, 158, 160f Dermatomyositis carcinoma with, 1383

in children, 1383 differential diagnosis of, 1387–1388 epidemiology of, 1381 etiology and pathogenesis of, 1385 historical aspects of, 1381 laboratory diagnosis of, 1384 pathologic changes in, 1384–1385 prognosis of, 1386 Raynaud phenomenon in, 1382 signs and symptoms of, 1382 skin changes in, 1382 in systemic autoimmune disease, 1383–1384 treatment of, 1385–1386 Dermoid cyst, 668, 683 Descending systems in pain modulation, 140 Desipramine, 1200, 1497t Desmin myopathy, 1401t Desmoid tumor, 1426 Desmoplastic infantile ganglioglioma, 670 Desmopressin, 420, 571 Deterioration index, 485 Detoxification clinics, 1189 Detrusor muscle, 537–539 Deutetrabenazine, 1071–1072 DEV (duck embryo vaccine), 750 Development and growth. See Growth and development Development quotient (DQ), 586 Developmental disorders autism. See Autism/autism spectrum disorders (Kanner-Asperger syndrome) causes of, 996–998 chromosomal abnormalities in, 1010–1013. See also Down syndrome (trisomy 21) classification of, 997–998, 997t clinical approach to, 1043 congenital cerebral motor disorders. See Congenital cerebral motor disorders craniospinal deformities. See Craniospinal deformities epilepsies of infancy and childhood, 1038. See also Epilepsy; Seizures general principles of, 996–998 hereditary developmental delay doublecortin mutations, 1045 Fragile X premutation syndrome of adults, 1044 Fragile X syndrome, 1012, 1043–1044 Partington syndrome, 1001t, 1044 Renpenning syndrome, 1044 Rett syndrome, 102, 1012, 1044 Williams syndrome, 489, 494, 600, 1012, 1044–1045

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Index intrauterine and neonatal infections in. See Intrauterine and neonatal infections management of, 1047 mild (nondysmorphic) developmental delay clinical features of, 1038–1039 diagnosis of, 1039–1040 genetic aspects of, 1039 phakomatoses. See Phakomatoses (congenital neuroectodermoses) protein-calorie malnutrition and, 1172–1173 restricted abnormalities, 1025 severe developmental delay clinical approach to, 1043 clinical characteristics of, 1040– 1042, 1041t etiology of, 1042 incidence of, 1040 intellectual disability in, 603–604, 604f tuberous sclerosis, 1013, 1014 uncomplicated, 1040 Developmental motor apraxia, 65 Developmental receptive dysphasia, 596 Developmental venous anomaly, 853, 853f Devic disease. See Neuromyelitis optica (NMO) Dexamethasone for bacterial meningitis, 704, 704t for brain abscess, 715 for cerebral edema, 645 for CIPD, 1320 for glioblastoma, 650 for high-altitude sickness, 1131 for hypertensive encephalopathy, 858 in LP, 14 for lumbar intervertebral disc herniation, 213–214 for malaria, 732 for status migrainosus, 188 Dexamethasone suppression test, 575 Dexmedetomidine, 904 Dextroamphetamine, 602 DFN genes, 302, 303t Diabetes insipidus acquired idiopathic, 570 in brain death, 368 causes of, 569–570 central, 570 congenital hypothalamic, 570 diagnosis of, 570–571 after head injury, 570, 881 hypothalamus in, 569–570 treatment of, 571

Ropper_Index_1519-1606.indd 1543

Diabetes mellitus abducens nerve palsy in, 276 amyotrophy in, 1304, 1346 atherosclerosis in, 775–776 in coma, 382t coma in, 371 glaucoma in, 243 ischemic optic neuropathy in, 256, 256f lumbar plexopathy in, 1304–1305 neuropathy in. See Diabetic neuropathy oculomotor nerve palsy in, 276 ophthalmoplegia in, 1304 prevalence and incidence of, 6t pupils in, 288 retinopathy in, 252 stroke in, 775–776 vision disorders in, 243, 248 Diabetic acidosis, 1134 Diabetic neuropathy acute mononeuropathies in, 1304 autonomic, 547, 1305 distal sensory polyneuropathy in, 1303–1304 incidence of, 1303 mononeuritis multiplex and radiculopathies in, 1303–1304 orthostatic hypotension and, 547 pathology and pathophysiology of, 1305 signs and symptoms of, 1303 syndromes of, 1303 treatment of, 1305–1306 Diabetic pseudotabes, 1303 Diacetylmorphine, 1190, 1193 Diagnostic and Statistical Manual of Mental Disorders (DSM), 1469 Dialysis, 1139 3,4-Diaminopyridine, 1445 Diastematomyelia, 1008 Diazepam for alcohol withdrawal seizures, 1185 in head injury treatment, 904 indications for, 1196 mechanism of action, 63 for seizures, 347t, 348t in spinal cord injury management, 1233 for status epilepticus, 354, 354t for stiff man syndrome, 1460 in tetanus treatment, 1205 Diazoxide, 1030 DIC (disseminated intravascular coagulation), 866–867 Dichlorodiphenyltrichloroethane (DDT), 1214 Dichlorphenamide, 1454 Dichotic listening, 493 Diencephalon, 798f

1543

Diethylene dioxide, 1215 Diffuse axonal injury (DAI), 86, 364, 886, 891t, 896f Diffuse infiltrative lymphocytosis syndrome (DILS), 756 Diffuse Lewy body disease (DLB). See Lewy body dementia Diffuse poliodystrophy, 755 Diffuse sclerosis, 918–919 Diffusion tensor imaging (DTI), 25 Diffusion-weighted imaging (DWI), 22 Dihydroergotamine, 187, 188 Dilaudid, 1192 DILS (diffuse infiltrative lymphocytosis syndrome), 756 Dimercaprol, 1211–1213 Dimethyl fumarate, 927 Diparesis, 593 Diphenhydramine, 1423, 1513 Diphenoxylate, 1190 Diphosphonate, 1427 Diphtheria, 1206, 1296–1297 Diplacusis, 297 Diplegia cerebrocerebellar, 1032 definition of, 65 infantile, 67, 593 spastic, 1029 Diplomyelia, 1008 Diplopia anatomy of, 271–272 binocular, 272 clinical features of, 273–275, 274f monocular, 272, 275 in MS, 916 in myasthenia gravis, 1434 in ocular palsies, 1376 in skew deviation of eyes, 280 Dipping, ocular, 283, 377 Disability functional diagnosis in, 3 intellectual and developmental, 603–604, 604f learning, 594–595 in vertigo, 313 Disconnection syndromes of cerebral cortex, 462, 464f, 483–485 in speech and language disorders, 495 Discrimination, sensory olfactory, 235 in parietal lobe lesions, 166 of speech, 298 testing of, 166–167 Disopyramide, 397 Disseminated intravascular coagulation (DIC), 866–867 Dissociated sensory loss, 170 Dissociative disorders, 1471

10/02/23 10:43 AM

1544

Index

Distal acquired demyelinating symmetrical neuropathy (DADS), 1320 Distractibility, 424 Disulfiram, 1179, 1189 Ditans, 188 Divergence insufficiency, 269 Divergent eye movements, 263 Dix-Hallpike maneuver, 310, 311f, 312, 312f Dizziness. See also Vertigo causes of, 306 describing, 6 in intracranial tumors, 647 nonvertiginous types of, 306–307 in panic attacks, 515 in postconcussion syndrome, 897 symptoms of, 302, 305 DJ-1, 1079 DMD mutation. See Duchenne muscular dystrophy (DMD mutation) DMPK mutation. See Myotonic dystrophy, type 1 DNET (dysembryoplastic neuroepithelial tumor), 670, 670f Docetaxel, 1216, 1302 DOK-7 mutation, 1446 Doll’s-head maneuver, 269, 373 Dominance, cerebral. See Cerebral hemisphere dominance Domperidone, 397 Donepezil, 1064, 1083 Dopamine age-related changes in, 612 in basal ganglia, 75–77 for Gilles de la Tourette syndrome, 104 in prolactin inhibition, 567–568 for restless legs syndrome, 409 in schizophrenia, 1509 for tardive dyskinesia, 102 Dopamine agonists, 1081t, 1082–1083 Dopamine β-hydroxylase serum levels, 545, 546 Dopamine receptors, 75–77 Dopaminergic fibers, 115 Dorsal horn, pain fibers terminating in, 136–137, 136f Dorsal medullary respiratory group, 555, 556f Dorsal midbrain syndrome, 268, 288 Dorsal root ganglia, 158–159, 168–169, 1276 Dothiepin, 1497t Double athetosis, 82, 505, 1031 Double cortex, 1001t “Double ring” sign, 258 Doublecortin mutations, 1045

Ropper_Index_1519-1606.indd 1544

Double-limb support phase of gait cycle, 121, 122f Doubting mania, 1475 Down syndrome (trisomy 21) Alzheimer disease and, 1011, 1061, 1062, 1078 clinical features of, 1010–1011 laboratory and pathologic findings in, 1011 prenatal screening for, 1011 Downbeat nystagmus, 282 Doxazosin, 545 Doxepin, 150, 1200 Doxycycline for brucellosis, 709 for catscratch fever, 708 for leptospirosis, 726 for Lyme disease, 726 for neurosyphilis, 724 for rickettsial disease, 730 for Whipple disease, 709 DQ (development quotient), 586 Dravet syndrome, 341 Dreaming function of, 406 neurophysiology of, 404–406 nightmares or frightening, 412 physiologic changes in, 403–406 Dressing apraxia, 65 Drivenness, 467–468, 529 Driving restrictions in epilepsy, 357 in narcolepsy, 419 Dromedary gait of Oppenheim, 128 Drooling, in Parkinson disease, 1075 Droopy shoulder syndrome, 223 Drop attacks, 339, 395, 671 Dropped head syndrome, 1377 Drowsiness. See also Fatigue definition of, 363 EEG in, 370 in head injury, 888–889 vs. narcolepsy, 417 Droxidopa, 547 DRPLA (dentatorubropallidoluysian atrophy, ATN1 mutation), 1072, 1096t, 1100–1101 Drug-induced disorders. See also specific drugs aggressive behavior, 526 anisocoria, 289 autonomic, 549 chorea, 81, 81t Churg-Strauss syndrome, 1307 coma, 372, 376–377, 544 confusional states, 432 dizziness, 307 dystonia, 84, 84t fatigue, 511 of hearing, 301

leukoencephalopathy. See Leukoencephalopathy, drug-induced myasthenic weakness, 1446–1447 myopathy, 1414–1418, 1415t nystagmus, 280 opsoclonus, 283–284 optic neuropathy, 257, 257t parkinsonian syndrome, 76, 1512t polyneuropathy. See Toxic polyneuropathy retinopathy, 251 seizures, 343–344 skin rash, 349 stupor, 375 tardive dyskinesia. See Tardive dyskinesia vasculitis, 859 vestibular neuritis, 313 vestibulopathy, 313 weakness, 1446–1447 Drunken or reeling gait, 123, 124 Drusen, in retina, 248, 251 DSM (Diagnostic and Statistical Manual of Mental Disorders), 1469 DTI (diffusion tensor imaging), 25 Dualism, 1469 Duane retraction syndrome, 277 Dubowitz syndrome, 1108t, 1111–1112 Duchenne muscular dystrophy (DMD mutation), 1391 clinical features of, 1374t, 1391–1392 creatine kinase levels in, 1374t, 1391, 1392 diagnosis of, 1393 genetic factors in, 1374t, 1391 incidence of, 1391 molecular biology of, 1393, 1393f onset of, 1374t pathology of, 1392–1393 Duck embryo vaccine (DEV), 750 Duloxetine, 1497t Dural metastases, 659 Dural sinus thrombosis, 865, 865f Dural venous sinuses, 710–711 Duret hemorrhage, 887 DUX4 mutation (facioscapulohumeral muscular dystrophy), 1394–1395, 1396t Dwarfism, 968, 1004–1005 DWI (diffusion-weighted imaging), 22 Dynorphin, 141 Dysarthria ataxic, 504–505 bulbar palsy in, 1377 in cerebellar disease, 117, 494 cortical, 505 differential diagnosis of, 1439 hyperkinetic, 505

10/02/23 10:43 AM

Index in lacunar stroke, 780 lower motor neuron, 504–505 neuromuscular, 504–505 rigid (extrapyramidal), 505 scanning, 117 slurring, 117 spastic (pseudobulbar), 505 of speech, 490 word mutism and, 501 Dysautonomia. See also Pandysautonomia familial, 1331 inherited, 548–549 paraneoplastic, 686 Dyscalculia, 477, 600, 1057 Dyschondroplasia, 1003 Dysdiadochokinesis, 116 Dysembryoplastic neuroepithelial tumor (DNET), 670, 670f Dysesthesia in brainstem lesions, 170 definition of, 161 in nutritional polyneuropathy, 1160 in peripheral neuropathy, 167, 1281–1282 Dysgeusia, 237 Dysgraphia, 496, 600 Dyskinesia, 80, 81, 85. See also Tardive dyskinesia Dyslexia. See also Word blindness ADHD and, 601 developmental, 599–600 treatment of, 600 in Wernicke aphasia, 498 Dysmetria, 116, 284 Dysmyelinating disorders, 908 Dysnomia, 472–473, 1058 Dysosmia, 232, 234–235, 237 Dysostosis, 1003, 1004 Dysostosis multiplex, 969 Dysphagia in bulbar palsy, 1377 causes of, 560–561 differential diagnosis of, 1439 after stroke, 561 Dysphasia, 490, 596 Dysphonia, 97, 490, 506–507, 1377 Dysplasia craniotubular bone, 1003 fibromuscular, 821 frontonasal, 1003 oculoauriculovertebral, 1004 septooptic, 1004 Dyspnea, 557–558 Dyspraxia, 494 Dysprosody, 595 Dysraphism, 215, 1006–1007, 1262 Dysreflexia, autonomic, 1231 Dyssynergia, 115, 116

Ropper_Index_1519-1606.indd 1545

Dystasia, hereditary areflexic, 1331–1332 Dystonia/dystonic disorders. See also specific diseases in causalgia, 147 drug-induced, 84, 84t focal. See Focal dystonias gait disorders in, 124t, 128 generalized, 84 genetic factors in, 84 hereditary, 84t, 1094 levodopa for, 84, 1080, 1093 in metabolic disease, 981 musculorum deformans, 83f, 84, 1092–1093 oromandibular, 84, 97 Parkinson disease, 1075. See also Parkinson disease paroxysmal choreoathetosis and, 85 periodic, 85 phenothiazines and, 1198 posture in, 83, 83f secondary, 84t torticollis, 1094 treatment of, 85 tremors in, 86t, 92 Dystonic lipidosis, juvenile, 966 Dystonic tremor, 86t, 92 Dystrophin, 1393–1394, 1393f Dystrophin-associated glycoproteins (DAGs), 1393, 1396–1397 Dystrophin-associated proteins (DAPs), 1393 DYT1 mutations, 1092–1093 E EAE (experimental allergic encephalomyelitis), 1243 Ear anatomy and physiology of, 292–297, 293f, 295f–296f inner, aplasia of, 302 middle, disorders of deafness. See Deafness myoclonus, 299 tinnitus, 299 pain in, 174, 198 Eastern equine encephalitis (EEE), 745, 746 EBV. See Epstein-Barr virus ECG. See Electrocardiogram Echinococcus, 733t, 734 Echo speech, 591 Echolalia, 490, 495, 1057 Eck fistula, 1134 Eclampsia, 346, 381t Ecstasy, 1202, 1204 ECT (electroconvulsive therapy), 1497–1498, 1513 Eculizumab, 868

1545

Edaravone, 1108 Edema, cerebral. See Cerebral edema Edinger-Westphal nucleus, 285–297, 286f Edrophonium, 1438 Edwards syndrome (trisomy 18), 1011 EEE (Eastern equine encephalitis), 746 EEG. See Electroencephalography Eflornithine, 732 EGFR mutations, 642t, 643, 649 Ehlers-Danlos syndrome, 634 eIF2B mutation (vanishing white matter disease), 954 Eighth cranial nerve. See Vestibulocochlear (eighth) nerve Ejaculation, 554 Elation, acute, 528 Elbow, epicondylitis of, 225 Elderly anatomic deterioration in, 608t atrial fibrillation in, 814 autonomic failure in, 548 central pontine myelinolysis in, 1143 cerebral atherosclerosis in, 612 cerebral blood flow in, 612 confusional states in, 432–433 fainting in, 398 falls in, 130, 610 frailty in, 607, 608t gait disorders in, 123, 124t, 130, 130f, 610 glaucoma in, 243 Guillain-Barré syndrome in, 613 head injury in, 888 headache in incidence of, 192 recurrent nocturnal, 190, 192 with temporal arteritis, 193–194 hyperthermia in, 548 hypothermia in, 548 motor functions in, 610–611 muscles of, 612–613 myasthenia gravis in, 1442 neurologic signs in, 608t normal-pressure hydrocephalus in, 625 orthostatic hypotension in, 548 personality changes in, 609–610 posture of, 130, 130f seizures in, 340f, 340t, 342–343 sensory functions in, 163, 165, 234, 236, 607–608 sleep in, 402, 403f transient global amnesia in, 449–450 transient unresponsiveness in, 369 urinary incontinence in, 610

10/02/23 10:43 AM

1546

Index

Electrical injuries, spinal cord, 1235 Electrocardiogram (ECG) in REM sleep, 420 during respiratory changes, 541–542 in sympathetic storm, 550 Electrocerebral silence, 32f, 33, 368 Electroconvulsive therapy (ECT), 1497–1498, 1513 Electroencephalography (EEG) abnormal recordings in, 33–35 age-related changes in, 33, 612 alpha waves in, 29f, 32, 370 in Alzheimer disease, 34 beta waves in, 32–33 in brain death, 28, 33, 368 in children, 33 in chronic fatigue syndrome, 513 in CJD, 32f, 34 in coma, 32f, 34 in concussion, 34 in confusional states, 429 in consciousness disorders, 370 in degenerative diseases, 34–35 in delirium tremens, 35 delta waves in, 30f, 33 in developmental delay, 1040 in drowsiness, 370 in electrocerebral silence, 32f, 33, 368 in encephalitis, 34 gamma rhythms in, 371 in hepatic encephalopathy, 32f, 34 in herpes simplex encephalitis, 747 in hypothyroidism, 34 in impaired consciousness, 34, 370 indications for, 28 in intracranial tumors, 34 in MS, 35 normal recordings in, 29f–31f, 32–33 occipital driving response in, 29f, 36 phase reversal in, 31f, 33 photic driving in, 29f, 33 in seizures absence, 31f, 33, 324 adolescent, 341 centrotemporal spikes in, 331 characteristics of, 33, 335–336 classification based on, 321 elderly, 342–343 infantile, 341 myoclonic, 324 neonatal, 340–341 occipital spikes in, 331 tonic-clonic, 34, 323 in sleep in AASM sleep scoring system, 400, 403t characteristics of, 335 fast-wave, 400 nonsynchronized or desynchronized, 400

Ropper_Index_1519-1606.indd 1546

with seizures, 414 slow wave, 400 synchronized, 400 vertex waves in, 400, 400f stroboscopic stimulation in, 29f–30f, 335 in stroke, 34, 788–789 in stupor, 369 in subacute sclerosing panencephalitis, 762 in syncope, 389, 396 technique for, 28–32 theta waves in, 33 voltage vs. time graph in, 28, 29f in Wernicke-Korsakoff syndrome, 35, 1157 Electrogustometer, 236 Electrolyte disorders, 343 Electromyography (EMG) action potentials in, 44–45, 44f in asterixis, 93 in Charcot-Marie-Tooth disease, 1328 in cramps, 1423 CRDs in, 47 in dermatomyositis, 1384 early recruitment in, 48 endplate spikes in, 45 in fasciculations, 46, 46f fibrillation potentials in, 46, 46f in Guillain-Barré syndrome, 1290 in IBM, 1387 insertional activity in, 45 interference pattern in, 45 abnormalities of, 48 jitter in, 49 MUPs in, 45, 47–48, 47f, 48f in myasthenia gravis, 1437–1438 in myokymia, 46, 47 in myotonia, 47, 47f in polymyositis, 1384 polyphasic potentials in, 47–48, 48f single-fiber, 48–49 in sleep, 400, 401f–402f in spasmodic torticollis, 99 of spine, 208 spontaneous activity in, abnormal, 46 technique of, 44–45 in tetanus, 1205 in thoracic outlet syndrome, 225 in tremors, 87f in trichinosis, 1379 Electronystagmography, 308 Electroolfactogram (EOG), 231 Eletriptan, 187t Eleventh (spinal accessory) nerve, 99–100, 1365–1366 ELISA. See Enzyme-linked immunosorbent assay (ELISA)

Elsberg syndrome, 552, 743 Embolism cerebral. See Cerebral embolism fibrocartilaginous, 221, 1255 retinal artery, 249, 249f in spinal cord, 1250, 1255 Embryonic development anatomic basis of, 581–582, 582t, 583f of cranium and brain genetic factors in, 1000, 1001t induction process in, 998 neuron migration and cortical development in, 999–1002, 1001t physiology of, 584–585 Emery-Dreifuss muscular dystrophy (EMD mutation), 1374t, 1394, 1394f EMG. See Electromyography (EMG) Emotional disturbances in confusional states, 425–426, 428–429 in frontal lobe lesions, 465 in limbic system disease. See Limbic system disease in temporal lobe lesions, 473 in temporal lobe seizures, 328 Emotions anatomy and physiology of. See Limbic system definition of, 520 James-Lange theory of, 522 language and, 489 pain perception and, 141, 145 Empty delta sign, 865 Empty sella syndrome, 678 Empyema, subdural, 709–710 Encephalitis. See also Encephalomyelitis; Meningoencephalitis anti-NMDA, 685–686 autoimmune, 935, 935t bacterial, 706–709 coma in, 381t EEG in, 34 lethargica, 414, 1076 limbic, 529, 684–686, 684t, 685f in Lyme disease, 725 postinfectious, 744 prevalence and incidence of, 5, 5f Rasmussen, 333 viral acute, 744 arboviral, 745–746 Eastern equine, 745, 746 etiology of, 744–745 herpes simplex. See Herpes simplex virus (HSV) encephalitis HHV-6, in stem cell transplant, 749

10/02/23 10:43 AM

Index lethargica, 763–764 in measles, 763 mechanisms of, 739–740 vs. meningitis, 743 pathways of, 739 vs. postinfectious encephalitis, 744 zoster, 752 von Economo, 404, 410–411, 763, 1076 Encephalocele, 1006 Encephalomyelitis acute disseminated. See Acute disseminated encephalomyelitis (ADEM) acute necrotizing hemorrhagic, 933–934, 933f in CLIPPERS, 934 experimental allergic, 1243 in graft-versus-host disease, 934–935, 934f myalgic, 513 paraneoplastic, 684–686, 684t, 685f Encephalomyelopathy, subacute necrotizing. See Subacute necrotizing encephalomyelopathy (Leigh disease) Encephalopathy with burns, 1140 CAR-T-cell-related, 1218 chronic traumatic, 899–900 Hashimoto, 1147–1148 hepatic. See Hepatic (portalsystemic) encephalopathy in HIV infection, 755, 755f hypertensive clinical features of, 856 differential diagnosis of, 1139 imaging techniques in, 856–857 pathophysiology of, 857–858 treatment of, 858 hypoxic-ischemic. See Hypoxicischemic encephalopathy vs. mania, 1493–1494 metabolic. See Metabolic encephalopathy neonatal, 1027–1028 nicotinic acid-deficiency, 1163 pancreatic, 1149 posterior reversible syndrome of, 343, 856–858 prion. See Subacute spongiform encephalopathy seizures in, 343 septic, 430, 433, 1140 subacute spongiform. See Subacute spongiform encephalopathy subpial, 697t thyroid, 1147–1149 toxic, 371–372, 382t, 526

Ropper_Index_1519-1606.indd 1547

Endarterectomy, carotid, 816–817 Endemic cretinism, 1148–1149 Endocarditis acute, 712 cerebral embolism from, 777 nonbacterial thrombotic, 866 subacute, 712 Endocrine system autonomic nervous system interactions with, 535, 537 disorders of Cushing disease. See Cushing disease Cushing syndrome, 575–576, 677, 1147 fatigue in, 511–512 myopathies in. See Myopathy(ies), endocrine in pituitary adenoma. See Adenoma, pituitary psychoses in, 1516–1517 Endogenous aggression, 517 Endogenous depression, 518. See also Depression Endogenous event-related evoked potentials, 39 Endolymph, 292, 293f, 309 Endoneurium, 1276, 1277f Endorphins, 141, 142f Endovascular thrombectomy, 810–811 ENG mutations, 1023 Enkephalin, 141, 142f Entacapone, 1081t, 1082 Enteroviruses, 760 Entrapment neuropathies, 1334, 1343, 1343t, 1348 Enuresis, nocturnal, 420, 603 Enzyme-linked immunosorbent assay (ELISA) in Lyme disease, 726, 1311 in viral meningitis, 741 EOG (electroolfactogram), 231 Eosinophilia, 735 Eosinophilia-myalgia syndrome, 1389, 1415t Eosinophilic diseases, 1307–1308 Eosinophilic fascitis, 1388–1389 Eosinophilic granuloma, 569 Eosinophilic granulomatosis with polyangiitis. See Churg-Strauss disease Eosinophilic meningoencephalitis, 735 Eosinophilic monomyositis, 1389 Eosinophilic polymyositis, 1389 Ependymal cells, 654 Ependymitis, 697t Ependymoblastoma, 654 Ependymocytes, 643 Ependymoma anaplastic, 654

1547

in children, 654 classification and grading of, 642t, 654, 666–667 clinical features of, 654, 667 of fourth ventricle, 654, 666–667, 666f genetic factors in, 642t, 654 imaging of, 654 incidence of, 666 pathology of, 654 prognosis of, 654 spinal, 1263 treatment of, 654 Ephedrine, 1202 Epicondylitis, 225 Epicritic system in pain, 134 “Epidemic encephalitis,” 745 Epidemic neuromyasthenia, 1381 Epidemic typhus, 729 Epidermal nevus syndrome, 1023 Epidermoid cyst, 668, 674 Epidural abscess in cauda equina, 1239 cranial, 710 spinal, 219, 1236, 1239–1240, 1240f, 1241 Epidural hematoma, 891t, 892, 892f Epidural lipomatosis, 1267 Epigastric region, 208 Epilepsia partialis continua, 332 Epilepsy. See also Seizures age-related changes in, 321, 322f, 340–343, 340f, 340t amnesia in, 328 behavioral and psychiatric disorders in, 330 benign childhood, with centrotemporal spikes, 331 clinical approach to, 339–346 in cortical development, 338t definition of, 320 driving restrictions and, 357 EEG in, 30f, 31f, 33–34, 335–336 electrical discharge in, 334–335 gelastic, 328, 572 genetic factors in, 334, 337–338, 338t hereditary deafness with, 1116–1117 in infants and children, 1038 in inherited metabolic diseases, 975–976 juvenile myoclonic, 325 Lafora-body polymyoclonus with, 973–974 myoclonus in, 94–95, 337–338, 338t nocturnal, 414 with occipital spikes, 331 partialis continua, 94 pathology of, 337–338 personality disorders and, 330 physical and mental activity in, 357 posttraumatic, 898–899

10/02/23 10:43 AM

1548

Index

Epilepsy (Cont.): in pregnancy, 344–345 prevalence and incidence of, 5, 5f, 6t, 320 procursiva, 328 psychosocial issues in, 357–370 reflex, 332 sudden unexplained death in, 330 surgery for, 356 syndromes of, 331–333 treatment of. See Seizures, treatment of in tuberous sclerosis, 1013, 1014 Epileptiform discharges, 33 Epimysium, 1370 Epinephrine, 287, 534 Epineurium, 1276, 1277f Episodic dyscontrol syndrome, 1483 Episodic memory, 446f, 447, 447t Epley maneuver, 312, 312f Epstein-Barr virus (EBV) infections vs. bacterial meningitis, 703 cerebral lymphoma and, 643 chronic fatigue syndrome and, 513 CNS lymphoma and, 658 infectious mononucleosis, 741, 745 in meningoencephalitis, 1038 Equilibrium in cervical spondylosis, 1259 in colloid cyst of third ventricle, 671 disorders of in basal ganglia disease, 79 in cerebellar disease, 117 describing, 6 dizziness. See Dizziness in gangliosidosis, 966 paroxysmal, 183 vertigo. See Vertigo in gait cycle, 122 physiology of, 305 vestibular system in, 292–293, 293f Equine gait, 124t, 126 Erb dystrophy. See Limb-girdle muscular dystrophy (LGMD) ERCC mutation (Cockayne syndrome), 955, 970 Erdheim medionecrosis aortica cystica, 821 Erdheim-Chester disease, 569 Erectile dysfunction, 547, 553–555 Erectile function neural pathways of, 554, 554f painful, 555 tests of, 544 Erethism, 1212 Ergotamine, 187, 191 Ergotism, 1207 Erythema chronicum migrans, 725 Erythrocyanotic headache, 196 Erythrocytes, in CSF, 14t, 15–16

Ropper_Index_1519-1606.indd 1548

Erythromelalgia, 149, 196, 551 Erythromycin, 708 Erythropoietic porphyria, 1297 Escitalopram, 1497t Escobar syndrome, 1446, 1446t Eslicarbazepine, 347t, 348t Esophoria, 272 Esotropia, 272 Essential mixed cryoglobulinemia, 1308 Essential narcolepsy, 419–420 Essential tremor, 86t, 87f, 88–89 Esthesioneuroblastoma, 233 Estrogen, cerebral infarction risk and, 829–830 Eteplirsen, 1404 Ethambutol, 718–719 Ethanol, 1179. See also Alcohol use and alcoholism Ethionamide, 719, 1302 Ethopropazine, in Parkinson disease treatment, 1083 Ethosuximide, 347t, 348t, 353 Ethylene glycol, 1182 Ethylene oxide, 1301 Etiologic diagnosis, 3, 4 Etomidate, 904 Euglycemia, 813 Eulenburg disease (paramyotonia congenita), 1448t, 1451–1452 Euphoria, 426, 528, 916–917 European blastomycosis, 727–728 Everolimus, 670, 1017 Evoked potentials in brain death, 369 brainstem auditory, 35t, 36–37, 37f endogenous event-related, 39 interpretation of, 35 in MS, 36, 921 somatosensory, 35t, 37–38, 38f technique of, 35 visual, 35t, 36, 36f Executive dysfunction, 440, 1058 Exercise headache after, 174, 176, 194–195 myalgia after, 1425 pain after, in inherited dysautonomia, 548 in Parkinson disease treatment, 1086 paroxysmal choreoathetosis in, 85 syncope induced by, 391 Exner writing area, 491 Exophoria, 272 Exophthalmic ophthalmoplegia, 1411–1412 Exostoses, multiple, 1268 Exotropia, 280 Expectancy circuits, 526 Experimental allergic encephalomyelitis (EAE), 1243

Expiration, respiratory neurons in, 556, 556f Explicit memory, 446, 446f, 447t Explosive personality disorder, 1471t, 1483–1484 External speech, 490 Exteroceptors, 155 Extinction, sensory, 171 Extracranial artery dissection, 198–199 Extramedullary hematopoiesis, 1268 Extraocular muscles abducens nerve lesions and, 273 action of, 271–272, 272f, 272t anatomy of, 263 diplopia in disorders of, 273–275, 274f innervation of, 269–271, 271f oculomotor nerve lesions and, 273 trochlear nerve lesions and, 273 Extrapyramidal motor system disorders in acquired metabolic diseases, 1144–1145 antipsychotics and, 1512, 1512t, 1513, 1513t clinicopathologic correlations of, 78, 78t congenital, 1031–1032 vs. corticospinal disorders, 70, 71t dysarthria in, 505 after head injury, 899 hereditary spastic paraplegia with, 1114 industrial toxins and, 1215 in inherited metabolic diseases aceruloplasminemia, 978 basal ganglionic and cerebellar calcification, 980–981, 980f with choreoathetosis and dystonia, 981 hypocupric myeloneuropathy, 978–979 Lesch-Nyhan syndrome, 979–980 osteopetrosis, 981 Parkinsonian syndromes. See Parkinsonian syndromes in manganese poisoning, 1212 in multiple system atrophy, 1087 Eye. See also Gaze; Pupils; Retina; Vision anterior chamber of, 240, 243 examination of, 239–241, 251 lens of, 240, 243 movements of. See Eye movements vascular supply of, 247 Eye movements anatomy and physiology of, 263–264, 265f, 269–271, 270f–272f bobbing, 283 in brain death, 367–368 in cerebellar disease, 117

10/02/23 10:43 AM

Index in Cogan syndrome, 269, 1025 in coma, 377–378 dipping, 283 divergent, 263 elicited, 377–378 in frontal lobe lesions, 465 horizontal, 264–266, 265f, 268 muscles for. See Extraocular muscles in near response, 268 nuclear and infranuclear disorders of, 263, 270–271 in ophthalmodynia, 174 in ophthalmoplegia, 277t, 278, 278t in Pelizaeus-Merzbacher disease, 955 in PSP, 1088 pursuit, 264, 267 rapid and nonrapid, in sleep, 339, 400, 402–406 saccadic, 263 skew deviation of, 266, 280 supranuclear control of, 263–269 in supranuclear palsy, 269 vergence, 269, 272 vertical, 266, 266f, 268–269, 269t in Wernicke-Korsakoff syndrome, 1155, 1155f, 1157 windshield-wiper oscillations, 283 Eyelids disorders of, 284–285 movements of in coma, 377–378 in myasthenia gravis, 1434 in parietal lobe lesions, 478 as reflex response, 284 ptosis of, 285, 1376 retraction of, 285 Eyestrain headache, 174, 176 F F waves, in nerve conduction studies, 42–43, 43f Fabry disease (GLA mutation) autonomic symptoms in, 548 biochemical abnormalities in, 950t, 985 clinical features of, 985, 1333–1334 neuropathy in, 1333–1334 stroke in, 829 treatment of, 985, 1334 Facet joints, 203, 204f, 217 Facet syndrome, 217 Facial (seventh) nerve anatomy of, 1358–1359, 1359f disorders of aberrant effects in recovery from, 1361–1362 Bell’s palsy. See Bell’s palsy bilateral palsy, 1361

Ropper_Index_1519-1606.indd 1549

blepharospasm, 1362–1363 colliculus, 1358 after head injury, 881 hemiatrophy, 1361 hemifacial spasm, 1362 in HIV/AIDS, 1360 in Lyme disease, 1311, 1360 in multiple cranial nerve palsies, 1368 myokymia, 1362 Ramsay Hunt syndrome, 1361 supranuclear palsy, 61, 61f with tumors, 1361 function testing of, 8 in taste sense, 236, 1358 Facial pain atypical, 199 in dental disorders, 199 in reflex sympathetic dystrophy, 200 in Tolosa-Hunt syndrome, 277 in trigeminal neuralgia, 196–197 Facial palsy bilateral, 1361 eyelid movements in, 285 in Lyme disease, 1311 in multiple cranial nerve palsies, 1368 in skull fracture, 881 in upper motor neuron disease, 61 Facioscapulohumeral muscular dystrophy (DUX4 mutation), 1394–1395, 1396t Fahr disease, 980 Failed back syndrome, 220 Faintness causes of, 387–388 common, 388–389 differential diagnosis of, 395–396 in elderly, 398 examination methods in, 396–397 feeling of, 387 functional, 394–395 in orthostatic hypotension, 547 treatment of, 397–398 Fajersztajn sign, 206 Falls in elderly, 130, 610 in gangliosidosis, 966 in narcolepsy, 417 in PSP, 1088 Famciclovir, 753 Familial amyloidosis. See Amyloidosis, familial Familial dementia, with spastic paraparesis, 1072 Familial developmentally delayed, 603–604, 604f Familial hypobetalipoproteinemia, 973 Familial insomnia, fatal, 410, 767–768

1549

Familial polymyoclonus. See Polymyoclonus, familial Familial rectal pain syndrome, 146–147 Familial spastic paraplegia, 1113–1114 Familial vestibulocerebellar syndrome, 316 Farber disease (lipogranulomatosis), 950t, 954, 960 Farsightedness, 272 Fascicles, muscle, 1370 Fasciculations in ALS, 1103 benign, 1375, 1458 with cramps, 1458–1459 EMG in, 46, 46f in peripheral neuropathy, 1283 Fasciculus anterolateral, 137 arcuate, 491, 499 fronto-occipital, 464 medial longitudinal, 265, 265f Fasciitis, eosinophilic, 1388–1389 Fast channel syndrome, 1446, 1446t Fastigial nucleus, 110f, 111, 113 Fat deposits, epidural, 1267 Fat embolism, cerebral. See Cerebral embolism, fat Fatal familial insomnia, 410, 767–768 Fatigue. See also Drowsiness in anemia, 512 chronic, 513–514 clinical significance of, 510–512 combat, 510 creatine kinase levels in, 513 definition of, 510 in depression, 518 differential diagnosis of, 514 drug-induced, 511 effects of, 510 in endocrine disorders, 511–512 with headache, 511 in hyperthyroidism, 511 incidence of, 515 in infections, 511 in metabolic disorders, 511–512 in MS, 917, 927 in myasthenia gravis, 1433–1434 in neurologic diseases, 512 in nutrition deficiencies, 511–512 in Parkinson disease, 512 postviral, 513–514 in pregnancy, 512 in psychiatric diseases, 512 in sleep apnea, 511 treatment of, 514 in uremia, 512 weakness and, 512 Fazio-Londe disease, 1108t, 1112–1113, 1366

10/02/23 10:43 AM

1550

Index

Fear acute, 528 vs. anxiety, 1473 obsessive, 1474 Fecal incontinence, 465, 466 Femoral nerve neuropathy, 1346–1347 Fencing posture, 414 Fentanyl, 151t, 1190, 1233 Ferguson-Critchley syndrome, 1114 Festinating (Parkinsonian) gait, 79, 124t, 126–127, 127f, 1074 Fetal alcohol syndrome, 1188–1189 Fetus anticonvulsant syndrome in, 345 fetal alcohol syndrome in, 1188–1189 growth and development of anatomic basis of, 581–582, 582t, 583f physiology of, 584–585 Fever in brain abscess, 714 headache with, 196 seizures in, 331–332, 341 in septic thrombophlebitis, 711 uveoparotid, 1361 FGFR mutations, 999, 1004 Fibrillation atrial. See Atrial fibrillation of muscle fibers, EMG in, 46, 46f Fibrinogen, 838 Fibromuscular dysplasia, 821 Fibromyalgia chronic fatigue syndrome and, 513 clinical features of, 1424–1425 definition of, 1425 differential diagnosis of, 149–150 headache in, 176 Fibular (common peroneal) nerve neuropathy, 1348 Fifth cranial nerve. See Trigeminal (fifth) nerve Fight-or-flight reaction, 515, 522, 525 Fine motor deficit, 594 Fingolimod, 927 Finnish familial amyloidosis, 1335 First (olfactory) cranial nerve, 230–232, 231f Fish mouth, 559 Fish poisoning, 163, 1208 Fish poisoning, neurotoxin, 1293 Fisher syndrome, 1289, 1290. See also Guillain-Barré syndrome (GBS) Fistula carotid–cavernous, 882 dural arteriovenous, 851–852, 852f Eck, 1134 FKRP mutation (limb-girdle muscular dystrophy 2), 1396 Flaccidity, 56

Ropper_Index_1519-1606.indd 1550

Flail-arm syndrome, 1378 FLAIR (fluid-attenuated inversion recovery), 22, 23f Flare response, cutaneous, 544 Flaviviruses, 745 Flechsig myelinogenic cycle, 583, 584f Flexibility, waxy, 80, 367, 426 Flexion injury, cervical, 1226 Flocculonodular lobe of cerebellum, 109, 110f, 117 Floppy infant syndrome, 593, 1033–1034, 1033t, 1110, 1111 Fluconazole, 728 Fludrocortisone acetate, 397, 547 Fluency of speech, 496, 497–498 Fluid homeostasis, 569–571 Fluid-attenuated inversion recovery (FLAIR), 22, 23f Flumazenil, 1136, 1196 Fluorescent treponemal antibody absorption (FTA-ABS) test, 720, 721f Fluoroquinolones, 1447 5-Fluorouracil, 1216 Fluoxetine in autism treatment, 1201 for bipolar disease, 1498–1499 for cranial herpes zoster, 197 mechanism of action, 1200 side effects of, 1497t Fluphenazine, 980 Flurazepam, 413, 1196 Flutter dysmetria, 284 Fluvoxamine, 1497t Flynn-Aird syndrome, 1117 FMR1 mutation, 1098–1099 fMRI (functional magnetic resonance imaging) , 27, 27f, 459, 525 Foam cells, in Niemann-Pick disease, 952 Focal dermal hypoplasia, 1006 Focal dystonias blepharospasm, 100 facial, 99f genetic factors in, 98 pathogenesis of, 98 spasmodic torticollis, 98–99 symptomatic restricted, 98 task-specific, 101 Foix syndrome, 1357t Foix-Alajouanine myelopathy, 1246 Foix-Jefferson syndrome, 682t Folate (vitamin B9) deficiency, 1164, 1301 Folic acid, 1174t Follicle-stimulating hormone (FSH), 566t, 567 Foot disorders in Charcot-Marie-Tooth disease, 1325 weakness, 1378

Footballer’s migraine, 179 Foot-drop gait, 126, 1330 Foramen magnum tumors, 681, 683, 683f, 1266 Forced duction tests, 278–279 Forearm ischemic exercise test, 1407 Foreign accent syndrome, 494, 502 Forgetfulness in anomic aphasia, 501 benign senescent, 440, 609 Fortification spectra, 179 Fosphenytoin, 347t, 348t, 354 Foster Kennedy syndrome, 234, 253 Fourth cranial nerve. See Trochlear (fourth) nerve Fovea, 244, 249, 249f FOXP2 gene, 598 Fractures cervical, 901 lumbar, 210 orbital, 901 of skull. See Skull fractures temporal bone, hearing loss in, 300 vertebral, 1227, 1228t, 1232–1233 Fragile X premutation syndrome of adults, 1044, 1098–1099 Fragile X syndrome, 1012, 1043–1044 Frailty, 607, 608t Franceschetti-Zwahlen-Klein syndrome, 1004 Frankel scale, 1228 Friedreich ataxia clinical features of, 126, 1095–1097 diagnosis of, 1097–1098 genetic factors in, 1096t laboratory testing in, 1097 pathology in, 1097 treatment of, 1098 variants of, 1097 Fright, extreme, 529 Frightening dreams, 412 Froehlich syndrome, 572–573 Frog-leg posture, 593 Froin syndrome, 1264 Froment sign, 90, 1074 Frontal lobe, 459, 462–465, 468 Frontal lobe lesions behavior/personality changes in, 467–468 bladder control in, 552 clinical effects of, 465–469 cognitive and intellectual changes in, 466–467 degeneration in, 441, 1065–1066 emotional disturbances in, 523 gait disorders in, 122, 124t, 129–130, 465–466 incontinence in, 466 initiative and spontaneity changes in, 467–468

10/02/23 10:43 AM

Index motor abnormalities in, 465–466 paralysis in, 465 personality changes in, 465 seizures in, 325–327, 414 speech and language disorders in, 465, 466 Frontonasal dysplasia, 1003 Frontopontocerebellar tract, 464 Frontotemporal degeneration (FTD), 1065–1066 Frovatriptan, 187t Frozen shoulder, 225 Fructose intolerance, 945t FSH (follicle-stimulating hormone), 566t, 567 FTA-ABS (fluorescent treponemal antibody absorption) test, 720, 721f Fucosidosis (FUCA1 mutation), 950t, 970 Fugue states prolonged, 333–334 psychogenic, 1476, 1478 Fukuda stepping test, 123 Fukutin mutation (limb-girdle muscular dystrophy 2), 1396 Fukuyama muscular dystrophy, 1001t, 1002, 1402t, 1403 Fulminant hepatic failure, 1137 FUNC scoring system, 836, 836t Functional diagnosis, 3 Functional imaging, 25–27 Functional magnetic resonance imaging (fMRI) , 27, 27f, 459, 525 Functional neurological disorders diagnosis of, 1480 etiology and pathogenesis of, 1479 historical aspects of, 1476 neurologic examination in, 10 pathophysiology of, 1479–1480 syndromes of amnesia, 1479 blindness, 1479 Briquet syndrome, 148, 333, 1476–1477 deafness, 302 pain, 1477–1478 paralyses, gait disorders, sensory loss, and tremors, 68, 93, 131, 1478–1479 psychogenic seizures, trances, and fugues, 333–334, 1478 vertigo, 306 vomiting, 1478 treatment of, 1480–1481 Funduscopic examination, 247 Fungal infections actinomycosis, 729 aspergillosis, 728

Ropper_Index_1519-1606.indd 1551

blastomycosis, 729 candidiasis, 728 coccidioidomycosis, 729 cryptococcosis, 727–728 CSF examination in, 14t, 18, 727 diagnosis of, 727 etiology of, 726–727 histoplasmosis, 729 meningitis in, 727 mucormycosis, 728–729 myelitis in, 1242 Furosemide, 632, 646 FXN mutation, 1095, 1096t G g factor of intelligence, 437 G proteins, 232, 235 GAA mutation (acid maltase deficiency), 512, 1406–1407, 1408t GABA. See Gamma-aminobutyric acid GABA-benzodiazepine theory, 1136 Gabapentin in depression treatment, 1496 for diabetic neuropathy, 1306 for Fabry disease, 1334 for neurosyphilis, 724 for nutritional polyneuropathy, 1161 for occipital neuralgia, 198 for pain, 151t for palatal tremor, 93 for postherpetic neuralgia, 753 for seizures, 347t, 348t, 349, 353 for spasms in MS, 928 in spinal cord injury management, 1233 GAD (glutamic acid decarboxylase), 689 Gadolinium, 24, 920 Gag reflex, 561 Gait age-related changes in, 610 in cervical spondylosis, 1259 disorders of. See Gait disorders of elderly, 610 examination of, 123 intoxicated or reeling, 123 normal cycle in, 121–122, 122f parkinsonian, 124t, 126–127, 127f, 1074–1075 posture in, 121–122 propulsion in, 122 righting reflexes in, 121, 122 stance in, 121–122, 122f swing phase of, 121, 122f tandem, 92 testing of, 9, 123 toppling, 124t, 125 in vertigo, 306 vestibular system in, 123, 125

1551

waddling, 124t, 128 weakness patterns in, 1378 Gait disorders in Alzheimer disease, 129 antalgic, 123 apraxia, 65, 118, 124, 124t, 129, 465–466 in basal ganglia disease, 78 in blindness, 123 in burning feet syndrome, 126. See also Burning feet syndrome in cerebellar disease, 117, 123–124, 124t in choreoathetosis, 128 in dementia, 129, 130, 441, 457 developmental delays and, 130–131 dromedary gait of Oppenheim, 128 in dystonia, 124t, 128 in elderly, 123, 124t, 130, 130f equilibrium in, 122 festination, 124t, 126–127, 127f in Friedreich ataxia, 1095 in frontal lobe lesions, 122, 124t, 129–130, 465–466 functional, 131, 1478 in hemiplegia and paraplegia, 124t, 126 in muscular dystrophy, 126 in normal-pressure hydrocephalus, 124t, 128–129, 625–626 orthostatic tremor, 92, 128 in progressive supranuclear palsy, 125, 127 in PSP, 1088 in psychogenic conditions, 131 rehabilitation measures for, 131 Romberg sign in, 130 sensory ataxia, 125–126 steppage gait, 124t, 126 Gait ignition failure, 129 Galactocerebrosidase deficiency. See Globoid cell leukodystrophy (Krabbe disease) Galactosemia, 243, 945–946, 987 Galactosialidosis, 950t GALC mutation. See Globoid cell leukodystrophy (Krabbe disease) GALNS mutation (Morquio disease), 968t, 969 Gambling, pathologic, 1084 Gamma globulin, in CSF, 17, 17t Gamma motor neurons, 55, 62, 63 Gamma rhythms, in EEG, 371 Gamma-aminobutyric acid (GABA) age-related changes in, 612 in alcohol pharmacology, 1180 in antiepileptic drug mechanisms, 351f in cortical-basal ganglia-thalamic circuit, 73, 74f–75f, 75

10/02/23 10:43 AM

1552

Index

Gamma-aminobutyric acid (GABA) (Cont.): in hepatic encephalopathy, 1136 in lower motor neuron, 56 Purkinje cells and, 114 for seizures, 347t in spasticity, 63 in West syndrome, 331 Gangliocytoma, 669–670 Ganglionitis, herpes zoster, 1342 Ganglionopathy, sensory acute, 1296 causes of, 169 clinical features of, 118, 168–169, 1281 diagnosis of, 1337t examination in, 167t idiopathic small-fiber, 1312 paraneoplastic, 686, 1299–1300 Gangliosidosis in adults, 986–987 GM1 biochemical abnormalities in, 950t infantile generalized, 953 in late infancy–early childhood, 966 GM2 childhood or juvenile, 975 infantile. See Tay-Sachs disease (GM2 gangliosidosis, hexosaminidase A deficiency) signs of, 959–960 Gangrenous ergotism, 1207 Garcin syndrome, 682t, 1367 Garin-Bujadoux syndrome, 725 Garland syndrome, 1304–1305 Gasserian ganglion, 1355, 1356f Gastrointestinal disorders in diabetic autonomic neuropathy, 547 in hypothalamic dysfunction, 574 motility disorders, 544 Gate-control theory of pain, 134–135 Gaucher disease (glucocerebrosidase deficiency) in adults, 987 biochemical abnormalities in, 950t differential diagnosis of, 959t infantile, 952, 958 late, 95, 975 in late infancy–early childhood, 966 signs of, 958, 959 Gaze in cerebellar disorders, 266–267 in frontal lobe lesions, 467 holding, 264 horizontal, 264–266, 265f, 268, 966 lateral, congenital lack of, 1025 nystagmus in, 267, 281 ocular muscles in, 271–272, 272f ping-pong, 283

Ropper_Index_1519-1606.indd 1552

vertical, 266, 266f, 268–269, 269t, 966 wrong-way, 268 GCH1 mutation, 1094 Gegenhalten, 80, 129 Gelastic epilepsy/seizures, 328, 572 General medical examination, 10 Generalized anxiety disorder, 516 Generalized tetanus, 1204–1205 Genetic testing, 49 Genetic therapy, 1404 Geniculate nuclei, 245 Geniculocalcarine pathway, 259, 479, 501 Geniospasm, 91 Gennari band or line, 479 Genome-wide array analysis (GWAS), 940 Gentamicin for bacterial meningitis, 704t for brucellosis, 709 for Listeria infections, 707 Gepants, 188 Geriatrics, 613 Germ cell tumors, 642t Germinal matrix hemorrhage, in premature infants, 1026–1027, 1026f Germinomas, 668–670 Gerontology, 613 Gerstmann syndrome, 477, 501, 600 Gerstmann-Sträussler-Scheinker syndrome, 767 Gestes, 98 GFAP mutation (Alexander disease), 956, 959 GH. See Growth hormone (GH) GHRH (growth hormone-releasing hormone), 567, 573 Giant cell arteritis. See Temporal arteritis Giant cerebral aneurysms, 846, 847f Gibbus, 206 Gigantism, 573, 1334 Gilles de la Tourette syndrome, 103–104, 1475–1476 Gillespie syndrome, 1032–1033 Gingival hyperplasia, 969 GLA mutation. See Fabry disease Glasgow Coma Scale in comatose patient evaluation, 376, 385 in head injury, 887, 887t, 890 in intracerebral hemorrhage, 836, 836t Glatiramer acetate (copolymer 1), 926 Glaucoma angle-closure, 240, 242 headache in, 176 intraocular pressure in, 243 open-angle, 242 visual fields in, 242

GLB1 mutation (Morquio disease), 953, 968t, 969. See also Gangliosidosis Glial cytoplasmic inclusions, 1088 Glioblastoma genetic factors in, 642t, 648, 649 incidence of, 641t, 643, 648 methylation status in, 650 MRI in, 648, 648f multifocal nature of, 648 natural history of, 649 pathology of, 648–649 prognosis of, 649 recurrent, 650 treatment of, 650 Gliomas and glioneuronal tumors. See also Astrocytoma; Glioblastoma of brainstem, 679–680, 680f classification of, 642t CSF in, 648 diagnosis of, 649–650 genetic factors in, 642t, 643, 649 incidence of, 641t, 643, 648 of optic nerve and chiasm, 258, 680 pineal, 668 pontine, 679–680, 680f Gliomatosis cerebri, 652, 652f Global aphasia, 495, 495t, 498–499 Global confusional state, 428, 430, 430t Globoid cell leukodystrophy (Krabbe disease) biochemical abnormalities in, 950t differential diagnosis of, 960t infantile, 953–954, 954f signs of, 958, 959 Globus pallidus, 71, 71f, 72f, 73, 77 Glomeruli, cerebellar, 115 Glomus jugulare tumors, 675 Glossodynia (burning mouth syndrome), 200, 237, 1366 Glossopharyngeal (ninth) nerve anatomy of, 1363 in multiple cranial nerve palsies, 1368 neuralgia of, 197, 391–392, 398, 1363 in taste sense, 236 Glottic spasm, 507 Glove-and-stocking distribution, of sensory loss, 168 Glucocerebrosidase deficiency. See Gaucher disease (glucocerebrosidase deficiency) Glucocorticoids. See Corticosteroids Glucose control of, in ischemic stroke, 786, 813 in CSF, 14t, 18–19, 717 in hypoglycemic encephalopathy, 1132

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Index Glue-sniffer’s neuropathy, 1215, 1301 Glutamate in cortical-basal ganglia-thalamic circuit, 73, 74f–75f in stroke, 785 Glutamate antagonists, 1081t Glutamic acid decarboxylase (GAD), 689 Glutaric acidemia, 946, 981 Glutaric aciduria type II, 1410 Gluteal muscle weakness, gait in, 128 Gluten ataxia, 1146 Glycine, in spasticity, 63 Glycogen storage diseases (glycogenoses) acid maltase deficiency (type II glycogenosis), 512, 1406–1407 branching enzyme deficiency, 1408 clinical features of, 1408t debranching enzyme deficiency (type III glycogenosis), 1407, 1409 in infants, 1033 less common, 1409 myopathy in, 1406, 1408t phosphorylase deficiency. See Phosphorylase deficiency (McArdle disease, PYGM deficiency) Glycoproteinoses, 950t Glymphatic system, 617 Gnathostomiasis, 733t GnRH (gonadotropin-releasing hormone), 567 Gold toxicity, 1214, 1301 Goldenhar syndrome, 1004 Golgi cells, 114, 115, 115f Golgi tendon organs, 56 Golodirsen, 1404 Gonadotropin, in pituitary adenoma, 676t Gonadotropin-releasing hormone (GnRH), 567 Go/no go test, 468 Gorlin syndrome, 665 Gower sign, 1378 Gower-Laing dystrophy, 1401t Gradenigo syndrome, 277, 1357, 1357t Gradenigo-Lannois syndrome, 682t Gradient-echo (GRE), 22 Graft-versus-host disease, 34f, 934–935 Gram stain, of CSF, 701 Grand mal (tonic-clonic) seizures, 34, 321, 323 Granular cerebral cortex, 462, 463f, 464 Granule cells, 230, 231f Granulomas, in congenital CMV, 1036 Granulomatosis with polyangiitis (Wegener granulomatosis) anosmia in, 234

Ropper_Index_1519-1606.indd 1553

cerebral vasculitis in, 862 mononeuropathy in, 1308 optic neuropathy in, 258 treatment of, 862–863 Granulomatous arteritis, intracranial, 861–862, 861f Granulomatous meningoencephalitis, 731 Granulomatous myositis, 1390 Graphemes, 492, 502 Graphesthesia, 166 Graves ophthalmopathy (thyroid orbitopathy), 279, 1411–1412 Gray communicating rami, 534 GRE (gradient-echo), 22 Growing pains, in children, 145 Growth and development abnormalities of, 573. See also Developmental diseases in adolescence. See Adolescents, growth and development of behavioral, 585–586 in children. See Children, growth and development of coordination disorders in, 594 in embryonic period. See Embryonic development in fetus. See Fetus in infancy. See Infants, growth and development of of intelligence. See Intelligence of language. See Language of muscles, 1372 in neonatal period. See Neonates, growth and development of of personality and social adaptation, 592 sensory, 589, 594 of sexual function. See Sexual function of speech. See Speech timescale of stages in, 582t Growth hormone (GH), 566t, 567, 573, 676t, 677 Growth hormone-releasing hormone (GHRH), 567, 573 Guamanian Parkinson-dementia-ALS complex, 1091 Guanethidine, 147, 1411 Guanfacine, 104 Guanidine hydrochloride, 1207 Guillain-Barré syndrome (GBS) acute axonal form of, 1289 clinical features of autonomic function disturbances, 546–547, 571, 1288–1289 back and radicular pain, 216 bowel dysfunction, 553 motor function impairment, 67, 1280 papilledema, 254

1553

pseudotumor cerebri, 631 reduced tendon reflexes, 1288 sensory symptoms, 1288 tremor, 90 weakness, 1288 differential diagnosis of, 545, 1292–1293, 1319 vs. CIDP, 1289, 1319 vs. myasthenia gravis, 1439 in elderly, 613 historical aspects of, 1288 in HIV infection, 756 incidence of, 1288 laboratory findings in, 1290 in Lyme disease, 725 Miller Fisher syndrome of, 118 pathogenesis and etiology of, 1290–1292, 1291f pathologic findings in, 1290 prognosis of, 1295 recurrent, 1338 treatment of, 1293–1295 variants of, 1289, 1289t Guillain-Mollaret triangle, 93, 112, 113f GUSB mutation (β-glucuronidase deficiency), 968t, 969 Gustatory nucleus, 236 Gustatory sense. See Taste sense Gustducin, 235 GWAS (genome-wide array analysis), 940 Gyromitra spp., 1208 H H reflex, in nerve conduction studies, 42, 43f H1N1 infection, 418, 745 Habit spasms, 102–103 Habituation, 1192 Haemophilus influenzae meningitis clinical features of, 699 epidemiology of, 698–699 laboratory tests in, 702 pathogenesis of, 699 prognosis of, 705–706 treatment of, 703, 705t Hair cells, of ear, 292, 293, 293f, 305 Hallermann-Streiff syndrome, 1004 Hallervorden-Spatz disease. See Neurodegeneration with brain iron accumulation (Hallervorden-Spatz disease) Hallucinations. See also Delirium in alcohol withdrawal, 1183 auditory pontine, 300, 472 in schizophrenia, 1505 in seizures, 300, 327, 472 in temporal lobe lesions, 300, 471–472

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1554

Index

Hallucinations (Cont.): in depression, 1490 in emotional disorders, 523 gustatory, 237, 327 in insomnia, 408 with methamphetamine, 1201 in narcolepsy, 418 olfactory, 232, 235, 327 in schizophrenia, 300, 1505 in seizures, 235, 237, 300 visual, 261, 327, 480–481 Hallucinogens, 1202–1204 Halogenated hydrocarbons, 1215 Haloperidol for Gilles de la Tourette syndrome, 104 in Huntington disease management, 1071 indications for, 1198 mechanism of action, 1198 Halothane, 355 Haltia-Santavuori disease, 950t. See also Neuronal ceroid lipofuscinoses Hamartoma characteristics of, 642 hypothalamic, 572 of iris, 1019, 1019f Hand alien hand syndrome and, 65 clumsy, in lacunar stroke, 780 weakness of, 1378 Handedness, 492–494 HaNDL (headache with neurologic deficits and CSF lymphocytosis), 183, 743 Hand-Schüller-Christian disease, 569, 570 Hanging head syndrome, 1377 Hangman’s fracture, 1228t HARP syndrome, 973 Hartnup disease (SLC6A19 mutation), 963, 1163 Hashimoto encephalopathy, 1147–1148 hCG (human chorionic gonadotropin), 669 HDCV (human diploid cell vaccine), 750 Head circumference, 998–999 Head impulse test, 308 Head injury. See also Concussion Alzheimer disease and, 1062 amnesia in, 888 in blast injuries, 883 blood pressure management in, 903 blunt or nonpenetrating, 897 cardiac arrest in, 890 carotid artery dissection in, 889 cervical fractures in, 901 in children

Ropper_Index_1519-1606.indd 1554

brain swelling in, 895 CT in, 888 persistent vegetative state and, 890 recovery from, 905 deceleration-acceleration forces in, 880 dementia following, 443 diffuse axonal injury in, 364, 891t Glasgow Coma Scale in, 887, 887t, 890 headache in, 888–889 imaging in, 19, 888, 888t incidence of, 879 intracerebral hemorrhage in. See Intracerebral hemorrhage, in head injury mechanisms of, 879–880, 880f minor, 887–889, 888t normal-pressure hydrocephalus and, 626 orbital fractures in, 901 paraplegia in, transient, 889 penetrating wounds and blast injuries, 883, 896 prognosis of, 890, 904–905 sequelae of autonomic dysfunction, 903–904 behavioral disorders, 897–898 cerebellar disorders, 899 delayed hemiplegia, 889 extrapyramidal disorders, 899 hydrocephalus, 900 migraine, 183 Parkinson disease, 899 persistent unresponsiveness, 889–890 postconcussion syndrome, 97 seizures, 344, 898–899 severe autonomic dysfunction in, 903–904 clinical features of, 884, 887 common sites of, 884–885, 885f coup and contrecoup lesions in, 884–885 CT in, 885–886, 886f diffuse axonal injury in, 886–887, 886f intracerebral hemorrhage in. See Intracerebral hemorrhage, in head injury mechanisms of, 884–885, 885f treatment of, 901–904 in shaken baby syndrome, 895–896 skull fractures in. See Skull fracture sleep disorders after, 410 subdural hygroma in, 891t, 894–895 vegetative state in, persistent, 890 vertigo in, 314

Head movements in spasmodic torticollis, 98 in tremors, 89 Headache. See also Migraine in addiction, 182 alarm clock. See Cluster headache alcohol use and, 174 analgesic, 174 with aneurysm, 175 in AVMs, 848 in brain abscess, 714 in carotid artery stroke syndrome, 792 in cerebrovascular disease, 175 in cervical spine disorders, 176, 196 in Chiari malformations, 195–196, 1009 cluster. See Cluster headache coughing and, 174, 194–195 in diffuse vasospasm, 858 duration of, 174 in elderly incidence of, 192 recurrent nocturnal, 190, 192 with temporal arteritis, 193–194 erythrocyanotic, 196 exertional, 175, 176, 194–195 eyestrain, 174 with fatigue, 511 febrile, 175, 196 in fibromyalgia, 176 food-related, 175 glaucoma and, 176 in head injury, 889 hemicrania continua, 192 histamine, 178t hot-dog, 175 in hypertension, 194, 196 hypnic, 192 ice-pick pain in, 145, 174 indomethacin-responsive. See Indomethacin-responsive headache intensity of, 173, 174 in intracerebral hemorrhage, 832 in intracranial hypotension, 176, 633–635 intracranial pressure in, 175, 193 in intracranial tumors, 179t, 193, 647 location of, 173–174 lying down and, 176 medical diseases associated with, 196 in meningitis, 176, 178t, 196 in menstrual cycle, 179 new daily persistent, 192 nutrition and food-associated, 175, 189 occipitonuchal, 647 of ocular origin, 176 overuse, 174

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Index pain mechanisms of, 140 in paranasal sinus disorders, 173 patient description of, 173 physical examination in, 173 in pituitary adenoma, 676 in postconcussion syndrome, 897 post-LP, 15, 176, 633–634, 633f posttraumatic, 192–193 premenstrual, 174 prevalence and incidence of, 5, 5f, 6t in pseudotumor cerebri, 194, 629 with psychiatric diseases, 192 in putaminal hemorrhage, 833 recurrent nocturnal, 190 after seizure, 196 sentinel, 840 sexual activity and, 195 in sinusitis, 176 in stroke, 775 with subarachnoid hemorrhage, 176, 178t with subdural hematoma, 192–193 in temporal arteritis, 179t, 193–194, 861 tension-type, 174, 178t, 191–192 terminology of, 173 third occipital nerve, 198 throbbing, 173, 175 thunderclap, 174, 180, 195, 195t, 412, 840 trochlear, 198 types of, 178–179t vacuum sinus, 176 weight-lifter’s, 194 whiplash injuries and, 193 Hearing. See also Deafness age-related changes in, 607 anatomy and physiology of, 292–297, 293f–294f assessment of, 8, 297 disorders of drug-induced, 301 hallucinations in, 300 hereditary, 302, 303t–304t loudness recruitment in, 298 in neurofibromatosis type 2, 301, 303t in neurosyphilis, 724 in seizures, 327 speech discrimination in, 298 in syphilis, 301 in temporal lobe lesions, 301, 470–471 Heart disorders congenital, brain abscess in, 713 syncope in, 389 Heart rate autonomic regulation of, 540–543, 541f–542f in coma, 375

Ropper_Index_1519-1606.indd 1555

Heartburn, 143 Heat syncope, 389 Heavy metal toxicity arsenic, 1211–1212 industrial toxins, 1214–1215 lead. See Lead poisoning manganese, 1212 mercury, 1212–1213 other metals, 1214 phosphorus and organophosphates, 1213–1214 thallium, 1214 Hebephrenic schizophrenia, 1507 Heerfordt syndrome, 1361 HELLP syndrome, 771, 858, 866–867 Hemangioblastoma of cerebellum, 667–668, 668f retinal, 249, 668 of spinal cord, 667–668 in von Hippel-Lindau disease, 667, 1023 Hemangiomas dermatomal, with spinal vascular malformations, 1023 of skin, 1005 spinal tumors and, 1023, 1254 Hematin, 1297 Hematomas cerebellar, 837–838 epidural, 891t, 892, 892f intracerebral, 889 intraventricular, 891t subdural. See Subdural hematoma Hematomyelia, 1252 Hematopoiesis, extramedullary, 1268 Hemiagnosia, pain, 150 Hemianopia bitemporal, 241f, 245, 258, 676 in pituitary tumors, 257 homonymous, 241f, 245, 258, 259, 795 Hemiatrophy, facial, 1361 Hemiballismus, 83, 802 Hemichorea, 81t, 82 Hemicrania, chronic paroxysmal, 190 Hemicrania continua, 192 Hemicraniectomy, 812 Hemidystonia, 84–85 Hemifacial spasm, 1362 Hemilaminectomy, 214 Hemimegalencephaly, 999 Hemiparesis alternating transitory, 66 with ataxia in lacunar stroke, 780 congenital, 593 gait disorders in, 126 in subdural hematoma, 894 Hemiparkinson-hemiatrophy syndrome, 1075

1555

Hemiplegia athetosis after, 82 characteristics of, 65 in children, 182, 183, 827 clasp-knife phenomenon in, 62 in coma, 376 congenital, 827 delayed, in head injury, 889 gait disorders in, 124t, 126 infantile, 1029–1030, 1030f lacunar, 780 in migraine, 66, 182, 183 pure motor, 58, 780 in stroke, 773 in upper motor neuron lesions, 60 Hemisection, of spinal cord, 169, 169f Hemisensory syndromes, 171 Hemispatial neglect, 475–476 Hemoglobin, in CSF, 16 Hemolytic uremic syndrome (HUS), 858, 868 Hemorrhage acute, 395 in AVMs, 847–848 Duret, 887 intracerebral. See Intracerebral hemorrhage in intracranial tumors, 854 intraventricular, 854 into muscle, 1426 perimesencephalic, 842 retinal, 248, 248f spinal, 219, 854–855, 1252, 1255 subarachnoid. See Subarachnoid hemorrhage in vitreous humor, 243 Hemorrhagic telangiectasia, hereditary, 1023 Heparin, 811, 866 Hepatic (portal-systemic) encephalopathy cerebral edema in, 1137 clinical features of, 382t, 1134–1135 EEG in, 32f, 34, 1135 fulminant hepatic failure in, 1137 laboratory findings in, 382t neuropathologic changes in, 1135–1136 pathogenesis of, 1136 in Reye syndrome, 1137–1138 risk factors for, 1134 toxins in, 371 treatment of, 1136–1137 Hepatic failure, fulminant, 1137 Hepatic paraplegia, 1104 Hepatocerebral degeneration, 90, 1144–1145

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1556

Index

Hepatolenticular degeneration (Wilson disease, ATP7B mutation) in adults, 986 clinical features of, 976–977 Kayser-Fleischer ring, 977, 977f rigidity, 80 tremor, 91, 976–977 copper metabolism in, 976 history of, 976 laboratory findings in, 977–978 neuropathologic changes in, 77, 978 prevalence of, 976 treatment of, 978 Herbicides, 1211 Herdchen lesions, 1055 Hereditary neuropathy with pressure palsies (HNPP), 1329 Hereditary sensory and autonomic neuropathy (HSAN), 1326t, 1330 Hereditary spastic paraplegia, 1113–1114, 1113t, 1332 Hering-Breuer reflex, 557 Herniation, of spinal cord, 1261. See also Brain, displacement and herniation of Heroin, 1190, 1192, 1194, 1204 Herpes simplex virus (HSV) encephalitis clinical features of, 343, 747 diagnosis of, 747–748, 748f epidemiology of, 744, 746–747 pathology of, 747 prognosis of, 748 treatment of, 748 Herpes simplex virus (HSV) infections aseptic meningitis, 741 Bell’s palsy, 1359–1360 chronic meningitis, 743 encephalitis. See Herpes simplex virus (HSV) encephalitis myelitis, 1237 pathways of, 739 Herpes zoster (shingles) clinical features of, 751–752 encephalitis, 752 myelitis, 752 plexitis, neuritis and ganglionitis, 1374 trigeminal nerve involvement, 1357 neonatal, 1038 occipitocollaris, 752 ophthalmic, 752–753 pathology and pathogenesis of, 750–751 postherpetic neuralgia following, 197 treatment of, 753 Heschl gyri, 470–472 Heteroplasmy, 942

Ropper_Index_1519-1606.indd 1556

Heterotopias, 1000, 1000f, 1001t Heterotypical cortex, 461 Heubner arteritis, 721 Heubner artery, 797, 797f HEXA gene mutation. See Tay-Sachs disease (GM2 gangliosidosis, hexosaminidase A deficiency) Hexacarbons, 1215 Hexosaminidase A deficiency, 952. See also Tay-Sachs disease (GM2 gangliosidosis, hexosaminidase A deficiency) HHV-6 encephalitis, in stem cell transplant, 749 Hiccup, 558–559 Hiccup, speech, 505 High-altitude (mountain) sickness, 1131 Hip disease, 207, 225 Hippocampal formation, 448, 449 Hippocampus, 448–449, 520, 521f Hippus, 286–287 Hirayama disease, 1260 Hirschsprung disease, 553 Histamine flare response and, 544 headache, 178t Histidinemia, 945t Histiocytes in bacterial meningitis, 697, 701 vacuolated, in Niemann-Pick disease, 952 Histiocytosis X, 569 Histoplasmosis, 729 History-taking in dementia and amnesia, 451–452 in headache, 173 for neurologic diagnosis, 6 neurologic examination and, 6–7 in stroke, 774 HIV infection clinical features of, 754–755 chorea, 82 dementia, 755 encephalopathy, 755, 755f facial palsy, 1360 myelopathy, 756, 1237–1238 myopathy, 756, 1380 peripheral neuropathy, 756, 1309, 1313–1314 retinal disorders, 251 complications of, 754t congenital, 1036 discovery of, 753–754 epidemiology of, 754 opportunistic infections and neoplasms with CMV infection, 757 CNS lymphoma, 656, 658, 756–757 cryptococcosis, 727, 757

HTLV-I myelopathy, 758 HTLV-II myelopathy, 758 syphilis, 719, 757 toxoplasmosis, 730–731, 730f, 756–757, 1036, 1380 tuberculosis and, 757 tuberculous meningitis, 716 VZV infections, 757 pathophysiology of, 754 in pregnancy, 1036 treatment of, 757 HLA antigens in ankylosing spondylitis, 218 in MS, 911 HMG-CoA reductase inhibitors. See Statins HMSN IV mutation, 1332–1333 HNPP (hereditary neuropathy with pressure palsies), 1329 Hoarding, 468 Hoarseness, 1363 Hodgkin disease, 1309 Hoffmann sign, 63, 1103 Hollenhorst plaques, 249, 249f Holmes type, cerebellar cortical ataxia, 1098, 1099f Holmes-Adie syndrome, 288 Holmgren test, 482 Holoprosencephaly, 1000, 1001–1002, 1001t Homocysteinemia, 965, 1163 Homocystinuria (CBS mutation), 829, 945t, 984–985, 1174t Homoplasmy, 942 Homosexuality, 568, 591–592 Homotypical cortex, 461–462 Homovanillic acid (HVA), 19 Homunculus motor, 59, 59f sensory, 160, 162f Hoover sign, 68, 131 Horizontal gaze, 264–266, 265f, 268, 966 Hormones. See also specific hormones of pituitary gland, 566–568, 566t in sleep-wake cycle, 403–404 in stress, 516 Horner syndrome autonomic nervous system dysfunction in, 548–549 bilateral, 287 causes of, 377 diagnosis of, 544 differential diagnosis of, 289 painful, 822 partial, 190 pupil alterations in, 287, 287f vocal cord paralysis in, 1365 Hot-dog headache, 175 HPRT1 mutation (Lesch-Nyhan syndrome), 979–980

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Index HRIG (human rabies immune globulin), 750 HSAN (hereditary sensory and autonomic neuropathy ), 1326t, 1330 HSV. See Herpes simplex virus (HSV) infections HTLV-I myelopathy. See Tropical spastic paraparesis HTLV-II myelopathy, 758 Hughes syndrome, 867–868 Human chorionic gonadotropin (hCG), 669 Human diploid cell vaccine (HDCV), 750 Human immunodeficiency viruses. See HIV infection Human rabies immune globulin (HRIG), 750 Hunt and Hess Scale, for subarachnoid hemorrhage, 841, 841t Hunter disease (IDS mutation), 968, 968t Huntingtin gene, 1068–1069 Huntington disease basal ganglia and thalamus in, 75f, 79 in children, 1070 clinical features of, 1069–1070 athetosis, 82 chorea, 77, 78t, 81, 1069 dementia, 1070 depression, 1490 gait disorders, 128 diagnosis of, 1071 differential diagnosis of, 1072 genetic factors in, 1068–1069, 1070–1071 incidence of, 1068 vs. neuroacanthocytosis, 1092 pathology and pathogenesis of, 77, 78t, 1070–1071, 1070f prevalence and incidence of, 6t treatment of, 1071–1072 Westphal or rigid variant of, 1069 Hurler disease (IDUA mutation), 968, 968t Hurst disease (acute necrotizing hemorrhagic encephalomyelitis), 933–934, 933f HUS (hemolytic uremic syndrome), 858, 868 Hutchinson pupil, 287 Hutchinson triad, 1037 HVA (homovanillic acid), 19 Hyaline bodies, 248–249 Hydatid disease, 733t, 734 Hydralazine, 1302, 1309 Hydranencephaly, 998–999

Ropper_Index_1519-1606.indd 1557

Hydrocephalus acute, 379, 624–625 in AVMs, 848 in bacterial meningitis, 697t in cerebellar hemorrhage, 835 chronic, dementia in, 443 congenital, 623, 624 in congenital CMV infection, 1036 infantile, 624 LP in, 13–14 in macrocephaly, 998–999 MRI of, 625f neuropathologic effects of, 625 normal-pressure. See Normalpressure hydrocephalus (NPH) obstructive, 623 occult, 624, 625f otitic, 711 pathogenesis of, 623–624 posttraumatic, 900 skull shape in, 624 in subarachnoid hemorrhage, 844 types of, 623 Hydrochlorothiazide, 1452 Hydrocodone, 1190 Hydrogen peroxide poisoning, 1215 Hydromorphone, 151t, 1190 Hydromyelia, 1270 Hydrops, endolymph, 309 Hydroxocobalamin, 1168 Hydroxyacyl-CoA dehydrogenase deficiency, 1410 Hydroxyamphetamine, 544 5-Hydroxyindoleacetic acid, 1495 Hygroma, subdural, 891t, 894–895, 999 Hypalgesia, 142, 142t, 161, 168 Hyperactivity-inattention disorders, 426–427 Hyperalgesia, 142, 142t, 146 Hyperammonemias, 946–947, 959 Hyperbilirubinemia, hereditary, 1032 Hypercalcemia, 1141–1142 Hypercapnic pulmonary disease, 382t, 1132 Hypercoagulable states, 866–869 Hyperekplexia, 97 Hypereosinophilic syndrome, 1307–1308 Hyperesthesia definition of, 142, 142t, 161–162 in nutritional polyneuropathy, 1160 in peripheral neuropathy, 1281 testing of, 9 Hyperexcitability of muscles, 1460–1461 of peripheral nerves, 1458 Hyperexplexia, 97 Hyperextension injuries, cervical, 1226 Hyperglycemia in encephalopathy, 1134 hyperosmolar nonketotic, 1134

1557

Hyperglycinemia, 946 Hyperhidrosis, 551 Hyperkalemia, 1141 Hyperkalemic periodic paralysis, 1448t, 1450–1451 Hyperkinetic dysarthria, 505 Hyperlipidemia, 242, 776 Hypermetria, 116, 267 Hypermetropia, 272 Hypernatremia, 1141 Hyperopia, 607 Hyperornithinemiahyperammonemiahomocitrullinemia, 946 Hyperosmia, 232, 234 Hyperosmolar therapy for hypertensive encephalopathy, 858 for intracranial pressure management, 902–903 Hyperpathia, 142, 142t, 162, 1160, 1281 Hyperreflexia, 61–63 Hypersensitivity denervation and, 146, 544 phenytoin, 352 Hypersexuality, 527–528 Hypersomnia, 414, 419–420 Hypersuggestibility, 1479–1480 Hypersynchrony of neurons, 334 Hypertelorism of Greig, 1003 Hypertension acute reactive, 833 in coma, 375–376 Cushing response in, 550 encephalopathy and. See Encephalopathy, hypertensive essential, 550 headache and, 175, 194, 196 in intracerebral hemorrhage, 832, 837 ischemic optic neuropathy in, 256, 256f in lacunar stroke, 780 in lupus erythematosus, 863 malignant, retinal changes in, 247–248, 248f orthostatic, neuropathy with, 547 in porphyria, 1297 retinal changes in, 247, 248f in stroke, 775 in Takayasu arteritis, 862 Hyperthermia in alcohol withdrawal, 1185 cerebellar effects of, 1146 in elderly, 548 malignant syndrome of. See Malignant hyperthermia in neuroleptic malignant syndrome, 1198–1199 periodic, 574

10/02/23 10:43 AM

1558

Index

Hyperthyroidism encephalopathy in, 1147 exophthalmic ophthalmoplegia (thyroid orbitopathy) in, 279, 1411–1412 fatigue in, 511 in myasthenia gravis, 1412 psychosis in, 1516 Hypertonic saline, 902–903 Hypertrophic neuropathy of infancy (Dejerine-Roussy syndrome), 171, 801, 1329 Hyperventilation central neurogenic, 379, 558 controlled, for cerebral edema, 646 faintness and, 395 for intracranial pressure management, 903 in panic attacks, 1472 Hypesthesia definition of, 161 in ganglionopathy, 168 in interruption of single peripheral nerve, 167 transient facial, 916 Hyphema, 243 Hypnic headache, 192 Hypnic starts, 411 Hypoalgesia, 142, 142t, 168 Hypobetalipoproteinemia, familial, 973 Hypocalcemia, 948–949, 1142 Hypocarbia for intracranial pressure management, 903 syncope in, 390 Hypochondriasis, 518, 1481, 1492 Hypocretin, 404 Hypocupric myeloneuropathy, 978–979, 1262 Hypogeusia, 237 Hypoglossal (twelfth) nerve, 1366 Hypoglycemia coma in, 382t dizziness in, 307 encephalopathy in, 1132–1134 faintness in, 395 functional/reactive, 1133 neonatal, 1030–1031 in neonatal seizures, 949 vasopressin levels in, 568 Hypogonadism with congenital ichthyosis and mental retardation, 1005 Hypokalemia in alcohol withdrawal, 1186 myopathy in, 1415t, 1417 treatment of, 1141 weakness in, 1141, 1454–1455

Ropper_Index_1519-1606.indd 1558

Hypokalemic periodic paralysis, 1447 familial, 1448t, 1453–1454 thyrotoxic, 1412, 1437, 1455 Hypokinesia, 73, 74f–75f, 78–79 Hypomagnesemia, in alcohol withdrawal, 1186 Hypomania, 1489, 1492 Hypomyelination, congenital, 1329 Hyponatremia ANF in, 572 pathogenesis of, 371 severe, 1140 in SIADH, 571, 1140–1141 treatment of, 1140–1141 Hypoparathyroidism, 980–981, 1145, 1459 Hypophonia, 505, 506 Hypophosphatemia, 1459 Hypophyseal duct tumor, 674–675 Hypoplasia focal dermal, 1006 optic nerve, 257 pontocerebellar, 1032 Hyposexuality, 528 Hyposmia, 232–234, 237 Hypotension in coma, 375 intracranial. See Intracranial hypotension orthostatic. See Orthostatic hypotension postprandial, 392 Hypothalamic syndromes cardiovascular disorders with, 574 cerebral salt wasting, 572 consciousness disorders in, 574–575 diabetes insipidus, 569–571 gastric lesions in, 574 global, 569 growth abnormalities in, 573 hamartoma, 572 Kleine-Levin syndrome, 414–415 periodic somnolence in, 575 personality disorders in, 574–575 pulmonary edema in, 574 sexual development disorders in, 572–573 SIADH, 571–572 temperature regulation in, 573–574 weight changes in, 573 Hypothalamus anatomy of, 565–566, 566f in autonomic regulation, 535 disorders of. See Hypothalamic syndromes in emotions, 522, 525 functions of, 565 hormones of, 566, 566t limbic connections of, 521–522, 522f neurons of, 565 in sarcoidosis, 569

in sexual development, 572–573 suprachiasmatic nucleus of, 404 tumors of, 569 ventrolateral preoptic nucleus of, 404, 405f Hypothermia chronic, 574 in elderly, 548 for hypoxic-ischemic encephalopathy, 1130 for intracranial pressure management, 903 spontaneous periodic, 574 Hypothyroidism EEG in, 34 myopathy in, 1412 neonatal, 1148–1149 neurologic symptoms of, 1148, 1323–1324 pseudomyotonia in, 1457 sleep in, 421 Hypotonia benign congenital, 1111 in cerebellar disease, 117–118 in chorea, 80 definition of, 56 infantile, 594 neonatal, 593 in spastic diplegia, 1029 in spinal muscular atrophy, 1110 in tabetic neurosyphilis, 723 in upper motor neuron lesions, 60 Hypoventilation syndrome congenital central, 558 primary, 416 Hypoxia generalized, 820–821 in obstructive sleep apnea, 416 Hypoxic-ischemic encephalopathy brain death from, 1128 causes of, 1126 clinical features of, 344, 1127–1128 imaging in, 1128, 1128f in neuroleptic malignant syndrome, 1199 neurologic syndromes following, 1129 physiology of, 1126–1127 prognosis of, 1129–1130 treatment of, 1130 Hypsarrhythmia, 331, 341 Hysteria, 1469, 1476. See also Functional neurological disorders Hysterical personality disorder, 1471t I IBM. See Inclusion body myositis (IBM) Ibuprofen, 151t I-cell disease, 969

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Index Ice-pick pain, 145, 174 Ichthyosis, with congenital hypogonadism and developmental delay, 1005 Ideation, bizarre, 529 Ideational apraxia, 64 Ideomotor apraxia, 64 IDH1 mutations, 642t, 643, 649 Idioglossia, 596 Idiopathic cervical dystonia, 98 Idiopathic eosinophilic syndrome, 1307–1308 IDS mutation (Hunter disease), 968, 968t IDUA mutation (Hurler disease), 968, 968t Iduronate sulfatase deficiency, 968 IgLON5, 413 Illusions, visual, 480 Imaging techniques angiography, 25, 26f CT. See Computed tomography (CT) DTI, 25 functional, 25–27, 25f MRI. See Magnetic resonance imaging (MRI) MRS, 25 myelography, 19, 21f, 208 perfusion, 25 PET. See Positron emission tomography (PET) SPECT, 27 ultrasonography, 28 Imipenem, 343 Imipramine, 150, 1200, 1497t Immature personality disorder, 1471t Immune checkpoint blockade therapy, 1218 Immune reconstitution syndrome (IRIS), 757, 926 Immune-mediated necrotizing myopathy (IMNM), 1382 Immunoglobulins in ataxia-telangiectasia, 1025 for CIDP, 1320 for dermatomyositis, 1385–1386 for Guillain-Barré syndrome, 1294–1295 in MS, 920 for myasthenia gravis, 1441 for myasthenic crisis, 1442 for paraproteinemia, 1316 for stiff man syndrome, 1460 Immunosuppressive drugs. See also specific drugs for MS, 926, 927 for myasthenia gravis, 1440–1441 neurotoxic effects of, 1215–1218 Implicit memory, 446, 446f, 447t Impulse disturbances, 426

Ropper_Index_1519-1606.indd 1559

Inarticulation, congenital, 596–597 Inattention, 171, 424 Inclusion body myositis (IBM) vs. ALS, 1107 clinical manifestations of, 1387 differential diagnosis of, 1387–1388 histology of, 1386 laboratory and biopsy features of, 1387 treatment of, 1387 Incontinence in cervical spondylosis, 1259 emotional, 523 fecal, 465, 466 urinary. See Bladder dysfunction Incontinentia pigmenti, 1005–1106 Indomethacin for chronic paroxysmal hemicrania, 190 for orthostatic hypotension, 397 for pain, 151t Indomethacin-responsive headache, 189, 189t, 190, 195 Induction process, 998 Industrial toxins, 1214–1215 Infantile spasms, 331 Infants. See also Neonates ADHD in, 601 Apgar score in, 585, 585t arachnoid cyst in, 671 ataxia in, 594 bacterial meningitis in, 700 beriberi in, 1159 botulism in, 1206 cerebral palsy in, 594 choreoathetosis in, 1031 congenital deafness in, 595–596 cranial malformations in, 998–999 deafness in, 594 epilepsy in, 1038 fetal alcohol syndrome in, 1188–1189 floppy, 1033–1034, 1033t, 1110, 1111 germinal matrix hemorrhage in, 1026–1027, 1026f growth and development of anatomic basis of, 582–583, 584f behavioral, 585–586 intelligence, 590 language, 590–591 motor, 586, 592–593 normal functions and delays in, 587t–588t personality and social adaption, 592 physiology of, 585–586 sensory, 580, 589 Hartnup disease in, 1163 hemiplegia and quadriplegia in, 827, 1029–1030, 1029f hydrocephalus in, 624

1559

hypertrophic neuropathy in, 171, 801, 1329 hypotonia in, 594 increased intracranial pressure in, 622 inherited metabolic diseases in diagnosis of, 958–960, 959t–960t lysosomal storage diseases. See Lysosomal storage diseases organic acidurias, 946 Moyamoya disease in, 824–825 neurologic examination in, 10 nystagmus in, 282, 955 Riley-Day familial dysautonomia in, 547–548 seizures in causes of, 340f, 340t characteristics of, 341, 1038 in pyridoxine deficiency, 1174t in West syndrome, 331 sleep in, 399, 402, 403f spasm in, 340 spinal muscular atrophy in, 1033, 1110 subacute necrotizing encephalomyelopathy in, 990 subdural empyema in, 709 thiamine deficiency in, 1159 timidity in, 525 Infarction cerebellar, 813 cerebral. See Ischemic stroke lacunar, 58 in muscles, 1426 myocardial, TIA and, 779 of optic nerve head, 255–256 spinal cord, 1250–1251, 1251f Infections bacterial. See Bacterial infections cestode, 733–735, 733t, 734f coma in, 382t confusional states in, 433 fatigue in, 511 fungal. See Fungal infections H1N1, 418 intrauterine and neonatal. See Intrauterine and neonatal infections leptospirosis, 726 Lyme disease. See Lyme disease myopathy in, 756, 1379–1381 nematode, 732–733, 733t in opioid use disorder, 1194 prion. See Prion diseases protozoal, 730–732 rickettsial, 729–730 seizures in, 343 spinal, 219 spirochetal. See Spirochetal infections

10/02/23 10:43 AM

1560

Index

Infections (Cont.): toxoplasmosis. See Toxoplasmosis trematode, 733t, 735, 735f viral. See Viral infections Infectious mononucleosis, 741, 745 Infectious vasculitis, 860 Inflammatory disorders, dementia in, 443 Influenza, 745, 1381 Infranuclear palsy, 263 Infundibulum, 566, 570 INH. See Isoniazid (INH) Inhibiting obsessions, 1475 Initiative disorders, 467–468 Inner speech, 490 Inocybe spp., 1208 Insecticides, 1211, 1213–1214, 1444t, 1447 Insight, 427, 452 Insomnia caffeine and, 408 fatal familial, 410, 767–768 hallucinations in, 408 primary, 407 psychological factors in, 407 rebound, 408 secondary, 407 symptoms of, 406 treatment of, 408 Inspiration, respiratory neurons in, 555–556, 556f Insulin, 1133, 1305 Integrin congenital muscular dystrophy, 1402t Intellectual and developmental disability, 603–604, 604f Intellectual obsessions, 1475 Intelligence creativity and, 438–439 definition of, 436 development of, 590, 603–604, 604f. See also Developmental diseases g factor of, 437 genetic factors in, 590 genius level, 438 in growth and development, 438 inherited metabolic diseases and changes in, 985–986 s factors of, 437 Spearman two-factor theory on, 437 Thurstone multifactorial theory on, 437–438 Intelligence quotient (IQ), 436–437 Intention tremors, 86t, 91, 116–117 Interferon-β-, 925–926 Interleukin-2, 1341 Intermittent explosive disorder, 1471t, 1483–1484 International Headache Society, 193

Ropper_Index_1519-1606.indd 1560

Internuclear ophthalmoplegia, 265–266, 279–280, 916 Internuclear palsy, 263 Interpositus nucleus, 111, 113 Interstitial edema, 644, 645 Interstitial nucleus of Cajal in horizontal gaze, 264 in vertical gaze, 266, 266f, 268 Intervertebral discs age-related changes in, 204 anatomy of, 203, 204f herniation of, cervical management of, 223 MRI in, 222–223, 231f symptoms at different levels, 211t, 221–222 herniation of, lumbar diagnosis of, 212–213, 213f in failed back syndrome, 220 nerve root compression in, 211–212, 211t, 212f physical examination in, 206 sciatica in, 210–211 symptoms of, 210–212, 211t treatment of, 213–214 intradural, 212 thoracic, 212 Intracerebral hemorrhage in amyloid angiopathy, 853, 855–856, 855f causes of, 772, 773t, 831, 831t, 853–855 cerebellar, 834f, 835 clinical syndrome of, 832–833 coma in, 381t course and prognosis of, 836–837, 836t in DIC, 866 Glasgow Coma Scale in, 836, 836t in head injury brainstem, 887 cerebral contusion and, 895 epidural hematoma, 891t, 892, 892f incidence of, 890 subarachnoid, 891t subdural. See Subdural hematoma hypertension treatment following, 837 imaging of, 832, 834f increased intracranial pressure in, 837 vs. ischemic stroke, 832 laboratory findings in, 836 leukoencephalopathy in, 854 in liver disorders, 853 lobar, 835–836 microbleeds in, 854 pathogenesis of, 832 pontine, 834f, 835 primary, 831–832

putaminal, 833–834, 834f sites of, 831 subarachnoid. See Subarachnoid hemorrhage thalamic, 834–835, 834f treatment of, 837–838 Intracranial arteries, 175, 824 Intracranial hypotension headache in, 175, 176 post-LP, 15, 633–635, 633f Intracranial pressure, 15, 617 Intracranial pressure, elevated in brain herniation, 621–622, 646 causes of, 621–622 cerebral edema and, 621–622, 645–646 cerebral perfusion pressure in, 620 in cerebral venous obstruction, 629 in children and infants, 622 clinical features of, 622 coma and signs of, 384 generalized brain swelling and, 622 headache in, 175, 176 in hydrocephalus, 624 in intracerebral hemorrhage, 837 in intracranial tumors, 622, 643–644, 664. See also specific tumors after ischemic stroke, 812–813 LP and, 14, 15 monitoring of, 622–623 papilledema in, 252–254, 253f, 254t physiology of, 620–621 plateau waves in, 621, 621f in pseudotumor cerebri, 630 pulsatile tinnitus in, 299 after severe head injury, 887, 901–903 signs of, 379 treatment of, 812–813, 901–903 vomiting in, 562 Intracranial tumors. See also specific types biology of, 642–643 classification and grading of, 641–642, 642t clinical characteristics of cerebral edema. See Cerebral edema cognitive function changes, 647 dizziness, 647 headache, 179t, 193, 647 hemorrhage, 854 increased intracranial pressure, 621–622, 643–644, 664. See also specific tumors localizing signs, 648 seizures, 647–648 sleep disorders, 410 vomiting, 647 EEG in, 34

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Index genetic features of, 643 histiogenic theory of, 643 incidence of, 641, 641t metastatic, 640, 658–661, 659f molecular features of, 643 pathophysiology of, 643–646, 643f radiation therapy for, 689–691, 690f, 691f vs. stroke, 775 Intradural disc rupture, 212 Intramuscular injections, myopathy due to, 1414, 1415t Intraocular pressure in glaucoma, 243 Intraspinal tumors. See Spinal cord tumors Intrauterine and neonatal infections bacterial meningitis, 1038 clinical features of, 1034 CMV, 1034, 1035–1036 EBV, 1038 herpes zoster, 1038 HIV infection, 1036 pathogenesis of, 1034 rubella, 763, 1034–1035 syphilis, 301, 720, 1037–1038 toxoplasmosis, 731, 1034, 1035f, 1037 viral encephalitis, 1038 Zika virus, 1036–1037 Intravascular lymphoma, 663–664 Intraventricular hematoma, 891t Involuntary movements, 80–82. See also Movement disorders Ion channel disease. See Channelopathies Iophendylate, in contrast myelography, 19 Iowa familial amyloidosis, 1335 Iproniazid, 1199 IQ (intelligence quotient), 436–437 Iridocyclitis, 176 Iridodonesis, 984 Iridoplegia, 273, 547 IRIS (immune reconstitution inflammatory syndrome), 757, 926 Iris, hamartoma of, 1019, 1019f Iron accumulation in brain (Hallervorden-Spatz disease), 84, 979, 979f Iron deficiency, 409 Irregular sleep-wake pattern, 411 Irritability, 517 Isaacs syndrome, 47, 689, 1459 Ischemia. See also Ischemic stroke; Transient ischemic attack cerebral. See Cerebrovascular disease, ischemic encephalopathy in. See Hypoxicischemic encephalopathy of limb, neuropathy in, 1309–1310

Ropper_Index_1519-1606.indd 1561

in optic neuropathy, 252, 253, 255–256, 256f pain in, 140 retinal, 249, 249f, 250f of spinal cord, 1250 Ischemic stroke. See also Cerebrovascular disease, ischemic anoxia in, 783 atherosclerosis in, 778–779 atrial fibrillation and, 776–777, 814 causes of, 772, 773t, 776–779 cerebral embolism in, 772, 776–778 course and prognosis of, 818–820 dementia following, 443 depression following, 819, 1490 embolic, 776–778 imaging techniques in, 774, 786–7879, 787f, 787t, 788f vs. intracerebral hemorrhage, 834 lacunar, 779–782, 809f neurological syndromes of anterior cerebral artery, 796–798, 796f anterior choroidal artery, 798 basilar artery, 805–807 carotid artery, 792–793 middle cerebral artery. See Middle cerebral artery (MCA) posterior cerebral artery. See Posterior cerebral artery (PCA) vertebral artery, 803–805, 804f pathophysiology of, 784 hematologic factors in, 786 metabolic and physiologic factors in, 784–786 vascular factors in, 783–784, 784f, 785f physical examination in, 789 prevention of anticoagulants for, 815 antiplatelet drugs for, 814–815 in asymptomatic carotid stenosis, 817–818 carotid stenosis treatment for, 816–817, 817f patent foramen ovale closure for, 815–816 statins for, 815 scales for evaluation of, 789–791, 790t–791t spasticity after, 819 treatment of in acute phase, 808 for cerebral edema, 812–813 endovascular thrombectomy for, 810–811

1561

for increased intracranial pressure, 836–837 intravenous thrombolytic agents for, 809–810, 810t medical management for, 813–814 physical therapy and rehabilitation in, 820 revascularization surgery for, 811 vertebral artery dissection in, 822–824 Island of Reil, 497 Islets of Langerhans, 535 Isocarboxazid, 1199, 1497t Isocortex, 460 Isoflurane, 355 Isometric contractions, 54, 543 Isoniazid (INH) polyneuropathy induced by, 1302 side effects of, 1218 for tremor in MS, 928 for tuberculous meningitis, 718–719 Isopropyl alcohol, 1182 Isotonic contractions, 54 Isovaleric acidemia, 946 Itch, sensation of, 158 J Jaccoud syndrome, 1357t Jackknife seizures, 331 Jackson syndrome, 802t Jacksonian seizures, 325–327 Jacod syndrome, 682t Jacod-Rollet syndrome, 682t Jaeger system, 239–240, 240f Jamais vu, 328 James-Lange theory of emotion, 522 Jansky-Bielschowsky disease, 950t, 967. See also Neuronal ceroid lipofuscinoses Japanese B encephalitis, 745, 758 Jargon aphasia, 498 Jarisch-Herxheimer reaction, 724 Jaw jerk reflex, 8, 63, 1355 Jefferson fracture, 1228t Jejunoileal bypass operations, 1146 Jendrassik maneuver, 9 Jerk nystagmus, 280 Jervell and Lange-Nielsen syndrome, 304t Jet lag, 411 Jitter, in EMG, 49 Jitters, in alcohol withdrawal, 1183 Joubert syndrome, 1032 Jugular foramen tumors, 682t, 1357t, 1365 Jugular ganglion, 1363, 1364f Jumping Frenchmen of Maine, 97 Junctional feet, 1370 Juvenile myoclonic epilepsy, 325

10/02/23 10:43 AM

1562

Index

K Kallmann syndrome, 58, 233, 572 Kanner-Asperger syndrome. See Autism/autism spectrum disorders (Kanner-Asperger syndrome) Kayser-Fleischer ring, 242, 976, 977f Kearns-Sayre syndrome. See Progressive external ophthalmoplegia (Kearns-Sayre syndrome) Kennedy syndrome (AR mutation), 1108t, 1112, 1361 Keratitis, 314 Keratopathy, band, 242 Kernicterus, 1031–1032 Kernohan-Woltman phenomenon, 373, 373f Ketamine for pain, 151t for postherpetic neuralgia, 197 for status epilepticus, 355 Keto analogues, 1137 Ketoacidosis alcoholic, 1186 diabetic, 1133 recurrent, 991 Ketogenic diet, 357 Ketorolac, 151t Ketotic acidemia, 946 Khat leaf, 1202 Kidney, juxtaglomerular apparatus of, 535 Kindling mechanism, in seizures, 334 Kinesis paradoxica, 1075 Kinesthesia, 164 Kinky-hair disease. See Menkes (kinky- or steely-hair) disease (ATP7A mutation) Kinsbourne syndrome, 284 Kjellin syndrome, 1114 Kjer optic neuropathy, 257 Kleine-Levin syndrome, 414–415, 575 Klinefelter syndrome, 1012 Klippel-Feil syndrome craniocervical anomalies in, 58, 1262 syncope in, 394 syringomyelia and, 1268, 1269 Klippel-Trenaunay-Weber syndrome, 1019, 1022, 1023, 1253 Klüver-Bucy syndrome, 527 Knee-buckling attacks, 395 Konzo, 1207–1208 Korsakoff syndrome. See also Wernicke-Korsakoff syndrome amnesia in, 445–446, 1133, 1154, 1156, 1158 anatomic basis of, 448–449 classification of, 449, 450t

Ropper_Index_1519-1606.indd 1562

confabulation in, 446 in paraneoplastic encephalitis, 684 in proximal PCA syndromes, 802 psychosis in, 1187 smell sense and, 234 Krause end bulbs, 156 Kraus-Weber test, 206 Krebs cycle, 1127 Krebs-Henseleit urea cycle, 946 Kufs disease (late juvenile and adult ceroid lipofuscinosis), 950t, 974–975, 986. See also Neuronal ceroid lipofuscinoses Kugelberg-Welander syndrome, 1111–1112 Kuru, 768 Kussmaul respirations, 375 Kyphoscoliosis, 1269 Kyphosis, 128 L La Crosse encephalitis, 745, 746 Labetalol, 1297 Lability, emotional, 523, 529 Labyrinth caloric stimulation of, 281, 308 in equilibrium, 305 function tests of, 308 nystagmus in disorders of, 281 vertigo in disorders of, 309–310, 314 Labyrinthitis, toxic, 314 Lacosamide, 347t, 348t, 353 Lacrimal function tests, 543–544 Lactate, in CSF, 17t Lactate dehydrogenase (LDH), 702 Lactic acidemia, 946 Lactic acidosis congenital, 956–957, 991, 1174t encephalopathy in, 371 in seizures, 336 Lactic dehydrogenase, 18 Lacunar stroke, 58, 779–782, 809f Lacunar TIA, 781 Lafora-body disease, 95, 337, 338t Lafora-body polymyoclonus with epilepsy, 973–974 Lalling, 590 Lambert-Eaton myasthenic syndrome cause of, 1444t clinical features of, 278, 546, 1374, 1444, 1444t diagnosis of, 1444–1445 motor nerve stimulation in, 44 vs. myasthenia gravis, 1443 paraneoplastic syndromes and, 687, 689, 1299 pathophysiology of, 1444 treatment of, 1444t, 1445

Laminectomy, 1267 Lamotrigine, 347t, 348t, 349, 352–353 Lancaster test, 275 Lance-Adams syndrome, 344, 1130 Landau maneuver, 593 Landouzy-Dejerine muscular dystrophy, 1394–1395 Landry ascending paralysis, 1288. See also Guillain-Barré syndrome (GBS) Landry-Guillain-Barré-Strohl syndrome, 1288. See also Guillain-Barré syndrome (GBS) Language. See also Speech and language disorders anatomy and physiology of, 490–492, 491f cerebral hemisphere dominance in, 489, 492–494 definition of, 489 in dementia, 441 development of, 590–591 elements of, 492 emotional, 489 learning of, 489–490 propositional or symbolic, 490 vs. speech, 490 syntax of, 492 LARGE congenital muscular dystrophy, 1402t Laryngeal neuralgia, 1365 Lasègue sign, 206 Lassitude, 510 Lateral bending test, 206 Lateral cutaneous nerve of thigh neuropathy, 1343t, 1346–1347 Lateral decubitus position, 207 Lateral gaze, congenital lack of, 1025 Lateral medullary (Wallenberg) syndrome anatomy of, 804f causes of, 802t clinical features of, 802t, 804–805 gait disorders in, 125 Horner syndrome in, 548 sensory disturbances in, 170 Lateral recess, spine, 204, 204f Lateral (transverse) sinus brain abscess in, 712 septic thrombophlebitis in, 711 thrombosis of, 865, 865f Lathyrism, 1207, 1262–1263 Laughing sickness, 768 Laughter involuntary uncontrollable, 523–524, 523t, 528–529 in seizures, 328 Launois-Bensaude disease, 1019, 1330 LCM virus, 741

10/02/23 10:43 AM

Index LDH (lactate dehydrogenase), 702 LDL (low-density lipoprotein), 776 L-dopa. See Levodopa Lead poisoning in adults, 1210–1211 in children, 1209–1210 neuropathy in, 1300–1301 papilledema in, 631 prevention of, 1210 Learning age-related changes in, 609 of language, 489–490 memorization in, 452 Learning disabilities, 594–595 Leber hereditary optic atrophy (Leber amaurosis), 257, 1004, 1115 Leeuwenhoek’s disease, 558 Left-handedness, 493 Leg movements of in coma, 376 periodic, of sleep, 408–410 in restless legs syndrome, 408–410 in painful legs–moving toes syndrome, 216 weakness patterns in, 1378 Legionella pneumophila infections, 708 Leigh disease. See Subacute necrotizing encephalomyelopathy (Leigh disease) Leitungsaphasie, 499. See also Conduction aphasia Lemieux-Neemeh syndrome, 1117 Lemniscal system, 160f, 161 Lennox-Gastaut syndrome developmental delay in, 342 myoclonus in, 95 seizures in, 324–325, 331 treatment of, 353 Lens of eye, 240, 243 Lenticulostriate vessels, 465 Lentiform nucleus, 70 Leprous polyneuritis, 1322–1323, 1323f Leptomeningitis, 1238. See also Meningitis Leptospira interrogans, 726 Leptospirosis, 725, 726 Lesch-Nyhan syndrome (HPRT1 mutation), 979–980 Letter-by-letter reading, 500 Letterer-Siwe disease, 569, 570 Leucovorin, 731 Leukemia, 662–663, 700, 743 Leukoaraiosis, 826 Leukocytes, in CSF, 14t, 15–16, 701 Leukodystrophies. See also Adrenoleukodystrophy characteristics of, 949 dementia in, 443 differential diagnosis of, 960t

Ropper_Index_1519-1606.indd 1563

globoid cell. See Globoid cell leukodystrophy (Krabbe disease) in inherited metabolic diseases, 981–984 metachromatic in adults, 983–984 biochemical abnormalities in, 950t differential diagnosis of, 960t, 965 in early childhood, 964–965, 965f in late childhood, 983–984 polyneuropathy in, 1334 nystagmus in, 283 orthochromatic, 984 sudanophilic, 954–955, 960t Leukoencephalopathy acute necrotizing hemorrhagic, 933–934, 933f in CADASIL, 182, 443, 826f, 827 in CARASIL, 827 delayed posthypoxic, 1129, 1129f drug-induced, 1217t from calcineurin inhibitors, 1217 from heroin, 1194 from methotrexate, 1216 from vincristine, 1217f hemorrhagic, 854 in HIV infection in, 755, 755f progressive multifocal. See Progressive multifocal leukoencephalopathy radiation-related, 662–663, 689, 690f Leukomalacia, periventricular, 67, 1027 Leukomyelitis, 1236 Levetiracetam for seizures, 347t, 348t, 349, 350, 353 for status epilepticus, 354–355, 354t Levodopa for dystonia, 84, 1080, 1093 history and trials of, 1081 in Huntington disease treatment, 1071–1072 in Lewy body dementia treatment, 1067 for manganese poisoning, 1212 in Parkinson disease treatment. See Parkinson disease, treatment of for PSP, 1090 Levofloxacin, 708 Levorphanol, 151t, 1190 Levy-Roussy syndrome, 1097 Lewy bodies, 1077–1078, 1077f, 1080f Lewy body dementia clinical features of, 1067 diagnosis of, 445 differential diagnosis of, 445 vs. subcortical dementia, 442 treatment of, 1067–1068

1563

Lexical agraphia, 503 LH (luteinizing hormone), 566t, 567 Lhermitte sign, 913, 1165, 1233 Lhermitte-Duclos disease, 669, 670f, 1024 Libido, 528, 554 Lidocaine, 152, 344, 1306 Ligand-gated channel disorders, 338t Light response, of pupils, 245, 269, 286, 286f Light-headedness, 305, 306 Lightning injuries, spinal cord, 1235–1236 Limb-girdle muscular dystrophy (LGMD) autosomal dominant (LGMD 1A-1E), 1374t, 1397 autosomal recessive (LGMD 2A and B), 1374t, 1396–1397 classification of, 1396–1397, 1396t with FKRP mutation (LGMD2), 1396 weakness patterns in, 1374t, 1378 Limbic system anatomy of, 520–521, 521f cell loss in, 611 physiology of, 521–522, 522f Limbic system disease emotional disturbances due to, 522–523, 523t acute fear, anxiety, elation, and euphoria, 528 aggressiveness, anger, rage, and violence, 524–526 altered sexuality, 527–528 bizarre ideation, 529 differential diagnosis of, 528–529 disinhibition of emotional expression, 523–524 in hallucinatory and pain states, 523 placidity and apathy, 526–527 paraneoplastic encephalitis, 684–686, 684t, 685f Limb-kinetic (sympathetic) apraxia, 64, 485 Lincoln-Oseretsky scale, 131 Linear sebaceous nevus syndrome, 1005 Linezolid, 343, 704t Lingual nerve, 236 Linguistic agraphia, 502–503 Lip biopsy, 1312 Lipid metabolism disorders, 1327t, 1409–1411 Lipid storage diseases, 1411 Lipidosis, juvenile dystonic, 966 Lipids, 17t, 18 Lipodystrophy, 1361

10/02/23 10:43 AM

1564

Index

Lipofuscinoses. See Neuronal ceroid lipofuscinoses (Batten disease) Lipogranulomatosis (Farber disease), 950t, 954, 960 Lipomas, multiple symmetrical, 1330 Lipomucopolysaccharidosis, 969 Liposarcoma, 1426 Lips, paralysis of, 504 LIS1 mutation, 1001t, 1002 Lisch nodules, 1019, 1019f Lisping, 598 Lissauer tract, 136 Lissencephaly, 1000, 1001–1002, 1001t, 1004 Listening, dichotic, 493 Listeria monocytogenes infections, 699, 705t, 707, 1034 Lisuride, 1082 Literal paraphasia, 498 Lithium for bipolar disease, 1498 for cluster headache, 191 overdose, 1201 seizures induced by, 344 side effects of, 1201, 1498 toxicity of, 1301 Little disease, 126, 1029 Liver disorders cerebral hemorrhages in, 853 encephalopathy and coma in. See Hepatic (portal-systemic) encephalopathy upper motor neuron disease and, 1104 Liver transplantation, 1336 Lobar atrophy, 1065–1066 Lobar hemorrhage, 835–836. See also Intracerebral hemorrhage Local tetanus, 1205 Localization, method of, 3–4 Localized hyperhidrosis, 551 Locked-in syndrome, 366, 557, 806 Lockjaw, 1204 Locus ceruleus, 611 Logopenic aphasia, 1066 Logorrhea, 503 Lomustine, 1217 Long QT syndrome, 394 Long thoracic nerve neuropathy, 1342–1343 Longitudinal fasciculus. See Medial longitudinal fasciculus Loperamide, 1190 Lorazepam for alcohol withdrawal seizures, 1185 for anxiety and panic attacks, 1474 mechanism of action, 1196 for seizures, 347t, 348t for status epilepticus, 354, 354t

Ropper_Index_1519-1606.indd 1564

Loudness recruitment, 298 Louis-Bar disease, 1024 Low back pain. See Back pain Low-density lipoprotein (LDL), 776 Lowe (oculocerebrorenal) syndrome, 957, 959, 960 Lower motor neurons anatomy and physiology of, 54–56 disorders of, 56, 64t, 504–505 Loxapine, 1197 LP. See Lumbar puncture (LP) LRRK2 mutation, 1079, 1079t, 1080 LSD (lysergic acid diethylamide), 1203, 1509, 1510 Lückenschädel, 999 Lumbar puncture (LP). See also Cerebrospinal fluid (CSF) examination in coma, 384 corticosteroid therapy for, 14 dry tap in, 14 headache following, 15, 176, 633–634, 633f indications for, 13 intracranial pressure and, 14, 15 risks of, 13–14 in stroke, 788–789 in subarachnoid hemorrhage from ruptured saccular aneurysm, 842 technique and complications of, 14–15 traumatic tap in, 15–16 Lumbar spine disorders. See also Back pain adhesive arachnoiditis, 217–218 anatomy of, 203–204, 204f ankylosing spondylitis, 218–219 arachnoiditis, 218f congenital anomalies, 215 diagnostic procedures in, 207–208 facet syndrome, 217 failed back syndrome, 220 fracture, 210 hemorrhage, intraspinal, 219 infections, 219 intervertebral disc herniation diagnosis of, 212–213, 213f failed back syndrome in, 220 nerve root compression in, 211–212, 211t, 212f physical examination in, 206 sciatica in, 210–211 symptoms of, 210–212, 211t treatment of, 213–214 metastases, 219 in neoplastic diseases, 219 in osteoarthritis, 217 physical examination in, 206–207, 207f

stenosis, 205, 216–217, 1259 traumatic, 208–210 types of pain in, 204–206 Lumbarization, 215 Lumbar-peritoneal shunting, 632 Lumbosacral joint, 203 Lumbosacral plexus neuropathies, 1345–1346, 1345t Lumefantrine, 732 Lung cancer intraspinal metastasis of, 1265, 1265f Lambert-Eaton syndrome in, 1374, 1444 Lupus erythematosus cerebral vasculitis in, 863 chorea in, 81 cognitive function in, 863 CSF in, 863 differential diagnosis of, 923 hypertension in, 863 MS and, 863 myelopathy in, 1246 neuropathies in, 1308–1309 seizures in, 343 Luria test, 468 Luschka foramen, 618, 623 Luteinizing hormone (LH), 566t, 567 Lyme disease clinical features of encephalitis, 725 facial palsy, 1360 Guillain-Barré syndrome, 725 neurologic manifestations, 725–726, 1310–1311 polyradiculitis and Bannwarth syndrome, 1311 diagnosis of, 725, 726, 1310 historical aspects of, 725 incidence of, 725 treatment of, 726, 1310 Lymphocytes, in bacterial meningitis, 697, 701 Lymphoma classification of, 642t EBV and, 643 incidence of, 641t intravascular, 663–664 nervous system involvement in, 683 primary CNS. See Primary CNS lymphoma vitreous infiltration in, 243 Lymphomatoid granulomatosis, 663 Lymphomatous meningitis, 661–662 Lyon phenomenon, 941 Lysergic acid diethylamide (LSD), 1203, 1509, 1510

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Index Lysosomal storage diseases biochemical abnormalities in, 949–951, 950t Alexander disease (GFAP mutation), 956, 959 Alpers disease (POLG mutation), 956, 958, 959t cerebrohepatorenal (Zellweger) disease, 957, 959 congenital lactic acidosis, 956–957, 991, 1174t differential diagnosis of, 959t gangliosidosis. See Gangliosidosis Gaucher disease. See Gaucher disease (glucocerebrosidase deficiency) globoid cell leukodystrophy. See Globoid cell leukodystrophy (Krabbe disease) leukodystrophies. See Leukodystrophies lipogranulomatosis (Farber disease), 950t, 954 Menkes (kinky- or steely-hair) disease, 957–958, 960 Niemann-Pick disease. See Niemann-Pick disease (sphingomyelinase deficiency) oculocerebrorenal (Lowe) syndrome, 957, 959, 960 Pelizaeus-Merzbacher disease. See Pelizaeus-Merzbacher disease spongy degeneration of infancy (Canavan-van BogaertBertrand disease), 955, 956f, 960f Tay-Sachs disease. See Tay-Sachs disease vanishing white matter disease, 954 visual disorders in, 251 M Machado-Joseph-Azorean disease (ATXN3 mutation), 1096t, 1100 Macrocephaly, 955, 956, 956f, 998–999, 998t Macropsia, 260, 328 Macula lutea cherry-red spot in. See Cherry-red spot, retinal degeneration of, age-related, 252 in optical tract lesions, 259 photostress test in examination of, 251 Maculae acusticae, 293, 293f Macular degeneration, 6t, 252, 1114

Ropper_Index_1519-1606.indd 1565

Macular star appearance, 251, 255 Mad cow disease, 765 Maddox rod test, 274–275 Magendie foramen, 618, 623 Magnesium, in CSF, 17t Magnesium sulfate, 858 Magnetic resonance angiography (MRA), 25, 26f, 788, 842 Magnetic resonance imaging (MRI) in ADEM, 931–932, 932f in adrenoleukodystrophy, 982, 983f in ALS, 1104, 1104f in Alzheimer disease, 1063, 1063f in amyloid angiopathy, 855f angiography in, 25, 26f in arachnoid cyst, 671 in astrocytoma, 651, 651f in AVMs, 849, 850f in bacterial meningitis, 702 in brain abscess, 713f, 715–716 of brain and spine, normal, 23f in brainstem glioma, 680f in CADASIL, 826, 826f in cavernous malformations, 852– 853, 853f in central pontine myelinolysis, 1143, 1143f of cerebellar peduncles, 111f in cervical disc herniation, 222–223, 231f in cervical spondylosis, 1258 in cervical spondylotic myelopathy, 1258f in Chiari malformations, 1009–1010, 1009f in children, 24 in colloid cyst of third ventricle, 671, 671f vs. CT, 19, 22t in dermatomyositis, 1384 DWI in, 24 in dysembryoplastic neuroepithelioma tumor, 670, 670f in ependymoma, 654 FLAIR technique in, 22, 23f functional, 27, 27f in glioblastoma multiforme, 648, 648f in gliomatosis cerebri, 652, 652f in graft-versus-host disease, 933, 934f GRE and, 22 in hemangioblastoma, 667, 668f in hepatic encephalopathy, 1134 in herpes simplex encephalitis, 747, 748f in HIV encephalopathy, 755, 755f in hydrocephalus, 625f in hypertensive encephalopathy, 856–857, 857f

1565

in hypoxic-ischemic encephalopathy, 1128, 1128f impaired cognitive function and, 24 in intracerebral hemorrhage, 832 in intracranial metastatic cancer, 659, 659f in lacunar stroke, 781, 809f in lymphoma, 657f in medulloblastoma, 665, 665f in meningioma, 655, 656f in MS, 914–915, 915f, 920–921 of muscles, 49 vs. myelography, 22 of normal-pressure hydrocephalus, 626 in oligodendroglioma, 653, 653f in optic nerve glioma, 680 in paraneoplastic cerebellar degeneration, 687, 687f in paraneoplastic limbic encephalitis, 685, 685f in pituitary microadenoma, 678f in polymyositis, 1384 in postinfectious myelitis, 1243, 1243f in pregnancy, 24 in primary CNS lymphoma, 657–658 in pseudotumor cerebri, 629 in PSP, 1089, 1089f in radiation leukoencephalopathy, 689–690, 690f safety and limitations of, 24, 25 in schizophrenia, 1509 in seizures, 336 in septic thrombophlebitis, 711 after shunting for hydrocephalus, 635, 635f in SMART syndrome, 691, 691f in spinal epidural abscess, 1239, 1240f of spine, 208 of spine, normal, 21f in stroke, 786, 787f, 787t, 788f in subacute spongiform encephalopathy, 766, 766f in subarachnoid hemorrhage, 841, 841f in subdural hematoma, 892 SWI and, 22 in tuberculous meningitis, 716f, 717, 718f in tuberous sclerosis, 1015–1016, 1016f in Wernicke-Korsakoff syndrome, 1157, 1157f Magnetic resonance spectroscopy (MRS), 25 Magnetic resonance venography (MRV), 788, 865, 865f Magnetic stimulation, 38–39 Malabsorption, 1173–1174, 1173t

10/02/23 10:43 AM

1566

Index

Malaria, 731–732, 860 Malignant hypertension, 247–248, 248f Malignant hyperthermia, 574, 1199, 1448t, 1455–1456 Malingering amnesia in, 454 anosmia in, 234 characteristics of, 1476, 1483 definition of, 1483 diagnosis of, 454 vs. functional disorders, 1483 pseudoseizures in, 333 Malnutrition, protein-calorie, 1153, 1172–1173 MAN2B1 mutation (mannosidosis), 950t, 969–970 Mandibular nerve, 1355, 1358 Mandibulofacial dysostosis, 1004 Manganese poisoning, 1212 Mania alcoholic, 1184 clinical presentation of, 1493–1494 doubting, 1475 vs. encephalopathy, 1493–1494 incidence of, 1489 vs. rage, 529 Manic-depressive disease. See Bipolar disease Manipulation, spinal, 209 Mannitol for brain abscess, 715 for cerebral edema, 645–646, 812 for intracerebral hemorrhage, 837 for intracranial pressure management, 902 in lead poisoning treatment, 1210 Mannosidosis (MAN2B1 mutation), 950t, 969–970 Manometer, in CSF pressure measurement, 15 MAO inhibitors. See Monoamine oxidase inhibitors Maple syrup urine disease, 945t, 947–948 Maprotiline, 1200, 1497t Marble bones, 981 Marburg variant, MS, 918, 919f Marche à petit pas, 124t, 129 Marchiafava-Bignami disease, 1171–1172 Marcus Gunn phenomena, inverse, 285 Marcus Gunn pupil, 245 Marfan syndrome, 634, 984, 1260 Marie-Strümpell arthritis. See Ankylosing spondylitis Marijuana, 1203 Marin Amat syndrome, 285 Markesbery-Griggs dystrophy, 1401t Maroteaux-Lamy disease (ARSB mutation), 968t, 969 Masitinib, 1109

Ropper_Index_1519-1606.indd 1566

Masked depression, 1488 Mass reflex, 549 Mast syndrome, 1072 Maternal lineage, 942 Maxillary nerve, 1355 MCA. See Middle cerebral artery McCardle disease. See Phosphorylase deficiency (McArdle disease, PYGM deficiency) MDMA (methylenedioxymethamphetamine), 1204 Measles, 763, 932 Mechanical-restrictive ophthalmoparesis, 278–279 Mechanoreceptors, 135, 155, 1370–1371 Meclizine, 309 Medial longitudinal fasciculus in horizontal gaze, 264–266, 265f ophthalmoplegia in, 279–280 rostral interstitial nucleus of, 264, 266, 266f, 268 in vertical gaze, 266, 266f, 268 in vestibular system, 295–296, 295f, 296f Medial medullary syndrome, 804, 804f Medial temporal sclerosis, 329, 329f, 337 Median cleft facial syndrome, 1003 Median nerve neuropathy, 1343–1344, 1343t Medulla oblongata corticospinal tract in, 57f, 58 disorders of lateral medullary syndrome, 125, 170, 804–805, 804f medial medullary syndrome, 804 pyramidal tract of, 60 Medullary arteries, spinal, 1249, 1249f Medullary reticular nuclei, 53 Medulloblastoma in children, 665 classification and grading of, 642t, 664–665 clinical features of, 665 genetic factors in, 642t, 665 imaging of, 665, 665f pathophysiology of, 664–665 treatment of, 665–666 Mefloquine, 732 Megacolon, congenital, 553 Meige syndrome, 100–101 Meissner corpuscles, 155, 156t, 157f, 158 Meissner plexus, 539 Melanoderma, 576 Melanoma intracranial metastasis of, 659 of meninges, 662 multiple cranial nerve palsies in, 1368 retinopathy in, 251 Melarsoprol, 732

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) clinical features of, 991 genetic factors in, 988t, 991 migraine in, 184 strokes in, 829, 829f Melatonin in circadian rhythms, 568 for insomnia, 408 for jet lag treatment, 411 pineal gland and, 568–569 in sleep-wake cycle, 404 Melioidosis, 707–708, 708f Melkersson-Rosenthal syndrome, 1361 Melphalan, 1317, 1319 Memantine, 1065 Memory age-related changes in, 439–440, 608–609 anatomy of, 448–449 assessment of, 7 in confusional states, 363, 425 in dementia, 442–443 disorders of. See Memory disorders episodic, 446f, 447, 447t explicit, 446, 446f, 447t implicit, 446, 446f, 447t in learning, 452 long-term, 446, 447t, 452 modality-based, 449 neuropsychology of, 446–448, 446f, 447t procedural, 446f, 447, 447t remote, 446f, 452 semantic, 446, 446f, 447t of sexual abuse, 449 short-term, 446, 446f, 447t, 452 smell sense and, 232 working, 363, 446f Memory disorders. See also Amnesia in Alzheimer disease, 1057, 1058 in Briquet syndrome, 1477 in cerebellar disease, 118 limbic system cell loss and, 611 in normal-pressure hydrocephalus, 626 in seizures, 328 in temporal lobe lesions, 449, 473 Memory span test, 452 Mendelian patterns of inheritance, 640–641 Ménière disease cochlear, 309 deafness in, 301, 309 gait disorders in, 125 nystagmus in, 309 tinnitus in, 299 treatment of, 309–310 vertigo in, 309–310

10/02/23 10:43 AM

Index Meningeal disorders in melanoma, 662 meningitis. See Meningitis oculoleptomeningeal amyloidosis, 637 opticochiasmatic arachnoiditis, 636 pachymeningitis, 636–637, 636f regional arachnoiditis, 636 superficial siderosis, 637 Meningioma age of onset of, 643 cellular origins of, 655 classification and grading of, 642t clinical features of, 655 genetic factors in, 642t imaging of, 655, 656f incidence of, 641t, 643, 654–655 intraspinal, 1263, 1264f of olfactory groove, 234, 679 seizures in, 655 of sphenoid ridge, 679 treatment of, 655–656 of tuberculum sella, 679 Meningitis. See also Meningoencephalitis bacterial anthrax, 701, 708 biology of, 697–68, 697t in children, 698–699 clinical features of, 343, 699–700 CSF examination in, 700–702 differential diagnosis of, 703 epidemiology of, 698–699 H. influenza. See Haemophilus influenzae meningitis imaging in, 702 incidence of, 698–699 in infants and neonates, 700 laboratory findings in, 702 meningococcal. See Meningococcal meningitis neonatal, 1038 nosocomial, 704 pathogenesis of, 699 pneumococcal. See Pneumococcal meningitis prognosis of, 705–706 recurrent, 702–703 treatment of, 703–705, 703t–705t tuberculous. See Tuberculous meningitis types of, 698 chemical, 742t, 743 coma in, 381t CSF examination in, 13–14, 14t deafness in, 301 in epidermoid cyst, 674 fungal, 727 headache in, 176, 178t, 196 in Lyme disease, 725 lymphomatous, 661–662 malignant, 661–662, 661f

Ropper_Index_1519-1606.indd 1567

Mollaret, 703 parasitic, 735 prevalence and incidence of, 5, 5f protozoal, 730–732 in syphilis, 720. See also Neurosyphilis viral (aseptic) acute, 740–741 causes of, 743–744 chronic and recurrent, 742–744, 742t differential diagnosis of, 703, 741–742 vs. encephalitis, 743 mechanisms of, 739–740 mumps, 741 pathways of, 739 Meningocele, 1006, 1007 Meningococcal meningitis clinical features of, 699 epidemiology of, 698 incidence of, 699 laboratory findings in, 702 prognosis of, 705–706 prophylaxis for, 705 treatment of, 703–704, 705t Meningoencephalitis amebic, 731, 733t anthrax, 708 Bartonella henselae, 251, 255, 708 in brucellosis, 207, 708–709 chronic, 697t in EBV infections, 1038 eosinophilic, 733t, 735 granulomatous, 731 L. monocytogenes, 707 Legionella, 708 M. pneumoniae, 706–707 in melioidosis, 707–708, 708f tremor in, 88 in Whipple disease, 283, 709 Meningomyelitis, 724, 1236, 1239. See also Myelitis Meningomyelocele, 1006–1007 Meningoradiculitis, 1236 Meningovascular syphilis, 721–722, 724. See also Neurosyphilis Menkes (kinky- or steely-hair) disease (ATP7A mutation), 957–958, 960 Menstrual cycle in Briquet syndrome, 1477 headache in, 174, 179, 183 sciatica in, 215 Menstrual migraine, 179, 183 Mental asthenia, 647 Mental fog, 900 Mental retardation, See Developmental Delay in congenital myotonic dystrophy, 1400 in muscular dystrophies, 1402t prevalence and incidence of, 6t

1567

Mental status examination, 7, 452, 453f, 609 MEOS (microsomal ethanol oxidizing system), 1179 Meperidine, 151t, 1192, 1200 Mepolizumab, 1308 Meralgia paresthetica, 1343t, 1346–1347 Mercury poisoning, 1212–1213, 1298, 1301 Merkel discs, 155–157, 156t, 157f Merlin, 1017 Meropenem for anthrax, 708 for bacterial meningitis, 704, 704t for brain abscess, 715 Merosin deficiency, 1402t, 1403 MERRF (myoclonic epilepsy with ragged red fibers), 988t, 991 Mescaline, 1203 Metabolic acidosis, 1142 Metabolic diseases acquired acute, 343 anosmia in, 233–234 cerebellar ataxia in, 1145–1146 classification of, 1126t consciousness disorders in. See Metabolic encephalopathy extrapyramidal syndromes in, 1144–1145 fatigue in, 511–512 myoclonus in, 95 prevalence and incidence of, 6t psychosis and dementia in, 1146–1149 inherited in adults, 986–987, 987t aminoacidopathies. See Aminoacidopathies in children. See Children, inherited metabolic diseases in diagnostic features of, 942–943 genetic abnormality patterns in, 940–941 in infants. See Infants, inherited metabolic diseases in inheritance patterns in, 940–941 leukodystrophies. See Leukodystrophies lysosomal storage diseases. See Lysosomal storage diseases mitochondrial. See Mitochondrial disorders in neonates. See Neonates, inherited metabolic diseases in neuropathy in, 1327t, 1332–1336 strokes in, 984–985 myopathies. See Metabolic myopathies

10/02/23 10:43 AM

1568

Index

Metabolic encephalopathy in acid-base disorders, 1142 aggressive behavior in, 526 in calcium disorders, 1141–1142 in carbon monoxide poisoning, 382t, 1130–1131, 1131f confusional state in, 429 consciousness disorders in, 371–372, 1125 with dialysis, 1139 differential diagnosis of, 1125 hepatic. See Hepatic (portalsystemic) encephalopathy in high-altitude sickness, 1131 in hypercapnic pulmonary disease, 382t, 1132 in hyperglycemia, 1134 in hypoglycemia, 1132–1134 hypoxic-ischemic. See Hypoxicischemic encephalopathy laboratory examination in, 1125–1126 in osmotic demyelination. See Central pontine myelinolysis (CPM) in potassium disorders, 1141 seizures in, 343 septic, 430, 433, 1140 in sodium disorders, 1140–1141 uremic, 1138–1140 in water balance disorders, 1140 Metabolic myopathies glycogen storage. See Glycogen storage diseases lipid, 1409–1411 pathophysiology of, 1405–1406 Metachromatic leukodystrophy. See Leukodystrophies, metachromatic Metamorphopsia, 250, 251, 480 Metaphysial spurring, 957 Metastases cerebellar, 660 cervical, 225 dural, 659 intracranial, 219, 640, 658–661, 659f lumbar, 219 skull, 659 spinal, 659, 1264–1265, 1265f Methacholine, 545 Methadone, 151t, 1190, 1193–1194 Methamphetamine, 1201–1202 Methanol intoxication, 257 Methemoglobin, 16 Methionine, 1166 Methotrexate administration of, 1216 adverse effects of, 662, 1216–1217 for dermatomyositis, 1386 for malignant meningitis, 662

Ropper_Index_1519-1606.indd 1568

for NMO, 930 for primary CNS lymphoma, 658 3-Methoxy-4-hydroxyphenylglycol, 1495 Methsuximide, 353 Methyl alcohol, 1182 Methyl bromide, 1301 Methyl n-butyl ketone, 1301 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), 73, 77, 1078 Methylcobalamin, 1166 Methylenedioxymethamphetamine (MDMA), 1204 Methylmalonic acidemia, 945t, 946 Methylmalonic aciduria, 947 Methylphenidate, 419, 602 Methylprednisolone for ADEM, 933 for dermatomyositis, 1385 in Guillain-Barré syndrome treatment, 1295 for MS, 925 in polyarteritis nodosa treatment, 1307 for polymyositis, 1385 Methysergide, 149 Metoclopramide, 187, 188, 1077 Metoprolol, 188 Metronidazole for brain abscess, 715 for subdural empyema, 710 for tetanus, 1205 toxicity of, 1218–1219 Mexiletine in muscular dystrophy treatment, 1405 for myotonia congenita, 1450 for pain, 151t, 152 Meyer loop, 470 MGUS (monoclonal gammopathy of undetermined significance), 1315 Michel defect, 302 Microadenomas, 676, 678f Microaneurysms, retinal, 248 Microbleeds, cerebral, 854 Microcephaly in Alpers disease, 956 causes of, 1002 in gangliosidosis, 953 genetic factors in, 1000, 1001t hereditary, 1002 Microdiscectomy, 214 Microencephaly, 998, 1002 Microgliacytes, 643 Microgyrias, 1001 Microphthalmia, 1004 Micropsia, 260, 328 Microsleep, 399

Microsomal ethanol oxidizing system (MEOS), 1179 Micturition bladder function in, 537–539, 552 in spinal cord lesions, 552 syncope after, 392 voluntary control of, 552 Midazolam for acute repetitive seizures, 356 mechanism of action, 1196 for status epilepticus, 354t, 355 in tetanus treatment, 1206 Middle cerebral artery (MCA) cortical branches of, 793, 793f ischemic stroke syndromes of in inferior division, 795 stem (M1) occlusion, 794–795 striatocapsular infarction, 794–795 in superior division, 795 penetrating or lenticulostriate branches of, 794, 794f, 796f Middle molecule theory, 1322 Midodrine, 397, 547, 1097 Migraine abdominal, 183 alternative patterns of, 180–181 in AVMs, 187, 849 basilar, 181, 315 in CADASIL, 182, 826 caffeine and, 179, 188 catamenial, 174, 179, 183 cerebrovascular disease and, 184–185 in children, 179, 181, 183 classic or neurologic, 178t, 179 clinical features of allodynia, 174 aura, 178t, 179, 186–188 hemicranial pain, 179 hemiplegia, 182 neurological symptoms, 179–180, 184, 186–187 seizures, 179, 180, 339 vertigo, 181, 307, 315 visual symptoms, 179–180, 180f common, 178t, 179 with CSF pleocytosis, 182–183 diagnosis of, 186–187 diet and, 189 duration of, 174 footballer’s, 179 genetic factors in, 182 after head injury, 183 hemiplegic, 66, 182, 183 imaging changes in, 185 location of, 173 mechanisms of, 175 in MELAS, 184 menstrual, 174, 179, 183 ocular, 181–182

10/02/23 10:43 AM

Index ophthalmoplegic, 181, 276 oral contraceptives and, 179, 184 pathogenesis of, 186–187 in pregnancy, 179, 183–184 prevalence and incidence of, 5, 5f prevention of, 188–189 retinal, 181–182, 250 in SMART syndrome, 691, 691f vs. stroke, 184, 778 throbbing in, 178t, 179 in TIA, 184–185 transient, in head injury, 889 transient global amnesia and, 450, 451 treatment of, 183, 187–188, 187t trigeminovascular complex in, 186–187 variants of, 180–183 Migratory sensory neuritis (Wartenberg syndrome), 1313 Millard-Gubler syndrome, 66, 802t Miller Fisher syndrome, 118, 1289, 1290 Miller-Dieker syndrome, 1001t, 1002 Miltefosine, 731 Mimocausalgia, 147 Minamata disease, 1212–1213 Minicore disease, 1420 Minimally conscious state, 365–366 Mini-Mental Status Examination (MMSE), 454, 609 Minocycline, 1309 Miosis, 287 Mirror focus, 335 Mirror movements, 61, 1257 Mirror therapy, 820 Mirror writing, 503 Mirtazapine, 1200, 1497t Missile injuries, 896 Mitochondrial disorders categories of, 988, 988t congenital lactic acidosis and recurrent ketoacidosis, 956–957, 991, 1174t deafness in, 302, 304t diagnosis of, 991–992 genetic factors in, 941–942 Kearns-Sayre syndrome. See Progressive external ophthalmoplegia (KearnsSayre syndrome) megaconial, 988 mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). See MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) myoclonic epilepsy with ragged red fibers (MERRF), 988t, 991

Ropper_Index_1519-1606.indd 1569

myopathies, 989, 1397–1398 neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome, 988t, 990–991 neuropathy in, 1333 pleoconial, 988 progressive external ophthalmoplegia. See Progressive external ophthalmoplegia (KearnsSayre syndrome) subacute necrotizing encephalomyelopathy. See Subacute necrotizing encephalomyelopathy (Leigh disease) Mitoxantrone, 930 Mitral cells, 230, 231f Mitral valve prolapse, 777–778 Mixed affective states, 1493 Mixed neuronal-glial tumors, 669, 670f Miyoshi dystrophy, 1401, 1401t MMN (multifocal motor neuropathy), 1321–1322 MMSE (Mini-Mental Status Examination), 454, 609 Möbius syndrome, 277, 1025, 1361, 1376 MoCA (Montreal Cognitive Assessment), 453f, 454, 609 Modafinil, 419 Modified Rankin Outcome Scale (mRS), 790t, 791 MOG (myelin oligodendrocyte glycoprotein), 912, 928 Mohr-Tranebjaerg syndrome, 304t Molindone, 1197 Mollaret meningitis, 703, 743 Molluscum fibrosum, 1018, 1018f Molybdenum cofactor deficiency, 948 Mondini defect, 302 Monge disease (chronic mountain sickness), 1131 Monoamine oxidase (MAO) inhibitors barbiturates with, 1200 for depression, 1496 interactions of, 1200 mechanism of action, 1199, 1495 for narcolepsy, 419 overdose of, 1199–1200 in Parkinson disease treatment, 1081t, 1084 side effects of, 1496, 1497t Monoclonal antibodies, for MS, 926 Monoclonal gammopathy of undetermined significance (MGUS), 1315 Monocular diplopia, 272, 275 Monocytosis, 707 Monomyositis, eosinophilic, 1389

1569

Mononeuropathy (mononeuritis multiplex) axillary nerve, 1343 brachial, 1342–1343. See also Brachial plexus disorders causes of, 1287t, 1306t celiac-sprue, 1313 characteristics of, 1285 common peroneal (fibular) nerve, 1348 in critical limb ischemia, 1309–1310 diabetic. See Diabetic neuropathy diagnosis of, 1337t femoral nerve, 1347 in herpes zoster, 1342. See also Herpes zoster (shingles) in HIV infection, 1313–1314. See also HIV infection idiopathic autonomic, 1312–1313 idiopathic sensory ganglionopathy, 1312 lateral cutaneous nerve of the thigh, 1346–1347 in Lyme disease. See Lyme disease median nerve, 1375–1376 migratory sensory neuritis, 1313 musculocutaneous nerve, 1343 obturator nerve, 1347 pathology of, 1280 radial nerve, 1343 in sarcoidosis, 1310 sciatic nerve. See Sciatic nerve disorders sensory perineuritis, 1313 in Sjögren syndrome. See Sjögren syndrome suprascapular nerve, 1343 tibial nerve, 1348 ulnar nerve, 1344–1345 vasculitic causes of, 1306–1307 in cryoglobulinemia, 1308 drug-induced, 1309 in eosinophilic disorders, 1307–1308 in granulomatosis with polyangiitis, 1308. See also Granulomatosis with polyangiitis (Wegener granulomatosis) isolated (nonsystemic), 1309 in lupus erythematosus, 1308–1309. See also Lupus erythematosus paraneoplastic, 1309 in polyarteritis nodosa, 1307 in rheumatoid arthritis, 1308 Mononucleosis, infectious, 741, 1361, 1368 Monophasia, 496

10/02/23 10:43 AM

1570

Index

Monoplegia, 65–66 Montreal Cognitive Assessment (MoCA), 453f, 454, 609 Mood, 425–426, 517 Mood (affective) disorder, 1489. See also Depression Moore lightning streaks, 243, 261 Morning shakes, in alcohol withdrawal, 88 Moro reflex/response, 585, 593 Morphemes, 492 Morphine, 1190, 1206 Morquio disease (GLB1 mutation), 953, 968t, 969 Morton neuroma, 149 Morvan syndrome (chorée fibrillaire), 1456–1457 Mosaicism, 941 Moschcowitz syndrome. See Thrombotic thrombocytopenic purpura (TTP) Mossy fibers, 114f, 115, 115f Motor compulsions, 1475 Motor cortex accessory, 462 anatomy of, 57f homunculus diagram of, 59, 59f lesions of, 465–466 paralysis in, 61–62 seizures in, 326–327 primary, 462, 463f supplementary, 59–60, 465, 466 Motor endplate, 1370, 1436, 1436f Motor function age-related changes in, 607, 610–611 anatomy of, 54–55 control of, 53 development of, 586, 592–593 disorders of, 53 congenital. See Congenital cerebral motor disorders in frontal lobe lesions, 465–466 in parietal lobe lesions, 63–64 in peripheral neuropathy, 1280–1281 in lacunar stroke, 780 magnetic stimulation of, 38–39 sensory function integrated with, 53, 155 structure of, 53 tests of, 8–9 Motor homunculus, 59, 59f Motor nerve conduction studies, 41t, 43–44, 43f Motor neuron(s), 55–56, 62, 63. See also Lower motor neurons; Upper motor neurons

Ropper_Index_1519-1606.indd 1570

Motor neuron diseases amyotrophic lateral sclerosis. See Amyotrophic lateral sclerosis (ALS) Fazio-Londe disease, 1108t, 1112–1113, 1366 Kennedy syndrome, 1108t, 1112, 1361 with liver disease, 1104 primary lateral sclerosis (PLS), 1102, 1106, 1268 progressive muscular atrophy (PMA), 1105, 1107 spinal muscular atrophy. See Spinal muscular atrophy (SMA) types of, 1102 Motor neuronopathy, 688, 1285 Motor points, 39 Motor unit, 1370 Motor unit potentials (MUPs), 45, 45f, 47–48, 47f, 48f Mountain (high-altitude) sickness, 1131 Mouth burning mouth syndrome and, 200, 237–248 facial pain and, 199 lip paralysis in, 504 taste buds in, 235–236 temporomandibular joint pain in, 199 Movement. See also Gait cerebral control of, 59–60 deceleration of, 116 decomposition of, in cerebellar disease, 115–116 of limbs, spontaneous, in coma, 376 rate, range, and force of, 115, 116 speed in initiation of, 116 Movement disorders alien hand syndrome, 65 apraxia. See Apraxia asterixis, 93 in cerebellar disorders, 115–118 vs. chorea, 80–81 clinicopathologic correlations of, 78, 78t in cortical-basal ganglionic degeneration, 1090 in corticostriatospinal degeneration, 1091 focal dystonias. See Focal dystonias gait disorders. See Gait disorders in Huntington disease, 1069 involuntary movements, 80–82 motor function tests in, 8–9 in multiple system atrophy, 1087 myoclonus. See Myoclonus in neuroacanthocytosis, 1091–1092

paralysis. See Paralysis in Parkinson disease. See Parkinson disease in PSP, 1088–1089 spasticity. See Spasticity startle syndromes, 97 tics and habit spasms, 103–105 tremors. See Tremors Movement stereotypies, 1042 Movements ballistic, 54 mirror, 61 pseudoathetoid, 686 ramp, 54 reflexes and, 54 Moxifloxacin, 708, 718 Moyamoya disease, 782, 824–825, 825f MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine), 73, 77, 1078 MRA. See Magnetic resonance angiography MRI. See Magnetic resonance imaging MRS (magnetic resonance spectroscopy), 25 mRS (Modified Rankin Outcome Scale), 790t, 791 MRV (magnetic resonance venography), 788, 865, 865f MSA. See Multiple system atrophy (MSA) MTTP mutation (Bassen-Kornzweig acanthocytosis), 973, 1333 Mucolipidoses, 950t, 959, 969 Mucopolysaccharidoses β-glucuronidase deficiency, 968t, 969 classification of, 967–968, 968t clinical features of, 968t enzyme abnormalities in, 968 Hunter disease (IDS mutation), 968, 968t Hurler disease (IDUA mutation), 968, 968t Maroteaux-Lamy disease (ARSB mutation), 968t, 969 Morquio disease (GLB1 mutation), 968t, 969 Sanfilippo disease, 968t, 969 Mucormycosis, 728–729, 860 Multifocal conduction block, 1321–1322 Multifocal motor neuropathy (MMN), 1321–1322 Multiple myeloma, 1316–1317 Multiple sclerosis (MS) acute and tumor-like, 918, 919f age at onset of, 910 in children, 918 clinical course and prognosis of, 921–922

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Index clinical features of in acute attacks, 916 early symptoms and signs, 913, 923 in established disease, 916–917 myelitis, 914–916, 915f ophthalmoplegia, 279–280 optic neuritis, 254, 913–914, 925 paraplegia, 67 peripheral neuropathy, 919 spasm, 85 typical, 909 CSF examination in, 14t, 17, 920 demyelination in, 912–913, 1244, 1357, 1357f diagnosis of, 909, 921, 922t differential diagnosis of, 922–924 EEG in, 35 epidemiology of, 910–911 etiology of, 910–911 evoked potentials in, 36, 921 genetic factors in, 911 histologic patterns in, 909 historical aspects of, 908 HLA antigens in, 911 imaging in, 920–921 lupus erythematosus and, 865 vs. NMO, 928–929 oligodendrocytes in, 910 pathogenesis of, 911–912 pathologic findings in, 909–910 plaque in, 909 pontine, 679 precipitating factors in acute attacks, 918 pregnancy in, 922 prevalence and incidence of, 5, 5f, 6t, 910, 911 primary progressive, 909 relapsing-remitting, 909 remyelination in, 913 spinal, 923–924 vs. stroke, 774 treatment of corticosteroids for, 924–925, 1244 general measures for, 927–928 glatiramer for, 926 history of, 924 immunosuppressants for, 927 interferons, 925–926 monoclonal antibodies for, 926 oral agents for, 926–927 tremor in, 91 vertigo in, 315 vision in, 913 vitamin D in, 910–911 white matter lesions in, 923 Multiple system atrophy (MSA) autonomic failure in, 393, 546–547 clinical features of, 1086–1087 diagnosis of, 1087

Ropper_Index_1519-1606.indd 1571

historical aspects of, 1086 with olivopontocerebellar atrophy (MSA-C), 547, 1087, 1099, 1099f pathology in, 1087–1088 REM sleep behavior disorder in, 411, 413 rigidity in, 79 striatonigral degeneration in, 1086 Mumps meningitis, 741 Munchausen’s syndrome, 1483 MUPs (motor unit potentials), 45, 47–48, 47f, 48f Murine typhus, 729 Murray Valley encephalitis, 745 Mus musculus, 741 Muscarinic receptors, 536 Muscle(s) actions and nerve root supply of, 1284t–1285t age-related changes in, 612–613, 1372 agonist or prime mover, 56–57 anatomy of, 1370–1372, 1371f antagonist, 56–57 articulatory, spasm of, 597 in ataxia-telangiectasia, 1024 atrophy of age-related, 1372 in denervation, 56, 66 in electrical injuries, 1235 peroneal, 1324 progressive, 1109–1113 benign fasciculations of, 1375, 1458 biopsy of, 50, 1375, 1384, 1385 congenital absence of (amyotonia), 1419 continuous fiber activity in, 1459 contractions of abnormalities and changes in, 1373–1376 idiomuscular, 1374 isokinetic, 1373 isometric, 54, 543 isotonic, 54 mechanism of, 1370 in myasthenic states, 1373–1374 contractures of congenital focal fibrous, 1418–1419 in Duchenne muscular dystrophy, 1391 fibrous (myostatic), 1375 flexion, 1383 passive stretching for, 1405 physiologic, 1375, 1407, 1457 pseudocontracture, 1375 Volkmann, 1375 cramps of. See Cramps CT of, 49 development of, 1372

1571

diseases of affecting membrane excitability, 1457–1458 approach to the patient with changes in contractile process, 1373–1376 topographic patterns of myopathic weakness, 1376–1379 with weakness and paralysis, 1284t–1285t, 1373 channelopathies. See Channelopathies with cramp, spasm, and pain, 1422–1423 localized masses, 1425–1427 muscular dystrophies. See Muscular dystrophies myalgic states, 1424–1425 differential diagnosis of, 1425 fibromyalgia. See Fibromyalgia polymyalgia rheumatica. See Polymyalgia rheumatica myopathies. See Myopathy(ies) neuromuscular junction disorders. See Neuromuscular junction disorders spinal muscular atrophy. See Spinal muscular atrophy (SMA) susceptibility differences in, 1371 extraocular. See Extraocular muscles fibers of, 1371 fibrillation of, EMG in, 46, 46f fixator, 54 hyperexcitability of, 1460–1461 imaging of, 49 in monoplegia, 66 MRI of, 49 myokymia in, 1459 pain in, 140, 1375 paralysis of single or group of, 1379 regeneration of, 1371–1372 relaxation of, 80 rippling of, 1374 of spine, 203, 205, 208–209 strength testing of, 8–9, 1373 stretch (tendon) reflex of, 55, 55f sustained isometric contraction of, 543 synergist, 54 tone of, 56 in cerebellar disease, 116, 117–118 in Huntington disease, 1069 rigidity in, 79–80 weakness of. See Weakness Muscle-eye-brain disease, 1001t, 1402t, 1403 Muscle-specific kinase (MuSK), 1438

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1572

Index

Muscular dystrophies Becker, 1374t, 1392–1393 classification of, 1374t, 1390–1391 congenital, 1402–1404, 1402t differential diagnosis of, 1388, 1403–1404 distal, 1400–1401, 1401t Duchenne. See Duchenne muscular dystrophy (DMD mutation) Emery-Dreifuss, 1374t, 1394, 1394f facioscapulohumeral, 1394–1395, 1396t Fukuyama, 1001t, 1002, 1403 gait disorders in, 126 historical aspects of, 1390–1391 infantile, 1033 Landouzy-Dejerine, 1394–1395 limb-girdle. See Limb-girdle muscular dystrophy (LGMD) myotonic. See Myotonic dystrophy oculopharyngeal, 1396t, 1398 scapuloperoneal, 1374t, 1395 treatment of, 1404–1405 Musculocutaneous nerve neuropathy, 1343 Mushroom poisoning, 1208 Music recognition, 471 Musician’s spasm, 101 MuSK (muscle-specific kinase), 1438 Mutilating hereditary sensory polyneuropathy, 1330 Mutism akinetic, 366, 426 in Broca aphasia, 496 word, 495t, 501 Myalgia with cramps and myoglobinuria, 1393 diseases associated with, 1424 exercise inducing, 1425 in fibromyalgia. See Fibromyalgia influenzal, 1381 in polymyalgia rheumatica. See Polymyalgia rheumatica Myalgic encephalomyelitis, 513 Myalgic-cramp-myoglobinuric syndrome, 1394 Myasthenia gravis in children, 1435 cholinergic crisis in, 1443 clinical grading of, 1434–1435 clinical manifestations of, 1433–1434, 1444t congenital, 1445–1446, 1446t course and prognosis of, 1435 depression in, 1439 diagnosis of accuracy of testing in, 1438–1439 AChR antibody measurements in, 1438

Ropper_Index_1519-1606.indd 1572

electrophysiologic testing in, 1437–1438 neostigmine testing in, 1438 differential diagnosis of, 1439–1440 vs. botulism, 1439 vs. Guillain-Barré syndrome, 1292–1293, 1439 vs. Lambert-Eaton myasthenic syndrome, 1443 in elderly, 1442 epidemiology of, 1433 etiology and pathogenesis of, 1437, 1444t historical aspects of, 1432–1433 with hyperthyroidism, 1412 incidence of, 1433 motor endplate alterations in, 1436, 1436f muscle contractions in, 1373 myasthenic crisis in, 1442–1443 neonatal, 1445 in pregnancy, 445 thymic and systemic disorders associated with, 1435–1437 thyrotoxicosis in, 1437 treatment of anticholinesterase drugs for, 1440, 1440t azathioprine and other immunosuppressive drugs for, 1440–1441 corticosteroids for, 1440 cyclophosphamide for, 1441 immunoglobulin for, 1441 mycophenolate for, 1441 plasma exchange for, 1441 thymectomy for, 1441–1442 weakness in, 1433–1434 Myasthenic crisis, 1442–1443 Myasthenic-myopathic syndrome of Lambert-Eaton. See Lambert-Eaton myasthenic syndrome MYCN oncogene, 642t, 643 Mycobacterium leprae, 1322 Mycophenolate in antiphospholipid antibody disease treatment, 868 for dermatomyositis, 1386 in myasthenia gravis treatment, 1441 for polymyositis, 1386 Mycoplasma, 196 Mycoplasma pneumoniae infections, 706–707, 745, 1381 Mycotic aneurysms, 845–847 Mydriasis, 287, 288 Myelin oligodendrocyte glycoprotein (MOG), 912, 928 Myelination, 582–583, 582t, 584f

Myelinolysis, central pontine. See Central pontine myelinolysis (CPM) Myelitis diffuse, disseminated, 1236 inflammatory and infectious bacterial, 1238 classification of, 1236–1237 fungal, 1242 in HIV infection, 756, 1237–1238 HTLV-I. See Tropical spastic paraparesis HTLV-II, 758 parasitic, 1242 sarcoid, 1238–1239. See also Sarcoidosis spinal cord abscess, 1238, 1241 spinal epidural abscess, 219, 1236, 1239–1240, 1240f, 1241 syphilitic, 724, 1238, 1239. See also Neurosyphilis tropical spastic paraparesis. See Tropical spastic paraparesis tuberculous, 219, 1241–1242, 1242f vertebral, 219, 1241 viral, 1237–1238 zoster, 752 longitudinally extensive, 1236 noninfectious inflammatory, 1237, 1242 in Behçet disease, 1247 Foix-Alajouanine myelopathy, 1246 in lupus erythematosus, 1246 in MS, 914–916, 915f, 1244. See also Multiple sclerosis (MS) neuromyelitis optica. See Neuromyelitis optica (NMO) paraneoplastic, 1247 postinfectious and postvaccinal, 1242–1244, 1243f in rheumatologic disease, 1246 in Sjögren syndrome, 1246–1247. See also Sjögren syndrome spinal arachnoiditis. See Arachnoiditis subacute spinal neuronitis, 1247–1248 transverse, 1236, 1243 Myelography, 19, 21f, 208 Myelomalacia, 1238 Myeloneuropathy, hypocupric, 978–979, 1262 Myeloopticoneuropathy, subacute, 1219 Myelopathy. See also Myelitis; Spinal cord disorders HTLV-I. See Tropical spastic paraparesis neoplastic. See Spinal cord tumors

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Index nutritional and toxic in copper deficiency, 978–979, 1262 lathyrism, 1207, 1262–1263 subacute combined degeneration of spinal cord, 908, 1262 paraneoplastic, 688 after radiation therapy, 1233–1235 after spinal anesthesia, 1236 in spinal column disorders. See Spinal column disorders surfer’s, 1251–1252 in syringomyelia. See Syringomyelia traction, 1008 Myeloradiculitis, 718 Myerson sign, 285, 1075 Myoadenylate deaminase deficiency, 1425 Myocardial infarction, 779 Myoclonic epilepsy with ragged red fibers (MERRF), 988t, 991 Myoclonus action, 96 Baltic, 95 causes of, 95t in cerebellar disease, 118 cherry-red spot, 95, 975 vs. chorea, 80–81 definition of, 93 dementia and, 96 diffuse, 94–96 essential, 94 focal, 94 hereditary essential benign, 1101–1102 in Lance-Adams syndrome, 1130 in middle ear, 299 in neonates, 411 ocular, 117 opsoclonus and, 1033 palatal, 92–93 pathophysiology of, 96 postanoxic, 96 regional, 94 segmental, 94 seizures and, 94–95, 324–325, 337–338, 338t in somnolescent starts, 411 spinal, 1247–1248 in subacute sclerosing panencephalitis, 763 in subacute spongiform encephalopathy, 766 Myoedema, 1374 Myofascial pain syndrome, 149–150 Myofibrillar myopathy, 1396t, 1403 Myofibrils, 1370, 1371f Myogelosis, 1376 Myoglobinuria, 1394, 1416

Ropper_Index_1519-1606.indd 1573

Myokymia EMG in, 46, 47 facial, 1362 muscle activity in, 1375, 1459 superior oblique, 276 Myonecrosis, 1194 Myopathy(ies) Bethlem, 1396t, 1402 congenital deformities absence of muscles (amyoplasia), 1419 arthrogryposis, 1375, 1418, 1418t focal fibrous contractures, 1418–1419 restricted nuclear amyotrophies, 1419 congenital structural, 1419–1420, 1419t, 1422 central core, 1419t, 1420–1421 centronuclear (myotubular), 1419t, 1421–1422 myofibrillar. See Muscular dystrophies nemaline (rod-body), 1419t, 1421 with tubular aggregates, 1422 critical illness, 560, 1295, 1413 in Cushing disease, 1413 desmin, 1401t drug- and toxin-induced, 1414–1418, 1415t endocrine in acromegaly, 1414 in adrenocortical insufficiency, 1414 corticosteroid, 1412–1413 in parathyroid disease, 1414 thyroid, 1411 in vitamin D deficiency, 1414 immune-inflammatory causes of, 1415t classification of, 1381 clinical features of, 1415t dermatomyositis. See Dermatomyositis historical aspects of, 1381 immune-mediated necrotizing, 1382 inclusion body myositis. See Inclusion body myositis (IBM) polymyositis. See Polymyositis infectious, 756, 1379–1381 mitochondrial, 989, 1397–1398, 1415t MUPs in, 48, 48f necrotizing (rhabdomyolysis), 1414–1416, 1415t, 1445 sarcoid, 1390. See also Sarcoidosis spinal muscular atrophy. See Spinal muscular atrophy (SMA) Ulrich, 1402 Myophosphorylase deficiency. See Phosphorylase deficiency (McArdle disease)

1573

Myositis granulomatous, 1390 inclusion body. See Inclusion body myositis (IBM) nodular, 1390 orbital, 1389–1390 Myositis ossificans, 1426–1427 Myotonia. See also Channelopathies acetazolamide-responsive, 1452 definition of, 1374 EMG in, 47, 47f generalized (Becker disease), 1448t, 1450 historical aspects of, 144 painful congenital, 1452 paradoxical, 1374, 1449 pathophysiology of, 1452–1453 percussion, 1374 Myotonia congenita (Thomsen disease) clinical features of, 68, 1449 diagnosis of, 47, 47f, 1450 genetic factors in, 1447, 1448t historical aspects of, 1449 pathophysiology of, 1452–1453 precipitating factors in, 1448t, 1449 ptosis in, 285 treatment of, 1448t, 1450 Myotonia fluctuans, 1452 Myotonia levior, 1449–1450 Myotonia permanens, 1452 Myotonic dystrophy congenital, 1400 proximal (DM2, CMBP mutation), 1398, 1400 type 1 (DM1, DPMK mutation) clinical features of, 1396t, 1398–1400 genetic factors in, 1396t pathologic features of, 1400 ptosis in, 285 vs. spinal muscular atrophy, 1111 Myotubes, 1372 Myotubular (centronuclear) myopathy, 1419t, 1421–1422 Myxedema, 1148–1149, 1517 N N-acetyl aspartate (NAA), 25 N-acetyl glutamate synthetase, 946 NAD (nicotinic acid dehydrogenase), 1179 NADH (nicotinamide adenine dinucleotide), 1179 Naegleria, 731 Nafcillin, 704, 704t Naffziger sign, 206 Nalmefene, 1191

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1574

Index

Naloxone for insensate patient, 384 mechanism of action, 141 in opioid overdose treatment, 1191 in opioid use disorder treatment, 1193, 1194 for spinal shock, 549 Naltrexone, 1189, 1193, 1194 Nanocephalic dwarfism, 1004 Naphthalene, 1215 Naproxen, 151t Naratriptan, 187t Narcissistic personality disorder, 1471t Narcolepsy, 417–419 Narcotic analgesics. See Opioid(s) NARP (neuropathy, ataxia, retinitis pigmentosa) syndrome, 988t, 990–991 Nasopharyngeal transitional cell carcinoma, 681 Natalizumab, 926 National Institute of Health Stroke Scale (NIHSS), 790, 790t Natriuresis, ANF in, 572 Nausea, hormone levels in, 568 Nebulin, 1370 Neck pain in, 220–226 stiffness of in bacterial meningitis, 699 in brain abscess, 714 in intracerebral hemorrhage, 833 in subarachnoid hemorrhage, 844 weakness of, 1377 wry, 999 Neck-tongue syndrome, 200, 1366 Necrosis, of spinal cord, 1229, 1234, 1245f Necrotic myelopathy, 1245f Necrotizing leukoencephalopathy, 662 Necrotizing myelitis, 1244–1246 Necrotizing myopathy (rhabdomyolysis), 1409, 1414–1416, 1415t Nefazodone, 1200, 1497t Neglect auditory, 478 hemispatial, 475–476 sensory, 171 visual, 477 Neglect syndromes, 424 Negri bodies, 749 Negro sign, 90 Neisseria meningitidis. See Meningococcal meningitis Nelson syndrome, 572 Nemaline (rod-body) myopathy, 1419t, 1421 Nematode infections, 732–733, 733t Neocerebellum, 109, 110t

Ropper_Index_1519-1606.indd 1574

Neocortex, 460 Neomycin, 1136 Neonates. See also Infants Apgar score in, 585, 585t ataxia in, 1032–1033 bacterial meningitis in, 700, 1038 botulism in, 1206 congenital rigidity in, 1460 cranial malformations in, 998–999 encephalopathy in, 1027–1028 growth and development of anatomic basis of, 582–583, 584f language, 591 motor, 586 physiology of, 585–586 sensory, 589 herpes zoster in, 1038 hypoglycemia in, 1030–1031 hypotonia in, 594 infections in. See Intrauterine and neonatal infections inherited metabolic diseases in biopterin deficiency, 945 branched-chain aminoacidopathies, 947–948 diagnosis of, 945t, 948–949 estimated frequency of, 944–945, 944t galactosemia. See Galactosemia hyperammonemias, 946–947 neurologic assessment of, 943–944 organic acidemias, 948 organic acidurias, 946 sulfite oxidase deficiency, 948 vitamin-responsive aminoacidopathies, 945, 1174t myasthenia gravis in, 1445–1446 myoclonus in, 411 myotonic dystrophy in, 1400 myxedema in, 1148–1149 seizures in in biopterin deficiency, 945 causes of, 340–341, 340f, 340t hypocalcemia and hypoglycemia in, 948–949 pyridoxine-dependent, 945 treatment of, 353 sleep in, 399 Neoplasia, 642 Neostigmine test, 1438 Neri sign, 206 Nerve(s) age-related changes in, 612–613 biopsy of, 50 imaging techniques for, 49 muscle actions and, 1284t–1285t Nerve conduction studies in back pain, 208 blink responses in, 43

CMAP amplitude in, 39–40, 40f, 41t in conduction block, 41–42 conduction velocities in, 40, 42f in demyelinating neuropathies, 43 distal latencies in, 40, 42f F waves in, 42–43, 43f H reflex in, 42, 43f motor, 41t, 43–44, 43f sensory, 40, 41t, 42f techniques for, 39 in thoracic outlet syndrome, 225 Nerve deafness. See Sensorineural deafness Nerve entrapment, 1334 Nerve injury, 149 Nervous system neoplasms. See Central nervous system neoplasms Nervousness, 515. See also Anxiety Neural tube, 998 Neuralgia ciliary, 190 cluster headache and, 190 of cranial nerves, 196–200 definition of, 146 glossopharyngeal, 197, 1363 syncope with, 391–392 in herpes zoster infections, 197 laryngeal, 1365 migrainous, 178t, 190 occipital, 198 petrosal, 190 postherpetic, 197, 753 sphenopalatine, 190 trigeminal (tic douloureux), 196–197 trigeminal, idiopathic, 1356 vagoglossopharyngeal, 197 vidian, 190 Neurasthenia, 512 Neurinoma of trigeminal ganglion, 674 Neuritic plaque, 611–612, 1059 Neuritis brachial, 1340–1342 experimental allergic, 1290 facial nerve, 1358 herpes zoster, 1342 lumbosacral plexus, 216 migratory sensory, 1313 of multiple cranial nerves, 1368 optic. See Optic neuritis retrobulbar, 255, 914 vestibular, 313 Neuroacanthocytosis, 1091–1092 Neuroaxonal dystrophy/degeneration (PLA2G6 mutation), 965–966 Neuroblastoma, 666 Neurocardiogenic syncope, 387, 390–391, 397 Neurocirculatory asthenia, 1472

10/02/23 10:43 AM

Index Neurodegeneration with brain iron accumulation (HallervordenSpatz disease), 84, 979, 979f Neuroectodermal tumors, primitive, 667 Neuroectodermoses, congenital. See Phakomatoses (congenital neuroectodermoses) Neuroepithelial tumors, 669, 670f Neurofibrillary tangles, 611–612, 1059–1062, 1059f Neurofibroma, 148, 672, 1263 Neurofibromatosis of von Recklinghausen cause and pathogenesis of, 1017 diagnosis of, 1020 epidemiology of, 1017 imaging of, 1020, 1021f treatment of, 1020 type 1 (NF1) café-au-lait spots in, 1018, 1018f carotid body tumor in, 675 cause of, 1017 clinical manifestations of, 1017–1019, 1018f, 1018t, 1019f hamartoma of iris in, 1019, 1019f incidence of, 672 molluscum fibrosum in, 1018, 1018f optic nerve glioma in, 258 vestibular schwannoma in, 672 type 2 (NF2) bilateral vestibular schwannoma in, 672, 672f, 1019 cause of, 1017 hearing loss in, 301, 303t Neurofibromin, 1017 Neurogenic claudication, 216 Neurogenic ergotism, 1207 Neurogenic inflammation, 140 Neurogenic or neuropathic pain, 146–148 Neurohypophysis, 567 Neuroleptic malignant syndrome (NMS) antipsychotics and, 1512t clinical features of, 574, 1198–1199 differential diagnosis of, 432, 1199 phenothiazines and, 1198 treatment of, 1199 Neurologic diagnosis anatomic, 3, 4 audiometry in, 49 biopsy of brain, nerve, muscle, and skin in, 50 common mistakes in, 5 CSF examination in. See Cerebrospinal fluid (CSF) EEG in. See Electroencephalography (EEG)

Ropper_Index_1519-1606.indd 1575

EMG in. See Electromyography (EMG) etiologic, 3, 4 evoked potentials in. See Evoked potentials functional, 3 general medical examination in, 10 genetic testing in, 49 history-taking for, 6 imaging techniques in. See Imaging techniques laboratory tests in, 11. See also specific tests magnetic stimulation of motor function in, 38–39 nerve conduction studies in. See Nerve conduction studies neurologic disease categories in, 4, 4t neurologic examination in, 6–10, 9t neuropsychological tests in, 49 pathologic, 3 perimetry in, 49 potential problems in, 11 repeated examinations in, 4 steps in, 3–4 syndromic, 3, 4 topographic, 3 treatment options and, 11–12 vestibular testing in, 49 Neurologic disease, prevalence and incidence of, 5, 5f, 6t Neurologic examination in anxiety, depression, psychosis and hysteria, 10 brief, 9t cerebral cortex function tests in, 7–8 in coma, 10, 376–379 cranial nerve tests in, 7–8 focus and thoroughness of, 7 gait and stance tests in, 9 history-taking and, 6–7 in infants and children, 10 of mental status, 7 motor function tests in, 8–9 of neonates with metabolic disease, 943–944 reflex testing in, 8–9 sensory function testing in, 9, 163–167 in spinal cord trauma, 1227–1229, 1229f symptoms of neurologic disorders and, 7 Neurological subspecialties, 4t Neurology, definition of, 3 Neurolymphomatosis, 657, 662 Neuroma acoustic. See Vestibular schwannoma formation of, 149 nerve pain in, 146 plexiform, 1019, 1020

1575

Neuromodulators, in basal ganglia, 77 Neuromuscular dysarthria, 504–505 Neuromuscular junction disorders congenital myasthenic syndromes, 1445–1446 drug-induced, 1447 Lambert-Eaton myasthenic syndrome. See Lambert-Eaton myasthenic syndrome myasthenia gravis. See Myasthenia gravis neonatal myasthenia gravis, 1445 oropharyngeal weakness in, 559 paraneoplastic, 689 respiratory disorders in, 559 toxin-related, 1447 Neuromyasthenia, epidemic, 1381 Neuromyelitis optica (NMO) clinical features of, 255, 929, 1245 diagnosis of, 929, 929f, 1245–1246 differential diagnosis of, 929–930 with IgG positivity, 929, 1245 imaging in, 1245, 1245f immunologic features of, 928, 1245 vs. MS, 928–929 paraneoplastic, 688 prevalence of, 929 treatment of, 930, 1246 Neuromyotonia, 284, 1456–1457, 1459 Neuron(s) granulovacuolar degeneration of, 1059 migration in embryonic cortical development, 999–1002, 1001t sensory, disorders of, 168–169 Neuronal cell adhesion protein antibodies, 413 Neuronal ceroid lipofuscinoses juvenile (Batten disease), 974 late juvenile and adult (Kufs disease), 974–975, 986 pathology of, 967 signs of, 958 types of, 950t, 967 Neuronitis, subacute spinal, 1247–1248 Neuronopathy motor, 688, 1285 sensory, 168–169, 1285, 1296 Neuropathic pain. See Pain, neurogenic or neuropathic Neuropathy. See also Mononeuropathy; Peripheral neuropathy; Polyneuropathy; specific nerves classification of, 1286t–1287t pathogenesis of, 1277–1278 topographic and clinical patterns of, 1283, 1285–1286 trigeminal, 1357f, 1358

10/02/23 10:43 AM

1576

Index

Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome, 988t, 990–991 Neuropsychological tests, 49 Neuroretinitis, 255 Neuroserpinopathy, 1068 Neurosyphilis asymptomatic, 721 clinical syndromes of, 720 congenital, 1037–1038 CSF examination in, 720 diagnosis of, 720–721, 721f etiology and pathogenesis of, 719–720 in HIV infection, 757 meningeal, 721, 1239 meningovascular, 721–722 nerve deafness and vestibulopathy in, 301, 724 optic atrophy in, 723–724 paretic, 722 spinal, 724, 1239 tabetic, 722–723 Neurotoxicology, 1177–1178 Neurotoxin fish poisoning, 1208, 1293, 1447 Neurotransmitters age-related changes in, 612 in Alzheimer disease, 1062 in autonomic nervous system, 536–537 in cerebellar cortex, 113–115, 114f, 115f in cortical-basal ganglia-thalamus circuit, 73, 74f–75f, 75–77 in corticospinal tract, 56 in ischemic stroke, 785–786 in limbic system, 522 in schizophrenia, 1509–1510 in spasticity, 63 in spinal shock, 549 Neutrophils, in CSF, 697, 701 New daily persistent headache, 192 New Orleans criteria, for CT after concussion, 888, 888t NF1. See Neurofibromatosis of von Recklinghausen, type 1 NF2. See Neurofibromatosis of von Recklinghausen, type 2 Niacin (nicotinic acid) deficiency (pellagra), 1162–1163 Nicotinamide, 1174t Nicotinamide adenine dinucleotide (NADH), 1179 Nicotinic acid dehydrogenase (NAD), 1179 Nicotinic receptors, 536 Niemann-Pick disease (sphingomyelinase deficiency) in adults, 987 biochemical abnormalities in, 950t

Ropper_Index_1519-1606.indd 1576

differential diagnosis of, 959t in infants, 952–953 in late infancy–early childhood, 966 signs of, 959 Nifedipine, 189, 551, 858 Nifurtimox, 732 Night eating, 413 Night palsy, 417. See also Narcolepsy Night terrors, 412 Nightmares, 412 NIHSS (National Institute of Health Stroke Scale), 790, 790t Nimodipine, 845 Ninth cranial nerve. See Glossopharyngeal (ninth) nerve Nissl bodies, 1162 Nitric oxide, 191–192, 537 Nitrobenzene, 1215 Nitrofurantoin, 1302 Nitrosoureas, 1217 Nitrous oxide, 1301 N-methyl-D-aspartate (NMDA) receptors age-related changes in, 612 in alcohol pharmacology, 1180 in CRPS, 147 in ischemic stroke, 786 NMO. See Neuromyelitis optica NMO spectrum disorders (NMOSD), 929, 1245–1246 NMS. See Neuroleptic malignant syndrome (NMS) Nociception, 134, 155 Nocturnal enuresis, 420, 603 Nocturnal epilepsy, 414 Nodes of Ranvier, 1277 Nodose ganglion, 1363, 1364f Nodular myositis, localized, 1390 Noïka-Froment sign, 1074 Noise exposure, hearing loss from, 301 Nonaka myopathy, with rimmed vacuoles, 1401t Nonconvulsive status epilepticus, 433–444 Non-Hodgkin lymphoma, 683 Nonparalytic poliomyelitis, 59 Nonpoliovirus poliomyelitis, 760, 760f Nonrapid eye movement sleep. See Sleep, NREM Nonrecruiting deafness, 298 Nonsteroidal anti-inflammatory drugs (NSAIDs), 187 Nontonal tinnitus, 298–299 Norepinephrine age-related changes in, 612 in autonomic failure, 546 in autonomic nervous system, 536

for blood pressure management, 903 in limbic system, 522 Normal-pressure hydrocephalus (NPH) diagnosis of, 626–627, 627f differential diagnosis of, 610, 1259 in elderly, 625 gait disorders in, 124t, 128–129, 625–626 in head injury, 626 imaging of, 626, 627f LP in, 626 memory disorders in, 626 monitoring, 627 vs. Parkinson disease, 1076 shunting for, 635, 635f treatment of, 627–629 Normokalemic periodic paralysis, 1451 Norrie disease, 1003–1004 Nortriptyline, 1200, 1497t NOTCH mutations, 827 Nothnagel syndrome, 802t NPH. See Normal-pressure hydrocephalus (NPH) NREM narcolepsy, 419–420 NREM (nonrapid eye movement) sleep. See Sleep, NREM NSAIDs (nonsteroidal antiinflammatory drugs), 187 Nuclear palsy, 263 Nucleoside reverse transcriptase inhibitors, 756 Nucleus of the tractus solitarius (NTS), 535, 537, 556f, 557, 561 Nucleus pulposus, 204, 205, 210, 213f Nurr1, 1079 Nutritional deficiencies in alcohol use and alcoholism. See Alcohol use and alcoholism, nutritional deficiencies in anosmia and, 233–234 cobalamin. See Vitamin B12 (cobalamin), deficiency of developmental delay and, 1042 fatigue in, 512 folate, 1164 in malabsorption, 1173–1174, 1173t in Marchiafava-Bignami disease, 1171–1172 optic neuropathy and, 257 pantothenic acid, 1164 pellagra, 1162–1163 polyneuropathy (neuropathic beriberi) in clinical features of, 1160–1161, 1160t, 1299, 1322 etiology of, 1159, 1299 pathologic features of, 1161 pathophysiology of, 1161 treatment and prognosis of, 1161

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Index protein-calorie malnutrition, 1173–1174 pyridoxine, 1163 riboflavin, 1162 in spinal spastic and ataxic syndrome, 1169 in Strachan syndrome, 1170 taste sense and, 236 thiamine. See Thiamine (vitamin B1), deficiency of vitamin A, 1169 vitamin D, 1169, 1414 vitamin E, 1096t, 1097, 1168–1169 in Wernicke-Korsakoff syndrome. See Wernicke-Korsakoff syndrome Nyctalopia, 239, 251 Nystagmus benign paroxysmal positional vertigo and, 310 in brainstem disorders, 282 caloric-induced, 281 central vs. peripheral origin of, 315, 315t, 316t in cerebellar disease, 117, 282 in children, 282 congenital, 282 convergence, 283 downbeat, 282 drug-induced, 280 gaze-evoked, 267, 282 infantile, 282, 955 jerk, 280 of labyrinthine origin, 281 latent, 282 in lateral medullary syndrome, 805 in Ménière disease, 309 in MS, 916 in ophthalmoplegia, 280–281 optokinetic, 264, 281 oscillopsia and, 281 palatal, 92 pendular, 92, 280, 282, 955 periodic alternating, 283 retraction, 283 seesaw, 283 upbeat, 282 vertigo and benign paroxysmal positional, 311f, 312f, 313 in caloric stimulation, 308 causes of, 307 vestibular, 281, 313 in Wernicke-Korsakoff syndrome, 1155, 1157 O Obsessive-compulsive disorder, 1471t, 1475–1476 Obstructive sleep apnea, 416 Obtundation, 363

Ropper_Index_1519-1606.indd 1577

Obturator nerve neuropathy, 1343t, 1347 Occipital condyle tumors, 682t Occipital driving response, in EEG, 29f, 36 Occipital lobe, 459, 462, 479 Occipital lobe lesions agnosias in, 481–483 anosognosia in, 480 clinical effects of, 479–483 cortical blindness in, 480 metamorphopsia in, 480 visual field defects in, 479–480 visual hallucinations in, 480–481 Occipital neuralgia, 198 Occipitonuchal headache, 647 Occult hydrocephalus, 624, 625f Ocrelizumab, 926 OCT (optical coherence tomography), 921 Octreotide, 678 Ocular bobbing, 283 Ocular dipping, 283, 377 Ocular flutter, 284 Ocular neuromyotonia, 284 Ocular tilt reaction, 280 Oculoauriculocephalic anomalies, 1004 Oculoauriculovertebral dysplasia, 1004 Oculocephalic reflexes, 373 Oculocerebral syndrome with hypopigmentation, 1004 Oculocerebrorenal (Lowe) syndrome, 957, 959, 960 Oculoencephalic defects, 1003–1004 Oculogyric crisis, 269, 283 Oculoleptomeningeal amyloidosis, 637 Oculomandibulodyscephaly with hypotrichosis, 1004 Oculomasticatory myorhythmia, 709 Oculomotor (third) nerve anatomy of, 269–270, 270f, 271f apraxia of, congenital, 269 disorders of causes of, 275t, 276 clinical effects of, 273 after head injury, 881 in horizontal gaze, 264–266, 265f in Huntington disease, 1069 in multiple cranial nerve palsies, 1368 ptosis in, 285 in temporal lobe herniation, 374t in vertical gaze, 266 in vertigo, 306 Oculopalatal tremor, 283 Oculopharyngeal dystrophy (PABN1 mutation), 1396t, 1398 Oculopharyngeal palsy. See Bulbar palsy Oculosympathetic syndrome. See Horner syndrome

1577

Odontoid fracture, 1228t Odontoid process abnormalities, 1261 Odor. See Smell sense Olanzapine, 1065, 1512, 1513t Olfactory bulb, 230–231, 231f Olfactory cortex, 231, 231f Olfactory fila, 230 Olfactory groove, 230, 234, 679 Olfactory (first) nerve, 230–232, 231f Olfactory receptor cells, 230 Olfactory sense, 230–232, 231f. See also Smell sense Olfactory striae, 231, 231f Olfactory tract, 230–231, 231f Oligodendrocytes, 643, 910 Oligodendroglioma clinical features of, 653 genetic factors in, 649, 653 incidence of, 641t intraspinal, 1263 MRI in, 653, 653f papilledema in, 254 treatment of, 653–654 Oligopeptides, 568 Oligosaccharidoses, 969–970 Olivary nuclei, 112 Olivopontocerebellar atrophy (OPCA), 547, 1086, 1099. See also Multiple system atrophy Oncogenes, 643 Ondansetron, 562 Ondine’s curse, 416, 558 One-and-a-half syndrome, 280, 916 Onuf nucleus, 534, 538–555 OPA3 mutation, 1114 Operculum, 497 Ophthalmic herpes, 752 Ophthalmic nerve, 881, 1355, 1358 Ophthalmodynia, 174 Ophthalmoparesis, 267, 278–279 Ophthalmoplegia acute, 278, 278t bilateral, 265, 278, 279, 916 cavernous sinus syndrome and, 277–278 chronic, 278 diabetic, 1304 dizziness in, 306 exophthalmic, 1411 in Guillain-Barré syndrome, 278, 1289 in Lambert-Eaton myasthenic syndrome, 278 medial longitudinal fasciculus in, 279–280 in migraine, 181, 276 in MS, 279–280 nystagmus in, 280–281 painful, 277t

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1578

Index

Ophthalmoplegia (Cont.): progressive external. See Progressive external ophthalmoplegia (Kearns-Sayre syndrome) temporal arteritis and, 194 thyroid, 279, 1411 unilateral, 278 Ophthalmoscopic examination, 240–241 Opiate receptors, 137 Opioid(s) clinical effects of, 1190 definition of, 1190 mechanism of action, 137, 141 for migraine, 182 naloxone reversal of, 141 overdose, 382t, 1190–1191 for pain, 150, 151t tolerance to, 1192 types of, 1190 Opioid addiction (opioid use disorder) abstinence (withdrawal) syndrome in, 1192–1193 diagnosis of, 1193 dysphoria in, 193 etiology and pathogenesis in, 1191–1192 euphoria in, 1191 incidence of, 1191 medical and neurologic complications of, 1194 pharmacologic criteria of, 1192 phases of, 1192 treatment of, 1193–1194 Opisthotonos, 1032 Oppositional resistance, 80 Opsoclonus, 96, 117, 283–284 Opsoclonus-myoclonus syndrome, 966–967, 1033 Opsoclonus-myoclonus-ataxia syndrome, 688 Optic ataxia, 475, 483 Optic atrophy hereditary spastic paraplegia with, 1114 Leber hereditary, 257, 1004, 1115 in papilledema, 253, 253f syphilitic, 723–724 Optic chiasm, 244, 244f, 258–269 Optic disc, 244, 252–253, 253f, 254t Optic (second) nerve diseases/lesions of atrophy. See Optic atrophy developmental abnormalities, 257–258 glioma, 258, 680 hereditary abnormalities, 257 hypoplasia, 258 neuritis. See Optic neuritis neuromyelitis optica. See Neuromyelitis optica (NMO)

Ropper_Index_1519-1606.indd 1578

neuropathy. See Optic neuropathy papilledema. See Papilledema in pseudotumor cerebri, 631–632 radiation-induced necrosis, 258 visual evoked potentials in, 36 visual impairment in, 244, 244f injury of, in head injury, 881 intraocular pressure increase affecting, 243 nerve fibers in, 239 in vestibuloocular reflex testing, 267 Optic neuritis causes of, 253, 254t clinical features of, 254, 254t diagnosis of, 254–255, 255f idiopathic, 255 in MS, 255, 913–914, 925 in neuromyelitis optica. See Neuromyelitis optica (NMO) treatment of, 925 Optic neuropathy causes of, 257t ischemic, 252, 253, 254t, 255–256, 256f nutritional, 256–257 paraneoplastic, 689 toxic, 256–257 Optic tract, 244, 244f, 246, 258–259 Optical coherence tomography (OCT), 921 Optokinetic nystagmus, 281 Oral contraceptives. See Contraceptives, oral Oral-buccal-lingual apraxia, 65 Orbit acute myositis of, 1389–1390 fracture of, 901 pseudotumor of, 277–278, 278f tumors of, 682t Orbitopathy, thyroid, 279, 1411 Orexin, 404–405, 405f Organ of Corti, 292, 293f, 298 Organic drivenness, 529 Organophosphate poisoning, 1213– 1214, 1444t, 1447 Orgasm, 528 Orgasmic headache, 195 Orientation to place and time, assessment of, 452 Ornithine transcarbamylase, 946 Orofaciodigital syndrome, 1003 Oromandibular dystonia, 84 Oropharyngeal weakness, 559 Orthochromatic leukodystrophies, 987 Orthostatic hypotension diagnosis of, 540–541, 541f, 542f dizziness in, 307 in elderly, 548 faintness in, 547 falls in elderly and, 610

idiopathic, 393 peripheral neuropathy and, 547 in striatonigral degeneration, 1085 sympathotonic, 546 syncope in, 387, 392–393 treatment of, 547 Orthostatic tremors, 86t, 92, 128 Oscillopsia, 261, 281, 305, 307, 313 Osler-Rendu-Weber disease, 712, 778, 1023 Osmolality, 1125–1126, 1133 Osmolarity, of CSF, 17t Ossification of posterior longitudinal ligament (OPLL), 1260 Osteoarthritis, 217, 220–221 Osteochondromas, 1268 Osteomalacia, 1459 Osteomyelitis, vertebral, 219, 1241 Osteoporosis familial, 981 in Morquio disease, 969 posttraumatic, 225 of spine, 204 Osteosclerotic myeloma, 1316–1317 Osuntokun syndrome, 1117 Otalgia, 198 Otitic hydrocephalus, 711 Otitis media, 300 Otolithic catastrophe of Tumarkin, 309 Otolithic membrane, 293, 293f, 309 Otorrhea, CSF, 702 Otosclerosis, 300 Ototoxic drugs, 300, 313 Out-of-body experiences, 472 Oxacillin, 704t, 715 Oxazepam, 1196 Oxcarbazepine, 347t, 348t, 352 Oxybutynin, 553, 927 Oxycephaly, 999 Oxycodone, 151t, 1190 Oxygen therapy, 191 Oxyhemoglobin, 16 Oxytocin, 568 P p53, 649 PABN1 mutation (oculopharyngeal dystrophy), 1396t, 1398 Pachygyrias, 1000, 1001 Pachymeningitis, 636–637, 636f, 1236 Pacinian corpuscles, 156, 156t, 157f, 158 Paclitaxel, 1216, 1302 Paget disease, of spine, 1260–1261 Paget-Schrötter syndrome, 224 Pain. See also Headache in amyloidosis, 1319 anatomy of, 134–140 dermatomal distribution of pain fibers in, 136

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Index descending systems in, 140 dorsal horn in, 136–137, 136f peripheral afferent pathways in, 135–136, 135t, 136f, 157 spinal afferent tracts in, 137–139, 138f, 139f thalamic terminus of pain fibers in, 139 thalamocortical projections in, 140 approach to the patient assessment in, 145–146 in myofascial pain syndrome and fibromyalgia, 149–150 in psychiatric diseases, 148 in rare and unusual disturbances of pain perception, 146 in undiagnosed medical disease, 146 in arm. See Arm pain assessment of, 163, 164 asymbolia for, 150 in back. See Back pain blood vessels as source of, 140 chronic of indeterminate cause, 148 mechanisms of, 148 treatment of, 150–152, 151t clinical and psychologic aspects of in chronic pain, 143 emotional reactions, 141, 145 nomenclature for, 142, 142t in referred pain, 143, 144f skin pain and deep sensitivity, 142–143 in compensation claims, 148, 220 congenital insensitivity to, 149, 1330 craniofacial. See also Headache anatomy of, 174–175 mechanisms of, 175–176, 185–186, 196–200 deafferentation, 143 deep, 142–143 depression and, 141, 145, 148, 1500 in ear, 174 emotional reactions to, 523 epicritic system in, 134 with exercise, in inherited dysautonomia, 548 facial. See Facial pain gate-control theory of, 134–135 hemiagnosia, 150 historical aspects of, 134–135 hysterical, 1477–1478 ice-pick, 145, 174 intractable, 148 in ischemia, 140 in muscles, 140 in neck, 220–226 in neurofibroma, 148

Ropper_Index_1519-1606.indd 1579

neurogenic or neuropathic, 146–148, 151–152 nociceptive, 146 in ophthalmoplegia, 277t, 278 in paroxysmal extreme pain disorder, 146 pattern or summation theory of, 134 perception of, 164 in peripheral neuropathy, 1281–1282 phantom, 134 physiology of, 140–142, 142f, 149 as predominant symptom, 146–148 protopathic system in, 134 sacral sparing, 137 sensory examination in, 164 sensory-discriminative aspects of, 137 in shoulder. See Shoulder pain specificity theory of, 134, 156–157 in swallowing, 561 sympathetically sustained, 146 temporomandibular joint, 199 terminology related to, 142, 142t thalamic, 171 treatment of ablative surgery for, 152–153 antidepressant and anticonvulsant drugs for, 151t, 156–157 graduated approach in, 150 in neuropathic pain, 151–152 nonmedical methods for, 153 opioids and opiates for, 150, 151t supplemental medications for, 150–151, 151t from tumors, 148 visceral, 137–139, 208 in whiplash injuries, 221 Paine syndrome, 1032–1033 Painful legs–moving toes syndrome, 216 Palate cleft, 598 myoclonus of, 92–93 paralysis of, 1206 tremors of, 86t, 92–93, 283 Paleocerebellum, 109, 110t Paleospinothalamic pathway, 137 Palilalia, 103, 490 Palinopsia, 260, 261, 328 Pallanesthesia, 161 Pallidum, 70–73 Palsy abducens, 77, 273, 274f, 275t, 1025 bibrachial, 1378 bicrural, 1378 bifacial, 1025, 1376–1377 brachial plexus, 1033–1034, 1378 bulbar. See Bulbar palsy cervical, 1377 facial. See Facial palsy

1579

functional, 1478–1479 horizontal gaze, 268, 966 ocular muscles, 1377 oculomotor, 273, 275t, 276 proximal limb-girdle, 1378 trochlear, 273, 274f, 275t, 276, 881 vertical gaze, 268–269, 269t, 966 Panayiotopoulos syndrome, 331 Pancoast tumor, 225 Pancreas, 535 Pancreatic encephalopathy, 1149 PANDAS (pediatric autoimmune neuropsychiatric disorders with streptococcal infection) syndrome, 104, 1475 Pandysautonomia, 545–546, 551, 1282, 1298 Panencephalitis, 762–763 Panhypopituitarism, 690 Panic attacks, 515–516, 1472 PANK mutation (neurodegeneration with brain iron accumulation), 84, 979, 979f Pantothenic acid deficiency, 1164 Papez circuit, 521 Papilledema acute, 253 chronic, 253, 253f in coma, 379 increased intracranial pressure and, 252–254, 253f, 254t, 622 lead poisoning and, 631 mechanisms of, 254 mild, 252–253, 253f optic disc swelling in, 252–253, 253f, 254t in pseudotumor cerebri, 253, 630 severe, 253, 253f in ventilatory failure, 559 Papillitis, 253, 254t, 255, 255f, 914 Papillomacular bundle, 244 Papillomas of choroid plexus, 667 Parachute response, 593 Paradoxical embolism, 777 Paradoxical respiration, 559 Paragangliomas, 675 Paragonimiasis, 733t Paralysis agitans. See Parkinson disease anosognosia and, 476 around-the-clock, 681 autonomic nervous system dysfunction in, 549 bibrachial, 1280 brachial plexus, 1339 in children, 66, 67 ciliary body, 1206 cruciate, 1232 definition of, 54 evaluation of, 1284t–1285t, 1373

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1580

Index

Paralysis (Cont.): flaccid, 1033–1034, 1033t in frontal lobe lesions, 465 functional (psychogenic), 68, 1478–1479 generalized, 1280, 1378–1379 hemiplegia. See Hemiplegia in Horner syndrome, 548 isolated, 65, 68 in lower motor neuron lesions, 56, 64t, 504–505 monoplegia, 65–66 normokalemic periodic, 1451 palatal, 1206 paraplegia in. See Paraplegia patterns of, 65–68 periodic. See Periodic paralysis in poliomyelitis, 759 quadriplegia. See Quadriplegia reflex, 143 sensorimotor, 1336 sensory changes in, 56 of single muscles, 1379 sleep, 412 in sleep disorders, 417–419 thyrotoxic hypokalemic periodic, 1412, 1437, 1455 tick, 1209, 1292 Todd, 326, 329, 335, 774, 1029 of tongue, 1366 triplegia, 67–68 in upper motor neuron lesions, 60–63, 64t vagal, 1364–1365 vocal cord, 1363, 1365 Paramedian arteries, syndromes of, 802, 802t Paramedian pontine reticular formation, in horizontal gaze, 264–266, 265f Paramyoclonus multiplex, 94 Paramyotonia congenita (Eulenburg disease), 1448t, 1451–1452 Paranasal sinus disorders, 173, 175–176 Paraneoplastic disorders autoantibodies associated with, 1299 cerebellar degeneration, 686–688, 687f chorea, 81 classification of, 683–684, 684t dysautonomia, 686 encephalomyelitis, 684–686, 684t, 685f motor neuronopathy, 688 myelitis, 1247 myelopathy, 688 neuromuscular, 689 opsoclonus-myoclonus-ataxia syndrome, 688 optic neuropathy, 689

Ropper_Index_1519-1606.indd 1580

polyneuropathy, 1299–1300 retinopathy, 251, 689 sensory neuronopathy, 686, 1299–1300 stiff person syndrome, 689. See also Stiff man (person) syndrome Paranoia, in Alzheimer disease, 1058 Paranoid personality disorder, 1471t, 1514–1515 Paranoid schizophrenia, 1507 Paranoid-delusional psychosis, 330 Paraparesis in Guillain-Barré syndrome, 1289 in MS, 914, 923–924 in peripheral neuropathy, 1280 Paraphasia, 498, 500 Paraphysis, 670 Paraplegia acute, 67 causes of, 66–67 chronic spinal, 67 clinical features of, 66–67 in extension, 1231 in flexion, 466, 1231 gait disorders in, 124t, 126 hepatic, 1134 hereditary spastic, 1113–1114, 1113t, 1332 in MS, 67, 914 parasympathetic and sympathetic paralysis in, 549 Pott, 718 transient, in head injury, 889 Paraproteinemia, 1315–1316 Parasitic infections meningoencephalitis in, 733t, 735 myelitis in, 1242 myopathy in, 1379–1380 Parastriate cortex, 479 Parasympathetic nervous system anatomy of, 532, 533f, 534 overactivity of, 549–550 physiology of, 536–537 in pupillary size and reactivity, 285–286, 286f Parathyroid gland diseases, 1414 Paratonia, 80, 129, 426 Parenchymal hemorrhage, 891t Paresis algesic, 1373 bilateral phrenic nerve, 559 definition of, 54 general, 722 in lower motor neuron disease, 56 Paresthesia definition of, 161, 162t in peripheral neuropathy, 167, 1281 sensory examination and, 163 vibratory, 163 in vitamin B12 deficiency, 1165

Paretic neurosyphilis, 722 Parietal lobe, 459, 473–474 Parietal lobe lesions agnosia in, 475–476 anosognosia in, 475–476 apraxia in, 64–65, 474, 476–477 auditory neglect in, 478 clinical effects of, 474–479 Gerstmann syndrome in, 477 memory in, 449 motor disorders in, 63–64 sensory disorders in, 166, 171, 474–475 visual disorders in, 477–478 Parinaud syndrome, 266, 668, 802t Parkin disease, 1080 Parkin protein, 1078, 1079, 1079t, 1080, 1080f Parkinson disease Alzheimer disease and, 1060, 1078 basal ganglia and thalamus physiology in, 73, 74f, 75–76 clinical features of, 1073–1075, 1073t depression, 1490 fatigue, 512 gait disorders, 79, 124t, 126–127, 127f, 1074 hypokinesia, 79 initial symptoms, 1073–1074, 1073t psychosis, 455, 1084 rigidity, 80, 1074 sleep disorders, 410–411 smell sense disturbances, 234 speech and language disorders, 505–506 tremors, 86t, 87f, 90–91, 1074 corticostriatospinal degeneration in, 1091 diagnosis of, 1076–1077 differential diagnosis of, 1076–1077 genetic factors in, 1078–1081, 1079t, 1080f after head injury, 899 incidence of, 1073 pathology and pathogenesis of, 77–78, 1077–1078 prevalence and incidence of, 5, 5f, 6t rating scale in, 1073 treatment of ablation of globus pallidus, 1085 amantadine for, 1083 ancillary, 1086 anticholinergic drugs for, 1083 deep brain stimulation for, 1085–1086 dopamine agonists for, 1082–1083 drugs commonly used in, 1081t levodopa for with carbidopa, 1081t, 1082 initiation of, 1082

10/02/23 10:43 AM

Index on-off phenomenon in, 1084 pharmacology of, 1081t side effects of, 528, 1084–1085 monoamine oxidase-B inhibitors for, 1083–1084 neuroprotective agents in, 1084 pharmacologic considerations in, 75–77 side effects of, 1084–1085 surgical, 1085 Parkinsonian syndromes drug-induced, 76, 1512t gait disorders in, 79, 124t, 126–127, 127f, 1074 hereditary forms of, 1094 hypokinesia and bradykinesia in, 78–79 in inherited metabolic diseases hepatolenticular degeneration. See Hepatolenticular degeneration (Wilson disease, ATP7B mutation) neurodegeneration with brain iron accumulation. See Neurodegeneration with brain iron accumulation (Hallervorden-Spatz disease) lower-half, 127, 130, 1076 MPTP in, 1078 in multiple system atrophy, 1087 phenothiazines and, 1198 physiology of, 73 postencephalitic, 90 after shunting for hydrocephalus, 635, 635f Parosmia, 232, 234–235 Paroxetine, 1200, 1497t Paroxysmal ataxias, 1101 Paroxysmal extreme pain disorder, 146 Parry-Romberg syndrome, 1361 Pars reticulata, 71–73 Parsonage-Turner syndrome, 1338, 1340–1342 Partington syndrome, 1001t, 1044 Parvovirus, 741, 1341 Passive diffusion, 618 Passive-aggressive personality disorder, 1471t Passive-dependent personality disorder, 1471t Passivity feelings, 425, 1505 Patau syndrome (trisomy 13), 1011 Patellar tendon reflex, 55f Patent foramen ovale, closure of, 815–816 Pathoclisis, 1177 Pathologic developmental delay, 603–604, 604f Pathologic diagnosis, 3 Pathologic wakefulness, 420

Ropper_Index_1519-1606.indd 1581

Patrick test, 207 Pattern shift visual evoked response (PSVER), 35t, 36, 36f Pattern theory of pain, 134 PCA. See Posterior cerebral artery PCR (polymerase chain reaction), 741–742, 746, 747 Pediatric autoimmune neuropsychiatric disorders with streptococcal infection (PANDAS) syndrome, 104, 1475 Pedunculopontine nuclei, 405 Pegvisomant, 677 Pelizaeus-Merzbacher disease, 955 clinical features of, 283, 955, 958, 960t diagnosis of, 960t genetic factors in, 955 Pellagra (niacin deficiency), 1162–1163 Pelvic ptosis, 128 Pelvifemoral muscular dystrophy. See Limb-girdle muscular dystrophy (LGMD) Pendred syndrome, hearing loss in, 304t Pendular nystagmus, 280, 282–283, 955 Penicillamine for lead poisoning, 1210 for mercury poisoning, 1213 myasthenic weakness induced by, 1447 in Wilson disease treatment, 978 Penicillin for bacterial meningitis, 703, 704t for brain abscess, 715 for leptospirosis, 726 for neurosyphilis, 724 side effects of, 343 for syphilis, 719 for tetanus, 1205 for Whipple disease, 709 Penis, erectile function of. See Erectile function Pentamidine, 732 Pentobarbital, 355, 1195 Penumbra, 774 Penumbra zone, 783 PEO. See Progressive external ophthalmoplegia (Kearns-Sayre syndrome) Perampanel, 347t, 348t Perception in confusional state, 424–425 of pain rare and unusual disturbances of, 149 testing of, 164 threshold for, 140–141 in visual object agnosia, 481

1581

Percussion myotonia, 1374 Perfect (absolute) pitch, 600 Perfusion imaging, 25, 788, 788f Perhexiline maleate, 1302 Periarteritis nodosa, 922 Perilymph, 292, 293f Perimesencephalic hemorrhage, 842 Perimetry, 49 Perimysium, 1370 Perineuritis, sensory, 1313 Perineurium, 1276, 1277f Periodic alternating nystagmus, 283 Periodic hyperthermia, 574 Periodic leg movements of sleep, 408–410 Periodic paralysis hyperkalemic, 1448t, 1450–1451 hypokalemic. See Hypokalemic periodic paralysis normokalemic, 1451 Periodic somnolence, 575 Periodic syndrome, 181, 183 Peripheral nerves A-α fiber type, 135t, 158 A-δ fiber type in pain mechanisms, 135t, 136, 136f, 157 in sensory pathways, 158 anatomy of, 1276–1277, 1277f A-β fiber type, 135t A-δ fiber type, 135 B fiber type, 135t C fiber type in pain mechanisms, 135, 135t, 136, 136f, 157 in sensory pathways, 158 cutaneous distribution of, 155, 156f diseases of. See Peripheral neuropathy hyperexcitability of, 1458 in pain mechanisms afferent pathways in, 135–136, 135t, 136f chronic, 143 dermatomal distribution of, 136 neuropathic or neurogenic, 146 pathologic reactions in, 1278–1280, 1278f prevalence and incidence of, 6t traumatic interruption of, 1348–1349 Peripheral neuropathy diagnosis of, 1285–1286 pathogenesis of, 1277–1280, 1278f symptomatology of autonomic dysfunction, 547, 1282–1283 deformity and trophic changes, 1282 fasciculations, cramps, and spasms, 1283

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1582

Index

Peripheral neuropathy, symptomatology of (Cont.): motor function impairment, 1280–1281 paresthesias, pain, and dysesthesias, 1281–1282 sensory ataxia and tremor, 1282 sensory loss, 1281 tendon reflex reduction, 1281 syndromes and causes of, 1286t–1287t topographic and clinical patterns of mononeuropathy, 1285. See also Mononeuropathy (mononeuritis multiplex) plexopathies, 1285. See also Plexopathies polyneuropathy, 1283, 1285. See also Polyneuropathy polyradiculopathy, 1217t, 1283, 1314. See also Polyradiculopathy sensory neuronopathy, 1285 Periventricular leukomalacia, 1027 Pernicious anemia, 1164, 1167–1168 Peroneal muscular atrophy, 1324 Peroneal nerve neuropathy, 1348 Peroxisomal disorders, 957 Personality age-related changes in, 609–610 concept of, 1470 development of, 592 Personality disorders in Alzheimer disease, 1058 characteristics of, 1471t classification of, 1470–1471, 1471t in epilepsy, 330 in frontal lobe lesions, 465, 467–468 in hypothalamic lesions, 574–575 Person-in-the-barrel syndrome, 1129 Pes cavus, 1327, 1330, 1331 PET. See Positron emission tomography Petrosal bone tumors, 682t, 1357t PEX1 mutation. See Cerebrohepatorenal (Zellweger) disease PEX7 mutation, 1332–1333 Peyote, 1203 Pfeiffer syndrome, 1003 pH, of CSF, 17t Phakomatoses (congenital neuroectodermoses) ataxia-telangiectasia, 1024–1025, 1024f categories of, 1013, 1013t dermatomal hemangiomas with spinal vascular malformations, 1023 epidermal nevus syndrome, 1023

Ropper_Index_1519-1606.indd 1582

neurofibromatosis. See Neurofibromatosis of von Recklinghausen Osler-Rendu-Weber disease, 712, 778, 1023 Sturge-Weber syndrome, 341, 1021– 1023, 1022f tuberous sclerosis. See Tuberous sclerosis (Bourneville disease) von Hippel-Lindau disease, 667, 675, 1023–1024 Phantom pain, 134 Phantosmia, 235 Pharmacokinetics, 1177 Phencyclidine, 432, 526, 1203–1204 Phenelzine, 1199, 1497t Phenobarbital mechanism of action, 1195 for seizures, 347t, 348t, 349, 352, 1185 for status epilepticus, 354t, 355 teratogenic effects of, 345 Phenol, 1215 Phenothiazines for neurosyphilis, 724 for schizophrenia, 1512 side effects of, 1198, 1512t types of, 1197 Phenylacetate, 947 Phenylalanine hydroxylase deficiency, 945t, 961–963 Phenylephrine, 240, 287, 903 Phenylketonurias, 945t, 961–963 Phenylpropanolamine, 1202 Phenytoin for Fabry disease, 1334 folate deficiency from, 1164 hypersensitivity, 352 for myotonia congenita, 1450 for nutritional polyneuropathy, 1161 overdose, 352 for pain, 151t polyneuropathy induced by, 1302 in pregnancy, 345 for seizures, 347t, 348t, 350, 351–352 side effects of, 81, 81t, 351–352 for somnambulism, 413 for status epilepticus, 354–355, 354t Pheromones, 230, 232 Phobic disorder, 1474 Phonation disorders, 504–507 Phonemes, 492, 498, 502 Phonologic agraphia, 503 Phonophobia, 179 Phosphenes, 243, 261 Phosphofructokinase deficiency (Tarui disease, PRKM mutation), 47, 1407, 1408t, 1457 Phosphoglycerate kinase deficiency, 1408t, 1409 Phosphorus, in CSF, 17t

Phosphorus poisoning, 1213–1214 Phosphorylase deficiency (McArdle disease, PYGM deficiency) clinical features of, 47, 512, 1407, 1408t diagnosis of, 47, 1407 physiologic contractures in, 1375, 1407, 1457 treatment of, 1407 Photic driving, in EEG, 29f, 33 Photophobia, 179 Photopsia, 179, 261 Photoreceptor cells, 244 Photostress test, macular, 251 Phthisis bulbi, 1003 Phycomycosis, 728–729 PHYH mutation, 1332–1333 Physiologic studies, 53 Physiologic tremors, 86–88, 86t, 87f Physostigmine, 287 Pial surface disorders, 1002 PICA (posteroinferior cerebellar artery), 803, 806 Pick bundle, 58 Pick disease, 441, 1065 Pickwickian syndrome, 416 Pierre Robin syndrome, 1005 Pilocarpine, 287 Pimavanserin, 455, 1068 Pimozide, 104 Pineal gland, 535, 568–569 Pineal tumors, 569, 642t, 668–669, 669f Pinealocytes, 569 Ping-pong gaze, 283 PINK, 1079–1080, 1079t Pinprick test of pain, 163, 164 Piriformis syndrome, 215 Pitch, 600 Pitres law, 494 Pituitary gland apoplexy. See Apoplexy, pituitary hormones of, 566, 566t ischemic necrosis of, 679 tumors of. See also Adenoma, pituitary diabetes insipidus in, 570 incidence of, 641t vision disorders in, 258 PLA2G6 mutation (neuroaxonal dystrophy/degeneration), 965–966 Placebo, pain perception and, 140, 153 Placidity, 526–527, 529 Placing reaction, 585, 593 Plagiocephaly, 999 Plant poisons, 1207–1208 Plantar reflexes, 9 Planum temporale, 493

10/02/23 10:43 AM

Index Plaque amyloid, 611, 1059, 1059f atheromatous, 778 in MS, 909 neuritic, 611–612, 1059 senile, 1059–1060 Plasma exchange for amyloidosis, 1319 for CIDP, 1320 for cryoglobulinemia, 1308 for dermatomyositis, 1385 for Guillain-Barré syndrome, 1294–1295 for MS, 925 for myasthenia gravis, 1441 for myasthenic crisis, 1442 for paraproteinemia, 1316 Plateau waves, 621, 621f Platinum toxicity, 1214, 1301 Platybasia, 924, 1261 Pleasure, 528 Plectin deficiency, 1147, 1446t Pleocytosis, CSF causes of, 18 characteristics of, 15 in meningitis, 701 migraine with, 182–183 in subdural empyema, 709 in viral myelitis, 1237 Plexitis brachial, 1340–1342 herpes zoster, 1342 lumbosacral, idiopathic, 1346 Plexopathies brachial. See Brachial plexus disorders characteristics of, 1285 diabetic lumbar, 1304–1305 in herpes zoster. See Herpes zoster (shingles) lumbosacral and crural, 1345–1348 syndromes of, 1287t PLS (primary lateral sclerosis), 1102, 1106, 1268 Plumbism. See Lead poisoning PMA (progressive muscular atrophy), 1105 PML. See Progressive multifocal leukoencephalopathy (PML) PNES (psychogenic nonepileptic seizures), 333–334, 1478 Pneumocephalus, 633, 882, 882f, 896 Pneumococcal meningitis clinical features of, 699 epidemiology of, 698 incidence 699, 699 laboratory findings in, 702 pathogenesis of, 699 prognosis of, 705 treatment of, 704, 705t

Ropper_Index_1519-1606.indd 1583

Pneumocranium, 633, 882, 882f Pneumonia, aspiration, 384 PNPLA2 mutation (Chanarin-Dorfman disease), 1411 POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, 1316–1317 Poikiloderma congenitale, 1005 Poikilothermia, 574 Poisons, plant, 1207–1208 Poker spine, 218 Poland syndrome, 1419 POLG mutation (Alpers disease), 956, 959t Poliomyelitis abortive, 758 clinical manifestations of, 758–759 definition of, 1236, 1237 etiology of, 758 nonparalytic, 758 nonpoliovirus, 760, 760f paralytic, 759 pathologic changes and clinicopathologic correlations in, 759 prevention of, 760 prognosis of, 760 treatment of, 759–760 Polyangiitis, granulomatosis with. See Granulomatosis with polyangiitis (Wegener granulomatosis) Polyarteritis nodosa, 862, 1307 Polycythemia vera, 868 Polydipsia, 570 Polyglucosan body disease, adult, 1072, 1330–1331 Polymerase chain reaction (PCR), 741–742, 746, 747 Polymicrogyria, 1000 Polymodal nociceptors, 135 Polymyalgia rheumatica differential diagnosis of, 1388 hip disease in, 225 muscle pain in, 861, 1424 shoulder pain in, 225 temporal arteritis in, 194 treatment of, 226 Polymyoclonus diffuse, 95–96 essential, 94 familial cherry-red spot myoclonus syndrome, 975 childhood or juvenile GM2 gangliosidosis, 975 dentatorubral cerebellar atrophy, 975

1583

juvenile ceroid lipofuscinosis, 974 Lafora-body, with epilepsy, 973–974 in late Gaucher disease, 975 late juvenile and ceroid lipofuscinosis, 974–975 hereditary, 1101–1102 with opsoclonus and ataxia, 666 pathophysiology of, 96 seizures with, 94–95, 325 Polymyositis carcinoma with, 1383 differential diagnosis of, 1387–1388 eosinophilic, 1389 etiology and pathogenesis of, 1385 historical aspects of, 1381 laboratory diagnosis of, 1384 pathologic changes in, 1384–1385 prognosis of, 1386 signs and symptoms of, 1382–1383 vs. spinal muscular atrophy, 1111 in systemic autoimmune disease, 1383–1384 treatment of, 1385–1386 Polyneuropathy acute inflammatory demyelinating. See Guillain-Barré syndrome (GBS) with acute motor paralysis and variable sensory and autonomic dysfunction, 1280–1281, 1286t acute autonomic polyneuropathy, 545–546, 1298 acute sensory neuronopathy, 1296 acute uremic polyneuropathy, 1296 associated with other disorders, 1298 critical illness polyneuropathy, 560, 1295–1296 diphtheritic polyneuropathy, 1296–1297 Guillain-Barré syndrome. See Guillain-Barré syndrome (GBS) paraneoplastic polyneuropathy, 1299–1300 porphyric polyneuropathy, 1297 toxic. See Toxic polyneuropathy asymmetrical and multifocal. See Mononeuropathy chronic acquired, 1315 alcoholic-nutritional, 1322. See also Nutritional deficiencies, polyneuropathy in amyloid neuropathy, 1317–1319. See also Amyloidosis in hypothyroidism, 1323–1324. See also Hypothyroidism

10/02/23 10:43 AM

1584

Index

Polyneuropathy, chronic acquired (Cont.): idiopathic small-fiber sensory polyneuropathy, 1281, 1324, 1324t, 1337t inflammatory demyelinating polyradiculoneuropathy. See Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) leprous polyneuritis, 1322–1323, 1323f multifocal motor neuropathy and multifocal conduction block, 1321–1322 in paraproteinemia, 1315–1316 in POEMS syndrome, 1316–1317 recurrent or relapsing, 1338 uremic, 1296, 1322 chronic inherited classification of, 1287t, 1325, 1326t–1327t clinical features of, 1324–1325 with metabolic disorders, 1327t abetalipoproteinemia, 973, 1333 acromegaly and gigantism, 1334. See also Acromegaly; Gigantism Fabry disease. See Fabry disease (GLA mutation) familial amyloidosis, 1326t, 1334–1336 metachromatic leukodystrophy, 1334 mitochondrial neuropathy, 1333 Refsum disease, 304t, 1332– 1333, 1338 Tangier disease, 1333, 1338 mixed sensorimotor-autonomic types Charcot-Marie-Tooth disease. See Charcot-Marie-Tooth disease hereditary neuropathy with pressure palsies (HNPP), 1329 hypertrophic neuropathy of infancy (Dejerine-Roussy syndrome), 171, 801, 1329 phenotype-genotype correlations in, 1329 sensory type, 1326t, 1329–1330, 1331 with cerebellar degeneration, 1332. See also Ataxia, cerebellar congenital insensitivity to pain, 149, 1330 hereditary sensory polyneuropathy, 1330

Ropper_Index_1519-1606.indd 1584

multiple symmetrical lipomas with sensorimotor polyneuropathy, 1330 polyglucosan disease, 1330–1331 recurrent brachial plexopathy. See Brachial plexus disorders Riley-Day familial dysautonomia. See Riley-Day familial dysautonomia Roussy-Lévy syndrome, 1331– 1332 with spastic paraplegia, 1114, 1332 diabetic. See Diabetic neuropathy diagnosis of, 1285, 1336–1338, 1337t drug-induced. See Toxic polyneuropathy in lightning injuries, 1236 in mercury poisoning, 1212 sensory disorders in, 167t, 168 with subacute sensorimotor paralysis, 1286t, 1298–1299 diabetic. See Diabetic neuropathy nutritional polyneuropathy. See Nutritional deficiencies, polyneuropathy in paraneoplastic. See Paraneoplastic disorders toxic. See Toxic polyneuropathy topographic and clinical patterns in, 1283, 1284t–1285t, 1285 Polyopia, 261, 275 Polyphasic potentials, in EMG, 47–48, 48f Polyradiculitis, 756, 1311 Polyradiculopathy sensory disorders in, 167t, 168 with and without meningeal infiltration, 1283, 1286t, 1314 Polysyndactyly, 1003 Pompe disease (GAA mutation), 950t, 1406–1407, 1408t Pons anatomy and physiology of, 57f, 58, 805, 807f–808f lesions of auditory hallucinations in, 300, 472 glioma, 679–680, 680f hemorrhage, 834f, 835. See also Intracerebral hemorrhage myelinolysis. See Central pontine myelinolysis (CPM) paramedian reticular formation of, in horizontal gaze, 264–266, 265f Pontocerebellar hypoplasia, 1032 Pontomesencephalic tegmentum, 538 Porencephaly, 998 Poriomania, 328

Porphyric polyneuropathy, 1297, 1338 Portal-systemic encephalopathy. See Hepatic (portal-systemic) encephalopathy Portuguese familial amyloidosis, 1335 Port-wine nevus, 1022 Positron emission tomography (PET) in Alzheimer disease, 1064 in anxiety, 517 of cerebral cortex, 459 in delirium, 432 in Lewy body dementia, 1067 in paraneoplastic cerebellar degeneration, 687 in persistent vegetative state, 365 in schizophrenia, 1509 in sleep, 406 in stuttering, 597 technique of, 27, 27f Postcentral gyrus, 473 Postconcussion syndrome, 193, 897 Posterior cerebral artery (PCA) branches of, 798–801, 799f, 800f ischemic stroke syndromes of bilateral, 803 cortical, 802–803 proximal, 799f, 800f, 801–802, 802t regions supplied by, 801f Posterior columns, 133, 158–159, 160f, 170 Posterior commissure, 266, 266f Posterior fossa, subdural hematoma in, 893 Posterior lobe of cerebellum, 109, 110f, 110t Posterior longitudinal ligament, ossification of, 1260 Posterior reversible encephalopathy syndrome (PRES), 856–858 Posteroinferior cerebellar artery (PICA), 803, 806 Posthemiplegic athetosis, 82 Postherpetic neuralgia, 197, 753 Posthypoxic syndromes, 1129 Postinfectious demyelinating disease, 255 Postinfectious encephalitis, vs. viral encephalitis, 744 Postinfectious myelitis, 931, 1242–1244, 1243f Postoperative confusional state, 433 Postpartum period brachial plexitis in, 1341 depression in, 1489, 1490–1491 psychosis in, 1515–1516 stroke in, 830 Postpolio syndrome, 1237 Postprandial hypotension, 392 Posttraumatic epilepsy, 898–899 Posttraumatic headache, 192–193

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Index Posttraumatic hydrocephalus, 900 Posttraumatic stress disorder (PTSD), 510, 516, 897 Postural orthostatic tachycardia syndrome, 393, 546 Posture antalgic, 206 assessment of, 8, 9 in asterixis, 93 in corticostriatospinal degeneration, 1091 in dystonia, 83f, 84 of elderly, 130, 130f fencing, 414 frog-leg, 593 in gait cycle, 121–122 heart rate response to changes in, 540–541 righting reflexes and, 79 in syncope, 392 tremors in maintenance of, 86–87, 86t, 87f Posturing, in coma, 378 Postvaccinal myelitis, 1242–1244 Postviral fatigue syndrome, 513–514 Potassium. See also Hyperkalemia; Hypokalemia in CSF vs. serum, 17t in myasthenia gravis treatment, 1440 Potassium channel disorders, 334, 338t, 1448t, 1456 Pott disease, 219, 1241, 1242f Pott paraplegia, 718 Power spectral analysis, 542 Prader-Willi syndrome, 572, 573, 972, 1012 Pramipexole, 409, 1081t, 1082–1083 Praxis, 7 Praziquantel, 734, 735 Precentral cortex, 462 Precocious puberty, 572, 668 Precocious reading and calculating, 600 Prednisolone, 1295 Prednisone for Bell’s palsy, 1360 for CIDP, 1320 for cluster headache, 191 for Lambert-Eaton myasthenic syndrome, 1445 for MS, 925 for myasthenia gravis, 1440 for myositis ossificans, 1427 for optic neuritis, 925 for POEMS, 1317 for polymyalgia rheumatica, 226 for pseudotumor cerebri, 632 for Sjögren syndrome, 1312 for temporal arteritis, 194, 861

Ropper_Index_1519-1606.indd 1585

for trichinosis, 1379 for Waldenström macroglobulinemia, 1317 Prefrontal areas, 464, 466 Pregabalin for diabetic neuropathy, 1306 for pain, 151t for postherpetic neuralgia, 197 for restless legs syndrome, 410 for seizures, 347t, 348t Preganglionic neurons of parasympathetic nervous system, 532, 534 of sympathetic nervous system, 534 Pregnancy alcohol use in, 1188–1189 antiepileptic drugs in, 344–345 in Briquet syndrome, 1477 chorea in, 81 CT in, 22 depression during and after, 1489, 1490–1491 exogenous toxins in, 1042 fatigue in, 512 folate deficiency in, 1164 HIV infection in, 1036 intrauterine infections in. See Intrauterine and neonatal infections iodine supplements in, 1149 migraine in, 179, 183–184 MRI in, 24 in MS, 922 myasthenia gravis in, 1443 olfactory sense in, 233 sciatica in, 215 seizures in, 344–345 stroke in, 830 subacute sclerosing panencephalitis in, 763 Premature ejaculation, 555 Premotor cortex, 59 Prepositus hypoglossi, 265 Prepyramidal pathway, 70 PRES (posterior reversible encephalopathy syndrome), 856–858 Presbycusis, 301, 607 Presbyopia, 607 Presbyosmia, 234 Presenilins, 1060f, 1061, 1062, 1062t Pressure cone, cerebellar, 646 Pressure palsy, hereditary neuropathy with, 1329 Pressure sense, 155, 156, 159, 159f Presyncope, 387 Pretibial (compartment) syndrome, 1426 Priapism, 555

1585

Primary CNS lymphoma B-cell, 656 clinical features of, 657 diagnosis of, 658 in HIV infection, 756–757 imaging of, 657–658, 657f incidence of, 641, 656 locations of, 657 prognosis of, 658 risk factors for, 658 T-cell, 657 treatment of, 658 Primary hypoventilation syndrome, 416 Primary lateral sclerosis (PLS), 1102, 1106, 1268 Primidone, 89, 349, 352 Primitive neuroectodermal tumor, 667 Prion diseases in cows, 765 discovery of, 764 encephalopathy. See Subacute spongiform encephalopathy familial fatal insomnia, 767–768 Gerstmann-Sträussler-Scheinker syndrome, 767 kuru, 767 olfactory sense and, 234 Prion protein, 764 Probenecid, 724 Procainamide, 1423, 1450, 1452 Procarbazine, 1216 Procedural memory, 446f, 447, 447t Prodrome, 322 Progressive bulbar palsy, 1105–1106 Progressive external ophthalmoplegia (Kearns-Sayre syndrome) clinical features of, 1376, 1397 genetic factors in, 988t, 989, 1397–1398 hearing loss in, 302, 304t Progressive multifocal leukoencephalopathy (PML) clinical features of, 761 diagnosis of, 761, 762f in HIV infection, 757 pathogenesis of, 761–762 treatment of, 762, 926 Progressive muscular atrophy (PMA), 1105, 1107 Progressive supranuclear palsy (PSP) clinical features in, 1088–1089, 1189f diagnosis of, 1089, 1089f historical aspects of, 1088 vs. Parkinson disease, 1077 pathology of, 1089–1090 treatment of, 1090 Prolactin inhibition of, 567–568 normal range of, 566t in pituitary adenoma, 676t, 677 secretion of, 404

10/02/23 10:43 AM

1586

Index

Promethazine, 187, 309, 1199 Pronator drift, 8 Propantheline, 398, 553, 927 Propionic acidemia, 945t, 946, 1072 Propofol in head injury treatment, 904 neurologic effects of, 344, 1197 in opioid use disorder treatment, 1193 for seizures, 347t, 348t for status epilepticus, 355 in tetanus treatment, 1206 Propoxyphene, 1190, 1192 Propranolol, 89, 188, 1474 Proprioception, 155, 160, 164–165, 305 Proprioceptive gait ataxia, 125–126 Proprioceptors, 155 Propulsion, in gait cycle, 122 Prosody, 493, 503 Prosopagnosia, 260, 481–482 Protein in CSF, 14t, 16 in herpes simplex encephalitis, 747 in meningitis, 701 in MS, 920 in papilledema, 254 vs. in serum, 17, 17t dystrophin-associated, 1393 prion, 764 synthesis, 1415t Protein 14-3-3 tests, 18 Protein C deficiency, 786 Protein-calorie malnutrition, 1153, 1173–1174 Protopathic system in pain, 134 Protozoal diseases, 730–732 Protriptyline, 1200 Proximal myotonic myopathy (DM2, CMBP mutation), 1396t, 1400 Prune belly, 1419 Psammoma bodies, 655 Pseudoabducens palsy, 280 Pseudoathetoid movements, 686, 1282 Pseudobulbar affective state, 523–524, 523t Pseudobulbar (spastic) dysarthria, 505 Pseudobulbar palsy, 67, 465, 1088–1089 Pseudocerebellar syndrome, 475 Pseudocontracture, 1375 Pseudocramp, 162t, 163 Pseudoephedrine, 1202 Pseudo-Hurler disease, 953. See also Gangliosidosis Pseudo-Hurler polydystrophy, 969 Pseudohypoparathyroidism, 980–981 Pseudomonas infections, 704 Pseudomyotonia, 1457 Pseudoneuroma, 1279 Pseudoradicular pain, 205

Ropper_Index_1519-1606.indd 1586

Pseudoseizures, 333 Pseudosixth palsy, 269 Pseudosyringomyelia, 168, 1270 Pseudotetany, 1423 Pseudothalamic pain syndrome, 475 Pseudotumor in muscles, 1426 orbital, 277–278, 278f Pseudotumor cerebri in AVM, 631 causes of, 631, 631t CT in, 630 definition of, 629 differential diagnosis of, 631 in Guillain-Barré syndrome, 631 headache in, 194, 627 increased intracranial pressure in, 630 MRI in, 630 optic nerve damage in, 632–633 papilledema in, 253, 630 pathophysiology of, 630 pulsatile tinnitus in, 299 treatment of, 630, 632–633 venous obstruction relief in, 632–633 visual loss in, 631–632 in vitamin A deficiency, 1169 Pseudouremia, 1138 Pseudo-von Graefe sign, 285 Psilocybin, 1203 PSP. See Progressive supranuclear palsy PSVER (pattern shift visual evoked response), 35t, 36, 36f Psychiatric diseases alcoholism with, 1190 anxiety. See Anxiety disorders back pain in, 219–220 bipolar disorder. See Bipolar (manicdepressive) disease depression. See Depression dizziness in, 306 epilepsy and, 330 fatigue in, 512 functional. See Functional neurological disorders headache with, 192 historical aspects of, 1469–1470 olfactory hallucinations in, 235 pain in, 148 psychosis. See Psychosis schizophrenia. See Schizophrenia seizures and, 330 Psychoactive drugs, 1202–1204 Psychogalvanic skin reflex, 302 Psychogenic nonepileptic seizures (PNES), 333–334, 1478 Psychomotor retardation, 426 Psycho-motor triad, 328 Psychopathy, 1469

Psychosis adrenocorticotropic hormone, 1516 in alcoholism, 1184 amnesia and, 330 confusional states in, 431 corticosteroid, 1147, 1516 in depression, 1491 endocrine, 1516–1517 after head injury, 898 in Korsakoff syndrome, 1187 in metabolic disease, 1146–1149 paranoid-delusional, 330 in Parkinson disease, 1084 in postpartum period, 1515–1516 seizures and, 330 thyroid, 1147–1149, 1516–1517 Psychotherapy, 1476, 1499 Ptosis, 285, 1376 PTSD (posttraumatic stress disorder), 510, 516, 897 PTT1 mutation. See Neuronal ceroid lipofuscinoses (Batten disease) Puberty. See also Adolescents failure of, 572 growth and development in, 583, 584f precocious, 572, 668 Pulmonary disease, hypercapnic, 1132 Pulmonary edema, neurogenic, 574 Pulmonary veins, in cerebral embolism, 778 Pulsatile tinnitus, 298–299 Pulseless disease. See Takayasu arteritis Punch-drunk syndrome (chronic traumatic encephalopathy), 899–900 Pupillodilator fibers, 286, 288 Pupils. See also Eye Adie, 548, 551 Adie tonic, 288, 288t Argyll Robertson, 288, 288t denervation hypersensitivity in, 544 in diabetes mellitus, 288 dilation for eye examination, 240 in Horner syndrome, 287, 287f Hutchinson, 288 light response of, 245, 269, 286, 286f size of age-related changes in, 286, 607 in brain death, 368 in coma, 376–377 drugs affecting, 289, 544 in tabetic neurosyphilis, 723 in temporal lobe herniation, 374, 374t unequal, 288–289, 289f springing, 288 Pure motor hemiplegia, 58, 780 Pure word blindness, 260, 500–501

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Index Pure word deafness, 301, 485, 494, 495t, 500 Purkinje cells, 111, 114, 115f Purpura brain, 854, 1140 thrombotic thrombocytopenic, 381t, 854, 868 Pursuit movements, of eyes, 264, 267 Putamen anatomy of, 70–73, 71f, 72f hemorrhage in, 833–834, 834f in Huntington disease, 1070 PYGM mutation. See Phosphorylase deficiency (McArdle disease) Pyknodysostosis, 1003 Pyknoepilepsy. See Absence seizures Pyramidal motor neurons, 60 Pyramidal tract, 54, 56, 60–61 Pyrazinamide, 718–719 Pyridostigmine, 397, 547, 1445 Pyridoxine (vitamin B6) deficiency of, 1163 for INH toxicity, 719 inherited neurologic disorders responsive to, 945, 1174t in porphyria treatment, 1297 toxicity of, 1163–1164, 1303 in Wilson disease treatment, 978 Pyrimethamine, 731, 1037, 1380 Q Q fever, 729, 730 QSART (quantitative sudomotor axon reflex test), 543 Quadrantanopia, 259, 798 Quadriceps femoris weakness, isolated, 1378 Quadriplegia definition of, 65 infantile, 1029–1030 pathophysiology of, 67–68 Quantitative sudomotor axon reflex test (QSART), 543 Queckenstedt test, 15, 620 Quetiapine in Alzheimer disease treatment, 1065 for bipolar disease, 1498–1499 in Lewy body dementia treatment, 1068 for schizophrenia, 1512, 1513t side effects of, 1513t Quinine in cramp management, 1423 for malaria, 732 for myotonia congenita, 1450 R “Rabbit” syndrome, 1512t Rabies, 745, 749–750 Rabies vaccine, 932–933

Ropper_Index_1519-1606.indd 1587

Racemosum venosum, 1253 Rachischisis, 1006–1007 Radial microbrain, 1002 Radial nerve neuropathy, 1343 Radiation therapy for AVM, 849–850 brachial neuropathy following, 1342 for cavernous malformation, 853 complications of delayed, 690 in intracranial tumors, 689–691, 690f leukoencephalopathy, 689–690, 690f optic nerve damage, 258 progressive myelopathy, 1234–1235 SMART syndrome, 691, 691f spinal cord injuries, 1233–1235 transient myelopathy, 1233–1234 for ependymoma, 654 for glioblastoma, 650 for intraspinal tumors, 1267 for leukemia, 662–663 for malignant meningitis, 662 for medulloblastoma, 665–666 for meningioma, 656 for metastatic intracranial, 660 for oligodendroglioma treatment, 653 for pituitary adenoma, 678–679 for primary CNS lymphoma, 658 for vestibular schwannoma, 673–674 Radicular arteries, 1249, 1249f Radicular-spinal cord syndrome, 1266 Radiculopathy characteristics of, 1283 diabetic, 1304–1305 in lumbar stenosis, 216–217 pain in, 168, 205, 221 sensory disorders in, 167t, 168 thoracoabdominal, 1304 Raeder syndrome, 822 Rage differential diagnosis of, 529 sham, 522 in temporal lobe seizures, 525 without seizure activity, 525–526 Ragged red fibers, 942, 988t, 991 Ramp movements, 54 Ramsay Hunt syndrome, 752, 975, 1361 Rapamycin, 1017 Rapid eye movement sleep. See Sleep, REM Rapid head impulse test, 308 Rapsyn, 1446 Rapsyn deficiency, 1446, 1446t Rasagiline, 1081t, 1084 Rasmussen syndrome, 332–333

1587

RASS (Richmond Agitation-Sedation Scale), 433 Rathke pouch, 674–675 Raymond-Foville syndrome, 802t Raynaud phenomenon, 224, 551, 1382 Raynaud syndrome, 550–551 RCVS (reversible cerebral vasoconstriction syndrome), 822, 858–859, 859f Reading in dyslexia, 498, 599–600 letter-by-letter, 500 precocious, 600 Reagin test, for syphilis, 720, 721f Rebound insomnia, 408 Recessive mutilating sensory polyneuropathy of childhood, 1330 Reciprocal inhibition, 55 Recruiting deafness, 298 Recruitment, auditory, 297 Rectal pain, familial syndrome of, 146 Recurrent inhibition, 55 Recurrent meningeal nerves, 203 Recurrent nocturnal headache, in elderly, 90, 192 Recurring utterance, 496 Red nucleus, 53, 70, 118f Red reflex, 240 Red-glass test, 274 Reeling gait, 123, 124 Referred pain, 143, 144f, 205 Reflex(es) Achilles, 212, 213 acoustic-stapedial, 298 age-related changes in, 607–608 antigravity, in gait cycle, 121–122 Bezold-Jarisch, 390 blink, 284, 1355 in brain death, 367–369 bulldog, 1106 ciliospinal pupillary, 287 cochleo-orbicular, 302 in coma, 363, 378 corneal, 284, 378, 1355 cutaneous or superficial, 63 in dementia, 441 fetal development of, 585 in Guillain-Barré syndrome, 1288 Hering-Breuer, 557 jaw jerk, 8, 1355 mass, 549 Moro, 585, 593 movements and, 54 in neonates and infants, 585, 586 in nutritional polyneuropathy, 1160 oculocephalic, 373, 374 patellar tendon, 55f plantar, 9 psychogalvanic skin, 302

10/02/23 10:43 AM

1588

Index

Reflex(es) (Cont.): righting in basal ganglia disease, 79 in gait cycle, 121, 122 in spasticity, 61–63 after spinal cord trauma, 1231 spinal flexion, 63 in swallowing, 560 tendon (stretch). See Tendon (stretch) reflexes testing of, 8–9 tonic neck, 593 vestibuloocular, 264, 267, 305 vestibulospinal, 305 visual fixation, 268 in vomiting, 561 Reflex epilepsy, 332 Reflex paralysis, 143 Reflex sympathetic dystrophy (RSD), 147. See also Complex regional pain syndrome (CRPS) Refractive errors, 239 Refsum disease, 304t, 1332–1333, 1338 Rejection behavior, 476 RELN mutations, 1001t, 1002 REM (rapid eye movement) sleep. See Sleep, REM Renal failure, acute, 1138–1139 Renal transplantation, 1139–1140 Renal tubular acidosis, 957 Renin, 537 Renpenning syndrome, 1044 Repetition, defective, 494–495 Reserpine, 76, 102, 1072 Respiration aberrant patterns of, 558–559 afferent influences on, 557 in brain death, 555 central motor mechanisms in, 555–559, 556f Cheyne-Stokes, 373, 374, 374t, 375, 378–379, 558 in coma, 375, 378–379 dyspnea in, 557–558 ECG during changes of, 541–542 heart rate and, 541–542 nervous system control of, 531, 555–559 in neuromuscular disorders, 559 nucleus tractus solitarius in, 556f, 557 paradoxical, 559 physiology of, 531 in poliomyelitis, 760 in sleep apnea, 416 voluntary control of, 557 Respiratory alternans, 559 Respiratory arrest, in cerebellar herniation, 646

Ropper_Index_1519-1606.indd 1588

Respiratory chain proteins, 942 Respiratory failure in Guillain-Barré syndrome, 1293 in muscular dystrophy, 1404–1405 Respiratory muscle weakness, 1377 Restless legs syndrome, 104, 408–410 Reticular activating system, 371 Reticular formation in alertness, 371 pontine paramedian formation, in horizontal gaze, 264–266, 265f in sleep-wake cycle, 405 Reticulospinal tract, 58–59, 62 Reticulum cell sarcoma. See Primary CNS lymphoma Retina anatomy of, 244, 244f, 246 blood supply of, 247 cherry-red spot in. See Cherry-red spot, retinal disorders of AVMs, 848 cancer-associated, 251 degenerative, 251 detachment, 243, 250 diabetic, 252 drug-induced, 251 exudates, 247–248, 248f hemorrhage, 248, 248f hereditary deafness with, 1116 in HIV infection, 251 ischemic, 249–250, 249f, 250f migraine, 181–182, 250 prevalence and incidence of, 6t serous, 250 examination of, 240, 247, 251–252 Retinal artery, central, 247, 249–250, 249f Retinal vein, 250, 914 Retinitis pigmentosa, 242, 1115–1116 Retinoblastoma, 666 Retinol, 630 Retinopathy in diabetes mellitus, 252 paraneoplastic, 251, 689 serous, 250 Retraction nystagmus, 283 Retraction syndrome, 277 Retrograde amnesia, 445, 450, 884, 1156 Retrolental fibrodysplasia, 1003 Retroparotid space tumors, 682t, 1357t Retropharyngeal syndrome, 682t Rett syndrome, 102, 1012, 1044 Reversible cerebral vasoconstriction syndrome (RCVS), 822, 858–859, 859f Reye syndrome, 706, 932, 947, 1137–1138 Rhabdomyolysis (necrotizing myopathy), 1409, 1414–1416, 1415t

Rhabdomyosarcoma, 1426 Rheumatoid arthritis of cervical spine, 221, 1260 gold preparations and toxicity in, 1301 neuropathy in, 1308 Rheumatoid spondylitis. See Ankylosing spondylitis Rhinencephalon, 520 Rhinorrhea, CSF, 634, 702, 882, 896 Rhodopsin, 251 Rhythmias, 1042 Riboflavin (vitamin B2 deficiency), 1162 Ribot law, 494 Ribot rule, 446 Ribs, cervical, 223, 224f Richmond Agitation-Sedation Scale (RASS), 433 Richner-Hanhart disease (hereditary tyrosinemia), 945t, 963 Rickettsial diseases, 729–730 Rifampin for anthrax, 708 for bacterial meningitis, 703 for catscratch fever, 708 for Legionella infections, 708 for leprous polyneuritis, 1323 for tuberculous meningitis, 718–719 Rifaximin, 1136 Right-handedness, 493 Righting reflexes, 79, 121, 122 Rigid (extrapyramidal) dysarthria, 503 Rigid spine syndrome, 1375, 1401, 1402t Rigidity congenital neonatal, 1460 decerebrate, 378 in muscle tone, 79–80 nuchal, 833 in Parkinson disease, 80, 1074 vs. spasticity, 79 in tetanus, 1204 Riley-Day familial dysautonomia autonomic symptoms of, 547–548 polyneuropathy in, 1331 tabetic syndrome in, 169 taste disorders in, 237 Riluzole, 1109 Rimmed vacuoles, 1387, 1398, 1401t Ring chromosomes, 1012 Rinne test, 297 Rippling, of muscles, 1374 Risperidone in Alzheimer disease treatment, 1065 for schizophrenia, 1512, 1513t side effects of, 1513t, 1514 Rituximab for antiphospholipid antibody, 868 for autoimmune encephalitis, 935 for cryoglobulinemia, 1308

10/02/23 10:43 AM

Index for MS, 926 for multifocal motor neuropathy, 1322 for NMO, 930 for polyarteritis nodosa treatment, 1307 for Sjögren syndrome, 1312 for stiff man syndrome, 1460 for Waldenström macroglobulinemia, 1317 Rivaroxaban, 814 Rivastigmine, 1068 Rizatriptan, 187, 187t Rochon-Duvigneaud syndrome, 682t Rocky Mountain spotted fever, 729 Rod-body (nemaline) myopathy, 1419t, 1421 Rodenticides, 1211 Rods and cones, 244, 244f Rolandic epilepsy, 331 Romberg masticatory spasm, 101 Romberg sign in ataxia, 118, 1096 in gait disorders, 130 in proprioception testing, 165 Romberg test, 9 Ropinirole, 409, 1081t, 1082–1083 Rosette formation, 665 Ross syndrome. See Adie pupil Rotator cuff injuries, 225 Roth spots, 248 Rothmund-Thompson syndrome, 1005 Rouget cells, 618 Roussy-Lévy syndrome, 1331–1332 RSD (reflex sympathetic dystrophy), 147. See also Complex regional pain syndrome (CRPS) Rubella, 763, 1034–1035 Rubeosis iridis, 243, 249 Rubinstein-Taybi syndrome, 1004–1005 Ruffini endings, 155, 156t, 157f, 157 Rum fits, 1184–1185 Russell-Silver syndrome, 1004 Russian spring-summer encephalitis, 332, 745 RYR1 mutation, 1377 S S factors of intelligence, 437 Sabin vaccine, 760 Saccades, 263, 264, 265f, 267 Saccadomania, 283 Saccular aneurysm, ruptured. See Subarachnoid hemorrhage, ruptured saccular aneurysm in Saccule, 292, 293, 293f, 296f, 305 Sacralization, 215

Ropper_Index_1519-1606.indd 1589

Sacroiliac joint anatomy of, 203 physical examination in disorders of, 207 strain of, 208, 215 Saethre-Chotzen syndrome, 1003 Sagittal sinus, thrombosis of, 865, 865f St. Louis encephalitis, 745, 746 Salaam seizures, 331 Salivary gland biopsy, 1312 Salk vaccine, 760 Salt wasting, cerebral, 572, 1141 Salt-and-pepper chorioretinitis, 1035 Sandhoff disease, 950t, 952, 959 Sanfilippo disease, 968t, 969 Santavuori-Haltia disease, 950t, 967. See also Neuronal ceroid lipofuscinoses Sarcoglycanopathies, 1396–1397 Sarcoidosis facial palsy in, 1361 hypothalamus in, 569 myelitis in, 1238–1239 myopathy in, 1390 neuropathy in, 1310 optic neuropathy in, 258 Sarcolemma, 1393 Sarcoma, 664 Sarcopenia, 612 Sarcoplasm, 1370 Sarcoplasmic reticulum, 1370, 1371f Satoyoshi syndrome, 1376, 1424 SAX1 mutation, 1114 SBE (subacute bacterial endocarditis), 712 Scalene muscles, 223 Scanning dysarthria, 117 Scaphocephalic head, 999 Scapulohumeral muscular dystrophy. See Limb-girdle muscular dystrophy (LGMD) Scapuloperoneal dystrophy, 1374t, 1395, 1401t Scheibe defect, 302 Schilder disease, 918–919, 960t Schindler disease, 950t Schistosomiasis, 733t, 735, 735f, 1242 Schizencephaly, 998, 1001t Schizoaffective state, 1489, 1511 Schizoid personality disorder, 1471t Schizophrenia in adolescents, 1511 alcoholism and, 1511 anxiety in, 1474 bizarre ideation in, 529 catatonic, 1506–1507, 1511 causation and mechanisms of, 1507–1508 environmental and developmental factors, 1508

1589

genetic factors, 1508 neuropathologic and neurophysiologic, 1508–1509 neurotransmitter alterations, 1509–1510 psychosocial, 1510 in children, 1511 clinical syndrome of, 1504–1505 course of, 1507 diagnosis of, 1505–1506, 1511 differential diagnosis of, 1510–1511 disorganized (hebephrenic), 1507 dopamine hypothesis of, 1509 early signs of, 603 hallucinations in, 300, 1505 historical aspects of, 1503–1504 hypochondriasis in, 1481 imaging in, 1509 in medical or surgical illnesses, 434 neurologic and neuropsychologic abnormalities in, 1507 olfactory hallucinations in, 235 paranoid, 1507 passivity feelings in, 425, 1505 personality disorders in, 1470 prevalence and incidence of, 6t, 1503 prognosis of, 1513–1514 subtypes of, 1506–1507 suicide in, 1505 vs. temporal lobe epilepsy, 1511 treatment of, 1511–1513, 1512t, 1513t Schmincke tumor, 681 Schmorl nodule, 212–222 Schneider syndrome, 1229, 1232 School dysfunction, 594 Schwabach test, 297 Schwann cells, 1277–1278 Schwannoma incidence of, 641t vs. neurofibroma, 672 of trigeminal ganglion, 674 vestibular, 314, 672–674, 672f, 673f Schwannomatosis, familial, 1019–1020 Schwannomin, 1017 Schwartz-Jampel syndrome, 1461 Sciatic nerve disorders in heroin users, 1194 neuropathy, 1347–1348 tumor-related, 215–216 Sciatic scoliosis, 206 Sciatica bilateral, 216 catamenial, 215 causes of, 210–211, 215–221 in menstrual cycle, 215 neuritis, 215 physical examination in, 205, 206 synovial cysts in, 215 treatment of, 214 with tumors, 215–216

10/02/23 10:43 AM

1590

Index

Scintillating scotoma, 179 Scleroderma, 1247 Sclerosis cortical laminar, 1172 diffuse, 918–919 medial temporal, 329, 329f, 337 multiple. See Multiple sclerosis (MS) primary lateral, 1102, 1106, 1268 tuberous. See Tuberous sclerosis (Bourneville disease) Sclerotomes, 136, 143, 144f, 158, 205 SCN4A mutation, 1452 Scoliosis, sciatic, 206 Scotoma arcuate, 243 cecocentral, 244 central, 259, 260 junctional, 241f, 245 scintillating, 179 Seidel, 243 Scratch-and-sniff test, 233 Scrub typhus, 729 Seckel bird-headed dwarfism, 1004 Secobarbital, 1195 Second cranial nerve. See Optic (second) nerve Sedative-hypnotic drugs, 382t, 431, 434. See also Barbiturates; Benzodiazepines Seesaw nystagmus, 283 Segawa disease, 84, 1094 Segmental demyelination, 1278–1279, 1278f, 1290, 1291f Seidel scotoma, 243 Seizures absence. See Absence (petit mal) seizures acute repetitive, 355–356 in adolescents, 325, 340f, 340t, 342 age-related changes in, 321, 322f, 340–343, 340f, 340t, 1038 in alcohol withdrawal, 1184–1185 in Alzheimer disease, 1057 amnesia in, 328, 339 anosmia and, 235 aphasia in, 326–327 aura in, 237, 307, 327 automatisms in, 328 in bacterial meningitis, 700 in cardiac arrest, 344 centrencephalic, 335 with centrotemporal spikes, 331 in cerebrovascular disease, 344 in children. See Children, seizures in classification of, 321, 321t, 322f clinical approach to, 339–346 in cocaine overdose, 1202 in coma, 372, 382t confusion following, 431 convulsive, 321

Ropper_Index_1519-1606.indd 1590

CSF in, 336 CT in, 336 differential diagnosis of, 339–340 driving restrictions and, 357 drug-induced, 343–344 in eclampsia, 346 EEG in. See Electroencephalography, in seizures in elderly, 340f, 340t, 342–343 electrical discharge in, 334–335 febrile, 331–332, 341 focal onset classification of, 325 definition of, 321 motor, 325–327 patterns of, 326t somatosensory, 327 temporal lobe, 327–328 types of, 321t frontal lobe, 325–327, 414 generalized onset motor (tonicclonic, grand mal), 321, 321t, 322f, 323–324 generalized onset non-motor. See Absence (petit mal) seizures genetic factors in, 334, 337–338, 338t hallucinations in auditory, 300, 327, 472 gustatory, 237 olfactory, 235, 327 after head injury, 344, 898–899 headaches and, 196 in hyperglycemic encephalopathy, 1133 in hypoxic-ischemic encephalopathy, 1130 in infants. See Infants, seizures in in infections, 343 in intracerebral hemorrhage, 833 in intracranial tumors, 647–648 jackknife or salaam, 95 Jacksonian, 326 kindling mechanism in, 334 laboratory tests in, 336 lactic acidosis in, 336 laughter in, 328 memory in, 328 in meningioma, 655 in metabolic disorders, 343 migraine and, 180, 339 mixed type of, 338t MRI in, 336 myoclonic characteristics of, 94–95, 325 EEG in, 324 progressive, 337–338, 338t in neonates. See Neonates, seizures in with occipital spikes, 331 in oligodendroglioma, 653

pathology of, 337–338 patient information in, 339 physical and mental activity in, 357–370 in posthypoxic syndromes, 1129 in pregnancy, 344–346 in psychiatric disorders, 330 psychogenic nonepileptic, 333–334, 1478 psychosocial issues in, 357–370 in pyridoxine deficiency, 1163 schizophrenia and, 1511 sensory, 320 in sleep, 414 in sleep deprivation, 344, 414 smell sense in, 235 in spastic diplegia, 1029 SSRIs and, 1200–1201 after stroke, 870 vs. stroke, 774 sudden unexplained death and, 330 surgery for, 356 vs. syncope, 339, 395–396 temporal lobe. See Temporal lobe seizures vs. TIA, 339 treatment of antiepileptic drugs for. See Antiepileptic drugs cannabinoids for, 357 ketogenic diet for, 357 surgical, 356 vagal nerve stimulation for, 356 in tuberous sclerosis, 1013–1014 uncinate, 235, 237, 327 vertiginous, 307, 327 vestibulogenic, 307 vision disorders in, 260, 327 in withdrawal syndromes, 343 witnesses to, 339 Selective serotonin reuptake inhibitors (SSRIs) for anxiety and panic attacks, 1474 for depression, 1084, 1496 mechanism of action, 1200, 1495 for night terrors, 412 for obsessive-compulsive disorder, 1476 for PTSD treatment, 516 seizures and, 1200–1201 serotonin syndrome and, 1201, 1496 side effects of, 1496, 1497t Selegiline, 1081t, 1497t Self-audible bruit, 675, 818 Semantic dementia, 1066 Semantic memory, 446, 446f, 447t Semantic pragmatic syndrome, 598 Semantic retrieval-organization syndrome, 598 Semantic substitution, 498

10/02/23 10:44 AM

Index Semantic-pragmatic disorder, 1046 Semicircular ducts, 292, 293f, 295, 305 Semicoma, 363 Semon’s law, 1364 Semont maneuver, 313 Senescence, 607 Senile plaque, 1059–1060 Sensitization process, pain perception and, 140 Sensorimotor paralysis, 1336 Sensorimotor spinal tract syndrome, 1265–1266 Sensorineural deafness bacterial infections in, 301 bilateral, 301 causes of, 297, 301–302 tinnitus in, 299 unilateral, 301 Sensory function. See also Hearing; Smell sense; Taste sense; Vision age-related changes in, 163, 165, 234, 236, 607–608 anatomy and physiology of, 155–158 in cervical spondylosis, 1257 cutaneous, 155–158, 156f, 156t, 157f development of, 589, 594 disorders of. See Sensory function disorders examination of, 163–167 extinction, 171, 476 inattention, 171 in lacunar stroke, 780 localization of stimulus in, 157, 166 motor function integrated with, 53, 155 neglect, 171 in paralysis, 56 pathways in, 158–162, 160f sensory units in, 157 in sleep, 411–412 terminology of, 162, 162t tests of, 9, 163–167 Sensory function disorders in brainstem lesions, 170–171 dissociated sensory loss, 170 functional, 171–172 in ganglionopathy, 167t, 168–169 hemisensory syndromes, 171 laboratory diagnosis of, 172 in leprous polyneuritis, 1322–1323 myelopathy, 167t, 170 in nutritional polyneuropathy, 1160 in parietal lobe lesions, 166, 171, 474–475 in Parkinson disease, 1075 patient descriptions of, 162–163 in polyneuropathy, 167t, 168, 1281 in polyradiculopathy, 167t, 168 in radiculopathy, 167t, 168

Ropper_Index_1519-1606.indd 1591

in spinal cord syndromes, 169–170, 169f, 1230–1231 suggestibility and, 171–172 tabetic syndrome, 167t, 169, 169f in thalamus lesions, 171 in vitamin B12 deficiency, 1165 Sensory ganglionopathy. See Ganglionopathy, sensory Sensory homunculus, 160, 162f Sensory nerve action potentials (SNAP), 40, 42f Sensory nerve conduction studies, 40, 41t, 42f Sensory nerves, 158 Sensory neuronopathy acute, 1296 clinical features of, 168–169, 1285 paraneoplastic, 686 Sensory neuropathy hereditary, 1326t, 1329–1332 painful, 1324t Sensory perineuritis, 1344 Sensory units, 157 Sentinel headache, 840 SEPN1 mutation, 1342 Septal nuclei, 448 Septic encephalopathy, 430, 433, 1140 Septohypothalamo-mesencephalic continuum, 520, 521f Septooptic dysplasia (de Morsier syndrome), 1004 Serologic tests, of CSF, 18 Serotonergic drugs, 859. See also specific drugs Serotonergic neurons, 115 Serotonin, 186, 522 Serotonin agonist drugs. See also specific drugs for cluster headache, 191 for migraine, 183, 187–188 Serotonin antagonists, 188 Serotonin syndrome, 1201, 1496 Serpins, 1068 Sertraline, 1200, 1497t Setting-sun sign, 266, 624 Severe developmental delay. See Developmental diseases Sex-linked inheritance, 941 Sexsomnia, 413 Sexual abuse, memory of, 449 Sexual function/activity altered, 527–528 desire in, 553 development of, 591–592 in adiposogenital dystrophy, 572–573 in failure of puberty, 572 hypothalamus in, 568, 572–573 in precocious puberty, 572 disinhibited, 527–528

1591

disorders of, 553–555 headache related to, 195 hyposexuality in, 528 neural system in, 554, 554f sexsomnia, 413 in temporal lobe seizures, 528 tests of, 544 Shadow syndromes, 1469 Shagreen patch, 1013, 1015, 1015f Shaken baby syndrome, 895–896 Shakes, 1183 Sham rage, 522 Shawl sign, 1382 Shellfish poisoning, 163 Shingles. See Herpes zoster Shock, spinal. See Spinal shock Shoulder pain causes of, 220, 225 in cervical disc herniation, 221–222 in polymyalgia rheumatica, 225 in thoracic outlet syndrome, 223–224, 224f Shoulder-hand syndrome, 147 Shrapnel injuries, 896 Shunting for arachnoid cyst, 672 for Chiari malformation, 1010 for colloid cyst of third ventricle, 671 for ependymomas of fourth ventricle, 667 lumbar-peritoneal, 632 for normal-pressure hydrocephalus, 627–629 parkinsonism and midbrain syndromes following, 635, 635f Shy-Drager syndrome, 393, 397, 1087. See also Multiple system atrophy (MSA) SIADH (syndrome of inappropriate antidiuretic hormone), 571–572, 1140–1141, 1290 Sialic acid storage disease, 950t Sialidosis, 950t, 969–970, 975 Sicard sign, 206 Sickle cell disease, 829, 869 Siderosis, of meninges, 637 SIDS (sudden infant death syndrome), 1409 Sildenafil, 256, 555 Simultanagnosia, 260, 482 Single nucleotide polymorphisms (SNPs), 997 Single-photon emission computed tomography (SPECT), 27, 1064, 1067 Sinus node, dysfunction of, 394 Sinus tracts, 1007–1008 Sinusitis, paranasal, 175–176, 266, 711 Sinuvertebral nerves, 203

10/02/23 10:44 AM

1592

Index

Sirolimus, 1217–1218 SIRS (systemic inflammatory response syndrome), 1295 Sixth cranial nerve. See Abducens (sixth) nerve Sjögren syndrome clinical features of, 236, 288 diagnosis of, 1311–1312 myelopathy in, 1246–1247 neuropathies associated with, 686, 1311–1314 treatment of, 1312 Sjögren-Larsson syndrome, 1005, 1114 Skew deviation, 117, 266, 280 Skin anomalies in developmental delay, 1005–1006 biopsy of, 50 in coma, assessment of, 376 in dermatomyositis, 1382 drug-induced rash of, 349 flare response in, 544 hemangiomas of, 1005 pain in, 142 in pellagra, 1162 sensory function of, 155–158, 156f, 156t, 157f temperature of, 543 Skin-resistance test, galvanic, 543 Skull basilar impression of, 924, 1261 in hydrocephalus, 624 imaging of, 19–28 metastases to, 659 nasopharyngeal growths eroding base of, 681 in platybasia, 1261 tumors of, 681, 682t Skull fractures basilar, 880–882, 881f brain injury and, 880 carotid–cavernous fistula following, 882 pneumocephalus, aerocele, and CSF leak following, 882, 882f SLC6A19 mutation (Hartnup disease), 963, 1163 SLC22A5 mutation (primary systemic carnitine deficiency), 1410 Sleep age-related changes in, 399, 402, 403f vs. coma, 363–364 continuous, 414 deprivation of, 344, 406–407, 414 disorders of. See Sleep disorders EEG in. See Electroencephalography (EEG), in sleep EMG in, 400, 401f–402f function of, 406 hormone secretion in, 403–404

Ropper_Index_1519-1606.indd 1592

in hypothyroidism, 421 neurophysiology of, 404–406 NREM cycles of, 400, 402 EEG of, 400, 401f–402f in narcolepsy, 419 in obstructive sleep apnea, 416 physiologic changes in, 403–406 PET in, 406 physiology of, 399–407 REM behavior disorder of, 339, 410–411, 413 cycles of, 400, 402, 403f ECG in, 420 EEG of, 400, 401f–402f in narcolepsy, 418–419 in nightmares, 412 in obstructive sleep apnea, 416 physiologic changes in, 403–406 sensory paroxysms in, 411–412 stages of, 399–403, 400f–403f Sleep disorders acroparesthesias, 420 advanced-sleep-phase syndrome, 411 anxiety in, 517 apnea, 415t, 416–417, 511 asomnia, 420 automatisms, 412–413 cataplexy, 417–419 Chiari malformations and, 410 circadian rhythm changes and, 411 in degenerative dementia, 440 delayed-sleep-phase syndrome, 411 enuresis, 420 after head injury, 410 hypersomnia, 414, 419–420 insomnia. See Insomnia in intracranial tumors, 410 irregular sleep-wake pattern, 411 jet lag, 411 in Kleine-Levin syndrome, 414–415 in medical illnesses, 420–421 narcolepsy, 417–419 in neurologic disease, 410–411 night terrors and nightmares, 412 nocturnal epilepsy, 414 paralysis, 412 in Parkinson disease, 410–411 periodic leg movements, 408–410 REM sleep behavior disorder, 410–411, 413 restless legs syndrome, 408–410 sensory sleep paroxysms, 411–412 somnambulism, 412–413 somnolescent starts, 411 Sleep drunkenness, 414, 420 Sleep latency, in narcolepsy, 419 Sleep palsies, 420

Sleepiness, excessive daytime, 415–417, 415t Sleeping sickness, 63–64, 414, 732 Sleepwalking, 412–413 Slit ventricle syndrome, 628 Slow channel syndrome, 1446, 1446t Slow stroke, 779 Slow virus infection, 764 Slurring dysarthria, 117 Sly disease (β-glucuronidase deficiency), 968t, 969 Small-fiber ganglionopathy, 1312 Small-fiber sensory polyneuropathy, 1281, 1324, 1324t, 1337t SMART (stroke-like migraine attacks after radiation therapy) syndrome, 691, 691f Smell sense age-related changes in, 234, 607 anatomy and physiology in, 230–232, 231f disorders of anosmia, 232–234, 232t, 881 causes of, 232t olfactory agnosia, 235 olfactory hallucinations, 235, 327 parosmia, 234–235 in seizures, 327 in temporal lobe lesions, 234, 235, 472 intensity of, 232 memory and, 232 taste sense and, 230, 232–235 testing of, 8, 233 Smith-Lemli-Opitz syndrome, 1004 Smith-Magenis syndrome, 1005 SMN mutations, 1110 SMON (subacute myeloopticoneuropathy), 1219 Snake venom toxins, 1208, 1444t, 1447 SNAP (sensory nerve action potentials), 40, 42f Sneddon syndrome, 867 Snellen chart, 239, 240f Snoring, in obstructive sleep apnea, 416 SNPs (single nucleotide polymorphisms), 997 Social behavior development, 592 Social behavior disorders aggressiveness, 517, 525–526, 526f in confusional states, 427 degenerative dementia, 441 Sociopathy in childhood and adolescence, 603 clinical description of, 1479–1483 historical aspects of, 1469, 1481–1482 treatment of, 1483

10/02/23 10:44 AM

Index Sodium in CSF, 17t, 618 disorders of in central pontine myelinolysis. See Central pontine myelinolysis (CPM) cerebral salt wasting, 572, 1141 diabetes insipidus. See Diabetes insipidus hypernatremia, 1141 hyponatremia, 1140–1141 seizures in, 334, 338t SIAD. See Syndrome of inappropriate antidiuretic hormone (SIADH) Sodium channelopathies. See Channelopathies, sodium Sodium oxybate, 419 Sodium phenylbutyrate, 1109 Soft sign, 594 Somatic sensations, 133 Somatoform disorders, 1471 Somatosensory cortex, 160, 473 Somatosensory evoked potentials, 35t, 37–38, 38f, 160 Somatosensory pathways, 158–162, 160f Somatotropin, in pituitary adenoma, 676t Somnambulism, 412–413 Somnolence, periodic, 575 Somnolescent starts, 411 Somnosis, 414 Sonic hedgehog gene, 1002 Sparganosis, 733t Spasm of articulatory muscles, 597 convergence, 269, 283, 1479 facial, 100–101 glottic, 507 habit, 102–103 hemifacial, 1362 in infants, 340 lingual, 100–101 masticatory, of Romberg, 101 in MS, 85, 917 oculogyric, 269 oromandibular, 100–101 in peripheral neuropathy, 1283 in spinal cord trauma, 1231 of spinal muscles, 205 task-specific, 101 in tetanus, 1205 tonic, 396 in torticollis, 98, 99f Spasmodic dysphonia, 97, 506–507 Spasmodic torticollis, 98, 99f Spasmus nutans, 282–283

Ropper_Index_1519-1606.indd 1593

Spastic motor disorders, congenital, 1028–1030, 1030f. See also Congenital cerebral motor disorders Spastic paraparesis familial dementia with, 1072 gait disorders in, 126 tropical. See Tropical spastic paraparesis Spastic paraplegia hereditary, 1113–1114, 1113t, 1332 polyneuropathy with, 1332 Spasticity in bulbar speech, 598 clasp-knife, 79 drug therapy in, 63 gait disorders in, 126 after ischemic stroke, 819 pathophysiology of, 61–62 vs. rigidity, 79 in spinal shock, 56, 62 weakness and, 62 Spatial summation, sensory, 157 Spearman two-factor theory on intelligence, 437 Specificity theory, 134, 156–157 SPECT (single-photon emission computed tomography), 27, 1064, 1067 Speech anatomy and physiology of, 490–492, 491f in confusional states, 425 development of, 590–591 discrimination of, 298 echo, 591 external, 490 fluency of, lack of, 496, 498 inner, 490 vs. language, 490 therapy and rehabilitation of, 503–504 whispering, 506 Speech and language disorders. See also Aphasia acquired stuttering, 506 in adolescents, 506 agraphia alexia with, 501 alexia without, 482, 484, 495t, 500–501 aphasic, 502 apraxic, 502 constructional, 502 lexical, 503 linguistic, 502–503 phonologic, 503 writing in, 502–503 in Alzheimer disease, 1056–1057, 1058

1593

anatomy of, 490–492, 491f in anterior cerebral artery stroke syndrome, 797 approach to patient with, 494–495 assessment of, 7 in cerebellar disease, 117 cerebral dominance in, 493–494 defective repetition, 494–495 developmental articulatory defects, 598 cluttered speech, 598 congenital amusia, 600 congenital deafness, 595–596 congenital inarticulation, 596–597 dyscalculia, 600 dysgraphia, 600 dyslexia, 599–600 precocious reading and calculating, 600 speech delay, 595 stuttering and stammering, 597 word deafness. See Word deafness disconnection syndromes in, 495 dysarthria. See Dysarthria dysphonia, 97, 490, 506–507 in frontal lobe lesions, 465, 466 hiccup in, 505 in Parkinson disease, 505–506 in putaminal hemorrhage, 834 in spastic diplegia, 1029 in temporal lobe lesions, 491 therapy and rehabilitation for, 503–504, 507 Speech therapy, 504, 598 Spelling difficulty, 600 Spetzler-Martin Scale, for AVM, 848, 848t SPG11 mutation, 1114 SPG15 mutation, 1114 SPG20 mutation, 1114 Sphenoid ridge, 679, 682t, 1357t Sphincter muscles, of bladder, 537–539, 538f Sphingolipidoses, 949, 950t Sphingomyelinase deficiency. See Niemann-Pick disease (sphingomyelinase deficiency) Spider bites, 1447 Spielmeyer-Sjögren disease, 950t. See also Neuronal ceroid lipofuscinoses Spina bifida, 215, 1006–1007, 1262 Spinal accessory (eleventh) nerve, 99–100, 1365–1366 Spinal afferent tracts for pain, 137–139, 138f, 139f Spinal arteries, 1249–1250, 1249f

10/02/23 10:44 AM

1594

Index

Spinal canal anatomy of, 203 hemorrhage in, 1252 Paget disease in, 1260–1261 stenosis of, 204, 1261 Spinal claudication, 205 Spinal column disorders ankylosing spondylitis, 207, 218–219, 1260 cervical dural sac myelopathy, 1260 cervical spondylosis. See Cervical spine disorders, spondylosis with myelopathy craniocervical junction anomalies, 1261–1262 inflammatory and infectious. See Myelitis, inflammatory and infectious lumbar stenosis, 216–217, 1259 ossification of posterior longitudinal ligament, 1260 Paget disease, 1260–1261 in rheumatoid arthritis, 1260 spinal cord herniation through dural tear, 1261 traumatic. See Spinal cord disorders, traumatic Spinal cord age-related changes in, 611 anatomy of segmental arrangement of nerve, 139f sensory pathways, 158, 160f vascular, 1249–1250, 1249f hemangioblastoma of, 668–669 Spinal cord disorders. See also Myelitis; Myelopathy arachnoiditis. See Arachnoiditis atlantoaxial dislocation, 221 bladder function in, 552 cervical. See Cervical spine/spinal cord disorders compression in atlantoaxial dislocation, 1261 causes of, 1267–1268 in intraspinal tumors. See Spinal cord tumors electrical injuries, 1235 in Friedreich ataxia, 1097 genetic and degenerative, 1268. See also Degenerative diseases lightning injuries, 1235–1236 micturition in, 552 in MS, 916, 923–924 muscular atrophy of. See Spinal muscular atrophy (SMA) neuromyelitis optica. See Neuromyelitis optica (NMO) patterns in, 1225 radiation injury, 1233–1235

Ropper_Index_1519-1606.indd 1594

spastic gait in, 126 syringomyelia. See Syringomyelia tethered cord, 1007–1008, 1008f, 1262 traumatic autonomic disorders in, 1230 central cord syndrome in, 1229, 1232 clinical effects of, 1230–1232. See also Spinal shock concussion in, 1227, 1232 epidemiology of, 1225–1226 evaluation of, 1227–1229, 1229f experimental, 1229–1230 flare response in, 544 fractures and dislocation, 1227, 1228t hemisection, 169–170, 169f historical aspects of, 1225 management of, 1232–1233 mechanisms of, 1225–1227 necrosis of, 1229 pathology of, 1229 posture in, 1231 reflex activity in, 1230–1232 sensory function in, 169–170, 169f, 1231–1232 spasm in, 1231 sympathetic and parasympathetic paralysis in, 549 transient, 1232 whiplash injuries in, 1226 tumors. See Spinal cord tumors vascular anatomy of, 1249–1250, 1249f in decompression sickness, 1255, 1284 dural arteriovenous fistula, 1252 embolism, 1255 fibrocartilaginous embolism, 1255 hemangioma, 1254 hemorrhage, 1252 infarction, 1250–1251, 1251f malformations. See Arteriovenous malformations (AVMs), spinal subdural hemorrhage, 1255 surfer’s myelopathy, 1251–1252 telangiectasia, 1254 Spinal cord tumors clinical features of back pain, 1265 intramedullary syringomyelic syndrome, 1266 radicular-spinal cord syndrome, 1266 sensorimotor spinal tract syndrome, 1265–1266 spinal syndromes, 1266 compression in, 1263, 1264f differential diagnosis of, 1266–1267 extramedullary, 1263, 1264f

hemangioma and, 1023 intramedullary, 1263–1265, 1264f, 1265f metastatic, 1264–1265, 1265f primary, 1263–1264, 1264f secondary, 1264 treatment of, 1267 Spinal flexion reflexes, 63 Spinal fluid pressure, in bacterial meningitis, 701 Spinal manipulation, 209 Spinal muscular atrophy (SMA) chronic childhood and juvenile proximal, 1111–1112 classification of, 1108t clinical manifestations of, 593, 1033, 1110–1111, 1422 differential diagnosis of, 1111 genetic factors in, 1108t, 1110 historical aspects of, 1110 infantile, 1102, 1108t, 1110 pathologic findings in, 1111 treatment of, 1111 Spinal nerve roots in cervical spondylosis, 1257 disorders of entrapment in lateral recess, 204 in intervertebral disc herniation, 211–212, 211t, 212f, 221–222 in spondylosis, 215 dorsal (sensory), 158–159, 159f lumbar, 204 spinal segments and, 1229f Spinal nerves, 203–204, 1276 Spinal pain, 151 Spinal roots, 1276 Spinal shock bladder function in, 552 clinical features of, 1230 neurotransmitters in, 549 pathophysiology of, 1230 spasticity in, 56, 61 stages of, 1230 Spinal standing, 1231 Spindle coma, 370, 410–411 Spine abscess in, 219, 1236 adhesive arachnoiditis of, 217–218, 218f age-related changes in, 204 anatomy and physiology of, 203–204, 204f, 1229f ankylosing spondylitis of, 218–219 bacterial osteomyelitis of, 1241 bamboo, 219 cervical, disorders of. See Cervical spine/spinal cord disorders curvature of, 206 degeneration of, 204 epidural abscess in, 1239–1240, 1240f

10/02/23 10:44 AM

Index facet syndrome of, 217 failed back syndrome and, 220 hemorrhage in, 219, 854–855 imaging of, 19–28, 21f, 207–208, 218 infections of, 219 ligaments of, 203, 204, 204f, 208–209 lumbar, disorders of. See Lumbar spine disorders metastases to, 659, 1263f, 1264–1265, 1265f muscles of, 203, 204, 205, 208–209 myelitis of. See Myelitis neoplastic diseases of, 219 osteoarthritis of, 217 osteoporosis of, 204 palpation and percussion of, 207 poker, 218 stability of, 203 traumatic injuries of. See Spinal cord disorders, traumatic tuberculous osteomyelitis of, 219, 1241, 1242f types of pain in disorders of, 204–206 Spinocerebellar ataxia, inherited, 1095, 1096t. See also Degenerative diseases, with progressive ataxia Spinocerebellar tracts, 109, 110t Spinocerebellum, 109, 110f, 110t Spinohypothalamic pathway, 137 Spinoreticulothalamic pathway, 137 Spinothalamic system, 133 Spinothalamic tract, in pain sensation, 137, 138f, 152 Spiramycin, 1037 Spirochetal infections CSF in, 14t, 18 leptospirosis, 725, 726 Lyme disease. See Lyme disease neurosyphilis. See Neurosyphilis Spirometra mansoni, 734 Splanchnic capacitance veins, 537 Splanchnic nerves, 537 Spondylitis, ankylosing, 207, 218–219, 1260 Spondylolisthesis, 207, 216 Spondylolysis, 215 Spondyloptosis, 216 Spondylosis, 215. See also Cervical spine/spinal cord disorders, spondylosis with myelopathy Spongy degeneration of infancy (Canavan-van BogaertBertrand disease), 955, 956f, 960t Spontaneity disorders, 467–468 Spontaneous periodic hypothermia, 574 Spot sign, 832, 833 Sprain of low back, 208–209

Ropper_Index_1519-1606.indd 1595

Sprengel deformity, 1418 Springing pupil, 288 Sprue, celiac, 1146 Spurling maneuver, 221 Square wave jerks, 284, 1096 SSRIs. See Selective serotonin reuptake inhibitors (SSRIs) Stammering, 597 Stance, 9, 124 Staphylococcus aureus infections, 704, 705t Stargardt disease, 1116 Startle response, 97 Startle syndromes, 97 Static ataxia, 1096 Statins myopathy induced by, 1415t, 1416–1417 polyneuropathy induced by, 1302 for secondary ischemic stroke prevention, 815 Status dysmyelinatus, 82 Status epilepticus characteristics of, 320, 323 etiology of, 354 nonconvulsive, 433–434 treatment of, 354–356, 354t Status marmoratus, 82, 1031 Status migrainosus, 182, 188 Steely-hair disease. See Menkes (kinky- or steely-hair) disease Stellate cells, 114, 115, 115f Stellate ganglion syndrome, 548–549 Stem cells in adult brain, 582 in muscular dystrophy treatment, 1404 transplant, HHV-6 encephalitis in, 749 Stenting, for carotid artery stenosis, 816 Steppage gait, 124t, 126 Stepping movements, in gait cycle, 121–122 Stereoanesthesia, 166 Steroid-responsive encephalopathy syndrome, 1147–1148 Stickler syndrome, 303t Stiff man (person) syndrome clinical features of, 128, 1459–1460 diagnosis of, 47 differential diagnosis of, 1460 paraneoplastic, 689 treatment of, 1460 Stilbamidine, 1302 Stimulants, 1201–1202 Stimulation-produced analgesia, 141 Stings, 1208 Stokes-Adams bradyarrhythmia attack, 387, 393

1595

Stomatodynia (burning mouth syndrome), 200, 237, 1366 Strabismus amblyopia and, 261 in children, 261, 272–273 comitant, 272 congenital, 263 in ocular palsies, 1376 paralytic, 272–273 Strachan syndrome, 1170 Straight-leg raising test, 205, 206 Strength testing, 8–9, 1373 Streptococcal infections chorea in, 81 Gilles de la Tourette syndrome and, 104 PANDAS syndrome and, 104 Streptococcus agalactiae, 706t Streptococcus pneumoniae. See Pneumococcal meningitis Streptomycin, 709 Stress, 510, 516–517 Stretch (tendon) reflex , 55, 55f, 593, 1281 Striate cortex, 479 Striatocapsular aphasia, 503 Striatonigral degeneration. See Multiple system atrophy (MSA) String sign, in carotid artery dissection, 822 Stroboscopic stimulation, in EEG, 29f–30f, 335 Stroke. See also Cerebrovascular disease; Transient ischemic attack assessment of, 773–774 atrial fibrillation and, 777 causes of, 773t in children and young adults, 827–829, 828t in coma, 870 CSF in, 14t, 17 depression after, 1490 diabetes mellitus and, 775–776 differential diagnosis of, 774–775 EEG in, 34 epidemiology of, 775 genetic factors in, 776, 827–829, 828t hemiplegia in, 773 hemorrhagic, 772, 773t intracerebral. See Intracerebral hemorrhage subarachnoid. See Subarachnoid hemorrhage history-taking in, 774 in hypercoagulable states, 866–869 hypertension and, 775 incidence of, 775 incomplete, 869

10/02/23 10:44 AM

1596

Index

Stroke (Cont.): inevident or misconstrued syndromes of, 869–870 in inherited metabolic diseases, 984–985 ischemic. See Ischemic stroke migraine and, 184 patient with history of, 869 in pregnancy and postpartum period, 830 prevalence and incidence of, 5, 5f, 6t risk factors for, 775–776, 829–831 seizures following, 870 slow, 779 Stroke-like migraine attacks after radiation therapy (SMART) syndrome, 691, 691f Strongyloidiasis, 733t Stroop color-naming test, 468 Strümpell-Lorrain disease, 1113–1114 Stump neuroma, 149 Stupor characteristics of, 363 drug-induced, 375 EEG in, 369 hepatic. See Hepatic (portalsystemic) encephalopathy in metabolic encephalopathy. See Metabolic encephalopathy neurologic examination in, 376–379 recurrent, 369 Sturge-Weber syndrome, 341, 1021–1023, 1022f Stuttering acquired, 506 in alcohol intoxication, 598 in child development, 597 PET in, 597 treatment for, 598 Subacromial bursitis, 220, 225 Subacute bacterial endocarditis (SBE), 712 Subacute combined degeneration, in spinal cord, 908, 1262 Subacute myeloopticoneuropathy (SMON), 1219 Subacute necrotizing encephalomyelopathy (Leigh disease) in adults, 987 differential diagnosis of, 959t genetic factors in, 990 in infants, 990 lactate elevation in, 988, 988t pathologic changes in, 990 signs of, 558, 958 Subacute respiratory failure, 559 Subacute sclerosing panencephalitis, 96, 762–763

Ropper_Index_1519-1606.indd 1596

Subacute spongiform encephalopathy clinical features of, 765–766 vs. corticostriatospinal degeneration, 1091 diagnosis of, 766–767, 766f differential diagnosis of, 766 EEG in, 32f, 34 epidemiology of, 765 management of, 767 neuropathology of, 764, 766 pathogenesis of, 765 Subaortic stenosis, 394 Subarachnoid hemorrhage causes of, 831t in cocaine use, 1202 coma in, 381t convexity, 847 CSF examination in, 14t, 15–16 in head injury, 891t headache in, 176, 178t onset of, 174 ruptured saccular aneurysm in, 838 anatomic-clinical correlations of, 844 clinical syndrome of, 839–841 genetic factors in, 839 grading scales for, 841, 841t hydrocephalus in, 843–844 incidence of, 838 laboratory findings in, 841–842, 841f, 843f, 844f prognosis of, 844–845 rebleeding in, 843 sites of, 838, 839f systemic changes associated with, 844 treatment of, 845–846 vasospasm in, 843, 844f syncope with, 394 Subarachnoid space, CSF in, 618, 623 Subarachnoid vessels, in bacterial meningitis, 698 Subaxial fracture-dislocation, 1228t Subclavian artery, 224, 804 Subclavian steal, 804 Subclavian vein, 224 Subcortical aphasia, 503 Subcortical dementia, 442, 916 Subcultural developmental delay, 604, 604f Subdural abscess, spinal, 1236, 1240 Subdural effusion, in bacterial meningitis, 697t, 698, 700 Subdural empyema, 709–710 Subdural hematoma acute, 192–193, 891t, 892–893, 893f chronic, 891t, 893–894, 894f coma in, 381t dementia and, 443 head enlargement with, 999

headache with, 192–193 in posterior fossa, 893 postoperative, 628 treatment of, 893, 894 Subdural hygroma head enlargement in, 999 in head injury, 891t, 894–895 Subfalcial herniation, 646 Subparaventricular zone, 404 Substance P, 137, 141, 142f, 565 Substantia nigra age-related changes in, 611 anatomy of, 70–73, 71f, 72f dopamine in, 75–76, 77 in Parkinson disease, 1077 physiology of, 73, 74f–75f Subthalamic nucleus, 70–73, 71f, 72f, 74f–75f Succimer, 1210 Sudanophilic leukodystrophies, 954–955, 960t, 982 Sudden infant death syndrome (SIDS), 1409 Sudden unexplained death in epilepsy (SUDEP), 330 Sudeck atrophy, 147, 225 Sudeck-Leriche syndrome, 225 Sudomotor function, 543, 551 Suicide, 1485, 1492, 1499–1500, 1505 Sulcation, 1001 Sulfadiazine, 731, 1037, 1380 Sulfite oxidase deficiency, 948, 985 Sulfones, 1323 Sumatriptan, 183, 187, 187t, 191, 859 Summation, 134, 157 SUNCT 190 Sundowning, 363, 429, 441 Sunset sign, 285 Supplementary motor cortex, 59–60, 465, 466 Suprachiasmatic nucleus, of hypothalamus, 404 Supranuclear palsy gait disorders in, 125, 127 progressive. See Progressive supranuclear palsy (PSP) vertical gaze in, 269 Suprascapular nerve neuropathy, 1343, 1343t Suprasellar area arachnoid cyst, 681 epidermoid cyst, 674–675 germinoma, 668 Suramin, 732 Surfer’s myelopathy, 1251–1252 Surgery, confusion following, 433 Susac syndrome, 863, 863f Susceptibility weighted imaging (SWI), 22 Suvorexant, 408

10/02/23 10:44 AM

Index Swallowing anatomy and physiology of, 560 aspiration in, 560–561 defects in. See Dysphagia neurologic basis of, 531, 560–561 pain on, 561 reflex, 560 syncope after, 392 Sweating disorders of, 551 in Parkinson disease, 1075 tests of, 543 Sweaty foot syndrome, 946 SWI (susceptibility weighted imaging), 22 “Swimmer’s itch,” 1242 Swing phase, of gait cycle, 121, 122f Swinging-flashlight test, 286 Swiss familial amyloidosis, 1335 Sydenham chorea, 81t, 82 Sylvian epilepsy, 331 Sympathectomy, thoracolumbar, 550 Sympathetic (limb-kinetic) apraxia, 64, 485 Sympathetic nervous system anatomy of, 533f, 534–535 in CRPS, 147 failure of, 392–393 Horner syndrome and, 287 physiology of, 536–537 pupillodilator fibers in, 286, 288 in syncope, 387–388 thoracolumbar trunk resection in, 550 Sympathetic (autonomic) storm, 396, 549–550, 903–904 Sympathetically sustained pain, 146 Sympathin, 536 Sympathotonic orthostatic hypotension, 546 Syncope in arrhythmias, 387, 388 in atrioventricular block, 393 cardiac output in, 388, 393–394 carotid sinus in, 389, 391, 397–398 causes of, 387–388 cerebral blood flow in, 390 in cerebrovascular disease, 394 clinical features of, 388–396 consciousness in, 389 convulsive, 389 deglutitional, 392 differential diagnosis of, 395–396 EEG in, 389, 396 examination methods for, 396–397, 540–541, 542f exercise-induced, 391 with glossopharyngeal neuralgia, 391–392 in heart disorders, 389 heat, 388–389

Ropper_Index_1519-1606.indd 1597

in hypocarbia, 390 micturition, 392 mixed, 541, 542f neurocardiogenic, 387, 390–391, 397 neurogenic, 389–392 in orthostatic hypotension, 387, 392–393 postural, 392 vs. seizures, 352, 395–396 sympathetic nervous system in, 387–388 treatment of, 397–398 tussive, 306, 392 of unknown cause, 395 Valsalva, 392 vasodepressor or vasovagal, 388–389, 391, 398, 541, 542f Syndactylic-craniocerebral anomalies, 1002–1003 Syndrome of inappropriate antidiuretic hormone (SIADH), 571–572, 1140–1141, 1290 Syndromic diagnosis, 3, 4 Synovial cysts, sciatica in, 215 Syntax, of language, 492 Synthetase syndromes, 1384 α-Synuclein, in Parkinson disease, 1078, 1079t Syphilis. See also Neurosyphilis congenital, 301, 720, 1037–1038 diagnosis of, 720, 721f etiology and pathogenesis of, 719–720 HIV infection and, 719, 757 incidence of, 719 meningomyelitis in, 1239 myelitis in, 1238 seronegative, 720 Syringobulbia, 1261, 1269 Syringomyelia Chiari malformation and, 1008, 1009 classification of, 1268 clinical features in, 1268–1269 diagnosis of, 1270, 1271f historical aspects of, 1268 pathogenesis of, 1270 sensory syndromes in, 169f, 170 traumatic, 1229 treatment of, 1270–1271 Syringotomy, 1271 Systematic desensitization, 1476 Systemic inflammatory response syndrome (SIRS), 1295 Systemic lupus erythematosus. See Lupus erythematosus T T cells, in MS, 912 T tubules, 1370, 1371f Tabetic gait ataxia, 125–126

1597

Tabetic neurosyphilis (tabes dorsalis), 118, 722–723 Tabetic syndrome, 167t, 168–169, 169f Tachycardia, 1297 Tacrolimus, 1217–1218 Tactile agnosia, 166 Tactile anesthesia, 161 Taenia multiceps, 734 Takayasu arteritis, 198, 394, 782, 862 Takotsubo cardiomyopathy, 396 Tamoxifen, 251 Tamsulosin, 545 Tandem gait, 92 Tandem walking test, 123 Tangier disease, 1333, 1338 Tapetoretinal degeneration, congenital. See Leber hereditary optic atrophy (Leber amaurosis) Tapia syndrome, 1357t Tardive dyskinesia drug-induced, 76, 80, 101–102, 1512t phenothiazines and, 76, 1198 treatment of, 102, 1513 Tarlov cysts, 215, 634 Tarsal tunnel syndrome, 1348 Tarui disease (phosphofructokinase deficiency, PFKM mutation), 47, 1407, 1408t, 1457 Tasimelteon, 411 Taste buds, 235–236 Taste sense age-related changes in, 236 anatomy and physiology of, 235–236 disorders of ageusia, 236–237, 237t in Bell’s palsy, 236 in head injury, 881 in seizures, 237, 327 smell sense and, 230, 232–234, 235 in temporal lobe lesions, 472 testing of, 236 facial nerve in, 236, 1358 Tau protein in Alzheimer disease, 1060, 1061, 1064 in chronic traumatic encephalopathy, 899–900 in CSF, 17 in frontotemporal degeneration, 1065 Tauroursodeoxycholic acid, 1109 Taurursodiol, 1109 Tay-Sachs disease (GM2 gangliosidosis, hexosaminidase A deficiency) biochemical abnormalities in, 950t, 951 differential diagnosis of, 959t in infants, 951–952, 951f macrocephaly in, 999 retinal cherry-red spot in, 951, 951f, 951t signs of, 958, 959

10/02/23 10:44 AM

1598

Index

Teichopsia, 179 Telangiectasia with ataxia. See Ataxia-telangiectasia hereditary hemorrhagic, 1023 of spinal cord, 1254 Teleopsia, 260 Teller acuity cards, 240 Temazepam, 408, 1196 Temozolomide, 650, 652, 654 Temperature, of skin, 543 Temperature regulation, in hypothalamic disorders, 573–574 Temperature sense anatomy and physiology in, 156 loss of, 164, 168 testing of, 164 Temporal arteritis blindness in, 861 cerebral vasculitis in, 860–861 diagnosis of, 193–194 headache in, 179t, 193–194, 861 ischemic optic neuropathy in, 256 ophthalmoplegia and, 193–194 pain in, 173, 174 polymyalgia rheumatica and, 194 treatment of, 194, 861 Temporal bone fractures, 300 Temporal gyri, 469 Temporal lobe anatomy and physiology of, 459, 469–470 auditory areas in, 297, 469 blood supply of, 469 functions associated with, 469–470 Temporal lobe lesions anatomy and physiology of, 462, 464 anomic aphasia in, 501 auditory agnosia in, 481 auditory hallucinations in, 300, 471–472 behavioral disorders in, 473 clinical effects of, 465–469 emotional disturbances in, 473 hearing disorders in, 301, 470–471 herniation, 373–374, 374t memory disorders in, 449, 473 oligodendroglioma. See Oligodendroglioma smell sense disturbances in, 234, 235, 472 speech and language disorders in, 491 taste sense disturbances in, 472 time perception disturbances in, 472 vestibular disturbances in, 472 vision disorders in, 470 word deafness in, 471

Ropper_Index_1519-1606.indd 1598

Temporal lobe seizures auditory hallucinations in, 472 characteristics of, 327–329 diagnosis of, 339 differential diagnosis of, 450, 1511 emotions in, 328, 528 rage in, 525 sexual function in, 528 smell sense in, 235 vision disorders in, 260 Temporal summation, 157 Temporomandibular joint pain, 199 Tendon jerk, 62 Tendon (stretch) reflexes , 55, 55f, 593, 1281 Tenecteplase, 808 Tennis elbow, 225 TENS (transcutaneous electrical nerve stimulation), 101 Tension pneumocranium, 882, 882f Tension-type headache, 174, 178t, 191–192 Tenth cranial nerve. See Vagus (tenth) nerve Teprotumumab, 279, 1412 Teratology, 345–346, 1013 Teratomas, 668 Terazosin, 545 Teriflunomide, for MS, 927 Terson syndrome, 248, 248f TERT mutations, 642t, 643 Testosterone, 525 Tetanospasmin, 1204 Tetanus, 1204–1206, 1457 Tetany, 1423 Tethered cord, 1007–1008, 1008f, 1262 Tetrabenazine, 102, 104, 1072 Tetracycline, 726, 1205 Tetralogy of Fallot, 394 Tetraplegia. See Quadriplegia Texture appreciation, testing of, 166 TGA (transient global amnesia), 449–451, 451f TH mutation (tyrosine hydroxylase deficiency), 963 Thalamus basal ganglia connections and, 73–75, 74f–75f cerebellar projections to, 112f cortical connections and, 73–75, 74f–75f, 140, 160 disorders of anomic aphasia in, 501 aphasia in, 503 ataxia in, 119 Dejerine and Roussy syndrome, 801 hemorrhage, 834–835, 834f. See also Intracerebral hemorrhage sensory loss in, 171

in Huntington disease, 75f, 79 nuclei of, in memory, 449 pain in, 171 in Parkinson disease, 73–75, 74f, 75 stimulation of, 89–90, 366 termination of pain fibers in, 139 Thalidomide, 1218, 1302 Thallium poisoning, 1214, 1298, 1301 Thermoanesthesia, 161 Thermohypesthesia, 161 Thermoreceptors, 135 Thermoregulatory sweat testing (TST), 543 Theta waves, in EEG, 33 Thiabendazole, 1379 Thiamine (vitamin B1) deficiency of in infants, 1159 nutritional polyneuropathy in, 1161 in Wernicke-Korsakoff syndrome. See Wernicke-Korsakoff syndrome inherited neurologic disorders responsive to, 1174t Thiopental, 1195 Third cranial nerve. See Oculomotor (third) nerve Third occipital nerve headache, 198 Third ventriculostomy, 628 Thomsen disease. See Myotonia congenita (Thomsen disease) Thoracic intervertebral disc protrusion, 212 Thoracic nerve, long, 1342–1343 Thoracic outlet syndrome, 223–225, 224f Thoracoabdominal radiculopathy, 1304 Thoracolumbar sympathectomy, 550 Thought insertion and withdrawal, 1504 Thought processes, 425, 452 Thrombectomy, endovascular, 810–811 Thrombocythemia, 868 Thrombocytosis, 868 Thrombolysis in Cerebral Infarction Score (TICI), 790t, 791 Thrombolytic agents, intravenous, 809–810, 810t Thrombophlebitis, 277, 710–712 Thrombosis in atherosclerosis and stroke, 778–779 basilar artery, 280, 805 cerebral vein, 864–866, 865f cortical vein, 344, 864–865 dural sinus, 865, 865f meningeal, 697t in muscles, 1426

10/02/23 10:44 AM

Index in nonbacterial endocarditis, 866 retinal vein, 250 septic, 710–712 subclavian vein, 224 in subdural empyema, 709 venous sinuses, 865–866, 865f, 1357t Thrombotic thrombocytopenic purpura (TTP), 381t, 854, 868 Thunderclap headache, 174, 180, 195, 195t, 412, 840 Thurstone multifactorial theory on intelligence, 437–438 Thymectomy, 1441–1442 Thymoma, 1435–1437, 1442 Thyroid disorders encephalopathies in, 1147–1148 hyperthyroidism. See Hyperthyroidism hypothyroidism. See Hypothyroidism myopathies in, 1411–1412 psychosis in, 1516–1517 Thyroid-stimulating hormone (TSH), 566t, 567, 676t, 677 Thyrotoxic hypokalemic periodic paralysis, 1412, 1437, 1455 Thyrotropin, in pituitary adenoma, 676t, 677 Thyrotropin-releasing hormone, 567 TIA. See Transient ischemic attack (TIA) Tiagabine, 353 Tibial muscular dystrophy, 1401t Tibial nerve neuropathy, 1348 Tic douloureux (trigeminal neuralgia), 196–197, 916, 917, 1356–1357 TICI (Thrombolysis in Cerebral Infarction Score), 790t, 791 Tick bites in Lyme disease, 725. See also Lyme disease paralysis in, 1209, 1292 Tics in akathisia, 104 characteristics of, 102–103 in Gilles de la Tourette syndrome, 103–104 in PANDAS syndrome, 104 Tilt-table testing, 390–391, 397, 540–541 Time orientation to, assessment of, 452 perception disturbances, 472 Timidity, 525 Timolol, 188 Tin toxicity, 1214 Tinel sign, 167 Tinnitus in basilar artery occlusion, 806 cisplatin and, 1216 in Ménière disease, 299 nontonal, 298–299

Ropper_Index_1519-1606.indd 1599

objective, 298 pulsatile, 298–299 subjective, 299 tonal, 299 treatment of, 299–300 Tissue plasminogen activators (tPA), 809–810, 810t, 838 Titin, 1370 Titubation, 117 Tizanidine in ALS treatment, 1109 mechanism of action, 63 for spasms, 131, 928 in spinal cord injury management, 1233 T-lymphotropic virus type I, 1380 TMB (transient monocular blindness) , 249, 782, 793 Tobacco-alcohol amblyopia, 257, 1169–1170 Tobramycin, 704t Tocilizumab, 194, 935 TOCP (triorthocresyl phosphate), 1213, 1301 Todd paralysis, 326, 329, 335, 774, 1029 Toe walking, 128, 1113 Tofersen, 1109 Tolerance to alcohol, 1180 to amphetamines, 1202 to chloral hydrate, 1196 to LSD, 1203 to marijuana, 1203 to mescaline, 1203 to opioids, 1192 to psilocybin, 1203 Tolosa-Hunt syndrome causes of, 1357t multiple cranial nerve palsies in, 1357t, 1368 ophthalmoplegia in, 277 treatment of, 278 Toluene, 1215 Tonal tinnitus, 299 Tongue in dysphagia, 560–561 innervation of, 236 paralysis of, 1366 in swallowing, 560 taste buds on, 235–236 Tonic innervation, 79 Tonic neck reflex, 593 Tonic-clonic (grand mal) seizures, 34, 321, 321t, 322–324 Tooth disorders, facial pain with, 199 Topiramate in alcohol dependence treatment, 1189 for seizures, 347t, 348t, 349, 353 Topographagnosia, 478, 482

1599

Topographic diagnosis, 3 Toppling gait, 124t, 125 Torsion dystonia, 8, 1092–1093 Torticollis congenital, 1419 restricted, 1094 spasmodic, 98–100, 99f Tortopia, 280 Torulosis, 727–728 Touch sensation agnosia of, 167 anatomy and physiology in, 156, 156t, 158 hemispheric dominance in, 166 loss of, 163, 164, 168, 475 testing of, 164 Tower skull, 999 Toxic labyrinthitis, 314 Toxic oil syndrome, 1389, 1415t Toxic polyneuropathy. See also specific substances acute, 1297–1298 subacute arsenical. See Arsenic poisoning drug-induced, 1300–1303 lead. See Lead poisoning metals and industrial agents, 1301 Toxicity encephalopathy in, 371–372, 382t, 526 heavy metal. See Heavy metal toxicity pyridoxine, 1163–1164 Toxoid, 1206 Toxoplasmosis clinical features of, 1380 congenital, 730, 1034, 1035f, 1037 in HIV infection, 730–731, 730f, 756–757, 1037, 1380 incidence of, 1380 treatment of, 731, 1037, 1380 tPA (tissue plasminogen activators), 809–810, 810t TPP1 mutation. See Neuronal ceroid lipofuscinoses (Batten disease) Traction myelopathy, 1008 Trailmaking test, 468 Tramadol, 151t, 344 Transcortical aphasia, 495, 495t, 496, 499–500 Transcranial magnetic stimulation, 38–39, 1498 Transcutaneous electrical nerve stimulation (TENS), 101, 153 Transient epileptic amnesia, 329, 450 Transient global amnesia (TGA), 449–451, 451f

10/02/23 10:44 AM

1600

Index

Transient ischemic attack (TIA) in antiphospholipid antibody disease, 867 in atherosclerosis, 779, 782 in carotid artery occlusion, 782, 792 causes of, 772, 773t definition of, 781 differential diagnosis of, 775, 779, 782–783 embolism in, 782 lacunar, 781 limb-shaking, 344 mechanism of, 782 migraine in, 184 patient with history of, 869 seizures in, 339 spinal, 1250 vertigo in, 307 Transient monocular blindness (TMB) , 249, 782, 793 Transplantation brain death and, 369 liver, 1336 renal, 1139–1140 Transtentorial herniation, 646 Transthyretin (TTR), 1334 Transverse sinus. See Lateral (transverse) sinus Transverse tubules, 1370 Tranylcypromine, 1199, 1497t Trauma, neurologic. See also Head injury back pain in, 208–210 in MS, 918 neck pain in, 221 peripheral nerves interrupted by, 1348–1349 prevalence and incidence of, 5, 6t in PTSD, 510, 516 vs. stroke, 774 Traumatic tap, 842 Trazodone, 1084, 1200, 1497t Treacher-Collins syndrome, 1004 TREM2, 1062t, 1063 Trematode infections, 733t, 735, 735f Tremors action, 86–88, 86t, 87f, 117 alcohol use and, 88 in alcohol withdrawal, 1183 alternate beat, 86t, 89 alternating, 1074 ataxic, 91, 117 in cerebellar disease, 86t, 91, 115–116 in Charcot-Marie-Tooth disease, 90 complex type, 93 definition of, 85–86 dystonic, 86t, 93 in elderly, 610–611 EMG in, 87f essential, 86t, 87f, 88–89, 95

Ropper_Index_1519-1606.indd 1600

functional (psychogenic), 93, 1479 in Guillain-Barré syndrome, 90 head movements in, 88 in hepatocerebral degeneration, 90 intention, 86t, 91, 116–117 motor function tests in, 8 in MS, 91 oculopalatal, 283 orthostatic, 86t, 92, 128 palatal, 86t, 92–93, 283 in Parkinson disease, 86t, 87f, 90–91, 1074 in peripheral neuropathy, 86t, 87f, 1282 physiologic, 86–88, 86t, 87f pill-rolling, 1074 in polyneuropathy, 90 in posture maintenance, 86–87, 86t, 87f resting, 1074 sedative-hypnotic drugs and, 88 types of, 86, 86t voice, 89 in Wilson disease, 91 Trendelenburg gait, 128 Treponema pallidum, 719, 720, 1034. See also Syphilis Triazolam, 1196 Trichinella spiralis, 1379 Trichinosis cerebral, 860 clinical features of, 732–733, 732t, 1379 diagnosis of, 732t, 1379 treatment of, 733, 1379–1380 Trichloroethylene, 1302 Trichpoliodystrophy (Menkes disease), 957–958, 960 Tricyclic antidepressants for anxiety and panic attacks, 1474 for depression, 1496 for diabetic neuropathy, 1306 mechanism of action, 1200, 1495 overdose of, 1200 for pain, 150 side effects of, 1496, 1497t in spinal cord injury management, 1233 Triethyltin, 1214 Trigeminal (fifth) nerve anatomy of, 270, 271f, 1355–1356, 1356f in blink reflex, 1355 in cranial pain, 175, 185–186 in cutaneous sensations, 160 diseases affecting, 1356–1358, 1357t autonomic cephalalgias, 190–191. See also Cluster headache ganglion schwannoma, 674 herpes zoster, 1357

multiple cranial nerve palsies, 1368 neuralgia. See Trigeminal neuralgia (tic douloureux) neuritis, 1358 neuropathy, 1357f, 1358 injury of, 881 in jaw jerk reflex, 1355 motor portion of, 1355 in olfactory sense, 232 sensory divisions of, 1355 in taste sense, 236 Trigeminal neuralgia (tic douloureux), 196–197, 916, 917, 1356–1357 Trigeminothalamic tract, 138f, 1355 Trigeminovascular complex in migraine, 186–187 Trihexyphenidyl, 102, 1081t, 1083, 1093 Trimethobenzamide, 309 Trimethoprim-sulfamethoxazole, 704t, 709 Trimethyltin, 1214 Triorthocresyl phosphate (TOCP), 1213, 1301 Triparesis, 67–68 Triple flexion response, 9, 63 Triplegia, 65, 67–68 Triptan drugs, 187, 187t Trisalicylate, for pain, 151t Trismus, 1204 Trisomy 13 (Patau syndrome), 1011 Trisomy 18 (Edwards syndrome), 1011 Trisomy 21. See Down syndrome (trisomy 21) Trochanteric bursitis, 207 Trochlear headache, 198 Trochlear (fourth) nerve anatomy of, 271, 271f disorders of causes of, 275t, 276–277 clinical effects of, 273, 274f after head injury, 276–277, 881 in multiple cranial nerve palsies, 1368 Tropheryma whipplei. See Whipple disease Trophic changes, 1282 Tropical spastic paraparesis clinical features of, 758 demyelination in, 908 diagnosis of, 1238 differential diagnosis of, 924, 1238 familial dementia with, 1072 HTLV-I and, 758, 1238 treatment of, 758 Tropicamide, 240 Tropomyosin, 1370 Troponin, 1370 Trousseau syndrome, 786 Troyer syndrome, 1114

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Index Trunk muscle weakness, 1377 Trypanosomiasis, 414, 732 L-Tryptophan, 1303 TSH (thyroid-stimulating hormone), 566t, 567, 676t, 677 TST (thermoregulatory sweat testing), 543 TTP (thrombotic thrombocytopenic purpura), 381t, 854, 868 TTR (transthyretin), 1334 Tuberculin skin tests, 717 Tuberculoma, 718, 718f Tuberculosis CSF in, 14t, 18 in HIV infection, 757 meningitis in. See Tuberculous meningitis myelitis in, 1241–1242 myeloradiculitis in, 718 spinal osteomyelitis in, 219, 1241, 1242f tuberculoma in, 718, 718f Tuberculous meningitis clinical features of, 716–717 in HIV infection, 716 laboratory studies in, 717 pathogenesis of, 716 pathologic findings in, 716 prognosis of, 719 serous, 718 treatment of, 718–719 Tuberculum sella, meningioma of, 679 Tuberomammillary nucleus, 404, 405f Tuberous sclerosis (Bourneville disease) clinical manifestations of, 1014–1015, 1014t, 1015f course and prognosis of, 1017 diagnosis of, 1016, 1016f epidemiology of, 1013–1014 etiology and pathogenesis of, 1014 genetic factors in, 1001t giant cell astrocytoma in, 670 pathology of, 1015–1016 treatment of, 1016–1017 d-Tubocurarine, 1447 Tubular aggregates, myopathy with, 1422 Tullio phenomenon, 306 Tumefactive MS, 918, 919f Tumors cavernous sinus, 682t cerebral embolism from, 778 congenital, 1008 desmoid, 1426 foramen magnum, 681, 683, 683f hearing loss with, 301 hypothalamus, 569 intracranial. See Intracranial tumors metastatic. See Metastases

Ropper_Index_1519-1606.indd 1601

in muscles, 1426 orbital, 682t pain from, 148 parotid gland, 1361 petrosal bone, 682t pineal gland, 569 pituitary. See Pituitary gland, tumors of retinopathy with, 251 retroparotid space, 682t Schmincke, 681 skull, 681, 682t smell sense in, 234 sphenoid ridge, 682t spinal cord. See Spinal cord tumors taste sense in, 237 Tuning-fork tests, 297 Turner syndrome, 603, 1012 Turricephaly, 999 Tussive syncope, 306, 392 Twitch-convulsive syndrome, 343 Two-point discrimination, 166, 474 Typhus, 729 Tyramine, 397 Tyrosine hydroxylase, 409 Tyrosine hydroxylase deficiency (TH mutation), 963 Tyrosine kinase inhibitors, 650 Tyrosinemia, 945t, 963 U Ubiquitin, 1060, 1079 UBQLN1, 1062t, 1063 UCP (urinary coproporphyrin), 1209 Uhthoff phenomenon, 255, 913 Ulcer, Cushing, 516, 574 Ulnar nerve neuropathy, 1343t, 1344–1345 Ulrich myopathy, 1402 Ultrasonography, 28 Umami taste, 235 Uncal syndrome, 373f, 374 Uncinate fits, 235 Uncinate seizures, 235, 237 Unconsciousness, 361. See also Consciousness Unified Parkinson Disease Rating Scale (UPDRS), 1073 Universal sensory loss, 1281 Unterberger stepping test, 123 Unterberger-Fukada maneuver, 308 Unverricht-Lundborg disease, 94, 337–338, 338t Upbeat nystagmus, 282 UPDRS (Unified Parkinson Disease Rating Scale), 1073 Upper motor neurons. See also Motor cortex anatomy and physiology of, 56–59, 57f disorders of, 60–63, 61f, 62f, 64t

1601

Upside-down vision, 280 Upward herniation, 646 Urea, in CSF, 18 Uremia coma in, 382t encephalopathy in, 1138–1140 fatigue in, 512 polyneuropathy in, 1296, 1322 Uremic twitch-convulsive syndrome, 1138 Uric acid, in CSF, 17t, 18 Urinary coproporphyrin (UCP), 1209 Urinary incontinence. See Bladder dysfunction Urine, retention of, 552 Usher syndrome, 302, 303t–304t Utilization behavior, 466 Utricle, 292, 293, 293f, 296f, 305 Utterance, recurring, 496 Uveitis, 243, 914 Uveoparotid fever, 1361 V V sign, 1382 Vacuoles, rimmed, 1387, 1398, 1401t Vacuum sinus headache, 176 Vagal-accessory nerve, 1365 Vagoglossopharyngeal neuralgia, 197 Vagus (tenth) nerve anatomy of, 1363, 1364f diseases affecting, 1364–1365 dysfunction of, 541–542 in multiple cranial nerve palsies, 1368 paraganglioma of, 675 stimulation of, for seizures, 356–357 in taste sense, 236 Valacyclovir, 753 Valproic acid in depression treatment, 1496 for juvenile myoclonic epilepsy, 325 for migraine prevention, 188 for palatal tremor, 93 for postherpetic neuralgia, 197, 753 in pregnancy, 345 for seizures, 347t, 348t, 349, 350, 352, 353 side effects of, 352 for status epilepticus, 354–355, 354t Valsalva maneuver, 389, 396, 542–543, 620 Valsalva syncope, 392 VAMA (VZV membrane antigen), 752 Vancomycin, 703, 703t, 704t, 715 Vanishing white matter disease (eIF2B mutation), 954 Vaptans (vasopressin receptor antagonists), 572 Varicella cerebellitis, 752

10/02/23 10:44 AM

1602

Index

Varicella zoster virus (VZV) infections. See also Herpes zoster in Bell’s palsy, 1360 in HIV infection, 757 myelitis in, 1237 Vascular endothelial growth factor (VEGF), 1131, 1305 Vasculitis cerebral in Behçet disease. See Behçet disease in Churg-Strauss angiitis, 862 in granulomatosis with polyangiitis. See Granulomatosis with polyangiitis (Wegener granulomatosis) granulomatous arteritis, 861–862, 861f infectious, 860 in lupus erythematosus, 863. See also Lupus erythematosus noninfectious inflammatory, 860 in polyarteritis nodosa, 862 in Susac syndrome, 863, 863f in Takayasu disease, 862. See also Takayasu arteritis in temporal arteritis. See Temporal arteritis zoster, 752–753 differential diagnosis of, 923 drug-induced, 859 neuropathy in, 1298, 1306–1307, 1309 spinal cord, 1246 Vasoconstriction, 543 Vasodepressor or vasovagal syncope, 388–389, 391, 398, 541, 542f Vasodilatation, 540, 542f, 543 Vasogenic edema, 644, 644f Vasomotor function, tests of, 543 Vasopressin, 568, 571, 676t. See also Antidiuretic hormone (ADH) Vasopressin receptor antagonists (vaptans), 572 Vasospasm diffuse cerebral, 858–859, 859f, 859t in hypertensive encephalopathy, 857 in subarachnoid hemorrhage, 843, 844f VDRL (venereal disease research laboratory) slide test, 720, 721f Vegetative state (unresponsive wakefulness) causes of, 364–365 after head injury, 890 in hypoxic-ischemic encephalopathy, 1127 laboratory features of, 365 persistent, 364

Ropper_Index_1519-1606.indd 1602

VEGF (vascular endothelial growth factor), 1131, 1305 Venezuelan equine encephalitis, 745 Venlafaxine, 1200, 1497t Venoms, 1208 Venous occlusion, cerebral, 629, 632–633 Ventral respiratory group, 555, 556f Ventricles, cerebral colloid cyst of, 670–671, 671f CSF circulation in, 618–619, 619f ependymoma of, 666–667, 667f medulloblastoma of, 665, 665f obstruction of, 623 shunting of, 627–629 Ventricular shunting, 627–629 Ventrolateral preoptic nucleus of hypothalamus, 404, 405, 405f Verapamil, 189, 191 Verbal agnosia, 500 Verbal auditory agnosia, 596 Verbal paraphasia, 498 Verbal stereotypy, 496 Vergence movements of eye, 269 Verger-Dejerine syndrome, 171 Vernet syndrome, 682t, 1357t Verocay bodies, 1020 Vertebral artery dissection of, 803–804, 822–824, 1250 ischemic stroke syndromes in, 803–805, 804f Vertebral column injuries, 1226. See also Spinal cord disorders, traumatic Vertebral osteomyelitis, 219, 1241 Vertical gaze control of, 266, 266f palsy of, 268–269, 269t, 966 in supranuclear palsy, 269 Vertigo. See also Dizziness ataxia and, 118–119 benign paroxysmal positional, 281, 310–313, 311f, 312f in brainstem disorders, 315–316, 315t, 316t causes of, 307–308 in cerebellar disorders, 307, 315 cervical, 307 in children, 314 clinical characteristics of, 305–307 describing, 6 disabling positional, 313 in gait ataxia, 306 in head injury, 314 labyrinthine, 309–310 in Ménière disease, 309–310 migrainous, 181, 307, 315 nystagmus and, 307, 308 in oculomotor disorders, 306 in paraneoplastic cerebellar degeneration, 687

psychogenic, 306 in seizures, 307, 327 symptoms of, 305 syndromes of, 316t in vestibular neuritis, 313 Vestibular nerve, 292–297, 293f, 295f–296f, 313 Vestibular nuclei, 53 Vestibular schwannoma, 314, 672–673, 672f, 673f Vestibular system anatomy and physiology of, 292–297, 293f–296f caloric stimulation of, 308 disorders of drug-induced, 313 gait disorders in, 123, 125 hearing loss in, 316t idiopathic bilateral, 313 in neurosyphilis, 724 in nystagmus, 281 schwannoma, 314 seizures and, 307 in temporal lobe lesions, 472 toxic bilateral, 313 vertiginous syndromes in, 316t in equilibrium, 305 tests of, 308 Vestibular testing, 49 Vestibulocerebellar pathways, 295f Vestibulocerebellum, 109, 110f, 116, 266–267, 295 Vestibulocochlear (eighth) nerve anatomy and physiology of, 292–297, 293f disorders of after head injury, 881–882 in multiple cranial nerve palsies, 1368 schwannoma, 672–674, 672f, 673f sensorineural deafness in, 297 Vestibuloocular reflex, 264, 267, 305 Vestibulospinal reflex, 305 Vestibulospinal tract, 59, 295, 295f, 296f in spasticity, 62 VGKC (voltage-gated potassium channel), 684t, 685, 685f VHL mutations, 1024 Vibration sense age-related changes in, 608 anatomy and physiology in, 155, 159 loss of, 163, 168, 1165 testing of, 9, 10, 165–166 Vibratory paresthesia, 163 Videofluoroscopy, in aspiration, 561 Vigabatrin for seizures, 347t, 348t, 353 side effects of, 251 for stiff man syndrome, 1460

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Index Villaret syndrome, 682t, 1357t Viltolasren, 1404 Vinblastine, 1215 Vincristine, 1215, 1301–1302, 1415t Vinorelbine, 1215 Violent behavior, 525–526, 526f, 529, 1181 Viral infections acute cerebellitis, 750 brachial neuritis following, 1341 central nervous system neoplasms and, 643 chronic, 760–761 of cranial nerves, 1367–1368 CSF in, 14t, 16–18 herpes simplex. See Herpes simplex virus (HSV) infections herpes zoster. See Herpes zoster HIV. See HIV infection mechanisms of, 739–740 meningitis. See Meningitis, viral (aseptic) myelitis in, 1237–1238 myopathies in, 1380–1381 pathways of, 739 poliomyelitis. See Poliomyelitis postherpetic neuralgia, 753 progressive multifocal leukoencephalopathy. See Progressive multifocal leukoencephalopathy progressive rubella panencephalitis, 763 rabies, 745, 749–750 subacute, 760–761 subacute sclerosing panencephalitis, 96, 762–763 Virions, 763 Visceral brain, 520, 535 Visceral function, central regulation of, 535–536 Visceral larva migrans, 733t Visceral pain, 137–139, 208, 723 Vision. See also Eye; Gaze; Pupils; Visual disorders age-related changes in, 243, 607 color, 260 examination of, 239–241, 240f migraine and, 179, 180f nonorganic loss of, 259 sudden painless monocular loss of, 249 Visual acuity, 239–241, 240f Visual agnosia, 259–260, 500 Visual allesthesia, 261 Visual Analog Pain Scale, 145 Visual cortex, 246, 246f, 463f Visual discrimination, 589

Ropper_Index_1519-1606.indd 1603

Visual disorders agnosia, 259–260, 481–483 approach to, 239–242 in botulism, 1207 in cerebral cortex lesions, 259–260 in choroidal artery stroke syndrome, 798 developmental, 594 episodic, 252, 252t in geniculocalcarine pathway lesions, 259 in lateral medullary syndrome, 805 in MS, 913–914 neurologic causes of, 243–247 nonneurologic causes of, 242–243 in occipital lobe lesions, 479–483 in optic nerve diseases, 254–258, 257t in papilledema, 252–254, 253f, 254t in parietal lobe lesions, 477–478 in pituitary adenoma, 258 in posthypoxic syndromes, 1129 prosopagnosia and, 481–482 in pseudotumor cerebri, 631–632 in retinal abnormalities, 247–252 in seizures, 260, 327 in temporal lobe lesions, 470 in vitamin B12 deficiency, 1165 Visual evoked potentials, 35t, 36, 36f Visual fields anatomy of, 246f concentric constriction of, 242 disorders of in geniculocalcarine pathway lesions, 259 in glaucoma, 242 in occipital lobe lesions, 479–480 in retinitis pigmentosa, 242 optic pathway lesions affecting, 245, 245f temporal crescent in, 259 testing of, 8, 241f, 242 Visual fixation reflex, 268 Visual neglect, 477 Visual object agnosia, 481 Visual simultanagnosia, 482 Visual verbal color anomia, 500 Visuospatial disorientation, 1058 Visuospatial perception, 7 Vitamin A deficiency, 1169 Vitamin B1. See Thiamine (vitamin B1) Vitamin B2 (riboflavin) deficiency, 1162 Vitamin B3 (niacin) deficiency, 1162–1163 Vitamin B6. See Pyridoxine (vitamin B6) Vitamin B9 (folate) deficiency, 1164, 1301 Vitamin B12 (cobalamin) deficiency of clinical manifestations of, 1164–1165, 1301

1603

diagnosis of, 1167–1168 imaging in, 1165, 1166f, 1168 neuropathologic changes in, 1165–1166, 1166f, 1301 optic neuropathy in, 257 pathogenesis of, 1166–1167 subacute combined degeneration in, 1164–1165, 1166f treatment of, 1168 inherited neurologic diseases responsive to, 1174t malabsorption of, 1174t Vitamin D deficiency of, 1169, 1414 malabsorption of, 1173t in MS, 910–911 Vitamin E deficiency of, 1096t, 1097, 1168–1169 malabsorption of, 1173t Vitamin K, 345, 838 Vitamin-responsive aminoacidopathies, 945 Vitreous humor, 243 Vocabulary development, 590–591 Vocal cord examination, 8 Vocal cord paralysis, 1363, 1365 Vogt-Koyanagi-Harada disease, 301, 703, 742–743 Voice, tremor of, 89 Volkmann contracture, 1375 Voltage-gated potassium channel (VGKC), 684t, 685, 685f Volvular epilepsy, 328 Vomeronasal olfactory system, 232 Vomiting anatomy and physiology of, 561 in coma, 375 cyclic syndrome of, 562 in elevated intracranial pressure, 562 functional, 1478 in intracerebral hemorrhage, 833 in intracranial tumors, 647 von Bechterew arthritis. See Ankylosing spondylitis von Economo encephalitis, 404, 410–411, 763, 1076 von Frey hair, 164 von Graefe sign, 285 von Hippel-Lindau disease, 667, 675, 1023–1024 von Recklinghausen disease. See Neurofibromatosis of von Recklinghausen VZIG (VZV immune globulin), 753 VZV. See Varicella zoster virus (VZV) infections VZV immune globulin (VZIG), 753 VZV membrane antigen (VAMA), 752

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1604

Index

W Waardenburg syndrome, 302, 303t, 963 Wada test, 493 Waddling gait, 124t, 128 WAIS (Wechsler Adult Intelligence Scale), 454, 485, 608–609 Wakefulness pathologic, 420 unresponsive. See Vegetative state (unresponsive wakefulness) Waldenström macroglobulinemia, 1317 Walker-Warburg syndrome, 1001t, 1002, 1004, 1402–1403, 1402t Wallenberg (lateral medullary) syndrome, 125, 170, 548, 802t, 804–805, 804f Wallerian degeneration, 1278f, 1279 Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome, 279 Warfarin in antiphospholipid antibody disease treatment, 867–868 in cerebral venous thrombosis treatment, 866 for ischemic stroke prevention, 815 reversal and resumption after intracerebral hemorrhage, 838 Warning leak, 840 Wartenberg plexitis, 216 Wartenberg syndrome (migratory sensory neuritis), 1313 Waterhouse-Friderichsen syndrome, 1142 Waxy flexibility, 80, 367, 426 Weakness in acromegaly, 1414 arm and shoulder, in posthypoxic syndromes, 1129 definition of, 54 differential diagnosis of, 1111 drug-induced, 1446–1447 evaluation of, 1284t–1285t, 1373 fatigue and, 512 in Guillain-Barré syndrome, 1288, 1289 hypokalemic, in primary aldosteronism, 1455 hypophosphatemic myopathic, 1414 in Lambert-Eaton myasthenic syndrome, 1443–1444 in muscular dystrophy Duchenne, 1391 facioscapulohumeral, 1395 limb-girdle, 1395 myotonic, 1398 in myasthenia gravis, 1433–1434 in myofibrillar myopathy, 1403 quadriceps femoris, isolated, 1378

Ropper_Index_1519-1606.indd 1604

restricted, 1388 spasticity and, 62 topographic patterns of bicrural palsy, 1378 bifacial palsy, 1025, 1376–1377 brachial palsy, 1033–1034, 1378 bulbar palsy. See Bulbar palsy cervical palsy, 1377 generalized paralysis of limb muscles, 1378–1379 isolated quadriceps femoris weakness, 1378 ocular palsies, 1376 proximal limb-girdle, 1378 in respiratory and trunk muscles, 1377–1378 Weber syndrome, 66, 802, 802t Weber test, 297 WEBINO (wall-eyed bilateral internuclear ophthalmoplegia) syndrome, 279 Wechsler Adult Intelligence Scale (WAIS), 454, 485, 608–609 Wechsler Intelligence Scale for Children, 1040 Wechsler Memory Scale, 485 Wechsler Preschool and Primary Scale, 1040 Wegener granulomatosis. See Granulomatosis with polyangiitis (Wegener granulomatosis) Weight changes, in hypothalamic disorders, 573 Weight reduction, for pseudotumor cerebri, 632 Weightlifter’s headache, 194–195 Welander distal dystrophy, 1400, 1401t Werdnig-Hoffmann disease. See Spinal muscular atrophy (SMA) Wernicke aphasia cerebral lesions in, 494 clinical features of, 495t, 497–498 in MCA stroke syndrome, 795 primary features of, 492 Wernicke area, 485, 490, 492, 498, 591 Wernicke-Korsakoff syndrome. See also Korsakoff syndrome clinical features of amnesia, 1156 ataxia, 1155, 1158 confabulation, 1156 consciousness and confusion disorders, 1155–1156 eye movement abnormalities, 1155, 1157–1158 frequency of, 1155f course of, 1157–1158 EEG in, 1157

etiology of, 1154 historical aspects of, 1154 imaging in, 1157, 1157f incidence of, 1154–1155 laboratory findings in, 1157, 1157f neuropathologic findings in, 1158 treatment of, 1158–1159 West Nile virus, 745, 746, 758, 1237 West syndrome, 324, 331, 341 Western equine encephalitis, 745 Westphal-Strümpell pseudosclerosis. See Hepatolenticular degeneration (Wilson disease) Whiplash injuries, 193, 221, 1226 Whipple disease, 283, 709 Whispering speech, 506 White communicating rami, 534 White matter lesions, 923 Williams syndrome, 489, 494, 600, 1012, 1044–1045 Wilson disease. See Hepatolenticular degeneration (Wilson disease) Windshield-wiper eyes, 283 Wisconsin card-sorting test, 468 Withdrawal from alcohol. See Alcohol use and alcoholism, withdrawal from from barbiturates, 1195–1196 from benzodiazepines clinical features of, 1196 delirium and, 431 management of, 434 seizures in, 343 from opioids, 1192–1193 Wohlfart-Kugelberg-Welander disease, 1102, 1103, 1108t Wolman disease, 950t Word blindness, 495t, 500–501. See also Dyslexia Word deafness congenital, 596 pure, 301, 485, 494, 495t, 500 in temporal lobe lesions, 471 Word mutism, 495t, 501 Working memory, 363, 446f Wright maneuver, 224 Writer’s cramp, 84, 98, 101 Writing in agraphia, 502–503 dyslexia and, 498, 599–600 Exner area of, 491 mirror, 503 Wrong-way gaze, 268 Wry neck, 999, 1419 X Xanthelasma, 243 Xanthoastrocytomas, 670 Xanthochromia, of CSF, 16, 842 Xanthomatosis, cerebrotendinous, 984

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Index Xeroderma pigmentosum, 1005 Xerostomia, 236 X-linked cardiomyopathy, 1394 X-linked disorders, 941. See also Muscular dystrophies Xylene, 1215 Xylocaine, 14 Y Yerkes-Dodson law, 515

Ropper_Index_1519-1606.indd 1605

Z Zafirlukast, 1307 Zellweger (cerebrohepatorenal) disease, 957, 959 Zidovudine (AZT), 756, 1380, 1415t Zika virus, 745, 1036–1037 Zinc protoporphyrin (ZPP), 1210 Zinc supplements, 1262

1605

Ziprasidone, 1513t Zolmitriptan, 183, 187, 187t Zolpidem, 1090 Zonisamide, 347t, 348t, 353 Zoster angiitis, 752–753 Zoster encephalitis, 752 Zoster myelitis, 752 Zygapophysial joints, 203, 204f Zygomycosis, 728–729

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